Welcome to the World of Ocular Oncology
Intraocular tumors of any type are uncommon. The most common primary
malignant tumor of the eye, uveal melanoma, occurs in 7 persons per million population per
year -- less than one tenth the incidence of lung cancer.1 Retinoblastoma
occurs as a childhood disease approximately as frequently as hemophilia.2 These
two intraocular tumors, related only by anatomic proximity, have very different histories.
Retinoblastoma was a uniformly fatal disease before the turn of the
century, when clinical diagnosis occurred late and left little chance of cure. Long-term
survival with retinoblastoma became feasible with the introduction of the ophthalmoscope,
which permitted diagnosis when the tumor was confined to the eye, and with the
acknowledgment of the concept that surgical removal of a globe that harbored
retinoblastoma could prevent hematogenous dissemination. As retinoblastoma survivors
reached adulthood, it was evident that some patients could transmit the tumor to their
offspring in an autosomal dominant fashion. The clinical marker for hereditary
retinoblastoma had a particularly gruesome manifestation: bilateral eye involvement. In
1971, Alfred Knudson proposed a two-hit mutational hypothesis based on the age of children
diagnosed with sporadic and inherited tumors.3 His hypothesis suggested that
the molecular basis of retinoblastoma resides in a set of recessive genes. The discovery
of deletions in chromosome 13 in some children with inherited retinoblastoma was a major
breakthrough.4 The race to identify the genetic trigger of retinoblastoma was
in full force by the early 1980s.5 The retinoblastoma gene is now the most
studied human suppressor cancer gene as well as a model for many other ostensibly
unrelated types of cancer.6
The history of uveal melanoma is not as glorious as that of
retinoblastoma but is just as fascinating. There is little evidence that modern diagnostic
and therapeutic techniques have substantially prolonged the lives of patients with uveal
melanoma since enucleation was introduced early in this century as standard therapy. The
role of enucleation in the management of uveal melanoma became the topic of an
international debate in 1978 when Lorenz E. Zimmerman and colleagues from the Armed Forces
Institute of Pathology postulated that this surgical technique may actually promote
hematogenous dissemination of melanoma and may hasten death.7
This hypothesis was supported by three clinical observations. First,
it is unusual to detect metastatic disease in patients with uveal melanoma before
treatment or during the first six months following enucleation. Second, the rarity of
pretreatment metastases (approximately 1% per year) is independent of the size of the
primary tumor. In other words, preoperative metastases are no more common in patients with
large tumors than in patients with small or medium tumors. Third, annual mortality rates
from metastatic melanoma (death density function) peak between two and four years for
small, medium, and large tumors. The temporal relationship of enucleation and death
suggested that as many as two thirds of tumor deaths may be related to enucleation.7
For several years, ocular oncologists struggled to find another (and better) explanation
for these observations.8 Editorials questioned whether a moratorium on
enucleation for uveal melanoma was needed until the safety of enucleation could be
resolved.9 Once therapies have gained widespread acceptance, however, it is
difficult (if not impossible) to go back and test their effectiveness.
The merits of the so-called Zimmerman hypothesis became academic
after the National Eye Institute launched the Collaborative Ocular Melanoma Study (COMS)
in 1986. This randomized clinical trial was designed to test two major null hypotheses:
(1) no difference in mortality exists for patients with medium-risk choroidal and
ciliary-body mel-anoma treated with iodine 125 plaque and enucleation and (2) no
difference in mortality exists for patients with high-risk choroidal and ciliary-body
melanoma treated with enucleation with or without preoperative external radiation.10
The principal endpoint for each group is time to death from metastatic melanoma. Several
of the major ocular oncology centers in the United States initially decided not to
participate in the study. Reasons were varied, but perhaps the most compelling argument
was based on the low likelihood that the study could detect a clinically meaningful
difference in treatment effect in the medium-risk melanoma group. Another concern was the
prolonged time interval from treatment to endpoint, since it was possible that new, more
promising therapies could be developed before the study ended.
The COMS was conceived and developed knowing that the natural
history of choroid melanoma had never been adequately documented. The COMS addressed one
aspect of this problem -- the natural progression of small melanoma (less than 3 mm in
height and 5 mm to 16 mm in basal diameter) to the time in its natural history that
warrants treatment. Several studies have shown that there is no increase in tumor-specific
mortality in patients with small choroidal melanoma whose tumors are observed for growth.11,12
Participation in a nonrandomized, prospective, follow-up study within the COMS was offered
to the subset of patients with small melanomas in order to determine the natural history
of these tumors. As of 1997, 204 patients with small tumors were enrolled in the COMS, and
27 of these patients died.13 Six deaths were melanoma related and four occurred
more than five years after enrollment. The mean age of patients with small melanomas was
60 years. The Kaplan-Meier five-year melanoma-specific mortality was 1% (95% CI: 0% to
2.5%). These results show that persons with a small choroidal melanoma have a much greater
risk of dying from causes other than melanoma within five years of diagnosis.
Tumors other than retinoblastoma and melanoma occur in the eye, and
they are often the harbingers of disease elsewhere. Choroidal metastasis is the most
frequently occurring intraocular malignancy and can be the initial manifestation of
systemic malignancy. Choroidal metastases resemble nonpigmented melanomas. They have a
similar appearance to melanoma on fluorescein angio-gram and show subtle echographic
differences on ultrasonography. Choroidal metastases, however, grow more rapidly and are
more likely to cause large exudative
retinal detachments.
The iris is an uncommon site of metastasis. In general, the
prognosis for survival is poor once metastatic disease is found in the eye. As survival in
systemic cancer patients improves, however, successful treatment of ocular metastases has
an increasingly important role in maintaining a good quality of life.
Primary ocular lymphoma is one of the most intriguing intraocular
tumors. Its relationship with primary central nervous system lymphoma and the propensity
of the tumor to proliferate in the subretinal pigment epithelial space, where no lymphoid
tissue exists, are just two fascinating aspects of this highly aggressive lymphoma. The
clinical manifestations of primary ocular lymphoma are notorious for mimicking benign
uveitic entities and thus delaying the correct diagnosis for months. The neoplastic cells
in ocular lymphoma can remain confined to the space between the retinal pigment epithelium
and Bruch’s membrane. Because the vitritis associated with these aggregates of
lymphoma often consists of reactive lymphocytes, vitreous biopsy can be nondiagnostic.
This has lead to the misconception that it is difficult to interpret intraocular cytology,
when, in fact, surgeons were not harvesting tumor cells. The positive yield from
intraocular biopsy can be increased in some cases if the surgeon performs an aspiration
biopsy via retinotomy in the subretinal pigment epithelial space.14 Primary
ocular lymphoma consists of large, cytologically atypical cells that stain positive for
leukocyte common antigen. Aspirates are usually associated with large amounts of necrotic
debris. Immunophenotypic analysis has been problematic in the past. Some early studies
failed to find any surface markers and concluded that ocular lymphoma was a null-cell
tumor. Pretreatment of cells with hyaluronidase has increased the yield of
immuno-pathologic studies.15
The articles in this issue of Cancer Control describe some of
the accomplishments, controversies, and failures in perhaps one of the most parochial
areas of oncology. If one theme runs through each of these papers, it is the growing need
of interdisciplinary collaboration. The solutions to problems in ocular oncology depend on
an understanding of the unique clinical and biologic features of eye tumors.
Curtis E. Margo, MD, MPH
Watson Clinic, Lakeland, Florida
References
1. Margo CE, Mulla Z, Billiris K. Incidence of surgically treated uveal melanoma by
race and ethnicity. Ophthalmology. 1998;105:1087-1090.
2. Tamboli A, Podgor MJ, Horm JW. The incidence of retinoblastoma in the United States:
1974 through 1985. Arch Ophthalmol. 1990;108:128-132.
3. Knudson AG Jr. Mutation and cancer: statistical study of retinoblastoma. Proc
Natl Acad Sci U S A. 1971;68:820-823.
4. Francke U. Retinoblastoma and chromosome 13. Cytogent Cell Genet. 1976;16:
131-134.
5. Friend SH, Bernards R, Rogelj S, et al. A human DNA segment with properties of the
gene that predisposes to retinoblastoma and osteosarcoma. Nature. 1986;323:643-646.
6. Xu HJ, Hu SX, Cagle PT, et al. Absence of retinoblastoma protein expression in
primary non-small cell lung carcinomas. Cancer Res. 1991;51:2735-2739.
7. Zimmerman LE, McLean IW, Foster WD. Does enucleation of the eye containing a
malignant melanoma prevent or accelerate the dissemination of tumour cells? Br J
Ophthalmol. 1978;62:420-425.
8. Manschot WA, van Peperzeel HA. Choroidal melanoma: enucleation or observation? A new
approach. Arch Ophthalmol. 1980;98:71-77.
9. Jakobeic FA. A moratorium on enucleation for choroidal melanoma. Am J Ophthalmol.
1979;87:842-846.
10. Collaborative Ocular Melanoma Study Group. Design and methods of a clinical trial
for a rare condition: the Collaborative Ocular Melanoma Study. COMS Report No. 3. Control
Clin Trials. 1993;14:362-391.
11. Gass JD. Observation of suspected choroidal and ciliary body melanomas for evidence
of growth prior to enucleation. Ophthalmology. 1980;87:523-528.
12. Augsburger JJ, Vrabec TR. Impact of delayed treatment in growing posterior uveal
melanomas. Arch Ophthalmol. 1993; 111:1382-1386.
13. The Collaborative Ocular Melanoma Study Group. Mortality in patients with small
choroidal melanoma. COMS Report No. 4. Arch Ophthalmol. 1997;115:886-893.
14. Pavan PR, Orteiza EE, Margo CE. Ocular lymphoma diagnosed by internal subretinal
pigment epithelium biopsy. Arch Ophthalmol. 1995;113:1233-1234.
15. Wilson DJ, Braziel R, Rosenbaum JT. Intraocular lymphoma.
Immunopathologic analysis of vitreous biopsy specimens. Arch Ophthalmol.
1992;110:1455-1458.
Back to Cancer Control Journal
Volume 5 Number 4