Understanding BCC Pathogenesis: Treatment Advancements and Challenges

Skin cancer is the most common form of cancer worldwide. Basal cell carcinoma (BCC) is the most common type of skin cancer,^1,2 with an estimated 1.3 to 1.5 million new cases of BCC diagnosed each year In the United States.³ The incidence of BCC is rising both in the United States and worldwide,^4,5 particularly in women under 40 years of age.⁵ BCC is also associated with a significant financial burden. A 2001 United States Medicare study determined the total annual cost of care for nonmelanoma skin cancer (NMSC)—approximately 80% BCC—was $426 million.⁶ Similarly high healthcare-related costs of NMSC have been reported in various other countries.⁷

BCC is generally a slow-growing tumor with a benign course when treated early.⁸ However, BCC can become locally aggressive or metastasize distally. When this happens, patients are faced with significant morbidity. While management options for patients with advanced BCC have historically been very limited, an effective treatment alternative—based on improved understanding of BCC pathogenesis—has recently emerged.^8,9 This approach targets the hedgehog (HH)/patched (PTCH) signaling pathway implicated in BCC pathogenesis.^8,10

There are at least 6 major histologic variants of BCC, including nodular (classic), superficial, micronodular, morpheaform (sclerosing), infiltrating, and basosquamous.^1,11,12 Nodular or superficial BCCs can be either pigmented or nonpigmented.

Distinguishing the different histological variants or BCC subtypes is important due to the variance in propensity for growth (aggressive vs less aggressive).^12-14 This helps stratify the tumor in terms of risk of recurrence or progression to advanced disease, influencing treatment selection. Classically, nodular and superficial BCCs are less aggressive or indolent-growth subtypes, whereas morpheaform/sclerosing, infiltrating, micronodular, and basosquamous BCCs are more aggressive forms of BCC.^12-14 However, a number of other factors are also associated with more aggressive phenotype and increased risk of recurrence or advanced disease, including larger tumor size, greater tumor depth, location on the midface or ears, prolonged duration, incomplete excision, and perineural or perivascular invasion.^2,12,15 Other suggested risk factors include recurrent disease, prior radiotherapy,and host immunosuppression.^15-17 Evidence linking immunosuppression with increased risk of recurrence or metastasis,however, is actually very limited (as noted in the 2012 NCCN guidelines).¹³ Delay in treatment is the biggest risk factor for metastasis. In terms of genetic markers, some studies suggest that elevated p⁵³ protein expression^18-21 and/or depressed bcl-2 protein expression^21-23 might portend more aggressive BCC. Incomplete understanding of the link between pathogenesis and prognosis is likely secondary to the lack of screening for metastatic disease, leading to late detection.

Most BCCs exhibit a clinical course that is characterized by slow growth and minimal invasion of local soft tissue.²⁴ Early treatment is associated with 5-year cure rates above 95%.^25-27 However, BCC occasionally advances aggressively, with deep tissue invasion that can cause disfigurement and/or be unsuitable for surgical therapy.²⁴ Much more rarely (estimated rate, 0.02% to 0.55%), BCCs metastasize regionally or distally.²⁸