Lung cancer

Overview

• Two biologically distinct cancers grouped under one clinical entry point: non-small cell lung cancer (NSCLC, about 80% of cases) and small cell lung cancer (SCLC, about 10-15%) share one workup but diverge at staging and treatment.
• The leading cause of cancer death worldwide; overall 5-year survival remains low at 17.7%.
• NSCLC subtypes: adenocarcinoma (most common, nearly all lung cancer in nonsmokers, peripheral), squamous cell carcinoma (smoking-linked, central, cough/hemoptysis), large cell carcinoma (undifferentiated, peripheral, often necrotic).
• SCLC is a neuroendocrine neoplasm almost exclusively caused by smoking, typically central with bulky mediastinal adenopathy and distant metastasis already present at diagnosis.
• Every workup answers two questions: cell type and stage; both, with performance status, determine treatment.

Epidemiology

• About 230,000 new US cases and more than 135,000 US deaths annually.
• Screening with annual low-dose CT reduces lung cancer mortality by 20% in heavy smokers (National Lung Screening Trial), driving the current US Preventive Services Task Force grade B recommendation.

Risk factors

• Cigarette smoking (active or secondhand), the dominant risk factor for both; risk scales with pack-years and is strongest for SCLC and squamous NSCLC.
• Environmental/occupational toxin exposure: asbestos, radon, metals, diesel fumes.
• Prior thoracic radiation, pulmonary fibrosis, human immunodeficiency virus (HIV) infection, family history of lung cancer, and alcohol use.
• Adenocarcinoma occurs in nonsmokers too, accounting for almost all lung cancer without a smoking history, so absent smoking does not exclude the diagnosis.

Pathophysiology

• Field carcinogenesis from tobacco carcinogens drives progressive genomic damage across the bronchial epithelium, explaining both the primary tumor and the elevated risk of a second primary lung cancer after treatment.
• Adenocarcinoma arises peripherally and is most enriched for targetable driver mutations (epidermal growth factor receptor [EGFR] mutation; anaplastic lymphoma kinase [ALK] or ROS proto-oncogene 1 [ROS1] translocation); squamous cell carcinoma arises centrally, causing cough/hemoptysis and postobstructive pneumonia or collapse.
• SCLC originates from central-airway neuroendocrine cells, growing and disseminating early, which is why most patients present with bulky mediastinal or distant disease rather than a resectable nodule.
• Paraneoplastic syndromes reflect ectopic hormone or antibody production, most from SCLC: syndrome of inappropriate antidiuretic hormone secretion (SIADH, rare in other lung tumors), ectopic adrenocorticotropic hormone (ACTH) causing Cushing syndrome, and Lambert-Eaton myasthenic syndrome; squamous NSCLC more often drives hypercalcemia of malignancy through parathyroid hormone-related protein.
• Local invasion causes regional syndromes: a superior sulcus (Pancoast) tumor invading the brachial plexus and stellate ganglion causes ipsilateral Horner syndrome; nodal compression of the superior vena cava (SVC) causes SVC syndrome.

Clinical features

• Most patients present with locally advanced or metastatic disease, because early lesions are typically asymptomatic and found incidentally or through screening.
• Cough, dyspnea, chest pain, weight loss, and hemoptysis are the most common presenting symptoms; NSCLC and SCLC present similarly, so symptoms alone do not distinguish histology.
• Central-airway symptoms (cough, hemoptysis, postobstructive pneumonia, lobar collapse) point toward a centrally located tumor (squamous cell NSCLC or SCLC).
• Findings that indicate advanced disease: consolidation, pleural effusion, bone tenderness, neurologic findings from metastasis.
• Regional invasion syndromes: Pancoast tumor with shoulder/arm pain and ipsilateral Horner syndrome; SVC syndrome with facial/upper-extremity swelling, plethora, and dilated neck/chest wall veins.
• Paraneoplastic presentations, especially with SCLC: hyponatremia from SIADH, Cushing syndrome from ectopic ACTH, Lambert-Eaton myasthenic syndrome (proximal weakness, distinct from myasthenia gravis), hypertrophic pulmonary osteoarthropathy (clubbing, long-bone periostitis, painful polyarthritis).
• An incidental or screen-detected asymptomatic nodule is how early disease presents; malignant CT features are under Diagnosis.

Differential diagnosis

• Pulmonary carcinoid tumor: low-grade neuroendocrine neoplasm (1-2% of lung cancers), no smoking association, monophonic wheeze/recurrent same-segment pneumonia; discriminator is low-grade histology.
• Adenoid cystic carcinoma: rare salivary-gland-type tumor (under 1% of lung cancers); discriminator is cribriform histopathology unlike NSCLC/SCLC on biopsy.
• Metastatic disease to the lung from head and neck, colon, kidney, breast, thyroid, or melanoma: discriminator is a known extrathoracic primary with immunohistochemistry matching that primary rather than a lung phenotype.
• Malignant pleural mesothelioma: asbestos exposure, 20-40 year latency; discriminator is pleural-based nodules/plaques/sheets rather than a discrete parenchymal mass.
• Community-acquired pneumonia or postobstructive pneumonia: discriminator is infiltrate resolution after antibiotics, not persistence; a persistent infiltrate prompts evaluation for an obstructing lesion.
• Benign pulmonary nodule (hamartoma or granuloma): discriminator is a smooth, fat-containing border without growth over 2 years.
• Tuberculosis or fungal infection (histoplasmosis, coccidioidomycosis): discriminator is positive culture or caseating granulomas with compatible exposure history.
• Sarcoidosis: bilateral hilar adenopathy can mimic locally advanced disease; discriminator is noncaseating granulomas with symmetric bilateral nodal involvement.
• Organizing pneumonia: discriminator is an organizing-pneumonia pattern (not malignant cells) on biopsy and resolution with corticosteroids.

Diagnosis

• The definitive diagnosis requires tissue histopathology; no imaging finding substitutes for biopsy-proven malignancy, and cell type must be established before staging and treatment.
• First, initial evaluation: history and physical examination, complete blood count, serum chemistries, and chest CT for any patient with a lung nodule/mass or concerning symptoms.
• Second, assess CT morphology for malignant features (irregular/spiculated borders, upper-lobe location, thick-walled cavitation, a solid component in a ground-glass lesion, interval growth); apply Fleischner follow-up intervals to an indeterminate subsolid nodule (detailed under Prevention).
• Third, PET scan to identify unsuspected mediastinal or distant disease, informing staging and the optimal biopsy site; sensitivity falls for nodules under 1 cm and slow-growing tumors like carcinoid.
• Fourth, obtain tissue at the single site that establishes both diagnosis and stage (central/mediastinal lesions by bronchoscopy, peripheral lesions by transthoracic needle aspiration), then stage definitively: NSCLC uses tumor-node-metastasis (TNM) staging (resectable I-II, locally advanced III, metastatic IV); SCLC uses the same TNM framework but treatment follows limited stage (one hemithorax and ipsilateral supraclavicular nodes fitting one radiation field) versus extensive stage (any disease beyond that).
• Finally, complete molecular and functional workup before treatment: for advanced adenocarcinoma or mixed histology, test EGFR, ALK, and ROS1 status and PD-L1 (programmed death ligand 1) expression; for SCLC, obtain CT of the thorax/abdomen/pelvis plus PET or bone scintigraphy and brain MRI regardless of symptoms; for surgical candidates, obtain FEV1 and DLCO to predict postoperative reserve.

Clinical pearl. In advanced-stage disease, do not biopsy the easiest accessible site reflexively; choose the single invasive test location that simultaneously establishes the diagnosis and the stage (for example a supraclavicular or mediastinal node rather than the primary lung mass), because that one procedure can spare the patient a second one.

Management

• First, define histology, stage, molecular alterations, PD-L1 status, and performance status; poor performance status does not benefit from chemotherapy or immunotherapy and warrants hospice referral.
• Early-stage NSCLC (stage I-II, resectable): lobectomy is preferred; if unresectable, stereotactic body radiation for small stage I tumors or conventional radiation for larger tumors. Add postoperative radiation for positive margins. For resected stage II-III, give adjuvant cisplatin 75 mg/m2 IV day 1 plus a partner every 21 days for 4 cycles (about 5% absolute 5-year mortality reduction), then surveil with exam and chest CT every 6 months for 2 years, then annually.
  • Adjuvant partner: pemetrexed 500 mg/m2 day 1 for adenocarcinoma, otherwise vinorelbine 25 mg/m2 IV days 1 and 8.
• Locally advanced NSCLC (stage III, unresectable, bulky nodal disease): concurrent cisplatin 50 mg/m2 IV plus etoposide 50 mg/m2 IV with thoracic radiation. If stable disease or response after 2+ cycles, consolidate with durvalumab 10 mg/kg IV every 2 weeks for up to 12 months. Selected T4-only or limited single-station nodal disease may be resectable with neoadjuvant/adjuvant therapy instead.
• Metastatic NSCLC (stage IV):
  • EGFR mutation positive: osimertinib 80 mg PO daily until progression.
  • ALK or ROS1 translocation positive: alectinib 600 mg PO twice daily until progression.
  • No driver mutation, PD-L1 50% or higher: single-agent pembrolizumab 200 mg IV every 3 weeks until progression or 24 months.
  • No driver mutation, any PD-L1 level: pembrolizumab plus cisplatin/carboplatin 75 mg/m2 IV day 1 plus pemetrexed 500 mg/m2 (adenocarcinoma) or gemcitabine 1,000 mg/m2 days 1 and 8 (squamous) every 21 days for 4-6 cycles, then continue pembrolizumab.
  • Bevacizumab 15 mg/kg IV every 3 weeks may be added to a non-immunotherapy doublet, non-squamous only; treat a solitary metastasis (often brain) with resection or stereotactic radiation, and start palliative care early.
• Limited-stage SCLC: cisplatin 60 mg/m2 IV day 1 plus etoposide 120 mg/m2 IV days 1-3 every 21 days with concurrent thoracic radiation, up to 6 cycles; if responsive, offer prophylactic cranial irradiation (avoid if age 60+ with cognitive-impairment risk or poor performance status).
• Extensive-stage SCLC: carboplatin AUC 5 IV day 1 plus etoposide 100 mg/m2 IV days 1-3 plus atezolizumab 1,200 mg IV day 1 every 21 days for up to 6 cycles, then atezolizumab alone until progression; consider prophylactic cranial irradiation if responsive and metastasis-free.
• Recurrent SCLC: retreat with the original platinum doublet if the interval since treatment exceeded 3 months; otherwise switch agent class. Prioritize goals of care and symptom control at every relapse.
• If dyspnea persists in advanced disease, reverse its cause first, then palliate: drain a malignant pleural effusion, relieve SVC syndrome or airway obstruction, and treat postobstructive pneumonia; for refractory air hunger give low-dose systemic morphine titrated to relief while dyspnea persists (appropriately dosed, it does not cause respiratory depression), plus upright positioning and a handheld fan. Give oxygen only for hypoxemia; inhaled opioids are ineffective.
• Emergent complications override routine sequencing: SVC syndrome and malignant spinal cord compression need urgent radiation or chemotherapy; massive hemoptysis needs airway protection and urgent bronchial artery embolization first.

Complications

• Superior vena cava syndrome from mediastinal nodal or tumor compression; lung cancer causes most cases.
• Malignant spinal cord compression from vertebral metastasis, needing same-day imaging and treatment.
• Brain metastases, common with NSCLC and especially SCLC.
• Massive hemoptysis from central airway or vascular invasion, an airway emergency.
• Postobstructive pneumonia, lobar collapse, and malignant pleural effusion from endobronchial obstruction or advanced (M1a) disease.
• Paraneoplastic/hormonal syndromes: SIADH hyponatremia, ectopic ACTH/Cushing syndrome, Lambert-Eaton myasthenic syndrome, hypertrophic pulmonary osteoarthropathy, hypercalcemia of malignancy.
• Second primary lung cancer and head/neck cancers in survivors with ongoing smoking exposure.
• Treatment toxicity: cisplatin nephrotoxicity/neuropathy, immune-mediated pneumonitis (higher risk after chemoradiation plus checkpoint inhibition), bevacizumab-related hemoptysis, thrombosis, or perforation.

Prognosis

• Overall 5-year survival is 17.7%, reflecting advanced-stage presentation in most patients.
• Resected stage I NSCLC: 60-70% 5-year survival; stage II: about 40%; resected stage I-IIIA overall: about 50%.
• Locally advanced (stage III) unresectable chemoradiation recurs in up to 90% of patients; durvalumab consolidation improves overall survival in responders.
• Metastatic NSCLC remains incurable for most patients; 5-year survival of 25-30% is reported with front-line pembrolizumab at PD-L1 50% or higher.
• SCLC recurs frequently even after limited-stage response; extensive-stage has the worst prognosis, carcinoid the best (10-year survival above 90% after resection).
• Smoking cessation after diagnosis lowers second-primary risk by 20-90% over the following 5 years.

Prevention

• Screen with annual low-dose CT in adults aged 50 to 80 years with at least a 20-pack-year smoking history who are current smokers or quit within the past 15 years (USPSTF grade B); stop once the patient has not smoked for 15 years, or if limited life expectancy or surgical ineligibility removes the benefit.
• Smoking cessation is the single highest-yield preventive step, lowering primary lung cancer risk and, after diagnosis, second-primary risk by 20-90%.
• Apply Fleischner Society follow-up to every incidental subsolid nodule: pure ground-glass under 6 mm, no follow-up; 6 mm or larger, CT at 6-12 months then every 2 years to 5 years; part-solid under 6 mm, no follow-up; part-solid 6 mm or larger, CT at 3-6 months then annual CT for 5 years if the solid component stays under 6 mm.
• Limit occupational exposure to asbestos, radon, and diesel fumes.

Key points

• Leading cause of cancer death worldwide; NSCLC (about 80%) and SCLC (about 10-15%) share a workup but diverge at staging and treatment.
• Definitive diagnosis requires tissue histopathology; in advanced disease, choose one biopsy site that establishes both diagnosis and stage.
• NSCLC staged by TNM (resectable I-II, locally advanced III, metastatic IV); SCLC staged as limited (fits one radiation field) versus extensive (distant spread).
• Early-stage NSCLC: lobectomy plus adjuvant cisplatin-based chemotherapy for resected stage II-III; radiation for nonsurgical candidates.
• Locally advanced NSCLC: concurrent chemoradiation, then consolidation durvalumab in responders; metastatic NSCLC: match therapy to EGFR/ALK/ROS1 and PD-L1 status.
• SCLC: cisplatin-etoposide chemoradiation for limited stage; carboplatin-etoposide-atezolizumab for extensive stage; prophylactic cranial irradiation for select responders.