WBC disorders Flashcards
wbc disorders
Deficiencies (leukopenias) Proliferations -Reactive -Neoplastic *9% of cancer deaths in adults *40% of cancer deaths in children <15 yrs
Leukopenia
Most commonly decrease in granulocytes Lymphopenias are less common -Congenital immunodeficiency states -Acquired *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
Leukemias
-Primarily involve the marrow with spillage of cells into the blood
Lymphomas
-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
-ALL>AML
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
immunophenotyping
TdT positive (95%) Positive for lineage specific markers (B or T)
Pre-B-cell tumors
karyotyping
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
kayotyping
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
CD5
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.
Morphology
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
Morphology
-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
-Pancytopenia
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 -Aggressive -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)
*Bleeding
*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
Immunophenotype -Heterogeneous expression of markers *Most have a combination of myeloid-associated antigens ~CD13, CD14, CD15, CD64, CD117 ~CD33 on myeloid progenitor cells Karyotype -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
Treatment
-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
variable
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 Indolent -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
-Exophthalmos
Many patients experience spontaneous regressions, others can be successfully treated with chemotherapy
Hypersplenism
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)
Thymoma
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
