A 38-year-old with acute renal insufficiency
David Cantu, M.D., Farzaneh Sayedian M.D., Ryan H. Livengood, M.D., Jeffrey A. Vos, M.D.
A 38-year-old Caucasian male presented with acute renal insufficiency. His past medical history was significant for hypertension, diabetes mellitus, chronic renal insufficiency, congestive heart failure, dyslipidemia, hepatitis C virus infection and cerebrovascular accident. Physical examination demonstrated anasarca, and CT scan showed cardiomegaly and right pleural effusions. As part of the patient’s evaluation, bone marrow biopsy and serum protein electrophoresis (SPEP) were performed.
The bone marrow biopsy showed an interstitial plasmacytosis that comprised 15-20% of the cellularity, best demonstrated by CD138 immunohistochemistry. Morphologically, most of these cells resemble mature plasma cells; however, a small subset showed lymphoplasmacytic features. By in-situ hybridization, a minority of plasma cells stained in a polyclonal pattern, while the majority failed to stain with either kappa or lambda light chains. Electrophoresis studies revealed an IgG heavy chain protein in the serum without any associated monoclonal light chains (Figure 1).
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γ heavy chain disease, also known as Franklin disease, is a lymphoproliferative disorder currently classified by the World Health Organization as a mature lymphoid disorder characterized by the production of monoclonal γ heavy chains without an associated light chain. γ heavy chain disease occurs equally in men and women. Although it has been described in children and young adults, Franklin disease is most frequent in the sixth decade of life. γ heavy chain disease is a lymphoplasmacytic disorder that produces a fragmented γ chain which lacks the light chain binding sites preventing the formation of a complete immunoglobulin. The abnormal protein consists of an Fc region of the heavy chain with a normal carboxy terminal end followed by an internal deletion of the V and the entire CH1 domain. γ heavy chain disease typically presents with lymphadenopathy, hepatomegaly, splenomegaly and/or involvement of Waldeyer's ring along with a defective secretion of IgG heavy chain. Bone marrow and peripheral blood involvement may be seen. Systemic symptoms like anorexia, fever, weakness, weight loss and recurrent bacterial infections are present in the majority of patients.
Palatal edema and swelling of the uvula related to involvement of Waldeyer's ring are often considered the hallmark of Franklin disease but only occur in 15% of patients. One-third of the patients may have an autoimmune disorder, most commonly rheumatoid arthritis. Autoimmune-related cytopenias (i.e., hemolytic anemia, leukopenia and thrombocytopenia) are frequent. In the peripheral blood, atypical lymphoplasmacytoid cells are present in about half of the patients as well as mature plasma cells. Eosinophilia has also been reported. The presence of plasma cells and lymphocytes in the circulation may morphologically mimic chronic lymphocytic leukemia or plasma cell leukemia. The patients have no lytic bone lesions, no Bence Jones proteinuria and no renal failure. The lymph nodes usually demonstrate a heterogeneous proliferation composed of lymphocytes, plasmacytoid lymphocytes, plasma cells, immunoblasts and eosinophils. When plasma cells predominate, the picture may simulate that of plasma cell myeloma or plasmacytoma. When eosinophils and macrophages are numerous, however, the histologic picture may be similar in appearance to angioimmunoblastic T-cell lymphoma or Hodgkin lymphoma. The bone marrow is affected in 30-60% of cases and is similarly infiltrated by lymphocytes, lymphoplasmacytoid cells and/or mature plasma cells. The degree of infiltration varies but may be focal; thus, an adequate biopsy is necessary to exclude Franklin disease with certainty. Although no histologic pattern is specific, the most common is that of a pleomorphic lymphoplasmacytic proliferation, often associated with eosinophilia as well as epithelioid and multinucleated giant cells, the latter of which may suggest a granulomatous lesion. The diagnosis is established by showing an IgG monoclonal protein devoid of an associated light chain by immunofixation in the peripheral blood, urine or both. Immunophenotypic studies show the proliferation of B-cells which contain monoclonal cytoplasmic gamma heavy chains without light chains. The malignant cells additionally express CD79a and CD20 on the lymphocytic component and CD138 on the plasma cell component. Aberrant co-expression of other markers such as CD5 and CD10 is typically negative.
Plasma cell myeloma (PCM) is characterized by the presence of a monoclonal protein in the serum (monoclonal gammopathy), monoclonal plasmacytosis and end-organ damage (hypercalcemia, renal insufficiency, anemia and/or lytic bone lesions). PCM is more common in older males with predominance in those of African American ethnicity. The most common paraprotein is IgG in 50% of cases, followed by IgA in 20%, free light chain in 20%, and IgM in 10% of cases. The spectrum of plasma cell dyscrasia in this disease category includes the following: monoclonal gammopathy of undetermined significance (MGUS) characterized by monoclonal gammopathy with bone marrow plasmacytosis <10% of cells and absence of end-organ damage; smoldering myeloma which shows monoclonal gammopathy and monoclonal marrow plasmacytosis >10% but without evidence of end-organ damage; non-secretory PCM characterized by monoclonal plasmacytosis without secretion of monoclonal proteins into serum and without significant end-organ damage; and plasma cell leukemia which is defined as the presence of circulating atypical plasma cells in peripheral blood comprising >20% of white blood cells.
Immunoproliferative small intestinal disease (IPSID) is the most common variant of heavy chain disease and is characterized by the presence of a monoclonal alpha chain paraprotein in the serum. It is most commonly seen in young adults of Mediterranean decent. Typical presenting symptoms include malabsorption and diarrhea due to dense infiltration of the gastrointestinal tract, especially the small intestine and mesenteric lymph nodes, by neoplastic plasma cells and lymphocytes. IPSID has been found in association with infection by Campylobacter jejuni, and may be related to neoplastic transformation in the setting of chronic inflammation. There is typically no bone marrow involvement, and serum protein electrophoresis usually shows no discrete band due to the aberrant nature of the IgA immunoglobulin. Immunofixation demonstrates the monoclonal IgA paraprotein by utilizing a specific anti-IgA antibody.
Mu heavy chain disease is slowly progressive, more common in adults, and resembles chronic lymphocytic leukemia. It is characterized by the presence of defective monoclonal mu heavy chains in the serum which usually require immunofixation for identification and cannot be detected in the urine. Neoplastic cells appear as small lymphocytes and vacuolated plasma cells commonly involving the spleen, liver, bone marrow and peripheral blood. Patients characteristically have hepatosplenomegaly without lymphadenopathy. The common abnormality is deletions among the VH region and CH1 region resulting in a mu heavy chain that cannot bind light chain.
Monoclonal immunoglobulin deposition diseases (MIDD) include primary amyloidosis, light chain deposition disease (LCDD), heavy chain deposition disease (HCDD) and light and heavy chain deposition disease (LHCDD) and result from plasmacytic (or lymphoplasmacytic) neoplasms which cause end-organ damage through the deposition of light chains, heavy chains or both. These diseases are mechanistically similar, but only primary amyloidosis forms β-pleated sheets ultrastructurally and shows apple-green birefringence on Congo red stain. MIDD may be associated with plasma cell myeloma (PCM), monoclonal gammopathy of undetermined significance (MGUS) or lymphoplasmacytic lymphoma (LPL). In LCDD, abnormal light chains are produced by multiple mutations of the immunoglobulin light chain variable region, while in HCDD, prematurely secreted heavy chains circumvent heavy chain binding protein due to deletion of the CH1 constant domain. In non-amyloidosis MIDD the abnormal light or heavy chains deposit in tissue as a non-fibrillary material causing organ dysfunction. Kidneys are most commonly affected.
In the presented case, the patient was symptomatic from disease at diagnosis with renal insufficiency, hepatosplenomegaly and cytopenias and his skeletal survey was normal. Therapy included a combination of bortezomib and dexamethasone; however, the patient’s current status is unknown. The prognosis for patients with gamma heavy chain disease is unpredictable, varying from indolent to rapidly progressive. The median survival has been reported to be 7.4 years and death often is attributed to other causes not related to the heavy chain disease.
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