编者按：眼肿瘤不仅会危害视力，恶性的眼肿瘤甚至危及患者的生命。常见的眼恶性肿瘤有成人的葡萄膜黑色素瘤以及儿童的视网膜母细胞瘤。ARVO2022会议期间，《国际眼科时讯》在会议现场采访到国际眼科专家Lauren A. Dalvin教授，分享了眼肿瘤诊断的特殊性以及葡萄膜黑色素瘤以及视网膜母细胞瘤现状和进展。
专家简介
Lauren A. Dalvin教授在2022年ARVO会议现场照片
Lauren A. Dalvin教授是梅奥医学中心的眼部肿瘤学专家，眼部肿瘤是其研究方向，包括葡萄膜黑色素瘤、结膜黑色素瘤和视网膜母细胞瘤。重点领域包括眼肿瘤临床数据库和组织库、葡萄膜黑色素瘤研究、结膜黑色素瘤研究、视网膜母细胞瘤的视网膜成像。
Dalvin教授对眼部肿瘤的研究涵盖发现和了解肿瘤形成和扩散的分子机制。随着研究进展，Dalvin教授的目标是开发新的治疗方法，进一步提高患者的存活率、眼睛存活率和视力结果。
Dalvin教授表示眼肿瘤是肿瘤学中一个特别的学科。大多数癌症患者的诊断依靠活检获得病理学证据，而眼睛是一个小且封闭的独特空间，活检可能会导致肿瘤扩散，因此医者们更倾向于根据临床检查和多模态成像诊断眼内肿瘤，如通过光学相干断层扫描、超声检查和荧光素血管造影术来观察眼部肿瘤的血流状态——这是人们能够直接观察肿瘤的少数几个地方之一。这一方法依赖丰富的临床经验，而非明确的病理学证据，颇具挑战性。目前研究热点是寻找侵入性较小且客观的诊断方法。随即，她就葡萄膜黑色素瘤、视网膜母细胞瘤及眼肿瘤继发青光眼的诊疗进展进行了翔实的介绍。Eye tumors are really a particularly interesting subject in oncology. Most patients who have a cancer diagnosis are diagnosed via a biopsy of the tumor tissue itself, and by doing that, we can give them a histopathologically confirmed diagnosis. Because the eye is such a small space and because we use it for vision, and everything is so delicate within the eye, and also because it is an enclosed space, and we sometimes worry that doing biopsies can cause the spread of tumor outside the eye, the eye is actually very unique and we tend to diagnose eye tumors based on a clinical exam and based on a combination of multimodal imaging features. We can actually do things like optical coherence tomography, ultrasonography and fluorescein angiography watching blood flow through tumors in the eye. It is one of the few places where we can really directly visualize a tumor, and because of that, and the dangers and risks associated with doing a biopsy, we tend to rely on these clinical features for a diagnosis. It is challenging in that way, because we are really relying on clinical judgement and experience, and it is not a definitive histopathologic diagnosis. Some of the things that are being worked on by others are ways in which we can get less invasive but objective diagnoses of these tumors.
葡萄膜黑色素瘤
葡萄膜黑色素瘤，治疗越早预后越好！定期筛查要到位
早期诊断对葡萄膜黑色素瘤治疗至关重要，治疗越早，预后越好。根据肿瘤细胞遗传学特征，较大的葡萄膜黑色素瘤扩散的风险甚至可能超过70%，较小的葡萄膜黑色素瘤转移的风险较低。目前面对高转移风险肿瘤的主要方式是密切监测，每三个月一次定期筛查常见的转移器官（肝和肺）；对于低转移风险的患者，建议每年筛查一次。若肿瘤已扩散，单器官受累比多器官受累预后要好。目前有很多成功治疗的案例：如对单叶肝脏转移瘤靶向消融治疗；对多器官转移受累的一线治疗为全身免疫疗法，近期一种能够提高葡萄膜黑色素瘤患者存活率的新药tebentafusp获得了美国FDA批准。Dalvin教授在采访中提到，希望未来出现更多针对性预防肿瘤转移的全身药物，尽管要实现这个目标仍有很长的路要走。
Our primary strategy with uveal melanoma is early diagnosis. If we can catch these tumors when they are small, we know that a smaller uveal melanoma has a much lower risk for metastatic disease. The earlier we catch it, the better the prognosis. Once we are in a situation where we have larger tumors, these can often have a really high risk for spread. Sometimes the risk of spread can be even greater than 70%, depending on the tumor cytogenetic profile. Once we are dealing with a high risk tumor, in the future we hope we are going to have some systemic medications that we can use to hopefully prevent metastatic disease, but for now, our approach is close monitoring. For patients who are at high risk for metastasis, we may initially screen their liver and lungs, because, as you said, they are the two most common primary metastatic sites, on an every three month basis at first, versus our lower risk patients, who we might stretch out more quickly to once a year screening, because we know that even with metastatic disease, early detection, even in just one organ, may be more treatable than if it is widespread. Once we have dealt with cancer that has spread, if we are dealing with single organ involvement, that is a better prognosis than multi-organ involvement. If we are dealing with just the liver, per se, and it is one lobe of the liver, then maybe we can apply targeted ablative therapies to that lobe of the liver. I have seen those done recently with some good success. Once we get beyond just single organ involvement, then we are talking about systemic immunotherapy as our frontline treatment these days. We have had recent approval of tebentafusp by the FDA in the United States, and this is the first drug that has actually shown some increased survival in patients with uveal melanoma. But we still have a long way to go. So a broad spectrum of approaches from trying to get the localized tumor in the eye to having to use systemic immunotherapy once the cancer has spread.
详解葡萄膜黑色素瘤的诊疗新进展
Dalvin教授阐述了目前葡萄膜黑色素瘤诊疗领域的相关新进展：
?房水活检：很多视网膜母细胞瘤的相关研究表明，房水活检是一种相对非侵入性的有效活检方式。目前这个方法还没有应用至葡萄膜黑色素瘤的诊断中，但已有研究团队开始这方面的研究，如果能够检测到房水中基因突变的生物标志物，可以帮助医者区分可疑的良性和恶性肿瘤，早期治疗。
?超广角成像：过去的眼底照相只能勉强看到眼底的后极部，很难顾及周边部。而超广角眼底成像的引入，使得人们能够发现很多以前忽略的细节，辅助检测早期病变和疾病进展。
?放疗与纳米粒子疗法：治疗原发性葡萄膜黑色素瘤的标准疗法是放疗，现在临床上有各种类型的放射疗法，如斑块放疗、伽马刀以及质子放疗，依据肿瘤的位置和大小，可以减少对视网膜和视神经的辐射毒性。此外，Aura纳米粒子疗法已经进入临床试验阶段，通过注射被标记的纳米粒子定位肿瘤，应用光动力激活纳米粒子使肿瘤细胞死亡，精准打击肿瘤，副作用小。
One of the things that is not yet available but that we hope will be available in the future is aqueous humor biopsy. There has been a lot of good work done on retinoblastoma tumors now showing that this is a valid way of doing a liquid biopsy that is relatively non-invasive, and now we are just starting to see the fruits of this labor in the uveal melanoma setting. If we can detect mutations in aqueous humor that could potentially help us differentiate between things like suspicious benign choroidal nevus and something that has actually transformed into melanoma, we can make sure we are treating at the earliest possible point. One thing that has practically helped to diagnose things earlier, I think, has been the introduction of wide field imaging. I have noticed that compared historically to when our fundus cameras could just barely see the back of the eye and not necessarily the peripheral fundus, I am getting referred a lot more nevi for which people have employed the Optos camera in optometry offices now. They are picking up a lot of things that may have been missed before on clinical exam. I think that some of these imaging techniques have really helped our comprehensivists detect small lesions at an early stage or something that has only just transformed, so that we are not waiting until we have a really large tumor in our office. How do we treat these things? The standard-of-care really has been radiation for primary uveal melanoma. Unfortunately, this hasn’t changed since the 1980s. We have looked at different modalities for using radiation, so we have plaque radiotherapy, gamma knife and proton. There may be advantages to sparing radiation toxicity to the retina and the optic nerve depending on tumor location and size. But there are some upcoming things that have been in clinical trials. The Aura nanoparticle therapy is where they inject particles that are tagged to go to uveal melanoma cells. They have done intravitreal injection, but also suprachoroidal injections of this, and then applied a photodynamic therapy laser that activates the nanoparticles to cause tumor cell death. That is potentially something that could treat these tumors without having as many vision threatening side effects as radiation. We are looking forward to seeing how that evolves.
视网膜母细胞瘤
高危视网膜母细胞瘤有哪些预警特征？
视网膜母细胞瘤患者的大面积脉络膜侵犯或视神经受累都被认为具有高转移风险。医生经常会面对肿瘤浸润至筛板以外视神经的患者，这些患者将在局部治疗后接受全身化疗，一般眼球摘除是这类晚期肿瘤患者的主要治疗方法。也有学者认为眼前节受累是视网膜母细胞瘤高转移风险的另一预警特征，此类患者也可以早期进行全身化疗。
Many times we are dealing with optic nerve invasion beyond the lamina cribrosa. We are dealing with what we call massive choroidal invasion, or any combination of optic nerve involvement with choroidal invasion is considered a high risk situation in retinoblastoma patients. These children should always be treated and followed up with systemic chemotherapy. Typically when we are dealing with those types of advanced tumors, enucleating the eye is the primary tumor treatment. Some people also consider anterior segment involvement and invasion into the front of the eye a high risk feature as well, so we may also consider early systemic chemotherapy in those children.
视网膜母细胞瘤开启“保眼治疗”时代
当前视网膜母细胞瘤强调保眼球治疗。一些国际合作组织试图就视网膜母细胞瘤的高危组织病理学特征达成共识，Dalvin教授认为这非常重要，这一举措能够使大家对于哪些患者处于高风险，以及什么时候需要化疗达成一致。对于儿童来说，接受全身化疗非常不容易，目前一些晚期肿瘤采用的动脉介入化疗取得了很好的疗效，特别是对C期和D期肿瘤。即使是E期肿瘤，结合玻璃体内化疗药物的注射也能够保住近一半患者的眼球。但是这些治疗措施对父母和儿童来说都是很大的考验，他们需要定期随访就诊，多次手术和化疗。如果是E期的患者，甚至一半几率会保眼失败，即使肿瘤控制住了，也可能伴随永久性视力丧失等后遗症。
对房水活检的研究是目前一大热点方向，分子遗传学标记物的找寻能够辅助检测疾病进展和疗效。Dalvin教授表示，希望未来房水的分子标记物能够告诉人们肿瘤对化疗是否敏感，对于敏感的患者，可以继续努力保眼治疗，而对于那些化疗不敏感的患者，或许可以让家长和儿童少经历一些不必要的痛苦。
This is so important. There have been some great international collaborations trying to come to consensus statements on this, and I think we really do need to have good agreement on which patients are at high risk, and what warrants chemotherapy, because that is not easy on a child to have to be exposed to systemic chemotherapy. In terms of deciding whether or not we should treat patients with globe salvage therapy, I think we are going to learn a lot more as we continue to investigate this aqueous humor liquid biopsy, because we are getting molecular markers now that can potentially predict whether or not a tumor is going to be chemosensitive, and whether or not we are going to be able to save it. For a lot of advanced tumors these days, we use intra-arterial chemotherapy for treatment, and really with very good success, especially in group C and D tumors. Even in group E tumors, now combined with intravitreal chemotherapy, we can save up to half of these eyes. But it is a lot for parents and children to go through. It’s a lot of office visits. It is a lot of trips to the operating room. And if we are dealing with a group E, then in 50% of cases, we are still going to lose. Even we get the tumor under control, sometimes the side effects are such that the eye is just too sick and not useful for vision anymore and is uncomfortable. I think some of these molecular markers in the future where we will have aqueous sampling will tell us if the tumor is likely to respond well to intra-arterial chemotherapy. For those patients that are likely to respond, we can go ahead and put in that effort to save the eye. But if something is doomed to not respond well to these treatments just based on its molecular genetics, we are not going to put the family and the child through that.
眼肿瘤导致继发性青光眼的机制及治疗方法
许多不同类型的眼肿瘤都有可能导致青光眼，常见的是葡萄膜黑色素瘤和视网膜母细胞瘤，除此之外还有一些其他的肿瘤。肿瘤继发青光眼的机制如下：
肿瘤直接侵袭：若肿瘤侵袭至睫状体或房角，可能会导致房角关闭，房水无法排出，从而使眼压升高继发青光眼。
治疗后瘢痕形成：这一现象在葡萄膜黑色素瘤患者中很常见，若肿瘤已经种植到房角，即使肿瘤本身没有阻碍房水流出，治疗后肿瘤退化留下的瘢痕组织也会阻塞房角继发青光眼。
治疗后新生血管：一些肿瘤到晚期会形成新生血管，但更多见于放疗后，视网膜缺血继发新生血管，新生血管蔓延到眼前节会导致房角关闭。
青光眼的常规治疗是通过建立引流通道，将房水引入球结膜下，但这种疗法对于眼肿瘤患者而言，存在肿瘤扩散的风险。由于忌惮肿瘤扩散，肿瘤继发青光眼的治疗方法十分有限：
抗VEGF药物球内注射：新生血管型青光眼可以采取玻璃体腔注射抗VEGF药物使其消退。
睫状体光凝术：破坏睫状体房水产生的功能，使房水减少，眼压下降。
A lot of different types of eye tumors can cause glaucoma. The most common things are really just the most common tumors that we deal with, which is what we have been talking about today - the uveal melanomas in adults and retinoblastomas in children. But there are others as well. The common mechanisms that we are dealing with one, direct tumor invasion. If we have tumors that affect the ciliary body, or that erode through to the angle of the eye, they can actually directly close the anterior chamber angle or pack the anterior chamber angle full of tumor cells so that fluid cannot drain out of the eye, and we get high pressure and glaucomatous damage. We also see some issues where we can have glaucomatous damage after treating tumors. I see that a lot in my uveal melanoma patients, especially with iris melanoma. If I have to irradiate the front of the eye with an iris melanoma, if it has seeded into the angle at all, even if the tumor itself hasn’t prevented aqueous humor drainage, it can end up causing scarring that prevents aqueous humor drainage when the tumor regresses leaving scar tissue. This can cause secondary glaucoma after treatment. The other thing that we often see, especially after treating tumors with radiation is neovascularization. Some tumors can present with neovascularization themselves if they are very advanced, but often after we irradiate, due to retinal ischemia, the eye tries to grow new blood vessels, and it never does a good job of trying to grow new blood vessels. It can’t really grow healthy ones, and these can actually come up to the front of the eye and zip the angle closed. Then we have to do things like anti-VEGF injections to cause regression of those. Unfortunately, it is very difficult to treat eyes that have had cancer that develop high pressure because we don’t want to cause cancer spread. So a lot of the treatments for glaucoma involve creating a drainage pathway for the fluid in the eye to escape into the sub-Tenon’s space and theoretically go back into the orbit. I often say we can’t do those types of surgeries due to the risk of cancer spreading behind the eye, even though we think we have treated the tumor. We are often left with things like CPC (cyclophotocoagulation) to kill off those parts of these eyes that are making the aqueous humor so we have less fluid production rather than helping fluid to escape.
总结：眼内肿瘤是一类特殊的肿瘤类型，早诊早治对于眼内肿瘤的预后至关重要。目前正在研究的技术和药物有助于个性化精准治疗的开展，增加保眼率，提高患者的存活率和生存质量。
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Linda Gareth
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