Update on the Pathogenesis of Enteropathy-Associated T-Cell Lymphoma.

EATL is an aggressive T-cell non-Hodgkin lymphoma with poor prognosis and is largely localized to the small intestine. EATL is closely associated with coeliac disease (CD) and is seen mostly in patients originating from Northern Europe. Various factors are associated with an increased risk of developing EATL, such as viral infection, advanced age, being male, and the presence of the HLA-DQ2 haplotype. Clonal rearrangements in the TCR-ß and γ genes have been reported in all EATL morphological variants with distinctive immunophenotypic characteristics. Although EATL can occur de novo, individuals with RCDII are at a higher risk of developing EATL. The cells of origin of EATL has been postulated to be normal small intestinal intraepithelial T-lymphocytes (IELs), and more recent evidence suggests a link between innate precursor IELs and EATL derived from refractory coeliac disease type II (RCDII). The immune microenvironment of mucosal cells within the small intestine enhances the process of neoplastic transformation of IELs into EATL. Cytokines such as IL-15 can activate and crucially deregulate the JAK-STAT signaling pathway by binding to receptors on the surface of IELs. Furthermore, mutations in the JAK/STAT pathway have been associated with RCDII-derived EATL.

SOHO State of the Art Updates and Next Questions | Challenging Cases in Rare T-Cell Lymphomas.

Mature T- and NK-cell neoplasms (MTNKN) collectively represent a rare disorder, representing less than 15% of all non-Hodgkin lymphoma (NHL) cases and qualifying for orphan disease designation by the U.S. Food and Drug Administration (FDA). These consist of 9 families in the fifth revised WHO classification of lymphoid neoplasms, which are made up of over 30 disease subtypes, underscoring the heterogeneity of clinical features, molecular biology, and genetics across this disease group. Moreover, the 5 most common subtypes (peripheral T-cell lymphoma, not otherwise specified; nodal TFH cell lymphoma, angioimmunoblastic type; extranodal NK-cell/T-cell lymphoma; adult T-cell leukemia/lymphoma; and ALK-positive or -negative anaplastic large cell lymphoma) comprise over 75% of MTNKN cases, so other subtypes are exceedingly rare in the context of all NHL diagnoses and consequently often lack consensus on best practices in diagnosis and management. In this review, we discuss the following entities-enteropathy-associated T-cell lymphoma (EATL), monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL), hepatosplenic T-cell lymphoma (HSTCL), subcutaneous panniculitis-like T-cell lymphoma (SPTCL), and primary cutaneous ɣδ T-cell lymphoma (PCGD-TCL) - with an emphasis on clinical and diagnostic features and options for management.

Clinical and Histopathological Features of an Italian Monocentric Series of Primary Small Bowel T-Cell Lymphomas.

The gastrointestinal (GI) tract is the most common extranodal site of occurrence of non-Hodgkin lymphomas. Most GI lymphomas are of B-cell lineage, while T-cell lymphomas are less frequent. The aim of our retrospective study was to depict the clinical-pathological profile of a series of patients affected by intestinal T-cell lymphomas (ITCL) and possibly define hallmarks of these neoplasms. A total of 28 patients were included: 17 enteropathy-associated T-cell lymphomas (EATL), 5 monomorphic epitheliotropic T-cell lymphomas (MEITL), 3 indolent T-cell lymphoproliferative disorders of the gastrointestinal tract (ITCLDGT), and 3 intestinal T-cell lymphomas not otherwise specified (ITCL-NOS). Celiac disease (CD) was diagnosed in around 70% of cases. Diagnosis of EATL showed a significant correlation with CD30 expression, whereas MEITL with angiotropism and CD56 positivity. ITCLDGT cases showed plasma cells infiltration. Peripheral lymphocytosis, the absence of a previous diagnosis of CD, an advanced Lugano clinical stage, and the histological subtype ITCL-NOS were significantly associated with worse survival at multivariate analysis. Our findings about the epidemiological, clinical, and histopathological features of ITCL were in line with the current knowledge. Reliable prognostic tools for these neoplasms are still lacking but according to our results lymphocytosis, diagnosis of CD, Lugano clinical stage, and histological subtype should be considered for patient stratification.

The spectrum of intestinal mature T- and NK-cell neoplasms in a tertiary center in Taiwan with a high frequency of perforation.

Primary intestinal T-cell lymphomas (PITLs) comprise enteropathy-associated T-cell lymphoma (EATL), monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL), extranodal NK/T-cell lymphoma (ENKTL), anaplastic large cell lymphoma (ALCL), and intestinal T cell lymphoma, NOS (ITCL-NOS). MEITL is composed of monomorphic medium cells expressing CD8 and CD56, with a cytotoxic phenotype. We retrospectively analyzed 77 cases of intestinal T-cell lymphomas, 71 primary and six secondary, at a tertiary center in Taiwan from 2001 to 2021. Perforation occurred in 57 (74%) patients, including 56 (73%) at presentation and one after chemotherapy. The primary cases included MEITL (68%), ENKTL (14%), ITCL-NOS (13%), ALCL (4%), and EATL (1%). The perforation rate was 90%, 70%, and 22% in MEITL, ENKTL, and ITCL-NOS cases, respectively (p < 0.0001, Fisher's exact test). Most (75%; n = 36) MEITL cases were typical; while seven (15%) had atypical morphology and five (10%) exhibited atypical immunophenotype. The tumor cells of ITCL-NOS were pleomorphic, with various expression of CD8 or CD56. All METIL, ITCL-NOS and ALCL cases were negative for EBER; while all ENKTL cases, either primary or secondary, were positive for cytotoxic granules and EBER. The prognosis of PITL was poor, with a medium survival of 7.0, 3.3, and 3.7 months among patients with MEITL, ENKTL, and ITCL-NOS, respectively. Of the six secondary cases, the primary tumors orginated from nasal ENKTL (n = 5) and cutaneous PTCL-NOS (n = 1). We showed a wide spectrum of intestinal T-cell lymphomas in Taiwan, with MEITL as the most common PITL, a high rate of perforation, and a wider morphological and immunophenotypic spectrum.

Cellular Origins and Pathogenesis of Gastrointestinal NK- and T-Cell Lymphoproliferative Disorders.

The intestinal immune system, which must ensure appropriate immune responses to both pathogens and commensal microflora, comprises innate lymphoid cells and various T-cell subsets, including intra-epithelial lymphocytes (IELs). An example of innate lymphoid cells is natural killer cells, which may be classified into tissue-resident, CD56bright NK-cells that serve a regulatory function and more mature, circulating CD56dim NK-cells with effector cytolytic properties. CD56bright NK-cells in the gastrointestinal tract give rise to indolent NK-cell enteropathy and lymphomatoid gastropathy, as well as the aggressive extranodal NK/T cell lymphoma, the latter following activation by EBV infection and neoplastic transformation. Conventional CD4+ TCRαß+ and CD8αß+ TCRαß+ T-cells are located in the lamina propria and the intraepithelial compartment of intestinal mucosa as type 'a' IELs. They are the putative cells of origin for CD4+ and CD8+ indolent T-cell lymphoproliferative disorders of the gastrointestinal tract and intestinal T-cell lymphoma, NOS. In addition to such conventional T-cells, there are non-conventional T-cells in the intra-epithelial compartment that express CD8αα and innate lymphoid cells that lack TCRs. The central feature of type 'b' IELs is the expression of CD8αα homodimers, seen in monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL), which primarily arises from both CD8αα+ TCRαß+ and CD8αα+ TCRγδ+ IELs. EATL is the other epitheliotropic T-cell lymphoma in the GI tract, a subset of which arises from the expansion and reprograming of intracytoplasmic CD3+ innate lymphoid cells, driven by IL15 and mutations of the JAK-STAT pathway.

Palliative Radiation Therapy without Chemotherapy for a Patient with Monomorphic Epitheliotropic Intestinal T Cell Lymphoma: A Case Report.

Monomorphic epitheliotropic intestinal T cell lymphoma (MEITL), which used to be known as type 2 enteropathy-associated T cell lymphoma, is a rare lymphoma and is generally treated with chemotherapy. However, the MEITL prognosis is poor, and intestinal lymphoma including MEITL has the risk of bowel perforation not only at presentation but also during chemotherapy. A 67-year-old man was diagnosed with MEITL after presenting in our emergency room with bowel perforation. He and his family did not opt for the administration of anticancer drugs because of the risk of bowel perforation. However, they wanted the patient to receive palliative radiation therapy without chemotherapy. This treatment shrunk the tumor size without causing severe complications or decline in the quality of life, until he accidentally died due to traumatic intracranial hematoma. Considering the potential efficacy and safety of this treatment, it should be studied in more patients with MEITL.

Enteropathy-associated T-cell lymphoma manifesting as non-specific abdominal pain: A case report highlighting the dangers of relying on Google Translate for clinical history taking.

We present the case of a 60-year-old man with non-specific abdominal pain. We explore how communication between doctor and patient was challenged by a language barrier. We also consider how the ability to take an accurate clinical history differed between Google Translate and an accredited medical phone translation service.

Primary Gastrointestinal T-Cell Lymphoma and Indolent Lymphoproliferative Disorders: Practical Diagnostic and Treatment Approaches.

Primary gastrointestinal (GI) T-cell neoplasms are extremely rare heterogeneous disease entities with distinct clinicopathologic features. Given the different prognoses of various disease subtypes, clinicians and pathologists must be aware of the key characteristics of these neoplasms, despite their rarity. The two most common aggressive primary GI T-cell lymphomas are enteropathy-associated T-cell lymphoma and monomorphic epitheliotropic intestinal T-cell lymphoma. In addition, extranodal natural killer (NK)/T-cell lymphoma of the nasal type and anaplastic large cell lymphoma may also occur in the GI tract or involve it secondarily. In the revised 4th World Health Organization classification, indolent T-cell lymphoproliferative disorder of the GI tract has been incorporated as a provisional entity. In this review, we summarize up-to-date clinicopathological features of these disease entities, including the molecular characteristics of primary GI T-cell lymphomas and indolent lymphoproliferative disorders. We focus on the latest treatment approaches, which have not been summarized in existing reviews. Further, we provide a comprehensive review of available literature to address the following questions: How can pathologists discriminate subtypes with different clinical prognoses? How can primary GI neoplasms be distinguished from secondary involvement? How can these neoplasms be distinguished from non-specific inflammatory changes at an early stage?

Enteropathy-Associated T cell Lymphoma.

PURPOSE OF REVIEW: Enteropathy-associated T cell lymphoma (EATL) is a rare subtype of mature T cell lymphoma. The available literature about this rare type T cell lymphoma is relatively limited. This article provides a summary and review of the available literature addressing this entity in terms of risk factors, pathogenesis, diagnostic, and therapeutic options. RECENT FINDINGS: EATL has two distinct subtypes. Type I EATL, now known as EATL, is closely, but not exclusively linked to celiac disease (CD), and it is primarily a disease of Northern European origin. It accounts for < 5% of peripheral T cell lymphoma (PTCL). Risk factors for EATL include advanced age, male sex, and most importantly, genetic susceptibility in the form of HLA-DQ2 homozygosity. The pathogenesis of EATL is closely related to celiac disease as it shares common pathogenic features with refractory celiac disease. The gold standard of diagnosis is histological diagnosis. EATL carries an aggressive course and a poor prognosis. Treatment of EATL includes surgery, induction chemotherapy, and consolidation in first complete remission and autologous stem cell transplant. The role of targeted and biologic therapies in newly diagnosed EATL patients along with relapsed, refractory cases is evolving and discussed in this review. EATL is an aggressive peripheral T cell lymphoma with poor overall treatment outcome using currently available therapy options. Clinical trials are considered the best approach for treatment of EATL. Early diagnosis and early referral to specialized centers would be the best way to deal with such patients. Development of new prognostic models and early surgical intervention are warranted. Prevention is where all the efforts should be spent, by counseling patients with CD regarding the importance of adherence to gluten-free diet and development of periodic surveillance programs in celiac disease patients for early detection of pre-lymphoma lesions.

Diagnostic approach to T- and NK-cell lymphoproliferative disorders in the gastrointestinal tract.

Most gastrointestinal NK and T cell lymphomas are aggressive in behavior, although in recent years a subset of indolent lymphoproliferative disorders have been described, which must be distinguished from their more malignant mimics. Intestinal T-cell lymphomas may arise from intra-epithelial lymphocytes and display epitheliotropism, such as enteropathy-associated T-cell lymphoma and monomorphic epitheliotropic intestinal T-cell lymphoma. They are both aggressive in behavior but differ in their clinic-pathological features. On the other hand, intra-epithelial lymphocytes are not prominent in intestinal T-cell lymphoma, NOS, which is a diagnosis of exclusion and probably represents a heterogeneous group of entities. Indolent lymphoproliferative disorders of NK- and T-cells of both CD8 and CD4 subsets share a chronic, recurring clinical course but display differences from each other. CD8+ T-cell lymphoproliferative disorder of GI tract has a low proliferative fraction and does not progress nor undergo large cell transformation. Whilst NK-cell enteropathy runs an indolent clinical course, it may display a high proliferation fraction. On the other hand, CD4+ indolent T-cell lymphoproliferative disorder displays variable proliferation rates and may progress or transform after a number of years. In Asia and South America, it is not uncommon to see involvement of the gastrointestinal tract by EBV-associated extranodal NK/T cell lymphoma, nasal type, which must be distinguished from NK cell enteropathy and EBV-associated mucocutaneous ulcers.

Small bowel T-cell lymphoma: a MEITL-ing diagnosis.

Monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL), previously known as Type-II enteropathy-associated T-cell lymphoma (EATL), is a rare subset of relatively aggressive lymphoma with a poor prognosis. We present a case of a previously healthy 59-year-old male with a 2-week history of abdominal distention who was found to have a non-bleeding ulcerated segment in the proximal jejunum secondary to MEITL. This exceedingly rare type of lymphoma usually presents with non-specific symptoms and can be challenging to diagnose. Our case demonstrates the importance of understanding the endoscopic and histological findings to allow the prompt diagnosis and treatment of this aggressive disease.

Characterization of the intestinal mucosal proteome in cats with inflammatory bowel disease and alimentary small cell lymphoma.

BACKGROUND: Current tests for diagnosis and differentiation of lymphoplasmacytic enteritis (LPE) and small cell lymphoma (SCL) in cats are expensive, invasive, and lack specificity. The identification of less invasive, more reliable biomarkers would facilitate diagnosis. OBJECTIVES: To characterize the mucosal proteome in endoscopically obtained, small intestinal tissue biopsy specimens. We hypothesized that differentially expressed proteins could be identified and serve as biomarker candidates for the differentiation of LPE and SCL in cats. ANIMALS: Six healthy control cats, 6 cats with LPE, and 8 cats with SCL. METHODS: The mucosal proteome was analyzed using 2-dimensional fluorescence difference gel electrophoresis (2D DIGE) and nanoflow liquid chromatography tandem mass spectrometry. For 5 proteins, results were verified by Western blot analysis. RESULTS: A total of 2349 spots were identified, of which 9 were differentially expressed with a ≥2-fold change between healthy cats and cats with LPE and SCL (.01 < P < .001). Eight of these 9 spots were also differentially expressed between cats with LPE and cats with SCL (P .001 < P < .04). However, Western blot analysis for malate dehydrogenase-1, malate dehydrogenase-2, apolipoprotein, annexin IV, and annexin V did not confirm significant differential protein expression for any of the 5 proteins assessed. CONCLUSIONS AND CLINICAL IMPORTANCE: Two-D DIGE did not identify potential biomarker candidates in the intestinal mucosa of cats with LPE and SCL. Future studies should focus on different techniques to identify biomarker candidates for cats with chronic enteropathies (CE).

Refractory Celiac Disease Type II: A Case Report and Literature Review.

We present an unusual case of 68-year-old male, who presented with acute abdomen, ulcerative jejunitis with perforation, and 2 months later with perforation of the sigmoid colon. We will also discuss difficulties in the delay in diagnosis of refractory celiac disease (RCD), specifically the atypical presentation, multiple surgeries, the consecutive failure of distinct therapeutic options, and multiple complications that occurred within the 3 months since first presentation.

Deregulation of miRNAs-cMYC circuits is a key event in refractory celiac disease type-2 lymphomagenesis.

A percentage of celiac disease (CD) patients develop refractory type-2 disease (RCD2), a condition associated with increased risk of enteropathy-associated T-cell-lymphoma (EATL) and without therapeutic option. Therefore, we profiled the miRNome in series of peripheral T-cell lymphomas (PTCLs), CD, RCD1 or 2 and in the murine interleukin-15 (IL15)-transgenic (TG) model of RCD. The transcriptome was analyzed in 18 intestinal T-cell lymphomas (ITLs). Bioinformatics pipelines provided significant microRNA (miRNA) lists and predicted targets that were confirmed in a second set of patients. Our data show that ITLs have a unique miRNA profile with respect to other PTCLs. The c-MYC regulated miR-17/92 cluster distinguishes monomorphic epitheliotropic ITL (MEITL) from EATL and prognosticates EATL outcome. These miRNAs are decreased in IL15-TG mice upon Janus kinase (JAK) inhibition. The random forest algorithm identified a signature of 38 classifier miRNAs, among which, the miR-200 and miR-192/215 families were progressively lost in RCD2 and ITL-CD, whereas miR-17/92 and C19MC miRNAs were up-regulated. Accordingly, SMAD3, MDM2, c-Myc and activated-STAT3 were increased in RCD2 and EATL tissues while JAK inhibition in IL15-TG mice restored their levels to baseline. Our data suggest that miRNAs circuit supports activation of STAT3 and c-Myc oncogenic signaling in RCD2, thus contributing to lymphomagenesis. This novel understanding might pave the way to personalized medicine approaches for RCD and EATL.

Gastrointestinal T- and NK-cell lymphomas and indolent lymphoproliferative disorders.

Primary gastrointestinal (GI) T- and NK-cell lymphomas constitute a heterogeneous group of uncommon and aggressive neoplasms, which have unique clinical and pathologic features. The intestines are the most frequent sites of disease, but almost any GI organ may be involved. Enteropathy associated T-cell lymphoma (formerly EATL type 1) and monomorphic epitheliotropic intestinal T-cell lymphoma (formerly EATL type 2) represent the two most common entities. However, other types of peripheral T-cell lymphomas can also occur in the GI tract or involve it secondarily. Moreover, indolent T- and NK-cell lymphoproliferative disorders (LPDs) of the GI tract have also recently been recognized. In this review, we describe the salient clinical, histopathologic, immunophenotypic, and molecular characteristics of primary GI T/NK-cell lymphomas and indolent LPDs, which form the basis for classification of the different entities, and an algorithmic approach to the diagnosis of these rare diseases.

An Unusual Case of Enteropathy-associated T-cell Lymphoma Type 2 with Pulmonary Metastasis.

Herein, we present a very rare case of enteropathy-associated T-cell lymphoma (EATL) type 2 with pulmonary metastasis which was biopsy-proven. This is a very rare type of lymphoma, and no case reports or studies of enteropathy-associated T-cell lymphoma with pulmonary metastatic disease were found in the literature review. This 64-year-old male, who presented with an acute abdomen, was found to have a perforation. Subsequent pathology of the resected specimen showed neoplastic cells consistent with EATL type 2. Four months post-diagnosis, the patient developed shortness of breath. Positron emission tomography (PET) scan revealed multiple metabolically active pulmonary nodules. A biopsy of the nodules was consistent with metastatic EATL type 2 involving the lungs.

Gastrointestinal non-Hodgkin lymphomas.

Although gastrointestinal (GI) tract is the most common extranodal site involved in non-Hodgkin lymphoma (NHL), primary gastrointestinal NHL (gNHL) is a rare problem which concerns about 10-15% of NHL patients and 30-40% of extranodal NHL patients. Lymphoid neoplasms may consist of mature B, T and (less commonly) extranodal NK/T cells. The most common diagnoses are diffuse large B-cell lymphoma and marginal zone lymphoma (MALT), but many other lymphomas may be found in the GI tract. There are a few well-known risk factors of gNHL and some of them affect treatment. The most frequent sites of occurrence are the stomach followed by small intestine and ileocecal region. In the last 2 decades, there has been a rapid development in the diagnosis, staging and management of GI lymphoma, but still some of such lymphomas, especially T-cell ones, are a therapeutic challenge. In this review, we present clinical and pathological features of GI lymphomas. We also describe the current status in diagnosis and treatment.

New/Revised Entities in Gastrointestinal Lymphoproliferative Disorders.

The gastrointestinal tract is a common extranodal site of involvement by lymphomas. These may be diagnostically challenging because they can mimic a variety of benign conditions and may be difficult to subclassify when malignant. The classification of gastrointestinal lymphomas is an evolving area with some recent changes. Although some of these entities are rare, they are important to recognize because of the variable clinical presentations, comorbidities, and treatment implications. This article explores new and revised entities in gastrointestinal lymphoproliferative disorders.

Anaplastic Large T-Cell Lymphoma in the Intestine of Dogs.

Anaplastic large T-cell lymphoma (ALTCL) is a rare subtype of non-Hodgkin T-cell lymphoma that occasionally occurs in the gastrointestinal tract of humans. Enteropathy-associated T-cell lymphoma (EATL) type 1 is the most common type of intestinal lymphoma in dogs, and ALTCL has not previously been reported in the intestinal tract of dogs. Thirteen dogs with intestinal masses diagnosed as intestinal lymphoma with anaplastic morphology were reviewed. Clinical data, including treatment protocols, were available for 11 cases. Immunohistochemistry for CD3, CD20, and CD30 was performed for all cases in addition to PCR for Antigen Receptor Rearrangements (PARR) for assessment of clonality. Eight (62%) of the cases presented with intestinal perforation, and all cases had 1 or more masses arising from the small intestine. Histologically, all cases were characterized by transmural infiltrates of large, CD3-positive and frequently CD30-positive cells. Neoplastic T cells had marked anisocytosis and anisokaryosis, prominent nucleoli, and occasionally indented to reniform nuclei. There was abundant necrosis and inflammation with occasional vascular invasion within neoplastic masses. All cases had a monoclonal T-cell receptor γ gene rearrangement. The median survival time was 5 days, with 1 dog surviving 2 years after the initial diagnosis. ALTCL can occur as an aggressive transmural lymphoma in the gastrointestinal tract of dogs and commonly causes intestinal perforation. ALTCL can be differentiated from EATL type 1 and might have implications for accurate prognostication and selection of therapeutic options in the future.

Pathogenesis of Enteropathy-Associated T Cell Lymphoma.

PURPOSE OF REVIEW: To provide an update on the pathogenesis of enteropathy-associated T cell lymphoma (EATL) and its relationship with refractory celiac disease (RCD), in light of current knowledge of immune, genetic, and environmental factors that promote neoplastic transformation of intraepithelial lymphocytes (IELs). RECENT FINDINGS: EATL frequently evolves from RCD type II (RCD II) but can occur "de novo" in individuals with celiac disease. Recurrent activating mutations in members of the JAK/STAT pathway have been recently described in EATL and RCD II, which suggests deregulation of cytokine signaling to be an early event in lymphomagenesis. Intraepithelial T cells are presumed to be the cell of origin of EATL (and RCD II). Recent in vitro molecular and phenotypic analyses and in vivo murine studies, however, suggest an origin of RCD II from innate IELs (NK/T cell precursors), which could also be the cell of origin of RCD II-derived EATL. The immune microenvironment of the small intestinal mucosa in celiac disease fosters the development of EATL, often in a multistep pathway.