Gene Summary

Gene:TRG; T-cell receptor gamma locus
Aliases: TCRG, TRG@
Summary:T cell receptors recognize foreign antigens which have been processed as small peptides and bound to major histocompatibility complex (MHC) molecules at the surface of antigen presenting cells (APC). Each T cell receptor is a dimer consisting of one alpha and one beta chain or one delta and one gamma chain. In a single cell, the T cell receptor loci are rearranged and expressed in the order delta, gamma, beta, and alpha. If both delta and gamma rearrangements produce functional chains, the cell expresses delta and gamma. If not, the cell proceeds to rearrange the beta and alpha loci. This region represents the germline organization of the T cell receptor gamma locus. The gamma locus includes V (variable), J (joining), and C (constant) segments. During T cell development, the gamma chain is synthesized by a recombination event at the DNA level joining a V segment with a J segment; the C segment is later joined by splicing at the RNA level. Recombination of many different V segments with several J segments provides a wide range of antigen recognition. Additional diversity is attained by junctional diversity, resulting from the random addition of nucleotides by terminal deoxynucleotidyltransferase. Several V segments of the gamma locus are known to be incapable of encoding a protein and are considered pseudogenes. Somatic rearrangement of the gamma locus has been observed in T cells derived from patients with T cell leukemia and ataxia telangiectasia. [provided by RefSeq, Jul 2008]
Databases:HGNC, GeneCard, Gene
Source:NCBIAccessed: 15 March, 2017

Cancer Overview

Research Indicators

Publications Per Year (1992-2017)
Graph generated 15 March 2017 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Biomarkers, Tumor
  • Translocation
  • Breast Cancer
  • Immunohistochemistry
  • Genes, Immunoglobulin
  • T-Cell Lymphoma
  • Genetic Recombination
  • Gamma-Chain T-Cell Antigen Receptor Gene Rearrangement
  • Adolescents
  • Adult T-Cell Leukemia-Lymphoma
  • DNA Primers
  • Reproducibility of Results
  • Skin Cancer
  • Infant
  • Polymerase Chain Reaction
  • Gene Rearrangement
  • Paraffin Embedding
  • TRG
  • Molecular Sequence Data
  • Acute Lymphocytic Leukaemia
  • T-Cell Antigen Receptors
  • Melanoma
  • Cutaneous T-cell lymphoma
  • Chromosome 7
  • Residual Disease
  • Southern Blotting
  • Biopsy
  • Immunophenotyping
  • Vascular Neoplasms
  • Thyroiditis, Autoimmune
  • Second Primary Cancer
  • Cancer DNA
  • Mycosis Fungoides
  • T-Lymphocyte Gene Rearrangement
  • Base Sequence
  • Childhood Cancer
  • B-Lymphocytes
  • Clone Cells
  • Protein Array Analysis
  • DNA Sequence Analysis
  • Receptors, Antigen, T-Cell, gamma-delta
  • Immunoglobulin Heavy Chains
Tag cloud generated 15 March, 2017 using data from PubMed, MeSH and CancerIndex

Specific Cancers (6)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: TRG (cancer-related)

Gress V, Wolfesberger B, Fuchs-Baumgartinger A, et al.
Characterization of the T-cell receptor gamma chain gene rearrangements as an adjunct tool in the diagnosis of T-cell lymphomas in the gastrointestinal tract of cats.
Res Vet Sci. 2016; 107:261-6 [PubMed] Related Publications
Feline alimentary lymphoma is the most common hematopoietic neoplasia in cats. It affects mainly the small intestines and is most frequently of T-cell origin. Evaluation of a fine needle aspirate is often the first step in the diagnostic work-up. Differentiation between a resident mature lymphocyte population as encountered in inflammatory bowel disease and small cell lymphoma cannot be achieved by cytology alone. Even full thickness biopsies evaluated by histopathology can be inconclusive. These cases warrant the application of complementary tools like PCR-based T-cell receptor (TCR) clonality testing for confirmation. The aim of this study was to optimize the DNA extraction protocol for formalin fixed and paraffin embedded tissues (FFPE) and to establish a heteroduplex analysis to enhance resolution of the PCR fragments of the T-cell receptor gamma (TCRG) V-J gene. The new protocols resulted in improved quantity and quality of the extracted DNA. Heteroduplex analysis of the samples improved the resolution of the electrophoresis results so that rules for interpretation of the different patterns could be established. Application of this improved setup detected clonal rearrangements in at least one TCRG primer reaction in 31 of 36 of our feline intestinal lymphoma samples after DNA quality testing.

O'Dwyer KM, Advani AS
When to Treat Adults Like Children: Optimizing Therapy for Lymphoblastic Lymphoma in Young Adults.
J Clin Oncol. 2016; 34(6):533-8 [PubMed] Related Publications
A 23-year-old man was urgently referred for evaluation of rapidly enlarging cervical lymphadenopathy, progressive dyspnea, fatigue, night sweats, and an unintentional weight loss of 25 pounds. A computed tomography scan of the neck performed 30 days before referral revealed bilateral cervical and supraclavicular lymphadenopathy (6 × 5 cm). A fine-needle aspirate of nasopharyngeal tissue demonstrated fibroadipose tissue. Tissue collected by core needle biopsy of a left internal jugular lymph node demonstrated a reactive lymph node but no malignancy. The patient was admitted to an academic medical center hospital. His physical examination was remarkable for bulky cervical and supraclavicular lymphadenopathy. A testicular examination was normal. The patient's lactate dehydrogenase concentration was 327 U/L (normal range, 118-225 U/L). A positron emission tomography scan revealed bilateral cervical and supraclavicular lymphadenopathy (6 × 5 cm with a standardized uptake value [SUV] of 14), a 1.3-cm subcutaneous nodule in the left thigh (SUV 16), and two 2.7-cm liver lesions (SUV 14). He underwent an excisional lymph node biopsy. The lymph node revealed effacement of the architecture by an interfollicular infiltrate of lymphoid cells (Fig 1). Mitotic figures were abundant (Ki-67 stain 80% to 90% positive) and there were multiple foci of tissue necrosis. The lymphoblasts were examined by flow cytometry and immunohistochemistry and expressed the T-cell markers CD2, CD3, CD4, and terminal deoxynucleotidyl transferase. A subpopulation of T cells was positive for both CD4 and CD8. Polymerase chain reaction studies revealed a clonal rearrangement of the T-cell receptor γ gene. A marrow aspirate and biopsy revealed normal trilineage hematopoiesis with no evidence of lymphoma and a normal male karyotype (46, XY). A lumbar puncture sample did not contain lymphoma cells. The patient's diagnosis was T-lymphoblastic lymphoma.

Yao J, Wang RH, Li B, et al.
Significance of detecting IgH and TCRγ gene rearrangements in patients with hemopoietic maligancies by real-time quantitative PCR.
Genet Mol Res. 2015; 14(4):12168-77 [PubMed] Related Publications
The aim of our study was to investigate the association of IgH and TCRγ gene rearrangements in hematological malignancies with the disease and clinical application. IgH and TCRγ gene rearrangements were determined in 69 paraffin and bone marrow specimens with SYBR Green I fluorescent dye and RQ-PCR method, including 21 paraffin-embedded tissues of the onset cases and 48 bone marrow samples, representing 15 ALL and 25 AML cases. After chemotherapy, 8 cases were NHL; the 10 cases of the negative control group were healthy people. Among the ALL cases, the IgH rearrangement occurred in 80.0%, the TCRγ rearrangement in 46.7%, and both gene rearrangements in 46.7%. Among the AML cases, the IgH rearrangement occurred in 72.0%, the TCRγ rearrangement in 68.0%, and both gene rearrangements in 60.0%. In the lymphoma cases, the IgH rearrangement occurred in 93.1%, the TCRγ rearrangement in 51.7%, and both gene rearrangements in 44.8%. In the negative control group, the 10 cases were all negative. There was the phenomenon of "sequence-non-fidelity" in the hematologic malignancies; the detection rate of both genes was much higher than that of the single gene. The application of the RQ-PCR method in the detection of IgH and TCRγ gene rearrangements in hematologic malignancies has important clinical significance in MRD monitoring.

Martinez-Escala ME, Guggina LM, Cotliar J, et al.
Cutaneous Involvement in a Case of Intravascular T-Cell Lymphoma With a γδ Phenotype.
Am J Dermatopathol. 2016; 38(2):e27-9 [PubMed] Related Publications
Intravascular lymphomas (IVL) are uncommon variants of extranodal non-Hodgkin which are usually difficult to diagnose because of their lack of clinical uniformity. Most cases are of B-cell differentiation followed by natural killer/T-cell differentiation and underlying CD30 lymphoproliferative conditions. Epstein-Barr virus is pathogenically related in most of the natural killer/T-cell variants, and the skin is a common site of presentation noted in approximately 40% of cases. Recently, cases with uncommon phenotypes have been described, expanding our understanding of the pathogenesis of this condition. In this report, we describe a 67-year-old man with a 3-month history of constitutional symptoms associated with linear purpuric macules on the trunk, pancytopenia, and high levels of serum lactate dehydrogenase. He had been followed for longstanding adenopathy and hepatosplenomegaly. Skin biopsy demonstrated a intravascular lymphocytic proliferation with positivity for CD3, CD2, CD5, and γδ T-cell receptor marker; in situ hybridization Epstein-Barr virus RNA was negative. The patient was subsequently treated with chemotherapy and allogenic stem cell transplant. He remains in complete remission 6 months posttransplant. Although the presence of hepatosplenomegaly led to consideration of a hepatosplenic T-cell lymphoma, it was pre-existing for several years making the diagnosis doubtful. To our knowledge, this is the first case report of an IVL γδ T-cell lymphoma.

Gu L, Hong L, Ling Z, et al.
Establishment and Characterization of a CD20-Positive NK/T-Cell Lymphoma Cell Line.
Clin Lab. 2015; 61(7):731-9 [PubMed] Related Publications
BACKGROUND: CD20 positive NK/T-cell lymphoma is extremely rare and difficult for clinical treatment. Due to the lack of an established cell model for this disease, less is known about its biological characterization and potential therapeutic options.
METHODS: A cell line of NK/T-cell lymphoma, which was enriched by magnetic sorting with proper cell surface markers (CD56) from peripheral blood mononuclear cells (PBMCs) drawn from a 21-year-old male patient with nasal angiocentric NK/T-cell lymphoma, was designated as ZQNK-29. Immunophenotypic analysis of ZQNK-29 was performed by flow cytometric and immunohistochemical analysis. Comparative genomic hybridization (CGH) analysis was used for cytogenetic analysis of ZQNK-29. Potential rearrangements of the immunoglobulin gene and Epstein-Barr virus (EBV) infection were examined by PCR and RT-PCR, respectively.
RESULTS: ZQNK-29 cells express the phenotypic T-cell marker (CD3), T cell activation markers (HLA-DR), markers for both NK and cytotoxic T lymphocytes (TIA-1), and B-lineage marker CD20; however, expression of CD56 was not detected in expanded ZQNK-29 cells although this NK cell surface marker was used as one of selective cell surface markers for the initial isolation of NK/T cells. RT-PCR analysis showed that the pattern of gene expressions for infected EBV was latency type III, with the expressions of LMP1, EBNA-1, and EBNA-2; no rearrangements were found in the heavy-chain of the immunoglobulin gene or in the y chain of the T cell receptors (TCRs) gene. CGH analysis demonstrated that ZQNK-29 possessed an abnormal karyotype, 46XY, 1p (dist)+, 4p (dist)+, 4q (mid)-, 5q (mid)-, 9q (dist)+, 16p (dist)+, 16q (dist)+, 17p+, 17q (dist)+, 19q (dist)+, 20p+, 20q+, 21q+, and 22q+. Of these, 1p (dist)+, which has been confirmed to be mitochondrial DNA amplification, is believed to be mainly caused by EBV infection.
CONCLUSIONS: ZQNK-29 is a well characterized premature human NK/T-cell lymphoma cell line with expression of the B-cell marker CD20 and will provide a useful pre-clinic model for characterization and potential therapeutic studies of the aggressive NK/T-cell lymphoma.

Sheng N, Li Z, Su W, et al.
A Case of Primary Cutaneous Aggressive Epidermotropic CD8+ Cytotoxic T-cell Lymphoma Misdiagnosed as Febrile Ulceronecrotic Mucha-Habermann Disease.
Acta Derm Venereol. 2016; 96(1):136-7 [PubMed] Related Publications

Goto-Koshino Y, Mochizuki H, Sato M, et al.
Construction of a multicolor GeneScan analytical system to detect clonal rearrangements of immunoglobulin and T cell receptor genes in canine lymphoid tumors.
Vet Immunol Immunopathol. 2015; 165(1-2):81-7 [PubMed] Related Publications
Polymerase chain reaction (PCR) amplification to detect immunoglobulin heavy chain (IgH) and T cell receptor γ-chain (TCRγ) gene rearrangements has recently become widely used as part of the diagnostic strategy for lymphoid tumors in dogs. In this study, we constructed a multicolor GeneScan analytical system to improve the sensitivity and resolution of the clonality analysis of antigen receptor gene rearrangements in dogs. We used 7 reactions per sample, with 2 PCR conditions, to amplify IgH/TCRγ and control genes. By using multicolor-labeled primers, these 7 PCR products could be combined into 3 tubes before capillary electrophoresis. Clonal rearrangement of the IgH/TCRγ genes was detected in 93.3% of dogs with multicentric lymphoma and 84.6% of dogs with gastrointestinal lymphoma. Detection sensitivity of the clonally expanded cells in the background of normal peripheral blood mononuclear cells was 1-10%. The multicolor GeneScan analytical system developed here may prove to be helpful for the diagnosis of lymphoid tumors in dogs.

Ladrigan MK, Poligone B
The spectrum of pigmented purpuric dermatosis and mycosis fungoides: atypical T-cell dyscrasia.
Cutis. 2014; 94(6):297-300 [PubMed] Related Publications
We report the case of a healthy 17-year-old adolescent boy with an unremarkable medical history who presented with an asymptomatic fixed rash on the abdomen, buttocks, and legs. The rash initially developed in a small area on the right leg 2 years prior and had progressed slowly. Prior biopsies were consistent with pigmented purpura. Clinical examination revealed multiple annular purpuric patches on the abdomen, buttocks, and legs covering approximately 20% of the body surface area without lymphadenopathy or hepatosplenomegaly. Additional biopsies demonstrated changes consistent with mycosis fungoides (MF). T-cell receptor g gene rearrangements demonstrated clonality. The patient was diagnosed with stage IB MF of the pigmented purpura-like variant. The patient responded well to psoralen plus UVA therapy. It has been proposed that pigmented purpuric dermatosis (PPD) is a form of cutaneous T-cell lymphoid dyscrasia and that T-cell gene rearrangement studies should be obtained for prognostic evaluation in patients with widespread disease. In our patient, the clinical appearance of the lesions, pathologic findings, and gene rearrangement studies led to the diagnosis of MF. Until the potential for evolution of PPD to malignant disease is better understood, further evaluation of MF in patients with an unusual presentation of pigmented purpura is warranted.

Argyris PP, Koutlas IG, Cooley S, et al.
Angioimmunoblastic T-cell lymphoma of the oral cavity presenting as gingival mass: report of the histopathologic and molecular characteristics of an unusual case featuring clonal T-cell receptor γ gene rearrangement by polymerase chain reaction.
Oral Surg Oral Med Oral Pathol Oral Radiol. 2014; 118(6):e198-204 [PubMed] Related Publications
Angioimmunoblastic T-cell lymphoma (AITL) is a rare neoplastic process constituting 15% to 20% of peripheral T-cell lymphomas. We report the clinicopathologic and molecular characteristics of an unusual intraoral manifestation of AITL. A 35-year-old white man with a history of AITL presented with a 2.5-cm, poorly circumscribed, erythematous, exophytic lesion occupying the free and attached buccal gingiva of the right maxillary lateral incisor and canine. Histopathologically, the tumor showed diffuse and intense polymorphic infiltration by small to medium-sized lymphocytes admixed with numerous eosinophils. The neoplastic cells showed strong and diffuse reactivity for CD2, CD3, CD4, CD10, and PD-1 (programmed cell death 1 [PDCD1]). Rare immunopositivity was seen with BCL6 (B-cell CLL/lymphoma 6) and CXCL13 (chemokine [C-X-C motif] ligand 13). Neoplastic cells were negative for CD7 and EBER ISH (Epstein-Barr virus-encoded small RNA in situ hybridization). CD21 did not show any increased follicular dendritic cell component. Polymerase chain reaction-based assay found monoclonal T-cell receptor γ (TRG) gene rearrangements. Diagnosis of recurrent/residual AITL was rendered. Chemotherapy was administered, with the intraoral tumor resolving completely 3 months later.

Wei Q, Papavassiliou P, Rehder C, et al.
T-cell prolymphocytic leukemia in a 63-year-old female with a pre-existing T-cell large granular lymphocytic leukemia: metachronous T-cell leukemias with discordant subset restrictions (CD4 versus CD8) and distinct clonal identities.
Pathol Res Pract. 2014; 210(12):1100-5 [PubMed] Related Publications
A 55-year-old female with T-cell large granular lymphocytic leukemia (T-LGL) (CD8+) was initially treated with anti-thymocyte globulin and then cyclosporine due to anemia/neutropenia. While the severity of cytopenia varied with the therapy, the T-LGL persisted. Eight years after the initial diagnosis, she developed lymphadenopathy and hepatosplenomegaly. A complete blood cell count revealed leukocytosis, anemia and thrombocytopenia with ∼ 80% lymphocytes. In contrast to the LGL cells, the blood lymphocytes at this time were medium-large in size and had oval/irregular nuclei, condensed chromatin, indistinct nucleoli and a moderate amount of basophilic cytoplasm, many with elongated vacuoles, and some with cytoplasmic projections. The abnormal lymphocytes comprised ∼ 30% of the bone marrow cellularity with interstitial infiltrates/aggregates. Immunophenotypic analyses demonstrated a T-cell neoplasm with features suggestive of T-cell prolymphocytic leukemia (T-PLL) (CD4+). Cytogenetic analysis revealed a novel clone with complex abnormalities. PCR-based TRG gene rearrangement studies detected a clonal amplicon distinct from that of the preexisting T-LGL. Because of the chronological sequence of the two T-cell neoplasms, this case was initially considered an aggressive transformation of T-LGL. However, this was ultimately excluded by a discordant CD4-subset restriction and the presence of a distinct clonal identity. While these two T-cell neoplasms may have intrinsic connections, the underlying pathogenesis remains to be investigated.

Jiang X, Yin W, Song J, et al.
Primary central nervous system extranodal NK/T cell lymphoma, nasal type, with antecedent hemophagocytic syndrome in a child.
Pediatr Dev Pathol. 2014 Nov-Dec; 17(6):482-6 [PubMed] Related Publications
Primary central nervous system (CNS) extranodal natural killer (NK)/T-cell lymphoma, nasal type (NKTCL), is an exceedingly uncommon entity. Here, we present a case of CNS NKTCL that manifested initially as hemophagocytic syndrome 4 months earlier in a 13-year-old girl. Histological examination revealed the cerebellum mass was composed of large-sized and atypical tumor cells, with an angiocentric and angiodestructive growth pattern and prominent necrosis. The tumor cells exhibited marked pleomorphism with conspicuous nucleoli and prominent mitotic activity. Immunohistochemical staining showed the tumor cells were positive for CD45, CD2, CD3ε, CD30, CD43, CD56, and granzyme B. Epstein-Barr virus--encoded ribonucleic acid was expressed in almost all of the nuclei of the lymphoma cells. The T-cell receptor γ chain gene rearrangement study showed no evidence of a clonal rearrangement. The patient was treated with etoposide and dexamethasone and died a few days after the operation. As far as we know, this case is the 1st pediatric and female patient of primary CNS NKTCL with antecedent hemophagocytic syndrome, which highlights the clinical data and is helpful for the diagnosis of this tumor.

Finalet Ferreiro J, Rouhigharabaei L, Urbankova H, et al.
Integrative genomic and transcriptomic analysis identified candidate genes implicated in the pathogenesis of hepatosplenic T-cell lymphoma.
PLoS One. 2014; 9(7):e102977 [PubMed] Free Access to Full Article Related Publications
Hepatosplenic T-cell lymphoma (HSTL) is an aggressive lymphoma cytogenetically characterized by isochromosome 7q [i(7)(q10)], of which the molecular consequences remain unknown. We report here results of an integrative genomic and transcriptomic (expression microarray and RNA-sequencing) study of six i(7)(q10)-positive HSTL cases, including HSTL-derived cell line (DERL-2), and three cases with ring 7 [r(7)], the recently identified rare variant aberration. Using high resolution array CGH, we profiled all cases and mapped the common deleted region (CDR) at 7p22.1p14.1 (34.88 Mb; 3506316-38406226 bp) and the common gained region (CGR) at 7q22.11q31.1 (38.77 Mb; 86259620-124892276 bp). Interestingly, CDR spans a smaller region of 13 Mb (86259620-99271246 bp) constantly amplified in cases with r(7). In addition, we found that TCRG (7p14.1) and TCRB (7q32) are involved in formation of r(7), which seems to be a byproduct of illegitimate somatic rearrangement of both loci. Further transcriptomic analysis has not identified any CDR-related candidate tumor suppressor gene. Instead, loss of 7p22.1p14.1 correlated with an enhanced expression of CHN2 (7p14.1) and the encoded β2-chimerin. Gain and amplification of 7q22.11q31.1 are associated with an increased expression of several genes postulated to be implicated in cancer, including RUNDC3B, PPP1R9A and ABCB1, a known multidrug resistance gene. RNA-sequencing did not identify any disease-defining mutation or gene fusion. Thus, chromosome 7 imbalances remain the only driver events detected in this tumor. We hypothesize that the Δ7p22.1p14.1-associated enhanced expression of CHN2/β2-chimerin leads to downmodulation of the NFAT pathway and a proliferative response, while upregulation of the CGR-related genes provides growth advantage for neoplastic δγT-cells and underlies their intrinsic chemoresistance. Finally, our study confirms the previously described gene expression profile of HSTL and identifies a set of 24 genes, including three located on chromosome 7 (CHN2, ABCB1 and PPP1R9A), distinguishing HSTL from other malignancies.

Ai X, Fu Q, Wang J, et al.
[Significance of BIOMED-2 standardized IG/TCR gene rearrangement detection in paraffin-embedded section in lymphoma diagnosis].
Zhonghua Xue Ye Xue Za Zhi. 2014; 35(6):495-8 [PubMed] Related Publications
OBJECTIVE: To explore the feasibility of detecting lymphoma with the application of BIOMED-2 standardized immunoglobulin/T cell receptor (IG/TCR) gene rearrangement system in formalin fixed paraffin-embedded (FFPE) tissue samples, and to discuss the relationship between the longest amplification fragment of extracted DNA and positive detection rate of different IGH V-J primers.
METHODS: DNA was extracted from 50 cases of FFPE tissue samples. Multiplex-PCR amplifications were performed and then the IG/TCR gene rearrangements were analyzed using BIOMED-2 standardized clonality analysis system.
RESULTS: (1)When the DNA concentration was diluted to 50-100 ng/μl from 100-500 ng/μl, the proportion of the longest amplification fragment (300-400 bp) of DNA was improved from 10.0% to 90.0% in 30 cases of diffuse large B cell lymphoma (DLBCL) wax roll samples (P<0.01). The positive rate of IGH+IGK was increased from 46.7% to 83.3%, the difference was statistically significant (P=0.006). The lengths of the longest amplification fragments of DNA were all longer than 300 bp in the paraffin section samples of DLBCL. The positive rate of IGH+IGK of these samples was 96.7%. The difference of the positive rate of IGH+IGK between the wax roll samples and the paraffin section samples had no statistical significance (P=0.195). (2)When the concentration of DNA was high, most of the longest amplification fragments of extracted DNA were 100 bp or 200 bp, and the detection rate of short fragment IGH FR3 was more stable than that of long fragment IGH FR1. (3)The clonality analysis of TCRG+TCRB in all 13 cases of peripheral T cell lymphoma samples showed positive results, while no positive IG/TCR clones were found in 7 cases of reactive lymphoid tissue hyperplasia in control group.
CONCLUSION: Dilution of DNA is the only method to improve not only the proportion of longest fragment amplification but also the detection rate of clonality. The detection rate of IGH FR3 would not be affected by the concentration of DNA. The application of BIOMED-2 standardized IG/TCR gene rearrangement system in FFPE tissue samples plays an important role in the lymphoma diagnosis.

Sugimoto KJ, Shimada A, Wakabayashi M, et al.
T-cell lymphoblastic leukemia/lymphoma with t(7;14)(p15;q32) [TCRγ-TCL1A translocation]: a case report and a review of the literature.
Int J Clin Exp Pathol. 2014; 7(5):2615-23 [PubMed] Free Access to Full Article Related Publications
A 22-year-old man sought medical advice for a swelling in the right side of the neck in December 2011. Histopathological examination of the lymph node biopsy initially suggested reactive lymphadenitis, on account of the only sparse presence of tumor cells. Bone marrow examination was performed in February 2012 revealed findings consistent with a diagnosis of T-cell lymphoblastic leukemia/lymphoma (T-LBL), and the patient was begun on remission induction therapy. The bone marrow showed an immature thymocytic pattern: cytoplasmic CD3+, surface CD3-, CD5+, CD4-, and CD8-. Re-assessment of the lymph node specimens revealed the same phenotype of the cells in the lymph node as that of the blasts in the bone marrow. In addition, a chromosomal aberration t(7;14)(p15;q32) was noted. The lymph node biopsy specimens were examined by paraffin-embedded tissue section-fluorescence in situ hybridization (PS-FISH), which revealed a fusion signal of T-cell receptor (TCR)γ gene (7p15) with T-cell leukemia/lymphoma 1A (TCL1A) gene (14q32.13). There have been at least 10 reported cases of T-LBL with t(7;14)(p15;q32), including the present case. However, this is the first reported case in which TCRγ-TCL1A translocation was confirmed by FISH.

Mok MM, Du L, Wang CQ, et al.
RUNX1 point mutations potentially identify a subset of early immature T-cell acute lymphoblastic leukaemia that may originate from differentiated T-cells.
Gene. 2014; 545(1):111-6 [PubMed] Related Publications
The RUNX1/AML1 gene is among the most frequently mutated genes in human leukaemia. However, its association with T-cell acute lymphoblastic leukaemia (T-ALL) remains poorly understood. In order to examine RUNX1 point mutations in T-ALL, we conducted an amplicon-based deep sequencing in 65 Southeast Asian childhood patients and 20 T-ALL cell lines, and detected RUNX1 mutations in 6 patients (9.2%) and 5 cell lines (25%). Interestingly, RUNX1-mutated T-ALL cases seem to constitute a subset of early immature T-ALL that may originate from differentiated T-cells. This result provides a deeper insight into the mechanistic basis for leukaemogenesis.

Poopak B, Saki N, Purfatholah AA, et al.
Pattern of immunoglobulin and T-cell receptor-δ/γ gene rearrangements in Iranian children with B-precursor acute lymphoblastic leukemia.
Hematology. 2014; 19(5):259-66 [PubMed] Related Publications
INTRODUCTION: Acute lymphoblastic leukemia (ALL) cells have unique rearranged immunoglobulin heavy chain (IgH), immunoglobulin light chain (IgK), and T-cell receptor (TCR) genes, which can be used as markers for clonality assay and evaluation of minimal residual disease. In this study, we have evaluated the pattern of IgH, IgK chains, and TCRG/D gene rearrangements in precursor-B ALL.
MATERIALS AND METHODS: In our prospective study, hyper-variable regions (CDRI and III) of IgH, TCRD (Vδ2-Dδ3 and Dδ2-Dδ3), TCRG (Vγ, VγI, and VγII), and IgK (Vκ-Kde) were studied in 126 cases with diagnosis of B-precursor ALL.
RESULTS: One hundred and fourteen (90.5%) out of 126 patients had clonal rearrangements of IgH using consensus primers for CDRI and/or CDRIII regions. Monoclonal, biclonal, and oligoclonal patterns were observed in 63 (57.8%), 38 (34.9%), and 6 (5.5%) patients with IgH (CDRIII) rearrangements, respectively. Clonal rearrangements of TCRG (Vγ) and VγI/II were present in 79.3 and 64.9% of patients, respectively, and only 5% of cases showed biclonal pattern. The VγII rearrangement was the most common (46.8%) type in TCRG. Vδ2-Dδ3 and Dδ2-Dδ3 partial gene rearrangements were observed in 47 (45.2%; n = 104) and 11 (16.6%; n = 66) patients, respectively. Biclonal/oligoclonal patterns were present in 13 (27.7%) and 2 (4.3%) cases with Vδ2-Dδ3 rearrangement, respectively. Only one patient had biclonal Dδ2-Dδ3 rearrangement. Clonal pattern of IgK-Kde was detected in 59 cases (67%; n = 88).
CONCLUSION: Our findings showed that clonal rearrangements of IgH and TCRD (Vδ2-Dδ3 and Dδ2-Dδ3) genes had similar patterns to other studies. Frequency of TCRG (VγI and VγII) and IgK rearrangements was found to be slightly higher than previous reports. Among the IgK rearrangements, VKI (25%) was the most common.

Wang E, Papavassiliou P, Wang AR, et al.
Composite lymphoid neoplasm of B-cell and T-cell origins: a pathologic study of 14 cases.
Hum Pathol. 2014; 45(4):768-84 [PubMed] Related Publications
We retrospectively analyzed 14 composite lymphoma/lymphoid neoplasms (CL) of B-cell/T-cell origins. These consisted of a spectrum of T-cell neoplasms in combination with different B-cell lymphomas/leukemias, with peripheral T-cell lymphoma and diffuse large B-cell lymphoma encountered most frequently for each respective neoplastic lineage. Histopathologic evaluation demonstrated 6 patterns of neoplastic distribution, including zone, inverted zone, diffuse mixed, regional/nodular mixed, compartmental, and segmental distributions. Four of 9 cases studied were positive for Epstein-Barr virus, all with a mixed pattern, suggesting that this pattern may predict an Epstein-Barr virus association. None of 14 cases was considered CL at the initial histologic evaluation. Only 6 (46.2%) of 13 cases had coexisting B-cell/T-cell neoplasms highlighted by immunohistochemistry, and the other 7 (53.8%) cases had 1 or both of the neoplastic components hidden. Flow cytometry detected both neoplastic lineages in 4 (44%) but failed to detect a clonal B-cell population in 4 (44%) and missed neoplastic T cells in 1 (11.1%) of 9 cases. Molecular testing detected clonal rearrangement of IGH/K gene in 11 (84.6%) of 13 cases, and clonal rearrangement of the TCRG/B gene in 13 (92.9%) of 14 cases, including 8 with identical amplicons detected in separate samples. CLs of B-cell/T-cell origin are heterogeneous in subtype combination and topographic pattern, often with one of the components histologically occult. A multidisciplinary approach is emphasized to establish a definitive diagnosis in these challenging cases.

Schumacher JA, Duncavage EJ, Mosbruger TL, et al.
A comparison of deep sequencing of TCRG rearrangements vs traditional capillary electrophoresis for assessment of clonality in T-Cell lymphoproliferative disorders.
Am J Clin Pathol. 2014; 141(3):348-59 [PubMed] Related Publications
OBJECTIVES: To design and evaluate a next-generation sequencing (NGS)-based method for T-cell receptor γ (TCRG) gene-based T-cell clonality testing on the Ion Torrent Personal Genome Machine (Life Technologies, Carlsbad, CA) platform.
METHODS: We analyzed a series of peripheral blood, bone marrow, and formalin-fixed paraffin-embedded tissue specimens with NGS vs traditional capillary electrophoresis methods.
RESULTS: Using a custom analysis algorithm that we developed, our NGS assay identified between 2,215 and 48,222 unique TCRG rearrangements in a series of 48 samples. We established criteria for assigning clonality based on parameters derived from both the relative and absolute frequencies of reads. In a comparison with standard capillary electrophoresis, 19 of 19 polyclonal samples and 24 of 27 samples that appeared clonal were in agreement. The three discrepant samples demonstrated some of the pitfalls of amplicon length-based testing. Dilution studies with T-lymphoid cell lines demonstrated that a known clonal sequence could be routinely identified when present in as few as 0.1% of total cells demonstrating suitability in residual disease testing. A series of samples was also analyzed on a second NGS platform and yielded very similar results with respect to the frequency and sequence of the clonal rearrangement.
CONCLUSIONS: In this proof-of-concept study, we describe an NGS-based T-cell clonality assay that is suitable for routine clinical testing either alone or as an adjunct to traditional methods.

Hsi AC, Kreisel FH, Frater JL, Nguyen TT
Clinicopathologic features of adult T-cell leukemias/lymphomas at a North American tertiary care medical center: infrequent involvement of the central nervous system.
Am J Surg Pathol. 2014; 38(2):245-56 [PubMed] Related Publications
Human T-cell lymphotropic virus type 1 is associated with adult T-cell leukemia/lymphoma (ATLL). Published series of ATLLs seen at a United States medical institution are rare. We present the features of 4 ATLLs diagnosed at our North American tertiary care medical center from 1990 to 2012. Despite the absence of a history of origin from an endemic region, all our ATLLs demonstrated evidence of human T-cell lymphotropic virus type 1 infection. Central nervous system (CNS) involvement by ATLL was uncommon in our series, and represented only 1.6% (1/64) of all CNS B-cell or T-cell lymphomas diagnosed over a 20+ year period at our institution. Review of the medical literature reveals that the majority of CNS-involved ATLLs present with the lymphoma or acute subtype, and complete remission is difficult to achieve in these cases. CNS involvement frequently occurs with a systemic disease, which carries an aggressive clinical course with poor prognosis. In addition, CNS involvement by ATLL can be the initial presentation or seen with relapsed disease, can be the only site or be associated with other tissue sites of involvement, and may manifest with variable clinical signs/symptoms. Our retrospective study reveals that ATLLs are rare mature T-cell lymphomas in a native North American population, but the clinical and histopathologic features of ATLLs from this nonendemic region are similar to those seen from other endemic regions. Early recognition of these rare ATLLs involving uncommon sites, such as the CNS, will help optimize treatment for these infrequent mature T-cell lymphomas.

Vigliar E, Cozzolino I, Picardi M, et al.
Lymph node fine needle cytology in the staging and follow-up of cutaneous lymphomas.
BMC Cancer. 2014; 14:8 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Lymph nodal involvement is an important clinical-pathological sign in primary cutaneous lymphoma (PCL), as it marks the transformation/evolution of the disease from localized to systemic; therefore the surveillance of lymph nodes is important in the staging and follow up of PCL. Fine needle cytology (FNC) is widely used in the diagnosis of lymphadenopathies but has rarely been reported in PCL staging and follow-up. In this study an experience on reactive and neoplastic lymphadenopathies arisen in PCL and investigated by FNC, combined to ancillary techniques, is reported.
METHODS: Twenty-one lymph node FNC from as many PCL patients were retrieved; 17 patients had mycosis fungoides (MF) and 4 a primary cutaneous B-cell lymphoma (PBL). In all cases, rapid on site evaluation (ROSE) was performed and additional passes were used to perform flow cytometry (FC), immunocytochemistry (ICC) and/or polymerase chain reaction (PCR) to assess or rule out a possible clonality of the corresponding cell populations.
RESULTS: FNC combined with FC, ICC, and PCR identified 12 cases of reactive, non specific, hyperplasia (BRH), 4 dermatopathic lymphadenopathy (DL), 4 lymph nodal involvement by MF and 1 lymph nodal involvement by cutaneous B-cell lymphoma.
CONCLUSIONS: FNC coupled with ancillary techniques is an effective tool to evaluate lymph node status in PCL patients, provided that ROSE and a rational usage of ancillary techniques is performed according to the clinical context and the available material. The method can be reasonably used as first line procedure in PCL staging and follow up, avoiding expensive and often ill tolerated biopsies when not strictly needed.

Miyata-Takata T, Takata K, Yamanouchi S, et al.
Detection of T-cell receptor γ gene rearrangement in paraffin-embedded T or natural killer/T-cell lymphoma samples using the BIOMED-2 protocol.
Leuk Lymphoma. 2014; 55(9):2161-4 [PubMed] Related Publications
While the use of polymerase chain reaction (PCR)-based clonality analysis of formalin-fixed paraffin-embedded (FFPE) tissue has recently become widespread, the detection sensitivity for lymphoma subtypes using FFPE samples is not well known. Here, we analyzed T-cell receptor γ chain (TCRG) gene rearrangement clonality in 100 cases of T- or natural killer (NK)/T-cell lymphoma and examined detection sensitivity according to lymphoma subtype. Clonality was detected in approximately 80% of the major T-cell lymphoma subtypes: peripheral T-cell lymphoma, not otherwise specified, 84% (21/25 cases); angioimmunoblastic T-cell lymphoma, 71% (15/21 cases); and adult T-cell leukemia/lymphoma, 80% (8/10 cases). The number of clonal peaks differed according to subtype. TCRG gene rearrangement was not detected in 63 cases of B-cell lymphoma or reactive lesions. Thus, clonality analysis can effectively and reliably detect TCRG gene rearrangement in T-cell lymphoma cases and could, therefore, be a useful diagnostic tool in routine practice.

Yasuda K, Matsuki Y, Kobari S, et al.
TCRγ rearrangement and Epstein- Barr virus are detected both in lymphadenopathy of adult-onset Still's disease and in accompanying peripheral T-cell lymphoma.
Pathol Int. 2013; 63(11):568-72 [PubMed] Related Publications

Shan GD, Hu FL, Yang M, et al.
Clonal immunoglobulin heavy chain and T-cell receptor γ gene rearrangements in primary gastric lymphoma.
World J Gastroenterol. 2013; 19(34):5727-31 [PubMed] Free Access to Full Article Related Publications
AIM: To study the diagnostic value of immunoglobulin heavy chain (IgH) and T-cell receptor γ (TCR-γ) gene monoclonal rearrangements in primary gastric lymphoma (PGL).
METHODS: A total of 48 patients with suspected PGL at our hospital were prospectively enrolled in this study from January 2009 to December 2011. The patients were divided into three groups (a PGL group, a gastric linitis plastica group, and a benign gastric ulcer group) based on the pathological results (gastric mucosal specimens obtained by endoscopy or surgery) and follow-up. Endoscopic ultrasonography (EUS) and EUS-guided biopsy were performed in all the patients. The tissue specimens were used for histopathological examination and for IgH and TCR-γ gene rearrangement polymerase chain reaction analyses.
RESULTS: EUS and EUS-guided biopsy were successfully performed in all 48 patients. In the PGL group (n = 21), monoclonal IgH gene rearrangements were detected in 14 (66.7%) patients. A positive result for each set of primers was found in 12 (57.1%), 8 (38.1%), and 4 (19.0%) cases using FR1/JH, FR2/JH, and FR3/JH primers, respectively. Overall, 12 (75%) patients with mucosal-associated lymphoid tissue lymphoma (n = 16) and 2 (40%) patients with diffuse large B-cell lymphoma (n = 5) were positive for monoclonal IgH gene rearrangements. No patients in the gastric linitis plastica group (n = 17) and only one (10%) patient in the benign gastric ulcer group (n = 10) were positive for a monoclonal IgH gene rearrangement. No TCR-γ gene monoclonal rearrangements were detected. The sensitivity of monoclonal IgH gene rearrangements was 66.7% for a PGL diagnosis, and the specificity was 96.4%. In the PGL group, 8 (100%) patients with stage IIE PGL (n = 8) and 6 (46.1%) patients with stage IE PGL (n = 13) were positive for monoclonal IgH gene rearrangements.
CONCLUSION: IgH gene rearrangements may be associated with PGL staging and may be useful for the diagnosis of PGL and for differentiating between PGL and gastric linitis plastica.

Hartmann S, Helling A, Döring C, et al.
Clonality testing of malignant lymphomas with the BIOMED-2 primers in a large cohort of 1969 primary and consultant biopsies.
Pathol Res Pract. 2013; 209(8):495-502 [PubMed] Related Publications
The introduction of the BIOMED-2 primers allowed for reliable comparisons of clonality testing data of malignant lymphomas from different laboratories. This study undertook a retrospective analysis of a large cohort of cases; 1862 cases involved the immunoglobulin heavy chain locus (IGH VH-JH), and 1527 cases involved the T cell receptor gamma locus (TCRG). We confirmed previously published clonality rates in various B cell, T cell, and Hodgkin lymphoma cases. In reactive lesions, clonality for the IGH locus was frequently accompanied by additional polyclonal background. Clonality for TCRG was found in a subgroup of diffuse large B cell lymphomas. On closer morphologic inspection, seven cases appeared to have arisen from an underlying peripheral T-cell lymphoma. Five cases with monoclonal TCRG rearrangements, originally diagnosed as Hodgkin lymphomas, were reclassified as T-cell lymphomas. TCRG clonality was very rarely only observed in Hodgkin lymphoma. In case of clear TCRG clonality a T-cell neoplasia must be ruled out on morphological grounds. By careful examination of the rearrangement patterns, including an assessment of a co-amplified polyclonal background, clonality testing provides a powerful tool which in concert with morphologic and immunohistochemical parameters can lead to a firm diagnosis.

Van Vlierberghe P, Ambesi-Impiombato A, De Keersmaecker K, et al.
Prognostic relevance of integrated genetic profiling in adult T-cell acute lymphoblastic leukemia.
Blood. 2013; 122(1):74-82 [PubMed] Free Access to Full Article Related Publications
Adult T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic tumor associated with poor outcome. In this study, we analyzed the prognostic relevance of genetic alterations, immunophenotypic markers, and microarray gene expression signatures in a panel of 53 adult T-ALL patients treated in the Eastern Cooperative Oncology Group E2993 clinical trial. An early immature gene expression signature, the absence of bi-allelic TCRG deletion, CD13 surface expression, heterozygous deletions of the short arm of chromosome 17, and mutations in IDH1/IDH2 and DNMT3A genes are associated with poor prognosis in this series. In contrast, expression of CD8 or CD62L, homozygous deletion of CDKN2A/CDKN2B, NOTCH1 and/or FBXW7 mutations, and mutations or deletions in the BCL11B tumor suppressor gene were associated with improved overall survival. Importantly, the prognostic relevance of CD13 expression and homozygous CDKN2A/CDKN2B deletions was restricted to cortical and mature T-ALLs. Conversely, mutations in IDH1/IDH2 and DNMT3A were specifically associated with poor outcome in early immature adult T-ALLs. This trial was registered at as #NCT00002514.

Gao LM, Liu WP, Yang QP, et al.
Aggressive natural killer-cell leukemia with jaundice and spontaneous splenic rupture: a case report and review of the literature.
Diagn Pathol. 2013; 8:43 [PubMed] Free Access to Full Article Related Publications
UNLABELLED: Aggressive natural killer cell leukemia/lymphoma (ANKL) is a rare aggressive form of NK-cell neoplasm. We report an uncommon case of 36-year-old male who showed jaundice and spontaneous splenic rupture. The diagnosis was established by the biopsy of liver and spleen. The monomorphous medium-size neoplastic cells infiltrated into portal areas and sinus of liver as well as the cords and sinus of the spleen. Necrosis, mitotic figures and significant apoptosis could be seen easily. These neoplastic cells demonstrated a typical immunophenotype of CD3ε+, CD56+, CD16+, Granzyme B+, TIA-1+. T-cell receptor γ (TCR-γ) gene rearrangement analysis showed germline configuration and the result of in situ hybridization for Epstein-Barr virus-encoded RNA (EBER-ISH) was positive. The patient has undergone an aggressive clinical course and died of multi-organ function failure 14 days later after admission. To the best of our knowledge, this is the first case of ANKL with spontaneous splenic rupture, and we should pay more attention to recognize it.
VIRTUAL SLIDES: The virtual slide(s) for this article can be found here:

Whitling NA, Shanesmith RP, Jacob L, et al.
Composite lymphoma of mycosis fungoides and cutaneous small B-cell lymphoma in a 73-year-old male patient.
Hum Pathol. 2013; 44(4):670-5 [PubMed] Related Publications
Composite lymphoma of T-cell and B-cell type is uncommon, and the one occurring primarily on skin is extremely rare. Herein, we report a unique case of composite lymphoma of mycosis fungoides and cutaneous small B-cell lymphoma in a 73-year-old male patient. The patient presented with multiple erythematous patches, plaques, and nodules on the upper arms, scalp, and trunk. Four punch biopsies of arm and scalp lesions demonstrated lymphoid infiltrate in superficial to deep dermis with a characteristic zone distribution of T-cell and B-cell components. T cells were distributed in papillary and perifollicular dermis and displayed a larger size with convoluted nuclei, whereas B cells were small sized, assuming nodular infiltrate in mid-deep dermis with coexpression of CD5. Molecular test detected clonal rearrangement of both TCRG and IGH/K genes with identical amplicons for each gene in all 4 biopsies. Clinical staging revealed no extracutaneous lesions. A multidisplinary approach is emphasized to establish a definitive diagnosis.

Matsushita Y, Takeshita M
Paediatric T-cell lymphoma of the appendix: a case report.
Diagn Pathol. 2013; 8:2 [PubMed] Free Access to Full Article Related Publications
UNLABELLED: A 7-year-old boy with no history of malnutrition or diarrhoea complained of acute abdominal pain, was diagnosed with acute appendicitis, and underwent appendectomy. Histologically, a diffuse infiltrate of large atypical lymphoid cells was found in the entire appendiceal wall. Immunohistochemical examination revealed that the tumour cells expressed T-cell receptor (TCR)-βF1, CD3, CD4, CD25, cytotoxic-related protein TIA1 and granzyme-B, but were negative for CD8, Foxp3, CD20, CD30 and CD56. Polymerase chain reaction (PCR) revealed clonal bands of TCR-γ gene products in the tumour tissue. No anti-cytomegalovirus antibody-positive cells were detected. In situ hybridization revealed no nuclear signals of Epstein-Barr virus (EBV)-encoded RNA. Helicobacter pylori infection was detected in tumour tissue by anti-East Asian cytotoxin-associated gene (Cag) A antibody and PCR using its specific primers. The patient received chemotherapy and has remained in remission for 2 years. To the best of our knowledge, only two cases of appendiceal T-cell non-Hodgkin lymphoma (NHL) have been reported, both in elderly patients. We believe that this is the first reported case of childhood CD4- and TIA1-positive cytotoxic T (Th1)-cell NHL in the appendix or gastrointestinal tract. Helicobacter pylori infection might be an initiator of atypical cytotoxic T-cell proliferation.
VIRTUAL SLIDES: The virtual slide(s) for this article can be found here:

Boone E, Verhaaf B, Langerak AW
PCR-based analysis of rearranged immunoglobulin or T-cell receptor genes by GeneScan analysis or heteroduplex analysis for clonality assessment in lymphoma diagnostics.
Methods Mol Biol. 2013; 971:65-91 [PubMed] Related Publications
The assessment of the presence of clonal lymphoproliferations via polymerase chain reaction (PCR)-based analysis of rearranged immunoglobulin (Ig) or T-cell receptor (TCR) genes is a valuable technique in the diagnosis of suspect lymphoproliferative disorders. Furthermore this technique is more and more used to evaluate dissemination of non-Hodgkin lymphoma and/or the presence of (minimal) residual disease. In this chapter we describe an integrated approach to assess clonality via analysis of Ig heavy chain (IGH), Ig kappa (IGK), TCR beta (TCRB), and TCR gamma (TCRG) gene rearrangements. The described PCR protocol is based on the standardized multiplex PCRs as developed by the European BIOMED-2 collaborative study (Concerted Action BMH4-CT98-3936). Furthermore it also includes the pre-analytical DNA isolation step from various tissues (formalin fixed paraffin-embedded tissue, fresh tissues, body fluids, peripheral blood and bone marrow), GeneScan analysis of labeled PCR products on a genetic analyzer, heteroduplex analysis of unlabeled PCR products, and post-analytical guidelines for the interpretation of the obtained "molecular morphology" patterns.

Lachenal F, Berger F, Cimarelli S, et al.
Primary cerebral angioimmunoblastic T-cell lymphoma.
J Clin Oncol. 2013; 31(5):e64-8 [PubMed] Related Publications

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