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Lung Tumors - Comprehensive Reference

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1. Overview & Classification

WHO Classification - Major Cell Types

LUNG TUMORS
│
├── PRIMARY MALIGNANT (Epithelial - Bronchogenic Carcinoma)
│   ├── NON-SMALL CELL LUNG CANCER (NSCLC) ~85%
│   │   ├── Adenocarcinoma (~40%) — most common overall
│   │   ├── Squamous Cell Carcinoma (~25-30%)
│   │   └── Large Cell Carcinoma (<10%)
│   │
│   └── SMALL CELL LUNG CANCER (SCLC) ~15%
│
├── NEUROENDOCRINE TUMORS
│   ├── Typical Carcinoid
│   ├── Atypical Carcinoid
│   ├── Large Cell Neuroendocrine Carcinoma (LCNEC)
│   └── Small Cell Lung Carcinoma (SCLC)
│
├── BENIGN TUMORS
│   ├── Hamartoma (most common benign lung tumor)
│   ├── Bronchial Adenoma
│   └── Bronchogenic Cyst
│
└── METASTATIC (Secondary)
    └── Most common: Breast, Colon, Kidney, Melanoma

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2. Risk Factors

• Harrison's Principles of Internal Medicine 22E, pp. 1332-1336

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3. Individual Tumor Types in Detail

3A. ADENOCARCINOMA

• Most common subtype in the United States and most countries
• Most frequent in never-smokers, women, younger adults (<60 years)
• Arises peripherally; shows glandular differentiation or mucin production
• Growth patterns: acinar, papillary, lepidic (formerly BAC), solid, or mixed
• 2021 WHO subtypes: adenocarcinoma in situ (AIS), minimally invasive (MIA), invasive
• Driver mutations (targetable): EGFR, ALK, KRAS, ROS1, BRAF, RET, MET, ERBB2, NTRK
• Mucinous lepidic subtype → usually KRAS-driven; signet ring subtype → ALK fusion

3B. SQUAMOUS CELL CARCINOMA

• Strongly linked to cigarette smoking (strongest correlation of all subtypes)
• Arises centrally from bronchial epithelium
• Shows keratinization and/or intercellular bridges; sheets of cells
• Produces PTH-related peptide → hypercalcemia (most common paraneoplastic endocrine syndrome)
• IHC: p40/p63 positive, TTF-1 negative

3C. LARGE CELL CARCINOMA

• Represents <10% of lung carcinomas
• Diagnosis of exclusion - lacks cytologic features of SCLC, glandular or squamous differentiation
• Requires morphologic examination of resected tumor + IHC
• Large cells with prominent nucleoli, moderate cytoplasm
• Most are immunophenotypically adenocarcinoma or squamous - only a small subset are truly "marker-null"

3D. SMALL CELL LUNG CANCER (SCLC)

• Most aggressive lung cancer; rapid doubling time, early dissemination
• Origin: pulmonary neuroendocrine cells (Kulchitsky cells)
• Histology: small cells, scant cytoplasm, ill-defined borders, finely granular chromatin ("salt and pepper"), absent nucleoli, high mitotic rate
• IHC markers: CD56, NCAM, synaptophysin, chromogranin, INSM1
• Staged as Limited Disease (LD) vs Extensive Disease (ED) (rather than TNM)
  • LD: confined to one hemithorax within a tolerable radiation field
  • ED: beyond one hemithorax, including malignant pericardial/pleural effusion
• Strongly associated with paraneoplastic syndromes (see below)

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4. Molecular Biomarkers & Targeted Therapy

• Grainger & Allison's Diagnostic Radiology, pp. 1124-1125

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5. Clinical Presentation

Symptoms by Location

CLINICAL PRESENTATION
│
├── CENTRAL TUMORS (SCC, SCLC)
│   ├── Cough, hemoptysis
│   ├── Wheezing, stridor
│   ├── Postobstructive pneumonia
│   └── Atelectasis
│
├── PERIPHERAL TUMORS (Adenocarcinoma)
│   ├── Often asymptomatic early
│   ├── Pleuritic chest pain
│   └── Pleural effusion
│
├── MEDIASTINAL INVOLVEMENT
│   ├── SVC syndrome (facial/arm swelling)
│   ├── Horner's syndrome (Pancoast tumor)
│   ├── Hoarseness (recurrent laryngeal nerve)
│   ├── Dysphagia (esophageal compression)
│   └── Phrenic nerve palsy
│
└── METASTATIC SYMPTOMS
    ├── Brain: headache, seizures, neuro deficits
    ├── Bone: pain, pathologic fractures, cord compression
    ├── Liver: hepatomegaly, RUQ pain
    └── Adrenal: usually asymptomatic

Paraneoplastic Syndromes

• Harrison's Principles of Internal Medicine 22E, pp. 1477-1486

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6. TNM Staging (AJCC 8th Edition - NSCLC)

TNM STAGING SYSTEM (IASLC/AJCC 8th Edition)

T - PRIMARY TUMOR
├── TX  Positive cytology, no lesion identified
├── T0  No evidence of primary tumor
├── Tis Carcinoma in situ
├── T1  ≤3 cm, surrounded by lung/visceral pleura, no bronchoscopic
│   ├── T1a ≤1 cm
│   ├── T1b >1 cm, ≤2 cm
│   └── T1c >2 cm, ≤3 cm
├── T2  >3 cm, ≤5 cm OR involves main bronchus / visceral pleura / atelectasis
│   ├── T2a >3 cm, ≤4 cm
│   └── T2b >4 cm, ≤5 cm
├── T3  >5 cm, ≤7 cm OR chest wall, pericardium, phrenic nerve / satellite nodule same lobe
└── T4  >7 cm OR diaphragm, mediastinum, heart, great vessels, trachea / satellite nodule different lobe

N - REGIONAL LYMPH NODES
├── N0  No nodes
├── N1  Ipsilateral peribronchial / hilar / intrapulmonary nodes
├── N2  Ipsilateral mediastinal / subcarinal nodes
└── N3  Contralateral mediastinal/hilar OR supraclavicular/scalene nodes

M - DISTANT METASTASIS
├── M0  No distant metastasis
├── M1a Within thoracic cavity (opposite lobe, pleural/pericardial effusion)
├── M1b Single extrathoracic metastasis
└── M1c Multiple extrathoracic metastases

STAGE GROUPINGS
Stage IA1  T1a N0 M0
Stage IA2  T1b N0 M0
Stage IA3  T1c N0 M0
Stage IB   T2a N0 M0
Stage IIA  T2b N0 M0
Stage IIB  T3 N0 M0 / T1-2 N1 M0
Stage IIIA T4 N0-1 / T1-3 N2 M0
Stage IIIB T1-2 N3 / T3-4 N2 M0
Stage IIIC T3-4 N3 M0
Stage IVA  Any T, Any N, M1a or M1b
Stage IVB  Any T, Any N, M1c

• Mulholland & Greenfield's Surgery 7e, p. 4271

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7. Diagnostic Workup

Approach to a Solitary Pulmonary Nodule (Flowchart from Harrison's 22E)

• Benign calcification pattern OR stability for 2 years on archival imaging → no further testing
• Low probability (<10%) → serial HRCT at 3, 6, 9, 12, 18, and 24 months
• Moderate probability (10-60%) → PET (if ≥1 cm), contrast CT, TTNA if peripheral, bronchoscopy if air-bronchus sign
• High probability / surgical candidate → Video-assisted thoracoscopic surgery (VATS) with frozen section; lobectomy if malignant
• TTNA: sensitivity >90%, but false-negative rate up to 20-30%; 15% pneumothorax risk

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8. Treatment

NSCLC Treatment by Stage

NSCLC TREATMENT ALGORITHM
│
├── Stage I-II (Resectable)
│   ├── Surgery (lobectomy preferred; segmentectomy/wedge if poor pulmonary reserve)
│   ├── Adjuvant chemotherapy (stages II-IIIA; cisplatin-based x4 cycles)
│   ├── From 2020+: Adjuvant osimertinib (EGFR+), adjuvant atezolizumab (PD-L1+)
│   └── SBRT for medically inoperable stage I
│
├── Stage IIIA-B (Locally Advanced)
│   ├── Concurrent chemoradiation (cisplatin/etoposide + RT)
│   └── Durvalumab consolidation (if no progression post-CRT, PD-L1 ≥1%)
│
└── Stage IV (Metastatic)
    ├── Test for driver mutations → Targeted therapy (TKI)
    └── If driver-negative → Immunotherapy ± chemotherapy by PD-L1 and histology

Targeted Therapy Flowchart for Stage IV NSCLC (from Harrison's 22E)

Immunotherapy Flowchart - Stage IV Driver-Mutation-Negative NSCLC

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SCLC Treatment Algorithm (from Harrison's 22E)

• Limited disease: Concurrent cisplatin + etoposide x4 cycles + thoracic RT → standard of care for >40 years. Adding atezolizumab or durvalumab to chemo now preferred in appropriate patients.
• Extensive disease: Carboplatin/etoposide + atezolizumab (IMpower133) or durvalumab (CASPIAN); superior PFS and OS vs chemo alone.
• Median survival: 12-20 months (LD), ~12 months (ED); despite 80% initial response rates, almost all relapse.
• Second-line: Topotecan (IV or oral) or lurbinectedin (35% response rate).
• PCI (Prophylactic Cranial Irradiation): Reduces brain metastasis risk in responders; controversial in ED.

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9. Chemotherapy by Histology (NSCLC)

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10. Summary Comparison Table

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11. Screening

• Low-dose CT (LDCT) screening is recommended for:
  • Age 50-80 years
  • ≥20 pack-year smoking history
  • Currently smoking or quit within the past 15 years
• Reduces lung cancer mortality by ~20% in high-risk populations (National Lung Screening Trial)

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Key Takeaways

1. Adenocarcinoma is now the most common lung cancer subtype, having surpassed squamous cell over the past 30 years due to changes in smoking habits.
2. The critical first distinction is SCLC vs NSCLC - they have fundamentally different biology, staging systems, and treatment approaches.
3. All advanced NSCLC should have molecular profiling before starting systemic therapy - targeted TKIs can be dramatically more effective than chemotherapy for driver-positive tumors.
4. PD-L1 expression and histology (squamous vs non-squamous) drive first-line immunotherapy decisions in driver-mutation-negative NSCLC.
5. SCLC, despite high initial chemotherapy response rates (up to 80%), almost universally relapses, making it one of the most challenging malignancies to treat.