David Nunns on behalf of the Gynae Guidelines Group Date:

Title of Guideline (must include the word Guideline (not protocol, policy, procedure etc) Borderline tumours of the ovary management and follow-up Author: Contact Name and Job Title Directorate & Speciality David Nunns Consultant Gynaecological Oncologist, NUH (on behalf of the gynae cancer MDT- clinical lead Jaf Abu) Family Health Date of submission 12.1.18 Explicit definition of patient group to which it applies (e.g. inclusion and exclusion criteria, diagnosis) Patients seen in gynaecology or oncology clinics Version 1 If this version supersedes another clinical guideline please be explicit about which guideline it replaces including version number. Statement of the evidence base of the guideline has the guideline been peer reviewed by colleagues? Evidence base: (1-6) 1 NICE Guidance, Royal College Guideline, SIGN (please state which source). 2a meta analysis of randomised controlled trials 2b at least one randomised controlled trial 3a at least one well-designed controlled study without 3b randomisation at least one other type of well-designed quasiexperimental study 4 well designed non-experimental descriptive studies (ie comparative / correlation and case studies) 5 expert committee reports or opinions and / or clinical experiences of respected authorities 6 recommended best practise based on the clinical experience of the guideline developer Consultation Process Ratified by: Target audience Review Date: (to be applied by the Integrated Governance Team) A review date of 5 years will be applied by the Trust. Directorates can choose to apply a shorter review date, however this must be managed through Directorate Governance processes. NA 5) British Gynae Cancer Society Guidance on Ovarian Cancer https://bgcs.org.uk/bgcs%20guidelines%2 0Ovarian%20Guidelines%202017.pdf Senior medical staff David Nunns on behalf of the Gynae Guidelines Group Date: 12.1.18 General gynaecologists and gynaeoncologists 12/01/2023 This guideline has been registered with the trust. However, clinical guidelines are guidelines only. The interpretation and application of clinical guidelines will remain the responsibility of the individual clinician. If in doubt contact a senior colleague or expert. Caution is advised when using guidelines after the review date.

Aims and purpose To guide the clinician (general gynaecologists and gynaeoncologists) on the management and follow-up of borderline tumours of the ovary. Background Patients with borderline tumours of the ovary account for 10% of all ovarian tumours. When correctly staged and malignancy excluded, the prognosis is excellent. The 5-year survival rate for such patients approaches 100%, however, the 10-year survival rate is 90-95%. Patients are commonly managed by general gynaecologists and a diagnosis made after resection on histology. All cases should be discussed at the gynaeoncology MDT as soon as possible and referred using the MDT referral form on the intranet. The desired outcome of management is complete staging, assessment of tumour risk, management of fertility concerns and surgical removal of all disease (the latter is linked to better survival compared to those patients with incomplete excision). 1

Algorithm for management and follow-of borderline tumours of the ovary (see text for peritoneal biopsy) Pathological types Borderline ovarian tumours are a subgroup of ovarian tumours that by definition have no evidence of stromal invasive histologically. Low risk patients usually behave in benign fashion and include the following; borderline endometrioid, clear cell, Brenner tumours and correctly diagnosed mucinous borderline tumours. o Mucinous borderline tumours typically present as large unilateral masses that are confined to the ovary. Non-ovarian mucinous tumours, including metastatic ovarian mucinous tumours associated with pseudomyxoma peritonei and metastatic mucinous carcinomas (Krukenberg tumours)(ronnett 2004). High risk patients include advanced stage disease, incompletely excised disease and some serous and sero-mucinous types. These are associated with a poorer prognosis. o Serous types with micropapillary and microacinar architecture have a greater association with extra-ovarian 2

disease and a higher incidence of recurrence and death from disease (Seidman 2000). They can be associated with microinvasion (small areas of invasion less than 5mm). Microinvasion is seen more commonly in pregnant patients but the presence of microinvasion does not alter the outcome (Mooney 1997). Women with stage I disease have the same outcome as the general population, irrespective of microinvasion (Bell 2001) o Serous borderline tumours can also be associated with peritoneal lesions that are termed implants (which influences final stage) Non invasive implants are when the implants are confined to peritoneal/ mesothelial lined surfaces and lack invasion of underlying tissue; these patients have a good prognosis. Invasive implants may occur and these patients need careful management and some patients have a poor prognosis. They should be reclassified as low grade ovarian cancers under the new FIGO classification of 2014. Preoperative management Currently there is no reliable means of preoperative detection of borderline tumours clinically and on imaging. Please refer to the NUH guidance Assessment, referral and initial management of ultrasound detected ovarian cysts for NUH gynaecology teams for further information on complex ovarian cysts. Intraoperative management There may be an intraoperative suspicion of a borderline tumour that was not suspected preoperatively (eg external papillary-like tumour on the surface of the ovary, ascites, evidence of peritoneal and omentum nodularity see appendix 1). If the patient has consented to oophorectomy then, o Take a sample of the ascites or carry out peritoneal washings prior to resection o Observe the other ovary for abnormality. In premenopausal women when there is external papillary-like tumour on the surface of the ovary it is not unreasonable to biopsy this disease. In a post-menopausal patient removal of the remaining ovary may be considered. There will be consent 3

issues in this situation and a judgement will have to made by the lead surgeon. o Take a generous omental biopsy if the omentum looks normal (eg at least 3x3cm). The omentum looks abnormal then, if possible, either remove the majority of the omentum with the disease, or take a generous omental biopsy which includes the disease. o Inspect all the peritoneal surfaces and take single or multiple biopsies if necessary (see below). Inspect the appendix. o If total resection of the disease is not possible (eg bowel involvement, fixed disease) then distinguishing between cancer and borderline disease is difficult. Please consider calling a colleague in gynaeoncology for advice or performing an oophorectomy and omentectomy if safe and discuss results with a member of the gynaeoncology team postoperatively. o Please document clearly intraoperative findings and take photographs if possible (so to plan any subsequent surgery). o Consider appendicectomy for apparent mucinous tumours (the ovarian tumour may be a metastasis). o Pelvic and para-aortic lymph node sampling to stage cases is not recommended in the absence of bulky lymph nodes. Peritoneal Biopsies What are peritoneal biopsies? o These are small superficial piece(s) of peritoneal tissue usually less than 1cm in size. Why are they beneficial? o knowledge of the histology assists in the diagnosis and staging of intra-abdominal gynaecological malignancy (eg borderline and malignant tumours) When should they be taken? At the primary operation (all gynaecologists). If intraoperatively a borderline/malignant tumour is suspected (eg exophytic growth on the ovary see clinical pictures in the appendix) then the gynaecologist is advised to look at all the peritoneal surfaces and biopsy any suspicious area of disease. Taking the biopsy is determined by the confidence of the gynaecologist as some site (eg pelvic sidewall) may be more difficult than others. Please document all findings in the notes. Restaging procedures (usually the gynaeoncologist). Peritoneal biopsies should be taken when there is a known diagnosis of borderline disease to support disease staging (see below) How should they be taken? 4

Follow-up Peritoneal biopsies are usually taken from the pelvis, paracolic gutters, anterior abdominal wall and subdiaphragmatic surfaces. It is important to avoid excessive diathermy artefact and suturing the defect is not usually necessary. Patients should be followed up as per the algorithm above. Patients who have been fully staged and who have had both ovaries removed can be followed up clinically. The three year follow-up period is likely to detect most (but not all) recurrences. Many patients are diagnosed post-operatively so additional surgery and /or follow-up may need to be considered based on fertility requirements, tumour type and fitness. The risk of recurrence in low-risk stage 1 disease is not clear but as a general guide o following oophorectomy the risk of a recurrent borderline tumour in the remaining ovary is 10%. o following cystectomy the risk of a recurrent borderline tumour in the same ovary approximately 30% (so completion oophorectomy is advised even if fertility is required) (Trillsch 2014) o Longer-term, the risk of malignant transformation is low overall (~2%), but is found in 30% of those with relapsed disease, although was much less frequent in women under 40 years of age at original diagnosis, compared to those aged over 40 years (12.0% versus 66.7%, P < 0.001) (Trillsch 2014). There is no evidence that routine follow-up is of value in detection of recurrence and cancer Ultrasound follow-up (preferably transvaginal route) should be reserved for those women who retain an ovary. Completion oophorectomy when the patient s family is complete can be considered but the evidence of benefit is not clear. Removal of the uterus is not considered an essential part of the primary treatment, but may be relevant if the patients will have hormone replacement therapy post-operatively or needed to excise all visible disease. There is unclear value in the routine CA125 based follow up. This needs discussion with the gynae cancer team (du Bois 2013) Relapse of borderline disease should be mainly treated surgically, if disease seems operable, since response to chemotherapy is poor. 5

There is no evidence-based indication for cytotoxic chemotherapy (Faluyi 2010) Appendix 1 clinical intraoperative images of abnormal ovaries consistent with borderline tumour of the ovary. External papillary-like tumour on the surface of the ovary (carry out small biopsy of external surface tumour approx. 5mm size) Peritoneal nodularity (take pictures and multiple peritoneal biopsies using biopsy forceps or diathermy scissors) 6

Peritoneal nodularity (take pictures and multiple peritoneal biopsies using biopsy forceps or diathermy scissors) Appendix 1 patient information sheet General advice on counselling patients on borderline tumours o It is not a cancer o Chemotherapy is rarely given o The prognosis is excellent o Referral to the gynae cancer team may be needed for ongoing management and follow-up 7

Use the patient information sheet developed by the charity Ovacome (http://www.ovacome.org.uk/wp- content/uploads/2016/02/fact-sheet-10-borderline- TUMOURS-2016.pdf) References Bell KA, Smith Sehdev AE, Kurman RJ. Refined diagnostic criteria for implants associated with ovarian atypical proliferative serous tumors (borderline) and micropapillary serous carcinomas. Am J Surg Pathol. 2001 Apr;25(4):419-32. PubMed PMID: 11257616. British Gynaecological Cancer Society (BGCS) Epithelial Ovarian / Fallopian Tube / Primary Peritoneal Cancer Guidelines: Recommendations for Practice https://bgcs.org.uk/bgcs%20guidelines%20ovarian%20guidelines%202017.pdf du Bois A, Ewald-Riegler N, de Gregorio N, Reuss A, Mahner S, Fotopoulou C, et al. Borderline tumours of the ovary: A cohort study of the Arbeitsgmeinschaft Gynakologische Onkologie (AGO) Study Group. Eur J Cancer. 2013 May;49(8):1905-14. PubMed PMID: 23490647. Faluyi O, Mackean M, Gourley C, Bryant A, Dickinson HO. Interventions for the treatment of borderline ovarian tumours. Cochrane Database Syst Rev. 2010 Sep 08(9):CD007696. PubMed PMID: 20824864. Pubmed Central PMCID: PMC4164822. Mooney J, Silva E, Tornos C, Gershenson D. Unusual features of serous neoplasms of low malignant potential during pregnancy. Gynecologic oncology. 1997 Apr;65(1):30-5. PubMed PMID: 9103387. Ronnett BM, Kajdacsy-Balla A, Gilks CB, Merino MJ, Silva E, Werness BA, et al. Mucinous borderline ovarian tumors: points of general agreement and persistent controversies regarding nomenclature, diagnostic criteria, and behavior. Hum Pathol. 2004 Aug;35(8):949-60. PubMed PMID: 15297962. Seidman JD, Kurman RJ. Ovarian serous borderline tumors: a critical review of the literature with emphasis on prognostic indicators. Hum Pathol. 2000 May;31(5):539-57. PubMed PMID: 10836293. Trillsch F, Mahner S, Woelber L, Vettorazzi E, Reuss A, Ewald-Riegler N, et al. Agedependent differences in borderline ovarian tumours (BOT) regarding clinical characteristics and outcome: results from a sub-analysis of the Arbeitsgemeinschaft Gynaekologische Onkologie (AGO) ROBOT study. Ann Oncol. 2014 Jul;25(7):1320-7. PubMed PMID: 24618151. 8