APMIS 107: 5.234'. 1999 Printed in Denmark . All rights reserved

Copvrinht 0 A P M I S 1999

ISSN 0903-4641

Synchronous occurrence of carcinoid tumour of the appendix and T-cell lymphoma of the ileum

A case report with review of the literature

C. E LINDBOE,' S. E. HOLM2 and A. K. LIE

Departments of 'Pathology and 2Surgery, Vest-Agder Central Hospital, Kristiansand, and 3Department of Pathology, The Norwegian Radium Hospital, University of Oslo, Oslo, Norway

Lindboe CE Holm SE & Lie AK. Synchronous occurrence of carcinoid tumour of the appendix and T-cell lymphoma of the ileum. A case report with review of the literature. APMIS 1999;107:523-8.

Carcinoid tumours of the gastrointestinal tract are often associated with other tumour types at various sites. However, only rarely has a lymphoma constituted the second tumour. In the present paper, we report the case of a 62-year-old woman who was operated on for a perforated T-cell lymphoma of the ileum and in whom an appendicular carcinoid tumour was incidentally discovered at surgery. It was possible to completely remove both tumours and postoperatively the patient underwent CHOP treatment. Ten months after surgery the patient is well, with no tumour manifestations. We also discuss problems concerning classification of the lymphoma on account of loss of the T-cell antigen

Key words: Carcinoid tumour; non-Hodgkin lymphoma; intestinal T-cell lymphoma; associated neo- plasms; gastrointestinal tract.

Christian Fredrik Lindboe, Department of Pathology, Vest-Agder Central Hospital, N-4604 Kristian- sand S, Norway.

CD45RO (UCHL-1).

Carcinoid tumours of the gastrointestinal tract, as well as having a tendency to occur at multiple sites, are frequently associated with tumours of other types. These tumours are mostly aden- ocarcinomas of the gastrointestinal tract, but tumours of various types and locations have been described (1-9). The carcinoid and the as- sociated neoplasm(s) may occur synchronously or metachronously, the associated tumour usually being discovered first (4, 9). However, there exist few reports of carcinoid tumours as- sociated with malignancies of the lymphoreticu- lar system ( 1 4 , 9, 10). In this paper we report the synchronous occurrence of a carcinoid tu- mour of the appendix and a T-cell lymphoma of

Received March 16, 1998. Accepted December 8, 1998.

the ileum. This combination of tumour types has to our knowledge previously only been re- ported once (10).

CASE REPORT

The patient was a 62-year-old woman who had suf- fered from bronchial asthma since the 1960s. Since the mid-1970s she had passed loose stools 1-2 times a day, but there had been no weight loss. Resection of a grade 1 rectal tubular adenoma was performed in 1992. She was admitted to the Department of Surgery, Vest-Agder Central Hospital, on 5 Novem- ber, 1997 because of acute increasing abdominal pain. On admittance, the abdomen was peritonitic and radiological examination revealed free air in the abdominal cavity. Laparotomy disclosed a tumour with central perforation in the ileum approximately 50 cm from the ileocoecal valve and also a tumorous

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118 bp 72 bp

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expansion of the distal appendix. There were no metastases in the liver or peritoneum. A resection of the small bowel lesion and an appendectomy were performed. The postoperative course was uneventful.

The 4 cm-long appendix had a yellow-orange mul- tinodular tumour in the distal part (maximal diam- eter 1.3 cm). Histological examination of this tumour revealed a typical carcinoid with growth in solid cell nests extending into the periappendicular fat tissue

(Fig. 1). The tumour cells showed a strong positive reaction for cytokeratin, neuron-specific enolase (NSE), chromogranin A and synaptophysin.

The resected 15 cm ileal segment showed a diver- ticulum-like pouch measuring 4 x 2 cm. with a 0.2 cm perforation centrally. In the affected area, the bowel wall was stiff, thickened, and had a homogeneous greyish cut surface (Fig. 2). Histological examination of the ileal lesion revealed massive diffuse infiltration

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APPENDICULAR CARCINOID AND ILEAL LYMPHOMA

Fig. 1. Carcinoid tumour infiltrating the periappendicular adipose tissue. Haematoxylin and eosin stain, X 108. Fig. 2. Diffuse thickening of the ileal wall due to infiltration of T-cell lymphoma. Part of the perforation channel in the centre (arrow), X2.5. Fig. 3. High-grade intestinal T-cell lymphoma. The nuclei are enlarged with distinct nucleoli. Several cells are undergoing mitosis or apoptosis. Haematoxylin and eosin stain, X 520. Fig. 4. High-grade intestinal T-cell lymphoma staining negative for CD45RO (UCHL-1) (a), and strongly positive for CD3 (b), X520. Fig. 5. Ethidium bromide-stained and UV-illuminated gel of PCR-amplified products from TCR-y gene re- arrangement with the VJylz primer pairs. Lane 1: DNA molecular weight standard. Lanes 2 and 3: Patient sample with reproducible monoclonal pattern within the expected size range of 75-95 base pairs (bp). Lane 4: Positive control (anaplastic large T- cell lymphoma). Lane 5: Reactive lymph node with polyclonal pattern. Lane 6: Negative control (no DNA present).

of a malignant non-Hodgkin lymphoma, which ex- tended from the lamina propria to the serosa. In the central part of the lesion there was a complete perfor- ation of the bowel wall with surrounding necrosis. The tumour cells had round medium-sized to large nuclei with 1-3 distinct nucleoli. There were 4@50 mitoses/lO HPF and many nuclei were undergoing apoptosis (Fig. 3). Nowhere was there a nodular (fol- licular) growth pattern. Immunohistochemical stain- ing of the tumour revealed diffuse strong positivity for CD45 (LCA), focal positivity for the B-cell marker CD20 (L-26), and negative staining for the T- cell antigen CD45RO (UCHL-1) (Fig. 4a). The Ki- 67 labelling index was 65%. There was a sharp de- marcation between the lymphoma and the adjacent mucosa, which, like sections from the unaffected bowel wall, did not reveal inflammation or villous atrophy. One lymph node from the mesentery was normal.

Based on the histological and immunohistochem- ical characteristics, the lymphoma was diagnosed as a high-grade non-Hodgkin lymphoma, without de- termining the cell lineage. However, when preparing this case for publication we regarded the tumour to

be a diffuse large B-cell lymphoma (REAL-classifi- cation). Our referees, who apparently doubted this classification, suggested the application of additional B-and T-cell antibodies. When staining the tumour with the B-cell marker CD79a, a staining pattern identical to that of CD20 was found. To our surprise, the pan-T-cell marker CD3 showed a strong positivity of all tumour cells in conformity with an intestinal T- cell lymphoma (REAL-classification) (Fig. 4b). This diagnosis was confirmed at the Department of Path- ology, the Norwegian Radium Hospital, where the tumour was also found to be negative for CD4, CD5, CD8 and CDlO. Clonal rearrangements of the T-cell receptor gamma (TCR-y) gene were investigated by polymerase chain reaction (PCR) as described by McCarthy et al. (11). A reproducible monoclonal pattern compatible with T-cell lymphoma was found (Fig. 5).

During the period 20 November, 1997 to 17 April, 1998, the patient completed eight series of CHOP treatment (sendoxan, adriamycin, oncovin and pred- nisone) without showing any side-effects and with normal blood cell counts. Thorough examination (in- cluding bone marrow biopsy) did not reveal any

TABLE 1. Previously reported cases of carcinoid tumours associated with lymphomas and leukaemias Author(s) and year Reference Case Location of Associated neoplasm of publication no. no. carcinoid(s) Type Location Pearson & Fitzgerald (1 949) 1 1 Ileum Plasmocytoma Lymph nodes, ovary Foreman (1952) 2 2 Appendix Lymphosarcoma Not reported

3 Ileum Myelomatosis Not reported Moertel et al. (1961) 3 4 Small bowel Chronic myeloge- -

neous leukaemia 5 Small bowel Lymphosarcoma Not reported

Kuiper et al. (1970) 4 6 Gastrointe- Lymphoma Not reported

Foucar et al. (1984) 10 7 Ileum T-cell lymphoma Jejunum Berner (1 992) 9 8 Small bowel Non-Hodgkin Ventricle

Present case - 9 Appendix T-cell lymphoma Ileum

stinal tract

lymphoma

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other lymphomatous manifestations. In June 1998 colonoscopy was performed because of persistent loose stools. There were no abnormal findings and the condition was regarded as irritable bowel syn- drome. However, no biopsies were taken. At routine follow-up at the end of August 1998, the patient was well with no signs of tumour recurrence or spread.

DISCUSSION

An association between gastrointestinal carci- noids and other types of tumour has been re- ported with a frequency in the range of approxi- mately 5 to 50% depending upon the selection criteria, e.g. surgical cases, biopsy series, au- topsy series etc. Most of the carcinoids with as- sociated malignancies are located in the ileum or appendix (2,4,9) in conformity with the pre- dilection sites for these tumours (2, 5, 6, 8, 12). As many as four synchronous (13) and five metachronous tumours ( 14) have been reported, and synchronous and metachronous occurrence seem to be similar (5 , 8). Most tumour types have been reported in association with carcino- ids, e.g. adenocarcinomas (3, 7, 8, 9), squamous cell carcinomas (1, 3, 12, 13), urothelial carci- nomas (3, 7), gliomas (3, 7, 15), hepatomas (2), mesotheliomas and leiomyosarcomas (9), and most organ systems have been involved.

Table 1 displays the eight previously reported cases of carcinoids with associated malignancies of the lymphoreticular system, including bone marrow. Two of these cases had non-Hodgkin lymphomas of the gastrointestinal tract, whereas the topographical location was not mentioned in four cases. In particular, the paper by Foucar et al. (10) is of relevance to the pres- ent case. Their patient was a 62-year-old man who had two jejunal resections within 8 months because of a T-cell lymphoma of cytotoxic/sup- pressor phenotype. He died 19 months after the first operation and autopsy revealed widespread lymphoma of the remaining small bowel and dissemination to several organ systems. In the ileum two incidental carcinoids (<2 cm) were found. In our case, however, we were not able to demonstrate a helper or suppressor subtype of the Tlymphocytes.

An important lesson to be learned from the present case concerns the problems with classi- fication of the lymphoma. Based on the negative

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immunostaining for CD20 (L-26) and CD45RO (UCHL-I), this tumour was first diagnosed as a high-grade non-Hodgkin lymphoma without specification of the cell lineage. However, when preparing this case for publication, we felt that the scattered groups of CD20-positive cells be- longed to the neoplastic cell population and the tumour was therefore considered to be a diffuse large B-cell lymphoma. In retrospect, these cells obviously represent reactive lymphocytes and remnants of the normal lymphoid tissue of the bowel mucosa. The application of additional B- and T-cell markers revealed a strong and uni- form positive staining for CD3 in conformity with a T-cell lymphoma. This diagnosis was sub- stantiated by the demonstration of a mono- clonal pattern of TCR-)I by PCR. The loss of one or more pan-T-cell markers in neoplastic T- lymphocytes is a well-documented phenomenon which may cause problems with the classifi- cation of T-cell lymphomas, as in our case (16, 17, 18). This case report demonstrates the im- portance of using a panel of different B- and T- cell antibodies and PCR to improve the diag- nostic accuracy.

Intestinal T-cell lymphomas (ITLs) constitute approximately 15-30% of all small bowel lym- phomas in the Western World (19, 20, 21) and most of them are of high histological grade (20, 21, 22). Many ITLs are obstructive or perforat- ing lesions (20, 22) unlike the usually polypous B-cell lymphomas. Intestinal T-cell lymphomas show no significant predominance of either sex and the mean age at diagnosis is about 55-60 years (16, 17, 20-24). Almost half of all ITLs occur in subjects with coeliac disease (20, 21). Our patient had complained of loose stools for many years, but sections from the resected ileal segment revealed no inflammatory reaction or villous atrophy outside the tumour area. Thus, our case must be regarded as a non-enteropa- thy-associated T-cell lymphoma (22). Most authors have found peripheral T-cell lym- phomas to have a worse prognosis than B-cell neoplasms (20, 24, 25) and Chott et al. (22) found a mortality of 740/0 and a median survival of only 4 months among 27 cases of ITLs. Un- favourable prognostic criteria are bowel pene- tration/perforation, high grade and multiple tu- mours (16, 20, 21), whereas terminal ileal loca- tion, complete surgical resection and postoperative chemotherapy are favourable

APPENDICULAR CARCINOID AND ILEAL LYMPHOMA

prognostic criteria (20, 21, 23). Our patient is still in good general health, without any tumour manifestations, 10 months after surgery. How- ever, long-term follow-up is necessary both with regard to possible late recurrence of the lymphoma as well as to development of ad- ditional malignant neoplasms. In this respect, it is of interest that our patient has also been treated for a rectal tubular adenoma, i.e. a pre- malignant lesion.

The pathogenetic mechanisms underlying the development of various tumour types in sub- jects with carcinoids remain unknown, but acti- vation of oncogenes and/or inactivation of tu- mour suppressor genes must be considered. Such mechanisms seem particularly relevant in cases with several associated tumours. Carcino- id tumours, as well as carcinomas of -the ven- tricle, may be induced by carcinogenic agents, such as for example nitrosamines (26, 27), and long-term hormone stimulation of neuroendoc- rine cells may cause neoplastic transformation, e.g. gastric carcinoids due to hypergastrinaemia (28, 29). Similar pathogenetic effects could also be active in locations outside the gastrointesti- nal tract, causing the various types of associated tumours.

We are indebted to R. Langholm, Department of Pathology, The Norwegian Radium Hospital, Uni- versity of Oslo, for reviewing the slides.

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