1 Hôpital Necker Enfants-Malades, Paris; 2 Hôpital de lHôtel-Dieu, Paris; 3 Centre Hospitalier du Mans, Le Mans; 4 Hôpital Georges Pompidou, Paris; 5 Hôpital C. Huriez, Lille; 6 Institut Paoli-Calmettes, Marseille; 7 Hôpital Pitié-Salpetrière, Paris; 8 Hôpital Cochin, Paris; 9 Hôpital Pierre Bénite, Lyon, France
Received 6 November 2002; revised 26 November 2002; accepted 13 January 2003
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Abstract |
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To describe better the clinical, biological, endoscopic and pathological presentations, as well as the outcome, of primary follicular lymphoma (FL) of the gastrointestinal (GI) tract.
Patients and methods:
From November 1983 to February 2001, 25 eligible patients with primary FL of the GI tract were retrieved from several French Departments of Pathology departments based on histological diagnosis and immunophenotype. Median age was 56 years (range 4471) with a sex ratio female/male of 2 (17/8).
Results:
Abdominal pain was the main presenting symptom followed by intestinal obstruction. The small intestine was the most common site of involvement. Lesions were unifocal in the majority of patients (15/25). A pattern similar to lymphomatous polyposis was observed in 50% (7/14) of patients. Twelve patients had stage I, 10 patients stage II and three patients stage IV disease, and there was minimal extra intestinal involvement. Lymphoma tissues were composed of neoplastic follicles, most of which were grade 1 according to the World Health Organization (WHO) classification. The immunophenotype of the lymphoma cells was CD20+, CD10+, bcl2+ and CD5. In tissue samples, IgH/bcl2 rearrangement at the MBR locus was present in 11 of 14 patients tested. Seven patients did not receive any treatment; four of them progressed after a median follow-up of 37.5 months. Treatment was otherwise heterogeneous, and complete remission was obtained in 15 patients which lasted for a median of 31 months. Relapses were either in the GI tract (n = 3) or outside the GI tract (n = 3). After a median follow-up of 34 months (range 5203), 22 patients were still alive (complete remission, 11; partial remission, three; stable disease, six; progressive disease, two).
Conclusions:
Primary FL of the GI tract is a predominantly female lymphoma that most frequently involves the small intestine. Since the endoscopic and clinical presentation may not be different from lymphomatous polyposis, which is often associated with mantle cell origin of tumor cells, it is mandatory to perform an immunohistological and, if possible, a molecular analysis of GI lymphoma. The course of the disease is indolent and does not differ from nodal FL. Thus, therapy may not be required unless significant clinical symptoms are present or until disease progression.
Key words: follicular, intestinal, lymphoma, primary
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Introduction |
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Patients and methods |
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Diagnostic and staging procedures
The clinical, biological, endoscopic and radiological data were collected directly from the referring physicians. The diagnostic work-up and staging procedures on presentation included patient history and complete physical examination, full blood cell count, serum lactate dehydrogenase, ß2-microglobulin, liver enzymes, alkaline phosphatase and creatinine levels, albumin level, chest X-ray, computed tomography (CT) scan of the chest, abdomen and the pelvis, endoscopic evaluation with multiple biopsies of the upper and lower GI tract, small bowel enema whenever available and bone marrow biopsy. Patients were staged according to the criteria of the recent International Workshop [11] (Table 1). In cases of surgical resection, the operating sheets and the histopathological certificates were used for the staging procedures. Those with predominantly GI disease with minimal extra intestinal lesions were not excluded [3]. Lesions were classified as multifocal when more than one lesion was observed.
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Molecular analysis
For the molecular study of IgH/bcl-2 rearrangements at the MBR locus, DNA was extracted either from frozen or paraffin-embedded tissue according to standardized methods [14]. A standard one-stage PCR assay was performed with MBR and JH consensus primers as previously described [15]. The final products were then size fractionated by agarose gel electrophoresis or resophor" (eurobio, France).
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Results |
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There was a clear female predominance with 17 females (68%) and eight males (32%). Median age at presentation was 56 years (range 4471). In most cases, clinical presentations were abdominal pain, change of bowel habit and/or abdominal obstruction (Table 2). Abdominal obstruction was usually seen when the small intestine was involved, and rectal bleedings were observed in rectal and distal colon involvement. Two patients presented with weight loss that was associated in one case with exsudative enteropathy, diarrhea and hypoalbuminaemia, and in another case with diarrhea. Presentation with iron deficiency anemia was associated, in one case, with obvious bleeding and with malabsorption in the second case. Acute abdominal pain was rare and was the presenting feature in one case with intestinal invagination. The entire intestine may be affected (Tables 3 and 4). The most frequent site of involvement was the small intestine, with a predilection for the ileum and ileo-cecal region, followed by the duodenum, although in some cases the entire intestine was affected (Tables 3 and 4). Lymphomas were unifocal in around half of cases (15/25; 56%). In the duodenum and the small intestine, lesions were unifocal in 44% and 38% of cases, respectively. In contrast, the majority of non-Hodgkins lymphomas of the colon, rectum and all gastric lymphomas (n = 3) were multifocal. A precise description of the endoscopic aspects was available for 14 patients. The macroscopic aspects were heterogeneous with ulcerations (n = 1), nodules and tumors (n = 3), infiltration with inflammatory aspect (n = 2) or invagination (n = 1). Strikingly, seven cases presented a polypoid aspect as seen in lymphomatous polyposis (Figure 1). Lactate dehydrogenase levels were normal in the majority of cases (n = 21/22) and ß2-microglobulin levels were normal in all tested patients (18 cases). According to the classification proposed by the International Workshop, 12 patients had stage I and 10 patients had stage II disease. Three patients with a minimal bone marrow infiltration of <5% were classified as stage IV disease (Table 1).
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Seven patients did not receive any treatment (NT) after diagnosisfive had unifocal tumors and two had multifocal lesions. Progression of disease was documented in four of them who then received subsequent therapy. Median time to progression was 37.5 months (range 487). It is noteworthy that one of these patients developed central nervous system involvement 4 months thereafter and died. Six patients were alive with stable disease at a median time of 25 months (range 887).
Eighteen patients received therapy at diagnosis (Table 6). The initial treatment was heterogeneous and consisted of complete surgical excision (CSR) alone (n = 4), chemotherapy alone (n = 10), complete surgical resection followed by chemotherapy (n = 2) or chemotherapy plus radiotherapy (n = 2). Complete remission was obtained in 15 patients (four after CSR, seven after chemotherapy alone, two after CSR plus chemotherapy and two patients after chemotherapy plus radiotherapy). One patient had a partial response, another one failed to respond and one patient was not evaluable because of early death from concomitant adenocarcinoma of the colon. Median duration of the first CR was 31 months (range 21120). Six patients (33%) subsequently relapsed. Four of them had multifocal disease at presentation and two unifocal lesions. Relapses occurred locally in one patient, locoregionally in two patients and outside the GI tract in three. They occurred after CSR (n = 1), CSR plus chemotherapy (n = 1), chemotherapy alone (n = 3) or chemotherapy plus radiotherapy (n = 1). All these relapses were sensitive to second-line chemotherapy. Four patients experienced second relapse and one patient a third relapse after chemotherapy. After a median follow-up of 42 months (range 5203), 16 patients were alive, either in complete remission (n = 11), partial remission (n = 3), progressive disease (n = 1) or with stable disease (n = 1). One patient relapsed with a large B-cell lymphoma in the GI tract at 21 months after complete resection and subsequently died from acute lymphoblastic leukemia 56 months after diagnosis.
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Discussion |
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Since PFLGI is very rare, it is difficult to provide a definitive therapeutic approach. The prognosis seems, however, not to be different from nodal FL with an indolent course even in the absence of specific treatment. Surgery and chemotherapy should be indicated only on the basis of clinical symptoms. Furthermore, and based on our findings, first-line chemotherapy does not seem to be beneficial unless clinical symptoms are important. Indeed, 33% of patients which were treated at diagnosis with surgery and/or chemotherapy and/or radiotherapy relapsed after a median time of 31 months, not that different from the median time to progression of the disease (37.5 months) in patients who did not receive any treatment.
In conclusion, FL of the GI tract is a predominantly female lymphoma with a predilection to the ileum. The clinical course is generally indolent and endoscopic appearance may be identical to lymphomatous polyposis, which indicates the need for immunophenotyping and even molecular biology studies for diagnosis. Therapeutic interventions are not indicated unless clinical symptoms are present or the disease is progressive.
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Acknowledgements |
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Footnotes |
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References |
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