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Editors: Feig, Barry W .; Berger, David H.

; Fuhrman, George
M.
Title: MD A nderson Surgical Oncology Handbook, The, 4th
Edition
Copyr i ght 2006 Li ppi ncott Wi l l i ams & Wi l ki ns
> F ro nt o f Bo o k > Edit o rs

Editors
Barry W . Feig M.D.
M. D. Ander son Cancer Center , Depar tment of Sur gical Oncology,
Houston, Texas
David H. Berger M.D.
M. D. Ander son Cancer Center , Depar tment of Sur gical Oncology,
Houston, Texas
George M. Fuhrman M.D.
M. D. Ander son Cancer Center , Depar tment of Sur gical Oncology,
Houston, Texas

Secondary Edi tor


Brian Brow n
Acqui si ti ons Edi tor
Julia Seto
Managi ng Edi tor
Dave Murphy
Pr oject Manager
Benjamin Rivera
Manufactur i ng Manager
A dam Glazer
Associ ate Di r ector of Mar keti ng
Stephen Druding
Cover Desi gner
TechBooks
Compositor

R.R. Donnelley, Craw fordsville


Pr inter

Contributors
Eddie K. A bdalla MD, FA CS
Assi stant Pr ofessor
Depar tment of Sur gical Oncology, The Univer sity of Texas, M. D.
Ander son Cancer Center , Houston, Texas
Syed A . A hmad MD
Assi stant Pr ofessor of Sur ger y
Division of Sur gical Oncology, Depar tment of Sur ger y, Univer sity of
Cincinnati Medical Center , Bar r ett Cancer Center , Cincinnati, Ohio
Daniel A lbo MD, PhD
Assi stant Pr ofessor of Sur ger y
Michael E. DeBakey Depar tment of Sur ger y, Baylor College of
Medicine; Chief, Section of G ener al Sur ger y and Sur gical Oncology,
Depar tment of Sur ger y, Michael E. DeBakey VA Medical Center ,
Houston, Texas
W addah B. A l-Refaie MD
Fel l ow
Division of Sur ger y, Depar tment of Sur gical Oncology, The
Univer sity of Texas, M. D. Ander son Cancer Center , Houston, Texas
Keith D. A mos MD
Fel l ow
Depar tment of Sur gical Oncology, The Univer sity of Texas, M. D.
Ander son Cancer Center , Houston, Texas
Robert H. I. A ndtbacka MD, CM
Fel l ow and Cl i ni cal Speci al i st
Depar tment of Sur gical Oncology, The Univer sity of Texas, M. D.
Ander son Cancer Center , Houston, Texas
Gildy V. Babiera MD, FA CS
Assi stant Pr ofessor
Depar tment of Sur gical Oncology, The Univer sity of Texas, M. D.

Ander son Cancer Center , Houston, Texas


Chad M. Barnett PharmD
Cl i ni cal Phar macy Speci al i st
Division of Phar macy, The Univer sity of Texas M. D. Ander son
Cancer Center , Houston, Texas
David H. Berger MD
Pr ofessor and Vi ce Chai r
Michael E. DeBakey Depar tment of Sur ger y, Baylor College of
Medicine, Oper ative Car e Line Executive, Michael E. DeBakey VA
Medical Center , Houston, Texas
Shanda H. Blackmon MD, MPH
Instr uctor
Thor acic & Car diovasc Sur ger y Depar tment, The Univer sity of Texas,
M. D. Ander son Cancer Center , Houston, Texas
Richard J. Bold MD
Associ ate Pr ofessor of Sur ger y
Depar tment of Sur ger y, Univer sity of Califor nia Davis; Chief,
Division of Sur gical Oncology, Univer sity of Califor nia Davis Cancer
Center , Sacr amento, Califor nia
Michael Bouvet MD
Pr ofessor
Depar tment of Sur ger y, Univer sity of Califor nia San Diego, La Jolla,
Califor nia
George J. Chang MD
Assi stant Pr ofessor
Depar tment of Sur ger y Oncology, The Univer sity of Texas M. D.
Ander son Cancer Center , Houston, Texas
Judy L. Chase PharmD, FA SHP
Coor di nator
Clinical Phar macy Ser vices, Division of Phar macy, The Univer sity of
Texas M. D. Ander son Cancer Center , Houston, Texas
Eugene A . Choi MD
Fel l ow

Depar tment of Sur gical Oncology, The Univer sity of Texas M. D.


Ander son Cancer Center , Houston, Texas
Janice N. Cormier MD, MPH
Assi stant Pr ofessor
Depar tment of Sur gical Oncology, The Univer sity of Texas, M. D.
Ander son Cancer Center , Houston, Texas
Keith A . Delman MD
Assi stant Pr ofessor
Division of Sur gical Oncology, Depar tment of Sur ger y, Winship
Cancer Institute, Emor y Univer sity, Atlanta, G eor gia
Colin P. N. Dinney MD
Pr ofessor
Depar tments of Ur ology and Cancer Biology, Chair man, Depar tment
of Ur ology, The Univer sity of Texas M. D. Ander son Cancer Center ,
Houston, Texas
Barry W . Feig MD, FA CS
Pr ofessor of Sur ger y
Depar tment of Sur gical Oncology, The Univer sity of Texas M. D.
Ander son Cancer Center , Houston, Texas
Jules A . Feledy Jr. MD
Depar tment of Reconstr uctive and Micr ovascular Sur ger y, The
Metr opolitan Institute F or Plastic Sur ger y, Washington, DC
W ayne A . I. Frederick MD
Associ ate Pr ofessor
Depar tment of Sur ger y, Howar d Univer sity; Associate Dir ector ,
Howar d Univer sity Cancer Center , Howar d Univer sity Hospital,
Washington, DC
George M. Fuhrman MD
Pr ogram Di r ector G eneral Sur ger y Resi dency
Atlanta Medical Center , Atlanta, G eor gia
Jeffrey E. Gershenw ald MD
Associ ate Pr ofessor
Depar tments of Sur gical Oncology and Cancer Biology, The

Univer sity of Texas M. D. Ander son Cancer Center , Houston, Texas


Ricardo J. Gonzalez MD
Fel l ow
Depar tment of Sur gical Oncology, The Univer sity of Texas M. D.
Ander son Cancer Center , Houston, Texas
A na M. Grau MD
Assi stant Pr ofessor
Depar tment of Sur ger y, Mehar r y Medical College and Vander bilt
Univer sity, Depar tment of Sur ger y, Nashville G ener al Hospital at
Mehar r y and Vander bilt Univer sity Medical Center , Nashville,
Tennessee
Mouhammed A . Habra MD
Fel l ow
Depar tment of Endocr ine Neoplasia and Hor monal Disor der s, The
Univer sity of Texas M. D. Ander son Cancer Center , Houston, Texas
Matthew M. Hanasono MD
Assi stant Pr ofessor
Depar tment of Plastic Sur ger y, The Univer sity of Texas M. D.
Ander son Cancer Center , Houston, Texas
Kelly L. Herne MD
Vol unteer faci l ty
Depar tment of Der matology, The Univer sity of Texas Houston
Medical School, Houston, Texas
W ayne L. Hofstetter MD
Assi stant Pr ofessor of Sur ger y
Depar tment of Thor acic and Car diovascular Sur ger y, The Univer sity
of Texas M. D. Ander son Cancer Center , Houston, Texas
F. Christopher Holsinger MD, FA CS
Assi stant Pr ofessor
Depar tment of Head and Neck Sur ger y, The Univer sity of Texas M.
D. Ander son Cancer Center , Houston, Texas
Kelly K. Hunt MD
Pr ofessor of Sur ger y, Chi ef

Sur gical Br east Section, Depar tment of Sur gical Oncology, Associate
Medical Dir ector , Nellie B. Connally Br east Center , The Univer sity of
Texas M. D. Ander son Cancer Center , Houston, Texas
Rosa F. Hw ang MD
Assi stant Pr ofessor of Sur ger y
Depar tment of Sur gical Oncology, The Univer sity of Texas, M. D.
Ander son Cancer Center , Houston, Texas
Sharon Renae Hymes MD
Associ ate Pr ofessor
Depar tment of Der matology, The Univer sity of Texas M. D. Ander son
Cancer Center , Houston, Texas
Jeffrey E. Lee MD, FA CS
Pr ofessor of Sur ger y
Depar tment of Sur gical Oncology, The Univer sity of Texas M. D.
Ander son Cancer Center , Houston, Texas
Jeffrey T. Lenert CDR, MC, USNR
Assi stant Pr ofessor
Depar tment of Sur ger y, Unifor med Ser vices Univer sity of Health
Sciences; Staff Sur gical Oncologist, Depar tment of Sur ger y, National
Naval Medical Center , Bethesda, Mar yland
Paul F. Mansfield MD, FA CS
Pr ofessor of Sur ger y
Division of Sur ger y, Depar tment of Sur gical Oncology, The
Univer sity of Texas M. D. Ander son Cancer Center , Houston, Texas
Ian E. McCutcheon MD
Pr ofessor
Depar tment of Neur osur ger y, The Univer sity of Texas M. D.
Ander son Cancer Center , Houston, Texas
Funda Meric-Bernstam MD
Associ ate Pr ofessor
Depar tment of Sur gical Oncology, The Univer sity of Texas, M. D.
Ander son Cancer Center , Houston, Texas
Kenneth A . New kirk MD

Assi stant Pr ofessor


Depar tment of Otolar yngology-Head and Neck Sur ger y, MEDSTARG eor getown Univer sity Medical Center , Washington, DC
A lexander A . Parikh MD
Assi stant Pr ofessor of Sur ger y
Division of Sur gical Oncology, Vander bilt Univer sity Medical Center ,
Nashville, Tennessee
Timothy M. Paw lik MD, MPH
Assi stant Pr ofessor
Depar tment of Sur ger y, Johns Hopkins School of Medicine, Johns
Hopkins Hospital, Baltimor e, Mar yland
Nancy D. Perrier MD
Associ ate Pr ofessor of Sur ger y
Depar tment of Sur gical Oncology, The Univer sity of Texas, M. D.
Ander son Cancer Center , Houston, Texas
James A . Reilly Jr. MD, FA CS
Sur gi cal Oncol ogi st, Di r ector Br east Car e Center
Depar tment of Sur ger y, Nebr aska Methodist Hospital, Omaha,
Nebr aska
Geoffrey L. Robb MD, FA CS
Pr ofessor and Chai r
Depar tment of Plastic Sur ger y, The Univer sity of Texas, M. D.
Ander son Cancer Center , Houston, Texas
Emily K. Robinson MD
Associ ate Pr ofessor
Depar tment of Sur ger y, The Univer sity of Texas M. D. Ander son
Cancer Center ; Medical Dir ector , Memor ial Her mann Cancer Center ,
Memor ial Her mann Hospital Texas, Medical Center , Houston, Texas
Steven E. Rodgers MD, PhD
Fel l ow
Depar tment of Sur gical Oncology, The Univer sity of Texas M. D.
Ander son Cancer Center , Houston, Texas
Jorge E. Romaguera MD

Pr ofessor
Depar tment of Lymphoma and Myeloma, The Univer sity of Texas M.
D. Ander son Cancer Center , Houston, Texas
Brian M. Slomovitz MD, MS
Cl i ni cal Fel l ow
Depar tment of G ynecologic Oncology, The Univer sity of Texas M. D.
Ander son Cancer Center , Houston, Texas
Pamela T. Soliman MD
Cl i ni cal Fel l ow
Depar tment of G ynecologic Oncology, The Univer sity of Texas M. D.
Ander son Cancer Center , Houston, Texas
Carmen C. Solorzano MD
Assi stant Pr ofessor
Depar tment of G ener al Sur ger y, Rush Univer sity; Dir ector ,
Depar tment of Endocr ine Sur ger y F ellowship, Rush Univer sity
Medical Center , Chicago, Illinois
Francis R. Spitz MD
Assi stant Pr ofessor of Sur ger y
Depar tment of Sur ger y, Hospital of Univer sity of Pennsylvania,
Philadelphia, Pennsylvania
Jeffrey J. Sussman MD, FA CS
Assi stant Pr ofessor of Sur ger y
Depar tment of Sur ger y, Univer sity of Cincinnati, Cincinnati, Ohio
Eva Thomas MD
Assi stant Pr ofessor
Depar tment of Br east Medical Oncology, The Univer sity of Texas M.
D. Ander son Cancer Center , Houston, Texas
George P. Tuszynski PhD
Pr ofessor
Depar tment of Neur oscience, Temple Univer sity, Philadelphia,
Pennsylvania
Douglas S. Tyler MD
Pr ofessor of Sur ger y, Chi ef Sur gi cal Oncol ogy, Vi ce Chai r man (VA

Ser vi ces)
Depar tment of Sur ger y, Duke Univer sity Medical Center , Dur ham,
Nor th Car olina
A ra A . Vaporciyan MD
Associ ate Pr ofessor
Depar tment of Thor acic & Car diovascular Sur ger y, The Univer sity of
Texas M. D. Ander son Cancer Center , Houston, Texas
Gauri R. Varadhachary MD
Assi stant Pr ofessor
Depar tment of G astr ointestinal Medical Oncology, The Univer sity of
Texas M. D. Ander son Cancer Center , Houston, Texas
Thomas N. W ang MD, PhD
Associ ate Pr ofessor, Attendi ng Physi ci an
Depar tment of Sur ger y, Medical College of G eor gia, Augusta,
G eor gia
Jeffrey D. W ayne MD
Assi stant Pr ofessor of Sur ger y
Depar tment of Sur ger y-Sur gical Oncology, Nor thwester n Univer sity
F einber g School of Medicine; Attending Physician, Depar tment of
Sur ger y, Nor thwester n Memor ial Hospital, Chicago, Illinois
Judith K. W olf MD
Associ ate Pr ofessor
Depar tment of G ynecologic Oncology, The Univer sity of Texas M. D.
Ander son Cancer Center , Houston, Texas
Christopher G. W ood MD
Associ ate Pr ofessor
Depar tments of Ur ology and Cancer Biology, The Univer sity of
Texas, M. D. Ander son Cancer Center , Houston, Texas
Jonathan Scott Zager MD
Fel l ow
Depar tment of Sur gical Oncology, The Univer sity of Texas M. D.
Ander son Cancer Center , Houston, Texas

Editors: Feig, Barry W .; Berger, David H.; Fuhrman, George


M.
Title: MD A nderson Surgical Oncology Handbook, The, 4th
Edition
Copyr i ght 2006 Li ppi ncott Wi l l i ams & Wi l ki ns
> F ro nt o f Bo o k > De dic a t io n

Dedication
To our w ives (Barbara, A drianne, and Laura) and families, for
their support, enthusiasm, and patience through our many
years of training and continued long hours spent in the care of
patients w ith cancer.

Editors: Feig, Barry W .; Berger, David H.; Fuhrman, George


M.
Title: MD A nderson Surgical Oncology Handbook, The, 4th
Edition
Copyr i ght 2006 Li ppi ncott Wi l l i ams & Wi l ki ns
> F ro nt o f Bo o k > F o re w o rd

Foreword
What ar e the components of contemporar y sur gi cal car e for the
pati ent bur dened by cancer ? The answer to thi s questi on i s to be
found i n the di sci pl i ne of sur gi cal oncol ogy, whi ch i s ar guabl y mor e
of a cogni ti ve than a techni cal sur gi cal speci al ty. Other than several
sur gi cal pr ocedur es that ar e onl y i nfr equentl y per for med outsi de of
cancer center s (such as tr i segmentectomy, hemi pel vec-tomy, and
r egi onal pancr eatectomy), the speci al ty of sur gi cal oncol ogy focuses
on i ntegrati ng sur ger y wi th other modal i ti es of cancer tr eatment
such as radi ati on oncol ogy and systemi c chemotherapy appr oaches.
Thi s i ntegrati on i s achi eved vi a the cr uci bl e of pr ospecti ve cl i ni cal
tr i al s that have emer ged as the hal l mar k of cl i ni cal sci enti fi c
r esear ch i n oncol ogy. To be effecti ve, the sur gi cal oncol ogi st must
under stand the natural bi ol ogy of sol i d tumor s i ncl udi ng thei r
i ncepti on, pr ol i ferati on, and di ssemi nati on. Such an under standi ng
al so i mpl i es a mor e than passi ng awar eness of the under l yi ng basi c
and transl ati onal sci ence that i s cur r entl y pushi ng the fr onti er s of
our under standi ng i n oncol ogy fur ther and fur ther.
In addi ti on to knowl edge about the natural bi ol ogy of tumor s, the
sur gi cal oncol ogi st must be i nti matel y awar e of the di agnosti c
opti ons i n the i ni ti al eval uati on of the tumor and the stagi ng
systems by whi ch a gi ven tumor can be descr i bed, pr ognosi s
ascer tai ned, and therapeuti c al gor i thms accessed. The appl i cabl e
tr eatments and thei r i ndi cati ons, r i sks, and benefi ts ar e cr i ti cal l y
i mpor tant as par t of thi s cogni ti ve ar mamentar i um. Mor eover, i n
thi s era of managed car e and cost contai nment, outcomes and
r esear ch-defi ned sur vei l l ance strategi es ar e al so a par t of the
knowl edge base of the practi ci ng sur gi cal oncol ogi st.
The tar geted audi ence of, The M. D. Ander son Sur gical Oncology
Handbook, now i n i ts four th edi ti on, i ncl udes sur geons-i n-trai ni ng
as wel l as sur geons of al l speci al ti es who ar e i n practi ce. Other
heal thcar e pr ofessi onal s wi l l no doubt fi nd thi s conci se manual to be

of use as a r eady r efer ence as wel l , i n much the same manner as


the fi r st and second edi ti ons of thi s book has been uti l i zed by the
oncol ogy communi ty at l ar ge. The cr edi t for thi s cur r ent handbook
bel ongs to the pr esent and for mer sur gi cal oncol ogy fel l ows at The
Uni ver si ty of Texas M. D. Ander son Cancer Center. These effor ts,
coupl ed wi th your own i nter est, wi l l hel p ensur e that the sol i d
tumor oncol ogy pati ent r ecei ves the best possi bl e mul ti modal i ty
car e avai l abl e. We hope that you fi nd thi s handbook useful i n thi s
cr i ti cal effor t.
Raphael E. Pol l ock M.D., Ph.D.
Head, Di vi si on of Sur ger y, Pr ofessor and Chai r man, Depar tment of
Sur gi cal Oncol ogy, M. D. Ander son Cancer Center, Houston, Texas

Editors: Feig, Barry W .; Berger, David H.; Fuhrman, George


M.
Title: MD A nderson Surgical Oncology Handbook, The, 4th
Edition
Copyr i ght 2006 Li ppi ncott Wi l l i ams & Wi l ki ns
> F ro nt o f Bo o k > P re fa c e

Preface
The M. D. Ander son Sur gical Oncology Handbook was wr i tten i n an
attempt to document the phi l osophi es and practi ces of the
Depar tment of Sur gi cal Oncol ogy at the M. D. Ander son Cancer
Center. The pur pose of the book i s to outl i ne basi c management
appr oaches based on our exper i ence wi th sur gi cal oncol ogy
pr obl ems at M. D. Ander son. The book i s i ntended to ser ve as a
practi cal gui de to the establ i shed sur gi cal oncol ogy pr i nci pl es for
tr eati ng cancer as i t i nvol ves each or gan system i n the body. Thi s
four th edi ti on has i ncl uded new chapter s on basi c sci ence and the
tr eatment of tumor s of unknown pr i mar y or i gi n. In addi ti on,
updated i nfor mati on has been added on new tr eatments and
pr ocedur es i ncl udi ng l ymphati c mappi ng for br east cancer and
mel anoma, hyper ther mi c i sol ated l i mb per fusi on for extr emi ty
mel anoma and sar coma, cr yosur ger y for l i ver tumor s, as wel l as
many other new advances i n tr eatment.
Thi s book i s wr i tten by cur r ent and for mer sur gi cal oncol ogy fel l ows
at M. D. Ander son. Al though the tar get audi ence for the fi r st edi ti on
was the sur gi cal house staff and sur gi cal oncol ogy trai nees, we
found that ther e was a si gni fi cantl y wi der appeal for the book acr oss
mul ti pl e di sci pl i nes and at var i ous l evel s of trai ni ng and exper i ence.
We have, ther efor e, wi dened the scope of the four th edi ti on to
r each thi s br oader gr oup. The author s r epr esent var i ous trai ni ng
pr ograms, and they have spent at l east two year s at the M. D.
Ander son Cancer Center studyi ng onl y sur gi cal oncol ogy. The
di ver si ty of author s al l ows us to pr esent the cur r ent opi ni ons and
practi ces of the M. D. Ander son Depar tment of Sur gi cal Oncol ogy,
al ong wi th other opi ni ons and tr eatment opti ons practi ced i n our
far-rangi ng sur gi cal trai ni ng. Al though ther e i s no seni or wel l known name associ ated wi th the book, the author s r epr esent 160
year s of sur gi cal trai ni ng; we have not, however, become dogmati c
and unyi el di ng i n our medi cal practi ces.

Thi s handbook i s not meant to encompass al l aspects of oncol ogy i n


mi nute detai l . Rather, i t i s an attempt to addr ess commonl y
encounter ed as wel l as contr over si al i ssues i n sur gi cal oncol ogy.
Whi l e other author s pr esent thei r opi ni ons and appr oaches as fi r ml y
establ i shed, we have tr i ed to poi nt out contr over si es and show
al ter nati ve appr oaches to these pr obl ems besi des our own.
We woul d l i ke to thank the sur gi cal staff at the M. D. Ander son
Cancer Center for thei r assi stance wi th the content of thi s book and
for thei r devoted teachi ng i n the hospi tal cl i ni cs, war ds, and
operati ng r ooms. In addi ti on, we woul d par ti cul ar l y l i ke to thank the
pati ents seen and tr eated at M. D. Ander son for thei r war mth and
appr eci ati on of our car e, as wel l as for thei r pati ence and
under standi ng of the l ear ni ng pr ocess.
B. W. F.
D. H. B.
G . M. F.

Editors: Feig, Barry W .; Berger, David H.; Fuhrman, George


M.
Title: MD A nderson Surgical Oncology Handbook, The, 4th
Edition
Copyr i ght 2006 Li ppi ncott Wi l l i ams & Wi l ki ns
> Ta ble o f C o nt e nt s > 1 - No ninva s iv e Bre a s t C a nc e r

1
Noninvasive Breast Cancer
Robert H. I. A ndtbacka
Funda Meric-Bernstam
Emily K. Robinson
Kelly K. Hunt
Noni nvasi ve br east cancer compr i ses two separate enti ti es: ductal
car ci noma i n si tu (DCIS) and l obul ar car ci noma i n si tu (LCIS). DCIS
i s defi ned as a pr ol i ferati on of epi thel i al cel l s confi ned to the
mammar y ducts, wher eas LCIS i s defi ned as a pr ol i ferati on of
epi thel i al cel l s confi ned to the l obul es. Nei ther DCIS nor LCIS has
demonstrabl e evi dence of i nvasi on thr ough the basement
membrane. Because they ar e noni nvasi ve, DCIS and LCIS do not
pose a r i sk of metastasi s.

Ductal Carcinoma in Situ


Epidemiology
Befor e the i ntr oducti on of scr eeni ng mammography, most cases of
DCIS r emai ned undetected unti l they for med a pal pabl e mass.
Wi despr ead use of r outi ne scr eeni ng mammography has r esul ted i n
a 10-fol d i ncr ease i n the r epor ted i nci dence of DCIS si nce the mi d1980s. In the Uni ted States, the i nci dence i s now 10 to 20 per
100,000 woman-year s, and some have esti mated that mor e than
58,000 new cases of DCIS wi l l be di agnosed i n 2006. The r epor ted
pr eval ence of DCIS has i ncr eased as the qual i ty and sensi ti vi ty of
mammography have i mpr oved, and DCIS cur r entl y accounts for 20%
to 44% of al l new scr een-detected br east neopl asms i n Nor th
Amer i ca, wi th 1 case of DCIS detected per 1,300 scr eeni ng
mammograms.

The medi an age r epor ted for pati ents wi th DCIS ranges fr om 47 to
63 year s, si mi l ar to that r epor ted for pati ents wi th i nvasi ve
car ci noma. Some studi es have r epor ted a tr end towar d a l ower
medi an age when DCIS i s detected dur i ng scr eeni ng exami nati ons.
The fr equency of a fami l y hi stor y of br east cancer among fi r stdegr ee r el ati ves of pati ents wi th DCIS (i .e., 10% 35% ) i s the same
as that r epor ted for women wi th i nvasi ve br east mal i gnanci es.
Other r i sk factor s for DCIS ar e the same as those for i nvasi ve
br east cancer and i ncl ude ol der age, pr ol i ferati ve br east di sease,
nul l i par i ty, and ol der age at the ti me of fi r st ful l -ter m pr egnancy.

Pathology
DCIS i s a pr ol i ferati on of mal i gnant cel l s that have not br eached the
ductal basement membrane and ar i se fr om ductal epi thel i um i n the
r egi on of the ter mi nal l obul ar-ductal uni t. DCIS pr obabl y r epr esents
one stage i n the conti nuum of hi stol ogi c pr ogr essi on fr om atypi cal
ductal hyper pl asi a to i nvasi ve car ci noma. DCIS compr i ses a
heter ogeneous gr oup of l esi ons wi th var i abl e hi stol ogi c ar chi tectur e,
mol ecul ar and cel l ul ar character i sti cs, and cl i ni cal behavi or.
Mal i gnant cel l s pr ol i ferate to obl i terate the ductal l umen, and ther e
may be an associ ated br eakdown of the myoepi thel i al cel l l ayer of
the basement membrane sur r oundi ng the
ductal l umen. Al so, DCIS has been l i nked wi th changes i n the
sur r oundi ng str oma r esul ti ng i n fi br obl ast pr ol i ferati on, l ymphocyte
i nfi l trati on, and angi ogenesi s. Al though the pr ocess i s poor l y
under stood, most i nvasi ve ductal car ci nomas ar e bel i eved to ar i se
fr om DCIS.

Classification of Ductal Carcinoma In Situ


DCIS i s general l y cl assi fi ed as one of fi ve subtypescomedo, sol i d,
cr i br i for m, mi cr opapi l l ar y, and papi l l ar ybased on di ffer ences i n the
ar chi tectural patter n of the cancer cel l s and nucl ear featur es.
Cr i br i for m, comedo, and mi cr opapi l l ar y ar e the most common
subtypes, al though two or mor e patter ns coexi st i n up to 50% of
cases.
The i denti fi cati on of factor s i ndi cati ve of aggr essi ve bi ol ogy has l ed
to a fundamental change i n the way noni nvasi ve br east cancer i s
cl assi fi ed. The ol d cl assi fi cati on system, a str i ctl y descr i pti ve
hi stol ogi c nomencl atur e, has been abandoned i n favor of a system
that i ncor porates these pr ognosti c factor s and strati fi es l esi ons

based on thei r l i kel i hood of r ecur r ence. Lagi os et al . (1989)


i denti fi ed hi gh nucl ear grade and comedo necr osi s as factor s
pr edi cti ve of l ocal r ecur r ence. At 8 year s, pati ents whose tumor s
had a hi gh nucl ear grade and comedo necr osi s had a 20% l ocal
r ecur r ence rate after br east conser vati on sur ger y and i r radi ati on,
compar ed wi th 5% for those pati ents whose tumor s di d not have
necr osi s and wer e a l ower nucl ear grade. Subsequentl y, Si l ver stei n
et al . (1995) devel oped the Van Nuys cl assi fi cati on i n whi ch thr ee
r i sk gr oups wer e di sti ngui shed based on the pr esence or absence of
hi gh nucl ear grade and comedo-type necr osi s: (1) nonhi gh-grade
DCIS wi thout comedo-type necr osi s, (2) nonhi gh-grade DCIS wi th
comedo-type necr osi s, and (3) hi gh-grade DCIS wi th or wi thout
comedo-type necr osi s. Si l ver stei n et al . found 31 cases of l ocal
r ecur r ence among 238 pati ents who under went br east-conser vi ng
sur ger y; the l ocal r ecur r ence rate was 3.8% i n gr oup 1, 11.1% i n
gr oup 2, and 26.5% i n gr oup 3. The 8-year actuar i al di sease-fr ee
sur vi val rate was 93% for gr oup 1, 84% for gr oup 2, and 61% for
gr oup 3. Other cl assi fi cati on systems have al so been pr oposed;
however, no si ngl e cl assi fi cati on system has been uni ver sal l y
accepted.

Multifocality
Mul ti focal DCIS i s general l y defi ned as DCIS pr esent i n two or mor e
foci separated by 5 mm i n the same br east quadrant. Most
i nvesti gator s bel i eve that mul ti focal di sease i n fact r epr esents
i ntraductal spr ead fr om a si ngl e focus of DCIS. By car eful ser i al
subsecti oni ng, Hol l and et al . (1990) demonstrated that mul ti focal
l esi ons that appear ed to be separate usi ng tradi ti onal pathol ogi cal
techni ques actual l y or i gi nated fr om the same focus i n 81 of 82
mastectomy speci mens.

Multicentricity
Mul ti centr i c DCIS i s defi ned as DCIS pr esenti ng as a separate focus
outsi de the i ndex quadrant. The r epor ted i nci dence of
mul ti centr i ci ty may depend on the extent of the pathol ogi cal r evi ew
and ther efor e var i es fr om 18% to 60% , but i s mor e l i kel y to be
ar ound 30% to 40% . Because mammar y l obul es ar e not
constrai ned by the ar ti fi ci al l y i mposed quadrant segr egati ons,
cur sor y pathol ogi cal exami nati on may i ncor r ectl y i nter pr et
conti guous i ntraductal spr ead as mul ti centr i ci ty. Appr oxi matel y 96%
of al l l ocal r ecur r ences after tr eatment of DCIS occur i n the same

quadrant as the i ndex l esi on, i mpl i cati ng r esi dual untr eated di sease
rather than mul ti centr i ci ty, and rai si ng questi ons about the
i mpor tance of mul ti centr i ci ty. The i nci dence of detecti on of DCIS i s
hi gher i n autopsy studi es than i n the general popul ati on, suggesti ng
that not al l DCIS l esi ons become cl i ni cal l y si gni fi cant.

Microinvasion
The Amer i can Joi nt Commi ttee on Cancer (AJCC) stagi ng system
(Si ngl etar y et al ., 2002) defi nes mi cr oi nvasi on as i nvasi on of br east
cancer cel l s thr ough the basement membrane at one or mor e foci ,
none of whi ch exceeds a di mensi on of 1 mm. A br east cancer wi th
mi cr oi nvasi on i s cl assi fi ed as a T1mi c tumor, wher eas DCIS i s
cl assi fi ed as T0. Mi cr oi nvasi on upstages the cancer fr om stage 0 to
stage 1 i n the AJCC stagi ng system.
The i nci dence of mi cr oi nvasi on i n DCIS var i es accor di ng to the si ze
and extent of the i ndex l esi on. Lagi os et al . (1989) r epor ted a 2%
i nci dence of mi cr oi nvasi on i n pati ents wi th DCIS measur i ng l ess
than 25 mm i n di ameter, compar ed wi th a 29% i nci dence of
mi cr oi nvasi on i n i ndex l esi ons l ar ger than 26 mm. The i nci dence of
mi cr oi nvasi on i s al so hi gher i n pati ents wi th hi gh-grade or comedotype DCIS tumor s wi th necr osi s and i n pati ents wi th DCIS tumor s
who pr esent wi th a pal pabl e mass or ni ppl e di schar ge. Some
i nvesti gator s have questi oned whether i t i s useful to di sti ngui sh
pur e DCIS fr om DCIS wi th mi cr oi nvasi on. By defi ni ti on, DCIS does
not have the abi l i ty to metastasi ze to axi l l ar y l ymph nodes or
di stant si tes, wher eas DCIS wi th mi cr oi nvasi on does. Axi l l ar y
metastasi s has been r epor ted i n 0% to 20% of pati ents wi th
mi cr oi nvasi ve DCIS. In addi ti on, pati ents wi th mi cr oi nvasi ve DCIS
have been shown to have a wor se pr ognosi s. Mi r z a et al . (2000)
r epor ted the l ong-ter m r esul ts of br east-conser vi ng therapy i n DCIS
and ear l y-stage (T1) br east cancer and noted that the 20-year
di sease-speci fi c sur vi val rates wer e better among pati ents wi th
DCIS than among pati ents wi th DCIS wi th mi cr oi nvasi on or T1
i nvasi ve tumor s. Pati ents wi th mi cr oi nvasi on and those wi th T1
tumor s had si mi l ar sur vi val rates. In a r etr ospecti ve study of 1,248
ser i al l y secti oned DCIS tumor s, de Mascar el et al . (2002) r epor ted a
10.1% i nci dence of axi l l ar y metastases i n cases of DCIS wi th a
cl uster of mi cr oi nvasi ve cel l s. Pati ents wi th DCIS had a better 10year di stant metastasi s-fr ee sur vi val rate than pati ents wi th
mi cr oi nvasi ve DCIS (98% and 91% , r especti vel y). The overal l
sur vi val rate was al so better i n pati ents wi th DCIS (96.5% vs.
88.4% ). The metastasi s-fr ee and overal l sur vi val rates wer e wor se

i n pati ents wi th i nvasi ve ductal car ci noma than i n pati ents wi th


mi cr oi nvasi ve DCIS. These r esul ts suggest that DCIS wi th
mi cr oi nvasi on shoul d be character i zed as a smal l i nvasi ve tumor
wi th a good outcome and that the therapeuti c appr oach for these
pati ents shoul d be si mi l ar to that for pati ents wi th i nvasi ve cancer.
However, fur ther study i s needed to i nvesti gate the bi ol ogy of
mi cr oi nvasi on.

Diagnosis
Clinical Presentation
Befor e the advent of r outi ne mammography, most pati ents wi th
DCIS pr esented wi th a pal pabl e mass, ni ppl e thi ckeni ng or
di schar ge, or Paget di sease of the ni ppl e. Occasi onal l y, DCIS was an
i nci dental fi ndi ng i n an other wi se beni gn bi opsy speci men. The
pal pabl e l esi ons wer e l ar ge, and up to 25% demonstrated associ ated
foci of i nvasi ve di sease. Now that scr eeni ng mammography i s mor e
pr eval ent, most cases of DCIS ar e di agnosed wi th of the ai d of
mammography al one when the tumor i s sti l l cl i ni cal l y occul t.
Pati ents wi th abnor mal i ti es detected by mammography shoul d al so
under go i magi ng of the contral ateral br east because 0.5% to 3.0%
of pati ents have synchr onous occul t abnor mal i ti es or cancer s i n the
contral ateral br east. Mammographi c i mages shoul d be compar ed
wi th pr evi ous i mages, i f avai l abl e, to establ i sh i nter val changes.

Mammographic Features
On a mammogram, DCIS can pr esent as mi cr ocal ci fi cati ons, a softti ssue densi ty, or both. Mi cr ocal ci fi cati ons ar e the most common
mammographi c mani festati on of DCIS (80% 90% ). DCIS accounts
for 80% of al l br east car ci nomas pr esenti ng wi th cal ci fi cati ons. Any
i nter val change fr om a pr evi ous mammogram i s associ ated wi th
mal i gnancy i n 15% to 20% of cases and most often i ndi cates i n si tu
di sease. Hol l and et al . (1990) descr i bed two di ffer ent cl asses of
mi cr ocal ci fi cati ons: (1) l i near branchi ng-type mi cr ocal ci fi cati ons,
whi ch ar e mor e often associ ated wi th hi ghnucl ear-grade, comedotype l esi ons; and (2) fi ne, granul ar cal ci fi cati ons, whi ch ar e
pr i mar i l y associ ated wi th mi cr opapi l l ar y or cr i br i for m l esi ons of
l ower nucl ear grade that do not show necr osi s. Al though the
mammographi c mor phol ogy of mi cr ocal ci fi cati ons suggests the
ar chi tectural type of DCIS, i t i s not al ways r el i abl e. Hol l and et al .

al so demonstrated that the mammographi c fi ndi ngs si gni fi cantl y


under esti mated the pathol ogi cal extent of di sease, par ti cul ar l y i n
cases of mi cr opapi l l ar y DCIS. Lesi ons wer e mor e than 2 cm l ar ger
by hi stol ogi c exami nati on than by mammographi c esti mati on i n 44%
of cases of mi cr opapi l l ar y l esi ons, compar ed wi th onl y 12% of cases
of the pur e comedo subtype. However, when magni fi cati on vi ews
wer e used i n the mammographi c exami nati on, the extent of di sease
was under esti mated i n onl y 14% of cases of mi cr opapi l l ar y tumor s.
Hence, magni fi cati on vi ews i ncr ease the i mage r esol uti on and ar e
better abl e to detect the mi cr ocal ci fi cati on shape, number, and
extent when compar ed wi th mammography al one and shoul d be used
r outi nel y i n the eval uati on of suspi ci ous mammographi c fi ndi ngs.

Other Imaging Modalities


Mammography r emai ns the standar d for radi ographi c eval uati on of
DCIS. The r ol e of other i magi ng modal i ti es, such as ul trasound and
magneti c r esonance i magi ng (MRI), has yet to be establ i shed for
DCIS. Ul trasound i s benefi ci al i n the eval uati on of a pal pabl e l esi on
and the assessment of r egi onal l ymph node basi ns, but i t i s not as
r el i abl e i n r outi ne br east scr eeni ng. Contrast-enhanced MRI i s al so
ver y sensi ti ve i n the detecti on of DCIS and i nvasi ve
cancer, but i t l acks speci fi ci ty. DCIS has a nonspeci fi c appearance
and nonspeci fi c ki neti c enhancement cur ves that can mi mi c
fi br ocysti c changes and other beni gn fi ndi ngs. The cost and
accessi bi l i ty of MRI al so make i t l ess feasi bl e as an effecti ve
scr eeni ng method. However, ther e i s evi dence that pati ents at hi gh
r i sk for br east cancer or those women wi th ver y nodul ar br easts
may benefi t fr om scr eeni ng wi th MRI.

Diagnostic Biopsy
Ster eotacti c cor e-needl e or vacuum-assi sted bi opsy i s the pr efer r ed
method for di agnosi ng DCIS. Cal ci fi cati ons that appear fai ntl y on
mammograms or that ar e deep i n the br east and cl ose to the chest
wal l may be di ffi cul t to tar get wi th ster eotacti c bi opsy. In addi ti on,
use of ster eotacti c bi opsy i n pati ents above the wei ght l i mi t of the
ster eotacti c system (about 135 kg [297 l b]) and i n pati ents wi th
smal l br easts may be i mpossi bl e. Pati ents who cannot r emai n pr one
or who cannot cooperate for the durati on of the pr ocedur e ar e al so
not good candi dates for ster eotacti c bi opsy. Bl eedi ng di sor der s and
the concomi tant use of anti coagul ants ar e r el ati ve
contrai ndi cati ons. Bi opsy speci mens shoul d be radi ographed to

document the sampl i ng of suspi ci ous mi cr ocal ci fi cati ons. Car e


shoul d be taken to mar k the bi opsy si te wi th a metal l i c cl i p i n the
event that al l mi cr ocal ci fi cati ons ar e r emoved wi th the bi opsy
pr ocedur e.
Because ster eotacti c cor e-needl e and vacuum-assi sted bi opsy
speci mens r epr esent onl y a sampl e of an abnor mal i ty obser ved on
mammography, the r esul ts ar e subject to sampl i ng er r or. Invasi ve
car ci noma i s found on exci si onal bi opsy i n 20% of pati ents i n whom
DCIS was di agnosed by a ster eotacti c cor e-needl e bi opsy. If the
cor e-needl e bi opsy r esul ts ar e di scor dant wi th the fi ndi ngs of
i magi ng studi es, an exci si onal bi opsy shoul d be per for med to
confi r m the di agnosi s. After di agnosi s usi ng ster eotacti c cor e-needl e
bi opsy, 30% to 50% of pati ents wi th atypi cal ductal hyper pl asi a and
20% of pati ents wi th radi al scar ar e found to have a coexi stent
car ci noma near the si te of the bi opsy. Ther efor e, when the fi nal
pathol ogi cal studi es fr om cor e-needl e bi opsy pr ocedur es i ndi cate
ei ther of these di agnoses, thi s shoul d be fol l owed by a sur gi cal
exci si onal bi opsy.
Pati ents who ar e not candi dates for ster eotacti c bi opsy or who have
ster eotacti c bi opsy r esul ts that ar e i nconcl usi ve or di scor dant wi th
the mammographi c fi ndi ngs shoul d under go exci si onal bi opsy. Thi s
techni que i s per for med wi th the assi stance of pr eoperati ve needl e
l ocal i z ati on of the mammographi c abnor mal i ty or of the pr evi ousl y
pl aced metal l i c cl i p mar ki ng the bi opsy si te. Speci men radi ography
i s essenti al to confi r m the r emoval of mi cr ocal ci fi cati ons of i nter est.
The exci si onal bi opsy shoul d be per for med wi th the ai m of obtai ni ng
a mar gi n-negati ve r esecti on that can ser ve as a defi ni ti ve sur ger y.

Treatment
The di agnosi s of DCIS i s fol l owed by a mastectomy or br eastconser vi ng sur ger y (al so r efer r ed to as segmental mastectomy,
l umpectomy, or wi de l ocal exci si on) per for med wi th needl e
l ocal i z ati on. Most pati ents who under go br east-conser vi ng sur ger y
r ecei ve postoperati ve radi ati on therapy to i mpr ove l ocal contr ol .
Postoperati ve endocr i ne therapy wi th tamoxi fen shoul d al so be
consi der ed for those pati ents whose tumor s ar e estr ogen r eceptor
posi ti ve.

Mastectomy Versus Breast-conserving


Therapy

Tradi ti onal l y, DCIS has been tr eated wi th mastectomy. However,


because br east-conser vi ng techni ques for i nvasi ve di sease have
been shown to be effecti ve l ocal therapy, the practi ce of tr eati ng a
noni nvasi ve condi ti on wi th a sur gi cal pr ocedur e mor e radi cal than
that used to tr eat i ts i nvasi ve counter par t has been questi oned. The
rati onal e for per for mi ng total mastectomy i n pati ents wi th DCIS i s
based on the hi gh i nci dence of mul ti focal i ty and mul ti centr i ci ty, as
wel l as on the r i sk of occul t i nvasi on associ ated wi th the di sease.
Thus, mastectomy r emai ns the standar d wi th whi ch other pr oposed
therapeuti c modal i ti es shoul d be compar ed. However, no pr ospecti ve
tr i al s have compar ed outcomes after mastectomy wi th those after
br east-conser vi ng sur ger y i n pati ents wi th DCIS. A r etr ospecti ve
r evi ew by Bal ch et al . (1993) documented a l ocal r el apse rate of
3.1% and a mor tal i ty rate of 2.3% after mastectomy for DCIS. The
cancer-r el ated mor tal i ty rate fol l owi ng mastectomy for DCIS was
1.7% i n a ser i es r epor ted by Fowbl e (1989) and ranged fr om 0% to
8% i n a r evi ew by Vezer i di s and Bl and (1994).
In one of the l ar gest studi es compar i ng br east-conser vi ng therapy
wi th mastectomy, Si l ver stei n et al . (1992) exami ned 227 cases of
DCIS wi thout mi cr oi nvasi on. In thi s nonrandomi zed study, pati ents
wi th tumor s smal l er than 4 cm wi th mi cr oscopi cal l y cl ear mar gi ns
under went br east-conser vi ng sur ger y and radi ati on therapy,
wher eas pati ents wi th tumor s l ar ger than 4 cm or wi th posi ti ve
mar gi ns under went mastectomy. The rate of di sease-fr ee sur vi val at
7 year s was 98% i n the mastectomy gr oup compar ed wi th 84% i n
the br east-conser vi ng sur ger y gr oup (p = 0.038), wi th no di ffer ence
i n overal l sur vi val rates. In a meta-anal ysi s, Boyages et al . (1999)
r epor ted a r ecur r ence rate of 22.5% , 8.9% , and 1.4% fol l owi ng
br east-conser vi ng sur ger y al one, br east-conser vi ng sur ger y wi th
radi ati on therapy, and mastectomy, r especti vel y. In pati ents who
under went br east-conser vi ng sur ger y al one, appr oxi matel y 50% of
the r ecur r ences wer e i nvasi ve cancer s. Al though r ecur r ence rates
ar e hi gher i n pati ents who under go br east-conser vi ng sur ger y than
i n pati ents who under go mastectomy, no sur vi val advantage has
been shown for the l atter gr oup.

Technique of Breast-conserving Surgery


The goal of br east-conser vi ng sur ger y i s to r emove al l suspi ci ous
cal ci fi cati ons and obtai n negati ve sur gi cal mar gi ns. Because DCIS i s
usual l y nonpal pabl e, br east-conser vi ng sur ger y i s most often
per for med wi th mammographi c needl e l ocal i z ati on. Intraoperati ve
or i entati on of the speci men wi th two or mor e mar ki ng sutur es i s

cr i ti cal for mar gi n anal ysi s. In addi ti on, speci men radi ography i s
essenti al to confi r m the r emoval of al l mi cr ocal ci fi cati ons. In
pati ents wi th extensi ve cal ci fi cati ons, bracketi ng of the
cal ci fi cati ons wi th two or mor e wi r es may assi st i n the exci si on of
al l suspi ci ous cal ci fi cati ons.
After whol e-speci men radi ography, the speci men shoul d be i nked
and then ser i al l y secti oned for pathol ogi cal exami nati on to eval uate
the mar gi n status and extent of di sease. Chagpar et al . (2003)
demonstrated that i ntraoperati ve mar gi n assessment wi th the use of
secti oned-speci men radi ography enabl ed r e-exci si ons to be
per for med at the same sur ger y i f the mi cr ocal ci fi cati ons extended to
the cut edge of the speci men, mi ni mi z i ng the need for second
pr ocedur es for mar gi n contr ol . After the i ntraoperati ve mar gi ns ar e
deemed adequate, the boundar y of the r esecti on cavi ty i s mar ked
wi th radi opaque cl i ps to ai d i n the pl anni ng of postoperati ve
radi ati on therapy and i n mammographi c fol l ow-up.
The i ntraoperati ve goal of br east-conser vi ng sur ger y i s to obtai n
tumor-fr ee mar gi ns of 1 cm i f possi bl e. Thi s goal i s based on the
data pr ovi ded by Hol l and et al . (1990), whi ch demonstrated that up
to 44% of l esi ons extended mor e than 2 cm fur ther on hi stol ogi c
exami nati on than that esti mated by mammography. However, i n
most women, a 1-cm mar gi n i s not cosmeti cal l y feasi bl e. Ther efor e,
what consti tutes an adequate mar gi n for DCIS r emai ns
contr over si al . Most sur geons advocate r e-exci si on for posi ti ve
sur gi cal mar gi ns, and many sur geons advocate r e-exci si on for cl ose
mar gi ns, usi ng var yi ng thr eshol ds of l ess than 1, 2, or 5 mm.
Neuschatz et al . (2002) r epor ted that r esi dual tumor was found on
r e-exci si on i n 41% of pati ents wi th DCIS wi th 0- to 1-mm mar gi ns,
31% of pati ents wi th 1- to 2-mm mar gi ns, and 0% of pati ents wi th
gr eater than 2-mm mar gi ns. Lesi on si ze was another pr edi ctor of
r esi dual DCIS.

Radiation Therapy
Most pati ents wi th DCIS who under go br east-conser vi ng sur ger y
r ecei ve postoperati ve radi ati on therapy. Thr ee pr ospecti ve
randomi zed studi es have eval uated the r ol e of radi ati on therapy
fol l owi ng br east-conser vi ng sur ger y for DCIS. In the Nati onal
Sur gi cal Adjuvant Br east and Bowel Pr oject (NSABP) B-17 tr i al , 818
women wi th l ocal i zed DCIS wer e randomi zed to br east-conser vi ng
sur ger y or br east-conser vi ng sur ger y pl us radi ati on therapy after

mar gi n-negati ve r esecti ons. At a fol l ow-up ti me of 12 year s,


radi ati on therapy was associ ated wi th a r educti on i n the cumul ati ve
i nci dence of noni nvasi ve i psi l ateral br east tumor s fr om 14.6% to
8.0% and wi th a r educti on i n the i nci dence of i nvasi ve i psi l ateral
br east tumor s fr om 16.8% to 7.7% . Ther e was no di ffer ence i n the
12-year overal l sur vi val rate i n the two gr oups, wi th 86% of women
al i ve i n the br east-conser vi ng sur ger y gr oup and 87% al i ve i n the
br east-conser vi ng sur ger y pl us radi ati on therapy gr oup. However,
58% of al l deaths occur r ed befor e any br east cancer event, and the
death of 12 pati ents (3.0% ) i n the br east-conser vi ng sur ger y gr oup
and 15 pati ents (3.6% ) i n the br east-conser vi ng sur ger y pl us
radi ati on therapy gr oup was attr i buted to i nvasi ve br east cancer.
The overal l benefi t of radi ati on therapy for pati ents wi th DCIS was
al so obser ved i n the Eur opean Or gani z ati on for Resear ch and
Tr eatment of Cancer 10853 tr i al (Jul i en et al ., 2000). In thi s tr i al ,
1,010 women wi th DCIS wer e randomi zed to br east-conser vi ng
sur ger y or br east-conser vi ng sur ger y pl us radi ati on therapy. At a
medi an fol l ow-up ti me of 4.25 year s, radi ati on therapy was
associ ated wi th a r educti on i n the i nci dence of noni nvasi ve
i psi l ateral br east tumor s fr om 8.8% to 5.8% and wi th a r educti on i n
the i nci dence of i nvasi ve i psi l ateral br east tumor s fr om 8.0% to
4.8% . The l ower r ecur r ence rates i n thi s tr i al when compar ed wi th
those i n the NSABP B-17 wer e attr i buted to the shor ter fol l ow-up
ti me.
A thi r d tr i al , whi ch was conducted by the Uni ted Ki ngdom
Coor di nati ng Commi ttee on Cancer Resear ch, al so confi r med the
benefi ts of radi ati on therapy for l ocal contr ol (Houghton et al .,
2003). After a medi an fol l ow-up ti me of 4.4 year s, ther e was a
r educti on i n the i nci dence of noni nvasi ve i psi l ateral br east tumor s
fr om 7% to 3% and a r educti on i n the i nci dence of i nvasi ve
i psi l ateral tumor s fr om 6% to 3% . The concl usi on fr om these thr ee
pr ospecti ve randomi zed tr i al s i s that the addi ti on of radi ati on
therapy fol l owi ng br east-conser vi ng therapy for DCIS r esul ts i n an
appr oxi matel y 50% r el ati ve r educti on i n br east cancer r ecur r ence.
Br east-conser vi ng sur ger y al one (i .e., wi thout radi ati on therapy)
has been suggested to be suffi ci ent i n a sel ect subgr oup of pati ents
wi th DCIS. Ini ti al data that suppor ted the use of br east-conser vi ng
sur ger y al one i n the tr eatment of DCIS came fr om a study by Lagi os
et al . (1989) i n whi ch 79 pati ents wi th mammographi cal l y detected
DCIS under went mar gi n-negati ve exci si on al one. After a fol l ow-up
ti me of 124 months, the l ocal r ecur r ence rate was 16% overal l

33% for the subgr oup of pati ents wi th hi gh-grade l esi ons and
comedo necr osi s ver sus onl y 2% for the pati ents wi th l ow- or
i nter medi ate-grade l esi ons.
Subsequentl y, Si l ver stei n et al . (1996) devel oped the Van Nuys
Pr ognosti c Index (VNPI) by combi ni ng thr ee stati sti cal l y si gni fi cant
pr edi ctor s of l ocal r ecur r ence: tumor si ze, mar gi n wi dth, and
pathol ogi cal cl assi fi cati on. Thi s i ndex was r ecentl y modi fi ed to
i ncl ude pati ent age as a stati sti cal l y si gni fi cant pr edi ctor of l ocal
r ecur r ence and i s now r efer r ed to as the Uni ver si ty of Souther n
Cal i for ni a (USC)/VNPI (Si l ver stei n, 2003). Numer i cal val ues rangi ng
fr om 1 (best pr ognosi s) to 3 (wor st pr ognosi s) ar e assi gned for each
of the four pr edi ctor s. A si ze scor e of 1, 2, and 3 i s gi ven to smal l
tumor s (15 mm), i nter medi ate tumor s (1640 mm), and l ar ge
tumor s (41 mm), r especti vel y. Mar gi n wi dth i s assi gned a scor e of
1 i f 10 mm or gr eater, 2 i f 1 to 9 mm, and 3 i f l ess than 1 mm. The
pathol ogi cal cl assi fi cati on i s 1 for nonhi gh-grade DCIS wi thout
necr osi s, 2 for nonhi gh-grade DCIS wi th necr osi s, and 3 for hi ghgrade DCIS wi th or wi thout necr osi s. Pati ent age i s assi gned a scor e
of 1 for gr eater than 60 year s, 2 for 40 to 60 year s, and 3 for l ess
than 40 year s. The sum of these r esul ts i s the USC/VNPI scor e, wi th
4 bei ng the l owest possi bl e scor e and 12 the hi ghest possi bl e scor e.
The USC/VNPI scor es of 706 pati ents wi th DCIS tr eated wi th br eastconser vi ng therapy wi th or wi thout radi ati on therapy wer e
r etr ospecti vel y deter mi ned, and outcomes wer e compar ed by usi ng
l ocal r ecur r ence as the endpoi nt. Among pati ents wi th a USC/VNPI
scor e of 4, 5, or 6, the addi ti on of radi ati on therapy di d not appear
to confer an advantage over exci si on al one for l ocal r ecur r ence-fr ee
sur vi val . In contrast, for pati ents wi th a USC/VNPI scor e of 7, 8, or
9, the absol ute 12-year l ocal r ecur r ence-fr ee sur vi val rate was 12%
hi gher among those who under went radi ati on therapy and
exci si on than among those who under went exci si on al one (73% vs.
61% ). Al though pati ents wi th a USC/VNPI scor e of 10, 11, or 12
showed the gr eatest benefi t wi th the addi ti on of radi ati on therapy,
l ocal r ecur r ence rates sti l l exceeded 40% i n 8 year s r egar dl ess of
i r radi ati on. Based on the USC/VNPI scor e, Si l ver stei n (2003)
pr oposed the fol l owi ng tr eatment schema for DCIS: wi de l ocal
exci si on al one for pati ents wi th a USC/VNPI scor e of 4 to 6, exci si on
pl us radi ati on therapy for pati ents wi th a USC/VNPI scor e of 7 to 9,
and mastectomy for pati ents wi th a USC/VNPI scor e of 10 to 12. The
USC/VNPI scor e may be a useful adjunct i n therapeuti c deci si on
maki ng; however, i ts val i di ty has yet to be tested pr ospecti vel y.

As i ndi cated by the USC/VNPI scor e, mar gi n wi dth i s an i ndependent


pr ognosti c factor for r ecur r ence. Si l ver stei n et al . (1999) eval uated
the r ol e of postoperati ve radi ati on therapy for pati ents wi th mar gi nnegati ve r esecti ons i n a r etr ospecti ve anal ysi s of 469 pati ents. Thi s
study compar ed pati ents wi th DCIS tr eated wi th br east-conser vi ng
sur ger y wi th and wi thout radi ati on therapy. They found that
postoperati ve radi ati on therapy di d not l ower the l ocal r ecur r ence
rate among pati ents wi th mar gi ns that wer e at l east 10 mm. In
contrast, even on r eanal ysi s of the NSABP B-17 data, al l pati ent
cohor ts benefi ted fr om radi ati on therapy, r egar dl ess of the cl i ni cal
or mammographi c tumor character i sti cs. F ur ther mor e, Wong et al .
(2003) r epor ted that a pr ospecti ve si ngl e-ar m tr i al of no radi ati on
therapy i n pati ents wi th grade 1 to 2 DCIS that was no mor e than
2.5 cm and exci sed wi th 1 cm or gr eater mar gi ns conducted at the
Dana-Far ber /Har var d Cancer Center was ter mi nated after a medi an
fol l ow-up of 3.3 year s because of the number of l ocal r ecur r ences
obser ved, 2.5% per pati ent-year cor r espondi ng to a 5-year rate of
12.5% .
Two pr ospecti ve studi es ar e cur r entl y i nvesti gati ng the r ol e of
obser vati on, tamoxi fen, and radi ati on therapy after br eastconser vi ng therapy i n good-r i sk pati ents. In the Easter n
Cooperati ve Oncol ogy G r oup E-5194 tr i al , pati ents wi th DCIS no
mor e than 2.5 cm and l ow or i nter medi ate grade, or DCIS no mor e
than 1 cm and hi gh grade and mar gi ns of at l east 3 mm, under go
br east-conser vi ng sur ger y al one. Tamoxi fen use i s al l owed for 5
year s postoperati vel y. In the Radi ati on Therapy Oncol ogy G r oup
9804 tr i al , pati ents wi th DCIS no mor e than 2.5 cm, l ow or
i nter medi ate grade, and mar gi ns of at l east 3 mm ar e randoml y
assi gned to postoperati ve radi ati on therapy or obser vati on wi th the
opti on of tamoxi fen use i n each gr oup. In both of these tr i al s, the
pr i mar y outcome wi l l be l ocal r ecur r ence. These tr i al s wi l l pr ovi de
val uabl e i nfor mati on about obser vati on al one i n pati ents who
under go br east-conser vi ng sur ger y for good-r i sk DCIS.
Some have esti mated that appr oxi matel y 20% of al l women
under goi ng br east-conser vi ng sur ger y who woul d benefi t fr om
radi ati on therapy do not r ecei ve i t as par t of thei r tr eatment. The
rates of radi ati on therapy use have been shown to var y, dependi ng
on the r egi on of the countr y that the pati ent l i ves i n and the age of
the pati ent. Al so, many pati ents choose mastectomy over br eastconser vi ng sur ger y for DCIS because they ar e not abl e to compl ete
6 weeks of dai l y radi ati on therapy because of soci al consi derati ons.
Other pati ents who ar e candi dates for

br east-conser vi ng sur ger y choose to under go a mastectomy because


of concer ns about posti r radi ati on compl i cati ons. In pati ents not
r ecei vi ng radi ati on therapy, l ocal r ecur r ences i n the br east tend to
occur i n the i mmedi ate vi ci ni ty of the br east-conser vi ng cavi ty.
Hence, the i mpact of whol e br east i r radi ati on i n r educi ng l ocal
r ecur r ence may be l i mi ted to the i mmedi ate sur r oundi ng ar ea of
i ni ti al i nvol vement. Based on thi s, some have suggested that
equi val ent l ocal contr ol can be achi eved by radi ati ng onl y the ti ssue
sur r oundi ng the r esecti on cavi ty. Accel erated par ti al br east
i r radi ati on i s a techni que wher e hi gh-dose radi ati on i s del i ver ed
onl y to the ar ea at hi ghest r i sk for r ecur r ence. The tr eatment i s
compl eted over 4 to 5 days, wher eas conventi onal whol e br east
exter nal beam radi ati on therapy r equi r es 5 to 6 weeks. Several
methods of accel erated par ti al br east i r radi ati on have been
descr i bed, i ncl udi ng brachytherapy vi a mul ti pl e catheter s pl aced i n
the br east par enchyma, l ocal i zed confor mal exter nal beam radi ati on
therapy, brachytherapy vi a bead or seed i mpl ants, si ngl e-dose
i ntraoperati ve radi ati on therapy, and brachytherapy vi a a bal l oon
catheter i nser ted i nto the cavi ty after br east-conser vi ng sur ger y.
The NSABP r ecentl y i ni ti ated the B-39 tr i al , i n whi ch pati ents wi th
no mor e than 3-cm i nvasi ve stage I or II br east cancer or DCIS wi l l
be randomi zed to adjuvant whol e br east exter nal beam radi ati on
therapy or accel erated par ti al br east i r radi ati on after under goi ng
mar gi n-negati ve br east-conser vi ng sur ger y. Pati ents wi l l r ecei ve
chemotherapy and endocr i ne therapy when appr opr i ate. The pr i mar y
endpoi nt wi l l be l ocal tumor contr ol , and the secondar y endpoi nts
ar e di sease-fr ee and overal l sur vi val , cosmeti c r esul ts, and
tr eatment toxi ci ty. Thi s tr i al wi l l pr ovi de val uabl e i nfor mati on about
the potenti al r ol e for accel erated par ti al br east i r radi ati on.

Endocrine Therapy
Two pr ospecti ve randomi zed tr i al s have eval uated the effect of
tamoxi fen on outcome i n pati ents tr eated wi th br east-conser vi ng
sur ger y for DCIS. In the NSABP B-24 tr i al , 1,804 women wi th DCIS
wer e randoml y assi gned to br east-conser vi ng sur ger y and radi ati on
therapy fol l owed by ei ther tamoxi fen at 20 mg per day or a pl acebo
for 5 year s. Si xteen per cent of the women i n thi s study had posi ti ve
r esecti on mar gi ns. Women who r ecei ved tamoxi fen had fewer br east
cancer events at 7 year s' fol l ow-up than di d the pl acebo gr oup
(10.0% vs. 16.9% ). Among those who r ecei ved tamoxi fen, the rate
of i psi l ateral i nvasi ve br east cancer was 2.6% at 7 year s compar ed

wi th 5.3% i n the contr ol gr oup. Tamoxi fen al so decr eased the 7year cumul ati ve i nci dence of contral ateral br east neopl asms
(i nvasi ve and noni nvasi ve) to 2.3% compar ed wi th 4.9% i n the
contr ol gr oup. The benefi t of tamoxi fen therapy al so extended to
pati ents wi th posi ti ve mar gi ns or mar gi ns of unknown status. Ther e
was no di ffer ence i n the 7-year overal l sur vi val rate, whi ch was
95% i n both the tamoxi fen and the pl acebo gr oups. Most deaths
occur r ed befor e r ecur r ence devel oped and wer e not necessar i l y
r el ated to br east cancer. A subanal ysi s based on estr ogen r eceptor
status i ndi cated that women wi th estr ogen r eceptor-posi ti ve DCIS
who r ecei ved tamoxi fen had a 59% r educti on i n thei r r el ati ve r i sk
of br east cancer events when compar ed wi th those who r ecei ved the
pl acebo. Among pati ents wi th
estr ogen r eceptor-negati ve DCIS, ther e was no added benefi t fr om
tamoxi fen.
In a second pr ospecti ve randomi zed tr i al (Uni ted Ki ngdom
Coor di nati ng Commi ttee on Cancer Resear ch), pati ents under went
br east-conser vi ng sur ger y and wer e randomi zed to no adjuvant
tr eatment, adjuvant radi ati on therapy or tamoxi fen, or adjuvant
radi ati on therapy pl us tamoxi fen. Pati ents wi th posi ti ve mar gi ns
wer e excl uded fr om thi s tr i al , and onl y 10% of the women wer e
younger than 50 year s ol d, compar ed wi th 33% i n the NSABP B-24
tr i al . After a medi an fol l ow-up ti me of 4.4 year s, Houghton et al .
(2003) r epor ted that radi ati on therapy had the gr eatest i mpact on
r educi ng i psi l ateral br east cancer events, wher eas tamoxi fen added
to radi ati on therapy di d not r esul t i n a si gni fi cant addi ti onal
benefi t. The r el ati vel y shor t fol l ow-up ti me and compl ex desi gn of
thi s tr i al makes i nter pr etati on of the r esul ts i n di r ect compar i son to
the NSABP B-24 tr i al di ffi cul t.
The deci si on of whether to use adjuvant tamoxi fen for pati ents wi th
DCIS shoul d be made on an i ndi vi dual basi s. The use of tamoxi fen
has been associ ated wi th vasomotor symptoms, deep vei n
thr ombosi s, pul monar y embol us, and i ncr eased cataract for mati on.
The r i sk of endometr i al cancer among pati ents who r ecei ve the dr ug
i s two to seven ti mes the nor m. Tamoxi fen may be associ ated wi th
i ncr eased rates of str oke and beni gn ovar i an cysts. Ther efor e, the
effects of tamoxi fen to r educe i psi l ateral br east tumor s and to
pr event contral ateral br east di sease shoul d be wei ghed agai nst the
r i sk of tamoxi fen use i n each pati ent. In addi ti on, tamoxi fen shoul d
be r eser ved for pati ents wi th estr ogen r eceptor-posi ti ve tumor s.
Ar omatase i nhi bi tor s have been shown to be benefi ci al i n the

adjuvant tr eatment of i nvasi ve br east cancer i n postmenopausal


women. These agents have fewer car di ovascul ar si de effects than
tamoxi fen and may be benefi ci al i n the adjuvant tr eatment of
pati ents wi th DCIS fol l owi ng br east-conser vi ng sur ger y. Two ongoi ng
randomi zed pr ospecti ve cl i ni cal tr i al sNSABP B-35 and the
Inter nati onal Br east Cancer Inter venti on Study (IBIS-II)ar e
compar i ng tamoxi fen wi th anastr ozol e fol l owi ng br east-conser vi ng
sur ger y i n pati ents wi th a di agnosi s of DCIS. Resul ts fr om these
tr i al s shoul d deter mi ne the r ol e of ar omatase i nhi bi tor s i n the
adjuvant tr eatment of DCIS.

Axillary Node Staging


Because DCIS i s a noni nvasi ve di sease, l ymph node i nvol vement i s
not expected. Thus, the r ol e for axi l l ar y l ymph node di ssecti on i s
l i mi ted, and node di ssecti on shoul d not be per for med on a r outi ne
basi s. In cases wher e pati ents have l ar ge tumor s (>4 cm) or
extensi ve mi cr ocal ci fi cati ons, a focus of i nvasi on can be mi ssed
because of l i mi ted pathol ogi cal sampl i ng, and such pati ents ar e at
r i sk for l ymph node metastasi s. Hence, pati ents who under go
mastectomy for l ar ge, hi gh-grade DCIS shoul d be consi der ed for
i ntraoperati ve l ymphati c mappi ng and senti nel l ymph node
di ssecti on because i t i s not possi bl e to per for m l ymphati c mappi ng
after a mastectomy i f i nvasi ve cancer i s found i n the mastectomy
speci men. Pati ents wi th l ar ge, hi gh-grade, or pal pabl e DCIS who ar e
under goi ng br east-conser vi ng sur ger y ar e al so potenti al candi dates
for i ntraoperati ve l ymphati c
mappi ng and senti nel l ymph node di ssecti on (di scussed i n detai l i n
Chapter 2). Di agnosi s of DCIS wi th the use of ster eotacti c cor eneedl e bi opsy i s associ ated wi th a 20% rate of concomi tant i nvasi ve
cancer on fi nal pathol ogi cal exami nati on, fur ther emphasi z i ng the
i mpor tance of senti nel l ymph node di ssecti on at the ti me of
mastectomy for l ar ge, hi gh-grade l esi ons. In a study by Cox et al .
(1998), the combi nati on of hematoxyl i n-eosi n stai ni ng and
i mmunohi stochemi str y r eveal ed that 6% of pati ents wi th newl y
di agnosed DCIS had metastati c di sease i n the senti nel nodes.
Kl auber-DeMor e et al . (2000) found that senti nel l ymph nodes wer e
posi ti ve for cancer among 12% of pati ents wi th DCIS consi der ed to
be at hi gh r i sk for i nvasi on and among 10% of pati ents who had
DCIS wi th mi cr oi nvasi on. Thi s r i sk must be wei ghed agai nst the r i sk
of l ymphedema associ ated wi th senti nel node di ssecti on i n each
pati ent.

Predictors of Local Relapse


Ther e ar e several featur es of DCIS that ar e associ ated wi th a l ess
favorabl e cl i ni cal cour se. Tradi ti onal pathol ogi cal var i abl es, such as
l ar ge tumor si ze (>3 cm), hi gh nucl ear grade, comedo-type
necr osi s, and i nvol ved mar gi ns of exci si on, ar e associ ated wi th a
gr eater r i sk of l ocal r ecur r ence, as pr evi ousl y di scussed. Invol ved
mar gi ns of r esecti on consti tute the most i mpor tant i ndependent
pr ognosti c var i abl e for pr edi cti ng l ocal r el apse. As descr i bed
pr evi ousl y, the USC/VNPI combi nes four si gni fi cant pr edi ctor s of
l ocal r ecur r ence: tumor si ze, mar gi n wi dth, pathol ogi cal
cl assi fi cati on, and pati ent age. In addi ti on to a young pati ent age
(<50 year s of age), a fami l y hi stor y of br east cancer i s associ ated
wi th an i ncr eased r i sk of l ocal r ecur r ence; however, these factor s
ar e not consi der ed contrai ndi cati ons for br east-conser vi ng therapy.
Mol ecul ar mar ker s, such as over expr essi on of HER-2/neu, nm23,
heat shock pr otei n, and metal l othi onei n; l ow expr essi on of p21
Waf1 and Bcl 2; and DNA aneupl oi dy have been associ ated wi th hi ghgrade comedo l esi ons, but thei r i mpor tance as i ndependent
pr ognosti c var i abl es i n DCIS has not been cl ar i fi ed.

Treatment and Outcome of Local Recurrence


The overal l sur vi val rate i n pati ents wi th DCIS i s excel l ent. In the
NSABP B-17 tr i al , onl y 27 deaths (3.3% ) attr i butabl e to br east
cancer had occur r ed after a medi an fol l ow-up ti me of 12 year s. In
the NSABP B-24 tr i al , 0.8% of the pati ents di ed as a consequence of
thei r br east cancer after 7 year s of fol l ow-up. In both tr i al s, and i n
other studi es, appr oxi matel y 50% of al l l ocal r ecur r ences wer e
i nvasi ve cancer s. The management of l ocal r ecur r ence depends on
the therapy the pati ent r ecei ved for the pr i mar y cancer. In cases of
l ocal r ecur r ence i n pati ents who under went br east-conser vi ng
sur ger y wi thout radi ati on therapy, r e-exci si on wi th negati ve
mar gi ns and postoperati ve radi ati on therapy consti tute tr eatment
opti ons. For pati ents who have r ecur r ent br east cancer after
r ecei vi ng br east-conser vi ng sur ger y and radi ati on therapy,
mastectomy i s usual l y the pr efer r ed tr eatment. If the r ecur r ent
tumor i s i nvasi ve, stagi ng of the axi l l ar y nodes i s per for med wi th
l ymphati c mappi ng and senti nel l ymph node di ssecti on or wi th
axi l l ar y l ymph node di ssecti on.
The pr ognosi s after tr eatment of l ocal r ecur r ence depends on
whether the r ecur r ence i s i nvasi ve or noni nvasi ve. Si l ver stei n et al .

(1998) found that among pati ents wi th i nvasi ve r ecur r ent di sease,
the 8-year di sease-speci fi c mor tal i ty rate was 14.4% , and the
di stant di sease pr obabi l i ty was 27.1% . In a fol l ow-up study, Romer o
et al . (2004) r epor ted a 10-year di sease-speci fi c mor tal i ty rate of
15% i n pati ents wi th i nvasi ve r ecur r ent di sease. Al though most
pati ents wi th r ecur r ent di sease after DCIS do sur vi ve, an i nvasi ve
r ecur r ence i s a ser i ous event. Pati ents wi th DCIS shoul d under go
l ong-ter m fol l ow-up for both r ecur r ent di sease and devel opment of
new i psi l ateral or contral ateral pr i mar y tumor s.

Surveillance
Fol l owi ng br east-conser vi ng sur ger y, a mammogram shoul d be
obtai ned to detect r esi dual mi cr ocal ci fi cati ons. In addi ti on, a
mammogram shoul d be obtai ned 4 to 6 months after the compl eti on
of radi ati on therapy to establ i sh a new basel i ne. Fol l ow-up of
pati ents after br east-conser vi ng sur ger y wi th or wi thout radi ati on
therapy shoul d i ncl ude annual or bi annual physi cal exami nati on and
annual mammography for the fi r st 5 year s, wi th an annual physi cal
exami nati on and mammogram ther eafter. Both pati ents who under go
br east-conser vi ng therapy and those who under go mastectomy
shoul d be moni tor ed cl osel y for new pr i mar y cancer s i n the
contral ateral br east. The r i sk of devel opment of a new pr i mar y
cancer i n the contral ateral br east after tr eatment of DCIS i s two to
fi ve ti mes gr eater than the r i sk of devel opment of a fi r st pr i mar y
br east cancer and i s appr oxi matel y the same as the r i sk of
devel opment of a new contral ateral pr i mar y cancer after i nvasi ve
cancer.

Current Management of Ductal Carcinoma In


Situ at The University of Texas M. D.
Anderson Cancer Center
An al gor i thm for the cur r ent tr eatment of DCIS at M. D. Ander son
Cancer Center i s outl i ned i n F i gur e 1.1. Pati ents di agnosed wi th a
mammographi c abnor mal i ty under go contral ateral mammography,
and the mammograms ar e compar ed wi th pr evi ous i mages, i f
avai l abl e. In cases i n whi ch DCIS i s suspected, magni fi cati on vi ews
ar e r outi nel y used to del i neate the abnor mal i ty fur ther. Ul trasound
i s al so fr equentl y used to assess tumor si ze, mul ti centr i ci ty, and
nodal status. Di agnosti c bi opsy i s per for med by usi ng a vacuumassi sted ster eotacti c cor e-needl e bi opsy techni que. When DCIS i s
di agnosed, the pathol ogi cal eval uati on detai l s the tumor type and

grade, as wel l as any evi dence of mi cr oi nvasi on. The status of both
the estr ogen and the pr ogester one r eceptor s i s deter mi ned and
r epor ted.
The choi ce of sur gi cal therapy i s based on several factor s, i ncl udi ng
tumor si ze and grade, mar gi n wi dth, mammographi c appearance,
and pati ent pr efer ence. The benefi ts and r i sks of br east-conser vi ng
sur ger y and mastectomy shoul d be di scussed i n detai l wi th each
pati ent. Most pati ents wi th DCIS ar e candi dates for br eastconser vi ng therapy, and the choi ce of thi s l ocal tr eatment does not
i nfl uence thei r overal l sur vi val . Mastectomy i s i ndi cated i n pati ents
wi th di ffuse, mal i gnant-appear i ng cal ci fi cati ons i n the br east and
per si stent posi ti ve mar gi ns after attempts at sur gi cal exci si on.
Al though tumor si ze i s not an absol ute i ndi cati on for

mastectomy, mastectomy i s often pr efer r ed for pati ents wi th l ar ge


(>4 cm i n di ameter ), hi gh-grade DCIS. Ther e ar e few data avai l abl e
on the effi cacy of br east-conser vi ng sur ger y for DCIS wi th i ndex
l esi ons gr eater than 4 cm i n di ameter. Mastectomy may al so be a
better choi ce when a pati ent's anxi ety over the possi bi l i ty of
r ecur r ence outwei ghs the i mpact a mastectomy woul d have on her
qual i ty of l i fe. Immedi ate br east r econstr ucti on shoul d be
consi der ed for al l pati ents who r equi r e or el ect mastectomy.
Intraoperati ve mar gi n assessment wi th secti oned-speci men
radi ography i s used for most pati ents under goi ng br east-conser vi ng
sur ger y and for pati ents wi th extensi ve cal ci fi cati ons under goi ng
ski n-spar i ng mastectomy. Re-exci si on i s usual l y r ecommended for
pati ents who have mar gi ns l ess than 2 mm on fi nal pathol ogi cal
exami nati on after br east-conser vi ng sur ger y.

F i gur e 1.1. Management of l obul ar car ci noma i n si tu (LCIS) and


ductal car ci noma i n si tu (DCIS) at M. D. Ander son. 1 Exci si onal
bi opsy i s per for med for pati ents wi th LCIS detected by cor eneedl e bi opsy anal ysi s. Exci si on i s per for med wi th the i ntent of
achi evi ng negati ve mar gi ns i n pati ents wi th pl eomor phi c LCIS.
2 A pathol ogy r evi ew i s per for med, whi ch i ncl udes deter mi ni ng
the tumor si ze, hi stol ogi c type, and nucl ear grade; r ul i ng out an
i nvasi ve component; deter mi ni ng the l ymph node status i f l ymph
node sur ger y was per for med; and deter mi ni ng the estr ogen and
pr ogester one r eceptor status. 3 Candi dates for br east-conser vi ng
sur ger y ar e those wi th uni centr i c di sease, whose rati o of tumor
si ze to br east si ze al l ows for an acceptabl e cosmeti c r esul t wi th
r esecti on mar gi ns gr eater than or equal to 2 mm. Note: Cl i ni cal
tr i al s ar e consi der ed the pr efer r ed tr eatment opti ons for el i gi bl e
pati ents. U/S, ul trasound.

Pati ents who under go mastectomy for DCIS r outi nel y under go
i ntraoperati ve l ymphati c mappi ng and senti nel l ymph node
di ssecti on. In pati ents who under go br east-conser vi ng sur ger y,
senti nel l ymph node di ssecti on i s per for med on an i ndi vi dual basi s
and pr i mar i l y r eser ved for cases wher e the DCIS i s pal pabl e or hi gh
grade or exhi bi ts comedo-type necr osi s.
Adjuvant radi ati on therapy i s r ecommended to r educe the r i sk of
l ocal r ecur r ence i n pati ents who under go br east-conser vi ng sur ger y.
Br east-conser vi ng sur ger y al one (wi thout radi ati on therapy) i s
consi der ed for sel ected pati ents wi th smal l (<1 cm i n di ameter ),
l ow-grade l esi ons that have been exci sed wi th mar gi ns of at l east 5
mm and who can be obser ved di l i gentl y for r ecur r ence. Par ti al
br east i r radi ati on i s offer ed on pr otocol onl y. Tamoxi fen i s offer ed
for 5 year s to women wi th estr ogen r eceptor-posi ti ve DCIS who do
not have a hi stor y of venous thr omboembol i sm or str oke.
Fol l owi ng sur gi cal r esecti on, pati ents under go annual physi cal and
cl i ni cal br east exami nati ons. Other or gani z ati ons, such as the
Nati onal Compr ehensi ve Cancer Networ k, r ecommend a physi cal
exami nati on ever y 6 months for 5 year s and annual l y ther eafter.
Whether thi s i mpr oves the detecti on of r ecur r ence and outcome i s
not known. Pati ents who r ecei ve br east-conser vi ng sur ger y and
radi ati on therapy under go a di agnosti c mammogram 6 months after
the compl eti on of radi ati on therapy and annual bi l ateral
mammograms ther eafter. If a mastectomy i s per for med,

the pati ent i s fol l owed wi th an annual di agnosti c contral ateral


mammogram.
Al l pati ents wi th DCIS ar e consi der ed for cl i ni cal tr i al s, whi ch ar e
the pr efer r ed tr eatment opti ons for el i gi bl e pati ents.

Lobular Carcinoma in Situ


LCIS was fi r st descr i bed as a di sti nct pathol ogi cal enti ty i n 1941.
Dur i ng the era that fol l owed, the tr eatment of LCIS was the same as
that of i nvasi ve car ci nomaradi cal mastectomy. Haagensen i s
cr edi ted wi th al ter i ng the tr eatment phi l osophy for LCIS. In thei r
r evi ew of 211 cases, Haagensen et al . (1978) noted a 17%
i nci dence of subsequent i nvasi ve car ci nomas among women i n whom
di sease was di agnosed as LCIS and tr eated by obser vati on al one
(wi thout sur ger y). The r i sk of devel opi ng a subsequent car ci noma
was equal for both br easts, and onl y si x pati ents di ed of br east
cancer. Haagensen concl uded that cl ose obser vati on for LCIS
al l owed for ear l y detecti on of subsequent mal i gnancy, wi th
associ ated hi gh cur e rates. Haagensen's rati onal e for obser vati on as
a tr eatment phi l osophy for LCIS was based on hi s vi ew that pati ents
wi th LCIS wer e at i ncr eased r i sk for i nvasi ve br east cancer but that
LCIS i tsel f di d not pr ogr ess i nto a mal i gnancy. However, mor e r ecent
wor k has i ndi cated that cer tai n types of LCIS may be i ndol ent
pr ecur sor s of i nfi l trati ng cancer and that sur gi cal r esecti on shoul d
be consi der ed i n sel ected subtypes of LCIS.

Epidemiology
The i nci dence of LCIS i s di ffi cul t to esti mate because the di agnosi s
i s most often made fol l owi ng a pur el y i nci dental fi ndi ng. LCIS i s
often not detectabl e by pal pati on, gr oss pathol ogi cal exami nati on,
or mammography. Eval uati on of mammographi c abnor mal i ti es has
found LCIS to be pr esent i n 0.5% to 1.3% of br east cor e-needl e
bi opsy speci mens and 0.5% to 3.9% of exci si onal br east bi opsy
speci mens.
Tradi ti onal l y, LCIS has been mor e commonl y r epor ted i n
pr emenopausal women than i n postmenopausal women. In
Haagensen's ser i es descr i bed pr evi ousl y, 90% of the pati ents wer e
pr emenopausal . In a r evi ew of the Sur vei l l ance, Epi demi ol ogy, and
End Resul ts pr ogram database, Li et al . (2002) r epor ted that fr om
1978 to 1998 the i nci dence of LCIS i ncr eased i n al l age gr oups, but
that i t i ncr eased the most i n women 50 to 79 year s ol d. The

i ncr ease i n i nci dence i n women 40 to 49 year s ol d conti nued to the


1987 to 1989 ti me per i od and then stabi l i zed, wher eas the
i nci dence i n women age 50 year s or ol der i ncr eased thr oughout the
study per i od. Dur i ng the 1996 to 1998 ti me per i od, the i nci dence of
LCIS was the hi ghest i n women 50 to 59 year s ol d (11.47/100,000
per son-year s) fol l owed by women 60 to 69 year s ol d (8.14/100,000
per son-year s). The r eason for thi s i ncr ease i n LCIS i s bel i eved to be
mul ti factor i al and par ti al l y the r esul t of i ncr eased use of scr eeni ng
mammography; ther efor e, an i ncr eased number of bi opsi es wer e
per for med for mammographi cal l y detected br east abnor mal i ti es.
Estr ogen has been hypothesi zed to pl ay an i mpor tant r ol e i n the
pathogenesi s of LCIS; thus, the i ncr eased use of hor mone
r epl acement therapy i n postmenopausal
women may al so account for the i ncr eased i nci dence of LCIS i n
women age 50 year s or ol der.
The theor y that LCIS r epr esents a mar ker of i ncr eased r i sk of
i nvasi ve br east car ci noma has tradi ti onal l y been suppor ted by the
fact that the mean age at di agnosi s i s 10 to 15 year s younger than
that for i nvasi ve cancer. However, as the i nci dence of LCIS has
i ncr eased i n women 50 year s of age and ol der, the i nci dence of
i nfi l trati ng l obul ar car ci noma i n thi s age gr oup has i ncr eased
concur r entl y, wher eas women younger than 50 year s ol d have not
exper i enced an i ncr ease i n i nvasi ve l obul ar car ci noma. Recentl y,
some have suggested that LCIS i s mor phol ogi cal l y and bi ol ogi cal l y
mor e heter ogeneous than pr evi ousl y r epor ted. Al though cl assi c LCIS
may not be associ ated wi th i nvasi ve l obul ar car ci noma, cases of
l ar ger, mor e pl eomor phi c LCIS l esi ons may r epr esent cl onal
pr ol i ferati on of cel l s that may pr ogr ess to i nvasi ve l obul ar
car ci noma. Mol ecul ar anal ysi s of LCIS and i nvasi ve l obul ar
car ci noma has r eveal ed l oss of or decr eased expr essi on of the cel l
sur face adhesi on mol ecul e E-cadher i n i n both tumor types. Thi s
contrasts wi th ductal car ci noma, i n whi ch E-cadher i n expr essi on i s
usual l y mai ntai ned. LCIS and i nvasi ve ductal car ci noma have al so
been shown to exhi bi t si mi l ar l oss of heter oz ygosi ty. In addi ti on, i n
an anal ysi s of 180 pati ents wi th LCIS tr eated wi th br east-conser vi ng
therapy, F i sher et al . (2004) r epor ted that ei ght of ni ne pati ents
(89% ) wi th i nvasi ve i psi l ateral br east car ci noma r ecur r ence had a
r ecur r ence of the l obul ar type. These data fur ther str engthen the
theor y that LCIS i s not onl y a mar ker for i ncr eased r i sk of i nvasi ve
br east cancer, but al so a di r ect pr ecur sor of i nvasi ve l obul ar
car ci noma.

Pathology
LCIS i s character i zed by an i ntraepi thel i al pr ol i ferati on of the
ter mi nal l obul ar-ductal uni t. The cel l s ar e sl i ghtl y l ar ger and pal er
than those that l i ne the nor mal aci ni , but the l obul ar ar chi tectur e
r emai ns i ntact. The cel l s have a homogeneous mor phol ogy and do
not di spl ay pr omi nent chr omati n. The cytopl asm-to-nucl eus rati o i s
nor mal , wi th i nfr equent mi toses and no necr osi s. The pr ol i ferati ng
cel l s do not penetrate the basement membrane. Recentl y, a
pl eomor phi c var i ant of LCIS wi th l ar ger nucl ei , central necr osi s, and
cal ci fi cati ons was descr i bed. Thi s var i ant may be mor e pr one to
pr ogr essi ng to i nvasi ve l obul ar car ci noma.
The di agnosi s of LCIS i nvol ves the di ffer enti ati on of LCIS fr om other
for ms of beni gn di sease and fr om i nvasi ve l esi ons. In the absence of
compl ete r epl acement of the l obul ar uni t, atypi cal l obul ar
hyper pl asi a i s the desi gnated pathol ogi cal ter m. Papi l l omatosi s i n
the ter mi nal ducts may r esembl e LCIS but l acks the character i sti c
i nvol vement of the aci ni . DCIS may extend r etr ograde i nto the
aci ni , but i t has a mor e character i sti c anapl asti c cel l mor phol ogy
and general l y expr esses E-cadher i n. LCIS i s contai ned wi thi n the
basement membrane and i s thus di sti ngui shed fr om i nvasi ve l obul ar
car ci noma.
Numer ous studi es have documented that LCIS i s mul ti focal and
mul ti centr i c. If di l i gentl y sought, foci can be found el sewher e i n the
br east i n al most al l cases. In addi ti on, LCIS i s i denti fi ed i n the
contral ateral br east i n 50% to 90% of cases. Thus, the pr esence of
LCIS r efl ects a phenotypi c mani festati on of a general i zed
abnor mal i ty pr esent thr oughout both br easts. As a r esul t, the
tr eatment of LCIS shoul d be di r ected not onl y at the i ndex l esi on,
but al so at both br easts.

Diagnosis
Clinical Presentation
Because LCIS i s usual l y not detectabl e by physi cal exami nati on or
mammography, i t i s most commonl y di agnosed as an i nci dental
fi ndi ng i n a br east bi opsy speci men. Ther efor e, the cl i ni cal
pr esentati on of pati ents wi th LCIS i s si mi l ar to that of pati ents
r equi r i ng br east bi opsy for fi br oadenoma, beni gn ductal di sease,
DCIS, or i nvasi ve br east cancer. Pati ents di agnosed wi th LCIS shoul d
under go bi l ateral di agnosti c mammography to excl ude other

mammographi c abnor mal i ti es. Ul trasound i s al so useful i n


eval uati ng suspi ci ous fi ndi ngs.

Treatment
Surgery
The opti mal cl i ni cal management of pati ents di agnosed wi th LCIS
wi th the use of a cor e-needl e bi opsy r emai ns contr over si al . In the
past, many sur geons opted to obser ve such pati ents because a
di agnosi s of LCIS was consi der ed a mar ker for i ncr eased r i sk of
br east cancer rather than a pr ecur sor of i nvasi ve cancer. However,
r ecent studi es by Ar pi no et al . (2004) and other s have r epor ted a
0% to 10% r i sk of synchr onous i nvasi ve br east cancer and a 0% to
50% r i sk of synchr onous DCIS i n pati ents di agnosed wi th LCIS by
cor e-needl e bi opsy speci mens. Hence, pati ents wi th LCIS di agnosed
by cor e-needl e bi opsy speci mens ar e now r ecommended to under go
sur gi cal exci si on to r ul e out synchr onous i nvasi ve cancer and DCIS.
In contrast wi th DCIS, ther e i s a l ack of pr ospecti ve randomi zed
tr i al s eval uati ng adjuvant tr eatment fol l owi ng sur gi cal exci si on of
LCIS. Most of the pati ents di agnosed wi th LCIS si nce the mi d-1970s
have under gone cl i ni cal obser vati on al one based on the
r ecommendati ons of Haagensen et al . (1978). In a study of pati ents
who under went obser vati on al one after mar gi n negati ve sur gi cal
exci si on of LCIS, F i sher et al . (2004) r epor ted an overal l 14.4%
i psi l ateral and 7.8% contral ateral br east cancer r ecur r ence rate
after 12 year s. Near l y 85% of i psi l ateral br east tumor r ecur r ences
wer e detected by mammography, and the r i sk of i psi l ateral
r ecur r ence was appr oxi matel y 1.6% per year. Mor e than 96% of al l
i psi l ateral r ecur r ences occur r ed i n the same quadrant as the
or i gi nal LCIS. Ni ne of 26 (34.6% [5.0% of the total ]) pati ents wi th
i psi l ateral r ecur r ence had an i nvasi ve tumor, an i nci dence that was
si mi l ar to that i n pati ents wi th contral ateral br east tumor
r ecur r ence (5.6% of the total ). However, the contral ateral
r ecur r ences occur r ed l ater. Onl y 2 of the 180 pati ents i n the study
di ed fr om br east cancer, r esul ti ng i n a br east cancer-speci fi c
mor tal i ty rate of 1.1% at 12 year s of fol l ow-up ti me. The fr ee
exci si on mar gi ns wer e bel i eved to have contr i buted to the l ow rate
of i nvasi ve i psi l ateral r ecur r ence. In another study of 100 pati ents
wi th LCIS, Ottesen et al . (2000) r epor ted a 13% i nvasi ve i psi l ateral
br east cancer r ecur r ence rate and a 16% overal l r ecur r ence rate. In
thi s study, mar gi n status was not eval uated, and the i nvasi ve

i psi l ateral br east tumor r ecur r ence rate was mor e than doubl e that
obser ved by F i sher et al . (2004). Hence, compl ete exci si on of LCIS
wi th negati ve mar gi ns may r esul t i n decr eased occur r ence of
i nvasi ve br east cancer. However, at the pr esent ti me, the data ar e
i nsuffi ci ent to r ecommend r e-exci si on to achi eve negati ve mar gi ns
for LCIS. F ur ther study of the var i ous LCIS subtypes i s needed to
deter mi ne whether pati ents wi th some subtypes woul d i ndeed
benefi t fr om r e-exci si on.
Contral ateral mi r r or-i mage br east bi opsy, a pr ocedur e advocated for
pati ents wi th LCIS i n the past, has fal l en out of favor because a
mi r r or-i mage bi opsy negati ve for LCIS does not el i mi nate the need
for cl ose obser vati on of the r emai ni ng br east ti ssue i n the
contral ateral br east. A vi abl e therapeuti c opti on for LCIS i s bi l ateral
pr ophyl acti c mastectomy. Thi s appr oach i s usual l y r eser ved for
pati ents who have addi ti onal r i sk factor s for br east cancer or who
exper i ence extr eme anxi ety r egar di ng the obser vati on and/or
chemopr eventi on opti ons. Because LCIS poses no r i sk of r egi onal
metastasi s, axi l l ar y node di ssecti on i s not r equi r ed. Immedi ate
br east r econstr ucti on shoul d be offer ed for pati ents who under go
pr ophyl acti c mastectomy for LCIS.

Endocrine Therapy and Chemoprevention


Another tr eatment opti on for pati ents wi th a di agnosi s of LCIS i s
chemopr eventi on wi th tamoxi fen. In the NSABP P-1 br east cancer
pr eventi on tr i al , F i sher et al . (1998) obser ved a 56% decr ease i n
the i nci dence of i nvasi ve br east cancer s i n a subset of women wi th
LCIS who r ecei ved tamoxi fen as compar ed wi th women wi th LCIS
who under went obser vati on al one. The annual haz ar d rate of
i nvasi ve cancer was 5.69 per 1,000 women who r ecei ved tamoxi fen
compar ed wi th 12.99 per 1,000 women who di d not. Postmenopausal
women wi th LCIS wer e el i gi bl e to be randomi zed between tamoxi fen
and ral oxi fene i n the NSABP P-2 tr i al , whi ch cl osed to accr ual i n
2004 (the Study of Tamoxi fen And Ral oxi fene). The fi r st r esul ts
fr om thi s tr i al ar e expected i n 2006.

Radiation Therapy
Adjuvant radi ati on therapy has not been eval uated speci fi cal l y for
the tr eatment of LCIS, and data ar e cur r entl y i nsuffi ci ent to
r ecommend thi s tr eatment on a r outi ne basi s. If synchr onous DCIS
or i nvasi ve br east cancer i s found i n an exci sed LCIS speci men, the
pati ent wi l l benefi t fr om radi ati on therapy and shoul d r ecei ve

tr eatment accor di ng to the gui del i nes for DCIS or i nvasi ve br east
cancer.

Surveillance
Fol l owi ng br east-conser vi ng therapy for LCIS, pati ents shoul d
under go annual or bi annual physi cal exami nati ons wi th bi l ateral
br east exami nati ons. They shoul d al so under go annual bi l ateral
di agnosti c mammography. Use of scr eeni ng ul trasound i n pati ents
wi th LCIS i s bei ng eval uated. Al so, pati ents who under go a bi l ateral
mastectomy wi th or wi thout r econstr ucti on shoul d under go an
annual physi cal exami nati on, and any suspi ci ous l esi ons shoul d be
eval uated wi th ul trasound and bi opsy anal ysi s.

Current Treatment of Lobular Carcinoma In


Situ at M. D. Anderson Cancer Center
The al gor i thm for tr eatment of pati ents wi th LCIS at M. D. Ander son
i s outl i ned i n F i gur e 1.1. Pati ents found to have LCIS by bi opsy
anal ysi s ar e eval uated wi th bi l ateral di agnosti c mammography i f not
per for med pr i or to obtai ni ng the bi opsy speci men. The new
mammograms ar e compar ed wi th pr evi ous i mages, i f avai l abl e.
Suspi ci ous l esi ons ar e fur ther eval uated wi th ul trasound, and
addi ti onal cor e-needl e bi opsy speci mens ar e obtai ned when
appr opr i ate.
Pati ents found to have a suspi ci ous abnor mal i ty on mammography
or ul trasound under go br east-conser vi ng therapy wi th exci si on of
the abnor mal i ty under needl e l ocal i z ati on. If they ar e found to have
synchr onous DCIS or i nvasi ve br east cancer, subsequent tr eatment
i s admi ni ster ed accor di ng to the gui del i nes for these tumor s. Reexci si on to attai n negati ve mar gi ns i s not r outi nel y per for med i n
pati ents found to have i sol ated cl assi cal LCIS i n an exci sed
speci men. If necessar y, r e-exci si on i s per for med to achi eve negati ve
mar gi ns i n pati ents wi th a di agnosi s of pl eomor phi c LCIS. Bi l ateral
pr ophyl acti c mastectomy i s r eser ved for pati ents wi th addi ti onal r i sk
factor s for br east cancer and pati ents who exper i ence extr eme
anxi ety r egar di ng the obser vati on and/or chemopr eventi on opti ons.
Pati ents who under go br east-conser vi ng therapy for LCIS do not
r outi nel y r ecei ve radi ati on therapy but ar e offer ed tamoxi fen i f they
ar e sui tabl e candi dates for anti estr ogen therapy.
After br east-conser vi ng sur ger y, pati ents under go annual physi cal

exami nati ons and bi l ateral di agnosti c mammography. Fol l owi ng a


bi l ateral pr ophyl acti c mastectomy wi th or wi thout r econstr ucti on,
pati ents ar e al so eval uated wi th the use of annual physi cal
exami nati ons, and any suspi ci ous l esi ons ar e i nvesti gated by usi ng
ul trasound and bi opsy anal ysi s when appr opr i ate.
Al l pati ents wi th LCIS ar e consi der ed for cl i ni cal tr i al s, whi ch ar e
the pr efer r ed tr eatment opti ons for el i gi bl e pati ents.

Recommended Reading
Ar pi no G , Al l r ed CG , Mohsi n SK, et al . Lobul ar neopl asi a on cor eneedl e bi opsycl i ni cal si gni fi cance. Cancer 2004;101:242.
Bal ch CM, Si ngl etar y SE, Bl and KI. Cl i ni cal deci si on-maki ng i n
ear l y br east cancer. Ann Sur g 1993;217:207.
Boyages J, Del aney G , Tayl or R. Pr edi ctor s of l ocal r ecur r ence
after tr eatment for ductal car ci noma i n si tua meta-anal ysi s.
Cancer 1999;85:616.
Chagpar A, Yen T, Sahi n A, et al . Intraoperati ve mar gi n
assessment r educes r eexci si on rates i n pati ents wi th ductal
car ci noma i n si tu tr eated wi th br east conser vi ng sur ger y. Am J
Sur g 2003;186:371.
Cox CE, Pendas S, Cox JM, et al . G ui del i nes for senti nel node
bi opsy and l ymphati c mappi ng of pati ents wi th br east cancer. Ann
Sur g 1998;227:645.
de Mascar el I, MacG r ogan G , Mathoul i n-Pl i ssi er S, et al . Br east
ductal car ci noma i n si tu wi th mi cr oi nvasi on: a defi ni ti on
suppor ted by a l ong-ter m study of 1248 ser i al l y secti oned ductal
car ci nomas. Cancer 2002;94:2134.
F i sher B, Costanti no J, Redmond C, et al . Lumpectomy compar ed
wi th l umpectomy and radi ati on therapy for the tr eatment of
i ntraductal br east car ci noma. N Engl J Med 1993;328:1581.
F i sher B, Costanti no JP, Wi cker ham DL, et al . Tamoxi fen for
pr eventi on of br east cancer : r epor t of the Nati onal Sur gi cal

Adjuvant Br east and Bowel Pr oject P-1 study. J Natl Cancer Inst
1998;90:1371.

F i sher B, Di gnam J, Wol mar k N, et al . Tamoxi fen i n tr eatment of


i ntraductal br east cancer : Nati onal Sur gi cal Adjuvant Br east and
Bowel Pr oject B-24 randomi sed contr ol l ed tr i al . Lancet
1999;353:1993.
F i sher B, Land S, Mamounas E, et al . Pr eventi on of i nvasi ve
br east cancer i n women wi th ductal car ci noma i n si tu: an update
of the Nati onal Sur gi cal Adjuvant Br east and Bowel Pr oject
Exper i ence. Semin Oncol 2001;28:400.
F i sher ER, Costanti no J, F i sher B, et al . Pathol ogi cal fi ndi ngs fr om
the Nati onal Sur gi cal Adjuvant Br east Pr oject (NSABP) Pr otocol
B-17. Cancer 1995;75:1310.
F i sher ER, Land SR, F i sher B, et al . Pathol ogi c fi ndi ngs fr om the
Nati onal Sur gi cal Adjuvant Br east and Bowel Pr oject: twel ve-year
obser vati ons concer ni ng l obul ar car ci noma i n si tu. Cancer
2004;100:238.
Fowbl e B. Intraductal noni nvasi ve br east cancer : a compar i son of
thr ee l ocal tr eatments. Oncology 1989;3:51.
Haagensen CA, Lome N, Lattes R, et al . Lobul ar neopl asi a (socal l ed l obul ar car ci noma i n si tu) of the br east. Cancer
1978;42:757.
Hol l and R, Hendr i cks JH, Ver beek AL, et al . Extent, di str i buti on,
and mammographi c/hi stol ogi cal cor r el ati ons of br east ductal
car ci noma i n si tu. Lancet 1990;335:519.
Houghton J, G eor ge WD, Cuz i ck J, et al . Radi otherapy and
tamoxi fen i n women wi th compl etel y exci sed ductal car ci noma i n
si tu of the br east i n the UK, Austral i a, and New Zeal and:
randomi sed contr ol l ed tr i al . Lancet 2003;362:95.
Jul i en J-P, Bi jker N, Fenti man IS, et al . Radi otherapy i n br east-

conser vi ng tr eatment for ductal car ci noma i n si tu: fi r st r esul ts of


the EORTC randomi sed phase III tr i al 10853. Lancet
2000;355:528.
Kl auber-DeMor e N, Tan LK, Li ber man L, et al . Senti nel l ymph
node bi opsy: i s i t i ndi cated i n pati ents wi th hi gh-r i sk ductal
car ci noma-i n-si tu and ductal car ci noma-i n-si tu wi th
mi cr oi nvasi on? Ann Sur g Oncol 2000;2:636.
Lagi os MD, Mar gol i n F R, Westdahl PR, et al . Mammographi cal l y
detected duct car ci noma i n si tu. Cancer 1989;63:618.
Li CI, Ander son BO, Dal i ng JR, et al . Changi ng i nci dence of
l obul ar car ci noma i n si tu of the br east. Br east Cancer Res Tr eat
2002;75:259.
Mi r z a NQ, Vl astos G , Mer i c F, et al . Ductal car ci noma-i n-si tu:
l ong-ter m r esul ts of br east-conser vi ng therapy. Ann Sur g Oncol
2000;7:656.
Neuschatz AC, Di Petr i l l o T, Stei nhoff M, et al . The val ue of br east
l umpectomy mar gi n assessment as a pr edi ctor of r esi dual tumor
bur den i n ductal car ci noma i n si tu of the br east. Cancer
2002;94:1917.
Ni el son M, Thomsen JL, Pr i mdahl U, et al . Br east cancer and
atypi a among young and mi ddl e-aged women: a study of 110
medi col egal autopsi es. Br J Cancer 1987;56:814.
Ottesen G L, G raver sen HP, Bl i cher t-Toft M, et al . Car ci noma i n
si tu of the femal e br east. 10 year fol l ow-up r esul ts of a
pr ospecti ve nati onwi de study. Br east Cancer Res Tr eat
2000;62:197.
Page DL, Dupont WD, Roger s LW, et al . Conti nued l ocal r ecur r ence
of car ci noma 1525 year s after a di agnosi s of l ow grade ductal
car ci noma i n si tu of the br east tr eated onl y by bi opsy. Cancer
1995;76:1197.
Romer o L, Kl ei n L, Wei Y, et al . Outcome after i nvasi ve

r ecur r ence i n pati ents wi th ductal car ci noma i n si tu of the br east.


Am J Sur g 2004;188:371.
Si l ver stei n MJ. The Uni ver si ty of Souther n Cal i for ni a/Van Nuys
pr ognosti c i ndex for ductal car ci noma i n si tu of the br east. Am J
Sur g 2003;186:337.
Si l ver stei n MJ, Cohl an BF, G i er son ED, et al . Ductal car ci noma i n
si tu: 227 cases wi thout mi cr oi nvasi on. Eur J Cancer
1992;28:630.

Si l ver stei n MJ, Lagi os MD, Crai g PH, et al . A pr ognosti c i ndex for
ductal car ci noma i n si tu of the br east. Cancer 1996;77:2267.
Si l ver stei n MJ, Lagi os MD, G r oshen S, et al . The i nfl uence of
mar gi n wi dth on l ocal contr ol of ductal car ci noma i n si tu of the
br east. N Engl J Med 1999;340:1455.
Si l ver stei n MJ, Lagi os MD, Mar ti no S, et al . Outcome after
i nvasi ve l ocal r ecur r ence i n pati ents wi th ductal car ci noma i n si tu
of the br east. J Clin Oncol 1998;16:1367.
Si l ver stei n MJ, Pol l er DN, Wai sman JR, et al . Pr ognosti c
cl assi fi cati on of br east ductal car ci noma i n si tu. Lancet
1995;345:1154.
Si ngl etar y SE, Al l r ed C, Ashl ey P, et al . Revi si on of the Amer i can
Joi nt Commi ttee on Cancer stagi ng system for br east cancer. J
Clin Oncol 2002;20:3628.
Vezer i di s MP, Bl and KI. Management of ductal car ci noma i n si tu.
Sur g Oncol 1994;3:309.
Wong JS, G add MA, G el man R, et al . Wi de r esecti on al one for
ductal car ci noma i n si tu (DCIS) of the br east. Pr oc Am Soc Clin
Oncol 2003;22:12.

Editors: Feig, Barry W .; Berger, David H.; Fuhrman, George


M.
Title: MD A nderson Surgical Oncology Handbook, The, 4th
Edition
Copyr i ght 2006 Li ppi ncott Wi l l i ams & Wi l ki ns
> Ta ble o f C o nt e nt s > 2 - Inva s iv e Bre a s t C a nc e r

2
Invasive Breast Cancer
Jonathan S. Zager
Carmen C. Solorzano
Eva Thomas
Barry W . Feig
Gildy V. Babiera

Epidemiology
Br east cancer i s a l eadi ng heal th concer n i n the Uni ted States
because i t i s the second most common cause of death among
Amer i can women (after l ung cancer ) and the l eadi ng cause of death
among women ages 40 to 50 year s. In 2005, appr oxi matel y 212,930
new cases wi l l be di agnosed, and near l y 40,870 br east cancerr el ated deaths wi l l occur. In the Uni ted States, whi te femal es have
the hi ghest i nci dence of br east car ci noma, and the i nci dence
i ncr eases wi th i ncr easi ng age. For an Amer i can woman, the l i feti me
r i sk of bei ng di agnosed wi th br east cancer i s 1 i n 7 or 14% , and the
l i feti me r i sk of dyi ng fr om br east cancer i s appr oxi matel y 3.4% .
Accor di ng to the Nati onal Cancer Insti tute's Sur vei l l ance,
Epi demi ol ogy, and End Resul ts Pr ogram, the i nci dence of br east
cancer i ncr eases rapi dl y dur i ng the four th decade of l i fe. After
menopause, the i nci dence conti nues to i ncr ease but at a much
sl ower rate, peaki ng i n the seventh and ei ghth decades of l i fe and
sl owl y l evel i ng off after 80 year s of age. The overal l i nci dence of
br east cancer i n al l races has i ncr eased over the l ast two decades
fr om appr oxi matel y 110 to 130/100,000 pati ents (al l races) to 114
to 140/100,000 pati ents fr om 1990 to 2000. F r om 1990 to 2001,
sur vi val rates i mpr oved steadi l y and si gni fi cantl y for women wi th
l ocor egi onal di sease i n al l age gr oups, and the age-adjusted br east
cancer mor tal i ty rate for whi te women i n the Uni ted States dr opped.

However, for Afr i can Amer i can women, the 5-year r el ati ve sur vi val
rates ar e l ower than those for whi te women for l ocal i zed di sease
(90% vs. 97% ), r egi onal di sease (66% vs. 79% ), and metastati c
di sease (15% vs. 23% ).
The rate of di agnosi s of r egi onal di sease decr eased i n the l ate
1980s i n the Uni ted States among women ol der than 40 year s. Thi s
decr ease l i kel y r efl ects the i ncr eased use of mammography i n the
ear l y 1980s. In contrast, the i ncr ease i n sur vi val rates i n the same
ti me per i od, par ti cul ar l y for women wi th r egi onal di sease, l i kel y
r efl ects i mpr ovements i n systemi c adjuvant therapy. Ther efor e, both
scr eeni ng mammography and i mpr oved therapy have pr obabl y
contr i buted to the r ecent decl i ne i n br east cancer mor tal i ty rates i n
the Uni ted States.

Risk Factors
The most i mpor tant r i sk factor for the devel opment of br east cancer
i s gender. The femal e-to-mal e rati o for br east cancer i s 100:1.
Ther efor e, thi s chapter focuses on r i sk factor s among women.
Si ngl etar y ni cel y summar i zed r i sk factor s for br east cancer i n a
2003 r evi ew ar ti cl e, and a si mpl i fi ed ver si on i s pr ovi ded i n Tabl e
2.1.

Table 2.1. Risk factors for breast cancer


and associated relative risks
Risk Factor

Category at Risk

Relative
Risk

Germline
mutations

BRCA-1 and
younger than 40
years old
BRCA-1 and 60
69 years old

200
15

Lobular

Proliferative
breast disease

carcinoma in situ
Ductal carcinoma
in situ

16.4
17.3

Personal history
of breast cancer

Invasive breast
cancer

6.8

Ionizing radiation
exposure

Hodgkin disease

5.2

Family history

First-degree
relative with
premenopausal
breast cancer
First-degree
relative with
postmenopausal
breast cancer

3.3
1.8

Age at first
childbirth
Hormone
replacement
therapy with
estrogen and
progesterone

Older than 30
years
Current user for
at least 5 years

1.71.9
1.3

Early menarche

Younger than 12
years

1.3

Late menopause

Older than 55
years

1.21.5

Singletary SE. Rating the risk factors for breast


cancer. Ann Surg 2003;237: 474.
G eneti c al terati ons pr edi sposi ng i ndi vi dual s to br east and ovar i an
cancer have r ecei ved much attenti on r ecentl y. Al though these gene
mutati ons ar e i nher i ted, onl y 5% to 10% of br east cancer s ar e
bel i eved to r esul t fr om an i nher i ted mutated gene. Autosomal
domi nant condi ti ons associ ated wi th an i ncr eased r i sk of br east
cancer i ncl ude Li -F raumeni syndr ome, BRCA-1 and BRCA-2
mutati ons, Mui r-Tor r e syndr ome, Cowden di sease, and Peutz-Jegher s
syndr ome (Tabl e 2.2). Al though autosomal domi nant, these
condi ti ons do not al ways exhi bi t 100% penetrance. Another
i nher i ted condi ti on that may be associ ated wi th br east cancer i s the
autosomal r ecessi ve di sor der ataxi a-tel angi ectasi a.
The most common geneti c anomal i es associ ated wi th an i ncr eased
r i sk of br east cancer ar e the BRCA-1 and BRCA-2 genes. The BRCA1 gene i s found on the l ong ar m of chr omosome 17q, and the BRCA2 gene i s found on chr omosome 13. Both BRCA-1 and BRCA-2
mutati ons ar e associ ated wi th an i ncr eased r i sk of ovar i an cancer,
but the r i sk i s hi gher i n BRCA-1. The r i sk of devel opi ng br east or
ovar i an cancer di ffer s wi th the exact si te of
the BRCA-1 mutati on on chr omosome 17q but ranges fr om 37% to
87% by age 70 for br east cancer and fr om 11% to 42% by age 60
for ovar i an cancer.

Table 2.2. Autosomal dominant conditions


associated with possible development of
breast cancer

Syndrome Defect

Associated
Condition or
Increased Risk for

Mutation of
chromosome
17q

Malignancies of the
breast, ovaries, and
possibly prostate
and colon

BRCA-2

Mutation of
chromosome
13q

Malignancies of the
breast (including
male), ovaries,
prostate, larynx,
and pancreas

LiFraumeni

Mutation in
the p53
gene on
chromosome
17p

Malignancies of the
breast, brain, and
adrenal glands;
soft-tissue sarcomas

Mutation in
DNA
mismatch
repair
genes
(hMLH1 and
hMSH2) on
chromosome
2p

Malignancies of the
breast and
gastrointestinal (GI)
and genitourinary
tracts; sebaceous
tumors (i.e.,
hyperplasia,
adenoma,
epithelioma,
carcinoma),
keratoacanthoma

Mutation in
the PTEN

Malignancies of the
breast, colon,
uterus, thyroid,

BRCA-1

Muir-Torre

Cowden

disease

PeutzJeghers

gene on
chromosome
10q

lung, and bladder;


hamartomatous
polyps in GI tract

Mutation in
the STK11
gene on
chromosome
19p

Malignancies of the
breast and
pancreas;
mucocutaneous
melanin deposition,
hamartomas of the
GI tract

A per sonal hi stor y of br east cancer i s a si gni fi cant r i sk factor for


the devel opment of cancer i n the contral ateral br east. The i nci dence
of contral ateral br east cancer i s 0.5% to 1.0% per year of fol l owup.
Exposur e to i oni z i ng radi ati on for the tr eatment of Hodgki n di sease
has been associ ated wi th a mar kedl y i ncr eased r i sk of br east cancer
i f the exposur e was befor e age 30 (r el ati ve r i sk i s 5.2). The r i sk i s
l ess i n the fi r st 15 year s after tr eatment than after 15 year s.
Nonpr ol i ferati ve br east di seases such as adenosi s, fi br oadenomas,
apocr i ne changes, duct ectasi a, and mi l d hyper pl asi a car r y no
i ncr eased r i sk of br east cancer. However, pr ol i ferati ve br east
di seases ar e associ ated wi th br east cancer to var i ous degr ees.
Moderate or fl or i d hyper pl asi a wi thout atypi a, papi l l omas, and
scl er osi ng adenosi s car r y a sl i ghtl y i ncr eased r i sk of br east cancer
(1.5 to 2 ti mes that of the general popul ati on). Atypi cal ductal or
l obul ar hyper pl asi a i s associ ated wi th a moderatel y i ncr eased r i sk of
devel opi ng br east cancer (4 to 5 ti mes). Lobul ar car ci noma i n si tu i s
associ ated wi th a hi gh r i sk of br east cancer (8 to 10 ti mes). These
r i sks appl y equal l y to both br easts, even i f the br east di sease was
uni l ateral .
Age i s an i mpor tant r i sk factor for the devel opment of br east cancer.
The r i sk that br east cancer wi l l devel op i n a whi te Amer i can woman
i n a si ngl e year i ncr eases fr om 1:207 at l ess than age 39 year s to

1:13 between ages 60 and 79.


A fami l y hi stor y of br east cancer i ncr eases a woman's r i sk of br east
cancer. The hi ghest r i sk i s associ ated wi th the pr esence of br east
cancer i n a young fi r st-degr ee r el ati ve wi th bi l ateral br east cancer.
The overal l r i sk depends on the number of r el ati ves wi th cancer,
thei r ages at di agnosi s, and whether the di sease was uni l ateral or
bi l ateral . For exampl e, a 30-year-ol d woman whose si ster had
bi l ateral br east cancer befor e age 50 has a cumul ati ve pr obabi l i ty of
br east cancer by age 70 of 55% . Thi s pr obabi l i ty decr eases to 8%
for a 30-year-ol d woman whose si ster devel oped uni l ateral br east
cancer after age 50.
A number of endogenous endocr i ne factor s have al so been
i mpl i cated as r i sk factor s i n br east cancer. The r i sk of br east cancer
for women who exper i ence menopause after age 55 i s twi ce that of
women who exper i ence menopause befor e age 44. Al though age at
menar che i s i mpor tant, age at onset of r egul ar menses may have a
l ar ger effect on r i sk. Women who began to have r egul ar ovul ator y
cycl es befor e age 13 have a four fol d gr eater r i sk than those whose
menar che occur r ed after age 13 and who had a 5-year del ay to the
devel opment of r egul ar cycl es. The cumul ati ve durati on of
menstr uati on may al so be i mpor tant. Women who menstr uate for
mor e than 30 year s ar e at gr eater r i sk than those who menstr uate
for l ess than 30 year s. Age at fi r st chi l dbi r th has a gr eater effect on
r i sk than the number of pr egnanci es. For exampl e, a woman who
had her fi r st chi l d befor e age 19 has hal f the r i sk of a nul l i par ous
woman. Women who have thei r fi r st chi l d between 30 and 34 year s
of age have the same r i sk as nul l i par ous women, and women who
have thei r fi r st chi l d after age 35 have a gr eater r i sk than
nul l i par ous women. These obser vati ons i ndi cate that the hor monal
mi l i eu at di ffer ent ti mes i n a woman's l i fe may affect her r i sk of
br east cancer.
Exogenous hor mone r epl acement therapy i s known to i ncr ease a
woman's r i sk of br east cancer (r el ati ve r i sk after 5 year s of
tr eatment i s 1.3). However, the benefi ts associ ated wi th hor mone
r epl acement therapy i ncl ude i ncr eased bone densi ty and fewer
postmenopausal symptoms. Ther efor e, tr eati ng physi ci ans shoul d
thor oughl y di scuss wi th thei r pati ents the r i sks and benefi ts of thi s
therapy.

Pathology
Invasi ve car ci nomas of the br east tend to be hi stol ogi cal l y

heter ogeneous tumor s. The vast major i ty of these tumor s ar e


adenocar ci nomas that ar i se fr om the ter mi nal ducts. Ther e ar e fi ve
common hi stol ogi c var i ants of mammar y adenocar ci noma:
1. Infiltr ating ductal car cinoma accounts for 75% of al l br east
cancer s. Thi s l esi on i s character i zed by the absence of speci al
hi stol ogi c featur es. It i s har d on pal pati on and gr i tty when
transected. It i s associ ated wi th var i ous degr ees of fi br oti c
r esponse. Often ther e i s associ ated ductal car ci noma i n si tu
(DCIS) wi thi n the speci men. Infi l trati ng ductal car ci nomas
commonl y metastasi ze to axi l l ar y l ymph nodes. The pr ognosi s
for pati ents wi th these tumor s i s poor er than that for pati ents
wi th some of the other hi stol ogi c subtypes (i .e., muci nous,
col l oi d, tubul ar, and medul l ar y). Di stant metastases ar e found
most often i n the bones, l ungs, l i ver, and brai n.
2. Infiltr ating lobular car cinoma i s seen i n 5% to 10% of br east
cancer cases. Cl i ni cal l y, thi s l esi on often has an ar ea of i l l defi ned thi ckeni ng wi thi n the br east. Mi cr oscopi cal l y, smal l cel l s
i n a si ngl e- or Indi an-fi l e patter n ar e character i sti cal l y seen.
Infi l trati ng l obul ar cancer s tend to gr ow ar ound ducts and
l obul es. Mul ti centr i ci ty and bi l ateral i ty ar e obser ved mor e
fr equentl y i n i nfi l trati ng l obul ar car ci noma than i n i nfi l trati ng
ductal car ci noma. The pr ognosi s for l obul ar car ci noma i s si mi l ar
to that for i nfi l trati ng ductal car ci noma. In addi ti on to
metastasi z i ng to axi l l ar y l ymph nodes, l obul ar car ci noma i s
known to metastasi ze to unusual si tes (e.g., meni nges and
ser osal sur faces) mor e often than do other for ms of br east
cancer.
3. Tubular car cinoma accounts for onl y 2% of br east car ci nomas.
The di agnosi s of tubul ar car ci noma i s made onl y when mor e than
75% of the tumor demonstrates tubul e for mati on. Axi l l ar y nodal
metastases ar e uncommon wi th thi s type of tumor. The pr ognosi s
for pati ents wi th tubul ar car ci noma i s consi derabl y better than
that for pati ents wi th other types of br east cancer.
4. Medullar y car cinoma accounts for 5% to 7% of br east cancer s.
Hi stol ogi cal l y, the l esi on i s character i zed by poor l y di ffer enti ated
nucl ei , a syncyti al gr owth patter n, a wel l -ci r cumscr i bed bor der,
i ntense i nfi l trati on wi th smal l l ymphocytes and pl asma cel l s, and
l i ttl e or no DCIS. The pr ognosi s for pati ents wi th pur e medul l ar y
car ci noma i s favorabl e; however, mi xed var i ants wi th i nvasi ve

ductal components wi l l have pr ognoses si mi l ar to i nvasi ve ductal


car ci noma.
5. Mucinous or colloid car cinoma consti tutes appr oxi matel y 3% of
br east cancer s. It i s character i zed by an abundant accumul ati on
of extracel l ul ar muci n sur r oundi ng cl uster s of tumor cel l s.
Col l oi d car ci noma i s sl ow gr owi ng and tends to be bul ky. If a
br east car ci noma i s pr edomi nantl y muci nous, the pr ognosi s i s
favorabl e.
Rar e hi stol ogi c types of br east mal i gnancy i ncl ude papi l l ar y,
apocr i ne, secr etor y, squamous cel l and spi ndl e cel l car ci nomas, and
car ci nosar coma. Infi l trati ng ductal car ci nomas occasi onal l y have
smal l ar eas contai ni ng one or mor e of these speci al hi stol ogi c types.
Tumor s wi th these mi xed hi stol ogi c appearances behave si mi l ar l y to
pur e i nfi l trati ng ductal car ci nomas.

Staging
Typi cal l y, br east cancer i s staged usi ng the Amer i can Joi nt
Commi ttee on Cancer (AJCC) gui del i nes. The AJCC TNM br east
cancer stagi ng system was updated i n 2003 and publ i shed i n the
si xth edi ti on of the AJCC Cancer Staging Manual. The most r ecent
TNM cl assi fi cati ons and stage gr oupi ngs for br east cancer ar e
summar i zed i n Tabl e 2.3.

Diagnosis
History and Physical Examination
The di agnosi s of br east cancer has under gone a dramati c evol uti on
si nce the mi d-1980s. Pr evi ousl y, 50% to 75% of al l br east cancer s
wer e detected by sel f-exami nati on. Subsequent to the wi despr ead
avai l abi l i ty of mammographi c scr eeni ng pr ograms, ther e has been a
shi ft towar d the di agnosi s of cl i ni cal l y occul t, nonpal pabl e l esi ons.
Despi te thi s tr end, eval uati on of a woman for br east cancer
conti nues to be based on a car eful hi stor y and physi cal
exami nati on.
The hi stor y i s di r ected at assessi ng cancer r i sk and establ i shi ng the
pr esence or absence of symptoms i ndi cati ve of br east di sease and
shoul d i ncl ude age at menar che, menopausal status, pr evi ous
pr egnancy, and use of oral contracepti ves or postmenopausal

r epl acement estr ogens. A per sonal hi stor y of br east cancer and
other cancer s tr eated wi th radi ati on or chemotherapy (e.g., Hodgki n
di sease) i s i mpor tant. In addi ti on, the fami l y hi stor y of br east
cancer or ovar i an cancer i n fi r st-degr ee r el ati ves (i .e., mother or
si ster ) shoul d be establ i shed. After the r i sk for br east cancer has
been deter mi ned, the pati ent shoul d be assessed for speci fi c
symptoms. Br east pai n and ni ppl e di schar ge ar e often, but not
al ways, associ ated wi th beni gn pr ocesses such as fi br ocysti c di sease
and i ntraductal papi l l oma. Mal ai se, bony pai n, and wei ght l oss ar e
rar e but may i ndi cate metastati c di sease.
Physi cal exami nati on by the heal th car e pr ovi der must constantl y
take i nto consi derati on the comfor t and emoti onal wel l -bei ng of the
pati ent. Exami nati on i s i ni ti ated by car eful vi sual i nspecti on wi th
the pati ent si tti ng upr i ght. Ni ppl e changes, gr oss asymmetr y, and
obvi ous masses ar e al l noted. The ski n must be car eful l y i nspected
for subtl e changes; these can range fr om sl i ght di mpl i ng to the
mor e dramati c peau d'or ange, war m or er ythematous appearance
associ ated wi th l ocal l y advanced or i nfl ammator y br east cancer. In
l ar ge or ptoti c br easts, the br easts shoul d be l i fted to faci l i tate
i nspecti on of the i nfer i or por ti on of the br east and i nframammar y
fol d. After car eful i nspecti on and wi th the pati ent r emai ni ng i n the
si tti ng posi ti on, the per i cl avi cul ar r egi ons ar e exami ned for
potenti al nodal di sease. Both axi l l ae ar e then car eful l y pal pated. If
pal pabl e, nodes shoul d be character i zed as to thei r number, si ze,
and mobi l i ty. Exami nati on of the axi l l a al ways i ncl udes pal pati on of
the axi l l ar y tai l of the br east; assessment of thi s ar ea i s often
over l ooked once the pati ent i s pl aced i n a supi ne posi ti on. Pal pati on
of the br east par enchyma i tsel f i s accompl i shed wi th the pati ent
supi ne and the i psi l ateral ar m pl aced over the head. The subar eol ar
ti ssues and each quadrant of both br easts ar e systemati cal l y
pal pated. Masses ar e

noted wi th r espect to thei r si ze, shape, l ocati on, consi stency, and
mobi l i ty.

Table 2.3. Current AJCC TNM classification


and stage grouping for breast carcinoma

Classification
and Stage
Definition
Grouping
Primary tumor (T)
TX

Primary tumor cannot be


assessed

T0

No evidence of primary tumor

Tis

Carcinoma in situ

Tis (DCIS)

Ductal carcinoma in situ

Tis (LCIS)

Lobular carcinoma in situ

Tis (Paget)

Paget disease of the nipple


with no tumor
Note: Paget disease associated
with a tumor is classified
according to the size of the
tumor.

T1

T1mic

Tumor 2 cm or less in greatest


dimension
Microinvasion 0.1 cm or less in
greatest dimension
Tumor more than 0.1 cm but

T1a

not more than 0.5 cm in


greatest dimension

T1b

Tumor more than 0.5 cm but


not more than 1 cm in greatest
dimension

T1c

Tumor more than 1 cm but not


more than 2 cm in greatest
dimension

T2

Tumor more than 2 cm but not


more than 5 cm in greatest
dimension

T3

Tumor more than 5 cm in


greatest dimension
Tumor of any size with direct
extension to

T4

T4a

T4b

1. chest wall or
2. skin, only as described as
follows
Extension to chest wall, not
including pectoralis muscle
Edema (including peau
d'orange) or ulceration of the
skin of the breast, or satellite

skin nodules confined to the


same breast
T4c

Both T4a and T4b

T4d

Inflammatory carcinoma

Regional lymph nodes (N)

NX

Regional lymph nodes cannot


be assessed (e.g., previously
removed)

N0

No regional lymph node


metastasis

N1

Metastasis in movable
ipsilateral axillary lymph
node(s)

N2

Metastases in ipsilateral
axillary lymph nodes fixed or
matted, or in clinically
apparent ipsilateral internal
mammary nodes in the absence
of clinically evident axillary
lymph node metastasis

N2a

Metastasis in ipsilateral axillary


lymph nodes fixed to one
another (matted) or to other

structures

N2b

N3

Metastasis only in clinically


apparent ipsilateral internal
mammary nodes and in the
absence of clinically evident
axillary lymph node metastasis
Metastasis in ipsilateral
infraclavicular lymph node(s),
or in clinically apparent
ipsilateral internal mammary
lymph node(s) and in the
presence of clinically evident
axillary lymph node
metastasis; or metastasis in
ipsilateral supraclavicular
lymph node(s) with or without
axillary or internal mammary
lymph node involvement

N3a

Metastasis in ipsilateral
infraclavicular lymph node(s)
and axillary lymph node(s)

N3b

Metastasis in ipsilateral
internal mammary lymph
node(s) and axillary lymph
node(s)

N3c

Metastasis in ipsilateral
supraclavicular lymph node(s)

Regional
lymph nodes
(pN)

pNX

Regional lymph nodes cannot


be assessed (e.g., previously
removed, not removed for
pathological study)

pN0

No regional lymph node


metastasis histologically, no
additional examination for
isolated tumor cells

pN0(i-)

No regional lymph node


metastasis histologically,
negative IHC

pN0(i+)

No regional lymph node


metastasis histologically,
positive IHC, no IHC cluster
greater than 0.2 mm

pN0(mol-)

No regional lymph node


metastasis histologically,
negative molecular findings
(RT-PCR)

pN0(mol+)

No regional lymph node


metastasis histologically,
positive molecular findings (RT-

PCR)

pN1mi

Micrometastasis (greater than


0.2 mm, none greater than 2.0
mm)

pN1

Metastasis in 1 to 3 axillary
lymph nodes, and/or in internal
mammary nodes with
microscopic disease detected
by sentinel lymph node
dissection but not clinically
apparent

pN1a

Metastasis in 1 to 3 axillary
lymph nodes

pN1b

Metastasis in internal
mammary nodes with
microscopic disease detected
by sentinel lymph node
dissection but not clinically
apparent

pN1c

Metastasis in 1 to 3 axillary
lymph nodes and in internal
mammary lymph nodes with
microscopic disease detected
by sentinel lymph node
dissection but not clinically
apparent

pN2

Metastasis in 4 to 9 axillary
lymph nodes, or in clinically
apparent internal mammary
lymph nodes in the absence of
axillary lymph node metastasis

pN2a

Metastasis in 4 to 9 axillary
lymph nodes (at least one
tumor deposit greater than 2.0
mm)

pN2b

Metastasis in clinically
apparent internal mammary
lymph nodes in the absence of
axillary lymph node metastasis

pN3

Metastasis in 10 or more
axillary lymph nodes, or in
infraclavicular lymph nodes, or
in clinically apparent ipsilateral
internal mammary lymph nodes
in the presence of 1 or more
positive axillary lymph nodes;
or in more than 3 axillary
lymph nodes with clinically
negative microscopic
metastasis in internal
mammary lymph nodes; or in
ipsilateral supraclavicular
lymph nodes

pN3a

Metastasis in 10 or more
axillary lymph nodes (at least
one tumor deposit greater than
2.0 mm), or metastasis to the
infraclavicular lymph nodes

pN3b

Metastasis in clinically
apparent ipsilateral internal
mammary lymph nodes in the
presence of 1 or more positive
axillary lymph nodes; or in
more than 3 axillary lymph
nodes and in internal
mammary lymph nodes with
microscopic disease detected
by sentinel lymph node
dissection but not clinically
apparent

pN3c

Metastasis in ipsilateral
supraclavicular lymph nodes

Distant metastasis (M)


MX

Distant metastasis cannot be


assessed

M0

No distant metastasis

M1

Distant metastasis

DCIS, ductal carcinoma in situ; LCIS, lobular

carcinoma in situ; IHC, immunohistochemistry;


RT-PCR, reverse transcriptase-polymerase
chain reaction.
Adapted from American Joint Committee on
Cancer (AJCC). AJCC Cancer Staging Manual.
6th ed. 2002.
Cr i ti cal anal ysi s of physi cal exami nati ons has shown that the exams
ar e often i nadequate for di ffer enti ati ng beni gn and mal i gnant br east
masses. Var i ous ser i es have i denti fi ed a 20% to 40% er r or rate,
even among exper i enced exami ner s. Because of the hi gh rate of
i naccuracy, any per si stent br east mass r equi r es addi ti onal
eval uati on. F ur ther mor e, for the di ffer enti ati on of a l ocal l y
advanced or i nfl ammator y br east car ci noma, a mul ti di sci pl i nar y
team consi sti ng of a medi cal oncol ogi st, sur geon, and radi ati on
oncol ogi st shoul d be consul ted to obtai n a consensus as to the
pati ent's cl i ni cal pr esentati on and the most appr opr i ate tr eatment
r egi men.

Evaluation of Palpable Lesions


The choi ce of i ni ti al di agnosti c eval uati on after the detecti on of a
br east mass shoul d be i ndi vi dual i zed for each pati ent accor di ng to
age, per cei ved cancer r i sk, and character i sti cs of the l esi on. For
most pati ents, mammographi c eval uati on i s an i mpor tant i ni ti al
step. Mammography i n thi s setti ng ser ves two pur poses, to assess
the r i sk of mal i gnancy for the pal pabl e l esi on and to scr een both
br easts for other nonpal pabl e l esi ons. Bi l ateral synchr onous cancer s
occur i n appr oxi matel y 3% of al l cases; at l east hal f of these l esi ons
ar e nonpal pabl e.
For a pal pabl e l esi on, mammograms may r eveal the stel l ate or
spi cul ated appearance typi cal of mal i gnancy. Cal ci fi cati ons, ni ppl e
changes, and axi l l ar y adenopathy may al so be vi sual i zed. The
pr esence or absence of these mammographi c fi ndi ngs can pr edi ct
mal i gnancy wi th an accuracy of 70% to 80% . Mammography i s l east
accurate i n younger pati ents wi th dense br easts; for thi s r eason, i t
i s rar el y used i n pati ents younger than the age of 30 year s for
scr eeni ng.
After mammographi c eval uati on, pal pabl e masses suspected to be

mal i gnant shoul d under go fi ne-needl e aspi rati on (F NA) bi opsy or,
pr eferabl y, cor e-needl e bi opsy. Some cl i ni ci ans advocate needl e
bi opsy at the ti me of i ni ti al eval uati on (i .e., befor e mammography).
For most pati ents bei ng tr eated at M. D. Ander son Cancer Center
(MDACC), bi opsy i s defer r ed unti l after mammographi c exami nati on
i s compl eted because a needl e-punctur e hematoma wi l l occasi onal l y
obscur e futur e radi ographi c eval uati on. For young pati ents wi th
dense br easts for whom mammography i s not i deal , needl e bi opsy
wi th or wi thout the ai d of ul trasonography i s the pr i mar y mode of
eval uati on. However, i f the l esi on can be vi sual i zed under
ul trasound, i t i s pr eferabl e to per for m needl e bi opsy wi th ul trasound
gui dance to confi r m that the needl e i s wi thi n the abnor mal i ty.
F NA wi th a 22-gauge needl e al l ows for accurate di ffer enti ati on
between cysti c and sol i d masses and pr ovi des mater i al for cytol ogi c
exami nati on but does not establ i sh an i nvasi ve component i f a
br east cancer di agnosi s i s made. Cysti c l esi ons cannot be
di ffer enti ated fr om sol i d l esi ons by mammography but ar e ver y wel l
character i zed by ul trasonography. Beni gn br east cysts typi cal l y yi el d
nonbl oody fl ui d and become nonpal pabl e after aspi rati on. Bl oody or
ser ous fl ui d shoul d be submi tted for cytol ogi c anal ysi s. The
i nci dence of mal i gnancy among br east cysts i s
appr oxi matel y 1% and i s l i mi ted al most excl usi vel y to cysts that
yi el d bl oody or ser ous fl ui d or have a r esi dual mass after aspi rati on.
Aspi rati on i s often curati ve; onl y one i n fi ve br east cysts wi l l r ecur,
and most of these ar e obl i terated wi th a second drai nage. If
per si stent, however, exci si on i s usual l y r ecommended.
For sol i d l esi ons, several passes thr ough the l esi on wi th the syr i nge
under constant negati ve pr essur e wi l l typi cal l y yi el d ampl e mater i al
for cytol ogi c eval uati on. The mater i al i s evacuated onto a
mi cr oscopi c sl i de and i mmedi atel y fi xed i n 95% ethanol . Mul ti pl e
studi es have demonstrated that F NA i s si mpl e, safe, and accurate i n
eval uati ng beni gn and mal i gnant br east masses. However, for
l esi ons i nter pr eted as mal i gnant, cytol ogi c eval uati on i s unabl e to
di ffer enti ate between i n si tu and i nvasi ve car ci noma. Cor e-needl e
bi opsy al l ows the pathol ogi st to di sti ngui sh i nvasi ve and i n si tu
car ci noma by pr ovi di ng a cor e of ti ssue for hi stopathol ogi cal
eval uati on.
Al though physi cal exami nati on, mammography, and needl e bi opsy
al l car r y a r i sk of er r or when used al one, the combi nati on of these
thr ee modal i ti es i s extr emel y accurate i n pr edi cti ng whether a
pal pabl e l esi on i s beni gn or mal i gnant. For l esi ons wi th equi vocal or

contradi ctor y r esul ts, open bi opsy i s the defi ni ti ve test. The MDACC
appr oach to pal pabl e and nonpal pabl e br east masses ar e outl i ned i n
F i gur es 2-1 and 2-2.

Evaluation of Nonpalpable Lesions


Because of the i ncr easi ng avai l abi l i ty of mammographi c scr eeni ng
pr ograms, the di agnosti c rate of nonpal pabl e br east cancer has r i sen
rapi dl y i n the Uni ted States. Si nce 1997, the Amer i can Cancer
Soci ety, the Nati onal Cancer Insti tute, and the Amer i can Col l ege of
Radi ol ogy have r el eased updated gui del i nes for br east cancer
scr eeni ng that ar e i n l ar ge par t based on new data publ i shed i n
1997. Each or gani z ati on r ecommends that women begi n r egul ar
scr eeni ng mammography i n thei r for ti es.
Mammographi c si gns of mal i gnancy can be di vi ded i nto two mai n
categor i es: mi cr ocal ci fi cati ons and densi ty changes.
Mi cr ocal ci fi cati ons can be cl uster ed or scatter ed. Densi ty changes
i ncl ude di scr ete masses, ar chi tectural di stor ti ons, and asymmetr i es.
The most pr edi cti ve mammographi c fi ndi ngs of mal i gnancy ar e
spi cul ated masses wi th associ ated ar chi tectural di stor ti on, cl uster ed
mi cr ocal ci fi cati ons i n a l i near or branchi ng ar ray, and
mi cr ocal ci fi cati ons associ ated wi th a mass. The Amer i can Col l ege of
Radi ol ogy devel oped the Br east Imagi ng Repor ti ng and Data System,
whi ch categor i zes mammographi c fi ndi ngs as fol l ows: I = negati ve
(no fi ndi ngs); II = beni gn appearance; III = pr obabl y beni gn
appearance (<2% chance of mal i gnancy); IV = fi ndi ngs suspi ci ous
for br east cancer (fur ther di vi ded i nto IVa, mi l dl y suspi ci ous, and
IVb, moderatel y suspi ci ous); and V = fi ndi ngs hi ghl y suspi ci ous for
br east cancer (>90% chance of br east cancer ).
Once scr eeni ng mammography demonstrates a suspi ci ous l esi on,
fur ther eval uati on i s necessar y for di agnosi s. For l esi ons i nter pr eted
as pr obabl y beni gn (i .e., wel l -defi ned, sol i tar y masses), car eful
counsel i ng and r epeat mammography i n 6 months may be
under taken i n pati ents at l ow r i sk for br east cancer. For cer tai n
l esi ons, ul trasonography may i denti fy a subset

of cysti c l esi ons that wi l l not r equi r e bi opsy. Ul trasonography may


al so be used to gui de fi ne-needl e or cor e-needl e bi opsy. For
suspi ci ous l esi ons, some for m of bi opsy i s r equi r ed. Ul trasoundgui ded bi opsy i s not useful for eval uati ng mi cr ocal ci fi cati ons
because they ar e typi cal l y not sonographi cal l y vi si bl e. However,

mammography-gui ded ster eotacti c br east bi opsy i s a useful


techni que for obtai ni ng ti ssue for di agnosi s fr om nonpal pabl e
l esi ons and mi cr ocal ci fi cati ons. The MDACC appr oach to nonpal pabl e
br east masses i s outl i ned i n F i gur e 2.1.

F i gur e 2.1. Uni ver si ty of Texas M. D. Ander son Cancer Center


al gor i thm for the wor kup of a pal pabl e br east mass.

F i gur e 2.2. Uni ver si ty of Texas M. D. Ander son Cancer Center


al gor i thm for the wor kup of a nonpal pabl e br east mass. BIRADS,
Br east Imagi ng Repor ti ng and Data System.

Ti ssue sampl i ng can be obtai ned wi th the Mammotome (Ethi con


Endo Sur ger y, Ci nci nnati , OH) devi ce, whi ch i s used at
MDACC i n conjuncti on wi th ster eotacti c gui ded i magi ng to obtai n
mul ti pl e cor e-needl e bi opsi es vi a a vacuum-assi sted cutti ng devi ce
pl aced thr ough a smal l 1/4-i n i nci si on r emovi ng or sampl i ng the
l esi on i n questi on and often some sur r oundi ng ti ssue.

Breast Biopsy Technique


When cor e-needl e bi opsy or F NA i s i mpossi bl e or i nappr opr i ate,
exci si onal br east bi opsy may be per for med. Exci si onal bi opsy may
ser ve both di agnosti c and l ocal tr eatment pur poses. The enti r e
suspi ci ous mass and a sur r oundi ng 1-cm r i m of nor mal ti ssue shoul d
be exci sed. An exci si onal bi opsy such as thi s wi l l ful fi l l the
r equi r ements for l umpectomy and avoi d subsequent r e-exci si on.

For ei ther pal pabl e or nonpal pabl e suspi ci ous l esi ons, pl anni ng an
opti mal open bi opsy mandates car eful consi derati on of at l east thr ee
i ssues. F i r st, the bi opsy si te may r equi r e futur e r e-exci si on for
br east conser vati on tr eatment. Second, the bi opsy si te must be abl e
to be i ncor porated i nto a futur e mastectomy i nci si on i f thi s for m of
tr eatment i s chosen. Thi r d, the bi opsy must be constr ucted i n a
cosmeti cal l y opti mal manner wi thout compr omi si ng oncol ogi c
pr i nci pl es. Al l br east bi opsi es shoul d be per for med wi th the
assumpti on that the tar get l esi on i s mal i gnant.
Bi opsi es ar e typi cal l y per for med i n an outpati ent setti ng.
Cur vi l i near i nci si ons ar e often used to take advantage of decr eased
l i nes of tensi on al ong Langer 's l i nes. Radi al scar s ar e general l y
avoi ded except i n the extr eme medi al (l ower ) aspect of the br east,
wher e mastectomy i nci si ons become radi al l y or i ented or i n the
extr eme l ateral posi ti on at the 2 or 3 o'cl ock posi ti on, wher e l ess
ski n wi l l need to be sacr i fi ced for a ski n-spar i ng mastectomy.
Ci r cumar eol ar i nci si ons have an obvi ous cosmeti c advantage but
may l ead to sacr i fi ce of ar eol ar ti ssue i f r e-exci si on i s r equi r ed.
Al though a smal l amount of per i pheral tunnel i ng i s acceptabl e to
mai ntai n an i nci si on wi thi n a potenti al mastectomy scar, extr eme
tunnel i ng to the per i pher y of the br east fr om a central per i ar eol ar
i nci si on must be avoi ded. Si tuati ng the i nci si on wel l away fr om the
abnor mal i ty for cosmeti c r easons not onl y makes i t vi r tual l y
i mpossi bl e to i denti fy the tumor bed i f r e-exci si on i s r equi r ed, but
al so r esul ts i n the r emoval of an i nor di nate amount of br east ti ssue.
Ther efor e, the i nci si on shoul d general l y be pl aced di r ectl y over the
mal i gnant l esi on to avoi d excessi ve ti ssue r emoval that may
compr omi se cosmeti c outcome or to pr event bei ng unabl e to l ocate
the tumor bed i f r e-exci si on i s r equi r ed. Pati ents who under go
br east-conser vi ng sur ger y shoul d have a separate axi l l ar y i nci si on
that i s not conti guous wi th the br east i nci si on. Separati ng these
i nci si ons pr ovi des a better cosmeti c outcome (the axi l l ar y drai n wi l l
cause the bi opsy cavi ty to become di stor ted i f they ar e not
separated).
For nonpal pabl e l esi ons, pr eoperati ve needl e l ocal i z ati on wi th a
sel f-r etai ni ng hook wi r e i s r equi r ed. Thi s pr ocedur e r equi r es car eful
communi cati on between the radi ol ogi st and the sur geon. For most
l esi ons, the l ocal i z i ng needl e i s pl aced under mammographi c
gui dance i nto the br east vi a the shor test di r ect path to the l esi on.
The sel f-r etai ni ng wi r e i s pl aced thr ough the needl e, and then the
needl e may or may not be r emoved at the di scr eti on of the sur geon.
Postl ocal i z ati on mammograms of the wi r e ar e

r evi ewed to confi r m that the wi r e i s wi thi n the tar geted ar ea.
Exci si onal bi opsy i s then per for med by exci si ng br east ti ssue ar ound
the wi r e ti p. For super fi ci al l esi ons, an el l i pse of ski n at the poi nt of
wi r e i nser ti on may be r emoved en bl oc wi th the under l yi ng br east
ti ssue. Postexci si on speci men radi ographs ar e essenti al to confi r m
the l ocal i zed tar get was r emoved. Often, the entr y si te of the wi r e
i s not di r ectl y over the tar geted l esi on, and thi s trajector y shoul d
be accounted for when the i nci si on i s pl aced on the br east.
Once the bi opsy speci men has been exci sed, i t must be handl ed
car eful l y. The sur geon shoul d note the or i entati on of the exci sed
br east ti ssue and then hand del i ver the speci men to the pathol ogy
depar tment. The l ateral , medi al , super i or, i nfer i or, super fi ci al , and
deep mar gi ns shoul d be i nked i n a col or-coded manner. Mater i al
shoul d be pr ocessed for r eceptor anal ysi s and fl ow cytometr y.
Cl osur e of the bi opsy i nci si on r equi r es meti cul ous hemostasi s. Deep
par enchymal sutur es often cause cosmeti cal l y unpl easi ng di stor ti on
of the r esi dual br east and shoul d be avoi ded. Drai ns ar e not used i n
the br east. The ski n i s cl osed wi th a subcuti cul ar sutur e, and a l i ght
dr essi ng i s pl aced.

Pretreatment Evaluation
Once the di agnosi s of br east cancer has been made, appr opr i ate
tr eatment pl anni ng i nvol ves eval uati ng the extent of di sease both
l ocal l y i n the br east and r egi onal nodes and of di stant si tes
(typi cal l y to the l ung, l i ver, and bone). For pati ents wi th stage I or
stage II br east cancer, thi s eval uati on i s usual l y l i mi ted to a
compl ete hi stor y and physi cal exami nati on, a chest radi ograph, and
eval uati on of ser um l i ver chemi str i es. The r outi ne use of bone scans
i n asymptomati c pati ents wi th appar ent ear l y-stage br east cancer
car r i es an extr emel y l ow yi el d; several studi es have demonstrated
onl y a 2% i nci dence of posi ti ve scan r esul ts i n thi s setti ng. In
contrast, up to 25% of asymptomati c pati ents wi th appar ent stage
III cancer have posi ti ve bone scan r esul ts; thus, r outi ne scanni ng i n
thi s popul ati on appear s wor thwhi l e. In the absence of i ncr eased
ser um l i ver chemi str i es or pal pabl e hepatomegal y, l i ver i magi ng i s
not used r outi nel y i n the pr eoperati ve eval uati on of pati ents wi th
ear l y-stage di sease.
Ul trasound i s r outi nel y used at MDACC to eval uate the axi l l ar y
nodal basi n and any suspi ci ous i nfracl avi cul ar, supracl avi cul ar, or
i nter nal mammar y adenopathy. Suspi ci ous nodes can be sampl ed by

ul trasound-gui ded F NA. Posi ti ve r esul ts i nfl uence the deci si on on


how to pr oceed wi th fur ther therapy. Pati ents wi th posi ti ve axi l l ar y
nodal F NAs can be schedul ed for an axi l l ar y l ymph node di ssecti on
(ALND) at the ti me of l umpectomy or mastectomy, ther efor e
avoi di ng senti nel l ymph node (SLN) bi opsy and a second sur ger y, or
they can be r efer r ed to the medi cal oncol ogi st for systemi c
neoadjuvant chemotherapy.

Treatment
Many of the cur r ent r ecommendati ons r egar di ng therapy for
i nvasi ve br east cancer have been i nfl uenced by the r esul ts of
randomi zed, pr ospecti ve cl i ni cal tr i al s per for med by the Nati onal
Sur gi cal Adjuvant Br east and Bowel Pr oject (NSABP). A summar y of
sel ected tr i al s i s pr esented i n Tabl e 2.4.

Early-Stage Breast Cancer (T1, T2, N0, N1)


Appr oxi matel y 75% of pati ents wi th br east cancer pr esent wi th
tumor s l ess than 5 cm i n di ameter and no evi dence of fi xed or
matted nodes. These pati ents wi th ear l y-stage br east cancer ar e
general l y tr eated (a) wi th br east conser vati on and radi ati on therapy
or total mastectomy wi th or wi thout r econstr ucti on and (b) wi th
eval uati on of the r egi onal nodes i n the for m of ALND or SNL bi opsy.

Breast Conservation Versus Mastectomy


Many pati ents wi th br east cancer can be effecti vel y tr eated wi th
br east-conser vi ng therapy (BCT). Si nce 1970, seven pr ospecti ve
randomi zed tr i al s compar i ng br east conser vati on strategi es wi th
radi cal or modi fi ed radi cal mastectomy have fai l ed to demonstrate
any sur vi val benefi t to the mor e aggr essi ve appr oach. Among these
tr i al s, the two most wi del y known wer e conducted by Har r i s et al .
(1992) at the Nati onal Cancer Insti tute i n Mi l an, Ital y, and by
F i sher et al . (1995) i n conjuncti on wi th the NSABP i n the Uni ted
States. The Mi l an tr i al was l i mi ted to pati ents wi th stage I br east
cancer (tumor l ess than 2 cm and negati ve axi l l ar y l ymph nodes)
and compar ed radi cal mastectomy wi th a br east conser vati on
strategy i nvol vi ng quadrantectomy, ALND, and radi ati on therapy. No
si gni fi cant di ffer ences i n l ocal contr ol , di sease-fr ee sur vi val , or
overal l sur vi val rate have been noted, even i n the most r ecent
fol l ow-up of these studi es al most 20 year s after thei r i ncepti on.
NSABP B-06 exami ned women wi th pr i mar y tumor s up to 4 cm i n

di ameter and N0 or N1 nodal status. Pati ents wer e randoml y


assi gned to modi fi ed radi cal mastectomy, l umpectomy wi th ALND, or
l umpectomy and ALND pl us radi ati on therapy. Hi stol ogi cal l y
negati ve mar gi ns wer e r equi r ed i n the br east conser vati on gr oups.
Di sease-fr ee and overal l sur vi val rates di d not di ffer si gni fi cantl y
among the thr ee gr oups, but the l ocal r ecur r ence rate was mar kedl y
r educed at 10 year s by radi ati on therapy (12% wi th radi ati on
therapy vs. 53% wi thout radi ati on therapy). These r esul ts uphel d
br east conser vati on as an appr opr i ate tr eatment for pati ents wi th
stage I or stage II br east cancer and made i t cl ear that radi ati on
therapy i s r equi r ed as an i ntegral par t of any br east conser vati on
strategy.
The cur r ent standar d for BCT at MDACC for l ocal contr ol of the
br east i s exci si on of the tumor wi th negati ve mar gi ns fol l owed by
radi ati on therapy at the appr opr i ate ti me. The use of systemi c
therapy i s based on age, tumor si ze, nodal i nvol vement, and
r eceptor status and i s gi ven befor e (neoadjuvant) or after
(adjuvant) sur ger y. A radi ati on oncol ogi st sees the pati ents after
compl eti on of sur ger y or adjuvant chemotherapy to deter mi ne
radi ati on dosi metr y and si mul ati on, and radi ati on therapy i s begun
3 to 4 weeks after sur ger y. A dose of 50 G y i s gi ven to the whol e
br east, and then 10 G y i s gi ven to the operati ve si te as a boost
usi ng tangenti al por ts and computer i zed dosi metr y.
The use of par ti al br east radi ati on therapy for BCT i nstead of whol e
br east i r radi ati on wi th a boost to the tumor si te i s

cur r entl y bei ng i nvesti gated. Advantages of par ti al br east


i r radi ati on i ncl ude shor ter tr eatment (5 days vs. 6 weeks); l ess
scatter radi ati on to the l ungs, hear t, and cor onar y vessel s; and l ess
ski n bur ni ng and desquamati on. Numer ous studi es ar e i n pr ogr ess
to eval uate the dosi metr y, si de effect pr ofi l es, and effi cacy of
par ti al br east i r radi ati on. Unti l the r esul ts of these studi es ar e
known, par ti al br east i r radi ati on shoul d be consi der ed exper i mental
and be per for med under pr otocol onl y. The del i ver y methods for
par ti al br east i r radi ati on cur r entl y under i nvesti gati on ar e radi ati on
therapy thr ough brachytherapy catheter s pl aced i ntraoperati vel y or
postoperati vel y and thr ee-di mensi onal confor mal radi ati on gi ven
exter nal l y to the br east postoperati vel y.

Table 2.4. Summary of selected NSABP


therapeutic trials for invasive breast cancer
Trial

Treatment

Outcome

NSABP
B-04

Total mastectomy
vs. total
mastectomy with
XRT vs. radical
mastectomy

No significant
difference in
disease-free or
overall survival
rates

NSABP
B-06

Total mastectomy
vs. lumpectomy
vs. lumpectomy
with XRT

No significant
difference in
disease-free or
overall survival
rates; addition of
XRT to
lumpectomy
reduced local
recurrence rate
from 39% to 10%

NSABP
B-13

Surgery alone vs.


surgery plus
adjuvant
chemotherapy in
node-negative
patients with
estrogen receptornegative tumors

Improved
disease-free
survival rate for
adjuvant
chemotherapy
group

Surgery alone vs.


surgery plus
adjuvant
tamoxifen in
node-negative
patients with
estrogen receptorpositive tumors

Improved
disease-free
survival rate for
adjuvant
tamoxifen group

NSABP
B-18

Neoadjuvant
chemotherapy
with doxorubicin,
cyclophosphamide,
or both for 4
cycles vs. the
same regimen
given
postoperatively

No significant
difference in
overall survival or
disease-free
survival rates
(53% and 70% at
9 years in the
postoperative
group and 69%
and 55% in the
preoperative
group)

NSABP
B-21

Lumpectomy plus
tamoxifen vs.
lumpectomy plus
tamoxifen plus
XRT vs.
lumpectomy plus
XRT for nodenegative tumors
<1 cm

Combination of
XRT and
tamoxifen was
more effective
than either alone
in reducing
ipsilateral breast
tumor recurrence

NSABP
B-14

NSABP
B-27

Neoadjuvant
chemotherapy
comparing AC 4
cycles then
surgery vs. AC
4 cycles,
docetaxel 4
cycles then
surgery vs.
surgery between 4
cycles of AC and 4
cycles of
docetaxel

Groups I and III


were combined
and compared
with group II;
clinical and
pathological
complete
response rates
increased
significantly
among patients
who received
preoperative AC
and docetaxel

NSABP
B-32

SLN biopsy
followed by
axillary dissection
vs. SLN biopsy
alone for clinically
node-negative
patients

SLN identification
rate was similar
in both groups,
accuracy was high
for both, negative
predictive value
was high for both

NSABP, National Surgical Adjuvant Breast and


Bowel Project; XRT, radiation therapy; AC,
doxorubicin (Adriamycin), cyclophosphamide;
SLN, sentinel lymph node.
Al though BCT and mastectomy r esul t i n equi val ent sur vi val rates for
pati ents wi th stage I or stage II di sease, the deci si on to conser ve
the br east must be made i ndi vi dual l y. Of utmost i mpor tance for the
success of BCT i s the pati ent's moti vati on and commi tment to

pr eser ve the br east and pr event advanced r ecur r ences: dai l y


outpati ent radi ati on tr eatments over 5 to 6 weeks ar e r equi r ed.
Mor e i mpor tant i s l ong-ter m fol l ow-up of the pr eser ved br east to
detect br east cancer r ecur r ences. Other factor s that must be
consi der ed i n maki ng the choi ce between mastectomy and br east
conser vati on sur ger y, ar e outl i ned i n Tabl e 2.5.
For extr emel y smal l br easts, the cosmeti c r esul t may be
unacceptabl e fol l owi ng l ocal exci si on, especi al l y for pati ents wi th
si zeabl e tumor s. For l ar ge or pendul ous br easts, l ack of uni for mi ty
i n radi ati on dosi ng may r esul t i n unattracti ve fi br osi s and
r etracti on. Pati ents may benefi t fr om mastectomy pl us
r econstr ucti on and per haps sur gi cal augmentati on or r educti on of
the
contral ateral br east. Pati ents wi th l ar ger tumor s mi ght al so be best
ser ved by mastectomy because of the poor cosmeti c outcome that
r esul ts when a l ar ge ar ea of the br east and the defect ar e r emoved.
Ver y l i ttl e data exi st i n a pr ospecti ve randomi zed setti ng for the
feasi bi l i ty of BCT i n pati ents wi th l ar ge tumor s. Khanna et al .
i nvesti gated the outcomes for 68 pati ents who under went BCT
wi thout the use of pr eoperati ve (neoadjuvant) chemotherapy for 4to 12-cm tumor s. The mean tumor di ameter was 5 cm, and the
medi an fol l ow-up was 48 months. The actuar i al l ocor egi onal
r ecur r ence rate was 8.5% , and no r ecur r ence occur r ed i n pati ents
who had negati ve sur gi cal mar gi ns. No si gni fi cant di ffer ence i n
di sease-fr ee sur vi val rates was noted for pati ents who under went
BCT and those who under went mastectomy. Ni nety-four per cent of
the pati ents who under went BCT r epor ted a favorabl e cosmeti c
outcome. Al ter nati vel y, a mor e attracti ve appr oach to tr eati ng T3
tumor s, or for pati ents wi th unfavorabl e br easttumor rati os, may
be neoadjuvant chemotherapy, whi ch may shr i nk the tumor to the
poi nt wher e br east conser vati on i s feasi bl e or cosmeti cal l y opti mal .

Table 2.5. Absolute and relative


contraindications to breast-conserving
therapy
Absolute contraindications

Prior radiotherapy to the breast or chest wall


Radiotherapy use during pregnancy
Diffuse suspicious or malignant-appearing
microcalcifications
Multicentric disease
Positive pathologial margin after multiple
attempts to obtain negative margins
Relative contraindications
Multifocal disease requiring two or more
separate surgical incisions
Active connective tissue disease involving the
skin (especially scleroderma and lupus)
Tumor size >5 cm (controversial)
Focally positive margins after multiple attempts
to obtain negative margins
Adapted from National Comprehensive Cancer
Network Guidelines, 2005.
Al though, ther e does not appear to be any di ffer ence i n overal l
sur vi val for pati ents who under go mastectomy or BCT for ear l ystage br east cancer. Ther e does appear to be a di ffer ence i n
r ecur r ence rates between the two sur gi cal tr eatment opti ons.
Attempts have been made to i denti fy pati ents wi th a hi gh rate of
l ocal r ecur r ence after BCT on the basi s of the hi stol ogy of the
pr i mar y tumor. To date, ther e have been no documented si gni fi cant
di ffer ences i n l ocal r ecur r ence by hi stol ogi c subtype. The r i sk of
l ocal r ecur r ence has been shown to be hi gher for women younger
than 35 year s and for women whose tumor s ar e gr eater than 2 cm
i n di ameter, r egar dl ess of l ymph node status. For pati ents wi th
posi ti ve l ymph nodes, nucl ear grade i s al so si gni fi cantl y cor r el ated
wi th r ecur r ence. The l ocal r ecur r ence rates for BCT quoted i n the
major publ i shed studi es (notabl y, the Mi l an study, NSABP B-06, and
the Dani sh Br east Cancer Cooperati ve G r oup study) range fr om
2.6% to 18% , whi ch i s sl i ghtl y hi gher than the range quoted for

mastectomy (2.3% to 13% ). In the Mi l an study, the 20-year cr ude


i nci dence rate for r ecur r ence was si gni fi cantl y hi gher for BCT than
for mastectomy (8.8% vs. 2.3% ) (p <0.001). However, ther e was no
si gni fi cant di ffer ence i n overal l sur vi val rates between BCT and
mastectomy i n any of these studi es. The ul ti mate goal of BCT for
pati ents wi th ear l y-stage br east cancer i s to pr ovi de an opti mal
cosmeti c r esul t wi thout compr omi si ng l ocal contr ol . Cl ear l y, a
mul ti di sci pl i nar y effor t coupl ed wi th car eful pati ent sel ecti on i s
cr i ti cal for the successful outcomes of BCT.

Locally Advanced Breast Cancer


Local l y advanced br east cancer encompasses tumor s wi th a br oad
range of bi ol ogi cal behavi or s. Thi s categor y i ncl udes tumor s that
ar e l ar ge or have extensi ve r egi onal l ymph node i nvol vement
wi thout evi dence of di stant metastati c di sease at i ni ti al
pr esentati on. These tumor s fal l i nto the categor y of stage III
di sease accor di ng to the AJCC system. Appr oxi matel y 10% to 20%
of al l pati ents wi th br east cancer have stage III di sease, whi ch
i ncl udes T3 tumor s wi th N1, N2, or N3 di sease; T4 tumor s wi th any
N cl assi fi cati on; or any T cl assi fi cati on wi th N2 or N3 r egi onal l ymph
node i nvol vement. Appr oxi matel y 25% to 30% of stage III br east
cancer s ar e i noperabl e at the ti me of di agnosi s.
Many l ocal l y advanced br east cancer s ar e di scover ed by a pati ent or
her spouse. The r emai ni ng ar e di scover ed dur i ng r outi ne physi cal
exami nati on. On occasi on, a di scr ete mass may not be pr esent;
rather, ther e i s a di ffuse i nfi l trati on of the br east ti ssue. These
pati ents pr esent wi th a br east that i s asymmetr i c, i mmobi l e, and
di ffer ent i n consi stency fr om the contral ateral br east. Seventy-fi ve
per cent of pati ents wi th stage III di sease wi l l have cl i ni cal l y
pal pabl e axi l l ar y or supracl avi cul ar l ymph nodes at the ti me of
di agnosi s. Thi s cl i ni cal fi ndi ng i s confi r med on pathol ogi cal
exami nati on i n 66% to 90% of pati ents. Of the pati ents wi th
posi ti ve nodes, 50% wi l l have mor e than four nodes i nvol ved. When
appr opr i ate stagi ng i s per for med, 20% of pati ents wi th stage III
di sease ar e found to have di stant metastases at pr esentati on.
Di stant metastases ar e al so the most fr equent for m of tr eatment
fai l ur e and usual l y appear wi thi n 2 year s of the i ni ti al di agnosi s.
Both F NA and cor e-needl e bi opsy can be used to confi r m br east
cancer i n these pati ents. These pr ocedur es ar e usual l y easi l y
per for med because of the l ar ge tumor si ze at pr esentati on. The
Hal sted radi cal mastectomy, whi ch was i ni ti al l y bel i eved to be the
tr eatment of choi ce for l ocal l y advanced br east cancer, has been

pr oven to be i nadequate for l ocal contr ol and l ong-ter m pati ent


sur vi val . In 1942, Haagensen r epor ted a 53% l ocal r ecur r ence rate
and a 0% 5-year overal l sur vi val rate among 1,135 pati ents wi th
stage III br east cancer who had under gone a Hal sted radi cal
mastectomy.
The fai l ur e of sur ger y al one to contr ol stage III br east cancer l ed to
the use of radi ati on therapy as a si ngl e-agent tr eatment modal i ty i n
thi s gr oup of pati ents. However, the r esul ts wi th
radi ati on therapy wer e i n some cases i nfer i or to those seen wi th
sur ger y al one. The 5-year overal l sur vi val and l ocal r ecur r ence
rates seen wi th radi ati on therapy al one have ranged fr om 10% to
30% and fr om 25% to 70% , r especti vel y.
Sur ger y pl us radi ati on therapy for l ocal l y advanced br east cancer
al so r esul ts i n poor overal l r esul ts. The l ack of effi cacy of the
combi nati on of two l ocal tr eatment modal i ti es confi r med that stage
III br east cancer i s a systemi c di sease. Al though l ocal contr ol
i ncr eased sl i ghtl y (but i nsi gni fi cantl y) wi th sur ger y pl us radi ati on
therapy, the 5-year overal l sur vi val rate was unchanged, and
pati ents conti nued to di e of di stant metastases.
In the ear l y 1970s, systemi c combi nati on chemotherapy was added
to the l ocal tr eatments for l ocal l y advanced br east cancer. Ini ti al
pr otocol s wer e desi gned to admi ni ster the chemotherapy after l ocal
tr eatment, but thi s sequence of tr eatment does not al l ow for
assessment of the effi cacy of the chemotherapy because al l
measurabl e di sease i s r emoved befor e admi ni strati on of the dr ugs.
The cur r ent practi ce i s to admi ni ster i nducti on chemotherapy befor e
any l ocal tr eatment. Thi s sequence al l ows for r educti on of the i ni ti al
tumor bur den befor e sur ger y, tr eatment of the potenti al systemi c
di sease wi thout del ay, and assessment of the r esponse of the tumor
to the tr eatment bei ng r ender ed.
Several cancer tr eatment center s have r epor ted exper i ences wi th
combi ned modal i ty therapy for l ocal l y advanced di sease. Al though
the pr otocol s di ffer among i nsti tuti ons wi th r espect to the speci fi c
chemotherapy r egi mens and the type of l ocal tr eatment, the studi es
have used i nducti on neoadjuvant chemotherapy fol l owed by l ocal
tr eatment (i .e., sur ger y, radi ati on therapy, or both) and subsequent
adjuvant chemotherapy. Many pati ents wi th l ocal l y advanced br east
cancer ar e now bei ng tr eated wi th thi s chemotherapy sandwi ch
appr oach.
Pati ents wi th l ocal l y advanced br east cancer ar e typi cal l y tr eated

wi th an anthracycl i ne-based r egi men and a taxane befor e sur ger y or


sandwi ched ar ound sur ger y. If postoperati ve chemotherapy i s
pl anned, i t shoul d pr ecede radi ati on therapy to avoi d i nter r upti ng
the tr eatment of systemi c di sease because di stant metastases ar e
the most fr equent for m of tr eatment fai l ur e. Adjuvant hor monal
therapy i s r outi nel y offer ed to al l pati ents wi th r eceptor-posi ti ve
tumor s once they have compl eted systemi c and l ocor egi onal
therapy.

Inflammatory Breast Cancer


Infl ammator y br east cancer i s a rar e, vi r ul ent for m of l ocal l y
advanced br east cancer. It r epr esents 1% to 6% of al l br east
cancer s and pr esents as er ythema, war mth, and edema of the
br east. Rapi d onset of symptoms (wi thi n 3 months) i s necessar y to
make the di agnosi s of i nfl ammator y car ci noma. The ti me cour se
di sti ngui shes i t fr om l ocal l y advanced br east cancer wi th secondar y
l ymphati c i nvasi on, whi ch usual l y pr ogr esses sl owl y over mor e than
3 months. Pai n i s al so pr esent i n hal f of pati ents wi th i nfl ammator y
br east cancer. Confusi on of the physi cal fi ndi ngs as symptoms of an
i nfecti ous pr ocess often r esul ts i n del ays i n di agnosi s and
tr eatment. Tumor embol i ar e often seen i n the subder mal
l ymphati cs on mi cr oscopi c exami nati on. Bi opsy for di agnosi s shoul d
i ncl ude a segment of i nvol ved ski n because a domi nant
mass i s usual l y not pal pabl e on physi cal exami nati on. Ul ti matel y,
the di agnosi s of i nfl ammator y br east car ci noma i s based on the
cl i ni cal eval uati on, whi ch i ncl udes the ti meframe for whi ch the si gns
and symptoms appear.
Infl ammator y car ci noma, si mi l ar to other for ms of l ocal l y advanced
br east cancer, i s a systemi c di sease. In a study of i nfl ammator y
car ci noma, l ocal therapy as the onl y tr eatment modal i ty r esul ted i n
poor outcomes; the medi an sur vi val was l ess than 2 year s, and the
5-year overal l sur vi val rate was 5% . The use of mul ti modal i ty
therapy i n these pati ents has i mpr oved l ocal contr ol and overal l
sur vi val rate over l ocal therapy al one. Standar d tr eatment i s
anthracycl i ne and then taxane-based chemotherapy, ei ther both
befor e sur ger y or sandwi ched ar ound sur ger y. Radi ati on i s
admi ni ster ed after compl eti on of al l sur ger y and systemi c therapy.
Pati ents whose di sease pr ogr esses dur i ng chemotherapy pr oceed to
pr eoperati ve radi ati on therapy or, i f the cancer i s operabl e, sur ger y.

Axillary Lymph Node Dissection


ALND i s sti l l the gol d standar d of car e when eval uati ng the drai ni ng
nodal basi n for l ymph node metastases. Al though ALND appear s to
contr i bute l i ttl e to overal l pati ent sur vi val , i t i s i mpor tant for
stagi ng and l ocal contr ol . ALND pr ovi des i nfor mati on wi th pr ognosti c
and tr eatment i mpl i cati ons for women under goi ng br east
conser vati on sur ger y or modi fi ed radi cal mastectomy. The r ol e of
the r outi ne use of ALND has been r edefi ned i n the past decade by
the wi despr ead use and devel opment of the SLN bi opsy techni que.
Never thel ess, an ALND i s sti l l consi der ed appr opr i ate as a fi r st l i ne
of tr eatment for l ocal contr ol and stagi ng of the axi l l ar y l ymph
nodes, par ti cul ar l y i n cer tai n si tuati ons such as (a) F NA bi opsypr oven axi l l ar y l ymph node metastases or (b) when ther e ar e
suspi ci ous and pal pabl e nodes i n the axi l l a.
The i nci dence of axi l l ar y l ymph node metastases i ncr eases as the
pr i mar y tumor gr ows. A substanti al pr opor ti on of pati ents wi th
appar ent ear l y-stage br east cancer pr esent wi th axi l l ar y nodal
metastases. In one study, 17% of pati ents wi th cl i ni cal l y staged
T1N0 di sease had hi stol ogi cal l y posi ti ve nodes; thi s fi gur e r ose to
27% for pati ents wi th cl i ni cal l y T2N0 staged di sease. Other studi es
have found that 10% of pati ents wi th tumor s smal l er than 0.5 cm
have posi ti ve axi l l ar y l ymph nodes. Tumor s 0.5 to 1.0 cm ar e
associ ated wi th posi ti ve axi l l ar y l ymph nodes i n 13% to 22% of
pati ents, and 1.1- to 2.0-cm tumor s ar e associ ated wi th l ymph node
metastases i n up to 30% of pati ents.
The contr i buti on of ALND to l ocal contr ol i s smal l but measurabl e. In
NSABP B-04, whi ch compar ed radi cal mastectomy wi th si mpl e
mastectomy (wi thout ALND) wi th and wi thout i r radi ati on, 40% of
pati ents wi th cl i ni cal l y negati ve axi l l ae had posi ti ve nodes at radi cal
mastectomy, and 1% of these pati ents eventual l y exper i enced
r ecur r ence i n the axi l l a. In pati ents wi th unoperated axi l l ae (si mpl e
mastectomy gr oup), 18% eventual l y devel oped cl i ni cal adenopathy
that r equi r ed del ayed ALND; four of these pati ents eventual l y
exper i enced r ecur r ence i n the axi l l a despi te del ayed ALND. No
sur vi val di sadvantage was seen for pati ents under goi ng del ayed
ver sus i mmedi ate ALND. Radi ati on was l ess effecti ve than ALND i n
pr eventi ng eventual r ecur r ence
i n the axi l l a, especi al l y among pati ents wi th cl i ni cal l y posi ti ve
nodes.
In addi ti on to contr i buti ng to l ocal contr ol , ALND pr ovi des stagi ng

and pr ognosti c i nfor mati on because nodal status i s a major


pr edi ctor of outcome. For al l pati ents wi th node-negati ve cancer, a
10-year sur vi val rate of at l east 70% may be anti ci pated. For
pati ents wi th 1 to 3 posi ti ve nodes thi s rate dr ops to 40% , and for
pati ents wi th 4 to 10 posi ti ve nodes the rate dr ops to l ess than
20% . Mi cr ometastati c nodal di sease (l ess than 2 mm i n di ameter )
car r i es a better pr ognosi s than macr ometastati c di sease.
The cur r ent standar d of car e i s an anatomi c l evel I or l evel II ALND
for al l pati ents wi th stage I or stage II br east cancer. For pati ents
wi th i nvasi ve br east cancer who ar e under goi ng BCT, ALND shoul d
be per for med vi a a separate axi l l ar y i nci si on that does not extend
anter i or to the pectoral i s fol d. ALND shoul d consi st of en bl oc
r emoval of l evel s I and II nodal ti ssue, and i f l evel III nodes ar e
gr ossl y or pathol ogi cal l y i nvol ved, r emoval of these nodes shoul d be
i ncl uded i n the ALND. However, r emoval of cl i ni cal l y negati ve l evel
III l ymph nodes i s of l i ttl e benefi t wi th r espect to stagi ng because
onl y 1% to 3% of stage I or stage II pati ents show l evel III
i nvol vement i n the absence of l evel I or l evel II di sease. Level III
di ssecti ons car r y a substanti al l y hi gher r i sk of subsequent
l ymphedema, especi al l y i f radi ati on therapy i s al so used. The l evel I
or l evel II ALND shoul d pr eser ve the l ong thoraci c and thoracodor sal
ner ves and avoi d str i ppi ng of the axi l l ar y vei n. A cl osed-sucti on
drai n i s pl aced and r emoved after the drai nage has suffi ci entl y
decr eased.
Pati ents wi th ear l y-stage di sease wi th a l ow r i sk of axi l l ar y l ymph
node i nvol vement may not r equi r e a ful l ALND, and SLN bi opsy may
be the best way to stage the axi l l ar y l ymph node i n these pati ents.
The best appr oach for pati ents wi th T1 tumor s mi ght be SLN bi opsy
to detect l ymph node metastases because SLN bi opsy pr ovi des
pr ognosti c i nfor mati on wi th pr esumabl y l ess mor bi di ty and hel ps
for mul ate a tr eatment strategy. Al though thi s appr oach may seem
r easonabl e, no nati onal consensus has cur r entl y been r eached
r egar di ng the use of SLN bi opsy.

Sentinel Lymph Node Biopsy


Identi fyi ng pati ents wi th metastases i n the axi l l ar y l ymph nodes
wi th ALND i s extr emel y i mpor tant for pr ognosi s, r egi onal tr eatment,
and l ocal contr ol . But because br east cancer si ze on pr esentati on
has become pr ogr essi vel y smal l er due to the wi despr ead use of
scr eeni ng mammography, the pr obabi l i ty of nodal i nvol vement has
al so decr eased. In addi ti on, the compl i cati ons associ ated wi th the
r outi ne use of ALND to deter mi ne axi l l ar y metastases has made i t

i ncr easi ngl y har d to justi fy thi s pr ocedur e i n cer tai n pati ent
popul ati ons. The chal l enge i s to use ALND onl y i n pati ents wi th
nodal metastases. A newer appr oach that enabl es sel ecti ve
l ymphadenectomy i s l ymphati c mappi ng and SLN bi opsy. The SLN i s
often defi ned as the fi r st l ymph node to r ecei ve l ymphati c drai nage
fr om a pr i mar y br east cancer and, ther efor e, the node most l i kel y to
contai n metastati c tumor cel l s. When SLN bi opsy i s per for med by an
exper i enced team consi sti ng of a sur geon, nucl ear medi ci ne
physi ci an, pathol ogi st, and operati ng r oom nur ses and techni ci ans,
the fi ndi ng of a tumor-fr ee SLN
al most i nvar i abl y i ndi cates that the pati ent has node-negati ve
br east cancer and need not under go fur ther axi l l ar y di ssecti on.
However, SLN bi opsy shoul d not be under taken unti l the team has
consi stentl y documented a hi gh rate of SLN i denti fi cati on and l ow
rate of fal se-negati ve SLNs.
SLN bi opsy i s an unstandar di zed standar d of car e. Contr over sy
exi sts as to whether the dye or radi oi sotope shoul d be i njected
i ntrapar enchymal l y, i ntrader mal l y, or subar eol ar l y; whether i t
shoul d be i njected the day befor e or the day of sur ger y; the dose of
the radi oi sotope; and whether bl ue dye, radi oi sotope, or both
shoul d be used. The pl ethora of l i teratur e on SLN bi opsy i n br east
cancer and the techni ques and i di osyncrasi es of thi s method exi st.
Most r epor ted studi es state: successful SLN detecti on i n 94% to
98% of pati ents, an accuracy rate of 97% to 100% , and a fal senegati ve rate of 0% to 15% .
SLN bi opsy can be per for med usi ng radi ol abel ed col l oi d, vi tal bl ue
dye, or both. Pr eoperati ve l ymphosci nti graphy, al though not
mandator y, can be used to i denti fy the SLN and document patter ns
of l ymphati c drai nage. A handhel d gamma counter, the ai d of vi si bl e
bl ue dye, or both can be used i ntraoperati vel y to l ocate the SLN.
SLN bi opsy may be unsuccessful i n pati ents wi th cer tai n cl i ni cal
pr esentati ons: (a) pal pabl e axi l l ar y adenopathy, (b) medi al
hemi spher e l ocati on of the pr i mar y tumor wher e pr eoperati ve
l ymphosci nti graphy di d not i denti fy an axi l l ar y SLN, (c) pr evi ous
axi l l ar y sur ger y because the l ymphati c drai nage fr om the pr i mar y
may be di stor ted, and (d) l ar ge bi opsy cavi ty (l ar ger than 6 cm)
because the l ymphati c drai nage fr om the sur r oundi ng br east ti ssue
may not be the same as that of the pr i mar y tumor.
An i mpor tant questi on i s the cl i ni cal si gni fi cance of SLN posi ti vi ty
as i ndi cated by i mmunohi stochemi cal anal ysi s but not by r outi ne

hematoxyl i n and eosi n stai ni ng. A better under standi ng of the


natural hi stor y of the di sease woul d hel p deter mi ne whether
subsequent axi l l ar y di ssecti on, axi l l ar y radi ati on therapy, or
adjuvant chemotherapy i s needed i n pati ents wi th mi cr ometastasi s
i n the SLN. Several r egi onal and nati onal studi es (Amer i can Col l ege
of Sur geons Oncol ogy G r oup Z0010/Z0011) ar e bei ng conducted to
addr ess the i ssues associ ated wi th thi s new techni que. The NSABP
B-32 i s a pr ospecti ve randomi zed phase III tr i al to assess whether
SLN bi opsy r esul ts i n the same pr ognosi s, r egi onal contr ol , and
overal l sur vi val rate as does ALND for i nvasi ve br east cancer s.
Pati ents wi th cl i ni cal l y negati ve nodes wer e randoml y assi gned to
SLN bi opsy wi th i mmedi ate ALND or to SLN bi opsy al one. In both
gr oups, a SLN was i denti fi ed i n 97% of pati ents, 26% of whom wer e
SLN posi ti ve. In 61.5% of the SLN-posi ti ve pati ents, the posi ti ve
SLNs wer e the onl y posi ti ve nodes. In the gr oups assi gned to SLN
bi opsy wi th i mmedi ate ALND, the fal se-negati ve rate was 9.7% , the
negati ve pr edi cti ve val ue was 96.1% , and the accuracy was 97.2% .
The i nvesti gator s concl uded that the rate of SLN i denti fi cati on was
si mi l ar i n both gr oups and that overal l accuracy and the negati ve
pr edi cti ve val ue wer e hi gh i n both gr oups.
Two other gr oups of pati ents that mi ght be consi der ed for SLN
bi opsy at the ti me of thei r defi ni ti ve sur ger y, but that ar e sti l l
rather contr over si al , ar e those r ecei vi ng total mastectomy for
noni nvasi ve cancer and hi gh-r i sk pati ents r ecei vi ng pr ophyl acti c
mastectomy. These two gr oups of pati ents may be at hi gh r i sk for
har bor i ng an occul t i nvasi ve cancer. Per for mi ng an SLN bi opsy at
the ti me of mastectomy may pr ecl ude the pati ent fr om havi ng to
under go a second operati on and an axi l l ar y l ymph node di ssecti on i n
the event that an occul t i nvasi ve cancer i s di scover ed after
hi stopathol ogi cal eval uati on of the mastectomy speci men.

Breast Reconstruction
For pati ents not under goi ng br east conser vati on, br east
r econstr ucti on shoul d be consi der ed a standar d opti on of cancer
therapy. Reconstr ucti on may i nvol ve autol ogous ti ssue, syntheti c
i mpl ants, or both. Al though sati sfactor y r esul ts can be obtai ned wi th
ei ther i mmedi ate or del ayed r econstr ucti on, MDACC physi ci ans favor
i mmedi ate r econstr ucti on for most pati ents, par ti cul ar l y those
unl i kel y to under go postmastectomy radi ati on therapy. Immedi ate
r econstr ucti on car r i es a substanti al psychol ogi cal benefi t for many
women and often al l ows a better cosmeti c r esul t. The i ni ti ati on of

adjuvant chemotherapy i s not si gni fi cantl y del ayed, and concer ns


that l ocal r ecur r ence may go undetected i n a r econstr ucted br east
ar e not wel l founded, especi al l y for T1 and T2 l esi ons. However, i f
the pati ent i s known to r equi r e postmastectomy radi ati on, the
pati ent i s often counsel ed to del ay the r econstr ucti on. Chapter 24
expands on the techni cal detai l s and potenti al opti ons for br east
r econstr ucti on.
At MDACC, al most hal f of the pati ents wi th br east cancer tr eated
wi th mastectomy under go i mmedi ate r econstr ucti on. Al though the
method of r econstr ucti on i s i ndi vi dual i zed, pedi cl ed or fr ee
transver se r ectus abdomi ni s myocutaneous fl aps ar e the most
commonl y used. Contral ateral augmentati on or r educti on may be
per for med to maxi mi ze symmetr y. For pati ents wi th bi l ateral br east
cancer who desi r e mastectomy or pati ents wi th a per cei ved hi gh r i sk
for a contral ateral second pr i mar y l esi on, si mul taneous
contral ateral pr ophyl acti c mastectomy wi th bi l ateral i mmedi ate
r econstr ucti on i s a vi abl e opti on. Counsel i ng r egar di ng the
possi bi l i ty of postmastectomy radi ati on and i ts subsequent
compl i cati ons to the r econstr ucted br east shoul d al ways be
di scussed wi th the pati ent.
MDACC physi ci ans typi cal l y per for m a ski n-spar i ng mastectomy i n
pati ents under goi ng i mmedi ate br east r econstr ucti on because
pr eser vati on of br east ski n al l ows for a mor e natural contour to the
r econstr ucted br east. No i ncr eased r i sk of l ocal r ecur r ence has been
obser ved for pati ents tr eated wi th ski n-spar i ng techni ques.

Current Treatment Standards for Systemic


Adjuvant Therapy
For node-posi ti ve and node-negati ve br east cancer pati ents,
deci si ons r egar di ng adjuvant chemotherapy must be i ndi vi dual i zed.
Cur r ent standar ds ar e based l ar gel y on pati ent age, l evel of
estr ogen r eceptor s expr essed by the tumor, si ze of the pr i mar y
tumor, and hi stol ogi c status of the axi l l a. Other factor s to consi der
ar e overal l heal th status, HER-2/neu oncogene ampl i fi cati on, and
nucl ear grade. G eneral gui del i nes r egar di ng the use of adjuvant
chemotherapy ar e pr esented i n Tabl e 2.6.

Cur r ent standar ds favor the use of mul ti dr ug combi nati on


chemotherapy i n al l pati ents except those wi th the most favorabl e

pr esentati on (i .e., node negati ve and pr i mar y tumor l ess than 1


cm). Resul ts fr om the Ear l y Br east Cancer Tr i al i sts Col l aborati ve
G r oup (EBCTCG ) i n 1995 and agai n i n 2000 i ndi cated that mul ti dr ug
chemotherapy si gni fi cantl y r educes di sease r ecur r ence and death i n
both node-posi ti ve and node-negati ve pati ents, r egar dl ess of stage,
menopausal status, r eceptor status, or pati ent age.

Table 2.6. Adjuvant chemotherapy


recommendations for patients with invasive b
carcinoma on the basis of axillary nodal sta
menopausal status, estrogen receptor expres
and tumor size
Nodal,
Menopausal, Tumor
Therapy
and ER
Size
Status

Comments

Positive node
Premenopausal

Negative

Any

Multidrug
combination
chemotherapy

Four to 8 c
of
anthracyclin
and taxane
combination
sequence a
the standar
for all node
positive
patients,

(CMF, CAF, or
AC; AC + Ta

Positive

regardless
ER or
menopausa
status; this
adjuvant
therapy has
been shown
prolong ove
survival

Multidrug
combination
chemotherapy
(CMF, CAF, or
AC; AC + T)
+ tamoxifen

Addition of
tamoxifen t
chemothera
prolongs ov
survival

Multidrug
combination
chemotherapy
(CMF, CAF, or
AC; AC + T)

Twenty per
reduction in
recurrence
11% reduct
in mortality
patients ag
50 to 69;
minimal dat
for patients
70

Tamoxifen 20
mg QD with

Combinatio

Postmenopausal

Negative

Positive

or without
multidrug
combination
chemotherapy
(CMF, CAF, or
AC; AC + T)

chemothera
and tamoxi
results in
longer over
survival tha
tamoxifen a

None;
consider
tamoxifen or
AI for
contralateral
risk reduction

Overall surv
after local
treatment a
is >90%; lo
toxicity and
beneficial
effects of
tamoxifen o
may justify
use

Consider
multidrug
combination
chemotherapy
(CMF, CAF, or
AC)

Prognostic
factors, suc
grade and H
2/neu statu
may be use
in selecting
patients for
chemothera

Negative node
Pre- or postmenopausal

Positive or
negative

<1
cm

1
cm
and
<2
cm
Negative

2
cm

Positive

1
cm

Multidrug
combination
chemotherapy
(CMF, CAF, or
AC)

Tamoxifen
with or
without
multidrug
combination
chemotherapy
(CMF, CAF, or
AC)

Reduction i
risk of
recurrence
equal to tha
observed in
node-positi
disease

Chemothera
is
recommend
for women
high-grade
tumors or T
lesions;
tamoxifen o
therapy is
recommend
for tumors
2 cm; decis
about the
addition of
cytotoxic
therapy for
pre- or
postmenopa
women sho
be made on
basis of
estrogen
receptor lev
performanc

status, and
tumor facto

ER, estrogen receptor; CMF, cyclophosphamide,


methotrexate, 5-fluorouracil; CAF; cyclophosphamid
doxorubicin (Adriamycin), 5-fluorouracil; AC,
doxorubicin (Adriamycin), cyclophosphamide; T,
taxane; QD, every day; AI, aromatase inhibitor.
a Addition of the taxane paclitaxel to 4 cycles of AC
treatment alternative.
Numer ous chemotherapy r egi mens ar e effecti ve i n the adjuvant
setti ng. The EBCTCG has shown that combi nati on chemotherapy i s
mor e effecti ve than si ngl e agents. Si x months of CMF
(cyl cophosphami de, methotr exate, and 5-fl uor ouraci l ) was the
standar d for many year s and i s sti l l used by some oncol ogi sts. The
anthracycl i nes doxor ubi ci n and epi r ubi ci n have become the mai nstay
of adjuvant chemotherapy. Thr ee months of the anthracycl i ne
r egi men AC (adr i amyci n and cycl ophosphami de) was shown to be
equi val ent to 6 months of CMF and i s ther efor e a commonl y used
r egi men i n the Uni ted States. However, the thr ee-dr ug
anthracycl i ne r egi mens FAC (5-fl uor ouraci l , adr i amyci n, and
cycl ophosphami de) and F EC ar e super i or to CMF and ar e thus
pr obabl y super i or to AC. Hence, the thr ee-dr ug r egi mens ar e
pr efer r ed at MDACC. For node-negati ve pati ents, acceptabl e
effecti ve adjuvant chemotherapy opti ons i ncl ude CMF, AC, FAC, and
F EC.
The taxanes pacl i taxel and docetaxel pl us anthracycl i nes have been
compar ed wi th anthracycl i nes al one i n node-posi ti ve pati ents. Thr ee
l ar ge randomi zed tr i al s have demonstrated a l onger di sease-fr ee
sur vi val ti me among node-posi ti ve pati ents who r ecei ved taxane
pl us anthracycl i ne. Thus, i t i s wi del y accepted that node-posi ti ve
pati ents shoul d r ecei ve AC, FAC, or F EC i n sequence or i n
combi nati on wi th pacl i taxel or docetaxel .
Chemotherapy i s typi cal l y gi ven ever y 3 weeks, al though emer gi ng
data have demonstrated si mi l ar effi cacy wi th weekl y or ever y-2week (dose dense) chemotherapy. The EBCTCG meta-anal ysi s has
shown that l ess than 3 months of chemotherapy i s i nsuffi ci ent and

mor e than 6 months i s unnecessar y. Stem cel l transpl ant has not
been shown to i mpr ove the overal l sur vi val rate and shoul d be used
onl y i n the context of a cl i ni cal tr i al .
Tamoxi fen, whi ch was or i gi nal l y r ecommended for the tr eatment of
postmenopausal women wi th estr ogen r eceptor-posi ti ve br east
cancer, i s now i ndi cated for a much br oader range of pati ents.
Regar dl ess of pati ent age or menopausal status, when used for the
standar d 5 year s, tamoxi fen i s associ ated wi th a 47% r educti on i n
the r i sk of br east cancer r ecur r ence and a 26% r educti on i n the r i sk
of death. Tamoxi fen therapy i s general l y wel l tol erated; tr eatmentl i mi ti ng adver se effects devel op i n l ess than 5% of pati ents. In
addi ti on to i ts anti tumor pr oper ti es, tamoxi fen i ncr eases bone
densi ty and r educes ser um chol ester ol l evel s. However, tamoxi fen
al so i ncr eases the i nci dence of endometr i al cancer and
thr omboembol i c events. Standar d tr eatment wi th tamoxi fen i s 5
year s. A meta-anal ysi s of fi ve randomi zed cl i ni cal tr i al s showed that
pati ents who wer e tr eated wi th tamoxi fen for 3 to 5 year s had a
gr eater r educti on i n r ecur r ence than di d pati ents tr eated for 1 to 2
year s (22% 8% vs. 7% 11% ). Data
fr om NSABP B-14 i ndi cated that 10 year s of tamoxi fen use offer no
sur vi val advantage over 5 year s. Tamoxi fen and chemotherapy
together achi eve an addi ti ve sur vi val benefi t.
The ar omatase i nhi bi tor s anastr ozol e, l etr ozol e, and exemestane
wor k by i nhi bi ti ng the ar omatase enz yme that catal yzes the
conver si on of adr enal cor ti coster oi ds to estr ogens and ther efor e
decr eases the pr oducti on of estr ogens i n postmenopausal women
onl y. The effi cacy and si de effect pr ofi l es of anastr ozol e and
tamoxi fen wer e compar ed i n postmenopausal women i n the ATAC
(Ar i mi dex, Tamoxi fen Al one or i n Combi nati on) tr i al , the l ar gest
br east cancer therapeuti c tr i al ever conducted. The r esul ts of the
tr i al demonstrated that i n adjuvant endocr i ne therapy for
postmenopausal pati ents wi th ear l y-stage br east cancer, anastr ozol e
r esul ted i n a hi gher di sease-fr ee sur vi val rate (86.9% vs. 84.5% ),
l onger ti me to r ecur r ence, and l ower i nci dence of contral ateral
br east cancer. The r esul ts al so demonstrated that the i nci dence of
endometr i al cancer, vagi nal bl eedi ng and di schar ge, cer ebr ovascul ar
events, venous thr omboembol i c events, and hot fl ashes occur r ed
si gni fi cantl y l ess fr equentl y wi th anastr ozol e, wher eas
muscul oskel etal di sor der s and fractur es occur r ed l ess fr equentl y
wi th tamoxi fen. As a r esul t of the ATAC tr i al , anastr ozol e i s now the
pr efer r ed hor mone therapy for postmenopausal pati ents wi th

r eceptor-posi ti ve br east cancer.


For pati ents al r eady taki ng tamoxi fen, r ecent studi es have
exami ned the r ol e of swi tchi ng fr om tamoxi fen to the ar omatase
i nhi bi tor exemestane after 2 to 3 year s of tamoxi fen or the
ar omatase i nhi bi tor, and l etr ozol e after 5 year s of tamoxi fen. Both
tr i al s demonstrated that swi tchi ng to the ar omatase i nhi bi tor s
i ncr eased the di sease-fr ee sur vi val rate. It i s uncl ear when an
ar omatase i nhi bi tor shoul d be i ni ti ated, and ongoi ng tr i al s ar e
compar i ng the ti mi ng and sequence of tamoxi fen and ar omatase
i nhi bi tor s.
Ther e i s no r ol e for ar omatase i nhi bi tor s i n pr emenopausal women,
and tamoxi fen r emai ns the gol d standar d for these pati ents.
Ongoi ng tr i al s ar e exami ni ng the useful ness of ovar i an abl ati on i n
addi ti on to tamoxi fen i n pr emenopausal pati ents, but ther e i s
cur r entl y no data to suppor t the r outi ne use of ovar i an abl ati on
outsi de of a cl i ni cal tr i al .

Systemic Neoadjuvant Therapy


The use of neoadjuvant chemotherapy has i ts or i gi ns i n the
management of i noperabl e l ocal l y advanced br east cancer. F ur ther
rati onal e for usi ng neoadjuvant therapy i ncl udes the potenti al to
downsi ze tumor s and subsequentl y be abl e to offer mor e pati ents
BCT, the abi l i ty to assess the i n vi vo r esponse to chemotherapeuti c
agents, and the theor eti cal ear l y tr eatment of di stant
mi cr ometastati c di sease. The di sadvantages of usi ng neoadjuvant
chemotherapy i ncl ude the possi bl e del ay of curati ve sur ger y,
psychosoci al factor s, subopti mal cl i ni cal and radi ol ogi c assessment
of the pr i mar y tumor, and the potenti al l oss of pr ognosti c
i nfor mati on.
The NSABP B-18 tr i al demonstrated that neoadjuvant chemotherapy
for operabl e pr i mar y br east cancer al l owed mor e pati ents to
successful l y under go br east conser vati on sur ger y and cor r el ated
cl i ni cal and pathol ogi cal r esponse to pr ognosi s.
However, i t al so demonstrated that ther e was no sur vi val advantage
wi th neoadjuvant chemotherapy over standar d adjuvant
chemotherapy. Ther efor e, i f the pati ent's pr i mar y tumor si ze at
i ni ti al pr esentati on pr ecl udes a good br east conser vati on outcome,
but the pr i mar y tumor has the potenti al to be downsi zed by
neoadjuvant chemotherapy and the woman desi r es br east
conser vati on sur ger y rather than mastectomy, neoadjuvant

chemotherapy shoul d be offer ed. Ther e i s sti l l potenti al for a hi gher


r i sk of r ecur r ence wi th conser vati ve sur ger y than wi th mastectomy,
r egar dl ess of whether neoadjuvant or adjuvant therapy i s used, and
thi s r i sk shoul d be di scussed wi th the pati ent.
The effect of di ffer ent chemotherapy r egi mens on tumor r esponse
can best be measur ed i n the neoadjvuant setti ng because thi s may
cor r el ate to pr ognosi s and to conti nued i mpr ovement of br eastconser vi ng sur ger y rates. The r esul ts fr om NSABP B-27 cl ear l y
demonstrated that four cycl es of AC pr eoperati vel y or four cycl es of
AC fol l owed by sur ger y wi th four cycl es of docetaxel postoperati vel y
was not as effi caci ous i n obtai ni ng a cl i ni cal or pathol ogi cal
compl ete r esponse as both four cycl es of AC fol l owed by four cycl es
of docetaxel i n the neoadjuvant setti ng. The addi ti on of docetaxel to
AC i ncr eased the cl i ni cal compl ete r esponse rate by 50% and near l y
doubl ed the pathol ogi cal compl ete r esponse rate compar ed wi th AC
al one.
At MDACC, the use of FAC or pacl i taxel i n the neoadjuvant setti ng
was eval uated. Pati ents wer e randoml y assi gned to r ecei ve
neoadjuvant FAC or pacl i taxel and then have l ocal therapy fol l owed
by addi ti onal FAC, XRT, (wi th or wi thout tamoxi fen) i f they wer e
postmenopausal and had r eceptor-posi ti ve tumor s. At 4 year s, the
di sease-fr ee sur vi val rate was not si gni fi cantl y di ffer ent between
the FAC and pacl i taxel gr oups (83% vs. 86% ), but the pathol ogi cal
compl ete r esponse rate was si gni fi cantl y better i n the FAC gr oup
(16.4% vs. 8.1% ).
Another tr i al exami ni ng a di ffer ent neoadjuvant chemotherapy
r egi men was the Aber deen tr i al . In thi s tr i al , the pati ents r ecei ved
four doses of CVAP (cycl ophosphami de, vi ncr i sti ne, doxor ubi ci n, and
pr edni sone) and then wer e exami ned for a cl i ni cal r esponse. Those
wi thout a compl ete r esponse went on to r ecei ve four doses of
docetaxel , and those wi th a compl ete r esponse wer e randoml y
assi gned to r ecei ve four mor e doses of CVAP or four cycl es of non
cr oss-r esi stant chemotherapy docetaxel . Thi s study demonstrated
the rate of br east-conser vi ng sur ger y was i mpr oved for those who
r ecei ved the noncr oss-r esi stant docetaxel (CVAP fol l owed by
docetaxel ) (67% ) compar ed wi th those who r ecei ved CVAP fol l owed
by mor e CVAP (48% ).
F i nal l y, the use of neoadjuvant chemotherapy pr ovi des r esear cher s
wi th oppor tuni ti es to i mpr ove chemotherapy use and pati ent
outcomes based on tumor r esponse. Newer techni ques such as
mi cr oar ray gene pr ofi l i ng ar e bei ng used to devel op a method of

cl assi fyi ng gene pr ofi l es associ ated wi th par ti cul ar tumor s that may
cor r el ate wi th pathol ogi cal compl ete r esponse. These data may
eventual l y i denti fy whi ch pati ents wi l l benefi t fr om a par ti cul ar
r egi men or whi ch pati ents can be spar ed systemi c therapy.

Trastuzumab
Trastuz umab (Her cepti n) i s a monocl onal anti body that tar gets the
HER-2/neu oncogene, whi ch codes for a gr owth factor that i s
over expr essed i n 25% to 30% of br east cancer s. The anti body wor ks
by bi ndi ng to the HER-2 gr owth factor r eceptor s pr esent on the
sur face of the cancer cel l s and ther eby downr egul ates the r eceptor s.
The effects of trastuz umab ar e r estr i cted to pati ents wi th HER2/neu-over expr essi ng tumor s. Trastuz umab i s effecti ve as a si ngl e
agent, but i t acts syner gi sti cal l y wi th numer ous chemotherapeuti c
agents, i ncl udi ng taxanes and vi nor el bi ne. For thi s r eason,
trastuz umab pl us chemotherapy i s the standar d of car e for pati ents
wi th HER-2/neu-ampl i fi ed, metastati c tumor s. Trastuz umab i s now
bei ng eval uated i n ear l i er-stage br east cancer.
In the neoadjuvant setti ng, trastuz umab pl us nonanthracycl i necontai ni ng chemotherapy has been shown i n var i ous smal l tr i al s to
i nduce a compl ete pathol ogi cal r esponse i n 19% to 35% of pati ents.
One of four ongoi ng tr i al s cur r entl y l ooki ng at the effecti veness of
an adjuvant r egi men contai ni ng trastuz umab pl us chemotherapy,
NSABP B-31 i s exami ni ng the use of doxor ubi ci n and
cycl ophosphami de fol l owed by pacl i taxel wi th or wi thout
trastuz umab. Resear cher s at MDACC exami ned the effi cacy of
neoadjuvant trastuz umab pl us pacl i taxel and F EC i n tr eati ng
operabl e HER-2/neu-posi ti ve br east cancer s and compar ed these
pati ents wi th pati ents who r ecei ved onl y pacl i taxel and F EC. The
r esul ts demonstrated that trastuz umab-based neoadjuvant therapy
r esul ted i n a si gni fi cantl y hi gher pathol ogi cal compl ete r esponse
rate. Because ther e have been r epor ts of congesti ve hear t fai l ur e i n
pati ents tr eated wi th trastuz umab, neoadjuvant or adjuvant
trastuz umab shoul d be used onl y i n the setti ng of cl i ni cal tr i al s unti l
the l ong-ter m car di ac safety data ar e known.

Surgical Considerations after Neoadjuvant


Chemotherapy
Ther e ar e numer ous factor s to consi der befor e usi ng neoadjuvant
chemotherapy to tr eat br east cancer. (a) Wi l l admi ni ster i ng

neoadjuvant chemotherapy conver t an other wi se l ar ge tumor


r equi r i ng mastectomy i nto one manageabl e by BCT? If not, then
neoadjuvant chemotherapy may not be desi rabl e because a
mastectomy wi l l need to be per for med ei ther way, and much of the
i nfor mati on (e.g., tumor si ze and l ymph node i nvol vement wi th
metastases) useful i n deter mi ni ng whether ther e i s a r ol e for
fur ther tr eatment wi th radi ati on may be l ost. (b) The tumor i n the
br east must be car eful l y l ocal i zed wi th a cl i p or per manent mar ker
befor e chemotherapy to ensur e pr oper l ocal i z ati on of the tumor
dur i ng sur ger y i n the event that the chemotherapy pr oduces a
compl ete cl i ni cal r esponse. (c) How much ti ssue shoul d be r emoved
dur i ng sur ger y after chemotherapy i s compl eted? The answer i s
debatabl e, but general l y al l gr oss di sease pl us any other suspi ci ous
ar eas wi th a r i m of nor mal -appear i ng ti ssue shoul d be r emoved. (d)
How shoul d the nodal basi n after neoadjuvant chemotherapy be
managed? One opti on i s to scr een the axi l l a befor e chemotherapy
wi th ul trasound or SLN bi opsy. If ther e ar e
ei ther cl i ni cal l y suspi ci ous nodes or nodes that appear to har bor
di sease, SLN bi opsy or ul trasound-gui ded F NA of the nodes i n
questi on coul d be per for med befor e the star t of chemotherapy to
confi r m metastases. If the r esul t of the bi opsy i s posi ti ve, then a
for mal ALND shoul d be per for med dur i ng defi ni ti ve sur ger y. A
negati ve ul trasound-gui ded F NA or SLN bi opsy r esul t pr oduces mor e
of a di l emma. In thi s si tuati on, whether to per for m SLN bi opsy or
ALND after chemotherapy i s uncl ear and i s cur r entl y bei ng
i nvesti gated by the Amer i can Col l ege of Sur geons Oncol ogy G r oup.
At MDACC, oncol ogi sts r outi nel y per for m SLN bi opsy after
neoadjuvant chemotherapy dur i ng defi ni ti ve sur ger y i f the pati ents
wer e cl i ni cal l y node negati ve by physi cal and ul trasound
exami nati ons pr i or to i ni ti ati ng chemotherapy.

Follow-Up After Primary Treatment of


Invasive Breast Cancer
After pr i mar y therapy for i nvasi ve br east cancer, pati ents must be
made awar e of the l ong-ter m r i sk for r ecur r ent or metastati c
di sease. Al though most studi es r epor t that r ecur r ences occur wi thi n
5 year s after pr i mar y therapy, r ecur r ences can occur mor e than 20
year s after pr i mar y therapy.
The publ i shed Amer i can Soci ety of Cl i ni cal Oncol ogy gui del i nes for
fol l ow-up i ndi cate that ther e i s no sur vi val advantage to r outi ne
l aborator y and radi ographi c studi es because ear l y detecti on of

metastati c di sease rar el y affects the overal l sur vi val rate. Instead,
pati ents shoul d meet wi th thei r doctor s for di scussi on of new
symptoms, physi cal exams, and year l y mammograms. Schedul ed
fol l ow-up vi si ts shoul d be under taken ever y 4 months for year s 1
and 2, ever y 6 months for year s 3 thr ough 5, and ever y 12 months
ther eafter. Monthl y sel f-exami nati on of the br easts i s al so
r ecommended. Mammography i s done 6 months after the compl eti on
of BCT to al l ow sur ger y- and radi ati on-i nduced changes to stabi l i ze,
and then year l y. For pati ents who have under gone mastectomy, a
contral ateral mammogram i s obtai ned year l y. Routi ne bone scans,
skel etal sur veys, and computed tomographi c scans of the abdomen
and brai n yi el d an extr emel y l ow rate of occul t metastases i n
other wi se asymptomati c pati ents and i s not cost-effecti ve for
pati ents wi th ear l y-stage br east cancer.

Locally Recurrent Breast Cancer


The ti me cour se, cl i ni cal si gni fi cance, and pr ognosi s of l ocal l y
r ecur r ent br east cancer var y dramati cal l y between pati ents
under goi ng BCT and those under goi ng mastectomy. Local r ecur r ence
rates of 5% to 10% at 8 to 10 year s have been r epor ted for
pati ents wi th conser ved br easts. Local r ecur r ence typi cal l y occur s
over a pr otracted ti me and i s associ ated wi th systemi c metastases i n
l ess than 10% of pati ents. Local r ecur r ence fol l owi ng l umpectomy i s
curabl e i n most cases; 50% to 63% of pati ents wi th l ocal r ecur r ence
wi l l r emai n di sease-fr ee 5 year s after sal vage mastectomy.
In contrast, l ocal chest wal l r ecur r ence fol l owi ng mastectomy
typi cal l y occur s wi thi n the fi r st 2 to 3 year s after sur ger y. It i s
associ ated wi th di stant metastases i n as many as two thi r ds of
pati ents and r esul ts i n eventual death for many. One thi r d of
pati ents wi th chest wal l r ecur r ence wi l l have concur r ent di stant
metastati c di sease, and wi thi n 1 year, hal f wi l l have di stant di sease.
The medi an sur vi val i n thi s setti ng i s 2 to 3 year s.
Al though uncl ear, pati ents wi th an appar entl y i sol ated l ocal
r ecur r ence after BCT can often be tr eated wi thout systemi c
cytotoxi c chemotherapy dependi ng on the stage at pr esentati on.
Any pati ent wi th a l ocal r ecur r ence, especi al l y chest wal l
r ecur r ences after mastectomy, shoul d under go compl ete r estagi ng
after detecti on of the r ecur r ence. For pati ents wi th a pur el y l ocal
r ecur r ence, sur gi cal exci si on pl us radi ati on therapy pr ovi des better
l ocal contr ol than does ei ther modal i ty al one.

Metastatic Breast Cancer


Metastati c br east cancer general l y cannot be cur ed, and tr eatment
i s mai nl y pal l i ati ve. The medi an sur vi val after detecti on of di stant
metastases i s 2 year s, but some pati ents l i ve for many year s. Other
than trastuz umab-based chemotherapy, chemotherapy rar el y
pr ol ongs sur vi val and i s di r ected at i mpr ovi ng tumor-r el ated
symptoms and sl owi ng the spr ead of the tumor. The most common
si te of di stant metastati c spr ead i s the osseous skel eton; other
common si tes ar e the soft ti ssues, l ymph nodes, l ungs, pl eura, and
l i ver. Cer tai n subtypes of br east cancer pr esent di ffer ent patter ns of
metastases. For exampl e, pati ents wi th rapi dl y gr owi ng, hor mone
r eceptor-negati ve, and poor l y di ffer enti ated tumor s ar e l i kel y to
have metastases to vi sceral or gans (e.g., l i ver, l ungs, brai n),
wher eas pati ents wi th sl owl y gr owi ng, hor mone r eceptor-posi ti ve,
and wel l -di ffer enti ated tumor s ar e l i kel y to devel op metastases to
bone and soft ti ssues and ar e l ess l i kel y to exhi bi t ear l y l i fethr eateni ng mani festati ons.
For pati ents wi th metastases, the deci si on to tr eat wi th systemi c
chemotherapy or hor monal therapy r ests on several i ssues: the si te
and extent of the di sease, hor mone r eceptor status, di sease-fr ee
i nter val , age, and menopausal status. Pati ents wi th sl owl y gr owi ng,
l i mi ted, and nonl i fe-thr eateni ng metastati c di sease and hor mone
r eceptor-posi ti ve or known hor mone-r esponsi ve tumor s ar e
general l y offer ed hor monal therapy as the fi r st therapeuti c
modal i ty. Because al l hor monal mani pul ati ons used today have a
better therapeuti c rati o than do cytotoxi c therapi es, the practi cal
r esul t of sequenti al hor monal therapi es i s that pati ents can be
acti vel y tr eated wi th few systemi c si de effects. When hor monal
therapy i s no l onger effecti ve, these pati ents pr oceed to
chemotherapy. For pati ents wi th mor e extensi ve (i .e., symptomati c)
or l i fe-thr eateni ng di sease and for al l pati ents wi th hor mone
r eceptor-negati ve br east cancer, combi nati on chemotherapy i s the
fi r st tr eatment of choi ce. Anthracycl i nes (e.g., doxor ubi ci n) and
taxanes (e.g., pacl i taxel , docetaxel ) ar e cur r entl y the most effecti ve
anti tumor agents agai nst metastati c br east cancer.
The choi ce of i ni ti al chemotherapy depends on the pati ent's age,
per for mance status, pr i or neoadjuvant and adjuvant chemotherapy,
and di sease-fr ee i nter val . Anthracycl i nes or taxanes ar e opti ons, as
ar e capeci tabi ne, vi nor el bi ne, and gemci tabi ne. Because metastati c
br east cancer i s i ncurabl e wi th standar d therapi es, enr ol l ment i n
cl i ni cal tr i al s i s al ways encouraged. Tar geted agents agai nst
epi der mal gr owth factor r eceptor, vascul ar endothel i al gr owth factor,

and other tumor-r el ated pr otei ns ar e acti vel y


under i nvesti gati on. Trastuz umab-based chemotherapy i s the
standar d of car e for those wi th HER-2/neu-ampl i fi ed tumor s;
however, for al l other pati ents, combi nati on chemotherapy has not
been shown to pr ol ong sur vi val over sequenti al si ngl e agents, and i t
i s associ ated wi th mor e i ntense si de effects. Thus, outsi de of a
cl i ni cal tr i al , pati ents wi th metastati c br east cancer ar e typi cal l y
tr eated wi th sequenti al si ngl e agents.

Breast Cancer and Pregnancy


The i nci dence of br east cancer, whi ch accounts for 2.8% of br east
mal i gnanci es, detected dur i ng pr egnancy i s 2 per 10,000 gestati ons.
The di agnosi s of br east cancer i s typi cal l y mor e di ffi cul t i n a
pr egnant woman because of a l ow l evel of suspi ci on based on a
general l y young pati ent age, the r el ati ve fr equency of nodul ar
changes i n the br east dur i ng pr egnancy, and the i ncr ease i n br east
densi ty dur i ng pr egnancy that r ender s mammographi c i magi ng l ess
accurate. For these and other r easons, di agnosi s of br east cancer
dur i ng pr egnancy i s fr equentl y del ayed. Thi s del ay, rather than
speci fi c di ffer ences i n the bi ol ogy of br east cancer between
pr egnant and nonpr egnant women, l i kel y expl ai ns the r el ati vel y
poor pr ognosi s for women wi th br east cancer detected dur i ng
pr egnancy. When matched for tumor stage, pr egnant women wi th
br east cancer appear to have a si mi l ar pr ognosi s as nonpr egnant
pati ents wi th br east cancer.
Because the accuracy of mammography i s l i mi ted i n thi s setti ng, al l
per si stent and suspi ci ous br east masses di scover ed dur i ng
pr egnancy shoul d under go eval uati on by F NA, cor e-needl e bi opsy, or
exci si onal bi opsy pl us an ul trasound exami nati on. Exci si onal bi opsy
under l ocal anesthesi a i s safe at any ti me dur i ng pr egnancy.
Inci si onal bi opsy i s not r ecommended for di agnosi s because of the
possi bi l i ty of the pati ents devel opi ng a fi stul a. Al though
contr over si al , when cancer i s di agnosed, mammography can sti l l be
per for med i n the gravi d femal e when the fetus i s shi el ded
adequatel y. Once a di agnosi s of mal i gnancy i s establ i shed,
tr eatment deci si ons ar e i nfl uenced by the speci fi c tr i mester of
pr egnancy. For women who want to compl ete thei r pr egnanci es, the
goal shoul d be curati ve tr eatment of the br east cancer wi thout
i njur y to the fetus. Ter mi nati on of pr egnancy i n the hope of
mi ni mi z i ng hor monal sti mul ati on of the tumor does not al ter
mater nal sur vi val and i s not r ecommended.

Sur gi cal tr eatment of gestati onal br east cancer i s general l y


i denti cal to that of nongestati onal br east cancer. Ther e i s no
evi dence that extra-abdomi nal sur gi cal pr ocedur es ar e associ ated
wi th pr ematur e l abor or that the typi cal l y used anestheti c agents
ar e teratogeni c. Modi fi ed radi cal mastectomy as pr i mar y therapy can
be under taken at any poi nt dur i ng pr egnancy wi thout undue r i sk to
the mother or fetus. For cancer detected dur i ng the thi r d tr i mester,
del ayi ng pr i mar y tr eatment for up to 4 weeks to al l ow for del i ver y
befor e sur ger y i s acceptabl e. If modi fi ed radi cal mastectomy i s
under taken dur i ng pr egnancy, br east r econstr ucti on shoul d not be
per for med si mul taneousl y; a symmetr i c r esul t i s i mpossi bl e unti l
the postpar tum appearance of the contral ateral br east i s known.
For women desi r i ng br east conser vati on, tr eatment i s compl i cated
by the fact that radi ati on therapy i s contrai ndi cated
dur i ng pr egnancy. For cancer s detected dur i ng the thi r d tr i mester,
l umpectomy and axi l l ar y di ssecti on can be per for med safel y usi ng
general anesthesi a, and radi ati on therapy can be del ayed unti l after
del i ver y. Longer del ays may be detr i mental to mater nal outcome,
al though the ti me l i mi t wi thi n whi ch radi ati on therapy must be
car r i ed out to mi ni mi ze the r i sk of l ocal r ecur r ence i s unknown.
It may be necessar y to admi ni ster cytotoxi c adjuvant chemotherapy
dur i ng pr egnancy, whi ch may rai se fear s of congeni tal
mal for mati ons. Most studi es have demonstrated no i ncr eased r i sk of
fetal mal for mati on associ ated wi th chemotherapy admi ni ster ed
dur i ng the second and thi r d tr i mester s. In contrast, chemotherapy
admi ni strati on dur i ng the fi r st tr i mester i s associ ated wi th an
i ncr eased i nci dence of spontaneous abor ti on and congeni tal
mal for mati on, especi al l y when methotr exate i s used.

Cystosarcoma Phyllodes
Cystosar coma phyl l odes r epr esents an uncommon fi br oepi thel i al
br east neopl asm and accounts for onl y 0.5% to 1% of br east
car ci nomas. These tumor s can occur i n women of al l ages, i ncl udi ng
adol escents and the el der l y, but most ar i se i n women between 35
and 55 year s of age. Cystosar coma phyl l odes ar e typi cal l y qui te
l ar ge and have a mean di ameter of 4 to 5 cm. Because phyl l odes
tumor s and fi br oadenomas ar e mammographi cal l y i ndi sti ngui shabl e,
the deci si on to per for m exci si onal bi opsy i s usual l y based on l ar ge
tumor si ze, a hi stor y of rapi d gr owth, and pati ent age. Pr edi cti ng
the behavi or of these tumor s on the basi s of hi stopathol ogi cal

featur es such as hi sti otype (beni gn vs. i ndeter mi nate vs.


mal i gnant), mar gi n status, str omal over gr owth, and si ze has been
di ffi cul t par tl y because of thei r rar i ty. Common si tes of metastases
fr om mal i gnant cystosar coma phyl l odes ar e l ung, bone, and
medi asti num.
Appr opr i ate tr eatment for phyl l odes tumor s i s compl ete sur gi cal
exci si on. Br east conser vati on sur ger y wi th appr opr i ate mar gi ns i s
the pr efer r ed pr i mar y therapy. The i nci dence of l ocal r ecur r ence
ranges fr om 5% to 15% for beni gn tumor s and 20% to 30% for
mal i gnant tumor s. Local r ecur r ences ar e typi cal l y sal vageabl e wi th
total mastectomy and do not affect the overal l sur vi val rate. For al l
phyl l odes tumor s, the l ow i nci dence of axi l l ar y nodal metastases
(l ess than 1% ) obvi ates l ymphadenectomy. The r epor ted rates of
di stant metastasi s for pati ents wi th mal i gnant tumor s range fr om
25% to 40% . The pr esence of str omal over gr owth may be the
str ongest pr edi ctor of di stant metastasi s and ul ti mate outcome. To
date, no r ol e for radi ati on therapy, chemotherapy, or hor monal
therapy has been establ i shed for thi s di sease.

Recommended Reading
Anonymous. Amer i can Joi nt Commi ttee on Cancer (AJCC). AJCC
Cancer Staging Manual. 6th ed. 2002. Spr i nger-Ver l ag publ i sher s.
Anonymous. Pol ychemotherapy for ear l y br east cancer : an
over vi ew of the randomi zed tr i al s. Ear l y Br east Cancer Tr i al i sts
Col l aborati ve G r oup. Lancet 1998;352:930.
Anonymous. Tamoxi fen for ear l y br east cancer : an over vi ew of
the randomi zed tr i al s. Ear l y Br east Cancer Tr i al i sts Col l aborati ve
G r oup. Lancet 1998;351:1451.

Bar navon Y, Wal l ack MK. Management of the pr egnant pati ent
wi th car ci noma of the br east. Sur g G ynecol Obstet
1990;171:347.
Baum M, Buzdar A, Cuz i ck J, et al . The ATAC (Ar i mi dex,
Tamoxi fen Al one or i n Combi nati on) Tr i al i sts G r oup. Anastr ozol e
al one or i n combi nati on wi th tamoxi fen ver sus tamoxi fen al one
for adjuvant tr eatment of postmenopausal women wi th ear l y-

stage br east cancer : r esul ts of the ATAC (Ar i mi dex, tamoxi fen
al one or i n combi nati on) tr i al effi cacy and safety update
anal yses. Cancer 2003;98:1802.
Braun S, Pantel K, Mul l er P, et al . Cytokerati n-posi ti ve cel l s i n
the bone mar r ow and sur vi val of pati ents wi th stage I, II, or III
br east cancer. N Engl J Med 2000;342:525.
Cady B. A contemporar y vi ew of axi l l ar y di ssecti on. Br east Dis
Year Book Q 2001;12:22.
Chaney AW, Pol l ack A, McNeese MD, et al . Pr i mar y tr eatment of
cystosar coma phyl l odes of the br east. Cancer 2000;89:1502.
F i sher B, Ander son S, Redmond CK, et al . Reanal ysi s and r esul ts
after 12 year s of fol l ow-up i n a randomi zed cl i ni cal tr i al
compar i ng total mastectomy wi th l umpectomy wi th or wi thout
i r radi ati on i n the tr eatment of br east cancer. N Engl J Med
1995;333:1456.
F i sher B, Br yant J, Wol mar k N, et al . Effect of pr eoperati ve
chemotherapy on the outcome of women wi th operabl e br east
cancer. J Clin Oncol 1998;16:2672.
F i sher B, Redmond C, F i sher ER, et al . Ten-year r esul ts of a
randomi zed cl i ni cal tr i al compar i ng radi cal mastectomy and total
mastectomy wi th or wi thout radi ati on. N Engl J Med
1985;312:674.
G i ul i ano AE. Senti nel l ymph node di ssecti on i n br east cancer.
Pr oc Am Soc Clin Oncol 2001;530.
G r eco M, Agr esti R, Casci nel l i N, et al . Br east cancer pati ents
tr eated wi thout axi l l ar y sur ger y: cl i ni cal i mpl i cati ons and bi ol ogi c
anal ysi s. Ann Sur g 2000;232:1.
G r odstei n F, Mei r S, G raham C, et al . Postmenopausal hor mone
therapy and mor tal i ty. N Engl J Med 1997;336:1769.
Har r i s JR, Li ppman ME, Ver onesi U, et al . Br east cancer. N Engl J

Med 1992;327:319, 390, 473.


Hender son IC. Ri sk factor s for br east cancer devel opment. Cancer
1993;71(suppl 6):2128.
Hor tobagyi G N. Tr eatment of br east cancer. N Engl J Med
1998;339:974.
Jemal A, Ti war i RC, Mur ray T, et al . Cancer Stati sti cs 2004. CA:
Cancer J Clin 2004;54:8.
Kei sch M, Vi ci ni F, Kuske RR, et al . Ini ti al cl i ni cal exper i ence wi th
the MammoSi te br east brachytherapy appl i cator i n women wi th
ear l y-stage br east cancer tr eated wi th br east-conser vi ng therapy.
Int J Radiat Oncol Biol Phys 2003;55:289.
Khanna MM, Mar k RJ, Si l ver stei n MJ, et al . Br east conser vati on
management of br east tumor s 4 cm or l ar ger. Ar ch Sur g
1992;9:1038.
Krag D, Weaver D, Ashi kaga T, et al . The senti nel node i n br east
cancer : a mul ti center val i dati on study. N Engl J Med
1998;339:941.
Kuer er HM, Hunt KK, Newman LA, et al . Neoadjuvant
chemotherapy i n women wi th i nvasi ve br east car ci noma:
conceptual basi s and fundamental sur gi cal i ssues. J Am Coll Sur g
2000;190:350.
McG ui r e WL, Cl ar k G M. Pr ognosti c factor s and tr eatment deci si ons
i n axi l l ar y node-negati ve br east cancer. N Engl J Med
1992;326:1756.
Mor r ow M, Har r i s JR, Schni tt SJ. Local contr ol fol l owi ng br eastconser vi ng sur ger y for i nvasi ve cancer : r esul ts of cl i ni cal tr i al s. J
Natl Cancer Inst 1995;87:1669.
Over gaar d M, Hansen PS, Over gaar d J, et al . Postoperati ve
radi otherapy i n hi gh-r i sk pr emenopausal women wi th br east
cancer who r ecei ve adjuvant chemotherapy. Dani sh Br east Cancer

Cooperati ve G r oup 82b Tr i al . N Engl J Med 1997;337:949.

Si ngl etar y SE. Rati ng the r i sk factor s for br east cancer. Ann Sur g
2003;237:474.
Si ngl etar y SE. Systemi c tr eatment after senti nel l ymph node
bi opsy i n br east cancer : who, what, and why? J Am Coll Sur g
2001;192:220.
SEER cancer r egi str y database. www.seer.cancer.gov
Sonnenschei n E, Toni ol o P, Ter r y MB, et al . Body fat di str i buti on
and obesi ty i n pr e- and postmenopausal br east cancer. Int J
Epidemiol 1999;28:1026.
Star en ED, Omer S. Hor mone r epl acement therapy i n
postmenopausal women. Am J Sur g 2004;188:136.

Editors: Feig, Barry W .; Berger, David H.; Fuhrman, George


M.
Title: MD A nderson Surgical Oncology Handbook, The, 4th
Edition
Copyr i ght 2006 Li ppi ncott Wi l l i ams & Wi l ki ns
> Ta ble o f C o nt e nt s > 3 - M e la no m a

3
Melanoma
Timothy M. Paw lik
Jeffrey E. Gershenw ald

Epidemiology
The i nci dence of i nvasi ve cutaneous mel anoma i n the Uni ted States
has been r i si ng by an average of 3% per year. An esti mated 68,780
cases of i nvasi ve mel anoma wi l l be di agnosed i n the Uni ted States
i n 2006. For Amer i cans, the cur r ent esti mated l i feti me r i sk of
devel opi ng mel anoma i s 1 i n 74; an esti mated 10,710 peopl e wi l l
di e of mel anoma i n 2006. The i nci dence of mel anoma has been
i ncr easi ng faster than that of any other cancer. The major
envi r onmental r i sk factor, exposur e to ul travi ol et B (UV-B)
radi ati on, i s r efl ected i n geographi c and ethni c patter ns of
mel anoma rates. Al though ther e i s some evi dence that the i ncr ease
i n mel anoma i nci dence has abated ver y r ecentl ypossi bl y as a
r esul t of i ncr eased ear l y detecti on, changes i n r ecr eati onal
behavi or, and i ncr eased sun pr otecti oni t i s uncl ear when the
mel anoma epi demi c wi l l peak and how geographi c patter ns wi l l
change over ti me. Ther e have been changes i n the di str i buti on and
stage of mel anoma at di agnosi s, wi th an i ncr ease i n thi nner l esi ons.
At pr esent, many mel anomas seen at many i nsti tuti ons ar e l ess
than 1 mm thi ck.

Risk Factors
Identi fyi ng r i sk factor s and esti mati ng an i ndi vi dual 's r i sk of
devel opi ng mel anoma ar e i mpor tant. Strati fyi ng pati ents by r i sk can
be cl i ni cal l y useful i n deter mi ni ng pr i mar y pr eventi on strategi es and
i n di r ecti ng the l evel of scr eeni ng. Pati ents i denti fi ed as bei ng at
hi gh r i sk for mel anoma shoul d be r ecr ui ted to pr eventi on tr i al s.

Mul ti pl e factor s can pl ace a pati ent at r i sk for devel opi ng


mel anoma:
1. Skin type: Peopl e wi th a whi te raci al backgr ound have at l east
ten ti mes the mel anoma i nci dence of Afr i can Amer i cans and
seven ti mes the mel anoma i nci dence of Amer i can Hi spani cs. In
addi ti on, whi te pati ents who ar e fai r or who have r ed hai r, l i ght
ski n, or bl ue eyes have a par ti cul ar pr opensi ty to be at
i ncr eased r i sk for mel anoma.
2. Age: The i nci dence of mel anoma i ncr eases wi th age. Data have
shown that the i nci dence of mel anoma i s si mi l ar i n women and
men younger than 50 year s and hi gher i n men than i n women
ol der than 50 year s.
3. G ender : In general , the i nci dence of mel anoma i s hi gher i n men
than i n women. Speci fi cal l y, a man's r i sk of mel anoma
devel opment over hi s l i feti me i s 1.7 ti mes a woman's r i sk.
4. Tanning bed use: The use of a tanni ng bed mor e than ten ti mes
per year i s associ ated wi th a doubl i ng i n the r i sk of mel anoma
for pati ents age 30 year s or ol der. Young pati ents who use
tanni ng booths mor e than ten ti mes per year have
mor e than seven ti mes the mel anoma r i sk of pati ents who do not
use tanni ng booths.
5. Pr evious melanoma: The r i sk of devel opi ng a second mel anoma
i n a pati ent who has had a mel anoma i s 3% to 7% ; thi s r i sk i s
mor e than 900 ti mes that of the general popul ati on.
6. Sunlight exposur e: Occasi onal or r ecr eati onal exposur e to
sunl i ght, especi al l y a hi stor y of sever e bl i ster i ng sunbur n, has
been associ ated wi th i ncr eased r i sk of mel anoma. Ther e i s a
cor r el ati on between the number of sever e and pai nful sunbur n
epi sodes and the r i sk of mel anoma; pati ents who have a hi stor y
of ten or mor e sever e sunbur ns ar e mor e than twi ce as l i kel y to
devel op a mel anoma compar ed wi th pati ents who have no hi stor y
of sunbur ns. It i s i mpor tant to note that even sunbur ns after the
age of 20 year s may be associ ated wi th an i ncr eased r i sk of
mel anoma. The effects of sunl i ght have been attr i buted to
exposur e to UV-B radi ati on, whi ch, accor di ng to hypotheti cal
mechani sms of mel anoma i nducti on, may account for
appr oxi matel y two-thi r ds of mel anomas.
7. Benign nevi: Al though a beni gn nevus i s most l i kel y not a

pr ecur sor of mel anoma, the pr esence of l ar ge number s of nevi


has been consi stentl y associ ated wi th an i ncr eased r i sk of
mel anoma. Per sons wi th mor e than 50 nevi , al l of whi ch ar e
gr eater than 2 mm i n di ameter, have 5 to 17 ti mes the
mel anoma r i sk of per sons wi th fewer nevi .
8. F amily histor y: A fami l y hi stor y of mel anoma i ncr eases a
per son's r i sk of mel anoma by thr ee to ei ght ti mes. Per sons who
have two or mor e fami l y member s wi th mel anoma ar e at a
par ti cul ar l y hi gh r i sk for devel opi ng mel anoma.
9. G enetic pr edisposition: Speci fi c geneti c al terati ons have been
i mpl i cated i n the pathogenesi s of mel anoma. At l east four
di sti nct genesl ocated on chr omosomes 1p, 6q, 7, and 9may
pl ay a r ol e i n mel anoma. A tumor suppr essor gene l ocated on
chr omosome 9p21 i s pr obabl y i nvol ved i n fami l i al and sporadi c
cutaneous mel anoma. Del eti ons or r ear rangements of
chr omosomes 10 and 11 ar e al so wel l documented i n cutaneous
mel anoma. Mor e r ecentl y, geneti c r esear ch has i denti fi ed
speci fi c var i ants that confer suscepti bi l i ty to cutaneous
mal i gnant mel anoma. Var i ants outsi de the codi ng r egi on of the
CDKN2A gene ar e associ ated wi th mel anoma pr edi sposi ti on. A
mutati on i n the 5 untransl ated end of CDKN2A generates a
novel upstr eam i ni ti ati on codon that abr ogates expr essi on of
p16, whi ch i s necessar y for tumor suppr essi on.
Another geneti c al terati on that may pl ay a r ol e i s mutati on i n
the B-RAF gene. RAF pr otei ns ar e a fami l y of ser i ne/thr eoni nespeci fi c pr otei n ki nases that for m par t of a si gnal i ng modul e that
r egul ates cel l pr ol i ferati on, di ffer enti ati on, and sur vi val . In
mammal s, ther e ar e thr ee i sofor ms: A-RAF, B-RAF, and C-RAF.
Recentl y, i t was shown that the B-RAF i sofor m i s mutated i n a
hi gh pr opor ti on (60% 70% ) of mel anomas. The major i ty of the
mutati ons that have been found i n B-RAF ar e somati c changes
pr esumed to be i nduced by envi r onmental factor s. Most studi es
have concl uded that
B-RAF i s not a mel anoma pr edi sposi ti on gene. Rather, some
i nvesti gator s have pr oposed a model i n whi ch B-RAF pl ays a key
r ol e i n pr otecti ng agai nst pr ogr essi on i n the ear l y stages of the
di sease. One mutati on, a gl utami c-aci d-for-val i ne substi tuti on at
posi ti on 600 (V600E), accounts for mor e than 90% of the B-RAF
mutati ons i n mel anoma. Thi s mutati on causes acti vati on of
downstr eam effector s of the mi togen-acti vated pr otei n ki nasesi gnal i ng cascade, l eadi ng to mel anoma tumor pr ogr essi on by an

unknown mechani sm.

10. Atypical mole and melanoma syndr ome: Pr evi ousl y known as
dyspl asti c nevus syndr ome, atypi cal mol e and mel anoma
syndr ome i s character i zed by the pr esence of l ar ge number s of
atypi cal mol es (dyspl asti c nevi ) that r epr esent a di sti nct
cl i ni copathol ogi cal type of mel anocyti c l esi on. They can be
pr ecur sor s of mel anoma and/or mar ker s of i ncr eased mel anoma
r i sk. Al though the actual fr equency of an atypi cal mol e
pr ogr essi ng to mel anoma i s smal l , pati ents wi th atypi cal mol e
and mel anoma syndr ome shoul d be obser ved cl osel y, and fami l y
member s shoul d al so be scr eened.

Clinical Presentation
Cl i ni cal featur es of mel anoma i ncl ude var i egated col or, i r r egul ar
rai sed sur face, i r r egul ar per i meter, and sur face ul cerati on. A bi opsy
shoul d be per for med on any pi gmented l esi on that under goes a
change i n si ze, confi gurati on, or col or. The so-cal l ed ABCDEs of
ear l y di agnosi s ar e an easy mnemoni c devi ce to hel p physi ci ans and
l ayper sons r emember the ear l y si gns of mal i gnant mel anoma. A
denotes l esi on asymmetr y, B bor der i r r egul ar i ty, C col or var i egati on,
D di ameter gr eater than 6 mm, and E a l esi on that i s evol vi ng or
enl ar gi ng.
When a pati ent pr esents wi th a l esi on suggesti ve of mel anoma, a
thor ough physi cal exami nati on must be per for med, wi th par ti cul ar
emphasi s on the ski n, al l nodal basi ns, and subcutaneous ti ssues.
Chest radi ography and l i ver functi on studi es shoul d be per for med i f
i nvasi ve mel anoma i s confi r med. F ur ther eval uati on i s based on
pathol ogi cal fi ndi ngs. In general , we di scourage r outi ne extensi ve
eval uati on wi th computed tomography or posi tr on emi ssi on
tomography (PET) because thei r yi el d i n the absence of symptoms,
abnor mal l aborator y fi ndi ngs, or abnor mal fi ndi ngs on chest
radi ography i s ver y l ow i n pati ents wi th pr i mar y mel anoma.

Melanoma BIOPSY
The choi ce of bi opsy techni que var i es accor di ng to the anatomi cal
si te, si ze, and shape of the l esi on. Defi ni ti ve therapy must be
consi der ed i n choosi ng a bi opsy techni que. Ei ther an exci si onal
bi opsy or an i nci si onal bi opsy usi ng a scal pel or punch i s acceptabl e.
An exci si onal bi opsy al l ows the pathol ogi st to most accuratel y
deter mi ne the thi ckness of the l esi on. For exci si onal bi opsi es, a

nar r ow mar gi n of nor mal -appear i ng ski n (13 mm) i s taken wi th the
speci men. An el l i pti cal i nci si on i s used to faci l i tate cl osur e. The
bi opsy i nci si on shoul d be or i ented to faci l i tate l ater wi de l ocal
exci si on (e.g., l ongi tudi nal l y on extr emi ti es) and mi ni mi ze the need
for a ski n graft to pr ovi de wound cl osur e. We r eser ve punch bi opsy
for l esi ons that ar e l ar ge, ar e l ocated on anatomi cal ar eas wher e
maxi mum pr eser vati on of sur r oundi ng ski n i s
i mpor tant, or can be compl etel y exci sed wi th a 6-mm punch. Punch
bi opsi es shoul d be per for med at the most rai sed or dar kest ar ea of
the l esi on. F ul l -thi ckness bi opsy i nto the subcutaneous ti ssue must
be per for med to per mi t pr oper mi cr ostagi ng of the l esi on (see the T
Stagi ng secti on l ater i n thi s chapter ).
Shave bi opsi es ar e di scouraged i f a di agnosi s of mel anoma i s bei ng
consi der ed. F i ne-needl e aspi rati on bi opsy may be used to document
nodal and extranodal mel anoma metastases but shoul d not be used
to di agnose pr i mar y mel anomas. In general , we send al l pi gmented
l esi ons for per manent-secti on exami nati on and per for m defi ni ti ve
sur ger y at a l ater ti me.

Pathology
Al though the pathol ogi cal anal ysi s pr i mar i l y consi sts of mi cr oscopi c
exami nati on of hematoxyl i n-eosi nstai ned tumor, several
mel anocyti c cel l mar ker s may al so be useful i n confi r mi ng the
di agnosi s of mel anoma. Two anti bodi es wi del y used i n
i mmunohi stochemi cal eval uati ons ar e S-100 and HMB-45. S-100 i s
expr essed not onl y by mor e than 90% of mel anomas, but al so by
several other tumor s and some nor mal ti ssues, i ncl udi ng dendr i ti c
cel l s. In contrast, the monocl onal anti body HMB-45 i s r el ati vel y
speci fi c (yet not as sensi ti ve) for pr ol i ferati ve mel anocyti c cel l s and
mel anoma. It i s ther efor e an excel l ent confi r mator y stai n for
neopl asti c cel l s when the di agnosi s of mel anoma i s bei ng
consi der ed. Recentl y, anti -MART-1 stai ni ng has al so been shown to
be useful i n the di agnosi s of mel anoma.
The major types of mel anoma ar e as fol l ows:
1. Super ficial spr eading melanomas consti tute the major i ty of
mel anomas (appr oxi matel y 70% ) and general l y ar i se i n a pr eexi sti ng nevus.
2. Nodular melanomas ar e the second most common type (15%
30% ). Nodul ar mel anomas pr ogr ess to i nvasi veness mor e qui ckl y

than other types; however, when depth of the mel anoma i s


contr ol l ed for, nodul ar mel anomas ar e associ ated wi th the same
pr ognosi s as other l esi ons.
3. Lentigo maligna melanomas consti tute a smal l per centage of
mel anomas (4% 10% ). These l esi ons occur i n sun-exposed
ar eas and ar e r el ated to sun exposur e. Lenti go mal i gna
mel anomas ar e typi cal l y l ocated on the faces of ol der whi te
women. Many year s can el apse befor e a l enti go mal i gna
mel anoma becomes i nvasi ve. In general , l enti go mal i gna
mel anomas ar e l ar ge (>3 cm at di agnosi s), fl at l esi ons and ar e
uncommon i n i ndi vi dual s younger than 50 year s. Al though these
l esi ons have tradi ti onal l y been bel i eved to be l ess aggr essi ve,
the pr ognosi s of pati ents wi th l enti go mal i gna mel anoma
ul ti matel y depends on the depth of i nvasi on.
4. Acr al lentiginous melanomas occur on the pal ms (pal mar ), sol es
(pl antar ), or beneath the nai l beds (subungual ), al though not al l
pal mar, pl antar, and subungual mel anomas ar e acral l enti gi nous
mel anomas. These mel anomas account for onl y 2% to 8% of
mel anomas i n whi te pati ents but for a substanti al l y hi gher
pr opor ti on of mel anomas (35% 60% ) i n dar ker-ski nned
pati ents. They ar e often l ar ge, wi th an average di ameter of
appr oxi matel y 3 cm.
5. Amelanotic melanomas ar e mel anomas that occur wi thout
pi gmentati on changes. These l esi ons ar e uncommon and ar e
mor e di ffi cul t to di agnose because of thei r l ack of pi gmentati on.
Factor s such as change i n si ze, asymmetr y, and i r r egul ar bor der s
suggest mal i gnancy and shoul d pr ompt a bi opsy.

Staging
The mel anoma stagi ng system has been r evi sed numer ous ti mes as
under standi ng of the di sease has evol ved. In 2002, the Amer i can
Joi nt Commi ttee on Cancer (AJCC) publ i shed a r evi sed stagi ng
system for cutaneous mel anoma i n the si xth edi ti on of the AJCC
Cancer Staging Manual. The r evi si ons r efl ect the r esul ts of an
extensi ve sur vi val anal ysi s of pr ognosti c factor s that was conducted
usi ng data fr om near l y 30,000 mel anoma pati ents. Featur es of the
r evi sed system i ncl ude new strata for pr i mar y tumor thi ckness,
i ncor porati on of pr i mar y tumor ul cerati on as an i mpor tant stagi ng
cr i ter i on i n both the tumor (T) and node (N) cl assi fi cati ons, r evi si on

of the N cl assi fi cati on to r efl ect the i mpor tance of r egi onal nodal
tumor bur den, and new categor i es for stage IV di sease (Tabl es 3.1
and 3.2).

T Classification
Br esl ow tumor thi ckness and tumor ul cerati on ser ve as the
domi nant pr ognosti c factor s i n the T cl assi fi cati on. A thi r d
pr ognosti c factorCl ar k l evel of i nvasi oni s i mpor tant for pati ents
wi th thi n (T1) pr i mar y l esi ons.
Br esl ow tumor thi ckness, measur ed i n mi l l i meter s, i s deter mi ned by
usi ng an ocul ar mi cr ometer to measur e the total ver ti cal hei ght of
the mel anoma fr om the granul ar l ayer to the ar ea of deepest
penetrati on. Cl ar k l evel of i nvasi on i s deter mi ned by usi ng an ocul ar
mi cr ometer to deter mi ne the depth of penetrati on i nto the der mi s.
Consi stent and uni for m data now suppor t the concl usi on that
measur ement of Br esl ow tumor thi ckness i s mor e r epr oduci bl e than
measur ement of Cl ar k l evel of i nvasi on and that Br esl ow tumor
thi ckness i s the mor e accurate pr edi ctor of outcome. Mor eover, the
AJCC Mel anoma Task For ce has adopted the Br esl ow depth val ues of
1, 2, and 4 mm as cut-offs for the T categor i es (Tabl e 3.1).
However, Cl ar k l evel of i nvasi on r emai ns an i mpor tant pr ognosti c
factor for pati ents wi th T1 l esi ons (Tabl e 3.1).
Pr i mar y tumor ul cerati on i s hi stopathol ogi cal l y defi ned as the
absence of an i ntact epi der mi s over l yi ng a por ti on of the pr i mar y
tumor. Impor tantl y, ul cerated mel anomas ar e associ ated wi th a
si gni fi cantl y wor se pr ognosi s than nonul cerated mel anomas of the
same thi ckness. In the T categor y of the AJCC stagi ng system, the
l etter a si gni fi es a nonul cerated l esi on, whi l e b si gni fi es an
ul cerated l esi on. Ul cerated pr i mar y mel anomas ar e cl assi fi ed i n the
same stage as nonul cerated l esi ons of the next hi gher T categor y
(e.g., T1b and T2a l esi ons ar e both stage Ib) (Tabl e 3.2).

N Classification
In both the pr evi ous ver si on of the AJCC stagi ng system and the
new, r evi sed ver si on, r egi onal nodal tumor bur den i s the most
i mpor tant pr edi ctor of sur vi val i n pati ents wi thout di stant

di sease. The descr i pti on of the nodal tumor bur den, however, was
mar kedl y r efi ned i n the l atest stagi ng system. Thi s change r efl ects
the i ncr easi ng use of cutaneous l ymphosci nti graphy, l ymphati c

mappi ng, and senti nel l ymph node bi opsy (SLNB), whi ch have
si gni fi cantl y enhanced the abi l i ty to detect nodal metastases i n the
r egi onal nodal basi n.

Table 3.1. 2002 American Joint Committee on


cancer TNM classification for cutaneous
melanoma
T
Thickness
Classification

Ulceration Status

T1

1.0 mm

a: Without
ulceration and
level II/III
b: With ulceration
or level IV/V

1.012.0 mm

a: Without
ulceration
b: With ulceration

2.014.0 mm

a: Without
ulceration
b: With ulceration

>4.0 mm

a: Without
ulceration
b: With ulceration

T2

T3

T4

No. of
N
Metastatic
Classification
Nodes

Nodal Metastatic
Mass

1 node

a:
Micrometastasis a
b:
Macrometastasis b

N2

23 nodes

a:
Micrometastasis
b:
Macrometastasis
c: In-transit
met(s)/satellite(s)
without
metastatic nodes

N3

4 or more metastatic nodes, or


matted nodes, or in-transit
met(s)/satellite(s) with metastatic
node(s)

N1

M
Site
Classification

Serum Lactate
Dehydrogenase
Level

M1a

Distant skin,
subcutaneous,
or nodal
metastases

Normal

M1b

Lung
metastases

Normal

All other
visceral
metastases

M1c

Any distant
metastasis

Normal

Elevated

Micrometastases are diagnosed after sentinel or


elective lymphadenectomy.
b Macrometastases are defined as clinically
detectable nodal metastases confirmed by
therapeutic lymphadenectomy or nodal metastases
that exhibit gross extracapsular extension.
Adapted from Balch CM, Buzaid AC, Soong SJ, et
al. Final version of the American Joint Committee
on Cancer staging system for cutaneous
melanoma. J Clin Oncol 2001;19:36353648, with
permission.

Table 3.2. 2002 American Joint Committee


on cancer stage groupings for cutaneous
melanoma
Clinical

Staginga

Pathological
Staging b

Tis

N0

M0

Tis

N0

M0

IA

T1a

N0

M0

T1a

N0

M0

T1b

N0

M0

T1b

N0

M0

T2a

N0

M0

T2a

N0

M0

T2b

N0

M0

T2b

N0

M0

T3a

N0

M0

T3a

N0

M0

T3b

N0

M0

T3b

N0

M0

T4a

N0

M0

T4a

N0

M0

IIC

T4b

N0

M0

T4b

N0

M0

III c

Any
T

N1
N2
N3

M0

T14a

N1a

M0

T14a

N2a

M0

T14b

N1a

M0

T14b

N2a

M0

T14a

N1b

M0

T14a

N2b

M0

IB

IIA

IIB

IIIA

IIIB

IIIC

IV
a

Any
T

Any
N

Any
M1

T1
4a/b

N2c

M0

T14b

N1b

M0

T14b

N2b

M0

Any T

N3

M0

Any T

Any
N

Any
M1

Clinical staging includes microstaging of the


primary melanoma and clinical and/or
radiologic evaluation for metastases. By
convention, it should be used after complete
excision of the primary melanoma with clinical
assessment for regional and distant
metastases.
b Pathological staging includes microstaging of
the primary melanoma and pathological
information about the regional lymph nodes
gained after partial or complete
lymphadenectomy. Pathological stages 0 and 1A
are the exceptions; patients with this stage of
disease do not require pathological evaluation
of the lymph nodes.
c There are no stage III subgroups for clinical
staging.
Adapted from Balch CM, Buzaid AC, Soong SJ,
et al. Final version of the American Joint

Committee on Cancer staging system for


cutaneous melanoma. J Clin Oncol
2001;19:36353648, with permission.
In the new stagi ng system, both the actual number of l ymph nodes
and the tumor bur den (mi cr oscopi c vs. macr oscopi c) wi thi n the node
ar e taken i nto account. Pati ents who have cl i ni cal l y negati ve l ymph
nodes but pathol ogi cal l y documented nodal
metastases ar e defi ned as havi ng mi cr oscopi c or cl i ni cal l y occul t
nodal metastases (desi gnated by the l etter a i n the N categor y of
the new stagi ng system). In contrast, pati ents wi th cl i ni cal evi dence
of nodal metastases that i s confi r med on pathol ogi cal exami nati on
ar e defi ned as havi ng macr oscopi c or cl i ni cal l y appar ent nodal
metastases (desi gnated by the l etter b i n the N categor y of the new
stagi ng system). Sur vi val rates for pati ents wi th macr oscopi c nodal
di sease ar e si gni fi cantl y wor se than rates for pati ents wi th
mi cr oscopi c nodal di sease. Data fr om the Wor l d Heal th Or gani z ati on
(WHO) Mel anoma Pr ogram showed that pati ents who under went
wi de l ocal exci si on and concomi tant el ecti ve r egi onal l ymph node
di ssecti on and wer e found on pathol ogi cal r evi ew to have
mi cr oscopi c nodal di sease far ed si gni fi cantl y better than pati ents
who under went wi de l ocal exci si on fol l owed by therapeuti c
l ymphadenectomy per for med when nodal di sease became cl i ni cal l y
evi dent (5-year sur vi val rates, 48.2% vs. 26.6% , p = 0.04).
Mul ti pl e studi es have demonstrated that the number of
pathol ogi cal l y i nvol ved l ymph nodes i s a domi nant and i ndependent
pr edi ctor of outcome i n pati ents wi th mel anoma. In the anal ysi s on
whi ch the new AJCC stagi ng system i s based, the best pr ognosti c
gr oupi ng of posi ti ve nodes was one ver sus two to thr ee ver sus four
or mor e. These cut-offs for number of posi ti ve nodes have ther efor e
been i ncor porated i nto the N cl assi fi cati on of the AJCC stagi ng
system.
Inter esti ngl y, the pr esence of tumor ul cerati on, a domi nant
pr ognosti c factor wi thi n the T cl assi fi cati on system, has al so been
shown to be an i ndependent adver se pr ognosti c factor i n pati ents
wi th r egi onal nodal di sease. In fact, ul cerati on of the pr i mar y tumor
was the onl y pr i mar y tumor pr ognosti c featur e that i ndependentl y
pr edi cted sur vi val i n pati ents wi th nodal metastases. As such,
pati ents wi th an ul cerated pr i mar y l esi on ar e upstaged wi thi n the N

categor y (as wel l as the T categor y) compar ed wi th pati ents wi th


si mi l ar nodal tumor bur den wi th a nonul cerated pr i mar y l esi on
(Tabl e 3.3).
The pr esence of cl i ni cal l y or mi cr oscopi cal l y detectabl e satel l i te
metastases ar ound a pr i mar y mel anoma or i n-transi t metastases
between the pr i mar y tumor and r egi onal l ymph nodes (see the
Management of In-transi t Metastases secti on l ater i n thi s chapter )
por tends a poor pr ognosi s. In r ecogni ti on of thi s i mpor tant concept
and i n vi ew of the si mi l ar sur vi val rates among pati ents wi th
satel l i te and i n-transi t metastases, the AJCC Mel anoma Task For ce
omi tted satel l i tosi s fr om the T categor y, i n whi ch i t was for mer l y
i ncl uded, and i n-transi t metastasi s or satel l i te(s) ar e now assi gned
a separate cl assi fi cati on, N2c. F ur ther mor e, because pati ents who
have both satel l i tes or i n-transi t metastases and concomi tant l ymph
node metastases have a wor se outcome than pati ents wi th ei ther
di sease featur e al one, pati ents wi th both mi cr osatel l i tes or i ntransi t metastases and l ymph node metastases ar e cl assi fi ed as N3,
r egar dl ess of the number of synchr onous metastati c l ymph nodes.

M Classification
Al l pr i mar y mel anomas associ ated wi th di stant metastati c di sease
ar e cl assi fi ed as stage IV. Wi thi n the M cl assi fi cati on ther e i s
onl y one gr oup, M1, but ther e ar e thr ee subcategor i es. The
subcategor i es r efl ect the fact that ther e ar e sur vi val di ffer ences
among pati ents wi th metastati c di sease, dependi ng on the
anatomi cal si tes of metastasi s. Di stant metastases to the ski n,
subcutaneous ti ssue, or di stant l ymph nodes ar e desi gnated M1a;
they ar e associ ated wi th a better pr ognosi s than metastases at any
other anatomi cal si te. Metastases to the l ung ar e associ ated wi th an
i nter medi ate pr ognosi s and ar e desi gnated M1b. Vi sceral metastases
ar e associ ated wi th the wor st pr ognosi s and ar e desi gnated M1c. In
general , the 1-year sur vi val rates of pati ents who have M1a, M1b,
and M1c di sease ar e 59% , 57% , and 41% , r especti vel y.

Table 3.3. Affect of ulceration on American


Joint Committee on cancer (AJCC) T
classification and 5-year survival
Ser um l actate dehydr ogenase (LDH) l evel i s i ncl uded i n the M
categor y because i n the anal ysi s on whi ch the new AJCC stagi ng
system i s based, ser um LDH l evel was one of the most i mpor tant
pr edi ctor s of poor pr ognosi s i n pati ents wi th metastati c di sease,
even after accounti ng for si te and number of metastases. Pati ents
wi th di stant metastases who have an el evated ser um LDH l evel at
the ti me of stagi ng ar e assi gned to categor y M1c, r egar dl ess of the
si te of thei r di stant metastases.

Metastatic Melanoma of Unknown Primary


Site
One ar ea of cl ear i nter est to the sur gi cal oncol ogi st i s metastati c
mel anoma of unknown pr i mar y si te. Appr oxi matel y 5% of pati ents
wi th mel anoma pr esent wi th metastati c di sease of the l ymph nodes
fr om an unknown pr i mar y tumor. Several studi es
have compar ed these pati ents wi th si mi l ar cohor ts of pati ents who
have equi val ent nodal status and a known pr i mar y si te i n ter ms of
r ecur r ence and sur vi val . Al though pati ents wi th unknown pr i mar y

tumor s wer e hi stor i cal l y bel i eved to have a wor se pr ognosi s, several
r ecent l ar ge studi es have contradi cted these ear l y fi ndi ngs. Pati ents
wi th metastati c mel anoma and an unknown pr i mar y tumor must be
exami ned car eful l y fr om scal p to toes for a potenti al pr i mar y tumor
si te. For the pur pose of studyi ng thi s subgr oup of pati ents, str i ct
cr i ter i a have been establ i shed i n the cour se of r etr ospecti ve
anal ysi s to excl ude pati ents wi th potenti al si tes of an occul t pr i mar y
tumor that may have been mi ssed Tabl e 3.4. In an i mpor tant study
fr om Memor i al Sl oan-Ketter i ng Cancer Center, publ i shed by Chang
and Knapper i n 1982, 166 pati ents wi th metastati c mel anoma of
unknown pr i mar y si te wer e r evi ewed r etr ospecti vel y. Thi s gr oup
compr i sed 4.4% of al l the mel anoma cases fol l owed dur i ng the
r evi ew per i od. These pati ents wer e compar ed on several parameter s
wi th a contr ol gr oup of pati ents who had known pr i mar y tumor s. Al l
pati ents had cl i ni cal stage II di sease accor di ng to the ol der stagi ng
cr i ter i a i n whi ch pati ents wi th suggesti ve pal pabl e l ymph nodes
wer e defi ned as havi ng cl i ni cal stage II di sease. The di str i buti on of
metastases i n pati ents wi th unknown pr i mar y tumor s was si mi l ar to
that i n pati ents wi th known pr i mar y tumor s. Most tumor s wer e
found i n the axi l l ar y l ymph nodes, and many wer e found i n the
gr oi n and cer vi cal r egi ons. Pati ents wi th cl i ni cal stage II di sease
had a 46% 5-year sur vi val rate and a 41% 10-year sur vi val rate, a
fi ndi ng si mi l ar for men and women. Pati ents who had r esi dual
di sease i n the l ymphadenectomy speci men, i ndi cati ng the pr esence
of mor e extensi ve l ymph node i nvol vement, had l ower sur vi val
rates. F i nal l y, pati ents who had pr ompt l ymphadenectomy had a
substanti al l y better pr ognosi s than those who had a del ay i n
tr eatment, wi th a thr eefol d i mpr ovement i n the 5- and 10-year
sur vi val rates. A second l ar ge ser i es fr om the John Wayne Cancer
Center r evi ewed 188 pati ents wi th l ymph node metastases fr om
unknown pr i mar y mel anoma and compar ed these wi th a gr oup of
pati ents wi th a known pr i mar y tumor. Several var i abl essuch as
age, gender, anatomi cal si te, and tr eatment wi th adjuvant
i mmunotherapywer e si mi l ar i n the two gr oups. In thi s gr oup of
pati ents wi th cl i ni cal stage II mel anoma, those wi th l ymph node
metastases fr om an
unknown pr i mar y mel anoma had no si gni fi cant i mpr ovement i n 5and 10-year sur vi val rates than pati ents wi th a known pr i mar y
mel anoma. Recentl y, a r etr ospecti ve anal ysi s fr om the Uni ver si ty of
Pennsyl vani a of 40 pati ents wi th mel anoma of unknown pr i mar y si te
r eveal ed that overal l 4-year sur vi val rate for these pati ents was
si gni fi cantl y hi gher than that for pati ents wi th equi val ent nodal

di sease and a known concur r ent pr i mar y mel anoma (57% vs. 19% ).
Si mi l ar l y, pati ents wi th mel anoma of unknown pr i mar y si te wi th
vi sceral metastases had l onger medi an sur vi val than those wi th
known pr i mar y tumor s.

Table 3.4. Metastatic melanoma of unknown


primary: Stringent definition of patient
population
Exclude patients with any of the following:
History of having had a mole, birthmark,
freckle, chronic paronychia, or skin blemish
previously excised, electrodesiccated, or
cauterized
Metastatic melanoma in one of the nodebearing areas and presentation with a scar
indicating previous local treatment in the
skin area drained by this lymphatic basin
No recorded physical examination of anus
and genitalia
Previous orbital enucleation or exenteration

Mor e r ecentl y, Cor mi er et al , fr om the Uni ver si ty of Texas M. D.


Ander son Cancer Center conducted a r etr ospecti ve anal ysi s of
consecuti ve pati ents wi th mel anoma (fr om 1990 to 2001) metastati c
to r egi onal l ymph nodes. Among these pati ents, 71 pati ents wi th
MUP and 466 contr ol l ed pati ents who had r egi onal l ymph node
metastases of a si mi l ar stage wi th a known pr i mar y si te wer e
i denti fi ed. The author s found that after they under went l ymph node
di ssecti on, pati ents wi th MUP wer e cl assi fi ed wi th Ni b di seases
(47% ), N2b di sease (14% ), or N3 di sease (39% ). Wi th a medi an
fol l ow-up of 7.7 year s, the 5-year and 10-year overal l sur vi val rate

wer e 55% and 44% , r especti vel y, for pati ents wi th MUP, compar ed
to 42% and 32% , r especti vel y, for the contr ol gr oup (P=0.04). By
mul ti var i ate anal yses, age 50 year s or ol der, mal e gender and N2b
or N3 di sease status wer e i denti fi ed as adver se pr ognosti cs factor s,
and MUP was i denti fi ed as a favorabl e pr ognosti c factor (haz ar d
rati o 0.61; 95% confi dence i nter val , 0.420.86; P=.006) for overal l
sur vi val . The author s concl uded that the r el ati vel y favorabl e l ongter m sur vi val of pati ents wi th MUP i n thi s study have a natural
hi stor y that i s si mi l ar to (i f not better than) the sur vi val of many
pati ents wi th Stage III di sease. Ther efor e, pati ents wi th MUP shoul d
be tr eated wi th an aggr essi ve sur gi cal appr oach wi th curati ve i ntent
and shoul d be consi der ed for stage III adjuvant therapy pr otocol s.

Management of Local Disease


Local contr ol of a pr i mar y mel anoma r equi r es wi de exci si on of the
tumor or bi opsy si tedown to but not i ncl udi ng the deep fasci a, and
wi th a mar gi n of nor mal -appear i ng ski n. The r i sk of l ocal r ecur r ence
cor r el ates mor e wi th tumor thi ckness than wi th mar gi ns of sur gi cal
exci si on. Thus, i t i s rati onal to var y sur gi cal mar gi ns accor di ng to
tumor thi ckness.

Margin Width
Hi stor i cal l y, even thi n mel anomas wer e exci sed wi th wi de mar gi ns
(35 cm). Studi es have demonstrated, however, that nar r ower
mar gi ns ar e associ ated wi th the same r ecur r ence rates as wi der
mar gi ns.
The fi r st randomi zed study i nvol vi ng sur gi cal mar gi ns for
mel anomas l ess than 2 mm thi ck was r epor ted by the WHO
Mel anoma G r oup. In an update of the study i ncl udi ng 612 pati ents
randoml y assi gned to a 1-cm or 3-cm mar gi n of exci si on, ther e wer e
no l ocal r ecur r ences among pati ents wi th pr i mar y mel anomas
thi nner than 1 mm. Ther e wer e four l ocal r ecur r ences
among the 100 pati ents wi th mel anomas 1 to 2 mm thi ck, and al l
four occur r ed i n pati ents wi th 1-cm mar gi ns. Ther e was no
si gni fi cant di ffer ence i n sur vi val between the 1- and 3-cm sur gi cal
mar gi n gr oups. These r esul ts demonstrate that a nar r ow exci si on
mar gi n (i .e., 1 cm) i s safe for thi n (<1 mm) mel anomas.
A mul ti -i nsti tuti onal pr ospecti ve randomi zed tr i al fr om F rance
compar ed 5- and 2-cm mar gi ns i n 319 pati ents wi th mel anomas at
l east 2 mm thi ck. Ther e wer e no di ffer ences i n l ocal r ecur r ence rate

or sur vi val between the two gr oups. A randomi zed cl i ni cal tr i al fr om


the Uni ted Ki ngdom compar ed 1- and 3-cm mar gi ns i n 900 pati ents
wi th mel anomas at l east 2 mm thi ck. Wi th a medi an fol l ow-up ti me
of 60 months, a 1-cm mar gi n was associ ated wi th a si gni fi cantl y
i ncr eased r i sk of l ocor egi onal r ecur r ence; however, overal l sur vi val
was si mi l ar i n the two gr oups. A randomi zed pr ospecti ve study
conducted by the Inter gr oup Mel anoma Commi ttee compar ed 2- and
4-cm radi al mar gi ns of exci si on for i nter medi ate-thi ckness
mel anomas (14 mm). Ther e was no di ffer ence i n l ocal r ecur r ence
rate between the two gr oups. For ty-si x per cent of pati ents i n the 4cm gr oup r equi r ed ski n grafts, wher eas onl y 11% of pati ents i n the
2-cm gr oup di d (p <0.001). Taken together, these data str ongl y
suppor t the use of a 2-cm mar gi n for i nter medi ate-thi ckness
l esi ons.
The opti mal mar gi n wi dth for thi ck mel anomas (>4 mm) i s sti l l
unknown. A r etr ospecti ve r evi ew of 278 pati ents wi th thi ck pr i mar y
mel anomas demonstrated that the wi dth of the exci si on mar gi n (2
cm vs. >2 cm) di d not si gni fi cantl y affect l ocal r ecur r ence, di seasefr ee sur vi val , or overal l sur vi val rates after a medi an fol l ow-up of
27 months.
Based i n l ar ge par t on the data fr om randomi zed, pr ospecti ve tr i al s,
several r ecommendati ons can be made for mar gi ns of exci si on
(Tabl e 3.5). Pati ents wi th i nvasi ve mel anoma l ess than 1 mm thi ck
can be tr eated wi th a 1-cm mar gi n of exci si on, wher eas pati ents
wi th mel anoma 2 to 4 mm thi ck can be tr eated wi th a 2-cm mar gi n.
For pati ents wi th mel anoma 1 to 2 mm thi ck, a si mpl e
r ecommendati on i s di ffi cul t because thi s pati ent popul ati on has
been studi ed i n several tr i al s eval uati ng a range of exci si on
mar gi ns. In general , a 2-cm mar gi n i s pr efer r ed i f anatomi cal l y
feasi bl e, and i n r egi ons of anatomi cal constrai nt (e.g., the face), a
1-cm mar gi n i s suffi ci ent. Thi s r ecommendati on i s based on the fact
that overal l sur vi val was si mi l ar for pati ents wi th 1- and 3-cm
mar gi ns i n the WHO tr i al . In pati ents wi th mel anoma thi cker than 4
mm, a 2-cm mar gi n i s pr obabl y safe, al though
no pr ospecti ve randomi zed tr i al s have speci fi cal l y addr essed thi s
thi ckness gr oup.

Table 3.5. Summary of recommendations for


excision margins

Tumor Thickness

Excision Margin

1 mm

1 cm

12 mm

12 cm

24 mm

2 cm

>4 mm

2 cma

a No

randomized prospective trials have


specifically addressed this cohort.

Wound Closure
If ther e i s any questi on about the abi l i ty to achi eve sui tabl e wound
cl osur e, a pl asti c or r econstr ucti ve sur geon shoul d be consul ted.
Opti ons for cl osur e i ncl ude pr i mar y cl osur e, ski n grafti ng, and l ocal
and di stant fl aps.
Pr i mar y cl osur e i s the method of choi ce for most l esi ons, but i t
shoul d be avoi ded when i t wi l l di stor t the appearance of a mobi l e
faci al featur e or i nter fer e wi th functi on. Many defects can be cl osed
usi ng an advancement fl ap, under mi ni ng the ski n and subcutaneous
ti ssues to per mi t pr i mar y cl osur e. Pr i mar y cl osur e usual l y r equi r es
that the l ongi tudi nal axi s of an el l i pti cal i nci si on be at l east thr ee
ti mes the l ength of the shor t axi s. Cl osur e of the wound edges i s
usual l y per for med i n two l ayer sa der mal l ayer of 3-0 or 4-0
undyed absor babl e sutur es and ei ther i nter r upted ski n cl osur e usi ng
3-0 or 4-0 nonabsor babl e sutur es or a r unni ng subcuti cul ar ski n
cl osur e usi ng 4-0 monofi l ament absor babl e sutur es. Thr ee l ayer s
ar e someti mes used.
Appl i cati on of a ski n graft i s one of the si mpl est r econstr ucti ve
methods used for wound cl osur e. Spl i t-thi ckness ski n grafts ar e
used most commonl y. For l ower-extr emi ty pr i mar y l esi ons, spl i tthi ckness grafts shoul d be har vested fr om the extr emi ty opposi te

the mel anoma. In general , ski n grafts shoul d be har vested fr om an


ar ea r emote fr om the pr i mar y mel anoma and outsi de the zone of
potenti al i n-transi t metastasi s. A ful l -thi ckness ski n graft can
pr ovi de a r esul t that i s both mor e durabl e and of hi gher aestheti c
qual i ty than a spl i t-thi ckness graft. F ul l -thi ckness grafts have most
commonl y been used on the face, wher e aestheti c consi derati ons
ar e most si gni fi cant. Donor si tes for ful l -thi ckness ski n graft to the
face shoul d be chosen fr om l ocati ons that ar e l i kel y to match the
col or of the face, such as the postaur i cul ar or pr eaur i cul ar ski n or
the supracl avi cul ar por ti on of the neck.
Local fl aps offer numer ous advantages for r epai r of defects that
cannot be cl osed pr i mar i l y, especi al l y on the di stal extr emi ti es and
on the head and neck. Col or match i s excel l ent, durabi l i ty of the
ski n i s essenti al l y nor mal , and nor mal sensati on i s usual l y
pr eser ved. Transposi ti on fl aps and r otati on fl aps of many var i eti es
have been used successful l y.
Di stant fl aps shoul d be used when suffi ci ent ti ssue for a l ocal fl ap i s
not avai l abl e and when a ski n graft woul d not pr ovi de adequate
wound coverage. Myocutaneous fl aps and fr ee fl aps can be used.
Di scussi on of such compl ex methods i s beyond the scope of thi s
chapter, but these techni ques ar e fami l i ar to pl asti c and
r econstr ucti ve sur geons and ar e di scussed i n gr eater detai l i n
Chapter 24.

Special Anatomical Sites


Fingers and Toes
Mor e than thr ee-four ths of subungual mel anomas i nvol ve ei ther the
gr eat toe or the thumb. A mel anoma l ocated on the ski n of a di gi t
or beneath the nai l shoul d be r emoved by a di gi tal
amputati on, wi th as much of the di gi t saved as possi bl e. In general ,
amputati ons ar e per for med at the mi ddl e i nter phal angeal joi nt of
the fi nger s or pr oxi mal to the di stal joi nt of the thumb. Mor e
pr oxi mal amputati ons ar e not associ ated wi th i mpr oved sur vi val . For
a mel anoma l ocated on a toe, an amputati on of the enti r e di gi t at
the metatar sal -phal angeal joi nt i s i ndi cated; for mel anomas of the
gr eat toe, the amputati on can be per for med pr oxi mal to the
i nter phal angeal joi nt. Lesi ons ar i si ng between two toes may r equi r e
amputati on of both toes.

Sole of the Foot


Exci si on of a mel anoma on the pl antar sur face of the foot often
pr oduces a si z abl e defect i n a wei ght-bear i ng ar ea. If possi bl e, a
por ti on of the heel or bal l of the pl antar sur face shoul d be r etai ned
to bear the gr eatest bur den of pr essur e. Wher e possi bl e, deep fasci a
over the extensor tendons shoul d be pr eser ved as a base for ski n
coverage. A pl antar fl ap, whi ch can be rai sed ei ther l ateral l y or
medi al l y, can pr ovi de wel l -vascul ar i zed l ocal ti ssue for wei ghtbear i ng ar eas, whi l e al so pr ovi di ng some sensati on. Mor e r ecentl y,
staged cl osur e of some pl antar mel anomas, par ti cul ar l y of the heel ,
have been per for med wi th i ni ti al use of a vacuum-assi sted cl osur e
devi ce to sti mul ate granul ati on ti ssue fol l owed by staged ski n graft
appl i cati on. Such an appr oach may obvi ate compl ex r econstr ucti on.

Face
Faci al l esi ons usual l y cannot be exci sed wi th mor e than a 1-cm
mar gi n because of adjacent vi tal str uctur es. The tumor di ameter,
the tumor thi ckness, and the tumor 's exact l ocati on on the face
must al l be consi der ed when mar gi n wi dth i s pl anned.

Breast
Wi de l ocal exci si on wi th pr i mar y cl osur e i s the tr eatment of choi ce
for mel anoma on the ski n of the br east; mastectomy i s not
general l y r ecommended. As wi th any tr unk l esi on,
l ymphosci nti graphy shoul d be done befor e sel ecti ve
l ymphadenectomy (see the Management of Regi onal Lymph Nodes
secti on l ater i n thi s chapter ) i f sel ecti ve l ymphadenectomy i s
i ndi cated on the basi s of pr i mar y tumor factor s.

Special Clinical Situations


Giant Congenital Nevi
A gi ant congeni tal nevus has been defi ned as a nevus that measur es
at l east 15 cm i n di ameter or at l east twi ce the si ze of the affected
per son's pal m. Pati ents wi th gi ant congeni tal nevi have an
esti mated 6% l i feti me r i sk of devel opi ng a mel anoma. Hal f of the
mel anomas that devel op i n gi ant congeni tal nevi devel op wi thi n the
fi r st 5 year s of l i fe. Deci si ons about the management of gi ant
congeni tal nevi ar e di ffi cul t because such l esi ons ar e often so
extensi ve that pr ophyl acti c sur gi cal exci si on i s i mpossi bl e. When

the l ocati on and si ze of a l esi on per mi t pr ophyl acti c exci si on,


exci si on shoul d be consi der ed befor e the age of 2 year s.

Mucosal Melanoma
Pati ents wi th tr ue mucosal mel anomai ncl udi ng mel anoma of the
mucosa of the head and neck, vagi na, and anal canal have a
general l y poor pr ognosi s, r egar dl ess of sur gi cal therapy. We usual l y
do not r ecommend an aggr essi ve sur gi cal appr oach to pati ents wi th
cl i ni cal l y l ocal i zed di sease. We r eser ve extended r esecti on for bul ky
or r ecur r ent tumor s and favor therapeuti c l ymphadenectomy over
el ecti ve l ymph node di ssecti on (see the Management of Regi onal
Lymph Nodes secti on l ater i n thi s chapter ). In par ti cul ar, we
r ecommend l ocal exci si on of anal mel anomas over abdomi noper i neal
r esecti on. Abdomi noper i neal r esecti on i s associ ated wi th much
gr eater mor bi di ty, l eaves the pati ent wi th a per manent col ostomy,
offer s no sur vi val advantage, and does not tr eat at-r i sk i ngui nal
nodes unl ess the pr ocedur e i s combi ned wi th gr oi n di ssecti on.
Adjuvant radi ati on therapy may be admi ni ster ed to pati ents wi th
mucosal mel anoma i n an attempt to decr ease the r i sk of
l ocor egi onal r ecur r ence.

Desmoplastic Melanoma
Desmopl asti c mel anoma i s an uncommon hi stol ogi c var i ant of
mel anoma that i s character i zed by unusual spi ndl e-cel l mor phol ogy
and the pr esence of fusi for m mel anocytes di sper sed i n a pr omi nent
col l agenous str oma. Cl assi cal l y pr esenti ng as a thi ck pr i mar y tumor,
desmopl asti c mel anoma i s associ ated wi th a hi gher i nci dence of
l ocal r ecur r ence than nondesmopl asti c mel anoma. Hi stol ogi cal l y,
desmopl asti c mel anoma may di spl ay mor phol ogi c heter ogenei ty.
Speci fi cal l y, some desmopl asti c mel anomas ar e character i zed by a
uni for m desmopl asi a that i s pr omi nent thr oughout the enti r e tumor
(pur e desmopl asti c mel anoma), wher eas other desmopl asti c
mel anomas appear to ar i se i n associ ati on wi th other hi stol ogi c
subtypes (mi xed desmopl asti c mel anoma). Di sti ngui shi ng the
phenotypi c heter ogenei ty of desmopl asti c mel anomas has been
r epor ted to be i mpor tant for strati fyi ng pati ents wi th r egar d to rate
of l ymph node metastasi s and pr ognosi s. Recent data i ndi cate that
pati ents wi th pur e desmopl asti c mel anoma have a l ower i nci dence of
posi ti ve senti nel l ymph nodes than do pati ents wi th mi xed
desmopl asti c mel anoma or nondesmopl asti c mel anoma. Al though
some author s have r epor ted a wor se pr ognosi s for pati ents wi th

desmopl asti c mel anoma, the major i ty of studi es have descr i bed a
better pr ognosi s for pati ents wi th desmopl asti c mel anoma compar ed
wi th pati ents who have nondesmopl asti c mel anoma of si mi l ar stage.
In a few studi es i n whi ch pur e desmopl asti c mel anoma was
di ffer enti ated fr om mi xed desmopl asti c mel anoma, pati ents wi th
mi xed desmopl asti c mel anoma had a gr eater r i sk of death or
metastati c di sease than pati ents wi th the pur e for m.

Pregnancy
The pr eci se i nfl uence of pr egnancy or hor monal mani pul ati on on the
cl i ni cal cour se of mal i gnant mel anoma has not been defi ned.
Because hi stor i cal case r epor ts suggested a poor outcome for
pr egnant women wi th mel anoma, some i nvesti gator s suggested
that mel anoma may be hor monal l y sti mul ated and ther efor e mor e
aggr essi ve i n pr egnant women. Mor e r ecentl y, mul ti pl e studi es have
documented overal l good outcomes for women wi th mel anoma
dur i ng pr egnancy.
A WHO study r epor ted that women who wer e di agnosed dur i ng
pr egnancy had a wor se pr ognosi s compar ed wi th women di agnosed
and tr eated befor e pr egnancy. The two gr oups of women i n thi s
study wer e not si mi l ar ; mean tumor thi ckness was 2.38 mm i n the
pr egnant women and 1.49 mm i n the nonpr egnant women. After
adjusti ng for thi s di ffer ence, ther e was no di ffer ence i n sur vi val .
Other studi es have si mi l ar l y shown that tumor s tend to be thi cker i n
pr egnant women than i n nonpr egnant women and that pr egnancy at
the ti me of di agnosi s i s not a si gni fi cant pr ognosti c factor i n
mul ti var i ate anal yses. In a r ecent l ar ge popul ati on-based study of
pr egnant women conducted over a 9-year per i od i n Cal i for ni a, ther e
was no evi dence of a mor e advanced stage, thi cker tumor s,
i ncr eased r i sk of metastasi s to l ymph nodes, or wor se sur vi val i n
pr egnant women. F ur ther mor e, mater nal and neonatal outcomes
wer e equi val ent to those of pr egnant women and thei r newbor ns
wi thout mel anoma.
In aggr egate, these data suppor t the concept that mal i gnant
mel anoma i s not mor e common, mor e aggr essi ve, or mor e l ethal
dur i ng pr egnancy. Sur ger y i s the tr eatment of choi ce i n pr egnant
pati ents wi th ear l y-stage mel anoma. Ther e i s no pr oof that abor ti on
pr otects the mother fr om subsequent devel opment of metastases.
Al though opi ni ons di ffer on pl anni ng pr egnancy after a di agnosi s of
mel anoma, the wei ght of evi dence does not demonstrate an

i ncr eased r i sk of devel opi ng metastati c di sease wi th pr egnancy.


F ur ther mor e, several studi es have found no associ ati on between
oral contracepti ve use and sur vi val i n mel anoma.

Management of Local Recurrence


Tr ue l ocal r ecur r ence i s defi ned as r ecur r ence at the si te of the
pr i mar y tumor, wi thi n or conti nuous wi th the scar, and i s most l i kel y
the r esul t of i ncompl ete exci si on of the pr i mar y tumor ; i t r epr esents
a r el ati vel y rar e patter n of r ecur r ence. In many cases, such l ocal
r ecur r ences may mor e appr opr i atel y be consi der ed per si stence of
the pr i mar y tumor. The pr ognosi s after a tr ue l ocal r ecur r ence i s
si gni fi cantl y better than that associ ated wi th i n-transi t di sease (see
the next secti on), and ther efor e the cor r ect cl assi fi cati on of l ocal
r ecur r ence ver sus i n-transi t di sease i s i mpor tant i n tr eatment
pl anni ng. A l ocal r ecur r ence consi sti ng of a si ngl e l esi on i n a
pati ent whose pr i mar y mel anoma had favorabl e pr ognosti c featur es
may be appr opr i atel y tr eated wi th exci si on al one. Pati ents wi th l ocal
r ecur r ences consi sti ng of mul ti pl e, smal l and super fi ci al l esi ons may
be tr eated i n a fashi on si mi l ar to that used to tr eat pati ents wi th i ntransi t di sease (see the next secti on).

Management of In-Transit Disease


Tradi ti onal l y, i n-transi t di sease has been descr i bed as r ecur r ent
l ocor egi onal di sease found i n the der mi s or subcutaneous ti ssue
between the pr i mar y mel anoma and the r egi onal l ymph node basi n.
Thi s patter n of r ecur r ence i s uni que to mel anoma and i s
r epor ted to occur i n 5% to 10% of mel anoma cases. Al though the
mol ecul ar deter mi nants and pathophysi ol ogy of i n-transi t di sease
ar e poor l y under stood, i n-transi t r ecur r ences ar e most l i kel y an
i ntral ymphati c mani festati on of mel anoma metastases. Independent
pr edi ctor s of i n-transi t r ecur r ence i ncl ude age gr eater than 50
year s, a l ower-extr emi ty pr i mar y tumor, i ncr easi ng Br esl ow depth,
ul cerati on, and posi ti ve senti nel l ymph node (SLN) status. Regi onal
nodal metastases occur i n about two-thi r ds of pati ents wi th i ntransi t di sease and, i f pr esent, ar e associ ated wi th l ower sur vi val
rates. Pr edi ctor s of di stant r ecur r ence among pati ents wi th i ntransi t r ecur r ence i ncl ude posi ti ve SLN status, i n-transi t tumor si ze
of at l east 2 cm, and di sease-fr ee i nter val befor e i n-transi t
r ecur r ence of l ess than 12 months. Inter esti ngl y, r ecent data
suggest that pati ents who pr esent wi th synchr onous di stant and i ntransi t di sease have a wor se di sease-speci fi c sur vi val compar ed wi th

pati ents who pr esent wi th onl y i n-transi t or di stant di sease.


Some have suggested that di ssecti on of the r egi onal nodal basi nby
ei ther SLNB or compl ete l ymphadenectomyi ncr eases the r i sk of i ntransi t metastases. These author s hypothesi ze that di ssecti on
di stur bs l ymph fl ow, l eadi ng to deposi ti on of metastati c cel l s i n the
i nter veni ng l ymphati c vessel s. A cr i ti cal anal ysi s of the data,
however, pr ovi des compel l i ng evi dence that nei ther SLNB nor
compl eti on l ymph node di ssecti on i n SLN-posi ti ve pati ents i ncr eases
the i nci dence of i n-transi t metastases. In a r ecent r evi ew of 2,018
pati ents wi th pr i mar y mel anomas at l east 1 mm thi ck tr eated over a
10-year per i od at the Sydney Mel anoma Uni t, ther e was no
si gni fi cant di ffer ence i n the rate of i n-transi t metastases between
pati ents tr eated wi th wi de l ocal exci si on al one (4.9% ) and those
tr eated wi th wi de l ocal exci si on and SLNB (3.6% ). Because the two
gr oups wer e si mi l ar i n ter ms of medi an tumor depth, rate of
ul cerati on, and Cl ar k l evel , these data str ongl y suppor t the concept
that ear l y nodal i nter venti on has l i ttl e i mpact on the natural hi stor y
of i n-transi t metastases. In a separate study of 1,395 pati ents fr om
The Uni ver si ty of Texas M. D. Ander son Cancer Center, pati ents wi th
a posi ti ve SLN had a si gni fi cantl y hi gher rate of i n-transi t
metastases (12% ) than pati ents wi th a negati ve SLN (3.5% ). Taken
together, these data i ndi cate that bi ol ogynot sur gi cal techni que
establ i shes the r i sk of i n-transi t metastases.
For pati ents wi th i n-transi t metastases confi ned to a l i mb that ar e
not amenabl e to standar d sur gi cal measur es (e.g., pati ents wi th
r ecur r ent and/or mul ti pl e i n-transi t metastases and pati ents wi th
l ar ge-bur den i n-transi t di sease), r egi onal chemotherapy techni ques
such as i sol ated l i mb per fusi on or, mor e r ecentl y, i sol ated l i mb
i nfusi on, may be consi der ed. Amputati on i s rar el y i ndi cated.

Hyperthermic Isolated Limb Perfusion


Hyper ther mi c i sol ated l i mb per fusi on wi th mel phal an has been used
to tr eat i n-transi t metastases of the extr emi ti es si nce the mi d1950s. Mel phal an i s cur r entl y the most acti ve si ngl e agent for use
i n hyper ther mi c i sol ated l i mb per fusi on. Overal l r esponse rates of
7% to 80% (compl ete r esponse rate, 46% ; par ti al r esponse rate,
34% ) can be achi eved, and the medi an r esponse
durati on i n pati ents wi th a compl ete r esponse ranges fr om 9 to 19
months. Nonrandomi zed studi es of hyper ther mi c l i mb per fusi on by
Li enar d et al . r epor ted a hi gh compl ete r esponse rate (90% ) wi th a

combi nati on of mel phal an, tumor necr osi s factor- (TNF -), and
i nter fer on- (IF N-) and a somewhat l ower r esponse rate wi th
mel phal an al one (52% ). The durabi l i ty of these r esponses has not
yet been r epor ted. F raker et al . r epor ted a 100% r esponse rate i n
pati ents tr eated wi th mel phal an al one and a 90% r esponse rate i n
pati ents tr eated wi th mel phal an, IF N-, and TNF -, al though the
l atter combi nati on r esul ted i n a hi gher compl ete r esponse rate
(80% vs. 61% ). A mul ti center randomi zed tr i al sponsor ed by the
Amer i can Col l ege of Sur geons Oncol ogy G r oup compar i ng mel phal an
al one wi th a combi nati on of mel phal an and TNF - for pati ents who
have i n-transi t metastases was r ecentl y cl osed to accr ual because
the i nter i m anal ysi s fai l ed to r eveal a benefi t for TNF -. As a r esul t,
TNF - i s not cur r entl y bei ng used i n the Uni ted States i n i sol ated
l i mb per fusi on pr ocedur es.
The r outi ne use of hyper ther mi c i sol ated l i mb per fusi on i n the
adjuvant setti ng has mar gi nal , i f any, benefi t. Al though a
randomi zed mul ti center phase III tr i al showed i ncr eased di seasefr ee i nter val i n pati ents wi th i n-transi t metastases and r egi onal
l ymph node metastasi s, thi s effect was transi ent and pr edomi nantl y
occur r ed i n pati ents wi th a mor e favorabl e pr ognosi s (tumor
thi ckness of 1.5 to 2.99 mm). Thi s study showed no benefi t of
i sol ated l i mb per fusi on wi th r espect to ti me to di stant metastasi s or
sur vi val durati on.
Al though hyper ther mi c i sol ated l i mb per fusi on may be effecti ve as
pr i mar y tr eatment for i n-transi t metastases, the i sol ated l i mb
per fusi on techni que i nvol ves a compl ex and i nvasi ve operati ve
pr ocedur e entai l i ng expensi ve equi pment, l ong operati ng ti mes, and
consi derabl e anci l l ar y staff. In an attempt to achi eve si mi l ar r esul ts
usi ng l ess compl ex techni ques, a new r egi onal chemotherapy
techni que, i sol ated l i mb i nfusi on, has r ecentl y been devel oped for
the management of i n-transi t metastases.

Isolated Limb Infusion


Isol ated l i mb i nfusi on i s essenti al l y a l ow-fl ow i sol ated l i mb
per fusi on per for med vi a per cutaneousl y i nser ted catheter s, but
wi thout oxygenati on of the ci r cui t (F i g. 3-1). In general , usi ng
standar d radi ol ogi c techni ques, catheter s ar e i nser ted
per cutaneousl y i nto the mai n ar ter y and vei n of the unaffected l i mb
and del i ver ed i ntravascul ar l y to the contral ateral tumor-bear i ng
extr emi ty. Under general anesthesi a, after a pneumati c tour ni quet
i s i nfl ated pr oxi mal l y, cytotoxi c agents (general l y mel phal an and
acti nomyci n-D) ar e i nfused thr ough the ar ter i al catheter and hand-

ci r cul ated wi th a syr i nge techni que for 20 to 30 mi nutes.


Pr ogr essi ve hypoxi a occur s because, i n contrast to i sol ated l i mb
per fusi on, no oxygenator i s used. The hypoxi a and aci dosi s
associ ated wi th i sol ated l i mb i nfusi on ar e therapeuti cal l y attracti ve
because numer ous cytotoxi c agents, i ncl udi ng mel phal an, appear to
damage tumor cel l s mor e effecti vel y under hypoxi c condi ti ons. In
fact, hypoxi a and aci dosi s have been r epor ted to i ncr ease the
cytotoxi c effects of mel phal an i n exper i mental model s by a factor of
thr ee. The Sydney Mel anoma Uni t has al so shown
that i sol ated l i mb i nfusi on wi th fotemusti ne after dacar baz i ne
chemosensi ti z ati on can be successful when gr oss l i mb di sease has
not been contr ol l ed by one or mor e i sol ated l i mb i nfusi ons wi th
mel phal an.

F i gur e 3.1. Schemati c drawi ng depi cti ng an i sol ated l i mb


i nfusi on. The catheter s ar e typi cal l y pl aced per cutaneousl y by an
i nter venti onal radi ol ogi st vi a the contral ateral extr emi ty, wi th
the catheter ti ps posi ti oned i n the tumor-bear i ng extr emi ty just
bel ow the i ngui nal l i gament i n the super fi ci al femoral ar ter y and
vei n. After i nfl ati on of the tour ni quet, chemotherapy i s manual l y
i nfused for 20 to 30 mi nutes, after whi ch the l i mb i s washed out
wi th 1 l i ter of nor mal sal i ne. (Repr i nted fr om Li ndner P,
Doubr ovsky A, Kam PC, et al . Pr ognosti c factor s after i sol ated
l i mb i nfusi on wi th cytotoxi c agents for mel anoma. Ann Sur g

Oncol 2002;9:127136, wi th per mi ssi on.)

At the compl eti on of the dr ug exposur e, the l i mb vascul atur e i s


fl ushed wi th a cr ystal l oi d sol uti on vi a the ar ter i al catheter, and the
effl uent i s di scar ded. Al though the l i mb ti ssues ar e exposed to the
cytotoxi c agent for onl y a shor t per i od (up to 30 mi nutes), ther e
appear s to be adequate cel l ul ar uptake for tumor cel l ki l l i ng.
Isol ated l i mb i nfusi on has been shown to yi el d r esponse rates
si mi l ar to those obser ved after conventi onal hyper ther mi c i sol ated
l i mb per fusi on; overal l r esponse rates of 85% (compl ete r esponse
rate, 41% ; par ti al r esponse rate, 44% ) have been achi eved i n at
l east one study. Because of the si mpl i ci ty of the i sol ated i nfusi on
techni que, i t may be a mor e attracti ve opti on for pati ents wi th
comor bi di ti es or the el der l y.

Toxicity and Morbidity


Hyper ther mi c i sol ated l i mb per fusi on and i sol ated l i mb i nfusi on can
be associ ated wi th potenti al l y si gni fi cant r egi onal adver se effects,
i ncl udi ng myonecr osi s, ner ve i njur y, compar tment syndr ome, and
ar ter i al thr ombosi s, someti mes necessi tati ng fasci otomy or even
major amputati on. Fol l owi ng i sol ated l i mb i nfusi on, r egi onal adver se
effects appear to be si mi l ar to those r epor ted after conventi onal
hyper ther mi c i sol ated l i mb per fusi on, wi th 41% of pati ents
exper i enci ng grade II toxi c effects and 53% exper i enci ng grade III
toxi c effects. Systemi c toxi c effects, i ncl udi ng hypotensi on and adul t
r espi rator y di str ess syndr ome, have someti mes been seen wi th the
addi ti on of TNF - to the per fusi on or i nfusi on r egi men. Because l i mb
per fusi on or i nfusi on r equi r es a hi gh degr ee of techni cal exper ti se
and i s associ ated wi th a si gni fi cant r i sk of compl i cati ons, the
pr ocedur e shoul d be per for med onl y i n center s that have exper i ence
wi th the techni que. At pr esent, ther e i s l i ttl e evi dence to justi fy the
use of pr ophyl acti c per fusi on or i nfusi on, except as par t of a cl i ni cal
tr i al .

Management of Regional Lymph Nodes


Regi onal l ymph nodes ar e the most common si te of mel anoma
metastasi s. Effecti ve pal l i ati on and someti mes cur e can be achi eved
i n pati ents wi th r egi onal metastases. F i ne-needl e aspi rati on or cor e
bi opsy can usual l y yi el d a di agnosi s i n pati ents who devel op
cl i ni cal l y enl ar ged r egi onal nodes. Open bi opsy i s rar el y war ranted.

The management of cl i ni cal l y negati ve r egi onal l ymph nodes has


been the focus of a l ong and someti mes contenti ous debate.
Hi stor i cal l y, some sur geons pr efer r ed to per for m l ymphadenectomy
onl y for cl i ni cal l y demonstrabl e nodal metastases. Thi s type of
exci si on has been ter med delayed or ther apeutic lymph node
dissection (TLND). Other sur geons have chosen to exci se the nodes
even when they appear ed nor mal i n pati ents who ar e at i ncr eased
r i sk of devel opi ng nodal metastases. Thi s exci si on has been ter med
immediate, pr ophylactic, or elective lymph node dissection (ELND).
Mor e r ecentl y, many sur geons have adopted a sel ecti ve appr oach to
r egi onal l ymph node di ssecti onthe techni que of i ntraoperati ve
l ymphati c mappi ng and SLN i denti fi cati on or i gi nal l y devel oped by
Mor ton et al .

Therapeutic Lymph Node Dissection


Wi th TLND, onl y pati ents wi th known metastases under go a major
l ymphadenectomy; thi s r educes the number of potenti al l y
unnecessar y l ymphadenectomi es and may not r educe the chance for
cur e. The di sadvantage of TLND i s that del ayi ng tr eatment unti l
l ymph node metastases ar e cl i ni cal l y evi dent may r esul t i n many
pati ents havi ng di stant mi cr ometastases at the ti me of
l ymphadenectomy. Chances for cur e may ther efor e be di mi ni shed.

Elective Lymph Node Dissection


ELND has the theor eti cal advantage of tr eati ng mel anoma nodal
metastases at a r el ati vel y ear l y stage i n the natural hi stor y of the
di sease. The di sadvantage of ELND i s that many pati ents under go
sur ger y when they do not have nodal metastasi s. Advocates of ELND
ar gue that pati ents wi th cl i ni cal l y negati ve, hi stol ogi cal l y posi ti ve
l ymph nodes at ELND have a better chance for sur vi val (50% 60% )
than do pati ents i n whom the r egi onal l ymph nodes ar e not
di ssected, and cl i ni cal l y appar ent metastases devel op i n the
r egi onal l ymph nodes dur i ng fol l ow-up (15% 35% ). None of four
randomi zed, pr ospecti ve studi es assessi ng ELND have demonstrated
an overal l sur vi val advantage for thi s techni que. Two tr i al s, one
fr om the WHO and another fr om the Mayo Cl i ni c, wer e ul ti matel y
cr i ti ci zed because the study popul ati ons wer e at l ow r i sk for occul t
nodal di sease, and pati ents wer e ther efor e unl i kel y to benefi t fr om
the pr oposed sur gi cal tr eatment.
Al though ELND does not offer a sur vi val benefi t to al l pati ents, two

r ecentl y compl eted pr ospecti ve randomi zed tr i al s that tar geted


hi gher-r i sk, cl i ni cal l y node-negati ve pati ents suggest that ELND may
have some sur vi val benefi t i n cer tai n pati ent subgr oups. In the
WHO ELND Tr i al , pati ents wi th tr uncal mel anoma at l east 1.5 mm
thi ck wer e randomi zed to wi de l ocal exci si on and ELND ver sus wi de
l ocal exci si on and obser vati on. Updated r esul ts fr om thi s tr i al
demonstrated that pati ents i n the ELND tr eatment ar m who wer e
found to have mi cr oscopi c nodal di sease at ELND had better overal l
sur vi val than di d pati ents i n whom pal pabl e adenopathy devel oped
after wi de exci si on al one. The l ong-ter m r esul ts of the Inter gr oup
Mel anoma Tr i al ar e si mi l ar. In thi s tr i al , pati ents wi th i nter medi atethi ckness mel anomas (1.04.0 mm) who under went wi de exci si on
and ELND wer e compar ed wi th a si mi l ar gr oup of pati ents who
under went wi de exci si on al one fol l owed by obser vati on of the
r egi onal nodal basi n. Al though thi s tr i al di d not demonstrate a
di ffer ence i n overal l 10-year sur vi val rates, four pr ospecti vel y
sel ected subgr oups wer e found to have si gni fi cantl y better 10-year
sur vi val wi th ELND than wi th nodal obser vati on: pati ents whose
pr i mar y tumor s wer e wi thout ul cerati on (84% vs. 77% ; p = 0.03);
pati ents wi th pr i mar y tumor thi ckness between 1.0 and 2.0 mm (vs.
thi cker ) (86% vs. 80% ; p = 0.03); pati ents wi th extr emi ty (vs.
tr uncal ) mel anoma (84% vs. 78% ; p = 0.05); and pati ents younger
than 60 year s (81% vs. 74% ; p = 0.03). The r esul ts of a r ecentl y
publ i shed mul ti center tr i al fr om G er many al so demonstrated an
absol ute sur vi val advantage, of at l east 13% , for pati ents wi th
posi ti ve nodes detected on SLNB compar ed wi th pati ents wi th
posi ti ve nodes detected dur i ng obser vati on of the nodal basi n.
Al though thi s anal ysi s was r etr ospecti ve, the r esul ts wer e
consi stent wi th the fi ndi ngs of the WHO study.
Taken together, these data cal l i nto questi on r ecommendati ons to
del ay l ymphadenectomy unti l pal pabl e nodal di sease devel ops; the
data al so suppor t the use of al ter nati ve appr oaches to per mi t ear l i er
i denti fi cati on of occul t nodal di sease. A mor e rati onal , sel ecti ve
appr oach, l ymphati c mappi ng and SLNB, has now been
wi del y adopted. Thi s techni que sati sfi es many pr oponents of both
ELND and TLND.

Intraoperative Lymphatic Mapping and


Sentinel Lymph Node Biopsy
Several i nvesti gator s have pr oposed i ntraoperati ve l ymphati c
mappi ng and SLNB as a mi ni mal l y i nvasi ve pr ocedur e for i denti fyi ng

the appr oxi matel y 20% of pati ents who har bor occul t mi cr oscopi c
di sease. Thi s appr oach i s someti mes ter med selective
lymphadenectomy.
Several studi es have demonstrated that the SLNs ar e the fi r st nodes
to contai n metastases, i f metastases ar e pr esent, and thus the
pathol ogi cal status of the SLNs r efl ects that of the enti r e r egi onal
nodal basi n. If the SLN l acks metastasi s, the r emai nder of the
r egi onal l ymph nodes i s unl i kel y to contai n di sease, and a
compl eti on l ymphadenectomy need not be per for med. Mul ti pl e
studi es have demonstrated that the fal se-negati ve rate for SLNB i s
l ess than 4% , wi th the pr edi cti ve val ue of a negati ve SLN
appr oachi ng 99% . Other studi es have confi r med the val i di ty of the
SLN concept and the accuracy of SLNB as a stagi ng pr ocedur e. It i s
i mperati ve, however, that the sur geon empl oyi ng SLNB have
adequate pathol ogy and nucl ear medi ci ne suppor t.

Technique
Lymphati c mappi ng and SLNB i s per for med at the ti me of wi de
exci si on of the pr i mar y tumor or bi opsy si te. Si nce the i ntr oducti on
of l ymphati c mappi ng and SLNB, the techni que has under gone
several r efi nements that have r esul ted i n i mpr oved detecti on of
SLNs.
Use of a vi tal bl ue dye (i sosul fan bl ue 1% ) to hel p i denti fy SLNs has
been par t of the l ymphati c mappi ng and SLNB pr ocedur e si nce i ts
i ntr oducti on. The bl ue dye i s i njected i nto the pati ent i ntrader mal l y
ar ound the i ntact tumor or bi opsy si te. The bl ue dye i s taken up by
the l ymphati c system and car r i ed vi a affer ent l ymphati cs to the
SLN. The drai ni ng nodal basi n i s expl or ed, and the affer ent
l ymphati c channel s and fi r st drai ni ng l ymph nodes (the SLNs) ar e
i denti fi ed by the uptake of the bl ue dye. Wi th the use of bl ue dye
al one, a SLN i s i denti fi ed i n appr oxi matel y 85% of cases. Al though
thi s i ni ti al appr oach was pr omi si ng, i t l eft 15% of pati ents unabl e to
benefi t fr om SLNB because no SLN was i denti fi ed.
Subsequentl y, two addi ti onal techni ques have been i ncor porated
that have si gni fi cantl y i mpr oved SLN l ocal i z ati on: (a) pr eoperati ve
l ymphosci nti graphy and (b) i ntraoperati ve i njecti on of techneti um99 (9 9 Tc)-l abel ed sul fur col l oi d accompani ed by i ntraoperati ve use of
a handhel d gamma pr obe. Pr eoperati ve l ymphosci nti graphy usi ng
9 9 Tc-l abel ed sul fur col l oi d per mi ts the i denti fi cati on of pati ents wi th
mul ti pl e drai ni ng nodal basi ns and pati ents wi th l ymphati c drai nage
to SLNs l ocated outsi de standar d nodal basi ns, i ncl udi ng

epi tr ochl ear, popl i teal , and ectopi c si tes (F i g. 3-2). In pati ents wi th
mel anomas that drai n to mul ti pl e r egi onal nodal basi ns, the
hi stol ogi c status of one drai ni ng basi n does not pr edi ct the status of
other basi ns. In one study, among

54 pati ents who under went an SLNB of an unusual nodal si te, 7


(13% ) had l ymph node metastases i n that l ocati on. In four of the
seven pati ents, the onl y posi ti ve SLN was fr om the unusual si te.
Ther efor e, i t i s par ti cul ar l y i mpor tant to i denti fy and assess al l atr i sk r egi onal nodal basi ns to pr oper l y stage the di sease.

F i gur e 3.2. Pr eoperati ve l ymphosci nti graphy. After i njecti on of


9 9 Tc-l abel ed sul fur col l oi d at the pr i mar y cutaneous mel anoma
si te (upper mi dl i ne back), pr eoperati ve l ymphosci nti graphy
r eveal ed (A ) drai nage to mul ti pl e nodal basi ns (bi l ateral neck
and l eft axi l l a), (B) i n-transi t/ectopi c senti nel l ymph nodes
(SLNs) i n the r i ght fl ank r egi on and r i ght axi l l a fr om a pr i mar y

tumor of the r i ght l ateral back, and (C) SLNs i n a r i ght l owerextr emi ty popl i teal fossa l ymph node basi n and a r i ght i ngui nal
l ymph node basi n fr om a pr i mar y tumor of the heel . (Photos
cour tesy of Jeffr ey E. G er shenwal d, MD.)

Pr obabl y the most i mpor tant devel opment i n the SLNB techni que
has been the i ntr oducti on of i ntraoperati ve l ymphati c mappi ng usi ng
a handhel d gamma pr obe. In thi s appr oach, 0.5 to 1.0 mCi of 9 9 Tcl abel ed sul fur col l oi d i s i njected i ntrader mal l y 1 to 4 hour s befor e
sur ger y. Dur i ng sur ger y, a handhel d gamma pr obe i s used to
transcutaneousl y i denti fy SLNs that wi l l be r emoved. The use of
both bl ue dye and radi ocol l oi d i ncr eases the sur geon's abi l i ty to
i denti fy the SLN (gr eater than 96% to 99% accuracy) compar ed
wi th the use of bl ue dye al one (84% accuracy). Al though most
cl i ni ci ans use thi s combi ned modal i ty appr oach, some favor the
si ngl e-agent strategy of 9 9 Tc-l abel ed sul fur col l oi d al one, and they
have r epor ted si mi l ar l y excel l ent r esul ts.

Side Effects
SLNB i s associ ated wi th substanti al l y fewer postoperati ve
compl i cati ons compar ed wi th ELND, whi ch i s character i zed by
compl ete r egi onal node exti r pati on. SLNB i s associ ated wi th l ess
extensi ve sur ger y and thus a l ower rate of si de effects. Mor eover,
the SLNB techni que i tsel f i s associ ated wi th substanti al l y fewer
postoperati ve compl i cati ons than ELND, i ncl udi ng l ower rates of
l ymphedema, pai n, numbness, and l oss of acti ve range of moti on. In
addi ti on, r ecent data have shown that the SLNB techni que does not
i ncr ease the i nci dence of i n-transi t r ecur r ence compar ed wi th wi de
l ocal exci si on al one.

Incidence and Predictors of Positive Sentinel


Lymph Nodes
Knowl edge of the factor s pr edi cti ve of a posi ti ve SLN i s useful for
counsel i ng pati ents r egar di ng tr eatment opti ons. In most studi es,
the i nci dence of posi ti ve SLNs i n pati ents under goi ng SLNB ranges
fr om 15% to 20% . However, mul ti var i ate anal yses have r eveal ed
several factor s that i ncr ease the r i sk of posi ti ve SLNs: i ncr eased
tumor thi ckness, ul cerati on, hi gh mi toti c i ndex, age younger than
50 year s, and axi al tumor l ocati on. In one r epor t, the i nci dence of a
posi ti ve SLN was 4% among pati ents wi th mel anomas 1.0 mm or

thi nner and 44% among pati ents wi th mel anomas thi cker than 4.00
mm (Tabl e 3.6). In the same r epor t, pati ents wi th ul cerated pr i mar y
tumor s had a hi gher i nci dence of SLN metastases compar ed wi th
those wi th nonul cerated l esi ons (35% vs. 12% , r especti vel y). The
i nci dence of SLN metastases by

AJCC stage i s shown i n F i gur e 3.3. The i nci dences of posi ti ve SLNs
for stages IA, IB, IIA, IIB, and IIC wer e 2% , 9% , 24% , 34% , and
53% , r especti vel y.

Table 3.6. Effect of ulceration on SLN metasta


tumor thickness (n = 1,375)

Positive SLN
Tumor
Total
Thickness Patients All
(mm)
(%)
(%)

Not
Ulcerated

Ulcera

AJCC
AJ
(%)
(%)
Stage b
St

1.00

28

IA

16

IB

1.01
2.00

38

12

11

IB

22

II

2.01
4.00

23

28

25

IIA

34

II

>4.00

11

44

33

IIB

53

II

All
Patients

100

17

12

35

SLN, sentinel lymph node; AJCC, American Joint Co


Cancer.
a Fisher exact test for each tumor thickness group.
b Stage groupings calculated using tumor thickness
data only.
Reprinted from Rousseau DL, Jr, Ross MI, Johnson
Revised American Joint Committee on Cancer stagin
accurately predict sentinel lymph node positivity in
negative melanoma patients. Ann Surg Oncol 2003;
with permission.

F i gur e 3.3. Inci dence of posi ti ve senti nel l ymph nodes (SLNs) by
Amer i can Joi nt Commi ttee on Cancer di sease stage (n = 1,375).
The di ffer ence between each stage i s stati sti cal l y si gni fi cant. The
inset shows the per centage of pati ents wi th a posi ti ve SLN wi thi n
each categor y. (Repr i nted fr om Rousseau DL, Jr, Ross MI,
Johnson MM, et al . Revi sed Amer i can Joi nt Commi ttee on Cancer
stagi ng cr i ter i a accuratel y pr edi ct senti nel l ymph node posi ti vi ty
i n cl i ni cal l y node-negati ve mel anoma pati ents. Ann Sur g Oncol
2003;10:569574, wi th per mi ssi on.)

Prognostic Value of Sentinel Lymph Node

Status
The pr ognosti c si gni fi cance of the pathol ogi cal status of the SLNs
has been convi nci ngl y demonstrated. Data fr om M. D. Ander son
Cancer Center demonstrated that SLN status was the most
si gni fi cant cl i ni copathol ogi cal pr ognosti c factor wi th r espect to
sur vi val i n pati ents wi th mel anoma. In an updated anal ysi s of 1,487
pati ents who under went SLNB (medi an tumor thi ckness, 1.5 mm),
the 5-year sur vi val rate for pati ents wi th posi ti ve SLNs was 73.3% ,
compar ed wi th 96.8% for pati ents wi th negati ve SLNs (F i g. 3-4) (J.
G er shenwal d, unpubl i shed data, 2005). Several other mul ti var i ate
r egr essi on anal yses have shown that r egi onal l ymph node status i s
the most power ful pr edi ctor of r ecur r ence (both r egi onal and
di stant) and sur vi val , even among pati ents wi th thi ck mel anomas.
Accor di ng to a r ecent anal ysi s of the AJCC database, 5-year sur vi val
rates for pati ents wi th stage III di sease range fr om 69% for
pati ents wi th onl y one mi cr oscopi cal l y posi ti ve l ymph node and a
nonul cerated pr i mar y mel anoma to 13% for pati ents wi th cl i ni cal l y
evi dent nodal di sease wi th mor e than thr ee pathol ogi cal l y i nvol ved
nodes and an ul cerated pr i mar y tumor.

F i gur e 3.4. Di sease-speci fi c sur vi val by senti nel l ymph node


(SLN) status i n 1,487 pati ents. SLN status was the most
si gni fi cant cl i ni copathol ogi al pr ognosti c factor wi th r espect to
sur vi val . The 5-year di sease-speci fi c sur vi val rate was 73.3% for
pati ents wi th posi ti ve SLNs, compar ed wi th 96.8% for pati ents
wi th negati ve SLNs.

The pr ognosti c i mpor tance of di sti ngui shi ng between mi cr oscopi cal l y
and macr oscopi cal l y posi ti ve l ymph nodes has been emphasi zed by
i ncor porati on of thi s cr i ter i on i nto the newl y
r evi sed mel anoma stagi ng system. The concept of tumor bur den wi l l
l i kel y be i mpor tant i n the era of SLNB as accurate mi cr oscopi c
stagi ng of SLNs becomes even mor e wi despr ead and pati ents ar e
better strati fi ed on the basi s of mi cr oscopi c tumor bur den i nto
si mi l ar r i sk subgr oups. In fact, several studi es have shown that the
di ameter of the l ar gest l ymph node tumor nodul e and the total
l ymph node tumor vol ume ar e si gni fi cant pr edi ctor s of r ecur r ence
and sur vi val . In one study, a tumor deposi t di ameter of 3 mm was
i denti fi ed as a si gni fi cant cut-off poi nt: The 3-year sur vi val
pr obabi l i ty was 86% for pati ents wi th a l ar gest tumor deposi t
di ameter of 3 mm or l ess and 27% for pati ents wi th a l ar gest
deposi t di ameter gr eater than 3 mm. In the futur e, as our
under standi ng of the si gni fi cance of mi cr oscopi c nodal tumor bur den
i s r efi ned, cl i ni cal deci si ons r egar di ng the need for and extent of
fur ther sur ger y or adjuvant therapy may al so be based on the
extent of mi cr oscopi c nodal tumor bur den.
The r ecentl y compl eted Mul ti center Sel ecti ve Lymphadenectomy
Tr i al -I was desi gned to assess whether a sel ecti ve appr oach to
r egi onal l ymphadenectomyl i mi ti ng compl ete nodal di ssecti on to
pati ents wi th mi cr oscopi c di sease i n SLNsconfer s a sur vi val benefi t
compar ed wi th wi de l ocal exci si on of the pr i mar y mel anoma and
obser vati on of the r egi onal nodal basi n. Pati ents wi th pr i mar y
cutaneous mel anomas at l east 1 mm thi ck or wi th Cl ar k l evel IV or
V tumor s wi th any Br esl ow thi ckness wer e el i gi bl e for the tr i al .
Pati ents wer e randoml y assi gned to wi de
exci si on al one pl us obser vati on or wi de exci si on pl us l ymphati c
mappi ng and SLNB, wi th subsequent compl eti on l ymphadenectomy i f
SLNs wer e posi ti ve. Al though thi s tr i al has r eached tar get accr ual ,
fi nal r esul ts ar e not yet avai l abl e. Resul ts fr om thi s i mpor tant study
shoul d hel p defi ne whether sel ecti ve l ymphadenectomy i s associ ated
wi th a sur vi val benefi t. Another tr i al , the Mul ti center Sel ecti ve
Lymphadenectomy Tr i al -II, wi l l expl or e the i mpact of compl eti on
l ymphadenectomy i n pati ents wi th a posi ti ve SLN.

Pathological Evaluation of Sentinel Lymph


Nodes

Pathol ogi sts have tradi ti onal l y exami ned the mul ti tude of l ymph
nodes obtai ned fr om a l ymphadenectomy by exami ni ng one
hematoxyl i n-eosi nstai ned secti on fr om each paraffi n bl ock. Thi s
conventi onal appr oach, however, can mi ss di sease i n SLNs, pr i mar i l y
because of sampl i ng er r or. In one study, 8 of 10 pati ents who
under went SLNB and subsequentl y devel oped r egi onal nodal fai l ur e
i n nodal basi ns that wer e negati ve for di sease accor di ng to
conventi onal hi stol ogi c exami nati on of SLNs had mi cr oscopi c di sease
detected when the SLNs wer e r eassessed usi ng speci al i zed
pathol ogi cal techni ques. Data fr om thi s and other studi es suggest
that fai l ur e to use speci al i zed techni ques, rather than fai l ur e to
cor r ectl y i denti fy SLNs, accounts for many cases of fal se-negati ve
fi ndi ngs on SLNB.
Wi th the SLNB techni que, fewer l ymph nodes ar e submi tted for
anal ysi s than ar e submi tted wi th compl ete l ymphadenectomy, and
the pathol ogi st can ther efor e focus on onl y those nodesthe SLNs
that ar e at the hi ghest r i sk. Cur r entl y, the combi nati on of
hematoxyl i n-eosi n assessment of several l evel s and
i mmunohi stochemi cal anal ysi s i s general l y consi der ed a standar d
practi ce i n assessi ng SLNs. Several anti bodi es di r ected agai nst
mel anoma-associ ated anti gens (S-100, HMB-45, tyr osi nase, MAG E3,
and MART-1) ar e r outi nel y used for i mmunohi stochemi cal
eval uati on. Because cer tai n anti bodi es have l ow speci fi ci ty (S-100)
and other s have l ow sensi ti vi ty (HMB-45, MAG E3, and tyr osi nase), a
panel of anti bodi es i s commonl y used. At our i nsti tuti on, thi s panel
i ncl udes HMB-45 and MART-1.
Because even the combi nati on of hi stol ogi c and
i mmunohi stochemi cal exami nati on of SLNs may fai l to i denti fy
i sol ated mel anoma cel l s or ol i gocel l ul ar deposi ts, some have
suggested a mol ecul ar-based appr oach to exami nati on of SLNs. Wi th
use of the r ever se transcr i ptase-pol ymerase chai n r eacti on (RTPCR), i t i s esti mated that one mel anoma cel l i n a backgr ound of 1
10 6 to 1 107 nor mal cel l s can be i denti fi ed. Some i nvesti gator s
have pr oposed, however, that thi s l evel of di agnosti c sensi ti vi ty may
actual l y over esti mate cl i ni cal l y r el evant di sease. Posi ti vi ty rates i n
studi es usi ng RT-PCR to eval uate SLNs for mi cr ometastati c
mel anoma range fr om 55% to 73% , compar ed wi th a rate of 30% ,
whi ch woul d be expected on the basi s of known cl i ni copathol ogi cal
r i sk factor s and patter ns of r ecur r ence. Some studi es show that the
pr ognosi s of pati ents wi th an SLN that i s posi ti ve by RT-PCR but
negati ve by hi stol ogi c or i mmunohi stochemi cal anal ysi s i s wor se
than that of pati ents who have SLNs negati ve by both techni ques.

Al though pr el i mi nar y r esul ts have been i ntr i gui ng, the tr ue cl i ni cal
si gni fi cance of posi ti ve RT-PCR fi ndi ngs i n a hi stol ogi cal l y negati ve
SLN i s sti l l unknown, i n par t because most studi es that have
addr essed thi s questi on to date had shor t fol l ow-up ti mes and di d
not compar e RT-PCR wi th cur r ent standar d hi stol ogi c techni ques. It
ther efor e r emai ns di ffi cul t to draw fi nal concl usi ons about the
pr ognosti c si gni fi cance of SLNs that ar e posi ti ve by RT-PCR but
negati ve by cur r ent conventi onal hi stol ogi c anal ysi s. Impor tantl y, at
l east one r ecent study suggests that pati ents wi th submi cr oscopi c
di sease detected by tyr osi nase RT-PCR do not have a hi gher
r ecur r ence r i sk than pati ents wi th RT-PCRnegati ve SLNs. The
r el ati ve cl i ni cal i mpor tance of conventi onal hi stol ogi c exami nati on,
ser i al secti oni ng, i mmunohi stochemi cal anal ysi s, and mol ecul ar
stagi ng i n pati ents under goi ng l ymphati c mappi ng and SLNB i s bei ng
eval uated i n a l ar ge, mul ti center, randomi zed, pr ospecti ve tr i al
known as the Sunbel t Mel anoma Tr i al .

Prediction of Metastatic Melanoma in


Nonsentinel Nodes
Cur r entl y, pati ents who have a mel anoma-posi ti ve SLN i denti fi ed on
SLNB subsequentl y under go compl eti on l ymphadenectomy. When the
non-SLNs ar e exci sed and eval uated by hematoxyl i n-eosi n stai ni ng
and i mmunohi stochemi str y, l ess than one-thi r d of compl eti on
l ymphadenectomy speci mens contai n addi ti onal nodes wi th
metastati c di sease. Because mor e than two-thi r ds of pati ents have
metastati c di sease i denti fi ed onl y i n SLNs, ther e has been i nter est
i n i denti fyi ng pati ents who, despi te havi ng a posi ti ve SLN, have a
l ow pr obabi l i ty of metastati c di sease i n non-SLNs.
In an anal ysi s of pr i mar y tumor and SLN character i sti cs, the
r el ati ve ar ea of tumor i n the SLN and the Br esl ow thi ckness of the
pr i mar y tumor most accuratel y pr edi cted the pr esence of tumor i n
non-SLNs. The densi ty of dendr i ti c l eukocytes i n the paracor tex al so
pr edi cted the pr esence of tumor i n non-SLNs. These thr ee featur es
al one and i n combi nati on wer e abl e to pr edi ct the pr esence of tumor
i n non-SLNs wi th hi gh accuracy. Al though these r esul ts ar e
i ntr i gui ng and war rant fur ther study, deci si ons r egar di ng compl eti on
l ymphadenectomy cannot yet be made str i ctl y on the basi s of
pr i mar y tumor or SLN character i sti cs. Compl eti on l ymphadenectomy
fol l owi ng i denti fi cati on of a posi ti ve SLN r emai ns the cur r ent
standar d of car e.

Current Practice Guidelines


In general , pati ents wi th cutaneous mel anoma ar e offer ed SLNB i f
the pr i mar y tumor i s at l east 1.0 mm thi ck, or i f the pr i mar y tumor
i s l ess than 1.0 mm thi ck, i f i t i s at l east Cl ar k l evel IV, i s
ul cerated, or demonstrates evi dence of r egr essi on and i f the pati ent
has no evi dence of metastati c mel anoma i n r egi onal l ymph nodes
and di stant si tes on physi cal exami nati on and stagi ng eval uati on.
Evi dence of ver ti cal gr owth phase, a pathol ogi cal featur e that has
been associ ated wi th an i ncr eased r i sk of l ymphati c metastases, has
al so been adopted as an i ndi cati on for SLNB. Recentl y, several
gr oups have offer ed SLNB to pati ents whose pr i mar y tumor s have a
hi gh mi toti c rate because thi s factor has al so been r epor ted to be a
str ong pr edi ctor of SLN posi ti vi ty.
When the SLNs ar e negati ve, no fur ther sur ger y i s per for med, and
the r emai ni ng r egi onal l ymph nodes ar e l eft i ntact. When the SLNs
show evi dence of metastati c di sease, compl eti on l ymphadenectomy
of the affected nodal basi n i s the cur r ent standar d of car e.
Pathol ogi cal eval uati on of compl eti on l ymphadenectomy speci mens
often r eveal s no addi ti onal di sease. However, i t i s i mpor tant to
r emember that compl eti on l ymphadenectomy speci mens ar e
r outi nel y assessed wi th standar d hi stol ogi c techni ques rather than
the mor e r i gor ous exami nati on r eser ved for SLNB speci mens. As a
r esul t, ther e may actual l y be addi ti onal di sease i n the compl eti on
nodal speci men that goes undetected. Thi s di sease woul d r epr esent
a potenti al sour ce of subsequent r ecur r ence i f i t wer e not r emoved.
Because such r ecur r ences ar e di ffi cul t to tr eat sur gi cal l y and may
contr i bute to si gni fi cant mor bi di ty, compl eti on l ymphadenectomy
per for med for mi cr oscopi c di sease pr ovi des the potenti al for
i mpr oved r egi onal contr ol . In addi ti on, i denti fyi ng pati ents wi th
mi ni mal di sease bur den by usi ng the SLN appr oach may hel p
i denti fy the gr oup of pati ents who may der i ve an i mpr oved sur vi val
benefi t fr om ear l y TLND. F ur ther mor e, knowl edge of the
pathol ogi cal status of the SLNs al l ows pr oper stagi ng and thus
faci l i tates deci si on maki ng r egar di ng adjuvant tr eatment.

Technical Considerations
Axillary Dissection
General

Axi l l ar y di ssecti on must be compl ete and i ncl ude the l evel III l ymph
nodes (F i g. 3-5). The ar m, shoul der, and chest ar e pr epar ed and
i ncl uded i n the sur gi cal fi el d.

Incision
We use a hor i zontal , sl i ghtl y S-shaped i nci si on begi nni ng anter i or l y
al ong the super i or por ti on of the pectoral i s major muscl e, traver si ng
the axi l l a over the four th r i b, and extendi ng i nfer i or l y al ong the
anter i or bor der of the l ati ssi mus dor si muscl e.

Skin Flaps
Ski n fl aps ar e rai sed anter i or l y to the mi dcl avi cul ar l i ne, i nfer i or l y
to the si xth r i b, poster i or l y to the anter i or bor der of the l ati ssi mus
dor si muscl e, and super i or l y to just bel ow the pectoral i s major
i nser ti on. The medi al si de of the l ati ssi mus dor si muscl e i s di ssected
fr ee fr om the speci men, exposi ng the thoracodor sal vessel s and
ner ve. The l ateral edge of the di ssecti on then pr oceeds cephal ad
beneath the axi l l ar y vei n. These maneuver s al l ow the r emai nder of
the di ssecti on to pr oceed fr om medi al to l ateral . The fatty and
l ymphati c ti ssue over the pectoral i s major muscl e i s di ssected fr ee
ar ound to i ts under sur face, wher e the pectoral i s mi nor muscl e i s
encounter ed. The i nter pectoral gr oove i s exposed.

Lymph Node Dissection


The medi al pectoral ner ve i s pr eser ved. The i nter pectoral nodes ar e
di ssected fr ee. The upper axi l l a i s exposed by br i ngi ng the pati ent's
ar m over the chest by adducti on and i nter nal r otati on. If nodes ar e
bul ky, the pectoral i s mi nor muscl e may be di vi ded to faci l i tate
exposur e. Di ssecti on pr oceeds fr om the apex of the axi l l a
i nfer ol ateral l y. Di ssecti on of the upper axi l l ar y l ymph nodes shoul d
be suffi ci entl y compl ete that the thoraci c outl et beneath the
cl avi cl e, Hal sted's l i gament, and subcl avi us muscl e ar e seen (F i g. 36). Fatty and l ymphati c
ti ssues ar e di ssected downwar d over the axi l l ar y vei n. The apex of
the di ssected speci men i s tagged. Di ssecti on then conti nues unti l
the thoracodor sal vessel s and the l ong thoraci c and thoracodor sal
ner ves ar e i denti fi ed. The fatty ti ssue between the two ner ves i s
separated fr om the subscapul ar i s muscl e. The speci men i s r emoved
fr om the l ateral chest wal l . Inter costobrachi al ner ves traver si ng the
speci men ar e sacr i fi ced. The speci men i s swept off the l ati ssi mus

dor si and ser ratus anter i or muscl es.

F i gur e 3.5. Lymphati c anatomy of the axi l l a showi ng the thr ee


gr oups of axi l l ar y l ymph nodes defi ned by thei r r el ati onshi p to
the pectoral i s mi nor muscl e. The hi ghest axi l l ar y nodes (l evel
III) medi al to the pectoral i s mi nor muscl e shoul d be i ncl uded i n
an axi l l ar y l ymph node di ssecti on for mel anoma. (F r om Bal ch
CM, Mi l ton G W, Shaw HM, et al ., eds. Cutaneous Melanoma.
Phi l adel phi a, Pa: Li ppi ncott; 1985, wi th per mi ssi on.)

Wound Closure
One 15F cl osed-sucti on catheter i s pl aced per cutaneousl y thr ough
the i nfer i or fl ap i nto the axi l l a. An addi ti onal catheter may be
i nser ted thr ough the i nfer i or fl ap and pl aced over the pectoral i s
major muscl e. The ski n i s cl osed wi th i nter r upted 3-0 undyed
absor babl e sutur es and r unni ng 4-0 subcuti cul ar undyed absor babl e
sutur es.

Postoperative Management
Sucti on drai nage i s conti nued unti l output i s l ess than 30 mL per
day. By appr oxi matel y 3 weeks, the sucti on catheter s ar e r emoved,
r egar dl ess of the amount of drai nage, to avoi d i nfecti on. Any

subsequent col l ecti ons of ser um ar e r emoved by needl e aspi rati on.
Mobi l i z ati on of the ar m i s di scouraged dur i ng the fi r st 7 to 10 days
after sur ger y. Over the
ensui ng 4 weeks, gradual mobi l i z ati on of the ar m i s encouraged.
The compl i cati on rate for axi l l ar y l ymph node di ssecti on i s l ow. The
most fr equent compl i cati on i s wound ser oma (see the Compl i cati ons
secti on).

F i gur e 3.6. Access to the upper axi l l a. The ar m i s draped so that


i t can be br ought over the chest wal l dur i ng the operati on. Thi s
faci l i tates r etracti on of the pectoral i s muscl es upwar d to r eveal
the l evel III axi l l ar y l ymph nodes. (F r om Bal ch CM, Mi l ton G W,
Shaw HM, et al ., eds. Cutaneous Melanoma. Phi l adel phi a, Pa:
Li ppi ncott; 1985, wi th per mi ssi on.)

Groin Dissection
For gr oi n di ssecti on, the pati ent i s pl aced i n a sl i ght fr og-l eg

posi ti on.

Incision
A r ever se l az y-S i nci si on i s made fr om super omedi al to the anter i or
super i or i l i ac spi ne, ver ti cal l y down to the i ngui nal cr ease, obl i quel y
acr oss the cr ease, and then ver ti cal l y down to the apex of the
femoral tr i angl e.

F i gur e 3.7. Techni que of i ngui nal l ymph node di ssecti on. (F r om
Bal ch CM, Mi l ton G W, Shaw HM, et al ., eds. Cutaneous
Melanoma. Phi l adel phi a, Pa: Li ppi ncott; 1985, wi th per mi ssi on.)

Skin Flaps
The l i mi ts of the ski n fl aps ar e medi al l y to the pubi c tuber cl e and
the mi dbody of the adductor magnus muscl e, l ateral l y to the l ateral
edge of the sar tor i us muscl e, super i or l y to above the i ngui nal
l i gament, and i nfer i or l y to the apex of the femoral tr i angl e. We
someti mes i ncor porate an el l i pse of ski n wi th the speci men.

Lymph Node Dissection


Di ssecti on i s car r i ed down to the muscul ar fasci a super i or l y (F i g. 3-

7). Al l fatty, node-bear i ng ti ssue i s swept down to the i ngui nal


l i gament and off the exter nal obl i que fasci a. Medi al l y, the sper mati c
cor d or r ound l i gament i s exposed, and nodal ti ssue i s swept
l ateral l y. Nodal ti ssue i s swept off the adductor fasci a to the femoral
vei n. At the apex of the femoral tr i angl e, the saphenous vei n i s
di vi ded. Lateral l y, nodal ti ssue i s di ssected off the sar tor i us muscl e
and the femoral ner ve. Wi th di ssecti on i n the pl ane of the femoral
vessel s, the nodal ti ssue i s el evated up to the l evel of the fossa
oval i s, wher e the saphenous vei n i s sutur e-l i gated at the
saphenofemoral juncti on. The speci men i s di ssected to beneath the
i ngui nal l i gament, wher e i t i s di vi ded. Cl oquet's node (the l owest
i l i ac node) i s sent as a separate speci men for fr ozen-secti on
exami nati on (F i g. 3-8).

Sartorius Muscle Transposition


The sar tor i us muscl e i s di vi ded at i ts or i gi n on the anter i or super i or
i l i ac spi ne (F i g. 3-9). The l ateral femoral cutaneous ner ve i s
pr eser ved. The pr oxi mal
two or thr ee neur ovascul ar bundl es goi ng to the sar tor i us muscl e
ar e di vi ded to faci l i tate transposi ti on. The muscl e i s pl aced over the
femoral vessel s and tacked to the i ngui nal l i gament, fasci a of the
adductor, and vastus muscl e gr oups. Dependi ng on the bul k of
di sease and pati ent anatomy, the saphenous vei n and sar tor i us
muscl es may be pr eser ved.

F i gur e 3.8. A : Lymphati c anatomy of the i ngui nal ar ea


demonstrati ng the super fi ci al and deep l ymphati c chai ns.
Cl oquet's node l i es at the transi ti on between the super fi ci al and
deep i ngui nal nodes. It i s l ocated beneath the i ngui nal l i gament
i n the femoral canal . B: The i l i ac nodes i ncl ude those on the
common and super fi ci al i l i ac vessel s and the obturator nodes.
Obturator nodes shoul d be exci sed as par t of an i l i ac nodal
di ssecti on. (F r om Bal ch CM, Mi l ton G W, Shaw HM, et al ., eds.
Cutaneous Melanoma. Phi l adel phi a, Pa: Li ppi ncott; 1985, wi th
per mi ssi on.)

Wound Closure
The ski n edges ar e exami ned for vi abi l i ty and tr i mmed back to
heal thy ski n, i f necessar y. Intravenous admi ni strati on of fl uor escei n
and a Wood's l amp may be used to i denti fy poor l y per fused ski n
edges. Two cl osed-sucti on drai ns ar e pl aced thr ough separate smal l
i nci si ons i nfer i or l y. One i s l ai d medi al l y
and the other i s l ai d l ateral l y wi thi n the operati ve wound. The

wound i s cl osed wi th i nter r upted 3-0 undyed absor babl e sutur es i n


the der mi s and fol l owed by ski n stapl es.

F i gur e 3.9. Transecti on of the sar tor i us muscl e at i ts or i gi n on


the anter i or super i or i l i ac spi ne i n pr eparati on for transposi ti on
over the femoral vessel s and ner ves. (F r om Bal ch CM, Mi l ton
G W, Shaw HM, et al ., eds. Cutaneous Melanoma. Phi l adel phi a,
Pa: Li ppi ncott, 1985; wi th per mi ssi on.)

Postoperative Management
The pati ent begi ns ambul ati ng the day fol l owi ng sur ger y; a customfi t el asti c stocki ng may be used dur i ng the day for 6 months. After
thi s per i od, the stocki ng may be di sconti nued i f no l eg swel l i ng
occur s.

Dissection of the Iliac and Obturator Nodes


We general l y per for m deep di ssecti ondi ssecti on of the i l i ac and
obturator nodesfor the fol l owi ng i ndi cati ons: (a) known
i nvol vement of the nodes r eveal ed by pr eoperati ve i magi ng studi es,
(b) mor e than thr ee gr ossl y posi ti ve nodes i n the super fi ci al l ymph
node di ssecti on speci men, or (c) metastati c di sease i n Cl oquet's
node by fr ozen-secti on exami nati on. To gai n access to the deep
nodes, we extend the ski n i nci si on super i or l y. The exter nal obl i que

muscl e i s spl i t fr om a poi nt super omedi al to the anter i or super i or


i l i ac spi ne to the l ateral bor der of the r ectus sheath. The i nter nal
obl i que and transver sus abdomi ni s muscl es ar e di vi ded, and the
per i toneum i s r etracted super i or l y. An al ter nati ve appr oach i s to
spl i t the i ngui nal l i gament ver ti cal l y, medi al to the femoral vei n.
The ur eter i s exposed as i t cour ses over the i l i ac ar ter y. Di ssecti on
conti nues i n fr ont of the exter nal i l i ac ar ter y to separate the
exter nal i l i ac nodes. The i nfer i or epi gastr i c ar ter y and vei n ar e
di vi ded, i f necessar y. Di ssecti on of the l ymph nodes conti nues
to the common i l i ac ar ter y. Nodes i n fr ont of the exter nal i l i ac vei n
ar e di ssected to the poi nt at whi ch the i nter nal i l i ac vei n pr oceeds
under the i nter nal i l i ac ar ter y. The pl ane of the per i toneum i s
traced al ong the wal l of the bl adder, and the fatty ti ssues and l ymph
nodes ar e di ssected off the per i vesi cal fat star ti ng at the i nter nal
i l i ac ar ter y. Di ssecti on i s compl eted on the medi al wal l of the
exter nal i l i ac vei n, and the nodal chai n i s fur ther separated fr om
the pel vi c fasci a unti l the obturator ner ve i s seen. Obturator nodes
ar e l ocated i n the space between the exter nal i l i ac vei n and the
obturator ner ve (i n an anter oposter i or di r ecti on) and between the
i nter nal i l i ac ar ter y and the obturator foramen (i n a cephal adcaudad di r ecti on). The obturator ar ter y and vei n usual l y need not
be di stur bed. The transver sus abdomi ni s, i nter nal obl i que, and
exter nal obl i que muscl es may be cl osed wi th r unni ng sutur es. The
i ngui nal l i gament, i f pr evi ousl y di vi ded, i s appr oxi mated wi th
i nter r upted nonabsor babl e sutur es to Cooper 's l i gament medi al l y
and to the i l i ac fasci a l ateral to the femoral vessel s.

Neck Dissection
Lymph node metastases fr om mel anomas i n the head and neck wer e
pr evi ousl y bel i eved to fol l ow a pr edi ctabl e patter n. However, i t i s
now known that l ymphati c drai nage fr om mel anomas of the head
and neck can be mul ti di r ecti onal and unpr edi ctabl e. ELND or SLNB
may be mi sdi r ected i n as many as 59% of pati ents i f the operati on
i s based on cl assi c anatomi cal studi es wi thout pr eoperati ve
l ymphosci nti graphy. These fi ndi ngs str ongl y suppor t the use of
l ymphosci nti graphy i n pati ents wi th mel anomas i n the head and
neck.
At M. D. Ander son, the tr eatment of choi ce for pati ents wi th
mel anoma i n the head and neck r egi on and cl i ni cal l y i nvol ved nodes
i s wi de l ocal exci si on of the pr i mar y l esi on wi th ei ther modi fi ed
radi cal neck di ssecti on or sel ecti ve neck di ssecti on, fol l owed by

adjuncti ve radi ati on therapy. In pati ents wi th l esi ons at l east 1.5
mm thi ck who have under gone sel ecti ve neck di ssecti on and i n
pati ents wi th nodal r el apse, adjuncti ve radi ati on therapy gi ves a
l ocor egi onal contr ol rate of 88% .
Mel anomas ar i si ng on the scal p or face anter i or to the pi nna of the
ear and super i or to the commi ssur e of the l i p can metastasi ze to
i ntrapar oti d l ymph nodes because these nodes ar e conti guous wi th
the cer vi cal nodes. When i ntrapar oti d nodes ar e cl i ni cal l y i nvol ved,
i t i s advi sabl e to combi ne neck di ssecti on wi th par oti d l ymph node
di ssecti on and then admi ni ster radi ati on therapy.

Complications
The most common acute postoperati ve compl i cati on of sel ecti ve
l ymphadenectomy i s wound i nfecti on. Rates range fr om 5% to 19% .
In an anal ysi s of data fr om the Sunbel t Mel anoma Tr i al , the
compl i cati ons associ ated wi th SLNB for mel anoma wer e eval uated i n
2,120 pati ents. Overal l , 96 (4.6% ) of the pati ents devel oped major
or mi nor compl i cati ons associ ated wi th SLNB, wher eas 103 (23.3% )
of 444 pati ents exper i enced compl i cati ons associ ated wi th SLNB pl us
compl eti on l ymph node di ssecti on. The author s concl uded that the
SLNB al one i s associ ated wi th si gni fi cantl y l ess mor bi di ty compar ed
wi th SLNB pl us compl eti on l ymph node di ssecti on.
Fol l owi ng for mal l ymphadenectomy, the rate of l ymphocel e or
ser oma for mati on i s 3% to 23% . Leavi ng sucti on catheter s i n pl ace
unti l the drai nage decr eases to 30 to 40 mL per day may r educe the
i nci dence of ser oma. However, pr ol onged use of catheter s i s
associ ated wi th a hi gher rate of i nfecti on. Lymphedema i s the most
ser i ous l ong-ter m compl i cati on of for mal l ymphadenectomy. Thr ee
ser i es have shown that the i nci dence of l eg edema after gr oi n
di ssecti on can be decr eased by pr eventi ve measur es, i ncl udi ng
per i operati ve anti bi oti cs, el asti c stocki ngs, l eg el evati on exer ci ses,
and di ur eti cs. Pr ophyl acti c measur es ar e i mpor tant because
r ever si ng the pr ogr essi on of edema i s di ffi cul t. Ski n fl ap pr obl ems
can occur wi th some fr equency. Expectant management of i schemi c
edges often r esul ts i n ful l -thi ckness necr osi s and pr ol onged
hospi tal i z ati on. Ther efor e, i f ski n fl ap edges ar e of questi onabl e
vi abi l i ty, we r etur n the pati ent to the operati ng r oom ear l y for fl ap
r evi si on. Cl i ni cal l y detectabl e deep vei n thr ombosi s i s uncommon.

Adjuvant Therapy

Interferon Alfa-2b
Hi gh-dose IF N al fa-2b i s appr oved by the U.S. Food and Dr ug
Admi ni strati on as adjuvant tr eatment for pati ents wi th mel anoma
who have a hi gh r i sk of r ecur r ence. Cur r entl y, pati ents wi th l ocal l y
r ecur r ent, nodal , i n-transi t, or satel l i te di sease shoul d be
consi der ed candi dates for adjuvant hi gh-dose IF N al fa-2b.
Appr oval of IF N al fa-2b was based on the r esul ts of the Easter n
Cooperati ve Oncol ogy G r oup (ECOG ) E1684 pr ospecti ve randomi zed
tr i al , whi ch assi gned pati ents to hi gh-dose IF N al fa-2b or
obser vati on after wi de l ocal exci si on. The IF N al fa-2b dosage was 20
mi l l i on uni ts/m2 /day i ntravenousl y for 4 weeks fol l owed by 10
mi l l i on uni ts per m2 thr ee ti mes a week subcutaneousl y for the next
48 weeks. Both node-posi ti ve and hi gh-r i sk node-negati ve (T4pN0)
pati ents wer e i ncl uded; the major i ty of pati ents had exper i enced
r ecur r ence of di sease i n the r egi onal nodes after pr i or wi de l ocal
exci si on. Al l pati ents under went ei ther ELND or TLND. Of the 287
pati ents enr ol l ed, 89% wer e node posi ti ve. IF N al fa-2b i mpr oved
medi an overal l sur vi val fr om 2.8 to 3.8 year s and i mpr oved 5-year
r el apse-fr ee sur vi val rates fr om 26% to 37% at a medi an fol l ow-up
of 7 year s. The benefi ci al effect of IF N al fa-2b was most pr onounced
i n the node-posi ti ve pati ents. Of note, the rate of toxi c effects was
hi gh: Two pati ents di ed, 67% of pati ents exper i enced grade 3 toxi c
effects, and 50% of pati ents ei ther stopped tr eatment ear l y or
r equi r ed dose r educti on.
A r ecent updated anal ysi s of E1684, at a medi an fol l ow-up of 12.6
year s, showed a per si stent gai n i n medi an overal l sur vi val (45.8
months for the IF N al fa-2b ar m vs. 32 months for obser vati on). The
sur vi val di ffer ence, however, was no l onger stati sti cal l y si gni fi cant,
possi bl y because deaths fr om i nter cur r ent i l l ness on both ar ms
over shadowed mel anoma-speci fi c mor tal i ty. The updated r esul ts di d
conti nue to show a hi ghl y si gni fi cant i mpr ovement i n r el apse-fr ee
sur vi val .
The E1690 tr i al , another ECOG tr i al , was i ni ti ated befor e a
si gni fi cant i mpact on sur vi val had been noted i n E1684. In E1690,
desi gned as a confi r mati on and extensi on of E1684, 642 pati ents
wi th hi gh-r i sk (stage IIb or III) mel anoma wer e randomi zed i n a
thr ee-ar m study to r ecei ve the E1684 hi gh-dose r egi men, l ow-dose
IF N al fa-2b (3 mi l l i on uni ts per m2 thr ee ti mes a week for 2 year s),
or obser vati on onl y. Seventy-fi ve per cent of the pati ents had nodal
metastases (50% had r ecur r ent di sease i n the r egi onal nodes).

Unl i ke E1684, E1690 al l owed entr y of pati ents wi th T4 pr i mar y


tumor s, r egar dl ess of whether l ymph node di ssecti on was
per for med, and 25% of the pati ents i n the tr i al had deep pr i mar y
tumor s (compar ed wi th 11% i n E1684).
In E1690, at a medi an fol l ow-up of 52 months, hi gh-dose IF N al fa2b demonstrated a r el apse-fr ee sur vi val benefi t exceedi ng that of
l ow-dose IF N al fa-2b or obser vati on. The 5-year esti mated r el apsefr ee sur vi val rates for hi gh-dose IF N al fa-2b, l ow-dose IF N al fa-2b,
and obser vati on wer e 44% , 40% , and 35% , r especti vel y (p = 0.03).
The r el apse-fr ee sur vi val benefi t was equi val ent for node-negati ve
and node-posi ti ve pati ents. As of thi s wr i ti ng, nei ther hi gh-dose nor
l ow-dose IF N al fa-2b has demonstrated an overal l sur vi val benefi t
compar ed wi th obser vati on.
An anal ysi s of sal vage therapy for pati ents whose di sease r el apsed
on E1690 demonstrated that a si gni fi cantl y l ar ger pr opor ti on of
pati ents i n the obser vati on ar m than i n the hi gh-dose IF N ar m
r ecei ved IF N al fa-contai ni ng sal vage therapy, whi ch may have
confounded i nter pr etati on of the sur vi val benefi t of assi gned
tr eatments. Some of the di scr epancy between the fi ndi ngs of E1684
and E1690 may be attr i butabl e to di ffer ences i n pati ent
demographi c pr ofi l es. E1690 i ncl uded pati ents wi th mor e favorabl e
di sease character i sti cs: Onl y 75% of pati ents wer e node posi ti ve,
and of these, 51% had nodal r ecur r ence. In E1690, 25% of pati ents
enr ol l ed wer e cl i ni cal stage II; i n E1684, 11% wer e pathol ogi cal
stage II. Pr esumabl y, some of the cl i ni cal stage II pati ents i n E1690
woul d have been pathol ogi cal stage III had l ymphadenectomy been
r equi r ed. An updated anal ysi s of E1690 wi th a medi an fol l ow-up of
7.2 year s has confi r med the study's or i gi nal concl usi ons.
ECOG tr i al E1694 was i ni ti ated to compar e the effi cacy and safety
of a gangl i osi de vacci ne wi th the effi cacy and safety of hi gh-dose
IF N al fa-2b i n pati ents wi th stage IIb or stage III mel anoma. The
gangl i osi de G M2 i s a ser ol ogi cal l y wel l -defi ned mel anoma anti gen
and the most i mmunogeni c gangl i osi de expr essed on mel anoma
cel l s. Pr el i mi nar y studi es had suggested that the anti body r esponse
to G M2 was cor r el ated wi th r el apse-fr ee and overal l sur vi val . In
E1694, 774 el i gi bl e pati ents wi th hi gh-r i sk mel anoma (tumor
thi ckness >4.0 mm or r egi onal l ymph node metastasi s) wer e
randomi zed to r ecei ve hi gh-dose IF N al fa-2b or G M2 vacci ne. The
study was cl osed ear l y by the data safety moni tor i ng boar d because
of the cl ear super i or i ty of IF N al fa-2b i n ter ms of both di sease-fr ee
and overal l sur vi val . The esti mated 2-year r el apse-fr ee sur vi val
rates wer e 62% i n the hi gh-dose IF N al fa-2b ar m and 49% i n the

G M2 vacci ne ar m. F ur ther mor e, anal ysi s of the haz ar d of r el apse


and death i n subgr oups based on the number of l ymph nodes
demonstrated the super i or i ty of IF N al fa-2b over G M2 i n al l nodal
subsets. E1694 al so showed a stati sti cal l y si gni fi cant benefi t for IF N
al fa-2b i n node-negati ve hi gh-r i sk pati ents.
A r ecent pool ed meta-anal ysi s of pr i mar y data fr om the
ECOG /Inter gr oup tr i al s of hi gh-dose IF N (n = 1,916) r eveal ed a
cl ear benefi t of hi gh-dose IF N al fa-2b i n ter ms of r el apse-fr ee
sur vi val and a mor e modest benefi t i n ter ms of overal l sur vi val
(odds rati o = 0.9, p = 0.05). Data fr om an updated anal ysi s of the
ECOG database demonstrated that (a) the sur vi val i mpact of IF N
al fa-2b was confi ned to r egi mens that i ncor porated both hi gh-dose
i nducti on and hi gh-dose subcutaneous mai ntenance; (b) r educti on
of haz ar d was obser ved ear l y; and (c) the r el apse-fr ee sur vi val
advantage was sustai ned off tr eatment, i n contrast to the mor e
l i mi ted r el apse-fr ee sur vi val advantage r epor ted by the l ow-dose
tr i al s.
Resul ts of tr i al s i nvesti gati ng l ow-dose IF N al fa-2b have been
di sappoi nti ng. The pr evi ousl y menti oned E1690 tr i al , a thr ee-ar m
tr i al that i ncl uded l ow-dose IF N al fa-2b as one of the tr eatments,
demonstrated a nonsi gni fi cant i mpr ovement i n r el apse-fr ee sur vi val
i n pati ents wi th hi gh-r i sk stage II or stage III mel anoma who
r ecei ved l ow-dose IF N al fa-2b for 2 year s. The modest i mpr ovement
i n the l ow-dose IF N al fa-2b ar m compar ed wi th the contr ol ar m
di sappear ed wi thi n 2 year s after therapy was stopped. The Eur opean
Or gani z ati on for Resear ch and Tr eatment of Cancer 18871 tr i al al so
demonstrated that a r egi men of ver y l ow-dose IF N al fa-2b (1 mi l l i on
uni ts per m2 ) i njected subcutaneousl y on al ter nate days for 1 year
di d not affect overal l sur vi val for pati ents wi th hi gh-r i sk mel anoma.
Because of the l ack of a demonstrabl e durabl e cl i ni cal benefi t, l owdose IF N al fa-2b has not been appr oved as adjuvant therapy for
mel anoma i n the Uni ted States.

Radiation Therapy
Al though sur ger y r emai ns the pr i mar y tr eatment for pati ents wi th
l ocal i zed mel anoma, avai l abl e data i ndi cate a need for i mpr oved
l ocor egi onal contr ol i n cases i n whi ch compl ete sur gi cal r esecti on i s
di ffi cul t or hi gh-r i sk featur es ar e noted pathol ogi cal l y. Factor s
associ ated wi th a hi gh r i sk of subsequent r egi onal basi n r ecur r ence
i ncl ude l ymph nodes at l east 3 cm i n si ze, four or mor e posi ti ve

l ymph nodes, the pr esence of extracapsul ar extensi on, and


r ecur r ent di sease after i ni ti al sur gi cal r esecti on. Retr ospecti ve and
phase II pr ospecti ve studi es have r eveal ed that adjuvant radi ati on
therapy can si gni fi cantl y i mpr ove the l ocor egi onal contr ol rate i n
these cl i ni cal setti ngs. In one study i n pati ents wi th l ymph node
metastases fr om mel anoma wi th hi gh-r i sk featur es, adjuvant
radi ati on therapy del i ver ed usi ng a hypofracti onated r egi men
r esul ted i n an 87% 5-year r egi onal nodal basi n contr ol rate,
super i or to the 50% to 70% l ocal contr ol rate achi eved wi th sur ger y
al one. The hypofracti onated r egi men was wel l tol erated and i s
conveni ent for such pati ents, i n whom sur vi val expectati ons may be
l ow. The i mpact of adjuvant radi ati on therapy on the i nci dence of
di stant metastasi s and overal l sur vi val has yet to be deter mi ned.
Si gni fi cant i mpr ovements i n outcome wi l l r equi r e commensurate
i mpr ovements i n systemi c di sease contr ol . The i mpor tance of l ocal
contr ol i n r educi ng mor bi di ty, however, shoul d not be
under esti mated, and futur e r esear ch goal s shoul d i ncl ude
randomi zed cl i ni cal tr i al s to fur ther defi ne the r ol e of adjuvant
radi ati on therapy al one or i n combi nati on wi th systemi c
therapy. In general , pati ents wi th mul ti pl e i nvol ved or matted
r egi onal nodes or wi th extracapsul ar extensi on of r egi onal
l ymphati c metastases shoul d be consi der ed for adjuvant radi ati on
therapy.

Chemotherapy
No confi r med studi es have demonstrated a benefi t of adjuvant
chemotherapy i n pati ents wi th mel anoma who ar e at hi gh r i sk for
r el apse. On the contrar y, a randomi zed tr i al of adjuvant dacar baz i ne
ver sus no adjuvant tr eatment showed a stati sti cal l y si gni fi cant
decr ease i n sur vi val i n the adjuvant tr eatment ar m. Adjuvant
chemotherapy shoul d be consi der ed onl y i n the context of a cl i ni cal
tr i al .

Management of Distant Metastatic Disease


Common si tes of di stant metastasi s i n mel anoma pati ents ar e, i n
or der of decr easi ng fr equency, ski n and subcutaneous ti ssues, l ung,
l i ver, and brai n. Pati ents wi th systemi c metastases have a poor
pr ognosi s. G eneral gui del i nes for choosi ng tr eatment modal i ti es
fol l ow, but no tr eatment for metastati c mel anoma has been pr oven
to pr ol ong sur vi val . Exper i mental tr eatments ar e an opti on for most
pati ents i n whom di stant metastases ar e di agnosed.

Surgery
Sur ger y i s a ver y effecti ve pal l i ati ve tr eatment for i sol ated
accessi bl e di stant metastases. Exampl es of accessi bl e l esi ons
i ncl ude i sol ated vi sceral metastases, i sol ated brai n metastases, and
occasi onal l y i sol ated l ung metastases.

Lesions Causing Gastrointestinal Tract


Obstruction
G astr oi ntesti nal tract obstr ucti on fr om metastati c mel anoma i s
usual l y due to l ar ge pol ypoi d l esi ons that mechani cal l y obstr uct the
bowel or act as a l ead poi nt for i ntussuscepti on. These submucosal
l esi ons ar e general l y r emoved by bowel r esecti on.

Pulmonary Metastases
The val ue of r esecti ng pul monar y metastases fr om mal i gnant
mel anoma i s contr over si al . In a study exami ni ng 65 pul monar y
r esecti ons per for med for hi stol ogi cal l y pr oven pul monar y
metastases di scover ed after tr eatment of the pr i mar y mel anoma,
the postthoracotomy actuar i al sur vi val rate was 25% at 5 year s
(medi an i nter val fr om pul monar y r esecti on to death, 18 months).
Sur vi val was not affected by the l ocati on, hi stol ogi c subtype,
Br esl ow thi ckness, or Cl ar k l evel of the pr i mar y tumor, or by the
type of r esecti on. Pati ents wi thout r egi onal nodal metastases befor e
thoracotomy had a medi an sur vi val of 30 months, compar ed wi th 16
months for al l other pati ents. The author s concl uded that pati ents
wi th i sol ated pul monar y metastases fr om mel anoma may benefi t
fr om r esecti on of metastases.

Liver Metastases
F i fteen to 20% of pati ents wi th metastati c mel anoma have l i ver
metastases. Hi stor i cal l y, the medi an sur vi val of pati ents wi th l i ver
metastases has ranged fr om 2 to 7 months. Chemotherapy i s of
l i mi ted effi cacy agai nst l i ver metastases, so sur gi cal r esecti on
may r epr esent the onl y potenti al l y curati ve opti on for pati ents wi th
mel anoma metastati c to the l i ver.
Some i nvesti gator s have suggested that r esecti on of hepati c
metastasi s i s not war ranted because of the associ ated di smal
pr ognosi s. Other i nvesti gator s have suggested that r esecti on may be

appr opr i ate onl y i n pati ents wi th an ocul ar pr i mar y tumor because
thei r cl i ni cal cour se i s better than that of pati ents wi th l i ver
metastases fr om cutaneous pr i mar y tumor s. In a r ecent ser i es of 40
pati ents who under went r esecti on of l i ver metastases fr om
mel anoma, 75% of the pati ents devel oped a subsequent r ecur r ence.
Pati ents wi th cutaneous mel anoma wer e si gni fi cantl y mor e l i kel y to
have a subsequent r ecur r ence outsi de the l i ver, suggesti ng that the
di sease i s systemi c at the ti me of hepati c r esecti on. No pati ent wi th
cutaneous mel anoma metastati c to the l i ver was al i ve at 5 year s.
Thus, sel ecti on of pati ents for r esecti on of hepati c metastases must
be i ndi vi dual i zed and i ncl ude an extensi ve eval uati on of the extent
of the di sease. We cur r entl y r ecommend that pati ents wi th l i mi ted
hepati c metastases who can be r ender ed sur gi cal l y fr ee of di sease
be consi der ed for hepati c r esecti on. However, because r ecur r ence
after r esecti on i s common, r esecti on shoul d be per for med as par t of
a mul ti di sci pl i nar y appr oach i n conjuncti on wi th systemi c therapy.

Brain Metastases
Mel anoma ranks behi nd onl y smal l -cel l car ci noma of the l ung as the
most common tumor that metastasi zes to the brai n. An unusual
featur e of brai n metastases i s thei r pr opensi ty for hemor r hage,
whi ch occur s much mor e fr equentl y wi th mel anoma brai n
metastases than wi th brai n metastases fr om other pr i mar y tumor s.
Hemor r hage occur s i n 33% to 50% of pati ents wi th brai n
metastases fr om mel anoma.
Sur gi cal exci si on (fol l owed i n sel ected cases by crani al i r radi ati on)
i s the tr eatment of choi ce i n the case of a sol i tar y, sur gi cal l y
accessi bl e brai n metastasi s. Tumor exci si on i s r el ati vel y safe,
al l evi ates symptoms i n most pati ents, and pr events fur ther
neur ol ogi c damage. Al though l ong-ter m di sease-fr ee sur vi val i s
uncommon, a rar e pati ent may l i ve mor e than 5 year s after sur ger y.
Radi ati on therapy i s pr efer r ed when the l esi ons ar e numer ous or ar e
l ocated i n ar eas that pr ecl ude a safe operati on. G amma kni fe
radi osur ger y i s al so an opti on for pati ents wi th smal l to medi um
brai n metastases who have a r easonabl e l i fe expectancy and no
si gns of i ncr eased i ntracrani al pr essur e.

Recurrent Distant Metastases


Unfor tunatel y, many pati ents under goi ng compl ete sur gi cal
r esecti on of di stant metastati c mel anoma (stage IV) devel op
r ecur r ent di sease. A r ecent study exami ned whether a second

metastasectomy coul d pr ol ong the sur vi val of pati ents wi th


r ecur r ent stage IV mel anoma. In thi s study, the r ecur r ent di sease
affected soft ti ssue, pul monar y, gastr oi ntesti nal , cer ebral , skel etal ,
and gynecol ogi c si tes. Medi an sur vi val fol l owi ng tr eatment for
r ecur r ent stage IV mel anoma was 18.2 months after compl ete
metastasectomy, compar ed wi th 12.5 months after a pal l i ati ve
sur gi cal pr ocedur e and 5.9 months after nonsur gi cal management.
The 5-year sur vi val rate was 20% for pati ents i n the compl ete
metastasectomy gr oup, compar ed wi th 7% for those i n the pal l i ati ve
sur ger y gr oup and 2% for those i n the nonsur gi cal gr oup. By
mul ti var i ate anal ysi s, the two most i mpor tant pr ognosti c factor s for
sur vi val fol l owi ng di agnosi s of r ecur r ent stage IV mel anoma wer e a
pr ol onged di sease-fr ee i nter val befor e r ecur r ence and compl ete
sur gi cal r emoval of the r ecur r ent di sease. These fi ndi ngs i ndi cate
that metastasectomy can pr ol ong the sur vi val of pati ents wi th
r ecur r ent stage IV mel anoma and shoul d be consi der ed i f al l
cl i ni cal l y evi dent tumor s can be r esected.

Radiation Therapy
In the tr eatment of cutaneous and l ymph node metastases wi th
radi ati on, most author s have obser ved i mpr oved r esponse rates wi th
hi gher fracti onal doses of radi ati on. The appr opr i ate dose
fracti onati on shoul d be based on nor mal ti ssue tol erance. Mul ti pl e
or r ecur r ent ski n or subcutaneous l esi ons may be tr eated
successful l y wi th hypofracti onated radi ati on therapy. Pr edi ctor s of a
r esponse to radi ati on therapy i ncl ude pr i mar y tumor l ocati on i n the
head and neck r egi on and total radi ati on dose above 40 G y; age,
gender, and hi stol ogi c subtype have no i mpact. Exter nal -beam
radi ati on therapy can pr ovi de l ong-ter m l ocal contr ol and effecti ve
pal l i ati on. Symptomati c bony metastases fr om mel anoma al so
fr equentl y r espond to exter nal -beam radi ati on therapy.

Chemotherapy
Si ngl e-agent chemotherapy r emai ns the standar d of car e for
systemi c chemotherapy i n pati ents wi th metastati c mel anoma.
Dacar baz i ne i s the dr ug of choi ce, wi th a r esponse rate of 16% .
Other dr ugs, i ncl udi ng ci spl ati n, pacl i taxel , docetaxel , and the
dacar baz i ne anal og, temozol omi de, have al so shown acti vi ty i n thi s
di sease. In a phase II tr i al of 56 pati ents tr eated wi th
temozol omi de, a compl ete r esponse was documented i n thr ee
pati ents (al l wi th l ung metastases) and a par ti al r esponse i n ni ne

pati ents (21% overal l r esponse rate).


Based on obser ved si ngl e-agent acti vi ty, several combi nati on
r egi mens have been i nvesti gated, and pr el i mi nar y r esul ts appear
pr omi si ng. The Dar tmouth r egi men (dacar baz i ne, ci spl ati n,
car musti ne, and tamoxi fen) was i ni ti al l y r epor ted to have an overal l
r esponse rate of 55% and compl ete r esponse rate of 20% . However,
subsequent mul ti center tr i al s have fai l ed to cor r oborate these
favorabl e r esul ts. In fact, i n randomi zed phase III tr i al s, the two
most acti ve combi nati on chemotherapy r egi mens, the Dar tmouth
r egi men and ci spl ati n, vi nbl asti ne, and dacar baz i ne, have not
pr oven to be super i or to si ngl e-agent dacar baz i ne i n ter ms of
overal l sur vi val . Other combi nati ons, such as temozol omi de and
ci spl ati n, have not been shown to have cl ear benefi ts i n ter ms of
r esponse rates but may be associ ated wi th a hi gher i nci dence of
grade 3 or grade 4 emesi s.
If no objecti ve r esponse i s obser ved after two or thr ee cour ses of a
par ti cul ar chemotherapy r egi men, i t i s usual l y pr udent to
di sconti nue that r egi men and consi der other appr oaches. In general ,
even when metastati c mel anoma r esponds to systemi c
chemotherapy, the durati on of the r esponse i s usual l y shor t, i n the
range of 3 to 6 months.

Vaccine and Biological Therapies


Mor ton et al . demonstrated that i ntral esi onal i njecti on of vi abl e
baci l l us Cal mette-G ur i n (BCG ) or gani sms coul d l ead to the
r egr essi on of i ntrader mal mel anoma metastasi s. Even mor e
si gni fi cantl y, uni njected l esi ons occasi onal l y r egr essed fol l owi ng
BCG therapy. Thi s fi ndi ng demonstrated the abi l i ty of the body's
i mmune system to destr oy mel anoma when pr oper l y sti mul ated,
l eadi ng to i nvesti gati ons of BCG as a potenti al therapy for
mel anoma. Al though several nonrandomi zed tr i al s usi ng hi stor i cal
contr ol s and two smal l randomi zed tr i al s of i ntral esi onal or
i ntral ymphati c BCG showed a stati sti cal l y si gni fi cant overal l sur vi val
benefi t i n favor of BCG , mul ti pl e other randomi zed tr i al s fai l ed to
substanti ate these fi ndi ngs. Nonethel ess, i nter est i n modul ati ng the
i mmune system to tr eat mel anoma has per si sted.

Monoclonal Antibodies
Monocl onal anti body therapy i s general l y wel l tol erated and has
shown acti vi ty i n phase I tr i al s i n pati ents wi th metastati c

mel anoma. Monocl onal anti bodi es have been used to tar get
radi ati on and potent pl ant toxi ns to tumor s, and anti -i di otype
anti bodi es have been used to sti mul ate i mmune r esponses.

Tumor Vaccines
Tumor vacci nes have been used i n the tr eatment of advanced
mel anoma and as adjuvant therapy for pati ents wi th hi gh-r i sk
mel anoma. These vacci nes may contai n (a) i r radi ated tumor cel l s,
usual l y obtai ned fr om the pati ent; (b) par ti al l y or compl etel y
pur i fi ed mel anoma anti gens; or (c) tumor cel l membranes fr om
mel anoma cel l s i nfected wi th vi r us (vi ral oncol ysates). Syntheti c
vacci nes contai ni ng genes that encode for tumor anti gens and the
pepti de anti gens themsel ves ar e al so bei ng eval uated, as ar e
vacci nes contai ni ng genes encodi ng for i mmune costi mul ator y si gnal
pr otei ns.
Al l ogenei c tumor cel l vacci nes, general l y pr epar ed fr om cul tur ed
cel l l i nes or l ysates ther eof, offer several potenti al i mpor tant
advantages over autol ogous tumor cel l vacci nes: Al l ogenei c vacci nes
ar e r eadi l y avai l abl e and can be standar di zed, pr eser ved, and
di str i buted i n a manner aki n to any other therapeuti c agent. To
date, the major i ty of studi es i nvol vi ng al l ogenei c tumor vacci nes
have been smal l , si ngl e-i nsti tuti on studi es. None of these have
demonstrated an unequi vocal benefi t for i mmunotherapy wi th
al l ogenei c tumor cel l s admi ni ster ed i n conjuncti on wi th BCG
compar ed wi th no tr eatment or tr eatment wi th BCG al one. Two
randomi zed studi es have been conducted i n whi ch al l ogenei c
mel anoma vacci nes wer e admi ni ster ed wi th or wi thout
cycl ophosphami de gi ven for 3 days pr i or to vacci nati on. The r esul ts
of these studi es have been confl i cti ng, wi th one suggesti ng a
decr ease i n suppr essor cel l acti vi ty and one suggesti ng an i ncr ease
i n suppr essor cel l acti vi ty and augmented anti body r esponse.
Novel vacci ne strategi es under i nvesti gati on i ncl ude admi ni strati on
of syntheti c pepti des based on known mel anoma T-cel l
anti gens, geneti c vacci nes, and combi nati ons of vacci nes wi th
cytoki nes or costi mul ator y mol ecul es. Mor ton et al . conducted
nonrandomi zed studi es of a pol yval ent mel anoma vacci ne
(Canvaxi n) i n pati ents wi th stage III or stage IV di sease. Matchedpai r anal yses of data fr om extensi ve phase 2 tr i al s demonstrated a
consi stent overal l sur vi val benefi t for Canvaxi n therapy i n stage III
mel anoma (5-year overal l sur vi val rate: 49% for Canvaxi n vs. 37%

for no vacci ne; p = 0.0001) and stage IV mel anoma (5-year overal l
sur vi val rate: 39% for Canvaxi n vs. 20% for no vacci ne; p =
0.0009). Vacci ne-i nduced i mmune r esponses have cor r el ated wi th
i mpr oved sur vi val after r esecti on of l ocal , r egi onal , and di stant
di sease. Two seperate phase 3 cl i ni cal tr i al s of Canvaxi n i n pati ents
wi th stage III or IV mel anoma wer e di sconti nued i n 2005 based on
the r ecommendati on of the data safety moni tor i ng boar d after an
i nter i m anal ysi s of the study data. The moni tor i ng boar d found that
the data wer e unl i kel y to pr ovi de si gni fi cant evi dence of a sur vi val
benefi t for Canvaxi n ver sus pl acebo i n pati ents wi th stage III or
stage IV mel anoma.
In 2002, the Southwest Oncol ogy G r oup publ i shed the r esul ts of a
l ar ge, randomi zed tr i al (S9035) compar i ng co-admi ni strati on of an
al l ogenei c mel anoma cel l l ysate (Mel aci ne) and detoxi fi ed
endotoxi n/mycobacter i al cel l wal l skel eton (DETOX) ver sus no
tr eatment i n pati ents wi th i nter medi ate thi ckness, node-negati ve
mel anoma. The pr i mar y ai m of thi s tr i al was to deter mi ne the effect
of the vacci ne on r el apse-fr ee sur vi val . A major secondar y ai m was
to deter mi ne i f the effecti veness of the vacci ne was based on
pati ents HLA cl ass I al l el e expr essi on. At a medi an fol l ow-up of 4.1
year s, ther e was no di ffer ence i n overal l r el apse-fr ee sur vi val
between the two gr oups. The pati ents i n the vacci ne ar m expr essi ng
at l east 2 M5 al l el es, however, had better di sease-fr ee sur vi val than
the cor r espondi ng pati ents i n the obser vati on ar m. F ur ther mor e,
vacci ne-ar m pati ents expr essi ng at l east 2 M5 al l el es had better
di sease-fr ee sur vi val than vacci ne-ar m pati ents expr essi ng fewer
than 2 M5 al l el es.

Cellular Therapies
Cel l ul ar therapi es al so exhi bi t some pr omi se. Rosenber g et al . at
the U.S. Nati onal Cancer Insti tute and other s have r epor ted thei r
exper i ences wi th adopti ve i mmunotherapy usi ng tumor-i nfi l trati ng
l ymphocytes and, mor e r ecentl y, dendr i ti c cel l s. An overal l r esponse
rate of 37% was seen i n pati ents wi th stage IV di sease. Newer
for ms of cel l ul ar-based therapy ar e bei ng devel oped, i ncl udi ng
effector cel l s fr om tumor vacci ne-pr i med l ymph nodes. Tr i al s usi ng
i n vi tr o pul sed dendr i ti c cel l i nfusi on ar e ongoi ng. In addi ti on, new
wor k i s exami ni ng whether pr efer enti al i nducti on of apoptosi s by
sequenti al 5-Az a-2 deoxycyti di ne-depsi pepti de (F R901228)
tr eatment i n mel anoma cel l s to i mpr ove r ecogni ti on of speci fi c
tar gets by cytol yti c T l ymphocytes may ser ve as a useful adjunct to
i mmunotherapy.

Immunotherapy
Immunotherapy wi th ei ther i nter l euki n (IL)-2 or IF N has
demonstrated r esponse rates of 10% to 15% i n appr opr i atel y
sel ected
pati ents. In pati ents who have a compl ete r esponse, r esponses can
be of gr eater durabi l i ty than those wi th chemotherapy. IL-2
pr omotes the pr ol i ferati on, di ffer enti ati on, and r ecr ui tment of T, B,
and NK cel l s and i ni ti ates cytol yti c acti vi ty i n a subset of
l ymphocytes. In pati ents who had a compl ete r esponse to IL-2, the
major i ty (86% ) r emai ned i n ongoi ng compl ete r emi ssi on fr om 39 to
mor e than 148 months. In pati ents wi th a par ti al r esponse, medi an
r esponse durati on has been 36 to 45 months. Al though the overal l
r esponse rate i s l ow (10% 15% ), the durabi l i ty of the r esponses l ed
the U.S. Food and Dr ug Admi ni strati on to appr ove hi gh-dose IL-2 for
metastati c mel anoma. However, IL-2 and IF N admi ni strati on ar e
associ ated wi th mul ti pl e si de effects; ther efor e, these agents shoul d
be admi ni ster ed onl y by physi ci ans exper i enced i n the management
of such therapi es. One major systemi c toxi c effect wi th hi gh-dose
IL-2 admi ni strati on i s capi l l ar y l eak syndr ome. Thi s toxi c effect i s,
for tunatel y, uncommon, but i t can be l i fe thr eateni ng.

Biochemotherapy
Mul ti pl e tr i al s have been conducted to i nvesti gate the benefi t of
combi ni ng bi ol ogi cal therapy wi th chemotherapy (so-cal l ed
bi ochemotherapy). These tr i al s i ndi cate that bi ochemotherapy i s
associ ated wi th hi gher r esponse rates and l onger medi an sur vi val s
than chemotherapy al one. Speci fi cal l y, phase I and II studi es have
eval uated combi nati ons of IL-2, IF N, and chemotherapy (ci spl ati n,
dacar baz i ne, or cycl ophosphami de). Pr el i mi nar y r esul ts fr om a
ser i es of smal l studi es usi ng combi nati ons of IL-2, IF N al fa, and
ci spl ati n have i ndi cated overal l r esponse rates of 40% . Recentl y, a
phase III tr i al was compl eted at M. D. Ander son that compar ed
i npati ent sequenti al bi ochemotherapy wi th tradi ti onal outpati ent
chemotherapy wi th r espect to r esponse, ti me to pr ogr essi on, overal l
sur vi val rate, and toxi ci ty. Al l pati ents had ei ther stage IV or
i noperabl e stage III di sease, an ECOG per for mance status of 0 to 3,
no symptomati c brai n metastases, no pr i or chemotherapy, and
adequate car di ac, hematol ogi c, and r enal r eser ves. The r esponse
rate was 48% wi th bi ochemotherapy and 25% wi th standar d
chemotherapy (p = 0.0001). The ti me to pr ogr essi on was 4.6

months wi th bi ochemotherapy and 2.4 months wi th standar d


chemotherapy (p = 0.0007). The medi an sur vi val was 11.8 months
wi th bi ochemotherapy and 9.5 months wi th standar d chemotherapy
(p = 0.055). Bi ochemotherapy di d i nduce sever e consti tuti onal toxi c
effectsmyel osuppr essi on, i nfecti ons, and hypotensi onbut al l of
these wer e found to be manageabl e on the general war d. In a mor e
r ecent phase II tr i al by the same gr oup, the addi ti on of IF N al fa-2a
to IL-2 was exami ned. Al though the r esponse rate for thi s r egi men
was l ow, durabl e r esponses wi th medi an sur vi val durati ons of 30+
months wer e seen i n sel ected pati ents. However, several phase III
tr i al s have not consi stentl y demonstrated an i mpr ovement i n ei ther
r esponse rates or overal l sur vi val .
Adopti ve i mmunotherapy combi ni ng nonmyel oabl ati ve chemotherapy
wi th hi gh-dose IL-2 i s another potenti al l y pr omi si ng therapeuti c
strategy cur r entl y under i nvesti gati on.

Follow-Up
Mel anoma has a mor e var i abl e and unpr edi ctabl e cl i ni cal cour se
than al most any other human cancer. At M. D. Ander son, the
schedul e of fol l ow-up eval uati ons for pati ents wi th mel anoma var i es
accor di ng to the r i sk of r ecur r ence. In general , pati ents wi th ear l ystage mel anoma (i n si tu or <1.0-mm thi ck, nonul cerated, l ymphnode negati ve) have fol l ow-up vi si ts ever y 6 months for 2 year s and
then annual l y. Pati ents wi th thi cker or ul cerated mel anomas and
those wi th posi ti ve l ymph nodes general l y r etur n for fol l ow-up vi si ts
mor e fr equentl yever y 3 to 4 months up to 3 year s, ever y 6
months dur i ng year s 3 and 4, and annual l y ther eafter. At each vi si t,
the pati ent under goes a physi cal exami nati on, ski n sur vey, chest
radi ography, and measur ement of LDH. Excepti ons to thi s r outi ne
cl i ni c vi si t ar e made for pati ents wi th mel anoma i n si tu, i n whom
chest radi ography and measur ement of LDH l evel s ar e not r outi nel y
per for med, and pati ents wi th thi n mel anomas, i n whom chest
radi ography and measur ement of LDH l evel s ar e general l y done
annual l y. Abnor mal fi ndi ngs may pr ompt fur ther wor kup. Par ti cul ar
attenti on shoul d be pai d to si gns or symptoms of central ner vous
system i nvol vement. Extensi ve radi ographi c eval uati on of
asymptomati c pati ents wi th AJCC stage I, stage II, or stage III
mel anoma who ar e cl i ni cal l y fr ee of di sease rar el y r eveal s
metastases and thus i s not r outi nel y per for med.

Recommended Reading
Al ber ti ni JJ, Cr use CW, Rapapor t D, et al . Intraoperati ve radi ol ymph-sci nti graphy i mpr oves senti nel l ymph node i denti fi cati on
for pati ents wi th mel anoma. Ann Sur g 1996;223:217224.
Al oi a TA, G er shenwal d JE. Management of ear l y-stage cutaneous
mel anoma. Cur r Pr ob Sur g 2005;42:468534.
Amer i can Joi nt Commi ttee on Cancer (AJCC). Mel anoma of the
ski n. In: G r eene F L, Page DL, F l emi ng ID, et al ., eds. AJCC
Cancer Staging Manual. 6th ed. New Yor k: Spr i nger-Ver l ag;
2002:239254.
Ang KK, Peter s L J, Weber RS, et al . Postoperati ve radi otherapy
for cutaneous mel anoma of the head and neck r egi on. Int J Radiat
Oncol Biol Phys 1994;30:795798.
Bafal oukos D, Tsoutsos D, Kal ofonos H, et al . Temozol omi de and
ci spl ati n ver sus temozol omi de i n pati ents wi th advanced
mel anoma: a randomi zed phase II study of the Hel l eni c
Cooperati ve Oncol ogy G r oup. Ann Oncol 2005;16:950957.
Bal ch CM. The r ol e of el ecti ve l ymph node di ssecti on i n
mel anoma: rati onal e, r esul ts, and contr over si es. J Clin Oncol
1988;6:163172.
Bal ch CM, Buz ai d AC, Atki ns MB, et al . A new Amer i can Joi nt
Commi ttee on Cancer stagi ng system for cutaneous mel anoma.
Cancer 2000;88:14841491.
Bal ch CM, Buz ai d AC, Soong SJ, et al . F i nal ver si on of the
Amer i can Joi nt Commi ttee on Cancer stagi ng system for
cutaneous mel anoma. J Clin Oncol 2001;19:36353648.
Bal ch CM, Soong S-J, Bar tol uccci AA, et al . Effi cacy of an el ecti ve
r egi onal l ymph node di ssecti on of 1 to 4 mm thi ck mel anomas for
pati ents 60 year s of age and younger. Ann Sur g 1996;224:255
266.

Bal ch CM, Soong S-J, G er shenwal d JE, et al . Pr ognosti c factor


anal ysi s of 17,600 mel anoma pati ents: val i dati on of the Amer i can
Joi nt Commi ttee on Cancer mel anoma stagi ng system. J Clin
Oncol 2001;19:36223634.

Bal ch CM, Soong S-J, Murad TM, et al . A mul ti factor i al anal ysi s of
mel anoma. II. Pr ognosti c factor s i n pati ents wi th stage I
(l ocal i zed) mel anoma. Sur ger y 1979;86:343351.
Bal ch CM, Soong S-J, Murad TM, et al . A mul ti factor i al anal ysi s of
mel anoma: III. Pr ognosti c factor s i n mel anoma pati ents wi th
l ymph node metastases (stage II). Ann Sur g 1981;193:377388.
Bal ch CM, Soong S-J, Ross MI, et al . Long-ter m r esul ts of a mul ti i nsti tuti onal randomi zed tr i al compar i ng pr ognosti c factor s and
sur gi cal r esul ts for i nter medi ate thi ckness mel anomas (1.0 to 4.0
mm). Inter gr oup Mel anoma Sur gi cal Tr i al . Ann Sur g Oncol
2000;7:8797.
Bal l o MT, Ang KK. Radi otherapy for cutaneous mal i gnant
mel anoma: rati onal e and i ndi cati ons. Oncology (Huntingt)
2004;18:99107, di scussi on 107110, 113114.
Bal l o MT, G ar den AS, Myer s JN, et al . Mel anoma metastati c to
cer vi cal l ymph nodes: can radi otherapy r epl ace for mal di ssecti on
after l ocal exci si on of nodal di sease? Head Neck 2005; 27:718
721.
Bal l o MT, Str om EA, Zagar s G K, et al . Adjuvant i r radi ati on for
axi l l ar y metastases fr om mal i gnant mel anoma. Int J Radiat Oncol
Biol Phys 2002;52:964972.
Bal l o MT, Zagar s G K, G er shenwal d JE, et al . A cr i ti cal assessment
of adjuvant radi otherapy for i ngui nal l ymph node metastases
fr om mel anoma. Ann Sur g Oncol 2004;11:10791084.
Bedr osi an I, Far i es MB, G uer r y Dt, et al . Inci dence of senti nel
node metastasi s i n pati ents wi th thi n pr i mar y mel anoma (< or =
1 mm) wi th ver ti cal gr owth phase. Ann Sur g Oncol 2000;7:262

267.
Buz ai d AC, Ross MI, Bal ch CM, et al . Cr i ti cal anal ysi s of the
cur r ent Amer i can Joi nt Commi ttee on Cancer stagi ng system for
cutaneous mel anoma and pr oposal of a new stagi ng system. J Clin
Oncol 1997;15:10391051.
Cannon-Al br i ght LA, G ol dgar DE, Meyer L J, et al . Assi gnment of a
l ocus for fami l i al mel anoma, MLM, to chr omosome 9p13-p22.
Science 1992;258:11481152.
Casci nel l i N, Morabi to A, Santi nami M, et al . Immedi ate or
del ayed di ssecti on of r egi onal nodes i n pati ents wi th mel anoma of
the tr unk: a randomi sed tr i al . Lancet 1998;351:793796.
Cho E, Rosner BA, Feskani ch D, et al . Ri sk factor s and i ndi vi dual
pr obabi l i ti es of mel anoma for whi tes. J Clin Oncol 2005;23:2669
2675.
Chung MH, G upta RK, Hsueh E, et al . Humoral i mmune r esponse
to a therapeuti c pol yval ent cancer vacci ne after compl ete
r esecti on of thi ck pr i mar y mel anoma and senti nel
l ymphadenectomy. J Clin Oncol 2003;21:313319.
Cl ar y BM, Brady MS, Lewi s JJ, et al . Senti nel l ymph node bi opsy
i n the management of pati ents wi th pr i mar y cutaneous
mel anoma: r evi ew of a l ar ge si ngl e-i nsti tuti onal exper i ence wi th
an emphasi s on r ecur r ence. Ann Sur g 2001;233:250258.
Cochran AJ, Wen DR, Huang RR, et al . Pr edi cti on of metastati c
mel anoma i n nonsenti nel nodes and cl i ni cal outcome based on the
pr i mar y mel anoma and the senti nel node. Mod Pathol
2004;17:747755.
Cor mi er JN, Xi ng Y, Feng L, et al . Metastati c mel anoma to l ymph
nodes i n pati ents wi th unknown pr i mar y si tes. Cancer
2006;106:20122020.
Daponte A, Asci er to PA, G ravi na A, et al . Temozol omi de and
ci spl ati n i n advanced mal i gnant mel anoma. Anticancer Res

2005;25:14411447.
Dudl ey ME, Wunder l i ch JR, Robbi ns PF, et al . Cancer r egr essi on
and autoi mmuni ty i n pati ents after cl onal r epopul ati on wi th
anti tumor l ymphocytes. Science 2002;298:850854.
Dudl ey ME, Wunder l i ch JR, Yang JC, et al . Adopti ve cel l transfer
therapy fol l owi ng non-myel oabl ati ve but l ymphodepl eti ng
chemotherapy for the tr eatment of pati ents wi th r efractor y
metastati c mel anoma. J Clin Oncol 2005;23:23462357.

El der DE, G uer r y DT, VanHor n M, et al . The r ol e of l ymph node


di ssecti on for cl i ni cal stage I mal i gnant mel anoma of
i nter medi ate thi ckness (1.513.99 mm). Cancer 1985;56:413
418.
Essner R, Bosti ck PJ, G l ass EC, et al . Standar di zed pr obe-di r ected
senti nel node di ssecti on i n mel anoma. Sur ger y 2000;127:2631.
Eton O, Buz ai d AC, Bedi ki an AY, et al . A phase II study of
decr escendo i nter l euki n-2 pl us i nter fer on-al pha-2a i n pati ents
wi th pr ogr essi ve metastati c mel anoma after chemotherapy.
Cancer 2000;88:17031709.
Eton O, Legha SS, Bedi ki an AY, et al . Sequenti al bi ochemotherapy
ver sus chemotherapy for metastati c mel anoma: r esul ts fr om a
phase III randomi zed tr i al . J Clin Oncol 2002;20:20452052.
Evans G R, F r i edman J, Shenaq J, et al . Pl antar fl ap
r econstr ucti on for acral l enti gi nous mel anoma. Ann Sur g Oncol
1997;4:575578.
F raker DL, Al exander HR, Andr i ch M, et al . Pal l i ati on of r egi onal
symptoms of advanced extr emi ty mel anoma by i sol ated l i mb
per fusi on wi th mel phal an and hi gh-dose tumor necr osi s factor.
Cancer J Sci Am 1995;1:122.
F raker DL, Al exander HR, Andr i ch M, et al . Tr eatment of pati ents
wi th mel anoma of the extr emi ty usi ng hyper ther mi c i sol ated l i mb

per fusi on wi th mel phal an, tumor necr osi s factor, and i nter fer on
gamma: r esul ts of a tumor necr osi s factor dose-escal ati on study.
J Clin Oncol 1996;14:479489.
G ar be C, Buttner P, Wei ss J, et al . Ri sk factor s for devel opi ng
cutaneous mel anoma and cr i ter i a for i denti fyi ng per sons at r i sk:
mul ti center case-contr ol study of the Central Mal i gnant Mel anoma
Regi str y of the G er man Der matol ogi cal Soci ety. J Invest Der matol
1994;102:695699.
G er shenwal d JE, Ber man RS, Por ter G , et al . Regi onal nodal basi n
contr ol i s not compr omi sed by pr evi ous senti nel l ymph node
bi opsy i n pati ents wi th mel anoma. Ann Sur g Oncol 2000;7:226
231.
G er shenwal d JE, Col ome MI, Lee JE, et al . Patter ns of r ecur r ence
fol l owi ng a negati ve senti nel l ymph node bi opsy i n 243 pati ents
wi th stage I or II mel anoma. J Clin Oncol 1998;16:22532260.
G er shenwal d JE, Mansfi el d PF, Lee JE, et al . Rol e for l ymphati c
mappi ng and senti nel l ymph node bi opsy i n pati ents wi th thi ck (>
or = 4 mm) pr i mar y mel anoma. Ann Sur g Oncol 2000;7:160165.
G er shenwal d JE, Pr i eto VG , Col ome-G r i mmer MI, et al . The
pr ognosti c si gni fi cance of mi cr oscopi c tumor bur den i n 945
mel anoma pati ents under goi ng senti nel l ymph node bi opsy. 36th
Annual Meeti ng of the Amer i can Soci ety of Cl i ni cal Oncol ogy;
2003; New Or l eans, La.
G er shenwal d JE, Pr i eto VG , Johnson M. AJCC stage III (nodal )
cr i ter i a accuratel y pr edi ct sur vi val i n senti nel node-posi ti ve
mel anoma pati ents. 3r d Inter nati onal Senti nel Node Congr ess;
2002; Yokohama, Japan.
G er shenwal d JE, Thompson W, Mansfi el d PF, et al . Mul ti i nsti tuti onal mel anoma l ymphati c mappi ng exper i ence: the
pr ognosti c val ue of senti nel l ymph node status i n 612 stage I or
II mel anoma pati ents. J Clin Oncol 1999;17:976983.
G er shenwal d JE, Tseng CH, Thompson W, et al . Impr oved senti nel
l ymph node l ocal i z ati on i n pati ents wi th pr i mar y mel anoma wi th

the use of radi ol abel ed col l oi d. Sur ger y 1998;124:203210.


G i l l M, Cel ebi JT. B-RAF and mel anocyti c neopl asi a. J Am Acad
Der matol 2005;53:108114.
G ray-Schopfer VC, da Rocha Di as S, Marai s R. The r ol e of B-RAF
i n mel anoma. Cancer Metastasis Rev 2005;24:165183.
Hancock BW, Har r i s S, Wheatl ey K, et al . Adjuvant i nter fer onal pha i n mal i gnant mel anoma: cur r ent status. Cancer Tr eat Rev
2000;26:8189.
Hawki ns WG , Busam KJ, Ben-Porat L, et al . Desmopl asti c
mel anoma: a pathol ogi cal l y and cl i ni cal l y di sti nct for m of
cutaneous mel anoma. Ann Sur g Oncol 2005;12:207213.

Haywar d N. New devel opments i n mel anoma geneti cs. Cur r Oncol
Rep 2000;2:300306.
Heaton KM, Sussman JJ, G er shenwal d JE, et al . Sur gi cal mar gi ns
and pr ognosti c factor s i n pati ents wi th thi ck (>4 mm) pr i mar y
mel anoma. Ann Sur g Oncol 1998;5:322328.
Hender son RA, Mossman S, Nai r n N, et al . Cancer vacci nes and
i mmunotherapi es: emer gi ng per specti ves. Vaccine 2005;23:2359
2362.
Hol l y EA, Aston DA, Cr ess RD, et al . Cutaneous mel anoma i n
women. I. Exposur e to sunl i ght, abi l i ty to tan, and other r i sk
factor s r el ated to ul travi ol et l i ght. Am J Epidemiol 1995;141:923
933.
Hol l y EA, Cr ess RD, Ahn DK. Cutaneous mel anoma i n women. III.
Repr oducti ve factor s and oral contracepti ve use. Am J Epidemiol
1995;141:943950.
Hsueh EC, Essner R, Foshag L J, et al . Pr ol onged sur vi val after
compl ete r esecti on of di ssemi nated mel anoma and acti ve
i mmunotherapy wi th a therapeuti c cancer vacci ne. J Clin Oncol

2002;20:45494554.
Jemal A, Devesa SS, Fear s TR, et al . Cancer sur vei l l ance ser i es:
changi ng patter ns of cutaneous mal i gnant mel anoma mor tal i ty
rates among whi tes i n the Uni ted States. J Natl Cancer Inst
2000;92:811818.
Jemal A, Si egel R, War d E, et al . Cancer stati sti cs, 2006. CA
Cancer J Clin 2006;56:106130.
Kammul a US, G hossei n R, Bhattachar ya S, et al . Ser i al fol l ow-up
and the pr ognosti c si gni fi cance of r ever se transcr i ptasepol ymerase chai n r eacti onstaged senti nel l ymph nodes fr om
mel anoma pati ents. J Clin Oncol 2004;22:39893996.
Kang JC, Wanek LA, Essner R, et al . Senti nel l ymphadenectomy
does not i ncr ease the i nci dence of i n-transi t metastases i n
pr i mar y mel anoma. J Clin Oncol 2005;23:47644770.
Ki r kwood JM, Ibrahi m JG , Sondak VK, et al . Hi gh- and l ow-dose
i nter fer on al fa-2b i n hi gh-r i sk mel anoma: fi r st anal ysi s of
i nter gr oup tr i al E1690/S9111/C9190. J Clin Oncol 2000;18:2444
2458.
Ki r kwood JM, Ibrahi m JG , Sosman JA, et al . Hi gh-dose i nter fer on
al fa-2b si gni fi cantl y pr ol ongs r el apse-fr ee and overal l sur vi val
compar ed wi th the G M2-KLH/QS-21 vacci ne i n pati ents wi th
r esected stage IIBIII mel anoma: r esul ts of i nter gr oup tr i al
E1694/S9512/C509801. J Clin Oncol 2001;19:23702380.
Ki r kwood JM, Manol a J, Ibrahi m J, et al . A pool ed anal ysi s of
Easter n Cooperati ve Oncol ogy G r oup and i nter gr oup tr i al s of
adjuvant hi gh-dose i nter fer on for mel anoma. Clin Cancer Res
2004;10:16701677.
Ki r kwood JM, Strawder man MH, Er nstoff MS, et al . Inter fer on
al fa-2b adjuvant therapy of hi gh-r i sk r esected cutaneous
mel anoma: the Easter n Cooperati ve Oncol ogy G r oup Tr i al EST
1684. J Clin Oncol 1996;14:717.

Komenaka I, Hoer i g H, Kaufman HL. Immunotherapy for


mel anoma. Clin Der matol 2004;22:251265.
Koops HS, Vagl i ni M, Suci u S, et al . Pr ophyl acti c i sol ated l i mb
per fusi on for l ocal i zed, hi gh-r i sk l i mb mel anoma: r esul ts of a
mul ti center randomi zed phase III tr i al . Eur opean Or gani z ati on for
Resear ch and Tr eatment of Cancer Mal i gnant Mel anoma
Cooperati ve G r oup Pr otocol 18832, the Wor l d Heal th Or gani z ati on
Mel anoma Pr ogram Tr i al 15, and the Nor th Amer i can Per fusi on
G r oup Southwest Oncol ogy G r oup-8593. J Clin Oncol
1998;16:29062912.
Krag DN, Mei jer SJ, Weaver DL, et al . Mi ni mal -access sur ger y for
stagi ng of mal i gnant mel anoma. Ar ch Sur g 1995;130:654658,
di scussi on 659660.
Li W, Stal l A, Shi ver s SC, et al . Cl i ni cal r el evance of mol ecul ar
stagi ng for mel anoma: compar i son of RT-PCR and
i mmunohi stochemi str y stai ni ng i n senti nel l ymph nodes of
pati ents wi th mel anoma. Ann Sur g 2000;231:795803.

Li enar d D, Ewal enko P, Del motte JJ, et al . Hi gh-dose r ecombi nant


tumor necr osi s factor al pha i n combi nati on wi th i nter fer on
gamma and mel phal an i n i sol ati on per fusi on of the l i mbs for
mel anoma and sar coma. J Clin Oncol 1992;10:5260.
Li ndner P, Doubr ovsky A, Kam PC, et al . Pr ognosti c factor s after
i sol ated l i mb i nfusi on wi th cytotoxi c agents for mel anoma. Ann
Sur g Oncol 2002;9:127136.
Li vi ngston PO, Wong G Y, Adl ur i S, et al . Impr oved sur vi val i n
stage III mel anoma pati ents wi th G M2 anti bodi es: a randomi zed
tr i al of adjuvant vacci nati on wi th G M2 gangl i osi de. J Clin Oncol
1994;12:10361044.
Mansfi el d PF, Lee JE, Bal ch CM. Cutaneous mel anoma: cur r ent
practi ce and sur gi cal contr over si es. Cur r Pr obl Sur g
1994;31:253374.

McCar thy WH, Shaw HM, Mi l ton G W. Effi cacy of el ecti ve l ymph
node di ssecti on i n 2,347 pati ents wi th cl i ni cal stage I mal i gnant
mel anoma. Sur g G ynecol Obstet 1985;161:575580.
McMaster s KM. The Sunbel t Mel anoma Tr i al . Ann Sur g Oncol
2001;8:41S43S.
McMaster s KM, Rei ntgen DS, Ross MI, et al . Senti nel l ymph node
bi opsy for mel anoma: how many radi oacti ve nodes shoul d be
r emoved? Ann Sur g Oncol 2001;8:192197.
Mi l ton G W, Shaw HM, McCar thy WH, et al . Pr ophyl acti c l ymph
node di ssecti on i n cl i ni cal stage I cutaneous mal i gnant
mel anoma: r esul ts of sur gi cal tr eatment i n 1319 pati ents. Br J
Sur g 1982;69:108111.
Mor ton DL. Immune r esponse to postsur gi cal adjuvant acti ve
i mmunotherapy wi th Canvaxi n pol yval ent cancer vacci ne:
cor r el ati ons wi th cl i ni cal cour se of pati ents wi th metastati c
mel anoma. Dev Biol (Basel) 2004;116:209217, di scussi on 229
236.
Mor ton DL, Foshag L J, Hoon DS, et al . Pr ol ongati on of sur vi val i n
metastati c mel anoma after acti ve speci fi c i mmunotherapy wi th a
new pol yval ent mel anoma vacci ne. Ann Sur g 1992;216:463482.
Mor ton DL, Wen DR, Wong JH, et al . Techni cal detai l s of
i ntraoperati ve l ymphati c mappi ng for ear l y stage mel anoma. Ar ch
Sur g 1992;127:392399.
Nor man J, Cr use CW, Espi nosa C, et al . Redefi ni ti on of cutaneous
l ymphati c drai nage wi th the use of l ymphosci nti graphy for
mal i gnant mel anoma. Am J Sur g 1991;162:432437.
O'Meara AT, Cr ess R, Xi ng G , et al . Mal i gnant mel anoma i n
pr egnancy. A popul ati on-based eval uati on. Cancer
2005;103:12171226.
Par mi ani G , Castel l i C, Ri vol ti ni L, et al . Immunotherapy of
mel anoma. Semin Cancer Biol 2003;13:391400.

Pawl i k TM, G er shenwal d JE. Senti nel l ymph node bi opsy i n


managi ng mel anoma. Contemp Sur g 2005;61:175182.
Pawl i k TM, Ross MI, G er shenwal d JE. Lymphati c mappi ng i n the
mol ecul ar era. Ann Sur g Oncol 2004;11:362374.
Pawl i k TM, Ross MI, Johnson MM, et al . Pr edi ctor s and natural
hi stor y of i n-transi t mel anoma after senti nel l ymphadenectomy.
Ann Sur g Oncol 2005;12:587596.
Pawl i k TM, Ross MI, Pr i eto VG , et al . Assessment of the r ol e of
senti nel l ymph node bi opsy for pr i mar y cutaneous desmopl asti c
mel anoma. 4th Annual Inter nati onal Senti nel Node Congr ess;
2004; Santa Moni ca, Cal i f.
Pawl i k TM, Ross MI, Thompson JF, et al . The r i sk of i n-transi t
mel anoma metastasi s depends on tumor bi ol ogy and not the
sur gi cal appr oach to r egi onal l ymph nodes. J Clin Oncol
2005;23:45884590.
Pawl i k TM, Sondak VK. Mal i gnant mel anoma: cur r ent state of
pr i mar y and adjuvant tr eatment. Cr it Rev Oncol Hematol
2003;45:245264.

Pawl i k TM, Zor z i D, Abdal l a EK, et al . Hepati c r esecti on for


metastati c mel anoma: di sti nct patter ns of r ecur r ence and
pr ognosi s for ocul ar ver sus cutaneous di sease. The Soci ety of
Sur gi cal Oncol ogy Annual Meeti ng; 2005; Atl anta, G a.
Por ter G A, Ross MI, Ber man RS, et al . How many l ymph nodes ar e
enough dur i ng senti nel l ymphadenectomy for pr i mar y mel anoma?
Sur ger y 2000;128:306311.
Por ter G A, Ross MI, Ber man RS, et al . Si gni fi cance of mul ti pl e
nodal basi n drai nage i n tr uncal mel anoma pati ents under goi ng
senti nel l ymph node bi opsy. Ann Sur g Oncol 2000;7:256261.
Rani er i JM, Wagner JD, Az uaje R, et al . Pr ognosti c i mpor tance of

l ymph node tumor bur den i n mel anoma pati ents staged by
senti nel node bi opsy. Ann Sur g Oncol 2002;9:975981.
Rei ntgen D, Bal ch CM, Ki r kwood J, et al . Recent advances i n the
car e of the pati ent wi th mal i gnant mel anoma. Ann Sur g
1997;225:114.
Rei ntgen D, Cr use CW, Wel l s K, et al . The or der l y pr ogr essi on of
mel anoma nodal metastases. Ann Sur g 1994;220:759767.
Rei ntgen DS, Cox EB, McCar ty KS, Jr, et al . Effi cacy of el ecti ve
l ymph node di ssecti on i n pati ents wi th i nter medi ate thi ckness
pr i mar y mel anoma. Ann Sur g 1983;198:379385.
Ri gel DS, Car ucci JA. Mal i gnant mel anoma: pr eventi on, ear l y
detecti on, and tr eatment i n the 21st centur y. CA Cancer J Clin
2000;50:215236, qui z 237240.
Rosenber g SA, Yannel l i JR, Yang JC, et al . Tr eatment of pati ents
wi th metastati c mel anoma wi th autol ogous tumor-i nfi l trati ng
l ymphocytes and i nter l euki n 2. J Natl Cancer Inst 1994;86:1159
1166.
Ross MI. Sur gi cal management of stage I and II mel anoma
pati ents: appr oach to the r egi onal l ymph node basi n. Semin Sur g
Oncol 1996;12:394401.
Ross MI, Rei ntgen D, Bal ch CM. Sel ecti ve l ymphadenectomy:
emer gi ng r ol e for l ymphati c mappi ng and senti nel node bi opsy i n
the management of ear l y stage mel anoma. Semin Sur g Oncol
1993;9:219223.
Rousseau DL, Jr, G er shenwal d JE. The new stagi ng system for
cutaneous mel anoma i n the era of l ymphati c mappi ng. Semin
Oncol 2004;31:415425.
Rousseau DL, Jr, Ross MI, Johnson MM, et al . Revi sed Amer i can
Joi nt Commi ttee on Cancer stagi ng cr i ter i a accuratel y pr edi ct
senti nel l ymph node posi ti vi ty i n cl i ni cal l y node-negati ve
mel anoma pati ents. Ann Sur g Oncol 2003;10:569574.

Shar ma A, Tr i vedi NR, Zi mmer man MA, et al . Mutant V599EB-Raf


r egul ates gr owth and vascul ar devel opment of mal i gnant
mel anoma tumor s. Cancer Res 2005;65:24122421.
Shi ver s SC, Wang X, Li W, et al . Mol ecul ar stagi ng of mal i gnant
mel anoma: cor r el ati on wi th cl i ni cal outcome. JAMA
1998;280:14101415.
Si m F H, Tayl or WF, Pr i tchar d DJ, et al . Lymphadenectomy i n the
management of stage I mal i gnant mel anoma: a pr ospecti ve
randomi zed study. Mayo Clin Pr oc 1986;61:697705.
Smi th MA, F i ne JA, Bar nhi l l RL, et al . Hor monal and r epr oducti ve
i nfl uences and r i sk of mel anoma i n women. Int J Epidemiol
1998;27:751757.
Sondak VK, Li u PY, Tuthi l l RJ, et al . Adjuvant i mmunotherapy of
r esected, i nter medi ate-thi ckness, node-negati ve mel anoma wi th
an al l ogenei c tumor vacci ne: overal l r esul ts of a randomi zed tr i al
of the Southwest Oncol ogy G r oup. J Clin Oncol 2002;20:2058
2066.
Sosman JA, Unger JM, Li u PY, et al . Adjuvant i mmunotherapy of
r esected, i nter medi ate-thi ckness, node-negati ve mel anoma wi th
an al l ogenei c tumor vacci ne: i mpact of HLA cl ass I anti gen
expr essi on on outcome. J Clin Oncol 2002;20:20672075.
Sumner WE, III, Ross MI, Mansfi el d PF, et al . Impl i cati ons of
l ymphati c drai nage to unusual senti nel l ymph node si tes i n
pati ents wi th pr i mar y cutaneous mel anoma. Cancer
2002;95:354360.
Sumner WE, III, Ross MI, Pr i eto VG . Patter ns of fai l ur e i n
pati ents wi th thi ck (> or = 4 mm) mel anoma under goi ng senti nel
node bi opsy. F i fth Wor l d Confer ence on Mel anoma; 2001; Veni ce,
Ital y.

Thompson JF, Kam PC. Isol ated l i mb i nfusi on for mel anoma: a
si mpl e but effecti ve al ter nati ve to i sol ated l i mb per fusi on. J Sur g

Oncol 2004;88:13.
Thompson JF, Kam PC, Waugh RC, et al . Isol ated l i mb i nfusi on
wi th cytotoxi c agents: a si mpl e al ter nati ve to i sol ated l i mb
per fusi on. Semin Sur g Oncol 1998;14:238247.
Thompson JF, McCar thy WH, Bosch CM, et al . Senti nel l ymph node
status as an i ndi cator of the pr esence of metastati c mel anoma i n
r egi onal l ymph nodes. Melanoma Res 1995;5:255260.
Travi s J. Cl osi ng i n on mel anoma suscepti bi l i ty gene(s). Science
1992;258:10801081.
van Pol l D, Thompson JF, Col man MH, et al . A senti nel node
bi opsy does not i ncr ease the i nci dence of i n-transi t metastasi s i n
pati ents wi th pr i mar y cutaneous mel anoma. Ann Sur g Oncol
2005;12:597608.
Ver onesi U, Adamus J, Bandi era DC, et al . Del ayed r egi onal l ymph
node di ssecti on i n stage I mel anoma of the ski n of the l ower
extr emi ti es. Cancer 1982;49:24202430.
Ver onesi U, Adamus J, Bandi era DC, et al . Ineffi cacy of i mmedi ate
node di ssecti on i n stage 1 mel anoma of the l i mbs. N Engl J Med
1977;297:627630.
Ver onesi U, Casci nel l i N, Adamus J, et al . Thi n stage I pr i mar y
cutaneous mal i gnant mel anoma. Compar i son of exci si on wi th
mar gi ns of 1 or 3 cm. N Engl J Med 1988;318:11591162.
Wang X, Hel l er R, VanVoor hi s N, et al . Detecti on of
submi cr oscopi c l ymph node metastases wi th pol ymerase chai n
r eacti on i n pati ents wi th mal i gnant mel anoma. Ann Sur g
1994;220:768774.
Wayne JD, Al bo D, Hunt KK. Anaphyl ati c r eacti on to i sosul fan
bl ue dye dur i ng senti nel l ymph node bi opsy i s mor e common i n
br east cancer than i n mel anoma. 37th Annual Meeti ng of the
Amer i can Soci ety of Cl i ni cal Oncol ogy; 2001; San F ranci sco,
Cal i f.

Wr i ghtson WR, Wong SL, Edwar ds MJ, et al . Compl i cati ons


associ ated wi th senti nel l ymph node bi opsy for mel anoma. Ann
Sur g Oncol 2003;10:676680.

Editors: Feig, Barry W .; Berger, David H.; Fuhrman, George


M.
Title: MD A nderson Surgical Oncology Handbook, The, 4th
Edition
Copyr i ght 2006 Li ppi ncott Wi l l i ams & Wi l ki ns
> Ta ble o f C o nt e nt s > 4 - No nm e la no m a Sk in C a nc e r

4
Nonmelanoma Skin Cancer
Kelly Herne
Sharon R. Hymes
Jeffrey E. Gershenw ald

Epidemiology and Etiology


Most nonmel anoma ski n cancer s (NMSCs) ar e ei ther basal cel l
car ci noma (BCC) or squamous cel l car ci noma (SCC). Together, these
cancer s account for appr oxi matel y 90% of al l mal i gnanci es of the
ski n. BCC exceeds SCC i n fr equency by a factor of 4 or 5 to 1 i n the
Uni ted States, Austral i a, and the Uni ted Ki ngdom. However, i n ar eas
of decr easi ng l ati tude such as Afr i ca, Japan, and Indonesi a, SCC i s
mor e common. The mal e-to-femal e rati o of NMSC i s 3:1, r efl ecti ng a
gr eater tendency among men to expose ski n to the sun. In addi ti on,
men ar e mor e l i kel y than women to have these cancer s on the l i ps,
ear s, and scal p, agai n r efl ecti ng patter ns of sol ar exposur e.
Many factor s contr i bute to the devel opment of NMSC, most notabl y
ul travi ol et (UV) radi ati on i n the for m of sunl i ght. UV radi ati on i s
accepted as the domi nant r i sk factor for the devel opment of both
SCC and BCC, al though the r el ati onshi p between UV radi ati on and
the devel opment of BCC i s l ess cl ear. Indeed, mutati ons of the p53
tumor suppr essor gene i nduced by UV l i ght ar e found i n mor e than
90% of SCCs but onl y 50% of BCCs. Another i mpor tant r i sk factor
for both types of cancer i s i mmunosuppr essi on, especi al l y i n
pati ents who have under gone or gan transpl antati on. These pati ents
tend to devel op NMSC, especi al l y SCC, mor e rapi dl y and wi th hi gher
fr equency than those i n the general popul ati on, and i t tends to
fol l ow a mor e aggr essi ve cour se. Pati ents wi th AIDS al so have an
i ncr eased i nci dence of NMSC, al though factor s such as human
papi l l oma vi r us (HPV) i nfecti on may act syner gi sti cal l y wi th UV

exposur e. HPV i nfecti on, especi al l y HPV16 and 18, has al so been
i mpl i cated i n the devel opment of anogeni tal SCC. Ar seni c exposur e
i n wel l dr i nki ng water and hydr ocar bon (tar ) exposur e have been
l i nked to both SCC and BCC.

Differential Diagnosis
Several other epi der mal tumor s common to the ski n can be ei ther
cl i ni cal l y confused wi th NMSC or ar e pr ecur sor s to NMSC.
Recogni ti on of these tumor s i s i mpor tant for both tumor
sur vei l l ance and cancer pr eventi on.
Sebor r heic ker atoses ar e beni gn pr ol i ferati ons of epi der mi s that
appear on any par t of the ski n, except mucous membranes, and
usual l y appear after age 30. They ar e not r el ated to sun exposur e
but ar e common on the face, neck, and tr unk, often i n l ar ge
number s. They i ni ti al l y appear as fl at br own macul es, eventual l y
becomi ng l ar ger, stuck on br own pl aques wi th dul l , cr umbl y
sur faces (F i g. 4.1A). Sebor r hei c keratoses can someti mes be
confused wi th mel anoma. Bi opsy of these l esi ons i s pr udent i f
sudden change i n si ze or col or occur s.

F i gur e 4.1. A : Sebor r hei c keratosi s. B: Acti ni c keratosi s. C:


Cutaneous hor n.

Actinic ker atoses (AKs) ar e pr emal i gnant l esi ons wi th the potenti al
to devel op i nto SCC. They ar e found mai nl y on l i ght-ski nned
i ndi vi dual s on sun-exposed ar eas. These l esi ons pr esent as ski ncol or ed, er ythematous, or br own i l l -defi ned patches wi th adher ent
scal es (F i g. 4.1B). The mean si ze i s appr oxi matel y 3 to 4 mm. These
l esi ons ar e extr emel y common on the face, scal p, ear s, and l i ps and
can often be better appr eci ated by pal pati on than by i nspecti on wi th
the naked eye.
Ker atoacanthoma i s a tumor that often occur s on ol der, sundamaged ski n, especi al l y on the neck and face. They may rapi dl y
gr ow as a r ed- or ski n-col or ed dome-shaped nodul es wi th a central
crater. Maxi mum si ze may be attai ned by 6 to 8 weeks, wi th sl ow
r egr essi on over a per i od of 2 to 12 months. Because these tumor s

can be confused both cl i ni cal l y and hi stol ogi cal l y wi th SCC,


conser vati ve exci si on i s r ecommended.
Cutaneous hor n i s a cl i ni cal descr i pti on for a gr owth that appear s as
a dense cone of epi thel i um r esembl i ng a hor n (F i g. 4.1C). They
range i n si ze fr om several mi l l i meter s to over a centi meter, ar e
general l y whi te or yel l owi sh i n col or, and appear on sun-exposed
ski n i n ol der i ndi vi dual s. Hi stol ogi cal l y, cutaneous hor ns can
devel op fr om beni gn l esi ons such as war ts or sebor r hei c keratoses
and fr om pr emal i gnant or mal i gnant l esi ons such as AK or SCC.
Bi opsy of these tumor s i s ther efor e al ways i ndi cated to r ul e out the
l atter.
Nevus sebaceus i s a beni gn tumor of the scal p that appear s at or
soon after bi r th as a yel l owi sh-orange, wel l -demar cated pl aque.
Ini ti al l y, the sur face has a smooth or waxy appearance that
gradual l y becomes mor e war ty or ver r ucous dur i ng puber ty. In
adul thood, appr oxi matel y 10% of these l esi ons devel op i nto BCC. It
i s ther efor e r ecommended that these l esi ons be exci sed or cl osel y
moni tor ed for the l i fe of the pati ent.

Basal Cell Carcinoma


BCC i s the most common cancer i n humans and the most common
type of ski n cancer. The i nci dence of BCC conti nues to r i se, wi th an
annual esti mated i nci dence of 200 per 100,000 i n the Uni ted
States. It i s bel i eved to ar i se fr om cel l s of the hai r fol l i cl e and i s
ther efor e found al most excl usi vel y on hai r-bear i ng ski n. Most
l esi ons ar e found on sun-exposed ar eas such as the head and neck,
but nonsun-exposed ar eas ar e al so at r i sk. These tumor s tend to
gr ow sl owl y, wi th eventual i nvasi on i nto l ocal str uctur es, i ncl udi ng
muscl e, car ti l age, and bone. Al though the bi ol ogi cal behavi or of BCC
i s character i zed by l ocal and someti mes di sfi gur i ng i nvasi veness,
metastasi s i s rar e, occur r i ng i n l ess than 0.05% of cases.
In general , the hi stol ogi c type of BCC i s pr edi cti ve of i ts behavi or.
Nodul ar BCC i s the cl assi c l esi on of thi s type of NMSC. It appear s as
a pi nk transl ucent nodul e, often descr i bed as pear l y. Over l yi ng
tel angi ectasi as and ul cerati on ar e al so common (F i g. 4-2). In dar kski nned i ndi vi dual s, these tumor s ar e often pi gmented and can
r esembl e mel anoma.
Super fi ci al BCC i s a var i ant that i s mor e common on the l i mbs and
tr unk, as wel l as on ar eas wi th l i ttl e or no sun exposur e. It pr esents
as a sl ow-gr owi ng, scal y pi nk pl aque and can easi l y be confused
wi th super fi ci al SCC or squamous cel l car ci noma i n si tu (Bowen's

di sease).
The scl er osi ng or mor pheafor m type r epr esents the rar est for m of
BCC and often the most di ffi cul t to r ecogni ze. It pr esents as a
poor l y defi ned i ndurated or scl er oti c pl aque, often mi staken for a
scar. In addi ti on, thi s type of BCC fr equentl y i s found to be l ar ger
hi stopathal ogi cal l y than cl i ni cal l y evi dent. Ther efor e, both di agnosi s
and tr eatment r emai n a chal l enge.

F i gur e 4.2. Nodul ar basal cel l car ci noma.

Squamous Cell Carcinoma


SCC i s the second most common type of cutaneous cancer. In the
Uni ted States, i t occur s at a fr equency one-fi fth that of BCC. The
devel opment of SCC i s pr i nci pal l y r el ated to two factor s: sol ar
damage and l i ghter ski n types. SCC devel ops fr om the kerati nocytes
of the epi der mi s. SCC i s al so found i n associ ati on wi th scar s or
ar eas of chr oni c i nfl ammati on such as non-heal i ng ul cer s. In
addi ti on, ther e ar e ver r ucous for ms of SCC found on the mucous
membranes of the oral cavi ty and geni tal s.
SCC has many cl i ni cal var i ants. As stated pr evi ousl y, i t can ar i se
fr om a pr ecur sor l esi on such as an AK or can devel op at the base of
a cutaneous hor n. Uncommonl y, i t pr esents de novo as a si ngl e
l esi on on other wi se nor mal -appear i ng ski n. The most common l esi on
i s found on a backgr ound of sun-damaged ski n, especi al l y on the

head, neck, or ar ms. The l esi ons ar e usual l y r ed, poor l y defi ned
pl aques or nodul es wi th an ul cerated, fr i abl e sur face (F i g. 4-3).
Bowen's di sease, or SCC i n si tu, i s character i zed by a wel l demar cated pi nk pl aque wi th a rai sed bor der and uni for m scal i ng
thr oughout.
SCC has a hi gher metastati c potenti al than does BCC, wi th an
overal l i nci dence of 2% to 3% . However, many factor s affect the
metastati c potenti al of any gi ven tumor, such as hi stol ogi c subtype
based on nucl ear pl eomor phi sm and cytol ogi c atypi a (Br oder
cl assi fi cati on IIV); SCC types II and hi gher ar e mor e l i kel y to
metastasi ze. In addi ti on, tumor si ze mor e than 2 cm and depth
mor e than 4 mm (si mi l ar to Br esl ow thi ckness for mel anoma) ar e
r i sk factor s for metastasi s. Anatomi c si te al so pl ays a r ol e i n the
tendency of SCC to metastasi ze. SCC of the l i p has a metastati c rate
up to 20% , and SCC of the ear, 11% . SCC ar i si ng i n scar s and other
ar eas of chr oni c i nfl ammati on ar e al so mor e l i kel y to metastasi ze,
wi th rates of 18% to 31% r epor ted. Regi onal l ymph nodes ar e the
most common metastati c si te, wi th di stant si tes such as bone, brai n,
and l ungs occasi onal l y r epor ted. For tumor s of the head and neck,
the par oti d gl and i s a common si te for metastases.

F i gur e 4.3. Squamous cel l car ci noma.

Syndromes Associated with Nonmelanoma


Skin Cancers

Xer oder ma pi gmentosum i s an autosomal r ecessi ve di sease that


occur s i n appr oxi matel y 1 i n 250,000 i ndi vi dual s and i s
character i zed by photophobi a, sever e sun sensi ti vi ty, and advanced
sun damage. Affected i ndi vi dual s have defecti ve DNA exci si on r epai r
on exposur e to UV radi ati on and devel op mal i gnanci es of the ski n
and eyes, i ncl udi ng mel anoma, SCC, and BCC, at a rate 1,000 ti mes
that of the general popul ati on. Aggr essi ve sun pr otecti on i n the
for m of ful l -body sun sui ts and r egul ar ski n exams i s i mpor tant.
Ideal l y, these pati ents shoul d onl y go outsi de at ni ght.
Nevoi d basal cel l syndr ome i s an autosomal domi nant di sor der
character i zed by the devel opment of mul ti pl e BCCs. These pati ents
ar e al so exqui si tel y sensi ti ve to radi ati on and shoul d not under go
radi ati on therapy or excessi ve sun exposur e. Often, these tumor s
ar e qui te smal l , number i ng i n the hundr eds on any gi ven ski n
sur face, and ar e thus di ffi cul t to moni tor and tr eat. Agai n, r egul ar
fol l ow-up and aggr essi ve sun avoi dance ar e i mpor tant.
Al bi ni sm i s an autosomal r ecessi ve di sor der character i zed by
decr eased or absent mel ani n i n the ski n and eyes. Pati ents may
devel op mul ti pl e SCCs, BCCs, and mel anomas.

Biopsy Techniques
Any cutaneous l esi on suspi ci ous for mal i gnancy shoul d be bi opsi ed
to assess pathol ogy. Changes noted by pati ents may be qui te subtl e
and i ncl ude i tchi ng, tender ness, bl eedi ng, or change i n si ze, col or,
or textur e. In addi ti on, l esi ons that pati ents do not r outi nel y
obser ve themsel ves, such as those on the back, poster i or l egs, and
buttocks, shoul d be car eful l y exami ned.
Bi opsy of pi gmented l esi ons shoul d be l i mi ted to punch or exci si onal
bi opsy techni ques i n whi ch the ful l thi ckness of the der mi s can be
eval uated i n the pathol ogi cal speci men. A punch bi opsy usual l y
ranges i n si ze fr om 2 to 8 mm and i nvol ves r emovi ng a r ound
cyl i nder of ti ssue, i deal l y to the l evel of the subcutaneous fat. Thi s
si te i s then sutur ed or l eft to granul ate. Often, enti r e l esi ons can be
r emoved for pathol ogi cal exami nati on; i f not, the most suspi ci ous
aspect of the tumor may be sampl ed.
Shave bi opsy i s an excel l ent techni que for super fi ci al l esi ons or
nonpi gmented l esi ons suspi ci ous for BCC or SCC. It i s al so a good
bi opsy techni que for cutaneous hor ns or keratoacanthomas,
pr ovi ded the base of the tumor i s i ncl uded i n the speci men. A shave
bi opsy i nvol ves i njecti ng l ocal anesthesi a i nto the epi der mi s and

upper der mi s to for m a pl umped up wheal bel ow the l esi on i n


questi on. A tangenti al sampl e i s per for med at the base of the wheal
wi th ei ther a ster i l e fl exi bl e razor bl ade or a no. 15 bl ade so that
mi d der mi s i s i ncl uded i n the bi opsy speci men. If per for med too
super fi ci al l y, i nvasi on i nto the der mi s cannot be eval uated, and
r ebi opsy may be i ndi cated.
Exci si on i nvol ves r emoval of the enti r e l esi on wi th a mar gi n of
cl i ni cal l y cl ear ti ssue and i s general l y used for cl assi c l esi ons such
as nodul ar or super fi ci al BCC or super fi ci al SCC. Mar gi ns can be
eval uated i n the speci men, and fur ther tr eatment i s often not
necessar y.

Treatment
The tr eatment of NMSC r equi r es car eful eval uati on of tumor si ze,
pathol ogi cal character i sti cs, anatomi cal l ocati on, age and overal l
heal th of the pati ent, cost to the pati ent, and cosmesi s. Tr eatment
modal i ti es can be di vi ded i nto sur gi cal and nonsur gi cal therapi es.
Sur gi cal exci si on i s the mai nstay of tr eatment of NMSC and i s
effecti ve for al l hi stol ogi c types of tumor s. Pr i mar y sur gi cal exci si on
wi th a mar gi n of cl i ni cal l y nor mal ti ssue al l ows subsequent
eval uati on of the enti r e speci men for cl ear sur gi cal mar gi ns.
Excisions with pr edeter mined mar gins ar e i deal l y per for med al ong
Langer 's l i nes of cl eavage to ensur e a good cosmeti c r esul t.
El l i pti cal exci si ons ar e usual l y per for med on the scal p, for ehead,
cheeks, chi n, tr unk, and extr emi ti es. When deal i ng wi th l esi ons on
the eyel i ds, al ar r i m of the nose, l i ps, and ear s, however, wedgeshaped exci si ons may mi ni mi ze di stor ti on.
Mohs mi cr ographi c sur ger y i s a useful modal i ty for l esi ons of the
head and neck, r ecur r ent or l ar ge (i .e., >2 cm) l esi ons, or l esi ons of
aggr essi ve hi stol ogi c type (e.g., scl er osi ng BCC or hi gh-grade SCC).
For NMSCs wi th metastati c potenti al , cl i ni cal eval uati on of r egi onal
l ymph nodes may be i ndi cated.
Mohs mi cr ographi c sur ger y i nvol ves r emoval of the cl i ni cal mar gi n
of the tumor under l ocal anesthesi a, wi th i mmedi ate
eval uati on of the mar gi ns i n fr ozen secti ons. Smal l i ncr emental
secti ons ar e r emoved unti l the mar gi ns ar e cl ear. Thi s techni que
pr eser ves nor mal ti ssue, thus al l owi ng for the best cosmeti c r esul t.
It al so ensur es that l ar ger l esi ons wi th subcl i ni cal extensi on ar e
enti r el y r emoved. Mohs mi cr ographi c sur ger y of pr i mar y NMSC of
the head and neck has a cur e rate (i .e., negati ve hi stol ogi c mar gi n)

of 99% . The r econstr ucti ve choi ces after Mohs sur ger y ar e si mi l ar
to those avai l abl e after tradi ti onal exci si on. Al though Mohs
mi cr ographi c sur ger y i s ti me-consumi ng, the benefi ts of super i or
cosmesi s and excel l ent cur e rates make i t a tr eatment of choi ce for
many pati ents.
Destr ucti ve techni ques for super fi ci al BCC and SCC i ncl ude
cur ettage, cr yotherapy, and l aser abl ati on. Cur ettage i nvol ves
debul ki ng the tumor under l ocal anesthesi a wi th a shar p cur ette
unti l fi r m under l yi ng der mi s i s r eached. The base i s hyphr ecated
and the pr ocess i s r epeated two or thr ee ti mes. Thi s techni que i s
r eser ved for smal l or super fi ci al tumor s.
Cr yotherapy i s a destr ucti ve method pr i mar i l y r eser ved for the
tr eatment of pr ecancer ous l esi ons such as AKs and occasi onal l y for
smal l super fi ci al BCCs or SCCs. Li qui d ni tr ogen i s ei ther sprayed
wi th a cr yogun or di r ectl y appl i ed to the l esi on wi th cotton-ti pped
appl i cator s for a per i od of ti me such that the vi si bl e thawi ng of the
l esi ons takes at l east 15 seconds (30 seconds for super fi ci al SCC or
BCC).
Laser abl ati on wi th a car bon di oxi de l aser may be consi der ed for
pr e-cancer ous l esi ons. However, fol l i cul ar i nvol vement may be
di ffi cul t to tr eat and l ead to r ecur r ence.
Nonsur gi cal therapi es for the tr eatment of NMSC i ncl ude radi ati on
and several topi cal therapi es. Radi ati on therapy i s often r eser ved
for pati ents unabl e or unwi l l i ng to under go sur gi cal tr eatment of
pr i mar y l esi ons and for the adjuvant tr eatment of r ecur r ent or
hi stol ogi cal l y aggr essi ve tumor s (e.g., those exhi bi ti ng per i neural
i nvasi on). In such pati ents, radi ati on therapy can be qui te useful for
tumor s of the face, especi al l y of the nose, l i ps, eyel i ds, and canthi .
However, the number of tr eatment sessi ons depends on the si ze and
l ocati on of the tumor. Al though pai nl ess, radi ati on therapy may be
associ ated wi th acute or chr oni c radi ati on-i nduced changes. For
hi gh-grade SCC wi th per i neural i nvol vement or i nvasi on i nto bone,
radi ati on therapy i s general l y r ecommended i n conjuncti on wi th
sur gi cal exci si on or Mohs mi cr ographi c sur ger y.
Topi cal therapi es for super fi ci al NMSC and AKs i ncl ude 5%
fl uor ouraci l (5-F U) and i mi qui mod cr eams. Tr eatment r egi mens for
AKs var y wi del y; i n general , 5-F U i s appl i ed to the enti r e affected
ar ea once or twi ce dai l y for a per i od rangi ng fr om 2 to 6 weeks.
Si gni fi cant er ythema, sti ngi ng, ooz i ng and cr usti ng ar e often
r epor ted, especi al l y wi th mor e aggr essi ve tr eatment r egi mens. 5-F U
can be appl i ed to an enti r e r egi on, such as the face, chest, ar ms, or

hands. Retr eatment several months l ater, ei ther wi th cr yotherapy or


other modal i ti es may be necessar y.
For the tr eatment of super fi ci al BCC, 5-F U can be appl i ed dai l y to
the tumor and to several mi l l i meter s of sur r oundi ng ski n for a
per i od of at l east 4 weeks. After a several -week r espi te, the ar ea i s
then eval uated cl i ni cal l y for r esi dual tumor. Bi opsy i s often
i ndi cated to ensur e adequate therapy.
Imi qui mod therapy for AKs and super fi ci al BCC has r ecentl y become
popul ar. For AKs, the cr eam i s appl i ed 2 non-consecuti ve days a
week for 16 weeks. In general , l ess i r r i tati on i s r epor ted wi th
i mi qui mod, except on mucosal ar eas such as the l i ps. Imi qui mod i s
al so appr oved for the tr eatment of super fi ci al BCC, al though not for
SCC. The cr eam shoul d be appl i ed 5 to 7 ni ghts a week for at l east
8 weeks. After a 2- to 3-month r espi te, the l esi on i s eval uated
ei ther cl i ni cal l y or hi stol ogi cal l y (r ebi opsy) to confi r m adequate
therapy. Thi s tr eatment r egi men i s often wel l tol erated and i s
par ti cul ar l y useful for mul ti pl e super fi ci al BCCs i n one ar ea, such as
the back or chest.
Photodynami c therapy i s cur r entl y under i nvesti gati on for the
tr eatment of AKs and super fi ci al BCC. A photosensi ti zermost
commonl y, ami nol evul i ni c aci di s appl i ed to the ski n and acti vated
wi th a l i ght sour ce. The tumor cel l s r etai n the photosensi ti zer for
l onger per i ods of ti me than nor mal cel l s, r esul ti ng i n pr efer enti al
ki l l i ng. Cur e rates for AKs ar e r epor ted to be as hi gh as 90% , but
no l ong-ter m data ar e avai l abl e for rates for super fi ci al BCC.
Chemopr eventi on wi th l ow-dose oral r eti noi ds for chr oni cal l y
i mmunosuppr essed pati ents who have under gone or gan
transpl antati on has shown some pr omi se i n the pr eventi on of SCC.
Ten year s after or gan transpl antati on, these pati ents have an 18fol d i ncr eased r i sk for the devel opment of SCC. However, l ong ter m
therapy i s needed as benefi ci al effects ar e often l ost when these
dr ugs ar e di sconti nued.

Screening and Prevention


Aggr essi ve scr eeni ng of pati ents at r i sk for ski n cancer i s essenti al
to mi ni mi ze the mor bi di ty and mor tal i ty of NMSC. Pati ents at r i sk
i ncl ude those wi th l i ght ski n types, i mmunosuppr essi on, and a
fami l y or per sonal hi stor y of ski n cancer. Ear l y exposur e to UV
shoul d be l i mi ted i n chi l dr en, wi th r egul ar use of sunscr een fr om an
ear l y age. Appr opr i ate SPF l evel and appl i cati on techni ques shoul d

be emphasi zed for al l pati ents, especi al l y appl i cati ons to the face
and neck.
Regul ar exami nati on of the ski n by a der matol ogi st i s r ecommended
for al l pati ents at r i sk for ski n cancer, on at l east a year l y basi s. For
pati ents wi th a hi stor y of AKs or NMSC, r egul ar fol l ow-up wi th a
der matol ogi st i s r ecommended. A compl ete ski n exam i ncl udes
exami nati on of the enti r e ski n sur face, i ncl udi ng the scal p, wi th
par ti cul ar attenti on to pr evi ous ar eas of ski n cancer. In addi ti on,
pati ents wi th a hi stor y of SCC shoul d under go a thor ough
exami nati on of al l r egi onal l ymph node basi ns to eval uate for
metastases.

Recommended Reading
Bol ogni a JL, Jor i z zo JL, Rapi ni RP. Der matology. Phi l adel phi a, Pa:
El sevi er Li mi ted; 2003.
Br odl and AG , Zi tel l i JA. Sur gi cal mar gi ns for exci si on of
cutaneous SCC. J Am Acad Der matol 1992;27(2pt):241248.
Chakrabar ty A, G ei sse JK. Medi cal therapi es for non-mel anoma
ski n cancer. Clin Der matol 2004;22(3):183188.
G upta AK, Cher man AM, Tyr i ng SK. Vi ral and nonvi ral uses of
i mi qui mod: a r evi ew. J Cutan Med Sur g 2005; May 5. 8(5):338
352.

Har wood CA, Leedham-G r een M, Lei gh IM, Pr oby CM. Low-dose
r eti noi ds i n the pr eventi on of cutaneous squamous cel l
car ci nomas i n or gan transpl ant r eci pi ents: a 16-year
r etr ospecti ve study. Ar ch Der matol 2005;141(4):456464.
Mi l l er SJ, Mor esi JM. Acti ni c keratosi s, basal cel l car ci noma and
squamous cel l car ci nomas. Der matology. Phi l adel phi a, PA:
El sevi er Li mi ted; 2003.
Pi er son DM, Bandel C, Ehr i g T, Cocker el l CJ. Beni gn epi thel i al
tumor s and pr ol i ferati ons. Der matology. Phi l adel phi a, PA:
El sevi er Li mi ted; 2003.

Ponten F, Lundeber g J. Pr i nci pl es of tumor bi ol ogy and


pathogenesi s of BCCs and SCCs. Der matology. Phi l adel phi a, PA:
El sevi er Li mi ted; 2003.
Smeets NW, Kr ekel s G A, Oster tag JU, et al . Sur gi cal exci si on vs
Mohs mi cr ographi c sur ger y for basal -cel l car ci noma of the face:
randomi sed contr ol l ed tr i al . Lancet 2004;364(9447):17661772.
Wol f DJ, Zi tel l i JA. Sur gi cal mar gi ns for basal cel l car ci noma.
Ar ch Der matol 1987;123(3):340344.

Editors: Feig, Barry W .; Berger, David H.; Fuhrman, George


M.
Title: MD A nderson Surgical Oncology Handbook, The, 4th
Edition
Copyr i ght 2006 Li ppi ncott Wi l l i ams & Wi l ki ns
> Ta ble o f C o nt e nt s > 5 - So ft- t is s ue a nd Bo ne Sa rc o m a

5
Soft-tissue and Bone Sarcoma
Keith A . Delman
Janice N. Cormier

Epidemiology
In 2005, an esti mated 9,400 new cases of soft-ti ssue sar coma wer e
di agnosed i n the Uni ted States, wi th 3,400 pati ents expected to di e
of the di sease. These rar e tumor s account for l ess than 1% of al l
newl y di agnosed adul t cancer s and 7% of al l newl y di agnosed
cancer s i n chi l dr en. Several di sti nct gr oups of sar comas have been
r ecogni zed: soft-ti ssue sar comas, bone sar comas
(osteosar comas/chondr osar comas), Ewi ng sar comas, and per i pheral
pr i mi ti ve neur oectoder mal tumor s.
Encompassi ng mor e than 50 hi stol ogi c types, soft-ti ssue sar comas
can occur anywher e i n the body. The major i ty of pr i mar y l esi ons
or i gi nate i n an extr emi ty (59% ), wi th the next most fr equent
anatomi cal si te of or i gi n bei ng the tr unk (19% ), fol l owed by the
r etr oper i toneum (13% ) and the head/neck r egi on (9% ). The most
common hi stol ogi c types of soft-ti ssue sar coma i n adul ts (excl udi ng
Kaposi sar coma) ar e mal i gnant fi br ous hi sti ocytoma (24% ),
l ei omyosar coma (21% ), l i posar coma (19% ), synovi al sar coma
(12% ), and mal i gnant per i pheral ner ve sheath tumor s (6% ).
Rhabdomyosar coma i s the most common soft-ti ssue sar coma of
chi l dhood and accounts for appr oxi matel y 250 cases annual l y.
Dur i ng the past 25 year s, a mul ti modal i ty tr eatment appr oach has
been successful l y appl i ed to pati ents wi th extr emi ty sar comas, and
thi s has l ed to i mpr ovements i n both sur vi val and qual i ty of l i fe.
However, pati ents wi th abdomi nal sar comas conti nue to have hi gh
rates of r ecur r ence and poor overal l sur vi val . The overal l 5-year
sur vi val rate for pati ents wi th al l stages of soft-ti ssue sar coma i s

50% to 60% . Of the pati ents who di e of sar coma, most wi l l succumb
to metastati c di sease, whi ch 80% of the ti me occur s wi thi n 2 to 3
year s of the i ni ti al di agnosi s.

Etiology
Numer ous factor s have been associ ated wi th an i ncr eased r i sk of
soft-ti ssue sar coma. These factor s ar e di scussed i n the fol l owi ng
secti ons.

Trauma
Al though pati ents wi th sar coma fr equentl y r epor t a hi stor y of
trauma i n the tumor ar ea, a causal r el ati onshi p has not been
establ i shed. Mor e often, a mi nor i njur y cal l s attenti on to a pr eexi sti ng tumor that may be accentuated by edema or a hematoma.

Occupational Chemicals
Exposur e to some her bi ci des such as phenoxyaceti c aci ds and wood
pr eser vati ves contai ni ng chl or ophenol s has been l i nked to an
i ncr eased r i sk for soft-ti ssue sar coma. Several chemi cal
car ci nogens, i ncl udi ng Thor otrast (thor i um oxi de), vi nyl chl or i de,
and ar seni c, have been associ ated wi th hepati c angi osar coma.
Exposur e to asbestos has been associ ated wi th mesothel i oma.

Previous Radiation Exposure


Exter nal radi ati on therapy i s a rar e but wel l -establ i shed cause of
soft-ti ssue sar coma. An 8- to 50-fol d i ncr ease i n the i nci dence of
sar comas has been noted for pati ents tr eated for cancer s of the
br east, cer vi x, ovar y, testes, and l ymphati c system. In addi ti on, the
r i sk for sar comas after radi ati on therapy i ncr eases wi th hi gher
dosage. The i nter val between i r radi ati on and the devel opment of
sar coma i s usual l y at l east 10 year s. In a r evi ew of 160 pati ents
wi th posti r radi ati on sar comas, the most common hi stol ogi c types
wer e osteogeni c sar coma, mal i gnant fi br ous hi sti ocytoma,
angi osar coma, and l ymphangi osar coma. Posti r radi ati on sar comas ar e
often di agnosed at a mor e advanced stage and ar e ther efor e
associ ated wi th a poor er pr ognosi s compar ed wi th other sar comas.

Chronic Lymphedema
In 1948, Stewar t and Tr eves wer e the fi r st to descr i be the

associ ati on of chr oni c l ymphedema fol l owi ng axi l l ar y di ssecti on wi th


subsequent l ymphangi osar coma. Lymphangi osar coma has al so been
obser ved i n pati ents fol l owi ng fi l ar i al i nfecti ons and i n the l ower
extr emi ti es of pati ents wi th congeni tal pr i mar y l ymphedema.

Genetic Predisposition
Speci fi c i nher i ted geneti c al terati ons have been associ ated wi th an
i ncr eased r i sk of bone and soft-ti ssue sar comas. For exampl e,
pati ents wi th G ar dner syndr ome (fami l i al pol yposi s) have a hi gher
than nor mal i nci dence of desmoi ds, pati ents wi th ger m-l i ne
mutati ons i n the tumor suppr essor gene p53 (Li -F raumeni
syndr ome) have a hi gh i nci dence of sar comas, and pati ents wi th von
Reckl i nghausen di sease who have abnor mal i ti es i n the
neur ofi br omatosi s type 1 gene have an i ncr eased r i sk of
neur ofi br osar comas. Soft-ti ssue sar comas can al so occur i n pati ents
wi th her edi tar y r eti nobl astoma as a second pr i mar y mal i gnancy.

Oncogene Activation
Oncogenes ar e genes that ar e capabl e of i nduci ng mal i gnant
transfor mati on and tend to dr i ve cel l s towar d pr ol i ferati on. Several
oncogenes have been i denti fi ed i n associ ati on wi th soft-ti ssue
sar comas, i ncl udi ng MDM2, N-myc, c-er B2, and member s of the r as
fami l y. Ampl i fi cati on of these genes has been shown to cor r el ate
wi th an adver se outcome i n pati ents wi th var i ous soft-ti ssue
sar comas.
Cytogeneti c anal ysi s of soft-ti ssue tumor s has l ed to the
i denti fi cati on of di sti nct chr omosomal transl ocati ons i n oncogenes
that ar e associ ated wi th cer tai n hi stol ogi c subtypes. These i ncl ude
the TLS-CHOP fusi on, whi ch i s obser ved i n myxoi d l i posar coma, and
the EWS-ATF 1 fusi on, whi ch i s obser ved i n cl ear-cel l sar coma,
among other s. The gene r ear rangements best character i zed to date
ar e those found i n Ewi ng sar coma, cl ear cel l sar coma, myxoi d
l i posar coma, al veol ar r habdomyosar coma, desmopl asti c smal l r ound
cel l tumor s, and synovi al sar coma.

Tumor Suppressor Genes


Tumor suppr essor genes pl ay a cr i ti cal r ol e i n suppr essi ng tumor
cel l gr owth. However, these genes can be i nacti vated as a r esul t of
her edi tar y or sporadi c mechani sms. Two genes that have shown the
gr eatest r el evance to soft-ti ssue tumor s ar e the r eti nobl astoma (Rb)

tumor suppr essor gene and the p53 tumor suppr essor gene.
Mutati ons or del eti ons i n Rb can l ead to the devel opment of
r eti nobl astoma, as wel l as sar comas of soft ti ssue and bone.
Mutati ons i n the p53 tumor suppr essor gene ar e the most common
mutati ons i n human sol i d tumor s and have been obser ved i n 30% to
60% of cases of soft-ti ssue sar comas.

Pathology
Sar comas ar e a heter ogeneous gr oup of tumor s that not onl y ar i se
pr edomi nantl y fr om the embr yoni c mesoder m, but can al so ar i se
fr om the ectoder m (e.g., per i pheral ner vous sheath tumor s).
Mesoder mal cel l s gi ve r i se to the connecti ve ti ssues di str i buted
thr oughout the body, i ncl udi ng per i car di um, pl eura, bl ood vessel
endothel i um, smooth and str i ated muscl e, bone, car ti l age, and
synovi um. These ar e the cel l s fr om whi ch near l y al l sar comas
or i gi nate. Consequentl y, sar comas devel op i n a wi de var i ety of
anatomi cal si tes.
Despi te the var i ous hi stol ogi c subtypes, sar comas have many
common cl i ni cal and pathol ogi cal featur es. The overal l cl i ni cal
behavi or of most types of sar coma i s si mi l ar and deter mi ned by
anatomi cal l ocati on (depth, speci fi cal l y r el ated to fasci al
boundar i es), grade, and si ze. The domi nant r oute of metastasi s i s
hematogenous. Tumor grade has been fi r ml y establ i shed to have
pr ognosti c si gni fi cance and has ther efor e been i ncor porated i nto the
stagi ng of soft-ti ssue sar comas. However, some exper ts have
suggested that the pathol ogi cal cl assi fi cati on i s far mor e i mpor tant
than grade when other pr etr eatment var i abl es ar e taken i nto
account. Tabl e 5.1 shows a br eakdown of the hi stol ogi c types of
tumor s by thei r aggr essi veness. Tumor s wi th l i ttl e or no metastati c
potenti al i ncl ude desmoi ds, atypi cal l i pomatous tumor s (al so cal l ed
wel l -di ffer enti ated l i posar coma), der matofi br osar coma pr otuberans,
and hemangi oper i cytomas. Those subtypes wi th an i nter medi ate r i sk
of metastati c spr ead i ncl ude myxoi d l i posar coma, myxoi d mal i gnant
fi br ous hi sti ocytoma, and extraskel etal chondr osar coma. Hi ghl y
aggr essi ve tumor s that have a substanti al metastati c potenti al
i ncl ude angi osar coma, cl ear cel l sar coma, pl eomor phi c and
dedi ffer enti ated l i posar coma, l ei omyosar coma, r habdomyosar coma,
and synovi al sar coma. Appr oxi matel y 15% of al l soft-ti ssue
sar comas occur i n the r etr oper i toneum. Appr oxi matel y 80% ar e
mal i gnant, wi th l i posar coma, fi br osar coma, l ei omyosar coma, and
mal i gnant fi br ous hi sti ocytoma accounti ng for the vast major i ty of
the hi stol ogi c types.

In as many as 25% to 40% of cases, exper t sar coma pathol ogi sts
may di sagr ee about speci fi c hi stol ogi c di agnoses or cr i ter i a for
defi ni ng tumor grade. Thi s l ow concor dance rate may stem fr om the
fact that few pathol ogi sts have the oppor tuni ty to study many of
these rar e tumor s dur i ng thei r car eer s. It al so emphasi zes the need
for mor e objecti ve mol ecul ar and bi ochemi cal mar ker s to i mpr ove
the accuracy of conventi onal hi stol ogi c assessment.

Table 5.1. Breakdown of sarcoma histologic


type by tumor aggressiveness
Low metastatic potential
Desmoid tumor
Atypical lipomatous tumor
Dermatofibrosarcoma protuberans
Hemangiopericytoma
Intermediate metastatic potential
Myxoid liposarcoma
Myxoid malignant fibrous histiocytoma
Extraskeletal chondrosarcoma
High metastatic potential
Alveolar soft part sarcoma
Angiosarcoma
Clear cell sarcoma (melanoma of soft parts)
Epithelioid sarcoma
Extraskeletal Ewing sarcoma
Extraskeletal osteosarcoma
Malignant fibrous histiocytoma
Liposarcoma (pleomorphic and
dedifferentiated)
Leiomyosarcoma
Neurogenic sarcoma (malignant schwannoma)

Rhabdomyosarcoma
Synovial sarcoma

Staging
The stagi ng cr i ter i a for soft-ti ssue sar comas i n the cur r ent ver si on
of the Amer i can Joi nt Commi ttee on Cancer (AJCC) stagi ng
gui del i nes consi st of the hi stopathol ogi cal grade (G ), tumor si ze and
depth (T), and the pr esence of metastases (di stant [M] or nodal [N])
(Tabl e 5.2). Thi s system does not appl y to vi sceral sar comas, Kaposi
sar coma, der matofi br osar coma, or desmoi d tumor s.

Histopathological Grade
Hi stopathol ogi cal grade r emai ns the most i mpor tant pr ognosti c
factor for deter mi ni ng di sease-fr ee and overal l sur vi val rate. In the
2002 AJCC stagi ng system, grades 1 and 2 (wel l and moderatel y
di ffer enti ated), N0, M0 l esi ons ar e cl assi fi ed as stage I l esi ons,
r egar dl ess of tumor si ze and depth. To accuratel y deter mi ne tumor
grade, an adequate ti ssue sampl e must be wel l fi xed, wel l stai ned,
and r evi ewed by an exper i enced sar coma pathol ogi st. The
pathol ogi cal featur es that defi ne grade i ncl ude cel l ul ar i ty,
di ffer enti ati on, pl eomor phi sm, necr osi s, and the number of mi toses.

Table 5.2. American Joint Committee on


cancer staging criteria for soft-tissue
sarcomas
Primary tumor (T)
TX

Primary tumor cannot be assessed

T0

No evidence of primary tumor

Tumor 5 cm in greatest dimension


T1

T1a

Tumor above superficial fascia

T1b Tumor invading or deep to


superficial fascia
Tumor >5 cm in greatest dimension
T2

T2a

Tumor above superficial fascia

T2b Tumor invading or deep to


superficial fascia
Regional lymph nodes (N)
NX

Regional lymph nodes cannot be


assessed

N0

No regional lymph node metastasis

N1

Regional lymph node metastasis

Distant metastasis (M)


MX

Distant metastasis cannot be assessed

M0

No distant metastasis

M1

Distant metastasis

Histopathological grade (G)


GX

Grade cannot be assessed

G1

Well differentiated

G2

Moderately differentiated

G3

Poorly differentiated

G4

Undifferentiated

Stage grouping
Stage I
A

G12, T1a
1b, N0, M0

(low grade, small,


superficial, and deep)

G12, T2a,
N0, M0

(low grade, large, and


superficial)

Stage II
A

G12, T2b,
N0, M0

(low grade, large, and


deep)

G34, T1a
1b, N0, M0

(high grade, small,


superficial, and deep)

G34, T2a,

(high grade, large, and

Stage
III

Stage
IV

N0, M0

superficial)

G34, T2b,
N0, M0

(high grade, large, and


deep)

Any G, any
T, N1, M0
(any metastasis)
Any G, any
T, N0, M1

Adapted from Greene FL, Page DL, Fleming ID,


et al., eds. Cancer Staging Manual. 6th ed.
Philadelphia, Pa: Lippincott-Raven; 2002, with
permission.

Tumor Size
Tumor si ze at pr esentati on i s al so an i mpor tant deter mi nant of
outcome. Sar comas have cl assi cal l y been strati fi ed i nto two gr oups
based on si ze: T1 l esi ons (5 cm) and T2 l esi ons (>5 cm). The 2002
AJCC stagi ng system conti nues to use depth (i .e., super fi ci al or
deep) to defi ne pr ognosi s. Extr emi ty soft-ti ssue sar comas that ar e
super fi ci al to the i nvesti ng muscul ar fasci a ar e desi gnated a l esi ons
i n the T scor e (Ta), wher eas tumor s deep to the fasci a and al l
r etr oper i toneal and vi sceral l esi ons ar e desi gnated b (Tb).

Nodal Metastases
Lymph node metastases ar e rar e, wi th l ess than 5% of soft-ti ssue
sar comas metastasi z i ng to the nodes. Nodal metastases ar e
associ ated wi th a poor pr ognosi s and conti nue to be cl assi fi ed as
stage IV di sease. A few hi stol ogi c subtypes, such as epi thel i oi d
sar coma, r habdomyosar coma, cl ear cel l sar coma, angi osar coma, and
mal i gnant fi br ous hi sti ocytoma, have been found to be associ ated
wi th a hi gher i nci dence of nodal i nvol vement (10% 20% ).

Distant Metastasis
Di stant metastases occur most fr equentl y i n the l ung. Resecti on of
the pul monar y l esi ons i n sel ected pati ents wi th i sol ated l ung
metastases may offer up to a 30% 5-year sur vi val rate. Other
potenti al si tes of metastasi s i ncl ude bone, brai n, and l i ver. Vi sceral
and r etr oper i toneal sar comas have a pr opensi ty to metastasi ze to
the l i ver and per i toneum.

Extremity Soft-Tissue Sarcomas


Mor e than 50% of soft-ti ssue sar comas or i gi nate i n an extr emi ty.
The most common hi stol ogi c subtypes that occur i n the extr emi ty
i ncl ude mal i gnant fi br ous hi sti ocytoma, l i posar coma, synovi al
sar coma, and fi br osar coma, al though var i ous other hi stol ogi c types
ar e al so seen i n the extr emi ti es.

Clinical Presentation
Most extr emi ty soft-ti ssue sar comas pr esent as an asymptomati c
mass, but the si ze at pr esentati on usual l y depends on the
anatomi cal si te of the tumor. For exampl e, al though a 2- to 3-cm
tumor may become r eadi l y appar ent on the back of the hand, a
tumor i n the thi gh may gr ow to 10 to 15 cm i n di ameter befor e i t
becomes appar ent. F r equentl y, trauma to the affected ar ea wi l l cal l
attenti on to the pr e-exi sti ng l esi on. Smal l l esi ons that on the basi s
of the cl i ni cal hi stor y r emai n unchanged for several year s may be
cl osel y obser ved wi thout bi opsy. However, al l other tumor s shoul d
be bi opsi ed.

Biopsy
Accurate pr eoperati ve hi stol ogi c di agnosi s i s a cr i ti cal step i n
deter mi ni ng the pr i mar y tr eatment of a soft-ti ssue sar coma. The
bi opsy shoul d yi el d enough ti ssue so that a pathol ogi cal di agnosi s
can be made wi thout i ncr easi ng the r i sk of compl i cati ons.
Cor e-needl e bi opsy and fi ne-needl e aspi rati on have been
demonstrated to be r el i abl e means of obtai ni ng enough mater i al
for an accurate pathol ogi cal di agnosi s to be made, par ti cul ar l y when
the pathol ogi cal fi ndi ngs cor r el ate cl osel y wi th cl i ni cal and i magi ng
fi ndi ngs. Bi opsy per for med under ul trasound or computed
tomography (CT) gui dance can i mpr ove the posi ti ve yi el d rate by

hel pi ng pathol ogi sts mor e accuratel y l ocate the needl e i n the tumor,
par ti cul ar l y i n pati ents wi th deep extr emi ty or r etr oper i toneal
tumor s.

Evaluation
The goal s of pr etr eatment radi ol ogi c i magi ng ar e to accuratel y
defi ne the l ocal extent of a tumor and to l ook for metastati c
di sease. Magneti c r esonance i magi ng (MRI) has suppl anted CT as
the i magi ng techni que of choi ce i n the eval uati on of soft-ti ssue
sar comas of the extr emi ty, except i n pati ents who do not have
access to MRI or who have a contrai ndi cati on to MRI, i n whom CT
r emai ns the pr eferabl e techni que. MRI accuratel y del i neates muscl e
gr oups and di sti ngui shes between bone, vascul ar str uctur es, and
tumor. In addi ti on, sagi ttal and cor onal vi ews al l ow thr eedi mensi onal eval uati on of anatomi cal compar tments.
CT r emai ns the i magi ng techni que of choi ce for eval uati ng
r etr oper i toneal sar comas. The cur r ent generati on of CT scanner s
can rapi dl y pr ovi de a detai l ed sur vey of the abdomen and pel vi s and
del i neate adjacent or gans and vascul ar str uctur es. A CT scan of the
abdomen and pel vi s shoul d be obtai ned when the hi stol ogi c
assessment of an extr emi ty sar coma r eveal s myxoi d l i posar coma,
because thi s hi stol ogi c subtype i s known to metastasi ze to the
abdomen. Chest CT i s used most often i n pati ents wi th hi gh-grade
l esi ons. Sear ches for bone and brai n metastases ar e rar el y
i ndi cated, unl ess a pati ent has symptoms of metastases to these
si tes.

Management of Local Disease


The success of l ocal tumor contr ol depends on several tumor- and
tr eatment-r el ated pr ognosti c factor s. In mul ti var i ate anal yses, hi gh
hi stol ogi c grade, l ar ge tumor si ze (>5 cm), posi ti ve sur gi cal
mar gi ns, and i ntraoperati ve vi ol ati on of the tumor capsul e have
been associ ated wi th a hi gh rate of l ocal r ecur r ence. Hi stol ogi c
grade and tumor si ze ar e the most si gni fi cant r i sk factor s for di stant
metastasi s and tumor-r el ated mor tal i ty.

Surgery
The type of sur gi cal r esecti on per for med i n pati ents wi th extr emi ty
soft-ti ssue sar comas i s deter mi ned by a number of factor s, i ncl udi ng
tumor l ocati on, tumor si ze, the depth of i nvasi on, the i nvol vement
of near by str uctur es, the need for ski n grafti ng or autogenous

ti ssue r econstr ucti on, and the pati ent's per for mance status. In the
1970s, 50% of pati ents wi th extr emi ty sar comas wer e tr eated wi th
amputati on for l ocal contr ol of thei r tumor s. However, despi te a
l ocal r ecur r ence rate of l ess than 10% fol l owi ng radi cal sur ger y,
l ar ge number s of pati ents conti nued to di e fr om metastati c di sease.
Thi s r eal i z ati on l ed to the devel opment and adopti on of other
methods of l ocal therapy that combi ned conser vati ve sur gi cal
exci si on wi th postoperati ve radi ati on therapy, wi th r esul tant l ocal
contr ol rates of 78% to 91% .
Wi de l ocal exci si on i s the pr i mar y tr eatment for pati ents wi th
extr emi ty sar comas. It i s i mpor tant, when pl anni ng sur ger y and
radi otherapy, to r emember that ther e i s general l y a zone of
compr essed r eacti ve ti ssue that for ms a pseudocapsul e ar ound the
tumor s and that tumor s may extend beyond thi s pseudocapsul e. The
i nexper i enced sur geon may mi stakenl y use thi s to gui de r esecti on.
The goal of l ocal therapy i s to r esect the tumor wi th a 2-cm mar gi n
of sur r oundi ng nor mal soft ti ssue. In some anatomi cal ar eas,
however, these mar gi ns ar e not attai nabl e because of the pr oxi mi ty
of vi tal str uctur es. When possi bl e, the bi opsy si te or tract shoul d
al so be i ncl uded en bl oc wi th the r esected speci men.
El ecti ve r egi onal l ymphadenectomy i s rar el y i ndi cated i n pati ents
wi th soft-ti ssue sar comas. However, i n pati ents wi th
r habdomyosar coma or epi thel i oi d sar coma wi th suspi ci ous cl i ni cal or
radi ol ogi c fi ndi ngs, fi ne-needl e aspi rati on of the l ymph nodes shoul d
be per for med pr eoperati vel y. In these rar e cases, a l ymph node
di ssecti on may be i ndi cated for r egi onal contr ol of the di sease. A
pr ospecti ve tr i al i s cur r entl y under way to eval uate the r ol e of
l ymphati c mappi ng and senti nel l ymph node bi opsy i n pedi atr i c
pati ents wi th extr emi ty r habdomyosar comas.
Ther e have been several studi es that have shown favorabl e l ocal
contr ol rates for pati ents wi th extr emi ty tumor s tr eated wi th
conser vati ve r esecti on combi ned wi th radi ati on therapy. For
exampl e, i n a smal l study fr om the Nati onal Cancer Insti tute, ther e
was no di ffer ence i n sur vi val among pati ents tr eated wi th
conser vati ve sur ger y pl us radi ati on therapy compar ed wi th pati ents
tr eated wi th amputati on. In 1985, on the basi s of the l i mi ted data
avai l abl e, the Nati onal Insti tutes of Heal th devel oped a consensus
statement r ecommendi ng l i mb-spar i ng sur ger y for the major i ty of
pati ents wi th hi gh-grade extr emi ty sar comas. However, amputati on
r emai ns the tr eatment of choi ce for pati ents whose tumor cannot be
gr ossl y r esected wi th a l i mb-spar i ng pr ocedur e that pr eser ves

functi on (<5% of cases).

Radiation Therapy
The pr i mar y goal of radi ati on therapy i s to opti mi ze l ocal tumor
contr ol . The evi dence for adjuncti ve radi ati on therapy i n pati ents
el i gi bl e for conser vati ve sur gi cal r esecti on comes fr om two
randomi zed tr i al s and a number of l ar ge si ngl e-i nsti tuti on r epor ts.
In one of these randomi zed tr i al s, conducted by the Nati onal Cancer
Insti tute, 91 pati ents wi th hi gh-grade extr emi ty tumor s wer e
tr eated wi th l i mb-spar i ng sur ger y fol l owed by chemotherapy al one
or radi ati on therapy pl us adjuvant chemotherapy. A second gr oup of
50 pati ents wi th l ow-grade tumor s wer e tr eated wi th r esecti on al one
ver sus r esecti on wi th radi ati on therapy. The 10-year l ocal contr ol
rate for al l pati ents r ecei vi ng radi ati on therapy was 98% compar ed
wi th 70% for those not r ecei vi ng radi ati on therapy.
In the second randomi zed tr i al , whi ch was per for med at Memor i al
Sl oan-Ketter i ng Cancer Center, 164 pati ents wer e randomi zed to
obser vati on or brachytherapy fol l owi ng conser vati ve sur ger y. The 5year l ocal contr ol rate for pati ents wi th hi gh-grade tumor s was 66%
i n the obser vati on gr oup and 89% i n the gr oup tr eated wi th
brachytherapy. Ther e was no si gni fi cant di ffer ence between the
gr oups of pati ents wi th l ow-grade tumor s.
Unti l r ecentl y, the pol i cy at the M. D. Ander son Cancer Center was
to admi ni ster radi ati on therapy as an adjunct to sur ger y for al l
pati ents wi th i nter medi ate- and hi gh-grade tumor s of any si ze.
However, because T1 tumor s ar e l ess fr equentl y associ ated wi th
l ocal r ecur r ences, radi ati on therapy for these pati ents i s cur r entl y
consi der ed on an i ndi vi dual basi s because i t may not confer a
si gni fi cant cl i ni cal benefi t. In fact, two r ecent studi es have fai l ed to
demonstrate an i mpr ovement i n the 5-year r ecur r ence or sur vi val
rates i n pati ents wi th smal l sar comas who r ecei ved postoperati ve
radi ati on therapy.

Preoperative Versus Postoperative Externalbeam Radiation Therapy


The opti mal ti mi ng of exter nal -beam radi ati on therapy for sar comas
l ocated ei ther i n an extr emi ty or i n the r etr oper i toneum r emai ns a
focus of acti ve i nvesti gati on. Cur r entl y, the onl y randomi zed tr i al
compar i ng pr eoperati ve and postoperati ve radi ati on therapy i s a

mul ti center tr i al per for med i n Canada. In thi s tr i al , fr om October


1994 to December 1997, pati ents wer e randomi zed to r ecei ve ei ther
50 G y of exter nal -beam radi ati on therapy pr eoperati vel y or 66 G y
of exter nal -beam radi ati on therapy postoperati vel y. One hundr ed
and ni nety pati ents wer e enter ed i nto the study. Wi th a medi an
fol l ow-up of 3.3 year s, the r ecur r ence and pr ogr essi onfr ee sur vi val
rates wer e si mi l ar between the gr oups, wi th the onl y stati sti cal l y
si gni fi cant di ffer ence bei ng i n the rates of wound compl i cati ons.
That i s, the i nci dence of wound compl i cati ons was 35% i n the
pati ents who r ecei ved pr eoperati ve therapy, but onl y 17% i n the
pati ents who r ecei ved postoperati ve radi ati on therapy.
At M. D. Ander son, despi te the potenti al for i ncr eased wound
pr obl ems, radi ati on therapy i s pr efer enti al l y gi ven pr eoperati vel y
for several r easons. F i r st, thi s enabl es mul ti di sci pl i nar y pl anni ng
wi th the radi ati on oncol ogi st, medi cal oncol ogi st, and sur geon to
occur ear l y i n the cour se of therapy whi l e the tumor i s i n pl ace.
Al so, pr eoperati ve radi ati on therapy al l ows l ower doses of radi ati on
to be del i ver ed to an undi stur bed ti ssue bed that i s potenti al l y
better oxygenated. In addi ti on, the si ze of the pr eoperati ve
radi ati on fi el ds and the number of joi nts i ncl uded i n the fi el ds i s
si gni fi cantl y smal l er than those of postoperati ve radi ati on fi el ds,
whi ch may r esul t i n an i mpr oved functi onal outcome.
Cr i ti cs of pr eoperati ve radi ati on therapy ci te the di ffi cul ty wi th the
pathol ogi cal assessment of mar gi ns and the i ncr eased i nci dence of
wound compl i cati ons as deter r ents to pr eoperati ve radi ati on
therapy. However, pl asti c sur ger y techni ques that i ncl ude advanced
ti ssue transfer pr ocedur es ar e bei ng used mor e fr equentl y i n
pati ents wi th such hi gh-r i sk wounds. The outcomes i n pati ents
tr eated i n thi s fashi on have been encouragi ng, wi th a hi gh success
rate (>90% ) of heal ed wounds fr om a si ngl e-stage operati on.

Brachytherapy
Brachytherapy, whi ch i nvol ves the pl acement of mul ti pl e catheter s
i n the tumor r esecti on bed, has been r epor ted to achi eve l ocal
contr ol rates comparabl e to those achi eved wi th exter nal -beam
radi ati on therapy. G ui del i nes have been establ i shed that
r ecommend pl aci ng the after l oadi ng catheter s at 1-cm i nter val s wi th
a 2-cm mar gi n ar ound the sur gi cal bed. Usual l y, after the fi fth
postoperati ve day, the catheter s ar e then l oaded wi th radi oacti ve
wi r es (i r i di um 192) that del i ver 42 to 45 G y to the tumor bed over

4 to 6 days. The fr equency of wound compl i cati ons associ ated wi th


brachytherapy i s si mi l ar to that seen for postoperati ve radi ati on
therapy (appr oxi matel y 10% ).
The pr i mar y benefi t of brachytherapy i s the shor ter overal l
tr eatment ti me of 4 to 6 days, compar ed wi th the 4 to 6 weeks
general l y consumed by pr eoperati ve or postoperati ve r egi mens.
Brachytherapy al so pr oduces l ess radi ati on scatter i n cr i ti cal
anatomi cal r egi ons (e.g., gonads, joi nts), wi th i mpr oved functi on a
potenti al cl i ni cal benefi t. Cost-anal ysi s compar i sons of
brachytherapy ver sus exter nal -beam radi ati on therapy have fur ther
shown that the char ges for adjuvant i r radi ati on wi th brachytherapy
ar e l ower than those for exter nal -beam radi ati on therapy.

Systemic Chemotherapy
Despi te i mpr ovements i n the l ocal contr ol rate, metastasi s and
death r emai n si gni fi cant pr obl ems for pati ents wi th hi gh-r i sk softti ssue sar comas. Thi s i ncl udes pati ents pr esenti ng wi th metastati c
di sease and l ocal i zed sar comas that ar e i n nonextr emi ty si tes, show
an i nter medi ate- or hi gh-grade hi stol ogy, or ar e l ar ge (T2). The
tr eatment r egi men for pati ents wi th hi gh-r i sk l ocal i zed di sease,
metastati c di sease, or both, often i ncl udes chemotherapy.
As a gr oup, sar comas i ncl ude hi stol ogi c subtypes that ar e ver y
r esponsi ve to cytotoxi c chemotherapy as wel l as subtypes that ar e
uni ver sal l y r esi stant to cur r ent agents. Onl y thr ee dr ugs,
doxor ubi ci n, dacar baz i ne, and i fosfami de, have consi stentl y
achi eved r esponse rates of 20% as si ngl e-agent tr eatments i n
pati ents wi th advanced soft-ti ssue sar comas. The major i ty of acti ve
chemotherapeuti c tr i al s have i ncl uded doxor ubi ci n as par t of the
tr eatment r egi men. The r esponse rate to i fosfami de has been found
to var y fr om 20% to 60% i n si ngl e-i nsti tuti on ser i es i n whi ch
hi gher-dose r egi mens have been used or i n whi ch i t has been gi ven
i n combi nati on wi th doxor ubi ci n.

Adjuvant (Postoperative) Chemotherapy


Indi vi dual randomi zed tr i al s of adjuvant chemotherapy have fai l ed
to demonstrate an i mpr ovement i n di sease-fr ee and overal l sur vi val
i n pati ents wi th soft-ti ssue sar comas. However, ther e ar e several
cr i ti ci sms of these i ndi vi dual tr i al s that may expl ai n why they fai l ed
to demonstrate i mpr ovement i n sur vi val . F i r st, the chemotherapy
r egi mens used wer e subopti mal , i n that si ngl e-agent dr ugs (most
commonl y doxor ubi ci n) wer e studi ed and dosi ng schedul es wer e l ess

i ntensi ve. Second, the sampl e si zes i n these tr i al s wer e not l ar ge


enough to al l ow the detecti on of cl i ni cal l y si gni fi cant di ffer ences i n
sur vi val . Thi r d, the major i ty of pati ents who di d not r espond to the
i ni ti al tr eatment r egi men wer e star ted on other chemotherapeuti c
r egi mens that potenti al l y affected di sease-fr ee and overal l sur vi val .
F i nal l y, most studi es i ncl uded pati ents at l ow r i sk for metastasi s and
death, that i s, those wi th smal l (<5 cm) and l ow-grade tumor s.
Hence, adjuvant chemotherapy for pati ents wi th soft-ti ssue
sar comas r emai ns contr over si al . To hel p settl e thi s i ssue, a for mal
meta-anal ysi s cal l ed the Sar coma Meta-Anal ysi s Col l aborati on was
conducted i n 1997. Thi s gr oup anal yzed the data on 1,568 pati ents
fr om 14 tr i al s of doxor ubi ci n-based adjuvant chemotherapy to
deter mi ne the effect of adjuvant chemotherapy on l ocal i zed,
r esectabl e soft-ti ssue sar comas. Wi th a medi an fol l ow-up of 9.4
year s, doxor ubi ci n-based chemotherapy was found to have
si gni fi cantl y l engthened the ti me to l ocal and di stant r ecur r ence and
the overal l r ecur r ence-fr ee sur vi val . However, the absol ute
i mpr ovement i n the overal l sur vi val rate for the enti r e gr oup was
onl y by 4% , whi ch was not stati sti cal l y si gni fi cant. When subsets of
pati ents wer e exami ned, ther e was a 7% i ncr ease i n the sur vi val
rate i n those pati ents wi th extr emi ty tumor s.

Neoadjuvant (Preoperative) Chemotherapy


The rati onal e for neoadjuvant/pr eoperati ve chemotherapy for softti ssue sar comas i s that, gi ven that onl y 30% to 50% of pati ents wi l l
r espond to standar d chemotherapeuti c r egi mens, i t enabl es the
oncol ogi st to i denti fy those sel ect pati ents i n whom speci fi c
r egi mens ar e effecti ve, as shown by measur i ng the pr i mar y tumor i n
si tu. Pati ents whose tumor s shr i nk after two or four cour ses
subsequentl y under go l ocal tr eatment wi th sur ger y and/or radi ati on
therapy, fol l owed by postoperati ve chemotherapy wi th the same
agents that wer e admi ni ster ed pr eoperati vel y. At the same ti me,
pati ents who do not r espond to shor t cour ses of pr eoperati ve
chemotherapy ar e spar ed the toxi c effects of pr ol onged
postoperati ve chemotherapy wi th agents to whi ch they ar e
i nsensi ti ve.
In an effor t to better assess the r ol e of chemotherapy, a cohor t
anal ysi s of the combi ned databases fr om both M. D. Ander son and
Memor i al Sl oan-Ketter i ng was r ecentl y per for med. The data on 674
pati ents wi th stage III extr emi ty sar coma who r ecei ved ei ther

pr eoperati ve or postoperati ve doxor ubi ci n-based chemotherapy wer e


r evi ewed to deter mi ne thei r outcomes (5-year di sease-speci fi c
sur vi val , as wel l as 5-year l ocal and di stant r ecur r ence rates) fr om
systemi c therapy. The 5-year di sease-speci fi c sur vi val rate was
61% , and the pr obabi l i ty of l ocal and di stant r ecur r ences at 5 year s
was 83% and 56% , r especti vel y. An i mpor tant concl usi on fr om thi s
study was that the cl i ni cal benefi ts of doxor ubi ci n-based
chemotherapy i n pati ents wi th hi gh-r i sk extr emi ty sar comas wer e
not sustai ned beyond 1 year after therapy. The i nvesti gator s then
went on to compar e thei r study wi th the Sar coma Meta-Anal ysi s
Col l aborati on and made the fol l owi ng obser vati ons. F i r st, the
pati ent popul ati on of the Sar coma Meta-Anal ysi s Col l aborati on was
mor e heter ogeneous than that of the cohor t study, i n that i t
i ncl uded pati ents wi th both pr i mar y and r ecur r ent extr emi ty and
nonextr emi ty sar comas. Second, ther e wer e al so fewer uncontr ol l ed
var i abl es i n the cohor t study. On the basi s of these fi ndi ngs, the
author s ur ged cauti on when r evi ewi ng studi es of chemotherapeuti c
r egi mens wi th a shor t-ter m fol l ow-up and concl uded that ther e
r emai ns no consensus r egar di ng the r ol e of chemotherapy i n
pati ents wi th l ocal i zed hi gh-r i sk soft-ti ssue sar comas.

Regional Chemotherapy/Isolated Limb


Perfusion
Isol ated l i mb per fusi on (ILP) i s an i nvesti gati onal appr oach for
tr eati ng extr emi ty sar comas i n the appr oxi matel y 10% of pati ents
wi th extr emi ty sar comas for whom amputati on i s the onl y opti on for
l ocal tr eatment. It has been used mai nl y as a l i mb-spar i ng
al ter nati ve i n these pati ents and consi sts of the r egi onal
admi ni strati on of hi gh-dose chemotherapy vi a ILP.
The techni que of ILP i nvol ves i sol ati on of the mai n ar ter y and vei n
of the per fused l i mb fr om the systemi c ci r cul ati on. The speci fi c
tumor si te deter mi nes the choi ce of the speci fi c anatomi cal
appr oach. Exter nal i l i ac vessel s ar e used for thi gh tumor s, femoral
or popl i teal vessel s for cal f tumor s, and axi l l ar y vessel s for upperextr emi ty tumor s. The vessel s ar e di ssected, and al l col l ateral
vessel s ar e l i gated. The vessel s ar e then cannul ated and connected
to a pump oxygenator si mi l ar to that used i n car di opul monar y
bypass. A tour ni quet or Esmar ch bandage i s appl i ed to the l i mb to
achi eve compl ete vascul ar i sol ati on. The chemotherapeuti c agents
ar e then added to the per fusi on ci r cui t and r eci r cul ated for 90
mi nutes. The temperatur e of the per fused l i mb i s mai ntai ned dur i ng

the enti r e pr ocedur e by both exter nal heati ng and war mi ng of the
per fusates. At the end of the pr ocedur e, the dr ugs ar e washed out
of the l i mb, the cannul as ar e r emoved, and the bl ood vessel s
r epai r ed.
Ther e ar e several pr obl ems wi th tr yi ng to i nter pr et the data fr om
studi es of ILP per for med to date. These pr obl ems i ncl ude the
heter ogeneous natur e of the pati ents tr eated and the wi de var i ety
of chemotherapeuti c agents used. Despi te these pr obl ems, favorabl e
r esponse rates of 18% to 80% wi th overal l 5-year sur vi val rates of
50% to 70% have been r epor ted.
Recentl y, i nter est has devel oped i n a l ess i nvasi ve techni que ter med
isolated limb infusion. Thi s techni que has al so been ter med
minimally invasive isolated limb per fusion. Regar dl ess of the
nomencl atur e, the pr ocedur e i nvol ves the pl acement of i nfusi on
catheter s by i nter venti onal radi ol ogi sts, after whi ch the pati ent i s
transfer r ed to the operati ng r oom wi th the catheter s i n pl ace. Under
i schemi c condi ti ons, chemotherapy i s admi ni ster ed vi a a
nonoxygenated bypass ci r cui t. The i schemi c condi ti ons ar e vi tal to
thi s techni que because thi s i s bel i eved to enhance the effi cacy of
the chemotherapeuti c agents. Cur r entl y, i sol ated l i mb i nfusi on i s
onl y avai l abl e as an exper i mental pr otocol at cer tai n center s.

Management of Local Recurrence


Di sease can r ecur i n up to 20% of pati ents wi th extr emi ty sar coma,
but pati ents wi th mi cr oscopi cal l y posi ti ve sur gi cal mar gi ns ar e the
ones i n whom the r i sk of l ocal r ecur r ence i s gr eatest. It r emai ns a
matter of contr over sy, however, as to what the i mpact of l ocal
fai l ur es i s on sur vi val and di stant di sease-fr ee sur vi val . Many
bel i eve r ecur r ence r epr esents a har bi nger of di stant metastati c
di sease. Regar dl ess, the adequacy of the sur gi cal r esecti on cl ear l y
pl ays a r ol e i n deter mi ni ng whether di sease r ecur s l ocal l y.
An i sol ated l ocal r ecur r ence shoul d be tr eated aggr essi vel y wi th
mar gi n-negati ve r e-r esecti on (possi bl y amputati on) pl us radi ati on
therapy. Pati ents pr evi ousl y tr eated wi th exter nal -beam
radi ati on therapy may be consi der ed for brachytherapy or
i ntraoperati ve radi ati on therapy. Several smal l studi es have shown
that pati ents wi th i sol ated l ocal r ecur r ences may be successful l y
r etr eated, wi th l ocal r ecur r ence-fr ee sur vi val rates appr oachi ng
72% .

Management of Distant Disease


Di stant metastases occur i n 40% to 50% of pati ents wi th
i nter medi ate- and hi gh-grade extr emi ty sar comas, compar ed wi th
onl y 5% of pati ents wi th l ow-grade sar comas. Most metastases to
di stant si tes occur wi thi n 2 year s of the i ni ti al di agnosi s. The
pr edomi nant si te of di stant metastases fr om pr i mar y extr emi ty
sar comas i s the l ung (73% of cases).
Lung metastases shoul d be r esected i f ther e ar e no extrapul monar y
metastases, the pati ent i s medi cal l y fi t enough to wi thstand a
thoracotomy, and the l esi ons ar e amenabl e to r esecti on. Lar ge
ser i es have r eveal ed 3-year sur vi val rates of 40% to 50% i n
pati ents wi th compl etel y r esected pul monar y metastases. A di seasefr ee i nter val of mor e than 12 months, the abi l i ty to r esect al l
metastati c di sease, age younger than 50 year s, and absence of
pr ecedi ng l ocal r ecur r ence wer e found to be i ndependent pr ognosti c
factor s i n a mul ti var i ate anal ysi s of pati ents who under went
r esecti on of pul monar y metastases.

General Recommendations
G eneral r ecommendati ons for the management of extr emi ty softti ssue sar comas ar e as fol l ows:
1. Soft-ti ssue tumor s that ar e enl ar gi ng or gr eater than 3 cm i n
di ameter shoul d be eval uated wi th radi ol ogi c i magi ng
(ul trasonography or CT), and a ti ssue di agnosi s made on the
basi s of fi ne-needl e aspi rati on or cor e-needl e bi opsy fi ndi ngs.
2. Eval uate for metastati c di sease once a sar coma di agnosi s i s
establ i shed: chest radi ography for l ow- or i nter medi ate-grade
l esi ons and T1 tumor s, and chest CT for hi gh-grade or T2
tumor s.
3. A wi de l ocal exci si on wi th 2-cm mar gi ns i s adequate therapy for
l ow-grade l esi ons and T1 tumor s.
4. Radi ati on therapy pl ays a cr i ti cal r ol e i n the management of T2
tumor s.
5. Pati ents wi th r ecur r ent hi gh-grade sar comas or di stant
metastati c di sease shoul d be consi der ed for pr eoperati ve
(neoadjuvant) or postoperati ve (adjuvant) chemotherapy.
6. An aggr essi ve sur gi cal appr oach shoul d be taken i n the

tr eatment of pati ents wi th an i sol ated l ocal r ecur r ence or


r esectabl e di stant metastases.

Retroperitoneal Sarcomas
F i fteen per cent of soft-ti ssue sar comas i n adul ts occur i n the
r etr oper i toneum. Most r etr oper i toneal tumor s ar e mal i gnant, and
appr oxi matel y one-thi r d ar e soft-ti ssue sar comas. The di ffer enti al
di agnosi s i n a pati ent pr esenti ng wi th a r etr oper i toneal tumor
i ncl udes l ymphoma, ger m cel l tumor s, and undi ffer enti ated
car ci nomas. The most common sar comas occur r i ng i n the
r etr oper i toneum ar e l i posar comas, mal i gnant fi br ous hi sti ocytomas,
and l ei omyosar comas.
Al though si gni fi cant advances i n our under standi ng of extr emi ty
soft-ti ssue sar comas have r esul ted i n i mpr oved tr eatments and
outcomes, si mi l ar pr ogr ess has not been achi eved i n our
under standi ng and tr eatment of r etr oper i toneal soft-ti ssue
sar comas. For several r easons, pati ents wi th r etr oper i toneal softti ssue sar comas general l y have a wor se pr ognosi s than those wi th
extr emi ty sar comas. One r eason i s that r etr oper i toneal soft-ti ssue
sar comas commonl y gr ow to l ar ge si zes befor e they become
cl i ni cal l y appar ent, by whi ch ti me they often i nvol ve i mpor tant vi tal
str uctur es, whi ch pr ecl udes sur gi cal r esecti on. A second r eason i s
that the sur gi cal mar gi ns that can be obtai ned ar ound these
sar comas ar e often i nadequate because of anatomi cal constrai nts.

Clinical Presentation
Retr oper i toneal sar comas general l y pr esent as l ar ge masses; near l y
50% ar e l ar ger than 20 cm at the ti me of di agnosi s. They typi cal l y
do not pr oduce symptoms unti l they gr ow l ar ge enough to compr ess
or i nvade conti guous str uctur es. On occasi on, pati ents may pr esent
wi th neur ol ogi c symptoms, r esul ti ng fr om the compr essi on of l umbar
or pel vi c ner ves, or obstr ucti ve gastr oi ntesti nal symptoms, r esul ti ng
fr om the di spl acement or di r ect tumor i nvol vement of an i ntesti nal
or gan.

Evaluation
The wor kup i n a pati ent wi th a r etr oper i toneal mass begi ns wi th an
accurate hi stor y that shoul d excl ude si gns and symptoms of
l ymphoma (e.g., fever, ni ght sweats). A compl ete physi cal

exami nati on wi th par ti cul ar attenti on to al l nodal basi ns and a


testi cul ar exami nati on i n mal es ar e cr i ti cal l y i mpor tant. Laborator y
assessment can be hel pful ; an i ncr eased l actate dehydr ogenase
concentrati on can be suggesti ve of l ymphoma, wher eas an i ncr eased
-human chor i oni c gonadotr opi n l evel , al pha-fetopr otei n l evel , or
both can i ndi cate a ger m cel l tumor.
The radi ol ogi c assessment shoul d i ncl ude a CT scan of the abdomen
and pel vi s to defi ne the extent of the tumor and i ts r el ati onshi p to
sur r oundi ng str uctur es, par ti cul ar l y vascul ar str uctur es. Imagi ng
shoul d i ncl ude the l i ver i n a sear ch for metastases and
di sconti nuous abdomi nal di sease. The ki dneys shoul d al so be
eval uated to assess bi l ateral r enal functi on. Thoraci c CT i s i ndi cated
to l ook for l ung metastases. A CT-gui ded cor e-needl e bi opsy i s
appr opr i ate for obtai ni ng a ti ssue di agnosi s i n pati ents pr esenti ng
wi th an equi vocal hi stor y, an unusual -appear i ng mass, an
unr esectabl e tumor, or di stant metastasi s and i n pati ents who ar e
potenti al l y el i gi bl e for a neoadjuvant pr otocol .

Management
Compl ete sur gi cal r esecti on i s the most effecti ve tr eatment for
pr i mar y or r ecur r ent r etr oper i toneal sar comas, but i t i s fr equentl y
not possi bl e. For exampl e, i n several r etr ospecti ve assessments of
pati ents wi th r etr oper i toneal sar coma, compl ete sur gi cal exci si on
was achi eved i n onl y 40% to 60% of pati ents. The effects of an
i ncompl ete sur gi cal r esecti on on outcome ar e qui te demonstrabl e. In
an anal ysi s of 500 pati ents wi th r etr oper i toneal soft-ti ssue
sar comas tr eated at Memor i al Sl oan-Ketter i ng Cancer Center, the
medi an sur vi val durati on of pati ents who under went
compl ete r esecti on was 103 months ver sus 18 months for pati ents
who under went i ncompl ete r esecti on, whi ch was no di ffer ent than
the sur vi val seen i n pati ents tr eated wi th obser vati on wi thout
r esecti on.
Sur gi cal r esecti on shoul d not be offer ed to pati ents unl ess
radi ographi c evi dence i ndi cates the potenti al for compl ete r esecti on,
al though pal l i ati ve sur gi cal pr ocedur es may be per for med to r educe
the symptoms of i ntesti nal obstr ucti on or bl eedi ng. In par ti cul ar,
pati ents wi th atypi cal l i pomatous tumor s, al so ter med welldiffer entiated liposar comas, may benefi t symptomati cal l y fr om
r epeated tumor debul ki ng.

Adjuvant Therapy
Chemotherapy has not been shown to be an effecti ve tr eatment for
r etr oper i toneal sar comas. Several center s have ongoi ng pr otocol s to
deter mi ne the r ol e of pr eoperati ve chemotherapy and radi ati on
therapy for these tumor s, but the fi ndi ngs fr om these studi es have
not yet been r el eased. A tr i al sponser ed by the Amer i can Col l ege of
Sur geon's Oncol ogy G r oup eval uati ng the benefi t of pr eoperati ve
radi ati on i n pati ents wi th r etr o per i toneal sar comas r ecentl y cl osed
for fai l ur e to meet accr ual tar gets.

Management of Recurrent Disease


Retr oper i toneal sar comas r ecur i n two-thi r ds of pati ents. In addi ti on
to r ecur r i ng l ocal l y i n the tumor bed and metastasi z i ng to the l ungs,
r etr oper i toneal l ei omyosar comas fr equentl y spr ead to the l i ver.
Retr oper i toneal sar comas can al so r ecur di ffusel y thr oughout the
per i toneal cavi ty (sar comatosi s). The appr oach to r esectabl e
r ecur r ent di sease after the tr eatment of a r etr oper i toneal sar coma
i s si mi l ar to the appr oach taken after the r ecur r ence of an
extr emi ty sar coma. However, the abi l i ty to r esect a r ecur r ent
r etr oper i toneal sar coma decl i nes pr eci pi tousl y wi th each r ecur r ence.
In a l ar ge ser i es of pati ents tr eated at Memor i al Sl oan-Ketter i ng
Cancer Center, the author s wer e abl e to r esect r ecur r ent tumor s i n
57% of pati ents wi th a fi r st r ecur r ence, but i n onl y 20% of pati ents
after a second r ecur r ence and 10% after a thi r d r ecur r ence.
Isol ated l i ver metastases, i f stabl e over several months, may be
amenabl e to r esecti on, radi ofr equency abl ati on, or
chemoembol i z ati on.
In as many as 25% of pati ents, wel l -di ffer enti ated l i posar coma may
r ecur i n a poor l y di ffer enti ated for m or devel op ar eas of
dedi ffer enti ati on. Dedi ffer enti ated r etr oper i toneal l i posar coma i s
mor e aggr essi ve wi th a gr eater pr opensi ty for di stant metastasi s
than i ts wel l -di ffer enti ated pr ecur sor.

Follow-up
The rati onal e behi nd fol l ow-up strategi es to detect the r ecur r ence of
any type of cancer i s that the ear l y r ecogni ti on and tr eatment of
r ecur r ent, l ocal , or di stant di sease can pr ol ong sur vi val . The i deal
fol l ow-up strategy shoul d ther efor e be easy to i mpl ement, accurate,
and cost-effecti ve.
The devel opment of metastases i s the pr i mar y deter mi nant of

sur vi val i n pati ents wi th soft-ti ssue sar coma. The si te of r ecur r ence
i s r el ated to the anatomi cal si te of the pr i mar y tumor. Extr emi ty
sar comas general l y r ecur i n the for m of di stant
pul monar y metastases, wher eas r etr oper i toneal or i ntra-abdomi nal
sar comas tend to r ecur as fr equentl y l ocal l y as they do i n the l ungs.
Whether the ear l y detecti on of r ecur r ence can i mpr ove overal l
sur vi val depends on the avai l abi l i ty of effecti ve therapeuti c
i nter venti ons. A few r epor ts i nvol vi ng smal l number s of pati ents
have shown that i t i s possi bl e to sal vage pati ents wi th r ecur r ent
l ocal di sease wi th radi cal r e-exci si on wi th or wi thout radi ati on
therapy. Si mi l ar l y, several gr oups have r epor ted on pati ents who
have exper i enced pr ol onged sur vi val fol l owi ng the r esecti on of
pul monar y metastases. These l i mi ted data for m the i mpetus for the
aggr essi ve sur vei l l ance strategi es taken i n pati ents wi th soft-ti ssue
sar comas.
The major i ty of soft-ti ssue sar comas that r ecur do so wi thi n the
fi r st 2 year s after the compl eti on of therapy. Pati ents shoul d
ther efor e be eval uated wi th a compl ete hi stor y and physi cal
exami nati on ever y 3 months wi th a chest radi ograph and tumor si te
i magi ng dur i ng thi s hi gh-r i sk per i od. If the chest radi ograph r eveal s
a suspi ci ous nodul e, a CT scan of the chest shoul d be obtai ned for
fur ther assessment. Most exper ts r ecommend that the tumor si te be
eval uated wi th ei ther MRI for an extr emi ty tumor or CT for i ntraabdomi nal or r etr oper i toneal tumor s. In some ci r cumstances,
ul trasonography can be used to l ook for the r ecur r ence of an
extr emi ty tumor ei ther l ocal l y or at a di stant si te. Fol l ow-up
i nter val s may be l engthened to ever y 6 months, wi th annual
i magi ng dur i ng year s 2 thr ough 5 after the compl eti on of therapy.
After 5 year s, pati ents shoul d be assessed annual l y and a chest
radi ograph shoul d be obtai ned.

Gastrointestinal Stromal Tumors


G astr oi ntesti nal str omal tumor s (G ISTs) consti tute the major i ty of
mesenchymal tumor s i nvol vi ng the gastr oi ntesti nal tract. It i s
esti mated that ther e ar e 2,500 to 6,000 cases per year i n the
Uni ted States. Al though the cl i ni cal pr esentati on of these tumor s
var i es dependi ng on the tumor si ze and anatomi cal l ocati on, most
tumor s ar e found i nci dental l y at the ti me of endoscopy or radi ol ogi c
i magi ng. G ISTs ar i se most fr equentl y i n the stomach (60% 70% ),
fol l owed by the smal l i ntesti ne (20% 25% ), col on and r ectum (5% ),

and esophagus (<5% ). Most G ISTs ar e sporadi c and, i n 95% of


cases, sol i tar y. Most pati ents wi th G ISTs pr esent i n the fi fth to the
seventh decades of l i fe, and these tumor s ar e equal l y di str i buted
between the gender s. Symptoms of these l esi ons i ncl ude pai n and
gastr oi ntesti nal bl eedi ng, wi th abdomi nal mass a fr equent fi ndi ng.
Si nce the l ate-1990s, i t has been r ecogni zed that G ISTs have
di sti ncti ve i mmunohi stochemi cal and geneti c featur es. G ISTs
or i gi nate fr om the i ntesti nal pacemaker cel l s (the i nter sti ti al cel l s
of Cajal ), whi ch expr ess CD117, a transmembrane tyr osi ne ki nase
r eceptor that i s the pr oduct of the c-KIT pr oto-oncogene. The
expr essi on of CD117 has emer ged as an i mpor tant defi ni ng featur e
of G ISTs, bei ng found i n near l y 95% of cases. The pathogenesi s of
these tumor s i s r el ated to mutati ons i n the c-KIT gene. Expl oi tati on
of thi s geneti c character i sti c has l ed to si gni fi cant i nr oads i nto the
devel opment of successful exper i mental therapy for these tumor s.

Treatment
Sur gi cal r esecti on r emai ns the tr eatment of choi ce for G ISTs.
However, despi te compl ete sur gi cal r esecti on, the major i ty of
pati ents (76% i n one study fr om Memor i al Sl oan-Ketter i ng Cancer
Center ) wi l l suffer l ocal r ecur r ence. Sal vage sur ger y for these
r ecur r ences i s associ ated wi th a 15-month medi an sur vi val .
Pr omi si ng pr ecl i ni cal r esul ts have been the dr i vi ng for ce for the
rapi d cl i ni cal devel opment of i mati ni b mesyl ate (G l eevec, for mer l y
known as STI571; Novar ti s), a sel ecti ve tyr osi ne ki nase i nhi bi tor of
c-KIT. Thi s agent r epr esents a novel i nter venti on and has
demonstrated the mer i ts of speci fi cal l y tar geted mol ecul ar therapi es
i n the management of oncol ogi c di seases. In Febr uar y 2002,
i mati ni b mesyl ate was appr oved by the U.S. Food and Dr ug
Admi ni strati on for use i n the tr eatment of G ISTs on the basi s of the
r esul ts of tr i al s conducted i n pati ents wi th metastati c and l ocal l y
advanced di sease (Tabl e 5.3). Ini ti al r esul ts have shown that near l y
54% of pati ents wi th G ISTs r espond to i mati ni b and that ther e i s no
benefi t to doses over 400 mg per day. Li ttl e i s cur r entl y known
about the opti mal l ength of tr eatment, the durati on of benefi t, or
the l ong-ter m toxi ci ty of thi s dr ug. At M. D. Ander son, ther e ar e
thr ee ongoi ng cl i ni cal pr otocol s i nvol vi ng the use of i mati ni b i n
di ffer ent setti ngs. The fi r st pr otocol i s par t of the Amer i can Col l ege
of Sur geons Oncol ogy G r oup Z9001 phase III pr ospecti ve
randomi zed tr i al ; i n i t, adjuvant i mati ni b tr eatment pl us sur ger y i s

bei ng compar ed wi th sur ger y al one i n pati ents wi th G ISTs who have
under gone R0 or R1 r esecti on. The second pr otocol (Z9000) i s a
phase II pr ospecti ve randomi zed study i n whi ch combi ned
pr eoperati ve and postoperati ve i mati ni b i s bei ng used for pati ents
wi th pr i mar y, r ecur r ent, or metastati c r esectabl e G IST. The thi r d
pr otocol i s a phase II tr i al that i s i nvesti gati ng whether
pr eoperati ve and postoperati ve i mati ni b wi l l r educe the r ecur r ence
rate i n pati ents wi th pr i mar y and r ecur r ent operabl e G IST.

Other Soft-Tissue Lesions


Sarcoma of the Breast
Sar comas of the br east ar e rar e tumor s, accounti ng for l ess than
1% of al l br east mal i gnanci es and l ess than 5% of al l soft-ti ssue
sar comas. Var i ous hi stol ogi c subtypes have been r epor ted to occur
wi thi n the br east, i ncl udi ng angi osar coma, str omal sar coma,
fi br osar coma, and mal i gnant fi br ous hi sti ocytoma. Cystosar coma
phyl l odes i s general l y consi der ed to be a separate enti ty fr om other
soft-ti ssue sar comas because these tumor s ar e bel i eved to or i gi nate
fr om hor monal l y r esponsi ve str omal cel l s of the br east and the
major i ty ar e beni gn.
As wi th sar comas at other anatomi cal si tes, the hi stopathol ogi cal
grade and si ze of the tumor ar e i mpor tant pr ognosti c factor s.
Li kewi se, the l i kel i hood of l ocal r ecur r ences i ncr eases as the tumor
si ze i ncr eases; tumor s smal l er than 5 cm ar e associ ated wi th better
overal l sur vi val . Local and di stant r ecur r ence ar e mor e common i n
pati ents wi th hi gh-grade l esi ons. Compl ete exci si on wi th negati ve
mar gi ns i s the pr i mar y therapy. Si mpl e mastectomy car r i es no
addi ti onal benefi t i f compl ete exci si on can be accompl i shed by
segmental mastectomy. Because of l ow rates

of r egi onal l ymphati c spr ead, axi l l ar y di ssecti on i s not r outi nel y
i ndi cated. Neoadjuvant chemotherapy or radi ati on therapy may be
consi der ed for pati ents wi th l ar ge, hi gh-r i sk tumor s.

Table 5.3. Summary of clinical trials of imatin


with advanced gastrointestinal st

Study,
Year

Phase

No. of
Overall
CR
Patients Response

PR

Van
Oosterom,
2001

36

53%

0%

53

Demetri,
2002

II

147

54%

0%

54

Verwiej,
2003

II

27

71%

4%

67

Rankin,
2004

III

746

400 mg daily

48%

3%

45

800 mg daily

48%

3%

45

400 mg daily

50%

5%

45

800 mg daily

54%

6%

48

Verwij,
2004

III

946

CR, complete response; PR, partial response.

Desmoids

Desmoi d tumor s do not metastasi ze and ar e consi der ed l ow-grade


sar comas. Appr oxi matel y hal f of these tumor s ar i se i n the
extr emi ty, wi th the r emai ni ng l esi ons l ocated on the tr unk or i n the
r etr oper i toneum. Abdomi nal wal l desmoi ds ar e associ ated wi th
pr egnancy and ar e bel i eved to ar i se as the r esul t of hor monal
i nfl uences. Pati ents wi th G ar dner syndr ome may have
r etr oper i toneal desmoi ds as an extracol oni c mani festati on of the
di sease. Sur gi cal r esecti on wi th wi de l ocal exci si on shoul d be the
pr i mar y therapy for desmoi d tumor s. Local r ecur r ence may occur i n
up to one-thi r d of pati ents. Adjuvant radi ati on therapy has been
associ ated wi th a r educed i nci dence of l ocal r ecur r ence.

Dermatofibrosarcoma Protuberans
Der matofi br osar coma pr otuberans i s a neopl asm ar i si ng i n the
der mi s that may occur anywher e i n the body. Appr oxi matel y 40%
ar i se on the tr unk, wi th most of the r emai ni ng tumor s di str i buted
between the head and neck and extr emi ti es. The l esi on pr esents as
a nodul ar, cutaneous mass that shows sl ow and per si stent gr owth.
Satel l i te l esi ons may be found i n pati ents wi th l ar ger tumor s. Wi de
l ocal exci si on i s r ecommended, al though r ecur r ence rates can be as
hi gh as 30% to 50% .

Bone Sarcomas
Epidemiology
Mal i gnant tumor s of the muscul oskel etal system consti tute 10% of
newl y di agnosed cancer s i n the popul ati on younger than 30 year s of
age, wi th 1,000 cases di agnosed annual l y i n the Uni ted States.
However, mal i gnant tumor s ar i si ng fr om the skel etal systems
r epr esent onl y 0.2% of al l pr i mar y cancer s. Osteosar coma and
Ewi ng sar coma ar e the two most common mal i gnant condi ti ons of
bone. Osteosar coma has a peak fr equency dur i ng adol escent gr owth,
wher eas Ewi ng sar coma occur s most fr equentl y i n the second decade
of l i fe.

Clinical Presentation
The most common pr esentati on of bone sar comas (Ewi ng sar coma or
osteosar coma) i s pai n or swel l i ng i n a bone or joi nt. As wi th softti ssue sar comas i n adul ts, often a traumati c event draws attenti on
to the swel l i ng and can thr ow off the cor r ect di agnosi s.
Osteosar coma most commonl y i nvol ves the metaphysi s of l ong

bones, especi al l y the di stal femur, pr oxi mal ti bi a, or humer us.


Ewi ng sar coma may i nvol ve fl at bones or the di aphysi s of tubul ar
bones such as the femur, pel vi s, ti bi a, and fi bul a. Ewi ng sar coma
may al so occur i n soft ti ssues. Chondr osar coma occur s most
commonl y i n the pel vi s, pr oxi mal femur, and shoul der gi r dl e.
Up to 25% of pati ents pr esenti ng wi th osteosar coma or Ewi ng
sar coma have metastati c di sease at pr esentati on. The most fr equent
metastati c si tes for osteosar coma i ncl ude the l ung (90% of cases)
and the bone (10% ), wher eas Ewi ng sar coma metastases occur i n
the l ung (50% ), bone (25% ), and bone mar r ow (25% ).

Staging
As wi th soft-ti ssue sar comas, hi stopathol ogi cal grade i s a cr uci al
component of the stagi ng of bone sar comas. The sur gi cal stagi ng
system for muscul oskel etal sar coma i s based on the system by
Enneki ng and i ncl udes pr ognosti c var i abl es such as hi stopathol ogi cal
grade (G ), the l ocati on of the tumor (T), and the pr esence or
absence of metastases (M). The thr ee stages ar e stage I, l ow grade
(G 1); stage II, hi gh grade (G 2); and stage III, G 1 or G 2 wi th the
pr esence of metastases (M1). Each stage i s then desi gnated a i f the
l esi on i s anatomi cal l y confi ned wi thi n wel l -del i neated sur gi cal
compar tments (T1) and b i f the l esi on i s l ocated beyond such
compar tments i n i l l -defi ned fasci al pl anes and spaces (T2).

Diagnosis
The eval uati on of pati ents wi th a suspected bone tumor shoul d
i ncl ude a thor ough hi stor y and physi cal exami nati on, pl ai n
radi ographs, and MRI of the enti r e affected bone. Bone scanni ng
and CT of the chest ar e al so necessar y.
On pl ai n radi ographs, mal i gnant bone tumor s show i r r egul ar
bor der s, and ther e i s often evi dence of bone destr ucti on and a
per i osteal r eacti on. Soft-ti ssue extensi on i s al so fr equentl y seen.

Biopsy
A cor e-needl e bi opsy i s the di agnosti c pr ocedur e of choi ce i n a
pati ent suspected of har bor i ng an osteosar coma. A cor e-needl e
bi opsy per for med under radi ographi c gui dance shoul d yi el d
di agnosti c fi ndi ngs i n al most al l cases of osteosar coma.

Treatment
Effecti ve mul ti modal i ty therapy for chi l dhood muscul oskel etal
tumor s has dramati cal l y i mpr oved the 5-year sur vi val rates fr om
10% to 20% i n 1970 to the cur r ent 60% to 70% . Li mb sal vage i s
the standar d tr eatment for most pati ents wi th osteosar coma.

Surgery
Whenever feasi bl e, l i mb sal vage i s the standar d sur gi cal appr oach
to bone sar comas. Successful l i mb-spar i ng sur ger y consi sts of thr ee
phases: tumor r esecti on, bone r econstr ucti on, and soft-ti ssue
coverage. Compl ete sur gi cal exti r pati on of the pr i mar y tumor and
any metastases i s essenti al i n pati ents wi th osteosar coma because
thi s tumor i s r el ati vel y r esi stant to radi ati on therapy.
It i s al so desi rabl e to r esect a Ewi ng sar coma, i f thi s can be done. If
sur gi cal r emoval wi th a wi de sur gi cal mar gi n can be achi eved, the
pr ognosi s i s favorabl e (12-year r el apsefr ee sur vi val of 60% ).
However, Ewi ng sar coma most typi cal l y i nvol ves the pel vi s wi th an
extensi ve soft-ti ssue mass that i nvades the pel vi c cavi ty, whi ch
makes i t di ffi cul t to car r y out radi cal sur ger y.
Sur gi cal r esecti on i s usual l y the onl y tr eatment i ndi cated for the
management of chondr osar comas because thi s type of tumor i s
unr esponsi ve to exi sti ng systemi c therapi es.

Chemotherapy
Chemotherapy has r evol uti oni zed the tr eatment of most bone
sar comas and i s consi der ed standar d car e for osteosar coma and
Ewi ng sar coma. The bl eak 15% to 20% sur vi val rate achi eved wi th
sur ger y al one dur i ng the 1960s has i mpr oved to 55% to 80%
thr ough the addi ti on of chemotherapy to sur gi cal r esecti on. The
ti mi ng of chemotherapy, the mode of del i ver y, and the dr ug
combi nati ons conti nue to be studi ed i n mul ti -i nsti tuti onal tr i al s, so
fur ther i mpr ovements i n the cl i ni cal outcome ar e anti ci pated.
Effecti ve agents i ncl ude doxor ubi ci n, ci spl ati n, methotr exate,
i fosfami de, and cycl ophosphami de. Randomi zed cl i ni cal tr i al s of
pati ents wi th osteosar coma have shown that the use of combi nati on
chemotherapy i n addi ti on to sur ger y r esul ts i n cur e rates of 58% to
76% . Pr eoperati ve chemotherapy i s an attracti ve opti on because i t
can l ead to the downstagi ng of tumor s, whi ch then enabl es the
maxi mal appl i cati on of l i mb-spar i ng sur ger y. In addi ti on, tumor

necr osi s fol l owi ng pr eoperati ve chemotherapy has been shown to be


the most i mpor tant pr ognosti c var i abl e deter mi ni ng sur vi val .
Mul ti agent chemotherapy has al so been demonstrated to be
essenti al i n the tr eatment of Ewi ng sar coma. Tr i al s spanni ng mor e
than 20 year s per for med by the Inter gr oup Study of Ewi ng's
Sar coma have establ i shed the effi cacy of mul ti dr ug r egi mens (i .e.,
r egi mens that i nvol ve combi nati ons of vi ncr i sti ne, doxor ubi ci n,
cycl ophosphami de, i fosfami de, and etoposi de) i n i ncr easi ng the 5year r el apsefr ee sur vi val rates to up to 70% i n pati ents wi th
nonmetastati c di sease. Agents cur r entl y bei ng i nvesti gated as
tr eatments for osteosar coma i ncl ude trastuz umab, i nhal ed
granul ocyte-macr ophage col ony-sti mul ati ng factor, and i mati ni b
mesyl ate, among other s.

Radiation Therapy
Because osteosar comas ar e general l y radi ati on r esi stant, radi ati on
therapy i s pr edomi nantl y used for the pal l i ati on of l ar ge,
unr esectabl e tumor s. In contrast, radi ati on therapy i s the pr i mar y
mode of tr eatment for most l ocal i zed Ewi ng sar comas. Pr eoperati ve
i r radi ati on may al so be consi der ed to r educe tumor vol ume befor e
sur gi cal r esecti on i s attempted.

Recurrent Disease
Bone tumor s di ssemi nate thr ough the bl oodstr eam and commonl y
metastasi ze to the l ungs and bony skel eton. In the past, onl y 10%
to 30% of pati ents pr esenti ng wi th detectabl e metastati c
osteosar coma became l ong-ter m di sease-fr ee sur vi vor s. Mor e r ecent
studi es have shown that combi ned modal i ty appr oaches consi sti ng of
sur gi cal r esecti on of the pr i mar y tumor and metastati c deposi ts i n
conjuncti on wi th mul ti agent chemotherapy can i mpr ove 5-year
di sease-fr ee sur vi val rates to up to 47% .
Ewi ng sar coma may r ecur i n the for m of di stant di sease as l ong as
15 year s after the i ni ti al di agnosi s. In a r etr ospecti ve anal ysi s of
241 pati ents wi th Ewi ng sar coma of the pel vi s, tumor vol ume,
r esponsi veness to chemotherapy, and adequate sur gi cal mar gi ns
wer e found to be the major factor s that i nfl uenced pr ognosi s.
Pati ents wi th suspected tumor r ecur r ence shoul d under go a
compl ete eval uati on to deter mi ne the extent of the di sease. The
r esecti on of pul monar y metastases has become the mai nstay of
tr eatment for pati ents wi th osteosar coma. Pr ognosi s can general l y

be deter mi ned by the r esponse to pr evi ous therapy, durati on


of r emi ssi on, and extent of metastases. Mul ti modal i ty therapy,
i ncl udi ng chemotherapeuti c agents not pr evi ousl y used, i s the
general r ecommendati on for tr eatment.

Sacrococcygeal Chordoma
The notochor dal r emnant i s the si te of or i gi n of thi s rar e tumor.
Chor domas ar e l ocal l y aggr essi ve tumor s that have a hi gh
pr opensi ty to r ecur. Because symptoms can be vague, di agnosi s can
be del ayed. Sur gi cal r esecti on shoul d i nvol ve a mul ti di sci pl i nar y
team that i ncl udes the sur gi cal oncol ogi st, neur osur geon, and
r econstr ucti ve pl asti c sur geon. A two-stage pr ocedur e i s used at M.
D. Ander son. At the fi r st stage, the bl ood suppl y to the tumor
ar i si ng fr om the i l i ac vessel s i s contr ol l ed thr ough an anter i or
appr oach. Several days l ater, the tumor i s r esected vi a a poster i or
appr oach. Radi ati on therapy shoul d be consi der ed because of hi gh
rates of l ocal r ecur r ence.

Recommended Reading
Amer i can Joi nt Commi ttee on Cancer. AJCC cancer staging
manual. 6th ed. Phi l adel phi a: Li ppi ncott-Raven, 2002.
Ar ndt CA, Cr i st WM. Common muscul oskel etal tumor s of chi l dhood
and adol escence. N Engl J Med 1999;341:342.
Ayal a AG , Ro JY, Fanni ng CV, et al . Cor e needl e bi opsy and fi neneedl e aspi rati on i n the di agnosi s of bone and soft ti ssue l esi ons.
Hematol Oncol Clin Nor th Am 1995;9:633.
Bal di ni EH, G ol dber g J, Jenner C, et al . Long-ter m outcomes after
functi on-spar i ng sur ger y wi thout radi otherapy for soft ti ssue
sar coma of the extr emi ti es and tr unk. J Clin Oncol 1999;17:3252.
Bar kl ey HT, Mar ti n RG , Romsdahl MM, et al . Tr eatment of soft
ti ssue sar comas by pr eoperati ve i r radi ati on and conser vati ve
sur gi cal r esecti on. Int J Radiat Oncol Biol Phys 1988;14:693.
Bi l l i ngsl ey KG , Bur t ME, Jara E, et al . Pul monar y metastases fr om
soft ti ssue sar coma: anal ysi s of patter ns of di sease and

postmetastasi s sur vi val . Ann Sur g 1999;229:602.


Bi l l i ngsl ey KG , Lewi s JJ, Leung DH, et al . Mul ti factor i al anal ysi s
of the sur vi val of pati ents wi th di stant metastasi s ar i si ng fr om
pr i mar y extr emi ty sar coma. Cancer 1999;85:389.
Brady MS, G aynor JJ, Br ennan MF. Radi ati on-associ ated sar coma
of bone and soft ti ssue. Ar ch Sur g 1992;127:1379.
Br ennan MF, Casper ES, Har r i son LB, et al . The r ol e of
mul ti modal i ty therapy i n soft ti ssue sar coma. Ann Sur g
1991;214:328.
Casson AG , Putnam JB, Natarajan G , et al . F i ve year sur vi val
after pul monar y metastasectomy for adul t soft ti ssue sar coma.
Cancer 1992;69:662.
Chang AE, Ki nsel l a T, G l atstei n E, et al . Adjuvant chemotherapy
for pati ents wi th hi gh-grade soft ti ssue sar comas of the
extr emi ty. J Clin Oncol 1988;6:1491.
Chang AE, Mator y YL, Dwyer AJ, et al . Magneti c r esonance
i magi ng ver sus computed tomography i n the eval uati on of soft
ti ssue tumor s of the extr emi ti es. Ann Sur g 1997;205:340.
Cor mi er JN, Huang X, Xi ng Y, et al . Cohor t anal ysi s of pati ents
wi th l ocal i zed, hi gh-r i sk, extr emi ty sar coma tr eated at two cancer
center s: chemotherapy-associ ated outcomes. J Clin Oncol
2004;22:4567.
Davi s AM, Bel l RS, G oodwi n PJ. Pr ognosti c factor s i n
osteosar coma: a cr i ti cal r evi ew. J Clin Oncol 1994;12:423.
Demetr i G D, von Mehr en M, Bl anke CD, et al . Effi cacy and Safety
of i mati ni b mesul ate i n advanced gastr oi ntesti nal str omal tumor s.
N Engl J Med 2002;47280.

Egger mont AM, Schraffor d T, Koops H, et al . Isol ated l i mb


per fusi on wi th tumor necr osi s factor and mel phal an for l i mb

sal vage i n 186 pati ents wi th l ocal l y advanced soft ti ssue


extr emi ty sar coma. The cumul ati ve mul ti center Eur opean
exper i ence. Ann Sur g 1996;224:756.
Ei l ber F R, Eckar dt J. Sur gi cal management of soft ti ssue
sar comas. Semin Oncol 1997;24:526.
Fong Y, Coi t DG , Woodr uff JM, Br ennan MF. Lymph node
metastasi s fr om soft ti ssue sar coma i n adul ts. Anal ysi s of data
fr om a pr ospecti ve database of 1772 sar coma pati ents. Ann Sur g
1993;217:72.
G eer RJ, Woodr uff J, Casper ES, et al . Management of smal l soft
ti ssue sar comas of the extr emi ty i n adul ts. Ar ch Sur g
1992;127:1285.
G l enn J, Si ndel ar WF, Ki nsel l a T, et al . Resul ts of mul ti modal i ty
therapy of r esectabl e soft ti ssue sar comas of the
r etr oper i toneum. Sur ger y 1985;97:316.
G utman H, Pol l ock RE, Benjami n RS, et al . Sar coma of the
br east: i mpl i cati ons for extent of therapy. The M. D. Ander son
exper i ence. Sur ger y 1994;116:505.
Hesl i n MJ, Smi th JK. Imagi ng of soft ti ssue sar comas. Sur g Oncol
Clin Nor th Am 1999;8:91.
Hoffmann C, Ahr ens S, Dunst J, et al . Pel vi c Ewi ng sar coma: a
r etr ospecti ve anal ysi s of 241 cases. Cancer 1999;85:869.
Huth JF, Ei l ber F R. Patter ns of metastati c spr ead fol l owi ng
r esecti on of extr emi ty soft ti ssue sar comas and strategi es for
tr eatment. Semin Sur g Oncol 1988;4:20.
Jaques DP, Coi t DG , Hajdu SI, et al . Management of pr i mar y and
r ecur r ent soft ti ssue sar coma of the r etr oper i toneum. Ann Sur g
1990;212:51.
Karakousi s CP, Pr oi maki s C, Rao U, et al . Local r ecur r ence and
sur vi val i n soft ti ssue sar comas. Ann Sur g Oncol 1996;3:255.

Lawr ence W Jr., Donegan WL, Natarajan N, et al . Adul t soft ti ssue


sar comas. A patter n of car e sur vey of the Amer i can Col l ege of
Sur geons. Ann Sur g 1987;205:349.
Levi ne EA. Pr ognosti c factor s i n soft ti ssue sar coma. Semin Sur g
Oncol 1999;17:23.
Lewi s JJ, Leung D, Woodr uff JM, Br ennan MF. Retr oper i toneal soft
ti ssue sar coma: anal ysi s of 500 pati ents tr eated and fol l owed at a
si ngl e i nsti tuti on. Ann Sur g 1998;228:355.
Li enar d D, Ewal enko P, Del motte JJ, et al . Hi gh-dose r ecombi nant
tumor necr osi s factor al pha i n combi nati on wi th i nter fer on
gamma and mel phal an i n i sol ati on per fusi on of the l i mbs for
mel anoma and sar coma. J Clin Oncol 1992;10:52.
Li ndber g RD, Mar ti n RG , Romsdahl MM, et al . Conser vati ve
sur ger y and postoperati ve radi otherapy i n 300 adul ts wi th soft
ti ssue sar comas. Cancer 1981;47:2391.
Local i o AS, Eng K, Ranson JHC. Abdomi nosacral appr oach for
r etr or ectal tumor s. Am Sur g 1980;179:555.
Maz anet R, Antman KH. Adjuvant therapy for sar comas. Semin
Oncol 1991;18:603.
Mi di s G P, Pol l ock RE, Chen NP, et al . Local l y r ecur r ent soft ti ssue
sar coma of the extr emi ti es. Sur ger y 1998;123:666.
Nati onal Insti tutes of Heal th consensus devel opment panel on
l i mb-spar i ng tr eatment of adul t soft ti ssue sar coma and
osteosar comas 1985;3:1.
Patel SR, Benjami n RS. New chemotherapeuti c strategi es for soft
ti ssue sar comas. Semin Sur g Oncol 1999;17:47.
Pez z i CM, Pol l ock RE, Evans HL, et al . Pr eoperati ve chemotherapy
for soft ti ssue sar coma of the extr emi ti es. Ann Sur g
1990;211:476.

Pi ster s PW, Har r i son LB, Leung DH, et al . Long-ter m r esul ts of a


pr ospecti ve randomi zed tr i al of adjuvant brachytherapy i n soft
ti ssue sar coma. J Clin Oncol 1996;14:859.
Pi ster s PWT, Har r i son LB, Woodr uff JM, et al . A pr ospecti ve
randomi zed tr i al of adjuvant brachytherapy i n the management of
l ow grade soft ti ssue sar comas of the extr emi ty and super fi ci al
tr unk. J Clin Oncol 1994;12:1150.

Pi ster s PW, Leung DH, Woodr uff J, et al . Anal ysi s of pr ognosti c


factor s i n 1,041 pati ents wi th l ocal i zed soft ti ssue sar comas of
the extr emi ti es. J Clin Oncol 1996;14:1679.
Pol l ock RE, Kar nel l LH, Menck HR, et al . The Nati onal Cancer Data
Base r epor t on soft ti ssue sar coma. Cancer 1996;78:2247.
Potter DA, Ki nsel l a T, G l atstei n E, et al . Hi gh-grade soft ti ssue
sar comas of the extr emi ti es. Cancer 1986;58:190.
Ramanathan RC, A'Her n R, F i sher C, et al . Modi fi ed stagi ng
system for extr emi ty soft ti ssue sar comas. Ann Sur g Oncol
1999;5:57.
Ranki n C, von Mehr en M, Bl anke C, et al . Conti nued pr ol ongati on
of sur vi val by i mati ni b i n pati ents wi th metastati c G IST. Update
of r esul ts fr om Nor th Amer i can Inter gr oup phase III study S0033.
Pr oc Am Soc Clin Oncol 2004: Abstr 9005.
Razek A, Per ez C, Tefft M, et al . Inter gr oup Ewi ng's sar coma
study: l ocal contr ol r el ated to radi ati on dose, vol ume and si te of
pr i mar y l esi on i n Ewi ng's sar coma. Cancer 1980;46:516.
Rosenber g SA, Tepper J, G l atstei n E, et al . The tr eatment of soft
ti ssue sar comas of the extr emi ti es: pr ospecti ve randomi zed
eval uati ons of (1) l i mb-spar i ng sur ger y pl us radi ati on therapy
compar ed wi th amputati on and (2) the r ol e of adjuvant
chemotherapy. Ann Sur g 1982;196:305.
Sar coma Meta-anal ysi s Col l aborati on. Adjuvant chemotherapy for

l ocal i zed r esectabl e soft ti ssue sar coma of adul ts: meta-anal ysi s
of i ndi vi dual data. Lancet 1997;350:1647.
Si nger S. New di agnosti c modal i ti es i n soft ti ssue sar coma. Semin
Sur g Oncol 1999;17:11.
Si nger S, Cor son JM, Demetr i G D, et al . Pr ognosti c factor s
pr edi cti ve of sur vi val for tr uncal and r etr oper i toneal soft ti ssue
sar coma. Ann Sur g 1995;221:185.
Stor m F K, Mahvi DM. Di agnosi s and management of
r etr oper i toneal soft ti ssue sar coma. Ann Sur g 1991;214:2.
Sui t HD, Manki n HJ, Wood WC, et al . Tr eatment of the pati ent
wi th stage M0 soft ti ssue sar coma. J Clin Oncol 1988;6:854.
Tanabe KK, Pol l ock RE, El l i s LM, et al . Infl uence of sur gi cal
mar gi ns on outcome i n pati ents wi th pr eoperati vel y i r radi ated
extr emi ty soft ti ssue sar comas. Cancer 1994;73:1652.
Van G eel AN, Pastor i no U, Jauch KW, et al . Sur gi cal tr eatment of
l ung metastases: the Eur opean Or gani z ati on for Resear ch and
Tr eatment of Cancer-soft ti ssue and bone sar coma gr oup study of
255 pati ents. Cancer 1996;77:675.
Van Ooster om AT, Judson IR, Ver wei j J, et al . Safety and effi cacy
of i mati ni b (STI571) i n metastati c gastr oi ntesti nal str omal
tumour s: a phase I study. Lancet 2001;14211423.
Var ma DG . Opti mal radi ol ogi c i magi ng of soft ti ssue sar comas.
Semin Sur g Oncol 1999;17:2.
Ver wei j J, Casal i PG , Zal cber g J, et al . Pr ogr essi on-fr ee sur vi val
i n gastr oi ntesti nal str omal tumour s wi th hi gh-dose i mati ni b:
radnomi sed trai l . Lancet 2004:112734.
Ver wei j J, van Ooster om A, Bl ay JY, et al . Imati ni b mesyl ate (STI571 G l i vec, G l eevec) i s an acti ve agent for gastr oi ntesti nal
str omal tumour s, but does not yi el d r esponse i n other soft-ti ssue
sar comas that ar e unsel ected for a mol ecul ar tar get. Resul ts fr om

an EORTC Soft Ti ssue and Bone Sar coma G r oup phase II study.
Eur J Cancer . 2003:200611.
Ver wei j J, van Ooster om A, Somer s R, et al . Chemotherapy i n the
mul ti di sci pl i nar y appr oach to soft ti ssue sar comas: EORTC soft
ti ssue and bone sar coma gr oup studi es i n per specti ve. Ann Oncol
1992;3 [suppl 2]:75.
Whool ey BP, Mooney MM, G i bbs JF, et al . Effecti ve fol l ow-up
strategi es i n soft ti ssue sar coma. Semin Sur g Oncol 1999;17:83.
Yang JC, Chang AE, Baker AR, et al . Randomi zed pr ospecti ve
study of the benefi t of adjuvant radi ati on therapy i n the
tr eatment of soft ti ssue sar comas of the extr emi ty. J Clin Oncol
1998;16:197.
Zahm SH, F raumeni JR Jr. The epi demi ol ogy of soft ti ssue
sar coma. Semin Oncol 1997;24:504.

Editors: Feig, Barry W .; Berger, David H.; Fuhrman, George


M.
Title: MD A nderson Surgical Oncology Handbook, The, 4th
Edition
Copyr i ght 2006 Li ppi ncott Wi l l i ams & Wi l ki ns
> Ta ble o f C o nt e nt s > 6 - C a nc e rs o f t he He a d a nd Ne c k

6
Cancers of the Head and Neck
Kenneth A . New kirk
F. Christopher Holsinger

Epidemiology and Pathogenesis


Cancer s of the head and neck r epr esent a r el ati vel y smal l , al bei t
si gni fi cant, gr oup of cancer s. The tr eatment of these mal i gnanci es i s
associ ated wi th si gni fi cant functi onal and aestheti c mor bi di ti es that
have a dramati c i mpact on pati ents qual i ty of l i fe. Al though the
major i ty of cancer s of the head and neck ar i se i n the upper
aer odi gesti ve tract and sal i var y gl ands, cancer s of the ski n, thyr oi d
gl and, and parathyr oi d gl ands deser ve speci al consi derati on and ar e
addr essed i n Chapter s 3, 4, and 16.
Cancer s of the head and neck r epr esent appr oxi matel y 3% of al l
cancer s i n the Uni ted States (and appr oxi matel y 6% wor l dwi de i n
2002), wi th appr oxi matel y 45,000 head and neck cancer s di agnosed
i n 2004. The major i ty of head and neck cancer s ar e di agnosed i n
the si xth to ei ghth decades, wi th mal es havi ng a 4:1 rati o. Tobacco
exposur e r epr esents the most si gni fi cant r i sk factor for cancer s of
the head and neck, wi th al cohol consumpti on bei ng both a
syner gi sti c and an i ndependent r i sk factor. The r i sk of tobaccor el ated head and neck cancer s i ncr eases pr opor ti onatel y wi th the
degr ee of exposur e. In addi ti on, for some pati ents, geneti c
i nstabi l i ty (e.g., hypophar yngeal cancer s associ ated wi th Pl ummerVi nson syndr ome), vi ral i nfecti ons (e.g., Ebstei n-Bar r vi r us [EBV]
associ ated wi th nasophar yngeal cancer, human papi l l oma vi r us
associ ated wi th tonsi l l ar cancer s), and occupati onal (e.g., saw dust
exposur es and si nonasal adenocar ci nomas) and envi r onmental
exposur es (e.g., ul travi ol et [UV] exposur e and l ower l i p cancer s,
betel nut use and buccal cancer s, r ever se ci gar ette smoki ng and

pal atal cancer s) have been i mpl i cated i n some head and neck
cancer s. A smal l gr oup of pati ents (par ti cul ar l y young pati ents wi th
oral tongue cancer s) have no i denti fi abl e r i sk factor s and have a
par ti cul ar l y aggr essi ve cour se. Some studi es suggest that the
di sease cour se may be mor e aggr essi ve i n Afr i can Amer i cans than i n
whi tes, wi th death rates for Afr i can Amer i can mal es bei ng twi ce that
for whi te mal es wi th the same di sease (l ar ynx and oral cavi ty
cancer s).

Pathology
Squamous cel l car ci noma (SCC) r epr esents the most common
hi stol ogi c type, accounti ng for mor e than 90% of tumor s. Tumor s
may have ei ther an ul cerati ve or an exophyti c gr owth patter n.
Hi stol ogi cal l y, the tumor s may be i n si tu or i nvasi ve. Hi stol ogi c
di ffer enti ati on (wel l , moderate, and poor l y di ffer enti ated) has been
r epor ted to have pr ognosti c i mpl i cati ons, but thi s has not been
uni ver sal l y confi r med. Basal oi d, spi ndl e-shaped SCCs and ver r ucous
car ci noma ar e bel i eved to be var i ants of SCC, and di sti ngui shi ng
among the var i ants may have pr ognosti c i mpl i cati ons.
Pr emal i gnant l esi ons, such as l eukopl aki a and er ythr opl aki a, ar e
associ ated wi th a hi gh r i sk of cancer devel opment.

Clinical Presentation, Evaluation, and


Prognosis
The cl i ni cal si gns and symptoms of cancer of the upper
aer odi gesti ve tract i s si te speci fi c. The most common pr esenti ng
symptom for head and neck cancer s i s pai n. Other symptoms that
ar e suggesti ve of cancer of the upper aer odi gesti ve tract ar e the
pr esence of a nonheal i ng ul cer, bl eedi ng, hoar seness, dysphagi a,
odynophagi a, otal gi a (r efer r ed pai n), faci al pai n, neck mass, or new
l esi on i ntraoral l y. Symptoms can occur secondar y to l ocal
destr ucti on or i nvol vement of adjacent str uctur es (neural , softti ssue, or bony i nvol vement). The cl i ni ci an shoul d be al er ted to the
fact that an adul t, wi th any of these si gns and symptoms that do not
r esol ve wi thi n 2 weeks, shoul d be r efer r ed to an exper i enced
cl i ni ci an for eval uati on.
Cl i ni cal exami nati on of the head and neck i ncl udes vi sual i nspecti on
and pal pati on (bi manual eval uati on) of the scal p, exter nal ear s, ear
canal s, mucous membranes of the eyes, nasal passages, oral cavi ty,
nasophar ynx, or ophar ynx, hypophar ynx, and l ar ynx. Exami nati on of

the l ar ynx and phar yngeal r egi ons ar e per for med by ei ther mi r r or
exami nati on or fl exi bl e endoscopy. Car e must be taken to exami ne
the major sal i var y gl ands vi sual l y and manual l y. A detai l ed crani al
ner ve exami nati on i s i mpor tant for documenti ng pr etr eatment
functi on because l ocal l y aggr essi ve cancer s may cause functi onal
defi ci ts pr etr eatment and because var i ous tr eatment modal i ti es may
be associ ated wi th posttr eatment dysfuncti on. Exami nati on of the
neck for spr ead to cer vi cal l ymph nodes of the upper jugul odi gastr i c
chai n i s i mpor tant pr ognosti cal l y. The gr oupi ng of cer vi cal nodes of
the jugul odi gastr i c chai n (F i g. 6-1) pr ovi des a uni for m system for
communi cati ng between cl i ni ci ans. Metastasi s to speci fi c nodal
gr oups or echel ons can be pr edi cti ve of the l ocati on of the pr i mar y
si te when pati ents pr esent wi th a cer vi cal metastasi s fr om an
unknown pr i mar y.
Bi opsi es of suspi ci ous l esi ons can be per for med i n ei ther the cl i ni c
or the operati ng r oom. Bi opsi es ar e per for med wi th ei ther a scal pel
or punch bi opsy for ceps of the pr i mar y l esi on or fi ne-needl e
aspi rati on (F NA) of suspi ci ous l ymph nodes. F NA of neck masses i s
as accurate as open bi opsy i n exper i enced cytopathol ogi sts hands
and i s pr efer r ed over open bi opsy to r educe the r i sk of tumor
spi l l age and seedi ng of the neck. Intraoperati ve panendoscopy
(di r ect l ar yngoscopy, esophagoscopy, nasal endoscopy, and
br onchoscopy) i s per for med to pr ovi de adequate ti ssue for di agnosi s
fr om ar eas i naccessi bl e i n the cl i ni c, to al l ow for better hemostasi s,
and to detai l the extent of the di sease for tr eatment pl anni ng.
Impr ovements i n fi ber-opti c technol ogy (e.g., transnasal
esophagoscopy) ar e expandi ng the scope of what can be eval uated
and successful l y bi opsi ed i n the cl i ni cal setti ng.
Radi ographi c i magi ng i ncl udes pl ai n x-rays, computed tomography
(CT) scans, magneti c r esonance i magi ng (MRI) scans, ul trasound,
and posi tr on emi ssi on tomography (PET) scanni ng. Chest x-rays hel p
deter mi ne the pr esence of di stant metastasi s
(appr oxi matel y 15% of pati ents) or second pr i mar i es (5% 10% ).
Panor ex fi l ms hel p deter mi ne whether mandi bl e i nvol vement i s
pr esent. CT scans fr om the skul l base to the cl avi cl es pr ovi de
detai l ed i nfor mati on on the extent of l ocal soft-ti ssue and bony
i nvol vement of upper aer odi gesti ve tract tumor s, and the pr esence
of r egi onal l y metastati c di sease to the upper cer vi cal jugul odi gastr i c
chai n.

F i gur e 6.1. Lymph node gr oups. Level IA, submental , and l evel
1B, submandi bul ar l ymph node gr oups; l evel s IIA and IIB, upper
jugul ar gr oup; l evel III, mi ddl e jugul ar gr oups; l evel IV, l ower
jugul ar gr oup; l evel s VA and VB, poster i or tr i angl e gr oup; l evel
VI, anter i or compar tment gr oup.

In general , pr ognosi s for upper aer odi gesti ve tract cancer s i s


deter mi ned by the si ze of the pr i mar y, as wel l as the pr esence of
r egi onal (cer vi cal ) nodal metastasi s and di stant metastasi s, wi th
bul ki er di sease bei ng associ ated wi th a wor se pr ognosi s. The
pr esence of nodal metastasi s decr eases sur vi val by 50% and i s
associ ated wi th an i ncr eased r i sk of di stant metastasi s. Stagi ng for
head and neck cancer i s based on the Amer i can Joi nt Commi ttee on
Cancer cl assi fi cati on and i s outl i ned i n Tabl e 6.1. The T stage
defi nes the si ze and extent of the pr i mar y; the N stage defi nes the
si ze, number, and l ocati on of nodal spr ead; and the M stage r efer s
to the pr esence or absence of di stant metastasi s. Appr oxi matel y
15% of head and neck cancer pati ents wi l l devel op di stant
metastasi s.

Table 6.1. American Joint Committee on

Cancer staging system for head and neck


cancers
Stage grouping
Stage
I

T1, N0, M0

Stage
II

T2, N0, M0

Stage
III

T3, N0, M0
T13, N1, M0
T4, N0 or N1, M0

Stage
IV

Any T, N2 or N3, M0
Any T, any N, M1

Primary tumor (T) dependent on anatomic


location
Regional lymph nodes (N)
N0

No regional lymph node metastasis

N2a

Metastasis in single ipsilateral lymph


node >3 cm but <6 cm

N2b

Metastasis in multiple ipsilateral lymph


nodes, none >6 cm

N2c

Metastasis in bilateral or contralateral


lymph nodes, none >6 cm

N3

Metastasis in a lymph node >6 cm

Metastatic disease
M0

No evidence of distant metastasis

M1

Evidence of distant metastasis

Adapted from Greene FL, Page DL, Fleming ID,


et al., eds. AJCC Cancer Staging Manual. 6th
ed. New York, NY: Springer-Verlag; 2002, with
permission.
In addi ti on to the tradi ti onal pr ognosti c mar ker s, depth of i nvasi on,
per i neural i nvasi on and per i vascul ar i nvasi on at the pr i mar y tumor
si te, and l ymph node extracapsul ar spr ead ar e associ ated wi th
wor se pr ognosi s. Sur vi val for ear l y-stage di sease (stages I and II)
acr oss si tes fal l s i n the 80% to 90% range, but dr ops to 3% to 40%
for stage III and IV di sease. Much r esear ch i s cur r entl y bei ng done
to i denti fy mor e sel ecti ve bi ol ogi cal and mol ecul ar pr edi cti ve and
pr ognosti c mar ker s, such as the expr essi on of mutated p53, and
epi der mal gr owth factor r eceptor expr essi on.
The mai nstay for tr eatment of ear l y-stage head and neck cancer i s
si ngl e modal i ty therapy, ei ther sur ger y or radi ati on therapy. Mor e
advanced di sease i s mor e appr opr i atel y tr eated wi th mul ti modal i ty
therapy. Chemotherapy has pl ayed an i ncr easi ng r ol e i n the pr i mar y
tr eatment of advanced head and neck cancer, i n addi ti on to
mai ntai ni ng i ts tradi ti onal r ol e i n tr eati ng r ecur r ent or unr esectabl e
di sease.

For most si tes (oral cavi ty, si nonasal , sal i var y gl ands), sur ger y i s
the tr eatment of choi ce for ear l y-stage di sease and pr ovi des the
best chance for cur e i f an adequate mar gi n of r esecti on i s obtai ned.
Li mi ti ng factor s may be the potenti al functi onal defi ci t
or cosmeti c defor mi ty to an or gan system, or the accessi bi l i ty of the
tumor to compl ete sur gi cal exti r pati on. Advances i n sur gi cal
r econstr ucti ve techni ques and pr ostheti cs have expanded the
envel ope of what i s appr opr i ate sur gi cal r emoval .
For ear l y-stage di sease at some si tes (l ar ynx, phar ynx), radi ati on
therapy i s as effecti ve a tr eatment modal i ty as sur ger y, wi th the
benefi t of pr eser vi ng anatomi cal str uctur es. For mor e advanced
di sease, radi ati on i s an i mpor tant adjunct pr eoperati vel y and
postoperati vel y i n contr ol l i ng l ocal and r egi onal di sease and i n
ster i l i z i ng mi cr oscopi c di sease. Indi cati ons for postoperati ve
radi ati on therapy ar e posi ti ve sur gi cal r esecti on mar gi ns, per i neural
or per i vascul ar i nvasi on, extracapsul ar spr ead, l ocal l y aggr essi ve
poor l y di ffer enti ated tumor s, tumor spi l l age dur i ng r esecti on, and
advanced-stage di sease. Al though i t pr ovi des the benefi t of
potenti al or gan pr eser vati on, radi ati on i s not wi thout si gni fi cant
functi onal defi ci ts. Mucosi ti s may be sever e wi th an acute onset. It
may al so be ver y pai nful , l eadi ng to dysphagi a. Xer ostomi a (dr y
mouth) and dysphagi a ar e often underappr eci ated but debi l i tati ng
l ong-ter m sequel ae. In addi ti on to sal i var y gl and dysfuncti on,
thyr oi d dysfuncti on and fi br osi s and scar r i ng of soft ti ssues ar e
potenti al l ong-ter m sequel ae of radi ati on therapy. Mul ti modal i ty
therapy i s the mai nstay of therapy for advanced (stage II and IV)
di sease.
An i mpor tant par t of tr eatment i s pr eser vati on of functi on
posttr eatment. Or gan-speci fi c system r ehabi l i tati on i s par ti cul ar l y
i mpor tant i n mai ntai ni ng adequate voi ce and swal l owi ng functi on.
Fol l ow-up for cancer s of the head and neck i s i mpor tant because
most r ecur r ences wi l l occur wi thi n 2 year s of tr eatment. At The
Uni ver si ty of Texas M. D. Ander son Cancer Center, fol l ow-up of
pati ents occur s ever y 3 months for the fi r st 2 year s postoperati vel y,
ever y 6 months for the next 3 year s, and year l y ther eafter unti l 5
year s. A chest x-ray and l i ver functi on studi es ar e per for med year l y.

Neck Dissection
Nodal metastases ar e associ ated wi th a 50% decr ease i n sur vi val .
Di sease of the neck can be tr eated effecti vel y wi th sur ger y and/or

radi ati on. Li mi ted di sease (si ngl e node) wi th no extracapsul ar


spr ead may be tr eated wi th si ngl e modal i ty therapy, whi l e mor e
advanced di sease may r equi r e combi nati on therapy.
Tradi ti onal l y, sur ger y of the neck consi sts of one of the fol l owi ng
types of neck di ssecti ons: r adical neck dissection (RND), modified
r adical neck dissection (MRND), and selective neck dissection. The
RND consi sts of r emoval of al l cer vi cal l ymph nodes i n l evel s I to V,
the ster nocl ei domastoi d muscl e, the i nter nal jugul ar vei n, and the
spi nal accessor y ner ve. The l i mi ts of the di ssecti on ar e the i nfer i or
bor der of the mandi bl e super i or l y, the cl avi cl e i nfer i or l y, the
trapez i us poster i or l y, the l ateral bor der of the ster nohyoi d muscl e
anter i or l y, and the deep cer vi cal fasci a over l yi ng the l evator
scapul ae and the scal ene muscl es deepl y. In an attempt to decr ease
postoperati ve mor bi di ty, the MRND was desi gned. It i s si mi l ar to the
RND but i nvol ves pr eser vati on of the spi nal accessor y ner ve,
i nter nal jugul ar vei n, and/or the ster nocl ei domastoi d muscl e.
A sel ecti ve neck di ssecti on i nvol ves r emoval of l i mi ted cer vi cal
l ymph node gr oups (l evel s IIII [a supr aomohyoid neck dissection],
l evel s IIIV [a later al neck dissection], l evel s IIV, VII, and
postocci pi tal and r etr oaur i cul ar nodes [a poster olater al neck
dissection]), al ong wi th pr eser vati on of the spi nal accessor y ner ve,
i nter nal jugul ar vei n, and ster nocl ei domastoi d muscl e. The type of
sel ecti ve neck di ssecti on per for med depends on the si te and
hi stol ogy of the pr i mar y tumor and the most common r outes of
l ymphati c spr ead. A supraomohyoi d neck di ssecti on i s per for med for
cl i ni cal l y l i mi ted (nonpal pabl e) spr ead fr om oral cavi ty cancer s, a
l ateral neck di ssecti on for cl i ni cal l y l i mi ted (nonpal pabl e) spr ead
fr om l ar ynx cancer s, and a poster ol ateral neck di ssecti on for ski n
cancer s (e.g., mel anoma, SCC) of the scal p. Of note, a l evel VI or
anter ior compar tment neck dissection i s used i n the management of
thyr oi d cancer, al ong wi th a l ateral neck di ssecti on. Mor e extensi ve
di sease encounter ed at sur ger y may war rant a mor e i nvol ved neck
di ssecti on. Al l pati ents under goi ng di ssecti on of the spi nal accessor y
ner ve wi l l have some for m of neur opraxi a and shoul d under go
postsur gi cal physi cal therapy r ehabi l i tati on.
In pati ents tr eated wi th sur ger y of the pr i mar y and neck di ssecti on
pr eradi ati on at M. D. Ander son, a sel ecti ve neck di ssecti on (e.g.,
supraomohyoi d neck di ssecti on for oral cavi ty cancer s, l ateral neck
di ssecti on for l ar yngeal cancer s) i s the pr ocedur e most commonl y
used for cl i ni cal l y occul t di sease. Cl i ni cal nodal di sease i s tr eated by
a MRND. For postradi ati on pati ents, a sel ecti ve neck di ssecti on

(l evel s II and III) i s the pr ocedur e of choi ce for per si stent


adenopathy, and i s associ ated wi th good l ocal -r egi onal contr ol and
functi onal outcomes.

Carcinoma of the Oral Cavity


The oral cavi ty i s the por ti on of the aer odi gesti ve tract fr om the
ver mi l l i on bor der of the l i ps to the juncti on of the har d and soft
pal ate and the ci r cumval l ate papi l l ae of the tongue. Thi s r egi on
anatomi cal l y i ncl udes the l i ps, buccal mucosa, gi ngi va, fl oor of
mouth, anter i or fl oor of mouth, anter i or two-thi r ds of the tongue,
har d pal ate, and r etr omol ar tr i gone r egi on. Oral cavi ty cancer
accounts for appr oxi matel y 3% of cancer s i n the Uni ted States, i s
the si xth most common cancer wor l dwi de, and compr i ses 30% of al l
head and neck cancer s. In 2005, i n the Uni ted States al one, an
esti mated 20,000 cancer s occur r ed i n the oral cavi ty, and
appr oxi matel y 5,000 deaths wer e attr i butabl e to oral cavi ty cancer s.
Men ar e mor e commonl y affected than women (34:1), and the
mean age of occur r ence i s i n the si xth to seventh decades.
Stagi ng of the pr i mar y i s based on the TNM stage, wi th si ze of the
pr i mar y tumor deter mi ni ng the T stage. T1 l esi ons measur e l ess
than 2 cm, T2 measur e fr om 2 to 4 cm, T3 measur e 4 cm, and T4
measur e gr eater than 4 cm or i nvol ve extensi on to l ocal ti ssues
(Tabl e 6.2).
Sur gi cal exci si on i s the mai nstay of therapy for oral cavi ty cancer s.
An adequate mar gi n of nor mal ti ssue (at l east 11.5 cm) i s taken to
ensur e pr oper r esecti on. Sur gi cal defects can be l eft to heal by
secondar y i ntenti on or ar e r epai r ed by pr i mar y cl osur e, spl i tthi ckness ski n grafti ng, l ocal r otati onal or advancement fl ap
r econstr ucti on, or fr ee fl ap r econstr ucti on for l ar ge defects. Neck
di ssecti ons ar e done for cl i ni cal l y evi dent nodal di sease and
el ecti vel y for l ar ge pr i mar y tumor s or tumor s wi th a depth of
i nvasi on gr eater than 4 mm or other poor pr ognosti c factor s as
l i sted pr evi ousl y. The tradi ti onal neck di ssecti on for oral cavi ty
l esi ons i s a supraomohyoi d neck di ssecti on (l evel s IIII), al though
some data exi st for i ncl udi ng l evel IV l ymph nodes due to the
possi bi l i ty of ski p metastasi s. Pr i mar y tumor s cl ose to the mi dl i ne
may r equi r e bi l ateral neck di ssecti ons because the r i sk of spr ead to
the contral ateral neck may be gr eater than 20% .

Table 6.2. Staging system for oral cavity


tumors
Tis

Carcinoma in situ

T1

Tumor 2 cm at greatest dimension

T2

Tumor >2 cm but not 4 cm at greatest


dimension

T3

Tumor >4 cm at greatest dimension

T4

Tumor invades adjacent structures (e.g.,


cortical bone, deep extrinsic muscle of
tongue, maxillary sinus, or skin)

Adapted from Greene FL, Page DL, Fleming ID,


et al., eds. AJCC Cancer Staging Manual. 6th
ed. New York, NY: Springer-Verlag; 2002, with
permission.
Radi ati on therapy i s gi ven i n the for m of exter nal -beam therapy or
brachytherapy i mpl ants (pr i mar y i nter sti ti al brachytherapy i mpl ants
ar e used for smal l l esi ons of the anter i or commi sur e of the l i p, oral
tongue, and fl oor of mouth [T1 l esi ons]). Radi ati on therapy i s onl y
rar el y used as the pr i mar y therapy and i s r eser ved for postoperati ve
tr eatment of pati ents at hi gh r i sk for l ocal -r egi onal r ecur r ence (i .e.,
l ar ge pr i mar y tumor s [T3 or T4], pr i mar y tumor s wi th cl ose or
posi ti ve mar gi ns, evi dence of per i neural or l ymphovascul ar
i nvasi on, tumor s wi th a depth of i nvasi on gr eater than 4 mm, nodal
metastasi s wi th evi dence of extracapsul ar spr ead, or mul ti pl e
posi ti ve nodes).
The pr ognosi s for ear l y l esi ons (T1 and T2) of the oral cavi ty i s

good, wi th a 5-year sur vi val of 80% to 90% . Sur vi val for advanced
l esi ons (T3 and T4) can range fr om 30% to 60% , dependi ng on the
factor s that affect pr ognosi s as outl i ned pr evi ousl y.

LIP
Cancer of the l i p accounts for appr oxi matel y 25% to 30% of oral
cavi ty cancer s, wi th gr eater than 90% bei ng SCC and gr eater than
90% occur r i ng on the l ower l i p. Smoki ng and sun exposur e ar e
major r i sk factor s. Sur ger y i s the tr eatment of choi ce for smal l
l esi ons, wi th the excepti on of commi ssur e l esi ons, whi ch may be
better tr eated wi th radi ati on. Cur e rates appr oachi ng 90% ar e
achi evabl e for ear l y l esi ons, wi th mor e advanced l esi ons havi ng a 5year sur vi val of l ess than 50% . Nodal metastases ar e associ ated
wi th l ar ge pr i mar y tumor s; tumor s of the upper l i p and commi ssur e,
as wel l as per i neural spr ead al ong the mental ner ve, por tends a
poor er pr ognosi s.

Buccal Mucosa
Buccal mucosa cancer s r epr esent 5% of oral cavi ty cancer s. Tobacco
smoki ng, al cohol use, smokel ess tobacco use, and betel nut use
have been associ ated wi th buccal cancer s. The r egi on near
the l ower thi r d mol ar i s a common si te for buccal cancer s, and
pati ents may pr esent wi th tr i smus due to i nvol vement of the
pter ygoi d muscl es. Cer vi cal metastases may be common (50% ) and
ar e associ ated wi th a poor pr ognosi s. Wi de l ocal exci si on i s the
tr eatment of choi ce, and a possi bl e mar gi nal mandi bul ectomy may
be necessar y to obtai n cl ear mar gi ns. Ear l y-stage di sease may be
associ ated wi th cur e rates i n the 60% to 70% range, whi l e
advanced tumor s have sur vi val of appr oxi matel y 40% . Local r egi onal r ecur r ence i s a si gni fi cant pr obl em. Sur vi val may be
i mpr oved wi th postoperati ve radi ati on. The sur gi cal defect may be
r econstr ucted wi th l ocal advancement fl aps (e.g., tongue) or may
r equi r e fr ee fl ap r econstr ucti on.

Floor of Mouth
Appr oxi matel y 10% to 15% of oral cavi ty cancer s occur i n the fl oor
of the mouth. Appr oxi matel y 50% of pati ents wi l l pr esent wi th
cer vi cal metastasi s, whi ch, as wi th other oral cavi ty si tes, i s a
pr edi ctor of poor pr ognosi s. Deep tongue muscl e and mandi bl e
i nvol vement i s fr equentl y seen, r equi r i ng par ti al gl ossectomy and

mar gi nal or segmental mandi bul ectomy wi th fr ee fl ap r econstr ucti on


to obtai n cl ean mar gi ns. Bi l ateral cer vi cal metastasi s i s not
uncommon. Overal l 5-year sur vi val rates range fr om 30% to 70% ,
wi th stages I and II appr oachi ng 70% to 80% and stage IV di sease
bei ng l ess than 50% .

Oral Tongue
Oral tongue (anter i or two-thi r ds of the tongue) car ci noma accounts
for appr oxi matel y 37% of esti mated new oral cavi ty cancer s i n
2005. Par ti al gl ossectomy wi th heal i ng by secondar y i ntenti on,
pr i mar y cl osur e, ski n grafti ng, or fr ee fl ap r econstr ucti on i s the
accepted tr eatment. In addi ti on to the si ze of the pr i mar y and
hi stol ogi c grade, tumor thi ckness al so has pr ognosti c si gni fi cance
for l ocal -r egi onal r ecur r ence, wi th l esi ons gr eater than 4 mm
havi ng a 40% to 50% i nci dence of nodal metastasi s. For tumor s of 4
mm or gr eater thi ckness, an i psi l ateral supraomohyoi d neck
di ssecti on (l evel s IIII) i s r ecommended for management of the
neck. Ther e ar e some data that suggest that a l evel IV di ssecti on
may be war ranted due to the pr esence of ski p metastasi s; however,
thi s i s usual l y done for pati ents metastasi s i n l evel s I to III. Ear l ystage tumor s have a good pr ognosi s (70% 80% 3-year sur vi val for
stages I and II and 40% 50% for stage III and IV di sease), whi l e
advanced l esi ons r equi r e combi ned modal i ty tr eatment. A smal l
subset of oral tongue cancer s occur s i n pati ents younger than 40
year s of age wi th no known r i sk factor s; these cancer s appear to be
mor e aggr essi ve and ther efor e war rant mor e aggr essi ve therapy.
Speech and swal l owi ng r ehabi l i tati on ar e essenti al for good
postoperati ve functi on. SCC of the base of the tongue behaves
di ffer entl y and i s r evi ewed i n the Cancer of the Or ophar ynx,
Nasophar ynx, and Hypophar ynx secti on l ater i n thi s chapter.

Hard Palate
Har d pal ate SCCs r epr esent appr oxi matel y 0.5% of al l oral cavi ty
cancer s i n the Uni ted States. Cancer s of the har d pal ate and gi ngi va
ar e tr eated wi th wi de l ocal exci si on. Tumor s wi thi n cl ose
pr oxi mi ty to or i nvol vi ng bone and l ar ge tumor s may r equi r e par ti al
pal atectomy or maxi l l ectomy to obtai n cl ear mar gi ns. Bony defects
ar e best r econstr ucted wi th a pal atal pr osthesi s or obturator. F i veyear cur e rates appr oach 40% to 70% i n pati ents wi thout nodal
di sease.

Cancer of the Larynx


In the Uni ted States, l ar ynx cancer s wi l l have an esti mated
i nci dence of 10,000 new cases i n 2005. Cancer s occur i n the si xth
to ei ghth decades wi th a mal e-to-femal e rati o of 4:1. Tobacco and
al cohol abuse ar e the most common r i sk factor s associ ated wi th
devel opment of l ar yngeal cancer. The l ar ynx i s di vi ded i nto thr ee
subsi testhe supr aglottis, glottis, and subglottisthat have
i mpl i cati ons for behavi or, tr eatment, and pr ognosi s.
The supr aglottis i s the por ti on of the l ar ynx above the l ar yngeal
ventr i cl e and bel ow the l ar yngeal sur face of the epi gl otti s. The
supragl otti s contai ns the epi gl otti s, ar ytenoi ds, ar yepi gl otti c fol ds,
fal se cor ds, and ventr i cl es. The l ymphati c drai nage i s i nto the upper
and mi d-jugul odi gastr i c chai n vi a the pyr i for m si nuses and i s
bi l ateral , whi ch makes addr essi ng both si des of the neck for a
supragl otti c cancer a necessi ty. Sensati on i s vi a the i nter nal branch
of the super i or l ar yngeal ner ve. Cancer s of the supragl otti s account
for 35% of l ar yngeal cancer s. The glottis i s the por ti on of the l ar ynx
that compr i ses the tr ue vocal fol ds. The l ymphati c drai nage i s
mi ni mal due to the cl ose adher ence of the mucosa to the under l yi ng
vocal l i gament. Sensati on i s vi a the super i or l ar yngeal ner ve.
G l otti c cancer s compr i se 65% of l ar yngeal cancer s. The subglottis
extends fr om the i nfer i or por ti on of the tr ue vocal fol ds to the
i nfer i or bor der of the cr i coi d car ti l age. Lymphati c drai nage i s vi a
effer ents that enter i nto the deep cer vi cal jugul odi gastr i c nodes and
the paratracheal and pr etracheal l ymph nodes bi l ateral l y. Subgl otti c
cancer s compr i se l ess than 5% of l ar yngeal cancer s. Subsi te
di vi si on i s i mpor tant for di agnosi s and tr eatment of ear l y tumor s;
however, i n advanced stages, l ar yngeal cancer s may have extensi ve
par aglottic (submucosal spr ead ar ound the l ar yngeal framewor k) and
tr ansglottic (extensi on acr oss subsi tes) spr ead. Stagi ng for
l ar yngeal cancer s var i es and i s l i sted i n Tabl e 6.3.
Pr esenti ng symptoms for l ar yngeal cancer s i ncl ude hoar seness,
pai n, dysphagi a, and r espi rator y di str ess. Eval uati on of the l ar ynx i s
essenti al for stagi ng of l ar yngeal cancer s. Impai r ed vocal fol d
mobi l i ty and subsi te extensi on por tend a mor e advanced cancer and
poor er pr ognosi s. Cancer s that affect the tr ue vocal fol d usual l y
pr esent ear l y due to the i mpai r ment i n functi on (voi ce and
r espi rati on). Supragl otti c cancer s usual l y pr esent l ate, wi th
submucosal and l ocal spr ead, and symptoms ar e due to i nvasi on of
l ocal ti ssues causi ng hoar seness, dysphagi a, odynophagi a, otal gi a
(r efer r ed pai n), and r espi rator y di str ess. Imagi ng of the l ar ynx (CT

scanni ng) i s i mpor tant i n deter mi ni ng l ocal extensi on of the pr i mar y


di sease, l ar yngeal car ti l age destr ucti on, and the pr esence of
cl i ni cal l y occul t di sease.

Treatment
Because gl otti c cancer s ar e the most common l ar yngeal cancer s
seen, these ar e di scussed i n detai l . The goal of tr eatment of
l ar yngeal cancer i s eradi cati on of the di sease, as wel l as
pr eser vati on of functi on and anatomy when possi bl e. Both sur ger y
and radi ati on pr ovi de excel l ent contr ol rates for T1 and T2 gl otti c
l esi ons. Esti mated 5-year sur vi val for al l cancer s of the l ar ynx i s
65% . Local contr ol rates i n the l i teratur e for both tr eatment
modal i ti es range fr om 70% to 100% , whi ch i mpr oves wi th sal vage
l ar yngectomy. T3 and T4 tumor s have contr ol rates i n the 80% to
85% and 60% to 70% range, r especti vel y. F i ve-year sur vi val for T1
and T2 l esi ons i s 80% to 90% , and for T3 and T4 di sease, 50% to
60% . Mor e advanced l ar yngeal cancer s r equi r e combi ned modal i ty
therapy wi th total l ar yngectomy (or a modi fi cati on ther eof ) and
postoperati ve radi ati on therapy.

Table 6.3. Staging system for cancers of the


larynx
Supraglottis
T1

Tumor confined to site of origin

T2

Tumor involving adjacent supraglottic


sites, without glottic fixation

T3

Tumor limited to the larynx, with fixation


and/or extension to the postericoid
medial wall of the pyriform sinus or preepiglottic space

T4

Massive tumor extending beyond the


larynx to involve the oropharynx, soft
tissues of the neck, or destruction of
thyroid cartilage

Glottis
T1

Tumor confined to vocal folds, with


normal vocal cord mobility

T1a

Limited to one vocal fold

T1b

Involves both vocal folds

T2

Tumor extension to supraglottis and/or


subglottis with normal or impaired vocal
cord mobility

T3

Tumor confined to larynx, with fixation of


the vocal cords

T4

Massive tumor, with thyroid cartilage


destruction and/or extension beyond the
confines of the larynx

Adapted from Greene FL, Page DL, Fleming ID,


et al., eds. AJCC Cancer Staging Manual. 6th
ed. New York, NY: Springer-Verlag; 2002, with
permission.

Surgery
Ear l y-stage gl otti c di sease may be tr eated effecti vel y wi th sur ger y
or radi ati on therapy. Sur gi cal opti ons for ear l y gl otti c di sease
i ncl ude vocal cor d str i ppi ng, transoral l aser mi cr osur ger y,
hemi l ar yngectomy, subtotal l ar yngectomy (supracr i coi d par ti al
l ar yngectomy [SCPL]), and total l ar yngectomy. The advantages of
sur ger y ar e compl ete exti r pati on of the di sease and r eser vati on of
other tr eatments (e.g., radi ati on) for futur e r ecur r ences. Both vocal
cor d str i ppi ng and l aser mi cr osur ger y may l eave the cor d wi th
scar r i ng that can make i t di ffi cul t to eval uate for r ecur r ence. A
ver tical par tial lar yngectomy ( VPL or hemilar yngectomy) i nvol ves
r emoval of hal f of the l ar ynx ver ti cal l y, as wel l as
pr eser vati on of hal f of the l ar ynx ver ti cal l y, to mai ntai n voi ce and
functi on. Pati ents wi th smal l vol ume di sease after radi ati on ar e
good candi dates for thi s pr ocedur e. For ear l y-stage supragl otti c
cancer s (T1 and T2), a supr aglottic or hor iz ontal lar yngectomy may
be per for med. The cr i coi d and at l east one ar ytenoi d i s pr eser ved
and sutur ed onto the base of the tongue, agai n i n an attempt to
pr eser ve adequate r espi rati on, voi ce, and swal l owi ng functi on.
Candi dates for thi s pr ocedur e r equi r e adequate pul monar y r eser ve
and car di ac functi on to pr event aspi rati on pneumoni a.
The SCPL i s an extended hor i zontal par ti al l ar yngectomy techni que
that pr eser ves the pati ent's nati ve voi ce and per mi ts near-total
l ar yngectomy wi thout per manent tracheostoma. SCPL can i ncl ude
r emoval of the fal se and tr ue vocal cor ds, the enti r e thyr oi d
car ti l age i ncl udi ng the enti r e paragl otti c spaces, and a por ti on or al l
of the supragl otti s and pr e-epi gl otti c space. In sel ected cases, one
ar ytenoi d may be r esected. Phonator y functi on and degl uti ti on i s
mai ntai ned by the movement of the spar ed ar ytenoi d(s) agai nst the
tongue base. It r epr esents a dramati c advance because i t uses the
pati ent's l ar yngeal framewor k to pr eser ve the pati ent's nati ve voi ce,
whi l e pr ovi di ng a tr ue en bl oc tumor r esecti on.
Total l ar yngectomy i s r eser ved for mor e advanced di sease (T3 and
T4) or pati ents who have fai l ed pr evi ous therapy and who ar e l i kel y
to have poor functi onal outcomes (voi ce and swal l owi ng) wi th voi cespar i ng sur gi cal pr ocedur es. A bi l ateral l ateral neck di ssecti on can
be per for med at the same ti me for mor e extensi ve di sease (a wi defi el d l ar yngectomy), and hemi - or total thyr oi dectomy i s per for med
for di sease that destr oys car ti l age or i nvol ves the pyr i for m si nuses,
subgl otti s, or paratracheal nodes. In cases wi th si gni fi cant

hypophar yngeal or cer vi cal esophageal extensi on, a


l ar yngophar yngectomy can be per for med and r epai r ed wi th a fr ee
ti ssue transfer mi cr ovascul ar r econstr ucti on. Postoperati ve radi ati on
i s typi cal l y gi ven i n advanced di sease. Speech pathol ogy
consul tati on i s essenti al pr eoperati vel y for adequate voi ce and
swal l owi ng r ehabi l i tati on postoperati vel y. Voi ce r ehabi l i tati on wi th
an el ectr ol ar ynx, tracheoesophageal punctur e, or esophageal speech
can l ead to good voi ce qual i ty. In addi ti on to bei ng moni tor ed for
r ecur r ence, pati ents al so need to be fol l owed for potenti al
hypothyr oi di sm (ei ther fr om sur ger y or radi ati on).

Radiation Therapy
G i ven the good rates of l ocal -r egi onal contr ol , radi ati on therapy has
been advocated as the tr eatment of choi ce for ear l y-stage di sease.
The advantages of radi ati on ar e spar i ng of the anatomy wi th
pr eser vati on of voi ce. The di sadvantages ar e postradi ati on sequel ae
(e.g., xer ostomi a, potenti al radi onecr osi s of the l ar yngeal
framewor k) and the i nabi l i ty to use radi ati on agai n i n the event of a
r ecur r ence. Postoperati ve radi ati on therapy i s typi cal l y gi ven to
pati ents wi th extensi ve pr i mar y di sease (submucosal spr ead, subsi te
extensi on [i .e., supra- or subgl otti c, extral ar yngeal extensi on]),
di sease wi th posi ti ve mar gi ns, mul ti pl e posi ti ve l ymph nodes, or
l ymph nodes wi th extracapsul ar spr ead, and pati ents r equi r i ng
pr el ar yngectomy tracheotomy (who have a hi gher r i sk of stomal
r ecur r ence).
Typi cal doses of pr i mar y radi ati on for ear l y l ar yngeal di sease ar e i n
the 65 to 70 G y range. For gl otti c cancer s, the radi ati on can be
focused on the pr i mar y si te due to the l ow i nci dence of nodal
metastasi s. For supragl otti c cancer s wi th a hi gher pr opensi ty of
cer vi cal metastasi s at the ti me of di agnosi s, fi el ds shoul d encompass
the pr i mar y nodal drai nage basi ns (l evel s IIV), wi th doses i n the
50 to 60 G y ranges.

Cancer of the Oropharynx, Nasopharynx, and


Hypopharynx
The phar ynx i s a tubul ar str uctur e that contai ns the l ar ynx. The
phar ynx can be di vi ded i nto thr ee anatomi cal subsi tes: the
nasophar ynx, the or ophar ynx, and the hypophar ynx. The anatomi cal
boundar i es of the or ophar ynx ar e the anter i or tonsi l l ar pi l l ar, uvul a
and base of tongue, and the val l ecul ar sur face of the epi gl otti s

i nfer i or l y. Incl uded i n thi s subsi te ar e the phar yngeal tonsi l s and
the base of tongue. The nasophar ynx i s separated fr om the
or ophar ynx by the soft pal ate. The boundar i es of the hypophar ynx
ar e the l ar yngeal sur face of the epi gl otti s, the pyr i for m si nuses, the
poster i or phar yngeal wal l , and the postcr i coi d ar ea above the
cr i cophar yngeus muscl e. Lymphati c drai nage for the nasophar ynx i s
the r etr ophar yngeal l ymph node basi n, the paraphar yngeal l ymph
nodes, and the upper and poster i or jugul odi gastr i c nodes.
Lymphati cs for the or ophar ynx ar e i n the deep, upper
jugul odi gastr i c chai n, whi l e the hypophar ynx drai ns i nto the mi dand l ower deep jugul odi gastr i c chai n. Bi l ateral cer vi cal metastases
ar e not uncommon. The paraphar yngeal space i s a potenti al space
l ocated outsi de the phar ynx pr oper. It i s pyrami dal shape and
extends fr om the skul l base to the hyoi d bone. Most tumor s of thi s
r egi on ar e beni gn; the most common tumor s ar i se fr om the deep
l obe of the par oti d gl and and i ncl ude unusual hi stol ogi c var i ants
such as pl eomor phi c adenomas, paragangl i omas, and neur ogeni c
tumor s (schwannomas and neur ofi br omas), rather than the common
squamous tumor s of the upper aer odi gesti ve tract.
The most common pr esenti ng symptoms ar e pai n, dysphagi a,
r efer r ed otal gi a, and a neck mass. In an attempt to cur e di sease
wi th decr eased mor bi di ty and to pr eser ve functi on (swal l owi ng),
exter nal -beam radi ati on (tonsi l , hypophar ynx, base of tongue) has
become the tr eatment of choi ce for or ophar yngeal and
hypophar yngeal cancer s. Sur vi val rates have been i n the 70% to
80% range for stage I and II di sease and 50% for stage II di sease.
Sur ger y i s r eser ved for smal l l esi ons and r ecur r ent di sease, due to
the i ncr eased mor bi di ty associ ated wi th sur ger y. Brachytherapy i s
al so used i n some center s for base of tongue tumor s.
Nasophar yngeal cancer s ar e mal i gnanci es that ar i se fr om or near
the fossa of Rosenml l er i n the nasophar ynx. These cancer s ar e
most commonl y seen i n r egi ons of Chi na and Afr i ca, wher e ther e i s
a str ong associ ati on wi th EBV. Indeed, EBV vi ral capsi d IgA anti gen
(VC) and ear l y anti gen IgA (EA) ti ter s ser ve as a tumor mar ker for
r ecur r ence. The average age at pr esentati on i s i n the fi fth and si xth
decades. Most pati ents pr esent wi th a pai nl ess neck mass, nasal
obstr ucti on, uni l ateral ser ous oti ti s medi a, or epi staxi s. Crani al
neur opathy (par ti cul ar l y i nvol vi ng crani al ner ves II, IV, V, and VI)
may occur as a r esul t of skul l base
i nvasi on, whi ch may be seen i n as many as 25% of pati ents. An
i r r egul ar mass i s seen on nasophar yngoscopy. Tumor s ar e cl assi fi ed

accor di ng to the Wor l d Heal th Or gani z ati on cl assi fi cati on (type I


bei ng wel l -di ffer enti ated kerati ni z i ng SCC, type II bei ng
nonkerati ni z i ng car ci noma, and type III bei ng poor l y di ffer enti ated
[undi ffer enti ated] car ci noma, whi ch i ncl udes l ymphoepi thel i omas
and anapl asti c car ci nomas).
The mai nstay of therapy i s ci spl ati n-based chemotherapy and
radi ati on therapy to the nasophar yngeal bed and pr i mar y drai ni ng
l ymph node echel ons. Tumor s ar e staged based on extent of di sease
wi th stage I tumor s l i mi ted to the nasophar ynx; stage II di sease
i nvol vi ng extensi on i nto the or ophar ynx, nasal fossa, and
paraphar yngeal space; stage III di sease i nvol vi ng extensi on i nto the
skul l base fossa and paranasal si nuses; and stage IV di sease
i nvol vi ng the i nfratemporal fossa, or bi t, and hypophar ynx, or wi th
i ntracrani al extensi on and/or cer vi cal adenopathy. F i ve-year
sur vi val for nasophar yngeal car ci noma i s l ess than 20% for type I
tumor s and appr oaches 50% for type II and III tumor s. Sur ger y may
be used for l i mi ted, ear l y-stage di sease, but i s associ ated wi th
si gni fi cant mor bi di ty. Neck di ssecti ons ar e per for med for r esi dual
di sease post chemoradi otherapy.
Cancer s of the hypophar ynx usual l y pr esent at advanced stages
(gr eater than 60% ar e stage III and IV) and ar e associ ated wi th
poor l ocal contr ol and sur vi val . The major i ty of cancer s occur i n the
pyr i for m si nus (70% 80% ), and nodal di sease at the ti me of
pr esentati on i s common (70% 80% ). Chemoradi ati on i s the
mai nstay of therapy, al though total l ar yngectomy or
l ar yngophar yngectomy may be sui tabl e for some pati ents. F i ve-year
sur vi val for hypophar yngeal cancer s i s di smal , rangi ng fr om 20% to
40% .

Cancer of the Nasal Cavity and Paranasal


Sinuses
The nasal cavi ty extends fr om the exter nal nasal dor sum and
pyr i for m aper tur e to the choana and the nasophar ynx, and fr om the
nasal fl oor (whi ch i s compr i sed of the maxi l l a anter i or l y and the
pal ati ne bone poster i or l y) to the nasal r oof (whi ch houses the
ol factor y bul bs and crani al ner ve I). The nasal septum, whi ch i s
composed of car ti l age anter i or l y and the vomer and per pendi cul ar
pl ate of the ethmoi d bones poster i or l y, separates the nose i nto
hal ves. The l ateral nasal wal l s house the osti a for the paranasal
si nuses; the nasofr ontal duct; and the i nfer i or, mi ddl e, and super i or
tur bi nates. The nasal cavi ty and paranasal si nuses ar e l i ned by

r espi rator y epi thel i um (pseudostrati fi ed ci l i ated col umnar


epi thel i um), except at the nasal vesti bul e, whi ch i s l i ned by
kerati ni z i ng squamous epi thel i um. The sensor y i nner vati on to the
nasal and paranasal mucosa i s fr om branches of the tr i gemi nal
ner ve (V1 and V2). The bl ood suppl y i s fr om the exter nal car oti d
(super i or l abi al , angul ar, and i nter nal maxi l l ar y ar ter i es) and
i nter nal car oti d (anter i or and poster i or ethmoi dal ar ter i es) ar ter i es.
Ther e ar e four pai r ed paranasal si nuses: the maxi l l ar y, fr ontal ,
ethmoi d, and sphenoi d si nuses. The si nuses communi cate wi th the
nasal cavi ty thr ough thei r osti a. The osti um of the maxi l l ar y si nus
drai ns under neath the mi ddl e tur bi nate at the osteomeatal compl ex,
as do the osti a of the anter i or and mi ddl e ethmoi d
si nuses. The fr ontal si nus drai ns thr ough the nasofr ontal duct
l ocated at the anter i or aspect of the nose. The osti a of the sphenoi d
si nuses ar e l ocated above and medi al to the super i or tur bi nate on
the face of the si nus. Lymphati c drai nage of the paranasal si nuses
occur s vi a the r etr ophar yngeal , paraphar yngeal , and deep upper
jugul odi gastr i c l ymph nodes.
The most common pr esenti ng symptoms for si nonasal tumor s ar e
uni l ateral nasal obstr ucti on, faci al pai n, faci al numbness, and
epi staxi s. Pati ents may al so pr esent wi th uni l ateral ser ous oti ti s
medi a (due to obstr ucti on of the eustachi an tube or i fi ce), epi phora,
or excessi ve tear i ng (due to obstr ucti on of the nasol acr i mal duct,
whi ch drai ns under neath the i nfer i or tur bi nate). Nodal metastases
ar e uncommon i n si nonasal mal i gnanci es. Occupati onal exposur es
ar e associ ated wi th cer tai n si nonasal mal i gnanci es (e.g., wood dust
wi th adenocar ci nomas, smoki ng ni ckel and heavy metal exposur es
wi th SCCs).
Eval uati on of the nose and paranasal si nuses i ncl udes exter nal and
endoscopi c i nspecti on. Bi opsi es of nasal and paranasal tumor s
shoul d be done cauti ousl y because of the r i sk of bl eedi ng and
cer ebr ospi nal fl ui d l eak due to i ntracrani al extensi on, and may
war rant i magi ng pr i or to bi opsy. Imagi ng (both CT scan and MRI
scan) i s i mpor tant i n deter mi ni ng the extent of the di sease (i .e.,
extensi on beyond the nose and paranasal si nuses i nto the brai n,
or bi t, skul l base, and i nfratemporal fossa). Contrast CT scan i s used
to deter mi ne the pr esence of bony destr ucti on and the vascul ar i ty
of the l esi on. MRI scanni ng i s hel pful i n del i neati ng the extent of
soft-ti ssue destr ucti on (i ntracrani al and i ntraor bi tal i nvol vement)
and di sti ngui shi ng tumor fr om i nspi ssated fl ui d on T2-wei ghted
i mages.

Beni gn tumor s of the nasal cavi ty i ncl ude nasal papi l l omas and
angi ofi br omas. Nasal papi l l omas ar e di vi ded i nto squamous and
Schnei der i an papi l l omas (the most common). Schnei der i an
papi l l omas usual l y pr esent wi th uni l ateral nasal obstr ucti on,
epi staxi s, and r hi nor r hea. Ther e ar e thr ee subtypes of Schnei der i an
papi l l omas: cyl i ndr i cal , septal , and i nver ti ng, the l atter two bei ng
the most common. Septal papi l l omas account for 50% of
Schnei der i an papi l l omas. They ar i se fr om the nasal septum, ar e
exophyti c i n natur e, and occur most commonl y i n mal es i n the thi r d
to si xth decades of l i fe. Inver ti ng papi l l omas most commonl y ar i se
fr om the l ateral nasal wal l , ar e pol ypoi d i n natur e, occur most
commonl y i n mal es (fi fth to ei ghth decades), and, as the name
i mpl i es, push the str oma i nwar d (hence, the ter m i nver ti ng
papi l l oma). Up to 15% of tumor s may har bor SCC, and ther e i s a
r i sk (10% ) of squamous degenerati on. Sur gi cal exci si on i s the
tr eatment of choi ce; thi s i nvol ves a medi al maxi l l ectomy, or an open
or endoscopi c r esecti on of the l ateral nasal wal l .
Angi ofi br omas ar e beni gn l ocal l y destr ucti ve vascul ar tumor s. They
ar e seen most commonl y i n young mal es (second to four th decades)
who pr esent wi th a hi stor y of uni l ateral nasal obstr ucti on and
r ecur r ent, r efractor y epi staxi s. It i s a smooth l obul ated mass ar i si ng
i n the poster i or l ateral nose near the sphenopal ati ne foramen
(der i ves i ts bl ood suppl y fr om the sphenopal ati ne ar ter y). Contrast
CT scan or MRI i s di agnosti c (anter i or bowi ng of the poster i or
maxi l l ar y si nus wal l [Hol man-Mi l l er si gn]). Offi ce bi opsy shoul d not
be per for med due to the r i sk of bl eedi ng.
Sur ger y fol l owi ng embol i z ati on (wi thi n 48 hour s) i s the tr eatment
of choi ce.
Si nonasal mal i gnanci es ar e rar e, accounti ng for l ess than 5% of
head and neck mal i gnanci es. The di ffer enti al for si nonasal
mal i gnanci es i ncl ude mucosal mel anomas, sar comas, SCCs,
si nonasal undi ffer enti ated car ci nomas (SNUCs), l ymphomas
(angi ocentr i c T-cel l l ymphoma), esthesi oneur obl astomas (al so cal l ed
ol factor y neur obl astomas), extramedul l ar y pl asmacytomas,
adenocar ci nomas, and adenoi d cysti c car ci nomas. Hematoxyl i n and
eosi n stai ni ng may onl y r eveal smal l bl ue cel l s, maki ng the
di agnosi s di ffi cul t. Immunohi stochemi cal anal ysi s i s i mpor tant i n
establ i shi ng the di agnosi s.
The most common type of si nonasal tumor i s SCC, occur r i ng
pr edomi nantl y i n mal es i n the si xth to ei ghth decades.

Hi stol ogi cal l y, they ar e si mi l ar to SCCs el sewher e i n the head and


neck. Mucosal mel anomas ar e rar e (1% 2% of al l mel anomas), wi th
a fai r l y equal mal e-to-femal e rati o. Up to one-thi r d may be
amel anoti c, and i mmunohi stochemi cal stai ni ng i s i mpor tant i n
establ i shi ng the di agnosi s. Sur vi val i s poor, wi th l ess than 30% of
pati ents al i ve at 5 year s. Esthesi oneur obl astoma i s a rar e tumor
ar i si ng fr om the ol factor y neur oepi thel i um wi th i ntranasal
extensi on. Epi staxi s, anosmi a, pai n, and nasal obstr ucti on ar e
common pr esenti ng symptoms. Combi ned nasal and i ntracrani al
sur ger y (crani ofaci al r esecti on) fol l owed by radi ati on i s the
pr efer r ed tr eatment. F i ve-year sur vi val appr oaches 70% for
r esectabl e di sease, al though ther e i s a hi gh i nci dence of l ocal
r ecur r ence. Angi ocentr i c T-cel l l ymphoma i s a non-Hodgki n
l ymphoma that may pr esent wi th nasal obstr ucti on, epi staxi s, and
l ocal ti ssue destr ucti on of the mi dl i ne mi dface (septum). The ti ssues
ar e fr i abl e and necr oti c on endoscopy. Mul ti pl e bi opsi es may be
needed to confi r m the di agnosi s. Radi ati on i s the tr eatment of
choi ce. Si nonasal sar comas ar e rar e and associ ated wi th a poor
pr ognosi s. Tr eatment usual l y i nvol ves some combi nati on of sur ger y
and radi ati on. Chemotherapy may be used, based on the hi stol ogi c
subtype. SNUC i s al so rar e and associ ated wi th a poor pr ognosi s.
Local extensi on i s common (i ntracrani al and i ntraor bi tal ).
Crani ofaci al r esecti on wi th postoperati ve radi ati on i s the tr eatment
of choi ce. Extramedul l ar y pl asmacytoma i s the most common type of
l ocal i zed pl asma cel l neopl asm i n the head and neck; yet, i t
accounts for l ess than 1% of al l head and neck neopl asms. Mal es
ar e mor e commonl y affected than femal es (3:1), and up to 70%
occur i n the head and neck. Nasal obstr ucti on and epi staxi s ar e
common. CT and MRI ar e nondi agnosti c, and bi opsy i s i mpor tant i n
establ i shi ng the di agnosi s. Stai ni ng for l ambda and kappa l i ght
chai ns confi r ms the di agnosi s. Systemi c wor kup for mul ti pl e
myel oma i s i mpor tant because these tumor s may pr ogr ess to
mul ti pl e myel oma i n up to 30% of cases. Radi ati on i s the tr eatment
of choi ce wi th l ocal contr ol rates of 70% to 80% and 5-year sur vi val
of 60% to 70% . Adenocar ci nomas and adenoi d cysti c car ci nomas ar e
commonl y seen i n si nus mal i gnanci es, and ar e associ ated wi th l ocal
extensi on and per i neural spr ead.
Sur ger y fol l owed by radi ati on has been the accepted tr eatment for
these di sor der s. Smal l tumor s ar e amenabl e to sur gi cal exti r pati on
vi a open or endoscopi c appr oaches. Smal l squamous cel l tumor s of
the nasal vesti bul e r espond wel l to brachytherapy.
However, due to the l ate pr esentati on of many si nonasal tumor s and

l ocal extensi on to the skul l base and or bi t, sur ger y may be


associ ated wi th hi gh mor bi di ty (e.g., neur ol ogi c sequel ae and
sacr i fi ce of the or bi t). Sur ger y may entai l a par ti al or total
r hi nectomy, par ti al or total maxi l l ectomy and adjacent si nuses
(ethmoi d and fr ontal ), or bi tal exenterati on, and combi ned
appr oaches wi th neur osur ger y for i ntracrani al extensi on
(crani ofaci al r esecti on). Neck di ssecti on i s r eser ved for cl i ni cal l y
gr oss di sease. Ther e ar e some data that suggest that pr eoperati ve
chemotherapy may be benefi ci al i n mi ni mi z i ng the extent of
sur ger y, but thi s r emai ns i nvesti gati onal . Pr ognosi s for si nonasal
mal i gnanci es i s poor, wi th overal l 5-year sur vi val rates of 20% to
30% . Sur vi val for ear l y-stage di sease (60% 70% for T1) i s better
than for l atter stages (10% 20% for T4).

Unknown Primary with Cervical Metastasis


Appr oxi matel y 2% to 9% of pati ents who pr esent wi th SCC
metastati c to the neck wi l l have an undi agnosed or unknown
pr i mar y at the ti me of pr esentati on. However, after car eful
eval uati on and wor kup, appr oxi matel y 90% of these pati ents wi l l
have a pr i mar y di agnosi s. Thus, onl y appr oxi matel y 10% of pati ents
have an unknown pr i mar y tumor. Al though per si stent adenopathy
can be associ ated wi th numer ous i nfl ammator y or i nfecti ous
condi ti ons (e.g., cat scratch di sease, atypi cal mycobacter i um),
mal i gnant cer vi cal adenopathy shoul d be suspected i n pati ents wi th
adenopathy that per si sts for mor e than 2 weeks after appr opr i ate
medi cal (anti bi oti c) therapy. The most common pathol ogy seen i s
ACC, al though l ymphoma, mel anoma metastasi s fr om the ski n, and
metastati c thyr oi d, l ung, and br east cancer may rar el y pr esent wi th
per si stent adenopathy i n the head and neck.
A thor ough hi stor y and physi cal , whi ch shoul d i ncl ude endoscopy to
r ul e out the pr i mar y, shoul d be per for med on al l pati ents. Random
bi opsi es of potenti al si tes ar e not r ecommended. However, goal di r ected bi opsi es of suspi ci ous ar eas and bi l ateral tonsi l l ectomy ar e
i ndi cated, dependi ng on the si te of the nodal metastasi s, because as
many as 25% of tonsi l s may har bor an occul t pr i mar y. The si te of
nodal metastasi s may i ndi cate the si te of the pr i mar y. For exampl e,
cysti c or l evel II adenopathy may suggest an or ophar yngeal pr i mar y
(base of tongue or tonsi l ), whi l e l evel V adenopathy may be
suggesti ve of a nasophar yngeal or thyr oi d pr i mar y and a
supracl avi cul ar node may suggest a l ung or gastr oi ntesti nal pr i mar y.
Common occul t upper aer odi gesti ve tract si tes for pr i mar y di sease
ar e the tonsi l , base of tongue, pyr i for m si nus, and nasophar ynx. If

F NA suggests a pr i mar y other than SCC, then an appr opr i ate,


systemi c metastati c wor kup needs to be per for med. Di r ected
di agnosti c i magi ng of the head and neck, such as CT or MRI
scanni ng, i s i mpor tant. The r ol e of PET scans has not been
establ i shed i n head and neck cancer s, but data ar e pr omi si ng i n the
setti ng of known and unknown pr i mar y di sease, dependi ng on the
vol ume of di sease pr esent.
Tr eatment for tr ue unknown cer vi cal pr i mar i es i s sur ger y (neck
di ssecti on), radi ati on, or sur ger y fol l owed by postoperati ve
radi ati on, ei ther to the nodal basi n al one or wi th el ecti ve i r radi ati on
of the most common mucosal si tes (i .e., the nasophar ynx,
or ophar ynx, hypophar ynx, and supragl otti s). Data suggest that
ther e may be a decr ease i n the occur r ence of an occul t pr i mar y wi th
the l atter appr oach. Some author s vi ew thi s as contr over si al and
r ecommend r eser vi ng radi ati on to the el ecti ve si tes unti l a pr i mar y
devel ops to r educe the mor bi di ty associ ated wi th radi ati on.
Sur ger y for squamous cel l pr i mar i es usual l y entai l s a sel ecti ve or
MRND. If ther e i s si ngl e nodal di sease wi th no poor pr ognosti c
cr i ter i a (e.g., extracapsul ar spr ead, mul ti pl e nodes, l ess than 3 cm),
then sur ger y al one or radi ati on al one may r esul t i n a good outcome.
For bul ki er, mor e aggr essi ve di sease, sur ger y (e.g., MRND, RND)
and radi ati on (usual l y postoperati ve, but someti mes pr eoperati ve) i s
the tr eatment of choi ce. Sur ger y i s al so i ndi cated for the di agnosi s
of metastati c wel l -di ffer enti ated thyr oi d cancer, whi ch woul d entai l
a total thyr oi dectomy and neck di ssecti on (l ateral and anter i or
compar tment).
Sur ger y for tumor s of i nfracl avi cul ar or i gi n (e.g., br east or
gastr oi ntesti nal ) must be car eful l y consi der ed i n l i ght of the hi gh
r i sk of systemi c metastasi s el sewher e i n the body. If the tumor i s
l i mi ted to the neck wi th no other di stant metastasi s, then sur ger y
and postoperati ve radi ati on may i mpr ove l ocal contr ol . For poor l y
di ffer enti ated tumor s suggesti ve of nasophar yngeal or i gi n, the
pr efer r ed tr eatment i s radi ati on.
F i ve-year sur vi val for tr eatment of unknown squamous cer vi cal
metastases appr oaches 40% to 60% i n many studi es, whether usi ng
sur ger y al one or sur ger y and radi ati on. Cl ose fol l ow-up i s i mpor tant
because the pr i mar y wi l l decl ar e i tsel f i n as many as 20% of
pati ents. Pr ognosi s for metastati c di sease fr om an i nfracl avi cul ar
pr i mar y i s poor, bei ng l ess than 10% i n most studi es.

Cancers of the Ear and Temporal Bones


The ear i s composed of the exter nal ear (pi nna, aur i cl e, and
exter nal canal ), the mi ddl e ear, and the i nner ear. The epi thel i um
over the exter nal ear i s squamous wi th adjacent adnexal and
gl andul ar (sebaceous) str uctur es, whi l e ci l i ated epi thel i um and
gl ands l i ne the mi ddl e ear. The framewor k of the aur i cl e and outer
thi r d of the exter nal canal i s compr i sed of el asti c car ti l age, whi l e
the i nner thi r d of the exter nal canal and mi ddl e ear i s made up of
the temporal bone.
Cancer s of the ear and temporal bones ar e rar e and account for l ess
than 1% of al l head and neck cancer s. Al though cutaneous
mal i gnanci es of the pi nna and aur i cl e ar e common, cancer s of the
temporal bone ar e rar e. The major i ty of tumor s of the ear i nvol ve
the aur i cl e (>80% ), fol l owed by the ear canal and mi ddl e ear and
mastoi d. Mal es ar e mor e commonl y affected, and sun exposur e i s a
major r i sk factor. SCC i s the most common hi stol ogi c cancer of the
outer ear, fol l owed by basal cel l car ci nomas. Rhabdomysar comas and
adenocar ci nomas can occur i n the mi ddl e ear. Pai n, aural ful l ness,
conducti ve hear i ng l oss, ul cerati on, and chr oni c otor r hea ar e
common pr esenti ng symptoms. Extensi on towar d the mi ddl e ear may
be associ ated wi th crani al neur opathi es such as faci al paral ysi s and
sensor i neural hear i ng l oss i n up to one-thi r d of pati ents.
Sur ger y i s often the pr efer r ed therapy for SCC and basal cel l
car ci nomas, al though radi ati on therapy may pl ay a r ol e i n hi ghl y
sel ected cases. Smal l l esi ons of the outer ear ar e tr eated
effecti vel y by par ti al or total aur i cul ectomy. Ear l y exter nal canal
l esi ons can be effecti vel y tr eated by sl eeve r esecti on. Lateral
temporal bone r esecti on i s r eser ved for l ar ge tumor s wi th medi al
extensi on, whi ch may i ncl ude par oti dectomy for par oti d nodal
metastasi s.
Sur vi val for cancer s of the outer ear appr oaches 90% for cancer s
confi ned to the aur i cl e, wi th decr easi ng pr ognosi s for those wi th
medi al extensi on and mi ddl e ear extensi on to l ess than 30% .
Temporal bone mal i gnanci es have a sur vi val rate of 20% to 30% at
5 year s.

Neoplasms of the Salivary Gland


Sal i var y gl and ti ssue i n the upper aer odi gesti ve tract consi sts of
thr ee pai r s of major sal i var y gl andspar oti d gl ands, submandi bul ar

or submaxi l l ar y gl ands, and subl i ngual gl andsand thousands of


mi nor sal i var y gl ands that exi st i n the mucosa of the l i ps, buccal
mucosa, har d and soft pal ate, and or ophar ynx. The par oti d gl ands
l i e l ateral and poster i or to the mandi bl e, and can be di vi ded i nto a
super fi ci al and a deep l obe by the cour se of the faci al ner ve. The
deep l obe of the par oti d gl and abuts the pr estyl oi d, paraphar yngeal
space, and deep l obe par oti d tumor s (e.g., pl eomor phi c adenomas)
ar e the most common tumor s i n thi s r egi on. The duct of the par oti d
gl and (Stenson duct) drai ns i ntraoral l y near the second maxi l l ar y
mol ar. Lymph nodes ar e pr esent i n the substance of the gl and, and
the nodal basi n for the par oti d gl and i s the pr eaur i cul ar and upper
jugul odi gastr i c nodes. Of note, the par oti d gl and and associ ated
l ymph nodes ar e a pr i mar y nodal drai nage basi n for scal p and
aur i cul ar mal i gnanci es, and a par oti dectomy shoul d be i ncl uded i n
any compr ehensi ve tr eatment of these mal i gnanci es. The
submandi bul ar gl ands ar e l ocated beneath the mandi bl e and thei r
ducts (Whar ton ducts), and drai n near the fr enul um of the tongue i n
the fl oor of the mouth. The mar gi nal mandi bul ar branch of the faci al
ner ve over l i es the gl and super fi ci al l y, the faci al vessel s (and
associ ated l ymph nodes) ar e i nti matel y associ ated wi th gl and, and
the l i ngual and hypogl ossal ner ves ar e cl osel y associ ated wi th the
deep sur face of the gl and. The subl i ngual gl ands ar e l ocated deep to
the mucosa of the fl oor of the mouth on top of the myl ohyoi d
muscl e.
Tumor s of the sal i var y gl ands can occur i n both major and mi nor
sal i var y gl ands, wi th the major i ty occur r i ng i n the major sal i var y
gl ands. The major i ty of tumor s occur i n the par oti d gl ands (90% ),
and the major i ty of these ar e beni gn (80% ). As the si ze of the
gl and decr eases, the r i sk of mal i gnancy i ncr eases, wi th 50% of
submandi bul ar gl and tumor s bei ng mal i gnant and 80% of subl i ngual
gl and tumor s bei ng mal i gnant. Some tumor s ar e associ ated wi th
pr evi ous radi ati on exposur e or smoki ng (e.g., War thi n tumor s).
However, the major i ty of sal i var y gl and tumor s have no i denti fi abl e
r i sk factor s.
Most sal i var y gl and tumor s pr esent as a pai nl ess mass, al though
rapi d gr owth and pai n may be seen but ar e not al ways suggesti ve of
mor e omi nous or aggr essi ve di sease because i nfl ammator y or
i nfecti ous di seases can pr esent wi th si mi l ar symptoms (e.g.,
par oti ti s or col l agen vascul ar di seases such as Sjgr en syndr ome or
Wegner granul omatosi s). Faci al paral ysi s, nodal metastasi s, and
l ocal ti ssue i nvasi on may be i ndi cati ve of a mor e

aggr essi ve di sease. Of note, Bel l pal sy (i di opathi c faci al ner ve


paral ysi s) i s a di agnosi s of excl usi on, and the pati ent wi th a sudden
faci al ner ve paral ysi s shoul d have a par oti d mal i gnancy (ei ther
pr i mar y or metastati c fr om a ski n pr i mar y) r ul ed out.
F NA i s hel pful i n establ i shi ng the di agnosi s but i s hi ghl y dependent
on the ski l l of the cytopathol ogi st (accuracy ranges fr om 60%
90% ). If an F NA cannot establ i sh the di agnosi s, then an open,
exci si onal bi opsy shoul d be per for med. In the case of the par oti d
gl and, an exci si onal bi opsy woul d entai l per for mi ng a super ficial
par otidectomy to i denti fy and pr eser ve the faci al ner ve. Inci si onal
bi opsy shoul d be avoi ded to pr event tumor vi ol ati on, tumor spi l l age,
and, i n the case of the par oti d gl and, faci al ner ve i njur y. CT and
MRI scans ar e hel pful i n detai l i ng the extent of di sease (e.g.,
paraphar yngeal space extensi on of deep l obe par oti d tumor s or skul l
base i nvol vement).
The major i ty of tumor s i n the sal i var y gl ands ar e beni gn, wi th
pl eomor phi c adenomas bei ng the most common. Other beni gn
tumor s i ncl ude War thi n tumor s (whi ch ar e associ ated wi th smoki ng
and ar e bi l ateral i n 10% of cases), monomor phi c adenomas, and
oncocytomas. Mal i gnant tumor s i ncl ude mucoepi der moi d car ci nomas,
adenoi d cysti c car ci nomas, adenocar ci nomas, and SCCs.

Treatment
Sur ger y i s the mai nstay of therapy for al l par oti d tumor s. For
beni gn tumor s, super fi ci al par oti dectomy and submandi bul ar gl and
exci si on ar e both di agnosti c and curati ve. Because of the i nti mate
r el ati onshi p of the par oti d gl and and submandi bul ar gl ands to the
faci al ner ve and i ts branches, as wel l as the mor bi di ty associ ated
wi th faci al ner ve paral ysi s, onl y gr oss i nvol vement of the ner ve by
tumor i s an i ndi cati on for sacr i fi ce. Pl eomor phi c adenomas ar e the
most common beni gn tumor s of the sal i var y gl ands. Car e must be
taken to r emove a r i m of nor mal ti ssue ar ound the tumor, as wel l as
to avoi d r uptur e of the pseudocapsul e and tumor spi l l age, to r educe
the r i sk of r ecur r ence.
Mal i gnant tumor s of the sal i var y gl ands typi cal l y r equi r e sur ger y
and radi ati on. The excepti ons ar e l ow-grade neopl asms (e.g., l owgrade mucoepi der moi d car ci nomas and pol ymor phous l ow-grade
adenocar ci nomas), whi ch may be tr eated wi th sur ger y al one.
Super fi ci al par oti dectomy i s i ndi cated for smal l l esi ons. For par oti d
tumor s wi th deep l obe extensi on, total par oti dectomy wi th faci al
ner ve pr eser vati on i s the tr eatment of choi ce. G r oss i nvol vement of

the faci al ner ve by tumor i s an i ndi cati on for sacr i fi ce of the ner ve.
In such cases, the ner ve shoul d be traced pr oxi mal l y (as far back as
the brai nstem, i f necessar y) unti l tumor i s cl ear ed. Thi s i s
especi al l y tr ue of adenoi d cysti c car ci nomas, whi ch ar e neur otr opi c
tumor s. Sacr i fi ce of the faci al ner ve shoul d be r epai r ed i mmedi atel y
ei ther by i nter posi ti onal ner ve grafti ng (usi ng the sural ner ve fr om
the l eg or medi al antebrachi al cutaneous ner ve fr om the ar m) or a
crani al ner ve XII to VII grafti ng. Par oti d tumor s wi th l ocal extensi on
(ski n or exter nal canal i nvol vement) may r equi r e a mastoi dectomy
(to trace the ner ve pr oxi mal l y) and r emoval of the l ateral par t of
the temporal bone. Exci si on of the submandi bul ar gl and and
adjacent faci al l ymph nodes i s the tr eatment for submandi bul ar
tumor s. As wi th the
par oti d, onl y gr oss i nvol vement wi th tumor i s an i ndi cati on for
ner ve sacr i fi ce (e.g., l i ngual and hypogl ossal ner ves), and l ocal
extensi on to sur r oundi ng ti ssues (e.g., fl oor of mouth muscul atur e,
tongue) necessi tates mor e radi cal sur ger y. Neck di ssecti on
(sel ecti ve) i s r eser ved for cl i ni cal l y appar ent neck di sease.
Radi ati on i s r eser ved for pr i mar y tr eatment of mal i gnant tumor s i n
pati ents who ar e poor sur gi cal candi dates or who do not want to
under go sur ger y, as wel l as for the postoperati ve tr eatment of hi ghgrade or r ecur r ent di sease. Adenoi d cysti c car ci nomas, hi gh-grade
mucoepi der moi d car ci nomas, hi gh-grade adenocar ci nomas, SCCs,
and metastati c di sease to the neck ar e typi cal l y i r radi ated. In
addi ti on, pati ents wi th pl eomor phi c adenomas that ar e r ecur r ent or
i nvol ve gr oss tumor spi l l age may be candi dates for postoperati ve
radi ati on. Doses to the pr i mar y tumor bed ar e i n the range of 50 to
70 G y.
F i ve-year sur vi val for beni gn tumor s appr oaches 100% , wi th the
gr eatest r i sk of r ecur r ence occur r i ng i n pati ents who have had
i nadequate i ni ti al operati ons. For mal i gnant tumor s, 5-year sur vi val
i s 70% to 90% for l ow-grade tumor s and 20% to 30% for hi ghgrade mal i gnanci es. Regi onal and di stant r ecur r ences range fr om
15% to 20% and ar e common i n tumor s wi th per i neural i nvasi on
(e.g., adenoi d cysti c car ci nomas). Adenoi d cysti c car ci nomas have a
pr opensi ty to spr ead al ong ner ves and metastasi ze to the l ung;
ther efor e, sur vei l l ance shoul d entai l i magi ng (i .e., MRI scans and
chest x-rays) to excl ude r ecur r ence.

Recommended Reading

Al -Sar raf M, LeBl anc M, G i r i PG , et al . Chemoradi otherapy ver sus


radi otherapy i n pati ents wi th advanced nasophar yngeal cancer :
phase III randomi zed i nter gr oup study 0099. J Clin Oncol
1998;16(4):13101317.
Ang KK, Ji ang G L, F rankenthal er RA, et al . Car ci noma of the
nasal cavi ty. Radiother Oncol 1992;24:163168.
Benner SE, Pajak TF, Li ppman SM, Ear l ey C, Hong WK. Pr eventi on
of second pr i mar y tumor s wi th i sotr eti noi n i n pati ents wi th
squamous cel l car ci noma of the head and neck: l ong-ter m fol l owup. J Natl Cancer Inst 1994;84:140141.
Byer s RM, Cl ayman G L, McG i l l D, et al . Sel ecti ve neck di ssecti ons
for squamous car ci noma of the upper aer odi gesti ve tract:
patter ns of r egi onal fai l ur e. Head Neck 1999;21:499505.
Byer s RM, Wol f PF, Bal l antyne AJ. Rati onal e for el ecti ve modi fi ed
neck di ssecti on. Head Neck Sur g 1988;10:160167.
Car rau RL, Segas J, Nuss DW, et al . Squamous cel l car ci noma of
the si nonasal tract i nvadi ng the or bi t. Lar yngoscope
1999;109:230235.
Cl ayman G L, Johnson CJ II, Mor r i son W, G i nsber g L, Li ppman SM.
The r ol e of neck di ssecti on after chemoradi otherapy for
or ophar yngeal cancer wi th advanced nodal di sease. Ar ch
Otolar yngol Head Neck Sur g 2001;172(2):135139.
Col l eti er PJ, G ar den AS, Mor r i son WH, G oepfer t H, G eara F, Ang
KK. Postoperati ve radi ati on for squamous cel l car ci noma
metastati c to cer vi cal l ymph nodes fr om an unknown pr i mar y
si te: outcomes and patter ns of fai l ur e. Head Neck
1998;20(8):674681.
Di az EM, Jr, Hol si nger F C, Zuni ga ER, Rober ts DB, Sor ensen DM.
Squamous cel l car ci noma of the buccal mucosa: one i nsti tuti on's
exper i ence wi th 119 pr evi ousl y untr eated pati ents. Head Neck
2003;25(4):267273.

Di sa JJ, Hu QY, Hi dal go DA. Retr ospecti ve r evi ew of 400


consecuti ve fr ee fl ap r econstr ucti ons for oncol ogi c sur gi cal
defects. Ann Sur g Oncol 1997;4(8):663669.

Eden BV, Debo RF, Lar ner JM, et al . Esthesi oneur obl astoma. Longter m outcome and patter ns of fai l ur ethe Uni ver si ty of Vi r gi ni a
exper i ence. Cancer 1994;73:25562562.
Fagan JJ, Col l i ns B, Bar nes L, D'Ami co F, Myer s EN, Johnson JT.
Per i neural i nvasi on i n squamous cel l car ci noma of the head and
neck. Ar ch Otolar yngol Head Neck Sur g 1998;124:637640.
Fee WE, Rober son JB, G offi net DR. Long-ter m sur vi val after
sur gi cal r esecti on for r ecur r ent nasophar yngeal cancer after
radi otherapy fai l ur e. Ar ch Otolar yngol Head Neck Sur g
1991;117(11):12331236.
Forasti er e A, Koch W, Tr otti A, Si dransky D. Head and neck cancer
[r evi ew]. N Engl J Med 2001;345(26):18901900.
For di ce J, Ker shaw C, El Naggar A, G oepfer t H. Adenoi d cysti c
car ci noma of the head and neck: pr edi ctor s of mor bi di ty and
mor tal i ty. Ar ch Otolar yngol Head Neck Sur g 1999;125:149152.
F rankenthal er RA, Byer s RM, Luna MA, Cal l ender DL, Wol f P,
G oepfer t H. Pr edi cti ng occul t l ymph node metastasi s i n par oti d
cancer. Ar ch Otolar yngol Head Neck Sur g 1993;119:517520.
F rankenthal er RA, Luna MA, Lee SS, et al . Pr ognosti c var i abl es i n
par oti d gl and cancer. Ar ch Otolar yngol Head Neck Sur g
1991;117:12511256.
G ar den AS, Mor r i son WH, Cl ayman G L, Ang KK, Peter s L J. Ear l y
squamous cel l car ci noma of the hypophar ynx: outcomes of
tr eatment wi th radi ati on al one to the pr i mar y di sease. Head Neck
1996;18:317322.
G ar den AS, Weber RS, Ang KK, Mor r i son WH, Matr e J, Peter s L J.
Postoperati ve radi ati on therapy for mal i gnant tumor s of mi nor

sal i var y gl ands. Cancer 1994;73(10):25632569.


G r eenber g JS, Fowl er R, G omez J, et al . Extent of extracapsul ar
spr ead: a cr i ti cal pr ognosti cator i n oral tongue cancer. Cancer
2003;97(6):14641470.
G wozdz JT, Mor r i son WH, G ar den AS, Weber RS, Peter s L J, Ang
KK. Concomi tant boost radi otherapy for squamous car ci noma of
the tonsi l l ar fossa. Int J Radiat Oncol 1997;39(1):127135.
Har r i son LB, Zel efsky MJ, Sessi ons RB, et al . Base of tongue
cancer tr eated wi th exter nal beam i r radi ati on pl us
brachytherapy: oncol ogi c and functi onal outcome. Radiology
1992;184:267270.
Hong WK, Endi cott J, Itr i LM, et al . 13-ci s Reti noi c aci d i n the
tr eatment of oral l eukopl aki a. N Engl J Med 1986;315:1501
1505.
Inducti on chemotherapy pl us radi ati on compar ed wi th sur ger y
pl us radi ati on i n pati ents wi th advanced l ar yngeal cancer. The
Depar tment of Veterans Affai r s Lar yngeal Cancer Study G r oup. N
Engl J Med 1991;324(24):16851690.
Johnson JT, Myer s EN, Hao SP, Wagner RL. Outcome of open
sur gi cal therapy for gl otti c car ci noma. Ann Otol Rhinol Lar yngol
1993;102:752755.
Jungehul si ng M, Schei dhauer K, Damm M, et al . 2[F ]-F l uor o2deoxy-D-gl ucose posi tr on emi ssi on tomography i s a sensi ti ve tool
for the detecti on of occul t pr i mar y cancer (car ci noma of unknown
pr i mar y syndr ome) wi th head and neck l ymph node
mani festati on. Otolar yngol Head Neck Sur g 2000;123:294301.
Khur i F R, Li ppman SM, Spi tz MR, et al . Mol ecul ar epi demi ol ogy
and r eti noi d chemopr eventi on of head and neck cancer. J Natl
Cancer Inst 1997;89:199.
Ki r chner JA, Cor nog JL, Hol mes RE. Transgl otti c cancer. Ar ch
Otolar yngol 1974;99:247251.

Kraus DH, Dubner S, Har r i son LB, et al . Pr ognosti c factor s for


r ecur r ence and sur vi val i n head and neck soft ti ssue sar comas.
Cancer 1994;74:697702
Kraus DH, Zel efsky MJ, Br ock HA, Huo J, Har r i son LB, Shah JP.
Combi ned sur ger y and radi ati on therapy for squamous cel l
car ci noma of the hypophar ynx. Otolar yngol Head Neck Sur g
1997;116:637641.

Laccour r eye H, Laccour r eye O, Wei nstei n G , Menar d M, Brasnu D.


Supracr i coi d l ar yngectomy wi th cr i cohyoi doepi gl ottopexy: a
par ti al l ar yngeal pr ocedur e for gl otti c car ci noma. Ann Otol Rhinol
Lar yngol 1990;99(6 pt 1):421426.
Laccour r eye H, Laccour r eye O, Wei nstei n G , Menar d M, Brasnu D.
Supracr i coi d l ar yngectomy wi th cr i cohyoi dopexy: a par ti al
l ar yngeal pr ocedur e for sel ected supragl otti c and transgl otti c
car ci nomas. Lar yngoscope 1990;100(7):735741.
Machtay M, Rosenthal DI, Her shock D, et al . Or gan pr eser vati on
therapy usi ng i nducti on pl us concur r ent chemoradi ati on for
advanced r esectabl e or ophar yngeal car ci noma: a Uni ver si ty of
Pennsyl vani a phase II tr i al . J Clin Oncol 2002;20(19):39643971.
Mendenhal l WM, Par sons JT, Str i nger SP, Cassi si NJ. Management
of Ti s, T1, and T2 squamous cel l car ci noma of the gl otti c l ar ynx.
Am J Otolar yngol 1994;15(4):250257.
Myer s EN, Al vi A. Management of car ci noma of the supragl otti c
l ar ynx: evol uti on, cur r ent concepts and futur e tr ends.
Lar yngoscope 1996;106:559567.
Myer s EN, Suen JC, eds. Cancer of the Head and Neck.
Phi l adel phi a, Pa: WB Saunder s; 1996.
Papadi mi trakopoul ou VA, Cl ayman G L, Shi n DM, et al .
Bi ochemopr eventi on for dyspl asti c l esi ons of the upper
aer odi gesti ve tract. Ar ch Otolar yngol Head Neck Sur g
1999;125:10831089.

Spi r o RH. Sal i var y neopl asms: over vi ew of a 35 year exper i ence
wi th 2807 pati ents. Head Neck Sur g 1986;8:177184.
Spi r o RH, DeRose G , Str ong EW. Cer vi cal node metastasi s of
occul t or i gi n. Am J Sur g 1983;146:441446
Spi r o RH, Huvos AG , Wong G Y, Spi r o JD, G necco CA, Str ong EW.
Pr edi cti ve val ue of tumor thi ckness i n squamous car ci noma
confi ned to the tongue and fl oor of the mouth. Am J Sur g
1986;152:345350.
Stei ner W. Resul ts of curati ve l aser mi cr osur ger y of l ar yngeal
car ci nomas. Am J Otolar yngol 1993;14:116121.
Ster n SJ, G oepfer t H, Cl ayman G , Byer s R, Wol f P. Or bi tal
pr eser vati on i n maxi l l ectomy. Otolar yngol Head Neck Sur g
1993;109:111115.
Ster n SJ, G oepfer t H, Cl ayman G , et al . Squamous cel l car ci noma
of the maxi l l ar y si nus. Ar ch Otolar yngol Head Neck Sur g
1993;119(9):964969.
Stur gi s EM, Potter BO. Sar comas of the head and neck r egi on.
Cur r Opin Oncol 2003;15(3):239252.
Ur ken ML, Wei nber g H, Buchbi nder D, et al . Mi cr ovascul ar fr ee
fl aps i n head and neck r econstr ucti on. Ar ch Otolar yngol Head
Neck Sur g 1994;120:633640.
Wanebo HJ, Koness RJ, MacFar l ane JK, et al . Head and neck
sar coma: r epor t of the Head and Neck Sar coma Regi str y. Soci ety
of Head and Neck Sur geons Commi ttee on Resear ch. Head Neck
1992;14:17.
Weber RS, Benjami n RS, Peter s L J, Ro JY, Achon O, G oepfer t H.
Soft ti ssue sar comas of the head and neck i n adol escents and
adul ts. Am J Sur g 1986;152(4):386392.
Weber RS, Ber key BA, Forasti er e A, et al . Outcome of sal vage

total l ar yngectomy fol l owi ng or gan pr eser vati on therapy: the


Radi ati on Therapy Oncol ogy G r oup tr i al 91-11. Ar ch Otolar yngol
Head Neck Sur g 2003;129(1):4449.

Editors: Feig, Barry W .; Berger, David H.; Fuhrman, George


M.
Title: MD A nderson Surgical Oncology Handbook, The, 4th
Edition
Copyr i ght 2006 Li ppi ncott Wi l l i ams & Wi l ki ns
> Ta ble o f C o nt e nt s > 7 - Tho ra c ic M a ligna nc ie s

7
Thoracic Malignancies
Shanda H. Blackmon
A ra A . Vaporciyan

Primary Neoplasms of the Lung


In 2005, l ung cancer accounted for an esti mated 163,510 deaths
and 172,570 new cases of cancer i n the Uni ted States. Al though
l ess publ i ci zed than br east or pr ostate cancer, l ung cancer i s the
most common cause of cancer-r el ated death i n both men and
women. Appr oxi matel y 30% of al l cancer deaths ar e attr i butabl e to
l ung cancer. However, as seen i n F i gur e 7.1, the overal l ageadjusted death rates for l ung cancer have begun to l evel off. Thi s
l evel i ng off i s attr i butabl e to an overal l decr ease i n the number of
mal es who smoke and no fur ther i ncr ease i n the number of women
who smoke. Unfor tunatel y, thi s good news i s counter ed by a
di stur bi ng i ncr ease i n smoki ng among cer tai n mi nor i ty and
adol escent age gr oups. The overal l 5-year sur vi val rate for l ung
cancer i s onl y 15% , pr i mar i l y because the di sease i s usual l y
advanced at pr esentati on. If found at an ear l y stage, the 5-year
sur vi val rate appr oaches 60% to 70% .

Epidemiology
Smoki ng i s the pr i mar y eti ol ogy i n mor e than 80% of l ung cancer s,
and secondhand smoke i ncr eases the r i sk of l ung cancer by 30% .
Despi te the str ong associ ati on of l ung cancer wi th smoki ng, such
cancer s devel op i n onl y 15% of heavy smoker s. G i ant bul l ous
emphysema and ai r way obstr ucti ve di sease can act syner gi sti cal l y
wi th smoki ng to i nduce l ung cancer, per haps because of poor
cl earance and trappi ng of car ci nogens. Industr i al and envi r onmental
car ci nogens have been i mpl i cated, i ncl udi ng r esi denti al radon gas,

asbestos, urani um, cadmi um, ar seni c, and ter penes.

Pathology
Lung cancer can be br oadl y separated i nto two gr oups: nonsmal l cel l l ung cancer s (NSCLCs) and smal l -cel l l ung cancer s (SCLCs). Thi s
i s a popul ar di vi si on because, for the most par t, NSCLC i s often
managed wi th sur ger y when the tumor i s l ocal i zed, wher eas SCLC i s
al most al ways managed nonsur gi cal l y wi th chemotherapy and
radi ati on therapy. The thr ee major types of NSCLC ar e
adenocar ci noma, squamous cel l car ci noma, and l ar ge-cel l car ci noma
(Tabl e 7.1).

Nonsmall-cell Lung Carcinoma


Adenocar cinoma i s the most common type of NSCLC and accounts for
mor e than 40% of cases. It i s the most common l ung cancer found
i n nonsmoker s and women. The l esi ons tend to be l ocated i n the
per i pher y and devel op systemi c metastases, even i n the face of
smal l pr i mar y tumor s.
Br onchoalveolar cell car cinoma i s a subset of adenocar ci noma,
whose i nci dence appear s to be i ncr easi ng. Thi s tumor i s mor e
fr equent i n women and nonsmoker s, and can pr esent as a si ngl e

mass, mul ti pl e nodul es, or an i nfi l trate. The cl i ni cal cour se can var y
fr om i ndol ent pr ogr essi on to rapi d di ffuse di ssemi nati on.

F i gur e 7.1. Annual age-adjusted cancer death rates for sel ected
cancer types i n mal es (top) and femal es (bottom), Uni ted States,
1930 to 2001.

Table 7.1. Frequency of histologic subtypes


of primary lung cancer

Cell Type

Estimated
Frequency (%)

Non-small-cell lung cancer


Adenocarcinoma

40

Bronchoalveolar

Squamous cell carcinoma


Large-cell carcinoma

25
7

Small-cell lung cancer


Small-cell carcinoma

20

Neuroendocrine, well
differentiated

Carcinoids

Squamous cell car cinoma accounts for appr oxi matel y 25% of al l l ung
cancer s. Most (66% ) pr esent as central l esi ons. Cavi tati on i s found
i n 7% to 10% of cases. Unl i ke adenocar ci noma, the tumor often
r emai ns l ocal i zed, tendi ng to spr ead i ni ti al l y to r egi onal l ymph
nodes rather than systemi cal l y.
Lar ge-cell car cinoma accounts for appr oxi matel y 7% to 10% of al l
l ung cancer s. Cl i ni cal l y, l ar ge-cel l car ci nomas behave aggr essi vel y,
wi th ear l y metastases to the r egi onal nodes i n the medi asti num and
di stant si tes such as the brai n.

Small-cell Lung Carcinoma

Small-cell car cinoma i s associ ated wi th neur oendocr i ne car ci noma


because of ul trastr uctural and i mmunohi stochemi cal si mi l ar i ti es.
Some pathol ogi sts thi nk smal l -cel l car ci nomas r epr esent a spectr um
of di sease begi nni ng wi th the wel l -di ffer enti ated, beni gn car ci noi d
tumor (Kul chi tsky I), i ncl udi ng the l ess di ffer enti ated atypi cal
car ci noi ds (Kul chi tsky II) or neur oendocr i ne car ci nomas, and endi ng
wi th the undi ffer enti ated smal l -cel l car ci nomas (Kul chi tsky III).
Smal l -cel l car ci nomas tend to pr esent wi th metastati c and r egi onal
spr ead, and ar e usual l y tr eated wi th chemotherapy wi th or wi thout
radi ati on therapy. Sur ger y i s onl y used to r emove the occasi onal
l ocal i zed per i pheral nodul e.
Car cinoids tend to ar i se fr om major br onchi and ar e central tumor s.
Metastasi s i s rar e. Immunohi stochemi cal l y, car ci noi ds expr ess
neur on-speci fi c enol ase, chr omograni n, and synaptophysi n vi r tual l y
wi thout excepti on.
Neur oendocr ine car cinomas or atypical car cinoids occur mor e
per i pheral l y than car ci noi ds and have a mor e aggr essi ve cour se,
al though sur ger y shoul d sti l l be consi der ed accor di ng to cl i ni cal
stage. Wi thout appr opr i ate i mmunostai ni ng, they may i nadver tentl y
be cl assi fi ed as l ar ge-cel l car ci nomas.

Diagnosis
Si gns and symptoms occur i n 90% to 95% of pati ents at the ti me of
di agnosi s. Intrapar enchymal tumor s cause cough, hemoptysi s,
dyspnea, wheez i ng, and fever (often due to i nfecti on fr om pr oxi mal
br onchi al tumor obstr ucti on). Regi onal spr ead of the tumor wi thi n
the thorax can l ead to pl eural effusi ons or chest wal l pai n. Less
common symptoms ar e super i or vena cava syndr ome, Pancoast
syndr ome (shoul der and ar m pai n, Hor ner syndr ome, and weakness
and atr ophy of the hand muscl es), and i nvol vement of the r ecur r ent
l ar yngeal ner ve, the phr eni c ner ve, the vagus ner ve, or the
esophagus. Paraneopl asti c syndr omes ar e found i n 10% of pati ents
wi th l ung cancer, most commonl y those wi th SCLC. These syndr omes
ar e numer ous and can affect endocr i ne, neur ol ogi c, skel etal ,
hematol ogi c, and cutaneous systems.
A standar d chest radi ograph (CXR) i s the i ni ti al di agnosti c study for
the eval uati on of suspected l ung cancer, fol l owed r outi nel y by
computed tomography (CT). CT shoul d i ncl ude i magi ng of the l i ver
and adr enal gl ands to r ul e out two common si tes for i ntraabdomi nal metastases. CT hel ps assess l ocal extensi on to other

thoraci c str uctur es and the pr esence of medi asti nal adenopathy. At
pr esent, magneti c r esonance i magi ng (MRI) adds l i ttl e to the
i nfor mati on gai ned by CT i magi ng. Posi tr on emi ssi on tomography
(PET), especi al l y i ntegrated PET-CT, has become a fr equent method
of di sti ngui shi ng beni gn fr om mal i gnant pul monar y nodul es.
Al though the accuracy of PET scanni ng i n eval uati ng a pul monar y
nodul e can exceed 90% i n some studi es, cl i ni ci ans shoul d be awar e
that fal se-negati ve PET scans occur i n pati ents wi th neopl asms
havi ng l ow metabol i c acti vi ty (car ci noi d and br onchi oal veol ar
neopl asms). Even wi th advances i n i magi ng, hi stol ogi c confi r mati on
wi l l fr equentl y be r equi r ed to di sti ngui sh beni gn fr om mal i gnant
di sease and to deter mi ne the hi stol ogi c type of cancer. For a
sol i tar y l esi on wi th a hi gh i ndex of suspi ci on, hi stol ogi c
confi r mati on can be obtai ned at the ti me of sur ger y (thoracotomy or
vi deo-assi sted thoraci c sur ger y [VATS]) usi ng fr ozen secti oni ng of a
wedge r esecti on or a needl e bi opsy. If i mmedi ate sur ger y i s not
appr opr i ate, then ti ssue can be obtai ned by sputum cytol ogy and
br onchoscopy (central l esi ons) or by fl uor oscopi c fi ne-needl e
aspi rati on (F NA), or CT-gui ded bi opsy (per i pheral l esi ons). Pati ents
wi th beni gn l esi ons shoul d be fol l owed for i nter val gr owth over a
per i od of at l east 2 year s.

Staging
The pr i mar y goal of pr etr eatment stagi ng i s to deter mi ne the extent
of di sease so pr ognosi s and tr eatment can be deter mi ned. In SCLC,
most pati ents pr esent wi th metastati c or advanced l ocor egi onal
di sease. A si mpl e two-stage system cl assi fi es the SCLC as l i mi ted or
extensi ve di sease. Li mi ted di sease i s confi ned to one hemi thorax,
i psi l ateral or contral ateral hi l ar or medi asti nal nodes, and
i psi l ateral supracl avi cul ar l ymph nodes. Extensi ve di sease has
spr ead to the contral ateral supracl avi cul ar nodes or di stant si tes
such as the contral ateral l ung, l i ver, brai n, or bone mar r ow. Stagi ng
for SCLC r equi r es a bone scan;
bone mar r ow bi opsy; and CT scans of the abdomen, brai n, and
chest.
Stagi ng of NSCLC has most r ecentl y i nvol ved a system pr oposed i n
1985: the Inter nati onal Lung Cancer Stagi ng System or
Inter nati onal Stagi ng System (ISS). Thi s system i s based on TNM
cl assi fi cati ons as shown i n Tabl e 7.2. Sur vi val rates for pati ents
wi th NSCLC by stage of di sease ar e shown i n F i gur e 7.2. Because of
heter ogenei ty wi thi n gr oups, fur ther modi fi cati ons to the ISS have

been pr oposed that i nvol ve spl i tti ng stage I i nto IA (T1N0) and IB
(T2N0) and stage II i nto IIA (T1N0) and IIB (T2N0) and movi ng the
good-pr ognosi s T3N0 pati ents (chest wal l i nvol vement wi thout nodal
spr ead) i nto IIB. Stagi ng of NSCLC i nvol ves a thor ough hi stor y and
physi cal exami nati on, CXR, and CT scans of the chest and upper
abdomen, wi th the adjuncti ve use of PET scanni ng when avai l abl e.
Unfor tunatel y, CT cannot defi ni ti vel y pr edi ct medi asti nal nodal
i nvol vement because not al l mal i gnant l ymph nodes ar e enl ar ged,
and many enl ar ged nodes ar e si mpl y l ar ger because of pr oxi mal
i nfecti on. Lymph nodes l ar ger than 1 cm have a 30% chance of
bei ng beni gn, wher eas l ymph nodes smal l er than 1 cm sti l l have a
15% chance of contai ni ng tumor. PET-CT has a hi gher negati ve
pr edi cti ve val ue i n the eval uati on of medi asti nal N2 di sease,
al though fal se posi ti ves can occur i n pati ents wi th i nfecti ous
granul omas, i nfl ammator y pr ocesses, and r heumatoi d nodul es. Most
i nvesti gator s agr ee that ti ssue confi r mati on of PET l ocal i zed
medi asti nal di sease and metastases i s r equi r ed. Because of the l ow
yi el d i n asymptomati c ear l y-stage pati ents (T1N0), a bone scan, CT,
or MRI of the brai n shoul d onl y be obtai ned when suspected by
hi stor y.

Treatment
Pretreatment Assessment
Once a pati ent has been staged cl i ni cal l y wi th noni nvasi ve tests, a
physi ol ogi cal assessment shoul d be per for med to deter mi ne the
pati ent's abi l i ty to tol erate di ffer ent therapeuti c modal i ti es. In
addi ti on to a general eval uati on of the pati ent's overal l medi cal
status, speci fi c attenti on shoul d be pai d to the car di ovascul ar and
r espi rator y systems. Car di ovascul ar scr eeni ng shoul d i ncl ude a
hi stor y and physi cal exami nati on, as wel l as a CXR and
el ectr ocar di ography. Pati ents wi th si gns and symptoms of si gni fi cant
car di ac di sease shoul d under go fur ther noni nvasi ve testi ng,
i ncl udi ng ei ther exer ci se testi ng, echocar di ography, or nucl ear
per fusi on scans. Si gni fi cant r ever si bl e car di ac pr obl ems shoul d be
addr essed befor e therapy (i .e., chemotherapy, radi ati on therapy, or
sur ger y).
The pul monar y r eser ve of pati ents wi th l ung cancer i s commonl y
di mi ni shed as a r esul t of tobacco abuse. Si mpl e spi r ometr y i s an
excel l ent i ni ti al scr eeni ng test to quanti fy a pati ent's pul monar y
r eser ve and abi l i ty to tol erate sur gi cal r esecti on. A pr edi cted
postoperati ve for ced expi rator y vol ume i n 1 second (F EV1 ) of l ess

than 0.8 L or l ess than 35% of pr edi cted postoperati ve F EV1 i s


associ ated wi th an i ncr eased r i sk of per i operati ve compl i cati ons,
r espi rator y i nsuffi ci ency, and death. The pr edi cted postoperati ve
F EV 1 i s esti mated by subtracti ng the contr i buti on of the l ung to be
r esected fr om the pr eoperati ve F EV1 . In cer tai n

i nstances, the l ung to be r esected does not contr i bute much to the
pr eoperati ve F EV1 because of tumor, atel ectasi s, or pneumoni ti s.
Thus, mor e accurate deter mi nati on of pr edi cted postoperati ve F EV1
can be obtai ned by per for mi ng a venti l ati on-per fusi on scan and
subtracti ng the exact contr i buti on of the l ung to be r esected. In
good per for mance pati ents wi th bor der l i ne spi r ometr y cr i ter i a,
oxygen consumpti on studi es can be obtai ned that measur e both
r espi rator y and car di ac capaci ty. A maxi mum oxygen consumpti on
(VO 2 max) of gr eater than 15 mL mi n- 1 kg - 1 i ndi cates l ow r i sk,
wher eas a VO2 max of l ess than 10 mL mi n- 1 kg - 1 i s associ ated wi th
hi gh r i sk (a mor tal i ty rate of mor e than 30% i n some ser i es).
Addi ti onal r i sk factor s for l ung r esecti on i ncl ude a pr edi cted
postoperati ve di ffusi ng capaci ty (DLCO)
or maxi mum venti l ator y venti l ati on (MVV) of l ess than 40% and
hyper car bi a (>45 mm CO2 ) or hypoxemi a (<60 mm O2 ) on
pr eoperati ve ar ter i al bl ood gases. In conjuncti on wi th cl i ni cal
assessment (6-mi nute wal k and number of fl i ghts of stai r s cl i mbed),
these tests can hel p i denti fy those pati ents at hi gh r i sk for
compl i cati ons dur i ng and after sur gi cal r esecti on.

Table 7.2. TNM descriptors


Primary tumor (T)

Tx

Primary tumor cannot be assessed or


tumor proven by the presence of
malignant cells in sputum or bronchial
washings but not visualized by imaging or

bronchoscopy
T0

No evidence of primary tumor

Tis

Carcinoma in situ

T1

Tumor 3 cm in greatest dimension,


surrounded by lung or visceral pleura,
without bronchoscopic evidence of
invasion more proximal than the lobar
bronchus a (i.e., not in the main bronchus)

T2

Tumor with any of the following features


of size or extent:
>3 cm in greatest dimension
Involving main bronchus, 2 cm distal to
the carina
Invading the visceral pleura
Associated with atelectasis or obstructive
pneumonitis that extends to the hilar
region but does not involve the entire
lung

T3

Tumor of any size that directly invades


any of the following: chest wall (including
superior sulcus tumors), diaphragm,
mediastinal pleura, parietal pericardium;
or tumor in the main bronchus <2 cm
distal to the carina but without
involvement of the carina; or associated
atelectasis or obstructive pneumonitis of
the entire lung

T4

Tumor of any size that invades any of the


followingmediastinum, heart, great
vessels, trachea, esophagus, vertebral
body, carinaor tumor with a malignant
pleural or pericardial effusion,b or with
satellite tumor nodule(s) within the
ipsilateral primary tumor lobe of the lung

Regional lymph nodes (N)


Nx

Regional lymph nodes cannot be assessed

N0

No regional lymph node metastasis

N1

Metastasis to ipsilateral peribronchial


and/or ipsilateral hilar lymph nodes, and
intrapulmonary nodes involved by direct
extension of the primary tumor

N2

Metastasis to ipsilateral mediastinal


and/or subcarinal lymph nodes(s)

N3

Metastasis to contralateral mediastinal,


contralateral hilar, ipsilateral or
contralateral scalene, or supraclavicular
lymph node(s)

Distant metastasis (M)


Presence of distant metastasis cannot be

Mx

assessed

M0

No distant metastasis

M1

Distant metastasis presentc

a The

uncommon superficial tumor of any size


with its invasive component limited to the
bronchial wall, which may extend proximally to
the main bronchus, is also classified T1.
b Most pleural effusions associated with lung
cancer are due to tumor. However, there are a
few patients in whom multiple cytopathological
examinations of pleural fluid show no tumor. In
these cases, the fluid is nonbloody and is not
an exudate. When these elements and clinical
judgment dictate that the effusion is not
related to the tumor, the effusion should be
excluded as a staging element, and the
patient's disease should be staged T1, T2, or
T3. Pericardial effusion is classified according
to the same rules.
c Separate metastatic tumor nodule(s) in the
ipsilateral nonprimary tumor lobe(s) of the lung
are also classified M1.

F i gur e 7.2. Cumul ati ve sur vi val accor di ng to cl i ni cal stage of


nonsmal l -cel l l ung cancer.

Pr eoperati ve trai ni ng wi th an i ncenti ve spi r ometer, i ni ti ati on of


br onchodi l ator s, wei ght r educti on, good nutr i ti on, and cessati on of
smoki ng for at l east 2 weeks befor e sur ger y can hel p mi ni mi ze
compl i cati ons and i mpr ove per for mance on spi r ometr y for pati ents
wi th mar gi nal pul monar y r eser ve.

Nonsmall-cell Lung Carcinoma


In ear l y-stage NSCLC, sur ger y i s a cr i ti cal par t of tr eatment.
Unfor tunatel y, mor e than 50% to 70% of NSCLC pati ents pr esent
wi th advanced di sease for whi ch sur ger y al one i s not an opti on. An
al gor i thm for tr eatment based on cl i ni cal stage i s pr esented i n
F i gur e 7.3. Physi ol ogi cal l y fi t pati ents wi th ear l y-stage l esi ons
(stage I or II) ar e tr eated wi th sur ger y. Defi ni ti ve radi ati on therapy
i s i ndi cated i f sur ger y cannot be tol erated. F i ve-year sur vi val rates
of 60% to 70% and 39% to 43% can be achi eved for pati ents wi th

stage I and II di sease, r especti vel y. Chest wal l i nvol vement wi thout
nodal spr ead (T3N0) was for mal l y consi der ed stage IIIa, but because
sur vi val rates of 33% to 60% have been achi eved wi th sur ger y,
they ar e now consi der ed as ear l y-stage l esi on (stage IIa). If these
pati ents cannot tol erate sur ger y because of poor medi cal status,
defi ni ti ve radi ati on can r esul t i n sur vi val rates of 15% to 35% .
The r emai nder of pati ents wi th stage IIIa di sease (N2 di sease or
chest wal l wi th nodal i nvol vement) cl assi cal l y has a poor r esponse
to sur ger y, wi th 5-year sur vi val rates of l ess than 15% . The
standar d tr eatment for these pati ents and those wi th stage IIIb or
IV i ncl udes chemotherapy (pl ati num-based doubl ets) and defi ni ti ve
radi ati on therapy for l ocal pal l i ati on. Impr oved sur vi val i s obtai ned
when chemotherapy i s combi ned wi th radi ati on therapy, al though
the compl i cati on rate i s i ncr eased.
A smal l subset of stage IIIb tumor s can be appr oached sur gi cal l y.
These tumor s ar e consi der ed stage IIIb because of l ocal extensi on
(T4N0) i nto adjacent str uctur es rather than systemi c spr ead (nodes,
hematogenous metastases) and may benefi t fr om aggr essi ve
sur gi cal r esecti on of the atr i um, car i na, or ver tebrae. Sur vi val rates
of up to 30% have been r epor ted. Metastati c di sease i s onl y tr eated
sur gi cal l y i n the unusual ci r cumstance of an i sol ated brai n
metastasi s wi th a node-negati ve l ung pr i mar y. Several r epor ts have
documented better l ocal contr ol (i n the brai n and l ung) wi th sur ger y
and a subset of l ong-ter m sur vi vor s. The pr esence of medi asti nal
nodes, however, contrai ndi cates sur gi cal r esecti on and mandates
radi ati on therapy for the l ung pr i mar y.

Surgery
Pneumonectomy
The r emoval of the whol e l ung was pr evi ousl y the most commonl y
per for med operati on for NSCLC; i t now accounts for onl y 20% of al l
r esecti ons. Al though a mor e

compl ete r esecti on i s accompl i shed usi ng pneumonectomy ver sus


par enchyma-conser vi ng techni ques (l obectomy), i t comes at the cost
of hi gher mor tal i ty (4% 10% ) and mor bi di ty wi thout cl ear sur vi val
benefi ts.

F i gur e 7.3. Al gor i thm for tr eatment of nonsmal l -cel l l ung


cancer.

Lobectomy
The si mi l ar sur vi val of pati ents tr eated by l obectomy ver sus
pneumonectomy, al ong wi th the l ower mor bi di ty and mor tal i ty (1%
3% ) associ ated wi th l obectomy, make l obectomy the pr efer r ed
method of r esecti on. Sl eeve l obectomi es and br onchopl asty
pr ocedur es i n whi ch por ti ons of the mai n br onchus ar e r emoved
wi thout l oss of the di stal l ung have fur ther decr eased the need for
pneumonectomi es.

Lesser Resections
Segmentectomi es and nonanatomi cal r esecti ons (wedge r esecti on
and l umpectomy) ar e associ ated wi th i ncr eased l ocal r ecur r ence
when compar ed wi th l obectomy. The general consensus r emai ns that
these pr ocedur es shoul d be per for med onl y i n hi gh-r i sk pati ents
wi th mi ni mal pul monar y r eser ve who coul d not tol erate a l obectomy.
The advent of CT scr eeni ng for l ung cancer has i denti fi ed mor e
subcenti meter cancer s. The use of l esser r esecti ons wi l l need to be
r eassessed for these types of cancer s.

Extended Operations
Recent i mpr ovements i n sur ger y and cr i ti cal car e have al l owed
cer tai n tumor s, pr evi ousl y consi der ed unr esectabl e, to be r emoved
wi th acceptabl e mor bi di ty and mor tal i ty. Car i nal sl eeve r esecti ons
and extended r esecti ons for super i or sul cus tumor s wi th
hemi ver tebr ectomy and i nstr umentati on of the spi ne can now be
per for med i n a smal l subset of pati ents whose tumor s wer e
pr evi ousl y consi der ed sur gi cal l y unr esectabl e. These pr ocedur es
shoul d onl y be per for med i n pati ents wi thout medi asti nal nodal
i nvol vement because 5-year sur vi val rates ar e l ess than 5% for
pati ents wi th extended r esecti ons i n the pr esence of nodal
i nvol vement.

Mediastinal Lymph Node Dissection


Compl ete medi asti nal l ymph node di ssecti on i mpr oves the accuracy
of l ung cancer stagi ng, i mpr oves i ndi cati ons for subsequent
adjuvant therapy, may decr ease l ocor egi onal r ecur r ence, and may
i mpr ove sur vi val . Ther e has been no i ncr ease i n mor bi di ty
associ ated wi th the addi ti on of a compl ete nodal di ssecti on i n
exper i enced hands.

Chemotherapy
Al most 50% of pati ents pr esent wi th extrathoraci c spr ead, and an
addi ti onal 15% ar e unr esectabl e because of l ocal l y advanced tumor.
In addi ti on, the l ong-ter m sur vi val for r esectabl e stage II and IIIa
tumor s r emai ns poor. Ther efor e, the use of adjuvant chemotherapy
to tr eat pati ents wi th unr esectabl e tumor s and i mpr ove the r esul ts
of sur ger y i s an ar ea of i ntense i nvesti gati on. A meta-anal ysi s of
these studi es demonstrated a sur vi val advantage usi ng pl ati numbased therapy, al though thi s di d not r each stati sti cal si gni fi cance.
These data spawned numer ous l ar ge adjuvant tr i al s i n Eur ope and
Amer i ca. The Eur opean study was the Inter nati onal Adjuvant Lung
Cancer Tr i al and enr ol l ed near l y 1,900 compl etel y r esected stage I,
II, and IIIA pati ents. The gr oup that r ecei ved ci spl ati num-based
doubl et therapy had a 4.1% i mpr ovement i n overal l sur vi val (p
<0.03). Si nce thi s publ i cati on, two addi ti onal posi ti ve tr i al s (NCIC
BR10 and CALG B 9633)
have been pr esented. Al though the i ncl usi on cr i ter i a wer e sl i ghtl y
di ffer ent, both studi es demonstrated a mor e than 30% i mpr ovement
i n sur vi val . These studi es have r equi r ed a si gni fi cant shi ft i n the

postoperati ve management of compl etel y r esected ear l y-stage l ung


cancer s. Al though the r i sk associ ated wi th adjuvant chemotherapy i s
smal l , i t must be consi der ed befor e i ni ti ati ng therapy. Ther efor e, we
now have al l pati ents wi th compl etel y r esected IB or hi gher stage
cancer s eval uated by an oncol ogi st for possi bl e adjuvant
chemotherapy.
Studi es exami ni ng the r ol e of neoadjuvant chemotherapy, common
i n the l ate 1990s, have been di ffi cul t to compl ete due to the data
r egar di ng adjuvant tr eatment. Al though mul ti modal i ty therapy has
achi eved a str ong foothol d, the opti mum ti mi ng of chemotherapy,
adjuvant ver sus neoadjuvant, r emai ns to be deter mi ned.

Small-cell Lung Carcinoma


Unl i ke NSCLC, SCLC tends to be di ssemi nated at pr esentati on and i s
ther efor e not amenabl e to cur e wi th sur ger y or thoraci c radi ati on
therapy al one. Wi thout tr eatment, the di sease i s rapi dl y fatal , wi th
few pati ents sur vi vi ng mor e than 6 months. For tunatel y, SCLC i s
ver y sensi ti ve to chemotherapy, and mor e than two-thi r ds of
pati ents achi eve a par ti al r esponse after systemi c therapy wi th
mul ti dr ug r egi mens. Tr eatment of SCLC ther efor e r evol ves ar ound
systemi c chemotherapy. An al gor i thm based on the extent of di sease
i s pr esented i n F i gur e 7.4. Compl ete r esponse i s seen i n as many as
20% to 50% of pati ents wi th l i mi ted di sease, but these r esponses
ar e not durabl e, and the 5-year sur vi val rate i s sti l l l ess than 10% .
Chemotherapeuti c r egi mens for SCLC most commonl y i ncl ude
combi nati ons of cycl ophosphami de, ci spl ati n, etoposi de, doxor ubi ci n,
and vi ncr i sti ne. Thoraci c radi ati on therapy has been shown to
i mpr ove l ocal contr ol of the pr i mar y tumor and i s often i ncl uded as
par t of the tr eatment for l i mi ted SCLC. In addi ti on, because brai n
metastases ar e noted i n 80% of pati ents wi th SCLC dur i ng the
cour se of thei r di sease, pati ents who show no evi dence of brai n
metastases on CT scans and who achi eve a good r esponse fr om
therapy ar e usual l y tr eated wi th pr ophyl acti c brai n i r radi ati on to
mi ni mi ze the chances of devel opi ng thi s mor bi d si te of tr eatment
fai l ur e.
A smal l r ol e for sur gi cal r esecti on of SCLC does exi st. Sol i tar y
per i pheral pul monar y nodul es wi th no evi dence of metastati c
di sease after eval uati on wi th bone scan, PET-CT, and CT of the
abdomen, brai n, and chest can be tr eated wi th l obectomy and
postoperati ve chemotherapy i f medi asti noscopy i s negati ve. In these
sel ect pati ents, a 5-year sur vi val rate of 50% has been achi eved for

T1N0, T2N0, and compl etel y r esected N1 di sease. Sur ger y for mor e
central l esi ons, however, has not been demonstrated to i mpr ove
sur vi val over that achi eved wi th chemotherapy and radi ati on
therapy al one.

Surveillance
The few tr eatment opti ons for tumor r ecur r ence i n NSLC have
l i mi ted the cost-effecti veness of aggr essi ve radi ol ogi c sur vei l l ance

fol l owi ng sur gi cal r esecti on. Never thel ess, ther e i s an i ncr eased
i nci dence of second pr i mar y l ung cancer s (2% per year ), and annual
or semi annual CXR may hel p detect these l esi ons. Any pati ent who
exper i ences symptoms i n the i nter i m shoul d al so be eval uated
aggr essi vel y for r ecur r ence or a new pr i mar y. The advent of l owdose hel i cal CT scanni ng may change thi s standar d, and i ts r ol e i n
the sur vei l l ance of r esected l ung cancer pati ents i s bei ng eval uated.
The l ung and l i ver ar e the most common si tes of metastases.
Pati ents wi th i sol ated l ung metastases can achi eve sur vi val rates of
25% to 40% i f compl ete sur gi cal r esecti on i s obtai ned. Because
metastases can r ecur, r esecti on i nvol ves nonanatomi cal wedge or
l aser r esecti ons to pr eser ve the l ung par enchyma.

F i gur e 7.4. Al gor i thm for tr eatment of smal l -cel l l ung cancer.

Metastatic Neoplasms to the Lung


Pathology
The bi ol ogy of the under l yi ng pr i mar y mal i gnancy deter mi nes the
behavi or of i ts metastases. Metastases may occur vi a
hematogenous, l ymphati c, di r ect, or aer ogenous r outes.

Diagnosis
Because of thei r pr edomi nantl y per i pheral l ocal i z ati on, most
pul monar y metastases r emai n asymptomati c, wi th fewer than 5%
showi ng symptoms at pr esentati on. Di agnosi s i s commonl y made
dur i ng radi ographi c fol l ow-up after tr eatment of the pr i mar y
mal i gnancy.
Routi ne CXR dur i ng sur vei l l ance after cancer tr eatment i s an
effecti ve means of scr eeni ng pati ents for pul monar y metastases.
Indeed, several studi es have demonstrated the i ncr eased sensi ti vi ty
of CT over standar d CXR. However, the cost-effecti veness of CT for
scr eeni ng r emai ns l ow, and no data as yet suggest that ear l y
detecti on wi th CT l eads to i mpr oved sur vi val . Pl anni ng of sur gi cal
i nter venti ons, however, shoul d be based on CT fi ndi ngs, even
though CT scanni ng sti l l mi sses appr oxi matel y 30% to 50% of the
nodul es found at sur ger y.
When mul ti pl e pul monar y nodul es ar e pr esent i n pati ents wi th a
known pr evi ous mal i gnancy, the l i kel i hood of metastati c di sease
appr oaches 100% . New sol i tar y l esi ons, however, can r epr esent
pr i mar y l ung cancer s because many of the r i sk factor s ar e si mi l ar.

Staging
No val i d stagi ng system exi sts for pul monar y metastases. The
Inter nati onal Regi str y of Lung Metastases has i denti fi ed thr ee
parameter s of pr ognosti c si gni fi cance: r esectabi l i ty, di sease-fr ee
i nter val , and number of metastases. The pr esent cr i ter i a for
r esectabi l i ty i ncl ude r esectabl e pul monar y nodul es, contr ol of the
pr i mar y tumor, adequate pr edi cted postoperati ve pul monar y
r eser ve, and no extrathoraci c metastases. Pati ents who meet these
cr i ter i a shoul d be offer ed metastasectomy. Favorabl e hi stol ogi es for

l ong-ter m sur vi val fol l owi ng r esecti on i ncl ude sar coma, br east,
col on, and geni tour i nar y metastases. Unfavorabl e hi stol ogi es
i ncl ude mel anomas, esophageal , pancr eati c, and gastr i c cancer s.

Treatment
Surgery
Pr eoperati ve eval uati on for r esecti on of pul monar y metastases i s
si mi l ar to that of any other pul monar y r esecti on. Because of the
i ncr eased r i sk of r ecur r ent metastases and need for futur e
thoracotomi es, par enchyma-conser vi ng pr ocedur es ar e per for med
whenever possi bl e (wedge r esecti on, l aser, or cauter y exci si on). The
var i ous sur gi cal appr oaches i ncl ude the fol l owi ng.
Median ster notomy al l ows bi l ateral expl orati on wi th one i nci si on.
Lesi ons l ocated near the hi l um can be di ffi cul t to r each, and
exposur e of the l eft l ower l obeespeci al l y i n pati ents wi th obesi ty,
car di omegal y, or an el evated l eft hemi di aphragmi s poor.
Bilater al anter othor acoster notomy (cl amshel l pr ocedur e) al l ows
excel l ent exposur e of both hemi thoraces, i ncl udi ng the l eft l ower
l obe, al though some sur geons thi nk the i nci si on i ncr eases
postoperati ve pai n.
Poster olater al thor acotomy i s a mor e common i nci si on for access to
the l ung. The l i mi tati on to one hemi thorax, however, necessi tates a
second staged operati on for r emovi ng bi l ateral metastases.
Thoracoscopi c r esecti on al l ows vi sual i z ati on of both hemi thoraces
dur i ng the same anestheti c. Pl eural -based l esi ons ar e ther efor e
easi l y vi sual i zed and exci sed. Unfor tunatel y, the abi l i ty to car eful l y
eval uate the par enchyma for deeper or smal l er nonvi sual i zed
l esi ons i s poor, and some r epor ts suggest an i ncr eased r i sk of l ocal
r ecur r ence wi th thoracoscopy.
At sur ger y, wedge r esecti ons wi th a 1-cm mar gi n ar e pr efer r ed. If
mul ti pl e nodul es wi thi n one segment, l obe, or l ung pr ecl ude
r esecti on of mul ti pl e wedges, then l aser r esecti ons can be
per for med.

Adjuvant Therapy
The r ol e of radi ati on therapy i n the tr eatment of pul monar y
metastases i s l i mi ted to the pal l i ati on of symptoms of advanced

l esi ons wi th extensi ve pl eural , bony, or neural i nvol vement. The


val ue of chemotherapy pr eoperati vel y or postoperati vel y r emai ns
contr over si al . Ther e ar e many i sol ated r epor ts of the benefi t of
chemotherapy, especi al l y when the pr i mar y tumor i s sensi ti ve (e.g.,
osteosar coma, teratoma, other ger m cel l tumor s). However,
i mpr ovements i n sur vi val ar e mor e di ffi cul t to achi eve when the
pr i mar y i s of other types.

Surveillance
The fr equency and i ntensi ty of fol l ow-up after r esecti on ar e
deter mi ned by the pr i mar y tumor but usual l y i nvol ve annual or
bi annual CT scans.

Neoplasms of the Mediastinum


The medi asti nal compar tment can har bor numer ous l esi ons of
congeni tal , i nfecti ous, devel opmental , traumati c, or neopl asti c
or i gi n. Ear l i er r ecommendati ons advocated a di r ect sur gi cal
appr oach to al l medi asti nal tumor s, wi th bi opsy or debul ki ng of
unr esectabl e l esi ons. However, r ecent advances i n i magi ng and
noni nvasi ve di agnosti c techni ques, as wel l as i mpr ovements i n
chemotherapy and radi ati on therapy, have l ed to a mor e
conser vati ve appr oach, wi th management deci si ons based on better
pr eoperati ve eval uati on.

Table 7.3. Overall incidence of mediastinal


tumors
Thymic

19 (3)a

Neurogenic

23 (39)a

Lymphoma

12

Germ cell

12

Cysts

18

Mesenchymal

Miscellaneous

a Numbers

in parentheses represent incidence


in children.

Pathology
A r ecent study combi ni ng ni ne pr evi ous ser i es was per for med to
better appr oxi mate the tr ue i nci dence of medi asti nal l esi ons (Tabl e
7.3). In adul ts, neur ogeni c and thymi c tumor s contr i bute 23% and
19% , r especti vel y, to the overal l i nci dence, wher eas i n chi l dr en
they contr i bute 39% and 3% , r especti vel y. Thi s secti on does not
attempt to descr i be the myr i ad cysti c and other rar e mi scel l aneous
l esi ons but i nstead concentrates on the mor e common di agnoses.
Neur ogenic tumor s i ncl ude schwannoma, neur ofi br oma,
gangl i oneur obl astoma, neur obl astoma, pheochr omocytoma, and
paragangl i oma. They ar e the most common tumor s ar i si ng i n the
poster i or compar tment.
Thymoma ar i ses fr om thymi c epi thel i um, al though i ts mi cr oscopi c
appearance i s a mi xtur e of l ymphocytes and epi thel i al cel l s.
Thymomas ar e cl assi fi ed as l ymphocyti c (30% of cases), epi thel i al
(16% ), mi xed (30% ), and spi ndl e cel l (24% ). Hi stol ogi c evi dence of
mal i gnancy i s di ffi cul t to obtai n because beni gn and mal i gnant
l esi ons can have si mi l ar hi stol ogi c and cytol ogi c featur es. Sur gi cal
evi dence of i nvasi on at the ti me of r esecti on i s the most r el i abl e
method of di ffer enti ati ng between mal i gnant and beni gn thymomas.
Lymphomas compr i se appr oxi matel y 50% of chi l dhood and 20% of
adul t anter i or medi asti nal mal i gnanci es. They ar e tr eated
nonsur gi cal l y but may r equi r e sur ger y to secur e a di agnosi s.
G er m cell tumor s ar e compr i sed of teratomas, semi nomas, and
nonsemi nomatous ger m cel l tumor s. Teratomas ar e the most
common and ar e mostl y beni gn. Mal i gnant teratomas ar e ver y rar e
and often wi del y metastati c at the ti me of di agnosi s. Semi nomas

pr ogr ess i n a l ocal l y aggr essi ve fashi on. Nonsemi nomatous


mal i gnant tumor s i ncl ude embr yonal car ci noma and
chor i ocar ci noma, both of whi ch car r y a poor pr ognosi s, and the
mor e favorabl e endoder mal si nus tumor.
Miscellaneous cysts and mesenchymal tumor s i ncl ude thyr oi d
goi ter s, thyr oi d mal i gnanci es, medi asti nal parathyr oi d
adenomas, br onchogeni c cysts, per i car di al cysts, dupl i cati ons,
di ver ti cul a, and aneur ysms.

Diagnosis
Medi asti nal l esi ons ar e most commonl y asymptomati c. When
symptoms do occur, they r esul t fr om compr essi on of adjacent
str uctur es or systemi c endocr i ne or autoi mmune effects of the
tumor s. Chi l dr en, wi th thei r smal l er chest cavi ti es, tend to have
symptoms at pr esentati on (two-thi r ds of chi l dr en vs. onl y one-thi r d
of adul ts) and mor e commonl y have mal i gnant l esi ons (gr eater than
50% ). Symptoms can i ncl ude cough, str i dor, and dyspnea (mor e
common i n chi l dr en), as wel l as symptoms of l ocal i nvasi on such as
chest pai n, pl eural effusi on, hoar seness, Homer syndr ome, upperextr emi ty and back pai n, parapl egi a, and di aphragmati c paral ysi s.
Chest radi ography r emai ns a mai nstay of di agnosi s. F i fty per cent of
l esi ons ar e di agnosed by CXR. The posi ti on of the tumor wi thi n the
medi asti num on l ateral pr ojecti on can hel p tai l or the di ffer enti al
di agnosi s (F i g. 7-5, Tabl e 7.4). The standar d for fur ther assessment
of the l esi on i s CT, speci fi cal l y wi th contrast enhancement. Cer tai n
tumor s and beni gn condi ti ons can be
di agnosed or str ongl y suggested by thei r appearance on CT scans.
Angi ography or MRI may be r equi r ed i f a major r esecti ve pr ocedur e
i s pl anned and vascul ar i nvol vement suspected. Nucl ear i magi ng
such as thyr oi d and parathyr oi d scanni ng, gal l i um scanni ng for
l ymphoma, and metai odobenz yl guani di ne scanni ng for
pheochr omocytomas may al so be i ndi cated.

F i gur e 7.5. Anatomi cal boundar i es of medi asti nal masses


accor di ng to one commonl y used cl assi fi cati on.

Table 7.4. Usual location of common primary


and cysts of mediastinum
Anterior
Compartment

Visceral
Compartment

Paravertebr

Thymoma

Enterogenous cyst

Neurilemoma
(schwannoma

Germ cell
tumors

Lymphoma

Neurofibroma

Lymphoma

Pleuropericardial
cyst

Malignant
schwannoma

Lymphangioma

Mediastinal
granuloma

Ganglioneuro

Hemangioma

Lymphoid
hamartoma

Ganglioneuro

Lipoma

Mesothelial cyst

Neuroblastom

Fibroma

Neuroenteric cyst

Paragangliom

Fibrosarcoma

Paraganglioma

Pheochromoc

Thymic cyst

Pheochromocytoma

Fibrosarcoma

Parathyroid
adenoma

Thoracic duct cyst

Lymphoma

Aberrant thyroid
The use of ser um mar ker s can be of some assi stance i n the
di agnosi s of some ger m cel l and neur oendocr i ne tumor s. In addi ti on,
the associ ati on of myastheni a gravi s wi th thymoma can al so assi st
i n the di agnosi s.
Because many medi asti nal tumor s ar e tr eated wi thout sur ger y, a
deter mi ned effor t shoul d be made to achi eve a ti ssue di agnosi s
noni nvasi vel y. F NA, wi th i ts r easonabl e sensi ti vi ty, i s an excel l ent
star ti ng poi nt, but the di agnosi s of l ymphoma can be di ffi cul t
because onl y a l i mi ted number of cel l s ar e r etr i eved. Br onchoscopy
and esophagoscopy can al so be useful i f symptoms or i magi ng
studi es suggest tumor i nvol vement.
If these pr ocedur es cannot faci l i tate a di agnosi s, then a

medi asti noscopy to access paratracheal l esi ons can be per for med.
Al though the r i sk of vascul ar or tracheobr onchi al i njur y i s pr esent,
the i nci dence of compl i cati ons i s ver y l ow i n exper i enced hands. If
mor e i nvasi ve pr ocedur es ar e r equi r ed to make the di agnosi s, an
anter i or or paraster nal medi asti notomy (Chamber l ai n pr ocedur e) or
thoracoscopy can be per for med. Rar el y, a ster notomy or
thoracotomy wi l l be r equi r ed to obtai n a ti ssue di agnosi s.

Staging
Stagi ng i s deter mi ned by the speci fi c hi stol ogi c character i sti cs and
i ts extent at the ti me of di agnosi s.

Treatment
Therapy, l i ke stagi ng, i s deter mi ned by the type of tumor and i ts
hi stol ogi c character i sti cs (Tabl e 7.5). The pr i mar y deter mi nati on to
be made i s whether the l esi on wi l l r equi r e r esecti on as par t of i ts
tr eatment or whether chemotherapy or radi ati on therapy i s
suffi ci ent. Thymomas shoul d al l be r esected, wi th the possi bi l i ty of
postoperati ve radi ati on therapy. Beni gn neur ogeni c tumor s ar e
someti mes obser ved i n ol der debi l i tated pati ents; however, i f the
pati ent i s other wi se heal thy or i f mal i gnant potenti al i s suspected,
then r esecti on shoul d be pur sued. G er m cel l tumor s shoul d be
tr eated on the basi s of thei r hi stol ogi c character i sti cs. In par ti cul ar,
beni gn teratomas shoul d be r esected, semi nomas shoul d be tr eated
wi th radi ati on therapy, and nonsemi nomatous tumor s shoul d be
tr eated i ni ti al l y wi th chemotherapy. In the subset of
nonsemi nomatous tumor s that have a r esi dual mass but negati ve
mar ker s, sur gi cal r esecti on shoul d be per for med to r ul e out r esi dual
tumor. Lymphomas shoul d not be r esected and shoul d be tr eated
wi th radi ati on therapy or chemotherapy on the basi s of thei r stage
and hi stol ogi c appearance (i .e., Hodgki n vs. non-Hodgki n).

Table 7.5. Frequency and treatment of


malignant chest wall tumors

Cell Type

Estimated
Frequency

Standard
Therapy

(%)
Chondrosarcoma

35

Surgical
resection

Plasmacytoma

25

Radiation +
chemotherapy

Ewing sarcoma

15

Surgery +
chemotherapy

Osteosarcoma

15

Surgery +
chemotherapy

Lymphoma

10

Chemotherapy
radiation

Surveillance
The fr equency and i ntensi ty of fol l ow-up after r esecti on ar e
deter mi ned by the pr i mar y tumor. CXR r emai ns the mai nstay of
sur vei l l ance, wi th CT scanni ng r eser ved for eval uati on subsequent
to abnor mal CXR fi ndi ngs.

Neoplasms of the Chest Wall


Pr i mar y chest wal l mal i gnanci es account for l ess than 1% of al l
tumor s, and i ncl ude a wi de var i ety of bone and soft-ti ssue l esi ons.
The absence of l ar ge ser i es makes the pr ospecti ve eval uati on of
tr eatment opti ons di ffi cul t. As mor e pati ents wi th these tumor s ar e
tr eated at l ar ge r efer ral i nsti tuti ons, the i ni ti ati on of mul ti i nsti tuti onal tr i al s wi l l hel p settl e some of the mor e contr over si al
aspects of therapy.

Pathology
Pr i mar y chest wal l tumor s i ncl ude chondr osar coma (20% ), Ewi ng

sar coma (8% 22% ), osteosar coma (10% ), pl asmacytoma


(10% 30% ), and, i nfr equentl y, soft-ti ssue sar coma.
Chondr osar comas ar i se fr om the r i bs i n 80% of cases and fr om the
ster num i n the r emai ni ng 20% . They ar e r el ated to pr i or chest wal l
trauma i n 12.5% of cases and ar e ver y r esi stant to radi ati on and
chemotherapeuti c agents. Ewi ng sar coma i s par t of a spectr um of
di sease havi ng pr i mi ti ve neur oectoder mal tumor s at one end and
Ewi ng sar coma at the other. Mul ti modal i ty therapy, i ncl udi ng both
radi ati on therapy and chemotherapy, has been shown to be
benefi ci al for thi s tumor. Osteosar comas ar e best tr eated wi th
neoadjuvant therapy, wi th pr ognosi s bei ng pr edi cted by the tumor 's
r esponse to chemotherapy. Pl asmacytoma confi ned to the chest
must be confi r med by eval uati ng the r emai ni ng skel etal system.
Sur ger y can then be used to confi r m the di agnosi s. If radi ati on
therapy i s unabl e to achi eve l ocal contr ol , then r esecti on may be
i ndi cated. Soft-ti ssue sar comas ar e rar e and ar e pr i mar i l y r esected.
Adjuvant therapy i s based on tumor hi stol ogi c fi ndi ngs.

Diagnosis
Chest wal l tumor s ar e asymptomati c i n 20% of pati ents, wher eas
the r emai ni ng 80% have an enl ar gi ng mass. F i fty per cent to 60% of
these pati ents wi l l have associ ated pai n. Radi ographi c assessment
usual l y i ncl udes CXR and CT; however, MRI i s bei ng used i nstead
wi th i ncr easi ng fr equency because of i ts abi l i ty to i mage i n mul ti pl e
pl anes wi th super i or anatomi cal di sti ncti on, whi ch can better r eveal
the extent of di sease than CT or pl ai n radi ography. Pathol ogi cal
di agnosi s i s made wi th F NA (64% accuracy) or cor e cutti ng bi opsy
(96% accuracy). Inci si onal bi opsi es shoul d be avoi ded i f possi bl e
because they may i nter fer e wi th subsequent sur gi cal tr eatment and
r econstr ucti on.

Staging
Chest wal l l esi ons ar e staged accor di ng to the pr i mar y tumor
i denti fi ed. Most pr ogr ess to pul monar y or hepati c metastases
wi thout l ymphati c i nvol vement.

Treatment
As outl i ned pr evi ousl y, the tr eatment of chest wal l l esi ons i s
deter mi ned by the di agnosi s. Most, wi th few excepti ons, r equi r e
r esecti on as par t of the tr eatment. Poster i or l esi ons r eachi ng deep

to the scapul a or that r equi r e r esecti on of l ess than two r i bs do not


r equi r e r econstr ucti on of the chest wal l . However, al l other l esi ons
r equi r e some for m of stabl e r econstr ucti ve techni que. A si mpl e
mesh cl osur e usi ng Mar l ex or Pr ol i ne mesh i s acceptabl e as l ong as
the mater i al i s secur ed i n posi ti on under tensi on. Some sur geons
bel i eve ther e i s a l oss of tensi l e str ength over ti me. A mor e r i gi d
pr osthesi s i s methyl methacr yl ate sandwi ched between two l ayer s of
Mar l ex mesh. Long-ter m ser oma for mati on pl agues al l types of
r epai r, par ti cul ar l y thi s l atter r epai r techni que.
If the chest wal l l esi on i nvol ves the over l yi ng muscl e or the ski n, a
l ar ge defect may be pr esent after r esecti on. Thi s may r equi r e a
muscl e fl ap for fi nal r econstr ucti on, especi al l y i f postoperati ve
radi ati on therapy i s consi der ed. Al though descr i pti on of the
techni ques avai l abl e i s beyond the scope of thi s manual , a
combi nati on of muscl e fl ap wi th pr i mar y ski n cl osur e, muscl e
fl ap wi th ski n grafti ng, or myocutaneous fl ap coverage can be used.

Surveillance
Once tr eated and i n r emi ssi on, chest wal l tumor s tend to r ecur
l ocal l y or wi th pul monar y or hepati c metastases. Regul ar fol l ow-up
wi th car eful exami nati on and CT scanni ng shoul d suffi ce to detect
al l si gni fi cant si tes of r ecur r ence.

Neoplasms of the Pleura


Ther e ar e two mai n types of pl eural neopl asms. The fi r st, mal i gnant
pl eural mesothel i oma, r emai ns an uncommon and hi ghl y l ethal
tumor wi th no adequate method of tr eatment. It behaves pr i mar i l y
as a l ocal l y aggr essi ve tumor wi th l ocal l y i nvasi ve fai l ur e after
therapy and onl y metastasi zes l ate i n i ts cour se. Its r el ati onshi p
wi th asbestos exposur e was suggested i n the 1940s and 1950s, and
cl ear l y establ i shed i n 1960. The second, a mor e l ocal i zed pl eural
tumor known as l ocal i zed fi br ous tumor of the pl eura, can al so
occur ; when mal i gnant, i t i s fr equentl y cl assi fi ed as a l ocal i zed
mesothel i oma.

Pathology
Local i zed mesothel i omas and mal i gnant l ocal i zed fi br ous tumor s of
the pl eura ar e ver y rar e. Ther e i s some contr over sy as to whether
these l esi ons ar e even mesothel i al at al l because no epi thel i al
component may be i denti fi abl e. Mor e commonl y, a beni gn l ocal i zed

fi br ous tumor of the pl eura i s found. However, di ffuse pl eural


mesothel i oma i s al ways a mal i gnant pr ocess. Ther e i s a 20-year
l atency for devel opment of thi s di sease after exposur e to asbestos.
A r ecent sur ge i n the i nci dence of thi s di sease r efl ects the
wi despr ead use of asbestos i n the 1940s and 1950s, and thi s sur ge
shoul d conti nue because mechani sms for l i mi ti ng occupati onal
asbestos exposur e wer e not i nsti tuted unti l the 1970s.
Mesothel i oma commonl y pr esents as an epi thel i al hi stol ogy and l ess
commonl y as a sar comatoi d or mi xed hi stol ogy. It can be har d to
di ffer enti ate thi s l esi on fr om metastati c adenocar ci noma.
Immunohi stochemi str y and el ectr on mi cr oscopy, however, have
ai ded i n establ i shi ng the di agnosi s.

Diagnosis
The pr esentati on of mesothel i oma i s often vague and nonspeci fi c,
wi th dyspnea and pai n common i n 90% of pati ents. Radi ographi c
di agnosi s i n the ear l y stage i s often di ffi cul t, wi th the fi ndi ngs
l i mi ted to a pl eural effusi on i n many cases. Even CT may fai l to
i denti fy any other abnor mal i ti es at thi s stage. The cl assi c fi ndi ng of
a thi ck, r estr i cti ve pl eural r i nd i s a l ate fi ndi ng. Thoracentesi s i s
di agnosti c i n 50% of pati ents, and pl eural bi opsy i s posi ti ve i n 33% .
If the di agnosi s r emai ns el usi ve, thoracoscopy i s di agnosti c i n 80%
of pati ents.

Staging
A stagi ng system for mesothel i oma has been pr oposed by Rusch and
the Inter nati onal Mesothel i oma Inter est G r oup (IMIG ) and i s shown
i n Tabl e 7.6.

Table 7.6. Staging of mesothelioma


T
TIa tumor limited to the ipsilateral
parietal, including mediastinal and

T1

diaphragmatic pleura
No involvement of the visceral pleura
Tib tumor involving the ipsilateral
parietal, including mediastinal and
diaphragmatic pleura
Scattered foci of tumor also involving
the visceral pleura
Tumor involving each of the ipsilateral
pleural surfaces (parietal, mediastinal,
diaphragmatic, and visceral pleura),
with at least one of the following
features:

T2

Involvement of diaphragmatic muscle


Confluent visceral pleural tumor
(including the fissures), or extension
of tumor from visceral pleura into
the underlying pulmonary
parenchyma
Describes locally advanced but
potentially resectable tumor
Tumor involving all ipsilateral pleural
surfaces (parietal, mediastinal,
diaphragmatic, and visceral pleura),
with at least one of the following
features:

T3

Involvement of the endothoracic


fascia
Extension into the mediastinal fat

Solitary, completely resectable focus


of tumor extending into the soft
tissues of the chest wall
Nontransmural involvement of the
pericardium

Describes locally advanced technically


unresectable tumor
Tumor involving all ipsilateral pleural
surfaces (parietal, mediastinal,
diaphragmatic, and visceral), with at
least one of the following features:

T4

Diffuse extension or multifocal


masses of tumor in the chest wall,
with or without associated rib
destruction
Direct transdiaphragmatic extension
of tumor to the peritoneum
Direct extension of tumor to the
contralateral pleura
Direct extension of tumor to one or
more mediastinal organs
Direct extension of tumor into the
spine
Tumor extending through to the
internal surface of the pericardium
with or without a pericardial
effusion, or tumor involving the
myocardium

Lymph nodes

NX

Regional lymph nodes cannot be


assessed

N0

No regional lymph node metastases

N1

Metastases in the ipsilateral


bronchopulmonary or hilar lymph nodes

N2

Metastases in the subcarinal or the


ipsilateral mediastinal lymph nodes,
including the ipsilateral internal
mammary nodes

N3

Metastases in the contralateral


mediastinal, contralateral internal
mammary, ipsilateral, or contralateral
supraclavicular lymph nodes

Metastases

MX

Presence of distant metastases cannot


be assessed

M0

No distant metastasis

M1

Distant metastasis present

Stage

Stage
I

I a T Ia N 0 M 0
I b T Ib N 0 M 0

Stage
II

T 2 N0 M 0

Stage
III

Any T3 M 0
Any N1 M 0
Any N2 M 0

Stage
IV

Any T4
Any N3
Any M1

Treatment
The tr eatment of mesothel i oma i s sti l l evol vi ng. Attempts at radi cal
r esecti ons, such as extrapl eural pneumonectomy, have l ed to some
i mpr ovements i n l ocal contr ol , but onl y l i mi ted i mpact on sur vi val at
the cost of a si gni fi cantl y i ncr eased operati ve r i sk. The addi ti on of
adjuvant radi otherapy can i ncr ease l ocal contr ol and the r emoval of
the enti r e l ung can faci l i tate i ts del i ver y. Unfor tunatel y, better l ocal
contr ol has l ed to an i ncr ease i n the number of pati ents who
succumb to systemi c di sease. The effecti veness of chemotherapy i s
l i mi ted, al though new agents may be on the hor i zon (i .e.,
Pemextr ed). By themsel ves, chemotherapy and radi ati on therapy
have had onl y l i mi ted effects, wi th l ess i mpact on pal l i ati on.

Surveillance
Mesothel i omas tend to r ecur l ocal l y. CT scans ar e r equi r ed to detect
r ecur r ences or fol l ow r esi dual di sease. Unfor tunatel y, tr eatment
opti ons ar e l i mi ted, but they do i ncl ude radi ati on therapy and
chemotherapy.

Recommended Reading

PET Scanning
Detter beck F C, Vansteenki ste JF, Mor r i s DE, Dooms CA, Khandani
AH, Soci nski MA. Seeki ng a home for a PET, par t 3: emer gi ng
appl i cati ons of posi tr on emi ssi on tomography i magi ng i n the
management of pati ents wi th l ung cancer. Chest
2004;126(5):16561666.

Erasmus JJ, Connol l y JE, McAdams HP, Roggl i VL. Sol i tar y
pul monar y nodul es: par t I. Mor phol ogi c eval uati on for
di ffer enti ati on of beni gn and mal i gnant l esi ons. Radiogr aphics
2000;20(1):4358.
Erasmus JJ, McAdams HP, Connol l y JE. Sol i tar y pul monar y
nodul es: par t II. Eval uati on of the i ndeter mi nate nodul e.
Radiogr aphics 2000;20(1):5966.
G onz al ez-Stawi nski G V, Lemai r e A, Mer chant F, et al . A
comparati ve anal ysi s of posi tr on emi ssi on tomography and
medi asti noscopy i n stagi ng non-smal l cel l l ung cancer. J Thor ac
Car diovasc Sur g 2003;126(6):19001905.
Reed CE, Har pol e DH, Posther KE, et al . Amer i can Col l ege of
Sur geons Oncol ogy G r oup Z0050 tr i al . Resul ts of the Amer i can
Col l ege of Sur geons Oncol ogy G r oup Z0050 tr i al : the uti l i ty of
posi tr on emi ssi on tomography i n stagi ng potenti al l y operabl e
non-smal l cel l l ung cancer. J Thor ac Car diovasc Sur g
2003;126(6):19431951.

Adjuvant Chemotherapy for Early-stage Lung


Cancer
The Inter nati onal Adjuvant Lung Cancer Tr i al Col l aborati ve
G r oup. Ci spl ati n-based adjuvant chemotherapy i n pati ents wi th
compl etel y r esected NSCLC. N Engl J Med 2004;350:351360.
Strauss G M, Her ndon J, Maddaus MA, et al . Randomi zed cl i ni cal
tr i al of adjuvant chemotherapy wi th pacl i taxel and car bopl ati n
fol l owi ng r esecti on i n stage IB non-smal l cel l l ung cancer

(NSCLC): r epor t of Cancer and Leukemi a G r oup B (CALG B)


Pr otocol 9633 [abstract 7019]. Pr oc Am Clin Oncol 2004;23:17b.
Wi nton TL, Li vi ngston R, Johnson D, et al . A pr ospecti ve
randomi zed tr i al of adjuvant vi nor el bi ne (VIN) and ci spl ati n (CIS)
i n compl etel y r esected stage Ib and II non-smal l cel l l ung cancer
(NSCLC) Inter gr oup JBR. 10 [abstract 7018]. Pr oc Am Clin Oncol
2004;23.

Additional References
Ander son BO, Bur t ME. Chest wal l neopl asms and thei r
management. Ann Thor ac Sur g 1994;58:1774.
Dar tevel l e PG . Extended operati ons for the tr eatment of l ung
cancer. Ann Thor ac Sur g 1997;63:12.
G i nsber g RJ, Rubi nstei n LV. Randomi zed tr i al of l obectomy ver sus
l i mi ted r esecti on for T1 N0 nonsmal l cel l l ung cancer : l ung
cancer study gr oup. Ann Thor ac Sur g 1995;60:615.
Jemal A, Mur ray T, War d E, et al . Cancer stati sti cs, 2005. CA
Cancer J Clin 2005;55(1):1030.
Mountai n CF. Revi si ons i n the i nter nati onal system for stagi ng
l ung cancer. Chest 1997;111:1710.
Nesbi tt JC, Putnam JB, Wal sh G L, et al . Sur vi val i n ear l y-stage
nonsmal l cel l l ung cancer. Ann Thor ac Sur g 1995;60:466.
Pastor i no U, Buyse M, F r i edel G , et al . Long-ter m r esul ts of l ung
metastasectomy: pr ognosti c anal yses based on 5206 cases. J
Thor ac Car diovasc Sur g 1997;113:37.
Rusch VW. The i nter nati onal mesothel i oma i nter est gr oup: a
pr oposed new i nter nati onal TNM stagi ng system for mal i gnant
pl eural mesothel i oma. Chest 1995;108:11221128.
Roth JA, Fossel l a F, Komaki R, et al . A randomi zed tr i al compar i ng
per i operati ve chemotherapy and sur ger y wi th sur ger y al one i n

r esectabl e stage III nonsmal l cel l l ung cancer. J Natl Cancer Inst
1994;86:673.
Shi el ds TW. Pr i mar y medi asti nal tumor s and cysts and thei r
di agnosti c i nvesti gati on In: Shi el ds TW, ed. Mediastinal Sur ger y.
Phi l adel phi a, Pa: Lea & Febi ger ; 1991.
Sugar baker DJ, Jakl i tsch MT, Li ptay MJ. Mesothel i oma and radi cal
mul ti modal i ty therapy: who benefi ts? Chest 1995;107:3455.
Wal sh G L, Mor i ce RC, Putnam JB, et al . Resecti on of l ung cancer
i s justi fi ed i n hi gh-r i sk pati ents sel ected by exer ci se oxygen
consumpti on. Ann Thor ac Sur g 1994;58:704.
Wal sh G L, O'Connor M, Wi l l i s KM, et al . Is fol l ow-up of l ung
cancer pati ents after r esecti on medi cal l y i ndi cated and cost
effecti ve? Ann Thor ac Sur g 1995;60:1563.

Editors: Feig, Barry W .; Berger, David H.; Fuhrman, George


M.
Title: MD A nderson Surgical Oncology Handbook, The, 4th
Edition
Copyr i ght 2006 Li ppi ncott Wi l l i ams & Wi l ki ns
> Ta ble o f C o nt e nt s > 8 - Es o pha ge a l C a rc ino m a

8
Esophageal Carcinoma
A lexander A . Parikh
A ra A . Vaporciyan
W ayne L. Hofstetter
Cancer of the esophagus i s uncommon, bel i eved to r epr esent
appr oxi matel y 1.5% of newl y di agnosed i nvasi ve mal i gnanci es i n
the Uni ted States; i t i s the ni nth most common mal i gnancy
wor l dwi de. It i s hi ghl y vi r ul ent, however, and causes 2% of al l
cancer-r el ated deaths. Sur gi cal r esecti on i s the mai nstay of therapy,
al though most cases ar e di agnosed at a l ate stage. Si nce the mi d1970s, the overal l 5-year sur vi val rate has i mpr oved fr om 3% to
onl y 15% . Recent tr eatment strategi es have i ncl uded mul ti modal i ty
appr oaches that combi ne sur ger y, radi ati on therapy, and
chemotherapy. These appr oaches have r esul ted i n 5-year sur vi val
rates of 40% to 75% i n the subset of pati ents who have a compl ete
hi stol ogi c r esponse after pr eoperati ve therapy.

Epidemiology
Car ci noma of the esophagus accounts for appr oxi matel y 15,000 new
cases and 13,000 deaths i n the Uni ted States each year. In the
past, squamous cel l car ci nomas (SCC) accounted for mor e than 95%
of cases, but i n r ecent year s, adenocar ci noma ar i si ng i n the
backgr ound of Bar r ett esophagus has become i ncr easi ngl y common,
and i t now accounts for mor e than 50% of the esophageal cancer s
at many major center s. Esophageal car ci noma, par ti cul ar l y SCC, has
substanti al geographi c var i ati on, fr om 1.5 to 7 cases per 100,000
peopl e i n most par ts of the wor l d, i ncl udi ng the Uni ted States, to
100 to 500 per 100,000 peopl e i n i ts endemi c ar eas such as
nor ther n Chi na, South Afr i ca, Iran, Russi a, and Indi a. Mal es have a
two to thr ee ti mes hi gher r i sk than femal es, and a seven to ten

ti mes hi gher r i sk for the devel opment of adenocar ci noma.


F ur ther mor e, i n the Uni ted States, SCC i s appr oxi matel y fi ve ti mes
mor e common among Afr i can Amer i cans than i t i s among whi tes,
wher eas adenocar ci noma occur s appr oxi matel y thr ee to four ti mes
mor e often i n whi tes, par ti cul ar l y i n men. The typi cal pati ent wi th
esophageal adenocar ci noma i s a mi ddl e-cl ass, over wei ght mal e i n
hi s si xti es or seventi es. Both major hi stol ogi c types ar e rar e i n
pati ents younger than 40 year s, but the i nci dence i ncr eases
ther eafter.

Etiology and Risk Factors


Several di ffer ent envi r onmental and geneti c r i sk factor s have been
i denti fi ed as potenti al causes of esophageal cancer s, par ti cul ar l y
SCC. In geographi c ar eas wher e esophageal cancer i s endemi c, such
as i n Chi na, di ets ar e defi ci ent i n vi tami ns A, C, r i bofl avi n, and
pr otei n, and have excessi ve ni trates and ni tr osami nes. F ungal
contami nati on of foodstuffs and the associ ated afl atoxi n pr oducti on
may be another i mpor tant r i sk factor.
The combi nati on of smoki ng and al cohol consumpti on has a
syner gi sti c effect on the devel opment of esophageal SCC,
i ncr easi ng the r i sk by as much as 44 ti mes. Other causes and r i sk
factor s i ncl ude SCC of the head and neck (pr esumabl y because of
the r i sk associ ated wi th al cohol and smoki ng), achal asi a (as hi gh as
30 ti mes i ncr eased r i sk), str i ctur es r esul ti ng fr om i ngesti on of
causti c agents such as l ye, Zenker di ver ti cul ae, esophageal webs i n
Pl ummer-Vi nson syndr ome, pr i or radi ati on, and fami l i al connecti ve
ti ssue di seases such as tyl osi s (50% have cancer by age 45 year s).
For adenocar ci noma, the pr i mar y eti ol ogi c factor i s Bar r ett
esophagus, wi th an esti mated annual i nci dence of mal i gnant
transfor mati on of 0.5% to 1% , r epr esenti ng a 125 ti mes gr eater
r i sk than that i n the general popul ati on. Si mi l ar to col on cancer s,
esophageal adenocar ci nomas ar e known to pr ogr ess thr ough a
metapl asi adyspl asi acancer sequence. G astr oesophageal r efl ux
di sease r esul ts i n the over exposur e of the esophageal mucosa to
aci d and bi l e. Speci fi cal l y, the conjugated bi l e sal ts (secondar y bi l e
aci ds) ar e bel i eved to syner gi sti cal l y damage the mucosa, l eadi ng to
i ncr eased DNA methyl ati on (as wel l as other geneti c and mol ecul ar
changes) and the for mati on of speci al i zed i ntesti nal metapl asi a
(Bar r ett mucosa) or car di ac metapl asi a. Both ar e r ecogni zed as
pr ecur sor l esi ons to esophageal /gastr oesophageal juncti on cancer s.
Obesi ty, tobacco use, and the eradi cati on of Helicobacter pylor i ar e

al so l i nked to the i ncr eased i nci dence of esophageal adenocar ci noma


i n the Uni ted States.

Pathology
Esophageal cancer i s seen i n two mai n hi stol ogi c types: SCC and
adenocar ci noma. In the Uni ted States, appr oxi matel y 20% of cases
of SCC i nvol ve the upper thi r d of the esophagus, 50% i nvol ve the
mi ddl e thi r d, and the r emai ni ng 30% extend fr om the di stal par t of
the esophagus to the gastr oesophageal juncti on. SCC rar el y i nvades
the stomach, and ther e i s usual l y a di scr ete segment of nor mal
mucosa between the cancer and the gastr i c car di a. In contrast,
near l y 97% of adenocar ci nomas devel op i n the mi ddl e and di stal
esophagus, and many extend i nto the stomach i f they ar e l ocated
near the gastr oesophageal juncti on. Cancer s ar i si ng i n Bar r ett
esophagus ar e bel i eved to compr i se upwar d of 70% of al l
adenocar ci nomas i nvol vi ng the di stal esophagus and
gastr oesophageal juncti on. They can var y i n l ength and range i n
contour fr om fl at, i nfi l trati ve l esi ons to fungati ng pol ypoi d masses.
Ul cerati on i s often pr esent and may even be deep enough to cause
per forati on. The typi cal esophageal car ci noma i s a ci r cumfer enti al ,
exophyti c, fungati ng mass that i s near l y or compl etel y transmural .
Access to the submucosal l ymphati cs al l ows tumor s to spr ead fr eel y
al ong a submucosal pl ane and pr esent wi th ver y l ong tumor s or
mul ti pl e mucosal l esi ons. Si mi l ar l y, ear l y metastases to l ymph
nodes or di stant si tes ar e common. Mi cr oscopi cal l y,
adenocar ci nomas can r esembl e cel l s i n the gastr i c car di a or col on,
and most ar e wel l or moderatel y di ffer enti ated. Si gnet r i ng
di ffer enti ati on on hi stol ogy may si gni fy a gastr i c car di a or i gi n, but
thi s i s not an absol ute r ul e.
Other l ess common pr i mar y mal i gnant neopl asms of the esophagus
i ncl ude neur oendocr i ne tumor s, gastr oi ntesti nal str omal tumor s,
var i ants of SCC or adenocar ci nomas (e.g., adenosquamous),
mel anomas, sar comas, and l ymphomas.

Clinical Features
Cl i ni cal pr esentati on i s general l y i nsi di ous, and typi cal symptoms
occur l ate i n the cour se of the di sease, usual l y pr ecl udi ng ear l y
i nter venti on. Most pati ents exper i ence symptoms for 2 to 6 months
befor e they seek medi cal attenti on. The most common symptom i s
pr ogr essi ve dysphagi a, whi ch occur s i n as many as 80% to 90% of

pati ents. Thi s i s usual l y a l ate si gn because 50% to 75% of the


esophageal l umen must be r educed befor e pati ents exper i ence thi s
symptom. Typi cal l y, mal i gnant dysphagi a wi l l begi n when the
esophageal functi onal di ameter appr oaches 12 to 13 mm, about the
si ze of a nor mal adul t endoscope. Wei ght l oss i s al so common, wi th
an esti mated mean wei ght l oss of 10 kg fr om the onset of symptoms
and wei ght l oss of gr eater than 10% of nor mal body wei ght has
been associ ated wi th decr eased l ong-ter m sur vi val i n many
publ i cati ons. Other symptoms i ncl ude var yi ng degr ees of
odynophagi a (i n appr oxi matel y 50% ), as wel l as emesi s, cough,
r egur gi tati on, anemi a, hematemesi s, and aspi rati on pneumoni a.
Hoar seness i s usual l y due to i nvasi on of the r ecur r ent l ar yngeal
ner ve, and Hor ner syndr ome i ndi cates i nvasi on of the sympatheti c
tr unk. Hematemesi s and mel ena usual l y i ndi cate fr i abi l i ty of the
tumor or i ts i nvasi on i nto major vessel s. Er osi on i nto the aor ta
r esul ti ng i n exsangui nati ng hemor r hage has been r epor ted.
Bl eedi ng fr om the tumor mass can occur i n 4% to 7% of pati ents.

Diagnostic Evaluation
Resul ts of the physi cal exami nati on depend i n l ar ge par t on the
degr ee of wei ght l oss and cachexi a. Enl ar ged cer vi cal or
supracl avi cul ar l ymph nodes can be bi opsi ed wi th fi ne-needl e
aspi rati on (F NA), and bone pai n shoul d be eval uated wi th a bone
scan to excl ude di stant metastases. Al l neur ol ogi c symptoms (e.g.,
headaches, vi sual di stur bances) shoul d al so be assessed wi th
computed tomography (CT) or magneti c r esonance i magi ng (MRI) of
the brai n.
Pl ai n poster oanter i or and l ateral chest radi ographs pr ovi de
assessment of the status of the pul monar y par enchyma (i .e.,
metastasi s, coexi sti ng br onchogeni c car ci noma, and pneumoni a). A
doubl e-contrast bar i um esophagogram pr ovi des i nfor mati on about
the l ocati on, l ength, and anatomi cal confi gurati on of the l esi on, as
wel l as an eval uati on of the stomach for evi dence of di sease or
abnor mal i ti es that woul d pr ecl ude i ts use as a condui t. The
esophagogram i s al so useful i n showi ng the degr ee of l umi nal
compr omi se or str i ctur e and the pr esence of a tumor-r el ated
tracheoesophageal fi stul a. CT scans of the chest and abdomen
shoul d al so be obtai ned to r ul e out the pr esence of l ocal i nvasi on of
medi asti nal str uctur es, adenopathy, and di stant metastasi s.
Posi tr on emi ssi on tomography (PET) i s bei ng used wi th i ncr easi ng
fr equency i n the di agnosti c stagi ng al gor i thm. When combi ned wi th
CT, i t has been shown to al ter the tr eatment cour se i n

appr oxi matel y 15% of pati ents studi ed, whi ch i n i tsel f has r ender ed
i t cost effi ci ent. Thi s modal i ty i s hel pful i n deter mi ni ng the
si gni fi cance of r egi onal adenopathy or di stant l esi ons and may car r y
pr ognosti c i nfor mati on i n ter ms of the l evel of i ni ti al nucl eoti de
uptake and mi dter m r esponse to pr eoperati ve tr eatment.
Upper endoscopy i s cur r entl y the most wi del y used techni que for the
di agnosi s of esophageal cancer. F l exi bl e endoscopy al l ows magni fi ed
vi sual obser vati on and hi stol ogi c sampl i ng of the esophagus, as wel l
as obser vati on of the stomach, pyl or us, and duodenum i n sear ch of
coexi sti ng di sease. Bi opsy and br ush cytol ogy can pr oduce
di agnosti c accuracy of near l y 100% wi th adequate sampl i ng, and
endoscopi c di l ati on of ti ght str i ctur es can be per for med to al l ow
passage of the endoscope beyond the tumor. The addi ti on of
endoscopi c ul trasound (EUS) can be used to pr edi ct the TNM stage
of the l esi on wi th r el i abl e accuracy. EUS i s most accurate i n
pr edi cti ng the depth of i nvasi on of the pr i mar y l esi on, and thi s can
l ead to ver y good i nsi ght to the potenti al of sur r oundi ng or gan
i nvol vement or l ymph node i nvol vement. Thoraci c, paraesophageal ,
paragastr i c, por tohepati c, and cel i ac l ymph nodes ar e r outi nel y
i denti fi ed and can be bi opsi ed vi a aspi rati on (F NA) for di agnosi s.
Tumor s that i nvol ve the upper or mi ddl e thi r d of the esophagus
shoul d be eval uated by fl exi bl e and/or r i gi d br onchoscopy to r ul e
out tracheobr onchi al i nvol vement.

Staging
The stagi ng system of the Amer i can Joi nt Commi ttee on Cancer uses
the TNM cl assi fi cati on and i s the most commonl y used system i n the
Uni ted States (Tabl e 8.1). Al though CT scanni ng i s pr obabl y the
most wi del y used noni nvasi ve stagi ng modal i ty, i ts accuracy i s qui te
l i mi ted. Overal l accuracy i n deter mi ni ng r esectabi l i ty and T stage
have been esti mated at 60% to 70% , wher eas accuracy i n
deter mi ni ng N stage i s general l y l ess than 60% . Accuracy i n
detecti on of metastati c di sease i s somewhat better, esti mated at
70% to 90% for l esi ons l ar ger than 1 cm. The use of combi ned
i magi ng wi th PET-CT has i mpr oved the accuracy of both tests. The
abi l i ty to combi ne anatomi cal i r r egul ar i ty to ar eas of abnor mal
F l our o-Deoxy G l ucose (F DG ) uptake on a super i mposed i mage
i ncr eases the pr edi cti ve val ue of PET al one or CT al one. Recent
studi es wi th thi s techni que have r epor ted overal l accuracy l evel s of
near l y 60% and 90% i n the abi l i ty to detect both l ocor egi onal nodal
metastases and di stant di sease, r especti vel y.

EUS i s pr obabl y the most accurate means cur r entl y avai l abl e for T
and N stagi ng. Repor ted overal l accuracy for T stagi ng i s 76% to
90% ; overal l accuracy i n pr edi cti ng r esectabi l i ty i s appr oxi matel y
90% to 100% for adenocar ci noma, but decr eases to 75% to 80% for
SCC. Studi es compar i ng EUS and CT scanni ng general l y agr ee that
EUS i s super i or i n overal l T stagi ng and assessment of r egi onal
l ymph nodes (70% 86% accuracy). The pr eci se di ffer enti ati on
between beni gn and mal i gnant nodes occasi onal l y r emai ns
pr obl emati c, however, due to mi cr ometastases that ar e undetectabl e
by EUS and enl ar ged i nfl ammator y l ymph nodes that ar e i ncor r ectl y
cl assi fi ed as metastati c. F NA can be hel pful i n maki ng thi s
di agnosi s. Mi ni mal l y i nvasi ve techni ques such as thoracoscopy and
l apar oscopy ar e i ncr easi ngl y i mpor tant i n the stagi ng of esophageal
cancer. Thoracoscopy al l ows vi sual i z ati on of the enti r e thoraci c
esophagus and the per i esophageal nodes (N1), when per for med
thr ough the r i ght hemi thorax, or the aor topul monar y and
per i esophageal nodes and the l ower esophagus, when per for med
thr ough the l eft chest. Lymph nodes can be

sampl ed for hi stol ogi c eval uati on, the pl eura can be exami ned, and
adjacent or gan i nvasi on (T4) can be confi r med. The overal l accuracy
for detecti ng l ymph node i nvol vement has been r epor ted to be as
hi gh as 81% to 95% . Lapar oscopy and l apar oscopi c ul trasonography
(LUS) ar e useful i n eval uati ng the per i toneum, l i ver, gastr ohepati c
l i gament, gastr i c wal l , di aphragm, and the per i gastr i c and cel i ac
l ymph nodes. Bi opsi es and per i toneal washi ngs can be per for med to
confi r m N1 and M1 di sease. These modal i ti es ar e especi al l y useful
i n pati ents wi th gastr oesophageal juncti on or pr oxi mal gastr i c
tumor s. In addi ti on, a feedi ng jejunostomy can be pl aced for
nutr i ti onal suppor t befor e tr eatment begi ns. Studi es have suggested
that the overal l accuracy of l apar oscopy i n stagi ng and
deter mi nati on of r esectabi l i ty i n esophageal cancer i s as hi gh as
90% to 100% , and that i nvasi ve stagi ng pr ocedur es may pr event
unnecessar y sur gi cal r esecti on i n as many as 20% of pati ents.
Pr ospecti ve compar i sons wi th CT and EUS have suggested that
l apar oscopy and LUS have super i or overal l accuracy i n stagi ng,
par ti cul ar l y for l ymph nodes and metastati c di sease.
Medi asti noscopy can al so pr ove hel pful to assess r egi onal l ymph
nodes (N1) at the r i ght and l eft paratracheal l ymph node stati ons,
al ong the mai nstem br onchi , i n the aor topul monar y wi ndow, or i n
the subcar i nal ar ea.

Table 8.1. TNM staging for esophageal


cancer
Primary tumor (T)
Tx

Primary tumor cannot be assessed

T0

No evidence of primary tumor

Tis

Carcinoma in situ

T1

Tumor invades lamina propria or


submucosa

T2

Tumor invades muscularis propria

T3

Tumor invades adventitia

T4

Tumor invades adjacent structures

Regional lymph nodes (N)


Nx

Regional nodes cannot be assessed

N0

No regional node metastasis

N1

Regional node metastasis

Distant metastasis (M)

Mx

Presence of distant metastasis cannot


be assessed

M0

No distant metastases
Distant metastasis
Tumors of the lower thoracic
esophagus
M1a
nodes
M1b

Metastasis in celiac lymph

Other distant metastasis

Tumors of the midthoracic esophagus


M1
M1a

Not applicable

M1b Nonregional lymph nodes or


other distant metastasis
Tumors of the upper thoracic
esophagus
M1a

Metastasis in cervical nodes

M1b

Other distant metastasis

Stage grouping

Stage
0

Tis

N0

M0

T1

N0

M0

T2

N0

M0

T3

N0

M0

T1

N1

M0

T2

N1

M0

T3

N1

M0

T4

Any N

M0

Stage
IV

Any T

Any N

M1

Stage
IVA

Any T

Any N

M1a

Stage
IVB

Any T

Any N

M1b

Stage
I
Stage
IIA

Stage
IIB

Stage
III

Adapted from Fleming ID, Cooper JS, Henson


DE, et al., eds. AJCC Manual for Staging of
Cancer. 5th ed. Philadelphia, Pa: LippincottRaven; 1997, with permission.

Treatment
Pati ents shoul d be appr oached wi th the i ntent of per for mi ng a
sur gi cal r esecti on as i t affor ds the best chance for l ong-ter m
sur vi val (F i g. 8-1). Because accurate cl i ni cal stagi ng i s so di ffi cul t,
al l pati ents who can physi ol ogi cal l y tol erate r esecti on and have no
cl i ni cal l y evi dent di stant metastases shoul d general l y under go
expl orati on. If di stant metastases or unr esectabl e advanced
l ocor egi onal di sease i s found at expl orati on, nonoperati ve pal l i ati on
shoul d be under taken because of the hi gh per i operati ve mor tal i ty
rate (appr oxi matel y 20% ) associ ated wi th pal l i ati ve sur gi cal bypass.
Di stal esophageal tumor s l ocated at the gastr oesophageal juncti on
can be managed by subtotal esophagectomy, esophagogastr ectomy,
or segmental esophagectomy wi th bowel i nter posi ti on. The extent of
gastr i c and esophageal i nvol vement, as wel l as the stage of the
pr i mar y tumor, shoul d gui de the sur geon to an appr opr i ate
appr oach. A subtotal esophagectomy thr ough a r i ght thoracotomy
and l apar otomy (Ivor Lewi s or Tanner-Lewi s esophagectomy) al l ows
for gener ous r esecti on of the stomach because the esophageal
r econstr ucti on takes pl ace i n the chest at the l evel of the az ygous
vei n. Local l y advanced tumor s wi th i nvol vement of the di stal
esophagus and pr oxi mal stomach l end themsel ves to thi s appr oach
because a l ymphadenectomy i s easi l y per for med i n two fi el ds and
negati ve mar gi ns can be obtai ned i n the stomach wi th l ess wor r y of
gastr i c necr osi s. However, tumor s wi th extensi ve i nvol vement of the
stomach and esophagus may r equi r e an esophagogastr ectomy, wi th
i nter posi ti on of smal l or l ar ge bowel for r econstr ucti on. Ear l y di stal
tumor s or shor t segment Bar r ett esophagus wi th hi gh-grade
dyspl asi a can be tr eated wi th segmental esophagectomy and smal l
bowel i nter posi ti on (Mer endi no pr ocedur e) or vagal -spar i ng
esophagectomy wi th gastr i c or bowel i nter posi ti on.

F i gur e 8.1. Al gor i thm for tr eatment of esophageal cancer.

Pr oxi mal l y l ocated (e.g., upper and mi desophageal ) tumor s often


r equi r e a total esophagectomy because i t i s di ffi cul t to achi eve
negati ve mar gi ns wi th segmental or subtotal r esecti ons (e.g., Ivor
Lewi s esophagectomy). G i ven the pr opensi ty for esophageal cancer s
to spr ead i n the submucosal l ymphati c system, i t i s r ecommended
that a mi ni mum of a 5-cm mar gi n, and pr eferabl y a 10-cm mar gi n,
shoul d be taken on the esophagus. Thi s i s a cr i ti cal deci si on-maki ng
factor when for mul ati ng a tr eatment al gor i thm for an i ndi vi dual
pati ent. The two most popul ar methods to achi eve a total or neartotal esophagectomy di ffer accor di ng to whether thoracotomy i s
used for esophageal mobi l i z ati on. The esophagus can be mobi l i zed
usi ng a r i ght thoracotomy wi th the condui t br ought ei ther thr ough
the poster i or medi asti num (pr efer r ed) or subster nal l y to the neck
for anastomosi s (McKowen appr oach). Al ter nati vel y, a transhi atal
esophagectomy can be per for med wi th mobi l i z ati on of the
i ntrathoraci c esophagus fr om the esophageal hi atus to the thoraci c
i nl et wi thout the need for thoracotomy. The advantage of the
transhi atal techni que i s that i t avoi ds thoracotomy whi l e achi evi ng a
compl ete r emoval of the esophagus. The potenti al di sadvantages of
thi s techni que i ncl ude a l i mi ted per i esophageal and medi asti nal
l ymphadenectomy, the r i sk of causi ng tracheobr onchi al or vascul ar
i njur y dur i ng bl unt di ssecti on of the esophagus, and potenti al l y
hi gher l ocor egi onal r ecur r ence rates. In addi ti on, the use of a

cer vi cal anastomosi s i s associ ated wi th a hi gher rate of anastomoti c


l eakage than an
i ntrathoraci c anastomosi s (12% vs. 5% , r especti vel y), al though the
mor bi di ty i s much l ess wi th a cer vi cal l eak than i t i s wi th a thoraci c
l eak. Other potenti al downsi des to a cer vi cal anastomosi s i ncl ude
phar yngeal r efl ux, noctur nal aspi rati on, pr ol onged swal l owi ng
dysfuncti on after sur ger y, and an i ncr eased i nci dence of r ecur r ent
l ar yngeal ner ve pal sy. Intrathoraci c anastomoses ar e hamper ed by
r efl ux and a str i ki ng i nci dence of r ecur r ent esophageal metapl asi a,
whi ch has been r epor ted to occur i n 80% of l ong-ter m sur vi vor s.
Pati ents that pr esent wi th cer vi cal esophageal car ci nomas have
several tr eatment opti ons. Advances i n chemoradi otherapy have
r el egated r esecti on of most l ocal i zed cer vi cal l esi ons to sal vage
pr ocedur es. Pati ents that have per si stent l ocor egi onal , l i mi ted
di sease after defi ni ti ve medi cal therapy ar e candi dates for
segmental r esecti ons wi th i mmedi ate or del ayed r econstr ucti on.
Smal l bowel , neck, or muscul ocutaneous fr ee fl aps ar e wel l sui ted to
esophageal r econstr ucti ons i n the cer vi cal ar ea, wi th or wi thout
phar yngol ar yngectomy. An al ter nati ve opti on for pati ents wi th
ear l y-stage di sease i s i mmedi ate r esecti on and r econstr ucti on. At
the other end of the spectr um, l engthy l esi ons wi th i nvol vement
i nto the thoraci c esophagus may r equi r e a compl ete esophagectomy
vi a a thr ee-fi el d appr oach.
Al though i t i s general l y agr eed that sur gi cal r esecti on i s the
pr i mar y for m of therapy for l ocal and l ocor egi onal di sease, gr eat
contr over sy r emai ns over the extent of the r esecti on necessar y and
over the val ue and extent of l ymphadenectomy. Ther e i s one gr oup
of thought that l ymph node metastases ar e mar ker s for systemi c
di sease and that r emoval of i nvol ved nodes i n most cases offer s no
sur vi val benefi t. However, many wel l -r espected and exper i enced
sur geons bel i eve that some pati ents wi th affected l ymph nodes can
be successful l y cur ed wi th an aggr essi ve sur gi cal appr oach that
focuses on wi de per i tumoral exci si on and extended
l ymphadenectomy usi ng a transthoraci c/thoracoabdomi nal and
cer vi cal appr oach (en bl oc esophagectomy). Ther e i s cur r entl y no
defi ni ti ve evi dence to suppor t ei ther phi l osophy; however, many
r epor ts that have focused on speci fi c subsets of pati ents i n stages
IIb to III have shown that pati ents who have under gone compl ete
l ymphadenectomy and have l ess than 10% of thei r r esected nodes
i nvol ved wi th metastati c di sease can sti l l l ook for war d to pr ol onged
sur vi val and excel l ent l ocor egi onal contr ol . The downsi de to thi s

appr oach i s that we ar e cur r entl y unabl e to pr edi ct whi ch pati ents
wi th l ocal l y advanced di sease woul d benefi t fr om i mmedi ate
r esecti on and extensi ve l ymphadenectomy ver sus neoadjuvant
chemoradi otherapy fol l owed by r esecti on. Pr oponents of radi cal
r esecti on have r epor ted i ncr eased sur vi val rates wi th mor e
extensi ve sur gi cal pr ocedur es and excel l ent l ocor egi onal contr ol ,
but most of these compar i sons have been r etr ospecti ve.
F ur ther mor e, i t i s uncl ear whether mor e extensi ve di ssecti on
actual l y l eads to i mpr oved sur vi val or whether these super i or
r esul ts ar e a functi on of mor e accurate stagi ng (stage mi grati on
effect). Recent pr ospecti ve randomi zed studi es i n the Uni ted States
and Wester n Eur ope have fai l ed to show any si gni fi cant di ffer ence i n
mor bi di ty, mor tal i ty, or r ecur r ence rates, or i n the overal l sur vi val
rate when compar i ng transhi atal esophagectomy wi th transthoraci c
or total thoraci c esophagectomy or when compar i ng the number of
l ymph
nodes r esected. Ei ther techni que i s acceptabl e, and i t i s unl i kel y
that a pr ospecti ve randomi zed tr i al wi l l ever be per for med that
coul d concl usi vel y pr ove an advantage i n overal l sur vi val rate wi th
a par ti cul ar type of sur ger y. The choi ce among sur gi cal r esecti on
techni ques shoul d be l eft to the pr efer ence of the sur geon and
i ndi vi dual i zed to the par ti cul ar character i sti cs of the pati ent. The
sal i ent poi nts that emer ge fr om hi stor i cal compar i sons of these
pr ocedur es i s that a transhi atal r esecti on has a tendency towar d
hi gher l ocor egi onal r ecur r ence, but a l ower i nci dence of ICU car e,
and does not r equi r e thoracotomy to compl ete.
Mi ni mal l y i nvasi ve esophagectomy i s gai ni ng popul ar i ty i n some
hi gh-vol ume center s. Pati ents wi th appr opr i ate l esi ons have the
opti on of under goi ng esophageal r esecti on wi th combi ned
thoracoscopi c and l apar oscopi c r esecti on fol l owed by a smal l neck
i nci si on wi th an esophagogastr i c anastomosi s per for med i n the neck.
Compl ete l apar oscopi c (transhi atal ) r esecti ons can al so be
accompl i shed, but agai n, thi s appr oach makes extensi ve en bl oc
r esecti on of medi asti nal l ymph nodes di ffi cul t. Ear l y r esul ts on
several hundr ed pati ents r esected i n thi s manner show no di ffer ence
i n sur vi val , and a for mal phase I/II tr i al i s cur r entl y under way.
Di sadvantages of thi s modal i ty i ncl ude a fai r l y steep l ear ni ng cur ve,
especi al l y for sur geons wi th l i mi ted l apar oscopi c esophageal
exper i ence, and pr ol onged anestheti c ti mes (al though ver y
exper i enced sur geons can effecti vel y r esect the esophagus i n a
si mi l ar amount of ti me as open pr ocedur es).

Reconstruction After Resection


The stomach, col on, and jejunum have al l been successful l y used as
r epl acement condui ts after esophagectomy. The stomach i s used far
mor e fr equentl y because of the ease of mobi l i z ati on, a hear ty and
r edundant bl ood suppl y, l i mi ted per i operati ve mor bi di ty, and the
need to per for m onl y one anastomosi s.
The col on i s a commonl y used al ter nati ve r epl acement condui t.
However, some sur geons pr efer thi s condui t over the stomach i n
younger pati ents who ar e expected to have a pr ol onged sur vi val
because i t pr ovi des a bar r i er between the stomach r emnant and the
r esi dual esophagus, and thi s may pr event si gni fi cant phar yngeal
r efl ux and futur e esophageal metapl asi a or dyspl asi a wi thi n the
esophageal r emnant. Ei ther the r i ght col on or the l eft col on can be
used, but the segment of l eft and transver se col on that i s suppl i ed
by the ascendi ng branch of the l eft col i c ar ter y, ar c of Ri ol an, and
the mar gi nal ar ter y i s general l y a better si ze match to the
esophagus and has mor e r el i abl e ar ter i al ar cades. The col oni c
ar ter i al anatomy shoul d be eval uated pr eoperati vel y by
ar ter i ography i n any pati ent who i s expected to have extensi ve
l i mi ti ng ather oscl er osi s or i s suspected to have had a pr evi ous
bowel r esecti on. Other wi se, i n pati ents wi th a na ve abdomen,
eval uati on of the vascul atur e can take pl ace i n the operati ng
theater. Another al ter nati ve i s CT or MR angi ography. Col onoscopy
i s necessar y to r ul e out pathol ogi cal condi ti ons, such as
tel angi ectasi a, pol yposi s, synchr onous neopl asm, or extensi ve
di ver ti cul osi s, that woul d pr ecl ude use of the col on.
Jejunal r econstr ucti on can be per for med for l esi ons anywher e i n the
esophagus. Segmental jejunal fr ee fl aps transfer r ed to the
neck have been used successful l y after r esecti on of hypophar yngeal
or upper cer vi cal esophageal tumor s. In thi s case, the mesenter i c
vessel s ar e usual l y anastomosed to the exter nal car oti d ar ter y and
the i nter nal jugul ar vei n. Pedi cl ed grafts ar e bei ng used when
segmental di stal esophageal r esecti on i s per for med for beni gn
l esi ons r equi r i ng r esecti on or confi r med (no evi dence of cancer i n
the speci men) shor t segment Bar r ett esophagus wi th hi gh-grade
dyspl asi a. Pedi cl ed jejunal fl aps wi th pr oxi mal mi cr ovascul ar
augmentati on wi l l al l ow for total esophageal r epl acement wi th the
smal l bowel .
F i nal l y, muscul ocutaneous fl aps ar e al so fr equentl y used for
segmental cer vi cal r econstr ucti on and can be har vested fr om any of

mul ti pl e ar eas wi th mi ni mal physi ol ogi cal or aestheti c effect.


Few pr ospecti ve studi es have been per for med to eval uate the use of
di ffer ent r epl acement condui ts, but evi dence fr om several
nonrandomi zed and smal l randomi zed tr i al s suppor ts that overal l
sur vi val i s unchanged r egar dl ess of the techni que used. Revi ew
per for med by Ur schel et al . was unabl e to r each defi ni ti ve r esul ts
that woul d cause one techni que to be favor ed over another. The
basi c pr i nci pl es ar e that the stomach has the most r el i abl e bl ood
suppl y, i s a hear ty condui t, and i s associ ated wi th the l owest
i mmedi ate postoperati ve mor bi di ty. Cer vi cal l eaks fr om a col on
i nter posi ti on tend to be wel l tol erated and str i ctur e rar el y occur s. If
str i ctur es do occur, they ar e mor e easi l y di l ated than those i n
esophagogastr i c anastomoses. G raft l oss can occur wi th any condui t
i n any posi ti on. Pyl or opl asty or pyl or omyotomy i s r equi r ed to avoi d
gastr i c stasi s secondar y to the di vi si on of the vagus ner ves dur i ng
esophagectomy. No di ffer ence has been seen i n the l eak rate or i n
the devel opment of str i ctur es between stapl ed and hand-sewn
anastomoses.

Results of Surgical Therapy


Mor tal i ty rates for transhi atal or transthoraci c esophagectomi es ar e
now l ess than 5% , and r eal i sti c mor bi di ty rates range fr om 35% to
65% . Overal l sur vi val rates after sur gi cal r esecti on cor r espond to
the stage of the di sease and var y fr om 5% to 50% . The 5-year
sur vi val rates have been r epor ted to be 60% to 90% for stage I,
30% to 60% for stage II, 5% to 30% for stage III, and 0% to 20%
for stage IV (F i g. 8-2). Unfor tunatel y, the vast major i ty (70% ) of
pati ents al r eady has stage III or IV di sease at di agnosi s.
When exami ni ng the patter n of fai l ur e after sur gi cal r esecti on, one
fi nds that most pati ents exper i ence ei ther di stant metastasi s or
both l ocor egi onal and di stant r ecur r ence, and a smal l per centage
exper i ence sol el y a r ecur r ence of l ocal i zed di sease. Novel tr eatment
modal i ti es focusi ng on the patter ns of fai l ur e need to be expl or ed to
i mpr ove on the r el ati vel y poor pr ognosi s affor ded by sur ger y al one
i n most pati ents wi th esophageal car ci noma.

Adjuvant Therapy
Resul ts of several randomi zed pr ospecti ve tr i al s on the use of
adjuvant radi ati on therapy (4556 G y) after r esecti on have been
publ i shed. Some studi es have shown the potenti al benefi t of
adjuvant radi otherapy i n speci fi c subsets of pati ents. Both those

under goi ng unpl anned yet noncurati ve (pal l i ati ve) esophagectomy
and those who ar e found to have stage III or hi gher di sease may
benefi t. Most woul d gi ve consi derati on for radi ati on therapy i n
pati ents wi th posi ti ve mar gi ns or R2 r esecti on as wel l , al though
ther e i s no sci enti fi c pr oof of benefi t. Tr eatment-r el ated toxi ci ty can
be sever e. Overal l , al though r educti ons i n l ocal r ecur r ences have
been noted and speci fi c subsets may benefi t, no si gni fi cant sur vi val
advantage has been found usi ng adjuvant radi otherapy for
esophageal car ci noma.

F i gur e 8.2. Sur vi val cur ves for pati ents wi th esophageal cancer.

Accor di ng to the r esul ts of pr ospecti ve randomi zed tr i al s,


postoperati ve combi nati on chemotherapy wi th var i ous agents,
i ncl udi ng 5-fl uor ouraci l (5-F U), ci spl ati n, mi tomyci n C, vi ndesi ne,
and pacl i taxel , al so has no pr oven r ol e i n the tr eatment of
compl etel y r esected l esi ons. F ur ther mor e, adjuvant chemotherapy i s
general l y poor l y tol erated, and many pati ents fai l to compl ete thei r
tr eatment r egi men. Thi s tr eatment modal i ty, ther efor e, i s not
r ecommended outsi de cl i ni cal tr i al setti ngs.
Adjuvant chemoradi otherapy may benefi t pati ents wi th esophageal
car ci noma. Thi s modal i ty has the advantage of better pati ent
sel ecti on because the pathol ogi cal stage wi l l gui de the deci si on to
pr oceed to therapy. Pati ents wi th a hi gh r i sk of r ecur r ence (stage
IIb and above) woul d be chosen to sel ecti vel y under go tr eatment.
Thi s may i ncr ease overal l sur vi val because the r esecti on rate

r emai ns hi gh (a fr equent cr i ti ci sm for neoadjuvant therapy i s that


overal l r esecti on rates dr op secondar y to tr eatment toxi ci ty), and
pati ents that ar e found to be ear l i er stage can avoi d the potenti al
toxi ci ty. In theor y, chemoradi otherapy may i ncr ease sur vi val by
decr easi ng both di stant and l ocal di sease. To date, ther e i s some
phase II evi dence that has shown pr omi si ng r esul ts, but compl i ance
wi th tr eatment has not been i deal and for mal pr ospecti ve,
randomi zed phase III tr i al s ar e needed befor e fi nal
r ecommendati ons can be made r egar di ng i ts effi cacy.

Neoadjuvant Therapy
Lar gel y because of the di ffi cul ty admi ni ster i ng adjuvant therapy to
postesophagectomy pati ents and the di sappoi nti ng r esul ts of tr i al s
wi th adjuvant chemotherapy or radi ati on monotherapy, r esear cher s
have tur ned thei r attenti on towar d the use of pr eoperati ve or
neoadjuvant therapy. Pr eoperati ve radi ati on therapy has been
i nvesti gated i n several pr ospecti ve randomi zed tr i al s, and the
r esul ts have been subjected to meta-anal ysi s. Despi te some i ni ti al
r esponse, the r esul ts of these tr i al s have shown mar gi nal overal l
benefi t i n ter ms of sur vi val rate. Pr eoperati ve radi ati on therapy
al one i s ther efor e not general l y r ecommended, even i n the face of
cl i ni cal tr i al s.
Al though r esul ts of phase II studi es of i nducti on chemotherapy had
been pr omi si ng, most of the subsequent pr ospecti ve randomi zed
tr i al s usi ng mul ti pl e di ffer ent agents and combi nati ons have fai l ed
to show any advantage i n r ecur r ence or sur vi val . Evi dence that
neoadjuvant chemotherapy was capabl e of si gni fi cant tumor
r esponse and even compl ete r esponses was r epor ted by mul ti pl e
author s. Compl ete r esponder s wer e al so found to have better
sur vi val rates than par ti al or nonr esponder s, and the R0 r esecti on
rate seemed to i mpr ove overal l . However, the net gai n i n sur vi val
was not si gni fi cantl y di ffer ent fr om contr ol s (sur ger y al one).
Conjectur e on the r easons for thi s ar e that nonr esponder s
fr equentl y far e wor se than contr ol s; the overal l r esecti on rate was
l ower i n pati ents under goi ng neoadjuvant therapy, ther eby
abol i shi ng any overal l benefi t; or ther e was a study desi gn fl aw,
possi bl y r epr esenti ng a -er r or. Unfor tunatel y, benefi ts seen i n
phase II tr i al s wer e mai nl y bel i eved to be secondar y to sel ecti on
bi as. In contrast, the l ar gest tr i al on i nducti on chemotherapy
i nvol vi ng mor e than 800 pati ents wi th esophageal car ci noma
(squamous and adeno) per for med i n Eur ope (MRC tr i al , 2002) di d

show a si gni fi cant sur vi val advantage over sur ger y al one. The fact
that the l ar gest U.S. i nter gr oup tr i al , however, fai l ed to fi nd any
advantage i n sur vi val rate wi th the same agents i n mor e than 400
pati ents l eaves the i ssue open for debate. At thi s poi nt, i nter est i n
chemotherapy as monotherapy neoadjuvant tr eatment has been
mostl y di ver ted to combi ned chemoradi otherapy.
Neoadjuvant chemoradi ati on therapy for esophageal car ci noma has
been shown to be feasi bl e and effecti ve. Phase II tr i al s have
r epor ted excel l ent overal l r esponse rates (compl ete r esponses i n
25% 35% ) and r el ati vel y decent compl i ance wi th therapy. Sur vi val
and l ocal contr ol compar e favorabl e to hi stor i cal contr ol s. However,
despi te the fact that ther e have been ei ght pr ospecti ve randomi zed
studi es, onl y one to date has shown a benefi t to thi s therapy over
sur ger y al one. Thi s study has been wi del y cr i ti ci zed, and the r esul ts
have not been r epeated i n any other randomi zed tr i al . Thi s tr i al ,
conducted at the Uni ver si ty of Dubl i n wi th 113 pati ents wi th
adenocar ci noma, eval uated neoadjuvant ci spl ati n pl us 5-F U and 40
G y of radi ati on wi th sur ger y al one. The i nvesti gator s r epor ted a
25% compl ete pathol ogi cal r esponse, as wel l as a si gni fi cant
i ncr ease i n medi an sur vi val (16 vs. 11 months) and 3-year sur vi val
rate (32% vs. 6% ) for the pati ents r ecei vi ng the neoadjuvant
tr eatment. Much of the debate over thi s study has focused on the
poor sur vi val i n the
sur ger y-onl y ar m of 6% at 3 year s, er rati c pr eoperati ve cl i ni cal
stagi ng, and questi ons of mi scal cul ati ons wi thi n the stati sti cs. The
seven other randomi zed tr i al s that have been per for med ar ound the
wor l d as mul ti -i nsti tuti onal and si ngl e i nsti tuti onal tr i al s have not
shown a si gni fi cant sur vi val advantage. The si gni fi cant contr i buti ons
of these wor ks, however, have i mpr oved our under standi ng of
esophageal cancer bi ol ogy. Locor egi onal r ecur r ence i s r epor ted to be
l ow after neoadjuvant chemoradi otherapy, and pati ents that have
had a compl ete r esponse far e ver y wel l . Pati ents who ar e
si gni fi cantl y downstaged (to N0 status) per for m equal to
pathol ogi cal l y si mi l ar l y staged pati ents who have under gone sur ger y
al one. Radi ati on to 50.4 G y i s equi val ent to hi gher doses of
radi ati on and i s wel l tol erated wi thout si gni fi cantl y i ncr easi ng
per i operati ve mor tal i ty (i n exper i enced center s).
Thr ee l ar ge meta-anal yses have been conducted on the use of
neoadjuvant chemoradi otherapy i n esophageal cancer. The tr end
towar d sur vi val advantage i n most of the smal l er tr i al s transl ated to
a si gni fi cant sur vi val advantage i n the thr ee publ i shed meta-

anal yses for tr eated pati ents. It i s pr obabl e that ther e i s an overal l
benefi t to chemoradi otherapy; however, a tr i al that woul d
adequatel y defi ne thi s woul d r equi r e appr oxi matel y 2,000 pati ents
and a decade or mor e to compl ete. F ur ther mor e, many cl i ni ci ans
have questi oned whether i ncl udi ng a sur ger y-onl y ar m i s
sci enti fi cal l y ethi cal for a tr i al thi s l ar ge and, ther efor e, ther e i s
doubt that thi s tr i al wi l l ever be per for med.

Definitive Radiation Therapy and


Chemoradiation Therapy
Al though sur gi cal r esecti on r emai ns the pr efer r ed therapy for
esophageal cancer, defi ni ti ve radi ati on therapy and chemoradi ati on
therapy have been used i n pati ents who ar e not candi dates for
sur gi cal r esecti on. Local contr ol rates ranged between 40% and
75% , and medi an and 2-year sur vi val rates ranged fr om 9 to 24
months and fr om 18% to 38% , r especti vel y. Several pr ospecti ve
randomi zed tr i al s have shown that defi ni ti ve chemoradi ati on
therapy i s super i or to radi ati on therapy al one i n the tr eatment of
esophageal cancer. Al though di r ect compar i sons agai nst sur gi cal
therapy (wi th or wi thout neoadjuvant therapy) have been attempted
i n the Uni ted States and Eur ope, both tr i al s have fai l ed to r ecr ui t
pati ents, l ar gel y because of physi ci ans r el uctance to accept a
nonsur gi cal appr oach i n pati ents who ar e operati ve candi dates. One
tr i al out of Eur ope that sought to eval uate the addi ti onal benefi t of
sur ger y after neoadjuvant chemoradi otherapy showed si gni fi cantl y
i mpr oved l ocor egi onal contr ol i n the sur ger y ar m compar ed wi th
chemoradi otherapy al one. At thi s ti me, ther efor e, defi ni ti ve
chemoradi ati on therapy shoul d be r eser ved for those pati ents who
ar e poor sur gi cal candi dates.

Other Therapeutic Modalities


In cer tai n par ts of the wor l d, par ti cul ar l y i n ar eas wher e esophageal
cancer i s endemi c, mass scr eeni ng and advances i n di agnosti c
techni ques have l ed to the detecti on of i ncr eased number s of
super fi ci al esophageal cancer s. Studi es fr om Japan and the Uni ted
States have suggested that for l esi ons confi ned to the epi thel i um
and l ami na pr opr i a, l ymphati c spr ead i s rar e. In some
of these pati ents, endoscopi c mucosal r esecti on i s a feasi bl e opti on,
al though exper i ence wi th thi s techni que i s sti l l l i mi ted. Abl ati on
therapy wi th Nd-YAG l aser or ar gon-beam coagul ati on ar e pr i mar i l y

used for pal l i ati on, but i n pati ents who ar e not candi dates for
sur ger y wi th super fi ci al cancer s and car ci noma i n si tu, these
methods can al so be useful . Al though exper i ence wi th these
techni ques i s l i mi ted, i nvesti gator s have r epor ted tumor-fr ee
sur vi val for several months after therapy, al though r ecur r ence rates
after about 1 year can be si gni fi cant. Si mi l ar l y, photodynami c
therapy has been used i n nonsur gi cal candi dates, and r esul ts of
pr el i mi nar y studi es i n pati ents wi th ear l y-stage tumor s have
suggested that tumor-fr ee sur vi val can l ast several months and that
compl ete r emi ssi on i s possi bl e i n some pati ents (at 2-year fol l owup). However, l ong-ter m studi es ar e sti l l needed.

Palliation for Unresectable Tumors


Common i ndi cati ons for pal l i ati on i n pati ents wi th advanced di sease
i ncl ude dysphagi a, pr esence of esophagor espi rator y fi stul a,
r ecur r ent bl eedi ng, and pr ol ongati on of sur vi val . Tumor debul ki ng
sur ger y has been per for med, and al though sur vi val durati on seems
somewhat i mpr oved r el ati ve to that i n pati ents who di d not under go
r esecti on, few randomi zed tr i al s have been per for med, and
mor bi di ty can be si gni fi cant. Other opti ons for pal l i ati on i ncl ude (a)
di l ati on, whi ch i s a safe and effecti ve method to r el i eve dysphagi a,
al though i t usual l y r equi r es mul ti pl e pr ocedur es; (b) stents, both
r i gi d and expandabl e, whi ch have become ver y popul ar i n r ecent
year s for r el i evi ng dysphagi a and for tr eati ng fi stul as and bl eedi ng;
(c) l aser therapy, whi ch has been effecti ve i n r el i evi ng dysphagi a
fr om shor ter str i ctur es and those wi th i ntral umi nal rather than
i nfi l trati ve gr owth; (d) photodynami c therapy, whi ch r esul ts i n
fewer per forati ons than do di l ati ons or l aser therapy and i s
tol erated better but r equi r es mor e fr equent sessi ons; (e) bi pol ar
el ectr ocauter y and coagul ati on wi th tumor pr obes that use heat to
destr oy tumor cel l s and cause ci r cumfer enti al i njur y; and (f )
brachytherapy, whi ch del i ver s radi oacti ve seeds i ntral umi nal l y.
Al l of these techni ques have advantages and di sadvantages, and
shor t-ter m success rates of 80% to 100% have been r epor ted. If
these tr eatment opti ons fai l , an endoscopi c pr osthesi s can often be
pl aced wi th good r esul ts. These techni ques ar e not wi thout
compl i cati ons, however, and ul cerati on, obstr ucti on, di sl ocati on, and
aspi rati on have al l been r epor ted. Recentl y, i mpr ovements i n
defi ni ti ve radi ati on therapy and chemotherapy have al so pr ovi ded
excel l ent means for shor t-ter m pal l i ati on. Wi th nonoperati ve
tr eatment, however, l ong-ter m l ocal contr ol i s sti l l poor (40%
l ocor egi onal fai l ur e). Whi ch method to use ther efor e depends on the

exper i ence of the physi ci an and the par ti cul ar needs and condi ti on
of the pati ent.

Surveillance
A bar i um swal l ow study shoul d be obtai ned i n the fi r st pr eoperati ve
month as a basel i ne study. Asymptomati c pati ents can be assessed
wi th year l y physi cal exami nati ons and chest radi ography. Any
symptoms (e.g., pai n, dysphagi a, wei ght l oss) shoul d be eval uated
aggr essi vel y wi th CT scanni ng, bar i um studi es, or
endoscopy. Beni gn str i ctur es at the anastomosi s shoul d be tr eated
wi th di l ati on. Unfor tunatel y, tr eatment opti ons ar e l i mi ted for
l ocor egi onal or di stant r ecur r ences. If radi ati on therapy was not
gi ven pr eoperati vel y or postoperati vel y, i t can be used al ong wi th
the pr evi ousl y menti oned nonoperati ve methods of pal l i ati on (i .e.,
di l ati on, stenti ng, l aser, photodynami c, or ther mal r esecti on).

Recommended Reading
Ajani JA. Cur r ent status of new dr ugs and mul ti di sci pl i nar y
appr oaches i n pati ents wi th car ci noma of the esophagus. Chest
1998;113(suppl 1):112S.
Aki yama H, Tsur umar u M, Udagawa H, et al . Esophageal cancer.
Cur r Pr obl Sur g 1997;34:767.
Bosset JF, G i gnoux M, Tr i boul et JP, et al . Chemoradi otherapy
fol l owed by sur ger y compar ed wi th sur ger y al one i n squamouscel l cancer of the esophagus. N Engl J Med 1997;337:161.
G ol dmi nc M, Madder n G , LePr i se E, et al . Oesophagectomy by
transhi atal appr oach or thoracotomy: a pr ospecti ve randomi zed
contr ol l ed tr i al . Br J Sur g 1993;80:367.
G or e RM. Esophageal cancer : cl i ni cal and pathol ogi c featur es.
Radiol Clin Nor th Am 1997;35:243.
Her skovi c A, Mar tz K, Al -Sar raf M, et al . Combi ned chemotherapy
and radi otherapy compar ed wi th radi otherapy al one i n pati ents
wi th cancer of the esophagus. N Engl J Med 1992;326:1593.

Kel sen DP, G i nsber g R, Pajak TF, et al . Chemotherapy fol l owed by


sur ger y compar ed wi th sur ger y al one for l ocal i zed esophageal
cancer. N Engl J Med 1998;339:1979.
Kol h P, Honor e P, Degauque C, et al . Ear l y stage r esul ts after
oesophageal r esecti on for mal i gnancy-col on i nter posi ti on ver sus
gastr i c pul l -up. Eur J Car diothor ac Sur g 2000;18:293300.
Knyr i m K, Wagner HJ, Bethge N, et al . A contr ol l ed tr i al of an
expansi l e metal stent for pal l i ati on of esophageal obstr ucti on due
to i noperabl e cancer. N Engl J Med 1993;329:1302.
Or r i nger MB, Mar shal l B, Iannettoni MD. Transhi atal
esophagectomy: cl i ni cal exper i ence and r efi nements. Ann Sur g
1999;230:392.
Roth JA, Pass HI, F l anagan MM, et al . Randomi zed cl i ni cal tr i al of
pr eoperati ve and postoperati ve adjuvant chemotherapy wi th
ci spl ati n, vi ndesi ne and bl eomyci n for car ci noma of the
esophagus. J Thor ac Car diovasc Sur g 1988;96:242.
Swi sher SG , Hol mes EC, Hunt KK, et al . The r ol e of neoadjuvant
therapy i n sur gi cal l y r esectabl e esophageal cancer. Ar ch Sur g
1996;131:819.
Swi sher SG , Hunt KK, Hol mes EC, et al . Changes i n the sur gi cal
management of esophageal cancer fr om 1970 to 1993. Am J Sur g
1995;169:609.
Ur ba SG , Or r i nger MB, Tur r i si A, et al . Randomi zed tr i al of
pr eoperati ve chemoradi ati on ver sus sur ger y al one i n pati ents
wi th l ocor egi onal esophageal car ci noma. J Clin Oncol
2001;19:305.
Ur schel JD. Does the i nter ponat affect outcome after
esophagectomy for cancer ? Dis Esophagus 2001;14(2):124130.
Wal sh TN, Noonan N, Hol l ywood D, et al . A compar i son of
mul ti modal therapy and sur ger y for esophageal adenocar ci noma.
N Engl J Med 1996;335:462.

Editors: Feig, Barry W .; Berger, David H.; Fuhrman, George


M.
Title: MD A nderson Surgical Oncology Handbook, The, 4th
Edition
Copyr i ght 2006 Li ppi ncott Wi l l i ams & Wi l ki ns
> Ta ble o f C o nt e nt s > 9 - G a s t ric C a nc e r

9
Gastric Cancer
W addah B. A l-Refaie
Eddie K. A bdalla
Syed A . A hmad
Paul F. Mansfield

Introduction
Because 95% of gastr i c cancer s ar e adenocar ci nomas, they ar e the
pr i mar y focus of thi s chapter on gastr i c cancer. As wi th other
cancer s, evol uti on i n the eval uati on and tr eatment of gastr i c
adenocar ci noma si nce the mi d-1990s has l ed to a shi ft i n the
management of thi s di sease. Now, l apar oscopy i s an essenti al
component of pr etr eatment stagi ng for r esectabl e gastr i c
adenocar ci noma. The Amer i can Joi nt Commi ttee on Cancer (AJCC)
stagi ng system has been al ter ed to consi der the number rather than
the l ocati on of nodes i nvol ved by metastati c tumor, whi ch has been
shown to yi el d a mor e accurate pr ognosi s i n pati ents wi th thi s
di sease. F i nal l y, evi dence that the combi nati on of chemoradi ati on
therapy and potenti al l y curati ve sur gi cal r esecti on i ncr eases
di sease-fr ee and overal l sur vi val durati on has l ed many
i nvesti gator s to r ecommend mul ti modal i ty tr eatment i n pati ents
wi th advanced r esectabl e gastr i c adenocar ci nomas. Thi s chapter
cover s the epi demi ol ogy, pr eoperati ve eval uati on, and sur gi cal and
adjuvant tr eatment of gastr i c cancer, as wel l as management of
advanced di sease. Less common tumor s such as gastr i c l ymphoma,
gastr i c car ci noi ds, and gastr oi ntesti nal str omal tumor s (G ISTs) of
the stomach ar e al so br i efl y di scussed.

Epidemiology
In the Uni ted States i n 2005, 21,860 new cases of adenocar ci noma

of the stomach and 11,550 deaths due to thi s di sease wer e


expected, whi ch woul d make gastr i c cancer the 14th most common
cancer and the 8th l eadi ng cause of cancer death i n the Uni ted
States. Ther e has been a decl i ne i n i ts i nci dence si nce the 1930s,
when gastr i c adenocar ci noma was the most common mal i gnancy i n
the countr y. Al though the r easons for the decr easi ng i nci dence ar e
suspected, they ar e not compl etel y cl ear. Nonethel ess, even though
the i nci dence of di stal gastr i c cancer i s decr easi ng i n the Uni ted
States, the i nci dence of pr oxi mal gastr i c tumor s conti nues to
i ncr ease. Cancer s of the gastr i c car di a cur r entl y account for near l y
50% of al l cases of gastr i c adenocar ci noma. Ther e ar e al so wi de
var i ati ons i n the i nci dence wor l dwi de: The appr oxi mate i nci dence of
gastr i c car ci noma i n the Uni ted States i s 10 cases per 100,000
peopl e, wher eas the i nci dence i n Japan i s upwar d of 78 cases per
100,000 peopl e, al though the i nci dence i s dr oppi ng i n Japan as wel l .
Nonethel ess, rates r emai n hi gh i n Kor ea and Costa Ri ca.
G ender- and ethni c gr oup-r el ated di ffer ences i nfl uence the
pr esentati on and outcome of gastr i c adenocar ci noma pati ents. In
par ti cul ar, gastr i c car di a tumor s ar e fi ve ti mes mor e common, and
noncar di a gastr i c tumor s ar e twi ce as common i n men as
i n women. In addi ti on, whi tes ar e affected twi ce as fr equentl y as
bl acks. However, the i nci dence i s al so hi gher i n l ow soci oeconomi c
popul ati ons, and the popul ati ons of devel opi ng countr i es.
Sur vi val rates i n pati ents wi th gastr i c cancer r emai n poor, wi th
vi r tual l y no change i n the overal l 5-year sur vi val rates rangi ng fr om
53% i n Japan to 10% i n Easter n Eur ope. A r ecent anal ysi s of the
Nati onal Cancer Data Base i n the Uni ted States r eveal ed a 6% to
12% better 5-year sur vi val rate for women than for men, for
pati ents wi th di stal as opposed to pr oxi mal tumor s, and for
Japanese or Japanese Amer i cans compar ed wi th member s of other
ethni c gr oups.

Risk Factors
Many factor s have been associ ated wi th an i ncr eased r i sk for
i ntesti nal -type gastr i c adenocar ci noma, wi th di et bel i eved to pl ay a
major r ol e. For exampl e, the i nci dence of gastr i c car ci noma tends to
be hi gh i n geographi c r egi ons wher e peopl e consume di ets hi gh i n
sal t and smoked foods. Indeed, ani mal studi es have shown that
pol ycycl i c hydr ocar bons and di methyl ni tr osami nes, substances
pr oduced after pr ol onged smoki ng of fi sh and meat, can i nduce

mal i gnant gastr i c tumor s. In contrast, di ets hi gh i n raw vegetabl es,


fr esh fr ui ts, vi tami n C, and anti oxi dants may be pr otecti ve.
In the Uni ted States, mal e gender, bl ack race, and l ow
soci oeconomi c cl ass ar e associ ated wi th a hi gher r i sk of gastr i c
car ci noma. Obesi ty i s associ ated wi th pr oxi mal gastr i c cancer s. A
speci fi c occupati onal haz ar d may exi st for metal wor ker s, mi ner s,
and r ubber wor ker s, as wel l as for wor ker s exposed to wood or
asbestos dust. Ci gar ette smoki ng poses a cl ear r i sk, possi bl y as a
r esul t of the associ ated decr eased vi tami n C l evel s, but al cohol
consumpti on has not been as consi stentl y cor r el ated wi th the
devel opment of gastr i c car ci noma. An associ ati on between gastr i c
car ci noma and bl ood gr oup A was fi r st descr i bed i n 1953, but the
r el ati ve r i sk i s onl y 1.2. Fami l i al cl uster i ng of gastr i c
adenocar ci noma, al though rar e, has been r epor ted and i s di scussed
mor e l ater i n thi s chapter.
Helicobacter pylor i, a gram-negati ve mi cr oaer ophi l i c bacter i um
l i vi ng wi thi n the mucous l ayer i n the gastr i c pi ts, has been
i mpl i cated i n the genesi s of gastr i c car ci noma. In keepi ng wi th thi s,
the i nci dence of H. pylor i i nfecti on i s i ncr eased i n ar eas wher e ther e
i s a hi gh rate of gastr i c cancer and i s i ncr eased among pati ents wi th
gastr i c cancer i n the Uni ted States. H. pylor i i s common i n pati ents
wi th di stal cancer but not i n pati ents wi th pr oxi mal cancer. It al so
appear s that ther e i s a mar ked geographi c associ ati on wi th H. pylor i
i nfecti on, i n that i t i s mor e pr eval ent i n the popul ati ons of
devel opi ng nati ons than i n i ndustr i al i zed nati ons. F ur ther mor e,
near l y 90% of pati ents wi th i ntesti nal -type gastr i c cancer have H.
pylor i detected i n adjacent, hi stol ogi cal l y nor mal mucosa, wher eas
onl y 32% of pati ents wi th di ffuse-type gastr i c cancer have thi s
fi ndi ng. Li kewi se, H. pylor i i s essenti al for the devel opment of
mucosa-associ ated l ymphoi d ti ssue (MALT) and gastr i c l ymphoma.
(Intesti nal - and di ffuse-type gastr i c cancer s ar e di scussed i n the
Pathol ogy secti on.) F i nal l y, the r i sk of adenocar ci noma appear s to
be i ncr eased i n pati ents wi th ser ol ogi c evi dence of i mmunogl obul i n
G anti body to H. pylor i bacter i al
pr otei ns and wi th i nfecti on of gr eater than 10 year s durati on. By
str ongl y i mpai r i ng the bi oavai l abi l i ty of vi tami n C, H. pylor i
i nfecti on appear s to hei ghten the r i sk for gastr i c cancer by causi ng
decr eased l evel s of ci r cul ati ng vi tami n C.
G astr i c pol yps ar e unusual and rar el y pr ecur sor s of gastr i c cancer.
Hyper pl asti c pol yps, the pol yps most commonl y found i n the
stomach, ar e beni gn l esi ons. The fi ndi ng of vi l l ous adenomas does,

however, i ndi cate an i ncr eased r i sk of mal i gnancy, not onl y wi thi n
the pol yp i tsel f, but al so el sewher e i n the stomach. However, vi l l ous
adenomas r epr esent onl y 2% of al l gastr i c pol yps.
Per ni ci ous anemi a i s associ ated wi th a 10% i nci dence of gastr i c
cancer, a r i sk that i s about thr ee to fi ve ti mes that seen i n the
nor mal popul ati on. Even though the r i sk of car ci noma devel opi ng i n
a chr oni c gastr i c ul cer i s smal l , of concer n i s the fact that up to
10% of pati ents wi th gastr i c car ci noma ar e mi sdi agnosed as havi ng
a beni gn gastr i c ul cer when eval uated by onl y a doubl e-contrast
study of the upper gastr oi ntesti nal tract. Al so, i ni ti al endoscopi c
bi opsi es may mi ss the cancer, thus r equi r i ng the endoscopy to be
r epeated to ensur e the ul cer has r esol ved. Operati ons for beni gn
pepti c ul cer s al so appear to be associ ated wi th an i ncr eased r i sk of
stomach cancer. Typi cal l y appear i ng 25 or mor e year s after
gastr ectomy for the tr eatment of gastr i c ul cer s, gastr i c stump
cancer has been var i ousl y r epor ted to occur fr om zer o to fi ve ti mes
mor e often i n pati ents who have had gastr ectomy than i n
i ndi vi dual s wi thout pr evi ous gastr i c r esecti on. Chr oni c atr ophi c
gastr i ti s and the i ntesti nal metapl asi a that often r esul t fr om these
pr ocedur es ar e al so r i sk factor s for gastr i c car ci noma but may not
be di r ect pr ecur sor condi ti ons. To date, no associ ati on has been
demonstrated between l ong-ter m H2 bl ockade and gastr i c cancer
i nci dence.
Mutati ons i n the CDH1 gene that encodes E-cadher in, an epi thel i al
cel l adhesi on mol ecul e, may be found i n i ntesti nal cancer s but ar e
mor e common i n di ffuse-type gastr i c cancer s. F ur ther mor e, defects
i n E-cadher i nmedi ated cel l adhesi on ar e character i sti c of di ffusetype gastr i c tumor s. It al so appear s that a CDH1 gene mutati on
occur s i n a cl uster of pati ents wi th her edi tar y di ffuse gastr i c cancer.
Ther efor e, pr ophyl acti c gastr ectomy i s offer ed to car r i er s of these
mutati ons. Vi r tual l y al l car r i er s of thi s mutati on so far have been
found to har bor an ear l y mal i gnancy i n the r esected speci men,
despi te negati ve i ni ti al endoscopy fi ndi ngs, poi nti ng to the
advi sabi l i ty of the gastr ectomy.
Vascular endothelial gr owth factor C (VEG F -C) i s a gl ycopr otei n that
bel ongs to the VEG F fami l y. VEG F s ar e cytoki nes that pl ay an
i mpor tant r ol e i n angi ogenesi s and, as shown i n r ecent studi es, i n
l ymphangi ogenesi s as wel l . Several i n vi vo and i n vi tr o studi es have
al so demonstrated that VEG F -C and VEG F -D pr omote the for mati on
of new l ymphati c channel s i n sol i d tumor s. In gastr i c
adenocar ci nomas, expr essi on of VEG F -C mRNA i s associ ated wi th
l ymphati c i nvasi on, l ymph node metastasi s, and possi bl y a l ess

favorabl e outcome.
Most r ecentl y, several geneti c al terati ons have been found to be
associ ated wi th gastr i c cancer. A study of p53 expr essi on i n 418
pati ents wi th gastr i c cancer r eveal ed p53 expr essi on i n mor e than
55% of tumor s; however, ther e was no cor r el ati on between p53
expr essi on and depth of i nvasi on, l ymph node i nvol vement,
or sur vi val . Other r epor ted r i sk factor s i ncl ude pr i or radi ati on
therapy and Epstei n-Bar r vi r us i nfecti on.

Pathology
Ni nety-fi ve per cent of gastr i c cancer s ar e adenocar ci nomas that
ar i se al most excl usi vel y fr om the mucous-pr oduci ng rather than the
aci d-pr oduci ng cel l s of the gastr i c mucosa. Lymphoma, car ci noi d,
l ei omyosar coma, G ISTs of the stomach, and adenosquamous and
squamous cel l car ci noma compr i se the r emai ni ng 5% of gastr i c
cancer s. In the Uni ted States, gastr i c cancer i s di vi ded i nto
ul cerati ve (75% ), pol ypoi d (10% ), sci r r hous (10% ), and super fi ci al
(5% ) subtypes on the basi s of macr oscopi c fi ndi ngs.
Adenocar ci noma of the stomach i s an aggr essi ve tumor, often
metastasi z i ng ear l y by both l ymphati c and hematogenous r outes and
di r ectl y extendi ng i nto adjacent str uctur es. Extensi on thr ough the
ser osal sur face can l ead to per i toneal tumor spr ead.
Accor di ng to the Laur en cl assi fi cati on, ther e ar e two hi stol ogi c types
of gastr i c adenocar ci noma: i ntesti nal and di ffuse. Each type has
di sti nct cl i ni cal and pathol ogi cal featur es. The i ntesti nal type i s
found i n geographi c r egi ons wher e ther e i s a hi gh i nci dence of
gastr i c cancer and i s character i zed pathol ogi cal l y by the tendency of
mal i gnant cel l s to for m gl ands. These tumor s ar e usual l y wel l to
moderatel y di ffer enti ated and associ ated wi th metapl asi a or chr oni c
gastr i ti s. They occur mor e commonl y i n ol der pati ents and tend to
spr ead hematol ogi cal l y to di stant or gans. The di ffuse type typi cal l y
l acks or gani zed gl and for mati on, i s usual l y poor l y di ffer enti ated,
and has many si gnet r i ng cel l s. If mor e than 50% of the tumor
contai ns i ntracytopl asmi c muci n, then i t i s desi gnated si gnet r i ng
type. Di ffuse-type tumor s ar e mor e common i n younger pati ents
wi th no hi stor y of gastr i ti s and spr ead transmural l y and by
l ymphati c i nvasi on. Di ffuse-type tumor s appear to be associ ated
wi th obesi ty. Al though the i nci dence of these tumor s var i es l i ttl e
fr om countr y to countr y, thei r overal l i nci dence appear s to be
i ncr easi ng wor l dwi de. Al though Laur en cl assi fi cati on separates

gastr i c tumor s i nto two types, the Wor l d Heal th Or gani z ati on
cl assi fi es them accor di ng to thei r hi stomor phol ogi c appearance,
whi ch i ncl udes tubul ar, muci nous, papi l l ar y, and si gnet r i ng cel l
types.
In the past, most gastr i c car ci nomas (60% 70% ) wer e found i n the
antr um. However, between 1980 and 1990, the pr opor ti on of gastr i c
car ci nomas ar i si ng i n the antr um decr eased, and the pr opor ti on
ar i si ng i n the car di a i ncr eased. Ni ne per cent of pati ents have tumor
that i nvol ves the enti r e stomach; thi s i s known as l i ni ti s pl asti ca or
l eather bottl e stomach, and the pr ognosi s for these pati ents i s
di smal . In general , gastr i c tumor s ar e mor e common on the l esser
cur ve of the stomach than on the gr eater cur ve. In the Uni ted
States, the i nci dence of synchr onous l esi ons i s 2.2% , compar ed wi th
an i nci dence of up to 10% i n Japanese pati ents wi th per ni ci ous
anemi a.

Clinical Presentation
G astr i c adenocar ci noma i s usual l y not associ ated wi th speci fi c
symptoms ear l y i n the cour se of the di sease. Pati ents often i gnor e
the vague epi gastr i c di scomfor t and i ndi gesti on that por tend the
cancer and may be tr eated pr esumpti vel y for beni gn di sease
for 6 to 12 months befor e di agnosti c studi es ar e per for med. Rapi d
wei ght l oss, anor exi a, and vomi ti ng ar e usual l y a si gn of advanced
di sease. These pr esenti ng featur es ar e si mpl y due to the pr esence
of a par ti al l y obstr ucti ng (ei ther mechani cal or physi ol ogi cal ) l esi on.
The most fr equent pr esenti ng symptoms of 1,121 pati ents at
Memor i al Sl oan-Ketter i ng Cancer Center wer e wei ght l oss, pai n,
vomi ti ng, and anor exi a. The epi gastr i c pai n i s usual l y si mi l ar to the
pai n caused by beni gn ul cer s and i s often r el i eved by eati ng food;
however, i t can mi mi c angi na. Dysphagi a i s usual l y associ ated wi th
tumor s of the car di a or gastr oesophageal juncti on. Antral tumor s
may cause symptoms of gastr i c outl et obstr ucti on. Al though ver y
rar e, l ar ge tumor s that di r ectl y i nvade the transver se col on may
pr esent wi th col oni c obstr ucti on. Physi cal exami nati on wi l l r eveal a
pal pabl e mass i n up to 30% of pati ents.
Appr oxi matel y 10% of pati ents pr esent wi th one or mor e si gns of
metastati c di sease. The most common i ndi cati ons of di stant
metastasi s ar e a pal pabl e supracl avi cul ar l ymph node (Vi r chow
node), a mass pal pabl e on r ectal exami nati on (Bl umer shel f ), a
pal pabl e per i umbi l i cal mass (Si ster Mar y Joseph node), asci tes,

jaundi ce, or a l i ver mass. The most common si te of hematogenous


spr ead i s the l i ver ; tumor al so fr equentl y spr eads di r ectl y to the
l i ni ng of the per i toneal cavi ty.
G astr i c tumor s may be associ ated wi th chr oni c bl ood l oss, but
massi ve upper gastr oi ntesti nal bl eedi ng i s rar e. In Japan, the hi gh
i nci dence of gastr i c cancer has l ed to r outi ne endoscopi c scr eeni ng;
as a r esul t, i n that countr y, mor e than 50% of gastr i c cancer s ar e
di agnosed at an ear l y stage.

Preoperative Evaluation
National Comprehensive Cancer Network
Guidelines for Initial Evaluation
The Nati onal Compr ehensi ve Cancer Networ k has devel oped
consensus gui del i nes for the cl i ni cal eval uati on and stagi ng of
pati ents suspected of havi ng gastr i c adenocar ci noma. The
r ecommended i ni ti al eval uati on i ncl udes a compl ete hi stor y and
physi cal exami nati on, l aborator y studi es (e.g., compl ete bl ood cel l
and pl atel et counts; measur ement of el ectr ol ytes, cr eati ni ne, and
l i ver functi on), chest radi ography, and computed tomography (CT) of
the abdomen and pel vi s. For pr oxi mal gastr i c tumor s, CT of the
chest i s al so per for med. Upper gastr oi ntesti nal contrast-enhanced
studi es ar e not mandator y. Esophagogastr oduodenoscopy i s
necessar y, and pr ovi des both ti ssue for a pathol ogi cal di agnosi s and
anatomi cal l y l ocal i zes the pr i mar y tumor i n mor e than 90% of
pati ents. Four to si x bi opsy speci mens and cytol ogi c br ushi ngs ar e
usual l y suffi ci ent for establ i shi ng an accurate di agnosi s. Thi s i ni ti al
wor kup enabl es the strati fi cati on of pati ents i nto two cl i ni cal stage
gr oups: those wi th l ocor egi onal di sease (AJCC stages IIII) and
those wi th systemi c di sease (AJCC stage IV) (Tabl e 9.1). Pal l i ati ve
therapy i s consi der ed i n pati ents wi th systemi c di sease, dependi ng
on thei r symptoms and functi onal status, because several
randomi zed studi es have shown a qual i ty of l i fe benefi t fr om
tr eatment i n pati ents wi th stage IV di sease. Pati ents wi th
l ocor egi onal di sease ar e fur ther strati fi ed on the basi s of thei r
functi onal status and comor bi d

condi ti ons. Addi ti onal studi es i n pati ents wi th l ocal i zed di sease
i ncl ude l apar oscopy and endoscopi c ul trasonography (EUS).
Pul monar y functi on tests may al so be necessar y i n sel ect pati ents.

Pati ents wi th l ocor egi onal di sease who ar e consi der ed candi dates for
sur ger y r ecei ve defi ni ti ve (fr equentl y mul ti modal i ty) therapy,
i ncl udi ng l apar otomy and r esecti on. Pati ents wi th occul t M1 di sease
found at l apar oscopy ar e consi der ed for pal l i ati ve therapy.

Table 9.1. TNM classification of carcinoma


of the stomach
Category Criteria
Primary tumor (T)
Tx

Primary tumor cannot be assessed

T0

No evidence of primary tumor

Tis

Carcinoma in situ

T1

Tumor invades lamina propria or


submucosa

T2

Tumor invades muscularis propria or


subserosa

T2a

Tumor invades muscularis propria

T2b

Tumor invades subserosa

T3

Tumor penetrates serosa (visceral


peritoneum) without invasion of
adjacent structures

T4

Tumor invades adjacent structures

Regional lymph nodes (N)


Nx

Regional lymph nodes cannot be


assessed

N0

No regional lymph node metastasis

N1

Metastases in 16 lymph nodes

N2

Metastases in 715 lymph nodes

N3

Metastases in >15 lymph nodes

Distant metastasis (M)


Mx

Distant metastasis cannot be


assessed

M0

No distant metastasis

M1

Distant metastasis

Stage grouping
Stage 0

Tis

N0

M0

Stage IA

T1

N0

M0

T1

N1

M0

Stage IB

Stage II

Stage
IIIA

Stage
IIIB

Stage IV

T2a/b

N0

M0

T1

N2

M0

T2a/b

N1

M0

T3

N0

M0

T2a/b

N2

M0

T3

N1

M0

T4

N0

M0

T3

N2

M0

T4

N13

M0

T13

N3

M0

Any T

Any N

M1

Adapted from Stomach. In: Greene FL, Page


DL, Fleming ID, et al., eds. AJCC Cancer
Staging Manual. 6th ed. New York, NY:
Springer-Verlag; 2002:99103, with
permission.

Upper Gastrointestinal Endoscopy and

Endoscopic Ultrasonography
Upper gastr oi ntesti nal endoscopy wi th bi opsy i s essenti al for the
di agnosi s of gastr i c tumor s and enabl es anatomi cal assessment of
the pr oxi mal extent of the tumor, tumor si ze, and, often, pr ovi ded
that l umi nal obstr ucti on does not pr event passage of the
gastr oscope beyond the tumor, the di stal extent of the tumor. Tumor
l ocati on can gui de sur gi cal or pal l i ati ve tr eatment pl anni ng. In
sel ected pati ents wi th advanced di sease,
esophagogastr oduodenoscopy enabl es pal l i ati ve tr eatment consi sti ng
of l aser abl ati on, di l atati on, or tumor stenti ng to be per for med.
Depth of tumor i nvasi on i s a major deter mi nant of stage and
di r ectl y cor r el ates wi th pr ognosi s. G astr i c mural EUS can achi eve
spati al r esol uti on of 0.1 mm, whi ch al l ows for a r easonabl y accurate
assessment of the degr ee of tumor penetrati on thr ough the l ayer s
of the gastr i c wal l . However, because EUS cannot r el i abl y
di sti ngui sh between tumor and fi br osi s (ei ther tr eatment r el ated or
secondar y to pepti c ul cerati on), EUS has some l i mi tati on and i s thus
used pr i mar i l y for i ni ti al stagi ng rather than for assessi ng r esponse
to neoadjuvant therapy.
Pathol ogi cal confi r mati on of pr eoperati ve EUS fi ndi ngs has shown
the overal l stagi ng accuracy of EUS to be 75% . However, EUS
cor r ectl y i denti fi es T2 l esi ons onl y 38.5% of the ti me; i t i s better at
i denti fyi ng T1 (80% ) and T3 (90% ) l esi ons. Techni cal i mpr ovements
and exper i ence have i mpr oved the accuracy of EUS i n the nodal
eval uati on of N1 di sease to appr oxi matel y 65% . The i nfor mati on
yi el ded by EUS-gui ded fi ne-needl e aspi rati on may fur ther i mpr ove
the accuracy of nodal stagi ng, but thi s techni que i s techni cal l y mor e
chal l engi ng. G i ven the operator dependence of EUS, i t i s l ar gel y
per for med at r egi onal r efer ral center s.

Computed Tomography
Abdomi nal and pel vi c CT i s per for med ear l y i n the overal l stagi ng of
pati ents wi th newl y di agnosed gastr i c cancer. Thi s al l ows
unnecessar y l apar otomy to be avoi ded i n many pati ents wi th
vi sceral metastati c di sease or mal i gnant asci tes. CT of the chest
may be r equi r ed for the compl ete stagi ng of pr oxi mal gastr i c
tumor s.
The major l i mi tati ons of CT as a stagi ng tool ar e i n the eval uati on
of ear l y gastr i c tumor s and smal l (<5 mm) metastases on per i toneal
sur faces or i n the l i ver. Even wi th the use of hel i cal CT scan, the
overal l accuracy i n deter mi ni ng tumor stage i s appr oxi matel y 66%

to 77% . CT can be used to accuratel y deter mi ne nodal stage i n 25%


to 86% of pati ents.

Laparoscopy and Laparoscopic


Ultrasonography
The val ue of fur ther stagi ng wi th l apar oscopy i s appar ent on
r ecogni ti on of the l ow sensi ti vi ty of CTeven hi gh-qual i ty hel i cal
CT per for med wi th gastr i c-speci fi c pr otocol s for the detecti on of
smal l (<5 mm) metastases on the per i toneal sur face. Lapar oscopy i s
done ei ther separatel y or i mmedi atel y befor e sur gi cal r esecti on. A
ful l techni cal descr i pti on of di agnosti c l apar oscopy i s beyond the
scope of thi s chapter. In br i ef, a l apar oscopi c i nspecti on i s usual l y
per for med i n a systemati c manner and i ncl udes a sear ch for
metastases on the per i toneal sur faces and the l i ver. Bi opsy of the
nodal basi n for stagi ng pur poses i s not r outi nel y per for med, but i t
can be done i n sel ected cases. When i t i s done, the l esser sac
shoul d be eval uated vi a the gastr ocol i c omentum. The i denti fi cati on
of advanced di sease affor ded by l apar oscopy al l ows many pati ents to
be spar ed an ul ti matel y nontherapeuti c l apar otomy. Pati ents wi th
smal l -vol ume metastati c di sease i n the per i toneum or l i ver
i denti fi ed at l apar otomy have a l i fe expectancy of onl y 3 to 9
months; thus, despi te some r epor ts that pal l i ati ve gastr ectomy may
confer a sur vi val advantage, such pati ents rar el y benefi t fr om
expectant pal l i ati ve r esecti on. An ar gument for per for mi ng a
second-l ook l apar oscopy can be made i n the case of pati ents who
r ecei ve neoadjuvant chemotherapy for unr esectabl e di sease and
appear to have a good cl i ni cal r esponse.
Resear cher s at Memor i al Sl oan-Ketter i ng Cancer Center and M. D.
Ander son Cancer Center have eval uated the feasi bi l i ty, yi el d, and
cl i ni cal benefi t of l apar oscopi c stagi ng after hi gh-qual i ty abdomi nal
CT stagi ng and found that l apar oscopy i denti fi ed CT-occul t
metastati c di sease i n 23% to 37% of pati ents. Mor eover, l ess than
2% of the pati ents i n whom CT-occul t metastases wer e i denti fi ed by
l apar oscopy r equi r ed subsequent l apar otomy for pal l i ati on. On the
basi s of the avai l abl e data, the Nati onal Compr ehensi ve Cancer
Networ k has i ntegrated l apar oscopy i nto the r ecommended r outi ne
stagi ng al gor i thm for pati ents wi th l ocor egi onal gastr i c cancer s and
sel ect pati ents wi th advanced gastr i c cancer.
Lapar oscopi c ul trasonography (LUS) has been pr oposed as a means
to over come some of the l i mi tati ons of l apar oscopy and to i mpr ove

the di agnosti c yi el d. However, the major i ty of studi es of LUS i n the


stagi ng of gastr i c cancer ar e di ffi cul t to i nter pr et because the use of
state-of-the-ar t pr el apar oscopy stagi ng (par ti cul ar l y CT) has var i ed,
and r esul ts have been r epor ted i n a manner that makes i t di ffi cul t
to deter mi ne the speci fi c added benefi t of LUS over hi gh-qual i ty CT
pl us l apar oscopy al one. G i ven the l i mi tati ons of the avai l abl e data,
the hi gh cost of LUS equi pment, and the operator-dependent natur e
of the techni que, i t i s best to r egar d LUS as r equi r i ng fur ther
i nvesti gati on to defi ne i ts r ol e.

Peritoneal Cytology
Cytol ogi c anal ysi s of per i toneal fl ui d or fl ui d obtai ned by per i toneal
l avage may i denti fy occul t car ci nomatosi s. For thi s r eason, many
i nsti tuti ons have i ncl uded the cytol ogi c assessment of per i toneal
fl ui d i n the pr eoperati ve stagi ng of pati ents. The fl ui d i s usual l y
obtai ned by per cutaneous or l apar oscopi c aspi rati on (wi th or
wi thout per i toneal l avage) per for med at the ti me of stagi ng
l apar oscopy. Per i toneal cytol ogi c anal ysi s can be r el ati vel y si mpl e
and fast and i s ther efor e al so feasi bl e i ntraoperati vel y, al though
one must be on the watch for fal se-posi ti ve r eadi ngs.
In most ser i es, pati ents wi th posi ti ve per i toneal cytol ogy fi ndi ngs
have a pr ognosi s si mi l ar to that of pati ents wi th macr oscopi c
vi sceral or per i toneal di sease (3- to 9-month medi an sur vi val ).
Some r esear cher s have i nvesti gated the i mpact of per i toneal
cytol ogy fi ndi ngs on outcome and noted that the medi an sur vi val i n
those wi th posi ti ve cytol ogy fi ndi ngs was 122 days; other s have
used i t as an i ndi cati on for neoadjuvant tr eatment rather than an
absol ute contrai ndi cati on to r esecti on. The pr i mar y concer ns
r egar di ng the use of per i toneal cytol ogy ar e the possi bi l i ty of fal seposi ti ve r esul ts and the fact that some r epor ts do not confi r m the
uni for ml y poor pr ognosi s i n pati ents wi th posi ti ve fi ndi ngs. G i ven
that cytol ogi c anal ysi s i s ver y much an operator-dependent vi sual
i nter pr etati on, effor ts ar e ongoi ng to devel op mor e sensi ti ve and
speci fi c techni ques for i denti fyi ng per i toneal di ssemi nati on,
i ncl udi ng i mmunostai ni ng and r ever se transcr i ptase-pol ymerase
chai n r eacti on testi ng for car ci noembr yoni c anti gen (CEA) mRNA.
Al though some success has been seen usi ng these techni ques
because they take mor e ti me than per i toneal cytol ogy, they may not
be practi cal for use i n the operati ng r oom.

Lymphatic Mapping
G i ven the essenti al r ol e of nodal status i n gastr i c cancer stagi ng
and the contr over sy that sur r ounds the extent of l ymphadenectomy,
ther e has been i nter est i n eval uati ng the feasi bi l i ty of senti nel
l ymph node mappi ng i n gastr i c cancer. However, unl i ke br east
cancer and mel anoma, l ymphati c drai nage of the stomach i s compl ex
and thus ther e i s a r i sk of a ski p metastasi s i n up to 15% of
cases. Al though l ymphati c mappi ng of stomach tumor s has been
most commonl y per for med vi a an open l apar otomy, i t has al so been
done usi ng a l apar oscopi c appr oach. Mappi ng agents such as
radi ocol l oi d wi th or wi thout vi tal dye and acti vated car bon par ti cl es
have been used. The i denti fi cati on rate var i es fr om 90% to 100% ,
and the sensi ti vi ty of the fi ndi ngs ranges fr om 61% to 100% .
However, l ymphati c mappi ng has several drawbacks. F i r st, the
number of pati ents wi th gastr i c cancer i n whi ch i t has been studi ed
i s smal l i n compar i son wi th mel anoma or br east cancer. Second, i t i s
associ ated wi th a fal se-negati ve rate as hi gh as 39% . Thi r d, the
number of senti nel l ymph nodes per pati ent i s qui te var i ed (two to
seven senti nel nodes per pati ent). Four th, the fi ndi ngs ar e
si gni fi cantl y di ffer ent i n the typi cal l y obese Wester n pati ents fr om
those i n Asi an pati ents, i n whom most of the studi es of l ymphati c
mappi ng have been done. Ther efor e, for these r easons, senti nel
l ymph node mappi ng for stomach cancer r emai ns i nvesti gati onal .

Other Studies
Posi tr on emi ssi on tomography (PET), whi ch esti mates tumor
metabol i sm on the basi s of the uptake of a radi otracermost
commonl y, fl uor odeoxygl ucosei s cur r entl y bei ng eval uated as a
stagi ng tool for gastr i c cancer. Thi s techni que may r eveal CT-occul t
metastases (par ti cul ar l y extra-abdomi nal di sease) and may be used
to assess r esponse to neoadjuvant therapy. Cur r ent drawbacks to
PET ar e i ts hi gh cost and i ts l i mi ted avai l abi l i ty.
Al so, the addi ti onal yi el d of PET over standar d stagi ng studi es i n the
eval uati on of gastr i c cancer has thus far not been shown.
Incr eased l evel s of (CEA) Chor i oembr yoni c Anti gen ar e seen i n onl y
30% of pati ents wi th gastr i c car ci noma. Because the CEA l evel i s
usual l y nor mal i n ear l y gastr i c cancer, CEA i s not a useful scr eeni ng
mar ker. Ser i al deter mi nati ons of the CEA l evel may be hel pful ,
however, i n detecti ng tumor r ecur r ence or i n moni tor i ng r esponse to
tr eatment i n pati ents who pr esent wi th an i ncr eased CEA l evel .

Staging Systems
Many stagi ng systems for gastr i c adenocar ci noma have been
pr oposed. The pathol ogi cal stagi ng system cur r entl y i n use
wor l dwi de i s the Uni on Inter nati onal e Contr el e Cancer
(UICC)/Amer i can Joi nt Commi ttee on Cancer (AJCC) TNM stagi ng
system, wi th the addi ti on of the ter m R status to denote r esi dual
di sease r emai ni ng after r esecti on. Several other l ar gel y abandoned
systems have been devel oped i n an attempt to descr i be both the
extent of disease and the r esul tant extent of r esection or
lymphadenectomy necessar y i n a gi ven pati ent. The var i ous stagi ng
systems i n use ar e expl ai ned as fol l ows.

American Joint Committee on Cancer Staging


System
The stagi ng of gastr i c adenocar ci noma has changed si gni fi cantl y
si nce the mi d-1990s. In 1997, the AJCC r el eased a r evi sed TNM
stagi ng system i n whi ch pati ents ar e strati fi ed on the basi s of the
number rather than the l ocati on of any i nvol ved l ymph nodes. In
2002, thi s TNM stagi ng system under went mi ni mal r evi si on i n the
most cur r ent AJCC stagi ng system (Tabl e 9.1). Sur vi val i s cl osel y
l i nked to the AJCC pathol ogi cal stage, par ti cul ar l y the nodal stage.
The val i di ty of the newer TNM stagi ng system i s now wel l
establ i shed. Because i t i s a pathol ogi cal rather than a cl i ni cal
stagi ng system, however, a pati ent's TNM status i s onl y ful l y known
fol l owi ng r esecti on. Thr ee i mpor tant cl i ni copathol ogi cal factor s have
been shown to r el i abl y strati fy pati ents i nto di sti nct gr oups wi th
di ffer ent r i sks of tumor-r el ated death: the depth of penetrati on of
the pr i mar y tumor thr ough the gastr i c wal l (T), the absence or
pr esence and extent of l ymph node i nvol vement (N), and the
absence or pr esence of di stant metastases (M). To adequatel y assess
N status, no fewer than 15 l ymph nodes shoul d be r etr i eved. If
metastasi s i s found i n mor e than 15 l ymph nodes (N3), thi s i s
consi der ed stage IV di sease. Some i nvesti gator s (e.g., Roder et al .,
1998) ar gued that sur vi val i s al so i ndependentl y pr edi cted by tumor
l ocati on (i .e., car di a as opposed to di stal tumor s) and suggested
that futur e AJCC stagi ng systems shoul d r efl ect the poor er
pr ognosi s for pati ents wi th pr oxi mal tumor s seen i n thei r anal yses.

Residual Disease: R Status


The R status, whi ch was fi r st descr i bed by Her manek and Wi tteki nd

i n 1994, i s commonl y used to descr i be the tumor status i n a pati ent


fol l owi ng r esecti on and i s desi gnated fol l owi ng pathol ogi cal
eval uati on of the r esecti on mar gi ns (Tabl e 9.2). R0 i ndi cates that
mi cr oscopi c mar gi ns ar e fr ee of tumor and that no gr oss or
mi cr oscopi c di sease r emai ns. R1 i ndi cates that al l gr oss di sease has
been exti r pated but that mi cr oscopi c mar gi ns ar e posi ti ve for tumor.
R2 i ndi cates that gr oss r esi dual di sease r emai ns. Long-ter m sur vi val
can be expected onl y i n pati ents who under go an R0 r esecti on for
gastr i c adenocar ci noma, and si gni fi cant effor t i s ther efor e made to
avoi d R1 or R2 r esecti ons.

Table 9.2. Current description of


completeness of resection based on
presence or absence of residual disease
following resection and pathological
evaluation of resection margins
Description

Gross or Pathological Extent of


Residual Disease

R0

No residual gross disease and


negative microscopic margins

R1

Microscopic residual disease only

R2

Gross residual disease

Japanese R System
The R status descr i bed i n the pr evi ous secti on shoul d not be
confused wi th an ol der Japanese cl assi fi cati on of gastr i c r esecti on
that al so i ncl uded an R status. Thi s R status has now been r epl aced
wi th a D status and i s menti oned her e for i nfor mati onal pur poses
onl y because i t has not been used after 1992.

Japanese Classification: Extent of Resection


The extent of pathol ogi cal l ymph node i nvol vement r el ati ve to the
scope of the l ymphadenectomy per for med i s the di sti ngui shi ng
character i sti c of the Japanese cl assi fi cati on scheme, whi ch i s based
on the assumpti on that extended l ymph node cl earance beyond the
l evel of pathol ogi cal i nvol vement may pr ol ong sur vi val . In yet
another Japanese system (Tabl e 9.3), the compl eteness of nodal
di ssecti on i s desi gnated D1 (r emoval of al l nodal ti ssue wi thi n 3 cm
of the pr i mar y tumor ), D2 (D1 pl us cl earance of hepati c, spl eni c,
cel i ac, and l eft gastr i c nodes), or D3 (total gastr ectomy,
omentectomy, spl enectomy, di stal pancr eatectomy, and cel i ac and
por tal l ymphadenectomy). Al though these cl assi fi cati ons ar e not
par t of the AJCC stagi ng system, the D ter mi nol ogy
i s i mpor tant i n compar i ng the r esul ts of sur gi cal therapy, as i s
di scussed l ater i n the chapter.

Table 9.3. D Nomenclature: extent of


surgical resection and lymphadenectomy
Description Regions Included in Resection
D1

Removal of all nodal tissue within


3 cm of the primary tumor

D2

D1 plus clearance of hepatic,


splenic, celiac, and left gastric
lymph nodes

D3

D2 plus omentectomy,
splenectomy, distal pancreatomy,
and clearance of porta hepatis
lymph nodes and para-aortic
lymph nodes

Surgical Treatment
As l ong as ther e i s no documented metastati c di sease, the sur gi cal
r esecti on of gastr i c tumor s i s the mai nstay of tr eatment. We
r ecommend a wi de macr oscopi cal l y negati ve mar gi n of 5 to 6 cm,
al ong wi th the en bl oc r esecti on of l ymph nodes and adher ent
sur r oundi ng or gans. D2 l ymphadenectomy, spar i ng the spl een and
di stal pancr eas, i s empl oyed i f i t can be done wi th l ow mor bi di ty and
mor tal i ty. The appr opr i ate sur gi cal pr ocedur e for a gi ven pati ent
must take i nto account the l ocati on of the l esi on and the known
patter n of spr ead.

Proximal Tumors
Pr oxi mal tumor s account for about 50% of al l gastr i c car ci nomas.
These tumor s ar e usual l y advanced at pr esentati on and ar e
associ ated wi th a poor er l ong-ter m pr ognosi s than ar e di stal
cancer s. Ther e ar e thr ee types of gastr oesophageal juncti on tumor s
accor di ng to the Si ewer t cl assi fi cati on: Type I ar e associ ated wi th
Bar r ett esophagus or tr ue esophageal cancer gr owi ng i nto the
gastr oesophageal juncti on, type II cancer s ar e tr ue juncti onal
tumor s that l i e wi thi n 2 cm of the squamocol umnar juncti on, and
type III cancer s ar e pr esent wi thi n the subcar di al r egi on of the
stomach. The opti mal sur gi cal management of type II and III
cancer s i s contr over si al . The opti ons i ncl ude total gastr ectomy and
pr oxi mal subtotal gastr ectomy. Because of the advanced stage of
most tumor s of the car di a at di agnosi s, some author s ar gue that any
operati on i s r eal i sti cal l y onl y a pal l i ati ve pr ocedur e and that,
ther efor e, one shoul d al ways per for m the si mpl er pr oxi mal subtotal
gastr ectomy, especi al l y because total gastr ectomy does not i mpr ove
pr ognosi s for pati ents wi th stage III and IV di sease. However, some
studi es have shown a poor er qual i ty of l i fe i n pati ents who under go
a pr oxi mal subtotal gastr ectomy than i n pati ents who under go a
total gastr ectomy.
At M. D. Ander son, we usual l y per for m a total gastr ectomy wi th a
Roux-en-Y r econstr ucti on and r egi onal l ymphadenectomy for
pr oxi mal gastr i c l esi ons. Thi s pr ocedur e has the advantage of
avoi di ng the al kal i ne r efl ux esophagi ti s often associ ated wi th
pr oxi mal subtotal gastr ectomy. F ur ther mor e, l ymph nodes al ong the
l esser cur vatur e, a common si te of spr ead, ar e easi l y r emoved
dur i ng a total gastr ectomy. Ther e i s al so no gr eater mor tal i ty or

mor bi di ty i n pati ents who under go total gastr ectomy compar ed wi th


those who under go a pr oxi mal subtotal gastr ectomy.

Midbody Tumors
Mi dstomach tumor s account for 15% to 30% of al l gastr i c cancer s.
For the same r easons as those gi ven for our appr oach to the
tr eatment of pr oxi mal tumor s, we r ecommend total gastr ectomy
wi th r egi onal l ymphadenectomy i f the node di ssecti on can be done
wi th l ow mor bi di ty.

Distal Tumors
Di stal tumor s account for appr oxi matel y 35% of al l gastr i c cancer s.
The standar d operati on for these l esi ons i s a di stal subtotal
gastr ectomy wi th appr opr i ate l ymphadenectomy. Subtotal
gastr ectomy entai l s r esecti on of appr oxi matel y thr ee-four ths of the
stomach, i ncl udi ng the major i ty of the l esser cur vatur e. Thi s
pr ocedur e i s per for med for two r easons. F i r st, randomi zed
pr ospecti ve tr i al s demonstrated no sur vi val benefi t to total
gastr ectomy over subtotal gastr ectomy. Second, the qual i ty of l i fe i s
better i n those who have subtotal gastr ectomy than i n those who
have total gastr ectomy.
Because studi es have shown that mi cr oscopi c i nvasi on beyond 6 cm
fr om the gr oss tumor i s rar e, we ther efor e r ecommend a 5- to 6-cm
l umi nal r esecti on mar gi n when possi bl e. Even i f thi s di stance i s
achi eved, however, the sur gi cal mar gi ns shoul d be eval uated by
fr ozen-secti on pr eparati ons.

Splenectomy
Spl enectomy i s not per for med unl ess the tumor adher es to or
i nvades the spl een or i ts vascul ar suppl y. Routi ne spl enectomy does
not i mpr ove sur vi val but does i ncr ease the mor bi di ty and mor tal i ty
associ ated wi th gastr ectomy i n wester n pati ents. If a spl enectomy i s
anti ci pated pr eoperati vel y because of tumor adher ence shown by CT,
we gi ve pneumococcal pol ysacchar i de, meni ngococcal , and
Haemophilus i nfl uenz a vacci nes befor e sur ger y. Ther e i s a l ar ge
ongoi ng tr i al i n Japan that i s speci fi cal l y exami ni ng the r ol e of
spl enectomy i n the tr eatment of pati ents wi th gastr i c
adenocar ci nomas.

Lymphadenectomy
Despi te pr ospecti ve randomi zed tr i al s, contr over sy sti l l exi sts about
the r ol e of extended l ymphadenectomy i n the tr eatment of gastr i c
cancer. Radi cal l ymphadenectomy was adopted based on an i ni ti al
r epor t publ i shed i n 1981 by Kodama et al . that descr i bed a sur vi val
benefi t for pati ents wi th ser osal or r egi onal l ymph node i nvol vement
who under went a D2 or D3 l ymphadenectomy (R2 or R3 i n the ol d
Japanese nomencl atur e). Speci fi cal l y, the 5-year sur vi val rate i n
pati ents who under went a radi cal l ymphadenectomy was 39% as
opposed to onl y 18% i n pati ents who under went D1
l ymphadenectomy. Many other nonrandomi zed studi es fr om Japan
have shown a si mi l ar l y si gni fi cant sur vi val benefi t i n pati ents
under goi ng radi cal l ymphadenectomy. Unfor tunatel y, Wester n
studi es have not been abl e to r epr oduce the Japanese r esul ts.
The r epor ted di ffer ences i n sur vi val seen i n Japanese and Wester n
studi es may have mul ti pl e r easons. One potenti al r eason i s that
most Japanese pati ents pr esent wi th ear l y-stage di sease, whi ch
makes overal l sur vi val appear better. However, stage for stage, the
di ffer ences ar e not qui te so dramati c. F ur ther mor e, the Japanese
appr oach to nodal di ssecti on and pathol ogi cal anal ysi s i s much mor e
meti cul ous than the appr oach used i n the West, and ther e i s l i kel y
to be an el ement of stage mi grati on. It i s not ver y common for
nodes di stant fr om the stomach to be eval uated i n the Uni ted
States. Al so, pr oxi mal tumor s, whi ch behave mor e aggr essi vel y, ar e
l ess common i n Japan than i n the West. F i nal l y, the mor e aggr essi ve
sur ger y per for med i n Japan may confer a smal l i ncr ease i n sur vi val
rates.
In 1996, Wanebo et al . r evi ewed the outcomes i n 18,346 pati ents
wi th gastr i c cancer whose r ecor ds had been gather ed i n a database
that i ncl uded i nfor mati on fr om 200 tumor r egi str i es i n the Uni ted
States. Compar ed wi th pati ents under goi ng D1 di ssecti on, pati ents
under goi ng D2 nodal di ssecti on (i ncl udi ng l ymph nodes 3 cm fr om
the pr i mar y tumor ) (Tabl e 9.3) had no i ncr ease i n the medi an
sur vi val ti me (D2, 19.7 months; D1, 24.8 months) or i n the 5-year
sur vi val rate (D2, 26.3% ; D1, 30% ). In 1987, Shi u et al .
r etr ospecti vel y r evi ewed 210 pati ents wi th gastr i c cancer tr eated at
Memor i al Sl oan-Ketter i ng Cancer Center and found that a
l ymphadenectomy that di d not i ncl ude l ymph nodes at l east one
echel on beyond the hi stol ogi cal l y i nvol ved nodes was pr edi cti ve of a
poor pr ognosi s. Thi s study al so showed that ther e was not a

si gni fi cant di ffer ence i n the mor bi di ty associ ated wi th D1 and D2


l ymphadenectomi es.
Thus far, fi ve randomi zed tr i al s eval uati ng the extent of
l ymphadenectomy for gastr i c cancer have been conducted. Thr ee
tr i al s compar ed D1 ver sus D2 l ymphadenectomy. Two tr i al s
compar ed D3 ver sus D2 or D1 l ymphadenectomy.
To compar e the mor bi di ty and outcome i n pati ents who under went
D1 and D2 l ymphadenectomy, Dent et al ., fr om South Afr i ca,
randomi zed 43 pati ents i nto each ar m. Those who under went D2
di ssecti on had a hi gher mor bi di ty rate (D1, 15% ; D2, 30% ; P =
0.06), l onger hospi tal stay (D1, 4.2 days; D2, 9.2 days; P <0.008),
and l onger operati ve ti me (D1, 1.8 hour s; D2, 2.5 hour s; P <0.001).
However, the 5-year sur vi val rate was si mi l ar i n both gr oups (D1,
69% ; D2, 67% ). In 2004, Bonenkamp et al . r epor ted on a study
conducted i n the Nether l ands i n whi ch 711 pati ents wer e
pr ospecti vel y randomi zed to under go D1 or D2 l ymphadenectomy.
Pati ents under goi ng the mor e extended l ymphadenectomy (D2) had
a si gni fi cantl y hi gher operati ve mor bi di ty rate (D2, 43% ; D1, 25% ;
P <0.001) and si gni fi cantl y hi gher mor tal i ty rate (D2, 10% ; D1,
4% ; P = 0.004). The 5-year r el apse rates (D1, 43% ; D2, 37% ) and
5-year sur vi val rates (D1, 45% ; D2, 47% ) wer e si mi l ar, however.
Si mi l ar r esul ts wer e obtai ned i n the Medi cal Resear ch Counci l tr i al
r epor ted i n the Uni ted Ki ngdom by Cuschi er i et al . i n 1999. In thi s
study, 400 pati ents wi th gastr i c adenocar ci noma wer e pr ospecti vel y
randomi zed, as i n the Dutch tr i al , to under go D1 or D2
l ymphadenectomy. Si mi l ar l y, ther e was no di ffer ence i n the overal l
5-year sur vi val rate between the two gr oups (D1, 35% ; D2, 33% ).
In thi s study, as i n the Dutch tr i al , pancr eati cospl enectomy
per for med as par t of the D2 r esecti on r esul ted i n i ncr eased
postoperati ve mor bi di ty and mor tal i ty. These data ther efor e do not
suppor t the r outi ne per for mance of D2 l ymphadenectomy i n pati ents
wi th gastr i c adenocar ci noma, par ti cul ar l y i f pancr eati cospl enectomy
i s necessar y to effect the di ssecti on.
In a compar i son of D1 and D3 l ymphadenectomy, Rober tson et al .,
fr om Hong Kong, randomi zed 54 pati ents to under go ei ther D1
l ymphadenectomy wi th subtotal gastr ectomy or D3
l ymphadenectomy wi th total gastr ectomy. In addi ti on to poor er
sur vi val i n the D3 gr oup, the hospi tal stay and bl ood l oss wer e
gr eater i n the pati ents i n the D3 gr oup than i n the D1 gr oup.
In 2004, the Japanese Cooperati ve Oncol ogy G r oup (JCOG 9501)
r epor ted the fi ndi ngs fr om a pr ospecti ve randomi zed tr i al eval uati ng

R0 gastr ectomy wi th D2 l ymphadenectomy ver sus


D2 pl us para-aor ti c l ymphadenectomy. In thi s mul ti center tr i al ,
sur geons exper i enced i n per for mi ng extended l ymphadenectomy
operated on mor e than 500 pati ents. In addi ti on to the pr eoperati ve
stagi ng, age younger than 75 year s and negati ve per i toneal l avage
cytol ogy fi ndi ngs wer e some of the i ncl usi on cr i ter i a. Ther e wer e
two deaths i n each ar m, accounti ng for a r emar kabl y l ow hospi tal
mor tal i ty of 0.8% . Al though the mor bi di ty rate i n pati ents who
under went the D2 pl us para-aor ti c l ymphadenectomy (28.1% ) was
hi gher than that i n the pati ents who under went the D2
l ymphadenectomy (20.9% ), the di ffer ence di d not r each stati sti cal
si gni fi cance. Pati ents who under went the D2 pl us para-aor ti c
l ymphadenectomy al so had l onger operati ons (P <0.001) wi th
i ncr eased bl ood l oss (P <0.001), and hence hi gher bl ood transfusi on
r equi r ements (P <0.001), than di d those who had onl y a D2
l ymphadenectomy. The sur vi val r esul ts of thi s tr i al ar e expected i n
2006.
At M. D. Ander son, spl een-spar i ng D2 l ymphadenectomy i s standar d.
Anal ysi s of pati ents who under went curati ve r esecti on after
neoadjuvant therapy at M. D. Ander son between 1991 and 1998
showed a per i operati ve mor tal i ty rate of 2% . Cur r ent standar d
r ecommendati ons i ncl ude a D1 di ssecti on (per i gastr i c
l ymphadenectomy), al though major center s conti nue to study the
potenti al benefi t and mor bi di ty associ ated wi th mor e extended nodal
di ssecti ons i n the setti ng of l ow operati ve mor tal i ty.

Surgical Technique
Total Gastrectomy
For a total gastr ectomy, the di ssecti on i s begun by separati ng the
omentum fr om the mesocol on. The r i ght gastr oepi pl oi c vessel s ar e
l i gated at thei r or i gi n, and the subpyl or i c nodes ar e r esected wi th
the speci men. The fi r st por ti on of the duodenum i s mobi l i zed and
di vi ded 2 cm di stal to the pyl or us. The gastr ohepati c l i gament i s
opened, and the l eft gastr i c ar ter y i s l i gated at i ts or i gi n. It i s
i mpor tant to r emember that an aber rant or accessor y l eft hepati c
ar ter y may or i gi nate fr om the l eft gastr i c ar ter y and r esi de i n the
gastr ohepati c l i gament. If an extended l ymphadenectomy i s done,
the cel i ac, hepati c ar ter y, and spl eni c ar ter y nodes ar e cl ear ed of
nodal ti ssue and r emoved al ong wi th the speci men. The shor t
gastr i c vessel s ar e l i gated sequenti al l y up to the gastr oesophageal

juncti on. Di ssecti on ar ound the gastr oesophageal juncti on can fr ee


up 7 to 8 cm of di stal esophagus, whi ch faci l i tates transecti on of the
esophagus wi th an adequate pr oxi mal mar gi n. Stay sutur es of 2-0
si l k ar e pl aced, and after the esophagus i s di vi ded, the r esecti on
mar gi ns ar e eval uated by fr ozen-secti on exami nati on. If the tumor
adher es to the spl een, pancr eas, l i ver, di aphragm, col on, or
mesocol on, the i nvol ved or gan or or gans ar e r emoved en bl oc.
Ther e ar e many types of r econstr ucti ons, but the one most
fr equentl y used i s a Roux-en-Y anastomosi s. If a si gni fi cant por ti on
of the di stal esophagus i s r esected, a l eft thoracoabdomi nal or r i ght
thoracotomy (Ivor-Lewi s appr oach) may be used. Al though some
studi es have shown that r econstr ucti on wi th pouches and l oops to
act as r eser voi r s ar e benefi ci al , the data ar e far fr om concl usi ve.
The one mor e advanced r econstr ucti on, whi ch makes
physi ol ogi cal sense and has data suppor ti ng the benefi t of the
pr ocedur e, i s jejunal i nter posi ti on between the esophagus and the
duodenum. In thi s r econstr ucti on, car e i s taken to ensur e the
i nter posi ti on l i mb i s at l east 45 cm l ong. A feedi ng jejunostomy
tube i s pl aced for postoperati ve nutr i ti onal suppor t.

Subtotal Gastrectomy
The mobi l i z ati on for subtotal gastr ectomy i s i denti cal to that for
total gastr ectomy descr i bed i n the pr ecedi ng secti on, except that
onl y appr oxi matel y 80% of the di stal stomach i s r esected. The
di ssecti on of the di stal shor t gastr i c vessel s i s per for med fi r st to
ensur e spl eni c pr eser vati on. The smal l r emnant of stomach that i s
l eft i s suppl i ed by the r emai ni ng shor t gastr i c vessel s and the
poster i or gastr i c ar ter y ar i si ng fr om the spl eni c ar ter y. We often use
Roux-en-Y r econstr ucti on after subtotal gastr ectomy, al though a
l oop gastr ojejunostomy (Bi l l r oth II) i s al so acceptabl e. Other
r ecommendati ons i ncl ude a Bi l l r oth I.
F i gur e 9.1 shows the M. D. Ander son tr eatment al gor i thm for
potenti al l y r esectabl e gastr i c car ci noma.

Complications of Surgery
Compl i cati ons of gastr i c r esecti on and thei r r el ati ve i nci dences ar e
gi ven i n Tabl e 9.4. The most devastati ng compl i cati on i s an
anastomoti c l eak, whi ch occur s i n 3% to 21% of pati ents. Because
l eaks can occur l ate, an i ntact anastomosi s ear l y i n the
postoperati ve per i od i s not a guarantee of an uncompl i cated cour se.

Oral feedi ng i s begun 5 to 7 days postoperati vel y i f the pati ent i s


asymptomati c. Upper gastr oi ntesti nal tract contrast studi es ar e
per for med on the basi s of cl i ni cal i ndi cati ons onl y (e.g., fever,
tachycar di a, tachypnea). Because the food r eser voi r i s gone, many
pati ents must i ni ti al l y change thei r eati ng habi ts such that they
consume si x smal l meal s per day, other wi se cal l ed a
postgastr ectomy di et. Al ter nati vel y, they may eat r egul ar meal s
pl us snacks. Suppl emental jejunostomy feedi ngs ar e star ted the
same day or the day after sur ger y and conti nued unti l oral i ntake i s
adequate. Wi thi n several months, most pati ents ar e abl e to i ncr ease
thei r i ntesti nal capaci ty and eat l ar ger meal s l ess fr equentl y (thr ee
or four meal s per day).
Less than 10% of pati ents wi l l devel op cl i ni cal l y si gni fi cant dumpi ng
syndr ome. Ear l y dumpi ng typi cal l y occur s 15 to 30 mi nutes after a
meal and i ncl udes di aphor esi s, abdomi nal cramps, pal pi tati ons, and
water y di ar r hea. Late dumpi ng i s usual l y associ ated wi th
hypogl ycemi a and hyper i nsul i nemi a. The medi cal management for
dumpi ng symptoms shoul d i ncl ude di etar y modi fi cati on (fi ber di et
and avoi dance of hyper osmol ar l i qui ds) and, i f r efractor y, a
somatostati n anal og.

F i gur e 9.1. The Uni ver si ty of Texas M. D. Ander son Cancer


Center al gor i thm for the eval uati on and tr eatment of potenti al l y
r esectabl e gastr i c adenocar ci noma. *Occasi onal l y, metastati c
di sease i s found at the ti me of open sur gi cal expl orati on for

tumor s bel i eved to be r esectabl e on the basi s of radi ol ogi c and


l apar oscopi c stagi ng. In thi s si tuati on, the deci si on to per for m
pal l i ati ve r esecti on i s made on an i ndi vi dual i zed basi s. Pati ents
wi th metastati c di sease have a di smal pr ognosi s (see text).

Table 9.4. Complications of gastric


resection
Complication

Percentage of Patients
Affected

Pulmonary

355

Infectious

322

Anastomotic

321

Cardiac

110

Renal
Bleeding
Pulmonary
embolus

18
0.35
14

Outcomes of Surgery
The overal l 5-year sur vi val rate i n pati ents wi th gastr i c cancer i n
most Wester n ser i es i s 10% to 21% , whi ch i s a consequence of the
hi gh pr opor ti on of tumor s that ar e at an advanced stage at

pr esentati on. Pati ents who under go potenti al l y curati ve r esecti on


have a sl i ghtl y better pr ognosi s (5-year sur vi val rate of 24% 57% ).
The 5-year sur vi val rate i n pati ents who under go curati ve r esecti on
i n Japan i s r epor ted to be at l east 50% . Overal l 5-year sur vi val
rates i n Japan and the Uni ted States by TNM stage ar e l i sted i n
Tabl e 9.5.
To deter mi ne gastr i c cancer di sease-speci fi c sur vi val fol l owi ng R0
r esecti on, r esear cher s fr om Memor i al Sl oan-Ketter i ng Cancer Center
devel oped an i nter nal l y val i dated pr ognosti c nomogram. In thi s
nomogram, var i abl es i ncl uded age, gender, tumor l ocati on, Laur en
cl assi fi cati on, si ze, number of posi ti ve and negati ve l ymph nodes,
and depth. The pr edi cti ve abi l i ty of thi s nomogram was compar ed
wi th that of the cur r ent AJCC stagi ng system i n 1,039 pati ents, and
the nomogram was found to be super i or i n pr edi cti ng both 5- and 9year di sease-speci fi c sur vi val (concor dance i ndex 0.80 vs. 0.77; P
<0.001). Li mi tati ons of thi s nomogram ar e that i t needs to be
exter nal l y val i dated and i t depends on several postoperati ve factor s.
Di sease r ecur r ence has been anal yzed i n autopsy, r eoperati ve, and
cl i ni cal ser i es. Some component of di sease r ecur r ence can be found
i n up to 80% of pati ents fol l owi ng gastr ectomy. In 1982, G under son
and Sosi n anal yzed patter ns of r ecur r ence i n a pr ospecti ve study of
109 pati ents who under went gastr i c r esecti on and subsequent
r eoperati on at the Uni ver si ty of Mi nnesota. Of the 107 eval uabl e
pati ents, 86 (80% ) had r ecur r ent di sease. Locor egi onal r ecur r ence
al one ar ose i n 22 (25.6% ) of these 86 pati ents, but per i toneal
seedi ng was a component of r ecur r ence i n 54% of pati ents. Isol ated
di stant metastases wer e uncommon but occur r ed as some
component of r ecur r ence i n 29% of pati ents.
In 1990, Landr y et al . fr om Massachusetts G eneral Hospi tal
anal yzed di sease r ecur r ence i n 130 pati ents tr eated by r esecti on
wi th curati ve i ntent. The overal l l ocor egi onal r ecur r ence rate was
38% (49/130); 21 pati ents (16% ) had l ocor egi onal r ecur r ence
al one, 28 pati ents (22% ) had l ocor egi onal r ecur r ence and di stant
metastasi s, and 39 pati ents (30% ) had di stant metastasi s
al one. However, when vi ewed onl y i n ter ms of the pati ents i n whom
tr eatment fai l ed, l ocor egi onal r ecur r ence devel oped i n 57%
(49/88). The r i sk of l ocor egi onal r ecur r ence i ncr eased wi th the
degr ee of tumor penetrati on thr ough the gastr i c wal l . The most
fr equent si tes of l ocor egi onal r ecur r ence wer e the gastr i c r emnant
at the anastomosi s, the gastr i c bed, and the r egi onal nodes. The
overal l i nci dence of di stant metastasi s was 52% (67 pati ents), and

the i nci dence of di stant metastasi s i ncr eased wi th advanci ng stage


of di sease. The overal l r ecur r ence rate was 68% (88 pati ents).

Table 9.5. Five-year survival rates after


gastrectomy with complete resection and >15
lymph nodes examined
5-Year Survival Rate (%)
United Statesa
AJCC
Stage

Japanese
Japan b Germany
All (n =
Americans (n =
(n =
32,532)
(n = 697) 587)
1,017)

IA

78

95

95

86

IB

58

75

86

72

II

34

46

71

47

IIIA

20

48

59

34

IIIB

18

35

25

IV

17

16

Overall

28

42

NR

NR

AJCC, American Joint Committee on Cancer; n,


number of patients; NR, not reported.

a Data

from Hundahl SA, Phillips JL, Menck HR. The


National Cancer Data Base Report on poor survival
of U.S. gastric carcinoma patients treated with
gastrectomy: fifth edition American Joint
Committee on Cancer staging, proximal disease,
and the different disease hypothesis. Cancer
2000;88:921932.
b Data from Ichikura T, Tomimatsu S, Uefuji K, et
al. Evaluation of the New American Joint
Committee on Cancer/International Union against
cancer classification of lymph node metastasis
from gastric carcinoma in comparison with the
Japanese classification. Cancer 1999;86:553558.
c Data from Roder JO, Bottcher K, Busch R, et al.
Classification of regional lymph node metastasis
from gastric carcinoma. German Gastric Cancer
Study Group. Cancer 1998;82:621631.
In 2004, D'Angel i ca r epor ted the patter ns of r ecur r ence i n 1,172
pati ents who under went R0 r esecti on at Memor i al Sl oan-Ketter i ng
Cancer Center. At a medi an fol l ow-up of 22 months, var i ous types of
tumor r ecur r ence had devel oped i n 42.3% of the 1,172 pati ents. In
thi s anal ysi s, di sease r ecur r ed i n 79% of pati ents wi th r ecur r ence
wi thi n the fi r st 2 year s of tr eatment. Locor egi onal r ecur r ence was
the most fr equent (54% ), fol l owed by di stant (51% ) and per i toneal
(29% ) r ecur r ence. On mul ti var i ate anal ysi s, factor s pr edi cti ve of
l ocor egi onal r ecur r ence wer e mal e gender and pr oxi mal l esi ons. The
medi an ti me to death fr om the ti me of r ecur r ence was 6 months.
Inter esti ngl y, the nodal status
and the extent of l ymphadenectomy wer e not associ ated wi th
l ocor egi onal r ecur r ence. Al though thi s anal ysi s i denti fi ed the
r ecur r ence patter n and pr edi ctor s of r ecur r ence, thi s r etr ospecti ve
study had some l i mi tati ons. F i r st, 26% of pati ents wi th r ecur r ence
di d not have a r ecur r ence patter n documented. Second,
postoperati ve fol l ow-up and adjuvant tr eatments wer e not

consi stent. The effect of adjuvant therapy on r ecur r ence was al so


not eval uated.

Early Gastric Cancer


In the ear l y 1960s, the Japanese defi ned ear l y gastr i c cancer as
car ci noma l i mi ted to the mucosa and submucosa, r egar dl ess of
whether ther e wer e l ymph node metastasi s. Thi s pathol ogi cal
cl assi fi cati on was based on the hi gh cur e rate i n thi s gr oup of
pati ents. In the Uni ted States, the pr opor ti on of pati ents wi th ear l y
gastr i c cancer at di agnosi s has i ncr eased si nce the mi d-1980s to
appr oxi matel y 10% to 15% . In Japan, aggr essi ve scr eeni ng has
r esul ted i n ear l y gastr i c cancer bei ng di agnosed i n gr eater than
50% of Japanese pati ents wi th gastr i c cancer. Not sur pr i si ngl y,
ther efor e, the mean age of pati ents at di agnosi s i s 63 year s i n
Wester n studi es, wher eas i t i s 55 year s i n Japanese studi es. Most
pati ents wi th ear l y gastr i c cancer pr esent wi th gastr oi ntesti nal
symptoms si mi l ar to those of pepti c ul cer di sease, i ncl udi ng
epi gastr i c pai n and dyspepsi a or even no symptoms.
Endoscopy i s cr i ti cal for the di agnosi s of ear l y gastr i c cancer. For
exampl e, i n col l ected Wester n ser i es, al though onl y 22% of ear l y
gastr i c cancer s wer e di agnosed wi th an upper gastr oi ntesti nal tract
bar i um study, 80% wer e di agnosed wi th endoscopy. The Japanese
have cl assi fi ed ear l y gastr i c cancer pathol ogi cal l y on the basi s of
gr oss endoscopi c appearance i nto thr ee basi c mor phol ogi c types:
type I, pr otr uded or pol ypoi d; type II, super fi ci al (IIa, el evated; Ii b,
fl at; IIc, depr essed); and type III, excavated or ul cerated. Ear l y
gastr i c cancer s i ncl ude al l TNM T1 tumor s.
Despi te a hi gh potenti al cur e rate, up to 10% to 15% of ear l y
gastr i c tumor s may be associ ated wi th posi ti ve l ymph nodes.
Ther efor e, al though gastr ectomy wi th D1 or D2 l ymphadenectomy
general l y r emai ns the tr eatment of choi ce i n Japan, speci fi c cr i ter i a
have been devel oped for i denti fyi ng pati ents who r equi r e onl y
endoscopi c mucosal r esecti on. Recogni ti on that tumor si ze (mucosal
ar ea), di ffer enti ati on, l ymphovascul ar i nvasi on, and submucosal
i nvasi on ar e si gni fi cant pr edi ctor s of nodal metastases i n pati ents
wi th T1 tumor s has al so pr ovi ded the means of i denti fyi ng sel ect
pati ents wi th ear l y tumor s who r equi r e l ess aggr essi ve tr eatment.
In 1994, Takekoshi r epor ted the fi ndi ngs fr om an anal ysi s of cases
of ear l y gastr i c cancer fr om 104 center s i n Japan. In par ti cul ar,
anal ysi s of the endoscopi c appearance (pr evi ousl y descr i bed) of
ear l y tumor s i n pati ents who under went mucosal r esecti on enabl ed
the for mul ati on of speci fi c cr i ter i a for the mucosal r esecti on of ear l y

gastr i c cancer s wi thout submucosal i nvasi on. Subsequent anal yses


have l ed to r efi nements i n the cr i ter i a that must be met to ensur e
the safe endoscopi c mucosal r esecti on of AJCC T1 gastr i c cancer s.
These cr i ter i a i ncl ude onl y the fol l owi ng: (a) wel l - or moderatel y
di ffer enti ated endoscopi c type I or Ii a tumor that i s l ess than 2 cm
i n ar ea, or (b) wel l - or moderatel y di ffer enti ated endoscopi c type Ii c
tumor, wi thout an ul cer scar, that i s l ess than 1 cm i n ar ea. The
i nci dence of nodal metastases
i n pati ents i denti fi ed by these cr i ter i a was 0.01% . Al though cl ose
endoscopi c fol l ow-up i s necessar y i n pati ents who under go thi s
l ocal i zed tr eatment, the cur e rate has exceeded 90% . Conventi onal
gastr ectomy wi th at l east a D1 l ymphadenectomy i s mandated i f
submucosal i nvasi on i s found on per manent ser i al secti oni ng i n a
pati ent after an endoscopi c mucosal r esecti on.

Adjuvant Therapy
Some for m of r ecur r ence devel ops i n most pati ents who under go a
potenti al l y curati ve r esecti on for gastr i c cancer. However, al though
adjuvant therapy i s needed i n these pati ents, r esul ts have general l y
been i nconsi stent. Onl y r ecentl y has a sur vi val benefi t of adjuvant
therapy been convi nci ngl y demonstrated. Unfor tunatel y, poor
tol erance of postoperati ve tr eatment i s an obstacl e that can
fr equentl y hamper the effecti veness of the tr eatment.

Postoperative Chemotherapy
Randomi zed tr i al s i nvesti gati ng the effects of adjuvant
chemotherapy al one on sur vi val after compl ete r esecti on of gastr i c
adenocar ci noma have pr oduced i nconsi stent r esul ts. Meta-anal yses
per for med to r esol ve thi s i ssue have al so yi el ded i nconsi stent
fi ndi ngs r egar di ng the i mpact of postoperati ve chemotherapy i n
gastr i c cancer. For exampl e, i n 2002, Janunger conducted a metaanal ysi s of 21 randomi zed studi es of adjuvant systemi c
chemotherapy and found sur vi val durati on was si gni fi cantl y better
i n those who r ecei ved postoperati ve chemotherapy than i n contr ol s
(odds rati o [OR] 0.84, 95% confi dence i nter val [CI] 0.740.96).
However, when the data fr om Asi an and Wester n studi es wer e
anal yzed separatel y, no sur vi val benefi ts wer e seen for the Wester n
pati ents tr eated wi th chemotherapy (OR 0.96; 95% CI 0.831.12).
G i ven the fl aws i n the conduct of some of the randomi zed tr i al s, the
author s noted that the r esul ts of thei r meta-anal ysi s shoul d be
i nter pr eted wi th cauti on when i t came to r ecommendi ng

postoperati ve chemotherapy i n pati ents wi th gastr i c cancer.


Li kewi se, Mar i et al . noted i n thei r 2000 meta-anal ysi s of 20
randomi zed tr i al s that adjuvant chemotherapy was associ ated wi th a
sur vi val benefi t (haz ar d rati o 0.82, 95% CI 0.750.89, P <0.001).
However, these author s wer e al so r el uctant to r ecommend adjuvant
chemotherapy i n pati ents wi th gastr i c cancer because of the
i nconsi stenci es i n the fi ndi ngs fr om meta-anal yses.

Postoperative External-beam Radiation


Therapy
Most studi es of radi ati on therapy for gastr i c cancer have exami ned
radi ati on therapy as an adjuvant to sur ger y or combi ned wi th
sensi ti z i ng chemotherapy (usual l y 5-fl uor ouraci l [5-F U]).
Studi es fr om the Mayo Cl i ni c i n the 1960s of l ow-dose bol us 5-F U
wi th 40 G y exter nal -beam radi ati on therapy ver sus radi ati on
therapy al one showed that combi nati on therapy i mpr oved sur vi val .
The i mpr ovement i n sur vi val was attr i buted to a radi ati onsensi ti z i ng effect of the chemotherapy because the 5-F U dose was
r el ati vel y l ow.
Two randomi zed studi es have exami ned pati ents assi gned to r ecei ve
no addi ti onal therapy or radi ati on therapy wi th concur r ent 5-F U
after compl ete tumor r esecti on. In thei r 1979 study of 142 pati ents,
Dent et al . found no benefi t fr om thi s combi ned
r egi men, al though the fi ndi ngs may have been i nfl uenced by the
fact that some pati ents may have had an i ncompl ete r esecti on and
the radi ati on therapy dose was onl y 20 G y. In a second study i n
1984, Moer tel et al . found a benefi t to chemotherapy pl us radi ati on
therapy, but the study r esul ts may have been skewed because ten
pati ents who wer e randomi zed to the exper i mental ar m r efused
tr eatment. Nonethel ess, i nter est was generated by thi s study
because the 5-year sur vi val rate was sl i ghtl y hi gher and the l ocal
r ecur r ence rate was l ower i n the adjuvant therapy gr oup than i n the
sur ger y-onl y gr oup.
Many i nvesti gator s bel i eve that the standar d of car e for pati ents
wi th r esectabl e gastr i c cancer has changed i n the past 5 year s on
the basi s of the nati onal i nter gr oup tr i al (INT-0116) i ni ti ated by the
Southwest Oncol ogy G r oup that eval uated two cycl es of 5-F U and
l eucovor i n fol l owed by radi ati on therapy wi th concur r ent
chemotherapy fol l owi ng R0 r esecti on of gastr i c adenocar ci noma
(MacDonal d et al ., 2001). Mor e than 600 pati ents wer e randomi zed;

of these, 556 wer e eval uabl e and wer e randoml y assi gned to
curati ve r esecti on (n = 275 pati ents) or curati ve r esecti on wi th
chemoradi ati on therapy (n = 281 pati ents) consi sti ng of 45 G y
exter nal -beam radi ati on therapy del i ver ed concur r entl y wi th 5-F U
and l eucovor i n. The fi r st cycl e used the Mayo Cl i ni c r egi men (425
mg/m 2 5-F U and 20 mg/m2 l eucovor i n) for 4 consecuti ve days,
fol l owed by concur r ent chemoradi ati on therapy, wi th chemotherapy
doses decr eased at thi s poi nt and near the end of radi ati on therapy.
One month after the compl eti on of radi ati on therapy, two addi ti onal
cycl es of 5-F U and l eucovor i n wer e gi ven. Thr ee deaths wer e
attr i buted to the adjuvant therapy (1% ), and mor bi di ty was
acceptabl e; however, onl y 65% of the pati ents wer e abl e to
compl ete the adjuvant tr eatment. Nonethel ess, adjuvant therapy
pr oduced a si gni fi cant i mpr ovement i n the di sease-fr ee and overal l
3-year sur vi val rates. The medi an sur vi val i n the sur ger y-onl y
gr oup was 27 months, compar ed wi th 36 months i n the
chemoradi ati on therapy gr oup; the 3-year sur vi val rates wer e 41%
and 52% , r especti vel y. Concer ns have been voi ced r egar di ng the
sur ger y per for med and the hi gh per centage of D0
l ymphadenectomi es, wi th some i nvesti gator s ar gui ng that the
pr i nci pal benefi t of thi s r egi men i s that i t makes up for subopti mal
sur ger y. Al though 54% of pati ents had what was descr i bed as l ess
than a D1 l ymphadenectomy, thi s tr i al di d not demonstrate any
di ffer ence i n overal l or r el apse-fr ee sur vi val among the thr ee node
di ssecti on gr oups (P = 0.80).

Intraoperative Radiation Therapy


Most of the data avai l abl e on i ntraoperati ve radi ati on therapy
(IORT) for gastr i c cancer comes fr om the 1981 r epor t of Abe and
Takahashi fr om Japan. In a pr ospecti ve nonrandomi zed tr i al , these
author s compar ed 110 pati ents tr eated wi th sur ger y al one wi th 84
pati ents tr eated wi th sur ger y pl us IORT. The 5-year sur vi val rates
wer e si mi l ar i n pati ents wi th stage I di sease; however, a suggesti on
of a sur vi val benefi t fr om IORT was seen i n pati ents wi th stage II,
III, or IV di sease. In contrast, a smal l (<40 pati ents) randomi zed
study of IORT done at the Nati onal Cancer Insti tute showed nei ther
a di sease-fr ee nor an overal l sur vi val benefi t fr om IORT, despi te a
mar ked decr ease i n the fr equency of l ocor egi onal
r ecur r ence. Other studi es of IORT have general l y exami ned i t i n
combi nati on wi th other therapi es (see the next secti on).

Neoadjuvant Therapy
The use of neoadjuvant chemotherapy i n the tr eatment of gastr i c
cancer evol ved fr om pr eoperati ve tr eatment strategi es used for
esophageal and r ectal cancer s. Wi l ke et al . al so spar ked i nter est i n
thi s tr eatment as a r esul t of thei r fi ndi ngs i n pati ents wi th l ocal l y
advanced gastr i c cancer (deemed unr esectabl e ei ther cl i ni cal l y or
i ntraoperati vel y) who under went R0 r esecti on after r ecei vi ng
systemi c pr eoperati ve chemotherapy. Ther e ar e several potenti al
advantages of neoadjuvant chemotherapy for gastr i c cancer (Ajani ,
1998; Mi nsky, 1996). These i ncl ude theor eti cal bi ol ogi cal
advantages (decr eased tumor seedi ng at sur ger y), and the potenti al
oppor tuni ty to assess tumor sensi ti vi ty to a chemotherapeuti c
r egi men. That i s, i f the tumor r esponds to the neoadjuvant therapy,
the same tr eatment can be conti nued postoperati vel y. Another
theor eti cal advantage i s an i mpr oved R0 r esecti on rate. An
advantage to pr eoperati ve radi ati on therapy i s smal l er tr eatment
vol ume and di spl acement of conti guous str uctur es by the i ntact
tumor l eadi ng to r educed radi ati on therapy toxi ci ty. F i nal l y, the
i nter val r equi r ed for neoadjuvant therapy pr ovi des a ti me i n whi ch
to eval uate for pr ogr essi on of di sease, thus i mpr ovi ng pati ent
sel ecti on for r esecti on. A potenti al di sadvantage of neoadjuvant
tr eatment i s that ther e i s a r i sk of over tr eati ng pati ents wi th ear l ystage di sease, al though i mpr oved pr etr eatment stagi ng wi th EUS
mi ni mi zes thi s r i sk.
The combi nati on of etoposi de, ci spl ati n, and ei ther 5-F U (ECF ) or
doxor ubi ci n as neoadjuvant tr eatment has been eval uated i n several
tr i al s. Cl i ni cal r esponse rates have ranged fr om 21% to 31% , and
compl ete pathol ogi cal r esponse rates have ranged fr om 0% to 15% .
Mul ti var i ate anal ysi s of the thr ee phase II tr i al s of neoadjuvant
therapy at M. D. Ander son (Lowy et al ., 1999) r eveal ed that the
r esponse to neoadjuvant chemotherapy was the si ngl e most
i mpor tant pr edi ctor of overal l sur vi val after such tr eatment for
gastr i c cancer.
Several i mpor tant l essons have been l ear ned fr om phase II tr i al s
r egar di ng the r ol e of neoadjuvant chemotherapy; the most
i mpor tant one has been that the tr eatment-r el ated toxi ci ti es ar e
acceptabl e. F ur ther mor e, as pr evi ousl y menti oned, the outcome i n
those who r espond to pr eoperati ve tr eatment i s better than that i n
nonr esponder s.
In 2005, sur vi val r esul ts of the UK Medi cal Resear ch Counci l
Adjuvant G astr i c Infusi on Chemotherapy (MAG IC) tr i al wer e

pr esented at the Amer i can Soci ety of Cl i ni cal Oncol ogy annual
meeti ng. In thi s mul ti -i nsti tuti onal , pr ospecti ve randomi zed tr i al ,
503 pati ents wi th stage II or hi gher gastr i c cancer wer e randomi zed
to r ecei ve pr eoperati ve chemotherapy fol l owed by sur ger y or to
under go sur ger y al one. Those randomi zed to the pr eoperati ve
tr eatment ar m r ecei ved thr ee cycl es of ECF, fol l owed by sur ger y and
then thr ee cycl es of ECF. Onl y 42% of pati ents compl eted thei r
postoperati ve r egi men. Both pr ogr essi on-fr ee sur vi val and overal l
sur vi val wer e i mpr oved i n the tr eatment ar m (0.001 and P = 0.009
r especti vel y). The 5-year sur vi val rate was 36% i n the tr eatment
pl us sur ger y gr oup and 23% i n the
sur ger y-onl y gr oup. Despi te these pr omi si ng r esul ts, the MAG IC
tr i al i s not wi thout some cr i ti ci sm. F i r st, the tr i al i ncl uded pati ents
wi th di stal esophageal cancer s, whi ch may affect the r esul ts of the
tr i al . Second, the stagi ng i n thi s tr i al may have been subopti mal
due to l ack of EUS or stagi ng l apar oscopy.
The appr oach to adjuvant therapy for gastr i c adenocar ci noma at M.
D. Ander son has been l ar gel y to del i ver the therapy pr eoperati vel y.
Mul ti modal i ty neoadjuvant therapy combi ni ng chemotherapy wi th
exter nal -beam radi ati on therapy i s conti nui ng to be studi ed. These
studi es ar e best exempl i fi ed by a pi l ot study of pr eoperati ve
chemoradi ati on therapy wi th IORT for r esectabl e gastr i c cancer done
at M. D. Ander son (Lowy et al ., 2001) i n whi ch 24 pati ents wer e
tr eated wi th 45 G y exter nal -beam radi ati on therapy and concur r ent
i nfusi onal 5-F U (300 mg/m2 ). Pati ents wer e r estaged 4 to 6 weeks
after compl eti ng tr eatment and, i f fr ee of di sease, under went
r esecti on and IORT (10 G y). Several fi ndi ngs wer e of si gni fi cant
i nter est. Twenty-thr ee (96% ) of the 24 pati ents compl eted
chemoradi ati on therapy, a rate si gni fi cantl y hi gher than that i n
tr i al s of postoperati ve adjuvant therapy. Four pati ents had
pr ogr essi on of di sease and di d not under go r esecti on; the r emai ni ng
19 pati ents under went r esecti on wi th D2 l ymphadenectomy and
IORT. The mor bi di ty and mor tal i ty rates wer e acceptabl e (32% and
one death; r especti vel y). Of the pati ents who under went r esecti on,
two (11% ) had compl ete pathol ogi cal r esponses, and 12 (63% ) had
si gni fi cant pathol ogi cal evi dence of a tr eatment effect.
In 2004, Ajani et al . demonstrated that a pathol ogi cal compl ete
r esponse (30% ) can be achi eved thr ough a thr ee-step appr oach i n
pati ents wi th l ocal i zed gastr i c adenocar ci noma. In thi s tr i al , 28 of
34 pati ents r ecei ved i nducti on chemotherapy (5-F U [200 mg/m2 /d],
l eucovor i n [20 mg/m2 ], and ci spl ati n [20 mg/m2 /d]), fol l owed by

chemoradi ati on therapy (45 G y pl us concur r ent 5-F U) and


gastr ectomy. R0 r esecti on was achi eved i n 70% of pati ents, and a
compl ete pathol ogi cal r esponse was noted i n 30% . At a medi an
fol l ow-up of 50 months, the medi an sur vi val was 33.7 months, and
2-year sur vi val rate was 54% . Ther e wer e two tr eatment-r el ated
deaths. Thi s mul ti -i nsti tuti onal tr i al thus al so demonstrated that a
pathol ogi cal r esponse to tr eatment i s associ ated wi th a si gni fcant
sur vi val benefi t.
To di scer n whether i t i s the pathol ogi cal r esponse to pr eoperati ve
chemotherapy, and not pr etr eatment parameter s, that deter mi ne a
pati ent's outcome, i n 2005, Ajani et al . r epor ted a pr ospecti ve
nonrandomi zed study of pr eoperati ve pacl i taxel -based
chemoradi ati on therapy. In thi s anal ysi s, 43 pati ents r ecei ved two
cycl es of 5-F U, ci spl ati n, and pacl i taxel for 28 days, fol l owed by
chemoradi ati on therapy. The radi ati on r egi men i ncl uded 25 fracti ons
of 1.8 G y up to a total dose of 45 G y. Then, pati ents under went
gastr ectomy wi th spl een-pr eser vi ng D2 l ymphadenectomy after
radi ographi c and endoscopi c r estagi ng. At the ti me of anal ysi s, 78%
of pati ents had under gone an R0 r esecti on, 20% had had a compl ete
pathol ogi cal r esponse, and 15% had had a par ti al pathol ogi cal
r esponse. In thi s study, R0 r esecti on (P <0.001), pathol ogi cal
compl ete r esponse (P = 0.02), pathol ogi cal par ti al r esponse (P =
0.006), and postsur gi cal T and N status (P = 0.01 and P <0.001,
r especti vel y) wer e factor s associ ated wi th
overal l sur vi val . Al though the author s acknowl edged the i mpor tance
of pr etr eatment parameter s i n the stagi ng of gastr i c cancer,
pathol ogi cal r esponse was a major deter mi nant of outcome.
In summar y, cur r ent tr i al s of neoadjuvant chemoradi ati on therapy
ar e yi el di ng pr omi si ng r esul ts; however, these r esul ts need to be
val i dated i n the setti ng of l ar ge, pr ospecti ve randomi zed tr i al s.

Management of Advanced Disease


Many pati ents (20% 30% ) pr esent wi th stage IV di sease, and an
addi ti onal 28% to 37% i ni ti al l y bel i eved to have l ocal i zed di sease
ar e found to have metastati c di sease after compl ete stagi ng. The 5year sur vi val rate for pati ents wi th stage IV di sease appr oaches
zer ohence, a l ar ge per centage of newl y di agnosed gastr i c cancer
pati ents ar e i ncurabl e. Because of thi s overal l l ow cur e rate for
gastr i c cancer and the advanced di sease stage at pr esentati on i n
many pati ents, pal l i ati on i s an essenti al component of gastr i c cancer

management. An appr opr i ate under standi ng and use of pal l i ati ve
techni ques i s ther efor e essenti al .
Opti mal pal l i ati on r el i eves or abates symptoms, whi l e causi ng
mi ni mal mor bi di ty and i mpr ovi ng the pati ent's qual i ty of l i fe.
Pr ol onged sur vi val i s general l y not a goal of pal l i ati ve tr eatment,
but pal l i ati on may r el i eve debi l i tati ng and potenti al l y l i fethr eateni ng pr obl ems, such as gastr oi ntesti nal bl eedi ng or gastr i c
outl et obstr ucti on, whi ch may di mi ni sh sur vi val .

Palliative Surgery
Sur gi cal pal l i ati on of advanced gastr i c cancer may i ncl ude r esecti on
or bypass al one or i n combi nati on wi th other i nter venti ons.
Compl ete stagi ng i s r equi r ed for deter mi nati on of the best pal l i ati ve
appr oach.
Pal l i ati on by endoscopi c means may be appr opr i ate for pati ents wi th
per i toneal di sease, hepati c metastases, extensi ve nodal metastases,
or asci tes and for pati ents wi th pr obl ems that i ncl ude bl eedi ng or
pr oxi mal or di stal gastr i c obstr ucti on. Both mor bi di ty and mor tal i ty
ar e r el ati vel y hi gh i n these pati ents wi th a shor t l i fe expectancy.
Laser r ecanal i z ati on or si mpl e di l atati on wi th or wi thout stent
pl acement can be used to tr eat obstr ucti on. Repeat endoscopy may
be r equi r ed at per i odi c i nter val s. Pati ents who under go stent
pl acement for gastr i c outl et obstr ucti on ar e fr equentl y abl e to eat
sol i d or semi sol i d food and may not r equi r e any fur ther i nter venti on
befor e death.
The sel ecti on of pati ents for pal l i ati ve r esecti on i s compl ex. In
pati ents wi th an excel l ent per for mance status, exper i enced
sur geons can per for m pal l i ati ve di stal gastr ectomy wi th mi ni mal
mor bi di ty and acceptabl e mor tal i ty rates. Pal l i ati ve total
gastr ectomy and esophagogastr ectomy, however, shoul d be
appr oached wi th gr eater cauti on because the mor bi di ty fr om these
pr ocedur es i s hi gher. Sur ger y achi eves good pal l i ati on l ess than
50% of the ti me. In 2004, Mi nor r etr ospecti vel y r evi ewed pati ents
who under went R1 or R2 r esecti ons and di vi ded them i nto pal l i ati ve
(R1/R2) r esecti ons and nonpal l i ati ve r esecti ons (R1/R2). They
r epor ted a per i operati ve mor tal i ty rate of 7% associ ated wi th
pal l i ati ve r esecti ons ver sus 4% associ ated
wi th nonpal l i ati ve r esecti ons; the medi an sur vi val was 8.3 and 13.5
months, r especti vel y (P <0.001).
Speci fi c i ndi cati ons for pal l i ati ve r esecti on, sur gi cal bypass (open or

l apar oscopi c), and endoscopi c pal l i ati on r emai n undefi ned. However,
assessment of mor bi di ty, mor tal i ty, and qual i ty of l i fe has r eveal ed
that car eful l y sel ected pati ents (par ti cul ar l y those wi thout
macr oscopi c metastati c di sease) may benefi t fr om pal l i ati ve
r esecti on. Advanced endoscopi c techni ques, i ncl udi ng l aser or
ar gon-beam tumor abl ati on and endoscopi c pl acement of coated
metal l i c stents, pr ovi de better pal l i ati on of dysphagi a than sur gi cal
bypass wi th l ower mor bi di ty. Mul ti modal i ty therapy consi sti ng of
radi otherapy, sur ger y, and endoscopy i s l i kel y to l ead to
i mpr ovements i n qual i ty of l i fe and l ower mor bi di ty wi th pal l i ati ve
therapy. However, ear l i er di agnosi s and advances i n curati ve
therapy ar e ul ti matel y the onl y way i n whi ch the hi gh i nci dence and
mor bi di ty associ ated wi th advanced di sease i n pati ents wi th gastr i c
adenocar ci noma wi l l be defi ni ti vel y r educed.

Palliative Chemotherapy
G i ven the mi ni mal sur vi val benefi t fr om combi nati on chemotherapy
i n pati ents wi th advanced gastr i c cancer, i nvesti gator s have debated
i ts r ol e ver sus that of best suppor ti ve car e. As a r esul t, four
randomi zed tr i al s have been conducted to assess the i mpact of
combi nati on chemotherapy on sur vi val and qual i ty of l i fe. The
combi nati on r egi mens i ncl uded FAMTX (5-F U, doxor ubi ci n, and hi ghdose methotr exate), F EMTX (5-F U, epi r ubi ci n, and hi gh-dose
methotr exate), and ELF (etoposi de, l eucovor i n, and 5-F U). Pati ents
who r ecei ved combi nati on chemotherapy had both better sur vi val
(39 months) and qual i ty of l i fe than di d pati ents gi ven best
suppor ti ve car e. Despi te thi s, the outcome fr om advanced gastr i c
cancer r emai ns poor.

Palliative Radiation Therapy


Ther e ar e several i sol ated case r epor ts descr i bi ng the benefi t of
radi ati on therapy for the pal l i ati ve tr eatment of advanced gastr i c
car ci noma. However, no l ar ge pr ospecti ve tr i al has demonstrated a
l ong-ter m benefi t fr om radi ati on therapy al one i n pati ents wi th
advanced di sease. Thi s modal i ty i s most l i kel y best used i n
combi nati on wi th chemotherapy, as descr i bed pr evi ousl y i n thi s
chapter.

Intraperitoneal Hyperthermic Perfusion


Intraper i toneal hyper ther mi c per fusi on has been exami ned i n
several tr i al s as a tr eatment for advanced gastr i c cancer. For

exampl e, i n 1988, Koga et al . r evi ewed thei r exper i ence wi th a


combi nati on of hyper ther mi a and mi tomyci n C as adjuvant
tr eatment for pati ents wi th per i toneal r ecur r ence of gastr i c cancer.
These r esear cher s r epor ted that thi s pr ocedur e was techni cal l y
feasi bl e and safe. In 1990, F uji moto et al . eval uated 59 pati ents
wi th advanced gastr i c cancer who under went gastr ectomy and wer e
then randoml y assi gned to r ecei ve ei ther no fur ther therapy or
i ntraper i toneal hyper ther mi c per fusi on. The pati ents tr eated wi th
per fusi on sur vi ved l onger than di d the contr ol s (1-year sur vi val rate
of 80% vs. 34% ). A si gni fi cant sur vi val benefi t was al so seen i n
pati ents wi th per i toneal seedi ng who under went per fusi on
wi th hyper ther mi c mi tomyci n C. Si mi l ar l y, i n 1996, Yonemura et al .
r epor ted that adjuvant hyper ther mi c i ntraper i toneal chemotherapy
wi th mi tomyci n C, etoposi de, and ci spl ati n after gastr i c r esecti on i n
pati ents wi th per i toneal seedi ng r esul ted i n compl ete r esponse i n 8
(19% ) of 43 pati ents and par ti al r esponses i n 9 (21% ) of 43
pati ents. A randomi zed tr i al conducted by Yu i n pati ents who wer e
tr eated at the ti me of compl ete r esecti on of tumor s that penetrated
the gastr i c ser osa but had no evi dence of per i toneal metastases
showed that hyper ther mi c i ntraper i toneal chemotherapy wi th
mi tomyci n C l ed to a r educed i nci dence of per i toneal r ecur r ence and
a smal l sur vi val advantage at 3 year s. In 2005, Yonemura et al .
pr ospecti vel y r evi ewed 107 pati ents wi th per i toneal di ssemi nati on
fr om gastr i c adenocar ci nomas. Over a 10-year per i od, 65 pati ents
under went cytor educti ve sur ger y i n combi nati on wi th
i ntraper i toneal hyper ther mi c per fusi on befor e 1995, and 42 pati ents
under went cytor educti ve sur ger y i n combi nati on wi th
i ntraper i toneal hyper ther mi c per fusi on wi th per i tonectomy after
1995. The per fusi on r egi men i ncl uded mi tomyci n C, ci spl ati n, and
etoposi de. Compl ete cytor educti ve sur ger y was achi eved i n 43% of
107 pati ents. Ther e was a 21% postoperati ve compl i cati on rate, and
ther e wer e thr ee postoperati ve deaths (al l i n the per i tonectomy
gr oup), accounti ng for 7% of the pati ents i n thi s gr oup. At a medi an
fol l ow-up of 46 months, the 5-year sur vi val rates i n those who had
compl ete and i ncompl ete cytor educti ve sur ger y wer e 13% and 2% ,
r especti vel y (P <0.001), wi th a medi an sur vi val of 19 and 7.8
months, r especti vel y. F ur ther mor e, the 5-year sur vi val rate for
pati ents who under went cytor educti ve sur ger y by per i tonectomy was
27% (P <0.001). Mul ti var i ate anal ysi s showed that compl ete
cytor educti ve sur ger y (P = 0.010) and per i tonectomy (P = 0.012)
wer e associ ated wi th a mor e favorabl e outcome. However,
per i tonectomy was al so associ ated wi th hi gher postoperati ve

mor bi di ty (43% ) and mor tal i ty (7% ) rates. Other center s, however,
have not found such encouragi ng r esul ts. Thi s techni que i s cur r entl y
under i nvesti gati on i n a few center s ar ound the wor l d.
In summar y, ther e i s no standar d tr eatment for pati ents wi th
per i toneal car ci nomatosi s stemmi ng fr om gastr i c adenocar ci noma
other than systemi c chemotherapy i n sel ected cases. Pr ospecti ve
randomi zed studi es ar e r equi r ed to cl ar i fy the r ol e of
i ntraper i toneal therapy i n thi s setti ng.

Immunotherapy and Hormonal Therapy


Numer ous i nvesti gator s have exami ned the use of i mmunol ogi c
agents al one and i n combi nati on wi th chemotherapy as adjuvant
tr eatment i n pati ents wi th advanced gastr i c adenocar ci noma, but
the fi ndi ngs have been confl i cti ng. In 1994, Maehara et al . r epor ted
that the rates of per i toneal r ecur r ence wer e si gni fi cantl y l ower and
sur vi val ti mes si gni fi cantl y l onger i n pati ents randoml y assi gned to
r ecei ve standar d chemotherapy pl us i ntraper i toneal i njecti ons of the
str eptococcal pr eparati on OK-432 than i n pati ents who r ecei ved
chemotherapy al one. Si mi l ar l y, data fr om Japan and Kor ea
suggested that i mmunochemotherapy consi sti ng of Micr obacter iumder i ved pol ysacchar i des pr ovi des a sur vi val benefi t i n pati ents
fol l owi ng potenti al l y curati ve r esecti on. However, mor e r ecent tr i al s
have not demonstrated any
di ffer ence i n sur vi val . For exampl e, i n 2004, Sato et al . conducted a
pr ospecti ve randomi zed tr i al i n pati ents wi th gastr i c
adenocar ci noma who under went ei ther R0 r esecti on fol l owed by
adjuvant OK-432 and 5-deoxy-5 fl uor our i di ne tr eatment (n = 144)
or R0 r esecti on onl y (n = 143). The 5-year sur vi val rate i n both
gr oups was vi r tual l y the same: 63.8% and 62.9% , r especti vel y (P =
0.7996). The outcome fr om adjuvant hor monal therapy wi th
tamoxi fen i n pati ents wi th advanced gastr i c cancer has al so been
di sappoi nti ng. Never thel ess, studi es of i mmunotherapy and
hor monal therapy ar e ongoi ng. The r ol e of i mmunomodul ator s i n
gastr i c cancer r emai ns to be defi ned.

Surveillance
We typi cal l y see pati ents ever y 3 months for the fi r st 2 year s
fol l owi ng curati ve r esecti on of gastr i c adenocar ci noma. At each
fol l ow-up, a car eful hi stor y and physi cal exami nati on ar e per for med,
al ong wi th l aborator y studi es (compl ete bl ood cel l count and l i ver

functi on tests). Chest radi ographs ar e obtai ned ever y 6 months, and
abdomi nal and pel vi c CT i s per for med 6 months after sur ger y and
then year l y ther eafter. Endoscopy shoul d be consi der ed at the end
of the fi r st year i n pati ents who have under gone subtotal
gastr ectomy and can then be done year l y for 4 to 5 year s. Pati ents
who r ecei ve pr otocol -based therapy often have mor e fr equent
stagi ng studi es, but thi s has never been pr oven to i mpact pati ent
sur vi val . Per haps the most i mpor tant r easons to fol l ow pati ents
cl osel y ar e to enabl e any postgastr ectomy sequel ae to be deal t wi th
and to acqui r e accurate r ecur r ence and sur vi val data on pati ents i n
cl i ni cal tr i al s.

Gastric Lymphoma
In contrast to the decr easi ng i nci dence of gastr i c adenocar ci noma,
the i nci dence of gastr i c l ymphoma i s steadi l y i ncr easi ng, wi th nonHodgki n l ymphomas now the second most common mal i gnancy of the
stomach after adenocar ci noma. H. pylor i appear s to be a causati ve
agent i n the devel opment of both gastr i c l ymphoma and MALT
l ymphoma. The stomach i s the most common si te of l ymphoma i n
the gastr oi ntesti nal tract, accounti ng for two-thi r ds of
gastr oi ntesti nal l ymphomas. The average age of pati ents wi th
gastr i c l ymphoma i s 60 year s. The most fr equent symptoms at the
ti me of pr esentati on ar e pai n (68% ), wei ght l oss (28% ), bl eedi ng
(28% ), and fati gue (16% ). Obstr ucti on, per forati on, and massi ve
bl eedi ng ar e uncommon.
Befor e the advent of endoscopy, the di agnosi s of gastr i c l ymphoma
was usual l y made at operati on. Endoscopy now per mi ts a cor r ect
ti ssue di agnosi s to be made i n appr oxi matel y 80% of cases. Most
l esi ons ar e l ocated i n the di stal stomach and spr ead l ocal l y by
submucosal i nfi l trati on. Once the di agnosi s has been made, a
car eful wor kupi ncl udi ng a physi cal exami nati on (wi th speci al
attenti on to adenopathy); r outi ne l aborator y tests, al ong wi th
l actate dehydr ogenase and 2-mi cr ogl obul i n deter mi nati ons; a bone
mar r ow bi opsy; chest radi ograph; and CT scan of the chest,
abdomen, and pel vi sshoul d be done to ful l y deter mi ne the extent
of di sease. Pathol ogi cal exami nati on shows most cases to be B-cel l
non-Hodgki n l ymphoma, and the di ffuse hi sti ocyti c subtype i s
pr edomi nant. The di sease i s staged usi ng the modi fi ed
Ann Ar bor stagi ng system (see Chapter 17). Hi stol ogi c grade and
pathol ogi cal stage ar e two var i abl es that i ndependentl y pr edi ct
sur vi val . However, one shoul d be fami l i ar wi th the i nter nati onal

i ndex when car i ng for these pati ents.


Tr eatment for MALT l ymphoma typi cal l y i ncl udes aci d suppr essi on
therapy (pr oton pump i nhi bi tor s or H2 bl ocker s), metr oni dazol e, and
other anti bi oti cs. Pati ents need cl ose endoscopi c sur vei l l ance to
both document r egr essi on and detect r el apse, as wel l as to
deter mi ne when anti -H. pylor i tr eatment shoul d be r epeated.
Exter nal -beam radi ati on (30 G y) and/or chemotherapy i s offer ed to
(a) those who do not r espond to an anti bi oti c eradi cati on r egi men
and (b) hi gh-r i sk pati ents (i .e., those wi th l ymph node i nvol vement
or t[11;18] chr omosomal transl ocati on). At pr esent, gastr i c
r esecti on i s rar el y per for med for pati ents wi th MALT l ymphomas.
The tr eatment of gastr i c l ymphoma var i es among i nsti tuti ons, wi th
some center s advocati ng sur ger y al one, al though the number s of
such i nsti tuti ons ar e decr easi ng, and other s advocati ng
chemotherapy and radi ati on therapy al one. Sur ger y i s necessar y i n
some cases to confi r m the di agnosi s. Sur gi cal r esecti on i s curati ve
i n pati ents wi th l ocal i zed di sease, al though hal f of r esected pati ents
r equi r e chemotherapy. Al though mor e accurate stagi ng i s obtai ned
at sur ger y, thi s i s not a suffi ci ent r eason to per for m r esecti on. If
sur ger y i s per for med, an attempt shoul d be made to r esect the ar ea
gr ossl y i nvol ved wi th l ymphoma but l eave gr ossl y nor mal stomach
i ntact. Negati ve mar gi ns ar e not necessar y for cur e. In a 1990
nonrandomi zed study of pati ents wi th stage I and II gastr oi ntesti nal
l ymphomas, Tal amonti et al . noted that sur ger y al one pr oduced a 5year sur vi val rate of 82% , wher eas radi ati on therapy pr oduced a 5year sur vi val rate of onl y 50% .
Many pati ents wi th gastr i c l ymphoma who under go i ni ti al r esecti on
al so r ecei ve chemotherapy. However, some author s have found no
sur vi val benefi t associ ated wi th adjuvant chemotherapy. Sti l l other
author s bel i eve that pati ents can benefi t fr om a combi nati on of
radi ati on therapy and chemotherapy wi thout any need for sur ger y.
In fact, 10-year sur vi val rates of 80% have been seen i n pati ents
wi th Ann Ar bor stage IE and IIE gastr i c l ymphoma tr eated wi th
chemotherapy al one.
At M. D. Ander son, pati ents wi th gastr i c l ymphoma ar e i ni ti al l y
tr eated wi th a chemotherapeuti c r egi men based on doxor ubi ci n and
cycl ophosphami de, wi th a compl ete r esponse documented i n mor e
than 80% of pati ents tr eated wi th thi s pr otocol . Pati ents wi th a hi gh
i nter nati onal i ndex (i ndi cati ve of aggr essi ve di sease) may be
candi dates for bone mar r ow transpl ant. Radi ati on therapy and
sur ger y ar e r eser ved for pati ents who do not have a compl ete

r esponse to chemotherapy or who have r ecur r ent di sease.

Gastric Carcinoids
Car ci noi ds of the stomach, fi r st r epor ted i n 1923, ar e a rar e enti ty
and di sti nct fr om other car ci noi d tumor s. Despi te ear l i er r epor ts i n
whi ch gastr i c car ci noi ds wer e r epor ted to consti tute onl y 2% of
car ci noi d tumor s, evi dence fr om the Sur vei l l ance, Epi demi ol ogy, and
End Resul ts database i s now suggesti ng that gastr i c car ci noi ds
consti tute up to 5% of al l car ci noi ds. Contemporar y data
fr om case ser i es ar e al so suggesti ng a r i si ng i nci dence of these
tumor s.
G astr i c car ci noi ds ar i se fr om enter ochr omaffi n-l i ke cel l s of the
fundus of the stomach. Owi ng to the r epor ted r el ati onshi p between
pr oton pump i nhi bi tor s and car ci noi ds seen i n rats, gastr i c
car ci noi ds have gai ned wi der r ecogni ti on. The pr esenti ng featur es of
gastr i c car ci noi ds ar e var i abl e; however, they ar e commonl y
di scover ed as an i nci dental fi ndi ng dur i ng the wor kup for other
symptoms, when a yel l ow nodul e i s found i n the fundus of the
stomach.
G astr i c car ci noi ds ar e cl assi fi ed i nto thr ee types: Type I car ci noi ds
ar e associ ated wi th type A chr oni c atr ophi c gastr i ti s, type II
car ci noi ds ar e associ ated wi th Zol l i nger-El l i son syndr ome wi th
mul ti pl e endocr i ne neopl asi a-I (MEN-I) syndr ome, and type III ar e
sporadi c gastr i c car ci noi ds. Type I car ci noi ds ar e the most common
type of gastr i c car ci noi d (65% 83% ) and ar e found pr edomi nantl y
i n women. These pati ents typi cal l y have el evated pl asma gastr i n
l evel s and l ow gastr i c aci d pr oducti on. On macr oscopi c exami nati on,
the l esi ons ar e mul ti centr i c, smal l (<1 cm), and l ocated i n the
fundus. Overal l , they gr ow sl owl y and rar el y metastasi ze to other
or gans. Type II gastr i c car ci noi ds ar e the l east common type,
accounti ng for 8% of cases wi th an equal gender di str i buti on.
Al though type II gastr i c car ci noi ds ar e associ ated wi th Zol l i ngerEl l i son syndr ome i n conjuncti on wi th MEN-1 syndr ome, they shar e
featur es wi th type I car ci noi ds, such as l ocati on i n the fundus,
mul ti centr i ci ty, el evated pl asma gastr i n l evel , and smal l si ze (<1
cm). Type III gastr i c car ci noi ds, whi ch ar e sporadi c car ci noi ds,
r epr esent 23% of cases and ar e found pr edomi nantl y i n men (80% );
the mean age of pati ents at di agnosi s i s 49 year s. Pati ents may
compl ai n of hi stami ne-pr oduci ng symptoms, such as cutaneous
fl ushi ng, br onchospasm, i tchi ng, and l acr i mati on. Unl i ke the other

two types of gastr i c car ci noi ds, sporadi c tumor s ar e si ngl e, sol i tar y,
often l ar ge (25 cm), and l ocated i n the antr um or fundus of the
stomach. F ur ther mor e, the natural cour se of type III gastr i c
car ci noi ds i s mor e aggr essi ve, wi th hepati c metastasi s found at
di agnosi s i n up to 50% of cases.
G astr i c car ci noi ds ar e di agnosed by both bi ochemi cal and hi stol ogi c
means. Upper gastr oi ntesti nal endoscopy, i ncl udi ng EUS, i s al so
essenti al to eval uate the number, si ze, extent, and l ocati on of
l esi ons. In addi ti on, the endoscopi st shoul d car eful l y l ook for
duodenal car ci noi ds, especi al l y i n pati ents wi th type II gastr i c
car ci noi ds associ ated wi th Zol l i nger-El l i sonMEN-I syndr ome.
Extensi ve gastr i c bi opsy shoul d be per for med i n those wi th
suspected gastr i c car ci noi ds, checki ng for hi stol ogi c chr omograni n,
featur es of dyspl asi a, mucosal atr ophy, and the degr ee of mucosal
i nvasi on. It appear s that the rate of di agnosi s cor r el ates wi th the
number of bi opsi es per for med. F ur ther mor e, CT of the abdomen i s
essenti al to excl ude metastasi s to the l i ver and nodal i nvol vement.
The type of gastr i c car ci noi d di ctates the natur e of tr eatment. For
pati ents wi th ei ther type I or II car ci noi ds, and wi th tumor s l ess
than 1 cm or wi th fewer than thr ee to fi ve l esi ons, tr eatment
typi cal l y consi sts of an endoscopi c pol ypectomy or endoscopi c
mucosal r esecti on, wi th endoscopi c sur vei l l ance ever y 6 months.
Endoscopi c mucosal r esecti on shoul d be appr oached wi th cauti on,
however, gi ven the r epor ts of posi ti ve mar gi ns i n tumor s r emoved
by thi s means. Antr ectomy or l ocal exci si on may be per for med i n a
young pati ent wi th an el evated gastr i n l evel who has r ecur r ent or
mul ti focal di sease. Thi s tr eatment wi l l decr ease gastr i n l evel s and
fr equentl y l eads to the r egr essi on of other tumor s. Ol der pati ents
wi th many l esi ons may be fol l owed i f the l esi ons ar e smal l . For
di ffuse or r ecur r ent di sease, a compl eti on gastr ectomy may be
r ecommended, dependi ng on the pati ent's age and cour se of
di sease. In contrast, those wi th type III di sease shoul d be
consi der ed for en bl oc r esecti on wi th l ymphadenectomy, dependi ng
on the tumor si ze, al though the hi gh i nci dence of hepati c metastasi s
shoul d temper thi s deci si on.
The pr ognosi s for pati ents wi th gastr i c car ci noi ds i s var i abl e and
depends mai nl y on the type. Several studi es have suggested that
the 5-year sur vi val rates for al l types of gastr i c car ci noi ds ar e
between 48% and 52% ; these studi es di d not categor i ze the
car ci noi ds accor di ng to thei r types, so di ffer ences i n the sur vi val
rates between the types wer e not shown. It appear s that the 5-year

sur vi val rates for pati ents wi th type I or II gastr i c car ci noi ds ar e
between 60% and 75% , al though l ymph node i nvol vement i s mor e
common i n type II di sease, whi ch woul d l i kel y transl ate i nto a l ower
rate. In contrast, the 5-year sur vi val rate i n pati ents wi th type III
gastr i c car ci noi ds i s l ess than 50% .
Fol l ow-up i n pati ents wi th gastr i c car ci noi ds pr i mar i l y consi sts of
pl asma chr omograni n deter mi nati ons. Pl asma gastr i n and ur i nar y 5hydr oxyi ndol eaceti c aci d (5-HIAA) l evel s may al so be eval uated,
al though ur i nar y 5-HIAA l evel s ar e l ess sensi ti ve.

Gastric Intestinal Stromal Tumors of the


Stomach
G ISTs ar e the most common mesenchymal tumor s of the stomach,
wi th the stomach bei ng the most common l ocati on of these tumor s
i n the gastr oi ntesti nal tract (40% ), fol l owed by the smal l i ntesti ne
(32% ). G ISTs of the stomach ar e pr edomi nantl y found i n mal es,
wi th a medi an age at di agnosi s of 63 year s. The pr esenti ng featur es
i n these pati ents ar e var i ed and i ncl ude bl eedi ng (38% ), abdomi nal
pai n (11.8% ), and r uptur e (1% ); 12% of pati ents have no
symptoms. The medi an si ze of G ISTs of the stomach i s 6 cm.
Regar dl ess of the l ocati on of these tumor s i n the stomach, R0
r esecti on r emai ns the tr eatment of choi ce, confer r i ng a 5-year
sur vi val of 55% . Several studi es have shown that the featur es
r ecommended i n the NIH gui del i nes, tumor si ze (>5 cm) and mi toti c
i ndex (>5/50 hpf ), ar e associ ated wi th a l ess favorabl e outcome. In
the l ar gest r etr ospecti ve anal ysi s of G ISTs of the stomach
per for med by Mi etti ten et al . i n 2005, tumor l ocati on i n the
gastr oesophageal juncti on or fundus, ul cerati on, coagul ati ve
necr osi s, and mucosal i nvasi on wer e found to be associ ated wi th a
poor outcome (P <0.001). Antral tumor s, however, wer e found to be
associ ated wi th a mor e favorabl e outcome (P <0.001).
Those pati ents wi th unr esectabl e or metastati c di sease ar e offer ed
tr eatment wi th Imati ni b (G l eevec, an oral tyr osi ne ki nase i nhi bi tor ).
They may then be r e-eval uated for potenti al r esecti on i f they
demonstrate r esponse to tr eatment. F ur ther speci fi c detai l s
r egar di ng G ISTs ar e di scussed i n Chapter 5.

Conclusion
Str i des ar e bei ng made i n the tr eatment of gastr i c cancer. However,

al though several di agnosti c modal i ti es ar e avai l abl e for stagi ng


gastr i c cancer and ongoi ng tr i al s of neoadjuvant tr eatment ar e
yi el di ng pr omi si ng r esul ts, better systemi c agents and betterdesi gned tr i al s ar e sti l l needed. Despi te the cur r ent pr ogr ess, the
outcome i n pati ents wi th gastr i c cancer general l y r emai ns poor. As
we enter the era of tar geted therapy, i t i s i mperati ve that such
therapy al so be devel oped for gastr i c cancer and that mol ecul ar
pr edi ctor s ar e i denti fi ed to hel p i n sel ecti ng appr opr i ate tr eatment
for pati ents.

Recommended Reading
Ajani JA, Baker J, Pi ster s PW, et al . Ir i notecan pl us ci spl ati n i n
advanced gastr i c or gastr oesophageal juncti on car ci noma.
Oncology (Huntingt) 2001;15:5254.
Ajani JA, Mansfi el d PF, Crane CH. Pacl i taxel -based
chemoradi otherapy i n l ocal i zed gastr i c car ci noma: degr ee of
pathol ogi c r esponse and not cl i ni cal parameter s di ctated pati ent
outcome. J Clin Oncol 2005;23:12371244.
Ajani JA, Mansfi el d PF, Janjan J, et al . Mul ti -i nsti tuti onal tr i al s of
pr eoperati ve chemoradi otherapy i n pati ents wi th potenti al l y
r esectabl e gastr i c car ci noma. J Clin Oncol 2004;22:22742280.
Ajani JA, Mansfi el d PF, Lynch PM, et al . Enhanced stagi ng and al l
chemotherapy pr eoperati vel y i n pati ents wi th potenti al l y
r esectabl e gastr i c car ci noma. J Clin Oncol 1999;17:24032411.
Ajani JA, Ota DM, Jessup JM, et al . Resectabl e gastr i c car ci noma.
An eval uati on of pr eoperati ve and postoperati ve chemotherapy.
Cancer 1991;68:15011506.
Al exander HR, G r em JL, Pass HI, et al . Neoadjuvant
chemotherapy for l ocal l y advanced gastr i c adenocar ci noma.
Oncology (Huntingt) 1993;7:3742.
Behr ns KE, Dal ton RR, van Heer den JA, Sar r MG . Extended l ymph
node di ssecti on for gastr i c cancer. Is i t of val ue? Sur g Clin Nor th
Am 1992;72:433443.

Bonenkamp JJ, Her mans J, Sasako M, et al . Extended l ymph-node


di ssecti on for gastr i c cancer. Dutch G astr i c Cancer G r oup. N Engl
J Med 1999;340:908914.
Bonenkamp JJ, Songun I, Her mans J, et al . Randomi sed
compar i son of mor bi di ty after D1 and D2 di ssecti on for gastr i c
cancer i n 996 Dutch pati ents. Lancet 1995;345:745748.
Boz zetti F, Bonfanti G , Bufal i no R, et al . Adequacy of mar gi ns of
r esecti on i n gastr ectomy for cancer. Ann Sur g 1982;196:685
690.
Bozetti F, Mar ubi ni E, Bonfanti G , et al . Total ver sus subtotal
gastr ectomy: sur gi cal mor bi di ty and mor tal i ty rates i n
mul ti center Ital i an randomi zed tr i al . The Ital i an G astr oi ntesti nal
Tumor Study G r oup. Ann Sur g 1997;226:613.
Brady MS, Rogatko A, Dent LL, et al . Effect of spl enectomy on
mor bi di ty and sur vi val fol l owi ng curati ve gastr ectomy for
car ci noma. Ar ch Sur g 1991;126:359364.
Bur ke EC, Kar peh MS, Conl on KC, et al . Lapar oscopy i n the
management of gastr i c adenocar ci noma. Ann Sur g
1997;225:262267.
Bur ke EC, Kar peh MS, Conl on KC, et al . Per i toneal l avage
cytol ogy i n gastr i c cancer : an i ndependent pr edi ctor of outcome.
Ann Sur g Oncol 1998;5:411415.
Cady B, Rossi RL, Si l ver man ML, Pi cci one W, Heck TA. G astr i c
adenocar ci noma. A di sease i n transi ti on. Ar ch Sur g
1989;124:303308.
Conl on KC, Kar peh MS. Lapar oscopy and l apar oscopi c ul trasound
i n the stagi ng of gastr i c cancer. Semin Oncol 1996;23:347351.

Cor r ea P, Shi ao YH. Phenotypi c and genotypi c events i n gastr i c


car ci nogenesi s. Cancer Res 1994;54:1941s1943s.

Cr ew KD, Neugut AI. Epi demi ol ogy of upper gastr oi ntesti nal
mal i gnanci es. Semin Oncol 2004;31:450464.
Cuschi er i A, Weeden S, F i el di ng J, et al . Pati ent sur vi val after D1
and D2 r esecti ons for gastr i c cancer : l ong-ter m r esul ts of the
MRC randomi zed sur gi cal tr i al . Sur gi cal Cooperati ve G r oup. Br J
Cancer 1999;79:15221530.
D'Angel i ca M, G onen M, Br ennan M, Tur nbul l A, Bai ns M, Kar peh
MS. Patter n of i ni ti al r ecur r ence i n compl etel y r esected gastr i c
adenocar ci noma. Ann Sur g 2004;240:808816.
D'Ugo DM, Pende V, Per si ani R, et al . Lapar oscopi c stagi ng of
gastr i c cancer : an over vi ew. J Am Coll Sur g 2003;196(6):965
974.
Davi es J, Chal mer s AG , Sue-Li ng HM, et al . Spi ral computed
tomography and operati ve stagi ng of gastr i c car ci noma: a
compar i son wi th hi stopathol ogi cal stagi ng. G ut 1997;41:314319.
Dent DM, Wer ner ID, Novi s B, et al . Pr ospecti ve randomi zed tr i al
of combi ned oncol ogi cal therapy for gastr i c car ci noma. Cancer
1979;44:385391.
Duff SE, Li C, Jez i or ska M, et al . Vascul ar endothel i al gr owth
factor s C and D l ymphangi ogenesi s i n gastr oi ntesti nal tract
mal i gnanci es. Br J Cancer 2003;89:426430.
Dupont JB, Lee JR, Bur ton G R, et al . Adenocar ci noma of the
stomach: r evi ew of 1,497 cases. Cancer 1978;41(3):941947.
Ear l e CC, Mar oun JA. Adjuvant chemotherapy after curati ve
r esecti on for gastr i c cancer i n non-Asi an pati ents: r evi si ti ng a
meta-anal ysi s of randomi sed tr i al s. Eur J Cancer 1999;35:1059
1064.
El l C, May A. Sel f-expandi ng metal stents for pal l i ati on of
stenosi ng tumor s of the esophagus and car di a: a cr i ti cal r evi ew.
Endoscopy 1997;29:392398.

Estape J, G rau JJ, Al cobendas F, et al . Mi tomyci n C as an adjuvant


tr eatment to r esected gastr i c cancer. A 10-year fol l ow-up. Ann
Sur g 1991;213:219221.
F uji i K, Isoz aki H, Okaji ma K, et al . Cl i ni cal eval uati on of l ymph
node metastasi s i n gastr i c cancer defi ned by the fi fth edi ti on of
the TNM cl assi fi cati on i n compar i son wi th the Japanese system.
Br J Sur g 1999;86:685689.
F uji moto S, Shr estha RD, Kokubun M, et al . Posi ti ve r esul ts of
combi ned therapy of sur ger y and i ntraper i toneal hyper ther mi c
per fusi on for far-advanced gastr i c cancer. Ann Sur g
1990;212:592596.
G astr oi ntesti nal Tumor Study G r oup. A compar i son of combi nati on
chemotherapy and combi ned modal i ty therapy for l ocal l y
advanced gastr i c car ci noma. Cancer 1982;49:17711777.
G eoghegan JG , Keane TE, Rosenber g IL, et al . G astr i c cancer : the
case for a mor e sel ecti ve pol i cy i n sur gi cal management. J R Coll
Sur g Edinb 1993;38(4):208212.
G oh PM, So JB. Rol e of l apar oscopy i n the management of
stomach cancer. Semin Sur g Oncol 1999;16:321326.
G r eenl ee RT, Mur ray T, Bol den S, et al . Cancer stati sti cs, 2000.
CA Cancer J Clin 2000;50:733.
G under son LL, Sosi n H. Adenocar ci noma of the stomach: ar eas of
fai l ur e i n a r e-operati on ser i es (second or symptomati c l ook):
cl i ni copathol ogi c cor r el ati on and i mpl i cati ons for adjuvant
therapy. Int J Radiat Oncol Biol Phys 1982;8:111.
Har tgr onk HH, van de Vel de CJ, Putter H, et al . Extended l ymph
node di ssecti on for gastr i c cancer : who may benefi t? F i nal r esul ts
of the randomi zed Dutch gastr i c cancer gr oup tr i al . J Clin Oncol
2004;22:20692077.
Hamazoe R, Maeta M, Kai bara N. Intraper i toneal
ther mochemotherapy for pr eventi on of per i toneal r ecur r ence of

gastr i c cancer. F i nal r esul ts of a randomi zed contr ol l ed study.


Cancer 1994;73:20482052.

Her manek P, Wi tteki nd C. Resi dual tumor (R) cl assi fi cati on and
pr ognosi s. Semin Sur g Oncol 1994;10:1220.
Her mans J, Bonenkamp JJ, Boon MC, et al . Adjuvant therapy after
curati ve r esecti on for gastr i c cancer : meta-anal ysi s of
randomi zed tr i al s. J Clin Oncol 1993;11:14411447.
Her mans J, Bonenkamp JJ. Meta-anal ysi s of adjuvant
chemotherapy i n gastr i c cancer : a cr i ti cal r eapprai sal [l etter ]. J
Clin Oncol 1994;12:877880.
Hundahl SA, Phi l l i ps JL, Menck HR. The Nati onal Cancer Data
Base Repor t on poor sur vi val of U.S. gastr i c car ci noma pati ents
tr eated wi th gastr ectomy: fi fth edi ti on Amer i can Joi nt Commi ttee
on Cancer stagi ng, pr oxi mal di sease, and the di ffer ent di sease
hypothesi s. Cancer 2000;88:921932.
Ichi kura T, Tomi matsu S, Uefuji K, et al . Eval uati on of the New
Amer i can Joi nt Commi ttee on Cancer /Inter nati onal Uni on agai nst
cancer cl assi fi cati on of l ymph node metastasi s fr om gastr i c
car ci noma i n compar i son wi th the Japanese cl assi fi cati on. Cancer
1999;86:553558.
Jatz ko G R, Li sbor g PH, Dent H, et al . A 10-year exper i ence wi th
Japanese-type radi cal l ymph node di ssecti on for gastr i c cancer
outsi de of Japan. Cancer 1995;76:13021312.
Jentschura D, Wi nkl er M, Str ohmei er N, et al . Qual i ty-of-l i fe after
curati ve sur ger y for gastr i c cancer : a compar i son between total
gastr ectomy and subtotal gastr i c r esecti on.
Hepatogastr oenter ology 1997;44:11371142.
Kattan MW, Kar peh MS, Maz umdar M, et al . Postoperati ve
nomogram for di sease-speci fi c sur vi val after an R0 r esecti on for
gastr i c car ci noma. J Clin Oncol 2003;19:36473650.

Kaji tani T. The general r ul es for gastr i c cancer study i n sur ger y
and pathol ogy. Par t I. Cl i ni cal cl assi fi cati on. Jpn J Sur g
1981;11:127139.
Kar peh MS, Kel sen DP, Tepper JE. Cancer of the stomach. In:
DeVi ta VT, Hel l man S, Rosenber g SA, eds. Cancer : Pr inciples and
Pr actice of Oncology, 6th ed. Phi l adel phi a, Pa: Li ppi ncott Wi l l i ams
& Wi l ki ns; 2001: 10921126.
Kodama Y, Sugi machi K, Soeji ma K, et al . Eval uati on of extensi ve
l ymph node di ssecti on for car ci noma of the stomach. Wor ld J Sur g
1981;5:241248.
Koga S, Hamazoe R, Maeta M, et al . Pr ophyl acti c therapy for
per i toneal r ecur r ence of gastr i c cancer by conti nuous
hyper ther mi c per i toneal per fusi on wi th mi tomyci n C. Cancer
1988;61:232237.
Kuntz C, Her far th C. Imagi ng di agnosi s for stagi ng of gastr i c
cancer. Semin Sur g Oncol 1999;17:96102.
Landr y J, Tepper JE, Wood WC, et al . Patter ns of fai l ur e fol l owi ng
curati ve r esecti on of gastr i c car ci noma. Int J Radiat Oncol Biol
Phys 1990;19:13571362.
Li ghtdal e CJ. Endoscopi c ul trasonography i n the di agnosi s,
stagi ng and fol l ow-up of esophageal and gastr i c cancer.
Endoscopy 1992;24(suppl 1):297303.
Lor di ck F, Stei n HJ, Peschel C, et al . Neoadjuvant therapy for
esophagogastr i c cancer. Br J Sur g 2004;91:540551.
Lowy AM, Fei g BW, Janjan N, et al . A pi l ot study of pr eoperati ve
chemoradi otherapy for r esectabl e gastr i c cancer. Ann Sur g Oncol
2001;8:519524.
Lowy AM, Mansfi el d PF, Leach SD, Ajani J. Lapar oscopi c stagi ng
for gastr i c cancer. Sur ger y 1996;119:611614.

Lowy AM, Mansfi el d PF, Leach SD, et al . Response to neoadjuvant


chemotherapy best pr edi cts sur vi val after curati ve r esecti on of
gastr i c cancer. Ann Sur g 1999;229:303308.
MacDonal d JS. G astr i c cancer : chemotherapy of advanced di sease.
Hematol Oncol 1992;10:342.
MacDonal d JS, Smal l ey S, Benedetti J, et al . Chemoradi otherapy
after sur ger y compar ed wi th sur ger y al one for adenocar ci noma of
the stomach or gastr oesophageal juncti on. N Engl J Med
2001;345:725730.

Maehara Y, Okuyama T, Kakeji Y, et al . Postoperati ve


i mmunochemotherapy i ncl udi ng str eptococcal l ysate OK-432 i s
effecti ve for pati ents wi th gastr i c cancer and ser osal i nvasi on. Am
J Sur g 1994;168:3640.
Makuuchi H, Ki se Y, Shi mada H, et al . Endoscopi c mucosal
r esecti on for ear l y gastr i c cancer. Semin Sur g Oncol
1999;17:108116.
Mansfi el d PF. Lymphadenectomy for gastr i c cancer. J Clin Oncol
2004;22:27592760.
Mi nsky BD. The r ol e of radi ati on therapy i n gastr i c cancer. Semin
Oncol 1996;23:390396.
Moer tel CG , Chi l ds DS, O'Fal l on JR, et al . Combi ned 5-fl uor ouraci l
and radi ati on therapy as a sur gi cal adjuvant for poor pr ognosi s
gastr i c car ci noma. J Clin Oncol 1984;2:12491254.
Monson JR, Donohue JH, McIl rath DC, et al . Total gastr ectomy for
advanced cancer. A wor thwhi l e pal l i ati ve pr ocedur e. Cancer
1991;68:18631868.
Nati onal Compr ehensi ve Cancer Networ k. NCCN practi ce
gui del i nes for upper gastr oi ntesti nal car ci nomas. Oncology
(Huntingt) 1998;12:179223.

Noguchi Y, Imada T, Matsumoto A, et al . Radi cal sur ger y for


gastr i c cancer. A r evi ew of the Japanese exper i ence. Cancer
1989;64:20532062.
Nomura A, Stemmer mann G N, Chyou PH, et al . Helicobacter pylor i
i nfecti on and gastr i c car ci noma among Japanese Amer i cans i n
Hawai i . N Engl J Med 1991;325:11321136.
Oi wa H, Maehara Y, Ohno S, et al . G r owth patter n and p53
over expr essi on i n pati ents wi th ear l y gastr i c cancer. Cancer
1995;75(suppl ):14541459.
Ono H, Kondo H, G otoda T, et al . Endoscopi c mucosal r esecti on
for tr eatment of ear l y gastr i c cancer. G ut 2001;48:225229.
Par sonnet J, Vander steen D, G oates J, et al . Helicobacter pylor i
i nfecti on i n i ntesti nal - and di ffuse-type gastr i c adenocar ci nomas.
J Natl Cancer Inst 1991;83:640643.
Roder JD, Bottcher K, Busch R, et al . Cl assi fi cati on of r egi onal
l ymph node metastasi s fr om gastr i c car ci noma. G er man G astr i c
Cancer Study G r oup. Cancer 1998;82:621631.
Rugge M, Cassar o M, Leandr o G , et al . Helicobacter pylor i i n
pr omoti on of gastr i c car ci nogenesi s. Dig Dis Sci 1996;41:950
955.
Sano T, Sasako M, Yamamoto S. G astr i c cancer sur ger y: r esul ts of
mor tal i ty and mor bi di ty of pr ospecti ve randomi zed contr ol l ed
tr i al s (JCOG 9501) compar i ng D2 and extended para-aor ti c
l ymphadenectomy. J Clin Oncol 2004;22:27672773.
Sar bi a M, Becker KF, Hofl er H. Pathol ogy of upper gastr oi ntesti nal
mal i gnanci es. Semin Oncol 2004;31:465475.
Sawyer s JL. G astr i c car ci noma. Cur r Pr obl Sur g 1995;32:101
178.
Shi u MH, Moor e E, Sander s M, et al . Infl uence of the extent of
r esecti on on sur vi val after curati ve tr eatment of gastr i c

car ci noma. A r etr ospecti ve mul ti var i ate anal ysi s. Ar ch Sur g
1987;122:13471351.
Shi u MH, Per r otti M, Br ennan MF. Adenocar ci noma of the
stomach: a mul ti var i ate anal ysi s of cl i ni cal , pathol ogi c and
tr eatment factor s. Hepatogastr oenter ology 1989;36:712.
Skor opad VY, Ber dov BA, Mar dynski YS, et al . A pr ospecti ve,
randomi zed tr i al of pr eoperati ve and i ntraoperati ve radi otherapy
ver sus sur ger y al one i n r esectabl e gastr i c cancer. Eur J Sur g
Oncol 2000;26:773779.
Smi th JW, Br ennan MF. Sur gi cal tr eatment of gastr i c cancer.
Pr oxi mal , mi d, and di stal stomach. Sur g Clin Nor th Am
1992;72:381399.
Smi th JW, Shi u MH, Kel sey L, et al . Mor bi di ty of radi cal
l ymphadenectomy i n the curati ve r esecti on of gastr i c car ci noma.
Ar ch Sur g 1991;126:14691473.

Songun I, Kei zer HJ, Her mans J, et al . Chemotherapy for operabl e


gastr i c cancer : r esul ts of the Dutch randomi sed FAMTX tr i al . The
Dutch G astr i c Cancer G r oup (DG CG ). Eur J Cancer 1999;35:558
562.
Stomach. In: G r eene F L, Page DL, F l emi ng ID, et al ., eds. AJCC
Cancer Staging Manual. 6th ed. New Yor k, NY: Spr i nger ; 2002:
99102.
Sugar baker PH, Yonemura Y. Cl i ni cal pathway for the management
of r esectabl e gastr i c cancer wi th per i toneal seedi ng: best
pal l i ati on wi th a ray of hope for cur e. Oncology 2000;58:96107.
Svedl und J, Sul l i van M, Li edman B, et al . Qual i ty of l i fe after
gastr ectomy for gastr i c car ci noma: contr ol l ed study of
r econstr ucti ve pr ocedur es. Wor ld J Sur g 1997;21:422433.
Tada M, Tanaka Y, Matsuo N, et al . Mucosectomy for gastr i c
cancer : cur r ent status i n Japan. J G astr oenter ol Hepatol 2000;15

[suppl ]:D98D102.
Takekoshi T. [G eneral vi ew of gastr i c cancer wi th depth i nvasi on
i nto muscl e l ayer (M cancer ) fr om a sur vey of r epor ts of the
Japanese Resear ch Soci ety for G astr i c Cancer ]. J G astr oenter ol
Mass Sur vey 1994;32:93132.
Tal amonti MS, Dawes LG , Joehl RJ, et al . G astr oi ntesti nal
l ymphoma. A case for pr i mar y sur gi cal r esecti on. Ar ch Sur g
1990;125:972976.
Wanebo HJ, Kennedy BJ, Chmi el J, et al . Cancer of the stomach. A
pati ent car e study by the Amer i can Col l ege of Sur geons. Ann
Sur g 1993;218:583592.
Wanebo HJ, Kennedy BJ, Wi nchester DP, et al . G astr i c car ci noma:
does l ymph node di ssecti on al ter sur vi val ? J Am Coll Sur g
1996;183:616624.
Weese JL, Har bi son SP, Sti l l er G D, et al . Neoadjuvant
chemotherapy, radi cal r esecti on wi th i ntraoperati ve radi ati on
therapy (IORT): i mpr oved tr eatment for gastr i c adenocar ci noma.
Sur ger y 2000;128:564571.
Yi m HB, Jacobson BC, Sal tz man JR, et al . Cl i ni cal outcome of the
use of enteral stents for pal l i ati on of pati ents wi th mal i gnant
upper G I obstr ucti on. G astr ointest Endosc 2001;53:329332.
Yonemura Y, Kawamura T, Bandou E, et al . Tr eatment of
per i toneal di ssemi nati on fr om gastr i c cancer by per i tonectomy
and chemohyper ther mi c per i toneal per fusi on. Br J Sur g
2005;92:370375.

Editors: Feig, Barry W .; Berger, David H.; Fuhrman, George


M.
Title: MD A nderson Surgical Oncology Handbook, The, 4th
Edition
Copyr i ght 2006 Li ppi ncott Wi l l i ams & Wi l ki ns
> Ta ble o f C o nt e nt s > 1 0 - Sm a ll Bo w e l M a ligna nc ie s a nd C a rc ino id Tum o rs

10
Small Bowel Malignancies and Carcinoid
Tumors
Keith D. A mos
Rosa F. Hw ang

Epidemiology
Mal i gnanci es of the smal l i ntesti ne ar e rar e, wi th an esti mated
5,400 new cases di agnosed i n the Uni ted States i n 2006. The smal l
i ntesti ne r epr esents 75% of the l ength and 90% of the sur face ar ea
of the al i mentar y tract, accounti ng for onl y 1% of gastr oi ntesti nal
(G I) neopl asms. Adenocar ci noma, car ci noi d, l ymphoma, and sar coma
account for the major i ty of smal l bowel mal i gnanci es. The i nci dence
of thi s rar e mal i gnancy i s 0.7 to 1.6 per 100,000 per sons, wi th a
sl i ght mal e pr edomi nance. Mean age at pr esentati on i s 57 year s.
Associ ated condi ti ons i ncl ude fami l i al pol yposi s, G ar dner syndr ome,
Peutz-Jegher s syndr ome, adul t (nontr opi cal ) cel i ac spr ue, von
Reckl i nghausen neur ofi br omatosi s, and Cr ohn di sease. In addi ti on,
i mmunosuppr essed pati ents such as those wi th i mmunogl obul i n A
(IgA) defi ci ency ar e bel i eved to be at i ncr eased r i sk of smal l bowel
mal i gnanci es. As many as 25% of affected pati ents have
synchr onous mal i gnanci es, i ncl udi ng neopl asms of the col on,
endometr i um, br east, and pr ostate gl and.
The peak i nci dence of car ci noi d tumor s i s i n the si xth and seventh
decades of l i fe, al though these tumor s have been r epor ted i n
pati ents as young as 10 year s. The si tes of or i gi n of car ci noi d
tumor s ar e shown i n Tabl e 10.1. Appr oxi matel y 85% of car ci noi d
tumor s ar e found i n the G I tract, wi th the appendi x bei ng the most
common si te. Noni ntesti nal si tes i ncl ude the l ungs, pancr eas, bi l i ar y
tract, thymus, and ovar y. Il eal car ci noi ds ar e the most l i kel y to
metastasi ze, even when smal l , i n contrast to appendi ceal car ci noi ds,

whi ch rar el y metastasi ze.

Risk Factors
Several di sti ncti ve character i sti cs of the smal l i ntesti ne may expl ai n
i ts r el ati ve spar i ng fr om mal i gnancy. Benzopyr ene hydr oxyl ase, an
enz yme that conver ts benzopyr ene to a l ess car ci nogeni c compound,
i s found i n l ar ge amounts i n the mucosa of the smal l i ntesti ne. In
contrast, anaer obi c bacter i a, whi ch conver t bi l e sal ts i nto potenti al
car ci nogens, ar e general l y l acki ng i n the smal l i ntesti ne. Unl i ke the
stomach or col on, the smal l i ntesti ne i s pr otected fr om the
tumor i geni c effects of an aci di c envi r onment and fr om the i r r i tati ng
effects of sol i d G I contents. In addi ti on, the rapi d transi t of l i qui d
succus enter i cus thr ough the smal l bowel i s bel i eved to r educe i ts
tumor i geni ci ty by mi ni mi z i ng the contact ti me between potenti al
enter i c car ci nogens and the mucosa. Secr etor y IgA, al so found i n
l ar ge quanti ti es i n the smal l i ntesti ne, safeguar ds agai nst oncogeni c
vi r uses.
G I dysfuncti on may pr edi spose the smal l i ntesti ne mucosa to
tumor i genesi s. Stasi s secondar y to par ti al obstr ucti on or bl i nd
l oop syndr ome l eads to bacter i al over gr owth and has been
i mpl i cated i n the devel opment of smal l i ntesti ne mal i gnanci es.

Table 10.1. Sites of origin of carcinoid


tumors
Tumor Site

Percentage of Cases

Stomach

2.8

Duodenum

2.9

Jejunoileum

25.5

Appendix

36.2

Colon

6.0

Rectum

16.4

Bronchus

9.9

Ovary

0.5

Miscellaneous

0.2

Unknown primary

3.3

Clinical Presentation
Small Bowel Malignancy
G I symptoms devel op i n 75% of pati ents wi th mal i gnant l esi ons of
the smal l bowel , compar ed wi th onl y 50% of pati ents wi th beni gn
tumor s. Si xty-fi ve per cent wi l l pr esent wi th i nter mi ttent abdomi nal
pai n that i s dul l and crampy and radi ates to the back, 50% wi th
anor exi a and wei ght l oss, and 25% wi th si gns and symptoms of
bowel obstr ucti on. Onl y 10% of pati ents wi th smal l bowel
mal i gnanci es wi l l devel op bowel per forati on, most commonl y those
wi th l ymphomas or sar comas. A pal pabl e abdomi nal mass i s pr esent
i n 25% of pati ents. Jaundi ce may be pr esent i n pati ents wi th
common bi l e duct obstr ucti on fr om ampul l ar y cancer. Epi sodi c
jaundi ce associ ated wi th guai ac-posi ti ve stool suggests an ampul l ar y
mal i gnancy.
The nonspeci fi ci ty of symptoms, when pr esent, fr equentl y r esul ts i n
a 6- to 8-month del ay i n di agnosi s. The cor r ect di agnosi s i s
establ i shed pr eoperati vel y i n onl y 50% of cases. Late detecti on and
i naccurate di agnosi s contr i bute not onl y to the advanced stage of
di sease at the ti me of sur ger y, but al so to a 50% rate of metastasi s
at pr esentati on and thus to the overal l poor pr ognosi s for pati ents
wi th mal i gnant tumor s of the smal l i ntesti ne.

Carcinoid Tumors

The pr esentati on of car ci noi ds var i es, dependi ng not onl y on thei r
physi cal character i sti cs and si te of or i gi n, but al so on whether they
ar e pr oduci ng substances that ar e hor monal l y acti ve. In general ,
most car ci noi ds ar e smal l , i ndol ent tumor s that ar e categor i zed
pathol ogi cal l y ei ther by mi cr oscopi c featur es or accor di ng to thei r
embr yol ogi c si te of or i gi n. The embr yol ogi c cl assi fi cati on of
car ci noi ds i s mor e commonl y used and i s outl i ned i n Tabl e 10.2.

Table 10.2. Characteristics of carcinoid tumor


by embryologic site of origin
Characteristics Foregut

Location

Histology

Midgut

Hindgut

Bronchus

Jejunum

Colon

Stomach

Ileum

Rectum

Pancreas

Appendix

Trabecular

Nodular,
solid
nest of
cells

Trabecula

Low

High

None

High

High

Normal

Secretion
Tumor 5-HT
Urinary 5HIAA

Carcinoid
syndrome
Other
endocrine
secretions

Yes

Yes

No

Frequent

Frequent

No

5-HIAA, 5-hydroxyindoleacetic acid; 5-HT, 5hydroxytryptamin or serotonin.


Thi s cl assi fi cati on system subdi vi des car ci noi ds i nto those of the
for egut (stomach, pancr eas, and l ungs), mi dgut (smal l bowel and
appendi x), or hi ndgut (col on and r ectum).
For egut car ci noi ds ar e mor e commonl y associ ated wi th an atypi cal
pr esentati on due to secr eti on of pepti de hor mone pr oducts other
than ser otoni n, such as gastr i n, adr enocor ti cotr opi c hor mone, or
gr owth hor mone. Pul monar y car ci noi ds ar e usual l y per i hi l ar, and
pati ents pr esent wi th r ecur r ent pneumoni a, cough, hemoptysi s, or
chest pai n. Ectopi c secr eti on of cor ti cotr opi n or gr owth hor moner el easi ng factor fr om these tumor s can pr oduce Cushi ng syndr ome
or acr omegal y, r especti vel y. G astr i c car ci noi ds ar e associ ated wi th
chr oni c atr ophi c gastr i ti s type A (CAG -A) i n 75% of cases,
pr edomi nantl y women, of whi ch hal f have per ni ci ous anemi a. These
tumor s ar e usual l y i denti fi ed on endoscopi c eval uati on for anemi a
or abdomi nal pai n and ar e l ocated i n the body or fundus of the
stomach. Another 5% to 10% of gastr i c car ci noi ds ar e associ ated
wi th Zol l i nger-El l i son syndr ome i n pati ents wi th mul ti pl e endocr i ne
neopl asi a type I. The r emai ni ng 15% to 25% of gastr i c car ci noi ds
ar e sporadi c and mor e fr equentl y appear i n men. Sporadi c for egut
car ci noi ds ar e associ ated wi th an atypi cal car ci noi d syndr ome, whi ch
i s bel i eved to be hi stami ne medi ated and exhi bi ted mai nl y as
i ntense er ythematous fl ushi ng, i tchi ng, conjuncti val suffusi on, faci al
edema, and occasi onal ur ti car i a.
Mi dgut car ci noi ds pr oduce symptoms of hor mone excess onl y when
bul ky or metastati c. Because 75% of the tumor s ar e l ocated i n the
di stal one-thi r d of the appendi x, l ess than 10% cause symptoms,
and the vast major i ty of appendi ceal car ci noi ds ar e found
i nci dental l y. Pati ents wi th smal l bowel car ci noi ds usual l y pr esent

wi th symptoms si mi l ar to those descr i bed for other smal l bowel


tumor s. Not uncommonl y, as a smal l bowel car ci noi d pr ogr esses, i t
i nduces fi br osi s of the mesenter y, whi ch may by i tsel f cause
i ntesti nal obstr ucti on and l ead to var yi ng degr ees of mesenter i c
i schemi a. Most pati ents wi th smal l bowel car ci noi ds pr esent wi th
metastases to l ymph nodes or to the l i ver.
Hi ndgut car ci noi ds tend to be cl i ni cal l y si l ent tumor s unti l they ar e
advanced. Two-thi r ds ar e found i n the r i ght col on wi th the average
tumor di ameter at pr esentati on bei ng 5 cm. They rar el y pr oduce
ser otoni n, even i n the pr esence of metastati c di sease. Pati ents wi th
hi ndgut tumor s most commonl y pr esent wi th bl eedi ng and
occasi onal l y exper i ence abdomi nal pai n.
The hor monal mani festati ons of car ci noi d tumor s (car ci noi d
syndr ome) ar e seen i n onl y 10% of pati ents and occur when the
secr etor y pr oducts of these tumor s gai n di r ect access to the
systemi c ci r cul ati on and avoi d metabol i sm i n the l i ver. Thi s cl i ni cal
syndr ome occur s i n the fol l owi ng si tuati ons: (a) when hepati c
metastases ar e pr esent; (b) when r etr oper i toneal di sease i s
extensi ve, wi th venous drai nage di r ectl y i nto the paraver tebral
vei ns; and (c) when the pr i mar y car ci noi d tumor i s outsi de the G I
tract, as wi th br onchi al , ovar i an, or testi cul ar tumor s. Ni nety
per cent of cases of car ci noi d syndr ome ar e seen i n pati ents wi th
mi dgut tumor s.
The mai n symptoms of car ci noi d syndr ome ar e water y di ar r hea,
fl ushi ng, sweati ng, wheez i ng, dyspnea, abdomi nal pai n,
hypotensi on, or r i ght hear t fai l ur e due to tr i cuspi d r egur gi tati on or
pul moni c stenosi s caused by endocar di al fi br osi s. The fl ush i s often
dramati c and i s an i ntense pur pl i sh col or on the upper body and
ar ms. Faci al edema i s often pr esent. Repeated attacks can l ead to
the devel opment of tel angi ectasi as and per manent ski n
di scol orati on. The fl ush can be pr eci pi tated by consumi ng al cohol ,
bl ue cheese, chocol ate, or r ed wi ne, and by exer ci se. The medi ator s
of these symptoms ar e shown i n Tabl e 10.3.
A l i fe-thr eateni ng for m of car ci noi d syndr ome cal l ed car cinoid cr isis
i s usual l y pr eci pi tated by a speci fi c event such as anesthesi a,
sur ger y, or chemotherapy. The mani festati ons i ncl ude an
i ntense fl ush, di ar r hea, tachycar di a, hyper tensi on or hypotensi on,
br onchospasm, and al terati on of mental status. The symptoms ar e
usual l y r efractor y to fl ui d r esusci tati on and admi ni strati on of

vasopr essor s.

Table 10.3. Clinical symptoms of carcinoid


syndrome and tumor products suspected of
causing them
Symptom

Tumor Product
Bradykinin

Flushing

Hydroxytryptophan
Prostaglandins
Vasoactive intestinal
polypeptide

Telangiectasia

Serotonin
Prostaglandins
Bradykinin
Bradykinin

Bronchospasm

Histamine
Prostaglandins

Endocardial
fibrosis

Serotonin

Glucose
intolerance

Serotonin

Arthropathy

Serotonin

Hypotension

Serotonin

Diagnostic Workup
Small Bowel Malignancies
A hi gh i ndex of suspi ci on i s essenti al to the ear l y di agnosi s and
tr eatment of smal l i ntesti ne mal i gnanci es. The pati ent pr esenti ng
wi th nonspeci fi c abdomi nal symptoms shoul d under go a compl ete
hi stor y, physi cal exami nati on, and scr eeni ng for occul t fecal bl ood.
Laborator y wor kup shoul d i ncl ude a compl ete bl ood cel l count,
measur ement of ser um el ectr ol yte l evel s, and l i ver functi on tests.
F ur ther l aborator y testi ng, i ncl udi ng measur ement of ur i nar y 5hydr oxyi ndol eaceti c aci d (5-HIAA), shoul d be di r ected by cl i ni cal
suspi ci on.
Retr ospecti ve r evi ews r epor t that 50% to 60% of smal l i ntesti ne
neopl asms ar e detected by usi ng conventi onal radi ographi c
techni ques, i ncl udi ng upper G I ser i es wi th smal l bowel
fol l owthr ough (UG I/SBF T) and enter ocl ysi s. Hypotoni c
duodenography, usi ng anti chol i ner gi c agents or gl ucagon to r educe
duodenal per i stal si s, may enhance di agnosti c yi el d to as hi gh as
86% for mor e pr oxi mal l y l ocated duodenal mal i gnanci es.
Tradi ti onal l y, computed tomography (CT) was not bel i eved to be
hel pful i n di agnosi ng smal l bowel neopl asms. However, several
r ecent r evi ews have shown that CT was abl e to detect abnor mal i ti es
i n 97% of pati ents wi th smal l bowel tumor s. Angi ography
demonstrates a tumor bl ush i n speci fi c subtypes of smal l bowel
mal i gnanci es, most notabl y, car ci noi d and l ei omyosar coma, but i s
rar el y i ndi cated i n the i ni ti al di agnosti c wor kup.
Enter oscopy shoul d be consi der ed when al l pr evi ous di agnosti c
studi es ar e negati ve. In 1991, Lewi s et al . r evi ewed the exper i ence
at Mt. Si nai Medi cal Center i n New Yor k wi th two endoscopi c

techni quespush enter oscopy and smal l bowel enter oscopyi n 258
pati ents wi th obscur e G I bl eedi ng. Push enter oscopy uses a
pedi atr i c col onoscope that i s passed oral l y and then pushed di stal l y
thr ough the smal l i ntesti ne, faci l i tati ng i ntubati on of the jejunum
60 cm di stal to the l i gament of Tr ei tz . Thi s techni que establ i shed a
di agnosi s i n 50% of pati ents exami ned. Smal l bowel enter oscopy,
whi ch uses a 120-degr ee, for war d-vi ewi ng, 2,560-mm, bal l oonti pped endoscope that i s car r i ed di stal l y by per i stal si s, per mi tted
i ntubati on of the ter mi nal i l eum i n 77% of cases wi thi n 8 hour s.
Upper G I endoscopy, when per for med to the l i gament of Tr ei tz , was
di agnosti c i n ei ght of ni ne pati ents wi th duodenal mal i gnanci es
r evi ewed by Our i el and Adams i n 2000.
Most r etr ospecti ve studi es r epor t onl y moderate success i n
di agnosi ng smal l bowel neopl asms pr eoperati vel y, wi th l ar ge ser i es
r epor ti ng a cor r ect pr eoperati ve di agnosi s i n onl y 50% of cases, the
r emai nder di agnosed at l apar otomy. Expl orator y l apar otomy r emai ns
the most sensi ti ve di agnosti c modal i ty i n eval uati ng a pati ent i n
whom smal l bowel neopl asm i s suspected and shoul d be consi der ed
i n the di agnosti c eval uati on of a pati ent wi th occul t G I bl eedi ng,
unexpl ai ned wei ght l oss, or vague abdomi nal
pai n. Di stal l y l ocated smal l bowel adenocar ci noma at or near the
i l eum i s di agnosed wi th l apar otomy i n 57% of pati ents, wi th UG I i n
21% of pati ents, and CT scan i n onl y 7% of pati ents. Because most
tumor s pr esent as l ar ge, bul ky l esi ons wi th l ymph node metastasi s,
l apar oscopy i s potenti al l y useful for establ i shi ng the di agnosi s of
mal i gnancy when the wor kup i s other wi se negati ve and for
obtai ni ng adequate ti ssue sampl es i f a di agnosi s of l ymphoma i s
suspected. Ear l y detecti on and tr eatment r emai n the most
si gni fi cant var i abl es i n i mpr ovi ng outcome fr om smal l bowel
mal i gnancy, necessi tati ng thoughtful and expedi ent di agnosti c
wor kup of pati ents pr esenti ng wi th vague abdomi nal symptoms.

Carcinoids
The di agnosi s of car ci noi d tumor i s made usi ng a combi nati on of
bi ochemi cal tests and i magi ng studi es. Overal l , appr oxi matel y 50%
of pati ents wi th car ci noi ds have el evated ur i nar y l evel s of 5-HIAA,
i r r especti ve of whether they have symptoms of car ci noi d syndr ome.
One study r epor ted 100% speci fi ci ty and 70% sensi ti vi ty of ur i nar y
5-HIAA for the pr esence of car ci noi d syndr ome and 5-HIAA l evel s
seem to cor r el ate wi th tumor bur den. Ur i nar y 5-HIAA l evel s can be
al ter ed by medi cati ons and cer tai n foods (e.g., bananas, wal nuts,

pi neappl es). When ur i nar y 5-HIAA l evel s ar e nondi agnosti c, a mor e


extensi ve wor kup shoul d be under taken, consi sti ng of measur ement
of ur i nar y 5-hydr oxytr yptami ne (5-HT, ser otoni n) and 5hydr oxytr yptophan (5-HPT), pl asma 5-HPT, pl atel et 5-HT, and ser um
l evel s of other secr etor y pr oducts such as chr omograni n A, neur onspeci fi c enol ase (NSE), substance P, and neur opepti de K. In wel l di ffer enti ated tumor s, the sensi ti vi ty of ser um chr omograni n A i s
between 80% and 100% and al so r efl ects tumor l oad. Chr omograni n
A can be used i n the detecti on of functi onal and nonfuncti onal
tumor s. An over vi ew of ser otoni n metabol i sm i s shown i n F i gur e
10.1.
Local i z ati on of the tumor may al so hel p confi r m the di agnosi s.
Br onchi al car ci noi ds ar e best vi sual i zed wi th a chest radi ograph or
CT scan. G astr i c, duodenal , col oni c, and r ectal car ci noi ds ar e
usual l y seen on endoscopy and bar i um studi es. Smal l i ntesti ne
car ci noi ds ar e i ni ti al l y eval uated as descr i bed for other smal l bowel
mal i gnanci es. Abdomi nal CT scan i s useful for assessi ng i nvol vement
of the r etr oper i toneum and pr esence of l i ver metastasi s. In
addi ti on, smal l bowel car ci noi ds have a spoke-wheel appearance on
CT due to extensi ve mesenter i c fi br osi s, and 70% of cases
demonstrate cal ci fi cati ons.
Nucl ear medi ci ne scans have al so been used i n l ocal i z ati on. Scans
usi ng Indi um 111 (1 1 1 In-penetr eoti de) or metai odobenz yl guani di ne
(MIBG ) radi ol abel ed wi th i odi ne 131 (1 3 1 I) can i denti fy pr i mar y or
metastati c car ci noi d tumor s appr oxi matel y 70% of the ti me, when
MIBG i s taken up by the tumor and stor ed i n i ts neur osecr etor y
granul es. The combi nati on of these two i magi ng modal i ti es
i ncr eases sensi ti vi ty to 95% . However, the sensi ti vi ty of detecti ng
bone metastases i s onl y 20% to 50% .
On occasi on, a pati ent may benefi t fr om angi ography or sel ecti ve
venous sampl i ng i f other di agnosti c maneuver s pr ove unsuccessful .

F i gur e 10.1. Bi ochemi cal steps i n the pr oducti on of 5hydr oxytr yptami ne (5-HT, ser otoni n) and 5-hydr oxyi ndol eaceti c
aci d (5-HIAA).

Staging
The Amer i can Joi nt Commi ttee on Cancer stagi ng system for smal l
bowel mal i gnanci es i s shown i n Tabl e 10.4.

Malignant Neoplasms
The di str i buti on of smal l bowel mal i gnanci es (r epor ted by Wei ss and
Yang i n a 1987 r evi ew of ni ne popul ati on-based cancer r egi str i es
par ti ci pati ng i n the Nati onal Cancer Insti tute's Sur vei l l ance,
Epi demi ol ogy, and End Resul ts Pr ogram) i s shown i n Tabl e 10.5.
Infor mati on on tumor bi ol ogy, modes of l ymphati c spr ead, and
patter ns of r ecur r ence for smal l bowel mal i gnanci es i s l i mi ted.
The most common hi stol ogi c types of mal i gnant tumor s of the smal l
i ntesti ne ar e adenocar ci noma (45.3% ), car ci noi d (29.3% ),
l ymphoma (14.8% ), and sar coma (10.4% ). Adenocar ci noma i s the
most common mal i gnancy i n the pr oxi mal smal l i ntesti ne, wher eas
car ci noi d i s the most common mal i gnancy i n the i l eum. Sar coma and
l ymphoma may devel op thr oughout the smal l i ntesti ne but ar e mor e
pr eval ent i n the di stal smal l bowel . Mutati ons of the Ki -r as gene ar e
found i n 14% to 53% of smal l i ntesti ne adenocar ci nomas and ar e
mor e pr eval ent i n duodenal , rather than jejunal or i l eal ,
adenocar ci nomas. In contrast, mutati ons of the APC gene ar e
uncommon i n smal l bowel car ci nomas, suggesti ng that these tumor s
ar i se thr ough a di ffer ent geneti c pathway than col or ectal

car ci nomas.

Adenocarcinoma
Pathology
Adenocar ci noma of the smal l i ntesti ne occur s most commonl y i n the
duodenum, wi th 65% of these neopl asms cl uster ed i n the

per i ampul l ar y r egi on. These tumor s i nfi l trate i nto the muscul ar i s
pr opr i a and may extend thr ough the ser osa and i nto adjacent
ti ssues. Ul cerati on i s common, causi ng occul t G I bl eedi ng and
chr oni c anemi a. Obstr ucti on may devel op fr om pr ogr essi ve gr owth
of appl e cor e l esi ons or l ar ge i ntral umi nal pol ypoi d masses. It can
mani fest as gastr i c outl et obstr ucti on i n cases of duodenal l esi ons
or sever e crampi ng pai n i n cases of mor e di stal l y l ocated l esi ons.
Appr oxi matel y 60% of tumor s ar e wel l - or moderatel y di ffer enti ated
tumor s, and 37% ar e si gnet r i ng and poor l y di ffer enti ated tumor s.

Table 10.4. American Joint Committee on


Cancer staging of small intestine
malignancies
Primary tumor (T)
T0

No evidence of primary tumor

Tis

Carcinoma in situ

T1

Tumor invades lamina propria or


submucosa

T2

Tumor invades muscularis propria

T3

Tumor invades through the muscularis


propria into the subserosa or into the
nonperitonealized perimuscular tissue
(mesentery or retroperitoneum) with
extension 2 cm

T4

Tumor perforates the visceral


peritoneum or directly invades other
organs or structures (includes other
loops of the small intestine, mesentery,
or retroperitoneum >2 cm, and
abdominal wall by way of serosa; for
duodenum only, invasion of the
pancreas)

Regional lymph nodes (N)


N0

No regional lymph node metastasis

N1

Regional lymph node metastasis

Distant metastasis (M)


M0

No distant metastasis

M1

Distant metastasis

Staging
Stage
0

Tis

N0

M0

Stage
I

T1-T2

N0

M0

Stage
II

T3-T4

N0

M0

Stage
III

Any T

N1

M0

Stage
IV

Any T

Any N

M1

Adapted from Greene FL, Page DL, Fleming ID,


et al., eds. AJCC Manual for Staging of Cancer.
6th ed. Philadelphia, Pa: Springer-Verlag, with
permission.

Table 10.5. Distribution of primary malignant


in the small intestine by subsite of cancer an
type as percentages of total (N = 1,4
Subsite
Specified

Adenocarcinoma

Carcinoid

Lymphom

Duodenum

21.9

1.3

0.8

Jejunum

14.7

2.5

5.1

Ileum
Total

8.7

25.5

8.9

45.3

29.3

14.8

Adapted from NCI SEER Registries 19731982. In:


Yang C. Incidence of histologic types of cancer of t
intestine. J Natl Cancer Inst 1987;78:653, with per

Clinical Course
Adenocar ci noma of the smal l bowel fol l ows a patter n of tumor
pr ogr essi on si mi l ar to that of col on cancer, wi th si mi l ar sur vi val
rates when compar ed stage for stage. Seventy per cent to 80% of
smal l bowel l esi ons ar e r esectabl e at the ti me of di agnosi s, wi th a
5-year sur vi val rate of 20% to 30% r epor ted for pati ents
under goi ng r esecti on. Appr oxi matel y 35% of pati ents have
metastasi s to r egi onal l ymph nodes at the ti me of di agnosi s, and an
addi ti onal 20% have di stant metastasi s. Mural penetrati on, nodal
i nvol vement, di stant metastasi s, and per i neural i nvasi on cor r el ate
wi th a poor pr ognosi s. Lar ge tumor si ze and poor hi stol ogi c grade
wer e al so associ ated wi th decr eased sur vi val i n a study fr om the
Uni ver si ty of Cal i for ni a, Los Angel es, but other s have not found the
same r el ati onshi p.
Adenocar ci noma of the smal l bowel i s known to be associ ated wi th
Cr ohn di sease, usual l y occur r i ng i n the di stal i l eum. Ri sk factor s
associ ated wi th devel opment of a smal l bowel cancer i n Cr ohn
di sease i ncl ude durati on of di sease, mal e gender, associ ated
fi stul ous di sease, and the pr esence of sur gi cal l y excl uded bowel
l oops.

Treatment
Wi de exci si on of the mal i gnancy and sur r oundi ng zones of
conti guous spr ead i s per for med to pr ovi de compl ete tumor cl earance
for l esi ons l ocated i n the jejunum and the i l eum. A r etr ospecti ve
r evi ew of 217 pati ents di agnosed wi th smal l bowel adenocar ci noma
tr eated at The Uni ver si ty of Texas M. D. Ander son Cancer Center
found that sur ger y was the pr i mar y defi ni ti ve tr eatment modal i ty i n
67% of pati ents. Tr eatment strategi es rangi ng fr om

pancr eati coduodenectomy to l ocal exci si on have been pr oposed for


the management of duodenal adenocar ci noma.
Pancr eati coduodenectomy has been touted as a super i or operati on
for duodenal adenocar ci noma because of i ts mor e radi cal cl earance
of the tumor bed and r egi onal l ymph nodes. In fact, some author s,
i ncl udi ng Lai et al . i n 1988, conti nue to r ecommend
pancr eati coduodenectomy for al l pr i mar y duodenal
adenocar ci nomas. However, segmental r esecti on for adenocar ci noma
of the duodenum sati sfi es the pr i nci pl es of en bl oc r esecti on,
wi thout the mor bi di ty of a pancr eati coduodenectomy, and shoul d be
consi der ed when techni cal l y feasi bl e.
Unl i ke pancr eati c cancer, whi ch di ffusel y i nfi l trates i nto the
sur r oundi ng soft ti ssues, adenocar ci noma of the duodenum extends
i nto adjacent ti ssues as a mor e l ocal i zed pr ocess. Ther efor e, tumorfr ee r esecti on mar gi ns, cr i ti cal to a curati ve exti r pati on,
may be achi eved wi thout necessar i l y r esecti ng a gener ous por ti on of
the sur r oundi ng soft ti ssues and adjacent or gans; however, the
tumor-fr ee status of r esecti on mar gi ns must be confi r med on
fr ozen-secti on eval uati on of the r esected speci men.
In a 1994 compar i son of pancr eati coduodenectomy to segmental
r esecti on for management of duodenal adenocar ci noma at M. D.
Ander son Cancer Center, Bar nes et al . found no si gni fi cant
di ffer ence i n sur vi val rates, but di d fi nd a di ffer ence i n 5-year l ocal
contr ol rates76% for pancr eati coduodenectomy and 49% for
segmental r esecti on. Several other r evi ews, i ncl udi ng those of
Lowel l et al . i n 1992, Joestl i ng et al . i n 1981, and van Ooi jen and
Kal sbeek i n 1988, whi ch compar ed sur vi val fol l owi ng
pancr eati coduodenectomy or segmental r esecti on for l esi ons i n the
thi r d and four th por ti ons of the duodenum, have demonstrated no
si gni fi cant di ffer ence i n 5-year sur vi val . In these studi es, a mor e
l i mi ted r esecti on, wi th a l ower rate of associ ated mor bi di ty and
mor tal i ty, pr ovi ded a sur vi val benefi t equal to that of a mor e
extensi ve r esecti on.
At M. D. Ander son, a pancr eati coduodenectomy i s per for med for
l esi ons i nvol vi ng the pr oxi mal duodenum to the r i ght of the super i or
mesenter i c ar ter y (SMA). A segmental r esecti on i s per for med for
duodenal l esi ons to the l eft of the SMA. Local exci si on i s consi der ed
for smal l l esi ons on the anti mesenter i c wal l of the second por ti on of
the duodenum. Two studi es have found a hi gher rate of
postoperati ve compl i cati ons fr om pancr eati coduodenectomy i n
pati ents wi th per i ampul l ar y mal i gnanci es than i n those wi th

pancr eati c adenocar ci noma, al though thi s di d not r esul t i n a hi gher


rate of per i operati ve mor tal i ty i n ei ther study. An i ncr eased
pancr eati c anastomoti c l eak rate was pr esent i n the gr oup wi th
duodenal car ci noma, pr esumabl y due to the fact that the pancr eas
i n these pati ents woul d be nor mal wi th a soft textur e, ther eby
i ncr easi ng the techni cal di ffi cul ty of the pancr eati c anastomosi s.

Experimental Therapy
El ectr on-beam i ntraoperati ve radi ati on therapy and exter nal -beam
radi ati on therapy have been admi ni ster ed at M. D. Ander son i n a
l i mi ted number of cases of mi cr oscopi c i nvol vement of r esecti on
mar gi ns or unr esectabl e di sease. However, adenocar ci noma of the
smal l i ntesti ne i s general l y consi der ed to be radi ati on r esi stant.
Chemotherapy, based on 5-fl uor ouraci l (5-F U) and ni tr osour eas, has
been r ecommended i n both the adjuvant setti ng and i n cases of
unr esectabl e di sease, yet most r etr ospecti ve studi es have fai l ed to
demonstrate a si gni fi cant r esponse to chemotherapy. Because most
center s have onl y l i mi ted exper i ence tr eati ng adenocar ci noma of
the smal l i ntesti ne, the effi cacy of chemotherapy needs fur ther
study, and pati ents shoul d conti nue to be enr ol l ed i n pr ospecti ve
randomi zed cl i ni cal tr i al s.

Carcinoid
Pathology
Car ci noi ds ar e known mai nl y for thei r abi l i ty to secr ete ser otoni n
and ar e the most common endocr i ne tumor s of the G I system. They
ar i se fr om enter ochr omaffi n cel l s, whi ch ar e l ocated
pr edomi nantl y i n the G I tract and mai nstem br onchi . In addi ti on to
ser otoni n, these tumor s can secr ete a number of bi ol ogi cal l y acti ve
substances (Tabl e 10.6), i ncl udi ng ami nes, tachyki ni ns, pepti des,
and pr ostagl andi ns.

Table 10.6. Biologically active substances


that can be secreted by carcinoid tumors
Amines

5-HT
5-HIAA
5-HTP
Histamine
Dopamine
Tachykinins
Kallikrein
Substance P
Neuropeptide K
Others
Prostaglandins
Pancreatic polypeptide
Chromogranins
Neurotensin
hCGa
hCGb
5-HT, 5-hydroxytryptamine; 5-HIAA, 5hydroxyindoleacetic acid; 5-HTP, 5hydroxytryptophan; hCG, human chorionic
gonadotropin.
Car ci noi d tumor s occur most fr equentl y i n the appendi x (40% ),
smal l i ntesti ne (27% ), r ectum (15% ), and br onchus (11% ). Smal l
bowel car ci noi ds occur most commonl y i n the ter mi nal 60 cm of the
i l eum as tan, yel l ow, or gray-br own i ntramural or submucosal
nodul es. The pr esence of mul ti pl e synchr onous nodul es i n 30% of
pati ents mandates car eful i nspecti on of the enti r e smal l i ntesti ne i n
these pati ents.

Clinical Course
Pr i mar y car ci noi d tumor s ar e i ndol ent, sl ow-gr owi ng l esi ons that
become symptomati c l ate i n the cour se of the di sease. Rar el y
ul cerati ve, these tumor s i nfi l trate the muscul ar i s pr opr i a and may

extend thr ough the ser osa to i nvol ve the mesenter y or


r etr oper i toneum and to pr oduce a character i sti cal l y i ntense
desmopl asti c r eacti on.
Metastati c di sease, pr esent i n 90% of symptomati c pati ents,
cor r el ates not onl y wi th the depth of i nvasi on, but al so wi th the si ze
of the pr i mar y l esi on. For car ci noi ds l ess than 1 cm, the r i sk of
metastasi s i s 2% for appendi ceal , 15% to 18% for smal l bowel , and
20% for r ectal pr i mar i es. If car ci noi d tumor s ar e gr eater than 2 cm,
33% of appendi ceal , 86% to 95% of smal l bowel , and al most al l
r ectal pr i mar i es have metastasi zed.
Di stant si tes of metastases i ncl ude the l i ver and, to a l esser degr ee,
the l ungs and bone. Ther e i s no wi del y accepted hi stol ogi c
cl assi fi cati on of car ci noi ds that accuratel y pr edi cts metastati c
behavi or. Mor phol ogi c cr i ter i a such as mi toti c acti vi ty, cytol ogi c
atypi a, and tumor necr osi s have been eval uated; however, these
featur es can be affected by i schemi a secondar y to mesenter i c
scl er osi s i n G I car ci noi ds. An