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Detailed clinicopathological characteristics and possible lymphomagenesis of type II intestinal enteropathy–associated T-cell lymphoma in Japan
Twenty-six Japanese cases of type II enteropathy-associated T-cell lymphoma (EATL) were examined. Multiple tumors throughout the small intestine were found in 15 patients (58%) and duodenal and colonic mucosal lesions in 8 and 6 cases, respectively. Histologically, intramucosal tumor spread and a zone of neoplastic intraepithelial lymphocytes (IELs) neighboring the main transmural tumors were detected in 20 (91%) and 17 (77%) of the 22 cases examined, respectively. Inside and outside of the IEL zone, some degree of enteropathy with many reactive small IELs and villous atrophy was detected in 11 cases (50%). Immunohistologically, many CD56/CD8-positive small IELs were found in the enteropathic lesions of 4 (36%) and 7 (64%) of these 11 cases. Lymphoma cells expressed tyrosine kinase receptor c-Met, serial p-MEK1/2, c-Myc, and Bcl2 in 18 (78%), 21 (91%), 11 (42%), and 19 (73%) of the total cases, respectively. By fluorescence in situ hybridization, chromosomal loci 7q31 (c-Met) and 8q24 (c-Myc) were amplified in 11 (65%) and 12 (71%) of the 17 cases analyzed. Gain of 7q31 and c-Met expression were significantly (p < 0.01) higher than in peripheral CD8-positive T-cell or CD56-positive NK-cell lymphomas. Enteropathy was seen near the IEL zone in type II EATL, and activation of the c-Met, MEK-MAPK pathway and c-Myc-Bcl2-mediated cell survival may play important roles in lymphomagenesis, converting enteropathy to type II EATL. Seven cases in the early clinical stages I and II-1 showed significantly (P < .01) better prognoses than did those in the advanced stages. Early detection of the mucosal lesions and tumors may improve patient prognosis.
Keywords: Bcl2, c-Met, c-Myc, Enteropathy-associated T-cell lymphoma, Enteropathy, Fluorescence in situ hybridization, MAPK, MEK.
Enteropathy-associated T-cell lymphoma (EATL) is a rare disorder most frequently seen in Caucasians of Northern European origin  . Approximately 80% of EATL tumors are composed mainly of type I CD30-positive large-cell lymphoma, frequently with multiple diffuse tumors in the small intestine. The remaining cases, classified as type II, are mainly CD56/CD8-positive monomorphic medium-sized lymphoma cells  . It is suggested that CD8-positive intraepithelial lymphocytes (IELs) in celiac disease will undergo conversion to CD8-negative, CD30-positive type I EATL and that the IELs may be the cellular origin of type I EATL  .
Comparative genomic hybridization (CGH) indicates that common chromosomal alterations in type I EATL and celiac disease are gains of 9q33–34, 1q22–q44, and 5q31–33, whereas gains of 9q3 and 8q24 (c-Myc) are typical in type II disease  and . On the other hand, there was no evidence of gains of 9q3, 1q3, or 5q3 by CGH in 20 Japanese type II lesions  . Human leukocyte antigen DQB1*02 homo- and heterozygosities, which are often found in cases of celiac disease and type I EATL  , were absent in the six type II cases. In East Asia, type II cases were common and had peculiar pathological and genetic findings , , and .
The precursor lesions of type II EATL have not been well documented. Celiac disease is characterized by an increase in reactive small IELs with villous atrophy and crypt hyperplasia in the duodenum and intestine  . Asian type II cases show prominent tumor epitheliotropism and some increase in small IELs with less enteropathy in the distant mucosal zone  . We tried to find lesions with characteristics of enteropathy that could be the precursors of neoplastic IEL zones and type II EATLs.
Celiac disease may be not involved in the etiology of Asian type II EALT cases  and . Various factors can cause enteropathy as a precursor of type II EATL. Helicobacter pylori infection and ulcerative colitis induce duodenitis with increased CD8-positive IELs  and . Helicobacter infection, especially of the East Asian type, elevates proto-oncogene c-Met signal transduction in epithelial cells, and aberrant c-Met expression contributes to neoplastic transformation of epithelial and B cells via the MEK-, mitogen-activated protein kinase (MAPK) pathway and c-Myc stabilization , , , and . The c-Met gene, located on chromosome 7q31, and its protein are frequently expressed in B-cell and occasionally in T-cell lymphoma  . Isochromosome 7q and gain of chromosome 8 are typical in cases of CD56-positive hepatosplenic T-cell lymphoma  .
We examined the expression of c-MET, MEK, and c-Myc proteins and gain of chromosomal loci 7q31 (c-Met) and 8q24 (c-Myc) in type II EATL via fluorescence in situ hybridization (FISH). Histologically, enteropathy with rare instances of crypt hyperplasia was found to some extent inside and outside the neoplastic IEL zone in half of the type II cases. We discuss the clinicopathological findings of enteropathy as a possible precursor of type II EATL, with lymphomagenesis via activation of the c-Met, MAPK, and c-Myc pathways, as well as the importance of early detection of the mucosal lesions and tumors.
2. Materials and methods
2.1. Case selection and clinical findings
Institutional ethnical approval was obtained for this study in compliance with the Declaration of Helsinki. A series of 34 Japanese patients with primarily intestinal T/NK-cell lymphoma were selected. Cases were first classified according to the World Health Organization (WHO) system of classification  ; two cases consisted of large-cell-type I EATL and 26 were monomorphic medium-sized type II EATL. Six cases were CD56-positive nasal-type NK-cell lymphomas with Epstein-Barr virus (EBV)-encoded RNAs (EBERs) detected by in situ hybridization. All of the type II EATL cases were seronegative for antibodies against human T-cell lymphotropic virus type 1 and had no EBER-positive lymphoma. No examinations of anti-endomysial IgA or anti-transglutaminase antibodies were performed because of the low incidence of celiac disease in Japan. Hypoproteinemia was defined as a total protein concentration of <6 g/dl in the serum. The tumor stages were classified according to the modified Ann Arbor staging system published by Lugano (cited by d’Amore et al.  ). For the 26 type II EATL cases, the outcome was determined by calculation of the cumulative survival time, and overall survival curves were generated using the Kaplan-Meier method and analyzed by the log-rank and generalized Wilcoxon tests.
2.2. Histology and immunohistochemistry
Tissue specimens were fixed with 20% formalin, embedded in paraffin, and stained with hematoxylin and eosin. Two cases consisted only of biopsy material. Detailed histologic examination was performed on the surgical specimens of the other 24 cases. For each sample, we examined four common histologic features in accordance with the findings described by Chan and associates  : (1) peripheral zone with intramucosal lymphoma-cell spread; (2) neoplastic IELs; (3) IEL zone; and (4) enteropathy. The medium-sized atypical lymphocytes with round, swollen nuclei in the mucosal epithelium were defined as neoplastic IELs. Enteropathy was defined as >40 IELs/100 epithelial cells with villous atrophy  . We used the term enteropathy instead of the modified Marsh classification of celiac disease because of the low frequency of crypt hyperplasia  .
For immunohistology staining, a panel of monoclonal and polyclonal antibodies was applied to formalin-fixed tumor samples using the ChemMate Envision method (Dako, Glostrup, Denmark); peroxidase reactions were developed using diaminobenzidine (DAB) as the substrate. Staining of CD20 (clone L26), CD3 (PS1), T-cell receptor (TCR)βF1 (8A3), TCRCγM1 (3.20), CD4 (4B12), CD5 (4C7), CD7 (272), CD8 (C81/44B), CD25 (4C9), CD30 (BerH2), CD56 (1B6), TIA-1 (2GP), c-Met (c-28), phosphorylated (p)-mitogen-activated protein kinase/extracellular signal-regulated kinase kinase (MEK)1/2 (S218/222), c-Myc (EP121), and Bcl2 (124) was performed after antigen retrieval. Samples in which >50% of the tumor cells were labeled with a particular antibody marker were classified as positive.
2.3. Fluorescence in situ hybridization
Dual-color probes (VYS-32-191002; Vysis, a division of Abbott Laboratories, Downer’s Grove, IL) for centromere (CEP) 7 and 7q31 (c-Met) region and other probes (06J37-008, 05J45-001; Abbott Laboratories, Abbott Park, IL) for CEP 8 and 8q24 (c-Myc) were used. The probe mixtures were applied to the slides, and hybridization proceeded overnight at 37°C. Slides were counterstained with 4′,6-diamidino-2-phenylindole (DAPI). For each case, the signals in about 200 cells were scored. Each tumor in which cells had three or more 7q31 (c-Met) or 8q24 (c-Myc) signals was scored as a gain. In seven cases of reactive lymphadenitis, more than three 7q31 or 8q24 signals were detected in <3% of the cells (range 1.1% to 1.8% [mean 1.52% ± 0.24%] for c-Met, and 0.9% to 2.4% [mean 1.92% ± 0.55%] for c-Myc). We set the cut-off at 5% for the c-Met and c-Myc probes. Twelve cases of CD56-negative, CD8-positive T-cell lymphoma and 15 of adult T-cell leukemia/lymphoma (ATL/L) mainly of the lymph nodes and 15 of CD56-positive nasal NK-cell lymphoma were selected to compare gain of c-Met and its protein in tumor tissues.
3.1. Case characteristics
The clinicopathologic findings from 26 type II EATL cases are summarized in Table 1 . The median patient age at diagnosis was 65 years (range 27–83 years), and 20 (77%) were male. Almost all patients complained of abdominal pain, which was caused by tumor perforation in 18 cases (69%). Continuous diarrhea with weight loss was reported in 10 cases (42%), and hypoproteinemia was noted in 16 (67%). Seven patients (27%) had a history of diarrhea and weight loss that lasted from 6 to 24 months (median 11 months). Seven (27%) and 4 (15%) patients had their main tumors in the jejunum or the ileum, respectively, and the remaining 15 (58%) had multiple tumors spread diffusely throughout the small intestine ( Fig. 1 ). Duodenal and gastric and large-intestinal lesions of lymphoma were found in 8 (31%), 3 (12%), and 6 (23%), respectively.
|CD56+ CD8+||CD56+ CD8–||CD56– CD8–|
|No. of cases||18||5||3||26|
|Median age (range)||60 (27–83)||65||80||65 (27–83)|
|Diarrhea (%)||8/16 (50)||1/3 (33)||1 (33)||10/22 (46)|
|Hypoproteinemia (%) a||13 (72)||2/3 (67)||1 (33)||16/24 (67)|
|Main site of tumor (%)|
|Jejunum||4 (22)||2 (40)||1 (33)||7 (27)|
|Ileum||1 (6)||3 (60)||0||4 (15)|
|Jejunum and ileum||13 (72)||0||2 (67)||15 (58)|
|With duodenum||7 (39)||0||1 (33)||8 (31)|
|50% survival (mo)||11||5||12||8|
|Peripheral zone (%)||14/15 (93)||3/4 (75)||3 (100)||20/22 (91)|
|IEL zone (%)||11/15 (73)||3/4 (75)||3 (100)||17/22 (77)|
|Neoplastic IELs (%)||10/15 (67)||2/4 (50)||2 (67)||15/22 (68)|
|Enteropathy (%) b||5/15 (33)||3/4 (75)||3 (100)||11/22 (50)|
a Serum protein concentration <6 g/dl.
b Increased IELs with villous atrophy.
Abbreviations: EATL, enteropathy-associated T-cell lymphoma; IELs, intraepithelial lymphocytes.
Jejunostomy or ileostomy was performed to remove the main tumor in 11 and 13 cases, respectively, and the other two patients did not receive surgical treatment because of the presence of multiple tumors. Seven CD56/CD8-positive patients (27%) without tumor perforation were classified as clinical stage I or II-1, and the other 19 (73%) were in stage IIE or IV. Cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) therapy was the main treatment in 21 cases, and one received an allogenic bone marrow transplant.
The estimated median survival of the 26 patients was 8 months, and the 3- and 5-year survival rates were both 32%. The 3-year survival rate of the seven patients in the early clinical stages without serosal penetration was 68% and that of the 19 in advanced stages was 12%. The EATL cases in the early stages had a significantly (P < .01) better prognosis than those in the advanced stages.
3.2. Histologic features
Twenty-four type II EATL cases showed ulcerative or superficial tumors or both with transmural invasion. Twenty (91%) of the 22 patients examined demonstrated marked intramucosal spread of lymphoma cells with submucosal invasion in the peripheral zone adjacent to the main tumor, and continuously proliferating lesions of IELs (IEL zone) were detected in 17 cases (77%). Numerous neoplastic IELs were found mainly in the peripheral and IEL zones of 15 cases (68%) ( Fig. 2 A). Twenty-one patients (96%) showed a mild increase in reactive small IELs outside the tumors. Enteropathy with a significant increase in reactive small IELs with or without villous atrophy was found to various extents inside and outside the IEL zone in 11 (50%) and 4 (18%) cases, respectively ( Figs. 2 B and 3 A–D). No widespread geographic necrosis was found in the tumor centers.
3.3. Immunohistology findings
The tumor-cell surface markers of the 26 type II EATLs are listed in Table 2 . Almost all lymphomas were positive for CD3 and T-cell intracellular antigen (TIA)-1. Eighteen cases were CD56/CD8 positive, five were CD56 positive, CD8 negative, and the remaining three were CD56/CD8 negative. Cells positive for TCRβF1 were detected in 10 instances (39%). Also, TCRCγM1-positive γδ T-cell lymphoma was found in seven type II EATL cases (27%), and was common in four (80%) of the five CD56-positive, CD8-negative cases ( Fig. 4 A). No type II EATL cases showed CD30-positive lymphoma cells. Tumor cells expressing CD7 were detected in 24 cases (92%), but not one lymphoma reacted with CD4 or CD5 antibodies. Only two cases (8%) were positive for CD25. With respect to reactive small IELs in enteropathy, a significant increase in CD56- or CD8-positive IELs was found in 4 (36%) and 7 (64%) of 11 cases, respectively ( Fig. 4 B).
|Antigens present||CD56+CD8+||CD56+ CD8–||CD56–CD8–||Total|
|No. of cases||18||5||3||26|
|CD3||18 (100)||5 (100)||2 (67)||25 (96)|
|TIA1||17 (94)||5 (100)||2 (67)||24 (92)|
|TCR βF1||8 (44)||1 (20)||1 (33)||10 (39)|
|TCR CγM1||3 (16)||4 (80)||0||7 (27)|
|CD56||18 (100)||5 (100)||0||23 (89)|
|CD8||18 (100)||0||0||18 (69)|
|c-Met||12/16 (75)||4 (80)||2/2 (100)||18/23 (78)|
|p-MEK1/2||15/16 (94)||4 (80)||2/2 (100)||21/23 (91)|
|c-Myc||8 (44)||3 (60)||0/2||11 (42)|
|Bcl2||15 (83)||4 (80)||0||19 (73)|
|Gain of 7q31||8/14 (57)||2/3 (67)||1/1 (100)||11/17 (65)|
|Gain of 8q24||9/14 (64)||2/3 (67)||1/1 (100)||12/17 (71)|
3.4. IHC expression and 7q31 and 8q24 FISH
Immunohistochemically, 18 (78%), 21 (91%), and 19 (73%) of the tumors showed intracytoplasmic reaction to c-Met, p-MEK1/2, and Bcl2, respectively ( Table 2 ; Figs. 4 C and 5 A). Weak nuclear reaction to c-Myc was detected in tumor cells of 11 cases (42%) ( Fig. 4 D). On FISH, more than 5% (5.1%–32%; median 12%) of the mononuclear cells showed a gain of 7q31 (c-Met) signals in 11 (65%) of 17 type II cases, and the 10 cases had a signal pattern indicative of isochromosome 7q ( Fig. 5 B). Eight (73%) of the 11 cases showed immunohistologic reaction to c-Met in the tumor cells. In the control tissues, more than 5% of the mononuclear cells showed a gain of 7q31 (c-Met) signals in one case each of CD8-positive T-cell lymphoma (8%) and CD56-positive NK-cell lymphoma (10%). Of the mononuclear cells, 6.9% to 12% exhibited a gain of 7q31 in 5 (42%) of 12 ATL/L cases. Expression of c-Met and gain of 7q31 in the two control groups were significantly (P < .01) lower than those in the type II EATL cases ( Table 3 ). More than 5% (6.4%–42%; median 26%) of the mononuclear cells in 12 (71%) of the available 17 type II cases had a gain of 8q24 (c-Myc) signals in their nuclei by FISH ( Table 2 ). Among the 12 cases, 9 (75%) had weak tumor nuclear reactions to c-Myc.
|Type II EATL||CD8+ T-cell lymphoma||CD56+ nasal
|Adult T-cell leukemia/lymphoma|
|c-Met||18/23 (78) a||3/12 (25) a||4/15 (27) a||6/15 (40)|
|Gain of 7q31||11/17 (65) a||1/12 (8) a||1/10 (10) a||5/12 (42) b|
a EATL significantly (P < .01) different from this group.
b No definite findings of isochromosome 7q31 were detected in three cases.
By imaging and histologic findings, diffuse thickening of the intestinal wall and enteropathy resulting from refractory celiac disease are frequently found in Caucasians with type I EATL and even in some type II cases  and . Here, we found multiple diffuse tumors throughout the small intestine in 15 type II cases (58%). Further, some evidence of enteropathy was seen inside and outside the IEL zone in half of the type II cases. However, only 7 (27%) of the patients with type II disease had a history of diarrhea, weight loss, and hypoproteinemia that lasted 6 to 24 months; therefore, it was difficult to define long-lasting enteropathy. Reportedly, four CD56-positive type II cases had the above enteropathy-related symptoms for 12 to 48 months as well as multiple diffuse intestinal tumors , , , and . Half of the European patients with type I EATL had shorter durations of clinical signs attributable to celiac disease  . The findings are suggestive of the notion that patients with type II EATL frequently have multiple intestinal mucosal lesions and tumors with a high incidence of enteropathy but less-frequent long-lasting enteropathy-like symptoms.
It was reported that Asian patients with type II EATL show a prominent neoplastic IEL zone without definite enteropathy and with shorter durations of clinical signs , , and . However, multiple whitish lesions of atrophic granular villi without tumor formation were reported to be prodromal or early lesions in three type II EATL cases, as noted by double-balloon and capsule endoscopy , , and . In this study, four patients had mucosal lesions with a significant increase in reactive IELs and with less villous atrophy, as described by Tan and associates  . Further, enteropathy with villous atrophy was found in half of the type II cases, and many CD56- or CD8-positive reactive small T-IELs or both were present in the lesions. Fourteen Asian patients with type II EATL showed no increase in chromosomes 1q2–4, 5q3, or 9q3 in tumor tissues on CGH  . Therefore, we suggest that other types of enteropathy, different from celiac disease, exist in type II EATL.
Helicobacter pylori induced a marked increase in duodenal CD8-positive T-IELs in 23 of 50 cases (46%); this finding overlapped with those of celiac disease  . In B6 mice with a Helicobacter infection, Peyer’s patches in the intestine play an important role in generating local and systemic interferon γ-producing T cells  . Aberrant c-Met expression by H. pylori infection is associated with disruption of tight junctions and polarity in epithelial cells via activation of the MEK-MAPK pathway  and . Further, in chronic B-cell lymphocytic leukemia, surface IgM stimulation rapidly increases MEK1/2-dependent c-Myc expression, which induces tumor-cell proliferation  . c-Myc induces the development of intestinal CD8-positive TCRαβ T-IELs in mice, which are subsequently maintained via Bcl2-dependent cell activity  .
Here, we found that in type II EATL cases, tumor cells frequently expressed c-Met (78%), p-MEK1/2 (91%), c-Myc (42%), and Bcl2 (73%). According to FISH, the copy number of 7q31 (c-Met) signals increased in 65% of the type II cases, which was significantly (P < .01) higher than the copy numbers in CD8-positive T-cell and CD56-positive NK-cell lymphomas. Further, weak nuclear reaction to new c-Myc antibody (clone: EP121), commonly found in Burkitt’s lymphoma with a chromosomal break at 8q24  , was detected in 9 (75%) of the 12 type II cases with a gain of 8q24 number. Gain of c-Met, serial p-MEK-MAPK-mediated cell activation and c-Myc-Bcl2-controlled cell survival may play a role in lymphomagenesis from enteropathy to type II EATL. Among tyrosine kinase inhibitors, one c-Met inhibitor abolished phosphorylation of c-Met and triggered a reduction of cell proliferation and apoptosis in c-Met-driven T-cell lymphoma in transgenic mice  . The c-Met inhibitor is potentially an important targeted therapy for the treatment of lymphoma. It is necessary to analyze further the key signaling pathways, including the c-MET-MAPK, in EATL.
Resident extrathymic T cells and their neoplasms are thought to be distributed in the liver, spleen, and skin, as well as the small intestine. Primary hepatosplenic T-cell lymphoma (PHTCL) consists of CD56-positive, CD8-negative/positive medium-sized cells. Isochromosome 7q, which is often confirmed with a 7q31 probe, and trisomy 8 are typical chromosomal aberrations in PHTCL  . By CGH, Baumgärtner et al.  demonstrated gains of 7q31 and 8q24 in 3 of 10 European type II EATL cases. Immunohistologic findings and chromosomal aberrations associated with type II EATL cases were similar to those of PHTCL. It is necessary to assess the characteristics of unique resident CD56-positive T cells and their neoplastic counterparts in the intestine and liver.
A good performance state and response to initial treatment led to better overall survival in 26 patients with type II EATL  . Seven patients in the early clinical stages had a significantly (P < .01) better prognosis than the 19 patients with advanced disease. In four patients in the early stages, the response to treatment was good, and progression of the disease was slowed , , , and . Early detection of enteropathy, mucosal lesions, and tumors of type II EATL may result in a good therapy response and long-term survival.
We thank Professor Yoshinao Oda, MD, Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, and Professor Takashi Yao, MD, Department of Human Pathology, School of Medicine, Juntendo University, for providing pathological materials and information from several cases. We are grateful to Masako Ishiguro, Tomoko Fukushige, Tomomi Okabe, and Kaori Saga for excellent technical assistance.
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a Department of Pathology, Faculty of Medicine, Fukuoka University, Fukuoka, 81400180, Japan
b Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, 814858, Japan
c Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, 814858, Japan
d Second Pathology Laboratory, Oita Red Cross Hospital, Oita, 8700033, Japan
e Pathology Laboratory, Oita Prefectural Hospital, Oita, 8708511, Japan
f Pathology Laboratory, National Organization Ureshino Hospital, Ureshino, 8430393, Japan
g Pathology Laboratory, Kenwakai Otemachi Hospital, Kitakyushu, 8038543, Japan
h Department of Pathology, Kawasaki Medical School, Kurashiki, 7010192, Japan
☆ Conflict of Interest: The authors have no significant relationships with or financial interest in any commercial activities pertaining to this article.
☆☆ Funding: This study was supported in part by a Grant-in-Aid for Scientific Research (No. 25460444) from the Ministry of Education, Science and Culture of Japan.
★ Running head: Possible lymphomagenesis of type II EATL
© 2014 Published by Elsevier B.V.