Case presentation: Dr Melis Canturk

A 27-year-old patient was referred to Koc University Hospital for evaluation of bilateral adnexal masses in August 2023. She had no notable medical or family history. Physical examination revealed a pelvic mass. Cancer antigen 125 (CA125) level was 125 U/mL, risk of ovarian malignancy algorithm (ROMA) score was 21.7%, and human epididymis protein 4 (HE4) level was 79.7 pmol/L. A pelvic ultrasound revealed bilateral multicystic adnexal masses measuring 8–9 cm in diameter, with suspicious papillary structures that demonstrated color score 2 in Doppler imaging, located on the cyst wall. Based on these findings, the pelvic mass was classified as an Ovarian-Adnexal Reporting and Data System (O-RADS) US Category 4 lesion. The upper abdomen CT scan revealed several lymph nodes in the para-aortic and inter-aortocaval regions, with the largest measuring 7 mm.

The patient was advised to undergo a laparotomy for the evaluation of the pelvic masses, with intra-operative frozen section analysis. It was explained that if intra-operative pathology evaluation indicated malignancy, a staging surgery would be performed. In the case of a borderline ovarian tumor, a fertility-sparing approach may be considered following a comprehensive assessment of the entire abdomen. The patient then underwent bilateral ovarian cystectomy, and intra-operative frozen sections of the ovarian cysts were reported as borderline ovarian tumors. Additionally, multiple implants over the pouch of Douglas peritoneum and the mesentery of the sigmoid colon were confirmed to be borderline ovarian tumor implants. The patient subsequently underwent omentectomy, appendectomy, and pelvic and para-aortic lymphadenectomy up to the renal vein due to suspicious lymph nodes observed on pre-operative imaging. The estimated operation time and blood loss were 180 min and 200 mL, respectively. There were no post-operative complications, and she was discharged on post-operative day 4.

Dr Nilgun Kapucuoglu: Please describe the findings on the final pathology

Final pathology identified a micropapillary variant of serous borderline ovarian tumor in both ovaries, with microinvasion at several sites and non-invasive epithelial implants in the pelvis, sigmoid colon, and bladder. Serous borderline ovarian tumor cells were also found in abdominal washing. Of a total of 41 lymph nodes removed, one was positive for metastasis of serous borderline ovarian tumor, and endosalpingiosis was detected (Figure 1). Immunohistochemical analysis showed positivity for the estrogen receptor and paired-box gene 8 (PAX-8).

Figure 1

Pelvic lymph node metastasis of serous borderline ovarian tumor from the first surgery (2023) (hematoxylin and eosin).

Dr Dogan Vatansever: How would you approach counseling this patient?

Borderline ovarian tumors, which account for approximately 10% of all epithelial ovarian tumors, are predominantly diagnosed at stage I in 80% of cases. Notably, one-third of these occur in young women who desire fertility preservation. Unlike invasive carcinomas, these tumors do not exhibit stromal invasion on histological examination and generally have a favorable prognosis. 1 2 However, 20–40% of cases are associated with non-invasive peritoneal implants and lymph node involvement. 1 Current literature provides mixed evidence regarding the effectiveness of systematic lymphadenectomy and adjuvant therapy to prevent recurrence. 2 Given the generally good prognosis, the National Comprehensive Cancer Network (NCCN) guideline recommends fertility-sparing surgery, which includes preserving the uterus and at least one ovary, as a viable treatment option.3 When counseling the patient, it is essential to consider that fertility-preserving surgery is associated with a higher risk of recurrence. 1 Additionally, the pathology results indicate a micropapillary subtype of serous borderline ovarian tumor, which further increases the likelihood of recurrence. 1 These factors highlight the need for meticulous histopathological evaluation to guide clinical management. Post-operatively, to monitor for potential recurrence, it is advisable to schedule follow-up appointments every 3 months, including physical examinations, CA125 tests (given the initially elevated levels), and imaging if recurrence is suspected for the first 2 years. 3

Dr Nilgün Kapucuoglu: What are the primary elements you consider during a pathological examination? What might be the pathogenesis of lymph node involvement in serous borderline tumors?

Several essential features should be described to ensure consistent terminology and to alert clinicians, which could influence post-operative management. Multiple non-branching filiform structures without fibrovascular cores that are five times longer than their width identify cribriform structures. 4 On the other hand, microinvasion is characterized by isolated eosinophilic cells or clusters within the stroma, each measuring less than 5 mm in their largest dimension. 4 These microinvasive structures often look like epithelial cells lining the papillae and surrounded by several spaces. Non-invasive implants are defined by the lack of invasion of the surrounding stroma. 4

Another debatable issue is lymph node involvement for serous borderline ovarian tumors where there is a lack of stromal invasion. A possible explanation might be the presence of endosalpingiosis, which involves benign ectopic Mullerian inclusions that may be linked to nodal involvement and are present alongside borderline ovarian tumors in 30–60% of cases. 1 4 Another theory proposes that ovarian tumor cells might fragment and spread as peritoneal implants, eventually metastasizing into lymphatic channels and nodes. 1 Also, the presence of Kirsten rat sarcoma viral oncogene homologue (KRAS) mutations in borderline ovarian tumors supports both theories 1 : while Alvarez et al 5 detected KRAS mutations in endosalpingiosis in patients with nodal involvement, Horn et al 6 found identical KRAS mutations in both ovarian tumors and lymph node deposits in three cases, which indicates a monoclonal origin for these deposits.

The discussion continues regarding various pathological features that raise concerns about a poorer prognosis and the risk of recurrence. Whether the presence of non-invasive implants during initial surgery signals a higher risk of recurrence remains unresolved. 1 2 Nonetheless, it is well-recognized that the micropapillary variant is pathologically more aggressive and linked to poorer outcomes.

The multidisciplinary tumor board reviewed the case and recommended oocyte cryopreservation, chemotherapy, and genetic consultation. Eight oocytes were preserved, and genetic consultation results were normal. The patient’s adjuvant treatment was started in October 2023, and the patient completed four cycles of chemotherapy with carboplatin and paclitaxel in December 2023.

Dr Didem Tunalı: What was the aim of adjuvant chemotherapy after surgery?

The patient was diagnosed with an advanced-stage serous borderline ovarian tumor. Despite the presence of non-invasive implants within the abdomen, the pathology report indicated lymph node involvement. Due to the patient’s young age, a fertility-sparing approach was chosen, although this approach carries a higher risk of recurrence. Additionally, the tumor displayed a micro-invasive pattern. Some clinicians associate the presence of micro-invasion, invasive implants on the peritoneum or positive nodal basin in borderline epithelial tumors with a poorer prognosis. Post-operative chemotherapy, similar to that used for low-grade serous ovarian cancer, may be considered in these cases.7 Retrospective studies also suggest adjuvant chemotherapy may benefit patients with stage III or IV borderline tumors after optimal debulking. 8 9 As a result, the decision to administer chemotherapy is open to debate; adjuvant chemotherapy with carboplatin and paclitaxel was decided at the tumor board to mitigate the risk of recurrence.

Following the conclusion of the final chemotherapy treatment in December 2023, an MRI showed no signs of recurrence, and the CA125 level was 6 U/mL. At the end of an 8-month follow-up period, in July 2024, an abdominal MRI revealed a 4 cm septated ovarian cyst along with left-sided hydrosalpinx, a 2 cm ovarian cyst containing a nodular lesion that showed contrast enhancement and thickening of the peritoneum (Figure 2). The thoracic CT scan showed no abnormalities. However, the positron emission tomography (PET)-CT scan revealed a suspicious mediastinal lymph node on the left side. The CA125 level was within normal limits. The case was re-evaluated by a multidisciplinary tumor board, which planned a laparotomy along with concurrent thoracoscopy to resect all visible suspicious tumor foci.

Figure 2

(A) T1 and (B) T2 weighted and (C) diffusion weighted MR images of bilateral adnexal masses before the second surgery (2024).

Dr Cagatay Taskiran: What would you discuss regarding subsequent management?

Recently, Westerman et al published a single-center retrospective study examining the outcomes of 507 patients diagnosed with borderline ovarian tumors, revealing a 28.5% risk of recurrence in the form of borderline or invasive tumor within 2 years for stage II–IV disease. 2 Among the clinical and histopathological factors, fertility-sparing surgery, International Federation of Gynecology and Obstetrics (FIGO) stage, micropapillary growth pattern, and microinvasion were significant risk factors for recurrence. 3 Given the patient’s age and associated risk factors, attempting fertility-sparing surgery was a worthwhile approach that did not negatively impact overall survival. However, clinicians should be mindful of the risk of malignant transformation into a low-grade ovarian tumor in case of recurrence. 2 Although the mentioned study could not perform an exploratory analysis due to a low number of cases, it was observed that all instances of malignant transformation involved the serous histotype, microinvasion, and micropapillary growth pattern. 2

The literature, mainly consisting of retrospective studies, debates whether lymph node involvement leads to a poor prognosis. 1 Considering all the risk factors, and the fact that the patient experienced recurrence within 8 months despite adjuvant chemotherapy, surgical debulking appears to be the most appropriate option for this patient.

During the second cytoreductive surgery, bilateral hydrosalpinx, a 4 cm pure cystic left ovarian cyst, and a 3 cm solid nodular right ovarian mass were detected. A cystectomy was performed, and intra-operative frozen section evaluation revealed a borderline ovarian tumor. Since bilateral ovarian cysts affected the entire ovarian tissue without remaining healthy tissue, a bilateral salpingo-oophorectomy was performed. Multiple implants were noted in the pouch of Douglas, along with a 4 cm metastatic mass invading the rectum, which was missed on the CT scan. To achieve no visible disease, low anterior resection with anastomosis was performed. No other metastasis was seen in the upper abdomen or lymph node basin. The thoracic surgery team performed a video-thoracoscopy and removed a mediastinal lymph node (Figure 3).

Figure 3

Mediastinal lymph node (2024). (A) Mediastinal lymph node recurrence of serous borderline ovarian tumor from the second surgery (hematoxylin and eosin). (B) PET CT image of mediastinal lymph node. (C) Intra-operative image of mediastinal lymph node.

The post-operative period was uneventful. Pathology results confirmed the presence of a micropapillary variant of serous borderline ovarian tumor in both ovaries (Figures 4 and 5). Non-invasive implants with a micropapillary pattern were seen on the right adnexa and the sigmoid colon (Figure 6). Of the two mediastinal lymph nodes examined, one had metastasis of a borderline serous ovarian tumor. No invasive cancer was detected. The tumor board re-evaluated the case. Given the micropapillary morphology of the non-invasive implants, adjuvant therapy, intravenous carboplatin and paclitaxel were advised. Next-generation sequencing and homologous recombinant deficiency (HRD) tests were ordered.

Figure 4

Serous borderline ovarian tumor from the second surgery (2024) (hematoxylin and eosin).

Figure 5

Micropapillary variant of serous borderline ovarian tumor from the second surgery (2024) (hematoxylin and eosin).

Figure 6

Non-invasive implant of serous borderline ovarian tumor from the second surgery (2024) (hematoxylin and eosin).

Dr Burak Giray: In view of the existing literature, could you provide an evaluation of this type of recurrence?

A recent review of the literature identified 26 cases of lymph node recurrence following a primary diagnosis of serous borderline ovarian tumor. 1 Among these, only two patients presented with paratracheal and pleural lymph node metastases, both of which ultimately transformed into low-grade serous ovarian cancer. 1 10 11 Regarding pleural nodal invasion by primary serous borderline ovarian tumors, only one case has been reported in the literature. 12 This involved a 48-year-old woman who presented with a lymph node at the tracheal bifurcation, causing shortness of breath. Immunohistochemical analysis of the lymph node metastasis was positive for ER [estrogen receptor] and PAX8, similar to our case. Although the decision to administer chemotherapy is open to debate, adjuvant chemotherapy with carboplatin and paclitaxel was decided at the tumor board to decrease the risk of recurrence. A subsequent PET scan revealed a 20 mm ovarian mass, which was surgically removed and diagnosed as a serous borderline ovarian tumor with a 4 mm focus of microinvasion. Post-operatively, the patient underwent six cycles of paclitaxel and carboplatin leading to the resolution of the mediastinal mass. 12 In light of the literature, the present case exemplifies a rare instance of serous borderline ovarian tumor recurrence with mediastinal lymph node metastasis.

Dr Didem Tunalı: What are the current adjuvant therapy options for this patient?

The presence of invasive implants in patients with borderline ovarian tumors is associated with a worse prognosis. The benefit of adjuvant therapy, particularly regimens used for low-grade serous ovarian cancer, such as IV carboplatin with either docetaxel or paclitaxel, is still under investigation for cases with invasive implants. However, there is no benefit for patients with non-invasive implants. 13 14 According to the NCCN guideline, observation is a category 2A recommendation for patients without invasive implants after R0 resection. 3

We also decided on an aromatase inhibitor, anastrozole, as maintenance therapy after the completion of chemotherapy as estrogen and progesterone receptors were both positive, and as data support the use of anastrozole for serous borderline ovarian tumors. The phase II PARAGON trial by Tang et al recently highlighted the clinical benefit of anastrozole, defined as complete or partial response or stable disease 12 weeks after treatment initiation, in 36 patients with recurrent low-grade serous ovarian cancer or serous borderline ovarian tumor. 15 Clinical benefit was observed in 61% of patients with recurrent ER and/or progesterone receptor (PR)-positive serous borderline ovarian tumor. 15 This treatment option could be discussed for high-risk serous borderline ovarian tumors, including the presence of lymph node metastasis or microinvasion and incomplete surgical resection without any further possibility of subsequent complete debulking, as well as in low-grade serous ovarian cancer. The most effective antihormonal treatment and its duration have not yet been determined. mitogen-activated extracellular signal-regulated kinase (MEK) inhibitors could represent a promising treatment strategy for serous borderline ovarian tumors. However, clinical trials are still lacking to determine whether mitogen-activated protein kinase 9MAPK) pathway-targeted treatments can be used to treat high-risk serous borderline ovarian tumors. Consequently, the absence of a standard systemic adjuvant treatment for borderline serous ovarian cancer, coupled with the lack of consensus on the most effective antihormonal therapy, creates uncertainty in patient selection, and complicates treatment decision.

The patient received her fifth and sixth cycles of intravenous carboplatin and paclitaxel chemotherapy in August 2024, and has not reported any signs of recurrence to date. The unusual recurrence of a serous borderline ovarian tumor within a short timeframe in a patient who opted for fertility preservation presents a significant challenge. The absence of intra-abdominal lymph node metastasis and the presence of rare mediastinal lymph node metastasis underscore the uniqueness of this case. Therefore, if a serous borderline ovarian tumor recurs, a comprehensive evaluation, including the abdomen and thorax, should be conducted to identify any atypical recurrences. In addition, radical surgery was performed aiming to resect intra-abdominal non-invasive implants and mediastinal lymph nodes to achieve R0 resection, which is the key factor to improve disease-free survival. Lastly, the absence of a consensus regarding indication, dose, and duration of adjuvant therapy highlights the importance of managing such complex cases at specialized tertiary centers.

Ethics statementsPatient consent for publication

Consent obtained directly from patient(s).

Ethics approval

This study involves human participants. The study is a case report, discussed in the format of the tumor board, and no institutional review board approval is required. Participants gave informed consent to participate in the study before taking part.