Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

Roberto N. Miranda, MD

Gross specimen of spleen involved by chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) shows diffuse enlargement with a miliary appearance of white pulp.

Chronic lymphocytic leukemia/small lymphocytic lymphoma involving spleen demonstrates expanded white pulp image and small lymphoid aggregates image in red pulp.



  • Chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL)


  • CLL and SLL are used as synonyms but have slightly different meanings

    • CLL is used for disease involving peripheral blood or bone marrow (leukemic)

    • SLL is used for disease restricted to lymph nodes or other extramedullary sites (nonleukemic)


  • CLL/SLL is a neoplasm of small B lymphocytes that typically involves blood, bone marrow, lymph nodes, and spleen

  • Neoplastic cells have characteristic immunophenotype

    • Surface immunoglobulin (Ig)(dim [+]), CD5(+), CD23(+)



  • Incidence

    • CLL is most common type of leukemia in western hemisphere

      • Uncommon or rare in eastern hemisphere

    • CLL/SLL shows genetic and familial predisposition

      • ˜ 5-10% of cases

  • Age

    • Median: 65 years (range: 43-82 years)

  • Gender

    • M:F ratio = 1.5:1


  • Diagnosis of CLL/SLL usually established by examination of blood and bone marrow

    • Lymph node biopsy is performed in nonleukemic cases

  • Splenic involvement is typically detected by radiologic imaging studies

    • Splenectomy can be performed to alleviate symptoms or cytopenias

    • Biopsy of spleen is rare


  • At time of CLL/SLL diagnosis, splenic involvement is often asymptomatic

    • 30% present with autoimmune manifestations, such as hemolytic anemia

Laboratory Tests

  • Persistent peripheral blood monotypic B-cell lymphocytosis, ≥ 5 x 109/L

Natural History

  • Most patients have indolent clinical course

  • In general, patients with splenomegaly &/or cytopenias have high-stage disease and shorter survival

  • Subset of patients develop higher grade, clinically aggressive neoplasm (Richter syndrome)

    • Diffuse large B-cell lymphoma (DLBCL)

      • Can arise in spleen

      • Often discrete mass with necrosis

    • Classical Hodgkin lymphoma

      • Can arise in spleen

      • Usually Epstein-Barr virus (EBV)(+)

  • Subset of patients develop prolymphocytoid transformation of CLL

    • Closely related to or variant of Richter syndrome

    • Increased (often > 55%) prolymphocytes in peripheral blood

    • Extensive involvement of bone marrow and usually marked splenomegaly

  • Chemotherapeutic CLL/SLL drug fludarabine is immunosuppressive

    • Patients are predisposed to infections

    • EBV is associated with atypical lymphoproliferative disorders in CLL/SLL patients

      • May resolve with antiviral therapy

    • Herpes simplex virus (HSV) infection/reactivation is common in CLL/SLL patients

      • HSV infection can clinically or histologically mimic transformation to large cell lymphoma


  • Surgical approaches

    • Splenectomy performed usually for refractory cytopenias or local symptoms

  • Drugs

    • Fludarabine, cyclophosphamide, and rituximab (FCR regimen)

      • This regimen was initiated at M.D. Anderson Cancer Center

      • Becoming popular for use when patients require chemotherapy

    • Many other chemotherapy regimens are used


  • Rai and Binet clinical staging systems are used to assess prognosis

  • 50% 5-year overall survival

  • Great interest in biologic markers to assess prognosis

    • Markers correlated with worse prognosis

      • Unmutated immunoglobulin variable region (IgV) genes

      • CD38 or ZAP70 expression

      • Chromosomal abnormalities: del(11q22-23), del(17p)/p53, del(6q)

    • Markers associated with better prognosis

      • Del(13q14.3)


Radiographic Findings

  • Various modalities show splenomegaly

  • FDG PET scan usually negative


General Features

  • Median weight: 1.4 kg (wide range: 0.2-7.1 kg)

  • Cut surface shows diffuse/miliary growth

    • Discrete tumor mass can occur in cases of large cell transformation


Histologic Features

  • CLL/SLL preferentially involves white pulp

    • White pulp nodules are expanded

    • Rarely, involvement mimics marginal zone pattern

  • Red pulp involvement as small aggregates or diffuse replacement of cords and sinuses

  • Proliferation centers (a.k.a. pseudofollicles) can be observed in spleen

    • Presence correlates with more extensive involvement

  • CLL/SLL can surround reactive germinal centers without mantle zones

    • So-called “naked” germinal centers

  • Splenic hilar lymph nodes

    • Lymph nodes show features of nodal CLL/SLL

      • Partial or total architectural replacement

      • Patent sinuses in cases with partial involvement

      • Proliferation centers

  • Bone marrow is usually involved in patients with CLL/SLL in spleen

    • 3 patterns: Diffuse, interstitial, or nodular

    • Nodular pattern uncommon if spleen is large

  • Richter syndrome

    • DLBCL is most common form of Richter syndrome

      • Sheets of large B cells that can replace both white and red pulp

      • Increased mitotic figures; ± necrosis

      • High proliferation rate (Ki-67 immunostaining)

      • ˜ 50-60% of DLBCL are clonally related to underlying CLL/SLL

    • Classical Hodgkin lymphoma

      • Reed-Sternberg and Hodgkin cells; background inflammatory cells

      • Necrosis common; usually EBV(+)

      • Much less common than DLBCL

Cytologic Features

  • Tumor cells are predominantly small with round nuclear contours, clumped chromatin, and scant cytoplasm

    • Scattered prolymphocytes or paraimmunoblasts

    • In some cases, CLL/SLL cells can show plasmacytoid differentiation

      • Can be associated with serum paraprotein; usually low level

  • Subset of CLL cases show atypical cytologic features

    • More irregular nuclear contours or large cells increased

    • Association with trisomy 12



  • CD19(+), CD20(+), CD79a(+), pax-5(+)

  • CD5(+), CD23(+), Bcl-2(+)

  • Usually low proliferation rate: < 10% (Ki-67)

  • CD10(−), Bcl-6(−), Cyclin-D1(−)

  • ZAP70 expression

    • Surrogate for unmutated IgV genes

    • Discordance between ZAP70 and molecular analysis in ˜ 20% of cases

    • Can be assessed by immunohistochemistry or flow cytometry

Flow Cytometry

  • Surface Ig(dim [+]), CD19(+), CD20(dim [+])

  • IgM(+), IgD(+)

  • CD5(+), CD23(+), CD43(+)

    • ˜ 5% of CLL/SLL cases are CD23(−)

  • CD3(−), CD10(−), CD22(−), CD79b(−), FMC7(−)

  • Atypical immunophenotypes occur in ˜ 10-20% of CLL/SLL

    • Bright surface Ig(+) or CD20(+), CD22(+), CD79b(+), or FMC7(+)

  • CD38 expression

    • Surrogate for unmutated IgV genes

    • Discordance between CD38 and molecular analysis in ˜ 20% of cases

    • Best assessed by flow cytometry


  • Usually performed on blood or bone marrow specimens

  • Abnormal karyotypes in ˜ 50% of cases

    • CLL/SLL cells grow poorly in culture

  • Trisomy 12 occurs in ˜ 20% of cases of CLL/SLL

    • Presence correlates with atypical morphologic or immunophenotypic features

  • Small subset (< 5%) of CLL/SLL cases have chromosomal translocations

    • Usually detected by FISH

In Situ Hybridization

  • FISH can detect cytogenetic abnormalities in ˜ 80% of cases

  • Panel has been designed to detect most common abnormalities

    • Probes for 13q14, 11q22, +12, 17p13, and 6q21

    • Target genes

      • Del(13q14.3): Possibly micro-RNA genes miR-16 and miR-15a

      • Del(11q22): Ataxia-telangiectasia mutated (ATM)

      • Trisomy 12: Unknown

      • Del(17p13): P53

      • Del(6q21): Unknown

Molecular Genetics

Jul 8, 2016 | Posted by in PATHOLOGY & LABORATORY MEDICINE | Comments Off on Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

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