Residency · Residency · Dermatology

Squamous Cell Carcinoma: Risk Stratification and the High-Risk Tumor

Epidemiology

Squamous cell carcinoma is the second most common skin cancer, with approximately 1.8 million cases per year in the United States and incidence increasing 3 to 10 percent annually. There is a male predominance of 2 to 3:1, and the head and neck are the most common locations. The risk increases dramatically in organ transplant recipients, who face a 65- to 250-fold increased incidence, with cardiac transplant patients at particularly high risk. Overall mortality is approximately 2 percent, but this figure is significantly higher for high-risk tumors, with an estimated 5,000 to 8,000 deaths per year in the United States.

Pathogenesis

The AK-to-SCC Continuum

Actinic keratoses represent intraepidermal neoplasia of atypically proliferating keratinocytes. The rate of progression from an individual AK to invasive SCC is estimated at 0.025 to 16 percent per lesion per year, a figure that remains highly debated. The concept of field cancerization describes UV-mutated keratinocyte clones throughout sun-damaged skin. Not all SCCs arise from clinically visible AKs; de novo SCC on chronically sun-damaged skin is common. The molecular progression typically involves p53 mutations as an early event, followed by RAS activation, NOTCH loss, and CDKN2A silencing.

SCC In Situ (Bowen Disease)

SCC in situ, also known as Bowen disease, shows full-thickness epidermal atypia without dermal invasion. It presents clinically as a well-demarcated, erythematous, scaly patch that slowly enlarges. Perianal and genital Bowen disease is frequently HPV-associated (types 16 and 18). Treatment options include topical 5-FU, imiquimod, cryotherapy, curettage and electrodesiccation, excision, and photodynamic therapy.

UV Radiation

Cumulative UVB exposure is the primary driver of cutaneous SCC, differing from melanoma in which intermittent intense exposure is more important. UV radiation produces characteristic C-to-T signature mutations in TP53, NOTCH1/2, and CDKN2A. The resulting high tumor mutational burden is clinically relevant because it predicts responsiveness to immunotherapy. UV-induced immunosuppression through depletion of Langerhans cells also contributes to SCC development.

Other Risk Factors

Additional risk factors include chronic immunosuppression (transplant, CLL, HIV), chronic wounds and scars (Marjolin ulcer), burns, radiation dermatitis, HPV infection (verrucous carcinoma, periungual and genital SCC), and chemical carcinogens such as arsenic, tar, and polycyclic aromatic hydrocarbons. Several genodermatoses predispose to SCC, including xeroderma pigmentosum, oculocutaneous albinism, and epidermolysis bullosa (especially the recessive dystrophic type).

<image>Clinical spectrum showing progression from actinic keratosis to squamous cell carcinoma in situ (Bowen disease) to invasive squamous cell carcinoma on sun-damaged skin</image>

Clinical Features

Well-differentiated SCC presents as a keratotic papule, nodule, or plaque, often with a central keratinous plug or cutaneous horn. Moderately differentiated tumors are firmer, more erythematous nodules with variable keratinization. Poorly differentiated SCC produces a fleshy, friable, sometimes ulcerated or hemorrhagic nodule that may lack keratinization entirely. Keratoacanthoma is a rapidly growing, dome-shaped nodule with a central keratin plug. It is classified by many authorities as a well-differentiated SCC, and while it can involute spontaneously, behavior is unpredictable and most experts recommend excision. Verrucous carcinoma is an exophytic, cauliflower-like, well-differentiated SCC with very low metastatic potential. Its variants include oral florid papillomatosis, the Buschke-Lowenstein tumor (genital), and epithelioma cuniculatum (plantar). It is HPV-associated.

Histopathology

Invasive SCC shows nests of atypical squamous epithelium extending through the basement membrane into the dermis. Well-differentiated tumors display abundant keratinization, keratin pearls, intercellular bridges, and low nuclear pleomorphism. Poorly differentiated tumors show minimal keratinization, high nuclear pleomorphism, numerous mitoses, and loss of intercellular bridges. Desmoplastic SCC demonstrates single cells and thin cords in desmoplastic stroma and behaves aggressively. Acantholytic (adenoid) SCC forms pseudoglandular spaces through acantholysis and can mimic adenocarcinoma. Spindle cell SCC requires immunohistochemistry (p40, CK5/6) to distinguish it from sarcoma or melanoma.

Risk Stratification

NCCN High-Risk Features

High-risk features include tumor diameter of 2 cm or greater on the trunk and extremities or 1 cm or greater on the head, neck, hands, feet, or genitalia. High-risk locations include the ear, lip, temple, and hair-bearing scalp. Invasion beyond subcutaneous fat, Clark level IV or V, or thickness of 6 mm or greater is high risk. Perineural invasion (especially involving named nerves or nerves 0.1 mm or larger), poorly differentiated or undifferentiated histology, desmoplastic, acantholytic, or spindle cell subtypes, recurrent tumors, immunosuppression, and prior radiation or chronic inflammation at the site are all high-risk features.

BWH (Brigham and Women's Hospital) Staging System

The BWH system is more clinically useful than AJCC for cutaneous SCC. It uses four risk factors: tumor diameter of 2 cm or greater, poor differentiation, perineural invasion of 0.1 mm or greater, and invasion beyond subcutaneous fat. T1 has zero risk factors (0 percent nodal metastasis). T2a has one risk factor (approximately 4 percent nodal metastasis). T2b has two to three risk factors (approximately 20 percent nodal metastasis). T3 has four risk factors or bone invasion (approximately 40 percent nodal metastasis).

BWH Risk Factors: diameter ≥ 2 cm, poor differentiation, PNI ≥ 0.1 mm, invasion beyond subcutaneous fat

AJCC 8th Edition (Head and Neck Cutaneous SCC)

AJCC staging applies only to head and neck cutaneous SCC, with no formal AJCC staging for non-head/neck sites. T1 is 2 cm or less, T2 is greater than 2 to 4 cm, T3 is greater than 4 cm or involves minor bone erosion, perineural invasion, or deep invasion beyond subcutaneous fat. T4a involves gross cortical bone or marrow invasion, and T4b involves skull base or axial skeleton invasion.

<image>Comparison chart of NCCN risk stratification features versus BWH staging system for cutaneous squamous cell carcinoma with corresponding metastatic rates</image>

Management

Surgical Excision

Low-risk SCC requires 4 to 6 mm clinical margins with postoperative margin assessment. High-risk SCC is best managed with Mohs micrographic surgery, which achieves a 97 percent cure rate for primary SCC and 90 percent for recurrent SCC. Mohs is indicated for high-risk locations, aggressive subtypes, perineural invasion, and recurrent tumors. Adequate deep margins extending into subcutaneous fat should be ensured. For SCC in situ, margins of 5 to 7 mm are recommended with standard excision, with Mohs reserved for recurrent or large lesions. Low-risk invasive SCC requires 4 to 6 mm margins, while high-risk invasive SCC requires Mohs or excision with margins of 6 mm or greater with comprehensive margin assessment.

Radiation Therapy

Radiation serves as an alternative primary therapy for inoperable tumors or poor surgical candidates. Adjuvant radiation is indicated for perineural invasion of large-caliber nerves (0.1 mm or greater or named nerves), positive surgical margins when re-excision is not feasible, extensive soft tissue or bone invasion, and multiple positive lymph nodes or extranodal extension. The 5-year local control rate is approximately 90 percent for primary radiation in select cases.

Lymph Node Management

Clinical nodal examination should be performed at every follow-up. Sentinel lymph node biopsy remains debated for cutaneous SCC but should be considered for BWH T2b/T3 tumors or large tumors with multiple high-risk features. It is not yet standard of care, and prospective data remain limited. Therapeutic lymph node dissection is performed for clinically positive nodes. CT or MRI is used for suspected deep invasion or perineural spread, and PET/CT for staging advanced disease.

Systemic Therapy for Advanced SCC

Cemiplimab (anti-PD-1) is FDA-approved for locally advanced or metastatic cutaneous SCC not amenable to curative surgery or radiation, with an overall response rate of approximately 47 percent, complete responses of 16 to 20 percent, and durable responses. Pembrolizumab is also FDA-approved for recurrent or metastatic cutaneous SCC with overall response rates of 34 to 50 percent. Checkpoint inhibitors are contraindicated in organ transplant recipients due to an approximately 40 percent risk of graft rejection. The high tumor mutational burden in UV-induced SCC predicts immunotherapy responsiveness. For patients who cannot receive immunotherapy, platinum-based chemotherapy (cisplatin, carboplatin) is used, along with EGFR inhibitors (cetuximab) as a second-line option with an overall response rate of approximately 28 percent.

SCC in Immunosuppressed Patients

Organ transplant recipients require special management considerations. Reduction of immunosuppression when possible, coordinated with the transplant team, is important. Switching from a calcineurin inhibitor to sirolimus (an mTOR inhibitor) may reduce SCC incidence. Acitretin at 10 to 25 mg per day serves as chemoprevention, reducing new SCCs by 25 to 30 percent. A lower threshold for Mohs surgery and closer follow-up intervals is warranted. Checkpoint inhibitors are generally contraindicated due to graft rejection risk.

<image>Clinical photograph of a high-risk squamous cell carcinoma on the lower lip showing a large ulcerated nodule, illustrating a high-risk anatomic site requiring aggressive management</image>

Follow-Up

Low-risk SCC requires follow-up every 6 to 12 months for 2 years, then annually for 5 years. High-risk SCC requires follow-up every 3 to 6 months for 2 years, every 6 to 12 months for years 3 through 5, then annually. Immunosuppressed patients require follow-up every 3 to 6 months indefinitely. Regional lymph node examination should be performed at every visit, and patients should be educated about sun protection and self-examination for recurrence and new primary lesions.

Clinical Pearls

SCC on the ear or lip carries a metastatic rate two to three times higher than other head and neck sites, mandating aggressive management. Perineural invasion is the most underappreciated high-risk feature; patients with perineural invasion of named nerves require adjuvant radiation and close surveillance. Rapidly growing keratoacanthomas may be clinically indistinguishable from well-differentiated SCC and should be treated as SCC rather than relying on spontaneous involution. In organ transplant recipients, field cancerization with innumerable AKs and SCCs is common, and acitretin chemoprevention combined with immunosuppression modification are critical adjunctive strategies. The BWH staging system outperforms AJCC for prognostication in cutaneous SCC and should be used alongside AJCC staging.

References

• NCCN Clinical Practice Guidelines: Squamous Cell Skin Cancer, Version 1.2024
• Karia PS, et al. Evaluation of American Joint Committee on Cancer, International Union Against Cancer, and Brigham and Women's Hospital tumor staging for cutaneous squamous cell carcinoma. J Clin Oncol. 2014;32(4):327-334
• Migden MR, et al. PD-1 blockade with cemiplimab in advanced cutaneous squamous-cell carcinoma. N Engl J Med. 2018;379:341-351
• Thompson AK, et al. Risk factors for cutaneous squamous cell carcinoma outcomes: a systematic review and meta-analysis. JAMA Dermatol. 2016;152(4):419-428
• Que SKT, et al. Cutaneous squamous cell carcinoma: Incidence, risk factors, diagnosis, and staging. J Am Acad Dermatol. 2018;78(2):237-247

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