Primary Intestinal Lymphoma: Clinicopathological Characteristics of 55 Patients.

INTRODUCTION: Gastrointestinal (GI) tract is the most common site of extranodal lymphoma accounting for 30-40% of the cases. In Western countries, stomach is the most common site of GI lymphoma, whereas in the Middle East and Mediterranean countries, small intestine is commonly involved. Studies about primary intestinal lymphoma (PIL) are heterogeneous in anatomical distribution, presentation, and histological subtypes. The present study was aimed at studying the anatomical distribution, histological subtypes, and clinical characteristics at tertiary care centers.
MATERIALS AND METHODS: The present study was retrospective, conducted between 2006 and 2020. Patient's data were collected from institutional medical records. PIL was diagnosed by Lewin's criteria. After histological diagnosis, PIL was classified as per the World Health Organization (WHO) criteria and staging was done according to the Ann Arbor classification as modified by Musshoff.
RESULTS: A total of 941 lymphoma cases were diagnosed during the study period between 2006 and 2020 consisting of 238 Hodgkin's lymphoma and 703 non-Hodgkin's lymphoma (NHL) cases. PIL constituted 5.8% of all lymphoma cases (55 out of 941) and 50.9% (55 of 108) of all primary GI lymphoma. Median age at diagnosis was 44 years and comprised predominantly males (85.45%). Diffuse large B-cell lymphoma (DLBCL) and mucosa-associated lymphoid tissue (MALT) lymphoma were the most common histological subtype (78%) seen. Two patients with primary Hodgkin's lymphoma involving the intestine were seen. T-cell lymphoma was seen in three (5.4%) patients. Ileocecal region was the most common site involved (27%). The common presenting complaints were intestinal obstruction (40%) requiring surgical resection and abdominal pain (32%). Majority of the patients presented in the early stages (I and II).
CONCLUSION: Our study demonstrates the pattern of distribution and various histological subtypes of PIL including the rare variants like primary intestinal Hodgkin's lymphoma. Relatively more number of patients presented with intestinal obstruction requiring surgery in comparison with other studies. HOW TO CITE THIS ARTICLE: Malipatel R, Patil M, Rout P, et al. Primary Intestinal Lymphoma: Clinicopathological Characteristics of 55 Patients. Euroasian J Hepato-Gastroenterol 2021;11(2):71-75.

Introduction

Overall, the incidence of lymphoma and extranodal lymphoma is increasing worldwide.[1,2] Gastrointestinal (GI) tract being one of the largest extranodal lymphatic organs is the most common site of extranodal lymphomas, accounting for 30–40% of all extranodal lymphomas.[3,4] GI lymphoma accounts for 1–4% of overall GI malignancies.[5] The anatomical distribution and histological subtype of GI lymphoma vary geographically possibly due to the difference in the prevalence of risk factors.[6,7] Stomach is the most common site of GI lymphoma followed by small and large intestine in Western countries, and majority of these lymphomas are diffuse large B-cell lymphoma (DLBCL) and extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT) type.[8,9] In contrast, primary small intestinal lymphoma accounts for 75% of the primary GI lymphomas in the Middle East and Mediterranean areas and vast majority of them are immunoproliferative small intestinal disease (IPSID).[10,11] The studies about the primary intestinal lymphoma (PIL) are scarce and are heterogeneous due to classification as small intestinal, ileocecal region and large intestinal lymphoma as separate entities.[6,7] The present study was done to ascertain the anatomical distribution, histological subtypes, and clinical characteristics of PIL at tertiary care centers.

Materials and Methods

It is a retrospective study conducted in the Departments of Gastroenterology and Pathology at St John's Medical College, Bengaluru, India, between 2006 and 2020. Patient's data were collected from institutional medical records. All patients who presented with intestinal symptoms like abdominal pain, diarrhea, GI bleeding, weight loss, intestinal obstruction/perforation, and detected to have tumor predominantly in the small or large intestine and histopathology showing lymphoma were included in the study, based on Lewin et al.'s definition.[12] Patients with systemic lymphomas involving the intestine were excluded. In all patients in whom surgery was not performed, enteroscopy-/colonoscopy-guided biopsy was done.

Based on the morphology, relevant Immunohistochemistry (IHC) markers were done. IHC panel consisted of pan-cytokeratin (CK), EMA, CD45 (LCA), CD3, CD20, CD79a, Bcl-2, CD10, CD5, CD23, cyclin-D1, Bcl-6, MUM-1, CD4, CD8, CD7, CD30, CD15, PAX5, CD138, CD56, Ki-67, kappa, lambda, ALK, CD34, Tdt, and granzyme B. Staging was done according to the Ann Arbor classification as modified by Musshoff.[13] Staging workup consisted of detailed history and complete physical examination, indirect laryngoscopy, and bone marrow examination; computed tomography scan of the chest, abdomen, and pelvis; positron-emission tomography (PET) scanning; and laparotomy in selected patients. PIL was classified according to the World Health Organization 2017 criteria.[14]

Results

A total of 941 lymphoma cases were diagnosed during the study period between 2006 and 2020 consisting of 238 Hodgkin's lymphoma and 703 NHL cases. PIL constituted 5.8% of all lymphoma cases (55 out of 941) and 50.9% (55 of 108) of all primary GI lymphoma. The median age at diagnosis was 44 years and comprised of 47 males (85.45%) with a male-to-female ratio of 5.8:1. The patient characteristics, clinical features, and the anatomical distribution of PIL are shown in Table 1. The various histological subtypes and staging at the time of diagnosis are shown in Table 2. There were eight patients with human immunodeficiency virus (HIV) infection. Overall, 26 (47%) patients underwent surgical resection. Diagnosis was established by enteroscopy-/colonoscopy-guided biopsy in 29 patients and in rest (26) after surgical resection. The enteroscopy/colonoscopy appearance included exophytic growth in 14, ulcerative lesion in 7, polyposis in 3, infiltrative lesion in 3, and stricture in 2 patients (Fig. 1).

Table 1

Patient characteristics, clinical features, and the anatomical distribution of primary intestinal lymphoma (55 patients)

Median age (years, range)	44 (7–85)
Clinical features: Subacute/acute intestinal obstruction Abdominal pain Gastrointestinal bleeding Abdominal mass Intestinal perforation Obstructive jaundice	22 (40%)18 (32.7%)4 (7.2%)4 (7.2%)4 (7.2%)3 (5.4%)
B symptoms	20 (36%)
Duration of symptoms (mean, months)	5.5
Anatomical distribution: Ileocecal junction Duodenum Colon Ileum Jejunum Multiple sites	15 (27.2)14 (25.45%)14 (25.45%)6 (10.9%)3 (5.45%)3 (5.45%)

Table 2

Primary intestinal lymphoma: histological subtypes and staging

Histologic subtypes: DLBCL MALT lymphoma Mantle cell lymphoma T-cell lymphoma Burkitt lymphoma Hodgkin's lymphoma	39 (70.9%)4 (7.2%)4 (7.2%)3 (5.4%)3 (5.4%)2 (3.6%)
Staging: I II-1 II-2 III IV	10226413

DLBCL, diffuse large B-cell lymphoma; MALT lymphoma, mucosa-associated lymphoid tissue lymphoma

Figs 1A to D

(A) Colonoscopy images showing exophytic growth involving the ileocecal valve; (B) Ulcerated lesion in ascending colon; (C) Stricturous lesion in descending colon; (D) Lymphomatous polyposis involving entire colon

Discussion

Our study findings demonstrate that PIL constitutes 5.8% of all lymphomas diagnosed over 15 years at our institute. Furthermore, PIL occurred predominantly in males with median age at diagnosis was 44 years which is in concordance with other studies. B-cell NHL is the most common histological subtype seen (90.9%). As observed in other studies, ileocecal junction is the most common site involved. However, higher proportion of patients (40%) are presented with subacute/acute intestinal obstruction requiring surgical resection.

The PIL was seen predominantly in males (M:F of 5.8:1) as observed in other studies.[6,15,16] The age of onset of PIL varied from 45–70 years in the published studies. However, median age at diagnosis in our study was 44 years, which was one decade earlier as compared to the presentation of primary gastric lymphoma as reported by us in the previous studies and in concordance with other studies.[15,17]

The main presenting symptoms of PIL vary from abdominal pain, weight loss, and GI bleeding to intestinal obstruction/perforation requiring surgery. The B symptoms such as fever, weight loss, and night sweat were seen in 18–52% of patients.[18,19]

In our study, 40% of patients, presented with acute/subacute intestinal obstruction and 7% with intestinal perforation requiring surgical resection which was bit more in comparison with the previously published studies which could be due to late presentation.[18,20] Abdominal pain was present in 32% and B symptoms in 36% of the patients.

Ileum and ileocecal regions are commonly involved in PIL (6.9–37.1%) probably due to high density of lymphoid tissue in these areas.[21-24] Ileocecal region was the most common site involved in our study accounting for 27% of the cases followed by duodenum and colon 25% each and the rest in ileum, jejunum, and multiple sites. Majority of the patients who underwent surgery are those where ileum and ileocecal regions were involved. Multiple, noncontagious sites (stomach, small bowel, and colon) were involved in three patients, two with mantle cell lymphoma and one Burkitt lymphoma.

Majority of the GI lymphoma including PIL are NHL of B-cell lineage.[15,25] DLBCL and MALT lymphoma were the most common histological subtype (78%) seen as reported in other studies (Figs 2A and B).[6,22,26] Primary intestinal Hodgkin's lymphoma is rare, reported only in the form of case reports and small series.[27,28] However, two patients with primary intestinal Hodgkin's lymphoma involving jejunum and descending colon were seen in our study (Fig. 2C). Enteropathy-associated T-cell lymphoma (EATL) is a distinct type of intestinal lymphoma that occurs in refractory/untreated celiac disease, which is reported from the places where celiac disease is common.[29] However, we did not find single patient with EATL as celiac disease is uncommon in South India. Non-EATL was seen in three patients involving duodenum and ileum (Fig. 2D). Mantle cell lymphoma is a subtype of B-cell NHL that can present as PIL, commonly involves the colon although entire GI tract can be involved.[30,31] Lymphomatous polyposis is the characteristic endoscopic appearance.[30] Mantle cell lymphoma was seen in three patients, involving entire GI tract in two and ileocecal junctions in another patient (Fig. 3A). Characteristic endoscopic appearance of lymphomatous polyposis was seen in all three patients. Burkitt lymphoma is an aggressive B-cell NHL that is present in three distinct forms: endemic, sporadic, and immunodeficiency-related. Burkitt lymphoma of the GI tract commonly is seen in children and young adults and often involves the ileum and ileocecal regions.[32] Burkitt lymphoma was seen in three patients involving multiple segments of GI tract in one and ileum and ileocecal regions in the other two, respectively (Fig. 3B). The HIV infection increases the risk of developing NHL by 60–200-folds.[33,34] However, with the availability of highly active antiretroviral therapy (HAART) for HIV infection, the risk of developing lymphoma has reduced significantly.[35,36] GI tract is involved in 30–50% of the HIV-associated extranodal NHL and usually of high-grade B-cell histology with involvement of multiple sites in the GI tract.[37] Overall, eight patients with PIL had associated HIV infection in our study. Patients with HIV infection were younger (median age 35 years) and had extensive involvement of GI tract as compared to patients without HIV infection.

Figs 2A to D

(A) DLBCL—Germinal center type: Sections from mucosal biopsy of ileocecal lesion/wall thickening showing diffuse sheets of medium-to-large monotonous lymphoid cells and CD10 positive (inset), × 400; (B) MALT lymphoma: lymphoepithelial lesions involving the intestinal crypts and intervening monocytoid cells with ample pale cytoplasm, × 400; (C) Classical Hodgkin's lymphoma: Sections from resected small intestine stricture showing mononuclear and multinucleated Reed–Sternberg cells in a reactive background and are CD15 immunostain membrane positive (inset), ×400; (D) T-cell-NHL: Sections from mucosal biopsy of duodenal ampullary lesion showing diffuse sheets of medium-sized atypical lymphoid cells with scant necrosis and are CD3 positive (inset), × 400

Figs 3A and B

(A) Mantle cell lymphoma: Sections from mucosal biopsy of colonic mass showing diffuse sheets of medium-sized monotonous atypical lymphoid cells that are cyclin D1 positive nuclear immunostain (inset), × 400; (B) Burkitt lymphoma: Sections from resected segment of jejunum with intussusception and polyps showing medium-to-large monotonous lymphoid cells with interspersed tingible body macrophages giving a starry sky pattern and high ki-67 proliferative index of 90% (inset), × 400

In conclusion, our study demonstrates the pattern of distribution and various histological subtypes of PIL including the rare variants like primary intestinal Hodgkin's lymphoma. We did not encounter patients with IPSID and EATL in our study. Relatively more number of patients presented with intestinal obstruction/perforation requiring surgery in comparison with other studies.