Lung Carcinoma - WHO Classification & Non-Small Cell Carcinoma

Robbins & Kumar Basic Pathology (Robbins Pathology)

Epidemiology & Overview

• ~237,000 new cases and ~130,000 deaths in the US (2022 data)
• Peak incidence: 5th-6th decade of life
• At diagnosis: >50% already have distant metastases; an additional 25% have regional lymph node involvement
• Overall 5-year survival (all stages): ~20%; even localized disease carries only ~50% 5-year survival
• Smoking is the dominant risk factor; ~90% of lung cancers occur in current or recent smokers
• Risk is 60x greater in heavy smokers (2 packs/day x 20 years) vs. nonsmokers

2021 WHO Classification (Table 11.5, Robbins)

The older division into SCLC and NSCLC was clinically driven: NSCLC (adenocarcinoma, squamous cell, large cell) tends to be more resectable and responds poorly to conventional chemotherapy as a group, whereas SCLC has almost always spread at presentation. With targeted therapy and checkpoint inhibitors now available for NSCLC subsets, the WHO adopted a more granular classification.

Non-Small Cell Lung Carcinoma (NSCLC)

1. Adenocarcinoma

• Most common in: women, never-smokers, individuals < 45 years
• Arises from peripheral lung parenchyma

• Atypical adenomatous hyperplasia (AAH)
• Adenocarcinoma in situ (AIS)
• Minimally invasive adenocarcinoma
• Invasive adenocarcinoma

• Peripheral location, often subpleural
• May show central scarring ("scar carcinoma")
• Can spread along alveolar walls (lepidic growth) - formerly "bronchioloalveolar carcinoma"

• Glandular architecture (acinar, papillary, micropapillary, solid, lepidic patterns)
• Mucin production present
• Prominent nucleoli; abundant cytoplasm

• EGFR and KRAS mutations are mutually exclusive (KRAS lies downstream of EGFR)
• Tumor suppressor abnormalities: 3p deletions (~80%), TP53 (~50%), p16/CDKN2A (~50%), RB (~20%)

• TTF-1 (thyroid transcription factor-1): positive
• Napsin-A: positive
• Mucin: present
• Neuroendocrine markers (chromogranin, synaptophysin): absent

2. Squamous Cell Carcinoma (SCC)

• Squamous metaplasia → Squamous dysplasia → Squamous cell carcinoma in situ → Invasive SCC

• Central hilar mass, often with cavitation
• May cause bronchial obstruction (post-obstructive pneumonia/atelectasis)
• Keratinization produces a pale, firm appearance

• Intracellular bridges (desmosomes)
• Keratin pearl formation
• Pleomorphic nuclei, coarse chromatin, prominent nucleoli

• TP53 mutations: ~50%
• p16/CDKN2A: ~50%
• 3p deletions: ~80%
• Paraneoplastic syndrome: PTH-rP (parathyroid hormone-related peptide) → hypercalcemia

• p40, p63: positive
• CK5/6: positive
• TTF-1: negative

3. Large Cell Carcinoma

• A diagnosis of exclusion - undifferentiated carcinoma that lacks glandular, squamous, or neuroendocrine features on light microscopy
• Peripheral location
• Large cells with vesicular nuclei and prominent nucleoli
• Sheets of undifferentiated cells without distinguishing architecture
• Large cell neuroendocrine carcinoma (LCNEC): grouped with neuroendocrine tumors in 2021 WHO; very aggressive; expresses synaptophysin, chromogranin, CD56

Comparison: NSCLC vs. SCLC (Table 11.6, Robbins)

Pathogenesis Summary

1. Direct DNA mutagenesis by carcinogens (polycyclic hydrocarbons, nitrosamines)
2. Metabolic activation via P-450 monooxygenase system
3. Synergistic interaction with occupational carcinogens (asbestos: 5x risk in nonsmokers; 55x in heavy smokers)

Paraneoplastic Syndromes in Lung Cancer

Treatment Implications by NSCLC Subtype

• Targeted therapy (TKIs): EGFR-mutant adenocarcinoma (erlotinib, gefitinib, osimertinib); ALK-fusion (crizotinib, alectinib); ROS1-fusion; KRAS G12C (sotorasib)
• Immune checkpoint inhibitors (anti-PD-1/PD-L1): Effective in NSCLC (unresponsive in SCLC); PD-L1 IHC guides selection but PD-L1-negative tumors may still respond
• Surgery: Resectable NSCLC only (SCLC is essentially always unresectable at presentation)
• Chemotherapy: NSCLC responds incompletely; SCLC responds initially but invariably recurs

CARCINOMA OF THE LUNG

INTRODUCTION

• Approximately 237,000 new cases and 130,000 deaths per year (USA, 2022)
• Peak incidence: 5th and 6th decades of life
• At diagnosis: >50% have distant metastases; an additional 25% have regional lymph node involvement
• Overall 5-year survival (all stages combined): ~20%
• Even when localized at diagnosis, 5-year survival is only ~50%
• Tobacco smoking is the most important risk factor - ~90% of lung cancers occur in current or recent smokers
• Risk is 60 times greater in heavy smokers (2 packs/day x 20 years) compared to nonsmokers

ETIOLOGY / RISK FACTORS

A. Tobacco Smoking (Most Important)

• Strong dose-response relationship - nearly linear correlation between frequency of lung cancer and pack-years of smoking
• Squamous cell carcinoma and small cell carcinoma have the strongest association
• Adenocarcinoma also shows association but is less strong
• Women are more susceptible to carcinogens in tobacco smoke than men
• Cessation of smoking reduces risk over time but never returns to baseline
• Passive (second-hand) smoking also increases risk

B. Occupational and Environmental Carcinogens

• Uranium (radioactive decay products - radon gas)
• Asbestos - 5x risk in nonsmokers; synergistic with smoking - ~55x risk in heavy smokers who are also asbestos-exposed
• Arsenic, chromium, nickel, vinyl chloride (inhalation of industrial dusts)

C. Genetic Susceptibility

• Polymorphisms in P-450 monooxygenase genes increase capacity to activate procarcinogens in cigarette smoke, increasing cancer risk
• "Mutagen-sensitive genotype" - individuals whose lymphocytes show chromosomal breakage after carcinogen exposure have >10-fold increased risk

WHO CLASSIFICATION (2021) - TABLE 11.5

Note: The older clinical division of lung cancers into SCLC (small cell lung cancer) and NSCLC (non-small cell lung cancer) was replaced by this more detailed WHO classification in 2015 (updated 2021). The old binary classification existed because NSCLC tumors are more likely to be resectable and respond poorly to conventional chemotherapy as a group, whereas SCLC has almost always metastasized at presentation. With targeted therapies and checkpoint inhibitors now available, the WHO adopted more granular histologic typing.

NON-SMALL CELL LUNG CARCINOMA (NSCLC)

1. ADENOCARCINOMA

• Most common primary lung tumor overall in recent years (replaced squamous cell carcinoma as smoking rates declined)
• Most common in: women, never-smokers, and individuals < 45 years
• Most common lung tumor arising in the lung periphery

Atypical Adenomatous Hyperplasia (AAH) → Adenocarcinoma in situ (AIS) → Minimally Invasive Adenocarcinoma → Invasive Adenocarcinoma

• This sequence is analogous to the adenoma-carcinoma sequence in the colon
• Bronchioalveolar stem cells (BASCs) at the bronchioalveolar duct junction are the proposed cells of origin - they accumulate the initiating mutations

• Peripheral gray-white nodule, often subpleural
• Central scarring may be present ("scar carcinoma")
• May spread along alveolar walls without destroying architecture (lepidic growth - formerly called bronchioloalveolar carcinoma)

1. Lepidic - tumor cells grow along pre-existing alveolar walls; least aggressive
2. Acinar - gland-forming pattern
3. Papillary - tumor cells on fibrovascular cores
4. Micropapillary - small papillary tufts without fibrovascular cores; poor prognosis
5. Solid - sheets of tumor cells without glandular architecture; mucin present
6. Mucinous - abundant extracellular mucin; formerly "colloid adenocarcinoma"

• EGFR and KRAS mutations are mutually exclusive (KRAS lies downstream of EGFR in the same signaling pathway)
• This genetic diversity has given rise to a new era of "personalized" lung cancer treatment

• 3p deletions: ~80%
• TP53 mutations: ~50%
• p16/CDKN2A mutations: ~50%
• RB mutations: ~20%

• TTF-1 (thyroid transcription factor-1): Positive
• Napsin-A: Positive
• Mucin (PAS/mucicarmine): Positive
• Neuroendocrine markers (chromogranin, synaptophysin, CD56): Absent

2. SQUAMOUS CELL CARCINOMA (SCC)

• Strongest association with smoking (along with small cell carcinoma)
• Previously the most common lung cancer; now second to adenocarcinoma
• Predominantly affects older men who are heavy smokers

Squamous Metaplasia → Squamous Dysplasia → Squamous Cell Carcinoma in situ → Invasive SCC

• Central hilar mass arising from a bronchus
• Gray-white, firm, irregular growth
• Frequently undergoes central cavitation (due to necrosis)
• May cause bronchial obstruction leading to post-obstructive pneumonia, atelectasis, or abscess

• Keratin pearl formation (concentric whorls of keratin)
• Intercellular bridges (desmosomes between cells)
• Pleomorphic nuclei with coarse chromatin
• Prominent nucleoli
• Abundant cytoplasm

• TP53 mutations: ~50%
• p16/CDKN2A: ~50%
• 3p deletions: ~80%
• KRAS, EGFR, ALK: Not seen (unlike adenocarcinoma)

• p40, p63: Positive
• CK5/6: Positive
• TTF-1: Negative
• Mucin: Absent

3. LARGE CELL CARCINOMA

• Peripheral location
• Large polygonal cells with vesicular nuclei and prominent nucleoli
• Tumor grows in sheets without any distinguishing architecture
• Mucin absent; neuroendocrine markers absent; squamous markers absent
• Large cell neuroendocrine carcinoma (LCNEC): A subtype grouped with neuroendocrine tumors in the 2021 WHO classification; highly aggressive; expresses synaptophysin, chromogranin, CD56

COMPARISON TABLE: SCLC vs. NSCLC (Table 11.6, Robbins)

PARANEOPLASTIC SYNDROMES IN LUNG CARCINOMA

TREATMENT IMPLICATIONS