I) Bronchial carcinoid tumors: These are neuroendocrine tumors that arise from Kulchitsky cells or stem cells in the bronchial or bronchiolar mucosa. They produce serotonin, ACTH, somatostatin, and bradykinins. Carcinoid tumors can also occur in the GIT (most common), lungs, thymus, biliary tract, and ovary. They are malignant tumors and are typically seen in middle-aged adults or children. There is no association with smoking.
They present with cough, hemoptysis, wheezing, chest pain, fever, and asthma-like symptoms. Metastases may occur to the liver, bone, adrenal glands, and brain. Carcinoid syndrome occurs if there is metastasis to the liver.
On gross examination, they appear as polypoid, smooth, cherry red, highly vascular endobronchial nodules. On histology, you see uniform sheets, trabeculae, or gland-like formations of polygonal cells with eosinophilic cytoplasm, along with a fibrovascular stroma. Rosette formation, palisading, bone formation, or amyloid deposition may be present. High grade features - such as increased mitotic figures, hyperchromatic nuclei, and necrosis - are associated with aggressive tumors and a poor prognosis. Neurosecretory granules are seen on electron microscopy. Chest X-ray may show hilar or perihilar tumors and central or peripheral nodules.
II) Squamous cell carcinoma of the lung: About 30% of non-small cell lung cancers (NSCLC) are squamous cell carcinomas (SCC). SCC arises from bronchial epithelium, and smoking is a major risk factor. The tumor is usually located in the proximal (larger) bronchi, which are exposed first to irritants and cigarette smoke.
On gross examination, cavitation and necrosis may be present. Microscopy shows sheets of polygonal neoplastic cells with keratinization, including keratin pearls, deeply eosinophilic dyskeratotic malignant cells, and intercellular bridges between polygonal cells. Nests of tumor cells may infiltrate adjacent lung tissue, which can also show mucosal dysplasia and metaplasia. Rarely, spindle-shaped cells may be seen.
III) Adenocarcinoma of the lung: This is the most common lung cancer in women and is often seen in non-smokers. It is typically peripheral and arises from smaller bronchioles and alveolar epithelium.
Histologic patterns include:
Clinically and on chest X-ray, it may resemble lobar pneumonia.
IV) Large cell carcinoma of the lung: This tumor has an undifferentiated histology, without specific features of small cell carcinoma, adenocarcinoma, or squamous cell carcinoma. It is associated with smoking and is highly malignant. Histology shows neoplastic cells with large nuclei and prominent nucleoli; rarely, clear cells with foamy cytoplasm may be seen.
V) Small cell carcinoma of the lung (oat cell carcinoma): Most cases develop due to smoking. Other causes include uranium mining and radon exposure. It is typically located centrally (hilar or central location). It originates from neuroendocrine cells and is associated with paraneoplastic syndromes due to ectopic hormone production.
If detected early, it has a good prognosis, but most small cell cancers are advanced at presentation. Tumor cells stain positive for neuroendocrine markers such as chromogranin, neuron-specific enolase, CD56, and synaptophysin. Histology shows sheets, clusters, and ribbons of uniform small round blue cells with prominent nuclei and minimal cytoplasm. Peripheral palisading and rosettes may be seen.
VI) Malignant Mesothelioma of the pleura: This tumor is typically seen in older adults and is more common in men. Implicated causes include asbestos exposure (especially amphibole or crocidolite), radiation, SV40 virus, and erionite (used in road work). Malignant mesothelioma develops after a long latent period of 20-40 years and is not associated with smoking.
Soluble mesothelin related peptide (SMRP) levels are elevated. On gross examination, it forms a thick, diffuse fleshy tumor over the parietal and visceral pleura, or it may appear as multiple nodules. Microscopy shows epithelioid, sarcomatoid (spindle-shaped cells), or mixed patterns, with invasion into stromal or adipose tissue. Asbestos bodies may be present. Epithelioid histology has a better prognosis than the sarcomatoid type. Immunohistochemistry is positive for calretinin, cytokeratin, WT1, and D2 40. Pleural effusion is often present.
VII) Metastases to lung and pleura: Metastases to the lungs are most commonly seen in colon, bladder, breast, and prostate cancers, as well as Wilms tumor, neuroblastomas, choriocarcinoma, melanoma, and sarcomas. Testicular and renal cell cancers can seed the lungs as tumor thrombi via the IVC. Typically, metastases from distant primary tumors reach the lungs through the pulmonary arteries.
Metastases usually appear as multiple, well-circumscribed, rounded lesions of varying sizes. Cannonball nodules are often seen in colon cancers. Thyroid and ovarian cancers may present with a miliary pattern. Primary tumors in the breast, lung, and ovaries frequently metastasize to the pleura, appearing as multiple pleural nodules.
Primary lung cancers commonly metastasize to the brain, bones, and adrenal glands. Small cell cancers preferentially metastasize to the liver and brain; adenocarcinoma to the brain; and squamous cell carcinomas tend to show local invasion. NSCLC has a tendency for unilateral or bilateral adrenal metastases.
Genetic mutations and lung cancer: Somatic mutations in TP53, EGFR (epidermal growth factor receptor), and K-RAS genes have been found in lung cancer cells. Inherited mutations are rare. Inherited syndromes such as Li-Fraumeni syndrome and inherited retinoblastoma syndromes are associated with a high risk of lung cancers. EGFR overexpression or amplification is seen in NSCLC. EGFR mutations affect tyrosine kinase function, resulting in tumorigenesis.
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