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.
Try two board-style Lung Cancer questions
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Question 1PulmonaryEasy
A 65-year-old man who currently smokes and has a 30-pack-year history presents to establish primary care and asks about lung cancer screening. He is asymptomatic, and his physical examination is normal. Which of the following is the most appropriate screening test?
APET scan every 2 years
BAnnual contrast CT chest
CAnnual sputum cytology
DAnnual low-dose CT chest
EAnnual chest radiography
Reveal answer & full explanation
Correct answer: D — Annual low-dose CT chest
APET scan every 2 years
BAnnual contrast CT chest
CAnnual sputum cytology
DAnnual low-dose CT chest✓
EAnnual chest radiography
Why Annual low-dose CT chest is correct
Per current USPSTF guidance, annual low-dose CT (LDCT) is recommended for adults aged 50–80 years with a ≥20 pack-year history who currently smoke or quit within the past 15 years.
This 65-year-old current smoker with a 30 pack-year history meets every eligibility criterion.
LDCT is the only modality shown to reduce lung cancer mortality (by roughly 20%) in a screening population (National Lung Screening Trial).
Why the others are wrong
Annual sputum cytology — Poor sensitivity, especially for peripheral tumors, and not a recommended screening test; a buzzword-matching trap for anyone who equates 'lung cancer' with sampling secretions.
Annual chest radiography — The PLCO trial showed chest radiography does not reduce lung cancer mortality, so it is not used for screening; the premature-closure choice based on an abandoned practice.
PET scan every 2 years — PET characterizes and stages known or indeterminate nodules rather than screening asymptomatic patients, and carries radiation and false-positive costs; a right-tool-wrong-setting trap.
Annual contrast CT chest — CT is the right modality, but lung cancer screening uses a low-dose, noncontrast protocol; a standard contrast-enhanced CT adds radiation dose and IV contrast risk, and the mortality reduction was shown with low-dose noncontrast CT (NLST); a right-modality-wrong-protocol trap.
Question 2PulmonaryMedium
A 68-year-old man with unresectable stage III squamous cell non-small cell lung cancer has just completed concurrent chemoradiotherapy with no evidence of disease progression on restaging. His Eastern Cooperative Oncology Group performance status is 1, and tumor PD-L1 expression is 40%. Which of the following is the most appropriate next step in management?
APlatinum-based chemotherapy consolidation
BObservation with serial imaging
CBevacizumab maintenance therapy
DDurvalumab consolidation for 12 months
EProphylactic cranial irradiation
Reveal answer & full explanation
Correct answer: D — Durvalumab consolidation for 12 months
APlatinum-based chemotherapy consolidation
BObservation with serial imaging
CBevacizumab maintenance therapy
DDurvalumab consolidation for 12 months✓
EProphylactic cranial irradiation
Why durvalumab consolidation for 12 months is correct
For unresectable stage III non-small cell lung cancer that has not progressed after concurrent chemoradiotherapy, consolidation with the anti-PD-L1 antibody durvalumab for up to 12 months is the standard of care, established by the PACIFIC trial.
Durvalumab improves both progression-free and overall survival compared with observation and is recommended regardless of PD-L1 level.
Consolidation should begin promptly (within about 6 weeks) after completion of chemoradiotherapy.
The patient's good performance status (ECOG 1) and absence of progression make him an appropriate candidate.
Why the others are wrong
Prophylactic cranial irradiation — Cranial irradiation lowers the rate of brain metastases in stage III non-small cell lung cancer but confers no survival benefit and is not standard after chemoradiotherapy; it belongs to limited-stage small cell disease (confused-with small cell).
Platinum-based chemotherapy consolidation — Additional consolidation chemotherapy after definitive chemoradiotherapy has not shown a survival benefit and is not standard (right-disease-wrong-step).
Observation with serial imaging — Forgoing durvalumab withholds a proven survival advantage and is inferior to consolidation immunotherapy (premature closure on watchful waiting).
Bevacizumab maintenance therapy — maintenance bevacizumab follows first-line chemotherapy in metastatic nonsquamous disease, but it is avoided in squamous histology because of the risk of serious pulmonary hemorrhage and has no role in consolidation after chemoradiotherapy for stage III disease (right-drug-wrong-histology).
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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
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 (IASLC 9th edition / AJCC Version 9, in use since January 2025) for NSCLC; SCLC traditionally classified as limited stage (confined to one hemithorax/single radiation port) vs extensive.
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; sample the most accessible site that also establishes the highest stage (e.g., biopsy of a palpable supraclavicular node, or thoracentesis of a pleural effusion)
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
Poorly differentiated; diagnosis of exclusion (no glandular, squamous or neuroendocrine differentiation on histology and IHC); aggressive
Small cell (SCLC)
~15%
Central
Rapid growth, early mets; paraneoplastic SIADH, Cushing, LEMS; staged as limited/extensive
Lung cancer histologic subtypes — clinical and biologic distinctions.
Treatment
First-line
NSCLC Stage I-II (early): surgical resection (lobectomy preferred, VATS) + mediastinal nodal sampling; SBRT for non-surgical candidates. After resection of stage II-IIIA: adjuvant cisplatin-based chemotherapy, then immunotherapy (atezolizumab if PD-L1 ≥1%, or pembrolizumab); EGFR-mutant: adjuvant osimertinib (ADAURA). Neoadjuvant or perioperative chemo-immunotherapy is an alternative for resectable tumors ≥4 cm or node-positive (CheckMate 816, KEYNOTE-671)
NSCLC unresectable Stage III (including any supraclavicular/scalene or contralateral mediastinal node = N3, stage IIIB/IIIC, which is regional disease, not M1): concurrent chemoradiation (cisplatin/carboplatin + etoposide/pemetrexed/paclitaxel + radiation), followed by consolidation durvalumab (PACIFIC trial), or osimertinib if EGFR-mutant (LAURA). Selected resectable N2 disease: neoadjuvant chemo-immunotherapy, then surgery
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), capmatinib (METex14). KRAS G12C is treated first-line like driver-negative disease (PD-L1-guided chemo-immunotherapy); sotorasib/adagrasib are approved only after prior systemic therapy
SCLC limited stage: concurrent chemoradiation (cisplatin/carboplatin + etoposide) then consolidation durvalumab (ADRIATIC); prophylactic cranial irradiation (or MRI brain surveillance in selected patients) if response
NSCLC second-line: docetaxel ± ramucirumab; nivolumab/pembrolizumab if not previously used; KRAS G12C: sotorasib or adagrasib after prior systemic therapy; EGFR progression on osimertinib: re-biopsy/NGS for resistance mechanisms, then platinum chemotherapy ± amivantamab (MARIPOSA-2)
SCLC second-line: tarlatamab (DLL3-directed bispecific T-cell engager; survival benefit over chemotherapy in DeLLphi-304), 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)
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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