The correct answer is C: Vismodegib.
Discussion: Basal cell carcinoma (BCC) is one of the most common forms of all neoplasia, comprising some 80% of all nonmelanoma skin cancers diagnosed each year in industrialized countries. In 2011, it is estimated that the 3.5 million nonmelanoma skin cancers diagnosed in the United States included 2.8 million BCCs. The lifetime risk for development of a BCC in a Caucasian individual in the United States has been remarkably stable in each published estimation, standing at about 30%. This common tumor is associated with an exceptionally low mortality rate, well under 1% among routine cases. Multiple destructive, excisional, and even topical modalities exist that adequately manage this banal neoplasm.
This particular patient, however, demonstrates a fairly rare phenomenon, namely, metastatic basal cell carcinoma. She fulfills the three generally accepted criteria for this process:
1) Nonmucosal origin of the primary BCC.
2) Verified identical histology within the index tumor and metastatic focus or foci.
3) Appearance of metastatic cancer that is sufficiently distant from the primary tumor to preclude spread simply due to direct extension.[3,4]
Metastatic BCC is certainly uncommon, with only about 300 cases appearing in the world's medical literature. Estimates of the prevalence of metastatic BCC ranges between 0.0028% and 0.55%, based upon extensive case series and literature meta-analysis.[6,7] Unlike routine BCC, metastatic BCC runs an aggressive course, with a heretofore expected median survival of 8 to 14 months.[7,8] Metastatic spread involves the regional lymph nodes (40% to 83%), lungs (35% to 53%), bones (20% to 28%), skin (10% to 17%), and liver (9%), in that order.[7-10] This patient had nodal, pulmonary, and osseous lesions, consonant with what might be expected in this situation.
What are the risk factors for development of metastatic BCC? A fair-complected individual (Fitzpatrick skin type I or II) with a prior history of extensive sun exposure and a personal or strong family history of nonmelanoma skin cancer is at highest risk from a demographic perspective. Both primary and metastatic BCC are uncommon in those with darker skin tones. The lesion size (> 10 cm), location (scalp, ear, scrotum), and duration (> 2.5 years) all play a role.[10-12] Also important are histologic factors: the presence of perineural and/or perivascular invasion places lesions at higher metastatic risk, as do selected inherently aggressive subtypes (basosquamous, micronodular, and morphea-like, in particular). Repeatedly recurrent lesions may also predispose to metastatic spread. Some authors suggest that metastatic BCC progresses more rapidly in women than in men, although the phenomenon itself is twice as common in men as it is in women.
Historically, most patients with metastatic BCC have presented for medical evaluation and treatment at a late stage. Nonetheless, even with early surgery augmented by radiotherapy and/or traditional chemotherapy (cisplatinum, bleomycin(Drug information on bleomycin), 5-fluorouracil), most patients' courses have been abysmal. As in other areas of cancer therapeutics, recent research elucidating the molecular basis of cancer development has led to the development of targeted molecular inhibitors. In the case of BCC, the so-called sonic hedgehog pathway has been found to be critical. Recent evidence from in vitro and in vivo studies has demonstrated that aberrant reactivation of the sonic hedgehog signaling pathway upregulates genes that promote cellular proliferation in some tumors, including BCC. Therefore, chemotherapeutic agents that inhibit this pathway have emerged as promising novel drugs for locally advanced or metastatic BCC not amenable to surgical treatment. In particular, GDC-0449 (vismodegib), an orally administrable small molecule belonging to the 2-arylpyridine class, often efficiently inhibits this signaling pathway in both syndromal and sporadic BCC. Clinical trials have led to remarkable responses in some advanced or metastatic BCC patients—responses so dramatic that the agent was recently approved by the Food and Drug Administration (FDA).[15,16] Side effects associated with the drug have proven to be quite manageable (abnormalities of taste, hair loss, and muscle spasms).[15-17] Although acquired resistance may limit the duration of response, use of this drug will lead to total or partial regression in some patients, turn some unresectable tumors into ones amenable to surgical intervention, or for other patients, provide at least progression-free survival (stable disease). Clearly, vismodegib represents a major advance in the management of BCC. For this reason, other sonic hedgehog pathway inhibitors are also currently under study.
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