A national population-based study provides insight in the origin of malignancies metastatic to the ovary

The relatively high incidence of metastases from CRC is remarkable. In the Netherlands, breast cancer is the most common type of cancer in women (31 %), whereas colorectal cancer accounts for 13 % [17]. Lung cancer is also fairly common (9 %) but relatively infrequently metastasizes to the ovaries. It is unclear why some primary tumor sites are more likely to metastasize to the ovaries than others.

Spread of appendiceal tumors to the ovaries is a notoriously complex phenomenon [18], which was also reflected in our findings. We found 65 low-grade appendiceal tumors (of which 62 associated with DPAM) and 104 appendiceal carcinomas (of which 24 associated with DPAM). Low-grade appendiceal tumor metastases in the ovaries were mostly also low grade, although some presented in the ovary as a carcinoma. Conversely, some appendiceal carcinomas manifested as DPAM, without ovarian involvement by carcinoma. PMCA was not diagnosed in any case which suggests that peritoneal involvement might have been underreported. However, extensive discussion of appendiceal tumors is beyond the scope of this study.

In our series, metastases from an unknown primary site made up the third largest group, with histological features suggestive of a primary site in 75 % of cases. Although this emphasizes the difficulties in distinguishing metastatic from primary malignancies, it is reasonable to believe that the actual number of cases with an unknown primary site is lower. For some patients, the primary site might have been diagnosed but considering factors such as age, physical condition, or prognosis, histological evidence might not have been sought. Incidentally, even though median age for several primary sites such as breast, lung, skin, endometrial, or bladder was significantly different, the wide range prevents age from being useful as a distinguishing feature.

The most frequently seen histological type of carcinoma was mucinous, originating from CRC in most cases. Primary ductal and lobular breast carcinomas were almost equally prevalent (7.1 and 6.7 % of our cases, respectively), even though lobular carcinomas account for only 5–15 % of all breast carcinomas. The loss of expression of the cell-cell adhesion molecule E-cadherin in lobular carcinomas has been suggested as an explanation for the more frequent spread of lobular carcinomas to the gynecological and gastrointestinal tract [19].

Side of the ovarian tumor (left or right) is a poor predictor of primary site, except for tumors originating from CRC. A left-sided ovarian tumor was more likely to originate from a left-sided CRC. Bilateral involvement of the ovaries occurred in half of the patients and was more common in patients with primary breast, stomach, and appendix carcinomas, whereas CRC more frequently presented with unilateral metastasis to the ovary. Interestingly, Petru et al. [20] found a significantly better 5-year survival rate in patients with unilateral compared to bilateral ovarian involvement. The different patterns of metastasis according to primary site, along with differences in survival, suggest that the metastatic routes followed might not be the same. Chang et al. [21] hypothesized that retrograde lymphatic spread might be responsible for ovarian metastases from gastrointestinal cancer. Our finding that most CRCs tend to metastasize only to the ipsilateral ovary suggests that continuous spread through the peritoneal cavity is involved. How often hematogenous spread is involved is not clear, although the tendency of breast cancer to metastasize to both ovaries supports this route. It is generally accepted that patterns of metastatic spread depend on specific characteristics of tumor cells with metastatic potential as well as the micro-environment of recipient tissue [22, 23, 24]. Between organs, properties of the extracellular matrix and vascular endothelial cells are different in terms of homing ligands and production of regulatory factors [25, 26]. While it is still not fully understood why some tumors preferentially metastasize to particular sites or bilateral rather than unilateral, direct transperitoneal spread is an important mechanism in our case series consisting mostly of primary malignancies in the abdomen or pelvis.

We only included histologically confirmed cases but did not revise histology. As for many cases, the criteria used to conclude that an ovarian malignancy was a metastasis from a primary elsewhere, were not available, these were not taken into consideration. While immunohistochemistry is often inconclusive, PAX-8 might prove useful as a marker relatively specific for mucinous ovarian carcinomas [27, 28]. A limitation of our study is its inclusion of patients from a geographically defined area only and in a specific time frame. However, comprehensive coverage of the whole Dutch population in the PALGA database does provide solid evidence of the site of primary malignancies metastatic to the ovary.

In summary, in our large patient series, colon is the most frequent primary site of a malignancy metastatic to the ovary, followed by endometrium and breast. Metastases from breast, stomach, and appendix carcinomas were mostly bilateral. Colorectal carcinoma metastases were mostly unilateral, with a trend for the side of CRC to correspond to the side of the ovarian metastasis. Mechanisms determining patterns of metastasis are still largely unclear, but our observations suggest that these might be different per primary tumor type.