Melanoma Institute Australia, The University of Sydney, Sydney, NSW, Australia; Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia; NSW Health Pathology, Sydney, NSW, Australia; Charles Perkins Centre, The University of Sydney, Sydney, NSW, Australia; Royal Prince Alfred Hospital, Sydney, NSW, Australia.
Princess Alexandra Hospital & Greenslopes Private Hospital, Brisbane, Qld, Australia; Queensland Melanoma Project, Princess Alexandra Hospital, Brisbane, Qld, Australia; Faculty of Medicine, University of Queensland, Brisbane, Qld, Australia.
Pathology. 2022 Feb;54(1):6-19. doi: 10.1016/j.pathol.2021.11.002. Epub 2021 Dec 20.
Targeted therapy (BRAF inhibitor plus MEK inhibitor) is now among the possible treatment options for patients with BRAF mutation-positive stage III or stage IV melanoma. This makes prompt BRAF mutation testing an important step in the management of patients diagnosed with stage III or IV melanoma; one that can help better ensure that the optimal choice of systemic treatment is initiated with minimal delay. This article offers guidance about when and how BRAF mutation testing should be conducted when patients are diagnosed with melanoma in Australia. Notably, it recommends that pathologists reflexively order BRAF mutation testing whenever a patient is found to have American Joint Committee on Cancer (AJCC)/Union for International Cancer Control (UICC) stage III or IV melanoma (i.e., any metastatic spread beyond the primary tumour) and that patient's BRAF mutation status is hitherto unknown, even if BRAF mutation testing has not been specifically requested by the treating clinician (in Australia, Medicare-subsidised BRAF mutation testing does not need to be requested by the treating clinician). When performed in centres with appropriate expertise and experience, immunohistochemistry (IHC) using the anti-BRAF V600E monoclonal antibody (VE1) can be a highly sensitive and specific means of detecting BRAF mutations, and may be used as a rapid and relatively inexpensive initial screening test. However, VE1 immunostaining can be technically challenging and difficult to interpret, particularly in heavily pigmented tumours; melanomas with weak, moderate or focal BRAF immunostaining should be regarded as equivocal. It must also be remembered that other activating BRAF mutations (including BRAF), which account for ∼10-20% of BRAF mutations, are not detected with currently available IHC antibodies. For these reasons, if available and practicable, we recommend that DNA-based BRAF mutation testing always be performed, regardless of whether IHC-based testing is also conducted. Advice about tissue/specimen selection for BRAF mutation testing of patients diagnosed with stage III or IV melanoma is also offered in this article; and potential pitfalls when interpreting BRAF mutation tests are highlighted.
靶向治疗（BRAF 抑制剂联合 MEK 抑制剂）现已成为 BRAF 突变阳性 III 期或 IV 期黑色素瘤患者的可能治疗选择之一。因此，快速进行 BRAF 突变检测成为管理 III 期或 IV 期黑色素瘤患者的重要步骤，有助于确保尽早启动最佳的系统治疗方案，避免延误。本文就澳大利亚黑色素瘤患者的诊断中何时以及如何进行 BRAF 突变检测提供指导建议。值得注意的是，本文建议病理学家在遇到 AJCC/UICC III 期或 IV 期黑色素瘤（即原发肿瘤以外的任何转移扩散）患者，且患者 BRAF 突变状态未知时，即使临床医生未特别要求进行 BRAF 突变检测，也应进行 BRAF 突变检测（在澳大利亚，医疗保险补贴的 BRAF 突变检测无需临床医生提出申请）。在具有适当专业知识和经验的中心进行检测时，使用抗 BRAF V600E 单克隆抗体（VE1）的免疫组织化学（IHC）可作为一种高度敏感和特异的 BRAF 突变检测方法，可作为一种快速且相对廉价的初始筛选检测。然而，VE1 免疫染色技术具有一定难度，且解读结果具有挑战性，尤其是在色素沉着严重的肿瘤中；免疫染色弱阳性、中等强度或局灶性的黑色素瘤应视为可疑结果。此外，还需记住，目前的 IHC 抗体无法检测到其他激活的 BRAF 突变（包括 BRAF），占 BRAF 突变的 10-20%左右。因此，只要可行，无论是否同时进行 IHC 检测，我们都建议进行基于 DNA 的 BRAF 突变检测。本文还就 III 期或 IV 期黑色素瘤患者的 BRAF 突变检测提供了有关组织/标本选择的建议，并强调了解读 BRAF 突变检测结果的潜在陷阱。
