Primary follicular lymphoma of the gastrointestinal tract a study

Annals of Oncology 14: 623–629, 2003

Original article

DOI: 10.1093/annonc/mdg168

? 2003 European Society for Medical Oncology

Primary follicular lymphoma of the gastrointestinal tract: a study of 25 cases and a literature review

G. Damaj 1*, V . Verkarre 1, A. Delmer 2, P. Solal-Celigny 3, I. Yakoub-Agha 5, C. Cellier 4,

F. Maurschhauser 5, R. Bouabdallah 6, V . Leblond 7, F. Lefrère 1, D. Bouscary 8, J. Audouin 2, B. Coiffier 9, B. Varet 1, T. Molina 2, N. Brousse 1 & O. Hermine 1

On behalf of the Groupe d’Etude des Lymphomes de l’Adulte

*Correspondence to: Dr G. Damaj, Department of Hematology,

Institut Paoli-Calmettes, 232 Boulevard St Marguerite, 13009 Marseille, France. Tel: +33-4-91223695; Fax: +33-4-91223579; E-mail: damajg@marseille.fnclcc.fr

1

H?pital Necker Enfants-Malades, Paris; 2H?pital de l’H?tel-Dieu, Paris; 3Centre Hospitalier du Mans, Le Mans; 4H?pital Georges Pompidou, Paris; 5

H?pital C. Huriez, Lille; 6Institut Paoli-Calmettes, Marseille; 7H?pital Pitié-Salpetrière, Paris; 8H?pital Cochin, Paris; 9H?pital Pierre Bénite, Lyon, France Received 6 November 2002; revised 26 November 2002; accepted 13 January 2003

Background: 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 diag-nosis and immunophenotype. Median age was 56 years (range 44–71) 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 involve-ment. 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 5–203), 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

Introduction

Non-Hodgkin ’s lymphomas of the gastrointestinal (GI) tract are the most common extra nodal lymphomas. They represent between 30% to 70% of all extra nodal lymphomas and constitute a hetero-geneous group of tumors with different clinical and pathological features [1, 2]. Multiple definitions of primary GI lymphoma exist; at least two of them are in use. The definition by Dawson et al. in 1966 was restricted to localized disease of stages IE and IIE,whereas that by Lewin et al. [3] required that patients exhibit GI

symptoms or a predominant lesion. The stomach is predomin-antly involved followed by the small intestine. High-grade lym-phomas are the most common histological subtype encountered in the GI tract, except in the stomach, where low grade B-cell lymphomas are dominant [1, 4, 5]. The phenotype is pre-dominantly of B-cell type (large cell, Burkitt ’s), whereas T-cell lymphomas are rare and usually arise in the small intestine [1].MALT type lymphomas are the most frequent low grade non-Hodgkin ’s lymphomas encountered in the GI tract. They account for 40% of all primary gastric lymphomas and remain, in the majority of cases, localized for a prolonged period of time with-out therapy [6]. Multiple lymphomatous polyposis represents <10% of primary GI lymphomas and are characterized by poor prognosis [7]. Follicular lymphomas (FL) are the second most

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common type of lymphomas among adults in western countries and typically arise in lymph nodes with spleen, liver and bone marrow involvement. They are characterized by their risk of transformation into high-grade lymphoma [8]. Primary extra nodal FL without peripheral lymphadenopathy is very uncom-mon. They constitute <7% of primary lymphoma of the GI tract in the few GI lymphoma series that have been reported [1, 5, 9,10]. Since diagnosis, prognosis and treatment of these lympho-mas remain largely unknown, we have, retrospectively, studied the clinical, biological and endoscopic characteristics, as well as the outcome, of 25 patients with primary follicular lymphoma of the gastrointestinal tract (PFLGI).

Patients and methods

Patients

From November 1983 to February 2001, 39 patients with a diagnosis of PFLGI were retrieved from the files of several French hematology and gastrointestinal departments. The search was based on histological and immunophenotype (CD20+, CD10+, BcL2+, CD5–) diagnosis. Patients were considered eligible for the study if they met the definition for primary GI non-Hodgkin ’s lymphoma as defined by Lewin et al. [3].

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, β2-micro-globulin, 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 Inter-national Workshop [11] (Table 1). In cases of surgical resection, the operating sheets and the histopathological certificates were used for the staging pro-cedures. 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.

Histological and immunohistochemical analysis

Slides or paraffin blocks were requested from the referring pathologists.Samples collected were reviewed by three pathologists. Samples were obtained from primitive digestive FL either at initial presentation (n = 24) or

at recurrence in one case (13 years after the initial small bowel resection).Seventeen cases were from biopsy samples and eight cases from surgical samples. Morphological analysis was performed on routine paraffin-embedded formalin fixed tissue stained with hematoxylin –eosin. We studied the following data: localization of FL, depth of tumoral infiltration, epithelial surface damage, infiltrative pattern (follicular or follicular and diffuse), per-centage of large cells (<5%, 5–15%, >15%) to classify FL into three subtypes (1, 2 or 3) according to the World Health Organization (WHO) classification [12, 13], cytological composition of the reactive inflammatory cells and the lympho-epithelial lesions. In surgical samples, size of tumor and lymph node infiltration were also noted. Phenotypic analysis was studied by immuno-histochemistry performed on paraffin-embedded or frozen sections using a three-stage indirect immunoperoxidase technique. Antibodies used were a polyclonal anti-CD 3 antibody (D AKO, Glostrup, Germany), monoclonal antibodies directed against CD 20, bcl2 and CNA-42 (D AKO), CD 5 and CD 10 (Novocastra, Newcastle, UK) and CD 43 (Immunotech, Marseille,France).

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).

Results

Patient characteristics

Of the 39 patients reported with a diagnosis of PFLGI, 14 cases were excluded due to secondary intestinal involvement (n = 3),incomplete medical records (n = 5) or stage III or IV disease with an important extra-intestinal involvement (lymph nodes or diffuse bone marrow infiltration) (n = 4). Two patients were reclassified as diffuse small B-cell lymphomas. Thus, a total of 25 cases were finally analyzed. One of these cases has already been reported [16].

There was a clear female predominance with 17 females (68%)and eight males (32%). Median age at presentation was 56 years (range 44–71). In most cases, clinical presentations were abdom-inal pain, change of bowel habit and/or abdominal obstruction (Table 2). Abdominal obstruction was usually seen when the

Table 1. Staging of gastrointestinal non-Hodgkin ’s lymphoma (GI-NHL) according to the International Workshop a a

Data from Rohatiner et al. [11].

Stage Criteria

I Tumor confined to the gastrointestinal (GI) tract Single primary site or multiple non-contiguous lesions II Tumor extending in abdomen from primary GI site Nodal involvement

II1Local (paragastric or paraintestinal)

II2Distant (mesenteric, para-aortic, paracaval, pelvic, inguinal)IIE Penetration of serosa to involve adjacent organs or tissues

IV

Disseminated extranodal involvement or a GI tract lesion with supradiaphragmatic nodal involvement

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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 mal-absorption in the second case. Acute abdominal pain was rare and

was the presenting feature in one case with intestinal invagin-ation. 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 intes-tine, lesions were unifocal in 44% and 38% of cases, respectively.In contrast, the majority of non-Hodgkin ’s 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 β2-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).

Pathological, phenotypical and molecular analysis The diagnosis of FL was carried out on samples obtained by endoscopy (n = 17) or by surgical resection (n = 8). The sites of the tumor and the pattern of lesions (unifocal or multifocal) is noted in Tables 3 and 4. No histological variations were observed between the different sites examined. The lymphoid proliferation consisted of neoplastic follicles mostly medium in size, uniform in shape and involving the mucosa. D iffuse infiltration of the muscular layer of the mucosa and/or superficial part of the sub-mucosa was seen in four cases. Tumoral infiltration of the surface epithelium was seen in two cases. Superficial ulceration was seen in two cases. Macroscopic examination noted a white and firm tumor mass the size of which varied from 2 to 8 cm (mean 4.6 cm)in width in two patients. Extension of the tumor was pan parietal

Table 2. Clinical and biological presenting features of primary follicular lymphoma of the gastrointestinal tract (PFLGI)

a

According to Rohatiner et al. [11] (Table 1).

B2M, β2-microglobulin; LDH, lactate dehydrogenase.

n

Patients 25Age (years)56Range 44–71Sex Male (%)8 (32)Female (%)17 (68)Clinical symptoms Abdominal pain 12Rectal bleeding/maelena 5Intestinal obstruction 5Rectal symptoms 4Diarrhea 3Flatting 3Weight loss

2Iron deficiency anemia 2Nausea or vomiting 2Fatigue 1Steatorrhea

1Intestinal invagination 1Perforation 1Abdominal mass 1Exsudative enteropathy 1Fever

1Biological marker LDH (normal/increased)21/1B2M (normal/increased)18/0Albumin (normal/decreased)16/2Histological grade Grade I 23/25Grade II 2/25Grade III 0/25Stage a

I

12II (II1, II2, IIE)10 (0, 9, 1)IV

3

Table 3. Anatomical distribution of initial localizations a

When more than one lesion is observed in one or more segment.b

Localizations were multiple in the duodenum, jejunum and ileum.c

Three were multiple.

Site Unifocal Multifocal a Lymphomatous polyposis aspects

Stomach 03Duodenum 452b

Jejunum 24Ileum 76Colon 144c Rectum 141Anus 01Total patients

15

10

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in six cases, limited to the sub mucosa in one case or muscular in one case. Peritoneal perforation was seen in one case. Among the six cases exhibiting mesenteric lymph nodes, four had tumoral infiltration. No alteration of the adjacent mucosa was seen. There were no villous atrophy or significant increase in the intra-epithelial lymphocyte number. The proliferation was CD20+, bcl2+ and CD10+, CD5– or CD43– in all cases (Table 5; Figure 2). Of the 14 patients analyzed for IgH/bcl2 gene rearrangements at the MBR locus, 11 cases were positive and four cases were negative.

Treatment and outcome

The indication for therapy was dominated by clinical symptoms. Only one patient was asymptomatic, in whom the diagnostic procedure was justified by the presence of mesenteric lymph nodes with intestinal and mesenteric thickening on an abdominal CT scan that was performed for another reason.

Seven patients did not receive any treatment (NT) after diag-nosis—five 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 4–87). 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 8–87).

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 21–120). 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 chemo-therapy. Four patients experienced second relapse and one patient a third relapse after chemotherapy. After a median follow-up of 42 months (range 5–203), 16 patients were alive, either in

Table 4. Anatomical distribution of multifocal localizations

Sites Stomach Duodenum Jejunum Ileum Colon Rectum Anus Stomach–102220 Duodenum1–34000 Jejunum03–3000 Ileum243–110 Colon2001–41 Rectum20014–1

Anus000011

Primary follicular lymphoma of the gastrointestinal tract a study

Figure 1. Multiple polypoid tumors of the duodenum.Table 5. Immunohistological study

a One of them had a IgH-bcl2 rearrangement and the others

developed a secondary nodal follicular lymphoma.

b Two of them were anti-CD43 negative (data not shown).

bcl2CD10CD5

Positive23180

Negative0220

Not done2a55b

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Primary follicular lymphoma of the gastrointestinal tract a study

complete remission (n = 11), partial remission (n = 3), progres-sive 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.

For all patients, the median follow-up was 34 months (range 5–203). Twenty-two patients were still alive (Figure 3) in com-plete remission (n = 11), partial remission (n = 3), stable disease (n = 6) or with progressive disease (n = 2). Three patients died from concomitant colic adenocarcinoma (n = 1), progression of the disease (n = 1) and acute lymphoblastic leukemia (n = 1) at 2,15 and 56 months, respectively.

Discussion

Primary gastrointestinal lymphoma is a heterogeneous and rela-tively rare disease accounting for 11–34% of all non-Hodgkin ’s lymphomas, with some regional variability in the frequency and histological type [1, 10, 17, 18]. Lymphomas in this setting are usually of the B-cell phenotype and are dominated by the diffuse large-cell subtype [1]. Histological subtypes of indolent lympho-mas are closely related to the site involved and are dominated

by the MALT type, which is primarily localized in the stomach

Figure 2. Histology and immunostaining of a follicular lymphoma from resected small intestine. Hematein section shows intestinal tumoral nodules in the mucosa and submucosa. Tumoral cells in the nodules express bcl2 and CD10 and do not express CD5.

Table 6. Treatment and outcome (median follow-up, 42 months)

a

Anthracycline-based chemotherapy.b

Relapse after initial treatment.IFN, interferon.

n

Patients 25Initial treatment No treatment

7Complete surgical resection 4Chemotherapy alone 10Chlorambucil 2Anthracyclines a

4Anthracyclines a + IFN 4Radiation + anthracyclines a 2Surgery + chemotherapy 2Pattern of relapse b

Locoregional 3Systemic

3Survival time (months)Mean (range)

34 (5–203)

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Primary follicular lymphoma of the gastrointestinal tract a study

[1, 19]. Primary follicular lymphomas of the gastrointestinal tract are very rare and constitute <7% of all non-Hodgkin ’s lympho-mas at this location [2, 5]. In our large group of patients, the median age is not different from that of nodal FL. In contrast to their nodal counterpart or to other primary GI lymphomas [8, 20],and in accordance with other reports on PFLGI [21, 22], a female predominance is observed. As with other GI malignancies, the initial clinical manifestations and, to some extent, the gross appearance of the lesions appears to be related to the site of GI involvement. Thus, obstructing masses or wall thickening was more frequent in small bowel involvement (5/5 cases), whereas polyps were predominant in the colon and rectum (5/7 cases). In accordance with a series by LeBrun et al. [22], the small intestine was the site preferentially involved. The high frequency of small intestine involvement is probably related to the relative abundance of normal lymphoid follicles in this region. The macroscopic appearance of PFLGI are very heterogeneous and there is no cor-relation with their histological characteristics. Lymphomatous polyposis constitutes 2% of primary GI lymphomas and corresponds, in the majority of cases, to mantle cell lymphoma [19]. A few isolated reports have suggested that lymphomatous polyposis might be made up from a heterogeneous group of lymphomas [22–26]. Strikingly, in our large group of patients,50% of PFLGI had an endoscopic aspect of multiple lymphoma-tous polyposis. These findings are important clinically, since mantle cell lymphoma has a poor prognosis and requires aggres-sive first-line high-dose therapy [27, 28]. Therefore, immuno-phenotyping with immunostaining for CD 5, CD 10, cyclin D 1and bcl2, and molecular biology studies looking for the presence of IgH /bcl2 or IgH /bcl1, are advisable in order to differentiate between a diagnosis of lymphomatous polyposis and that of FL.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.

Acknowledgements

The authors thank Drs O. Boulat, A. Le Pourhiet-Lemevel and P. Soubeyran for providing medical cases, Drs J. Bri ère, F. Carnot, D. Damotte, B. Fabiani,P. Gaulard and I. Soubeyran for providing pathological samples and Dr G.Ivanov for grammatical corrections.

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