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Summary Table

Category	Details
Risk Factors	Chronic UV exposure, fair skin, immunosuppression (organ transplant recipients), prior radiation, chronic wounds/scars/ulcers, HPV infection, genodermatoses (albinism, xeroderma pigmentosum, epidermolysis bullosa), photosensitizing drugs (doxycycline, fluoroquinolones), precancerous lesions (actinic keratosis, Bowen disease)
Etiology	Malignant transformation of supra-basal keratinocytes in the epidermis, most commonly driven by cumulative UV-induced DNA damage (pyrimidine dimer formation)
Patient Presentation	Slow-growing, non-healing, crusted or ulcerated skin lesion on a sun-exposed area (face, neck, dorsum of hands, upper back, ears, lower lip)
Classic Physical Exam	Firm, indurated, flesh-colored to erythematous papule, plaque, or nodule with central ulceration or overlying keratinous crust; may be papillomatous or exophytic; rolled or ill-defined borders in higher-risk variants
Key Diagnostic Results	Dermoscopy: linear irregular/serpentine vessels, hairpin vessels, glomerular/coiled vessels, white circles, central keratin mass with ulceration. Histopathology (gold standard): nests of atypical squamous cells with keratin pearl formation and intercellular bridges
Management	Surgical excision with 4-6 mm margins or Mohs micrographic surgery (preferred for high-risk); adjuvant radiotherapy for unresectable cases; cemiplimab or pembrolizumab for locally advanced/metastatic disease
Keywords	"Non-healing ulcer on sun-exposed skin," "keratin pearl," "pearly/keratotic nodule with central crater," "immunosuppressed transplant patient with skin lesion," "Marjolin ulcer" (SCC arising in chronic scar/wound)

1. Pathophysiology

Cutaneous squamous cell carcinoma (cSCC) arises from the malignant proliferation of epidermal keratinocytes in the supra-basal layer. The primary driver is cumulative ultraviolet (UV) radiation, particularly UVB, which induces pyrimidine dimer mutations in the TP53 tumor suppressor gene. Loss of p53 function removes a critical checkpoint for DNA repair and apoptosis, allowing damaged keratinocytes to accumulate further mutations and proliferate unchecked.

This explains the clinical predilection for chronically sun-exposed areas: the face, ears, lower lip, neck, dorsal hands, and forearms. The disease follows a well-characterized progression from precursor lesions (actinic keratosis representing dysplasia confined to the lower epidermis) to carcinoma in situ (Bowen disease, where full-thickness epidermal dysplasia is present but the basement membrane is intact) to invasive SCC (where atypical keratinocytes breach the basement membrane and invade the dermis).

Immunosuppression accelerates this pathway dramatically. Organ transplant recipients on chronic immunosuppressive regimens (azathioprine, cyclosporine) have a 65-250 fold increased risk of developing cSCC because impaired immune surveillance fails to eliminate UV-damaged and virally-transformed keratinocytes. In this population, HPV co-infection plays a synergistic role by inactivating p53 through E6 oncoprotein and Rb through E7 oncoprotein.

Chronic inflammation and scarring (burns, lupus discoid, lichen sclerosus, chronic ulcers) create a microenvironment of persistent epithelial regeneration with reduced immune oversight. SCC arising from these chronic wounds is termed Marjolin ulcer and tends to be more aggressive with higher metastatic potential compared to UV-driven SCC.

The metastatic potential of cSCC overall is relatively low (2-5%), but certain features substantially elevate this risk: tumor thickness greater than 6 mm, perineural invasion, poor differentiation (desmoplastic subtype), immunosuppression, and location on the ear or lip. Metastasis follows a predictable route via lymphatic drainage to regional lymph nodes before hematogenous spread.

2. Classification and Clinical Manifestation

Risk Stratification (Local cSCC)

Feature	Low Risk	High Risk	Very High Risk
Location/Size	Trunk, extremities, ≤2 cm	Trunk/extremity >2 cm to ≤4 cm; OR head, neck, hands, feet, pretibial, anogenital (any size)	>4 cm (any location)
Clinical borders	Well-defined	Ill-defined	--
Primary vs. recurrent	Primary	Recurrent	--
Immunosuppression	Absent	Present	--
Radiation/chronic inflammation hx	Absent	Present	--
Neurologic symptoms	Absent	Present	--
Rapid growth	Absent	Present	--
Differentiation	Well or moderate	--	Poorly differentiated
Histologic subtype	No adenoid, adenosquamous, or metaplastic features	Adenoid, adenosquamous, or metaplastic features present	Desmoplastic SCC
Thickness/Depth of invasion	<2 mm, no subcutaneous invasion	2-6 mm	>6 mm or subcutaneous invasion
Perineural invasion	Absent	Present	Named nerve involvement or nerve ≥0.1 mm in dermis
Lymphovascular invasion	Absent	Absent	Present

Clinical Appearance by Stage

Subtype	Appearance
cSCC in situ (Bowen disease)	Erythematous, scaly patch or slightly elevated plaque; resembles eczema or psoriasis but is fixed and unilateral
Invasive cSCC	Papulonodular, papillomatous, or exophytic lesion with ulceration; often with overlying keratinous crust
Keratoacanthoma variant	Dome-shaped nodule with a central keratin-filled crater; rapid growth over weeks followed by potential spontaneous regression

TNM Staging (AJCC 8th Edition)

Stage	T	N	M
0	Tis	N0	M0
I	T1 (≤20 mm)	N0	M0
II	T2 (>20-40 mm)	N0	M0
III	T3 (>40 mm) or T1/T2 upstaged by high-risk pathologic features	N0 or N1	M0
IVA	T1-T3 with N2/N3, or T4 (bone invasion) with any N	Any	M0
IVB	Any T	Any N	M1

Note that T1 or T2 can be upstaged to T3 if any of the following high-risk pathologic features are present: depth of invasion (DOI) beyond subcutaneous fat or tumor thickness >6 mm, perineural invasion of a named nerve or nerve ≥0.1 mm, or minor bone erosion.

3. Diagnostic Workup

Test	Role	Key Findings
Complete skin examination + dermoscopy	Best initial test	Linear irregular/serpentine vessels, hairpin/looped vessels, glomerular vessels, white circles, white pearl/clod central keratin, central keratin with blood spot, ulceration
Histopathology (punch/excisional biopsy)	Gold standard / confirmatory test	Atypical squamous cell nests invading dermis, keratin pearls, intercellular bridges; assessed for differentiation grade, depth, and perineural/lymphovascular invasion
Regional lymph node palpation	Baseline clinical staging	Palpable, firm, fixed lymphadenopathy suggests nodal metastasis
CT / MRI	Indicated when bone, nerve, or soft tissue invasion is suspected	Evaluates perineural spread, bone erosion, and extent of local invasion
Sentinel lymph node biopsy (SLNB)	Consider for very high-risk or recurrent high-risk cSCC without clinically palpable nodes	Identifies occult nodal metastasis to guide adjuvant treatment
Reflectance confocal microscopy (RCM)	Noninvasive in vivo imaging at cellular resolution	Maps tumor extent and margins without biopsy; useful for surgical planning
High-frequency ultrasound (HFUS) + Doppler	Noninvasive assessment of tumor depth and vascularity	Measures tumor thickness through all skin layers; Doppler maps neovascular patterns

Dermoscopy is the first-line tool for evaluating any suspicious skin lesion. In cSCC, the progression from in situ to invasive disease has recognizable dermoscopic correlates. Early in situ lesions show clustered glomerular (coiled) vessels on an erythematous background with surface scale. As the lesion becomes micro-invasive, the vascular pattern shifts to hairpin vessels, linear irregular vessels, and the appearance of a central keratotic mass with or without ulceration. Frankly invasive cSCC displays polymorphic vascular patterns (a mix of linear irregular, hairpin, and glomerular vessels) overlying a white-to-yellow keratinous structureless area, often with central ulceration.

Histopathologic examination remains the gold standard and is mandatory for definitive diagnosis. The biopsy must be deep enough to assess the depth of invasion, differentiation grade, and presence of perineural or lymphovascular invasion, as these directly determine risk stratification and treatment planning. A shave biopsy that only captures superficial tissue is inadequate for invasive lesions; punch biopsy or excisional biopsy is preferred.

Imaging (CT or MRI) is not routine for low-risk cSCC. It is reserved for cases where clinical examination suggests deep invasion into bone, cartilage, or cranial nerves. MRI is superior for evaluating perineural invasion, particularly along cranial nerve V (trigeminal) branches, which is a common route of spread for head and neck cSCC.

SLNB is considered preoperatively for very high-risk cSCC or recurrent high-risk cSCC that lacks clinically evident lymphadenopathy. The role of SLNB in cSCC is less established than in melanoma, but it provides useful prognostic information and may guide decisions about adjuvant therapy.

4. Management and Treatment

Risk Category	Primary Treatment	Alternatives / Adjuncts
Low risk	Wide local excision (4-6 mm margins) or Mohs micrographic surgery	Electrosurgery/curettage, cryotherapy (in situ only), topical 5-FU or imiquimod (in situ only), radiotherapy
High risk	Mohs micrographic surgery or wide excision (4-6 mm margins); consider SLNB	Multidisciplinary approach (chemoradiation) if surgery not feasible
Very high risk	Radiologic staging (CT/MRI) first; consider SLNB; consider neoadjuvant systemic therapy; Mohs or wide excision (4-6 mm margins)	Multidisciplinary approach if surgery not feasible
Locally advanced / metastatic (unresectable)	Cemiplimab 350 mg IV q3 weeks or Pembrolizumab 200 mg IV q3 weeks	Cisplatin-based chemoradiation; carboplatin + paclitaxel; cetuximab

Surgical Management (Mainstay for All Resectable cSCC)

Surgical excision is the primary treatment across all risk categories. For low-risk lesions, standard excision with 4-6 mm clinical margins and frozen section or permanent section margin assessment is adequate. Mohs micrographic surgery is preferred for high-risk and very high-risk tumors because it provides complete circumferential and deep margin assessment (100% margin evaluation) while preserving maximum normal tissue. Mohs is particularly valuable for tumors on cosmetically or functionally sensitive areas (periorbital, nasal, auricular, lip) and for recurrent tumors where tissue planes are distorted by scarring.

Non-Surgical Local Options

For cSCC in situ (SCCIS) in patients who are not surgical candidates or for lesions in low-risk locations, several alternatives exist. Topical 5-fluorouracil (5-FU) applied to the lesion for several weeks destroys dysplastic keratinocytes through thymidylate synthase inhibition. Imiquimod 5% cream (note: not yet available in Indonesia per PERDOSKI guidelines) is a topical immune response modifier that stimulates local interferon and cytokine production. Cryotherapy with liquid nitrogen is another option for superficial in situ disease. Electrosurgery with curettage can be performed for lesions not on terminal hair-bearing skin (not scalp, pubic area, axillae, or beard area in males) and only when the procedure does not reach subcutaneous depth.

Photodynamic therapy (PDT) using aminolevulinic acid (ALA) or methyl aminolevulinate followed by light irradiation is an additional option for in situ disease (also not yet widely available in Indonesia).

Radiotherapy

Radiotherapy serves as a primary treatment alternative when surgery is not feasible (due to comorbidities, cosmetic concerns, or patient refusal) and as adjuvant therapy post-excision when margins are positive or close, or when perineural invasion of named nerves is present. It is the firstline non-surgical option.

Reconstruction

Following excision, reconstruction is tailored to the defect size and location: primary closure for smaller defects, skin grafts, local flaps, pedicled flaps, or free flaps (microsurgery) for larger or anatomically complex defects. Regional lymph node dissection is indicated when there is clinical or pathologic evidence of nodal involvement.

Systemic Therapy

Systemic therapy is reserved for locally advanced, recurrent, or metastatic cSCC that is not amenable to surgery or curative radiotherapy.

Preferred first-line agents (immune checkpoint inhibitors): Cemiplimab (anti-PD-1) 350 mg IV every 3 weeks and pembrolizumab (anti-PD-1) 200 mg IV every 3 weeks are the preferred systemic agents. These work by blocking the PD-1/PD-L1 interaction, restoring T-cell mediated anti-tumor immunity.

Combination chemoradiation regimens (concurrent with radiotherapy): Cisplatin is the preferred radiosensitizer. Alternatives include cetuximab (anti-EGFR), cisplatin + 5-FU, or carboplatin with or without paclitaxel.

Second-line / refractory disease: If patients do not meet criteria for or progress on immune checkpoint inhibitors, options include capecitabine, cisplatin alone, carboplatin, or cetuximab as single agents.

Biologic and targeted agents (less established): gefitinib, imatinib, isotretinoin, interferon.

Chemoprevention (for High-Risk Populations)

For immunosuppressed patients (especially renal transplant recipients): oral acitretin reduces the incidence of new non-melanoma skin cancers. Nicotinamide (vitamin B3) 500 mg twice daily has been shown to reduce the rate of new cSCC in high-risk patients. Vitamin D (1,25(OH)D) supplementation is also recommended. For low-risk populations, beta carotene has lower-level evidence (2C). Universal recommendations include UV avoidance counseling and consistent sunscreen use.

5. Differential Diagnosis and Distractors

Differential	Why It Looks Similar	Key Discriminator
Actinic keratosis (AK)	Scaly, erythematous lesion on sun-exposed skin in elderly patients; both share UV etiology	AK is a flat, rough, sandpaper-textured patch without induration, ulceration, or nodularity. It is a precursor, not yet invasive. SCC is indurated, often nodular or ulcerated
Bowen disease (SCC in situ)	Erythematous scaly plaque on sun-exposed skin; histologically full-thickness dysplasia	Bowen disease is well-demarcated, flat, non-ulcerated, confined to the epidermis. The key distinction is that the basement membrane is intact on biopsy (no dermal invasion)
Basal cell carcinoma (BCC)	Non-melanoma skin cancer on sun-exposed areas; can also ulcerate	BCC classically has pearly, translucent rolled borders with telangiectasia. It grows more indolently and almost never metastasizes. SCC has a keratinous/crusty surface and higher metastatic potential
Melanoma (nodular type)	Pigmented or amelanotic nodule that may ulcerate	Melanoma arises from melanocytes, not keratinocytes. Dermoscopy shows irregular pigment network, blue-white veil, atypical vascular pattern. SCC dermoscopy shows keratin and polymorphic vessels
Keratoacanthoma	Rapidly growing dome-shaped nodule with central keratin plug; histologically resembles well-differentiated SCC	Keratoacanthoma classically shows rapid growth over 4-6 weeks followed by spontaneous involution. Many pathologists consider it a well-differentiated SCC variant and recommend excision regardless
Lupus discoid	Chronic, scarring, erythematous plaque on sun-exposed areas	Lupus discoid shows follicular plugging, central atrophy, and peripheral hyperpigmentation. It is an autoimmune process, not neoplastic. However, chronic discoid lupus scars can give rise to SCC (Marjolin-type transformation)

6. Traps and High-Yield Pearls

The most common way students lose points on SCC questions is by confusing it with basal cell carcinoma. Both are non-melanoma skin cancers on sun-exposed areas, but the vignette will plant differentiating clues: SCC is described as a keratotic, crusted, or ulcerated nodule, often arising from a pre-existing actinic keratosis or scar, while BCC is described with pearly, translucent, rolled borders and telangiectasia. If the stem mentions a lesion arising in a chronic burn scar, old radiation site, or chronic draining sinus, the answer is SCC (Marjolin ulcer), not BCC.

Another frequent trap involves immunosuppressed patients. When the stem describes an organ transplant recipient on cyclosporine or azathioprine who develops a new skin lesion, students often default to Kaposi sarcoma (HHV-8) or lymphoma. The highest-yield association is actually SCC, which is the most common malignancy in transplant recipients and occurs at dramatically higher rates than in the general population.

Watch for questions testing risk stratification logic. A small, well-differentiated SCC on the trunk is low-risk and can be treated with standard excision. The same tumor on the lip, ear, or temple, or one with perineural invasion or poor differentiation, jumps to high or very high risk and demands Mohs surgery or wider margins plus possible adjuvant therapy. The question is testing whether you recognize that location and histopathologic features override size in determining management intensity.

For treatment questions, remember the hierarchy: surgery first for all resectable cSCC. Radiotherapy is a firstline alternative only when surgery is contraindicated. Systemic immunotherapy (cemiplimab, pembrolizumab) enters the picture only for unresectable locally advanced, recurrent, or metastatic disease. A question offering cemiplimab as the answer for a small, resectable SCC is a distractor designed to test whether you skip the surgical step.

Finally, do not forget that Bowen disease (SCC in situ) and actinic keratosis are on the same continuum as invasive SCC. The test-writer may present an evolving lesion, asking you to recognize the transition from precursor to carcinoma based on changes in induration, ulceration, or rapid growth, which signal invasion through the basement membrane.

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