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Peripheral T cell lymphoma, not otherwise specified (PTCL/ NOS), and peripheral T cell lymphoma, angioimmunoblastic type (AILT), can be distinguished according to their gene expression profile. Eightythree differentially expressed genes are plotted in the matrix.
Source publication
Peripheral T cell lymphomas (PTCL) account for about 12% of lymphoid tumours worldwide. Almost half show such morphological and molecular variability as to hamper any further classification, and to justify their inclusion in a waste-basket category termed "not otherwise specified (NOS)". The latter term is used for neoplasms with aggressive present...
Context in source publication
Context 1
... the course of the same study, we found that all ALCLs tended to cluster together -irrespective of their ALK positivity or negativity -showing a signature distinct from those of PTCL/NOS and AITL. 20 More recently, we succeeded in identifying a gene signature discriminating between PTCL/NOS and AITL (fig 2). 22 In addition, the observed AITL global profile strengthened its derivation from the follicular T helper lymphocyte (FT H L), as originally proposed by Rüdiger et al 83 and de Leval et al. 17 Among upregulated genes, were those encoding for CXC13, PD1 and vascular endothelial growth factor (VEGF). ...
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Citations
... T-follicular helper cell lymphomas is a group of T-cell neoplasms of postulated TFH cell origin, as reflected by the expression of the TFH immunophenotype and gene expression signature [3,4]. PTCL-NOS, on the other hand, are defined by their T-cell lineage but lack other more distinctive features of specific T-cell lymphoma entities [5,6]. These subtypes encompass a wide spectrum of cellular composition, cytologic, and immunophenotypic features that overlap with each other as well as with reactive lymphoid processes, making molecular testing an indispensable part of the diagnostic work-up. ...
Background
The diagnosis of T-cell lymphomas is typically established through a multiparameter approach that combines clinical, morphologic, immunophenotypic, and genetic features, utilizing a variety of histopathologic and molecular techniques. However, accurate diagnosis of such lymphomas and distinguishing them from reactive lymph nodes remains challenging due to their low prevalence and heterogeneous features, hence limiting the confidence of pathologists. We investigated the use of microRNA (miRNA) expression signatures as an adjunctive tool in the diagnosis and classification of T-cell lymphomas that involve lymph nodes. This study seeks to distinguish reactive lymph nodes (RLN) from two types of frequently occurring nodal T-cell lymphomas: nodal T-follicular helper (TFH) cell lymphomas (nTFHL) and peripheral T-cell lymphomas, not otherwise specified (nPTCL).
Methods
From the formalin-fixed paraffin-embedded (FFPE) samples from a cohort of 88 subjects, 246 miRNAs were quantified and analyzed by differential expression. Two-class logistic regression and random forest plot models were built to distinguish RLN from the nodal T-cell lymphomas. Gene set enrichment analysis was performed on the target genes of the miRNA to identify pathways and transcription factors that may be regulated by the differentially expressed miRNAs in each subtype.
Results
Using logistic regression analysis, we identified miRNA signatures that can distinguish RLN from nodal T-cell lymphomas (AUC of 0.92 ± 0.05), from nTFHL (AUC of 0.94 ± 0.05) and from nPTCL (AUC of 0.94 ± 0.08). Random forest plot modelling was also capable of distinguishing between RLN and nodal T-cell lymphomas, but performed worse than logistic regression. However, the miRNA signatures are not able to discriminate between nTFHL and nPTCL, owing to large similarity in miRNA expression patterns. Bioinformatic analysis of the gene targets of unique miRNA expression revealed the enrichment of both known and potentially understudied signalling pathways and genes in such lymphomas.
Conclusion
This study suggests that miRNA biomarkers may serve as a promising, cost-effective tool to aid the diagnosis of nodal T-cell lymphomas, which can be challenging. Bioinformatic analysis of differentially expressed miRNAs revealed both relevant or understudied signalling pathways that may contribute to the progression and development of each T-cell lymphoma entity. This may help us gain further insight into the biology of T-cell lymphomagenesis.
... malic enzyme 2 | glutamine metabolism | redox homeostasis | MYC | T cell lymphomas T cell lymphomas (TCLs) are a group of biologically and clinically heterogeneous lymphoblastic tumors (1). T cells acquire various genetic aberrations during and/or after maturation, leading to the development of T-lymphoblastic malignancies (2). Although novel chemotherapy, targeted therapy, or immunotherapy have revolutionized the treatment of human lymphoma, the overall prognosis for patients with TCL is inferior to that of B cell lymphoma, and the survival rate for patients with relapsed TCL remains low (3). ...
T cell lymphomas (TCLs) are a group of rare and heterogeneous tumors. Although proto-oncogene MYC has an important role in driving T cell lymphomagenesis, whether MYC carries out this function remains poorly understood. Here, we show that malic enzyme 2 (ME2), one of the NADPH-producing enzymes associated with glutamine metabolism, is essential for MYC-driven T cell lymphomagenesis. We establish a CD4-Cre; Myc flox/+transgenic mouse mode, and approximately 90% of these mice develop TCL. Interestingly, knockout of Me2 in Myc transgenic mice almost completely suppresses T cell lymphomagenesis. Mechanistically, by transcriptionally up-regulating ME2, MYC maintains redox homeostasis, thereby increasing its tumorigenicity. Reciprocally, ME2 promotes MYC translation by stimulating mTORC1 activity through adjusting glutamine metabolism. Treatment with rapamycin, an inhibitor of mTORC1, blocks the development of TCL both in vitro and in vivo. Therefore, our findings identify an important role for ME2 in MYC-driven T cell lymphomagenesis and reveal that MYC-ME2 circuit may be an effective target for TCL therapy.
... With further workup, phenotypic cell markers have historically acted as surrogates for the prediction of mortality risk. One such marker used for prognostication involves Ki-67, an indicator for cell proliferation, with a higher Ki-67 staining at variable cut-offs reported by several studies to be predictive of poor outcomes (12)(13)(14). A high serum lactate dehydrogenase (LDH) level, as well as the presence of tumor Epstein-Barr Virus (EBV) infection assessed by EBV-encoded RNA (EBER) positivity, had also been identified to be predictors of worse prognosis (13,15,16). ...
... In the subset of tumors harboring an IDH2 mutation, an overwhelming majority of patients additionally presented with concurrent RHOA and TET2 mutations, suggesting some interlink between the genetic pathways underlying these four mutations in AITL oncogenesis. This is further characterized by TFH lymphocyte derivation and the presence of FYN, CXCL13, PD1 and vascular endothelial growth factor (VEGF) expression in recognized AITL, along with descriptions of a proliferation of follicular dendritic cells and malignant TFH cells within close proximity high endothelial venules in pathological samples (12,49,50). In PTCL-TFH, RHOA mutations were also frequently detected, albeit at lower frequency than AITL (51). ...
Peripheral T-cell lymphoma (PTCL) and natural killer/T-cell lymphoma (NKTCL) are rare subtypes of non-Hodgkin’s lymphoma that are typically associated with poor treatment outcomes. Contemporary first-line treatment strategies generally involve the use of combination chemoimmunotherapy, radiation and/or stem cell transplant. Salvage options incorporate a number of novel agents including epigenetic therapies (e.g. HDAC inhibitors, DNMT inhibitors) as well as immune checkpoint inhibitors. However, validated biomarkers to select patients for individualized precision therapy are presently lacking, resulting in high treatment failure rates, unnecessary exposure to drug toxicities, and missed treatment opportunities. Recent advances in research on the tumor and microenvironmental factors of PTCL and NKTCL, including alterations in specific molecular features and immune signatures, have improved our understanding of these diseases, though several issues continue to impede progress in clinical translation. In this Review, we summarize the progress and development of the current predictive biomarker landscape, highlight potential knowledge gaps, and discuss the implications on novel therapeutics development in PTCL and NKTCL.
... New molecular genetic markers will also assist clinical investigators in designing improved therapies. According to their gene expression profile PTCL/NOS, with frequent extranodal and bone-marrow involvement exhibit the upregulation of FN1, LAMB1, COL1A2, COL3A1, COL4A1, COL4A2, and COL12A1 in addition, it revealed the deregulation of genes involved in apoptosis such as MOAP1, ING3, GADD45A, and GADD45B and chemoresistancegenes such as CYR61 and NNMT.12 ...
Background
Peripheral T‐Cell Lymphoma Not Otherwise Specified (PTCL‐NOS) is a rare type of non‐Hodgkin T‐cell lymphoma which frequently seen in immunocompromised individuals. It is estimated that only 2% of lymphomas are located on the buccal mucosa. In this case report, we present a 34‐year‐old male with a PTCL diagnosis.
Case
A 34‐year‐old immune‐competent male presented with a buccal progressive ulcerated lesion. Histopathologic and immunohistochemical findings were compatible with PTCL‐NOS and classified as stage IIEA according to the Ann Arbor staging. The patient underwent chemotherapy followed by radiotherapy. He remained disease‐free after 12 months of follow‐up.
Conclusion
Although lymphoma is uncommon in the oral cavity, physicians especially dentists in ordinary dental checkups should consider persistent progressive lesions as an important differential diagnosis of lymphoma.
... 5 Currently, T-cell NHLs (T-NHLs) are diagnosed with a discrete set of immunohistochemical markers in combination with clinical and pathological features; however, 30% to 50% of cases cannot be classified using current methods and are categorized as PTCL-NOS, which represents the most prevalent PTCL group. 6,7 To better understand the pathobiology, in-depth genomic approaches, including gene expression profiling (GEP), [8][9][10][11][12][13] copy number alteration analysis, [14][15][16] and next-generation sequencing, have been performed in major PTCL subgroups. [17][18][19][20] These efforts have generated robust molecular classifiers for PTCL entities and meaningful subclassification of PTCL-NOS. ...
Peripheral T-cell lymphomas (PTCLs) are heterogenous T-cell neoplasms often associated with epigenetic dysregulation. We investigated de novo DNA methyltransferase 3A (DNMT3A) mutations in common PTCL entities, including angioimmunoblastic T-cell lymphoma and novel molecular subtypes identified within PTCL-not otherwise specified (PTCL-NOS) designated as PTCL-GATA3 and PTCL-TBX21. DNMT3A-mutated PTCL-TBX21 cases showed inferior overall-survival, with DNMT3A mutated residues skewed towards the methyltransferase domain and dimerization motif (S881-R887). Transcriptional profiling demonstrated significant enrichment of activated CD8+ T-cell cytotoxic gene signatures in the DNMT3A-mutantPTCL-TBX21 cases, which was further validated using immunohistochemistry. Genome-wide methylation analysis of DNMT3A-mutantversus wild-type PTCL-TBX21 cases demonstrated hypomethylation in target genes regulating IFN-g, TCR signaling and EOMES, a master transcriptional regulator of cytotoxic effector cells. Similar findings were observed in a murine model of PTCL with Dnmt3a loss (in-vivo) and further validated in-vitro by ectopic expression of DNMT3A-mutants (DNMT3A-R882, -Q886, -V716, versus WT) in CD8+T-cell line, resulting in T-cell activation and EOMES upregulation. Furthermore, stable, ectopic expression of the DNMT3A-mutants in primary CD3+ T-cell cultures resulted in the preferential outgrowth of CD8+ T-cells with DNMT3AR882H mutation. Single-cell-RNA-seq analysis of CD3+ T-cells revealed differential CD8+ T-cell subset polarization, mirroring findings in DNMT3A-mutated PTCL-TBX21 and validating the cytotoxic and T-cell memory transcriptional programs associated with the DNMT3AR882H mutation. Our findings indicate that DNMT3A mutations define a cytotoxic subset in PTCL-TBX21 with prognostic significance, thus may further refine pathological heterogeneity in PTCL-NOS and suggest alternative treatment strategies for this subset.
... Until now, the molecular pathology of this tumor is poorly understood [1,2]. Nonetheless, gene expression profile (GEP) studies indicated consistent abnormalities in selected pathways [3][4][5][6][7][8][9]. More recently, next generation sequencing (NGS) studies revealed some of the molecular bases sustaining the transcriptional abnormalities. ...
... 6 Immunohistochemistry in T/NK PTLD shows strong positivity for CD3, negative for CD 7, and strong CD 4 positivity in case of lymph nodal involvement as seen in our patient. 5,7 The outcome in T/NK PTLD is poor and is even poorer in the T/NK NOS subtype. Previous experiences show a median survival of 3 months and the overall 5-year survival of 32%. ...
Introduction
Post-transplant lymphoproliferative disorder or PTLD is a rare complication seen in the post liver transplant period. The commonest subtype is B cell PTLD which is usually associated with Epstein Barr virus infection. T cell PTLD is rare and the association with EBV is again rarer.
Case
Our patient, a 21 year old young adult presented to us with generalized lymphadenopathy, 5 years post liver transplant period. The biopsy of lymph node was suggestive of Peripheral T cell lymphoma not otherwise specified, which was associated with EBV infection. The PET-CT scan showed stage 3 disease. He was treated with standard CHOEP (cyclophosphamide, doxorubicin, etoposide, vincristine and prednisolone) chemotherapy and is currently in remission.
Conclusion
Peripheral T cell lymphoma not otherwise specified is a rare subtype of PTLD and its association with EBV is even more rare. A few patients can achieve complete remission with standard chemotherapy.
... One has also to take into account that in a small subset of cases the tumor cell size was variable within the same histological section and ranges from small to medium-sized or large cells (14). (21,22). A cytotoxic phenotype was not associated with CD4 or CD8 expression and was not linked to prognosis, which was in line with several studies on nodal PTL NOS (22)(23)(24)(25). ...
... Remarkably, we observed an unusually high rate of aberrant CD20 expression in one fifth of the cases. CD20 could represent an interesting therapeutic target, as reported in a few cases of nodal PTL NOS (21,22). CD20(+) cutaneous PTL NOS does not express other B-cell markers, allowing distinction from B-cell lymphomas. ...
... In nodal PTL NOS a high proliferative activity is well-documented to predict a poor prognosis (21,22,24,30). Other factors, such as CD4/CD8 phenotype have been discussed, but remain controversial (1, 21, 24, 31). ...
Background:
Cutaneous peripheral T-cell lymphoma, not otherwise specified (PTL NOS) is an aggressive, but poorly characterized neoplasm.
Objectives:
The EORTC cutaneous lymphoma taskforce (CLTF) investigated 33 biopsies of 30 patients with primary cutaneous PTL NOS to analyze their clinical, histological, immunophenotypic features and outcome.
Methods:
Retrospective analysis of clinical data and histopathological features by an expert panel.
Results:
PTL NOS manifested clinically either with solitary or disseminated rapidly grown ulcerated tumors or disseminated papulo-nodular lesions. Histologically, a mostly diffuse or nodular infiltrate in the dermis and often extending into the subcutis was found. Epidermotropism was rarely present and only mild and focal. Unusual phenotypes were frequent, e.g. CD3+/CD4-/CD8- and CD3+/CD4+/CD8+. Moreover, 18% of the cases exhibited an aberrant expression of the B-cell marker CD20 by the tumor cells. All solitary tumors were located on the limbs and presented a high expression of GATA-3 but this did not correlate with outcome and therefore could not serve as a prognostic factor. The prognosis was shown to be generally poor with 10 of 30 patients (33%) dying of lymphoma within the follow-up of 36 months (mean value; range 3-144). The survival rates were 61% after 3 years (CI 43 - 85%) and 54% after 5 years (CI 36 - 81%). Small to medium-sized morphology of tumor cells was associated with a better outcome than medium to large or large tumor cells. Age, gender, clinical stage, CD4/CD8 phenotype and GATA-3 expression were not associated with prognosis. Chemotherapy was the most common treatment modality, but surgical excision and/or radiotherapy may represent an appropriate first-line treatment for solitary lesions.
Conclusions:
PTL NOS shows an aggressive course in most patients independent of initial presentation, age and phenotype. Cytomorphology was identified as a prognostic factor. The data indicate a need for more effective treatment modalities in PTL NOS.
... Finally, high expression of cell proliferation marker Ki-67 should also contribute to the aggressive course in our patient, because PTCL, NOS showing Ki-67 expression > 80% is reported to herald a worse prognosis (13). ...
... The cells in PTCL-NOS more frequently expressed CD2, CD3, CD4, and CD43, while they less often expressed epithelial membrane antigen (EMA) or cytotoxic proteins than ALK-negative ALCL, while ALK-negative ALCL tumors were more likely to be positive for cytotoxic markers [12]. In European Society for Medical Oncology Clinical Practice Guidelines, having the following IHC criteria was more in favor with the diagnosis of PTCL-NOS: positive cells to CD4, CD8 markers; a drop-off of CD5 and CD7; and TCR rearrangement of αβ and γδ [13,14]. ...
Background:
Primary orbital peripheral T-cell lymphoma, not otherwise specified is an exceedingly rare disorder with a very poor outcome, and to the best of our knowledge only a few cases have been reported in the English literature. We present the youngest reported case describing the successful outcome after management with a thorough review of the English literature of all the reported cases of primary peripheral T-cell lymphoma, not otherwise specified.
Case presentation:
Our patient is a 3-year-old Syrian boy who presented with gradual progressive orbital swelling. A physical examination showed a left orbital dystopia and a superior medial displacement of the globe. Extraocular motility was limited in upward elevation of his left eye. A computed tomography scan and magnetic resonance imaging of his orbit showed a mass involving the lateral and inferior walls of his left orbit and extending intraconally. A diagnosis of peripheral T-cell lymphoma, not otherwise specified was made by careful histopathological examination and Berlin-Frankfurt-Munster protocol was initiated. A 6-month follow up with orbital magnetic resonance imaging showed no sign of orbital or brain involvement.
Conclusions:
Through this report we emphasize two takeaway lessons: (1) always have a high level of suspicion of this entity regardless of the age of the patient; and (2) careful histopathological examination is very important for prompt confirmation of the diagnosis and early commencement of proper treatment.
