Endoscopic and clinicopathological characteristics of colorectal T/NK cell lymphoma

Background Colorectal T/natural killer (NK)-cell lymphomas (TNKCL) are very rare. Endoscopic and clinicopathological characteristics of colorectal TNKCL have not been clearly demonstrated. In this study, we demonstrated the clinical characteristics of colorectal TNKCL. Methods Endoscopic and clinicopathological characteristics were investigated in 27 patients with colorectal monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL), adult T-cell leukemia/lymphoma (ATLL), and other types of TNKCL. Results Nine TNKCL patients (33%) were classified as MEITL, 11 (41%) as ATLL, and seven (26%) as other. Four patients with Epstein-Barr Virus-positive (EBV+) TNKCL, two indolent T-cell lymphoproliferative disorder and one anaplastic large cell lymphoma were included in the other group. Endoscopically, six MEITL (67%) and five ATLL (46%) showed diffuse-infiltrating type, in which the main endoscopic lesion was edematous mucosa in MEITL, while aphthoid erosion and edematous mucosa were typical in ATLL. Ulcerative type was identified in four other group patients (57%), including two EBV+ TNKCL. An increase in atypical T-intraepithelial lymphocytes (T-IELs) was noted in seven MEITL (88%) and six ATLL (60%) patients, but not in the other group (0%) patients. Five MEITL patients (56%) showed features of lymphocytic proctocolitis with increased CD8+ T-IELs. Conclusions MEITL and ATLL occasionally invaded the colorectum, and primary involving MEITL was observed. Diffuse infiltrating type was the characteristic endoscopic finding in colorectal MEITL and ATLL, while ulcerative type was observed in the other group. Features of lymphocytic proctocolitis may be prodromal findings of MEITL.

The current study reported 27 patients with colorectal TNKCL, with MEITL and ATLL patients accounting for more than two-thirds of the patient population. Detailed endoscopic and clinicopathological characteristics were demonstrated in the TNKCL patients. Furthermore, features of lymphocytic proctocolitis was detected in MEIT L patients. The relationship between lymphocytic proctocolitis and TNKCL was discussed.

Patient selection and clinical findings
Institutional ethical approval was obtained in compliance with the Declaration of Helsinki (institutional review board approval number: U20-06-006). We retrospectively retrieved records and samples of TNKCL of the GI tract from 106 patients (32 MEITL, 61 ATLL, 13 other types of TNKCL) taken between 1990 and 2018 at the Department of Pathology, Fukuoka University. Histological classification was performed according to the World Health Organization (WHO) classification and reference of intestinal EBV+ TNKCL in 2017 [6][7][8]10]. The current study focused on 27 Japanese patients with colorectal TNKCL. Clinical stage was determined according to the Lugano classification [18].

Endoscopic examination
All 27 patients underwent endoscopic examination of the upper and/or lower GI tract. A video endoscope (Olympus Medical System, Tokyo, Japan) was used for all endoscopic examinations. The endoscopic images or records were reviewed retrospectively by experienced endoscopists (H.I, F.H). Biopsy specimens were taken from the stomach and/or small intestine and/or colon by standard biopsy forceps for histologic examination. Endoscopic findings of the main lesions of colorectal TNKCL were classified into three types based on a previous classification [19]: 1) diffuse infiltrating (colitislike or proctocolitis-like lesion); 2) ulcerative (including stricturing and non-stricturing); and 3) polypoid (localized) (Fig. 1).

Statistical analysis
Clinicopathological data were analyzed using the chisquared test and Fisher's exact test. A P-value of < 0.05 was considered statistically significant. Overall survival (OS) curves of all examined patients were generated using the Kaplan-Meier method and analyzed by the log-rank test.

Pathological and immunohistological findings of colorectal TNKCL
The pathological and immunohistological findings of 27 colorectal TNKCL patients are summarized in Table 3. Histologically, all nine MEITL patients (100%) had monomorphic medium-sized cell lymphoma, while eight ATLL patients (73%) had pleomorphic medium-sized cell lymphoma. In the other group, one EBV+ CD56+ TNKCL and two indolent TLPD (42%) were composed of pleomorphic medium-sized cell lymphoma, and three EBV+ CD56 negative TNKCL and one ALCL (57%) showed monomorphic large cell lymphoma. Seven of eight MEITL patients (88%) and six of 10 ATLL (60%) showed an increase in atypical IELs in the overlying epithelium and in glands in and near the tumors. These findings were not observed in other group patients (0%). Five MEITL patients (56%) showed features of lymphocytic proctocolitis, in which an increase in reactive small IELs was found in the background nonneoplastic mucosa (Fig. 3a, b), and one ATLL (9%) showed an increase

Analysis of patient prognosis
The 50% OS of nine MEITL patients was 9.5 months, that of 11 ATLL was 9 months, and that of five other group patients was over 240 months. There was no prognostic difference in OS between MEITL and ATLL  patients (Fig. 4a). The 50% OS of the five patients (three MEITL, one EBV+ CD56 negative TNKCL and one indolent TLPD) in the early stages (I and II1) was more than 240 months. The 50% OS of 20 patients in the advanced stages (II2, IIE and IV) was 8.5 months. There was no significant difference between the early and advanced stages (P = 0.063) (Fig. 4b).

Discussion
Previous studies have shown that endoscopically, eight of 15 MEITL lesions (53.3%) and eight of 10 EBV+ TNKCL (80%) showed the ulcero-infiltrative type in 42 GI TNKCL [16]. Infiltrating and superficial/erosive type lesions were rarely found in each of the above histological groups. Another study demonstrated that nine intestinal EBV+ CD56+/negative TNKCL patients showed ulcerative (n = 5) and protruding (n = 4) type lesions [8]. Furthermore, 34 of 47 EBV+ CD56+ TNKCL patients (72.3%) frequently showed multiple ulcerative lesions [21]. In the current study, the ulcerative type was frequently encountered in four of seven other group patients (57%), in which two EBV+ CD56 negative TNKCL were included. Six MEITL patients (67%) and five ATLL (46%) mainly showed the diffuse infiltrating type. Although ulcerating and polypoid type lesions were also found in resting MEITL and ATLL patients, the diffuse infiltrating type was a frequently encountered characteristic of colorectal MEITL and ATLL, which was different from that of EBV+ TNKCL as well as B-cell lymphoma [3,8,16,21]. Further detailed studies are necessary to clarify the endoscopic difference among MEITL, ATLL and EBV+ TNKCL. Small intestinal MEITL mostly showed intramucosal spreading of lymphoma cells with neoplastic CD103+ and CD8+ T-IELs [11]. It was reported that lymphoma cells in 21 of 31MEITL (68%) as well as 31 of 56 GI ATLL patients (55%) showed expression of CD103 homing receptor of T-IELs, and ATLL had similar histopathological characteristics to MEITL with respect to increased atypical and reactive T-IELs [20]. The endoscopic findings of MEITL have been reported as edematous mucosa with mosaic and diffuse mucosal thickening patterns, and shallow ulceration, as well as ulcerative type tumors in the small intestine [22]. The endoscopic findings of GI-involved acute type ATLL showed superficial spreading-type lesions (equal to the diffuse infiltrating type) in 12 of 23 lesions (52%) [23]. In the current study, more than two colorectal lymphomatous lesions were frequently found in MEITL (78%) and ATLL (64%) patients. Histologically, increased atypical T-IELs were found in MEITL (88%) and ATLL (60%) patients. Although MEITL and GI ATLL showed distinct disease entities, the endoscopic and pathological characteristics of colorectal MEITL were similar to those of ATLL.
A multicenter study from the Asia Lymphoma Study Group identified 38 MEITL patients, and the involved sites were the small intestine and stomach (5%), small intestine (63%), small and large intestine (16%), and large intestine (18%) [11]. MEITL can discontinuously expand into the mucosa along the entire GI tract. Aoyama et al. reported a primary colonic MEITL patient with Lugano clinical stage I, having mucosal edema and multiple ulcers in the transverse, splenic flexure, and sigmoid colon [24]. The current study also demonstrated that three MEITL patients (33%) had primarily presenting colorectal lesions. Endoscopically, six MEITL patients (67%) showed diffuse infiltrating type with more than two lymphomatous lesions in the whole colorectum. A previous study reported two colonic MEITL patients with clinicopathological features that mimicked those of ulcerative colitis and lymphocytic colitis, and the latter had a history of 'lymphocytic colitis' 6 months before [25]. Although collagenous sprue, microscopic (lymphocytic and collagenous) colitis, and celiac disease show distinct clinical entities, these diseases reveal similar features of Fig. 4 Overall survival (OS) curves in 25 patients with colorectal TNKCL. a 50% OS rates of MEITL, ATLL and other group were 9.5 months, 9 months, and more than 240 months, respectively. There was no statistical difference between MEITL and ATLL. b The 50% OS of five patients with primary colorectal TNKCL in early stages (I or II1) was over 240 months, and that of 20 patients in advanced stages was 8.5 months. There was no statistical difference between the two groups (P = 0.063) colitis with an increase in T-IELs [26,27]. Five examined MEITL patients (56%) had features of lymphocytic proctocolitis with reactive small T-IELs, and the findings were almost similar to lymphocytic colitis, in which more than 20 IELs per 100 epithelial cells and no or few distorted crypts were detected [28]. The features of lymphocytic proctocolitis may be characteristic of background mucosa in colorectal and other GI MEITL. Cumulative studies are necessary to clarify the relationship between lymphocytic proctocolitis and MEITL.
The prognosis of GI TNKCL patients is worse, and 1and 3-year OS rates were 57 and 26%, respectively, in 42 intestinal MEITL patients [29]. Among them, OS of MEIT L patients with Lugano clinical stages I, II1, and II2 was 18.8 months, which was significantly better than 4.9 months in stages IIE and IV (P = 0.01). The Lugano stage as well as the performance scales were important prognostic factors. Clinical stages in 55 GI EBV+ TNKCL patients and 61 GI-involved ATLL were also indicated as a significant prognostic factor (P < 0.001 and P = 0.017, respectively) [9,23]. In the current study, only six of 27 colorectal TNKCL patients (22%) were found with stage I and II1 disease, and the 50% OS of the five was more than 240 months. The major symptom of examined colorectal TNKCL patients was chronic diarrhea. Thus, the clinical symptoms as well as the features of lymphocytic proctocolitis with CD8+ T-IELs may be important in detecting the early stages of colorectal TNKCL.

Conclusions
MEITL, ATLL and other types of TNKCL occasionally involved the colorectal regions, and primary and concurrently involved colorectal MEITL was recognized. The endoscopic and clinicopathological characteristics of colorectal MEITL and ATLL revealed diffuse infiltrating lesions with increased atypical T-IELs. However, features of lymphocytic proctocolitis in the background mucosa were characteristic of colorectal MEITL. Primary colorectal MEITL patients in the early clinical stages were rarely identified and showed a rather prolonged clinical course. It is important to recognize endoscopic and clinicopathological characteristics including features of lymphocytic proctocolitis to detect early-stage colorectal TNKCL.