Prognosis of Uveal Melanoma in 500 Cases Using Genetic Testing of Fine-Needle Aspiration Biopsy Specimens

Ocular oncologists require a strong indication for intraocular biopsy before the procedure can be performed because it carries a risk for serious eye complications and the dissemination of malignant cells. The purpose of this review is to evaluate the extent to which this restricted practice is supported by evidence from previous reports and to outline our main indications and contraindications. The different intraocular biopsy techniques in the anterior and posterior segment are discussed with a focus on our preferred method, fine-needle aspiration biopsy (FNAB). In the literature, complications are typically under-reported, which reduces the possibilities of evaluating the risks correctly and of making fair comparisons with other biopsy methods. In FNAB, the exact placement of the needle is critical, as is an accurate assessment of the size of the lesion. Fine-needle aspiration biopsy is usually not a reliable diagnostic tool in lesions < 2 mm in thickness. It is very advantageous to have a cytopathologist present in the operating theatre or close by. This ensures adequate sampling and encourages repeated biopsy attempts if necessary. This approach reduces false negative results to < 3%. Adjunct immunocytochemistry is documented to increase specificity and is essential for diagnosis and management in about 10% of cases. In some rare pathological processes the diagnosis depends ultimately on the identification of specific cell markers. An accurate diagnosis may have a decisive influence on prognosis. The cytogenetic prognostications made possible after FNAB are reliable. Biopsy by FNA has a low complication rate. The calculated risk for retinal detachment is < 4%. Intraocular haemorrhage is frequently observed, but clears spontaneously in nearly all cases. Only a single case of epibulbar seeding of malignant cells at the scleral pars plana puncture site of transvitreal FNAB has been documented. Endophthalmitis has been reported and adequate standard preoperative preparation is obligatory. An open biopsy is still an option in the anterior segment, but has been abandoned in the posterior segment. Although vitrectomy-based procedures are becoming increasingly popular, we recommend using FNAB as part of a stepwise approach. A vitrectomy-assisted biopsy should be considered in cases where FNAB fails. In any adult patient with suspected intraocular malignancy in which enucleation is not the obvious treatment, the clinician should strive for a diagnosis based on biopsy. When the lesion is too small for biopsy or the risks related to the procedure are too great, it is reasonable to be reluctant to biopsy. The standards applied in the treatment of intraocular malignant diseases should be equivalent to those in other fields of oncology. Our view is controversial and contrary to opinion that supports current standards of care for this group of patients.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1755-3768.2009.01637.x

Fine-needle aspiration biopsy and other biopsies in suspected intraocular malignant disease: a review

Objective To evaluate the feasibility of genetic testing of uveal melanoma using fine-needle aspiration biopsy (FNAB) Methods We reviewed the clinical records of all patients of the Ocular Oncology Service at Wills Eye Hospital with the diagnosis of uveal melanoma who underwent FNAB for genetic testing for chromosome 3 status between November 1, 2005, and March 1, 2006 The FNAB was performed immediately before plaque radiotherapy The specimens underwent genetic analysis using DNA amplification and microsatellite assay to determine the presence of monosomy 3 Results A total of 140 eyes of 140 patients with uveal melanoma were sampled for chromosome 3 abnormalities using FNAB Monosomy 3 was found in 44 cases (31%), disomy 3 was found in 76 cases (54%), and the genomic DNA yield was insufficient for genetic analysis in 20 cases (14%) Monosomy 3 was found in 16 of 61 small melanomas (26%), 24 of 67 medium melanomas (36%), and 4 of 12 large melanomas (33%) Adequate DNA was achieved in 97% of cases using a 27-gauge needle via the transvitreal tumor apex approach and in 75% of cases using a 30-gauge needle via the transscleral tumor base approach Factors predictive of monosomy 3 included greater tumor basal dimension (P = 02) and greater distance from the optic disc (P = 02) Transient localized vitreous hemorrhage was found in 46% of eyes No cases of diffuse vitreous hemorrhage, retinal detachment, or tumor recurrence along the biopsy tract were found Conclusion We found that in most cases, FNAB provides adequate DNA for genetic analysis of uveal melanoma using microsatellite assay

https://jamanetwork.com/journals/jamaophthalmology/articlepdf/419674/ecs70005_1017_1024.pdf

Chromosome 3 Analysis of Uveal Melanoma Using Fine-Needle Aspiration Biopsy at the Time of Plaque Radiotherapy in 140 Consecutive Cases: The Deborah Iverson, MD, Lectureship

Uveal melanoma (UM) is the most common primary cancer of the eye and has a strong propensity for metastasis. Although there have been many recent improvements in the diagnosis and treatment of UM, and only 2-4% of patients present with detectable metastasis, up to half of patients are at risk for dying of metastatic disease. Clinicopathologic factors are not accurate enough for individualized patient care. Chromosomal alterations have been used for prognostic purposes, but the routine clinical use of these methods is limited by their susceptibility to sampling error resulting from tumor heterogeneity, limited clinical validation, lack of standardized testing platforms, and high technical failure rates. In contrast, the DecisionDx-UM gene expression profile test is a stand-alone platform which requires no other information for maximal prognostic accuracy and which circumvents many of the drawbacks of chromosomal methods through the use of a highly sensitive microfluidics, PCR-based platform that simultaneously measures the expression of 15 carefully selected genes from primary uveal melanoma samples obtained by fine needle biopsy. Low metastatic risk is reported as Class 1, and high metastatic risk as Class 2. The test allows patients to be stratified into risk categories such that high-risk patients can be offered intensive metastatic surveillance and adjuvant therapy while low-risk patients can be spared these interventions. This test is now used as part of the standard of care in many ocular oncology centers.

The DecisionDx-UM Gene Expression Profile Test Provides Risk Stratification and Individualized Patient Care in Uveal Melanoma.

Uveal melanoma (UM) is a rare tumour with a high propensity to metastasize. Although no effective treatment for metastases yet exists, prognostication in UM is relevant for patient counselling, planning of follow-up and stratification in clinical trials. Besides conventional clinicopathologic characteristics, genetic tumour features with prognostic significance have been identified. Non-random chromosome aberrations such as monosomy 3 and gain of chromosome 8q are strongly correlated with metastatic risk, while gain of chromosome 6p indicates a low risk. Recently, mutations in genes such as BAP1, SF3B1 and EIF1AX have been shown to be related to patient outcome. Genetics of UM is a rapidly advancing field, which not only contributes to the understanding of the pathogenesis of this cancer, but also results in further refinement of prognostication. Concomitantly, advances have been made in the use of genetic tests. New methods for genetic typing of UM have been developed. Despite the considerable progress made recently, many questions remain, such as those relating to the reliability of prognostic genetic tests, and the use of biopsied or previously irradiated tumour tissue for prognostication by genetic testing. In this article, we review genetic prognostic indicators in UM, also comparing available genetic tests, addressing the clinical application of genetic prognostication and discussing future perspectives for improving genetic prognostication in UM.

https://scholarlypublications.universiteitleiden.nl/access/item%3A2951549/view

Genetic prognostication in uveal melanoma

PURPOSE. Cytogenetic prognostication of choroidal melanoma, particularly monosomy 3 detections, is limited to enucleated eyes or resected tumors. The authors developed an in vivo technique to detect monosomy 3 using transscleral fine needle aspiration biopsy (FNAB). METHODS. Eight eyes with medium-sized choroidal melanoma were included in this prospective study. A 25-gauge transscleral FNAB was performed during surgical procedure for brachyther-apy, just before applying the radioactive plaque over the tumor base. Sampled material underwent fluorescence in situ hybridization (FISH) with centromeric probes for chromosome 3. Follow-up was >12 months. RESULTS. Transscleral FNAB yielded sufficient material in 7 of 8 eyes (87.5 %). Five of seven eyes had monosomy 3. No early or late complications were detected. CONCLUSIONS. This study demonstrates that medium choroidal melanomas may be safely sampled by intraoperative transscleral FNAB to detect monosomy 3 in vivo.

In vivo detection of monosomy 3 in eyes with medium-sized uveal melanoma using transscleral fine needle aspiration biopsy.

Intraocular tumor diagnosis is based on clinical findings supported by additional imaging tools, such as ultrasound, optical coherence tomography and angiographic techniques, usually without the need for invasive procedures or tissue sampling. Despite improvements in the local treatment of uveal melanoma (UM), the prevention and treatment of the metastatic disease remain unsolved, and nearly 50% of patients develop liver metastasis. The current model suggests that tumor cells have already spread by the time of diagnosis, remaining dormant until there are favorable conditions. Tumor sampling procedures at the time of primary tumor diagnosis/treatment are therefore now commonly performed, usually not to confirm the diagnosis of UM, but to obtain a tissue sample for prognostication, to assess patient’s specific metastatic risk. Moreover, several studies are ongoing to identify genes specific to UM tumorigenesis, leading to several potential targeted therapeutic strategies. Genetic information can also influence the surveillance timing and metastatic screening type of patients affected by UM. In spite of the widespread use of biopsies in general surgical practice, in ophthalmic oncology the indications and contraindications for tumor biopsy continue to be under debate. The purpose of this review paper is to critically evaluate the role of uveal melanoma biopsy in ophthalmic oncology.

Uveal Melanoma Biopsy: A Review.

Background
Monosomy 3 is a highly specific marker for poor prognosis in posterior uveal melanoma. Unfortunately, cytogenetic prognostication is limited to enucleated eyes or resected tumors. The aim of this study was to evaluate mid-term natural history and safety of in vivo detection of chromosome 3 status in posterior uveal melanomas undergoing plaque brachytherapy.

In vivo monosomy 3 detection of posterior uveal melanoma: 3-year follow-up.

Purpose
Circumstantial evidence suggests that development of uveal melanoma may be associated to two different pathogenetic pathways, either loss of chromosome 3 or extra copies of 6p (+6p). Chromosome 3 monosomy (−3) is detected in approximately half of uveal melanomas, and is strongly linked to metastatic disease, whereas +6p accounts for one-fourth of uveal melanomas with no clear clinical correlations. The aim of our study was to verify if the analysis of chromosomes 3 and 6 was able to distinguish two groups of patients for translating this approach in the clinical practise as prognostic tool.

FISH analysis of chromosomes 3 and 6 on fine needle aspiration biopsy samples identifies distinct subgroups of uveal melanomas.

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In vivo detection of monosomy 3 in eyes with medium-sized uveal melanoma using transscleral fine needle aspiration biopsy.

Uveal Melanoma Biopsy: A Review.

In vivo monosomy 3 detection of posterior uveal melanoma: 3-year follow-up.

FISH analysis of chromosomes 3 and 6 on fine needle aspiration biopsy samples identifies distinct subgroups of uveal melanomas.