Epidermotropic Cytotoxic T-cell Lymphoma Research Articles

Primary cutaneous, epidermotropic mycosis fungoides-like presentation: critical appraisal and description of two novel cases, broadening the spectrum of ALK+ T-cell lymphoma.

Leading from a two-case series, including two patients receiving a diagnosis of epidermotropic T-cell lymphoma, featuring a mycosis fungoides (MF)-like clinical pattern and ALK expression and molecular alteration, we performed a critical appraisal of ALK+ primary cutaneous T-cell lymphomas (pcTCL). Considering our patients and the literature, 32 cases were retrieved, 7 of which featured an MF-like clinical picture over a 4-to-20-year period. MF-like cases show distinctive histology, comprising a predominantly epidermotropic infiltration of small-to-large, atypical-to-pleomorphic, with few anaplastic cells, negligible-to-intense CD30-expression, and a CD4+/cytotoxic granule+ phenotype. These features should prompt a search for ALK expression captured by the ALK D5F3 clone. Bona fide ALK+ pcTCL is very rare, and existent data suggest the presence of a broader pattern of disease, including instances mimicking MF and/or primary cutaneous CD8+ aggressive epidermotropic cytotoxic T-cell lymphoma. The major challenges in dealing with this subset include prodromal phases, misinterpreted as inflammatory dermatosis or parapsoriasis/early phase MF both clinically and histologically, while recognition of its ALK-driven biology is hampered both by the unusual clinic-pathologic pattern of the disease, which stands apart from the classical (i.e., nodal) picture of ALK+ anaplastic large cell lymphoma and by the low sensitivity of ALK1 clone. Data on its optimal management are far from being conclusive: An MF-like approach is currently chosen, but depending on CD30 and, most notably, ALK expression, a targeted therapy could be envisaged in advanced stages, as clinical response to ALK inhibition was documented in one patient.

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.

Classifications of cutaneous lymphomas and lymphoproliferative disorders: An update from the EORTC cutaneous lymphoma histopathology group.

The classification of primary cutaneous lymphomas and lymphoproliferative disorders (LPD) is continuously evolving by integrating novel clinical, pathological and molecular data. Recently two new classifications for haematological malignancies including entities of cutaneous lymphomas were proposed: the 5th edition of the WHO classification of haematolymphoid tumours and the International Consensus Classification (ICC) of mature lymphoid neoplasms. This article provides an overview of the changes introduced in these two classifications compared to the previous WHO classification. The main changes shared by both classifications include the downgrading of CD8+ acral T-cell lymphoma to CD8+ acral T-cell LPD, and the recognition of entities that were previously categorized as provisional and have now been designated as definite types including primary cutaneous small or medium CD4+ T-cell LPD, primary cutaneous gamma/delta T-cell lymphoma, primary cutaneous CD8+ aggressive epidermotropic cytotoxic T-cell lymphoma, Epstein-Barr virus-positive mucocutaneous ulcer. Both classifications consider primary cutaneous marginal zone B-cell clonal neoplasm as an indolent disease but use a different terminology: primary cutaneous marginal zone lymphoma (WHO) and primary cutaneous marginal zone LPD (ICC). The 5th WHO classification further introduces and provides essential and desirable diagnostic criteria for each disease type and includes chapters on reactive B- or T-cell rich lymphoid proliferations formerly referred as cutaneous pseudolymphomas, as well as histiocyte and CD8 T-cell rich LPD in patients with inborn error of immunity. As already emphasized in previous lymphoma classifications, the importance of integrating clinical, histological, phenotypic and molecular features remains the crucial conceptual base for defining cutaneous (and extracutaneous) lymphomas.

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

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 CD8+ Aggressive Epidermotropic Cytotoxic T-Cell Lymphoma (PCAECTCL) Descriptors and Clinicopathologic Determinants of Survival: Analysis of a Pooled Database

Introduction: Primary Cutaneous CD8+ Aggressive Epidermotropic Cytotoxic T-cell lymphoma (PCAECTCL) is a rare provisional clinical entity and a subtype of cutaneous T-cell lymphoma. It is characterized by cytotoxic T-cells that primarily involve the epidermis causing rapidly progressive epidermal necrosis and extensive skin ulcers. PCAECTCL is often resistant to conventional chemotherapy and is usually associated with a poor prognosis. We conducted this pooled database analysis to delineate key disease characteristics and clinicopathologic determinants of survival in this rare provisional 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 128 cases. Kaplan-Meier survival curves were constructed. Cox proportional hazards model and Log-rank tests were used to assessing the influence of demographic and clinicopathologic factors on overall survival (OS). Results: A total of 128 patients with confirmed PCAECTCL were identified. The median age was 62, with a peak incidence between 60 and 75 years. There was a male predominance with M:F ratio of 1.9. The median duration of symptoms prior to diagnosis was 6 months. Most of the patients presented with stage IIB (75%), followed by IB (13%), IA(7%), IVB(3%), and IIA(1%). Constitutional symptoms (CS), hemophagocytic syndrome, and ulceration/necrosis were present in 6%, 33%, 1.5%, and 45%, respectively. PCAECTCL widely metastasized in 62% of the cases, mainly to mucocutaneous tissues and visceral organs (83%), which included testicles (11%) and CNS (22%). PCAECTCL immunophenotype consisted of: CD2(37%), CD3(99%), CD5(40%), CD7(66%), CD30(16%), CD45RA(77%), CD56(6%), Granzyme B(72%), TIA-1(100%), and a median Ki-67 score of 70%. The median OS of the whole group was 20 months. OS was significantly impacted as age increased from <40 to 40-59 and > 60 (34 vs. 27 vs. 12 months, p=0.0003). Combination chemotherapy and stem cell transplant were statistically superior to no treatment, with a median OS of 17, 50, and 1 months, respectively (p=0.0002). Males tended to have shorter OS than females (13 vs. 24 months). Similarly, the presence of CS tended to have a shorter OS (6 vs. 21 months). OS was not impacted by stage or immunohistochemical features. Conclusions: This study presents updated clinicopathologic data from a pooled cohort of patients with PCAECTCL. It details the features of this rare provisional entity and identifies the clinical, immunohistochemical, and treatment modalities that are major determinants of OS.

Deregulation of JAK2 signaling underlies primary cutaneous CD8+ aggressive epidermotropic cytotoxic T-cell lymphoma.

Primary cutaneous CD8+ aggressive epidermotropic cytotoxic T-cell lymphoma (pcAECyTCL) is a rare variant of cutaneous T-cell lymphoma with an aggressive clinical course and a very poor prognosis. Until now, neither a systematic characterization of genetic alterations driving pcAECyTCL has been performed, nor effective therapeutic regimes for patients have been defined. Here, we present the first highresolution genetic characterization of pcAECyTCL by using wholegenome and RNA sequencing. Our study provides a comprehensive description of genetic alterations (i.e., genomic rearrangements, copy number alterations and small-scale mutations) with pathogenic relevance in this lymphoma, including events that recurrently impact genes with important roles in the cell cycle, chromatin regulation and the JAKSTAT pathway. In particular, we show that mutually exclusive structural alterations involving JAK2 and SH2B3 predominantly underlie pcAECyTCL. In line with the genomic data, transcriptome analysis uncovered upregulation of the cell cycle, JAK2 signaling, NF-κB signaling and a high inflammatory response in this cancer. Functional studies confirmed oncogenicity of JAK2 fusions identified in pcAECyTCL and their sensitivity to JAK inhibitor treatment. Our findings strongly suggest that overactive JAK2 signaling is a central driver of pcAECyTCL, and consequently, patients with this neoplasm would likely benefit from therapy with JAK2 inhibitors such as Food and Drug Adminstration-approved ruxolitinib.

Primary cutaneous lymphomas in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL): A series of 12 cases

Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) is associated with an increased risk of a second malignancy. We conducted a retrospective clinicopathologic review of 12 patients with CLL/SLL who developed a second lymphoma in the skin. Demographic data, clinical information, and histopathology from 31 biopsies were recorded. Cases of secondary cutaneous involvement by CLL/SLL (leukemia cutis) and non-primary cutaneous lymphomas were excluded. A wide variety of primary cutaneous lymphomas was identified, including classic mycosis fungoides (3), cutaneous marginal zone lymphoma (2), primary cutaneous peripheral T-cell lymphoma unspecified (2), folliculotropic mycosis fungoides (1), Sézary syndrome (1), cutaneous gamma-delta T-cell lymphoma (1), cutaneous CD8+ aggressive epidermotropic cytotoxic T-cell lymphoma (1), and cutaneous anaplastic large cell lymphoma (1). A male predominance was observed, and the average age was 74.1 years. In all patients, CLL/SLL predated the development of the second lymphoma, which was aggressive in the majority of cases (58%). Aggressive cytotoxic T-cell lymphomas, generally rare neoplasms, were relatively common (30%). CLL/SLL patients may develop a second lymphoma in the skin, which may be aggressive. Atypical cutaneous lymphoid infiltrates in this patient population should not be assumed to represent secondary CLL/SLL involvement and require thorough immunohistochemical analysis.

Challenges in early diagnosis of primary cutaneous CD8+ aggressive epidermotropic cytotoxic T-cell lymphoma: a case series of four patients

Primary cutaneous aggressive epidermotropic CD8+ cytotoxic T-cell lymphoma (AECTCL) is a rare and aggressive lymphoma characterised by ulcerated lesions and a poor prognosis. To present a case series of four previously misdiagnosed AECTCL patients and discuss the importance of early diagnosis. All patients in this study were identified from the database of the Dermatology Department of the Medical School of Bezmialem Vakif University, based on clinical and histopathological diagnosis of AECTCL between 2010 and 2018. AECTCL cases may mimic many benign dermatoses and accurate diagnosis may be delayed. Because of its poor prognosis, early diagnosis of AECTCL may be helpful in improving the likelihood of patient survival, but further study is needed to address the challenges in diagnosing this rare and aggressive lymphoma.

Malodorous Skin Lesions in a Diabetic Patient: Infectious Versus Neoplastic

Abstract Primary cutaneous CD8+ aggressive epidermotropic cytotoxic T-cell lymphoma is a rare entity accounting for &lt;1% of all cutaneous T-cell lymphomas. Almost all patients present with generalized skin lesions. This type of lymphoma has an extremely aggressive course with a median survival of 12 months. It tends to spread to other visceral sites, but lymph nodes are usually spared. We describe a case of a 59-year-old male with multiple necrotic malodours ulcers for several months. The first lesion was on his left thigh, followed by another lesion on his right chest and right eyelid. Medical history revealed newly diagnosed diabetes mellitus. The patient received antibiotics, presumptively for infectious etiology of the skin lesion, with no improvement. The right thigh lesion was excised and histomorphologic examination revealed a deep dermal proliferation of large-sized pleomorphic cells with marked pagetoid epidermotropism and skin ulceration. The adnexal skin structures were invaded by the lesion. The lesional cells were immunoreactive for CD3, CD7, CD8, and granzyme B; they were negative for CD4, CD5, CD56, and CD30. The immunophenotype confirms the entity that we have at hand in addition to the similar clinical picture that the patient presented with. This disease usually shows clonal TR gene rearrangements; nonetheless, no specific mutational aberration has been described. Our patient received chemotherapy; however, new lesions continued to erupt and he opted to proceed with palliative care. Clinical information is needed to give this diagnosis as it may look identical to a variant of lymphomatoid papulosis (type D), CD8-positive cutaneous T-cell lymphoma. We present this case due to the importance of clinical pathologic coloration to prevent misdiagnosis with mimickers as the ones pointed out earlier, and it is a provisional rare entity in the 2018 WHO classification of Tumors of Haematopoietic and Lymphoid Tissues.

Cutaneous Lymphoproliferative Disorders: What's New in the Revised 4th Edition of the World Health Organization (WHO) Classification of Lymphoid Neoplasms.

Cutaneous lymphoproliferative disorders remain a challenging aspect of dermatopathology, in part due to the rarity of the entities and extreme variability in clinical outcomes. Although many of the entities remain unchanged, the approach to some of them has changed in the new 2016 classification scheme of the World Health Organization. Chief among these are Epstein-Barr virus-associated lymphoproliferative disorders such as Epstein-Barr virus-associated mucocutaneous ulcer and hydroa vacciniforme-like lymphoproliferative disorder, primary cutaneous CD8+ aggressive epidermotropic cytotoxic T-cell lymphoma, primary cutaneous acral CD8+ T-cell lymphoma, primary cutaneous CD4+ small/medium T-cell lymphoproliferative disorder, and breast implant-associated anaplastic large cell lymphoma. In addition, translocations and gene rearrangements such as those involving the 6p25.3 locus have started to inform diagnosis and classification of anaplastic large cell lymphoma and lymphomatoid papulosis. In this review, we will examine what is new in the diagnostic toolbox of cutaneous lymphoproliferative disorders.

Rare T-Cell Subtypes.

There are a number of rare T-cell lymphoma subtypes that may be encountered in clinical practice. In recent years, improved immunohistochemical techniques and molecular tumor profiling have permitted refinement of some of the diagnostic categories in this group, as well as the recognition of distinct conditions not previously well elucidated. In this chapter, we cover the diagnostic and clinical features of some of the more common of these conditions, including subcutaneous panniculitis-like T-cell lymphoma, cutaneous gamma-delta T-cell lymphoma, enteropathy-associated T-cell lymphoma, monomorphic epitheliotropic intestinal T-cell lymphoma, primary cutaneous CD8-positive aggressive epidermotropic cytotoxic T-cell lymphoma, CD4-positive small/medium T-cell lymphoproliferative disorder, and acral CD8-positive T-cell lymphoma. Given the rarity of these conditions, optimal treatments approaches are not always well established, not least as data from large-scale clinical trials are lacking. In this chapter, we aim to provide a summation of current thinking around best treatment, as well as highlighting some controversies in the management of these diagnoses.

Array-based CGH of primary cutaneous CD8+ aggressive EPIDERMO-tropic cytotoxic T-cell lymphoma.

Primary cutaneous CD8+ aggressive epidermotropic cytotoxic T-cell lymphoma (pcAECyTCL) is a rare provisionally categorized cutaneous lymphoma characterized by an aggressive course. Its pathogenesis and molecular mechanisms are still unknown, and only two individual cases have so far been molecularly characterized. The aim of this study was to define the pattern of numerical chromosomal alterations in tumor samples taken from 20 patients with pcAECyTCL at the time of diagnosis by means of array-comparative genomic hybridization (a-CGH). a-CGH detected numerous genomic aberrations in all the patients and, putting these together as a whole, they affected all the chromosomes. However, no specific profile of recurrent copy number alterations (CNAs) was found. Most of the gains involved regions previously described in other aggressive cutaneous lymphomas such as 7q, 8q24.3, and 17q, whereas the most significant CNA was the loss of 9p21.3 (CDKN2A-CDKN2B), which has already been found in a variety of malignant tumors and is associated with aggressive cutaneous T-cell lymphomas. In brief, CGH analysis revealed a large number of CNAs with only few recurring regions that probably do not represent driving events. The genomic instability found in this aggressive variant of cutaneous lymphoma may therefore be a secondary event but, at the time of the diagnosis of pcAECyTCL, the genomic integrity of tumor cells is already compromised.

Primary cutaneous ‘indolent’ epidermotropic cytotoxic T-cell lymphoma

Introduction: Primary cutaneous CD8-positive aggressive epidermotropic T-cell lymphoma is a rare and poorly characterized variant of cutaneous lymphoma still considered a provisional entity in the 2016 World Health Organization Classification of Cutaneous lymphomas.

Aggressive rare T cell lymphomas with manifestation in the skin: A monocentric cross-sectional case study

Rare T- or NK-cell lymphomas with cutaneous manifestation may display a highly aggressive clinical course and major diagnostic/therapeutic challenges. This report describes our experiences with different lymphomas of this rare category and the therapeutic options used. This retrospective, descriptive, monocentric, cross-sectional case study, identified 4 rare aggressive T-/NK-cell lymphomas with manifestation in the skin, which were diagnosed in a tertiary care centre over a period of 4 years. Two patients had an Epstein-Barr virus-associated extranodal NK/T-cell lymphoma and 2 patients had a primary cutaneous CD8+ aggressive epidermotropic cytotoxic T-cell lymphoma. Concomitant extracutaneous involvement was observed in 2 of all 4 patients. Two patients had fulminant disease progression and resistance to chemotherapy. Two patients underwent allogeneic haematopoietic stem cell transplantation, which resulted in one complete remission and one partial remission. This report emphasizes the importance of an early diagnostic work-up and a prompt aggressive therapeutic approach.

New Therapies and Immunological Findings in Cutaneous T-Cell Lymphoma.

Primary cutaneous lymphomas comprise a group of lymphatic malignancies that occur primarily in the skin. They represent the second most common form of extranodal non-Hodgkin’s lymphoma and are characterized by heterogeneous clinical, histological, immunological, and molecular features. The most common type is mycosis fungoides and its leukemic variant, Sézary syndrome. Both diseases are considered T-helper cell type 2 (Th2) diseases. Not only the tumor cells but also the tumor microenvironment can promote Th2 differentiation, which is beneficial for the tumor cells because a Th1 environment enhances antitumor immune responses. This Th2-dominant milieu also underlies the infectious susceptibility of the patients. Many components, such as tumor-associated macrophages, cancer-associated fibroblasts, and dendritic cells, as well as humoral factors, such as chemokines and cytokines, establish the tumor microenvironment and can modify tumor cell migration and proliferation. Multiagent chemotherapy often induces immunosuppression, resulting in an increased risk of serious infection and poor tolerance. Therefore, overtreatment should be avoided for these types of lymphomas. Interferons have been shown to increase the time to next treatment to a greater degree than has chemotherapy. The pathogenesis and prognosis of cutaneous T-cell lymphoma (CTCL) differ markedly among the subtypes. In some aggressive subtypes of CTCLs, such as primary cutaneous gamma/delta T-cell lymphoma and primary cutaneous CD8+ aggressive epidermotropic cytotoxic T-cell lymphoma, hematopoietic stem cell transplantation should be considered, whereas overtreatment should be avoided with other, favorable subtypes. Therefore, a solid understanding of the pathogenesis and immunological background of cutaneous lymphoma is required to better treat patients who are inflicted with this disease. This review summarizes the current knowledge in the field to attempt to achieve this objective.

NK/T-cell lymphoma, nasal type, γδ T-cell lymphoma, and CD8-positive epidermotropic T-cell lymphoma-clinical and histopathologic features, differential diagnosis, and treatment.

The cytotoxic lymphomas of the skin constitute a heterogeneous group of rare lymphoproliferative diseases that are derived from mature T cells and natural killer (NK) cells that express cytotoxic molecules (T-cell intracellular antigen- 1, granzyme A/B, and perforin). Although frequently characterized by an aggressive course and poor prognosis, these diseases can have variable clinical behavior. This review delivers up-to-date information about the clinical presentation, histopathologic features, differential diagnosis, and therapy of extranodal NK/T-cell lymphoma, nasal type, primary cutaneous gamma delta T-cell lymphoma, and primary cutaneous CD8+ aggressive epidermotropic cytotoxic T-cell lymphoma.

Transplantation in the Treatment of Primary Cutaneous Aggressive Epidermotropic Cytotoxic CD8-Positive T-Cell Lymphoma.

Primary cutaneous aggressive epidermotropic cytotoxic CD8 positive T-cell lymphoma (CD8+ PCAETL) is a rare subtype of peripheral T-cell lymphoma with poor outcomes and without a standardized treatment strategy. Allogeneic hematopoietic stem cell transplantation (HSCT) has been suggested as a potential curative therapy. We conducted a retrospective case series. We identified 8 patients with the diagnosis of CD8+ PCAETL, 4 of whom also underwent allogeneic HSCT. Eight patients were treated at our center with combination chemotherapy and several novel agents, including histone deacetylase inhibitors, brentuximab, and pralatrexate. Patients underwent a median of 8.5 treatments before HSCT. Six of the 8 patients examined, including all 4 who received an HSCT, were alive at their last follow-up. Allogeneic HSCT is a promising treatment modality for CD8+ PCAETL. Because of the aggressive nature of this disease and lack of sustained remission with currently available therapies, HSCT should be considered early in the course of treatment. Two novel agents, brentuximab and pralatrexate, showed significant activity against CD8+ PCAETL, and may be incorporated earlier in the treatment course.

Primary cutaneous aggressive epidermotropic cytotoxic T-cell lymphomas: reappraisal of a provisional entity in the 2016 WHO classification of cutaneous lymphomas

Primary cutaneous CD8-positive aggressive epidermotropic T-cell lymphoma is a rare and poorly characterized variant of cutaneous lymphoma still considered a provisional entity in the latest 2016 World Health Organization Classification of Cutaneous lymphomas. We sought to better characterize and provide diagnostic and therapeutic guidance of this rare cutaneous lymphoma. Thirty-four patients with a median age of 77 years (range 19–89 years) presented primarily with extensive annular necrotic plaques or tumor lesions with frequent mucous membrane involvement. The 5-year survival was 32% with a median survival of 12 months. A subset of 17 patients had a prodrome of chronic patches prior to the development of aggressive ulcerative lesions. We identified cases with lack of CD8 or αβ T-cell receptor expression yet with similar clinical and pathological presentation. Allogeneic stem cell transplantation provided partial or complete remissions in 5/6 patients. We recommend the term primary cutaneous aggressive epidermotropic cytotoxic T-cell lymphoma as this more broad designation better describes this clinical-pathologic presentation, which allows the inclusion of cases with CD8 negative and/or αβ/γδ T-cell receptor chain double-positive or double-negative expression. We have identified early skin signs of chronic patch/plaque lesions that are often misdiagnosed as eczema, psoriasis, or mycosis fungoides. Our experience confirms the poor prognosis of this entity and highlights the inefficacy of our standard therapies with the exception of allogeneic stem cell transplantation in selected cases.

Hematopoietic stem cell transplantation in advanced cutaneous T‐cell lymphoma

We retrospectively reviewed data pertaining to five patients with cutaneous T-cell lymphoma (CTCL) who had received hematopoietic stem cell transplantation (HSCT) between 2004 and 2015 at Kurume University Hospital, along with their clinical data until March 2016. For patients with advanced CTCL eligible for HSCT, autologous HSCT was performed when they responded well to chemotherapy, and allogeneic HSCT was selected for patients with advanced mycosis fungoides (MF)/Sézary syndrome (SS) and CTCL other than MF/SS with poor chemosensitivity. Two patients (primary cutaneous anaplastic large cell lymphoma and primary cutaneous CD8+ aggressive epidermotropic cytotoxic T-cell lymphoma) who responded well to chemotherapy received autologous HSCT: one patient was alive in partial remission and the other died due to therapy-related acute myeloid leukemia without disease relapse. In the remaining three patients with MF or SS, allogeneic HSCT was performed. Although one patient with MF died due to disease progression, the remaining two patients were alive in complete remission. Although there were two deaths in this study, the outcomes were considered satisfactory.