Monomorphic epitheliotropic intestinal T-cell lymphoma: Clinical, endoscopic and pathological features

Abstract

BACKGROUND

Monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL) is a rare, aggressive T-cell lymphoma involving the gastrointestinal tract, which was previously classified as enteropathy-associated T-cell lymphoma type II (EATL II).

AIM

To improve the understanding and diagnostic accuracy of MEITL, this study analyzed its clinical, endoscopic, and pathological characteristics.

METHODS

Patients who were diagnosed with MEITL or EATL II at Peking Union Medical College Hospital between August 2012 and June 2025 were retrospectively enrolled. Additionally, cases with confirmed diagnoses of EATL II or MEITL were retrieved from PubMed and Web of Science. Clinical symptoms, medical history, auxiliary examinations, endoscopic and pathological findings were collected for all included patients.

RESULTS

Among the 26 MEITL patients in Peking Union Medical College Hospital, the most common symptoms were weight loss (73%) and abdominal pain (65%), with 96% showing small intestinal involvement. Endoscopic findings in 10 patients showed mucosal edema (100%), roughness (100%), and villous blunting (90%). A review of 130 published MEITL cases revealed similar clinical profiles but heterogeneous endoscopic features. Ulceration (66%) was the most frequent in 64 cases with available data. Integrated analysis of 156 patients, stratified by a prediagnostic surgical history, showed nonsurgical group more frequently presented with diarrhea and weight loss (P < 0.001); surgical group had higher incidence of bowel perforation (P < 0.001) and higher expression of T-cell intracellular antigen 1 and granzyme B (P < 0.05), indicating aggressiveness.

CONCLUSION

Recognizing the characteristic symptoms and endoscopic features of MEITL is essential for improving the diagnostic accuracy and early identification of this rare and aggressive lymphoma.

Key Words: Monomorphic epitheliotropic intestinal T-cell lymphoma; Endoscopic features; Clinical characteristics; Pathological characteristics; Diagnosis

Core Tip: This study analyzed 26 cases from Peking Union Medical College Hospital and 130 literature-reported cases of monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL). It found heterogeneous endoscopic manifestations. The Peking Union Medical College Hospital cohort mainly presented with subtle mucosal changes (edema, roughness, villous blunting), which may be early endoscopic signs of MEITL. Ulceration was the main endoscopic feature in the literature cohort, likely indicating disease progression. Multi-site deep biopsy combined with imaging is crucial for early accurate diagnosis of MEITL. Two clinical subtypes (acute aggressive and chronic consumptive) were identified, with distinct symptoms and pathological features, providing value for personalized clinical management.

INTRODUCTION

Monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL) is a rare and aggressive form of intestinal non-Hodgkin lymphoma that originates from intraepithelial lymphocytes (IEL). It was initially classified as enteropathy-associated T-cell lymphoma (EATL) type II and was formally designated as MEITL in the 2016 World Health Organization classification of tumors of hematopoietic and lymphoid tissues[1]. EATL type I is more common in Western countries and is strongly associated with celiac disease[2]. In contrast, MEITL has no clear association with celiac disease and predominantly occurs in Asian and Hispanic populations.

MEITL predominantly affects older adults, with a median age at onset of 58-62 years and a male predominance[3]. Clinically, MEITL lacks specific manifestations. Patients often present with abdominal pain, diarrhea, weight loss, or abdominal distension, and some patients may develop acute abdominal symptoms due to intestinal perforation or obstruction. Because of its rapid disease progression, most patients are diagnosed at advanced stages, with a very poor prognosis. The reported median survival time for MEITL is approximately 7 months, and the 1-year overall survival rate is less than 40%[4]. Therefore, early recognition and accurate diagnosis are crucial for improving patient outcomes, with endoscopy and imaging playing key roles in the early detection of the disease[5].

However, owing to the extreme rarity of MEITL, most published reports are limited to case studies or small cohorts, and systematic summaries are lacking, resulting in frequent misdiagnoses and delayed diagnoses. In this study, the characteristics of 26 MEITL patients diagnosed at Peking Union Medical College Hospital (PUMCH) between 2012 and 2025 were systematically analyzed and integrated with data from 130 reported cases worldwide to comprehensively summarize the clinical manifestations, endoscopic features, and pathological characteristics of MEITL. Additionally, differences among clinical subtypes were explored, aiming to provide evidence-based guidance for diagnosis and management.

MATERIALS AND METHODS

Study subjects

Retrospective cohort from PUMCH: Patients who were diagnosed with MEITL, as confirmed by pathology, at the Departments of Gastroenterology and Hematology, PUMCH, between August 2012 and June 2025, were retrospectively included. The inclusion criteria were as follows: (1) Fulfillment of the 2016 World Health Organization diagnostic criteria for MEITL, defined by diffuse infiltration of monomorphic T lymphocytes with marked epitheliotropism in pathological specimens; immunohistochemical positivity for CD3, CD8, and CD56; and negative results for Epstein-Barr virus-encoded RNA (EBER) in situ hybridization; and (2) Complete clinical data, including demographic information, clinical symptoms, laboratory tests, endoscopic or imaging findings. The exclusion criteria were: (1) Unclear diagnosis or confirmation of other lymphoma subtypes (e.g., EATL type I or natural killer/T-cell lymphoma); and (2) Incomplete clinical data with missing key information. Ultimately, 26 patients were included.

Literature cohort: A systematic search was conducted in PubMed and Web of Science from database inception to June 2025 using the following terms: “monomorphic epitheliotropic intestinal T-cell lymphoma”, “MEITL”, “type II enteropathy-associated T-cell lymphoma”, “EATL II”, “type II intestinal enteropathy-associated T-cell lymphoma”, and “enteropathy-associated T-cell lymphoma type II”. The inclusion criteria were: (1) Case reports or small case series; (2) Cases pathologically confirmed as MEITL or EATL II, using diagnostic criteria consistent with this study; and (3) Availability of complete demographic, clinical, laboratory, endoscopic, and pathological data. The exclusion criteria were: (1) Duplicate cases; (2) Incomplete data; and (3) Review articles or basic research studies. Ultimately, 109 publications reporting 130 cases were included.

Data collection

Demographic data, clinical manifestations, laboratory results, imaging, endoscopic findings and pathological features were recorded using standardized forms. Endoscopic data for patients in the retrospective cohort from PUMCH were retrieved from the Endoscopy Center database of the Department of Gastroenterology and reviewed by senior endoscopists to document characteristic endoscopic features.

(1) Demographic characteristics: Sex, age at diagnosis, and geographic region of residence; (2) Clinical symptoms: Weight loss, abdominal pain, diarrhea, fever (temperature ≥ 37.3 °C), intestinal obstruction, intestinal perforation, ascites, and gastrointestinal bleeding; (3) Laboratory parameters: Anemia (hemoglobin < 120 g/L for men, < 110 g/L for women), hypoalbuminemia (serum albumin < 35 g/L), elevated C-reactive protein (CRP > 10 mg/L), elevated high-sensitivity CRP (> 8 mg/L), β2-microglobulin (β2-MG; normal range 0.7-1.8 mg/L) and baseline lactate dehydrogenase (LDH; normal range 0-250 U/L); (4) Sites of involvement: Stomach, small intestine (duodenum/jejunum/ileum), and colorectum, confirmed by endoscopy or imaging; (5) Imaging features: Abdominal computed tomography (CT) findings, including bowel wall thickening, bowel dilation, and multiple enlarged lymph nodes; (6) Endoscopic features: Mucosal edema, mucosal roughness (granular surface), villous blunting, lymphangiectasia-like changes, mosaic patterns, mucosal hyperemia, erosion, ulceration, and nodular elevation; and (7) Pathological features: Immunohistochemical markers [CD2, CD3, CD4, CD5, CD7, CD8, CD56, CD20, T-cell intracellular antigen 1 (TIA-1), granzyme B, and Ki-67] and EBER in situ hybridization results.

Statistical analysis

Statistical analyses were performed using R version 4.3.3. For categorical variables (e.g., symptom incidence and immunophenotype positivity), Pearson’s χ² test was used to compare groups when the sample size was ≥ 5 and Fisher’s exact test was applied when the sample size was < 5. A significance level of α = 0.05 was used, and P < 0.05 was considered to indicate statistical significance.

RESULTS

Clinical, endoscopic and pathological features of the PUMCH cohort

Among the 26 MEITL patients, 15 (57.7%) were male and 11 (42.3%) were female, with a median age at diagnosis of 61 years (range, 37-82 years). The most common symptoms were abdominal pain and/or diarrhea, including weight loss (19/26, 73.1%), abdominal pain (17/26, 65.4%), and diarrhea (9/26, 34.6%). The incidences of intestinal obstruction and perforation prior to diagnosis were both 26.9% (7/26), and one additional patient developed intestinal perforation during chemotherapy. The detailed clinical characteristics of the cohort are summarized in Table 1. Laboratory findings revealed elevated β2-MG (8/8, 100%), elevated high-sensitivity CRP (9/10, 90%), hypoalbuminemia (15/18, 83.3%), anemia (13/20, 65%), and an increased erythrocyte sedimentation rate (3/9, 33.3%), while no patients had elevated LDH levels.

Table 1 Monomorphic epitheliotropic intestinal T-cell lymphoma clinical characteristics: Peking Union Medical College Hospital and literature cohort, %.

Characteristic	PUMCH cohort (n = 26)	Literature cohort (n = 130)	P value
Clinical characteristics
Sex (male:female)	15:11	87:42	0.370
Median age, years (range)	61 (37-82)	61 (35-83)
Weight loss	73 (19/26)	46 (60/130)	0.012a
Abdominal pain	65 (17/26)	59 (77/130)	0.558
Diarrhea	35 (9/26)	39 (51/130)	0.659
Fever	31 (8/26)	48 (21/44)	0.164
Intestinal obstruction	27 (7/26)	18 (23/130)	0.276
Intestinal perforation	31 (8/26)	35 (45/130)	0.705
Laboratory findings
Anemia	65 (13/20)	60 (31/52)	0.675
Hypoalbuminemia	83 (15/18)	92 (36/39)	0.368
Elevated CRP	90 (9/10)	86 (25/29)	1.000
Elevated LDH	0 (0/16)	31 (11/35)	0.011a
Elevated β2-MG	100 (8/8)
Sites of involvement
Stomach	0	10 (13/126)	0.126
Small intestine	96 (25/26)	84 (106/126)	0.128
Colon and rectum	15 (4/26)	25 (32/126)	0.323
Imaging features
Bowel wall thickening	83 (15/18)	56 (54/96)	0.037a
Bowel dilation	39 (7/18)	20 (19/96)	0.076
Lymph node enlargement	61 (11/18)	23 (22/96)	0.001a
Endoscopic features
Diffuse involvement	60 (6/10)
Mucosal edema	100 (10/10)	27 (17/64)	< 0.001a
Rough/granular surface	100 (10/10)	19 (12/64)	< 0.001a
Villous blunting	90 (9/10)	23 (15/64)	< 0.001a
Lymphangiectasia-like change	80 (8/10)
Mosaic pattern	40 (4/10)
Mucosal hyperemia	60 (6/10)	16 (10/64)	0.005a
Nodular elevations	40 (4/10)	6 (4/64)	0.010a
Erosion	20 (2/10)	17 (11/64)	1.000
Ulceration	30 (3/10)	66 (42/64)	0.042a
Mass-like lesion	0	16 (10/64)	0.339

^aP < 0.05.

PUMCH: Peking Union Medical College Hospital; CRP: C-reactive protein; LDH: Lactate dehydrogenase; β2-MG: Β2-microglobulin.

With respect to the sites of involvement, the small intestine was the primary affected organ (25/26, 96.2%), with only 4 patients (15.4%) showing colorectal involvement and no cases involving the stomach. Bone marrow aspiration was performed in 10 patients, with suspected involvement in 2. Among the 18 patients who underwent abdominal CT, the imaging features included bowel wall thickening (15/18, 83.3%), multiple enlarged lymph nodes (11/18, 61.1%), and bowel dilation (7/18, 38.9%).

Ten of the 26 patients underwent endoscopic examination at PUMCH. Sites of gastrointestinal involvement included the duodenum (2/10), jejunum (3/10), proximal ileum (3/10), distal ileum (4/10), and colorectum (1/10). Endoscopic findings were generally subtle, including mucosal edema (10/10, 100%), mucosal roughness or granular surface (10/10, 100%), villous blunting (9/10, 90.0%), lymphangiectasia-like changes (8/10, 80.0%), blurred vascular patterns (6/10, 60.0%), mucosal hyperemia (6/10, 60.0%), mosaic patterns (4/10, 40.0%), nodular elevations (4/10, 40.0%), ulceration (3/10, 30.0%), erosion (2/10, 20.0%), and intestinal stricture (3/10, 30.0%). The endoscopic images from some typical patients are shown in Figure 1. The diagnostic yield of endoscopic biopsy was 50.0% (13/26), with the remaining 13 patients requiring surgical or core needle specimens for diagnosis.

Figure 1 Endoscopic findings in patients with monomorphic epitheliotropic intestinal T-cell lymphoma. A: Duodenum showing a mosaic pattern; B: Small intestinal mucosa with a large ulcer covered by dirty exudate, without bleeding; C: Small intestinal mucosa exhibiting edema and clustered villous blunting, with partial villous loss; D: Distal ileum with diffuse hyperemia and edema and granular mucosal changes.

Pathologically, 23 patients provided analyzable reports. The typical histological features of MEITL included diffuse infiltration of monomorphic medium-sized lymphocytes with round nuclei and pale cytoplasmic borders and prominent epitheliotropism, usually without necrosis or a significant inflammatory response[6]. The tumor cells exhibited high proliferative activity, with Ki-67 overexpression (> 50%) observed in 19/23 patients (82.6%). Representative histopathological and immunophenotypic findings are shown in Figure 2. The immunohistochemical findings were as follows: EBER- (17/17, 100%), CD7+ (14/14, 100%), CD3+ (21/22, 95.5%), CD5- (16/17, 94.1%), CD10- (13/14, 92.9%), CD4- (15/17, 88.2%), CD2+ (9/11, 81.8%), CD56+ (16/20, 80.0%), TIA-1+ (12/15, 80.0%), Bcl2+ (8/10, 80.0%), and CD8+ (16/21, 76.2%). A subset of patients were CD20+ (6/22, 27.2%).

Figure 2 Histopathological and immunophenotypic profiles of monomorphic epitheliotropic intestinal T-cell lymphoma patients. A: The tumor cells demonstrate transmural invasion (ultra-low magnification preview); B: The mucosa shows a dense, monomorphic infiltrate of lymphoma cells, characterized by prominent epitheliotropism with infiltration of the surface epithelium by numerous neoplastic cells (hematoxylin and eosin, × 40); C and D: The tumor cells are predominantly small to medium-sized with round or slightly irregular nuclei, dense chromatin and frequent mitotic figures, accompanied by a minor population of larger cells (hematoxylin and eosin, × 400); E: Immunohistochemical staining shows that the tumor cells are positive for CD2, CD3, CD7, CD8, and CD56 but negative for CD20, CD5, and CD4. Staining for CD5 and CD4 highlights a minor population of reactive background T lymphocytes. Epstein-Barr virus-encoded RNA in situ hybridization is negative, which helps to exclude extranodal natural killer/T-cell lymphoma (× 200). EBER: Epstein-Barr virus-encoded RNA.

Comparative analysis of clinical characteristics between the literature cohort and the PUMCH cohort

As shown in Table 1, among the 130 literature-reported MEITL patients, the male-to-female ratio was approximately 2:1. In terms of clinical features, only the incidence of weight loss was significantly lower in the PUMCH cohort (P = 0.012), while the incidence of other symptoms was not significantly different. Laboratory findings revealed that LDH was significantly more frequently elevated (11/35, 31.4%) in the literature cohort than in the PUMCH cohort (P = 0.011).

In terms of sites of involvement, the literature cohort included the stomach (13/126, 10.3%), central nervous system (13/130, 10.0%), lungs and thoracic cavity (19/130, 14.6%), and bone marrow (10/130, 7.7%), with occasional reports of skin, liver, gallbladder, bladder, pancreas, and ocular involvement[7-12]. Imaging features such as bowel wall thickening (P = 0.037) and multiple lymph node enlargement (P = 0.001) were significantly less frequent in the literature cohort than in the PUMCH cohort.

Endoscopic findings were described for 64 cases in the literature, with notable differences from those in the PUMCH cohort. Unlike the PUMCH cohort, ulceration was the most common feature in the literature cohort (42/64, 65.6%), and the difference was statistically significant (P = 0.042). In contrast, compared with those in the PUMCH cohort, subtle mucosal changes, including mucosal edema (17/64, 26.6%), mucosal roughness or granular surface (12/64, 18.8%), villous blunting (15/64, 23.4%), and mucosal hyperemia (10/64, 15.6%), were significantly less frequent in the literature cohort. Additionally, mass-like lesions were observed in 15.6% of the literature cases (10/64), while no mass-like lesions were identified in the PUMCH cohort. Statistical analysis indicated that patients without endoscopic ulcers were more likely to present with diarrhea (P = 0.002), weight loss (P = 0.003), and elevated CD4+ expression (P = 0.02), suggesting that these patients may exhibit a chronic, cachectic clinical phenotype.

The pathological characteristics of patients in the literature cohort were consistent with those in the PUMCH cohort. Additionally, some patients in the literature cohort exhibited the following immunophenotypic features: CD79α- (87.5%, 14/16), CD30- (90.9%, 50/55), CD103+ (90.9%, 10/11), Pax5- (100%, 8/8), cyclinD1- (100%, 12/12), and Bcl6- (92.3%, 12/13).

Differences in clinical characteristics between nonsurgical and surgical groups prior to diagnosis

By combining the PUMCH cohort (26 cases) with the literature cohort (130 cases), a total of 156 patients were included and stratified into a surgical group (78 patients) and a nonsurgical group (76 patients) on the basis of whether surgery was performed prior to diagnosis. The nonsurgical group exhibited a longer disease course than the surgical group. And the nonsurgical group predominantly exhibited chronic symptoms, with higher incidences of diarrhea (54.0% vs 24.4%, P < 0.001) and weight loss (65.8% vs 37.2%, P < 0.001). In contrast, the surgical group mainly presented with acute manifestations, with a significantly higher rate of intestinal perforation (53.8% vs 14.5%, P < 0.001). The nonsurgical group also had significantly greater involvement of the stomach (13.5% vs 2.6%, P = 0.016) and colorectum (35.1% vs 13.2%, P = 0.002), whereas small intestinal involvement was comparable between the groups (P = 0.322).

Immunohistochemical analysis revealed that the surgical group had significantly higher positivity rates for TIA-1 (100% vs 80.0%, P = 0.005) and granzyme B (80.6% vs 50.0%, P = 0.015), indicating stronger cytotoxicity and more aggressive tumor behavior. Previous studies have reported that the expression of granzyme B, TIA-1, and perforin is associated with activated cytotoxic phenotypes and that the positive expression of these genes is positively correlated with the depth of tumor infiltration[13]. The detailed data are presented in Table 2.

Table 2 Clinical characteristics: Prediagnostic surgical vs non-surgical groups, %.

Characteristic	Total (n = 156)	Non-surgical group (n = 76)	Surgical group (n = 78)	P value
Male	66 (102/155)	70 (53/76)	62 (48/77)	0.334
Female	34 (53/155)	30 (23/76)	38 (29/77)	0.334
Clinical symptoms
Abdominal pain	60 (94/156)	55 (42/76)	65 (51/78)	0.199
Diarrhea	38 (60/156)	54 (41/76)	24 (19/78)	< 0.001a
Constipation	3 (5/156)	3 (2/76)	4 (3/78)	0.671
Vomiting	9 (14/156)	7 (5/76)	12 (9/78)	0.284
Abdominal distension	21 (32/156)	22 (17/76)	19 (15/78)	0.631
Hematochezia	7 (11/156)	8 (6/76)	6 (5/78)	0.721
Fever	41 (29/70)	43 (16/37)	41 (13/32)	0.826
Weight loss	51 (79/156)	66 (50/76)	37 (29/78)	< 0.001a
Intestinal obstruction	19 (30/156)	20 (15/76)	19 (15/78)	0.937
Intestinal perforation	34 (53/156)	14 (11/76)	54 (42/78)	< 0.001a
Ascites	6 (10/156)	7 (5/76)	6 (5/78)	0.966
Bleeding	3 (4/156)	5 (4/76)	0	0.057
Sites of involvement
Stomach	9 (13/152)	14 (10/74)	3 (2/76)	0.016a
Small intestine	86 (130/152)	82 (61/74)	88 (67/76)	0.322
Colon and rectum	24 (36/152)	35 (26/74)	13 (10/76)	0.002a
Laboratory findings
Anemia	61 (44/72)	68 (27/40)	53 (17/32)	0.213
Hypoalbuminemia	89 (51/57)	89 (32/36)	90 (19/21)	1.000
Elevated CRP	87 (34/39)	87 (20/23)	88 (14/16)	1.000
Pathological features
CD2+	74 (20/27)	86 (12/14)	58 (7/12)	0.190
CD3+	99 (136/138)	98 (61/62)	99 (73/74)	1.000
CD4-	81 (88/109)	84 (41/49)	78 (46/59)	0.456
CD5-	86 (83/96)	92 (35/38)	82 (47/57)	0.232
CD7+	100 (58/58)	100 (32/32)	100 (25/25)	1.000
CD8+	90 (121/135)	88 (57/65)	91 (62/68)	0.513
CD56+	95 (129/136)	94 (60/64)	97 (68/70)	0.425
CD20+	13 (12/93)	20 (7/35)	9 (5/56)	0.129
TIA-1+	93 (65/70)	80 (20/25)	100 (43/43)	0.005a
Granzyme B+	68 (40/59)	50 (11/22)	81 (29/36)	0.015a

^aP < 0.05.

CRP: C-reactive protein; TIA-1: T-cell intracellular antigen 1.

DISCUSSION

Clinical features of MEITL

In this study, the data from 26 MEITL patients diagnosed at PUMCH were integrated with the data from 130 globally reported cases to systematically analyze and summarize the clinical, pathological, and endoscopic features of the disease. MEITL patients commonly present with weight loss, abdominal pain, and diarrhea, although some cases present acutely with perforation or obstruction, indicating heterogeneity in clinical phenotypes. Endoscopic features in the PUMCH cohort were dominated by mucosal edema, roughness, and villous blunting, whereas ulcers were more frequently observed in the literature cohort, suggesting differences across populations or timing of diagnosis. The pathological diagnosis relied on the histological hallmark of diffuse infiltration by monomorphic small-to-medium lymphocytes with epitheliotropism and a typical immunophenotype (CD3+, CD8+, CD56+, and EBER-), although some patients exhibited histological and immunological heterogeneity.

Notably, all 8 MEITL patients tested for β2-MG in this study had elevated serum levels. However, owing to the limited number of tested cases and the absence of published literature on the association between β2-MG and MEITL, the clinical significance of this finding requires further validation. Previous studies have confirmed that the serum β2-MG level can serve as an independent prognostic factor in peripheral T-cell lymphoma, not otherwise specified, with elevated levels indicating poorer outcomes[14]. Moreover, simultaneously increased serum levels of β2-MG, LDH, and CRP have been identified as an independent risk factor for disease progression and survival in patients with diffuse large B-cell lymphoma[15]. These findings suggest that β2-MG, in combination with other clinical or molecular markers (such as LDH, CRP, tumor protein 53 mutations and MYC abnormalities), could be incorporated into a diagnostic or prognostic evaluation model applicable to MEITL. However, this hypothesis remains to be validated through large-sample studies.

Familiarity with the endoscopic features of MEITL can facilitate more efficient and accurate disease diagnosis

Endoscopic manifestations of MEITL exhibit notable population heterogeneity and disease-stage associations. In the PUMCH cohort, patients predominantly showed mucosal edema, roughness, a granular surface, and villous blunting, while the incidence of ulceration was significantly lower than that reported in the literature (30% vs 66%). These findings are consistent with those of Ishibashi et al[16], who reported that diffuse mucosal edema and granular changes, with or without villous atrophy, serve as important early endoscopic clues for MEITL[16], whereas ulcers typically appear during disease progression. Further analysis of the literature cohort revealed that non-Asian patients had a higher incidence of intestinal obstruction prior to diagnosis (P = 0.047). In line with the study by Veloza et al[17], these findings suggest that Western patients may develop acute and severe symptoms because of rapid disease progression.

In terms of diagnostic efficiency, the endoscopic diagnostic rate of MEITL in the PUMCH cohort was only 50.0%, primarily because of the lack of specific endoscopic features. In addition to common findings such as mucosal edema and villous blunting, some patients exhibit a “mosaic pattern”, which can easily be confused with inflammatory bowel disease or malabsorption syndromes[5,18]. This underscores the need for clinicians to maintain a high index of suspicion for these nonspecific endoscopic changes. Early recognition may allow for a definitive diagnosis and treatment before perforation or obstruction occurs, thereby improving therapeutic opportunities and the prognosis. Further analysis of the literature cohort revealed that patients with small intestinal involvement had a significantly lower endoscopic diagnostic rate than those with upper or lower gastrointestinal involvement and were more likely to have deeper mucosal infiltration. Considering the complex anatomy of the small intestine and the hidden nature of deep lesions, for suspected cases, clinicians should adopt a pathological strategy of "multiple-site and deep-tissue sampling", combined with imaging modalities such as double-balloon enteroscopy and contrast-enhanced abdominal CT, to improve diagnostic sensitivity and avoid delays caused by relying on a single examination[19].

In summary, in clinical practice, the presence of nonspecific endoscopic findings such as mucosal edema, rough or granular mucosa, and villous blunting in the small intestine should raise suspicion for MEITL. Multiple-site, multisample biopsy, supplemented when necessary with enteroscopy and imaging studies (such as CT, positron emission tomography-CT, etc.), is recommended to improve the diagnostic yield[20]. Failure to identify and diagnose the disease early often allows progression to deep ulceration, ultimately resulting in severe complications such as perforation or bleeding, which significantly increase the treatment difficulty and mortality risk.

Pathological features of MEITL are closely associated with disease behavior

Histopathological examination is the gold standard for diagnosing MEITL. Tumor tissue is generally divided into three regions: The central tumor area, the peripheral zone, and the IEL proliferation area. The central tumor area is characterized by diffuse infiltration of monomorphic small-to-medium lymphocytes; the peripheral zone shows tumor cells extending laterally along the mucosa, and the IEL proliferation area contains small lymphocytes or morphologically near-normal lymphocytes, resembling an inflammatory response, which can easily lead to misdiagnosis[21,22]. Therefore, in clinical pathology practice, multiple biopsies from different sites should be obtained to improve diagnostic accuracy. Notably, some MEITL cases may exhibit atypical pathological features, including nonmonomorphic cells, necrosis, angiocentric infiltration, or a “starry-sky” pattern. Previous studies have suggested that MYC overexpression and tumor protein 53 mutation may be closely associated with these atypical morphological characteristics[23].

The typical immunophenotype of MEITL is CD3+ CD8+ CD56+ EBER-, although approximately 13% (12/93) of patients in this cohort exhibited CD20 positivity. Previous studies have suggested that aberrant expression of B-cell–related markers may be associated with better survival outcomes[17]; however, owing to incomplete prognostic follow-up in this cohort, this observation could not be further validated. CD4 positivity was significantly associated with the absence of endoscopic ulcers, but its clinical significance in MEITL remains unclear. Case reports have indicated that small intestinal CD4+ T-cell lymphomas may represent a subtype with indolent clinical behavior, although this has not been confirmed in large-scale, multicenter studies[24,25]. In MEITL research, CD4+ cases are rare and have not been sufficiently studied. Therefore, recognizing this uncommon variant and excluding other CD4+ T-cell lymphoma subtypes is critical for accurate MEITL diagnosis[26]. These pathological features not only expand the understanding of the biological behavior of MEITL but also provide potential reference markers for precise clinical diagnosis, differential diagnosis, and prognostic stratification.

Whether surgery was performed prior to diagnosis reflects clinical heterogeneity

This study proposed a clinical classification of MEITL patients into two groups on the basis of whether surgical intervention occurred prior to diagnosis: The “acute aggressive type” (surgical group) and the “chronic consumptive type” (nonsurgical group). Although no statistically significant difference in median overall survival was observed between the two subgroups, this classification has important clinical and biological relevance because it accurately delineates two distinct modes of clinical presentation in MEITL, which may reflect inherent heterogeneity in tumor biology.

The acute aggressive type typically manifests as acute abdominal emergencies such as intestinal perforation or obstruction. The expression of cytotoxic proteins such as TIA-1 and granzyme B is high in tumor cells of this subtype, suggesting stronger local tissue invasiveness and destructive potential. In contrast, the chronic consumptive type is characterized by prolonged nonspecific diarrhea and weight loss. Given its indolent and protracted course, this chronic form is particularly susceptible to diagnostic delay. This classification system provides clear warning signs and differential diagnostic clues for clinicians across different specialties (e.g., emergency medicine and gastroenterology), thereby potentially improving early recognition.

Thus, clinical subtyping based on a prediagnostic surgical history is valuable primarily for guiding differentiated clinical management pathways rather than for prognostic stratification. For patients with the chronic consumptive subtype, if unexplained chronic diarrhea is present, MEITL should be considered in the differential diagnosis, and more proactive endoscopic evaluation with deep tissue biopsy should be advocated to reduce diagnostic delay, thereby improving survival outcomes. For those with the acute aggressive subtype, a multidisciplinary approach should be established to ensure seamless integration of emergency surgery and postoperative systemic therapy. Future studies should further integrate molecular and genetic profiles within this clinical framework to elucidate the core mechanisms driving the distinct clinical phenotypes, ultimately paving the way for more targeted and individualized treatment strategies.

Strengths and limitations of this study

The main strengths of this study are as follows. First, it serves as a large-scale retrospective cohort of MEITL patients, providing a comprehensive overview of patients’ clinical, imaging, endoscopic, and pathological features. By integrating data from 130 cases reported in the literature, this study offers a broad perspective on the heterogeneity of this disease. Second, by combining clinical, endoscopic, and pathological characteristics, this study highlights nonspecific endoscopic features such as mucosal edema and villous shortening, which, when interpreted alongside typical immunophenotypes, may improve early recognition and diagnosis of MEITL, potentially enhancing patient outcomes. Finally, on the basis of stratification according to whether surgery was performed prior to diagnosis, this study identified two distinct clinical subtypes of MEITL: The acute highly aggressive form and the chronic cachectic form. This classification has potential utility for early diagnosis and the development of personalized clinical management pathways in MEITL.

However, several limitations should be noted. First, the study is a single-center, retrospective analysis with a relatively small sample size, and incomplete follow-up and laboratory data may limit the representativeness of the findings. Second, the literature cohort may be affected by publication bias and incomplete data, restricting comparability and homogeneity. Third, this study lacks molecular-level analyses, making it difficult to fully elucidate disease mechanisms. Future studies should aim for multicenter collaboration to increase the sample size, enhance case registration and follow-up, and integrate molecular pathology with prospective research to reduce biases and strengthen the reliability of the findings.

CONCLUSION

This study focuses on enhancing the early diagnosis rate of MEITL, a disease characterized by highly heterogeneous clinical phenotypes ranging from highly aggressive to chronic cachectic presentations. Imaging and endoscopic evaluations play crucial roles in early detection, while histopathological features are closely associated with the underlying biological behavior of the disease. Early recognition and accurate diagnosis are essential for improving patient outcomes, and further exploration of the underlying molecular mechanisms may provide novel avenues for targeted therapies and individualized management strategies.

ACKNOWLEDGEMENTS

We sincerely thank the medical staff from the Departments of Gastroenterology, Hematology, and Pathology at Peking Union Medical College Hospital for their valuable support in patient data collection, specimen processing, and endoscopic imaging analysis. We also appreciate the contributions of all study participants and their families for their trust and cooperation throughout the research. Additionally, we would like to acknowledge the colleagues who provided critical comments and suggestions during the manuscript preparation, which greatly improved the quality of this work.