What non‑surgical treatment options are available for an elderly patient with keratoacanthomatous‑type cutaneous squamous cell carcinoma who is not a surgical candidate?

Non-Surgical Treatment Options for Keratoacanthomatous SCC in Elderly Patients

For elderly patients with keratoacanthomatous-type SCC who are not surgical candidates, radiation therapy is the primary recommended treatment option, with intralesional methotrexate as an alternative for select cases.

Primary Treatment: Radiation Therapy

Radiation therapy should be considered as the first-line non-surgical treatment when surgery is not feasible, with the understanding that cure rates may be lower than surgical approaches 1. Multiple radiation modalities are available:

• Superficial radiation therapy, brachytherapy, or external electron beam therapy can be used for treatment 1
• Weekly hypofractionated radiotherapy (8 Gy per week for 7-8 weeks) has demonstrated excellent outcomes in elderly patients unfit for surgery, with a 95.7% overall response rate at 12 weeks and minimal side effects 2
• Smaller and thinner tumors respond better to radiation therapy 1
• Radiation provides effective symptom control, achieving bleeding and pain relief in all cases 2

Alternative Treatment: Intralesional Therapy

Intralesional methotrexate is the most commonly used agent for keratoacanthoma-type lesions and represents a cosmetically and functionally superior alternative to surgery while providing similar outcomes 3. Other intralesional options include:

• 5-fluorouracil (second most common) 3
• Interferon alpha 3

Important caveat: Histopathological confirmation before starting intralesional treatment is essential to prevent misdiagnosis of true invasive SCC as keratoacanthoma 3.

Emerging Option: Immunotherapy

For locally advanced disease in elderly patients, immunotherapy with checkpoint inhibitors (cemiplimab or pembrolizumab) combined with hypofractionated radiotherapy represents a promising paradigm 4, 5. This approach:

• Addresses the high prevalence of PD-L1 in cutaneous SCC 4
• Shows high response rates with acceptable toxicity 4
• Can be followed by hypofractionated radiotherapy for residual disease 4

Treatments NOT Recommended

The following modalities should be avoided for invasive keratoacanthomatous SCC:

• Topical therapies (imiquimod or 5-fluorouracil) are explicitly not recommended for invasive SCC based on available data 1
• Photodynamic therapy (PDT) is not recommended, and notably, PDT has been reported to cause exacerbation or induction of well-differentiated SCC or keratoacanthoma 1
• Cryosurgery may only be considered for low-risk lesions when more effective therapies are contraindicated, but has limited evidence 1

Treatment Algorithm for Elderly Non-Surgical Candidates

1. Confirm histopathology to distinguish true keratoacanthoma from invasive SCC 3
2. Assess tumor risk stratification (size, location, depth, differentiation, perineural invasion) 1
3. For low-risk tumors: Consider radiation therapy or intralesional methotrexate 1, 3
4. For locally advanced disease: Consider immunotherapy with checkpoint inhibitors, potentially combined with hypofractionated radiotherapy 4, 5
5. Ensure palliative care consultation for symptom management and quality of life optimization 1

Critical Pitfalls to Avoid

• Do not use topical therapies or PDT for invasive disease, as these have insufficient evidence and PDT may paradoxically worsen keratoacanthomatous lesions 1
• Do not assume all keratoacanthomas are benign—they can transform into or represent invasive SCC, requiring histologic confirmation 3
• Recognize that non-surgical cure rates are lower than surgical approaches, requiring informed discussion with patients and families 1