The document attached has been archived with permission from the editor of the Medical Journal of Australia. An external link to the publisher’s copy is included.Yoon-Sim Yap, Adrian Cummins, Peter Blumbergs, Jennifer Hardingham, Sunil Dabadghao and John Norma

Blumbergs, P.

Cummins, A.

Dabadghao, S.

Hardingham, J.

Norman, R.

Yap, Y.

The Medical Journal of Australia

Carbonnel F

Ashton‐Key M

Tutt ANJ

Shams PN

Crossref

Lymphomatous infiltration of the peripheral nervous system in enteropathy‐associated T‐cell lymphoma

Adelaide Research &amp; Scholarship

 PUBLISHED VERSION   Yap, Yoon-Sim; Cummins, Adrian Gerard; Blumbergs, Peter Charles; Hardingham, Jennifer Elizabeth; Dabadghao, Sunil; Norman, Robert John  Lymphomatous infilration of the peripheral nervous system in enteropathy-associated T-cell lymphoma Medical Journal of Australia, 2005; 182(7):348-349  This article is available from the Medical Journal of Australia at:   http://www.mja.com.au/public/issues/182_07_040405/yap10553_fm.html                          http://hdl.handle.net/2440/17523  PERMISSIONS   This document has been archived with permission from the editor of the Medical Journal of Australia, 26 April 2007.    LESSONS FRO M PRACTICELymphomatous infiltration of the peripheral nervous system in enteropathy-associated T-cell lymphomaThe Medical Journal of Australia ISSN: 0025-729X 4 April 2005 182 7 348-349©The Medical Journal of Australia 2005www.mja.com.auLessons from Practiceserology and thyroid function tests were normal. Paraproelectrophoresis. Magnetic resonance imaging (MRI) of thpatchy periventricular areas of high signal not suggestiveHer systemic symptoms of fever, sweats and weight loss doses of cyclophosph mide (1 g/m2), despite worsening After 3 months, the patient relapsed with recurrence of pprogressively rose to 838 U/L. Neuropathy progressed towalk. Reflexes were lost, with a glove-and-stocking patteoemain C liac disease is associated with an increased risk oflignancy.1 Most of these tumours are T-cell lymphomas,contrast to the common sporadic B-cell lymphomas thatusually occur in the gastrointestinal tract.Enteropathy-associated T-cell lymphoma (EATL) often presentsas refractory sprue. The risk of EATL usually decreases to a lowlevel after adhering to a gluten-free diet for 5 years. Commonsymptoms of presentation include diarrhoea, abdominal pain andweight loss. Patients may also present with acute bleeding, perfora-tion or obstruction.2 Our patient presented with weight loss,pyrexia and, subsequently, neuropathy. Clinical deteriorationdespite compliance with a gluten-free diet should raise suspicionof EATL. Conversely, as coeliac disease may be undiagnosed at thetime of presentation of the intestinal lymphoma, patients with T-cell lymphoma or a gut primary localisation should be tested forcoeliac disease. Endoscopy with biopsy is usually the test ofchoice. Laparotomy is performed in some instances, especiallywhen patients present with an acute abdomen.Our case illustrates a number of interesting features. First, adefinitive diagnosis of EATL may be elusive, and persistence in2 Positive CD3 immunostaining of lymphocytesClinical recordA 53-year-old woman with a 10-year history of coeliac disease controlled by a gluten-free diet presented with a 6-month history of dramatic weight loss and pyrexia. Physical examination showed wasting and peripheral oedema. Plasma albumin level was 23 g/L (normal, 34–48 g/L). Computed tomography of head, neck, chest, abdomen and pelvis, gallium and positron emission tomography scans, liver biopsy and bone marrow biopsy were normal. The serum lactate dehydrogenase (LDH) level was 466 U/L (normal, 110–230 U/L), raising the possibility of occult malignancy, especially enteropathy-associated T-cell lymphoma (EATL). Endoscopic duodenal biopsy revealed mild increase in intraepithelial lymphocytes, crypt hyperplasia and villous abnormality in keeping with coeliac disease. Molecular clonality studies of the lymphoid cells in the duodenal biopsy yielded a monoclonal band of T-cell receptor (TCR) γ gene rearrangement in two separate series of biopsies taken 6 weeks apart.Refractory sprue was diagnosed, and the patient received sequential trials of prednisolone, cyclosporin A and infliximab without benefit. High dose cyclophosphamide (2 g/m2) was administered 3 months later for presumed EATL. This resulted in immediate resolution of the fever and improved weight gain.The patient subsequently complained of paraesthesiae in her feet. Neurological examination was normal. Nerve conduction studies suggested an early axonal sensory peripheral neuropathy. Vitamin B12, folate, vitamin A-tocopherol, red blood cell transaminase and transketolase studies, vasculitic screen, glycated haemoglobin, syphilis tein was not detected in serum e brain showed non-specific  of the suspected lymphoma. responded to two further neurological symptoms.yrexia, and the serum LDH level  the point where she could not rn of sensorimotor disturbance. A repeated nerve conduction study confirmed severe axonal sensorimotor peripheral neuropathy affecting both upper and lower limbs. Cerebrospinal fluid was normal, and there were no malignant cells. Repeated investigations, including brain MRI and upper gastrointestinal endoscopy, did not reveal any further evidence of malignancy.A right sural nerve biopsy showed severe loss of myelinated nerve fibres, and many of the surviving fibres showed varying stages of axonal degeneration (Box 1) associated with a sparse, patchy endoneurial mononuclear cell infiltrate in some fascicles and prominent endoneurial fibrosis on trichrome stain. The CD45RB immunostain showed increased numbers of immunopositive endoneurial lymphoid cells that showed immunopositivity with the T-cell markers CD3 (Box 2) and CD5. The CD68 immunostain showed increased endoneurial macrophages, and ultrastructural assessment confirmed macrophage phagocytosis of degenerate myelinated fibres. CD20 immunostain was negative. The Congo red stain for amyloid was negative. A TCRγ clonality study of the nerve biopsy showed a monoclonal band identical to the previous band detected in the duodenal biopsies, confirming infiltration of the nerve by T-cell lymphoma (Box 3).Subsequent treatment with cyclophosphamide, doxorubicin and dexamethasone was complicated by Enterococcus faecalis septicaemia and florid disseminated intravascular coagulation, leading to the patient’s death.1 Nerve fibres in varying stages of axonal degenerationLongitudinal section.Transverse section.348 MJA • Volume 182 Number 7 • 4 April 2005LESSONS FRO M PRACTICEobtaining histological confirmation iswarranted. The elevated serum lactatedehydrogenase (LDH) level raised thepossibility of an underlying malignancy.Second, in patients with refractory sprue,a clonal TCRγ rearrangement often pre-cedes the onset of overt T-cell lymphoma,which constitutes an early or cryptic formof EATL.3-5 The difficulty is distinguishingantigen-dependent T cells from neoplasticT cells. Management decisions may haveto be based on DNA clonality studiesalone. Finally, although central nervoussystem involvement has been reported,6,7to our knowledge this is the first reportedcase of peripheral nerve involvement inEATL. Clinical evidence of peripheralneuropathy is observed in 0.1% to 8% ofpatients with malignant lymphomas,8 andneurotoxic chemotherapeutic agents arefrequently presumed to be the cause.Peripheral nerve involvement in T-celllymphomas is very uncommon.8-10 It isalso interesting that the infiltrative neu-ropathy progressed relentlessly despite aninitial good response of systemic symp-toms to cyclophosphamide.Both refractory sprue and EATL carry avery poor prognosis, with a 5-year survivalrate of 11%. This is related to the unre-sponsive malabsorption in cryptic EATL,which is often diagnosed late. Associatedmalabsorption and malnutrition make tol-erance of chemotherapy difficult, andtreatment-related complications such asgastrointestinal bleeding and perforation also worsen prognosis.2Favourable outcomes with multi-drug therapy generally occur inpatients who have minimal gastrointestinal symptoms before thediagnosis of lymphoma and can tolerate therapy.Chemotherapy should be considered for all patients and shouldconstitute drugs active in intermediate- and high-grade lym-phoma. A variety of regimens, including CHOP (cyclophospha-mide, doxorubicin, vincristine and prednisolone), have been used.The optimal cytotoxic regimen is unclear, as data are limited touncontrolled retrospective case series. The role of salvage treat-ments and high-dose chemotherapy at relapse also remains to beinvestigated.2 Earlier diagnosis and development of more effectivetreatments are required to improve the outcome for these patients.Yoon-Sim Yap,* Adrian G Cummins,† Peter Blumbergs,‡Jennifer Hardingham,§ Sunil Dabadghao,¶ John Norman***Medical Oncology Registrar, †Gastroenterologist§Principal Medical Scientist, ¶Haematology Registrar**Haematologist/oncologist, The Queen Elizabeth Hospital, Adelaide, SA‡Professor and Head of Neurology, Hanson Institute Centre forNeurological Diseases, Institute of Medical and Veterinary ScienceAdelaide, SA. yongxiny@hotmail.comAcknowledgements: We wish to thank Drs H Nicholson and I Pollard forreferring the patient.Competing interests: None identified.1 Askling J, Linet M, Gridley G, et al. Cancerincidence in a population-based cohort of indi-viduals hospitalized with celiac disease or der-matitis herpetiformis. Gastroenterology 2002;123: 1428-1435.2 Gale J, Simmonds PD, Mead GM, et al. Enterop-athy-type intestinal T-cell lymphoma: clinical fea-tures and treatment of 31 patients in a singlecenter. J Clin Oncol 2000; 18: 795-803.3 Cellier C, Delabesse E, Helmer C, et al. Refrac-tory sprue, coeliac disease, and enteropathy-associated T-cell lymphoma. Lancet 2000; 356:203-208.4 Carbonnel F, Grollet-Bioul L, Brouet JC, et al. Arecomplicated forms of celiac disease cryptic T-celllymphomas? Blood 1998; 92: 3879-3886.5 Ashton-Key M, Diss TC, Pan L, et al. Molecularanalysis of T-cell clonality in ulcerative jejunitisand enteropathy-associated T-cell lymphoma.Am J Pathol 1997; 151: 493-498.6 Tutt ANJ, Brada M, Sampson SA. Enteropathyassociated T cell lymphoma presenting as anisolated CNS lymphoma three years after diag-nosis of coeliac disease: T cell receptor polymer-ase chain reaction studies failed to show theoriginal enteropathy to be a clonal disorder. Gut1997; 40: 801-803.7 Shams PN, Waldman A, Dogan A, et al. Ataxia inthe setting of complicated enteropathy: doublejeopardy. J Neurol Neurosurg Psychiatry 2002;72: 527-529.8 Gherardi R, Gaulard P, Prost C, et al. T-celllymphoma revealed by a peripheral neuropathy.Cancer 1986; 58: 2710-2716.9 Peris K, Fargnoli M, Berardelli A, et al. Peripheralnervous system involvement in a patient withlarge T-cell lymphoma arising from a pre-existingmycosis fungoides. Br J Dermatol 1998; 139: 299-301.10 Atiq OT, DeAngelis LM, Rosenblum M, PortlockCS. Cutaneous T-cell lymphoma presenting withdiffuse lymphomatous infiltration of the periph-eral nerves: response to combination chemo-therapy. Am J Clin Oncol 1992; 15: 212-215.(Received 10 Aug 2004, accepted 5 Jan 2005) ❏3 Polyacrylamide gel electrophoresis of T-cell receptorsLane 1, positive control; lane 2, negative control; lane 3, normal (polyclonal) control; lanes 4 and 5, duodenal biopsy, 12 Apr 2002; lanes 6 and 7, duodenal biopsy, 19 Jul 2002; lanes 8 and 9, nerve tissue, 9 Oct 2002.Lessons from practice• Coeliac disease is associated with an increased risk of malignancy, especially intestinal lymphoma or enteropathy-associated T-cell lymphoma (EATL).• EATL often presents as refractory sprue, but definitive diagnosis may be difficult and requires T-cell clonality studies.• Earlier diagnosis and development of more effective treatments are warranted to improve the poor outcome in these patients.MJA • Volume 182 Number 7 • 4 April 2005 349