Background
Enteropathy-associated T-cell lymphoma (EATL) is uncommon worldwide but occurs more frequently in areas with a high prevalence of coeliac disease, particularly in Northern Europe and America [
1]. In the recent World Health Organization (WHO) classification, EATL is classified into two types. In Northern Europe and America, ~80 % of type I EATL cases consist of CD103- and CD30-positive, CD56- and CD8-negative large-cell lymphomas. These cases are closely associated with the occurrence of coeliac disease [
2]. In patients with type II EATL, which is now referred to as monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL), complications of coeliac disease are rare. Most MEITLs are CD103-, CD56-, and CD8-positive, CD30-negative monomorphic lymphomas with small- to medium-sized cells [
3]. In East Asia, type I EATL is rare, consistent with the rarity of coeliac disease. The latter is characterized by an allergic reaction to gluten and an association with HLA-DQ 2(B1*02) and DQ8 serotypes [
2,
4,
5]. MEITL is predominantly located in the small intestine but the background presence of enteropathy is controversial [
3,
6]. In East Asia, MEITL typically lacks the persistent clinicopathological features of enteropathy, in contrast to a worldwide study in which a clinical history of coeliac disease was determined in four of 15 (27 %) patients with MEITL [
7]. Compared with the general population, patients with coeliac disease have a 70-fold higher risk of microscopic (lymphocytic or collagenous) colitis accompanied by either an edematous or a normal-looking mucosa [
8]. Here we provide a detailed report of the endoscopic and pathological findings of four Japanese patients with multiple lesions of gastrointestinal (GI) MEITL complicating the duodenal and intestinal enteropathy-like lesions and microscopic (lymphocytic) foci of proctocolitis characterized by increased numbers of intraepithelial lymphocytes (IELs) [
8‐
10]. These cases demonstrate that variants of coeliac disease may be present in East Asian patients with MEITL and thus the necessity of a random whole-GI-tract biopsy in this group of MEITL patients.
Discussion
There are several reports in the literature describing gastroduodenal and colorectal tumors of MEITL and type I EATL, both in European and in East Asian patients [
3,
6,
13,
14]. In the latter group, gastric, duodenal, and colorectal MEITL tumors were reported in three (12 %), eight (31 %), and six (23 %) of the 26 cases of MEITL, respectively [
13]. In their study of European patients, Schmitt-Graff et al. reported tumorous lesions in six of 20 cases of MEITL (30 %) [
14]. In our study, patient 1 had depressed lesions and an edematous mucosa, with tumor cells in the stomach, duodenum, and colorectum. Patients 2 and 4 had ulcerative or submucosal tumors in the duodenum and an edematous mucosa with tumor cells in the colorectum. Patient 3 had diffusely granular mucosal lesions, with tumor cells in the duodenum and multiple ulcerated colorectal tumors. Thus, our study demonstrates that MEITL can expand discontinuously into the mucosa along the entire course of the GI tract.
The endoscopic findings in 12 of the 15 reported cases of MEITL included circumferential ulcerated tumors and an edematous and granular mucosa, with a nodular or mosaic pattern, in the duodenum, jejunum, and ileum (Table
3) [
15‐
24]. In addition, in all four patients, the non-neoplastic lesions consisted of an edematous or granular mucosa, with or without villous atrophy, in the duodenum and intestine. In patient 1, a cerebriform or flat mucosal pattern with villous atrophy was seen in the duodenum on magnifying endoscopy with NBI. These findings are typical of coeliac disease [
25]. Endoscopically, our study shows that an edematous and granular mucosa, with or without villous atrophy, in the duodenum and intestine is characteristic of the non-neoplastic and prodromal lesions of MEITL.
Table 3
Endoscopic findings of duodenum, intestine and colorectum in reported cases of MEITL
1 | 77/M | Duodenum: Edematous mucosa | |
| | Jejunum: Mass with circumferential ulcers | |
2 | 56/M | Sigmoid colon: Edematous mucosa, multiple discrete ulcers | |
| | Rectum: Edematous mucosa, multiple discrete ulcers | |
3 | 63/F | Ileum: Edematous mucosa | |
| | Appendix: Submucosal tumor-like mass | |
4 | 52/F | Jejunum: Edematous mucosa | |
| | Ileum: Shallow circumferential ulcers | |
5 | 65/M | Jejunum: Widespread white granular villi | |
6 | 70/M | Jejunum: Edematous mucosa, fusion on villi, multiple small shallow ulcers | |
7 | 60/M | Duodenum: Fine granular patterns with ulcers | |
| | Jejunum: Fine granular patterns with ulcers | |
| | Ileum: Edematous mucosa, circumferential ulcers | |
8 | 16/M | Ileocecum: Multifocal irregular ulcers | |
9 | 62/M | Duodenum: Huge ulcer | |
10 | 54/M | Jejunum; Multiple discrete ulcers | |
11 | 71/M | Ascending colon: Huge ulcerated tumor | |
| | Left side colon: Ordinary-looking mucosa | |
12 | 67/M | Cecum: Hyperemic, thickened mucosa with central ulcer | |
| | Descending colon: Fresh-like flat thickened lesion | |
13 | 50/M | Ileum: Circumferential shallow ulcers | |
| | Ascending colon: An ulcerative lesion with hyperemic edematous mucosa | |
14 | 48/M | Jejunum: Diffuse mucosal thickening and nodularity with multiple shallow ulcers | |
15 | 55/F | Jejunum: Encircling ulcer, edematous mucosa with innumerable fine granular elevations and shallow ulcers | |
Microscopic colitis consists of lymphocytic and collagenous colitis with >20 IELs per 100 surface epithelial cells and no or little architectural distortion of the crypts [
10]. While of uncertain etiology, both lymphocytic and collagenous microscopic colitis are occasionally seen in patients with coeliac disease, hypothyroidism, diabetes mellitus, and rheumatoid arthritis [
26]. In three reported cases of colonic MEITL, ulcerated tumors and hyperemic as well as normal-looking mucosa outside the tumors were detected (cases 2, 11, and 12 in Table
3) [
15,
23,
24]. However, only the patient described by Kim et al. had colonic MEITL characterized by presumably normal mucosa with tumor cell invasion [
23]. All four of our MEITL patients had an edematous and presumably normal colorectal mucosa, with an increased number of IELs, and without tumor cells outside the tumors. If lymphocytic proctocolitis is detected it must be distinguished from prodromal lesions of MEITL, even in East Asian patients. This study supports the importance of performing a random biopsy of the whole GI tract to detect the spread of MEITL and to identify the underlying non-neoplastic disorders.
Duodenitis, enteritis, and lymphocytic proctocolitis with increased T-IELs were features of all four cases described herein. In addition, the T-IELs were positive for CD103, CD3, CD7, and CD8 and negative for CD56 and CD5. These findings are similar to those of coeliac disease [
9,
27]. In East Asia, rather than type II EATL, these findings were referred to as MEITL, because of the absence of background histological findings of enteropathy [
3]. However, persistent diarrhea and weight loss have been reported in Asian patients with MEITL, and histologically confirmed enteropathy-like lesions were detected in eight of 69 cases of intestinal T/NK-cell lymphoma (12 %), including seven cases of MEITL [
28]. Kikuma et al. [
13] also reported the presence of some degree of enteropathy-like lesions in 11 of 22 MEITL patients (50 %). Coeliac disease characterized by anti-gliadin and anti-transglutaminase antibodies is rare in East Asia, whereas based on array comparative genomic hybridization, six of eight (75 %) Asian patients with MEITL had a gain of chromosome 9q34, as is frequently found in refractory coeliac disease and type I EATL [
2,
29]. Thus, variants of coeliac disease may play a role in inducing MEITL. However, refractory coeliac disease, suggesting of prodromal lesion of type I EATL, frequently has CD8-negative and occasionally CD30-positive T-IELs in duodenum and intestine [
9]. Further, Narismägi et al. [
30] demonstrated that mutations of STAT5, JAK3, and G-protein-coupled receptor are common features of MEITL. Thus, type I EATL and MEITL may include a variety of oncogenes in lymphomagenesis. It is necessary to find etiological factors in patients with variant of coeliac disease and MEITL.
Acknowledgements
We are grateful to Tomoko Fukushige, Masako Ishiguro, Tomomi Okabe, and Kaori Saga for their excellent technical assistance.