Name

Heavy chain diseases

ICD-O-2 Morphology

9762/3: Heavy chain disease
9763/3: Gamma heavy chain disease
Effective 1992 - 2000

ICD-O-3 Morphology

9762/3: Heavy chain disease
Effective 2001 and later

Reportable

for cases diagnosed 1992 and later

Primary Site(s)

See Module 7
See abstractor notes for the most common sites of involvement for the different variants.

Grade

Not Applicable

Module Rule

None

Alternate Names

Alpha heavy chain disease (AHCD)
Franklin disease
Gamma HCD
Gamma heavy chain disease (GHCD)
Heavy chain disease, NOS
HCD
Immunoproliferative small intestinal disease
IPSID
Mediterranean lymphoma
Mu heavy chain disease (MHCD)

Definition

The heavy chain diseases (HCD) are three rare B-cell neoplasms characterized by the production of monoclonal immunoglobulin heavy chains (IgG in gamma HCD, IgA in alpha HCD, and IgM in mu HCD) and typically no light 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
Possible insertions of DNA of unknown origin

Immunophenotyping

CD5 and CD10 negative (AHCD)
CD20+ CD5-, CD10- on marginal zone cells (AHCD)
CD20-, DC138+ on plasma cells (AHCD)
CD79a and CD20 on lymphocytic component (AHCD)
Express B-cell antigens (AHCD)
Monoclonal cytoplasmic alpha chain without light chain on plasma cells and marginal zone cells (GHCD)
Monoclonal cytoplasmic gamma chain without light chains (GHCD)
Monoclonal cytoplasmic Mu heavy chain, with or without monotypic light chain (MHCD)

Treatments

Chemotherapy
Other therapy

Transformations from

None

Corresponding ICD-9 Codes

203.8 Other immunoproliferative neoplasms
273.2 Other paraproteinemias

Corresponding ICD-10 Codes

C88.1 Alpha heavy chain disease
C88.2 Gamma heavy chain disease
C88.3 Immunoproliferative small intestinal disease

Corresponding ICD-10-CM Codes (U.S. only)

C88.2 Heavy chain disease (effective October 01, 2015)
C88.3 Immunoproliferative small intestinal disease (effective October 01, 2015)
C88.8 Other malignant immunoproliferative diseases (effective October 01, 2015)
C88.9 Malignant immunoproliferative disease, unspecified (effective October 01, 2015)

Signs and Symptoms

Abdominal pain (alpha)
Anorexia (gamma)
Diarrhea (alpha)
Fever (alpha & gamma)
Hypocalcemia (alpha)
Malabsorption (alpha)
Recurrent bacterial infections (gamma)
Vasculitis (gamma)
Wasting (alpha)
Weakness (gamma)
Weight loss (gamma)

Progression and Transformation

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)

Sources

Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J (Eds):
WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues (Revised 4th edition)
IARC: Lyon 2017
Section: Mature B-cell neoplasms
Pages: 237-240

International Classification of Diseases for Oncology, Third Edition, First Revision. Geneva: World Health Organization, 2013.
Section: ICD-O-3.1 (2011) Morphological Codes
Pages: http://codes.iarc.fr/codegroup/2
Glossary