Recurrence of borderline ovarian tumor during pregnancy – is wait-and-see approach a possible strategy? Case report and literature review

The results of conservative (fertility-sparing) treatment in borderline ovarian tumors vary depending on age and histological type.

Borderline ovarian tumors: Guidelines from the French national college of obstetricians and gynecologists (CNGOF)

Study question How do borderline ovarian tumors (BOTs) at different oncological stages affect safety (presence of occult lesions) and quality of the ovarian reserve? Summary answer The ovarian follicle pool is decreased in women with BOTS, especially at younger age, and oncological safety is compromised in more advanced oncological stages. What is known already The clinical decision-making balancing the type of surgical treatment (radical or fertility-sparing) with the the risk of recurrence is still controversial for women diagnosed with BOTs at different oncological stages. The same is for the use of adjuvant techniques like oocyte or ovarian tissue cryopreservation to optimize the likelihood of fertility recovery. The prevalence of occult lesions in healthy-looking ovarian cortex, which may be managed by surgery or cryopreservation, has not been analyzed in all tumor types. Moreover, the status of the ovarian follicle pool may be affected by tumoral masses, making fertility preservation even more challenging in these patients. Study design, size, duration Multicentric retrospective study involving Cliniques Universitaires Saint Luc in Brussels (Belgium) and Macedonio Melloni hospital in Milan (Italy). Forty-two women at reproductive age (15-45 years) diagnosed with borderline ovarian tumors (BOTs), including 24 serous, 14 mucinous and 4 endometrioid BOTs were included. Participants/materials, setting, methods Histological samples of ovarian cortex surrounding tumors were analyzed to characterize the follicle pool (follicle density, classification and atresia rates) and results were compared with an aged-matched population of 45 subjects with non-ovarian pathologies. Any occult malignant lesions in healthy-looking cortex were investigated using tumor-specific markers (cytokeratin 7 and mucin 1), while immune system infiltration was quantified by CD3 for tumor-infiltrating lymphocytes (TILs) and CD68 for tumor associated macrophages (TAMs). Main results and the role of chance Occult ovarian lesions were observed in 5 out of 39 cases (12.8%). These included one mucinous stage-I BOT (1/13), one serous stage-I BOT (1/13), and 3 advanced-stage serous BOTs (3/11). Three 3 cases were excluded from the analysis because no cortex was available. Notably, follicle density was significantly lower in subjects diagnosed with ovarian tumors than in controls (p < 0.001) at a younger age, while no difference was detected in older patients. Significantly greater follicle atresia was encountered in the ovarian tumor group than in controls (20.1 ± 8.8% vs 9.2 ± 9.4%, p < 0.001) at all ages, but no difference was detected in follicle classification parameters (primordial and growing follicle rates). Mucinous BOTs exhibited lower follicle density than serous BOTs (98.8 ± 152.8 vs 225.8 ± 220.7, p < 0.01), although no age difference was evidenced. Although mucinous BOTS had also significantly bigger volume than serous BOTs, no significant correlation between follicle density and tumoral volume was found. Other factors like tumor microenvironment may play a role in ovarian follicle pool damage. Both TILs and TAMs were found in ovarian tumors irrespective of histotype, but no link was established with the status of the ovarian reserve. Limitations, reasons for caution Although this study helped to elucidate the risk profile of different types of epithelial ovarian tumors, observing that late-stage BOTs ran a 27% (3/11) risk of occult ovarian lesions, further research is needed to identify predictive markers. Wider implications of the findings Personalized counseling for fertility preservation is required in case of BOTs. Fertility-sparing surgery and adjuvant gamete preservation should be considered, balancing any oncological risks against tumor stage and histotype and fertility potential, especially at a younger age. Trial registration number NA

Borderline ovarian tumors: French guidelines from the CNGOF. Part 2. Surgical management, follow-up, hormone replacement therapy, fertility management and preservation

Conservative surgery in ovarian borderline tumours: A meta-analysis with emphasis on recurrence risk

Is MRI a useful tool to distinguish between serous and mucinous borderline ovarian tumours?

Tumeurs frontières de l’ovaire. Recommandations pour la pratique clinique du CNGOF — Épidémiologie et facteurs de risques de récidive, modalités de surveillance et intérêt d’une chirurgie de clôture

Population-based evidence regarding risk of ovarian cancer after a borderline ovarian tumor (BOT) is sparse. We aimed to examine the incidence of specific types of ovarian cancer in women with serous or mucinous BOTs in a nationwide cohort study with up to 36 years of follow-up. Using the nationwide Danish Pathology Data Bank, we identified 4,281 women with a BOT (2,058 serous BOTs and 2,223 mucinous BOTs) in Denmark during 1978-2012. We computed standardized incidence ratios (SIRs) to compare the incidence of ovarian cancer among women with BOTs compared to general population rates. We found that a serous BOT was especially and strongly associated with subsequent serous ovarian cancer (SIR = 9.2; 95% CI: 6.8-12.2), and that a mucinous BOT was strongly related to mucinous ovarian cancer (SIR = 18.6; 95% CI: 10.8-29.8). The SIRs remained elevated ≥10 years after a serous BOT and up to 5-9 years after a mucinous BOT. The increased incidence of serous ovarian cancer in women with a serous BOT was mostly pronounced in women <50 years at the serous BOT diagnosis. In conclusion, women with a serous BOT experience long-term increased incidence of serous ovarian cancer, and women with a mucinous BOT have long-term elevated incidence of mucinous ovarian cancer compared to the general population. This is the first population-based study to show compelling evidence of the histo-specific increased risk of ovarian cancer following specific types of BOTs. Thus, these results are supportive of the hypothesis that BOTs may be precursor lesions to carcinomas of the corresponding histologic type.

Tumeurs frontières de l’ovaire. Recommandations pour la pratique clinique du CNGOF – Texte court

The pathogenesis and molecular mechanisms of ovarian low malignant potential (LMP) tumors or borderline ovarian tumors (BOTs) have not been fully elucidated to date. Surgery remains the cornerstone of treatment for this disease, and diagnosis is mainly made by histopathology to date. However, there is no integrated analysis investigating the tumorigenesis of BOTs with open experimental data. Therefore, we first utilized a functionome-based speculative model from the aggregated obtainable datasets to explore the expression profiling data among all BOTs and two major subtypes of BOTs, serous BOTs (SBOTs) and mucinous BOTs (MBOTs), by analyzing the functional regularity patterns and clustering the separate gene sets. We next prospected and assembled the association between these targeted biomolecular functions and their related genes. Our research found that BOTs can be accurately recognized by gene expression profiles by means of integrative polygenic analytics among all BOTs, SBOTs, and MBOTs; the results exhibited the top 41 common dysregulated biomolecular functions, which were sorted into four major categories: immune and inflammatory response-related functions, cell membrane- and transporter-related functions, cell cycle- and signaling-related functions, and cell metabolism-related functions, which were the key elements involved in its pathogenesis. In contrast to previous research, we identified 19 representative genes from the above classified categories (IL6, CCR2 for immune and inflammatory response-related functions; IFNG, ATP1B1, GAS6, and PSEN1 for cell membrane- and transporter-related functions; CTNNB1, GATA3, and IL1B for cell cycle- and signaling-related functions; and AKT1, SIRT1, IL4, PDGFB, MAPK3, SRC, TWIST1, TGFB1, ADIPOQ, and PPARGC1A for cell metabolism-related functions) that were relevant in the cause and development of BOTs. We also noticed that a dysfunctional pathway of galactose catabolism had taken place among all BOTs, SBOTs, and MBOTs from the analyzed gene set databases of canonical pathways. With the help of immunostaining, we verified significantly higher performance of interleukin 6 (IL6) and galactose-1-phosphate uridylyltransferase (GALT) among BOTs than the controls. In conclusion, a bioinformatic platform of gene-set integrative molecular functionomes and biophysiological pathways was constructed in this study to interpret the complicated pathogenic pathways of BOTs, and these important findings demonstrated the dysregulated immunological functionome and dysfunctional metabolic pathway as potential roles during the tumorigenesis of BOTs and may be helpful for the diagnosis and therapy of BOTs in the future.

Introduction Borderline ovarian tumours (BOT) have a good prognosis with a 5–8% recurrence rate. Although complete staging is the standard surgical treatment; when they occur in younger women, fertility preservation is important. Since the effect of fertility-preserving surgery on recurrence remains inconclusive, in the present study we examined the clinicopathological factors in residual/recurrent BOT. Methods BOT diagnosed between 2010 and 2020 were retrieved using electronic records for women Results In total, 74 BOT cases were reviewed which consisted of 42 (56.8%) serous BOT, 29 (39.2%) mucinous BOT and 3 (4.1%) seromucinous BOT. Amongst the 13 residual/recurrent BOT, all but one were serous BOT. More than half of residual/recurrent BOT had normal CA125 at presentation. The mean age was similar to the non-recurrent BOTs. Laparoscopic cystectomy was the most common initial treatment. Bilateral tumours were seen at initial surgery in 3/13 (23.1%). The time to residual/recurrent tumour ranged from 1 to 96 months. The residual/recurrent tumours were seen in the same ovary in 3/13 (23.1%), in opposite ovary in 5/13 (38.5%) and at extraovarian sites in 5/13 (38.5%). Only 2 of the 13 cases showed focal micropapillary pattern. Cytology samples were examined in 7 cases and 5 of these reported presence of epithelial cells. Majority of residual/recurrent BOT were stage 1 at initial diagnosis. All but 2 patients are currently disease free. Conclusions Our study highlights clinicopathological factors associated with residual/recurrent BOT in young females undergoing fertility-preserving surgery.

To evaluate if morphometric features (mitotic activity index, volume percentage of epithelium, and DNA ploidy) are prognostic markers in borderline ovarian tumors (BOTs). Ninety-three serous and mucinous consecutive BOTs diagnosed between 1989 and 2002 were studied. In all tumors, mitotic activity index, volume percentage of epithelium, and DNA ploidy were determined prospectively. Consecutively, age at diagnosis, calculated tumor volume, International Federation of Gynecology and Obstetrics (FIGO) stage, and treatment by extensive staging were evaluated after a median follow-up of 52 months. Serous BOTs presented at a younger age (P<0.05), with smaller volume (P<0.001), with higher FIGO stage (P<0.001), and were more frequently bilateral (P<0.001) than mucinous BOTs. Patients with serous BOT (P<0.05) and beyond stage Ia (P<0.01) showed worse recurrence-free survival. No prognostic significance could be established for DNA ploidy or morphometry. The previously claimed prognostic power of DNA ploidy and morphometry could not be corroborated in this prospective study and can therefore not be recommended to direct clinical management in BOTs. In contrast, histologic subtype and FIGO stage seem to be stable prognosticators in BOTs.

Tumeurs frontières de l’ovaire. Recommandations pour la pratique clinique du CNGOF – Prise en charge thérapeutique des stades précoces

Ovarian tumors of low malignant potential, often termed "borderline tumors," have been defined as those that have some but not all of the morphologic features of malignancy (i.e., they are not invasive). With the use of data obtained by the western Washington population-based Cancer Surveillance System for 1975-83, the incidence of serous and mucinous borderline epithelial ovarian tumors was analyzed, as well as the survival of women who developed them. The incidence of borderline tumors increased with increasing age, although at a pace somewhat slower than that of malignant ovarian tumors. There was an upward trend in the incidence of borderline tumors starting in the late 1970's, a trend not present for malignant tumors. Only 12% of borderline tumors were not confined to the ovary, as opposed to 40% of malignant Grade I and 73% of other malignant ovarian neoplasms. At 5 years following diagnosis, the survival of women with borderline tumors was 93% that of the general female population. This percentage varied little by stage or histologic type. Given the reduced survival of women with these ovarian tumors and the lack of a sharp histologic distinction between borderline and Grade I malignant lesions, it is recommended that borderline ovarian tumors be routinely ascertained by population-based cancer registries.

To analyse the performance of IOTA ADNEX model for the differentiation of histological subtypes of borderline ovarian tumours (BOT). Retrospective analysis of ultrasound (US) dataset of patients diagnosed with BOT on the final histology was done at the tertiary oncology centre in the period of 2009–2016. The IOTA ADNEX model (web application) was used to calculate the absolute risk (AR) and the relative risk (RR) for the mass being BOT. 57 (72.2%) of patients were diagnosed with serous BOTs (s_BOTs) and 22 (27.8%) with mucinous BOTs (m_BOTs). Without CA-125, according to AR, the ADNEX correctly classified 37 (64.9%) serous and 12 (54.5%) mucinous BOTs with no difference between the groups. According to RR, the test correctly differentiated 44 (77.2%) serous BOTs and 15 (68.2%) mucinous BOTs (p=0.409 between the groups). When tumours were classified according to RR, the performance of ADNEX increased by 35% and 30% in s_BOTs and m_BOTs groups respectively (p<0.05). When CA-125 was added, according to AR, 35 (68.6%) of s_BOTs and 11 (57.9%) m_BOTs were correctly classified. According to RR, 41 (80.4%) of s_BOTs and 14 (73.7%) of m_BOTs were classified correctly. The performance of ADNEX model increased by 37.5% in both groups when differentiating tumours according to RR vs. AR (p<0.05). The mean AR and RR was significantly higher in s_BOTs compared to m_BOTs group (30.8% vs. 18.1% and 4.89 vs. 2.88, respectively; p=0.002). However, when CA-125 was added, the difference of mean AR (29.4% vs. 21.4%) and RR (4.67 vs. 3.39) slightly decreased and was no longer significant (p=0.106). IOTA ADNEX model works well in differentiating BOTs of different histological subtypes. The performance is better when tumours are differentiated according to the RR and the values of risk are higher in serous BOTs compared to mucinous ones.