interesting case reviewlasop.com/pgs/hdouts/2010-05_agrawal.pdfinteresting case review renuka...
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Interesting Case Review
Renuka Agrawal, MDDept. of Pathology
City of Hope National Medical CenterDuarte, CA
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• 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: 20x109 cells/L; no prior marrow evaluation
History
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Bone marrow trephine core
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Bone marrow clot section
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CD20
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CD20 on spindle cells
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Pax-5
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CD5
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CD5
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CD43
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CD117
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++CD43
Round cells Spindly cells
CD20 + +
CD3 - -
Pax5 + -
CD5 + -
CD23 + -
CKIT - +
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++CD43
CLL Spindly cells
CD20 + +
CD3 - -
Pax5 + -
CD5 + -
CD23 + -
CKIT - +
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++CD43
CLL Spindly cells
CD20 + +
CD3 - -
Pax5 + -
CD5 + -
CD23 + -
CKIT - +
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Aspirate smear
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Flow cytometry
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CD138
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Kappa Lambda
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++CD43
Round cells Spindly cells
CD138 - +
Kappa - +
Lambda - -
CD20 + +
CD5/ CD23/Pax5
+ -
CKIT - +
CyclinD-1 - -
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CLL Spindly cells
CD138 - +
Kappa - +
Lambda - -
CD20 + +
CD5/ CD23/Pax5
+ -
CKIT - +
CyclinD-1 - -
CD43 + +
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CLL Spindly cells
CD138 - +
Kappa - +
Lambda - -
CD20 + +
CD5/ CD23/Pax5
+ -
CKIT - +
CyclinD-1 - -
CD43 + +
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CLL Myeloma
CD138 - +
Kappa - +
Lambda - -
CD20 + +
CD5/ CD23/Pax5
+ -
CKIT - +
CyclinD-1 - -
CD43 + +
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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. 2008 Mar;32(3):379-82.
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Cytological variations of neoplastic plasma cells(other than: flame / mott / morular / grape cells & thesaurocytes)
Variant MimicsWell-differentiated Normal / reactive
Cleaved, multilobated and monocytoid cell Poorly differentiated carcinoma, lymphoma and myeloid or monocytic leukemia
Pleomorphic Anaplastic carcinomaand anaplastic large cell lymphoma
Blastic Large cell non-Hodgkin lymphoma
Signet-ring cell (rare) Metastatic carcinoma
Small cell CLL/SLL and ALL
Histiocytoid Storage disorder
Clear cell (rare) Germ cell tumor or clear cell carcinoma
Spindle cell Mesenchymal tumor
Oncocytic (rare) Oncoytoma
S S Banerjee, S Verma & J H Shanks. Morphological variants of plasma cell tumors. Histopathology. 2004 Jan; 44 (1):2-8.
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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
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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), 859-861
– Persistent (>1month) peripheral blood lymphocytosis (>5x109 cells/L) of mature-appearing 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): <5x109 cells/L Landgren O et al. B-cell clones as early markers for chronic lymphocytic leukemia. N Eng J Med 2009; Vol 360(7), 659-667 (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
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Flow cytometry
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“Biclonal” lymphoproliferative disorders
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. 2994-3002.
• 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 formationwithin 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
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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
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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…..
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Lymphoma cells
Myeloma cells
IgH positive control
IgH normal control
The CLL cells and neoplastic plasma cells have same size of PCR products
Electrogram showing IgH PCR
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IgH 2a PCR products sequences
The CLL cells and neoplastic plasma cells have same rearranged sequences
LymphomasCell sequences from 2a PCR
Myeloma Cell sequences from 2a PCR
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• 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
Back to history...
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In conclusion…
• Plasma cell myeloma can be CKIT+
• CLL can evolve into myeloma
• CLL can have more than one clone
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Thank you!