Chapter 106. Plasma Cell Disorders (Part 10) Heavy Chain Diseases The heavy chain diseases are rare lymphoplasmacytic malignancies. Their clinical manifestations vary with the heavy chain isotype. Patients secrete a defective heavy chain that usually has an intact Fc fragment and a deletion in the Fd region. Gamma, alpha, and mu heavy chain diseases have been described, but no reports of delta or epsilon heavy chain diseases have appeared. Molecular biologic analysis of these tumors has revealed structural genetic defects that may account for the aberrant chain secreted. Gamma Heavy Chain Disease (Franklin's Disease) This disease affects individuals of widely different age groups and countries of origin. It is characterized by lymphadenopathy, fever, anemia, malaise, hepatosplenomegaly, and weakness. Its most distinctive symptom is palatal edema, resulting from involvement of nodes in Waldeyer's ring, and this may progress to produce respiratory compromise. The diagnosis depends on the demonstration of an anomalous serum M component [often <20 g/L (<2 g/dL)] that reacts with anti-IgG but not anti-light chain reagents. The M component is typically present in both serum and urine. Most of the paraproteins have been of the gamma 1 subclass, but other subclasses have been seen. The patients may have thrombocytopenia, eosinophilia, and nondiagnostic bone marrow. Patients usually have a rapid downhill course and die of infection; however, some patients have survived 5 years with chemotherapy. Alpha Heavy Chain Disease (Seligmann's Disease) This is the most common of the heavy chain diseases. It is closely related to a malignancy known as Mediterranean lymphoma, a disease that affects young persons in parts of the world where intestinal parasites are common, such as the Mediterranean, Asia, and South America. The disease is characterized by an infiltration of the lamina propria of the small intestine with lymphoplasmacytoid cells that secrete truncated alpha chains. Demonstrating alpha heavy chains is difficult because the alpha chains tend to polymerize and appear as a smear instead of a sharp peak on electrophoretic profiles. Despite the polymerization, hyperviscosity is not a common problem in alpha heavy chain disease. Without J chain–facilitated dimerization, viscosity does not increase dramatically. Light chains are absent from serum and urine. The patients present with chronic diarrhea, weight loss, and malabsorption and have extensive mesenteric and paraaortic adenopathy. Respiratory tract involvement occurs rarely. Patients may vary widely in their clinical course. Some may develop diffuse aggressive histologies of malignant lymphoma. Chemotherapy may produce long-term remissions. Rare patients appear to have responded to antibiotic therapy, raising the question of the etiologic role of antigenic stimulation, perhaps by some chronic intestinal infection. Chemotherapy plus antibiotics may be more effective than chemotherapy alone. Immunoproliferative small intestinal disease (IPSID) is recognized as an infectious pathogen–associated human lymphoma that has association with Campylobacter jejuni. It involves mainly the proximal small intestine resulting in malabsorption, diarrhea, and abdominal pain. IPSID is associated with excessive plasma cell differentiation and produces truncated alpha heavy chain proteins lacking the light chains as well as the first constant domain. Early-stage IPSID responds to antibiotics (30–70% complete remission). Most untreated IPSID patients progress to lymphoplasmacytic and immunoblastic lymphoma. Mu Heavy Chain Disease The secretion of isolated mu heavy chains into the serum appears to occur in a very rare subset of patients with chronic lymphocytic leukemia. The only features that may distinguish patients with mu heavy chain disease are the presence of vacuoles in the malignant lymphocytes and the excretion of kappa light chains in the urine. The diagnosis requires ultracentrifugation or gel filtration to confirm the nonreactivity of the paraprotein with the light chain reagents, because some intact macroglobulins fail to interact with these serums. The tumor cells seem to have a defect in the assembly of light and heavy chains, because they appear to contain both in their cytoplasm. There is no evidence that such patients should be treated differently from other patients with chronic lymphocytic leukemia (Chap. 105). Further Readings Ghobrial IM et al: Waldenström macroglobulinaemia. 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IPSID is associated with excessive plasma cell differentiation and produces truncated alpha heavy chain proteins lacking the light chains