Heavy chain disease

Name
Heavy chain disease
ICD-O-2 Morphology
9762/3
Effective 1992 - 2000
ICD-O-3 Morphology
9762/3
Effective 2001 and later
Reportable
for cases diagnosed 1992 and later
Primary Site(s)
See Module 7
See abstractor notes for the most common primary sites for the different variants.

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Grade
6 - B-cell
Module Rule
None
Alternate Names
Alpha heavy chain disease
Franklin disease
Gamma HCD
Gamma heavy chain disease
HCD
Immunoproliferative small intestinal disease
IPSID
Mu heavy chain disease
Definition
Heavy chain diseases (HCD) include three rare B-cell neoplasms that produce monoclonal heavy chains and typically no light chains. The monoclonal immunoglobulin component is composed of either IgG (Gamma HCD), IgA (Alpha HCD), or IgM (Mu HCD).

These lymphoplasmacytic proliferative disorders are characterized by the uncontrolled production of abnormal (incomplete) immunoglobulin heavy chains that cannot combine with light chains to form complete Ig molecules. Specific subtypes may be identified by serum protein electrophoresis, but immunoelectrophoresis or immunofixation may also be needed to detect the variably-sized heavy chains.
Abstractor Notes
Heavy chain diseases are rare. There are several different variants.

Note that heavy chain deposition disease is not the same as HCD; the deposition term is non-reportable and would be coded 9769/1, if collected.

1. Gamma heavy chain disease (Gamma HCD) - a variant of lymphoplasmacytic lymphoma (9671/3) but is a distinct and separate disease. It may involve the lymph nodes, Waldeyer ring, gastrointestinal tract, and other extranodal sites, plus the bone marrow, liver, spleen, and peripheral blood. Most patients have systemic symptoms and generalized disease, including lymphadenopathy and hepatosplenomegaly. Prognosis is extremely variable. Low-grade disease may respond to chemotherapy.

2. Mu heavy chain disease - resembles CLL (9823/3) because of its small, round lymphocytes but it is a distinctly different entity. This is the rarest HCD. It involves spleen, liver, bone marrow, and peripheral blood. Peripheral lymphadenopathy is usually not present. Hepatosplenomegaly is frequent. The disease usually progresses slowly.

3. Alpha heavy chain disease - the most common HCD, is a variant of extranodal marginal zone lymphoma of MALT (9699/3) but it is classified with the other HCD’s. It mainly occurs in young adults and involves the gastrointestinal tract, mainly the small intestine and mesenteric lymph nodes. Gastric and colonic mucosa may be involved. The bone marrow and other organs are usually not involved. Rare respiratory tract involvement is described. Antibiotic therapy (coded as chemotherapy) is very effective on Alpha heavy chain disease. A newer term for alpha HCD is immunoproliferative small intestinal disease (IPSID); these terms had separate codes before 2010.

4. Immunoproliferative small intestinal disease - this variant was recently added to the growing list of infectious pathogen-associated human lymphomas. IPSID involves mainly the proximal small intestine. Geographically, IPSID is most prevalent in the Middle East and Africa.
Definitive Diagnostic Methods
Bone marrow biopsy
Genetic testing
Histologic confirmation
Immunophenotyping
Genetics Data
Deletions in Alpha, Gamma, or Mu heavy chain gene
Incomplete immunoglobulin molecule
Possible insertions of DNA of unknown origin
Immunophenotyping
Alpha heavy chain disease:
CD5 and CD10 negative
CD20+ CD5-, CD10- on marginal zone cells
CD20-, DC138+ on plasma cells
CD79a and CD20 on lymphocytic component
Express B-cell antigens
Gamma heavy chain disease:
Monoclonal cytoplasmic alpha chain without light chain on plasma cells and marginal zone cells
Monoclonal cytoplasmic gamma chain without light chains
Monoclonal cytoplasmic Mu heavy chain, with or without monotypic light chain
Mu heavy chain disease:
Treatments
Chemotherapy
Other treatments
Transformations to
Alpha heavy chain disease is the only variant that transforms to DLBCL
Transformations from
None
Corresponding ICD-9 Codes
203.8 Other immunoproliferative neoplasms
273.2 Other paraproteinemias
Corresponding ICD-10 Codes
C88.2 Gamma heavy chain disease
C88.3 Immunoproliferative small intestinal disease
C88.1 Alpha heavy chain disease
Corresponding ICD-10-CM Codes (effective October 1, 2015 U.S. only)
C88.2 Heavy chain disease
C88.3 Immunoproliferative small intestinal disease
Signs and Symptoms
Abdominal pain (alpha)
Anorexia (gamma)
Diarrhea (alpha)
Fever (alpha & gamma)
Hemolytic anemia (gamma)
Hepatosplenomegaly (mu)
Hypocalcemia (alpha)
Malabsorption (alpha)
Recurrent bacterial infections (gamma)
Rheumatoid arthritis (gamma)
Vasculitis (gamma)
Wasting (alpha)
Weakness (gamma)
Weight loss (gamma)
Recurrence and Metastases
None
Epidemiology and Mortality
Age: 20-30 years peak incidence, involves young age group (alpha)
Age: 60 years median age (gamma and mu)
Country: Israel, Egypt, Saudi Arabia, North Africa (alpha)
Country: Immunoproliferative small intestinal disease (IPSID) occurs in the Middle East, Cape region of South Africa and other tropical and subtropical locations
Incidence: most common of the heavy chain diseases (alpha)
Incidence: very rare (gamma and mu)
Sex: slight male predominance (gamma)
Sex: no male or female predominance (alpha and mu)