17.3 Cutaneous Squamous Cell Carcinoma & Keratoacanthoma

17.3 Cutaneous Squamous Cell Carcinoma & Keratoacanthoma

Epidemiology, Risk Factors & Pathogenesis

Cutaneous squamous cell carcinoma (cSCC) is an invasive malignant epithelial neoplasm arising from the suprabasal and basal keratinocytes of the epidermis and its adnexal structures. It represents the second most common form of non-melanoma skin cancer in European populations, accounting for approximately 20% of all cutaneous malignancies. Unlike basal cell carcinoma, which primarily correlates with intermittent burning sun exposure, cSCC shows a direct, linear correlation with total cumulative lifetime ultraviolet radiation (UVR) exposure.

Profound Risk in Solid Organ Transplant Recipients (OTRs)

Patients maintained on chronic therapeutic immunosuppression following solid organ transplantation (kidney, heart, lung, liver) constitute the highest-risk cohort encountered in dermato-oncology:

• Epidemiological Shift: OTRs experience a 65- to 100-fold increased incidence of cSCC compared to age-matched immunocompetent populations.
• Inversion of the BCC:cSCC Ratio: In the general immunocompetent population, the ratio of BCC to cSCC is approximately 4:1. In solid organ transplant recipients, this ratio completely reverses to 1:3 or 1:4, with cSCC dramatically outnumbering BCC.
• Aggressive Biological Course: Post-transplant cSCCs exhibit elevated recurrence rates, multiple synchronous primary lesions, early regional lymph node dissemination, and a 5- to 10-fold higher metastatic rate (8% to 10% versus 2% to 4% in immunocompetent hosts).
• Pharmacological Carcinogenicity:
  • Azathioprine: Causes accumulation of 6-thioguanine within cellular DNA. When exposed to UVA radiation, 6-thioguanine generates reactive oxygen species, crosslinks DNA, and induces selective mutagenic transversion mutations.
  • Calcineurin Inhibitors (Cyclosporine, Tacrolimus): Inhibit nuclear factor of activated T-cells (NFAT), block p53-dependent DNA damage repair and apoptosis, and upregulate tumor-promoting transforming growth factor-beta (TGF-β) and vascular endothelial growth factor (VEGF).
  • mTOR Inhibitor Benefit: Switching maintenance immunosuppression from calcineurin inhibitors to mammalian target of rapamycin (mTOR) inhibitors (e.g., sirolimus, everolimus) significantly reduces the incidence of secondary cSCCs through direct antiproliferative and antiangiogenic actions.

Viral Oncogenesis and Host Predispositions

• Human Papillomaviruses (Beta-HPV): Genus beta-HPVs (types 5, 8, 15, 20, 38) act as co-carcinogens with UV radiation. The viral oncoproteins E6 and E7 inhibit UV-induced apoptosis by promoting the degradation of the pro-apoptotic protein Bak and attenuating p53-dependent DNA repair. This synergy is classically seen in patients with epidermodysplasia verruciformis (EV), an autosomal recessive disorder caused by germline mutations in EVER1/TMC6 or EVER2/TMC8.
• Mucosal / Anogenital HPV: Genus alpha high-risk HPVs (types 16 and 18) are primary drivers of squamous cell carcinoma of the anogenital region, periungual skin, and oropharynx, operating through direct E6-mediated p53 ubiquitination and E7-mediated retinoblastoma protein (pRb) degradation.
• Chemical Carcinogenesis: Chronic exposure to inorganic arsenic (contaminated drinking water, historic Fowler's solution) causes palmar/plantar keratoses and multiple aggressive cSCCs. Polycyclic aromatic hydrocarbons (coal tar, soot, pitch, shale oil) cause industrial cutaneous carcinomas (e.g., historic scrotal cancer in chimney sweeps, described by Percivall Pott in 1775).
• Genodermatoses:
  • Xeroderma Pigmentosum (XP): Autosomal recessive deficiency in the nucleotide excision repair (NER) enzymes (XPA through XPG), resulting in a >10,000-fold increased risk of non-melanoma skin cancer, including aggressive cSCC, under age 20.
  • Recessive Dystrophic Epidermolysis Bullosa (RDEB): Caused by biallelic mutations in COL7A1 (encoding type VII collagen). Chronic blister-wound-healing cycles trigger early, highly metastatic, lethal cSCCs originating in chronic non-healing scar beds.
  • Oculocutaneous Albinism: Congenital absence of protective eumelanin, leading to extensive UV-induced keratinocyte neoplasia.

Marjolin Ulcer: Carcinoma in Chronic Wounds and Scars

A Marjolin ulcer is an aggressive cutaneous squamous cell carcinoma arising within sites of chronic, unhealed, repetitive inflammation, cicatrisation, or tissue destruction:

• Etiological Sites: Chronic full-thickness burn scars (thermal or chemical), chronic venous stasis ulcers, osteomyelitis fistulae/sinus tracts, decubitus ulcers, and longstanding hidradenitis suppurativa.
• Latency and Presentation: Long latency period averaging 20 to 30 years from the initial injury. The lesion presents as a persistent, non-healing ulcer with indurated, raised, everted edges, foul-smelling vegetative tissue, or sudden bleeding and rapid enlargement.
• Prognostic Severity: Marjolin ulcers are notoriously aggressive, with regional lymph node metastases reported in roughly a quarter to a third of patients in published series. Radical surgical excision with wide margins and regional lymph node staging is mandatory.

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Clinical Presentation and Spectrum

• Morphology: A firm, indurated, flesh-colored, erythematous, or yellowish hyperkeratotic nodule or an elevated, verrucous plaque. Ulceration with hard, raised, rolled, or everted borders and a necrotic, crusted floor is common.
• Palpation: Deep dermal and subcutaneous induration is the most reliable clinical sign distinguishing invasive cSCC from superficial precancerous actinic keratoses.
• Anatomic Distribution: Scalp of balding males, forehead, ears (helix and antihelix), periorbital and temporal skin, bridge of the nose, lower lip, and dorsal hands.
• Actinic Cheilitis (Solar Cheilosis): Premalignant dysplasia affecting the vermilion border of the lower lip caused by chronic solar damage. Presents with persistent scaling, dry peeling, pallor, atrophy, transverse fissuring, and loss of the distinct sharp vermilion-cutaneous demarcation. Because the lower lip contains an extensive, rich dermal and submucosal lymphatic plexus, cSCC arising in actinic cheilitis carries an elevated rate of regional submental and submandibular lymph node metastasis (10% to 15%).

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Keratoacanthoma: Biology, Clinical Course and Current Consensus

Keratoacanthoma (KA) is a distinctive, rapidly growing, crateriform epidermal neoplasm with marked squamous differentiation.

                          Classic Keratoacanthoma Life Cycle
                                          │
       ┌──────────────────────────────────┼──────────────────────────────────┐
       ▼                                  ▼                                  ▼
1. PROLIFERATIVE PHASE            2. MATURE / STATIONARY PHASE        3. INVOLUTIONAL PHASE
• Explosive rapid growth           • Stable size (1 to 2.5 cm)         • Central horn is shed
• 4 to 8 weeks duration            • Symmetrical, dome-shaped          • Apoptosis and necrosis
• Symmetric dome nodule with       • Central crateriform plug of       • Spontaneous regression over
  central keratin dimple             compact keratin; smooth shoulders   6 to 12 months leaving
                                                                         a puckered cribriform scar

Clinical Presentation and Natural History

• Growth Kinetics: Remarkable for its explosive proliferation: an asymptomatic lesion expands from a small papule into a 1 to 2.5 cm dome-shaped nodule within 4 to 8 weeks, far outstripping the growth velocity of typical cSCC.
• Classic Morphology: Symmetrical, firm, flesh-colored or pink, dome-shaped nodule with smooth, telangiectatic shoulders and a large, central, crateriform plug filled with cohesive, compact keratin.
• The Three Phases: Proliferative phase (weeks 1–8) → Stationary/mature phase (weeks 8–16) → Involutional/regressive phase (months 4–12), where keratinocyte apoptosis results in lesion expulsion and healing with a depressed, puckered, cribriform scar.

Current Oncological and Pathological Consensus

• The Diagnostic Dilemma: Histologically, keratoacanthoma displays a crateriform architecture with an overhanging "lip" or buttress of normal epidermis and large, glassy, eosinophilic keratinocytes. However, partial, superficial, or shave biopsies frequently miss invasive, atypical squamous cell carcinoma cords infiltrating deeply at the base.
• Modern Management Mandate: Complete spontaneous regression cannot be guaranteed, and numerous lesions that clinically resemble keratoacanthomas progress to deeply invasive, destructive, and metastatic carcinomas.
• European Guideline Standard: Keratoacanthoma is classified and managed as a well-differentiated cutaneous squamous cell carcinoma. Complete surgical excision with standard safety margins is required. Non-interventional observation is obsolete and dangerous.

Syndromic Keratoacanthomas

• Ferguson-Smith Syndrome (Multiple Self-Healing Squamous Epitheliomas): Autosomal dominant disorder linked to chromosome 9q22 caused by loss-of-function mutations in the TGFBR1 (transforming growth factor-beta receptor 1) gene. Patients develop dozens to hundreds of destructive keratoacanthomas beginning in youth, which undergo spontaneous ulceration and involution leaving disfiguring cribriform scars.
• Generalized Eruptive Keratoacanthomas of Grzybowski: Extremely rare, sporadic, adult-onset disorder characterized by thousands of tiny, pruritic, 1- to 3-mm follicular papules with central keratotic plugs across the entire skin surface, oral mucosa, and larynx.
• Muir-Torre Syndrome: Autosomal dominant variant of Lynch syndrome (HNPCC) caused by germline mutations in DNA mismatch repair (MMR) genes (MSH2, MLH1, MSH6, PMS2). Clinically defined by the coexistence of sebaceous neoplasms (sebaceoma, sebaceous adenoma, sebaceous carcinoma) or multiple keratoacanthomas with sebaceous differentiation alongside internal visceral adenocarcinomas (predominantly colorectal and genitourinary).

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Histopathological Grading and Subtypes

Histopathologically, cSCC is characterized by irregular nests, cords, and sheets of malignant squamous keratinocytes invading downward through the basement membrane into the dermis and subcutaneous adipose tissue.

Broders Histological Grading of Differentiation

Histological differentiation correlates with clinical recurrence and metastatic risk:

• Grade 1 (Well-Differentiated, >75% mature keratinocytes): Retains abundant eosinophilic cytoplasm, prominent intercellular bridges (desmosomes), and numerous concentric keratin horn pearls (laminated layers of keratinized cells). Nuclear pleomorphism and mitotic activity are minimal.
• Grade 2 (Moderately Differentiated, 50% to 75% mature keratinocytes): Moderately enlarged, pleomorphic, hyperchromatic nuclei, increased mitotic figures (including suprabasal and atypical forms), and smaller, poorly formed keratin pearls with less prominent desmosomes.
• Grade 3 (Poorly Differentiated, 25% to 50% mature keratinocytes): Markedly atypical, pleomorphic cells with high nuclear-to-cytoplasmic ratios, abundant atypical mitoses, and minimal keratinization without distinct horn pearl formation.
• Grade 4 (Undifferentiated / Anaplastic, <25% mature keratinocytes): Highly anaplastic, bizarre sheets of spindle-shaped or polygonal cells showing no desmosomes, no keratinization, and high mitotic indices. Crucial Immunohistochemical Panel: Poorly differentiated cSCC must be differentiated from malignant melanoma, atypical fibroxanthoma (AFX), and leiomyosarcoma:
  • Positive in cSCC: p40, p63, high-molecular-weight cytokeratins (CK5/6, CK14).
  • Negative in cSCC: S100 and SOX10 (ruling out melanoma); CD10/procollagen-1 without cytokeratin (pointing to AFX); desmin and smooth muscle actin (ruling out leiomyosarcoma).

Distinct Histopathologic Variants

• Acantholytic (Pseudoglandular / Adenoid) cSCC: Marked loss of desmosomal intercellular cohesion creates tubular, pseudoglandular lumen-like spaces lined by dysplastic acantholytic cells. Carries a significantly higher rate of local recurrence and regional lymph node metastasis.
• Spindle Cell cSCC: Composed of atypical, pleomorphic spindle cells streaming through a fibrotic or myxoid stroma, most often arising in chronically irradiated or severely sun-damaged facial skin. Must be stained with p40/p63 and cytokeratins to avoid misdiagnosis as sarcoma or AFX.
• Verrucous Carcinoma: Low-grade, extremely well-differentiated, exophytic, wart-like, cauliflower-shaped tumor with broad, bulbous, pushing rete ridges ("elephant feet") invaginating into the deep dermis without true infiltrative single-cell invasion. Metastasis is rare, but local tissue destruction is relentless. Subtypes include Ackerman tumor (oral cavity), Buschke-Löwenstein tumor (anogenital region), and epithelioma cuniculatum (plantar foot).

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High-Risk cSCC Features and AJCC 8th Edition Staging

Identifying high-risk clinical and histopathologic features is critical for selecting surgical margins, deciding on Mohs micrographic surgery, performing sentinel lymph node biopsy, and selecting adjuvant radiotherapy.

High-Risk Criteria (European Consensus & AJCC Criteria)

1. Tumor Diameter: Maximum clinical diameter ≥ 2 cm (AJCC T2 starts at 2 cm) or ≥ 4 cm (AJCC T3).
2. Histological Depth / Thickness: Breslow depth > 6 mm or deep invasion extending beyond the subcutaneous adipose tissue (Clark Level V; invasion into fascia, muscle, or perichondrium).
3. Perineural Invasion (PNI): Malignant keratinocyte infiltration into the perineural space of cutaneous or subcutaneous nerves. High-risk PNI is defined as involvement of nerves measuring ≥ 0.1 mm in diameter or involvement of named, deep cranial nerves, predisposing to extensive silent cranial nerve track invasion toward the skull base.
4. Histological Differentiation: Poorly differentiated or undifferentiated (Grade 3 or 4) histology.
5. Anatomical Site: High-risk anatomic locations: ears (helix, antihelix, canal), vermilion border of the lip, temple, scalp, and anogenital region.
6. Lymphovascular Invasion (LVI): Tumor emboli present within endothelial-lined lymphatic or blood vessels.
7. Etiological Background: Development within a Marjolin ulcer, chronic non-healing wound, osteomyelitis sinus, or prior radiation field.
8. Host Immune Status: Chronic immunosuppression (solid organ transplant recipient, chronic lymphocytic leukemia, HIV).
9. Recurrence Status: Any tumor recurring after prior surgical excision or radiotherapy.

AJCC 8th Edition Staging System (Head and Neck Cutaneous SCC)

Regional Lymph Node Staging (N Category)

• N1: Metastasis in a single ipsilateral lymph node, ≤ 3 cm in greatest dimension, without extranodal extension (ENE-).
• N2a: Single ipsilateral node, > 3 cm to ≤ 6 cm, without extranodal extension (ENE-).
• N2b: Multiple ipsilateral lymph nodes, none > 6 cm, without extranodal extension (ENE-).
• N2c: Bilateral or contralateral lymph nodes, none > 6 cm, without extranodal extension (ENE-).
• N3a: Any lymph node > 6 cm in greatest dimension, without extranodal extension (ENE-).
• N3b: Metastasis in any lymph node with clinically overt or histologically confirmed extranodal extension (ENE+).

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Diagnostic Workup and Clinical Staging

1. Clinical Examination: Thorough visual and tactile inspection of the primary tumor (evaluating mobility over underlying bone and fascia) combined with mandatory bilateral palpation of regional lymph node basins (parotid gland, cervical chains, axillary, and inguinal basins).
2. High-Resolution Regional Nodal Ultrasound: The gold standard primary imaging modality for screening regional lymph nodes in high-risk cSCC. Possesses higher sensitivity and specificity than physical palpation for detecting subclinical nodal metastases. Any lymph node demonstrating loss of the normal fatty hilum, rounded shape, or peripheral vascularity should undergo ultrasound-guided fine-needle aspiration (FNA) or core biopsy.
3. Contrast-Enhanced CT or MRI: Indicated for T3 and T4 tumors, suspected periosteal/bone invasion, extensive perineural invasion (MRI is superior for tracing retrograde tracking along cranial nerves V and VII toward the skull base), or confirmed regional lymph node metastasis.
4. Sentinel Lymph Node Biopsy (SLNB): An evolving technique in dermato-oncology. European consensus panels do not recommend routine SLNB for all cSCCs, but endorse its consideration in specialized multidisciplinary centers for very high-risk cSCCs (e.g., diameter > 4 cm, multiple concurrent high-risk features, or Marjolin ulcers) without clinical or radiologic nodal disease.

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Surgical and Adjuvant Management

                                    cSCC Management Pathway
                                               │
            ┌──────────────────────────────────┴──────────────────────────────────┐
            ▼                                                                     ▼
      LOW-RISK cSCC                                                         HIGH-RISK cSCC
  • Size < 2 cm in low-risk site                                        • Size ≥ 2 cm, depth > 6 mm
  • Well/moderately differentiated                                      • High-risk site: Ear, lip, temple
  • Breslow depth ≤ 6 mm; no PNI                                       • Poorly differentiated, PNI ≥ 0.1 mm
  • Immunocompetent host                                                • Marjolin ulcer, OTR host
            │                                                                     │
            ▼                                                                     ▼
   Wide Local Excision with                                              MOHS Micrographic Surgery (MMS) /
   5 mm Clinical Margins                                                 CCDMA Margin Assessment
   (Taken into subcutaneous fat)                                         OR Wide Excision (6 to 10 mm Margins)
                                                                                  │
                                                                                  ▼
                                                                         Nodal Staging (Ultrasound)
                                                                         + Multidisciplinary Review
                                                                                  │
                                                                                  ▼
                                                                         Adjuvant Radiotherapy
                                                                         (If close/positive margins, extensive
                                                                          PNI, bone invasion, or ENE+ nodes)

Surgical Resection Margins

• Standard Excision for Low-Risk cSCC: The EADO guideline (2023) recommends a 5 mm peripheral clinical safety margin, excising the tumour en bloc into the subcutaneous fat.
• Standard Wide Local Excision for High-Risk cSCC (when MMS is unavailable): A peripheral clinical margin of 6 to 10 mm is recommended, down to fascia, perichondrium, or periosteum as needed. Complex flap reconstruction should wait until clear (R0) margins are confirmed.
• Mohs Micrographic Surgery (MMS) / CCDMA: The definitive surgical gold standard for high-risk cSCC. Indicated for tumors on the ears, lips, eyelids, nose, temples, tumors ≥ 2 cm, tumors with perineural invasion, recurrent tumors, or lesions with ill-defined borders. Reduces local recurrence rates from ~10–15% down to 3–5%.

Indications for Postoperative Adjuvant Radiotherapy (RT)

Adjuvant fractionated external beam radiotherapy (e.g., 50–60 Gy in 2 Gy fractions) is indicated in the presence of:

1. Positive or close (< 1–2 mm) surgical margins where further surgical re-excision is technically impossible or would cause unacceptable anatomical compromise.
2. Substantial perineural invasion, particularly involvement of named cranial nerves or nerve branches ≥ 0.1 mm in diameter.
3. Gross cortical bone, periosteal, or deep skeletal muscle invasion.
4. Multiple regional lymph node metastases or the presence of extranodal extension (ENE+) following lymphadenectomy.
5. Frail, non-surgical patients with inoperable primary tumors.

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Advanced, Inoperable & Metastatic cSCC: Immune Checkpoint Inhibition

For decades, advanced cSCC unresectable by surgery and incurable with radiotherapy had dismal survival outcomes, with toxic platinum-based chemotherapy (cisplatin/carboplatin with 5-FU) yielding short-lived responses lasting only 3 to 6 months.

The Hypermutated Genome of cSCC

Because cSCC results from decades of cumulative solar ultraviolet radiation, it harbors the highest median tumor mutational burden (TMB) of any solid human malignancy, frequently exceeding 50 mutations per megabase (mut/Mb). This massive burden of UV-induced DNA mutations generates abundant neoantigens, rendering cSCC intensely immunogenic and exquisitely responsive to T-cell checkpoint blockade.

Cemiplimab: The First-Line Standard of Care

Cemiplimab is a recombinant, high-affinity, fully human IgG4 monoclonal antibody that binds to the Programmed Cell Death-1 (PD-1) receptor, preventing its interaction with PD-L1 and PD-L2 on tumor and stromal cells. This relieves inhibitory signaling in exhausted tumor-infiltrating CD8+ T lymphocytes, unleashing durable antitumor cytotoxicity.

• Regulatory Approval: Approved by the European Medicines Agency (EMA) and US FDA as first-line systemic therapy for patients with locally advanced or metastatic cSCC who are not candidates for curative surgery or curative radiation.
• Dosing Regimen: 350 mg administered as an intravenous infusion over 30 minutes every 3 weeks.
• Pivotal Clinical Trial Evidence (EMPOWER-CSCC-1):
  • Objective Response Rate (ORR): Approximately 45% to 50% across locally advanced and metastatic cohorts, with complete responses (CR) achieved in ~15% to 20% of patients.
  • Durability of Response: Responses are remarkably rapid (median time to response ~2 months) and prolonged, with over 80% of responding patients maintaining response at 12 months.
• Alternative Anti-PD-1 Agent: Pembrolizumab (200 mg IV every 3 weeks or 400 mg IV every 6 weeks) showed activity in the KEYNOTE-629 trial and is approved in the US (FDA) for recurrent/metastatic or locally advanced cSCC; it is not EU-licensed for cSCC.

Critical Clinical Trap: Immune Checkpoint Inhibitors in Organ Transplant Recipients

Solid organ transplant recipients (OTRs) carry the highest burden of lethal, advanced cSCC. However, administering anti-PD-1 checkpoint inhibitors (cemiplimab, pembrolizumab) or anti-CTLA-4 antibodies (ipilimumab) to allograft recipients carries catastrophic risk:

• Allograft Rejection Crisis: Immune checkpoint inhibition non-specifically activates alloreactive T-cell clones against human leukocyte antigens (HLA) on the donor graft. Allograft rejection is reported in roughly 40% of treated OTRs in pooled case series.
• Graft Loss: Rejection episodes in kidney transplant recipients frequently result in irreversible graft necrosis, return to hemodialysis, or death; in heart or lung recipients, allograft rejection is almost universally fatal.
• Oncological Strategy in OTRs: In organ transplant recipients with advanced cSCC, anti-PD-1 therapy is strictly a treatment of last resort after extensive multidisciplinary consultation between dermato-oncology and transplant surgery teams. Preferred alternative options include EGFR inhibitors (e.g., cetuximab), chemotherapy (carboplatin/paclitaxel), palliative radiotherapy, or switching immunosuppression to mTOR inhibitors alongside careful, monitored steroid pulses.