Isabel Alvarado-Cabrero, M.D., Ph.D., Adriana Rodríguez-Gómez, M.D., Jorge Castelan-Pedraza, M.D., and Raquel Valencia-Cedillo, M.D.

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1 AND QUANTITATIVE CYTOPATHOLOGY AND AQCHANALYTICAL HISTOPATHOLOGY An Official Periodical of The International Academy of Cytology and the Italian Group of Uropathology ARTICLES Metastatic Ovarian Tumors A Clinicopathologic Study of 150 Cases Isabel Alvarado-Cabrero, M.D., Ph.D., Adriana Rodríguez-Gómez, M.D., Jorge Castelan-Pedraza, M.D., and Raquel Valencia-Cedillo, M.D. OBJECTIVE: To determine the frequency of metastatic ovarian tumors and to identify their clinicopathologic features. STUDY DESIGN: A total of 150 patients with pathologically confirmed metastatic ovarian carcinoma who were treated between 1995 and 2011 at the Mexican Oncology Hospital were identified by retrospective review. Clinicopathologic data were analyzed. RESULTS: Metastatic ovarian carcinoma accounted for 15.7% of all ovarian malignancies. The primary sites of nongynecologic tumors were the colon (30%), stomach (16%), appendix (13%), breast (13%), pancreas (12%), biliary tract (15%), and liver (4%). Gynecologic primary sites were the uterine cervix (4%) and the uterine body (23%). Primary malignancies were detected first in 66 patients (44%) and simultaneously with ovarian metastasis in 53 patients (35.3%). An ovarian mass was the first manifestation of disease in 20.6% of the cases. The patients ranged in age from 26 to 72 years (mean, 51). Krukenberg tumors were found in 35 patients (23%). The cut surfaces of the ovaries were solid in 68 patients, solid-cystic in 38, and multicystic in 44. CONCLUSION: Metastatic ovarian carcinomas are an important group of ovarian neoplasms, constituting 15.7% of all ovarian malignancies. Most of them arise from the gastrointestinal tract. (Anal Quant Cytopathol Histopathol 2013;35: ) Keywords: diagnosis, metastasis, neoplasia, ovary. For a small pelvic organ, the ovary is a relatively common site of metastasis. 1 The reason for this is uncertain, but vascularity plays an important role as metastases are relatively more frequent in younger women than in postmenopausal women. 2,3 Although metastatic ovarian tumors are thought to account for 10 30% of malignant ovarian tumors, it is difficult to know the precise incidence of ovarian metastasis. 1,3 In many cases there is a known history of a primary tumor, but on occasion From the Department of Pathology, Mexican Oncology Hospital, Mexico, D.F., Mexico. Dr. Alvarado-Cabrero is Chief of Pathology. Drs. Rodríguez-Gómez, Castelan-Pedraza and Valencia-Cedillo are Pathologists. Address correspondence to: Isabel Alvarado-Cabrero, M.D., Ph.D., Av. San Luis Potosí #143, Col Roma, México 06700, D.F., México (keme2.tijax12@gmail.com). Financial Disclosure: The authors have no connection to any companies or products mentioned in this article /13/ /$18.00/0 Science Printers and Publishers, Inc. 241

2 242 Alvarado-Cabrero et al presentation is with symptoms related to an ovarian mass or an ovarian mass is discovered incidentally in a patient with no known history of malignancy. In such cases the primary tumor may not manifest itself until sometime later. 4 Metastatic tumors can be confused with primary tumors of the ovary. This is because the tumors histopathologically similar to primary ovarian neoplasms also most commonly metastasize to the ovary. 5,6 Most ovarian metastases arise from the gastrointestinal tract, breast, and gynecologic organs. Although advances in image analysis have contributed to the detection of lesions, metastatic ovarian tumors from nongynecologic organs are rarely diagnosed before primary treatment. 7 The distinction of metastatic ovarian carcinoma from a primary malignant neoplasia is crucial to its subsequent management, and diagnostic misinterpretation may have important consequences for the patient. 8 In this case series we analyze 150 cases of metastatic tumors to the ovaries, describing their clinical and pathologic features. Materials and Methods We extracted information from our collected institutional database on all patients with ovarian tumors surgically treated at the Mexican Oncology Hospital, National Medical Center. The records of 950 patients with ovarian malignancies between January 1995 and December 2011 were examined, and cases of metastatic disease to the ovary were selected for detailed review. We recorded patient information, including age, menopause status, origin of the primary malignancy, and bilaterality. Gross features of the ovaries that were recorded included tumor size, surface involvement, and characteristic on sectioning. Hematoxylin and eosin (H&E) stained sections of one or both ovaries affected by metastatic tumors were reviewed in all cases. The diagnosis of ovarian metastatic lesions was based on standard criteria. 5 We evaluated the utility of an immunohistochemical panel of 4 antibodies in 46 carcinomas metastatic to the ovary. The primary sites were the colon (26%), stomach (22%), appendix (18%), breast (12%), and pancreas (17%). The block chosen was the most representative based on H&E evaluation. Immunohistochemical stains were performed on 3 μm paraffin-embedded sections using the avidinbiotin-peroxidase method with antibodies against cytokeratin (CK) 7 (DakoCytomation, Carpinteria, California, U.S.A.), CK 20 (DakoCytomation), monoclonal carcinoembryonic antigen (DakoCytomation), and estrogen receptor (SP1, Thermo Fisher Scientific, Fremont, California, U.S.A.). Results Metastatic ovarian tumors accounted for 150 (15.7%) of the 950 ovarian malignancies. The age of the patients ranged from years (mean, 51 years) at the time of diagnosis of ovarian metastasis. Ninety-two (61.3%) patients were premenopausal and 58 (38.6%) were postmenopausal. Symptoms related to the ovarian tumors were present in 53% of patients, while 34% of patients had symptoms related to the primary tumor. Eighty of the patients (53.3%) presented with a pelvic mass and abdominal or pelvic pain, 24 (16%) with symptoms of bowel obstruction, 22 (15%) with fever and debilitating abdominal pain, 3 (2%) with jaundice due to the presence of an intrahepatic tumor, and 2 (1.3%) with transvaginal hemorrhage. Six (4%) patients had endocrine symptoms such as breast tenderness or postmenopausal bleeding as a result of stromal luteinization in the ovarian stroma. Thirteen patients (8.6%) were asymptomatic and were found to have ovarian tumors on routine gynecologic examination (Table I). Omental and/or peritoneal metastatic lesions were seen at presentation in all patients. Nine cases (6%) originated from gynecologic organs, and 141 (94%) originated from nongynecologic organs. The primary sites of gynecologic tumors were the uterine cervix (4%) and the uterine body (2%). The primary sites of nongynecologic tumors were colon (30%), stomach (16%), appendix (13%), breast (13%), pancreas (12%), biliary tract (5%), and liver (4%) (Figure 1). Table I Clinical and Pathologic Features of Ovarian Metastatic Tumors Feature No. % Premenopausal patients Postmenopausal patients Bilaterality Ovarian mass detected prior to primary tumor Ovarian tumor size < 10 cm Heterogeneous appearance of the carcinoma Ovarian surface implants Lymphovascular invasion Single cell infiltration Extraovarian disease

3 Volume 35, Number 5/October 2013 Metastatic Ovarian Tumors 243 Figure 1 Distribution of metastatic ovarian tumors based on their origin. Primary malignancies were detected first in 66 patients (44%) and simultaneously with ovarian metastasis in 53 patients (35.3%). In 31 of the 150 cases (20.6%) an ovarian mass was the first manifestation of disease. There was a known history of breast cancer in 16 of the patients (80%), with ovarian metastasis from breast cancer. Eighty-two (54.6%) ovarian metastases from extragenital cancer were bilateral, while in gynecologic cancers bilater- al metastases were identified in 4 patients (2.6%). Thirty-five (23%) of the metastatic tumors were histologically determined to be Krukenberg tumors with signet ring cells, and 18 (51.4%) of them originated from the stomach. Figure 2 Ovarian metastasis of pancreatic adenocarcinoma. Sectioned surface of a solid and cystic ovarian mass. Figure 3 Surface implants. This implant has a densely hyaline stroma with mucin and is plaque-like (H&E stain, 10). Pathologic Findings Gross Features. The tumors ranged in size from 5 26

4 244 Alvarado-Cabrero et al Figure 4 Metastatic colorectal adenocarcinoma in the ovary with extensive dirty necrosis (H&E stain, 10). cm (median, 12 cm) in greatest dimension. Gross examination revealed that 68 (45%) tumors were solid, 38 (25%) were solid and cystic (Figure 2), while 44 (29%) were multicystic. The appearances of the external surface in 150 tumors were recorded as smooth in 36 and irregular and nodular in 114. Microscopic Features General Features. On microscopic examination the presence of tumor on the surface of the ovary (surface implants) was present in 26 cases (17.3%) (Figure 3). A total of 46 tumors (30.6%) had a heterogeneous appearance of the carcinoma with well- A differentiated mucinous glands juxtaposed with infiltrating small gland adenocarcinoma. The presence of vascular invasion and single cell infiltration was seen in 62 (41.3%) and 22 (14.6%) cases, respectively. Histologic examination revealed that 36 of 45 metastatic colorectal adenocarcinomas involving the ovary were composed of glands of moderate to large size lined by highly atypical nonmucinous cells, mimicking an endometrioid adenocarcinoma. Eight tumors (18%) with predominantly mucinpoor epithelium, a branching villoglandular papillary architecture, and micropapillary pattern simulated endometrioid and serous adenocarcinoma, respectively. The presence of dirty necrosis and glands with a cribriform architecture arranged at the periphery of the necrotic material ( garland pattern ) were seen in 85% of the cases (Figure 4). All gastric adenocarcinomas involving the ovary were composed of signet ring cells; also, gland differentiation was present in most of the tumors. A peculiar feature was the presence of tubules, which was noted in 8 of the 24 cases (33.3%). In 12 of the 20 cases (60%) with an appendiceal tumor, an ovarian mass was the first manifestation of disease; also, the appendiceal tumor gave rise to pseudomyxoma peritonei in 8 (40%) of the patients. The ovarian tumors in these cases had a stroma obliterated by multilocular cysts (Figure 5), the locules contained abundant thick mucin, and the mucinous cells lining the cyst were tall, columnar, and engorged with mucin. Components that resem- B Figure 5 (A) Ovarian tumor secondarily involved by spread of a low-grade appendiceal adenocarcinoma, with a jelly-like material. (B) The mucinous cells are particularly tall and mucin-rich (H&E stain, 40).

5 Volume 35, Number 5/October 2013 Metastatic Ovarian Tumors 245 bled either typical mucinous tumor of borderline malignancy or one with intraepithelial carcinoma were observed in 4 cases (20%). Six of the 18 (33.3%) metastatic pancreatic adenocarcinomas involving the ovary resembled a primary ovarian mucinous tumor. They had bland areas, similar to that seen in primary benign and borderline mucinous cystadenomas. Fourteen (70%) of the metastatic breast carcinomas to the ovary had a cribriform and papillary pattern. Diffuse sheets of metastatic lobular carcinoma cells were seen in 6 cases (30%). A total of 8 cases (5%) of carcinoma of the extrahepatic bile ducts with ovarian spread were found. The majority of these tumors mimicked a primary mucinous tumor, usually adenocarcinoma, but 2 cases had an appearance similar to a borderline or benign mucinous neoplasia, with the whole or much of the tumor exhibiting a maturation phenomenon. We were able to study only 5 cases (4%) of hepatocellular carcinoma metastatic to the ovary. An insular, trabecular and pseudoglandular pattern was seen in all cases; however, the presence of bile was seen in only 2 of the cases. Similar to other secondary adenocarcinomas from nongynecologic organs, all metastatic endocervical adenocarcinomas involving the ovary had a deceptively bland appearance and closely mimicked a primary ovarian benign or borderline mucinous tumor. Table II Immunohistochemical Expression Patterns in Differential Diagnostic Considerations of Ovarian Metastatic Carcinomas MCR MGC MAC MBC MPC (N = 12) (N = 10) (N = 8) (N = 8) (N = 8) Antibody No. (%) No. (%) No. (%) No. (%) No. (%) CK 7 Negative 7 (58) 4 (40) 5 (62) 0 (0) 3 (38) Positive 5 (42) 6 (60) 3 (38) 8 (100) 5 (62) CK 20 Negative 0 (0) 5 (50) 0 (0) 8 (100) 4 (50) Positive 12 (100) 5 (50) 8 (100) 0 (0) 4 (50) CEA Negative 0 (0) 2 (20) 0 (0) 8 (100) 2 (25) Positive 12 (100) 8 (80) 8 (100) 0 (0) 6 (75) ER Negative 12 (100) 9 (90) 8 (100) 2 (25) 8 (100) Positive 0 (0) 1 (10) 0 (0) 6 (75) 0 (0) MCR = metastatic colorectal carcinoma, MGC = metastatic gastric carcinoma, MAC = metastatic appendiceal carcinoma, MBC = metastatic breast carcinoma, MPC = metastatic pancreatic carcinoma, CEA = carcinoembryonic antigen, ER = estrogen receptor. We found only 3 (2%) patients with endometrial cancer and ovarian metastasis; all 3 cases were of endometrioid type. The presence of deep myometrial invasion, lymphovascular space invasion in the myometrium, and the absence of ovarian endometriosis in all 3 cases favored the diagnosis of metastatic involvement of the ovary. Expression of CK 7, CK 20, carcinoembryonic antigen, and estrogen receptor was observed in 27 (58%), 29 (63%), 34 (73%), and 7 (15%) patients, respectively. Expression of the 4 biomarkers according to tumor categories is shown in Table II. All cases of metastatic colorectal and appendiceal adenocarcinomas were diffusely positive for CK 20 and carcinoembryonic antigen. Most cases of metastatic breast cancer were positive for CK 7 and estrogen receptor. Discussion The reported frequency of metastatic tumors in the ovary varies by study design (e.g., autopsy versus surgical material) and the country of origin; however, it ranges from 10 30% of all malignancies. 1-6 In our series metastatic ovarian tumors accounted for 150 (15.7%) of the 950 ovarian malignancies. Lee 9 reported that 13.6% of their patients with ovarian malignancies had metastatic ovarian cancer. Webb et al 10 reported that metastatic ovarian tumors accounted for 28% of 1,285 cases of malignant ovarian tumors. On the other hand, Yada- Hashimoto et al, 11 Santesson et al, 12 and Ulbright et al 13 reported the incidence of ovarian metastasis to be 21.1%, 6%, and 7%, respectively. The diagnosis of a metastatic tumor is often missed by the pathologist because the existence of a concurrent or prior tumor in another organ is either unknown or disregarded. 14 In some cases a search for an extraovarian primary tumor must be conducted postoperatively based on the pathologist s suspicion that the ovarian tumor is metastatic In the present study primary malignancies were detected first in 44% of the patients and simultaneously with ovarian metastasis in 35.3% of the cases. In 31 patients (20.6%) an ovarian mass was the first manifestation of disease. In this series study, the average age of patients with metastatic ovarian cancer was 51 years. The mean age of patients with metastatic ovarian cancer is approximately 10 years lower than that of patients with primary ovarian cancer. 1,2 According to the available data, patients with metastatic ovarian cancer are typically younger than those with malig-

6 246 Alvarado-Cabrero et al nant ovarian tumor of epithelial origin. This is attributed to the greater vascularity of the ovaries prior to menopause. 15 In our series 59% of the cases were from the gastrointestinal tract; colorectal cancer was the most common primary tumor (30%), followed by stomach cancer (16%). Our data are consistent with the findings of Lee et al, 9 who found in their series that > 70% of ovarian metastases were from the gastrointestinal tract, 41% from the colon, and 30% from the stomach. The ovaries have been recognized for many decades as an anatomic site prone to involvement by metastatic carcinoma and by metastatic colorectal carcinoma in particular. Among women diagnosed with colorectal adenocarcinoma, 3.4% are found to have ovarian involvement by metastatic disease at some point in their clinical course. 16,17 There are geographic variations in incidence of secondary ovarian tumors which can be explained by variable prevalence of certain primary malignancies. 2,7,9 In a study in Japan, metastatic ovarian cancer was identified in as high as 40% of all ovarian neoplasms. This could be explained by the fact that, regionally, stomach cancer is the most common cancer in that country. 18,19 The designation of Krukenberg tumor is often used loosely for any metastatic carcinoma within the ovary, and this is to be avoided. 5 The term should be reserved for those metastatic adenocarcinomas with > 10% component of signet ring cells and no evidence of another specific diagnosis, such as clear cell carcinoma or any other primary neoplasm that rarely has signet ring cells. 20 In this series Krukenberg tumor accounted for 23% of metastatic ovarian tumors. The primary tumor was most frequently located in the stomach (75%). Woodruff and Novak 21 reported that Krukenberg tumor accounted for 2.8% (48/1,700) of metastatic ovarian tumors, and 40% (19/48) of Krukenberg tumors originated from gastric cancer. Ovarian metastases are bilateral in around 70% of the cases. 18,21 In this series 57% of patients were found to have bilateral ovarian metastasis. A similar rate of bilateral involvement (54.5%) was observed by Lee et al. 9 On the other hand, Robboy et al 22 reported a rate of bilateral ovarian involvement of 88%. The history of a tumor outside the ovary with certain features of a primary tumor at the extraovarian site, and a resemblance to the ovarian tumor, is the most straightforward clue to the metastatic nature of an ovarian tumor. 21 However, metastatic tumors can be confused with primary tumors of the ovary, most likely due to the fact that the tumors histopathologically similar to primary ovarian tumors most commonly metastasize to the ovary. In general, especially with mucinous carcinomas but not exclusively, features favoring a metastatic rather than a primary ovarian neoplasm, especially if present in constellation, include bilateral ovarian involvement, relatively small size, nodular pattern of ovarian involvement, microscopic surface deposits of tumor, marked lymphovascular invasion (especially in the ovarian hilum), and extraovarian spread, among others. An algorithm has been proposed to assist diagnosis, in which all bilateral mucinous and those unilateral tumors < 10 cm are classified as metastatic carcinomas, whereas unilateral tumors 10 cm are classified as primary ovarian mucinous carcinomas. 23 In our series the proposed algorithm correctly classified metastatic tumors in 82% of about 90 metastatic mucinous adenocarcinomas, similar to results in the Khuramornpong et al 24 series, in which the algorithm correctly classified primary and metastatic tumors in 84% of 68 cases. These findings showed that the size of the neoplasm is a useful discriminator between a primary and secondary mucinous carcinoma; however, it is important to note that size alone is not a reliable parameter in distinguishing between a primary and secondary carcinoma in the ovary since metastatic colorectal and endocervical carcinomas provide the greatest number of exceptions to the criteria. 25 Mimicry of a primary mucinous tumor by a metastasis is a well know phenomenon. It should be borne in mind that many metastatic mucinous carcinomas involving the ovary contain morphologically bland foci resembling benign and borderline mucinous cystadenoma, a so-called maturation phenomenon. 5,6,20 In this series adenocarcinomas of the pancreas, biliary tract, appendix, and uterine cervix most commonly metastasized to the ovary, resembling a primary mucinous carcinoma. On the other hand, 62% of metastatic colorectal adenocarcinomas mimicked a primary ovarian endometrioid adenocarcinoma since they had minimal intracytoplasmic mucin; however, the presence in most of them of dirty necrosis, segmental necrosis, and a garland-like growth pattern favored a metastatic colorectal adenocarcinoma. Also in this series, 3 patients (2%) were found to have metastasis from endometrial carcinomas.

7 Volume 35, Number 5/October 2013 Metastatic Ovarian Tumors 247 Criteria have been established for determining whether these tumors represent independent primaries or metastasis. The presence of deep myometrial invasion, lymphovascular space invasion in the myometrium or ovary, and the absence of ovarian endometriosis are features favoring metastatic involvement of the ovary. 5,6 Although the appearances of metastatic tumors vary widely depending on the origin and morphology of the parent tumor, in this report we found some general features that suggested to the pathologist the possibility of metastasis: 17.3% of the cases had a nodular distribution with evidence of surface deposits; 46 tumors (30.6%) had a heterogeneous appearance; and the presence of vascular invasion and single cell infiltration was seen in 41.3% and 14.6% of cases, respectively. Moreover, the finding of tumor at another site is also very helpful information in suggesting a metastatic tumor as most primary mucinous carcinomas are Stage I. 6,25 All patients in this study had extraovarian disease at presentation. When the characteristic gross and microscopic distinguishing features are lacking between primary ovarian carcinomas and metastatic adenocarcinomas, immunohistochemistry may be very useful. Immunoreactivity with antibodies against CK 7 and CK 20 was seen in 42% and 100%, respectively, of metastatic colorectal adenocarcinomas. Immunostains for CK 7 and CK 20 have been studied extensively in the distinction between colorectal (CK7 /CK20+) and ovarian primaries (CK7+/ CK20 or CK20+). There is some degree of overlap, however, and a panel of stains should be used. 26 In summary, metastatic tumors are an important group of ovarian neoplasms (15.7%), occurring more frequently in younger patients compared to primary malignancies. 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8 248 Alvarado-Cabrero et al records. Obstet Gynecol 1968;32: Young RH: From Krukenberg to today: The ever present problems posed by metastatic tumors in the ovary: Part I. Historical perspectives, general principles, mucinous tumors including the Krukenberg tumor. Adv Anat Pathol 2006;13: Woodruff JD, Novak ER: The Krukenberg tumor: Study of 48 cases from the ovarian registry. Obstet Gynecol 1960;15: Robboy SJ, Scully RE, Norris HJ: Carcinoid metastatic to the ovary: A clinicopathologic analysis of 35 cases. Cancer 1979; 33: Seidman JD, Kurman RJ, Ronnet 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: Khunamornpong S, Suprasert PS, Pojchamarnwiputh S, Na Chiangmai W, Settakorn J, Siriaunkgul S: Primary and metastatic mucinous adenocarcinomas of the ovary: Evaluation of the diagnostic approach using tumor size and laterality. Gynecol Oncol 2006;101: Lerwill M, Young RH: Mucinous tumors of the ovary. Diagn Histopathol 2008;14: McCluggage WG: Recent advances in immunohistochemistry in gynaecological pathology. Histopathology 2002;40: