Unknown risk of the reintroduction of malignant cells in a Danish cohort of women autotransplanted with ovarian tissue.

31 03 2011

To the Editor:

Ovarian cryopreservation appears to hold much promise for fertility preservation of women undergoing gonadotoxic therapy. In the Netherlands, cryopreservation of ovarian tissue has been performed for a number of cancer patients. No autotransplantation of ovarian tissue has been performed thus far, due (amongst other reasons) to concerns about the risk of reintroducing the malignancy with the transplant.

The available literature on this subject is not unequivocal. For example, Shaw et al. (1) have shown in a mouse model that lymphoma can be transmitted to the recipient by both fresh and frozen ovarian tissue grafts. Kim et al. (2), on the other hand, reassuringly demonstrated that none of the mice that were xenografted with human ovarian tissue fragments derived from patients with (non)Hodgkin lymphoma developed disease.

It is therefore with great interest that we read the recent article by Schmidt et al. (3), describing their results concerning the autotransplantation of cryopreserved ovarian tissue in a heterogeneous cohort (with regard to their disease) of Danish women with radio- or chemotherapy-induced premature ovarian failure. Remarkably, the authors did not provide any data on whether screening for residual disease was actually performed, and if so, by which method(s). This is even more striking considering the paper by the same research group (Rosendahl et al, 4), reporting that ovarian cortex was actually found to harbor leukemic cells, as determined by PCR.

As a consequence, these authors recommended not to autotransplant ovarian tissue in these patients. We realize that, inherent to their diffuse growth pattern, leukemic tumors are much more likely to disseminate to ovarian tissue compared to solid tumors. We still think, however, that also in patients with solid tumors, the risk of metastases in the transplant deserves to be properly addressed.

In addition, we are very much interested in how the patients were counseled on the risk of reintroducing the malignancy, prior to the autotransplantation.

Lobke Bastings, M.D.a,b
Johan R. Westphal, Ph.D.a
Catharina C.M. Beerendonk, M.D., Ph.D.a
Didi D.M. Braat, M.D., Ph.D.a
Ronald Peek, Ph.D.a

aRadboud University Nijmegen Medical Center
Department of Obstetrics and Gynecology
Nijmegen, The Netherlands

bJeroen Bosch Hospital
Department of Obstetrics and Gynecology
‘s Hertogenbosch
The Netherlands

References
1. Shaw JM, Bowles J, Koopman P, Wood ED, Trounson AO. Fresh and cryopreserved ovarian tissue samples from donors with lymphoma transmit the cancer to graft recipients. Hum Reprod. 1996;11(8):1668-73.

2. Kim SS, Radford J, Harris M, Varley J, Rutherford AJ, Lieberman B, Shalet S, Gosden R. Ovarian tissue harvested from lymphoma patients to preserve fertility may be safe for autotransplantation. Hum Reprod. 2001;16(10):2056-60.

3. Schmidt KL, Rosendahl M, Ernst E, Loft A, Andersen AN, Dueholm M, Ottosen C, Andersen CY. Autotransplantation of cryopreserved ovarian tissue in 12 women with chemotherapy-induced premature ovarian failure: the Danish experience. Fertil Steril. 2011 Feb;95(2):695-701.

4. 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(6):2186-90.

Published online in Fertility and Sterility doi:10.1016/j.fertnstert.2011.03.105

The Authors Respond:

We thank the authors for their interest in our paper and for the issues raised regarding the risk of reintroduction of a malignant disease following autotransplantation of cryopreserved ovarian tissue.

We fully agree with the authors that patients suffering from leukemia should presently not be offered autotransplantation due to the risk of residual malignant cells harboring in the cortical tissue, as we and others have previously demonstrated (1-3). Indeed, none of the 12 patients in the present study had leukemia, and to the best of our knowledge, no women with leukemia have been transplanted worldwide.

There is good evidence that the patients who are offered ovarian tissue cryopreservation (OTC) rarely have ovarian metastases, as the indication in itself requires low-stage disease. We have recently published a study on 51 patients with breast cancer whose ovarian cryopreserved cortical biopsies were examined by histological and immunohistochemical analysis and showed no signs of metastases (4). This has also been demonstrated in a large series by another group (5).

Ovarian cortical biopsies from at least 82 patients suffering from Hodgkin lymphoma undergoing OTC have been evaluated. One biopsy from a single patient with stage IIIB disease was suspicious for involvement of the malignancy, whereas all other biopsies showed no sign of malignant infiltration (6). Similarly, ovarian cortex from 21 patients with non-Hodgkin lymphoma were without evidence of malignant cell infiltration (2,7). It is also reassuring that despite around 30 published transplantations of ovarian tissue worldwide due to malignant disease, no cases with relapse due to the graft have yet been reported.

We always have approval from the the patient’s oncologist or hematologist before any autotransplantation procedure is performed, and if they have any reservations we refrain from doing it. The potential risks involved in the procedure are presented to the patient in detail and discussed with her prior to any transplantation, and the operation will not be performed without her informed consent. Additionally, we never offer OTC to patients with disseminated disease, and therefore the risk of metastases to the ovary in patients with solid tumours is very low. You can, however, never be 100% sure that there are not a few malignant cells present in the particular cortical fragment that is autotransplanted, and a histological or immunohistochemical examination of a neighboring cortical fragment of that same ovary cannot eliminate this risk. Notwithstanding, it is very reassuring that there have been no cases of reintroduction of the disease due to the transplanted tissue in any of our 12 patients with autotransplanted tissue after a minimum of 24 months and a maximum of 96 months of follow-up.

We believe, that if you decide to offer ovarian tissue cryopreservation as fertility preservation to cancer patients, you should be willing to offer to transplant it in concert with the patient and her oncologist in cases where neither the nature of her disease nor the literature provides any evidence of an increased risk of malignant cells in the ovarian tissue.

Kirsten Tryde Schmidt, Ph.D.a,b
Mikkel Rosendahl, Ph.D.b
Erik Ernst, Ph.D.c
Anne Loft, M.D.a
Anders Nyboe Andersen, D.M.Sc.a
Claus Yding Andersen, D.M.Sc.b

aThe Fertility Clinic
Copenhagen University Hospital
Rigshospitalet
Copenhagen, Denmark

bThe Laboratory of Reproductive Biology
Copenhagen University Hospital
Rigshospitalet
Copenhagen, Denmark

cInstitute of Anatomy and Department of Obstetrics and Gynecology
University of Aarhus
Aarhus, Denmark

References
1. Rosendahl M, Andersen MT, Ralfkiaer E, Kjeldsen L, Andersen MK, Andersen CY. Evidence of residual disease in cryopreserved ovarian cortex from female patients with leukaemia. Fertil Steril 2010; 94;2186-90.

2. 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 camcer patients. Hum Reprod 2008; 23:1007-13.

3. Dolmans MM, Marinescu C, Saussoy P, Van Langendonckt A, Amorim C, Donnez J. Reimplantation of cryopreserved ovarian tissue from patients with acute lymphoblastic leukemia is potentially unsafe. Blood 2010; 116:2908-14

4. Rosendahl M, Wielenga VT, 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 Jan 11. [Epub ahead of print].

5. Sánchez-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; 24:2238-43.

6. Bittinger SE, Nazaretian SP, Gook DA, Parmar C, Harrup RA, Stern CJ. Detection of Hodgkin lymphoma within ovarian tissue. Fertil Steril 2011; 95:803.e3-6.

7. 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.

Published online in Fertility and Sterility doi:10.1016/j.fertnstert.2011.03.106

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