Two Distinct Syndromes of Lymphoma-Associated Amyloidosis: Findings From a Case Series.

Light chain (AL) amyloidosis has a rare but recognized association with non-Hodgkin lymphoma; however, limited information regarding this association exists. We present the clinical features and outcomes of patients with lymphoma -associated AL amyloidosis identified at Princess Margaret Hospital (PMH). We describe two distinct syndromes of lymphoma-associated amyloidosis: 1) peritumoral amyloidosis in which amyloid deposition occurs in the immediate vicinity of the lymphoma and 2) systemic amyloidosis where deposition is in sites remote from the underlying lymphoma.

Cases were identified retrospectively at PMH by survey of hematologists and a pathologist. The International Consensus Criteria (ICC) (Gertz et al., 2005) were used to determine organ involvement by amyloid.

We identified 10 patients with lymphoma -associated AL amyloidosis seen between 1997 and 2008. The median age was 69 (52-81) and 50% were female.

Five patients had peritumoral amyloidosis. All had extranodal marginal zone lymphoma, MALT subtype (MALT lymphoma).A monoclonal immunoglobulin (M-protein), as determined by serum protein electrophoresis (SPEP) and free light chain (FLC) analysis, was undetectable in two patients, was present in trace amount in two patients and detected but not quantified in a fifth. Of the patients with detectable M-protein, the isotype was IgM in two and IgG in one. Four had lambda light chain restriction while biclonality was questioned in the fifth. All but one patient had single organ involvement by amyloid with lung and soft tissues being the only sites affected. Rectal biopsies and fat pad aspirates, when performed, were negative. Four patients received systemic therapy: two patients were treated with chlorambucil, one received melphalan and prednisone, and one received rituximab, cyclophosphamide, and prednisone followed by rituximab maintenance. Radiographic follow-up of pulmonary lesions in two patients did not identify significant change in lymphoma/amyloid related abnormality. No complete responses were seen. Despite therapy, three patients experienced continuing local symptoms at the site of lymphoma/amyloid involvement while one remained asymptomatic. A fifth patient, untreated at last follow up, was asymptomatic. No patients with peritumoral amyloidosis were found to develop systemic amyloidosis even after a median follow up of 11 months (3-60 mo).

The other five patients had lymphoma with systemic amyloidosis. These patients had lymphoma restricted to the bone marrow with histology showing lymphoplasmacytic lymphoma (LPL) in three and small B cell lymphoma with plasmacytic differentiation in two (differential diagnosis LPL vs marginal zone lymphoma). An IgM M-protein was detectable in all five patients. Waldenstrom's macroglobulinemia was therefore present in at least three patients. High levels of M-protein were detected by SPEP in four patients (mean 31 g/L) and FLC analysis in one. Kappa was more common than lambda light chain restriction (3:2). Amyloid was detected in a median of three organs (1-5) including cardiac involvement in four patients. Four patients received multiple lines of therapy with first line being R-CVP in three and ASCT in a fourth. Organ responses, as defined by the ICC, in sites affected by amyloid were not observed. Three of the four treated patients had >50% reductions in M-protein levels, but none had complete haematological response. Response of the underlying lymphoma, which would have required repeat biopsy, was not assessed. Median follow up was 30 months (4-100) with one patient dying of sepsis, one developing therapy-related AML and three surviving with ongoing symptoms of congestive heart failure, dyspnea and/or neuropathy.

Lymphoma-associated amyloidosis presents as two distinct syndromes which are associated with characteristic clinical, laboratory and pathologic features. Patients with peritumoural amyloidosis have low level M-protein expression with predominant lambda light chain restriction, symptoms confined to the site of their MALT lymphoma and poor radiological responses to systemic therapy. Patients with systemic amyloidosis have high M-protein levels with a uniform IgM isotype, lymphoma localized to the bone marrow, multiorgan involvement by amyloid and worse outcomes. Future studies aimed at better defining prognosis and optimal treatment in these patients are warranted.

Kukreti:Celgene: Honoraria.