Mature B-cell neoplasms

Question 1

What is the prototypical immunophenotype of CLL/SLL?

Answer 1

CD19+, CD20 weak, CD22 weak (B-cell markers)

CD5+, CD23+

CyclinD1-

Question 2

What is the threshold requirement in peripheral blood for a diagnosis of CLL/SLL?

Answer 2

5 x 10⁹/L lymphocytosis with a proven CLL immunophenotype.

(or, 5000/uL)

Question 3

In what demographics is CLL most (or least) common?

Is it known to be familial?

Answer 3

Seen about 2x in men, and is very rare in Asians.

It is the most common familial leukemia, with ~7.5x risk with a positive first-degree family member.

Question 4

What is the cell of origin of CLL/SLL?

Answer 4

Probably, CLL/SLL arises from an antigen-experienced B-cell.

Question 5

What are the clinical manifestations of CLL/SLL?

Answer 5

Usually asymptomatic (discovered incidentally on routine CBCs). In rarer cases, can present with lymphadenopathy, hepatosplenomegaly, B-symptoms, or cytopenic symptoms (from bone marrow involvement).

Question 6

Describe the morphologic appearance of CLL/SLL in peripheral blood.

Answer 6

A predominance of small, round, mature-looking lymphocytes. Dense chromatin clumping gives a “cracked mud” appearance,

Rarer “atypical” cases can have more abundant cytoplasm.

Question 7

Describe the morphologic appearance of CLL/SLL in bone marrow, lymph node, and spleen.

Answer 7

Infiltration with a bland small mature round lymphocyte population, which may form “proliferation foci” (nodules of larger paraimmunoblasts or prolymphocytes).

Proliferation foci are rarely seen in bone marrow. Spleen can have a miliary nodular appearance.

Question 8

Recall four subtypes/variants of CLL.

Answer 8

Atypical/mixed: Exhibits larger neoplastic cells and has an overall more aggressive clinical course.

with plasmacytoid differentiation: Probably overlaps with LPL.

with Reed-Sternberg cells: May be an incidental finding or indicate Richter transformation to cHL.

Mu heavy chain disease: Very rare form with little adenopathy but more organ infiltration.

Question 9

Recall some negative prognostic markers in CLL/SLL.

Answer 9

CD38 expression

CD49d expression

ZAP-70 expression (corresponds to IGHV unmutated phenotype)

Question 10

What are the most common genetic abnormalities in CLL/SLL?

Answer 10

13q14 deletion: Most common (70% of cases), corresponds to usualy phenotype and portends good prognosis.

Less common are trisomy 12, 11q23 deletion, and 17p deletion.

Question 11

What is a Richter transformation? How common is it? What molecular changes are implicated?

Answer 11

Transformation of a CLL/SLL to a more aggressive lymphoma, usually DLBCL but sometimes HL or others.

It occurs in about 2-10% of CLL/SLL patients.

May result from mutations in TP53, CDKN2A, or activation of C-MYC or NOTCH1.

Question 12

What differential diagnoses must be ruled out in the workup of CLL/SLL?

Answer 12

Polyclonal B-cell proliferations (reactive, “benign polyclonal lymphocytosis”)

Mantle cell lymphoma (can be CD5+ and have similar morphology)

Follicular lymphoma (expresses germinal center markers)

Question 13

What is monoclonal B-cell lymphocytosis (MBL)?

How is it managed?

Answer 13

An asymptomatic clonal proliferation of mature lymphocytes analogous to CLL but not quite reaching the diagnostic requiresments of CLL. It bears the same immunophenotype and genetics as CLL.

It is generally monitored, as only 1%/yr will progress to CLL.

Question 14

What is B-prolymphocytic leukemia (B-PLL)?

Answer 14

A controversial (and possibly wastebasket) entity defined by a peripheral blood (>55%) proliferation of B-prolymphocytes.

Question 15

What is Waldenstrom macroglobulinemia, and what disease is it associated with?

Answer 15

An IgM monoclonal paraprotein, which can cause hyperviscosity symptoms and organ dysfunction.

It is associated mainly with lymphoplasmacytic lymphoma.

Question 16

What genetic aberration is most classically seen in cases of lymphoplasmacytic lymphoma?

Answer 16

MYD88 L265P mutation

Question 17

What is Bing-Neel syndrome?

Answer 17

CNS involvement by a lymphoplasmacytic lymphoma (LPL); manifests neurologic symptoms and may be diagnosable on CSF cytology.

Question 18

How does lymphoplasmacytic lymphoma usually present?

Answer 18

IgM paraprotein can cause hyperviscosity, cryoglobulinemia, renal failure, arthralgias and neuropathy.

Question 19

Describe the typical lesional cell morphology in lymphoplasmacytic lymphoma.

What other pathologic feature can be seen in peripheral blood?

Answer 19

Mature lymphocytes with plasmacytoid features (clumped chromatin, eccentric nucleus, perinuclear hof) and Russell (cytoplasm) and Dutcher (nuclear) bodies.

Rouleaux formation may be present due to IgM paraprotein.

Question 20

Describe the “classic” architectural pattern of lymph node involvement by LPL.

Answer 20

Subtotal architectural effacement with interfollicular proliferation of the lymphoplasmacytic tumor cells. Increased mast cells or hemosiderin may be present.

Question 21

Describe the immunophenotype of lymphoplasmacytic lymphoma (LPL) cells.

Answer 21

Expresses pan-B-cell antigens: CD19, CD20, CD22, CD79a, FMC7, Pax5.

Also expresses plasma cell markers: CD138, MUM1. Does not express CD56.

Usually does not stain CD5 or CD10.

Question 22

What conditions are associated with MYD88 L265P mutations?

Answer 22

Lymphoplasmacytic lymphoma

Some cases of MGUS also exhibit.

Question 23

What is cold agglutinin disease, and how can it be distinguished from Waldenstrom macroglobulinemia?

Answer 23

In cold agglutinin disease, an IgM paraprotein binds red cell I antigen, usually associated with mycoplasma infection.

It has less severe clonal B-cell expansion and infiltration. MUM1 should not be expressed, and MYD88 L265P should be absent.

Question 24

What reactive lymphadenopathies should be considered in the differential with lymph node involvement by lymphoplasmacytic lymphoma (LPL)?

Answer 24

Luetic lymphadenitis

IgG4-related lymphadenopathy

Castleman’s disease (plasma cell variant) - IgA or IgG restricted!

Question 25

How can LPL be distinguished from PCM with t(11;14)?

Answer 25

Both have small lymphoplasmacytic morphology; PCM with t(11;14) should not express CD19, while LPL should not express CD56.

Question 26

How does hairy cell leukemia usually present clinically?

Answer 26

One or more cytopenias, almost always including monocytopenia (“leukopenic leukemia”)

Palpable splenomegaly is common, unlike lymphadenopathy.

Question 27

How is hairy cell leukemia treated?

Answer 27

2CdA (cladribine) and anti-B cell therapy (eg. Rituximab) for refractory cases. Vemurafenib may also be helpful.

Question 28

Describe the morphology of hairy cell leukemia on peripheral smears.

Answer 28

Large lymphocytes (1.5-2x normal) with fine hairy cytoplasmic projections. Nuclei has dispersed granular chromatin without nucleoli. Cytoplasmic granules may be present.

Question 29

Describe the morphology of hairy cell leukemia on bone marrow biopsy.

Answer 29

Interstitial or diffuse proliferation of “fried egg” tumor lymphocytes with significant fibrosis and reduction in residual hematopoiesis. Plasma cells and mast cells may be increased.

Question 30

Describe the morphology of hairy cell leukemia on bone marrow aspirate smears

Answer 30

Aspirate smears are usually nondiagnostic due to excessive fibrosis (“dry tap”).

Question 31

What distinctive immunophenotypic markers are seen in hairy cell leukemia?

Answer 31

CD11c+

CD25+

CD103+

CD123+ (not in HCLv)

BRAF

Question 32

What is the most common genetic abnormality in hairy cell leukemia?

Answer 32

BRAF V600E mutations.

(although cyclin D can be mildly increased by IHC, it is usually not rearranged)

Question 33

Distinguish HCLv from classical hairy cell leukemia.

Answer 33

HCLv morphologically resembles HCL, but otherwise is completely different: No BRAF mutations, leukocytosis (no monocytopenia), negative CD25/CD123 staining (still CD11c/CD103+). Worse prognosis.

Question 34

In the evaluation of a peripheral blood clonal B-cell proliferation, what entity must be ruled out before a diagnosis of “low-grade B cell lymphoma” can be rendered?

Answer 34

Hairy cell leukemia

(REVIEW THIS WITH AN ATTENDING; GET AN EXPLANATION)

Question 35

A patient presents with monocytopenia, but the bone marrow core biopsy appears normal. What diagnostic entity should be considered, and how could it be evaluated on the core biopsy?

Answer 35

Hairy cell leukemia; cells can be subtle and interstitial so order a CD20.

Question 36

How do cases of splenic marginal zone lymphoma (SMZL) clinically present?

Answer 36

Most patients have splenomegaly. Some may have autoimmune hemolysis and/or IgM paraproteinemia.

Question 37

What is the prognosis of splenic marginal zone lymphoma (SMZL)? How is it managed?

Answer 37

Has a fairly good prognosis with low 5yr mortality. Treated with monitoring or anti-B-cell therapy (rituximab, BR).

Question 38

Describe the morphology of splenic marginal zone lymphoma (SMZL) on splenic sections.

Answer 38

White pulp follicles are surrounded or infiltrated with a biphasic lesion with pale staining cells in the marginal zone and darker cells in the interior of the follicle. Residual germinal center may be present.

Red pulp is almost always diffusely involved.

Question 39

Describe the morphology splenic marginal zone lymphoma (SMZL) in bone marrow and lymph nodes.

Answer 39

Bone marrow: Intertrabecular lymphoid aggregates of CD20+ cells.

Lymph node: Same micronodular proliferation of small cells as in splenic sections.

Question 40

Describe the morphology of splenic marginal zone lymphoma (SMZL) in peripheral blood.

Answer 40

Neoplastic B-cells have some villous morphlogy (formerly called “splenic lymphoma with villous lymphocytes”)

Question 41

What are some distinct immunophenotypic features of splenic marginal zone lymphoma (SMZL)?

Answer 41

IgD+, BCL2+. Rarely p53+.

MIB-1 and BCL-2 are very useful for diagnosis…

Question 42

Describe the staining patterns of MIB-1 and BCL-2 in a splenic section of splenic marginal zone lymphoma (SMZL).

Answer 42

MIB-1: The tumor cells and residual germinal center cells are highlights, creating a “targetoid” staining pattern.

BCL-2: Only the tumor cells are highlighted, resulting in an annular staining pattern.

Question 43

What is the most common genetic abnormality in splenic marginal zone lymphoma (SMZL)?

Answer 43

A plurality (but not majority) of cases have 7q deletions. These cases are often IgVH mutated?

Note: No cyclin or MALT1 translocations.

Question 44

What is splenic diffuse red pulp small B-cell lymphoma (SDRPSBL)?

Answer 44

A variant of SMZL with predominantly red pulp splenic involvement without follicle replacement. It may express IgG instead of IgD.

Question 45

How can LPL with splenic involvement be distinguished from SMZL?

Answer 45

SMZL generally does not cause as severe an IgM paraproteinemia as LPL.

LPL often harbors MYD88 L265P mutations, whereas SMZL does not.