Abstract
Background
Transplantation of frozen/thawed ovarian tissue from patients with a malignant condition is associated with a risk of re-introduction of the disease as the tissue usually is removed before anti-cancer therapy and may thus contain malignant cells. We review studies investigating the presence of malignant cells in cryopreserved ovarian tissue from patients with malignant disease and based on the strength of the evidence, recommendations for transplantations are proposed.
Materials and methods
A systematic review of the literature. All peer reviewed studies evaluating the presence of malignant cells in cryopreserved human ovarian tissue were included. Data were searched in Pubmed and Embase with no language restrictions.
Results
The majority of the reviewed papers were casuistic reports and few of the included papers were specifically designed to search for malignant cells. Ovarian tissue from 422 patients has been subject to testing for malignant cells by imaging, histology, immunohistochemistry, molecular biology, animal- or clinical transplantation. In 31 (7 %) of the cases the applied test raised suspicion of malignant cell infiltration. No transplantation-related relapse of cancer has been reported after 33 transplantations of frozen/thawed ovarian cortex.
Conclusion
The quality and strength of the evidence is generally low and prospective studies are needed. The risk of re-introducing a malignant condition when transplanting ovarian tissue depends on the particular disease. Based on the available data, the risk was estimated: Leukaemia: HIGH. Gastrointestinal cancers: MODERATE. Breast cancer, sarcomas of the bone and connective tissue, gynaecological cancers, Hodgkin’s and Non-Hodgkin’s Lymphoma: LOW.
Similar content being viewed by others
References
Abir R, Feinmesser M, Yaniv I, Fisch B, Cohen IJ, Ben-Haroush A, et al. Occasional involvement of the ovary in Ewing sarcoma. Hum Reprod. 2010;25:1708–12.
Akar ME, Carrillo AJ, Jennell JL, Yalcinkaya TM. Robotic-assisted laparoscopic ovarian tissue transplantation. Fertil Steril. 2011;95:1120–8.
Amorim CA, Dolmans MM, David A, Jaeger J, Vanacker J, Camboni A, et al. Vitrification and xenografting of human ovarian tissue. Fertil Steril. 2012;98:1291–8.
Andersen CY, Rosendahl M, Byskov AG, Loft A, Ottosen C, Dueholm M, et al. Two successful pregnancies following autotransplantation of frozen/thawed ovarian tissue. Hum Reprod. 2008;23:2266–72.
Andersen CY, Silber S, Berghold SH, Stener Jørgensen J, Ernst E. Long-term duration of function of ovarian tissue transplants: case reports. Reprod Biomed Online. 2012;25:128–32.
Azem F, Hasson J, Ben-Yosef D, Kossoy N, Cohen T, Almog B, et al. Histologic evaluation of fresh human ovarian tissue before cryopreservation. Int J Gynecol Pathol. 2010;29:19–23.
Bigorie V, Morice P, Duvillard P, Antoine M, Cortez A, Flejou JF, et al. Ovarian metastases from breast cancer: report of 29 cases. Cancer. 2010;116:799–804.
Bittinger SE, Nazaretian SP, Gook DA, Parmar C, Harrup RA, Stern CJ. Detection of Hodgkin lymphoma within ovarian tissue. Fertil Steril. 2011;95:803–6.
Dath C, Van Eyck AS, Dolmans MM, Romeu L, Delle VL, Donnez J, et al. Xenotransplantation of human ovarian tissue to nude mice: comparison between four grafting sites. Hum Reprod. 2010;25:1734–43.
de Waal YR, Thomas CM, Oei AL, Sweep FC, Massuger LF. Secondary ovarian malignancies: frequency, origin, and characteristics. Int J Gynecol Cancer. 2009;19:1160–5.
Demeestere I, Simon P, Buxant F, Robin V, Fernandez SA, Centner J, et al. Ovarian function and spontaneous pregnancy after combined heterotopic and orthotopic cryopreserved ovarian tissue transplantation in a patient previously treated with bone marrow transplantation: case report. Hum Reprod. 2006;21:2010–4.
Demeestere I, Simon P, Emiliani S, Delbaere A, Englert Y. Fertility preservation: successful transplantation of cryopreserved ovarian tissue in a young patient previously treated for Hodgkin’s disease. Oncologist. 2007;12:1437–42.
Demeestere I, Simon P, Moffa F, Delbaere A, Englert Y. Birth of a second healthy girl more than 3 years after cryopreserved ovarian graft. Hum Reprod. 2010;25:1590–1.
Dittrich R, Lotz L, Keck G, Hoffmann I, Mueller A, Beckmann MW, et al. Live birth after ovarian tissue autotransplantation following overnight transportation before cryopreservation. Fertil Steril. 2012;97:387–90.
Dittrich R, Mueller A, Binder H, Oppelt PG, Renner SP, Goecke T, et al. First retransplantation of cryopreserved ovarian tissue following cancer therapy in Germany. Dtsch Arztebl Int. 2008;105:274–8.
Dolmans MM, Donnez J, Camboni A, Demylle D, Amorim C, Van LA, et al. IVF outcome in patients with orthotopically transplanted ovarian tissue. Hum Reprod. 2009;24:2778–87.
Dolmans MM, Marinescu C, Saussoy P, Van LA, Amorim C, Donnez J. Reimplantation of cryopreserved ovarian tissue from patients with acute lymphoblastic leukemia is potentially unsafe. Blood. 2010;116:2908–14.
Donnez J, Dolmans MM, Demylle D, Jadoul P, Pirard C, Squifflet J, et al. Livebirth after orthotopic transplantation of cryopreserved ovarian tissue. Lancet. 2004;364:1405–10.
Donnez J, Silber S, Andersen CY, Demeestere I, Piver P, Meirow D, et al. Children born after autotransplantation of cryopreserved ovarian tissue. a review of 13 live births. Ann Med. 2011;43:437–50.
Donnez J, Squifflet J, Jadoul P, Demylle D, Cheron AC, Van LA, et al. Pregnancy and live birth after autotransplantation of frozen-thawed ovarian tissue in a patient with metastatic disease undergoing chemotherapy and hematopoietic stem cell transplantation. Fertil Steril. 2011;95:1787.e1–4.
Donnez J, Squifflet J, Van Eyck AS, Demylle D, Jadoul P, Van LA, et al. Restoration of ovarian function in orthotopically transplanted cryopreserved ovarian tissue: a pilot experience. Reprod Biomed Online. 2008;16:694–704.
Ernst E, Bergholdt S, Jorgensen JS, Andersen CY. The first woman to give birth to two children following transplantation of frozen/thawed ovarian tissue. Hum Reprod. 2010;25:1280–1.
Ernst E, Kjærsgaard M, Birkebæk NH, Clausen N, Andersen CY. Stimulation of puberty in a girl with chemo - and radiation therapy induced ovarian failure by transplantation of a small part of her frozen/thawed ovarian tissue. Eur J Cancer. 2012. doi:10.1016/j.ejca.2012.09.028.
Evens AM, Hutchings M, Diehl V. Treatment of Hodgkin lymphoma: the past, present, and future. Nat Clin Pract Oncol. 2008;5:543–56.
Fogh J, Tiso J, Orfeo T, Sharkey FE, Daniels WP, Fogh JM. Thirty-four lines of six human tumor categories established in nude mice. J Natl Cancer Inst. 1980;64:745–51.
Friedman O, Orvieto R, Fisch B, Felz C, Freud E, Ben-Haroush A, et al. Possible improvements in human ovarian grafting by various host and graft treatments. Hum Reprod. 2012;27:474–82.
Giovanella BC, Stehlin Jr JS, Williams Jr LJ, Lee SS, Shepard RC. Heterotransplantation of human cancers into nude mice: a model system for human cancer chemotherapy. Cancer. 1978;42:2269–81.
Gook DA, Edgar DH, Borg J, Archer J, Lutjen PJ, McBain JC. Oocyte maturation, follicle rupture and luteinization in human cryopreserved ovarian tissue following xenografting. Hum Reprod. 2003;18:1772–81.
Gook DA, McCully BA, Edgar DH, McBain JC. Development of antral follicles in human cryopreserved ovarian tissue following xenografting. Hum Reprod. 2001;16:417–22.
Greve T, Clasen-Linde E, Andersen MT, Andersen MK, Sørensen SD, Rosendahl M, et al. Cryopreserved ovarian cortex from patients with leukemia in complete remission contains no apparent viable malignant cells. Blood. 2012;120:4311–6.
Guyatt GH, Oxman AD, Kunz R, Falck-Ytter Y, Vist GE, Liberati A, et al. Going from evidence to recommendations. BMJ. 2008;336:1049–51.
Guyatt GH, Oxman AD, Kunz R, Vist GE, Falck-Ytter Y, Schunemann HJ. What is “quality of evidence” and why is it important to clinicians? BMJ. 2008;336:995–8.
Guyatt GH, Oxman AD, Vist GE, Kunz R, Falck-Ytter Y, Alonso-Coello P, et al. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. BMJ. 2008;336:924–6.
Horvath TJ, Schindler AE. Ovarian metastases in breast carcinoma. Fortschr Med. 1977;95:358–60.
Imamura T, Huang CC, Minowada J, Moore GE. Heterologous transplantation of human hematopoietic cell lines. Cancer. 1970;25:1320–31.
Insabato L, De RG, Franco R, D’Onofrio V, Di VD. Ovarian metastasis from renal cell carcinoma: a report of three cases. Int J Surg Pathol. 2003;11:309–12.
Jaffrey BJ, Lair SV, Hudson JW, Lozzio BB, Machado EA, Chase DC. Heterotransplantation of human neoplasms. J Oral Surg. 1979;37:16–20.
Jemal A, Ward E, Thun M. Declining death rates reflect progress against cancer. PLoS One. 2010;5:e9584.
Khan MA, Dahill SW, Stewart KS. Primary Hodgkin’s disease of the ovary. Case report. Br J Obstet Gynaecol. 1986;93:1300–1.
Kim SS, Lee WS, Chung MK, Lee HC, Lee HH, Hill D. Long-term ovarian function and fertility after heterotopic autotransplantation of cryobanked human ovarian tissue: 8-year experience in cancer patients. Fertil Steril. 2009;91:2349–54.
Kim SS, Radford J, Harris M, Varley J, Rutherford AJ, Lieberman B, et al. Ovarian tissue harvested from lymphoma patients to preserve fertility may be safe for autotransplantation. Hum Reprod. 2001;16:2056–60.
Kristensen SG, Rasmussen A, Byskov AG, Andersen CY. Isolation of pre-antral follicles from human ovarian medulla tissue. Hum Reprod. 2011;26:157–66.
Kyono K, Doshida M, Toya M, Sato Y, Akahira J, Sasano H. Potential indications for ovarian autotransplantation based on the analysis of 5,571 autopsy findings of females under the age of 40 in Japan. Fertil Steril. 2010;93:2429–30.
Liu LY. Metastatic cancer in the ovary—report of 57 cases. Zhonghua Zhong Liu Za Zhi. 1989;11:464–7.
Lock RB, Liem N, Farnsworth ML, Milross CG, Xue C, Tajbakhsh M, et al. The nonobese diabetic/severe combined immunodeficient (NOD/SCID) mouse model of childhood acute lymphoblastic leukemia reveals intrinsic differences in biologic characteristics at diagnosis and relapse. Blood. 2002;99:4100–8.
Lotz L, Montag M, Van der Ven H, von Wolff M, Mueller A, Hoffmann I, et al. Xenotransplantation of cryopreserved ovarian tissue from patients with ovarian tumors into SCID mice—no evidence of malignant cell contamination. Fertil Steril. 2011;95:2612–4.
Meirow D, Baum M, Yaron R, Levron J, Hardan I, Schiff E, et al. Ovarian tissue cryopreservation in hematologic malignancy: ten years’ experience. Leuk Lymphoma. 2007;48:1569–76.
Meirow D, Ben YD, Prus D, Poliack A, Schenker JG, Rachmilewitz EA, et al. Ovarian tissue banking in patients with Hodgkin’s disease: is it safe? Fertil Steril. 1998;69:996–8.
Meirow D, Biederman H, Anderson RA, Wallace WH. Toxicity of chemotherapy and radiation on female reproduction. Clin Obstet Gynecol. 2010;53:727–39.
Meirow D, Hardan I, Dor J, Fridman E, Elizur S, Ra’anani H, et al. Searching for evidence of disease and malignant cell contamination in ovarian tissue stored from hematologic cancer patients. Hum Reprod. 2008;23:1007–13.
Meirow D, Levron J, Eldar-Geva T, Hardan I, Fridman E, Zalel Y, et al. Pregnancy after transplantation of cryopreserved ovarian tissue in a patient with ovarian failure after chemotherapy. N Engl J Med. 2005;353:318–21.
Meyer LH, Debatin KM. Diversity of human leukemia xenograft mouse models: implications for disease biology. Cancer Res. 2011;71:7141–4.
Oktay K. Spontaneous conceptions and live birth after heterotopic ovarian transplantation: is there a germline stem cell connection? Hum Reprod. 2006;21:1345–8.
Oktay K, Buyuk E, Veeck L, Zaninovic N, Xu K, Takeuchi T, et al. Embryo development after heterotopic transplantation of cryopreserved ovarian tissue. Lancet. 2004;363:837–40.
Oktay K, Newton H, Mullan J, Gosden RG. Development of human primordial follicles to antral stages in SCID/hpg mice stimulated with follicle stimulating hormone. Hum Reprod. 1998;13:1133–8.
Oktay K, Turkcuoglu I, Rodriguez-Wallberg KA. Four spontaneous pregnancies and three live births following subcutaneous transplantation of frozen banked ovarian tissue: what is the explanation? Fertil Steril. 2011;95:804–10.
Perrotin F, Marret H, Bouquin R, Fischer-Perrotin N, Lansac J, Body G. Incidence, diagnosis and prognosis of ovarian metastasis in breast cancer. Gynecol Obstet Fertil. 2001;29:308–15.
Povlsen C, Rygaard J. Growth of human tumors in the nude mouse. In: Bloom BR, David JR, editors. In vitro methods in cell-mediated and tumor immunity. New York: Academic; 1976. p. 701–11.
Radford JA, Lieberman BA, Brison DR, Smith AR, Critchlow JD, Russell SA, et al. Orthotopic reimplantation of cryopreserved ovarian cortical strips after high-dose chemotherapy for Hodgkin’s lymphoma. Lancet. 2001;357:1172–5.
Revel A, Laufer N, Ben MA, Lebovich M, Mitrani E. Micro-organ ovarian transplantation enables pregnancy: a case report. Hum Reprod. 2011;26:1097–103.
Rosendahl M, Andersen CY, Ernst E, Westergaard LG, Rasmussen PE, Loft A, et al. Ovarian function after removal of an entire ovary for cryopreservation of pieces of cortex prior to gonadotoxic treatment: a follow-up study. Hum Reprod. 2008;23:2475–83.
Rosendahl M, Andersen MT, Ralfkiaer E, Kjeldsen L, Andersen MK, Andersen CY. Evidence of residual disease in cryopreserved ovarian cortex from female patients with leukemia. Fertil Steril. 2010;94:2186–90.
Rosendahl M, Loft A, Byskov AG, Ziebe S, Schmidt KT, Andersen AN, et al. Biochemical pregnancy after fertilization of an oocyte aspirated from a heterotopic autotransplant of cryopreserved ovarian tissue: case report. Hum Reprod. 2006;21:2006–9.
Rosendahl M, Schmidt KT, Ernst E, Rasmussen PE, Loft A, Byskov AG, et al. Cryopreservation of ovarian tissue for a decade in Denmark: a view of the technique. Reprod Biomed Online. 2011;22:162–71.
Rosendahl M, Timmermans WV, Nedergaard L, Kristensen SG, Ernst E, Rasmussen PE, et al. Cryopreservation of ovarian tissue for fertility preservation: no evidence of malignant cell contamination in ovarian tissue from patients with breast cancer. Fertil Steril. 2011;95:2158–61.
Roux C, Amiot C, Agnani G, Aubard Y, Rohrlich PS, Piver P. Live birth after ovarian tissue autograft in a patient with sickle cell disease treated by allogeneic bone marrow transplantation. Fertil Steril. 2010;93:2413–9.
Sanchez M, Novella-Maestre E, Teruel J, Ortiz E, Pellicer A. The Valencia programme for fertility preservation. Clin Transl Oncol. 2008;10:433–8.
Sanchez-Serrano M, Crespo J, Mirabet V, Cobo AC, Escriba MJ, Simon C, et al. Twins born after transplantation of ovarian cortical tissue and oocyte vitrification. Fertil Steril. 2010;93:268–3.
Sanchez-Serrano M, Novella-Maestre E, Rosello-Sastre E, Camarasa N, Teruel J, Pellicer A. Malignant cells are not found in ovarian cortex from breast cancer patients undergoing ovarian cortex cryopreservation. Hum Reprod. 2009;24:268.e11–3.
Schmidt KL, Andersen CY, Loft A, Byskov AG, Ernst E, Andersen AN. Follow-up of ovarian function post-chemotherapy following ovarian cryopreservation and transplantation. Hum Reprod. 2005;20:3539–46.
Schmidt KL, Ernst E, Byskov AG, Nyboe AA, Yding AC. Survival of primordial follicles following prolonged transportation of ovarian tissue prior to cryopreservation. Hum Reprod. 2003;18:2654–9.
Schmidt KT, Rosendahl M, Ernst E, Loft A, Andersen AN, Dueholm M, et al. Autotransplantation of cryopreserved ovarian tissue in 12 women with chemotherapy-induced premature ovarian failure: the Danish experience. Fertil Steril. 2011;95:695–701.
Seshadri T, Gook D, Lade S, Spencer A, Grigg A, Tiedemann K, et al. Lack of evidence of disease contamination in ovarian tissue harvested for cryopreservation from patients with Hodgkin lymphoma and analysis of factors predictive of oocyte yield. Br J Cancer. 2006;94:1007–10.
Shimada M, Kigawa J, Nishimura R, Yamaguchi S, Kuzuya K, Nakanishi T, et al. Ovarian metastasis in carcinoma of the uterine cervix. Gynecol Oncol. 2006;101:234–7.
Silber S, Kagawa N, Kuwayama M, Gosden R. Duration of fertility after fresh and frozen ovary transplantation. Fertil Steril. 2010;94:2191–6.
Silber SJ. Ovary cryopreservation and transplantation for fertility preservation. Mol Hum Reprod. 2012;18:59–67.
Silber SJ, DeRosa M, Pineda J, Lenahan K, Grenia D, Gorman K, et al. A series of monozygotic twins discordant for ovarian failure: ovary transplantation (cortical versus microvascular) and cryopreservation. Hum Reprod. 2008;23:1531–7.
Stern CJ, Toledo MG, Hale LG, Gook DA, Edgar DH. The first Australian experience of heterotopic grafting of cryopreserved ovarian tissue: evidence of establishment of normal ovarian function. Aust N Z J Obstet Gynaecol. 2011;51:268–75.
Telfer EE, McLaughlin M. Natural history of the mammalian oocyte. Reprod Biomed Online. 2007;15:288–95.
Tryde Schmidt KL, Yding AC, Starup J, Loft A, Byskov AG, Nyboe AA. Orthotopic autotransplantation of cryopreserved ovarian tissue to a woman cured of cancer—follicular growth, steroid production and oocyte retrieval. Reprod Biomed Online. 2004;8:448–53.
Van Eyck AS, Bouzin C, Feron O, Romeu L, Van LA, Donnez J, et al. Both host and graft vessels contribute to revascularization of xenografted human ovarian tissue in a murine model. Fertil Steril. 2010;93:1676–85.
Yada-Hashimoto N, Yamamoto T, Kamiura S, Seino H, Ohira H, Sawai K, et al. Metastatic ovarian tumors: a review of 64 cases. Gynecol Oncol. 2003;89:314–7.
Young RH, Kozakewich HP, Scully RE. Metastatic ovarian tumors in children: a report of 14 cases and review of the literature. Int J Gynecol Pathol. 1993;12:8–19.
Funding
The financial support from the Danish Cancer Society (DP05112/ R2-A41-09-S2) and the University Hospital of Copenhagen is gratefully acknowledged.
Author information
Authors and Affiliations
Corresponding author
Additional information
Capsule Cryopreserved ovarian tissue from cancer patients may contain malignant cells capable of causing relapse of the malignancy if the tissue is retransplanted. The literature is reviewed and the estimated risk of reintroduction of the most common malignancies in case of retransplantation of the tissue is proposed.
Rights and permissions
About this article
Cite this article
Rosendahl, M., Greve, T. & Andersen, C.Y. The safety of transplanting cryopreserved ovarian tissue in cancer patients: a review of the literature. J Assist Reprod Genet 30, 11–24 (2013). https://doi.org/10.1007/s10815-012-9912-x
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10815-012-9912-x