Taiwanese Journal of Obstetrics & Gynecology 54 (2015) 201e203

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Taiwanese Journal of Obstetrics & Gynecology

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Research Letter Advanced endocervical adenocarcinoma metastatic to the ovary presenting as primary ovarian cancer

Hsu-Dong Sun a, b, Sheng-Mou Hsiao a, Yi-Jen Chen b, c, Kuo-Chang Wen b, c, Yiu-Tai Li d, 1, * Peng-Hui Peter Wang b, c, e, f, g, , 1 a Department of Obstetrics and Gynecology, Far Eastern Memorial Hospital, New Taipei City, Taiwan b Department of Obstetrics and Gynecology, National Yang-Ming University School of Medicine, Taipei, Taiwan c Division of Gynecology, Department of Obstetrics and Gynecology, Taipei Veterans General Hospital, Taipei, Taiwan d Department of Obstetrics and Gynecology, Kuo General Hospital, Tainan, Taiwan e Immunology Center, Taipei Veterans General Hospital, Taipei, Taiwan f Department of Nursing, National Yang-Ming University School of Nursing, Taipei, Taiwan g Department of Medical Research, China Medical University Hospital, Taichung, Taiwan article info

Article history: A 54-year-old menopausal woman (G3P3) visited the emer- Accepted 21 October 2014 gency room due to acute sudden onset of abdominal pain after several weeks of abdominal fullness. Her past medical history was unremarkable. She did not have any Pap smears since the birth of her last child (28 years previously). Physical examination revealed a protuberant and tense abdomen, but the cervix was essentially normal. Transvaginal ultrasound revealed a 15 cm complex cystic mass lesion located at the right adnexal area accompanied with Dear Editor, massive ascites, but the uterus and the left ovary seemed to be normal. Computed tomography identified and confirmed the above Cervical squamous cell carcinoma (SCC) and adenocarcinoma finding (Fig. 1). Serum tumor markers, including CA 125, CA 199, may involve the ovary. Although it is not difficult to diagnose in and CEA were 286.0 U/mL, 209.0 U/mL, and 226.0 ng/mL, respec- most cases, on very rare occasions the presentation may show tively. Other investigations, including hematological and symptoms related to an ovarian mass, with the cervical cancer biochemical tests, a chest X-ray, and upper and lower gastrointes- being undetected, especially endocervical adenocarcinoma [1,2]. tinal (GI) tract evaluations were within normal limits. This is important because the challenge of diagnosing primary Under the diagnosis of ovarian malignancy, the patient under- endocervical adenocarcinoma occurs especially in women who went a laparotomy. During surgery, a right ovarian cystic complex show no symptoms, and have a grossly normal cervix and a mass with a mucinous component (Fig. 2) accompanied with negative Pap smear [3]. The spread of cervical malignancy (both massive ascites (7000 mL) and peritoneal carcinomatosis was SCC and adenocarcinoma) is often through lymphatic drainage or found. The immediate frozen pathology report favored a diagnosis direct invasion [4]; except some reports show that endocervical of adenocarcinoma-mucinous type. Therefore, the patient under- adenocarcinoma carries a higher risk of ovarian metastases than went an optimal debulking surgery, including total hysterectomy SCC of the cervix [5]. There is an apparent difference in the treat- (Fig. 3), bilateral salpingo-oophorectomy, infracolic omentectomy ment strategy for advanced cervical cancers and ovarian cancers and retroperitoneal lymph node sampling, and multiple biopsies. [6,7]. Therefore, making an accurate diagnosis before planning However, the final pathologic report was primary uterine endo- therapy is of paramount importance. The following is a case report cervical adenocarcinoma. of advanced cervical adenocarcinoma metastatic to the ovary Pathologic features included hyperchromatic dysplasia of the mimicking primary ovarian cancer. mucinous glandular cells of the uterine endocervix; the mucinous tumor occupied the whole layer of the endocervix and extended to the lower segment of the uterine body. Other sections of the right * Corresponding author. Division of Gynecology, Department of Obstetrics and ovary, appendix, omentum, abdominal wall, and mesentery all Gynecology, Taipei Veterans General Hospital, and National Yang-Ming University showed tumor metastases with floating mucinous tumor cells School of Medicine, 201, Section 2, Shih-Pai Road, Taipei, Taiwan. within an extensive mucin pool. E-mail addresses: [email protected] (Y.-T. Li), [email protected], [email protected] (P.-H.P. Wang). The patient was treated with adjuvant systemic chemotherapy 1 Drs. Li and Wang contributed equally to this article. (8 cycles of topotecan [Hycamtin Injection, GlaxoSmithKline, San http://dx.doi.org/10.1016/j.tjog.2014.10.005 1028-4559/Copyright © 2015, Taiwan Association of Obstetrics & Gynecology. Published by Elsevier Taiwan LLC. All rights reserved. 202 H.-D. Sun et al. / Taiwanese Journal of Obstetrics & Gynecology 54 (2015) 201e203

Fig. 3. Uterus specimen shows tumor invasion to the whole thickness of the uterine cervix.

can accurately classify a substantial majority of tumors [8].In addition, the concept is that gynecological organ-related diseases should always be kept in mind with women presenting with ascites and adnexa masses, regardless of size status, accompanied with Fig. 1. Computed tomography showing a 15 cm circumscribed, oval, and heteroge- massive ascites [10,11]; therefore, the tendency to diagnose pri- neously hypodense mass with a moderately enhancing solid component. mary ovarian cancer is always made, as with our current case, based on its relatively high prevalence compared with other possibilities. Polo di Torrile, Parma, Italy], plus cisplatin [Abiplatin Injection, Yemelyanova and colleagues [12] reported that violations of these Pharmachemie B.V. for TEVA Pharma B.V., Haarlem, The rules occurred most frequently with pancreatic, small and large Netherlands]), and was still alive at 15 months after the initial bowel, and endocervical primary tumors, as these can give rise to operation. This case report is of educational value to clinicians, for metastatic tumors that are large, unilateral, and often cystic masses. the following reasons. Furthermore, a gross cystic, solid, or mixed cystic and solid Firstly, although secondary ovarian malignancies are not rare, appearance can be seen in borderline, primary mucinous carci- the diagnosis is still challenging. The most likely metastatic tumors noma, and metastatic ovarian tumors and does not help to distin- mimicking primary ovarian mucinous tumors are those of the GI, guish between them [8]. pancreatic or biliary tract, and endocervical adenocarcinomas [8,9]; Thirdly, the extent of disease may be helpful in differentiating fi our current case report ts into this grouping. The woman in the between primary and metastatic mucinous tumors [9]. Most pri- current case had no apparent symptoms and also had a negative mary mucinous ovarian carcinomas are usually early FIGO stage (I cytological screening test (a negative Pap smear), all of which and II) at presentation [13,14]. Further information includes a contributed to the delayed diagnosis. smooth surface with no excrescences or surface implants [8]. Secondly, it is widely accepted that a simple algorithm using Pathological features may be useful in making a distinction. Find- tumor size and laterality (bilateral tumors of any size, or unilateral ings favoring a secondary ovarian tumor include: (1) an infiltrative < ¼ ¼ tumor 10 cm metastatic; unilateral tumor 10 cm primary) invasion pattern; (2) small glands or tubules and single cells; (3) lymphovascular space invasion; (4) a nodular growth pattern of infiltrating tumor with intervening ovarian tissue containing normal ovarian structures, often with stromal desmoplasia; (5) hilar involvement; (6) microscopic surface invasion; and (7) the presence of signet ring cells [8]. By contrast, features favoring a primary ovarian tumor include: (1) an expansible invasion pattern with a back-to-back neoplastic gland without intervening stroma; (2) complex papillary patterns: (3) mural nodules with solid areas of a cyst wall containing an anaplastic carcinoma or sarcoma component; (4) background endometriosis; and (5) association with primary ovarian sex -cord or germ cell tumor [8]. Even with the assistance of pathologic evaluation, and especially during frozen pathology, many cases are still considered to be primary ovarian cancers. Recent evidence supports the possible role of informative immunohistochemistry in distinguishing primary from secondary mucinous ovarian cancers [15e17]. McCluggage [17] extensively reviewed the topic of the use of immunohistochemistry to distin- guish between primary and metastatic ovarian mucinous neo- Fig. 2. A complex cystic right ovarian mass with a mucinous component. plasms. Immunohistochemical analysis of primary ovarian H.-D. Sun et al. / Taiwanese Journal of Obstetrics & Gynecology 54 (2015) 201e203 203

Table 1 Frequently used immunohistocytologic markers of primary and secondary ovarian mucinous carcinomas.

Tumors Primary Secondary

Markers Intestinal Mullerian Colorectal Pancreatic Biliary Gastric Cervical

CK7 þ/þþ þþ Neg þ/þþ þ/þþ þ/þþ þþ CK20 þ/þþ Neg þþ Neg/þ Neg/þ Neg/þ Neg/þ CDX2 þ Neg þþ þ þ þ Neg/þ CA 125 Neg þþ Neg þ/þþ þ/þþ Neg þþ CA 19-9 þþ Neg/þþþþþþþþþNeg CEA þ/þþ Neg þþ þ/þþ þ/þþ þ/þþ þ/þþ p16 Neg Neg Neg/þ Neg Neg Neg þþ ER Neg þþ Neg Neg Neg Neg Neg/þ DPC4 þþ þþ þþ þ/þþ þ/þþ þþ þþ PAX8 þþ þþ Neg Neg Neg Neg Neg/þ

þ¼focal positive; þþ ¼ diffuse positive; CK ¼ cytokeratin; CDX2 ¼ nuclear transcription factor CDX2; CA ¼ carbohydrate antigen; CEA ¼ carcinoembryonic antigen; DPC4 ¼ nuclear transcription factor DPC4; Neg ¼ negative; PAX8 ¼ paired box transcription factor 8. mucinous neoplasms demonstrates CK7 reactivity, but metastatic References ovarian tumor from the lower GI tract is often positive to CK20. In addition, since human papilloma virus (HPV) is absent or only [1] McCluggage WG, Wilkinson N. Metastatic neoplasms involving the ovary: a review with an emphasis on morphological and immunohistochemical fea- rarely detected in primary ovarian neoplasia (more than 90% of tures. Histopathology 2005;47:231e47. cervical adenocarcinomas of “usual” histological type are HPV [2] Khor TS, Brennan BA, Leung YC, Sengupta S, Stewart CJ. Cervical adenocarci- positive), if the diagnosis is challenged, a HPV test could be tried in noma metastatic to the ovary mimicking primary ovarian carcinoma. Pa- thology 2009;41:397e400. our current case. Finally, we list the frequently used markers in [3] Sun L, Wang PH, Lee CH, Fu TF, Chou MM, Ke YM, et al. Clinical parameters Table 1, and these markers could provide additional information to associated with absence of endocervical/transformation zone component in help diagnosis. conventional cervical Pap smear. Taiwan J Obstet Gynecol 2015 [in press]. We may attempt to use tumor markers to distinguish primary [4] Wang PH, Chang YH, Yang YH, Chang WH, Huang SY, Lai CR, et al. Outcome of patients with bulky IB ( 6 cm) cervical squamous cell carcinoma with and from secondary, but the value is limited, since CA 125, CA 19-9, and without cisplatin-based neoadjuvant chemotherapy. Taiwan J Obstet Gynecol CEA levels might be elevated in both conditions. A recent publica- 2014;53:330e6. tion from Japan proposed new predictive algorithms for diagnosing [5] Elishaev E, Gilks CB, Miller D, Srodon M, Kurman RJ, Ronnett BM. Synchronous and metachronous endocervical and ovarian neoplasms: evidence supporting primary and metastatic mucinous carcinomas of the ovary, interpretation of the ovarian neoplasms as metastatic endocervical adeno- including a combination of tumor size, patient age, serum CA19-9 carcinoma simulating primary ovarian surface epithelial neoplasms. Am J Surg e and serum CA 125, which provided more accurate pre- and intra- Pathol 2005;29:281 94. [6] Huang BS, Sun HD, Hsu YM, Chang WH, Horng HC, Yen MS, et al. Clinical operative diagnoses [18]; however, this approach also failed to help presentation and outcome of adult-type granulosa cell tumors: A retrospec- in our reported case. Radiological examinations, such as ultrasound tive study of 30 patients in a single institute. J Chin Med Assoc 2014;77:21e5. and computed tomography, added little information about this [7] Wiebe E, Denny L, Thomas G. Cancer of the cervix uteri. Int J Gynaecol Obstet 2012;119(Suppl. 2):S100e9. patient, because she presented with an ovarian cystic mass lesion [8] Leen SL, Singh N. Pathology of primary and metastatic mucinous ovarian accompanied with massive ascites. neoplasms. J Clin Pathol 2012;65:591e5. Finally, our current patient could be considered as an accidental [9] Sun HD, Tsai CC, Hsiao SM, Wei MC, Wang KC, Wang PH. Primary gallbladder carcinoma presenting as advanced-stage ovarian cancer. Taiwan J Obstet diagnosis of far-advanced cervical cancer (FIGO Stage IV). Although Gynecol 2012;51:443e5. surgery might not be the treatment of choice, the patient was [10] Horng HC, Teng SW, Lai CR, Chang WH, Chang YH, Yen MS, et al. Prognostic treated with immediate postoperative adjuvant systemic chemo- factors of primary fallopian tube cancer in a single institute in Taiwan. Int J e therapy of eight cycles of topotecan plus cisplatin with a 15-month Gynecol Obstet 2014;127:77 81. [11] Lai CR, Yen MS, Wang PH. Neoplasm in the trocar site and peritoneal papillary disease-free survival, suggesting that this strategy in the manage- serous cystadenocarcinoma. Taiwan J Obstet Gynecol 2014;53:139e40. ment of patients in a similar situation could be considered. How- [12] Yemelyanova AV, Vang R, Judson K, Wu LS, Ronnett BM. Distinction of primary ever, a recent report from the University of Texas Southwestern and metastatic mucinous tumors involving the ovary: analysis of size and laterality data by primary site with reevaluation of an algorithm for tumor Medical Center suggested that surgical evaluation of adnexal classification. Am J Surg Pathol 2008;32:128e38. masses in patients with cervical cancer can be considered to opti- [13] Wang PH, Yuan CC, Juang CM, Lai CR, Yen MS, Chao HT, et al. Primary mize treatment outcomes, since the authors found that 23% of epithelial ovarian carcinoma in Taiwanese women. Eur J Gynecol Oncol 2001;22:57e60. surgically managed patients and 57% of conservatively managed [14] Wang PH, Yuan CC, Shyong WY, Chiang SC, Chao JY, Yen MS, et al. Optimal patients had disease recurrence (p ¼ 0.05), but the authors also debulking surgery seems to be an independent prognostic factor in patients suggested that patients with cystic masses less than 8 cm and with FIGO IIIC primary epithelial ovarian carcinoma. J Chin Med Assoc 2000;63:220e5. complex masses less than 5 cm in size can be expectantly managed [15] Young RH. From Krukenberg to today: the ever present problems posed by [19]. Our patient had a 15 cm adnexa mass, suggesting that this metastatic tumors in the ovary. Part II. Adv Anat Pathol 2007;14:149e77. accidental removal of metastatic ovarian tumor secondary to [16] Young RH. From Krukenberg to today: the ever present problems posed by metastatic tumors in the ovary: part I. Historical perspective, general princi- endocervical adenocarcinoma was an acceptable choice, according ples, mucinous tumors including the Krukenberg tumor. Adv Anat Pathol to the above-mentioned report [19]. 2006;13:205e27. In conclusion, endocervical adenocarcinoma metastatic to the [17] McCluggage WG. Immunohistochemistry in the distinction between pri- ovary mimicking a primary ovarian tumor is still a challenge. Based mary and metastatic ovarian mucinous neoplasms. J Clin Pathol 2012;65: 596e600. on this report, effort should be made to minimize the risk of a [18] Maeda-Taniguchi M, Ueda Y, Miyake T, Miyatake T, Kimura T, Yoshino K, et al. delayed diagnosis of primary endocervical adenocarcinoma. Metastatic mucinous adenocarcinoma of the ovary is characterized by advanced patient age, small tumor size, and elevated serum CA125. Gynecol Obstet Invest 2011;72:196e202. Conflicts of interest [19] Nagel CI, Thomas SK, Richardson DL, Kehoe SM, Miller DS, Lea JS. Adnexal masses requiring surgical intervention in women with advanced cervical e The authors have no conflicts of interest relevant to this article. cancer. Gynecol Oncol 2014;134:552 5.