Gut, 1992, 33, 135-137 135 Intestinal lymphangiectasia associated with angiofollicular hyperplasia (Castleman's disease) Gut: first published as 10.1136/gut.33.1.135 on 1 January 1992. Downloaded from

S F Moss, D M Thomas, C Mulnier, I G McGill, H J F Hodgson

Abstract as a solitary, symptomless, mediastinal mass A patient presenting with predominantly characterised histologically by lymphoid follicle gastrointestinal symptoms and a history of like structures with prominent proliferation of myocardial infarction was found to have blood vessels.3 Two subtypes are described, , hepatosplenomegaly, para-aortic probably representing the extremes of a , thrombocytosis, and apara- spectrum of appearances.4 The hyaline vascular proteinaemia. A jejunal specimen type is by far the more common, while the showed lymphangiectasia and histology of the plasma cell variant is more likely to be associated and lymph nodes showed angio- with systemic symptoms, particularly when the follicular hyperplasia or Castleman's disease condition is multicentric rather than solitary. of the hyaline vascular type. This association has not previously been described and, more- in Departments ofMedicine over, systemic symptoms are unusual this Case history and Histopathology, variant of Castleman's disease. A 49 year old female teacher presented with a Royal Postgraduate four year history of malaise and one year of Medical School, abdominal swelling, and the passage of Hammersmith Hospital, nausea, London Intestinal lymphangiectasia is an uncommon loose watery stools three times daily. Over this S F Moss entity characterised by dilated lymphatics within time she had lost 10 kg in weight. She also D M Thomas the gut. It may be primary or secondary to complained of numbness in both feet and of the C Mulnier H J F Hodgson lymphatic obstruction in a number of inflamma- symptoms of Raynaud's phenomenon affecting tory or neoplastic conditions' or in right heart the left arm. Breathlessness prevented her from Department of Medicine, failure, where the lymphatic return from the climbing more than two flights of stairs. Two Torbay Hospital, Devon intestine may be compromised. It may present years previously she had suffered an uncompli- I G McGill http://gut.bmj.com/ Correspondence to: with the consequences of protein losing entero- cated transmural inferior myocardial infarction. Dr S F Moss, Department of pathy and is occasionally associated with At this time she had a mild thrombocytosis with Gastroenterology, Royal Postgraduate Medical School, immunodeficiency caused by the loss of T cells a platelet count of 600 x 109/1 but no other risk Hammersmith Hospital, into the intestinal lumen.2 factors for ischaemic heart disease. She was Du Cane Road, London W12 OHS. Castleman's disease, or angiofollicular lymph taking aspirin (75 mg daily) and bumetanide Accepted for publication node hyperplasia, is a rare lymphoproliferative with potassium. 2 April 1991 disorder of unknown aetiology. It usually occurs On physical examination there were no signs on October 3, 2021 by guest. Protected copyright.

Figure 1: High power magnification ofjejunal mucosa showing lymphangiectasia. (Original magnification x400.) 136 Moss, Thomas, Mulnier, McGill, Hodgson Gut: first published as 10.1136/gut.33.1.135 on 1 January 1992. Downloaded from

Figure 2: High power magnification oflymph node showingfollicle like structures. (Original magnification x250.)

of and no lymphadenopathy. There splenectomy were performed together with a were ascites, moderate , and a liver biopsy. sensory peripheral neuropathy in a glove and Histology of the lymph nodes showed partial stocking distribution. replacement of the normal architecture by All haematological indices, including a bone structures comprising concentric rings of small marrow trephine, were normal except for a surrounding small follicle centres raised platelet count of 600x 109/1. The alkaline containing hyalinised vessels that were occasion- http://gut.bmj.com/ phosphatase value was high at 176 iu/l but she ally seen to enter the follicle radially (Fig 2). The had normal transaminase activities and total interfollicular areas showed proliferating blood concentrations. An IgA lambda para- vessels. protein was detected in the serum by immuno- The spleen showed expansion of the white fixation, at a concentration ofless than 1 g/l. The pulp with similar follicle like structures and the following investigations were either negative or overall appearances were those of multicentric, within the normal range: urea and electrolytes, hyaline vascular Castleman's disease. The liver on October 3, 2021 by guest. Protected copyright. autoantibodies, cryoglobulin, complement, biopsy was essentially normal. ferritin, protein electrophoresis, C reactive After operation, the platelet count doubled to protein, and red cell and serum folate. Electro- 1200x 10/1 and hepatic alkaline phosphatase myograph showed a mixed demyelinating and activity was 375 iu (normal < 130). axonal neuropathy. Bone marrow examination now showed Urinary protein excretion was 0-4 g/24 hours increased numbers of megakaryocytes and and Bence-Jones protein was not detected. lymphocytes with a 7-10% eosinophilia. Abdominal paracentesis showed a straw T receptor gene rearrangement coloured cellular exudate (protein 50 g/l and a studies showed a discrete T cell clone in the cell count of 5 4x 109/1, with 68% lymphocytes, ascitic fluid that was not seen in the peripheral 26% monocytes, and 4% neutrophils). Faecal blood. There was no evidence of an abnormal B excretion was slightly raised at 5 9 g/24 hours. cell clone. A jejunal mucosal biopsy specimen showed Eight months later, the peripheral blood lymphangiectasia with a normal villous architec- showed a persistent thrombocythaemia and also ture (Fig 1). A reduced intraepithelial lympho- a raised haematocrit (0 5) and red cell volume cyte count of 8 per 100 epithelial cells (normal (when corrected for plasma volume) consistent 18 0), was consistent with this diagnosis5 and the with polycythaemia. This was considered abnormal mucosa further excluded the possi- evidence ofthe development ofa myeloprolifera- bility that the specimen had been taken from a tive process and in view of this and of the slowly localised lymphangiectatic cyst. In this condi- progressive neurological symptoms, treatment tion, more often seen in older patients, the with cyclophosphamide and prednisolone was mucosa is normal.6 begun. Computed tomogram confirmed the enlarged spleen and also showed mild hepatomegaly and para-aortic lymphadenopathy. Discussion Because of the strong clinical suspicion of an Our patient exhibited a number of systemic intra-abdominal lymphoma, a laparotomy and features usually associated with the plasma cell Intestinal lymphangiectasia associated with angiofollicular lymph node hyperplasia (Castleman's disease) 137

variant of Castleman's disease, including weight 2 Strober W, Wochner RD, Carbone PP, Waldmann TA. Intestinal lymphangiectasia: a protein losing enteropathy loss, fever, thrombocythaemia,7 paraprotein- with hypogammaglobulinaemia, lymphocytopaenia and aemia,' peripheral neuropathy,78 and myocardial impaired homograft rejection. i Clin Invest 1967; 46: 1643- infarction.9 56. Other reported features include 3 Castleman B, Iverson L, Menendez VP. Localised mediastinal Gut: first published as 10.1136/gut.33.1.135 on 1 January 1992. Downloaded from and lymph node hyperplasia resembling . Cancer 1956; amyloidosis'° anaemia (which may be due to 9: 822-30. circulating antierythrocyte antibody)." 4 Keller AR, Hochholzer L, Castleman B. Hyaline vascular and The pathogenesis of Castleman's disease is plasma cell types of giant lymph node hyperplasia of mediastinum and other locations. Cancer 1972; 29: 670-83. unknown but a number oflines ofevidence point 5 Myszor MF, Davidson A, Hodgson HJF. The local mucosal to it being an immunoproliferative condition. immune system in intestinal lymphangiectasia. J Clin Lab Immunol 1988; 26: 1-3. Monoclonal plasma cell populations have been 6 Steinar A, Gundersen R. Submucous lymphatic cysts of the shown in some cases the . Acta Pathol Microbiol Scand [B] 1983; 91: of plasma cell type'2 3 191-4. and T cell gene rearrangements have been associ- 7 Hineman VL, Phyliky RL, Banks PM. Angiofollicular lymph ated with Epstein-Barr virus incorporation.'3 node hyperplasia and peripheral neuropathy: association with monoclonal gammopathy. Mayo Clin Proc 1982; 57: These abnormalities seem confined to the multi- 379-82. centric form of the disease. Moreover, produc- 8 Donaghy M, Hall PA, Gawler J, et al. Peripheral neuropathy associated with Castleman's disease. J Neurol Sci 1989; 89: tion ofthe cytokine interleukin 6 by Castleman's 253-67. nodes 9 Case records of the Massachusetts General Hospital. N Engil has been shown both in vitro'4 and in Med 1987; 316: 606-18. vivo.'" Our patient had T cell gene rearrange- 10 West KP, Morgan DA, Lauder I. Angiofollicular lymph node hyperplasia with amyloidosis. Postgrad Med J 1989; 65: ment in the ascitic fluid though not in the peri- 108-11. pheral blood. 11 Steinberg JL, Huang PL, Ljubich P, Lee-Huang S. Anti- One study reports a high rate ofprogression of erythropoietin antibody in hyperviscosity syndrome associ- ated with giant lymph node hyperplasia (Castleman's the hyaline vascular form to angiomatous neo- disease). BrJHaematol 1990; 74: 543-44. plasms'6 but as the morphology of Castleman's 12 Hall PA, Donaghy M, Cotter FE, Stansfeld AG, Levison DA. An immunohistochemical and genotypic study ofthe plasma nodes may resemble that seen in nodes draining cell form of Castleman's disease. Histopathology 1989; 14: malignant tumours, in autoimmune conditions, 333-46. 13 Hanson CA, Frizzera G, Patton DF, et al. Clonal rearrange- in HIV infection, and in Kaposi's sarcoma'7 this ment for immunoglobulin T cell receptor genes in systemic association remains unproved. Castleman's disease: association with Epstein-Barr virus. AmJ Pathol 1988; 131: 84-91. Castleman's disease may present to the gastro- 14 Yabuhara A, Yanagisawa M, Murata T, et al. Giant lymph enterologist in a number of ways - as hepato- node hyperplasia (Castleman's disease) with spontaneous production of high levels of B cell differentiation factor splenomegaly, abdominal lymphadenopathy, or activity. Cancer 1989; 63: 260-5. as a mass in the stomach or pancreas.'8 '9 How- 15 Yoshizaki K, Matsuda T, Nishimoto N, et al. Pathogenic significance of interleukin-6 (IL-6/BSF-2) in Castleman's ever, intestinal lymphangiectasia secondary to disease. Blood 1989; 74: 1360-7. this condition has not previously been described 16 Gerald W, Kostianovsky M, Rosai J. Development ofvascular neoplasia in Castleman's disease: report of7 cases. AmJSurg and in this patient is probably a result ofthe para- Pathol 1990; 14: 603-14. aortic and mesenteric lymphadenopathy of 17 Frizzera G. Castleman's disease: more questions than answers. Hum Pathol 1985; 16: 202-5. http://gut.bmj.com/ multicentric Castleman's disease. 18 Yebra M, Vargas JA, Menendez VP, et al. Gastric Castleman's disease with a lupus-like circulating anticoagulant. Am J Gastroenterol 1989; 84: 566-70. 1 Strober W. In: Bouchier IAD, Allan RN, Hodgson HJF, 19 LeVan TA, Clifford S, Staren ED. Castleman's tumour Keighley MRB, eds. Textbook ofgastroenterology. London: masquerading as a pancreatic neoplasm. Surgery 1989; 106: Baillire Tindall, 1984: 598-615. 884-7. on October 3, 2021 by guest. Protected copyright.