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Substantial under-reporting of endometriosis-associated cancer risk due to research methodological design flaws

Improper stratification obscures true extent of risk for endometriosis-associated cancers:

More than 120 years ago, early endometriosis researchers, like Dr. Thomas Cullen, were actually already speculating about whether certain atypical forms of endometriosis* had some association with certain cancers.

Flash forward to modern times and this association is well-established in the peer-reviewed literature, with most (but not all!) of the world’s leading endometriosis experts not only acknowledging the association, but now report that endometriosis confers an increased risk of developing certain cancers. (The degree of risk, risk factors, and other crucial details continue to be debated). With these new insights over the past few decades, scientists have now recognized a new phenotype of ovarian cancer called “endometriosis-associated ovarian cancer (EAOC).” As Cullen and others suspected a century ago, histologically atypical endometriotic lesions are generally now considered precursor (premalignant) lesions as well, but our modern understanding is that essentially any form of endometriosis has the potential for malignant transformation.

Given these established insights, it’s disheartening to see that the peer-reviewed literature on endometriosis often fails to follow basic risk stratification modeling principles when it comes to distinguishing different endometriotic tissues. Risk stratified tumor analysis is the standard of care in the field of oncology, as it helps researchers and physicians determine prognoses, as well as which treatments may work best for patients, depending on the type of biopsied cancer tumor.

When it comes to assessing for cancer risks associated with different types of endometriotic lesion, risk stratification techniques must be performed in order to impart clinically meaningful and accurate assessments.  Unfortunately, this careful stratification hasn’t always been done in past research on endometriosis and its associated risk of undergoing malignant transformation. One example of a research study design methodology flaw involving improper stratification of ovarian endometriomas led to a massive, nearly 10-fold under-reporting of cancer risk, with the researchers noting that:

When the analysis was stratified by endometriosis type, ovarian endometriosis increased the risk for endometrioid and clear cell histotypes even more (4.72 [2.75–7.56] and 10.1 [5.50–16.9], respectively).

Although this is just one study, the results are actually applicable to dozens of other peer-reviewed articles which have also incorrectly calculated cancer risk by lumping all forms of endometriosis together, when a risk stratified approach should have been taken, so that each endometriotic phenotype could be assigned its own estimated risk value.

Put starkly, this means that a significant number of research articles, from the last 30 years or so, have substantially under-report the true risk that ovarian endometriomas in particular, impart for malignant transformation. These are not merely academic musings we are talking about. Rather, such misleading research has, no doubt, translated to potentially or actual catastrophic outcomes for patients, who may not have been given critical information about necessary screening and follow-up care, which would have been advised given increased risk factors.

As with any complex disease with multiple phenotpyes/subtypes and multifatorial pathogenesis, like endometriosis, following the gold standards of risk stratification modeling is crucial if we are to obtain clinically meaningful and translational research results. Without proper stratification, we will miss important clues that affect treatment efficacy, prognosis, and the assessment of risk factors for cancer.

In the case of endometriosis, there is so much heterogeneity between not only lesions within different patients, but even within the same patient and same tissue. Despite the tremendous variations, researchers have been able to identify three main subtypes of endometriosis:

1) Superficial peritoneal lesions;
2) Ovarian endometriomas; and
3) Deeply infiltrating endometriosis (DIE).

Given so many unknowns, not all researchers agree that these subtypes represent different phenotypes. Even without a consensus, these three categories must also be considered simplifications, as there are actually other recognized subtypes of endometriosis, including polypoid endometriosis, histologically atypical endometriosis, iatrogenic endometriosis, and abdominal wall endometriosis.

While there is ongoing debate about whether these subtypes truly represent different phenotypes or whether they (merely) reflect different developmental stages of endometriosis, what can be established is that these different subtypes do often exhibit differential gene expression, as well as significant molecular, genetic, and histological differences. Taken together, these differences translate to tremendous clinical variation, including different symptoms, rate of disease progression, prognoses, and differential reactions to commonly prescribed medications for endometriosis.

Considering that so many variables are at play, this is why it’s so crucial that researchers carefully distinguish between different lesions, not just in terms of where they were located in the body, but also with respect to clinical data, such as the reported symptoms, age of the patient, stage of disease, menstrual cycle phase, and whether the tissue was exposed to hormonal or other medications, just to name a few.  (In fact, it was this careful tissue analysis and correlating a patient’s symptoms to thinly sliced biopsy specimen for histological examination, which helped the famous Austrian pathologist, Karl von Rokitansky, to become the first (in the modern era) to microscopically identify endometriosis as a separate histopathological entity in 1860).  These issues of tissue handling and labeling are so crucial, that there’s even a global initiative of the Endometriosis Phenome and Biobanking Harmonisation Project).

As you can see, the complexity of endometriosis naturally requires a more fastidious approach to research, beginning with tissue handling, but continuing with applying the highest standards to peer-reviewed publications, which exert such significant influence on clinical decision-making that directly impact patients.  Whatever reforms are made, we know gold standard care cannot be achieved if gold standard research methodologies are not followed.

This is why our team is collaborating with endometriosis researchers from around the world, to help develop new endometriosis research protocols for all future endometriosis studies. The adoption of oncological principles, from surgical debulking with wide margins, to risk stratification, to tissue handling harmonization, is just one of many changes that would make a tremendous difference, and we urge journal editors in chief and review boards to consider enforcing these standards for all future endometriosis studies. Otherwise, we’ll continue to see severely methodologically flawed medical literature published year after year, which, in turn, contributes to flawed clinical decision-making that can adversely impact patient outcomes.

*Prior to Sampson, who coined the term “endometriosis” in a landmark 1925 paper, endometriosis was referred to by many other names, including catamenial hemotocyles, adenomyomas externa, and even strangulation of the womb in ancient times).


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