Department of Dermatology, Westmead Hospital, Westmead, NSW 2145, Australia.
Br J Dermatol. 2012 Nov;167(5):1153-60. doi: 10.1111/j.1365-2133.2012.11155.x. Epub 2012 Oct 5.
Inhibitors of mutant BRAF are emerging as standard of care in patients with metastatic melanoma carrying relevant oncogenic mutations. Cutaneous reactions are frequent and significant. We conducted a systematic prospective dermatological review of all patients enrolled at a single institution in the phase I/II clinical trial of the mutant BRAF inhibitor dabrafenib (GSK2118436).
To identify the cutaneous manifestations of the BRAF inhibitor dabrafenib; to form diagnostic criteria to standardize the diagnosis of verrucal keratotic squamoproliferative lesions; and to bring awareness to the medical community of the importance of dermatological assessment of patients taking dabrafenib.
Patients enrolled in the phase I/II trial (n = 43) were monitored for the development of new skin lesions. Each new lesion was photographed, a clinical diagnosis recorded and, where appropriate, a biopsy taken. Human papillomavirus (HPV) and p16 immunohistochemistry analyses were performed.
The most frequently observed lesions were verrucal keratotic squamoproliferative lesions (49%), Grover's disease (27%) and reactive hyperkeratotic lesions on the soles, at points of friction (22%). Eighteen squamous cell carcinomas (SCCs) occurred in 20% of patients. Most SCCs appeared between weeks 6 and 24 following commencement of therapy on both sun-damaged and nonsun-damaged skin. All SCCs were well differentiated, five were of the keratoacanthoma type, and two were SCC in situ. Other lesions observed included seborrhoeic keratoses, epidermal cysts, acneiform eruptions, hair loss and changes in hair structure. HPV was negative in 15 of the 16 tissues studied and p16 expression was higher in SCCs compared with verrucal keratoses.
Administration of the mutant BRAF inhibitor dabrafenib is associated with induction of keratinocytic proliferation, which in some cases develops features of low-grade malignancy. Highly oncogenic HPV infection is unlikely to be a contributor to the formation of SCCs or verrucal keratoses.
在携带相关致癌突变的转移性黑色素瘤患者中，BRAF 突变抑制剂已成为标准治疗方法。皮肤反应频繁且严重。我们对一家机构的 I/II 期临床试验中的所有患者进行了系统的前瞻性皮肤科检查，这些患者均接受了 BRAF 突变抑制剂 dabrafenib（GSK2118436）治疗。
确定 BRAF 抑制剂 dabrafenib 的皮肤表现；制定诊断标准，以规范疣状角化性鳞片状增生性病变的诊断；并使医学界认识到对接受 dabrafenib 治疗的患者进行皮肤科评估的重要性。
对参加 I/II 期试验的患者（n=43）进行了新皮肤病变的发展监测。对每个新病变进行拍照，记录临床诊断，并在适当情况下进行活检。进行了人乳头瘤病毒（HPV）和 p16 免疫组化分析。
最常观察到的病变是疣状角化性鳞片状增生性病变（49%）、Grover 病（27%）和脚底、摩擦点的反应性过度角化病变（22%）。18 例鳞状细胞癌（SCC）发生于 20%的患者。大多数 SCC 出现在治疗开始后的第 6 周至 24 周，发生于阳光损伤和非阳光损伤的皮肤。所有 SCC 均为高分化，其中 5 例为角化棘皮瘤型，2 例为原位 SCC。观察到的其他病变包括脂溢性角化病、表皮囊肿、痤疮样皮疹、脱发和毛发结构改变。在研究的 16 个组织中，有 15 个 HPV 为阴性，与疣状角化病相比，SCC 中 p16 的表达更高。
BRAF 突变抑制剂 dabrafenib 的给药与角质形成细胞增殖有关，在某些情况下，增殖会发展为低度恶性肿瘤的特征。高度致癌性 HPV 感染不太可能是 SCC 或疣状角化病形成的原因。
