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)


Treatment: Basal Cell Carcinoma

Principles of Basal Cell Carcinoma Management

The initial evaluation of BCC includes a complete history and physical examination and biopsy of the suspicious lesion. The histologic subtype and anatomic location are important considerations in the management of BCCs and the determination of the optimal treatment. Although most subtypes are amenable to standard surgical excision, some, such as the infiltrative, morpheaform, and micronodular forms, are best treated with Mohs micrographic surgery. Superficial BCCs can be treated successfully with cryosurgery, curettage and electrodesiccation (C&E), topical imiquimod or 5-fluorouracil therapy, photodynamic therapy (PDT), or systemic therapy.

Optical coherence tomography (OCT) imaging is a new, alternative method for diagnosing BCCs noninvasively and monitoring them; however, the availability and use of this technology are limited to a few specialized centers around the world.

Initial Therapy

First-line therapy: Surgical excision

Surgical excision with a 4 mm margin of normal tissue is usually optimal. The specimen should be sent for a pathological evaluation to ensure adequacy of the excision. If the margins are positive, Mohs micrographic surgery or further resection with complete circumferential margin assessment should be performed. Surgical excision with margins has been reported to achieve 5-year disease-free rates of over 98% for BCC.

In cases when surgery is not possible (e.g., elderly persons, the debilitated, clinically indistinct margins or extensive areas) or contraindicated, radiation therapy can provide excellent results.

For superficial or small (under 1 cm) lesions of the trunk, cryosurgery and C&E provide an acceptable cure rate with good cosmetic outcomes. C&E scars may be unsightly, and so, this is not the preferred treatment for facial lesions and is not recommended for large primary BCC, morpheaform, or recurrent BCC. Complications of cryosurgery include scarring and postinflammatory pigmentary changes and should also be used with caution in cosmetically sensitive areas.

Indications for Mohs micrographic surgery:

  • BCCs ≥ 6 mm located in high-risk areas (central face, nose, lips, eyelid, eyebrows, periorbital skin, chin, mandible, ears, preauricular and postauricular areas, temples, hands, feet) or ≥ 10 mm in other areas of the face (cheeks, forehead, scalp, and neck) or tumors ≥ 20 mm on the trunk or limbs.
  • Aggressive pathological features include perineural invasion, morpheaform, basosquamous, sclerosing, mixed infiltrative, or micronodular forms in any portion of the tumor.
  • Recurrent BCCs.
  • Lesions with clinically indistinct margins.
  • Previously excised lesions in which histologic margins were positive.
  • Tumors that will require extensive reconstruction to repair the surgical defect.

Alternative Therapy

Curettage and Electrodesiccation (C&E)

  • C&E is the process of alternatively scraping away tumor tissue with a curette down to a firm layer of normal dermis and denaturing the area by electrodessication.
  • 5-year cure rate reported to be between 91% and 97% for select patients.
  • Not recommended in areas with terminal hair growth, such as the scalp, pubic or axillary region, and beard region in males, due to the high risk of the tumor extending down follicular structures.
  • If subcutaneous tissue is reached during the procedure, conversion to standard excision should be done.
  • Side effects include hypopigmentation and scarring.
  • The use of curettage alone or curettage followed by imiquimod has been reported; however, larger studies are needed to confirm the efficacy of these treatments.

Topical Imiquimod 5% Cream

Imiquimod is a Toll-like receptor 7 agonist, which induces interferon-alpha and other cytokines to promote Th1-type immunity.

  • In general, imiquimod is used for the treatment of primary superficial BCCs in low-risk sites.
  • The selection of imiquimod over surgical excision for superficial BCCs includes patient-specific factors, such as preference to avoid surgery and potential comorbidities that are associated with surgical excision.
  • Most studies on imiquimod recommend application 5 times per week for a total of 6 weeks, with histological clearance rates of 80% to 85% 12 weeks after treatment. Cure rates (no recurrence after 3 and 5 years) of between 81% to 84% have been reported.
  • Local reactions, including erythema, edema, pain, vesicles, ulceration, and eschar formation are observed frequently. Topical imiquimod can be associated with systemic effects, including fatigue and an influenza-like illness.
  • Close clinical follow-up in the following months is necessary to monitor for adequate treatment and tumor recurrence.

5-Fluorouracil (5-FU) 5% Cream or Solution

  • 5-FU is a topically applied chemotherapeutic agent that has been approved by the US FDA for the treatment of superficial BCCs. Application is daily for up to 12 weeks.
  • Local reactions including erythema, edema, pain, vesicles, ulceration, and eschar formation are observed frequently.
  • Close clinical follow-up in the following months is necessary to monitor for adequate treatment and for tumor recurrence.

Photodynamic Therapy (PDT)

  • Although it is not approved by the US FDA for the treatment of BCCs, PDT is approved for this use in some European countries and may be considered for patients with many or refractory lesions—especially for superficial BCCs and certain thin nodular BCCs when surgery is contraindicated. This treatment is not recommended for high-risk BCC.
  • Superficial BCCs respond well to PDT, with primary clearance rates of 92% to 97% at 12 weeks and a 9% recurrence rate at 12 months. Low-risk thin nodular BCCs that are treated with PDT should be monitored frequently for recurrence, because the efficacy is typically not as good.
  • The cosmetic outcome of this treatment is considered to be superior to that of surgery.
  • A topical photosensitizer (aminolevulinic acid, such as Levulan Kerastick, and methyl aminolevulinate,such as Metvix) is applied to the skin in the medical office and allowed to incubate for 30–60 minutes or up to 3 hours (depending on the photosensitizer) prior to exposure to a light source for approximately 10–15 minutes, during which destruction of the tumor cells occurs.
  • Several different light sources are currently available for the activation of the photosensitizer:
      • Aktilite: 630 nm red LED light, 37 J/cm2.
      • BLU-U: 417 nm peak emission, 10 J/ cm2.
      • RhodoLED: red LED light, 635 nm peak emission, 37 J/c cm2.
      • Other light sources that emit red light with a continuous spectrum of 570–670 nm.
      • Lasers provide an additional form of light source for activation with deeper penetration.
      • PDT using daylight has been shown to be successful in the treatment of actinic keratoses (AKs) but has not been studied for the treatment of BCCs.
  • Strict photoprotection is necessary for 48 hours after PDT to avoid excessive photosensitization.
  • Post-procedure erythema, edema, and inflammation are expected and may linger for 5–7 days after each treatment.
  • Several treatments, at 3- to 4-week intervals, may be required.
  • Before the photosensitizer is applied, skin lesionsshould be prepared by removing superficial scale and crust by curettage; other techniques include topical keratolytics, tape stripping, microdermabrasion, fractional CO2laser, microneedling, and elevation of skin temperature.
  • There are many variables that are associated with the efficacy of PDT, including irradiance, light source, photosensitizer, incubation time, skin preparation, frequency of treatments, and exposure time of light source. Therefore, close follow-up is needed to assess the efficacy and to monitor for recurrence.

Radiotherapy (RT)

  • Different techniques of RT can be used in the treatment of BCC, including electron beam radiation therapy (EBRT) and brachytherapy (BT),
  • RT should be considered for older patients (> 70 years), patients with a preference for non-surgical treatments, and poor surgical candidates  including those who receive medications that affect coagulation and platelet function and those with significant comorbidities.
  • Tumors in locations that are considered not ideal for surgery, including nasal ala, nasal tip, nasal bridge, lower eyelid, medial canthus, and helix, and large, deep, or inoperable lesions, including those that extend into the cranial cavity, may be considered for RT.
  • RT can also be used preoperatively or postoperatively as adjunctive therapy for certain BCCs or patients.
  • RT should be avoided in younger patients for whom other treatment options are available, due to the many unwanted long-term side effects of radiation, such as permanent alopecia, radiation dermatitis, and a high risk for future NMSCs.
  • RT has local control rates of 90% to 95%, making it a cosmetically and functionally suitable treatment option.
  • The appropriate dose and schedule of therapy depend on the patient, type of radiation treatment, and tumor factors.
  • A field margin of 5–10 mm beyond macroscopic disease or a surgical site is usually adequate.

Vismodegib

  • Hedgehog inhibitor for the treatment of advanced local or metastatic basal cell carcinoma.  Vismodegib has also been used for treatment and prophylaxis in patients with nevoid BCC syndrome (Gorlin syndrome).
  • Significant side effects include teratogenicity, muscle spasms and dysgeusia (often associated with significant weight loss), alopecia, asthenia, diarrhea, nausea, and fatigue.
  • Mean duration of therapy is 36 weeks.

Sonidegib

  • Another hedgehog pathway inhibitor that is also approved by the FDA for the treatment of patients with locally advanced BCC that has recurred following surgery or radiotherapy or who are not candidates for surgery or radiotherapy.
  • Similar objective response rate between 200 mg/day and 800 mg/day, but the higher dose is associated with greater adverse effects.
  • Common adverse effects include muscle spasms, dysgeusia, alopecia, nausea, weight decrease, and fatigue. Elevated creatinine is also frequently observed and is one of the most common Grade 3–4 adverse events, along with elevated lipase. 

Subsequent Therapy

  • Patient education with respect to pathogenesis and natural history of BCCs is essential. Sun protection must be stressed.
  • Monitoring for recurrence as well as new lesions during the first 2 years after diagnosis is very important. A total of 30% to 50% of patients with prior BCC will develop another BCC within 5 years.
  • Patients with a history of BCC should have a full-body skin examination every 6 months during the first 2 years. An annual full-body skin examination thereafter is indicated to identify future development of tumor recurrence and new skin cancers.

Basal Cell Nevus Syndrome (Gorlin Syndrome)

Basal cell nevus syndrome is a rare, autosomal dominant condition that is characterized by early onset BCCs. Patients may develop hundreds of BCCs over a lifetime, varying in size from a pinpoint to > 5 cm. Associated findings include palmar or plantar pits, skeletal deformities, teeth/jaw abnormalities (cysts), and, rarely, the development of tumors in other organs, in addition to skin. Significant cosmetic disfigurement may result from skin cancers and their multiple treatments, and frequent clinical evaluation is necessary for close monitoring for tumor recurrence and development of new lesions.

Initial Therapy

  1. Surgical excision of all tumors is the best therapy and is performed if possible following the guidelines for the management of routine BCCs.
  2. Genetic counseling and examination of family members are important.
  3. Strict sun protection (avoidance) must be stressed.
  4. Evaluate the patient for associated conditions, especially jaw cysts and malignancies.

Subsequent Therapy

  • PDT may be helpful for field treatment of multiple lesions and early treatment of clinically occult lesions.
  • RT is not indicated for patients with basal cell nevus syndrome and for morpheaform BCCs, which are relatively radioresistant, and radiation itself may lead to future NMSCs in this already vulnerable population.
  • Vismodegib and sonidegib may be considered for the treatment of multiple and/or aggressive BCCs; however, the age and reproductive ability of the patient should be considered prior to the start. Significant side effects including teratogenicity, muscle spasms, dysgeusia (often associated with significant weight loss), alopecia, diarrhea, nausea, and fatigue may limit the use of these drugs.

Pitfalls

  • Do not underestimate the potential for cosmetic disfigurement due to BCC. Attempts should be made to identify lesions early and to eradicate each one completely.
  • In the case of a non-healing ulcer on the skin, always exclude the diagnosis of a skin tumor.
  • Following surgical removal of skin tumors, a histopathological examination is necessary to confirm the clinical diagnosis and excision margins.
  • RT should be avoided in younger patients, patients with basal cell nevus syndrome, and those with DNA repair deficiencies, such as xeroderma pigmentosum (XP), due to an increased risk of NMSC in these patients.