LAUSR

In a recent issue of Gynecologic Oncology Turashvili and colleagues from Memorial Sloan Kettering Cancer Center reported on a series of 74 women with concurrent carcinoma involving endometrium and ovary, 19 of which were considered independent primary ‘synchronous’ tumors by the reporting pathologists (Turashvili et al., 2018). This might naively seem to be a curious phenomenon; synchronous tumors involving two different sites, arising independently, would surely be an uncommon occurrence, apart from examples of metastasis within the genital tract i.e. endometrium to ovary or ovary to endometrium, given that the risk factors for endometrial and ovarian carcinoma are different. This is not a vanishingly rare occurrence, however, and in practice such cases come up for discussion with some regularity at our tumor boards. Just how commonly one encounters synchronous carcinomas involving endometrium and ovary depends on how you perform your literature search. A cursory look at the literature will tell you that 5% of “endometrial carcinomas” and 10% of “ovarian carcinomas” are associated with synchronous tumors in the ovary or endometrium, respectively (Zaino et al., 2001; Soliman et al., 2004). In 2018, though, we would want a more penetrating look at this question. Ovarian carcinoma is not a single disease and considering it as such masks important differences between the histotypes. For example, synchronous endometrial involvement is rare with high-grade serous, low-grade serous or mucinous carcinomas of ovary, but synchronous endometrial carcinoma or atypical hyperplasia can be present in up to half of patients with the endometriosis-associated forms of ovarian carcinoma (endometrioid, clear cell or mixed endometrioid/clear cell) (Chui et al., 2014; Heitz et al., 2014a). Endometrial carcinoma histotypes, unlike ovarian carcinoma histotypes, do not define diseases with consistent molecular abnormalities, and the 4 Cancer Genome Atlas-based molecular subtypes of endometrial carcinoma can be considered to be analogous to the 5 histotypes of ovarian carcinoma, in that they define diseases with different risk factors, precursor lesions, response to therapy and outcome (The Cancer Genome Atlas Network, 2013; Kommoss et al., 2018). Synchronous ovarian carcinoma is seen in hypermutated endometrial carcinomas with mismatch repair deficiency (MMRd), ultramutated endometrial carcinomas with mutations in the exonuclease domain of polymerase-epsilon (POLE), and endometrial carcinomas with low mutation burden/few somatic copy number abnormalities (characterized by wildtype p53 expression and absence of molecular features of the other three molecular subtypes, variously referred to a no specific molecular profile (NSMP) or p53wt)[unpublished data]. The challenge presented by synchronous carcinomas of endometrium and ovary is not related to the high-grade tumors with disseminated disease; these are clearly metastases, and most arise in the endometrium. The problematic aspect of synchronous carcinomas of ovary and endometrium is the observation that most such tumors are low-grade (grade 1 or 2) endometrioid carcinomas involving both ovary and endometrium, that typically do not involve other anatomic sites, and are associated with a favorable outcome, at least relative to what would be expected were these advanced stage endometrial carcinomas with extrauterine spread (Ulbright and Roth, 1985; Heitz et al., 2014b). This led to the reasonable conclusion that such tumors must be independent primary tumors, and histopathological criteria were proposed to allow separation of synchronous endometrial and ovarian carcinomas into those that are independent primary tumors and those that are metastatic (typically from endometrium to ovary), with the former staged as two independent primary tumors (Scully et al., 1998). As noted by Turashvili et al., these criteria can be difficult to apply in practice as some cases are indeterminate, with features supportive of both independent primary tumors and a single tumor with metastasis. This approach to primary site assignment has remained in use for decades and has largely withstood the test of time in clinical practice. In 2016, however, two independent studies established that synchronous endometrial and ovarian carcinoma, even though classified as independent primary tumors based on the existing criteria, were clonally related, by demonstrating identical mutations present in both endometrial and ovarian tumors (Anglesio et al., 2016; Schultheis et al., 2016). Even tumors of different histotype in ovary and endometrium e.g. clear cell and endometrioid, were demonstrably clonally related. We have existed since then in a state of cognitive dissonance, in that we continue to classify tumors as “independent primary carcinomas of ovary and endometrium” in practice, while knowing them to be clonally related i.e. metastasis. The situation is very similar to what occurred a few years ago when we designated most extra-uterine highgrade serous carcinomas as ovarian primaries, using criteria of longstanding, even though the accumulating data clearly demonstrated that the fallopian tube was the primary site (Singh et al., 2015). Just as this led to new criteria for primary site assignment being developed for tubal/ovarian carcinomas, we now need an approach to synchronous endometrial and ovarian carcinomas that can reconcile the new genomic information with clinical practice. In their study, Turashvili et al. take the important step of setting aside assignment of primary site, instead refocusing the discussion on the risk of recurrence. This is important because of the possibility of overtreatment if there is overemphasis on primary site assignment which, if guided by the molecular results, would lead to synchronous endometrial and ovarian carcinomas being considered advanced stage. In looking past primary site assignment and stage, and looking instead at what matters most to the patients, i.e. outcome, they point the way past our current impasse, where clinical practice and our knowledge of tumor biology are at odds. In their study they attempt to identify risk groups that can guide treatment decisions, based on regression analysis. The first stratification point is between endometrioid (low risk) and non-endometrioid (high-risk). So far so good, but the issue of ‘synchronous’ primaries only ever related to low grade endometrioid carcinomas at both sites. Furthermore the clinically relevant goal is