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Perspective
Cryopreservation and Autotransplantation
of Ovarian Tissue in Cancer Patients: Is It Safe?
Lobke Bastings, MD, Catharina C.M. Beerendonk, MD, PhD,
Johan R. Westphal, PhD, Didi D.M. Braat, MD, PhD, and Ron Peek, PhD
Keywords: counseling, cryopreservation, autotransplantation, ovarian tissue, fertility preservation, safety
Oncological therapy may severely compromise the
future fertility of girls and young women with cancer
and thereby limit their quality of life. Various strategies to
preserve fertility before the start of gonadotoxic treatment
have been proposed, such as in vitro fertilization (IVF), in-
tracytoplasmic sperm injection (ICSI), vitrification of oocytes,
and cryopreservation of ovarian tissue.
1
Unfortunately, not
all of these techniques are suitable for pre-pubertal girls and
adolescents. Not only do IVF and ICSI require a male partner
or donor sperm for fertilization, procedures using gonado-
trophin administration and oocyte retrieval are considered
inappropriate for sexually immature patients.
2
In case of ovarian tissue cryopreservation, neither
hormonal stimulation nor a stable relationship is necessary.
These characteristics make ovarian tissue cryopreservation
especially suitable for adolescents and the only option
available for fertility preservation in pre-pubertal girls.
1,2
Furthermore, as ovarian tissue can be obtained directly after
diagnosis, there is only minimal interference with cancer
treatment.
1
The main aim of cryopreservation of ovarian tissue is to
restore reproductive potential by retransplanting the tissue.
This can be performed once the patient has overcome her
disease and wishes to conceive but experiences premature
ovarian insufficiency due to the cancer treatment.
1,3
Although
the technique of ovarian tissue autotransplantation and sub-
sequent autografting is still considered experimental, 16 live
births have already been reported; 12 of these children were
born to 9 women who survived cancer.
3,4
As no central registration for ovarian tissue cryopreserva-
tion or autotransplantation exists, the total number of pro-
cedures carried out worldwide is unknown.
5
Nevertheless,
a considerable number of cryopreservation and autotrans-
plantation procedures have been reported,
6–14
indicating that
cryopreservation of ovarian tissue have been performed
on a large scale in the past decade. Therefore, the number
of cancer survivors requesting autotransplantation of their
ovarian tissue is anticipated to increase considerably in the
near future.
5
Although autotransplantation procedures are already be-
ing performed in oncological patients worldwide, the risks of
recurrent malignancy due to transmission of cancer cells via
the ovarian graft still remains largely unknown. This infor-
mation is critical for proper counseling and clinical decision
making for cancer survivors considering autotransplantation,
as well as for newly diagnosed oncological patients.
1,5
Here,
we discuss ovarian tissue autotransplantation-related safety
issues and make recommendations for future research and
patient counseling.
Why Is There Concern About the Safety
of Ovarian Tissue Autotransplantation?
The alarm was raised on the safety of ovarian tissue auto-
transplantation in cancer survivors for the first time in 1996.
At that time, healthy mice transplanted with fresh or cryo-
preserved ovarian tissue from mice with lymphoma devel-
oped the disease and died, though one mouse that received
cryopreserved tissue remained healthy.
15
A later xeno-
transplantation study also showed that acute lymphoblastic
leukemia was transmitted to recipient animals via human
ovarian grafts.
16
By using histology or polymerase chain reaction (PCR),
cancer cells have been detected in the ovaries from patients
with leukemia and Ewing sarcoma.
16–18
Apart from these
findings, it is known from clinical experience that different
types of oncological diseases have the potential to metastasize
to the ovaries. For example, breast cancer, a common indica-
tion for ovarian tissue cryopreservation,
9,11–13
has been re-
peatedly demonstrated to metastasize to the ovaries.
19,20
In contrast to these alarming results, other studies report
more reassuring findings when it comes to the safety of
ovarian tissue autotransplantation. Several studies failed to
show the presence of malignant cells in ovarian cortical tissue
Department of Obstetrics and Gynecology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
JOURNAL OF ADOLESCENT AND YOUNG ADULT ONCOLOGY
Volume 2, Number 1, 2013
ªMary Ann Liebert, Inc.
DOI: 10.1089/jayao.2012.0017
31
Journal of Adolescent and Young Adult Oncology 2013.2:31-34.
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from patients with breast cancer,
21,22
lymphoma,
23,24
and
various other oncological diseases.
25
Several authors have tried to provide guidance for clini-
cal decision making and counseling by classifying differ-
ent oncological diseases as having a low, intermediate, or
high risk of ovarian involvement based on the literature
available.
26–28
However, the absolute magnitude of the
risk of ovarian metastasis remains unclear, with some dis-
eases being classified in different risk categories in various
publications.
How to Assess the Risk of Oncological Relapse due
to the Reintroduction of Tumor Cells via Transplantation
One of the pivotal issues when assessing this risk of relapse
is the chance that malignant cells derived from a certain tumor
type and stage are present in the ovaries at the time ovarian
tissue is cryopreserved. Therefore, an overview of epidemio-
logical data on ovarian metastasis in different primary tumor
types, as well as the use of valid diagnostic tools with which
the involvement of the ovaries can be assessed in each indi-
vidual cancer patient, would be useful.
Histology and polymerase chain reaction
Minimal residual disease in ovarian tissue from cancer pa-
tients can bedetected by using histology and/or PCR.
16–18,22–25
During histological examination, the presence of cancer cells
may go unnoticed.
18
PCR is much more sensitive than his-
tology, but tumor-specific PCRs are available for only a lim-
ited number of oncological diseases. In addition, a positive
PCR signal does not provide information about the viability of
tumor cells present in the positive tissue, nor about their
ability to cause relapse after transplantation.
Cortical strips from the same ovary analyzed by PCR may
give different results with respect to the detection of cancer
cells, indicative of sampling bias.
18
As the ovarian strips that
are analyzed by histology or PCR are no longer available for
transplantation purposes, it remains uncertain whether the
strips that are actually used for transplantation purposes are
indeed devoid of cancer cells.
In conclusion, histology and PCR may provide information
about the incidence of minimal residual oncological disease
in the ovarian tissue, but do not guarantee that transplanta-
tion is safe.
Xenotransplantation
Prior to performing an autotransplantation of ovarian
tissue to the human recipient, one or a few cortical fragments
may be xenografted to a suitable immunodeficient host
animal.
15,16,23
Should the recipient animal develop malignant
disease, the tissue obviously contains tumor cells, as with the
mice that developed intraperitoneal leukemic masses after
being grafted with frozen-thawed ovarian tissue from pa-
tients with leukemia.
16
However, if the animals remain heal-
thy, this still offers no guarantee for safe autotransplantation,
as there is again inevitable sample bias.
29
In addition, growth
of the cancer cells might be different in the humans and im-
munocompromised animals.
Follow-up after autotransplantation of ovarian tissue
The duration of follow-up after autotransplantation of
ovarian tissue is still relatively short, and transplantations
have not yet been performed on a large scale.
3,5,8
Therefore,
the safety of autotransplantation cannot be ensured by the
follow-up data currently available. Finally, one should con-
sider that the available follow-up data might be biased by
selective reporting, as no central registration exists.
5
Epidemiological data on the incidence
of ovarian metastases
Follow-up of patients with a certain type of tumor or re-
ports from prophylactic oophorectomy during tumor resec-
tion may provide information about the incidence of ovarian
involvement. However, cancer patient follow-up studies in-
vestigating the incidence of ovarian involvement do not al-
ways clearly describe how they assessed the presence of
ovarian involvement; tumor stage, prior treatment, and other
important prognostic variables may also not be described.
With such a large number of confounding factors left un-
specified, it is quite difficult to extract useful information from
this type of report. Therefore, studies should provide clear
information about tumor types, stages, patient characteristics,
and other relevant prognostic factors, as well as details of the
research methods used. Studies meeting these strict criteria
may be scarce, and a systematic literature search for these
reports is strongly advisable.
One of the difficulties in interpreting epidemiological data
is that these reports include patients who did not have their
ovarian tissue cryopreserved. This means that for a large
number of cases, their ovaries have been exposed to radio- or
chemotherapy that may have eliminated minimal residual
disease in this organ. This is generally not the case in patients
who did opt for ovarian tissue cryopreservation. In addition,
although clinical studies may provide information about the
incidence of clinically relevant ovarian metastases during the
follow-up period, they do not inform about the percentage of
patients who have minimal ovarian involvement at the time
of cancer diagnosis. As a result, it is difficult to estimate the
significance of a single tumor cell in cryopreserved ovarian
tissue, as its capacity to develop into a metastatic lesion after
autotransplantation is unknown.
Conclusion and Recommendations
In conclusion, the available information for counseling
cancer survivors with regard to their risk of oncological re-
lapse after ovarian tissue autotransplantation is insufficient.
In addition, data from different types of studies cannot be
interpreted unambiguously.
It is clear that data on the risk of reintroducing tumor cells
with ovarian transplant are necessary, as a growing number
of patients are expected to request cryopreservation and au-
totransplantation in the near future. We would therefore like
to make the following recommendations.
First, we propose the creation of a database in which all
cancer-related cryopreservation and autotransplantation
cases are registered, including follow-up data. Registration
should preferably take place on an international level. The
European Society of Human Reproduction and Embryology
(ESHRE; Task Force Fertility Preservation), the International
Society for Fertility Preservation (ISFP), or the American So-
ciety for Reproductive Medicine (ASRM) may provide the
necessary infrastructure for such a registry, and would be
logical candidates for setting up this initiative. The
32 BASTINGS ET AL.
Journal of Adolescent and Young Adult Oncology 2013.2:31-34.
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anonymous data from the resulting database should be
available to all clinicians who counsel cancer patients on fer-
tility preservation, ensuring that unbiased follow-up data will
be available as soon as possible.
Next, we suggest performing additional research to im-
prove knowledge and introduce new options into clinical
practice. Studies focusing on the diagnosis and clinical sig-
nificance of minimal residual disease in the ovary will be
pivotal. In addition, further research is needed on techniques
that circumvent the risk of reintroducing cancer cells via au-
totransplantation, such as xenotransplantation of ovarian
tissue followed by IVF, in vitro maturation (IVM),
1,30
and
oocyte formation from stem cells.
31
To date, autotransplanta-
tion of ovarian tissue is the only clinically available option to
restore fertility after ovarian tissue cryopreservation.
1
For
current patient counseling, a systematic review of the available
data on ovarian involvement in neoplastic disease is therefore
urgently needed. Together with the follow-up data from au-
totransplantations, this review will facilitate counseling for
today’s patients who are confronted with fertility preservation
choices.
These recommendations should lead to improvements in
our ability to select the most suitable fertility preservation
option for each individual patient. Until then, we strongly feel
that both clinicians and patients should be aware of the un-
certainties regarding autotransplantation safety.
Acknowledgments
The work of R. Peek was funded by the KiKa Foundation.
Author Disclosure Statement
No competing financial interests exist.
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Address correspondence to:
Lobke Bastings, MD
Department of Obstetrics and Gynecology
Radboud University Nijmegen Medical Centre
PO Box 9101, 6500 HB
Nijmegen
The Netherlands
Email: l.bastings@obgyn.umcn.nl
34 BASTINGS ET AL.
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This article has been cited by:
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