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Intraocular biopsy using special forceps: A new instrument and refined surgical technique
Abstract
The aim was to investigate the Essen biopsy forceps as a new instrument and surgical approach for biopsy of intraocular tumours. Biopsy is indicated for assessment of any uncertain intraocular process or confirmation for presumed diagnosis before treatment. There is increasing interest for further genetic and immunocytological information in order to characterise the neoplasm, especially grading and prognosis of micrometastasis in uveal melanoma. The authors have developed a new surgical technique using special intraocular biopsy forceps.
Twenty patients with uncertain intraocular subretinal tumour underwent biopsies carried out using the special Essen biopsy forceps. Biopsies were obtained through sutureless 23-gauge three-port vitrectomy. A small retinotomy tumour specimen was taken by the forceps branches. For further processing, the specimens were flushed out into a sterile tube and then sent to pathologists.
The prebioptical tumour had a mean thickness of 3.48 mm (1.1 to 9.8 mm). In all cases (n=20) biopsies (0.3-2.1 mm in size) were obtained, in 19 cases (95%) allowing precise histological and immunohistochemical typing of the lesions following cytoblock embedding. Uveal melanoma was diagnosed in 50% (n=10), choroidal metastasis in 15% (n=3) and choroidal naevus in 15% (n=3); other diagnoses (n=3) included choroidal haemangioma, B cell lymphoma and old subretinal haemorrhage. Apart from three patients with temporary punctual bleeding on the surface, there were no intra- and postoperative complications.
Biopsy using special forceps is a promising new approach and precise surgical procedure. Especially for small intraocular tumours, this technique has the advantage in providing enough tissue for improved histological examination and presenting a low risk for complications.
... Another technique, more recently described, consists of an intraocular biopsy using the vitreous cutter or special forceps penetrating directly into the tumor and is highly effective in obtaining a tissue sample (Akgul et al., 2011;Bagger et al., 2013;Konstantinidis et al., 2014;Sen et al., 2006;Seregard et al., 2013). A transscleral incisional biopsy with forceps, recently described by Angi et al. in cases of choroidal melanomas, could yield more successful histological analysis (Angi et al., 2017). ...
... FNAB yielded adequate cytological material in 88% of cases. Furthermore, when no primary tumor is identified by systemic workup, tissue sampling has been shown to successfully confirm the metastatic nature of the lesion and identify its origin in most cases (Akgul et al., 2011;Konstantinidis et al., 2014;Sen et al., 2006). ...
... This method was shown to yield larger tissue samples with a 92% chance of successful diagnosis (Sen et al., 2006). Another variation of this technique is to use biopsy forceps after small incision at the chosen biopsy site (Akgul et al., 2011;Seregard et al., 2013). ...
The most frequent site of ocular metastasis is the choroid. The occurrence of choroidal metastases has increased steadily due to the longer survival of metastatic patients and the improvement of diagnostic tools. Fundoscopy, ultrasonography, and fluorescein angiography are now complemented by indocyanine green angiography and optical coherence tomography. Choroidal tumor biopsy may also confirm the metastatic nature of the tumor and help to determine the site of the primary malignancy. There is currently no consensus on the treatment strategy. Most patients have a limited life expectancy and for these complex treatments are generally not recommended. However, recent advances in systemic therapy have significantly improved survival of certain patients who may benefit from an aggressive ocular approach that could preserve vision. Although external beam radiation therapy is the most widely used treatment, more advanced forms of radiotherapy that are associated with fewer side effects can be proposed in select cases. In patients with a shorter life expectancy, systemic therapies such as those targeting oncogenic drivers, or immunotherapy can induce a regression of the choroidal metastases, and may be sufficient to temporarily decrease visual symptoms. However, they often acquire resistance to systemic treatment and ocular relapse usually requires radiotherapy for durable control. Less invasive office-based treatment, such as photodynamic therapy and intravitreal injection of anti-VEGF, may also help to preserve vision while reducing time spent in medical settings for patients in palliative care. The aim of this review is to summarize the current knowledge on choroidal metastases, with emphasis on the most recent findings in epidemiology, pathogenesis, diagnosis and treatment.
... Transvitreal biopsy using an Essen forceps (Akgul et al. 2011) requires a 23G 3 port pars plana vitrectomy followed by a 0.6 mm incision in the retina to allow advancement of the open Essen forceps into the tumour (Akgul et al. 2011). The sample is grasped by the forceps and withdrawn through the vitreous cavity and scleral port. ...
... Transvitreal biopsy using an Essen forceps (Akgul et al. 2011) requires a 23G 3 port pars plana vitrectomy followed by a 0.6 mm incision in the retina to allow advancement of the open Essen forceps into the tumour (Akgul et al. 2011). The sample is grasped by the forceps and withdrawn through the vitreous cavity and scleral port. ...
... The sample is grasped by the forceps and withdrawn through the vitreous cavity and scleral port. The procedure entails a potential risk tumour seeding in samples larger than 0.6 mm, as they can get stuck at the entry site of the scleral port (Akgul et al. 2011). ...
... Transvitreal biopsy using an Essen forceps is a suture-less procedure that requires a 23-G 3 port pars plana vitrectomy, followed by a 0.6 mm incision in the retina to allow the advancement of the open Essen forceps into the tumor [39]. The sample is grasped by the forceps and withdrawn through the vitreous cavity and scleral port. ...
... The sample is grasped by the forceps and withdrawn through the vitreous cavity and scleral port. The procedure may provide for a larger tissue specimen but entails a theoretically potential risk of tumor seeding in samples larger than 0.6 mm, as they can get stuck at the entry site of the scleral port [39]. The main advantage of using Essen biopsy forceps is the large amount of tissue obtained by the procedure [26]. ...
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.
... From July 2012, trans-scleral FNAB of anterior tumours was replaced by incisional biopsy with Essen forceps. 13 ...
... The Essen forceps have been especially designed for intraocular tumour biopsy. The standard use is through sutureless 23-gauge three-port vitrectomy, as first described by Akgul et al. 13 The novelty introduced by author BED and used for all patients in group 2 undergoing transcleral biopsy is their usage through a fine scleral opening under a lamellar scleral flap, allowing direct access to the tumour with resultant increased tissue yield. 14 This improved yield in turn increased the number of patients for whom genetic analysis was undertaken and an individualised prognostication curve generated using the 'Liverpool UM Prognosticator Online' (LUMPO), which also incorporates clinical, histological and genetic parameters. ...
Background
Accurate survival prognostication for patients with uveal melanoma (UM) enables effective patient counselling and permits personalised systemic surveillance for the early detection of metastases and, in high-risk patients, enrolment in any trials of systemic adjuvant therapy. The aim of this work is to determine the success of prognostic UM tumour biopsy using an improved surgical approach and optimised sample handling workflow.
Methods
Patients with UM treated by primary radiotherapy between 2011 and 2013 and who underwent a prognostic biopsy with cytology, multiplex ligation-dependent probe amplification and/or microsatellite analysis were included. The main outcomes and measures were success of cytology and genetic studies, and surgical complications.
Results
The cohort comprised 232 patients with UM having a median age of 59 years (range, 25–82) at treatment. The median largest basal diameter was 11.4 mm (range, 4.1–20.8) and tumour height was 3.4 mm (range, 0.7–10.3). Ciliary body involvement was noted in 42 cases. Treatment consisted of Ru-106 brachytherapy in 151 cases (65%) and proton beam radiotherapy in 81 cases (35%). With improvements in surgical techniques and laboratory methods over time, cytology success increased from 92% (131/142) to 99% (89/90) and the numbers of samples with sufficient DNA for genetic testing increased from 79% (104/131) to 93% (83/89). Overall, chromosome 3 loss was noted in 64/187 (34%) cases. Surgical complications, including transient localised bleeding, vitreous haemorrhage and retinal perforation, decreased over time. Eight patients required additional surgery.
Conclusions
Improved surgical techniques and laboratory methods yielded successful cytology and genetic information in the majority of cases.
Precis
Analysis of data from 232 patients with uveal melanoma undergoing prognostic tumour biopsy demonstrated that improved surgical techniques and laboratory methods yielded successful cytology and genetic information in 99% and 89% of cases, respectively.
... Hlavní výhodou použití Essenových bioptických kleští je větší velikost získaného vzorku. U vzorků větších než 0,6 mm s sebou ale tato technika nese potenciálně vyšší riziko diseminace tumoru, protože vzorek nebo jeho části mohou uvíznout ve sklerálním portu [4,23]. ...
In intraocular tumors, diagnosis is usually based on clinical examination and imaging without the need for invasive surgery or tissue sampling. The diagnosis can be confirmed by biopsy, however, in the case of intraocular malignancy, the biopsy is considered controversial. Due to the development of uveal melanoma cytogenetic prognostics and the progression in generalised uveal melanoma treatment, intraocular melanoma biopsy is becoming increasingly important. Diagnostic biopsy of intraocular tumors is indicated in cases of diagnostic uncertainty for findings with conflicting non-invasive test results and for small melanocyte lesions. Tumor prognostic biopsy is performed to obtain a tissue sample for tumor cytogenetic testing, which can help to determine the prognosis and specific metastatic risk of the patient. For anterior segment tumors, anterior chamber fluid sampling, thin-needle iris biopsy, punch biopsy, surgical biopsy or biopsy using vitrectomy may be used. For posterior segment tumors, procedures include transscleral or transretinal thin-needle biopsy, vitrectomy-assisted biopsy, punch biopsy, endoresection or transscleral exoresection. Complications of intraocular melanoma biopsy include too small or non-valuable sample collection, intra-tumoral heterogeneity, intra-ocular trauma and induction of intraocular or extraocular tumor dissemination.
... The first is an incisional surgical biopsy to obtain material from the suspicious iris mass sufficient for diagnostic purposes, without removal of the whole tumor. 11,3,22,23,46 The second is an excisional resection of the tumor mass to obtain material for histopathological diagnosis, but also with the potential for cure. 62 Both approaches have their advantages and disadvantages. ...
Corneal transplantation is the most commonly performed human tissue transplantation procedure worldwide. Because of the large number of transplants, corneal graft failure has become one of the most common indications for corneal transplantation. The relatively recently developed lamellar transplant techniques have brought about specific potential complications leading to graft failure that may require different approaches to repeat transplantation other than penetrating keratoplasty. On the other hand, these new lamellar techniques also provide novel ways of rescuing failed penetrating grafts, with potential advantages over successive penetrating keratoplasties, such as reduced intraoperative risks and faster visual rehabilitation. We summarize the incidence and risk factors of graft failure for penetrating and lamellar (stromal and endothelial) corneal transplants and discuss the various surgical alternatives currently available to rescue such failed grafts, with a focus on the reported outcomes and limitations.
... [7] предложены к использованию тонкостенные конической формы иглы (наружный диаметр рабочего конца -27G), подтвердившие свою пригодность при проведении экспериментальной ТИАБ на энуклеированных глазах. При проведении ТИАБ in vivo в 2011 г. для повышения информативности предложена техника трехпортовой витрэктомии, при которой для забора опухолевой ткани используется витреотом 25G, а позднее -27G [13][14][15][16][17]. Подобная методика, так же как и использование витреальных щипцов [13], являясь более инвазивной и травматичной, не приобрела широкого распространения, несмотря на высокую информативность биопсийных образцов [3]. ...
Purpose: To present our experience of fine needle aspiration biopsy (FNAB) of intraocular tumors.Material and methods: Within 3 years FNAB was performed in 154 eyes (154 patients) for prognostic (n= 121) and diagnostic purposes (n=33). The mean tumor thickness in group of diagnostic FNAB was 6.0 mm (range, 2.3-10.5 mm), in prognostic – 5.5 mm (range, 2.0-11.3 mm). Transscleral, transvitreal and transcorneal FNABs were performed using our new custom designed thin-wall 25 and 27G needles by our improved FNAB technique. All samples were analyzed cytologically.In cases of uveal melanoma (UM) genetic testing (GT) was performed to estimate prognosis. Cytogenetic and molecular-genetic tests on cells and remnant liquid were held in cases of UM.Results: Cytologycally informative materials was obtained in 136 of 154 (88%) FNAB samples. Diagnostic FNAB yield was revealed to be 97% (n=32): in 20 cases UM was detected, in 8 – metastases, in 3 – intraocular lymphoma and in 1 – subretinal hemorrhage. Prognostic FNAB revealed either spindle or round-shaped cells of UM in 104 of 121 cases (informative value – 86%). No signs of tumor growth within the scleral track were seen. In 2 cases vitreous hemorrhage was seen that required vitrectomy. The average follow-up period was 11 months (3 to 41 months). No severe complications were detected.Conclusion: Our FNAB improved technique allows to provide excellent tissue samples suitable for differential diagnosis and estimating prognostic with no severe complications.
... Bei sehr flachen Läsionen kann die OCT-Angiographie hilfreich sein [20][21][22]. In einigen Fällen ist zur Diagnosesicherung eine Probebiopsie notwendig [23][24][25][26][27][28]. Neben einer konventionellen Histooder Zytopathologie kann dann auch eine molekularbiologische Untersuchung der Probe erfolgen, die auch zur Risikostratifizierung genutzt werden kann. ...
Background
Personalized medicine in the oncological care of patients aims to ensure the best possible outcome for patients by tailoring the diagnostics and treatment to the individual. This goal also applies to patients with uveal melanoma (UM).
Objective
The aim of this article is to define the present and future potential of personalized medicine and maximize its benefits in patients with UM.
Methods
This article gives an overview of current theranostics for UM and describes a recent paradigm shift in diagnostics and the potential impact of new therapeutic developments.
Results
Treatment is initiated when the diagnosis of UM is histologically confirmed or is very probable based on clinical characteristics. Current treatment concepts are primarily influenced by various factors, such as the anatomical features of the primary tumor, situation of the contralateral eye and also the age, health status and wishes of the patient. The current treatment and control of the primary tumor are very successful but they have little influence on the development of metastases and life expectation. The life expectation of the patient essentially depends on the timing of the diagnosis and treatment of the UM. The liquid biopsy is a new diagnostic tool that supports an early decision for a more invasive diagnostic procedure or treatment. Molecular biological techniques enable a risk stratification and provide a foundation for decision making for neoadjuvant forms of treatment.
Conclusion
The present concept of personalized medicine for UM is restricted to the treatment of the primary tumor. New diagnostic options, such as liquid biopsy and molecular genetic investigations help to acquire a better understanding of the mechanisms involved and provide the foundation for precision medicine in the development of further personalized treatment concepts.
... In a single case, the affected eye was treated by enucleation. Transretinal tumor biopsy was performed as previously described by Akgul et al. [37]. ...
Several tumors, including uveal melanoma, show somatic mutations of GNAQ/GNA11. Circumscribed choroidal hemangioma is a benign tumor that becomes symptomatic in adulthood. In some patients, morphologic examination of biopsies is required for differential diagnosis between amelanotic choroidal melanoma and circumscribed choroidal hemangioma. Here, we report the results of GNAQ/GNA11 mutation analysis in samples from circumscribed choroidal hemangioma. Deep amplicon sequencing (Illumina MiSeq, San Diego, CA, USA) of positions R183 and Q209 of GNAQ and GNA11 in tissue samples from 33 patients with histologically diagnosed circumscribed choroidal hemangioma. All patients underwent biopsy or enucleation at our clinic between 2008 and 2018. To enable detection of variant alleles at low fractions, read depth exceeded 15,000-fold. DNA for genetic analysis was prepared from either snap-frozen (n = 22) or FFPE (n = 11) tissue samples. Samples from 28/33 patients (85%) showed a somatic missense mutation of GNAQ (c.626 A > G) predicted to result in p.Q209R. Variant allele fraction was variable (range 2.3% to 28%). Variants of GNAQ resulting in p.Q209 are characteristic for circumscribed choroidal hemangiomas. It appears that the GNAQ mutation spectrum in this tumor is narrow, possibly restricted to p.Q209R. Moreover, the spectrum is distinct from that of uveal melanoma, in which alterations resulting in p.Q209R are very rare.
... On the contrary, the latter is, without a doubt, a well-established tool. It is at the same time safe and eye globe conserving [5] . It allows establishing or confirming a diagnosis in clinically inconclusive cases and provides important prognostic information [6] . ...
Background/aims:
To report a case and the histopathology of uveal melanoma cell seeding following transretinal tumor biopsy for a suspected uveal lesion.
Methods:
Interventional case report.
Results:
A 66-year-old male presented with a pigmented perilimbal episcleral lesion overlying an intraocular mass at the pars plana, 3.5 years after transretinal biopsy and ruthenium plaque brachytherapy for a choroidal melanoma at the posterior pole. The patient underwent enucleation of the eye. Histopathology confirmed a recurrence of uveal melanoma with intra- and extrascleral tumor portions. Serial sections revealed the posterior border of this newfound pars plana melanoma separated from the radiation scar by a viable and tumor-free choroidal area, thus failing to establish a continuity between secondary and primary tumor.
Conclusion:
Transretinal tumor biopsy is of high diagnostic and prognostic value in the management of uveal lesions, but also bears the potential risk for tumor cell seeding.
... [21] Likewise, an intraocular forceps is specifically designed to retrieve tumor sample through a retinotomy (Essen forceps). [22] A close cooperation between the ophthalmic oncologist and the ophthalmic pathologist is essential because the tumor samples are usually very small and could easily be lost during processing. Cytopatholologist must interpret the cellular features within the clinical context. ...
Biopsy involves the surgical removal of a tissue specimen for histopathologic evaluation. Most intraocular tumors are reliably diagnosed based on the clinical evaluation or with noninvasive diagnostic techniques. However, accurately diagnosing a small percentage of tumors can be challenging. A tissue biopsy is thus needed to establish a definitive diagnosis and plan the requisite treatment. From fine-needle aspiration biopsy (FNAB) to surgical excision, all tissue collection techniques have been studied in the literature. Each technique has its indications and limitations. FNAB has been reported to provide for 88-95% reliable and safe ophthalmic tumor diagnosis and has gained popularity for prognostic purposes and providing eye conserving treatment surgeries. The technique and instrumentation for biopsy vary depending upon the tissue involved (retina, choroid, subretinal space, vitreous, and aqueous), suspected diagnosis, size, location, associated retinal detachment, and clarity of the media. The cytopathologist confers a very important role in diagnosis and their assistance plays a key role in managing and planning the treatment for malignancies.
... Suction of the subretinal material is performed via a connected syringe. Specialized subretinal biopsy forceps can be placed into the tissue to obtain a sample as well (Akgul et al. 2011 ). Depending on the size and location of the biopsy, laser and gas tamponade are not always needed. ...
Ocular and adnexal T-cell lymphoma represents a rare non-Hodgkin’s lymphoma and is mostly secondary to systemic malignancies. The known etiology is mainly due to genetic predisposition and/or viral infections in different subsets of T-cell lymphoma. Both primary and metastatic T-cell lymphoma can invade intraocular and adnexal tissues. Clinical presentations vary largely based on the different intraocular and adnexal sites that are affected. Pathology based on intraocular/adnexal biopsies is the gold standard for diagnosis. Other diagnostic techniques, including ocular/orbital imaging, immunogenotyping, and molecular diagnosis, are also useful adjuncts to pathological diagnosis and subclassification. Current treatment is based on localized radiotherapy and chemotherapy in patients with local disease and combined with systemic high-dose methotrexate chemotherapy and/or stem cell transplantation in patients with systemic malignancy.
... 13 14 Transscleral biopsies were performed either as fine needle aspiration biopsy with a 25-gauge needle attached to a 20 mL syringe by flexible plastic tubing; or as an incisional scleral flap biopsy, where a lamellar scleral flap was created, and tumour samples were obtained with Essen forceps as previously described. 15 Four tumours treated with Ru 106 -RT underwent biopsy immediately before the insertion of plaque; in a single case, the patient underwent biopsy 2 weeks after Ru 106 -plaque insertion (patient 2). Patients whose CMs were treated with PBRT underwent biopsy on the last day of treatment. ...
Coupland SE, et al. Br J Ophthalmol 2015;0:1–7. doi:10.1136/bjophthalmol-2015-307057
... 38 Specifically designed intraocular forceps to retrieve tumor sample through retinotomy (Essen Forceps) allows histological and immunohistochemistry typing. 39 ...
A majority of intraocular tumors can be diagnosed based on clinical examination and ocular imaging studies, which obviate the need for diagnostic ophthalmic fine needle aspiration biopsy (FNAB). Overall, diagnostic accuracy of ophthalmic FNAB is high but limited cellularity can compromise the diagnostic potential of ophthalmic aspirate samples. The role of ophthalmic FNAB is limited in retinal tumors. Orbital FNAB should be considered in the evaluation of lacrimal gland tumors, orbital metastasis, and lymphoproliferative lesions. Negative cytologic diagnosis of malignancy should not be considered unequivocal proof that an intraocular malignancy does not exist. With improved understanding of genetic prognostic factors of uveal melanoma, ophthalmic FNAB is gaining popularity for prognostic purposes in combination with eye conserving treatment of the primary tumor. In special clinical indications, ancillary studies such as immunohistochemistry and FISH can be performed on ophthalmic FNAB samples. Assistance of an experienced cytopathologist cannot be overemphasized.
... In collaboration with the Dutch Ophthalmic Research Center Akgul et al. developed the Essen biopsy forceps as new method for intraocular biopsy [4]. Herein we demonstrate our experience with this method and show its accuracy in providing enough tissue allowing a combined histopathological and immunohistochemical examination. ...
Purpose. To present initial experience with a novel biopsy method, the Essen biopsy forceps. Therefore, two patients with diagnostic suspicion of uveal melanoma underwent biopsy for histopathological confirmation. Case Presentation. Two patients presented with painless unilateral vision reduction. Ultrasound revealed the diagnostic suspicion of uveal melanoma. Therefore, biopsy with the Essen biopsy forceps using a sutureless 23-gauge three-port vitrectomy system was performed. The specimens were then submitted to a pathologist and processed. Histopathology of the obtained specimen confirmed the diagnostic suspicion of choroid melanoma in both patients. Conclusion. Essen biopsy forceps is a very practicable alternative method to the FNAB, allowing a combined histopathological and immunohistochemical examination for achieving high diagnostic accuracy at minimal risk.
... Interim results suggest that our success rates have not been as high as those reported by some other authors (Shields et al., 2011). Biopsy forceps have been developed to enhance the yield (Akgul et al., 2011). ...
The surgical management of iris melanoma has evolved over the last century. Traditionally, iris melanoma has been treated by tumor resection or enucleation, with radiation therapy as an alternative. More recently, biopsy techniques and minimally invasive tumor resection techniques have been described. While a consensus on specific indications for intraocular fine-needle aspiration biopsy (FNAB) is absent, it is primarily utilized when a definitive diagnosis cannot be made based on clinical examination and ancillary testing alone. Twenty-five- to thirty-gauge needles are commonly used for ocular FNAB. Minimally invasive iridectomy can also be performed using a 20- or 25-gauge vitrector or a 25-gauge Rycroft canula to obtain tissue. Intraocular forceps (23-gauge Essen forceps) have been modified to improve biopsy sample yield. Excisional techniques include standard iridectomy, small incision iridectomy, and iridocyclectomy depending upon the size and location of the iris melanoma.
The majority of choroidal tumours are diagnosed accurately with clinical examination and the additional data obtained from non-invasive imaging techniques. Choroidal biopsies may be undertaken for diagnostic clarity in cases such as small melanocytic or indeterminate lesions, identifying the primary tumour in the case of choroidal metastases or the subclassification of rarer conditions such as uveal lymphoma. There is however an increasing use of biopsy techniques for prognostication in uveal melanoma. This review explores the main indications and surgical techniques for tumour acquisition, and the optimised approach utilised by the current authors to improve successful yield for histological and genetic analysis.
Introduction
Sampling of uveal tumors using fine-needle aspiration biopsy (FNAB) or vitrectomy cutter choroidal biopsy (VCCB) has become part of the standard of care in diagnosis and prognosis of uveal melanomas and borderline melanocytic uveal tumors. For early adopters, the use of FNAB (or VCCB) has shown that benefits of tumor sampling far outweigh the risks, particularly with respect to the ability to confirm tumor diagnostic and prognostic testing.
Areas covered
This manuscript will review the different techniques used to obtain small samples of uveal tumors with minimal disruption of the ocular tissues, briefly discuss clinical applications and complications of FNAB and VCCB, and ways in which to improve specimen yield and patient outcomes.
Expert opinion
The published literature shows a lack of uniformity in indication and surgical techniques among ocular oncologists performing FNAB and VCCB. This fact can potentially lead to discrepant results that include variable rates of success in obtaining a sufficient specimen and a wide range of complications, from intraocular hemorrhage, retinal detachment to anecdotal cases of seeding of the biopsy needle track and extraocular tumor extension. Uniform indications and surgical techniques would allow comparison among different centers and protocols to minimize and manage complications.
Purpose
To systematically evaluate and compare the effects of using small gauge needles and vitrectors on the ability to obtain adequate diagnostic and prognostic uveal melanoma biopsy specimens.
Design
Comparative evaluation of biopsy instruments.
Methods
Survival of uveal melanoma cells was evaluated in vitro following needle aspiration. Five therapeutically enucleated eyes were sampled in triplicate for ex vivo diagnostic biopsy experiments with 25-gauge (25-G) needle, 27-gauge (27-G) needle, and 27-G vitrector. During surgery in eight patients, paired diagnostic transscleral FNABs were performed using both 25-G and 27-G needles. A review of cytologic specimens was performed by a panel of three expert cytopathologists. A retrospective chart review was performed to evaluate 100 consecutive tumors undergoing prognostic biopsy for gene expression profiling to assess the relationship between needle gauge and prognostic adequacy.
Results
No significant cell shearing of uveal melanoma cells occurred in vitro with 25-G, 27-G, or 30-G needles. For ex vivo biopsy samples, diagnostic yield was 100% using 25-G needle (5/5) or 27-G vitrector (5/5), but 60% using a 27-G needle (3/5). For in vivo samples, no difference in diagnostic yield was found between 25-G (75%, 6/8) or 27-G (75%, 6/8) needle sizes. Of 100 molecular prognostic biopsy samples evaluated, 65 were obtained using 27-G needles; for these biopsies, the prognostic yield was 65/65 (100%).
Conclusions
For diagnostic biopsy of uveal melanoma, a larger gauge needle or a 27-G vitrector may have better overall cellularity and diagnostic yield when compared to a 27-G needle. However, for much more common molecular prognostic testing, 27-G needle provided adequate sample in 100% (65/65) of cases, and a larger needle provided no additional benefit.
Iris lymphomas are rare malignant neoplasms arising either as primary tumors in the iris or as secondary tumors involving the iris. We summarize previously published data and make recommendations for work-up strategies for cases of suspected iris lymphoma. Our objective is to provide a structured overview of the typical clinical symptoms and signs, the pathologic, ophthalmic as well as hematologic work-up for diagnosis, treatment, and follow-up of iris lymphomas and offer a flowchart on how to diagnose and treat these tumors.
Purpose:
To investigate whether early detection and treatment of uveal melanoma by screening was associated with a lower mortality rate.
Methods:
Retrospective assessment of prospectively collected data comparing 132 patients with uveal melanoma referred by the National Diabetic Screening Service with 608 control patients referred through other means.
Results:
Mean tumor diameter was smaller in the diabetic screening group (11.1 mm vs. 12.5 mm) as was tumor thickness (3.4 mm vs. 5.4 mm). The prevalence of high-risk monosomy 3 was also lower (17/40, 43% vs. 62/110, 56%). Despite a higher rate of systemic comorbidities in the patients diagnosed through screening and despite older age at diagnosis, the 5-year all-cause mortality was similar in both groups (17% vs. 20%); however, the metastatic mortality was lower in the diabetic screening group (11/132, 8% vs. 95/608, 16%).
Conclusion:
Despite higher rates of comorbidities, the patients detected at diabetic screening had a lower 5-year mortality rate. The diabetic screening programme enabled detection and treatment of posterior uveal melanomas at an earlier stage. However, the confounding factors of lead and length time bias are not to be ignored.
The ophthalmologist may be the first physician to detect disseminating disease as uveal metastasis may be the first presenting symptom, particularly with breast cancer and adenocarcinoma of the lung. Autopsy studies have shown microscopically detectable uveal metastases in 9.3% of all fatal cancer cases. Although the estimated incidence of uveal metastasis is 20,000 patients per annum in the United States, most of these patients are probably never seen by an ophthalmologist as they may be asymptomatic. Metastatic tumors may occur anywhere in the uvea including the iris, ciliary body, and choroid. The vast majority of metastatic tumors, however, develop in the choroid at the posterior pole due to the increased vascular supply, whereas metastases to the iris are relatively rare. In the majority of patients with uveal metastases, a primary tumor is known from the history. Sarcomas very exceptionally metastasize to the uvea. Blurred vision, floaters, and photopsia are the key symptoms of choroidal metastasis and are related to the intraocular mass itself as well as the associated exudative retinal detachment. Metastatic tumors in the anterior uvea may induce episcleritis and enlarged sentinel vessels. Frequently, choroidal metastases are bilateral and multifocal, predominantly placoid shaped, pale, or yellowish with indistinct margins. Systemic workup is needed if there is no history of a primary tumor. A full-body PET/CT is helpful to detect an unknown primary tumor, and in cases with suspected breast carcinoma or lymphoma, an MRI of the brain is essential because of the well-known coincidence of uveal and cerebral metastases with these tumors. Intraocular biopsy of a suspected lesion is indicated when the diagnosis cannot be ascertained by other, less invasive procedures. The decision to treat uveal metastatic tumors is complex and is made in consultation with the oncologist and radiation oncologist.
Lymphoid proliferations of the uvea can be divided into two main groups: (a) primary uveal tumors and (b) secondary intraocular manifestations of systemic lymphoma. Although the exact frequency of the latter is not known, they are not unusual, particularly in leukemia where intraocular (mainly choroidal) involvement may occur in as many as 80–90% of patients at some point in the course of the disease. Primary uveal lymphoma is rare and, unlike vitreoretinal lymphoma, is usually indolent in nature. Uveal lymphoma can be further divided according to location, primary choroidal lymphoma, primary ciliary body lymphoma, and primary iridal lymphoma, with the former being the most common.
Alternatives to fine-needle aspiration biopsy include vitreous cutter aspiration biopsy, incisional biopsy, and excisional biopsy. Vitreous cutter aspiration biopsy is performed with a 25- or 27-gauge vitreous cutter using a three-port, sutureless vitrectomy kit, without vitrectomy, retinopexy, or tamponade. Incisional biopsy of choroidal or ciliary body melanomas can be performed with Essen forceps through a deep sclerotomy under a superficial lamellar scleral flap, using tissue glue to close the flap and seal the wound, thereby preventing seeding of tumor cells into surrounding tissues. Excisional biopsy involves removal of the entire tumor, using techniques described elsewhere. Biopsy can be performed to establish a diagnosis (e.g., to differentiate melanoma from nevus or metastasis), or to identify the likely source of a metastasis, when the primary tumor is unknown, or to estimate the survival probability of a patient with uveal melanoma, by performing genetic tumor typing. Close collaboration with the laboratory is essential.
Purpose: Monosomy 3 (M3) in uveal melanoma (UM) obtained after enucleation is significantly associated with metastatic death. With improved biopsy techniques, samples from patients treated with eye-preserving methods have become available. As the choice of treatment depends on tumour size, patients treated with eye-preserving brachytherapy tend to have smaller tumours. It has to be determined if M3 is a valid marker for prognosis of these patients.
Methods: Follow-up and clinical data were collected from a total of 451 UM patients: 291 patients were treated by brachytherapy. Tumour tissue was sampled by transretinal biopsy using the 23-gauge Essen biopsy forceps prior to therapy in 114 of them. Chromosome 3 status was determined by microsatellite analysis. Data were compared to those from 160 patients treated by enucleation.
Results: Chromosome 3 status correlates significantly with disease-related survival in both patient groups. The proportion of tumours with M3 is lower in the brachytherapy group compared to patients treated with enucleation (25/77 32% and 102/144 71%, respectively).
Conclusions: M3 is a valid marker for poor prognosis in uveal melanoma later treated by brachytherapy. The higher proportion of D3 tumours might explain, at least in part, the more favourable prognosis of patients treated by brachytherapy.
Purpose:
To review the indications for and the methods of obtaining biopsies in eyes with uveal melanoma. In addition, this review provides recommendations for avoiding biopsy-related complications and discusses the future directions of biopsy techniques for uveal melanoma.
Methods:
This review is based on a presentation by the authors (PM and MM) at the 2017 Duke Advanced Vitreoretinal Surgery Course and an extensive literature review using PubMed.
Results:
Transscleral and transvitreal fine-needle aspiration biopsy, and transvitreal vitrectomy-assisted biopsy techniques are described. The use of 25- and 27-gauge needles and vitreous cutters through a transvitreal approach are most commonly used. Complications are uncommon but may include vitreous hemorrhage, retinal detachment, and rarely, extraocular extension. Proper technique and precautions will minimize the occurrence of these rare complications.
Conclusion:
Biopsy of uveal melanoma either using a needle or vitrectomy-assisted procedures is safe and these techniques continue to improve with new vitreoretinal surgical advances.
Metastasen sind die häufigsten intraokularen Malignome. Aufgrund seiner ausgeprägten Gefäßversorgung ist die Aderhaut die häufigste Lokalisation intraokularer Metastasen (ca. 90 %). Weniger als 10 % der intraokularen Metastase befinden sich in der Iris und/oder dem Ziliarkörper, während die Netzhaut und der Glaskörper seltener betroffen sind. Die meisten intraokularen Metastasen sind Karzinome; bei Frauen ist das Mammakarzinom der häufigste Primärtumor, bei Männern das Lungenkarzinom. In der Literatur sind aber intraokulare Metastasen von praktisch allen menschlichen Malignomen beschrieben. In diesem Übersichtsartikel werden neben der Pathologie intraokularer Metastasen deren klinisches Erscheinungsbild, nicht-invasive und invasive diagnostische Prozeduren sowie die pathologische Aufarbeitung von zytologischen und histologischen Proben, die durch Feinnadelaspirationsbiopsie oder mittels spezieller Biopsiepinzette gewonnen werden, beschrieben.
Correct biopsy technique is critical in the diagnosis and management of ocular and adnexal lymphoma. The decision of what tissue to biopsy should take into account the ease of access to tissue, potential damage to surrounding vital structures, and risk for vision loss. Specific techniques will be reviewed in this chapter for various clinical scenarios including anterior segment, vitreous, subretinal, choroidal, and orbital biopsy.
Biopsy involves the removal of a tissue sample, laboratory analysis and interpretation of the results. The usual objective of biopsy has been to establish or confirm a diagnosis [1]. For example, biopsy is useful when clinical examination fails to distinguish a melanoma from a nevus or metastasis. Even when there is a confident clinical diagnosis, biopsy may be performed to determine the tumour subtype. For example, when a choroidal metastasis is diagnosed in a patient who does not have a past history of systemic malignancy, morphological and immunohistochemical examinations of the biopsy may indicate the likely site of the primary tumor so that investigations can be targeted accordingly. Increasingly, uveal melanoma biopsy is being performed to enhance prognostication, by integrating histologic and genetic findings with clinical tumor stage [2].
Fine needle aspiration biopsy (FNAB) of tumors has a long history. The first intraocular biopsy was performed by Hirschberg in 1868. Since the publication of a major report by Jakobiec in 1979, FNAB is increasingly used in the evaluation of ophthalmic tumors. The safety and reliability of ophthalmic FNAB have been reported by several other investigators with adequacy rates of 88–95 %.
To report the cytologic characteristics of uveal melanoma.
This is a prospective, single-center study of consecutive patients.
All patients with a clinical diagnosis of uveal melanoma from May 2009 to July 2013 who underwent prognostication fine-needle aspiration biopsy (FNAB) were included.
The cytologic characteristics of uveal melanoma were analyzed for 150 consecutive patients with a clinical diagnosis of uveal melanoma who were treated at the Cleveland Clinic Cole Eye Institute between May 2009 and August 2012.
Cellular features of all cases were analyzed for cell type, presence of melanin, nuclear grade, tumor-infiltrating lymphocytes, and necrosis. Cytology was then correlated with histopathology in enucleated eyes.
A total of 150 patients were included. Seven samples of tumor resections were excluded from the study because they were studied by impression smears. A total of 143 FNAB samples of 143 patients formed the basis for analysis. Fifty-three percent of the patients were male, and the average age for all patients was 60 years. Transcorneal (n = 8), transscleral (n = 71), and transvitreal (n = 64) approaches were used. Of 143 samples, 131 were adequate. Among these, spindle cells were observed in 98% (63% mixed and 35% spindle only), whereas only epithelioid cells were observed in 2 samples. Melanin granules were observed in 80% of samples. Tumor nuclear grade (atypia) increased with tumor height and by tumor location (least atypia with iris tumors).
Cytologic features such as spindle cells and melanin granules, present in 98% and 80% of samples, respectively, are important cytologic diagnostic features. Tumor nuclear grade (atypia) increased with tumor height. Iris melanoma has bland features compared with ciliary and choroidal melanoma.
Copyright © 2015 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.
Background The aim of this retrospective report is to describe our experience with the Essen-23G biopsy forceps (Akgül forceps) for biopsies of pigmented iris tumours.
Methods In this retrospective study of cases between October 2012 and September 2013, patients with iris tumours and clinical signs for malignancy underwent biopsy to secure the diagnosis. The Essen-23G-forceps was used to grasp and extract tissue through a clear corneal incision. Eventual entry and bimanual manipulation with a 23G mini-scissors was achieved through a second incision. Tissue samples were fixed in a sterile tube for further histopathological and immunohistochemical evaluation.
Results Seven eyes of seven patients underwent biopsy using the forceps. The average thickness of the iris tumours was 1.07±0.79 mm. A second corneal incision for scissoring in a bimanual technique was necessary in 5 cases (71%). In 6 cases (85%), a precise histological and immunohistochemical diagnosis was achieved. Complications were limited to minute bleeding at the biopsy site and one case of relative pupil enlargement (anisocoria) without further refractive issues.
Conclusions Iris tumour biopsies can be successfully approached using a cavernous 23G intraocular forceps with a low risk for procedure-related complications. The conical interior design allows for removal of whole tissue pieces with minimal manipulative artefacts. An optional bimanual access through a second corneal incision and use of a 23G scissors provides better efficacy.
Die transretinale Tumorbiopsie gewinnt einen zunehmend höheren Stellenwert in der Diagnostik intraokularer Raumforderungen. Moderne Techniken der transretinalen Biopsie können die histopathologische Diagnose vor Beginn der Therapie sichern. Zusätzlich können durch die molekulargenetische Analyse maligner Melanome der Uvea Hochrisikotumoren mit hohem Metastasierungsrisiko identifiziert werden. Die unterschiedlichen Biopsietechniken, Indikationen und Anwendungsgebiete werden deshalb im Folgenden dargestellt.
Background:
Prognosis evaluation of patients with choroidal and ciliary melanoma has experienced recent progress through tumour sampling and cytogenetic analysis of metastatic risk. By allocating tumor extension, height and linear basal diameter to defined TNM stages, an estimation of prognosis can also be made without invasive tissue sampling.
Methods:
Therapeutic strategies of organ preserving irradiation using different sources have clearly come to the forefront.
Results:
Due to microscopic haematogenous spreading of tumour cells prior to treatment, the metastatic risk following radiation of any form is not influenced in comparison to primary enucleation.
Conclusion:
However, metastatic disease still remains a fatal condition which currently may only be influenced by early detection and treatment of uveal melanomas.
Transretinal biopsy of intraocular tumors plays a decisive role as a diagnostic tool in ocular oncology. A biopsy is indicated to confirm a clinical diagnosis before treatment and allows identification of high risk melanomas of the uvea with a high potential of metastasis by molecular genetic evaluation of the specimen. This review will focus on the various biopsy techniques and indications for this method.
This thesis presents the author's experience with diagnostic intraocular fine needle aspiration biopsy in 18 patients with a suspected metastatic choroidal or ciliary body tumor. The author has reviewed the literature on biopsy of intraocular tumors and has specified what he believes to be valid indications for diagnostic biopsy of posterior uveal tumors. He has evaluated the accuracy, limitations, and complications of diagnostic fine needle aspiration biopsy in this series and others, and he has suggested methods for improving the recovery of sufficient cells for cytologic diagnosis and lessening the risks of tumor cell seeding during the biopsy. The author has concluded that fine needle aspiration biopsy appears to be a relatively safe, generally reliable means of establishing the pathologic diagnosis of a choroidal or ciliary body tumor in highly selected patients suspected of having metastatic cancer. In spite of its apparent safety and reliability, however, the author has cautioned against the routine use of fine needle aspiration biopsy in patients with posterior uveal tumors since its long-term safety has not been established. The author has suggested that diagnostic fine needle aspiration biopsy of posterior uveal tumors be performed only in medical centers where there can be input from and cooperation among ophthalmologists, ophthalmic pathologists, and cytopathologists who are experienced in the diagnosis of intraocular malignancies.
Based upon the author's considerable experience of trans-scleral resection of malignant melanoma of the choroid, a technique has been developed for the biopsy of tissues of the posterior segment of the eye. Its use in the management of atypical malignancy posing diagnostic difficulty and in the investigation of selected case of acute retinal necrosis, uveitis and retinal pigment epitheliopathy is described. In 34 trans-scleral biopsies of choroid, RPE and in some cases, retina, an adverse result occurred in only one case, this it was thought being due to not including pars plana vitrectomy as part of the biopsy technique. Pars plana vitrectomy is now regarded as an integral part of this form of biopsy.
We used an investigational technique for the biopsy of intraocular tumors to aid in the diagnosis of three choroidal tumors. A three-port trans-pars plana vitrectomy was performed in conjunction with retinotomy, tumor biopsy, endophotocoagulation, and air-fluid exchange. Vitrectomy was used to decrease the amount of traction secondary to retained vitreous after intraocular surgery. Retinotomy sites were chosen under microscopic control to avoid large caliber retinal vessels. Then a modified tumor-aspiration technique, together with endophotocoagulation and aspiration of intraoperative vitreous hemorrhages, provided an opportunity to sample tumor tissue continually at varied depths. We have added standard vitreous surgery concepts, techniques, and instrumentation to produce vitrectomy retinotomy aspiration biopsy of choroidal tumors.
Twenty-two fine needle (30 gauge) aspirations were performed in eyes enucleated for the clinical diagnosis of melanoma. Cytologic preparations were evaluated for adequacy of material, and needle tracts were evaluated for tumor implantation. A scleral marking method was used to identify all needle tracts. The number of tumor cells in tracts of direct transscleral aspirates was compared to those in tracts of indirect aspirates that traversed the anterior chamber or vitreous. Cellular material obtained with 30-gauge needles was sufficient for the diagnosis of malignant melanoma in all but one case. While 14 of 21 (67%) of all fine needle aspiration tracts and eight of 15 (53%) of indirect tracts contained tumor cells, the number of tumor cells was less than that associated with tumor growth in experimental models. Indirect aspirate tracts contained significantly fewer cells than tracts of direct aspirates (P less than .001).
When noninvasive techniques fail to confirm or rule out the suspicion of a malignant lesion, fine needle aspiration biopsy may provide an efficient, economical and relatively safe method of obtaining material for cytological study. The technique may also be valuable for intraoperative morphological evaluation. Traumatic complications produced by fine (21-25 gauge) needles are infrequent and almost never serious, and concerns about tumor seeding through the procedure have been largely dispelled by recent studies. Reliable results require a high level of skill in performing the aspiration procedure and in cytologically examining the small amount of material obtained. The authors review the history, applications, techniques and complications of fine needle aspiration biopsy, presenting guidelines for and illustrations of its use in specific ophthalmic situations.
We have performed fine needle aspiration biopsy of 21 solid intraocular tumors as a diagnostic technique prior to treatment of these tumors. Indications for biopsy included major diagnostic uncertainty, suspected cancer metastasis to the choroid without other evidence of systemic malignancy, and patient insistence on biopsy confirmation of the diagnosis prior to treatment. This paper presents the instrumentation and techniques that we have used in our intraocular fine needle aspiration biopsies and reviews the complications of biopsy that we have encountered.
This study was performed to ascertain the diagnostic accuracy rate of non-invasive tests in patients with presumed uveal melanomas scheduled to be treated with either irradiation or cyclochoroidectomy.
One hundred consecutive patients who had non-invasive tests followed by fine needle aspiration biopsy (FNAB) as prior alternative treatment were analysed retrospectively.
In 86 cases the diagnosis of uveal melanoma was confirmed on FNAB. In five cases false negative results were obtained. In nine patients a diagnosis other than a uveal melanoma was made on the basis of cytopathology. No significant morbidity and no evidence of tumour spread occurred.
In presumed uveal melanomas eligible for treatment with alternative therapies, the diagnostic accuracy of non-invasive tests is not as good as with larger tumours that require enucleation. Fine needle aspiration biopsy data resulted in correct management of 9% of cases that were thought to have uveal melanomas on non-invasive tests, but had other lesions on cytopathological evaluation.
To describe an intraocular biopsy technique that allows accurate histopathologic diagnosis in cases of clinically unclassifiable uveal tumors.
Retrospective noncomparative consecutive interventional case series.
Intraocular biopsies were performed by a vitreous cutter either by a two-port clear cornea approach in 11 patients with unclassifiable iris tumors or by a three-port pars plana vitrectomy in 23 patients with unclassifiable choroidal tumors. Specimens were formalin fixed and paraffin processed. Hematoxylin-eosin and periodic acid-Schiff stains were performed in all cases, with additional immunohistochemical stains using the alkaline phosphatase, antialkaline phosphatase method in cases that could not be conventionally classified.
Clinical observation and histopathologic examination of intraocular biopsies.
In 97% of cases (n = 33) a definite diagnosis could be established by the biopsy specimen. A melanoma could be diagnosed in 73% of cases (n = 8) of iris tumors and in 57% of cases (n = 13) of posterior intraocular tumors. Other diagnoses included nevus, metastasis, vasoproliferative tumor, hemorrhage, gliosis, and scleritis. Complications were encountered in four cases: a vitreous hemorrhage occurred twice, an inconclusive biopsy result, and an intraocular tumor spread occurred once, respectively. No increased tumor-related mortality was observed after a mean follow-up of 44 months.
Intraocular biopsy by a vitreous cutter allows the histopathologic examination of formalin-fixed paraffin-embedded tumor tissue. This increases the diagnostic accuracy, avoiding the risk of extraocular tumor spread seen with transscleral biopsy techniques.
To evaluate the presence of chromosome 3 monosomy in small choroidal melanoma using fine-needle aspiration biopsy (FNAB).
Noncomparative case series.
Fifty-six patients with small choroidal melanoma measuring 3 mm or less in thickness who were undergoing plaque radiotherapy.
Fine-needle aspiration biopsy was used at the time of plaque radiotherapy to sample tumor cells using a 27-gauge long needle via an indirect transvitreal approach into the tumor apex for postequatorial tumors or a 30-gauge short needle via a direct transscleral approach into the tumor base for preequatorial tumors.
Chromosome 3 monosomy in small choroidal melanoma.
The median tumor thickness was 2.6 mm. Monosomy 3 was found in 15 (27%) cases and disomy 3 was found in 32 (57%) cases. In 9 (16%) cases, genomic DNA yield was insufficient for genetic analysis. Fine-needle aspiration biopsy with a 27-gauge needle transvitreal approach provided quantity sufficient for genetic testing in 31 (97%) of 32 cases versus 16 (67%) of 24 cases sampled with a 30-gauge transscleral technique. Compared with disomy 3 tumors, monosomy 3 tumors were statistically more likely to occur in older patients (P = 0.040). Monosomy 3 (versus disomy 3) tumors showed thickness of more than 2 mm in 100% (vs. 84%), subretinal fluid in 87% (vs. 94%), symptoms in 40% (vs. 56%), orange pigment in 93% (vs. 81%), and margin of 3 mm or less to the optic disc in 20% (vs. 50%). There was no statistical difference between monosomy 3 and disomy 3 tumors in the presence or number of these clinical factors. However, small choroidal melanomas with monosomy 3 mutation were more likely to have had documented growth (63%) compared with those with disomy 3 (25%; P = 0.025; odds ratio, 5.00).
Using FNAB at the time of plaque radiotherapy, monosomy 3 was found in approximately 27% of small choroidal melanomas, more often in older patients and tumors with documented growth. Transvitreal biopsy into the tumor apex provided better yield compared with transscleral biopsy into the tumor base.