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Alpha-Chain Disease and Related Small-Intestinal Lymphoma: a Memorandum *

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Alpha-Chain Disease and Related Small-Intestinal Lymphoma: a Memorandum * Alpha-chain disease and related small-intestinal lymphoma: a Memorandum * Primary intestinal lymphotias are remarkably frequent in the Mediterranean region and South-West Asia. They are usually found in young persons from. the lower socio- economic strata of the population. These conditions sometimes present a premalignant phase characterized by plasmacytic infiltration of the small intestine. It has been reported that early treatment of cases with antibiotics is followed by complete remission, suggesting that some environmental factors may be responsible for the disease. Some patients have an abnormal alpha-chain protein in their serum. This Memorandum reviews the present knowledge of the clinical, immunological, epidemiological, and therapeutic aspects of this condition. Primary intestinal lymphomas are remarkably pre- lymphoma in man. Uniquely, the association of a valent in the Mediterranean region and South-West disordered immune response and the development Asia (1, 12, 26) and have a number of characteristic of immunoblastic sarcoma, possibly from the same features. They are most frequent in young patients clone of cells, can be studied in a cell population from underprivileged backgrounds who present with that synthesizes a distinctive marker protein. a malabsorption syndrome resulting from extensive Over the last decade data have accumulated from and diffuse infiltration of the wall of the small intes- isolated case studies in diverse regions and the time tine, predominantly by plasma cells. Clinical studies now seems opportune to initiate a new phase of suggest evolution from a premalignant cellular infil- research into this condition. As a first step, a co- trate to frank neoplasia involving more primitive ordinated international collaborative effort is essen- immunoblasts. tial to collate the data available and to establish The frequency of primary intestinal lymphomas standard nomenclatures, diagnostic criteria and among populations exposed to conditions of poor therapeutic responses so as to lay the groundwork hygiene (35) and evidence for complete remissions for systematic research into the etiopathogenesis and induced in early cases by oral antibiotic therapy (30), epidemiology of the disease. This Memorandum implicate environmental factors in the pathogenesis reviews the present knowledge about this disease. of this disorder. Since ingested microorganisms are Since in the early stage it does not appear to be a a powerful proliferative stimulus to the secretory truly malignant lymphoma, in this Memorandum IgA system (7), the premalignant phase of the dis- the condition is termed " immunoproliferative small- ease may represent an aberrant immune response by intestinal disease" (IPSID). the secretory IgA system to sustained, topical, anti- genic stimulation. The study of diffuse primary intestinal lymphomas therefore offers important op- CLINICAL FEATURES portunities for research into the pathogenesis of The major clinical features of IPSID are remark- ably uniform. They are (4, 8, 22, 24, 37): chronic * This Memorandum was drafted by the signatories listed diarrhoea, abdominal pain, abdominal distension, on pages 622-623. Reprints of the Memorandum and full de- nausea and vomiting, marked weight loss. tails of a proposed programme to study the disease (including protocols for the study of patients) can be obtained from Less common features include (17, 23, 24): oedema, Immunology, World Health Organization, Avenue Appia, tetany, low-grade fever (high temperatures are rare), 1211 Geneva 27, Switzerland. A French translation of this Memorandum will be published in a future issue of the melaena. Bulletini. An occasional presentation is that of an acute 3558 - 615 - BULL. WORLD HEALTH ORGAN., Vol. 54, 1976 616 MEMORANDUM abdomen due to obstruction, perforation, or intus- (i) limited bacteriological studies of stools have susception of the small intesine (1, 3, 10). not revealed any consistent pathogens: in several The diarrhoea may have features of steatorrhoea cases, bacterial overgrowth associated with bile-salt or may be very watery and at times so copious as to deconjugation in jejunal fluid and an antibiotic require urgent fluid and electrolyte replacement. The responsive 14C-glycocholate breath test has been severity of diarrhoea has on occasions led to hypo- observed (J. C. Rambaud, unpublished results). kalaemic nephropathy with polyuria. Radiological findings Population at risk Barium studies in IPSID patients frequently reveal Although IPSID is seen mainly in the second and an abnormal small-intestinal pattern, usually more third decade, cases have been noted in all age groups. marked in the upper small intestine (2, 4, 10, 26). There are no clear sex differences. The disease affects Findings include: (a) a characteristic coarse mucosal populations of diverse ethnic and geographical ori- pattern with a pseudopolypoid appearance, (b) stric- gins (34). There is a predilection for certain ethnic tures and segmentation, and (c) impression by groups in the same geographical region (26). The extrinsic nodes. patients described have mostly been from the low These findings are suggestive but are not diag- socioeconomic strata (33). nostic for this disease. Occasionally the appearances of osteoarthropathy are also noted (10). Absence of Presenting signs mediastinal adenopathy and radiological features of The common presenting signs include (8, 22, 24): osteomalacia should be emphasized. Abdominal emaciation, clubbing of fingers and toes, abdominal lymphoangiography may be abnormal but this inves- mass, abdominal tenderness, oedema. Occasionally tigation has limited value in the investigation of this tetany is found. Palpable peripheral nodes are a rare disease. presenting sign. It should be emphasized that hepatosplenomegaly Biopsy findings is not a presenting feature of the disease. Peroral mucosal biopsies at multiple sites have proved essential to the diagnosis and management Laboratory findings of the disease. Plasmacytic infiltration may occasion- Routine laboratory tests are not diagnostic. Abnor- ally be noted in the colon, rectum, stomach, naso- malities usually relate to malabsorption or loss of pharynx, bone marrow, or peripheral blood. substances through the gastrointestinal tract. These include: Laparotomy Although laparotomy often reveals thickening of (a) malabsorption of fat, xylose, folate, and vita- the B12 with intrinsic factor. and vita- small-intestinal wall, mesenteric lymph node min Fat, xylose, enlargement, and a small spleen absence of are at least (19), min B12 malabsorption partially respon- these findings on gross examination does not exclude sive to antibiotics; the diagnosis. (b) hypocalcaemia, hypomagnesaemia and hypo- kalaemia; Course of the disease (c) hypocholesterolaemia; The course of the disease in the absence of ther- (d) mild anaemia, usually hypochromic-eosino- apy is progressive deterioration, usually culminating philia and lymphopenia are not usually found; in frank malignancy with consequent obstruction, intussusception, or perforation of the small intes- (e) hypoalbuminaemia and protein-losing enter- tine (1). The course may be interrupted by periods opathy; of improvement. Death is usually due to either (f) elevated alkaline phosphatase, often of intes- cachexia and infection or complications of localized tinal origin (8, 24, 27); tumour. Dissemination of the immunoblastic tumour outside the abdomen is a rare, late event of the (g) positive occult blood in stool may be found; disease (1, 3). (h) a variety of parasites have been associated The time lapse between initial symptoms and diag- with the disease, Giardia being the most frequent; nosis ranges from one month to six years. ALPHA-CHAIN DISEASE AND RELATED SMALL-INTESTINAL LYMPHOMA 617 HISTOPATHOLOGY OF IMMUNOPROLIFERATIVE that is evident in the gut is not clear, since it may SMALL-INTESTINAL DISEASE signify either a reaction pattern identical to that in ( MEDITERRANEAN TYPE ") (IPSID) the intestinal mucosa or actual dissemination of malignant cells to the mesenteric lymph nodes. The histological features of this disorder are A histopathological classification a of this disorder characteristic of the clinical syndrome of the so- is as follows: called Mediterranean lymphoma with malabsorp- (a) diffuse, dense, compact, and apparently benign tion, which is commonly associated with the presence lympho-proliferative mucosal infiltration, in the serum of alpha-heavy-chain disease (aHCD) (i) pure plasmacytic protein (15, 29). The aHCD protein may occasionally (ii) mixed lympho-plasmacytic; be found in immunoblastic intestinal lymphomas not apparently associated with diffuse lympho-plasma- (b) as in (a), plus circumscribed " immunoblastic" cytic infiltration of the lamina propria of the mucosa. sarcoma(s), in either the intestine and/or mesen- The diffuse plasma-cell infiltration at the time of teric lymph nodes; clinical presentation is usually massive, causing wide (c) diffuse " immunoblastic" or plasmacytic sar- separation of the crypts of Lieberkiihn and obliter- coma with or without demonstrable, apparently ation of the villous architecture, without, however, benign lympho-plasmacytic infiltration. significant impairment of the integrity of the surface epithelium (24). In some instances, obliteration of IMMUNOGLOBULIN ABNORMALITIES IN IPSID the villi is not complete, and focal areas in which the villous architecture is preserved but in which A characteristic immunoglobulin abnormality is the villous stroma is heavily
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