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

Clinical and Pathological Characteristics and Outcomes Among Patients With Subcutaneous Panniculitis-like T-Cell Lymphoma and Related Adipotropic Lymphoproliferative Disorders

IMPORTANCE: There is a knowledge gap about subcutaneous panniculitis-like T-cell lymphoma (SPTCL) owing to its rarity and diagnostic difficulty, resulting in an absence of well-documented large case series published to date. OBJECTIVE: To generate consensus knowledge by a joint multi-institutional review of SPTCL and related conditions. DESIGN, SETTING, AND PARTICIPANTS: This retrospective clinical and pathological review included cases initially diagnosed as SPTCL at 6 large US academic centers. All cases were reviewed by a group of pathologists, dermatologists, and oncologists with expertise in cutaneous lymphomas. Through a process of group consensus applying defined clinical and pathological diagnostic criteria, the cohort was classified as (1) SPTCL or (2) adipotropic lymphoproliferative disorder (ALPD) for similar cases with incomplete histopathological criteria for SPTCL designation. EXPOSURES: Cases of SPTCL diagnosed between 1998 and 2018. MAIN OUTCOMES AND MEASURES: The main outcome was disease presentation and evolution, including response to therapy, disease progression, and development of hemophagocytic lymphohistiocytosis. RESULTS: The cohort of 95 patients (median [range] age, 38 [2-81] years; female-to-male ratio, 2.7) included 75 cases of SPTCL and 20 cases of ALPD. The clinical presentation was similar for both groups with multiple (61 of 72 [85%]) or single (11 of 72 [15%]) tender nodules mostly involving extremities, occasionally resulting in lipoatrophy. Hemophagocytic lymphohistiocytosis (HLH) was only observed in SPTCL cases. With a mean follow-up of 56 months, 60 of 90 patients (67%) achieved complete remission with a median (range) of 3 (1-7) cumulative therapies. Relapse was common. None of the patients died of disease progression or HLH. Two patients with ALPD eventually progressed to SPTCL without associated systemic symptoms or HLH. CONCLUSIONS AND RELEVANCE: In this case series of patients initially diagnosed as having SPTCL, results showed no evidence of systemic tumoral progression beyond the adipose tissue. The SPTCL experience in this study confirmed an indolent course and favorable response to a variety of treatments ranging from immune modulation to chemotherapy followed by hematopoietic stem cell transplantation. Morbidity was primarily associated with HLH

Global patterns of care in advanced stage mycosis fungoides/Sezary syndrome: a multicenter retrospective follow-up study from the Cutaneous Lymphoma International Consortium

ABSTRACT Background Advanced-stage mycosis fungoides (MF)/Sezary syndrome (SS) patients are weighted by an unfavorable prognosis and share an unmet clinical need of effective treatments. International guidelines are available detailing treatment options for the different stages but without recommending treatments in any particular order due to lack of comparative trials. The aims of this second CLIC study were to retrospectively analyze the pattern of care worldwide for advanced-stage MF/SS patients, the distribution of treatments according to geographical areas (USA versus non-USA), and whether the heterogeneity of approaches has potential impact on survival. Patients and methods This study included 853 patients from 21 specialist centers (14 European, 4 USA, 1 each Australian, Brazilian, and Japanese). Results Heterogeneity of treatment approaches was found, with up to 24 different modalities or combinations used as first-line and 36% of patients receiving four or more treatments. Stage IIB disease was most frequently treated by total-skin-electron-beam radiotherapy, bexarotene and gemcitabine; erythrodermic and SS patients by extracorporeal photochemotherapy, and stage IVA2 by polychemotherapy. Significant differences were found between USA and non-USA centers, with bexarotene, photopheresis and histone deacetylase inhibitors most frequently prescribed for first-line treatment in USA while phototherapy, interferon, chlorambucil and gemcitabine in non-USA centers. These differences did not significantly impact on survival. However, when considering death and therapy change as competing risk events and the impact of first treatment line on both events, both monochemotherapy (SHR = 2.07) and polychemotherapy (SHR = 1.69) showed elevated relative risks. Conclusion This large multicenter retrospective study shows that there exist a large treatment heterogeneity in advanced MF/SS and differences between USA and non-USA centers but these were not related to survival, while our data reveal that chemotherapy as first treatment is associated with a higher risk of death and/or change of therapy and thus other therapeutic options should be preferable as first treatment approach

Cutaneous lymphoma international consortium study of outcome in advanced stages of mycosis fungoides and Sézary syndrome: effect of specific prognostic markers on survival and development of a prognostic model

Advanced-stage mycosis fungoides (MF; stage IIB to IV) and Sézary syndrome (SS) are aggressive lymphomas with a median survival of 1 to 5 years. Clinical management is stage based; however, there is wide range of outcome within stages. Published prognostic studies in MF/SS have been single-center trials. Because of the rarity of MF/SS, only a large collaboration would power a study to identify independent prognostic markers. PATIENTS AND METHODS: Literature review identified the following 10 candidate markers: stage, age, sex, cutaneous histologic features of folliculotropism, CD30 positivity, proliferation index, large-cell transformation, WBC/lymphocyte count, serum lactate dehydrogenase, and identical T-cell clone in blood and skin. Data were collected at specialist centers on patients diagnosed with advanced-stage MF/SS from 2007. Each parameter recorded at diagnosis was tested against overall survival (OS). RESULTS: Staging data on 1,275 patients with advanced MF/SS from 29 international sites were included for survival analysis. The median OS was 63 months, with 2- and 5-year survival rates of 77% and 52%, respectively. The median OS for patients with stage IIB disease was 68 months, but patients diagnosed with stage III disease had slightly improved survival compared with patients with stage IIB, although patients diagnosed with stage IV disease had significantly worse survival (48 months for stage IVA and 33 months for stage IVB). Of the 10 variables tested, four (stage IV, age > 60 years, large-cell transformation, and increased lactate dehydrogenase) were independent prognostic markers for a worse survival. Combining these four factors in a prognostic index model identified the following three risk groups across stages with significantly different 5-year survival rates: low risk (68%), intermediate risk (44%), and high risk (28%). CONCLUSION: To our knowledge, this study includes the largest cohort of patients with advanced-stage MF/SS and identifies markers with independent prognostic value, which, used together in a prognostic index, may be useful to stratify advanced-stage patients

Estudi in vivo sobre la rellevància del sistema immune innat en la patogènia de la epidermòlisi ampul·lar adquirida

Introducció. L’epidermòlisi ampul·lar adquirida (EBA) és una malaltia crónica autoinmune caracteritzada per la presència d’anticossos circulants i amb afinitat per la col·làgena VII (CVII), la qual es troba a la membrana basal (MB) dermo-epidèrmica. Es manifesta clinicament per la presència d’ampul·les tenses i erosions que afecten tant a membranes mucoses com a pell. Components del sistema de la immunitat innata han demostrat estar involucrats en el dany tissular, concretament són el sistema del complement, els receptors dels anticossos i els neutròfils. La proteïna Rac2 és una GTPasa que participa en la quimotaxi dels neutròfils i en la generació d’espècies reactives d’oxígen mitjançant l’activació de l’enzim NADPH oxidasa. La insuficiència pulmonar aguda és una síndrome induïda per una resposta immune a partir del reclutament de neutròfils, afavorint el dany tissular i causant el distrés respiratori agut. Estudis realitzats in vivo sobre ratolins amb Rac2 genoanul.lat (Rac2 GA) o mitjançant el bloqueig farmacològic amb un inhibidor de Rac2 (NSC23766) han demostrat disminuir el dany tisular pulmonar. Objectius. Estudi in vivo de la funció de la proteïna Rac2 en el desenvolupament del dany tissular mitjançant un model experimental de la EBA. Materials i mètodes. La malaltia de l’EBA es va induïr mitjançant la transferència passiva d’anticossos contra un fragment murí de la CVII (mCVIICr). IgG anti-mCVIICr es va obtenir mitjançant la immunització de conills. El sérum de conills immunitzats i no immunizats es va purificar i concentrar per a èsser injectat als ratolins. Es van realitzar dos grups d’experiments amb ratolins Rac2 GA (total de n=10) i en ratolins de soca salvatge (SS) com a controls positius (n=3). En el mateix moment, ratolins Rac2 GA (n=4) van ser injectats amb IgG inespecífica de conill com a controls negatius. Es va realitzar un tercer grup d’experiments on ratolins de SS van ser pre-tractats amb dexametasona (n=3), dapsona (n=5) i NSC23766 (n=3), un inhibidor soluble experimental de Rac2. Es va realizar valoració clínica, biòpsies de pell, immunoflorescència directa (IFD) i assaig d’immunoadsorció lligat a enzim (ELISA). Resultats. El ratolins SS injectats amb IgG anti-mCVIICr van desenvolupar la malaltia de l’EBA, amb una severitat significativament augmentada amb elevades dosis d’anticossos (p=.05). En canvi, cap ratolí Rac2 GA injectat amb IgG anti-mCVIICr va desenvolupar malaltia, encara que hi havia depòsit d’IgG i C3 a la MB, i es van detectar IgG anti-mCVIICr circulants. Els ratolins SS pre-tractats amb NSC23766 dexametasona, i dapsona van desenvolupar EBA amb una tendència inicial de menor severitat de la malatia, pero sense diferències estadísticament significatives durant el període d’observació en comparació al grup de controls positius (p=0.8). Conclusions. Donat que l’EBA no es va desenvolupar en ratolins Rac2 GA després de la transferència passiva d’IgG anti-mCVIICr, suggereix una evident implicació de la proteïna Rac2 en la patogènia de l’EBA. Aleshores, proposem la proteïna de Rac2 com a diana terapéutica potencial per poder disenyar teràpies específiques per l’EBA i altres malaties mediades per IgG. No obstant, no hi ha encara disponible un inhibidor eficaç del Rac2 per èsser utilitzat com a tractament.Background: Epidermolysis bullosa acquisita (EBA) is a chronic autoimmune disorder characterized by the presence of circulating and tissue-bound autoantibodies against collagen VII (CVII), a protein localized at the dermal-epidermal basement membrane zone (BMZ). It is clinically manifested with tense blisters and erosions involving mucocutaneous tissues. Parts of the innate immune system have been demonstrated to be involved in tissue damage, particularly components of the complement system, antibodies’ receptors and neutrophils. Specifically, Rac2 protein is a GTPase involved in chemotaxis of neutrophils and reactive oxygen species synthesis through NADPH oxidase activation. Acute lung injury (ALI) is a syndrome induced by the immune response where the recruitment of neutrophils favors tissue damage evolving into an acute respiratory distress syndrome. In vivo studies performed in Rac2 knock-out (KO) mice and the pharmacological inhibition of Rac2 (NSC23766) in ALI have demonstrated a decrease in lung tissue injury. Objectives: To investigate the role of Rac2 protein in tissue injury developed in an in vivo experimental mouse model of EBA. Materials and Methods: EBA phenotype was induced by passive transfer of antibodies against a fragment of murine CVII (mCVIICr). Anti-mCVIICr IgG was obtained after rabbit immunization. IgG from immunized and non-immunized rabbits (used as negative controls) were purified and concentrated to inject mice. Two sets of experiments were performed with Rac2 KO mice (total n=10) and wild type mice as positive controls (n=3) by injecting rabbit anti-mCVIICr IgG. At the same time, a set of Rac2 KO mice (n=4) were injected with unspecific rabbit IgG as negative controls. A third set of experiments consisted in injecting rabbit anti-mCVIICr IgG in mice pre-treated with dexamethasone (n=3), dapsone (n=5) and NSC23766 (n=3), an experimental soluble inhibitor of Rac2. Clinical assessments, histology of skin biopsies, direct immunofluorescence (DIF), and enzyme-linked immunosorbent assays (ELISA) were performed. Results: WT mice injected with anti-mCVIICr IgG successfully developed the EBA phenotype, with significantly increased disease severity with higher doses of IgG (p=.05). In contrast, none of the Rac2 KO mice injected with anti-mCVIICr IgG developed the EBA phenotype, even though IgG and C3 were deposited at the BMZ, and circulating anti-mCVIICr IgG was detected by ELISA. Pre-treated WT mice with NSC23766, dexamethasone and dapsone developed disease initially with a trend of milder disease severity, yet we found no statistically difference in body surface area involvement at the end of the observation period when compared with positive controls (p=0.08). Conclusions: The fact that EBA lesions were not developed in Rac2 KO mice after the passive transfer of anti-mCVIICr IgG clearly suggests the involvement of Rac2 protein in EBA pathogenesis. Therefore, we propose Rac2 as a potential target for designing therapies specific for EBA and other IgG-mediated disease. However, an effective Rac2 inhibitor to be used as therapy is not yet available

Estudi in vivo sobre la rellevància del sistema immune innat en la patogènia de la epidermòlisi ampul·lar adquirida

Introducció. L’epidermòlisi ampul·lar adquirida (EBA) és una malaltia crónica autoinmune caracteritzada per la presència d’anticossos circulants i amb afinitat per la col·làgena VII (CVII), la qual es troba a la membrana basal (MB) dermo-epidèrmica. Es manifesta clinicament per la presència d’ampul·les tenses i erosions que afecten tant a membranes mucoses com a pell. Components del sistema de la immunitat innata han demostrat estar involucrats en el dany tissular, concretament són el sistema del complement, els receptors dels anticossos i els neutròfils. La proteïna Rac2 és una GTPasa que participa en la quimotaxi dels neutròfils i en la generació d’espècies reactives d’oxígen mitjançant l’activació de l’enzim NADPH oxidasa. La insuficiència pulmonar aguda és una síndrome induïda per una resposta immune a partir del reclutament de neutròfils, afavorint el dany tissular i causant el distrés respiratori agut. Estudis realitzats in vivo sobre ratolins amb Rac2 genoanul.lat (Rac2 GA) o mitjançant el bloqueig farmacològic amb un inhibidor de Rac2 (NSC23766) han demostrat disminuir el dany tisular pulmonar. Objectius. Estudi in vivo de la funció de la proteïna Rac2 en el desenvolupament del dany tissular mitjançant un model experimental de la EBA. Materials i mètodes. La malaltia de l’EBA es va induïr mitjançant la transferència passiva d’anticossos contra un fragment murí de la CVII (mCVIICr). IgG anti-mCVIICr es va obtenir mitjançant la immunització de conills. El sérum de conills immunitzats i no immunizats es va purificar i concentrar per a èsser injectat als ratolins. Es van realitzar dos grups d’experiments amb ratolins Rac2 GA (total de n=10) i en ratolins de soca salvatge (SS) com a controls positius (n=3). En el mateix moment, ratolins Rac2 GA (n=4) van ser injectats amb IgG inespecífica de conill com a controls negatius. Es va realitzar un tercer grup d’experiments on ratolins de SS van ser pre-tractats amb dexametasona (n=3), dapsona (n=5) i NSC23766 (n=3), un inhibidor soluble experimental de Rac2. Es va realizar valoració clínica, biòpsies de pell, immunoflorescència directa (IFD) i assaig d’immunoadsorció lligat a enzim (ELISA). Resultats. El ratolins SS injectats amb IgG anti-mCVIICr van desenvolupar la malaltia de l’EBA, amb una severitat significativament augmentada amb elevades dosis d’anticossos (p=.05). En canvi, cap ratolí Rac2 GA injectat amb IgG anti-mCVIICr va desenvolupar malaltia, encara que hi havia depòsit d’IgG i C3 a la MB, i es van detectar IgG anti-mCVIICr circulants. Els ratolins SS pre-tractats amb NSC23766 dexametasona, i dapsona van desenvolupar EBA amb una tendència inicial de menor severitat de la malatia, pero sense diferències estadísticament significatives durant el període d’observació en comparació al grup de controls positius (p=0.8). Conclusions. Donat que l’EBA no es va desenvolupar en ratolins Rac2 GA després de la transferència passiva d’IgG anti-mCVIICr, suggereix una evident implicació de la proteïna Rac2 en la patogènia de l’EBA. Aleshores, proposem la proteïna de Rac2 com a diana terapéutica potencial per poder disenyar teràpies específiques per l’EBA i altres malaties mediades per IgG. No obstant, no hi ha encara disponible un inhibidor eficaç del Rac2 per èsser utilitzat com a tractament.Background: Epidermolysis bullosa acquisita (EBA) is a chronic autoimmune disorder characterized by the presence of circulating and tissue-bound autoantibodies against collagen VII (CVII), a protein localized at the dermal-epidermal basement membrane zone (BMZ). It is clinically manifested with tense blisters and erosions involving mucocutaneous tissues. Parts of the innate immune system have been demonstrated to be involved in tissue damage, particularly components of the complement system, antibodies’ receptors and neutrophils. Specifically, Rac2 protein is a GTPase involved in chemotaxis of neutrophils and reactive oxygen species synthesis through NADPH oxidase activation. Acute lung injury (ALI) is a syndrome induced by the immune response where the recruitment of neutrophils favors tissue damage evolving into an acute respiratory distress syndrome. In vivo studies performed in Rac2 knock-out (KO) mice and the pharmacological inhibition of Rac2 (NSC23766) in ALI have demonstrated a decrease in lung tissue injury. Objectives: To investigate the role of Rac2 protein in tissue injury developed in an in vivo experimental mouse model of EBA. Materials and Methods: EBA phenotype was induced by passive transfer of antibodies against a fragment of murine CVII (mCVIICr). Anti-mCVIICr IgG was obtained after rabbit immunization. IgG from immunized and non-immunized rabbits (used as negative controls) were purified and concentrated to inject mice. Two sets of experiments were performed with Rac2 KO mice (total n=10) and wild type mice as positive controls (n=3) by injecting rabbit anti-mCVIICr IgG. At the same time, a set of Rac2 KO mice (n=4) were injected with unspecific rabbit IgG as negative controls. A third set of experiments consisted in injecting rabbit anti-mCVIICr IgG in mice pre-treated with dexamethasone (n=3), dapsone (n=5) and NSC23766 (n=3), an experimental soluble inhibitor of Rac2. Clinical assessments, histology of skin biopsies, direct immunofluorescence (DIF), and enzyme-linked immunosorbent assays (ELISA) were performed. Results: WT mice injected with anti-mCVIICr IgG successfully developed the EBA phenotype, with significantly increased disease severity with higher doses of IgG (p=.05). In contrast, none of the Rac2 KO mice injected with anti-mCVIICr IgG developed the EBA phenotype, even though IgG and C3 were deposited at the BMZ, and circulating anti-mCVIICr IgG was detected by ELISA. Pre-treated WT mice with NSC23766, dexamethasone and dapsone developed disease initially with a trend of milder disease severity, yet we found no statistically difference in body surface area involvement at the end of the observation period when compared with positive controls (p=0.08). Conclusions: The fact that EBA lesions were not developed in Rac2 KO mice after the passive transfer of anti-mCVIICr IgG clearly suggests the involvement of Rac2 protein in EBA pathogenesis. Therefore, we propose Rac2 as a potential target for designing therapies specific for EBA and other IgG-mediated disease. However, an effective Rac2 inhibitor to be used as therapy is not yet available

Cutaneous T-cell Lymphoma and Pruritus: The Expression of IL-31 and its Receptors in the Skin

Approximately 88% of cutaneous T-cell lymphoma (CTCL) patients are affected by pruritus that responds poorly to current antipruritic therapies. Interleukin (IL)-31, a Th2 cytokine, has been found to be increased in the serum of CTCL patients and to correlate with itch severity. This study investigated the role of IL-31 and its receptors (IL-31 receptor-alpha [IL-31RA] and OSMRβ) in the skin of CTCL patients with mild versus moderate/severe pruritus. Expression levels of IL-31, IL-31RA, and OSMRβ in the skin were measured using immunohistochemistry and correlated to pruritus severity and disease stage. In CTCL patients with moderate/severe pruritus, IL-31 was significantly elevated in the epidermis and dermal infiltrate, while IL-31RA and OSMRβ were significantly elevated only in the epidermis. Furthermore, epidermal IL-31 levels correlated to itch severity. These results show that IL-31 may play a role in CTCL pruritus by exerting indirect effects on sensory nerves through epidermal neoplastic T cells and keratinocytes to transmit itch