CASE REPORT Clinical and Experimental Rheumatology 2002; 20: 848-850. Lymphoepithelioma-like ABSTRACT dition improved subsequently but her carcinoma of the parotid Ly m p h o ep i t h e l i o m a - l i ke carc i n o m a arthritis relapsed three years later. X- (LELC) is an Epstein-Barr virus (EBV) rays showed erosion of the carp a l gland in a patient with related malignancy. It is not a common bones, radioulnar joints of hands, tarsal rheumatoid arthritis condition and is usually found in the bones and metat a rsal bones of both head and neck region. We describe the feet. Her therapy was switched to aza- M.Y. Mok, W.H. Shek1, d evelopment of LELC involving the thioprine 100mg daily in 1990 and she R.W.S. Wong in a patient with rheu - responded well. m atoid art h ritis (RA) who had been In November 2000, she was incidental- Department of Medicine and 1Department re c e iving long-term azat h i o p ri n e. A ly found to have swelling of her right of Pathology, University of Hong Kong, brief review is also made on the clinical parotid gland.There were no other pal- Queen Mary Hospital, Hong Kong. presentation and histological features p able lymph glands in the cerv i c a l , Mo Yin MOK, MRCP, FHKAM (Rheuma- of LELC and the association of RA with axillary and groin regions. Her com- tology), Rheumatology Fellow; Wai Hung EBV related diseases. The latter may plete blood count was normal and liver SHEK, MB BS, FHKAM (Pathology), be attributed to an increase in risk of and renal function tests we re unre- Senior medical officer; Raymond Woon malignancy associated with RA or as a m a rk able ex c ept for mildly elevat e d Sing WONG, MRCP, FHKAM (Rheuma- result of the long-term immunosuppres - g l o bulin level of 47 (normal 24-36) tology), Rheumatology Consultant. sive used. g/L. Ery t h ro cyte sedimentation rat e Please address correspondence to: was 77 mm/hr and c-reactive protein Dr. Mo Yin Mok, Rheumatology Fellow, Case report was < 0.4 (normal < 1) mg/dl. Clinical- Department of Medicine, Queen Mary A 52-year-old lady was diagnosed to ly there was no active synovitis to Hospital, Pokfulam Road, Hong Kong. have rheumatoid arthritis (RA) in 1987 account for the elevated inflammatory Received on January 28, 2001; accepted when she presented with polyarthritis markers. Trucut biopsy of the parotid in revised form on June 4, 2002. involving small finger joints, wrists and mass showed syncytial sheets of cohe- © Copyright CLINICAL AND ankles. She denied dry eyes and dry sive epithelial tumour cells in a back- EXPERIMENTAL RHEUMATOLOGY 2002. . Shirm e r ’s test was negat ive. ground of heavy ly m p h o p l a s m a cy t i c There was no evidence of extra-articu- infiltrate (Fig. 1). These epithelial tu- Key words: Azathioprine, lympho- lar manifestations of the disease. Her mour cells we re cy t o l ogi c a l ly malig- epithelial lesion, nasopharyngeal r h e u m atoid factor was elevated (229 nant with prominent nucleoli, and their carcinoma, tumour. IU/ml, normal < 30 IU/ml). Her anti- epithelial nature was confirmed by the ex t ra c t able nu clear antigen antibody s t rong immu n o re a c t ivity for cyt o ke r - s t atus was negat ive. She was give n atin (CAM5.2). In situ hy b ri d i z at i o n hydroxychloroquine 200 mg daily for (ISH) study showed that the tumour more than 6 months with no clinical cells we re positive for Epstein-Barr improvement and oral gold (auranofin v i ru s - re l ated RNA (EBER), f u rt h e r 6 mg daily) was used instead. Her con- confirming the morphologic diagnosis

Fig. 1. Syncytial sheets of malignant cells against a heavy background of lymphoplasmacytic cells.

848 LELC in rheumatoid arthritis / M.Y. Mok et al. CASE REPORT of a lymphoepithelioma-like carcinoma to be of diagnostic value for determina- To our knowledge, there has not been (LELC) (Fi g. 2). She had taken a tion of the possible site of pri m a ry a ny case rep o rt of LELC arising in cumulative dose of 279.9 g of azathio- tumor in patients presenting with nodal patients with autoimmune diseases. All prine at that time and she was asked to metastatic disease. the 9 patients mentioned in the above withhold the medication. s e ries had no fe at u res sugge s t ive of She was refe r red to the ENT surgeo n Discussion Sjögren’s syndrome. It has been shown for nasophary n geal ex a m i n ation. Th e LELC of the major salivary gland is a that patients with RA have an increased na s o p h a r ynx was smooth and blind bi- rare disease, and affects mainly Orien- risk of developing malignancies, par- opsy showed normal histology. She was tals. The main histological differentia- ticularly EBV related lymphoprolifera- then refe r red to the rad i o l o gist for local tion of LELC is lymphoepithelial si a l - tive disease (6). A case-control study ra d i o t h e rapy. Her parotid mass sub- ad e n i t i s , a condition that not uncom- by Baecklund et al. on a cohort of sided after rad i o t h e r apy but her condi- m o n ly affects the saliva ry glands in p atients with RA showed that the tion was complicated by marked dry patients with autoimmune disease. In increase in risk of was re- mouth and . Nystat i n LELC, the epithelial tumor cells show lated to RA disease regardless of drug suspension and Dispirin mouthwa s h malignant cy t o l ogic fe at u res. ISH treatment (7). On the other hand, al- wer e pres c r ibed for symptomatic rel i e f . study for EBER is extremely useful in though LELC has not been reported in Th e re was no indication for disease that it is positive in LELC (3), but is p o s t - t ransplant pat i e n t s , E B V- re l at e d modifying agents at this juncture, as the negative in lymphoepithelial sialadeni- lym p h o p ro l i fe r ati ve diseases have been art h r itis status had remained quiescent. tis (4). For patients with LELC of the well described after various immuno- To summarise, we report here a lady parotid gland, it is important, however, suppressive regimens involving differ- suffering from seropositive RA treated to exclude a primary nasopharyngeal ent combinations of azathioprine, pred- with azathioprine for 10 years and dev- c a rcinoma because it is stat i s t i c a l ly nisolone, cyclosporine A and anti-thy- eloped LELC in her parotid gland. m o re common to find a metastat i c mocyte globulin (8). It is likely to be LELC classically occurs in the naso- LELC than primary LELC in the par- the degree of immu n o s u p p re s s i o n , p h a rynx in the Orientals. Vi rt u a l ly otid gland. rather than the particular regimen that 100% of LELC of the nasopharynx are Our patient was found to have LELC is the most important predisposing fac- Epstein-Barr virus-related. LELC can involving the right parotid gland with- tor. EBV-related lymphoma that devel- also occur elsewhere in the body, such out a concurrent nasophary n geal le- oped in patients with RA has also been as major salivary glands, thyroid gland, sion. A previous series reporting nine d e s c ribed in patients re c e iving long- thymus, stomach, lung and a variety of Chinese patients with LELC of the sali- term methotrexate (9). Our patient had other sites (1). Intere s t i n g ly, t h o s e vary gland showed a predilection for been taking azathioprine for more than LELCs that occur in organs derive d female patients with a median age of 10 years (cumulative dose 279.9 g) and from the embryonic foregut are EBV- fifty years. One-third of the patients in it remains possible that long-term use related (2). This strong association of t h at series died within twe n t y - s i x of azat h i o p rine confe rs immu n o s u p- such tumors with EBV has been found months (5). pressive effect similar to methotrexate. A meta-analysis of articles published between 1966 and 1998 on the inci- dence of cancer in RA patients suggest- ed the increase in risk of lymphoma was pro b ably re l ated to azat h i o p ri n e use (10). Long-term azathioprine use alone (range of total cumulative do s e s of 89-260 g) has also been shown to induce acute myeloid leukemia in p atients with autoimmune diseases (two systemic and one RA). Azathioprine is postulated to behave as a mutagen that leads to chro- mosomal ab e rrations involving the chromosome 7 (11). In summary, we described here a pa- tient with RA who had been receiving long-term azathioprine and was com- plicated by EBV-related LELC of the p a rotid gland. We also postulate the increase in risk of EBV-related malig- Fig. 2. In situ hybridization showing EBER in the nuclei of the tumour cells. nancies may be related to the underly-

849 CASE REPORT LELC in rheumatoid arthritis / M.Y. Mok et al. ing RA or immu n o s u p p re s s ive dru g gland: Lack of evidence of association with TELIUS N, KLARESKOG L: Disease activity use, but additional studies are neces- E p s t e i n - B a rr virus. Hum Pathol 1996; 27: and risk of lymphoma in patients with rheu- 851-3. m atoid art h ritis; nested case-control study. sary to confirm or refute this hypothe- 3. LEUNG SY, CHUNG LP, YUEN ST, HO CM, BMJ 1998; 317: 180-1. sis. Rheumatologists should neverthe- WONG MP, CHAN SY:Lymphoepithelial car- 8. HANTO DW, FRIZZERA G, GAIL-PECZALSKA less maintain a high index of suspicion cinoma of the salivary gland: in situ detection K J, SIMMONS R L: E p s t e i n - B a rr viru s , i m- for clinical manifestation of LELC as of Epstein-Barr virus. J Clin Pathol 1995; 48: munodeficiency and B cell lymphoprolifera- 1022-7. tion. Transplantation 1985; 39: 461-72. well as other lymphoproliferative dis- 4. CHAN JK, YIP T T, TSANG W Y, POON Y F, 9. GEORGESCU L, QUINN GC, SCHWARTZMAN ease in these patients. Pat h o l ogi s t s WONG CS, MA VW: Specific association of S, PAGET S A: Lymphoma in patients with should also be aware of this associa- E p s t e i n - B a rr virus with ly m p h o ep i t h e l i a l r h e u m atoid art h ri t i s : A s s o c i ation with the tion, and not to misdiagnose LELC as c a rcinoma among tumors and tumor like disease state or methotrex ate tre at m e n t . lesions of the salivary gland. Arch Pathol Lab Semin Arthritis Rheum 1997; 25: 794-804. ly m p h o epithelial . ISH Med 1994; 118: 994-7. 10. VASSILOPOULOS D,WALTUCK J, CLAKE G, study for EBER is helpful in this diffi- 5. KUO T, HSUEH C:Ly m p h o ep i t h e l i o m a - l i ke FARHI DC, WILLIAMS J, FANUCCHI M P: cult differential diagnosis. salivary gland carcinoma in Taiwan: A cli- R eve rs i ble Epstein-Barr virus associated T nico-pathological study of nine cases demon- cell non-Hodgkin’s lymphoma in pat i e n t s s t rating a strong association with Epstein with rheumatoid arthritis undergoing chronic Reference Barr virus. Histopathology 1997; 31: 75-82. i m mu n o s u p p re s s ive therapy. J Rheumat o l 1. IE Z Z O N I J C , GAFFEY MJ, WEISS L M:Th e 6. VAN DE RIJN M,CLEARY ML, VARIAKOJIS D, 1998; 25: 389-91. role of Epstein-Barr virus in lymphoepithe- WARNKE RA, CHANG PP, KAMEL OW: 11. KWONG Y L , AU W Y, LIANG RH: A c u t e l i o m a - l i ke carc i n o m a s . Am J Clin Pat h o l Epstein-Barr virus clonality in lymphoma oc- myeloid leukemia after azat h i o p rine tre at- 1995; 103: 308-15. curring in patients with rheumatoid arthritis. ment for autoimmune diseases: a s s o c i at e d 2. SHEK TW, LUK IS, NG IO , LO CY:Lympho- Arthritis Rheum 1996; 39: 638-42. with -7/7q-. Cancer Cenet Cytogenet 1998; ep i t h e l i o m a - l i ke carcinoma of the thy ro i d 7. BAECKLUND E, EKBOM A, SPAREN P, FEL- 104: 94-7.

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