Making a Difference: Distinguishing Two Primaries From Metastasis in Synchronous Tumors of the Ovary and Uterus

Abstract

For women with early-stage ovarian or endometrial cancers, prognosis is very good, with overall survival for both sites between 80% and 90%. This stands in stark contrast to metastatic disease (advanced stage), where the overall survival is less than 15%. We have long recognized that subtypes of disease also inform these statistics, with high-grade serous carcinomas conferring a far worse prognosis compared with others, including low-grade serous or endometrioid tumors. Yet even with our present understanding, a not uncommon finding is the diagnosis of women with carcinoma at both the ovary and the uterus (a situation that occurs in up to 10% of patients), raising the question of synchronous primaries or of metastatic disease. The implications of these clinical senarios are very relevant: If a conclusion of synchronous primaries is made, then prognosis should be excellent and hence no further treatment beyond surgery is required for cure. However, the finding of metastatic disease (from the ovary to the uterus or vice versa) will substantially change the prognostic implications, with these patients having a higher risk of recurrence and death from metastatic disease. In addition, this differential diagnosis can change therapeutic recommendations, with metastatic disease requiring more aggressive adjuvant therapy. Thus, the issue is both a biologic and clinical one.

There has been previous molecular analysis to attempt to determine the relationship between synchronous lesions of the ovary and endometrium. Most of it has focused on high-grade lesions. Several molecular studies have supported the hypothesis of independent origin by demonstrating different patterns of X chromosome inactivation and dissimilar mutations in PTEN, p53, or K-ras (1,2).

Only a 53% concordance rate between genetic and histopathologic diagnosis for synchronous primary tumors was seen in a study based on loss of heterozygosity pattern (3). In contrast, a subset of these tumors has been shown to result from germline abnormalities in genes involved in Lynch Syndrome, including MSH2, MSH6, MLH1) (4). These tumors by definition are independent. Unfortunately, there is little comparable data for low-grade tumors.

In this issue, two papers aim to evaluate the relationship between synchronous uterine and ovarian tumors in order to determine whether they are clonally related or distinctly different tumors. In the first, Anglesio and colleagues (5) address this issue by evaluating synchronous low-grade endometrial and ovarian cancers (SEOs) using a targeted gene panel. Their dataset included 18 SEO pairs, 11 of which were felt clinically and pathologically to be independent primaries and seven of which were deemed clinically indeterminate (as to their relationship) or were otherwise felt to be metastatic. Using targeted deep-sequencing techniques, they identified evidence of clonality in all but two tumors, suggesting that the majority of SEOs are not independent but rather reflect metastases. In the second study, Schultheis et al. (6) evaluate a set of tumors from five patients, each presenting with endometrioid carcinomas in the ovary and in the uterus. Using whole-exome massively parallel sequencing, they reach a similar conclusion—that these SEOs display similar patterns of somatic mutations and gene copy number alterations. Taken together, these datasets, which use differing molecular techniques, come to the same conclusion—that these tumors are often clonally related, representing metastatic disease from one site to the other (ie, from the ovary to the uterus or vice versa).

These findings are in conflict with the clinical outcomes often seen in SEOs. That is, the majority of outcomes show that the prognosis is quite good, and this is used as evidence of independent primaries (consistent with the thought that prognosis is based on the finding that both tumors were early stage at diagnosis) (7). So, how do we reconcile the findings of this paper with the clinical outcomes?

Anglesio and colleagues propose the phenomenon of “restricted” metastatic potential for some SEOs. Low-grade tumors that arise in the uterus or ovary may be able to detach without undergoing apoptosis, but their ability to spread is restricted to the other site and hence exposure occurs only to a limited microenvironment. They coin the term “microenvironment restriction” as a dominant trait that defines these SEOs and thus sets them apart from other primary tumors, including high-grade serous carcinomas, which have a predilection to spread widely through hematogenous and lymphatic and intraperitoneal means. This is certainly consistent with what is known about the biologic and clinical behavior of low-grade tumors. These tumors are indolent in their clinical course and have an entirely different biology from high-grade tumors. The remaining critical issues include defining both the molecular features of the tumor and its micro-environment, which determines the unique biologic and clinical features of these tumors.

For women with low-grade SEOs, the findings are important. Given these results from two different groups, they suggest that SEOs are not independent but rather represent isolated metastatic phenomenon. In contrast to the general prognostic information that heralds a finding of “metastatic” disease, these findings suggest that this truly is a unique phenomenon, that women in this situation remain with a good prognosis following surgery, and that systemic treatment need not be administered. This is another example of precision coming to oncology, and it is a welcome finding among the community of specialists in gynecologic oncology and to our patients.