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Dr West

Does Tumor Grade Matter in NSCLC?

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Historically, the main task of pathologists in lung cancer has been to divide them into small cell lung cancer and non-small cell lung cancer. Beyond that, there is now more of an emphasis than there used to be on trying to clarify whether a NSCLC tumor is a squamous cell carcinoma, adenocarcinoma, large cell, or another subtype, partly because we now have drugs approved just for certain subtypes (avastin for non-squamous tumors only) and others that are commonly observed to have a higher response rate in some histologies (lung cancer categories based on microscopic appearance) than others (sucha s EGFR inhibitors consistently showing a high response rate in adenocarcinomas/bronchioloalveolar carcinomas compared with other subtypes). Several members have asked questions similar to the one reported in a recent paper from the Mayo Clinic (abstract here): is the grade of the tumor, ranging from well differentiated to moderately differentiated to poorly differentiated and even undifferentiated, associated with a better or worse prognosis for a person?

What do we mean by differentiation? The degree of differentiation of a tumor is how much it looks like normal, non-mutant lung cells. Well differentiated lung cancers are pretty close to normal appearing, while poorly and undifferentiated lung cancers look completely wild, not like the cell they originated from. It’s important to note that pathologists can readily and reproducibly say a well differentiated cancer is an adenocarcinoma, for instance, but a poorly differentiated tumor may be said to resemble an adenocarcinoma by one pathologist, while another pathologist may think that the same tumor is a poorly differentiated squamous cell carcinoma (and even give different results when the same pathologist reads a tumor at two different times). So there is a good concordance (agreement) of pathology findings only for the better differentiated tumors. In addition, there are not clear standards of what constitutes moderate differentiation and what consistutes poor differentiation, so this will differ somewhat from one pathologist to another.

But for prostate cancer, for instance, Gleason score for prostate cancer, which is a measure of differentiation, is one of the most important predictors of outcome and is used routinely in predicting outcome and altering treatment plans. And the Bloom-Richardson score for breast cancer tumors is also widely used in a similar capacity. But we’ve been slow to formally recognize the histologic grade as an important predictor in lung cancer, even though most of us who treat a lot of lung cancer realize that it is a useful factor. For instance, in my prior post on bronchioloalveolar carcinoma (BAC) being potentially over-treated by conventional standards for NSCLC, I likened some indolent BAC tumors (which should be well differentiated, by definition) to a similar situation as low-grade prostate cancer, which we know can be present in many older men but not be a real threat to their survival because a low grade prostate cancer can be so slow growing.

So this study from the Mayo Clinic looked at over 5000 NSCLC lung tumors that came through that institution from 1997 through 2003, plus another 700+ that were diagnosed in that area but outside of the Mayo Clinic, all of varying stages and receiving various treatments. They collected information on the grade and histologic subtype (adeno, squamous, etc.) of the tumor, as well as stage, age and gender of the patient, smoking history, treatment received, and every other variable they could identify. They found that well differentiated NSCLC tumors were more likely to be adenocarcinomas, to be found in women and never-smokers, and were also more likely to be diagnosed at an earlier stage, while poorly and undifferentiated cancers were more likely to be seen men, to be squamous or especailly large cell, to be found in recent or current smokers, and to be diagnosed at a later stage. Of course, there was a lot of variability in all of these, but those are the trends. Holding the other variables constant in a multi-variable analysis, they found that patients with well differentiated NSCLC tumors (a total of 668 of 5018 total tumors) had a significantly better survival than patients with moderately differentiated tumors (a total of 2111), who in turn had a better survival than patients with poorly differentiated (1410 of 5018) or undifferentiated tumors (the remaining 829). Poorly differentiated and undifferentiated tumors did not differ significantly, both being nasty and the most threatening. The survival differences held true no matter whether you were looking just within the same stage, at just women or just men, looking only at adenocarcinomas or squamous tumors, and no matter what treatment was given. Across all of these variables, people with well differentiated tumors did the best, and poorly/undifferentiated tumors did the worst, with moderately differentiated tumors in between. Specifically, patients with moderately differentiated tumors had a 40% worse survival than those with well-differentiated tumors, those with poorly differentiated tumors had a 70% worse survival, and the people with undifferentiated NSCLC tumors had an approximately 80% worse survival vs. well-differentiated tumors. Here’s the figure showing the very different survival for the different tumor grades:

Grade Unadjusted and Px (click to enlarge)

All in all, grade was the third most important factor in predicting survival, behind stage (which is designed to predict outcome) and treatment given (largely determined by stage, and also affected by other issues like health of the patient). The analysis also showed that women had a 25% better survival than men, older patients didn’t do as well as younger patients (65 as a cut-off), there was a trend toward better survival among never-smokers vs. current or former smokers that wasn’t quite significant (only about 10% difference), and people with adenocarcinomas did a little better overall than patients with squamous cancers (about an 8% difference).

Because well differentiated tumors present at an earlier stage and have several other favorable characteristics associated with them, while poorly differentiated tumors have many other unfavorable characteristics commonly seen with them, it is important to separate out the overlapping variables. Once you do that, the differences aren’t as dramatic, but they still show that the folks with well differentiated tumors are doing better than the ones with moderately or poorly or undifferentiated cancers:

Grade adjuusted Px in NSCLC

The investigators found that the same trends applied to the tumors from other people in the county, seen and treated outside of the Mayo Clinic, so it wasn’t just a phenomenon of something special about the patients who found their way to their institution.

Finally, they looked at 1302 tumors that were resected and noted that the recurrence rate for poorly/undifferentiated, moderately differentiated, and well differentiated tumors was 47.3%, 32.7%, and 20.8% respectively. Looked at another way, poorly and undifferentiated tumors were 2.1 times as likely to recur, and moderately differentiated tumors 1.4 times as likely to recur as well differentiated tumors after surgery.

This could have been analyzed a little differently to look at moderately differentiated tumors as the benchmark, which would have shown that well-differentiated tumors do better than average, while poorly/undifferentiated tumors do somewhat worse than average. You don’t necessarily use the best cases as the standard. It doesn’t matter much, since the data are the same, and the only thing that matters is what you measure against. But you can see from the total numbers that well differentiated tumors were a real minority of cases, at 13%, while more than 40% were moderately differentiated.

We’ve been looking at fancy gene signatures and other molecular markers for the use in potentially refining our treatment plans for individual patients, but it’s worth remembering that tumor grade may be one of the more important factors that doesn’t require sending tissue for cutting edge molecular analysis. While some older studies haven’t shown a clear association of outcomes with tumor grade, several of these older trials were just too small to say anything definitive. It is worth noting that there are long-term survivors with poorly differentiated, high grade cancers, and there are patients with well differentiated low grade tumors that recur and can be very threatening. At the same time, we need to remember that pathologists don’t all agree on which tumor is moderately differentated and which are well differentiated. The real world is a continuum, with a lot of gray areas between these neat categories. Nevertheless, this very large study convinced me that along with the fancier, newer technology approaches we have to help us refine our predictions of who might be better or less well served by adjuvant chemo, and which patients we might want to treat less aggressively and be optimistic that they might do particularly well. Grade isn’t the most important factor, but I would say it’s one that probably deserves to be factored in the overall equation.


9 Responses to Does Tumor Grade Matter in NSCLC?

  • ortizbazurto says:

    Dr. West:

    Again thanks for the timely posts and all your efforts on our behalf.

    I was wondering if there were other clinical factors that correlated with tumor differentiation. In particular, SUV PET score (seems logical to expect that well-differentiated tumors will have a smaller SUV that poorly differentiated tumors) and EGFR mutations (perhaps well-differentiated adenos are more likely to have the mutation).

    Another question that I have is if there is some data on the location of recurrences related to the tumor differentiation (such as well-differentiated tumors may tend to recur more “locally” than extrapulmonary…).

    Finally, do you think that this type of info may chance oncologists practices? For example, if you had a stage IB resected patient, will a poorly differentiated tumor push you to recommend adjuvant chemo after resection?

    Many thanks again.

    Carlos

  • Dr West
    Dr West says:

    Carlos,

    Yes, SUV does correlate with tumor grade, so that well differentiated tumors are typically the ones with a lower SUV than the poorly differentiated tumors. And there have been some studies that have correlated higher SUV with worse outcomes. These haven’t been big studies, but oncologists do use them to informally get a bearing on how high or low the risk is for an individual person’s tumor to be aggressive or indolent.

    I’m not aware of data on recurrence patterns associated with degree of differentiation, except that BAC tumors are well-differentiated and almost always recur within the lungs only. The ones that get out of the lungs have an invasive, less differentiated component, so there is at least some association, and there may be some literature out there, but it’s not a commonly used concept.

    And I’ve been thinking about how these variables play in treatment decisions. You’re generally not going to change treatment for metastatic disease based on whether it’s moderately or poorly differentiated. It’s at the margins that I think these points would be most valuable, such as when you’re on the fence about a stage IB patient and trying to decide whether they should receive adjuvant therapy. Either choice is defensible, but I’d be much more inclined to recommend chemo for someone with a poorly differentiated IB tumor and much less likely to recommend it for someone with a well-differentiated stage IB tumor. And just like Dr. Nevins is doing in looking at the high risk stage IA patients to identify which in that group might benefit from adjuvant chemo, you could potentially select them based on histologic characteristics like grade, which would be a lot less technologically hip, but is available everywhere. And importantly, if we got good at it, we could separate out the stage II patients who have tumors with features suggesting no need for adjuvant treatment, saving them that toxicity. But at this point I wouldn’t do these things that are currently outside of the bounds of current standards of practice except in a research setting.

    -Dr. West

  • blaze100 says:

    Hi Dr West, Every time I look at these charts I get scared. Survival just keeps dropping and dropping as time grows. Are breast cancer survival graphs similar? Can you post any lc survival graphs for BAC? Thanks. Barb

  • Dr West
    Dr West says:

    Barb,

    I’m sorry if I seem to be bludgeoning people with things they don’t want to see. Some people want as much information as they can get, and some would be happier not knowing all of the details, of advanced lung cancer in particular.

    The survival curves for lung cancer don’t plateau at the right as much as breast cancer does. Breast cancer is more treatable overall, and it tends to be more responsive to chemo and often hormone therapies. While advanced/metastatic breast cancer is not a curable situation, the survival does tend to be longer. For some patients, treatment can be continued for many years and it can be a more chronic situation than advanced lung cancer tends to be.

    On the other hand, some lung cancer patients, including many with BAC and some without, have an indolent or quite responsive lung cancer that can go on for years. Although those lung cancer curves go downward as time goes by, most don’t go all the way down to the bottom of the graph, so some patients are living for years and years. And these are results of groups of patients, but individual patient results are at all ends of that curve.

    I’ll try to write on BAC soon and include a more favorable curve. In the meantime, BAC curves should look similar to the one for well-differentiated lung cancer, which is a bit more encouraging. But it’s hard to talk about lung cancer without acknowledging that there’s a lot of bad stuff that happens with it.

    -Dr. West

  • hubbie says:

    I have been a little puzzled trying to reconcile published statistics on life expectancy with the slow progression of cancer in some patients with bac or with bac features. Are these cancers rare so that they have little effect on published statistics? Are they increasing in relative #s due to the decrease in smoking? Lately could we just be diagnosing earlier so that it seems some are living longer than a few years ago? I greatly appreciate your insights on these questions.

  • blaze100 says:

    Hi Dr. West, No, you are not clobbering us with unwanted info. :-) We need info.

    I was hoping for earlier leveling out, but then every random would experience some drop. The graph can’t go back up after all. Barb

  • Dr West
    Dr West says:

    The cancers we see still follow a full range of natural history/behavior. Some are terribly resistant to treatment and lead to rapid decline no matter what we do, while other cancers, including many BACs (more than others, but also some other lung cancers, too), can have a much, much slower progression that goes out years (often no matter what we do, right or wrong, in trying to treat it). But BAC still is only small minority of lung cancer, even including the folks who have a combination of invasive adenocarcinoma and some BAC features (which can behave more like regular NSCLC or BAC depending on which is the dominant component).

    The curves don’t go down to 0. There are generally a small proportion who are extending out toward the right edge of the curve. But a small proportion won’t impact the median, which is a half-way point. A treatment that cures 25% of patients but doesn’t improve the outcome for the other 75% won’t actually improve the median survival, but the curve will plateau on the right a lot higher than it used to, which is something we all hope to see. There aren’t a lot of plateaus on lung cancer curves, but it’s still a good thing if the curves aren’t as steep as they used to be.

    And to answer the question of BAC on the rise, there’s still some debate about that, but there’s certainly some data that BAC and never-smoker lung cancer comprise a growing fraction of the lung cancer world, but it’s still a small piece.

    -Dr. West

  • partoftheteam says:

    I’ve been reading and following some of your work on CANCER cures, and I’d like to if possible to receive some help and or knowledge for my wife Sue.
    Just to give you a bit of background info. My beautiful wife Sue is 56 years young , 63 kgs and 160cm in height. She has stage iv “ NON SMALL CELL BRONCHOALVEOLAR CARCINOMA ‘ mucus forming, ( lung cancer ) as you would be aware that this type is reasonable rare in a person of this age when she first was diagnosed . In 2002 Sue had a lobectomy in the right upper area then it came back, then she had a wedge resection, then radiation f. ablation, then two years ago a six week course of radiation. Has not mastasized. The latest tumor in the nodular region adjacent to the level of the arch of the azygos vein., and cysts in liver, right kidney and right ovary. Then another six weeks of radiation treatment the side effect and damage it will do as some of the new radiation will cross over the old treatment area accumulative to approx. 80 greys. Also six months after that she had a new technique similar to radiation ablation where they microwave the tumor on the end of a needle in a different part of the lung to remove another cancer growth . Sue has had various alternative treatments on 12 January 2011 In June 2013 had chemo Carboplatin and Gemcitabine… had double phenomena hospitalized again I swear that we spend as much time in hospitals as do doctors lol. Then the whole right side lung removed in August 2013. With this Sue’s symptoms became much better then. But this didn’t last long and a month ago came back with massive speed and a vengeance. We have mixed it up with convention medicine and natural that’s possibly why she’s hung in there so long. Where not giving up she’s the strongest person that I’ve ever known. And as the doctors and specialists have given up except for more palliative chemo. Could you please reply with your opinions of success or not etc using Pemetrexed (Alimta) they wish to IV this in 3 week cycles.. Some of the markers that have been tested for and found wanting are EGFR, K-RAS, & M-BAC as far as my memory serves. May go back and try alternative again. Don’t you find it unusual that in the last 60 years that we’ve had so called advanced cancer treatment ie chemo radiation etc that they on their own have very rarely cured anyone and that Rockefeller introduced chemo and radiation to American universities way back at the beginning. Sorry I tend to ramble a bit. Any help and or workable knowledge would be greatly appreciated.

    Kind Regards in advance.
    Wayne

  • Dr West
    Dr West says:

    I’m sorry about your wife’s diagnosis.

    Unfortunately, mucinous BAC is notoriously difficult to treat and all too often follows the pattern of recurrence you describe.

    Alimta (pemetrexed) is a chemotherapy that I would say is probably the most active ones against BAC, at least high among them. It’s very strong for adenocarcinomas (all BACs are adenocarcinomas), and many experts have seen gratifying responses in patients with BAC who have received Alimta, including those with both mucinous and non-mucinous BAC.

    Because BAC tends to follow a slow pattern, I’m not so sure that the natural therapies you are inclined to give credit to actually add anything, but there’s no way to prove that. I just hate to have people presume that natural therapies are helpful with no acctual evidence — I would be more convinced if her cancer ever shrank on a natural therapy and no other intervention. But I admit that we all have our biases, and my personal bias is that complementary and alternative medicines don’t deserve to be credited with being helpful just because people wish them to be.

    I would also say that we’ve had many remarkable improvements in curing many cancers and far more effectively treating many others. I don’t really know what you’re trying to say about a lack of advances in cancer treatment over 60 years, but I’d say that I don’t agree at all, nor do I think that the evidence remotely supports your view that there have not been meaningful improvements from chemo and radiation over 60 years.

    -Dr. West

    -Dr. West

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