Sections View Full Chapter Figures Tables Videos Annotate Full Chapter Figures Tables Videos Supplementary Content + DEFINITION Download Section PDF Listen +++ ++ The heavy-chain diseases (HCDs) are neoplastic disorders of B cells that produce monoclonal immunoglobulins (Ig) consisting of truncated heavy chains without attached light chains. In decreasing order of incidence, HCD involves synthesis of defective α, γ, or μ heavy chains. The diagnosis is established from immunofixation of serum, urine, or secretory fluids in the case of α-HCD or from immunohistologic analysis of the proliferating lymphoplasmacytic cells in nonsecretory disease. There is a high frequency of autoimmune disorders preceding or concurrent with the diagnosis of HCD, particularly γ-HCD. Table 70–1 summarizes the clinical features of the three types of HCD. ++Table Graphic Jump LocationTABLE 70–1SUMMARY OF FEATURES OF THE HEAVY-CHAIN DISEASESView Table||Download (.pdf) TABLE 70–1 SUMMARY OF FEATURES OF THE HEAVY-CHAIN DISEASES Feature Type of Heavy-Chain Disease α γ μ Year described 1968 1964 1969 Incidence Rare Very rare Very rare Age at diagnosis Young adult (< 30 years) Older adult (60–70 years) Older adult (50–60 years) Demographics Mediterranean region Worldwide Worldwide Structurally abnormal monoclonal protein IgA IgG IgM MGUS phase No Rarely Rarely Urine monoclonal light chain No No Yes Urine abnormal heavy chain Small amounts Often present Infrequent Sites involved Small intestine, mesenteric lymph nodes Lymph nodes, marrow, spleen Lymph nodes, marrow, liver, spleen Pathology Extranodal marginal zone lymphoma (MALT or IPSID) Lymphoplasmacytoid lymphoma Small lymphocytic lymphoma, CLL Associated diseases Infection, malabsorption Autoimmune diseases None Therapy Antibiotics, chemotherapy Chemotherapy Chemotherapy CLL, chronic lymphocytic leukemia; Ig, immunoglobulin; IPSID, immunoproliferative small intestinal disease; MALT, mucosa-associated lymphoid tissue; MGUS, monoclonal gammopathy of undetermined significance. Adapted with permission from Witzig TE, Wahner-Roedler DL: Heavy chain disease, Curr Treat Options Oncol 2002 Jun;3(3):247–254. + ETIOLOGY AND PATHOGENESIS Download Section PDF Listen +++ ++ The etiology of γ-HCD and μ-HCD is unknown. In α-HCD, the lymphoplasmacytic infiltration of the intestinal mucosa is thought to be a response of the alimentary tract immune system to protracted luminal antigenic stimulation. A causal relationship between infection and pathogenesis is supported by a response to antibiotics in some cases. + CLINICAL AND LABORATORY FEATURES Download Section PDF Listen +++ +++ γ-HCD ++ Median age at presentation is in the late sixties. Clinical features are different than those of myeloma because renal disease and osteolytic lesions rarely occur. This form of HCD has various clinical and pathologic features that can be divided into three broad categories: — Disseminated lymphoproliferative disease: approximately 60% of patients — Localized proliferative disease: approximately 25% of patients — No apparent proliferative disease: approximately 15% of patients Most γ-HCD proteins are dimers of truncated heavy chains without associated light chains. The serum protein electrophoretic pattern is extremely variable, but a monoclonal peak is detected in over two-thirds of patients. The median value of the monoclonal spike at diagnosis in one study of 19 patients was 1.6 g/dL. The amount of HCD protein in the urine usually is small (< 1 g/24 h) but may reach 20 g/24 h. Patients commonly have moderate, normochromic, normocytic anemia. Autoimmune hemolytic anemia has been reported. Bone lesions are rare. +++ α-HCD ++ This form of HCD defined by the recognition of truncated monoclonal α chains without associated light chains. Characteristic sharp spike of monoclonal gammopathy is not found on serum protein electrophoresis. Identification of the α-HCD protein depends on immunoselection or immunofixation. Majority of cases have been reported in northern Africa, Israel, and surrounding Middle Eastern countries. At presentation, the patients commonly are in their teens or early twenties. Common clinical features on presentation include recurrent or chronic diarrhea, weight loss, fevers, and/or growth retardation. Digital clubbing is a frequent finding. Moderate hepatomegaly occurs in about 25% of patients. Mesenteric lymphadenopathy is common, sometimes presenting as an abdominal mass, whereas extra-abdominal lymphadenopathy is rare. In many cases, the abnormal heavy chain only can be found in the intestinal secretions. The jejunum is the usual site of involvement, with dense plasma-cell infiltration of the mucosa appearing during early stage disease (stage A). Infiltration of more blastic-appearing plasma cells is found extending beyond the lamina propria into the muscularis layer during later stages (stages B and C). Spread of neoplastic lymphoplasmacytic cell infiltration to mesenteric lymph nodes is characteristic of stage C disease. Immunoproliferative small intestinal disease is applied to small intestinal lesions with pathologic features identical to those of α-HCD regardless of the type of immunoglobulin synthesized. +++ μ-HCD ++ Median age at presentation is in the late fifties. Infiltration of marrow with lymphocytes and plasma cells is common. Patients may have osteolytic lesions or pathologic fractures. Anemia is frequent. Lymphocytosis and thrombocytopenia are uncommon. Two-thirds of patients have monoclonal Ig light chains in the urine. Patients present symptoms of a lymphoproliferative malignancy (eg, chronic lymphocytic leukemia, B-cell lymphoma, Waldenström macroglobulinemia, or multiple myeloma). Diagnosis typically requires a combination or electrophoretic, immunoelectrophoretic, immunofixation, and immunophenotypic techniques. In a minority of cases, the Ig heavy chain can be identified by electrophoresis of serum or urine samples as a discrete homogenous band of β mobility. Immunoelectrophoresis and/or immunofixation are required to detect an Ig heavy-chain protein that does not react with either anti-κ or anti-λ antisera. Immunophenotypic analyses of biopsy material can reveal lymphoplasmacytic cells that stain positive for cytoplasmic Ig heavy chain, but not for Ig light chain. Bence Jones proteinuria is found in over half the cases of μ-HCD. Cases of nonsecretory μ-HCD have been reported. The presence of vacuolated plasma cells in the marrow of a patient with a lymphoplasmacytic proliferative disorder should always suggest the possibility of μ-HCD. + DIFFERENTIAL DIAGNOSIS Download Section PDF Listen +++ ++ All patients presenting with a lymphoplasmacytic cell proliferative disorder should be evaluated for γ-HCD and μ-HCD. The digestive form of α-HCD should be differentiated from other B-cell lymphomas. + TREATMENT, COURSE, AND PROGNOSIS Download Section PDF Listen +++ +++ γ-HCD ++ Clinical course is variable and, thus, depends on the clinical features. Survival ranges from 1 month to over 20 years. Patients with lymphadenopathy on presentation have a more aggressive course than do patients with little evidence of lymphoproliferative disease. The amount of serum γ-HCD protein usually parallels the severity of the associated malignant disease. Disappearance of the monoclonal component from serum and urine associated with apparent complete response has been induced by chemotherapy, radiotherapy, or surgical removal of a localized lymphatic mass. In an asymptomatic patient, therapy is usually not necessary. In symptomatic patients with a low-grade lymphoplasmacytic malignancy, a trial of chlorambucil may be beneficial. Melphalan and prednisone can be used if the proliferation is predominantly plasmacytic. A trial of cyclophosphamide, vincristine, and prednisone with or without doxorubicin is reasonable for patients with evidence of a progressive lymphoplasmacytic cell proliferative process or high-grade B-cell lymphoma. Rituximab monotherapy was given in two cases, resulting in clinical responses in both. +++ α-HCD ++ Clinical course is variable but generally progressive in the absence of therapy. Antibiotic therapy with tetracycline, metronidazole, or ampicillin is indicated for stage A disease patients who do not have parasitic infection. — Antibiotic therapy can result in complete response in 70% of patients. Patients with stage B or C disease or stage A lesions without improvement after a 60-month course of antibiotic treatment should be given chemotherapy. The treatment regimens are those commonly used to treat B-cell lymphoma (eg, R-CHOP). Surgical resection should be considered for focal or bulky transmural lymphomatous tumors in the gastrointestinal tract and extramedullary plasmacytoma. Autologous hematopoietic stem cell transplantation has been recommended for patients with advanced or refractory disease. +++ μ-HCD ++ There is no specific therapy for μ-HCD. Chemotherapy is similar to that used in chronic lymphocytic leukemia (see Chap. 55) or in myeloma (see Chap. 68). Clinical course is variable, with survival ranging from 1 month to 11 years after appearance of symptoms. ++ For a detailed discussion, see Dietlind L. Wahner-Roedler and Robert A. Kyle: Heavy-Chain Disease, Chap. 110 in Williams Hematology, 9th ed.