In this subset analysis of advanced stage primary epithelial carcinoma of the ovary, the reviewers reclassified the majority (57% to 63%) of the mucinous carcinomas as metastatic to the ovary rather than primary to the ovary. These results are disturbing but not surprising. Many, if not most, of the carcinomas described and reported in some of the classic papers on mucinous ovarian carcinoma are now suspected to have represented occult metastatic mucinous tumors. However, even at present, no gold standard exists by which primary mucinous adenocarcinomas can be distinguished from those that are metastatic to the ovary. (2
) Immunohistochemistry with a variety of antibodies, including CDX2, villin, beta catenin, CEA, MUC2, MUC5, Dpc4, and the presence and distribution of CK7 and CK 20, have been employed to assist in the distinction of primary from metastatic mucinous carcinomas, and this has reduced but not eliminated misclassification of these tumors. (2
) The addition of an immunohistochemical panel (with antibodies such as CK 7, CK 20, and CDX-2) for all of the mucinous adenocarcinomas on this protocol would have increased the ability to correctly distinguish primary mucinous ovarian carcinomas from those metastatic to that site, but it was not mandated in the protocol, and it was performed in only a few of the cases. Interestingly, in several of these cases, the immunohistochemical results supported the interpretation of the lesions as metastatic from the colon, but the women were still enrolled on this protocol that was limited to women with advanced stage primary ovarian carcinoma.
Ulbright et al, and Lee and Young, have identified partially overlapping sets of gross and microscopic characteristics that are more often associated with primary or metastatic carcinomas involving the ovary. (14
) Interpretative judgment is still required since no single feature or group of features provides high sensitivity coupled with high specificity. In this study, the three review pathologists independently classified the tumors based on an assessment of 12 of the criteria of Lee and Young. (9
) While each of the reviewers disagreed with the submitting interpretation in about 60% of cases, there was a high degree of agreement among the reviewers independent classification, with unanimity of classification in 68% of cases.
Using the laterality and size algorithm that all bilateral mucinous carcinomas of the ovary and all unilateral carcinomas less than 13 cm in diameter are metastatic, 29 of 41 (70%) tumors were reclassified as metastatic, similar to the result obtained from using the constellation of criteria. (23
) This rule is reported to correctly classify almost 90% of mucinous ovarian neoplasms as primary or metastatic. However, it should be noted that the rule was derived from a set of mucinous tumors obtained by a retrospective review of cases at the Johns Hopkins Hospital.(23
) In that study, twenty-one tumors were considered to be primary mucinous adenocarcinoma of the ovary. The distribution by stage was not provided, but in a previous study including the same institution, the majority were of early stage. (3
) In another study of 220 primary ovarian carcinomas from the Washington Hospital Center, six were mucinous carcinoma and only one of these was of advanced stage. (26
) Bilateral involvement of the ovaries is very uncommon in stage I mucinous carcinoma. However, bilateral involvement is typical in advanced stage serous carcinoma, and it might also be common in advanced stage mucinous carcinoma. Since most mucinous carcinomas of the ovary are stage I and advanced tumors were so uncommon in those prior studies, this would have influenced the creation of the classification criteria. There is little existing data on the pattern of spread and distribution of tumor specifically for advanced stage mucinous carcinoma of the ovary. Most publications have not described in detail the presence of bilateral involvement or its location in the contralateral ovary in cases of advanced stage mucinous carcinoma.(3
) Consequently, the size and laterality algorithm may correctly classify most mucinous ovarian tumors, but it may not do so for those few primary mucinous carcinomas that are of advanced stage. (It may be appropriate to consider modification of the portion of the rule that classifies all bilateral tumors as metastatic, in order to permit small foci of surface involvement of the contralateral ovary in the presence of other extra-ovarian disease.)
The OS for women with a reviewer diagnosis of advanced stage primary mucinous carcinoma of the ovary was not significantly different from that of the women with tumors interpreted as metastatic, using either the size and laterality algorithm or the constellation of criteria. An examination of the estimated relative death rates for each of the pathologic characteristics revealed that possibly the absence of signet ring cells, an infiltrative pattern of invasion, and small neoplastic glands, were each associated with longer survival. The later two features were among the five statistically best discriminators of primary from metastatic mucinous carcinomas of the ovary in the study by Lee and Young.(9
) However, in contrast to their study, we did not find that bilaterality or an expansile pattern of invasion discriminated effectively those likely to survive from those likely to die of tumor.
There are several limitations to this study that are shared with most retrospective analyses of large international clinical trials, including the inability to obtain or perform immunohistochemical stains on each case, and the availability of only a limited number of slides from most cases. Confirmation of the pathologic interpretation of many of these tumors as metastatic to the ovary would be helpful, but is lacking. While the protocol required notification of the identification of subsequent primary tumors, there may have been under-diagnosis of such. Evaluation for a second primary tumor may not be as aggressive for women with advanced widespread adenocarcinomas, especially since gastrointestinal involvement is so common in advanced stage ovarian carcinoma and the mean overall survival was so short. Nevertheless, in the absence of identification of any second primary site of neoplasm in the followup of any of these 44 women, it is possible, although highly unlikely, that all of the tumors in this study represent advanced stage mucinous adenocarcinomas of the ovary. The strengths of this study include the large number of total cases of advanced ovarian carcinoma, the large number of cases submitted as mucinous carcinoma (greatly exceeding that of any prior study), the uniform staging requirements, standardized chemotherapy, and ability to track survival data.
Most importantly, we found that the OS for women with advanced stage mucinous carcinomas (whether arising in the ovary or carcinoma metastatic to that site) is significantly less than that for women with advanced stage serous carcinoma (median survival of 14 months versus 42 months, respectively). This could reflect either an intrinsic aggressive behavior of mucinous ovarian carcinoma or its resistance to agents that are effective in the treatment of serous carcinoma. These results are very similar to those reported by Hess. et al. (35
who identified 27 cases of FIGO Stage III or IV mucinous carcinoma of the ovary over an eight year interval They found an OS of 12 months for patients with mucinous ovarian carcinoma vs 37 months for controls with ovarian carcinoma of non-mucinous histology. We support their recommendation that consideration should be given to future investigation of therapy of advanced mucinous carcinoma of the ovary with agents that are effective in treating carcinomas of the gastrointestinal tract. From a pragmatic perspective, given our limitations in diagnostic classification, at the current time it may not be as critical therapeutically or prognostically to distinguish advanced stage primary ovarian from metastatic mucinous adenocarcinomas of the ovary, since the behavior of the tumors is so poor for both subsets of patients. However, efforts should continue to find methods to correctly classify these tumors since effective chemotherapy in the future might be limited to one subset based on the site of origin.
In conclusion, we found that advanced stage primary mucinous carcinoma of the ovary is very rare (0.5–1.5% of advanced ovarian epithelial invasive neoplasms), and that 61% (27/44) of the patients enrolled on this protocol as primary mucinous carcinomas were probably metastatic carcinoma to the ovary. This conclusion rests on the assumption that the published and generally accepted criteria applied by the reviewers to make this distinction are accurate, since no further investigation into identification of non-ovarian sites of origin was possible in this international study. While it would be ideal to have immunohistochemical or molecular assays that are highly specific for gastrointestinal or müllerian mucinous tumors, none have been identified to date. Surprisingly, there was no significant difference in survival between the groups of women with ovarian and non-ovarian mucinous carcinomas. However, we found that advanced stage primary mucinous ovarian carcinoma is highly lethal, with a significantly shorter survival than that of women with serous carcinoma. It is reasonable to consider the use of chemotherapeutic agents that are effective in treating carcinomas of the gastrointestinal tract in future trials of this tumor.