Wednesday, February 22, 2012

Endometriosis and cancer: When a "breakthrough" may not be all that

There is an interesting new study that was just published online at the Lancet Oncology. It is a pooled analysis of a bunch of case-control studies to explore the association between endometriosis and certain types of ovarian cancer. Here is the abstract:


Endometriosis is a risk factor for epithelial ovarian cancer; however, whether this risk extends to all invasive histological subtypes or borderline tumours is not clear. We undertook an international collaborative study to assess the association between endometriosis and histological subtypes of ovarian cancer.


Data from 13 ovarian cancer case—control studies, which were part of the Ovarian Cancer Association Consortium, were pooled and logistic regression analyses were undertaken to assess the association between self-reported endometriosis and risk of ovarian cancer. Analyses of invasive cases were done with respect to histological subtypes, grade, and stage, and analyses of borderline tumours by histological subtype. Age, ethnic origin, study site, parity, and duration of oral contraceptive use were included in all analytical models.


13 226 controls and 7911 women with invasive ovarian cancer were included in this analysis. 818 and 738, respectively, reported a history of endometriosis. 1907 women with borderline ovarian cancer were also included in the analysis, and 168 of these reported a history of endometriosis. Self-reported endometriosis was associated with a significantly increased risk of clear-cell (136 [20·2%] of 674 cases vs 818 [6·2%] of 13 226 controls, odds ratio 3·05, 95% CI 2·43—3·84, p<0·0001), low-grade serous (31 [9·2%] of 336 cases, 2·11, 1·39—3·20, p<0·0001), and endometrioid invasive ovarian cancers (169 [13·9%] of 1220 cases, 2·04, 1·67—2·48, p<0·0001). No association was noted between endometriosis and risk of mucinous (31 [6·0%] of 516 cases, 1·02, 0·69—1·50, p=0·93) or high-grade serous invasive ovarian cancer (261 [7·1%] of 3659 cases, 1·13, 0·97—1·32, p=0·13), or borderline tumours of either subtype (serous 103 [9·0%] of 1140 cases, 1·20, 0·95—1·52, p=0·12, and mucinous 65 [8·5%] of 767 cases, 1·12, 0·84—1·48, p=0·45).


Clinicians should be aware of the increased risk of specific subtypes of ovarian cancer in women with endometriosis. Future efforts should focus on understanding the mechanisms that might lead to malignant transformation of endometriosis so as to help identify subsets of women at increased risk of ovarian cancer.


Ovarian Cancer Research Fund, National Institutes of Health, California Cancer Research Program, California Department of Health Services, Lon V Smith Foundation, European Community's Seventh Framework Programme, German Federal Ministry of Education and Research of Germany, Programme of Clinical Biomedical Research, German Cancer Research Centre, Eve Appeal, Oak Foundation, UK National Institute of Health Research, National Health and Medical Research Council of Australia, US Army Medical Research and Materiel Command, Cancer Council Tasmania, Cancer Foundation of Western Australia, Mermaid 1, Danish Cancer Society, and Roswell Park Alliance Foundation.
Alas, I do not have access to the full article (paywall), so cannot go though it in a detailed way. Nevertheless, we can try to put these findings in perspective. So, briefly, the investigators put together data from many case-control studies and discovered that the risk of some, though not all, ovarian cancers was 2-3 times higher in the presence of endometriosis than in its absence, and concluded that clinicians should be aware of this increase in risk. Fair? But you know I am going to deconstruct it, right? Here we go.

By now we all understand what a case-control study is, right? It is a study where cases (those patients with the disease of interest) are compared to controls (subjects who are in all ways the same as the cases with the exception that they do not harbor the disease in question). So the study identifies subjects with an outcome, and follows them backward to the exposure that is of interest vis-a-vis this outcome. These studies are notoriously difficult to do well, particularly when it comes to the choice of a control, and very few do it well in my experience. I cannot comment on the current conglomeration of 13 of them, so will not venture a guess on whether some or how many of them may lead us astray. Though these studies are difficult, for various reasons they are the way to go when examining an uncommon outcome. So the choice of the design is legit.

No, let's examine the risk for misclassification for both the disease and the exposure. I think you will agree that a case of ovarian cancer is difficult to misclassify, so I will not pick on this as a potentially major threat to the validity. But what about endometriosis? This is a chameleonic condition that is probably way under-recognized. Its symptoms and signs are varied and, unless the studies required a look "inside," which I sincerely doubt they did -- note, the abstract states that this exposure was self-reported -- there is a very real and grave threat to validity here. Ever heard of recollection bias? If such exists, then more women with cancer are likely to report symptoms that may be indicative of endometriosis than those without cancer. So, the observed increase in the risk of ovarian CA in the presence of endometriosis may be due to just that -- a recollection bias.

These limitations notwithstanding, the authors felt that the study was a breakthrough (emphasis mine):
"This breakthrough could lead to better identification of women at increased risk of ovarian cancer and could provide a basis for increased cancer surveillance of the relevant population, allowing better individualization of prevention and early detection approaches such as risk-reduction surgery and screening,” lead author Celeste Leigh Pearce, at the University of Southern California, Los Angeles, said in a journal news release. 
What does Dr. Pearce mean by "increased cancer surveillance?" Is she talking about screening women with endometriosis because of this possibly heightened risk? And if so, is this really wise? Let's simulate some of these numbers.

Let us suppose that endometriosis does indeed increase the risk of ovarian cancer 2-3-fold. This means that the incidence now goes from 13 per 100,000 women up to 39 per 100,000. Let us now also assume that there is a test that is 99% sensitive (able to identify ovarian CA when it is present) and 99% specific (able to demonstrate that no ovarian CA is present when it is not present). Recall that at the population incidence of ovarian CA, the USPSTF does not recommend screening due to a very high risk of a false positive. The question is does this 3-fold elevation in risk change the positive predictive value of screening substantially enough for it now to be recommended? I think I know the answer, but let's go through the exercise anyway, just to be explicit.
Disease present
Disease absent

So, the corresponding positive predictive value is... drum roll, please... 3.7%. This means that out of 100 women who have tested positive, fully 96 have a false positive result and are now likely to be subjected to invasive procedures. If we imagine that a test can have near-perfect specificity of 99.99% (no test that I know of can come close to this in any consistent way), still 20% of all positive results are false positives. So, is this indeed food for screening thought? I really don't think so, particularly given that the current risk calculation is likely a gross over-estimate.

So, there you have it. I don't think I am engaging in hyperbole when I say that "breakthrough" is very likely an overstatement.                  


  1. Thank you for this thorough review of this recent study supposedly linking endometriosis with ovarian cancer risk. The World Endometriosis Society has come to the same conclusion as yourself, and said so publicly ( It is regretful that the press has chosen to "jump on the cancer headline" rather than how shameful it is that almost no funding is provided to understand the pain mechanisms in endometriosis to improve treatments for the millions of women living daily with this disease. That is indeed a headline - but it probably doesn't sell papers.

  2. Thanks for your comment, Lone. I agree that is is disappointing how the medial have handled the study. Yet I cannot help but be even more disappointed by the authors' comments and the overblown importance of the findings.

  3. I think it's pretty fascinating that so much effort was put into the "numbers" of this study but then you didn't compare those with available data on CA125 - just sayin' - b/c I think the study was meant to point out a possible link for ANY screening that would mean potentially LESS invasive measures. Since I'm going through this b.s. as we speak, after 3 years of "self-reporting" with no screening of any kind, I think it is an encouraging study. Look, I have been doing everything but camp on my GP's doorstep to get any recognition that there's a problem greater than PCOD or PMDD - they could've done a laparscopy a long time ago and I can damn well tell you that would've been far less invasive than what I'm facing now. The only reason endometriosis has been diagnosed was b/c I went to the ER for what I thought was PID, which I've had before. Turns out I had a 5 cm mass that's now 12 cm 3 months later. Keep in mind after being told about my possible "endometrioma" my Dr. says it's just a ruptured cyst and that she couldn't justify sending me to Gyn w/o trying Ibuprophin therapy for 2 months and then they'd do another follow-up ultrasound/trans-vag. Guess what? Clearly not a ruptured cyst and I'm facing a total hysterectomy and not one Dr. will answer any of my questions or entertain the notion that there's any other option than total hysterectomy. What??? How did this ridiculousness EVER happen????? I can damn well tell you 3 years ago when I showed up complaining of physical symtoms that mirrored ovarian cancer - and I had every single one - I also "self-reported" an extensive family history of reproductive cancers and other things, oh, like ENDOMETRIOSIS AND PID! None of the women in my family with PID ever had an IUD like I did, however, all of us were never found to have an STD to blame it on. I have trotted out every woman within the last 5 generations to try to get someone to listen to me and have been repeatedly told that genetics are not a "conclusive" risk factor, usually with a shrug. seems clear to me it is cheaper for the hospitals/insurance companies to open me up and take out the whole kit-and-kaboodle to avoid further risk/complications and wasting precious funds studying female reproductive system disorders and their relationship to cancer - you know, like that whole "get rid of it" conundrum but it's funny how it takes on a different meaning depending on your age. I feel certain it's actually more expensive, because some patients, like me, bother to ask questions instead of just believing everything the surgeon says because they have "self-reported" themselves as God.