- Development of multiple, sometimes thousands, of BCCs beginning early in life
- Over the patient's lifetime the multitude of BCCs requiring surgical excision can eventually lead to significant cosmetic deformity and morbidity.
- Patients with BCNS commonly have depressive symptoms.
- Life expectancy is not significantly different from patients without BCNS.
- Premature death occurs in less than 10% of patients with BCNS.
- If early death does occur it is usually due to medulloblastoma or metastatic BCC.
- Treatment options for basal cell carcinomas are challenging in BCNS due to the sheer number of BCCs which develop.
- Moh's micrographic surgery, 5% imiquimod, PDT or even vismodegib are all primarily based on sporadic BCCs. The therapy of patients with basal cell nevus syndrome must be individualized to the patient (Lam, Dermatol Surg 2013).
- Multidisciplinary management of patients is critical owing to the multitude of organ systems that may be involved.
- Topical 5% imiquimod, tretinoin and 5-fluorouracil have all been utilized for BCCs in basal cell nevus syndrome patients with varying success, these are most effective for superficial basal cell carcinomas (Lam, Dermatol Surg 2013).
- Oral high dose isotretinoin has been advocated by some to treat small (<1 cm lesions) and prevent new lesions, however a previous study assessing this found that only 8% of patients had complete clinical and pathological regression of their BCCs while all patients experienced moderate to severe toxicity (Bree, Am J Med Genet 2011).
- Hedgehog pathway inhibitors (e.g., Vismodegib (Erivedge); Genentech, South San Francisco, CA, USA; GDC-0449)
- Selective inhibitors of the Hedgehog pathway which bind to Smo and prevent downstream activation of the Hedgehog pathway
- Vismodegib gained FDA approval in January 2012 for metastatic or locally advanced and unresectable BCC.
- A recent prospective study assessed the utility of vismodegib in patients with BCNS. In this study 42 patients with BCNS were randomized in a 2:1 fashion to vismodegib or placebo. The study found that the treatment group had a statistically significant reduction in the number of new surgically eligible BCCs which developed, and this treatment effect was seen as early as one month into therapy. Vismodegib was also found to reduce the size of pre-existing surgically eligible BCCs and interestingly the palmar and plantar pits also disappeared during therapy. This study was ended early due to the significant response in the treatment arm. However, it is important to note that 54% of patients discontinued therapy early due to side effects, the most common side effects were dysgeusia, muscle cramps, hair loss and weight loss. The dysgeusia and muscle cramps typically resolved within one month of discontinuing therapy. Only one patient was able to complete the full 18 month course of therapy (Tang, NEJM 2012).
- One of the major considerations of Vismodegib therapy is whether the tumor suppressive effects can be maintained after discontinuation of the drug and to what extent; this is an area of ongoing research (Cowey, Dermatol Ther 2013).
- Tazarotene (topical retinoid)
- Based on its efficacy in treating BCCs in PTCH1 knock out mice, there was interest in the use of tazarotenein prevention of BCC in patients with BCNS.
- A recent phase 2 clinical trial of topical tazarotene in patients with BCNS unfortunately found only a 6% response rate and the authors concluded that there was no evidence of either a chemo-preventative nor chemotherapeutic effect of tazarotene in patients with BCNS (Tang, Cancer Prev Res 2014).
- LDE225 is a SMO inhibitor which is currently in clinical trials in both an oral and a topical form. Early trials have shown a positive response to both forms and further studies are currently underway (Cowey, Dermatol Ther 2013).
Radiotherapy must be used with extreme caution in patients with basal cell nevus syndrome owing to their propensity to form additional basal cell carcinomas at the irradiated site, sometimes many years after the radiation therapy.
- It has been recently established that patients with BCNS have a decreased expression of aldehyde dehydrogenase 1A1, which is thought to lead to their increased incidence of radiation induced tumors.5 Although radiotherapy is often used to treat medulloblastoma in patients with BCNS, the use of radiotherapy to treat cutaneous BCCs is typically avoided (Lam, Dermatol Surg 2013).
Surgical excision with clear pathological margins of at least 4 mm is the gold standard of therapy for BCCs amenable to resection.
Moh's micrographic surgery can be beneficial for BCCs on the face in particular where preservation of normal tissue is of utmost importance.
The challenge in patients with BCNS is that they have the potential to develop hundreds of basal cell carcinomas over their lifetime, thus making repeated surgical excision necessary and leading to significant morbidity (Lam, Dermatol Surg 2013).
Other management considerations
Photodynamic therapy (PDT) has been reported in several case reports in the literature to be a potential option for sustained prevention and treatment of patients with BCNS, since its mechanism of action is through oxidative damage rather than ionizing radiation.
- Some clinicians advocate that it should be the first-line therapy for individuals with basal cell nevus syndrome and multiple lesions.
- Patients are typically treated with PDT alone for lesions less then 2 mm thick and systemic photosensitizers are added for lesions thicker than 2 mm.
- Clearance rates for BCCs have ranged from 56-100% depending on the series.
- There is some evidence that PDT may also have a chemopreventative role, with several small case series showing a decreased incidence of new lesions following PDT.
- Drawback to the use of PDT is that the treatment sessions can be very painful (Schweiger J Drugs Dermatol 2010).
Carbon dioxide (CO2) and pulsed dye laser (PDL) have been used in several case reports.
- Success of these treatments is variable.
- Higher rates of success with more superficial BCCs.
- A single case report has demonstrated success with a 755 nm Alexandrite laser in a patient with massive tumor burden. The Alexandrite laser, due to its longer wavelength, is able to penetrate the entire dermis and in this single case report the authors found an 83% clearance rate (clinical and histological) at 7 months. This has been suggested as a treatment modality that warrants further study (Lam, Dermatol Surg 2013; Ibrahimi, Lasers Surg Med 2011).
Common treatment responses, follow-up strategies
Patients with BCNS have been shown to have a favorable response to a variety of treatment modalities.
The challenge with BCNS is that although the cure rates for an individual BCC lesion is similar to that of sporadically occurring BCCs, the patient with BCNS is at a much higher risk of developing subsequent BCCs owing to the germ-line PTCH-1 mutation.