RESUMEN
BACKGROUND: Merkel cell carcinoma (MCC) is a neuroendocrine carcinoma, associated with Merkel cell polyomavirus. MCC admixed with squamous cell carcinoma (SCC) is unassociated with polyomavirus, and is genetically distinct. OBJECTIVE: We sought to distinguish clinically and dermoscopically between MCC and SCC/MCC. METHODS: We compared patient data for SCC/MCC (n = 26) and MCC (n = 20), and reviewed clinical and dermoscopic images (n = 9) of SCC/MCC. RESULTS: Patients with SCC/MCC were older (median 76.5 vs 69 years) and more often male (77% vs 60%), and had more nonmelanoma skin cancer (85% vs 25%), malignant extracutaneous tumors (25% vs 5%), lymphoproliferative disorders (23% vs 10%), and immunodeficient/proinflammatory states (77% vs 35%). In all, 58% of SCC/MCC versus 10% of MCC were clinically diagnosed nonmelanoma skin cancer. Patients with SCC/MCC had more metastases (77% vs 40%), more treatment failures (53% vs 45%), shorter survival (41 vs 54 months), and more death from disease (50% vs 40%). SCC/MCC demonstrated marked scale (7/9), and telangiectasia (1/9). Dermoscopically, small dotted and short linear irregular peripheral vessels and central milky-red areas with large-diameter arborizing vessels were seen. LIMITATIONS: The rarity of SCC/MCC limits available data. CONCLUSIONS: SCC/MCC is aggressive, arising within elderly patients' chronically ultraviolet-exposed skin, often in the setting of immunosuppression or inflammation. Dermoscopically, polymorphous vessels in lesions suspicious for nonmelanoma skin cancer are suggestive.
Asunto(s)
Carcinoma de Células de Merkel/patología , Carcinoma de Células Escamosas/patología , Dermoscopía/métodos , Neoplasias Primarias Múltiples/patología , Neoplasias Cutáneas/patología , Factores de Edad , Anciano , Anciano de 80 o más Años , Biopsia con Aguja , Carcinoma de Células de Merkel/diagnóstico , Carcinoma de Células de Merkel/mortalidad , Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas/mortalidad , Bases de Datos Factuales , Femenino , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Invasividad Neoplásica/patología , Estadificación de Neoplasias , Neoplasias Primarias Múltiples/diagnóstico , Neoplasias Primarias Múltiples/mortalidad , Pronóstico , Estudios Retrospectivos , Medición de Riesgo , Factores Sexuales , Neoplasias Cutáneas/diagnóstico , Neoplasias Cutáneas/mortalidad , Tasa de Supervivencia , Resultado del TratamientoRESUMEN
The choice of therapy for primary cutaneous B-cell lymphoma (PCBCL) relies on correct histopathologic classification and the exclusion of systemic disease. In part II of this continuing medical education article, we will review the available therapies for the different types of PCBCL. Primary cutaneous follicle center lymphoma (PCFCL) and primary cutaneous marginal zone lymphoma (PCMZL) are indolent tumors with an excellent prognosis. They are managed similarly with local therapy, such as radiotherapy or surgical excision, for isolated disease and observation for asymptomatic multifocal presentations. Relapses are common in both PCFCL and PCMZL, but overall survival remains excellent. Primary cutaneous diffuse large B-cell lymphoma (both leg type and other) has a much poorer prognosis than indolent PCBCL, and it often requires an aggressive approach with radiation therapy and/or multiagent chemotherapy. Investigational approaches hold promise for the treatment of these malignancies, particularly primary cutaneous diffuse large B-cell lymphoma.
Asunto(s)
Linfoma de Células B de la Zona Marginal/terapia , Linfoma Folicular/terapia , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Linfoma de Células B Grandes Difuso/radioterapia , Neoplasias Cutáneas/terapia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Terapia Combinada , Humanos , Linfoma de Células B de la Zona Marginal/cirugía , Linfoma Folicular/cirugía , Neoplasias Cutáneas/cirugíaRESUMEN
Primary cutaneous B-cell lymphomas (PCBCLs) are defined as lymphomas with a B-cell phenotype that present in the skin without evidence of systemic or extracutaneous disease at initial presentation, after adequate staging. In non-Hodgkin lymphomas, the skin is the second most common site of extranodal involvement after the gastrointestinal tract. PCBCLs are histologically very similar to their nodal counterparts, and these histologic similarities can lead to confusion about both therapy and prognosis. This article will summarize the clinical, pathologic, and diagnostic features of the 3 main types of PCBCL: primary cutaneous follicle center lymphoma, primary cutaneous marginal zone lymphoma, and primary cutaneous diffuse large B-cell lymphoma, leg-type, and the appropriate evaluation and staging procedures for each of these entities.
Asunto(s)
Linfoma de Células B de la Zona Marginal/diagnóstico , Linfoma Folicular/diagnóstico , Linfoma de Células B Grandes Difuso/diagnóstico , Neoplasias Cutáneas/diagnóstico , Diagnóstico Diferencial , Humanos , Linfoma de Células B de la Zona Marginal/clasificación , Linfoma de Células B de la Zona Marginal/patología , Linfoma Folicular/clasificación , Linfoma Folicular/patología , Linfoma de Células B Grandes Difuso/clasificación , Linfoma de Células B Grandes Difuso/patología , Neoplasias Cutáneas/clasificación , Neoplasias Cutáneas/patologíaRESUMEN
Gammaherpesvirus-associated neoplasms include tumors of lymphocytes, epithelial cells, and endothelial cells (ECs). We previously showed that, unlike most cell types, ECs survive productive gammaherpesvirus 68 (γHV68) infection and achieve anchorage-independent growth, providing a cellular reservoir for viral persistence. Here, we demonstrated autophagy in infected ECs by analysis of LC3 localization and protein modification and that infected ECs progress through the autophagosome pathway by LC3 dual fluorescence and p62 analysis. We demonstrate that pharmacologic autophagy induction results in increased survival of infected ECs and, conversely, that autophagy inhibition results in death of infected EC survivors. Furthermore, we identified two viral oncogenes, v-cyclin and v-Bcl2, that are critical to EC survival and that modify EC proliferation and survival during infection-induced autophagy. We found that these viral oncogenes can also facilitate survival of substrate detachment in the absence of viral infection. Autophagy affords cells the opportunity to recover from stressful conditions, and consistent with this, the altered phenotype of surviving infected ECs was reversible. Finally, we demonstrated that knockdown of critical autophagy genes completely abrogated EC survival. This study reveals a viral mechanism which usurps the autophagic machinery to promote viral persistence within nonadherent ECs, with the potential for recovery of infected ECs at a distant site upon disruption of virus replication.
Asunto(s)
Autofagia , Células Endoteliales/virología , Gammaherpesvirinae/fisiología , Infecciones por Herpesviridae/virología , Oncogenes/genética , Proteínas Virales/metabolismo , Animales , Autofagia/genética , Línea Celular , Supervivencia Celular , Células Cultivadas , Células Endoteliales/patología , Células Endoteliales/fisiología , Gammaherpesvirinae/genética , Gammaherpesvirinae/metabolismo , Gammaherpesvirinae/patogenicidad , Infecciones por Herpesviridae/patología , Pulmón/citología , Ratones , Ratones Transgénicos , Proteínas Oncogénicas/genética , Proteínas Oncogénicas/metabolismo , Oncogenes/fisiología , Proteínas Virales/genéticaRESUMEN
A variety of human diseases are associated with gammaherpesviruses, including neoplasms of lymphocytes (e.g. Burkitt's lymphoma) and endothelial cells (e.g. Kaposi's sarcoma). Gammaherpesvirus infections usually result in either a productive lytic infection, characterized by expression of all viral genes and rapid cell lysis, or latent infection, characterized by limited viral gene expression and no cell lysis. Here, we report characterization of endothelial cell infection with murine gammaherpesvirus 68 (gammaHV68), a virus phylogenetically related and biologically similar to the human gammaherpesviruses. Endothelial cells supported gammaHV68 replication in vitro, but were unique in that a significant proportion of the cells escaped lysis, proliferated, and remained viable in culture for an extended time. Upon infection, endothelial cells became non-adherent and altered in size, complexity, and cell-surface protein expression. These cells were uniformly infected and expressed the lytic transcription program based on detection of abundant viral gene transcripts, GFP fluorescence from the viral genome, and viral surface protein expression. Additionally, endothelial cells continued to produce new infectious virions as late as 30 days post-infection. The outcome of this long-term infection was promoted by the gammaHV68 v-cyclin, because in the absence of the v-cyclin, viability was significantly reduced following infection. Importantly, infected primary endothelial cells also demonstrated increased viability relative to infected primary fibroblasts, and this increased viability was dependent on the v-cyclin. Finally, we provide evidence for infection of endothelial cells in vivo in immune-deficient mice. The extended viability and virus production of infected endothelial cells indicated that endothelial cells provided a source of prolonged virus production and identify a cell-type specific adaptation of gammaherpesvirus replication. While infected endothelial cells would likely be cleared in a healthy individual, persistently infected endothelial cells could provide a source of continued virus replication in immune-compromised individuals, a context in which gammaherpesvirus-associated pathology frequently occurs.