Malignant tumors of the respiratory tract

I) Bronchial carcinoid tumors: They are neuroendocrine tumors arising from Kulchitsky cells or stem cells of the bronchial or bronchiolar mucosa. They produce serotonin, ACTH, somatostatin and bradykinins. Other areas for carcinoid tumors are 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 are seen to the liver, bone, adrenal glands and brain. Carcinoid syndrome will occur if there is metastasization to the liver. On gross appearance, they are polypoid, smooth, cherry red, highly vascular, endobronchial nodules. On histology, uniform sheets, trabeculae or gland-like formations made of polygonal cells with eosinophilic cytoplasm are seen. A fibrovascular stroma is seen. Rosette formation, palisading, bone formation or amyloid deposition may be seen. High grade, increased mitotic figures, hyperchromatic nuclei and necrosis are associated with aggressive tumors and bad prognosis. Neurosecretory granules are seen on electron microscopy. X ray chest will show hilar or perihilar tumors and central or peripheral nodules.

II) Squamous cell carcinoma of the lung: About 30% non-small cell lung cancers or NSCLC are squamous cell cancers or SCC. It arises from bronchial epithelium. Smoking is a risk factor. The tumor is seen in the proximal or larger bronchi, as they are exposed to irritants and cigarette smoke first. On gross examination, areas of cavitation and necrosis are seen. Microscopic examination shows sheets of polygonal, neoplastic cells and keratinization in the form of keratin pearls, deeply eosinophilic dyskeratotic malignant cells and intercellular bridges between polygonal cells. Nests of tumor cells can be seen infiltrating the adjacent areas of the lung, which may also show mucosal changes of dysplasia and metaplasia. Rarely, spindle-shaped cells may be seen.

III) Adenocarcinoma of the lung: It is the most common lung cancer in women and is often seen in non-smokers. It is often located peripherally and arises from the smaller bronchioles and alveolar epithelium. Histologically, it may be acinar (with predominantly gland-like structures), papillary (develops from old scars, papillary projections seen), bronchiolo-alveolar (shows mucus secreting cuboidal or columnar cells and papillary forms, Clara cells) or solid carcinomas (no acini, tubules or papillae). It may clinically and on X-ray chest look like lobar pneumonia.

IV) Large cell carcinoma of the lung: It has an undifferentiated histology, with no specific features of small cell cancer, adenocarcinoma or squamous cell carcinoma. It is associated with smoking and is highly malignant. Histology shows neoplastic cells with large nuclei and prominent nucleoli and rarely clear cells with foamy cytoplasm.

V) Small cell carcinoma of the lung (oat cell carcinoma): Most cases develop as a result of smoking. Other causes are uranium mining and radon exposure. It is located in a 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 the time of presentation. Tumor cells will be 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 are seen.

VI) Malignant Mesothelioma of the pleura: It is typically seen in older age, more commonly in men. Asbestos exposure (especially amphibole or crocidolite form), radiation, SV40 virus and erionite (used in road work) are implicated. Malignant mesothelioma develops after a long latent period of 20-40 years. It is not associated with smoking. Soluble mesothelin related peptide or SMRP levels are elevated. On gross appearance, it forms a thick, diffuse fleshy tumor over the parietal and visceral pleura or multiple nodules. Microscopy shows epithelioid, sarcomatoid (spindle shaped cells) or mixed cells with stromal or adipose tissue invasion. Asbestos bodies are seen. Epithelioid histology carries a better prognosis than sarcomatoid type. Immunohistochemistry stains positive for calretinin, cytokeratin, WT1 and D2 40. Pleural effusion is often present.

VII) Metastases to lung and pleura: Metastases to lungs are most commonly seen in colon, bladder, breast, prostate cancers, Wilms tumor, neuroblastomas, choriocarcinoma, melanoma and sarcomas. Testicular and renal cell cancers can seed the lungs as tumor thrombi via IVC. Typically, metastases from distant primary tumors occur through the pulmonary arteries. Metastases are seen as multiple, well circumscribed, rounded lesions of varying sizes. Cannonball nodules are often seen in colon cancers. Thyroid and ovarian cancers present with a miliary pattern. Primary tumors in the breast, lung and ovaries frequently metastasize to the pleura. They appear as multiple pleural nodules.

Primary lung cancers metastasize to the brain, bones and adrenal glands. Small cell cancers preferentially metastasize to the liver and brain; adenocarcinoma to brain and local invasion in squamous cell carcinomas. 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. Rarely, inherited mutations are seen. Inherited syndromes such as Li-Fraumeni syndrome and inherited retinoblastoma syndromes are associated with high risk of lung cancers. EGFR overexpression or amplification is seen in NSCLC. EGFR mutations affect tyrosine kinase function resulting in tumorigenesis.