Lymphoplasmacytic Lymphoma (LPL)

(Waldenstrom Macroglobulinemia)

Epidemiology and Etiology:

• Older adults (avg 63y)
• May be associated with HCV infection
• Treatment with antiviral agents may cause regression of the lymphoma
• Unclear if the HCV has a transforming potential in lymphocytes or if it is antigen-driven (like MALT lymphoma)
• Mast cells may help drive the proliferation of LPL
• Genetic susceptibility
• Occasional occurrence in families
• Occupational exposures

Common sites:

• Commonly involving:
• bone marrow
• lymph nodes
• spleen
• peripheral blood (some)

Gross features:

Histologic features:

• diagnosis of exclusion:
• lack features of other lymphomas that can show plasmacytoid maturation containing cytoplasmic immunoglobulin
• B-CLL
• Marginal zone lymphoma
• Follicular lymphoma
• Lacking pseudofollicles, neoplastic follicles, monocytoid B cells
• Diffuse growth pattern
• Lacking pseudofollicles
• mixture of cell types:
• plasmacytes
• +/ - Dutcher bodies
• small lymphocytes
• in-between those 2
• abundant basophilic cytoplasm
• lymphocyte-like nuclei
• rare immunoblasts
• some cases show an increase in the number of immunoblasts (may have worse prognosis)
• reactive epithelioid histiocytes maybe
• mast cells maybe
• Dutcher bodies
• Eosinophilic nuclear pseudoinclusions (immunoglobulins)
• Bright pink, round, with a partial clear rim (artifact)
• Bone marrow:
• Nodular lymphoid aggregates and / or diffuse interstitial lymphoid infiltrate
• Increased mast cells often
• Peripheral blood film:
• Rouleaux
• WBC count typically lower than CLL
• Mixture of cell types:
• Small lymphocytes
• Plasma cells
• Plasmacytoid lymphocytes

Immunophenotype:

Marker:	Sensitivity:	Specificity:
IgM (surface and cytoplasmic) Sometimes IgG Rarely IgA
sIgD	-/+
cIg
CD38
CD5 (neg)
CD10 (neg)
CD23 (neg)
CD19, 20, 22, 79a
CD43	+/-
CD25	-/+

Molecular features:

• None specific
• Clonal rearrangement of immunoglobulin heavy and light chains
• Somatic mutations in variable (V)-region genes
• Suggesting arising from a B cell population that have undergone antigen-driven selection
• del(6)(q) (over half of BM-based cases) (infrequent in tissue-based LPL) (poor prognosis maybe)
• nonspecific
• trisomy 4 (20%)
• infrequent trisomy 3 and trisomy 18
• lacking other B-cell lymphoma-associated translocations such as those involving CCND1, MALT1, BCL10
• BCL2 translocations rarely
• Rearrangement of PAX-5 gene was previously reported as frequent, but actually is rarely if ever found
• t(9;14)(p13;q32)
• PAX-5 encodes B cell specific activator protein (BSAP)
• Important in early B cell development
• Gene expression profile homogeneous
• Similar to CLL and normal B cells
• Not similar to myeloma
• Upregulated IL6

Other features:

• Indolent clinical coarse typically
• Asymptomatic patients typically not treated
• Median survival 5-10y
• may progress to DLBCL (immunoblastic) (poor prognosis)
• poor prognostic factors:
• advanced age
• PB cytopenias esp. anemia
• Performance status
• High beta-2 microglobulin levels
• IgM serum paraprotein (monoclonal protein) (majority)
• >3g/dl
• Minority have IgM and IgG together or other paraproteins
• Gamma heavy chain disease variant:
• autoimmune phenomena
• hyperviscosity (10-30%)
• reduced visual acuity
• CVAs
• Cryoglobulinemia
• Neuropathy (10%)
• Autoimmune / cryoglobulinemia / paraprotein deposition
• Diarrhoea
• Deposits of IgM in the GI tract
• Coagulopathies
• IgM binding to clotting factors, platelets, fibrin
• Hodgkin lymphoma has been reported

References:

• WHO blue book 2001, 2008
• Dr. Fernandes