RESUMO
Serous tubal intraepithelial carcinoma (STIC) is regarded as the origin of most high-grade serous carcinomas (HGSC). After a diagnosis of isolated STIC, risk of developing HGSC is substantial. Since surveillance cannot detect HGSC in time to cure the disease, there is no consensus on the optimal treatment after a diagnosis of isolated STIC, but chemotherapy is considered one of the possible strategies. In this case report, we describe 2 women with advanced-stage HGSC treated with 3 cycles of neoadjuvant chemotherapy followed by interval debulking surgery. In both women, histopathological examination showed a complete histopathological tumor response, but a vital STIC was found in both cases. The 2 cases presented here indicate that STICs may not respond to chemotherapy. Further research focused on the underlying biology and chemosensitivity of STIC, as well as the effectiveness of treatment to prevent HGSC in case of isolated STIC, is needed.
RESUMO
OBJECTIVE: The pathogenesis of serous ovarian carcinoma (SOC) is still unknown. Recently, endometrial intraepithelial carcinoma (EIC) was proposed to be the precursor lesion of SOC. This study examines the model of EIC as precursor for SOC. METHODS: Cases of SOC with a noninvasive or superficially invasive serous lesion, a hyperplastic lesion with/without atypia, or EIC in the endometrium were selected for inclusion in this study. Tissue sections from both ovaries, the fallopian tubes, and the uterus were extensively reviewed by an expert gynecopathologist. For both EIC and SOC, immunostaining for p53, Ki-67, estrogen receptor, and progesterone receptor; TP53 mutation analysis; and in situ ploidy analysis were performed. RESULTS: Nine cases of SOC with concurrent EIC in the endometrium were identified. Immunostaining for p53, Ki-67, estrogen receptor, and progesterone receptor revealed almost identical expression patterns and similar intensities in each pair of EIC and coincident SOC. Identical TP53 mutations were found in SOC and coinciding EIC in 33% of the cases, suggesting a clonal origin. DNA ploidy analysis, as a marker for neoplastic progression, demonstrated an increased number of aneuploid nuclei in SOC compared to their corresponding EIC (P = 0.039). In addition, the mean amount of DNA per nucleus in SOC was higher (ie, more aneuploid) compared to EIC (P = 0.039). CONCLUSION: This study provides a first indication of EIC as possible precursor lesion for SOC. This finding could have major clinical implications for future ovarian cancer management and underscores EIC as a possible target for early SOC detection and prevention.
Assuntos
Carcinoma in Situ/patologia , Cistadenocarcinoma Seroso/patologia , Neoplasias do Endométrio/patologia , Neoplasias Primárias Múltiplas/patologia , Neoplasias Ovarianas/patologia , Lesões Pré-Cancerosas/patologia , Idoso , Idoso de 80 Anos ou mais , Carcinoma in Situ/diagnóstico , Carcinoma in Situ/genética , Carcinoma in Situ/metabolismo , Estudos de Coortes , Cistadenocarcinoma Seroso/diagnóstico , Cistadenocarcinoma Seroso/genética , Cistadenocarcinoma Seroso/metabolismo , Análise Mutacional de DNA , Neoplasias do Endométrio/diagnóstico , Neoplasias do Endométrio/genética , Neoplasias do Endométrio/metabolismo , Feminino , Genes p53 , Humanos , Imuno-Histoquímica , Pessoa de Meia-Idade , Neoplasias Primárias Múltiplas/diagnóstico , Neoplasias Primárias Múltiplas/genética , Neoplasias Primárias Múltiplas/metabolismo , Neoplasias Ovarianas/diagnóstico , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/metabolismo , Ploidias , Lesões Pré-Cancerosas/diagnóstico , Lesões Pré-Cancerosas/genética , Lesões Pré-Cancerosas/metabolismoRESUMO
INTRODUCTION AND HYPOTHESIS: Pelvic organ prolapse (POP) and other disorders, such as varicose veins and joint hypermobility, have been associated with changes in collagen strength and metabolism. We hypothesized that these various disorders were more prevalent in both POP patients and their family members. METHODS: In this study, the prevalence of various collagen-associated disorders, including POP, was compared between POP patients (n = 110) and control patients (n = 100) and their first and second degree family members. RESULTS: POP patients reported a higher prevalence of varicose veins, joint hypermobility and rectal prolapse and were more likely to have family members with POP as compared to the control group (p < 0.01). In contrast, the family members of the POP group did not report a higher prevalence of collagen-associated disorders compared to the family members of the control group (p = 0.82). CONCLUSIONS: POP and other collagen-associated disorders may have a common aetiology, originating at the molecular level of the collagens.
Assuntos
Instabilidade Articular/epidemiologia , Prolapso de Órgão Pélvico/epidemiologia , Varizes/epidemiologia , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Estudos de Coortes , Doenças do Colágeno/epidemiologia , Comorbidade , Feminino , Humanos , Pessoa de Meia-Idade , Países Baixos/epidemiologia , PrevalênciaRESUMO
Lichen sclerosus is considered to be the precursor lesion of vulvar squamous cell carcinoma, of which only 2-5% progress to squamous cell carcinoma. Differentiated vulvar intraepithelial neoplasia (VIN) has been proposed to be the direct precursor lesion, but this is a recently recognized, and a difficult to diagnose, entity, which may easily be mistaken for a benign dermatosis. The aim of this study was to test the hypothesis that of all lesions that have been diagnosed as lichen sclerosus in the past, a part might currently be diagnosed as differentiated VIN, and to identify histopathological differences between lichen sclerosus lesions with and without progression to vulvar squamous cell carcinoma. All lichen sclerosus slides were revised by two expert gynecopathologists and histopathological characteristics were documented. After revision of lichen sclerosus biopsies without progression (n = 61), 58 were reclassified as lichen sclerosus. Revision of lichen sclerosus biopsies with progression yielded concordant diagnoses in 18 of 60 cases (30%). Of 60 lesions, 25 (42%) were reclassified as differentiated VIN. The median time from differentiated VIN to vulvar squamous cell carcinoma was shorter (28 months) than that from lichen sclerosus to vulvar squamous cell carcinoma (84 months) (P < 0.001). Lichen sclerosus that progressed to squamous cell carcinoma, but did not meet the criteria for differentiated VIN, more often showed parakeratosis (P = 0.004), dyskeratosis (P < 0.001), hyperplasia (P = 0.048) and basal cellular atypia (P = 0.009) compared with lichen sclerosus without progression. In conclusion, differentiated VIN diagnosis has been frequently missed and is associated with rapid progression to squamous cell carcinoma. Patients with lichen sclerosus with dyskeratosis and parakeratosis, hyperplasia and/or basal cellular atypia should be kept under close surveillance as these lesions also tend to progress to squamous cell carcinoma.
Assuntos
Carcinoma in Situ/patologia , Carcinoma de Células Escamosas/patologia , Progressão da Doença , Vulva/patologia , Líquen Escleroso Vulvar/patologia , Neoplasias Vulvares/patologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Pessoa de Meia-IdadeRESUMO
AIMS: The aetiology of vulvar squamous cell carcinomas (SCC) that are not causally associated with high-risk human papillomavirus remains largely elusive. The aim of this study was to analyse the inflammatory response in its presumed precursor lesions, lichen sclerosus (LS) and differentiated vulvar intraepithelial neoplasia (dVIN), and provide evidence that dVIN is a likely precursor of vulvar SCC. METHODS AND RESULTS: Immunohistochemical analyses for CD4+, CD8+, CD20+, CD68+, S100+ and tryptase-positive immune cells were performed and quantified in LS (n = 7), dVIN (n = 19), SCC (n = 11), and normal vulvar tissue (n = 8). The subepithelial inflammatory response in dVIN and SCC was comparable, but absent in LS. Abundant intraepithelial mast cells were observed in dVIN only, and confirmed by electron microscopy, toluidine blue staining and cKIT expression. Adjacent keratinocytes displayed increased proliferation as determined by MIB-1 positivity. Electron microscopy revealed intraepithelial mast cell degranulation. Intraepithelial mast cells were not or infrequently observed in vulvar hyperplasia (n = 13), condylomata acuminata (n = 5), keratinocytic intraepidermal neoplasia of sun-exposed skin (n = 15), epidermal hyperplasia of head and neck (n = 12), and psoriasis (n = 3). CONCLUSIONS: These data indicate that dVIN can be recognized by intraepithelial mast cells and that they might promote the progression of dVIN to SCC.
Assuntos
Carcinoma de Células Escamosas/imunologia , Mastócitos/citologia , Lesões Pré-Cancerosas/imunologia , Neoplasias Vulvares/imunologia , Biomarcadores Tumorais/metabolismo , Carcinoma de Células Escamosas/patologia , Diferenciação Celular , Progressão da Doença , Feminino , Humanos , Imuno-Histoquímica , Mastócitos/imunologia , Mastócitos/ultraestrutura , Lesões Pré-Cancerosas/patologia , Lesões Pré-Cancerosas/ultraestrutura , Neoplasias Vulvares/patologia , Neoplasias Vulvares/ultraestruturaRESUMO
OBJECTIVE: The objective of the study was to quantify vessel type and density in lichen sclerosus (LS) to find a marker for its malignant potential. STUDY DESIGN: Quantitative analysis was performed on paraffin-embedded tissue samples of 28 patients with LS (7 adjacent to vulvar squamous cell carcinoma, 21 solitary) and immunohistochemical staining for CD34 (vascular and lymphangiogenic lymph endothelial cells), D2-40 (lymphatic-specific marker), and alpha-SMA (pericyte marker). Electron microscopy was performed on fresh tissue. RESULTS: No significant differences in vessel density or other vessel parameters could be demonstrated between the 2 groups. In hyalinized lesions, vessel diameter, and alpha-SMA positivity was reduced compared with nonhyalinized lesions. Electron microscopy revealed detachment of pericytes from vascular endothelial cells and increased thickening of basement membrane, whereas endothelial cell function did not appear strongly impaired. CONCLUSION: Malignant potential of LS cannot be predicted by vessel characteristics. Hyalinization in LS is associated with pericyte detachment from the basal lamina of vascular endothelial cells.
Assuntos
Carcinoma de Células Escamosas/patologia , Lesões Pré-Cancerosas/patologia , Líquen Escleroso Vulvar/patologia , Neoplasias Vulvares/patologia , Biópsia por Agulha , Vasos Sanguíneos/patologia , Transformação Celular Neoplásica/patologia , Feminino , Humanos , Imuno-Histoquímica , Vasos Linfáticos/patologia , Microscopia Eletrônica , Inclusão em Parafina , Probabilidade , Prognóstico , Estatísticas não Paramétricas , Vulva/patologia , Vulva/ultraestruturaRESUMO
Tumors are complex tissues composed of neoplastic cells, soluble and insoluble matrix components and stromal cells. Here we report that in melanoma, turn-over of type I collagen (Col(I)), the predominant matrix protein in dermal stroma affects melanoma progression. Fibroblasts juxtaposed to melanoma cell nests within the papillary dermis display high levels of Col(I) mRNA expression. These nests are enveloped by collagen fibers. In contrast, melanoma-associated fibroblasts within the reticular dermis express Col(I) mRNA at a level that is comparable to its expression in uninvolved dermis and reduced amount of collagen protein can be observed. To determine the significance of Col(I) expression in melanoma, we pharmacologically inhibited its transcription in a porcine cutaneous melanoma model by oral administration of halofuginone. When administered before melanoma development, it reduced melanoma incidence and diminished the transition from microinvasive toward deeply invasive growth by limiting the development of a tumor vasculature. Whereas invasive melanoma growth has been correlated with increased blood vessel density previously, our data for the first time demonstrate that the proangiogenic effect of Col(I) expression by fibroblasts and vascular cells precedes the development of invasive melanomas in a de novo tumor model.
Assuntos
Colágeno Tipo I/metabolismo , Melanoma/metabolismo , Invasividade Neoplásica , Neovascularização Patológica/metabolismo , Neoplasias Cutâneas/metabolismo , Inibidores da Angiogênese/farmacologia , Animais , Colágeno Tipo I/efeitos dos fármacos , Humanos , Imuno-Histoquímica , Hibridização In Situ , Melanoma/irrigação sanguínea , Melanoma/patologia , Invasividade Neoplásica/fisiopatologia , Piperidinas/farmacologia , Quinazolinonas/farmacologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Neoplasias Cutâneas/irrigação sanguínea , Neoplasias Cutâneas/patologia , Suínos , Porco MiniaturaRESUMO
Oxidative phosphorylation in the mitochondria is an important energy-producing process for eukaryotic cells, but this process can also result in producing potentially cell-damaging side products. Oxygen is the final proton acceptor in this cascade of electron/proton transfer and results in harmless water. The electron transfer, however, is not completely efficient and results in the production of reactive oxygen species (ROS). Low amounts of these ROS are important for cellular-signalling pathways. Excessive ROS, however, can induce cell damage that can culminate in cell death. Therefore, the cell has developed an antioxidant network to scavenge excessively produced ROS. In general, the balance between the production and scavenging of ROS leads to homeostasis. Disturbance of this equilibrium can alter normal cellular processes; it often occurs in tumour cells. In this review, the role of ROS in cutaneous melanoma development and progression is described. Cutaneous melanoma arises from epidermal melanocytes in skin, which is a relatively hypoxic tissue. ROS are generated as a result of increased metabolism of transformed cells, immune reaction against the developing tumour, ultraviolet radiation, melanin production and an altered antioxidant system. Knowledge of the role of ROS in melanoma development and the mechanisms that alleviate oxidative stress can aid in the development of better antimelanoma therapies.
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Antioxidantes/metabolismo , Melaninas/biossíntese , Melanoma/tratamento farmacológico , Melanoma/metabolismo , Mitocôndrias/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Neoplasias Cutâneas/metabolismo , Animais , Transporte de Elétrons , Humanos , Melanoma/imunologia , Melanoma/secundário , Oxirredução , Fosforilação Oxidativa , Estresse Oxidativo , Transdução de Sinais , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/imunologiaAssuntos
Carcinoma in Situ/patologia , Carcinoma de Células Escamosas/patologia , Neoplasias Vulvares/patologia , Carcinoma in Situ/epidemiologia , Carcinoma de Células Escamosas/epidemiologia , Diferenciação Celular , Progressão da Doença , Feminino , Humanos , Incidência , Lesões Pré-Cancerosas/epidemiologia , Lesões Pré-Cancerosas/patologia , Fatores de Risco , Neoplasias Vulvares/epidemiologiaRESUMO
Loss of the tumour suppressor PTEN is frequent in human melanoma, results in MAPK activation, suppresses senescence and mediates metastatic behaviour. How PTEN loss mediates these effects is unknown. Here we show that loss of PTEN in epithelial and melanocytic cell lines induces the nuclear localization and transcriptional activation of ß-catenin independent of the PI3K-AKT-GSK3ß axis. The absence of PTEN leads to caveolin-1 (CAV1)-dependent ß-catenin transcriptional modulation in vitro, cooperates with NRAS(Q61K) to initiate melanomagenesis in vivo and induces efficient metastasis formation associated with E-cadherin internalization. The CAV1-ß-catenin axis is mediated by a feedback loop in which ß-catenin represses transcription of miR-199a-5p and miR-203, which suppress the levels of CAV1 mRNA in melanoma cells. These data reveal a mechanism by which loss of PTEN increases CAV1-mediated dissociation of ß-catenin from membranous E-cadherin, which may promote senescence bypass and metastasis.
Assuntos
Caderinas/metabolismo , Caveolina 1/genética , Melanócitos/metabolismo , Melanoma/genética , PTEN Fosfo-Hidrolase/genética , Neoplasias Cutâneas/genética , Ativação Transcricional/genética , beta Catenina/metabolismo , Animais , Western Blotting , Linhagem Celular Tumoral , Retroalimentação Fisiológica , GTP Fosfo-Hidrolases/genética , Quinase 3 da Glicogênio Sintase/metabolismo , Glicogênio Sintase Quinase 3 beta , Humanos , Imuno-Histoquímica , Melanoma/metabolismo , Proteínas de Membrana/genética , Camundongos , Camundongos Transgênicos , MicroRNAs , Microscopia de Fluorescência , Fosfatidilinositol 3-Quinases/metabolismo , Prognóstico , Proteínas Proto-Oncogênicas c-akt/metabolismo , Neoplasias Cutâneas/metabolismoRESUMO
Evolution of neoplastic cells has generally been regarded as a cumulative intrinsic process resulting in altered cell characteristics enabling enhanced growth properties, evasion of apoptotic signals, unlimited replicative potential and gain of properties enabling the ability to thrive in ectopic tissues and in some cases, ability to metastasize. Recently however, the role of the neoplastic microenvironment has become appreciated largely due to the realization that tumors are not merely masses of neoplastic cells, but instead, are complex tissues composed of both a non-cellular (matrix proteins) and a cellular 'diploid' component (tumor-associated fibroblasts, capillary-associated cells and inflammatory cells), in addition to the ever-evolving neoplastic cells. With these realizations, it has become evident that early and persistent inflammatory responses observed in or around many solid tumors, play important roles in establishing an environment suitable for neoplastic progression by providing diverse factors that alter tissue homeostasis. Using cutaneous melanoma and squamous cell carcinoma as tumor models, we review the current literature focussing on inflammatory and tumor-associated fibroblast responses as critical mediators of neoplastic progression for these malignancies.
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Carcinoma de Células Escamosas/patologia , Colágeno/metabolismo , Proteínas da Matriz Extracelular/metabolismo , Melanoma/patologia , Neoplasias Cutâneas/patologia , Células Estromais/citologia , Animais , Carcinoma de Células Escamosas/irrigação sanguínea , Carcinoma de Células Escamosas/metabolismo , Citocinas/metabolismo , Humanos , Melanoma/irrigação sanguínea , Melanoma/metabolismo , Neovascularização Patológica/metabolismo , Neoplasias Cutâneas/irrigação sanguínea , Neoplasias Cutâneas/metabolismo , Células Estromais/metabolismoRESUMO
Progression of human cutaneous primary melanoma is, among others, accompanied by de novo expression of activated leukocyte cell adhesion molecule (ALCAM/CD166) and enhanced activity of proteolytic cascades in the invasive, vertical growth phase (VGP) of lesions. The homophilic cell adhesion function of wild-type ALCAM mediates homotypic clustering of melanoma cells and would, thus, antagonize cell release from the primary tumor, an early prerequisite for metastasis. Stable transfection of a transmembrane, amino-terminally truncated ALCAM (DeltaN-ALCAM) into metastatic cells diminished cell clustering mediated by wild-type ALCAM. We have addressed the biological effects of DeltaN-ALCAM on tumorigenicity and found that the relief of cell clustering constraints promoted motility in vitro and the transition from expansive tumor growth to tissue invasion in reconstructed skin in culture. In a transplant tumor model, the changes were reflected in reduced subcutaneous tumor growth and in accelerated, spontaneous lung metastasis. These data indicate that the intact cell adhesion function of ALCAM may both favor primary tumor growth and represent a rate-limiting step for tissue invasion from VGP melanoma. ALCAM induction could, thus, provide an attractive target for proteolysis as a part of a more complex cellular program that couples growth and migration and facilitates dissemination.
Assuntos
Molécula de Adesão de Leucócito Ativado/metabolismo , Melanoma/metabolismo , Neoplasias Cutâneas/metabolismo , Molécula de Adesão de Leucócito Ativado/genética , Animais , Adesão Celular , Linhagem Celular Tumoral , Feminino , Humanos , Neoplasias Pulmonares/secundário , Melanoma/fisiopatologia , Melanoma/secundário , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Transplante de Neoplasias , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/fisiopatologia , Transfecção , Transplante HeterólogoRESUMO
Activated leukocyte cell adhesion molecule (ALCAM/CD166) is a progression marker of a variety of cancers, including melanoma, and is a marker for mesenchymal stem cells. ALCAM expression triggers matrix metalloproteinase activity and correlates with the transition between superficial melanoma growth and deep dermal invasion in vivo. We previously showed that manipulating ALCAM functionality could both decrease and increase melanoma invasion, depending on the manner by which ALCAM function was altered. How ALCAM exerts these opposing invasive phenotypes remained elusive. In the present study, we analyzed differences in melanoma cell gene expression in two- and three-dimensional cultures as function of ALCAM-mediated adhesion. We identified a cluster of genes highly responsive to ALCAM functionality and relevant for melanoma invasion. This cluster is characterized by known invasion-related genes similar to L1 neuronal cell adhesion molecule and showed a remarkable induction of several innate immune genes. Unexpectedly, we identified major variations in the expression of genes related to an immunological response when modulating ALCAM function, including complement factors C1r and C1s. The expression and function of these proteinases were confirmed in protein assays and in vivo. Together, our results demonstrate a link between ALCAM functionality and the immune transcriptome, and support the assumption that ALCAM-ALCAM interactions could function as a cell signaling complex to promote melanoma tumor invasion.
Assuntos
Molécula de Adesão de Leucócito Ativado/metabolismo , Imunidade Inata/genética , Melanoma/genética , Invasividade Neoplásica/genética , Metástase Neoplásica/genética , Neoplasias Cutâneas/genética , Molécula de Adesão de Leucócito Ativado/genética , Adesão Celular , Contagem de Células , Complemento C1r/metabolismo , Complemento C1s/metabolismo , Perfilação da Expressão Gênica , Humanos , Melanoma/imunologia , Melanoma/metabolismo , Análise em Microsséries , Fenótipo , RNA Mensageiro/metabolismo , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/metabolismo , Células Tumorais Cultivadas , Regulação para CimaRESUMO
Melanoma progression is a multistep progression from a common melanocytic nevus through the radial growth phase, the invasive vertical growth phase finally leading to metastatic spread into distant organs. Migration and invasion of tumor cells requires secretion of proteases to facilitate remodeling of the extracellular matrix including basement membranes. Here we used a reconstructed skin model to investigate melanoma growth and invasion in vitro. Using this model we show that the dermoepidermal basement membrane prevents the invasion of metastatic melanoma BLM and MV3 cells in the absence of a stratified epidermis. In the reconstructed skin model, matrix metalloproteinase-9, a protease activated early in melanoma development, is secreted by the keratinocytes and subsequently activated by an unknown soluble factor secreted by the melanoma cells. The dynamic interplay between keratinocytes and melanoma cells is further shown by an altered growth pattern of melanoma cells and the finding that a reconstructed epidermis induces invasion. Overall, our findings show that the invasive behavior of melanoma cells is determined by the melanoma cells themselves, but that the interplay between surrounding keratinocytes and the melanoma cells plays an important role in melanoma invasion.
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Queratinócitos/fisiologia , Melanoma/patologia , Neoplasias Cutâneas/patologia , Pele , Comunicação Celular/fisiologia , Proliferação de Células , Células Cultivadas , Humanos , Queratinócitos/patologia , Modelos Biológicos , Invasividade Neoplásica , Metástase Neoplásica , Técnicas de Cultura de Órgãos/métodos , Pele/patologia , Fenômenos Fisiológicos da Pele , Engenharia Tecidual/métodos , Alicerces TeciduaisRESUMO
Adhesion molecules endow tumor cells with the necessary cell-cell contacts and cell-matrix interactions. As such, adhesion molecules are involved in cell signalling, proliferation and tumor growth. Rearrangements in the adhesion repertoire allow tumor cells to migrate, invade and form metastases. Besides these membrane-bound adhesion molecules several soluble adhesion molecules are detected in the supernatant of tumor cell lines and patient body fluids. Truncated soluble adhesion molecules can be generated by several conventional mechanisms, including alternative splicing of mRNA transcripts, chromosomal translocation, and extracellular proteolytic ectodomain shedding. Secretion of vesicles (ectosomes and exosomes) is an alternative mechanism mediating the release of full-length adhesion molecules. Soluble adhesion molecules function as modulators of cell adhesion, induce proteolytic activity and facilitate cell signalling. Additionally, adhesion molecules present on secreted vesicles might be involved in the vesicle-target cell interaction. Based on currently available data, released soluble adhesion molecules contribute to cancer progression and therefore should not be regarded as unrelated and non-functional side products of tumor progression.
Assuntos
Moléculas de Adesão Celular/metabolismo , Neoplasias/metabolismo , Adesão Celular/fisiologia , Comunicação Celular/fisiologia , Movimento Celular/fisiologia , Progressão da Doença , Humanos , Neoplasias/patologiaRESUMO
Intratumoral hypoxia has been associated with poor prognosis in several solid tumors. The aim of this study was to determine whether the hypoxia-associated markers glucose transporter (GLUT)-1 and carbonic anhydrase (CA)-IX expression and preoperative hemoglobin (Hb) levels correlate with presence of inguinofemoral or distant metastases, and disease-free survival (DSS) in vulvar squamous cell carcinoma (SCC) patients. Vulvar SCC (n=103) were reviewed for histopathological characteristics by an expert gynecopathologist and stained for GLUT-1 and CA-IX. Clinical data and preoperative Hb levels were obtained from medical records. No significant correlations were observed between GLUT-1 or CA-IX expression patterns and preoperative Hb levels, presence of inguinofemoral or distant metastases and DSS. However, anemic patients (Hb<11.2 g/dL) had significantly more inguinofemoral metastases and lower Hb level was an independent prognostic factor for a worse DSS (p<0.001). The number of comorbidic conditions was inversely correlated with preoperative Hb level. Preoperative Hb levels are associated with poor DSS for vulvar SCC patients, whereas tumor hypoxia reflected by GLUT-1 and CA-IX expression does not have a predictive value. Because preoperative Hb levels inversely correlated with the number of comorbidic conditions and not with GLUT-1 or CA-IX expression, it is most likely that preoperative Hb levels represent overall physical condition.
Assuntos
Antígenos de Neoplasias/metabolismo , Anidrases Carbônicas/metabolismo , Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas/metabolismo , Transportador de Glucose Tipo 1/metabolismo , Hemoglobinas/metabolismo , Neoplasias Vulvares/diagnóstico , Neoplasias Vulvares/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/metabolismo , Anidrase Carbônica IX , Carcinoma de Células Escamosas/patologia , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Valor Preditivo dos Testes , Prognóstico , Estudos Retrospectivos , Neoplasias Vulvares/patologiaRESUMO
The molecular pathogenesis of human papilloma virus-unrelated vulvar squamous cell carcinoma is not well known. Whether malignant progression of lichen sclerosus and differentiated vulvar intraepithelial neoplasia to vulvar squamous cell carcinoma could be accompanied by altered DNA content has not been studied extensively. DNA content in isolated nuclei of microdissected normal vulvar epithelium (n = 2), lichen sclerosus (n = 9), differentiated vulvar intraepithelial neoplasia (n = 13), and squamous cell carcinoma (n = 17) from 22 patients was measured via DNA image cytometry. For additional analysis, 6 differentiated vulvar intraepithelial neoplasia lesions were selected, bringing the number of patients to 28. p53 expression was determined by immunohistochemistry on consecutive tissue sections. Thirty-eight percent (5/13) of differentiated vulvar intraepithelial neoplasia lesions and 65% (11/17) of squamous cell carcinomas were DNA aneuploid or tetraploid. In lesions that contained differentiated vulvar intraepithelial neoplasia and adjacent squamous cell carcinoma, the ploidy status of differentiated vulvar intraepithelial neoplasia did not exceed that of squamous cell carcinoma. We observed a strong correlation between high p53 expression and DNA aneuploidy. This relation was also present at the level of a single nucleus, measured by sequential image cytometry of p53 immunohistochemistry followed by DNA image cytometry on formalin-fixed tissue sections. Similarly, we found p53-positive nonproliferating cells with increased DNA content in the superficial compartment of 6 additional solitary differentiated vulvar intraepithelial neoplasia lesions that were not associated with squamous cell carcinoma, indicating ascending aneuploid cells from the basal compartment. DNA ploidy measurements suggest that differentiated vulvar intraepithelial neoplasia has a higher malignant potential than lichen sclerosus and thus is a more likely precursor of squamous cell carcinoma. Furthermore, high p53 expression correlates with increased DNA content and aneuploidy; but it requires further research to unveil a possible causal relation.
Assuntos
Aneuploidia , Carcinoma in Situ/metabolismo , Carcinoma de Células Escamosas/metabolismo , DNA/genética , Lesões Pré-Cancerosas/metabolismo , Proteína Supressora de Tumor p53/biossíntese , Neoplasias Vulvares/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma in Situ/genética , Carcinoma in Situ/patologia , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patologia , Proliferação de Células , DNA de Neoplasias/genética , Epitélio/metabolismo , Epitélio/patologia , Feminino , Humanos , Pessoa de Meia-Idade , Lesões Pré-Cancerosas/genética , Lesões Pré-Cancerosas/patologia , Vulva/metabolismo , Vulva/patologia , Líquen Escleroso Vulvar/genética , Líquen Escleroso Vulvar/metabolismo , Líquen Escleroso Vulvar/patologia , Neoplasias Vulvares/genética , Neoplasias Vulvares/patologiaRESUMO
OBJECTIVE: The purpose of the present study is to investigate the trends in incidence of both usual (u) and differentiated (d) vulvar intraepithelial neoplasia (VIN) separately, their malignant potential and the relation with other HPV related anogenital lesions in the Netherlands during a 14-year-period. METHODS: The incidences of both types of VIN and vulvar SCC were retrieved from the Nationwide Netherlands Database of Histo- and Cytopathology. Population data were retrieved from the Database of Statistics Netherlands. RESULTS: In the study period, the incidence of uVIN and dVIN increased, while the incidence of vulvar SCC remained stable. The overall percentage of uVIN patients that were later diagnosed with vulvar SCC was 5.7%, which was significantly lower than the percentage for dVIN patients (32.8%). In addition to this 5.6-fold increased conversion rate, the time of progression from dVIN to SCC development was significantly shorter than that of uVIN (p=0.005). Percentage of uVIN patients that were later diagnosed with SCC significantly increased with age (p=0.005), whereas the time to SCC significantly shortened with age (p=0.05). Forty-one percent of uVIN patients had a past, concomitant or future HPV-associated lesion of the lower genital tract, which is in contrast to the 3% for dVIN patients. CONCLUSIONS: An increase in diagnoses of both uVIN and dVIN has not led to an increase in vulvar SCC incidence. The malignant potential of dVIN is higher than that for uVIN. For uVIN the malignant potential increases with age.
Assuntos
Carcinoma in Situ/epidemiologia , Carcinoma de Células Escamosas/epidemiologia , Neoplasias Vulvares/epidemiologia , Adulto , Distribuição por Idade , Idoso , Carcinoma in Situ/diagnóstico , Bases de Dados Factuais , Progressão da Doença , Feminino , Neoplasias dos Genitais Femininos/epidemiologia , Neoplasias dos Genitais Femininos/virologia , Humanos , Incidência , Pessoa de Meia-Idade , Países Baixos/epidemiologia , Infecções por Papillomavirus/complicações , Infecções por Papillomavirus/epidemiologia , Fatores de Tempo , Neoplasias Vulvares/diagnósticoRESUMO
PURPOSE: High-risk human papilloma virus (HPV) plays a role in the development of a subset of vulvar squamous cell carcinomas. Uncertainty exists about the true impact of HPV in this tumor type because conflicting reports have been published with diverging prevalence rates. This study was done to fine tune the role of high-risk HPV infection in vulvar squamous cell carcinoma development in relation to clinical prognosis. EXPERIMENTAL DESIGN: 130 vulvar squamous cell carcinomas of patients with known survival data were analyzed for histology of the adjacent lesion (differentiated or HPV-associated usual vulvar intraepithelial neoplasia), in relation to p16(INK4A) expression as marker of HPV activity, and presence and integration of high-risk HPV DNA. RESULTS: Usual vulvar intraepithelial neoplasia was present adjacent to vulvar squamous cell carcinoma in 25 of 130 cases. Usual vulvar intraepithelial neoplasia-associated squamous cell carcinomas had high p16(INK4A) expression, and 24 of 25 squamous cell carcinomas contained integrated high-risk HPV DNA. Differentiated vulvar intraepithelial neoplasia was found adjacent to 105 of 130 vulvar squamous cell carcinomas. High-risk HPV was detected in 11 (10.5%) differentiated vulvar intraepithelial neoplasia-associated vulvar squamous cell carcinoma but correlated with high p16(INK4A) expression in only one case. Integration of viral DNA was never observed in differentiated vulvar intraepithelial neoplasia-associated squamous cell carcinomas, which suggests that a causal relationship of high-risk HPV in differentiated vulvar intraepithelial neoplasia-associated tumors is highly unlikely. The disease-specific survival of the differentiated vulvar intraepithelial neoplasia-associated vulvar squamous cell carcinoma patients was significantly worse compared with patients with a usual vulvar intraepithelial neoplasia-associated tumor. CONCLUSIONS: High-risk HPV is causally associated with the development of usual vulvar intraepithelial neoplasia associated squamous cell carcinomas, which comprise 19% of all vulvar squamous cell carcinomas, but not with differentiated vulvar intraepithelial neoplasia-associated vulvar squamous cell carcinomas. Differentiated vulvar intraepithelial neoplasia-associated vulvar squamous cell carcinomas have a significantly worse prognosis.
Assuntos
Carcinoma in Situ/virologia , Carcinoma de Células Escamosas/virologia , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , Papillomaviridae/patogenicidade , Infecções por Papillomavirus/complicações , Neoplasias Vulvares/virologia , Biomarcadores Tumorais/metabolismo , Carcinoma in Situ/metabolismo , Carcinoma in Situ/patologia , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Inibidor p16 de Quinase Dependente de Ciclina/genética , Feminino , Genótipo , Humanos , Países Baixos , Papillomaviridae/genética , Papillomaviridae/isolamento & purificação , Infecções por Papillomavirus/patologia , Reação em Cadeia da Polimerase , Lesões Pré-Cancerosas/complicações , Lesões Pré-Cancerosas/patologia , Prognóstico , Risco , Neoplasias Vulvares/metabolismo , Neoplasias Vulvares/patologiaRESUMO
Activated leukocyte cell adhesion molecule (ALCAM/CD166/MEMD), a marker of various cancers and mesenchymal stem cells, is involved in melanoma metastasis. We have exploited a secreted NH(2)-terminal fragment, sALCAM, to test the hypothesis that ALCAM coordinates tissue growth and cell migration. Overexpression of sALCAM in metastatic melanoma cells disturbed clustering of endogenous ALCAM and inhibited activation of matrix metalloproteinase-2 (MMP-2). Exposure of HT1080 fibrosarcoma cells to sALCAM similarly inhibited MMP-2, suggesting a broader effect on ALCAM-positive tumor cells. In contrast to the previously reported, promotive effects of an NH(2)-terminally truncated, transmembrane variant (DeltaN-ALCAM), sALCAM impaired the migratory capacity of transfected cells in vitro, reduced basement membrane penetration in reconstituted human skin equivalents, and diminished metastatic capacity in nude mice. Remarkably, L1 neuronal cell adhesion molecule (L1CAM/CD171), another progression marker of several cancers including melanoma, was suppressed upon sALCAM overexpression but was up-regulated by DeltaN-ALCAM. The partially overlapping and opposite effects induced by alternative strategies targeting ALCAM functions collectively attribute an integrative role to ALCAM in orchestrating cell adhesion, growth, invasion, and proteolysis in the tumor tissue microenvironment and disclose a therapeutic potential for sALCAM.