Cutaneous Γδ T-cell Lymphoma Research Articles

Update on primary cutaneous T-cell lymphomas rare subtypes

Rare subtypes of cutaneous T-cell lymphomas (CTCL) include four entities, primary cutaneous γδ T-cell lymphoma, primary cutaneous CD8+ aggressive epidermotropic cytotoxic T-cell lymphoma, and primary cutaneous CD4+ small/medium T-cell lymphoproliferative disorders, primary cutaneous acral CD8+ T-cell lymphoma, which were previously considered provisional and are now included in the new 5th World Health Organization classification of hematolymphoid tumors as distinct entities. An updated summary of the clinical, histological, and genomic characteristics of these uncommon CTCL subtypes is given in this review, with a focus on the growing body of knowledge regarding their classification and possible treatment strategies.

Orbital panniculitis-like T-cell lymphoma and review of literature

A 27-year-old patient without a pertinent past medical history presented with chronic orbital inflammation and compressive optic neuropathy. Orbital biopsy with adequate histological and immunohistochemical staining was necessary to identify the disease as subcutaneous panniculitis-like T-cell lymphoma, a rare entity which has only been published as presenting in the orbit on four previous occasions. Immunohistochemical staining is necessary to differentiate the disease from a more benign condition, lupus erythematosus panniculitis, and a more malignant condition, primary cutaneous γδ T-cell lymphoma. The former can be managed with immunosuppression, while the latter may require more aggressive chemotherapy.

Clinicopathologic Determinants of Subcutaneous Panniculitis-like T-Cell Lymphoma (SPTCL) Clinical Outcomes: Analysis of a Pooled Database

Introduction Subcutaneous Panniculitis-like T-cell Lymphoma (SPTCL) is a rare subtype of extra-nodal Peripheral T-cell Lymphoma. SPTCL was initially described as an aggressive T-cell lymphoma frequently associated with hemophagocytic syndrome (HPS) and requiring aggressive multiagent chemotherapy. In 2005, this entity was restricted to SPTCL with αβ phenotype, a less aggressive entity compared to its γδ counterpart, currently known as primary cutaneous γδ T-cell lymphoma. We conducted this analysis to explore the determinants of clinical outcomes in this little-known subtype of Peripheral T-cell Lymphoma. Methods To study the demographic characteristics, molecular and immunohistochemical signatures, therapeutic interventions, survival, and prognostic factors, we compiled a pooled database of 214 cases. Descriptive statistics were calculated. Cox proportional-hazards model and Log-rank tests were used to assess the influence of demographic and clinicopathologic factors on overall survival (OS) and disease-free survival (DFS). Results A total of 214 patients with confirmed SPTCL diagnosis were identified. The median age was 34 years with a peak incidence between ages 13 and 26. There was a female predominance with F:M ratio of 1.7. Upon presentation, 12% had lymphadenopathy, 12% had hepatosplenomegaly, and 27% had bone marrow involvement. No extra-nodal or extra-cutaneous involvement were reported. The most common clinical presentations were nodular skin changes (87%) followed by constitutional symptoms (57%). Fifteen and ten percent of SPTCL patients had history of immune-deregulatory disorders and immunosuppressive therapies, respectively. HPS occurred in 24% of the cases. Fat necrosis and dermal involvement were noted in 9% and 17%. The median duration of symptoms prior to diagnosis was 4 months. Median DFS of the whole group was 60 months. While the median OS of the whole group was not reached, the mean overall survival was 73 months. OS was not impacted by sex, constitutional symptoms, immunocompromising factors, presence of lymphadenopathy, hepatosplenomegaly, or bone marrow involvement. OS was not impacted by histological or immunohistochemical features though there was a trend for better OS as well as DFS for TIA-1 expressors. OS and DFS declined as age increased from <19 to 20-39 and >40 years. HPS negatively impacted OS and DFS, but with borderline significance with the latter. Attaining complete remission positively impacted both OS and DFS. Stem cell transplant positively impacted OS and DFS, but with borderline significance with the former. Conclusions This study presents a comprehensive clinicopathologic data from a pooled cohort of patients with SPTCL. It describes the clinicopathologic features of SPTCL and identifies major clinical, immunohistochemical, and therapeutic modalities that are major determinants of OS and DFS in this rare disease.

Genetics Abnormalities with Clinical Impact in Primary Cutaneous Lymphomas.

Simple SummaryThe genetic landscape of cutaneous T-cell lymphomas analyzed by sequencing high throughput techniques shows a heterogeneous somatic mutational profile and genomic copy number variations in the TCR signaling effectors, the NF-κB elements, DNA damage/repair elements, JAK/STAT pathway elements and epigenetic modifiers. A mutational and genomic stratification of these patients provides new opportunities for the development or repurposing of (personalized) therapeutic strategies. The genetic heterogeneity in cutaneous B-cell lymphoma parallels with the specific subtype. Damaging mutations in primary cutaneous diffuse large B-cell lymphoma of the leg type, involving MYD88 gene, or BCL6 and MYC translocations or CDKN2A deletions are useful for diagnostic purposes. The more indolent forms, as the primary cutaneous lymphoma of follicle center cell (somatic mutations in TNFRSF14 and 1p36 deletions) and the cutaneous lymphoproliferative disorder of the marginal zone cells (FAS gene), present with a more restricted pattern of genetic alterations.Primary cutaneous lymphomas comprise a heterogeneous group of extranodal non-Hodgkin lymphomas (NHL) that arise from skin resident lymphoid cells and are manifested by specific lymphomatous cutaneous lesions with no evidence of extracutaneous disease at the time of diagnosis. They may originate from mature T-lymphocytes (70% of all cases), mature B-lymphocytes (25–30%) or, rarely, NK cells. Cutaneous T-cell lymphomas (CTCL) comprise a heterogeneous group of T-cell malignancies including Mycosis Fungoides (MF) the most frequent subtype, accounting for approximately half of CTCL, and Sézary syndrome (SS), which is an erythrodermic and leukemic subtype characterized by significant blood involvement. The mutational landscape of MF and SS by NGS include recurrent genomic alterations in the TCR signaling effectors (i.e., PLCG1), the NF-κB elements (i.e., CARD11), DNA damage/repair elements (TP53 or ATM), JAK/STAT pathway elements or epigenetic modifiers (DNMT3). Genomic copy number variations appeared to be more prevalent than somatic mutations. Other CTCL subtypes such as primary cutaneous anaplastic large cell lymphoma also harbor genetic alterations of the JAK/STAT pathway in up to 50% of cases. Recently, primary cutaneous aggressive epidermotropic T-cell lymphoma, a rare fatal subtype, was found to contain a specific profile of JAK2 rearrangements. Other aggressive cytotoxic CTCL (primary cutaneous γδ T-cell lymphomas) also show genetic alterations in the JAK/STAT pathway in a large proportion of patients. Thus, CTCL patients have a heterogeneous genetic/transcriptional and epigenetic background, and there is no uniform treatment for these patients. In this scenario, a pathway-based personalized management is required. Cutaneous B-cell lymphoma (CBCL) subtypes present a variable genetic profile. The genetic heterogeneity parallels the multiple types of specialized B-cells and their specific tissue distribution. Particularly, many recurrent hotspot and damaging mutations in primary cutaneous diffuse large B-cell lymphoma of the leg type, involving MYD88 gene, or BCL6 and MYC translocations and BLIMP1 or CDKN2A deletions are useful for diagnostic and prognostic purposes for this aggressive subtype from other indolent CBCL forms.

Abstract 4097: Clinicopathologic descriptors of subcutaneous panniculitis-like T-cell lymphoma (SPTCL): Analysis of a pooled database of a rare entity

Abstract Introduction: SPTCL is a rare primary cutaneous T-cell lymphoma. SPTCL was initially described as an aggressive cutaneous T-cell lymphoma frequently associated with hemophagocytic syndrome (HPS) and requiring aggressive multiagent chemotherapy. In 2005, this entity was restricted to SPTCL with αβ phenotype, a less aggressive entity compared to its γδ counterpart, currently known as primary cutaneous γδ T-cell lymphoma. We conducted this analysis to explore the clinicopathologic characteristics of this little-known primary cutaneous T-cell entity. Methods: In order to study the demographic characteristics, molecular and immunohistochemical signatures, therapeutic interventions, survival, and prognostic factors, we compiled a pooled database of 214 cases. Descriptive statistics were calculated. Cox proportional-hazards model and Log-rank tests were used to assess the influence of demographic and clinicopathologic factors on overall survival (OS). Results: A total of 214 patients with confirmed SPTCL diagnosis were identified. The median age was 34 years with a peak incidence between ages 13 and 26. There was a female predominance with F:M ratio of 1.7. Upon presentation, 12% had lymphadenopathy, 12% had hepatosplenomegaly, and 27% had bone marrow involvement. No extra-nodal or extra-cutaneous involvement were reported. Cases expressed CD2 (8%), CD3 (85%), CD4(10%), CD5(10%), CD7 (9%), CD8 (77%), CD56 (6%), Granzyme-B (33%), and TIA-1 (34%). None of the cases expressed CD30. The most common clinical presentations were nodular skin changes (87%) followed by constitutional symptoms (57%). Fifteen and ten percent of SPTCL patients had history of immune-deregulatory disorders and immunosuppressive therapies, respectively. HPS occurred in 24% of the cases. Karyorrhexis, fat necrosis, and dermal involvement were noted in 15%, 9%, and 17%. The median duration of symptoms prior to diagnosis was 4 months. Median OS of the whole group was not reached while the mean OS was 73 months. OS was not impacted by sex, constitutional symptoms, immunocompromising factors, presence of lymphadenopathy, hepatosplenomegaly, or bone marrow involvement. OS was not impacted by histological or immunohistochemical features either. While older age and the occurrence of HPS negatively impacted OS, attaining complete remission positively impacted OS. Conclusions: This study presents a comprehensive clinicopathologic data from a pooled cohort of patients with SPTCL. It describes the clinicopathologic features of SPTCL and identifies major determinants of OS in this rare disease. Citation Format: Philip A. Haddad, Nowell Ganey. Clinicopathologic descriptors of subcutaneous panniculitis-like T-cell lymphoma (SPTCL): Analysis of a pooled database of a rare entity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4097.

Gamma/Delta (γδ) T Cells: The Role of the T-Cell Receptor in Diagnosis and Prognosis of Hematologic Malignancies.

There are 2 types of T cells: αβ and γδ T cells, named based on the composition of the T-cell receptor. γδ T cells are rare, making up 0.5%-10% of T cells. Although most leukemias, lymphomas, and immune-mediated conditions derive from αβ T cells, a handful of rare but important diseases are generally derived from γδ T cells, particularly primary cutaneous γδ T-cell lymphoma, hepatosplenic T-cell lymphoma, and monomorphic epitheliotropic intestinal T-cell lymphoma. There are also malignancies that may evince a γδ TCR phenotype, including large granulocytic lymphocyte leukemia, T-cell acute lymphobplastic leukemia (T-ALL), and mycosis fungoides, although such cases are rare. In this article, we will review the genesis of the T-cell receptor, the role of γδ T cells, and the importance of TCR type and methods of detection and outline the evidence for prognostic significance (or lack thereof) in lymphomas of γδ T cells. We will also highlight conditions that rarely may present with a γδ TCR phenotype and assess the utility of testing for TCR type in these diseases.

A case of primary cutaneous γδ T-cell lymphoma with initial symptoms in the tongue

A case of primary cutaneous γδ T-cell lymphoma with initial symptoms in the tongue

Gamma/delta T‐cell lymphoma with mycosis fungoides‐like clinical course transforming to “T‐cell‐receptor‐silent” aggressive lymphoma: Description of one case

Primary cutaneous γδ T-cell lymphomas (PCGDTLs) are a heterogeneous group of lymphomas representing about 1% of primary cutaneous T-cell lymphomas (CTCLs) and mostly regarded as clinically aggressive. Current WHO-EORTC classification recognizes different clinic-pathologic subsets of PCGDTL, but it suggests that cases showing a mycosis fungoides (MF)-like clinical presentation and histopathology should be classified as MF irrespective of phenotype for their indolent course. Herein, we describe a case of γδ-MF, featuring at onset a granulomatous pattern, with subsequent clinical worsening signaled by the development of an ulcero-necrotic lesion and systemic dissemination, leading to death in 5 months. Clinical progression was sustained by a shift to mature T-cell lymphoma composed of medium to large-sized blastoid T-cells featuring a T-cell receptor (TCR) silent immunophenotype.

Phase 2 Study of E7777, a Diphtheria Toxin Fragment-Interleukin-2 Fusion Protein, in Japanese Patients with Relapsed or Refractory Peripheral and Cutaneous T-Cell Lymphoma

Phase 2 Study of E7777, a Diphtheria Toxin Fragment-Interleukin-2 Fusion Protein, in Japanese Patients with Relapsed or Refractory Peripheral and Cutaneous T-Cell Lymphoma

C‐C chemokine receptor 4 expression in CD8+ cutaneous T‐cell lymphomas and lymphoproliferative disorders, and its implications for diagnosis and treatment

Patients with aggressive CD8+ cutaneous T-cell lymphomas (CTCLs) progress rapidly and respond poorly to therapy. Confounding treatment planning, there is clinicopathological overlap between aggressive CD8+ CTCLs and other lymphoproliferative disorders (LPDs). Hence, improved diagnostic methods and therapeutic options are needed. The aim of this study was to examine C-C chemokine receptor 4 (CCR4) expression as a diagnostic and therapeutic biomarker in CD8+ CTCLs/LPDs. Forty-nine cases (41 patients) with CD8+ CTCLs/LPDs were examined, including CD8+ mycosis fungoides (MF) (n=14), aggressive epidermotropic CD8+ cytotoxic T-cell lymphoma (AETCL) (n=8), subcutaneous panniculitis-like T-cell lymphoma (SPTCL) (n=7), CD30+ LPDs (n=6), primary cutaneous γδ T-cell lymphoma (GDTCL) (n=6), and others (n=8). Immunohistochemical tissue staining was performed with a CCR4 monoclonal antibody on formalin-fixed paraffin-embedded tissue sections. CCR4 immunostaining was graded as percentage infiltrate, i.e. high (>25%) and low (≤25%), and the results were correlated with clinicopathological diagnoses. CCR4 expression was seen in 69% of the studied cases. Any CCR4 positivity was seen in all CD8+ MF cases, in 83% of CD30+ LPD cases, in 75% of AETCL cases, in 33% of GDTCL cases, and in none of the SPTCL cases. High CCR4 expression was seen in 79% of CD8+ MF cases versus 33% of CD30+ LPD cases, in 17% of GDTCL cases, and in 12.5% of AETCL cases. Patients with more advanced MF stage had higher CCR4 expression. CCR4 immunohistochemistry may be an adjunct in distinguishing advanced CD8+ MF from other CD8+ CTCLs/LPDs. Although CCR4 expression may justify therapeutic targeting of this receptor in CD8+ MF, the role of such therapies in other CD8+ CTCLs/LPDs is not yet clear.

Volumetric Modulated Arc Therapy and 3-Dimensional Printed Bolus in the Treatment of Refractory Primary Cutaneous Gamma Delta Lymphoma of the Bilateral Legs

Primary cutaneous gamma-delta T-cell lymphoma (PCGDTL) is an aggressive subtype that comprises <1% of cutaneous T-cell lymphomas. 1 Guitart J. Weisenburger D.D. Subtil A. et al. Cutaneous γδ T-cell lymphomas: A spectrum of presentations with overlap with other cytotoxic lymphomas. Am J Surg Pathol. 2012; 36: 1656-1665 Google Scholar , 2 Phan A. Veldman R. Lechowicz M.J. T-cell lymphoma epidemiology: The known and unknown. Curr Hematol Malig Rep. 2016; 11: 492-503 Google Scholar , 3 Foppoli M. Ferreri A.J.M. Gamma-delta t-cell lymphomas. Eur J Haematol. 2015; 94: 206-218 Google Scholar Deep dermal and subcutaneous lesions are common and may be necrotic or ulcerated. 4 Tripodo C. Iannitto E. Florena A.M. et al. Gamma-delta T-cell lymphomas. Nat Rev Clin Oncol. 2009; 6: 707-717 Google Scholar Radiation therapy (RT) is an effective treatment for patients with localized PCGDTL, using doses from 30 to 36 Gy. However, RT poses a challenge for patients with widespread subcutaneous disease because irradiating the core of limbs increases the risk of lymphedema, vascular leakage, and fibrosis. 5 El-Bared N. Wong P. Wang D. Soft tissue sarcoma and radiation therapy advances, impact on toxicity. Curr Treat Options Oncol. 2015; 16: 19 Google Scholar Techniques such as total skin electron beam therapy do not adequately penetrate to the depth of subcutaneous PCGDTL lesions: degraded 9 MeV electrons, 80% dose at 0.7 cm, and 50% dose at 1.25 cm. 6 Hoppe R.T. Mycosis fungoides: Radiation therapy. Dermatol Ther. 2003; 16: 347-354 Google Scholar , 7 Chinn D.M. Chow S. Kim Y.H. Hoppe R.T. Total skin electron beam therapy with or without adjuvant topical nitrogen mustard or nitrogen mustard alone as initial treatment of T2 and T3 mycosis fungoides. Int J Radiat Oncol Biol Phys. 1999; 43: 951-958 Google Scholar Volumetric modulated arc therapy (VMAT), a form of intensity modulated radiation therapy, is an effective technique to treat circumferential surfaces while sparing the inner body. 8 Servy A. Kramkimel N. Franck N. Park S. Kirova Y.M. Helical tomotherapy in oncodermatology: Case report of circumferential cutaneous lymphoma treated by this optimized radiotherapy. Cancer Radiother. 2014; 18: 136-138 Google Scholar A reproducible bolus that covers extended irregular surfaces would simplify setup and minimize air gaps that can cause dosimetric distortion. We present a patient with extensive bilateral leg involvement with PCGDTL who achieved remission after treatment with VMAT, using 3-dimensional printed bolus and positioning to irradiate each leg individually.

T-cell receptor-δ expression and γδ+ T-cell infiltrates in primary cutaneous γδ T-cell lymphoma and other cutaneous T-cell lymphoproliferative disorders.

The diagnosis of cutaneous γδ T-cell lymphoma (GDTCL) requires the identification of γδ chains of the T-cell receptor (TCR). Our aim in this study was, by using a new monoclonal antibody (mAb) against TCRδ, to evaluate TCRδ expression in formalin-fixed paraffin-embedded (FFPE) skin tissue from TCRγ+ cutaneous T-cell lymphoma (CTCL), and to assess TCRδ expression within a spectrum of other cutaneous lymphoproliferative disorders (CLPDs). Twelve cases (10 patients) with TCRγ+ CTCL and 132 additional CLPD cases (127 patients) were examined, including mycosis fungoides (MF) (n = 60), cutaneous GDTCL (n = 15), subcutaneous panniculitis-like T-cell lymphoma (SPTCL) (n = 11), and CD30+ lymphoproliferative disorder (LPD) (n = 24). Clone H-41 against TCRδ was used on a Leica Bond-3 automated stainer to label FFPE slides. H-41 immunostaining was graded as percentage infiltrate: high (50-100%), moderate (10-49%), and low (0-9%). In TCRγ+ tumours, 12 of 12 (100%) patients showed TCRδ expression comparable to TCRγ expression. No (0%) TCRγ+ cases were negative for TCRδ. In all CLPDs, TCRδ expression was as follows: GDTCL, 16 of 20 cases (14 of 15 patients) high, two moderate, and two low; MF, 0 of 60 cases high, nine moderate, and 51 low; CD30+ LPD, one of 24 cases high, two moderate, and 21 low; and SPTCL, 0 of 11 cases (0 of 9 patients) high, two moderate, and two low. Three MF-like cases and one SPTCL-like case showed high expression; the remainder showed low expression. mAb H-41 against TCRδ matches TCRγ in immunostaining FFPE tissues from GDTCL, supporting H-41 as a replacement for mAb γ3.20. TCRδ expression in our study suggests that the true occurrence of γδ+ non-GDTCL CTCL/CLPD may be lower than suggested by the recent literature.

Immunophenotypic Shifts in Primary Cutaneous γδ T-Cell Lymphoma Suggest Antigenic Modulation: A Study of Sequential Biopsy Specimens.

Primary cutaneous γδ T-cell lymphoma (PCGD TCL), an aggressive type of lymphoma, accounts for approximately 1% of all primary cutaneous lymphomas. We have occasionally observed changes in T-cell antigen expression (immunophenotypic [IP] shift) over time, a phenomenon that is considered rare in T-cell lymphoma including cutaneous T-cell lymphoma. Therefore, we assessed sequential biopsies of PCGD TCL for possible IP shifts of the lymphoma cells. We searched for cases of PCGD TCL with consecutive biopsies to perform a comprehensive immunohistochemical analysis of paired specimens. A median of 12 markers per case was tested. We evaluated the percentage of neoplastic lymphocytes and determined the differential expression of antigens (gain, loss, increase or decrease). We identified 9 patients with PCGD TCL with consecutive biopsies. All (100%) cases had IP shifts of at least 1 antigen, whereas overall 22 pairs of markers were shifted: gain of reactivity occurred in 7 (31.8%) and loss in 3 (13.6%); increased reactivity in 4 (18.2%) and decreased in 8 (36.4%). Molecular analysis of TCRγ showed identically sized monoclonal rearrangements between biopsy pairs in 4/4 (100%) patients. There was no correlation between IP shifts and the clinical appearance of lesions, histopathologic or cytologic features, or molecular rearrangements. IP shifts are common in PCGD TCL, occurring in all patients in this study and involving a variety of antigens. IP shifts do not seem to be linked to changes in the T-cell clone and are without obvious clinical or morphologic correlates. The occurrence of IP shifts in PCGD TCL suggests that antigen modulation may be involved in pathogenesis. IP shifts are somewhat frequent in T-cell lymphoma; however, it does not suggest a second neoplasm, and molecular studies can be used to determine clonal identity.

Primary Cutaneous T-Cell Lymphomas Showing Gamma-Delta (γδ) Phenotype and Predominantly Epidermotropic Pattern are Clinicopathologically Distinct From Classic Primary Cutaneous γδ T-Cell Lymphomas.

Primary cutaneous gamma-delta (γδ) T-cell lymphoma is a rare disease that typically involves the dermis and subcutis. Cases of primary cutaneous T-cell lymphomas showing γδ phenotype and predominantly epidermotropic pattern (EγδTCL) are not well defined. In this series, cases of primary cutaneous T-cell lymphomas showing γδ phenotype were reviewed and classified as predominantly epidermotropic (EγδTCL) when >75% of lymphoma cells resided in the epidermis or predominantly dermal and/or subcutaneous (DSγδTCL). Clinical, pathologic, and immunophenotypic features were compared in 27 biopsies from 13 patients of EγδTCL and 13 biopsies from 7 patients of DSγδTCL. The lymphoma cells were diffusely positive for CD3 and T-cell receptor (TCR)γ, mostly positive for granzyme B and TIA-1, variably positive for CD8, CD7, and CD30, and negative for CD4 and TCRβ. Two patients with EγδTCL had dissemination to lymph nodes and 1 to the lung; 1 patient with DSγδTCL had gastrointestinal involvement. The median survival of patients with EγδTCL was not reached, and with a median follow-up of 19.2 months, 3/13 died. In contrast, the median survival of patients with DSγδTCL was 10 months, and after a median follow-up of 15.6 months, 5/5 died (P<0.01). EγδTCL is a rare presentation of cutaneous T-cell lymphoma that can be distinguished from DSγδTCL based on the extent of epidermotropism and has a better prognosis and longer median survival than DSγδTCL. However, although EγδTCL resembles mycosis fungoides clinically and histologically, a subset of EγδTCL is more likely to behave more aggressively than typical mycosis fungoides.

Hematopoietic stem cell transplantation for primary cutaneous γδ T-cell lymphoma and refractory subcutaneous panniculitis-like T-cell lymphoma

The panniculitic T-cell lymphomas (TCLs) comprise 2 distinct entities, αβ subcutaneous panniculitis-like TCL (SPTCL) and the γδ cutaneous TCLs with pannicular involvement primary cutaneous γδ (PCGD)-TCL. Although outcomes for most patients with SPTCL are favorable, those with PCGD-TCLs generally have an inferior outcome, and treatment strategies have not been well defined. Allogeneic hematopoietic stem cell transplantation (HSCT) has been shown to be a potentially curative strategy in aggressive TCLs and in refractory and advanced-stage mycosis fungoides. We sought to analyze the outcomes of HSCT for panniculitic cutaneous TCL. Fourteen patients (4 SPTCL, 10 PCGD-TCL) presented with primarily pannicular T-cell infiltrates. Seven patients underwent allogeneic HSCT from matched-related donors and matched-unrelated donors of which 4 (57%) are alive (1 SPTCL, 3 PCGD-TCL) at 7.8, 6.9, 6.2, and 0.25 years. Two patients underwent autologous HSCT (1 SPTCL, 1 PCGD-TCL) and both are alive at a median follow-up of 1.91 years. This study is limited by its retrospective nature and small sample size because of the rarity of SPTCL and PCGD-TCL. Aggressive therapy followed by allogeneic HSCT is a promising treatment modality for patients with PCGD-TCL.

γδ T-cell-rich variants of pityriasis lichenoides and lymphomatoid papulosis: benign cutaneous disorders to be distinguished from aggressive cutaneous γδ T-cell lymphomas.

T cells with a γδ phenotype have been associated with aggressive lymphomas. Yet, inflammatory skin disorders and low-grade lymphoproliferative disorders have rarely been described with a predominant γδ T-cell infiltrate. To review our experience and determine the clinical relevance of the γδ T-cell phenotype in lymphomatoid papulosis (LyP) and pityriasis lichenoides (PL). A retrospective dermatopathology file review looking for LyP and PL characterized by a γδ T-cell phenotype was performed. Clinical manifestations and course, histological features and molecular data were analyzed. Six of 16 cases of LyP and four of 23 cases diagnosed as PL during a 5-year period (2009-14) were identified. The median follow-up for the whole group was 16months (range 3-64), showing an indolent clinical course in all cases. The detection of a predominantly γδ T-cell phenotype in papular lymphoid-rich infiltrates in the absence of other lesions is not associated with a clinically aggressive course. γδ T-cell-rich variants of LyP and PL may reflect a spectrum of related conditions. This is a single academic centre retrospective chart review of a relatively small sample.

Primary Cutaneous γδ T-Cell Lymphoproliferative Disorder Following a Stingray Puncture: A Case Report

Introduction: Primary cutaneous γδ T-cell lymphoma (PCGD-TCL) is a rare neoplasm, of unknown etiology, composed of mature, activated, γδ T cells with a cytotoxic phenotype, usually presenting as plaques or nodules with ulceration. PCGD-TCL, which has been classified as a distinct entity in the 2008 World Health Organization classification, often fails to respond to polychemotherapy and radiation therapy with a poor prognosis although some cases demonstrate relatively indolent behavior.Objective: We report a case of cutaneous γδ T-Cell lymphoproliferative disorder following a stingray puncture and mimicking PCGD-TCL.Case report: A 33-year-old man was referred for a generalized skin rash of seven years duration. In 2007, a stingray punctured his right ankle and one week later he developed cellulitis that responded to IV antibiotics. Five months later, multiple small, red spots appeared at the site of the puncture first and then on both ankles and gradually spread to the lower legs and torso. In 2011, arthralgias in knees and hands were successfully treated with oral prednisone, and his rash also improved transiently. Eosinophilia of up to 31% fell to 10% on prednisone but persisted. At presentation to MDACC in Dec 2012, on physical exam there was a red capillaritis-like fixed exanthem from the waist down. Small nodules were present on his right lower leg and back. Flow cytometry of peripheral blood showed CD8+ T cells with partial loss of CD5 and CD7, and partial expression of CD56 and CD57. Bone marrow was negative. PET scan showed a few small skin nodules without lymphadenopathy. Increased serum beta-2-microglobulin (2.6 mg/L) and lactate dehydrogenase (680 IU/L) were noted. Multiple biopsies from capillaritis and nodules showed perivascular, periadnexal, and subcutaneous infiltrates of small to medium sized CD8+ T cells, eosinophils, and CD68+/S100+ histiocytes. Anti-CD1a staining highlighted scattered, small clusters of dendritic cells with a small subset of Langerin+ cells. There were scattered mast cells as highlighted by anti-tryptase. Molecular studies showed T-cell receptor γ chain gene rearrangements identical in skin and peripheral blood.Discussion : This patient developed generalized capillaritis, arthralgias, and neuropathy following a stingray puncture, an injury occurring in approximately 2000 people annually in the USA. In one other patient with a stingray puncture, a skin biopsy taken four days later showed central hemorrhagic necrosis with surrounding infiltrate of eosinophils and lymphoid cells, which were mainly CD3+, CD4+ and TIA+. Both cases suggest a host immunological reaction with eosinophils to stingray toxin venom. In particular, stingray venom contains tetraspanins which are known to activate macrophages and induce chemotaxis of eosinophils. The presence of CD68+/S100+ histiocytes and CD1a+/Langerin+ cells in our patient suggests activation of the classic macrophage- maturation pathway, leading to proliferation of CD8+ T-cells and promotion of anti-tumor immunity. Human Vδ1+ γδ T cells are known to recognize phospholipid antigens presented by CD1a+ cells. We hypothesize that tetraspanins in stingray toxin may have induced chemotaxis for eosinophils and promoted CD8+ immunosurveillance by controlling the antigen presentation process and macrophage activation.Summary: Although this patient’s skin lesions had several poor prognostic factors (monoclonal TCR γ in skin and peripheral blood, elevated lactic dehydrogenase and beta-2-microglobulin, and CD8+ cytotoxic markers), unlike PCGD-TCL his clinical course was indolent over 7 years and his lesions responded to oral prednisone. Therefore, we conclude that this patient developed a PCGD-TCL- like immune reaction to stingray venom similar to that reported against tetraspanins. Further studies are needed to confirm this mechanism. DisclosuresNo relevant conflicts of interest to declare.

Primary Cutaneous γδ T-Cell Lymphoma and Hemophagocytic Syndrome.

Primary cutaneous γδ T-cell lymphoma and hemophagocytic syndrome (HPS) is a very rare disease process with only 41 cases of this type of lymphoma published to date. We report the case of a 56-year-old woman who developed high-grade fevers and multiple nonhealing bilateral lower extremity ulcers associated with a recent diagnosis of Ackerman syndrome. Multiple lesion biopsies yielded a differential diagnosis including sarcoidosis and lupus panniculitis. Each biopsy site developed into a poorly healing wound. After extensive rheumatologic and dermatologic workup, failed courses of hyperbaric oxygen and corticosteroids, and the development of worsening fevers, the diagnosis of γδ T-cell lymphoma was made. The objective of this article was to illustrate a very rare case of a rapidly progressing cutaneous lymphoma while stressing the importance of a surgical approach to nonhealing wounds and biopsy in chronic wounds.An aggressive multidisciplinary approach including infectious disease, hematology/oncology, nephrology, plastic surgery, and interventional pulmonology was used. Medical approaches included several courses of corticosteroids and antineoplastics. Our surgical approach included numerous excision and debridements of her nonhealing ulcers with removal of necrotic tissue. It also included placement of cadaveric epidermal graft, and bovine tendon collagen cross-linked with glycosaminoglycans with a silicone matrix bilayer (Integra, Plainsboro, NJ) combined with multiple local myocutaneous advancement flaps. This approach demonstrated clinical improvement in wound healing. Pathological examination of several lesions included immunohistochemistry staining, flow cytometry, and molecular studies.The diagnosis of primary cutaneous γδ T-cell lymphoma was made based on a pathology specimen. Subsequent imaging showed numerous pulmonary nodules later determined to be pulmonary Aspergillosis. Additionally, she developed a constellation of clinical and laboratory features defined as the HPS. Despite medical therapy and improved wound healing, she died to seizures that left her comatose, thought to be secondary to central nervous system advancement of her HPS. The patient eventually died after care was withdrawn.Cutaneous forms of lymphoma must be considered in the differential diagnosis of atypical cutaneous lesions or nonhealing wounds. There should be no delay in performing a skin biopsy to obtain a tissue diagnosis. A surgical approach to wounds clearly demonstrates improved wound healing.

Clinicopathological analysis of 17 primary cutaneous T-cell lymphoma of the γδ phenotype from Japan.

Primary cutaneous γδ T-cell lymphoma (PCGD-TCL) is an aggressive lymphoma consisting of clonal proliferation of mature activated γδ T-cells of a cytotoxic phenotype. Because primary cutaneous γδ T-cell lymphoma is a rare disease, there are few clinicopathological studies. In addition, T-cell receptor (TCR) γδ cells are typically immunostained in frozen sections or determined by TCRβ negativity. We retrospectively analyzed 17 primary cutaneous T-cell lymphomas of the γδ phenotype (CTCL-γδ) in a clinicopathological and molecular study using paraffin-embedded sections. Among 17 patients, 11 had CTCL-γδ without subcutaneous panniculitis-like T-cell lymphoma (SPTCL) features and six had CTCL-γδ with SPTCL features. Immunophenotypically, some significant differences were found in CD8 and CD56 positivity between our patient series of CTCL-γδ patients with SPTCL features and SPTCL-γδ patients described in the previous literature. A univariate analysis of 17 CTCL-γδ patients showed that being more than 60 years old, presence of visceral organ involvement, and small-to-medium cell size were poor prognostic factors. In addition, the 5-year overall survival rate was 42.4% for the CTCL-γδ patients without SPTCL features and 80.0% for those with SPTCL features. Consequently, there was a strikingly significant difference in overall survival among SPTCL, CTCL-γδ with SPTCL features and CTCL-γδ without SPTCL features (P = 0.0005). Our data suggests that an indolent subgroup may exist in CTCL-γδ. Studies on more cases, including those from other countries, are warranted to delineate the clinicopathological features and the significance in these rare lymphomas.

Primary cutaneous γδ-T cell lymphoma with hemophagocytic syndrome in a child

A 13-year-old girl presented with multiple recurrent cutaneous plaques for more than six months,which had been aggravated with intermittent fever for five months.No obvious systemic abnormality was found.Dermatological examination revealed multiple,non-ulcerative,painless,infiltrative,indurated,poorly marginated,purple subcutaneous plaques measuring 3-1 1 cm in diameter with slight squamation in bilateral buttocks and lower limbs.Laboratory investigations showed bicytopenia with the white blood cell count being (0.03-3.7) × 109/L and red blood cell count being (2.8-4.4) × 1012/L,a normal platelet count,hypofibrinogenemia (1.79 g/L) and low proportion of natural killer cells (4.6％).Bone marrow smear showed active proliferation of cells,decreased proportion of granulocytes,presence of a few indefinitely classified cells,and phagocytosis.Reticulocytes were easily seen in the bone marrow smear.Pathologically,no obvious abnormality was observed in the epidermis or dermis,while the subcutaneous adipose tissue,especially fat lobules and some interlobular septa,was extensively infiltrated by large-to medium-sized lymphoid cells with pleomorphic and twisted nuclei as well as a small amount of cytoplasm; necrosis and phagocytosis of nuclear debris and lymphocytes were visible.The atypical lymphoid cells stained positive for CD3,T-cell intracellular antigen-1,granzyme B and TCRγδ with partial loss of CD5 and CD7,but negative for CD56,CD4,CD8 and TCRαβ.No Epstein-Barr virus-encoded RNA (EBER) was detected by in situ hybridization.Based on these findings,a diagnosis of primary cutaneous γδ-T cell lymphoma with hemophagocytic syndrome was made. Key words: Lymphoma, T-cell, cutaneous; Lymphohistiocytosis, hemophagocytic