Summary This section provides a comprehensive overview of primary lung tumours, focusing on carcinomas as the most prevalent type. It details the aetiology, pat
Summary This section provides a comprehensive overview of primary lung tumours, focusing on carcinomas as the most prevalent type. It details the aetiology, pathogenesis, and molecular aspects of lung cancer, including the significant impact of smoking and other environmental factors. The morphology of major histological subtypes like adenocarcinoma, squamous cell carcinoma, large cell carcinoma, and small cell lung carcinoma is described, alongside their respective precursor lesions and characteristic genetic mutations. The comparison between small cell lung carcinoma (SCLC) and non-small cell lung carcinoma (NSCL C) highlights their distinct clinical behaviours and treatment implications. The section also covers the spread patterns, clinical manifestations, paraneoplastic syndromes, and treatment strategies for lung tumours, emphasizing the advent of targeted therapies and immune checkpoint inhibitors. Additionally, it discusses carcinoid tumours, a less common but distinct group of neuroendocrine neoplasms originating in the lungs. Key Points - ~95% of primary lung tumours are carcinomas , with the remaining 5% comprising carcinoids, mesenchymal malignancies, lymphomas, and benign lesions. - Hamartoma is the most common benign lung tumour, appearing as a discrete "coin lesion" on imaging. - Carcinoma of the lung is the leading cause of cancer-related deaths in industrialized countries, with peak incidence in the fifties and sixties. - Four Major Histologic Types of lung carcinoma are Adenocarcinoma, Squamous cell carcinoma, Small cell carcinoma, and Large cell carcinoma. - Smoking is the most important aetiological factor, accounting for ~90% of lung cancers. - Asbestos exposure synergizes with tobacco smoke, significantly increasing lung cancer risk. - Key Targetable Mutations in lung adenocarcinomas include EGFR, KRAS, and ALK rearrangements, driving personalized treatment approaches. - Small Cell Lung Carcinoma (SCLC) is highly aggressive, virtually always metastatic at diagnosis, and treated with systemic chemotherapy. - Non-Small Cell Lung Carcinoma (NSCLC) is more likely to be resectable and may respond to targeted therapies. - Carcinoid Tumours are low-grade neuroendocrine carcinomas, often resectable and curable, with typical and atypical subtypes. - Pleural lesions include effusions (transudates and exudates), pneumothorax, haemothorax, chylothorax, and malignant mesothelioma. - Malignant Mesothelioma is a rare cancer of mesothelial cells, strongly linked to asbestos exposure with a long latent period. - Upper Respiratory Tract Lesions encompass acute infections (pharyngitis, epiglottitis, laryngitis) and neoplasms like nasopharyngeal carcinoma, laryngeal papilloma, and carcinoma of the larynx. - Carcinoma of the Larynx is predominantly squamous cell carcinoma, with glottic tumours having a better prognosis due to early symptoms and less lymphatic spread. Detailed Notes Overview of Primary Lung Tumours - ~95% of primary lung tumours are carcinomas. - The remaining 5% consist of carcinoids, mesenchymal malignancies (fibrosarcomas, leiomyomas), lymphomas, and benign lesions. - The most common benign tumour is Hamartoma . It is typically spherical, small (1–4 cm), and appears as a discrete "coin lesion" on imaging. It is composed mainly of mature cartilage admixed with fat, fibrous tissue, and blood vessels. Clonal cytogenetic abnormalities have been confirmed, technically classifying it as a benign neoplasm rather than a true hamartoma. Carcinoma of the Lung - Most important cause of cancer-related deaths in industrialised countries. - Leading cause of cancer deaths in both men and women. - Estimated ~221,200 new cases and 158,040 deaths in the USA (2016 figures). - Peak incidence occurs in the fifties and sixties . - At diagnosis, 50% of patients already have distant metastases, and an additional 25% have regional lymph node disease. - The overall 5-year survival is approximately 16% , a figure that has not changed significantly over 35 years. - Even with disease localised to the lung, the 5-year survival is only 45%. Four Major Histologic Types: Type Key Features :---------------------- :------------------------------------------------------------------------------- Adenocarcinoma Most common overall; most common in women, non-smokers, and those 10-fold increased risk. Molecular Pathogenesis — Sequential Mutations: - The stepwise accumulation of driver mutations parallels the histologic progression of lung cancer. - An early event involves the inactivation of tumour suppressor genes on chromosome 3p , which can be found even in the benign bronchial epithelium of smokers, indicating a "field effect." - Late events include mutations in the TP53 tumour suppressor and the KRAS oncogene. - Loss of 3p is found in benign bronchial epithelium, suggesting that large areas of respiratory mucosa are mutagenised. Key Targetable Mutations (mainly in adenocarcinomas): - EGFR mutations: Found in ~10% of whites and ~30% of Asians, particularly in non-smoking women. Tumours with these mutations are sensitive to EGFR inhibitors, though responses are often short-lived. EGFR and KRAS mutations are mutually exclusive as KRAS lies downstream of EGFR. - KRAS mutations: Occur in ~30% of adenocarcinomas. - ALK rearrangements: Found in 4–6% of adenocarcinomas, often in non-smokers, and can present with signet ring morphology. - ROS1, HER2, c-MET mutations: Each can be targeted by specific drugs, contributing to the era of "personalised" lung cancer treatment. Each kinase is optimally targeted by a different drug. Precursor Lesions: - Adenocarcinoma sequence: Atypical adenomatous hyperplasia (AAH) → adenocarcinoma in situ (AIS) → minimally invasive adenocarcinoma → invasive adenocarcinoma. - Squamous cell carcinoma sequence: Basal cell hyperplasia → squamous metaplasia → squamous dysplasia → carcinoma in situ → invasive carcinoma. This sequence shows a linear correlation with cigarette smoke intensity. - Bronchioalveolar stem cells (BASCs): These multipotent cells at the bronchioloalveolar duct junction are postulated to incur the initiating hit (e.g., a somatic KRAS mutation) after lung injury, escape checkpoint mechanisms, and lead to pulmonary adenocarcinomas. Morphology of Individual Subtypes Adenocarcinoma: - Usually peripherally located , although they can also occur near the hilum. - They grow slowly and form smaller masses than other subtypes but metastasise widely at an early stage . - Growth patterns include acinar (gland-forming), papillary, mucinous (often multifocal with a pneumonia-like consolidation), and solid (requires mucin stains to confirm adenocarcinomatous differentiation). - Atypical Adenomatous Hyperplasia (AAH): A well-demarcated focus ≤5 mm, composed of cuboidal to low-columnar cells with nuclear hyperchromasia, pleomorphism, and prominent nucleoli. It is monoclonal and shares molecular aberrations (e.g., KRAS mutations) with adenocarcinomas. - Adenocarcinoma in situ (AIS) (formerly bronchioloalveolar carcinoma): ≤3 cm, characterized by growth along pre-existing alveolar structures (lepidic growth) with preservation of alveolar architecture. Tumour cells grow in a monolayer along alveolar septa without stromal invasion or desmoplasia (if present, it indicates invasive adenocarcinoma). AIS can be nonmucinous, mucinous, or mixed. - TTF-1 (thyroid transcription factor-1) is positive in the majority of pulmonary adenocarcinomas and is an important immunohistochemical marker. Squamous Cell Carcinoma: - More common in men and closely correlated with smoking history. - Centrally located , arising in major bronchi. - They spread to local hilar nodes first and disseminate outside the thorax later than other histologic types. - Large lesions may exhibit central necrosis, leading to cavitation . - The precursor lesion is squamous metaplasia/dysplasia in the bronchial epithelium, progressing to carcinoma in situ, which can persist for several years.