Gut, 1992, 33, 135-137

Intestinal lymphangiectasia associated withangiofollicular lymph node hyperplasia(Castleman's disease)

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

Departments of Medicineand Histopathology,Royal PostgraduateMedical School,Hammersmith Hospital,LondonS F MossD M ThomasC MulnierH J F Hodgson

Department of Medicine,Torbay Hospital, DevonI G McGillCorrespondence to:Dr S F Moss, Department ofGastroenterology, RoyalPostgraduate Medical School,Hammersmith Hospital,Du Cane Road, LondonW12 OHS.Accepted for publication2 April 1991

AbstractA patient presenting with predominantlygastrointestinal symptoms and a history ofmyocardial infarction was found to haveascites, hepatosplenomegaly, para-aorticlymphadenopathy, thrombocytosis, and apara-proteinaemia. A jejunal biopsy specimenshowed lymphangiectasia and histology of thespleen and lymph nodes showed angio-follicular hyperplasia or Castleman's diseaseof the hyaline vascular type. This associationhas not previously been described and, more-over, systemic symptoms are unusual in thisvariant of Castleman's disease.

Intestinal lymphangiectasia is an uncommonentity characterised by dilated lymphatics withinthe gut. It may be primary or secondary tolymphatic obstruction in a number of inflamma-tory or neoplastic conditions' or in right heartfailure, where the lymphatic return from theintestine may be compromised. It may presentwith the consequences of protein losing entero-pathy and is occasionally associated withimmunodeficiency caused by the loss of T cellsinto the intestinal lumen.2

Castleman's disease, or angiofollicular lymphnode hyperplasia, is a rare lymphoproliferativedisorder ofunknown aetiology. It usually occurs

as a solitary, symptomless, mediastinal masscharacterised histologically by lymphoid folliclelike structures with prominent proliferation ofblood vessels.3 Two subtypes are described,probably representing the extremes of aspectrum of appearances.4 The hyaline vasculartype is by far the more common, while theplasma cell variant is more likely to be associatedwith systemic symptoms, particularly when thecondition is multicentric rather than solitary.

Case historyA 49 year old female teacher presented with afour year history of malaise and one year ofnausea, abdominal swelling, and the passage ofloose watery stools three times daily. Over thistime she had lost 10 kg in weight. She alsocomplained of numbness in both feet and of thesymptoms of Raynaud's phenomenon affectingthe left arm. Breathlessness prevented her fromclimbing more than two flights of stairs. Twoyears previously she had suffered an uncompli-cated transmural inferior myocardial infarction.At this time she had a mild thrombocytosis witha platelet count of 600 x 109/1 but no other riskfactors for ischaemic heart disease. She wastaking aspirin (75 mg daily) and bumetanidewith potassium.On physical examination there were no signs

Figure 1: High powermagnification ofjejunalmucosa showinglymphangiectasia. (Originalmagnification x400.)

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Moss, Thomas, Mulnier, McGill, Hodgson

Figure 2: High powermagnification oflymph nodeshowingfollicle likestructures. (Originalmagnification x250.)

of heart failure and no lymphadenopathy. Therewere ascites, moderate splenomegaly, and asensory peripheral neuropathy in a glove andstocking distribution.

All haematological indices, including a bonemarrow trephine, were normal except for araised platelet count of 600x 109/1. The alkalinephosphatase value was high at 176 iu/l but shehad normal transaminase activities and totalglobulin concentrations. An IgA lambda para-protein was detected in the serum by immuno-fixation, at a concentration of less than 1 g/l. Thefollowing investigations were either negative orwithin the normal range: urea and electrolytes,autoantibodies, cryoglobulin, complement,ferritin, protein electrophoresis, C reactiveprotein, and red cell and serum folate. Electro-myograph showed a mixed demyelinating andaxonal neuropathy.

Urinary protein excretion was 0-4 g/24 hoursand Bence-Jones protein was not detected.Abdominal paracentesis showed a straw

coloured cellular exudate (protein 50 g/l and acell count of 5 4x 109/1, with 68% lymphocytes,26% monocytes, and 4% neutrophils). Faecal fatexcretion was slightly raised at 5 9 g/24 hours.A jejunal mucosal biopsy specimen showed

lymphangiectasia with a normal villous architec-ture (Fig 1). A reduced intraepithelial lympho-cyte count of 8 per 100 epithelial cells (normal18 0), was consistent with this diagnosis5 and theabnormal mucosa further excluded the possi-bility that the specimen had been taken from alocalised lymphangiectatic cyst. In this condi-tion, more often seen in older patients, themucosa is normal.6Computed tomogram confirmed the enlarged

spleen and also showed mild hepatomegaly andpara-aortic lymphadenopathy.

Because of the strong clinical suspicion of anintra-abdominal lymphoma, a laparotomy and

splenectomy were performed together with aliver biopsy.

Histology of the lymph nodes showed partialreplacement of the normal architecture bystructures comprising concentric rings of smalllymphocytes surrounding small follicle centrescontaining hyalinised vessels that were occasion-ally seen to enter the follicle radially (Fig 2). Theinterfollicular areas showed proliferating bloodvessels.The spleen showed expansion of the white

pulp with similar follicle like structures and theoverall appearances were those of multicentric,hyaline vascular Castleman's disease. The liverbiopsy was essentially normal.

After operation, the platelet count doubled to1200x 10/1 and hepatic alkaline phosphataseactivity was 375 iu (normal < 130).Bone marrow examination now showed

increased numbers of megakaryocytes andlymphocytes with a 7-10% eosinophilia.T lymphocyte receptor gene rearrangement

studies showed a discrete T cell clone in theascitic fluid that was not seen in the peripheralblood. There was no evidence of an abnormal Bcell clone.

Eight months later, the peripheral bloodshowed a persistent thrombocythaemia and alsoa raised haematocrit (0 5) and red cell volume(when corrected for plasma volume) consistentwith polycythaemia. This was consideredevidence of the development ofa myeloprolifera-tive process and in view of this and of the slowlyprogressive neurological symptoms, treatmentwith cyclophosphamide and prednisolone wasbegun.

DiscussionOur patient exhibited a number of systemicfeatures usually associated with the plasma cell

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Intestinal lymphangiectasia associated with angiofollicular lymph node hyperplasia (Castleman's disease) 137

variant of Castleman's disease, including weightloss, fever, thrombocythaemia,7 paraprotein-aemia,' peripheral neuropathy,78 and myocardialinfarction.9 Other reported features includeamyloidosis'° and anaemia (which may be due tocirculating antierythrocyte antibody)."The pathogenesis of Castleman's disease is

unknown but a number of lines ofevidence pointto it being an immunoproliferative condition.Monoclonal plasma cell populations have beenshown in some cases of the plasma cell type'2 3andT cell gene rearrangements have been associ-ated with Epstein-Barr virus incorporation.'3These abnormalities seem confined to the multi-centric form of the disease. Moreover, produc-tion of the cytokine interleukin 6 by Castleman'snodes has been shown both in vitro'4 and invivo.'" Our patient had T cell gene rearrange-ment in the ascitic fluid though not in the peri-pheral blood.One study reports a high rate ofprogression of

the hyaline vascular form to angiomatous neo-plasms'6 but as the morphology of Castleman'snodes may resemble that seen in nodes drainingmalignant tumours, in autoimmune conditions,in HIV infection, and in Kaposi's sarcoma'7 thisassociation remains unproved.

Castleman's disease may present to the gastro-enterologist in a number of ways - as hepato-splenomegaly, abdominal lymphadenopathy, oras a mass in the stomach or pancreas.'8 '9 How-ever, intestinal lymphangiectasia secondary tothis condition has not previously been describedand in this patient is probably a result ofthe para-aortic and mesenteric lymphadenopathy ofmulticentric Castleman's disease.

1 Strober W. In: Bouchier IAD, Allan RN, Hodgson HJF,Keighley MRB, eds. Textbook of gastroenterology. London:Baillire Tindall, 1984: 598-615.

2 Strober W, Wochner RD, Carbone PP, Waldmann TA.Intestinal lymphangiectasia: a protein losing enteropathywith hypogammaglobulinaemia, lymphocytopaenia andimpaired homograft rejection. i Clin Invest 1967; 46: 1643-56.

3 Castleman B, Iverson L, Menendez VP. Localised mediastinallymph node hyperplasia resembling thymoma. Cancer 1956;9: 822-30.

4 Keller AR, Hochholzer L, Castleman B. Hyaline vascular andplasma cell types of giant lymph node hyperplasia ofmediastinum and other locations. Cancer 1972; 29: 670-83.

5 Myszor MF, Davidson A, Hodgson HJF. The local mucosalimmune system in intestinal lymphangiectasia. J Clin LabImmunol 1988; 26: 1-3.

6 Steinar A, Gundersen R. Submucous lymphatic cysts of thesmall intestine. Acta Pathol Microbiol Scand [B] 1983; 91:191-4.

7 Hineman VL, Phyliky RL, Banks PM. Angiofollicular lymphnode hyperplasia and peripheral neuropathy: associationwith monoclonal gammopathy. Mayo Clin Proc 1982; 57:379-82.

8 Donaghy M, Hall PA, Gawler J, et al. Peripheral neuropathyassociated with Castleman's disease. J Neurol Sci 1989; 89:253-67.

9 Case records of the Massachusetts General Hospital. N EngilMed 1987; 316: 606-18.

10 West KP, Morgan DA, Lauder I. Angiofollicular lymph nodehyperplasia with amyloidosis. Postgrad Med J 1989; 65:108-11.

11 Steinberg JL, Huang PL, Ljubich P, Lee-Huang S. Anti-erythropoietin antibody in hyperviscosity syndrome associ-ated with giant lymph node hyperplasia (Castleman'sdisease). BrJHaematol 1990; 74: 543-44.

12 Hall PA, Donaghy M, Cotter FE, Stansfeld AG, Levison DA.An immunohistochemical and genotypic study ofthe plasmacell form of Castleman's disease. Histopathology 1989; 14:333-46.

13 Hanson CA, Frizzera G, Patton DF, et al. Clonal rearrange-ment for immunoglobulin T cell receptor genes in systemicCastleman's disease: association with Epstein-Barr virus.AmJ Pathol 1988; 131: 84-91.

14 Yabuhara A, Yanagisawa M, Murata T, et al. Giant lymphnode hyperplasia (Castleman's disease) with spontaneousproduction of high levels of B cell differentiation factoractivity. Cancer 1989; 63: 260-5.

15 Yoshizaki K, Matsuda T, Nishimoto N, et al. Pathogenicsignificance of interleukin-6 (IL-6/BSF-2) in Castleman'sdisease. Blood 1989; 74: 1360-7.

16 Gerald W, Kostianovsky M, Rosai J. Development of vascularneoplasia in Castleman's disease: report of 7 cases. AmJSurgPathol 1990; 14: 603-14.

17 Frizzera G. Castleman's disease: more questions than answers.Hum Pathol 1985; 16: 202-5.

18 Yebra M, Vargas JA, Menendez VP, et al. Gastric Castleman'sdisease with a lupus-like circulating anticoagulant. Am JGastroenterol 1989; 84: 566-70.

19 LeVan TA, Clifford S, Staren ED. Castleman's tumourmasquerading as a pancreatic neoplasm. Surgery 1989; 106:884-7.

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