ABSTRACT Here we present a transgender male adolescent with an androgen receptor-positive serous borderline ovarian tumour in the setting of testosterone treatment for medical gender

transition. To our knowledge, this is the second report of borderline tumour in a transgender individual and the first in an adolescent, an age group in which borderline tumours are

extremely rare. We discuss the specific considerations of treating ovarian tumours in the transgender male population, the incompletely understood role of androgens in the genesis of ovarian

epithelial neoplasia, and an emphasis on assessing cancer risk in transgender patients based on patient anatomy. SIMILAR CONTENT BEING VIEWED BY OTHERS NATIONWIDE POPULATION-BASED STUDY OF

patients presenting for gender-affirming care has increased. Transmasculine individuals, those who are designated female at birth and have a masculine gender identity, may elect treatment

with exogenous testosterone to produce secondary sex characteristics in line with their gender identity.1 The effects of testosterone therapy on the ovaries is incompletely understood with

conflicting data in the literature. Some studies report polycystic ovarian pathology following testosterone treatment, with others reporting no treatment sequelae.2 Independent of concerns

surrounding testosterone treatment, many transmasculine individuals are electing to retain their uterus, fallopian tubes, and ovaries and require screening for malignancies involving these

organs. We present a trans-male adolescent with an androgen receptor (AR)-positive serous borderline tumour (SBT) discovered shortly after starting on testosterone therapy. Because of the

small number of cases of ovarian neoplasms in adolescents, with even fewer in the transgender population, the potential role of sex steroids in the genesis and pathogenesis of these tumours

is largely unknown. Gynaecologic and medical providers treating trans youth must take into account each patient’s goals with regard to hormone therapy and gender-affirming surgery while

simultaneously assessing health risks associated with patient anatomy. This case report was prepared using the CARE guidelines.3 CASE PRESENTATION A 17-year-old transgender male with

obesity, anxiety, and no prior abdominal surgical history presented to the emergency room with acute right lower quadrant pain and nausea. Medications included fluoxetine, norethindrone

acetate to achieve menstrual suppression, begun 7 months prior, and subcutaneous testosterone cypionate, begun 12 weeks prior. Past medical and gynaecologic history included normal

development with menarche at age 13 years and regular menstrual cycles until initiation of testosterone and norethindrone acetate. Exam demonstrated a palpable, tender, mobile mass extending

4 cm above the umbilicus. Laboratory evaluation was reassuring. Ultrasound demonstrated a large right-sided mass with solid and cystic components and absent vascular flow. Due to concern

for adnexal torsion, urgent surgery was recommended. After counselling regarding the risk, benefits, and fertility implications of ovarian cystectomy versus salpingo-oophorectomy, the

patient and his parents elected salpingo-oophorectomy. He expressed plans for future gender-affirming surgery, including gonad removal. Intra-operative examination under anaesthesia showed

Tanner V pubic hair, hirsutism, and clitoromegaly. A midline vertical incision was made. The right adnexa was torted three times in the presence of a large right ovarian mass with an intact

ovarian capsule. A right salpingo-oophorectomy was performed. Inspection of the uterus, left tube and ovary, omentum, and palpation of the upper abdomen, liver edge, diaphragm, and pelvic

and para-aortic lymph nodes showed no gross abnormalities. An omental biopsy and pelvic washings were performed. Pathological examination showed a 15 × 14 × 9 cm tumour, with tan-red fleshy

excrescences lining the internal surface (Fig. 1a). Histologically, there was a proliferation of cuboidal to columnar epithelial cells showing eosinophilic cytoplasm and arranged in

papillary fronds (Fig. 1b, c). The tumour was confined to the ovary without evidence of invasion or implantation. Immunostaining for AR (AR441, DAKO, Carpinteria, CA) showed nuclear staining

in lesional cells (Fig. 1d). A diagnosis of serous papillary borderline tumour (atypical proliferative serous tumour), International Federation of Gynecology and Obstetrics stage IA, was

rendered. Postoperative treatment, monitoring, and further gender-affirming hormone therapy were discussed by a multidisciplinary team involving paediatric endocrinology, oncology,

gynaecology, pathology, and adult medical oncology. In the absence of peritoneal implants or extra-ovarian disease, the tumour was considered low risk. Given the potential for contralateral

ovarian disease after removal of an SBT, surveillance of the remaining ovary was recommended. Testosterone was restarted 2 months following the surgery after discussing risks and benefits

with the patient and his family. He continued on norethindrone acetate daily to obtain adequate menstrual suppression. Surveillance ultrasound of the remaining ovary obtained 6 months

postoperatively was normal. DISCUSSION We present an SBT in a trans-male adolescent receiving testosterone for medical gender transition. The sole previous report of SBT in a transmasculine

individual occurred in a 38-year-old receiving testosterone therapy.4 Other ovarian neoplasms reported in this setting include one serous cystadenoma,4 two mature cystic teratomas,5 and one

endometrioid adenocarcinoma.6 Ovarian epithelial tumours are rare in adolescents and carry a more favourable 10-year survival rate than the same diagnoses in adults.7 SBTs are non-invasive

ovarian epithelial tumours distinct from frank carcinoma. In our paediatric hospital, borderline tumours account for <1% of ovarian neoplasms among patients aged <21 years.8,9 The

overall survival for patients with stage 1 disease does not differ from the general population. The role of testosterone treatment in tumour progression is uncertain as a putative role for

androgens and the AR in the development or proliferation of ovarian tumours has not been established. Androgen signalling has a role in granulosa cell maturation and differentiation,

although in vitro exposure of ovarian cancer cell lines to androgens does not result in cell proliferation.10 Patients with polycystic ovary syndrome (PCOS), who are exposed to high levels

of endogenous androgens, have not shown an increased risk in ovarian cancer overall; however, Olsen et. al. showed a modest increased risk of SBT in overweight women with PCOS and high

circulating androgens (odds ratio 2.6, 95% confidence interval 1.0–6.1).11 Clinical studies have failed to show an association between elevated androgen levels and ovarian cancer risk,12 and

attempts to treat chemotherapy-refractive ovarian tumours with androgen deprivation have yielded moderate responses at best in small numbers of patients.13 Prior studies investigating

endogenous androgens may not be applicable to exogenous testosterone treatment given to achieve male range levels and, in the case of transgender youth, for pubertal induction. The presence

of a sex hormone-sensitive cancer is a contraindication to testosterone therapy, but there are no formal recommendations for the use of testosterone in patients with SBT. Given the

importance of gender-affirming therapy, which has been shown to reduce suicide risk and improve overall well-being,14 our multi-disciplinary team carefully weighed the risks and benefits of

restarting testosterone therapy and, in the context of a completely resected tumour and ambiguous risks associated with endogenous steroids, ultimately recommended restart. Appropriate

tumour surveillance was also unclear as there is no data to guide management in this area. The team recommended at least 5 years of periodic transvaginal ultrasounds of the contralateral

ovary unless oophorectomy was completed sooner. While transvaginal ultrasounds were deemed of higher sensitivity, transabdominal were prioritised given patient preference. Attempts to

estimate the prevalence of reproductive cancers in the transgender population have been unsuccessful. Current guidelines suggest routine screening based on retained internal organs in line

with cisgender screening recommendations.15 Keeping in mind that significant barriers to care exist for transgendered persons, all providers must be cognizant of and consider the health

risks posed by each patient’s anatomy, for example, that transmasculine patients may retain their ovaries, and should screen patients appropriately. This manuscript details the first

reported borderline ovarian tumour in a transmasculine adolescent receiving testosterone. The role that testosterone treatment played in the development, growth, and recurrence risk of his

tumour is largely unknown. Further study regarding the prevalence and management of ovarian tumours in transmasculine individuals is needed. We propose the creation of a tumour registry for

reproductive tract tumours in the transgender population to gather longitudinal data and increase our understanding of the role that gender-affirming hormones play in the origin and

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references ACKNOWLEDGEMENTS The authors would like to thank the patient and his family. AUTHOR INFORMATION Author notes * These authors contributed equally: Kate Millington, Katherine Hayes

* These authors jointly supervised this work: Amanda French, Jennifer Veneris, Allison O’Neill AUTHORS AND AFFILIATIONS * Division of Endocrinology, Boston Children’s Hospital, Boston, MA,

USA Kate Millington, Sarah Pilcher & Stephanie Roberts * Division of Gynecology, Boston Children’s Hospital, Boston, MA, USA Katherine Hayes & Amanda French * Department of

Pathology, Boston Children’s Hospital, Boston, MA, USA Sara O. Vargas * Division of Gynecologic Oncology, Dana-Farber Cancer Institute, Boston, MA, USA Jennifer Veneris * Dana-Farber Cancer

Institute, Boston Children’s Hospital, Boston, MA, USA Allison O’Neill Authors * Kate Millington View author publications You can also search for this author inPubMed Google Scholar *

Katherine Hayes View author publications You can also search for this author inPubMed Google Scholar * Sarah Pilcher View author publications You can also search for this author inPubMed 

Google Scholar * Stephanie Roberts View author publications You can also search for this author inPubMed Google Scholar * Sara O. Vargas View author publications You can also search for this

author inPubMed Google Scholar * Amanda French View author publications You can also search for this author inPubMed Google Scholar * Jennifer Veneris View author publications You can also

search for this author inPubMed Google Scholar * Allison O’Neill View author publications You can also search for this author inPubMed Google Scholar CONTRIBUTIONS K.M., K.H., and A.F.

drafted the initial manuscript. S.O.V. prepared the figure. S.R., A.M., S.O.V., J.V., A.F., and A.O.N. provided critical review and editing. All authors reviewed and approved the final

manuscript. CORRESPONDING AUTHOR Correspondence to Kate Millington. ETHICS DECLARATIONS ETHICS APPROVAL AND CONSENT TO PARTICIPATE The need for ethics approval and consent was deemed

unnecessary. The subject provided informed consent to participate. CONSENT TO PUBLISH Written consent for publication was obtained from the subject. DATA AVAILABILITY Clinical data from this

case was abstracted from the electronic medical record in a de-identified manner. COMPETING INTERESTS The authors declare no competing interests. FUNDING INFORMATION This work was supported

by National Institutes of Health grants T32 DK007699. ADDITIONAL INFORMATION NOTE This work is published under the standard license to publish agreement. After 12 months the work will

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http://creativecommons.org/licenses/by/4.0/. Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Millington, K., Hayes, K., Pilcher, S. _et al._ A serous borderline ovarian tumour

in a transgender male adolescent. _Br J Cancer_ 124, 567–569 (2021). https://doi.org/10.1038/s41416-020-01129-4 Download citation * Received: 11 May 2020 * Revised: 25 September 2020 *

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