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Review of Hematology malignacies on USMLE Step 1
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Know the morphology and diagnostic importance of the Reed Sternberg cell and its variants in Hodgkin Lymphomas
Know the major subtypes of Hodgkin lymphomas along with morphology and patient demographics per Table 13-8 in Robbins pathology text with emphasis on the 2 most common types.
Identify Auer rods in the cytoplasm of myleoblasts in AML and know that they are particularly prominent in acute promyelocytic leukemia with t(15;17)
Know the pathogenesis, morphology, clinical features and prognosis of myelodysplasia
Know the major categories of myeloproliferative disorders and their common pathogenetic mechanism (tyrosine kinase mutations).
Know the molecular pathogenesis (Philadephia chromosome t(9;22) with resultant BCR-ABL fusion gene), morphology, clinical features and prognosis of chronic myeloid leukemia.
Know the pathogenesis, morphology, clinical features and prognosis of polycythemia vera (PCV), essential thrombocytosis(ET) and myelofibrosis
Be familiar with major forms of Langerhans cell histiocytosis including Letterer-Siwe disease, eosinophilic granuloma and pulmonary forms along with their morphology.
Peripheral T-cell lymphoma, unspecified – worse prognosis than diffuse large B-cell lymphoma
Anaplastic large-cell lymphoma (ALK positive) – rearrangement of ALK gene on chromosomes 2p23 “hallmark cells” with horseshoe shaped nuclei with good prognosis
Adult T-cell leukemia/lymphoma-CD4+ T cells with human T-cell leukemia retrovirus type I infection (HTLV-1) in Japan, West Africa, Caribbean
Mycosis Fungoides/Sezary syndrome Large Granular Lymphocytic leukemia- rheum.
assoc. Extranodal NK/T-cell lymphoma associated with
EBV infections
Mycosis Fungoides/Sezary SyndromeLimited to skin in early stages as plaques or
patches. Misdiagnosed as psoriasis commonly. Epidermal collections of atypical lymphocytes are known as Pautrier’s Microabscesses.
Advanced stage with nodal or organ involvement, and circulating clonal T cells in blood are called Sezary Cells.
Chronic illness, typically older patients, incurable.Treatment with topical nitrogen mustard, electron
beam XRT, PUVA (psoralen with UV-A light)Sezary Syndrome treated with chemotherapy.
Copyright ©2005 American Society of Hematology. Copyright restrictions may apply.
Kadin, M. ASH Image Bank 2005;2005:101309
Figure 3. Collection of atypical lymphocytes with convoluted (ceribriform) nuclei in epidermis
Copyright ©2005 American Society of Hematology. Copyright restrictions may apply.
Kadin, M. ASH Image Bank 2005;2005:101309
Figure 2. Epidermotropism of atypical lymphocytes with cerebriform nuclei
Copyright ©2004 American Society of Hematology. Copyright restrictions may apply.
Kadin, M. ASH Image Bank 2004;2004:101260
Figure 3. Higher magnification of Sezary cell with convoluted nulceus and small nucleoli
First four types are “classical” forms of HL since Reed-Sternberg cells have similar immunophenotype (CD 15 and 30 positive)The non-classical lymphocyte predominance differs from the classical types in that the RS cells have markers typical of germinal center B cells,such as CD20 and BCL6 and are negative for CD15 and CD30.
HL arises in a single node or chain of nodes and spreads first to anatomically contiguous lymphoid tissues (NHL may occur in extranodal sites and spread unpredictably) The order of spread is predictable: nodal disease
first, then splenic, hepatic and finally involvement of marrow and other tissues
HL has distinctive morphologic features characterized by neoplastic giant cells called Reed-Sternberg cells (RS cells) RS cells are derived from germinal center or post-
germinal center B cells RS cells release factors attracting reactive
lymphocytes, macrophages, and granulocytes
Hodgkin LymphomaMore often localized to
a single axial group of nodes (cervical, mediastinal, para-aortic)
Orderly spread by contiguity
Mesenteric nodes and Waldeyer ring rarely involved
Extra-nodal presentation rare
Non-Hodgkin lymphomaMore frequent
involvement of multiple peripheral nodes
Noncontiguous spreadWaldeyer ring and
mesenteric nodes commonly involved
Extra-nodal presentation common
~8000 new cases in USA each year. Average age at diagnosis is 32 years
and is one of the most common cancers of young adults and adolescents (occurs in older people as well)
First human cancer to be successfully treated with radiation therapy and chemotherapy and is curable in most cases
RS cells originate from a germinal center or post-germinal center B cell but fail to express most B cell-specific genes Activation of the transcription factor NF-kappaB
(possibly by EBV infection or other mechanism) and turns on genes that promote lymphocyte survival and proliferation (EBV infected B cells in mononucleosis have a resemblance to RS cells)
RS cells secrete a wide variety of cytokines and chemokines inciting a florid accumulation of reactive cells in tissues involved by classical HL
RS cells are aneuploid and have diverse clonal chromosomal aberrations
http://www.cytojournal.com/viewimage.asp?img=CytoJournal_2010_7_1_20_70966_f7.jpg
Copyright ©2002 American Society of Hematology. Copyright restrictions may apply.
Kadin, M. ASH Image Bank 2002;2002:100484
Figure 8. Nodular sclerosis involving lymph node in Hodgkin lymphoma - low magnification
Acute myeloid leukemias Myelodysplastic syndromes Myeloproliferative disorders
Neoplastic proliferation arising in hematopoietic precursor cells resulting in overgrowth of myeloblasts and other immature cells of myeloid lineage
Diagnosis based on at least 20% myeloid blasts in the bone marrow
Myeloblasts – delicate nuclear chromatin, two to four nucleoli and more cytoplasm than lymphoblasts Cytoplasm may contain azurophilic granules
(peroxidase positive) and Auer rods(needle like azurophilic granules)
Auer rods particularly prominent in acute promyelocytic leukemia with a t(15;17)
Sometime blasts are entirely absent from blood (aleukemic leukemia) therefore need a bone marrow in pancytopenic patients to rule out leukemia
May differentiate along monocytic, erythroid and megakaryocytic lines Monoblasts – folded or lobulated nuclei, no Auer rods
and nonspecific esterase-positive.
Acute lymphoblastic leukemia Acute myeloid leukemia
A group of clonal stem cell disorders characterized by maturation defects associated with ineffective hematopoiesis
High risk of transformation to acute myeloid leukemia
Disease of the elderly (mean age of onset is 70 years)
Frequently discovered incidentally while asymptomatic
Symptoms are due to pancytopenia (pancytopenia occurs because the abnormal cells stay within the bone marrow) Weakness, infections and hemorrhage
Primary (idiopathic) Secondary to previous genotoxic drug or
radiation therapy (t-MDS)Appears 2 to 8 years after exposureTransformation to AML occurs more rapidly
and frequently
Refractory anemia Refractory anemia with ring sideroblasts Refractory anemia with excess blasts Refractory anemia with excess blasts in
transformation Chronic myelomonocytic leukemia
Poorly understood since abnormal progenitor cells undergo apoptosis at an increased rate yet somehow gain a selective advantage over any remaining normal marrow progenitors
Clonal chromosomal abnormalities include monosomies 5 and 7, deletions of 5q,7q and 20q and trisomy 8
Bone marrow usually hypercellular at DX but may be hypo- or normocellular
Dysplastic or disordered differentiation affecting the erythroid, granulocytic, monocytic and megakaryocytic lineages
Peripheral blood smear may show Pseudo-Pelger-Huet cells (neutrophils with only 2 lobes and some lack any segmentation), giant platelets, macrocytes, and poikilocytes with a monocytosis
Blasts may make up less than 10% of WBC in peripheral smear
Erythroid series Ringed sideroblasts-erythroblasts with iron-
laden mitochondria Megaloblastoid maturation (like B12 and folate
def) Nuclear abnormalites of red cell precursors
Granulocytic Decreased secondary granules, toxic
granulation and/or Dohle bodies Pseudo-Pelger-Huet cells only two nuclear lobes
Megakaryoctyes Single nuclear lobes or multiple separate nuclei
(pawn ball megakaryocytes) Myeloid blasts may be increased but less
than 20% of marrow
Median survival varies from 9 to 29 months but some may live for 5 years or more
Worse prognosis with Increased blasts (increased progression to AML) Multiple clonal chromosomal abnormalities Severe cytopenia
Younger patients – bone marrow transplant Older patients treated supportively with
antibiotics, blood transfusion A subset of older patients have improvement
with thalidomide-like drugs and DNA methylase inhibitors which improve hematopoiesis
Common denominator in the myeloproliferative disorders are tyrosine kinase mutations (normally growth factors bind to surface receptors of normal progenitor cells and activate tyrosine kinases which turn on pathways promoting growth and survival)
Categories of myeloproliferative disordersChronic myeloid leukemia (CML)Polycythemia VeraEssential thrombocytosisPrimary myelofibrosis
Mostly disease of adults occurring in the 5th to 6th decades
Leukocytosis often exceeding 100,000 cells per cubic mm consisting of neutrophils, bands, metamyelocytes, myelocytes, eos and basophils with blasts less than 10%
Platelets are increased Hypercellular marrow with increased
numbers of maturing granulocytic precursors and increased megakaryocytes
Sea-blue histiocytes scattered in bone marrow (macros with abundant wrinkled, green-blue cytoplasm)
Spleen is greatly enlarged from extensive extramedullary hematopoiesis
May also have mild hepatomegaly and lymphadenopathy from extramedullary hematopoiesis
Copyright ©2002 American Society of Hematology. Copyright restrictions may apply.
Maslak, P. ASH Image Bank 2002;2002:100363
Figure 1. High power view of peripheral smear of a patient with CML reveals neutrophils and some immature myeloid forms including blasts (arrow) (MacNeal Tetrachrome 1000x)
Copyright ©2001 American Society of Hematology. Copyright restrictions may apply.
Maslak, P. ASH Image Bank 2001;2001:100202
Figure 3. CML
Copyright ©2001 American Society of Hematology. Copyright restrictions may apply.
Maslak, P. ASH Image Bank 2001;2001:100202
Figure 5. CML
Copyright ©2001 American Society of Hematology. Copyright restrictions may apply.
Maslak, P. ASH Image Bank 2001;2001:100202
Figure 10. CML
A chimeric BCR-ABL gene derived from portions of the BCR gene on chromosome 22 and the ABL gene on chromosome 9
In more than 90% of cases BCR-ABL is created by a reciprocal (9;22)(q34;q11) translocation called the Philadelphia chromosome
BCR-ABL directs the synthesis of a constitutively active BCR-ABL tyrosine kinase Drives growth factor independent proliferation
and survival of bone marrow progenitors It does not interfere with differentiation resulting
in mature cells Detection of the BCR-ABL fusion gene through
PCR or chromosomal analysis
Chronic Myeloid Leukemia (CML)Chronic Myeloid Leukemia (CML)
Insidious onset with non-specific symptoms Splenomegaly may produce a “dragging”
sensation in abdomen or may get acute splenic infarct
Slow progression After ~ 3 years, accelerated phase in 50%
with increasing anemia and thrombocytopenia with additional cytogenetic abnormalities
After 6 to 12 months, accelerated phase terminates in a blast crisis (lymphoid or myeloid)
Median survival 3 years
Bone marrow transplant in young patients which is curative in 75% of cases performed during the stable phase
Imatinib, a BCR-ABL inhibitor, results in sustained hematologic remission in greater than 90% of patents; however, does not extinguish the CML “stem cell”
Characterized by increased marrow production of red cells, granulocytes and platelets with SXs from RBC increase.
PCV associated with mutations in the tyrosine kinase JAK2 gene leading to proliferation of hematopoietic cells independent of growth factors (less proliferative drive than CML)
Erythropoietin levels are low
Relative polycythemia is an increased RBC count due to a decrease in PV for example dehydration RBC mass is normal
Absolute polycythemia is an increase in bone marrow production of RBCs with increase in count and mass Appropriate absolute polycthemia is a response to
hypoxemia in smokers or other chronic lung disease or at altitude or cyanotic CHD
Inappropriate absolute polycythemia PCV or POLYCYTHEMIA VERA is an INAPPROPRIATE
ABSOLUTE POLYCYTHEMIA with a low erythropoietin. Ectopic EPO or erythropoietin production, i.e. RCC
Hypercellular marrow (trilineage) with only subtle increase in RBC progenitor
Mild organomegaly from congestion Peripheral blood has increased
basophils and large platelets Late in course of disease, extensive
marrow fibrosis is present with extramedullary hematopoiesis in the spleen and liver leading to organomegaly
Occurs in adults of middle age with incidence of 1-3 per 100,000 per year
SXs occur due to hyperviscosity from increased RBC count
Patients are plethoric and cyanotic due to stagnation and deoxygenation of blood in peripheral vessels
Headache, dizziness, hypertension, and gastrointestinal SXs
Most ominous is thrombosis and hemorrhage
Gout Increased breakdown of nucleated cells with
uric acid production from purines Increased histamine release from mast
cellsPruritus after bathing (mast cells
degranulate after change in skin temperature
Peptic ulcer disease – Histamine stimulates gastric acid production
Without Rx, death from bleeding or thrombosis occurs in months
With phlebotomy, ~10 year median survival
PCV evolves into a “spent” phase with development of myelofibrosis in 15 to 20% after ~ 10 years
Extramedullary hematopoeisis develops PCV transforms to AML in ~2%
Associated with JAK2 (50% of cases) or MPL (5-10% of cases) a receptor tyrosine kinase normally activated by thrombopoietin.
Unknown why JAK 2 causes PCV in some and ET in others
JAK2 or MPL signaling renders the progenitors thrombopoietin-independent leading to hyperproliferation
Mild increase in bone marrow cellularity Megakaryocytes are markedly increased
in number and in abnormally large forms
Delicate reticulin fibers in bone marrow Peripheral smears show abnormally
large platelets with mild leukocytosis Modest extramedullary hematopoiesis
with mild organomegaly in ~50% of patents
Copyright ©2003 American Society of Hematology. Copyright restrictions may apply.
Maslak, P. ASH Image Bank 2003;2003:100634
Figure 3. A clustering of megakaryocytes is often noted in essential thrombocythemia
Copyright ©2003 American Society of Hematology. Copyright restrictions may apply.
Maslak, P. ASH Image Bank 2003;2003:100634
Figure 1. Giant megakaryocytes can be seen alongside unilobed megakaryocytes in this bone marrow aspirate from a patient with essential thrombocythemia
Incidence 1-3 per 100,000 per year Occurs past 60 years old but may be seen
in younger people Dysfunction of platelets leads to
thrombosis and hemorrhage Erythromelalgia, a throbbing and burning
of hands and feet caused by occlusion of small arterioles by platelet aggregates (may be seen in PCV)
Indolent disease with median survival of 12 to 15 years.
Rx with “gentle” chemotherapy
Hallmark of disease is development of obliterative marrow fibrosis
JAK2 mutations present in 50 to 60% of cases
MPL mutations in 1 to 5% of cases Main pathologic feature is extensive
deposition of collagen in the marrow by non-neoplastic fibroblasts which displaces hematopoietic elements
Likely caused by inappropriate release of fibrogenic factors (PDGF and TGF-B) from neoplastic megakaryocytes.
Extramedullary production is disordered resulting in severe cytopenias
Initially, hypercellular marrow of all lineages Megakaryocytes are large, dysplastic and
abnormally clustered Peripheral blood may show leukocytosis and
thrombocytosis With progression, marrow is hypocellular
and fibrotic with clusters of atypical megakaryocytes with hematopoietic elements in dilated sinusoids due to fibrosis
Late, fibrotic marrow is converted into bone, which is called “osteosclerosis”
Extramedullary hematopoiesis causes severe splenomegaly (up to 4000 grams) with subcapsular splenic infarcts
Moderate hepatomegaly Peripheral blood smear shows:
Teardrop cells(dacrocytes)Leukoerythroblastosis (premature release of
nucleated erythroid progenitors and early granulocyte progenitors)
Abnormally large platelets Basophilia
Copyright ©2007 American Society of Hematology. Copyright restrictions may apply.
Fukumoto, J. et al. ASH Image Bank 2007;2007:6-00064
Figure 1. Bone marrow fibrosis (hematoxylin and eosin stain, low power)
Copyright ©2007 American Society of Hematology. Copyright restrictions may apply.
Fukumoto, J. et al. ASH Image Bank 2007;2007:6-00064
Figure 3. Bone marrow fibrosis (Trichrome stain, low power)
Copyright ©2009 American Society of Hematology. Copyright restrictions may apply.
Baden, H. S. ASH Image Bank 2009;2009:9-00033
Figure 5. Bone marrow trephine biopsy: showing thick coarse reticulin fibers (Grade 4 fibrosis)
Less common than PCV and ET Age > 60 years Progressive anemia and splenomegaly
with leukoerythroblastosis Decreased white counts and platelets as
disease progresses AML transformation occurs in 5 to 20% Bleeding, thrombosis, intercurrent
infections are complications Median survival is 3 to 5 years
Histocytosis-proliferative disorders of dendritic cells or macrophages
Langerhans cell-immature dendritic cell Mutlifocal multisystem Langerhans cell
histiocytosis (Letter-Siwe disease) Usually occurs before age 2 Cutaneous lesions along with multiorgan infiltration With chemo, 5 year survival is 50%
Eosinophilic granuloma-proliferation of Langerhans cells admixed with eosinophils, lymphocytes, plasma cells and neutrophils, typically arises in bones
Pulmonary Langerhans cell histiocytosis may be reactive proliferation in smokers
Langerhans cells have abundant vacuolated cytoplasm and vesicular nuclei containing linear grooves or folds
Birbeck granules in the cytoplasm are pentalaminar tubules, with a dilated terminal end producing a tennis racket appearance.
A Pardanani, T L Lasho, C Finke, C A Hanson and A Teffer. Prevalence and clinicopathologic correlates of JAK2 exon 12 mutations in JAK2V617F-negative polycythemia veraJAK2 exon 12 mutations in polycythemia vera. Leukemia 21, 1960-1963 (September 2007)
American Society of Hematology Image Bank
Chronic Myeloid Leukemia Polycthemia Vera: eMedicine Hematology from http://emedicine.medscape.com
John L. Frater, MD, Martin S. Tallman, MD, Daina Variakojis, MD, Brian J. Druker, MD, Debra Resta, RN, Mary Beth Riley, RN, MSN, OCN, Mary Ann Hrisinko, MT(ASCP), LoAnn C. Peterson. Chronic Myeloid Leukemia Following Therapy With Imatinib Mesylate (Gleevec). American Journal of Clinical Pathology. 2003;119(6).
Lyons J. Pathology of Leukemia I and II presentation. LMU/DCOM.
Robbins and Cotran Pathologic Basis of Disease 8th edition