To our knowledge, there have been no reports of transmission of a systemic
malignancy from a donor to a recipient by corneal transplantation. Known cases
of transmission of disease by transplanted corneal tissue have involved infectious
1 case of intraocular tumor.15 Corneal tissue
from donors who have died of malignancy (with the exception of leukemia, lymphoma,
and retinoblastoma) has been considered safe for transplantation.15-19 In
contrast, there have been many reports of transmission of systemic malignancy
from donor to recipient by solid organ transplantation. The donor origin of
one case of tumor transmission by solid organ transplantation was proven conclusively
by DNA typing.20 We report the first known
instance, to our knowledge, of transmission of a systemic malignancy by corneal
transplantation, proven by DNA analyses.
A 22-year-old man sought treatment in June 1992 because of a 2-week
history of slight irritation of his right eye and an area of discoloration
of his right iris. He had undergone a right corneal graft for keratoconus
in November 1990 (19 months previously). The left eye was densely amblyopic
and had not been grafted. At a review 2 months prior to the June 1992 visit,
the right eye was quiet, with no evidence of a mass, and a corrected visual
acuity of 20/20.
Two months later, the visual acuity in the right eye was 20/40 with
correction, improving with pinhole to 20/20. There was a vascularized, nonpigmented
mass approximately 4.0 × 2.5 mm, arising from the inferotemporal iris
between the 6- and 8-o'clock positions and extending into the angle (Figure 1A). The eye was inflamed, with dilated
episcleral vessels adjacent to the mass, keratic precipitates, anterior chamber
cells, and an inferotemporal posterior synechia. Indented funduscopy revealed
a localized retinal dialysis but no evidence of ciliary body involvement.
There was no evidence of posterior segment involvement on ultrasound and computed
tomography. Results of a full clinical examination were unremarkable, and
an intensive screen for systemic malignancy was negative. The provisional
diagnosis was a granulomatous reaction to a foreign body, although malignancy
could not be excluded. During the next week, the mass grew rapidly and it
was decided in consultation with the patient and his family to proceed to
A, Preoperative appearance of
the right eye at the initial examination in June 1992. The vascularized, nonpigmented
mass can be seen extending from the 6- to 8-o'clock positions on the face
of the iris and into the anterior chamber angle. The corrected visual acuity
was 20/40 (20/20 with pinhole). B, Postoperative appearance of the right eye
in September 1992 showing the iris defect. The graft and the lens are relatively
clear. The corrected visual acuity was 20/60.
A partial-thickness scleral incision was made 2 mm from the limbus and
a flap was raised, extending into clear cornea. A block of inner sclera including
the scleral spur and the trabecular meshwork was excised. The iris was then
prolapsed into the wound and a sector including the mass, the adjacent iris
root, the face of the ciliary body, and the anterior ciliary processes was
removed. The incision was closed and cryotherapy was applied to the posterior
wound margin and the area of retinal dialysis. The immediate postoperative
course was uneventful apart from a transient hyphema. Three weeks after the
operation, the right eye was quiet and the visual acuity was 20/30 with pinhole.
Histologic examination of the iris mass revealed a poorly differentiated
adenocarcinoma with associated inflammation. In view of the narrow margins
around the mass and the probability of a persistent tumor in the adjacent
angle, the patient's right eye received 10 000 rad (100 Gy) of 125iodine plaque radiotherapy to a depth of 3 mm at the limbus from
4- to 10-o'clock position. At the time of removal of the plaque, a scleral
buckle was placed at the site of the retinal dialysis.
At subsequent follow-up, there was a transient fall in visual acuity
to 20/60 due to decreased clarity of the corneal graft (Figure 1B). The graft gradually cleared, and at the most recent
follow-up nearly 10 years after the initial examination, the best-corrected
visual acuity had improved to 20/30. There had been no evidence of primary
adenocarcinoma in the recipient at any stage during this follow-up and no
evidence of metastasis.
The corneal donor's medical records were retrieved and reviewed. The
donor had impaired vision in both eyes and it was established that an ophthalmic
examination had been performed in the weeks prior to death. The results of
that examination had revealed bilateral choroidal masses consistent with choroidal
metastases. The donor died in November 1990 of disseminated, poorly differentiated
adenocarcinoma. The primary tumor was thought to originate from the bowel.
An autopsy was not carried out but a percutaneous biopsy of a lung lesion
had been performed 6 months prior to the donor's death. The histologic examination
of the specimen had showed adenocarcinoma. A small sample of this specimen
was still available and, together with the lesion from the recipient's iris
and blood sample, was submitted for genetic analysis. Results of molecular
analysis suggested that the recipient's iris tumor had arisen from the corneal
The recipient of the donor's other cornea was traced and examined for
evidence of tumor. The grafted eye was quiet and clear, with no evidence of
tumor transmission. This recipient remained well in this and subsequent follow-up.
No other tissues from the corneal donor were used for transplantation.
The biopsy tissue was submitted for routine pathologic examination.
For light microscopy, the formalin-fixed tissue was embedded in paraffin and
sections were stained with hematoxylin-eosin and a variety of specific commercial
The DNA was extracted from the tissue samples by incubation at 55°C
in the presence of sodium dodecyl sulfate and proteinase K.21 Two
extractions in phenol-chloroform were followed by a precipitation of the purified
DNA in absolute alcohol at −70°C. Patient and donor tissue samples
were extracted from paraffin blocks (fresh or fixed unprocessed tissue not
required). DNA was amplified and typed at the DQα locus using the commercial Roche molecular systems typing kit (F.
Hoffman La Roche Ltd, Basel, Switzerland). The DQ locus
on chromosome 6 contains the genes that encode for HLA class II (HLA-D).22 There are 6 common DQ alleles
detected by the kit (DQ 1.1, 1.2, 1.3, 2, 3, 4) that determine 21 possible
genotypes. Appropriate negative (water) and positive (known 1.1, 4) controls
were used. The reaction mix was amplified using 32 cycles of 94°C for
1 minute, 60°C for 30 seconds, 72°C for 30 seconds, and a final elongation
of 72°C for 8 minutes. Amplified DNA was typed using the probing strips
with 9 probes on their surfaces23 and a
hybridization temperature of 55°C for 20 minutes.
The specimen consisted of a segment of iris and ciliary body structures
and the mass, which measured approximately 5 × 3 × 3 mm (Figure 2). Arising from the anterior surface
of the iris and extending into the loose iris stroma was a malignant neoplasm
with well-developed papillary architecture. The tumor comprised fibrovascular
cores surrounded by focally stratified large epithelial cells with lightly
eosinophilic cytoplasm, large irregular ovoid nuclei, and 1 or 2 prominent
nucleoli. The cells were nonpigmented and occasional cells were vacuolated.
Deeper parts of the tumor contained small solid nests of cells and occasional
multinucleated cells. There was a high mitotic rate but no necrosis. The scleral
spur was sectioned separately and showed occasional tumor cells adherent to
the endothelium and trabecular meshwork but no scleral invasion. The tumor
cells stained for cytokeratin but were negative for S100 protein. The tumor
was diagnosed as a poorly differentiated adenocarcinoma. Further histologic
stains for placenta-like alkaline phosphatase and α-fetoprotein (for
testicular carcinoma) and thyroid globulin (for thyroid carcinoma) were negative.
Histologic examination of the
tumor (hematoxylin-eosin, original magnification ×25). The anterior
surface of the iris with the loose, papillary structured tumor is above and
the iris pigment epithelium below. See text for details.
Genetic analysis of the recipient revealed alleles 1.1 and 1.3. The
donor analysis revealed alleles 1.2 and 3. The alleles detected in the tumor
sample contained both alleles from the recipient (1.1, 1.3) and allele 3,
also found in the biopsy sample from the donor (Table 1 and Figure 3).
Because of the nature of this testing kit, the 1.2 allele can be hidden in
this configuration; thus, its presence cannot be excluded or confirmed in
the tumor specimen. To confirm the presence of the 1.2 allele in the iris
tumor, DNA sequencing would be required. This was precluded by the small initial
DQ test results showing (from
top to bottom): graft recipient, donor, iris tumor, negative (water), and
positive (known 1.1. 4) samples. The graft recipient sample shows matches
at 1.1 and 1.3. The donor sample shows matches at 1.2 (one of 1.2. 1.3, and
4; not 4; not 1.1; not 1.3) and 3. The iris tumor sample shows matches at
1.1, 1.3, and 3, and possibly 1.2 (at least one of 1.2, 1.3, and 4; not 4
[the structure of the test neither confirms nor excludes 1.2 in this configuration]).
AmpliType is an Applied Biosystems (Foster City, Calif) product.
The results of the molecular analyses almost conclusively demonstrate
that the iris tumor, a poorly differentiated adenocarcinoma, arose from the
corneal donor. The presence of the 3 allele in the tumor specimen can only
be explained by the presence of donor cells in the tumor. The 1.2 allele was
not detected in the tumor because of the typing kit methods. The tissue-typing
kit is designed to detect 6 common DQ alleles. In
normal circumstances, only 2 alleles would be present, and the kit relies
partly on the exclusion of possible alleles for full typing (Table 1 and Figure 3).
Therefore, because there could have been as many as 4 alleles, the kit was
not able to confirm or exclude the presence in the iris tumor of the 1.2 allele
from the donor.
The only alternative explanation for the presence of the 3 allele in
the iris tumor sample is that there was a mutation in the recipient's iris
tissue of either the 1.1 or 1.3 allele to a configuration that could be read
by the 3 probe. Such a mutation would require 5 specific and independent replacement
mutations, with the statistical probability that this could happen by chance
in less than 1 in 10 million.
Transmission of systemic malignancy by solid organ transplantation has
been recognized for many years.24-39 The
Cincinnati Transplant Tumor Registry reported 142 cadaver organ donations
from patients with unrecognized malignancies, leading to 64 cases of recipient
disease (45%).38 Twenty-six (72%) of 36
recipients with distant metastases died of their tumors. Stringent criteria
and procedures have been introduced in an attempt to reduce the incidence
of this often-fatal complication but occasional cases are still reported.36,39 The tumors most likely to evade
detection are small and clinically silent but capable of early metastasis.29,38
The use of closely matched donors and the systemic immunosuppression
required for the survival of solid organ transplantations is thought to increase
the viability of an inadvertently transmitted malignancy.24,25,29,36 There
have been several cases of successful treatment of a transplanted tumor by
removing the transplanted organ, withdrawing immunosuppression, and in some
cases, adding chemotherapy or radiation.24,25,27,30,34,39 In
a previous report, a 57-year-old woman received a closely matched (6 of 6
HLA antigen matched) renal transplant, but 3 months later began to develop
complications from what proved to be a malignant melanoma originating from
the kidney donor. She died despite treatment, and an autopsy revealed a widely
disseminated tumor. The large amount of tissue available made identification
of the HLA-DQ alleles and several other polymorphisms
feasible. These showed that despite the close antigen match, the donor and
tumor differed from the recipient in 1 HLA-DQ allele.
Three of 4 polymorphisms also showed that the donor and tumor were identical
but differed from the recipient.20
Our case represents the first documented case of transmission of a systemic
malignancy by corneal transplantation. The clarity, avascularity, and small
mass of the cornea make the accidental transmission of a viable number of
tumor cells very unlikely, and with the exception of 1 case of transmission
of retinoblastoma by corneal transplantation reported more than 60 years ago,15 this has never been known to occur. Similarly,
there has been no evidence of tumor transmission by transplantation of corneas
from donor eyes with primary choroidal melanomas.40 In
addition, corneal graft recipients very rarely receive systemic immunosuppression.
For these reasons, the exclusion criteria for corneal donors have not been
as strict as those for other organ donors.2,17,18
However, the avascularity of the cornea and anterior chamber and the
postoperative use of topical steroids may favor tumor transmission. This risk
was raised by Zakov et al,41 who described
a case in which micrometastases were found close to the excision margin of
the corneoscleral button in a donor eye. However, there was no evidence of
transmission of malignancy in this case or in a retrospective analysis of
403 cases of corneal transplantation at the Massachusetts Eye and Ear Infirmary
(Boston) between 1965 and 1968.16 Since
these reports, it has been considered safe to use such donors for corneal
further support from a recent retrospective review of 143 patients.19 However, direct evidence of the malignant potential
of micrometastatic tumor cells has been shown.42 Furthermore,
anterior chamber–associated immune deviation at least theoretically
might explain how situations such as our patient's arise. Experimentally it
has been shown in mice that immune privilege is extended to foreign tumor
cells in the anterior chamber. These foreign tumor cells survive and progressively
grow in the immune deviant anterior chamber environment.43
In our case, the finding of bilateral choroidal masses in the donor
during a clinical examination makes it highly likely that there was metastatic
adenocarcinoma in both eyes at the time of death. Presumably there were small
numbers of malignant cells adherent to the corneal endothelium at the time
of harvesting, and some or all of these cells proliferated in the recipient
anterior segment. To date there has been no evidence of extraocular spread.
It is interesting that the tumor did not become apparent for 19 months
after the date of transplantation, despite the apparent rapid growth at presentation
and the poorly differentiated histologic characteristics. It is well known
that even some very aggressive tumors, such as poorly differentiated breast
adenocarcinomas, may not recur for up to 5 years after excision of the primary
Another factor that may have played a part in this case is that the
original implanted tumor cell(s) may not have had a blood supply on the avascular
graft endothelium. Their growth may have been slow until a cell reached a
vascular supply on the iris or trabecular meshwork. The recipient's immune
system may have partially controlled the tumor while it was small, losing
control as it grew bigger.
Evidence from patients with a solid organ tumor who have developed transplanted
malignancies shows that it is possible for a competent immune system to overcome
such a malignancy if the tumor load is not too great.24,25,27,30,34,39 Such
immune modulation of tumor growth is thought to be mediated by natural killer–mediated
mechanisms.45 The recommended management
is to remove as much of the tumor as possible, withdraw immunosuppression,
and consider the use of adjunctive radiation or chemotherapy.24,25,27,29,30,34,38 The
graft recipient in this report had a competent immune system and a poorly
matched donor, unlike most solid organ transplant recipients. There was evidence
of an immune response to the tumor clinically, prior to excisional biopsy,
and on histologic examination. After excision cryotherapy46 and
local radiation, the residual tumor load was almost certainly negligible if
not nil. After nearly 10 years of careful follow-up, the recipient has remained
free of problems. Although we continue to be vigilant, we are increasingly
confident that the tumor has been "cured" and that the patient's immune response
has eliminated any remaining tumor cells.
Eye bank procedures currently exclude all donors with proven1-10,15 or
likely potential to transmit disease to recipients.12,17,18,47-49 Although
this case demonstrates a new risk of transmission of donor disease to a recipient,
it should be interpreted with caution. As many as 40% of donors in most eye
banks have died of disseminated malignant tumors and therefore have potential
micrometastases to the eye.41 Despite these
large numbers of donors, no case of transmission has previously been noted.16,19
At this stage, on the evidence of 1 case, the risk of such transmission
must be very low. Even if transmission occurs, the factors of probable poor
tissue match, lack of immunosuppression, and small tumor load make the prognosis
for patient survival excellent and for retention of the eye good. It would
clearly be prudent, however, to exclude potential donors with known ocular
metastases. All recipients need careful long-term follow-up and a high degree
of suspicion for malignancy in unusual iris presentations.
The authors have no financial interest in any of the instruments or
techniques used in this article.
We acknowledge the assistance of Jerry A. Shields, MD, and Ralph Eagle
Jr, MD (Wills Hospital, Philadelphia, Pa) and Derek Sherwood, FRCOphth (Nelson
Hospital, New Zealand) in the treatment of this patient, and the resources
of the New Zealand National Eye Bank.
Corresponding author and reprints: Phillip J. Polkinghorne, FRCOphth,
Department of Ophthalmology, Auckland Hospital, Private Bag 92024, Auckland,
New Zealand (e-mail: email@example.com).
D Possible person to person transmission of Creutzfeldt-Jacob disease. N Engl J Med.
1974;290692- 693Google Scholar
AG Complications of keratoplasty. Am J Ophthalmol.
1975;79907- 912Google Scholar
JL Flavobacterium endophthalmitis following keratoplasty: use of a tissue
culture medium-stored cornea. Arch Ophthalmol.
1976;941907- 1909Google ScholarCrossref
JV Pneumococcal endophthalmitis following grafting of corneal tissue from
a (cadaver) kidney donor. Ann Ophthalmol.
1977;9435- 440Google Scholar
SR Cryptococcal endophthalmitis after corneal transplantation. N Engl J Med.
1978;298825- 826Google ScholarCrossref
DS Torulopsis glabrata endophthalmitis after keratoplasty with an organ-cultured
cornea. Arch Ophthalmol.
1978;961019- 1022Google ScholarCrossref
et al. Human-to-human transmission of rabies virus by corneal transplant. N Engl J Med.
1979;300603- 604Google ScholarCrossref
RM Transfer of bacterial infection by donor cornea in penetrating keratoplasty. Am J Ophthalmol.
1979;87130- 132Google Scholar
HD Endophthalmitis following penetrating keratoplasty. Ophthalmology.
1983;9038- 39Google ScholarCrossref
JP Donor to host transmission of streptococcal infection by corneas stored
in McCarey-Kaufman medium. Cornea.
1984;3105- 108Google ScholarCrossref
A Assessment of the infectivity of corneal buttons taken from hepatitis
B surface antigen seropositive donors. Br J Ophthalmol.
1995;796- 9Google ScholarCrossref
R Review of the risk of HIV infection through corneal transplantation
in the United States. J Am Optom Assoc.
1994;65173- 178Google Scholar
B Transmission of rabies by corneal graft. Cornea.
1996;15431- 433Google ScholarCrossref
B Creutzfeldt-Jakob disease via dural and corneal transplants. J Neurol Sci.
1998;160128- 139Google ScholarCrossref
B The development of glioma in the eye to which the cornea of a patient,
who suffered from glioma, was transplanted. Acta Soc Ophthalmol Jap.
1939;431763- 1767Google Scholar
et al. Corneal donor material selection. Ophthalmology.
1981;88139- 145Google ScholarCrossref
Eye Bank Association of America, Medical Standards, November 1999. Washington, DC Eye Bank Association of America1999;
B Cancer transmission through corneal transplantation. Cornea.
2001;20680- 682Google ScholarCrossref
et al. Identification of donor melanoma in a renal transplant recipient. Diagn Mol Pathol.
1992;1266- 271Google ScholarCrossref
B Purification of DNA from formaldehyde fixed and paraffin embedded human
tissue. Biochem Biophys Res Comm.
1985;130118- 126Google ScholarCrossref
HA Generation of single stranded DNA by the polymerase chain reaction
and its application to direct sequencing of the HLA DQA locus. Proc Natl Acad Sci U S A.
1988;857652- 7656Google ScholarCrossref
HA Genetic analysis of amplified DNA with immobilized sequence-specific
oligonucleotide probes. Proc Natl Acad Sci U S A.
1989;866230- 6234Google ScholarCrossref
et al. Immunologic rejection of human cancer transplanted with a renal allograft. N Engl J Med.
1968;278479- 483Google ScholarCrossref
H Transplanted carcinoma in an immunosuppressed patient. Transplantation.
1970;971- 74Google ScholarCrossref
G Transplantation of malignant melanoma with cadaver kidney. Transplantation.
1972;13619- 620Google ScholarCrossref
J Metastatic choriocarcinoma transplanted with cadaver kidney. Cancer.
1977;31317- 1321Google ScholarCrossref
I Metastatic malignant melanoma transplanted via a renal homograft. Cancer.
1978;412426- 2430Google ScholarCrossref
et al. Accidental transplantation of bronchial carcinoma from a cadaver donor
to two recipients of renal allografts. J Clin Pathol.
1981;34109- 115Google ScholarCrossref
et al. Transmission of medulloblastoma from cadaver donor to three organ transplant
recipients. Transplant Proc.
JW Accidental transplantation of malignant tumor from a donor to multiple
1987;44449- 450Google ScholarCrossref
et al. Inadvertent transplantation of choriocarcinoma into four recipients. Transplant Proc.
1988;2098- 100Google Scholar
P Misdiagnosis of metastatic cerebral choriocarcinoma in female cadaver
donors. Transplant Proc.
1988;20776- 777Google Scholar
F Regression of an adenocarcinoma transmitted by a cadaver kidney graft. Transplantation.
1988;46777- 779Google ScholarCrossref
I Transmission of cancer with donor organs. Transplant Proc.
1988;20739- 740Google Scholar
et al. Organ transplantation with undetected donor neoplasm. Transplant Proc.
K Transmission of cancer with cadaveric donor kidneys. Transplant Proc.
I Donor transmitted disease: cancer. Transplant Proc.
1991;232629- 2631Google Scholar
et al. Transmission of glioblastoma multiforme to two kidney transplant recipients
from the same donor in the absence of ventricular shunt. Transplantation.
1993;55682- 683Google ScholarCrossref
WM Outcome of corneal grafting with donor tissue from eyes with primary
choroidal melanomas: a retrospective cohort comparison. Arch Ophthalmol.
1995;113753- 756Google ScholarCrossref
DM Corneal donor material selection. Am J Ophthalmol.
1978;86605- 610Google Scholar
et al. Malignant potential and cytogenetic characteristics of occult disseminated
tumor cells in esophageal cancer. Cancer Res.
2000;606836- 6840Google Scholar
J Ocular immune privilege and the Faustian dilemma: the Proctor lecture. Invest Ophthalmol Vis Sci.
1996;371940- 1950Google Scholar
NP Management of local/regional recurrence: role of radiation oncology. Bland
EMeds. The Breast: Comprehensive
Management of Benign and Malignant Diseases.
Pa WB Saunders Co1998;1244- 1255Google Scholar
et al. Natural killer cell-dependent suppression of systemic spread of human
lung adenocarcinoma cells by monocyte chemoattractant protein-1 gene transfection
in severe combined immunodeficient mice. Cancer Res.
2000;607002- 7007Google Scholar
TJ In vivo destruction of tumor tissue by cryoablation can induce inhibition
of secondary tumor growth: an experimental study. Cryobiology.
2001;4249- 58Google ScholarCrossref
HD Risk of prion disease transmission from ocular donor tissue transplantation. Cornea.
1999;182- 11Google ScholarCrossref
M Creutzfeldt-Jakob disease and the eye, I: background and patient management. Eye.
2000;14263- 290Google ScholarCrossref
et al. Eye banking and screening for Creutzfeldt-Jakob disease. Arch Ophthalmol.
2001;119721- 726Google ScholarCrossref