A young nulliparous woman with right ovarian serous borderline tumor and left ovarian micropapillary serous carcinoma

Introduction: serous borderline tumor (sbt) of low malignant potential (LMP) is heterogeneous group, neither wholly benign nor frankly malignant. It usually involves premenopausal age patients, has good prognosis and may recur even after 20 years. Decades later, transformation to low grade serous carcinoma can occur in 7%, mandating prolonged follow-up. ten and 20 years survival in stage I is 95% and 80% respectively. Micropapillary type and invasive tumor implants warrant treatment like carcinoma and need adjuvant chemotherapy. case report: We present the case of a 25-year-old nullipara, married for four years who had ovarian cystectomy one year back. she reported to our institute with massive ascites and failure of anti-tubercular treatment of three months. Diagnostic tap revealed cells Vinita Jaggi Kumar1, Dhruv Jain2, Asit Mridha3, Sidharth Nanda3, Jyotica Jain4, Rajesh Kumar Grover5 Affiliations: 1MBBS, MD, MRCOG, Department of Surgical oncology (Gynecological Oncology Division, Delhi State Cancer Institute (Govt. of NCT), Dilshad Garden, Delhi, India; 2MBBS, MD, Assistant Professor, Department of Onco Pathology, Delhi State Cancer Institute (Govt. of NCT), Dilshad Garden, Delhi, India; 3MBBS, MD, Assistant Professor, Clinical Oncology, Delhi State Cancer Institute (Govt. of NCT), Dilshad Garden, Delhi, India; 4MBBS, MD, Associate Professor, Clinical oncology, Delhi State Cancer Institute (Govt. of NCT), Dilshad Garden, Delhi, India; 5MBBS, MD, PGDHHM, Director, Radiation Oncology, Delhi State Cancer Institute (Govt. of NCT), Dilshad Garden, Delhi, India. Corresponding Author: Dr. Vinita Jaggi Kumar, Delhi State Cancer Institute (Govt. of NCT Delhi), Dilshad Garden, Delhi, India; Postal Code-110095; Ph: +91 9560390112; Fax: +9111-22110505; Email: drvinitakumar@yahoo.co.in Received: 16 November 2012 Accepted: 1 June 2013 Published: 01 September 2013 suggestive of metastatic adenocarcinoma. bilateral complex adnexal masses with ascites were seen on computed tomography (ct) scan. cA125 was 191 U/mL. thorough staging laparotomy i.e., inspection and palpation of abdomen and pelvic organs, ascitic fluid cytology, bilateral salpingo-oophorectomy, and bilateral pelvic and aortocaval lymph nodes sampling up to inferior mesenteric artery level, along with supracolic and infracolic omentectomy, and multiple peritoneal biopsies was carried out. Uterus was preserved. In our patient while right ovarian tumor was the benign type of sbt, the left ovarian tumor was the aggressive micropapillary type of sbt. conclusion: this case emphasizes the need of subclassification of serous borderline tumors showing a broad spectrum of clinical and biological behavior from benign to low grade carcinoma. We suggest that in patients of reproductive age with infertility and adnexal masses, despite malignant cells in ascites, serous borderline tumor should be kept as a differential diagnosis and conservative surgery be offered.

suggestive of metastatic adenocarcinoma. bilateral complex adnexal masses with ascites were seen on computed tomography (ct) scan. cA125 was 191 U/mL. thorough staging laparotomy i.e., inspection and palpation of abdomen and pelvic organs, ascitic fluid cytology, bilateral salpingo-oophorectomy, and bilateral pelvic and aortocaval lymph nodes sampling up to inferior mesenteric artery level, along with supracolic and infracolic omentectomy, and multiple peritoneal biopsies was carried out. Uterus was preserved. In our patient while right ovarian tumor was the benign type of sbt, the left ovarian tumor was the aggressive micropapillary type of sbt. conclusion: this case emphasizes the need of subclassification of serous borderline tumors showing a broad spectrum of clinical and biological behavior from benign to low grade carcinoma. We suggest that in patients of reproductive age with infertility and adnexal masses, despite malignant cells in ascites, serous borderline tumor should be kept as a differential diagnosis and conservative surgery be offered.

IntroDUctIon
Serous borderline tumors (SBT) of ovary are an enigmatic group which are neither wholly benign nor frankly malignant. They occur mostly in premenopausal age group, have favorable prognosis, with 10 years survival rate of nearly 95% for stage 1 tumors. They may recur even after 20 years, hence they are labeled as low malignant potential (LMP) tumors. About half of all LMP tumors are serous tumors [1]. Mean age of borderline serous tumors is 40 years, which is two decades earlier than invasive cancer. [2] According to FIGO and WHO, stromal invasion, defined as destructive infiltrative growth, is the sole criterion used to distinguish SBT from invasive serous carcinomas [2].
Furthermore, SBT have been subclassified into benign and malignant types according to their biologic behavior. Micropapillary serous carcinoma (MPSC) is a proliferative, serous, ovarian neoplasm, characterized by a micropapillary pattern. Though it lacks destructive infiltrative growth, yet it behaves as a low-grade invasive carcinoma, hence is more aggressive than a typical ovarian serous borderline tumor. They are also associated with extraovarian invasive peritoneal implants and more frequent recurrences than in typical ovarian serous borderline tumors. [3] In absence of invasive implants, MPSC does not imply unfavourable prognosis, and is much closer in its biologic behaviour to SBT than to serous carcinomas, hence it is retained in LMP category [4,5]. Typical SBT as well as those with noninvasive implants are placed at lower end of proliferative spectrum.
We present the case of a patient who presented with massive ascites and bilateral ovarian tumors who was taken up for laparotomy and on surgical staging was diagnosed as bilateral borderline ovarian tumors in stage 1C with typical non-invasive SBT in right ovary and more aggressive non-invasive micropapillary type SBT in left ovary.

cAsE rEPort
On 24th June 2010, a nulliparous female, aged 25 years, married for four years, presented with progressive abdominal distension due to massive ascites ( Figure 1). There was no history of fertility inducing drugs but one year back, she had undergone ovarian cystectomy in a private hospital, the details of which were not available. There was loss of appetite and weight but no history of hormone intake. She had hypomenorrhea. There were no signs and symptoms of bowel disturbance or any family history of cancer. On examination, she was emaciated with hugely protuberant abdomen due to ascites. There was mild bilateral pedal edema but no lymphadenopathy, or hepatosplenomegaly. Vague mass was palpable in suprapubic area. Perspeculum examination showed, normal cervix displaced backwards. On bimanual pelvic examination, uterus was not felt separately but incorporated in bilateral adnexal masses, which were felt through both fornixes. A large tumor about 6x5 cm, hard to feel was impacted in pouch of douglas. Rectal mucosa was smooth and mobile. Investigations revealed normal hepatic, renal and hematological profile. Preoperative serum Ca125 (marker for ovarian carcinoma) was 191 U/mL, CEA (colon carcinoma), CA19.9 (gallbladder and pancreatic carcinoma) and CA 72.4 (pancreatic and gastric carcinoma), b-hCG (germ cell tumor of ovary), AFP (hepatobiliary malignancy and germ cell tumor of ovary) were normal. Contrast computed tomography (CT) scan revealed huge ascites with bilateral, complex, solid cystic adnexal heterogeneous mass, which measured 8x10 cm on the right side and 7x8 cm on the left side. Uterus, liver, gallbladder, spleen, pancreas, both kidneys, bones and joints were normal. No significant retroperitoneal lymphadenopathy was seen. Computed tomography scan was suggestive of bilateral ovarian tumors with ascites.
First diagnostic ascitic fluid tap revealed clear yellow, serous fluid with atypical cell clusters suspicious of malignancy, while second tap was suggestive of metastatic adenocarcinoma ( Figure 2). Adenosine deaminase (ADA) test which is indicative of tubercular etiology was performed in the ascitic fluid. Its value was in the normal range, thus ruling out abdominal tuberculosis.
Upper gastrointestinal tract endoscopy revealed grade 1 esophageal varices, at the lower end at 3' O clock position. Stomach and duodenum were normal. Colonoscopy could not be done due to improper bowel preparation. Endometrial biopsy revealed secretory endometrium with no evidence of malignancy and PAP smear was normal.
On 25th July 2010, after informed consent the patient underwent staging exploratory laparotomy. Surgery included inspection and palpation of abdomen and pelvic organs, ascitic fluid cytology, bilateral salpingooophorectomy, bilateral pelvic and aortocaval lymph nodes sampling up to inferior mesenteric artery level, along with supracolic and infracolic omentectomy, and multiple peritoneal biopsies. Both the fallopian tubes were also removed, however, uterus was preserved.
Peroperatively, six liters of clear, straw colored ascitis. On gross appearance uterus was normal, no normal, ovary seen. The ovaries were replaced by ovarian tumors. The ovarian tumors were separate but together they were impacted in the pelvis. Moreover, the left ovarian tumor was adherent to the sigmoid mesentery. The plane of cleavage was maintained. Liver, under surface of diaphragm, abdominal and pelvic peritoneum, ileal mesentery, stomach, small and large intestines and omentum were normal. Left pelvic lymph nodes and para-aortic lymph nodes were palpable and enlarged and were thoroughly dissected, while on the right side they were not enlarged and were palpated to be normal. Hence, right nodes sided were only sampled.
Histopathology revealed right ovary to be 5.4x5.0 cm, multicystic with solid papillary fronds, without any breach of capsule ( Figure 3). Left ovary was 6.5x5.8 cm and similar to the right ovary ( Figure 3). Right ovarian tumor did not show any destructive stromal invasion. Mild nuclear atypia with low mitosis and psammoma bodies were seen (Figure 4). It was labeled as non-invasive serous borderline tumor, of typical type following WHO classification. While no stromal invasion was there in left ovarian tumor as well, there were foci of fused solid areas and occasional mitosis, in foci of >5 mm in length ( Figure  5). It was labeled as non-invasive SBT, micropapillary type (micropapillary serous carcinoma). Omentum, appendix, peritoneal biopsies, pelvic and para-aortic lymph nodes were devoid of metastasis or implants.
Immediate postoperative recovery was uneventful. Drain was kept until stitch removal on postoperative day-12 as there was substantial amount of fluid from the drain. Postoperatively her CA 125 was 5.89 U/mL. Subsequent to discussion with our clinical oncology team, decision of adjuvant chemotherapy, was taken to give, keeping in view the biologic behavior of micropapillary type of left ovarian tumor. Postoperative recovery was uneventful but after first cycle of chemotherapy she developed parietal wall abscess. The abscess burst through the surgical stitch line and drained massive amount of pus which tested sterile on culture. Tests for tuberculosis performed on the pus were negative. Wound was debrided and left to heal by secondary intention. After this initial delay, she uneventfully completed six cycles of three weekly chemotherapy with carboplatin and paclitaxel. Currently, she is disease free for one and half years with latest report of CA 125 of 4.32 U/mL and normal CT scans of abdomen and pelvis.

DIscUssIon
Micropapillary serous carcinoma (MPSC) is a proliferative, serous ovarian neoplasm which is without destructive infiltrative growth but still behaves as a lowgrade invasive carcinoma and hence considered as an in situ form of serous carcinoma [6]. In the absence of invasive implants, MPSC has favorable prognosis with   biologic behavior similar to serous borderline tumors [7,8].
Twenty-six cases of MPSC were identified in a review of 400 cases of ovarian SBT. None of the stage 1 patients had recurrence, but in higher stages 50% died of the disease. Twenty-four (92%) of MPSC cases were SBT associated. It was concluded that micropapillary type of SBT may progress to invasive carcinoma in some instances [8]. Drescher et al. studied significance of DNA content and nuclear morphology as prognostic factors to predict aggressiveness of borderline ovarian tumors and to guide adjuvant chemotherapy. [9] Clinical presentation of LMP tumors is with abdominal distension, pain, and pelvic mass which is same as that of malignant tumors. Young patients have associated infertility or pregnancy. History of infertility increases the risk of LMP tumors with odds ratio (OR) of 1.9, while use of infertility drugs has OR of 4. [10] In patients with serous borderline tumors, after ovarian cystectomy, 8-15% patients have recurrence in the ipsilateral or contra lateral ovarian tissue. Bilaterality or synchronous and metachronous tumors are common and seen in about 40% patients [10].
In our patient there was bilateral involvement of ovaries; the tumors in right and left ovary were separate. While right ovary had benign type of typical borderline serous tumor, the left ovary had noninvasive borderline serous tumor of micropapillary type, which as the literature suggests is a more aggressive subtype. Preoperatively ascitic fluid cytology did have malignant cells, however there were no implants detected in the peritoneal lining. About 80% of low malignant potential (LMP) tumors are diagnosed in stage 1. Some have extraovarian tumor implants on peritoneal surface of pelvis or abdomen or both. Though some consider these implants to represent metastasis, yet others consider them to represent synchronous extraovarian proliferations arising from surface coelomic epithelium as a result of multifocal field change. Spontaneous regression of extraovarian foci has been reported following resection of ovarian primary tumor. [11] These extraovarian tumor implants could be invasive or non-invasive. Serous borderline tumors with invasive implants and micropapillary type of ovarian serous borderline tumors are aggressive subgroups and are classified as carcinomas. They are associated with poor prognosis and are treated with adjuvant chemotherapy. [4,11] The LMP or borderline neoplasms have 10 years survival rate of 95% for stage 1 patients.
[2] Overall survival is 90-95% at 5 years and 80% at 20 years. In another study, disease-specific survival was >95% for patients with lowstage (stage I) tumors and approximately 65% for patients with highstage (stage II-IV) tumors.
Thus, although both the typical type of borderline serous tumors and micropapillary type of serous borderline tumors appear to be noninvasive histologically, the former tumor is benign, while the latter behaves like a low grade carcinoma. Poor prognosis for MPSC prompts clinicians to use adjunctive chemotherapy [4]. According to FIGO and WHO, stromal invasion defined as destructive infiltrative growth is the sole criterion used to distinguish SBT from invasive serous carcinomas. An aggressive subgroup of proliferative serous lesions with micropapillary projections are named as micropapillary serous carcinoma (MPSC). These tumors and SBT with invasive implants may be associated with malignant behavior [5].
Serous borderline tumors have a very favorable prognosis, but complete surgical staging and prolonged follow-up are advised because pelvic recurrence and occasionally transformation to invasive carcinoma may occur, albeit over delayed period of time. Designation of benign subgroup of SBTs as "atypical proliferative tumors" is not recommended because it discourages complete surgical staging and follow-up. Advanced stage tumors with noninvasive implants are common and behave in a benign fashion, and can be safely treated conservatively.
Although histologically ovarian MPSC lack stromal invasion and therefore are qualified by FIGO and WHO guidelines for inclusion in borderline category, clinically they behave more aggressively than typical serous borderline tumors. Hence, the SBTs associated with invasive implants and SBT-MPSC could behave as low grade carcinoma and their management should be seen in this light.
Various subtypes of serous borderline tumors are summarized in Table 1. [12]   concLUsIon We suggest, that in cases in reproductive age group with infertility and adnexal masses, despite presence of malignant cells in ascites we should keep serous borderline tumors in mind and offer conservative surgery.
Our case suggests that MPSC and typical type of SBT represent two ends of a broad spectrum of clinical and biologic behaviour seen in low malignant potential ovarian tumors. The MPSC are associated and probably arise from SBT and may account for few cases of SBT which progress to invasive carcinoma. There is the need of subclassification of serous borderline tumors. *********

Author contributions
Vinita Jaggi Kumar -Conception and design, Acquisition of data, Analysis and interpretation of data, Drafting the article, Final approval of the version to be published Dhruv Jain -Conception and design, Analysis and interpretation of data, Critical revision of the article, Final approval of the version to be published Asit Mridha -Acquisition of data, Drafting the article, Final approval of the version to be published Sidharth Nanada -Conception and design, Drafting the article, Final approval of the version to be published Jyotica Jain -Analysis and interpretation of data, Critical revision of the article, Final approval of the version to be published R K Grover -Conception and design, Critical revision of the article, Final approval of the version to be published