Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma



Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma


Roberto N. Miranda, MD






Key Facts


Terminology



  • CLL/SLL is neoplasm of small B lymphocytes that typically involves peripheral blood (PB), bone marrow (BM), lymph nodes, and spleen


  • CLL is used for disease involving PB or BM (leukemic)


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


Clinical Issues



  • CLL is most common leukemia in western hemisphere


  • Splenic involvement by CLL/SLL is typically detected by radiologic imaging


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


  • Splenectomy can be performed to alleviate symptoms or refractory cytopenias


Microscopic Pathology



  • Expansion of white pulp forming uniform nodules


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


  • Lymphocytes are round to slightly irregular with clumped chromatin and scant cytoplasm


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


Ancillary Tests



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


  • CD5(+), CD23(+), Ki-67(low)


  • Unmutated Ig variable (V) genes predicts poorer prognosis



    • ZAP70 or CD38 expression correlates with unmutated IgV genes







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.


TERMINOLOGY


Abbreviations



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


Synonyms



  • 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)


Definitions



  • 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(+)


CLINICAL ISSUES


Epidemiology



  • 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


Site



  • 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


Presentation



  • 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


Treatment



  • 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


Prognosis



  • 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)


IMAGE FINDINGS


Radiographic Findings



  • Various modalities show splenomegaly


  • FDG PET scan usually negative


MACROSCOPIC FEATURES


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


MICROSCOPIC PATHOLOGY


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


ANCILLARY TESTS


Immunohistochemistry



  • 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


Cytogenetics



  • 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

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

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