Beruflich Dokumente
Kultur Dokumente
– Introduction
– Incidence
– Epidemiology
– Molecular Pathogenesis
– Initial Assessment
– Treatment of Extremity and Trunk Wall Sarcoma
– Special Clinical Situations
– Gastrointestinal Stromal Tumors
– Desmoids
– Dermatofibrosarcoma
– Protuberans
– Pediatric Sarcomas
Soft tissue tumours
• Introduction
– The term 'soft tissue' refers to the extraskeletal connective tissue
that accounts for more than 50 per cent of body weight.
– It includes muscle, tendon, fat, fascia, and synovium.
– These all arise embryologically from the mesenchyme.
– Although soft tissue tumors are all thought to arise from primitive
mesodermal tissue, they vary widely in their histologic appearance
and in the mature tissue type that they resemble.
– By convention, tumors arising in the peripheral nerves are also
grouped with soft tissue tumors, as their presentation and
treatment are similar.
• Benign soft tissue tumors such as lipoma or benign fatty
tumor closely resemble specific normal adult tissues.
• They exhibit little tendency to local invasion, rarely recur after
local excision, and do not metastasize.
• Malignant soft tissue tumors are termed sarcomas (from the
Greek 'sarkoma', meaning fleshy growth), while malignant
tumors arising from epithelial tissues are termed
carcinomas.
• Exceptions to this generalization are tumors arising from
the endothelium of blood or lymphatic vessels, or the
mesothelial lining of body cavities, which are grouped with
soft tissue tumors.
• A classification has been developed by Enzinger using the principle
of similarity of histologic appearance to normal tissues (Table 1).
• Unlike most other human neoplasms, the soft tissue tumors are not
grouped simply into benign or malignant.
• Occupying a middle ground between sarcomas and benign
neoplasms is a group of locally aggressive tumors such as
desmoid tumors, aggressive fibromatoses, atypical lipomas, and
aggressive neurofibromas.
• These do not metastasize and are not called sarcomas, but
require more comprehensive treatment than do other benign soft
tissue tumors because their characteristics locally resemble
malignant behavior.
• Incidence
– Benign tumors of soft tissue are far more common than sarcomas,
outnumbering them by about 100:1 in biopsy series.
– As many lipomas and hemangiomas are never submitted for biopsy
examination, the actual ratio is probably considerably higher.
– Lipomas are the most common human neoplasm.
– Sarcomas are rare when the volume of tissue from which they may arise
is considered, with an annual age-adjusted incidence of about 2:100 000.
– Just over 5000 soft tissue sarcomas are diagnosed annually in the United
States, for example, accounting for 0.7 per cent of newly diagnosed
invasive cancers (excluding squamous and basal cell carcinoma of the
skin).
– In children under 15 years of age they account for over 6 per cent of all
cancers.
• Epidemiology
• Molecular epidemiology
– The pathogenesis of most soft tissue tumors is poorly understood.
– Genetic factors are associated with certain benign tumors:
• about 5 per cent of lipomas and angiolipomas are multiple and familial.
– Soft tissue sarcomas have no established genetic predisposition, but
occur with increased frequency in patients with genetically transmitted
conditions such as intestinal polyposis, Gardner's syndrome, and
basal cell nevus syndrome.
– Patients with von Recklinghausen's disease have a 15 per cent
chance of developing a soft tissue sarcoma.
– This is associated with NF1 gene expression.
• As the germ cell mutations associated with these conditions are defined, the
association with sarcomas of soft tissue is being studied and appears to
reflect the loss of tumor suppressor activity of certain genes.
• The mutations of RB genes responsible for retinoblastoma are also
associated with an increased risk of later sarcoma.
• Mutations of the RB genes are seen in sporadic sarcomas as well.
• p53, another tumor suppressor gene, is found to exhibit germline mutations
in the Li-Fraumeni families who are at increased risk for sarcoma.
• This gene is also found to be mutated in sporadic sarcomas.
• This is a very active field of investigation.
• It is hoped that certain genetic markers will be predictive of response to
certain therapies, for instance sensitivity to radiation or to certain cytotoxic
agents, and allow therapy to be specifically tailored to a given tumor.
• Some experimental models suggest the feasibility of this approach.
• p53 nuclear overexpression and loss of pRB expression are both associated with
increased tumor grade, but such work remains at an investigational level without
clinical integration.
• The investigation into the molecular mechanism of the development of Kaposi's
sarcoma in association with AIDS has been a model for future research in this field.
• Kaposi's sarcoma has been found to be linked to the presence of human herpes
virus 8 (HHV-8).
• It is found in all types of Kaposi's sarcoma, not only those that are AIDS associated.
• The role of HHV-8 has proved quite complex with the initial tumor arising as an
angiohyperplastic–inflammatory lesion mediated by inflammatory cytokines and
angiogenic factors triggered by the infection.
• Over time this reactive lesion evolves into a sarcoma, demonstrated by monoclonal
growth in the later nodular lesions.
• Chemical carcinogenesis
– Chemical carcinogens have been implicated in anecdotal reports but no
link has been established.
– Exposure to dioxin, phenoxyacetic acid, or to agent orange (containing
dioxin) has not been shown convincingly to have an association with
development of sarcomas in case–control studies, yet conflicting results
have been published.
• Trauma or foreign bodies
– Although trauma is often incidental to the discovery of a soft tissue
tumor by a patient, no evidence exists of any link between the two.
– Anecdotal reports of sarcoma occurring in association with foreign bodies
such as bullets and shrapnel pieces exist, but prospective studies of large
numbers of patients with metallic or Silastic implants have not shown any
associated tumor development.
• Chronic lymphedema
• There is an increased incidence of lymphangiosarcoma in lymphedematous extremities, first
described in women's arms following radical mastectomy (Steward–Treves' syndrome).
• It has also been seen in lymphedema resulting from filariasis confirming the association with
the lymphedema rather than breast cancer or chest wall irradiation.
• Radiation
• Radiation exposure is associated with a later incidence of sarcoma estimated at between 2
and 4/1000 patients after 10 years.
• Although any type of soft tissue sarcoma can arise,
– malignant fibrous histiocytoma,
– angiosarcoma,
– lymphangiosarcoma, or
– extraskeletal osteosarcoma are most common.
• Most soft tissue tumors arise in individuals in whom no predisposing factor can be identified.
• Benign tumors of soft tissue
• Non-aggressive benign tumors
• Lipomas are among the most common benign tumors.
• They are usually subcutaneous, not tethered or fixed to the underlying fascia,
multilobulated, and vary greatly in size.
• Angiolipomas contain many small vessels and are usually tender or painful.
– Their major significance is their confusion with liposarcomas.
– A biopsy should be taken or they should be removed when evidently growing, when
larger than 5 cm, or if symptomatic.
• Biopsies should be taken of
– large lipomas, or
– those tethered to fascia or
– deep to the fascia, as recommended for liposarcomas.
• Neurofibromas and neurilemmomas both arise from
Schwann cells.
– Simple excision is curative, but when they arise in nerves of clinical
significance, every effort should be made to preserve the affected
nerve.
– Multiple neurofibromas are seen in patients with von
Recklinghausen's disease and are too numerous to be removed: 10
to 15 per cent of these patients will develop neurogenic sarcomas.
– Neurofibromas should be removed when they undergo rapid
enlargement or if they become painful, as well as for cosmetic
reasons.
• Dermatofibromas, also called sclerosing hemangiomas,
occur in the skin and have a very characteristic
appearance.
• They are usually about 1 cm in diameter and do not tend to
grow.
• Excision is curative when desired.
• Myxomas and mesenchymomas present as soft tissue
tumors; the diagnosis is made histologically.
– They are almost always cured by simple excision.
– Mesotheliomas arise in the pleura, pericardium, or peritoneum.
– They project but do not infiltrate and are usually cured by excision.
• Hemangiomas are vascular neoplasms that are usually
present at birth in the head and neck area, but they can be
anywhere.
• Most congenital hemangiomas regress spontaneously by
the age of 5 years, even if they grow rapidly during the first
months of life.
• It is extremely rare for such lesions to compromise vital
structures, but low-dose radiation to a very focused field may
be used to treat this situation.
• Hemangiomas of extremities may not regress, and can result
in limb enlargement.
• Such patients are often best treated by angiographic
embolization, or sometimes by surgical dearterialization.
• The hemangioma may involve bone, and surgery too near the
tumor may be accompanied by severe or even fatal
hemorrhage.
• Lymphangiomas are similar tumors which can be surgically
excised.
• Conservative management of both of these tumor types
allows preservation of function and achieves a favorable
cosmetic result.
• Ongoing definition of mediators of growth of these lesions is
leading to anecdotal reports of dramatic response to therapy
with targeted biologic modulators and specific cytokines.
• This is a rapidly evolving clinical aspect of research in
angiogenesis.
• Ganglions are fibrous walled cysts, most commonly
seen on the dorsal surface of the wrist.
• They result from an excrescence of synovial tissue and
are filled with synovial fluid.
• Simple excision is usually curative.
• They are easily confused with giant cell tumors of the
tendon sheath, which are also most commonly seen in the
wrist or hand and are also treated by simple excision.
• Leiomyomas most commonly arise from the smooth muscle
of the uterus and gastrointestinal tract. Leiomyoblastomas are
similar to leiomyomas, but tend to grow large and to develop
areas of hemorrhage and cystic degeneration. Both are
treated by simple excision.
• Nodular fasciitis has often been mistaken for a fibrosarcoma.
• These tumors usually occur in the superficial or deep fascia
and grow rapidly when they first appear.
• In weeks to months they reach 3 to 5 cm and then usually
stop growing.
• They are generally eliminated by simple excision.
• Aggre s s ive be nign tumors
• De s mo id tumo rs or ag g re s s ive fibro mato s is ca n a ris e from a ny fa s cia l
tis s ue .
– The s e le s ions a re re ma rka ble for the ir infiltrative nature and fall into two
g ro ups .
1.Abdo minal de s mo id tumo rs a ris e from the mus cula r wa ll of the a bdome n,
– ofte n in a s s ocia tion with a bdomina l incis ions , a nd
– a re e s pe cia lly common in pos tpa rtum wome n, in whom the y ma y be re la te d to
hormona l cha nge s a nd s urgica l tra uma .
– If re s e cte d to cle a r ma rgins the y s e ldom re cur.
2.Extra-abdo minal de s mo id tumo rs be ha ve more a ggre s s ive ly.
– The y a re common a bout the s houlde r or within a n e xtre mity, whe re the y infiltra te
diffus e ly.
– Although the s e tumors do not me ta s ta s ize , the y ca us e loca l de s truction of
function.
– S urgica l re s e ction s hort of a mputa tion is ofte n impos s ible , but wide re s e ction is
the pre fe rre d tre a tme nt whe n it ca n be a ccomplis he d with minima l morbidity.
– Re s e ction to clos e ma rgins or to pos itive ma rgins is ge ne ra lly followe d by
re curre nce .
• The hormona l milie u ma y a ffe ct de s moid tumors , a nd
tre a tme nt with pro g e s te ro ne , tamo xife n, indo me thac in,
and as c o rbic ac id ha ve a ll be e n re porte d to induce
re mis s ions .
• The s e the ra pie s a re a s s ocia te d with minima l toxicity a nd
de s e rve furthe r s tudy, but the y us ua lly fa il to produce a
re s pons e .
• Atypic al lipo mas and atypic al fibro us his tio c yto mas
– a re ge ne ra lly loca te d de e p in the s oft tis s ue or mus cle ;
– the y a ppe a r a typica l his tologica lly a nd a lthough the y do not
me ta s ta s ize the y te nd to re cur loca lly a fte r re s e ction, pa rticula rly if
wide ma rgins a re not a chie ve d.
• De rmato fibro s arc o ma pro tube rans
– a ris e s ins idious ly in the s kin or s ubcuta ne ous tis s ue .
– The s e tumors do not me ta s ta s ize , e ve n whe n multiply re curre nt, but the y
be ha ve loca lly a s though ma ligna nt.
– It is importa nt to a chie ve control a t the time of firs t re s e ction, with
ge ne rous (at le as t 2 c m) ma rgins to minimize the ris k of furthe r
re curre nce .
– Ha lf of a ll pa tie nts tre a te d with s imple e xcis ion a nd more limite d ma rgins
will s uffe r re curre nce ; a mputa tion ma y be re quire d a nd de a th ma y re s ult.
– Ra dia tion the ra py a s a s upple me nt to cons e rva tive re s e ction a ppe a rs
be ne ficia l but ha s not be e n s ubje ct to controlle d tria l.
– Ra dia tion ha s be e n us e d in pla ce of ve ry ra dica l re s e ction in s ome
pa tie nts with a fa vora ble re s ult.
So ft Tis s ue Sarco mas
• S a rcoma s a re a he te ro g e ne o us g ro up o f ne o plas ms tha t a ris e pre domina ntly
from ce lls of the e mbryo nic me s o de rm.
• While the majority of s a rcoma s a re s o ft tis s ue s arc o mas , othe r type s of s a rcoma
include
– bo ne s arc o mas (o s te o s arc o ma, c ho ndro s arc o ma, and
– rare bo ne tumo rs like c ho rdo ma, ang io s arc o ma, and le io myo s arc o ma o f bo ne ) and
– Ewing ’s s arc o ma/ pe riphe ral primitive ne uro e c to de rmal tumo r, which ca n occur
e ithe r in the bone or in the s oft tis s ue s .
• Mos t primary s o ft tis s ue s arc o mas origina te in
– an e xtre mity (50%–60%);
– the ne xt mo s t c o mmo n s ite s are the trunk (19%),
– re tro pe rito ne um (15%), and
– he ad and ne c k (9%).
• The a na tomic s ite of a prima ry s a rcoma influe nce s tre a tme nt a nd outcome .
• Soft tis s ue s a rcoma s include more tha n 50 his tologic s ubtype s
• His torica lly, the mos t common s ubtype s in a dults (e xcluding Ka pos i’s
s a rcoma ) we re
– malig nant fibro us his tio c yto ma (28%),
– lipo s arc o ma (15%),
– le io myo s arc o ma (12%),
– s yno vial s arc o ma (10%), and
– malig nant pe riphe ral ne rve s he ath tumo r (6%).
• Toda y, ma ligna nt fibrous his tiocytoma is cla s s ifie d a s e ithe r
le io myo s arc o ma, ple o mo rphic undiffe re ntiate d s arc o ma,
myxo fibro s arc o ma, o r de diffe re ntiate d lipo s arc o ma ba s e d on ce llula r
diffe re ntia tion a nd ge ne tics .
• Embryo nal/alve o lar rhabdo myo s arc o mas a re the mos t common s oft
tis s ue s a rcoma s of childhood, whe re a s ple o mo rphic rhabdo myo s arc o ma
occurs pre domina ntly in a dults , a nd a lthough it s ha re s pa rt of the na me , it
ha s a diffe re nt biology a nd s hould no t be tre ate d as a pe diatric s arc o ma.
• Soft tis s ue s a rcoma (STS ) is a colle ctive te rm for a n unus ua l a nd
dive rs e group of ma ligna ncie s tha t a ris e from ce lls of the e mbryonic
me s ode rm.
• Although tis s ue s de rive d from the me s ode rm conta in a pproxima te ly
75% o f the c e lls in the human bo dy, s a rcoma s re pre s e nt only 1%
o f adult tumo rs and 15% o f pe diatric tumo rs .
• Sa rcoma s ma y occur a nywhe re in the body a nd compris e more tha n
50 dis tinct his tologic s ubtype s .(from ACS)
– Appro ximate ly 43% o f STSs o c c ur in the e xtre mitie s
– 15% in the re tro pe rito ne um
– 10% in the trunk
– 19% in the vis c e ra, and
– 13% in o the r lo c atio ns .
• S oft tis s ue s a rcoma s a ccount for a pproxima te ly 1% of a ll ne w
ca nce r dia gnos e s .
• Almos t ha lf of a ll pa tie nts dia gnos e d with the dis e a s e
e ve ntua lly die a s a re s ult of the ca nce r.
• S oft tis s ue s a rcoma s ca n occur a nywhe re in the body, but
mos t origina te in(from curre nt)
– an e xtre mity (59%),
– the trunk (19%),
– the re tro pe rito ne um (15%), o r
– the he ad and ne c k (9%).
• Ove ra ll, s a rcoma s a ffe ct 5 to 6 individua ls pe r 100,000
inha bita nts pe r ye a r,a ccounting for le s s tha n 1% o f all
malig nanc ie s in a dults a nd 15% o f malig nanc ie s in
c hildre n.
• Nb
– 80%-s o ft tis s ue ,20%-bo ne
• Me s e nc hyme is a type of tis s ue cha ra cte rize d by loos e ly a s s ocia te d
ce lls tha t lac k po larity a nd a re s urrounde d by a la rge e xtra ce llula r
ma trix.
• Me s e nchyma l ce lls a re a ble to de ve lop into the tis s ue s of
the lympha tic a nd circula tory s ys te ms , a s we ll a s conne ctive
tis s ue s throughout the body, s uch a s bone a nd ca rtila ge .
• A s a rcoma is a ma ligna nt ca nce r of me s e nchyma l ce lls .
• Me s e nchyme is cha ra cte rize d morphologica lly by a
promine nt ground s ubs ta nce ma trix conta ining a loos e a ggre ga te
of re ticula r fibrils a nd uns pe cia lize d ce lls .
• Me s e nchyma l ce lls ca n migra te e a s ily, in contra s t to e pithe lial c e lls ,
which lac k mo bility and are o rg anize d into c lo s e ly adhe re nt
s he e ts , a nd a re pola rize d in a n apic al-bas al o rie ntatio n.
• Sa rcoma s a re a ra re a nd he te roge ne ous group of ma ligna nt tumors
of me s e nchyma l origin tha t compris e le s s tha n 1 pe rce nt of a ll a dult
ma ligna ncie s a nd 12 pe rce nt of pe dia tric ca nce rs .
• Approxima te ly 80 pe rce nt of s a rcoma s origina te from s oft tis s ue a nd
the re s t from bone .
• The re a re a bout 11,930 ne w ca s e s of s oft tis s ue s a rcoma dia gnos e d
e a ch ye a r in the Unite d Sta te s , with 4870 de a ths .
• The his topa thologic s pe ctrum of s a rcoma s is broa d, pre s uma bly
be ca us e the e mbryonic me s e nchyma l ce lls from which the y a ris e
ha ve the ca pa city to ma ture into s tria te d s ke le ta l a nd s mooth
mus cle , a dipos e a nd fibrous tis s ue , bone , a nd ca rtila ge .
• Although e ctode rma l in origin, ma ligna nt tumors a ffe cting pe riphe ra l
ne rve s a re include d be ca us e of s imila ritie s in the ir clinica l be ha vior,
ma na ge me nt, a nd outcome .
• 2 Appro ximate ly two thirds o f s o ft tis s ue s arc o mas aris e in the
e xtre mitie s ; the re ma ining o ne third is dis tribute d be twe e n the
re tro pe rito ne um, trunk, a bdome n, he a d, a nd ne ck.
• 3 Multimo dality tre atme nt, inc luding s urg ic al re s e c tio n,
radiatio n the ra py, a nd, in s e le cte d ca s e s , s ys te mic che mothe ra py,
ha s be e n a pplie d to pa tie nts with loca lly a dva nce d, high-gra de ,
e xtre mity s a rcoma s .
• 4 Ove rall 5-ye ar s urvival rate fo r patie nts with all s tag e s o f s o ft
tis s ue s a rcoma is 50% to 60%.
• 5 The s e rare tumo rs ac c o unt fo r le s s than 1% o f c anc e r in
a dults (e s tima te d 10,000 ca s e s pe r ye a r in the Unite d Sta te s ) a nd
re pre s e nt 15% of ca nce rs in childre n.
• 6 The tre atme nt alg o rithm fo r s o ft tis s ue s arc o mas
de pe nds on tumor s tag e , s ite , and his to lo g y.
• 7 Of the patie nts who die o f s arc o ma, mo s t will
s uc c umb to me tas tatic dis e as e in the lung s , which
80% o f the time o c c urs within 2 to 3 ye ars o f the initial
diag no s is .
• 8 Pro g re s s in the unde rs tanding o f s o ft tis s ue
s arc o ma bio lo g y is crucia l for the de ve lopme nt of ne w
tre a tme nts .
• Ana tomic dis tribution
– Soft tiss ue sa rcoma s occur at all ana tomic body site s , and their
freque ncy is no t a s imple func tio n of abundanc e of the
tis s ue type .
– Lipos a rcoma s are not common in the large fatty de posits of the
abdominal wall; while in the thigh, a freque nt site , the y often
arise de e p in the mus c le mas s , rathe r tha n in the
subcuta ne ous fat.
• Howe ve r, s ome his tologic type s of s oft tis s ue s a rcoma ha ve a pre dile ction
for ce rta in a na tomic s ite s .
• As a n e xa mple , o nly 14 pe rc e nt of a ll s oft tis s ue s a rcoma s pre s e nt in the
uppe r e xtre mity.
• In contra s t, 40 to 50 pe rce nt of a ll e pithe lio id s arc o mas a ris e on the
fo re arm and finge r
• Epithe lio id s arc o mas
– A ma ligna nt tumour of unce rta in diffe re ntia tion c o mpo s e d o f no dule s and
g arlands of ro unde d, g las s y e o s ino philic c e lls circums cribing a re a s of ce ntra l
hya liniza tion a nd ne cros is .
– The ce lls conta in cytoke ra tins .
– This tumour cha ra cte ris tica lly occurs in s upe rficia l s oft tis s ue s of the dis tal
po rtio ns o f the e xtre mitie s o f ado le s c e nts and yo ung adults .
• Thig h, butto c k, and g ro in — 46
pe rc e nt
• Uppe r e xtre mity — 13 pe rc e nt
• To rs o — 18 pe rc e nt
• Re tro pe rito ne um — 13 pe rc e nt
• He ad and ne c k — 9 pe rc e nt
Ana tomic distribution and site -s pe cific histologic subtype s of 7563 cons e cutive STS se e n at the University of
Texa s MD
Approxima te relation of age to incide nce of various type s of sa rcoma . Continuous line indica te s
pe a k incide nce of tumor. Dotte d line indica te s re duc e d inc ide nc e o f tumor.
• Exce pt for malig nant pe riphe ral ne rve s he ath tumo rs
in pa tie nts with ne uro fibro mato s is , s a rcoma s do not
s e e m to re s ult from progre s s ion or de diffe re ntia tion of a
be nig n s o ft tis s ue tumo r.
• While mos t s a rcoma s a re of unknown ca us e , a fe w
s a rcoma s ubtype s ha ve be e n obs e rve d in s e tting s
s ug g e s ting e tio lo g y.
• In ne arly all ins tance s , s a rcoma s a re thought to a ris e de
no vo and no t fro m a pre e xis ting be nig n le s ion.
• The re is no cle a rly de fine d e tiology in mos t ca s e s of s oft
tis s ue s a rcoma , but a numbe r of a s s ocia te d or
pre dis pos ing fa ctors ha ve be e n ide ntifie d.
• The s e include
– g e ne tic pre dis po s itio n,
– e xpo s ure to radiatio n o r c he mo the rapy,
– c he mic al c arc ino g e ns ,
– c hro nic irritatio n, and
– lymphe de ma.
GENETIC PREDISP OSITION
• Some pa tie nts , pa rticula rly childre n, ha ve a fa milia l pre dis pos ition to
ca nce r
• Li-Fraume ni s yndro me
– As ma ny a s 7 pe rc e nt of childre n with soft tiss ue sa rcoma s ma y ha ve Li-
Fra ume ni syndrome (LFS)
– The LFS is inhe rite d a s a n auto s o mal do minant trait, a nd is prima rily
cha ra cte rize d by
• s o ft tis s ue and bo ne s arc o mas
• bre as t c anc e r;
• brain tumo r,
• le uke mia, and
• adre no c o rtic al c anc e r o c c urring be fo re the ag e o f 45
– A ge rmline muta tion in the p53 tumo r s uppre s s o r g e ne is fo und in mo s t
affe c te d familie s
• FAP and Gardne r's s yndro me
– The re is a high freque ncy of intra a bdominal de s moid tumors
among pa tients with familial ade no mato us po lypo s is or
Gardner's s yndrome
• Re tinobla s toma
– Sa rcoma s of soft tiss ue and bone , pa rticularly os te os a rcoma ,
de velop late r in life in surviving pa tients with retinoblas toma
(RB), pa rticularly of the familial or bilate ral type , in which
individuals inherit a mutant co py of RB
• Ne urofibroma tos is
– Some of the multiple be nign ne urofibroma s of vo n
Rec kling haus e n's dise a s e (type 1 ne urofibromato s is , NF1)
ca n unde rgo maligna nt cha nge to malig nant peripheral nerve
s he ath tumors
• (MPNS Ts , including ne uro fibro s arc o mas , malig nant s c hwanno mas )
• Radiatio n Expo s ure
– Exte rnal radiation the ra py is a rare but well-es ta blishe d risk
factor for soft tiss ue sa rcoma tha t ma y be as s ociate d with
radiatio ninduc e d mutatio ns of the p53 ge ne
– The incide nce of sa rcoma among pa tients who are often
trea te d with radiation for ca nce r of the breas t, cervix, ovary,
tes te s , or lymphatic s ys te m is 8 to 50 time s the ge neral-
po pulatio n ris k
• In a re vie w of 160 pa tie nts with pos tirra dia tion s a rcoma s ,
the mos t common his tologic type s we re
– os te o g e nic s arco ma,
– malig nant fibrous his tio c yto ma,
– ang io s arco ma, and
– lymphang io s arco ma.
• The ris k of de ve loping a s a rcoma incre a s e d with ra dia tion
dos e , a nd the me dia n time be twe e n ra dia tion the ra py a nd
dia gnos is of s a rcoma wa s 10 ye ars .
• Oc c upatio nal Che mic al Expo s ure
• Expos ure to he rbicide s s uch a s phe noxya ce tic a cids a nd
to wood pre s e rva tive s conta ining chlorophe nols ha s be e n
linke d to a n incre a s e d ris k of s oft tis s ue s a rcoma
• Trauma
• Although pa tie nts with s a rcoma ofte n re port a his tory of
tra uma , no c aus al re latio ns hip has be e n e s tablis he d.
• More ofte n, a minor injury c alls atte ntio n to a pre -
e xis ting tumo r.
• Chro nic Lymphe de ma
– In 1948, Ste wa rt and Treve s first de s cribe d the as s ociation
be twe e n chronic lymphe de ma afte r axillary diss e ction and
subs e que nt lympha ngios a rcoma
– Lympha ngios a rcoma ha s be e n es tima te d to occur in 0.07% of
patie nts who underg o axillary no de dis s e c tio n.
– It als o ha s be e n reporte d to occur afte r filarial infections and in
the lowe r extre mities of pa tients with conge nital lymphe de ma .
– Lymphang io s arco ma is ge ne rally an ag gre s s ive tumor;
averag e s urvival of patie nts with lymphang io s arco ma is 19
mo nths .
• The ge ne tics of s a rcoma s s e gre ga te into two major type s :
– thos e with s pe c ific ge ne tic alteratio ns and us ually simple
karyotype s , including fusion ge ne s due to reciprocal
transloca tions (eg, PAX3-FKHR in alve olar
rha bdomyos a rcoma s ) or spe cific point muta tions (eg, c-kit
muta tions in ga s trointe s tinal stromal tumors [GIST]), and
– thos e with no ns pe c ific ge ne tic alteratio ns and complex,
unbala nce d karyotype s , reflecte d by nume rous ge ne tic los s e s
and gains (eg, os te os a rcoma , MFH, lipos a rcoma s othe r tha n
the myxoid type , angios a rcoma , leiomyos a rcoma ).
• Sa rcoma s ca n be broa dly cla s s ifie d into thre e groups
a ccording to the ge ne tic e ve nts unde rlying the ir
de ve lopme nt:
– s pe c ific trans lo c atio ns or ge ne amplific atio n,
– de fining onc o g e nic mutatio ns , and
– co mple x ge no mic rearrang e me nts .
• In ge ne ra l, s a rcoma s re s ulting from ide ntifia ble mole cula r
e ve nts te nd to occur in yo ung e r patie nts with his to lo g y
s ug g e s ting a c le ar line o f diffe re ntiatio n.
• In contra s t, s a rcoma s witho ut ide ntifiable g e ne tic
cha nge s or e xpre s s ion profile s igna ture s te nd to occur in
olde r pa tie nts a nd e xhibit ple omorphic cytology a nd p53
dys func tio n
• Trans lo catio n-As s o c iate d Sarc o mas
• To da te , tra ns loca tions ha ve be e n ide ntifie d in 14 s ubtype s of
s oft tis s ue s a rcoma , a ccounting for 20% to 30% of a ll
s a rcoma s
• Tra ns loca tions re s ult in in-fra me ge ne fus ion, which in turn
re s ults in fus e d products e ncoding oncoprote ins tha t function
a s tra ns criptiona l a ctiva tors or re pre s s ors .
• The be s t cha ra cte rize d ge ne fus ions a re in Ewing’s s a rcoma
(EWS -FLI1), cle a r ce ll s a rcoma (EWS -ATF1), myxoid/round
ce ll lipos a rcoma (TLS CHOP), a lve ola r rha bdomyos a rcoma
(PAX3-FHKR), de s mopla s tic s ma ll round ce ll tumor (EWS -
WT1), a nd s ynovia l s a rcoma (S S 18-S S X).
• Fus ion ge ne –re la te d s a rcoma s ha ve be e n e s tima te d to
a ccount for 30% o r more of a ll s a rcoma s .
• Dire ct or indire ct inte ra ctions be twe e n fus ion tra ns cripts a nd
ce ll cycle re gula tors ha ve be e n e lucida te d by s e ve ra l
inve s tiga tor a nd ide ntify the s e tra ns cripts a s pote ntia lly
promis ing mole cula r the ra pe utic ta rge ts .
• Howe ve r, fus ion ge ne s in s a rcoma ha ve be e n s ucce s s fully
ta rge te d in only a fe w ca s e s , in which fus ion re s ulte d in
ove re xpre s s ion of a growth fa ctor or growth fa ctor re ce ptor.
• S e ve ra l growth fa ctors a nd the ir re ce ptors (e .g., e pide rma l
growth fa ctor re ce ptor) pre vious ly re porte d to pla y a n
importa nt role in a utocrine or pa ra crine s timula tion of
ca rcinoma growth ha ve be e n a s s ocia te d with high his tologic
gra de a nd poor prognos is in s oft tis s ue s a rcoma s .
• Amplificatio n-As s o ciate d Sarc o mas
– Oncoge ne s a re ge ne s tha t ca n induce ma ligna nt tra ns forma tion a nd
te nd to drive ce ll prolife ra tion.
– S e ve ra l oncoge ne s ha ve be e n a s s ocia te d with s oft tis s ue s a rcoma s ,
including MDM2, N-myc, c-erbB2, and members of the ras family.
– These oncogenes produce s pe cific oncoprote ins tha t e ithe r pla y a role
in nucle a r function a nd ce llula r s igna l tra ns duction or function a s
growth fa ctors or growth fa ctor re ce ptors .
– This typica lly occurs in de diffe re ntia te d lipos a rcoma , whe re the
a mplifica tion of MDM2 drives the neoplastic process.
– Amplification of these ge ne s ha s be e n s hown to corre la te with
a dve rs e outcome in s e ve ra l type s of s oft tis s ue s a rcoma .
• Onc o g e nic Mutatio ns
• GISTs a re the cla s s ic e xa mple of s a rcoma s in which
tumorige ne s is is prima rily drive n by a s ingle a ctiva ting
muta tion, in the ge ne e ncoding KIT re ce ptor tyros ine
kina s e or pla te le t-de rive d growth fa ctor re ce ptor-α
(PDGFRA)
• Co mple x Ge no mic Re arrang e me nts
• The la rge s t group of s a rcoma s is the group with comple x
cytoge ne tic a lte ra tions , which include s high-gra de s pindle
ce ll s a rcoma s a nd ple omorphic s a rcoma s .
• Ma ny s a rcoma s in this group e xhibit ina ctiva tion of tumor
s uppre s s or ge ne s .
• The two ge ne s mos t re le va nt to s oft tis s ue s a rcoma a re
re tinobla s toma (Rb) and p53.
• Muta tions or de le tions in Rb ca n le a d to re tinobla s toma , the
mos t common ma ligna nt ocula r ne opla s m of childhood.
• S urvivors of re tinobla s toma a re a t ris k for de ve loping s oft
tis s ue a nd bone s a rcoma s la te r in life .
• Pa tie nts with ge rmline muta tions in p53 (Li-Fra ume ni
s yndrome ) ha ve a high incide nce of s oft tis s ue s a rcoma s
• Muta nt p53 expression is thought to correlate with poor ove ra ll
s urviva l.
• S tra te gie s to ta rge t p53 mutation a re be ing inve s tiga te d for
tre a tme nt of s ome s a rcoma s .
• Ne urofibroma tos is type 1 (von Re cklingha us e n’s dis e a s e )
occurs in a pproxima te ly 1 of e ve ry 3000 pe ople a nd is due to
va rious muta tions in the NF-1 tumo r s uppre s s o r g e ne ,
loca te d on chromos ome
• Pa tie nts with ne uro fibro mato s is type 1 have an e s timate d
3% to 15% additio nal ris k of ma ligna nt dis e a s e compa re d
with the ge ne ra l popula tion life time ris k, including ma ligna nt
pe riphe ra l ne rve s he a th tumors (MPNS T) a nd GIST.
• In turn, 25% to 50% of pa tie nts with MPNS T ha ve a muta tion
in NF-1.
• INITIAL ASS ES SMENT
• The clinica l be ha vior of mos t s oft tis s ue s a rcoma s is de te rmine d by
a na tomic loca tion (de pth in re latio n to the inve s ting fas c ia), his tologic
s ubtype a nd gra de of a ggre s s ive ne s s , a nd s ize .
• The domina nt pa tte rn of me ta s ta s is is he ma toge nous , primarily to the
lung s .
• Lymph node me ta s ta s is is ra re (affe c ting <5% o f patie nts ) e xce pt in a
fe w his tologic s ubtype s , including
– e pithe lio id s arco ma,
– pe diatric rhabdo myo s arc o ma,
– cle ar ce ll s arco ma,
– ang io s arco ma, and,
– mo re rare ly, s yno vial s arco ma and myxo fibro s arc o ma
Nb
• Dis ta nt s ite s of me ta s ta s e s va ry in a ccorda nce with the tumor
his to lo g y and the s ite o f the primary tumo r.
• Extre mity s a rcoma s mos t commonly me ta s ta s ize to the lung,
whe re a s abdo minal and re tro pe rito ne al s a rcoma s more
fre que ntly me ta s ta s ize to the live r, with the lung be ing a
s e conda ry s ite of me ta s ta tic impla nta tion.
• In a ddition, the re a re a fe w s arco mas that te nd to
me tas tas ize to re giona l lymph node s
• The s e diffe ring pa tte rns of me ta s ta tic s pre a d mus t be
ca re fully cons ide re d during the initia l e va lua tion of s a rcoma
pa tie nts .
Incide nce of Nodal Meta s ta s e s for Sele cte d Sa rcoma s
• The fa milial polypos is ge ne on chromos ome 5 ha s be e n e xte ns ive ly s tudie d.[5, 22]
• Fibros a rcoma
• Immunos ta ining with vime ntin, a lpha s mooth mus cle a ctin, mus cle a ctin,
a nd de s min a re he lpful in dis tinguis hing the tumors in the diffe re ntia l
dia gnos is of de s moid tumors .
• APC ge rmline muta tions in a ppa re ntly s pora dic de s moid tumor pa tie nts
who ha ve no clinica l or fa milia l s igns of fa milia l a de noma tous polypos is
(FAP) but ha ve a fa mily his tory of colore cta l ca rcinoma in a t le a s t one
fa mily me mbe r
• The y re porte d tha t pa tie nts with s pora dic de s moid tumors a nd no clinica l
or la bora tory s igns of FAP ma y not ne e d to be routine ly te s te d for ge rmline
muta tions of the APC ge ne . Howe ve r, pe rforming a n APC muta tiona l
a na lys is ins te a d of othe r te s ts (e g, e s opha goga s troduode nos copy,
comple te colonos copy) ma y be a more time - a nd cos t-e ffe ctive pla n
• Ima ging Studie s
– Prima ry surge ry with ne ga tive surgica l ma rgins is the most succe s s ful prima ry trea tme nt moda lity for de s moid tumors .
Pos itive ma rgins after surge ry reflect a high risk for recurre nce .[28]
– In thos e pa tients who refus e surge ry or are not surgica l ca ndida te s , the options be low ma y be conside re d.
– Ra diation the ra py ma y be us e d as a trea tme nt for recurre nt dise a s e or as primary the ra py to avoid mutilating surgica l
res e ction. It ma y be us e d postope ra tively, pre ope ra tively, or as the sole treatme nt.[29]
– Pha rma cologic the ra py with antiestroge ns and pros ta glandin inhibitors ma y also be us e d.
– In ca s e s of recurre nt extra -a bdomina l de s moid tumors in which surgery is contraindica te d or in ca s e s of recurre nce , a
che mothe ra pe utic regime n of doxorubicin, da ca rba zine , and ca rboplatin ma y be effective. Intra -a bdomina l de s moid
tumors as a pa rt of Ga rdne r syndrome ma y res pond to sys te mic doxorubicin, and ifosfamide ca n be us e ful for pa tients
with complications from the tumor.[30] Polyche mothe ra py ha s be e n us e d[31] and ca n be combine d with targete d
the ra py with imatinib.[32]
– Expa nde d knowledge of familial ade noma tosis polypos is–de s moid tumor molecular unde rpinnings ma y aid in the
de velopme nt of nove l the ra pe utic strate gies .
• Excis ion of Tumor
• Aggres s ive , wide surgica l res e ction is the trea tme nt of choice .[34, 35] Complete surgica l
excis ion of de s moid tumors is the most effe ctive method of cure . This some time s
ne ce s s ita te s remova l of most of a n a nte rior compa rtment of a leg. Exte ns ive ca s e s ma y
require excis ion plus a djuva nt trea tme nt including che mothe ra py a nd repe a t surgery.[36] In
se lecte d pa tients , ra dica l res e ction with intra opera tive ma rgin eva lua tion by froze n se ctions
followed by immedia te mes h recons truction ma y be a sa fe a nd effe ctive proce dure providing
de finitive cure yet minimizing functiona l limita tions .[37]
• Evide nce sugge s ts tha t pregna ncy doe s not a dve rs ely a ffect surgica l outcome s .[38]
• Les ions involving the extremitie s a nd de e p soft tiss ue s of the trunk ha ve a highe r risk of
recurre nce , a s do Ga rdne r syndrome–a s socia te d les ions in othe r loca tions.[39]
• For tumors tha t a re a symptoma tic or nonprogres s ive , some prefe r a wa it-a nd-s e e a pproa ch.
• DERMATOFIBROSARCOMA PROTUBERANS
• De rma tofibros a rcoma protube ra ns is a rare lo w-g rade
s arco ma aris ing in the de rmis tha t ra re ly me ta s ta s ize s but is
loca lly a ggre s s ive .
• The ove ra ll a nnua l incide nce ha s be e n e s tima te d a t ca s e s pe r
million individua ls , a nd the incide nce is highe r a mong bla cks
tha n white s (6.5 vs . 3.9 pe r millio n pe r ye ar).
• Approxima te ly 40% o f cas e s aris e o n the trunk, a nd mos t of
the re ma ining tumors a re dis tribute d be twe e n the he ad and
ne ck and the e xtre mitie s .
• De rma tofibros a rcoma protube ra ns pre s e nts a s a no dular,
c utane o us mas s tha t grows s lowly a nd pe rs is te ntly.
• Sate llite les io ns ma y be found in pa tie nts with la rge r
tumors .
• Sta nda rd tre a tme nt is wide lo c al exc is io n, which
ge ne ra lly re s ults in lo c al rec urre nc e rate s o f les s than
10%.
• Although loca l re curre nce ra te s a s high a s 30% to 50%
ha ve be e n re porte d in popula tion-ba s e d s e rie s , the
a s s ocia te d 5-ye ar s urvival rate is g reate r than 99%.
• De rma tofibros a rcoma protube ra ns a ris e s from a s pe cific chro mo s o mal
trans loc atio n involving chro mo s o me s 17 and 22, in which the colla ge n 1 α 1 ge ne
is fus e d to the ge ne for PDGF β-cha in (PDGFB).
• The re s ulta nt de re gula te d e xpre s s ion of PDGFB le ads to co ntinuo us activatio n of
the PDGFR prote in tyro s ine kinas e , which promote s tumor ce ll growth.
• The ide ntifica tion of this chromos oma l tra ns loca tion in more than 90% of cas e s of
de rma tofibros a rcoma protube ra ns ha s le d to the de velopme nt of targe te d the rapy.
• Inhibiting PDGFR with imatinib ha s be e n s hown to induce clinica l a nd ra diologic
improve me nt in pa tie nts with unre s e ctable de rmatofibro s arc o ma protube rans .
• The s e da ta ha ve re s ulte d in the a pprova l by the U.S . Food a nd Drug Adminis tra tion
of imatinib for tre a tme nt of pa tie nts with loca lly a dva nce d de rma tofibros a rcoma
protube ra ns .
• PEDIATRIC S ARCOMAS
• Soft tiss ue sa rcoma s in childre n a re rela tively ra re, a ccounting for 7% to 8% of all pedia tric
ca nce rs a nd totaling a pproxima tely 600 ne w ca s e s per yea r.
• Pe dia tric sa rcoma s ha ve tra ditiona lly be e n divide d into two groups:
– rhabdo myo s arco ma and
– No nrhabdo myo s arco ma s o ft tis s ue s arco mas .
• Rhabdo myo s arc o ma
• Ass ocia te d with skele ta l muscle, rha bdomyos a rcoma s a re the most common soft tiss ue
tumors a mong childre n younge r tha n 15 yea rs a nd ca n occur a t a ny site compris e d of
stria te d muscle.
• Pa tie nts with the s e tumors gene ra lly pres e nt with a pa inles s enla rging ma ss ;
– abo ut 24% o f tumo rs are lo cate d in the g enito urinary s ys te m,
– 20% in the extremitie s ,
– 20% in the he ad and ne c k,
– 16% in the paramening e al reg io n, and
– 22% in o ther s ite s
• Rha bdomyos a rcoma is a s mall round ce ll tumor tha t de mons tra te s mus cle
diffe re ntia tion upon light micros copy a nd immunohis toche mica l a na lys is .
• Two prima ry his tologic s ubtype s a ccount for 90% of ca s e s :
– embryo nal (70%) and
– alve o lar (20%).
• Alve ola r rha bdomyos a rcoma is a s s ocia te d with cyto g e ne tic trans loc atio n
[t(2:13)(q35:q14)] in 85% to 90% of cas e s a nd [t(1:13)(p36:q14)] in 10% of cas e s .
• The s e tra ns loca tions a ffe ct biologic a ctivity a t the le vels of prote in function a nd ge ne
e xpre s s ion, the re by a ffe cting the co ntro l of ce ll gro wth, apopto s is ,
diffe re ntiatio n, and motility and ultimate ly co ntributing to tumorig e nic
be havio r.
• Whe re a s alve olar rhabdo myo s arc o mas ofte n ha ve tra ns loca tions , mos t
e mbryona l rha bdomyos a rcoma s ha ve a n allelic los s a t chromos ome 11p15.5 tha t is
thought to ina ctiva te a tumor s uppre s s or ge ne .
• Both of the s e dis tinct mole c ular s ubtype s of rhabdo myo s arc o ma a re thought to
ha ve s imila r alte ra tions in downs tre am targe ts s uch as the p53 and Rb
pathways .
• Comple te s urgica l re s e ction is the tre a tme nt of choice for
rha bdomyos a rcoma whe n function a nd cos me s is ca n be
pre s e rve d.
• Pa tie nts who a re a ble to unde rgo a comple te tumor re s e ction
with ne ga tive (group I) or micros copic s urgica l ma rgins (group
II) a re a ble to unde rgo le s s inte ns ive s ys te mic the ra py a nd
s till ha ve ove ra ll s urviva l ra te s a pproa ching 90%.
• At s ome a na tomic s ite s , in pa rticula r the he ad and ne ck and
g e nito urinary s ys te m, s urge ry is ofte n a voide d be ca us e the
a s s ocia te d morbidity wo uld be s ubs tantial.
– Re ce nt findings s ugge s t tha t che mo the rapy alo ne ca n a de qua te ly
control ma ny s uch tumors .
• Unlike othe r s oft tis s ue s a rcoma s , rha bdomyos a rcoma s
ha ve a high pro pe ns ity fo r lymph no de me tas tas is ,
with ra te s up to 20% to 30% fo r s ites s uch a s the
e xtre mitie s , pa ra te s ticula r node s , a nd pros ta te .
• Lymph no de s ampling and, mo re rec e ntly, s e ntine l
lymph node ma pping ha ve be e n us e d to e va lua te
reg io nal no de s tatus in c hildre n with
rhabdo myo s arc o ma.
• About 15% to 20% of patie nts with rhabdo myo s arc o ma ha ve dis ta nt me ta s ta s is
a t pre s e nta tion, mos t commonly (40%–50% of cas e s ) to the lungs , followe d by
bone marrow and bone .
• Howe ve r, all patie nts with rhabdo myo s arc o ma a re a s s ume d to ha ve
microme ta s ta tic dis e a s e a t pre s e nta tion.
• The re fore , multiage nt che mo the rapy is re comme nde d for all pa tie nts with
rha bdomyos a rcoma .
• Combina tion re gime ns including vincris tine , dactino myc in, and
cyc lo pho s phamide continue to be the ba s is of e ffe ctive cura tive the ra py.
• Although va rious combina tions including doxorubicin, ifos fa mide , cis pla tin, a nd
e topos ide ha ve be e n s hown to be a ctive a ga ins t rha bdomyos a rcoma , the y ha ve not
improve d outcome s .
• Ra dia tion the ra py is give n to mos t pa tie nts with micros copic re s idual dis e a s e (group
II) a fte r re s e ction.
• The prognos is for childre n with rha bdomyos a rcoma s is
re la te d to tumor s ite , s urgica l-pa thologic grouping, a nd
tumor his tology.
• The 5-ye a r dis e a s e -fre e s urviva l ra te for a ll pa tie nts ha s
be e n re porte d to be 65%.
• Five -ye a r dis e a s e -fre e s urviva l ra te s for pa tie nts in groups
I, II, III, a nd IV ha ve be e n re porte d to be 84%, 74%, 62%,
a nd 23%, re s pe ctive ly.
• Nonrha bdomyos a rcoma Soft Tis s ue Sa rcoma s
– Approxima te ly 60% o f s o ft tis s ue s arco mas in childre n are
no nrhabdo myo s arco mas .
– The s e include nume rous his tologic s ubtype s , which a re ge ne ra lly
ca te gorize d into four groups :
• (a) fibros arc o ma,
• (b) Kapos i’s s arco ma,
• (c) othe r “s pe cifie d” s oft tis s ue s arco mas (e .g., s ynovia l, a ngios a rcoma ,
he ma ngiope ricytoma , le iomyos a rcoma , lipos a rcoma , a nd e xtra os s e ous
Ewing’s s a rcoma ), a nd
• (d)“uns pe cifie d” s oft tis s ue s arco ma.
– The mos t common s ubtype s a re s yno vial s arco ma, MPNS T, and
fibro s arco ma.
• No s ingle his tology a ccounts for more tha n 15% of a ll ca s es .
• As with a dult tumors , the eva lua tion of the s oft tis s ue ma s s begins
with a his tory and phys ic al examinatio n follo we d by imag ing ,
whic h us ually inc lude s MRI.
• A CT s ca n of the che s t is important for evaluatio n of metas tatic
dis eas e .
• A core ne e dle biops y is gene ra lly require d to es ta blis h a dia gnos is .
• Surge ry rema ins the prima ry trea tme nt of nonrha bdomyos a rcoma ,
a nd loca l control of la rge, high-gra de tumors is improve d with
ra dia tion the ra py.
• The prognos tic fa ctors for childre n with nonrha bdomyos a rcoma a re
s imila r to thos e for a dults , a nd the role of che mothe ra py for high-ris k
tumors is uncle a r, a s for a dults .