肺癌高分化和低分化的理解，也许我们大多数人有理解偏差
A topic that came up in a recent expert round table case discussion was the issue of how to manage a patient with a lung cancer for which the pathology report says “NSCLC not otherwise specified (NOS)”, or “poorly differentiated NSCLC, NOS”. What does this actually mean, and what does it mean in terms of treatment options?Tumors of pretty much all types are categorized by their tumor grade, how “differentiated” they are, which basically means, “how much do the cancer cells look like the cells they started out as?”. Different cells of the body start out as stem cells, which means that they’re not specialized to be any special kind of cell, like one that detects light in the back of the retina, lines the esophagus, or is optimized for lung function. Most cells of the body are differentiated, so that the appearance under a microscope shows that it’s a liver cell, part of the kidney filtering mechanism, heart muscle, etc.
Cancer cells, however, have mutations in them that make them grow and divide faster than other cells (that’s why they make a tumor that pushes other tissues aside), and they usually have several. As they grow and divide, they often make sloppy copies of their DNA that leads to more mutations. Cancers therefore are made of cells that may look a lot like the normal cells they originated from (well-differentiated), or they have lots of mutations that make the cells look so chaotic that they don’t look at all like the cells they started out as (poorly differentiated).
Today, oncologists want to know whether a non-small cell lung cancer (NSCLC) is an adenocarcinoma, squamous cell carcinoma, large cell neuroendocrine carcinoma, etc. But about 20% of the time on various studies, we get an answer back of “NSCLC not otherwise specified”. As explained by Dr. Matt Horton, expert lung cancer pathologist, a lung tumor may be classified as NSCLC NOS because of either of two reasons:
1) there isn’t enough tissue, because the biopsy material was very scant, or
2) the tumor is so poorly differentiated that even with all of the material in the world, a good pathologist couldn’t identify the underlying NSCLC histology
Dr. Horton says that many of the conclusions of NOS are because there isn’t enough pathology material to review, and now there is an ever-growing list of reasons for why we’d want to ensure that this isn’t a problem. First, knowing whether a cancer is a squamous cell carcinoma or an adenocarcinoma or another subtype is important for deciding whether it’s appropriate for patients to get Avastin (bevacizumab) (sincethe risk of serious or even fatal bleeding complications is considerably higher in patients with squamousNSCLC who receive an anti-angiogenic agent like Avastin) or Alimta (pemetrexed) (because the evidence shows that Alimta isn’t effective in patients with a squamous NSCLC). Second, there’s now a growing role for collecting enough tissue to due testing for specific mutations like EGFR, possibly an ALK rearrangement, and arguably K-RAS. With the field moving to molecularly-based treatment plans for specific molecular defects, and more clinical trials and treatments being dependent on molecular testing, it’s necessary to have tissue to do these studies on.
But sometimes even with a resected early stage cancer, a situation in which a pathologist has all of the tumor tissue he or she could want, it’s not possible to make a good histologic assignment because the cancer cells just look too chaotic under the microscope. A study from ASCO 2009 showed that, as you’d expect, expert pathologists from academic centers tend to have agreement in their interpretation of NSCLCsubtype than community-based pathologists, but neither groups really agree consistently on poorly differentiated tumors. Essentially, this is just saying the same thing we’d say about interpreting ambiguous lesions on scans, or treating aggressive and resistant cancers: the hard ones are hard for everyone. In fact, there is also evidence that, stage for stage, patients with poorly differentiated cancers don’t tend to do as well as patients with better differentiated cancers. This is probably because they’re also more aggressive. The cancers that are so chaotic that experts can’t determine the histologic subtype are also likely to grow and divide very quickly, and be far less likely to have a specific mutation like EGFR or an ALK mutation driving them — instead, they’re driven by a combination of many, many mutations.
It’s worth noting that there are companies now studying the “molecular signature” of a poorly differentiated cancer that promises to clarify whether a tumor is actually a squamous NSCLC or adenocarcinoma or otherNSCLC subtype. Companies like Biotheranostics can do detailed molecular typing, and others exist as well. I don’t generally use these, because I think that there may well be something different about a cancer that requires this kind of assessment to know its histology than the ones that a pathologist can assign. I wouldn’t presume that a cancer that is so poorly differentiated that you need molecular testing to determine that it’s a lung adenocarcinoma will act the same as a better differentiated adenocarcinoma.
So practically speaking, what does it mean if a cancer is so poorly differentiated that you can’t assign a histology? First, these tend to be very unlikely to carry an EGFR mutation or ALK rearrangement, so I would favor chemo-based treatment and wouldn’t prioritize testing for every molecular marker under the sun early in the workup. As I mentioned above, these tumors have a tendency to be bad actors, but we still treat them basically the same as other NSCLC tumors. I personally am less enthused about using Avastin in patients with a very poorly differentiated tumor, though the ECOG study that showed a survival benefit with Avastin added to chemo included 20% of patients with NSCLC NOS, and they really didn’t have increased bleeding at all. Still, I’m a little more concerned that bleeding could be an issue, particularly if the cancer is in the central part of the chest and near any major blood vessels. That said, other experts, including ones included in the case discussion from the beginning of this post, are still comfortable giving Avastin to patients with NSCLC NOS, so it’s clearly a debatable question.
The other issue is whether to give Alimta to patients with a poorly differentiated NSCLC that can’t be assigned a histology. The approval of Alimta is now for patients with non-squamous NSCLC, and NSCLCstill is considered non-squamous if it isn’t called squamous. Still, it’s not clear that patients with a very poorly differentiated cancer will benefit as much as the patients with a moderately differentiated adenocarcinoma. When other chemo agents commonly used for NSCLC aren’t dependent on the histology, I and I believe most oncologists favor an alternative to Alimta as a first line approach and tend to relegate it to a later choice. This isn’t the same situation as being potentially more dangerous than other options, but we’d always want to use agents with the best probability of success as our first treatment.
This is certainly a tough area, and it’s also a moving target. More and more of the field is becoming dependent on the tissue (“the tissue is the issue“), and we may move toward identifying particular mutations and genetic patterns associated with better results with chemo A vs. chemo B, but right now this is the state of the field.
不懂，麻烦给说说行吗。．
最近一个专家讨论的话题是，怎样管理一个肺癌病人，当病理报告写着“NOS
或低分化小细胞肺癌“ 这到底意味着什么？是不是意味着不同的治疗方案？
基本上所有的肿瘤都被划分为不同的肿瘤级别，它们的分化程度多高，简单
说是指它们有多像当它们是原来的正常的细胞时候的样子。身体不同部位的
细胞是由干细胞开始的，这意味着在最开始的时候，它们没有分化为特殊的
细胞如视网膜细胞，食道管细胞，或者优化为肺细胞。人身体的大部分细胞
都是分化的，所以在显微镜下你能区分肝细胞，肾细胞，心脏细胞等。
然而肿瘤细胞由于突变，使得它们生长和分裂得比其他细胞更快（这是为什
么肿瘤常常压挤周围的细胞，而且它们常常有几种突变。当他们生长和分裂
的时候，它们常常很随意地复制它们的DNA导致更多的突变。因此，癌细胞
有时候由那些看起来还像原器官的细胞组成（高分化），或者它们有很多次
突变让他们看起来乱糟糟的而且不像原器官的细胞（低分化）。
今天，肿瘤学家想要查明是否病人的非小细胞肺癌是腺癌，鳞状细胞癌，大细胞神经内分泌癌等，但是有将近20%的各类研究表明，我们得到的结论是非小细胞肺癌NOS.病理学专家医生Matt Horton解释道，一个肺癌肿瘤被归类为非小细胞肺癌NOS，因为以下两个原因: 1，没有足够的组织，因为活检材料非常有限。
2，肿瘤是非常低分化的，以致于最好的病理学家也无法确认非小细胞肺癌类型。
Dr Horton说很多NOS结论的做出，都是因为没有足够的活检组织。现在有越来越多的原因来解释为什么我们需要确认这个一个问题。首先，首先，知道，是否癌症是鳞状细胞癌或腺癌或其他亚型决定是否适合阿瓦斯丁（贝伐单抗的患者是很重要的）因为鳞状非小细胞肺癌患者接受抗血管生成剂如阿瓦斯丁， 严重的甚至是致命的出血性并发症的风险是相当高的 或 力比泰（培美曲塞）（因为有证据表明，力比泰不是有效的鳞状非小细胞肺癌患者的治疗方法。）。第二，收集足够多的活检组织变得越来越重要，因为一些基因测试，如EGFR,ALK,K-RAS突变的测试。当我们转移到针对特殊的分子缺陷进行基于分子的治疗时，更多的临床试验和治疗将基于分子检测。这就必须取得活检组织来做这些研究。 但有时即使有早期切除的组织，病理学家即使拥有所有的他需要的肿瘤组织，他也没办法确定病理，因为癌细胞在显微镜下看起来太乱。 ASCO 2009的一项研究结果表明，正如你所期望的，学术中心的病理学专家往往比社区病理学家在非小细胞肺癌的亚型上更能达到一致。但是两者都很难在低分化肿瘤上达成一致。本质上，我们认为，对于辨别有侵略性的，顽固的癌症，难以治疗的癌症，对任何方式来说都难以治疗。实际上，有证据表明，低分化肺癌的病人预后没有高分化的病人好。这也许是因为他们的细胞更具有侵略性。这些专家不能确定病理分类的癌细胞分裂得非常的快，而且更少可能地会有EGFR或者ALK突变来驱动它们，它们可能是有很多不同类型的突变组合所驱动的 后面有两段没翻译，关键写的是，一般来说，如果是低分化，很小可能有EGFR或ALK突变，如果是低分化，有的医生一般用Avastin，我倾向于用力比泰，因为Avastin有时候会导致出血，如果肿瘤靠近大血管，将会有生命危险。 看了这篇文章，有些粗浅的理解，癌症细胞分裂比正常细胞快，复制DNA时，不像正常细胞那么仔细，DNA变异，是生物进化的原因，也是癌症细胞耐药的原因。低分化的肺癌容易耐药，也正由于肿瘤细胞里存在多种不同的突变，没有一种占主导，所以很难说对EGFR抑制剂敏感，一般来说靠化疗放疗才有些效果。而且，对于低分化的癌细胞，越用抑制剂压制它，越容易产生突变变异，就好象用手挤压一个水球一般，水很容易从指缝中跑出去。所以用放化疗对付他们会有效些。 太深奥了，看不懂，但我的理解是高分化 和中分化，低分化是有区别的，但中分化和低分化区别不是太大，中分化和低分化的肿瘤看的更凌乱，像刺猬。 高分化相对来说比较规整，有棱有角的更接近良性瘤的样子。