Interesting Case Review. Renuka Agrawal, MD Dept. of Pathology City of Hope National Medical Center Duarte, CA

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1 Interesting Case Review Renuka Agrawal, MD Dept. of Pathology City of Hope National Medical Center Duarte, CA

2 History 63 y/o male with h/o CLL for 10 years Presents with worsening renal function and hypercalcemia H/o jejunal GIST (Sx-2003; on Gleevec) WBC: 20x10 9 cells/l; no prior marrow evaluation

3 Bone marrow trephine core

4 Bone marrow clot section

5 CD20

6 CD20 on spindle cells

7 Pax-5

8 CD5

9 CD5

10 CD43

11 CD117

12 Round cells Spindly cells CD CD3 - - Pax5 + - CD5 + - CD CD CKIT - +

13 CLL Spindly cells CD CD3 - - Pax5 + - CD5 + - CD CD CKIT - +

14 CLL Spindly cells CD CD3 - - Pax5 + - CD5 + - CD CD CKIT - +

15 Aspirate smear

16 Flow cytometry

17 CD138

18 Kappa Lambda

19 Round cells Spindly cells CD Kappa - + Lambda - - CD CD5/ + - CD23/Pax5 CKIT - + CD CyclinD-1 - -

20 CLL Spindly cells CD Kappa - + Lambda - - CD CD5/ + - CD23/Pax5 CKIT - + CyclinD CD43 + +

21 CLL Spindly cells CD Kappa - + Lambda - - CD CD5/ + - CD23/Pax5 CKIT - + CyclinD CD43 + +

22 CLL Myeloma CD Kappa - + Lambda - - CD CD5/ + - CD23/Pax5 CKIT - + CyclinD CD43 + +

23 CKIT and plasma cells Never expressed in normal plasma cells 50% in MGUS, 33% myeloma, 8% relapse Expression associated with more indolent presentation and better prognosis Bataille R et al. CD117 (c-kit) is aberrantly expressed in a subset of MGUS and multiple myeloma with unexpectedly good prognosis. Leuk Res Mar;32(3):

24 Cytological variations of neoplastic plasma cells (other than: flame / mott / morular / grape cells & thesaurocytes) Variant Well-differentiated Cleaved, multilobated and monocytoid cell Pleomorphic Blastic Signet-ring cell (rare) Small cell Histiocytoid Clear cell (rare) Spindle cell Oncocytic (rare) Mimics Normal / reactive Poorly differentiated carcinoma, lymphoma and myeloid or monocytic leukemia Anaplastic carcinoma and anaplastic large cell lymphoma Large cell non-hodgkin lymphoma Metastatic carcinoma CLL/SLL and ALL Storage disorder Germ cell tumor or clear cell carcinoma Mesenchymal tumor Oncoytoma S S Banerjee, S Verma & J H Shanks. Morphological variants of plasma cell tumors. Histopathology Jan; 44 (1):2-8.

25 CLL- bone marrow infiltration Patterns: Interstitial Nodular Diffuse Mixed (nodular and diffuse) Rozman et al (Br J Haematol 1981, 63 cases): Interstitial and nodular better than diffuse Gray et al (Cancer 1974, 115 cases): Nodular and mixed: median survival 9 years Diffuse: 2 years

26 CLL - diagnosis Most common leukemia of adults in western countries Diagnostic criteria (NCI Sponsored Working Group): Binet J et al. Perspectives on the use of new diagnostic tools in the treatment of chronic lymphocytic leukemia. Blood 2006; Vol 107(3), Persistent (>1month) peripheral blood lymphocytosis (>5x10 9 cells/l) of matureappearing lymphocytes in the absence of other causes Circulating lymphocytes with dim CD20+, CD19+/CD5+, CD23+, FMC7- and weak intensity surface immunoglobulin Monoclonal B-lymphocytosis (MBL): <5x10 9 cells/l Landgren O et al. B-cell clones as early markers for chronic lymphocytic leukemia. N Eng J Med 2009; Vol 360(7), (77,469 healthy adults) 3-5% in general population over age 50 5% progress to CLL- prediagnostic clone Same IgVH mutation status and light chain restriction

27 Flow cytometry

28

29 Biclonal lymphoproliferative disorders 4.8% in B-cell disorders (suspected by immunophenotyping and confirmed by molecular analysis) The two B-cell subsets often display either different sig or different levels of the same sig, usually with other phenotypic differences 2 diseases: MCL/FL, FL/CLL, MCL/CLL, CLL/LCL or HCL/CLL Reflect either different maturation stages or subclone formation within the original malignant tumor stem cell line. B-CLL with 2 or more clones have lower WBC count, more frequently display splenomegaly, and require early treatment Maria-Luz Sanchez et al. Incidence and clinicobiologic characteristics of leukemic B-cell chronic lymphoproliferative disorders with more than one B-cell clone. Blood, 15 October 2003, Vol. 102, No. 8, pp

30 Transformation of CLL Development of an aggressive lymphoma that appears morphologically different from the low-grade indolent lymphoma in the background Occurs in 5% to 10% of CLL cases Disease progression, resistance to therapy, poor prognosis Appearance of complex chromosomal changes that were not present earlier Prolymphocytic transformation Richter s transformation (RT) Hodgkin variant of RT Plasma cell neoplasm

31 Clonal evolution in this case? Recent FISH analysis at our center: Monosomy 13 TP53/17P13.1 (Previous cytogenetic or molecular studies not known) Detection/exclusion of identical clone: Microdissection of the 2 separate infiltrates from the clot section PCR analysis..

32 Electrogram showing IgH PCR Lymphoma cells Myeloma cells IgH positive control IgH normal control The CLL cells and neoplastic plasma cells have same size of PCR products

33 IgH 2a PCR products sequences Lymphomas Cell sequences from 2a PCR Myeloma Cell sequences from 2a PCR The CLL cells and neoplastic plasma cells have same rearranged sequences

34 Back to history... No details of GIST No known history of plasma cell dyscrasia Lost to follow-up after case reviewed Possibilities include: GIST misdiagnosis (jejunal tumor was in fact a CKIT+ plasmacytoma?) May have clinical, radiological, and laboratory evidence of myeloma? Plan: Procure GIST paraffin block for further evaluation Attempt to acquire information on current status

35 In conclusion Plasma cell myeloma can be CKIT+ CLL can evolve into myeloma CLL can have more than one clone

36 Thank you!

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