Histological Features Associated With Vemurafenib-Induced Skin Toxicities

Abstract

Dermatologic toxicities (DTs) associated with vemurafenib therapy include actinic keratosis (AK), verruca vulgaris (VV), keratoacanthoma (KA), and invasive squamous cell carcinoma (SCC), which may share histological features. The authors report the histological features to aid in distinguishing among these DTs. A 3-year retrospective examination of the authors' surgical pathology database was conducted and 141 cases of vemurafenib-associated DTs from 33 patients were identified. DTs were categorized into 3 groups: (1) cutaneous epithelial proliferations (CEP), (2) melanocytic lesions, and (3) inflammatory dermatoses. The authors compared the groups using analysis of variance, and P<0.05 was considered significant. CEP (n=120) accounted for 85% of all DTs biopsied. The most frequent diagnosis in the CEP category was VV (40%), followed by invasive SCC (24%) and AK (21%). KA was diagnosed in 3% of CEP. Histologically, AK, VV, KA, and invasive SCC may demonstrate similar morphological features in superficial sampled specimens. The mitotic rate was significantly higher in invasive SCC than other CEP (P<0.003). The median tumor thickness of SCC was 2.60 mm. Evaluating the base of the keratinized lesion will aid in distinguishing the histological type of CEP and the management of the DTs; thus, a deep shave or punch biopsy may be warranted for patients who received vemurafenib therapy.

Diverse types of dermatologic toxicities from immune checkpoint blockade therapy

“…Alterations in epidermal keratinocytes and epidermal melanocytes do occur, but in contrast to patients undergoing BRAF inhibitor (BRAFi) therapy, keratinocytic proliferations are not as frequent with immune checkpoint blockade therapy. 58,59 Acantholytic dyskeratosis (e.g. Grover's disease) may be encountered with BRAFi therapy as well as with immune checkpoint antibody blockade.…”

Regressed melanocytic nevi secondary to pembrolizumab therapy: an emerging melanocytic dermatologic effect from immune checkpoint antibody blockade

“…1,10,11,13,[20][21][22][23][24][25][26]29,31 Comparison of the types of dermatologic effect from immune checkpoint antibody blockade therapy (e.g., pembrolizumab) and small-molecule inhibitors (e.g., vemurafenib and dabrafenib) reveals some similarities and differences (Table 2). 12,17,[33][34][35][36][37][38][39][40][41][42][43][44][45][46][47] In general, melanocytic dermatologic effect may manifest as changing nevi, regression, tumoral melanosis, or development of new melanocytic nevi or melanoma, and has been reported in patients treated with either immune checkpoint antibody blockade therapy or targeted therapy. 12,13,34 However, in our experience, the development of a second cutaneous melanoma appears more frequently in patients receiving BRAFi therapy.…”

“…12 Immunobullous reactions are unique to immune checkpoint therapy; 16,17 in contrast, BRAF inhibitors are more commonly associated with verruca, keratoacanthoma [KA], or squamous cell carcinomas. 35 Acantholytic dermatitis (Grover disease) can be seen with either immune checkpoint antibody blockade therapy or small-molecule inhibitors. 19 The different types of dermatologic toxicity and effect on melanocytes observed in patients treated with either immune checkpoint antibody blockade or targeted therapy with small-molecule inhibitors appear to be reflective of the mechanism of action of these therapeutic agents.…”

Systematic review and meta-analysis of prevalence of dermatological toxicities associated with vemurafenib treatment in patients with melanoma

“…Analysis of the prevalence of all-grade cSCC associated with heterogeneity in patients with melanoma was performed for eight studies. [7][8][9]11,12,[15][16][17] Testing for interstudy heterogeneity gave significant results [Q = 85.56; P < 0.01; I 2 = 91.8% (high heterogeneity was I 2 > 50%)]. The random-effects model meta-analysis indicated that the overall prevalence of all-grade cSCC was 18.00% (95% CI 0.12-0.26%) in patients assigned to vemurafenib ( Fig.…”