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Case 36 - Discussion

Hematopathology Case

 

 

CD3 CD5
CD20 CD79a
CD10 BCL6
BCL1 BCL2
   
  • FLOW CYTOMETRY
    • A kappa monotypic B-cell population is detected, positive for CD5, CD19, CD20 (dim) and CD23, and are negative for CD10, CD38 and ZAP70
  • CYTOGENETICS REPORT
    • INTERPRETATION: Cytogenetic analysis revealed the presence of an abnormal clone characterized by a reciprocal translocation involving the long arms of chromosomes 12 and 14.
    • NOMENCLATURE: 46,XY,t(12;14)(q13;q32)
  • FISH CYTOGENETICS REPORT
    • RESULTS: Positive for an IgH (14q32) rearrangement (81%)
    • INTERPRETATION: ABNORMAL. Molecular cytogenetic studies were positive for a rearrangement of the IgH region at 14q32 in 81% of the interphase cells from this bone marrow specimen. Specifically, these results are positive for the t(12;14) seen in this patient's G-band study. Additional studies were negative for a t(11;14), trisomy 12 and deletions of 11q22.3, 13q14, 13q34 and 17p13.1. Negative for CHOP (12q13) rearrangement.
  • DIAGNOSIS: Small lymphocytic lymphoma/Chronic lymphocytic leukemia

Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL)

The Key Features

  • Small mature lymphocytes, round nuclei, condensed chromatin, smudge cells, prolymphocytes

  • Positive: CD5 and CD23

  • Weak: CD20, CD22, CD79b, CD11c, surface light chain

  • Negative: CD10, FMC7, Cyclin D1

  • Better prognosis: mutated IgVH, deletions at 13q14

  • Worse prognosis: germline IgVH, CD38+, ZAP70+, trisomy 12, deletions at 11q22-23

CLINICAL FEATURES

  • CLL is the most common leukemia in the Western world and comprises 90% of chronic lymphoid leukemias; SLL/CLL accounts for 6.7% of NHL;

  • Age: most patients>50 years, median 65 years; M:F=2:1;

  • CLL: lymphocyte count in bone marrow and peripheral blood >5109/L, possible <5109/L provided typical morphology and immunoprofile;

  • SLL: absence of bone marrow or blood involvement;

  • Clinical features: most patients asymptomatic, or fatigue, infection, autoimmune hemolytic anemia, hepatosplenomegaly, lymphadenopathy, or extranodal involvement.

MICROSCOPIC FINDINGS

  • Lymph node and spleen

    • Architecture: effacement of the lymph node with a  pseudofollicular pattern; occasionally intrafollicular infiltrate; In the spleen, white pulp is often prominently involved and also red pulp;

    • Pseudofollicles: pale areas containing a continuum of small, medium and larger cells in dark background of small cells; prolymphocytes: medium size, nuclei with dispersed chromatin and small nucleoli; para-immunoblasts: medium to large size, round to oval nuclei with dispersed chromatin and central eosinophilic nucleoli and slightly basophilic cytoplasm. The pseudofollicles are MUM1 positive, whereas the reactive germinal centers are negative for MUM1.. In ~20% of CLL/SLL cases, the proliferative centers can be BCL1+, but lack t(11;14) and expression of SOX11 (Am J Clin Pathol. 2012, 138(1):132-9)

    • Cytology: predominantly small cells, slightly larger than normal lymphocytes; round nuclei with clumped chromatin and occasional a small nucleolus; low mitotic activity; in some cases, the small lymphoid cells show moderated nuclear irregularity, resembling MCL; occasionally, tumor cells may present plasmacytoid differentiation.

  • Bone marrow and blood

    • Small cells, clumped chromatin, and scant clear to basophilic cytoplasm, nucleoli indistinct or absent, frequent smudge cells and basket cells;

    • Prolymphocytes usually <2%; CLL with increased prolymphocytes, 10%<prolymphocytes<50%;

    • Bone marrow involvement may be nodular, interstitial, diffuse or combined; paratrabecular aggregates are not typical;

  • Some CLL cases may show atypical morphology with variable proportional atypical lymphocytes (cleaved cells, prolymphocytes and large lymphocytes) with characteristic CLL immunophenotype;

  • Richter syndrome: transformation to DLBCL (3.0% of CLL) is characterized by confluent sheets of large cells that paraimmunoblasts or immunoblast-like; or transformation into Hodgkin lymphoma (0.5% of CLL).

SUBTYPES

  • CLL of naive B-cell origin: 40-50%, no somatic mutations of IgVH;

  • CLL of post-germinal center B-cell origin: 50-60%, with somatic mutation of IgVH, better survival.

DIFFERENTIAL DIAGNOSES

  CLL/SLL B-PLL HCL SMZL FL MCL
sIg + (dim) + + + + +
CD19 + + + + + +
CD20 + (dim) + + + + +
CD22 + + + + +
FMC7 + + + + +
CD79b + + + + +
CD5 + +
CD23 + +/− +/−
CD25 +/− +
CD11c +/− + +/−
CD103 +
CD10 +

IMMUNOHISTOCHEMISTRY AND SPECIAL STAINS

  • Positive: weak or dim surface IgM or IgM and IgD, CD5, CD19, CD20 (weak), CD22 (weak), CD79a, CD23, CD43, CD11c (weak);

  • Negative: CD10, cyclin D1, FMC7 and CD79b

CYTOGENETIC STUDIES

  • Del(13q14): >50%, MIR15A and MIR16-1, favorable prognosis

  • Tri 12: < 20%, often associated with atypical morphology

  • Del (11q22-q23): ~ 20%, ATM

  • Del (17p13): 5-10%, TP53, adverse prognosis

TRANSFORMATION
  • Prolymphocytoid transformation: progressive increase in prolymphocytes

  • Richter's syndrome: mostly DLBCL, rarely Hodgkin's lymphoma, mostly but not always clonally related, fludarabine therapy → increased transformation and often EBV related

TREATMENT AND PROGNOSIS

  • Indolent, median survival of CLL 7 years, and median survival of SLL 5 years

  • Favorable: CD38-, ZAP-70-, germline IGH@V, pre-GC

  • Unfavorable: CD38+, ZAP-70+, unmutated IGH@V, post-GC, <55 years old

REFERENCES

  • Practical Diagnosis of Hematologic Disorders, Fourth Edition. By Carl R. Kjeldsberg, 2006.
  • Hematopathology, 2011, Jaffe