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Chapter 70: Heavy-Chain Diseases

DEFINITION

  • 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 70–1SUMMARY OF FEATURES OF THE HEAVY-CHAIN DISEASES
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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

  • 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

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 ...

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