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Primary Management of an Extremely Large, Invasive Mucinous Ovarian Adenocarcinoma   
Lisa N. Abaid, M.D., M.P.H.1, Nazila Zekry, M.D.2, Amir Ronaghi, M.D.3, Bram H. Goldstein, Ph.D.1
Gynecologic Oncology Associates, Hoag Cancer Center, Newport Beach, CA 926631, Hoag Memorial Hospital Presbyterian, Department of Pathology, Newport Beach, CA 926632, Memorial Care Imaging Center at Orange Coast, Fountain Valley, CA3 .


Contact address: Bram H. Goldstein, Ph.D., Gynecologic Oncology Associates, 351 Hospital Road, Suite 507, Newport Beach, CA 92663.
Tel: (949) 642-5165
Fax: (949) 646-7157
Email: bram@gynoncology.com

Request for reprints: Bram Goldstein, Ph.D., Gynecologic Oncology Associates, 351 Hospital Road, Suite 507, Newport Beach, CA 92663.




Abstract
Mucinous tumors are typically benign lesions although they can be aggressive and exhibit stromal invasion. Studies have reported on extremely large mucinous ovarian malignancies that have invaded the abdomen and pelvis.  We describe the history of a 52 year-old woman who presented with a 40 cm mucinous ovarian neoplasm that weighed nearly 22 kg.  This is one of the largest cases of mucinous ovarian adenocarcinoma reported in the literature. Mucinous ovarian tumors are often associated with a favorable prognosis although when they are extremely large, disease management can be relatively precarious because of the potential for cardiovascular and intraoperative complications. 

Keywords mucinous ovarian tumors; large abdominal mass; patient management













Introduction
Mucinous tumors exhibit intra-cytoplasmic mucin and originate from surface epithelium and stroma [1]. These lesions are composed of distinct, histologic variants, including benign mucinous cystadenoma, mucinous tumors of low malignant potential, and invasive mucinous carcinoma [2]. Invasive mucinous tumors have a particularly aggressive disposition and feature small glands, nests or individual cells that theoretically coincide with extensive stromal invasion [3]. 
Clinically, invasive mucinous carcinomas are frequently evaluated within the context of their presenting characteristics, namely bilaterality, stage at diagnosis, potential for lymphatic dissemination and elevated serum tumor levels [3, 4]. When distinguishing between primary and metastatic mucinous neoplasms, size and laterality can be determining factors [4]; primary tumors tend to be larger and unilateral, compared with metastatic lesions, which have a proclivity for the gastrointestinal tract, pancreas, cervix, breast, and uterus [5].
Mucinous ovarian malignancies can be decidedly large at presentation and occupy the entire abdominopelvic cavity [1, 2, 6, 7]. Select, reported cases have documented lesion sizes ranging from 22-26 cm in diameter, some of which exceeded 15 kg [8].  In the current study, we report on the history and management of a woman diagnosed with an immense, complex and cystic mass that was revealed to be invasive, mucinous ovarian cystadenocarcinoma. 
Case Report 
A 52 year-old, nulligravid woman presented with significant pelvic pain and abdominal distension to the Emergency Room in July 2017. An ultrasound revealed a large, right-sided complex mass concerning for an ovarian carcinoma (Figure 1). Her preoperative CA-125 was 75 U/mL, CA-19-9 was 643 U/mL and CEA was 2.9 ng/mL. The patient�s medical history was significant for type II diabetes.
In August 2017, the patient underwent a total abdominal hysterectomy with bilateral salpingo-oophorectomy, infra-colic omentectomy, bilateral pelvic lymph node dissection, right para-aortic lymph node dissection, and complete surgical debulking. Intraoperatively, a cystic and solid mass containing thick, mucinous material was encountered; thereafter, the intact mass was extracted through the incision with no spillage into the abdominal cavity. Hemostasis was attained with an estimated blood loss of 250 mL. The patient tolerated the procedure well and no intraoperative complications were observed. 
The ovarian mass, which measured 40 x 35 x 30 cm (Figure 2) and weighed 21.5 kg, was submitted for frozen section. Frozen section diagnosis indicated invasive adenocarcinoma and immuno-histochemical staining demonstrated that the malignant cells were positive for pancytokeratin, p53, PAX 8 and CK7; the final pathologic diagnosis revealed a stage IIIA, poorly differentiated, invasive mucinous adenocarcinoma (Figure 3). Ovarian surface involvement and noninvasive implants were absent; the pelvic and para-aortic lymph nodes were negative for malignancy.
Postoperatively the patient is doing well with limited follow-up. In September 2017, she commenced six cycles of intravenous paclitaxel (80 mg/m2) on days 1, 8, and 15 of a 21-day cycle and carboplatin (AUC 6) on day 1. Her gastrointestinal tract was evaluated with an upper endoscopy and colonoscopy, which excluded a primary gastrointestinal malignancy. 
Discussion
Invasive mucinous ovarian adenocarcinomas are very rare and comprise less than 2% of surface epithelium ovarian malignancies [9]. The neoplasm�s precise incidence may be confounded by the varying appearance of metastatic mucinous adenocarcinoma, which is potentially misclassified as the primary disease [4]. Primary mucinous adenocarcinomas of the ovary are usually large, unilateral, smooth and viscous masses [10, 11]; additionally, they are typically diagnosed at an earlier age and characterized by an expansile growth or complex papillary pattern with attendant, luminal necrosis [12].
Metastatic mucinous adenocarcinoma is often bilateral with a multinodular, external surface [13]. The neoplasm ranges from entirely solid to multi-cystic. However, there is some difficulty in assessing large mucinous tumors, especially via frozen section [14]. Hence, when attempting to confirm the diagnosis, representative immuno-histochemical staining (e.g., pancytokeratin, p53, CK7 and PAX 8) and judicious clinical judgment are essential. Moreover, when affirming the presence of metastatic disease, one may scrutinize the presence of ovarian capsular implants, vascular invasion, and infiltrative, glandular growth [4, 15]. 
We present the unusual history of a woman who presented with a 21.5 kg invasive mucinous adenocarcinoma of the ovary that measured 40 cm in diameter. Previous studies have reported on large mucinous ovarian tumors although rarely have they approached the size of the patient in the current study. Jagtap et al. documented the management of a 26 cm mucinous cystadenocarcinoma of the ovary that weighed 9.5 kg [1]. Similarly, Forster et al. [7] described their experience with a 26 cm, borderline mucinous ovarian tumor that was 3.9 kg. A further review of the literature revealed a patient with a 50.75 kg mucinous ovarian carcinoma, which was metastatic to the coxa and femur [2].
	Initially, primary mucinous ovarian carcinomas are treated with surgical debulking and staging. Adjuvant chemotherapy presumably accords some clinical benefit and consistent with the Gynecologic Oncology Group/Gynecologic Cancer Intergroup Study [16], we utilized carboplatin and paclitaxel with our patient; alternatively, bevacizumab, oxaliplatin and capecitabine have been evaluated in the management of this disease [3]. 
Conclusion
Patients with mucinous ovarian carcinoma generally have a favorable prognosis [12]. However, when these neoplasms present with increased size, they are increasingly difficult to manage due to the attendant risk for cardiovascular and intraoperative complications [2, 8]. Ultimately, since primary mucinous ovarian neoplasms present significant diagnostic and clinical difficulties, histopathology may be essential to determining the appropriate management for this disease [1]. Additional investigation that further evaluates the precise manner in which to diagnose and treat mucinous ovarian carcinomas is warranted.
Compliance with Ethical Standards
All authors deny any conflicts of interest
Acknowledgement 
This study was supported by the Women�s Cancer Research Foundation. 
References
1. Jagtap SV, Dhawan SD, Jagtap SS, Kshirsagar NS (2014) Mucinous cystadenocarcinoma of the ovary presenting as a giant pelvic-abdominal mass. Int J Med Sci Public Health 3: 1305-7.
2. Nakamura M, Saitoh M, Miyamoto S, Kubo Y, Tomita H, Andoh A (2005) Case of a giant mucinous ovarian carcinoma with bone metastasis. J Obstet Gynaecol Res 31:576-8.
3. Brown J, Frumovitz M (2014) Mucinous tumors of the ovary: current thoughts on diagnosis and management. Curr Oncol Rep 16:389.
Forster A, Samaras N, Graf C, Tille JC, Samaras D (2013) Giant mucinous ovarian tumor. Am J Med Sci 345:400.
4. Seidman JD, Kurman RJ, Ronnett BM (2003) Primary and metastatic mucinous adenocarcinomas in the ovaries: incidence in routine practice with a new approach to improve intraoperative diagnosis. Am J Surg Pathol 27:985�993.
5.  HYPERLINK "https://www.ncbi.nlm.nih.gov/pubmed/?term=Rouzbahman%20M%5BAuthor%5D&cauthor=true&cauthor_uid=25583738" Rouzbahman M,  HYPERLINK "https://www.ncbi.nlm.nih.gov/pubmed/?term=Chetty%20R%5BAuthor%5D&cauthor=true&cauthor_uid=25583738" Chetty R (2015) Republished: mucinous tumours of appendix and ovary: an overview and evaluation of current practice. Postgrad Med J 91:41-5.
6. Katke RD (2016) Giant mucinous cystadenocarcinoma of ovary: A case report and review of literature. J Midlife Health 7:41-4.
7. Forster A, Samaras N, Graf C, Tille JC, Samaras D (2013) Giant mucinous ovarian tumor. Am J Med Sci 345:400.
8. Kim YT, Kim JW, Choe BH (1999) A case of huge ovarian cyst of 21-year-old young woman. J Obstet Gynaecol Res 25:275-9.
9. Heintz AP, Odicino F, Maisonneuve P, Quinn MA, Benedet JL, Creasman WT, et al (2006) Carcinoma of the ovary. FIGO 26th Annual Report on the Results of Treatment in Gynecological Cancer. Int J Gynaecol Obstet 95:S161-92.
10. Lee KR, Young RH (2003) The distinction between primary and metastatic mucinous carcinomas of the ovary: gross and histologic findings in 50 cases. Am J Surg Pathol 27:281�292.
11. Guerrieri C, H�gberg T, Wingren S, Fristedt S, Simonsen E, Boeryd B (1994) Mucinous borderline and malignant tumors of the ovary. A clinicopathologic and DNA ploidy study of 92 cases. Cancer 74:2329�2340.
12. Simons M, Ezendam N, Bulten J, Nagtegaal I, Massuger L (2015) Survival of Patients With Mucinous Ovarian Carcinoma and Ovarian Metastases: A Population-Based Cancer Registry Study. Int J Gynecol Cancer 25:1208-15.
13. Boger-Megiddo I, Weiss NS (2005) Histologic subtypes and laterality of primary epithelial ovarian tumors. Gynecol Oncol 97:80�3.
14. De Decker K, Speth S, Ter Brugge HG, Bart J, Massuger LFAG, Kleppe M, et al (2017) Staging procedures in patients with mucinous borderline tumors of the ovary do not reveal peritoneal or omental disease. Gynecol Oncol 144:285-289. 
15. Jung ES, Bae JH, Lee A, Choi YJ, Park JS, Lee KY (2010) Mucinous adenocarcinoma involving the ovary: comparative evaluation of the classification algorithms using tumor size and laterality. J Korean Med Sci 25:220-5.
16. Frumovitz M, Schmeler KM, Malpica A, Sood AK, Gershenson DM (2010) Unmasking the complexities of mucinous ovarian carcinoma. Gynecol Oncol 117:491�6.

Figure 1. Ultrasound demonstrates a 35 cm complex cystic lesion with several solid nodular components, largest measuring 6.2 cm in diameter.� Flow within the solid component is noted.
Figure 2. Gross photograph of the mucinous ovarian cystadenocarcinoma
Figure 3a. The tumor is well differentiated with an expansile pattern and area exhibiting villus architecture that resembles a borderline tumor.
Figure 3b. The epithelium lining the cysts is proliferative and highly atypical, with acute inflammation and necrotic debris present in the lumen.


 











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                                                                                                                       Abaid et al.                                                                                              




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