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Klufas MA, Itty S, McCannel CA, Glasgow BJ, Moreno C, McCannel TA. Variable Results for Uveal Melanoma–Specific Gene Expression Profile Prognostic Test in Choroidal Metastasis. JAMA Ophthalmol. 2015;133(9):1073–1076. doi:10.1001/jamaophthalmol.2015.1790
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We report our experience with uveal melanoma–specific gene expression profile (GEP) testing on a series of choroidal metastatic tumors confirmed by cytopathology so that clinicians may be aware that receiving a class 1 or class 2 test result in nonmelanoma is possible.
Retrospective review of all cytopathology and DecisionDx-UM GEP reports between January 2012 to December 2014 from intraoperative fine-needle aspiration biopsy of choroidal tumors undergoing brachytherapy. Four patients were identified to have cytopathology consistent with a nonmelanoma primary. All 4 patients presented with a unilateral, single choroidal tumor, which was treated with iodine-125 brachytherapy and underwent intraoperative fine-needle aspiration biopsy for cytopathology and uveal melanoma–specific GEP testing for molecular prognostication. Gene expression profile testing of the choroidal tumor in each patient revealed class 1A in 3 patients and class 2 in 1 patient.
Conclusions and Relevance
DecisionDx-UM GEP may be a helpful test for molecular prognostication in patients with uveal melanoma; however, class 1 and class 2 test results are indeed possible in the setting of a nonmelanoma malignancy. We recommend that cytopathology and/or other melanoma-specific testing be performed in all cases of suspected choroidal melanoma because GEP with this assay is unable to rule out the diagnosis of a choroidal melanoma.
New molecular technologies, including cytogenetic analysis, multiplex-ligation probe amplification (MLPA), and gene expression profiling (GEP), may provide prognostic information regarding the risk for metastasis in the setting of primary uveal melanoma.1-3 Patients with uveal melanoma want knowledge of metastatic prognosis regardless of the impact on medical management.4
DecisionDx-UM GEP (Castle Biosciences) is a commercially available test that examines 15 genes (including 3 control genes) to generate prognostic subgroups (class 1: low metastatic risk and class 2: high metastatic risk) for uveal melanoma.5-7 Although the DecisionDx-UM test is not marketed as a diagnostic test, it is frequently used without cytopathology to confirm the diagnosis and may be used instead of cytopathology to determine the metastatic potential of a suspicious choroidal tumor. A tumor that is found to be class 1 might continue to be observed, whereas a tumor found to be class 2 might be promptly treated, despite the lack of evidence that treating a primary uveal melanoma alters a patient’s risk for metastasis.8
We report 4 cases of choroidal metastatic tumors, for which the DecisionDx-UM GEP provided an irrelevant test result to illustrate that GEP testing alone may misdirect diagnosis in the absence of cytopathology or other melanoma-specific testing such as chromosome 3 status.
DecisionDx-UM is a gene expression profiling (GEP) test that provides prognostic information regarding the risk for metastasis in the setting of primary uveal melanoma.
DecisionDx-UM GEP may provide an inapplicable test result in nonmelanoma tissue.
DecisionDx-UM GEP test results cannot confirm nor rule out a diagnosis of uveal melanoma.
DecisionDx-UM GEP should be interpreted in conjunction with melanoma-specific cytopathology testing.
This study, which was conducted from January 2012 to December 2014, was approved by the institutional review board of the University of California, Los Angeles. Written consent was obtained from all patients.
A man in his 80s with a medical history of prostate cancer treated with external radiation and hormone therapy 11 years previously presented with blurry vision, pain, and photopsia in the left eye.
Distance best-corrected visual acuity (BCVA) in the affected left eye was 20/125. Dilated fundus examination (DFE) of the eye revealed a superotemporal choroidal tumor with serous retinal detachment (Figure, A and B). Ultrasonography findings revealed a dome-shaped lesion of 4.65 mm in height and greatest basal diameter of 15.19 mm, with medium internal reflectivity by A-scan.
The patient underwent iodine-125 brachytherapy with intraoperative fine-needle aspiration biopsy (FNAB). Gene expression profile testing revealed class 1A. Cytopathology revealed findings consistent with metastatic prostate cancer.
A woman in her 60s with a medical history of a benign breast cyst presented with 3 weeks of distorted vision in the right eye.
Best-corrected VA was 20/25 in the affected right eye. Dilated fundus examination of the right eye revealed an elevated choroidal tumor involving the macula with serous retinal detachment (Figure, C and D). Ultrasonography findings revealed an irregularly shaped lesion of 3.25 mm in height and greatest basal diameter of 12.60 mm, with medium reflectivities by A-scan.
The patient underwent iodine-125 brachytherapy with intraoperative FNAB. Gene expression profile testing revealed class 1A. Cytopathology revealed numerous cells suggestive of neoplasm but was nondiagnostic. Additional workup revealed metastatic neuroendocrine lung cancer.
A woman in her 70s with a medical history of lung cancer treated with chemotherapy and radiation and no history of metastatic disease presented with blurry vision and pain in the left eye for 3 weeks.
Best-corrected VA in the left eye was 20/70. Examination of the left eye revealed dilated inferior episcleral vessels. Dilated fundus examination of the left eye revealed an inferotemporal peripheral choroidal tumor (Figure, E and F). Ultrasonography findings revealed a dome-shaped lesion of 7.56 mm in height and greatest basal diameter of 16.54 mm, with low-to-medium reflectivities by A-scan.
Additional systemic workup revealed stable findings with no progression of the primary treated lung cancer. From a systemic standpoint, the medical oncologist felt the choroidal lesion was highly unlikely to represent a metastatic lesion based on the systemic workup. The patient underwent iodine-125 brachytherapy with intraoperative FNAB. Gene expression profile testing reported class 1A. Cytopathology revealed findings consistent with metastatic small-cell lung carcinoma.
A man in his 60s presented with shadowing and distortion of vision in the left eye for 2 months. He had no history of systemic cancer.
Best-corrected VA in the left eye was 20/40. Dilated fundus examination of the left eye revealed a choroidal tumor superotemporal to the macula with serous retinal detachment (Figure, G and H). Ultrasonography findings revealed a dome-shaped lesion of 2.66 mm in height with greatest basal diameter of 11.19 mm, with mostly medium internal reflectivities by A-scan.
The patient underwent iodine-125 brachytherapy with intraoperative FNAB. Gene expression profile testing revealed class 2, with a discriminant value of 0.02. Cytopathology was consistent with metastatic lung cancer.
We report the first case series, to our knowledge, of GEP test results in choroidal metastatic tumors. Uveal melanoma–specific GEP testing may provide both class 1A and class 2 results for nonuveal melanoma tissue. A single case report has been previously published by Seider et al,9 which also demonstrated that the DecisionDx-UM GEP test may errantly provide prognostic information on a solitary choroidal metastatic lesion.
Choroidal metastatic tumors that are asymptomatic may be observed.10 If vision is affected, the standard treatment for these tumors may be external beam radiotherapy. In cases of focal choroidal metastatic disease, iodine-125 brachytherapy may also be considered. Given that patients with uveal melanoma may often have other malignancies,11,12 it is not uncommon to find 2 separate malignancies in a given patient. At our center and others, cases of choroidal metastatic tumors may be treated with brachytherapy. Intraoperative FNAB for tissue may be performed in such cases, particularly if a tissue diagnosis is necessary for staging purposes.
DecisionDx-UM is a prognostic test that has been reportedly validated in lesions clinically diagnosed as choroidal melanoma. However, the study that validated the DecisionDx-UM test confirmed the diagnosis of uveal melanoma by cytopathology in only 79.7% of tumor samples included in the analysis.7 As our series indicated, DecisionDx-UM can indeed provide class 1 and class 2 results when analyzing nonuveal melanoma tissue; the test does not distinguish between different choroidal lesions including choroidal melanoma vs nonmelanoma vs choroidal nevus. The class 2 expression pattern for a uveal melanoma at high risk for metastasis may be similar to the expression profile of dedifferentiated metastatic cancer. It is surprising that 3 of the 4 cases in our series of choroidal metastasis revealed a class 1 result; this further emphasizes that the test has not been validated to provide prognostic information in nonmelanoma samples and underscores the importance of obtaining a biopsy also for cytopathology for diagnostic confirmation, particularly in cases where additional molecular testing may be performed.
In situations where the diagnosis of choroidal melanoma is uncertain, alternative molecular tests are available that provide diagnostic and prognostic information of tissue samples. Multiplex ligation-dependent probe amplification,13 which is now commercially available for choroidal melanoma (Impact Genetics), provides information on tumor DNA rather than RNA, which is examined in the GEP test. Multiplex ligation-dependent probe amplification has the ability to detect aberrations in up to 45 chromosomal loci in a single assay. Tissue can also be sequenced for GNAQ or GNA11 mutations,14 which may aid in ruling in a diagnosis of primary uveal melanoma when no chromosomal abnormalities are present with MLPA.
Care must be taken to properly and accurately interpret results to eliminate confounding data and diminish ocular misdiagnosis. One must proceed with caution when interpreting the result of any test beyond the clinical scenario for which it was validated. At our center, it is standard practice to submit biopsy material for cytopathology in addition to molecular prognostic testing. We feel that cytopathologic confirmation is requisite in any biopsy setting particularly when material is obtained for molecular prognostication. Continued studies are needed to investigate the weaknesses and strengths of evolving molecular prognostic tests that can potentially provide critical information to patients.
Corresponding Author: Tara A. McCannel, MD, PhD, University of California, Los Angeles, 100 Stein Plaza, Los Angeles, CA 90095 (firstname.lastname@example.org).
Submitted for Publication: February 3, 2015; final revision received April 19, 2015; accepted April 23, 2015.
Published Online: June 18, 2015. doi:10.1001/jamaophthalmol.2015.1790.
Author Contributions: Drs Klufas and T. A. McCannel had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Klufas, Itty, C. A. McCannel, T. A. McCannel.
Acquisition, analysis, or interpretation of data: All authors.
Drafting of the manuscript: Klufas.
Critical revision of the manuscript for important intellectual content: All authors.
Statistical analysis: Klufas.
Obtained funding: T. A. McCannel.
Administrative, technical, or material support: Klufas, C. A. McCannel, Glasgow, Moreno, T. A. McCannel.
Study supervision: Klufas, C. A. McCannel, T. A. McCannel.
Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr C. A. McCannel reported receiving personal fees from Dutch Ophthalmic and grants from Genentech. Dr T. A. McCannel has served as a paid consultant for Novartis and as an unpaid consultant on the Advisory Board of Impact Genetics. No other disclosures were reported.
Funding/Support: This research was supported by an unrestricted grant from Research to Prevent Blindness and the George E. and Ruth Moss Trust (support for all aspects of research at University of California, Los Angeles Ophthalmic Oncology Center). Support of vitreoretinal surgery fellowship training was provided by the Thelma and William Brand Fellow and Abe Meyer Memorial Fellow at UCLA Stein Eye Institute (Dr Klufas).
Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.