Ocular Melanoma

Definition
Ocular melanoma, a rare cancer, is a disease in which cancer (malignant) cells are found in
the part of the eye called the uvea. The uvea contains cells called melanocytes. When these
cells become cancerous, the cancer is called a melanoma. The uvea includes the iris (the
colored part of the eye), the ciliary body (a muscle in the eye), and the choroid (a layer of
tissue in the back of the eye). The iris opens and closes to change the amount of light
entering the eye. The ciliary body changes the shape of the lens inside the eye so it can
focus. The choroid layer is next to the retina, the part of the eye that makes a picture. If
there is melanoma that starts in the iris, it may look like a dark spot on the iris. If melanoma
is in the ciliary body or the choroid, a person may have blurry vision or may have no
symptoms, and the cancer may grow before it is noticed. Ocular melanoma is usually found
during a routine eye examination, when a doctor looks inside the eye with special lights and
instruments.

The chance of recovery (prognosis) depends on the size and cell type of the cancer, where
the cancer is in the eye, and whether the cancer has spread.

Ocular Melanoma Locations

Ocular melanoma can occur in a variety of ocular tissue.

Iris
Ocular melanomas of the iris occur in the front colored part of the eye. Iris
melanomas usually grow slowly and do not usually spread to other parts of the body.

Ciliary body/choroid (small size)

Ocular melanomas of the ciliary body and/or choroid occur in the back part of the
eye. They are grouped by the size of the tumor. Small size ciliary body or choroidal
melanoma is 2 to 3 millimeters or less thick.

Ciliary body/choroid (medium/large size)

Ocular melanomas of the ciliary body and/or choroid occur in the back part of the
eye. They are grouped by the size of the tumor. Medium/large size ciliary body or
choroid melanoma is more than 2 to 3 millimeters thick.

Extraocular extension
The melanoma has spread outside the eye by extending through the wall of the eye,
the sclera.

Recurrent
Recurrent disease means that the cancer has come back (recurred) after it has been
treated.

Metastatic
Metastatic melanoma means that the tumor has spread far from the eye, usually to
the liver.

Symptoms
Most melanomas of the iris, ciliary or choroid are initially completely asymptomatic. As the
tumor enlarges, the tumor may cause distortion of the pupil (iris melanoma), blurred vision
(ciliary body melanoma) or markedly decreased visual acuity from a secondary retinal
detachment caused by a choroidal melanoma. Most melanomas are detected by routine
ophthalmic examination which should include dilation of the pupil and detailed examination
of the posterior aspect of the eye to detect choroidal melanomas. Like most early cancers,
an early melanoma is usually a silent cancer.

Determining that the Lesion is a Malignant Melanoma

One of the difficulties in diagnosing small melanomas is that it can be very difficult to
differentiate a small malignant melanoma from a benign pigmented tumor, such as an iris or
choroidal nevus. At present there is no definitive test that clearly differentiates a nevus from
a small malignant melanoma. Even with special biopsy techniques, such as fine needle
aspiration of the lesion, it can be very difficult to differentiate a benign nevus from a
malignant melanoma. A distinguishing feature of a small malignant melanoma from a nevus
is that the malignant melanoma progressively grows and enlarges. Thus, small lesions may
initially be observed to determine if the lesion remains static or shows evidence of
progressive growth.

The symptoms described above may not necessarily mean that you have ocular melanoma.
However, if you experience one or more of these symptoms, contact your eye doctor for a
complete exam.

Treatment
Once a definite diagnosis of malignant melanoma is made, possible therapies depend on the
location and size of the tumor. Metastatic melanoma can be difficult to treat. In this
situation, the ocular melanoma has spread far from the eye and typically has spread to the
liver.

Surgery
Small melanomas of the iris or ciliary body can sometimes by successfully treated with
surgery. An iridectomy refers to removal of part of the iris where the tumor is present. An
iridocyclectomy refers to part of the iris and the adjacent ciliary body where the tumor is
present. With very large tumors, the only possible option is removal of the eye, which is
called enucleation. Following removal of the eye, an artificial eye is placed in the socket.
With today's techniques, it can be extremely difficult to differentiate the artificial eye from
the adjacent normal eye.

Radiation Therapy
A special form of radiation therapy has shown to be very effective in treating malignant
melanomas of the ciliary body or choroid. This special form of radiation therapy is called
plaque therapy which consists of suturing a small metallic object, containing radioisotopes,
to the wall of the eye adjacent to the base of the tumor. Once the tumor has received
sufficient radiation to destroy the tumor, the plaque is again removed surgically.

The Collaborative Ocular Melanoma Study

The Collaborative Ocular Melanoma Study (COMS) is the largest study of the treatment
therapies of ocular melanoma. The COMS initially addressed the question whether additive
therapy (radiation therapy) would be of benefit to patients with large choroidal malignant
melanoma. In patients with large melanomas, the only reasonable option is removal of the
eye, which is called enucleation. Despite removal of the eye, these patients have an
increased risk of subsequently developing metastatic disease and dying from their ocular
melanoma. In COMS, with full patient agreement, patients were randomized to enucleation
of the eye or preoperative radiation followed by enucleation of the eye. Unfortunately, both
groups had essentially identical outcomes. The preoperative radiation did not reduce
subsequent metastatic disease.

Patients with medium tumors can be treated with either enucleation or a special form of
radiation therapy, called plaque therapy. Plaque therapy consists of a small gold carrier
(something like a small bottle cap), which contain radioactive seeds that can destroy or
inactivate tumors. The plaque is sutured to the wall of the eye (sclera) in the operating room
and is left in place until the tumor is destroyed.

The COMS evaluated whether enucleation or plaque therapy would be more effective in
preventing subsequent metastatic disease. With full patient agreement, patients were
randomized to either enucleation or plaque therapy and followed for 10 years to determine
which therapy would reduce metastatic disease and death. The study showed that plaque
therapy is equally effective as removal of the eye in preventing metastatic disease and
death. Thus plaque therapy has become the standard of care for most patients with ocular
melanoma.

Collaborative Ocular Melanoma Study (COMS)

Small-sized Choroidal Melanoma Study:

Small melanomas can be watched for growth prior to treatment. Should growth occur, then
the patient knows the melanoma will eventually destroy the vision and increase the chance
that cancer cells will spread to other parts of the body. The Collaborative Ocular Melanoma
Study (COMS) was interested in how many small melanomas would grow and over what
period of time. The COMS found that more than 25% of small melanomas were found to
grow (within 2 years of follow-up). Since choroidal melanoma growth is the best predictor for
vision loss and increased risk of metastasis, this COMS finding underscores the need to
follow patients with small melanomas closely after diagnosis.

Medium-sized Choroidal Melanoma Study:

The medium-sized tumor study was designed to determine if iodine-125 plaque-irradiation is
better, equal, or worse than enucleation (removal of the eye) for the prevention of
metastasis. In this study, half of enrolled patients were treated by enucleation and the other
half underwent plaque radiation therapy. Patients were followed for evidence of recurrence
and metastatic melanoma.

Half of enrolled patients were treated by enucleation and the other half underwent plaque
radiation therapy. Patients were followed for evidence of recurrence and metastatic
melanoma.

The COMS medium-tumor trial concluded that there is no significant difference between
these two treatment options with respect to survival. COMS centers had followed 80% of
patients for at least 5 years at the time they issued their report. Therefore, COMS found no
evidence that removing the eye is a better treatment than iodine-125 plaque radiation
therapy for preventing spread of choroidal melanomas.

Large-sized Choroidal Melanoma Study:

Large-melanoma trial was designed to see if radiation before enucleation (removal of the
eye) would prevent metastasis. The idea was to see if pre-operative irradiation would
sterilize any cells that might break free during surgery. The other half of the patients did not
receive radiation before their surgery.

The Large-sized Choroidal Melanoma Study concluded that patients who received 2000 rads
(cGy) of external irradiation to their eye before it was removed, had an equal chance of
developing metastatic disease as compared to those who were treated by enucleation
(removal of the eye) alone.

http://www.malignantmelanomainfo.com/BG-pages/Mtreatment.htm#t4
Malignant Melanoma of the Eye

What is it ~
Melanoma is a malignant tumor that most often arises in the skin. Less commonly, it is
found in the eye and other sites in the body. In the eye, melanoma arises from the
pigmented cells (melanocytes) of the uvea (iris, ciliary body or choroid). Melanoma carries
the potential to spread from the eye to other parts of the body. Larger melanomas carry
greater potential to spread than smaller tumors.

Who gets it ~
Melanoma affects approximately 2,000 to 2,500 people in the United States each year. It
affects about 6 people per million population per year. Importantly, melanoma of the eye
typically occurs in fair skinned, blue or green- eyed men and women. Rarely is this tumor
found in dark skinned individuals. Hence, it is relatively rare in Asia and Africa.

What causes it ~
The cause of melanoma is unknown. It has not been related to nutrition, smoking, drinking
or any environmental cause. Chronic sun exposure may play a role, but this is debatable.
Melanoma almost always affects only one eye and it is not hereditary so family members are
not at increased risk for this cancer. It can develop in an otherwise healthy patient.

What does it look like ~

The appearance of melanoma depends on its size and location, whether it is in the front of
the eye, in the iris, or in the back of the eye, the choroid. Iris melanoma appears as a brown
or yellow nodule on the iris, sometimes with discoloration of the remainder of the iris due to
tumor seeds. Iris melanoma is usually visible to the patient. Iris melanoma can cause
glaucoma and cataract, but most patients with glaucoma or cataract do not have melanoma.
Choroidal melanoma appears as a brown or yellow tumor in the back of the eye and is not
visible to the patient. Based on tumor thickness, choroidal melanoma is classified into small
(0-3mm), medium (3-8mm), and large (>8mm). Small tumors might resemble a benign
choroidal nevus or freckle.

Risk factors that identify which small tumors are melanoma include:
• Thickness > 2 mm
• Subretinal fluid over the tumor
• Symptoms of flashing lights, floaters, or vision loss
• Orange pigment over the tumor
• Margin of the tumor near the optic disc

These important factors were initially identified by our team on the Ocular Oncology Service
at Wills Eye Institute. Our findings are based on years of research. These factors have been
published and tested in various reports in ophthalmic medical journals such as
Ophthalmology, Archives of Ophthalmology, Current Opinion in Ophthalmology and others.
Using these factors to identify small melanoma could be life-saving.

Medium and large choroidal melanoma can assume a dome shape or even a mushroom
shape appearance as they enlarge. Often they produce overlying subretinal fluid (retinal
detachment) that is associated with vision loss. Growth of the tumor through the wall of the
eye into the overlying soft tissues is called extraocular extension and is more worrisome.

Goals of Treatment ~
The goal of treatment of a patient with uveal melanoma is to save the patient’s life. If
possible, salvage of the eye and vision is achieved.

In the past, surgical removal (enucleation) was the only method to treat uveal melanoma.
Over the past three decades, improved conservative treatment methods have been
developed to save the eye as well as the patient’s life. The choice of treatment method
depends on several factors including the age and health of the patient and the size, location,
thickness and growth pattern of the tumor. The management methods include observation,
laser photocoagulation, transpupillary thermotherapy, plaqueradiotherapy, local resection,
enucleation, exenteration and combination of these methods.

Observation ~
Some small, inactive melanomas are observed, especially if they occur in an elderly patient.
Monitoring of the tumor every few months with examination, photography, ultrasonography
and other tests is advised and if growth is detected, then interventional treatment is
provided.

Laser Photocoagulation ~
Laser photocoagulation is used occasionally for small melanoma of the eye. Often, several
sessions of laser are necessary over a few months. Currently, laser is most commonly used
to treat radiation related side effects in the retina rather than treatment directly to the
tumor.

Transpupillary Thermotherapy ~
This method provides focal heat to a tumor via a infrared beam directed through the pupil
into the tumor. It is often coupled with radiotherapy.

Plaque Radiotherapy ~
Plaque radiotherapy is currently the most common form of treatment for uveal melanoma. It
is used for small, medium, or large melanoma, but the side effects of treatment increase
with increasing tumor size. This technique involves a small radiation plaque that is the size
of a nickel and is surgically applied to the eye directly over the tumor. The plaque has
carefully placed radioactive seeds on the side that faces the sclera. The seeds are carefully
arranged on the plaque by specially trained radiation oncologists and physicists. After it is
prepared, the plaque is sterilized and placed on the eye surgically by the ocular oncologist.
It is left in place for 4 to 7 days to provide 8,000 centigray of radiation to the entire tumor.
The remainder of the body receives only a tiny amount of radiation, about the equivalent of
1 chest xray. The radiation plaque is then removed in the operating room and the patient is
discharged to home the day of plaque removal.

After plaque removal, the patient and his/her belongings are not radioactive. The goal of this
treatment is to destroy the tumor and prevent it from spreading to other parts of the body.
The radiation causes gradual shrinkage of the tumor to a smaller, visible scar. The brain,
opposite eye, and other parts of the body show no effect from the plaque.

The effects of radiation on the tumor are seen in 3 to 6 months after treatment. In a less
than 5% of patients, the tumor does not respond appropriately and a second plaque is
necessary or the eye might need to be removed (enucleation). Radiation can affect the
normal structures of the involved eye and cause cataract, glaucoma, and vision loss from
hemorrhage, retinal edema, or optic nerve dysfunction. After radioactive plaque treatment,
double vision for a few weeks to months might occur due to eye muscle imbalance.
Fortunately, this usually clears on its own, and patients rarely need to have special prism
eyeglasses or the muscles surgically balanced.

Local Resection ~
Resection of uveal melanoma is a method of surgically removing the entire tumor from the
eye and leaving the remainder of the eye intact. This is most often used for iris or ciliary
body melanoma.

The surgery is performed in the operating room and typically requires 2 to 4 hours of tedious
microscopic dissection. Only a few places in the world are capable of this difficult surgery
because it requires a high level of skill. Following surgery, the doctor will monitor for wound
leak, cataract, blood in the eye, retinal detachment and other side effects. Some patients
need additional radiation. Fortunately, most eyes tolerate this surgery well.

Enucleation ~
Prior to the 1960’s the usual treatment for choroidal melanoma was enucleation (removal of
the entire eyeball). Enucleation is still used to treat some large melanomas and even some
medium or small melanomas where other treatments will not work.

Enucleation is performed in the operating room. The eye is removed and a ball implant
(about the size of the eye) is placed in the remaining empty orbit. The eyelids and eye
muscles remain. The patient is discharged from the hospital wearing a heavy patch. In 6
weeks, the patient visits an ocularist (an artist who designs artificial eyes) and a prosthesis
(artificial plastic eye) is designed to match the remaining eye. The artificial eye is quite
natural in appearance and in some cases shows a remarkable match to the opposite eye.
Even though the artificial eye can move, the movement is not as full as the real eye. There
is no surgery at present to transplant an entire eye.
After enucleation, there is a reduced visual field to the side of the artificial eye and there is
some loss of depth perception as well. Many of the skills of depth perception are relearned
with time and most patients continue with their same jobs and activities without difficulty.

Protective lens made of polycarbonate are advised to be worn at all times in the form of
glasses during the day or goggles during activities or sports. Recommended reading for
vision in one eye is a book entitled “A Singular View. The Art of Seeing with One Eye“ by
Frank Brady, available online at www.amazon.com.

Exenteration ~
Exenteration is reserved for patients whose tumor has grown through the wall of the eye
into the orbit. This surgery involves removing the eye as well as the surrounding eyelids and
orbit. Fortunately, it is rarely necessary.

Combination Methods ~
Management of uveal melanoma typically involves a combination of methods such as plaque
radiotherapy followed by transpupillary thermotherapy or local resection followed by plaque
radiotherapy. Combination of methods can improve tumor control.

Prognosis

Uveal melanoma can lead to serious, life-threatening metastasis (spread of the tumor).
Overall, 20% of patients develop melanoma metastasis but it may be more or less than 20%
depending on the other factors. It is believed that metastasis usually occurs many months or
years before the melanoma causes symptoms or is treated. Fortunately, most patients do
not develop metastasis. Several factors predict who is at risk for metastasis and these
include: tumor location in the ciliary body, tumor size greater than 15 mm, and tumor cell
type epithelioid as well as others.

Our oncology team is a strong advocate of early treatment of uveal melanoma when the
tumor is small to prevent metastatic spread. Several published studies have shown that
plaque radiotherapy and local resection are as effective as enucleation in the prevention
of metastasis.

Marilyn C. Kincaid, MD (Moffitt cancer center)

Enucleation has been the standard therapeutic intervention for malignant
melanoma of the uveal tract, but alternative approaches offer hope for tumor
control and vision preservation.
Background: Malignant melanoma of the uveal tract is a rare malignancy but a significant
cause of mortality and visual loss. Approximately 50% of patients diagnosed with a
melanoma of the choroid or ciliary body will die of the disease within 15 years of
enucleation.
Methods: The author reviewed the current literature on the clinical findings, epidemiology,
and treatment of uveal melanoma.
Results: Methods of diagnosis have improved substantially in the past several years,
although clinical diagnosis by an experienced examiner remains the standard in eyes with
clear media. Ultrasound is the most useful adjunctive technique. While enucleation has
been the mainstay of therapeutic intervention, alternative therapies -- especially different
types of irradiation -- offer hope for tumor control and vision preservation. The Collaborative
Ocular Melanoma Study, a multicenter national trial, is designed to provide long-term data
on the natural history as well as therapeutic intervention.
Conclusions: Malignant melanoma of the uveal tract can be diagnosed clinically with more
confidence than ever before. It is also possible in many cases to retain the eye and
functional vision while controlling the tumor. However, unanswered questions remain about
the natural history and optimal therapy of uveal melanoma.

Introduction

Malignant melanoma, the most common primary intraocular malignancy, is a neoplasm of

the uveal tract. This is the pigmented layer of the eye that includes the iris, ciliary body, and
choroid. The iris is the readily visible, most anterior portion. While the iris is perceived as
giving the eye its color, such as blue, green, hazel, or brown, the melanocyte is the only
pigment-synthesizing cell of the uveal tract. The amount of melanin varies according to
racial and familial characteristics, and light diffraction explains the other aspects of iris
color. The iris functions as a diaphragm, constantly altering the size of the pupil according to
the ambient light.

The ciliary body is continuous with the iris, and it lines the sclera anteriorly. Its functions
include secretion of aqueous fluid and alteration of the shape of the crystalline lens for the
purpose of focusing. Posterior to it is the choroid, which lines the remainder of the sclera and
functions as a source of oxygen and nutrients for the overlying retina.

Epidemiology

Uveal malignant melanoma is an uncommon tumor, occurring in six persons per million
per year in the United States. It is more common in lightly pigmented persons and is
infrequently seen in nonwhite races. It is estimated that the frequency of uveal malignant
melanoma in American black persons is less than one eighth of the incidence in whites. In a
series from a pathology referral center, eyes from black individuals represented a little more
than 1% of the entire series, and mortality rates were similar for blacks and whites. 1 The risk
is also low in native Americans,2 African Americans, and Asians. Uveal melanoma is the most
common noncutaneous melanoma, with a frequency of approximately 12% that of
melanomas of the skin.3

Approximately half of all persons diagnosed with a melanoma of the choroid or ciliary
body will die of the disease within 15 years of enucleation. Interestingly, the rate of
metastasis overall has not decreased during this century, despite advances in therapy.
There is some indication that radiation therapy with tumor control may improve survival,4
but the numbers are small and duration of follow-up is relatively short. Survival with
metastatic disease is poor.3 Iris melanomas, in contrast, are much more benign in their
natural history, and local excision is usually curative when deemed necessary, 5 probably
because of the small size and readily visible location of iris melanomas.

The differences between cutaneous and uveal melanomas are intriguing. Melanomas of
the skin have been increasing in frequency over the last several decades, while such a trend
is less evident with ocular melanomas. Moreover, the rate of death from cutaneous
melanomas has also been rising in recent decades, whereas the death rate from uveal
melanoma has remained steady over the same period. In addition, the incidence of
cutaneous melanomas appears to be dependent on latitude, presumably reflecting exposure
to ultraviolet light. This trend has not been evident with uveal melanoma.3 A single case-
control study6 did suggest a risk for uveal melanoma with ultraviolet exposure from both
sunlight (as assessed by latitude) and sunlamps used for tanning melanoma, but the
numbers are small and remain to be supported by larger studies.
 Uveal melanoma shows a peak incidence at 55 years of age. Melanoma is slightly more
common in men as shown in several series, but it is unclear whether this is a primary effect
of gender or a secondary effect that is related to either an occupational or recreational
exposure.3 Uveal melanoma is unusual in children. 3 In one large clinical series,7
approximately 1% of all uveal melanomas occurred in patients 20 years of age or younger,
and only one patient died. These results contrast a previous series8 in which the mortality
rate for younger patients was similar to that for older patients.

Certain diseases and conditions may predispose to melanoma. Xeroderma pigmentosum,

an inherited disorder of DNA repair, is characterized by innumerable skin cancers, including
melanoma. Four patients have been reported to have uveal melanoma out of a total of
approximately 830 patients in the literature. While this is far fewer than the number of skin
cancers in such individuals, it is calculated to be about 23 times the rate of uveal melanoma
in the general population.9

Another predisposing condition is ocular or oculodermal melanocytosis. Ocular

melanocytosis is a developmental condition in which the ocular surface (the episclera) and
the uveal tract are hyperpigmented. When the surrounding skin is also involved, it is called
oculodermal melanocytosis, or nevus of Ota. The orbit and meninges can also be involved.
These two conditions are more prevalent in Asians, although uveal melanoma is rare in this
group. However, when either of these types of melanocytosis occurs in whites, the incidence
of uveal melanoma increases by approximately 30-fold, presumably due to the greater
numbers of melanocytes in the uveal tract.10

The relationship, if any, between the dysplastic nevus syndrome and uveal melanoma is
controversial. Individual cases have been reported as having both dysplastic nevi and uveal
melanoma, but no series shows a higher than chance association between the two.3

It has been suggested that pregnancy may enhance growth and metastases in melanoma.
However, large series fail to support this assertion. 11 A search for estrogen and progesterone
receptors in choroidal melanoma showed no evidence for such receptors.12

Melanomas are rarely bilateral. However, the number of patients with bilateral
involvement is greater than would be predicted by chance alone, thus implying a possible
genetic predisposition. Singh and associates13 found eight patients with bilateral uveal
melanoma in a large clinical series of 4,500 cases. No specific syndrome was identified other
than ocular melanocytosis in two of the eight patients.

Melanomas generally occur as sporadic tumors. However, there are kindreds with
melanoma, implying a possible familial trait. In one series of 4,500 patients with
melanoma,14 17 individuals had first-degree relatives with uveal melanoma. Statistically,
only one such family would be expected, thereby implying a greater than random chance
occurrence. The specific gene or trait, however, remains to be identified.14

Iris melanomas are a subset of uveal melanomas that tend to have a more benign
course.15 Only approximately 10% of all uveal melanomas arise in the iris.3 It is uncertain
whether this is because they are intrinsically different biologically or whether this simply
reflects earlier diagnosis and their extremely small size. Iris melanomas are more readily
detected because of their visibility. Moreover, the cornea acts as a magnifying lens, which
makes them appear larger than they actually are.

Diagnosis and Evaluation

 Patients with choroidal melanoma may present with complaints of visual loss, but many
melanomas cause no symptoms and are discovered on routine ocular examination. In eyes
with clear media, visual inspection by ophthalmoscopy remains the most reliable method for
diagnosis.16

Iris melanomas appear as single or multiple elevated lesions arising in the iris stroma.
Pigmentation ranges from inapparent to dark brown. Occasionally there is diffuse iris
involvement with minimal elevation, manifest as a monocular iris color change. Because the
iris is visible, melanomas of the iris can be discovered by patients themselves (Fig 1).
Assessing malignant potential can be difficult, even in those lesions with documented
growth, since iris nevi may also grow. Iris melanomas can involve the angle and extend into
the ciliary body or through the sclera. Alternatively, the first manifestation of a ciliary body
melanoma may be the appearance of a peripheral iris lesion.5

Melanomas of the ciliary body or choroid typically appear as discrete solid tumors.
Melanomas of the choroid present as solid tumors beneath the retina (Fig 2). A secondary
serous sensory retinal detachment adjacent to the tumor occurs frequently; this detachment
can be responsible for visual loss, even if the tumor does not involve the submacular choroid
directly. In addition, there can be retinal degeneration with pigmentary changes overlying
the apex of the tumor. The surface of some melanomas shows a patchy orange pigment,
found ultrastructurally to be lipofuscin, in macrophages and retinal pigment epithelium.17

Frequently, a choroidal melanoma breaks through Bruch’s membrane, extending into the
subsensory retinal space (Fig 3). Bruch’s membrane is a basement membrane-connective
tissue complex lying between the retinal pigment epithelium and the choriocapillaris, the
capillary network of the choroid. Clinically, such tumors have a mushroom or collar-button
shape. While this configuration is not diagnostic for melanoma, it is highly characteristic.
Melanomas taking on this configuration may, on rare occasions, cause vitreous hemorrhage
with symptoms of sudden visual loss. It is theorized that venous return in the portion of the
tumor internal to Bruch’s membrane is impeded due to the constricting effect of Bruch’s
membrane.18 Tumors with a collar-button configuration examined histologically show dilated
vessels in the internal portion with inconspicuous vascularity in the external portion.

As noted above, the retina overlying the tumor may show degenerative changes,
occasionally to the point of complete attenuation with tumor perforation into the vitreous
cavity. Discohesive cells may proliferate within the vitreous cavity19 or along the retinal
surface, causing a patchy pigmentation resembling retinitis pigmentosa.20

Serial observation of growth rates of melanomas may give some clues to prognosis. In
one retrospective study,21 the growth rate and the estimation of doubling time were
assessed for 145 patients. Estimates of doubling time ranged from less than six months to
more than four years, with a median of 1.4 years. More rapid growth and doubling times
predicted metastatic disease and radiation treatment failure.21

While the discrete, solitary tumor is the most frequent configuration, uveal melanomas
can take on a diffuse pattern in which much of the uveal tract is uniformly thickened. This
configuration is rare, occurring in approximately 5% of cases.22 Patients typically have poorly
differentiated tumors and early metastases.23 Rarely, melanomas can be multicentric in one
or both eyes.24

A rare syndrome has been described by Barr et al25 in which patients have bilateral diffuse
uveal melanocytic tumors associated with a systemic malignancy. These patients died of
their primary malignancy, but they did not develop metastatic melanoma. Much of the
ocular melanocytic proliferation was benign, although there were areas of malignant
transformation. The authors speculated that humoral factors may play a role, but the precise
relationship between the melanocytic proliferations and the systemic malignancy remains
unclear.

Melanomas can also diffusely involve the ciliary body in a pattern called ring melanoma.
Such tumors can be difficult to diagnose since there is relatively little visible mass effect and
since they occur in a diagnostically "silent" area of the eye. 26 Clinically, the only sign of the
melanoma may be focally increased pigmentation of the angle, anterior face of the ciliary
body, or adjacent peripheral iris.27 Transilluminating the globe can occasionally help to show
tumor size. This technique can be useful for delineating anteriorly located melanomas and is
an excellent method to assess the basal size of the tumor. Ultrasound may also be useful to
document these relatively silent tumors.

Other presentations of melanoma are less typical. Secondary glaucoma can occur through
several mechanisms. Indeed, intraocular melanoma is part of the differential diagnosis in
eyes with unilateral glaucoma. If the tumor extends through the retina or arises in the ciliary
body or the iris, discohesive cells can collect in the trabecular meshwork and impede
aqueous outflow. This form of secondary glaucoma is called melanomalytic glaucoma.28
Necrotic melanomas can release viable and necrotic cells along with free pigment and
pigment laden macrophages, thereby causing a similar condition.19 Tumors of the ciliary
body and the iris, especially if extensive, can also involve the trabecular meshwork directly.
Another mechanism occurs when large choroidal and ciliary body tumors shift the lens- iris
diaphragm forward, causing secondary pupil block glaucoma.

Ultrasound is the most useful ancillary technique, although the findings are characteristic
rather than specific for melanoma.16 Both A-scan and B-scan ultrasound shows choroidal
melanomas to have low to moderate internal reflectivity, sometimes called acoustic
hollowing because part of the tumor typically appears dark on B scan. The A scan is
accurate in helping to estimate the height of the tumor, which aides in distinguishing thin
melanomas from nevi and in assessing growth over time. The choroid just beneath the
melanoma often shows artifactual excavation, an ultrasonically lucent area just beneath the
choroid. B scans typically show orbital shadowing, an ultrasonically dark area posterior to
the sclera behind the tumor. Ultrasound will also disclose the collar-button shape of the
tumor if it has broken through Bruch’s membrane and any extraocular extension of the
tumor.29

Ultrasound is particularly useful in the diagnosis of melanoma in eyes in which the

posterior pole cannot be visualized directly. Melanomas in such eyes are often unsuspected.
One series estimated that up to 20% of all eyes with opaque media harbor a melanoma.30
Probably more recent figures would be lower, but such cases continue to occur. Melanomas
themselves can cause a dense vitreous hemorrhage that obscures them from view. Because
of the possibility of unsuspected melanoma, ultrasound should be done routinely in all eyes
with opaque media.30 Eyes with a unilateral dense cataract may also contain an unsuspected
melanoma that may have caused the cataract by direct pressure on the lens; diagnostic
ultrasound should be obtained to rule out this possibility.31

Fluorescein angiography is another technique that can supply supporting evidence for the
diagnosis of melanoma. Approximately two thirds of cases in one series showed a "double
circulation" pattern, which is characteristic of melanomas that have broken through Bruch’s
membrane.32 This "double-circulation" pattern refers to the filling of the retinal vessels
overlying the tumor, superimposed on dilated vessels within the tumor itself. This pattern
can sometimes be seen in melanomas that have not extended through Bruch’s membrane.
The retinal pigment epithelium is frequently altered overlying choroidal melanomas, and
focal defects are seen as "hot spots" as they leak fluorescein.
 Melanomas that have invaded the retina may show vascular anastomoses between the
tumor and the retina, as well as leaking microaneurysms in the retinal vessels overlying the
tumor. Other typical fluorescein patterns include areas of retinal capillary nonperfusion and
blockage of larger retinal vessels. None of these findings, however, is diagnostic for
melanoma, and not all melanomas demonstrate these patterns.32

Indocyanine green angiography is an alternative technique for imaging choroidal

vasculature. The excitation and emission wavelengths are in the near-infrared range, a
region in the spectrum where melanin is relatively transparent. Thus, indocyanine green
angiography shows details of choroidal circulation more effectively than does fluorescein.
This technique can be combined with scanning laser confocal microscopy to study the
vasculature at a particular level. In two patients, the clinical findings could be correlated
with the histologic configurations of the tumor vessels, allowing a possible estimate of
prognosis.33 The relationship of the tumor vascular patterns seen histologically and the
prognosis are discussed more fully below.

Magnetic resonance imaging (MRI) has been proposed as a helpful diagnostic technique
because melanin is paramagnetic and has specific characteristics (enhanced proton
relaxation with shortened T1 and T2 relaxation times) on imaging. However, melanomas
vary in degree of pigmentation as well as other intrinsic features so that the so-called
"characteristic" pattern is seen in only approximately 20% of cases.34 Since MRI is expensive
and currently is not as sensitive as other methods, its routine use is not indicated.

Fine-needle aspiration biopsy is a technique that may be useful in the differential

diagnosis in selected cases. A needle is inserted directly into the tumor from the vitreous
side, and the tumor is sampled for cytologic analysis. In this way, benign simulating lesions
can be diagnosed, thus avoiding a mistaken enucleation or radiation treatment. 35 As with
any sampling technique, both false-negative and false-positive results may be obtained, but
in experienced hands and with a cytopathologist experienced in evaluating ocular
specimens, this technique is both sensitive and specific. In one study of 53 patients with a
variety of histologically determined diagnoses,36 only one false positive and two false
negatives occurred. Fine-needle aspiration also can be useful as a predictor of subsequent
metastasis in patients undergoing radiation therapy. In a study of 116 patients about to
undergo either plaque or external irradiation,37 fine-needle aspiration was performed just
before treatment. The percentage of epithelioid cells correlated strongly with survival and
with tumor recurrence. However, as is always the caveat with fine-needle aspiration, the
sampled area may not be representative of the entire tumor.38

A general physical examination and additional tests are done to diagnose metastatic
disease. The most frequent site of metastasis is the liver, so the workup should include liver
enzyme levels, and, if indicated, liver ultrasound or scan. Early liver metastases can be
difficult to diagnose, which is unfortunate since prompt palliative treatment may enhance
survival somewhat. In one series,39 patients whose metastases were symptomatic and who
received no treatment survived a median of one year, while those whose metastases were
found on screening examination and who were treated survived for a mean of somewhat
more than three years. Whether prophylactic treatment for possible metastasis before it is
clinically evident would enhance survival is not known. 39 Other frequent sites of metastatic
disease are the lung and the central nervous system. The skin and subcutaneous tissue and
the skeleton are other reported sites.40 Overall, however, once metastasis has occurred,
survival is poor, and no treatment has been found to be effective.41

A number of lesions can simulate melanoma, especially those that appear dark clinically.
Over time, the numbers of eyes removed for the mistaken diagnosis of melanoma has
diminished considerably, due to both more accurate preoperative diagnosis and a greater
awareness of simulating lesions. The rate of false-positive diagnoses has dropped from
12.5% in 1970 to 1.4% in 1980. 42 In the first report from the Collaborative Ocular Melanoma
Study,43 only two of 413 enucleated eyes were diagnosed incorrectly, for a rate of 0.48%.
More recent figures from this same study gave a rate of 0.33% (five of 1,527 eyes).41 These
results, however, may not be generalizable to all clinical practices, 44 although large clinical
centers with considerable experience are likely to have similar results.

Melanocytic nevi can simulate small melanomas, and the clinical differentiation between
the two can be difficult. Moreover, some previously diagnosed small melanomas have, upon
further review of the histology, been reclassified as nevi since they were only minimally
elevated and had benign cytology.45 A particular type of nevus, the magnocellular nevus or
melanocytoma, can grow to be very large. Melanocytomas can arise anywhere in the uveal
tract, although the most common location is adjacent to the optic nerve head.
Melanocytomas are black, in contrast to the beige, tan, or brown color of melanomas.
Growth of melanocytomas does not necessarily indicate malignant transformation.46

Metastatic tumors can simulate amelanotic melanomas. However, they tend to be

bilateral and multifocal. The patient usually has a known primary, although lung carcinomas
are notorious for presenting as metastatic eye disease.47 While metastatic tumors can have
a variety of presentations, they typically are thinner than melanomas and amelanotic and
often are a creamy yellow, with overlying retinal pigment epithelial mottling. 48 Choroidal
lesions can also mimic scleritis,49 uveitis,50 and vitritis.51 Metastatic lesions of the iris may
resemble the Koeppe and Busacca nodules of sarcoid.52

Subretinal blood, particularly blood beneath the retinal pigment epithelium, can appear as
a dark, rounded lesion simulating a melanoma. With time, this blood will disappear or be
replaced by a fibrous scar. Diseases such as age-related macular degeneration can present
with subretinal pigment epithelial blood beneath the macular or extramacular disciform scar,
simulating melanoma. The disciform scar itself can be elevated enough, with variegated
pigmentation, to simulate a melanoma.

Retinal pigment epithelial proliferation occurs in response to many stimuli, including

ocular trauma, intraocular infection and inflammation, and retinal detachment. Sometimes
the resulting masses become quite large and nodular, posing a diagnostic problem.
Diagnostic fine-needle aspiration has been helpful in some cases.35

Choroidal hemangioma can simulate melanoma. These lesions may be solitary and
unassociated with systemic disease, or they may be part of the Sturge-Wever syndrome.
Hemangiomas are orange-red in appearance, nearly the same color as the fundus, and
usually do not change size appreciably. Ultrasound shows more internal reflectivity than is
typical for melanoma.53 There has been a single case report of a choroidal hemangioma
assuming a mushroom-shaped configuration.54

Choroidal osteoma, an idiopathic or postinflammatory discrete bony lesion, can resemble

an amelanotic melanoma by ophthalmoscopy, but it can be diagnosed by its characteristic
ultrasound or computed tomographic (CT) scan appearance.42 Osteomas are typically
juxtapapillary and, for unexplained reasons, tend to be more frequent in girls. Osteomas are
amelanotic lesions with minimal elevation. They typically appear as yellow-white and may
show slow growth. Because of the bony nature of these lesions, the ultrasound shows high
reflectivity, even with low intensity.55 Prior intraocular and periocular inflammation has been
suggested as the cause of these lesions in some patients, but for most, the pathogenesis is
obscure.56

Histology
 Because for years the standard therapy for melanomas was enucleation, the descriptive
histology of these tumors has been thoroughly studied. Two different types of tumor cells
have been described -- spindle and epithelioid. Spindle cells have elongated nuclei and
relatively scant cytoplasm (Fig 4). By light microscopy, the cells may appear to form a
syncytium but, as disclosed by electron microscopy, individual cells do have a plasma
membrane. In Callender’s original scheme,57 spindle cells were of two types -- A and B.
Spindle A cells, the most nearly benign type, had fine nuclear chromatin and a chromatin
stripe along the nucleus. The slightly plumper B cells had a single, round nucleolus. Other
cells, usually seen in larger tumors, are more discrete, larger, and more pleomorphic. They
have a round or oval nucleus and relatively abundant cytoplasm, and they are associated
with a worse prognosis. Because they resemble epithelial cells, they are called epithelioid
cells (Fig 5).

Callender undertook the first classification of uveal melanomas by histologic criteria and
categorized them into six groups.57 This classification system has subsequently been
modified to correlate with prognosis more precisely.58 The modified Callender classification is
still the most widely used scheme. However, it remains a subjective analysis, not easily
reproducible or consistently applied between different pathologists. 59 This is at least partly
due to the fact that the division between spindle and epithelioid cells is an artificial one;
tumor cell morphology represents a continuum. 58 An objective histologic classification would
be valuable, particularly for comparison of results from different institutions. Several
potential methods have been devised to assess prognosis more objectively.

One technique measures the mean of the nucleolar area using a computerized system to
sample routinely stained slides in a random fashion. The standard deviation of the mean of
the nucleolar area (thus a measure of both size and variation in size) derived from 50
random, computer-selected high-power fields has been shown to be an excellent predictor of
prognosis by some investigators. Tumors with larger nucleoli and with more variation in size
have a worse prognosis. The nucleolar size and variation correlate closely with the modified
Callender classification; thus, this method simply provides an objective method for
classification.58 In another series, nucleolar size also was useful in helping to differentiate iris
melanomas from nevi.60 Others, however, have not been able to confirm these results.61

An alternative method of evaluation looks at vascular supply to the tumor. 61 Nine different
vascular patterns have been described and categorized by staining routinely processed
slides with periodic acid-Schiff to enhance the vascular characteristics of the tumor. Of these
nine, only one (the closed-loop configuration) was a significant predictor of death from
melanoma.38 The investigators were able to amplify their prognostic data by scanning the
images into a computer to enhance and to quantify the relative area taken up by the
vascular patterns. They found that cross-sectional tumor area combined with presence and
amount of particular vascular patterns resulted in a high prediction of death from
metastases.62 Other investigators have not found the presence of vascular loops to be as
strong a predictor as was the measurement of the mean diameter of the largest nucleoli or
the cell type.63

Quantification of nucleolar organizer regions has also been correlated with prognosis.
Nucleolar organizer regions are those areas of the nucleolar DNA that direct ribosomal RNA
transcription and production of ribosomal proteins. Silver stains can be modified to highlight
these areas. By this technique, benign nevi were found to have a mean of fewer than two
such regions per cell, whereas melanomas had more than four. These measurements also
correlated with tumor size and mitotic index.64 These results need to be duplicated with a
larger series since this study had relatively few cases. More study, possibly with pooling of
cases from several laboratories, is needed to refine and compare all of these techniques.
Therapy

Twenty years ago, eyes with suspected ciliary body and choroidal melanoma were
enucleated routinely. In 1978, Zimmerman and colleagues65 challenged this traditional
approach to therapy by suggesting that enucleation might actually hasten death from
metastatic disease. They observed a postenucleation rise in mortality that peaked at
approximately two years after surgery. Presumably, compression on the globe during the
enucleation procedure caused tumor cells to exit via the vortex veins, thus causing
metastasis. Not all agreed with these conclusions.66 One difficulty was the lack of data on
the natural history of the tumor. Relatively few patients had refused enucleation, and they
did not constitute a random sample of all patients with melanoma. Moreover, relatively little
work had been done on alternative methods of therapy. A salutary effect of the observations
of Zimmerman et al, however, was that clinicians took a more cautious approach. No longer
were patients rushed to enucleation; rather, time was taken to be more certain of the
diagnosis and to document tumor growth more carefully.

One difficulty with this tumor is the wide variety of behaviors it exhibits. In one patient, a
melanoma remained stable, apparently dormant, for many years, then suddenly grew,
metastasized, and killed the patient. In another case, a choroidal melanoma that was
manifest as a rapidly enlarging lesion in an area of the fundus documented photographically
as tumor free 16 months earlier. These are two extremes, but they illustrate how varied the
biologic activity of this tumor can be.41

Much work has been done in the past 20 years to develop alternative methods of therapy,
particularly for those eyes with good vision. The most frequently used alternative method is
radiation therapy. Radiation kills a tumor either by producing free radicals that destroy
cellular DNA immediately or by induction of mutations that go on to kill tumor cells over a
protracted period of time. Radiation also induces vascular fibrosis and secondary hypoxia,
which again may take time to cause tumor cell death. Thus, radiation provides both short-
and long-term effects.67

Radiation can be given as an alternative to enucleation or as a preliminary treatment

before enucleation in order to decrease the likelihood of metastasis. No large-scale data are
available to evaluate the effectiveness of this approach, although in vitro studies confirm its
effectiveness in sterilizing tumor cells.67 In one series,68 survival after proton-beam
irradiation was compared to survival after enucleation, and there was essentially no
difference. Recent reports indicate that mortality rates are similar for patients whose eyes
were enucleated for complications attributed to irradiation as for patients whose eyes were
irradiated but not removed. In contrast, patients whose eyes were removed because of
radiation failure had poorer survival.4

The most frequently used system for delivering radiation is plaque radiotherapy
(brachytherapy). A metal shield containing small radioactive seeds is sutured to the outside
of the sclera overlying the tumor. The radiation dose is principally delivered to the base of
the tumor, with a gradual lessening toward the apex. The plaque size is designed to include
a margin of 2 mm around the tumor. It is left in place until the calculated dose of radiation
has been delivered, approximately five to seven days, then it is removed. Several different
isotopes have been used including cobalt 60, ruthenium 106, iodine 125, and palladium
103.67 Cobalt-60 was one of the first isotopes used for plaque therapy for choroidal
melanoma. It is a high-energy gamma emitter, and thus there is a risk of damage to normal
ocular structures several millimeters away from the source. Iodine 125, probably the most
frequently used isotope at present, is also a gamma emitter but at a much lower energy.
Thus, designing protective shields is easier and normal ocular structures are at less risk.69
 Another method of delivering radiation to the tumor involves charged particles, either
helium ions or protons, from an external source. The irradiation beam is roughly cylindrical
in shape, and the design of this system takes advantage of the Bragg peak effect, the
behavior of charged particles penetrating a tumor, to ensure that a more consistent dose is
delivered to the entire tumor with less irradiation of nearby normal structures. However,
because the radiation dose is delivered externally, anterior structures receive more radiation
than they would with a plaque.67 Histologic studies of eyes receiving proton-beam irradiation
show similar patterns of tumor necrosis and overlying retinal changes as are seen following
iodine 125 brachytherapy.70

Modifications of laser therapy and radiotherapy have been tried in a limited number of
cases, and these techniques have shown promise for the future. Transpupillary diode laser
therapy in conjunction with ruthenium-106 plaque therapy has been tried in 50 patients, and
all but one patient showed a reduction in tumor size.71 Another protocol used a microwave
generator attached to the sclera in a manner similar to plaque radiotherapy, as a radiation
sensitizer, and the involved eye subsequently received radiation plaque therapy. While
follow-up results were similar, the eyes receiving preradiation thermotherapy could be
treated effectively with lower radiation doses.72 Others have tried near-infrared
thermotherapy without radiation for small, posteriorly located tumors, since the heat
generated by the diode laser reaches a thickness of 4 mm. Of 100 treated patients, 94
responded with tumor shrinkage.73 The results of the studies are encouraging, although
larger series and longer follow-up are needed.

One problem with all forms of radiation therapy is that numerous complications can
ensue, primarily due to radiation vasculopathy.74 Neovascular glaucoma has been the most
serious problem with external-beam radiation.75 The long-term results in terms of survival for
external-beam radiation vs enucleation have been approximately equal.68 Smaller tumors
and those away from the fovea have tended to do better in terms of vision retention.76

Other modes of therapy are available for a limited number of tumors. Laser
photocoagulation can be used to ablate small thin tumors, although how much tumor
necrosis actually occurs remains controversial.77 Some tumors have recurred years later.78

Small tumors, especially those located relatively anteriorly, can occasionally be excised
using an eye-sparing technique known as sclerouvectomy (eyewall resection). The entire
tumor is removed en bloc, and a replacement piece of banked sclera is used to repair the
surgical defect. A modification of en bloc resection is lamellar sclerouvectomy, which
preserves the outer sclera and helps maintain the integrity of the eye. Some have claimed
good results with this technique in selected patients, 79 but others caution that melanoma
cells commonly invade the adjacent sclera and that cells can be present at the margin of the
resected tissue.80

Future Directions: The Collaborative Ocular Melanoma Study

The Collaborative Ocular Melanoma Study (COMS), a multicenter national trial, was begun
due to the controversy and uncertainty surrounding optimal treatment of uveal melanoma.
This study is funded by the National Eye Institute of the National Institutes of Health.
Enrollment of patients with ciliary body or choroidal melanoma began in 1987. Patients have
been sorted into three groups: those with small, medium, and large tumors. 81 Those with
small tumors (up to 3 mm in elevation) are observed for tumor growth; if growth is sufficient
to place the tumor in the medium group and if the patient remains eligible and willing, the
eye is randomized for treatment. Patients with medium tumors (those between 3 mm and 8
mm in thickness and up to 16 mm in largest basal diameter) are randomized to either
enucleation or plaque irradiation with iodine 125.81 Nearly 1,200 patients have been enrolled
in this arm of the study.41 Large tumors (greater than 8 mm in elevation and 16 mm in basal
diameter) are randomized to receive external irradiation or no irradiation before standard
enucleation.81 The cutoff between medium and large tumors was changed from 8-mm
elevation to 10-mm elevation partway through the recruitment period. 67 Before enrollment
closed in 1994, 1,003 patients were enrolled in this arm of the study.41

Part of the purpose of the COMS is to assess the natural history of the tumor in order to
design effective management and also to evaluate therapy in a nonbiased fashion. Also, the
study includes assessment of quality of life as well as vision retention in patients whose
tumors are irradiated.41 As with other multicenter trials, one objective is to standardize
observation and treatment criteria so that patients from different institutions can be
compared. Developing standardized criteria is the only way we will be able to obtain
sufficient data on a large enough group of patients to draw valid conclusions about natural
history and treatment. A weakness of the study is that external charged particle treatment
was not included. Also, there is no plan to compare efficacy of different plaque isotopes.

More than a decade has passed since recruitment for the COMS began. Some preliminary
results have been published recently, and one report82 confirms the very high accuracy rate
of clinical diagnosis. Of a total of 1,532 eyes enucleated as part of the protocol, all but five
were histologically confirmed as containing melanomas, for a rate of 99.7%. Four of the five
erroneously diagnosed eyes contained metastatic adenocarcinoma, and one had a
hemangioma.

Initial mortality figures from the trial of treatment options for large melanomas also were
recently published.83 Approximately 80% (801 of 1,003) of the patients enrolled have been
followed for five years or longer. Based on these patients, the estimated five-year survival
rates were 57% for enucleation alone and 62% with pre-enucleation irradiation, a
statistically insignificant difference. It is possible that longer duration may accentuate a
small difference.

Results for the trial of enucleation vs brachytherapy for medium-sized tumors are not yet
available. Previous experience would suggest that any difference in outcome between these
two options also probably will be small, although it may still be clinically important. Any
major advance in therapy for uveal melanoma will depend on gaining insights into the
timing and mechanisms of metastasis.