T-cell Lymphoma Presenting Neutrophilic Inflammation in the Cerebrospinal Fluid.

A 66-year-old woman presented with upper abdominal pain and weakness in the limbs. She had bilateral uveitis and gastric ulcers. A neurological examination revealed tetraparesis and sensory disturbance in the right arm. A cerebrospinal fluid (CSF) examination showed polymorphonuclear pleocytosis with elevated pro-inflammatory cytokine levels. Magnetic resonance imaging showed brain lesions and a long spinal cord lesion. She was initially diagnosed with neuro-Behçet's disease and was treated with corticosteroids, resulting in no improvement. A gastric mucosa biopsy indicated T-cell lymphoma colocalizing with neutrophils. The cytokine-mediated neutrophilic inflammation probably caused characteristic CSF and histopathological features. It is noteworthy that T-cell lymphoma may present with CSF neutrophilic inflammation.

Lysophosphatidic acid promotes survival of T lymphoma cells by altering apoptosis and glucose metabolism.

Lysophosphatidic acid (LPA) is a bioactive lipid, which plays an indispensable role in various physiological and pathological processes. Moreover, an elevated level of LPA has been observed in malignancies of different origins and implicated in their progression via modulation of proliferation, apoptosis, invasion and metastasis. Interestingly, few recent reports suggest a pivotal role of LPA-modulated metabolism in oncogenesis of ovarian cancer. However, little is understood regarding the role of LPA in the development and progression of T cell malignancies, which are considered as one of the most challenging neoplasms for clinical management. Additionally, mechanisms underlying the LPA-dependent modulation of glucose metabolism in T cell lymphoma are also not known. Therefore, the present study was undertaken to explore the role of LPA-altered apoptosis and glucose metabolism on the survival of T lymphoma cells. Observations of this investigation suggest that LPA supports survival of T lymphoma cells via altering apoptosis and glucose metabolism through changing the level of reactive species, namely nitric oxide and reactive oxygen species along with expression of various survival and glucose metabolism regulatory molecules, including hypoxia-inducible factor 1-alpha, p53, Bcl2, and glucose transporter 3, hexokinase II, pyruvate kinase muscle isozyme 2, monocarboxylate transporter 1, pyruvate dehydrogenase kinase 1. Taken together' the results of the present investigation decipher the novel mechanisms of LPA-mediated survival of T lymphoma cells via modulation of apoptosis and glucose metabolism.

Linfoma anaplásico de grandes células relacionado ao implante mamário: revisão sistemática da literatura / Breast implant-associated anaplastic large-cell lymphoma: a systematic literature review

O linfoma anaplásico de grandes células associado ao implante de mama (Breast Implant Associated Anaplastic Large Cell Lymphoma - BIA-ALCL) é uma doença maligna recentemente descoberta, rara e possivelmente associada aos implantes mamários texturizados. Essa revisão da literatura teve como objetivo trazer novas atualizações acerca da epidemiologia, fisiopatologia e fatores de risco para desenvolvimento do BIAALCL. Foi realizado o levantamento de dados do período de dezembro de 2018 a fevereiro de 2019, através das bases de dados PUBMED, LILACS e Scielo sendo selecionados 10 artigos publicados entre 2016 e 2018. Foi encontrada uma incidência variando entre 2,8:100.000 a 1:3 milhões de pacientes com implantes mamários. Os dados coletados corroboram para a teoria de que não há uma relação direta de causa e efeito entre os implantes mamários, mormente os texturizados, e o desenvolvimento do BIA-ALCL, podendo esses ser considerados somente como fatores de risco e não agentes causadores. A teoria fisiopatológica mais aceita é a de que os implantes mamários com maior área de superfície levariam a formação de maior biofilme por maior adesão bacteriana gerando inflamação crônica mais proeminente, levando ao gatilho para a transformação maligna das células T. As informações explicitadas nessa revisão devem auxiliar na ampliação de estudos acerca da doença e criação de políticas públicas para a prevenção e diagnóstico precoce de tal enfermidade. Pelos dados encontrados há necessidade de que cirurgiões plásticos realizem acompanhamento mais próximo de seus pacientes, assim como orientem os pacientes antes das cirurgias sobre a existência da doença.

Breast implant-associated anaplastic large-cell lymphoma (BIA-ALCL) is a newly discovered and rare cancer possibly associated with textured breast implants. This literature review investigates its epidemiology, pathophysiology, and risk factors. PubMed, LILACS, and SciELO databases were searched from December 2018 to February 2019, and 10 articles published between 2016 and 2018 were selected. The incidence of BIA-ALCL ranged from 2.8:100,000 to 1:3 million breast implants. The obtained data corroborate the hypothesis that there is no direct cause and effect relationship between breast implants, especially textured implants, and BIA-ALCL, and these implants can be considered risk factors but not causative factors. The most accepted hypothesis on disease pathophysiology is that breast implants with larger surface areas may promote bacterial adhesion and biofilm formation, leading to severe chronic inflammation, triggering the malignant transformation of T cells. This review provides knowledge on BIA-ALCL and helps develop and implement public policies for disease prevention and timely diagnosis. The data highlight that long-term follow up is necessary and that surgeons should advise patients of the potential risk of developing BIA-ALCL before performing the implant surgery.

Six-year-old boy with mediastinal mass.

Lymphoblastic lymphomas account for 20-30% of all non-Hodgkin lymphomas (NHL) in children, and most cases of childhood lymphoblastic lymphoma are T-cell type (T-LL). T-LL occurs most frequently in late childhood and adolescence; with male predominance of 2:1.We present a paediatric case with a right sided mediastinal mass causing mediastinal shift diagnosed as T-LL.

The utility of flow cytometry in differentiating NK/T cell lymphoma from indolent and reactive NK cell proliferations.

BACKGROUND: The WHO defines three categories of NK cell malignancies; extra nodal NK/T cell lymphoma (NKTCL), aggressive NK cell leukemia, and the provisional entity chronic lymphoproliferative disorder of NK cells (CLPD-NK). Although the flow cytometric (FC) phenotype of CLPD-NK has been described, studies on FC phenotype of NKTCL are limited. To the best of our knowledge ours is the first study to compare the phenotype of NKTCL, CLPD-NK, reactive NK lymphocytosis (RNKL), and normal NK cells using eight color (8C) FC. METHODS: Specimens analyzed using the Euroflow8C NK Lymphoproliferative Disorder (NKLPD) panel between 2011 and 2014 were identified from our database. All samples were analyzed on the FACSCantoII cytometer. NK cells were identified as CD45+, smCD3-, CD19-, CD56+ and normal T-cells served as internal controls. RESULTS: The majority of NKTCL were CD56 bright, CD16 dim, CD57-, and CD94+. CLPD-NK and RNKL were predominantly CD56+ or dim with positive expression of CD16 and CD57 and weak CD94 expression. Antigen based statistical analyses showed robust division of samples along the NKTCL/normal CD56 bright NK cell and CLPD-NK/RNKL/normal CD56 positive NK cell groups. CONCLUSIONS: It was concluded that FC can reliably distinguish NKTCL from CLPD-NK, normal NK cells of CD56+ phenotype, and RNKL. It was proposed that the typical phenotype for NKTCL is: CD56 bright, CD16 dim with positive CD2, CD7, CD94, HLADR, CD25, CD26, and absent CD57. This resembles the phenotype of the CD56 bright immunoregulatory subset of NK cells which we therefore hypothesize is the cell of origin of NKTCL. © 2017 International Clinical Cytometry Society.

Condensin II mutation causes T-cell lymphoma through tissue-specific genome instability.

Chromosomal instability is a hallmark of cancer, but mitotic regulators are rarely mutated in tumors. Mutations in the condensin complexes, which restructure chromosomes to facilitate segregation during mitosis, are significantly enriched in cancer genomes, but experimental evidence implicating condensin dysfunction in tumorigenesis is lacking. We report that mice inheriting missense mutations in a condensin II subunit (Caph2nes) develop T-cell lymphoma. Before tumors develop, we found that the same Caph2 mutation impairs ploidy maintenance to a different extent in different hematopoietic cell types, with ploidy most severely perturbed at the CD4+CD8+ T-cell stage from which tumors initiate. Premalignant CD4+CD8+ T cells show persistent catenations during chromosome segregation, triggering DNA damage in diploid daughter cells and elevated ploidy. Genome sequencing revealed that Caph2 single-mutant tumors are near diploid but carry deletions spanning tumor suppressor genes, whereas P53 inactivation allowed Caph2 mutant cells with whole-chromosome gains and structural rearrangements to form highly aggressive disease. Together, our data challenge the view that mitotic chromosome formation is an invariant process during development and provide evidence that defective mitotic chromosome structure can promote tumorigenesis.

Cytomegalovirus Pneumonia after Anti-CC-chemokine Receptor 4 Monoclonal Antibody (Mogamulizumab) Therapy in an Angioimmunoblastic T-cell Lymphoma Patient.

Angioimmunoblastic T-cell lymphoma (AITL) is an aggressive T-cell lymphoma. A 63-year-old man was diagnosed with AITL. He received 6 cycles of CHOP therapy, but showed progressive disease. Subsequently, he received ESHAP chemotherapy; however, it was not effective. He received mogamulizumab (an anti-CCR4 monoclonal antibody). After 4 cycles, his respiratory condition worsened and he was diagnosed with cytomegalovirus (CMV) pneumonia. Despite antiviral and antibiotic therapy, he died. We speculate that the combination of progressive lymphoma with mogamulizumab and chemotherapy likely caused CMV pneumonia. Because mogamulizumab therapy causes immunosuppression, if CMV pneumonia is suspected, then rapid treatment should be initiated.

Thyroid status modulates T lymphoma growth via cell cycle regulatory proteins and angiogenesis.

We have shown in vitro that thyroid hormones (THs) regulate the balance between proliferation and apoptosis of T lymphoma cells. The effects of THs on tumor development have been studied, but the results are still controversial. Herein, we show the modulatory action of thyroid status on the in vivo growth of T lymphoma cells. For this purpose, euthyroid, hypothyroid, and hyperthyroid mice received inoculations of EL4 cells to allow the development of solid tumors. Tumors in the hyperthyroid animals exhibited a higher growth rate, as evidenced by the early appearance of palpable solid tumors and the increased tumor volume. These results are consistent with the rate of cell division determined by staining tumor cells with carboxyfluorescein succinimidyl ester. Additionally, hyperthyroid mice exhibited reduced survival. Hypothyroid mice did not differ significantly from the euthyroid controls with respect to these parameters. Additionally, only tumors from hyperthyroid animals had increased expression levels of proliferating cell nuclear antigen and active caspase 3. Differential expression of cell cycle regulatory proteins was also observed. The levels of cyclins D1 and D3 were augmented in the tumors of the hyperthyroid animals, whereas the cell cycle inhibitors p16/INK4A (CDKN2A) and p27/Kip1 (CDKN1B) and the tumor suppressor p53 (TRP53) were increased in hypothyroid mice. Intratumoral and peritumoral vasculogenesis was increased only in hyperthyroid mice. Therefore, we propose that the thyroid status modulates the in vivo growth of EL4 T lymphoma through the regulation of cyclin, cyclin-dependent kinase inhibitor, and tumor suppressor gene expression, as well as the stimulation of angiogenesis.

The role of vascular endothelial growth factor and matrix metalloproteinases in canine lymphoma: in vivo and in vitro study.

BACKGROUND: Canine lymphoma represents the most frequent haematopoietic cancer and it shares some similarities with human non-Hodgkin lymphoma. Matrix metalloproteinases (MMPs) and vascular endothelial growth factor (VEGF) play a coordinated role during invasion and proliferation of malignant cells; however, little is known about their role in canine haematologic malignancies. The aim of this study was to investigate the mRNA and protein expression of VEGF and the most relevant MMPs in canine lymphoma. Lymph node aspirates from 26 B-cell and 21 T-cell lymphomas were collected. The protein expression levels of MMP-9, MMP-2 and VEGF-A were evaluated by immunocytochemistry, and the mRNA levels of MMP-2, MMP-9, MT1-MMP, TIMP-1, TIMP-2, RECK, VEGF-A and VEGF-164 were measured using quantitative RT-PCR. RESULTS: MT1-MMP, TIMP-1 and RECK mRNA levels were significantly higher in T-cell lymphomas than in B-cell lymphomas. Higher mRNA and protein levels of MMP-9 and VEGF-A were observed in T-cell lymphomas than in B-cell lymphomas and healthy control lymph nodes. A positive correlation was found between MMP-9 and VEGF-A in T-cell lymphomas. Moreover, MMP-9, MT1-MMP, TIMP-1 and VEGF-A were expressed at the highest levels in high-grade T-cell lymphomas. CONCLUSIONS: This study provides new information on the expression of different MMPs and VEGF in canine lymphoma, suggesting a possible correlation between different MMPs and VEGF, immunophenotype and prognosis.

Two hot spot mutant p53 mouse models display differential gain of function in tumorigenesis.

Mutant p53 proteins not only lose their tumor-suppressor function but some acquire oncogenic gain of function (GOF). The published mutp53 knock-in (KI) alleles (R172H, R270H, R248W) manifest GOF by broader tumor spectrum and more metastasis compared with the p53-null allele, but do not shorten survival. However, whether GOF also occurs with other mutations and whether they are all biologically equal is unknown. To answer this, we created novel humanized mutp53 KI mice harboring the hot spot alleles R248Q and G245S. Intriguingly, their impact was very different. Compared with p53-null mice, R248Q/- mice had accelerated onset of all tumor types and shorter survival, thus unprecedented strong GOF. In contrast, G245S/- mice were similar to null mice in tumor latency and survival. This was associated with a twofold higher T-lymphoma proliferation in R248Q/- mice compared with G245S/- and null mice. Moreover, R248Q/- hematopoietic and mesenchymal stem cells were expanded relative to G245S/- and null mice, the first indication that GOF also acts by perturbing pretumorous progenitor pools. Importantly, these models closely mirror Li-Fraumeni patients who show higher tumor numbers, accelerated onset and shorter tumor-free survival by 10.5 years when harboring codon R248Q mutations as compared with Li-Fraumeni patients with codon G245S mutations or p53 deletions/loss. Conversely, both KI alleles caused a modest broadening of tumor spectrum with enhanced Akt signaling compared with null mice. These models are the first in vivo proof for differential oncogenic strength among p53 GOF alleles, with genotype-phenotype correlations borne out in humans.

EZH2 overexpression in natural killer/T-cell lymphoma confers growth advantage independently of histone methyltransferase activity.

The role of enhancer of zeste homolog 2 (EZH2) in cancer is complex and may vary depending on the cellular context. We found that EZH2 is aberrantly overexpressed in the majority of natural killer/T-cell lymphoma (NKTL), an aggressive lymphoid malignancy with very poor prognosis. We show that EZH2 upregulation is mediated by MYC-induced repression of its regulatory micro RNAs and EZH2 exerts oncogenic properties in NKTL. Ectopic expression of EZH2 in both primary NK cells and NKTL cell lines leads to a significant growth advantage. Conversely, knock-down of EZH2 in NKTL cell lines results in cell growth inhibition. Intriguingly, ectopic EZH2 mutant deficient for histone methyltransferase activity is also able to confer growth advantage and rescue growth inhibition on endogenous EZH2 depletion in NKTL cells, indicating an oncogenic role of EZH2 independent of its gene-silencing activity. Mechanistically, we show that EZH2 directly promotes the transcription of cyclin D1 and this effect is independent of its enzymatic activity. Furthermore, depletion of EZH2 using a PRC2 inhibitor 3-deazaneplanocin A significantly inhibits growth of NK tumor cells. Therefore, our study uncovers an oncogenic role of EZH2 independent of its methyltransferase activity in NKTL and suggests that targeting EZH2 may have therapeutic usefulness in this lymphoma.

Inducible expression and pathophysiologic functions of T-plastin in cutaneous T-cell lymphoma.

A molecular feature of Sézary syndrome (SS) is the abnormal expression of T-plastin by malignant T cells. Herein, we investigated the molecular mechanisms involved in T-plastin synthesis and the functions of this actin-binding protein, with a special interest in chemoresistance and migration. We confirm the specific expression of T-plastin in peripheral blood lymphocytes (PBLs) from SS patients and its total absence in PBLs from patients with mycosis fungoides, inflammatory cutaneous or hematologic diseases, and from healthy volunteers. Only 3 of 4 SS patients did constitutively express T-plastin. To assess whether T-plastin expression was inducible, T-plastin-negative PBLs were stimulated by phorbol 12-myristate 13-acetate and ionomycin. Our results demonstrate that T-plastin synthesis was induced in negative PBLs from SS patients, other studied patients, and healthy volunteers. Both constitutive and calcium-induced T-plastin expression was down-regulated by calcineurin inhibitors and involved nuclear factor of activated T cells transcription pathway. Constitutive T-plastin expression in SS was associated with resistance to etoposide-induced apoptosis and cell migration toward chemokines (TARC/CCL17, IP-10). In conclusion, T-plastin is a marker restricted to malignant lymphocytes from SS patients and plays a role for cell survival and migration. This opens new strategies for the treatment of SS advanced stages.

Angioimmunoblastic T-cell lymphoma: the effect of initial treatment and microvascular density in 31 patients.

The objectives of this study are to explore the clinical features and treatment outcomes and to investigate the correlation between microvessel density (MVD) and survival in patients with angioimmunoblastic T-cell lymphoma (AITL). We retrospectively analyzed clinical and follow-up data of 31 patients treated in two hospitals during 1995-2009 histologically proven AITL. We also assessed MVD in the lump of 31 previously untreated patients using α-CD34 immunohistochemical staining. The median age of the 31 patients was 48 years, eighty percent of the patients were in an advanced stage. 67.7% of them had B symptoms, with the follow-up of 2-13 years, the 5-year overall survival rate was 25.8%. The response rates (RR) of CHOP group and COP (cyclophosphamide, vincristine and prednisolone) group are 76.5 and 75%, respectively, which is no significant difference (P=0.894). RR did not differ whether chemotherapy regimens contained anthracycline or not. The 3-year PFS rate for patients who received COP and CHOP regimen was 25.4 and 35.3% (P=0.562), while 5-year OS rates were 25.0 and 29.4%, respectively (P=0.667). The median PFS for patients with high MVD and low MVD were 15.1 and 30.0 months (P=0.048), while the median OS were 20 and 45 months, respectively (P=0.038). Patients who were sensitive to initial chemotherapy COP regimen have the similar therapeutic effect to CHOP regimen. Patients with high MVD measured in the microenvironment had worse PFS and OS than AITL patients with low expression.

Fyn is not essential for Bcr-Abl-induced leukemogenesis in mouse bone marrow transplantation models.

The Bcr-Abl oncogene causes human Philadelphia chromosome-positive (Ph(+)) leukemias, including B-cell acute lymphoblastic leukemia (B-ALL) and chronic myeloid leukemia (CML) with chronic phase (CML-CP) to blast crisis (CML-BC). Previous studies have demonstrated that Src family kinases are required for the induction of B-ALL, but not for CML, which is induced by Bcr-Abl in mice. In contrast, it has been reported that Fyn is up-regulated in human CML-BC compared with CML-CP, implicating Fyn in the blast crisis transition. Here, we aimed to delineate the exact role of Fyn in the induction/progression of Ph(+) leukemias. We found that Fyn is expressed in mouse hematopoietic cells at varying stages of development, including c-kit(+)Sca-1(+)Lin(-) cells. Notably, Fyn is highly expressed in some of human lymphomas, but not in human Ph(+) leukemias including CML-BC. In mouse bone marrow transplantation models, mice transplanted with wild-type or Fyn-deficient bone marrow cells transduced with Bcr-Abl showed no differences in the development of B-ALL or CML-like diseases. Similarly, Fyn deficiency failed to impact the development of myeloid CML-BC induced by Bcr-Abl and Hes1. Elevated expression of Fyn was not found in mouse samples of Bcr-Abl-mediated CML- and CML-BC-like diseases. Thus, Fyn is not required for the pathogenesis of Bcr-Abl-mediated leukemias.

Primary intestinal non-Hodgkin's lymphoma: a clinicopathologic analysis of 81 patients.

AIM: To analyze the clinicopathologic features and the prognosis of primary intestinal lymphoma. METHODS: Patients were included in the study based on standard diagnostic criteria for primary gastrointestinal lymphoma, and were treated at Sun Yat-sen University Cancer Centre between 1993 and 2008. RESULTS: The study comprised 81 adults. The most common site was the ileocaecal region. Twenty-two point two percent patients had low-grade B-cell lymphoma. Fifty-one point nine percent patients had high-grade B-cell lymphoma and 25.9% patients had T-cell lymphoma. Most patients had localized disease. There were more patients and more early stage diseases in the latter period, and the origin sites changed. The majority of patients received the combined treatment, and about 20% patients only received nonsurgical therapy. The wverall survival and event-free survival rates after 5 years were 71.6% and 60.9% respectively. The multivariate analysis revealed that small intestine and ileocaecal region localization, B-cell phenotype, and normal lactate dehydrogenase were independent prognostic factors for better patient survival. Surgery based treatment did not improve the survival rate. CONCLUSION: Refined stratification of the patients according to the prognostic variables may allow individualized treatment. Conservative treatment may be an optimal therapeutic modality for selected patients.

Effect of chemokine receptors CCR7 on disseminated behavior of human T cell lymphoma: clinical and experimental study.

BACKGROUND: The expression of chemokine receptors CCR7 has been studied in relation to tumor dissemination and poor prognosis in a limited number of cancers. No such studies have been done on CCR7 expression in non-Hodgkin's lymphoma (T-NHL). Our aim in this paper is to investigate the association between CCR7 expression and progression and prognosis of T-NHL. METHODS: 1) Analysis of clinical data: The specimens were obtained from 41 patients with T-NHL and 19 patients with lymphoid hyperplasia. Their corresponding clinicopathologic data were also collected. The expression levels of CCR7, MMP-2, and MMP-9 were examined by immunohistochemical staining. 2) Human T-NHL cell lines Hut 78 (cutaneous T-cell lymphoma) and Jurkat (adult T-cell leukemia/lymphoma) were cultured. The invasiveness of the two cell lines were measured with a Transwell invasion assay, and then used to study the effects of chemokine receptors on T-NHL invasion and the underlying molecular mechanism. The transcript and expression of CCR7 were evaluated using RT-PCR and western blotting. RESULTS: 1) The higher CCR7 and MMP-9 expression ratios were significantly associated with multiple lesions and higher stage III/IV. Moreover, a positive correlation was observed between CCR7 and MMP-9 expression. 2) The Hut 78 cell line was more invasive than the Jurkat cells in the Transwell invasion assay. The transcript and expression levels of CCR7 were significantly higher in Hut78 than that of Jurkat cell line. The T-NHL cell lines were co-cultured with chemokine CCL21 which increased the invasiveness of T-NHL cell. The positive association between CCL21 concentration and invasiveness was found. 3) The stronger transcript and expression of PI(3)K, Akt and p- Akt were also observed in Hut78 than in Jurkat cell line. CONCLUSIONS: High CCR7 expression in T-NHL cells is significantly associated with lymphatic and distant dissemination as well as with tumor cell migration and invasion in vitro. Its underlying mechanism probably involves the PI(3)K/Akt signal pathway.

Proteasome inhibitor bortezomib targeted tumor-endothelial cell interaction in T-cell leukemia/lymphoma.

Endothelial cells have special relevance in tumor progression. Here, we investigated the effect of the proteasome inhibitor bortezomib on tumor-endothelial cell interaction in T-cell leukemia/lymphoma. In vitro, T-leukemia/lymphoma cell lines and primary T-leukemia/lymphoma cells were cultured with endothelial cells, either together or separately in Millicell Hanging Cell Culture system, the latter permits mutual cell exchange. At clinically achievable concentrations, in addition to a direct cytotoxicity on T-leukemia/lymphoma cells, bortezomib inhibited tumor cell adhesion to endothelial cells and endothelial cell migration toward tumor cells. In vivo, a murine tumor xenograft model was achieved by subcutaneous injection of Jurkat cells. Bortezomib also triggered an inhibition on tumor-endothelial cell contact and subsequent tumor cell infiltration. Cell adhesion molecule intracellular cell adhesion molecule-1 expression was significantly downregulated both on the tumor cells and on the endothelial cells. Taken together, bortezomib could not only act on tumor cells themselves but also abrogate tumor cell interaction with endothelial cells. This delineates another therapeutic mechanism of bortezomib in T-cell malignancies.

Enteropathy-associated T-cell lymphoma: a review on clinical presentation, diagnosis, therapeutic strategies and perspectives.

INTRODUCTION: Enteropathy-associated T-cell lymphoma (EATL) is a rare complication of celiac disease (<1% of lymphomas) and has a poor prognosis. METHODS: International literature review with PubMed search (up to January 2009) of pathophysiological, clinical and therapeutic data. RESULTS: EATL is found in patients with a mean age of 59 years, often with a complication that signals its diagnosis. Refractory celiac disease (RCD), equivalent to low-grade intraepithelial T-cell lymphoma, could be an intermediary between celiac disease and high-grade invasive T-cell lymphoma. The median survival is 7 months, with no significant difference between stages; the cumulative 5-year survival is less than 20%. The poor prognosis is determined by disease that has often spread before it is diagnosed (50%), multifocal involvement of the small bowel (50%), poor general health status and undernutrition, and recurrence of complications (infections, perforations, gastrointestinal haemorrhages, occlusions), thus delaying the chemotherapy and contributing to frequent chemotherapy resistance. There is currently no effective and consensual treatment: preventive surgery for complications is controversial, and the results of chemotherapy are disappointing. The classic CHOP protocol (combination of doxorubicin-cyclophosphamide-vincristine-prednisone) does not have satisfactory results and survival remains poor, especially in patients with underlying RCD. High-dose chemotherapy with autotransplantion seems to only improve the prognosis in localised forms. Allogeneic bone marrow transplantation was not evaluated. In all, 1/3 of patients, being unfit for treatment, die before 3 months and half of treated patients stop chemotherapy prematurely due to inefficacy, intolerance and/or complications. CONCLUSION: Improvement of the prognosis requires collaboration in order to compose a national cohort, to evaluate new diagnostic and therapeutic strategies and to define prognostic factors.