A Multicenter Study Validates the WHO 2022 Classification for Conjunctival Melanocytic Intraepithelial Lesions With Clinical and Prognostic Relevance.

Several nomenclature and grading systems have been proposed for conjunctival melanocytic intraepithelial lesions (C-MIL). The fourth "WHO Classification of Eye Tumors" (WHO-EYE04) proposed a C-MIL classification, capturing the progression of noninvasive neoplastic melanocytes from low- to high-grade lesions, onto melanoma in situ (MIS), and then to invasive melanoma. This proposal was revised to the WHO-EYE05 C-MIL system, which simplified the high-grade C-MIL, whereby MIS was subsumed into high-grade C-MIL. Our aim was to validate the WHO-EYE05 C-MIL system using digitized images of C-MIL, stained with hematoxylin and eosin and immunohistochemistry. However, C-MIL cases were retrieved from 3 supraregional ocular pathology centers. Adequate conjunctival biopsies were stained with hematoxylin and eosin, Melan-A, SOX10, and PReferentially expressed Antigen in Melanoma. Digitized slides were uploaded on the SmartZoom platform and independently scored by 4 ocular pathologists to obtain a consensus score, before circulating to 14 expert eye pathologists for independent scoring. In total, 105 cases from 97 patients were evaluated. The initial consensus diagnoses using the WHO-EYE04 C-MIL system were as follows: 28 benign conjunctival melanoses, 13 low-grade C-MIL, 37 high-grade C-MIL, and 27 conjunctival MIS. Using this system resulted in 93% of the pathologists showing only fair-to-moderate agreement (kappa statistic) with the consensus score. The WHO-EYE05 C-MIL system (with high-grade C-MIL and MIS combined) improved consistency between pathologists, with the greatest level of agreement being seen with benign melanosis (74.5%) and high-grade C-MIL (85.4%). Lowest agreements remained between pathologists for low-grade C-MIL (38.7%). Regarding WHO-EYE05 C-MIL scoring and clinical outcomes, local recurrences of noninvasive lesions developed in 8% and 34% of the low- and high-grade cases. Invasive melanoma only occurred in 47% of the cases that were assessed as high-grade C-MIL. This extensive international collaborative study is the first to undertake a comprehensive review of the WHO-EYE05 C-MIL scoring system, which showed good interobserver agreement and reproducibility.

Enlarging Orbital Rim Mass Due to Old Pencil Injury.

A 54-year-old female noticed a 2-month history of an enlarging left inferomedial orbital rim mass. The patient remembered a pencil injury at approximately 7 years of age. Her complete ophthalmic examination was otherwise unremarkable. She underwent CT orbital imaging, demonstrating a centrally hyperdense lesion along the left inferomedial orbital rim. There was no involvement of the nasolacrimal duct system. The patient underwent an excisional biopsy. The pathology disclosed noncaseating granulomatous inflammation to particulate black material consistent with graphite.

GNAQ Mutations in Diffuse and Solitary Choroidal Hemangiomas.

PURPOSE: GNAQ mutations have been identified in port wine stains (both syndromic and nonsyndromic) and melanocytic ocular neoplasms. This study investigates the presence of GNAQ mutations in diffuse (those associated with Sturge-Weber syndrome [SWS]) and solitary choroidal hemangiomas. PARTICIPANTS: Tissue from 11 patients with the following diagnoses: port wine stain (n = 3), diffuse choroidal hemangioma (n = 1), solitary choroidal hemangioma (n = 6), and choroidal nevus (n = 1). METHODS: Ten specimens were interrogated with Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets, a hybridization capture-based next-generation sequencing assay for targeted deep sequencing of all exons and selected introns of 468 key cancer genes in formalin-fixed, paraffin-embedded tumors. Digital polymerase chain reaction was used to detect GNAQ Q209 mutation in 1 specimen. MAIN OUTCOME MEASURES: Detection of GNAQ codon-specific mutation. RESULTS: Activating somatic GNAQ mutations (c.547C > T; p.Arg183Cys) were found in 100% (3 of 3) of the port wine stain and in the diffuse choroidal hemangioma. Somatic GNAQ mutations (c.626A > T; p.Gln209Leu) were found in 100% (6 of 6) of the solitary choroidal hemangiomas and (c.626A > C; p.Gln209Pro) in the choroidal nevus. CONCLUSIONS: GNAQ mutations occur in both diffuse and solitary hemangiomas, although at distinct codons. An R183 codon is mutant in diffuse choroidal hemangiomas, consistent with other Sturge-Weber vascular malformations. By contrast, solitary choroidal hemangiomas have mutations in the Q209 codon, similar to other intraocular melanocytic neoplasms.

Embarking on a Journey of Discovery: Developing Transitional Skill Sets through a Scholarly Concentration Program.

PROBLEM: Medical student participation in research enhances appreciation of the scientific literature and the conduct of investigation, and may lead to an interest in academic medicine. Independent medical student research offers frequently overlooked opportunities to develop and assess professional practice abilities, including project design and implementation, interprofessional team communication, and time management. These skills, useful to physicians, are often challenging for medical students to master as they transition into clinical careers. To address this challenge, we designed and embedded interventional modalities into a highly mentored and longitudinal scholarly concentration component of the curriculum. INTERVENTION: The Embark scholarly concentration program incorporates traditional research training with the development of professional practice skills essential for transitioning to clinical practice. The program includes individualized and just-in-time components enabling student access to information and feedback specific to their projects and development of professional practice skills. CONTEXT: The Embark program is a required longitudinal component of the Oakland University William Beaumont School of Medicine undergraduate medical curriculum. The Embark program consists of courses that inform and facilitate a required longitudinal independent research project. OUTCOME: A retrospective evaluation of the Embark program's success with development of professional practice skills through the lens of both faculty and student perceptions included analysis of project records and course evaluation feedback. Evaluation of individual student development of transitional skill ability is possible through both quantitative and qualitative analysis of data collected from student project records. More than 80% of course evaluation commentary on strengths of the program addressed activities related to professional practice skills. To systematize the evaluation of these data sources, we have piloted a framework, iSAIL, designed to assess student development in these skills during the planning and conduct of a research project. LESSONS LEARNED: By developing professional practice skills in the context of a scholarly concentration program, medical students can build a foundation for future engagement in research while they develop skills to overcome challenges that they are likely to encounter in their clinical careers. Modalities designed to evaluate individualized student development of professional practice skills through research participation define program successes and may lead to the identification of additional resources needed by students. By offering medical students opportunities to develop professional practice skills within the protected environment of an independent research project, this scholarly concentration program provides a valuable opportunity to influence the early development of skills necessary throughout their clinical careers.

Globe dislocation and optic nerve avulsion following all-terrain vehicle accidents.

Purpose: Open-air motor vehicles present unique trauma risks to the eyes and face. We describe two patients who suffered a crash while riding an all-terrain vehicle (ATV), leading to globe dislocation with optic nerve avulsion in order to raise awareness about the risks associated with ATV accidents. Observations: In both cases, the injury was caused by high-speed trauma to the orbit involving a tree branch. One patient sustained a life threatening arrythmia requiring a short stay in the intensive care unit, and both patients required emergent surgical management and eventual socket reconstruction. Conclusions and Importance: These cases highlight the need for greater advocacy on behalf of rider safety. The authors encourage ophthalmologists to counsel patients who use ATVs to wear helmets, seatbelts, and protective eyewear to prevent these types of injuries in the future.

Microbial profile of lacrimal system Dacryoliths in American Midwest patient population.

PURPOSE: Dacryoliths of the canalicular pathway are classically attributed to Actinomyces species as the most common organism. However, global shifts toward Streptococcus and Staphylococcus species have been reported. The objective of this article is to update the American Midwest epidemiology of lacrimal system dacryoliths for targeted clinical treatment. MATERIALS AND METHODS: A retrospective chart review from January 2015 to 2021 of patients with a history of surgical procedure for lacrimal removal of dacryolith for canaliculitis, canalicular obstruction, dacryocystitis, and nasolacrimal duct obstruction was included. Specimens were sent for histopathological evaluation and microbial culture. RESULTS: A total of 48 specimens were included. The most common organism isolated for canalicular pathology was Actinomyces spp (23%), followed by Staphylococcus spp (21%) and Streptococcus spp (19%). Histopathological staining accounted for 45% of Actinomyces isolation when culture data inconclusive. In a subgroup analysis of lacrimal sac dacryoliths, the most common organism was Staphylococcus spp (29%). Actinomyces species were not isolated from the lacrimal sac or nasolacrimal duct. CONCLUSION: Actinomyces maintains a microbial predominance in canalicular dacryoliths and requires careful culture and histopathological analysis for its fastidious nature. Lacrimal sac and nasolacrimal duct dacryolith found no isolates of Actinomyces, and the most common organism was Staphylococcus.

Validation of the Newly Proposed World Health Organization Classification System for Conjunctival Melanocytic Intraepithelial Lesions: A Comparison with the C-MIN and PAM Classification Schemes.

PURPOSE: We sought to compare the sensitivity, specificity, accuracy, and interobserver agreement of the two most commonly used classification systems for conjunctival melanocytic intraepithelial lesions with the new World Health Organization (WHO) classification. DESIGN: Retrospective case series and evaluation of classification systems. METHODS: We reviewed the pathology and medical records of all patients who underwent a primary biopsy procedure for conjunctival primary acquired melanosis (PAM) at Wills Eye Hospital between 1974 and 2002 who had ≥36 months of follow-up. Data collected included age, sex, clinical findings, recurrence, and progression to melanoma. Twelve ophthalmic pathologists analyzed scanned hematoxylin and eosin-stained virtual microscopic slides using 3 classification systems: PAM, conjunctival melanocytic intraepithelial neoplasia, and the WHO 4th edition classification of conjunctival melanocytic intraepithelial lesions. Observer agreement, sensitivity, specificity, and diagnostic accuracy of each classification system were assessed. RESULTS: There were 64 patients who underwent 83 primary excisions with cryotherapy for conjunctival PAM who had adequate tissue for histopathologic evaluation. The interobserver agreement in distinction between the low- and high-grade lesions was 76% for PAM, 67% for conjunctival melanocytic intraepithelial neoplasia, and 81% for WHO classification system. Low-grade lesions provided the greatest interpretative challenge with all 3 classification systems. The 3 classification systems had comparable accuracy of 81%-83% in their ability to identify lesions with potential for recurrence. CONCLUSIONS: This study highlights the comparable strengths and limitations of the 3 classification systems for conjunctival melanocytic intraepithelial lesions and suggests that the simplified WHO classification scheme is appropriate for evaluation of these lesions.

Interplay of mechanical and binding properties of Fibronectin type I.

Fibronectins (FNs) are a major component of the extracellular matrix (ECM), and provide important binding sites for a variety of ligands outside and on the surface of the cell. Similar to other ECM proteins, FNs are consistently subject to mechanical stress in the ECM. Therefore, it is important to study their structure and binding properties under mechanical stress and understand how their binding and mechanical properties might affect each other. Although certain FN modules have been extensively investigated, no simulation studies have been reported for the FN type I (Fn1) domains, despite their prominent role in binding of various protein modules to FN polymers in the ECM. Using equilibrium and steered molecular dynamics simulations, we have studied mechanical properties of Fn1 modules in the presence or the absence of a specific FN-binding peptide (FnBP). We have also investigated how the binding of the FnBP peptide to Fn1 might be affected by tensile force. Despite the presence of disulfide bonds within individual Fn1 modules that are presumed to prevent their extension, it is found that significant internal structural changes within individual modules are induced by the forces applied in our simulations. These internal structural changes result in significant variations in the accessibility of different residues of the Fn1 modules, which affect their exposure, and, thus, the binding properties of the Fn1 modules. Binding of the FnBP appears to reduce the flexibility of the linker region connecting individual Fn1 modules (exhibited in the form of reduced fluctuation and motion of the linker region), both with regard to bending and stretching motions, and hence stabilizes the inter-domain configuration under force. Under large tensile forces, the FnBP peptide unbinds from Fn1. The results suggest that Fn1 modules in FN polymers do contribute to the overall extension caused by force-induced stretching of the polymer in the ECM, and that binding properties of Fn1 modules can be affected by mechanically induced internal protein conformational changes in spite of the presence of disulfide bonds which were presumed to completely abolish the capacity of Fn1 modules to undergo extension in response to external forces.

Optical Coherence Tomography Characteristics of the Choroid Underlying Congenital Hypertrophy of the Retinal Pigment Epithelium.

PURPOSE: This study evaluates and characterizes the choroid underlying congenital hypertrophy of the retinal pigment epithelium (CHRPE). METHODS: Retrospective observational study of CHRPE at least 2 mm in diameter. Choroidal vascular architecture was qualitatively examined. Choroidal thickness was measured by 2 independent observers using enhanced depth imaging spectral domain optical coherence tomography. RESULTS: Forty-six eyes of 46 patients with CHRPE were included. Thirty-two lesions had imaging sufficient for analysis. Haller's layer was healthy in 18 (56%), thin in 13 (41%), and absent in 1 (2%). Sattler's layer was atrophic in 30 (94%), and choriocapillaris was atrophic in 31 (97%). CHRPE with thinned Haller's layer had significantly larger diameter. The mean sub-CHRPE choroidal thickness was 82.4 ± 7.9 µm, compared to a thickness of 148.4 ± 9.6 µm in the normal adjacent choroid (p < 0.0001). Mean retinal thickness overlying the CHRPE was 77.3 ± 4.3 µm, compared to a retinal thickness of 137.8 ± 2.9 µm overlying the normal adjacent choroid (p < 0.0001). Sub-CHRPE choroidal thickness was a mean of 56.2 ± 3.1% of the adjacent normal choroidal thickness. CONCLUSION: The underlying choroid CHRPE is thinner than the adjacent normal choroid. All layers of the choroid can be thin with a preference of the inner Sattler's and choriocapillaris layers.

Alveolar rhabdomyosarcoma with neuroendocrine/neuronal differentiation: report of 3 cases.

The aim of this study is to report the clinicopathologic characteristics of 3 cases of alveolar rhabdomyosarcoma with neuroendocrine/neuronal differentiation. Specimens of 3 cases of alveolar rhabdomyosarcoma were studied using histologic, immunohistochemical, ultrastructural, and molecular genetic techniques. The patients were a 19-year-old man with metastatic alveolar rhabdomyosarcoma in a groin lymph node, a 16-year-old girl with alveolar rhabdomyosarcoma of the perineum, and a 20-year-old man with recurrent orbital alveolar rhabdomyosarcoma. Microscopically, case 1 was composed of compact sheets of medium to large tumor cells. Cases 2 and 3 were small blue round cell tumors. Cases 1 and 3 were solid throughout, whereas case 2 demonstrated alveolar and solid architecture. By immunohistochemistry, the following markers were positive: desmin (3/3), myogenin (3/3), synaptophysin (3/3), and chromogranin (2/3). Ultrastructurally, sarcomeric filaments were seen in all cases, while neuroendocrine granules were detected only in case 1. PAX:FKHR fusion transcript was identified in case 2, case 3 had a variant PAX3 transcript, and case 1 was negative. The data presented expands the known differentiation of alveolar rhabdomyosarcoma.

Sudden Death in a Child With Ocular Lesions.

This case report describes a patient treated for ocular lesions who died suddenly at age 8 years and was diagnosed postmortem with Carney complex.

3D medical volume reconstruction using web services.

We address the problem of 3D medical volume reconstruction using web services. The use of proposed web services is motivated by the fact that the problem of 3D medical volume reconstruction requires significant computer resources and human expertise in medical and computer science areas. Web services are implemented as an additional layer to a dataflow framework called data to knowledge. In the collaboration between UIC and NCSA, pre-processed input images at NCSA are made accessible to medical collaborators for registration. Every time UIC medical collaborators inspected images and selected corresponding features for registration, the web service at NCSA is contacted and the registration processing query is executed using the image to knowledge library of registration methods. Co-registered frames are returned for verification by medical collaborators in a new window. In this paper, we present 3D volume reconstruction problem requirements and the architecture of the developed prototype system at http://isda.ncsa.uiuc.edu/MedVolume. We also explain the tradeoffs of our system design and provide experimental data to support our system implementation. The prototype system has been used for multiple 3D volume reconstructions of blood vessels and vasculogenic mimicry patterns in histological sections of uveal melanoma studied by fluorescent confocal laser scanning microscope.

Dealing With Deans and Academic Medical Center Leadership: Advice From Leaders.

The 2017 Association of Pathology Chairs Annual Meeting included a session for department chairs and other department leaders on "how to deal with deans and academic medical center leadership." The session was focused on discussing ways to foster positive relationships with university, medical school, and health system leaders, and productively address issues and opportunities with them. Presentations and a panel discussion were provided by 4 former pathology chairs who subsequently have served as medical deans and in other leadership positions including university provost, medical center CEO, and health system board chair. There was a strong consensus among the participants on how best to deal with superiors about problems, conflicts, and requests for additional resources and authority. The importance of teamwork and accountability in developing a constructive and collaborative relationship with leaders and peers was discussed in detail. Effectiveness in communication, negotiation, and departmental advocacy were highlighted as important skills. As limited resources and increased regulations have become growing problems for universities and health systems, internal stress and competition have increased. In this rapidly changing environment, advice on how chairs can interact most productively with institutional leaders is becoming increasingly important.

Vancomycin-Associated Hemorrhagic Occlusive Retinal Vasculitis: A Clinical-Pathophysiological Analysis.

PURPOSE: To derive novel insights into the pathophysiology of vancomycin-related hemorrhagic occlusive retinal vasculopathy (HORV) through a careful clinicopathologic correlation. METHODS: We retrospectively reviewed the clinical and pathologic course of 2 consecutive patients who developed HORV. The clinical history, multimodal imaging, ultrasound biomicroscopy (UBM), and intraoperative and histologic findings are reported. RESULTS: Both patients presented with decreased vision and eye pain within 1 week following otherwise uncomplicated cataract extraction and were diagnosed with HORV after endophthalmitis was ruled out. Both patients presented with significant ocular discomfort that progressively worsened, and both experienced a dismal visual outcome despite early aggressive medical and surgical therapy. One patient requested enucleation for a blind and painful eye. Upon histologic examination of this eye, the iris and ciliary body appeared to be infarcted with separation of the iris and ciliary epithelia from their adjacent stromal components. These findings were corroborated by UBM of the second patient. Histologic examination of the posterior segment demonstrated severe hemorrhagic necrosis of the neurosensory retina and an occlusive nonarteritic vasculopathy of the retina and choroid. The choroid was thickened by prominent nongranulomatous chronic inflammation accompanied by a glomeruloid proliferation of small vessels. The inflammatory infiltrate was almost exclusively confined to the choroid and consisted of predominantly T cells. There was conspicuous absence of inflammatory cells in the retina and no histologic evidence of leukocytoclastic vasculitis. CONCLUSIONS: HORV is a rare condition that can lead to profound vision loss. Significant ocular pain can be a presenting sign of HORV in cases with severe iris and ciliary body ischemia. Although it has been suggested that HORV is a form of leukocytoclastic retinal vasculitis, the histologic findings herein indicate that the pathophysiology is more complex. It is grounded in a necrotizing retinal vasculopathy in the absence of retinal vasculitis, chronic nongranulomatous choroiditis, and an unusual glomeruloid proliferation of endothelial cells in the choroid and elsewhere in the eye.

Modeling the behavior of uveal melanoma in the liver.

PURPOSE: To model the behavior of uveal melanoma in the liver. METHODS: A 15-muL suspension of metastatic MUM2B or either primary OCM1 or M619 uveal melanoma cells was injected into the liver parenchyma of 105 CB17 SCID mice through a 1-cm abdominal incision. Animals were killed at 2, 4, 6, or 8 weeks after injection. Before euthanatization, 3% FITC-BSA buffer was injected into the retro-orbital plexus of one eye of three mice. Liver tissues were examined by light and fluorescence microscopy, and were stained with human anti-laminin. Vasculogenic mimicry patterns were reconstructed from serial laser scanning confocal microscopic stacks. RESULTS: OCM1a cells formed microscopic nodules in the mouse liver within 2 weeks after injection and metastasized to the lung 6 weeks later. By contrast, M619 and MUM2B cells formed expansile nodules in the liver within 2 weeks and gave rise to pulmonary metastases within 4 weeks after injection. Vasculogenic mimicry patterns, composed of human laminin and identical with those in human primary and metastatic uveal melanomas, were detected in the animal model. The detection of human rather than mouse laminin in the vasculogenic mimicry patterns in this model demonstrates that these patterns were of tumor cell origin and were not co-opted from the mouse liver microenvironment. CONCLUSIONS: There are currently no effective treatments for metastatic uveal melanoma. This direct-injection model focuses on critical interactions between the tumor cell and the liver. It provides for translationally relevant approaches to the development of new modalities to detect small tumor burdens in patients, to study the biology of clinical dormancy of metastatic disease in uveal melanoma, to design and test novel treatments to prevent the emergence of clinically manifest liver metastases after dormancy, and to treat established uveal melanoma metastases.

Using the direct-injection model of early uveal melanoma hepatic metastasis to identify TPS as a potentially useful serum biomarker.

PURPOSE: To develop a method to screen for serum biomarkers of early hepatic metastasis from uveal melanoma. METHODS: Cytokeratin 18 (TPS) was identified from gene expression profiles as protein generated by highly invasive uveal melanoma cells. Sera were collected from two groups of 15 SCID mice 2 weeks after injection of either tissue culture medium or MUM2B human metastatic uveal melanoma cells into the mouse liver. Serum TPS levels were assayed in 53 healthy human controls, 64 uveal melanoma patients who were disease free for at least 10 years, and 37 patients with metastatic uveal melanoma. RESULTS: After 2 weeks, small hepatic nodules (0.1-2.8 mm; mean, 0.80 mm) developed in 11 of 15 mice injected with MUM2B cells. Serum TPS levels in media-injected mice (84.7 U/L) were substantially lower than levels in MUM2B-injected mice (601 mug/L). TPS levels were significantly higher (P < 0.0001) in patients with metastatic uveal melanoma (139.63 +/- 22.20) than in healthy controls (54.23 +/- 0.01) or in patients free of disease (69.29 +/- 9.76). Significant differences were found between TPS levels before and after the development of hepatic metastases (P < 0.01), and serum TPS levels became elevated in four patients at least 6 months before the detection of hepatic metastases by abdominal ultrasonography. CONCLUSIONS: The direct-injection model of uveal melanoma in the mouse liver may be used to screen for potential serum biomarkers of metastatic uveal melanoma.

Comparing vasculogenic mimicry with endothelial cell-lined vessels: techniques for 3D reconstruction and quantitative analysis of tissue components from archival paraffin blocks.

We previously described techniques to generate 3-dimensional reconstructions of the tumor microcirculation using immunofluorescence histochemistry and laser scanning confocal microscopy on serial sections from archival formalin-fixed, paraffin-embedded tissues. By aligning sequential z-stacks in an immersive visualization environment (ImmersaDesk), the need to insert fiduciary markers into tissue was eliminated. In this study, we developed methods to stitch overlapping confocal z-series together to extend the surface area of interest well beyond that captured by the confocal microscope objective and developed methods to quantify the distribution of markers of interest in 3 dimensions. These techniques were applied to the problem of comparing the surface area of nonendothelial cell-lined, laminin-rich looping vasculogenic mimicry (VM) patterns that are known to transmit fluid, with the surface area of endothelial cell-lined vessels in metastatic uveal melanoma to the liver in 3 dimensions. After labeling sections with antibodies to CD34 and laminin, the surface area of VM patterns to vessels was calculated by segmenting out structures that labeled with laminin but not with CD34 from those structures labeling with CD34, or CD34 and laminin. In metastatic uveal melanoma tissues featuring colocalization of high microvascular density [66.4 microvessels adjusted for 0.313 mm2 area (range 56.7 to 72.7)] and VM patterning, the surface area of VM patterns was 11.6-fold greater (range 10.8 to 14.1) than the surface provided by CD34-positive vessels. These methods may be extended to visualize and quantify molecular markers in 3 dimensions in a variety of pathologic entities from archival paraffin-embedded tissues.

Serum markers to detect metastatic uveal melanoma.

BACKGROUND: Osteopontin (OPN) is overexpressed in metastatic uveal melanoma (UM). S-100beta and melanoma-inhibitory activity (MIA) serum levels are elevated in metastatic cutaneous melanoma. The ability of OPN, S-100beta and MIA serum levels to be used as non-invasive markers for detecting metastatic UM was tested. PATIENTS AND METHODS: OPN, S-100beta and MIA levels were measured by ELISA assays in 18 patients with metastatic UM and in 38 patients who were disease-free (DF) for at least 10 years after treatment of the primary tumor. Paired serum samples from 8 patients before and after development of metastasis were analyzed. Forty-four healthy controls (C) were compared to the other two groups. RESULTS: Serum OPN, MIA, and S-100beta levels were significantly higher in patients with metastatic UM as compared to patients who were DF for at least 10 years after treatment (p = 0.0001) or with age-matched controls. Serum OPN, MIA and S-100beta levels were significantly higher (p < 0.005) after metastasis formation than before the clinical detection of metastasis in the 8 patients. Receiver operator characteristic analysis was performed for metastatic patients vs. DF and vs. C, and the area under the curve was calculated for each marker and for the combination of the 3 markers, which was 91%. CONCLUSION: Elevated serum OPN, MIA and S-100beta levels correlate with metastatic UM to the liver. When used in combination, these markers provide a highly sensitive and specific method to detect hepatic metastases and therefore provide for earlier therapeutic intervention that can prolong survival.