---

Premalignant Lesions of the Skin

---

1. Actinic Keratosis (Solar Keratosis)

Pathogenesis & Epidemiology

• The elderly
• Lighter Fitzpatrick skin phototypes (I-II)
• History of chronic cumulative sun exposure
• Immunosuppressed patients (organ transplant recipients have markedly increased risk)

Clinical Features

Clinical Subtypes

Malignant Potential

Treatment

• Cryotherapy (liquid nitrogen) - the most widely used method; single freeze-thaw cycle of 8-10 seconds; 1-2 mm margin; cure rates up to 99% reported. Longer freeze times for hypertrophic AKs.
• Surgical excision - reserved for suspicious lesions needing histology

• Topical 5-fluorouracil (5-FU) 5% or 0.5% - induces inflammatory destruction of dysplastic keratinocytes
• Topical imiquimod 5% or 3.75% - immunomodulator (TLR-7 agonist)
• Diclofenac 3% gel (Solaraze) - COX-2 inhibitor mechanism
• Ingenol mebutate gel - short-duration treatment
• Photodynamic therapy (PDT) - may have better cosmetic outcomes than cryotherapy for individual lesions (Cochrane review)
• Topical calcipotriol + 5-FU - combination showing efficacy in recent systematic review (PMID: 38783539)

---

2. Bowen's Disease (Squamous Cell Carcinoma in Situ)

Definition & Features

• Common on sun-exposed sites (face, scalp, dorsal hands, lower legs)
• Genital variant: Erythroplasia of Queyrat (glans penis) - presents as a red, velvety plaque

Malignant Potential

• Fewer than 5% of cutaneous Bowen's disease lesions progress to invasive SCC
• However, 10%-30% of genital lesions (erythroplasia of Queyrat) become invasive - Dermatology 2-Volume Set 5e

Treatment

• 5-FU topical or imiquimod
• Photodynamic therapy
• Cryotherapy (though cure rates are lower - ~50% in some studies with 2 freeze-thaw cycles)
• Surgical excision with 4-5 mm margins
• Radiotherapy: 40-50 Gy in 10-20 fractions - 5-year cure rates of 98-100%

---

3. Dysplastic Nevus (Atypical Nevus / Clark Nevus)

Background

Genetics

• ~25-33% of familial melanoma cases have germline mutations in CDKN2A (p16/INK4A) on chromosome 9p - encodes an inhibitor of CDK4, suppressing cell proliferation
• Mutations in CDK4 account for a smaller subset of familial melanomas

Clinical Features

• Size: Usually 5-12 mm (common acquired nevi are ≤6 mm)
• Color: Variegated tan, brown, and pink; the pink component is in the macular portion
• Border: Irregular, indistinct
• Structure: A macular component is always present, often surrounding a papular center ("fried egg" appearance)
• Predominate on the back and sun-exposed areas
• Sporadic dysplastic nevi occur in 5-20% of the general population and are not necessarily a marker for DNS

Histology

Management

• Mild-to-moderate dysplasia with clear margins: observation
• Severe dysplasia: complete excision with 2-5 mm margins
• DNS patients: regular full-body skin examinations, sun protection, education on ABCDE criteria

---

4. Lentigo Maligna (Melanoma In Situ on Photodamaged Skin)

• Presents as a slowly growing, irregular, tan-to-brown hyperpigmented patch on the face of elderly patients (most common on the cheek/nose)
• Is the in situ form of lentigo maligna melanoma (LMM)
• May involve large areas making simple excision difficult
• Treatment: Surgical excision with 5-10 mm margins; radiotherapy (35-100 Gy in 5-10 large fractions; or 40-50 Gy in 10-20 fractions) is a well-established alternative with 5-year cure rates of 90-95%, especially in elderly patients where size/location prohibits excision - Dermatology 2-Volume Set 5e

---

5. Leukoplakia and Erythroplakia (Oral/Mucocutaneous)

Leukoplakia

• Affects ~3% of the world's population
• 5-25% of lesions are premalignant
• All leukoplakias must be considered precancerous until proven otherwise by histology
• Risk factors: tobacco (all forms), alcohol, HPV infection
• Histology ranges from simple hyperkeratosis with acanthosis to severe dysplasia and carcinoma in situ
• Robbins, Cotran & Kumar Pathologic Basis of Disease

Erythroplakia

• A red, velvety, possibly eroded area in the oral cavity, level with or slightly depressed relative to surrounding mucosa
• Much less common than leukoplakia but far more ominous
• Histology: approximately 90% show severe dysplasia, carcinoma in situ, or minimally invasive carcinoma
• Intermediate form: Speckled erythroplakia (mixed red-white)

---

6. Other Notable Premalignant Conditions

---

Summary Table

---

---

Granulomatous Lesions of the Skin

---

Classification Overview

---

1. Granuloma Annulare (GA)

Overview

Histology

• Palisading granuloma: epithelioid histiocytes arranged in a palisade around a central zone of degenerated collagen and increased mucin (distinguishes it from necrobiosis lipoidica)
• Interstitial pattern: scattered histiocytes between collagen bundles without true palisading

Clinical Variants

• Tends to affect children and young-to-middle-aged adults
• One or a few lesions on lateral/dorsal fingers, hands, dorsal feet, elbows, or ankles
• Erythematous to violaceous, thinly bordered plaques or papules that spread peripherally while undergoing central involution - forming annular (ring-shaped) lesions
• Overlying skin remains normal; lesions never ulcerate

• 50% clear within 2 years; recur in 40%

• Association with autoimmune thyroiditis in women

• Affects mostly women in the fifth and sixth decades, also adolescents
• Hundreds of lesions; symmetric papular or annular eruption favoring the nape of neck, upper trunk, proximal extremities; face, genitals spared
• Associated with diabetes mellitus and dyslipidemia (elevated cholesterol, triglycerides, LDL)

• Predominantly in children under 6 years
• Firm, skin-colored to pink nodules, often on the scalp, lower legs, hands, buttocks

• Rare; central umbilication with elimination of altered dermal material through the epidermis
• May occur on fingers, hands, and trunk

Associations & Triggers

• Koebner (isomorphic) response
• Can occur in healed herpes zoster areas
• Drug-induced GA: allopurinol, gold, diclofenac, calcium channel blockers, biologics
• Sun-exposed areas (actinic granuloma - O'Brien variant)

Management

• Intralesional triamcinolone - for localized disease
• Potent topical corticosteroids ± occlusion
• Cryotherapy
• Generalized: hydroxychloroquine, dapsone, isotretinoin, PUVA, narrowband UVB, cyclosporine, biologics (TNF inhibitors, JAK inhibitors)

---

2. Necrobiosis Lipoidica (NL)

Epidemiology

• Mean age of onset: ~30 years; women 3:1 over men
• 60% occur in type 1 (insulin-dependent) diabetic patients; 20% in pre-diabetic individuals
• NL precedes diabetes by ~2 years in 15% of cases
• Prevalence of NL in diabetics: only 0.3-3% (uncommon marker despite strong association)
• Diabetes control does not correlate with disease activity

Clinical Features

• Classically on the anterior pretibial shins (bilateral); also ankles, calves, thighs, feet
• Early: small, sharply bordered red-brown papules with slight scale
• Established: well-defined oval/round plaques with depressed, waxy, sulfur-yellow center with prominent telangiectasias ("glazed porcelain" appearance) and a raised violaceous border
• Ulceration occurs in 13-35% of cases on the legs - the most serious complication
• Rare: squamous cell carcinoma arising in chronic ulcers
• Overlapping associations with GA and sarcoidosis

Histology

• At low magnification: layered palisaded granulomas with pale-pink degenerated collagen alternating with amphophilic-staining histiocytes - involving the full thickness of the reticular dermis and often panniculus
• Key distinguishing features from GA:
  • No increased mucin in centers of granulomas
  • No normal dermis between granulomas (in GA, intervening collagen is relatively normal)
  • Thinned overlying epidermis with loss of rete ridges
  • Plasma cells prominent
  • Punch biopsy specimens appear rectangular (not tapered) due to dermal firmness

Management

• Potent topical glucocorticoids - may slow early progression
• Intralesional triamcinolone to active border (risk of ulceration)
• Short-term systemic glucocorticoids for active disease
• Aspirin + dipyridamole (variable results)
• Wound care for ulcerated lesions
• Tacrolimus, thalidomide, ciclosporin, anti-TNF agents reported in case series

---

3. Sarcoidosis (Cutaneous)

Pathogenesis

• Autoimmune etiology
• Inorganic dusts/particles (zirconium, talc, beryllium)
• Infectious triggers: mycobacterial DNA sequences identified in ~25% of sarcoidal tissues; M. tuberculosis catalase-peroxidase (mKatG) protein proposed as a triggering antigen
• Transmissibility via Kveim reagent; sarcoidal granulomas in organ recipients from donors with sarcoidosis
• JAK/STAT pathway activation - basis for emerging JAK inhibitor therapy

Histology

• Naked (sarcoidal) granulomas: tight clusters of epithelioid histiocytes and multinucleated giant cells with minimal or absent surrounding lymphocytic infiltrate ("naked" appearance)
• Schaumann bodies (calcified concentric lamellated inclusions) and asteroid bodies in giant cells
• No caseation necrosis (unlike tuberculosis)

Spectrum of Cutaneous Manifestations

• Erythema nodosum - non-granulomatous panniculitis; seen in acute (Lofgren syndrome) sarcoidosis; generally indicates good prognosis

Lofgren Syndrome

Management of Cutaneous Sarcoidosis

• Topical/intralesional corticosteroids - first-line for localized disease
• Hydroxychloroquine - effective for cutaneous and hypercalcemia
• Methotrexate - for refractory/widespread disease
• TNF inhibitors (adalimumab, infliximab) - for lupus pernio and refractory disease
• JAK inhibitors - topical ruxolitinib and oral agents emerging as options (recent 2025 systematic review PMID: 40192197)

---

4. Cutaneous Tuberculosis

Categories Based on Route of Infection

Diagnosis

• PPD (tuberculin skin test) / IGRA: positive in paucibacillary forms (lupus vulgaris, TB verrucosa cutis)
• AFB smear + culture (gold standard; positive mainly in multibacillary forms)
• PCR for mycobacterial DNA - detects even in tuberculids
• Histology: caseating granulomas in most forms

Treatment

---

5. Leprosy (Hansen's Disease)

• Type 1 (reversal): sudden upgrading of cell-mediated immunity; acute inflammation in existing lesions
• Type 2 (ENL - erythema nodosum leprosum): immune complex-mediated; in BL/LL; tender erythematous nodules + systemic features

---

6. Foreign Body Granulomas

---

Key Histologic Comparisons

---