Jim Exam 6 HemeOnc

What is a key feature of normal bone marrow?

Trilineage hematopoiesis

What are the components seen in trilineage hematopoiesis?

(1) Megakaryocytes (2) Erythroid precursor colonies (3) Granulocytic precursors and mature forms

What is the most immature cell of the erythroid lineage?

Pronormoblast

What changes occur during erythroid maturation?

(1) Cell size decreases (2) Cytoplasm ratio increases (3) Nuclear size decreases and disappears

What is the immature cell of the granulocytic lineage?

Myeloblast

What changes occur during granulocytic maturation?

(1) Cell size decreases (2) Nuclear size decreases (3) Nucleus goes from round, fine chromatin to segmented, dark chromatin (3) Formation of primary and secondary granules

What are key features of myeloblasts?

(1) Large nucleus with fine chromatin (2) Prominent nucleoli (3) Scant/variable cytoplasm

What laboratory processes are utilized in a lymphoma workup?

(1) Surgical pathology (2) Cytology (3) Flow cytometry (4) FISH (5) Molecular studies

What is the goal of the lymphoma workup?

(1) Characterize the cell type (2) Understand genetic abnormalities

What is immunophenotyping?

Using markers (antigens) expressed by cells and their patterns to identify cells

What state does tissue need to be in for a proper lymphoma workup?

Fresh

What are two forms of molecular studies?

PCR and DNA sequencing

What are the zones of a normal germinal center?

(1) Dark zone (2) Light zone (3) Mantle zone (4) T cell zone

What cells are found in the dark zone?

Centroblasts (noncleaved, rapidly proliferating B cells)

Tingible body macrophages (phagocytose apoptotic B cells)

What cells are found in the light zone?

Centrocytes (smaller, cleaved cell derived from centroblasts)

Folicular dendritic cells

Th cells

What cells are found in the mantle zone?

Naïve B cells

What is the role of Tingible body macrophages?

Phagocytize dead B cells (which can be seen in their cytoplasmic debris)

What does CD20 staining on a germinal center do?

Highlights B cells in the follicle

What does CD3 staining on a germinal center do?

Highlights T cells in the interfollicular area

What does BCL2 staining on a normal germinal center do?

Absent/negative in normal germinal centers since BCL2 has antiapoptotic activity

What is the Pelger Huet anomaly?

The nuclear hyposegmentation of neutrophils and other granulocytic cells

What causes a Pelger Huet anomaly?

A lamin B receptor mutation causing defects in the scaffolding proteins of the cell

What causes Pseudo Pelger Huet?

(1) Certain medications (2) Infections (3) Myeloproliferative neoplasms

How does Pelger Huet present?

May be clinically silent or involve soft tissue infections

What is Chediak Higashi Syndrome?

Failure of neutrophils to properly respond to chemotactic signals and failure of giant lysosome granule function

What causes Chediak Higashi Syndrome?

Mutations in the lysosomal trafficking regulator (LYST) gene leading to the failure of microtubule formation

How does Chediak Higashi Syndrome present?

Soft tissue abscesses with S. aureus, platelet issues, Schwann cell issues, NK and T cells

What causes Chronic Granulomatous Disease?

Mutations in NADPH oxidase in phagocytes, leading to impaired destruction of phagocytosed microorganisms

What test is used to screen for Chronic Granulomatous Disease?

Nitroblue Tetrazolium test (NBT)

Describe briefly how results of the Nitroblue Tetrazolium Test are interpreted

In normal neutrophils, granules stain blue; in abnormal neutrophils, the cytoplasm does not have stained granules

How does Chronic Granulomatous Disease present?

Severe recurrent bacterial and fungal infections in any organ

What is lymphadenitis?

Inflammation of LNs, usually due to infection

What is granulomatous lymphadenitis?

Inflammation of LNs leading to the formation of granulomas

What are causes of granulomatous lymphadenitis?

(1) TB (2) Fungal infections (3) Cat scratch disease (4) Sarcoidosis

What characteristic histology is seen in granulomatous lymphadenitis?

Asteroid bodies

What are the acute leukemias?

(1) B-ALL (2) T-ALL (3) AML

What are the cells of origin for B-ALL, T-ALL, and AML?

(1) B-ALL = immature B cells (2) T-ALL = immature T cells (3) AML = Hematopoietic stem cell or early myeloid progenitor

What leukemia is indicated by the replacement of marrow by lymphoid blasts and no Auer rods are seen?

ALL, immunophenotyping would determine B or T cell origin

What leukemia is indicated by the replacement of marrow by myeloid blasts and Auer rods are present?

AML

What is the most common childhood neoplasm?

B-ALL

Describe the pathogenesis of B-ALL

Arises in the marrow and replaces normal marrow elements with lymphoid blasts, causing symptoms related to anemia, thrombocytopenia, and neutropenia

What areas can serve as reservoirs for B-ALL often attributed to relapse?

CNS and testis

What would be seen in the peripheral blood smear of a B-ALL patient?

Abnormal amount of lymphoblasts

What are favorable factors for B-ALL prognosis?

(1) 1-10 yrs old (2) Female (3) WBC < 50 x 109/L (4) No CNS disease

What is a common but unfavorable mutation seen in B-ALL?

BCR-ABL mutation due to a 9;22 translocation (Philadelphia chromosome)

What feature may be seen in T-ALL but not B-ALL?

Mediastinal masses / thymus involvement

How does Acute Myeloid Leukemia (AML) typically arise?

From a preexisting myeloproliferative neoplasm or MDS

What are most symptoms of AML related to?

Marrow failure

What would a bone marrow aspirate from an AML patient show?

Marrow filled with myeloblasts

What mutations are found in 10% of AML cases?

IDH1 or IDH2 mutations

What is a very medically significant variant of AML?

Acute Promyelocytic Leukemia (APL)

What is the predominant cell type in APL?

Promyelocytes with characteristic bilobed nuclei, coarse granules, and Auer rods

What mutation causes APL?

PML-RARA caused by a 15;17 translocation

How is APL treated?

All-trans retinoic acid (ATRA) is administered with a presumptive diagnosis of APL due to its severity as a coagulopathy

What is Myelodysplastic Syndrome (MDS)?

A large group of myeloid neoplasms that lack the defining feature of AML but are characterized by maturation defects associated with ineffective hematopoiesis and a high risk of transformation to AML

What does the marrow look like in MDS?

(1) Marrow is filled with dysplastic cells (2) Erythroid cells form with iron deposits in the mitochondria - "ring sideroblasts" (3) Megakaryocytes are hypolobated

What does a TP53 mutation in MDS prognostically indicate?

Poor outcome

What are myeloproliferative neoplasms?

A group of neoplasms characterized by the presence of mutated and constitutively active tyrosine kinases or other acquired aberrations of signaling factors leading to growth factor independence

What is a common clinical finding associated with myeloproliferative neoplasms?

Extramedullary hematopoiesis

What are the transformations that myeloproliferative neoplasms can undergo?

(1) A "spent phase" resembling primary myelofibrosis (2) A "blast crisis" resembling AML

What triggers transformation to a blast crisis or spent phase?

Acquisition of additional somatice mutations

List the myeloproliferative neoplasms

(1) CML (2) CNL (3) CEL (4) PM (5) PCV (6) ET

What is the distinguishing feature of CML in comparison to the other myeloproliferative neoplasms?

BCR-ABL gene caused by a 9;22 translocation (Philadelphia chromosome)

What is seen in the peripheral blood smear in CML?

(1) Marked nontoxic neutrophilia (2) Left shift to blasts (3) Basophilia (4) Thrombocytosis

How does the spleen look in CML?

Enlarged due to extramedullary hematopoiesis, possibly causing infarcts

Describe the onset and progression of CML

(1) Onset is insidious (2) Usually accelerates to a blast crisis (3) Rarely progresses to a spent phase

What is CNL and what mutation is it associated with?

(1) Marked toxic neutrophilia (2) Minimal left shift (3) CSF3R mutation

What is CEL and what mutation is it associated with?

(1) Marked eosinophilia (2) PDGFR mutations (3) Be sure to exclude other causes such as parasites and allergies

What is primary myelofibrosis (PM)?

Development of obliterative marrow fibrosis that reduces the marrow capacity causing cytopenias and extensive extramedullary hematopoiesis

What causes PM?

Inappropriate release of fibrogenic factors from neoplastic megakaryocytes

What are characteristic findings of PM?

(1) Leukoerythroblastosis (2) Myelophthisis (3) Dacrocytes (4) Hepatosplenomegaly

What is leukoerythroblastosis?

Immature myeloid and erythroid cells in the blood

What is myelophthisis?

Process of bone marrow infiltration causing extramedullary hematopoiesis

What are dacrocytes?

Teardrop-shaped RBCs indicative of marrow fibrosis

How does the marrow progress in PM?

Initially hypercellular due to abnormal megakaryocytes but becomes hypocellular and fibrotic

What mutation is associated with PM?

JAK2 mutation

What is polycythemia vera (PCV)?

Characterized by erythrocytosis

What mutation is associated with PCV?

JAK2 mutation

What causes most of the symptoms related to PCV?

Increased RBC mass causes increased blood volume and viscosity causing congestion of tissues, thromboses, infarctions, and hemorrhages

What does the peripheral blood smear show in PCV?

Basophilia

What does the bone marrow look like in PCV?

Hypercellular

How does PCV usually progress?

Usually to a spent phase (resembling PM), and rarely to a blast crisis

What is essential thrombocythemia (ET)?

Thrombocytosis due to clonal proliferation of megakaryocytes in the bone marrow

What mutation is associated with ET?

JAK2 mutation

How does ET usually progress?

Usually to a spent phase (resembling PM), and rarely to a blast crisis

What are the general characteristics of Hodgkin Lymphoma?

(1) Localized to a single axial group of LNs (2) Orderly spread by contiguity (3) Mesenteric nodes and Waldeyer ring are rarely involved (4) Extranodal involvement is uncommon

What are the general characteristics of non-Hodgkin Lymphoma?

(1) Usually involves multiple LN groups (2) Noncontiguous spread (3) Mesenteric nodes and Waldeyer ring are commonly involved (4) Extranodal involvement is common

What are the key diagnostic features of Hodgkin lymphoma?

(1) Reed-Sternberg giant cells (2) Robust but ineffective immune response to the RS cells (3) Arises in a single LN or chain of LNs with contiguous spread

What are features of Reed-Sternberg cells?

(1) Large (2) Enormous multilobate nucleus (3) Prominent nucleoli (4) Abundant eosinophilic cytoplasm (5) Cells can have two mirror-image nuclei with a prominent nucleolus and a clear zone

What are lacunar cells?

A RS cell variant

What are the subtypes of Hodgkin Lymphoma?

(1) Nodular sclerosis (2) Mixed cellularity (3) Lymphocyte rich (4) Lymphocyte Depletion (5) Nodular lymphocyte predominant

Of the subtypes, which is the only non-classical HL?

Nodular lymphocyte predominant

Where does HL arise from?

Germinal center B cells

What is a frequently implicated etiology of HL that can often be seen in the RS cells?

EBV

How does HL usually manifest clinically?

Painless lymphadenopathy

What is the NHL of immature B cells?

B-Lymphoblastic Lymphoma/Leukemia (B-LBL)

Describe B-LBL

(1) High grade neoplasm of immature B cells (2) Common in children and young adults (3) Histology shows sheets of lymphoblasts with a B cell immunophenotype

What are the indolent NHLs of mature B cells?

(1) Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL) (2) Follicular lymphoma (3) MALT lymphoma (4) Mantle Cell lymphoma (5) Hairy cell lymphoma

What is the difference between CLL and SLL?

They are essentially identical, only differing in the extent of involvement

What is the most common leukemia of adults in the Western World?

CLL