White Cell Disorders I

WHITE CELL DISORDERS I & II
Title:
Date & Time:
Date & Time:
II)
Lecturer:
White Cell Disorders I & II

Monday, November 12, 2012 at 12 nooon (White Cell Disorers I)
Wednesday, November 14, 2012 at 12 nooon (White Cell Disorers
The Pathology Team
QUIZBANK -- Blood & Lymph #'s 133-139, 178-333

INTRODUCTION
You will refer to this material every time you feel a large lymph node or
spleen, or have a patient with an abnormal CBC.
"Leukemias and lymphomas" is the most difficult unit in Medical
Pathology except for glomerular disease. You can't learn it if you are not
continually asking yourself, "Why?"
You are already familiar with the development of the different kinds of
white cells, and the locations of lymphoid tissue throughout the body
(lymph nodes, Waldeyer's ring, Peyer's patches, spleen, large airways).
T-cell zones: thymus, lymph node parafollicular cortex, splenic
white pulp near arteriole
B-cell zones: germinal centers and their mantles, splenic white
pulp at its margins
Among circulating lymphocytes, 80% are T-cells, and 20% are Bcells.
* You are also familiar with the common reaction patterns of
various white blood cells: acute inflammation, pus, granulomas,
and accumulations within phagocytes. (There's no need, for
example, to talk right now about xanthomas, lipogranulomas, etc.,
etc.)
Mycobacterial lymphadenitis
Pittsburgh Pathology Cases
In discussing diseases that affect numbers of white blood cells in the

peripheral blood, it is much more useful to talk about ABSOLUTE CELL
COUNTS than "percentage counts".
Of course, you can estimate the absolute count by multiplying the
total WBC count x the % for a particular cell.
Healthy absolute counts:
Basophils: * few- 100/cu mcL (heads up -- basophil granules
are soluble and can wash out during slide preparation)
Eosinophils: few- maybe 400 (fewer in AM, more in PM)
(* "Hypereosinophilia" was once defined to be more
than 1500 for more than six months without an
obvious reason, and some evidence of organ
involvement; today, as soon as one of the
hypereosinophilic syndromes causing organ damage
is suspected, diagnose if you can and start treatment
even if you can't)
Lymphocytes: 1200-3400 (* 3000-7000 for kids)
T4 helper lymphocytes: >=1000
Monocytes: 100- 590
Neutrophils: 1800-6500
Note that "95% lymphocytes" might mean either
agranulocytosis (if the total white count is 2000) or chronic
lymphocytic leukemia (if the total white count is 100,000).
This is why I like white cell differential counts reported in
absolute numbers, and why all labs do this nowadays.
* Current smokers average 25% higher neutrophil counts;
those who've quit in the last five years still average higher
(Am. J. Clin. Path. 107: 64, 1997). This won't matter in your
clinical decision-making.
A good "normal range" for total white count is 4000-11000/cu mcL.

"Leukocytosis" is present when the white count exceeds
12,000/cu mcL.
The most important "white cell diseases" are neoplastic. These are:
(1) the MALIGNANT LYMPHOMAS (HODGKIN'S AND NONHODGKIN'S), solid tumors of lymphocytes (the rare tumors that
truly arise from monocyte-macrophages are also included here;
no one knows the true cell of origin of the malignant cells of
Hodgkin's disease, which is also included here)
(2) the LEUKEMIAS and their close relatives, the
MYELOPROLIFERATIVE DISORDERS, in which sick
hematopoietic stem cells proliferate
(3) the PLASMA CELL DISORDERS, which typically produce
antibodies and/or fragments thereof
(4) the LANGERHANS CELL HISTIOCYTOSIS FAMILY
("histiocytosis X"; "disseminated histiocytosis") of quasi-cancers,
much less common than the others
Probably because it is so easy to harvest the cells, and since
chemotherapy has been more successful for these diseases than
for most other cancers, a tremendous amount of study has gone
into clarifying their molecular pathology.
There can be no such thing as a truly benign neoplasm of white
blood cells, since by their very nature they infiltrate tissues. Some
of these entities (for example, the acute leukemias) are far more
aggressive than others ("benign plasmacytoma", "benign
monoclonal gammopathy").
White cell markers oversimplified:
TdT: immature lymphocytes
E-rosettes: T-cells
{16282} E-rosette, around a T-cell
CD3, CD4, CD8, TcR, TcR, TcR, TCR, others: the more
mature T-cells (various kinds)
CD1a (T6): some T-cells, all Langerhans macrophages
CD5: mantle cell lymphoma, many CLL
* CD10 (CALLA): most B-cells (mantle cell lymphoma is negative)
CD15: Most Reed-Sternberg cells; some others
* CD19: B-cells, but not plasma cells
* CD20: all but the most primitive B-cells, but not plasma cells
* CD22: most B-cells (EBV receptor)
* CD34 : primitive blood cells -- great for counting "blasts" in
leukemia / preleukemia
CD45 ("common leukocyte antigen" / LCA): all white cells
(* exception: Reed Sternberg cells and some leukemias)
* CD65: Most consistent marker for the natural-killer lymphocytes,
non-B, non-T cells making up maybe 10% percent of your
circulating white cells. (They tend to be big and have granules.
Update on their neoplasms: Cancer 112: 1425, 2008).
CD68: common macrophages
* CD79a: The mantle lights up best
BCL-2 (apoptosis-preventer): turned OFF during hypermutation
(i.e., germinal centers); turned ON in most nodular lymphomas
surface Ig(M, etc): B-cells
kappa, lambda: mature B-cells, plasma cells -- especially useful
for showing clonality (i.e., neoplasia)
* Future pathologists only: To look for clonality, you can also
have the lab check to see if the rearrangements that
produce the specificity of a lymphocyte for a specific antigen
are clonal (IgH Gene Clonality for B-cells, TcR-gamma

Gene Clonality for T-cells).
cyclin D1: mantle cell lymphoma stains strongly
cytoplasmic Ig: plasma cells
* nonspecific esterase: monocytes
Fc receptor: B-cells, monocytes
TRAP: hairy-cell leukemia
HLA-D/DR /Ia: Langerhans cells and other antigen-presenting
macrophages; some other cells
lysozyme: monocytes
* alpha1-antichymotrypsin: monocytes
erythrophagocytosis: monocytes
(myelo-)peroxidase: granulocytes
* Sudan black: granulocytes
* chloroacetate esterase: neutrophils, basophils, mast cells
platelet markers: megakaryocytes
* PAS+ diffusely: erythrocytes, megakaryocytes/platelets
* PAS+ chunks ("blocks"): immature lymphocytes or M6 leukemia
S-100, CD1/T6: dendritic ("Langerhans") macrophages
I would ask you NOT to worry about differentiation markers beyond
what's been listed above. A pathologist MUST know them, as a Hodgkin
or non-Hodgkin lymphoma cannot be properly classified without
immunohistochemistry (update Arch. Path. Lab. Med. 132: 441, 2008). A
sub-subclassification for epidemiologists: Blood 110: 685, 2007.
* There has been talk of diagnosing and classifying lymphomas

based on little biopsies (less invasive than taking out a whole
lymph node.) As you'd expect, unless there's an easy trademark
finding or two (mantle-cell lymphoma, T-lymphoblastic lymphoma),
it can't be done reliably (Am. J. Clin. Path. 128: 474, 2007).
* {16517} neutrophil, chloroacetate esterase stain
Monocyte
Eosinophil and lymphocyte
WebPath Photo
WebPath Photo
Basophil
White Cell Quiz!
WebPath Photo
WebPath Photo
Lymphocyte and neutrophil
Lots of neutrophils
WebPath Photo
WebPath Photo
Neutrophilia
Text and photomicrographs. Nice.
Human Pathology Digital Image Gallery
NEUTROPENIA: A low absolute neutrophil count in the peripheral blood

for any reason. (NOTE: "Leukopenia" is a not-very-useful word that describes
any low total white count.)
Possible causes include
SUPPRESSION OF GRANULOPOIESIS
"The aplastic anemias" (better, "bone marrow failure")
Bad stuff in the marrow
Space-occupying lesions ("myelophthisic anemias")

Solid cancers
Granulomas
Hematologic malignancies that suppress
granulopoiesis (i.e., some leukemias and lymphomas)
DNA problems
Cancer chemotherapy
Radiation sickness
"The megaloblastic anemias"
Hereditary cyclic (q. 3 wk., severe; dominant mutation
usually in the ELA2 elastase gene, molecular biology
Blood 92: 2629, 1998; one cause is mutated
neutrophil elastase that itself damages the cellular
machinery; also Nat. Genet. 35: 90, 2003; Blood 108:
493, 2006)
* Shwachman-Diamond (genetic, also fatty pancreas)
Typhoid fever
Occasional virus infections (mild suppression,
especially parvo B19 (Am. Fam. Phys. 75: 373,
2007))
* Some childhood acute leukemias going back to the
stem cells
* MYELOKATHEXIS (group of genetic diseases with
accelerated neutrophil precursor apoptosis; surviving
neutrophils are hypersegmented and have very long
bars between nuclear lobes: Blood 95: 320, 2000;
Am. J. Hem. 62: 106, 1999).
* Kostmann's -- genetic disease (several loci); almost
all of the developing neutrophils die at the myelocyte
stage. The usual cause of very low absolute

neutrophil count at birth and after.
Idiopathic
* The lab machine didn't count them.
The blood sat in EDTA too long and the
neutrophils stuck together.
The patient has one of leukemias /
preleukemias in which the neutrophils don't
make much myeloperoxidase, and the machine
used the myeloperoxidase reaction to count
neutrophils
EXCESS DESTRUCTION OF NEUTROPHILS
Autoimmune (rare, think of lupus)
Hypersplenism (see below)
Sequestration in a rapidly-growing abscess (??)
Idiopathic
DRUGS: The mechanisms are typically obscure (Ann. Int.
Med. 146: 657, 2007).
This is a dread complication seen with many different
medications.
The most common offenders today:
carbimazole
clozapine
dapsone
dipyrone
methimazole
procainamide
propylthiouracil
rituximab
sulfasalazine
ticlopidine
PERSONAL-TRIVIAL
Some people of African descent people just have
slightly low neutrophil counts
Some women get a mild neutropenia around their
periods
AGRANULOCYTOSIS is a time-honored misnomer for
neutropenia sufficiently severe to put a person at risk for serious
infection (i.e., neutrophil counts of 1000 or less, often much less;

<500 is a big emergency).
The first sign is typically mouth ulcers ("there's lots of germs
in there") with their pseudomembranes laden with infectious
bacteria and/or fungi.
* There may also be ulcers in the cecum; these can
actually kill ("acute typhlitis") by providing a portal of
entry to the blood for bacteria.
Later, the body is overwhelmed by bacteria, with death
ensuing in a few days. Until the very end, patients are likely
to complain only of "just not feeling quite right".
The usual cause of "agranulocytosis" problems is
medications. Future docs: If you notice that somebody has
an absolute neutrophil count <1800 or so, stop all
medications that can be stopped, and check again in a
week.
LYMPHOCYTOPENIA is less common and less perplexing than
neutropenia. Think of hereditary immunodeficiency, HIV, radiation injury,
marasmus/kwashiorkor, Cushing's syndrome, or just "stress".
Apart from AIDS, the most important cause clinically is "multiple
organ failure" of the severely sick / very septic; lymphocytes
undergo apoptosis throughout the body, and this is mirrored in
lymphoid depletion at autopsy (J. Imm. 174: 3765 2005).
LEUKOCYTOSIS: It's worth remembering the following NON-NEOPLASTIC
CAUSES OF ELEVATED WHITE CELL COUNTS. Most of them make sense:
You remember that in health, about half the neutrophils in the blood are
circulating, and the other half are marginated, at any time.
LOTS OF NEUTROPHILS ("granulocytosis"):
o pyogenic bacterial infection (the usual cause)
o burns
o widespread tissue necrosis from any cause

(don't forget surgery and myocardial infarcts)
o late pregnancy (common, mild)
o really bad "collagen-vascular disease"
o just plain "stress", nausea, and/or physical pain (un-marginates
neutrophils)
glucocorticoids and epinephrine do the same thing;
glucocorticoids also prevent neutrophils from entering
tissues
NOTE: Typhoid patients and some super-septic patients may
become neutropenic because granulopoiesis is suppressed
and/or all the neutrophils have emigrated from the blood. Beware
of relying on white count as your chief marker for infection!
NOTE: The super-sick, septic patient is likely to have TOXIC
GRANULATION (extra-prominent azurophilic granules),
CYTOPLASMIC VACUOLES ("from doing all that phagocytosis"),
and/or DOHLE BODIES (rough endoplasmic reticulum remnants).
By contrast, if the neutrophil count simply rises from acute pain
and "stress", there will be no toxic granulation, vacuolization, or
left shift. More about these in "Clinical Pathology".
{13646} Dohle body
{13661} Dohle body
{16213} Dohle body
* Future pathologists: The latter two "Dohle bodies" are
fakes; they are from cases of May-Hegglin's (say "MuhHAY-lun") semi-disease, an autosomal dominant trait with
too-few, too-big platelets and lots of "Dohle bodies" and big
granules; the neutrophils function normally. May-Hegglin
"Dohle bodies" are actually non-muscle myosin A, gene
mutated in May-Hegglin: Nat. Genet. 26: 106, 2000;
Blood 97: 1147, 2001. There are several different
phenotypes at the locus (Blood 102: 529, 2003).
NOTE: LEFT SHIFT refers to presence of immature white cells

("bands") in the peripheral blood, i.e., they're being mobilized
early from the bone marrow. To tell an extreme case (WBC>up to
100,000 or so, i.e., a LEUKEMOID REACTION, as in sepsis,
overwhelming TB , or carcinomatosis) from chronic granulocytic
leukemia (see below), remember the following:
(1) In chronic granulocytic leukemia, the LEUKOCYTE
ALKALINE PHOSPHATASE tends to be low. In sepsis and
the non-leukemic myeloproliferative disorders, it tends to be
high.
Leukocyte alkaline phosphatase is a completely
different test from the "serum alkaline phosphatase"
on the chemical profile. DON'T talk about them
together.
(2) In chronic granulocytic leukemia, the ABSOLUTE
BASOPHIL COUNT is generally high, too. This would be
unusual in sepsis.
(3) In chronic granulocytic leukemia, there is virtually always
a switch of material between chromosomes 9 and 22 (i.e.,
the PHILADELPHIA CHROMOSOME (Ph') or at least its
molecular equivalent). You won't see this except in cancer.
(4) And of course, toxic granulation (very easy-to-see
granules on stained blood; nobody really knows why)/ toxic
vacuolization says "infection", not "leukemia".
(5) When in doubt, it's a leukemoid reaction. An indolent
leukemia can wait for a few days; deadly infection can't.
Philologists: RIGHT SHIFT refers to the hypersegmented
granulocyte nuclei of pernicious anemia (etc., any major
impediment to normal DNA synthesis will produce this
"megaloblastic" change). "Right" and "left" derive from
spaces on the old do-it-by-hand tally sheets.
The machine-counting of immature neutrophils has always been a
challenge. Review and new equipment: Am. J. Clin. Path. 128:
454, 2007. Today we know that the band count is very low in
health, around one white cell in 500.
Hypersegmented poly
WebPath Photo
Hypersegmented poly
Pernicious anemia
KU Collection
LOTS OF EOSINOPHILS (big review Mayo Clin. Proc. 80: 75, 2005):
The "Loeffler" family of eosinophil-mediated diseases -- now being
sorted out; while most remain idiopathic, a few have known mutations
CHRONIC EOSINOPHILIC LEUKEMIA, an entity removed from the
Loeffler's wastebasket by the discovery of FIP1L1-PDGFRalpha
(Haematol 95: 696, 2010) -- treat with imatinib.
type I immune injury
food allergy, hay fever, eczema, extrinsic asthma (supposedly -you won't be impressed)
bronchocentric granulomatosis (aspergillus superinfection in
asthma; this one's important)
* hyper-IgE ("Job's") immunodeficiency
Tissue parasites
ascariasis
filariasis (includes "tropical eosinophilia" of the Far East -- future
pathologists: filaria worms will be pushed to the "feather edge" of
the smear)
onchocerciasis
strongyloidiasis
trichinosis
echinococcus
visceral larva migrans (dog and cat roundworms)

cutaneous larva migrans (dog and cat hookworms)
Drug allergy (most any; but notoriously gold therapy for arthritis, where
eosinophilia is almost expected)
Hodgkin's disease (a large minority of cases)
Churg-Strauss (a vasculitis, often with granulomas, usually with ANCA;
it's not clear whether this is a separate disease, or simply the way
Wegener's / polyarteritis manifests in folks with allergies)
Dermatitis herpetiformis
Familial hypereosinophilia (locus unknown, autosomal dominant, mild:
Blood 103: 4050, 2004)
* Well's eosinophilic cellulitis
Eosinophilia-myalgia syndrome (from the tainted tryptophan)
* Any AIDS patient with a rash (Am. J. Med. 102: 449, 1997)
* Pemphigus (I don't know why)
* Dermatitis herpetiformis
* Crohn's
* Acute liver transplant rejection (almost all have it, no one knows why)
Dermatomyositis
Polyarteritis nodosa (don't miss this one)
* Kimura's angiolymphoid hyperplasia with eosinophilia (very high IgE,
eosinophil-lymphoid pseudotumors of head and neck, germinal centers
loaded with eosinophils; marked peripheral eosinophilia; common in
middle-aged Asian men, Asia, rare elsewhere; making the call
Pediatrics 110: e-39, 2002; probably a low-grade lymphoproliferative
disorder Am. J. Surg. Path. 26: 1083, 2002; Arch. Path. Lab. Med. 131:
650, 2007)
* mastocytosis with eosinophilia (molecular signature known, response

to imatinib/Gleevic likely)
* T-cell neoplasms making interleukin-5: NEJM 341: 1141, 1999
* "Clonal eosinophilia" -- FIP1L1-PDGFRA fusion gene
* Eosinophilic leukemia -- looks like CML without proof of clonality
NOTE: In the developed world, among clinically healthy patients with
isolated elevated eosinophil counts, you will often not find the cause.
NOTE: I did CBC's for years on medical students, many of whom have
hay fever, etc., and have never found one with an elevated eosinophil
count.
NOTE: Remember that eosinophilic counts are up in the afternoon and
down in the morning because the morning's cortisol surge suppresses
them; I'd suggest taking a serious look at an absolute eosinophil count
over 350 or so in the morning, and over 650 in the afternoon.
NOTE: The "Loeffler's eosinophilic" problems are a curious, mixed-bag
of diseases with excessive numbers of eosinophils in various tissues
that cause tissue damage.
The most common form is probably caused by a benign neoplasm
of some sort, hidden somewhere, with a fusion gene called
FIP1L1-PDFGRA (Cancer 110: 955, 2007) This has sometimes
responded well to imatinib.
Sometimes the underlying problem is a proliferation of mutated Tcells producing excessive eosinophil attractants (NEJM 330: 35,
1994).
* In other cases, the eosinophils themselves seem to be the
mutated clone: Blood 93: 1651, 1999.
In 2004, I predicted the success of the anti-IL5 antibody
mepolizumab as treatment (J. Allerg. Clin. Imm. 113: 115, 2004); it
has been a spectacular success (NEJM 358: 1215, 2008).
{14099} eosinophilic leukocytes (buffy coat)

{09207} eosinophil granule with crystal (electron micrographs; these crystals
will combine to form large Charcot-Leyden crystals under some conditions)
Eosinophilia
LOTS OF MONOCYTES:
typhoid fever
bad granulomatous problems
TB
brucellosis
Crohn's disease
leprosy
deep fungi
sarcoidosis
others
* chronic autoimmune disease
rheumatoid arthritis is worth remembering
* rickettsial disease (often; red flag)
* disseminated cancer (occasionally)
LOTS OF LYMPHOCYTES:
"infectious mononucleosis" (see below)
whooping cough ("pertussis"; little cleaved lymphocytes; the toxin keeps
the T-cells from homing to lymphoid tissue; Am. J. Clin. Path. 114: 35,
2000)
infectious lymphocytosis (mild kids' disease, with T-cells, caused by
various non-herpes viruses notably coxsackie B2 ; a "chronic form" also
exists without marrow abnormalities; leave this to the pediatric
hematologists; Acta. Paed. 74: 633, 2008.)
"transient stress lymphocytosis" (absolute counts 4000-10000; on the

evidence we've overlooked this for years; all major lymphocyte subsets
go up, and neutrophils go up too: Am. J. Clin. Path. 117: 819, 2002)
* really bad "collagen-vascular disease"
* phenytoin ("Dilantin") or para-amino salicylic acid ("PAS") therapy
NOTE: INFECTIOUS MONONUCLEOSIS is a family of diseases

featuring fever, malaise, fatigue, lymphadenopathy, and circulating
benign atypical lymphocytes. The syndrome results from first meeting
one of these four micro-organisms: (1) Epstein Barr virus ; (2)
cytomegalovirus ; (3) toxoplasmosis ; (4) HIV.
BENIGN ATYPICAL LYMPHOCYTES are activated cells (B- or T-) seen
typically in the blood in "infectious mononucleosis" and certain other
infections; you may see a few in any viral illness.
There is no such thing as a "typical atypical lymphocyte." There
are three "Downey" types:
Lymphocytes just a bit larger than usual, with a nuclear cleft
and dark cytoplasm
Most familiar: the cytolasm is abundant and pale, bluer
where the red cells indent them; the nucleoli are small, the
nucleoplasm is reticulated
immunoblasts -- big cells, bit nucleoli, plenty of blue-staining

cytoplasm
Probably more important in spotting infectious mono and telling it
from leukemia when you're a beginner is that when there are
bunch of "atypical lymphocytes", no two look the same.
Infectious mononucleosis
Blood picture
WebPath Photo
Infectious Mononucleosis
LOTS OF BASOPHILS:
chronic myelogenous leukemia
other "chronic myeloproliferative disorders"
polycythemia vera
* primary hemorrhagic ("essential") thrombocythemia
* supposedly in lots of other things; this will not be important
clinically.
NOTE: None of these "classic findings" is either particularly sensitive, or
particularly specific, for any particular disease. Use this information in
the setting of the "whole person".
ODD NEUTROPHILS:
We have already mentioned CHRONIC GRANULOMATOUS DISEASE,

a poorly-named group of defects in the ability of neutrophils to kill
common bacteria, with the macrophages needing to become involved
as well.
The most familiar is "X-linked chronic granulomatous disease",
which has now been cured by gene therapy (Nat. Med. 12: 401,
2006).
FAMILIAL MEDITERRANEAN FEVER, longmysterious, has now yielded up its secrets.
The cause is a lack of pyrin, a neutrophil
protein that slows down neutrophils when
enough have reached an area. Gene found
Cell90: 797, 1997; molecular genetic
diagnosis: Ann. Int. Med. 129: 539, 1998.
Lacking pyrin, neutrophils mob body
cavities every once in a while. In addition
to fever, patients may have pleuritis,
arthritis, peritonitis, and/or a hot rash
(looks like a strep infection) on the
ankles.
Colchicine, famous for its ability to slow
down neutrophils (as in acute gout),
controls the attacks and prevents the dread
complication of secondary amyloidosis.
As you can imagine, acute FMF can mimic
many diseases. The amyloidosis AA that
often develops in these patients can mimic
most of the rest. Don't miss it.

* A similar, thankfully-rare periodic fever
syndrome is caused by a mutation in the
TNF-receptor (TNFR1): Blood 108: 1320,
2006. Yet another is caused by mutated
cryopyrin (includes serious neurologic
problems; anti-interleukin-1 treatment
brings about full resolution: Neurology 74:
1267, 2010).
You recall CHEDIAK-HIGASHI SYNDROME, in which there are several

problems with organelle membrane synthesis. synthesis.
Neutrophil lysosomes are large and prominent (they fuse with
each other) and do not fuse with phagosomes, so there's poor
bacterial killing and a lot of infections.
Melanosomes don't form properly, so there is partial albinism.
The lack of platelet dense granules results in a bleeding tendency.
* The gene has been cloned (LYST, lysosomal traffic regulator).
Most of these patients go on to develop a lethal non-neoplastic
hyperplasia of the lymphocytes. Marrow / stem cell transplant is
now routine and prevents this. Review Blood 95: 979, 2000.
* There is a report that long-term survivors of bone marrow
transplantation develop a neurodegenerative disease after
decades (Blood 106: 40, 2005). Stay tuned.
In the autosomal dominant PELGER-HUET ANOMALY,
the neutrophil nuclei fail to segment normally, producing
"peanuts" and "pince-nez eyeglasses". ("Look! This
clinically healthy patient has a horrible left shift /
leukemia!") This is a fairly common laboratory curiosity
(maybe one person in 5000), and of no significance. Explain
to the physician and the patient, and check their close kin
before somebody gets sick and everybody gets confused
(Am. J. Clin. Path. 137: 358, 2012). (* Double doses get no
segmentation whatever. And they don't seem to have any
obvious troubles with bacteria or anything else: Acta.
Hem. 66: 59, 1981. "Look! This clinically healthy patient

has all myelocytes!" "No, look around, they're pelgeroid.")
* Acquired / pseudo-Pelger-Huet can been seen
when there are mutations (i.e., myelodysplasia,
leukemia) or for some mysterious reason as a
medication side-effect (Arch. Path. Lab. Med. 130:
93, 2006; Am. J. Clin. Path. 135: 291, 2011). These
tend to be a minority of neutrophils, tend to be
hypogranular, and tend to have denser chromatin. Let
us worry about them.
{16208} Pelger-Huet, one dose

{16209} Pelger-Huet, one dose
{13658} Pelger-Huet, two doses
Pelger-Huet
Blood picture
WebPath Photo
Pseudo-Pelger Huet
AFIP
Wikimedia Commons
* ALDER-REILLY ANOMALY merely refers to large,

mucopolysaccharide-laden granules in some of the storage diseases
(Hunter's, Hurler's, Tay-Sach's, occasionally as an acquired trait in
myelodysplasia). You will see it in all five types of white blood cells.
Don't mistake this for "toxic granulation."
* Thankfully rare: Lack of endothelial adhesion molecules for
phagocytes (J. Clin. Invest. 103: 97, 1999) or lack of CD18 integrin on
neutrophils (Blood 91: 1520, 1998).
Bacilli in neutrophil vacuoles: Usually DF2 (dog bite)
* And you know that drumsticks are the inactivated X-chromosomes of
lyonization.
MORULAE OF EHRLICHIOSIS can help you diagnose this famous
"spotless fever"; this "granulocytic" variant of ehrlichiosis can be fatal
(NEJM 334: 209, 1996). "Morule" is Latin for "mulberry".
Ehrlichiosis
Morules in macrophages
CDC photo
NORMAL LYMPH NODE ANATOMY

LYMPH NODES are soft (i.e., reticulin-framework) ovoids, up to about 2
cm in health. Afferent lymphatics penetrate and travel within their
capsules (metastatic cancer first sets up here). Afterwards, lymph
percolates through the cortex, and then the medulla, leaving by the
hilum.
Within the cortex, there are generally some germinal centers
("lymphoid follicles"), sites of actively-proliferating B-cells. Each
germinal center is surrounded by a mantle of resting B-cells,
which are in turn surrounded by "parafollicular" T-cells. (If there is
no antigenic stimulus, you'll see only "primary follicles" of sleepy
B-cells in the cortex.)
The next time you get to look at a germinal center under the
microscope, check out those proliferating B-cells. The
sequence from small B-cell to plasma cell is interesting and
unsung in most histology courses. You'll need to know this
to understand classical acconts of lymphomas:
Resting small B-lymphocyte
Small cleaved ("clefted", i.e., folded-nucleus) B-lymphocyte
Large cleaved B-lymphocyte
Small non-cleaved B-lymphocyte
[NOTE: This cell is as large as a large cleaved B-lymphocyte]
Large non-cleaved B-lymphocyte
B-immunoblast
Memory B-cells . . and . . Plasma cells
Within the medullary cords, expect to see a mix of B- and T-cells and
plasma cells. The sinusoids are lined by fixed phagocytes.
Despite the elegant pictures in histology books, lymph nodes are
seldom "normal", especially in adults.
LYMPHADENITIS: Inflammation of the lymph nodes
ACUTE LYMPHADENITIS described in "Big Robbins" is not much more
than the hyperplasia in a reactive node.
Localized lymphadenitis is most often due to a bacterial infection
in the area drained by the lymph node.
Really bad cases have polys and even abscess formation
within the nodes. The end result will be a scarred-up lymph
node. You have one or more.
Generalized lymphadenitis suggests a systemic viral infection.
"Mesenteric adenitis", often indistinguishable from acute
appendicitis, is caused by Yersinia enterocolitica.
Acute lymphadenitis, since it comes up suddenly and stretches
the capsule, is likely to make the node tender.
CHRONIC NON-SPECIFIC LYMPHADENITIS falls in one of three
distinctive patterns.
FOLLICULAR HYPERPLASIA (i.e., lots and lots of big follicles)
results from longstanding contact with organisms or "other things"
that stimulate the B-cells. If perplexed, think of:
toxoplasmosis (* look for mini-granulomas touching the
germinal centers at their edges, this is supposedly
pathognomonic; some of these are groups of macrophages;
some are big "monocytoid B-cells" especially in the
medulla)
rheumatoid arthritis (often lots of plasma cells)
syphilis (plasma cells in the medulla, mini-granulomas,

spirochetes)
AIDS-related complex / persistent generalized
lymphadenopathy of HIV infection.
common variable immunodeficiency (ineffective B-cell
activation)
{36371} toxoplasmosis; many bugs in a cell
{40654} toxoplasmosis; tissue reaction (lame-looking granulomas)
Syphilis in a lymph node
Yutaka Tsutsumi MD
Toxoplasma
lymphadenitis
Yutaka Tsutsumi MD
Follicular hyperplasia
WebPath Photo
WebPath Photo
HIV lymphadenopathy
WebPath Photo
Yutaka Tsutsumi MD
PARACORTICAL LYMPHOID HYPERPLASIA (i.e., lots and lots of

lymphocytes, including turned-on ones, in the T-cell regions of the
cortex -- often easiest to recognize the the presence of prominent
blood vessels) results from longstanding contact with organisms
or "other things" that stimulate the T-cells. If perplexed, think of
infectious mononucleosis, CMV
phenytoin ("Dilantin") exposure
weird reactions to a vaccine
infectious mononucleosis family (those angry T-killers, etc.;
* expect to see lots of big lymphoid cells with pale
cytoplasm, plenty of necrosis and mitotic figures; see any

CMV cells?; this can be a real fooler for lymphoma, see
Arch. Path. Lab. Med. 117: 269, 1993)
lupus (look for frank vasculitis and even regions of
infarction)
SINUS HYPERPLASIA (formerly "sinus histiocytosis"; i.e.,
sinusoids with swollen endothelial cells and lots of histiocytes). If
perplexed, think of:
nodes draining a cancer (by no means specific!)
* nodes injected with permanent radiology contrast medium
("lymphangiogram dye") or for some reason containing
mineral oil ("oleogranulomas")
Whipple's disease (Whipple cells)
* Castleman's giant angiofollicular lymphoid hyperplasia (far
beyond your learning objectives; NEJM 330: 642, 1994);
one cause (especially when multifocal and rich in plasma
cells) seems to be herpes 8 / KSHV (Am. J. Path. 151:
1517, 1997; West. J. Med. 167: 38, 1997; Blood 93: 3643,
1999). It is a famous cause of paraneoplastic pemphigus
(Lancet 363: 525, 2004).
Castlemanosis
Great photos
* hemolysis (Coombs-positive, or macrophages

rendered hungry by infection; the latter situation is
"erythrophagocytic reticulosis")
* "sinus histiocytosis with massive

lymphadenopathy and lymphocyte
emperipolesis" (Rosai-Dorfman disease): a
presumably viral, generally self-limited semidisease of young people. B- and T-cells live
inside macrophages ("emperipolesis"), which
in turn light up with S100 and for lipid.
There is a more ominous extranodal form as
well. No one understands it.
Rosai-Dorfman
S100 for dendritic macrophages
Wikimedia Commons
MIXTURES OF THE ABOVE cause diagnostic problems.

In all the above, capillary endothelial cells are likely to be
hyperplastic (rare in cancer).
The most common cause of "unexplained" lymph node
enlargement, especially in the groin: DERMATOPATHIC
LYMPHADENITIS, melanin and sebum-laden nodes
draining chronically inflamed skin. You're likely to see a mix
of reaction types.
{35609} dermatopathic lymphadenitis (the red-brown is melanin, the white is
sebum)
WARNING: Any of these patterns can be (and occasionally is)
mistaken for malignant lymphoma by the inept. Note that the
finding of mitotic figures or necrosis doesn't necessarily point to
malignancy, while the presence of a variety of cell shapes actually
suggests a benign diagnosis. Know your pathologist, and ask for
consultation if you are in doubt.
GRANULOMAS
Granulomas with central CASEOUS NECROSIS are probably
tuberculosis, some other mycobacterial infection (atypical
mycobacteria, leprosy)
Well-made granulomas with NOTHING else are probably

sarcoidosis. Also remember Crohn's, berylliosis, and nodes
draining Hodgkin's disease.
Granulomas with PUS in their centers are probably caused by one
of the following: (1) lymphogranuloma venereum , (2) cat scratch
fever, (3) brucellosis, (4) plague , (5) tularemia , (6) glandersmelioidosis, and (7) other yersinia infections. If you can find none
of these, consider (8) X-linked chronic granulomatous disease
(the neutrophil dysfunction problem).
* Granulomas with central necrosis with much karyorrhexis but no
pus: Kikuchi-Fujimoto. See below.
Tuberculous lymphadenitis
Great labels
Romanian Pathology Atlas
Bartonellosis
Cat scratch fever
Yutaka Tsutsumi MD
You have probably already seen the Warthin-Finkeldey giant cells of

measles within germinal centers. They show variable immunologic
markers -- B-cell, T-cell, and/or dendritic macrophages. Some have
intranuclear measles virus inclusions; some do not.
* KIKUCHI-FUJIMOTO NECROTIZING HISTIOCYTIC
LYMPHADENITIS (J. Am. Acad. Derm. 59: 130, 2008; Am. J. Clin.
Path. 131: 174, 2009): Nobody knows the cause of what seems to be a
viral illness (the herpes family exonerated Arch. Path. Lab. Med. 131:
604, 2007); the molecular biology is not that of a lymphoma: Am. J. Clin.
Path. 117 627, 2002. Nepalese study: Arch. Path. Lab. Med. 127: 1345,
2003. Big review Am. J. Clin. Path. 122: 141, 2004. It looks like lupus in
the lymph node, but there's lots more cytotoxic CD8+ than CD4+ T-cells.
I've got a story about this I'll tell you personally.
Subacute necrotizing lymphadenitis
Kikuchi's disease
Yutaka Tsutsumi MD
LYMPHADENOPATHY is a clinician's word for a big lymph node.
NON-HODGKIN'S LYMPHOMAS: By definition, monoclonal, malignant tumors

of the B- or T-cells, and not of plasma cells, and not Hodgkin's disease. By
custom, soft tumors of monocytes are included here because they look
similar.
These are the common primary tumors arising in the lymphoid tissue
(lymph nodes, tonsils, adenoids, spleen, Peyer's patches, non-epitehlial
thymus) and there are some special cases. (We cover CNS lymphomas
in the "neuro" section; the outlook for primary CNS lymphoma is still
"dismal": Cancer 110: 1803, 2007.)
There are about forty kinds at most recent count, each with its own
personality. Together, the non-Hodgkin's lymphomas are common.
Update, with a focus on molecular markers: Br. Med. J. 362: 139, 2003;
also Lancet 362: 139, 2003; J. Clin. Path. 58: 561, 2005.
Most pathologists use the 2008 World Health Organization
classification. It is elaborate even by WHO standards and only the
highlights can be covered here.
Lymphomas and Plasma Cell Neoplasms
"Pathology Outlines"
Nat Pernick MD
CD Markers
Nat Pernick MD
Lymphomas
Bryan Lee
Lung lymphoma
Lung pathology series
Dr. Warnock's Collection
FCC lymphoma
B-cell lymphoma
Diffuse large cell lymphoma

Heart
B-cell lymphoma
Large cell
Follicular lymphoma, spleen

AFIP
Wikimedia Commons
The non-Hodgkin's lymphomas are a subject of perennial

fascination for pathologists. Making the diagnosis ("benign or
malignant?") is often tough, and classifying the non-Hodgkin's
lymphomas (hereinafter "lymphomas") was a major international
competitive sport through the 1980's.
Today, the ongoing fascination is in the chromosomal translocations that
are the primary way in which white blood cells acquire mutations. In
most of the leukemias and lymphomas, the genome is usually NOT
destabilized.
Today, several translocations actually define a particular leukemia
or lymphoma. * Now-classic review of the translocations: Arch.
Path. Lab. Med. 127: 1148, 2003. Molecular probes now routinely
detect translocations missed by conventional cytogenetics (Am. J.
Clin. Path. 135: 921, 2011).
Students often find this subject especially difficult to understand. Hence,
the focus in this section on "Rules".
RULE: All monoclonal proliferations of lymphocytes are best considered
malignant. (Some monoclonal plasma cell proliferations might be
benign.)
RULE: Most non-Hodgkin lymphomas are somewhat more common in

men, with the most pronounced difference probably being Tlymphoblastic lymphoma (> 2:1).
RULE: Blacks and children almost never get nodular lymphomas.
RULE: A few specific lymphomas have one or more special risk factors
(i.e., helicobacter causes the MALT lymphoma of the stomach; gluten
enteropathy "sprue" causes a curious pair of T-cell lymphomas:
Gastroent. 132: 1902, 2007; Am. J. Clin. Path. 127: 701, 2007).
A history of radiation supposedly increases one's risk for
lymphoma.
"Lymphomas of the immunocompromised" are sometimes real
neoplasms, sometimes virally-induced hyperplasias.
* Ataxia-telangiectasia (homozygotes, probably heterozygotes) is
a risk factor for most lymphomas and lymphoid leukemias.
Chronic hepatitis C virus infection is now recognized as placing
patients at increased risk, and eliminating the virus reduces this
risk (Am. J. Med. 120: 1034, 2007).
Sjogren's syndrome (J. Imm. 180: 5130, 2008; Blood 111: 4029,
2008) gives 6x the risk for B-cell lymphomas overall; there are
several types (MALT, follicular and large B-cell, famously marginal
zone lymphoma).
Hashimoto's thyroiditis also places a person at increased risk for
B-cell lymphomas (update J. Clin. Path. 61: 438, 2008). Gluten
enteropathy / celiac sprue gives an increased risk for T-cell
lymphoma. Does effective treatment reduce the risk? Yes! (Dig.
Dis. Sci. 53: 972, 2008) No! (Am. J. Med. 115: 191, 2003).
The increased risk to rheumatoid arthritis patients, also very wellknown (Arth. Rheum. 48: 963, 2008 confirmed this but discredited
the idea that non-arthritic relatives are at extra risk).
Environmental risk factors for lymphoma are poorly-understood;
currently there's an interest in herbicides and pesticides (I think it
could be real but a relatively minor risk -- Am. J. Epidem. 147:
891, 1998, Occup. Environ. Med. 60: E11, 2003; Acta Haem. 116:
153, 2006; "only chlordane" Canc. Ep. 15: 251, 2006 from the
NIH; Env. Health Perspect. 111: 179, 2003 -- any link to persistent
organochlorides must be weak; others) and hair-coloring agents
(U.S.; review Cancer Inv. 18: 467, 2000 & Cancer Causes &
Control 10: 617, 1999 from the FDA; relationship if any is clearly
weak; Am. J. Pub. Health 88: 1767, 1998 no animal model), as
well as the African poinsettia (Burkitt's).
RULE: At surgery or autopsy, lymphoma tissue feels like "fish flesh" (i.e.,
there is very little fibrosis) or "firm rubber" (i.e., there is some fibrosis but
not much).
RULE: Fatigue, malaise, night-sweats, fever, and weight loss are the
usual symptoms (if any) of these diseases. These are called the
"B symptoms" used in staging. The cause, which must involve
cytokines, has proved remarkably elusive.
A significant number (in some series, as many as half) of patients
with "fever of unknown origin" prove to have non-Hodgkin's or
Hodgkin's lymphoma.
RULE: A majority of lymphomas arise in the lymph nodes (one or more
groups). Several groups of nodes may pop up at once. Nodular
lymphomas almost always arise in lymph nodes.
RULE: A large minority arise in extra-nodal lymphoid tissue, i.e.,
Waldeyer's ring, stomach, terminal ileum, skin, marrow.
RULE: When lymphomas arise in lymph nodes, they present as nontender enlargement.
RULE: Lymphomas metastasize to other lymphoid tissues (nodes,
spleen, etc.), and eventually to the marrow, blood ("leukosarcoma", less
often "lymphemia") and other organs. Low-grade lymphomas
metastasize as small nodules, while high-grade lymphomas metastasize
as bulky masses.
RULE: Mitotic figure counts tell the growth rate of a lymphoma, but
unless the mitotic figures are bizarre, they do not help distinguish it from
a benign lymph node. (Have you ever "counted mitoses" in a normal
germinal center? Try it!)
RULE: The lower the grade of the lymphoma, the MORE likely the bone
marrow is to be involved at the time of diagnosis. Paradoxical, no?
RULE: Lymphomas tend to spread to sites according to their B-cell or Tcell origin. B-cell tumors go to the germinal centers, their mantles, and
the outsides of the splenic white pulp. T-cell tumors to the anterior
mediastinum, paracortical regions of nodes, insides of splenic white
pulp, etc. Skin lymphomas are usually of T-cell origin.
RULE: The malignant cells of lymphomas are MORE uniform than the
mix of cells normally seen in lymphoid tissue, and they recapitulate
some phase in the life history of either normal B-cells or T-cells. Don't
expect to see much "cytologic atypia" in a lymphoma. Remember that
the genome is usually not destabilized in lymphomas. (Especially,
immunoblastic lymphomas can look pretty wild.)
RULE: Lymphomas that grow as nodules within a lymph node ("trying to
be germinal centers") are called NODULAR or FOLLICULAR
(synonyms). They are always of B-cell origin, and the lymphoma cells
will closely resemble one of the forms in the sequence from resting Blymphocyte to plasma cell.
{23581} nodular lymphoma
Nodular lymphoma
Nodular lymphoma
WebPath Photo
KU Collection
RULE: Nodular lymphomas tend to be indolent lesions with natural

histories that are relatively unaffected by classical chemotherapy.
Historically, they have been incurable, though this seems to be
changing. Each nodular lymphoma has a better prognosis than its
diffuse counterpart, and is likely to transform into it sooner or later. This
makes sense, since follicle formation is a sign of good differentiation.
Less often, a nodular lymphoma transforms into a diffuse large-cell or
immunoblastic lymphoma.
* A lymphoma with two different morphologic appearances and
genetic clones is a "composite lymphoma". This is fairly common,
and may represent transformation of one lymphoma into another
by additional mutations, or two separate malignant tumors.

Getting it worked out: Am. J. Clin. Path. 99: 445, 1993; Am. J.
Path. 154: 1857, 1999; NEJM341: 764, 1999. The most familiar
(CLL/WDLL mixed in with follicular lymphoma) is two different
clonal tumors (Am. J. Clin. Path. 137: 647, 2012).
RULE: Most nodular lymphomas of all kinds feature one of two
characteristic translocations, either t(11;14) or t(14;18). Each involves
the immunoglobulin heavy-chain region on chromosome 14. This is
brought into contiguity either with the bcl1 / PRAD / cyclin D1 oncogene
on chromosome 11 or the bcl-2 oncogene on chromosome 18.
* A majority of adults have some t(14;18) lymphocytes on board if
you look hard: NEJM 356: 741, 2007.
Diffuse lymphoma
Great labels
Diffuse lymphoma
WebPath Photo
Diffuse B-cell lymphoma

Gross and microscopic
Wikimedia Commons
bcl-2 produces a protein on the inside of mitochondria

that prevents the cell from undergoing apoptosis.
RULE: Small lymphocytic lymphoma ("well-differentiated lymphocytic
lymphoma", "the solid phase of chronic lymphocytic leukemia"), in which
the cells perfectly resemble normal lymphocytes, is always diffuse,
never nodular.
RULE: The histologic type of a lymphoma is much more important than
its stage in determining prognosis. (This is the opposite of Hodgkin's
disease.)
RULE: Large, polyclonal, benign proliferations of lymphocytes may
occur anywhere there is lymphoid tissue, and have earned the dubious
name PSEUDOLYMPHOMA. Distinguishing these from real lymphomas

is a challenge.
Also remember that certain autoimmune diseases feature heavy
polyclonal lymphoid infiltration of salivary glands (Sjogren's),
thyroid (Hashimoto's), islets (type I diabetes), or kidneys
(autoimmune interstitial nephritis).
* For some reason, Lyme disease produces pseudolymphomas
in the ear lobes. No one has a clue why.
RULE: Pathologists trying to distinguish malignant lymphomas from
benign lymph node hyperplasias and pseudolymphomas pay special
attention to:
(1) EFFACEMENT OF THE NORMAL LYMPH NODE
ARCHITECTURE;
(2) CELL UNIFORMITY ("monotony", suggests lymphoma, but
even follicular lymphomas are infiltrated by the same benign cells
as grow in a germinal center);
* (3) Presence of macrophages laden with nuclear debris
(TINGIBLE BODY MACROPHAGES, a sign that the process is
EITHER benign OR a high-grade lymphoma, because in lowgrade lymphomas you won't see much apoptosis);
(4) Widespread bcl-2 protein staining is a pretty good sign that
this is lymphoma.
Tingible body macrophages
WebPath Photo
(5) VASCULAR PROLIFERATION (new vessels suggest the

process is benign), and;
(6) INVASION of surrounding tissue ("capsular transgression",
suggests lymphoma).
(7) NECROSIS (apart from apoptosis) is common in some

lymphomas, and of course in necrotizing infections, but
uncommon in difficult benign lesions.
(8) If "follicles"/"nodules" are present, the ABSENCE OF A
MANTLE of small lymphocytes around the light side of the follicle
suggests malignancy.
* In AIDS, mantles are likely to absent. Why?
(9) Today's pathologist, asking "Is this lymphoma?", begins as
follows:
If it is apparently made of small lymphoid cells, the
pathologist stains for kappa and lambda (monoclonality is
lymphoma, polyclonality is non-malignant), and a bcl2 stain
if there are nodules (positive staining indicates lymphoma).
If it is apparently made of large lymphoid cells, the
pathologist will order a CD45 (leukocyte common antigen,
positive in lymphomas), a few other lymphocyte markers,
cytokeratins (negative in lymphomas), and a few melanoma
markers (negative in lymphomas).
Lymphoma in lymph node
Invasion of surrounding fat
Tom Demark's Site
(10) We also want DNA studies for the TYPICAL GENE

ARRANGEMENTS, both for diagnosis and to look for residual
disease.
* Prognosticating and depth-analyzing aggressive B-cell
lymphomas by their mutations: Nat. Med. 8: 13 & 68, 2002. More:
NEJM 350: 1828, 2004. This is now standard.
{09040} electron micrograph of a malignant lymphoid cell. Note the lack of
distinguishing features.
* RULE: Lymphomas in the liver generally center on the portal areas.
This also applies to Hodgkin's disease.
RULE: Most lymphomas (Hodgkin's and non-Hodgkin's) may cause

generalized dysfunction of benign B-cells (hypogammaglobulinemia),
with resulting tendency to infection.
CLASSIFICATION SCHEMES:
Anyone using the terms "lymphosarcoma", "giant follicular
lymphoma", or "reticulum cell sarcoma" in today's medicine is
terribly out of date.
* THE 1966 RAPPAPORT CLASSIFICATION is archaic but still
popular. It was based on certain incorrect (but once-useful)
assumptions about the nature of the cells seen in these lesions:
"Well-differentiated lymphocyte"... looks like a normal
resting lymphocyte
"Poorly-differentiated lymphocyte"... doesn't look like a
normal resting lymphocyte, but is smaller than an
endothelial cell
"Histiocyte"... bigger than an endothelial cell, and has lots of
cytoplasm
"Undifferentiated cell"... bigger than an endothelial cell, and
has only a little cytoplasm
Lymphomas were further sub-divided into "nodular" and
"diffuse", depending on their growth pattern. Despite its
limitations, the Rappaport system was useful as lymphomas
were being sorted out.
* THE 1974 LUKES-COLLINS CLASSIFICATION was based on
primitive immunotyping and closer examination of the morphology
of the cells, which were compared to those in the centers of
normal germinal follicles. Activated-type B-cells from smallcleaved through large-noncleaved cells were appropriately called
FOLLICULAR CENTER CELLS. Even more exciting were the
IMMUNOBLASTS, very big round cells with very big round nuclei
bearing in their centers a single very big nucleolus (I call them
"eyeball cells").
* THE 1982 WORKING FORMULATION was a consensus of

experts based only on morphology. It worked nicely until it was
superseded by the Revised European-American system. You'll still
find people using these terms.
LOW GRADE LYMPHOMAS (untreated survival has
historically been is around 10 years)
Small lymphocytic
Small lymphocytic, plasmacytoid
Follicular, small cleaved cell
Follicular, mixed small-cleaved and large cell
INTERMEDIATE GRADE LYMPHOMAS (untreated survival
has historically been around 5 years)
Follicular, large cell
Diffuse, small cleaved cell
Diffuse, mixed small-cleaved and large cell
Diffuse, large cell
HIGH GRADE (quick death untreated, but we have been
curing these with classical chemotherapy since the 1970's)
Large-cell immunoblastic (B- or T-cell)
T-Lymphoblastic
Small noncleaved cell (Burkitt's, etc.)
MISCELLANEOUS
Mycosis fungoides / Szary syndrome
Adult T-cell leukemia/lymphoma with HTLV-1
THE REVISED EUROPEAN-AMERIAN CLASSIFICATION OF

LYMPHOID NEOPLASMS ("REAL"), released in 1993, ws based on
newer work with differentiation markers. Its present formulation includes
slight alterations (most recently in 2001) by the W.H.O. It also includes
the lymphoid leukemias and plasma cell tumors, but not the tumors of
monocytes/macrophages.
MATURE B-CELL NEOPLASMS
Chronic lymphocytic leukemia / small lymphocytic
lymphoma
B-cell prolymphocytic leukemia
Lymphoplasmacytic lymphoma / Waldenstrom's
Splenic marginal zone lymphoma (i.e., replaces white pulp)
Plasma cell neoplasms
Plasma cell myeloma
Extramedullary plasmacytoma
Monoclonal immunoglobulin deposition diseases (i.e.,
amyloid B/AL, others)
Heavy chain diseases
MALT lymphoma ("extranodal marginal zone B cell
lymphoma", "mucosal-associated lymphoid tissue" of
stomach, thyroid, salivary glands, etc.; t(11:18))
Nodal marginal zone B lymphoma
Follicular cell lymphoma (the old "nodular lymphoma")
Mantle cell lymphoma (t(11:14))
Hairy cell leukemia
Diffuse large B-cell lymphoma (the most common nonHodgkin's lymphoma, making up about 1/3 of cases
altogether; most are "DLCBL not otherwise specificied" but
there are a few special entities that you don't need to worry
about now)
Mediastinal (thymic) large B-cell lymphoma
Intravascular large B-cell lymphoma
Primary effusion lymphoma
Burkitt's lymphoma / leukemia (t(8:14))
Lymphomatoid granulomatosis (the B-cell attract huge
numbers of non-neoplastic T-cells)
MATURE T-CELL AND NATURAL KILLER (NK) NEOPLASMS
NOTE: T-cell lymphomas are recognized as such by their
having mutations of the T-cell surface receptor proteins.
T-cell prolymphocytic leukemia

T-cell large granular lymphocytic leukemia (this "CLL"
variant causes early anemia / marrow burnout; update Am.
J. Clin. Path. 136: 289, 2011)
Aggressive NK cell leukemia
Adult T-cell leukemia/lymphoma
Extranodal NK/T cell lymphoma, nasal type
Enteropathy-type T-cell lymphoma
Hepatosplenic T-cell lymphoma
Blastic NK cell lymphoma
Mycosis fungoides / Sezary syndrome
Primary cutaneous CD30-positive T-cell lymphoproliferative
disease
Primary cutaneous anaplstic large cell lymphoma
Lymphomatoid papulosis (obscure skin disease)
Angioimmunoglastic T-cell lymphoma
Peripheral T-cell lymphoma, unspecified
Anaplastic T-cell large-cell lymphoma
HODGKIN'S
Nodular lymphocyte-predominant Hodgkin's
Classic Hodgkin's
Nodular sclerosis
Mixed-cellularity
Lymphocyte-rich
Lymphocyte depleted
IMMUNODEFICIENCY-REALTED LYMPHOPROLIFERATIVE
DISORDERS (probably listed separately by the W.H.O. because
they're clinically different and probably have viral etiologies
With a primary immune disorder
With HIV
Post-transplant (after bone marrow / stem cell transplant,
these are often the donor's cells; also remember "donor cell
leukemia": Blood 109: 2688, 2007)
With methotrexate
* The immunomodulators (anti-TNF-alpha agents, anti-CD11a
agents, anti-interleukin-2 receptor / CD25 agents, anti-interluekin1 receptor agents) probably do NOT result in an overall increase
in lymphoproliferative disease despite the WHO; however, people

on these medicines are prone to develop lymphoid hyperplasias
(Mod. Path. 22: 1532, 2009).
Here are the most common ones:
Adults (all are peripheral B-cell lesions):
Chronic lymphocytic leukemia / small lymphocytic
lymphoma
Follicular lymphoma
Plasmacytoma / plasma cell myeloma
Diffuse large B-cell lymphoma
Children:
Precursor B-cell leukemia
Precursor T-cell leukemia
Burkitt's lymphoma / leukemia
SMALL LYMPHOCYTIC LYMPHOMA ("well-differentiated lymphocytic
lymphoma", "the solid phase of chronic lymphocytic leukemia")
This B-cell lymphoma is composed of cells that look like neverstimulated, resting lymphocytes, of the sort seen adjacent to
germinal centers. They look normal but don't work. (* Maybe this
is why this lymphoma never forms nodules.)
{23575} small lymphocytic lymphoma. There is a small vessel running across
the picture. Use the endothelial cell nuclei to gauge the sizes of cells.
Pathologists often identify "proliferation centers", discrete clumps
of somewhat larger cells that supposedly give rise to the normallooking tumor cells. These are supposed to be pathognomonic of
CLL/SLL.
The bone marrow is always involved at the time of diagnosis, and
if the cells spill into the bloodstream, "chronic lymphocytic
leukemia" is said to be present. See below.
Patients are generally older adults. Despite systemic involvement,
the disease progresses very slowly, and seldom kills.
Around 30% of these patients eventually develop a more

aggressive B-cell lymphoma (including 1% who get a very
aggressive one, i.e., RICHTER'S SYNDROME), as in CLL.
{23854} CLL, transforming into a more aggressive cancer. Note the numerous
small lymphocytes and the blasts.
Well-differentiated lymphocytic lymphoma
Tom Demark's Site
LYMPHOPLASMACYTIC LYMPHOMA (Am. J. Clin. Path. 136:

195, 2011) features cells with slightly more abundant, purple cytoplasm
and production of monoclonal paraproteins. As a rule, these diseases
are somewhat more aggressive than generic small cell lymphocytic
lymphoma, and they usually produce a paraprotein.
* Most of these feature the translocation t(9;14), causing aberrant
expression of PAX5.
WALDENSTROM'S MACROGLOBULINEMIA produces large amounts
of IgM pentamers. In addition to the problems seen in any lymphoma,
patients suffer with hyperviscosity syndrome (nosebleeds / bleeding
gums / bleeding from other mucosal surfaces; dizziness / headache /
other neuro problems; eye problems; maybe other problems; look for
"sausage link" retinal veins). Like "regular small lymphocytic lymphoma",
This is a disease of the elderly.
It tends to be indolent and requires therapy only when the blood
becomes too viscous; after treatment, the malignant cells stay
around but may not cause further troubles (Am. J. Clin. Path. 135:
365, 2011).
* Future pathologists: Look in the nuclei for "Dutcher bodies",
masses of IgM (similar to the familiar "Russell bodies", but in the
nucleus). These let you be confident that you're looking at
lymphoma. Transformation into a more aggressive cancer can
supervene as in the more familiar small lymphocytic lymphoma.
* New suggested criteria for Waldenstrom's: Am. J. Clin.
Path. 116: 420, 2001.
* While Waldenstrom's is the most common cause of the

hyperviscosity syndrome, you may also see it in some plasma cell
myeloma patients, or when there are too many red cells (usually
in polycythemia vera), or too many white cells (usually in chronic
myelogenous leukemia), or one of the diseases with way too
many chylomicrons, or with a cryoglobylin or very bad polyclonal
gammopathy, or with way or too many platelets (the reasons are
complicated, involving platelet-endothelium interactions, and
unlike the others, the blood probably won't be hyperviscous in the
lab).
Waldenstrom's
ALPHA HEAVY-CHAIN DISEASE (now moved along with the

other heavy-chain diseases into the plamsa-cell neoplasms
section of the W.H.O. classification) typically affects the small
bowel and is fairly common in the Near-East. Most victims are
young adults, who present with malabsorption.
{13673} heavy chain disease; plasmacytoid cells in intestinal mucosa
* This transforms into the aggressive "Mediterranean
abdominal lymphoma", a B-cell immunoblastic lymphoma.
{19504} Mediterranean lymphoma, small bowel
Alpha heavy chains are also produced by MALT lymphomas.
GAMMA HEAVY-CHAIN DISEASE is a marker for a more
aggressive lymphoma that generally affects the elderly. Look for
big tonsils.
MU HEAVY CHAIN DISEASE generally turns leukemic early.
DIFFUSE LARGE B-CELL LYMPHOMA
The most common of the non-Hodgkin's lymphomas.
Before genetic profiling, we knew that CHOP chemotherapy has

cured around 40-50% of these lymphomas. Trying to sort out
which ones responded was one of the first successful applications
of microarray gene expression technology (Nature 403: 503,
2000; Nat. Med. 8: 68, 2002). For practical work, there are six
genes whose expression tell the prognosis (NEJM 350: 1828,
2008; update PNAS 105: 13520, 2008).
Watch for discovery of the mutations underlying this variability.
CARD11 as an oncogene: Science 319: 1656, 2008.
* This lymphoma is so common that even the ophthalmologists
have a series of cases starting in the orbit (Am. J. Ophth. 154: 87,
2012).
* These can pop up in the stomach, and if helicobacter is present,
eradicating it can cure the tumor, just as in the more familiar
MALTomas -- Blood 119: 4838, 2012.
MANTLE CELL LYMPHOMA (Hum. Path. 31: 7, 2002; Arch. Path. Lab.
Med. 132: 1346, 2008)
A B-cell lymphoma that bears markers of primitive mantle cells
(CD5+), diffuse or nodular, and often grows wrapped around
normal germinal centers, which is where it appears to begin (Am.
J. Clin. Path. 136: 276, 2011).
It always features t(11;14), involving cyclin D1 (bcl-1, CCND1)
(assay Am. J. Path. 154: 1449, 1999; Blood 93: 1372, 1999;
cyclin D1 is easy to stain for in sections), which is brought
adjacent to an enhancer of the IgH gene.
It's a disease mostly of older men, and often arises extranodally. It
is quite aggressive and hard-to-treat. Reports of cures may be
premature.
Future clinicians: Watch the proteosome inhibitor
bortezomib, which so far seems to be the most promising
thing we have for mantle cell lymphoma (J. Clin. Onc. 24:
4867, 2006).
* Don't worry about the details for pathologists. There are extraaggressive "blastoid" and "pleomorphic" subtypes, etc., etc.,
MALT LYMPHOMA ("maltoma", named for its occurrence on on mucosal
surfaces, of course) is now defined by its a trademark translocation
t(11;18) and fusion protein (API2/MALT1; AM. J. Path. 162: 1113, 2003),
or one of the related translocations.
Remember that helicobacter infection is the one known cause of
lymphomas (?) in the stomach (Blood 102: 1012, 2003). It's been
known for over a decade that eradicating helicobacter "often cures
the lymphoma". If the t(11;18) translocation is present, a cure is
less likely (Lancet 357: 39, 2001). Update on eradicating
"lymphoma" by eradicating helicobacter: Cancer 104: 532, 2005.
Many (but by no means all) Hashimoto and Sjogren-associated
lymphomas are MALT type.
* Since the MALT lymphoma cells have the markers of B-cells that
are just learning to fight a specific antigen, it makes sense that the
presence of the antigen keeps the lymphoma going. Someone
else can explain the molecular biology.
* Some pathologists consider these a subcategory of marginal
zone lymphoma, as in the alternate names for the tumor in the
new classification.
MARGINAL ZONE LYMPHOMA ("marginal cell lymphoma"; Am. J. Clin.
Path. 117: 698, 2002)
An indolent, nodular or diffuse, B-cell lymphoma that often arises
extranodally, famously in the spleen (a defined subtype:
Hematology 13: 27, 2008; Am. J. Surg. Path. 31: 438, 2007), or
orbit (Arch. Path. Lab. Med. 132: 1405, 2008).
Like mantle lymphomas, it tends to grow around benign germinal
centers.
Dermatopathologists are especially familiar with these, as they
tend to arise in the skin at sites of ongoing immune activation -infamously Lyme disease acting as a promoter
(Histopathology 37: 501, 2000).
FOLLICULAR LYMPHOMAS (CB/CC lymphoma)

Formerly divided into "small-cleaved", "mixed small-cleaved and
large cell" and "large-cell" subcategories, it's now pretty clear that
most of these lymphomas are mixtures of centroblasts (large Bcells with non-cleaved nuclei) and centrocytes (cleaved B-cells) -both resemble cells in the germinal centers. They grow as nodules
surrounded by benign lymphocytes (mostly T-cells).
The "small cells" / centrocytes look like normal lymphocytes
except for one or more clefts up the nucleus ("buttock cell", etc.),
and they lack the marbly heterochromatin.
The World Health Organization has a grading system:
Grade 1 (fewer than 5 centroblasts per high power field -indolent disease
Grade 2 (6-15 centroblasts perh high power field -- indolent

disease
Grade 3a (mostly centroblasts with some centrocytes -indolent disease
Grade 3b (almost all centroblasts -- uncommon, aggressive

disease
Patients are usually in middle-aged or older. The bone marrow is

usually involved at the time of diagnosis. The translocation
t(14;18), with bcl2, is usual.
If only a mass is discovered and there are no symptoms, most
physicians today recommend doing nothing; it takes an average
of 3 years for symptoms to appear. Today they are easy to treat
initially, but tend recur repeatedly after treatment begins, each

time sooner than last.
About half of these transform into a diffuse B-cell lymphoma; the
transformation is often accompanied by generalized symptoms
(perhaps for the first time) and the disease becomes harder to
manage.
{23599} mixed lymphoma; use the endothelial cell at 2:30 as a size marker
{23683} mixed lymphoma
{23596} nodular large-cell; at this power, just appreciate the nodularity
Large cell lymphoma
Large cell lymphoma
WebPath Photo
WebPath Photo
Telling nodular lymphomas from hyperplastic germinal centers:

Lymphoma nodules are usually bcl-2+; germinal centers are
usually bcl-2 negative
Lymphoma nodules lack the light-side / dark-side we usually
see in germinal centers
Lymphoma nodular will generally show clonality (i.e., allkappa or all-lambda); germinal centers always have a mix
Lymphoma nodules efface the normal underlying
architecture of the lymph node
Lymphoma nodules often grow back-to-back and crowd one
another, while germinal centers stay clear of one another
Lymphoma nodules may show mantles like normal germinal
centers, but they tend to be thin
MORE LYMPHOMAS
{23590} diffuse small cleaved lymphoma (all you can tell is that it is small
cleaved)
{23593} diffuse small cleaved lymphoma (all you can tell is that it is diffuse)
{46344} diffuse small cleaved lymphoma, marrow
Small cleaved lymphocyte in blood
Ed Lulo's Pathology Gallery
ANAPLASTIC LARGE CELL LYMPHOMA (Arch. Path. Lab.

Med. 135: 19, 2011) is rather less aggressive than the other large
ones. The famous "hallmark cells", with multilobular, horseshowshaped nuclei are required for diagnosis. This cancer also
features t(2;5) with production of a fusion product oncogene
(NPM/ALK, Blood 93: 3088 & 3913, 1999) and is now called
"ALK+ / anaplastic lymphoma kinase", a fusion product involving
nucleophosin (update Am. J. Clin. Path. 130: 628, 2008; the
Italians try a lymphoma vaccine that works in mice Nat. Med. 14:
676, 2008).
* The ALK inhibitor crizotinib is finding use here as well as in
the small minority of lung cancers, mostly in never-smokers,
that overexpress it (NEJM 363: 1693, 2010.) * Future
pathologists: Expect it to light up with CD30/Ki1. Of course,
you can also stain for ALK, which usually lights up.
When primary in the breast, the woman commonly has
implants, and perhaps this is the first genuine link between
a disease -- though vanishingly rare -- and the implants
(JAMA 300: 2030, 2008).
{08787} large-cell lymphoma
{15389} large-cell lymphoma
{23647} * "angioimmunoblastic lymphadenopathy", a T-cell lymphoma with
vascular proliferation -- note the vessels and the monomorphic cell infiltrate)
* Some of the larger-celled lymphomas may be indistinguishable
on H&E from the rare TRUE HISTOCYTIC LYMPHOMA (an
oxymoron; histiocytes are not lymphocytes). The immunostaining

and chromosomal studies will clarify everything.
{23674} true histiocytic lymphoma, trust me
The old "immoblastic lymphoma" of the Working Classification
was a mix of several different B- and T-cell lymphomas.
EFFUSION LYMPHOMAS, in the body cavities without a solid
phase, are usually seen in immunosuppressed people and always
are caused by KSHV (herpes 8 ) (Lancet 346: 883, 1995;
Lancet 347: 980 & 1042, 1996). KSHV is now required for case
definition (Cancer 111: 224, 2007).
{10935} lymphoma arising in thyroid; my case
{10937} lymphoma arising in thyroid; my case. Notice that the lymphocytes
are growing within a follicle.
Body cavity lymphoma and Hodgkin's
Post-Transplant Neoplasia
Great site
Transplant Pathology
Internet Services
{00245} immunoblastic lymphoma

{10691} immunoblastic lymphoma, cytology
{08017} lymphoma in the heart
{11630} lymphoma in the pericardial space
{11633} lymphoma, primary in the heart
{20227} lymphoma, primary in the stomach
Post-transplant lymphoproliferation

T-LYMPHOBLASTIC LYMPHOMA
This is the most important pediatric lymphoma (typically a
teenaged's guy's disease); it is the solid counterpart to T-cell
acute lymphoblastic leukemia.
* These smallish T-cells have convoluted (i.e., more than one
cleft) nuclei, though they are not as complex as in Szary
syndrome (below). Immunologists note similarities with baby,
intra-thymic T-cells. The usual t(14;21) and its molecular biology:
Proc. Nat. Acad. Sci. 97: 3497, 2000. There is often a gain-offunction mutation of NOTCH: Nat. Med. 13: 1203, 2007.
In keeping with its thymocyte origin, it typically presents itself in
the anterior mediastinum (i.e., thymus area).
The prognosis has historically been not-so-good. Try a new
chemotherapy protocol.
{00242} T-lymphoblastic lymphoma. Trust me.
BURKITT'S LYMPHOMA ("small non-cleaved cell lymphoma", * one of
Rappaport's "undifferentiated lymphomas"; Lancet 379: 1234, 2012)
A famous B-cell tumor, the most common childhood cancer where
malaria is endemic. It is the fastest-growing human solid tumor.
Most often, the childhood variant arises in the jaw.
{46189} African Burkitt's
{49035} African Burkitt's
Burkitt's lymphoma
Missionary site
Burkitt's lymphoma
Patient and photomicrograph
KU Collection
Burkitt's lymphoma
Starry sky
KU Collection
Burkitt's
Bryan Lee
Burkitt's
NCI
Wikimedia Commons
Burkitt's after transplant

Burkitt's
Section
Wikimedia Commons
Burkitt's
Smear
Wikimedia Commons
The Epstein-Barr virus is part of the cause, but obviously

not the whole story. These tumors also have a famous
translocation that places the oncogene myc on chromosome 8
under the control of the IgH regulator on chromosome 14. (* Less
often, myc joins the kappa chain gene on 2, or lambda on 22).
NOTE: We've already seen that many lymphomas in
immunosuppressed patients, both inside and outside the
CNS, are strongly linked to the Epstein-Barr virus . Many,
but not all, have Burkitt-like histopathology. Nowadays we
call these "post-transplantation lymphoproliferative
disorders", and they tend to regress if immunosuppression
can be discontinued.
* For some reason, the Kaposi virus doesn't seem to
cause post-transplant lymphoproliferative disease
(Am. J. Clin. Path. 131: 632, 2009).
Epstein-Barr
Post-transplantation lymphoproliferative disorder
WebPath Photo
The lymphoma cells are strikingly uniform, with big blue

nuclei, and deep blue cytoplasm laden with lipid droplets. Tingible
body macrophages loaded with this lipid appear as white "stars"

against the blue "sky".
The "starry sky" appearance of Burkitt's is a favorite exam

question. Just to confuse you, tingible body macrophages
appear as similar "stars" against the not-so-blue-as-Burkitt's
"sky" of a normal lymph node. Despite "Big Robbins", the
stars of Burkitt's are more conspicuous than other tingiblebody macrophages because they are heavily laden with
lipid.
{23620} Burkitt's lymphoma, lipid drops
{46336} Burkitt's lymphoma, lipid drops
{23611} Burkitt's lymphoma, good starry sky
{46332} Burkitt's lymphoma, good starry sky
{23641} * Burkitt's, methyl green pyronine (the red "pyroninophilia" merely
tells us that the cytoplasm is rich in ribosomes)
{46326} African Burkitt's, tonsils
AFRICAN BURKITT'S, almost always EBV-positive, is generally
curable with chemotherapy, if you can get it to the victims.
By contrast, AMERICAN BURKITT'S, a sporadic disease of young
people and the immunocompromised, may be EBV-positive or
EBV-negative. It can produce masses most anywhere, and has a
worse prognosis.
MYCOSIS FUNGOIDES / SZARY SYNDROME (Lancet 371: 945,

2008.
Lymphomas of the epidermis and upper dermis, composed of
large T4-cells with very elaborately infolded ("cerebriform")
nuclear membranes. The distinctive "Pautrier microabscesses"
(misnamed) are clusters of these T-cells within the epidermis.
In "mycosis fungoides" (Latin for "Toadstools! Toadstools!"),
patients suffer from red, peeling skin for some years, then enter a
plaque and eventually a tumor phase, in which the patient looks
horrible and has lymphoma throughout the body.
{40003} mycosis fungoides
{12747} mycosis fungoides, plaque phase
{24740} mycosis fungoides, histopathology; note Pautrier microabscesses
{12759} mycosis fungoides, Pautrier microabscesses
{13793} mycosis fungoides, Pautrier microabscess
{13796} mycosis fungoides cells in a lymph node (look how wiggly the nuclear
membranes are)
{09042} mycosis fungoides cell, electron micrograph
In "Szary syndrome", the red skin does not transform into
tumors. Instead, the cells circulate in the blood as a leukemia. The
disease is slowly progressive, and survival for several years is
usual.
{12757} Szary patient
{16544} Szary cell
{23722} Szary cell
{15409} Szary cell
* These are still probably incurable. Vorinostat, the novel
chemotherapeutic agent that inhibits acetylation of nucleosomes
(?!), was approved in 2006 and seems to work nicely for
otherwise-intractable T-cell cutaneous lymphoma. See Blood 109:

31, 2007.
ADULT T-CELL LEUKEMIA-LYMPHOMA
A rare, very aggressive malignancy of T-helper cells.
It is strongly linked to the HTLV-I retrovirus, which is transmitted
like AIDS, binds to the same receptor (CD4), is neurotrophic, and
lies dormant for a long time. (All about HTLV-1: Lancet 353: 1951,
1999).
We now check all donor blood for this virus.
* The malignancy is preceded by polyclonal T-cell
hyperplasia, due to induction of T-cell IL-2 receptors by the
virus.
* Have a pathologist show you the distinctive "flower cell"
lymphocytes in the blood in the leukemia.
* Hypercalcemia is common in this disease; the molecular
biology is curious, and involves the leukemic cells turning
into osteoclasts (Blood 99: 634, 2002).
The disease (like the virus) is more common in Japan and the
Caribbean. HTLV-I in Japan: Lancet 343: 213, 1994.
* Don't worry about the cancers of monocyte-macrophage origin.
MALIGNANT HISTIOCYTOSIS ("histiocytic medullary reticulosis"), a
very aggressive, fortunately rare cancer of blood-cell-eating true
macrophages, is worth mentioning here. Not a cancer, but also deadly....
HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS, a sometimes-genetic
(often perforin), sometimes-acquired (triggered by infection or
rheumatologic disease: Pediatrics 118: e216, 2006; Blood 106: 3090,
2005; South. Med. J. 100: 208, 2007) illness. The macrophages go
crazy and destroy the body (Am. J. Clin. Path. 137: 786, 2012).
{23668} malignant histiocytosis with erythrophagocytosis
Epstein-Barr hemophagocytic syndrome

Yutaka Tsutsumi MD
TREATING THE NON-HODGKIN'S LYMPHOMAS: This is HUGE news.

We've already mentioned some of the novel agents that are working.
Rituximab "Rituxan", an antibody against CD20, is revolutionizing
treatment of B-cell lymphomas (Am. J. Clin. Path. 119: 472, 2003;
Blood 101: 949, 2003; NEJM 366: 2008, 2012; lots more). Also watch
for 90-Yttrium-ibrituxomab tiuxetan (Blood 99: 4336, 2002; Cancer 94: 1349,
2002). Perhaps most exciting so far: I131-tositumomab, radioactive antiCD20, with a high five-year symptom-free survivals in follicular
lymphomas. Much success reported for indolent diffuse non-Hodgkin's
lymphoma with chemotherapy plus radioimmunotherapy (90-Yttriumibritumomab tuixetan: Cancer 112: 856, 2008). Update on about a
dozen monoclonals for B-cell lymphoma: NEJM 359: 613, 2008. Claim
of cures with non-myelogenic ablative transplantation (with or without
90yttrium ibritunonab tiuxetin): Blood 119: 6373, 2012.
Future pathologists: In patients treated with rituximab who perish,
you'll see profound depletion of normal B-cells throughout the
body for as long as a year after treatment (Am. J. Clin. Path. 130:
604, 2008).
HODGKIN'S DISEASE ("Hodgkin's lymphoma"; J. Clin. Path. 55: 162, 2002)
A common (7500 cases/year in the U.S.), usually-curable cancer that
typically affects young adults. (There is a second peak in older adults;
their disease tends to be more aggressive.)
Risk factors are ill-defined, and "epidemics" could perhaps be
statistical accidents. Family members are at several times
increased risk, and a monozygous twin is at 100 times the base
risk (NEJM 332: 413, 1995).
A previous history of Epstein-Barr infectious mononucleosis
supposedly triples one's risk for Hodgkin's disease. This has held
up and having Epstein-Barr virus on board places one at an
increased risk, but exactly what the relationship is remains
obscure (possible mechanisms: Blood 106: 4345, 2005). Of
course, many Hodgkin's patients are EBV-negative (Blood 106:
2444, 2005).
* Hodgkin's disease is rare in the Orient. For some reason,

pediatric Hodgkin's is common in the poor nations.
* Hodgkin's disease is a recognized complication of AIDS, though
less typical than non-Hodgkin's lymphomas. Not surprisingly,
AIDS patients with Hodgkin's disease tend to lack lymphocytes
(Cancer 67: 1865, 1991).
The malignant cell is the REED-STERNBERG CELL, but until the late
stages of the disease, the tumor masses are composed primarily of
inflammatory cells responding to the cancer.
You must recognize the
CLASSIC REEDSTERNBERG CELL:
15-45 microns
o
across
o
multilobed
nucleus (often appears
"binucleate"), with
lobes appearing as
mirror images of one
another
large, red owleye nucleoli,

surrounded by clear
nuclear sap
pink-tolavender cytoplasm
CD15 positive
(except nodular
lymphocyte
predominant subtype)
{23560} Reed-Sternberg cell

{20057} Reed-Sternberg cell
{36398} Reed-Sternberg cell, not H&E; cytology
{36401} Reed-Sternberg cell, not H&E; cytology

{40423} Reed-Sternberg cell, mitosis
Hodgkin's
Great labels
Hodgkin's with Reed-Sternberg variants

Great labels
Hodgkin's Disease ("Hodgkin's granuloma"

is an ancient misnomer.)
Hodgkin's disease
Nice Reed-Sternberg cell
KU Collection
Hodgkin's, node
Hodgkin's, liver
WebPath Photo
WebPath Photo
Reed-Sternberg cells
Reed-Sternberg cell
WebPath Photo
WebPath Photo
Hodgkin's disease, spleen

AFIP
Wikimedia Commons
Hodgkin's
H&E
Wikimedia Commons
Everybody accepts the 1965 RYE CLASSIFICATION of Hodgkin's

disease with the W.H.O. modification that separated-out nodular
lymphocyte predominant.
NODULAR LYMPHOCYTE PREDOMINANT:

In this illness, there are sheets of lymphocytes and some
RS-like cells. However, the RS cells don't even immunostain
like in other forms of Hodgkin's (they are CD15-, CD45+, Bcell markers are positive), and it's probably "not really
Hodgkin's, maybe a dysplasia": old work Blood 87: 2428,
1996; Am. J. Path. 146: 812, 1995; different mutations
Blood 101: 706, 2003; long-term follow-up supports the
good prognosis but a few patients transform to a diffuse
large B-cell lymphoma (Cancer 116: 631, 2010).
The main reason to "type" Hodgkin's is to rule this in or out,
since it's noted for late recurrence (NEJM 318: 214, 1998).
CLASSICAL LYMPHOCYTE PREDOMINANT: A background of
normal, monotonous, small lymphocytes.
{46338} Lymphocyte predominant Hodgkin's
{46339} Lymphocyte predominant Hodgkin's
Reed-Sternberg cells of any kind may be rare! See
NEJM 319: 246, 1988.
This variant generally announces itself in a single group of
nodes, and almost all patients get cured by today's
therapies.
Don't diagnose "chronic lymphocytic leukemia" or "small
lymphocytic lymphoma" in a young person until you've
sectioned through the block in your search for the
diagnostic cell.
MIXED CELLULARITY: There are many Reed-Sternberg cells and
variants, in a background of lymphocytes, plasma cells,
eosinophils, and histiocytes. This variant can present at any
stage.
{23539} mixed cellularity Hodgkin's disease
LYMPHOCYTE DEPLETION: Mostly cancer cells, little else.

Probably the Hodgkin's cells have taken additional mutations.
* The background may be lots of poorly-woven collagen
("diffuse fibrosis variant") or just reticulin ("reticular variant"),
with wildly anaplastic cells.
The disease often (but not always) presents at late stage.
Future pathologists: You won't make this diagnosis unless
there's a recognizable Reed-Sternberg cell or a previous
diagnosis of Hodgkin's disease.
{23524} lymphocyte depleted Hodgkin's disease. Just plain anaplastic.
NODULAR SCLEROSIS: This features lacunar Reed-Sternberg
variants and a tendency for the lesion to become crisscrossed by
dense collagen bands. The prognosis is generally good.
{23542} nodular sclerosing Hodgkin's disease
{23545} nodular sclerosing Hodgkin's disease
{23548} lacunar Reed-Sternberg variants
{23551} lacunar Reed-Sternberg variant
Nodular sclerosing Hodgkin's
Bryan Lee

WebPath Photo
Lacunar cells
WebPath Photo
WebPath Photo
NOTE: There are subtypes of each common type....

Sex ratios: Nodular sclerosis is a bit more common in women. All
the other forms are more common in men.
Having described this elegant classification scheme, I am almost
sorry to have to add that the prognosis for any particular case of
Hodgkin's disease is determined by stage, rather than by type.

Almost all patients with stage I or IIA disease are now cured. This
drops to around 50% for patients presenting at stage IV.
Lymphocyte predominant presents at low stage, mixed
cellularity at low or high stage, lymphocyte depletion
presents at high stage, and nodular sclerosis is often a
mediastinal mass. These differences account for "different
prognosis for different Hodgkin's types".
* Update on treating Hodgkin's, including recognizing
people with good prognosis for whom the most intensive
therapies can be avoided (Blood 120: 822, 2012).
REED-STERNBERG VARIANTS are also malignant.
MONONUCLEAR REED-STERNBERG-LIKE CELLS ("Hodgkin
cells") have single-lobed nuclei and one nucleolus. They may be
seen in any variant of Hodgkin's disease.
* LP CELLS (* "L&H cells") have scanty cytoplasm, big knobby
nuclei, and small nucleoli. They are seen in lymphocyte
predominance Hodgkin's disease.
LACUNAR REED-STERNBERG CELLS have abundant, pale
cytoplasm (* an artifact of formalin fixation). They are seen in
nodular sclerosis Hodgkin's disease.
POLYLOBULATED REED-STERNBERG CELLS ("popcorn cells")
look like good Reed-Sternberg cells, except that the nucleoli aren't
so impressive. They are typical of mixed cellularity Hodgkin's
disease.
* PLEOMORPHIC REED-STERNBERG CELLS are anaplastic
versions of the familiar form. They make up the bulk of the tumor
in lymphocyte depletion Hodgkin's disease.
REED-STERNBERG CELL RULES:
While a classic Reed-Sternberg-like cell may appear in other
diseases (even "infectious mono"), its presence in the proper
background (see below) gives the diagnosis of Hodgkin's disease.
You must see a CLASSIC Reed-Sternberg cell before making the

diagnosis.
Hodgkin's begins as an enlarged node or group of nodes. While we do
not test you on staging, everybody knows these basics (used for a
majority of non-Hodgkin's lymphomas too):
Stage I... one node group or organ
Stage II... one side of the diaphragm
Stage III... both sides of the diaphragm
Stage IV...marrow, or two extra-lymphatic organs
"A" means no systemic symptoms
"B" means fever, weight loss (>10%), or night-sweats.
The classic Hodgkin's fever is the "Pel-Ebstein", or intermittent
spiking fever.
{20056} Hodgkin's disease in a cervical node (we would of course diagnose
this only with microscopy)
{46348} Hodgkin's disease in the spleen
{46349} Hodgkin's disease in the spleen
Hodgkin's disease spreads predictably along contiguous groups of
lymph nodes. As it spreads, there may be transformation:
Lymphocyte predominant turns into mixed cellularity or
lymphocyte depletion.
Mixed cellularity turns into lymphocyte depletion.
Nodular sclerosis generally keeps its type.
When I was in college, I had a classmate who I was told "might end up
being the first human cured of Hodgkin's disease." He died, but the fact
that Hodgkin's is now cured so often is one of the 20th century's great
triumphs. Even chemoresistant Hodgkin's now seems to be getting
cured sometimes using a new protocol (with autologous stem cells,
Cancer 113: 1344, 2008).
Minor mysteries of medicine:

(1) Hodgkin's patients often notice pain at sites of disease after they
drink alcohol.
(2) Hodgkin's patients often have cutaneous anergy, even early in their
disease.
INTRODUCING THE LEUKEMIAS
Leukemia
Packed marrow
WebPath Photo
Leukemia
Packed marrow
WebPath Photo
Leukemia / myelodysplasia
Nat Pernick MD
Leukemia ("white blood"), discovered and named of course by

Virchow, is a generic term for replacement of the bone marrow by
cancerous blood cells. These usually (but not always; many acute
leukemias are initially "aleukemic") are spilling over into the
bloodstream; in any case, expect a "packed marrow" except in early
CLL.
The story of progress in the treatment of the leukemias, all considered
incurable when I was in college, is described in Cancer 113(7S): 1933,
2008.
{23848} packed marrow; * this was late-stage CLL
{36032} packed marrow; * this was AML
{12347} packed marrow; * this was AML
ACUTE LEUKEMIAS ("poorly differentiated leukemias") are
overgrowths of cells that fail to mature (BLAST CELLS). These diseases
are very aggressive, and cause death in weeks or months.
{16243} blast with Auer rods
{29475} lymphoid blasts, pap stain. Big pale nuclei.
M3
AFIP
Wikimedia Commons
Acute promyelocytic leukemia

Good Auer rods
KU Collection
Auer rods
WebPath Photo
HOW TO SPOT A BLAST: (review from "Histology")

scanty cytoplasm
big nucleus with mostly euchromatin
nucleoli
Future pathologists: You cannot tell whether a generic,
undifferentiated "blast cell" is lymphoid or myeloid without
doing special stains and/or chromosomal studies noted
above. You'll learn below that Auer rods are sure markers
for myeloid differentiation. Of course, today you must use
immunohistochemistry (easy approach Arch. Path. Lab.
Med. 132: 462, 2008).
* Auer rods in preleukemia: Am. J. Clin. Path. 124:
191, 2005.
These cells are not especially fast-growing, but they fail to mature.
Even if they do not "crowd out" their healthy neighbors, they tend
to inhibit normal production of other blood cells.
Acute leukemia presents abruptly as one of the cytopenias
(anemia, neutropenia, and/or thrombocytopenia). Bone pain is
likely to result from expansion of the marrow and infiltration of the
periosteum.
Later, involvement of other organs is common. Brain involvement
is especially troublesome. T-cell leukemias often produce a mass
in the anterior mediastinum (why?).
{23842} acute lymphocytic leukemia, brain

{08734} acute leukemia, liver; as you would expect, the leukemia is blue
{08735} acute leukemia, liver
{08736} acute leukemia, liver
Acute Lymphoblastic Leukemia
Peripheral smear
KU Collection
Death typically results from hemorrhage (cerebral, GI, other),

and/or infection (neutropenia, chemotherapy), and/or
complications of bone marrow / stem cell transplantation.
{06269} fatal cerebral hemorrhage in leukemia
{01735} brain and dura, acute leukemia
The biology of the acute leukemias is very well-studied (still
interesting Lancet 349: 118, 1997). The refractory ones have
pumps to remove chemotherapy drugs, etc., etc.
By contrast, CHRONIC LEUKEMIAS ("well-differentiated leukemias")
feature cancer cells that do mature (more or less), and that have a
natural history measured in years.
Like acute leukemia patients, these patients may present with a
cytopenia problem. Or they may have problems from a high white
("leukostasis" plugging small vessels), or may notice
lymphadenopathy or organomegaly, or the high white count may
be an incidental finding on "routine lab".
RULE: Marrow cells (most leukemias, extramedullary
hematopoiesis) in the spleen involve the red pulp.
Lymphomas in the spleen (at least the B-cell type) involve
the white pulp.
RULE: Any leukemia can involve the lymph nodes and
make them large, but the enlargement is seldom so
spectacular as in Hodgkin's or non-Hodgkin's lymphoma.
RULE: Any leukemia (or lymphoma) can involve the liver,

but enlargement is usually not spectacular. Hodgkin's and
non-Hodgkin's lymphomas will first appear in the portal
areas.
LYMPHOID LEUKEMIAS recall the various kinds of normal
lymphocytes, and MYELOID ("myelogenous", or better, "granulocytic")
leukemias recall a normal granulocyte.
You remember that MYELOCYTES, the precursors of
granulocytes, are the most common cell in normal bone marrow
(MYELO-); hence their name.
Cell turnover in the leukemias (and the closely-related polycythemia
vera and primary myelofibrosis) is much increased, placing these
patients at risk for gout. The risk increases further when cancer cells are
dying by the pound during therapy. The thoughtful oncologist gives
prophylactic medication.
ACUTE LYMPHOBLASTIC LEUKEMIA ("ALL"; diagnosis Am. J. Clin.
Path. 111: 467, 1999)
Acute lymphoblastic leukemia
Bone marrow
WebPath Photo
Acute lymphoblastic leukemia

Peripheral smear
WebPath Photo
Acute Lymphoblastic Leukemia

ALL
This is the familiar "childhood leukemia", with peak age in four year old
kids. Adult ALL is less common.
* Authoritative mega-review for pathologists considering a
diagnosis of leukemia in a child: Am. J. Clin. Path. 109(4S1):9S,
1998.
{12410} ALL (all you can tell from the smear is "blasts")
ALL seems to strike at random. Radiation exposure is a known risk

factor, Down's syndrome kids are at 15x the normal risk, a patient's
identical twin has a 20% risk.
* A curious claim that could be true is the idea that leukemia is an
unusual response to one or more as-yet-unidentified viruses met
at the wrong age; one finding that seems to be robust is a strong
correlation between leukemia rates and the diversity of origins,
i.e., new immigrants, in an area (Br. Med. J. 313: 1297, 1996;
Lancet 349: 344, 1997.)
Rachel Carson's unfortunate (i.e., false and inflammatory)
discussion of leukemia in "Silent Spring" is now history. She was
right about the danger of DDT to birds' eggs, and her manipulation
of the data on leukemia is a minor blot on the memory of a great
science writer. Nobody's perfect. Today, there's no serious
discussion of the old alleged link between insecticide exposure
and leukemia (* the one paper I could find from the decade 19972007, Canc. Ep. 16: 1172, 2007, looks like recall bias).
* Pathologists and oncologists used to subclassify acute lymphoblastic leukemia
by blast morphology ("FAB classification"; stands for "French-American-British"):
L1: 85%... Cells <= 2x the diameter of a normal lymphocyte; smooth
nuclei; more common in kids
L2: 14%... Bigger cells, lots of clefts, often nucleoli; more common in
adults
L3: 1%... Even bigger cells, Liquid Burkitt's lymphoma; t(8;14) and
everything
{23746} L1
{23833} L1, special stain (cytoplasm is brown)
{23860} L2
{13982} L2, bone marrow
{23758} L3; note the lipid
{13985} L3
ALL-L1
AFIP
Wikimedia Commons
Burkitt's leukemia
Bone marrow
KU Collection
L3 is a distinct entity, but L1 and L2 aren't especially useful. Here's a moremodern immunophenotypic classification:
B-cell... 80%... * CD19+...* several subclasses exist
"pre-B"/"null", with surface Ig and TdT, carries a good prognosis;
Burkitt's / "mature B" / L3 is ominous
T-cell... 15%... * "intra-thymic markers, like T-lymphoblastic lymphoma";
chances of a cure are much less than with B-cell disease
Nothing... uncommon today...* markers are negative; there is only HLADR.
Apart from the fact that all L3's (Burkitt's) are B-cell tumors, there is little
correlation between the two systems.
In 2002, the World Health Organization proposed the following system, which
seems to be generally accepted now:
1. Acute lymphoblastic leukemia / lymphoma (all the old L1's and L2's go
here)
Precursor B acute lymphoblastic leukemia / lymphoma
t(12;21) TEL/AML-1
t(1:19) PBX/E2A
t(9,22) ABL/BCR (Philadelphia chromosome of course)
T(V,11) V/MLL
Precursor T acute lymphoblastic leukemia / lymphoma (* future

pathologists: stain for CD7)
2. Burkitt's leukemia / lymphoma (all the old L3's go here

3. Biphenotypic acute leukemia
More for cytogeneticists and prognosticators:
Hyperdiploidy (especially "high hyperdiploidy", >50 chromosomes, all good

standard ones), present in a large minority of B-cell ALL's, confers a good
prognosis.
* Fans of crackpot science please take note: If the "independent thinker /
persecuted genius" claim that cancer is not caused by mutations but by
nondisjunction, this curious fact about leukemia would not be true.
Adults with ALL are often "Philadelphia-positive", and kids can be, too
(* the latter confers a bad prognosis: NEJM 342: 998, 2000). Several other
bad-prognosis translocations, including the Burkitt t(8:14), and the AML
variant of the Philadelphia chromosome, are known.
t(12;21) and del(9p) give a relatively favorable prognosis.
Almost all children with ALL get a complete remission on current therapy. Around
90% get apparent cures on today's regimens (NEJM 366: 1445, 2012).
The prognosis for adults is still guarded. Cure rates for teens are now
about as good as for young children (J. Clin. Onc. 29: 386, 2011).
Pccasionally the disease appears in older adults with less chance of cure.
* Precursor T-cell ALL and MLL gene-rearranged leukemias are
exceptions that are more refractory to cure.
{23857} ALL in the liver
{32027} ALL in the liver
{34513} ALL in the brain
{49316} ALL in the kidney
{49343} ALL in the testis
* In 1987, Coby Howard,who had ALL and a relapse, and belonged to a family
that did not work and received Medicaid as part of welfare, didn't get his
$100,000 bone marrow transplant that had maybe 25% chance of working (J.
Clin. Onc. 5: 1348, 1987 is from that era) because of Oregon's health-care
rationing, which was intended to spend the Medicaid money where it was most
likely to do the most overall public good. Pressure groups (liberal, conservative),
of course, had a field-day with Coby's death. During the activity at the legislature
that followed, it was pointed out that many working people who did not have
health insurance were dying because they lacked access both to transplants and
to far more basic services. Taxpayers understandably resent being forced to pay
for health benefits for others that they cannot get for their own children.
Remember poor Coby's name, and the principle.
ACUTE MYELOID LEUKEMIA ("AML", "acute myelogenous leukemia", "poorly
differentiated granulocytic leukemia", "acute non-lymphocytic leukemia", "ANLL", etc.)
This is the common acute leukemia of adults (the incidence increases with age,
but young adults are often affected, and occasionally children are affected).
Although most cases are idiopathic, many things are known to increase risk.
These include:
o Down's syndrome (trisomy 21 -- especially AML-M7)
o those fragile chromosome syndromes

Bloom's
ataxia telangiectasia
Fanconi's anemia (a complex genetic disorder; * gene FancC
Blood 94: 1, 1999; leukemias Cancer 97: 425, 2003.)
o benzene exposure (* supposedly the metabolites inhibit a topoisomerase:
Blood 98: 830, 2001)
o ethylene oxide exposure
o ionizing radiation exposure ("we estimate one case per 10000 childhood
CT scans" -- Lancet 380: 499, 2012).
o previous cancer chemotherapy (NEJM 322: 52, 1990 is still good;

remember the alkylating agents and anthracyclines; the risk from adjuvant
breast cancer therapy is minimal if any Cancer 101: 1529, 2004)
o any "myelodysplastic syndrome" ("preleukemia")
o any "chronic myeloproliferative syndrome" ("blast crisis" -- * many of these

patients enter "leukemia transformation" by acquiring a mutated SRSF2;
see Blood 119: 4480, 2012)
primary myelofibrosis
polycythemia vera rubra
"essential" hemorrhagic thrombocythemia
"idiopathic aplastic anemia" (usually T-cell autoimmune)
The cancer arises out of a background of mutated marrow cells that typically
include granulocytic and other (erythroid and/or monocyte precursors). All are
likely to show some abnormalities (* good tipoff: megakaryocytes with nonlobulated nuclei).
The FAB classification (Ann. Int. Med. 103: 614 & 620, 1985) is worth knowing at
the recognition level (though it is of little interest to practicing oncologists, who
are today much more concerned about the molecular lesions):
M0: "minimally differentiated AML"; undifferentiated myeloblasts without

myeloperoxidase (* new criteria Am. J. Clin. Path. 115: 876, 2001)
M1: "acute myeloblastic leukemia without maturation"; undifferentiated

myeloblasts with myeloperoxidase; just maybe a few Auer rods
M2: "acute myeloblastic leukemia with granulocytic maturation"; the most
common; some promyelocytic differentiation, maybe a few Auer rods;
* t(8;21) is distinctive, with fusion AML1/ETO
M3: "acute promyelocytic leukemia"; very granular promyelocytes, often
many Auer rods, DIC (* from annexin II on the surfaces that activates
plasmin: NEJM 340: 944, 1999; not the full story Thromb. Res. 113: 109,
2005); * t(15;17) and * t(11;17) are distinctive, and (KNOW:) involve the
vitamin A receptor (RAR; discovery Blood 77: 1418 & 1657, 1991).
All-trans retinoic acid (* "tretinoin") matures these cells: NEJM 324:
1385, 1991; NEJM 27: 385, 1992; Blood 85: 2643, 1995; Blood 94:
39, 1999 (* discovered by the Mainland Chinese, who attributed
their success to lack of regulation of human research.... Do any of
our "ethicists" want to "refuse to use this data which was acquired
immorally"?)
* Retinoic acid plus G-CSF for the difficult t(11;17) subtype:
Blood 94: 39, 1999. Diagnostic stain Blood 86: 862, 1995.
Arsenic trioxide (!) was introduced into the treatment of M3 (first
positive report NEJM 340: 1043, 1999. Taken in combination with
the retinoic acid derivatives, the new protocols produce cures (Nat.
Med. 14: 1333, 2008; NEJM 360: 928, 2009.)
M4: myeloid and monocytic differentiation (* a subtype M4eo has
eosinophilis all over the marrow)
Acute Myelomonocytic Leukemia
M5: monocytic differentiation only; * t(9;11)(p22;q23) is typical of

M5a; 9p22 is beta-interferon receptor, while 11q23 is the MLL (myeloidlymphoid leukemia gene; common in infant and adult leukemias, though
not childhood leukemias (Proc. Nat. Acad. Sci. 88: 10735, 1991; Blood 94:
283, 1999) as well as adult AML
* MLL also forms a fusion product with MEN-1 (which is adjacent)
and a src-like gene on chromosome 19 (Proc. Nat. Acad. Sci. 94:
2563, 1999) in t(11;19) leukemias; this fusion product inhibits p53's
product (Blood 93: 3216, 1999).
* M5a is "acute monoblastic leukemia" with very primitive-looking

blasts bearing monocyte markers; M5b is "acute monocytic
leukemia" with a dented nucleus and granules.
M6: "acute erythroid leukemia"; features of red cell precursors
predominate; "Di Guglielmo's erythroleukemia" (* future pathologists: look
for d-PAS-positive chunks in the cytoplasm)
M7: "acute megakaryoblastic leukemia"; platelet markers; acute marrow
fibrosis (* PDGF effect; reticulin); acute megakaryoblastic leukemia is a
childhood leukemia (Am. J. Clin. Path. 122-S: S33, 2004).
Rarities not in the schema include acute basophilic leukemia, acute
eosinophilia, and several others.
The World Health Organization's 2002 attempt to reclassify the acute
myelogenous leukemias in terms of their mutations and clinical antecedents
(Blood 100: 2292, 2002) met with mixed reviews; you will find it in research
papers. A new version came out in 2008.
o AML with a characteristic genetic abnormality (several are listed; generally
better prognosis)
o AML with multilineage dysplasia (i.e., arising from myelodysplastic
syndrome, polycythemia vera, myeloid metaplastia, etc., etc.; WHO claims
poor prognosis but this is disputed Blood 1111: 1855, 2008)
o AML resulting from previous radiation or chemotherapy (generally poorer
prognosis)
o AML not otherwise categorized -- unfortunately, a very long list based on
morphology
o "Acute leukemia of ambiguous lineage" -- both T-cell and B-cell markers,
or neither T-cell nor B-cell markers
Researchers expressing ongoing dissatisfaction with the WHO 2002 system (for
example, the fact that 40-50% of adults with AML have no cytogeneic abnormality
at diagnosis) are looking forward to a future classification based on individual
mutations, instead.
* Watch FLT3 (a tyrosine kinase), nucleophosmin (NPM1 -- the most-often
mutated gene in AML and now stainable in some normal-karyotype AML's:
Am. J. Clin. Path. 133: 34, 2010; now used as a guide to treatment and to
screen for residual disease Arch. Path. Lab. Med. 135: 994, 2011),
"myeloid/lymphoid mixed-lineage leukemia gene" (MLL) and mutations
and overexpressions in numerous others. Studies are now being designed

focusing on different treatments depending on these mutations. ALso often
mutated rather than translocated in AML is DNMT3A, which makes the
prognosis more ominous (NEJM 363: 2424, 2010. Update on the genetics
of acute myeloid leukemia: NEJM 366: 1079, 2012
Be all this as it may, we begin making the distinction among the many variants of
AML from one another, and from ALL, by morphology and by the stains listed
earlier in the unit. AUER RODS are red-staining, rod-shaped crystalloids made of
primary granules (you can see them especially well if you stain for peroxidase). If
present, they prove that a blast is "myeloid" and not "lymphoid".
{12338} AML. Note promyelocyte in center.
{16245} blast, and not much else, M1
{13988} blasts, and not much else, M1
{23830} blast, * chloroacetate-esterase (+), M1
{13940} blast, * chloroacetate-esterase (+), M1
{23839} blast, M1; note nucleolus.
{23770} blasts with a few granules, M2
{13991} blasts with a few granules, M2
{16249} blast with Auer rod, M2
{12344} blast with Auer rod, M2 or maybe M3
{14010} blast with great Auer rods
{23776} blasts with lots of granules, M3
{13997} semi-monocyte like blasts, M4; note indented nucleus and gray cytoplasm
{10133} semi-monocyte like blasts, M4
{13937} non-specific esterase in M4
{23800} monocyte-like blasts in M5
{23949} erythroleukemia, M6. If you don't recognize the malignant cells as red-cell
precursors, please check out a histology book.
{14007} erythroleukemia, M6
{16273} erythroleukemia, M6, PAS-positive chunks
{16274} megakaryocytic blasts, M7. See the platelets budding?
{23812} megakaryocytic blasts, M7
{23821} megakaryocytic blasts, M7
{23818} megakaryocytic blasts, PAS-positive, M7

{46340} gingival involvement; this is common in M4 & M5
AML
M2
Acute myeloid leukemia

Tom Demark's Site
M4-Eo
With eosinophils
Wikimedia Commons
M3
AFIP
Wikimedia Commons
M2
AFIP
Wikimedia Commons
M2
AFIP
Wikimedia Commons
Auer rods in blasts

AFIP
Wikimedia Commons
M7 marrow
Tiny megakaryocytes
Wikimedia Commons
M1
AFIP
Wikimedia Commons
M6
AFIP
Wikimedia Commons
M0
AFIP
Wikimedia Commons
M6
Weird normoblasts in circulation
Wikimedia Commons
M5b
AFIP
Wikimedia Commons
M5a
AFIP
Wikimedia Commons
M4
AFIP
Wikimedia Commons
M5 -- electron micrograph
Dented nucleus
Wikimedia Commons
Untreated AML is fatal in a few weeks. Today, many AML patients have prolonged
survival and probably cures.
The prognosis depends primarily on the cytogenetics. The major papers
came from the early 2000's (Blood 96: 4075, 2000; Blood 100: 4325,
2002).
"Favorable prognosis" features t(8:21), t(15:17), del(9q) and/or
inv(16)/t(16;16).
"Adverse prognosis" features -5 / del(5q), -7 / del(7q), -17, -18,
inv(3)/t(3;3), t(6;9), t(9;22) and/or complicated cytogenetics (i.e.,
three or more unrelated abnormalities).
The others, including those with no chromosomal abnormalities, are
"intermediate prognosis."
Acute promyelocytic leukemia has the best response to treatment, with
98% adjusted six-year survival (Blood 110: 59, 2007).
A solid growth of myeloblasts is a CHLOROMA or GRANULOCYTIC SARCOMA
or NONLEUKEMIC MYELOID SARCOMA. This most malignant of solid tumors
turns green (Greek "chloros", as "chlorine" or "chlorophyll") on exposure to air
(why?) It's not common, but is treated as, and responds similarly to, AML, with a
somewhat better chance of cure (Cancer113: 1370, 2008).
TRANSIENT MYELOPROLIFERATIVE DISORDER ("transient leukemia") is

seen in the first weeks of life in around 10% of children with Down's trisomy 21.
The white count rises very high with many blasts (tending to be knobby, like
megakaryoblasts, or else to resemble minimally differentiated AML), and platelets
are likely to be high. There are usually not many blasts in the marrow, but there's
a tendency to involve the liver. It usually self-cures, but these children are at risk
for later acute myeloid / megakaryocytic leukemia (signature mutation in both
conditions in GATA1: Lancet 361: 1617, 2003; Blood 101: 4301, 2003;
Blood 102: 2960, 2003; J. Ped. 687, 2006; Blood 111: 2991, 2008); the
occasional child without Down's who gets transient myeloproliferative disorder in
the nursery is at similar risk.
THE MYELODYSPLASTIC SYNDROMES ("THE PRELEUKEMIAS", Carl Sagan's
disease): Mayo Clin. Proc. 70: 673, 1995; Am. J. Clin. Path. 119(S1): S-58, 2003.
This is a family of disorders in which there are problems in producing red cells,
granulocytes, and platelets. What has happened is that the normal precursor cell
that gives rise to all three has been replaced by a mutant clone.
Various karyotypic abnormalities have been described in the majority of
these people (Virch. Arch. A 421: 47, 1992).
* A 5q- predicts a good response to the thalidomide analogue
lenalodomide (NEJM 352: 549, 2005). * Isochromosome 17q, still
mysterious, is a common lone abnormality (Blood 94: 225, 1999); my late
mother, who received radiation as a child for osteomyelitis, had Ph'negative CML with just this signature; this is also a common known hit in
CML's progression to blast crisis.
Unlike most of the other neoplasms of white cells, several genes are
known in which point mutations confer an unfavorable prognosis
(NEJM 364: 2496, 2011).
* Subclassification is useful. The old FAB classification:
1. Refractory anemia (poor hemoglobinization,
too few red cells)
2. Refractory anemia with ringed sideroblasts
(>15% of nucleated red cells)
3. Refractory anemia with excess blasts (5-20% myeloblasts)
4. Refractory anemia with excess blasts in transformation (20-30%
myeloblasts)
5. Chronic myelocytic leukemia

Ask your hematologist what this all means. The World Health Organization
put out a new, more-elaborate clasification with criteria in 2002
(Blood 100: 2292, 2002) and tweaked it in 2008 with instructions on how
to distinguish cell types; leave it to us.
* Somatic mutation in the ringed-sideroblast form SF3B1:
NEJM 365: 1384, 2011).
Most patients are older adults, who sometimes are symptomatic. In the more
aggressive forms, death follows in a few years. Often these patients are
asymptomatic, and the problem is detected on routine screening.
As you would expect, this disease pattern has a propensity to transform into
acute myeloid leukemia, and does so in a large minority of cases.
<="" a="">
Myelodysplastic syndrome
Odd megakaryocyte / giant platelet
AFIP
CHRONIC MYELOID LEUKEMIA ("chronic myelogenous leukemia", "welldifferentiated granulocytic leukemia"): all about it Lancet 370: 1127, 2007
This is cancer of the myeloid stem cells in which there is overgrowth of normallymaturing myeloid cells
Radiation and exposure to chemicals (notably benzene) are known risk
factors. Most of the time, the disease seems to strike at random.
Patients typically have high counts of neutrophils and their precursors
(and almost always basophils). These are normal (functionally and
morphologically) for all intents and purposes, except that for some reason
they lack cytoplasmic alkaline phosphatase.
Preposterously high white counts (>100,000 or so) are likely to

result in white cells plugging important small vessels ("leukostatic
ischemia" of the brain, etc.)
While the spleen is likely to be enlarged in all the common
leukemias, chronic myeloid leukemia typically produces huge
spleens (down almost to the pubic hair). There will usually be some
little infarcts.
Occasional CML cases have predominance of basophils (itchy) or
eosinophils. Serum vitamin B12 is likely to be elevated due to
elevation of its binding protein; this can happen in other
myeloproliferative disorders.
{10769} CML, splenomegaly
{10763} CML, peripheral blood
{12359} CML
{23863} CML (note the basophil)
{23866} CML, leukocyte alkaline phosphatase stain (black; note the cells are not
stained black)
CML, liver
Great labels
Chronic granulocytic leukemia

Smear
WebPath Photo
Chronic myelogenous leukemia

Peripheral smear
KU Collection

Automated profile
WebPath Photo

Smear
WebPath Photo
Both granulocytic series and "benign" monocytes and erythroid

precursors bear the distinctive Philadelphia chromosome, a
translocation between chromosomes 9 and 22. This produces a
new gene (bcr/c-abl) which is a potent oncogene. Even
"Philadelphia negative" cases have this new gene.
Imatinib (STI571, Gleevic), which inhibits the kinase
produced by this new gene, and some others cancer
kinases, is one of the great successes of biotechnology

(NEJM 346 645, 2002; NEJM 347: 472, 2002; for blast crisis
Cancer 103: 2099, 2005).
* Dasatinib, a new and perhaps even-more-effective
inhibitor of BCR-ABL kinase: NEJM 362: 2260, 2010.
Nilotinib: NEJM 362: 2251, 2010.
{12371} Philadelphia chromosome
Philadelphia chromosome
WebPath Photo
The disease eventuates, after a few years, in BLAST CRISIS, with or

without (50%/50%) a previous accelerated phase. Blasts appear in the circulation
in large numbers (30% or more), and death follows quickly as they overwhelm
the marrow and body. This is not very treatable.
* Determining the clinical phase of CML by labs: Cancer 106: 1306, 2006.
"Accelerated phase" has begun when there are 10-29% blasts or >30%
blasts-and-promyelocytes in blood or marrow, persistently large spleen,
lots of basophils, big spleen or thrombocytosis unresponsive to therapy, or
thromcytopenia unresponsive to therapy.
{23869} CML, blast crisis
{12365} CML, blast crisis
Traditional chemotherapy with busulfan or hydroxyurea controls symptoms
during the chronic phase but neither speeds nor delays blast crisis.
Newer therapies (alpha-interferon with or without cytarabine) suppress the
leukemic clone and do prolong survival.
Historically, the only hope for a cure was allogenic bone marrow
transplantation. Watch the outcome of people treated long-term with the
new biotech products.
In around 30% of these cases, the blasts express lymphoid differentiation
(TdT, etc.) T-cell blast crisis: Am. J. Cln. Path. 107: 168, 1997.
WARNING: The following "myeloproliferative diseases" are all "tumors of the
multipotent myeloid stem cell", and can transform into one another (usually from
a mild one to a bad one):
polycythemia vera rubra
hemorrhagic ("essential") thrombocythemia

idiopathic "aplastic anemia"
"APLASTIC ANEMIA" (updates Ann. Int. Med. 136: 534, 2002; Lancet 365: 1647, 2005;
Blood 110: 1603, 2007)
This uncommon, dread illness features the disappearance of the precursors of
granulocytes, erythrocytes, and platelets. (It is poorly-named.)
In the 1990's, it became clear that most cases of aplastic anemia are caused by
T-cell-mediated attacks on the hematopoietic marrow. This explains why...
o a direct marrow / stem cell transplant from an identical twin never takes in
this disease;
o bone marrow / stem cell transplant after anti-thymocyte treatment is often
curative
o anti-thymocyte globulin plus cyclosporine restores marrow function to
most of these patients, most often permaently (JAMA 289: 1130, 2003)
o children with severe combined immunodeficiency who get graft-vs.-host
disease from a blood transfusion develop aplastic anemia
A key to the autoimmunity in aplastic anemia may have been discovered. Many
of these people have a clone of T-cells with mutated perforin (Blood 109: 5234,
2007), the same locus that's mutated in familial hemophagocytic
lymphohistiocytosis.
Other cases of acquired aplastic anemia seem to be the result of running out of
telomere length during aging. Some families and some individuals have less
telomerase than others (to oversimplify, but the impact seems real): NEJM 352:
1413, 2005.
Once uniformly fatal, the disease is now often controllable using marrow / stem
cell transplantation and/or immunosuppression (Blood 108: 2509, 2006).
Aplastic anemia
WebPath Photo
CHRONIC LYMPHOCYTIC LEUKEMIA ("CLL", "well-differentiated lymphocytic

leukemia"; "the liquid phase of well-differentiated lymphocytic lymphoma", etc.)
Lancet 371: 1017, 2008.
CLL / Melanoma
CLL
CLL
CLL and melanoma together in marrow

Pittsburgh Illustrated Case
Chronic lymphocytic leukemia

WebPath Photo

Peripheral smear
KU Collection

Classic drawing
Adami & McCrae, 1914
Chronic Lymphocytic Leukemia

B-CLL, good smudges

AFIP
Wikimedia Commons
CLL in liver
Great labels
This indolent cancer is a clone of B-cells that multiply slowly and do nothing
useful. The diagnosis is made by finding a count of 5000 or more lymphocytes of
appropriate phenotype circulating in the blood.
If the cells have nucleoli, it's more likely to be called B-cell prolymphocytic
leukemia and to behave more aggressively.
Often you can find growth centers (where the cells are slightly larger and
perhaps show nucleoli) in solid-phase well-differentiated lymphocytic
lymphoma; these have the same molecular markers as classic CLL.
"T-cell CLL", with a peripheral smear looking like CLL, is now renamed "Tcell prolymphocytic leukemia", an uncommon and aggressive disease.
There are of course T-cell receptor rearrangements, and most often
inv 14(q11;q32).
The one known risk factor is ataxia-telangiectasia (homozygotes, very likely

heterozygotes), and not surprisingly, this gene is often mutated in sporadic cases
(Lancet 353: 26, 1999.)
We know of no other specific risk factors, not even a history of radiation.
* CLL has a few common genetic markers but they also occur in other B-cell
neoplasms (Semin. Hem. 36: 171, 1999.
o del 13q14 is common; nobody knows the deleted anti-oncogene.
o t 11;14, the bcl1 gene meets IgG, is also common
o Many cases of B-cell CLL have trisomy 12 (you can see this in a variety of
other B-cell problems.)
o A few others have turned up recently. Stay tuned (NEJM 365: 2497, 2011).
The disease is often an incidental finding, when a CBC shows preposterously a
high lymphocyte count.
In many of these patients, vimentin is lacking in the cytoskeleton of the
neoplastic cells. Hence these cells are fragile on smears. Crushed CLL
cells are called "smudges", and it now seems that the higher percentage
of smudges, the better the prognosis (Mayo Clin. Proc. 82: 449, 2007).
{08784} CLL
{12389} CLL
{12404} CLL going bad (some blasts)
{12386} CLL with smudges
Paraneoplastic syndromes are more troublesome in this disease than in most
other leukemias.
Around 15% of patients get autoimmune hemolytic anemia.
The lymphocytes do somewhat suppress the heathy plasma cells, and the
patients have troubles with infections.
* A few percent develop a marker paraprotein, usually kappa IgM, or get
mu heavy chain disease.
Patients with anemia or thrombocytopenia from CLL survive around 2 years.
Asymptomatic people with CLL as an incidental finding generally survive more
than ten years.
A few percent of patients develop a diffuse large-cell lymphoma.

This is the rapidly-fatal RICHTER'S SYNDROME (NEJM 324: 1267,
1991); predisposing factors remain mysterious (Cancer 67: 997,
1991).
* Around 1% of CLL terminates as ALL ("blast crisis of CLL").
* PROLYMPHOCYTIC LEUKEMIA is an uncommon, aggressive
variant of CLL.
Chemotherapy for end-stage CLL: NEJM 330: 319, 1994. No miracles.
* It will not surprise you to learn that many people have "pre-CLL", or
"monoclonal B-cell lymphocytosis", detectable only by zealous search for
the mutated cells by pathologists. Each year there's only about 1% chance
of transformation (NEJM 359: 638, 2008; don't look for it Blood 119: 4358,
2012).
HAIRY CELL LEUKEMIA (Mayo Clin. Proc. 87: 67, 2012)
This distinctive leukemia is named for the many hair-like projections on its
surface.
It was of unknown histogenesis (* confusing surface markers) until its
molecular genetics and antigenic markers established it as a B-cell
neoplasm" (Blood 104: 250, 2004; Am. J. Clin. Path. 125: 251, 2006).
Patients have circulating "hairy lymphocytes"; usually have big spleens
and are sometimes anemic, neutropenic, and/or thrombocytopenic.
Treatment is often unnecessary or can be delayed until the disease gets
symptomatic. Bone marrow aspiration is likely to be unsuccessful (dry tap)
"because the cellular hairs tangle with one another" (* more likely,
because TGF-beta1 from the tumor induces extra reticulin fibrosis: J. Clin.
Inv. 113: 676, 2004.
The hairs are quite distinctive, and the diagnosis is clinched by the finding of
TARTRATE-RESISTANT ACID PHOSPHATASE (TRAP) in these cells.
* Future pathologists: The other "hairy" B-cell neoplasm is "lymphoma with
villous lymphocytes", usually in the spleen. The distinctions are subtle, and
the immunotyping of tumors is often variable. Arch. Path. Lab. Med. 124:
1710, 2000.
The genetics of hairy cell leukemia are finally being discovered. A trademark
(probably driver) BRAF mutation (to the familiar BRAF V600E known from other
tumors) has just been found in each of 48 hairy-cell patients (NEJM 364: 2305,
2011; assays Blood 119: 3151, 2012; Am. J. Clin. Path. 138: 153, 2012).
During the 20th century, the only treatment for this disease was splenectomy,
which helped. Today, most patients get a lasting remission after taking a course
of cladribine (2-chlorodeoxyadenosine, 2-CdA) or pentostatin (deoxycoformycin,
a purine analogue that's a naturally-occurring antibiotic). Update Cancer 104:
2442, 2005; Blood 109: 3672, 2007. These can be repeated is required if the
disease recurs (which it often doesn't), and there are additional treatments that
give results if the disease becomes resistant.
* There is a variant that features mutated p53 instead of BRAF V600# and is
much more common in men and is harder to treat. There's also a Japanese
variant that responds very well to cladribine.
{23872} hairy cell leukemia
{10766} hairy cell leukemia, spleen (top; normal at bottom)
{16543} hairy cell leukemia, TRAP stain (red)
{23881} hairy cell leukemia, bone marrow biopsy (trust me)
{42117} big spleen in hairy cell leukemia, foot ruler
Hairy cell leukemia
Peripheral smear
KU Collection
POLYCYTHEMIA VERA ("Osler's polycythemia", "P. V. rubra", etc.; Mayo Clin. Proc. 78:
174, 2003; Arch. Path. Lab. Med. 130: 1126, 2006)
By convention, POLYCYTHEMIA (a better synonym is ERYTHROCYTOSIS)
describes an abnormally high hemoglobin. Classification:
ABSOLUTE POLYCYTHEMIA (i.e., increased circulating red cell mass):
PRIMARY POLYCYTHEMIA (i.e., the main problem is with the red
cells)
Polycythemia vera rubra
NOTE: Cancer of the normoblasts (i.e., AML-M6) isn't
considered a polycythemia
SECONDARY POLYCYTHEMIA (i.e., the main problem is

elsewhere)
Effective renal arterial hypoxia
Emphysema
Sleep apnea
Tetralogy of Fallot
Hemoglobins with too much oxygen affinity
Etc., etc.
For a first-person story of injectable bioengineered
erythropoietin and bicycle racing, including how
athletes beat the tests by infusing huge amounts of
normal saline by vein moments before having their
hematocrits checked, see Sci. Am. 298(4): 82, 2008.
Genetic errors in erythropoietin production or sensitivity
("familial erythrocytosis", for example HIF2A: NEJM 358:
162, 2008)
Erythropoietin-producing tumors
Renal cell carcinoma
* Hepatocellular carcinoma
* Cerebellar hemangioblastoma (?!)
Anabolic steroid users
After kidney transplant (over-zealous proximal tubule
produces erythropoietin)
Altitude (above about 10,000 feet for a long time? Expect
problems. Stroke risk: Stroke 26: 562, 1995. Pulmonary vein
thrombosis: Hum. Path. 21: 601, 1990.
"Primary familial polycythemia" / "congenital primary
erythrocytosis" (truncated erythropoietin receptor stuck in the
"on" position; (J. Clin. Invest. 102: 124, 1999)
* Erythropoietin-dependent polycythemias (altitude, posttransplant) can be ameliorated using ACE inhibitors, which is
puzzling: Lancet 359: 663, 2002.
RELATIVE POLYCYTHEMIA (i.e., dehydration)
Polycythemia vera is a proliferation of stem cells (again, the common precursors
of red cells, granulocytes, and megakaryocytes). This time, they are very
erythropoietin-sensitive and mostly mature into red cells.
The cells are the common ancestors of red cells, neutrophils, and
megakaryocytes. Over the course of years, these stem cells replace the
normal stem cells of the marrow. Their progeny, however, are fully
functional. (Neutrophils even have normal alkaline phosphatase levels.)
In addition to a high red cell count, white cells and platelets are likely to be
high.
On biopsy, expect to see a very hypercellular marrow, with all cell lineages
increased. In the late stages, there is often marrow fibrosis ("burned out
PVR", "postpolycythemic phase", * PDGF effect?) or replacement by
blasts (transformation to acute myelogenous leukemia -- still no good
treatment Cancer 104: 1032, 2005).
The trademark mutation in JAK2 (NEJM 356: 444, 2007) that is usually
present (* JAK2V617F) is now famous. Mouse with the mutation -Blood 120: 166, 2012.
JAK2 is central to polycythemia vera, essential thrombocytosis, and
primary myelofibrosis, as it is the tyrosine kinase for the cytokine
receptors that stimulate production of red cells (polycythemia vera),
megakaryocytes (essential thrombocytosis), and neutrophils
(primary myelofibrosis), explaining the overlap and transformations.
There are always additional mutations in other genes. Some
germline alleles are much more likely than others to mutate into the
really bad allele (Nat. Genet. 41: 385 & 450 & 455 & 446, 2009).
The new JAK2 inhibitors are now (2011) widely used.
This is a disease of older middle-age. Until the last stages, patients are troubled
primarily by the increased volume of hyperviscous blood.
This causes congestion of most organs ("the plethoric face", etc.)
More troubling, the stasis of gooey blood in the veins promotes clotting.
Or distended veins can rupture (GI bleeding, hemorrhagic stroke).

Eventually these patients get platelet problems, too, which does not help
the bleeding tendency.
Minor mystery of medicine: Itching after taking a hot shower is very
suggestive of PVR.
The mainstay of treatment for polycythemia vera is regular phlebotomy, to
keep the red cell count down.
These patients' survival curves are nearly as good as normal folks.
For all three of the JAK2 diseases, the major killer is the tendency
of the disease to turn into acute myelogenous leukemia.
The once-popular practice of giving these patients radioactive
phosphorus resulted in a greatly increased rate of transformation to
acute leukemia, turning a not-so-bad, easy-to-control disease into a
lethal, untreatable one. Later, the same thing happened with trials
of chemotherapy.
The traditional criteria for the diagnosis of PVR:
A1... Increased RBC mass (>=36 mL/kg; >=32 mL/kg; the math comes to
a hematocrit of 52 for a man, 46 for a woman)
A2... Normal arterial PO2
A3... Splenomegaly
B1... Platelets greater than 400,000/L
B2... WBC >=12,000/L
B3... Leukocyte alkaline phosphatase over 100 in the absence of evidence
of infection
B4... Elevated serum vitamin B12.
Make the diagnosis if:
(1) You have A1 + A2 + A3, or
(2) A1 + A2 + any two B's.
In 2007, the World Health Organization suggested requiring two major
criteria (hemoglobin >18.5 g/dL;for men, >16.5 g/dL for women, plus a
functionally active JAK2 mutation. Minor criteria are one of these -characteristic bone marrow morphology, too-low serum erythropoietin, and
the ability of red cell colonies to grow in tissue culture without
erythropoietin.
* Thrombosis, the most troublesome aspect of this disease, seems to be much
less of a problem if patients are simply given low-dose aspirin (NEJM 350: 114,
2004).
Polycythemia
PRIMARY MYELOFIBROSIS ("myelofibrosis with myeloid metaplasia";

"agnogenic myeloid metaplasia"; "myelosclerosis"); JAMA 303: 2513, 2010; Mayo Clin.
Proc. 87: 25, 2012
Primary myelofibrosis is a proliferation of neoplastic stem cells in the bone
marrow (which merely becomes hypercellular) and the red pulp of the spleen
(which enlarges greatly). For some reason, the marrow tends to develop
increased reticulin / collagenize, "burn out" and become fibrotic.
* The WHO criteria require (1) megakaryocyte proliferation and atypia and
usually fibrosis of the marrow; (2) not being one of the other recognizable
myeloprolifeative diseases; (3) some clonal marker such as JAK2 or one
of the others or at least not chronic inflammation or cancer; (4) Two of the
following: leukoerythroblastic smear; increased serum LDH; anemia;
palpable spelen. These are going to be discarded when the molecular
signatures are better-defined.
Historically, ionizing radiation and benzene exposure are known risk
factors.
We know it's tumor since there's a group of common translocations;
however, which ones are present doesn't impact prognosis at least much
(Cancer 107: 2801, 2006). Most now seem to have mutated JAK2, and it
seems likely this will soon define the disease.
By definition, BCR-ABL (t(9;22), Philadelphia chromosome) is
absent.
As in polycythemia vera, the cells that enter the blood are fully functional.
This time, there is no tendency to over-produce red cells; neutrophils may
be super-abundant and "left-shifted" (Philadelphia-chromosome negative,
of course), or there may be neutropenia, or the WBC may be normal.
Platelets are unaffected or even increased (until maybe very late).
This is a disease of older adults. Patients are most likely to be troubled by

feeling full after they've eaten just a little (why?).
Examine the peripheral smear. Red cells made in the spleen tend to be
teardrop-shaped (one form of "poikilocyte"), and nucleated red-cell
precursors from the spleen are more likely to escape into the circulating
blood. Leukocyte alkaline phosphatase is likely to be high.
* The year 2010 saw the first medication effective for primary
myelofibrosis, an inhibitor of JAK1/JAK2, whether or not the latter bears
the trademark mutation (NEJM 363: 1117, 2010). Ruxolitinib, a JAK1 and
JAK2 inhibitor for myelofibrosis: NEJM 366: 787 & 799, 2012).
{12302} teardrop reds
NOTE: The important term LEUKOERYTHROBLASTIC SMEAR refers to
the presence in the bloodstream of young red cells and immature
granulocytes. You'll see this when they are "being pushed out of their
place of origin too fast":
bone marrow infiltration
metastatic carcinoma
lymphoma
leukemia
bone marrow hyperplasia / extramedullary hematopoiesis
severe hemolysis, etc.
After this process has been underway for several years, the bone marrow
undergoes dense fibrosis. Long mysterious, it is now clear that the marrow
fibroblasts are responding to over-production of PDGF (platelet-derived growth
factor) and * transforming growth factor-beta produced by abnormal
megakaryocytic cells.
{13799} myelofibrosis, marrow core biopsy
{24788} myelofibrosis, marrow core biopsy
{13802} myelofibrosis, reticulin stain
Patients with "myeloid metaplasia / myelofibrosis" ultimately die of
cytopenia or transformation to acute leukemia. Not surprisingly, those that
eventually transform into acute leukemia tend to have a few circulating

blasts at diagnosis (Cancer 112: 2726, 2008).
The old term "agnogenic" means "of unknown cause" (i.e., it's a synonym for
"idiopathic"; compare "agnostic").
* Diagnosticians: Unexplained myelofibrosis WITHOUT splenomegaly
suggests M7 AML, burning-out CML, or burned-out polycythemia vera;
look also for carcinoma cells.
* Autoimmune myelofibrosis may result from lupus or "just happen"; future
pathologists recognize it by the absence of any abnormalities of the
remaining marrow cells, and clusters of lymphocytes. Am. J. Clin.
Path. 116: 211, 2001.
PLASMA CELL MYELOMA ("multiple myeloma", "malignant plasmacytoma") NEJM 336:
1657, 1997; Lancet 363: 875, 2004; for pathologists dealing with the difficult diagnostic
cases Am. J. Clin. Path. 136: 168, 2011 (let us worry about them).
This is cancer of the plasma cells (i.e., cancer of B-cells that are differentiated
enough to secrete an immunoglobulin and/or a light chain (kappa or lambda,
though of course never both), or at least to look like plasma cells).
Myeloma is only slightly less common than leukemia or lymphoma. The typical
patient is in his or her fifties.
The etiology is obscure, and the disease seems to strike at random.
* About 80% have myeloma patients have a translocation involving IgH
and any of several oncogenes; this is also usual in "benign monoclonal
gammopathy" (update Am. J. Clin. Path. 132: 361, 2009).
* Blacks have a slightly increased rate.
The term "multiple myeloma" comes from its tendency to make multiple holes
("lytic lesions") in the bone marrow ("myelo-") and nearby cortex. The effect is
mediated, at least in part, by lymphotoxin (TNF-beta). Cancer of plasma cells
always involves bone, but only about half of cases feature real "punched-out" xray lesions. The remaining patients have diffuse disease and suffer precocious
osteoporosis. I have never used the term "multiple myeloma" and urged others
not to do so either, and it finally (2008) seems to be going out of use.
* Future clinicians / hardcore pathology students: Here are your CRITERIA FOR THE
DIAGNOSIS OF PLASMA CELL MYELOMA!
A. Major criteria
Plasmacytoma on tissue biopsy
>30% plasma cells in bone marrow
IgG spike >3.5 gm/dL or IgA spike >2.0 gm/dL or kappa or lambda light chain
excretion >1 gm/day
B. Minor criteria
10-30% plasma cells in the bone marrow
Monoclonal immunoglobulin spike smaller than the above
Lytic bone lesions
Reduced normal immunoglobulins <50% of normal
PLASMA CELL MYELOMA: Two majors, OR one major and one minor OR three minors
including the first two.
INDOLENT MYELOMA: More than 30% bone marrow plasma cells, IgG spike <7 gm/dL
or IgA spike <s;5 gm/dL; fewer than three lytic lesions; no anemia, hypercalcemia, or
renal involvement
SMOLDERING MYELOMA: 10-30% plasma cells in the marrow, major criterion spike
present, no lytic lesions; no anemia, hypercalcemia, or renal involvement
MONOCLONAL GAMMOPATHY OF UNCERTAIN SIGNIFICANCE: <10% plasma cells in
the marrow (but who wants to check?); spike present but too small for major criterion; no
lytic bone lesions no anemia, hypercalcemia, or renal involvement
{08462} bony lesions of myeloma (skull and spine)

{27327} bony lesions of myeloma (skull)
{13769} skull lesions of myeloma
{10760} skull lesions of myeloma
{10754} bone lesions of myeloma
{10757} osteoporosis of myeloma
{46197} femur lesions in myeloma
{46198} rib lesions in myeloma
{27329} spike, probably monoclonal gammopathy of uncertain significance, since
normal albumin and gamma seem not to be suppressed
Plasma cell myeloma
Marrow smear
Wikimedia Commons
Plasma cell myeloma

Bone marrow smear
KU Collection
Myeloma skull
Myeloma skull
WebPath Photo
WebPath Photo
Myeloma marrow
Myeloma cells, section
WebPath Photo
WebPath Photo
Myeloma cells, section
Myeloma cells, smear
WebPath Photo
WebPath Photo
The monoclonal protein (immunoglobulin or chain) produced by an abnormal

clone of multiple myeloma cells is called the M-PROTEIN.
If there's a complete antibody, you'll see it on serum protein
electrophoresis.
Free light chains may be produced along with, or instead of, a complete
immunoglobulin. They pass easily through the glomerular basement
membrane, so you will probably not find them in the bloodstream if the
kidneys are working. Instead, they accumulate in the urine, where they are
called BENCE-JONES PROTEIN. About 2/3 of myeloma patients produce
Bence-Jones protein.
Later on, Bence-Jones protein plugs up the renal tubules, and

contributes to "myeloma kidney", which we'll study in the "renal
pathology" section.
You remember that plasma cell myeloma is an important cause of
amyloidosis AL, which doesn't help renal function, either.
Here's a breakdown on types of M-proteins:
55%...IgG
25%...IgA
1%... IgE, IgD, or IgM monomer
18%... Bence-Jones protein only
1%... no M-protein.
A PARAPROTEIN is an abundant, useless, monoclonal protein in the
bloodstream. All M-proteins are paraproteins; you'll meet others. Lots of an
M-protein will produce rouleaux formation; we'll talk more about this in
"Clinical Pathology".
NOTE: As a rule, plasma cell myeloma does not make IgM pentamers.
Waldenstrom's does this, and you won't see the typical bone changes.
To make the diagnosis, you will want to find an overabundance (>15% or so) or
sheets of plasma cells (typical or weird-looking) on bone marrow.
{16554} plasma cell myeloma, cells
{16556} plasma cell myeloma, cells
{13772} plasma cell myeloma, marrow aspirate
{27330} plasma cell myeloma, marrow aspirate
{13775} plasma cell myeloma, bone marrow section
{10751} * "grape cell"
{42054} * "flame cell" (named for its staining properties)
Normally, only around 3% of bone marrow cells are plasma cells, but
whenever there is widespread B-cell activation, their number can increase
substantially.
* Future pathologists: In reactive plasmacytic disorders, plasma cells
encircle the vessels. In plasma cell myeloma, you'll probably find plasma
cells encircling fat cells.
Patients are now often getting apparent cures. Paraneoplastic problems are the
greatest problem in plasma cell myeloma. Be alert for:
o osteoporosis
o pathologic fractures
o hypercalcemia (several mechanisms)
o infections (myeloma cells suppress normal plasma cells)
o anemia and neutropenia (crowding out of normal cells)
o kidney failure (precipitate and/or amyloid)
o * myeloma neuropathy (infiltration, compression, vincristine)
o amyloidosis B (10% of myeloma patients; cardiac problems)
o plasma cell leukemia (a terminal stage)
{17273} myeloma kidney, Bence-Jones casts with foreign body reaction
{17274} myeloma kidney, Bence-Jones casts with foreign body reaction
The tumor generally excites no fibrous or osteoblastic response. At autopsy, the
tumor masses (if distinguishable) look and feel like reddish-gray jelly.
Prognosis is much better, nowadays due both to chemotherapy and to
bisphosphonate management of bone disease. The ongoing "total therapy"
studies is reporting prolonged remissions (cures?) in many patients (updates
Blood 112: 3115, 2008; Cancer 133: 355, 2008; Cancer 112: 2720, 2008). The
monoclonal bortezomib (proteasome inhibitor) is very promising (updates
Cancer 110: 1042, 2007; Cancer 112: 1529, 2008). Thalidomide for refractory
myeloma NEJM 341: 1565, 1999. This is now mainstream.
The disease often simply smolders, and if there are no symptoms,
perhaps it's best just to give bisphosphonates prophylactically
(Cancer 113: 1588, 2008).
OTHER PLASMA-CELL PROBLEMS ("plasma cell dyscrasias", an archaic term)
There are a variety of other MONOCLONAL PLASMA CELL PROLIFERATIONS.
We already looked at WALDENSTROM'S MACROGLOBULINEMIA and
the HEAVY-CHAIN DISEASES under "non-Hodgkin's lymphomas". These
are cancers of small lymphocytes with "plasmacytoid" features.
SOLITARY PLASMACYTOMAS may appear benign grossly and
microscopically, and they may or may not produce immunoglobulins.
Those in bone almost always recur as plasma cell myeloma.
Those in extra-osseous sites ("plasmacytic lymphoma") may often

be resected for cure.
MONOCLONAL GAMMOPATHY OF UNCERTAIN SIGNIFICANCE

("MGUS", the old "benign monoclonal gammopathy") affects maybe 3-5%
of older adults (prevalence NEJM354: 1362, 2006; old texts are wrong to
suggest it is less common than plasma cell myeloma).
This is best considered a benign, disseminated proliferation of
plasma cells with some potential to transform into malignancy.
The tumor cells produce a single, complete immunoglobulin
(usually IgG) that may be detected on serum protein
electrophoresis.
Maybe 1/4 of these people eventually go on to get sick from plasma
cell myeloma, amyloidosis AL, or macroglobulinemia (Mayo Clin.
Proc. 68: 26, 1993); newer work gives the rate at about 1%/year
(NEJM 346: 564, 2002)
AMYLOIDOSIS B may arise in this setting, and probably all noncancer-related amyloidosis AL cases have a hyperactive clone of
plasma cells.
Smoldering myeloma (NEJM 356: 2582, 2007) features 10% or
more plasma cells in the marrow, and an M-protein of myeloma
proportions, but no signs of end-organ damage. It often, but not
always, proceeds to myeloma over the years.
MGUS
* POEMS may arise: polyneuropathy, organomegaly,

endocrinopathy (thyroid/gonads), monoclonal gammopathy (usually
IgA-lambda), and skin changes. The molecular etiology remains
elusive (Am. J. Resp. Crit. Care Med. 157: 907, 1998).
* CRYOGLOBULINEMIA TYPE I is a monoclonal immunoglobulin

of marginal solubility. More about this in "Clinical Pathology"!
Follow these people up for decades, and around one in four will get
some kind of serious gammopathy (Mayo Clin. Proc. 68: 26, 1993).
POLYCLONAL ACTIVATION OF PLASMA CELLS ("polyclonal gammopathy") is

a common finding in clinical medicine. Situations worth remembering:
o really bad, long-term infections
o lupus, rheumatoid arthritis, other "autoimmune"
o liver disease
o AIDS
THE LANGERHANS CELL HISTIOCYTOSIS FAMILY ("LCH", "Histiocytosis X",
"disseminated histiocytosis"; * R&F "differentiated histiocytosis" is a typo); review for
clinicians J. Ped. 127: 1, 1995; Cancer 85: 2278, 1999.
A group (probably a continuum) of lesions that are probably honest-to-goodness

tumors of Langerhans-type histiocytes, a class of dendritic macrophages.
Langerhans cells in health and disease are characterized by intracellular

BIRBECK GRANULES ("histiocytosis X bodies"), pentalaminar tennisracket shaped structures of unknown significance.
* Langerin, a lectin specific to stimulated Langerhans cells:
Immunity 12: 71, 2000.
{09095} Birbeck granules
{09097} Birbeck granules
Histiocytosis X
Histiocytosis X with Birbeck granules
Eosinophilic granuloma of the lung

In tissue, you will probably see a range of cells from "blasts" to welldifferentiated Langerhans cells.
The former claim that histiocytosis X is "polyclonal" probably
resulted from confusion of the tumor cells with non-neoplastic
inflammatory cells that had entered the tumor. By the mid-1990's
we knew the disease was clonal, hence a real neoplasm
(NEJM 331: 154, 1994; Br. Med. J. 310: 74, 1995; Lancet 344:
1717, 1994).
Future pathologists: Histiocytosis X and the dendritic macrophages from
which it derives stain for CD1/T6. They also stain with S-100.
The old names are passing out of use, but you might perhaps see the
syndromes:
LETTERER-SIWE DISEASE ("acute disseminated histiocytosis",
"multifocal multisystem LCH") affects small children and involves most of
the body's organs. These children are now often cured with elaborate
chemotherapy.
{23392} Letterer-Siwe disease. Weird histiocytes ("coffee-bean nuclei, even"). Trust me.
EOSINOPHILIC GRANULOMA ("unifocall LCH"; "granuloma" is an
unfortunate misnomer) causes solitary bone lesions in young people. The
histiocytes have coffee-bean nuclei and are admixed with eosinophils.

Modest treatment generally is curative. There is a variant that affects the
lungs of smokers.
{13688} eosinophilic granuloma
{13691} eosinophilic granuloma
{09043} eosinophilic granuloma, EM, coffee-bean nucleus (left) and eosinophil (right)
HAND-SCHLLER-CHRISTIAN DISEASE ("multifocal unisystem LCH",
affects the skull bones and perhaps -- look for diabetes insipidus,
proptosis, lytic skull lesions, fever, and rash. It's intermediate between the
other two in severity.
And not in the classic scheme, but recognized now thanks to improved
pathology techniques, CUTANEOUS LANGERHANS CELL
HISTIOCYTOSIS, a disease of infants that often self-cures (Arch.
Derm. 146: 149, 2010).
{10481} Hand-Schller-Christian disease. Weird histiocytes. Trust me.
{21779} skull in Hand-Schller-Christian disease
* CHESTER-ERDHEIM DISEASE ("lipid granulomatosis"; "cholesterol granulomatosis")
is a rare illness in which lipid-laden non-dendritic-type macrophages infiltrate the
tissues. Thankfully rare, it is clonal and seems to be a neoplasm (Hum. Path. 30: 1093,
1999).
THE SPLEEN AND ITS PROBLEMS
* Every man has his own ways of courting the female sex. I should not, myself, choose
to do it with photographs of spleens, diseased or otherwise.
-- Agatha Christie, "The Moving Finger"
Normal spleen
WebPath Photo
Big spleen
Briish
ITP case
The healthy spleen weighs 50-250 gm or less. You remember that the cells right
around the arteries in the white pulp are T-cells, that there are likely to be B-cell
nodules, and that the Littoral cells lining the sinuses express both macrophage
and endothelial markers.
The spleen almost never gets biopsied, as it is so likely to rupture.
SPLENOMEGALY must be substantial (800 gm or so) to be palpable. Causes

worth remembering:
INFECTIONS
Malaria (huge spleens)
Infectious mononucleosis family (see above)
Bacterial endocarditis (don't miss this one)
Most other bad infections (NOTE: A "septic spleen" feels soft, unlike
most of the other big spleens)
CONGESTION (if longstanding, becomes "fibrocongestive")
Cirrhosis
Right-sided heart failure
Splenic vein thrombosis
Sludging of red cells
Sicklers
Polycythemia vera
Waldenstrom's
Others
Others
DISEASES OF WHITE CELLS
Chronic myelogenous leukemia (huge spleens)
Primary myelofibrosis (huge spleens)
Hairy cell leukemia (very large spleens)
All the other ones
SPLENIC OVER-DESTRUCTION OF BLOOD CELLS
Hereditary spherocytosis
Hemoglobinopathies and bad thalassemia
Immune hemolytic anemia
Immune thrombocytopenic purpura
IMMUNOREACTIVE HYPERPLASIA
Lupus
Rheumatoid arthritis
Graft rejection
STORAGE DISEASES (huge spleen)
Gaucher's (very big, wadded-kleenex macrophages)
Niemann-Pick's (very big, foamy macrophages)
Hunter's
Hurler's
SARCOIDOSIS
AMYLOIDOSIS (sago, lard)
HYPERSPLENISM is said to be present when an enlarged spleen destroys
normal formed elements of blood too readily. The three causes you'll probably
see are: (1) cirrhosis; (2) rheumatoid arthritis (the serious "Felty's syndrome"),
and (3) Gaucher's disease. It's also one cause of thrombocytopenia in some
leukemia and lymphoma patients.
{00239} Gaucher's disease, spleen
{09864} Gaucher's disease, spleen
{16216} Gaucher's disease, watered-silk ("wadded kleenex") cell from spleen
The only proof that hypersplenism was the problem is that the blood
counts get better when the spleen is removed.
Big spleen
From a cirrhotic
WebPath Photo
ACCESSORY SPLEENS (one or more) are present somewhere in the abdomen

in about 25% of autopsies. If you need a splenectomy for a medical disease (i.e.,
immune thrombocytopenic purpura, hereditary spherocytosis), you must hope
that your surgeon does not overlook a large accessory spleen.
Reed-Sternberg cells
WebPath Photo
Big spleen
Some myeloproliferative disorder
WebPath Photo
Splenomegaly
Urbana Atlas of Pathology
SEPTIC SPLEEN ("nonspecific acute splenitis") is typical of serious bacterial

infections. Loaded with polys and abnormally soft, the old gourmet pathologists
made the comparison to "tomato paste", which is very much resembles.
Exactly why the spleen becomes like this in deaths from sepsis, and never
anything else, remains as mysterious as sepsis itself. You'll see profound
loss of the B-cells and T-helper cells around the white pulp, and apoptosis
of the dendritic reticular cells that maintain the structure of the spleen
(NEJM 348: 138, 2003).
HYPERPLASTIC SPLEEN usually means large germinal follicles in the white
pulp. Think of systemic autoimmune disease, infectious mononucleosis, graft
rejection, etc., etc.
In INFECTIOUS MONONUCLEOSIS, the spleen also becomes infiltrated
with activated T-cells that give a malignant appearance. The capsule is
stretched and infiltrated, making it more fragile. You're unlikely to see such
a spleen unless it is removed because of rupture (sports, overzealous
physical exam).
* Future pathologists: Telling hyperplasias from lymphomas in the spleen
is one of your toughest calls. For help, see Am. J. Clin. Path. 99: 486,
1993.
INFARCTS are common in the spleen, and may result from atheroembolization
(the twisty splenic artery is the most severely affected in the body), left-sided
endocarditis, or infiltrative disease.
Infarcts
WebPath Photo
* Necrosis in a blood-bloated spleen (typically, in sicklers) is likely to

produce iron- and calcium-rich scars called GAMNA-GANDY BODIES.
The "autosplenectomized" spleen of an older sickle-cell disease patient is
mostly composed of such scars.
Sickle cell disease
Autosplenectomy
WebPath Photo
PRIMARY NEOPLASMS of the spleen are uncommon. Benign tumors are

almost never of any importance. Any lymphoma or endothelial neoplasm can
arise here. METASTASES to the spleen are expected in most leukemias and
Hodgkin's and non-Hodgkin's lymphomas, but carcinomas and sarcomas very
seldom grow in the spleen.
RUPTURED SPLEEN results from blows (hard if you're healthy, lighter blows
suffice for those with infectious mononucleosis; remember CPR as a cause Br.
Med. J. 322: 480, 2001). Intraperitoneal hemorrhage results in a trip to surgery. If
a lot of pulp escapes into the peritoneal cavity, the patient may heal with
hundreds of mini-spleens over the peritoneal cavity (SPLENOSIS).
You remember the difference between sections and smears, right?
* SLICE OF LIFE REVIEW: BLOOD CELLS

10110 ff blood
{10766} leukemia, hairy cell and normal
{12275} anemia, iron deficiency; normal
{13715} lymphocyte, normal
{13868} red blood cell, normal blood
{13910} red blood cell, normal
{14702} polymorphonuclear leukocyte, normal
{14708} eosinophil, normal
{14709} eosinophil, normal
{14710} basophil, normal
{14711} basophil, normal
{14712} monocyte, normal
{14716} lymphocyte, large
{14717} lymphocyte, large
{14722} reticulocytes, normal

{14723} reticulocytes, normal
{14724} red blood cell, abnormal
{14725} red blood cell, abnormal
{14726} platelets, normal
{14727} platelets, normal
{14728} pronormoblast, normal
{14729} pronormoblast, normal
{14730} basophilic normoblast, normal
{14731} basophilic normoblast, normal
{14732} normoblast
{14733} normoblast
{14734} polymorphonuclear leukocyte & * lymphocyte
{14735} polymorphonuclear leukocyte & * lymphocyte
{14736} normoblast series
{14737} normoblast series labelled
{14738} myelocyte, normal
{14740} * granulocyte series
{14741} * granulocyte series (labelled)
{14742} myelocyte, band form
{14743} myelocyte, band form
{14751} myelocyte & megakaryocyte, normal
{14752} myelocyte & megakaryocyte, normal
{15193} plasma cell, #23
{15205} thymus, adult
{15564} thymus, normal
{16175} red blood cell, normal
{20783} monocyte
{20784} platelets, circulating blood
{20785} monocyte
{46538} red cell, normal
* SLICE OF LIFE REVIEW: LYMPHOID ORGANS

{11750} spleen, normal
{11753} lymph node, normal
{11805} spleen, normal unfixed
{14753} thymus, human fetal
{14754} thymus, human fetal
{14755} thymus, juvenile
{14761} hassall's corpuscles
{14765} thymus (septum)
{14766} thymus (septum)
{14769} spleen, pulp
{14770} spleen, pulp
{14771} spleen (trabeculae), normal
{14772} spleen (trabeculae), normal
{14773} spleen (trabecular artery), normal
{14774} spleen (germinal center), normal
{14775} spleen (germinal center), normal
{14776} spleen (venous sinus), normal
{14777} spleen (venous sinus), normal
{14778} spleen (scanning em)
{14779} spleen (scanning em)
{14782} lymph node cortex, normal
{14783} lymph node cortex, normal
{14784} lymph node, medulla
{15189} lymph node and subcapsular sinus, #23
{15190} lymph node, primary nodule
{15191} lymph node, germinal center
{15194} spleen, #24
{15195} spleen, * red pulp and white pulp

{15196} spleen, central artery
{15197} spleen, central artery and germinal cent
{15198} spleen, trabeculae
{15199} thymus, #25
{15200} thymus, cortex
{15201} thymus, hassall's corpuscle
{15202} thymus, medulla
{15203} thymus, epithelial reticular cell
{20799} lymph node, overview
{20800} lymph node, cortex
{20802} lymph node, subcapsular sinus
{20803} lymph node, secondary nodule
{20804} lymph node, primary nodule
{20805} spleen, normal histology
{20806} spleen, red pulp
{20807} spleen, white pulp
{20808} spleen, central artery
{20809} spleen, red pulp
{20810} spleen, secondary nodule
{20811} spleen, trabecula
{20812} thymus, overview
{20813} thymus, medulla
{20814} thymus, cortex
{20815} thymus, hassall's corpuscle
{20827} tonsil, palatine
{20828} tonsil, pharyngeal
{36350} lymph node, normal cytology
{36353} lymph node, normal cytology
x
Pri

White Cell Disorders I

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WHITE CELL DISORDERS I & II

White Cell Disorders I & II

QUIZBANK -- Blood & Lymph #'s 133-139, 178-333

In discussing diseases that affect numbers of white blood cells in the

A good "normal range" for total white count is 4000-11000/cu mcL.

are clonal (IgH Gene Clonality for B-cells, TcR-gamma

* There has been talk of diagnosing and classifying lymphomas

Eosinophil and lymphocyte

White Cell Quiz!

Lymphocyte and neutrophil

NEUTROPENIA: A low absolute neutrophil count in the peripheral blood

Space-occupying lesions ("myelophthisic anemias")

stage. The usual cause of very low absolute

infection (i.e., neutrophil counts of 1000 or less, often much less;

o widespread tissue necrosis from any cause

NOTE: LEFT SHIFT refers to presence of immature white cells

visceral larva migrans (dog and cat roundworms)

* mastocytosis with eosinophilia (molecular signature known, response

{14099} eosinophilic leukocytes (buffy coat)

"transient stress lymphocytosis" (absolute counts 4000-10000; on the

NOTE: INFECTIOUS MONONUCLEOSIS is a family of diseases

immunoblasts -- big cells, bit nucleoli, plenty of blue-staining

We have already mentioned CHRONIC GRANULOMATOUS DISEASE,

most of the rest. Don't miss it.

You recall CHEDIAK-HIGASHI SYNDROME, in which there are several

Hem. 66: 59, 1981. "Look! This clinically healthy patient

{16208} Pelger-Huet, one dose

* ALDER-REILLY ANOMALY merely refers to large,

NORMAL LYMPH NODE ANATOMY

syphilis (plasma cells in the medulla, mini-granulomas,

PARACORTICAL LYMPHOID HYPERPLASIA (i.e., lots and lots of

cytoplasm, plenty of necrosis and mitotic figures; see any

* hemolysis (Coombs-positive, or macrophages

* "sinus histiocytosis with massive

MIXTURES OF THE ABOVE cause diagnostic problems.

Well-made granulomas with NOTHING else are probably

You have probably already seen the Warthin-Finkeldey giant cells of

LYMPHADENOPATHY is a clinician's word for a big lymph node.

NON-HODGKIN'S LYMPHOMAS: By definition, monoclonal, malignant tumors

Dr. Warnock's Collection

Diffuse large cell lymphoma

Follicular lymphoma, spleen

The non-Hodgkin's lymphomas are a subject of perennial

RULE: Most non-Hodgkin lymphomas are somewhat more common in

RULE: Nodular lymphomas tend to be indolent lesions with natural

by additional mutations, or two separate malignant tumors.

Diffuse B-cell lymphoma

bcl-2 produces a protein on the inside of mitochondria

name PSEUDOLYMPHOMA. Distinguishing these from real lymphomas

(5) VASCULAR PROLIFERATION (new vessels suggest the

(7) NECROSIS (apart from apoptosis) is common in some

(10) We also want DNA studies for the TYPICAL GENE

RULE: Most lymphomas (Hodgkin's and non-Hodgkin's) may cause

* THE 1982 WORKING FORMULATION was a consensus of

THE REVISED EUROPEAN-AMERIAN CLASSIFICATION OF

T-cell prolymphocytic leukemia

in lymphoproliferative disease despite the WHO; however, people

Around 30% of these patients eventually develop a more

LYMPHOPLASMACYTIC LYMPHOMA (Am. J. Clin. Path. 136:

* While Waldenstrom's is the most common cause of the

ALPHA HEAVY-CHAIN DISEASE (now moved along with the

Before genetic profiling, we knew that CHOP chemotherapy has

FOLLICULAR LYMPHOMAS (CB/CC lymphoma)