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Purpose: The aim of this study was to discuss the clinical and translational content of the literature as well as advancement in our knowledge pertaining to retinoblastoma and uveal melanoma that were
published from January to December 2013.
Design: This study is a literature review.
Methods: The search terms retinoblastoma and uveal melanoma were
used in a MEDLINE literature search. Abstracts were studied, and the most
relevant articles were selected for inclusion and further in-depth review.
Results: In retinoblastoma, fewer eyes are lost because of the expanded
use of ophthalmic artery chemosurgery and intravitreal melphalan, and
the past year marks a deepening in our understanding of these modalities. Knowledge on the genetic underpinnings of uveal melanoma has
broadened to include genes associated with a favorable prognosis. This
is accompanied by promising results in the treatment of metastatic uveal
melanoma.
Conclusions: This past year, there were important advancements in
our knowledge of retinoblastoma and uveal melanoma.
Key Words: uveal melanoma, retinoblastoma, ophthalmic oncology, cancer
(Asia-Pac J Ophthalmol 2014;3: 241Y256)
ancers involving the eye are rare compared with lung, prostate, and breast cancer. They pose a special challenge because they can inuence both vision and life. Progress in the eld
focuses on these 2 elements: improving efcacy to treat the disease and save a life as well as limiting the consequence of treatment to maintain vision. Retinoblastoma and uveal melanoma
(UM) are the most common primary intraocular malignancies in
pediatric and adult patients, respectively. There are considerable
clinical, translational, and basic science efforts directed toward
furthering our understanding of these diseases, and each year,
our comprehension of these tumors advances. Here, we review
last years published contributions and highlight the major ndings. We divide the discussion of each tumor into clinical and
translational sections, with further subdivisions within.
RETINOBLASTOMA
Retinoblastoma is the most common primary intraocular
tumor of children, with approximately 5000 cases per year
worldwide. Throughout the world, survival rates vary widely,
from well lower than 50% and up to 99% in the United States
and Europe. The history of retinoblastoma treatment is of increasingly localized delivery of therapy with the aims of superior efcacy, while limiting adverse effects. The knowledge
gained this past year presented no exception to these goals.
From the Ophthalmic Oncology Service, Department of Surgery, Memorial
Sloan Kettering Cancer Center, New York, NY.
Received for publication April 30, 2014; accepted July 2, 2014.
The authors have no funding or conicts of interest to declare.
Reprints: Jasmine H. Francis, MD, Memorial Sloan Kettering Cancer Center,
70 E. 66th St, New York, NY 10065. E-mail: francij1@mskcc.org.
Copyright * 2014 by Asia Pacic Academy of Ophthalmology
ISSN: 2162-0989
DOI: 10.1097/APO.0000000000000079
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Thampi et al
Valero Garcia et al3
Bracco et al5
Shields et al9
Francis et al7
Schaiquevich et al10
Subject
No. Eyes
IC Rb
Naive
Previously Treated
F/u, mo
First report
First report
Melphalan OAC only
After failed systemic chemotherapy
OAC with plaque
OAC vs peri/systemic
20
5
52
14
15
18
AYE
NR
B and D
D and E
BYE
RE: IIIYV
50%
88%
2 y KM 48%
63%
14.5
NR
39.6
2 y KM 78%
2 y 57%
18 mo 79.4%
1 y KM 87%
19
30
F/u indicates follow-up; IC Rb, International Classication of Retinoblastoma; KM, KaplanYMeier estimate; NR, not reported; peri, periocular chemotherapy; RE, Reese-Ellsworth Classication.
described the utility of carboplatin in ophthalmic artery chemotherapy infusions.7 Carboplatin has a number of advantages: besides having low systemic and ocular toxicity (it does not result in
the medial periocular erythema seen with melphalan), it does not
require ltration before administration, and unlike melphalan, its
stability deems it time insensitive.7 Although its superiority to
melphalan has not been established, it is an attractive drug choice,
particularly for treating the fellow eye in a bilateral case that has
already met the melphalan dose limit (0.4 mg/kg).7
As groups are becoming more accustomed to OAC and
extending its use to treat less advanced eyes, there are reports of
combining its use with other modalities, including systemic
chemotherapy and brachytherapy (Table 1). Shields and associates8 report on 14 eyes (IC D and E) that received primary
intravenous followed by secondary intra-arterial chemotherapy,
the latter of which was necessary because of recurrent tumor,
subretinal seeds, vitreous seeds, or persistent vitreous seeding.
A median of 3 intra-arterial infusions were required, resulting in
a 57% globe salvage at a mean of 2 years of follow-up and no
metastatic event.8 The authors describe the use of salvage OAC
for eyes that have failed systemic chemotherapy and in which
enucleation is the alternative and assert that OAC can save just
more than half (57%) of these eyes without evidence for an
increased risk for metastases.8
Francis et al9 evaluated 15 eyes (IC BYE) on the efcacy and
toxicity of plaque brachytherapy after intra-arterial chemosurgery
for both adjuvant and salvage treatment of retinoblastoma eyes.
Despite 12 of 15 eyes having localized vitreous seeding, the
18-month Kaplan-Meier estimate of ocular survival was 79.4%.9
The study also found that ocular complications were statistically more frequent in eyes with a shorter latency between the
2 treatment modalities (Figs. 1, 2).9 The authors concluded that
brachytherapy after OAC is effective, with the majority of eyes
maintaining stable or improved electroretinogram recordings.9
In Argentina, they demonstrated that OAC is superior to sequential periocular and intravenous chemotherapy as a salvage
treatment of relapsed retinoblastoma.10 In their study of 18 eyes,
OAC was more effective, with 1-year Kaplan-Meier estimates of
ocular survival being 87% compared with 10% in eyes treated
with periocular and intravenous chemotherapy.10 The systemic
toxicity prole of OAC was deemed more favorable with no cases
of neutropenia, compared with 5 episodes of grade 4 neutropenia
in the periocular/systemic chemotherapy group.10
Aside from reports of OACs superiority, there were some
cases of more obscure consequences related to the treatment.
There was a rst report describing blue toe syndrome: a distal
peripheral vascular complication secondary to OAC for retinoblastoma.11 The authors presumed it to result from thrombus
formation due to intimal injury from the needle, guide wire, or
catheter manipulation.11 In addition, another case described
cataract formation in a patient who had received repetitive intraarterial chemosurgery, but in an eye that also had viable tumor
seeding on the lens, the ciliary body, and the anterior chamber.12
The group from London looked at the visual outcome after
intra-arterial melphalan by evaluating 14 eyes with good visual
potential and healthy foveola.13 They found that 42% of eyes had
severe visual loss, which the authors attributed to technical
difculties in catheterization and toxicity from nonYage-adjusted
melphalan doses.13 As the authors pointed out, the majority of
eyes retained good vision and the other eyes had better vision
compared with the alternative of enucleation.13
Finally, there were a couple of reports that taught us about
vascular anatomy and supply, as it related to OAC. One case
described a macular tumor (IC C) responding to 2.5 mg of intraarterial melphalan, despite the presence of an infantile hemangioma competing for arterial blood supply.14 Another group
used gadolinium-enhanced magnetic resonance imaging (MRI),
to demonstrate that the superselective infusion of chemotherapy
FIGURE 1. Representative retinoblastoma case treated with combination plaque brachytherapy and OAC. A, Before treatment, vitreous
seeds were observed in the periphery. B, These vitreous seeds were successfully treated after plaque brachytherapy and OAC.
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FIGURE 2. Representative retinoblastoma case treated with intravitreal melphalan. A, Before treatment, recurrent tumor with vitreous
seeding is apparent. B, After intravitreal melphalan (and OAC), the tumor has regressed and vitreous seeding is no longer visible.
into the ophthalmic artery delivers drug to the tumor and the
subretinal space.15
Intravitreal Chemotherapy
Historically, any technique that breached the ocular surface
of retinoblastoma eyes was avoided for fear of extraocular extension. Previously, there had been insufcient evidence to determine how risky this was for retinoblastoma patients. However,
this past year, Smith and Smith16 surveyed the worlds literature
on intravitreal injections to determine the associated risk for tumor
spread. Including 1304 injections during a mean follow-up of
72.1 months, they calculated that the proportion of patients with
extraocular tumor spread secondary to intravitreal injection was
0.007.16 They concluded that the risk for tumor dissemination
after intravitreal injections is rare and potentially attributable to
safety techniques that have been adopted.16
The year 2012 marked a resurgence in the use of intravitreal
melphalan for the treatment of retinoblastoma, in large part because of seminal articles from Munier et al17,18 on the injection
technique and its efcacy. This past year, the same group gave us
a current account of their intravitreal injection technique and
perspectives for the future.19 They described eligibility criteria
(excluding patients with nonviable vitreous tumor or nontumorous
vitreous material and unidentiable retinal source of seeding) and
revisited their safety-enhanced injection procedure.18 They discussed their dose escalation starting at 20 Kg and increasing
to 30 Kg at 2- to 4-Kg increments according to older patient
age, diffuse or high-density disease, as well as previous intraarterial or intravitreal melphalan.19 Finally, the superior efcacy of
this technique is reafrmed with 2-year Kaplan-Meier ocular survival estimates at 84.1%.19 Similar to the technique previously
reported by Munier et al, a single case report from China documents the successful treatment of vitreous seeding with 6 intravitreal injections of melphalan 20 mg/0.05 mL.20 No retinal
toxicity was mentioned.
Ghassemi and Amoli offered the rst report on the histopathology of eyes clinically treated with intravitreal melphalan.21
Eight eyes were enucleated (because of phthsis or recurrent
tumor or at the patients request) and examined, with no evidence
of tumor involvement at the needle site.21 All 6 eyes treated
with 10 Kg of melphalan had viable retinal tumor, although only
2 eyes had viable vitreous seeds.21 The 2 eyes injected with 50 Kg
of melphalan demonstrated no viable tumor cells but had appreciable retinal toxicity with gliosis, vascular occlusion, retinal necrosis, hemorrhage, and neovascularization.21 These results speak
to the narrow window for intravitreal melphalan injections, such
that the dose is high enough to effectively kill the tumor but not so
high that it destroys the retina.
In an effort to study alternatives to melphalan, Buitrago et al22
reported their preclinical ndings of intravitreal topotecan in rabbit
* 2014 Asia Pacic Academy of Ophthalmology
Systemic Chemotherapy
Whereas our center and others abandoned rst-line systemic chemotherapy for the treatment of retinoblastoma, other
centers continue to use it as their standard of care. Bartuma et al24
report on their 10-year experience with systemic chemotherapy
at a Swedish national referral center. They looked at 46 eyes in
24 patients, all of whom had hereditary retinoblastoma and were
primarily treated with 4 to 6 cycles of vincristine, etoposide, and
carboplatin.24 Ocular survival was 100% for group A (n = 8), 88%
for group B (n = 25), 0% for group C (n = 1), 9% for group D (n =
11), and 0% for group E (n = 1).24 There were no cases of metastases, no trilateral retinoblastoma, 1 osteosarcoma, and no deaths.24
Berry and colleagues looked at the long-term outcome of
55 group D eyes treated with triple-drug chemoreduction and
low-dose intensity-modulated radiation therapy as salvage for
recurrent tumor.25 Chemoreduction-only was required in 47%
of eyes (n = 26/55), whereas 29 eyes had recurrent tumor, of
which 24 were irradiated. The mean follow-up was 54.2
months. Kaplan-Meier ocular survival estimates were 82% at 1
year and dropped to 68% at 60 months. Strikingly, the 12-month
Kaplan-Meier ocular survival estimate for eyes receiving
chemoreduction and focal treatment was only 41%. Dened as at
least 20/200 or x and follow vision, the authors nd that more
than half of the eyes in their series retained useful vision. It is
striking that the ocular survival of eyes receiving systemic chemotherapy alone was less than half the calculated rates in similar
eyes receiving intra-arterial chemosurgery.26 In our cohort, the
2-year ocular salvage of naive eyes with vitreous and subretinal
seeding is 83% [95% condence interval (CI), 27%Y97%].26
High-Risk Retinoblastoma
There continues to be controversy over the utility of adjuvant systemic chemotherapy for high-risk retinoblastoma, and
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Extraocular Retinoblastoma
On the subject of extraocular retinoblastoma, groups debated on the appropriate staging system. Chantada et al31 compared 4 different staging systems for extraocular retinoblastoma
by retrospectively reviewing disease-free survival (dened as
extraocular relapse) in 533 patients. They concluded that only the
International Retinoblastoma Staging System (IRSS) accurately
identied all high-risk patients with microscopically disseminated disease.31 Similarly, only the IRSS and St. Jude Childrens
Research Hospital systems provided stage assignments with
increasing risk for extraocular relapse.31 They further added that
3 histopathological factors (focal choroidal invasion, anterior
chamber, and prelaminar optic nerve invasion) could safely be
omitted for staging because they were of little predictive value.31
Meanwhile, Radhakrishnan and colleagues32 proposed a new
staging system to predict event-free and overall survival in
patients with IRSS stage III (regional extension) treated with
neoadjuvant chemotherapy. The staging system was based on
postchemotherapy optic nerve characteristics including extent of
involvement, optic nerve thickening, and contrast enhancement.32
The study demonstrated that distal optic nerve involvement (dened as thickening or enhancement of 95 mm of intraorbital,
optic canal, or intracranial nerve) was signicantly associated
with worse outcome.32 This was particularly predictive of outcome compared with globe perforation, extrascleral extension, or
proximal optic nerve enhancement without thickening.32
In a prospective study, Sethi et al33 followed 36 eyes with
extraocular retinoblastoma in India and, on the basis of histopathology, determined that 75% of eyes contained viable tumor
after neoadjuvant systemic chemotherapy. They conrmed previous ndings that prolonged lag time from initial symptoms to
start of treatment was related to increased risk for extraocular
retinoblastoma.33
* 2014 Asia Pacic Academy of Ophthalmology
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Finally, Chantada et al34 describe the consensus of the International Society of Pediatric Oncology-Pediatric Oncology in
Developing Countries and their recommendations for graduatedintensity treatment of retinoblastoma in developing countries.
Recommendations for treatment vary according to disease classication (laterality and extent of disease) and treatment
settingVwhich is divided into 3 according to a countrys available
resources and technology.34
Pineal Cysts/Pineoblastoma
This past year, there was some attention to the subject of pineal
gland abnormalities in retinoblastoma patients. Ramasubramanian
and associates reviewed the cases of 408 retinoblastoma patients
and determined that 8% of patients had a pineal gland cyst.35 The
prevalence of pineal cysts in the healthy pediatric population is
believed to be approximately 1% to 2% (although, on the basis of
autopsy ndings, this number may be much higher). The higher
reported incidence in retinoblastoma patients is consistent with the
ndings of other groups, which have suggested a relationship
between germline retinoblastoma and pineal cysts.36,37
Furthermore, they investigated the prevalence of pineoblastomaV
a malignancy that can afict germline retinoblastoma patients
in the rst decade of life. Ramasubramanian and associates detected pineoblastoma in 1% of patients, all of whom exclusively
carried a germline RB1 mutation.35 This is in line with previous
ndings that demonstrate a reduced incidence of pineoblastoma in
the postirradiation era.38 However, because of the small numbers,
the authors admit that there was no statistically signicant data to
support the role of previous treatment in reducing the incidence of
pineoblastoma in this patient population,35 including the protective role of systemic chemotherapy. Furthermore, Chantada et al27
similarly reported that 1.5% (n = 177) of their retinoblastoma
patients developed pineoblastoma, and all 3 patients received systemic chemotherapy before the development of trilateral disease.
Long-term Follow-up
Our group catalogued the long-term medical outcomes in
survivors of extraocular retinoblastoma. Nineteen patients treated
between 1992 and 2009 were included, with a median follow-up
of 7.8 years (2Y17.8 years) from extraocular retinoblastoma diagnosis.39 All patients received conventional chemotherapy (cisplatin
or carboplatin, cyclophosphamide, vincristine, and etoposide) for
their diagnosis of extraocular retinoblastoma, plus high-dose
chemotherapy with autologous stem cell transplantation (n = 17)
and/or consolidative EBRT (n = 15).39 We reported that the most
common long-term nonvisual outcomes were hearing loss, 79%
(n = 15); short stature, 37% (n = 7); and secondary malignancies, 31% (n = 6).39 All patients with grade 3 hearing loss had
been exposed to platinum agents: all had received cisplatin as
part of their conventional chemotherapy and 7 of 8 had been treated
with high-dose carboplatin.39 The 6 patients with secondary
Country Specic
An English group examined secondary and subsequent
tumors in 1927 retinoblastoma patients, and like other reports,
they show that retinoblastoma survivors are at increased risk for
secondary cancers compared with the general population.41
Their standardized incidence ratios for all secondary tumors were
13.7 (95% CI, 11.3Y16.5) and 1.5 (95% CI, 0.9Y2.3) for heritable
and nonheritable cases, respectively.41 In line with other cohorts,
the predominant secondary cancers were leiomyosarcoma, osteosarcoma, and skin melanoma.41 They also discuss the increased
risk for uterine leiomyosarcoma, which was previously reported
by our group.42
In fact, this last year brought reports from other countryspecic cohorts. Alkode et al43 describe the efcacy of vincristine and carboplatin for advanced retinoblastoma in Saudi
Arabia. Gunduz and colleagues described their 192 Turkish
patients with both intraocular and extraocular retinoblastoma.44
A group from Singapore calculated their 5-year survival rate for
unilateral and bilateral retinoblastoma as 97% (n = 35) and 76%
(n = 16), respectively.45 They cited advanced presentation as
well as noncompliance with treatment and follow-up as reasons
for the lower survival rate compared with Western countries.45 Similar woes regarding late presentation and poor acceptance of enucleation were echoed by groups from Beijing46 and
Tamilnadu, India.47 Work from Uttar Pradesh, India, reports that half
its patients abandoned treatment, and this was related to rural back
ground, nancial constraint, and hesitancy toward enucleation.48
They found that telephone calls were better at tracing patients
TABLE 2. Detection Rates for the RB1 Gene in Studies From January to December 2013
Bilateral
Author
Ahani et al49
Saliminejad et al50
Seo et al51
Price et al52
Unilateral
Method
Specimen
No.
Det %
No.
Det %
MLPA
AMRS-PCR
Exon sequence, MLPA
Combined*
66
65
16
167
16.6
43.1
93.8
96
55
56
9.1
3.6
42
9.5
*Combined indicates conformational analysis with sequencing, dosage analysis, methylation testing, and loss of heterozygosity analysis.
AMRS indicates amplication refractory mutation system; Det %, detection percentage (percentage with detected mutation).
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Genetics
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Local Recurrence
There were 2 articles on the subject of recurrence after
radiation of the primary UM. Caujolle et al74 examined local
recurrence of UM after proton beam therapy. Their rate of local
recurrence was 6.1% at 5 years (n = 1102). Contrary to previous
reports, they found that distance from the macula and the papilla, initial ciliary body involvement, and treatment margin
were not signicant risk factors of local recurrence.74 Like other
studies, they determined that local recurrence was signicantly
associated with increased risk for metastases and death: 10-year
TABLE 3. Outcome and Ocular Complications After Stereotactic Radiation in Studies From January to December 2013
Author
11
Sarici et al
Suesskind et al73
Treatment
No.
Patients
F/u,
mo
Mets-Free
Tumor
Control
Ocular
Survival
Stereotactic
Stereotactic
Stereotactic with resection
50
60
18
40
34
23
5 y 86%
3 y 73%
3 y 85%
5 y 90%
3 y 85%
3 y 100%
5 y 83%
3 y 77%
3 y 87%
Cat
Rad Ret
NVG
34%
30%
62%
20%
14%
22%
0%
Cat indicates cataract; F/u, follow-up; Mets-free, metastases-free survival; Rad ret, radiation retinopathy.
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Radiation Complications
Although the visual potential for UM eyes treated with radiation is superior to enucleated eyes, the consequences of radiation usually do impair vision and adversely alter ocular
architecture. Three articles described side effects of radiation, all
with differing radiotherapy approaches. In one, Kaliki and associates76 calculated the risk for scleral necrosis after brachytherapy for UM to be 1.4% in their cohort of 5057 patients.
Approximately half of these cases remained stable, whereas the
other half had progressive necrosis.76 Three patients developed
scleral perforation.76 They determined that risk factors of necrosis included increased tumor thickness, elevated scleral radiation
dose, and location (ciliary body or peripheral tumors).76 However,
as the authors point out, the latter factor is likely due to easier
identication.76
On the subject of another radiation technique, Klingenstein
et al77 looked at quality of life in UM patients treated with
Cyberknife. They used the Short FormY12 Health Survey,
which measures outcome of physical and mental health but is
not ophthalmology specic.77 Because of continuous improvement in mental health, they conclude that Cyberknife radiosurgery may aid in attenuation of emotional distress.77
They conrmed that concomitant glaucoma had a signicant
impact on social function and mental health.77 Finally, with
modern proton treatment of UM, the rate of NVG ranges between 15% and 31%.78 In a report by Mishra et al,78 their 5-year
rate of NVG in 704 patients receiving proton beam for UM was
12.7%, and the rate of NVG-related enucleation was 4.9%.
Like previous studies, risk factors of NVG include increased
tumor height, larger diameter, and older age of the patient.78
Dose and location relative to both anterior and posterior structures were also important: NVG was more likely if ciliary body
and lens involvement was more than 30% or if the entire optic
disc and macula receive more than 28 GyVhighlighting the
importance of tissue-sparing planning.78 In a cohort of 171
choroidal melanoma patients treated with proton beam radiation, Cassoux and colleagues conrmed that endoresection after
irradiation signicantly reduced the risk for NVG when compared
with proton beam alone.79
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Other
In a country-specic study, a group from Taiwan described
26 patients who were diagnosed during a 16-year period and received enucleation for their medium or large UM.89 Salient features include a high percentage of patients (12%) with metastases
at diagnosis, which is higher than the 1% to 3% quoted in other
studies and may be a result of selection bias.89 Overall, 46% of
patients developed metastases at a medianof 18.5 (0Y168) months
after diagnosis, and they died at a median of 5 (1Y12) months
after disseminated disease was detected.89 In line with other
studies, tumor size and histopathological cell type were signicantly associated with survival.89
TABLE 4. Outcome After Ipilimumab for Metastatic Uveal Melanoma in Studies From January to December 2013
Author
97
Luke et al
Maio et al98
Kelderman et al100
No. Patients
Dose,
mg/kg
F/u, mo
Response
Rate
Progression-Free
Overall
Survival, mo
1-y OS, %
1-y PFS, %
39
82
22
3 or 10
3
3
12.6
5.6
6.3
2 (5.1%)
4 (5%)
1 (4.5%)
6 (15.4%)
24 (29%)
1 (4.5%)
9.6
6
5.2
31
27
11
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Hepatic-Directed Therapy
Another approach for oligometastatic disease includes
hepatic-directed therapy, and 3 articles published on this topic in
2013 investigated the use of surgical resection, radioembolization, and isolated hepatic perfusion (IHP). In the Liverpool Uveal
Melanoma Liver Metastases Pathway, 155 patients underwent
surveillance with 6 monthly liver MRI scans and then staged with
additional radiographic studies and laparoscopy. Seventeen patients had liver resection and 1 had radiofrequency ablation, with
an R0 resection rate of 88.2% and an overall median survival of
27 months. Patients with unresectable disease were treated palliatively and had a signicantly lower median survival of 8 months.
Eleven patients had recurrent disease, grade II complications were
found in 3 patients, and grade III complications were found in a
single patient.
Radioembolization (with resin-based 90yttrium labeled microspheres) as locoregional therapy for hepatic metastases was
analyzed in a group of 13 uveal melanoma patients. It was a mixed
group consisting of both naive and previously treated patients as
well as those with and without extrahepatic disease: the hepatic
tumor load was greater than 25% in the vast majority of patients.
At 2 to 3 months after therapy, radiographic response was 77%
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Immune System
This past year, Bronkhorst and Jager provided a concise summary of the inammatory underpinnings of uveal melanoma.107
Because older patients with identical melanomas have a worse
prognosis, it is believed that reduced immune surveillance may
result in worse outcome for oncology patients or, on the other
hand, that stimulating an immune response (such as via an
abscopal effect) may enhance the hosts response to destroying
cancer cells. For this reason, there is work that focuses on the
interaction of the immune system and uveal melanoma, and this
past year saw a number of such articles. Achberger et al108 explored
serum markers for metastatic disease in 6 UM patients before and
after the development of disseminated disease. They evaluated circulating immune cells using immunomagnetic beads and cellular
levels of immune regulatory miRs by quantitative PCR assays.108
They found that the presence of metastases was associated with
changes in circulating immune cells that are consistent with
lower immune surveillance.108 microRNAs also participate in
immune regulation, with some providing negative feedback and
others amplifying the immune response.108 As the metastases
became apparent, the authors measured increasing levels of
several immune regulating miRs in the plasma (including miRs125b, 146a, 155, 20a, and 223) and decreasing miRs-181a.108
These miRs were derived from circulating leukocytes and could
not be specied to particular immune cell populations.108 The
authors assert that this discovery may enhance our understanding
of the immunoregulatory role of UM.108
Chemokine receptors CCR7 and CXCR4 are both expressed
by other cancers and are thought to be involved in metastases:
CCR7 inuences transport through the regulation of integrins and
CXCR4 correlates with epithelioid cell type.109 van den Bosch
et al109 compared immunohistochemical expression of CCR7 and
CXCR4 in enucleated specimens of patients with metastatic disease (n = 19) and those without metastatic disease (n = 30). There
was strong cytoplasmic staining for CCR7 in 76% of metastatic
patients and 0% of metastases-free patients.109 Although CCR7
has previously been shown to have a strong expression in UM
cells, this group demonstrates its association with poor patient
survival and suggests its role as a prognostic marker.109 Conversely and perhaps confounded by lack of detection using the
immunohistochemistry, expression of CXCR4 had no correlation
with survival.109
Bronkhorst and Jager previously demonstrated that monosomy 3 UMs contained more protumoral M2 macrophages compared with disomy 3 tumors.110 Last year, Herwig and colleagues
conrmed that a higher M2/M1 ratio was present in tumors with a
class II RNA proleVagain validating that a higher M2 macrophage inltration is associated with a poor prognosis.111 Although
peroxisome proliferator-activated receptor F (PPAR-F) can promote the alteration of M1 macrophages toward the M2 phenotype,
this group found no statistically signicant association with RNA
prole class.111
Finally, Vu et al112 investigated inammatory cells in eyes removed for UM, comparing primary with secondary enucleationsV
* 2014 Asia Pacic Academy of Ophthalmology
Genetic Underpinnings
Unlike cutaneous melanomas, UMs have a relatively few
genetic alterations with recurrent chromosomal gains and losses
as well as a relatively low burden of single-nucleotide variants
and structural variants.113 For now, mutually exclusive GNAQ
and GNA11 are the most commonly mutated driver oncogenes,
whereas BAP1 is the tumor suppressor gene that is most often
mutated. This past year, a number of groups described novel
mutations (SF3B1 and EIFIAX), which are thought to be more
prevalent in low-risk melanoma.
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251
BRCA1-Associated Protein 1
66
Harbour et al have shown that 84% of metastasizing predominantly class 2 UMs have mutations in BRCA1-associated
protein 1 (BAP1), and this may occur as a somatic or a germline
mutation. In recent work with UM cells, they demonstrate that
ribonucleic acid interference-mediated depletion of BAP1 results
in acquisition of a stem-like cell phenotype. They have previously
found that histone deacetylase inhibitors can revert primary class
2 UM cells to a class 1 phenotype and, in this current study,
demonstrated that histone deacetylase inhibitors can restore the
expression of genes that guide melanocyte differentiation and that
are downregulated by loss of BAP1.122 They deduce that BAP1 is
essential for the preservation of melanocyte identity in UM, and
depletion of BAP1 results in UMs assuming a stem-like cell
phenotype.122 This past year, it was determined that analysis of
BAP1 protein expression by immunohistochemistry was a useful
prognostic tool. Not only is it an efcient and cost-effective test,
but the method could effectively identify patients with an aggressive form of the disease and a poor overall survival.123
SF3B1/EIFIAX
This past year, 3 groups identied the presence of SF3B1
mutations in UM. SF3B1 encodes a subunit of the splicing
factor 3b protein complex, which is part of the U2 small nuclear
ribonucleoprotein complex that engages in the splicing of preRNAs.124 Two groups used exome sequencing124,125 whereas
another used whole genome sequencing126 to identify SF3B1
mutations, and in expanded studies, these were shown to occur
in 15% to 18.6% of UM tumors. Matching normal blood samples did not have a mutation, indicating its somatic nature.124
Mutations occurred almost exclusively in codon 625, encoding
an alteration of arg625. An overwhelming majority of SF3B1
mutations occurred in disomy 3 tumors (29%) compared with
monosomy 3 tumors (3%) and was associated with favorable
prognostic features and better diagnosis.124Y126 An additional
mutation in EIFIAX was identied in 24% of tumors (n = 16/66)
and was likewise more common in disomy 3 tumors (48%)
compared with monosomy 3 tumors (3%).125 Mutations in
SF3B1 and EIFIAX were more prevalent in tumors with partial
monosomy 3 (loss of 3q and retention of 3p), suggesting that
these tumors may have a similar characteristic to disomy 3 tumors.125 This discovery offers an additional means of prognostication through the genetic composition of UM.
Lake et al127 analyzed single nucleotide polymorphism
array analysis in 4 subgroups of UM: (1) disomy 3 with longterm survival, (2) monosomy 3 that metastasized, (3) disomy 3
that metastasized, and (4) monosomy 3 with long-term survival.
The latter 2 groups are relatively rare occurrences for UM.127
They found that amplication of the CNKSR3 gene was the most
common abnormality in patients with monosomy 3 tumors and
long-term survival.127 An increase in CNKSR3 protein expression was correlated with better patient survival.127 In fact,
there was a signicant and direct correlation between gene amplication, increased protein expression, and longer patient survival.127 CNKSR3 is involved in transepithelial sodium transport
and, through interactions with RAS and RAF, is implicated in
normal cell proliferation and differentiation.127 The mechanism
by which CNKSR3 may inuence the development of UM metastases is still to be determined.
Nonchoroidal Melanoma
Mutations in the telomerase reverse transcriptase (TERT)
promoter have been found in a wide variety of human cancers.128
The mutations occur in the catalytic subunit of the telomerase
holoenzyme and result in increased TERT expression.128 With the
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Targeted Treatment
Patient-derived xenograft models have proven to be useful
investigational platforms, particularly as pharmacological test
beds. However, there is some concern of genetic instability in the
transplantation process. Last year, Laurent et al demonstrated that
patient-derived UM xenografts not only maintained genetic features during transplantation but also expressed genetic stability
during the course of in vivo maintenance.130 Specically, they
observed that only 3% of the 22,517 genes studied were
differentially expressed between patient tumors and their corresponding xenografts.130 Most importantly, the expression status
of BAP1 and the MAPKinase pathway were conserved.130 The
authors deduce that their work supports the utility of this xenograft
model in preclinical pharmocological assessments.130
There have been a number of preclinical studies that have
attempted to tease out pathways implicated in UM and to test their
respective targeted treatments. Epidermal growth factor receptor
(EGFR), GNAQ, (also known as protein kinase B [PKB]), protein
kinase C (PKC), and notch signaling were the subject of articles
published in the past year and are discussed here. In a study by
Amaro et al,131 29% (14/48) of UM enucleated tumor specimens
and 21% (3/14) of UM cell lines were found to overexpress
EGFR. For the human tumors, this expression was independent of
clinical risk factors, chromosome 3 status, or disease-free survival.131 The authors analyzed cell line response to getinib, an
EGFR-specic tyrosine kinase inhibitor, and to cetuximab, an
anti-EGFR antibody.131 The response to getinib was minimal,
but cetuximab triggered natural killer cells to lyse EGFR-positive
cell lines and release tumor necrosis factor >.131 The authors
suggest that their ndings provide rationale to attempt clinical
treatment of EGFR-positive UM with these EGFR modulators.131
Apigenin, a avonoid known to inhibit the growth and invasion of
a number of cancers, was studied by another group. In UM cell
lines (SP6.5 and C918), it was found to inhibit the expression
and secretion of VEGF via suppression of ERK1/2 and PI3K/Akt
pathways.132
With the use of UM cell culture and small interfering
RNAYmediated GNAQ knockdown, Ambrosini et al133 conrmed
that mutant GNAQ signals to both MEK and AKT. Combination
treatment with MEK inhibitor (selumetinib) and AKT inhibitor
(MK2206) induced a synergistic degradation of cell viability.133
This cell death was associated with activation of adenosine
monophosphate-activated protein kinase in GNAQ-mutant cells,
suggesting cell death by autophagy (as opposed to apoptosis).133
Similarly, when applied to a xenograft mouse model, the authors
found effective inhibition of tumor growth with the combined inhibition of MEK and AKT, suggesting a possible target in UM
patients.133
In a similar platform using UM cell culture with knockdown of GNAQ by small interfering RNA, Chen et al134 looked
at combination PKC and MEK inhibition. Downstream
* 2014 Asia Pacic Academy of Ophthalmology
Copyright 2014 Asia Pacific Academy of Ophthalmology. Unauthorized reproduction of this article is prohibited.
&
CONCLUSIONS
This past year marks important incremental advancements
in the eld of ophthalmic oncology. In retinoblastoma, there
continues to be an expanded use of OAC for the treatment of intraocular disease. Furthermore, we continue to deepen our knowledge on the risks, safety, toxicity, and efcacy of intravitreal
melphalan for the treatment of vitreous seeds. We have extended
our understanding of the genetic basis of UM to include genes
that are associated with a favorable prognosis, in addition to
developing our comprehension of those genes that are related to a
poor prognosis. Finally, we have evidence of promising drugs for
the treatment of metastatic disease, with response rates surpassing
all historical results.
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