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Classifications

Harrison's Chapter

ICD-O Morphology

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Inheritance

1

BAP1 Tumor Predisposition Syndrome (germline BAP1) HP:0000006

Most ocular melanoma is sporadic, but a minority of uveal melanoma arises in BAP1 tumour predisposition syndrome, an autosomal dominant cancer predisposition caused by a heterozygous germline BAP1 pathogenic variant. Uveal melanoma is its commonest associated cancer, ahead of malignant mesothelioma, cutaneous melanoma and renal cell carcinoma, and BAP1-related uveal melanoma behaves as an aggressive class-2 tumour. Germline testing is warranted for young-onset, bilateral or multifocal disease, or a personal or family history of the syndrome's other tumours; carriers need annual dilated eye examinations from age 11-18 years.

Autosomal dominant inheritance Penetrance: INCOMPLETE

Show evidence (5 references)

PMID:27748099 SUPPORT Human Clinical

"BAP1 tumor predisposition syndrome (BAP1-TPDS) is associated with an increased risk for a specific skin lesion, BAP1-inactivated melanocytic tumors (BIMT; formerly called atypical Spitz tumors), and the following cancers, in descending order of frequency: uveal (eye) melanoma (UM), malignant..."

GeneReviews establishes uveal melanoma as the commonest cancer of BAP1-TPDS and the syndrome's tumour spectrum.

PMID:27748099 SUPPORT Human Clinical

"The diagnosis of BAP1-TPDS is established in a proband by identification of a heterozygous germline pathogenic variant in BAP1 on molecular genetic testing."

Confirms the heterozygous germline mechanism underlying the autosomal dominant inheritance asserted here.

PMID:27748099 PARTIAL Human Clinical

"The penetrance, natural history, life-time cancer risk for carriers, and frequencies of BAP1-associated tumors are yet to be fully determined."

Supports recording penetrance as INCOMPLETE/undetermined rather than asserting a figure.

+ 2 more references

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Subtypes

5

Uveal Melanoma (choroid, ciliary body, iris) MONDO:0006486

GNAQ hgnc:4390 GNA11 hgnc:4379 BAP1 hgnc:950

Melanoma of the uveal tract, accounting for the large majority of ocular melanomas and for essentially all primary intraocular melanoma in adults. Initiated by GNAQ/GNA11 (or CYSLTR2/PLCB4) activating mutations, stratified prognostically by BAP1/SF3B1/EIF1AX status and chromosome 3/8q copy number, and characterised by haematogenous liver-dominant metastasis. Curated in depth as its own dismech entry (Uveal_Melanoma).

Choroidal Melanoma
Ciliary Body Melanoma
Iris Melanoma

Show evidence (1 reference)

PMID:41097064 SUPPORT Human Clinical

"Uveal melanoma is predominantly driven by mutations in GNAQ and GNA11, along with alterations in BAP1, SF3B1, and EIF1AX, which are key prognostic determinants."

Establishes uveal melanoma as the GNAQ/GNA11-driven arm of ocular melanoma with BAP1/SF3B1/EIF1AX prognostic stratification.

Choroidal Melanoma MONDO:0003878

Uveal melanoma of the choroid, the commonest site (approximately 90% of uveal melanomas). Typically presents as a pigmented dome-shaped or collar-button subretinal mass with exudative retinal detachment, or is found incidentally on routine fundus examination.

Show evidence (1 reference)

PMID:19667335 SUPPORT Human Clinical

"Of the 7256 eyes with choroidal melanoma, the mean tumor thickness was 5.5 mm and metastasis occurred in 8%, 15%, and 25% at 3, 5, and 10 years, respectively."

Choroidal melanoma accounted for 7256 of 8033 uveal melanoma eyes in this series (about 90%), the site predominance asserted here, with its associated metastasis rates.

Ciliary Body Melanoma MONDO:0003912

Uveal melanoma arising in the ciliary body. Uncommon (roughly 6-7% of uveal melanomas) but adversely prognostic because it is detected late and ciliary-body involvement is itself an adverse AJCC staging feature.

Show evidence (1 reference)

PMID:19667335 SUPPORT Human Clinical

"Of the 492 eyes with ciliary body melanoma, the mean tumor thickness was 6.6 mm and metastasis occurred in 12%, 19%, and 33% at 3, 5, and 10 years, respectively."

Ciliary body melanoma was 492 of 8033 eyes (about 6%) and carried markedly higher metastasis rates than choroidal or iris melanoma, supporting both the frequency and the adverse-prognosis claims made here.

Iris Melanoma MONDO:0004064

Uveal melanoma arising in the iris, the least common uveal site (roughly 3%). Presents one to two decades earlier than posterior uveal melanoma and is usually visible as an enlarging pigmented iris lesion, sometimes with heterochromia, corectopia or secondary glaucoma; prognosis is generally favourable because of early detection and smaller tumour size.

Show evidence (1 reference)

PMID:19667335 SUPPORT Human Clinical

"Of the 285 eyes with iris melanoma, the mean tumor thickness was 2.7 mm and metastasis occurred in 0.5%, 4%, and 7% at 3, 5, and 10 years, respectively."

Iris melanoma was 285 of 8033 eyes (about 3.5%), the smallest and thinnest tumours with by far the lowest metastasis rates, supporting the rarity and favourable prognosis asserted here.

Conjunctival Melanoma (ocular-surface/mucosal) MONDO:0002096

BRAF hgnc:1097 NRAS hgnc:7989 NF1 hgnc:7765

Melanoma of the conjunctival epithelium, most often bulbar and near the limbus. This is NOT a uveal melanoma and must not be conflated with one: it is an ocular-surface mucosal melanoma whose driver landscape (BRAF, NRAS, NF1, TERT promoter, UV signature) resembles cutaneous rather than uveal melanoma, it usually arises from a conjunctival melanocytic intraepithelial precursor lesion, and it spreads first through conjunctival lymphatics to regional nodes rather than by the liver-dominant haematogenous route of uveal disease. Incidence is roughly 1 per million per year and rising.

Show evidence (2 references)

PMID:41097064 SUPPORT Human Clinical

"Conversely, conjunctival and eyelid melanoma exhibits greater molecular similarity to cutaneous melanoma, commonly involving BRAF, NRAS, NF1, and TERT promoter mutations."

Directly supports treating conjunctival melanoma as a molecularly distinct, cutaneous-like arm of ocular melanoma rather than a uveal subtype.

PMID:34015548 SUPPORT Human Clinical

"CoM is characterized by mutations that have also been identified in cutaneous melanoma, e.g. in BRAF, NRAS and TERT. These mutations are distinct from the mutations found in uveal melanoma (UM), affecting genes such as GNAQ, GNA11, and BAP1."

Explicitly contrasts the conjunctival and uveal driver landscapes, justifying the split modelled here.

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Pathophysiology

13

Gq/G11 Alpha Subunit Activating Mutation

The initiating lesion of uveal melanoma is a somatic activating mutation in the heterotrimeric G-protein alpha subunits GNAQ or GNA11, occurring almost always at Q209 (in the Ras-like domain, the residue essential for GTP hydrolysis) and less often at R183. Loss of intrinsic GTPase activity locks the alpha subunit in its GTP-bound, constitutively active state, turning it into a dominant-acting oncogene. GNAQ and GNA11 mutations are mutually exclusive and together account for roughly 83% of primary uveal melanomas; the rare GNAQ/GNA11-wild-type tumours instead carry activating CYSLTR2 p.Leu129 or PLCB4 p.Asp630 mutations, which enter the same pathway one step above or below. These are early events, present already in benign uveal naevi, and are not themselves prognostic.

choroidal melanocyte CL:4030000

GNAQ hgnc:4390 GNA11 hgnc:4379 CYSLTR2 hgnc:18274 PLCB4 hgnc:9059

phospholipase C-activating G protein-coupled receptor signaling pathway GO:0007200 ↑ INCREASED

GTPase activity GO:0003924 ↓ DECREASED

uvea UBERON:0001768

Downstream

PLC-beta/PKC/MAPK Cascade Activation Active Gq/G11 stimulates phospholipase C-beta, releasing diacylglycerol that activates protein kinase C and thence the RAF-MEK-ERK cascade.

Hippo-Independent YAP Activation Gq alpha additionally signals through a Trio-Rho/Rac circuit to activate the transcriptional coactivator YAP, in parallel with and independently of the PLC-beta arm.

Show evidence (2 references)

PMID:19078957 SUPPORT Human Clinical

"The mutations occur exclusively in codon 209 in the Ras-like domain and result in constitutive activation, turning GNAQ into a dominant acting oncogene."

Establishes the Q209 mechanism (loss of GTP hydrolysis) and the dominant oncogene status of mutant GNAQ.

PMID:21083380 SUPPORT Human Clinical

"Of the uveal melanomas we analyzed, 83% had somatic mutations in GNAQ or GNA11. Constitutive activation of the pathway involving these two genes appears to be a major contributor to the development of uveal melanoma."

Quantifies the combined GNAQ/GNA11 mutation burden and identifies constitutive pathway activation as the major initiating contributor.

PLC-beta/PKC/MAPK Cascade Activation

Constitutively GTP-bound Gq/G11 activates phospholipase C-beta, generating diacylglycerol that activates protein kinase C, which in turn engages the RAF-MEK-ERK cascade (with RASGRP3 as an important uveal-melanoma-specific link) and the PI3K-AKT-mTOR axis. This is the growth-factor-independent mitogenic output of the initiating lesion. Critically, uveal melanomas achieve MAPK activation without BRAF or NRAS mutation, which is the mechanistic reason cutaneous-melanoma BRAF-directed therapy is inapplicable to uveal disease and the rationale for PKC inhibitors such as darovasertib.

choroidal melanocyte CL:4030000

protein kinase C signaling GO:0070528 ↑ INCREASED MAPK cascade GO:0000165 ↑ INCREASED

Downstream

Uveal Melanocyte Transformation and Intraocular Tumour Growth Sustained ERK signalling drives cell-cycle entry and anchorage-independent growth of uveal melanocytes.

Show evidence (1 reference)

PMID:19078957 SUPPORT In Vitro

"Uveal melanomas display MAP-kinase activation15, but none of the uveal melanomas we examined in our study showed mutations in BRAF or NRAS"

Establishes that uveal melanoma has MAPK activation despite lacking the BRAF/NRAS mutations that drive cutaneous melanoma, i.e. an alternative route into the same cascade.

Hippo-Independent YAP Activation

In parallel with the PKC/MAPK arm, oncogenic Gq alpha activates the Hippo-pathway transcriptional coactivator YAP through a Trio-Rho/Rac GTPase circuit that promotes actin polymerisation. This activation is independent of both phospholipase C-beta and the canonical Hippo kinase cascade, and Gq-driven uveal melanoma cell growth is YAP-dependent - making YAP/TAZ a distinct therapeutic node from the MAPK arm.

choroidal melanocyte CL:4030000

Rho protein signal transduction GO:0007266 ↑ INCREASED actin cytoskeleton organization GO:0030036 ↑ INCREASED

Downstream

Uveal Melanocyte Transformation and Intraocular Tumour Growth YAP-dependent transcriptional programmes contribute to the growth of Gq-driven uveal melanoma cells alongside the MAPK arm.

Show evidence (1 reference)

PMID:24882515 SUPPORT In Vitro

"Furthermore, we show that Gαq promotes the YAP-dependent growth of uveal melanoma cells, thereby identifying YAP as a suitable therapeutic target in uveal melanoma, a GNAQ/GNA11-initiated human malignancy."

Establishes YAP dependence of Gq-driven uveal melanoma growth and its status as a therapeutic node.

Uveal Melanocyte Transformation and Intraocular Tumour Growth

Convergent PKC/MAPK and YAP signalling transforms a uveal melanocyte into a growth-factor-independent clone that expands as an intraocular mass, most often in the choroid (about 90%), less often the ciliary body (about 6-7%) or iris (about 3%). Expansion under the retina produces exudation and secondary retinal detachment; anterior tumours can distort the iris and obstruct aqueous outflow. Because the globe is a closed, non-distensible compartment, growth is symptomatic disproportionately early relative to tumour bulk - yet up to about 30% of tumours are still asymptomatic at diagnosis and are found on routine fundoscopy.

choroidal melanocyte CL:4030000

cell population proliferation GO:0008283 ↑ INCREASED

uvea UBERON:0001768

Downstream

Uveal Melanoma The expanding transformed uveal melanocyte clone is the intraocular melanoma itself.

Reduced Visual Acuity Tumour involvement of the macula, exudation, or obstruction of the visual axis reduces acuity.

Visual Field Defect A tumour mass and its associated serous retinal detachment produce a field defect corresponding to the involved retinal sector.

Exudative Retinal Detachment Subretinal exudation from the tumour surface separates the neurosensory retina from the retinal pigment epithelium.

Photopsia Mechanical traction and detachment at the tumour-retina interface produce perceived flashes of light.

Vitreous Floaters Tumour-associated vitreous cells, pigment dispersion, or haemorrhage are perceived as floaters.

Secondary Glaucoma Anterior (iris/ciliary body) tumours and neovascularisation obstruct aqueous outflow and raise intraocular pressure.

Ocular Pain Large tumours, secondary glaucoma and anterior-segment involvement cause ocular pain.

BAP1 Loss with Monosomy 3 The established tumour clone is the substrate on which the later, prognosis-determining secondary driver event is acquired.

Secondary Splicing/Translation-Factor Driver Stratification Disomy-3 tumour clones instead acquire SF3B1 or EIF1AX mutations, defining the intermediate- and low-risk molecular classes.

Show evidence (1 reference)

PMID:39200222 SUPPORT Human Clinical

"Uveal melanoma (UM) is the most common intraocular malignancy in adults."

Confirms the intraocular tumour that this node describes is the commonest adult intraocular malignancy.

BAP1 Loss with Monosomy 3

The single strongest determinant of metastatic risk in uveal melanoma is biallelic inactivation of BAP1, a nuclear deubiquitinase acting in chromatin regulation and the DNA-damage response, on chromosome 3p21.1. Inactivation typically combines a somatic truncating or ubiquitin-hydrolase-domain mutation on one allele with loss of the other chromosome 3 (monosomy 3). Integrative TCGA analysis showed that BAP1 loss follows monosomy 3 in the evolutionary sequence and imposes a globally distinct DNA methylation state, defining the class-2 / poor-prognosis phenotype with epithelioid morphology and early metastasis. A minority of patients carry a germline BAP1 variant (BAP1 tumour-predisposition syndrome), which also raises risk of mesothelioma, cutaneous melanoma and clear-cell renal carcinoma.

choroidal melanocyte CL:4030000

BAP1 hgnc:950

protein deubiquitination GO:0016579 ↓ DECREASED chromatin organization GO:0006325 ⚠ ABNORMAL

Downstream

Haematogenous Dissemination Without Lymphatic Drainage BAP1-null, monosomy-3 tumours are the clones that seed distant metastasis; BAP1 loss was found in 84% of metastasising tumours.

Show evidence (2 references)

PMID:21051595 SUPPORT Human Clinical

"Inactivating somatic mutations were identified in the gene encoding BRCA1-associated protein 1 (BAP1) on chromosome 3p21.1 in 26 of 31 (84%) metastasizing tumors, including 15 mutations causing premature protein termination and 5 affecting its ubiquitin carboxyl-terminal hydrolase domain."

The landmark observation linking BAP1 inactivation to metastasising uveal melanoma, with the variant classes described here.

PMID:28810145 SUPPORT Human Clinical

"We show that BAP1 loss follows M3 occurrence and correlates with a global DNA methylation state that is distinct from D3-UM."

Establishes the temporal ordering of monosomy 3 before BAP1 loss and the associated epigenomic reprogramming asserted in this node.

Secondary Splicing/Translation-Factor Driver Stratification

In disomy-3 tumours, which rarely metastasise, the secondary driver is instead a hotspot mutation in the splicing factor SF3B1 (predominantly Arg625, altering RNA splicing genome-wide) or an N-terminal in-frame mutation in the translation-initiation factor EIF1AX. Both are essentially mutually exclusive with BAP1 loss. SF3B1 mutation marks intermediate risk with characteristically late relapse; EIF1AX mutation marks the lowest-risk class. Together with BAP1 these three genes define the prognostic stratification that governs surveillance intensity after successful local treatment.

choroidal melanocyte CL:4030000

SF3B1 hgnc:10768 EIF1AX hgnc:3250

mRNA splicing, via spliceosome GO:0000398 ⚠ ABNORMAL

Downstream

Haematogenous Dissemination Without Lymphatic Drainage Disomy-3 SF3B1/EIF1AX tumours retain a real but much lower and often later metastatic hazard than BAP1-null disease; SF3B1-mutant tumours in particular can relapse many years after treatment.

Show evidence (2 references)

PMID:23313955 SUPPORT Human Clinical

"Here, we describe mutations occurring exclusively at codon 625 of the SF3B1 gene, encoding splicing factor 3B subunit 1, in low-grade uveal melanomas with good prognosis."

Establishes the SF3B1 Arg625 hotspot and its association with lower-grade, better-prognosis uveal melanoma.

PMID:23793026 SUPPORT Human Clinical

"Using exome sequencing, we identified recurrent somatic mutations in EIF1AX and SF3B1, specifically occurring in uveal melanomas with disomy 3, which rarely metastasize."

Ties both SF3B1 and EIF1AX mutation to the disomy-3, rarely metastasising class described in this node.

Haematogenous Dissemination Without Lymphatic Drainage

The uveal tract has no lymphatic drainage, so uveal melanoma disseminates exclusively by the blood. Tumour cells intravasate directly into the dense choroidal vasculature and enter the systemic circulation, often long before the primary tumour is treated - which is why excellent local control does not prevent metastatic death. Dissemination is believed to be an early event, with occult micrometastases persisting in a dormant state for years to decades; fewer than 2% of patients have radiologically detectable metastases at diagnosis, yet a third to a half develop them over the following 15 years. This is the mechanistic point at which uveal and conjunctival melanoma diverge most sharply.

cell migration GO:0016477 ↑ INCREASED

uvea UBERON:0001768

Downstream

Hepatic Metastatic Colonisation Circulating uveal melanoma cells preferentially arrest, survive and colonise the hepatic sinusoidal niche.

Show evidence (2 references)

PMID:19078957 SUPPORT Human Clinical

"One category, uveal melanoma, arises from melanocytes within the choroidal plexus of the eye and is biologically distinct from cutaneous melanoma by characteristic cytogenetic alterations4 and a very strong propensity to metastasize to the liver5."

Documents the strong hepatic metastatic propensity that this dissemination node feeds.

PMID:34839428 SUPPORT Human Clinical

"In contrast to cutaneous melanoma derivation, metastases mostly occur via hematogenous spread, in the absence of lymphatic drainage of the eye."

Directly sources this entry's hinge claim - that the eye lacks lymphatic drainage, so uveal melanoma disseminates haematogenously - which is what distinguishes the uveal from the conjunctival arm.

Hepatic Metastatic Colonisation

Approximately half of uveal melanoma patients ultimately develop metastatic disease, and it is overwhelmingly hepatotropic - the liver is the first and dominant site in around 90% of cases, with lung and bone distant seconds. Colonisation of the liver, not intravasation, is the rate-limiting step; dormant micrometastases must acquire an angiogenic and immune-evasive programme in the hepatic niche before becoming clinically detectable. Once liver metastasis is established, historical median survival is on the order of 6-12 months and hepatic tumour burden is the leading cause of death, which is why liver-directed therapy remains central to management.

positive regulation of angiogenesis GO:0045766 ↑ INCREASED

liver UBERON:0002107

Downstream

Hepatic Metastasis Colonisation of the hepatic parenchyma manifests clinically as liver metastases on surveillance imaging.

Low Tumour Mutational Burden and Checkpoint Refractoriness Established metastatic disease is the clinical setting in which the low-neoantigen, immunologically cold phenotype becomes therapeutically decisive.

Show evidence (1 reference)

PMID:35227015 SUPPORT Human Clinical

"Despite improvements in the treatment of primary tumours, approximately 50% of patients with UM will develop metastases. In 90% of cases the liver is the first site of metastasis, however the mechanisms underlying this hepatic tropism have not been elucidated."

Directly documents the hepatotropic metastatic pattern that defines this node.

Low Tumour Mutational Burden and Checkpoint Refractoriness

Unlike UV-driven cutaneous melanoma, uveal melanoma carries a very low tumour mutational burden (of the order of 0.5 mutations per megabase) and therefore presents few neoantigens. Combined with the immune-privileged ocular environment, this yields an immunologically cold tumour in which PD-1 and CTLA-4 blockade - transformative in cutaneous melanoma - achieves only marginal response rates. This is an important negative mechanistic claim for this entry: the presence of a checkpoint axis is NOT the operative mechanism here, and the entry deliberately does not declare conformance to the immune_checkpoint_blockade module. The therapeutic solution instead bypasses neoantigen dependence altogether by redirecting T cells against a lineage antigen.

T cell CL:0000084

immune response to tumor cell GO:0002418 ↓ DECREASED

Downstream

gp100-Directed T-Cell Redirection Because neoantigen-dependent checkpoint blockade fails, therapy instead redirects T cells against the melanocyte lineage antigen gp100 presented on HLA-A*02:01.

Show evidence (2 references)

PMID:34551229 SUPPORT Human Clinical

"Uveal melanoma is a disease that is distinct from cutaneous melanoma, with a low tumor mutational burden and a 1-year overall survival of approximately 50% in patients with metastatic uveal melanoma."

States the low tumour mutational burden and the poor metastatic survival that together define this node.

PMID:38627362 SUPPORT Human Clinical

"Immune checkpoint inhibition has shown success in treating metastatic cutaneous melanoma but has limited efficacy against metastatic uveal melanoma, a rare variant arising from the immune privileged eye."

States directly that checkpoint blockade, which succeeds in cutaneous melanoma, has limited efficacy in uveal melanoma arising from the immune-privileged eye - the central claim of this node.

gp100-Directed T-Cell Redirection

Uveal melanoma cells retain melanocytic lineage antigen expression, including glycoprotein 100 (gp100/PMEL). Tebentafusp is an immune-mobilising monoclonal T-cell receptor against cancer (ImmTAC): an affinity-enhanced soluble TCR that binds a gp100 peptide presented by HLA-A*02:01, fused to an anti-CD3 effector arm that recruits and activates any polyclonal T cell irrespective of its own specificity. This side-steps the low-neoantigen problem entirely, and it is the first mechanism to deliver a randomised overall-survival benefit in metastatic uveal melanoma. The obligatory dependence on HLA-A*02:01 presentation restricts eligibility to roughly half of patients, and the on-target/off-tumour attack on normal gp100-positive melanocytes produces the characteristic early rash and cytokine-mediated pyrexia.

T cell CL:0000084

PMEL hgnc:10880

T cell mediated cytotoxicity GO:0001913 ↑ INCREASED

Show evidence (2 references)

PMID:34551229 SUPPORT Human Clinical

"Overall survival at 1 year was 73% in the tebentafusp group and 59% in the control group"

The randomised phase 3 survival result establishing that this mechanism is clinically effective.

PMID:37870955 SUPPORT Human Clinical

"At a minimum follow-up of 36 months, median overall survival was 21.6 months in the tebentafusp group and 16.9 months in the control group (hazard ratio for death, 0.68; 95% confidence interval, 0.54 to 0.87)."

Confirms the survival benefit is durable at three years.

Conjunctival Melanocytic Intraepithelial Neoplasia

The conjunctival arm of ocular melanoma begins in a fundamentally different compartment - the stratified squamous/mucosal epithelium of the conjunctival surface, which is UV-exposed and lymphatic-bearing. Most conjunctival melanomas arise from a precursor field of atypical intraepithelial melanocytic proliferation (conjunctival melanocytic intraepithelial lesion, formerly primary acquired melanosis with atypia); a minority arise in a pre-existing naevus or de novo. Because the precursor is a diffuse field rather than a discrete mass, incomplete excision leaves residual atypical epithelium and drives the high (roughly a third to a half) local recurrence rate that dominates conjunctival melanoma morbidity.

melanocyte CL:0000148

conjunctiva UBERON:0001811

Downstream

UV-Associated BRAF/NRAS/NF1 Driver Activation Within the atypical intraepithelial field, acquisition of a cutaneous-melanoma-type MAPK driver converts the precursor to invasive melanoma.

Show evidence (1 reference)

PMID:39335093 SUPPORT Human Clinical

"This review aims to provide a comprehensive clinical overview of the current knowledge regarding Co-M, its epidemiology, pathogenesis, presentation, diagnosis and recent changes in the classification of its precursor lesions, management, and recent advances in novel biological therapies for..."

Confirms that conjunctival melanoma has a recognised, recently reclassified precursor-lesion pathway, as modelled by this node.

UV-Associated BRAF/NRAS/NF1 Driver Activation

Conjunctival melanoma is driven by the mutation spectrum of cutaneous, not uveal, melanoma: activating BRAF (commonly V600E) and NRAS (commonly Q61) mutations, NF1 loss, and TERT promoter mutations, on a UV-signature mutational background. GNAQ, GNA11 and BAP1 - the defining uveal genes - are not the drivers here. The practical corollary is that BRAF/MEK-targeted therapy and PD-1 blockade, which fail in uveal melanoma, are the rational (if still evidence-thin) systemic options in conjunctival melanoma. This node is the reason the two arms must be curated separately.

melanocyte CL:0000148

BRAF hgnc:1097 NRAS hgnc:7989 NF1 hgnc:7765 TERT hgnc:11730

MAPK cascade GO:0000165 ↑ INCREASED

conjunctiva UBERON:0001811

Downstream

Conjunctival Lymphatic and Regional Nodal Spread Invasive conjunctival melanoma gains access to conjunctival lymphatics and disseminates first to regional lymph nodes.

Conjunctival Melanocytic Lesion Driver acquisition within the intraepithelial field produces the visible pigmented or amelanotic invasive conjunctival mass.

Show evidence (2 references)

PMID:34015548 SUPPORT Human Clinical

"Targeted therapies that are successful in cutaneous melanoma may therefore be useful in CoM."

States the therapeutic corollary of the cutaneous-like driver landscape asserted by this node.

PMID:41097064 SUPPORT Human Clinical

"Conversely, conjunctival and eyelid melanoma exhibits greater molecular similarity to cutaneous melanoma, commonly involving BRAF, NRAS, NF1, and TERT promoter mutations."

Names exactly the BRAF/NRAS/NF1/TERT driver set modelled in this node.

Conjunctival Lymphatic and Regional Nodal Spread

Unlike the uvea, the conjunctiva has a rich lymphatic network. Conjunctival melanoma therefore metastasises first and predominantly to the regional (preauricular, submandibular, cervical) lymph nodes, with distant spread to lung, liver and brain occurring later. Regional nodal metastasis is a substantial contributor to conjunctival melanoma mortality; specific nodal and disease-specific-mortality rates are not asserted here because no quotable figure could be verified against a cached source (see notes). This lymphatic-first route is the direct mechanistic opposite of uveal melanoma's lymphatic-free, liver-dominant haematogenous route, and it is why sentinel-node assessment is relevant in conjunctival but not uveal disease.

cell migration GO:0016477 ↑ INCREASED

conjunctiva UBERON:0001811

Show evidence (3 references)

PMID:39335093 SUPPORT Human Clinical

"Co-M is often misdiagnosed or overlooked, leading to vision loss either from the destructive effects of the tumour or side effects of therapy, facial disfigurement from radical surgery, and death from metastases."

Documents that conjunctival melanoma is a metastasising, lethal disease requiring the dissemination node modelled here.

PMID:32698034 SUPPORT Human Clinical

"Tumor-positive lymph nodes were found in 33 of 197 patients (16.8%), prompting recommendations for adjuvant treatments."

Directly documents regional lymph-node metastasis in eyelid and conjunctival malignancy - the lymphatic route this node asserts. Note the AAO cohort is mixed (85 of 197 were conjunctival melanoma), so the 16.8% figure is not conjunctival-melanoma-specific and no rate is asserted in the description.

PMID:32698034 SUPPORT Human Clinical

"Sentinel lymph node biopsy is a promising procedure in patients with eyelid and conjunctival malignancy, and it is useful in identifying sentinel lymph nodes."

Supports the entry's claim that sentinel-node assessment is relevant in conjunctival - but not uveal - ocular melanoma.

✶

Histopathology

2

Melanocytic Neoplasm OBLIGATE

All ocular melanomas are melanocytic neoplasms. Diagnosis is supported by immunohistochemistry for melanocytic markers (SOX10, S100, Melan-A/MART1, HMB45); nuclear BAP1 immunostaining is additionally used in uveal melanoma as a surrogate for BAP1 inactivation and hence metastatic risk.

Show evidence (1 reference)

PMID:41097064 SUPPORT Human Clinical

"Although sharing some histopathological features with cutaneous melanoma, these tumours are characterized by distinct molecular and biological profiles with direct implications for prognosis and treatment."

Confirms ocular melanomas are histopathologically melanocytic tumours while being molecularly distinct from cutaneous melanoma.

Epithelioid Cell Morphology

Uveal melanomas are classified by cell type as spindle, mixed or epithelioid. Epithelioid morphology - large cells with abundant cytoplasm, prominent nucleoli and distinct cell borders - is strongly adverse, tracks with BAP1 loss and monosomy 3, and is one of the classic histological predictors of metastasis.

Show evidence (2 references)

PMID:12601021 SUPPORT Human Clinical

"Monosomy 3 was associated with epithelioid cells (chi(2) test, P < 0.001), PAS-positive loops (chi(2), P = 0.001), LBD (Mann-Whitney test, P = 0.002), CB involvement (chi(2) test, P = 0.008), and metastasis-related death (log rank analysis, P = 0.0003)."

Names epithelioid cytomorphology directly and ties it statistically to monosomy 3 and to metastasis-related death - exactly the association claimed here.

PMID:12601021 SUPPORT Human Clinical

"The absence of monosomy 3 is predictable only in patients who have small, spindle-cell tumors."

The converse observation - spindle-cell morphology marks the favourable, disomy-3 end of the cell-type spectrum described here.

⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

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Phenotypes

10

Digestive 1

Hepatic Metastasis FREQUENT Neoplasm of the liver HP:0002896

Show evidence (1 reference)

PMID:35227015 SUPPORT Human Clinical

"Despite improvements in the treatment of primary tumours, approximately 50% of patients with UM will develop metastases. In 90% of cases the liver is the first site of metastasis"

Documents that about half of uveal melanoma patients metastasise and that the liver is the first site in 90%, the hepatotropic pattern this phenotype records.

Eye 7

Uveal Melanoma Uveal melanoma HP:0007716

Show evidence (1 reference)

PMID:39200222 SUPPORT Human Clinical

"Uveal melanoma (UM) is the most common intraocular malignancy in adults."

Establishes uveal melanoma as the dominant intraocular manifestation of ocular melanoma.

Reduced Visual Acuity FREQUENT Reduced visual acuity HP:0007663

Show evidence (1 reference)

PMID:34775516 SUPPORT Human Clinical

"Thirty-four patients (49%) presented with blurred vision."

Blurred vision (decreased visual acuity) was the commonest presenting symptom, in 49% of an enucleation cohort - supporting the FREQUENT frequency band assigned here.

Visual Field Defect OCCASIONAL Visual field defect HP:0001123

Show evidence (1 reference)

PMID:34775516 SUPPORT Human Clinical

"18 (26%) with a shadow in the visual field"

Quantifies a visual-field shadow as the presenting symptom in 26% of an enucleation cohort, supporting the OCCASIONAL (5-29%) frequency band assigned here.

Exudative Retinal Detachment Retinal detachment HP:0000541

Show evidence (1 reference)

PMID:19667335 PARTIAL Human Clinical

"Clinical factors predictive of metastasis by multivariate analysis included increasing patient age, ciliary body location, increasing tumor diameter, increasing tumor thickness, having a brown tumor, and the presence of subretinal fluid, intraocular hemorrhage, or extraocular extension."

Subretinal fluid - the exudative retinal detachment described by this phenotype - is documented as a recognised clinical feature of uveal melanoma in an 8033-eye series, and is independently predictive of metastasis.

Photopsia OCCASIONAL Photopsia HP:0030786

Show evidence (1 reference)

PMID:34775516 SUPPORT Human Clinical

"7 (10%) with photopsia and/or floaters"

Quantifies photopsia (reported jointly with floaters) as the presenting symptom in 10% of patients, supporting the OCCASIONAL frequency band.

Vitreous Floaters OCCASIONAL Vitreous floaters HP:0100832

Show evidence (1 reference)

PMID:34775516 SUPPORT Human Clinical

"7 (10%) with photopsia and/or floaters"

Quantifies floaters (reported jointly with photopsia) as the presenting symptom in 10% of patients, supporting the OCCASIONAL frequency band.

Secondary Glaucoma OCCASIONAL Glaucoma HP:0000501

Constitutional 1

Ocular Pain OCCASIONAL Ocular pain HP:0200026

Other 1

Conjunctival Melanocytic Lesion Abnormal conjunctiva morphology HP:0000502

Show evidence (1 reference)

PMID:39335093 SUPPORT Human Clinical

"Conjunctival melanoma (Co-M) is an aggressive, invasive eye and eyelid cancer."

Supports the existence and aggressive nature of the conjunctival surface lesion described by this phenotype.

🧬

Genetic Associations

11

GNAQ (Activating somatic driver mutation (Q209, less often R183))

Gene: GNAQ hgnc:4390 relationship_type: SOMATIC_DRIVER variant_origin: SOMATIC

Show evidence (1 reference)

PMID:19078957 SUPPORT Human Clinical

"Here we report frequent somatic mutations in the heterotrimeric G protein alpha-subunit, GNAQ, in blue naevi (83%) and ocular melanoma of the uvea (46%)."

Reports the somatic GNAQ mutation frequency in uveal ocular melanoma.

GNA11 (Activating somatic driver mutation (Q209, less often R183))

Gene: GNA11 hgnc:4379 relationship_type: SOMATIC_DRIVER variant_origin: SOMATIC

Show evidence (1 reference)

PMID:21083380 SUPPORT Human Clinical

"Mutations affecting Q209 in GNA11 were present in 7% of blue nevi, 32% of primary uveal melanomas, and 57% of uveal melanoma metastases."

Gives the GNA11 mutation frequencies in primary and metastatic uveal melanoma described in the notes.

BAP1 (Tumour suppressor loss (biallelic, usually with monosomy 3))

Gene: BAP1 hgnc:950 relationship_type: SOMATIC_DRIVER variant_origin: GERMLINE_AND_SOMATIC

Show evidence (1 reference)

PMID:21051595 SUPPORT Human Clinical

"One tumor harbored a frameshift mutation that was germline in origin, thus representing a susceptibility allele."

Documents both the somatic and the germline (susceptibility) origin of BAP1 inactivation recorded here.

SF3B1 (Hotspot splicing-factor mutation (predominantly Arg625))

Gene: SF3B1 hgnc:10768 relationship_type: SOMATIC_DRIVER variant_origin: SOMATIC

Show evidence (1 reference)

PMID:23313955 SUPPORT Human Clinical

"Thus, uveal melanoma is among a small group of cancers associated with SF3B1 mutations, and these mutations denote a distinct molecular subset of uveal melanomas."

Establishes SF3B1 mutation as defining a distinct molecular subset of uveal melanoma.

EIF1AX (N-terminal in-frame translation-initiation-factor mutation)

Gene: EIF1AX hgnc:3250 relationship_type: SOMATIC_DRIVER variant_origin: SOMATIC

Show evidence (1 reference)

PMID:23793026 SUPPORT Human Clinical

"Targeted resequencing showed that 24 of 31 tumors with disomy 3 (77%) had mutations in either EIF1AX (15; 48%) or SF3B1 (9; 29%)."

Quantifies EIF1AX mutation within the disomy-3, low-risk class.

CYSLTR2 (Activating receptor mutation (p.Leu129Gln) in GNAQ/GNA11-wild-type tumours)

Gene: CYSLTR2 hgnc:18274 relationship_type: SOMATIC_DRIVER variant_origin: SOMATIC

Show evidence (2 references)

PMID:27089179 SUPPORT Human Clinical

"We analyzed genomics data from 136 uveal melanoma samples and found a recurrent mutation in CYSLTR2 (cysteinyl leukotriene receptor 2) encoding a p.Leu129Gln substitution in 4 of 9 samples that lacked mutations in GNAQ, GNA11, and PLCB4 but in 0 of 127 samples that harbored mutations in these genes."

The discovery paper, giving the exact p.Leu129Gln substitution, the restriction to GNAQ/GNA11/PLCB4-wild-type tumours, and the mutual exclusivity asserted here.

PMID:27089179 SUPPORT In Vitro

"The Leu129Gln CysLT2R mutant protein constitutively activates endogenous Gαq and is unresponsive to stimulation by leukotriene."

Establishes the activating, receptor-level mechanism acting upstream of Gq that this entry describes.

PLCB4 (Activating mutation (p.Asp630Tyr) in GNAQ/GNA11-wild-type tumours)

Gene: PLCB4 hgnc:9059 relationship_type: SOMATIC_DRIVER variant_origin: SOMATIC

Show evidence (2 references)

PMID:26683228 SUPPORT Human Clinical

"we found a recurrent mutation in PLCB4 (c.G1888T, p.D630Y, NM_000933), which was validated using Sanger sequencing."

The discovery paper, giving the exact p.Asp630Tyr hotspot asserted here.

PMID:26683228 SUPPORT Human Clinical

"PLCB4 p.D630Y mutations are mutually exclusive with mutations in GNA11 and GNAQ, consistent with PLCB4 being the canonical downstream target of the former gene products."

Establishes both the mutual exclusivity with GNAQ/GNA11 and PLCB4's position immediately downstream of Gq, exactly as described here.

BRAF (Activating somatic driver mutation (V600E) in conjunctival melanoma)

Gene: BRAF hgnc:1097 relationship_type: SOMATIC_DRIVER variant_origin: SOMATIC

Show evidence (1 reference)

PMID:35544941 SUPPORT Human Clinical

"BRAF V600E mutation was observed in three biopsies (25%), similar to NRAS Q61X (25%). Recurrences occurred in all patients with positive BRAF or NRAS mutation"

Reports BRAF V600E frequency and its association with recurrence in a conjunctival melanoma series.

NRAS (Activating somatic driver mutation (Q61) in conjunctival melanoma)

Gene: NRAS hgnc:7989 relationship_type: SOMATIC_DRIVER variant_origin: SOMATIC

Show evidence (1 reference)

PMID:35544941 SUPPORT Human Clinical

"BRAF and NRAS mutations may be risk factors for recurrence and shorter survival in conjunctival melanoma, which would make these patients candidates for targeted therapies"

Supports NRAS as an adverse prognostic driver and a targeted-therapy indication in conjunctival melanoma.

NF1 (Loss-of-function mutation in conjunctival melanoma (cutaneous-like triple-wild-type arm))

Gene: NF1 hgnc:7765 relationship_type: SOMATIC_DRIVER variant_origin: SOMATIC

Show evidence (1 reference)

PMID:41097064 SUPPORT Human Clinical

"commonly involving BRAF, NRAS, NF1, and TERT promoter mutations."

Names NF1 among the recurrent conjunctival melanoma drivers.

TERT (Promoter mutation (UV-signature) in conjunctival melanoma)

Gene: TERT hgnc:11730 relationship_type: SOMATIC_DRIVER variant_origin: SOMATIC

Show evidence (2 references)

PMID:34015548 SUPPORT Human Clinical

"CoM is characterized by mutations that have also been identified in cutaneous melanoma, e.g. in BRAF, NRAS and TERT."

Names TERT among the cutaneous-like conjunctival melanoma mutations.

PMID:34071371 SUPPORT Human Clinical

"TERT promoter mutations were most common (54%), but BRAF (46%), NRAS (21%), BAP1 (18%), PTEN (14%), c-KIT (7%), and SF3B1 (4%) mutations were also observed. No mutations in GNAQ, GNA11, and EIF1AX were found."

The single strongest statement of this entry's central divergence thesis - conjunctival melanoma carries the cutaneous driver set and, critically, NO mutations in GNAQ, GNA11 or EIF1AX, the genes that define the uveal arm.

💊

Medical Actions

9

Plaque Brachytherapy

Action: episcleral plaque brachytherapy Ontology label: Brachytherapy NCIT:C15195

Episcleral radioactive plaque (typically iodine-125 or ruthenium-106) sutured over the tumour base. The globe-preserving first-line local therapy for most small and medium uveal melanomas, achieving high local control. Radiation retinopathy, maculopathy, optic neuropathy, cataract and neovascular glaucoma are the principal late toxicities. Local control does not reduce metastatic risk, because dissemination generally predates treatment.

Mechanism Target:

INHIBITS Uveal Melanocyte Transformation and Intraocular Tumour Growth — Ionising radiation delivered to the tumour base ablates the transformed uveal melanocyte clone while preserving the globe.

Show evidence (1 reference)

PMID:29765944 SUPPORT Human Clinical

"A corresponding increase was observed in radiation as primary treatment selection (1.3% from 1973 to 1975 vs. 68.3% from 2012 to 2013)."

Documents radiotherapy displacing surgery as the primary local treatment for uveal melanoma in the United States.

Proton Beam Radiotherapy

Action: proton beam radiation therapy Ontology label: Proton Beam Radiation Therapy NCIT:C66897

Charged-particle external-beam radiotherapy delivering a sharply conformal dose via the Bragg peak. Used for tumours unsuitable for plaque brachytherapy - large tumours, juxtapapillary or macular locations - with comparable local control.

Mechanism Target:

INHIBITS Uveal Melanocyte Transformation and Intraocular Tumour Growth — Conformal charged-particle irradiation ablates the intraocular tumour with a steep dose fall-off that spares adjacent critical ocular structures.

Show evidence (1 reference)

PMID:39456591 SUPPORT Human Clinical

"Proton therapy offers significant advantages for thicker uveal melanomas (over 8 mm) due to its unique physical properties, including a rapid dose fall-off that protects critical structures like the retina and optic nerve."

Documents the Bragg-peak dose fall-off and the specific indication for thicker tumours and optic-nerve proximity described in this treatment.

Enucleation

Action: eye enucleation Ontology label: Eye Enucleation NCIT:C198837

Surgical removal of the globe. Reserved for very large tumours, extensive ciliary-body or optic-nerve involvement, extrascleral extension, or a blind painful eye. Excellent local control at the cost of the eye, and - as the SEER-era data show - without a corresponding survival advantage over globe-preserving radiotherapy.

Mechanism Target:

INHIBITS Uveal Melanocyte Transformation and Intraocular Tumour Growth — Removal of the globe physically eliminates the intraocular tumour.

Show evidence (1 reference)

PMID:29765944 SUPPORT Human Clinical

"There was a decline in patients treated with surgery alone (94.2% from 1973 to 1975 vs. 24.7% from 2012 to 2013)."

Documents the historical role of enucleation and its decline as globe-preserving options matured.

Tebentafusp

Action: Pharmacotherapy NCIT:C15986

Agent: tebentafusp NCIT:C94208

A gp100 x CD3 bispecific ImmTAC (immune-mobilising monoclonal T-cell receptor against cancer): an affinity-enhanced soluble T-cell receptor that binds the gp100 peptide-HLA-A*02:01 complex on melanoma cells, fused to an anti-CD3 arm that recruits polyclonal T cells to kill them. The first and only systemic agent with a randomised overall-survival benefit in metastatic uveal melanoma, sustained at three years. Restricted to HLA-A*02:01-positive patients (roughly half). Toxicity is dominated by early, self-limiting cytokine-mediated events and by on-target attack on normal melanocytes - rash in 83%, pyrexia in 76%, pruritus in 70% - but discontinuation for toxicity is rare (2%).

Mechanism Target:

ACTIVATES gp100-Directed T-Cell Redirection — Tebentafusp is the agent that instantiates this mechanism, bridging the gp100-HLA-A*02:01 complex on tumour cells to CD3 on polyclonal T cells.

INHIBITS Hepatic Metastatic Colonisation — Redirected T-cell killing of gp100-positive metastatic deposits is the route by which tebentafusp prolongs survival in liver-dominant disease.

Show evidence (2 references)

PMID:34551229 SUPPORT Human Clinical

"CONCLUSIONS: Treatment with tebentafusp resulted in longer overall survival than the control therapy among previously untreated patients with metastatic uveal melanoma."

The pivotal randomised phase 3 conclusion establishing tebentafusp's survival benefit.

PMID:37870955 SUPPORT Human Clinical

"The most common treatment-related adverse events of any grade in the tebentafusp group were rash (83%), pyrexia (76%), pruritus (70%), and hypotension (38%)."

Documents the characteristic toxicity profile described here.

Immune Checkpoint Blockade

Action: immunotherapy Ontology label: Immunotherapy NCIT:C15262

Agent: pembrolizumab NCIT:C106432 ipilimumab NCIT:C2654 nivolumab NCIT:C68814

Anti-PD-1 (pembrolizumab, nivolumab) and anti-CTLA-4 (ipilimumab) antibodies, alone or combined. Included here specifically to record a negative result: despite transforming cutaneous melanoma, checkpoint blockade has only marginal activity in metastatic uveal melanoma, because the tumour's low mutational burden yields few neoantigens and the ocular microenvironment is immune-privileged. It remains a fallback when tebentafusp is unavailable or the patient is not HLA-A*02:01-positive, and is a more rational option in conjunctival melanoma, whose immunobiology resembles cutaneous melanoma.

Mechanism Target:

MODULATES Low Tumour Mutational Burden and Checkpoint Refractoriness — Checkpoint blockade acts on this node but is largely defeated by it: relieving PD-1/CTLA-4 inhibition cannot generate a response when few neoantigens are presented in the first place.

Show evidence (2 references)

PMID:34551229 PARTIAL Human Clinical

"In this open-label, phase 3 trial, we randomly assigned previously untreated HLA-A*02:01-positive patients with metastatic uveal melanoma in a 2:1 ratio to receive tebentafusp (tebentafusp group) or the investigator's choice of therapy with single-agent pembrolizumab, ipilimumab, or..."

Checkpoint inhibitors constituted the comparator arm that tebentafusp outperformed, quantifying their limited benefit in metastatic uveal melanoma.

PMID:34015548 SUPPORT Human Clinical

"While immunotherapy is currently sparsely effective in intraocular tumours such as UM, the similarities between CoM and cutaneous melanoma (including in their immunological tumour micro environment) provide hope for the application of immunotherapy in CoM"

Directly supports both halves of this treatment's framing - checkpoint blockade is sparsely effective in uveal disease but rational in conjunctival melanoma.

Wide Local Excision with Adjuvant Cryotherapy

Action: excision with adjuvant margin cryosurgery Ontology label: Cryosurgery NCIT:C15215

The standard local treatment for conjunctival melanoma: a "no-touch" complete excision with wide margins and careful specimen orientation, combined with cryotherapy to the conjunctival margins to eradicate residual atypical intraepithelial melanocytes. Adjuvant topical mitomycin C or interferon, plaque or proton radiotherapy, and - for orbital invasion - exenteration are added according to margin status, multifocality and depth of invasion. Recurrence remains common because the precursor lesion is a field rather than a discrete mass.

Mechanism Target:

INHIBITS Conjunctival Melanocytic Intraepithelial Neoplasia — Margin cryotherapy ablates residual atypical intraepithelial melanocytes, addressing the precursor field that drives recurrence.

INHIBITS UV-Associated BRAF/NRAS/NF1 Driver Activation — Complete no-touch excision physically removes the invasive driver-mutant clone.

Show evidence (1 reference)

PMID:39335093 PARTIAL Human Clinical

"Due to its rarity, there is limited evidence for diagnosis and management; hence, there is no standardised treatment and not all cases are referred to a specialised ocular oncology centre."

Records the important caveat that conjunctival melanoma management is not standardised and rests on limited evidence, which is why this treatment is curated as PARTIAL.

Percutaneous Hepatic Perfusion with Melphalan

Action: percutaneous hepatic perfusion Ontology label: Percutaneous Hepatic Perfusion NCIT:C148433

Agent: melphalan CHEBI:28876

Liver-directed regional chemotherapy: melphalan is infused into the hepatic artery while hepatic venous effluent is captured and filtered extracorporeally, delivering a hepatic dose far above what systemic administration would tolerate. This is the therapeutic answer to the hepatotropism modelled in this entry - the liver is the dominant and often only metastatic site, so treating it regionally is disease-appropriate rather than palliative. In a randomised study against best alternative care, all efficacy endpoints favoured melphalan/hepatic delivery system, though the trial converted to a single-arm design because of slow accrual and its comparative analyses are therefore exploratory. Other liver-directed options used in practice include resection or ablation of oligometastatic disease, and chemo-, radio- or immunoembolization.

Mechanism Target:

INHIBITS Hepatic Metastatic Colonisation — Regional high-dose chemotherapy is delivered to the hepatic niche in which metastatic uveal melanoma colonises and grows.

Show evidence (2 references)

PMID:40192993 SUPPORT Human Clinical

"Melphalan/Hepatic Delivery System (Melphalan/HDS) is a drug/medical device combination used for liver-directed treatment of unresectable mUM patients."

Identifies the liver-directed modality curated here and its indication in unresectable metastatic uveal melanoma.

PMID:40192993 PARTIAL Human Clinical

"Exploratory analyses of efficacy endpoints showed numerical differences consistently favoring the Melphalan/HDS arm versus BAC (median overall survival: 18.5 vs. 14.5 months; median progression-free survival: 9.1 vs. 3.3 months; objective response rate: 27.5% vs. 9.4%; and disease control..."

Gives the efficacy signal. Marked PARTIAL because the trial was amended to a single-arm design and the authors themselves designate these comparisons exploratory rather than confirmatory.

BAP1 Carrier Ocular Surveillance and Genetic Counselling

Action: Genetic Counseling NCIT:C15240

For individuals with a germline BAP1 pathogenic variant, GeneReviews recommends annual dilated eye examination from age 11-18 years (or puberty) with referral to an ocular oncologist for any pigmented lesion, alongside cascade genetic testing of at-risk relatives once a familial variant is known. Because BAP1-related uveal melanoma behaves like a class-2 / monosomy-3 tumour, treatment of a detected tumour should follow the more aggressive pathway rather than being de-escalated for early detection. This is a surveillance and counselling intervention, not a mechanism-directed therapy, so it deliberately carries no target_mechanisms link.

Show evidence (3 references)

PMID:27748099 SUPPORT Human Clinical

"UM: annual dilated eye examinations beginning at age 11-18 years or at puberty with referral to ocular oncologist for any pigmented lesions."

GeneReviews surveillance recommendation for uveal melanoma in BAP1 carriers, as described here.

PMID:27748099 SUPPORT Human Clinical

"UM treatment should be the same as the more aggressive class 2 or monosomy 3 tumors because of the increased aggressiveness of BAP1-related UM."

GeneReviews management guidance that BAP1-related uveal melanoma be treated as aggressive class-2 disease, exactly as stated here.

PMID:27748099 SUPPORT Human Clinical

"Once a germline BAP1 pathogenic variant has been identified in an affected family member, predictive testing for at-risk family members and prenatal and preimplantation genetic testing are possible."

Supports the cascade-testing component of this intervention.

Darovasertib

Action: Pharmacotherapy NCIT:C15986

Agent: darovasertib NCIT:C124796

An oral selective protein kinase C inhibitor targeting the PKC node immediately downstream of mutant Gq/G11 - the most direct available pharmacological attack on the initiating lesion of uveal melanoma. In phase 2 neoadjuvant/adjuvant evaluation for localised disease (NCT05907954), with endpoints including tumour shrinkage, conversion from enucleation to radiation, and metastasis-free survival. Investigational; not standard of care.

Mechanism Target:

INHIBITS PLC-beta/PKC/MAPK Cascade Activation — Selective PKC inhibition interrupts the cascade at the step immediately downstream of the constitutively active Gq/G11 alpha subunit.

Show evidence (1 reference)

clinicaltrials:NCT05907954 SUPPORT Human Clinical

"Neoadjuvant/adjuvant IDE196 (darovasertib) in patients with primary uveal melanoma"

Names darovasertib specifically and its neoadjuvant/adjuvant use in primary uveal melanoma, replacing an earlier generic pathway-inhibitor quote that did not mention the drug.

🌍

Environmental Factors

3

Ultraviolet Radiation Exposure

Ultraviolet exposure is a credible aetiological factor for conjunctival melanoma, which is an ocular-surface tumour carrying a UV mutational signature and cutaneous-type drivers. Its role in posterior uveal melanoma is far weaker and contested: the choroid is sun-shielded, uveal melanoma has a low mutational burden without a dominant UV signature, and the R183 mutations that do show C-to-T transitions are a small minority of drivers. This asymmetry should not be flattened into a single "UV causes ocular melanoma" claim.

Show evidence (2 references)

PMID:21083380 PARTIAL Human Clinical

"These alterations are characteristic mutational patterns induced by ultraviolet light23,24 and are found with markedly increased frequency in cutaneous melanomas arising on sun-exposed skin."

Shows a UV-type signature at the minority R183 site in uveal melanoma while the dominant Q209 site lacks it, supporting the partial and site-restricted UV contribution described here.

PMID:41097064 SUPPORT Human Clinical

"Conversely, conjunctival and eyelid melanoma exhibits greater molecular similarity to cutaneous melanoma, commonly involving BRAF, NRAS, NF1, and TERT promoter mutations."

The cutaneous-like driver landscape of conjunctival melanoma is the molecular correlate of its UV aetiology.

Arc Welding Exposure

Occupational arc-welding exposure is a reported but not firmly established risk association for uveal melanoma. It is included here because GeneReviews lists avoidance of arc welding as an explicit primary-prevention measure for germline BAP1 carriers, making it actionable in that population even though causality in the general population remains uncertain.

Show evidence (1 reference)

PMID:27748099 SUPPORT Human Clinical

"Prevention of primary manifestations: UM: avoid arc-welding."

GeneReviews Agents/Circumstances to Avoid guidance naming arc welding as a uveal melanoma exposure to avoid in BAP1-TPDS.

Oculodermal Melanocytosis (Nevus of Ota)

Congenital oculodermal melanocytosis is an established host risk factor for uveal melanoma. It shares the same initiating lesion - nevus of Ota carries somatic GNAQ mutations - providing a genetic link between the benign melanocytic proliferation and the malignancy that occasionally arises in it. Absolute risk remains low (of the order of 1 in 400).

Show evidence (1 reference)

PMID:19078957 SUPPORT Human Clinical

"Our findings identify GNAQ as a genetic link between nevus of Ota and uveal melanoma and help explain why nevi of Ota are a risk factor for uveal melanoma7. The risk is small, as only about 1 in 400 nevi of Ota progress to uveal melanoma"

Directly establishes nevus of Ota as a uveal melanoma risk factor and quantifies the small absolute risk.

🔀

Differential Diagnoses

6

Conditions with similar clinical presentations that must be differentiated from Ocular Melanoma:

Choroidal Naevus

Overlapping Features A benign choroidal melanocytic lesion, orders of magnitude commoner than choroidal melanoma and the single most frequent lesion to be distinguished from it. Naevi and melanomas share the same GNAQ/GNA11 initiating mutation, so the distinction is not molecular but clinical and morphological.

Distinguishing Features

Flat or minimally elevated (under about 2 mm thickness) and under about 5 mm in basal diameter, whereas melanoma is thicker and larger
No subretinal fluid, orange lipofuscin pigment, or symptoms; each of these features shifts the diagnosis toward melanoma
Stable on serial imaging - documented growth is the decisive discriminator
Overlying drusen or a surrounding halo favour a naevus; ultrasonographic acoustic hollowness favours melanoma

Show evidence (1 reference)

PMID:19078957 SUPPORT Human Clinical

"In our experiments, GNAQ behaves similar to the oncogenes, BRAF and NRAS, in that its mutation is insufficient for full progression to melanoma."

Explains why the naevus/melanoma distinction cannot be made on the shared GNAQ driver alone and must rest on clinical and morphological features.

Choroidal Haemangioma Not Yet Curated MONDO:0021542

Overlapping Features A benign vascular choroidal tumour that can mimic an amelanotic choroidal melanoma, presenting with an elevated subretinal mass and exudative detachment.

Distinguishing Features

Orange-red colour rather than pigmented
High internal reflectivity on A-scan ultrasonography, whereas melanoma is characteristically low-reflective and acoustically hollow
Early intense hyperfluorescence with late washout on indocyanine-green angiography
Diffuse (rather than circumscribed) choroidal haemangioma suggests Sturge-Weber syndrome

Choroidal Metastasis Not Yet Curated MONDO:0044913

Overlapping Features Metastatic carcinoma to the choroid is actually the commonest intraocular malignancy overall - commoner than primary uveal melanoma - most often from breast or lung primaries, and must be excluded before treating a presumed primary melanoma.

Distinguishing Features

Creamy-yellow and plateau-shaped rather than pigmented and dome or collar-button shaped
Frequently multifocal and bilateral, whereas uveal melanoma is almost always unilateral and unifocal
Usually accompanied by a known extraocular primary tumour and systemic disease
High internal reflectivity on ultrasonography

Retinoblastoma MONDO:0008380

Overlapping Features The commonest primary intraocular malignancy of childhood, and the key age-based differential for an intraocular mass. Arises from the retina via biallelic RB1 inactivation, not from melanocytes.

Distinguishing Features

Presents in early childhood, about 95% before age 5, versus adult onset for uveal melanoma
Arises in the retina and is non-pigmented
Characteristic intralesional calcification on ultrasound or CT, which uveal melanoma does not show
Leukocoria or strabismus as presenting signs
Definitive on RB1 genetics and on histology (Flexner-Wintersteiner rosettes)

Show evidence (1 reference)

PMID:39200222 PARTIAL Human Clinical

"Uveal melanoma (UM) is the most common intraocular malignancy in adults."

The qualifier "in adults" is the axis on which retinoblastoma, the commonest paediatric intraocular malignancy, is separated from uveal melanoma.

Conjunctival Naevus Not Yet Curated MONDO:0006172

Overlapping Features A benign conjunctival melanocytic lesion, and the principal differential for a pigmented conjunctival spot. Common, usually juxtalimbal, and typically present since childhood or adolescence.

Distinguishing Features

Characteristically contains clear intralesional cysts
Mobile over the underlying sclera, whereas melanoma may be fixed
Stable in size and pigmentation over years; new adult-onset pigmentation or documented growth favours melanoma
Confined to the bulbar conjunctiva; palpebral or forniceal involvement favours melanoma and warrants excisional biopsy
Absence of feeder vessels and of surrounding flat diffuse pigmentation

Ocular Surface Squamous Neoplasia Not Yet Curated MONDO:0971056

Overlapping Features The main non-melanocytic differential for a limbal ocular-surface mass, spanning conjunctival intraepithelial neoplasia to invasive squamous cell carcinoma. Shares the UV-exposed limbal niche and the risk-factor profile (UV, fair skin, older age, immunosuppression, HPV) with conjunctival melanoma.

Distinguishing Features

Gelatinous, papilliform or leukoplakic pink-to-white appearance rather than a pigmented lesion
Prominent feeder vessels at the limbus
Amelanotic conjunctival melanoma can look very similar and is a recognised source of misdiagnosis, so clinical appearance alone is not sufficient
Histology with melanocytic immunohistochemistry (SOX10, Melan-A, HMB45) is definitive

Show evidence (1 reference)

PMID:39335093 PARTIAL Human Clinical

"Co-M is often misdiagnosed or overlooked, leading to vision loss either from the destructive effects of the tumour or side effects of therapy"

Confirms that conjunctival melanoma is frequently misdiagnosed, which is why the ocular-surface differential is clinically important.

🔬

Clinical Trials

2

NCT03070392 PHASE_III ACTIVE_NOT_RECRUITING

IMCgp100-202: randomised open-label phase 3 trial of tebentafusp versus investigator's choice (pembrolizumab, ipilimumab or dacarbazine) in previously untreated HLA-A*02:01-positive metastatic uveal melanoma. The trial that established the first overall-survival benefit in this disease. Curated as PHASE_III on the strength of the NEJM report ("In this open-label, phase 3 trial"); note that the ClinicalTrials.gov registered title still reads "A Phase II Randomized, Open-label, Multi-center Study", a legacy of an earlier protocol version.

Target Phenotypes: Uveal melanoma HP:0007716 Neoplasm of the liver HP:0002896

Show evidence (2 references)

PMID:34551229 SUPPORT Human Clinical

"(Funded by Immunocore; ClinicalTrials.gov number, NCT03070392; EudraCT number, 2015-003153-18.)."

Identifies the NCT registration for the pivotal tebentafusp trial.

clinicaltrials:NCT03070392 SUPPORT Human Clinical

"To evaluate the overall survival of HLA-A\\*0201 positive adult patients with previously untreated advanced UM receiving IMCgp100 compared to Investigator's Choice of dacarbazine, ipilimumab, or pembrolizumab."

ClinicalTrials.gov record giving the trial's overall-survival primary objective and the checkpoint-inhibitor comparator arm.

NCT05907954 PHASE_II UNKNOWN

Neoadjuvant and adjuvant darovasertib (IDE196), an oral PKC inhibitor, in localised ocular melanoma. Endpoints include tumour shrinkage, conversion of planned enucleation to globe-preserving radiation, reduction of radiation dose to critical ocular structures, and long-term recurrence and metastasis outcomes.

Target Phenotypes: Uveal melanoma HP:0007716

Show evidence (1 reference)

clinicaltrials:NCT05907954 SUPPORT Human Clinical

"Neoadjuvant/adjuvant IDE196 (darovasertib) in patients with primary uveal melanoma"

ClinicalTrials.gov record confirming the neoadjuvant/adjuvant darovasertib trial in primary uveal melanoma.

{ }

Source YAML

click to show

name: Ocular Melanoma
creation_date: '2026-08-01T05:30:00Z'
description: >-
  Ocular melanoma is a malignant melanocytic neoplasm arising from the
  structures of the eye or ocular adnexa. It is not one homogeneous disease:
  the dominant form is uveal melanoma (choroid, ciliary body, iris), the
  commonest primary intraocular malignancy of adults, while conjunctival
  melanoma is a much rarer ocular-surface (mucosal) melanoma that is
  biologically distinct. Uveal melanoma is initiated by near-mutually-exclusive
  activating mutations in the Gq/G11 alpha subunits GNAQ and GNA11 (and, in
  wild-type tumours, CYSLTR2 or PLCB4), which drive constitutive
  PLC-beta/PKC/MAPK signalling and Hippo-independent YAP activation. Prognosis
  is stratified by a secondary driver acquired later in tumour evolution:
  BAP1 loss with monosomy 3 confers high metastatic risk, SF3B1 mutation an
  intermediate or late risk, and EIF1AX mutation a low risk. Roughly half of
  uveal melanoma patients ultimately metastasise, almost exclusively via a
  haematogenous, hepatotropic route, and metastatic disease is largely
  refractory to immune-checkpoint blockade because the tumour mutational
  burden is low. Tebentafusp, a gp100 x CD3 ImmTAC bispecific, is the first
  agent to improve overall survival in metastatic disease but is restricted to
  HLA-A*02:01-positive patients. Conjunctival melanoma, by contrast, resembles
  cutaneous melanoma (BRAF, NRAS, NF1 and TERT promoter mutations, UV
  signature), usually arises from a conjunctival melanocytic intraepithelial
  precursor, and spreads first to regional lymph nodes.
categories:
- Ocular Malignancy
- Oncogene-Driven Cancer
category: Cancer
synonyms:
- eye melanoma
- melanoma of the eye
- intraocular melanoma
parents:
- ocular cancer
- melanoma
disease_term:
  preferred_term: ocular melanoma
  term:
    id: MONDO:0006325
    label: ocular melanoma

has_subtypes:
- name: Uveal Melanoma
  display_name: Uveal Melanoma (choroid, ciliary body, iris)
  description: >-
    Melanoma of the uveal tract, accounting for the large majority of ocular
    melanomas and for essentially all primary intraocular melanoma in adults.
    Initiated by GNAQ/GNA11 (or CYSLTR2/PLCB4) activating mutations, stratified
    prognostically by BAP1/SF3B1/EIF1AX status and chromosome 3/8q copy number,
    and characterised by haematogenous liver-dominant metastasis. Curated in
    depth as its own dismech entry (Uveal_Melanoma).
  subtype_term:
    preferred_term: uveal melanoma
    term:
      id: MONDO:0006486
      label: uveal melanoma
  children:
  - Choroidal Melanoma
  - Ciliary Body Melanoma
  - Iris Melanoma
  locations:
  - preferred_term: uvea
    term:
      id: UBERON:0001768
      label: uvea
  genes:
  - preferred_term: GNAQ
    term:
      id: hgnc:4390
      label: GNAQ
  - preferred_term: GNA11
    term:
      id: hgnc:4379
      label: GNA11
  - preferred_term: BAP1
    term:
      id: hgnc:950
      label: BAP1
  evidence:
  - reference: PMID:41097064
    reference_title: 'Ocular Melanoma: A Comprehensive Review with a Focus on Molecular
      Biology.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Uveal melanoma is predominantly driven by mutations in GNAQ and GNA11,\
      \ along with alterations in BAP1, SF3B1, and\nEIF1AX, which are key prognostic\
      \ determinants."
    explanation: Establishes uveal melanoma as the GNAQ/GNA11-driven arm of ocular
      melanoma with BAP1/SF3B1/EIF1AX prognostic stratification.
- name: Choroidal Melanoma
  description: >-
    Uveal melanoma of the choroid, the commonest site (approximately 90% of
    uveal melanomas). Typically presents as a pigmented dome-shaped or
    collar-button subretinal mass with exudative retinal detachment, or is
    found incidentally on routine fundus examination.
  subtype_term:
    preferred_term: malignant choroid melanoma
    term:
      id: MONDO:0003878
      label: malignant choroid melanoma
  locations:
  - preferred_term: optic choroid
    term:
      id: UBERON:0001776
      label: optic choroid
  evidence:
  - reference: PMID:19667335
    reference_title: Metastasis of uveal melanoma millimeter-by-millimeter in 8033
      consecutive eyes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Of the 7256 eyes with choroidal melanoma, the mean tumor \nthickness was\
      \ 5.5 mm and metastasis occurred in 8%, 15%, and 25% at 3, 5, and 10 \nyears,\
      \ respectively."
    explanation: Choroidal melanoma accounted for 7256 of 8033 uveal melanoma eyes in
      this series (about 90%), the site predominance asserted here, with its associated
      metastasis rates.
- name: Ciliary Body Melanoma
  description: >-
    Uveal melanoma arising in the ciliary body. Uncommon (roughly 6-7% of uveal
    melanomas) but adversely prognostic because it is detected late and
    ciliary-body involvement is itself an adverse AJCC staging feature.
  subtype_term:
    preferred_term: malignant ciliary body melanoma
    term:
      id: MONDO:0003912
      label: malignant ciliary body melanoma
  locations:
  - preferred_term: ciliary body
    term:
      id: UBERON:0001775
      label: ciliary body
  evidence:
  - reference: PMID:19667335
    reference_title: Metastasis of uveal melanoma millimeter-by-millimeter in 8033
      consecutive eyes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Of the 492 eyes with ciliary body melanoma, the mean tumor \nthickness\
      \ was 6.6 mm and metastasis occurred in 12%, 19%, and 33% at 3, 5, and \n10 years,\
      \ respectively."
    explanation: Ciliary body melanoma was 492 of 8033 eyes (about 6%) and carried
      markedly higher metastasis rates than choroidal or iris melanoma, supporting both
      the frequency and the adverse-prognosis claims made here.
- name: Iris Melanoma
  description: >-
    Uveal melanoma arising in the iris, the least common uveal site (roughly
    3%). Presents one to two decades earlier than posterior uveal melanoma
    and is usually visible as an enlarging pigmented iris lesion, sometimes
    with heterochromia, corectopia or secondary glaucoma; prognosis is
    generally favourable because of early detection and smaller tumour size.
  subtype_term:
    preferred_term: iris melanoma
    term:
      id: MONDO:0004064
      label: iris melanoma
  locations:
  - preferred_term: iris
    term:
      id: UBERON:0001769
      label: iris
  evidence:
  - reference: PMID:19667335
    reference_title: Metastasis of uveal melanoma millimeter-by-millimeter in 8033
      consecutive eyes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Of the 285 eyes with iris melanoma, the mean tumor thickness was \n2.7\
      \ mm and metastasis occurred in 0.5%, 4%, and 7% at 3, 5, and 10 years, \nrespectively."
    explanation: Iris melanoma was 285 of 8033 eyes (about 3.5%), the smallest and
      thinnest tumours with by far the lowest metastasis rates, supporting the rarity
      and favourable prognosis asserted here.
- name: Conjunctival Melanoma
  display_name: Conjunctival Melanoma (ocular-surface/mucosal)
  description: >-
    Melanoma of the conjunctival epithelium, most often bulbar and near the
    limbus. This is NOT a uveal melanoma and must not be conflated with one:
    it is an ocular-surface mucosal melanoma whose driver landscape (BRAF,
    NRAS, NF1, TERT promoter, UV signature) resembles cutaneous rather than
    uveal melanoma, it usually arises from a conjunctival melanocytic
    intraepithelial precursor lesion, and it spreads first through conjunctival
    lymphatics to regional nodes rather than by the liver-dominant
    haematogenous route of uveal disease. Incidence is roughly 1 per million
    per year and rising.
  subtype_term:
    preferred_term: malignant conjunctival melanoma
    term:
      id: MONDO:0002096
      label: malignant conjunctival melanoma
  locations:
  - preferred_term: conjunctiva
    term:
      id: UBERON:0001811
      label: conjunctiva
  genes:
  - preferred_term: BRAF
    term:
      id: hgnc:1097
      label: BRAF
  - preferred_term: NRAS
    term:
      id: hgnc:7989
      label: NRAS
  - preferred_term: NF1
    term:
      id: hgnc:7765
      label: NF1
  evidence:
  - reference: PMID:41097064
    reference_title: 'Ocular Melanoma: A Comprehensive Review with a Focus on Molecular
      Biology.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Conversely, conjunctival and\neyelid melanoma exhibits greater molecular\
      \ similarity to cutaneous melanoma,\ncommonly involving BRAF, NRAS, NF1, and\
      \ TERT promoter mutations."
    explanation: Directly supports treating conjunctival melanoma as a molecularly
      distinct, cutaneous-like arm of ocular melanoma rather than a uveal subtype.
  - reference: PMID:34015548
    reference_title: 'Conjunctival melanoma: New insights in tumour genetics and immunology,
      leading to new therapeutic options.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "CoM is characterized by mutations that have also been identified in\
      \ \ncutaneous melanoma, e.g. in BRAF, NRAS and TERT. These mutations are distinct\
      \ \nfrom the mutations found in uveal melanoma (UM), affecting genes such as\
      \ GNAQ, \nGNA11, and BAP1."
    explanation: Explicitly contrasts the conjunctival and uveal driver landscapes,
      justifying the split modelled here.

prevalence:
- subtype: Uveal Melanoma
  population: United States (SEER 1973-2013, all races)
  measure_type: ANNUAL_INCIDENCE
  prevalence_class: BAND_1_9_PER_1000000
  rate_per_100000: 0.52
  rate_low: 0.5
  rate_high: 0.54
  notes: >-
    Reported as a mean age-adjusted incidence of 5.2 per million per year
    (95% CI 5.0-5.4), normalised here to 0.52 per 100,000 per year.
  evidence:
  - reference: PMID:29765944
    reference_title: 'Uveal Melanoma: 5-Year Update on Incidence, Treatment, and Survival
      (SEER 1973-2013).'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The mean age-adjusted incidence was 5.2 per million (95% \nCI 5.0-5.4)."
    explanation: SEER-derived age-adjusted annual incidence of uveal melanoma in the
      United States.
- subtype: Conjunctival Melanoma
  population: Worldwide
  measure_type: ANNUAL_INCIDENCE
  prevalence_class: BAND_1_9_PER_1000000
  rate_per_100000: 0.1
  notes: >-
    Reported as a global incidence of approximately 1 in a million per year,
    rising at a rate ratio of about 1.4 and increasing sharply above age 65.
  evidence:
  - reference: PMID:39335093
    reference_title: 'Conjunctival Melanoma: A Clinical Review and Update.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Its global incidence of ~1 in a million is increasing at a rate ratio\
      \ of ~1.4, \nbut this rises sharply in over 65-year-olds."
    explanation: Provides the conjunctival melanoma incidence figure and its rising
      trend, confirming it is far rarer than uveal melanoma.

pathophysiology:
- name: Gq/G11 Alpha Subunit Activating Mutation
  biological_scale: MOLECULAR
  role: trigger
  conforms_to: sustaining_proliferative_signaling#Oncogenic Growth-Signal Lesion
  mechanism_confidence: ESTABLISHED
  description: >-
    The initiating lesion of uveal melanoma is a somatic activating mutation in
    the heterotrimeric G-protein alpha subunits GNAQ or GNA11, occurring almost
    always at Q209 (in the Ras-like domain, the residue essential for GTP
    hydrolysis) and less often at R183. Loss of intrinsic GTPase activity locks
    the alpha subunit in its GTP-bound, constitutively active state, turning it
    into a dominant-acting oncogene. GNAQ and GNA11 mutations are mutually
    exclusive and together account for roughly 83% of primary uveal melanomas;
    the rare GNAQ/GNA11-wild-type tumours instead carry activating CYSLTR2
    p.Leu129 or PLCB4 p.Asp630 mutations, which enter the same pathway one step
    above or below. These are early events, present already in benign uveal
    naevi, and are not themselves prognostic.
  locations:
  - preferred_term: uvea
    term:
      id: UBERON:0001768
      label: uvea
  cell_types:
  - preferred_term: choroidal melanocyte
    term:
      id: CL:4030000
      label: choroidal melanocyte
  molecular_functions:
  - preferred_term: GTPase activity
    modifier: DECREASED
    term:
      id: GO:0003924
      label: GTPase activity
  biological_processes:
  - preferred_term: phospholipase C-activating G protein-coupled receptor signaling
      pathway
    modifier: INCREASED
    term:
      id: GO:0007200
      label: phospholipase C-activating G protein-coupled receptor signaling pathway
  genes:
  - preferred_term: GNAQ
    term:
      id: hgnc:4390
      label: GNAQ
  - preferred_term: GNA11
    term:
      id: hgnc:4379
      label: GNA11
  - preferred_term: CYSLTR2
    term:
      id: hgnc:18274
      label: CYSLTR2
  - preferred_term: PLCB4
    term:
      id: hgnc:9059
      label: PLCB4
  evidence:
  - reference: PMID:19078957
    reference_title: Frequent somatic mutations of GNAQ in uveal melanoma and blue
      naevi.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The mutations occur exclusively in codon 209 in the Ras-like domain\
      \ and \nresult in constitutive activation, turning GNAQ into a dominant acting\
      \ oncogene."
    explanation: Establishes the Q209 mechanism (loss of GTP hydrolysis) and the dominant
      oncogene status of mutant GNAQ.
  - reference: PMID:21083380
    reference_title: Mutations in GNA11 in uveal melanoma.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Of the uveal melanomas we analyzed, 83% had somatic mutations in \n\
      GNAQ or GNA11. Constitutive activation of the pathway involving these two genes\
      \ \nappears to be a major contributor to the development of uveal melanoma."
    explanation: Quantifies the combined GNAQ/GNA11 mutation burden and identifies
      constitutive pathway activation as the major initiating contributor.
  downstream:
  - target: PLC-beta/PKC/MAPK Cascade Activation
    description: >-
      Active Gq/G11 stimulates phospholipase C-beta, releasing diacylglycerol
      that activates protein kinase C and thence the RAF-MEK-ERK cascade.
    evidence:
    - reference: PMID:19078957
      reference_title: Frequent somatic mutations of GNAQ in uveal melanoma and blue
        naevi.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Signaling pathways downstream of GNAQ include activation of protein\
        \ kinase C family members via the release of diacylglycerol (DAG) by phospholipase\
        \ Cβ."
      explanation: States the Gq to PLC-beta to DAG to PKC arm of the cascade that
        this edge asserts.
  - target: Hippo-Independent YAP Activation
    description: >-
      Gq alpha additionally signals through a Trio-Rho/Rac circuit to activate
      the transcriptional coactivator YAP, in parallel with and independently of
      the PLC-beta arm.
    evidence:
    - reference: PMID:24882515
      reference_title: Hippo-independent activation of YAP by the GNAQ uveal melanoma
        oncogene through a trio-regulated rho GTPase signaling circuitry.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "We found that Gαq stimulates YAP through a \nTrio-Rho/Rac signaling\
        \ circuitry promoting actin polymerization, independently of \nphospholipase\
        \ Cβ and the canonical Hippo pathway."
      explanation: Directly supports a PLC-beta-independent, Hippo-independent Gq-to-YAP
        edge.

- name: PLC-beta/PKC/MAPK Cascade Activation
  biological_scale: MOLECULAR
  role: central_effector
  conforms_to: sustaining_proliferative_signaling#Constitutive Mitogenic Pathway Activation
  mechanism_confidence: ESTABLISHED
  description: >-
    Constitutively GTP-bound Gq/G11 activates phospholipase C-beta, generating
    diacylglycerol that activates protein kinase C, which in turn engages the
    RAF-MEK-ERK cascade (with RASGRP3 as an important uveal-melanoma-specific
    link) and the PI3K-AKT-mTOR axis. This is the growth-factor-independent
    mitogenic output of the initiating lesion. Critically, uveal melanomas
    achieve MAPK activation without BRAF or NRAS mutation, which is the
    mechanistic reason cutaneous-melanoma BRAF-directed therapy is inapplicable
    to uveal disease and the rationale for PKC inhibitors such as darovasertib.
  cell_types:
  - preferred_term: choroidal melanocyte
    term:
      id: CL:4030000
      label: choroidal melanocyte
  biological_processes:
  - preferred_term: protein kinase C signaling
    modifier: INCREASED
    term:
      id: GO:0070528
      label: protein kinase C signaling
  - preferred_term: MAPK cascade
    modifier: INCREASED
    term:
      id: GO:0000165
      label: MAPK cascade
  evidence:
  - reference: PMID:19078957
    reference_title: Frequent somatic mutations of GNAQ in uveal melanoma and blue
      naevi.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Uveal melanomas display MAP-kinase activation15, but none of the uveal\
      \ melanomas we examined in our study showed mutations in BRAF or NRAS"
    explanation: Establishes that uveal melanoma has MAPK activation despite lacking
      the BRAF/NRAS mutations that drive cutaneous melanoma, i.e. an alternative route
      into the same cascade.
  downstream:
  - target: Uveal Melanocyte Transformation and Intraocular Tumour Growth
    description: >-
      Sustained ERK signalling drives cell-cycle entry and anchorage-independent
      growth of uveal melanocytes.
    evidence:
    - reference: PMID:19078957
      reference_title: Frequent somatic mutations of GNAQ in uveal melanoma and blue
        naevi.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "In addition, GNAQ knock-down in OMM1.3 cells causes a substantial\
        \ decrease in cell number (Figure 3b), loss of anchorage independent growth\
        \ (Figure 3c) and a marked increase in sub-G0/G1 population (Figure 3d) as\
        \ compared to control cells."
      explanation: Loss-of-function knockdown reverses proliferation and anchorage-independent
        growth, showing the cascade is required for the transformed phenotype.

- name: Hippo-Independent YAP Activation
  biological_scale: MOLECULAR
  role: amplifier
  mechanism_confidence: ESTABLISHED
  description: >-
    In parallel with the PKC/MAPK arm, oncogenic Gq alpha activates the
    Hippo-pathway transcriptional coactivator YAP through a Trio-Rho/Rac
    GTPase circuit that promotes actin polymerisation. This activation is
    independent of both phospholipase C-beta and the canonical Hippo kinase
    cascade, and Gq-driven uveal melanoma cell growth is YAP-dependent -
    making YAP/TAZ a distinct therapeutic node from the MAPK arm.
  cell_types:
  - preferred_term: choroidal melanocyte
    term:
      id: CL:4030000
      label: choroidal melanocyte
  biological_processes:
  - preferred_term: Rho protein signal transduction
    modifier: INCREASED
    term:
      id: GO:0007266
      label: Rho protein signal transduction
  - preferred_term: actin cytoskeleton organization
    modifier: INCREASED
    term:
      id: GO:0030036
      label: actin cytoskeleton organization
  evidence:
  - reference: PMID:24882515
    reference_title: Hippo-independent activation of YAP by the GNAQ uveal melanoma
      oncogene through a trio-regulated rho GTPase signaling circuitry.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Furthermore, we show that Gαq promotes the YAP-dependent growth of uveal\
      \ \nmelanoma cells, thereby identifying YAP as a suitable therapeutic target\
      \ in uveal \nmelanoma, a GNAQ/GNA11-initiated human malignancy."
    explanation: Establishes YAP dependence of Gq-driven uveal melanoma growth and
      its status as a therapeutic node.
  downstream:
  - target: Uveal Melanocyte Transformation and Intraocular Tumour Growth
    description: >-
      YAP-dependent transcriptional programmes contribute to the growth of
      Gq-driven uveal melanoma cells alongside the MAPK arm.
    evidence:
    - reference: PMID:24882515
      reference_title: Hippo-independent activation of YAP by the GNAQ uveal melanoma
        oncogene through a trio-regulated rho GTPase signaling circuitry.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Furthermore, we show that Gαq promotes the YAP-dependent growth of\
        \ uveal \nmelanoma cells"
      explanation: Directly asserts the YAP-to-growth edge in uveal melanoma cells.

- name: Uveal Melanocyte Transformation and Intraocular Tumour Growth
  biological_scale: TISSUE
  role: central_effector
  conforms_to: sustaining_proliferative_signaling#Growth-Factor-Independent Proliferation
  mechanism_confidence: ESTABLISHED
  description: >-
    Convergent PKC/MAPK and YAP signalling transforms a uveal melanocyte into a
    growth-factor-independent clone that expands as an intraocular mass, most
    often in the choroid (about 90%), less often the ciliary body (about 6-7%) or
    iris (about 3%). Expansion under the retina produces exudation and
    secondary retinal detachment; anterior tumours can distort the iris and
    obstruct aqueous outflow. Because the globe is a closed, non-distensible
    compartment, growth is symptomatic disproportionately early relative to
    tumour bulk - yet up to about 30% of tumours are still asymptomatic at
    diagnosis and are found on routine fundoscopy.
  locations:
  - preferred_term: uvea
    term:
      id: UBERON:0001768
      label: uvea
  cell_types:
  - preferred_term: choroidal melanocyte
    term:
      id: CL:4030000
      label: choroidal melanocyte
  biological_processes:
  - preferred_term: cell population proliferation
    modifier: INCREASED
    term:
      id: GO:0008283
      label: cell population proliferation
  evidence:
  - reference: PMID:39200222
    reference_title: 'Uveal Melanoma: Comprehensive Review of Its Pathophysiology,
      Diagnosis, Treatment, and Future Perspectives.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Uveal melanoma (UM) is the most common intraocular malignancy in adults.
    explanation: Confirms the intraocular tumour that this node describes is the commonest
      adult intraocular malignancy.
  downstream:
  - target: Uveal Melanoma
    description: >-
      The expanding transformed uveal melanocyte clone is the intraocular
      melanoma itself.
  - target: Reduced Visual Acuity
    description: >-
      Tumour involvement of the macula, exudation, or obstruction of the visual
      axis reduces acuity.
    evidence:
    - reference: PMID:34775516
      reference_title: Vasculogenic mimicry correlates to presenting symptoms and
        mortality in uveal melanoma.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Thirty-four patients (49%) presented with blurred vision."
      explanation: Blurred vision was the commonest presenting symptom of the intraocular
        tumour, supporting this tumour-growth-to-acuity-loss edge.
  - target: Visual Field Defect
    description: >-
      A tumour mass and its associated serous retinal detachment produce a field
      defect corresponding to the involved retinal sector.
    evidence:
    - reference: PMID:34775516
      reference_title: Vasculogenic mimicry correlates to presenting symptoms and
        mortality in uveal melanoma.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "In multivariate regression, retinal detachment (RD), presence of VM,\
        \ and PAS density ≥ median were independent predictors of a shadow"
      explanation: Retinal detachment was an independent predictor of the visual-field
        shadow, directly supporting this tumour-and-detachment to field-defect edge.
  - target: Exudative Retinal Detachment
    description: >-
      Subretinal exudation from the tumour surface separates the neurosensory
      retina from the retinal pigment epithelium.
    evidence:
    - reference: PMID:19667335
      reference_title: Metastasis of uveal melanoma millimeter-by-millimeter in 8033
        consecutive eyes.
      supports: PARTIAL
      evidence_source: HUMAN_CLINICAL
      snippet: "the presence of subretinal\
        \ fluid, intraocular hemorrhage, or \nextraocular extension"
      explanation: Subretinal fluid is documented as a tumour-associated clinical finding
        in this 8033-eye series, supporting the tumour-to-exudative-detachment edge.
  - target: Photopsia
    description: >-
      Mechanical traction and detachment at the tumour-retina interface produce
      perceived flashes of light.
    evidence:
    - reference: PMID:34775516
      reference_title: Vasculogenic mimicry correlates to presenting symptoms and
        mortality in uveal melanoma.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "7 (10%) with \nphotopsia and/or floaters"
      explanation: Photopsia was a documented presenting symptom of the intraocular
        tumour in 10% of patients, supporting this edge.
  - target: Vitreous Floaters
    description: >-
      Tumour-associated vitreous cells, pigment dispersion, or haemorrhage are
      perceived as floaters.
    evidence:
    - reference: PMID:34775516
      reference_title: Vasculogenic mimicry correlates to presenting symptoms and
        mortality in uveal melanoma.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "7 (10%) with \nphotopsia and/or floaters"
      explanation: Floaters were a documented presenting symptom of the intraocular
        tumour in 10% of patients, supporting this edge.
  - target: Secondary Glaucoma
    description: >-
      Anterior (iris/ciliary body) tumours and neovascularisation obstruct
      aqueous outflow and raise intraocular pressure.
  - target: Ocular Pain
    description: >-
      Large tumours, secondary glaucoma and anterior-segment involvement cause
      ocular pain.
  - target: BAP1 Loss with Monosomy 3
    description: >-
      The established tumour clone is the substrate on which the later,
      prognosis-determining secondary driver event is acquired.
  - target: Secondary Splicing/Translation-Factor Driver Stratification
    description: >-
      Disomy-3 tumour clones instead acquire SF3B1 or EIF1AX mutations, defining
      the intermediate- and low-risk molecular classes.

- name: BAP1 Loss with Monosomy 3
  biological_scale: MOLECULAR
  role: driver
  mechanism_confidence: ESTABLISHED
  description: >-
    The single strongest determinant of metastatic risk in uveal melanoma is
    biallelic inactivation of BAP1, a nuclear deubiquitinase acting in chromatin
    regulation and the DNA-damage response, on chromosome 3p21.1. Inactivation
    typically combines a somatic truncating or ubiquitin-hydrolase-domain
    mutation on one allele with loss of the other chromosome 3 (monosomy 3).
    Integrative TCGA analysis showed that BAP1 loss follows monosomy 3 in the
    evolutionary sequence and imposes a globally distinct DNA methylation state,
    defining the class-2 / poor-prognosis phenotype with epithelioid morphology
    and early metastasis. A minority of patients carry a germline BAP1 variant
    (BAP1 tumour-predisposition syndrome), which also raises risk of
    mesothelioma, cutaneous melanoma and clear-cell renal carcinoma.
  cell_types:
  - preferred_term: choroidal melanocyte
    term:
      id: CL:4030000
      label: choroidal melanocyte
  biological_processes:
  - preferred_term: protein deubiquitination
    modifier: DECREASED
    term:
      id: GO:0016579
      label: protein deubiquitination
  - preferred_term: chromatin organization
    modifier: ABNORMAL
    term:
      id: GO:0006325
      label: chromatin organization
  genes:
  - preferred_term: BAP1
    term:
      id: hgnc:950
      label: BAP1
  evidence:
  - reference: PMID:21051595
    reference_title: Frequent mutation of BAP1 in metastasizing uveal melanomas.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Inactivating somatic mutations were identified in the gene encoding\
      \ \nBRCA1-associated protein 1 (BAP1) on chromosome 3p21.1 in 26 of 31 (84%)\
      \ \nmetastasizing tumors, including 15 mutations causing premature protein \n\
      termination and 5 affecting its ubiquitin carboxyl-terminal hydrolase domain."
    explanation: The landmark observation linking BAP1 inactivation to metastasising
      uveal melanoma, with the variant classes described here.
  - reference: PMID:28810145
    reference_title: Integrative Analysis Identifies Four Molecular and Clinical Subsets
      in Uveal Melanoma.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We show that BAP1 loss follows M3 occurrence and correlates with a global\
      \ DNA \nmethylation state that is distinct from D3-UM."
    explanation: Establishes the temporal ordering of monosomy 3 before BAP1 loss
      and the associated epigenomic reprogramming asserted in this node.
  downstream:
  - target: Haematogenous Dissemination Without Lymphatic Drainage
    description: >-
      BAP1-null, monosomy-3 tumours are the clones that seed distant metastasis;
      BAP1 loss was found in 84% of metastasising tumours.
    evidence:
    - reference: PMID:21051595
      reference_title: Frequent mutation of BAP1 in metastasizing uveal melanomas.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "These findings implicate loss of BAP1 in \nuveal melanoma metastasis\
        \ and suggest that the BAP1 pathway may be a valuable \ntherapeutic target."
      explanation: The authors' own causal interpretation of BAP1 loss as implicated
        in uveal melanoma metastasis.

- name: Secondary Splicing/Translation-Factor Driver Stratification
  biological_scale: MOLECULAR
  role: modifier
  mechanism_confidence: ESTABLISHED
  description: >-
    In disomy-3 tumours, which rarely metastasise, the secondary driver is
    instead a hotspot mutation in the splicing factor SF3B1 (predominantly
    Arg625, altering RNA splicing genome-wide) or an N-terminal in-frame
    mutation in the translation-initiation factor EIF1AX. Both are essentially
    mutually exclusive with BAP1 loss. SF3B1 mutation marks intermediate risk
    with characteristically late relapse; EIF1AX mutation marks the lowest-risk
    class. Together with BAP1 these three genes define the prognostic
    stratification that governs surveillance intensity after successful local
    treatment.
  cell_types:
  - preferred_term: choroidal melanocyte
    term:
      id: CL:4030000
      label: choroidal melanocyte
  biological_processes:
  - preferred_term: mRNA splicing, via spliceosome
    modifier: ABNORMAL
    term:
      id: GO:0000398
      label: mRNA splicing, via spliceosome
  genes:
  - preferred_term: SF3B1
    term:
      id: hgnc:10768
      label: SF3B1
  - preferred_term: EIF1AX
    term:
      id: hgnc:3250
      label: EIF1AX
  evidence:
  - reference: PMID:23313955
    reference_title: Recurrent mutations at codon 625 of the splicing factor SF3B1
      in uveal melanoma.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here, we describe mutations occurring exclusively at codon 625 of the\
      \ SF3B1 gene, encoding splicing factor 3B subunit 1, in low-grade uveal \nmelanomas\
      \ with good prognosis."
    explanation: Establishes the SF3B1 Arg625 hotspot and its association with lower-grade,
      better-prognosis uveal melanoma.
  - reference: PMID:23793026
    reference_title: Exome sequencing identifies recurrent somatic mutations in EIF1AX
      and SF3B1 in uveal melanoma with disomy 3.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Using exome sequencing, we \nidentified recurrent somatic mutations\
      \ in EIF1AX and SF3B1, specifically \noccurring in uveal melanomas with disomy\
      \ 3, which rarely metastasize."
    explanation: Ties both SF3B1 and EIF1AX mutation to the disomy-3, rarely metastasising
      class described in this node.
  downstream:
  - target: Haematogenous Dissemination Without Lymphatic Drainage
    description: >-
      Disomy-3 SF3B1/EIF1AX tumours retain a real but much lower and often later
      metastatic hazard than BAP1-null disease; SF3B1-mutant tumours in
      particular can relapse many years after treatment.
    evidence:
    - reference: PMID:23793026
      reference_title: Exome sequencing identifies recurrent somatic mutations in
        EIF1AX and SF3B1 in uveal melanoma with disomy 3.
      supports: PARTIAL
      evidence_source: HUMAN_CLINICAL
      snippet: "Resequencing of ten uveal melanomas with disomy 3 that developed metastases\
        \ identified SF3B1 mutations in three tumors, none of which targeted Arg625."
      explanation: Shows that disomy-3 tumours can still metastasise and that a non-Arg625
        SF3B1 subset is enriched among those that do; supports the edge as a lower-hazard,
        not absent, route.

- name: Haematogenous Dissemination Without Lymphatic Drainage
  biological_scale: ORGANISM
  role: effector
  conforms_to: invasion_and_metastasis#Circulatory Survival and Extravasation
  mechanism_confidence: ESTABLISHED
  description: >-
    The uveal tract has no lymphatic drainage, so uveal melanoma disseminates
    exclusively by the blood. Tumour cells intravasate directly into the dense
    choroidal vasculature and enter the systemic circulation, often long before
    the primary tumour is treated - which is why excellent local control does
    not prevent metastatic death. Dissemination is believed to be an early
    event, with occult micrometastases persisting in a dormant state for years
    to decades; fewer than 2% of patients have radiologically detectable
    metastases at diagnosis, yet a third to a half develop them over the
    following 15 years. This is the mechanistic point at which uveal and
    conjunctival melanoma diverge most sharply.
  locations:
  - preferred_term: uvea
    term:
      id: UBERON:0001768
      label: uvea
  biological_processes:
  - preferred_term: cell migration
    modifier: INCREASED
    term:
      id: GO:0016477
      label: cell migration
  evidence:
  - reference: PMID:19078957
    reference_title: Frequent somatic mutations of GNAQ in uveal melanoma and blue
      naevi.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: One category, uveal melanoma, arises from melanocytes within the choroidal
      plexus of the eye and is biologically distinct from cutaneous melanoma by characteristic
      cytogenetic alterations4 and a very strong propensity to metastasize to the
      liver5.
    explanation: Documents the strong hepatic metastatic propensity that this dissemination
      node feeds.
  - reference: PMID:34839428
    reference_title: Robotic Extended Ultrasound-Guided Distal Pancreatectomy for Pancreatic
      Metastases from Uveal Melanoma.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In contrast to cutaneous melanoma derivation, metastases mostly occur\
      \ via hematogenous \nspread, in the absence of lymphatic drainage of the eye."
    explanation: Directly sources this entry's hinge claim - that the eye lacks
      lymphatic drainage, so uveal melanoma disseminates haematogenously - which is
      what distinguishes the uveal from the conjunctival arm.
  downstream:
  - target: Hepatic Metastatic Colonisation
    description: >-
      Circulating uveal melanoma cells preferentially arrest, survive and
      colonise the hepatic sinusoidal niche.
    evidence:
    - reference: PMID:35227015
      reference_title: Liver metastasis in uveal melanoma - treatment options and
        clinical outcome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "In 90% of cases the liver is the first site of \nmetastasis, however\
        \ the mechanisms underlying this hepatic tropism have not been \nelucidated."
      explanation: Supports the hepatotropic direction of this dissemination edge.

- name: Hepatic Metastatic Colonisation
  biological_scale: ORGANISM
  role: outcome
  conforms_to: invasion_and_metastasis#Metastatic Colonization
  mechanism_confidence: ESTABLISHED
  description: >-
    Approximately half of uveal melanoma patients ultimately develop metastatic
    disease, and it is overwhelmingly hepatotropic - the liver is the first and
    dominant site in around 90% of cases, with lung and bone distant seconds.
    Colonisation of the liver, not intravasation, is the rate-limiting step;
    dormant micrometastases must acquire an angiogenic and immune-evasive
    programme in the hepatic niche before becoming clinically detectable. Once
    liver metastasis is established, historical median survival is on the order
    of 6-12 months and hepatic tumour burden is the leading cause of death,
    which is why liver-directed therapy remains central to management.
  locations:
  - preferred_term: liver
    term:
      id: UBERON:0002107
      label: liver
  biological_processes:
  - preferred_term: positive regulation of angiogenesis
    modifier: INCREASED
    term:
      id: GO:0045766
      label: positive regulation of angiogenesis
  evidence:
  - reference: PMID:35227015
    reference_title: Liver metastasis in uveal melanoma - treatment options and clinical
      outcome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Despite \nimprovements in the treatment of primary tumours, approximately\
      \ 50% of patients \nwith UM will develop metastases. In 90% of cases the liver\
      \ is the first site of \nmetastasis, however the mechanisms underlying this hepatic\
      \ tropism have not been \nelucidated."
    explanation: Directly documents the hepatotropic metastatic pattern that defines
      this node.
  downstream:
  - target: Hepatic Metastasis
    description: >-
      Colonisation of the hepatic parenchyma manifests clinically as liver
      metastases on surveillance imaging.
    evidence:
    - reference: PMID:35227015
      reference_title: Liver metastasis in uveal melanoma - treatment options and clinical
        outcome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "In 90% of cases the liver is the first site of \nmetastasis"
      explanation: Establishes that hepatic colonisation is the clinical manifestation
        of metastasis in the great majority of cases.
  - target: Low Tumour Mutational Burden and Checkpoint Refractoriness
    description: >-
      Established metastatic disease is the clinical setting in which the
      low-neoantigen, immunologically cold phenotype becomes therapeutically
      decisive.

- name: Low Tumour Mutational Burden and Checkpoint Refractoriness
  biological_scale: CELLULAR
  role: adaptive_escape
  mechanism_confidence: ESTABLISHED
  description: >-
    Unlike UV-driven cutaneous melanoma, uveal melanoma carries a very low
    tumour mutational burden (of the order of 0.5 mutations per megabase) and
    therefore presents few neoantigens. Combined with the immune-privileged
    ocular environment, this yields an immunologically cold tumour in which PD-1
    and CTLA-4 blockade - transformative in cutaneous melanoma - achieves only
    marginal response rates. This is an important negative mechanistic claim
    for this entry: the presence of a checkpoint axis is NOT the operative
    mechanism here, and the entry deliberately does not declare conformance to
    the immune_checkpoint_blockade module. The therapeutic solution instead
    bypasses neoantigen dependence altogether by redirecting T cells against a
    lineage antigen.
  cell_types:
  - preferred_term: T cell
    term:
      id: CL:0000084
      label: T cell
  biological_processes:
  - preferred_term: immune response to tumor cell
    modifier: DECREASED
    term:
      id: GO:0002418
      label: immune response to tumor cell
  evidence:
  - reference: PMID:34551229
    reference_title: Overall Survival Benefit with Tebentafusp in Metastatic Uveal
      Melanoma.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Uveal melanoma is a disease that is distinct from cutaneous \nmelanoma,\
      \ with a low tumor mutational burden and a 1-year overall survival of \napproximately\
      \ 50% in patients with metastatic uveal melanoma."
    explanation: States the low tumour mutational burden and the poor metastatic survival
      that together define this node.
  - reference: PMID:38627362
    reference_title: Uveal melanoma immunogenomics predict immunotherapy resistance
      and susceptibility.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Immune checkpoint inhibition has shown success in treating metastatic\
      \ cutaneous \nmelanoma but has limited efficacy against metastatic uveal melanoma,\
      \ a rare \nvariant arising from the immune privileged eye."
    explanation: States directly that checkpoint blockade, which succeeds in cutaneous
      melanoma, has limited efficacy in uveal melanoma arising from the immune-privileged
      eye - the central claim of this node.
  downstream:
  - target: gp100-Directed T-Cell Redirection
    description: >-
      Because neoantigen-dependent checkpoint blockade fails, therapy instead
      redirects T cells against the melanocyte lineage antigen gp100 presented
      on HLA-A*02:01.
    evidence:
    - reference: PMID:34551229
      reference_title: Overall Survival Benefit with Tebentafusp in Metastatic Uveal
        Melanoma.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Tebentafusp is a bispecific protein consisting of an affinity-enhanced\
        \ T-cell \nreceptor fused to an anti-CD3 effector that can redirect T cells\
        \ to target \nglycoprotein 100-positive cells."
      explanation: Describes precisely the redirection strategy that this edge asserts
        as the response to checkpoint refractoriness.

- name: gp100-Directed T-Cell Redirection
  biological_scale: CELLULAR
  role: therapeutic_vulnerability
  mechanism_confidence: ESTABLISHED
  description: >-
    Uveal melanoma cells retain melanocytic lineage antigen expression,
    including glycoprotein 100 (gp100/PMEL). Tebentafusp is an immune-mobilising
    monoclonal T-cell receptor against cancer (ImmTAC): an affinity-enhanced
    soluble TCR that binds a gp100 peptide presented by HLA-A*02:01, fused to an
    anti-CD3 effector arm that recruits and activates any polyclonal T cell
    irrespective of its own specificity. This side-steps the low-neoantigen
    problem entirely, and it is the first mechanism to deliver a randomised
    overall-survival benefit in metastatic uveal melanoma. The obligatory
    dependence on HLA-A*02:01 presentation restricts eligibility to roughly half
    of patients, and the on-target/off-tumour attack on normal gp100-positive
    melanocytes produces the characteristic early rash and cytokine-mediated
    pyrexia.
  cell_types:
  - preferred_term: T cell
    term:
      id: CL:0000084
      label: T cell
  biological_processes:
  - preferred_term: T cell mediated cytotoxicity
    modifier: INCREASED
    term:
      id: GO:0001913
      label: T cell mediated cytotoxicity
  genes:
  - preferred_term: PMEL
    term:
      id: hgnc:10880
      label: PMEL
  evidence:
  - reference: PMID:34551229
    reference_title: Overall Survival Benefit with Tebentafusp in Metastatic Uveal
      Melanoma.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Overall survival at 1 year was 73% in the tebentafusp group and 59%\
      \ in the control group"
    explanation: The randomised phase 3 survival result establishing that this mechanism
      is clinically effective.
  - reference: PMID:37870955
    reference_title: Three-Year Overall Survival with Tebentafusp in Metastatic Uveal
      Melanoma.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "At a minimum follow-up of 36 months, median overall survival was 21.6\
      \ \nmonths in the tebentafusp group and 16.9 months in the control group (hazard\
      \ \nratio for death, 0.68; 95% confidence interval, 0.54 to 0.87)."
    explanation: Confirms the survival benefit is durable at three years.

- name: Conjunctival Melanocytic Intraepithelial Neoplasia
  biological_scale: TISSUE
  role: trigger
  mechanism_confidence: ESTABLISHED
  description: >-
    The conjunctival arm of ocular melanoma begins in a fundamentally different
    compartment - the stratified squamous/mucosal epithelium of the conjunctival
    surface, which is UV-exposed and lymphatic-bearing. Most conjunctival
    melanomas arise from a precursor field of atypical intraepithelial
    melanocytic proliferation (conjunctival melanocytic intraepithelial lesion,
    formerly primary acquired melanosis with atypia); a minority arise in a
    pre-existing naevus or de novo. Because the precursor is a diffuse field
    rather than a discrete mass, incomplete excision leaves residual atypical
    epithelium and drives the high (roughly a third to a half) local recurrence
    rate that dominates conjunctival melanoma morbidity.
  locations:
  - preferred_term: conjunctiva
    term:
      id: UBERON:0001811
      label: conjunctiva
  cell_types:
  - preferred_term: melanocyte
    term:
      id: CL:0000148
      label: melanocyte
  evidence:
  - reference: PMID:39335093
    reference_title: 'Conjunctival Melanoma: A Clinical Review and Update.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This review aims to provide a \ncomprehensive clinical overview of the\
      \ current knowledge regarding Co-M, its \nepidemiology, pathogenesis, presentation,\
      \ diagnosis and recent changes in the \nclassification of its precursor lesions,\
      \ management, and recent advances in \nnovel biological therapies for personalised\
      \ treatment of this disease."
    explanation: Confirms that conjunctival melanoma has a recognised, recently reclassified
      precursor-lesion pathway, as modelled by this node.
  downstream:
  - target: UV-Associated BRAF/NRAS/NF1 Driver Activation
    description: >-
      Within the atypical intraepithelial field, acquisition of a
      cutaneous-melanoma-type MAPK driver converts the precursor to invasive
      melanoma.
    evidence:
    - reference: PMID:34071371
      reference_title: Molecular Genetics of Conjunctival Melanoma and Prognostic Value
        of TERT Promoter Mutation Analysis.
      supports: PARTIAL
      evidence_source: HUMAN_CLINICAL
      snippet: "TERT promoter mutations were most common (54%), but BRAF (46%), NRAS\
        \ (21%), BAP1"
      explanation: Quantifies the driver mutations actually present in invasive
        conjunctival melanoma. Supports the driver-acquisition end of this edge; the
        precursor-to-invasion transition itself is described but not separately
        evidenced, so the item is marked PARTIAL.

- name: UV-Associated BRAF/NRAS/NF1 Driver Activation
  biological_scale: MOLECULAR
  role: driver
  mechanism_confidence: ESTABLISHED
  description: >-
    Conjunctival melanoma is driven by the mutation spectrum of cutaneous, not
    uveal, melanoma: activating BRAF (commonly V600E) and NRAS (commonly Q61)
    mutations, NF1 loss, and TERT promoter mutations, on a UV-signature
    mutational background. GNAQ, GNA11 and BAP1 - the defining uveal genes -
    are not the drivers here. The practical corollary is that BRAF/MEK-targeted
    therapy and PD-1 blockade, which fail in uveal melanoma, are the rational
    (if still evidence-thin) systemic options in conjunctival melanoma. This
    node is the reason the two arms must be curated separately.
  locations:
  - preferred_term: conjunctiva
    term:
      id: UBERON:0001811
      label: conjunctiva
  cell_types:
  - preferred_term: melanocyte
    term:
      id: CL:0000148
      label: melanocyte
  biological_processes:
  - preferred_term: MAPK cascade
    modifier: INCREASED
    term:
      id: GO:0000165
      label: MAPK cascade
  genes:
  - preferred_term: BRAF
    term:
      id: hgnc:1097
      label: BRAF
  - preferred_term: NRAS
    term:
      id: hgnc:7989
      label: NRAS
  - preferred_term: NF1
    term:
      id: hgnc:7765
      label: NF1
  - preferred_term: TERT
    term:
      id: hgnc:11730
      label: TERT
  evidence:
  - reference: PMID:34015548
    reference_title: 'Conjunctival melanoma: New insights in tumour genetics and immunology,
      leading to new therapeutic options.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Targeted therapies that are successful in cutaneous melanoma \nmay therefore\
      \ be useful in CoM."
    explanation: States the therapeutic corollary of the cutaneous-like driver landscape
      asserted by this node.
  - reference: PMID:41097064
    reference_title: 'Ocular Melanoma: A Comprehensive Review with a Focus on Molecular
      Biology.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Conversely, conjunctival and\neyelid melanoma exhibits greater molecular\
      \ similarity to cutaneous melanoma,\ncommonly involving BRAF, NRAS, NF1, and\
      \ TERT promoter mutations."
    explanation: Names exactly the BRAF/NRAS/NF1/TERT driver set modelled in this
      node.
  downstream:
  - target: Conjunctival Lymphatic and Regional Nodal Spread
    description: >-
      Invasive conjunctival melanoma gains access to conjunctival lymphatics and
      disseminates first to regional lymph nodes.
  - target: Conjunctival Melanocytic Lesion
    description: >-
      Driver acquisition within the intraepithelial field produces the visible
      pigmented or amelanotic invasive conjunctival mass.

- name: Conjunctival Lymphatic and Regional Nodal Spread
  biological_scale: ORGANISM
  role: consequence
  mechanism_confidence: ESTABLISHED
  description: >-
    Unlike the uvea, the conjunctiva has a rich lymphatic network. Conjunctival
    melanoma therefore metastasises first and predominantly to the regional
    (preauricular, submandibular, cervical) lymph nodes, with distant spread to
    lung, liver and brain occurring later. Regional nodal metastasis is a
    substantial contributor to conjunctival melanoma mortality; specific nodal
    and disease-specific-mortality rates are not asserted here because no
    quotable figure could be verified against a cached source (see notes).
    This lymphatic-first route is the direct
    mechanistic opposite of uveal melanoma's lymphatic-free, liver-dominant
    haematogenous route, and it is why sentinel-node assessment is relevant in
    conjunctival but not uveal disease.
  locations:
  - preferred_term: conjunctiva
    term:
      id: UBERON:0001811
      label: conjunctiva
  biological_processes:
  - preferred_term: cell migration
    modifier: INCREASED
    term:
      id: GO:0016477
      label: cell migration
  evidence:
  - reference: PMID:39335093
    reference_title: 'Conjunctival Melanoma: A Clinical Review and Update.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Co-M is often \nmisdiagnosed or overlooked, leading to vision loss either\
      \ from the destructive \neffects of the tumour or side effects of therapy, facial\
      \ disfigurement from \nradical surgery, and death from metastases."
    explanation: Documents that conjunctival melanoma is a metastasising, lethal disease
      requiring the dissemination node modelled here.
  - reference: PMID:32698034
    reference_title: 'Sentinel Lymph Node Biopsy for Eyelid and Conjunctival Malignancy:
      A Report by the American Academy of Ophthalmology.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Tumor-positive lymph nodes were found in 33 of 197 patients \n(16.8%),\
      \ prompting recommendations for adjuvant treatments."
    explanation: Directly documents regional lymph-node metastasis in eyelid and
      conjunctival malignancy - the lymphatic route this node asserts. Note the AAO
      cohort is mixed (85 of 197 were conjunctival melanoma), so the 16.8% figure is
      not conjunctival-melanoma-specific and no rate is asserted in the description.
  - reference: PMID:32698034
    reference_title: 'Sentinel Lymph Node Biopsy for Eyelid and Conjunctival Malignancy:
      A Report by the American Academy of Ophthalmology.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Sentinel lymph node biopsy is a promising procedure in patients \nwith\
      \ eyelid and conjunctival malignancy, and it is useful in identifying \nsentinel\
      \ lymph nodes."
    explanation: Supports the entry's claim that sentinel-node assessment is relevant
      in conjunctival - but not uveal - ocular melanoma.

phenotypes:
- category: Ocular
  name: Uveal Melanoma
  diagnostic: true
  subtype: Uveal Melanoma
  description: >-
    An intraocular melanocytic malignancy of the uveal tract. This is the
    dominant presentation of ocular melanoma and the commonest primary
    intraocular malignancy of adults; approximately 90% arise in the choroid.
  phenotype_term:
    preferred_term: Uveal melanoma
    term:
      id: HP:0007716
      label: Uveal melanoma
  evidence:
  - reference: PMID:39200222
    reference_title: 'Uveal Melanoma: Comprehensive Review of Its Pathophysiology,
      Diagnosis, Treatment, and Future Perspectives.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Uveal melanoma (UM) is the most common intraocular malignancy in adults.
    explanation: Establishes uveal melanoma as the dominant intraocular manifestation
      of ocular melanoma.
- category: Ocular
  name: Conjunctival Melanocytic Lesion
  diagnostic: true
  subtype: Conjunctival Melanoma
  description: >-
    A growing pigmented (brown or black) or amelanotic conjunctival lesion,
    most often on the bulbar conjunctiva near the limbus, sometimes with feeder
    vessels. This is the presenting sign of conjunctival melanoma. Coded to the
    generic conjunctival-morphology HPO term because HPO has no dedicated
    conjunctival melanoma class; the specific diagnosis is carried by the
    Conjunctival Melanoma subtype and its MONDO binding.
  phenotype_term:
    preferred_term: Conjunctival melanocytic lesion
    term:
      id: HP:0000502
      label: Abnormal conjunctiva morphology
  evidence:
  - reference: PMID:39335093
    reference_title: 'Conjunctival Melanoma: A Clinical Review and Update.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Conjunctival melanoma (Co-M) is an aggressive, invasive eye and eyelid
      cancer.
    explanation: Supports the existence and aggressive nature of the conjunctival
      surface lesion described by this phenotype.
- category: Ocular
  name: Reduced Visual Acuity
  frequency: FREQUENT
  description: >-
    Blurred or reduced vision occurs when the tumour involves the macula, causes
    exudation or retinal detachment, or obstructs the visual axis. Up to about
    30% of uveal melanomas are asymptomatic at diagnosis and are found on
    routine examination, so acuity loss is common but not universal.
  phenotype_term:
    preferred_term: Reduced visual acuity
    term:
      id: HP:0007663
      label: Reduced visual acuity
  evidence:
  - reference: PMID:34775516
    reference_title: Vasculogenic mimicry correlates to presenting symptoms and mortality
      in uveal melanoma.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Thirty-four patients (49%) presented with blurred vision."
    explanation: Blurred vision (decreased visual acuity) was the commonest presenting
      symptom, in 49% of an enucleation cohort - supporting the FREQUENT frequency band
      assigned here.
- category: Ocular
  name: Visual Field Defect
  frequency: OCCASIONAL
  description: >-
    A field defect - classically described by patients as a "shadow" in the
    field of vision - corresponding to the tumour location and the extent of
    any associated exudative retinal detachment. Reported as the presenting
    symptom in about a quarter of patients, and notable because an isolated
    field shadow correlates with vasculogenic mimicry and worse prognosis.
  phenotype_term:
    preferred_term: Visual field defect
    term:
      id: HP:0001123
      label: Visual field defect
  evidence:
  - reference: PMID:34775516
    reference_title: Vasculogenic mimicry correlates to presenting symptoms and mortality
      in uveal melanoma.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "18 (26%) with \na shadow in the visual field"
    explanation: Quantifies a visual-field shadow as the presenting symptom in 26% of
      an enucleation cohort, supporting the OCCASIONAL (5-29%) frequency band assigned
      here.
- category: Ocular
  name: Exudative Retinal Detachment
  description: >-
    Serous separation of the neurosensory retina caused by exudation from the
    surface of a choroidal melanoma. It is a classic accompanying sign of
    choroidal melanoma and a common route to vision loss.
  phenotype_term:
    preferred_term: Retinal detachment
    term:
      id: HP:0000541
      label: Retinal detachment
  evidence:
  - reference: PMID:19667335
    reference_title: Metastasis of uveal melanoma millimeter-by-millimeter in 8033
      consecutive eyes.
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "Clinical factors predictive of metastasis by multivariate analysis included\
      \ increasing patient age, ciliary \nbody location, increasing tumor diameter,\
      \ increasing tumor thickness, having a \nbrown tumor, and the presence of subretinal\
      \ fluid, intraocular hemorrhage, or \nextraocular extension."
    explanation: Subretinal fluid - the exudative retinal detachment described by this
      phenotype - is documented as a recognised clinical feature of uveal melanoma in
      an 8033-eye series, and is independently predictive of metastasis.
- category: Ocular
  name: Photopsia
  frequency: OCCASIONAL
  description: >-
    Perceived flashes of light arising from vitreoretinal traction and
    detachment at the tumour-retina interface. Photopsia and floaters together
    accounted for the presenting symptom in about 10% of one enucleation
    cohort.
  phenotype_term:
    preferred_term: Photopsia
    term:
      id: HP:0030786
      label: Photopsia
  evidence:
  - reference: PMID:34775516
    reference_title: Vasculogenic mimicry correlates to presenting symptoms and mortality
      in uveal melanoma.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "7 (10%) with \nphotopsia and/or floaters"
    explanation: Quantifies photopsia (reported jointly with floaters) as the presenting
      symptom in 10% of patients, supporting the OCCASIONAL frequency band.
- category: Ocular
  name: Vitreous Floaters
  frequency: OCCASIONAL
  description: >-
    Floaters from tumour-associated vitreous cells, dispersed pigment, or
    vitreous haemorrhage. Reported jointly with photopsia in about 10% of
    patients at presentation.
  phenotype_term:
    preferred_term: Vitreous floaters
    term:
      id: HP:0100832
      label: Vitreous floaters
  evidence:
  - reference: PMID:34775516
    reference_title: Vasculogenic mimicry correlates to presenting symptoms and mortality
      in uveal melanoma.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "7 (10%) with \nphotopsia and/or floaters"
    explanation: Quantifies floaters (reported jointly with photopsia) as the presenting
      symptom in 10% of patients, supporting the OCCASIONAL frequency band.
- category: Ocular
  name: Secondary Glaucoma
  frequency: OCCASIONAL
  description: >-
    Raised intraocular pressure from anterior-segment tumour involvement, angle
    infiltration, or neovascularisation. Most relevant to iris and ciliary-body
    melanoma.
  phenotype_term:
    preferred_term: Glaucoma
    term:
      id: HP:0000501
      label: Glaucoma
- category: Ocular
  name: Ocular Pain
  frequency: OCCASIONAL
  description: >-
    Pain from a large intraocular tumour, secondary glaucoma, or extrascleral
    extension; a common indication for enucleation in a blind painful eye.
  phenotype_term:
    preferred_term: Ocular pain
    term:
      id: HP:0200026
      label: Ocular pain
- category: Systemic
  name: Hepatic Metastasis
  frequency: FREQUENT
  description: >-
    Metastatic melanoma deposits in the liver. Roughly half of uveal melanoma
    patients develop metastases and the liver is the dominant site in around
    90%, typically detected on surveillance imaging rather than by symptoms or
    by abnormal liver function tests, which cannot exclude hepatic metastasis.
  phenotype_term:
    preferred_term: Neoplasm of the liver
    term:
      id: HP:0002896
      label: Neoplasm of the liver
  evidence:
  - reference: PMID:35227015
    reference_title: Liver metastasis in uveal melanoma - treatment options and clinical
      outcome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Despite \nimprovements in the treatment of primary tumours, approximately\
      \ 50% of patients \nwith UM will develop metastases. In 90% of cases the liver\
      \ is the first site of \nmetastasis"
    explanation: Documents that about half of uveal melanoma patients metastasise and
      that the liver is the first site in 90%, the hepatotropic pattern this phenotype
      records.

histopathology:
- name: Melanocytic Neoplasm
  finding_term:
    preferred_term: Melanocytic Neoplasm
    term:
      id: NCIT:C7058
      label: Melanocytic Neoplasm
  frequency: OBLIGATE
  diagnostic: true
  description: >-
    All ocular melanomas are melanocytic neoplasms. Diagnosis is supported by
    immunohistochemistry for melanocytic markers (SOX10, S100, Melan-A/MART1,
    HMB45); nuclear BAP1 immunostaining is additionally used in uveal melanoma
    as a surrogate for BAP1 inactivation and hence metastatic risk.
  evidence:
  - reference: PMID:41097064
    reference_title: 'Ocular Melanoma: A Comprehensive Review with a Focus on Molecular
      Biology.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Although sharing some \nhistopathological features with cutaneous melanoma,\
      \ these tumours are \ncharacterized by distinct molecular and biological profiles\
      \ with direct \nimplications for prognosis and treatment."
    explanation: Confirms ocular melanomas are histopathologically melanocytic tumours
      while being molecularly distinct from cutaneous melanoma.
- name: Epithelioid Cell Morphology
  finding_term:
    preferred_term: uveal epithelioid cell melanoma
    term:
      id: NCIT:C35780
      label: Uveal Epithelioid Cell Melanoma
  diagnostic: false
  subtype: Uveal Melanoma
  description: >-
    Uveal melanomas are classified by cell type as spindle, mixed or
    epithelioid. Epithelioid morphology - large cells with abundant cytoplasm,
    prominent nucleoli and distinct cell borders - is strongly adverse, tracks
    with BAP1 loss and monosomy 3, and is one of the classic histological
    predictors of metastasis.
  evidence:
  - reference: PMID:12601021
    reference_title: 'Monosomy 3 in uveal melanoma: correlation with clinical and histologic
      predictors of survival.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Monosomy 3 was associated with epithelioid cells \n(chi(2) test, P <\
      \ 0.001), PAS-positive loops (chi(2), P = 0.001), LBD \n(Mann-Whitney test, P\
      \ = 0.002), CB involvement (chi(2) test, P = 0.008), and \nmetastasis-related\
      \ death (log rank analysis, P = 0.0003)."
    explanation: Names epithelioid cytomorphology directly and ties it statistically
      to monosomy 3 and to metastasis-related death - exactly the association claimed
      here.
  - reference: PMID:12601021
    reference_title: 'Monosomy 3 in uveal melanoma: correlation with clinical and histologic
      predictors of survival.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The absence of monosomy 3 is predictable \nonly in patients who have\
      \ small, spindle-cell tumors."
    explanation: The converse observation - spindle-cell morphology marks the
      favourable, disomy-3 end of the cell-type spectrum described here.

genetic:
- name: GNAQ
  gene_term:
    preferred_term: GNAQ
    term:
      id: hgnc:4390
      label: GNAQ
  relationship_type: SOMATIC_DRIVER
  variant_origin: SOMATIC
  association: Activating somatic driver mutation (Q209, less often R183)
  subtype: Uveal Melanoma
  notes: >-
    Initiating oncogenic driver of uveal melanoma, mutated in roughly 45% of
    primary tumours and mutually exclusive with GNA11. Q209L/Q209P abolish
    intrinsic GTPase activity, locking Gq alpha in its active GTP-bound state.
  evidence:
  - reference: PMID:19078957
    reference_title: Frequent somatic mutations of GNAQ in uveal melanoma and blue
      naevi.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here we report frequent somatic mutations in the heterotrimeric G \n\
      protein alpha-subunit, GNAQ, in blue naevi (83%) and ocular melanoma of the\
      \ uvea \n(46%)."
    explanation: Reports the somatic GNAQ mutation frequency in uveal ocular melanoma.
- name: GNA11
  gene_term:
    preferred_term: GNA11
    term:
      id: hgnc:4379
      label: GNA11
  relationship_type: SOMATIC_DRIVER
  variant_origin: SOMATIC
  association: Activating somatic driver mutation (Q209, less often R183)
  subtype: Uveal Melanoma
  notes: >-
    Paralogue of GNAQ and functionally equivalent driver, mutated in about 32%
    of primary uveal melanomas but 57% of uveal melanoma metastases - the
    enrichment in metastases is the inverse of GNAQ and suggests GNA11-mutant
    tumours are the more aggressive of the two.
  evidence:
  - reference: PMID:21083380
    reference_title: Mutations in GNA11 in uveal melanoma.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mutations affecting Q209 in GNA11 were present in 7% of blue nevi, 32%\
      \ of \nprimary uveal melanomas, and 57% of uveal melanoma metastases."
    explanation: Gives the GNA11 mutation frequencies in primary and metastatic uveal
      melanoma described in the notes.
- name: BAP1
  gene_term:
    preferred_term: BAP1
    term:
      id: hgnc:950
      label: BAP1
  relationship_type: SOMATIC_DRIVER
  variant_origin: GERMLINE_AND_SOMATIC
  association: Tumour suppressor loss (biallelic, usually with monosomy 3)
  subtype: Uveal Melanoma
  notes: >-
    The dominant prognostic gene in uveal melanoma. Somatic inactivation with
    monosomy 3 defines the class-2, high-metastatic-risk phenotype. A minority
    of patients carry a germline BAP1 pathogenic variant, constituting BAP1
    tumour-predisposition syndrome (uveal melanoma, mesothelioma, cutaneous
    melanoma, clear-cell renal carcinoma), which warrants genetic counselling
    and cascade testing.
  evidence:
  - reference: PMID:21051595
    reference_title: Frequent mutation of BAP1 in metastasizing uveal melanomas.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "One tumor harbored a frameshift mutation that was germline in origin,\
      \ thus \nrepresenting a susceptibility allele."
    explanation: Documents both the somatic and the germline (susceptibility) origin
      of BAP1 inactivation recorded here.
- name: SF3B1
  gene_term:
    preferred_term: SF3B1
    term:
      id: hgnc:10768
      label: SF3B1
  relationship_type: SOMATIC_DRIVER
  variant_origin: SOMATIC
  association: Hotspot splicing-factor mutation (predominantly Arg625)
  subtype: Uveal Melanoma
  notes: >-
    Occurs in roughly 20-25% of uveal melanomas, largely in disomy-3 tumours,
    and marks an intermediate-risk class characterised by late relapse.
  evidence:
  - reference: PMID:23313955
    reference_title: Recurrent mutations at codon 625 of the splicing factor SF3B1
      in uveal melanoma.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Thus, uveal melanoma is among a small group of \ncancers associated\
      \ with SF3B1 mutations, and these mutations denote a distinct \nmolecular subset\
      \ of uveal melanomas."
    explanation: Establishes SF3B1 mutation as defining a distinct molecular subset
      of uveal melanoma.
- name: EIF1AX
  gene_term:
    preferred_term: EIF1AX
    term:
      id: hgnc:3250
      label: EIF1AX
  relationship_type: SOMATIC_DRIVER
  variant_origin: SOMATIC
  association: N-terminal in-frame translation-initiation-factor mutation
  subtype: Uveal Melanoma
  notes: >-
    Marks the lowest-risk uveal melanoma class; nearly always found in disomy-3
    tumours and essentially mutually exclusive with BAP1 loss.
  evidence:
  - reference: PMID:23793026
    reference_title: Exome sequencing identifies recurrent somatic mutations in EIF1AX
      and SF3B1 in uveal melanoma with disomy 3.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Targeted resequencing showed that 24 of 31 tumors with disomy 3 (77%)\
      \ had mutations in \neither EIF1AX (15; 48%) or SF3B1 (9; 29%)."
    explanation: Quantifies EIF1AX mutation within the disomy-3, low-risk class.
- name: CYSLTR2
  gene_term:
    preferred_term: CYSLTR2
    term:
      id: hgnc:18274
      label: CYSLTR2
  relationship_type: SOMATIC_DRIVER
  variant_origin: SOMATIC
  association: Activating receptor mutation (p.Leu129Gln) in GNAQ/GNA11-wild-type
    tumours
  subtype: Uveal Melanoma
  notes: >-
    Alternative initiating driver in roughly 2-4% of uveal melanomas, acting one
    step upstream of Gq by constitutively activating the cysteinyl leukotriene
    receptor 2 that couples to it.
  evidence:
  - reference: PMID:27089179
    reference_title: Recurrent activating mutations of G-protein-coupled receptor CYSLTR2
      in uveal melanoma.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We analyzed genomics data from 136 uveal \nmelanoma samples and found\
      \ a recurrent mutation in CYSLTR2 (cysteinyl \nleukotriene receptor 2) encoding\
      \ a p.Leu129Gln substitution in 4 of 9 samples \nthat lacked mutations in GNAQ,\
      \ GNA11, and PLCB4 but in 0 of 127 samples that \nharbored mutations in these\
      \ genes."
    explanation: The discovery paper, giving the exact p.Leu129Gln substitution, the
      restriction to GNAQ/GNA11/PLCB4-wild-type tumours, and the mutual exclusivity
      asserted here.
  - reference: PMID:27089179
    reference_title: Recurrent activating mutations of G-protein-coupled receptor CYSLTR2
      in uveal melanoma.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The Leu129Gln CysLT2R mutant protein \nconstitutively activates endogenous\
      \ Gαq and is unresponsive to stimulation by \nleukotriene."
    explanation: Establishes the activating, receptor-level mechanism acting upstream
      of Gq that this entry describes.
- name: PLCB4
  gene_term:
    preferred_term: PLCB4
    term:
      id: hgnc:9059
      label: PLCB4
  relationship_type: SOMATIC_DRIVER
  variant_origin: SOMATIC
  association: Activating mutation (p.Asp630Tyr) in GNAQ/GNA11-wild-type tumours
  subtype: Uveal Melanoma
  notes: >-
    Rare (about 2.5%) initiating driver acting immediately downstream of Gq, at
    the phospholipase C-beta step; mutually exclusive with GNAQ/GNA11 and
    CYSLTR2 mutations.
  evidence:
  - reference: PMID:26683228
    reference_title: Deep sequencing of uveal melanoma identifies a recurrent mutation
      in PLCB4.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we found a recurrent mutation in PLCB4 (c.G1888T, p.D630Y, NM_000933),\
      \ which was \nvalidated using Sanger sequencing."
    explanation: The discovery paper, giving the exact p.Asp630Tyr hotspot asserted
      here.
  - reference: PMID:26683228
    reference_title: Deep sequencing of uveal melanoma identifies a recurrent mutation
      in PLCB4.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "PLCB4 p.D630Y mutations are mutually exclusive with \nmutations in GNA11\
      \ and GNAQ, consistent with PLCB4 being the canonical \ndownstream target of\
      \ the former gene products."
    explanation: Establishes both the mutual exclusivity with GNAQ/GNA11 and PLCB4's
      position immediately downstream of Gq, exactly as described here.
- name: BRAF
  gene_term:
    preferred_term: BRAF
    term:
      id: hgnc:1097
      label: BRAF
  relationship_type: SOMATIC_DRIVER
  variant_origin: SOMATIC
  association: Activating somatic driver mutation (V600E) in conjunctival melanoma
  subtype: Conjunctival Melanoma
  notes: >-
    Present in roughly a quarter to a third of conjunctival melanomas and
    essentially absent from uveal melanoma. Associated with recurrence and
    systemic dissemination, and the rationale for BRAF/MEK-directed therapy in
    unresectable conjunctival disease.
  evidence:
  - reference: PMID:35544941
    reference_title: 'BRAF and NRAS prognostic values in conjunctival melanoma: analysis
      and literature review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "BRAF V600E \nmutation was observed in three biopsies (25%), similar\
      \ to NRAS Q61X (25%). \nRecurrences occurred in all patients with positive BRAF\
      \ or NRAS mutation"
    explanation: Reports BRAF V600E frequency and its association with recurrence
      in a conjunctival melanoma series.
- name: NRAS
  gene_term:
    preferred_term: NRAS
    term:
      id: hgnc:7989
      label: NRAS
  relationship_type: SOMATIC_DRIVER
  variant_origin: SOMATIC
  association: Activating somatic driver mutation (Q61) in conjunctival melanoma
  subtype: Conjunctival Melanoma
  notes: >-
    Present in a similar fraction of conjunctival melanomas to BRAF and, like
    BRAF, associated with recurrence and systemic dissemination. NRAS-mutant
    conjunctival melanoma may carry the greater metastatic risk of the two.
  evidence:
  - reference: PMID:35544941
    reference_title: 'BRAF and NRAS prognostic values in conjunctival melanoma: analysis
      and literature review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "BRAF and NRAS mutations may be risk factors for recurrence and \nshorter\
      \ survival in conjunctival melanoma, which would make these patients \ncandidates\
      \ for targeted therapies"
    explanation: Supports NRAS as an adverse prognostic driver and a targeted-therapy
      indication in conjunctival melanoma.
- name: NF1
  gene_term:
    preferred_term: NF1
    term:
      id: hgnc:7765
      label: NF1
  relationship_type: SOMATIC_DRIVER
  variant_origin: SOMATIC
  association: Loss-of-function mutation in conjunctival melanoma (cutaneous-like
    triple-wild-type arm)
  subtype: Conjunctival Melanoma
  notes: >-
    Completes the cutaneous-melanoma-style BRAF/NRAS/NF1 driver trichotomy in
    conjunctival melanoma. NF1 loss de-represses RAS and activates MAPK
    signalling in BRAF/NRAS-wild-type tumours.
  evidence:
  - reference: PMID:41097064
    reference_title: 'Ocular Melanoma: A Comprehensive Review with a Focus on Molecular
      Biology.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: commonly involving BRAF, NRAS, NF1, and TERT promoter mutations.
    explanation: Names NF1 among the recurrent conjunctival melanoma drivers.
- name: TERT
  gene_term:
    preferred_term: TERT
    term:
      id: hgnc:11730
      label: TERT
  relationship_type: SOMATIC_DRIVER
  variant_origin: SOMATIC
  association: Promoter mutation (UV-signature) in conjunctival melanoma
  subtype: Conjunctival Melanoma
  notes: >-
    TERT promoter mutations reactivate telomerase and are a UV-signature
    hallmark shared with cutaneous melanoma; they are not a feature of uveal
    melanoma.
  evidence:
  - reference: PMID:34015548
    reference_title: 'Conjunctival melanoma: New insights in tumour genetics and immunology,
      leading to new therapeutic options.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "CoM is characterized by mutations that have also been identified in\
      \ \ncutaneous melanoma, e.g. in BRAF, NRAS and TERT."
    explanation: Names TERT among the cutaneous-like conjunctival melanoma mutations.
  - reference: PMID:34071371
    reference_title: Molecular Genetics of Conjunctival Melanoma and Prognostic Value
      of TERT Promoter Mutation Analysis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "TERT promoter mutations were most common (54%), but BRAF (46%), NRAS\
      \ (21%), BAP1 \n(18%), PTEN (14%), c-KIT (7%), and SF3B1 (4%) mutations were\
      \ also observed. No \nmutations in GNAQ, GNA11, and EIF1AX were found."
    explanation: The single strongest statement of this entry's central divergence
      thesis - conjunctival melanoma carries the cutaneous driver set and, critically,
      NO mutations in GNAQ, GNA11 or EIF1AX, the genes that define the uveal arm.

inheritance:
- name: BAP1 Tumor Predisposition Syndrome (germline BAP1)
  description: >-
    Most ocular melanoma is sporadic, but a minority of uveal melanoma arises in
    BAP1 tumour predisposition syndrome, an autosomal dominant cancer
    predisposition caused by a heterozygous germline BAP1 pathogenic variant.
    Uveal melanoma is its commonest associated cancer, ahead of malignant
    mesothelioma, cutaneous melanoma and renal cell carcinoma, and BAP1-related
    uveal melanoma behaves as an aggressive class-2 tumour. Germline testing is
    warranted for young-onset, bilateral or multifocal disease, or a personal or
    family history of the syndrome's other tumours; carriers need annual dilated
    eye examinations from age 11-18 years.
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  penetrance: INCOMPLETE
  evidence:
  - reference: PMID:27748099
    reference_title: BAP1 Tumor Predisposition Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "BAP1 tumor predisposition syndrome (BAP1-TPDS) is \nassociated with an\
      \ increased risk for a specific skin lesion, BAP1-inactivated \nmelanocytic tumors\
      \ (BIMT; formerly called atypical Spitz tumors), and the \nfollowing cancers,\
      \ in descending order of frequency: uveal (eye) melanoma (UM), \nmalignant mesothelioma\
      \ (MMe), cutaneous melanoma (CM), renal cell carcinoma"
    explanation: GeneReviews establishes uveal melanoma as the commonest cancer of
      BAP1-TPDS and the syndrome's tumour spectrum.
  - reference: PMID:27748099
    reference_title: BAP1 Tumor Predisposition Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The diagnosis of BAP1-TPDS is established in a proband by \nidentification\
      \ of a heterozygous germline pathogenic variant in BAP1 on \nmolecular genetic\
      \ testing."
    explanation: Confirms the heterozygous germline mechanism underlying the autosomal
      dominant inheritance asserted here.
  - reference: PMID:27748099
    reference_title: BAP1 Tumor Predisposition Syndrome.
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "The penetrance, natural history, \nlife-time cancer risk for carriers,\
      \ and frequencies of BAP1-associated tumors \nare yet to be fully determined."
    explanation: Supports recording penetrance as INCOMPLETE/undetermined rather than
      asserting a figure.
  - reference: PMID:27748099
    reference_title: BAP1 Tumor Predisposition Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "GENETIC COUNSELING: BAP1-TPDS is inherited in an autosomal dominant manner.\
      \ Most \nindividuals diagnosed with BAP1-TPDS have an affected parent (an affected\
      \ parent \nmay have BAP1-related tumors that differ from those of the proband).\
      \ Some \nindividuals have BAP1-TPDS as the result of a de novo pathogenic variant."
    explanation: GeneReviews Genetic Counseling section establishing the autosomal
      dominant mode, the usual affected parent, and the de novo route asserted here.
  - reference: PMID:27748099
    reference_title: BAP1 Tumor Predisposition Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Each \nchild of an individual with BAP1-TPDS has a 50% chance of inheriting\
      \ the BAP1 \npathogenic variant."
    explanation: The 50% transmission risk that underpins the cascade-testing
      recommendation described here.

environmental:
- name: Ultraviolet Radiation Exposure
  presence: PRESENT
  description: >-
    Ultraviolet exposure is a credible aetiological factor for conjunctival
    melanoma, which is an ocular-surface tumour carrying a UV mutational
    signature and cutaneous-type drivers. Its role in posterior uveal melanoma
    is far weaker and contested: the choroid is sun-shielded, uveal melanoma has
    a low mutational burden without a dominant UV signature, and the R183
    mutations that do show C-to-T transitions are a small minority of drivers.
    This asymmetry should not be flattened into a single "UV causes ocular
    melanoma" claim.
  effect: RISK_FACTOR
  evidence:
  - reference: PMID:21083380
    reference_title: Mutations in GNA11 in uveal melanoma.
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "These alterations are characteristic mutational patterns induced by\
      \ \nultraviolet light23,24 and are found with markedly increased frequency in\
      \ \ncutaneous melanomas arising on sun-exposed skin."
    explanation: Shows a UV-type signature at the minority R183 site in uveal melanoma
      while the dominant Q209 site lacks it, supporting the partial and site-restricted
      UV contribution described here.
  - reference: PMID:41097064
    reference_title: 'Ocular Melanoma: A Comprehensive Review with a Focus on Molecular
      Biology.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Conversely, conjunctival and\neyelid melanoma exhibits greater molecular\
      \ similarity to cutaneous melanoma,\ncommonly involving BRAF, NRAS, NF1, and\
      \ TERT promoter mutations."
    explanation: The cutaneous-like driver landscape of conjunctival melanoma is the
      molecular correlate of its UV aetiology.
- name: Arc Welding Exposure
  presence: PRESENT
  description: >-
    Occupational arc-welding exposure is a reported but not firmly established
    risk association for uveal melanoma. It is included here because GeneReviews
    lists avoidance of arc welding as an explicit primary-prevention measure for
    germline BAP1 carriers, making it actionable in that population even though
    causality in the general population remains uncertain.
  effect: RISK_FACTOR
  evidence:
  - reference: PMID:27748099
    reference_title: BAP1 Tumor Predisposition Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Prevention of primary manifestations: UM: avoid arc-welding."
    explanation: GeneReviews Agents/Circumstances to Avoid guidance naming arc welding
      as a uveal melanoma exposure to avoid in BAP1-TPDS.
- name: Oculodermal Melanocytosis (Nevus of Ota)
  presence: PRESENT
  description: >-
    Congenital oculodermal melanocytosis is an established host risk factor for
    uveal melanoma. It shares the same initiating lesion - nevus of Ota carries
    somatic GNAQ mutations - providing a genetic link between the benign
    melanocytic proliferation and the malignancy that occasionally arises in it.
    Absolute risk remains low (of the order of 1 in 400).
  effect: RISK_FACTOR
  evidence:
  - reference: PMID:19078957
    reference_title: Frequent somatic mutations of GNAQ in uveal melanoma and blue
      naevi.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Our findings identify GNAQ as a genetic link between nevus of Ota and
      uveal melanoma and help explain why nevi of Ota are a risk factor for uveal
      melanoma7. The risk is small, as only about 1 in 400 nevi of Ota progress to
      uveal melanoma
    explanation: Directly establishes nevus of Ota as a uveal melanoma risk factor
      and quantifies the small absolute risk.

treatments:
- name: Plaque Brachytherapy
  description: >-
    Episcleral radioactive plaque (typically iodine-125 or ruthenium-106)
    sutured over the tumour base. The globe-preserving first-line local therapy
    for most small and medium uveal melanomas, achieving high local control.
    Radiation retinopathy, maculopathy, optic neuropathy, cataract and
    neovascular glaucoma are the principal late toxicities. Local control does
    not reduce metastatic risk, because dissemination generally predates
    treatment.
  therapeutic_modality: RADIOTHERAPY
  treatment_term:
    preferred_term: episcleral plaque brachytherapy
    term:
      id: NCIT:C15195
      label: Brachytherapy
  target_mechanisms:
  - target: Uveal Melanocyte Transformation and Intraocular Tumour Growth
    treatment_effect: INHIBITS
    description: >-
      Ionising radiation delivered to the tumour base ablates the transformed
      uveal melanocyte clone while preserving the globe.
  evidence:
  - reference: PMID:29765944
    reference_title: 'Uveal Melanoma: 5-Year Update on Incidence, Treatment, and Survival
      (SEER 1973-2013).'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A corresponding increase \nwas observed in radiation as primary treatment\
      \ selection (1.3% from 1973 to 1975 \nvs. 68.3% from 2012 to 2013)."
    explanation: Documents radiotherapy displacing surgery as the primary local treatment
      for uveal melanoma in the United States.
  notes: >-
    The SEER analysis also shows that this shift to globe-preserving radiation
    did not improve five-year relative survival, which is the clearest available
    demonstration that local therapy choice does not alter metastatic outcome.
- name: Proton Beam Radiotherapy
  description: >-
    Charged-particle external-beam radiotherapy delivering a sharply conformal
    dose via the Bragg peak. Used for tumours unsuitable for plaque
    brachytherapy - large tumours, juxtapapillary or macular locations - with
    comparable local control.
  therapeutic_modality: RADIOTHERAPY
  treatment_term:
    preferred_term: proton beam radiation therapy
    term:
      id: NCIT:C66897
      label: Proton Beam Radiation Therapy
  target_mechanisms:
  - target: Uveal Melanocyte Transformation and Intraocular Tumour Growth
    treatment_effect: INHIBITS
    description: >-
      Conformal charged-particle irradiation ablates the intraocular tumour with
      a steep dose fall-off that spares adjacent critical ocular structures.
  evidence:
  - reference: PMID:39456591
    reference_title: Proton Therapy in Uveal Melanoma.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Proton therapy offers significant \nadvantages for thicker uveal melanomas\
      \ (over 8 mm) due to its unique physical \nproperties, including a rapid dose\
      \ fall-off that protects critical structures \nlike the retina and optic nerve."
    explanation: Documents the Bragg-peak dose fall-off and the specific indication
      for thicker tumours and optic-nerve proximity described in this treatment.
- name: Enucleation
  description: >-
    Surgical removal of the globe. Reserved for very large tumours, extensive
    ciliary-body or optic-nerve involvement, extrascleral extension, or a blind
    painful eye. Excellent local control at the cost of the eye, and - as the
    SEER-era data show - without a corresponding survival advantage over
    globe-preserving radiotherapy.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: eye enucleation
    term:
      id: NCIT:C198837
      label: Eye Enucleation
  target_mechanisms:
  - target: Uveal Melanocyte Transformation and Intraocular Tumour Growth
    treatment_effect: INHIBITS
    description: >-
      Removal of the globe physically eliminates the intraocular tumour.
  evidence:
  - reference: PMID:29765944
    reference_title: 'Uveal Melanoma: 5-Year Update on Incidence, Treatment, and Survival
      (SEER 1973-2013).'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "There was a decline in patients treated with surgery alone \n(94.2%\
      \ from 1973 to 1975 vs. 24.7% from 2012 to 2013)."
    explanation: Documents the historical role of enucleation and its decline as globe-preserving
      options matured.
- name: Tebentafusp
  description: >-
    A gp100 x CD3 bispecific ImmTAC (immune-mobilising monoclonal T-cell
    receptor against cancer): an affinity-enhanced soluble T-cell receptor that
    binds the gp100 peptide-HLA-A*02:01 complex on melanoma cells, fused to an
    anti-CD3 arm that recruits polyclonal T cells to kill them. The first and
    only systemic agent with a randomised overall-survival benefit in metastatic
    uveal melanoma, sustained at three years. Restricted to HLA-A*02:01-positive
    patients (roughly half). Toxicity is dominated by early, self-limiting
    cytokine-mediated events and by on-target attack on normal melanocytes -
    rash in 83%, pyrexia in 76%, pruritus in 70% - but discontinuation for
    toxicity is rare (2%).
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: tebentafusp
      term:
        id: NCIT:C94208
        label: Tebentafusp
  target_mechanisms:
  - target: gp100-Directed T-Cell Redirection
    treatment_effect: ACTIVATES
    description: >-
      Tebentafusp is the agent that instantiates this mechanism, bridging the
      gp100-HLA-A*02:01 complex on tumour cells to CD3 on polyclonal T cells.
  - target: Hepatic Metastatic Colonisation
    treatment_effect: INHIBITS
    description: >-
      Redirected T-cell killing of gp100-positive metastatic deposits is the
      route by which tebentafusp prolongs survival in liver-dominant disease.
  evidence:
  - reference: PMID:34551229
    reference_title: Overall Survival Benefit with Tebentafusp in Metastatic Uveal
      Melanoma.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "CONCLUSIONS: Treatment with tebentafusp resulted in longer overall survival\
      \ than \nthe control therapy among previously untreated patients with metastatic\
      \ uveal \nmelanoma."
    explanation: The pivotal randomised phase 3 conclusion establishing tebentafusp's
      survival benefit.
  - reference: PMID:37870955
    reference_title: Three-Year Overall Survival with Tebentafusp in Metastatic Uveal
      Melanoma.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The most common treatment-related adverse events of any grade in the\
      \ tebentafusp group were rash (83%), pyrexia (76%), pruritus \n(70%), and hypotension\
      \ (38%)."
    explanation: Documents the characteristic toxicity profile described here.
- name: Immune Checkpoint Blockade
  description: >-
    Anti-PD-1 (pembrolizumab, nivolumab) and anti-CTLA-4 (ipilimumab)
    antibodies, alone or combined. Included here specifically to record a
    negative result: despite transforming cutaneous melanoma, checkpoint
    blockade has only marginal activity in metastatic uveal melanoma, because
    the tumour's low mutational burden yields few neoantigens and the ocular
    microenvironment is immune-privileged. It remains a fallback when
    tebentafusp is unavailable or the patient is not HLA-A*02:01-positive, and
    is a more rational option in conjunctival melanoma, whose immunobiology
    resembles cutaneous melanoma.
  therapeutic_modality: MONOCLONAL_ANTIBODY
  treatment_term:
    preferred_term: immunotherapy
    term:
      id: NCIT:C15262
      label: Immunotherapy
    therapeutic_agent:
    - preferred_term: pembrolizumab
      term:
        id: NCIT:C106432
        label: Pembrolizumab
    - preferred_term: ipilimumab
      term:
        id: NCIT:C2654
        label: Ipilimumab
    - preferred_term: nivolumab
      term:
        id: NCIT:C68814
        label: Nivolumab
  target_mechanisms:
  - target: Low Tumour Mutational Burden and Checkpoint Refractoriness
    treatment_effect: MODULATES
    description: >-
      Checkpoint blockade acts on this node but is largely defeated by it:
      relieving PD-1/CTLA-4 inhibition cannot generate a response when few
      neoantigens are presented in the first place.
  evidence:
  - reference: PMID:34551229
    reference_title: Overall Survival Benefit with Tebentafusp in Metastatic Uveal
      Melanoma.
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "In this open-label, phase 3 trial, we randomly assigned previously untreated\
      \ HLA-A*02:01-positive patients with metastatic uveal melanoma in a 2:1 \nratio\
      \ to receive tebentafusp (tebentafusp group) or the investigator's choice of\
      \ \ntherapy with single-agent pembrolizumab, ipilimumab, or dacarbazine (control\
      \ \ngroup)"
    explanation: Checkpoint inhibitors constituted the comparator arm that tebentafusp
      outperformed, quantifying their limited benefit in metastatic uveal melanoma.
  - reference: PMID:34015548
    reference_title: 'Conjunctival melanoma: New insights in tumour genetics and immunology,
      leading to new therapeutic options.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "While immunotherapy is currently sparsely effective in \nintraocular\
      \ tumours such as UM, the similarities between CoM and cutaneous \nmelanoma\
      \ (including in their immunological tumour micro environment) provide \nhope\
      \ for the application of immunotherapy in CoM"
    explanation: Directly supports both halves of this treatment's framing - checkpoint
      blockade is sparsely effective in uveal disease but rational in conjunctival
      melanoma.
- name: Wide Local Excision with Adjuvant Cryotherapy
  description: >-
    The standard local treatment for conjunctival melanoma: a "no-touch"
    complete excision with wide margins and careful specimen orientation,
    combined with cryotherapy to the conjunctival margins to eradicate residual
    atypical intraepithelial melanocytes. Adjuvant topical mitomycin C or
    interferon, plaque or proton radiotherapy, and - for orbital invasion -
    exenteration are added according to margin status, multifocality and depth
    of invasion. Recurrence remains common because the precursor lesion is a
    field rather than a discrete mass.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: excision with adjuvant margin cryosurgery
    term:
      id: NCIT:C15215
      label: Cryosurgery
  target_mechanisms:
  - target: Conjunctival Melanocytic Intraepithelial Neoplasia
    treatment_effect: INHIBITS
    description: >-
      Margin cryotherapy ablates residual atypical intraepithelial melanocytes,
      addressing the precursor field that drives recurrence.
  - target: UV-Associated BRAF/NRAS/NF1 Driver Activation
    treatment_effect: INHIBITS
    description: >-
      Complete no-touch excision physically removes the invasive driver-mutant
      clone.
  evidence:
  - reference: PMID:39335093
    reference_title: 'Conjunctival Melanoma: A Clinical Review and Update.'
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "Due to its rarity, there is limited \nevidence for diagnosis and management;\
      \ hence, there is no standardised treatment \nand not all cases are referred\
      \ to a specialised ocular oncology centre."
    explanation: Records the important caveat that conjunctival melanoma management
      is not standardised and rests on limited evidence, which is why this treatment
      is curated as PARTIAL.
- name: Percutaneous Hepatic Perfusion with Melphalan
  description: >-
    Liver-directed regional chemotherapy: melphalan is infused into the hepatic
    artery while hepatic venous effluent is captured and filtered
    extracorporeally, delivering a hepatic dose far above what systemic
    administration would tolerate. This is the therapeutic answer to the
    hepatotropism modelled in this entry - the liver is the dominant and often
    only metastatic site, so treating it regionally is disease-appropriate rather
    than palliative. In a randomised study against best alternative care, all
    efficacy endpoints favoured melphalan/hepatic delivery system, though the
    trial converted to a single-arm design because of slow accrual and its
    comparative analyses are therefore exploratory. Other liver-directed options
    used in practice include resection or ablation of oligometastatic disease,
    and chemo-, radio- or immunoembolization.
  therapeutic_modality: DEVICE
  treatment_term:
    preferred_term: percutaneous hepatic perfusion
    term:
      id: NCIT:C148433
      label: Percutaneous Hepatic Perfusion
    therapeutic_agent:
    - preferred_term: melphalan
      term:
        id: CHEBI:28876
        label: melphalan
  target_mechanisms:
  - target: Hepatic Metastatic Colonisation
    treatment_effect: INHIBITS
    description: >-
      Regional high-dose chemotherapy is delivered to the hepatic niche in which
      metastatic uveal melanoma colonises and grows.
  evidence:
  - reference: PMID:40192993
    reference_title: An Open-label, Randomized Study of Melphalan/Hepatic Delivery System
      Versus Best Alternative Care in Patients with Unresectable Metastatic Uveal Melanoma.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Melphalan/Hepatic Delivery System (Melphalan/HDS) is a drug/medical device\
      \ combination used for \nliver-directed treatment of unresectable mUM patients."
    explanation: Identifies the liver-directed modality curated here and its indication
      in unresectable metastatic uveal melanoma.
  - reference: PMID:40192993
    reference_title: An Open-label, Randomized Study of Melphalan/Hepatic Delivery System
      Versus Best Alternative Care in Patients with Unresectable Metastatic Uveal Melanoma.
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "Exploratory analyses of \nefficacy endpoints showed numerical differences\
      \ consistently favoring the \nMelphalan/HDS arm versus BAC (median overall survival:\
      \ 18.5 vs. 14.5 months; \nmedian progression-free survival: 9.1 vs. 3.3 months;\
      \ objective response rate: \n27.5% vs. 9.4%; and disease control rate: 80.0% vs.\
      \ 46.9%)."
    explanation: Gives the efficacy signal. Marked PARTIAL because the trial was
      amended to a single-arm design and the authors themselves designate these
      comparisons exploratory rather than confirmatory.
  notes: >-
    Only percutaneous hepatic perfusion is curated as a discrete treatment because
    it is the liver-directed modality with randomised comparative data. Resection
    or ablation of oligometastatic disease, chemoembolization, radioembolization
    and immunoembolization are all used in practice but are supported here only by
    the deep-research narrative, so they are described rather than asserted.
- name: BAP1 Carrier Ocular Surveillance and Genetic Counselling
  description: >-
    For individuals with a germline BAP1 pathogenic variant, GeneReviews
    recommends annual dilated eye examination from age 11-18 years (or puberty)
    with referral to an ocular oncologist for any pigmented lesion, alongside
    cascade genetic testing of at-risk relatives once a familial variant is
    known. Because BAP1-related uveal melanoma behaves like a class-2 /
    monosomy-3 tumour, treatment of a detected tumour should follow the more
    aggressive pathway rather than being de-escalated for early detection.
    This is a surveillance and counselling intervention, not a mechanism-directed
    therapy, so it deliberately carries no target_mechanisms link.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:27748099
    reference_title: BAP1 Tumor Predisposition Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "UM: \nannual dilated eye examinations beginning at age 11-18 years or\
      \ at puberty with \nreferral to ocular oncologist for any pigmented lesions."
    explanation: GeneReviews surveillance recommendation for uveal melanoma in BAP1
      carriers, as described here.
  - reference: PMID:27748099
    reference_title: BAP1 Tumor Predisposition Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "UM treatment should be the same as the more \naggressive class 2 or monosomy\
      \ 3 tumors because of the increased aggressiveness \nof BAP1-related UM."
    explanation: GeneReviews management guidance that BAP1-related uveal melanoma be
      treated as aggressive class-2 disease, exactly as stated here.
  - reference: PMID:27748099
    reference_title: BAP1 Tumor Predisposition Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Once a germline BAP1 pathogenic variant has been identified \nin an affected\
      \ family member, predictive testing for at-risk family members and \nprenatal and\
      \ preimplantation genetic testing are possible."
    explanation: Supports the cascade-testing component of this intervention.
- name: Darovasertib
  description: >-
    An oral selective protein kinase C inhibitor targeting the PKC node
    immediately downstream of mutant Gq/G11 - the most direct available
    pharmacological attack on the initiating lesion of uveal melanoma. In
    phase 2 neoadjuvant/adjuvant evaluation for localised disease
    (NCT05907954), with endpoints including tumour shrinkage, conversion from
    enucleation to radiation, and metastasis-free survival. Investigational;
    not standard of care.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: darovasertib
      term:
        id: NCIT:C124796
        label: Darovasertib
  target_mechanisms:
  - target: PLC-beta/PKC/MAPK Cascade Activation
    treatment_effect: INHIBITS
    description: >-
      Selective PKC inhibition interrupts the cascade at the step immediately
      downstream of the constitutively active Gq/G11 alpha subunit.
  evidence:
  - reference: clinicaltrials:NCT05907954
    reference_title: (Neo)Adjuvant IDE196 (Darovasertib) in Patients With Localized
      Ocular Melanoma
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Neoadjuvant/adjuvant IDE196 (darovasertib) in patients with primary uveal
      melanoma
    explanation: Names darovasertib specifically and its neoadjuvant/adjuvant use in
      primary uveal melanoma, replacing an earlier generic pathway-inhibitor quote
      that did not mention the drug.

clinical_trials:
- name: NCT03070392
  phase: PHASE_III
  status: ACTIVE_NOT_RECRUITING
  description: >-
    IMCgp100-202: randomised open-label phase 3 trial of tebentafusp versus
    investigator's choice (pembrolizumab, ipilimumab or dacarbazine) in
    previously untreated HLA-A*02:01-positive metastatic uveal melanoma. The
    trial that established the first overall-survival benefit in this disease.
    Curated as PHASE_III on the strength of the NEJM report ("In this open-label,
    phase 3 trial"); note that the ClinicalTrials.gov registered title still reads
    "A Phase II Randomized, Open-label, Multi-center Study", a legacy of an earlier
    protocol version.
  target_phenotypes:
  - preferred_term: Uveal melanoma
    term:
      id: HP:0007716
      label: Uveal melanoma
  - preferred_term: Neoplasm of the liver
    term:
      id: HP:0002896
      label: Neoplasm of the liver
  evidence:
  - reference: PMID:34551229
    reference_title: Overall Survival Benefit with Tebentafusp in Metastatic Uveal
      Melanoma.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "(Funded by Immunocore; ClinicalTrials.gov number, NCT03070392; EudraCT\
      \ \nnumber, 2015-003153-18.)."
    explanation: Identifies the NCT registration for the pivotal tebentafusp trial.
  - reference: clinicaltrials:NCT03070392
    reference_title: A Phase II Randomized, Open-label, Multi-center Study of the Safety
      and Efficacy of IMCgp100 Compared With Investigator Choice in HLA-A*0201 Positive
      Patients With Previously Untreated Advanced Uveal Melanoma
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: To evaluate the overall survival of HLA-A\\*0201 positive adult patients
      with previously untreated advanced UM receiving IMCgp100 compared to Investigator's
      Choice of dacarbazine, ipilimumab, or pembrolizumab.
    explanation: ClinicalTrials.gov record giving the trial's overall-survival primary
      objective and the checkpoint-inhibitor comparator arm.
- name: NCT05907954
  phase: PHASE_II
  status: UNKNOWN
  description: >-
    Neoadjuvant and adjuvant darovasertib (IDE196), an oral PKC inhibitor, in
    localised ocular melanoma. Endpoints include tumour shrinkage, conversion of
    planned enucleation to globe-preserving radiation, reduction of radiation
    dose to critical ocular structures, and long-term recurrence and metastasis
    outcomes.
  target_phenotypes:
  - preferred_term: Uveal melanoma
    term:
      id: HP:0007716
      label: Uveal melanoma
  evidence:
  - reference: clinicaltrials:NCT05907954
    reference_title: (Neo)Adjuvant IDE196 (Darovasertib) in Patients With Localized
      Ocular Melanoma
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Neoadjuvant/adjuvant IDE196 (darovasertib) in patients with primary uveal
      melanoma
    explanation: ClinicalTrials.gov record confirming the neoadjuvant/adjuvant
      darovasertib trial in primary uveal melanoma.
  notes: >-
    Recruitment status is recorded as UNKNOWN rather than asserted: the cached
    ClinicalTrials.gov summary does not expose a recruitment-status field, so no
    status claim is made. No peer-reviewed results publication was available at
    the time of curation.

diagnosis:
- name: Ophthalmic examination and ocular ultrasonography
  description: >-
    Uveal melanoma is usually diagnosed clinically by an ocular oncologist,
    without biopsy, on dilated fundus examination (slit-lamp examination for
    anterior tumours) combined with A- and B-scan ultrasonography. Ultrasound is
    the workhorse: melanoma is characteristically low-reflective and acoustically
    "hollow", which separates it from the high-reflectivity of choroidal
    haemangioma and metastasis. Optical coherence tomography and fundus
    autofluorescence add subretinal-fluid and lipofuscin detail that discriminate
    a small melanoma from a naevus.
  diagnosis_term:
    preferred_term: ultrasound imaging
    term:
      id: NCIT:C17230
      label: Ultrasound Imaging
  results: >-
    A dome-shaped or collar-button pigmented choroidal mass with low internal
    reflectivity, acoustic hollowness and subretinal fluid supports uveal melanoma.
  evidence:
  - reference: PMID:34775516
    reference_title: Vasculogenic mimicry correlates to presenting symptoms and mortality
      in uveal melanoma.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The tumor \neye had also been examined with slit lamp biomicroscopy,\
      \ \nultrasonography, and fundus photography."
    explanation: Documents the actual diagnostic work-up used in a uveal melanoma
      cohort - slit-lamp biomicroscopy, ultrasonography and fundus photography - which
      is precisely the modality set curated here.
  - reference: PMID:34775516
    reference_title: Vasculogenic mimicry correlates to presenting symptoms and mortality
      in uveal melanoma.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The tumor's api-\ncal thickness, largest basal diameter (LBD), and location\
      \ in \nthe choroid had been noted."
    explanation: Confirms that tumour thickness, largest basal diameter and choroidal
      location are the measurements this examination yields - the parameters that drive
      staging and the naevus-versus-melanoma distinction.
- name: Prognostic molecular and cytogenetic testing
  description: >-
    Fine-needle aspiration or resection tissue is used for prognostication rather
    than for diagnosis. Chromosome 3, 8q and 6p status is assessed by FISH, SNP
    array, MLPA or NGS, with sequencing of BAP1, SF3B1 and EIF1AX. This is what
    assigns a tumour to the high-risk (monosomy 3 / BAP1-null / class 2),
    intermediate (SF3B1) or low-risk (disomy 3 / EIF1AX / class 1) group that the
    pathophysiology section models, and it sets hepatic surveillance intensity.
  diagnosis_term:
    preferred_term: genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  results: >-
    Monosomy 3 with BAP1 loss indicates high metastatic risk; disomy 3 with
    EIF1AX mutation indicates low risk; SF3B1 mutation indicates intermediate risk
    with characteristically late relapse.
  evidence:
  - reference: PMID:28810145
    reference_title: Integrative Analysis Identifies Four Molecular and Clinical Subsets
      in Uveal Melanoma.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Comprehensive multiplatform analysis of 80 uveal melanomas (UM) identifies\
      \ four \nmolecularly distinct, clinically relevant subtypes: two associated with\
      \ \npoor-prognosis monosomy 3 (M3) and two with better-prognosis disomy 3 (D3)."
    explanation: Establishes the chromosome-3-anchored molecular classification that
      this test assigns.
  - reference: PMID:23793026
    reference_title: Exome sequencing identifies recurrent somatic mutations in EIF1AX
      and SF3B1 in uveal melanoma with disomy 3.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mutations were infrequent (2/35; \n5.7%) in uveal melanomas with monosomy\
      \ 3, which are associated with poor \nprognosis."
    explanation: Supports the mutual near-exclusivity of the SF3B1/EIF1AX and monosomy-3
      groups that makes this a discriminating prognostic test.
- name: Melanocytic immunohistochemistry and nuclear BAP1 staining
  description: >-
    On biopsy or enucleation specimens, melanocytic lineage is confirmed with
    SOX10, S100, Melan-A/MART1 and HMB45. Loss of nuclear BAP1 immunostaining is
    used as an inexpensive surrogate for BAP1 inactivation and therefore for
    high metastatic risk, and it is also the key discriminator against
    non-melanocytic ocular-surface lesions such as ocular surface squamous
    neoplasia.
  diagnosis_term:
    preferred_term: immunohistochemical test
    term:
      id: NCIT:C51944
      label: Immunohistochemical Test
  results: >-
    Positive melanocytic markers confirm melanoma; loss of nuclear BAP1 staining
    indicates a BAP1-inactivated, high-risk tumour.
  evidence:
  - reference: PMID:21051595
    reference_title: Frequent mutation of BAP1 in metastasizing uveal melanomas.
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "Inactivating somatic mutations were identified in the gene encoding \
      BRCA1-associated protein 1 (BAP1) on chromosome 3p21.1 in 26 of 31 (84%) \
      metastasizing tumors"
    explanation: Establishes BAP1 inactivation as the marker that nuclear BAP1
      immunostaining is used to detect; the immunohistochemical surrogate itself is
      described rather than separately evidenced, hence PARTIAL.
- name: Hepatic metastatic surveillance imaging
  description: >-
    Because roughly half of uveal melanoma patients metastasise, almost always to
    the liver, and because local control does not change that risk, risk-adapted
    hepatic imaging (ultrasound, CT or MRI) is performed indefinitely after
    treatment, with interval set by the molecular risk group. A clinically
    important negative: normal liver function tests do NOT exclude hepatic
    metastasis and must not be used as a substitute for imaging.
  diagnosis_term:
    preferred_term: diagnostic imaging
    term:
      id: NCIT:C16502
      label: Diagnostic Imaging Testing
  results: >-
    Detection of hepatic lesions on surveillance imaging establishes metastatic
    disease, typically before symptoms and often with normal liver chemistry.
  evidence:
  - reference: PMID:37628989
    reference_title: Genetic and Epigenetic Features of Uveal Melanoma-An Overview and
      Clinical Implications.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "however, the absence of rising LFT values cannot lead to the exclusion\
      \ of liver metastases."
    explanation: Sources the clinically important negative recorded here - normal liver
      function tests cannot rule out hepatic metastasis.
  - reference: PMID:34775516
    reference_title: Vasculogenic mimicry correlates to presenting symptoms and mortality
      in uveal melanoma.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The metastasis screen-\ning of the liver was then repeated by ultrasonography\
      \ or by \nCT semi-annually for a 5-year period after diagnosis."
    explanation: Documents a real hepatic surveillance protocol - repeat liver
      ultrasonography or CT at six-monthly intervals - matching the risk-adapted
      imaging described here.

differential_diagnoses:
- name: Choroidal Naevus
  description: >-
    A benign choroidal melanocytic lesion, orders of magnitude commoner than
    choroidal melanoma and the single most frequent lesion to be distinguished
    from it. Naevi and melanomas share the same GNAQ/GNA11 initiating mutation,
    so the distinction is not molecular but clinical and morphological.
  distinguishing_features:
  - Flat or minimally elevated (under about 2 mm thickness) and under about 5 mm
    in basal diameter, whereas melanoma is thicker and larger
  - No subretinal fluid, orange lipofuscin pigment, or symptoms; each of these
    features shifts the diagnosis toward melanoma
  - Stable on serial imaging - documented growth is the decisive discriminator
  - Overlying drusen or a surrounding halo favour a naevus; ultrasonographic
    acoustic hollowness favours melanoma
  evidence:
  - reference: PMID:19078957
    reference_title: Frequent somatic mutations of GNAQ in uveal melanoma and blue
      naevi.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: In our experiments, GNAQ behaves similar to the oncogenes, BRAF and NRAS,
      in that its mutation is insufficient for full progression to melanoma.
    explanation: Explains why the naevus/melanoma distinction cannot be made on the
      shared GNAQ driver alone and must rest on clinical and morphological features.
  notes: >-
    Deliberately left with NO bound disease_term. MONDO has no distinct
    "choroidal naevus" class at the time of curation, and the nearest ocular
    melanocytic-naevus concept - nevus of Ota / oculodermal melanocytosis
    (MONDO:0016984) - is a periorbital-dermal and scleral melanocytosis, not a
    choroidal naevus; binding it here would be semantically wrong. Per the
    dismech review convention, no term is preferable to a misleading one. A
    dedicated choroidal-naevus MONDO term is a candidate new-term request.
    Nevus of Ota is separately (and correctly) curated in this entry as a uveal
    melanoma risk factor under environmental.
- name: Choroidal Haemangioma
  description: >-
    A benign vascular choroidal tumour that can mimic an amelanotic choroidal
    melanoma, presenting with an elevated subretinal mass and exudative
    detachment.
  distinguishing_features:
  - Orange-red colour rather than pigmented
  - High internal reflectivity on A-scan ultrasonography, whereas melanoma is
    characteristically low-reflective and acoustically hollow
  - Early intense hyperfluorescence with late washout on indocyanine-green
    angiography
  - Diffuse (rather than circumscribed) choroidal haemangioma suggests
    Sturge-Weber syndrome
  disease_term:
    preferred_term: hemangioma of choroid
    term:
      id: MONDO:0021542
      label: hemangioma of choroid
- name: Choroidal Metastasis
  description: >-
    Metastatic carcinoma to the choroid is actually the commonest intraocular
    malignancy overall - commoner than primary uveal melanoma - most often from
    breast or lung primaries, and must be excluded before treating a presumed
    primary melanoma.
  distinguishing_features:
  - Creamy-yellow and plateau-shaped rather than pigmented and dome or
    collar-button shaped
  - Frequently multifocal and bilateral, whereas uveal melanoma is almost always
    unilateral and unifocal
  - Usually accompanied by a known extraocular primary tumour and systemic
    disease
  - High internal reflectivity on ultrasonography
  disease_term:
    preferred_term: metastatic malignant neoplasm in the eye
    term:
      id: MONDO:0044913
      label: metastatic malignant neoplasm in the eye
- name: Retinoblastoma
  description: >-
    The commonest primary intraocular malignancy of childhood, and the key
    age-based differential for an intraocular mass. Arises from the retina via
    biallelic RB1 inactivation, not from melanocytes.
  distinguishing_features:
  - Presents in early childhood, about 95% before age 5, versus adult onset for
    uveal melanoma
  - Arises in the retina and is non-pigmented
  - Characteristic intralesional calcification on ultrasound or CT, which uveal
    melanoma does not show
  - Leukocoria or strabismus as presenting signs
  - Definitive on RB1 genetics and on histology (Flexner-Wintersteiner rosettes)
  disease_term:
    preferred_term: retinoblastoma
    term:
      id: MONDO:0008380
      label: retinoblastoma
  evidence:
  - reference: PMID:39200222
    reference_title: 'Uveal Melanoma: Comprehensive Review of Its Pathophysiology,
      Diagnosis, Treatment, and Future Perspectives.'
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: Uveal melanoma (UM) is the most common intraocular malignancy in adults.
    explanation: The qualifier "in adults" is the axis on which retinoblastoma, the
      commonest paediatric intraocular malignancy, is separated from uveal melanoma.
- name: Conjunctival Naevus
  description: >-
    A benign conjunctival melanocytic lesion, and the principal differential for
    a pigmented conjunctival spot. Common, usually juxtalimbal, and typically
    present since childhood or adolescence.
  distinguishing_features:
  - Characteristically contains clear intralesional cysts
  - Mobile over the underlying sclera, whereas melanoma may be fixed
  - Stable in size and pigmentation over years; new adult-onset pigmentation or
    documented growth favours melanoma
  - Confined to the bulbar conjunctiva; palpebral or forniceal involvement
    favours melanoma and warrants excisional biopsy
  - Absence of feeder vessels and of surrounding flat diffuse pigmentation
  disease_term:
    preferred_term: conjunctival nevus
    term:
      id: MONDO:0006172
      label: conjunctival nevus
- name: Ocular Surface Squamous Neoplasia
  description: >-
    The main non-melanocytic differential for a limbal ocular-surface mass,
    spanning conjunctival intraepithelial neoplasia to invasive squamous cell
    carcinoma. Shares the UV-exposed limbal niche and the risk-factor profile
    (UV, fair skin, older age, immunosuppression, HPV) with conjunctival
    melanoma.
  distinguishing_features:
  - Gelatinous, papilliform or leukoplakic pink-to-white appearance rather than
    a pigmented lesion
  - Prominent feeder vessels at the limbus
  - Amelanotic conjunctival melanoma can look very similar and is a recognised
    source of misdiagnosis, so clinical appearance alone is not sufficient
  - Histology with melanocytic immunohistochemistry (SOX10, Melan-A, HMB45) is
    definitive
  disease_term:
    preferred_term: ocular surface squamous neoplasia
    term:
      id: MONDO:0971056
      label: ocular surface squamous neoplasia
  evidence:
  - reference: PMID:39335093
    reference_title: 'Conjunctival Melanoma: A Clinical Review and Update.'
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "Co-M is often \nmisdiagnosed or overlooked, leading to vision loss either\
      \ from the destructive \neffects of the tumour or side effects of therapy"
    explanation: Confirms that conjunctival melanoma is frequently misdiagnosed, which
      is why the ocular-surface differential is clinically important.

classifications:
  icdo_morphology:
    classification_value: Melanoma
  harrisons_chapter:
  - classification_value: ONCOLOGY_HEMATOLOGY

notes: >-
  Scope and relationship to sibling entries. This entry is the umbrella
  (root-with-subtypes) node for ocular melanoma. The uveal arm is curated in
  greater depth in the separate Uveal_Melanoma entry (MONDO:0006486), which
  declares this entry as a parent; the material here is deliberately organised
  around what the umbrella adds - the uveal-versus-conjunctival contrast, the
  driver-to-prognosis chain, the hepatotropic dissemination mechanism, and the
  checkpoint-refractory/ImmTAC therapeutic logic.

  Module conformance decisions. Conformance is declared against
  sustaining_proliferative_signaling (all three module nodes: the GNAQ/GNA11
  lesion as the oncogenic growth-signal lesion, the PLC-beta/PKC/MAPK cascade as
  constitutive mitogenic pathway activation, and uveal melanocyte transformation
  as growth-factor-independent proliferation) and against
  invasion_and_metastasis at its Circulatory Survival and Extravasation and
  Metastatic Colonization nodes, which is where uveal melanoma's lymphatic-free
  haematogenous route and hepatic-niche colonisation genuinely sit.

  Conformance to immune_checkpoint_blockade is deliberately NOT declared. That
  module models adaptive immune resistance in which an anti-tumour T-cell
  response drives PD-L1 upregulation and exhaustion - a mechanism whose
  therapeutic corollary is that checkpoint inhibition works. Uveal melanoma is
  the opposite case: the tumour mutational burden is low, few neoantigens are
  presented, checkpoint blockade is largely ineffective, and the therapeutic
  solution (tebentafusp) works precisely by bypassing neoantigen-dependent
  recognition. Declaring that conformance would assert the wrong mechanism.
  Conformance to genome_instability_mutation is likewise withheld: uveal
  melanoma is a low-mutational-burden cancer whose progression is driven by a
  small number of specific chromosomal events (monosomy 3, 8q gain) rather than
  by a mutator phenotype.

  Curation caveats. HPO has no dedicated conjunctival melanoma class, so the
  conjunctival presenting lesion is coded to the generic HP:0000502 and disease
  identity is carried by the MONDO:0002096 subtype binding. MONDO likewise has
  no distinct choroidal naevus class, so the choroidal-naevus differential is
  deliberately left with NO bound disease_term - the nearest concept, nevus of
  Ota (MONDO:0016984), is a periorbital-dermal and scleral melanocytosis rather
  than a choroidal naevus, and binding it would be misleading. A dedicated
  choroidal-naevus MONDO term is a reasonable new-term request. Nevus of Ota is
  separately and correctly curated here as a uveal melanoma risk factor under
  environmental. Cytogenetic events
  (monosomy 3, 8q gain, 6p gain) and the DecisionDx-UM gene-expression-profile
  classes are described in prose but are not curated as structured genetic items
  because they are chromosomal and transcriptional, not gene-level, assertions.

references:
- reference: PMID:41097064
  title: 'Ocular Melanoma: A Comprehensive Review with a Focus on Molecular Biology.'
  found_in:
  - Ocular_Melanoma-deep-research-falcon.md
- reference: PMID:39335093
  title: 'Conjunctival Melanoma: A Clinical Review and Update.'
  found_in:
  - Ocular_Melanoma-deep-research-falcon.md
- reference: PMID:39055896
  title: Biological characteristics and clinical management of uveal and conjunctival
    melanoma.
  found_in:
  - Ocular_Melanoma-deep-research-falcon.md
- reference: PMID:39200222
  title: 'Uveal Melanoma: Comprehensive Review of Its Pathophysiology, Diagnosis, Treatment,
    and Future Perspectives.'
  found_in:
  - Ocular_Melanoma-deep-research-falcon.md
- reference: PMID:38920653
  title: Recent Advances in Molecular and Genetic Research on Uveal Melanoma.
  found_in:
  - Ocular_Melanoma-deep-research-falcon.md
- reference: PMID:37628989
  title: Genetic and Epigenetic Features of Uveal Melanoma-An Overview and Clinical
    Implications.
  found_in:
  - Ocular_Melanoma-deep-research-falcon.md
- reference: PMID:37870955
  title: Three-Year Overall Survival with Tebentafusp in Metastatic Uveal Melanoma.
  found_in:
  - Ocular_Melanoma-deep-research-falcon.md
- reference: PMID:34775516
  title: Vasculogenic mimicry correlates to presenting symptoms and mortality in uveal
    melanoma.
- reference: PMID:19667335
  title: Metastasis of uveal melanoma millimeter-by-millimeter in 8033 consecutive
    eyes.
- reference: PMID:39456591
  title: Proton Therapy in Uveal Melanoma.
- reference: PMID:27748099
  title: BAP1 Tumor Predisposition Syndrome.
  tags:
  - GeneReviews

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References & Deep Research