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Review

Conjunctival Melanoma: A Clinical Review and Update

by
Karam Butt
1,
Rumana Hussain
2,3,
Sarah E. Coupland
1,3 and
Yamini Krishna
1,3,*
1
National Specialist Ophthalmic Pathology Service, Liverpool Clinical Laboratories, Liverpool University Hospitals NHS Foundation Trust, Liverpool L7 8YE, UK
2
St Paul’s Eye Unit, Liverpool University Hospitals NHS Foundation Trust, Liverpool L7 8YE, UK
3
Department of Eye and Vision Science, Institute of Life Course and Medical Science, University of Liverpool, Liverpool L7 8TX, UK
*
Author to whom correspondence should be addressed.
Cancers 2024, 16(18), 3121; https://doi.org/10.3390/cancers16183121
Submission received: 19 July 2024 / Revised: 6 September 2024 / Accepted: 9 September 2024 / Published: 10 September 2024
(This article belongs to the Special Issue Current Progress and Research Trends in Ocular Oncology)
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Abstract

:

Simple Summary

Conjunctival melanoma (Co-M) is a rare and aggressive eye surface cancer. It is often misdiagnosed or overlooked, leading to late diagnosis. Co-M can cause sight loss and even eye loss, impacting quality-of-life. The numbers of new cases globally are rising at alarming rates. There is no standard treatment for Co-M and management varies between eye cancer centres. In ~25% of cases the cancer spreads elsewhere in the body, which can lead to death. The aim of this review is to concisely present what is currently known about Co-M presentation, its development and progression, clinical management and outcomes, and finally summarise future directions for research into novel therapies.

Abstract

Conjunctival melanoma (Co-M) is an aggressive, invasive eye and eyelid cancer. Its global incidence of ~1 in a million is increasing at a rate ratio of ~1.4, but this rises sharply in over 65-year-olds. Although rare, Co-M has a devastating impact on the lives of those who develop it. 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. 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. Recent progress in cancer immunology and genetics have revolutionised the treatment of cutaneous melanomas, which share some similarities to Co-M. Importantly, a better understanding of Co-M and its precursor lesions is urgently needed to lead to the development of novel targeted and immunotherapies both for local tumour control and disseminated disease. 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 personalised treatment of this disease.

1. Introduction

Conjunctival melanoma (Co-M) is a rare, aggressive invasive ocular surface cancer, which is often misdiagnosed or overlooked and causes significant visual disabilities, poor quality of life and even death from metastases. They occur most commonly in fair-skinned populations, with the overall incidence being approximately 0.46 cases per 1,000,000 persons per year [1,2], representing around 0.25% of melanomas at all sites and 5% of all ocular melanomas. It is the second most prevalent malignancy of the conjunctiva after squamous cell carcinoma [3] originating from the basal melanocytes in the conjunctival epithelium. The majority (~70%) of Co-M cases develop from conjunctival melanocytic intraepithelial lesions (C-MIN/PAM with atypia), while others arise from pre-existing naevi or are de novo [3,4].
Previous studies have often grouped Co-M with uveal melanoma as an ocular melanoma: the latter is the most common primary intraocular malignancy in adults, arising in the choroid, ciliary body or iris; however, uveal melanoma is embryologically, biologically and clinically very different to Co-M [5,6,7,8,9]. Unlike uveal melanoma, Co-M is a mucosal melanoma with histological and functional similarities to cutaneous melanoma [10,11] and similar genetic alterations. These include UV-related driver mutations in the BRAF, NF1 and RAS genes and copy number variations [6,12,13,14,15,16,17,18,19]. BRAF and NRAS mutations are present in ~30% and ~14–25% of Co-M, respectively, with the NRAS mutant Co-M being associated with higher metastatic risk [13,16]. Transcriptomic studies of Co-M that have focussed on the immune tumour microenvironment have also demonstrated high PDL1-expression and a transcriptomic subtype enriched with immune-system-related genes (immune cell-types) [12,20,21].
Clinically, Co-M most often presents in the bulbar conjunctiva, near the limbus, but can affect any part of the conjunctiva and even invade the neighbouring structures in advanced cases [4,22]. Lesions vary from amelanotic to brown pigmented or even black in colour. There is no standardised treatment; however, management includes surgical excision +/− adjuvant cryotherapy, topical chemotherapy, brachytherapy, proton beam radiotherapy or photon external beam radiation and, in advanced cases with local tissue invasion, radical orbital exenteration [18,22,23,24,25,26,27]. Postoperative complications and tumour recurrence rates are high (33–45%), warranting life-long follow-up [4,28,29,30,31]. Metastases to the lymph nodes are common (~25%) but may also involve the liver, lungs and brain, with ~27% 5-year disease-specific mortality rates [32,33].
Despite recent successes with targeted and immunotherapies in cutaneous melanoma, data on Co-M treated with similar therapies (anti-BRAF/anti-MEK/anti-PDL1) are promising but limited, often stemming from a single patient or small case series with inoperable or advanced disease prior to surgery [34,35,36,37,38].
This review article aims to summarise the current understanding of Co-M and explore new advancements in the knowledge of Co-M pathophysiology, classification, prognostication and its treatment developments.

2. Epidemiology

The incidence of Co-M has increased over the last 5 decades [14,39] and ranges from 0.3 to 0.8 per million per year, being highest in Northern Europe and North America. The estimated number of new cases per year is 130 in the USA and 320 in Europe [18]. Populations of Asian or African descent are less commonly affected [2,40,41,42,43]. A study in the US found that fair-skinned people had the highest incidence rate of Co-M, comprising 91.2% of cases compared to 2.4% in patients of Afro-Caribbean descent [44]. However, with majority of data coming from predominantly North America or Europe, there is very limited data on other ethnic groups. Co-M mainly affects patients in their fifth or sixth decades and above; it is rare in children and there is no gender predilection [14,39,40,45,46]. The disease-specific survival rate for Co-M is approximately 82.9% at 5 years and 69.3% at 10 years [30,40].

3. Precursor Lesions, Aetiology and Pathogenesis of Co-M

Approximately 70% of Co-Ms arise from conjunctival melanocytic intraepithelial lesions (C-MIL), also known as conjunctival melanocytic intraepithelial neoplasia (C-MIN) or primary acquired melanosis (PAM) with atypia, whilst a smaller proportion develop from pre-existing naevi or are de novo [3,4,47,48]. C-MIL, a precursor or preinvasive disease to Co-M, encompass a spectrum of morphological changes ranging from melanocytic hyperplasia through degrees of melanocytic atypia to melanoma in situ [49]. C-MIL shares the same demographics but may occasionally occur in teenagers and young adults. In a North American analysis of 311 eyes with C-MIL, 96% of the cases were in White individuals and 4% were in Blacks, Hispanics, or Asians, with a patient age range of 15–90 years (mean: 56 years) [23,50].
Both C-MIL and Co-M most frequently develop in the interpalpebral zone, suggesting an association with ultraviolet (UV) radiation [45], with a number of studies revealing UV signatures (C > T transitions) [12,51,52,53]. However, both can also develop in non-sun-exposed sites, but the mechanisms for this are unknown [18].
Driver mutations and copy number variations in multiple chromosomes have been described in Co-M, with high-frequency mutations in the NF1 (33–50%), BRAF (29–46%), NRAS (11–26%) and ATRX (25%) genes [6,7,12,13,14,15,16,17,54,55,56,57,58,59]. The latter often occurs together with an NF1 mutation [13]. NRAS mutations are associated with higher metastatic risk [13,17]. TERT promoter mutations have also been identified in up to 54% of Co-Ms [13,17,60,61] and even in PAM with atypia (~8%) [62]. While activating TERT promoter mutations are associated with a poor prognosis, mutually exclusive inactivating ATRX mutations appear to be associated with a better prognosis [13,17,36,60]. Cisarova et al. demonstrated that the TGCA-proposed genomic classification of cutaneous melanoma (defined by the most frequently mutated genes: BRAF, NF1, RAS and triple wild-type) was also applicable to Co-M [12]. A summary of the common gene mutations is presented in Table 1. Other rarer mutations have been reported in the genes, such as CTNNB1, ACSS3, RET, TP53, CKIT, TET2, CDKN2A, MAPK2, RAC1, MET, SF3B1, GNAQ and GNA11 [12,13,16,63,64,65]. Transcriptomic studies in Co-M focusing on the immune tumour microenvironment have demonstrated high PDL1-expression, and a transcriptomic subtype enriched with immune-system-related genes (immune cell-types) [12,20,21]

4. Clinical Presentation and Assessment

Co-M is often unilateral and can affect any part of the conjunctiva, but commonly presents on the bulbar surface, near the limbus (Figure 1). Invasion of the cornea, eyelid, sclera or orbit may occur in advanced tumours [4]. The lesions vary in size, shape and colour. Nodular masses may be well circumscribed, while flat lesions may have irregular, ill-defined margins, especially where there is adjacent C-MIL. Their colour may range from amelanotic (pinkish) to various shades of brown or even black and be patchy or mixed within the one lesion [70]. Patients may present on noticing a mass with/without pigmentation on their eye but can also have significant visual morbidities, such as irritation/burning with redness and reflex tearing, dry eye, pain, vision disturbance, double vision or vision loss [4,71,72].
The differential diagnoses of Co-M include benign conjunctival nevi, extraocular extension of uveal melanoma or melanocytoma (black lesions), pigmented conjunctival squamous cell carcinoma or, very rarely, metastasis of cutaneous melanoma. In amelanotic lesions, the differentials also include conjunctival squamous intraepithelial neoplasia, squamous cell carcinoma or lymphoma [72]. Lack of cysts (often observed in conjunctival nevi), tumour haemorrhage, large/deep tumours, tortuous feeder vessels, adherence to underlying and invasion into surrounding structures, and multifocal lesions favour melanoma over conjunctival nevus [73]. Histological assessment in a specialist centre regularly reporting ophthalmic specimens is essential for accurate diagnosis and grading.
C-MIL are unilateral but most often multifocal, can involve any part of the conjunctiva (bulbar, limbal, forniceal and palpebral, in order of decreasing frequency) (Figure 1) and may extend to the caruncle, plica and cornea. They appear as mobile, flat, irregular brown-pigmented conjunctival discolorations that may change over time [14,22,23,39,40,50]. Rarely, C-MIL can be amelanotic, making it diagnostically challenging [22,23]. Differential diagnoses of C-MIL include benign epithelial melanosis, oculodermal melanocytosis, conjunctival nevi, Co-M, pigmented conjunctival squamous intraepithelial neoplasia [74], Addison’s disease [75], post-inflammatory hyperpigmentation and conjunctival tattooing [76].
Imaging of all conjunctival melanocytic lesions involves regular anterior segment photo-documentation (including with eversion of eyelids), slit lamp biomicroscopy and possibly ultrasound (to estimate tumour thickness or look for orbital involvement). There are recent developments in anterior segment optical coherence tomography [77,78] and in vivo reflectance confocal microscopy [79]. Where Co-M has locally extended into the eyelid, and particularly if there is any suspicion of orbital or nasolacrimal invasion, MRI has a critical role in the assessment; diffusion and perfusion-weighted imaging can help in differentiating Co-M from other eyelid masses [80].

5. Histomorphological Features

Co-M shares similar histomorphological features to those of cutaneous or other mucosal invasive melanomas [81]. The intraepithelial (radial) component can be nested, pagetoid, lentiginous or, rarely, absent. It can also extend beyond the invasive component and involve adjacent structures. The invasive stromal (vertical) component can comprise nests or sheets of atypical melanocytes with cytomorphology ranging from small naevoid-type cells to highly atypical pleomorphic melanocytes with spindle or epithelioid types. Nuclei can be hyperchromatic with inconspicuous nucleoli or vesicular with prominent eosinophilic nucleoli (Figure 2). Ulceration, mitotic activity, angiotropism, satellites in transit metastases and neurotropism may be seen. A pre-existing nevus also may be present. Melanophages and variable lymphocytic infiltrate are also often observed. Increased mitoses (>5.5 mitoses/mm2) have been associated with nodal metastasis; ulceration and a greater tumour thickness have been associated with increased mortality, similar to skin melanoma [82,83].
The key histomorphological features in C-MIL are the increased cellularity/hyperplasia of the intraepithelial conjunctival melanocytes with increasing cytological atypia, but the basement membrane remains intact [81,84,85]. The spectrum of cytological features ranges from small melanocytes with nuclear hyperchromasia and scant cytoplasm to severely atypical large pleomorphic epithelioid cells with ample cytoplasm and prominent eosinophilic nucleoli. The range of atypical architectural patterns include linear hyperplasia of the basal melanocytes to a confluent lentiginous spread, intraepithelial nests, pagetoid growth and full-thickness epithelial involvement by atypical melanocytes, i.e., melanoma in situ. Nests, pagetoid spread and confluent growth extend upward from the basal epithelium, displacing squamous and/or goblet cells; however, there should be no evidence of invasive growth [49,81,84,85]. Epithelioid cell morphology with cytological atypia, nesting and pagetoid spread are associated with an increased risk of recurrence and progression to Co-M [23,81,84,86,87].
Terminologies more commonly used to classify these lesions include PAM with atypia and C-MIN and the most recently validated C-MIL [85,88]. Various grading or scoring systems have been used for C-MIL [22,75,84,85,87,89,90,91]. The grading of the cytological atypia in PAM (mild, moderate or severe), which was similar to those used in the skin and other mucosal sites [84,86], suffered from poor reproducibility between pathologists. The C-MIN scoring system was based on architectural features (i.e., horizontal and vertical spread) and cytological atypia but could be time consuming and complex [89].
In 2018, the fourth ‘WHO Classification of Eye Tumours’ proposed the C-MIL classification, simplifying the grading of these lesions and capturing their risk of disease progression to invasive melanoma [92]. This comprised: (1) low-grade C-MIL (corresponding to PAM with or without mild atypia or C-MIN scores 1–2; (2) high-grade C-MIL (PAM with moderate to severe atypia or C-MIN 3–5); and (3) conjunctival melanoma in situ (PAM with severe atypia involving > 75% of the epithelium or a C-MIN score > 5). The system was validated in 2021 and it was found that all three classification systems (C-MIL, C-MIN and PAM) had comparable accuracy in their ability to identify lesions with potential for recurrence [85]. In 2022, the editorial panel of the fifth edition decided to revise the classification scheme because the low-grade C-MIL in the fourth edition incorporated both non-neoplastic and neoplastic melanocytic proliferations. This led to the current system as summarised in Table 2 [49]. This was validated by a large international collaborative study and found to have substantial interobserver agreement, good reproducibility, be predictive of recurrence and invasive disease and, importantly, inform clinical treatment thresholds [88]. Photomicrographs demonstrating the C-MIL scoring grades are presented in Figure 3 [88].
All conjunctival melanocytic lesions immunohistochemically show MelanA (MART1), S100, SOX10, HMB45 (the latter should only be present in superficial areas of naevi) and MITF (Melanocyte Inducing Transcription Factor). Nuclear expression of PRAME (Preferentially expressed Antigen in Melanoma), cyclin D1 positivity and loss of p16 on immunohistochemistry can also be helpful in distinguishing Co-M from naevi or low-grade C-MIL (both PRAME and cyclin D1 negative, p16 positive) [57,88,93,94,95,96]. PD-L1 may be expressed [97].
Melanoma in situ and Co-M are staged by the AJCC/UICC TNM eighth edition system, which has been validated for the development of metastasis and survival [98,99,100].

6. Treatment and Prognosis

Approximately 70% of all Co-M arises from high-grade C-MIL [75]; hence, there is an absolute clinical need to know when to treat patients [22,23,88]. There is no standard-of-care treatment for C-MIL or Co-M; consequently, management varies considerably between ophthalmic and specialised ocular oncology centres. This includes: surgical excision (wide local) +/− amniotic membrane allograft and +/− adjuvant cryotherapy, topical chemotherapy (mitomycin C, 5-fluorouracil or interferon alpha-2b), radiotherapy (brachytherapy, proton beam or photon external beam) or radical orbital exenteration for advanced cases with local tissue invasion [4,22,23,32,72].
The reported usefulness of sentinel lymph node biopsy (SLNB) is variable (in terms of clinical management and sensitivity of pickup) but has been shown to be effective for Co-Ms > 2 mm thickness and/or >10 mm in diameter [101].
The postoperative complication rate (vision loss, scarring, limbal stem cell failure, ulceration/non-healing defects, etc.) and risk of tumour recurrence are very high (33–61%), warranting close life-long follow-up [4,28,29,30,31,72]. Lymph node metastases are common (~25–52%; preauricular, parotid, submandibular and/or cervical nodes, depending on Co-M location) but metastasis may also involve the liver, lungs and brain (11–42%). Indicators/risk factors of poor prognosis for nodal and systemic metastases include a non-epibulbar locations, ulceration and increased tumour thickness [32,33,47,48,82,83]. The 5-year and 10-year disease-specific mortality rates are ~14–27% and 25–35%, respectively [4,30,32,33,47,48,72,102]. Similarly to the risk of metastases, tumour-related death has been associated with a de novo origin, non-bulbar conjunctival location, nodular growth, multifocal lesions and sentinel lymph node positivity [4,30,43,83,103].
The use of genetics for prognostication in Co-M is currently limited. However, as mentioned above, Co-M has genetic alterations similar to those of cutaneous melanoma, and advances in characterising Co-M genetics are offering insight into potential targeted therapies that are already in use for the treatment of cutaneous melanoma. Data on Co-M (anti-BRAF; anti-MEK; anti-PD-L1) with targeted/immunotherapies have shown promising results but are limited, with only those from small case series or single case studies in patients with inoperable disease or as first-line therapy prior surgery in advanced cases [18,34,35,38,104]. A summary of the targeted, immune checkpoint inhibitor and combination therapies is presented in Table 3 [34,35,38,51,105,106,107,108,109,110,111,112,113,114,115,116,117]. A Phase 2 clinical trial using a combination of axitinib and nivolumab in untreated advanced or metastatic mucosal melanoma (head and neck and conjunctival; NCT05384496) is underway.

7. Future Direction and Conclusions

Co-M is a rare, aggressive, invasive eye and eyelid cancer with increasing global incidence. Given the rarity of Co-M, international collaboration is pivotal to obtain sufficient numbers in order to progress translational research and enlist Co-M patients into clinical trials. The recent developments in cancer genetics and immunology present exciting new frontiers for better understanding Co-M pathogenesis and, importantly, provide new targets for therapy. Insight into the molecular drivers for Co-M development and its integration with clinical and histomorphological evaluation will allow earlier diagnosis, improve risk stratification and prognostication, and identify patients for specific therapies (i.e., ‘personalised/precision medicine’). This will further enable the development of clear management guidelines and enrolment into targeted therapies earlier than current practice, facilitating improved outcomes in this rare disease.

Author Contributions

Conceptualization, Y.K.; writing—original draft preparation, K.B. and Y.K.; writing—review and editing, K.B., Y.K., R.H. and S.E.C.; supervision, Y.K. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Conflicts of Interest

The authors declare no conflicts of interest.

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Cancers 16 03121 g001
Figure 1. Anterior segment photographs of low- and high-grade C-MIL (preinvasive disease) and Co-M (invasive disease). The actual grading was confirmed on histomorphological assessment.
Figure 1. Anterior segment photographs of low- and high-grade C-MIL (preinvasive disease) and Co-M (invasive disease). The actual grading was confirmed on histomorphological assessment.
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Cancers 16 03121 g002
Figure 2. Co-M histological micrographs. Haematoxylin and eosin staining photomicrographs showing an orbital exenteration specimen with Co-M at low magnification (top left), medium (top right) and higher magnification (bottom left).
Figure 2. Co-M histological micrographs. Haematoxylin and eosin staining photomicrographs showing an orbital exenteration specimen with Co-M at low magnification (top left), medium (top right) and higher magnification (bottom left).
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Figure 3. Photomicrographs representing the C-MIL grading system. Haematoxylin and eosin section with corresponding immunohistochemistry for each of the C-MIL scoring grades [88].
Figure 3. Photomicrographs representing the C-MIL grading system. Haematoxylin and eosin section with corresponding immunohistochemistry for each of the C-MIL scoring grades [88].
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Table 1. Common genetic mutations in the conjunctival naevi, primary acquired melanosis (PAM) without atypia, PAM with atypia, and conjunctival melanoma (Co-M). The number of cases and their respective percentages are presented. NAD = No available data.
Table 1. Common genetic mutations in the conjunctival naevi, primary acquired melanosis (PAM) without atypia, PAM with atypia, and conjunctival melanoma (Co-M). The number of cases and their respective percentages are presented. NAD = No available data.
Conjunctival Naevi (%)PAM without Atypia (%)PAM with Atypia (%)Prevalence in
Co-M (%)
BRAF14/28 (50%) [54]
13–23 (56%) [58]
7/37 (19%) [55]
9/12 (75%) [14]
15/35 (43%) [57]		0/11 (0%) [54]
0/17 (0%) [55]		0/4 (0%) [54]
0/13 (0%) [55]
2/8 (25%) [14]		4/15 (27%) [64]
3/21 (14%) [5]
12/22 (55%) [7]
23/78 (29%) [56]
2/5 (40%) [54]
10/39 (26%) [55]
39/111 (35%) [14]
4/53 (8%) [65]
31/101 (31%) [13]
16/47 (34%) [16]
13/28 (46%) [17]
4/14 (29%) [12]
23/78 (29%) [60]
11/31 (35%) [57]
5/22 (23%) [59]
16/63 (25%) [15]
7/15 (47%) [66]
3/12 (25%) [67]
10/38 (26%) [61]
1/8 (13%) [51]
NRAS9/23 (39%) [58]NADNAD0/11 (0%) [64]
14/78 (18%) [56]
25/95 (26%) [13]
5/47 (11%) [16]
6/28 (21%) [17]
1/14 (7%) [12]
11/63 (17%) [15]
4/15 (27%) [66]
3/12 (25%) [67]
5/38 (13%) [61]
3/8 (38%) [51]
KIT0/5 (0%) [63]NAD1/3 (33%) [63]1/13 (8%) [64]
0/42 (0%) [56]
0/8 (0%) [63]
6/53 (11%) [65]
2/47 (4%) [16]
2/28 (7%) [17]
TERT0/56 (0%) [62]0/14 (0%) [62]2/25 (8%) [62]12/38 (32%) [61]
16/39 (41%) [62]
20/47 (43%) [60]
15/24 (54%) [17]
9/14 (64%) [12]
34/78 (43%) [60]
7/15 (47%) [66]
26/58 (45%) [68]
NF1NADNADNAD21/63 (33%) [15]
29/74 (39%) [13]
7/14 (50%) [12]
17/47 (36%) [16]
3/15 (20%) [66]
1/5 (20%) [69]
3/8 (38%) [51]
ATRX0/16 (0%) [68] *0/6 (0%) [68] *2/5 (40%) [68] *17/68 (25%) [13]
5/8 (63%) [51]
8/59 (14%) [68] *
1/5 (20%) [69]
* ATRX protein detection by immunohistochemistry.
Table 2. The 2022 WHO classification of conjunctival melanocytic intraepithelial lesions (C-MIL) [49].
Table 2. The 2022 WHO classification of conjunctival melanocytic intraepithelial lesions (C-MIL) [49].
WHOAcceptable Alternative Terminology Increased Cellularity Histologic Features Progression Risk to Invasive Melanoma
Not applicable Benign melanosis
C-MIN (grades 0–1)
PAM without atypia		No/minimalConjunctival hypermelanosis (increased pigment in epithelial cells without melanocytic hyperplasia or atypia). Slight or focal melanocytic hyperplasia without atypia (parabasal melanocytes with condensed round nuclei, smaller than basal epithelial cell, inconspicuous nucleoli and inconspicuous cytoplasm) may be seen.None
Low-grade C-MILPAM with mild atypia
C-MIN (grades 2–4)		YesPredominantly basilar melanocytic proliferation with low-grade atypia (dendritic or small to moderate size polyhedral, usually non-epithelioid melanocytes with round to irregular nuclear contours, often nuclear hyperchromasia, inconspicuous nucleoli and inconspicuous or scant cytoplasm).Lower
High-grade C-MILPAM with moderate to severe atypia
C-MIN (grade 5–10)		YesMore confluent basilar and significant non-basilar proliferation of melanocytes with high-grade atypia (moderate to severe), evidence of intraepithelial nested and/or pagetoid growth and epithelioid cell cytomorphology.Higher
High-grade C-MILMelanoma in situYesThe term melanoma in situ may be used for (1) the most atypical high-grade C-MILs involving close to full thickness of the epithelium or (2) histologically obvious melanomas without documented evidence of subepithelial invasion.Highest
Table 3. Reported cases of targeted, immune checkpoint inhibitor and combination therapies used in primary and metastatic Co-M.
Table 3. Reported cases of targeted, immune checkpoint inhibitor and combination therapies used in primary and metastatic Co-M.
Study Patient Co-MPrimary Treatment Agent(s) Used Dosage (s) Outcome Adverse Reactions
Indicated for primary Co-M
[105]80y, female BRAF mutation Exenteration (rejected)Vemurafenib -Successful tumour response Tumour decreased in size 8 kg weight loss
Nausea, vomiting, headache
[35]94y, FemaleBulbar to eyelidNone (rejected exenteration) First—Pembrolizumab
Second—Pembrolizumab and ipilimumab 		Pembrolizumab, 200 mg;
Ipilimumab, 1 mg/kg		Progression
Died after 5 months 		None reported
[35]76y, MaleRecurrence Cornea to eyelid Local treatments and topical interferon-alpha chemotherapyFirst—ipilimumab
Second—Pembrolizumab
Third—Pembrolizumab and IFN-alpha		Pembrolizumab, 2 mg/kg every 3 weeksIpilimumab—no response
Pembrolizumab—minimal response, then complete with IFN-alpha		Ipilimumab—adrenal insufficiency
Pembrolizumab—dermatitis
[35]84y, FemaleRecurrence Cornea to eyelid Excision
Cryotherapy
Topical mitomycin
Eye plaque brachytherapy 		First—Pembrolizumab
Second—Pembrolizumab and ipilimumab
Third—Pembrolizumab, ipilimumab and IFN-alpha 		Pembrolizumab, 200 mg;
Ipilimumab, 1 mg/kg;
IFN-alpha, 3 million units per eyelid 		Pembrolizumab—minimal success
Pembrolizumab and ipilimumab—progression 		None reported
[106]53y, Female Bulbar to tarsal None Pembrolizumab 200 mg every 3 weeks Complete reduction of pigment and disease free 12 months of follow up Cutaneous pruritus
[51]70s y, FemaleBRAF v600e Diffuse bulbar and anterior orbit, lower eyelid margin
Left eye 		None Dabrafenib and trametinib -Regression after 3 months then excision
No local recurrence
Developed metastasis 1 year later		None reported
[107]61y, female Right upper eyelid and superior bulbar conjunctiva
BRAF v600e mutation
Recurrence 		Excision
Cryotherapy 		Dabrafenib and trametinib
Changed to vemurafenib after 1.5 months Changed to pembrozilumab after 3.5 months
Vemurafenib restarted after 2 months in addition to cobimetinib 		-Nearly complete resolution 1-month post-treatment
No evidence of distant spread of disease 23 months later 		Dabrafenib and trametinib—nausea and vomiting
[108]52y, male Right eye BRAF v600e
Mutlifocal recurrence 		Incisional biopsy Dabrafenib
Trametinib 		Dabrafenib twice daily 150 mg
Trametinib daily 2 mg 		Complete resolution after 10 months
Metastasis free after 15 months 		Fevers
Elevated liver enzymes
[109]60s, maleMultifocal recurrence, orbital and intraocular invasionExcision
Cryotherapy 		Pembrolizumab 150 mg every 3 weeks—18 cycles Alive without diseaseNone reported
Indicated for metastatic disease
[110]45y, male Metastatic Co-M (nodal, subcutaneous, pulmonary, osseous)
BRAF mutation v600e		Resection Vemurafenib960 mg twice daily Improvement in pain and subjective tumour regression after 1 month Disease progression 2 months into treatment. Enlarged paraspinal mass.
[111]53y, femaleMetastatic Co-M (orbit, parotid gland, lung, brain)
BRAF mutation v600e		Excision
Cryotherapy
Mitomycin eye drops
Enucleation 		Vemurafenib960 mg twice daily,
then changed to 720 mg twice daily due to skin rash 		Initially good response and reduction of mets; after 4 months reappearance of mets and death Skin rash
[38]70y, male Metastatic Co-M (parotid gland and lymph node)
BRAF mutation v600e		Excisional biopsy Dabrafenib
Trametinib		Dabrafenib (150 mg twice daily)
Trametinib (2 mg daily)		Reduction of lymph node metastasis activity Fever
[112]59y, female Metastatic Co-M (Oropharyngeal wall)
BRAF mutation v600		Excision Vemurafenib 960 mg twice daily, then later changed to 480 mg twice daily due to diarrhoea and skin rash Full symptomatic recovery after 1 month
Developed breast cancer 		Arthralgia, diarrhoea, skin rash
[112]51y, Male Co-M recurrence with metastasis (lymph)
No BRAF mutation 		Excision
Lymphadenectomy 		Pembrolizumab 2 mg/kg every 3 weeks Complete resolution of subcutaneous lesions None noted, patient on complete remission
[34]68y, Female Co-M recurrence
Metastasis—lung
BRAF v600e mutation		Resection
Topical mitomycin C
Exenteration, sentinel lymph node biopsy 		First—Pembrolizumab
Second—Ipilimumab and dacarbazine		Pembrolizumab, 2 mg/kg every 3 weeks;
Ipilimumab, 3 mg/kg;
Dacarbazine, 800–1000 mg/m2 		Pembrolizumab—stable at 6 months Ipilimumab and dacarbazine—hepatotoxicity
[34]58y, Female Co-M recurrence to orbit
Metastasis—lung and liver 		Multiple resections
Orbital exenteration 		nivolumab3 mg/kg every 2 weeks Complete resolution or orbit and metastasis lesions Elevated liver enzymes
[34]28y, FemaleCo-M recurrence
Metastasis—breast, lung and bone 		Excision
Cryotherapy
Topical mitomycin C 		nivolumab3 mg/kg every 2 weeksComplete resolution None reported
[34]47y, FemaleCo-M recurrence
Metastasis—lung 		Excision
Cryotherapy
Radiotherapy Topical interferon
Mitomycin C 		nivolumab3 mg/kg every 2 weeksResolution of lung metastasis and free from disease 7 months after nivolumab Diarrhoea
[34]74y, MaleCo-M recurrence
Metastasis—lung 		Multiple excision nivolumab3 mg/kg every 2 weeksDecrease in tumour size
Disease free 1 month after nivolumab		Colitis
[113]72y, MaleRecurrent Co-M
Metastasis—Lung and lymph 		Debulking and sentinel lymph node biopsy
Radioactive iodine 125		Ipilimumab 3 mg/kg every 3 weeks Satisfactory response to treatment and excellent local tumour control Mild fatigue
[35]72y, FemaleEpibulbar
BRAF v600k Metastasis—liver, lung, bone, skin, lymph node		Local excision and topical chemotherapy Ipilimumab and nivolumab Ipilimumab, 3 mg/kg;
Nivolumab, 1 mg/kg 		Resolution of subcutaneous nodulesReduction of systemic tumour burdenHepatotoxicity Colitis
[35]76y, FemaleNRAS mutation
Metastasis—lymph, skin 		Excision
Cryotherapy Topical mitomycin chemotherapy 		First—ipilimumab
Second—ipilimumab Third—Pembrolizumab		Ipilimumab, 3 mg/kg;
Pembrolizumab, 200 mg 		Ipilimumab—new skin metastases and lymph metastases None reported
[114]71y, Male Co-M recurrence
BRAF v600e
Metastasis—bone and liver		Excision
Cryotherapy Vemurafenib		Nivolumab
Dabrafenib and trametinib 		-Died 24 months after combined therapyVemurafenib—keratinous nodules
[114]72y, Male Bulbar BRAF v600e Co-M with lymph node metastasis Excision
Cryotherapy
Mitomycin C eye drops 		Dabrafenib and trametinib -No signs of recurrence after 6 months None reported
[106]66y, MaleFornix and orbit
Metastasis—lung and liver 		None Ipilimumab and nivolumab -Resolution of lesion and good response to metsPituitary failure
[115]60y, female Recurrent conjunctival melanoma NRAS mutation
Liver metastasis		Excision at 3 and 7 months Cryotherapy Ipilimimab and nivolumab—2 cycles Nivolumab—3 cycles
Pembrolizumab—9 cycles 		Ipilimimab 3 mg/kg
Nivolumab, 1 mg/kg
Nivolumab, 240 mg every 2 weeks 2 cycles, then 480 mg every 4 weeks
Pembrol zumab, 200 mg 		Remained stable after 2 years Ipilimimab and nivolumab—hepatitis
Nivolumab—infusion reaction
[116]89y, female Recurrence BRAF v600e right conjunctiva
Distant metastasis 		Resection Encorafenib
Binimetinib 		Encorafenib 450 mg once daily;
Binimetinib 45 mg twice daily 		Reduction in size of primary tumour and distant metastases after 6 months None reported
[117]60y, female Recurrence and metastasis to lymph and nasal cavity (BRAF negative)Excisional biopsy
Cryotherapy 		Ipilimumab
Nivolumab 		Ipilimumab 1 mg/kg;
Nivolumab 3 mg/kg		25% reduction in size of nasal cavity mass, which persisted after 16 months
No evidence of recurrence at one-year follow-up 		None reported
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Butt, K.; Hussain, R.; Coupland, S.E.; Krishna, Y. Conjunctival Melanoma: A Clinical Review and Update. Cancers 2024, 16, 3121. https://doi.org/10.3390/cancers16183121

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Butt K, Hussain R, Coupland SE, Krishna Y. Conjunctival Melanoma: A Clinical Review and Update. Cancers. 2024; 16(18):3121. https://doi.org/10.3390/cancers16183121

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Butt, Karam, Rumana Hussain, Sarah E. Coupland, and Yamini Krishna. 2024. "Conjunctival Melanoma: A Clinical Review and Update" Cancers 16, no. 18: 3121. https://doi.org/10.3390/cancers16183121

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