Squamous Cell Carcinoma (SCC) - FCPS Exam Prep

Overview

CUTANEOUS SCC

Epidemiology

• Second most common skin malignancy (after BCC)
• Higher incidence in males (except lower leg lesions)
• Arises on sun-exposed sites in older adults with lighter skin types
• Responsible for ~8,000 deaths/year from metastatic disease (roughly equal to metastatic melanoma)

Risk Factors / Etiology

Pathogenesis / Molecular Genetics

• TP53 mutations - most common; found in actinic keratoses (early event); occur at pyrimidine dimer sites (UV signature)
• RAS activating mutations - increase proliferation
• NOTCH loss-of-function - Notch receptors normally regulate squamous differentiation; loss promotes uncontrolled growth
• UV light also causes transient defect in cutaneous innate immunity

Morphology

• In situ: sharply defined, red, scaly plaques (Bowen's disease)
• Invasive: nodular, keratotic/scaly, may ulcerate; raised indurated borders

• In situ: atypical hyperchromatic nuclei at ALL levels of epidermis (full-thickness atypia)
• Invasive (well-differentiated): polygonal cells in orderly lobules, abundant keratinization, keratin pearls (whorled concentric lamellae of keratin - pathognomonic)
• Invasive (poorly differentiated): highly anaplastic cells, foci of necrosis, only abortive single-cell keratinization (dyskeratosis); may need IHC for keratins to confirm
• Variable degrees of differentiation between these extremes

Clinical Features & Prognosis

• Most discovered small and easily resectable
• ~4-5% have regional lymph node metastases at diagnosis
• Metastasis risk increases with: greater thickness, deeper invasion into subcutis, location near ear/lips
• Actinic keratosis-derived SCC: locally aggressive but slow to metastasize
• Burn scar/ulcer/non-sun-exposed SCC: more aggressive biologically
• Treatment of metastatic disease: high mutational burden → responds well to immune checkpoint inhibitors (first-line for metastatic disease); also sensitive to radiotherapy

HEAD & NECK SCC (HNSCC)

• ~95% of all head and neck cancers are SCC
• 6th most common neoplasm worldwide; >650,000 cases/year globally

Two Distinct Pathogenic Pathways:

• Oral cavity (ventral tongue, floor of mouth, lower lip, soft palate, gingiva)
• Mutations: TP53, RAS, NOTCH (same as cutaneous)
• "Field cancerization" concept: multiple independent clones develop throughout mucosa due to chronic carcinogen exposure → risk of synchronous/metachronous second primaries

• Oropharynx: tonsillar crypts, base of tongue (~90% of tonsillar SCC = HPV+)
• HPV-16 most common subtype (high-risk)
• Spread via orogenital sex
• E6 oncoproteins inhibits p53; E7 inhibits RB
• Overexpress p16 (cyclin-dependent kinase inhibitor) - used as surrogate marker
• Far fewer somatic mutations than tobacco-associated
• Better prognosis than tobacco-associated HNSCC

Additional Regional Risk Factors

• India/SE Asia: betel nut/paan chewing (areca nut + slaked lime + tobacco in betel leaf)
• Lower lip: sunlight and pipe smoking
• In India: chewing tobacco

Morphology

• Early: raised firm pearly plaques or irregular verrucous mucosal thickening, surrounded by leukoplakia/erythroplakia
• Advanced: ulcerated, protruding masses with irregular indurated/rolled borders
• Histology: well-differentiated keratinizing to anaplastic/sarcomatoid
• Degree of keratinization does not correlate with biologic behavior
• Metastasis: cervical lymph nodes (regional); mediastinal lymph nodes, lungs, liver (distant)

LUNG SCC

• Second most common lung carcinoma subtype (after adenocarcinoma, which is now most common)
• Strongly associated with smoking
• Arises centrally near major bronchi from areas of squamous metaplasia → squamous dysplasia → SCC in situ → invasive SCC
• Associated with TP53 and RB mutations
• Often presents with obstructive symptoms, hemoptysis, post-obstructive pneumonia

ESOPHAGEAL SCC

• Common in developing countries and high-risk geographic areas (esophageal cancer belt: Iran, China, parts of Africa)
• Risk factors: alcohol, tobacco, achalasia, Plummer-Vinson syndrome, hot beverages, nitrosamines
• Histology: nests of malignant keratinocytes, glassy cytoplasm, nucleoli, keratin pearls

SUMMARY TABLE - SCC across Sites

HIGH-YIELD FCPS POINTS

1. Keratin pearls (whorled concentric lamellae of keratin) = pathognomonic of well-differentiated SCC
2. UV light = most important cause of cutaneous SCC; mutations occur at pyrimidine dimer sites in TP53
3. Xeroderma pigmentosum = defective nucleotide excision repair → exceptionally high risk
4. Actinic keratosis = premalignant precursor; TP53 mutation is early event
5. Marjolin's ulcer = SCC arising in chronic burn scars/ulcers - more aggressive than sun-induced SCC
6. HPV-16 = key in oropharyngeal and genital SCC; E6 inhibits p53, E7 inhibits RB; p16 overexpression as IHC marker
7. Field cancerization = multiple independent neoplastic clones from chronic mucosal carcinogen exposure
8. SCC in situ = full-thickness epithelial atypia (cf. actinic keratosis = only basal layer atypia)
9. Metastatic cutaneous SCC responds to immune checkpoint inhibitors (high mutational burden)
10. Lung SCC = central, from squamous metaplasia; strongly smoking-associated
11. p16 overexpression = surrogate marker for HPV-positive HNSCC; these have better prognosis