Basal Cell Carcinoma



Basal Cell Carcinoma


Elise Ng

Arielle Kauvar



BACKGROUND

Basal cell carcinoma (BCC) is the most prevalent malignant tumor of the skin. It is seen most often in fair-skinned middle-aged to older adults. Multiple clinicopathologic subtypes exist, the most common of which are the nodular, superficial, and pigmented variants. Less common subtypes include morpheaform, micronodular, cystic, basosquamous, and fibroepithelioma of Pinkus.


PRESENTATION

The clinical appearance of tumors often correlates with the subtype. Nodular BCCs tend to present as pearly papules with telangiectasias and rolled borders, whereas superficial tumors present as thin, erythematous scaly plaques, pigmented tumors display heavy pigmentation, and morpheaform tumors appear as scarlike, firm plaques. BCC is typically a slow-growing and locally destructive tumor, but a small subset can grow rapidly and behave more aggressively. Nevertheless, BCC carries a low mortality rate and metastasis is rare, estimated to occur in only 0.0028% to 0.5% of cases.1




PATHOGENESIS

Multiple risk factors are associated with the development of BCC. The predominant risk factor is ultraviolet light (UV) exposure, with heavy exposure in the childhood to adolescent years leading to latent onset of BCCs in adulthood.3 Accordingly, tumors are usually found on sun-damaged or previously irradiated skin. UVA, UVB, and ionizing radiation all increase the risk for BCC, and the cumulative effect, timing, and location of exposure are complex variables contributing to this increased risk.4 Other important risk factors include phenotypic characteristics that confer a greater susceptibility to damage by UV or ionizing radiation, such as fair complexion (Fitzpatrick type I and II skin), light (blond or red) hair color, and light eye color. Patients with underlying disorders such as albinism, in which skin pigmentation is absent, and xeroderma pigmentosum, in which there is a defect in DNA repair, are also at increased risk. In patients with nevoid basal cell carcinoma (Gorlin) syndrome, mutations in the PTCH1 (patched 1) gene, which codes for the sonic hedgehog receptor (SHH), are responsible for the development of BCCs.1,2,5

BCC is a tumor derived from the basal cells of the epidermis. Tumor cells carry a variety of mutations that drive proliferation. The most common genetic alteration is a mutation in the PTCH1 gene, which codes for Patched, the SHH receptor. Truncating mutations and allelic loss leading to loss of heterozygosity are most frequently observed. In tumors with an intact PTCH gene, activating mutations in the SMO gene, which codes for the Smoothened (SMO) receptor, have been detected. These two proteins are key components of the Hedgehog signaling pathway, which plays a critical
role in cell proliferation and development. Activation of SMO triggers activation of the transcription factor Gli, which in turn leads to transcription of downstream target genes. Patched normally inhibits SMO signaling. Inactivating mutations in Patched or activating mutations in Smoothened thus lead to uncontrolled cell proliferation.2

Point mutations in the p53 tumor suppressor gene comprise the second most common genetic abnormality in BCCs. The majority of these mutations are missense mutations C → T and CC → TT base substitutions, which are UV signature mutations. Less commonly, mutations in the CDKN2A locus, which encodes p16 and p14ARF proteins, which are critical for cell cycle arrest. Dysfunction of these proteins leads to uncontrolled cell proliferation. Interestingly, tumors can consist of subclones that share a common mutation but differ with respect to subsequent second or third mutations.

In addition to the mutations found in the nests of BCC tumor cells, interactions between BCC cells and surrounding stromal fibroblasts are critical to the continued tumor growth and survival exhibited by these tumors. BCC stroma demonstrates upregulation of growth factor receptors for PDGF, whereas tumor cells express the PDGF ligand. The rarity of BCC metastasis has been hypothesized to be attributable to this cross talk and the dependence of BCC tumor cells on its surrounding stroma.2

Jun 29, 2020 | Posted by in Dermatology | Comments Off on Basal Cell Carcinoma
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