Clinical Reference / Therapeutic Strategies / Non-Melanoma Skin Cancers (NMSC): Basal Cell Carcinoma (BCC) and Squamous Cell Carcinoma (SCC)

Non-Melanoma Skin Cancers (NMSC): Basal Cell Carcinoma (BCC) and Squamous Cell Carcinoma (SCC)


Principles of Squamous Cell Carcinoma Management

The diagnosis of SCC is based on biopsy; a superficial biopsy may reveal only an in situ (epidermal) component and may miss the invasive component that is underlying or adjacent to the area of the biopsy. Close clinical follow-up is therefore necessary.

Initial Therapy

First-line therapy: Surgical excision

  • For lesions < 2 cm, a 4–6 mm margin is recommended.
  • For lesions ≥ 2 cm or with other high-risk features (histologic grade ≥ 2, invasion of subcutaneous tissue), a 9 mm margin is recommended.
  • Pathologic evaluation of the margins should be performed to ensure adequacy of resection.
  • Surgical excision has demonstrated cure rates with long-term follow-up (> 5 years) of 91% or higher.
  • Careful palpation of regional lymph nodes before surgery is required. If there are palpable lymph nodes or abnormal lymph nodes that are identified by imaging studies during the initial evaluation, fine needle aspiration (FNA) or biopsy is recommended to assess for metastatic disease.
  • Imaging for staging should be performed if any concern for metastasis exists.
  • Mohs micrographic surgery is recommended for high-risk squamous cell carcinoma.
  • Sentinel lymph node biopsy (SNLB) for high-risk patients can be considered; however, the criteria for selecting patients for SLNB are unclear.
  • Adjuvant chemotherapy for patients with high-risk SCC post-surgery or as a supplement to RT in non-surgical candidates can be considered. Although there are no drugs that are currently approved by the FDA specifically for the treatment of cutaneous high-risk SCC, off-label use of 5-fluorouracil/cisplatin, paclitaxel/cisplatin, or 5 fluorouracil/carboplatin has been reported with mixed results. Sustained remission is low, and the tolerability of these agents can be a challenge, particularly in older, frailer patients.
  • Targeted immunologic therapies can be considered, because they show promising results. Epidermal growth factor receptor inhibitors, such as cetuximab, have been FDA-approved for the treatment of locally or regionally advanced mucosal SCC of the head and neck and may be used off-label for cutaneous SCC. Anti-programmed cell death protein 1 inhibitors, including nivolumab and pembrolizumab, have been used for unresectable cutaneous SCC.

Alternative Therapy

  • Mohs surgery can be considered in some cases.
  • Destructive measures (curettage and electrodesiccation or cryotherapy) may be used in the treatment of low-risk SCCs, but they are not optimal, because they do not provide margins for pathologic confirmation of adequacy of resection. Retrospective and observational data with long-term follow-up (> 5 years) report cure rates of between 95% and 96%, (mostly low-risk SCC). Curettage and electrodesiccation should not be used in areas with terminal hair, such as the scalp, groin and axillary region, and the beard region in males.
  • For large high-risk lesions in patients who are not good surgical candidates, and in patients with multiple lesions, RT may be considered.
  • Adjuvant radiation may be considered for SCC with large nerve involvement or with positive margins after definitive surgery. Many studies suggest that postoperative RT for patients with perineural invasion may improve local control.
  • Superficial therapies, including imiquimod and 5-fluorouracil, should be reserved for patients with SCC in situ due to their poor penetration beyond the epidermis. SCC in situ that is treated with imiquimod has shown a clearance rate of 73%. Slightly lower clearance rates have been shown with 5-fluorouracil.
  • Patients with multiple and/or clinically aggressive lesions may require systemic retinoid therapy (acitretin, such as Soriatane) for chemoprophylaxis of future recurrence or development of primary lesions. Low doses of these agents may be given with informed consent. Therapy must be lifelong. Chronic toxicity, especially skeletal, has limited the effectiveness of the retinoids.

Subsequent Therapy

  • Close clinical follow-up, with careful examination of the surgical site, draining lymph nodes, and the rest of the patient’s exposed skin should be performed.
    • Patients with low-risk cutaneous SCC, monitoring for recurrence or new cancers should occur at least every 3 to 6 months during the first 2 years after initial diagnosis. If no recurrence or new lesions, then exams should occur every 6 to 12 months for another 3 years, then annually for life.
    • For patient with high risk SCC, monitoring for recurrence should occur every 1 to 3 months for 1 year, then every 2 to 4 months for 1 year, every 4 to 6 months for another 3 years, and then every 6 to 12 months for life.
    • For patients with regional disease, surveillance using CT with contrast may be warranted to screen for recurrence in the regional lymph node basin or distant metastatic disease.
  • Because these lesions are usually found on sun-exposed areas and because photodamage is likely an important factor in the pathogenesis of SCC, photoprotection should be emphasized.

 Prophylaxis for High-Risk SSC Patients

  • For patients with a high risk of field cancerization, topical options include 5-FU, imiquimod, ingenol mebutate, diclofenac, and topical retinoids.
  • For large areas, 5-FU is the topical treatment of choice, because other agents (e.g., imiquimod) come in small packages and can lead to cytokine release and subsequent systemic effects when used over large surface areas.
  • There are mixed results on the use of topical retinoids, with some studies showing a reduction in AKs and others showing no difference.
  • Photodynamic therapy with 5-aminolevulinic acid or methylated aminolevulinate has been used successfully for the treatment of superficial SCC and AKs, although with less efficacy than surgery. Activation with blue light was approved by the US FDA in 2001, and more recently, the use of daylight PDT has had equal results but has generated less pain.
  • Nicotinamide, an amide form of vitamin B3, enhances the repair of UV-induced DNA damage. In a randomized trial in Australia, the use of daily nicotinamide demonstrated reduction in new SCCs and AKs. Side effects are minimal, but patients must avoid combining it with niacin, which can lead to flushing.