Pulmonary · PANCE / PANRE

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

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
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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