squamous cell lung cancer

**Epidemiology/Risk factors:** Strongest association with cigarette smoking (more than adenocarcinoma, which is the most common type in nonsmokers and overall). More common in men. Other risks include radon and asbestos (asbestos is more classically linked to mesothelioma and adenocarcinoma).

**Pathophysiology:** Chronic irritation leads to a stepwise progression: squamous metaplasia of bronchial epithelium, then dysplasia, then carcinoma in situ, then invasive carcinoma. Common molecular changes include TP53 mutation, CDKN2A (p16) inactivation, and FGFR1 amplification. Loss of Rb or p16 pathways drives cell cycle dysregulation. EGFR mutations and ALK rearrangements are uncommon (more typical of adenocarcinoma).

**Location/Gross:** Central, hilar mass arising from a major bronchus. Frequently cavitates (central necrosis with an air-fluid level). Can cause bronchial obstruction, leading to post-obstructive pneumonia, atelectasis, hemoptysis, and cough.

**Histology:** Keratin pearls, intercellular bridges (desmosomes), and dyskeratosis. Immunohistochemistry is positive for p40, p63, and CK5/6, and usually negative for TTF-1 and napsin A (which are positive in adenocarcinoma).

**Clinical significance/Paraneoplastic syndromes:** - Hypercalcemia from PTHrP secretion (high-yield). Labs show high calcium with low PTH. - Hypertrophic osteoarthropathy and clubbing. - Local spread: Pancoast tumor (superior sulcus) causes Horner syndrome (ptosis, miosis, anhidrosis), C8-T1 arm pain and weakness. Superior vena cava syndrome and recurrent laryngeal nerve involvement (hoarseness) can also occur.

**Diagnosis:** CXR/CT showing a central cavitating mass, confirmed by bronchoscopy with biopsy or CT-guided biopsy. Staging uses PET-CT and mediastinal sampling (EBUS).

**Treatment:** Resectable stage I-II disease: surgical resection (lobectomy), with adjuvant or neoadjuvant therapy per stage. Unresectable stage III: concurrent chemoradiation, followed by durvalumab consolidation. Advanced disease: platinum-based chemotherapy with PD-1/PD-L1 immunotherapy (e.g., pembrolizumab). Bevacizumab is contraindicated in squamous histology because of the risk of fatal hemoptysis. Pemetrexed is ineffective/not used in squamous histology (works in nonsquamous).

**Board pearls and comparisons:** - Squamous: central, cavitary, smoking, PTHrP hypercalcemia. - Adenocarcinoma: peripheral, most common overall, nonsmokers, EGFR/ALK/KRAS, TTF-1+, can be associated with scars (scar carcinoma). - Small cell: central, ADH (SIADH), ACTH (Cushing), Lambert-Eaton, neuroendocrine (chromogranin+, synaptophysin+). - Large cell: peripheral, anaplastic, poor prognosis, may secrete beta-hCG. - Another cavitating lung lesion differential: TB, abscess, granulomatosis with polyangiitis, septic emboli.