Diagnóstico e prognóstico dos tumores pulmonares neuroendócrinos mediante microscopia eletrônica e análise multivariavel de agrupamento / Using electron microscopy and multivariate cluster analysis to determine diagnosis and prognosis in cases of neuroendocrine lung carcinoma

OBJECTIVE: To establish reproducible electron microscopic criteria for identifying the four major types of neuroendocrine tumors of the lung: carcinoid; atypical carcinoid; large cell neuroendocrine carcinoma; and small cell carcinoma. METHODS: Measurements were made on electron micrographs using a digital image analyzer. Sixteen morphometric variables related to tumor cell differentiation were assessed in 27 tumors. The examination under electron microscopy revealed that all of the tumors could be classified as belonging to one of the four categories listed above. Cluster analysis of the morphometry variables was used to group the tumors into three clusters, and Kaplan-Meier survival function curves were employed in order to draw correlations between each cluster and survival. RESULTS: All three clusters of neuroendocrine carcinomas were found to be associated with survival curves, demonstrating the prognostic significance of electron microscopic features. The tumors fell into three well-defined clusters, which represent the spectrum of neuroendocrine differentiation: typical carcinoid (cluster 1); atypical carcinoid and large cell neuroendocrine carcinoma (cluster 2); and small cell carcinoma (cluster 3). Cluster 2 represents an intermediate step in neuroendocrine carcinogenesis, between typical carcinoid tumors and small cell carcinomas. CONCLUSIONS: Our findings confirm that electron microscopy is useful in making the diagnosis and prognosis in cases of lung tumor.

OBJETIVO: Estabelecer, com ajuda do microscópio eletrônico, critérios que possibilitem uma diferenciação mais exata entre os quatro tipos maiores de tumores neuroendócrinos pulmonares: tumor carcinóide típico e atípico, carcinoma de grandes células neuroendócrino e carcinoma de pequenas células. MÉTODOS: Todos os tumores foram avaliados morfometricamente e 16 variáveis foram relacionadas com diferenciação das células tumorais; estas variáveis foram analisadas sob microscopia eletrônica com ajuda de um analisador de imagem digital em 27 tumores. A avaliação através da microscopia eletrônica revelou que todos os tumors investigados podiam ser classificados a um dos quarto tipos listados acima. A análise das variáveis morfométricas foi usada para agrupar os tumores em três grandes grupos, os quais foram relacionados à sobrevivência pelas curvas de Kaplan Meier. RESULTADOS: Os três grupos de carcinoma neuroendócrino associaram-se às curvas da sobrevivência, as quais mostraram características ultrastruturais na microscopia eletrônica de significância prognóstica distinta. Os tumores foram contidos em três grupos bem definidos, que representam o espectro da diferenciação neuroendócrina: tumor carcinóide (grupo 1); tumor carcinóide atípico e carcinoma de grandes células neuroendócrino (grupo 2); e carcinoma de pequenas células (grupo 3). O grupo 2 representa um espectro intermediário na carcinogênese neuroendócrina, entre o carcinóide típico e o carcinoma de pequenas células. CONCLUSÕES: Nossos achados confirmam que a microscopia eletrônica é uma ferramenta útil no diagnóstico e prognóstico dos casos de tumores pulmonares.

Câncer de pulmão: histologia, estádio, tratamento e sobrevida / Lung cancer: histology, staging, treatment and survival

OBJETIVO: Analisar os principais tipos histológicos, estádio, tratamento e sobrevida dos portadores de câncer de pulmão. MÉTODOS: Estudo retrospectivo a partir da análise dos prontuários de pacientes acompanhados no Hospital das Clínicas da Faculdade de Medicina de Botucatu, num período de seis anos. RESULTADOS: De janeiro de 2000 a janeiro de 2006, foram acompanhados 240 doentes com câncer de pulmão, com predominância do sexo masculino (64 por cento). O tipo histológico mais freqüente foi o carcinoma escamoso (37,5 por cento), seguido pelo adenocarcinoma (30 por cento), carcinoma neuroendócrino (19,6 por cento) e carcinoma de grandes células (6,6 por cento). Apenas 131 pacientes (54,6 por cento) foram tratados. Destes, 52 pacientes (39,7 por cento) foram submetidos à quimioterapia exclusiva, 32 (24,4 por cento) realizaram quimioterapia associada à radioterapia e 47 (35,9 por cento) foram submetidos à cirurgia associada ou não à quimioterapia exclusiva e/ou radioterapia. Somente 27 pacientes (20,6 por cento) foram submetidos à cirurgia exclusiva.Em relação ao estadiamento, 34,4 por cento apresentavam, no momento do diagnóstico, estádio IV, 20,6 por cento estádio IIIB, 16,8 por cento estádio IIIA e os outros 28,2 por cento pertenciam aos estádios I e II. A sobrevida em cinco anos foi de 65 por cento para o estádio I e 25 por cento para os estádios remanescentes. CONCLUSÕES: O tipo histológico predominante foi o carcinoma escamoso e o de menor freqüência foi o carcinoma de grandes células. A maioria se encontrava em estádio avançado ao diagnóstico, estando nos estádios iniciais menos de 30 por cento dos casos. Isto justifica a baixa sobrevida e a pequena quantidade de pacientes submetidos ao tratamento cirúrgico exclusivo, em comparação à maioria que foi submetida à quimioterapia exclusiva.

OBJECTIVE: To analyze principal histological types of lung cancer, as well as the staging, treatment and survival of lung cancer patients. METHODS: This was a retrospective study based on the analysis of medical charts of patients treated at the Botucatu School of Medicine Hospital das Clínicas over a six-year period. RESULTS: From January of 2000 to January of 2006, 240 patients with lung cancer, most (64 percent) of whom were male, were treated. The most common histological type was squamous cell carcinoma (37.5 percent), followed by adenocarcinoma (30 percent), neuroendocrine carcinoma (19.6 percent) and large cell carcinoma (6.6 percent). Only 131 patients (54.6 percent) were treated. Of those, 52 patients (39.7 percent) received only chemotherapy, 32 (24.4 percent) were treated with chemotherapy combined with radiotherapy, and 47 (35.9 percent) were submitted to surgery alone or surgery accompanied by chemotherapy, with or without radiotherapy. Only 27 patients (20.6 percent) were submitted to surgery alone. Concerning staging, 34.4 percent presented stage IV at the time of diagnosis, 20.6 percent presented stage IIIB, 16.8 percent presented stage IIIA, and the remaining 28.2 percent were classified as stage I or II. Five-year survival was 65 percent for those in stage I and 25 percent for those in the remaining stages. CONCLUSIONS: Of the various histological types, the most common was squamous cell carcinoma and the least common was large cell carcinoma. Most cases presented advanced stages at the moment of diagnosis, and less than 30 percent of the cases presented early stages. This accounts for the low survival rate and the small number of patients submitted to surgical treatment alone, the majority being submitted to chemotherapy alone.

p53 immunostaining is correlated with reduced survival and is not correlated with gene mutations in resected pulmonary large cell carcinomas

Malignancy of pulmonary large cell carcinomas (LCC) increases from classic LCC through LCC with neuroendocrine morphology (LCCNM) to large cell neuroendocrine carcinomas (LCNEC). However, the histological classification has sometimes proved to be difficult. Because the malignancy of LCC is highly dependent on proteins with functions in the cell cycle, DNA repair, and apoptosis, p53 has been targeted as a potentially useful biological marker. p53 mutations in lung cancers have been shown to result in expression and protein expression also occurs in the absence of mutations. To validate the importance of both p53 protein expression (by immunostaining) and p53 gene mutations in lung LCC (by PCR-single strand conformational polymorphism analysis of exons 5, 6, 7, and 8) and to study their relationships with clinical factors and sub-classification we investigated the correlation of p53 abnormalities in 15 patients with LCC (5 classic LCC, 5 LCNEC, and 5 LCCNM) who had undergone resection with curative intent. Of these patients, 5/15 expressed p53 and none had mutant p53 sequences. There was a negative survival correlation with positive p53 immunostaining (P = 0.05). After adjustment for stage, age, gender, chemotherapy, radiotherapy, and histological subtypes by multivariate analysis, p53 expression had an independent impact on survival. The present study indicates that p53 assessment may provide an objective marker for the prognosis of LCC irrespective of morphological variants and suggests that p53 expression is important for outcome prediction in patients with the early stages of LCC. The results reported here should be considered to be initial results because tumors from only 15 patients were studied: 5 each from LCC, LCNEC and LCCNM. This was due to the rarity of these specific diseases.