Chapter 70: Heavy-Chain Diseases

• 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.

• 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.

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.

• 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.

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.