Ed Friedlander, M.D., Pathologist
scalpel_blade@yahoo.com
No texting or chat messages, please. Ordinary e-mails are welcome.
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Cyberfriends: The help you're looking for is probably here.
Welcome to Ed's Pathology Notes, placed here originally for the convenience of medical students at my school. You need to check the accuracy of any information, from any source, against other credible sources. I cannot diagnose or treat over the web, I cannot comment on the health care you have already received, and these notes cannot substitute for your own doctor's care. I am good at helping people find resources and answers. If you need me, send me an E-mail at scalpel_blade@yahoo.com Your confidentiality is completely respected. No texting or chat messages, please. Ordinary e-mails are welcome.
DoctorGeorge.com is a larger, full-time service.
There is also a fee site at
www.afraidtoask.com.
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With one of four large boxes of "Pathguy" replies. |
I'm still doing my best to answer
everybody.
Sometimes I get backlogged,
sometimes my E-mail crashes, and sometimes my
literature search software crashes. If you've not heard
from me in a week, post me again. I send my most
challenging questions to the medical student pathology
interest group, minus the name, but with your E-mail
where you can receive a reply.
Numbers in {curly braces} are from the magnificent Slice of Life videodisk. No medical student should be without access to this wonderful resource.
KCUMB Pathology Club
Freely have you received, freely give. -- Matthew 10:8. My
site receives an enormous amount of traffic, and I'm
still handling dozens of requests for information weekly, all
as a public service.
Pathology's modern founder,
Rudolf
Virchow M.D., left a legacy
of realism and social conscience for the discipline. I am
a mainstream Christian, a man of science, and a proponent of
common sense and common kindness. I am an outspoken enemy
of all the make-believe and bunk that interfere with
peoples' health, reasonable freedom, and happiness. I
talk and write straight, and without apology.
Throughout these notes, I am speaking only
for myself, and not for any employer, organization,
or associate.
Special thanks to my friend and colleague,
Charles Wheeler M.D.,
pathologist and former Kansas City mayor. Thanks also
to the real Patch
Adams M.D., who wrote me encouragement when we were both
beginning our unusual medical careers.
If you're a private individual who's
enjoyed this site, and want to say, "Thank you, Ed!", then
what I'd like best is a contribution to the Episcopalian home for
abandoned, neglected, and abused kids in Nevada:
My home page
Especially if you're looking for
information on a disease with a name
that you know, here are a couple of
great places for you to go right now
and use Medline, which will
allow you to find every relevant
current scientific publication.
You owe it to yourself to learn to
use this invaluable internet resource.
Not only will you find some information
immediately, but you'll have references
to journal articles that you can obtain
by interlibrary loan, plus the names of
the world's foremost experts and their
institutions.
Alternative (complementary) medicine has made real progress since my
generally-unfavorable 1983 review. If you are
interested in complementary medicine, then I would urge you
to visit my new
Alternative Medicine page.
If you are looking for something on complementary
medicine, please go first to
the American
Association of Naturopathic Physicians.
And for your enjoyment... here are some of my old pathology
exams
for medical school undergraduates.
I cannot examine every claim that my correspondents
share with me. Sometimes the independent thinkers
prove to be correct, and paradigms shift as a result.
You also know that extraordinary claims require
extraordinary evidence. When a discovery proves to
square with the observable world, scientists make
reputations by confirming it, and corporations
are soon making profits from it. When a
decades-old claim by a "persecuted genius"
finds no acceptance from mainstream science,
it probably failed some basic experimental tests designed
to eliminate self-deception. If you ask me about
something like this, I will simply invite you to
do some tests yourself, perhaps as a high-school
science project. Who knows? Perhaps
it'll be you who makes the next great discovery!
Our world is full of people who have found peace, fulfillment, and friendship
by suspending their own reasoning and
simply accepting a single authority that seems wise and good.
I've learned that they leave the movements when, and only when, they
discover they have been maliciously deceived.
In the meantime, nothing that I can say or do will
convince such people that I am a decent human being. I no longer
answer my crank mail.
This site is my hobby, and I do not accept donations, though I appreciate those who have offered to help.
This page was last updated November 12, 2009.
During the fourteen years my site has been online, it's proved to be
one of the most popular of all internet sites for undergraduate
physician and allied-health education. It is so well-known
that I'm not worried about borrowers.
I never refuse requests from colleagues for permission to
adapt or duplicate it for their own courses... and many do.
So, fellow-teachers,
help yourselves. Don't sell it for a profit, don't use it for a bad purpose,
and at some time in your course, mention me as author and KCUMB as my institution. Drop me a note about
your successes. And special
thanks to everyone who's helped and encouraged me, and especially the
people at KCUMB
for making it possible, and my teaching assistants over the years.
Whatever you're looking for on the web, I hope you find it,
here or elsewhere. Health and friendship!
QUIZBANK Blood & Lymph #'s 133-139, 178-333
Describe the distribution of lymphoid tissue in humans, with special reference to B- and T-cell zones.
Describe the microanatomy of the lymph nodes. Sketch the sequence by which a B-cell develops into
a plasma cell, and name each stage.
Distinguish relative and absolute counts of various white cells, and explain why absolute counts are
more meaningful. Calculate an absolute count by multiplying the total and percentage counts. Give
the healthy absolute counts for lymphocytes, monocytes, eosinophils, and neutrophils.
Given a name of a white cell marker, tell what cell(s) it identifies. Given a white cell type, mention its
major markers.
Given a patient with neutropenia and a history, come up with a reasonable differential diagnosis.
Describe the typical cause and course of agranulocytosis. Recognize the major causes of lymphopenia.
Give a reasonable differential diagnosis for granulocytosis, eosinophilia, and lymphocytosis. Tell how
to distinguish chronic myelogenous leukemia from leukemoid reaction. Describe possible peripheral
(i.e., circulating) white cell pictures in sepsis. Mention the significant disease association for increased
absolute basophil count.
Describe the important non-neoplastic causes of lymphadenopathy, and how each looks under the
microscope. Describe "infectious mononucleosis syndrome", and name its four principal etiologic
agents.
Explain how a pathologist distinguishes a malignant lymphoma from a worrisome reactive (benign)
lymph node. Do this yourself for an easy case.
Apply the unifying "rules" in this handout to clinical problems about non-Hodgkin's lymphomas.
Explain how the classic Rappaport system differs from the International Working system
and the Revised European-American system of lymphoma
nomenclature. Recognize the names of the low, middle, and high grade lymphomas.
Given the name of a non-Hodgkin's lymphoma, recognize its distinctive features. Identify non-Hodgkin's lymphomas based on
their idiosyncratic markers, etiologies, or epidemiologies.
Explain current thinking about the pathogenesis of Hodgkin's disease. Describe its epidemiology,
subtypes, and prognosis. Given a description of the background, name the subtype, and vice versa.
Give a short account of the World Health Organization's system of
classifying the acute leukemias, and directions that future classifications
will probably take. Describe the major kinds of leukemia in detail. Cite their etiologies (if known), pathogenesis, natural
histories, subclasses, diagnostic features, and current prognosis. Do the same for the myelodysplastic
syndromes, polycythemia vera, and "myelofibrosis with myeloid metaplasia".
Describe the pathogenesis, symptoms, signs, lab findings, diagnosis, typical course, and major
complications of plasma cell myeloma. Recognize and prognosticate the other "plasma cell disorders".
Recognize the noteworthy causes of polyclonal gammopathy.
Explain current thinking about Langerhans cell histiocytosis (histiocytosis X).
Given an enlarged spleen and the opportunity to ask questions, come up with a reasonable differential
diagnosis. Describe the common findings in spleens at autopsy.
Name the lymphoma and/or leukemia caused by with each of these viruses:
Epstein-Barr virus Correctly define and use the following terms:
agranulocytosis
Identify the following elements in peripheral and/or marrow smears:
all five type of normal white cells
Shown an appropriate peripheral smear, tell when each disease might be present:
Pelger-Huet anomaly
Identify all the following cells in microscopic sections:
normal lymphocytes
Identify each of the following disease patterns under the microscope:
follicular hyperplasia
Draw or recognize a Birbeck granule and describe its significance.
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 B-cells.
* 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.)
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
Eosinophils: few- maybe 400 (fewer in AM, more in PM) 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 NON-HODGKIN'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, αβTCR, γδTCR, 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
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
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)
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.
* {16517} neutrophil, chloroacetate esterase stain
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 * 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).
Idiopathic
* The lab machine didn't count them.
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).
The most common offenders today: 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.
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".
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"):
(don't forget surgery and myocardial infarcts)
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
* Future pathologists: The latter two "Dohle bodies" are fakes; they are
from cases of May-Hegglin's (say "Muh-HAY-lun") semi-disease, an
autosomal dominant trait with too-few, too-big platelets and lots of "Dohle bodies"; 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 (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 / 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.
LOTS OF EOSINOPHILS (big review Mayo Clin. Proc. 80: 75, 2005):
The "Loeffler" family of eosinophil-mediated diseases
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)
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
* 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, 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)
* Idiopathic syndrome (rare -- T-cell clone makes interleukin 5: NEJM 341: 1141, 1999)
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.
Sometimes the underlying problem is a proliferation of
mutated T-cells 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
spectacular (NEJM 358: 1215, 2008).
{14099} eosinophilic leukocytes (buffy coat)
LOTS OF MONOCYTES:
typhoid fever
bad granulomatous problems
TB
* 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"; 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 "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 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.
The nucleoli are small, the nucleoplasm is reticulated,
and the cytoplasm is typically blue, at least where the red cells indent them.
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.
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 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.
You recall CHEDIAK-HIGASHI SYNDROME, in which there are several problems with
organelle membrane synthesis.
synthesis.
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 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.
* 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).
{16208} Pelger-Huet, one dose
* 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). 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
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:
I am presently adding clickable links to
images in these notes. Let me know about good online
sources in addition to these:
MedEdPORTAL -- American Association of Medical Colleges. Primarily for medical school faculty.
Pathology Education Instructional Resource -- U. of Alabama; includes a digital library
Pathopic -- Swiss site; great resource for the truly hard-core
Syracuse -- pathology cases
Alabama's Interactive Pathology Lab
"Companion to Big Robbins" -- very little here yet
Alberta Tumor Photos -- and lots more. Highly recommended.
Bristol Biomedical
Image Archive
Chilean Image Bank -- General Pathology -- en Español
Chilean Image Bank -- Systemic Pathology -- en Español
Connecticut
Virtual Pathology Museum
Australian
Interactive Pathology Museum
Semmelweis U.,
Budapest -- enormous pathology photo collection
Iowa Skin
Pathology
Loyola
Dermatology
History of Medicine -- National Library of Medicine
KU
Pathology Home
Page -- friends of mine
The Medical Algorithms Project -- not so much pathology, but worth a visit
National Museum of Health & Medicine -- Armed Forces Institute of Pathology
Telmeds -- brilliant site by the medical students of Panama (Spanish language)
U of
Iowa Dermatology Images
U Wash
Cytogenetics Image Gallery
Urbana
Atlas of Pathology -- great site
Visible
Human Project at NLM
Karolinska Institutet -- pathology links
Johns Hopkins CPC's
U. of Virginia Case Studies
Oklahoma Teaching Cases
Indiana U. Teaching Cases
SUNY Histopathology
West Virginia Case of the Month
Upstate NY Cases -- works only on some browsers
Society for ultrastructural pathology -- electron microscope cases
WebPath:
Internet Pathology
Laboratory -- great site
My team:Ed Lulo's Pathology Gallery
Also:
Bryan Lee's Pathology Museum
Dino Laporte: Pathology Museum
Tom Demark: Pathology Museum
Dan Hammoudi's Site
Medmark Pathology -- massive listing of pathology sites
Estimating the Time of Death -- computer program right on a webpage
Pathology Field Guide -- recognizing anatomic lesions, no pictures
St.
Jude's Ranch for Children
I've spent time there and they are good. Write "Thanks
Ed" on your check.
PO Box 60100
Boulder City, NV 89006--0100
More of my notes
My medical students
Clinical
Queries -- PubMed from the National Institutes of Health.
Take your questions here first.
HealthWorld
Yahoo! Medline lists other sites that may work well for you
We comply with the
HONcode standard for trustworthy health
information:
verify
here. 
"Heme-Onc Pathology"
Virginia Commonwealth U.
Great pictures
Bone Marrow & Lymph Nodes
Photo Library of Pathology
U. of Tokushima
Breast / Heme (?!)
Taiwanese pathology site
Good place to go to practice
Hematopathology
Surgical Pathology Atlas
Nice photos, hard-core
Tulane Pathology Course
Great for this unit
Exact links are always changing
Problems in Bone Marrow Path
Histopathology and essay
For pathologists
Lymph Node Exhibit
Virtual Pathology Museum
University of Connecticut
Hematology Atlas
Nivaldo Medeiros MD
Brazilian Pathologist
Lymph-related organs
Brown Digital Pathology
Some nice cases
HTLV-I
HTLV-II
HIV
Auer rod
Bence-Jones protein
blast
bcr/abl oncogene
chloroma / granulocytic sarcoma
cleaved (clefted) lymphocyte
convoluted lymphocyte
cryoglobulin
Dohle body
gammopathy, monoclonal
gammopathy, polyclonal
leukemia
leukemia, aleukemic
leukocyte alkaline phosphatase
leukocytosis
leukoerythroblastic smear
leukopenia
lymphadenopathy
lymphoma
M-protein
myeloid / myelogenous
myeloma
neutropenia
paraprotein
Pautrier microabscess
Philadelphia chromosome
polycythemia (absolute, relative, 1,2)
pseudolymphoma
tingible body macrophage
toxic granulation
Pelger-Huet anomaly
circulating blasts
Auer rods
teardrop reds
acute leukemia (subtype If possible)
chronic myelogenous leukemia
chronic lymphocytic leukemia
hairy cell leukemia
myelofibrosis with myeloid metaplasia ("agnogenic myeloid metaplasia")
Sézary's syndrome
small cleaved lymphocytes
large lymphocytes
immunoblasts
normal plasma cells
normal eosinophils
classic Reed-Sternberg cells and their major variants
sinus hyperplasia ("sinus histiocytosis")
nodular non-Hodgkin's lymphoma
diffuse non-Hodgkin's lymphoma
Hodgkin's disease (& subtype If obvious)
Sézary's syndrome / Mycosis fungoides
Burkitt's lymphoma
myelofibrosis
extramedullary hematopoiesis in spleen
plasma cell myeloma
(* "hypereosinophilia" is more than 1500 for more than six months without an obvious reason,
and some evidence of organ involvement)
* 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).
Neutrophilia
Text and photomicrographs. Nice.
Human Pathology Digital Image Gallery
(Am. Fam. Phys. 75: 373, 2007))
This is a dread complication seen with many different medications.
* 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.
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).
{13661} Dohle body
{16213} Dohle body
, or carcinomatosis) from chronic granulocytic
leukemia (see below), remember the following:
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.
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.
{09207} eosinophil granule with crystal (electron micrographs; these crystals will combine to form large
Charcot-Leyden crystals under some conditions)
Eosinophilia
Text and photomicrographs. Nice.
Human Pathology Digital Image Gallery
brucellosis
Crohn's disease
leprosy
deep fungi
sarcoidosis
others
; a "chronic form" also exists without
marrow abnormalities; leave this to the pediatric hematologists; Acta. Paed. 74: 633, 2008.)
;
(2) cytomegalovirus;
(3) toxoplasmosis;
(4) HIV.
Infectious Mononucleosis
Text and photomicrographs. Nice.
Human Pathology Digital Image Gallery
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, long-mysterious, 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 Cell 90: 797, 1997;
molecular genetic diagnosis: Ann. Int. Med. 129: 539, 1998.
infection) on the ankles.
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.
In the autosomal dominant PELGER-HUET ANOMALY, the neutrophil nuclei fail to segment fully, producing
"peanuts" and "pince-nez eyeglasses". ("Look! This clinically healthy patient has a horrible left shift / leukemia!")
This is a fairly common laboratory curiosity, and of no significance. (* 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!")
{16209} Pelger-Huet, one dose
{13658} Pelger-Huet, two doses
can help you diagnose
this famous "spotless fever"; this "granulocytic" variant
of ehrlichiosis can be fatal (NEJM 334: 209, 1996).
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:
(* 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)
(plasma cells in the medulla, mini-granulomas, spirochetes)
{36371} toxoplasmosis; many bugs in a cell
{40654} toxoplasmosis; tissue reaction (lame-looking granulomas)
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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
cells?; this can be a real
fooler for lymphoma, see Arch. Path. Lab. Med. 117: 269, 1993)
SINUS HYPERPLASIA (formerly "sinus histiocytosis"; i.e., sinusoids with swollen endothelial cells and lots of histiocytes). If perplexed, think of:
/ 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).
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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) glanders-melioidosis, 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.
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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): 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. I've got a story about this I'll tell you personally.
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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 hte 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.)
Together, the 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.
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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. Especially in the lymphomas, the genome is usually NOT destabilized. Review of the translocations: Arch. Path. Lab. Med. 127: 1148, 2003.
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 T-lymphoblastic 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).
"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 well-known (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 non-tender 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 T-cell 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 B-lymphocyte to plasma cell.
{23581} nodular lymphoma
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; NEJM 341: 764, 1999.
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.
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 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 low-grade
lymphomas you won't see much apoptosis);
(4) Widespread bcl-2 protein staining is a pretty good sign that
this is lymphoma.
(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.
(9) Today's pathologist, asking "Is this lymphoma?", begins as follows:
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).
Diffuse lymphoma
WebPath Photo
Diffuse B-cell lymphoma
Gross and microscopic
Wikimedia Commons
produces pseudolymphomas in the ear lobes. No one has a clue why.
Tingible body macrophages
WebPath Photo
* In AIDS, mantles are likely to absent. Why?
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).
(10) We also want DNA studies for the TYPICAL GENE ARRANGEMENTS, both for diagnosis and to look for residual
disease.
{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 small-cleaved 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 / Sézary syndrome
Adult T-cell leukemia/lymphoma with HTLV-1
MATURE T-CELL AND NATURAL KILLER (NK) NEOPLASMS
T-cell prolymphocytic leukemia
Angioimmunoglastic T-cell lymphoma
HODGKIN'S
Here are the most common ones:
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 never-stimulated, 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.
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.
LYMPHOPLASMACYTIC LYMPHOMA, 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.
WALDENSTROM'S MACROGLOBULINEMIA produces large amounts of IgM pentamers. In addition to the
problems seen in any lymphoma, patients suffer with hyperviscosity syndrome (dizziness, eye problems,
other problems; look for "sausage link" retinal veins). Like "regular small lymphocytic lymphoma",
This is a disease of the elderly.
* 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.
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
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. About 80% of the old "diffuse large-cell lymphoma"
cases express B-cell antigens but not T-cell antigens.
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.
MANTLE CELL LYMPHOMA (Hum. Path. 31: 7, 2002; Arch. Path. Lab. Med. 132: 1346, 2008)
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).
It's a disease mostly of older men, and often arises extranodally.
It is quite aggressive and hard-to-treat, but there are now reports of cures.
* Don't worry about the details for pathologists. There is an extra-aggressive
"blastoid" morphologic subtype, 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).
Many (but by no means all) Hashimoto and Sjogren-associated lymphomas are MALT type.
* 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)
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
Formerly divided into "small-cleaved", "mixed small-cleaved
and large cell" and "large-cell" subcategories,
it's now pretty clear that most of them are mixed.
The "small cells"
look like normal lymphocytes except
for one or more clefts up the nucleus ("buttock cell", etc.),
and they lack the marbly heterochromatin.
The "large cells" can be cleaved or noncleaved.
Both kind of cells are "centrocytes", since you find them in
the active regions of germinal centers.
Patients are usually older adults. The bone marrow is usually involved at the time of diagnosis.
The translocation t(14;18), with bcl2, is usual.
About half of these transform into a diffuse B-cell lymphoma.
{23599} mixed lymphoma; use the endothelial cell at 2:30 as a size marker
{23596} nodular large-cell; at this power, just appreciate the nodularity
Telling nodular lymphomas from hyperplastic germinal centers:
MORE LYMPHOMAS
{23590} diffuse small cleaved lymphoma (all
you can tell is that it is small cleaved)
{23581} nodular lymphoma
ANAPLASTIC LARGE T-CELL LYMPHOMA is rather less aggressive
than the other large ones. The famous "hallmark cells", with multilobular,
horseshow-shaped 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).
So far, the new biotech therapies don't seem to help for the T-cell
lymphomas: Cancer 103: 2091, 2005.
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
* 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
EFFUSION LYMPHOMAS, in the body cavities without a solid phase,
are usually seen in immunosuppressed people and always
are caused by KSHV (herpes 8 {10935} lymphoma arising in thyroid; my case
{00245} immunoblastic lymphoma
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 Sézary 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-of-function 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")
A famous B-cell tumor endemic in children in the African malaria belt. Most often, the African variant
arises in the jaw.
{46189} African Burkitt's
The Epstein-Barr virus 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
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
tingible-body macrophages because
they are heavily laden with lipid.
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 / SÉZARY 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
In "Sézary 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} Sézary patient
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.
* For some obscure reason hypercalcemia is common in this disease.
The disease (like the virus) is more common in Japan and the Caribbean. HTLV-I in Japan: Lancet
343: 213, 1994.
* Darwin's world. HTLV-I is as old as the great human migrations of the stone age. See Proc. Nat.
Acad. Sci. 91: 1124, 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 (infection-triggered: Pediatrics 118: e216, 2006;
Blood 106: 3090, 2005;
South. Med. J. 100: 208, 2007) illness.
{23668} malignant histiocytosis with erythrophagocytosis
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 * 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.
{23560} Reed-Sternberg cell
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+, B-cell markers are positive), and it's
probably "not really Hodgkin's, maybe a dysplasia":
Blood
87: 2428, 1996;
Am. J. Path. 146: 812, 1995; different mutations Blood 101: 706, 2003.
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
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
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".
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:
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)
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 ("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
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
HOW TO SPOT A BLAST: (review from "Histology")
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).
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
Death typically results from hemorrhage (cerebral, GI, other), and/or infection (neutropenia,
chemotherapy), and/or complications of bone marrow transplantation.
{06269} fatal cerebral hemorrhage in 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 agnogenic myeloid
metaplasia) 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)
This is the familiar "childhood leukemia", with peak age in four year old kids. Adult ALL is less
common.
{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 1997-2007, 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
L3 is a distinct entity, but L1 and L2
aren't especially useful. Here's a more-modern immunophenotypic classification:
B-cell... 80%... * CD19+...* several subclasses exist
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 HLA-DR.
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:
3. Biphenotypic acute leukemia
More for cytogeneticists and prognosticators:
Hyperdiploidy (>50 chromosomes), present in a large minority of B-cell ALL's, confers a good
prognosis.
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
85% get apparent cures.
The prognosis for adults is still guarded. Cure rates for young adults are now around 50%;
occasionally the disease appears in older adults with less chance of cure.
{23857} ALL in the liver
* 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:
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 non-lobulated 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); * t(15;17)
and * t(11;17) are distinctive, and (KNOW:)
involve the vitamin A receptor (RARα; 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)
M5: monocytic differentiation only; * t(9;11)(p22;q23) is typical of M5a; 9p22 is beta-interferon receptor, while 11q23
is the MLL
(myeloid-lymphoid 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.
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. 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.
Untreated AML is fatal in a few weeks.
Today, many AML patients have prolonged survival and probably
cures.
"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 (Cancer 113: 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), and platelets are likely to
be high. It self-cures, but these children are at risk for later acute 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.
* 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.
* 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).
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.
CHRONIC MYELOID LEUKEMIA ("chronic myelogenous leukemia", "well-differentiated
granulocytic leukemia"): all about it Lancet 370: 1127, 2007
This is cancer of the myeloid stem cells in which there is overgrowth of normally-maturing 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
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.
{12371} Philadelphia chromosome
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.
{23869} 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
myelofibrosis with (agnogenic) myeloid metaplasia
idiopathic "aplastic anemia"
chronic myelogenous leukemia
Historically, many patients have been exposed to drugs or chemicals.
Exposure to benzene, which used to be
a household chemical, is notorious.
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...
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 transplantation and/or immunosuppression (Blood 108: 2509, 2006).
CHRONIC LYMPHOCYTIC LEUKEMIA ("CLL", "well-differentiated lymphocytic leukemia"; "the
liquid phase of well-differentiated lymphocytic lymphoma", etc.) Lancet 371: 1017, 2008.
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 "T-cell 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.)
* CLL has a few common genetic markers but they also occur in other B-cell neoplasms
(Semin. Hem. 36: 171, 1999.
The disease is often an incidental finding, when a CBC shows preposterously a high lymphocyte count.
{08784} CLL
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).
HAIRY CELL LEUKEMIA
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).
There is a modest male predominance. Patients have pancytopenia and circulating "hairy lymphocytes";
they survive for several years. The distinctive physical finding is massive splenomegaly. Bone marrow
aspiration is likely to be unsuccessful "because the cellular hairs tangle with one another."
The hairs are quite distinctive, and the diagnosis is clinched by the finding of
TARTRATE-RESISTANT ACID PHOSPHATASE (TRAP) in these cells.
Until recently, the only treatment for this disease was splenectomy, which helped.
Today, most patients get a lasting remission
after taking 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.
* Hairy cell leukemia and adolescent mediastinal T-lymphoblastic lymphoma
are both much more common among men. Maybe this means they're virus-related.
Somebody might ask you this sometime.
{23872} hairy cell leukemia
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" (truncated
erythropoietin receptor;
(J. Clin. Invest. 102: 124, 1999)
* Erythropoietin-dependent polycythemias (altitude, post-transplant) 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).
There is a trademark mutation in JAK2 (NEJM 356: 444, 2007) that is usually present
* JAK2V617F if you are curious).
Erlotinib, the anti-lung-cancer EGFR tyrosine kinase inhibitor, also inhibits the
mutant JAK2V617F. Watch for this as a treatment.
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.
Patients can expect to survive for ten years or more, with control of most of their problems, until the
disease transforms into something else.
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.
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.
New criteria will probably be changed to (1) low serum erythropoietin
and (2) studying the ability of cultured normoblasts to grow without
erythropoietin (Mayo Clin. Proc. 74: 159, 1999). Or perhaps
the JAK2 trademark mutation will define the illness.
* 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).
MYELOFIBROSIS WITH MYELOID METAPLASIA ("agnogenic myeloid metaplasia"; "primary
idiopathic myelofibrosis", "myelosclerosis")
Agnogenic myeloid metaplasia 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, "burn out" and become fibrotic.
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). About half have mutated JAK2.
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.
{12302} teardrop reds
NOTE: The important term LEUKOERYTHROBLASTIC SMEAR refers to the presence in the bloodstream of young
red cells and young granulocytes. You'll see this when they are "being pushed out of their place of
origin too fast":
bone marrow infiltration
agnogenic myeloid metaplasia
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
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 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.
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.
* 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" x-ray 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!
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)
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
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
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:
{17273} 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.
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 NEJM 354: 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 non-cancer-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.
* 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:
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 tennis-racket shaped structures of unknown significance.
{09095} Birbeck granules
In tissue, you will probably see a range of cells from "blasts" to well-differentiated 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
HAND-SCHÜLLER-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.
{10481} Hand-Schüller-Christian disease. Weird histiocytes. Trust me.
* 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 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)
Agnogenic myeloid metaplasia (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
The only proof that hypersplenism was the problem is that the blood counts get better when the spleen
is removed.
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.
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.
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.
* 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.
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? "It is futile," I said,
You lie," he cried,
--Stephen Crane
10110 ff blood
{10766} leukemia, hairy cell and normal
BIBLIOGRAPHY / FURTHER READING
I urge anyone interested in learning more about
diseases of the white blood cells
to consult these standard textbooks.
In my notes, the most helpful current
journal references are embedded in the text.
Students using these during lecture strongly prefer this.
And because the site is constantly being updated,
numbered endnotes would be unmanageable.
What's available online, and for whom, is always changing.
Most public libraries will be happy to help you get an article
that you need. Good luck on your own searches, and again,
if there is any way in which I can help you, please contact me at
scalpel_blade@yahoo.com.
No texting or chat messages, please. Ordinary e-mails are welcome.
Health and friendship!
Lymphoma in lymph node
Invasion of surrounding fat
Tom Demark's Site
* 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.
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
MALT lymphoma ("extranodal marginal zone B cell lymphoma", "mucosal-associated lymphoid tissue" of stomach, thyroid, salivary glands, etc.; t(11:18))
Extramedullary plasmacytoma
Monoclonal immunoglobulin deposition diseases (i.e., amyloid B/AL, others)
Heavy chain diseases
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 non-Hodgkin's lymphoma)
Mediastinal (thymic) large B cell lymphoma
Intravascular large B cell lymphoma
Primary effusin lymphoma
Burkitt's lymphoma / leukemia (t(8:14))
Lymphomatoid granulomatosis (the B-cell attract huge numbers of non-neoplastic T-cells)
NOTE: T-cell lymphomas are recognized as such by their having
mutations of the T-cell surface receptor proteins.
T-cell large granular lymphocytic leukemia
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)
Peripheral T-cell lymphoma, unspecified
Anaplastic T-cell large-cell lymphoma
Nodular lymphocyte-predominant Hodgkin's
IMMUNODEFICIENCY-REALTED LYMPHOPROLIFERATIVE DISORDERS (probably listed separately
by the W.H.O. because they're clinically different and probably
have viral etiologies
Classic Hodgkin's
Nodular sclerosis
Mixed-cellularity
Lymphocyte-rich
Lymphocyte depleted
With a primary immune disorder
With HIV
Post-transplant (after bone marrow transplant, these are often the donor's cells; also remember "donor cell leukemia": Blood 109: 2688, 2007)
With methotrexate
Adults (all are peripheral B-cell lesions):
Chronic lymphocytic leukemia / small lymphocytic lymphoma
Children:
Follicular lymphoma
Plasmacytoma / plasma cell myeloma
Diffuse large B-cell lymphoma
Precursor B-cell leukemia
Precursor T-cell leukemia
Burkitt's lymphoma / leukemia
Pathologists often identify "proliferation centers", discrete clumps of somewhat
larger cells that supposedly give rise to the normal-looking tumor
cells. These are supposed to be pathognomonic of CLL/SLL.
Well-differentiated lymphocytic lymphoma
Tom Demark's Site
* Most of these feature the translocation t(9;14), causing aberrant
expression of PAX5.
A B-cell lymphoma that bears markers of primitive mantle cells (CD5+, * CD10+),
diffuse or nodular, and
often grows wrapped around normal germinal centers.
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).
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.
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).
{23683} mixed lymphoma
{23581} nodular lymphoma
{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
* Future pathologists: Expect it to light up with CD30/Ki1.
Of course, you can also stain for ALK, which usually lights up.
{15389} large-cell lymphoma
{23647} * "angioimmunoblastic lymphadenopathy",
a T-cell lymphoma with vascular proliferation -- note the vessels and the monomorphic cell infiltrate)
Peripheral T-cell neoplasm
Virginia
Good pictures
Primary thymic lymphoma
Virginia
Good pictures
The old "immoblastic lymphoma" of the Working Classification
was a mix of several different B- and T-cell lymphomas.
)
(Lancet 346: 883, 1995; Lancet 347: 980 & 1042, 1996).
KSHV is now required for case
definition (Cancer 111: 224, 2007).
{10937} lymphoma arising in thyroid; my case. Notice that the lymphocytes are growing within a
follicle.
Body cavity lymphoma and Hodgkin's
Lung pathology series
Dr. Warnock's Collection
Post-transplant lymphoproliferation
Pittsburgh Pathology Cases
Post-Transplant Neoplasia
Great site
Transplant Pathology Internet Services
{10691} immunoblastic lymphoma, cytology
{10724} immunoblastic lymphoma
{10772} immunoblastic lymphoma
{23623} immunoblastic lymphoma
{23689} immunoblastic lymphoma
{08017} lymphoma in the heart
{11630} lymphoma in the pericardial space
{11633} lymphoma, primary in the heart
{20227} lymphoma, primary in the stomach
{15446} lymphoma, primary in the stomach
{15542} lymphoma, primary in the stomach
{49035} African Burkitt's
Burkitt's
Section
Wikimedia Commons
Burkitt's
Smear
Wikimedia Commons
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).
.
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
{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
{40004} mycosis fungoides
{12747} mycosis fungoides, plaque phase
{12751} mycosis fungoides
{12754} mycosis fungoides
{13117} mycosis fungoides
{13781} mycosis fungoides
{13784} mycosis fungoides
{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
{16544} Sézary cell
{23722} Sézary cell
{15409} Sézary 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.
Primary Effusion Lymphoma
This is usually from KSHV
Virginia Pathology Cases
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; lots more).
Also watch for Y-ibrituxomab tiuxetan (Blood 99: 4336, 2002;
Cancer 94: 1349, 2002). Perhaps most exciting so far: I131-tositumomab, radioactive anti-CD20,
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 (90Y-ibritumomab tuixetan: Cancer 112:
856, 2008).
Update on about a dozen monoclonals for B-cell lymphoma: NEJM 359: 613, 2008.
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).
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).
You must recognize the CLASSIC 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 with Reed-Sternberg variants
Great labels
Romanian Pathology Atlas
Reed-Sternberg Cell
Spectacular photomicrograph
Brazilian Medical Students
Hodgkin's disease, spleen
AFIP
Wikimedia Commons
_mixed_cellulary_type.jpg){kind=small}
Hodgkin's
H&E
Wikimedia Commons
{46339} Lymphocyte predominant Hodgkin's
{46342} mixed cellularity Hodgkin's disease
{46343} mixed cellularity Hodgkin's disease
{23545} nodular sclerosing Hodgkin's disease
{23548} lacunar Reed-Sternberg variants
{23551} lacunar Reed-Sternberg variant
{46348} Hodgkin's disease in the spleen
{46349} Hodgkin's disease in the spleen
Leukemia / myelodysplasia
"Pathology Outlines"
Nat Pernick MD
{36032} packed marrow; * this was AML
{12347} packed marrow; * this was AML
{29475} lymphoid blasts, pap stain. Big pale nuclei.
* Auer rods in preleukemia: Am. J. Clin. Path. 124: 191, 2005.
{08734} acute leukemia, liver; as you would expect, the leukemia is blue
{08735} acute leukemia, liver
{08736} acute leukemia, liver
{01735} brain and dura, acute leukemia
Acute Lymphoblastic Leukemia
Text and photomicrographs. Nice.
Human Pathology Digital Image Gallery
* Authoritative mega-review for pathologists considering
a diagnosis of leukemia in a child: Am. J. Clin. Path. 109(4S1):9S, 1998.
{23833} L1, special stain (cytoplasm is brown)
{23860} L2
{13982} L2, bone marrow
{23758} L3; note the lipid
{13985} L3
"pre-B"/"null", with surface Ig and TdT, carries a good prognosis;
Burkitt's / "mature B" / L3 is ominous
1. Acute lymphoblastic leukemia / lymphoma (all the old L1's and L2's go here)
2. Burkitt's leukemia / lymphoma (all the old L3's go here
{32027} ALL in the liver
{34513} ALL in the brain
{49316} ALL in the kidney
{49343} ALL in the testis
Bloom's
ataxia telangiectasia
Fanconi's anemia (a complex genetic disorder; * gene
FancC Blood 94: 1, 1999; leukemias Cancer 97: 425, 2003.)
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.
Acute Myelomonocytic Leukemia
Text and photomicrographs. Nice.
Human Pathology Digital Image Gallery
* Watch FLT3 (a tyrosine kinase), nucleophosmin (NPM1), "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. Update Blood 109: 431, 2006.
{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
{13994} blasts with lots of granules, M3
{16254} blasts with lots of granules, M3
{10109} 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
{40449} monocyte-like blasts in M5
{40451} monocyte-like blasts in M5
{23803} non-specific esterase in M5
{14001} monocyte-like blasts in M5
{13928} non-specific esterase 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
{16267} erythroleukemia, M6
{23836} erythroleukemia, M6
{23806} 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
Acute myeloid leukemia
Types (not "stages"); some
mislabelled; Virginia
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).
Various karyotypic abnormalities have been described in the majority of
these people (Virch. Arch. A 421: 47, 1992).
.jpg){kind=small}
Myelodysplastic syndrome
Odd megakaryocyte / giant platelet
AFIP
{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)
Chronic granulocytic leukemia
Automated profile
WebPath Photo
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). Watch for more.
Chronic granulocytic leukemia
Philadelphia chromosome
WebPath Photo
* 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.
{12365} CML, blast crisis
"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.)
a marrow transplant from an identical twin never takes in this disease;
Aplastic anemia
WebPath Photo
CLL and melanoma together in marrow
Pittsburgh Illustrated Case
Chronic lymphocytic leukemia
Classic drawing
Adami & McCrae, 1914
Chronic Lymphocytic Leukemia
Text and photomicrographs. Nice.
Human Pathology Digital Image Gallery
.jpg){kind=small}
B-CLL, good smudges
AFIP
Wikimedia Commons
We know of no other specific risk factors, not even a history of radiation.
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).
{12389} CLL
{12404} CLL going bad (some blasts)
{12386} CLL with smudges
* 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.
{10766} hairy cell leukemia, spleen (top; normal at bottom)
{16543} hairy cell leukemia, TRAP stain (red)
{23875} hairy cell leukemia, TRAP stain (red)
{13925} hairy cell leukemia, TRAP stain (red)
{16541} hairy cell leukemia, TRAP stain (red)
{23881} hairy cell leukemia, bone marrow biopsy (trust me)
{42117} big spleen in hairy cell leukemia, foot ruler
* Watch JAK2. Some germline alleles are much more likely than others to mutate into the really bad allele (Nat. Genet. 41: 385 & 450 & 455 & 446, 2009).
Polycythemia
Text and photomicrographs. Nice.
Human Pathology Digital Image Gallery
By definition, BCR-ABL (t(9;22), Philadelphia chromosome) is absent.
{24788} myelofibrosis, marrow core biopsy
{13802} myelofibrosis, reticulin stain
5q- syndrome
Virginia
Good pictures
* The common translocation t(4;14) brings the fibroblast growth factor 3
receptor (on 4; Nat. Genet. 16: 260, 1997) and a novel gene
(Blood 92: 3025, 1998) into control of IgH, the heavy chain gene,
on 14.
A. Major criteria
B. Minor criteria
PLASMA CELL MYELOMA: Two majors, OR one major and one minor OR three minors including the first two.
{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
25%...IgA
1%... IgE, IgD, or IgM monomer
18%... Bence-Jones protein only
1%... no M-protein.
{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)
{17274} myeloma kidney, Bence-Jones casts with foreign body reaction
The disease often simply smolders, and if there are no symptoms,
perhaps it's best just to give bisphosphonates prophylactically (Cancer 113: 1588, 2008).
MGUS
Pittsburgh Pathology Cases
* Langerin, a lectin specific to stimulated
Langerhans cells: Immunity 12: 71, 2000.
{09097} Birbeck granules
Histiocytosis X
Pittsburgh Illustrated Case
Histiocytosis X with Birbeck granules
Lung pathology series
Dr. Warnock's Collection
Eosinophilic granuloma of the lung
Lung pathology series
Dr. Warnock's Collection
{13691} eosinophilic granuloma
{09043} eosinophilic granuloma, EM, coffee-bean nucleus (left) and eosinophil (right)
{21779} skull in Hand-Schüller-Christian disease
* 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"
{09864} Gaucher's disease, spleen
{16216} Gaucher's disease, watered-silk ("wadded kleenex") cell from spleen
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).
Sickle cell disease
Autosplenectomy
WebPath Photo
* I SAW A MAN PURSUING
I saw a man pursuing the horizon;
Round and round they sped.
I was disturbed at this;
I accosted the man.
"You can never -- "
And ran on.
(1871-1900)
* SLICE OF LIFE REVIEW: BLOOD CELLS
{12275} anemia, iron deficiency; normal
{13715} lymphocyte, normal
{13868} red blood cell, normal blood
{13910} red blood cell, normal
{14702} polymorphonuclear leukocyte, normal
{14703} polymorphonuclear leukocyte, normal
{14704} polymorphonuclear leukocyte, normal
{14705} polymorphonuclear leukocyte, normal
{14705} polymorphonuclear leukocyte, normal
{14706} polymorphonuclear leukocyte, normal
{14707} polymorphonuclear leukocyte, normal
{14708} eosinophil, normal
{14709} eosinophil, normal
{14710} basophil, normal
{14711} basophil, normal
{14712} monocyte, normal
{14713} monocyte, normal
{14714} monocyte, normal
{14715} monocyte, normal
{14716} lymphocyte, large
{14717} lymphocyte, large
{14718} lymphocyte, normal
{14719} lymphocyte, normal
{14720} lymphocyte, normal
{14721} lymphocyte, normal
{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
{14739} myelocyte, normal
{14740} * granulocyte series
{14741} * granulocyte series (labelled)
{14742} myelocyte, band form
{14743} myelocyte, band form
{14744} myelocyte, normal
{14745} myelocyte, normal
{14746} myelocyte, normal
{14747} myelocyte, normal
{14748} myelocyte, normal
{14749} myelocyte, normal
{14750} myelocyte, normal
{14751} myelocyte & megakaryocyte, normal
{14752} myelocyte & megakaryocyte, normal
{15193} plasma cell, #23
{15205} thymus, adult
{15564} thymus, normal
{15565} thymus, normal
{15566} thymus, normal
{15567} thymus, normal
{16175} red blood cell, normal
{20782} polymorphonuclear leukocyte, normal
{20783} monocyte
{20784} platelets, circulating blood
{20785} monocyte
{26230} polymorphonuclear leukocyte, normal
{40179} thymus, normal
{46538} red cell, normal
* SLICE OF LIFE REVIEW: LYMPHOID ORGANS
{11750} spleen, normal
{11751} spleen, normal
{11753} lymph node, normal
{11797} spleen, normal
{11805} spleen, normal unfixed
{14753} thymus, human fetal
{14754} thymus, human fetal
{14755} thymus, juvenile
{14756} thymus, juvenile
{14757} thymus, adult
{14758} thymus, adult
{14759} thymus, juvenile
{14760} thymus, juvenile
{14761} hassall's corpuscles
{14762} hassall's corpuscles
{14763} hassall's corpuscles
{14764} hassall's corpuscles
{14765} thymus (septum)
{14766} thymus (septum)
{14767} spleen, normal
{14768} spleen, normal
{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)
{14780} lymph node, normal
{14781} lymph node, normal
{14782} lymph node cortex, normal
{14783} lymph node cortex, normal
{14784} lymph node, medulla
{14785} lymph node, medulla
{14786} lymph node, normal
{14787} lymph node, normal
{15189} lymph node and subcapsular sinus, #23
{15190} lymph node, primary nodule
{15191} lymph node, germinal center
{15192} lymph node, medulla
{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
{15568} spleen, normal
{15569} spleen, normal
{15570} spleen, normal
{15571} spleen, normal
{15769} spleen, normal
{15770} spleen, normal
{20200} spleen, normal
{20799} lymph node, overview
{20800} lymph node, cortex
{20801} lymph node, medulla
{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
{24782} lymph node, normal
{24783} lymph node, normal
{36344} lymph node, normal
{36347} lymph node, normal
{36350} lymph node, normal cytology
{36353} lymph node, normal cytology
Pathology of Bone Marrow and Blood Cells
Henry's Clinical Diagnosis and Management by Laboratory Methods
Robbins and Cotran Pathologic Basis of Disease
Rosai and Ackerman's Surgical Pathology
Rubin's Pathology: Clinicopathologic Foundations of Medicine
Silverberg's Surgical Pathology
Wintrobe's Clinical Hematology
| Visitors to www.pathguy.com reset Jan. 30, 2005: |
Ed says, "This world would be a sorry place if
people like me who call ourselves Christians
didn't try to act as good as
other
good people
."
Prayer Request
Teaching Pathology
If you have a
Second Life
account, please visit my teammates and me at the
Medical Examiner's office.
PathMax -- Shawn E. Cowper MD's
pathology education links
Ed's Autopsy Page
Notes for Good Lecturers
Small Group Teaching
Socratic
Teaching
Preventing "F"'s
Classroom Control
"I Hate Histology!"
Ed's Physiology Challenge
Pathology Identification
Keys ("Kansas City Field Guide to Pathology")
Ed's Basic Science
Trivia Quiz -- have a chuckle!
Rudolf
Virchow on Pathology Education -- humor
Curriculum Position Paper -- humor
The Pathology Blues
Ed's Pathology Review for USMLE I
Metastatic malignant melanoma
Virginia
Good pictures
Hairy cell leukemia
Virginia
Good pictures
Pathological Chess
Taser Video
83.4 MB
7:26 min
White Cell Quiz!
Hypersegmented poly
Pseudo-Pelger Huet
Ehrlichiosis
Nodular lymphoma
Burkitt's lymphoma
Burkitt's lymphoma
Burkitt's lymphoma
Burkitt's
Hodgkin's disease
Reed-Sternberg cell
M3
Acute promyelocytic leukemia
Acute Lymphoblastic Leukemia
ALL-L1
Burkitt's leukemia
M4-Eo
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M2
M2
Auer rods in blasts
M7 marrow
M1
M6
M0
M5b
M5a
M4
M5 -- electron micrograph
Chronic myelogenous leukemia
Chronic lymphocytic leukemia
Hairy cell leukemia_MG_stain.jpg){kind=small}
Plasma cell myeloma
Plasma cell myeloma
Normal spleen
Big spleen
Reed-Sternberg cells
Big spleen
Infarcts