Interesting Case Review

Renuka Agrawal, MDDept. of Pathology

City of Hope National Medical CenterDuarte, CA

• 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

Bone marrow trephine core

Bone marrow clot section

CD20

CD20 on spindle cells

Pax-5

CD5

CD5

CD43

CD117

++CD43

Round cells Spindly cells

CD20 + +

CD3 - -

Pax5 + -

CD5 + -

CD23 + -

CKIT - +

++CD43

CLL Spindly cells

CD20 + +

CD3 - -

Pax5 + -

CD5 + -

CD23 + -

CKIT - +

++CD43

CLL Spindly cells

CD20 + +

CD3 - -

Pax5 + -

CD5 + -

CD23 + -

CKIT - +

Aspirate smear

Flow cytometry

CD138

Kappa Lambda

++CD43

Round cells Spindly cells

CD138 - +

Kappa - +

Lambda - -

CD20 + +

CD5/ CD23/Pax5

+ -

CKIT - +

CyclinD-1 - -

CLL Spindly cells

CD138 - +

Kappa - +

Lambda - -

CD20 + +

CD5/ CD23/Pax5

+ -

CKIT - +

CyclinD-1 - -

CD43 + +

CLL Spindly cells

CD138 - +

Kappa - +

Lambda - -

CD20 + +

CD5/ CD23/Pax5

+ -

CKIT - +

CyclinD-1 - -

CD43 + +

CLL Myeloma

CD138 - +

Kappa - +

Lambda - -

CD20 + +

CD5/ CD23/Pax5

+ -

CKIT - +

CyclinD-1 - -

CD43 + +

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.

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.

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

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

Flow cytometry

“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

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

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…..

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

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

• 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...

In conclusion…

• Plasma cell myeloma can be CKIT+

• CLL can evolve into myeloma

• CLL can have more than one clone

Thank you!