RESUMO
To test the hypothesis that Merkel cell polyomavirus (MCPyV) can infect cells of the lymphoid system, we analyzed 353 specimens, including 152 non-Hodgkin lymphomas, 44 Hodgkin lymphomas, 110 benign lymph nodes, 27 lymph nodes with metastasis, and 20 extranodal tissue samples. MCPyV DNA was detected by quantitative PCR in 13 (6.6%) of 196 lymphomas, including 5 (20.8%) of 24 chronic lymphocytic leukemia specimens, and in 11 (10%) of 110 benign lymph nodes, including 8 (13.1%) of 61 samples of reactive hyperplasia and 3 (10.3%) of 29 normal lymph nodes. Other samples were MCPyV negative. Sequence analysis of 9 virus-positive samples confirmed the identity of MCPyV; 3 viral strains were represented. Immunohistochemical testing showed that 1 T-cell lymphoma expressed MCPyV T-antigen. These findings suggest that the lymphoid system plays a role in MCPyV infection and may be a site for MCPyV persistence.
Assuntos
Carcinoma de Célula de Merkel/virologia , Linfonodos/virologia , Infecções por Polyomavirus/epidemiologia , Polyomavirus/classificação , Infecções Tumorais por Vírus/epidemiologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , DNA Viral/isolamento & purificação , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Nova Escócia/epidemiologia , Infecções por Polyomavirus/virologia , Infecções Tumorais por Vírus/virologia , Adulto JovemRESUMO
Adipophilin is a monoclonal antibody against a protein on the surface of intracellular lipid droplets, and it was recently shown to be expressed in sebocytes and sebaceous lesions. This study examines adipophilin expression in various sebaceous lesions and other cutaneous tumors with a clear cell histology that may mimic sebaceous differentiation. A total of 117 cutaneous clear cell lesions including 16 sebaceous adenomas, 25 sebaceous carcinomas, 8 basal cell carcinomas, 12 squamous cell carcinomas, 6 xanthomas, 10 xanthelasmas, 10 xanthogranulomas, 4 balloon cell nevi, 5 trichilemmomas, 8 clear cell hidradenomas, and 13 metastatic renal cell carcinomas were examined using immunohistochemistry for the expression of adipophilin. Of these 117 lesions, 42 (36%) were from the periocular region. Adipophilin was expressed in 16 of 16 (100%) sebaceous adenomas, 23 of 25 (92%) sebaceous carcinomas, 10 of 10 (100%) xanthelasmas, 9 of 10 (90%) xanthogranulomas, 6 of 6 (100%) xanthomas, and 9 of 13 (62.5%) metastatic renal cell carcinomas. The characteristic staining pattern differed between sebaceous and non-sebaceous tumors with the former showing a membranous vesicular pattern and the latter being more granular. Adipophilin expression was not seen in any of the other lesions with clear cell histology, basal cell carcinomas, or squamous cell carcinomas, including cases that had focal clear cell differentiation. Adipophilin can be valuable in an immunohistochemical panel when evaluating cutaneous lesions with clear cell histology as it identifies intracytoplasmic lipid vesicles in sebaceous and xanthomatous lesions. In periocular lesions, it is effective in helping to exclude basal cell carcinoma and squamous cell carcinoma when sebaceous carcinoma is under consideration. Adipophilin expression is not as useful for the differential diagnosis that includes metastatic renal cell carcinoma, a rare but important, diagnostic differential. The pattern of adipophilin reactivity is important to observe as membranous vesicular staining is suggestive of intracellular lipids whereas granular cytoplasmic reactivity is not.
Assuntos
Biomarcadores Tumorais/análise , Peptídeos/metabolismo , Neoplasias das Glândulas Sebáceas/metabolismo , Neoplasias das Glândulas Sebáceas/patologia , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Feminino , Humanos , Imuno-Histoquímica , Lactente , Masculino , Proteínas de Membrana , Pessoa de Meia-Idade , Neoplasias de Anexos e de Apêndices Cutâneos/metabolismo , Neoplasias de Anexos e de Apêndices Cutâneos/patologia , Perilipina-2 , Adulto JovemRESUMO
Indeterminate fibrohistiocytic lesions of the skin share histological and immunohistochemical features of both benign fibrous histiocytoma/dermatofibroma and dermatofibrosarcoma protuberans (DFSP). Unlike dermatofibroma, DFSP harbors recurrent genetic aberrations resulting in the fusion of COL1A1 on chromosome 17 and PDGFB on chromosome 22. Because indeterminate fibrohistiocytic lesions share some features with DFSP, they were evaluated for the possible presence of COL1A1-PDGFB chimeric transcripts. Twelve formalin-fixed paraffin-embedded cases were examined for COL1A1-PDGFB chimeric transcripts using a previously validated sensitive multiplex reverse transcriptase-polymerase chain reaction assay. The median patient age was 52.5 years (33-70 years) with 9 females and 3 males. The most common site was the extremities (n = 8) followed by the trunk (n = 2) and the head and neck region (n = 2). All demonstrated the expected reactivity for both CD34 and factor XIIIa, and the majority focally infiltrated into subcutaneous fat. Of the 6 patients with follow-up, 2 had residual tumor excised, but no patient developed a recurrence. None of the tumors harbored COL1A1-PDGFB fusion transcripts identified by reverse transcriptase-polymerase chain reaction. Although indeterminate fibrohistiocytic lesions share some features with DFSP, the lack of COL1A1-PDGFB chimeric transcripts suggests that they are distinct entities.
Assuntos
Quimera/genética , Colágeno Tipo I/genética , Dermatofibrossarcoma/genética , Histiocitoma Fibroso Benigno/genética , Proteínas Proto-Oncogênicas c-sis/genética , Neoplasias Cutâneas/genética , Adulto , Idoso , Biópsia , Quimera/metabolismo , Colágeno Tipo I/metabolismo , Cadeia alfa 1 do Colágeno Tipo I , Dermatofibrossarcoma/diagnóstico , Dermatofibrossarcoma/metabolismo , Diagnóstico Diferencial , Feminino , Regulação Neoplásica da Expressão Gênica , Histiócitos/metabolismo , Histiócitos/patologia , Histiocitoma Fibroso Benigno/diagnóstico , Histiocitoma Fibroso Benigno/metabolismo , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Prevalência , Proteínas Proto-Oncogênicas c-sis/metabolismo , Estudos Retrospectivos , Pele/metabolismo , Pele/patologia , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologiaRESUMO
BACKGROUND: The p27(KIP1) and p57(KIP2) proteins belong to the CIP/KIP family of cyclin-dependent kinase inhibitors involved in the growth arrest and cellular senescence. High levels of p27(KIP1) unexpectedly have been detected in invasive malignant melanomas (MM), whereas the role of p57(KIP2) in melanocytic lesions is unknown. We therefore chose to study the expression of p27(KIP1) and p57(KIP2) in melanocytic neoplasms. DESIGN: The expression of p27(KIP1) and p57(KIP2) were examined by immunohistochemistry in 40 melanocytic neoplasms and by Western blot analysis in cultured human melanocytes. RESULTS: Expression of both nuclear p27(KIP1) and p57(KIP2) (> 10% of cells with nuclear labeling) was observed in most cases with non-proliferating melanocytes (8/10, benign nevi and 9/10 DN, dysplastic nevi), but in only a few cases containing proliferating melanocytes (3/11 RN, recurrent nevi and 2/9 MM, melanoma) (p < 0.002). In proliferating melanocytes, there was an inverse correlation of nuclear expression of p27(KIP1) and p57(KIP2) in both RN (p27(KIP1) = 3/11 RN and p57(KIP2) = 8/11 RN) and MM (p27(KIP1) = 7/9 MM and p57(KIP2) = 2/9 MM) (p < 0.05). Western blot analysis detected p57(KIP2) only in proliferating melanocytes. p27(KIP1) was detected in both proliferating and senescent melanocytes. CONCLUSION: The difference in expression patterns of p27(KIP1) and p57(KIP2) in proliferating and senescent melanocytes suggests the interplay between these proteins may play a functional role in melanocytic tumorigenesis.
Assuntos
Inibidor de Quinase Dependente de Ciclina p57/biossíntese , Regulação Neoplásica da Expressão Gênica , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Melanócitos/metabolismo , Melanoma/metabolismo , Neoplasias Cutâneas/metabolismo , Proliferação de Células , Células Cultivadas , Senescência Celular , Inibidor de Quinase Dependente de Ciclina p27 , Humanos , Melanócitos/patologia , Melanoma/patologia , Neoplasias Cutâneas/patologiaRESUMO
Late-stage malignant melanoma continues to pose a significant therapeutic challenge, despite numerous recent advances in our understanding of the molecular and genetic pathways leading to tumor development and progression. Dr Scott McNutt was among the first researchers to employ the cutting edge technology, electron microscopy, to the study of cutaneous neoplasms. This work provided the foundation for more recent studies using molecular pathology to examine disease in the context of aberrant interactions between cellular signaling pathways in the so-called 'interactome'. Understanding the functional interrelationships of aberrant signaling networks in melanoma may lead to the development of novel therapies for advanced disease. This mini review will focus on few of the proteins that likely significantly contribute to the melanoma disease interactome.
Assuntos
Melanócitos/metabolismo , Melanoma/genética , Transdução de Sinais/fisiologia , Neoplasias Cutâneas/genética , Humanos , Melanócitos/patologia , Melanoma/metabolismo , Melanoma/fisiopatologia , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/fisiopatologiaRESUMO
A 7-year-old girl presented with pain and progressive swelling on the left plantar surface. Biopsy of a 2.5 cm mass showed nests of large round to oval neoplastic cells with abundant amphophilic to clear cytoplasm, prominent nucleoli and high mitotic activity. Occasional cells showed spindled morphology. Infrequent melanin pigment was present. Melanocytic markers (HMB45, S-100) were diffusely positive. A diagnosis of clear cell sarcoma of soft tissue (CCSS) was made, and the mass was re-excised with negative margins. 28 months later, a 1.0 cm pulmonary nodule was identified and wedge excision showed metastatic CCSS. Cytogenetics showed a complex karyotype (unbalanced translocation der(12;14)(q10;q10), additional chromosome 22 material of unknown origin). Although the CCSS translocation t(12;22)(q13;q12) was not identified, EWSR1 gene rearrangement was detected by fluorescence in situ hybridization (FISH). Reverse transcription polymerase chain reaction (RT-PCR) showed an EWS-ATF1 fusion transcript, confirmed by direct sequencing. CCSS requires differentiation from malignant melanoma, because of overlapping clinical presentations, sites of involvement, histomorphology, immunocytochemical profiles and ultrastructure. In many circumstances, definitive diagnosis is only possible with confirmation of the CCSS-defining translocation.
Assuntos
Rearranjo Gênico , Hibridização in Situ Fluorescente , Proteínas de Fusão Oncogênica/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Sarcoma de Células Claras/diagnóstico , Neoplasias de Tecidos Moles/diagnóstico , Fatores de Transcrição/genética , Biomarcadores Tumorais/análise , Proteínas de Ligação a Calmodulina/genética , Criança , Feminino , Humanos , Proteína EWS de Ligação a RNA , Proteínas de Ligação a RNA/genética , Sarcoma de Células Claras/química , Sarcoma de Células Claras/genética , Sarcoma de Células Claras/cirurgia , Neoplasias de Tecidos Moles/química , Neoplasias de Tecidos Moles/genética , Neoplasias de Tecidos Moles/cirurgia , Translocação Genética , Resultado do TratamentoRESUMO
Atypical fibroxanthoma (AFX) is a rare cutaneous spindle-cell neoplasm. The tumor occurs most commonly in sun-damaged skin of the head and neck in elderly patients. A small subset of patients (approximately one in five cases) is middle-aged and presents with AFX of the trunk or extremities in areas without evidence of actinic damage. We report an unusual case of AFX of the lower leg in an 81-year-old woman with extensive actinic damage.
Assuntos
Histiocitoma Fibroso Benigno/patologia , Neoplasias Cutâneas/patologia , Idoso de 80 Anos ou mais , Feminino , Histiocitoma Fibroso Benigno/cirurgia , Humanos , Extremidade Inferior/patologia , Neoplasias Cutâneas/cirurgiaRESUMO
Melanocytic lesions in certain locations (eg, genital, breast, acral) may have histologic and clinical features simulating melanoma. Here we describe a group of lesions from the lower distal extremity and analyze their histologic features and possible relation to dysplastic nevi (DN) and melanomas. One hundred fifteen melanocytic lesions from the ankle were retrieved from January 1990 to August 2006 from the files of M. D. Anderson Cancer Center and were classified as benign melanocytic nevi (BN; n=17), DN (n=35), melanomas (MM; n=52), and melanocytic nevi of the ankle with atypical features (MNAAF; ie, cases that did not readily fit in any of the previous categories, n=11). Data analyzed included clinical (age and sex) and histologic features (circumscription, symmetry, cohesiveness of nests, suprabasal melanocytes, confluence, single-cell proliferation, nuclear chromasia, size, and nucleolar features). Follow-up was collected for all MNAAF. MNAAF differ from the other types of lesions in regard to sex incidence (73% in women). The median age of those patients MNAAF was 47 years (range 29 to 76 y). All MNAAF showed moderate-severe architectural disorder whereas 78% showed only mild-moderate cytologic atypia. No MNAAF cases had recurred after follow-up (4 mo to 13 y). This study highlights a group of melanocytic lesions located on the ankle that share histologic features with acral nevi, DN, and melanoma. These lesions are more predominant in females and have moderate to severe architectural atypia but only mild-moderate cytologic atypia. After complete excision, follow-up data indicate an apparently benign outcome. Pathologists should be aware of this type of lesions to avoid overdiagnosis of melanoma.
Assuntos
Erros de Diagnóstico/prevenção & controle , Síndrome do Nevo Displásico/patologia , Sarda Melanótica de Hutchinson/patologia , Nevo Pigmentado/patologia , Lesões Pré-Cancerosas/patologia , Neoplasias Cutâneas/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Tornozelo , Biomarcadores Tumorais/metabolismo , Diagnóstico Diferencial , Síndrome do Nevo Displásico/metabolismo , Feminino , Humanos , Sarda Melanótica de Hutchinson/metabolismo , Masculino , Melaninas/metabolismo , Pessoa de Meia-Idade , Nevo Pigmentado/metabolismo , Lesões Pré-Cancerosas/metabolismo , Estudos Retrospectivos , Neoplasias Cutâneas/metabolismoRESUMO
PURPOSE: Most studies accept a multistep pathogenic process in melanoma that may include the phases of benign nevi and dysplastic nevi, melanoma, and metastatic melanoma. Dysregulation of cellular proliferation and apoptosis is probably involved in melanoma progression and response to therapy. We have studied the expression of galectin-3, a beta-galactoside-binding protein involved in apoptosis, angiogenesis, and cell proliferation, in a large series of melanocytic lesions, and correlated the expression with clinical and histologic features. EXPERIMENTAL DESIGN: Tissue microarray blocks of 94 melanocytic lesions were semiquantitatively evaluated by immunohistochemistry for the cytoplasmic or nuclear expression of galectin-3. RESULTS: Primary and metastatic melanomas expressed galectin-3 at a significantly higher level than nevi in both cytoplasm and nuclei (P<0.0073). There was a significant association between anatomic source (as indirect indication of level of sun-exposure) and cytoplasmic and nuclear expression. Lymph node and visceral metastases had a higher level of expression than s.c. lesions (P<0.004). Interestingly, there was an almost significant finding of worse survival in those patients with lesions showing higher levels of cytoplasmic than nuclear galectin-3 expression (log-rank test, P=0.06). CONCLUSIONS: Melanocytes accumulate galectin-3 with tumor progression, particularly in the nucleus. The strong association of cytoplasmic and nuclear expression in lesions of sun-exposed areas suggests an involvement of UV light in activation of galectin-3.
Assuntos
Galectina 3/metabolismo , Melanoma/etiologia , Melanoma/metabolismo , Neoplasias Cutâneas/etiologia , Neoplasias Cutâneas/metabolismo , Luz Solar/efeitos adversos , Biomarcadores Tumorais/metabolismo , Citoplasma/metabolismo , Progressão da Doença , Intervalo Livre de Doença , Regulação Neoplásica da Expressão Gênica , Humanos , Linfonodos/metabolismo , Linfonodos/patologia , Metástase Linfática/patologia , Melanoma/terapia , Nevo/metabolismo , Nevo Pigmentado/metabolismo , Proteínas Nucleares/metabolismo , Neoplasias Cutâneas/terapia , Análise Serial de TecidosRESUMO
Immunohistochemical analysis has consistently shown that cyclin E is up-regulated in human malignant melanomas in vivo. Here we analyzed such expression in more detail and show that cyclin E is overexpressed and present in low molecular weight (LMW) isoforms in metastatic melanoma and in a subset of primary invasive melanoma tumor tissues, but not in benign nevi. Human metastatic melanoma cell lines, but not normal melanocytes, also expressed the LMW cyclin E forms. The biological significance of these findings was established by showing that overexpression of two LMW cyclin E forms named cyclin E truncated 1 [cyclinE(T1)] and cyclin E truncated 2 [cyclinE(T2)] in a low tumorigenic and non-metastatic primary cutaneous melanoma cell line generated angiogenic tumors with prominent perineural invasion compared with full-length cyclin E. In addition, cyclin E(T1)- and cyclin E(T2)-expressing melanoma cells displayed a dramatic increase in the incidence and number of metastases in an experimental lung metastasis assay. Together, these results indicate that the LMW cyclin E forms are functional and likely act as regulators of human melanoma tumor progression and invasion.
Assuntos
Ciclina E/biossíntese , Melanoma/irrigação sanguínea , Melanoma/metabolismo , Animais , Western Blotting , Quinases relacionadas a CDC2 e CDC28/metabolismo , Proteínas de Ciclo Celular/metabolismo , Ciclina E/genética , Ciclina E/metabolismo , Quinase 2 Dependente de Ciclina , Inibidor de Quinase Dependente de Ciclina p21 , Humanos , Masculino , Melanoma/genética , Melanoma/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Peso Molecular , Metástase Neoplásica , Transplante de Neoplasias , Neovascularização Patológica/metabolismo , Isoformas de Proteínas , Transfecção , Transplante HeterólogoRESUMO
At the end of the last decade, sporadic melanomas were still considered a genetic black box. Fortunately, in the last few years the box has been opened bringing to light melanoma-relevant oncogenes, aberrant signal transduction pathways, critical alterations in the melanoma cell cycle that go beyond p16INK4a, and melanoma- microenvironment interactions that are essential for tumor progression. This review will discuss some of the latest findings in melanoma research including the critical role of the MAPK pathway in the genesis of melanoma and senescence of nevi, the paradoxical tumor suppressor and oncogenic activities of the transcription factor MITF, and the unexpected oncogenic activities of the low molecular weight forms of cyclin E.
Assuntos
Genes Neoplásicos , Melanoma/enzimologia , Melanoma/fisiopatologia , Fator de Transcrição Associado à Microftalmia/fisiologia , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Neoplasias Cutâneas/enzimologia , Neoplasias Cutâneas/fisiopatologia , Ciclo Celular , Proliferação de Células , Transformação Celular Neoplásica , Inibidor p16 de Quinase Dependente de Ciclina/fisiologia , Epigênese Genética , Genótipo , Humanos , Melanoma/genética , Mutação , Fenótipo , Transdução de Sinais , Neoplasias Cutâneas/genéticaRESUMO
We describe a case of primary neuroendocrine carcinoma arising from the anterior vaginal wall of a 67-year-old woman. Primary neuroendocrine carcinoma of the vagina is a rare entity with only 25 previously reported cases in the literature. In previous reports, these tumors have not been distinguished from primary neuroendocrine carcinoma of the skin (Merkel cell carcinoma). The tumor was composed of cells that showed neuroendocrine-type nuclear features with hyperchromasia, nuclear molding, occasional small nucleoli, and a chromatin pattern that was finely granular. The tumor cells were positive for cytokeratin 20 (CK20), neuron specific enolase, pancytokeratin, epithelial membrane antigen, and chromogranin A expression. Ki-67, a marker of proliferation, was also positive in>90% of cells. The tumor cells showed intense expression of Bcl-2 oncoprotein and mild to moderate expression of c-KIT. Synaptophysin, neurofilament, CD45, CD56, CD10, S-100, HMB-45, cytokeratin 7, and thyroid transcription factor 1 were negative. This pattern of staining is consistent with a Merkel cell carcinoma. This is the first report of a primary neuroendocrine carcinoma of the vagina with a Merkel cell phenotype. Previous studies have not distinguished primary neuroendocrine carcinoma of the vagina from Merkel cell carcinoma of the skin. Positive expression of CK20 in primary small cell carcinoma of the vagina might represent a Merkel cell carcinoma subtype of this tumor.
Assuntos
Carcinoma de Célula de Merkel/patologia , Carcinoma Neuroendócrino/patologia , Neoplasias Cutâneas/patologia , Neoplasias Vaginais/patologia , Idoso , Biomarcadores Tumorais/análise , Carcinoma de Célula de Merkel/classificação , Carcinoma de Célula de Merkel/metabolismo , Carcinoma Neuroendócrino/classificação , Carcinoma Neuroendócrino/metabolismo , Diagnóstico Diferencial , Feminino , Humanos , Imuno-Histoquímica , Neoplasias Cutâneas/classificação , Neoplasias Cutâneas/metabolismo , Tomografia Computadorizada por Raios X , Neoplasias Vaginais/classificação , Neoplasias Vaginais/metabolismoRESUMO
To assess the diagnostic accuracy of margin evaluation of melanocytic lesions using en face frozen sections compared with standard paraffin-embedded sections, we studied 2 sets of lesions in which en face frozen sections were used for analysis of surgical margins (13 from malignant melanomas [MMs] and 10 from nonmelanocytic lesions [NMLs]). Routine permanent sections were cut after routine processing. The slides were mixed and coded randomly. Fifteen dermatopathologists examined the cases separately. Margin status was categorized as positive, negative, or indeterminate. Kappa statistics were calculated per dermatopathologist and per case. One case from each group was excluded because epidermis was not available in the routine sections. Of 330 evaluations (22 cases, 15 dermatopathologists), there were 132 diagnostic discrepancies (40.0%): 66 each for MM and NML (mean per case for both diagnoses, 6). In 9 instances (6.8%), the change was from positive (frozen) to negative (permanent) and in 43 (32.6%), from negative (frozen) to positive (permanent). There was poor agreement between frozen and permanent sections (kappa range per dermatopathologist, -0.1282 to 0.6615). If permanent histology is considered the "gold standard" for histologic evaluation, en face frozen sections are not suitable for accurate surgical margin assessment of melanocytic lesions.
Assuntos
Citodiagnóstico/métodos , Erros de Diagnóstico/prevenção & controle , Secções Congeladas , Melanoma/patologia , Neoplasias Cutâneas/patologia , Idoso , Diagnóstico Diferencial , Humanos , Melanoma/cirurgia , Pessoa de Meia-Idade , Cirurgia de Mohs/métodos , Inclusão em Parafina , Reprodutibilidade dos Testes , Neoplasias Cutâneas/cirurgiaRESUMO
CONTEXT: Cutaneous primary invasive malignant melanoma often is classified by its histologic appearance. Major recognized histologic subtypes of melanoma include superficial spreading, lentigo maligna melanoma, nodular, and acral lentiginous. More recently, it has been shown that most primary invasive melanomas harbor nonrandom genetic or biochemical aberrations that correlate with anatomic site or with the amount of cutaneous exposure to sunlight. It also is generally accepted that most primary invasive melanomas are preceded by an intraepidermal atypical melanocytic proliferation that lacks invasive capability (melanoma in situ). OBJECTIVE: To focus on lentigo maligna, the preinvasive/in situ form of melanoma located on chronically sun-damaged skin. DATA SOURCES: Review of the literature and the authors' personal experiences. CONCLUSIONS: A better understanding of the earliest stage of melanoma progression, including the contribution of chronic exposure to ultraviolet radiation, may lead to improved classification schemes that direct more effective targeted or personalized therapies for patients.
Assuntos
Sarda Melanótica de Hutchinson/patologia , Neoplasias Cutâneas/patologia , Pele/patologia , Humanos , Estadiamento de Neoplasias , Luz SolarRESUMO
CONTEXT: The diagnosis of recurrent nevus poses a potential challenge to practicing pathologists. Although most recurrent nevi show uniform microscopic findings and pose no great diagnostic difficulty, a few cases exhibit some histopathologic features similar to, and in some cases indistinguishable from, melanoma. Historically, the term pseudomelanoma has been used in the literature to describe such recurrent nevi, although this label has the potential for confusion and is no longer the favored term for recurrent pigmented melanocytic nevi. OBJECTIVE: To describe historical, histopathologic, and immunohistochemical features of recurrent pigmented melanocytic nevi and to review briefly the literature surrounding the mechanism of recurrence. DATA SOURCES: Published peer-reviewed literature and the authors' personal experience. CONCLUSIONS: Recognition of the histopathologic pattern of recurrent nevi leads the pathologist to the correct diagnosis in most cases; however, in particularly challenging specimens or in circumstances in which there is insufficient clinical history, immunohistochemical studies have proved helpful in distinguishing recurrent nevi from melanoma.
Assuntos
Melanoma/patologia , Nevo/patologia , Neoplasias Cutâneas/patologia , Diagnóstico Diferencial , Humanos , Imuno-Histoquímica , Melanoma/metabolismo , Nevo/metabolismo , Recidiva , Neoplasias Cutâneas/metabolismoRESUMO
The SKI protein represses the TGF-beta tumor suppressor pathway by associating with the Smad transcription factors. SKI is upregulated in human malignant melanoma tumors in a disease-progression manner and its overexpression promotes proliferation and migration of melanoma cells in vitro. The mechanisms by which SKI antagonizes TGF-beta signaling in vivo have not been fully elucidated. Here we show that human melanoma cells in which endogenous SKI expression was knocked down by RNAi produced minimal orthotopic tumor xenograft nodules that displayed low mitotic rate and prominent apoptosis. These minute tumors exhibited critical signatures of active TGF-beta signaling including high levels of nuclear Smad3 and p21(Waf-1), which are not found in the parental melanomas. To understand how SKI promotes tumor growth we used gain- and loss-of-function approaches and found that simultaneously to blocking the TGF-beta-growth inhibitory pathway, SKI promotes the switch of Smad3 from tumor suppression to oncogenesis by favoring phosphorylations of the Smad3 linker region in melanoma cells but not in normal human melanocytes. In this context, SKI is required for preventing TGF-beta-mediated downregulation of the oncogenic protein c-MYC, and for inducing the plasminogen activator inhibitor-1, a mediator of tumor growth and angiogenesis. Together, the results indicate that SKI exploits multiple regulatory levels of the TGF-beta pathway and its deficiency restores TGF-beta tumor suppressor and apoptotic activities in spite of the likely presence of oncogenic mutations in melanoma tumors.
Assuntos
Proteínas de Ligação a DNA/metabolismo , Técnicas de Silenciamento de Genes , Melanoma , Proteínas Proto-Oncogênicas/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Animais , Proteínas de Ligação a DNA/genética , Humanos , Masculino , Melanoma/metabolismo , Melanoma/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Invasividade Neoplásica , Fosforilação , Inibidor 1 de Ativador de Plasminogênio/genética , Inibidor 1 de Ativador de Plasminogênio/metabolismo , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Interferência de RNA , Transdução de Sinais/fisiologia , Proteína Smad3/genética , Proteína Smad3/metabolismo , Transplante Heterólogo , Células Tumorais CultivadasRESUMO
BACKGROUND: Renal cell carcinoma marker (RCC-Ma) is a monoclonal antibody against a normal renal proximal tubule antigen. RCC-Ma expression is relatively specific for primary clear cell renal cell carcinoma. Its expression in cutaneous metastasis of renal cell carcinoma (MRCC) and other cutaneous clear cell lesions has not been studied. METHODS: One hundred and thirty-seven cutaneous clear cell lesions including eight xanthomas, 32 xanthelasmas, 25 xanthogranulomas, seven balloon cell nevi, six clear cell hidradenomas, 29 sebaceous adenomas, six sebaceous epitheliomas, eight sebaceous carcinomas, and 16 MRCC were examined using immunohistochemistry for the expression of RCC-Ma. RESULTS: RCC-Ma was expressed in 10 of 16 (62.5%) MRCC, all with greater than 20% of cell labeling. Of these, 4 of 10 (40%) labeled with a membranous pattern and 6 of 10 (60%) labeled with both a membranous and a cytoplasmic pattern. RCC expression was not seen in any of the other clear cell lesions (p < 0.001). Furthermore, lack of expression in each of the other diagnostic groups was significant when each group was compared with the MRCCs (p < 0.01 at least for each group). CONCLUSIONS: Our study demonstrates that RCC may be a valuable component of a panel of immunohistochemical markers when evaluating cutaneous clear cell lesions.
Assuntos
Anticorpos Monoclonais , Biomarcadores Tumorais/análise , Carcinoma de Células Renais/secundário , Neoplasias Renais/patologia , Neoplasias Cutâneas/secundário , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Renais/metabolismo , Criança , Pré-Escolar , Diagnóstico Diferencial , Humanos , Imuno-Histoquímica , Lactente , Neoplasias Renais/metabolismo , Pessoa de Meia-Idade , Neoplasias Cutâneas/metabolismoRESUMO
The proteins SKI and SnoN are implicated in processes as diverse as differentiation, transformation and tumor progression. Until recently, SKI was solely viewed as a nuclear protein with a principal function of inhibiting TGF-beta signaling through its association with the Smad proteins. However, new studies suggest that SKI plays additional roles not only inside but also outside the nucleus. In normal melanocytes and primary non-invasive melanomas, SKI localizes predominantly in the nucleus, whereas in primary invasive melanomas SKI displays both nuclear and cytoplasmic localization. Intriguingly, metastatic melanoma tumors display nuclear and cytoplasmic or predominantly cytoplasmic SKI distribution. Cytoplasmic SKI is functional, as it associates with Smad3 and prevents its nuclear localization mediated by TGF-beta. SKI can also function as a transcriptional activator, targeting the beta -catenin pathway and activating MITF and NrCAM, two proteins involved in survival, migration and invasion. Intriguingly, SKI appears to live a dual life, one as a tumor suppressor and another as a transforming protein. Loss of one copy of mouse ski increases susceptibility to tumorigenesis in mice, whereas its overexpression is associated with cancer progression of human melanoma, esophageal, breast and colon. The molecular reasons for such dramatic change in SKI function appear to result from new acquired activities. In this review, we discuss the mechanisms by which SKI regulates crucial pathways involved in the progression of human malignant melanoma.
Assuntos
Transformação Celular Neoplásica , Melanoma/fisiopatologia , Neoplasias Cutâneas/fisiopatologia , Animais , Citoplasma/química , Proteínas de Ligação a DNA , Progressão da Doença , Humanos , Camundongos , Proteínas Proto-Oncogênicas , Transdução de SinaisRESUMO
BACKGROUND: CD10, the Common Acute Lymphoblastic Leukemia Antigen, is a neutral endopeptidase commonly used as a marker of early B-cell differentiation in the classification of lymphomas. Neoplasms of other histogenesis may express CD10, including renal cell carcinoma. Renal cell carcinoma metastatic to the skin (MRCC) can simulate other more common clear cell lesions in which expression of CD10 has not been described. METHODS: Fifty-two cutaneous clear cell lesions including xanthomas (CX), xanthelasmas (XA), xanthogranulomas (XG), balloon cell nevi (BCN), nodular/clear cell hidradenomas (CCH), and MRCC were examined by immunohistochemistry for the expression of CD10, noting frequency and pattern of labeling. RESULTS: CD10 was expressed in 32/35 of the xanthomatous lesions (CX, XA, and XG), 3/3 MRCC, but only 2/8 BCN and 2/6 CCH. BCN and CCH expressed CD10 in fewer than 10% of the clear cells, whereas all MRCC and most xanthomatous lesions had labeling in greater than 10% (p < 0.001). Xanthomatous lesions exhibited a predominantly membranous pattern of labeling compared to the cytoplasmic pattern of MRCC (p < 0.025). CONCLUSIONS: Cutaneous clear cell lesions of different histogenesis express CD10, limiting its use as a specific diagnostic marker for MRCC. Among other clear cell lesions, however, BCN and CCH have a lower frequency of labeling than does MRCC, and xanthomatous lesions show a membranous pattern compared to the cytoplasmic pattern of MRCC, BCN, and CCH. This latter observation may be indicative of altered protein function or trafficking.
Assuntos
Adenocarcinoma de Células Claras/metabolismo , Neprilisina/metabolismo , Neoplasias Cutâneas/metabolismo , Adulto , Idoso , Feminino , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Distribuição TecidualRESUMO
BACKGROUND: A common problem in the routine examination of melanoma re-excision scars occurs when a few or rare mildly atypical cells are present within the scar, raising the question of residual disease. Little is known about the derivation of these cells. Because the normal cutaneous wound-healing process is reparative, we hypothesized that these atypical cells may be reactive proliferating Schwann cell precursors. METHODS: The expression of the Schwann cell differentiation markers p75NGFR, CD56/N-CAM and GAP-43 was examined by immunohistochemistry in scars of wide local re-excisions for melanoma and non-melanoma tumors. Expression of S100, gp100 (with HMB45) and MART1 was also analyzed by immunohistochemistry. RESULTS: All melanoma and non-melanoma re-excision specimens contained mildly atypical, spindled or epithelioid cells within the scar. They varied in number from case to case and expressed S100, p75NGFR, CD56/N-CAM or GAP-43 but not gp100 (with HMB45) or MART1. Rare epithelioid non-melanoma cells within the superficial dermis expressed MART-1. CONCLUSIONS: Atypical cells are present in re-excision scars from melanoma and non-melanoma cases. They demonstrate early Schwann cell differentiation and appear to proliferate during the scarring process. The use of anti-MART-1 alone in the examination of melanoma re-excisions specimens may be inadequate as it may label rare, superficially located, non-melanoma cells within the scar.