Two distinct syndromes of lymphoma associated AL amyloidosis: A case series and review of the literature

Light chain (AL) amyloidosis has a rare association with non-Hodgkin lymphoma (NHL). Both peritumoral and systemic AL amyloidosis have been reported, but a detailed description of these syndromes is lacking. We describe 10 patients with lymphoma associated AL amyloidosis. NHL patients with peritumoral amyloidosis had low or undetectable levels of monoclonal (M) protein, mostly single organ involvement (lung or soft tissue), and underlying extranodal marginal zone lymphoma, mucosa associated lymphoid tissue subtype. NHL patients with systemic amyloidosis had high levels of M-protein, multiorgan involvement with frequent cardiac involvement, and predominantly underlying lymphoplasmacytic lymphoma. Systemic amyloidosis was associated with inferior outcomes. Light chain (AL) amyloidosis is most commonly found in association with plasma cell disorders, but 2–4% of cases arise in the setting of a B-cell lymphoma [1-3]. Lymphoma associated AL amyloidosis has a distinct set of features including association with circulating IgM monoclonal (M) protein and a predilection for amyloid involvement of the lung and lymph nodes [3-5]. Cases of lymphoma with either systemic or peritumoral amyloid deposition have been reported in the literature [1-10]. In systemic amyloidosis, the amyloid is deposited in sites remote from the underlying lymphoma whereas in peritumoral amyloidosis deposition is within the immediate vicinity of malignant cells. Below, we present a series of patients with lymphoma associated AL amyloidosis and describe clinical and laboratory features that differentiate patients with peritumoral and systemic amyloidosis. Patients were identified retrospectively by survey of hematologists and a lymphoma pathologist at our institution. Information was gathered by review of patient charts. Cases were included if evidence of both lymphoma and AL amyloid was found. Lymphoma diagnosis was based upon the World Health Organization classification of lymphoid neoplasms [11]. Amyloid was diagnosed in tissue sections by a positive Congo red staining reaction showing characteristic apple green birefringence in polarized light. A diagnosis of AL amyloidosis was made if one or more of the following conditions was met: (1) immunostaining for AA amyloid was negative, (2) Congo red staining was resistant to potassium permanganate treatment, (3) cells within or immediately adjacent to the amyloid deposits showed definite light chain-restricted staining for kappa or lambda or (4) a detectable M-protein was present by serum protein electrophoresis (SPEP) or free light chain (FLC) analysis. Determination of organ involvement by amyloid was based upon the International Consensus Criteria [12]. Peritumoral amyloidosis was diagnosed when AL amyloid was identified in contiguity with tissue consistent with a lymphoma by WHO criteria. The presence of isolated light chain restricted lymphoid or lymphoplasmacytic cells in the setting of an AL amyloid infiltrate was not considered to be in itself sufficient for the diagnosis of a lymphoma. Patients with localized amyloidosis, defined by the absence of an underlying systemic disorder such as lymphoma, were not included in this series. Ten patients with lymphoma associated AL amyloidosis were identified between 1997 and 2008 (Table I). The median age at diagnosis was 69 years (range 52–81) and 50% were women. Patients presented either with masses or organ dysfunction secondary to amyloid infiltration. The median number of organs involved by amyloid was 1.5 (range 1–5). Soft tissue and lung were the sites most commonly affected. Renal involvement was uncommon with only one affected patient. Lambda light chain restriction was found more commonly than kappa light chain restriction, in a ratio of two to one. M-protein isotype was IgM in seven patients and IgG in one patient. Two patients did not have detectable M-protein. Five patients had a diagnosis of extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma), three had lymphoplasmacytic lymphoma (LPL), and two had small B cell lymphoma with plasmacytic differentiation (SBLPD) of the bone marrow where the differential diagnosis included LPL and marginal zone lymphoma. When immunophenotypic data was available, the cells were always CD19 and CD20 positive and CD5, CD10, and CD23 negative. A variety of treatment regimens were used (Table II). Repeat biopsies were not pursued, and responses were determined by physical examination, laboratory studies, computed tomography and echocardiography where applicable. Three of the four patients with paraprotein levels suitable for evaluation of a treatment effect had >50% decreases in paraprotein levels, with the fourth having stable disease. No organs affected by amyloid met criteria for either a partial or complete response by the International Consensus Criteria. When repeat imaging was performed, the radiographic appearances of masses containing amyloid (with or without associated lymphoma) were not significantly changed. No patient experienced a response to therapy suggesting a complete response of the underlying lymphoma although biopsy confirmation of disease persistence was not pursued in any case. After median follow up of 11 months, one patient with congestive heart failure and nephrotic syndrome died of sepsis and a second developed acute myelogenous leukemia 6 years after an autologous stem cell transplant. Of the remaining patients at last follow up, three had symptoms referable to amyloid induced organ dysfunction, one had dyspnea with a possible contribution from amyloidotic pulmonary infiltration, two had local symptoms referable to soft tissue masses and two were asymptomatic. Two patterns of amyloid deposition were evident in the cases reviewed. In five patients, amyloid was found in close association with clusters or sheets of cells expressing monoclonal cytoplasmic immunoglobulin (peritumoral amyloidosis). Pathologic description was either of areas of lymphomatous infiltration within a mass of amyloid or, conversely, collections of amyloid within larger cellular tumor masses. In all cases the underlying lymphoma contained plasmacytoid cells expressing monoclonal immunoglobulin and was consistent with a diagnosis of MALT lymphoma. Features supporting this diagnosis included the presence of a t(11;18) (MALT1) rearrangement in one patient, lymphoepithelial lesions in two patients, and the isolated presence of a clonal lymphoid infiltrate with lymphoplasmacytic differentiation in a typical site of MALT lymphoma in the remaining two cases. Amyloid involvement in these patients was restricted to pulmonary and soft tissues with four of five patients having single organ involvement. All biopsy specimens revealed close association of amyloid and lymphoma with two exceptions: one fine needle aspirate of a subcutaneous nodule in one patient and a core breast biopsy in a second contained amyloid without a clonal infiltrate. In two patients, biopsy proven lymphoma was found in sites without evident amyloid involvement although it is not clear that this possibility was thoroughly addressed in either case. M-protein quantity was of trace amount in two patients, undetectable in two patients and not quantified by SPEP in one. Immunoperoxidase analyses of the involved tissues showed that four patients had lambda light chain restriction while a fifth patient showed apparent biclonality with one lambda restricted population and a smaller, separate, kappa restricted population. Bone marrow biopsies were negative in two, suspicious but nondiagnostic in two and of inadequate quality for evaluation in one. Amyloid related symptoms, when present, were generally local in nature and of mild to moderate severity. The other five patients had amyloidosis in sites remote from the underlying lymphoma (systemic amyloidosis). Three patients had Waldenström macroglobulinemia (WM) with histologic examination revealing LPL while two others had SBLPD of the bone marrow and IgM gammopathy. In all cases, high levels of M-protein were detected by SPEP or FLC analysis. Two patients had lambda and three patients kappa light chain restriction. A median of three organs (range 1–5) was involved by amyloid with lung and soft tissue again being the most common sites of deposition. In contrast to the peritumoral amyloid cases, involvement of other organs was common including cardiac involvement in four of five patients. Outcomes in this group were poor with one patient dying as a complication of cardiac and renal involvement, a second developing treatment related AML, and clinically significant symptoms related to amyloid induced organ dysfunction in the remaining three. AL amyloidosis is an uncommon but well recognized complication of lymphoma in general and WM in particular. In our series of 10 patients, we demonstrate that cases are readily categorized as either peritumoral or systemic AL amyloidosis with each type showing distinctive and clinically significant features. Patients with peritumoral amyloidosis tended to have single organ involvement of either lung or soft tissue associated with MALT lymphoma and trace or undetectable M-protein levels. Patients with systemic amyloidosis had multiorgan involvement with high M-protein levels and underlying WM. Although two of the systemic amyloidosis cases were signed out as SBLPD, isolated bone marrow involvement, lack of morphologic features suggesting an alternative entity and high IgM levels are most consistent with a diagnosis of WM. These patterns are consistent with data reported in previously published cases and case series [1-10]. The features of patients in three series of IgM-associated amyloidosis [2, 4, 5] and two series of lymphoma associated amyloidosis [1, 3] mirror those of our own with systemic amyloidosis: the majority of patients had underlying LPL/WM, high levels of M-protein and multiorgan involvement by amyloid. Pulmonary and soft tissue involvement by amyloid was common in all five reports, but heart and nerve involvement was also frequent. By contrast, one series and a number of case reports describe patients with characteristics much like our own with peritumoral amyloidosis: underlying MALT lymphoma, low or undetectable levels of M-protein, and isolated amyloid involvement of lung or soft tissue occurring in a peritumoral distribution [6-10]. No cases of transformation from a peritumoral to a systemic syndrome have been documented suggesting that pathophysiologic mechanisms in these entities are distinct. Most patients in our series received alkylator based therapy with or without rituximab. In patients with peritumoral amyloidosis, response assessment was limited by low or undetectable pretreatment levels of M-protein. Radiographic resolution of lesions containing lymphoma and amyloid was not seen following treatment. Although persistent amyloid obscuring a response of the underlying lymphoma cannot be ruled out, stable disease is more likely given the low intensity of therapy used. Despite the absence of an appreciable response, progressive disease with worsening amyloid related symptoms was not observed in patients with peritumoral amyloidosis. In the published literature, death as a complication of peritumoral amyloidosis has been described, but most patients are reported to remain minimally affected or asymptomatic over prolonged follow up with little or no treatment [6-9]. These data support a symptom-directed treatment strategy similar to that used in many low grade lymphomas. By contrast, median survivals of 11 to 49 months have been reported in the three larger series of patients with the systemic amyloidosis syndrome [2, 4, 5]. In our series, patients with systemic amyloidosis achieved only partial reductions of M-protein and none had organ responses. All patients continued to experience moderate to severe amyloid related symptoms at last follow up including one patient who died as a complication of cardiac and renal involvement. Shortened survival, particularly in light of frequent cardiac involvement, is expected in the remaining patients. In view of the above, efforts to achieve a complete hematologic response with more intensive therapy should be considered although data to support this approach are limited at the present time [13]. In summary, we describe the clinical, laboratory, and pathologic features of lymphoma associated peritumoral and systemic AL amyloidosis that justify their consideration as distinct syndromes. While a more indolent course in the former may permit symptom-directed local or low intensity systemic therapy, poor outcomes in the latter likely justify intensive approaches aimed at complete suppression of pathologic light chain production. Future studies aimed at better defining the optimal treatment of these patients are warranted.