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ORIGINAL ARTICLE Table of Contents   
Year : 2010  |  Volume : 53  |  Issue : 3  |  Page : 455-459
Primary intestinal T cell lymphomas in Indian patients - In search of enteropathic T cell lymphoma

1 Department of Pathology, Tata Memorial Hospital, Parel, Mumbai-400 012, India
2 Department of Medical Oncology, Tata Memorial Hospital, Parel, Mumbai-400 012, India

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Date of Web Publication22-Oct-2010


Objective: This series of six intestinal T cell lymphomas (ITCL) attempts to document enteropathy-associated T cell lymphoma (EATCL) in India. Materials and Methods: A total of six ITCL were selected from 170 gastrointestinal lymphomas in last 10 years. Results: The cases studied included EATCL (4), ITCL with a CD4 positive phenotype (1) and ITCL NK/T cell type (1). Of the four EATCL, two occurred in the ileum, one in right colon and one in duodenum. In three EATCL cases, there was history of celiac disease or lactose intolerance and enteropathic changes were noted in the adjacent mucosa. These tumors had CD3+/CD8+/CD56 (+/-)/CD4-/ Granzyme B+ immunophenotype. One EATCL was monomorphic small cell type (type II EATCL) with a CD3+/CD8-CD56+/CD4-/ Granzyme B+ phenotype. EBER- ISH (Epstein Barr virus coded RNA's- in situ hybridization) revealed positive tumor cells in ITCL NK/T cell type and in bystander cells in three EATCL. Conclusion: ITCL are rare in Indian patients but do occur and comprise a mixture of the enteropathic and non-enteropathic subtypes.

Keywords: Celiac disease, enteropathy, intestinal lymphoma, T cell lymphoma

How to cite this article:
Shet T, Karpate A, Bal M, Gupta S, Gujral S, Nair R. Primary intestinal T cell lymphomas in Indian patients - In search of enteropathic T cell lymphoma. Indian J Pathol Microbiol 2010;53:455-9

How to cite this URL:
Shet T, Karpate A, Bal M, Gupta S, Gujral S, Nair R. Primary intestinal T cell lymphomas in Indian patients - In search of enteropathic T cell lymphoma. Indian J Pathol Microbiol [serial online] 2010 [cited 2022 Aug 9];53:455-9. Available from: https://www.ijpmonline.org/text.asp?2010/53/3/455/68274

   Introduction Top

Intestinal T cell lymphomas are divided as enteropathy associated T cell lymphoma (EATCL), EATCL like lymphoma without enteropathy and non-EATCL type of lymphomas. [1] EATCL is a rare type of T cell lymphoma that was first described in 1978 by Isaacson and Wright [2] and accounts for fewer than 5% of all gastrointestinal tract (GIT) lymphomas. [3] EATCL predominantly affects the jejunum though it can occur at any site in the GIT like stomach and colon. Histologically, two unique histological types of EATCL have been documented. [3],[4] Eighty per cent of cases belong to the pleomorphic anaplastic EATCL, which is usually associated with enteropathy / celiac disease and has large cells with a CD3+/CD4-/ CD56+/-/CD8+/- but HLA- DQ2/DQ8 positive phenotype. The other variant is the monomorphic small cell type of EATCL that occurs without a history of celiac disease, has variable association with enteropathy, is less often HLA- DQ2/DQ8 positive and has tumor cells with the CD 8 + /CD56+ phenotype. [4] Though histological classification is of less importance in the patient prognosis, type II EATCL occurs sporadically and is more common in the Eastern continents. As there is no report of EATCL from India, we sought to evaluate the incidence and pattern of ITCL with a view to evaluate the existence of EATCL in a cancer referral center in India.

   Materials and Methods Top

Pathology archives were screened to collect all gastrointestinal lymphomas. Of the 170 cases of gastrointestinal lymphomas accessioned in the last eight years, 10 Non Hodgkin's lymphomas occurred in the intestine (either small intestine or colon) and had a T cell phenotype with expression of mature T cell markers CD3 /CD43. Of these, four were anaplastic large cell lymphomas (ALCL) and six had a peripheral T cell phenotype. Of the anaplastic large cell lymphomas three patients had secondary involvement of the ileum or colon (all ALK1 positive) and one was a primary colonic ALK1 negative ALCL with subsequent dissemination. As ALCLs were likely to have different etiopathogenetic mechanisms they were excluded and the remaining six cases were studied in details to evaluate their association with enteropathy, the histological spectrum, immunophenotype and association with Epstein Barr Virus (EBV) infection. Patient details were obtained from records and in the four-referral cases patients were contacted to obtain follow up information. We have only one referral case on refractory celiac disease in the last five years and that case too was excluded.

Four of the six cases were referral cases and we had only paraffin blocks from the excised specimens while two cases were primarily treated at our institute. We used the sole criteria for increase in intraepithelial lymphocytes (>40 / 100 enterocytes in jejunum and > 20/100 enterocytes in ileum) to document enteropathy as suggested in a prior study, [5] though we additionally also documented crypt hypertrophy and villous atrophy.

Immunohistochemistry was done using avidin biotin complex method using the following antibodies: - LCA(T29/33, DAKO, Denmark, monoclonal, 1:100), CD3(DAKO, Denmark, polyclonal, 1:100), CD43(DF-T1, DAKO, Denmark, monoclonal, 1:100), CD 56(BC 56C04, Biocare, USA, monoclonal, 1:50), CD4(1F6, Novocastra, Newcastle, UK, 1:20), CD8(1A5, Novocastra, Newcastle UK, monoclonal, 1:20),), Granzyme B (11F1, Novocastra, Newcastle, UK, monoclonal, 1:20). EBER- ISH (Epstein Barr virus (EBV) coded RNA's- in situ hybridization) was done using the Novocastra kit. EBER-1 and EBER-2 encoded RNA sequences were detected using fluorescein labeled oligonucleotide probes. After dewaxing and dehydrating, the sections were incubated with 100ml of proteinase K, immersed in water, dehydrated and air-dried. After probe application, probe hybridization solution was applied onto slides and incubated for two hours at 37 o C. Hybridization products were identified with alkaline phosphatase conjugated rabbit antibodies to fluorescein isothiocyanate (FITC). The chromogenic development was processed in nitroblue tetrazolium (NBT)/5-bromo-4-cholro-3-indolyl phosphate (BCIP). A positive signal was recognized as intense blue/ black nuclear staining under a light microscope. Positive and negative controls were processed simultaneously. T cell receptor rearrangement was performed in one case by RTPCR on paraffin embedded tissues.

   Results Top

ITCL (excluding ALCL) comprised 3.5% (6/170) of all gastrointestinal tract lymphomas at our institute. The summary of the clinical details, pathological findings and follow-up of these patients are summarized in [Table 1]. The original histologic diagnosis (without the extended immunoprofile subsequently performed) in three patients was peripheral T cell lymphoma and three cases was enteropathy associated T cell lymphoma. Of the six cases after immunophenotyping, four could be classified as EATCL, Case 2 was an intestinal T cell lymphoma (ITCL) with a CD4 positive phenotype and one case was classified as ITCL possibly of NK/T cell type. Findings in all six patients are presented to document the spectrum of ITCL in India.
Table 1: A summary of clinical features and pathological classifi cati on in the six cases

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Clinical Findings

All patients were males and presented with loss of weight and appetite with fever with abdominal pain. Subsequently they were operated for either intestinal obstruction or perforation before a biopsy diagnosis could be done. Case 2 [Table 1] was operated with a clinical impression of an adenocarcinoma. The age of patients ranged from 17- 56 years. Two patients had history of celiac disease and were on treatment, while one patient gave history of lactose intolerance. In one case though there was no history of celiac disease, enteropathic changes were noted in the adjacent mucosa. Ileum was the chief site involved in the EATCL cases, while colon was affected in the non EATCL ITCL.

Gross Eamination Findings

In all cases resections revealed necrotic mass involving variable length of intestine and in five cases there was associated perforative peritonitis. In all patients the disease involved the local site and peritoneum but two patients had additional nodal involvement.

EATCL (n=4)

Of the four EATCL, two occurred in the ileum, one in right colon and one in duodenum. Three tumors (in patients with history of enteropathy) revealed atypical variably pleomorphic frequently large, often nucleolated lymphoid cells which infiltrated and perforated the small intestine [Figure 1]. One tumor had cells with plasmacytoid cytoplasm mimicking a plasma cell tumor. The tumor cells had a CD3+/CD8+/CD56+/-/CD4-/ Granzyme B+ immunophenotype and frequently showed necrosis and angioinvasion. Adjacent mucosa showed enteropathy related changes with increased intraepithelial lymphocytes that were of the phenotype similar to the main tumor in all three cases. One case was classified as EATCL even though the patient had no history of enteropathy in view of enteropathic changes in mucosa adjacent to tumor in the histologic sections and the small cell morphology of the primary tumor. This tumor revealed monomorphic small appearing cells like type II EATCL but had CD3+/CD8-CD56+/CD4-/ Granzyme B+ phenotype unlike the CD8+/CD56+ phenotype described in a typical type II EATCL. All tumors were negative on EBER-ISH (Epstein Barr virus coded RNA's- in situ hybridization), however, positive bystander reactive cells were observed in three EATCL with history of enteropathy. The reactive EBER positive cells were submucosal collections of reactive B cells away from the tumor and the intratumoral plasma cells.
Figure 1 :Histological features in EATCL to show (a) Diff use infi ltrati on of ileum by atypical lymphoid cells (H and E, 25). (b) Large pleomorphic cells in EATCL type I with nucleoli (H and E, ×400) (c) CD 8 positi ve
intraepithelial lymphocytes in adjacent mucosa (ABC, ×400)

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Non EATCL ITCL (n = 2)

The CD4 expressing ITCL had small monomorphic cells infiltrating entire colon quite similar to type II ITCL but these strongly expressed CD3 and CD4 and lacked CD8, CD56 and Granzyme B [Figure 2]. The second non EATCL-ITCL was a NK/T cell lymphoma that occurred in a 17 year old boy. This tumor revealed large pleomorphic cells with large areas of fibrinoid necrosis and infarction [Figure 3]. Morphologically, this tumor was no different from the EATCL's described above except that necrosis was more extensive. The tumor cells expressed NK/T cell markers and had a CD3+/CD8-/CD56+/CD4-/ Granzyme B+ immunophenotype. Strong EBER-ISH signals were noted in all tumor cells in this case [Figure 3]. This tumor also lacked clonal T cell receptor rearrangement further hinting at the possibility of NK cell derivation.
Figure 2 :(a) Lymphoma composed of small monomorphic cells (H and E, 40). (b) Strong CD4 expression in all cells (ABC, ×400)

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Figure 3 :NK/T cell lymphoma with (a) Large atypical lymphoid cells with fi brinoid necrosis (b) Strong nuclear hybridizati on signals on EBER-ISH (EBR-ISH, ×200)

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All patients with EATCL received CHOP (Cyclophosphamide, Hydroxydaunorubicin, Oncovin and Prednisolone) chemotherapy but eventually all progressed and succumbed to the disease. Both the patients with non EATCL type of ITCL were lost to follow-up.

   Discussion Top

ITCL form a spectrum of tumors with different etiopathogenetic mechanisms, which include enteropathy-associated lymphomas, and EBV associated natural killer (NK) cell tumors. This small study from India documents that ITCL is rare in our patient's forming only 3.5% of all gastrointestinal lymphomas.

The incidence of EATCL in the West is higher than in the Eastern continent with an incidence of 0.10 per 100,000 per year reported from Netherlands. [6] EATCL is rare in Asia and in a report of 18 cases of T cell lymphomas in GIT from Japan none had a preceding diagnosis of celiac disease. [7] Though ITCL were rare, association with celiac disease and EATCL were documented in this study. Given the high prevalence of celiac disease in patients with lactose intolerance, it is possible the patient with lactose intolerance also had celiac disease. Thus in all three patients had history of celiac disease. [8] Clinically, association of celiac disease with EATCL is variable and substantial patients do not give history of celiac disease. [3] Gains of 9q33-q34 are reported in 70% of EATCL and this may serve as a diagnostic marker for EATCL. [3] Though the cases we discuss were not evaluated for gains of 9q33-q34, the acute presentation, morphology and immunophenotype is within the spectrum of EATCL. The large pleomorphic type of EATCL was more common and only one case could be putatively labelled as type II EATCL (case1). This is in contrast to most Asian countries like Taiwan and Japan, which document the type II EATCL. [7],[9]

Celiac disease is known in India but is far more common in children than adults mostly because of under reporting of cases and the reported frequency of one in 310 is thought to be an under-assessment. [10] With the documentation of more cases of celiac disease the incidence of detection of EATCL in India is also likely to rise. Clinical course of EATCL is rapidly progressing and highly aggressive and the same course was observed in all patients with EATCL in this study. The present regimens used for therapy of EATCL thus seem inadequate and there is a need to evaluate impact of newer protocols for T cell lymphomas in EATCL.

The non EATCL spectrum in our series included a CD4 positive ITCL and an EBV positive ITCL possibility of NK/T cell origin. Small intestinal CD4 expressing T cell lymphomas were described in 1999 with 6 cases of this entity described in small intestine till date. [11],[12] Most reports of small intestinal CD4 positive ITCL document indolent behavior and long survival. [11] These tumors are thought to arise from normal CD4 positive T cells in lamina propria in the small intestine. Mucosal lymphoid follicles with CD 4 positive cells have been identified in adult human colon, thus the occurrence of a CD4 positive ITCL is not unexpected within the colon. [13] We could not confirm the better behavior of the CD4 expressing ITCL in colon as the patient was lost to follow-up after therapy.

Around 13% of gastrointestinal T cell lymphomas show association with Epstein Barr virus (EBV). [14] Though EBV association with EATCL has been described, EBV is more common in non-EATCL type of ITCL. [15] Though some early reports documented high incidence of EBV in celiac disease associated EATCL, subsequent reports confirmed a lack of association of EBV with celiac disease associated EATCL. [14] EATCL in West show lesser degree of association with the EBV while Chinese patients with ITCL show high incidence of association with EBV. [15],[16]

In lieu of the association with celiac disease lack of association with EBER in our Indian EATCL was expected. Though the tumor cells lack EBV, EBER1 positive reactive bystander cells are noted in 58% of intestinal T cell lymphomas, most of the times these are reactive B cells but sometimes they are plasma cells. [15] The presence of EBER in the bystander cells as found in this study and others indicates that the EBV infection occurred after the clonal expansion of T cells or the EBER negative tumour cells represent loss of the viral episome, which at some point in tumour progression no longer confers a proliferative or survival advantage to tumour cells. [15]

Primary intestinal nasal-type NK-cell lymphomas are exceptionally rare and are usually associated with very poor prognosis. [17] Most cases are associated with EBV and show the germline TCR (T cell receptor) gene rearrangement. It is useful to note that CD56 expression is not equivalent to NK-cell lymphoma and CD3+/ CD56+ but EBER negative lymphomas are usually peripheral T-cell lymphomas with clonal TCR gene rearrangement. Also morphologically these tumors overlap with EATCL. Though we could not confirm the germline TCR, the absence of clonal TCR gene rearrangement with strong EBER positivity helped in confirming the diagnosis. This case also illustrates that extranodal NK cell lymphomas in India are not uncommon and have similar association with EBV as their nasal counterparts.

To conclude, these short series documents that ITCL are rare in India, but EATCL associated with celiac disease is observed. The documentation of lack of association with EBV is also in tune with the pattern of EATCL described in the West rather than Eastern continents. With more cases of celiac disease being described possibly the numbers and spectrum of EATCL in India will expand in future. Rare tumors with CD4 or NK/T cell phenotype may be observed in our patient population and hence as prognostically they are different a wide immunophenotypic panel is required in ITCL.

   Acknowledgment Top

Mr. Suhas Dhende for the immunohistochemistry in all cases.

   References Top

1.Chott A, Dragosics B, Radaszkiewicz T. Peripheral T-cell lymphomas of the intestine. Am J Pathol 1992;141:1361-71.  Back to cited text no. 1      
2.Isaacson PG, Wright DH. Malignant histiocytosis of the intestine: Its relationship to malabsorption and ulcerative jejunitis. Hum Pathol 1978;9:661-77.   Back to cited text no. 2      
3.Zettl A, deLeeuw R, Haralambieva E, Muller-Hermelink HK. Enteropathy-type T-cell lymphoma. Am J Clin Pathol 2007;127:701-6.  Back to cited text no. 3      
4.Isaacson PG, Chott A, Ott G, Stein H. Enteropathy associated T cell lymphoma. In: Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, et al. editors. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissue. 4th ed. Lyon, France: IARC; 2008. p. 289-91.   Back to cited text no. 4      
5.Chott A, Haedicke W, Mosberger I, Fφdinger M, Winkler K, Mannhalter C, et al. Most CD56+ intestinal lymphomas are CD8+CD5-T-cell lymphomas of monomorphic small to medium size histology. Am J Pathol 1998;153:1483-90.  Back to cited text no. 5      
6.Verbeek WH, Van De Water JM, Al-Toma A, Oudejans JJ, Mulder CJ, Coupι VM. Incidence of enteropathy--associated T-cell lymphoma: a nation-wide study of a population-based registry in The Netherlands. Scand J Gastroenterol 2008;43:1322-8.  Back to cited text no. 6      
7.Katoh A, Ohshima K, Kanda M, Haraoka S, Sugihara M, Suzumiya J, et al. Gastrointestinal T cell lymphoma: predominant cytotoxic phenotypes, including alpha/beta, gamma/delta T cell and natural killer cells. Leuk Lymphoma 2000;39:97-111.  Back to cited text no. 7      
8.Ojetti V, Nucera G, Migneco A, Gabrielli M, Lauritano C, Danese S, et al. High prevalence of celiac disease in patients with lactose intolerance. Digestion 2005;71:106-10.   Back to cited text no. 8      
9.Chuang SS, Liao YL, Liu H, Lin SH, Hsieh PP, Huang WT, et al. The phenotype of intraepithelial lymphocytes in Taiwanese enteropathy associated T-cell lymphoma is distinct from that of the West. Histopathology 2008;53:234-6.  Back to cited text no. 9      
10.Yachha SK, Poddar U. Celiac disease in India. Indian J Gastroenterol 2007;26:230-7.  Back to cited text no. 10      
11.Svrcek M, Garderet L, Sebbagh V, Rosenzwajg M, Parc Y, Lagrange M, et al. Small intestinal CD4+ T-cell lymphoma: a rare distinctive clinicopathological entity associated with prolonged survival. Virchows Arch 2007;451:1091-3.   Back to cited text no. 11      
12.Carbonnel F, d'Almagne H, Lavergne A, Matuchansky C, Brouet JC, Sigaux F, et al. The clinicopathological features of extensive small intestinal CD4 T cell infiltration. Gut 1999;45:662-7.  Back to cited text no. 12      
13.Junker Y, Bode H, Wahnschaffe U, Kroesen A, Loddenkemper C, Duchmann R, et al. Comparative analysis of mononuclear cells isolated from mucosal lymphoid follicles of the human ileum and colon. Clin Exp Immunol 2009;156:232-7.   Back to cited text no. 13      
14.De Bruin PC, Jiwa NM, Oudejans JJ, Radazkiewicz T, Meijer CJ. Epstein Barr virus in primary gastrointestinal lymphomas. Association with gluten sensitive enteropathy pathology features and immunophenotype. Am J Pathol 1995;146:861-7.  Back to cited text no. 14      
15.Quintanilla-Martνnez L, Lome-Maldonado C, Ott G. Primary non-Hodgkin's lymphoma of the intestine: high prevalence of Epstein-Barr virus in Mexican lymphomas as compared with European cases. Blood 1997;89:644-51.  Back to cited text no. 15      
16.Zhang WY, Li GD, Liu WP, Ouyang Q, Ren XC, Li FY, et al. Features of intestinal T-cell lymphomas in Chinese population without evidence of celiac disease and their close association with Epstein-Barr virus infection. Chin Med J 2005;118:1542-8.  Back to cited text no. 16      
17.Chuang SS, Jung YC. Natural killer cell lymphoma of small intestine with features of enteropathy but lack of association with celiac disease. Hum Pathol 2004;35:639-42.  Back to cited text no. 17      

Correspondence Address:
Tanuja Shet
309/31, Prabhudarshan, S.S. Nagar, Amboli, Andheri (W), Mumbai-400 058
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0377-4929.68274

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  [Figure 1], [Figure 2], [Figure 3]

  [Table 1]

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