Lung Carcinoma: Overview, Squamous Cell Carcinoma & Small Cell Carcinoma

Overview of Lung Carcinoma

WHO Classification (2021, Simplified)

• NSCLC (adenocarcinoma + SCC + large cell) ~ 84%
• Small cell carcinoma ~ 13-15%
• Neuroendocrine (carcinoid) ~ 1-2%

Pathogenesis

• Early event: Loss of chromosomal material on 3p (found even in benign bronchial epithelium of smokers - "field effect")
• Late events: TP53 mutations, KRAS oncogene mutations
• Adenocarcinoma-specific targetable mutations: EGFR, KRAS, ALK, ROS1, HER2, MET

Part 1: Squamous Cell Carcinoma (SCC)

Epidemiology & Risk Factors

• ~25% of all lung cancers in the USA
• Strongly linked to smoking - the most important risk factor
• More common in men than women
• Historically central (2/3 were hilar/airway-associated), but there has been a trend toward more peripheral SCC over the past 2 decades - possibly linked to the shift from unfiltered to filtered cigarettes

Pathogenesis & Precursor Lesions

Normal epithelium → Basal cell hyperplasia → Squamous metaplasia → Squamous dysplasia → Carcinoma in situ → Invasive SCC

Gross Pathology

• Central location - arises in major bronchi, spreads first to local hilar nodes
• Dissemination outside the thorax occurs later than other subtypes
• Large lesions may undergo central necrosis → cavitation

Histology

1. Intercellular bridges (Panel A in SCC image)
2. Intracellular keratinization of individual cells (Panel B)
3. Keratin pearls - concentric whorls of keratinized cells (Panel B, arrow; Panel C in Robbins image)

Immunohistochemistry

• Positive: p63, p40 (splice variant of p63) - nuclear expression
• Negative: TTF-1 and napsin A (adenocarcinoma markers)

Paraneoplastic Syndromes

• Hypercalcemia - via PTHrP (parathyroid hormone-related peptide) - most characteristic paraneoplastic syndrome of SCC
• SIADH can also occur (though more typical of SCLC)

Part 2: Small Cell Carcinoma (SCLC)

Epidemiology

• ~10-15% of all lung cancers
• Most aggressive pulmonary tumor - often widely disseminated at diagnosis

• 80% present at advanced stage (III or IV)

• Most cases present as a perihilar mass
• Unlike NSCLC, low-dose CT screening does NOT significantly improve detection of early-stage SCLC

Pathogenesis

• Precursor lesions for SCLC have NOT been clearly described (unlike SCC)
• Virtually all SCLC have bi-allelic loss of function mutations in both TP53 and RB1 (~90% each)
• 3p deletions: ~90%
• p16/CDKN2A mutations: only ~10% (contrast with NSCLC ~50%)
• KRAS and EGFR mutations: absent/rare (major distinction from adenocarcinoma)

Origin

Typical carcinoid → Atypical carcinoid → Large cell neuroendocrine carcinoma → Small cell carcinoma

Histology

1. Solid sheetlike or nested growth architecture
2. Scant pale cytoplasm - gives impression of "small" cell size (actually 2-3x the size of a lymphocyte)
3. Fragile nuclear envelopes - nuclear "smudging" and nuclear "molding" (cells conforming to each other's shape)
4. Finely granular chromatin ("salt and pepper")
5. Absent or inconspicuous nucleoli
6. High mitotic rate + extensive necrosis
7. Azzopardi effect - basophilic encrustation of vascular walls by DNA from necrotic tumor cells (see Panel F in Robbins image)

IHC Profile

• Positive: Synaptophysin, chromogranin A, CD56 (neuroendocrine markers); dense-core granules on electron microscopy
• Ki-67: Usually >80% (very high proliferation)
• Positive: Epithelial membrane antigen (EMA), CEA, cytokeratins
• Negative: TTF-1 and napsin A (adenocarcinoma markers)

Staging

Treatment & Prognosis

• Very sensitive to chemotherapy and radiotherapy but invariably recurs
• Surgery is rarely indicated - usually only for T1-2 N0-1 (stage I/II) peripheral lesions
• LS-SCLC: Etoposide + cisplatin + concurrent thoracic radiation → response rate 85-90%, complete response 50-60%; median survival 18-24 months; 2-year survival 40-50%
• ES-SCLC: Chemotherapy alone → response rate 75-85%, complete response only 15-25%; median survival 7-11 months; 2-year survival <5%
• Prophylactic cranial irradiation (PCI) reduces brain metastasis risk
• Checkpoint inhibitors: SCLC is largely unresponsive (unlike NSCLC)
• Targeted therapies: currently unavailable
• Overall 10-year survival: only ~5%

Part 3: Robbins Pathology Composite - All Types

Comparison Table: SCLC vs NSCLC (Robbins Table 11.6)

Paraneoplastic Syndromes Summary

Common Clinical Features of All Lung Carcinomas

• Chronic cough, hemoptysis, expectoration (early)
• Hoarseness (recurrent laryngeal nerve involvement)
• Chest pain, dyspnea
• Superior vena cava syndrome (compression/invasion)
• Pancoast tumor - apical tumor invading brachial/cervical sympathetic plexus → ulnar distribution pain + Horner syndrome (enophthalmos, ptosis, miosis, anhidrosis) + 1st/2nd rib destruction
• Pleural or pericardial effusions
• Virchow's node - left supraclavicular node involvement
• Metastatic symptoms - brain (neurologic changes), liver (hepatomegaly), bone (pain), adrenal (rarely adrenal insufficiency)