OBJECTIVE
Ovarian tissue cryopreservation (OTC) is the only method of fertility preservation (FP) for prepubertal females and females who cannot delay their cancer treatment, as it requires no prior hormonal stimulation (1). In settings of ovarian malignancy or metastasis to the ovaries, there are additional OTC considerations regarding the surgical removal of ovarian tissue and future fertility restoration. The following cases describe the viability of OTC in situations involving ovarian malignancy as well as the importance of routine tissue biopsies and pathologic examination for diagnostic information that can best inform FP counseling of patients and families. These are the first cases of such findings at the Fertility & Hormone Preservation & Restoration (FHPR) program, a multidisciplinary oncofertility program at a tertiary academic children’s hospital.
STUDY DESIGN
Two cases were reviewed regarding the OTC process, including the counseling, oophorectomy, routine tissue biopsy, pathologic evaluation, and decision regarding tissue storage. Please see supplementary material for further details.
RESULTS
CASE ONE: DISCOVERY OF PREVIOUSLY UNKNOWN METASTATIC DISEASE IN OVARY
A 13-year-old, Tanner stage 5 patient presented with a new diagnosis of stage 4 PAX3-FOXO1 fusion positive alveolar rhabdomyosarcoma of the left hand. Initial PET/CT scans indicated no evidence of ovarian metastasis. The estimated total cyclophosphamide equivalent dose (CED) of her treatment plan was 30,800 mg/m2, which is associated with a high increased risk of developing premature ovarian insufficiency (POI) (2, 3). After extensive counseling, the patient and family opted for OTC.
The patient underwent a right unilateral oophorectomy (see Figure 1). In accordance with institutional protocol, a 4 mm by 1.0 cm punch biopsy was taken from the ovary for routine pathology evaluation.
Figure 1:
Ovarian images of case one (A-C) and case two (D-G). (A) Intraoperative view of pelvis during laparoscopic oophorectomy. Arrow demonstrating enlarged left ovary with peripheral cyst. (B) Gross image of right ovary after oophorectomy, which measured 4.25 cm × 3.50 cm (length × width) with a weight of 10.53 g. (C) Ovarian section cut into strips for processing. (D) Intraoperative view of right ovary during laparoscopic oophorectomy. (E) Gross image of right ovary after oophorectomy prior to bisecting. (F) Right ovary bisected along the long axis; one section sent to pathology (which measured 2.5 cm × 1.0 cm × 0.4 cm, length × width × height) and the other section sent to the gonadal tissue processing suite (which measured 2.37 cm × 0.78 cm, length × width, and weighed 0.4672 g). (G) Bisected ovarian section cut into strips for processing.
Evaluation of the specimen indicated germ cell-containing follicles and revealed previously unknown ovarian metastasis of rhabdomyosarcoma. The family was counseled on future risks associated with auto-transplantation of thawed ovarian tissue and reintroduction of malignancy. The patient and family proceeded with long-term storage of the tissue.
CASE TWO: PRIMARY OVARIAN MALIGNANCY
A 4-year-old, Tanner stage 1 patient presented with a pT1c1 right ovarian Sertoli-Leydig cell tumor, treated initially with right ovarian cystectomy followed by partial right oophorectomy once initial diagnosis was confirmed.
Following chemotherapy, a right completion oophorectomy was recommended. The estimated CED of the planned chemotherapy was less than 4,000 mg/m2, which is associated with a minimal increased risk of developing POI (2, 3). However, the patient’s newly confirmed DICER-1 mutation increases risk for new malignancies with potential need for additional gonadotoxic treatment (4). After FP discussion, the family chose to proceed with cryopreservation of any ovarian tissue removed during surgery and not used for pathology.
The FHPR and pathology team jointly devised a plan; the ovary would be bisected, with half sent to pathology and half sent for OTC processing. A larger biopsy size was intentionally selected to increase the likelihood of identifying any residual malignancy.
The patient underwent an uncomplicated right complete oophorectomy with no gross abnormalities noted. After oophorectomy, the ovary was bisected (see Figure 1), and the bisected section with the cortical scar from prior partial oophorectomy was sent for evaluation.
Pathology confirmed normal ovarian tissue with no significant pathologic changes or residual tumor. The family was notified and proceeded with long-term storage of the tissue, with the understanding that additional examination of saved tissue would be needed prior to re-implantation.
CONCLUSION
Our findings demonstrate the importance of a routine biopsy and pathologic evaluation during the OTC process to clarify crucial information and implications regarding patient diagnosis (including discovery of ovarian metastasis) and potential future fertility restoration options. Furthermore, biopsy size may need to be individually personalized (see Figure 2). Ultimately, this paper highlights the complex considerations of surgery and pathology required to navigate FP cases of pediatric patients with ovarian malignancy or metastasis. Additional research in in vitro follicle growth and maturation from OTC tissue is needed to create options for biological children while alleviating risk of reintroducing malignancies that may occur in auto-transplantation (5).
Figure 2:
Algorithm for approaching fertility preservation in patients with diagnosis and/or treatment that places their fertility at risk. Primary ovarian malignancy versus unsuspected metastatic involvement of the ovaries will determine the size of the biopsy sent to pathology for evaluation.
Supplementary Material
Attestation Statement:
Data regarding any of the subjects in the study has not been previously published unless specified
Data will be made available to the editors of the journal for review or query upon request
ACKNOWLEDGEMENTS
The FHPR team gratefully acknowledges Grace Schwartz BS and Luhan Tracy Zhou MS for their expertise in processing pediatric ovaries for ovarian tissue cryopreservation. We appreciate Pauline Chou MD for providing expert advice regarding pathologic evaluation and oversight of these cases.
Funding Statement:
The authors thank the generous supporters of Fertility & Hormone Preservation & Restoration research, Suzanne & Michael Burns, Mary and Ralph Gesualdo Family Foundation, and the Debicki Foundation (MML). Additional support was provided by the Warren & Eloise Batts Endowment (MML). ET was supported in part by National Institutes of Health/National Cancer Institute training grant T32 CA009560 and National Research Service Award F30HD107966–01.
Footnotes
Disclosure Statement:
Melissa J. Bak - Disclosure: none
Doris Farje – Disclosure: none
Elizabeth L. Tsui – Disclosure: NIH/NCI T32 CA009560, NRSA F30HD107966–01, T32GM008152 grants
Timothy B. Lautz – Disclosure: none
Monica M. Laronda – Disclosure: NIH U01HD110336, NIH R01HD104683 grants
Erin E. Rowell – Disclosure: none
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