L89-L92 - Hematopathology I-IV Flashcards
How are hematopoietic neoplasms classified?
- State of maturity of the neoplastic cells (acute = very immature = blasts vs. chronic = differentiated = mature)
- Cell type involved (Lymphoid vs. Myeloid)
What neoplasms are included in the Acute classification?
- Lymphoid: acute lymphoblastic leukemia
2. Myeloid: acute myeloid leukemia
What neoplasms are included in the Chronic classification?
- Lymphoid: chronic leukemias, lymphomas, and plasma cell disorders
- Myeloid: myeloproliferative disorders
What are leukemias?
Malignant neoplasms of the hematopoietic cells characterized by diffuse replacement of the bone marrow by neoplastic cells; these cells usually spill over into the peripheral blood
What are lymphomas?
Proliferations arising as discrete tissue masses
How are ALL and AML similar?
Both have an accumulation of neoplastic blast cells. These suppress normal hematopoiesis, leading to anemia, neutropenia, and thrombocytopenia.
What are the clinical features of acute leukemias?
- Abrupt stormy onset
- Symptoms: fatigue (anemia), fever (infection due to neutropenia), bleeding (thrombocytopenia)
- Generalized lymphadenopathy, splenomegaly, hepatomegaly (ALL > AML)
- CNS involvement (ALL > AML)
80% of acute leukemias in children are ___. Most cases occur in individuals younger than 15 y/o, with a peak incidence of about ___ y/o.
ALL; 4
Which type of acute leukemia is more common in adults? What is the median age?
AML; 50 years
What are the neoplastic cells in ALL?
Lymphoblasts - pre-B and pre-T cells
Approximately 85% of ALLs are pre ___ cell neoplasms that manifest as childhood leukemias.
B
What are the special clinical features of T-ALL?
- Presents in adolescent males with thymic involvement manifesting as a mass in the mediastinum
- Initially presents as a lymphoma, but is followed by a leukemic phase
How is ALL diagnosed?
Lymphoblasts with scant basophilic cytoplasm and fine nuclear chromatin (not clumpy); nuclear convolutions
True or false - morphology alone differentiates ALL from AML.
False - additional analysis is necessary
What are the markers used to diagnose ALL?
- T (CD 1, 2, 3, 4, 5, 7, 8) or B (CD 19, 20, 22) cell markers
- Terminal deoxynucleotidyl transferase (TdT) *
How do cells positive for TdT stain?
Brown on immunohistochemistry
Up to 90% of ALL patients have numerical or structural changes in the chromosomes of the leukemic cells, correlating with immunophenotype and sometimes prognosis. What are common changes?
- Hyperdiploidy (>50 chromosomes)
- t(12;21) - most common
- t(9;22) (BCR-ABL), Philadelphia chromosome
What is the prognosis of ALL in chidlren?
95% remission
80% cure
What are favorable prognostic indicators for ALL?
Age 2-10
Hyperdiploidy
t(12;21)
What are unfavorable prognostic indicators for ALL?
Age under 2
Adolescent or adult presentation
t(9;22)
What are the types of AML?
- AML with recurrent genetic abnormalities
- AML arising from myelodysplastic syndrome (MDS)
- Therapy-related
- NOS
What are myelodysplastic syndromes?
Clonal stem cell disorders showing defective and ineffective hematopoiesis with increased risk for transformation to AML
What are the types of MDS?
- Primary
2. Therapy-related (following chemo/radiation)
Discus the pathophysiology of MDS.
- Hypercellular marrow with peripheral cytopenia indicates ineffective hematopoiesis
- Clonal cytogenic abnormalities (5q-, monosomy 7)
- Stem cell damage
What morphologic abnormalities are seen in all lineages in MDS?
- Nuclear irregularity
- Nuclear budding
- Multinucleation
- Separated nuclear lobes (megakaryocyte)
What is the prognosis of MDS?
Median survival 9-29 months (primary) or 4-8 months (secondary)
In acute pro-myelocytic leukemia (t(15;17)), pro-coagulants released by leukemic cells may produce ___.
DIC
What does the fusion gene encode in acute pro-myelocytic leukemia (t(15;17))?
Abnormal retinoic acid receptor that blocks myeloid cell differentiation
How is acute pro-myelocytic leukemia treated?
All-trans-retinoic acid
How is AML diagnosed?
- > 20% myeloblasts
- Cytochemical stains - myeloperoxidase (stains brown) or alpha naphtyl butyrate esterase (orange)
- Flow cytometry (CD13, 33, 34, 117)
- Auer rods **
What are good prognostic indicators for AML?
t(15;17), t(8;21), or inversion of chromosome 16
What are poor prognostic indicators for AML?
Translocations involving chromosome 11q23
What are the 3 types of chronic leukemias?
- Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL)
- Hairy cell leukemia
- Adult T-cell leukemia/lymphoma
What is the most common leukemia of adults in the Western world?
CLL
CLL is a B-cell neoplasm that typically expresses what CD?
5 (pan T-cell), 20, 23
What mutations are seen in CLL?
Trisomy 12, 11q-, 13q-, deletion of 17p (p53)
What are clinical features of CLL?
- Elderly patients with immune dysfunction and hypogammaglobulinemia
- Some patients have autoimmune hemolytic anemia
What is Richter syndrome/transformation?
Higher grade process of CLL that is very aggressive
What indicates a good prognosis for CLL/SLL?
Those with IGH mutations
What are the two cell types involved in CLL/SLL?
- Small round lymphocytes with condensed chromatin and scant cytoplasm
- Fewer larger cells (pro-lymphocytes)
What is seen on peripheral blood smear in CLL/SLL?
Typical small lymphocytes with scant cytoplasm; smudge cells; cracked earth appearance, soccer ball appearance
What is hairy cell leukemia?
Cells have cytoplasmic projections
How do patients with hairy cell leukemia present?
Middle aged men
Pancytopenia, monocytopenia, splenomegaly, heptomegaly, infections
What does cytochemical staining of hair cell leukemia show?
Tartrate resistant acid phosphatase
What is the treatment and prognosis for hairy cell leukemia?
Gentle chemotherapy
Excellent
What does hairy cell leukemia look like on smear?
Cytoplasmic production
Round-oval nucleus
Where is Adult T-cell leukemia/lymphoma seen frequently?
Not US - southern Japan, West Africa, Caribbean
How do patients with Adult T-cell leukemia/lymphoma present?
Skin lesions, hepatosplenomegaly, lymphocytosis, hypercalcemia
CD4 positive T-cells cause a tumor
What causes adult T-cell leukemia/lymphoma?
HTLV-1 (virus)
How does Adult T-cell leukemia/lymphoma appear on peripheral smear?
Floret cells
What are the two categories of lymphomas?
Non-Hodgkin and Hodgkin
What are the categories of Non-Hodgkin lymphomas?
B-cell: follicular, mantle cell, Burkitt, and diffuse large B-cell
T-cell
What are some causes of lymphoma?
- Chromosomal abnormalities
- Immune deficiences
- Viruses
- Bacteria (H. pylori in gastric MALT lymphoma)
- Radiation
What type of lymphoma is seen in Africa?
Endemic Burkitt
What type of lymphoma is seen in the Mediterranean?
MALT
What type of lymphoma is seen in Asia?
Peripheral T-cell
How is lymphoma diagnosed?
Lymph node or tissue biopsy
What are the important B cell markers?
CD 19, 20
What are the important T cell markers?
CD 2, 3, 4, 5, 7, 8
What are the important myeloid markeres?
CD13, 33, Myeloperoxidase
What lymphoma constitutes 40% of adult non-Hodkins lymphomas?
Follicular lymphoma
How does follicular lymphoma present?
Painless lymphadenopathy
What is the treatment for follicular lymphoma?
Anti-CD20 antibody
What cells are seen in follicular lymphoma?
Small cells with cleaved/irregular nuclei (centrocytes) and larger cells with open nuclear chromatin and several nucleoli (centroblasts)
What is the immunophenotype of follicular lymphoma?
CD 10, 19, 20
Can also do a stain for BCL-2, which will be overexpressed
What are the genotypic findings of follicular lymphoma?
t(14;18) - BCL2/IGH fusion causes BCL2 over-amplification (anti-apoptotic)
How does follicular lymphoma appear on histology and grossly?
Lots of follicles with little space between them; can see white follicles on spleen grossly
Which lymphoma makes up 4% of NHLs?
Mantle cell lymphoma
Mantle cell lymphoma is seen in what population?
Older males
Describe the cells of mantle cell lymphoma?
Small cells with irregular nuclei
What is the immunophenotype of mantle cell lymphoma?
CD5, 19, 20
What is the genotypic finding in mantle cell lymphoma?
t(11;14) Cyclin D1-IGH fusion, causes cyclin D1 over-amplification (increased proliferation)
Burkitt lymphoma is common in what population?
Children/young adults
In Burkitt lymphoma, most tumors present at extranodal sites. What is common in the endemic and non-endemic forms?
Endemic (African) - mandible
Non-endemic: abdomen
Describe the tumor cells in Burkitt lymphoma.
Round cells, smaller than DLCL, larger than CLL
Increased number of histiocytes surrounded by clear spaces - starry sky pattern
What is the immunophenotype of Burkitt lymphoma?
CD10, 19, 20
In the African form of Burkitt, most are latently infected with ___.
EBV
What are the genotypic findings of Burkitt lymphoma?
t(8;14) MYC/IGH fusion, causes MYC over-amplification (increased proliferation)
Which lymphoma causes about 35% of adult NHLs?
Diffuse large B-cell lymphoma
What is the median age of diffuse large B-cell lymphoma patients?
60 y/o
What are the two distinct subtypes of diffuse large B-cell lymphoma?
Germinal center B-cell (GCB)
Activated B-cell (ABC)
What is the immunophenotype of diffuse large B-cell lymphoma?
CD20
What are the genetic mutations in diffuse large B-cell lymphoma?
t(14;18) - 30%
BCL6 locus rearrangements on 3q27 (30-40%)
Some have t(14;18) MYC translocations or BCL6
Describe the cell appearance in diffuse large B-cell lymphoma.
Large, vesicular bubbly chromatin
What is the presentation of peripheral T-cell lymphoma (PTCL) NOS?
Lymphadenopathy, eosinophilia, pruritis, fever, weight loss
What is the histologic feature of PTCL?
None - lots of heterogeneity, may see eosinophilia and angiogenesis
What is the age involvement of Hodgkin lymphoma?
Bimodal - young adults/adolescents and older adults
What are the 2 types of Hodgkin lymphoma?
Classical and nodular lymphocyte predominant
What are the 4 types of classical Hodgkin lymphoma?
Lymphocyte rich
Mixed cellularity
Lymphocyte depleted
Nodular sclerosis
Discuss the pathogenesis of Hodgkin lymphoma.
Clonal neoplastic disorder arising from B cells
Reactive cells are most likely due to the cytokines secreted by RS cells
NF-kappa-B activation by EBV is common
Discuss the histology of Hodgkin lymphoma.
- Reed-Sternberg cells (owl-eye)
- RS-cell variants (mononuclear, Lacunar)
- Reactive lymphocytes, histiocytes, and granulocytes
- Eosinophils
What are the CD markers for the classical types of HL?
CD15, 30
What are the CD markers for the nodular lymphocyte predominant HL?
CD20, 45
What are the types of plasma cell neoplasms?
- Multiple myeloma (plasma cell myeloma)
- Monoclonal gammopathy of undetermined significant (MGUS)
- Waldenstrom’s macroglobulinemia
What is Waldenstrom’s macroglobulinemia?
Related disorder that shows high levels of IgM M-spike and hyperviscosity of blood, with underlying lymphoplasmacytic lymphoma
What causes Waldenstrom’s macroglobulinemia?
MYD88 gene mutation
What happens in multiple myeloma?
Monoclonal plasma cell proliferation dependent on cytokines, especially IL-6, involving bone marrow and typically skeleton at multiple sites
What is the diagnostic criteria for multiple myeloma?
M-protein in serum or urine IgG (60%), IgA (25%)
Bone marrow showing clonal plasmacytosis or presence of a plasmacytoma
What organ damage is seen in multiple myeloma?
CRAB: hyperCalcemia Renal insufficiency Anemia Bone lesions - can see lytic lesions
How does multiple myeloma appear on smear?
Malignant plasma cell has globules
What is the median age of multiple myeloma?
70 years
What are the clinical features of multiple myeloma?
- Suppression of humoral immunity leading to recurrent infections
- Bence-Jones proteinuria causes renal insufficiency
- AL Amylodiosis
What is the most common plasma cell neoplasm?
MGUS
What are the 4 types of chronic myeloproliferative disorders?
- Chronic myelogenous leukemia (CML)
- Polycythemia vera
- Primary myelofibrosis
- Essential thrombocytosis
What is the general target of neoplastic transformation in the myeloproliferative disorders? What is the exception?
Multipotent myeloid progenitor cell; CML - can have both lymphoid and myeloid
What are common features of chronic MPDs?
- Splenomegaly
- Terminate in a spent phase - marrow fibrosis and peripheral blood cytopenias
- All can progress to acute leukemia
What is the common pathogenic feature of MPDs?
Mutated, constitutively activated tyrosine kinases that lead to growth factor independent proliferation
What is the mutation in CML?
BCR-ABL fusion gene
What is the mutation in polycythemia vera?
JAK2 point mutations
What is the mutation in ET and primary myelofibrosis?
JAK2, CALR, MPL point mutations
How is CML distinguished from other MPDs?
Philadelphia chromosome t(9;22) - leads to BCR-ABL fusion gene that encodes for a protein with tyrosine kinase activity
In CML, the bone marrow is often close to ___% cellular.
100
How do you differentiate between CML and Leukemoid reactions based on the peripheral blood?
1. WBC CML - >50,000/microL Leuk - <50,000/microL 2. Segs CML - all stages of maturation Leuk - almost all mature 3. LAP score CML - reduced Leuk - elevated
How do you differentiate between CML and Leukemoid reactions based on the bone marrow?
1. M:E ratio CML - >10:1 Leuk - <10:1 2. Splenomegaly CML - marked Leuk - variable
Also
1. BCR-ABL mutation
CML - present
Leuk - absent
Discuss the clinical presentation of CML.
Onset is insidious
Nonspecific initial symptoms
Slow progression
How is CML treated?
Allogeneic bone marrow transplant, INF-alpha, targeted biologic inhibitors of BCR-ABL (Imatinib/Gleevec)
Discuss the pathophysiology of primary myelofibrosis.
Excessive collagen deposition in the BM, secretion of PDGF and TGF-beta by neoplastic megakaryocytes, displacement of stem cells/normal marrow elements, extramedullary hematopoiesis
What are the phases of primary myelofibrosis?
Early: hypercellular bone marrow with tri-lineage hematopoiesis, clustered megakaryocytes, minimal fibrosis
Late: fibrotic marrow, clusters of abnormal megakaryocytes, sclerotic bone formation
What is a smear clue for primary myelofibrosis?
Tear drop cells
How does the BM appear in primary myelofibrosis?
Sclerotic bone, fibrosis, hypercellular, reticulin stain (black strands)
What happens in essential thrombocytosis?
Proliferation of megakaryocytic lineage cells