美国德克萨斯大学西南医学中心Charles M. Balch教授访谈

　　Oncology Frontier: The Clark level is used to describe some anatomical requirements of melanoma and that is still a recommendation in the NCC guidelines. Is it still a good indicator of metastasis as far as melanoma?

　　《肿瘤瞭望》：Clark分级是按照解剖层次来描述黑色素瘤，它仍是NCCN指南推荐的使用的分级标准之一。对于黑色素瘤而言，Clark分级是一个较好的转移预测因子吗？

　　Prof. Balch: So the Clarks level invasion， first defined by Wallace Clark more than 50 years ago， measures how deep into the skin an invasive melanoma grows. It actually requires a fair amount of interpretation from pathologists and therefore is not as reproducible as other methods such as Tumor thickness， ulceration and mitotic rate. If you account for those three features， thickness， ulceration and mitotic rate， the Clarks level of invasion has no longer any ability to predict survival level as an independent factor. However， it is one of the features that can still independently predict risk of lymph node metastasis so the application of this that we use in our clinical practice is with the occasional patients with thin melanomas defined as T-1 melanomas that is they have a level for invasion or ulceration or a mitotic rate of 1 per mm square or greater， or any combination of those then we would discuss with our patient about doing a sentinel node biopsy because of their increased risk of sentinel node metastasis. But more or less the Clarks level of invasion is no longer used in staging because it does not predict survival independent of the other features that we use.

　　Balch教授：Wallace Clark于50多年前提出了Clark侵袭分级，用于测量黑色素瘤入侵皮肤的深度。它相当大程度上依赖于病理学专家的分析和判断，因此不像其他的因素，比如肿瘤厚度、溃疡和有丝分裂率等那样，易于复制测量。而且，相较于黑色素瘤的这其他三个特征：厚度、溃疡和有丝分裂率，Clark侵袭分级无法同它们一样成为生存率的独立预测因子。然而，Clark侵袭分级仍可独立预测淋巴结转移，所以，当我们在临床中遇到T1期薄黑色素瘤患者，若肿瘤入侵达到一定深度，或存在溃疡，或有丝分裂率为1/mm² 或更高，或者前述情况一同出现，我们会建议患者做前哨淋巴结活检，因为此类型患者前哨淋巴结转移的风险提高了。但或早或晚，Clark侵袭分级将不再用于肿瘤分期，因为它无法像其他因素那样独立地预测生存率。

　　Oncology Frontier: When you’re treating melanoma early on it is critical to make sure we identify the high risk patients for metastasis later. There is an editorial published around JCO 2012 and it had recommended using Striata based on the features of the tumor; patient age， thickness of the melanoma. Are these features equally weighed and valued or is there a coefficient method that you use to assess the risk?

　　《肿瘤瞭望》：发表于2012年美国《临床肿瘤学杂志》的一篇社论曾推荐根据肿瘤不同特征进行风险分层。像患者年龄、黑色素瘤厚度这些特征，在分层中是否具备相同权重和价值？或者您有其他同样有效的方法，来预测黑色素瘤的转移风险吗？

　　Prof. Balch: Sure， the study you are referring to in the Journal of Clinical Oncology by Adele Green and her group was a population based study in Queensland， Australia; which essentially showed that 96% of patients who presented with thin melanoma were still alive 10 years later. So it is a very good risk group， however if one looks at the literature in other studies but largely those that have gotten to a tertiary center or a melanoma specialized center， so there maybe some referral biased of high risk than melanomas. That we calculate that around 15% of those thin melanomas actually have additional adverse features such as higher mitotic rate， presence or absence of ulceration or level of invasion that might be associated with an increase risk of dying compared to patients who don’t have those features. We’ve also published data that revealed that patient age may also have an important impact including in T-1 melanomas where as younger patients have a lower risk of dying where as older patients even if they have negative lymph nodes have a higher risk of dying just based upon patient age as yet another independent factor.

　　Balch教授：你提到的发表于美国《临床肿瘤学杂志》上的那篇文章，是由Adele Green和同事们在澳大利亚昆士兰州开展的一项研究。该项研究的主要结果显示，96%的薄黑色素瘤患者可以存活10年或者更长时间，因此肿瘤入侵深度是一个很好的风险分层因素。然而，还有其他的一些研究报道，主要是来自于黑色素瘤专科中心，当然，因为该类医院更容易收到具有高转移风险的患者，所以其研究结果存在一定的偏差。这些研究统计显示，实际上，15%的薄黑色素瘤患者具备诸如高有丝分裂率，存在或缺乏溃疡和有一定的入侵深度等不良预测因素，较其他不具备这些因素的患者而言，他们有更高的死亡风险。发表的数据还提示，在T1期黑色素瘤患者中，年龄也是一个重要的独立预测因子，年轻的患者死亡率较低，而老年患者，即使无淋巴结转移，仍存在较高的死亡率。

　　Oncology Frontier: So with the age and thickness of the skin is it a function of the breaking down of the skin later in age that can cause a difference?

　　《肿瘤瞭望》：老年患者的这一高风险性，是由于年龄增长，皮肤结构和功能减弱，使肿瘤更容易入侵吗？

　　Prof. Balch: All of the features I mentioned are cruder surrogates of something more fundamental in the biology of the tumor or the host response so it is very possible that melanoma in extremes of age that is the very young and the very old maybe different biological subsets of melanoma and or it may be a reflection of immune competence. So younger patients who have more immune competence can deal with metastatic melanoma as a foreign invader and so patients don’t clinically die of metastatic disease whereas older patients may have less immune competence and therefore may be more vulnerable to melanoma spreading， growing and eventually causing the death of the patient.

　　Balch教授：我之前提到的所有因素，都是肿瘤生物学或机体自身反应的表现。因此，发生于年龄很小或年龄很大的两极人群的黑色素瘤，有很大可能是肿瘤的不同生物亚型，或是一种免疫功能的不同反应。年龄较小的患者，免疫功能相对较强，机体可以抗击转移性黑色素瘤入侵，因此较少因转移性疾病而死亡。然而，年龄较大的患者，因为免疫功能相对较弱，因此更易使黑色素瘤发生播散、生长，直至最终死亡。

　　Oncology Frontier: The Sentinel Lymph Node Biopsy is usually recommended for patients with intermediate thickness melanoma， so a complete dissection is recommended for all patients with positive SLN Biopsy. Can you share some preliminary results of the Selective Lymphadanectomy? trial?

　　《肿瘤瞭望》：一般在中等厚度的黑色素瘤患者中，推荐进行前哨淋巴结活检。当活检结果为阳性时，推荐进行淋巴结清扫。您能和我们分享一些关于选择性淋巴结切除术多中心临床试验（Multicenter Selective Lymphadenectomy Trial， MSLT-1）的初步数据吗？

　　Prof. Balch: Refer to the paper published in the New England Journal of Medicine published in February 14， 2014 earlier this year for which I wrote the editorial to that article. This trial which is the largest surgical trial ever conducted had 2000 patients and the longest follow up clearly showed that for all of the patients in the study including for the first time as reported patients with thick melanomas that there was a staging value sorting patients into different risks of dying based upon whether the Sentinel Node contained metastatic disease or whether the lymph node was negative. So for the staging purposes we’ve recommended for all patients with T2， T3 and T4 lesions that is a thickness greater than 1 that they have a Sentinel Node procedure unless there was some risk to the procedure itself or the patient had some significant cause for morbidity such as heart disease or lung disease that wouldn’t make them a candidate for further aggressive surgeries or systemic therapy. Now in addition to that we’ve recommended among the high rate of risk patients with thin melanomas that wasn’t part of the study but in other studies that they may be candidates for having the Sentinel Node procedure in order to identify that very small sub-group of patients that have nodal metastasis and have a higher risk of dying even though at the outset they appear to be in the group with a favorable prognosis based upon tumor thickness. So part of the message for physicians treating patients is that we cannot just use one feature of melanoma such as tumor thickness to make clinical decisions we need to use the composite of these things to characterized the patients into different risk groups for developing lymph node metastases or distant metastasis from which they would ultimately die and use that to better personalize their therapy so that low risk patients we can still safely do less treatment but in high risk patients if we can identify them then it’s appropriate to do more aggressive surgical treatment and maybe systemic treatment with the newer agents of targeted therapy of immunotherapy.

　　Balch教授：2014年2月14日《新英格兰杂志》上发表了这项多中心试验的最终分析结果，我为此写过社论。这是该学术领域迄今为止最大的一项外科临床试验，对2000多例患者进行了研究分析，随访时间也是迄今最长的。其结果清晰地显示，所有参与研究的患者，包括厚黑色素瘤患者，根据前哨淋巴结是否受侵，可划分入不同的风险等级。根据分期，我们推荐所有T2、T3和T4期患者，即入侵深度超过1 mm的患者，进行前哨淋巴结活检，除非患者不适合该类操作，或者该类操作可能导致患者死亡，比如一些患有心脏病和肺部疾病的患者，不适合进一步接受更为积极的外科手术或系统治疗，因此不强调积极接受前哨淋巴结活检。对于未纳入本项研究的薄黑色素瘤患者而言，从入侵深度较浅的角度来看，他们具备较好的预后，然而其他一些研究结果也显示，极小一部分部分薄黑色素瘤患者也可出现淋巴结转移和高死亡风险，因此也可能适合接受前哨淋巴结活检。

　　以上研究结果告诉我们，在临床工作中，不能只依据黑色素瘤的单一特征，比如入侵深度，来做临床决定，我们需要综合考虑多项因素，将患者进行风险分层，区分患者是否容易发生淋巴结转移和远处转移及死亡，以更好地开展个性化治疗。这样，低风险的患者可以安全地接受相对适当而保守的治疗，而高风险的患者则需要采取更为积极的外科手术，或采用免疫靶向治疗中的新药进行系统治疗。