Diagnosis of Bronchogenic Carcinoma

1. Clinical Evaluation

• SIADH (inappropriate ADH) - small cell lung cancer (SCLC)
• Ectopic ACTH / Cushing syndrome - SCLC
• Hypercalcemia (PTHrP) - squamous cell carcinoma
• Hypertrophic pulmonary osteoarthropathy - adenocarcinoma
• Lambert-Eaton myasthenic syndrome - SCLC

2. Initial Imaging

Chest X-Ray (CXR)

• Hilar mass or enlargement
• Peripheral pulmonary nodule or mass
• Unilateral pleural effusion
• Mediastinal widening
• Collapse/consolidation (post-obstructive)
• Elevated hemidiaphragm (phrenic nerve palsy)

Chest CT Scan (with IV contrast)

• Primary tumor: size, location, satellite nodules, atelectasis, invasion of adjacent structures (T stage)
• Lymph node status: nodes >1 cm short-axis diameter are considered pathologically enlarged - 62% of nodes 10-15 mm are malignant, 90% of nodes >15 mm are malignant; however, CT alone has pooled sensitivity of only 51% and specificity of 86% for mediastinal nodal metastases
• Extrathoracic disease: pleural effusion, pericardial effusion, pleural nodules, adrenal lesions (found in 4-18% but up to 50% are benign)

CT chest showing discrete mediastinal nodal enlargement (radiographic group B disease) - Fishman's Pulmonary Diseases

3. Advanced Imaging

PET-CT (18-FDG)

• Sensitivity 96%, specificity ~85% for malignancy
• More sensitive and specific than CT for mediastinal lymph node assessment (pooled sensitivity 74%, specificity 85%)
• In patients with enlarged mediastinal nodes: sensitivity up to 100%, specificity 78%
• False positives occur with inflammatory processes (infections, sarcoid, vasculitis, recent surgery, immunotherapy reaction)
• False negatives occur with low-grade malignancies, small lesions (<0.8-1.0 cm), and hyperglycemia
• Approximately 20% of patients with normal mediastinal nodes on both CT and PET will still have occult malignant mediastinal disease

MRI Brain

Bone Scan / Skeletal Survey

4. Tissue Diagnosis - Biopsy Techniques

1. Histopathologic classification (NSCLC vs. SCLC; subtyping within NSCLC)
2. Immunohistochemistry (IHC) markers
3. Molecular/genomic testing for actionable mutations
4. PD-L1 expression for immunotherapy eligibility

Bronchoscopy

• Flexible bronchoscopy: preferred for central, endobronchial lesions; allows direct visualization, biopsy, brushings, and bronchoalveolar lavage (BAL)
• Endobronchial Ultrasound (EBUS) with Transbronchial Needle Aspiration (TBNA): the current standard for mediastinal and hilar lymph node sampling; can reach stations 2R, 2L, 4R, 4L, 7, 10, 11, and 12
• Navigational bronchoscopy (electromagnetic or radial EBUS): extends reach to peripheral lesions

CT-Guided Transthoracic Needle Aspiration/Biopsy (TTNA/TTNB)

• Best for peripheral lesions not reachable by bronchoscopy
• High sensitivity (~90%) for peripheral nodules
• Risk of pneumothorax (~20-25%)

Endoscopic Ultrasound (EUS/EUS-FNA)

• Complements EBUS, particularly for stations 5, 7, 8, and 9 (posterior and inferior mediastinum)
• Combined EBUS + EUS gives the highest diagnostic yield for mediastinal staging

Surgical Biopsy

• Mediastinoscopy: gold standard for mediastinal staging; accesses stations 2R/L, 4R/L, 7
• Video-Assisted Thoracoscopic Surgery (VATS): for pleural effusion/nodules, parenchymal lesions, or accessible lymph nodes not reachable by less invasive methods
• Anterior mediastinotomy (Chamberlain procedure): for stations 5 and 6 (aortopulmonary window, para-aortic)

Other Sites

• Supraclavicular / scalene lymph node biopsy: if palpable nodes present
• Pleural fluid cytology: for effusions (with repeat thoracentesis if initial cytology is negative)
• Bone marrow biopsy: in SCLC with suspected marrow involvement

5. Histopathologic Classification (WHO 2015/2021)

Non-Small Cell Lung Cancer (NSCLC) - ~87% of all cases

Small Cell Lung Cancer (SCLC) - ~13%

• Central location, rapid doubling time
• Neuroendocrine features: synaptophysin+, chromogranin A+, CD56+, TTF-1+ (diffuse)
• Ki-67 very high (>70-90%)
• Almost universally associated with smoking

6. Molecular / Biomarker Testing

7. TNM Staging (IASLC 8th Edition)

• T1a: ≤1 cm; T1b: >1-2 cm; T1c: >2-3 cm
• T2: >3-5 cm, or invades visceral pleura/main bronchus/causes atelectasis to hilum
• T3: >5-7 cm, or invades chest wall/pericardium/phrenic nerve, or separate nodule in same lobe
• T4: >7 cm, or invades mediastinum/heart/great vessels/carina/spine, or nodule in different ipsilateral lobe

• N0: none; N1: ipsilateral pulmonary/hilar; N2: ipsilateral mediastinal/subcarinal; N3: contralateral mediastinal/hilar or supraclavicular

• M0: none; M1a: contralateral lung nodule, pleural/pericardial effusion or nodules; M1b: single extrathoracic metastasis; M1c: multiple extrathoracic metastases (one or more organs)

• Stage I: T1-T2a, N0 (surgically resectable)
• Stage II: T1-T3, N1 or T3 N0 (surgical ± adjuvant)
• Stage III: N2-N3 or T4 (multimodality)
• Stage IV: M1 (systemic therapy)

SCLC Staging

• Limited stage: confined to ipsilateral hemithorax and regional nodes within a single tolerable radiation port (broadly TNM stages I-III) - chemoradiation with curative intent
• Extensive stage: beyond one radiation port, contralateral nodal involvement, malignant effusions, or distant metastases (60-65% of SCLC) - chemotherapy ± palliative radiation

8. Radiographic Staging Groups for Mediastinal Evaluation

9. Laboratory Investigations

• CBC (anaemia, thrombocytopenia suggest marrow involvement)
• LFTs, ALP (hepatic or bony metastases)
• Serum calcium (hypercalcaemia in squamous cell carcinoma)
• Serum sodium (hyponatraemia in SIADH/SCLC)
• Renal function (contrast for imaging, nephrotoxic chemotherapy)
• LDH (prognosis in SCLC)

10. Summary Diagnostic Algorithm

Suspected Lung Cancer (CXR abnormality / symptoms)
        ↓
Chest CT (chest + upper abdomen, IV contrast)
        ↓
PET-CT (metabolic staging, exclude occult metastases)
        ↓
Determine radiographic staging group (A, B, C, D)
        ↓
Tissue Biopsy (least invasive approach first):
  - Peripheral: CT-guided TTNB
  - Central/endobronchial: Bronchoscopy
  - Mediastinal nodes (Groups B & C): EBUS-TBNA ± EUS
  - If above fail: Mediastinoscopy / VATS
        ↓
Histopathology + IHC subtyping
        ↓
Molecular profiling (NSCLC): EGFR, ALK, ROS1, KRAS, BRAF, 
                               MET, RET, NTRK, PD-L1
        ↓
Clinical TNM Stage assignment → Treatment planning

• Over 75% of patients present at locally advanced or metastatic stage; only ~25% have early-stage disease at diagnosis
• CT alone is insufficient for mediastinal staging (sensitivity only 51%); PET-CT and EBUS are required
• Clinical and pathologic TNM stages disagree in ~48% of NSCLC cases, with most patients being clinically understaged
• Histologic subtyping and molecular profiling are now inseparable from diagnosis - targeted therapy depends entirely on them
• SCLC is staged using the limited/extensive two-stage system, though TNM applies and carries prognostic value