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Lung cancer diagnosis is a challenge since it is also one of the most frequently diagnosed cancers. Diagnostic challenges are deeply related to the development of personalized therapy and molecular and precise histological characterizations of lung cancer. When addressing these features, it is very important to acknowledge the issue of tumour heterogeneity, as it imposes several questions. First of all, lung cancer is a very heterogeneous disease, at a cellular and histological level. Cellular and histological heterogeneity are addressed with emphasis on the diagnosis, pre-neoplastic lesions, and cell origin, trying to contribute to a better knowledge of carcinogenesis. Molecular intra-tumour and inter-tumour heterogeneity are also addressed as temporal heterogeneity. Lung cancer heterogeneity has implications in pathogenesis understanding, diagnosis, selection of tissue for molecular diagnosis, as well as therapeutic decision. The understanding of tumour heterogeneity is crucial and we must be aware of the implications and future developments regarding this field.

Lung cancer is still one of the most frequent cancers in the world, with a high mortality rate. Bronchial-pulmonary carcinomas are still undergoing morphological, immunohistochemical and genetic characterization, with important clinical implications. The characterization of preneoplastic lesions may bring a better understanding of carcinogenesis. Bronchial-pulmonary carcinomas and preneoplastic lesions of epidermoid carcinoma were studied using immunohistochemical and molecular pathology techniques, on a morphological pattern-based approach. Basal cell origin was proposed for preneoplastic epidermoid carcinoma lesions, where Ki67, p53 and EGFR constitute biomarkers of agressiveness. EGFR amplification is not the main mechanism for overexpression in preneoplastic lesions. High EGFR gene copy number and EGFR overexpression may play a role in epidermoid carcinoma carcinogenesis. EGFR mutations are rare. Epidermoid carcinomas with solid, large or clear cell phenotype or with CK7 or Vimentin (EMT phenotype) expression should be submitted to EGFR mutational analysis. Expression differences between adenocarcinoma patterns reinforce the importance of pattern classification due to their implications for diagnosis, pathogenic understanding and therapeutic outcome. There was higher expression of the gene products studied in adenocarcinomas compared to normal tissue, reinforcing their importance in adenocarcinoma carcinogenesis. Non-smoking female adenocarcinomas were diagnosed in earlier stages and showed higher ERCC1 expression. Advanced stages (IIA and IIIA) adenocarcinomas were characterized by higher Ki67, APC, ERCC1 expressions and lower TTF1 expression, reflecting more mitotically aggressive adenocarcinomas and a possible non-TRU origin. Solid patterns showed lower expression of nuclear TTF1 and higher expression of Ki67, reflecting aggressive biological behaviour, to be reported to clinicians avoiding poorly differentiated carcinoma reports. TTF1 provides significant guidance for therapy concerning lung adenocarcinoma as EGFR mutations were more frequent in TTF1 positive TRU-type adenocarcinomas. On the other hand TTF1 negative adenocarcinomas, some representing non-TRU adenocarcinomas are less prone to harbour EGFR mutations. Three clusters of adenocarcinoma patterns were identified: 1 – papillary; 2 – solid; and 3 – lepidic/BA, acinar and micropapillary. Molecular markers related to therapy resistance were explored and were found to demonstrate higher MRP1 and LRP expression in adenocarcinomas, indicating acquisition of drug-resistance mechanisms during carcinogenesis. Micropapillary, solid and also lepidic patterns showed ERCC1 expression indicating a capacity for Cisplatin-adducts removal. EGFR mutations were generally present in all the patterns of the same adenocarcinoma reinforcing mutational evaluation in small biopsies. Complex EGFR mutations and KRAS and EGFR mutations coexistence were detected, demonstrating molecular complexity. FGFR1 protein expression was present in the majority of the bronchial-pulmonary carcinomas, and is higher in adenocarcinomas and pleomorphic carcinomas. Higher expression in pleomorphic carcinomas may reflect the importance of FGFR1 controlling EMT pathways. FGFR1 amplification is identified in adenocarcinomas (14.7%), epidermoid carcinomas (20.8%), adenosquamous carcinoma (25%) and pleomorphic carcinomas (30%), without significant differences. Although FGFR1 amplification has been observed more frequently in epidermoid carcinomas than in adenocarcinomas, these results suggest that the other histological types harbouring FGFR1 amplification, such as adenosquamous, pleomorphic carcinomas, adenocarcinomas and even small cell lung carcinoma, may benefit from targeted therapy. Bronchial-pulmonary carcinomas have particular biological, clinical and therapeutic implications. The importance of precise pathological diagnosis, adenocarcinoma patterns recognition, and bronchial-pulmonary carcinogenesis related to biomarker predictive value for targeted therapy is highlighted.

Lung cancer is still one of the most frequent cancers in the world, with a high mortality rate. Bronchial-pulmonary carcinomas are still undergoing morphological, immunohistochemical and genetic characterization, with important clinical implications. The characterization of preneoplastic lesions may bring a better understanding of carcinogenesis. Bronchial-pulmonary carcinomas and preneoplastic lesions of epidermoid carcinoma were studied using immunohistochemical and molecular pathology techniques, on a morphological pattern-based approach. Basal cell origin was proposed for preneoplastic epidermoid carcinoma lesions, where Ki67, p53 and EGFR constitute biomarkers of agressiveness. EGFR amplification is not the main mechanism for overexpression in preneoplastic lesions. High EGFR gene copy number and EGFR overexpression may play a role in epidermoid carcinoma carcinogenesis. EGFR mutations are rare. Epidermoid carcinomas with solid, large or clear cell phenotype or with CK7 or Vimentin (EMT phenotype) expression should be submitted to EGFR mutational analysis. Expression differences between adenocarcinoma patterns reinforce the importance of pattern classification due to their implications for diagnosis, pathogenic understanding and therapeutic outcome. There was higher expression of the gene products studied in adenocarcinomas compared to normal tissue, reinforcing their importance in adenocarcinoma carcinogenesis. Non-smoking female adenocarcinomas were diagnosed in earlier stages and showed higher ERCC1 expression. Advanced stages (IIA and IIIA) adenocarcinomas were characterized by higher Ki67, APC, ERCC1 expressions and lower TTF1 expression, reflecting more mitotically aggressive adenocarcinomas and a possible non-TRU origin. Solid patterns showed lower expression of nuclear TTF1 and higher expression of Ki67, reflecting aggressive biological behaviour, to be reported to clinicians avoiding poorly differentiated carcinoma reports. TTF1 provides significant guidance for therapy concerning lung adenocarcinoma as EGFR mutations were more frequent in TTF1 positive TRU-type adenocarcinomas. On the other hand TTF1 negative adenocarcinomas, some representing non-TRU adenocarcinomas are less prone to harbour EGFR mutations. Three clusters of adenocarcinoma patterns were identified: 1 – papillary; 2 – solid; and 3 – lepidic/BA, acinar and micropapillary. Molecular markers related to therapy resistance were explored and were found to demonstrate higher MRP1 and LRP expression in adenocarcinomas, indicating acquisition of drug-resistance mechanisms during carcinogenesis. Micropapillary, solid and also lepidic patterns showed ERCC1 expression indicating a capacity for Cisplatin-adducts removal. EGFR mutations were generally present in all the patterns of the same adenocarcinoma reinforcing mutational evaluation in small biopsies. Complex EGFR mutations and KRAS and EGFR mutations coexistence were detected, demonstrating molecular complexity. FGFR1 protein expression was present in the majority of the bronchial-pulmonary carcinomas, and is higher in adenocarcinomas and pleomorphic carcinomas. Higher expression in pleomorphic carcinomas may reflect the importance of FGFR1 controlling EMT pathways. FGFR1 amplification is identified in adenocarcinomas (14.7%), epidermoid carcinomas (20.8%), adenosquamous carcinoma (25%) and pleomorphic carcinomas (30%), without significant differences. Although FGFR1 amplification has been observed more frequently in epidermoid carcinomas than in adenocarcinomas, these results suggest that the other histological types harbouring FGFR1 amplification, such as adenosquamous, pleomorphic carcinomas, adenocarcinomas and even small cell lung carcinoma, may benefit from targeted therapy. Bronchial-pulmonary carcinomas have particular biological, clinical and therapeutic implications. The importance of precise pathological diagnosis, adenocarcinoma patterns recognition, and bronchial-pulmonary carcinogenesis related to biomarker predictive value for targeted therapy is highlighted.