Commentary on Development of Basal Cell Carcinoma With Squamous Differentiation During Vismodegib Treatment

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This timely case report by Feigenbaum and colleagues1–4 from the University of Texas Southwestern Medical Center adds to the growing body of literature describing the development of squamous differentiation in basal cell carcinomas (BCCs) after vismodegib treatment. In this case, the BCC with squamous differentiation appeared after the initiation of vismodegib for 4 biopsy-proven nodular BCCs which initially responded to treatment. The BCC with squamous differentiation required 4 stages of Mohs surgery and bony resection with otolaryngology to completely excise.
The mechanism by which squamous differentiation develops during Hedgehog signaling pathway inhibition by drugs such as vismodegib includes rat sarcoma/mitogen-activated protein kinase activation.5 Because of this possibility, close skin surveillance after vismodegib initiation is required.
To combat both BCC resistance and development of squamous differentiation, treatments other than targeting smoothened in the Hedgehog signaling pathway through vismodegib will need to be instituted. In many cases, the highest chance of cure will be from excision, particularly if the resistant lesion is found early and the original unresectable BCC has at least partially responded to smoothened inhibition.6 In situations where excision is neither curative nor a good treatment option, adding radiation treatment may be beneficial in select patients.7
Other nontargeted modalities, such as immunotherapy for BCC or basosquamous tumors, are currently being studied. Recently, the authors reported an incidental finding of BCC regression in a patient receiving cytotoxic T-lymphocyte–associated antigen-4 (CTLA-4) inhibition with ipilimumab for a concurrent metastatic melanoma,8 suggesting that immunotherapy may have activity against BCC. An investigator-initiated clinical trial targeting a different immune pathway is underway to examine the activity of the programmed death-1 (PD-1) inhibitor, pembrolizumab, against advanced BCC (NCT02690948).
For squamous cell carcinomas (SCCs), this group has published a case series of patients with unresectable SCCs in which responses to PD-1 inhibition were observed.9 Clinical trials investigating the safety and efficacy of PD-1 inhibitors for unresectable or metastatic cutaneous SCCs are in progress (e.g., NCT02760498). Because basosquamous tumors have both basaloid and squamous histology, PD-1 inhibitors are an attractive potential modality to address this mixed histology, as theoretically, this class of drugs could target both cell types. This hypothesis remains to be studied in ongoing clinical trials.

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