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葡萄膜黑色素瘤是来源于眼内脉络膜、虹膜或者睫状体黑色素细胞的一种常见的眼部恶性肿瘤, 起病隐匿，通常不容易早期发现，易通过血行途径转移到肝脏。与皮肤原发性黑色素瘤相比，眼部黑色素瘤患者的转移风险要高得多。一旦转移，死亡率极高，10年死亡率为50%，明显高于大多数其他的黑色素瘤亚型。另外，眼部黑色素瘤的亚型具有不同的遗传特征。ARVO 2022会议上，《国际眼科时讯》特邀哥本哈根大学Jens Folke Kiilgaard教授，就葡萄膜黑色素瘤的热点、难点问题展开论述。
不同分期的葡萄膜黑色素瘤，治疗策略相异
葡萄膜黑色素瘤的治疗策略与肿瘤位置关系密切：位于前房的肿瘤，如虹膜上肿瘤，通过手术途径切除肿瘤效果较好；位于后房的肿瘤，通过放射治疗效果较好。虽然有一些手术可用于切除眼后段的肿瘤，但难度很大。葡萄膜黑色素瘤较为棘手的问题是出现肿瘤转移。目前人们尚无有效方法治疗肿瘤转移，即使是新型药物 “tebentafusp”（基于Gp -100的蛋白质），但它似乎仅对一小部分患者起作用。所有免疫疗法均不起作用，但人们并不清楚其原理。
The location of tumors is important, because the anteriorly located tumors, such as on the iris, would most likely be treated with a surgical approach with the removal of the complete tumor. Posterior tumors are most likely going to have some kind of radiation, either as a proton beam or plaque therapy where the agent is sutured directly to the eye and removed after a certain time. There are surgical ways to remove tumors that occur in the posterior segment, but it is difficult. The big problem with uveal melanoma is the metastatic state. The metastatic state is a problem because we don’t have good treatments for this tumor type, even though we have this new Gp-100-based protein, tebentafusp, which seems to be working in some patients, but only a small group of patients. All the other immune therapies aren’t working. We don’t know why that is.
基因突变可导致葡萄膜黑色素瘤出现及扩散
原发或转移性的葡萄膜黑色素瘤没有典型症状，故自查并不能发现这种疾病。现代医学中，通过拍摄眼底照片筛查此类肿瘤患者是一个很好的方法。越早发现肿瘤，越早治疗，意味着更高的生存率。葡萄膜黑色素瘤的发病率相当低，因此，在人群中筛查该病患者是一项艰巨的任务。一些成像技术可用于葡萄膜黑色素瘤全身转移的检测，如肝脏的超声或磁共振扫描。有文章表明，超声波和磁共振都能发现肿瘤，但磁共振在检测转移肿瘤的数量方面更好。另外，尽管葡萄膜黑色素瘤可能会扩散到全身，但无需定期检查身体的其他部位。葡萄膜黑色素瘤的遗传学变化主要受基因突变影响，如CYSTLR2或PLCβ4突变；其次是肿瘤抑制基因发生功能丧失性突变，肿瘤快速增长。当然，也有发生频率不那么高的突变，如SF3B1突变，其使RNA剪接失调，导致细胞生长和转移。当出现这些不好的突变时，葡萄膜黑色素瘤则开始扩散。
We detect tumors earlier than we used to. People don’t have any symptoms from these tumors, either from the primary tumor or from the metastatic tumors. So self-reported sickness is not a very good indicator for finding disease. But modern screening where people wear glasses and are having pictures taken of their fundus seems to be a very good way to screen for these patients. Nevi are very common inside the eye, and if you have to screen all populations in order to find the very few melanomas, it would be a huge task. It might be that optometrists would be taking photos of eyes and detecting tumors earlier, and earlier treatment means better survival. It seems the genetic changes involved start with a few changes with driver mutations like CYSTLR2 or PLCβ4, then there is the second hit, which is most likely the bad one where the tumor suppression genes disappear, and now there is rapid growth of the tumor. They start to spread when these bad mutations happen. There are also other events that are less prevalent, like the SF3B1 mutations, where there is a splicing problem that causes cell growth and ultimately they will metastasize. For the detection of systemic disease, we only have imaging techniques like ultrasound or MR scans of the liver. There are papers out now showing there is no difference in detecting the tumors with ultrasound or MR, but MR is much better at detecting the amount of metastasis. We don’t regularly screen the rest of the body, even though it can spread throughout.
葡萄膜黑色素瘤与皮肤黑色素瘤突变的差异
紫外线可导致皮肤黑色素瘤，这也是其与葡萄膜黑色素瘤的主要区别。如果在太阳直射下，不采取任何保护措施，黑色素细胞将受到大量紫外线辐射，导致成千上万种基因突变的发生，常见的基因突变有BRAF V600、NRAS和KIT。葡萄膜黑色素瘤发生的基因突变非常少，比皮肤黑色素瘤中非常罕见的一个亚群“蓝痣”的突变还要少。目前已知的突变仅3-8个。其中GNAQ、GNA11、CYSTLR2或PLCβ4像是启动车辆的发动机；而引发很坏结果的SF3B1则像是松开了车辆的刹车。可能是由于突变负担低，免疫疗法对这些黑色素瘤效果不佳。
The major difference between the cutaneous melanomas and the ocular melanomas is that the cutaneous melanoma is driven by UV light. If you go out into the sun and do not protect yourself, your melanocytes will experience huge amounts of UV radiation, and that causes myriads of mutations. There are thousands of mutations. The bigger mutations are from BRAF V600, NRAS and KIT. In uveal melanoma, there is very low mutation occurring. We only see 3-8 mutations, and these are mainly driven by initiator genes, where GNAQ, GNA11, CYSTLR2 or PLCβ4 turn on the engine in the vehicle, and the resultant bad one, SF3B1, that is basically taking off the brakes. So there are very few mutations, and compares to a subgroup of cutaneous melanomas, called blue nevi, which are very rare in the skin. It is probably because of the low mutational burden that immune therapies don’t work on these melanomas.
葡萄膜黑色素瘤诊治领域的新药物、新技术
基本上，在过去的20年里，这类肿瘤的治疗并没有发生什么变化，依旧是靠近距放射治疗和质子束辐射治疗。有新的药物可以治疗小黑色素瘤，即把纳米粒子注射到血液中，然后用激光激活粒子。但这仍在研究中，主要困难是光不能很好地穿透到色素肿瘤，只能治疗肿瘤表面而无法治疗肿瘤更深的部分。对于葡萄膜黑色素瘤转移性疾病的检测，这次会议上的很多海报都在讨论一点：人们需要找到其他的检测方法。对于新技术，唯一真正的新产品是tebentafusp，它是治疗葡萄膜黑色素瘤和转移性疾病的重大突破，但只对少数患者有效。
Basically, not a lot has happened over the last 20 years in the treatment of these tumors. It is the same - brachytherapy and proton beam radiation. There are new drugs that could be treatments for small melanomas that are nanoparticles injected into the blood stream and then activated with a laser, but these are still under development, and the problem is that the light does not penetrate well into a pigmented tumor - you only treat the surface and not the deeper parts of the tumor. For the detection of systemic disease, there are a lot of posters at this conference actually dealing with that point - that we need to find other ways to detect it. In new technology, the only real new product is tebentafusp, which has been a major breakthrough in the treatment of uveal melanoma and metastatic disease, but it only works in a small population of patients.
小结：新诊疗技术和新药物的出现，增加了葡萄膜黑色素瘤的早期诊断率，减少了漏诊、误诊，提高了患者的保眼率和中位生存期，为患者带来福音。