Basal Cell Carcinoma

Clinical Features
Basal cell carcinoma is by far the most common cancer with nearly 1 million new cases per year in the US. Despite the high incidence, the number of deaths attributed to basal cell carcinoma is very low. Examples of metastasizing basal cell carcinoma are extraordinarily rare (Tavin et al., 1995). Despite the low metastatic rate, basal cell carcinoma can cause significant morbidity secondary to direct invasion of adjacent tissues, especially when the primary tumor is on the face or near an eye.

Basal cell carcinomas can have a variety of clinical appearances including flat red spots [http://tray.dermatology.uiowa.edu/BCC-003.htm], a shiny papule with telangiectatic superficial blood vessels [http://tray.dermatology.uiowa.edu/BCC-004.htm], a slightly depressed scar, or an ulcerated mass [http://tray.dermatology.uiowa.edu/BCC-009.htm]. Definitive diagnosis is established by histopathological examination of a skin biopsy. Several treatment modalities are available that result in removal or destruction of basal cell carcinomas, including excision, electrodessication and curettage, or treatment with liquid nitrogen (Martinez and Otley, 2001). For lesions adjacent to sensitive structures on the face, Moh's micrographic surgery is frequently performed. In addition, topical application of the immunomodulator Imiquimod appears to be effective in the some basal cell carcinomas, particularly superficial variants (Marks et al., 2001).

Pathology
Basal cell carcinomas have a wide variety of histologic appearances. Most commonly, superficial and/or nodular variants are observed. Characteristic features include a dermal proliferation of basaloid cells in islands, strands or nests, separated by fibromyxoid tumor stroma and frequently exhibiting an artifactual space between epithelial nests and adjacent stroma. The peripheral row of cells typically is aligned (palisades) and mitotic figures and apoptotic cells are common. Variants of basal cell carcinoma include superficial, nodular, micronodular,infiltrating, sclerosing(morpheaform), metatypical, infundibulocystic, nodulocystic, adenoid, and clear cell. Follicular or sebaceous differentiation may also be observed. Occasionally perineural invasion is present which is associated with a higher rate of local recurrence. Basal cell carcinomas with follicular differentiation appear similar to other follicular neoplasms including trichoepithelioma, trichoblastoma, and basaloid follicular hamartoma.

superficial	nodular
micronodular	infiltrating
sclerosing

Biology
Familial predisposition to basal cell carcinoma is a characteristic of basal cell nevus/Gorlin's syndrome (OMIM #109400). Other features of basal cell nevus syndrome include palmoplantar pitting, odontogenic keratocysts of the jaw, increased incidence of medulloblastoma and rhabdomyosarcoma, calcification of the falx cerebri, and several bony/skeletal changes including frontal bossing, kyphoscoliosis, and rib abnormalities. Linkage to 9q22 was established and mutations in the Patched gene were demonstrated in several kindreds. Patched (PTCH1) is homologous to the Drosophila segment polarity gene by the same name that acts in the Hedgehog pathway. The wealth of information generated by analysis of the Hedgehog signaling pathway has greatly advanced the understanding of the genetic changes resulting in human basal cell carcinoma. The Hedgehog pathway involves binding of the Hedgehog ligand to Patched, inactivating the ability of patched to inhibit the Smoothened cell surface protein. Uninhibited Smoothened activity results in activation of the GLI1 transcription factor which is frequently overexpressed in basal cell carcinoma ( Ghali et al., 1999). PTCH1 mutations or deletion have been demonstrated in both familial and sporadic basal cell carcinoma. Activating Smoothened mutations have been documented in about 20 % of sporadic basal cell carcinoma cases (Lam et al., 1999) and rare cases of PTCH2 mutations have been reported (Narang et al., 1999).

Several other inherited human conditions have an increased incidence of basal cell carcinoma or other adnexal neoplasms. These include Basex syndrome (OMIM #301845), Rombo syndrome (OMIM #180730) Spiegler-Brooke syndrome (OMIM #605041)/familial cylindromatosis (OMIM #132700). Multiple familial trichoepitheliomas (OMIM #601606) Multiple infundibulocystic basal cell carcinomas (OMIM #604451) basaloid follicular hamartoma syndrome (OMIM #605827), Muir-Torre syndrome (OMIM #158320), and Cowden's syndrome (OMIN #158350)/Banayan-Riley-Ruvalcaba (OMIM #153480).

Mouse models of basal cell carcinoma and adnexal neoplasms
Basal cell carcinoma has a variety of clinical and pathological appearances, many of which are characteristic. Less common forms such as the infundibulocystic type and basal cell carcinomas with follicular differentiation morphologically overlap with a wide variety of follicular/adnexal neoplasms. Alteration of the Hedgehog pathway in genetically engineered mice has resulted in a diverse array of adnexal neoplasms, some of which bear some resemblance to certain forms of human basal cell carcinoma (LeBoit, 2000). Examination of a subset of the tumors generated in Ptch+/- mice and K5-Gli-1 mice by a panel of dermatopathologists and veterinary pathologists resulted in the consensus opinion that the tumors were complex follicular germinative neoplasms, and although in some instances shared some features of basal cell carcinoma, would not have been classified as such in a blinded fashion ( Bosenberg et al., 2002 in prep). The panel recommends the use of the general diagnostic term "basaloid follicular neoplasm" with further descriptors appropriate for the morphology of the particular case.