恶性黑色素瘤：流行病学、诊断和治疗方法概述(下)

1、恶性黑色素瘤：流行病学、诊断和治疗方法概述(下) 尊敬的各位订阅用户：光动力技术微信平台每周三晚上8：30准时向您推送最新皮科资讯，感谢支持！文章转载：皮肤科周迅然而，即便是黑色素瘤组织病理学诊断的专家，也可能在疑难病例方面存在很大分歧。这些罕见的疑难病例包括Spitz痣（Spitz痣样黑色素瘤），一些蓝色型黑素细胞性肿瘤，和儿童期黑色素瘤。近期刚划分的类型是恶性潜能未定的黑素细胞病变。免疫组化被广泛用于色素性病变的诊断中。自产生该项技术以来，已引入几个特定黑色素瘤的标记，如HMB-45，Melan-A，MART等。现今，仅单个标记物并不能确切区分黑色素瘤和痣。免疫组织化学主要用于查证特定肿瘤

2、的黑素细胞来源。近年来，除组织病理学免疫组织化学外，研究DNA拷贝数畸变的分子技术揭示了有趣的发现：即FISH（荧光原位杂交）和CGH（比较基因组杂交）已被用于皮肤病理学诊断。目前为止，这些技术至少代表在黑色素瘤诊断方法中的一种进步。No.3手术切除黑色素瘤（尤其是非转移性黑色素瘤）的主要治疗方法为手术切除。如果可能，完全切除活检应优先于切开活检,从而确保选择最小样本和恰当的Breslow厚度测量。然而，对于大型、粘膜或临床上非典型病变，切开活检仍有使用价值，并且显示对预后无影响。切除边界应依据肿瘤的Breslow厚度确定。标准的狭窄边界适合原发性皮肤黑色素瘤。由于恶性雀斑样黑色素瘤，生殖器黑

3、色素瘤和肢端雀斑样黑色素瘤的皮损为多灶性（除了部分皮损消退）且边界不清，因而需要更宽的安全边界。手术计划制定应包括评估3D安全边界 (图1)。Fig. 1 a Melanoma arising from a giant melanocytic nevus. An ulceration could be seen at the lower end of the lesion because of the infiltrative and destructive growth pattern. b Lentigo maligna melanoma. c Acral localized (acrol

4、entiginous) melanoma. d Multiple melanomas. e Amelanotic melanoma on the scalp图1. a 由巨大的黑色素细胞痣引起的黑色素瘤。由于皮损呈浸润性和破坏性生长，因而其下端可见溃疡。b恶性雀斑样黑色素瘤。c 肢端局限性（肢端雀斑样）黑色素瘤。d 多发性黑色素瘤。e 头皮无色素性黑色素瘤。采用Mohs显微描记手术治疗面部和肢端皮损可实现保留组织和更好的美容效果。在这种情况下，建议采用垂直位的病理标本,因为其可导致大约10%的患者更新分期。手术也可用于肿瘤减积的治疗方法和转移性肿瘤的姑息疗法。对于黑色素瘤分期，前哨淋巴结活检已

5、成为一种检测区域转移（通过超声波或MRI不可见）的重要预后工具。但该方法是否具备任何治疗学意义仍存在争议。No.4放射疗法放射疗法是另一种可选择的治疗方法，适应证包括不可切除的原发性黑色素瘤，广泛侵袭的皮肤转移性肿瘤，伴功能和结构损伤的骨转移肿瘤，以及脑转移瘤等。No.5辅助疗法辅助疗法可用于非转移性，但风险性高的II或III期黑色素瘤患者。在所有已发表的研究和Meta分析的报道中，高剂量的IFN-2b是第一个也是唯一可辅助治疗黑色素瘤的药剂，并且提高了无病生存率。然而，患者依从性受到毒副作用影响，仅少数患者进行2年以上的治疗。许多皮肤-肿瘤学中心也提供摄入低剂量的IFN-(3×30

6、0万/周) 18-24个月的治疗方法。研究抗CTLA-4抗体易普利姆玛和MAGE-3疫苗作为辅助疗法的III期临床试验正在进行中。No.6外用/病灶内治疗外用/病灶内治疗的主要缺点是破坏妨碍组织病理检查，因此临床上无法区分侵入性黑色素瘤而可能错过治疗。咪喹莫特可作为手术的一种替代疗法，并在所选定的恶性雀斑样黑色素瘤患者中已进行研究。其有效率为75%，依据个体差异可发展为炎性反应。其他治疗方式包括激光、冷冻疗法、电化学疗法、瘤内注射IL-2 (interleukin-2)，以及IFN-可用于孤立性皮肤转移性黑素瘤。No.7转移性疾病的系统性疗法对不可手术的IV期黑色素瘤患者（区域性和远处转移）可

7、采用系统性治疗。尽管尚未有效的系统性疗法可延长生存期，增加无病生存期以及减轻症状。多年以来，达卡巴嗪一直被视为标准治疗，但近期研究显示其消退率低于12 %。联合不同细胞激素和细胞生长抑制剂（如替莫唑胺、福莫司汀和长春地辛）治疗，达卡巴嗪的有效率可能增加，但总生存期(OS)不变。近来显示出达卡巴嗪可正调节瘤细胞的NKG2D配体，激活NK和CD8 T细胞。这些发现为结合达卡巴嗪与减低免疫抑制作用的免疫治疗药物治疗提供了理论依据。需服用多种药剂的化学疗法并未提高疗效（无病生存率或OS），但增加了毒副作用，并且降低了黑色素瘤患者的生活质量。尽管单药治疗的耐药性发生是其主要缺点，但是，目前正在研究的靶向

8、疗法前景乐观。与达卡巴嗪相比，维罗非尼（BRAF抑制剂）对BRAF V600E突变个体可达到约50%的肿瘤有效，明显延长了无进展期和OS。已报道的副作用有光敏性，非黑色素皮肤癌的发生和罕见的BRAF单纯性黑色素瘤。在临床试验中，达拉菲尼（另一种BRAF抑制剂）显示出相似疗效，但与维罗非尼相比，其毒性较低。曲美替尼（MEK抑制剂）与BRAF抑制剂疗效相同，比达卡巴嗪更为有效，但不会促进皮肤癌发展。近期研究显示，联合多种药剂治疗可实现更好的疗效并且可降低患者耐药性。联合用药达拉菲尼与曲美替尼延长了无进展存活期（76% vs 54%对药物联用vs单药治疗完全或部分反应），但并未明显减少增生性皮损。多

9、种免疫疗法被用于治疗转移性黑色素瘤，IFN-和IL-2疗效不大并且毒副作用明显。易普利姆玛(抗CTLA-4抗体)可延长OS，有效率约15 %，最常见的副作用为免疫问题，预期的非特异性免疫刺激性行为方式。可联合易普利姆玛与其他药剂(如达卡巴嗪)治疗，疗效更佳；或用于单药治疗先前对BRAF抑制剂有耐药性的转移性疾病患者。下附英文原文：Nevertheless, even in experts in histopathologic diagnosis of melanoma there may be a considerable disagreement in problematic cases 1

10、6. Among these rare difficult cases are Spitz nevi (spitzoid melanocytic tumors), some blue-type melanocytic tumors, and melanocytic tumors in childhood. A more recently differentiated type is the melanocytic lesion of uncertain malignant potential 17.Immunohistochemistry is widely used for diagnosi

11、s of pigmented lesions. Since the establishment of this technique, several markers have been introduced as specific for melanoma; e.g., HMB-45, Melan-A, MART, etc. Today, there is no single marker which is reliably able to distinguish melanoma from nevus. Immunohistochemistry is mainly used to verif

12、y the melanocytic origin of a given tumor. In recent years molecular techniques beyond histopathology and immunhistochemistry investigating aberrations in DNA copy number revealed interesting results. Namely the FISH (fluorescence in-situ-hybridization) and CGH (comparative genomic hybridization) ha

13、ve been used in diagnostic dermatopathology. So far, these techniques at least represent one further mosaic stone in the diagnostic algorithm for melanoma 18, 19. Surgical excision The primary treatment method, especially for non-metastatic melanomas, is surgical excision. A total excisional biopsy

14、is preferred to incisional biopsy, when possible, to ensure minimal sample selection and proper Breslow thickness assessment. Nevertheless, incisional biopsies are still valuable in large, mucosal, or clinically atypical lesions and are shown to have no impact on prognosis 20.Excision margins should

15、 be determined according to Breslow thickness of the tumor. Standard narrow margins are appropriate for primary skin melanoma. Lentigo maligna melanoma, genital melanoma and lentiginous acral melanomas require sometimes wider safety margins due to the multifocality (in case of partial regression) an

16、d poor delineation of the lesion 21. Surgery planning should include assessment of the need of 3D safety margins evaluation (Fig. 1).Facial and acral lesions could be managed with Mohs micrographic surgery for its tissue sparing effect and better cosmetic outcome. Vertical pathology of the debulking

17、 specimen is advised in this case as it might lead to upstaging in about 10 % of the patients 22. Surgery is also helpful in tumor debulking approaches and in palliative therapy of metastasis. For melanoma staging sentinel lymph node biopsy has become an important prognostic tool detecting regional

18、metastases not visible by either ultrasound or MRI. It is still debatable whether the procedure has any therapeutic implication or not 23. Radiation therapy Radiation therapy is an alternative treatment for nonresectable primary melanomas, in-transit extensive skin metastases, bone metastases with f

19、unctional and structural impairment, and brain metastases 24.Adjuvant therapy Adjuvant treatment is indicated in patients without metastases but with high-risk, stage II or III, melanomas. High-dose interferon- -2b is the first and only agent approved for adjuvant therapy for melanoma with improveme

20、nt in disease-free survival reported across nearly all published studies and meta-analyses 24. However, compliance is significantly affected by toxicity and few patients tolerate the therapy for more than 2 years 25. Many dermato-oncology centers also offer a low dose therapy with interferon alpha (

21、3 × 3 million/ week) for 1824 months. Phase III trials studying the anti- CTLA-4 antibody ipilimumab and the MAGE-3 vaccine as an adjuvant therapy are currently ongoing.Topical/intralesional treatment The main disadvantage of topical/intralesional treatment is that destruction precludes histolo

22、gical examination and hence clinically indistinguishable invasive melanomas could be missed with the resulting under-treatment. Imiquimod has been studied as an alternative to surgery in selected patients with lentigo maligna. Its response rate is about 75 % and depends on the individual ability to

23、develop an inflammatory reaction 26. Other treatment modalities such as laser, cryotherapy, electrochemotherapy, intralesional IL-2 (interleukin-2), and IFN- can be used for isolated skin metastases 21.Systemic therapy in metastatic disease Inoperable stage IV melanomas with regional or distant meta

24、stases are indicated for systemic treatment. Although not curative, systemic therapies prolong survival, increase the disease-free period, and alleviate symptoms.Dacarbazine has been the standard of treatment for many years, but recent trials show remission rates of less than 12 % 21. The response r

25、ate might be increased with combination of different cytokines and cytostatic agents, such as temozolamide, fotemustine, and vindesine, but the overall survival (OS) time remains unchanged. Dacarbazine was recently shown to upregulate NKG2D ligands on tumor cells, activating NK and CD8 T cells. Thes

26、e findings provide a rationale to combine dacarbazine with immunotherapeutic agents that relieve immunosuppression 27. Multidrug chemotherapy does not result in better results (disease free survival or OS) but increases toxicity and reduces the quality of life of melanoma patients 28.Targeted therap

27、ies are currently under research and show promising results, although resistance development in monotherapy is a frequent major drawback. Vemurafenib, a BRAF inhibitor, achieves about 50 % tumor response in BRAF V600E mutation carriers with significantly longer progression-free and OS in comparison

28、to dacarbazine 29. Photosensitivity and development of non-melanoma skin cancer and rarely BRAF naive melanomas have been reported as side effects. Another BRAF inhibitor, dabrafenib, has shown similar results in clinical trials with a comparable effectiveness and less toxicity compared to vemurafenib 30. The MEK inhibitor, trametinib, is equally effective to the BRAF inhibitors, more effective than dacarbazine, but does not promote skin cancer development 31. Recent studies reveal that the combination of various agents could result i