RESUMEN
Adult T-cell leukemia-lymphoma (ATLL) is an aggressive Human T-cell Leukemia Virus Type 1 (HTLV-1)-driven malignancy. Although Western hemisphere (Afro-Caribbean and South American) patients face worse prognoses, our understanding of ATLL molecular drivers derives mostly from Japanese studies. We performed multi-omic analyses to elucidate the genomic landscape of ATLL in Western cohorts. Recurrent deletion and/or damaging mutations involving FOXO3, ANKRD11, DGKZ, and PTPN6 implicate these genes as potential tumor suppressors. RNA-seq, published functional data and in vitro assays support the roles of ANKRD11 and FOXO3 as regulators of T-cell proliferation and apoptosis in ATLL, respectively. Survival data suggest ANKRD11 mutation may confer a worse prognosis. Japanese and Western cohorts, in addition to acute and lymphomatous subtypes, demonstrated distinct molecular patterns. GATA3 deletion was associated with unfavorable chronic cases. IRF4 and CARD11 mutations frequently emerged in relapses after interferon therapy. Our findings reveal novel putative ATLL driver genes and clinically relevant differences between Japanese and Western ATLL patients.
RESUMEN
The Epstein-Barr virus (EBV) is a DNA virus that infects 90% of the human population, is responsible for certain cutaneous lymphomas (extranodal NK/T-cell lymhoma, hydroa vacciniforme lymphoproliferative disorder, lymphomatoid granulomatosis, others), and can be associated with a variety of cutaneous manifestations (eg, infectious mononucleosis, severe mosquito bite allergy, chronic active EBV disease, Gianotti-Crosti syndrome). EBV-related skin disorders are frequent in certain populations (South and Cental America, Africa, Asia, and Oceania) and can be diagnostically challenging. The human T-lymphotropic virus type-1 is a retrovirus, which is known to be associated with adult T-cell leukemia/lymphoma, neurologic disorders, but also cutaneous non-neoplastic manifestations (infective dermatitis, infections, and infestations). We performed an updated revision of the clinical dermatologic and histopathologic findings associated with the cutaneous non-neoplastic and preneoplastic disorders occurring in association with the EBV and human T-lymphotropic virus type-1.
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Infecciones por Virus de Epstein-Barr , Virus Linfotrópico T Tipo 1 Humano , Trastornos Linfoproliferativos , Humanos , Herpesvirus Humano 4 , Infecciones por Virus de Epstein-Barr/complicaciones , Piel/patología , Trastornos Linfoproliferativos/complicacionesRESUMEN
Viral-induced cutaneous T-cell lymphomas are an uncommon group of lymphoproliferative disorders characterized by a viral infection of T and natural killer (NK) cells. This group of cutaneous T-cell lymphomas is more commonly encountered in Asians and Native Americans from Central and South America compared with Western populations. Viral-associated lymphoproliferative disorders include a spectrum of entities that range from nonneoplastic lesions, such as chronic active Epstein-Barr virus infection and infective dermatitis to malignant diseases, such as extranodal NK/T-cell lymphoma, hydroa vacciniforme-like T-cell lymphoma, and adult T-cell leukemia/lymphoma. This review article will focus on hydroa vacciniforme-like lymphoproliferative disorder, extranodal NK/T-cell lymphoma, adult T-cell leukemia/lymphoma, lymphomatoid granulomatosis, and Epstein-Barr virus-positive mucocutaneous ulcers. We will review the pathogenesis of these conditions and the challenges of making a timely diagnosis in early-stage disease and discuss the common clinicopathologic manifestations, mutational landscape, and approaches to treat these highly aggressive and frequently lethal types of lymphoma.
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Trastornos Linfoproliferativos , Enfermedades de la Piel , Educación Médica Continua , Trastornos Linfoproliferativos/patología , Trastornos Linfoproliferativos/terapia , Trastornos Linfoproliferativos/virología , Enfermedades de la Piel/patología , Enfermedades de la Piel/terapia , Enfermedades de la Piel/virología , Infecciones por Virus de Epstein-Barr , Linfoma Cutáneo de Células T/patología , Linfoma Cutáneo de Células T/terapia , Linfoma Cutáneo de Células T/virología , Neoplasias Cutáneas/patología , Neoplasias Cutáneas/terapia , Neoplasias Cutáneas/virología , Hidroa Vacciniforme/patología , Hidroa Vacciniforme/terapia , Leucemia-Linfoma de Células T del Adulto/patología , Leucemia-Linfoma de Células T del Adulto/terapia , Granulomatosis Linfomatoide/patología , Granulomatosis Linfomatoide/terapiaRESUMEN
BACKGROUND: Cutaneous T-cell lymphomas are rare, generally incurable, and associated with reduced quality of life. Present systemic therapies rarely provide reliable and durable responses. We aimed to assess efficacy and safety of brentuximab vedotin versus conventional therapy for previously treated patients with CD30-positive cutaneous T-cell lymphomas. METHODS: In this international, open-label, randomised, phase 3, multicentre trial, we enrolled adult patients with CD30-positive mycosis fungoides or primary cutaneous anaplastic large-cell lymphoma who had been previously treated. Patients were enrolled across 52 centres in 13 countries. Patients were randomly assigned (1:1) centrally by an interactive voice and web response system to receive intravenous brentuximab vedotin 1·8 mg/kg once every 3 weeks, for up to 16 3-week cycles, or physician's choice (oral methotrexate 5-50 mg once per week or oral bexarotene 300 mg/m2 once per day) for up to 48 weeks. The primary endpoint was the proportion of patients in the intention-to-treat population achieving an objective global response lasting at least 4 months per independent review facility. Safety analyses were done in all patients who received at least one dose of study drug. This trial was registered with ClinicalTrials.gov, number NCT01578499. FINDINGS: Between Aug 13, 2012, and July 31, 2015, 131 patients were enrolled and randomly assigned to a group (66 to brentuximab vedotin and 65 to physician's choice), with 128 analysed in the intention-to-treat population (64 in each group). At a median follow-up of 22·9 months (95% CI 18·4-26·1), the proportion of patients achieving an objective global response lasting at least 4 months was 56·3% (36 of 64 patients) with brentuximab vedotin versus 12·5% (eight of 64) with physician's choice, resulting in a between-group difference of 43·8% (95% CI 29·1-58·4; p<0·0001). Grade 3-4 adverse events were reported in 27 (41%) of 66 patients in the brentuximab vedotin group and 29 (47%) of 62 patients in the physician's choice group. Peripheral neuropathy was seen in 44 (67%) of 66 patients in the brentuximab vedotin group (n=21 grade 2, n=6 grade 3) and four (6%) of 62 patients in the physician's choice group. One of the four on-treatment deaths was deemed by the investigator to be treatment-related in the brentuximab vedotin group; no on-treatment deaths were reported in the physician's choice group. INTERPRETATION: Significant improvement in objective response lasting at least 4 months was seen with brentuximab vedotin versus physician's choice of methotrexate or bexarotene. FUNDING: Millennium Pharmaceuticals Inc (a wholly owned subsidiary of Takeda Pharmaceutical Company Ltd), Seattle Genetics Inc.
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Linfoma Cutáneo de Células T , Calidad de Vida , Protocolos de Quimioterapia Combinada Antineoplásica , Brentuximab Vedotina , Humanos , Inmunoconjugados , Recurrencia Local de NeoplasiaRESUMEN
BACKGROUND: Hypopigmentation in hypopigmented mycosis fungoides (MF) is thought to result from the action of CD8+ cells on melanocytes. Here, we investigated the immunophenotype and melanocytic markers in hypopigmented MF lesions. METHODS: Specimens of hypopigmented lesions and normal skin from 18 patients with hypopigmented MF and specimens of non-hypopigmented lesions from 8 patients with classic/conventional MF were subjected to neoplastic immunophenotyping and melanocyte immunostaining with Melan-A, tyrosinase, stem cell factor receptor (CD117) and microphthalmia-associated transcription factor (MiTF). RESULTS: The CD8+ immunophenotype was more common in hypopigmented MF lesions (14/18) than in conventional MF lesions (1/8, p = 0.0033). There was a main effect of specimen type (hypopigmented MF lesion, hypopigmented MF normal skin, conventional MF lesion) on the number of melanocytes stained with Melan-A (median number/mm basal membrane, 1.97 vs. 4.77 vs. 5.42, respectively, p = 0.0046), tyrosinase (2.19 vs. 4.02 vs. 5.26, p = 0.0114), CD117 (4.29 vs. 7.81 vs. 5.45, p = 0.0064), and MiTF (2.75 vs. 4.43 vs. 4.98, p = 0.005). CONCLUSIONS: These results confirm previous findings of fewer melanocytes and CD117-positive melanocytes in hypopigmented MF and showed reduced MiTF identification, which is crucial for the function and survival of melanocytes. Thus cytotoxic CD8+ cell action may determine CD117/MiTF dysfunction, causing hypopigmentation.
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Hipopigmentación , Melanocitos/patología , Micosis Fungoide , Neoplasias Cutáneas , Adulto , Anciano , Estudios Transversales , Femenino , Humanos , Hipopigmentación/metabolismo , Hipopigmentación/patología , Masculino , Persona de Mediana Edad , Micosis Fungoide/metabolismo , Micosis Fungoide/patología , Estudios Retrospectivos , Neoplasias Cutáneas/metabolismo , Neoplasias Cutáneas/patologíaRESUMEN
Primary cutaneous CD30(+) lymphoproliferative disorders (CD30(+) LPDs) are the second most common form of cutaneous T-cell lymphomas and include lymphomatoid papulosis and primary cutaneous anaplastic large-cell lymphoma. Despite the anaplastic cytomorphology of tumor cells that suggest an aggressive course, CD30(+) LPDs are characterized by an excellent prognosis. Although a broad spectrum of therapeutic strategies has been reported, these have been limited mostly to small retrospective cohort series or case reports, and only very few prospective controlled or multicenter studies have been performed, which results in a low level of evidence for most therapies. The response rates to treatment, recurrence rates, and outcome have not been analyzed in a systematic review. Moreover, international guidelines for staging and treatment of CD30(+) LPDs have not yet been presented. Based on a literature analysis and discussions, recommendations were elaborated by a multidisciplinary expert panel of the Cutaneous Lymphoma Task Force of the European Organization for Research and Treatment of Cancer, the International Society for Cutaneous Lymphomas, and the United States Cutaneous Lymphoma Consortium. The recommendations represent the state-of-the-art management of CD30(+) LPDs and include definitions for clinical endpoints as well as response criteria for future clinical trials in CD30(+) LPDs.
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Linfoma Anaplásico Cutáneo Primario de Células Grandes/terapia , Papulosis Linfomatoide/terapia , Estudios de Casos y Controles , Estudios de Cohortes , Unión Europea , Humanos , Antígeno Ki-1 , Linfoma Anaplásico Cutáneo Primario de Células Grandes/diagnóstico , Papulosis Linfomatoide/diagnóstico , Guías de Práctica Clínica como Asunto , Pronóstico , Sociedades Médicas , Estados UnidosRESUMEN
BACKGROUND: Topical photodynamic therapy (PDT) is an approved treatment for superficial nonmelanoma skin cancers. To enhance photosensitizer penetration into the epidermis, microneedling (MN) devices or ablative carbon dioxide lasers are combined with PDT. OBJECTIVES: To compare the efficacy and safety of MN-assisted PDT with that of conventional PDT in human skin field cancerization. MATERIALS AND METHODS: Ten patients with multiple actinic keratoses (AKs) and photodamage were randomized to receive conventional methyl aminolevulinate (MAL) with previous gentle curettage on one side of the face and MAL-PDT combined with 1.5-mm-length MN on the other side after MAL application. After a 90-minute incubation, patients were illuminated with a red light-emitting diode and evaluated for improvement of photodamage, clearance of AKs, and side effects before and after 30 and 90 days. RESULTS: At day 30, global scores for photodamage, mottled pigmentation, roughness, and sallowness improved on both sides (p < .05), but fine lines improved only on the MN-PDT side (p = .004). At day 90, facial erythema (p = .04) and coarse wrinkles (p = .002) also improved on the MN-PDT side, in addition to fine lines for conventional MAL-PDT (p = .01). Erythema (p = .009), edema (p = .01), crusting (p = .01), and pain (p = .004) were more common and intense on the MN-PDT side. One patient developed a secondary bacterial infection at day 7 on the MN-PDT side. Average AK clearance was 88.3%, with no difference between the sides. CONCLUSION: Microneedling-assisted PDT is a safe and effective method and can produce superior cosmetic results to conventional MAL-PDT for improving photodamaged skin. Further larger prospective studies are needed to determine whether the addition of MN decreases actinic keratosis.
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Ácido Aminolevulínico/análogos & derivados , Queratosis Actínica/tratamiento farmacológico , Láseres de Gas , Fotoquimioterapia/métodos , Neoplasias Cutáneas/tratamiento farmacológico , Anciano , Ácido Aminolevulínico/administración & dosificación , Femenino , Humanos , Masculino , Persona de Mediana Edad , Dimensión del Dolor , Fármacos Fotosensibilizantes/administración & dosificaciónRESUMEN
BACKGROUND: Mycosis fungoides (MF) and Sézary syndrome (SS) are the most prevalent cutaneous lymphomas. They were not described in a large Brazilian cohort yet. We aimed, with this single-center, retrospective cohort analysis, to describe the characteristics and outcomes of MF/SS in a tertiary public health service in Brazil. METHODS: MF/SS patients evaluated at the University of São Paulo Medical School between 1989 and 2018 were included. Data were collected at diagnosis. Demographic, clinical, histopathological, immunopathological, molecular, laboratory, and follow-up data were analyzed. RESULTS: Among 727 patients, 92.6% (673) were diagnosed with MF, 7.4% (54) with SS. There were 51.2% (372) of males, 48.8% (355) of females. The median age was 51.8 years; it was higher in erythrodermic MF (60.2) and SS (60.9). Among MF, 41.8% (281) had classic MF, 4.9% (33) folliculotropic MF, 1.8% (12) granulomatous slack skin, and 0.3% (2) pagetoid reticulosis. Common subtypes included erythrodermic (14.1%, 95), hypopigmented (10.8%, 73), and poikilodermatous MF (10.8%, 73). Extracutaneous involvement was rare. Five, 10, 20, and 30-year overall survival rates were 97.3%, 92.4%, 82.6%, and 82.6% for early-stage, and 58.6%, 42.7%, 20.8%, and 15.4% for advanced-stage disease, respectively. After multivariate analysis, SS diagnosis, folliculotropic MF, erythrodermic MF, clinical stage, age (≥60 years), increased lactate dehydrogenase, and large cell transformation conferred poorer prognosis. CONCLUSIONS: We observed a higher percentage of hypopigmented MF compared to the literature, and demographic (older age) and prognostic (poorer prognosis) similarities between erythrodermic MF and SS, suggesting a possible relationship between these erythrodermic lymphomas. Factors associated with a poorer prognosis were compatible with the literature.
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Micosis Fungoide , Síndrome de Sézary , Neoplasias Cutáneas , Brasil/epidemiología , Estudios de Cohortes , Femenino , Humanos , Masculino , Persona de Mediana Edad , Micosis Fungoide/diagnóstico , Micosis Fungoide/epidemiología , Micosis Fungoide/terapia , Estadificación de Neoplasias , Pronóstico , Estudios Retrospectivos , Síndrome de Sézary/diagnóstico , Síndrome de Sézary/epidemiología , Síndrome de Sézary/terapia , Neoplasias Cutáneas/diagnóstico , Neoplasias Cutáneas/epidemiología , Neoplasias Cutáneas/terapiaRESUMEN
Coronavirus disease 2019 (COVID-19) brought the world to its knees. As each nation grappled with launching an effective response while simultaneously minimizing repercussions on health care systems, economies, and societies, the medical and scientific landscape shifted forever. In particular, COVID-19 has challenged and transformed the field of dermatology and the way we practice. In this article, dermatologists from 11 countries share insights gained from local experience. These global perspectives will help provide a better framework for delivering quality dermatologic care and understanding how the field has evolved during this medical crisis.
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COVID-19/epidemiología , Toma de Decisiones Clínicas/métodos , Dermatología/organización & administración , Accesibilidad a los Servicios de Salud/organización & administración , Enfermedades de la Piel/terapia , Centros Médicos Académicos , COVID-19/prevención & control , Humanos , Comunicación InterdisciplinariaRESUMEN
The primary analysis of the phase 3 ALCANZA trial showed significantly improved objective responses lasting ≥4 months (ORR4; primary endpoint) and progression-free survival (PFS) with brentuximab vedotin vs physician's choice (methotrexate or bexarotene) in CD30-expressing mycosis fungoides (MF) or primary cutaneous anaplastic large-cell lymphoma (C-ALCL). Cutaneous T-cell lymphomas often cause pruritus and pain; brentuximab vedotin improved skin symptom burden with no negative effects on quality of life. We report final data from ALCANZA (median follow-up, 45.9 months). Adults with previously treated CD30-expressing MF/C-ALCL were randomly assigned to brentuximab vedotin (n = 64) or physician's choice (n = 64). Final data demonstrated improved responses per independent review facility with brentuximab vedotin vs physician's choice: ORR4; 54.7% vs 12.5% (P < .001); complete response, 17.2% vs 1.6% (P = .002). Median PFS with brentuximab vedotin vs physician's choice was 16.7 months vs 3.5 months (P < .001). Median time to the next treatment was significantly longer with brentuximab vedotin than with physician's choice (14.2 vs 5.6 months; hazard ratio, 0.27; 95% confidence interval, 0.17-0.42; P < .001). Of 44 patients in the brentuximab vedotin arm who experienced any-grade peripheral neuropathy, (grade 3, n = 6; grade 4, n = 0), 86% (38 of 44) had complete resolution (26 of 44) or improvement to grades 1 and 2 (12 of 44). Peripheral neuropathy was ongoing in 18 patients (all grades 1-2). These final analyses confirm improved, clinically meaningful, durable responses and longer PFS with brentuximab vedotin vs physician's choice in CD30-expressing MF or C-ALCL. This trial was registered at https://www.clinicaltrials.gov as #NCT01578499.
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Linfoma Cutáneo de Células T , Médicos , Neoplasias Cutáneas , Adulto , Brentuximab Vedotina , Humanos , Linfoma Cutáneo de Células T/tratamiento farmacológico , Calidad de Vida , Neoplasias Cutáneas/tratamiento farmacológicoRESUMEN
INTRODUCTION: Mycosis fungoides (MF), the most common type of cutaneous T-cell lymphoma, can lead to disfiguring lesions, debilitating pruritus and frequent skin infections. This study assessed response to brentuximab vedotin in patients with MF in the phase III ALCANZA study. METHODS: Baseline CD30 levels and large-cell transformation (LCT) status were centrally reviewed in patients with previously-treated CD30-positive MF using ≥2 skin biopsies obtained at screening; eligible patients required ≥1 biopsy with ≥10% CD30 expression. Patients were categorised as CD30min < 10% (≥1 biopsy with <10% CD30 expression), or CD30min ≥ 10% (all biopsies with ≥10% CD30 expression) and baseline LCT present or absent. Efficacy analyses were the proportion of patients with objective response lasting ≥4 months (ORR4) and progression-free survival (PFS). RESULTS: Clinical activity with brentuximab vedotin was observed across all CD30 expression levels in patients with ≥1 biopsy showing ≥10% CD30 expression. Superior ORR4 was observed with brentuximab vedotin versus physician's choice in patients: with CD30min < 10% (40.9% versus 9.5%), with CD30min ≥ 10% (57.1% versus 10.3%), with LCT (64.7% versus 17.6%) and without LCT (38.7% versus 6.5%). Brentuximab vedotin improved median PFS versus physician's choice in patients: with CD30min < 10% (16.7 versus 2.3 months), with CD30min ≥ 10% (15.5 versus 3.9 months), with LCT (15.5 versus 2.8 months) and without LCT (16.1 versus 3.5 months). Safety profiles were generally comparable across subgroups. CONCLUSION: These exploratory analyses demonstrated that brentuximab vedotin improved rates of ORR4 and PFS versus physician's choice in patients with CD30-positive MF and ≥1 biopsy showing ≥10% CD30 expression, regardless of LCT status. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov, NCT01578499.
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Antineoplásicos Inmunológicos/uso terapéutico , Brentuximab Vedotina/uso terapéutico , Conducta de Elección , Técnicas de Apoyo para la Decisión , Antígeno Ki-1/metabolismo , Micosis Fungoide/tratamiento farmacológico , Médicos/estadística & datos numéricos , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Estudios de Seguimiento , Humanos , Agencias Internacionales , Masculino , Persona de Mediana Edad , Micosis Fungoide/metabolismo , Micosis Fungoide/patología , Médicos/psicología , Pronóstico , Estudios Retrospectivos , Tasa de Supervivencia , Adulto JovenRESUMEN
BACKGROUND: Brentuximab vedotin was approved for adult patients with CD30-expressing cutaneous T-cell lymphoma treated with prior systemic therapy based on improved response rates and progression-free survival with brentuximab vedotin (1.8 mg/kg once every 3 weeks; ≤16 cycles) versus physician's choice (methotrexate/bexarotene; ≤48 weeks) in the phase III ALCANZA study. Quality of life (QoL) in ALCANZA patients was also examined. METHODS: QoL measures in ALCANZA were based on the Skindex-29, Functional Assessment of Cancer Therapy-General (FACT-G) and European QoL 5-dimension (EQ-5D) questionnaires. RESULTS: Mean maximum reduction from the baseline Skindex-29 symptom domain score (key secondary end-point) was greater with brentuximab vedotin than physician's choice (-27.96 versus -8.62); the difference, -18.9 (95% confidence interval -26.6, -11.2; adjusted p < 0.001), exceeded the study-defined minimally important difference (9.0-12.3). Mean changes from baseline to end-of-treatment visit total FACT-G scores were similar with brentuximab vedotin and physician's choice (0.15 versus -2.29). EQ-5D changes were also comparable between arms. Among brentuximab vedotin-treated patients with peripheral neuropathy (PN), mean maximum reduction in Skindex-29 symptom domain was -35.54 versus -11.11 in patients without PN. PN had no meaningful effect on FACT-G and EQ-5D QoL scores. CONCLUSIONS: In summary, brentuximab vedotin produced superior reductions in symptom burden compared with physician's choice, without adversely impacting QoL. QoL was unaffected by the presence of PN in brentuximab vedotin-treated patients. CLINICAL TRIAL REGISTRATION: NCT01578499.
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Brentuximab Vedotina/uso terapéutico , Linfoma Cutáneo de Células T/tratamiento farmacológico , Calidad de Vida , Neoplasias Cutáneas/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Resistencia a Antineoplásicos/efectos de los fármacos , Femenino , Humanos , Linfoma Cutáneo de Células T/epidemiología , Linfoma Cutáneo de Células T/patología , Linfoma Cutáneo de Células T/psicología , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/epidemiología , Recurrencia Local de Neoplasia/psicología , Medición de Resultados Informados por el Paciente , Psicometría/métodos , Neoplasias Cutáneas/epidemiología , Neoplasias Cutáneas/patología , Neoplasias Cutáneas/psicología , Encuestas y Cuestionarios , Resultado del Tratamiento , Adulto JovenRESUMEN
Mantle cell lymphoma (MCL) commonly involves extranodal sites, usually as a manifestation of disseminated disease. In rare cases, MCLs may arise as a primary tumor in the skin. Blastoid mantle cell lymphoma (BV-MCL) is a rare variant and has a more aggressive clinical course. The phenotype of BV-MCL is characterized as CD20+, CD5+, cyclin D1+, CD23-, and CD10-. Interphase fluorescence in situ hybridization shows a characteristic t(11;14) fusion pattern. We report a case of a BV-MCL arising in skin as primary cutaneous MCL with the characteristic immunophenotype and translocation.
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Linfoma de Células del Manto/genética , Linfoma de Células del Manto/patología , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/patología , Translocación Genética , Anciano , Biopsia , Cromosomas Humanos Par 11 , Cromosomas Humanos Par 14 , Humanos , Hibridación Fluorescente in Situ , Masculino , FenotipoRESUMEN
BACKGROUND: Primary cutaneous lymphomas (PCLs) and pseudolymphomas presenting as single pink-red nodules/tumors are highly unspecific and include a wide differential diagnosis. OBJECTIVE: To describe the dermoscopic characteristics of PCL/pseudolymphoma. METHODS: In this retrospective, case-control study, we evaluated the dermoscopic features of patients with solitary PCL/pseudolymphoma tumors and compared them to a control group of non-lymphomatous, nonpigmented, solitary tumors (e.g., basal cell carcinoma, amelanotic melanoma, etc). RESULTS: We included 14 patients with PCL/pseudolymphomas and 35 controls. T-cell and B-cell lymphoma proportions were 28.6% (n = 4) and 71.4% (n = 10), respectively. Compared to controls, most lymphomas presented dermoscopically with orange color (71.4% vs. 14.2%, P < 0.001), follicular plugs (85% vs. 2.8%, P < 0.001), and as organized lesions (85% vs. 31.4%, P = 0.001). Coexistence of orange color and follicular plugs had an odds ratio (OR) of 2.8 (P < 0.001), highly suggestive of PCL . The kappa index for independent observers was 0.66, 0.49, 0.43 for orange background, follicular plugs, and organized lesion, respectively. Histopathologic correlation was performed in six PCL cases and showed dense diffuse and perifollicular lymphocytic infiltrate in all cases and keratin plugs in five of six cases, possibly correlating with the orange color and the follicular plugs, respectively. CONCLUSION: Primary cutaneous lymphomas/pseudolymphomas present with characteristic dermoscopic findings irrespective of immunohistochemical subtype.
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Linfoma de Células B/diagnóstico por imagen , Linfoma Cutáneo de Células T/diagnóstico , Seudolinfoma/diagnóstico por imagen , Neoplasias Cutáneas/diagnóstico por imagen , Piel/patología , Adulto , Anciano , Anciano de 80 o más Años , Biopsia , Carcinoma Basocelular/diagnóstico por imagen , Estudios de Casos y Controles , Dermoscopía , Diagnóstico Diferencial , Femenino , Humanos , Linfoma de Células B/patología , Linfoma Cutáneo de Células T/patología , Masculino , Melanoma Amelanótico/diagnóstico por imagen , Persona de Mediana Edad , Seudolinfoma/patología , Estudios Retrospectivos , Piel/diagnóstico por imagen , Neoplasias Cutáneas/patologíaRESUMEN
BACKGROUND: Basal cell carcinomas (BCC), squamous cell carcinomas (SCC) and cutaneous malignant melanoma (MM) are solid skin cancers derived from different cell types, with different ability to metastasize. Several subtypes of integrins and matrix metalloproteinases (MMP) have been related to malignization and metastasis processes. This work aimed at a quantitative evaluation of skin cancers expressing eight integrins and MMP2 genes. METHODS: Expression of integrins and MMP2 genes was evaluated on fresh tumor biopsies from BCC, SCC and MM, and respective controls, by the reverse transcriptase polychain reaction (RT-PCR) technique. RESULTS: More than 90% tumors expressed alpha6a, beta1, beta3 and beta6 (non-melanoma), and alpha5a, alpha6a and MMP2 (MM). Up to 100% controls also expressed beta1 and beta3. The results were significant for alpha6a in BCC (p = 0.026), alpha6b in SCC (p = 0.035), alpha2a in BCC (p = 0.003), beta5 and beta6 in BCC (p = 0.005). MMP2 was expressed in 100% MM (p = 0.0004). CONCLUSION: Integrin subunits alpha2a and alpha6a would be interesting targets for BCC anti-tumor therapy, as well as alpha6b in case of SCC. The elevated number of BCC expressing alpha2 and alpha6, and of MM expressing alphav and MMP2, corroborate literature data.
Asunto(s)
Carcinoma Basocelular/genética , Carcinoma de Células Escamosas/genética , Regulación Neoplásica de la Expresión Génica , Integrinas/genética , Metaloproteinasa 2 de la Matriz/genética , Melanoma/genética , Neoplasias Cutáneas/genética , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Carcinoma Basocelular/metabolismo , Carcinoma Basocelular/patología , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patología , ADN de Neoplasias/análisis , Femenino , Humanos , Integrinas/metabolismo , Masculino , Metaloproteinasa 2 de la Matriz/metabolismo , Melanoma/metabolismo , Melanoma/patología , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Neoplasias Cutáneas/metabolismo , Neoplasias Cutáneas/patologíaRESUMEN
BACKGROUND: Folliculotropic mycosis fungoides (FMF) is a cutaneous T-cell lymphoma mainly affecting the hair follicle, which seems to represent a place of immune privilege phenomenon. OBJECTIVES: To explore a possible role of immune privilege (IP) in FMF analyzing the major histocompatibility complex (MHC) expression. METHODS: Immunohistochemistry for HLA-G and MHC-II was performed to formalin-fixed paraffin-embedded cutaneous skin biopsies of FMF patients (n = 43), conventional mycosis fungoides (CMF; n = 13), alopecia areata (AA; n = 13), and normal scalp skin (NS; n = 12). RESULTS: HLA-G expression was lower in FMF (34%: 14/41) and CMF (18%: 2/11) groups compared to alopecia areata (92%:11/12) and normal scalp skin group (100%: 12/12). MHC-II expression in hair follicle was greater in the FMF group (18/42: 43%) compared to AA (0%) and NS (0%). HLA-G and MHC-II expression in cellular infiltrate had no difference among FMF and CMF groups and was different compared to the AA group. CONCLUSIONS: Our data support the hypothesis of disruption of immune privilege based on the lower expression of HLA-G and higher expression of MHC-II in the follicular epithelium in mycosis fungoides compared to alopecia areata and normal scalp skin. The lack of difference between FMF and CMF groups did not support the role of these molecules as a driver of folliculotropism. The expression of MHC molecules seems to be different between neoplastic and inflammatory infiltrates. The definitive significance of expression of the MHC molecules remains unclear, and more studies are necessary to fully understand the role of these molecules in cutaneous lymphomas.
Asunto(s)
Linfoma Cutáneo de Células T/inmunología , Linfoma Cutáneo de Células T/patología , Micosis Fungoide/inmunología , Micosis Fungoide/patología , Neoplasias Cutáneas/inmunología , Neoplasias Cutáneas/patología , Factores de Edad , Anciano , Biopsia con Aguja , Brasil , Distribución de Chi-Cuadrado , Estudios de Cohortes , Femenino , Antígenos HLA-G/inmunología , Folículo Piloso/patología , Histocompatibilidad , Humanos , Inmunohistoquímica , Incidencia , Linfoma Cutáneo de Células T/epidemiología , Masculino , Persona de Mediana Edad , Micosis Fungoide/epidemiología , Invasividad Neoplásica/patología , Estadificación de Neoplasias , Estudios Prospectivos , Factores Sexuales , Neoplasias Cutáneas/epidemiología , Estadísticas no ParamétricasRESUMEN
Sézary syndrome (SS) is a leukemic variant of cutaneous T cell lymphoma (CTCL), and the neoplastic CD4+ T cells of SS patients undergo intense clonal proliferation. Although Sézary cells have been studied extensively, studies on adaptive immunity regarding CD8+T cells are scarce. This study aimed to investigate activation marker expression in CD8+ T cells according to the differentiation stages and IL-7/IL7Rα axis responses of patients with SS. Moreover, this study aimed to verify the soluble forms of CD38, sCD127 and IL-7 in serum. Although the SS patients of our cohort had reduced numbers of CD8+ T cells, they exhibited higher percentages of CD8+CD38+ T cells, mainly effector/memory CD8+ T cells, than the control group. In contrast, down-regulated expression of the activation markers CD127/IL-7R and CD26 was found in the CD8+ T cells of SS patients. High serum levels of sCD38 and sCD127 and scarce serum levels of IL-7 were detected, emphasizing the immune activation status of SS patients. Moreover, CD8+ T cells from SS patients exhibited IL-7 unresponsiveness to STAT5 phosphorylation and Bcl-2 expression, and IL-7 priming partially restored IFNγ production. Our findings showed a chronic activation profile of CD8+ T cells, as an attenuated cytotoxic profile and impaired IL-7 responsiveness was observed, suggesting chronic activation status of CD8+ T cells in SS patients.
Asunto(s)
Carcinoma Basocelular , Neoplasias Cutáneas , Brasil/epidemiología , Carcinoma Basocelular/inducido químicamente , Carcinoma Basocelular/epidemiología , Estudios de Casos y Controles , Humanos , Hidroclorotiazida/efectos adversos , Proyectos Piloto , Neoplasias Cutáneas/inducido químicamente , Neoplasias Cutáneas/epidemiologíaRESUMEN
Sézary syndrome (SS), an aggressive and leukemic form of cutaneous T-cell lymphoma, usually results in shortened survival. Improving innate immunity in SS by targeting natural killer (NK) cells with Toll-like receptor (TLR) agonists could be an interesting modulatory strategy. We evaluated the NK cell populations in SS patients assessing activating and inhibitory receptors expression and profiled the differential expression of TLR signaling pathway genes in unstimulated NK cells and after TLR7/8 stimulation. We observed preserved CD56bright NK cells and a low percentage of CD56dim NK cells in the peripheral blood of SS patients compared to those in the healthy control group. Both NK cell populations showed down-modulation of NKG2C and NKG2D expression, which was associated with high serum levels of the soluble form of NKG2D ligands. In contrast, an expansion of "memory" CD57+ NKG2C+ NK cells and high cytomegalovirus antibody titers were detected in SS patients. Profiling of the TLR signaling genes in NK cells from SS patients showed an abundance of differentially expressed genes (DEGs) in NK cells in the unstimulated condition, with mostly up-regulation of NFκB/JNK p38 pathway genes, but there was down-regulation of type I (IFN-α/ß) and II (IFN-γ) interferon and IL-12A. After activation of NK cells with TLR7/8 agonist, the down-regulated genes correlated with the IFN response, and IL-12 became up-regulated, together with other antitumor factors. NK cell activation with a dual agonist for TLR7 and TLR8 is able to induce the expression of IFN-γ and type I IFN, which can improve immunity in SS patients.