NOP14 inhibits melanoma proliferation and metastasis by regulating Wnt/ß-catenin signaling pathway

Malignant melanoma is an aggressive skin cancer with a high mortality rate. Nucleolar protein 14 (NOP14) has been implicated in cancer development. However, the role of NOP14 in malignant melanoma progression remains largely unclear. In this study, we observed that malignant melanoma tissue showed NOP14 down-regulation compared to melanocytic nevi tissues. Moreover, we observed that NOP14 expression was significantly associated with melanoma tumor thickness and lymph node metastasis. NOP14 overexpression in melanoma cells suppressed proliferation, caused G1 phase arrest, promoted apoptosis, and inhibited melanoma cell migration and invasion. Further investigations revealed that NOP14 overexpression reduced the expression levels of Wnt3a, β-catenin, and GSK-3β of the Wnt/β-catenin pathway. In summary, we demonstrated that NOP14 inhibited melanoma cell proliferation and metastasis by regulating the Wnt/β-catenin signaling pathway.

Virus polioma en carcinoma de células de Merkel / Polyoma virus in Merkel cell carcinoma

Introducción: El carcinoma de células de Merkel (MCC) es un tumor cutáneo maligno agresivo y de mal pronóstico. La incidencia es mayor en adultos hombres, caucásicos, con edad promedio de 70 años. Feng et al, lograron aislar un nuevo virus en muestras de este tumor, que denominaron virus polioma de células de Merkel (MCPyV). Se ha intentado establecer una relación causal entre el virus y MCC. El virus está integrado al genoma y produciría mutaciones específicas. En muestras de MCC, se ha detectado expresión de oncoproteinas virales (antígenos T) que promueven la replicación viral y tumorogénesis

Introduction: Merkel cell carcinoma (MCC) is an aggressive malignant cutaneous tumor with poor prognosis. Most cases affect elder patient with an average of 70 years of age. Feng et al isolated a new virus, the Merkel cell carcinoma polyoma virus (MCPyV). A causal relationship between MCPyV y MCC has been established. The virus is integrated in the genome and pro-duces specific mutations. MCC samples show ex-pression of viral oncoproteins (T antigens) that promote viral replication and tumorogenesis.

Early Gastric Cancer with Cellulitis-like Skin Metastasis / 대한소화기학회지

Skin metastasis from internal carcinoma rarely occurs and it has an incidence of 0.7% to 9%. Although the prognosis of the skin metastases varies considerably depending on the type of the primary malignancy, presence of metastatic skin cancer usually implies a widespread systemic disease and a high mortality. A 50-year-old Korean male patient visited Dankook University Hospital for evaluation of skin rash on his whole abdomen of about 1 month's duration. He had undergone laparoscopy-assisted distal gastrectomy due to early gastric cancer about 3 months ago. He did not complain of any noticeable symptoms like febrile sense or pruritus. Skin biopsy was performed on the periumbilical area at previous port site and around the scar. Microscopic examination revealed multiple malignant cells in lymphatic spaces, consistent with metastatic carcinoma. He was therefore diagnosed with isolated skin metastasis from early gastic cancer. Because of patient's poor liver function, systemic chemotherapy could not be performed and only best supportive care was provided. Herein, we report a rare case of cellulitis-like skin metastasis from early gastric cancer with a brief review of the literature.

Melanoma de tipo animal / Animal-type melanoma

Lo que se ha dado en llamar melanoma de tipo animal es un tumor aún no bien determinado ni clasificado. Tiene similitudes clínicas e histopatológicas con el melanoma que se observa en los caballos de pelaje tordillo: un infiltrado alarmante, denso y extenso, de células que ocupan toda la dermis y aún el celular subcutáneo, acompañado sin embargo de un pronóstico benigno y larga sobrevida. El nombre propuesto por Zembowicz et ál., melanocitoma epitelioide pigmentado, parece más adecuado para esta rara variante de melanoma.

Animal-type melanoma is a rare distinct variant of melanoma, charac-terized by a dense proliferation of epithelioid and spindle-shaped mela-nocytes occupying the dermis and the hypodermis, and resembles theheavily pigmented melanomas as seen in grey horses. Only a limitednumber of cases have been reported and, as such, the clinical character-istics of this melanoma variant are incompletely understood. Despite thehigh mean thickness of the tumors, reports indicate a less aggressive behavior and a better outcome of this tumor when compared with conven-tional melanoma, but the underlying pathways related to this particularoutcome are still unknown. As proposed by Zembowicz et ál., the term‘pigmented epithelioid melanocitoma’ seems much more suitable.

Associação entre acrocórdons e resistência à insulina / Association between skin tags and insulin resistance

FUNDAMENTOS: Acrocórdons são lesões dermatológicas comuns na população e estão associados ao diabetes mellitus, à obesidade, à resistência insulínica e à aterosclerose. A identificação precoce de pacientes com resistência insulínica pode ter papel preventivo primário. OBJETIVO: Avaliar a associação entre presença de acrocórdons cervicais ou axilares e resistência insulínica. MÉTODOS: Estudo transversal com pacientes dermatológicos adultos atendidos em hospital universitário. Casos foram definidos como portadores de mais de cinco acrocórdons cervicais e/ou axilares. A resistência insulínica foi estimada pelo índice HOMA-IR. Resultados foram ajustados pelas demais covariáveis de risco para resistência insulínica conhecidos, a partir de regressão logística múltipla. RESULTADOS: Avaliaram-se 98 casos e 103 controles, que não diferiram entre si quanto à idade ou ao gênero. Acrocórdons se associaram diretamente aos valores de HOMA-IR (Odds Ratio = 1,4), hipertrigliceridemia e índice de massa corpórea, independentemente do ajuste por diabetes mellitus, idade, fototipo, gênero, história de diabetes mellitus familiar e relação cintura/quadril. Níveis qualitativamente elevados de HOMA-IR (> 3,8) também evidenciaram associação significativa (Índice de probabilidade = 7,5). CONCLUSÕES: Presença de múltiplos acrocórdons se associou à resistência insulínica, independentemente dos demais fatores de risco.

BACKGROUND: Skin tags are dermatological lesions commonly found in the general population and have been associated with diabetes mellitus, obesity, insulin resistance and atherosclerosis. Early detection of patients with insulin resistance may play an important preventive role. OBJECTIVE: To evaluate the association between skin tags in the neck or axillary regions and insulin resistance. METHODS: A cross-sectional study involving adult patients receiving care at a university teaching hospital. Cases were defined as patients with > 5 skin tags in the neck region and/or axillae. Insulin resistance was estimated using the HOMA-IR index. Results were adjusted for the other known covariates of risk for insulin resistance using a multiple logistic regression model. RESULTS: Ninety-eight cases and 103 controls were evaluated. There was no difference between the groups with respect to age or gender. Skin tags were directly associated with HOMA-IR values (odds ratio = 1.4), hypertriglyceridemia and body mass index, irrespective of adjustment for diabetes mellitus, age, skin phototype, gender, family history of diabetes mellitus or hip/waist ratio. Qualitatively elevated HOMA-IR levels (>3.8) were also significantly associated (odds ratio = 7.5). CONCLUSIONS: The presence of multiple skin tags was strongly associated with insulin resistance irrespective of other risk factors.

Expressão de marcadores de proliferação celular e apoptose no carcinoma espinocelular de pele e ceratose actínica / Expression of cell proliferation and apoptosis biomarkers in skin spinocellular carcinoma and actinic keratose

FUNDAMENTOS: O câncer de pele é o mais frequente tipo de câncer humano e mostra aumento de sua incidência. Em muitos casos, antes do surgimento do carcinoma, instala-se uma lesão precursora, ceratose actínica, podendo evoluir para carcinoma espinocelular. Estudos buscam determinar os parâmetros com significado prognóstico na predição daqueles tumores que terão comportamento mais agressivo. OBJETIVO: Avaliar a expressão dos marcadores de proliferação celular (PCNA, Ki-67) e apoptose (p53, Bcl-2), em portadores de carcinoma espinocelular e ceratose actínica. MÉTODO: Foram estudadas amostras de 30 pacientes: sendo dez portadores do carcinoma espinocelular; dez de ceratose actínica e dez indivíduos livres de lesões submetidos à blefaroplastia. RESULTADOS: A proteína p53 foi expressa em todos os casos estudados, embora apresentassem padrões quantitativos diferentes. O Bcl-2 foi expresso em baixa intensidade. Em seis casos de ceratose actínica, nas peles de blefaroplastia, e negativo nos casos de carcinoma espinocelular. O PCNA exibiu expressão intensa, em todas as amostras. O Ki-67 apresentou expressão variável, nos casos de carcinoma e de ceratose, e negativo na pele de pálpebra. CONCLUSÃO: A expressão do Ki-67 e a não-expressão de Bcl-2, no grupo CEC, indica intensificação da atividade proliferativa. Ao passo que, a maior expressão de p53 e Bcl-2, no grupo CA, sugere imortalização celular.

BACKGROUND: Skin cancer is the most frequent type of human cancer and has shown an increase in its incidence. In many cases, before the onset of the carcinoma, there might be a precursor lesion - actinic keratosis, which can develop into squamous cell carcinoma. Studies have been carried out in order to etermine the parameters that have prognostic significance in predicting those tumors which have more aggressive behavior. OBJECTIVE: To evaluate the expression of markers of cell proliferation (PCNA, Ki-67) and apoptosis (p53,Bcl-2) in patients with squamous cell carcinoma and actinic keratosis. METHOD: We studied samples from 30 patients, ten patients of squamous cell carcinoma, ten with actinic keratosis and ten lesion-free samples from blepharoplasty. RESULTS: p53 protein was expressed in all cases with different quantitative patterns. Bcl-2 was expressed at low intensity in six cases of actinic keratosis in the skin from blepharoplasty and negative in cases of squamous cell carcinoma. PCNA showed intense expression in all samples. Ki-67 showed variable expression in cases of keratosis and carcinoma and negative in the skin from the eyelid. CONCLUSION: The high expression of Ki-67 associated with low expression of Bcl-2 indicates proliferation in the carcinoma group. Thus, expression of p53 and Bcl-2 in patients with actinic keratosis indicates cell immortalization.

Expressão de metaloproteinases de matriz e de seus inibidores teciduais em carcinomas basocelulares / Expression of matrix metalloproteinasis and their tissue inhibitors in basal cell carcinoma

INTRODUÇÃO: Aproximadamente 80 por cento das neoplasias malignas de pele não-melanomas são carcinomas basocelulares (CBC). Apesar das raras metástases, esses tumores são localmente agressivos. As metaloproteinases de matriz (MMPs), especialmente as MMP-2 e 9, são importantes no processo de invasão. Em contrapartida, os inibidores teciduais das MMPs (TIMPs) têm como principal função a inibição dessas enzimas. OBJETIVO: Investigar a associação de variáveis clinicopatológicas de pacientes portadores de CBC com a expressão de MMP-2, MMP-9, TIMP-1 e TIMP-2. MATERIAL E MÉTODOS: Foram selecionados 31 casos de CBC, sendo então obtidos, retrospectivamente, os dados referentes a idade, sexo e tamanho da lesão. Cortes histológicos das lesões foram submetidos a reação imuno-histoquímica pela técnica estreptavidina-biotina-peroxidase para detecção dos antígenos de interesse. Índices de imunomarcação foram construídos e comparados com os dados previamente obtidos. RESULTADOS: Observou-se correlação significativa entre idade e tamanho da lesão (R = 0,532; p = 0,008). Não foram observadas correlações significativas entre as outras variáveis e a expressão imuno-histoquímica dos antígenos de interesse. CONCLUSÃO: A expressão das metaloproteinases e de seus inibidores teciduais não parece ser influenciada pelos parâmetros investigados. Estudos adicionais são necessários para melhor compreensão de sua associação com o comportamento biológico do CBC.

INTRODUCTION: Approximately 80 percent of non-melanoma skin neoplasias are basal cell carcinomas (BCC). Although metastasis is rare, BBC carcinomas are locally aggressive tumors. Matrix metalloproteinases (MMPs), mainly MMP-2 and MMP-9, play an important role on the invasion process. On the other hand, tissue inhibitors of MMPs (TIMPs) have the main function of inhibiting these enzymes. OBJECTIVE: To investigate the association of clinical-pathological variables of BCC patients with the expression of MMP-2 and MMP-9, TIMP-1 and TIMP-2. Methods: Thirty-one BCC cases were selected. Gender, age of the patients and size of the lesions were obtained retrospectively. Histological cuts of the lesions were exposed to immunohistochemistry reaction by use of the streptavidine-biotin peroxidase technique in order to detect antigens. Immunomarking parameters were established and compared with previous data. RESULTS: A significant correlation between age and size of the lesion was observed (R = 0.532; p = 0.008). No significant correlations between other variables and immunohistochemical expression of antigens were observed. CONCLUSION: The expression of MMPs and TIMPs does not seem to be influenced by the parameters investigated in this work. Additional studies should be made to better understand its association with the biological behavior of basal cell carcinomas.

Selective expression of progesterone receptor in malignant melanoma was inversely correlated with PCNA / 华中科技大学学报（医学）（英德文版）

To investigate the role of progesterone receptor (PR) expression in malignant melanoma (MM), PR and proliferative cell nuclear antigen (PCNA) expression were immunohistochemistrically evaluated in a series of 35 specimens of MM, and the correlation between the immunohistochemistrical findings and clinicopathological data was also analyzed. PR expression was detected in 25.7% (9/35) of the patients with MM. No PR expression was observed in nevi. PR expression was inversely correlated with PCNA expression (r=-0.353, P=0.026). PR expression was slightly increased in females, subjects aged under 55 y, those with ulceration, non-acral subtype and diagnosis delay longer than 1 y, but the difference was not statistically significant. Selective expression of progesterone receptor in malignant melanoma might be correlated with inhibited tumor growth.

Pleomorphic hyalinizing angiectatic tumour of soft parts: a case report and review of the literature

Pleomorphic hyalinizing angiectatic tumour (PHAT) is a recently described, rare, low-grade soft tissue neoplasm. The lesion is characterized by clusters of hyalinized and thrombosed ectatic vessels alternating with a variably cellular stroma composed of atypical cells, many with intranuclear pseudoinclusions. Other features are inflammatory cell infiltration, haemosiderin deposits, focal calcificationand minimal to absent mitoses. No metastases have so far been described; however, the local recurrence rate has been found to be high. To date, approximately 60 such cases of PHAT and its precursor, “early PHAT”, have been described in the world literature. We report the first known case of PHAT from this institution which occurred in the left loin of a 77-year old woman. Three years previously, a smaller lesion excised from the same location had been called an ancient schwannoma on histology. This is the most commondifferential diagnosis offered for this entity even though the two differ in immunohistochemical profile. ‘Early PHAT’ was also identified on the periphery of the recurrent lesion.

El tumor pleomórfico hialinizante angioectásico (TPHA) – entidad rara, de reciente descripción – es un neoplasma del tejido blando, de bajo grado. La lesión se caracteriza por la presencia de racimos de vasos ectásicos trombosados e hialinizados, que alternan con un estroma celular variable compuesto de células atípicas, muchas de ellas con pseudoinclusiones intranucleares. Otrascaracterísticas son: la infiltración celular inflamatoria, los depósitos hemosiderínicos, la calcificaciónfocal, y la mitosis mínima o ausente. Hasta el presente no se han descrito metástasis. Sin embargo, se ha hallado que la tasa de recurrencia local es alta. Hasta la fecha, aproximadamente 60 de estos casos de TPHA y su precursor el “TPHA temprano”, han sido descritos en la literatura mundial. Reportamosel primer caso de TPHA conocido de esta institución – una anciana de 77 años de edad, a quién se le presentó en la región lumbar izquierda. Tres años antes, una lesión más pequeña extirpada del mismolugar, hubiera sido llamada un schwannoma antiguo en histología. Este es el diagnóstico diferencial más común ofrecido para esta entidad, aun cuando los dos difieren en cuando a perfilimunohistoquímico. El TPHA temprano fue identificado también en la periferia de la lesión recurrente.

B cell lymphoma with unusual clinical cutaneous presentation.

Cutaneous B cell lymphoma (CBCL) is a lymphoproliferative disorder of neoplastic B cell of the skin. These are rarer than T cell lymphomas. Commonly, the presenting features of CBCL are plaques or nodules. Here is a case report of CBCL with a very unusual presentation of cutaneous horns. The patient was managed by a combination chemotherapy and local radiotherapy only. He is disease-free for about the last five years. The case has been presented because of its rarity and its management protocol.

P16(INK4A) expression in Bowen's disease and Bowenoid papulosis.

BACKGROUND: Bowen's disease (BD) is a skin carcinoma in situ occurring over the entire body surface. It shares similar histopathological features with Bowenoid papulosis (BP) of the genitalia, but differs in etiology and clinical course. Increased p16(INK4A) (p16) tumor suppressor protein expression has been demonstrated in relation to the progression of cutaneous squamous neoplasms. OBJECTIVE: To evaluate the difference in p16 expression between Bowen's disease and Bowenoid papulosis. MATERIAL AND METHOD: Biopsies of 46 cases of BD in the period 1994 - 2003 and 14 cases of BP during 1987 - 2003 in the Anatomical Pathology Unit, Department of Pathology, Faculty of Medicine, Prince of Songkla University, Thailand were studied by immunohistochemical methods using the P16 kit (CINTec Histology Kit, clone E6H4, Code-Nr. K5334, DakoCytomation, Denmark). Nuclear/cytoplasmic immunoreactivity in more than 10% of neoplastic cells was considered positive. RESULTS: P16 expression was positive in 37 of 46 BD cases (80.4%) which was higher than that of BP (6 of 14 cases or 42.9%) (p value < 0.05, Chi-square test). The expression among the three groups of BD: extragenital (28 of 35), chronic arsenical-related (7 of 8) and genital lesions (2 of 3) was not significantly different (p value = 0.734, Chi-square test). CONCLUSION: P16 expression was more frequent in BD than BP. This suggests a possible association between p16 expression and tumorigenesis of these lesions.

Angiosarcoma of scalp: a case report.

Cutaneous angiosarcomas are rare and constitute less than 1% of all malignant mesenchymal tumours. Most angiosarcomas of skin arise in the following clinical settings: 1. face and scalp of elderly 2. following lymphoedema and 3. post radiation. We present a case of an elderly man presenting with scalp lesion of 18 months duration. Histological examination of the biopsy revealed features of an angiosarcoma, which showed imunohistochemical positivity for factor VIII related antigen.

Tetraspanin CD9 induces MMP-2 expression by activating p38 MAPK, JNK and c-Jun pathways in human melanoma cells

Expression of matrix metalloproteinase-2 and -9 (MMP-2 and MMP-9), which correlates with tumor invasion and metastasis, has been known to be regulated by several intracellular signaling pathways. Since the CD9 membrane protein has been implicated in signal transduction and malignant progression of cancer cells, we examined the functional involvement of CD9 in the regulation of MMP-2 and MMP-9 expression by using stable CD9 transfectant clones of MelJuso human melanoma cells. The CD9 cDNA-transfected cells with elevated CD9 expression displayed increased MMP-2 and decreased MMP-9 expression when compared with the mock transfectant cells. Among several signal pathway inhibitors tested, SB203580 and SP600125, which inhibit p38 MAPK and JNK respectively, completely blocked the CD9-stimulated MMP-2 expression. Phosphorylation levels of p38 MAPK and c-Jun in MelJuso cells were also significantly increased by CD9 transfection. In addition, the down-regulation of p38 MAPK and JNK by siRNA transfection resulted in a decrease in MMP-2 expression by MelJuso cells. Promoter analysis and gel shift assay showed that the CD9-induced MMP-2 expression is mediated by a functional AP-1 site through interactions with AP-1 transcription factors including c-Jun. These results suggest that CD9 induces MMP-2 expression by activating c- Jun through p38 MAPK and JNK signaling pathways in human melanoma cells.

Nucleolar organizer regions (NORs) in simple and proliferating trichilemmal cysts (pilar cysts and pilar tumors).

Simple trichilemmal cysts or pilar cysts and pilar tumors are relatively rare entities often under-reported by pathologists. The pilar cysts are thought to proliferate and progress to pilar tumors. These pilar tumors can further undergo malignant change. We analyzed 25 pilar cysts and eight pilar tumors, including three with atypia and one malignant pilar tumor, with a view to study the above progression and assess the degree of cell proliferation using the Nucleolar Organizer Regions (AgNORs). There was a progressive increase in the AgNOR count from one dot per nucleus in pilar cysts to 1.5-2 in benign pilar tumors. AgNORs in pilar tumors with atypia (2.8) was more than the benign pilar tumors but were definitely less than the malignant pilar tumors (3.5). The malignant pilar tumor showed bizarre AgNORs and cells with as many as eight to nine AgNORs. Thus AgNOR counts suggested that there is a progressive increase in the degree of cell proliferation and thereby the AgNOR staining from pilar cysts to pilar tumors. This AgNOR staining could also be used to assess the cell proliferation in case of pilar tumors with atypia where it is difficult to rule out malignancy.

Expression of CD40 and Fas Ligand in Bowen's Disease, Squamous Cell Carcinoma and Basal Cell Carcinoma

Impaired regulation of apoptosis is known to be associated with the development of various cancers, and Fas/Fas-ligand (FasL) is known to play an important role in apoptosis. CD40 is a cell surface receptor, which when ligated modulates apoptosis in some cell types. The expressions of CD40 and FasL were examined in 10 normal skins, 7 Bowen's disease skins, 10 squamous cell carcinomas (SCCs) and 12 basal cell carcinomas (BCCs) immunohistochemically. In the normal epidermis, CD40 was more highly expressed in the keratinocytes of the squamous cell and granular layers than in those of the basal layer, and FasL expression was observed in the cell membrane of keratinocytes at the basal and squamous cell layers. CD40 expression was significantly higher in SCCs than in normal or Bowen's disease skin, while FasL expression was significantly higher in Bowen's disease than in SCCs. BCCs expressed the lowest levels of CD40 and FasL. These results suggest that altered CD40 and FasL expression may be related with the progression of SCC, and the marked reduced expression of CD40 and FasL may explain the biologic behavior of BCCs.

Biología molecular y mocrometástasis del melanoma cutáneo / Molecular biology and micrometastasis in cutaneous melanoma

Las controversias en el manejo de la enfermedad ganglionar ha permanecido en discusión desde hace 20 años. Los recientes avances tecnológicos en biología molecular y las nuevas técnicas quirúrgicas mediante la detección del ganglio centinela han permitido identificar con mayor precisión un grupo seleccionado de pacientes que se habrán de beneficiar en el control local de la enfermedad y en la supervivencia, al efectuarse disecciones ganglionares de manera electiva ante la presencia de metástasis ganglionar microscópica y con la administración de terapias sistémicas ante la detección temprana de micrometástasis a distancia. Mediante el empleo de los marcadores de membrana de las células con melanoma, el uso de anticuerpos monoclonales nos permiten identificar el fenotipo de las lesiones melanocíticas, que pueden ser empleadas en inmunohistopatología e inmunocentellografía. Finalmente, el advenimiento de las técnicas de transcriptasa reversa, aunado a las de la reacción en cadena de polimerasa, ha permitido una mayor sensibilidad en la detección de la enfermedad micrometastásica, modificándose de manera significativa y haciendo má precisa la estadificación de los pacientes con melanoma. El empleo de estas técnicas es factible en nuestro medio por su costo y sencillez. Con base en ellas es posible diagnosticar micrometástasis en aproximadamente el 33 por ciento de pacientes clasificados en estadio I (lesiones < 0.76 mm), en quienes no se identificarían metástasis ganlgionares mediante técnicas de hematoxilina eosina. El 50 por ciento de estos enfermos podrían recibir una terapia locorregional más agresiva con el consecuente beneficio en la supervivencia. Sin embargo, en la actualidad, estas técnicas únicamente son empleadas de manera rutinaria en estudios protocolizados