1. health and fitness
2. disease

About this guide
If you’re reading this introduction, it means you are probably
either a) covering hematopathology in your pathology class
right now, or b) studying for boards. Either way, you’ve come
to the right study guide! Inside, you’ll find a comprehensive
(but not oppressive) review of both benign and malignant
hematopathology, neatly summarized and nicely illustrated.
Whether you have a read-the-text-straight-through kind of
mind, or a looking-at-pictures mind, or a question-working
mind, you’ll find it easy to work your way through this guide.
Extra help
If you are stuck, or frustrated, or if something just doesn’t
make sense, feel free to email me at
pathology@pathologystudent.com. I’ll do my best to get you
unstuck and back on track.
© 2013 Pathology Student
Table of Contents
1. Introduction… … … … … … … … … … … … … … p. 5
2. Anem ia… … … … … … … … … … … … … … … … p. 12
3. Benign leukocytoses… … … … … … … … … .. p. 39
4. Leukemia… … … … … … … … … … … … … … … p. 46
Acute myeloid leukemia………………….. p. 48
Myelodysplastic syndromes……………… p. 59
Acute lymphoblastic leukemia…………… p. 60
Chronic myeloproliferative disorders…….. p. 65
Chronic lymphoproliferative disorders…… p. 72
5. Myeloma… … … … … … … … … … … … … … … .. p. 78
6. Lymph node disorders… … … … … … … … … . p. 80
Benign lymph node disorders……………. p. 80
Non-Hodgkin lymphoma…………………. p. 83
Hodgkin disease………………………….. p. 93
7. Reference section… … … … … … … … … … … . p. 96
8. Study questions… … … … … … … … … … … … . p. 102
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The Complete (but not obsessive) Hematopathology Guide
page 2
List of Diseases
A ne m ia
Iron-deficiency anemia
Megaloblastic anemia
Hemolytic anemias
Hereditary spherocytosis
G6PD deficiency
Sickle cell anemia
Thalassemia
Warm autoimmune hemolytic anemia
Cold autoimmune hemolytic anemia
Microangiopathic hemolytic anemia
Anemia of chronic disease
Anemia of chronic renal disease
Anemia of chronic liver disease
Aplastic anemia
Be ni gn le ukoc ytose s
Benign neutrophilia
Benign lymphocytosis
Other leukocytoses
Le uk e m ia
Acute myeloid leukemia
AML with genetic abnormalities
AML with FLT3 mutation
AML with multilineage dysplasia
AML, therapy-related
AML, not otherwise classified
Myelodysplastic syndromes
Acute lymphoblastic leukemia
T-cell ALL
B-cell precursor ALL
Burkitt leukemia
Chronic myeloproliferative disorders
Chronic myeloid leukemia
Chronic myelofibrosis
Polycythemia vera
Essential thrombocythemia
Chronic lymphoproliferative disorders
Chronic lymphocytic leukemia
Hairy cell leukemia
Prolymphocytic leukemia
Large granular lymphocyte leukemia
M ye lom a
Lym p h n ode d isorde rs
Benign lymph node disorders
Non-Hodgkin lymphoma
Small lymphocytic lymphoma
Marginal zone lymphoma
Mantle cell lymphoma
Follicular lymphoma
Mycosis fungoides/Sézary syndrome
Diffuse large B-cell lymphoma
Lymphoblastic lymphoma
Burkitt lymphoma
Adult T-cell leukemia/lymphoma
Hodgkin disease
Nodular lymphocyte predominance
Nodular sclerosis
Mixed cellularity
Lymphocyte rich
Lymphocyte depletion
Chronic Leukemias
Chronic leukemias are very different from acute leukemias. Chronic leukemias are for the most part
diseases of older adults (acute leukemias occur in both children and adults). They appear in an
insidious fashion and have a relatively good prognosis (as opposed to acute leukemias, which
have a stormy onset and poor prognosis). In addition, chronic leukemias are composed of fairly
mature-appearing hematopoietic cells (as opposed to acute leukemias, which are composed of
blasts).
There are two kinds of chronic leukemias: myeloid and lymphoid. Instead of being reasonable, and
calling them “chronic myeloid leukemias” and “chronic lymphoid leukemias,” the powers that be
dubbed the two divisions “chronic myeloproliferative disorders” and “chronic lymphoproliferative
disorders.” These names are not so great, in my opinion, since these are not just “disorders” –
they are real leukemias! But no one asked me.
Pathophysiology
The chronic leukemias are malignant, monoclonal proliferations of mostly mature myeloid or
lymphoid cells in the bone marrow (and blood). These leukemias progress more slowly than acute
leukemias. So early on, the marrow is involved – but not totally replaced – by malignant cells. Still,
it is hard for the normal white cells to function properly. The lymphoid cells, in particular, have a
hard time making normal immunoglobulin in certain chronic lymphoproliferative disorders. One of
the major causes of mortality in these patients is infection. As the chronic leukemias evolve, more
and more of the marrow is replaced by tumor, and eventually there is little room for normal white
cells to grow.
Clinical Features
Chronic leukemias present in over a period of weeks or months. Patients might have splenomegaly
(which shows up as a dragging sensation or fullness in the left upper quadrant of the abdomen),
lymphadenopathy, or a general feeling of malaise and fatigue. Some patients are asymptomatic at
diagnosis, and the disease is picked up on a routine blood smear or CBC. Likewise, the clinical
course is different in chronic leukemia. In many cases of chronic leukemia, patients can live for
years without treatment at all.
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The Complete (but not obsessive) Hematopathology Guide
page 4
Chronic Myeloproliferative Disorders
The chronic myeloproliferative disorders are malignant clonal proliferations of a pluripotent stem
cell that lead to excessive proliferation of myeloid cells in the blood and bone marrow. What that
means in plain English is that a stem cell somewhere way back (before it’s even committed to the
neutrophil line, or red cell line) goes bad and starts proliferating like crazy – so you wind up with a
marrow packed with cells from all the myeloid lineages (the official name is “panhyperplasia”).
Usually, one particular myeloid lineage predominates in this growth fest – so you’ll see a ton of all
the myeloid cells, but the majority are neutrophils, or red cells, or megakaryocytes. So the chronic
myeloproliferative disorders have been divided into four types according to what is proliferating
most:
•
•
•
•
Chronic myeloid leukemia (tons of neutrophils and precursors)
Polycythemia vera (tons of red cells and precursors)
Essential thrombocythemia (tons of platelets and megakaryocytes)
Chronic myelofibrosis (tons of everything…then nothing! See below.)
Chronic myeloproliferative disorders:
CML, PV, ET, and
chronic myelofibrosis
We’ll consider each of these separately because they are very different clinically and
morphologically. But they do have some common features: all of them have a high white count
with a left shift, a hypercellular marrow, and splenomegaly.
Chronic myeloid leukemia
Chronic myeloid leukemia (CML) is a chronic myeloproliferative disorder characterized by a marked
proliferation of neutrophils (and precursors) in the bone marrow and blood. All cases have a t(9;22),
also known as the Philadelphia chromosome (it’s the 22 that’s officially the Philadelphia
chromosome).
CML has a t(9;22).
Clinical Features
CML frequently occurs in patients who are around 40 or 50. It does not occur in children (though
there is a separate disease similar to CML, called juvenile CML, that does occur in kids). Usually,
the onset is slow, with a long asymptomatic period, followed by fevers, fatigue, night sweats and
abdominal fullness. On physical exam, patients usually have an enlarged spleen. Hepatomegaly
and lymphadenopathy may also be present.
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The Complete (but not obsessive) Hematopathology Guide
page 5
There are three clinical stages, or phases, of CML: chronic phase, accelerated phase and blast
crisis. Patients generally present in chronic phase and then progress to one or both of the other
phases.
Chronic phase
•
High but stable number of neutrophils and precursors.
•
Stable hemoglobin and platelet count.
•
Easily controlled by therapy.
•
With traditional treatment (not imatinib, see below), usually lasts 3-4 years; is then followed
by accelerated phase and/or blast crisis.
Accelerated phase
•
Characterized by a change in the patient's previously stable state.
•
Usually see increasing leukocytosis, decreasing hemoglobin and platelet count.
•
May terminate in this stage, or may progress to blast crisis.
•
Usually fatal within several months.
Chronic myeloid leukemia:
marked neutrophilia,
left shift, and basophilia
Blast crisis
•
Characterized by a marked increase in blasts (myeloblasts or lymphoblasts).
•
Usually fatal within a few weeks or months.
Morphology
Blood
The blood smear shows a marked neutrophilia with a left shift. The left shift is a little weird in that it
is not evenly distributed between all the neutrophil stages. There are tons of neutrophils at all
stages of development, but there are relatively more myelocytes and segmented neutrophils (and
relatively less of the other stages). There are a few myeloblasts around (which you don’t see in
normal blood, of course) but they don’t number more than 2 or 3%.
Here’s an interesting thing: patients with CML almost always have a basophilia. That’s actually one
of the first things that happens in the development of the disease! There are few if any other
reasons for a basophilia. So if you see this in a patient, even if they don’t have the typical findings
of CML (big white count with lots of neutrophils and precursors), you should rule out CML!
The platelet count may be increased (because of all the megakaryocytes around in the bone
marrow).
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C ML: blo o d
The Complete (but not obsessive) Hematopathology Guide
page 6
Bone marrow
The bone marrow is hypercellular, with a pan-myeloid hyperplasia (all the myeloid cells are
increased – neutrophils and precursors, red cell precursors, megakaryocytes). However, if you look
closely, you’ll see that the neutrophils and precursors make up the bulk of the cells. Later in the
course of the disease, the marrow may become fibrotic. You can detect this using a reticulin stain.
This is not a good sign.
Pathophysiology
All cases of CML have a translocation between chromosomes 9 and 22, resulting in what’s
commonly known as the Philadelphia chromosome (Ph). This designation refers to the new
chromosome 22 that results from the translocation. Nobody talks about poor chromosome 9. The
translocation places the c-abl proto-oncogene on chromosome 9 next to the bcr gene on
chromosome 22. A new, fusion gene is created: the bcr-abl gene. The bcr-abl gene encodes a
protein called p210, which increases tyrosine kinase activity and disrupts the cell cycle.
Here’s a weird fact: the Philadelphia chromosome is found not only in the myeloid cells, but also in
some B lymphocytes! That’s weird, considering that this is a myeloid lesion with no apparent
changes in the lymphoid cells. This probably means that the initial bad cell (the one that became
malignant) was a very early stem cell, one that hadn’t even committed itself to myeloid or lymphoid
lineage yet, and the Philadelphia chromosome is present in all the descendents of that cell. Further
supporting this idea is the fact that when patients enter blast crisis, the blasts can be lymphoid!
C ML: bo ne mar ro w
Treatment and Prognosis
In the old days, CML was treated with myelosuppressive agents like hydroxyurea, and then if the
patient had a match and could tolerate it, allogeneic bone marrow transplant was performed. That
was the only hope for a cure.
Recently, a new drug called imatinib (or Gleevec) was developed that targets the messed-up
tyrosine kinase receptor activity in CML. It has been like a miracle for many patients – even patients
in the later stages of the disease. In fact, we don’t even know what the typical prognosis of CML is
anymore, because these patients are still living with the disease. This drug has turned CML into a
chronic but treatable disease, like diabetes, for many patients. It’s one of the happiest leukemia
research stories ever.
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The Complete (but not obsessive) Hematopathology Guide
page 7
Chronic myelofibrosis
Chronic myelofibrosis, also called idiopathic myelofibrosis or agnogenic myeloid metaplasia, is a
chronic myeloproliferative disorder characterized by panmyelosis, bone marrow fibrosis, and
extramedullary hematopoiesis. In real words: the bone marrow at first is markedly hypercellular, but
over time, it becomes fibrotic, and the hematopoietic cells go elsewhere (most often, to the spleen)
to try to make a home.
Clinical Features
Like the other chronic leukemias, chronic myelofibrosis is a disease of older adults. The peak age is
in the late 50s. The disease presents over a relatively long period of time, with symptoms of
splenomegaly (left upper quadrant pain and fullness, epigastric pressure) and anemia (weakness,
fatigue, and palpitations). A small number of patients are asymptomatic at diagnosis. Physical
examination shows massive splenomegaly in most patients, as well as signs of anemia (pallor,
tachycardia).
C hro nic myelo fib ro sis : bl oo d
Chronic myelofibrosis:
Morphology
Blood
The blood smear shows a leukoerythroblastosis (remember this term from benign leukocytoses? If
not, see page 41). There are lots of teardrop red cells in the blood due to the tight spaces (fibrotic
marrow, big spleen) the red cells have to squeeze through. The platelets are often weird looking
(large and hypogranular).
marrow fibrosis,
extramedullary hematopoiesis
and teardrop red cells
Bone marrow
Early on, the marrow is hypercellular, with a pan-myeloid hyperplasia. Megakaryocytes, in
particular, are markedly increased in number. Later on, the marrow becomes fibrotic, and in the
end stages of the disease, it is entirely replaced by fibrotic tissue, with very few remaining
hematopoietic cells.
Pathophysiology
The cause of the fibrosis is still not completely worked out. The fibroblasts are benign – so why are
they so active? It’s probably a result of megakaryocyte stimulation. Megakaryocytes are known to
release cytokines that stimulate fibrosis – and in chronic myelofibrosis, there are tons of
megakaryocytes around. So this seems like a plausible explanation.
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C hro nic myelo fib ro sis : bo ne marro w
The Complete (but not obsessive) Hematopathology Guide
page 8
Treatment and Prognosis
Chronic myelofibrosis has a relatively long course (mean survival is 5 years). Treatment usually
consists of supportive measures (like red cell transfusions) and myelosuppressive therapy (like
hydroxyurea) if the patient can tolerate it. The cause of death in patients with chronic myelofibrosis
is usually marrow failure. A small number of patients undergo leukemic transformation (meaning
that they develop an acute leukemia – like the blast crisis phase we talked about in CML).
Interestingly, the acute leukemia can be either myeloid or lymphoid!
Polycythemia Vera
Polycythemia vera (PV) is a chronic myeloproliferative disorder characterized by panmyelosis, with
an erythroid predominance. In real words: the marrow is stuffed with myeloid cells, and most of
them are red cell precursors. The blood shows a markedly increased red cell count.
“Polycythemia" just means an increase in red blood cell mass. It may be:
•
Primary (polycythemia vera or true polycythemia): increase in red blood cells caused by an
intrinsic abnormality of myeloid cells (no ↑ in erythropoietin).
•
Secondary: increase in red blood cells caused by ↑ secretion of erythropoietin, which may
be appropriate (e.g., high-altitude living) or inappropriate (e.g., a paraneoplastic syndrome
related to a solid tumor).
To distinguish between primary and secondary polycythemia, and to differentiate PV from other
chronic myeloproliferative disorders, a polycythemia vera study group came up with the following
Polycythemia Vera Study Group Criteria (how creative). To diagnose PV, you need either (1) A1,
A2, and A3, or (2) A1, A2, and any two from B:
A (m ajor)
A1
A2
A3
criteria
Increased RBC mass
Normal O2 saturation in blood
Splenomegaly
B (minor)
B1
B2
B3
B4
criteria
Thrombocytosis
High WBC without infection
Increased leukocyte alkaline phosphatase (see box at right) without infection
Increased serum B12 level
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Polycythemia vera:
tons of red cells
Things to make you look smart
Q. What is leuko cyte alk aline
pho sp hatas e ( LA P )?
A. LAP is an enzyme present in
normal neutrophils. It is strangely
absent in the neutrophils in CML – so
it was used in the olden days (before
cytogenetics) to distinguish between a
benign neutrophilia and CML. LAP is
expressed at normal levels in the
neutrophils in PV. Why is that? Who
knows! But it’s important – because if
you have a lot of neutrophils around,
and you think it’s a chronic
myeloproliferative disorder, you could
do an LAP. If it was low or zero, that
would be a pretty good indicator of
CML. If it was increased, it could be
PV (you’d still have to rule out
infection though). Nowadays, we use
other means to diagnose these
disorders. But you’ll still hear people
(and books) talk about the LAP. So
now you know.
The Complete (but not obsessive) Hematopathology Guide
page 9
Clinical Features
Polycythemia vera, like the other chronic leukemias, is a disease of older adults; the mean age at
diagnosis is 60. Symptoms and signs are related to the massive increase in red cell mass. Patients
may have headaches, weakness, pruritis and dizziness (from increased blood volume); they may
also have symptoms of vascular stasis, thrombosis or infarction (from increased blood viscosity).
Physical examination may show hepatosplenomegaly, and something called “plethora,” which
means ruddiness or redness of the head and neck.
Morphology
Blood
For most of the course of the disease, the red cell count is markedly increased. So are the white
cell count and the platelet count. Towards the end stages of the disease, though, the marrow can
become pooped out (the official name for this is “spent phase”) and quit making red cells. Then the
patient’s red cell count goes down, and the patient may even become anemic.
Bone marrow
The marrow is hypercellular, with a pan-myeloid hyperplasia. Red cells make up the bulk of the
myeloid cells in the marrow. Towards the end of the disease, however, the marrow may become
fibrotic, and red cell production may decrease.
Pathophysiology
Recently, a unique genetic abnormality was found to be present in virtually all patients with
polycythemia vera. There is a normal signaling pathway present in all kinds of organisms, from
slime molds to humans, called the JAK-STAT (Janus kinase-signal transducer and activator of
transcription) pathway. It’s a pretty cool pathway because it transmits signals from outside of the
cells (like growth hormone signals) to the nucleus of the cell without the need for second
messengers (which most other receptors need to use). It turns out that myeloid growth and
development is mediated, in part, by this pathway. Patients with polycythemia vera have a
mutation in the JAK part of this pathway (specifically, in the JAK-2 gene), which makes the JAK
think it’s getting signals when it’s not. So cells with this mutation are constantly getting signals to
grow! The mutation has been found in virtually all cases of polycythemia vera (making it a great tool
for differentiating primary from secondary polycythemia), and in a significant number of patients
with chronic myelofibrosis and essential thrombocythemia too.
Virtually all cases of
polycythemia vera have a
JAK-2 mutation
Treatment and Prognosis
Treatment usually involves phlebotomy, with or without myelosuppressive drugs. Survival is long
(average 9 - 14 years). Dangers include thrombosis, hemorrhage, and transformation into acute
leukemia.
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page 10
Essential Thrombocythemia
Essential thrombocythemia (ET) is a chronic myeloproliferative disorder characterized by
panmyelosis, with a megakaryocytic predominance. Meaning: the marrow is stuffed full of myeloid
cells, and the predominating cell is the megakaryocyte. The blood shows a markedly increased
platelet count.
tons of platelets
The diagnosis of ET is basically one of exclusion. You have to rule out benign causes of
thrombocytosis and all of the other chronic myeloproliferative disorders. Here are the criteria:
•
Platelet count must be >600 x 109/L (normal = 150 – 450).
•
Hgb must be <13 g/dL or RBC mass must be normal (excludes PV).
•
Philadelphia chromosome must be absent (excludes CML).
•
Marrow must lack fibrosis (excludes chronic myelofibrosis).
•
All other causes of thrombocytosis (e.g., iron deficiency anemia, cancer) must be excluded.
Clinical Features
ET usually occurs in patients over 50, but occasionally it occurs in young women. Symptoms are
those related to thrombotic phenomena (like myocardial infarction, stroke, and deep venous
thrombosis). Some patients also have excessive bleeding, which you wouldn’t expect, if you have
all those platelets around. The cause is a secondary (or acquired) von Willebrand disease! Weird.
Physical examination may reveal mild splenomegaly, pallor and tachycardia (if the patient is
anemic), and purpura and ecchymoses (if the patient has developed a secondary von Willebrand
disease).
ET : blo od
Morphology
Blood
The blood shows a ton of platelets - usually the count is over a million. The platelets usually look
abnormal; they are often large and/or hypogranular.
Bone marrow
The bone marrow shows normal to increased cellularity, and tons of megakaryocytes, which are
often described as being “back-to-back.”
Treatment and Prognosis
The main aim of treatment is to reduce the chances of hemorrhage or thrombosis. Usually platelet
pheresis or myelosuppressive drugs are used to lower the platelet count. Aspirin is also used to
decrease the risk of clotting. Most patients survive at least 5-8 years. Death is usually related to
hemorrhage or thrombosis, but a small number of cases undergo leukemic transformation.
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ET : bo ne marro w
The Complete (but not obsessive) Hematopathology Guide
page 11