RESUMEN
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.
Asunto(s)
Trastornos Linfoproliferativos , Neoplasias Cutáneas , Humanos , Neoplasias Cutáneas/patología , Neoplasias Cutáneas/clasificación , Trastornos Linfoproliferativos/patología , Trastornos Linfoproliferativos/clasificación , Trastornos Linfoproliferativos/diagnóstico , Linfoma Cutáneo de Células T/patología , Linfoma Cutáneo de Células T/clasificación , Linfoma Cutáneo de Células T/diagnóstico , Organización Mundial de la SaludRESUMEN
BACKGROUND: The proportion of Merkel cell carcinomas (MCCs) in solid-organ transplant recipients (SOTR) harbouring Merkel cell polyomavirus (MCPyV) is unknown, as are factors affecting their outcomes. OBJECTIVE: To describe clinicopathological features of MCC in SOTR, investigate the tumoral MCPyV-status and identify factors associated with tumour outcomes. METHODS: Retrospective, international, cohort-study. MCPyV-status was investigated by immunohistochemistry and polymerase chain reaction. RESULTS: A total of 30 SOTR and 44 consecutive immunocompetent patients with MCC were enrolled. SOTR were younger at diagnosis (69 vs. 78 years, P < 0.001). Thirty-three percent of SOTR MCCs were MCPyV-positive vs. 91% of immunocompetent MCCs (P = 0.001). Solid-organ transplantation was associated with an increased cumulative incidence of progression (SHR: 3.35 [1.57-7.14], P = 0.002), MCC-specific mortality (SHR: 2.55 [1.07-6.06], P = 0.034) and overall mortality (HR: 3.26 [1.54-6.9], P = 0.002). MCPyV-positivity and switching to an mTOR inhibitor (mTORi) after MCC diagnosis were associated with an increased incidence of progression (SHR: 4.3 [1.5-13], P = 0.008 and SHR: 3.6 [1.1-12], P = 0.032 respectively) in SOTR. LIMITATIONS: Retrospective design and heterogeneity of SOTR cohort. CONCLUSIONS: MCPyV appears to play a less prominent role in the aetiopathogenesis of MCC in SOTR. SOTR have a worse prognosis than their immunocompetent counterparts and switching to an mTORi after the diagnosis of MCC does not improve progression.
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Carcinoma de Células de Merkel , Poliomavirus de Células de Merkel , Trasplante de Órganos , Infecciones por Polyomavirus , Neoplasias Cutáneas , Infecciones Tumorales por Virus , Carcinoma de Células de Merkel/patología , Humanos , Trasplante de Órganos/efectos adversos , Estudios Retrospectivos , Neoplasias Cutáneas/patología , Serina-Treonina Quinasas TOR , Infecciones Tumorales por Virus/complicacionesRESUMEN
BACKGROUND: Histopathological classification of basal cell carcinoma (BCC) has important prognostic and therapeutic implications, but reproducibility of BCC subtyping among dermatopathologists is poor. OBJECTIVES: To obtain a consensus paper on BCC classification and subtype definitions. METHODS: A panel of 12 recognized dermatopathologists (G12) from nine European countries used a modified Delphi method and evaluated 100 BCC cases uploaded to a website. The strategy involved five steps: (I) agreement on definitions for WHO 2018 BCC subtypes; (II) classification of 100 BCCs using the agreed definitions; (III) discussion on the weak points of the WHO classification and proposal of a new classification with clinical insights; (IV) re-evaluation of the 100 BCCs using the new classification; and (V) external independent evaluation by 10 experienced dermatopathologists (G10). RESULTS: A simplified classification unifying infiltrating, sclerosing, and micronodular BCCs into a single "infiltrative BCC" subtype improved reproducibility and was practical from a clinical standpoint. Fleiss' κ values increased for all subtypes, and the level of agreement improved from fair to moderate for the nodular and the unified infiltrative BCC groups, respectively. The agreement for basosquamous cell carcinoma remained fair, but κ values increased from 0.276 to 0.342. The results were similar for the G10 group. Delphi consensus was not achieved for the concept of trichoblastic carcinoma. In histopathological reports of BCC displaying multiple subtypes, only the most aggressive subtype should be mentioned, except superficial BCC involving margins. CONCLUSIONS: The three BCC subtypes with infiltrative growth pattern, characteristically associated with higher risk of deep involvement (infiltrating, sclerosing, and micronodular), should be unified in a single group. The concise and encompassing term "infiltrative BCCs" can be used for these tumors. A binary classification of BCC into low-risk and high-risk subtypes on histopathological grounds alone is questionable; correlation with clinical factors is necessary to determine BCC risk and therapeutic approach.
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Carcinoma Basocelular , Neoplasias Cutáneas , Carcinoma Basocelular/patología , Consenso , Humanos , Márgenes de Escisión , Reproducibilidad de los Resultados , Neoplasias Cutáneas/patologíaRESUMEN
BACKGROUND: Cutaneous peripheral T-cell lymphoma, not otherwise specified (PTL NOS) is an aggressive, but poorly characterized neoplasm. OBJECTIVES: The European Organization for Research and Treatment of Cancer cutaneous lymphoma taskforce (EORTC CLTF) investigated 33 biopsies of 30 patients with primary cutaneous PTL NOS to analyse their clinical, histological, immunophenotypic features and outcome. METHODS: Retrospective analysis of clinical data and histopathological features by an expert panel. RESULTS: Cutaneous PTL NOS manifested clinically either with solitary or disseminated rapidly grown ulcerated tumours or disseminated papulo-nodular lesions. Histologically, a mostly diffuse or nodular infiltrate in the dermis and often extending into the subcutis was found. Epidermotropism was rarely present and only mild and focal. Unusual phenotypes were frequent, e.g. CD3+ /CD4- /CD8- and CD3+ /CD4+ /CD8+ . Moreover, 18% of the cases exhibited an aberrant expression of the B-cell marker CD20 by the tumour cells. All solitary tumours were located on the limbs and presented a high expression of GATA-3 but this did not correlate with outcome and therefore could not serve as a prognostic factor. The prognosis was shown to be generally poor with 10 of 30 patients (33%) dying of lymphoma within the follow-up of 36 months (mean value; range 3-144). The survival rates were 61% after 3 years (CI, 43-85%) and 54% after 5 years (CI, 36-81%). Small to medium-sized morphology of tumour cells was associated with a better outcome than medium to large or large tumour cells. Age, gender, clinical stage, CD4/CD8 phenotype and GATA-3 expression were not associated with prognosis. Chemotherapy was the most common treatment modality, but surgical excision and/or radiotherapy may represent an appropriate first-line treatment for solitary lesions. CONCLUSIONS: Cutaneous PTL NOS shows an aggressive course in most patients independent of initial presentation, age and phenotype. Cytomorphology was identified as a prognostic factor. The data indicate a need for more effective treatment modalities in PTL NOS.
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Linfoma Cutáneo de Células T , Linfoma de Células T Periférico , Neoplasias Cutáneas , Humanos , Linfoma de Células T Periférico/tratamiento farmacológico , Pronóstico , Estudios Retrospectivos , Neoplasias Cutáneas/terapiaRESUMEN
BACKGROUND: Early-stage mycosis fungoides (MF) includes involvement of dermatopathic lymph nodes (LNs) or early lymphomatous LNs. There is a lack of unanimity among current guidelines regarding the indications for initial staging imaging in early-stage presentation of MF in the absence of enlarged palpable LNs. OBJECTIVES: To investigate how often imaging is performed in patients with early-stage presentation of MF, to assess the yield of LN imaging, and to determine what disease characteristics promoted imaging. METHODS: A review of clinicopathologically confirmed newly diagnosed patients with cutaneous patch/plaque (T1/T2) MF from PROspective Cutaneous Lymphoma International Prognostic Index (PROCLIPI) data. RESULTS: PROCLIPI enrolled 375 patients with stage T1/T2 MF: 304 with classical MF and 71 with folliculotropic MF. Imaging was performed in 169 patients (45%): 83 with computed tomography, 18 with positron emission tomography-computed tomography and 68 with ultrasound. Only nine of these (5%) had palpable enlarged (≥ 15 mm) LNs, with an over-representation of plaques, irrespectively of the 10% body surface area cutoff that distinguishes T1 from T2. Folliculotropic MF was not more frequently imaged than classical MF. Radiologically enlarged LNs (≥ 15 mm) were detected in 30 patients (18%); only seven had clinical lymphadenopathy. On multivariate analysis, plaque presentation was the sole parameter significantly associated with radiologically enlarged LNs. Imaging of only clinically enlarged LNs upstaged 4% of patients (seven of 169) to at least IIA, whereas nonselective imaging upstaged another 14% (24 of 169). LN biopsy, performed in eight of 30 patients, identified N3 (extensive lymphomatous involvement) in two and N1 (dermatopathic changes) in six. CONCLUSIONS: Physical examination was a poor determinant of LN enlargement or involvement. Presence of plaques was associated with a significant increase in identification of enlarged or involved LNs in patients with early-stage presentation of MF, which may be important when deciding who to image. Imaging increases the detection rate of stage IIA MF, and identifies rare cases of extensive lymphomatous nodes, upstaging them to advanced-stage IVA2.
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Micosis Fungoide , Neoplasias Cutáneas , Humanos , Ganglios Linfáticos/diagnóstico por imagen , Ganglios Linfáticos/patología , Micosis Fungoide/diagnóstico por imagen , Micosis Fungoide/patología , Estadificación de Neoplasias , Pronóstico , Estudios Prospectivos , Neoplasias Cutáneas/diagnóstico por imagen , Neoplasias Cutáneas/patologíaRESUMEN
BACKGROUND: Key pathogenic events of psoriasis and atopic eczema (AE) are misguided immune reactions of the skin. IL-17C is an epithelial-derived cytokine, whose impact on skin inflammation is unclear. OBJECTIVE: We sought to characterize the role of IL-17C in human ISD. METHODS: IL-17C gene and protein expression was assessed by immunohistochemistry and transcriptome analysis. Primary human keratinocytes were stimulated and expression of cytokines chemokines was determined by qRT-PCR and luminex assay. Neutrophil migration towards supernatant of stimulated keratinocytes was assessed. IL-17C was depleted using a new IL-17C-specific antibody (MOR106) in murine models of psoriasis (IL-23 injection model) and AE (MC903 model) as well as in human skin biopsies of psoriasis and AE. Effects on cell influx (mouse models) and gene expression (human explant cultures) were determined. RESULTS: Expression of IL-17C mRNA and protein was elevated in various ISD. We demonstrate that IL-17C potentiates the expression of innate cytokines, antimicrobial peptides (IL-36G, S100A7 and HBD2) and chemokines (CXCL8, CXCL10, CCL5 and VEGF) and the autocrine induction of IL-17C in keratinocytes. Cell-free supernatant of keratinocytes stimulated with IL-17C was strongly chemotactic for neutrophils, thus demonstrating a critical role for IL-17C in immune cell recruitment. IL-17C depletion significantly reduced cell numbers of T cells, neutrophils and eosinophils in murine models of psoriasis and AE and led to a significant downregulation of inflammatory mediators in human skin biopsies of psoriasis and AE ex vivo. CONCLUSION: IL-17C amplifies epithelial inflammation in Th2 and Th17 dominated skin inflammation and represents a promising target for the treatment of ISD.
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Dermatitis Atópica/inmunología , Interleucina-17/inmunología , Psoriasis/inmunología , Animales , Movimiento Celular , Modelos Animales de Enfermedad , Expresión Génica , Humanos , Inflamación/inmunología , Queratinocitos/inmunología , Ratones , Neutrófilos/inmunología , Células Th17/inmunología , Células Th2/inmunologíaAsunto(s)
Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Hemangiosarcoma/tratamiento farmacológico , Nivolumab/uso terapéutico , Cuero Cabelludo/patología , Neoplasias Cutáneas/tratamiento farmacológico , Anciano de 80 o más Años , Femenino , Neoplasias de Cabeza y Cuello/patología , Hemangiosarcoma/patología , Humanos , Piel/patología , Neoplasias Cutáneas/patología , Resultado del TratamientoRESUMEN
A 20-year-old woman presented with a 2-month history of an acute symmetrical eruption, manifesting as asymptomatic ill-defined erythematous macules and hyperkeratotic papules on the palms. The patient was a renal transplant recipient, and the lesions had developed 2 months post-transplantation. Histologically, the eruption shared features of a reactive inflammatory condition called papular eruption of atypical CD8+ lymphocytes as well as primary cutaneous acral CD8+ T-cell lymphoma (a provisional indolent entity in the new World Health Organisation classification of lymphoid neoplasms, 2016). The latter disorder has been described to occur at acral sites in immunocompetent patients, whereas the former has previously been described only in patients infected with human immunodeficiency virus. The lesions in our patient healed after topical treatment with corticosteroids and alteration of immunosuppressive therapy, supporting the role of immunosuppression in this case. We classified our patient's condition as lying in the spectrum of the aforementioned two conditions, but the relationship between both diseases remains to be clarified. Awareness of these unusual conditions may prevent the use of unnecessary aggressive therapies in similar patients.
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Linfocitos T CD8-positivos , Dermis/patología , Mano/patología , Huésped Inmunocomprometido , Trasplante de Riñón , Trastornos Linfoproliferativos/patología , Enfermedades de la Piel/patología , Corticoesteroides/uso terapéutico , Femenino , Humanos , Inmunosupresores/efectos adversos , Trastornos Linfoproliferativos/tratamiento farmacológico , Trastornos Linfoproliferativos/inmunología , Enfermedades de la Piel/tratamiento farmacológico , Enfermedades de la Piel/inmunología , Adulto JovenRESUMEN
BACKGROUND: The stromal vascular fraction (SVF) of adipose tissue consists of cellular subpopulations with distinct regenerative potential. OBJECTIVE: To investigate the regenerative capacities of autologous SVF cells in the treatment of chronic leg ulcers of venous (VLU) and arterial-venous (AVLU) origin. METHODS: Multimorbid ulcer patients received a singular topical treatment with 9-15 × 106 SVF cells, separated from abdominal lipoaspirates by digestion with collagenase and neutral protease and applied immediately after isolation. The primary endpoints were the change in wound size 12 weeks after treatment and evaluation of adverse events. Secondary endpoints included the time to complete wound epithelialization and change in pain levels. Postoperative wound treatment modalities and treatment of comorbidities were not intensified compared with pre-operative management. Follow-up period was at least 6 months. RESULTS: Sixteen elderly ulcer patients (seven with VLU, nine with AVLU) were treated as described. All VLU patients (median ulcer size: 48.25 cm2 ) and four of nine AVLU patients showed complete epithelialization of the ulcers within 71-174 days. In three patients with large ulcerations on both legs, ulcerations on the non-treated, contralateral leg also epithelialized. Patients reported a considerable rapid decrease in pain intensity by 2.5 points on average on a visual scale from 1 to 5 within the first 2 weeks after treatment. The patients were followed up for 9-44 months (median: 30 months). No severe side-effects were observed. CONCLUSIONS: The use of SVF cells presents an effective, minimally invasive option for the treatment of VLU and AVLU even in multimorbid patients. In patients with larger predominantly ischaemic AVLU and comorbidities, one-time application of the used amounts of SVF cells was not sufficient in the majority of cases.
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Úlcera de la Pierna/cirugía , Trasplante de Células Madre , Grasa Subcutánea/citología , Anciano , Anciano de 80 o más Años , Arterias , Enfermedad Crónica , Femenino , Humanos , Masculino , Persona de Mediana Edad , Proyectos Piloto , Estudios Prospectivos , VenasRESUMEN
BACKGROUND: Epidermodysplasia verruciformis (EV) is a genodermatosis leading to infections with cutaneous HPV, persistent plane warts and a high rate of non-melanoma skin cancer (NMSC). Biallelic loss-of-function mutations in TMC6 and TMC8 are known to be causative. OBJECTIVE: The aim of this study was to report EV-causing mutations in four patients with EV and to give an overview of all described patients with EV. PATIENTS AND METHODS: We investigated four patients with classical features of EV from two families. All patients were affected by plane warts with typical EV histology since early childhood, and ß-HPVs were detected on their skin. One patient had recurring cutaneous squamous cell carcinomas (cSCC) and carcinomas in situ (Bowen type). We sequenced both TMC6/8 for disease-causing mutations and quantified levels of gene expression. We also performed a systematic literature review to discuss these patients in the context of previously reported cases, mutations already identified, as well as HPV types. RESULTS: Three patients of one family carried a homozygous splice site mutation in TMC8 resulting in aberrantly spliced transcripts that were not degraded. By contrast, no TMC6/8 mutation was detected in the patient from the other family. A systematic literature review revealed 501 described patients with EV. Around 40% of patients with EV analysed for genetic alterations carried no mutation in TMC6/8. While ß-HPVs were identified in the majority of cases, α-HPVs were detected in several individuals. CONCLUSION: The relatively high proportion of EV patients without mutation in TMC6/8 indicates the existence of EV-causing mutations in additional, presently unknown gene(s). However, a homozygous TMC8 splice site mutation in our patients resulted in aberrant transcripts which cannot retain the healthy phenotype. The literature review revealed that HPV-5 is the most commonly identified HPV in patients with EV, but HPV-3, HPV-14 and HPV-20 were unexpectedly identified more frequently than HPV-8.
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Epidermodisplasia Verruciforme/genética , Proteínas de la Membrana/genética , Mutación , Infecciones por Papillomavirus/complicaciones , Empalme del ARN , Adolescente , Niño , Epidermodisplasia Verruciforme/complicaciones , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
BACKGROUND: Immunotherapy has gained importance with the development of new effective cancer treatments. Immune checkpoint inhibitors (ICI) are monoclonal antibodies that promote Tcell mediated tumor immune rejection. Checkpoint blockade also carries the risk of inducing autoimmune reactions ("immune related adverse events", irAEs). The diagnosis and classification of irAEs constitute a new and important field in pathology. AIM: Practice-oriented review of the diagnosis and classification of irAEs. MATERIALS AND METHODS: Structured, selective literature review based on PubMed und UpToDate ® online. RESULTS: The most common irAEs affect the skin, the gastrointestinal tract, the liver, and the respiratory system. The correct diagnosis and classification of irAEs by an interdisciplinary care team is essential for appropriate therapy and the prevention of long-term sequelae. Other important irAEs affect the endocrine organs, the heart, the joints, the kidneys and the nervous system. Because of their rarity and/or limited options for bioptic diagnosis, only limited data on the morphology and pathophysiology of these irAEs are currently available. Autopsies carried out after ICI therapy constitute an important element of quality control and allow better documentation of the incidence and pathogenesis of irAEs. DISCUSSION: Pathology plays a central role in the diagnosis and treatment of irAEs. Future studies may contribute to a better mechanistic understanding of irAEs for individualized knowledge-based risk assessment.
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Anticuerpos Monoclonales/efectos adversos , Factores Inmunológicos/efectos adversos , Inmunoterapia/efectos adversos , Neoplasias/patología , Neoplasias/terapia , HumanosRESUMEN
BACKGROUND: Unilesional mycosis fungoides (UMF) and pagetoid reticulosis (PR) are variants of mycosis fungoides. Conventional therapy comprises surgical excision or radiotherapy, which may be associated with long-term side effects, especially when the lesion is located at a special site like the palms and soles. Therefore, alternative treatment options are needed to treat solitary lesions in the case of UMF or PR. Recently, topical photodynamic therapy (PDT) has been described to be an efficient and non-invasive therapeutical option with excellent clinical outcome. OBJECTIVE: The objective of this study was to report a 43-year-old woman with plantar UMF treated successfully with PDT, and to compare our findings with the data on PDT in UMF and PR reported in the literature. METHODS: The literature was analysed for articles on UMF and PR, respectively, treated with topical PDT. Various parameters including form of PDT and response to treatment were analysed and compared with our case. RESULTS: A total of 24 patients were documented with 24 lesions treated with PDT, either using aminolevulinic acid (ALA) or methylaminolevulinate (MAL). In average, a single lesion was treated 4 times with PDT. In 21 cases (88%), complete response could be achieved, whereas three cases (13%) showed partial remission. None of the cases showed stable or progressive disease. CONCLUSIONS: PDT is a safe, efficient and non-invasive therapeutical approach for the treatment of UMF and PR. It has no long-standing adverse events and therefore is of high therapeutic value especially in cases of UMF and PR located at special sites like the palms and soles. We propose to include topical PDT as therapeutic option for the treatment of UMF and PR in future guidelines on the management MF.