Primary Endometrioid Adenocarcinoma of the Ovary vs. Metastatic Endocervical Adenocarcinoma to the Ovary. Charles Zaloudek, M.D. Department of Pathology, University of California San Francisco, CA

Clinical History The patient was a 44-year-old woman who had a LEEP cone in 2002 that revealed adenocarcinoma of the cervix. Treatment was by vaginal hysterectomy, which showed residual adenocarcinoma invasive to a depth of 3.5 mm. Subsequently, she had a vaginectomy and bilateral pelvic lymph node dissections, which revealed no residual disease or lymph node metastases. We were unable to obtain the cervical specimens for review. Figure 1 Click to view with ImageScope Click to view with a Web-Based Viewer She developed vaginal bleeding and abdominal pain in October, 2004 and during her evaluation the gynecologist performed a pelvic ultrasound. It showed a large cystic pelvic mass with an appearance that was suspicious for ovarian cancer. A gynecologic oncologist performed a bilateral salpingo-oophorectomy, omentectomy, and lymph node dissection. No tumor was identified anywhere except in the left ovary, which was cystic and greatly enlarged. It measured 29 cm in diameter and weighed 1192 gm. The exterior was smooth except for fibrous adhesions. The cyst had been drained prior to receipt in the pathology department; other than the drainage site, the capsule was intact. On cut section, the tumor was partly cystic and partly solid, with variably sized solid tan masses accounting for about 50% of the total tumor volume. The largest solid nodule measured 9 cm. The right tube and ovary were unremarkable. Following evaluation of the histology the pathologist made a diagnosis of grade 1 endometrioid adenocarcinoma of the ovary. Microscopic Findings The tumor is composed of variably sized atypical glands, papillae, and cysts lined by tall columnar cells with stratified hyperchromatic nuclei. Mitotic figures are numerous. The tumor cells have pale somewhat frothy appearing cytoplasm. In some cells, the cytoplasm has a basophilic appearance with apical vacuoles. The glands and cysts contain mucin and sloughed tumor cells. The original diagnosis was endometrioid adenocarcinoma of the ovary. A primary endometrioid adenocarcinoma with this growth pattern would be architectural grade 1 based on its purely glandular growth pattern. The nuclei, however, are quite atypical and there are numerous mitotic figures. It is somewhat unusual to see an endometrioid adenocarcinoma with a low architectural grade and a high nuclear grade; this type of discordance always raises the possibility of a metastasis. Given the history, an alternative diagnostic consideration is metastatic endocervical adenocarcinoma. We thought that the appearance of the tumor cells and certain aspects of the growth pattern suggested metastatic endocervical adenocarcinoma. Accordingly, we performed several immunohistochemical studies to try to determine whether the ovarian tumor was primary or metastatic. The following immunohistochemical stains were evaluated: Stain Result P16 Positive Monoclonal CEA Positive PASD Positive staining of tumor cell cytoplasm Vimentin Negative ER Negative PR Negative Differential Diagnosis: Primary endometrioid adenocarcinoma of the ovary vs. metastatic endocervical adenocarcinoma to the ovary. Discussion Metastatic carcinoma is common in the ovary, accounting for 5-10% or more of ovarian tumors in large series. A variety of findings can help determine whether an ovarian carcinoma is primary or metastatic: the gross pathologic findings, the microscopic appearance of the tumor, and the results of immunohistochemical stains. Gross pathologic findings depend to a certain extent on the primary site of the carcinoma, but certain features suggest the possibility of a metastasis. These include tumor implants on the surfaces of the ovaries, bilateral tumors, small tumors, and multinodular growth as seen on cross sections through an ovarian mass. The gross findings may suggest a specific primary site. For example, typical examples of metastatic colorectal cancer are bilateral, have a smooth surface, and are cystic or solid and cystic, with the cysts containing mucoid secretions. [1, 2] In one study, 90% of mucinous carcinomas were correctly classified as primary or metastatic by assuming that all mucinous tumors that were bilateral or smaller than 10 cm were metastatic, and all unilateral mucinous tumors larger than 10 cm were primary. [3] This rule works best for mucinous adenocarcinomas, as a study of mucinous and nonmucinous metastatic colorectal carcinoma showed that 33 of 86 ovarian metastases were unilateral and of those, 20 were 10 cm or greater in diameter. [4] Metastatic stomach cancer usually has the appearance of a Krukenberg tumor in which the ovaries retain their shape but are symmetrically or asymmetrically enlarged, with solid firm tan or white edematous cut surfaces that are honeycombed with small mucinous cysts. Most other types of metastatic tumors are solid or solid and cystic and grow as multiple nodules in the cortex and medulla, often with implants on the surface. Metastases from sites in the female genital tract to the ovaries can cause particular problems in differential diagnosis because synchronous primary tumors can occur, and the histologic appearance of metastatic tumors can mimic that of primary ovarian carcinomas. Endometrial adenocarcinomas of endometrioid and serous types are the most common genital carcinomas to metastasize to the ovaries. Gross pathologic findings that suggest that the ovarian carcinoma might be metastatic include: the endometrial carcinoma is large and deeply invasive, the ovarian tumor is small, the ovarian tumor is multinodular and solid, the ovarian tumor is bilateral, surface implants are present on the ovary, and extraovarian metastases are present in a distribution characteristic of endometrial adenocarcinoma (i.e., lymph node metastases more likely than peritoneal metastases). [5] Synchronous or metachronous ovarian tumors are uncommon in women with cervical cancer. Brown et al found only 1 patient with a microscopic ovarian metastasis and 1 with a synchronous ovarian endometrioid adenocarcinoma among 107 women operated on for stage I adenocarcinoma of the cervix. [6] Wu et al found ovarian metastases in 10 of 1413 patients operated on for cervical cancer (6 squamous cell carcinoma and 4 adenocarcinoma). [7] Most other authors have reported similar findings. Studies of consultation cases show a higher rate of coexistence of ovarian and cervical neoplasms. Kaminski and Norris reported that 25 of 161 women (16%) with cervical cancer had ovarian tumors which were thought to be primary in 14 cases and metastatic in 11. [8] The primary tumors included 4 benign cystic teratomas, 3 serous cystadenomas, 1 mucinous cystadenoma, and 1 bilateral serous carcinoma detected 20 years after the cervical cancer was treated. These tumors appear to represent second primary neoplasms, but some of the synchronous and metachronous adenocarcinomas that were regarded as ovarian primaries by the authors might well have been metastatic. The only ovarian tumors they regarded as metastatic occurred in patients with high grade and high stage cervical neoplasms. LiVolsi et al found that 4 of 26 women with mucinous adenocarcinomas of the cervix had synchronous mucinous tumors in the ovaries (2 borderline, 2 adenocarcinoma). [9] Although they had an "endocervical" phenotype, the ovarian tumors were regarded as separate primary neoplasms. Two of the 4 patients died of tumor. Young and Scully described 16 cases in which patients with mucinous adenocarcinomas of the cervix had mucinous ovarian tumors. [10] Ten of the cervical cancers were minimal deviation adenocarcinomas. The ovarian tumors were viewed as ovarian primaries in 10 patients, as metastases from the cervix in 3, and in 3 cases the ovaries were thought to contain both primary and metastatic carcinoma. Eight patients died of tumor, 1 was alive with tumor when lost to followup, 3 were alive and well, 2 were lost to followup, and 2 were recent cases with no followup. Large deeply invasive cervical carcinomas are more likely to spread to the ovaries, typically in a pattern similar to that described above for metastatic endometrial cancers. [11] However, even small superficial cervical adenocarcinomas can metastasize to the ovaries. [12] In this case, the unilateral tumor, the absence of surface growth, and the large size suggest a primary carcinoma. Microscopic features that raise the possibility that an ovarian tumor might be metastatic include a bilateral, multinodular growth pattern, implants on the surface of the ovary, numerous emboli of metastatic carcinoma in lymphatic spaces, especially in the hilum and mesovarium, and an unusual microscopic pattern for a primary ovarian tumor, such as goblet cells in an inappropriate histologic setting, a signet ring cell appearance or an Indian file pattern of invasion. [13] Luteinization of the stroma occurs around some metastatic tumors, [1, 2] but it also occurs around primary ovarian tumors and does not necessarily imply that a tumor is metastatic. In this case, many of the findings are compatible with a primary tumor, but the nuclear grade and mitotic index is inappropriately high for the low architectural grade and the histologic appearance of the tumor cells, with intracytoplasmic mucin, is unusual for a primary adenocarcinoma. The tumor cells resemble those typical of endocervical adenocarcinoma. These days, immunohistochemical and other special studies often play a key role in determining whether an ovarian cancer is primary or metastatic, and immunostains were key in indicating that this ovarian tumor was metastatic. Strategies for differentiating between cervical and endometrial adenocarcinomas have been developed, and the same techniques can be applied to this case to determine whether the ovarian tumor is metastatic cervical adenocarcinoma or a primary endometrioid adenocarcinoma of the ovary. Endocervical adenocarcinoma tends to be a mucinous adenocarcinoma, although the degree of mucin production is highly variable. In this case, a PAS-diastase stain was strongly positive in the cytoplasm of the tumor cells. In endometrioid carcinoma, staining is usually limited to the apical surfaces of the cells while the cytoplasm is negative. It has been known for some time that endocervical adenocarcinomas often show positive cytoplasmic and membranous staining for carcinoembryonic antigen (CEA). Endometrioid adenocarcinomas, on the other hand, are typically negative for CEA but show positive staining for vimentin, usually in the subnuclear cytoplasm and on the cell membranes. [14] Staining for vimentin is usually negative in endocervical adenocarcinoma. [15] Immunostains for estrogen and progesterone receptors add further information, since strong positive staining for hormone receptors is much more likely in endometrial than endocervical adenocarcinoma. [16, 17] Interpretation of mucin stains and immunostains can be complicated by the fact that some cervical adenocarcinomas exhibit an endometrioid pattern of differentiation and some endometrial adenocarcinomas show mucinous differentiation. [18] Finally, the addition of a test for human papillomavirus (HPV) is particularly helpful, since most cervical adenocarcinomas are HPV related, while endometrioid endometrial carcinoma is not. [17] HPV testing, either by PCR or in situ hybridization, is not available in most pathology departments. A cell cycle associated protein, p16, is overexpressed in cervical cancers because the HPV E7 protein inactivates Rb. An immunostain for p16 is available and provides a widely available surrogate test for the presence of HPV. [19, 20]. Similar testing should be applicable to the differential diagnosis between a primary ovarian carcinoma and a metastasis from a cervical adenocarcinoma, since ovarian cancer is thought to be unrelated to HPV. In this case, we found strong positive staining for monoclonal CEA and p16, and absence of staining for vimentin, ER and PR, which suggests that the ovarian cancer is a metastasis from the cervix, even though the cervical carcinoma was reported to be small and no lymph node metastases were detected. In a recent publication, Elishaev et al tested endocervical and ovarian tumors from 10 patients for HPV and performed immunostains for p16. [12] The ovarian tumors were discovered concurrently with the cervical tumors in 5 cases, subsequent to the cervical tumors in 3 cases, and prior to the cervical tumors in 2 cases. Eight of the ovarian tumors were unilateral and 7 were 10 cm or more in diameter; the largest measured 30 cm. The cervical tumors varied in size, but in three cases the cervical tumors were superficial and difficult to differentiate from adenocarcinoma in situ. HPV DNA was identified in all 10 tumor pairs by in situ hybridization or PCR and diffuse strong staining for p16 was present in every case. These findings strongly support the interpretation that the ovarian tumors represent metastases from the cervix, not primary ovarian tumors. The clinical outcome was better than might be expected, as 7 of 8 women with followup were alive and well and only one was under therapy for adenocarcinoma. In summary, it is difficult to differentiate between metastatic endocervical adenocarcinoma and primary ovarian endometrioid or mucinous adenocarcinoma. In fact, standard criteria for differentiating between primary and metastatic tumors are likely to be misleading in this situation and additional testing is required. The following special stains can be helpful in the differential diagnosis: Test Metastatic Endocervical Adenocarcinoma Primary Ovarian Adenocarcinoma CK7 Positive Positive CEA Positive Negative in endometrioid Positive in mucinous HPV in situ hybridization Positive Negative P16 Positive, diffuse strong Negative or focal and weak ER Negative Positive PR Negative Positive Vimentin Negative Positive References Lash RH, Hart WR. Intestinal adenocarcinomas metastatic to the ovaries. A clinicopathologic evaluation of 22 cases. Am J Surg Pathol. 1987; 11:114-121. Daya D, Nazerali L, Frank GL. Metastatic ovarian carcinoma of large intestinal origin simulating primary ovarian carcinoma: A clinicopathologic study of 25 cases. Am J Clin Pathol. 1992; 97:751-758. Seidman JD, Kurman RJ, Ronnett BM. Primary and metastatic mucinous adenocarcinomas in the ovaries: incidence in routine practice with a new approach to improve intraoperative diagnosis. Am J Surg Pathol. 2003; 27:985-993. 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