Lung Cancer (Small Cell and Non-Small Cell)
Leading cause of cancer death — NSCLC (~85%) and SCLC (~15%) with distinct biology and treatment.
Also known as: lung cancer, NSCLC, SCLC, adenocarcinoma, squamous cell carcinoma, small cell lung cancer
Overview
Malignancy arising from bronchial epithelium or alveolar cells. Two principal categories: non-small cell lung cancer (NSCLC — adenocarcinoma, squamous cell, large cell) and small cell lung cancer (SCLC — neuroendocrine, aggressive). Modern therapy is driven by histology, molecular markers, and PD-L1 status.
Epidemiology
Leading cause of cancer death in the US (~125,000 deaths/year). 5-year overall survival ~25% (improving with screening and targeted therapy). Median age at diagnosis ~70. Adenocarcinoma is most common subtype, including in never-smokers.
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Risk factors
- Tobacco smoking (causes ~85% of cases; quantified in pack-years)
- Secondhand smoke
- Radon exposure (second leading cause overall)
- Asbestos (synergistic with smoking)
- Occupational: arsenic, chromium, nickel, silica, diesel exhaust
- Air pollution, prior radiation therapy, HIV
- Family history, COPD, pulmonary fibrosis
Pathophysiology
Carcinogen-induced DNA damage accumulates in bronchial/alveolar epithelium → driver mutations (EGFR, KRAS, ALK, ROS1, BRAF, MET, RET, NTRK, HER2) in adenocarcinoma; TP53 and RB inactivation typical in SCLC. Tumor growth, local invasion, lymphatic and hematogenous spread (brain, bone, liver, adrenals).
Clinical presentation
Symptoms
- Persistent cough, change in chronic cough quality
- Hemoptysis (any unexplained hemoptysis in smoker >40 warrants imaging)
- Dyspnea, chest pain (pleuritic if pleural involvement)
- Constitutional: weight loss, anorexia, fatigue
- Hoarseness (recurrent laryngeal nerve)
- Symptoms of metastases: bone pain, focal neurologic deficits, headaches, seizures
Signs / physical exam
- Fixed monophonic wheeze (endobronchial obstruction)
- Clubbing, supraclavicular lymphadenopathy
- Horner syndrome (ptosis, miosis, anhidrosis) and brachial plexopathy — Pancoast (superior sulcus) tumor
- Superior vena cava syndrome — facial swelling, distended neck and chest veins, plethora (more common in SCLC)
- Paraneoplastic findings: SIADH (SCLC), Cushing (SCLC), Lambert-Eaton myasthenic syndrome (SCLC), hypercalcemia (squamous), HPOA
Classic findings
Pancoast tumor: shoulder pain + Horner syndrome + arm weakness. SVC syndrome with right upper lobe mass. Hypercalcemia in squamous cell. SIADH or Cushing in SCLC.
Differential diagnosis
- Pneumonia / lung abscess — Acute febrile course; resolves with antibiotics; non-resolving consolidation should prompt repeat imaging
- Tuberculosis — Cavitary disease, hemoptysis, weight loss; positive AFB/IGRA
- Granulomatous disease (sarcoid, histo, cocci) — Bilateral hilar adenopathy + parenchymal nodules; serology and biopsy
- Pulmonary metastases from other primary — Multiple bilateral nodules with feeding vessel; primary malignancy history; cannonball mets
- Hamartoma (benign) — Smooth, well-circumscribed, popcorn calcification, low growth rate
- Carcinoid tumor — Endobronchial mass with recurrent infections; can secrete serotonin (carcinoid syndrome)
- Lymphoma — Mediastinal mass, B symptoms, lymphadenopathy elsewhere; biopsy
Diagnostic workup
Diagnostic criteria
Definitive diagnosis requires tissue (histology + molecular and immunohistochemistry). TNM staging (8th edition) for NSCLC; SCLC traditionally classified as limited stage (confined to one hemithorax/single radiation port) vs extensive.
Labs
- CBC, CMP (including calcium), LDH
- Coagulation studies if procedures planned
Imaging
- Chest CT with contrast — characterize mass, mediastinal nodes, pleural disease
- PET-CT — staging (FDG avidity, distant metastases)
- MRI brain — staging for stage II-IV NSCLC and all SCLC (high incidence of brain mets)
- Bone scan if PET not available
Other studies
- Tissue diagnosis: bronchoscopy with biopsy/EBUS, CT-guided percutaneous biopsy, mediastinoscopy, VATS
- Molecular testing on NSCLC adenocarcinoma: EGFR, ALK, ROS1, BRAF V600E, KRAS G12C, MET exon 14, RET, NTRK, HER2 + PD-L1 IHC
- Pulmonary function tests, cardiopulmonary assessment for surgical candidates
- Screening: USPSTF 2021 — annual low-dose CT for ages 50-80 with ≥20 pack-year history who currently smoke or quit within 15 years
Diagnostic algorithm
| Subtype | % of Cases | Location | Distinctive Features |
|---|---|---|---|
| Adenocarcinoma (NSCLC) | ~40% | Peripheral | Most common in never-smokers; driver mutations (EGFR, ALK, ROS1); requires molecular testing |
| Squamous cell (NSCLC) | ~25-30% | Central | Cavitation; hypercalcemia via PTHrP; smoking-associated |
| Large cell (NSCLC) | ~5% | Peripheral | Poor differentiation; aggressive |
| Small cell (SCLC) | ~15% | Central | Rapid growth, early mets; paraneoplastic SIADH, Cushing, LEMS; staged as limited/extensive |
Treatment
First-line
- NSCLC Stage I-II (early): surgical resection (lobectomy preferred, VATS) + mediastinal nodal sampling; SBRT for non-surgical candidates
- NSCLC Stage III: concurrent chemoradiation (cisplatin/carboplatin + etoposide/pemetrexed/paclitaxel + radiation), followed by consolidation durvalumab (PACIFIC trial)
- NSCLC Stage IV (metastatic), no driver mutation: immunotherapy ± chemotherapy — pembrolizumab monotherapy if PD-L1 ≥50%; pembrolizumab + carboplatin/pemetrexed (nonsquamous) or carboplatin/paclitaxel (squamous) otherwise (KEYNOTE-189, -407)
- NSCLC driver-positive: targeted therapy — osimertinib (EGFR), alectinib/lorlatinib (ALK), crizotinib/entrectinib (ROS1), dabrafenib+trametinib (BRAF V600E), sotorasib/adagrasib (KRAS G12C), capmatinib (METex14)
- SCLC limited stage: concurrent chemoradiation (cisplatin/carboplatin + etoposide) + prophylactic cranial irradiation if response
- SCLC extensive stage: platinum + etoposide + atezolizumab or durvalumab (IMpower133, CASPIAN)
- Smoking cessation at any stage
Second-line / adjunct
- NSCLC second-line: docetaxel ± ramucirumab; nivolumab/pembrolizumab if not previously used; targeted therapy switch for acquired resistance (e.g., osimertinib for EGFR T790M)
- SCLC second-line: lurbinectedin or topotecan
- Palliative: external beam radiation for symptomatic bone metastases, SVC syndrome, brain mets (whole-brain or stereotactic)
- SVC syndrome management: head elevation, steroids, diuretics, radiation, endovascular stent
- Malignant pleural effusion: indwelling tunneled catheter or pleurodesis
- Pain control, palliative care integration early (Temel NEJM 2010)
Complications
- Metastases to brain, bone, liver, adrenal
- SVC syndrome, malignant pleural effusion, pericardial effusion/tamponade
- Post-obstructive pneumonia
- Paraneoplastic syndromes: SIADH, Cushing, Lambert-Eaton, HPOA, hypercalcemia (PTHrP), digital clubbing
- Treatment toxicities: pneumonitis (radiation, immune checkpoint inhibitors), neutropenia, neuropathy
PANCE pearls
- USPSTF 2021 expanded LDCT screening to 50-80 years with ≥20 pack-years, current or quit within 15 — broader than prior 2013 criteria.
- Pancoast (superior sulcus) tumor: shoulder/arm pain + Horner syndrome + T1 nerve root involvement — usually NSCLC.
- Squamous cell — hypercalcemia from PTHrP, central location. Adenocarcinoma — peripheral location, most common in never-smokers, drives molecular testing.
- SCLC — central, paraneoplastic SIADH/Cushing/LEMS, rapidly progressive; stage as limited vs extensive (not TNM in everyday practice).
- Always send NSCLC adenocarcinoma for molecular markers AND PD-L1 — drives first-line therapy choice.
References
- USPSTF 2021 — Screening for Lung Cancer: US Preventive Services Task Force Recommendation Statement (USPSTF, JAMA 2021)
- NLST — Reduced Lung-Cancer Mortality with Low-Dose Computed Tomographic Screening (NLST Research Team, NEJM 2011)
- PACIFIC — Durvalumab after Chemoradiotherapy in Stage III NSCLC (Antonia et al., NEJM 2017)
- KEYNOTE-189 — Pembrolizumab + Pemetrexed-Platinum for Metastatic Nonsquamous NSCLC (Gandhi et al., NEJM 2018)
- IMpower133 — First-Line Atezolizumab + Chemotherapy in Extensive-Stage SCLC (Horn et al., NEJM 2018)
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