Chapter 83: Neoplasms of the Lung¶
Chapter 83 | Part 4: Oncology and Hematology
KEY CLINICAL POINTS¶
- Lung cancer is the leading cause of cancer-related mortality globally, with ~1.8 million deaths annually. Smoking remains the primary risk factor, accounting for ~85% of cases.
- The TNM staging system (8th edition) is critical for determining treatment strategies, with stage I NSCLC having a 5-year survival rate of ~63% with surgical resection.
- Immunotherapy (e.g., pembrolizumab, atezolizumab) has transformed treatment for PD-L1-positive NSCLC, with significant survival benefits in stage III and IV disease.
- Targeted therapies (e.g., EGFR TKIs, ALK inhibitors) are effective in specific molecular subtypes, with response rates up to 80% in EGFR-mutant NSCLC.
- SCLC is highly aggressive with rapid progression, treated with concurrent chemoradiation for limited-stage disease and platinum-based chemotherapy for extensive-stage disease.
1. DEFINITION & OVERVIEW¶
Lung cancer encompasses malignancies arising from the respiratory epithelium, including small-cell lung cancer (SCLC) and non-small-cell lung cancer (NSCLC). NSCLC includes adenocarcinoma, squamous cell carcinoma, and large-cell carcinoma. SCLC is characterized by rapid growth, early metastasis, and responsiveness to chemotherapy.
Table 83-1: Genetic Alterations with Existing Therapies in NSCLC¶
| GENE | ALTERATION | FREQUENCY IN NSCLC (%) | TYPICAL HISTOLOGY |
|---|---|---|---|
| ALK | Rearrangement | 3–7% | Adenocarcinoma |
| ALK | Mutation | 1–3% | |
| EGFR | Mutation | 10–35% | Adenocarcinoma |
| EGFR | Mutation | 2–4% | |
| KRAS | Mutation | 15–25% | Adenocarcinoma |
| KRAS | Amplification | 2–4% | |
| MET | Amplification | 2–4% | Adenocarcinoma |
| ROS1 | Rearrangement | 1–2% | Adenocarcinoma |
| RET | Rearrangement | 1–2% | Adenocarcinoma |
| NTRK | Rearrangement | 1–2% | Adenocarcinoma |
1.1 Histopathologic Classification¶
NSCLC is classified into four main types: adenocarcinoma (most common in never-smokers), squamous cell carcinoma (linked to tobacco use), large-cell carcinoma, and neuroendocrine tumors (SCLC). Adenocarcinoma is increasingly common in never-smokers and women.
1.2 Molecular Subtypes¶
Key molecular drivers include EGFR mutations (10–15% of NSCLC), ALK rearrangements (3–7% of NSCLC), KRAS mutations (15–25% of NSCLC), and ROS1 fusions (1–2% of NSCLC).
2. EPIDEMIOLOGY¶
Lung cancer is the leading cause of cancer mortality globally, with ~1.8 million deaths in 2020. Incidence peaks in individuals aged 65–74 years. Smoking accounts for ~85% of cases, with 10–15% of patients having a family history of lung cancer. Never-smokers account for ~15% of cases, with adenocarcinoma being more common in this group.
Table 83-2: Benefits and Harms of LDCT Screening¶
| LDCT | CXR |
|---|---|
| 4 in 1000 fewer died from lung cancer | 13 in 1000 |
| 5 in 1000 fewer died from all causes | 70 in 1000 |
| 223 in 1000 had at least 1 false alarm | 365 in 1000 |
| 18 in 1000 had a false alarm leading to invasive procedure | 25 in 1000 |
| 2 in 1000 had a major complication from invasive procedure | 3 in 1000 |
2.1 Demographics¶
Incidence is higher in males (235,000 new cases in 2024) and increases with age, peaking at 70–74 years. African Americans have higher age-adjusted rates than Caucasians. Never-smokers account for ~15% of cases, with adenocarcinoma being more common.
2.2 Screening¶
LDCT screening reduces lung cancer mortality by 20% in high-risk populations (55–74 years, ≥ 30 pack-years smoking history). The NLST demonstrated a 20% reduction in mortality with LDCT compared to CXR.
3. ETIOLOGY & PATHOPHYSIOLOGY¶
Tobacco smoke is the primary cause, with ~85% of cases linked to smoking. Environmental carcinogens (asbestos, radon) and genetic factors (TP53, RB1 mutations) also contribute. Molecular mechanisms include driver mutations (EGFR, KRAS, ALK) and epigenetic changes.
Table 83-3: Presenting Signs and Symptoms of Lung Cancer¶
| SYMPTOM AND SIGNS | RANGE OF FREQUENCY |
|---|---|
| Cough | 8–75% |
| Weight loss | 0–68% |
| Dyspnea | 3–60% |
| SYMPTOM AND SIGNS | RANGE OF FREQUENCY |
|---|---|
| Chest pain | 20–49% |
| Hemoptysis | 6–35% |
| Bone pain | 6–25% |
| Clubbing | 0–20% |
| Fever | 0–20% |
| Weakness | 0–10% |
| Superior vena cava obstruction | 0–4% |
| Dysphagia | 0–2% |
| Wheezing and stridor | 0–2% |
3.1 Genetic Mutations¶
Key mutations include EGFR (exon 19 deletion, L858R), KRAS (G12C), ALK rearrangements, and ROS1 fusions. These drive tumor growth and are targets for therapy.
3.2 Paraneoplastic Syndromes¶
Common syndromes include hypercalcemia (PTH-related), SIADH, and Cushing’s syndrome. These are more prevalent in SCLC and can mimic metastatic disease.
4. CLINICAL FEATURES¶
Most patients present with advanced disease (stage III/IV). Common symptoms include cough, hemoptysis, weight loss, and dyspnea. Paraneoplastic syndromes (e.g., SIADH, Cushing’s) are common in SCLC.
Table 83-4: Clinical Findings Suggestive of Metastatic Disease¶
| SYMPTOMS ELICITED IN HISTORY | CLINICAL FINDINGS ON PHYSICAL EXAMINATION |
|---|---|
| Constitutional: weight loss >10 lb | Lymphadenopathy (>1 cm) |
| Musculoskeletal: pain | Hoarseness, superior vena cava syndrome |
| Neurologic: headaches, syncope, seizures, extremity weakness, recent change in mental status | Bone tenderness, hepatomegaly (>13 cm span) |
| Focal neurologic signs, papilledema | |
| Soft-tissue mass |
4.1 Localized Disease¶
Stage I/II NSCLC presents with localized tumors. Stage III involves regional lymph node involvement. Stage IV has distant metastases (bone, brain, liver).
4.2 Metastatic Disease¶
Metastases to bone, brain, liver, and adrenal glands are common. Brain metastases occur in ~10% of patients, often in SCLC. Skeletal metastases cause pain and pathologic fractures.
5. DIAGNOSTIC APPROACH¶
Diagnosis requires tissue sampling (biopsy, cytology) and imaging (CT, PET). Biomarker testing (EGFR, ALK, ROS1) guides targeted therapy. PD-L1 expression determines immunotherapy eligibility.
Table 83-5: TNM Staging System for Lung Cancer (8th Edition)¶
| PRIMARY TUMOR (T) | NODES (N) | METASTASES (M) |
|---|---|---|
| T1: £3 cm | N0: No regional lymph node metastases | M0: No distant metastasis |
| T1mi: Minimally invasive adenocarcinoma | N1: Ipsilateral peribronchial/hilar lymph nodes | M1a: Separate tumor nodule(s) in contralateral lobe |
| T2: >3 cm but £5 cm | N2: Mediastinal/subcarinal lymph nodes | M1b: Single distant metastasis |
| T3: >5 cm but £7 cm | N3: Contralateral mediastinal/hilar lymph nodes | M1c: Multiple distant metastases |
| T4: >7 cm or invasion of mediastinum, heart, great vessels | N3: Contralateral mediastinal/hilar lymph nodes | M1: Distant metastasis |
5.1 Imaging¶
LDCT is preferred for screening. PET-CT improves staging accuracy. MRI is essential for brain metastases. Bone scans detect skeletal metastases.
5.2 Biomarker Testing¶
Next-generation sequencing (NGS) identifies actionable mutations. PD-L1 testing ( ≥ 1% or ≥ 50%) guides immunotherapy selection.
6. MANAGEMENT & TREATMENT¶
Treatment depends on stage and molecular profile. Early-stage NSCLC is managed with surgery (lobectomy) and adjuvant chemotherapy. Advanced disease uses immunotherapy, targeted therapy, or chemoradiation.
Table 83-6: TNM Stage Groupings, 8th Edition¶
| T/M | SUBCATEGOR Y | N0 | N1 | N2 | N3 |
|---|---|---|---|---|---|
| T1a | IA1 | IIB | IIIB | IIIA | IIIB |
| T1b | IA2 | IIB | IIIB | IIIA | IIIB |
| T1c | IA3 | IIB | IIIB | IIIA | IIIB |
| T2a | IB | IIB | IIIB | IIIA | IIIB |
| T2b | IIA | IIB | IIIA | IIIB | IIIC |
| T3 | IIB | IIIA | IIIB | IIIC | IIIC |
| T4 | IIIA | IIIA | IIIB | IIIC | IVB |
| M1a | IVA | IVA | IVA | IVA | IVB |
| M1b | IVA | IVA | IVA | IVA | IVB |
| M1c | IVB | IVB | IVB | IVB | IVB |
6.1 Early-Stage NSCLC¶
Surgical resection (lobectomy) is the standard for stage I/II. Adjuvant chemotherapy (e.g., platinum-based) improves survival. Radiation may be used for inoperable cases.
6.2 Advanced NSCLC¶
First-line treatment includes immunotherapy (pembrolizumab, atezolizumab) for PD-L1 ≥ 50%, or chemotherapy with immunotherapy for PD-L1 ≥ 1%. Targeted therapy for EGFR/ALK mutations.
7. PROGNOSIS & COMPLICATIONS¶
5-year survival for stage I NSCLC is ~63% with surgery. Prognosis worsens with advanced stage. Complications include treatment-related toxicity (e.g., pneumonitis, myelosuppression), paraneoplastic syndromes, and metastatic disease.
Table 83-7: Assessment of Risk of Cancer in Patients with Solitary Pulmonary Nodules¶
| VARIABLE | LOW RISK | INTERMEDIATE RISK | HIGH RISK |
|---|---|---|---|
| Diameter (cm) | <1.5 | 1.5–2.2 | ‡2.3 |
| Age (years) | <45 | 45–60 | >60 |
| Smoking status | Never smoker | Current smoker (<20 cigarettes/d) | Current smoker (>20 cigarettes/d) |
| Smoking cessation | Quit ‡7 years ago | Quit <7 years ago | Never quit |
| Characteristics of nodule margins | Smooth | Scalloped | Spiculated |
7.1 Survival Rates¶
Stage I: 63% 5-year survival. Stage II: 50–60%. Stage III: 15–30%. Stage IV: <10%.
7.2 Treatment Toxicity¶
Chemotherapy: myelosuppression, mucositis. Radiation: esophagitis, pneumonitis. Immunotherapy: immune-related adverse events (e.g., colitis, pneumonitis).
8. SPECIAL CONSIDERATIONS¶
Pregnancy, pediatric, and elderly populations require tailored approaches. Never-smokers and women have distinct clinical profiles. SCLC has a poor prognosis with limited treatment options.
Table 80-1: Phase 3 Trials of EGFR TKIs in EGFR-Positive NSCLC¶
| TRIAL | THERAPY | NO. OF PATIENTS | ORR (%) | PFS (MONTHS) |
|---|---|---|---|---|
| IPASS | Cisplatin/paclitaxel | 129 | 47 | 6.3 |
| IPASS | Gefitinib | 132 | 71 | 9.3 |
| OPTIMAL | Cisplatin/gemcitabin e | 72 | 36 | 4.6 |
| OPTIMAL | Erlotinib | 82 | 83 | 13.1 |
| WJTOG3405 | Cisplatin/docetaxel | 89 | 31 | 6.3 |
| WJTOG3405 | Gefitinib | 88 | 62 | 9.2 |
| LUX-LUNG 3 | Cisplatin/paclitaxel | 115 | 23 | 6.9 |
| TRIAL | THERAPY | NO. OF PATIENTS | ORR (%) | PFS (MONTHS) |
|---|---|---|---|---|
| LUX-LUNG 3 | Afatinib | 230 | 56 | 11.1 |
| LUX-LUNG 6 | Cisplatin/gemcitabin e | 122 | 23 | 5.6 |
| LUX-LUNG 6 | Afatinib | 242 | 67 | 11.0 |
| ARCHER 1050 | Gefitinib | 225 | 72 | 9.2 |
| ARCHER 1050 | Dacomitinib | 227 | 75 | 14.7 |
| FLAURA | Erlotinib or gefitinib | 277 | 76 | 16.7 |
| FLAURA | Osimertinib | 279 | 80 | 17.2 |
| FLAURA2 | Osimertinib/chemoth erapy | 279 | 83 | 25.5 |
| FLAURA2 | Osimertinib | 278 | 76 | 16.7 |
| MARIPOSA | Amivantamab/lazerti nib | 429 | 86 | 23.7 |
| MARIPOSA | Osimertinib | 429 | 85 | 16.6 |
8.1 Never-Smokers¶
Adenocarcinoma is more common in never-smokers. Molecular testing is critical for targeted therapy.
8.2 SCLC in Elderly¶
Elderly patients with SCLC have higher mortality and are often treated with palliative chemotherapy.
9. KEY POINTS & CLINICAL PEARLS¶
- Lung cancer is the leading cause of cancer mortality globally, with smoking as the primary risk factor. 2. Early detection with LDCT reduces mortality by 20% in high-risk populations. 3. Molecular testing is critical for selecting targeted therapies (EGFR, ALK, ROS1). 4. Immunotherapy improves survival in PD-L1-positive NSCLC. 5. SCLC is highly aggressive with poor prognosis, requiring concurrent chemoradiation for limited-stage disease.