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wbc disorders

Deficiencies (leukopenias)
*9% of cancer deaths in adults
*40% of cancer deaths in children <15 yrs



Most commonly decrease in granulocytes
Lymphopenias are less common
-Congenital immunodeficiency states
*Advanced HIV infection
*Corticosteroid treatment


Neutropenia / Agranulocytosis

Decreased numbers of neutrophils
Typically < 1000 cells/µl
Extremely susceptible to bacterial and fungal infections


Neutropenia / Agranulocytosis causes

Inadequate or ineffective granulopoiesis
-Aplastic anemia, leukemia, chemotherapy, other drugs
Accelerated removal or destruction of neutrophils
-Immune-mediated injury (some drug induced)
-Increased peripheral utilization (overwhelming infection)
-Splenic sequestration (enlarged spleen / hypersplenism)


Neutropenia / Agranulocytosis morphology

Depends on the cause
-Increased or decreased granulocytic precursors in marrow


Neutropenia / Agranulocytosis clinical

Malaise, chills, fever, weakness, fatigability
Ulcerative lesions of the mucosa of the mouth and pharynx


Reactive Leukocytosis

Increased numbers of leukocytes that can be caused by microbial or non-microbial stimuli
Relatively non-specific
Classified by white cell series affected
May mimic leukemia (leukemoid reactions)
-Acute viral infections in children
-Severe chronic infections


Infectious Mononucleosis

Acute, self-limited disease of adolescents and young adults
-Fever, sore throat, generalized lymphadenitis
-Reactive lymphocytes in peripheral blood
-Antibody and T cell response to EBV
-Resolves in 4-6 weeks
B cells that are latently infected by EBV undergo polyclonal activation and proliferation
-These cells produce the heterophil antibodies detected by the monospot test


Infectious Mononucleosis clinical

Virus-specific cytotoxic T cells appear as reactive lymphocytes in the blood
Enlarged spleen (300-500g) is present in most cases
-Fragile and prone to rupture
Liver function is almost always transiently impaired
-Jaundice is unusual


Infectious Mononucleosis

Atypical presentations can be confused with other diseases
-Lymphoma, rubella, viral hepatitis, FUO
A normal immune system is extremely important in controlling the proliferation EBV-infected B cells
-Bone marrow and organ transplant patients
*Post-transplant lymphoproliferative disorder
-X-linked lymphoproliferative disorder


Reactive Lymphadenitis

Infections and non-microbial inflammatory stimuli can cause lymph node enlargement
Can be acute or chronic
Most are non-specific histologically


Acute Nonspecific Lymphadenitis

Most often confined to a local group of lymph nodes
Can be generalized in systemic bacterial or viral infections
Nodes are enlarged and tender
-Nodes show large germinal centers
-Pyogenic organisms may be associated with neutrophil infiltration
*Infection may involve the overlying skin (draining sinuses)
*Nodes may be fluculant (abscess formation)


Chronic Nonspecific Lymphadenitis

Follicular hyperplasia
Paracortical hyperplasia
Sinus histiocytosis


Follicular hyperplasia

B cell activation
-Rheumatoid arthritis, toxoplasmosis, early HIV


Paracortical hyperplasia

T cell activation
-Viruses, post-vaccination, drugs


Sinus histiocytosis

Distention and prominence of sinusoids, infiltration by macrophages
-Often encountered in nodes draining cancers


Cat Scratch Disease

Self-limited lymphadenitis caused by Bartonella henselae
Primarily a disease of childhood (90% are <18 years old)
Regional lymphadenopathy, most in neck or axilla, two weeks after a feline scratch
Lymphadenopathy regresses over the next 2-4 months, in most patients


Cat Scratch Disease

Rarely patients develop encephalitis, osteomyelitis, or thrombocytopenia
Histologically, lymph node shows sarcoid-like granulomas that may undergo central necrosis with the accumulation of neutrophils
-Organism can be visualized only by special techniques
Frequently confused clinically with lymphoma


Neoplastic Proliferations of White Cells

Lymphoid neoplasms
-Non-Hodgkin lymphomas, Hodgkin disease, lymphocytic leukemias, plasma cell dyscrasias and related disorders
Myeloid neoplasms
-Acute myelogenous leukemias, chronic myeloproliferative disorders, myelodysplastic syndromes
Histiocytic neoplasms
-Langerhans cell histiocytoses


Lymphoid Neoplasms

-Primarily involve the marrow with spillage of cells into the blood
-Produce masses in the lymph nodes and other tissues
Plasma cell dyscrasias
-Masses within bones
-Systemic symptoms due to production of complete or partial monoclonal immunoglobulin


Lymphoid Neoplasms

Despite their tendencies, all lymphoid neoplasms have the potential to spread to lymph nodes and other tissues, especially liver, spleen, and bone marrow
Lymphomas and plasma cell tumors can spill into the blood
Because of the overlap, lymphoid neoplasms can only be distinguished based on the appearance and molecular characteristics of the tumor cells


Lymphoid Neoplasms

Classified based on a combination of morphologic, phenotypic, genotypic, and clinical features
Lymphomas are divided into two groups
-Non-Hodgkin lymphoma (NHL)
-Hodgkin lymphoma


Lymphoid Neoplasms general principles

B- and T-cell tumors are composed of cells arrested or derived from specific stages of their normal differentiation (lineage-specific and maturity markers)
Most common lymphomas of adults are derived from follicular center or post-follicular center B cells (somatic hypermutation and immunoglobulin class switching)
All lymphoid neoplasms are monoclonal (antigen receptor gene and protein analysis)
Lymphoid neoplasms often disrupt normal immune regulatory mechanisms (immunodeficiency or autoimmunity)
Tumor is widely disseminated at the time of diagnosis (only systemic therapy can be curative)
-Only possible exception is Hodgkin lymphoma


Acute Leukemias

Principle pathogenetic problem in acute leukemia is a block in differentiation
-Leads to the accumulation of immature leukemic blasts in the marrow
-Suppresses normal hematopoiesis
-Bone marrow failure


Acute Leukemias clinical symptoms

Abrupt stormy onset
-Present within 3 months of onset of symptoms
Symptoms related to depression of marrow function
-Fatigue, fever, bleeding
Bone pain and tenderness
-Marrow expansion, subperiosteal infiltration
Generalized lymphadenopathy, splenomegaly, and hepatomegaly
CNS manifestations
-Headache, vomiting, nerve palsies from meningeal spread
-Children>Adults, ALL>AML


Acute Leukemias lab findings

Blasts in peripheral blood and bone marrow
WBC count: 100,000 cells/µl
Anemia is almost always present
Platelet count usually < 100,000 platelets/µl
Neutropenia is common
Uncommonly blasts may be absent from the peripheral blood (aleukemic leukemia)
Greatly important to distinguish ALL from AML


Precursor B- and T-Cell Lymphoblastic Leukemia/Lymphoma

Aggressive tumors composed of lymphoblasts
Occur predominantly in children and young adults
B and T cell tumors are morphologically indistinguishable
-B-cell appear in bone marrow and peripheral blood as leukemias
-T-cell commonly present as thymus masses and often progress rapidly to a leukemic phase, others seem to involve only the marrow at presentation
-Both take on the appearance of an acute lymphoblastic leukemia (ALL) at some time during their course


ALLs constitute 80% of childhood leukemias

Peak incidence is age 4, most are pre-B-cell
Pre-T-cell is most common in males 15-20 yrs of age


Precursor B- and T-Cell Lymphoblastic Leukemia/Lymphoma

TdT positive (95%)
Positive for lineage specific markers (B or T)


Pre-B-cell tumors

Good outcome
-Hyperdiploidy (>50 chromosomes/cell) is most common
-t(12;21) involving TEL1 and AML1 genes
Poor outcome
-Translocations involving MLL on 11q23
-Philadelphia chromosome


Pre-T-cell tumors

Completely different group of rearrangements
None predict outcome
55-60% have activating mutations in NOTCH1


Precursor B- and T-Cell Lymphoblastic Leukemia/Lymphoma prognosis

Children 2-10 yrs old have the best prognosis
-Most can be cured, 96% achieve remission
-Age is associated with pre-B-cell tumors and “good” chromosomal aberrations
Worse outcome variables
-Male gender
-10 yrs old
-High leukocyte count at diagnosis


Small Lymphocytic Lymphoma/ Chronic Lymphocytic Leukemia

Morphologically, phenotypically, and genotypically identical disorders
Differ only in extent of peripheral blood involvement
-Lymphocytosis >4,000/µl is CLL, if not it’s SLL
-Most patients are CLL
CLL is the most common leukemia of adults in the Western world


Small Lymphocytic Lymphoma/ Chronic Lymphocytic Leukemia pathophysiology

Neoplasm of mature B cells
The neoplastic B-cells suppress normal B-cell function, often resulting in hypogammaglobulinemia
15% of patients have autoantibodies to red blood cells
Tumor cells tend to displace normal marrow elements with time


Small Lymphocytic Lymphoma/ Chronic Lymphocytic Leukemia morphology

Small, mature-looking lymphocytes
Lymph nodes, bone marrow, spleen, and liver are involved in almost all cases
Absolute lymphocytosis in PB
-Neoplastic lymphocytes are fragile
-Produces “smudge cells” on smear


Small Lymphocytic Lymphoma/ Chronic Lymphocytic Leukemia Immunophenotype

Pan-B-cell markers CD19, CD20, CD23
Surface Ig


Small Lymphocytic Lymphoma/ Chronic Lymphocytic Leukemia Karyotype

50% abnormal
-Trisomy 12
-Deletion 11 and 12
-Translocations rare


Small Lymphocytic Lymphoma/ Chronic Lymphocytic Leukemia Molecular

Somatic hypermutation of Ig segments
If absent, worse prognosis


Small Lymphocytic Lymphoma/ Chronic Lymphocytic Leukemia clinical

Often asymtomatic at diagnosis
Symptoms include easy fatigability, weight loss, anorexia
Generalized lymphadenopathy and hepatosplenomegaly in 50-60%
Leukocyte count is highly variable from near normal to >200,000
Hypogammaglobulinemia develops late in about 50% (increased susceptibility to bacterial infection)
Autoimmune hemolytic anemia and thrombocytopenia are seen less commonly
Course is variable: mean survival 4-6 years
Tends to transform to more aggressive tumors like a prolymphocytic leukemia or diffuse large B cell lymphoma: mean survival < 1 year


Follicular Lymphoma morphology

40% of adult NHL in the U.S.
Lymph nodes effaced by nodular proliferations
Tumor cells resemble normal follicular center B cells


Follicular Lymphoma Immunophenotype/Molecular

Pan-B-cell markers (CD19, CD20, CD10)
BCL6, transcription factor for follicular center transformation
BCL2, not on normal follicular B cells
Somatic hypermutation of Ig genes


Follicular Lymphoma Karyotype

t(14;18) fuses BCL2 to IgH
Leads to inappropriate expression of BCL2 protein, prevents apoptosis


Follicular Lymphoma clinical

Occurs in older persons, M=F
Painless lymphadenopathy (freq generalized), other visceral site involvement is uncommon
Bone marrow is almost always involved at the time on diagnosis
Median survival 7-9 years, not easily curable
40% progress to diffuse large B cell lymphoma, with or without treatment
-Much less curable than de novo tumor


Mantle Cell Lymphoma morphology

4% of NHL, older males
Cells resemble normal mantle zone of lymphoid follicles
Diffuse or vaguely nodular pattern
Marrow involved in majority
20% have peripheral blood involvement
Frequent involvement of the GI tract


Mantle Cell Lymphoma Immunophenotype

Surface IgM and IgD
Pan-B-cell markers CD19 and CD20
CD5 (like CLL/SLL)
Cyclin D1 protein


Mantle Cell Lymphoma Karyotype/Molecular

t(11;14), cyclin D1 gene to IgH locus
Dysregulates the expression of cyclin D1
No somatic hypermutation, naïve B cell origin


Mantle Cell Lymphoma clinical

Fatigue and lymphadenopathy
Generalized disease involving bone marrow, spleen, liver, and often GI tract
Aggressive and incurable
Mean survival, 3-5 years


Diffuse Large B Cell Lymphoma

50% of adult NHL
Several forms of NHL sharing features
-B cell phenotype, diffuse growth pattern, and aggressive clinical history


Diffuse Large B Cell Lymphoma Immunophenotype/ Molecular

Mature B cell tumors
-Pan-B-cell markers (CD19, CD20)
-Many express surface IgM or IgG
-Somatic hypermutation of Ig genes


Diffuse Large B Cell Lymphoma karyotype

30% have t(14;18) involving BCL2 (may be transformed follicular lymphoma)
1/3 have rearrangements of BCL6
Higher fraction have mutations of BCL6


Diffuse Large B Cell Lymphoma Subtypes

EBV in setting of AIDS and post-transplant
Kaposi sarcoma herpesvirus (or HHV-8) associated with primary effusion lymphomas, usually immunosuppressed patients
Mediastinal large B cell lymphoma
-Young females
-Spreads to abdominal viscera and CNS


Diffuse Large B Cell Lymphoma clinical

Median age 60 years, but can present at any age (15% of childhood lymphomas)
Rapidly enlarging mass at one or several sites
-Extranodal presentation is common (GI tract, brain are more common but anywhere is possible)
-Liver, spleen, and marrow involvement is not common at time of diagnosis
Aggressive tumors that are rapidly fatal, if untreated
-Complete remission can be achieved in 60-80% with intensive combination chemotherapy
-50% remain disease free for several years and are often cured


Burkitt Lymphoma

Endemic form: African
Sporadic form: Other areas including U.S.
Histologically identical; clinical and virological differences
-African almost 100% EBV
-Sporadic only 15-20% EBV
-Starry sky pattern
-Basophilic cytoplasm with lipid vacuoles


Burkitt Lymphoma Immunophenotype/ Molecular

Surface IgM, kappa or lambda light chains
Pan-B-cell markers (CD19 ,CD20) and CD10
Somatic hypermutation


Burkitt Lymphoma Karyotype

t(8;14), t(2;8), or t(8;22)
MYC to heavy or light chain loci


Burkitt Lymphoma clinical

Mainly children and young adults
-30% of childhood NHL in U.S.
Usually arises at extranodal sites
-African: Maxilla or mandible
-U.S.: Abdominal tumors (bowel, retroperitoneum, and ovaries)
-Leukemic presentations are uncommon but do occur (must distinguish from ALL)
Extremely fast growing
Majority of patients can be cured (young patients)


Extranodal Marginal Zone Lymphoma

Low grade mature B cell tumor
Arises in MALT
Develops in setting of autoimmune disorders or chronic infection
-H. pylori associated gastric MALT lymphoma
*May regress with antibiotic therapy
-Other MALT tumors can be cured by radiotherapy or local excision
t(1;14) BCL10 and IgH
t(11;18) MALT1 and IAP2


Hairy Cell Leukemia

Indolent B cell tumor
Leukemic cell with fine, hairlike cytoplasmic projections
-TRAP (tartrate resistant acid phosphatase) stain is positive
Manifestations due to infiltration of marrow and spleen
-Splenomegaly, often massive
Lymphadenopathy is distinctly rare
Extremely sensitive to chemotherapeutic agents, esp. purine nucleosides
-Complete durable responses
-Overall excellent prognosis


Mycosis Fungoides and Sézary Syndrome

Neoplastic CD4+ T cells that home to skin
-Often referred to as cutaneous T cell lymphomas
-Erythrodermic rash to plaque to tumor phases
-Progressive disease, nodal and visceral
Sézary Syndrome
-Generalized exfolic erythroderma and tumor cells (Sézary cells) in blood
-25% of plaque and tumor phase have circulating tumor cells
Erythrodermic phase survive for years
Plaque, tumor, Sézary syndrome: 1-3 years


Adult T Cell Leukemia/Lymphoma

Caused by HTLV-1
-Endemic in southern Japan, Caribbean basin, and West Africa
-HTLV-1 also causes transverse myelitis
Malignant CD4+ lymphocytes
Extremely aggressive disease
-Median survival 8 months
-15-20% will have a chronic disease course indistinguishable from cutaneous T cell lymphoma


Peripheral T Cell Lymphoma

Heterogeneous group of tumors
15% of NHL
In general
-Disseminated disease at presentation
-Respond poorly to therapy


Plasma Cell Disorders

Originate from a clone of B cells that differentiates into plasma cells and secrete complete or partial immunoglobulin (M component)
Most common in middle-aged and elderly persons
Major variants
-Multiple myeloma
-Localized plasmacytoma
-Lymphoplasmacytic lymphoma
-Heavy-chain disease
-Primary or immunocyte-associated amyloidosis
-Monoclonal gammopathy of undetermined significance


Multiple Myeloma

Most common of the malignant plasma cell dyscrasias
Clonal proliferation of neoplastic plasma cells in the bone marrow
-Associated with multifocal lytic lesions throughout the skeletal system
Peak incidence between age 50 and 60


Multiple Myeloma pathophysiology

IL-6 supports the proliferation, produced by fibroblasts and macrophages in the bone marrow
Multiple translocations involving IgH locus
-Fusion partners include: cyclin D1, fibroblast growth factor receptor 3, cyclin D3, and MYC (late)
M component
-IgG 60%, IgA 20-25%, light chains only 15-20%
-Rarely IgM, IgD, or IgE
-Free light chains are excreted in the urine (Bence-Jones proteins)
-Frequently complete immunoglobulins and excess light chains are produced


Multiple Myeloma clinical

Bone pain (infiltration by tumor cells)
-Pathological fractures, hypercalcemia, marrow replacement
Recurrent infections (suppression of normal immunoglobulin secretion)
Hyperviscosity syndrome
Renal insufficiency (50% of patients)
-Bence-Jones proteins and other reasons
Amyloidosis (5-10% of patients)
Median survival 4-5 years, not curable


Lymphoplasmacytic Lymphoma

Peak incidence around age 60
Cells are small lymphocytes to plasmacytic lymphocytes to plasma cells
Behaves like an indolent B cell lymphoma
-Usually involves multiple lymph nodes, bone marrow, and spleen at diagnosis
Produces an M component
-IgM in most cases
-No free light chains
-No lytic bone lesions
-Often large amounts are produced


Lymphoplasmacytic Lymphoma clinical

Waldenström macroglobulinemia
-Accounts for most of the clinical symptoms of this disease
-A hyperviscosity syndrome resulting from large amounts of IgM produced by the tumor
*Visual impairment (tortuosity and distention of retinal veins, retinal hemorrhage and exudates)
*Neurologic problems (headaches, dizziness, tinnitus, deafness, stupor)
*Cryoglobulinemia (Raynaud phenomenon, cold urticaria)
Median survival 4-5 years, incurable progressive


Monoclonal Gammopathy of Undetermined Significance

Term applied to monoclonal gammopathies in asymptomatic individuals
1-3% of asymptomatic healthy individuals over age 50 have M protein in their serum
Precursor lesion that should be considered a form of neoplasia
-Develop into a well-defined plasma cell dyscrasia at a rate of 1% per year
-Need to rule out other forms of monoclonal gammopathy


Hodgkin Lymphoma

Distinctive group of neoplasms separated from the NHLs
-Morphologically characterized by distinctive neoplastic giant cells, called Reed-Sternberg (RS) cells, admixed with reactive nonmalignant inflammatory cells
-Associated with somewhat distinctive clinical features
-Stereotypical pattern of spread that allows different treatment
It is a tumor of germinal center B cells


Hodgkin Lymphoma
five subtypes

Nodular sclerosis
Mixed cellularity
Lymphocyte predominance
Lymphocyte rich
Lymphocyte depletion


Hodgkin Lymphoma Nodular sclerosis

Most common form
M=F, adolescents and young adults
Lower cervical, supraclavicular, mediastinal nodes
Lacunar cell variant of the RS cell
-CD15, CD30 positive
-No B or T cell specific markers
Nodules of lymphoid tissue separated by collagen bands
Excellent prognosis


Hodgkin Lymphoma mixed cellularity

25% of all cases
Most common in pts > age 50
Male predominance
Classic RS cells (CD15, CD30)
Heterogeneous cellular infiltrate
-Small lymphocytes, eosinophils, plasma cells, benign histiocytes
More disseminated disease and systemic manifestations (fever, night sweats, weight loss)


Hodgkin Lymphoma lymphocyte predominance

5% of Hodgkin lymphoma
Small lymphocytes and histiocytes
Lymphohistiocytic (L&H) variant of RS cells
-Have B cell markers
Isolated cervical or axillary lymphadenopathy
Excellent prognosis


Hodgkin lymphoma is quite different from other B cell lymphomas

Lack the common translocations
Different patterns of gene expression
Role of EBV
-70% of mixed cellularity type and some nodular sclerosis type have EBV genome
-Hyperactivation of NF-κB, transcription factor that promotes B cell proliferation and protects from pro-apoptotic signals


Hodgkin lymphoma Inflammatory infiltrate and RS cells seem to secrete factors that support each other

IL-5, TGFβ, IL-13 from RS cells
CD30 ligand from inflammatory cells


Hodgkin Lymphoma clinical

Painless lymphadenopathy
Clinical stage is most important prognostic indicator
-Radio- and chemotherapy
-5 year survival
*Stage I-A or II-A: near 100%
*IV-A or IV-B: 50%
-Therapy related secondary malignancies


Myeloid Neoplasms

Arise from hematopoietic stem cells
Typically give rise to monoclonal proliferations that replace normal bone marrow


Myeloid Neoplasms categories

Acute myelogenous leukemias
Chronic myeloproliferative disorders
Myelodysplastic syndromes


Acute myelogenous leukemias

Neoplastic cells blocked at an early stage of myeloid development
Immature cells can exhibit features of granulocytic, erythroid, monocytic, or megakaryocytic differentiation
Accumulate in the marrow, replace normal elements, and circulate in the peripheral blood


Chronic myeloproliferative disorders

Neoplastic clone retains the ability to undergo terminal differentiation but exhibits increased or dysregulated growth
Increase in one or more cell lines in the peripheral blood


Myelodysplastic syndromes

Terminal differentiation in a disordered and ineffective fashion
Dsyplastic marrow precursors
Peripheral cytopenias


Myeloid Neoplasms

The lines between these disorders sometimes blur
Myelodysplastic syndromes and chronic myeloproliferative disorders can often transform into a picture of AML
Some disorders have features of both myelodysplastic syndromes and chronic myeloproliferative disorders


Acute Myelogenous Leukemia

Affects primarily older adults, median age 50
Fatigue and pallor, bleeding, infection
Present shortly after onset of symptoms
Can present as a discrete mass (granulocytic sarcoma)
Diagnosis and classification are based on morphologic, histochemical, immunophenotypic, and karyotypic studies
-Karyotyping is most predictive of outcome


Acute Myelogenous Leukemia Pathophysiology

Most are associated with acquired mutations in transcription factors that inhibit normal myeloid differentiation
-Insufficient to cause disease alone
Complementary mutations in a number of other genes that promote enhanced proliferation and survival (e.g., FLT3)


Acute Promyelocytic Leukemia and t(15;17)

Fusion gene between retinoic acid receptor α (RARA) gene and PML gene
Abnormal PML/RARA proteins block differentiation at the promyelocyte stage
Pharmacologic doses of retinoic acid overcome the block and allow the cells to differentiate into neutrophils and die
-Result: Clearance of tumor cells and remission
-Very specific, other AMLs don’t respond
-Patients will relapse if treated with retinoic acid alone, but combination chemotherapy gives an excellent prognosis


Acute Myelogenous Leukemia morphology

At least 20% of bone marrow cellularity is composed of myeloid blasts or promyelocytes
Auer rods are distinctive red staining needle-like structures
-Found only in myeloid blasts
-Aggregated primary granules


Acute Myelogenous Leukemia Histochemistry

Granulocytic differentiation
-Myeloperoxidase positive
-Auer rods are strongly positive
Monocytic differentiation
-Lysosomal nonspecific esterase positive


Acute Myelogenous Leukemia Immunophenotype
& karyotype

-Heterogeneous expression of markers
*Most have a combination of myeloid-associated antigens
~CD13, CD14, CD15, CD64, CD117
~CD33 on myeloid progenitor cells
-Several characteristic translocations


Acute Myelogenous Leukemia classification

AMLs are diverse in terms of genetics, predominant line of differentiation, and maturity of cells
French-American-British classification
-Line of differentiation and maturity
-Limited prognostic value
WHO classification
-Takes prognostic variables into account


Acute Myelogenous Leukemia prognosis

AML is a devastating disease
“Good-risk” has 50% long-term disease free survival
Overall, 15-30% long-term disease free survival with conventional chemotherapy
More aggressive approaches, bone marrow transplantation


Myelodysplastic Syndromes

Bone marrow partially or wholly replaced by the progeny of a transformed multipotential stem cell that retains the capacity to differentiate into red cells, granulocytes, and platelets but in an ineffective and disordered way
-Marrow hypercellular or normocellular
-Peripheral blood cytopenias
-Clone is genetically unstable, may transform into acute leukemia
-Most cases are idiopathic
-Chemotherapy with alkylating agents and ionizing radiation exposure are risk factors


Myelodysplastic Syndromes

70% have a cytogenetically abnormal clone identified
-Loss of 5 or 7
-Deletions of 5q or 7q
Marrow is populated by abnormal appearing precursors
May be due to immunological suppression normal stem cells in some cases
10-40% develop into AML


Myelodysplastic Syndromes clinical

Most patients 50-70 years old
Infections, anemia, bleeding
Response to chemotherapy is poor
Some respond to immunosuppressants
Prognosis is variable
Median survival 9-29 months


Chronic Myeloproliferative Disorders

Hyperproliferation of neoplastic myeloid progenitors that retain the capacity for terminal differentiation
-Increase of one or more cell lines in peripheral blood
-Tend to seed secondary hematopoietic organs (liver, spleen, lymph nodes)
*Hepatosplenomegaly caused by extramedullary hematopoiesis and mild lymphadenopathy


Chronic Myeloproliferative Disorders

Mutated tyrosine kinases is a common theme
-Generate high intensity of signals for growth and survival
Most patients fall into one of four diagnostic entities
-Chronic myelogenous leukemia (CML)
-Polycythemia vera (PCV)
-Essential Thrombocythemia
-Primary myelofibrosis


Chronic Myelogenous Leukemia

Principally affects adults between 25 and 60 years of age
15-20% of all leukemias


Chronic Myelogenous Leukemia Pathophysiology

CML is a disorder of a pluripotent stem cell
Uniformly has an acquired genetic abnormality, the BCR-ABL fusion gene
-t(9;22), the derivative chromosome 22 is often called the Philadelphia chromosome
-95% have Ph chromosome
-5% have a sub-cytogenetic level molecular rearrangement or multiple chromosome cytogenetic translocations
-Philadelphia chromosome is also present in 25% of adults with ALL and rare cases of adults with AML


Chronic Myelogenous Leukemia Tyrosine kinase domain of ABL is fused to BCR

Fusion protein has tyrosine kinase activity
Decreases requirements for growth factors by activating the growth factor receptor
Growth and survival enhanced
Granulocytic cells most affected
Proliferating CML progenitors retain the capacity for terminal differentiation


Chronic Myelogenous Leukemia morphology

Leukocyte count elevated, often >100,000
Predominantly neutrophils, metamyelocytes, and myelocytes
-Basophils and eosinophils may be prominent
Usually <5% myeloblasts
Thrombocytosis is typical
Marrow is hypercellular
Splenomegaly from extramedullary hematopoiesis


Chronic Myelogenous Leukemia clinical course

Slow onset, nonspecific symptoms
Extreme splenomegaly
Differentiate from a leukemoid reaction
-Philadelphia chromosome
-Leukocyte alkaline phosphatase
*Low in CML, high if reactive leukocytosis or other MPD


Chronic Myelogenous Leukemia clinical course contin

Slow progression, untreated median survival 3 years
50% of patients enter an accelerated phase
-Increasing anemia, thrombocytopenia, additional cytogenetic abnormalities
Accelerated phase leads to blast crisis
-Acute leukemia (30% ALL, 70% AML)
50% of patients seem to enter blast crisis without an accelerated phase
-Bone marrow transplant is definitive therapy
*Curative in 70%, can carry a high risk
-Tyrosine kinase inhibitors


Polycythemia Vera

Excessive neoplastic proliferation and maturation of erythroid, granulocytic, and megakaryocytic elements
Most obvious clinical signs and symptoms are related to the absolute increase in red cell mass
-Need to differentiate from relative polycythemia or reactive polycythemia
-Low levels of erythropoietin in serum in PCV
90% have mutation in JAK2, a tyrosine kinase


Polycythemia Vera morphology

Anatomic changes stem from increased blood volume and viscosity
-Liver and spleen enlargement
Due to increased viscosity and vascular stasis, thromboses and infarctions are common
-Heart, spleen, kidney
Hemorrhages occur in 1/3 of patients
Basophilia in peripheral blood
Marrow is hypercellular with some marrow fibrosis present in 10% at time of diagnosis


Polycythemia Vera clinical course

Appears insidiously, usually in late middle age
Plethoric and somewhat cyanotic
Basophil histamine release
-Pruritis, peptic ulceration
Thrombotic and hemorrhagic tendencies as well as hypertension
-Headache, dizziness, GI symptoms, hematemesis, melena are all common
Gout (10%) or asymptomatic hyperuricemia
RBC count 6-10 million, hematocrit 60% common


Polycythemia Vera clinical course contin

Without treatment, death occurs within months from vascular complications
With therapeutic phlebotomies, median survival is about 10 years
With prolonged survival, PCV can develop into a “spent phase” characterized by marrow fibrosis and a shift in hematopoiesis to the spleen which enlarges massively
Transformation to AML occurs in 2-15% of patients


Primary Myelofibrosis

A myeloproliferative disorder where marrow fibrosis occurs early in the disease
Hematopoiesis shifts to the spleen, liver, and lymph nodes
-Extreme splenomegaly and hepatomegaly develop
-Hematopoiesis is disordered and inefficient
Fibrosis is thought to be due to growth factors secreted by neoplastic megakaryocytic cells stimulating normal marrow fibroblasts
JAK2 mutation (same as PCV) in 50% of cases


Primary Myelofibrosis diagnosis

Usually has marrow fibrosis at time of diagnosis
-Markedly abnormal peripheral blood smear
*Red cells abnormal shapes, nucleated erythroid precursors, immature white cells (metamyelocytes and myelocytes), basophilia
*Platelets abnormal in size, shape, and function
*May resemble CML, but no Ph chromosome
-Hyperuricemia and gout


Primary Myelofibrosis outcome

Median survival 4-5 years
5-15% transform to AML


Langerhans Cell Histiocytosis

Langerhans cells are immature dendritic cells found most prominently in the skin
Different clinical forms are believed to be variations of the same basic disorder
Cells are histiocytic in appearance rather than dendritic
-HLA-DR +, CD1 +
-HX bodies (Birbeck granules) in the cytoplasm


Langerhans Cell Histiocytosis Acute disseminated Langerhans cell histiocytosis (Letterer-Siwe disease)

Usually occurs in children <2, occasionally in adults
Multifocal cutaneous lesions composed of Langerhans cells, resembles seborrheic skin eruptions
Hepatosplenomegaly, lymphadenopathy, pulmonary lesions, destructive osteolytic bone lesions
Anemia, thrombocytopenia, recurrent infections
*Otitis media and mastoiditis
Clinical picture may resemble acute leukemia
Untreated, rapidly fatal
Intensive chemotherapy, 50% survive 5 years


Langerhans Cell Histiocytosis Unifocal and Multifocal Langerhans Cell Histiocytosis (eosinophilic granuloma)

Expanding, erosive accumulations of Langerhans cells usually within the medullary cavities of bones
Histiocytes mixed with eosinophils, lymphocytes, plasma cells, and neutrophils
Similar lesions may also be found in the skin, lungs, or stomach


Langerhans Cell Histiocytosis unifocal lesions

Usually skeletal
Asymptomatic or pain and tenderness
May cause pathologic fracture
-Heal spontaneously
-Cured by local excision or irradiation


Langerhans Cell Histiocytosis Multifocal lesions

Usually affects children
Present with fever, diffuse skin eruptions (scalp and ears), frequent bouts of otitis media, mastoiditis, upper respiratory tract infections
May cause mild lymphadenopathy, hepatomegaly, splenomegaly
50% involvement of posterior stalk of pituitary causing diabetes insipidus
Hand-Schüller-Christian triad
-Calvarial bone defects
-Diabetes insipidus
Many patients experience spontaneous regressions, others can be successfully treated with chemotherapy



An enlarged spleen removes excessive numbers of circulating formed blood elements
-Platelet removal is more common and more severe
-Red cell removal
-Neutrophil removal


Thymic hyperplasia

Associated with the appearance of lymphoid follicles in the medulla
Present in most patients with myasthenia gravis, also can be seen in other autoimmune diseases (SLE, rheumatoid arthritis)



Neoplastic thymic epithelial cells
-Benign thymomas (60-70%)
*Cytologically and biologically benign
-Malignant thymoma type I (20-25%)
*Cytologically benign but biologically aggressive
-Malignant thymoma type II (5%)
*Thymic carcinoma
*Cytologically malignant, behaves like a cancer
Typically arise in middle adult life