Premalignant Lesions of the Skin

I. PRECURSORS OF SQUAMOUS CELL CARCINOMA

1. Actinic Keratosis (Solar Keratosis)

• Rough, erythematous macule or papule with white-to-yellow scale, < 1 cm diameter
• Located on head, neck, dorsal hands, forearms, bald scalp - areas of highest cumulative UV exposure
• May itch or be tender, especially hyperkeratotic variants
• Lesions can spontaneously regress, but then reappear

• Lower epidermis shows cytologic atypia with basal cell hyperplasia or atrophy
• Hyperkeratosis with parakeratosis (retention of nuclei in stratum corneum)
• Dermal solar (actinic) elastosis - thickened blue-gray elastic fibers
• When full-thickness epidermal atypia is present, this is classified as SCC in situ (grade III / Bowen disease)

Seborrheic keratosis (left, clinical and microscopic) and clusters of pigmented lesions (right) - Robbins & Kumar Basic Pathology

• Cryotherapy (liquid nitrogen): open spray, single freeze-thaw cycle 8-10 seconds; most widely used. 1-2 mm freeze margin. Cure rates ~99% in some series. - Fitzpatrick's Dermatology
• 5-Fluorouracil (5-FU) cream: field treatment for multiple lesions
• Imiquimod 5% cream: immune-mediated destruction
• Photodynamic therapy (PDT): ALA or methyl-ALA + light; clearance 50-70% single session, up to 90% with repeat. Especially effective on face and scalp. - Andrews' Diseases of the Skin
• Diclofenac 3% gel, ingenol mebutate
• Topical calcipotriol + 5-FU: a recent systematic review (2024) confirms efficacy of this combination for AK and Bowen's disease

2. Squamous Cell Carcinoma In Situ (Bowen Disease)

• Slowly growing, well-demarcated, scaly, erythematous plaque
• Most common on sun-exposed sites
• Must be distinguished clinically from eczema and psoriasis (biopsy is important)

• Full-thickness atypia of the epidermis with dyskeratosis, nuclear pleomorphism, and apoptosis - more florid than in AK
• Atypical keratinocytes extend down adnexal structures (hair follicles, sweat glands)
• Diffuse confluent parakeratosis; mitoses frequent
• Basal layer is usually spared (palisading small compressed basaloid keratinocytes at the base - key distinguishing feature from invasive SCC)

• Erythroplasia of Queyrat: SCC in situ of the glans penis - bright red, velvety plaque; higher malignant potential
• Bowenoid papulosis: HPV-associated SCC in situ of the genitalia in younger patients

3. Actinic Cheilitis

• Confluent actinic keratoses on the lower lip vermilion
• Lip appears dry, scaly, cracked, atrophic with loss of clear vermilion border
• Higher progression risk than cutaneous AK due to thin epidermis and persistent UV exposure
• Treatment: PDT, 5-FU, vermilionectomy (lip shave) for extensive cases

4. Keratoacanthoma (KA)

• Rapidly growing crateriform nodule with a central keratin-filled plug, arising in hair-bearing sun-exposed skin of middle-aged to elderly patients
• Classic course: rapid growth over 6-8 weeks, then spontaneous involution over months
• Histologically resembles well-differentiated SCC - many pathologists regard it as a low-grade SCC variant rather than a truly benign entity
• Important subtypes: Keratoacanthoma centrifugum marginatum (expands peripherally without central healing), generalized eruptive KA (Grzybowski variant)
• Management: Excision is preferred (also provides full histology); some advocate curettage or intralesional methotrexate - Andrews' Diseases of the Skin

5. Cutaneous Horn (Cornu Cutaneum)

• A clinical descriptor, not a diagnosis - refers to a projecting column of compacted keratin
• The underlying pathology may be AK (most common), SCC, verruca vulgaris, seborrheic keratosis, KA, or trichilemmoma
• A biopsy of the base is mandatory to determine the underlying lesion
• "If the base is red and inflamed, suspect SCC" - Fitzpatrick's Dermatology

II. PRECURSORS OF MELANOMA

6. Lentigo Maligna (Hutchinson's Melanotic Freckle)

• Melanoma in situ arising on photodamaged skin of elderly patients
• Large, flat, irregularly pigmented patch - typically on the face and neck
• Preinvasive phase (radial growth only) - becomes lentigo maligna melanoma once vertical growth and dermal invasion occur (least common melanoma subtype, 5-10% of cases)
• Rate of progression: variable, reported between 2% and 33% - K.J. Lee's Essential Otolaryngology
• Treatment: Wide local excision with 5-10 mm margins; imiquimod 5% topical is effective for inoperable/large lesions; radiotherapy (40-50 Gy) achieves 5-year cure rates of 90-95% - Dermatology 5e

7. Dysplastic (Atypical) Nevus

FIG. 22.20 Dysplastic nevus. (A) Numerous irregular nevi on the back; lesions >5 mm, irregular borders, variable pigmentation. (B) Characteristic parallel bands of fibrosis in superficial dermis. - Robbins & Kumar Basic Pathology

• Larger than ordinary nevi: often > 5 mm, may number in the hundreds
• Variable pigmentation (variegation) with irregular, ill-defined borders
• Flat macule to slightly raised plaque with "pebbly" surface
• Occur on sun-exposed AND non-sun-exposed sites

• Compound nevi with architectural and cytologic atypia
• Enlarged junctional nests with "bridging" (fusion of adjacent nests)
• Lentiginous hyperplasia: single nevus cells replacing basal layer
• Nuclear atypia with angulated, hyperchromatic nuclei
• Sparse lymphocytic infiltrate + linear dermal fibrosis (lamellar fibroplasia) + melanin in dermal macrophages

• Familial dysplastic nevus syndrome: lifetime melanoma risk approaches 100% - Robbins & Kumar Basic Pathology
• Sporadic cases: only individuals with 10 or more dysplastic nevi have markedly increased risk
• Most melanomas arise de novo rather than from a preexisting nevus; dysplastic nevi are best viewed as markers of risk rather than obligate precursors

8. Congenital Melanocytic Nevus

• Present at birth; occurs in 1-2% of newborns
• Risk of melanoma transformation depends on size:
  • Small (<1.5 cm) and medium (1.5-20 cm): minimal increased risk
  • Giant/large congenital nevus (>20 cm): approximately 10% lifetime risk of melanoma - K.J. Lee's Essential Otolaryngology
• Associated syndrome: neurocutaneous melanosis - melanotic CNS neoplasms + giant congenital nevi

III. ORAL/MUCOSAL PREMALIGNANT LESIONS (Relevant to Skin-Adjacent Sites)

Leukoplakia

• White mucosal plaque that cannot be rubbed off and cannot be classified as another disease
• < 10% of isolated leukoplakias prove to be carcinoma or severe dysplasia on biopsy

Erythroplakia

• Fiery red mucosal patch - much higher malignant potential than leukoplakia
• Histology ranges from severe dysplasia to frank carcinoma in situ in most biopsied cases
• Speckled erythroplakia (mixed red-white) has intermediate risk

IV. Summary Table

V. General Principles of Management

1. Sun protection (SPF 30+, protective clothing, avoiding peak UV hours) - primary prevention
2. Regular skin surveillance - especially in fair-skinned individuals, immunosuppressed, transplant patients
3. Biopsy any lesion with atypical features or that does not respond to treatment
4. Field therapy for patients with multiple/diffuse AKs (5-FU, imiquimod, PDT, ingenol mebutate)
5. Treat all SCC in situ (Bowen disease) regardless of perceived invasive risk
6. Dermoscopy aids diagnosis and monitoring of pigmented lesions

• Dermatology 2-Volume Set 5e (Bolognia et al.)
• Robbins & Kumar Basic Pathology (Robbins Pathology)
• Fitzpatrick's Dermatology (2-volume edition)
• Andrews' Diseases of the Skin - Clinical Dermatology
• K.J. Lee's Essential Otolaryngology
• Recent systematic review on topical calcipotriol + 5-FU for AK and Bowen disease (PMID 38783539)