Monomorphic epitheliotropic intestinal T-cell lymphoma: report of four cases and literature review

Abstract

Monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL), also known as type II enteropathy-associated T-cell lymphoma, is a rare malignant lymphoma of the extranodal lymphoid tissue derived from interepithelial T lymphocytes. MEITL is a primary intestinal T-cell lymphoma with a challenging diagnosis and aggressive progression, and it can invade other extraintestinal sites. In this study, we report four patients diagnosed with MEITL. All patients presented with abdominal pain, and one patient was admitted because of acute intestinal perforation. Two patients presented with unformed defecation and diarrhea. All patients carried the immunophenotypes CD3, CD7, CD8, CD20, and CD56, and the Ki-67 index ranged 60% to 90%. Three cases were analyzed using next-generation sequencing. One case displayed possibly relevant alterations of CREBBP, NOTCH2, SETD2, and STAT5B, and another case exhibited definite alteration of NOTCH1, possibly relevant alterations of CCND1 and DNMT3A, and potentially relevant alterations of HISTH3B, IGLL5, KMT2C, and KRAS. Different chemotherapy regimens were used, but the prognosis was poor. Hence, we illustrated that because of its low incidence, challenging diagnosis, and difficult treatment, further therapeutic improvements are urgently warranted.

Introduction

Enteropathy-associated T-cell lymphoma (EATL) is a rare primary intestinal T-cell lymphoma that was originally categorized into two subtypes. However, following the 2016 revision of the World Health Organization classification of lymphoid neoplasms, ¹ these two subtypes have been considered distinct entities. Type I EATL, previously termed classic EATL, is known simply as EATL. It exhibits a strong association with celiac disease, and it is mainly found in Western countries, especially northern Europe. Type II EATL, now renamed as monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL), is less frequently associated with celiac disease, and it appears more commonly in Asian countries. It is a rare malignant lymphoma of the extranodal lymphoid tissue that arises from interepithelial T lymphocytes. It carries a challenging diagnosis and poor prognosis, and it is typified by aggressive progression and the invasion of other organs. MEITL is characterized by small-to-medium-sized, usually monomorphic T-cells that express CD3, CD8, CD56, megakaryocyte-associated tyrosine kinase, and TIA-1. In addition, immunohistochemical expression of spleen tyrosine kinase (SYK) was identified as a distinctive feature of MEITL (95%) compared with EATL (0%). ²

In addition, SETD2 was found to be the most frequently silenced gene in EATL, and the loss of SETD2 plays an important role in the oncogenesis of EATL and T-cell development. ³ Roberti et al. further reported the unique genetic profile of MEITL, which was characterized by highly recurrent loss-of-function SETD2 alterations and mutations affecting the JAK/STAT and MAPK pathways. The JAK/STAT pathway mutations include recurrent STAT5B (60%), JAK3 (46%), and SH2B3 (20%) mutations, including the STAT5B V712E activating variant. ⁴

In this study, we report four patients diagnosed with MEITL, including their clinical characteristics (Table 1) and immunohistochemistry results (Table 2).

Table 1.

Primary tumor site, extra-gastrointestinal site, clinical presentation, and treatment in four cases.

Case/No.	Age/sex	Primary tumor site	Extra-gastrointestinal site	Clinical presentation	Treatment
1	74/F	Small intestine	–	Abdominal pain, increased defecation, small intestinal perforation	Two cycles of CHOP, chidamide
2	54/M	Gastric body	Lungs	Abdominal pain, shortness of breath, discontinuously coughing	Three cycles of CHOP, one cycle of EPOCH, chidamide
3	56/M	Colon	Adrenal gland	Upper abdominal pain, deformed defecation	One cycle of CHOP, PBSCH (failed), one cycle of IVE, one cycle of E-POCH + P
4	65/M	Small intestine	Central nervous system	Abdominal pain, small intestinal perforation	Seven cycles of CHOP, chidamide

CHOP, cyclophosphamide, liposome doxorubicin, vincristine, and prednisone; EPOCH, etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin; PBSCH, peripheral blood stem cell harvesting; IVE, ifosfamide, etoposide, and epirubicin; E-POCH+P, etoposide, vindesine, pirarubicin, cyclophosphamide, pegaspargase, and dexamethasone.

Table 2.

Immunohistochemical staining pattern of the lymphoma cells in MEITL.

Case/No.	1	2		3	4
		Stomach	Lungs
CD2		−			+
CD3	+	+	+	++	+
CD4	+	+		−	+
CD5				−	+
CD7	+	+			+
CD8	+	+		+	+
CD20	+	−	+	++	+
CD38				−	+
CD56	+	+		+	+
CD68			+
CD79a					+
CD99				+
Ki-67	80%+	90%+	80%+	85%+	60%+
CK	−	+	−	−	+
TIF-1			+
Vimentin			+
Bcl-2				+	+
Granzyme B					+
c-MYC				60%+
TLA-1		+
Perforin					+
MPO					+

CK, creatine kinase; MPO, myeloperoxidase.

Case report

This project was approved by the Ethics Committee of the First Hospital of China Medical University (approval number: [2023]562; approval date: 1 November 2023). Patients provided consent for treatment, and all patient details have been de-identified. The reporting of this study conforms to the CARE guidelines. ⁵ Patients (or their families) have provided written or verbal informed consent or verbal informed consent.

Case 1

In October 2019, a woman in her early 70s presented with persistent abdominal pain without obvious causes that had lasted for 20 days. During this period, she occasionally experienced diarrhea with non-forming feces four times a day. These symptoms worsened over 10 days, and the patient lost 5 kg in weight. After admission, further examinations were performed. Routine blood examination revealed a white blood cell count of 9.54 × 10⁹/L, hemoglobin level of 100 g/L, and platelet count of 309 × 10⁹/L. Her lactate dehydrogenase (LDH) and β2-microglobulin levels were 163 U/L and 2.31 mg/L, respectively. Abdominal computed tomography (CT) revealed segmental thickening of the small intestine in the pelvic cavity, with slightly increased density of the surrounding fat space and multiple enlarged lymph nodes. Furthermore, pelvic enhanced magnetic resonance imaging (MRI) disclosed localized thickening of the intestinal wall of the small intestine in the pelvis, and lymphoma was highly suspected. The patient underwent abdominal lymph node puncture in November 2019. Hyperplasia of lymphoid tissue was observed microscopically. No abnormal monoclonal plasma cells were found by bone marrow aspirate immunotyping. Positron emission tomography (PET)-CT revealed high 18F-fluorodeoxyglucose (FDG) accumulation in the partially thickened wall of the intestinal canal in the abdominal cavity (Figure 1(a)) and nodular shadows near the lesions and in the left lower abdomen, suggestive of invasion by the malignant lesion. She underwent exploratory laparotomy under general anesthesia to remove the small intestinal mass with perforation. The immunohistochemistry results (Table 2) were consistent with the diagnosis of MEITL (Lugano stage IB). The prognostic index for T-cell lymphoma (PIT) score of this patient was 1 point. In addition, no clinically significant genetic mutations were identified by further lymphoma polygenic mutation detection.

Figure 1.

Physical and imaging examination of patients’ lesions. (a) PET-CT revealed high FDG accumulation [SUVmax = 15.8] in the partial thickening wall of the intestinal canal in the abdominal cavity. (b) A 3.0- × 2.5-cm² shallow uplifted lesion is visible on the larger curved side of the gastric body with a slight depression and hyperemia in the central part. Peripheral banded ulcers and filthy moss are present around the depression. (c) Localized glandular hyperplasia of the duodenum. (d) PET-CT revealed diffuse and uneven high FDG accumulation in the colon and rectum (SUVmax = 11.4, SUVmax = 11.8 after delayed imaging). (e) PET revealed multiple patchy and nodular mixed density shadows in both lungs with high FDG accumulation (SUVmax = 9.3). (f) Characteristic hematoxylin and eosin staining of pulmonary monotonous lymphocytes. (g, h) On immunohistochemistry, the gastric body was positive for CD3 and CD8 and (i) PET-CT indicated that the intestinal wall in the right abdominal cavity and descending colon were thickened with high FDG accumulation, and these findings considered to indicate malignant lesions. PET-CT, positron emission tomography-computed tomography; FDG, 18F-fluorodeoxyglucose; SUVmax, maximum standardized uptake value.

The patient received two cycles of cyclophosphamide, liposome doxorubicin, vincristine, and prednisone (CHOP) and 30 mg of chidamide twice a week after discharge. After the second CHOP cycle, the patient experienced abdominal pain, fever, and intestinal perforation. Unfortunately, the patient recovered poorly after surgery and abandoned treatment in March 2020.

Case 2

In January 2021, a man in his early 50s presented with a 4-month history of abdominal pain that was aggravated by eating cold food. However, the patient had no symptoms of diarrhea. From onset, the patient lost 10 kg in weight. The patient visited a local hospital and underwent various examinations. At that time, gastroduodenoscopy revealed superficial gastritis and a descending duodenal mass. In addition, multiple ulcerations of the small intestinal mucosa were observed on capsule endoscopy. Therefore, the patient was administered supportive treatment in December 2020. After 1 month, the patient developed shortness of breath and discontinuous coughing. Pulmonary CT revealed interstitial inflammation.

As his abdominal and respiratory symptoms worsened, he was admitted to our hospital, and further examinations were performed. Routine blood examination revealed a white blood cell count of 6.15 × 10⁹/L, hemoglobin level of 131 g/L, and platelet count of 378 × 10⁹/L. His LDH and β2-microglobulin levels were 168 U/L and 2.79 mg/L, respectively. No abnormalities were found during routine blood or physical examination. Gastroduodenoscopy and colonoscopy revealed ulcerations in the gastric body (Figure 1(b)) and ascending colon, as well as glandular hyperplasia of the duodenum (Figure 1(c)). Small intestinal three-dimensional (3D)-CT revealed segmental wall thickening of the left lower quadrant jejunum, slightly thicker duodenal wall, and slightly enlarged mesenteric lymph nodes. Superficial lymph node ultrasonography revealed thickening of the lymph node cortex of the right supraclavicular fossa with uneven hypoechoic flow. PET-CT confirmed gastrointestinal (Figure 1(d)) and pulmonary abnormalities (Figure 1(e)). Subsequently, biopsy of the lesions was performed in February 2021. Hematoxylin and eosin staining and immunostaining (Table 2) indicated T-cell lymphoma in the gastric body and pulmonary system, consistent with EATL involving pulmonary tissue (Figure 1(f–h)). The patient then underwent bone marrow puncture. Immunophenotyping revealed no abnormalities, and the lymphoma clonal gene rearrangement test was negative. However, mutations in STAT5B, SETD2, and JAK3 were detected using next-generation sequencing. In summary, the main diagnosis MEITL (Lugano stage IVB) with pulmonary metastasis. The patient’s PIT score was 0 points.

The patient received two cycles of CHOP and one cycle of etoposide, prednisone, vincristine, cyclophosphamide, and liposomal doxorubicin, and the dose was slightly adjusted according to the patient’s tolerance. At the same time, chidamide (30 mg twice a week) was administered orally. However, after three courses of chemotherapy, the patient developed intractable diarrhea and received long-term symptomatic treatment without achieving a better curative effect. We did not use methotrexate because of its mucosal damage side effects, such as mucosal damage. Afterward, the patient subsequently completed another cycle of CHOP therapy. Unfortunately, the patient experienced multiple-organ failure and suddenly died in July 2021.

Case 3

In September 2019, a man in his early 50s complained of right upper abdominal pain for 2 months and deformed defecation for 1 month. After admission, the routine blood test results included a white blood cell count of 8.21 × 10⁹/L, hemoglobin level of 142 g/L, and platelet count of 408 × 10⁹/L. The patient’s LDH, serum albumin, and C-reactive protein levels were 234 U/L, 37.4 g/L, and 22 mg/L, respectively. Full abdominal enhanced 3D-CT revealed occupying lesions in the descending colon and small intestine in the right lower abdomen, highly suggestive of malignant lesions and occupying lesions in the right adrenal space, and the possibility of metastasis could not be excluded. PET-CT indicated thickening of the intestinal wall in the right abdominal cavity and descending colon with high FDG accumulation, indicating a malignant lesion (Figure 1(i)). In addition, enlarged lymph node shadows next to the intestinal tube, multiple lymph node shadows in the retroperitoneum, nodules in the pelvis, a soft tissue mass shadow of the right adrenal gland, and the full left adrenal gland all exhibited increased metabolism, and these lesions were considered metastases of malignant tumors. Color Doppler ultrasonography of the left and right lower quadrants illustrated that the colonic hepatic flexure, splenic flexure, partial intestinal wall thickening of the jejunum, and enlargement of the right lower quadrant mesenteric lymph node were all lymphomas. The patient underwent lymph node aspiration in September 2019. The pathological results indicated that the structure of the lymph node was destroyed, and atypical cells were diffusely distributed with large, hyperchromatic, and markedly heteromorphic nucleoli, in which vacuoles were visible and pathological mitoses were easily visible. The bone puncture results suggested no bone marrow involvement. In summary, this patient was highly suspected to have MEITL IVB with a PIT score of 0 points based on immunohistochemistry (Table 2). Several mutant genes were discovered by genetic sequencing, including NOTCH1, CCND1, DNMT3A, HISTH3B, IGLL5, KMT2C, and KRAS, the first of which was a disease-associated mutation.

In terms of treatment, the patients first received one cycle of CHOP chemotherapy. Full abdominal CT 1 month later revealed space-occupying lesions in the right lower abdomen and enlargement of multiple surrounding lymph nodes, which were consistent with lymphoma, as well as thickening of the omentum and peritoneum and nodules of the serous membrane of the descending colon, which were considered metastatic disease. The space-occupying lesion in the right adrenal gland was enlarged compared with that in the initial assessment, and the left adrenal gland was also enlarged. Hence, we chose ifosfamide, etoposide, and epirubicin for second-line chemotherapy. In addition, we attempted autologous peripheral blood stem cell harvesting (PBSCH). However, owing to the patient’s acute cardiac insufficiency and low number of CD34⁺ cells, PBSCH was unsuccessful. Complete abdominal CT after second-line chemotherapy indicated that the lesions of the small intestine in the right lower abdomen and the thickening of the omentum were significantly reduced compared with the previous findings, and the space-occupying lesions of the right adrenal gland were also reduced compared with the initial findings. Full abdominal CT 2 days before the third cycle of chemotherapy revealed an increase in the size of bilateral adrenal space-occupying lesions. Considering that the intestinal lesions had shrank, the adrenal lesions did not change significantly, the patient was in poor physical condition, and mobilization of autologous peripheral blood hematopoietic stem cells failed, high-dose chemotherapy was inappropriate for the third time. The patient received chidamide (30 mg twice a week) combined with etoposide, vindesine, pirarubicin, cyclophosphamide, pegaspargase, and dexamethasone chemotherapy. One week later, the patient developed septic shock owing to severe myelosuppression. Blood cultures suggested infection by Candida tropicalis. His vital signs remained unstable after active treatment. Finally, the patient discontinued the treatment, and he was discharged in January 2020.

Case 4

A man in his early 60s was admitted to the emergency department of our hospital with digestive tract perforation and severe abdominal pain in April 2019. Routine blood examination revealed a white blood cell count of 8.82 × 10⁹/L, hemoglobin level of 163 g/L, and platelet count of 314 × 10⁹/L. Abdominal CT revealed abnormal small intestinal blood flow in the middle and lower abdomen, which was accompanied by perforation and peritonitis changes, and small intestine-occupying lesions in the left lower abdomen, which were suspected to be mesenchymomas. The patient was diagnosed with acute diffuse peritonitis, and he underwent partial resection of the small intestine. Histopathological examination revealed diffuse patchy and irregular small lymphocytes with hyperchromatic nuclei and obvious atypia, which, combined with the immunohistochemical profile (Table 2), were consistent with a diagnosis of MEITL. The patient underwent a more comprehensive examination. His LDH and β2-microglobulin levels were 194 U/L and 2.14 mg/L, respectively. Bone marrow immunohistochemistry detected no abnormal monoclonal plasma cells or phenotypes. Through gene sequencing, CREBBP, NOTCH2, SETD2, and STAT5B mutations were found to be potentially associated with the disease. This patient’s PIT score was 1 point.

The patient was scheduled for seven cycles of CHOP, and he received 30 mg of chidamide twice a week after discharge. PET-CT after three cycles revealed an increase in the shadow of the anterior abdomen and increased metabolism, mostly considered postoperative changes. After six cycles of CHOP, repeat PET-CT revealed no new malignancy, indicating that the patient’s condition was under certain control and clinically stable. However, a month after the seventh cycle, the patient developed symptoms such as headache, nausea, and vomiting, which was considered to indicate central recurrence. The disease progressed rapidly, and the patient eventually died in February 2020.

Discussion

Owing to the lack of characteristic clinical manifestations, MEITL is often misdiagnosed as a simple gastrointestinal disease initially or as sudden-onset acute intestinal perforation. More than 50% of cases of MEITL are diagnosed because of intestinal perforation or obstruction, and emergency surgery is required in approximately 40% of cases. ⁶ Three of our patients had abdominal pain, two had symptoms of unformed defecation and diarrhea, and one was admitted because of acute intestinal perforation, consistent with previous cases. MEITL usually affects the small intestine, especially the jejunum, more rarely affecting the stomach, duodenum, appendix, and large intestine. Because of its aggressive nature, MEITL can spread to extra-gastrointestinal sites, including the peripheral lymph nodes, lungs, liver, and central nervous system. Case 2 exhibited lung involvement, Case 3 exhibited adrenal gland involvement, and Case 4 had a late-stage central recurrence. Bone marrow involvement accounts for approximately 5% of cases, ⁷ but it was not observed in our cases.

Currently, MEITL is considered a separate entity from EATL because of new discoveries regarding their molecular pathogeneses and distinct histopathological and immunohistochemical profiles. In MEITL, SETD2, STAT5B, or JAK3 mutations and enrichment of STAT5B and STAT3 have been found, and clonal rearrangement of TCR genes is detected in most cases.^4,7,8 Among these mutations, SETD2 alteration is the most common. Tomita et al. reported that alterations in the tumor suppressor gene SETD2 were caused by mutations and/or loss of the corresponding 3p21 locus. ⁹ Yamagishi et al. found that multiple mutations in the TCR, STAT3, and Notch pathways were related to the accumulation of transcriptome abnormalities in founder clones. In evolutionary clones with different mutation patterns, enhanced proliferative potential is usually detected, indicating that severe hyperproliferation mediated by key factors (such as MYC) is a key step in the latter carcinogenesis process. ¹⁰ In our cohort, no significant gene mutation was found in Case 1, Case 3 displayed definite alteration of NOTCH1, possibly relevant alterations of CCND1 and DNMT3A and potentially relevant alterations of HISTH3B, IGLL5, KMT2C, and KRAS, and Case 4 exhibited possibly relevant alterations of CREBBP, NOTCH2, SETD2, and STAT5B. Sanchez-Martin et al. indicated that the oncogenic activity of NOTCH1 in T-ALL was strictly dependent on MYC upregulation, making the NOTCH1–MYC regulatory circuit an emerging attractive therapeutic target for T-ALL. ¹¹ This finding also has certain guiding significance for the treatment of cases such as Case 3. In CHOP-resistant DLBCL, mutations in NOTCH2 cause proteins to escape the ubiquitin-dependent proteolytic machinery, leading to protein stabilization and activation of the oncogenic RAS signaling pathway. These findings establish the rationale for therapeutic strategies aimed at targeting the oncogenic pathway activated in NOTCH2-mutated DLBCL. ¹² However, the correlation between the NOTCH2 gene and the pathogenesis of MEITL is less clear.

The pathological features of MEITL represent another challenge in diagnosis. The tumor can be divided into three zones: central tumor zone, peripheral zone, and intraepithelial lymphocytosis zone. ¹³ The central tumor zone is characterized by lymphoma cells that are generally medium-sized with inconspicuous nucleoli and a rim of pale or clear cytoplasm. No inflammatory background or marked necrosis is observed. The peripheral zone is characterized by the lateral spread of lymphoma into the mucosa, with less involvement of the submucosa and intestinal wall. ⁷ Meanwhile, the characteristic of the intraepithelial lymphocytosis zone is the infiltration of small or normal lymphocytosis in the epithelium, ¹³ which resembles a normal inflammatory response, leading to misdiagnosis. Therefore, repeated biopsies at various locations are necessary. Immunohistochemical analysis indicated that the tumor cells were always positive for CD3, CD8, and CD56 and negative for EBV, and Ki-67 expression was always high. Most lymphoma cells are CD5-negative and T-cell receptor (TCR)-positive. ¹ Our cases were consistent with previous studies. Mutzbauer et al. reported that SYK, a non-receptor type protein tyrosine kinase that is structurally and functionally related to ZAP-70 and is usually not expressed in mature T-cells under physiological conditions, could serve as a distinctive marker to differentiate MEITL and EATL in the diagnostic setting with high statistical significance owing to the hypomethylation of the SYK promoter in MEITL, abrogating the physiological SYK negativity in tumor cells and methylation in EATL. ²

MEITL is a highly aggressive malignancy associated with overall survival (OS) of only 7 months and progression-free survival (PFS) of 1 month. ¹⁴ A multicenter retrospective analysis of 42 patients with MEITL revealed that young age, good performance status, early Lugano stage, complete response, and the receipt of autologous stem cell transplantation (ASCT) were associated with improved OS. ⁸ According to a previous report, MEITL rarely disseminates to the body cavities. Pan et al. found that azurophilic granules could be identified by Wright–Giemsa staining in tumor cells, and the occurrence of malignant effusion was a poor prognostic sign for MEITL. ¹⁵ Veloza et al. identified TP53 and STAT5B mutations and MYC expression as unfavorable prognostic factors and found that concurrent TP53 and STAT5B mutations have a strikingly negative effect on survival. ¹⁶

Treatment complications in MEITL include small intestinal perforation, obstruction, gastrointestinal bleeding, and infection, causing poor prognosis and high mortality rates. ¹⁷ The previous treatment regimens mainly include anthracycline-based chemotherapy with or without surgical resections, resulting in poor natural course with 5-year PFS of approximately 3.2% and OS of 19.7%. ¹⁸ Given the ineffectiveness of anthracycline-based chemotherapy, high-dose chemotherapy with ASCT has been reported, lead to promising improvements in therapeutic efficacy. ¹⁹ In addition, a study assessed novel approaches in the treatment of EATL. Compared with traditional anthracycline-based chemotherapy, induction therapy with ifosfamide, etoposide, and epirubicin alternating with intermediate-dose methotrexate achieved higher remission rates and lower mortality. ¹⁹ With advances in CAR-T therapy, it is also being used in patients with CD30-positive EATL. ²⁰

Conclusion

We reported four cases of MEITL. To confirm this disease, it is necessary to perform pathological biopsy in the early stage, especially when general treatment does not provide obvious relief and the symptoms of the patient are progressing quickly. Moreover, because of the aggressive nature of the disease, patients might not benefit from conservative chemotherapy. Further exploration of chemotherapy regimens is needed for patients in poor physical condition and those who cannot tolerate high chemotherapy doses. Regarding prognostic stratification and targeted therapy, if we have a better understanding of relevant mutations, comprehensive genomic profiling will provide a wealth of information in the future.