Medical School · Year 1 · Respiratory · includes a quiz and discussion video

Lecture 11: Lung Cancer

Unit 1.8: Respiratory System

Learning Objectives

By the end of this lecture, students will be able to:

1. Describe the epidemiology and risk factors for lung cancer
2. Classify lung cancers by histologic type and molecular features
3. Explain the clinical presentation of lung cancer including paraneoplastic syndromes
4. Describe the staging and diagnostic approach to lung cancer
5. Explain treatment options based on histology and stage
6. Describe lung cancer screening guidelines

Epidemiology and Risk Factors

Lung cancer remains the second most common malignancy in both men and women and, more significantly, the leading cause of cancer-related death worldwide. Understanding its epidemiology and risk factors is essential for prevention and early detection.

Incidence and Mortality

Lung cancer affects hundreds of thousands of individuals annually. Despite advances in treatment, overall 5-year survival remains approximately 20% when all stages are combined. However, prognosis varies dramatically by stage at diagnosis: patients with localized disease have 5-year survival approaching 60%, while those with distant metastases have survival rates in the single digits. This stage-dependent prognosis underscores the importance of early detection.

Risk Factors

Cigarette smoking is by far the dominant risk factor, responsible for 85-90% of lung cancer cases. Risk increases in a dose-dependent manner with pack-years of exposure, with heavy smokers having 10-30 times the risk of nonsmokers. Risk begins to decline after smoking cessation but remains elevated for 10-15 years and never returns fully to baseline. Secondhand smoke exposure increases risk by 20-30%.

Radon, a naturally occurring radioactive gas that accumulates in basements and enclosed spaces, is the second leading cause of lung cancer. Occupational exposures to asbestos, arsenic, chromium, nickel, and other industrial carcinogens contribute to risk, with asbestos having a synergistic relationship with smoking that multiplicatively increases risk. Air pollution contributes a modest increase in population-level risk. Prior lung diseases including COPD and pulmonary fibrosis independently elevate risk, likely due to chronic inflammation and altered repair mechanisms. Family history suggests genetic susceptibility, with first-degree relatives of lung cancer patients having 1.5-2 times baseline risk.

Notably, approximately 15% of lung cancers occur in never-smokers, with distinct molecular profiles and often better response to targeted therapies.

<image>Panel A: Pie chart of lung cancer risk factor contributions with smoking occupying 85-90% as the largest red section, radon as the second largest orange slice, occupational exposures in yellow, air pollution as a small gray slice, and other genetic factors in blue. Panel B: Dose-response curve with pack-years of smoking on the x-axis and relative risk on the y-axis, showing steep initial rise then plateauing at high exposure levels. Panel C: Inset timeline of risk reduction after smoking cessation showing steep decline over the first 5 years, gradual decline over 10-15 years, with a dashed line indicating never-smoker baseline that is never fully reached. Panel D: Five-year survival bar chart by stage at diagnosis showing localized disease at approximately 60%, regional disease at approximately 35%, and distant metastatic disease at approximately 5%.</image>

Classification of Lung Cancer

Lung cancer classification is based on histology, with the fundamental distinction being between non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). This division has critical implications for treatment and prognosis.

Non-Small Cell Lung Cancer

NSCLC comprises approximately 85% of lung cancers and includes three major subtypes. Adenocarcinoma is now the most common type (40% of cases), typically arising in the lung periphery. It is the most frequent type in nonsmokers, women, and young patients, and most commonly harbors targetable driver mutations. Histologically, adenocarcinoma forms glandular structures and produces mucin. Precursor lesions progress from atypical adenomatous hyperplasia through adenocarcinoma in situ.

Squamous cell carcinoma accounts for 25-30% of lung cancers and characteristically arises centrally in the major bronchi. It has the strongest association with smoking and develops through a sequence of squamous metaplasia, dysplasia, and carcinoma in situ before becoming invasive. Histologic hallmarks include keratinization with keratin pearl formation and intercellular bridges. Squamous cell carcinoma has a propensity for cavitation due to central necrosis and is associated with hypercalcemia from PTH-related peptide (PTHrP) secretion.

Large cell carcinoma, comprising about 10% of NSCLC, is a diagnosis of exclusion—a poorly differentiated neoplasm lacking features of adenocarcinoma or squamous cell carcinoma. It tends to occur peripherally and has an aggressive course.

Small Cell Lung Cancer

SCLC represents approximately 15% of lung cancers and is almost exclusively seen in smokers. Tumors typically arise centrally in major airways. Histologically, cells appear as small "oat-shaped" cells with scant cytoplasm, high nuclear-to-cytoplasmic ratio, and nuclear molding where cells press against each other. The mitotic rate is extremely high. SCLC is highly aggressive with early metastasis and is classified as limited stage (confined to one hemithorax) or extensive stage (beyond one hemithorax) rather than using TNM staging. Despite initial chemosensitivity, SCLC typically recurs and is associated with multiple paraneoplastic syndromes due to neuroendocrine differentiation.

<image>Panel A: Bronchial tree diagram with tumor locations marked: adenocarcinoma in the peripheral lung at the right lower lobe, squamous cell carcinoma at a central bronchial bifurcation, and small cell lung cancer as a large central hilar mass. Panel B: Adenocarcinoma microscopic view showing glandular structures with cells arranged in acini with mucin-containing lumens, labeled with TTF-1 positive marker, bordered in purple. Panel C: Squamous cell carcinoma microscopic view showing keratin pearls as pink whorled structures and intercellular bridges between cells, labeled with p40 positive marker, bordered in orange. Panel D: Small cell carcinoma microscopic view showing sheets of small dark blue cells with molded nuclei, high nuclear-to-cytoplasmic ratio, and numerous mitoses, labeled with synaptophysin and CD56 positive markers, bordered in dark blue.</image>

Molecular Features and Targeted Therapy

The advent of molecular profiling has transformed NSCLC management, enabling targeted therapy for patients with specific driver mutations. Comprehensive genomic testing is now standard of care for advanced NSCLC.

Driver Mutations

Oncogenic driver mutations promote tumor growth through constitutive activation of growth signaling pathways. When present, targeted inhibition often produces dramatic responses. KRAS mutations occur in 25-30% of adenocarcinomas, primarily in smokers. Previously considered undruggable, the KRAS G12C mutation can now be targeted by sotorasib and similar agents. EGFR mutations occur in 10-15% of adenocarcinomas in Western populations but up to 50% in Asian patients. They are more common in nonsmokers, women, and those of Asian descent. Tyrosine kinase inhibitors (TKIs) like osimertinib produce high response rates and prolonged progression-free survival. ALK rearrangements occur in 3-7% of adenocarcinomas, typically in younger nonsmokers. ALK inhibitors (alectinib, lorlatinib) are highly effective. ROS1 rearrangements (1-2%) share clinical features with ALK and respond to crizotinib and other agents. Other targetable alterations include BRAF V600E (dabrafenib plus trametinib), RET fusions (selpercatinib), MET exon 14 skipping mutations (capmatinib), and NTRK fusions (larotrectinib).

PD-L1 Expression

For patients without actionable driver mutations, immune checkpoint inhibitor therapy is guided by PD-L1 expression on tumor cells. High PD-L1 expression (≥50%) predicts benefit from pembrolizumab monotherapy as first-line treatment. Lower PD-L1 expression (1-49%) supports combination chemoimmunotherapy. Even PD-L1-negative tumors may respond to combination regimens.

Importance of Testing

All patients with advanced non-squamous NSCLC should undergo comprehensive molecular testing, preferably by next-generation sequencing to detect all actionable alterations simultaneously. Testing in squamous cell carcinoma is reasonable in nonsmokers or light smokers, as driver mutations occasionally occur. Results guide first-line therapy selection and identify eligibility for clinical trials.

<image>Panel A: Pie chart of driver mutation frequencies in adenocarcinoma showing KRAS at 25-30% as the largest green slice, EGFR at 15% in blue, ALK at 5% in purple, and smaller slices for ROS1, BRAF, RET, MET, and NTRK, with a substantial unknown/other section. Panel B: Each mutation connected to its corresponding targeted therapy: KRAS G12C to sotorasib, EGFR to osimertinib, ALK to alectinib and lorlatinib, with pill icons for each agent. Panel C: Testing algorithm sidebar showing tissue biopsy leading to next-generation sequencing panel, branching to driver found with targeted therapy or no driver with PD-L1 check guiding immunotherapy with or without chemotherapy. Panel D: Patient demographic silhouettes associated with each mutation: EGFR with Asian female nonsmoker, ALK with young nonsmoker, and KRAS with smoker profile.</image>

Clinical Presentation

Lung cancer often presents with symptoms, though early-stage disease may be asymptomatic and detected incidentally or through screening.

Local Symptoms

Tumors within the lung produce symptoms through airway involvement and local invasion. Cough is present in most patients, reflecting airway irritation or obstruction. Hemoptysis ranges from blood-streaked sputum to massive hemorrhage and should always prompt evaluation. Dyspnea results from airway obstruction, pleural effusion, or parenchymal disease. Chest pain, particularly with pleuritic quality, suggests pleural or chest wall invasion. Wheeze localized to one area suggests bronchial obstruction. Post-obstructive pneumonia occurs when tumor obstructs a bronchus, causing distal infection that may not clear despite antibiotics.

Regional Spread

Extension beyond the lung produces distinct clinical syndromes. Superior vena cava (SVC) syndrome results from tumor compression or invasion of the SVC, causing facial and upper extremity swelling, plethora, and venous distension. It is most common with small cell and squamous cell carcinomas. Hoarseness indicates recurrent laryngeal nerve involvement, particularly with left-sided tumors where the nerve loops under the aortic arch. Phrenic nerve paralysis causes hemidiaphragm elevation and dyspnea. Esophageal compression produces dysphagia.

Pancoast Tumor

A Pancoast tumor (superior sulcus tumor) arises at the lung apex and invades surrounding structures. Patients present with shoulder pain radiating down the arm, often along the C8-T1 dermatome. Brachial plexus involvement causes arm weakness and atrophy. Horner syndrome—the classic triad of ptosis, miosis, and anhidrosis—develops from invasion of the stellate ganglion disrupting sympathetic fibers to the face.

Superior Vena Cava Syndrome

SVC obstruction presents with progressive facial swelling, particularly periorbital edema worse in the morning, neck swelling, headache, and dyspnea. Physical examination reveals facial plethora (redness), jugular venous distension, and dilated chest wall collateral veins. Treatment often requires urgent intervention with stenting, radiation, or chemotherapy depending on histology.

<image>Panel A: Anterior view of a patient with local pulmonary symptoms labeled including cough, hemoptysis, dyspnea, and wheeze, with a chest X-ray insert showing post-obstructive pneumonia distal to a hilar mass. Panel B: Neck and upper chest region showing SVC syndrome with facial swelling, plethora, jugular venous distension, and dilated collateral veins, plus hoarseness from recurrent laryngeal nerve involvement. Panel C: Pancoast tumor at the right lung apex invading the brachial plexus with C8-T1 roots labeled, pain radiation diagram down the medial arm, and Horner syndrome illustrated with ptosis, miosis, and anhidrosis. Panel D: Sagittal view of mediastinal structures including SVC, recurrent laryngeal nerve, phrenic nerve, and esophagus with potential invasion sites marked for each structure.</image>

Metastatic Disease and Paraneoplastic Syndromes

Common Metastatic Sites

Lung cancer spreads to predictable locations, with symptoms reflecting organ involvement. Brain metastases present with headache, seizures, focal neurological deficits, or cognitive changes. Bone metastases cause localized pain and pathological fractures. Liver involvement produces hepatomegaly and elevated liver enzymes. Adrenal metastases are common but usually asymptomatic. The contralateral lung may develop satellite nodules.

Paraneoplastic Syndromes

Paraneoplastic syndromes are remote effects of cancer not attributable to direct tumor invasion, metastasis, infection, or treatment. They are particularly common with SCLC due to its neuroendocrine differentiation.

Hypercalcemia of malignancy occurs most commonly with squamous cell carcinoma, caused by secretion of PTH-related peptide (PTHrP), which mimics parathyroid hormone action. Patients present with confusion, constipation, polyuria, and weakness ("bones, stones, groans, and moans"). Treatment includes hydration and bisphosphonates.

The syndrome of inappropriate antidiuretic hormone (SIADH) is classically associated with SCLC. Ectopic ADH secretion causes water retention and dilutional hyponatremia. Laboratory findings show low serum osmolality with inappropriately concentrated urine. Treatment includes fluid restriction and addressing the underlying malignancy.

Cushing syndrome from ectopic ACTH production is another SCLC-associated syndrome. Unlike pituitary Cushing disease, ectopic ACTH often presents with severe hypokalemia and hyperglycemia rather than classic cushingoid features, due to the rapidity of onset.

Lambert-Eaton myasthenic syndrome (LEMS) occurs with SCLC due to antibodies against voltage-gated calcium channels at the neuromuscular junction. Unlike myasthenia gravis, LEMS produces proximal weakness that improves with repeated use, and autonomic symptoms (dry mouth, constipation) are common. EMG shows characteristic incremental response with repeated stimulation.

Hypertrophic pulmonary osteoarthropathy produces digital clubbing and periostitis of long bones, causing deep, aching bone pain. Radiographs show periosteal new bone formation.

<image>Panel A: Central diagram showing squamous cell carcinoma in orange connecting to hypercalcemia with PTHrP molecule, elevated calcium lab panel, and symptom icons for confusion, bone pain, kidney stones, and constipation. Panel B: SCLC in dark blue connecting to SIADH with ADH molecule, laboratory values showing low sodium, low serum osmolality, and high urine osmolality, and brain showing confusion and seizures. Panel C: Ectopic Cushing syndrome from SCLC showing ACTH arrows, laboratory values with high cortisol and low potassium, and hyperglycemia icon; Lambert-Eaton syndrome showing antibodies attacking calcium channels at the neuromuscular junction with proximal weakness and EMG incremental response tracing. Panel D: Hypertrophic pulmonary osteoarthropathy with clubbed fingers and periostitis of long bones, shown alongside the complete tumor-to-syndrome association map.</image>

Diagnosis

Imaging

The diagnostic evaluation begins with chest imaging. Chest radiograph may reveal a lung mass, nodule, hilar enlargement, or mediastinal widening. CT chest with contrast provides detailed characterization of the primary tumor, nodal involvement, and identifies other abnormalities. Certain radiographic features suggest malignancy: spiculated margins (irregular, sunburst-like), larger size, and upper lobe location. Cavitation is common with squamous cell carcinoma. Ground-glass opacities may represent adenocarcinoma in situ. A central hilar mass suggests squamous cell or small cell carcinoma. PET-CT is essential for staging, as FDG uptake identifies metabolically active tumor and nodal or distant metastases. Brain MRI is performed in all patients with SCLC and those with locally advanced or metastatic NSCLC, as brain metastases are common and may be asymptomatic.

Tissue Diagnosis

Histological confirmation is mandatory before treatment. The approach depends on tumor location. Bronchoscopy is preferred for central lesions, allowing direct visualization and biopsy. Endobronchial ultrasound (EBUS) and endoscopic ultrasound (EUS) access mediastinal lymph nodes, providing both diagnostic tissue and staging information. CT-guided transthoracic needle biopsy is used for peripheral lesions not accessible bronchoscopically. Thoracentesis obtains cells from malignant pleural effusions. Surgical biopsy (video-assisted thoracoscopic surgery or thoracotomy) is reserved for cases where less invasive methods fail.

Solitary Pulmonary Nodule Evaluation

Incidentally discovered pulmonary nodules require systematic evaluation. Risk of malignancy increases with size, spiculated margins, upper lobe location, older age, and smoking history. For nodules smaller than 6 mm, no follow-up may be needed in low-risk patients, while high-risk patients should have CT at 12 months. Nodules 6-8 mm warrant CT surveillance at 6-12 months. Nodules larger than 8 mm should undergo PET-CT and consideration of biopsy or surgical resection. Risk calculators help quantify malignancy probability and guide management.

<image>Panel A: Imaging modalities in sequence: chest X-ray showing a right upper lobe mass marked with circle, CT chest with zoomed view showing spiculated margins, pleural tail, and central necrosis features of the mass. Panel B: PET-CT showing FDG-avid primary tumor and contralateral mediastinal node with SUV values displayed, and brain MRI showing a ring-enhancing metastasis. Panel C: Tissue acquisition methods including bronchoscopy with scope and biopsy forceps in central airways, EBUS with ultrasound probe sampling a subcarinal node, CT-guided biopsy with needle through chest wall into a peripheral nodule, and thoracentesis draining pleural fluid. Panel D: Solitary pulmonary nodule management flowchart with size categories of less than 6 mm, 6-8 mm, and greater than 8 mm, each with corresponding follow-up surveillance and intervention recommendations.</image>

Staging

Accurate staging is essential for treatment planning and prognostication. NSCLC uses TNM staging, while SCLC uses a simplified limited versus extensive stage system.

NSCLC Staging (TNM)

The T (primary tumor) stage reflects tumor size and local invasion. T1 tumors are 3 cm or smaller, T2 are 3-5 cm or involve main bronchus, T3 are 5-7 cm or invade chest wall or pericardium, and T4 are larger than 7 cm or invade mediastinal structures.

The N (nodal) stage describes lymph node involvement. N0 indicates no nodal disease. N1 indicates ipsilateral hilar or peribronchial nodes. N2 indicates ipsilateral mediastinal nodes. N3 indicates contralateral mediastinal or supraclavicular nodes—a poor prognostic finding that generally precludes surgical resection.

The M (metastasis) stage indicates distant spread. M0 is no distant metastasis. M1a includes malignant pleural or pericardial effusion and contralateral lung nodules. M1b indicates a single extrathoracic metastasis. M1c indicates multiple extrathoracic metastases.

Stage Groupings and Prognosis

Combining TNM elements produces stage groupings that predict survival. Stage IA (T1N0M0) has 77-92% 5-year survival. Stage IB through IIB represent progressively worse prognosis. Stage IIIA through IIIC are locally advanced with survival ranging from 13-36%. Stage IV (any M1) carries the poorest prognosis, with 5-year survival below 10%.

SCLC Staging

SCLC is staged as limited or extensive rather than using TNM. Limited stage disease is confined to one hemithorax and regional lymph nodes—essentially a tumor volume that can be encompassed in a single radiation field. Extensive stage disease extends beyond this definition; most patients present with extensive disease.

<image>Panel A: NSCLC T staging on a frontal chest diagram showing T1 as a small peripheral nodule 3 cm or less, T2 involving the main bronchus, T3 invading the chest wall shown with ribs, and T4 invading the mediastinum. Panel B: N staging showing lymph node stations at N1 at the hilum, N2 at the ipsilateral mediastinum, and N3 at the contralateral mediastinum and supraclavicular region; M staging showing M1a with pleural effusion, M1b with a single brain metastasis, and M1c with multiple organ metastases. Panel C: SCLC staging showing limited stage as tumor within a radiation field outline on one hemithorax and extensive stage showing tumor extending beyond with distant metastases. Panel D: Survival curve graph showing 5-year survival percentages decreasing progressively from Stage IA at approximately 85% through Stage IV at less than 5%.</image>

Treatment - NSCLC

Treatment of NSCLC depends on stage at presentation, with curative intent for early-stage disease and palliative systemic therapy for advanced disease.

Stage I-II: Early-Stage Disease

Surgery is the primary treatment for early-stage NSCLC. Lobectomy (removal of one lobe) is the standard of care for resectable tumors. Pneumonectomy (removal of entire lung) is required for centrally located tumors. Sublobar resection (segmentectomy or wedge resection) is appropriate for small tumors or patients with limited pulmonary reserve. Adequate pulmonary function is required; generally, FEV1 should exceed 1.5 L for lobectomy.

Adjuvant therapy reduces recurrence risk after surgery. Platinum-based chemotherapy is recommended for completely resected stage II-III disease. Adjuvant osimertinib is now standard for resected EGFR-mutant NSCLC. Adjuvant atezolizumab (immunotherapy) benefits select patients with PD-L1-positive resected disease.

Stage III: Locally Advanced Disease

Stage III disease presents heterogeneous clinical scenarios. Potentially resectable stage IIIA disease may benefit from neoadjuvant chemoimmunotherapy followed by surgery. Unresectable stage IIIA and stage IIIB disease is treated with definitive concurrent chemoradiation, followed by consolidation durvalumab (immunotherapy) for patients with stable disease and no progression.

Stage IV: Metastatic Disease

Treatment selection for metastatic NSCLC depends on molecular profiling. For patients with actionable driver mutations, targeted therapy is first-line: osimertinib for EGFR mutation, alectinib or lorlatinib for ALK rearrangement, and appropriate agents for other alterations. For patients without driver mutations, treatment is guided by PD-L1 expression. High PD-L1 (≥50%) supports pembrolizumab monotherapy or chemoimmunotherapy. Lower PD-L1 levels are treated with chemoimmunotherapy combinations.

<image>Panel A: Stage I-II treatment pathway showing surgery with lobectomy illustration of right middle lobe removal, followed by post-operative adjuvant chemotherapy with platinum doublet plus or minus targeted therapy with osimertinib or immunotherapy with atezolizumab based on biomarkers. Panel B: Stage III treatment branches showing resectable IIIA with neoadjuvant chemoimmunotherapy followed by surgery, and unresectable disease with concurrent chemoradiation followed by durvalumab consolidation immunotherapy. Panel C: Stage IV with driver mutation pathway leading to targeted therapy pill bottle icons for EGFR, ALK, ROS1, and other alterations with key drugs labeled. Panel D: Stage IV without driver mutation pathway leading to immunotherapy with or without chemotherapy guided by PD-L1 expression shown as a bar graph with 50% or greater and less than 50% thresholds determining treatment selection.</image>

Treatment - SCLC

Small cell lung cancer treatment differs fundamentally from NSCLC due to its aggressive biology and initial chemosensitivity.

Limited Stage

Limited stage SCLC is potentially curable with aggressive multimodality therapy. Treatment combines platinum-based chemotherapy (cisplatin or carboplatin plus etoposide) with concurrent thoracic radiation therapy. The chemotherapy and radiation should begin simultaneously to maximize tumor control. Patients achieving good response should receive prophylactic cranial irradiation (PCI), which reduces the substantial risk of brain metastases and improves survival. Median survival with optimal treatment is 15-20 months, with approximately 20% of patients achieving long-term survival.

Extensive Stage

Extensive stage SCLC represents the majority of cases at diagnosis. First-line treatment is platinum-etoposide chemotherapy combined with immunotherapy (atezolizumab or durvalumab), which has modestly improved survival compared to chemotherapy alone. Thoracic radiation may be considered for patients with good response to systemic therapy. PCI is considered for patients with treatment response, though its benefit is less clear than in limited stage disease. Median survival with extensive stage disease remains approximately 10-12 months despite high initial response rates.

Disease Characteristics

Several features characterize SCLC biology and treatment. The tumor is initially very chemosensitive, with response rates exceeding 80%. However, recurrence is the rule rather than exception, and second-line responses are less robust. Recurrent disease often shows chemotherapy resistance. Brain metastases are extremely common, justifying PCI in responding patients. Surgery plays minimal role except rarely in truly limited stage I disease (small peripheral nodule without nodal involvement), which represents fewer than 5% of cases.

<image>Panel A: Limited stage SCLC treatment showing concurrent chemoradiation with platinum plus etoposide infusion and radiation beam targeting a hilar mass administered simultaneously on a timeline, with prophylactic cranial irradiation depicted as whole-brain radiation. Panel B: Limited stage survival data showing median 15-20 months with 20% long-term survivors. Panel C: Extensive stage SCLC showing first-line chemotherapy plus immunotherapy with atezolizumab or durvalumab icons, optional consolidative thoracic radiation and prophylactic cranial irradiation for responders, with median survival of 10-12 months. Panel D: Central panel of SCLC treatment characteristics showing high initial response rate bar exceeding 80%, common recurrence with resistance indicated by downward arrow, and high brain metastasis risk with brain icon and percentage.</image>

Lung Cancer Screening

Screening programs aim to detect lung cancer at an early, curable stage, improving outcomes in high-risk populations.

USPSTF Recommendations

Current screening guidelines recommend annual low-dose CT (LDCT) for individuals meeting all of the following criteria: age 50-80 years, 20 or more pack-years of smoking history, and currently smoking or quit within the past 15 years. Screening should be discontinued once an individual has not smoked for 15 years or develops a health problem substantially limiting life expectancy or the ability to undergo curative treatment.

Benefits

The National Lung Screening Trial (NLST) demonstrated 20% reduction in lung cancer mortality with LDCT compared to chest radiography. Additional studies have confirmed this benefit. Screening shifts stage at diagnosis toward earlier, more curable stages—the fundamental mechanism of mortality reduction. Many screen-detected cancers are stage I, with 5-year survival exceeding 80% with treatment.

Harms and Limitations

Screening has significant limitations. False positives are common: approximately 25% of screened individuals have nodules detected, the vast majority of which are benign. False positives cause anxiety and may lead to unnecessary procedures with associated morbidity. Overdiagnosis refers to detection of slow-growing cancers that would never have caused clinical symptoms during a patient's lifetime—these patients undergo treatment without benefit. Cumulative radiation exposure from annual CT scanning, though low per scan, may have long-term implications.

Nodule Management

Positive screening results require systematic evaluation using protocols such as Lung-RADS, which categorizes findings and provides management recommendations. Most small nodules are followed with serial CT imaging. Larger or suspicious nodules may require PET-CT, biopsy, or surgical resection. Risk calculators help quantify the probability of malignancy and guide intensity of workup.

<image>Panel A: Screening eligibility criteria checklist including age 50-80 with clock icon, 20 or more pack-years with cigarette pack icon, and current smoker or quit within 15 years with calendar showing quit date. Panel B: LDCT procedure showing patient in CT scanner with resulting image of a small circled nodule, and mortality reduction graph comparing LDCT to chest X-ray demonstrating 20% reduction with confidence interval. Panel C: Screening harms including pie chart of 25% nodule detection rate with large green benign section and small red malignant section, anxiety icon, and cumulative radiation exposure dose diagram. Panel D: Lung-RADS classification flowchart showing categories 1 through 4 with corresponding follow-up recommendations ranging from negative to suspicious, guiding nodule management decisions.</image>

Summary

Lung cancer is the leading cause of cancer death, with cigarette smoking accounting for 85-90% of cases. Never-smokers represent 15% of cases and often have targetable driver mutations.

NSCLC comprises 85% of lung cancers and includes adenocarcinoma (peripheral, mutations common), squamous cell carcinoma (central, smoking-associated, PTHrP hypercalcemia), and large cell carcinoma.

SCLC comprises 15% of lung cancers, is almost exclusively smoking-related, arises centrally, behaves aggressively with early metastasis, and is associated with paraneoplastic syndromes (SIADH, Cushing, Lambert-Eaton).

Molecular testing is essential for advanced NSCLC: EGFR, ALK, ROS1, and KRAS G12C mutations have effective targeted therapies. PD-L1 expression guides immunotherapy use.

Staging for NSCLC uses TNM; SCLC uses limited versus extensive stage classification.

Early-stage NSCLC is treated with surgery and adjuvant therapy. Locally advanced disease receives chemoradiation with consolidation immunotherapy. Metastatic disease treatment is guided by molecular profiling.

SCLC is treated with chemoimmunotherapy; limited stage receives concurrent thoracic radiation, and responding patients should receive prophylactic cranial irradiation.

Lung cancer screening with annual LDCT is recommended for high-risk individuals aged 50-80 with 20 or more pack-years and reduces mortality by 20%.

Key Terms

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