OBJECTIVE:The aim of this research is to identify germline genetic variants that predispose to uveal melanoma (UM) using data from nine studies involving 5839 individuals with UM (3853 novel) and 349,863 healthy controls. METHODS:Five novel UM genome-wide association studies (GWAS) were performed and included for meta-analysis with four previously published UM GWAS. A fixed-effects inverse-variance weighted (IVW) meta-analysis was performed by combining data from these nine UM case-control cohorts. A follow-up transcriptome-wide association study (TWAS) was conducted to identify candidate target genes at UM risk loci. Genetic correlations with melanoma-related phenotypes were measured to elucidate UM's genetic architecture. RESULTS:We identify nine linkage disequilibrium (LD)-independent loci (three novel) with an IVW P value of less than 5 × 10-8. TWAS analysis indicates five potential target genes, including MOB3B, RBAK, and MTSS1, which have established links to multiple cancer types. We note a significant genetic correlation (rg = 0.31, P = 0.01) between UM and cutaneous melanoma (CM), and a non-significant but consistent correlation with naevus count (rg = 0.25, P = 0.08). CONCLUSIONS:This meta-analysis offers new insights into the genetic architecture of UM, highlights potential therapeutic targets, and explores the genetic relationship with CM and skin pigmentation.

Introduction: Iris metastases are a rare initial presentation of a systemic malignancy, managed with chemotherapy and radiotherapy in most cases. These cases provide visual documentation of iris metastasis resolution following chemotherapy and radiotherapy and illustrate potential adverse effects associated with treatment response, including intraocular pressure variations and development of iris synechiae. Case Presentation: Two cases presented to metropolitan hospitals with ocular pain, which on ophthalmic review, revealed the presence of vascularised iris lesions. One case had a history of lung adenocarcinoma, on maintenance chemotherapy in addition to palliative radiotherapy to other metastatic deposits (case 1), whilst the other had no known history of malignancy (case 2). Case 2 required extensive investigations to obtain a histopathological diagnosis and stage the malignancy, after which he received chemotherapy followed by radiotherapy. In contrast, case 1 proceeded with immediate management with radiotherapy, followed by chemotherapy. Following the commencement of either treatment modality, tumour response was noted, with corresponding elevations in intraocular pressure, which was managed with topical glaucoma eye drops in addition to systemic acetazolamide. Both cases experienced complete remission of their iris metastases, though case 1 had extensive iris synechiae and case 2 passed away due to a rapid decline in their systemic malignancy. Conclusion: Our case offers a unique visual insight into the impact of both systemic chemotherapy and localised radiotherapy on uncommon iris metastases, with sequential images taken at each stage of treatment. We underscore the importance of continual monitoring of the intraocular pressure during treatment, as tumour response was associated with elevated intraocular pressures in both of these cases. We hypothesise that this may be due to a combination of tumour liquefaction and hyphaema blocking trabecular meshwork outflow. Finally, despite treatment of the iris metastasis, patients may be left with residual iris synechiae, requiring additional surgical intervention to manage the intraocular pressure.

9510 Background: Darovasertib is a protein kinase C (PKC) inhibitor with meaningful activity in metastatic uveal melanoma (UM) due to its effect on PKC delta downstream of canonical GNAQ/GNA11 mutations. To date, its clinical activity in patients with localized primary disease has not been assessed in either neoadjuvant or adjuvant settings. Methods: Patients planned for enucleation with localized UM were treated in an initial safety cohort with darovasertib 300mg BID for 1 month (n=3 patients), and then following DSMB agreement in an expansion cohort for up to 6 months (n=12 patients) as neoadjuvant treatment prior to definitive management (enucleation, plaque brachytherapy or EBRT) across 3 Australian centers. All patients were eligible to receive up to 6 months of adjuvant treatment with darovasertib at investigator discretion after definitive management of their primary tumour. Tumour volume was calculated by the rotational ellipsoid method. Results: 15 patients (male n=7, female n=8; median age 62 years (range, 33-76 years)) were enrolled. At baseline, AJCC tumor stages were T3a (n=5), T3b (n=4), T4a (n=4), T4b (n=2), and the median tumor size (maximum thickness/diameter/volume) was 9.7mm/ 15.6 mm/ 2463 mm 3 . At datalock; 11/15 patients had completed primary treatment, 4/15 remained on neoadjuvant treatment, 6 patients received adjuvant darovasertib after primary treatment of their UM with 3 patients completing the planned 6-months . Median tumor shrinkage (maximum height/base/volume change) was 11.2%/ 7.6%/ 22.7% after 1 month of treatment and 31.7%/ 11.9% /45.3% after 6 months. At datalock, 6/9 (66%) currently completed neoadjuvant patients were converted to plaque brachytherapy (n=5) or EBRT (n=1) with 3 ongoing. One patient with high-risk cytogenetic features had relapsed with metastatic disease despite receiving 6-months of neoadjuvant darovasertib and another 6-months of adjuvant treatment. Treatment emergent adverse events included postural hypotension (Gr1/2 – 13/13%), syncope (Gr3 – 13%), rash (Gr1/2 – 33/5%), pruritis (Grr1 – 13%), dizziness (Gr1 – 27%), fatigue (Gr1/2 – 30/5%), nausea (Gr1/2 – 73/6%), vomiting (Gr1 – 40%), and diarrhea (Gr1 – 60%). Updated results, histopathological and genomic outcomes will be presented. Conclusions: NADOM provides the first evidence that a globe-salvage neoadjuvant treatment strategy in UM is feasible, safe, and efficacious. The results suggest that PKC inhibition with darovasertib can induce clinically meaningful tumor shrinkage in patients with primary UM patients who otherwise require enucleation. Larger trials are in now progress (NCT05907954) to further quantify visual and oncological outcomes. Clinical trial information: 05187884.

Uveal melanoma (UM) and nonacral cutaneous melanoma (CM) are distinct entities with varied genetic landscapes despite both arising from melanocytes. There are, however, similarities in that they most frequently affect people of European ancestry, and high penetrance germline variants in BAP1, POT1 and CDKN2A have been shown to predispose to both UM and CM. This study aims to further explore germline variants in patients affected by both UM and CM, shedding light on the underlying genetic mechanism causing these diseases. Using exome sequencing we analysed germline DNA samples from a cohort of 83 Australian patients diagnosed with both UM and CM. Eight (10%) patients were identified that carried pathogenic mutations in known melanoma predisposition genes POT1, MITF, OCA2, SLC45A2 and TYR. Three (4%) patients carried pathogenic variants in genes previously linked with other cancer syndromes (ATR, BRIP1 and MSH6) and another three cases carried monoallelic pathogenic variants in recessive cancer genes (xeroderma pigmentosum and Fanconi anaemia), indicating that reduced penetrance of phenotype in these individuals may contribute to the development of both UM and CM. These findings highlight the need for further studies characterising the role of these genes in melanoma susceptibility. Germline variants predisposing uveal and cutaneous melanoma are identified using exome sequencing. Created with .image

ObjectiveThe objective of this study was to determine whether combining verteporfin-based photodynamic therapy (PDT) and transpupillary thermotherapy (TTT) achieves adequate tumour control while maintaining visual acuity in individuals with small choroidal melanoma of amelanotic, melanotic, and variable pigmentation.DesignIndividuals with posterior choroidal melanomas up to 3 mm in height underwent verteporfin-based PDT followed by immediate TTT. Further combined laser therapy was performed if a poor response was noted at 12 weeks or beyond. Tumours that demonstrated significant further growth were treated with brachytherapy or enucleation. A total of 37 eyes of 37 patients from the Terrace Eye Centre in Brisbane, Australia were studied. Average age of participants was 59.62 ± 12.45 years, and 17 of 37 participants were female (46%).MethodsThis was a retrospective, noncomparative interventional study.ResultsSeven of the 37 participants (19%) had recurrence of their tumour requiring further brachytherapy or enucleation. There was no statistically significant difference in visual acuity before and after treatment. There were no baseline characteristics that predicted treatment outcome. Ten individuals developed complications including epiretinal membrane (16%), scotoma (8%), cataract (3%), and macular edema (3%). No individuals experienced extraocular extension or progressed to metastatic disease. The mean follow-up time was 49 months.ConclusionCombined PDT and TTT achieved 81% tumour control in this study while preserving visual acuity. However, higher rates of local recurrence compared with brachytherapy warrant close follow-up to identify recurrences early.

BACKGROUND:To report the clinicopathological features and epidemiology of iris melanoma in Queensland, Australia. METHODS:This was a retrospective study of 86 patients with iris melanoma treated between 2001 and 2022 at the Queensland Ocular Oncology Service, Brisbane, Australia. Main outcome measures included demographics, clinical and phenotypic features, age-adjusted incidence and relative survival. RESULTS:Eighty-six patients (63% female) were included. Mean age was 54 years (range 17-82 years). The majority of patients (97%) were Caucasian, with blue eyes, fair skin and Fitzpatrick Skin Type I or II. Demographic features and clinical history showed a tendency for high ultraviolet radiation (UVR) exposure in the cohort. Histopathology was available in 69 cases (82%), and of these, 77% tumours were of spindle cell origin, with low-risk genetic profiles. Patients were followed for a mean of 8 years (median 7, range 1-21 years) after diagnosis, and only one case of metastasis was documented. CONCLUSIONS:The association of iris freckles, history of UVR exposure and dermatologic findings supports the role of UVR in iris melanoma. Occupation and avocation history, as well as evaluation of iris freckles may offer an easily accessible way of stratifying the risk of an individual for development of UVR-related uveal melanoma.

ObjectiveTo describe the development of a web-based data collection tool to track the management and outcomes of uveal melanoma patients.DesignDescription of a clinical registry.ParticipantsPatients with uveal melanoma.MethodsA panel of expert ocular oncologists, with input from other relevant specialties and individuals with expertise in registry development, collaborated to formulate a minimum data set to be collected to track patient centred, real-world outcomes in uveal melanoma. This data set was used to create the Fight Tumour Blindness! (FTB!) registry within Save Sight Registries.ResultsThe data set to be collected includes patient demographics and medical history, baseline visit, follow-up visit including tumour treatment, metastatic staging and surveillance, pathology, and patient-reported questionnaires. The inbuilt mechanisms to ensure efficient and complete data collection are described.ConclusionsThe FTB! registry can be used to monitor outcomes for patients with uveal melanoma. It allows benchmarking of outcomes and comparisons between different clinics and countries.

TPS9612 Background: Darovasertib (Daro) is a novel inhibitor of PKC, that has pre-clinical activity in GNAQ/GNA11 tumours including ocular melanoma. A recently completed clinical trial of Daro monotherapy in metastatic OM with a response rate of 11%, and DCR of 78% with only mild manageable toxicity, suggesting utility in localized disease and in the adjuvant setting. Methods: NADOM is an investigator-initiated window-of-opportunity phase 2 clinical trial open in 3 centers across Australia. Eligible patients include patients planned for enucleation, ECOG 0-1 with adequate organ function. The primary objective is the feasibility and safety of neoadjuvant Daro in a pilot cohort of 12 patients. Secondary objectives include the effect of Daro on circulating biomarkers (including CTCs and ctDNA), imaging assessments (MRI, FDG-PET and ocular ultrasound), pharmacokinetic and pharmacodynamic correlates and radiographic PFS in the adjuvant setting. Treatment comprises a neo-adjuvant period of treatment of up to 6 months at ophthalmologist discretion with Daro (300mg bid) before definitive management. Patients who demonstrated radiological, biomarker or clinical response are then offered an adjuvant period of treatment for up to 6 months following integrated consensus at multi-disciplinary ocular oncology meetings. DSMB meetings are scheduled to ensure clinical and peri-operative safety regularly. Enrolment commenced in November 2022 and accrual is ongoing in the 6 month neo-adjuvant cohort. Results: To date, an initial safety cohort of 1 month of neo-adjuvant treatment has been cleared following DSMB review. Conclusions: Recruitment is ongoing and expected to complete in late 2023. Clinical trial information: NCT05187884 .

Merkel cell carcinoma (MCC) of the conjunctiva is rare. We report the case of a 73-year-old man who presented with unilateral foreign body sensation and blurred vision. A rapidly enlarging conjunctival lesion was identified and excised. The histopathological diagnosis was poorly differentiated squamous cell carcinoma, later reclassified as neuroendocrine / Merkel cell carcinoma following excision on subsequent recurrence. The patient developed lymph node and widespread metastatic disease. The challenges of diagnosing MCC at this site are discussed and the literature on treatment options for this aggressive disease is reviewed.

Background To report a case of Fuchs’ adenoma occurring in an eye with a large choroidal melanoma. We have reviewed the literature to describe the clinical presentation, ultrasound characteristics and pathological features of these entities. Case presentation A 69-year-old Caucasian man presented with vision loss from a large choroidal melanoma. Enucleation showed an incidental Fuchs’ adenoma in the same eye. Whole-exome sequence analysis was also performed on the patient’s blood and melanoma, which showed a rarely-reported ATRX mutation. Conclusions Fuchs’ adenoma is an under-diagnosed benign age-related hyperplasia of the non-pigmented ciliary epithelium (NPCE). Given its location and characteristics, it can be mistaken for choroidal melanoma and clinicians are reminded how to differentiate between these pathologies and that they may co-exist.

Lymphoma of the conjunctiva is an ocular malignancy derived from clonal proliferation of lymphocytes. The majority of conjunctival lymphoma is extranodal marginal zone B-Cell lymphoma (EMZL), however diffuse large B-cell (DLBCL), follicular (FL), mantle cell (MCL) and T- cell subtypes are also seen. Clinical manifestations are non-specific, but include unilateral or bilateral painless salmon-pink conjunctival lesions. Approaches to treatment have centered around local immunomodulation, often with Interferon-α2b or Rituximab (anti-CD20 monoclonal antibody) with or without radiation. Although conjunctival lymphoma is generally considered an indolent disease, recent advances in next-generation sequencing have improved clinicians’ ability to predict future recurrence or systemic disease through assessment of cytogenic and molecular features. In this paper, we review the classification, clinical features, diagnostic techniques, and emerging strategies for management and prognostication of conjunctival lymphomas.

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Pathogenic germline variants in protection of telomeres 1 ( POT1 ) result in a tumour predisposition syndrome (POT1-TPDS), which includes cutaneous melanoma (CM), glioma, chronic lymphocytic leukaemia (CLL), colorectal cancer, thyroid cancer and sarcoma.1 Through whole-genome sequencing (WGS) of 20 Australian individuals affected with both CM and uveal melanoma (UM), our study identified two truncating variants in POT1 . Functional analyses assessing telomere length indicated longer telomeres in variant carriers, compared with healthy age-matched controls, similar to observations in CM patients with loss-of-function POT1 variants.2 The risk for development of cancers such as CM and UM is influenced by genetics. In UM, this has mainly been attributed to loss-of-function variants in BAP1 .3 Predisposition in CM is largely due to multiple low-penetrance susceptibility alleles; however, 5%–12% of cases report first-degree or second-degree relatives with CM and in a proportion of these families disease segregates with high-penetrance single gene variants in CDKN2A , CDK4 and the telomere maintenance genes POT1 , ACD , TERF2IP and TERT (reviewed in ref 4). Pathogenic germline variants in POT1 result in an increase in telomere length and susceptibility to many cancer types including CM, glioma, CLL, thyroid cancer, colorectal cancer, angiosarcoma1 and osteosarcoma,5 now termed the POT1-TPDS. There is also recent evidence to suggest histological differences in melanomas of POT1 variant carriers versus non-carriers, highlighting the importance of telomere dysfunction on tumour biology.6 POT1 binds to telomeric single-stranded DNA (ssDNA) overhangs, preventing telomerase accessibility. Highly conserved oligonucleotide/oligosaccharide-binding (OB) folds in POT1 are essential for specific binding to ssDNA, and loss of function of these OB domains leads to increased telomere elongation due to an inability to inhibit telomerase. Certain germline missense variants occurring in these OB domains, and other protein truncating variants, have been reported to disrupt POT1 function, leading to …

Uveal melanoma (UM) is the most common intraocular tumour in adults and despite surgical or radiation treatment of primary tumours, ~50% of patients progress to metastatic disease. Therapeutic options for metastatic UM are limited, with clinical trials having little impact. Here we perform whole-genome sequencing (WGS) of 103 UM from all sites of the uveal tract (choroid, ciliary body, iris). While most UM have low tumour mutation burden (TMB), two subsets with high TMB are seen; one driven by germline MBD4 mutation, and another by ultraviolet radiation (UVR) exposure, which is restricted to iris UM. All but one tumour have a known UM driver gene mutation ( GNAQ, GNA11, BAP1, PLCB4, CYSLTR2, SF3B1, EIF1AX ). We identify three other significantly mutated genes ( TP53 , RPL5 and CENPE ).

Objective To evaluate the incidence and management of recurrent periocular sebaceous gland carcinoma at a tertiary ocular oncology service in the United Kingdom. Methods This was a retrospective cohort study of 62 patients with sebaceous gland carcinoma treated between 2004 and 2017. A total of 10 eyes were treated for local recurrence. The following variables were recorded: age and sex of patient; tumour location, histological subtype; recurrence type; treatment and outcome. Results Of the 62 cases with eyelid SGC, 10 (16%) had recurrences during the study period and satisfied inclusion criteria. There were six (60%) females and four males in the recurrent group. The mean time interval between initial excision and tumour recurrence was 37 months (median 23 months; range 4 to 84 months). Four patients received cryotherapy to the lids and conjunctiva to control recurrent disease and two patients were treated with topical or intralesional chemotherapy. Four patients (40%) underwent orbital exenteration during the study period. Metastasis occurred in 20% over a mean follow-up of 113 months (median 106; range 47-184 months). Conclusions The risk factors for local recurrence of SGC after wide excision with paraffin section control were reported, and an approach to these recurrent lesions was proposed. The results of this study will help guide surgeons dealing with the medical and surgical conundrum of recurrent disease. The risk of recurrence is highest in the first 2 years after initial excision.

INTRODUCTION:Conjunctival nevi are the most common tumor of the ocular surface. There are some rare reports of so-called 'giant' conjunctival nevi. We report a case of a 47-year-old female with a cutaneous and ocular surface giant congenital melanocytic nevus and describe her clinical course.CASE DESCRIPTION:This is a retrospective case report of a single patient. A 47-year-old female with a history of biopsy-proven periorbital congenital melanocytic nevus, with an associated giant conjunctival nevus presented for structural and functional rehabilitation. Serial surgeries were performed and excised tissue was sent for histopathological and genetic examination. The conjunctival nevus had a low tumor mutation burden, and of the 647 somatic mutations, only one occurred within a protein coding region, namely NRAS p.Gln61Arg.CONCLUSION:This is the first reported adult case including genomic analysis of an ocular surface giant congenital melanocytic nevus. The case shows a possible association between periorbital congenital melanocytic nevi and giant conjunctival nevi, and underscores the possible role that targeted drug therapies may have in malignant transformation of these conditions.

Retinal vasoproliferative tumours (VPT) are uncommon entities and may be idiopathic (74%) or secondary to a pre-existing ocular disease (26%).1Shields C.L. Shields J.A. Barrett J. De Potter P. Vasoproliferative tumors of the ocular fundus: classification and clinical manifestations in 103 patients.Arch Ophthalmol. 1995; 113: 615-623Crossref PubMed Scopus (193) Google Scholar These lesions can be associated with macular epiretinal membrane formation or cystoid macular edema. There is a lack of evidence-based consensus on best treatment for exudative lesions; however, cryotherapy is favoured.1Shields C.L. Shields J.A. Barrett J. De Potter P. Vasoproliferative tumors of the ocular fundus: classification and clinical manifestations in 103 patients.Arch Ophthalmol. 1995; 113: 615-623Crossref PubMed Scopus (193) Google Scholar, 2Rennie I.G. Retinal vasoproliferative tumours.Eye. 2010; 24: 468-471Crossref PubMed Scopus (29) Google Scholar, 3Fairooz P. Manjanda V. Shields C.L. Kaliki S. Shields J.A. Cryotherapy-induced release of epiretinal membrane associated with retinal vasoproliferative tumour.Retina. 2014; 34: 1644-1650Crossref PubMed Scopus (19) Google Scholar A 59-year-old female was referred with a 4-week history of distortion of the right vision due to epiretinal membrane. Visual acuity was 20/60 OD and 20/10 OS. The left eye was normal, while examination of the right eye revealed an epiretinal membrane at the macula with an inferotemporal vasoproliferative tumour (VPT) in the retinal periphery (Fig. 1A). Optical coherence tomography documented the epiretinal membrane (Fig. 1B). Ultrasonography (BScan, 20 MHz) confirmed the density of the VPT (Fig. 1C). The patient declined any treatment and at 6-month follow-up; vision had improved to 20/20 OD. Examination revealed a posterior vitreous detachment and that there had been spontaneous devascularisation and detachment of the peripheral vasoproliferative lesion and epiretinal membrane (Fig. 1D). Optical coherence tomography showed normal macular architecture (Fig. 1E), while ultrasound confirmed the release of the VPT (Fig. 1F). Vasoproliferative tumours have been noted to have a predilection for the inferior temporal retina and are frequently (31%) associated with macular epiretinal membranes or fibrosis.2Rennie I.G. Retinal vasoproliferative tumours.Eye. 2010; 24: 468-471Crossref PubMed Scopus (29) Google Scholar Small, asymptomatic peripheral lesions are often managed conservatively; however, if the lesion has associated exudation or detachment, treatment may be warranted. Fairooz and colleagues recently reported a series of 16 cases treated with cryotherapy, resulting in release of the associated epiretinal membrane.3Fairooz P. Manjanda V. Shields C.L. Kaliki S. Shields J.A. Cryotherapy-induced release of epiretinal membrane associated with retinal vasoproliferative tumour.Retina. 2014; 34: 1644-1650Crossref PubMed Scopus (19) Google Scholar To our knowledge, our case is the first in the literature documenting spontaneous VPT detachment with associated epiretinal membrane release. In some cases, even with visually significant epiretinal membrane, a trial of observation may be warranted. The authors have no proprietary or commercial interest in any materials discussed in this article. Download .xml (.0 MB) Help with xml files

Purpose: To describe the clinical features in a series of 8 patients with cytologically proven granulomatous vitritis in the context of systemic malignancy. Design: Retrospective case review series from 2004 through 2018 to identify all cases of cytologically proven granulomatous vitritis and to analyze its disease associations and causes. Participants: Twenty-three patients with a cytologic diagnosis of granulomatous vitritis were identified, 8 of whom demonstrated systemic malignancy. Main outcome measures: To identify a clinical profile of the 8 cases of granulomatous vitritis occurring in the setting of systemic malignancy, focusing on the timing of the eye presentation compared with the timing of the systemic malignancy. Methods: Patients with a cytologic diagnosis of granulomatous vitritis seeking treatment from 2004 through 2018 were included in this retrospective case series. Case notes were recalled and reviewed for demographic features, medical history, presenting symptoms, investigations, surgical procedures, and follow-up. Results: Twenty-three patients were diagnosed cytologically with granulomatous vitritis. Ten of 23 patients (43%) showed autoimmune and infectious causes, 5 of 23 patients (22%) showed were idiopathic causes, and 8 of 23 patients' (35%) disease was associated with systemic malignancy. In the latter group, the median age at presentation was 70 years (range, 55-89 years). Six patients showed bilateral disease, and the remaining 3 showed unilateral disease. Three of 8 patients showed primary systemic malignancy diagnosed after eye symptoms and 5 of 8 showed malignancy before the eye symptoms. These latter 5 patients all demonstrated a major relapse, metastasis, or both at the time of eye symptoms. Conclusions: Paraneoplastic vitritis is primarily a disease of older age, with 67% of those affected older than 65 years. Ophthalmologists should maintain a high index of suspicion of paraneoplastic cause in bilateral posterior segment inflammation of uncertain origin, presenting for the first time, or heralding malignancy recurrence or metastasis in known cases of malignancy. (C) 2019 by the American Academy of Ophthalmology

Optic nerve hemangioblastoma is a rare tumor that is usually unilateral and most commonly occurs in the context of von Hippel-Lindau disease. Differential diagnosis is based on clinical history and imaging. Magnetic resonance imaging with gadolinium enhancement is the most useful imaging modality as it can reveal flow voids and an absence of dural attachment, differentiating optic nerve hemangioblastoma from other more commonly encountered optic nerve tumors. Optic nerve hemangioblastoma are usually well-circumscribed vascular lesions composed of stromal cells and vascular endothelial cells. These lesions are diagnosed at a mean age of 37 years and can be asymptomatic, but over time, patients may develop reduction in vision, proptosis, and pain. Surgical excision is well described via orbital, transsphenoidal, or transcranial approaches. Given the risks associated with surgery, a stepwise conservative approach is advocated by most clinicians in the absence of severe symptoms. Although uncommon, this optic nerve tumor should be considered in young patients presenting with pain, proptosis, and optic nerve pallor, with or without a history of von Hippel-Lindau disease.