Acute abdominal perforation as a clinical presentation of coeliac disease.

Intestinal perforation is described in coeliac disease in the setting of refractoriness or Enteropathy-Associated T-cell Lymphoma (EATL). We report the case of a man with untreated coeliac disease who presented intestinal perforation and was diagnosed with EATL over one year later.

Patients with enteropathy-associated T-cell lymphoma in the United States from 2000 to 2018: SEER data-base analysis.

BACKGROUND: Enteropathy-Associated T-Cell Lymphoma (EATL) is a rare lymphoma of T-cell origin associated with celiac disease. There is limited evidence in the literature about the incidence and causes of death in patients with EATL. METHODS: We performed a retrospective study through analyzing the Surveillance, Epidemiology, and End Results (SEER) data base to determine the incidence, trends and causes of death of patients with EATL in the U.S from 2000 to 2018. Baseline characteristics with treatment options (surgery, radiotherapy, and chemotherapy), status of patients either alive, dead due to cancer itself or other non-cancerous causes with listing of those non-cancerous causes was retrieved. Sub-group analysis based on sex was also done. Multiple latency periods (<2 year, 2-5, 6-10, 11-15, and more than 15 years) were analyzed following EATL diagnosis. RESULTS: There were 259 EATL patients, majority were aged 70-74 years old (n = 36, 13.9%), predominantly males 155 (59.8%), most common in whites, (76.4%, n = 198), EATL was the only primary tumor in 177 (68.3%) cases, most common site was small bowel at different sites 84 (32.4%) followed by jejunum specifically 57 (22%), majority went for surgical resection (69.9%, n = 181) followed by chemotherapy (47.5%, n = 123), 217 (83.7%) died during follow-up in this study, CONCLUSION: EATL is a rare entity, mostly seen in males, between 70 and 74 years, and mostly originated in the small bowel. With over 80% death in five-year follow up period, EATL patients showed better survival if they underwent chemotherapy. More studies are needed for further understanding of this rare entity.

[Difficulties in diagnosing intestinal T-cell lymphoma. Case report].

The article describes a rare diagnosis of monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL), due to its veiled by a number of so-called "masks" of enteropathies. A detailed analysis of all clinical, morphological and immunohistochemical data made it possible to establish the correct diagnosis. The revealed pathology is extremely rare in practice, even among specialists in hematology. The article demonstrates the main stages of both a complex diagnosis and an attempt at therapy for this aggressive form of intestinal lymphoma.

PEG-Asparaginase Single-Agent Rescue in an Advanced Case of Monomorphic Epitheliotropic Intestinal T Cell Lymphoma.

PURPOSE: MEITL is a very rare and highly aggressive peripheral T cell lymphoma with poor prognosis and for which there is no standard treatment. Treatment options for patients patients with relapsed/refractory disease are scarce and the choice of an appropriate rescue still represents an unmet need. METHODS: Here, we report the case of a 65-year-old woman affected by MEITL, progressing after initial treatment with an anthracycline-based chemotherapy and surgery, who received single-agent PEG-asparaginase salvage therapy at our institution. RESULTS: PEG-asparaginase single-agent rescue proved to be rapidly effective in controlling the disease and its associated paraneoplastic features. Nevertheless, toxicity was high and the patient died due to a treatment-related complication. CONCLUSION: The case we described brings new evidences on the effectiveness of PEG-asparaginase therapy in MEITL patients. Whether PEG-asparaginase should be included in the treatment course of MEITL patients could be the subject of future studies.

Monomorphic epitheliotropic intestinal T-cell lymphoma comprises morphologic and genomic heterogeneity impacting outcome.

Monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL) is a rare aggressive T-cell lymphoma most reported in Asia. We performed a comprehensive clinical, pathological and genomic study of 71 European MEITL patients (36 males, 35 females, median age 67 years). The majority presented with gastrointestinal involvement and had emergency surgery, and 40% had stage IV disease. The tumors were morphologically classified into two groups: typical (58%) and atypical (i.e., non-monomorphic or with necrosis, angiotropism or starry-sky pattern) (42%), sharing a homogeneous immunophenotypic profile (CD3+ [98%] CD4- [94%] CD5- [97%] CD7+ [97%] CD8+ [90%] CD56+ [86%] CD103+ [80%] cytotoxic marker+ [98%]) with more frequent expression of TCRgd (50%) than TCRab (32%). MYC expression (30% of cases) partly reflecting MYC gene locus alterations, correlated with non-monomorphic cytology. Almost all cases (97%) harbored deleterious mutation(s) and/or deletion of the SETD2 gene and 90% had defective H3K36 trimethylation. Other frequently mutated genes were STAT5B (57%), JAK3 (50%), TP53 (35%), JAK1 (12.5%), BCOR and ATM (11%). Both TP53 mutations and MYC expression correlated with atypical morphology. The median overall survival (OS) of 63 patients (43/63 only received chemotherapy after initial surgery) was 7.8 months. Multivariate analysis found a strong negative impact on outcome of MYC expression, TP53 mutation, STAT5B mutation and poor performance status while aberrant B-cell marker expression (20% of cases) correlated with better survival. In conclusion, MEITL is an aggressive disease with resistance to conventional therapy, predominantly characterized by driver gene alterations deregulating histone methylation and JAK/STAT signaling and encompasses genetic and morphologic variants associated with very high clinical risk.

[A Case of Monomorphic Epitheliotropic Intestinal T-Cell Lymphoma Causing Perforation of the Small Intestine].

Monomorphic epitheliotropic intestinal T-cell lymphoma(MEITL)is very rare and aggressive subtype of lymphoma with poor prognosis. A 60-year-old man complaining of abdominal pain was underwent partial resection of the jejunum for panperitonitis with a small intestinal perforation. The histopathological and immunohistochemical findings led to the diagnosis of MEITL. Postoperative course was uneventful. One month after the operation, the patient was scheduled for 6 courses of CHOP regimens. He presented with bowel obstruction twice during the 3 courses of CHOP. As the recurrence of MEITL could not be ruled out, diagnostic laparoscopy was performed. Laparoscopic findings revealed no recurrence and adhesive small bowel obstruction. The patient was followed closely without treatment after 6 courses of CHOP. The patient has been alive without recurrence 18 months after the resection. We reported a case of monomorphic epithelial intestinal T- cell lymphoma causing jejunal perforation.

Long term survival of Enteropathy-associated T-cell Lymphoma (EATL) with intracranial metastasis: letter to the Editor.

We read the article by Chuan YY et al (1) with interest when we searched the literature to guide our care for a patient with Enteropathy-associated T-cell Lymphoma (EATL) with intracranial metastasis. Chuan YY et al (1) reported a patient with EATL developed intracranial involvement and died nine months after the initial diagnosis. They also summarized previous studies and found the survival after initial diagnosis was no longer than sixteen months.

Successful early diagnosis of monomorphic epitheliotropic intestinal T-cell lymphoma manifesting as chronic diarrhea and hypokalemia using video capsule endoscopy and double-balloon enteroscopy.

Monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL), formerly known as enteropathy-associated T-cell lymphoma (EATL) type II, is a rare disease with a poor prognosis that is often diagnosed when patients present with intestinal perforation or obstruction. Our patient, a man in his 60 s, had a 5-month history of persistent watery diarrhea. Upper and lower gastrointestinal endoscopy, abdominal computed tomography (CT), and stool culture results were unremarkable. He was admitted to our hospital 8 months later with a weight loss of 20 kg, general fatigue, and hypokalemia. Contrast-enhanced CT of the abdomen revealed mild thickening and contrast enhancement of the small intestinal wall. Video capsule endoscopy and double-balloon enteroscopy were performed to reveal a broad ulcer in the jejunum and multiple erosions throughout the small intestine. Examination of the biopsy specimens showed infiltration of atypical lymphocytes with pale cytoplasm in the glandular epithelium. The atypical lymphocytes were positive for CD3, CD8, CD56, granzyme B, and T-cell intracellular antigen-1 by immunostaining. Early diagnosis of MEITL was made, and the patient survived for 21 months with continuous chemotherapy. Aggressive examination of the small intestine is effective for the early diagnosis of serious diseases, such as MEITL, in patients with chronic diarrhea of unknown origin.

CD30 + Primary intestinal T-cell lymphoma (unclassified) masquerading as chronic inflammation: a case report.

BACKGROUND: Primary intestinal T-cell lymphomas are uncommon malignancies that pose a diagnostic dilemma, because the clinical features and imaging findings commonly overlap with those encountered in inflammatory bowel diseases. CASE PRESENTATION: The current clinical case report describes the clinical history, laboratory findings and histopathological analysis from a patient with non-specific gastrointestinal symptoms with a presumptive clinical diagnosis of inflammatory bowel disease, and two intestinal biopsy specimens with non-specific findings. Due to the persistent symptoms a third biopsy was consistent with primary intestinal T-cell lymphoma, a diagnosis that was elusive for months after the initial presentation. Clinical correlation with laboratory and histopathological findings is required to establish a definitive diagnosis and to further stratify the patients. In addition, the neoplastic cells featured partial expression of CD30, which had relevant therapeutic implications. CONCLUSIONS: Suspicion for an intestinal T-cell lymphoproliferative disorder should always exist in patients with persistent abdominal symptoms with no clear etiology. The current discussion provides a summary and review of the key diagnostic histological features for the classification of primary intestinal T-cell lymphomas. In addition, the discussion describes how specific the histological findings are relevant for the clinical management decisions.

Endoscopic features and clinical outcomes of enteropathy-associated T-cell lymphoma: A tertiary center retrospective study.

METHODS: In this retrospective study, we investigated the endoscopic and clinical features of patients with EATLs at a tertiary center, from January 2008 to October 2020. RESULTS: From a total of 248 patients with primary intestinal lymphoma, only 11 patients were finally diagnosed with EATLs, all of which were EATL type II. Men were affected twice as commonly as women. The median patient age was 47 years. The most common initial symptom was diarrhea (63.6%). Five patients (45.4%) were at late stage (IV) at diagnosis. The endoscopic appearances were classified into four distinct types: ulcerative type (54.5%), epithelial mass type (18.2%), diffuse infiltration type (9.1%), and nodular type (18.2%). The small bowel was the most common site of involvement (72.7%). The initial endoscopic impression of lymphoma was made in only 3 patients (27.3%). Only 4 patients (36.4%) were histologically confirmed as having EATLs based on the initial biopsy specimen. Five patients (45.5%) received emergency surgery. The median overall survival (OS) was 8 months. The use of chemotherapy and the absence of emergency surgery were associated with a significantly better median OS (P < 0.05). CONCLUSIONS: EATL may show various endoscopic appearances, and its prognosis is poor. Endoscopists should obtain more knowledge of EATL in order to make an early diagnosis.

Oncogenetic landscape of lymphomagenesis in coeliac disease.

OBJECTIVE: Enteropathy-associated T-cell lymphoma (EATL) is a rare but severe complication of coeliac disease (CeD), often preceded by low-grade clonal intraepithelial lymphoproliferation, referred to as type II refractory CeD (RCDII). Knowledge on underlying oncogenic mechanisms remains scarce. Here, we analysed and compared the mutational landscape of RCDII and EATL in order to identify genetic drivers of CeD-associated lymphomagenesis. DESIGN: Pure populations of RCDII-cells derived from intestinal biopsies (n=9) or sorted from blood (n=2) were analysed by whole exome sequencing, comparative genomic hybridisation and RNA sequencing. Biopsies from RCDII (n=50), EATL (n=19), type I refractory CeD (n=7) and uncomplicated CeD (n=18) were analysed by targeted next-generation sequencing. Moreover, functional in vitro studies and drug testing were performed in RCDII-derived cell lines. RESULTS: 80% of RCDII and 90% of EATL displayed somatic gain-of-functions mutations in the JAK1-STAT3 pathway, including a remarkable p.G1097 hotspot mutation in the JAK1 kinase domain in approximately 50% of cases. Other recurrent somatic events were deleterious mutations in nuclear factor kappa-light-chain-enhancer of activated B-cells (NF-κB) regulators TNFAIP3 and TNIP3 and potentially oncogenic mutations in TET2, KMT2D and DDX3X. JAK1 inhibitors, and the proteasome inhibitor bortezomib could block survival and proliferation of malignant RCDII-cell lines. CONCLUSION: Mutations activating the JAK1-STAT3 pathway appear to be the main drivers of CeD-associated lymphomagenesis. In concert with mutations in negative regulators of NF-κB, they may favour the clonal emergence of malignant lymphocytes in the cytokine-rich coeliac intestine. The identified mutations are attractive therapeutic targets to treat RCDII and block progression towards EATL.

Immunophenotyping of intraepithelial lymphocytes in canine chronic enteropathy and intestinal T-cell lymphoma using endoscopic samples.

Human enteropathy-associated T-cell lymphoma (EATL) is considered to be derived from intraepithelial lymphocytes (IELs); however, the origin of canine intestinal T-cell lymphoma (ITCL) remains unclear. Histological, immunohistochemical, and clonality examinations were performed using endoscopically collected canine duodenum samples of mucosal lesions of chronic enteropathy (CE; 73 cases) and ITCL without transmural neoplastic mass lesions (64 cases). Histopathological examinations revealed the intraepithelial accumulation of lymphocytes (called "intraepithelial lymphocytosis") in 54/73 CE cases (74%) and the epitheliotropism of neoplastic lymphocytes in 63/64 ITCL cases (98%). Immunohistochemically, IELs in CE with intraepithelial lymphocytosis (IEL+CE) were diffusely immunopositive for CD3, with scattered immunopositivity for CD5, CD8, CD20, and granzyme B (GRB). The percentage of CD8+ in CD3+ IELs was significantly lower in IEL+CE than in CE without intraepithelial lymphocytosis (IEL-CE). Double-labeling immunohistochemistry revealed a high percentage of GRB expression in CD8- IEL among IEL+CE. Among 64 ITCL cases, CD3 was immunopositive in 64 (100%), CD5 in 22 (34%), CD8 in 8 (13%), CD20 in 12 (19%), CD30 in 13 (20%), and GRB in 49 (77%). In CD3+ cells, Ki67 immunopositivity was highest in ITCL, intermediate in IEL+CE, and lower in IEL-CE. A clonal TCR gene rearrangement was detected in 1/19 IEL-CE cases (5%), 15/54 IEL+CE (28%), and 38/58 ITCL (66%). These results indicate that the immunophenotype of canine ITCL (CD8-GRB+) is similar to that of the increased IELs in CE. The high proliferative activity and clonality of T cells in IEL+CE suggest that canine ITCL originates from these IELs, similar to human EATL.

[Patient with Monomorphic Epitheliotropic Intestinal T-Cell Lymphoma with Small Intestinal Perforation Development during Chemotherapy].

Monomorphic epitheliotropic intestinal T-cell lymphoma(MEITL)is classified under type Ⅱ enteropathy-associated T-cell lymphoma(EATL). It is a rare disease with a low incidence rate. This study reports a case of a patient with MEITL who developed small intestinal perforation during chemotherapy. The patient was a 55-year-old woman who presented to a previous clinic with epigastric pain. Enteroscopy results showed a map-like ulcer in the jejunum. Examination of the tissue specimen collected from this site suggested T-cell lymphoma. The patient was referred to our hospital for chemotherapy. Seven days following the initiation of chemotherapy, an abdominal computed tomography(CT)revealed free air, leading to a diagnosis of gastrointestinal perforation. Emergency surgery was performed. Intraoperatively, bowel perforation and a degenerative ulcer were observed at 95 cm and 80 to 115 cm from the Treitz' ligament, respectively. In addition, all-layer intestinal necrosis was noted 150 and 90 cm from the terminal ileum. Total resection and anastomosis were performed. Postoperatively, the patient developed sepsis due to chemotherapy-related pancytopenia but recovered. She was discharged on postoperative day 24. Subsequently, positron emission tomography(PET)-CT revealed residual intestinal tumor cells and peritoneal dissemination. Chemotherapy was initiated, but there was no response. The patient died after 6.5 months. A radical treatment for MEITL has not yet been established. More case reports are needed to improve the prognosis of this disease.

Lymphomatous effusion of monomorphic epitheliotropic intestinal T-cell lymphoma is characterized by azurophilic granules and is a dismal sign: Report of two new cases with literature review.

Lymphoma involving serous effusion is uncommon. The diagnosis of effusion lymphoma may be challenging, particularly when the lymphoid cells are small to medium-sized, which would be difficult for differentiating reactive effusions from low grade lymphomas. Monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL) is an uncommon type of aggressive intestinal T cell lymphoma with a median survival of 7 months. MEITL rarely disseminates to the body cavities. To date, there are only three reported cases of MEITL with malignant effusion. Here we report two additional cases of MEITL with lymphoma cells involving the pleural effusion and the ascites, respectively. Review of the three literature cases and our two new cases of MEITL with malignant effusion, cytoplasmic azurophilic granules were identified in both the two cases with Liu stain. The median survival time was 1.5 months after the occurrence of malignant effusion, even shorter than the median survival in patients with MEITL. Although the case number is small, malignant effusion seems to be a poor prognostic factor of MEITL.

Monomorphic Epitheliotropic Intestinal T-Cell Lymphoma With Secondary Cutaneous Involvement: A Diagnostic Challenge.

ABSTRACT: A 45-year-old woman presented with a solitary breast nodule that histologically corresponded to a dense dermal/subcutaneous infiltration of atypical cytotoxic T-lymphocytes (CD3+, CD8+, CD56+, TIA-1+, CD5-, CD4-, CD30-, EBV-), resembling subcutaneous panniculitic T-cell lymphoma. The presence of TCRδ gene rearrangement and the absence of ßF1 expression let to suspect the diagnosis of primary cutaneous γδT-cell lymphoma. As a consequence of jejunum perforation following chemotherapy treatment, a mucosal atypical lymphoid infiltration with marked epitheliotropism was observed in the resected intestinal sample, and the diagnosis of monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL) was finally established. Disease progression appeared with multiple erythematous plaques showing a dense lichenoid atypical cytotoxic T-cell infiltrate with intense epidermotropism, mimicking primary cutaneous epidermotropic aggressive CD8+ T-cell lymphoma. MEITL is an uncommon and aggressive peripheral T-cell lymphoma that often presents in adults with gastrointestinal symptoms. Secondary cutaneous involvement is a rare phenomenon that may show clinicopathologic and immunohistochemical features that overlap with different subtypes of primary cutaneous cytotoxic T-cell lymphomas. In the absence of gastrointestinal symptoms, the diagnosis may be challenging, and only the evidence of underlying MEITL may allow to establish the definite diagnosis.

Monomorphic Epitheliotropic Intestinal T-cell Lymphoma: A Study of Four Cases and Review of Literature.

Monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL) is a rare primary and highly aggressive intestinal T-cell lymphoma derived from intraepithelial lymphocytes. MEITL is previously designated as type II enteropathy-associated T cell lymphoma (EATL). Unlike to classic form of EATL, MEITL is not associated with celiac disease. The diagnosis of MEITL is very challenging and the clinical outcome of patients with MEITL is very poor. Herein we describe a series of four patients diagnosed with MEITL identified upon a 10-year institutional retrospective review. Histopathologic examination of these cases revealed monotonous population of medium sized cells infiltrating intestinal mucosa, positive for CD3, CD8 and CD56 in all four cases. Two patients had the combination chemotherapy; however, the average survival time was only 7.5 months for these two patients after diagnosis. The aim of the present case series is to highlight the pathology, diagnosis and clinical course of the patients with MEITL based on the current literature.

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.