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Case 214 - Discussion

Hematopathology Case

 

This is a classic case of CLL with increased prolymphocytes (~20%). The typical CLL cells are monotonous and small with round nuclei, highly condensed chromatin, inconspicuous nucleoli and scant agranular cytoplasm. Frequent smudge cells and basket cells are noted. Prolymphocytes are larger and have a round nucleus, more delicate chromatin, single distinct nucleolus, and abundant cytoplasm.

 

Chronic lymphocytic Leukemia

The Key Features

  • CLL: monotonous round cells, condensed chromatin, inconspicuous nucleoli and scant agranular cytoplasm. Frequent smudge cells

  • SLL: monotonous, small round cells with pseudofollicles

  • Positive: CD5 and CD23

  • Negative or weak: CD20, CD22, CD79b, CD11c

  • Negative: CD10, FMC7, Cyclin D1

  • Worse prognosis: germline IgVH, CD38+, ZAP70+, trisomy 12, del( 11q22-23), del 17p

  • Better prognosis: mutated IgVH, deletions at 13q14

CLINICAL FEATURES

  • Most common leukemia in the Western world and comprises 90% of chronic lymphoid leukemias; SLL 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

  • 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

  • Peripheral blood

    o Lymphocytosis of ≥5 109/L, ≥3 months

    o Monotonous small round nuclei, highly condensed chromatin, inconspicuous nucleoli

    o Scant agranular cytoplasm

    o Frequent smudge cells and basket cells

    o Larger atypical cells: irregular nuclear contours, usually < 2%, if conspicuous = atypical CLL, cytogenetic assessment recommended

    o Prolymphocytes: larger nucleus, single distinct nucleolus; if de novo and >55% = B-cell prolymphocytic leukemia

  • Lymph node

    • Architecture: effacement of the lymph node with a  pseudofollicular pattern; occasionally intrafollicular infiltrate

    • Cytology: predominantly small cells, slightly larger than normal lymphocytes; round nuclei with clumped chromatin and occasional a small nucleolus; low mitotic activity

    • Pseudofollicules: 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; higher Ki-67

  • Spleen: miliary micronodules, white pulp

  • Bone marrow

    • Focal nodular, interstitial, diffuse, or solid

    • Nonparatrabecular

    • Typically no proliferation centers and true germinal centers

SUBTYPES

o Atypical Chronic Lymphocytic Leukemia

   Predominant CLL morphology and immunophenotype, but not all classic features. Need to exclude other lymphoma/leukemia

   Morphology: subsets (usually 10% - 15%) larger, greater nuclear irregularity, a prominent nucleolus of prolymphocytes, or have plasmacytoid features

   Immunophenotype: may mimic MCL

   Atypical features noted in both blood and lymph node specimens

   May be linked to distinct genotypic subtypes

   Linked to more advanced stage, adverse outcome, rapid disease progression

o CLL with Plasmacytoid Differentiation

   Predominantly small lymphocytes, with up to 25% or more plasmacytoid form

   Many (but not all) patients have significant serum or urine monoclonal protein in the, although rarely exceeds 3 g/dL

   del(7)(q32)

   DDX: lymphoplasmacytic lymphoma typical clinical presentations, lack of proliferation foci and characteristic CLL immunophenotype

o CLL with Reed-Sternberg Cells

   Large, pleomorphic cells with morphologic features of Reed-Sternberg cells

   Admixed sparsely with otherwise typical CLL/SLL or Hodgkin's lymphomatous transformation (discrete region with typical Hodgkin's milieu)

   Association with Epstein-Barr virus

   May or may not directly transformed from background CLL/SLL

o Mu Heavy-Chain Disease

   Similar to CLL/SLL, but defective mu chain without an associated variable region

   Usually infiltrate bone marrow, liver and spleen by a mature lymphocytosis with admixed vacuolated plasma cells

   Generally no significant lymphadenopathy

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

o Positive: CD5, CD23, CD19, CD43

o Weak: CD20, sIg, CD22, CD11c

o Negative: CD10, FMC7, CD25, CD79b

o Variants: bright CD20 and FMC7, or absent CD5

CYTOGENETIC STUDIES

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

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

o Del (11q22-q23): ~ 20% CLL, ATM

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

TREATMENT AND PROGNOSIS

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

  • Unfavorable: CD38+, ZAP-70+, unmutated IGH@ V, post-GC

  • Transformation of CLL, 2-12%

    • Prolymphocytoid transformation: progressive increase in prolymphocytes

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

REFERENCES

  • Practical Diagnosis of Hematologic Disorders, Fourth Edition. By Carl R. Kjeldsberg, 2006.
  • Pathology and genetics of tumours of haematopoietic and lymphoid tissues. World Health Organization classification of tumours. Lyon (France): IARC Press; 2008

  • Hematopathology: Expert Consult. 2010