Disease |
Topography (ICD-O3): typical form: C17 and C26.0; Small intestine, intestinal tract. Respiratory variant: C39.9; Respiratory tract. Lymphomatous variant: C77.9, C22.0, C42.2; Lymph nodes, liver, spleen. |
Phenotype / cell stem origin |
Variant of lymphoplasmacytic lymphoma, resembling mucosa-associated lymphoid tissue lymphoma (MALT) |
Etiology | Deletions, insertions or point mutations in the constant 1 (CH1) domain of the IgH are acquired during the process of somatic hypermutation. These mutations typically result in: 1- inability to bind and form a quaternary structure with IgL chain; and 2- inability to bind to the chaperone heat shock protein 78 (HSP 78) which mediates proteasomal degradation of free IgH. As a result, free IgH can be detected in both serum and urine. Although an infectious etiologic agent is suspected, none have been definitively identified to date.(Seligmann, 1975) |
Epidemiology | Predominantly low socio-economical status individuals in their 20s-30s in the Mediterranean, North Africa, and Middle East are affected, with a slight male predominance.(Wahner-Roedler and Kyle, 2005) |
Clinics | Alpha HCD typically involves the small intestine (predominantly duodenum and jejunum) and presents as a malabsorption syndrome with symptoms and signs related to the severity and duration of involvement. Abdominal discomfort, diarrhea, weight loss, anasarca, and ascites are typically present.(Doe et al., 1972) Patients can report nausea and emesis, while alopecia, amenorrhea, and growth retardation are present in severe cases. Common laboratory findings are mild-to-moderate hypochromic anemia; hypocalcemia; hypokalemia; hypomagnesemia; and generalized vitamin and mineral deficiencies.(Bianchi et al., 2014) Intestinal isoform of alkaline phosphatase is typically elevated. Microbiologic studies of biopsy or stool specimens should be conducted to rule out the presence of an overt infectious agent.(Parsonnet and Isaacson, 2004) Indeed, Campylobacter Jejuni has been isolated in some cases of alpha HCD, although a clear etiopathogenic relationship between C. Jejuni infection and alpha HCD has not been clearly established.(Lecuit et al., 2004; Peterson, 2004) Upper endoscopy is the diagnostic test of choice, given the common involvement of duodenum and jejunum. Five different histologic patterns of digestive mucosa involvement have been reported: infiltrative, nodular, ulcerative, mosaic, and isolated fold thickening; infiltrative and nodular are the most specific and sensitive for diagnosis.(Halphen et al., 1986) Patients with lymphomatous variant of alpha HCD present with generalized lymphadenoapthies and hepatosplenomegaly; while dyspnea and hypoxemia in the context of diffuse pulmonary infiltrates and restrictive pattern of respiratory function is the typical clinical presentation of respiratory variant of alpha HCD. Hilar adenopathy, skin rash, and peripheral blood eosinophilia have been reported in the respiratory HCD variant.(Stoop et al., 1971; Takahashi et al., 1988) |
Pathology | The abnormal Ig alpha heavy chain can manifest as hypogammaglobulinemia or result in a normal serum protein electrophoresis (SPEP). A broad monoclonal band migrating in the α2-β region may be identified via immunofixation with anti IgA serum. The lymphoma variant associated with alpha HCD resembles mucosa-associated lymphoid tissue (MALT) and has been defined as immunoproliferative small intestine disease (IPSID) in this context.(Al-Saleem and Al-Mondhiry, 2005) Pathologic analysis of IPDIS reveals a dense lymphoplasmacytic infiltrate of plasma cells admixed with small B lymphocytes separating the crypts and causing villous atrophy.(Isaacson et al., 1989; Fine and Stone, 1999) Lymphoplasmacytic cells are monoclonal for cytoplasmic alpha chain in the absence of a light chain; plasma cells are CD138+ and CD20 negative; and the small B lymphocytes express pan B-cell markers and lack CD5 and CD10 expression.(Wahner-Roedler and Kyle, 1992; Fine and Stone, 1999) |
|  |
|
| Panel A: Low magnification view of H&E staining of duodenal biopsy in a patient with alpha HCD shows dense lymphocytic infiltration of lamina propria, associated with blunting of villous structures and spreading of crypts. Panel B: Higher magnification view of pathologic specimen in A shows lymphocytic infiltrate to be predominantly comprised of atypical plasma cells with characteristic relatively abundant eosinophilic, pink cytoplasm, eccentric nuclei, and dispersed chromatin. Upon immunohistochemistry (IHC) staining, plasma cells are largely positive for IgA (Panel C) and negative for IgM (Panel D), distinguishing alpha HCD infiltrate from classical MALT. IHC staining for κ and λ light chains was negative on this specimen (panel not shown). Panels C and D from Dr. Judith A. Ferry, Massachusetts General Hospital. Reproduced with permission from Bianchi et al. Oncology, 2014;28(1):45-53. |
|
Cytogenetics | Unknown |
Genes | Unknown |
Treatment | Even in the absence of an identified infectious agent on biopsy or stool specimens, a prolonged trial (> 6 months) of broad antimicrobial therapy with ampicillin, metronidazole or tetracycline is generally recommended in an attempt to alleviate malabsorption symptoms.(1976) Antibiotic therapy should be appropriately tailored if an infectious agent is identified. Response rates to antibiotic therapy between 33% and 71% have been reported in early stage disease, although recurrence is frequent.(Ben-Ayed et al., 1989; Salem and Estephan, 2005) Total abdominal radiation or doxorubicin-based combination therapy are therapeutic options for refractory disease. CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone), CHVP (cyclophosphamide, doxorubicin, teniposide and prednisone) and ABV (doxorubicin, bleomycin and vinblastine) have activity against refractory, advanced alpha HCD, and are superior to doxorubicin-free regimens such as COPP (cyclophosphamide, vincristine, procarbazine, and prednisolone). A CR rate of 64% with 5 year OS of 67% has been reported after treatment with combination chemotherapy.(Akbulut et al., 1997) Surgical debulking can be implemented following systemic chemotherapy, and high dose chemotherapy followed by autologous hematopoietic stem cell transplantation should be considered in patients with relapsed/refractory disease. (Martin and Aldoori, 1994) |
Evolution | The natural history of alpha HCD is local progression leading to complications such as small bowel obstruction or perforation, followed by systemic spread systemically.(Bianchi et al., 2014) |
Prognosis | The outcome is good in antibiotic-responsive, early disease. In the advanced disease and relapsed setting, a CR rate of 64% with 5 year OS of 67% has been reported after treatment with combination chemotherapy.(Akbulut et al., 1997) |
Five-year results of the treatment of 23 patients with immunoproliferative small intestinal disease: a Turkish experience |
Akbulut H, Soykan I, Yakaryilmaz F, Icii F, Aksoy F, Haznedaroglu S, Yildirim S |
Cancer 1997 Jul 1;80(1):8-14 |
PMID 9210703 |
|
Immunoproliferative small intestinal disease (IPSID): a model for mature B-cell neoplasms |
Al-Saleem T, Al-Mondhiry H |
Blood 2005 Mar 15;105(6):2274-80 |
PMID 15542584 |
|
Bull World Health Organ |
Alpha-chain disease and related small-intestinal lymphoma: a memorandum |
1976;54(6):615-24 |
PMID 829415 |
|
Treatment of alpha chain disease |
Ben-Ayed F, Halphen M, Najjar T, Boussene H, Jaafoura H, Bouguerra A, Ben Salah N, Mourali N, Ayed K, Ben Khalifa H, et al |
Results of a prospective study in 21 Tunisian patients by the Tunisian-French intestinal Lymphoma Study Group Cancer |
PMID 2920354 |
|
The heavy chain diseases: clinical and pathologic features |
Bianchi G, Anderson KC, Harris NL, Sohani AR |
Oncology (Williston Park) 2014 Jan;28(1):45-53 |
PMID 24683718 |
|
Five cases of alpha chain disease |
Doe WF, Henry K, Hobbs JR, Jones FA, Dent CE, Booth CC |
Gut 1972 Dec;13(12):947-57 |
PMID 4119805 |
|
Heavy-chain diseases |
Fermand JP, Brouet JC |
Hematol Oncol Clin North Am 1999 Dec;13(6):1281-94 |
PMID 10626151 |
|
Alpha-heavy chain disease, Mediterranean lymphoma, and immunoproliferative small intestinal disease: a review of clinicopathological features, pathogenesis, and differential diagnosis |
Fine KD, Stone MJ |
Am J Gastroenterol 1999 May;94(5):1139-52 |
PMID 10235185 |
|
Frequent occurrence of deletions and duplications during somatic hypermutation: implications for oncogene translocations and heavy chain disease |
Goossens T, Klein U, Küppers R |
Proc Natl Acad Sci U S A 1998 Mar 3;95(5):2463-8 |
PMID 9482908 |
|
Diagnostic value of upper intestinal fiber endoscopy in primary small intestinal lymphoma |
Halphen M, Najjar T, Jaafoura H, Cammoun M, Tufrali G |
A prospective study by the Tunisian-French Intestinal Lymphoma Group Cancer |
PMID 3756829 |
|
Heavy chain diseases |
Harris NL, I.P., Grogan TM, Jaffe ES |
2008 In WHO Classification of Tumours of the Haematopoietic and Lymphoid Tissues. C.E. Swerdlow SH, Harris NL, et al., editor IARC, Lyon. 196-199. |
|
Immunoproliferative small-intestinal disease |
Isaacson PG, Dogan A, Price SK, Spencer J |
An immunohistochemical study Am J Surg Pathol |
PMID 2512818 |
|
Immunoproliferative small intestinal disease associated with Campylobacter jejuni |
Lecuit M, Abachin E, Martin A, Poyart C, Pochart P, Suarez F, Bengoufa D, Feuillard J, Lavergne A, Gordon JI, Berche P, Guillevin L, Lortholary O |
N Engl J Med 2004 Jan 15;350(3):239-48 |
PMID 14724303 |
|
Immunoproliferative small intestinal disease: Mediterranean lymphoma and alpha heavy chain disease |
Martin IG, Aldoori MI |
Br J Surg 1994 Jan;81(1):20-4 |
PMID 8313111 |
|
Case records of the Massachusetts General Hospital |
Munshi NC, Digumarthy S, Rahemtullah A |
Case 13-2008 A 46-year-old man with rheumatoid arthritis and lymphadenopathy |
PMID 18434654 |
|
Bacterial infection and MALT lymphoma |
Parsonnet J, Isaacson PG |
N Engl J Med 2004 Jan 15;350(3):213-5 |
PMID 14724298 |
|
Immunoproliferative small intestinal disease associated with Campylobacter jejuni |
Peterson MC |
N Engl J Med 2004 Apr 15;350(16):1685-6; author reply 1685-6 |
PMID 15084705 |
|
Immunoproliferative small intestinal disease: current concepts |
Salem PA, Estephan FF |
Cancer J 2005 Sep-Oct;11(5):374-82 |
PMID 16259867 |
|
Alpha chain disease: immunoglobulin abnormalities, pathogenesis and current concepts |
Seligmann M |
Br J Cancer Suppl 1975 Mar;2:356-61 |
PMID 810152 |
|
Alpha-chain disease: a new immunoglobulin abnormality |
Seligmann M, Danon F, Hurez D, Mihaesco E, Preud'homme JL |
Science 1968 Dec 20;162(3860):1396-7 |
PMID 4177362 |
|
Alpha-chain disease with involvement of the respiratory tract in a Dutch child |
Stoop JW, Ballieux RE, Hijmans W, Zegers BJ |
Clin Exp Immunol 1971 Nov;9(5):625-35 |
PMID 4111693 |
|
A new form of alpha-chain disease with generalized lymph node involvement |
Takahashi K, Naito M, Matsuoka Y, Takatsuki K |
Pathol Res Pract 1988 Nov;183(6):717-23 |
PMID 3222174 |
|
Heavy chain diseases |
Wahner-Roedler DL, Kyle RA |
Best Pract Res Clin Haematol 2005;18(4):729-46 |
PMID 16026747 |
|