Primary Cutaneous Gamma-delta T-cell Research Articles

Rapidly Progressive Primary Cutaneous Gamma Delta T-Cell Lymphoma With FYN Gene Alteration.

Primary cutaneous gamma delta T-cell lymphoma (PCGDTCL) is a rare type of non-Hodgkin lymphoma accounting for <1% of primary cutaneous T-cell lymphomas. The exact cause of PCGDTCL is not known, however, it is thought that chronic antigen exposure in the skin may lead to immune dysregulation at the site, resulting in abnormal proliferation of mature, post-thymic cytotoxic gamma delta T cells. Mutations are the most common genetic alteration seen in PCGDTCL, while structural abnormalities such as gene fusions are not common. We report a case of PCGDTCL with atypical immunophenotypic features, including expression of CD5 with lack of cytotoxic marker expression, and a structural alteration leading to FYN deletion at exon 8. Recently, it was described that a deletion of the area between FYN exon 8 and TRAF3IP2 intron 2 results in a novel FYN::TRAF3IP2 fusion in peripheral T-cell lymphoma, not otherwise specified. We describe our patient's clinical course, differential diagnosis, and potential implications of FYN deletion on disease pathogenesis. To our knowledge, this is the first report of an FYN structural alteration to be described in PCGDTCL.

Abstract 813: Primary cutaneous gamma-delta T-Cell lymphoma in the United States: A nationwide analysis of demographics and survival outcomes among the Hispanic population

Abstract BACKGROUND: Primary Cutaneous Gamma-Delta T-Cell Lymphoma (PCGDTCL) is a rare subtype of cutaneous T-cell lymphoma (CTCL) that, despite comprising &amp;lt;1% of cutaneous lymphomas, has gained recognition in recent years as an entity separate from other rare CTCLs. (LeukemiaPMID 35732829) A 5 year survival of 11% demonstrates a low response to current available therapies. (BloodPMID 30635287, Clin Hematol Int.PMID 35950208) Due to lack of consistency in behavior between CTCLs, there exists a need for studies of demographic, clinical, and survival disparities, including between Hispanics (HI) vs. non-Hispanics (NH). METHODS: Data were analyzed on PCGDTCL patients in the United States reported to the National Cancer Database (NCDB) between 2004-2019. Demographic and treatment characteristics were compared between ethnic groups. Kaplan-Meier and Cox regression analyses were used to compare OS between populations. Multivariate analysis and propensity score matching was performed with adjustment for age, stage, co-morbidity score, and insurance status, type of facility and great circle distance. RESULTS: Among 132 PCGDTCL patients studied (5% HI, 92% NH), the HI group was younger at diagnosis than NH (49.5y vs. 60y) (p=0.384); The majority of HI (50%) was diagnosed between 2010-2012 vs 2017-2019 for NH (45%) (p=0.673). Most of HI and NH were white (67% vs 79%). Private insurance was the most prevalent type in HI (67%) vs government sponsored for NH (49%). The most non-Insured group was NH (3%) vs HI (0%). The most prevalent bracket for Census Median Income (2008-2012) was $63,000+ for both HI (50%) and NH (31%). 17% HI vs 13%. NH had median income &amp;lt;$38,000. For Charlson-Deyo Score (comorbidities score), HI had 0% =/&amp;gt; 2 score, vs NH 6%. NCI-designated comprehensive cancer centers were the most prevalent type of facility providing care for HI (100%) and NH (56%) Survival probability (OS) at 2, 5 and 10y (HI vs NH) were (80% vs 48%), (80% vs 44%), and (80% vs 26%), respectively. Median survival time (MS) was not reached for HI vs 1.9 years for NH. Overall survival (OS) difference favored HI (p=0.13) On multivariate analysis, there was no independent variable associated with better or worse OS. Interestingly, the propensity matched analysis demonstrated significant MS difference between HI vs NH (median not reached vs. 1.35 years). CONCLUSION: There was no significant difference in OS between groups; however, the weighed MS favored the HI cohort, likely in part due to the difference in numbers between cohorts. The drastically low survival in all demographics is consistent with prior studies. These results demonstrate an unmet need for more comprehensive studies with the potential inclusion of correlatives looking at intrinsic biologic characteristics that may offer insight into druggable targets, aiming for improvement in survival outcomes for this rare lymphoma. Citation Format: Katherine Thiel, Rosa White, Qianqian Liu, Joel Michalek, Adolfo Enrique Diaz Duque. Primary cutaneous gamma-delta T-Cell lymphoma in the United States: A nationwide analysis of demographics and survival outcomes among the Hispanic population [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 813.

A Rare Case of Primary Cutaneous Gamma-Delta T-cell Lymphoma with Aberrant B-cell Marker Expression.

Primary cutaneous gamma-delta T-cell lymphoma (PCGDTL) is a rare and diagnostically challenging primary skin lymphoma. We present a case of a 78-year-old otherwise healthy man who developed nonhealing nodules on his right posterior calf. Initial biopsy showed a dense, atypical, lymphoid infiltrate with gamma-delta and cytotoxic T-cell immunophenotypes. The diagnosis of PCGDTL was rendered; however, concurrent flow cytometry revealed expression of aberrant B-cell markers, including CD19 and cytoplasmic CD79a. Subsequent immunohistochemical studies corroborated this result. We report the extremely rare phenomenon of aberrant B-cell marker expression in PCGDTL, the first formally reported case to our knowledge.

Panniculitic primary cutaneous gamma delta T-cell lymphoma with concomitant features of autoimmune disease emphasizing a pathophysiologic continuum of lupus profundus with the panniculitic T cell lymphomas

Certain T-cell lymphomas exhibit unique homing properties of the neoplastic lymphocytes for the subcutaneous fat. There are two primary forms of subcutaneous panniculitic lymphomas of T-cell origin. One falls under the designation of primary cutaneous gamma-delta T-cell lymphomas (PGD-TCL) whereby there is dominant involvement of the fat defininng a panniculitic form of PGD-TCL. The neoplastic cells are of the gamma-delta subset and are either double negative for CD4 and CD8 and/or can express CD8. They often have an aggressive clinical course. The other form of panniculitic T-cell lymphoma falls under the designation of subcutaneous panniculitis-like T-cell lymphoma (SPTCL). It represents a subcutaneous lymphoma derived from CD8+ T cells of the alpha-beta subset and typically has an indolent course. These two forms of panniculitic T-cell lymphoma exhibit overlapping histologic features with lupus profundus (LP), a putative form of panniculitic T-cell dyscrasia. We present three cases of PGD-TCL of the fat in the setting of lupus erythematosus (LE) (two cases) and dermatomyositis (DM) (one case), respectively. There were concurrent features of LE and DM in their lymphoma biopsies in two cases while a prior biopsy in one was interpreted as LP. In this latter case, the LP diagnosis presaged the diagnosis of panniculitic PGD-TCL by three years. One patient diagnosed with panniculitic PGD-TCL had hemophagocytic syndrome after developing a lupus-like complex including certain supportive serologies such as antibodies to double-stranded DNA following initiation of statin therapy. The second patient presented with PGD-TCL and concomitant features of anti-nuclear matrix 2 (NXP2) DM. The third patient presented in 2003 with LP and overlying skin features of acute LE, initially responding to Plaquenil, and then four years later was diagnosed with PGD-TCL heralded by Plaquenil treatment resistance. Two of the patients died of their lymphoma. All biopsies showed a characteristic histopathology of PGD-TCL. In two cases, the PGD-TCL was associated with overlying LE-cutaneous findings; another case had skin changes of lymphocyte-rich DM. In two cases, the MXA stain was strikingly positive, the surrogate type I interferon marker that is typically upregulated in biopsies of LE and DM. There are eight prior reported cases describing SPTCL with concomitant cutaneous changes of LE. In six cases there was an established history of LE, including LP responding initially to Plaquenil, similar to one of our cases. In the context of SPTCL or panniculitic PGD-TCL, panniculitic T-cell lymphomas can be associated with concomitant clinical and histologic features of LE or DM, including an upregulated type I interferon signature. Identifying histologic features associated with either of these prototypic autoimmune conditions should not be considered exclusionary to diagnosing any panniculitic T-cell lymphoma. A clinical, histomorphologic, and pathophysiologic continuum exists with LP, SPTCL and panniculitic PGD-TCL.

499 - The Impact of Stem Cell Transplant on Clinical Outcomes of Primary Cutaneous Gamma-Delta T-Cell Lymphoma, Primary Cutaneous CD8+ Aggressive Epidermotropic Cytotoxic T-Cell Lymphoma, and Subcutaneous Panniculitis-like T-Cell Lymphoma: Analysis of Pooled Databases of Rare Cutaneous Extra-Nodal T-Cell Lymphoma Entities

499 - The Impact of Stem Cell Transplant on Clinical Outcomes of Primary Cutaneous Gamma-Delta T-Cell Lymphoma, Primary Cutaneous CD8+ Aggressive Epidermotropic Cytotoxic T-Cell Lymphoma, and Subcutaneous Panniculitis-like T-Cell Lymphoma: Analysis of Pooled Databases of Rare Cutaneous Extra-Nodal T-Cell Lymphoma Entities

Primary Cutaneous Gamma-Delta T-Cell Lymphoma (PCGDTCL) Descriptors and Clinicopathologic Determinants of Survival: Analysis of a Pooled Database

Introduction Primary Cutaneous Gamma-Delta T-cell Lymphoma (PCGDTL) is a rare clinical entity that represents <1% of all cutaneous lymphomas. It is characterized by clonal proliferation of mature, activated T-cells expressing the T-cell receptor (TCR) γ/δ and cytotoxic molecules. PCGDTL is often resistant to conventional chemotherapy and is usually associated with poor prognosis. We have conducted this pooled database analysis to delineate key disease characteristics and clinicopathologic determinants of survival in this rare cutaneous 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 140 cases. Kaplan-Meier survival curves were constructed. 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 140 patients with confirmed PCGDTCL were identified. The median age was 54 years with peak incidence between ages 52 and 65 years. There was no sex preponderance. The median duration of symptoms prior to diagnosis was 9 months. Eighty percent of patients presented with >4 lesions with an average size of 3.4cm. The disease involved mostly the lower extremities followed by the upper extremities, trunk, and lastly the face. Almost all the lesions involved the dermis with 48% involving the epidermis. Twenty-four percent of the lesions presented with ulceration and 30% had fat necrosis. Patients presented with constitutional symptoms in 28%, splenomegaly 6%, lymphadenopathy 16%, and hemophagocytic syndrome (HPS) 13%. Compared to no treatment, combination chemotherapy and stem cell transplant (SCT) were statistically superior with median OS months of 2, 16, and not reached respectively (p<0.0001). Age inversely correlated with survival while time from symptoms to diagnosis has a positive correlation. CD30+ imparted a survival advantage while HPS was detrimental to OS, both at borderline significance. Visceral involvement was also associated with a worse median OS (9.5 vs 18 months). OS was not impacted by sex, size of the lesions, or subcutaneous involvement. While solitary disease and absence of constitutional symptoms and bone marrow involvement seemed to have better OS, they did not reach statistical significance. Conclusions This study presents an updated clinicopathologic data from a pooled cohort of patients with PCGDTCL. It details the features of this rare disease and identifies the clinical, immunohistochemical, and treatment modalities that are major determinants of OS.

Clinical Characteristics, Treatment Patterns, and Outcomes of Cytotoxic Cutaneous T-Cell Lymphomas

Introduction Cytotoxic cutaneous T-cell lymphomas (CCTCLs) are an uncommon group of neoplasms defined by expression of at least one cytotoxic marker (e.g. TIA-1, granzyme B, or perforin). Due to their rarity, comparatively little is known about their presentation and overall course. Here, we present a detailed retrospective experience of patients with CCTCLs, focusing on their clinicopathologic and molecular characteristics, treatment details, and survival outcomes. Methods The Stanford University Cutaneous Lymphoma Database was queried to gather data on patients with CCTCLs seen between 1995-2020, including the following diagnoses: subcutaneous panniculitis-like T-cell lymphoma (SPTCL), primary cutaneous gamma-delta T-cell lymphoma (PCGDTCL), primary cutaneous CD8+ aggressive epidermotropic cytotoxic T-cell lymphoma (PCAECTCL), and unclassified CCTCLs (CCTCL-NOS). Clinical and laboratory data, including clinical suspicion of hemophagocytic syndrome (HPS), were extracted from the electronic medical record. Treatment data were recorded, including use of radiotherapy (RT), pralatrexate, romidepsin, brentuximab vedotin (BV), combination chemotherapy, allogeneic stem cell transplant (allo-SCT), and others. We evaluated time to next treatment (TTNT), calculated as the start date of one line of therapy to the start date of next line of therapy, in addition to overall survival (OS) and factors predictive of outcome. A subset of patients was evaluated with a clinically validated high-throughput sequencing panel for hematopoietic and lymphoid neoplasms (Heme-STAMP) covering 164 genes. Results 46 patients were included: 22 (47.8%) SPTCL, 13 (28.2%) PCGDTCL, 3 (6.5%) PCAECTCL, and 8 (17.3%) CCTCL-NOS. Mean age at diagnosis was 55.7 years (range: 14.9 - 87.4). Most patients (87%) presented with generalized skin lesions, while involvement of lymph nodes (22.2%), viscera (8.9%), or bone marrow involvement (3.1%) were uncommon. Clinical suspicion for HPS was noted in 23 (50%) patients. Median lines of therapy received was 2.5 (range: 1-12). Median TTNT (mTTNT) from first-line therapy was 8.5 months, second-line 5.3 months, and third-line 7.8 months. Variation in mTTNT was observed between CCTCL subtypes. In patients with SPTCL, mTTNT from first and second-line therapy were 10.2 and 24.0 months, respectively. In patients with PCGDTCL, mTTNT after first-line therapy was 11.1 months, decreasing sharply thereafter (0.5-3.1 mo. for 2nd-5th lines). Patients with PCAECTCL had short mTTNT of less than 3 months for all lines of treatment. Patients with CCTCL-NOS exhibited more heterogeneity (mTTNT 2.9 - 9.1 mo. for 1st-5th lines). The most commonly used treatments were combination chemotherapy (n=24 instances, mTTNT 7.2 mo.), pralatrexate (n=18, mTTNT 11.6 mo.), romidepsin (n=17, mTTNT 2.4 mo.), RT (n=16, mTTNT 3 mo.), and BV (n=11, mTTNT 3.7 mo.). Median TTNT varied between CCTCL subtypes and was generally longest in patients with SPTCL. 2- and 5-year OS were 73.5% and 64.2%, respectively. Significant differences were observed between CCTCL subtypes (Figure 1).Age > 60 was associated with worse survival (2-year OS 42.3% vs. 100%, p < .0001). Extracutaneous involvement was not associated with outcome (2-year OS 60.6% vs. 69.1%, p=0.5), nor was documented clinical suspicion for HPS (2-year OS 82.2% vs. 64.8%, p=0.21). Patients undergoing allo-SCT (n=9) had superior OS (2-year OS 100% vs. 66.1%, p=0.03) (Figure 2). Thirteen (28.3%) patients had data available from Heme-STAMP testing; every patient who underwent testing had at least one identified mutation. The most frequently occurring somatic mutations included TP53 (n=3), TERT (n=3), and JAK1 (n=3). Conclusions CCTCLs are rare entities with heterogeneous presentation, response to therapy, and survival. Chemotherapy remains an effective treatment, and we identify pralatrexate as a promising single agent option. Allo-SCT offers curative potential in eligible patients. Given wide variation in disease behavior, treatment intensity should be tailored to each individual's clinical phenotype to optimally balance risk and benefit. Further efforts to define the molecular basis of CCTCLs are urgently needed to aid in the identification of more effective therapies. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Primary cutaneous gamma delta T-cell lymphoma: a unique polymorphic cutaneous presentation with hemophagocytic lymphohistiocytosis, and bone marrow Acremonium kiliense infection.

article: Primary cutaneous gamma delta T-cell lymphoma: a unique polymorphic cutaneous presentation with hemophagocytic lymphohistiocytosis, and bone marrow Acremonium kiliense infection - Italian Journal of Dermatology and Venereology 2022 October;157(5):466-7 - Minerva Medica - Journals

Hist-PO-03 - Primary cutaneous gamma-delta T-cell lymphoma: a devastating malignancy in wolf’s clothing in 13 patients

Hist-PO-03 - Primary cutaneous gamma-delta T-cell lymphoma: a devastating malignancy in wolf’s clothing in 13 patients

Expression pattern and diagnostic utility of BCL11B in mature T- and NK-cell neoplasms

BCL11B is an essential transcription factor for T-cell lineage commitment and differentiation, and its dysregulation has been shown to be associated with T-cell tumourigenesis. In this study, we investigated BCL11B expression by immunohistochemical analysis in 120 cases of mature T-cell lymphoma, 34 B-cell lymphomas, 11 NK-cell neoplasms and 17 reactive cutaneous conditions. All cases of mycosis fungoides (n=23), primary cutaneous CD4+ small/medium T-cell lymphoproliferative disorder (n=8) and T-prolymphocytic leukaemia (n=6) were positive for BCL11B and the staining intensity was higher than that of reactive T-cells. Fourteen of 15 (93%) cases of angioimmunoblastic T-cell lymphoma, 10 of 12 (83%) T-large granular lymphocytic leukaemia and 14 of 20 (70%) peripheral T-cell lymphoma, not otherwise specified, were also positive for BCL11B with an intensity comparable to reactive T-cells. Other T-cell neoplasms were uncommonly positive including one of three (33%) cases of primary cutaneous gamma delta T-cell lymphoma, one of four (25%) cases of subcutaneous panniculitis-like T-cell lymphoma, one of four (25%) cases of hepatosplenic T-cell lymphoma, and one of 20 (5%) cases of anaplastic large cell lymphoma (8 ALK-positive, 12 ALK-negative). T-cells in reactive cutaneous infiltrates were also positive for BCL11B, but staining intensity was much weaker than in mycosis fungoides. All NK-cell (n=11) and B-cell neoplasms (n=34) were negative for BCL11B. In conclusion, BCL11B shows a distinct expression pattern in various T-cell neoplasms. BCL11B appears to have utility as another T-cell marker and may be useful in the differential diagnosis of lymphoid neoplasms.

A Registry-Based Geodemographic Assessment of Non-Hodgkin Lymphoma Subtypes in North Carolina

Background: Non-Hodgkin lymphoma (NHL) is the most common hematologic malignancy in the United States. NHL comprises a heterogeneous group of over 40 histological subtypes, each of which has distinct genetic, morphologic and clinical features. While NHL epidemiology as a single entity has been well-characterized using population-based cancer registry data, the epidemiology of NHL subtypes is not well understood and even less data are available for rarer subtypes. We aimed to determine geodemographic correlates for NHL subtypes in North Carolina to provide rarely reported epidemiologic characterization of each distinct malignancy.Methods: Demographic data were obtained on all NHL subtypes reported in persons >18 years of age from 2009-2019 from the North Carolina Central Cancer Registry (NCCCR). NHL subtypes were determined based on World Health Organization International Classification of Diseases for Oncology,Third Edition (ICD-O-3) Morphology codes provided by NCCCR. Crude incidence and mortality rates were estimated per 100,000 persons for the 10-year period using 2019 population data from the U.S Census Bureau. Urban and rural residence designations were based on zip code using rural-urban commuting codes developed by the Rural Health Research Center. County tier designations were used as markers of economic prosperity, with 3 being most prosperous, and provided by the North Carolina Department of Commerce. Data are being mapped using ESRI ArcMap 10.8.1.Results: A total of 25,627 incident cases of NHL and 9,930 associated deaths were reported between 2009 and 2019 in North Carolina. Therefore, the standard NHL incidence and mortality rates are 24.1 and 9.3 per 100,000 persons. For incident NHL cases, median age at diagnosis was 68 years (range 19-103), 55% were male and 45% female. Most (83%) identified as white, 14% as black, and 3% as other. Median age at death was 70 years (range 19-106). Twenty-eight NHL subtypes were identified with the four most common NHL subtypes being Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL), Diffuse Large B Cell Lymphoma (DLBCL), Follicular Lymphoma (FL), and Marginal Zone Lymphoma with 6.54, 6.42, 3.55, and 2.0 cases (per 100,000 persons), respectively. Least common subtypes included Intravascular Large B Cell Lymphoma, Primary Effusion Lymphoma, Primary Cutaneous Gamma Delta T-cell Lymphoma (PCGD-TCL) and Subcutaneous Panniculitis-Like T-cell Lymphoma, all with 0.01 cases per 100,000 persons (or 15, 14, 9 and 6 cases respectively). The distribution of NHL subtypes varied according to demographics with several notable findings. DLBCL had the highest crude mortality rate of 2.98 deaths/100,000 persons, followed by CLL (2.12 deaths/100,000 persons), FL (0.98 deaths/100,000 persons) and Lymphoma NOS (0.51 deaths/100,00 persons). Mediastinal Large B-cell Lymphoma (MLBCL) was diagnosed in the youngest individuals with median age of 36 (range 20-74), whereas PCGD-TCL occurred in the oldest with median age of 74 (range 31-99). Primary Effusion Lymphoma had the highest male predominance (93%) and MLBCL had the highest female predominance (73%). Mantle Cell Lymphoma had the highest predominance of persons who identify as white (90%), Anaplastic Large Cell Lymphoma (ALK+/-) with those who identify as black (66%), and Primary Effusion Lymphoma with those who identify as other (14%). Predominance of rurality and county tier designations varied by NHL subtype.Conclusions: A registry-based assessment of NHL subtypes illustrates the heterogeneous nature of this group of malignancies and highlights significant variation in the geodemographic features of each subtype. Evaluating geodemographic correlates deepens our understanding of NHL subtypes and can inform populations at risk for each unique NHL subtype. [Display omitted] DisclosuresDittus: BeiGene: Other: Advisory Board; Seattle Genetics: Research Funding; AstraZeneca: Research Funding; Genentech: Research Funding.

Epi-P-07 - Indolent primary cutaneous T-cell gamma delta lymphomas: a first illustrated series of 5 cases

Introduction: Primary cutaneous gamma delta T-cell lymphomas (PCGDTCL) are rare, representing less than 1% of all cutaneous lymphomas. The aetiology is uncertain but involves chronic antigen stimulation and immunosuppression. PCGDTCL are a defined entity of the EORTC WHO classification of 2018 with various clinical presentations, most often manifesting as nodules or infiltrated plaques. The prognosis is generally poor and macrophage activation syndrome may occur. Treatment is mostly aggressive yet resistance to multiple chemotherapy or radiation therapy is common leading to frequent relapses.

078 Drug targeting and comparative transcriptomics of alpha-beta subcutaneous panniculitis-like T-cell lymphoma and primary cutaneous gamma delta T-cell lymphoma

078 Drug targeting and comparative transcriptomics of alpha-beta subcutaneous panniculitis-like T-cell lymphoma and primary cutaneous gamma delta T-cell lymphoma

High incidence of adnexotropism in cytotoxic cutaneous lymphomas

Primary cutaneous gamma-delta T-cell lymphoma (PCγδTCL) and primary cutaneous aggressive epidermotropic T-cell lymphomas (PCAETCL) are rare aggressive cytotoxic cutaneous lymphomas (CyCL) often difficult to diagnose. Histopathologically, PCAETCL and PCγδTCL may resemble mycosis fungoides (MF) and the presence of adnexotropism in CyCL (CyCL) contributes to this diagnostic challenge, especially in the setting of atypical and double-negative phenotypes. In this retrospective study clinical data and histopathological section of 91 patients were analyzed for signs of clinical and histopathological signs adnexotropism. Adnexotropism was identified in 48.4% (44/91) of cases, including PCAETCL (40.9%, 18/44), PCγδTCL and cytotoxic cutaneous lymphomas, not otherwise specified (CyCTCL, NOS) (43.2%, 19/44 and 15.9%, 7/44). Comparison between disease-related mortality with Kaplan-Meier survival analysis of non-adnexotropic vs adnexotropic CyCL did not show any significant difference between the two groups (P=0.8). Clinically they present with patches, plaques, and tumors and commonly with ulceration, but follicular prominence or alopecia are rare. Clinical signs of adnexotropism such as alopecia and hypo- or anhidrosis were rarely seen. Adnexotropism is a common finding in CyCL, especially in PCAETCL. Adnexotropic CyCL may be histopathologically difficult to distinguish from folliculotropic mycosis fungoides. A comprehensive IHC panel should be routinely performed in such cases.

Primary cutaneous gamma-delta T-cell lymphoma: Two cases and a review of the literature

Background: Primary cutaneous gamma delta T cell lymphoma (PCGD TCL) is a rare and rapidly progressive cutaneous malignancy that can be diagnostically challenging. Purpose: To improve characterization of the clinical and histologic features of PCGD-TCL. Methods: We present two patients with PCGD TCL and review an additional 97 PCGD TCL cases from the English literature. Results: A 51 year old male with biopsy proven psoriasis and a previously healthy 31 year old male with vitiligo developed PCGD-TCL. Initial biopsy specimens in both patients suggested tumor stage mycosis fungoides (MF), but subsequent histopathology confirmed PCGD TCL. Ninety-seven patients were identified in the literature, mostly males (53%) with a mean age of 55.2 years. Lesions most commonly involved the lower (60%) and upper (30%) extremities and existed a mean of 26 months before diagnosis. The most common immunohistochemical markers were EBV(-), CD3(+), CD4(-), CD5(-), CD7(-), CD8(-), CD30(-), CD56(+), granzyme-B(+), perforin(+), and βF1(-). Radiation and CHOP chemotherapy were the most common interventions and 52% of patients died. Conclusion: PCGD TCL is a devastating disease that can clinically and histologically mimic more common dermatologic conditions, such as psoriasis and MF, and its diagnosis may require multiple biopsies and review by a multi specialty pathology team.

Comparative Transcriptomics of Alpha-Beta Subcutaneous Panniculitis-like T-Cell Lymphoma and Primary Cutaneous Gamma Delta T-Cell Lymphoma

Background: Subcutaneous lymphomas are a heterogeneous group of diseases with variable clinical behavior that ranges from a lymphoproliferative disorder to an aggressive cytotoxic lymphoma. Subcutaneous panniculitis-like T-cell lymphoma (SPTCL) is an uncommon, often indolent cutaneous lymphoma that localizes to the subcutaneous adipose tissue. These tumors exhibit an alpha/beta phenotype (abSPTCL). Primary cutaneous gamma-delta T-cell lymphoma (PCgdTCL) is a rare, highly aggressive lymphoma that frequently involves the subcutaneous adipose tissue. The goal of this study is to identify key inflammatory and oncogenic pathways in SPTCL and PCgdTCL to determine which mutational or expression patterns differentiate abSPTCL and PCgdTCL. A comprehensive catalog of cancer gene expression profiles generated via RNA sequencing on patient samples is essential to understand tumorigenesis and to develop effective therapies. Methods: We performed transcriptomic profiling analysis using RNA sequencing in lesional skin biopsies from patients of abSPTCL (n=10), PCgdTCL (n=9), and controls (n=5). Differential analyses were performed on the entire transcriptomic profiles among the 3 groups. Results: Although the transcriptomic profiles of abSPTCL and PCgdTCL samples had similarities, there were notable differences between these groups that may elucidate unique pathways that propagate each disease. In contrast to abSPTCL, PCgdTCL samples demonstrated upregulation of cell motility and proliferation, and downregulation of pathways involving apoptosis and tumor necrosis factor production. The most significantly upregulated gene pathways in both abSPTCL and PCgdTCL samples were those involving immune and inflammatory response, viral defense, type I interferon signaling, interferon-gamma-mediated signaling, and positive regulation of T cell proliferation. The most significantly downregulated gene pathways in the two groups were those involving cell adhesion, rRNA processing and translation, and extracellular matrix organization. The top 5 upregulated immune response and downregulated cell adhesion hub genes for abSPTCL highlighted by gene interaction network analysis included: TNF, CTLA4, CD86, IL10, CCR5 &amp; ITGB5, ITGA8, VWF, APP, CDH5, respectively. Conclusion: Our transcriptomic profiling pinpoints disease-related enrichment pathways and gene functions in abSPTCL and PCgdTCL patients, which may shed light on molecular mechanisms that drive disease activity. Hub genes in abSPTCL represent potential drug targets for further development of novel therapies. Disclosures Mangold: Kirin:Membership on an entity's Board of Directors or advisory committees;Elorac:Research Funding;Sun Pharma:Research Funding;MiRagen:Research Funding;Solagenix:Research Funding.

STAT3 Mutations and Anemia with Pure Red Cell Aplasia Are the Distinctive Features of T Cell Receptor Gamma Delta Type Large Granular Lymphocyte Leukemia

Large granular lymphocytic leukemia (LGLL) is a heterogenous group of disorders. The clinical presentations of LGLL are highly variable; it may present with neutropenia or anemia, complicated with recurrent infections, autoimmune diseases such as rheumatoid arthritis, and neurological symptoms, requiring therapeutic interventions. It may present only with indolent laboratory changes without any symptoms. The cytological phenotypes of LGLL also vary and they commonly include CD8+TCR αβ-type, CD4+TCR αβ-type, and NK cell-type. NK cell-type LGLL is designated as chronic lymphoproliferative disorder of NK cells (CLPD-NK). TCR γδ-type LGLL (γδT-LGLL) is even rarer and it often confers cytopenia. The genetic backgrounds of LGLL with CD8+TCRαβ-type, CD4+TCRαβ-type and NK cell-type have been elucidated with the recent sequencing technologies. JAK/STAT signaling genes and chromatin-modifying genes were frequently mutated in the non-leukemic counterpart of the lymphoid malignancies with γδ TCR immunophenotypes, such as hepatosplenic T-cell lymphoma, monomorphic epitheliotropic intestinal T-cell lymphoma and primary cutaneous gamma delta T-cell lymphoma. However, the genetic basis of γδT-LGLL and the genetic-phenotypic associations remain unclear. The aim of this study is to identify clinical and genetic characteristics of γδT-LGLL in comparison with other LGL leukemias. In total, 56 LGLL patients were recruited; six patients with γδT-LGLL, 25 CD8+ TCRαβ type, 8 CD4+TCR αβ type and 17 CLPD-NK, in this study. All cases were negative for EBV. The median age of patients with γδT-LGLL was 48 years old and five of them were male. The median LGL counts and hemoglobin level were 1.81 ×109/L (range; 0.60-4.42) and 5.8 g/dL (range; 3.0-11.2), respectively. All patients with γδT-LGLL had anemia and/or neutropenia, although no patients were thrombocytopenic. 4 patients presented with pure red cell aplasia. Common immunophenotypes of γδT cells were CD2+ CD3+ CD4-CD7+. 3 patients were CD8+. CD16, CD56 and CD57 were positive in 3, 0, and 1 patient, respectively. γδT cells of all patients showed a monoclonal pattern of TCRγ gene rearrangements with BioMed 2 protocol. We performed amplicon sequencing of entire coding regions of STAT3, STAT5B and TNFAIP3 genes and allele-specific PCR for several hot spot regions of STAT3 and STAT5B genes using extracted DNA from mononuclear cells of peripheral blood. Mutations in STAT3 and TNFAIP3 were identified in 100% (6/6) and 17% (1/6), respectively. Among the10 STAT3 mutations identified, 5 were located in the SH-2 domain, while other 3 were in coiled-coiled domain and the other 2 were in the DNA binding domain. The median variant allele frequencies of STAT3 was 2.0% (0.7-22.6) and STAT3 mutations were restricted to sorted γδT cells in all 3 patients examined. No patient was positive for STAT5B mutations, including N642H and Y665F with allele specific PCRs. One of 5 patients who were treated with cyclosporin A was refractory. Two patients were treated with cyclophosphamide, showing clinical improvements. The patients with γδT-LGLL were younger than those with other types of LGLL (P=0.048) and anemia and STAT3 mutations were significantly more frequent in γδT-LGLL (P value; 0.003 and 0.02, respectively). PRCA was a consistent cause of anemia in γδT-LGLL. Low frequency of STAT5B mutations among γδT-LGLL patients was in contrast to other aggressive γδT cell lymphoma in which STAT5B frequently mutated. The clinical characteristics of γδT-LGLL patients may be defined by younger age and the anemia due to pure red cell aplasia, and the frequent STAT3 mutations might be a novel molecular marker for γδT-LGLL. Disclosures Yamane: Pfizer: Research Funding; Celgene: Honoraria; Bristol-Meyers Squibb: Research Funding; Chugai Pharmaceutical: Consultancy, Research Funding; Astellas Pharma: Research Funding; Eli Lily and Company: Research Funding. Ishida:Eli Lily and Company: Research Funding; Astellas Pharma: Research Funding; Pfizer: Research Funding; Bristol-Meyers Squibb: Research Funding; Chugai Pharmaceutical: Consultancy, Research Funding; Celgene: Honoraria.

Primary cutaneous gamma-delta T-cell lymphoma masquerading as severe soft tissue infection

N/A- Case report

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.

Silent T-cell receptor cutaneous T-cell lymphoma associated to a clonal plasma cell proliferation.

Within T-cell lymphomas (TCL) there are 2 entities expressing gamma-delta TCR: hepatosplenic gamma-delta T-cell lymphoma (HSGDTL) and the primary cutaneous gamma-delta T-cell lymphoma (PCGDTL). PCGDTL is a rare form of Tcell lymphoma with specific tropism for skin that have a dismal prognosis. Although even rarer, there have been reports of TCL with loss of expression of the TCR, which have been termed peripheral TCL TCR-silent type. We report the case of a cutaneous TCR-silent type lymphoma associated to a clonal plasma cell proliferation with an ominous outcome that led to a lot of discussion in its classification. Due to the aggressiveness of the disease and the scant evidence about therapy in this strange entity the outcome was fatal. We report a unique case of a TCR-silent cutaneous TCL with an exceptional histopathology, prolonged clinical evolution and a subsequent plasma cell clonal expansion.