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Simple Summary: Conjunctival melanoma (CM) is an aggressive cancer with an unmet need for prognostic biomarkers and more effective treatments. In recent years, a rapid increase in available epigenetic technologies and epigenetic modulation-based treatment options has led to the development/implementation of various epi-drugs in the cancer field. Like other cancers, CM occurrence and prognosis are also believed to be influenced by multiple genetic and epigenetic factors. While the genetic understanding of CM has been significantly improved in recent decades, the epigenetic understanding of CM remains limited. A relatively small number of CM epigenetics studies published to date have revealed some potential biomarkers and/or therapeutic targets; however, their results warrant replication in independent and larger studies/samples. Furthermore, not all epigenetic aspects of CM have been investigated in published studies; hence, an in-depth understanding of CM epigenetics remains largely incomplete. Additional studies are therefore urgently needed to advance our epigenetic understanding of CM and improve clinical outcomes by taking advantage of new therapy options driven by epigenetic knowledge. The purpose of this article is to provide a literature review of the epigenetic understanding of conjunctival melanoma (CM), with a primary focus on current gaps in knowledge and future directions in research. CM is a rare aggressive cancer that predominantly affects older adults. Local recurrences and distant metastases commonly occur in CM patients; however, their prediction and management remain challenging. Hence, there is currently an unmet need for useful biomarkers and more effective treatments to improve the clinical outcomes of these patients. Like other cancers, CM occurrence and prognosis are believed to be influenced by multiple genetic and epigenetic factors that contribute to tumor development/progression/recurrence/spread, immune evasion, and primary/acquired resistance to therapies. Epigenetic alterations may involve changes in chromatin conformation/accessibility, post-translational histone modifications or the use of histone variants, changes in DNA methylation, alterations in levels/functions of short (small) or long non-coding RNAs (ncRNAs), or RNA modifications. While recent years have witnessed a rapid increase in available epigenetic technologies and epigenetic modulation-based treatment options, which has enabled the development/implementation of various epi-drugs in the cancer field, the epigenetic understanding of CM remains limited due to a relatively small number of epigenetic studies published to date. These studies primarily investigated DNA methylation, ncRNA (e.g., miRNA or circRNA) expression, or RNA methylation. While these initial epigenetic investigations have revealed some potential biomarkers and/or therapeutic targets, they had various limitations, and their findings warrant replication in independent and larger studies/samples. In summary, an in-depth understanding of CM epigenetics remains largely incomplete but essential for advancing our molecular knowledge and improving clinical management/outcomes of this aggressive disease. [ABSTRACT FROM AUTHOR]

Introduction: Conjunctival melanoma (CM) is a rare but potentially lethal ocular malignancy that arises from melanocytes in the conjunctiva. Its clinical presentation can mimic other more common conjunctival lesions, such as squamous cell carcinoma (SCC), leading to diagnostic challenges. Case Presentation: We present a case of CM initially misdiagnosed as conjunctival SCC due to overlapping clinical features. Conclusion: CM presenting as nonpigmented, conjunctival tumor is a diagnostic challenge. Clinicians should maintain a high index of suspicion for conjunctival melanocytic or amelanotic lesions, particularly those with atypical features. [ABSTRACT FROM AUTHOR]

Conjunctival melanoma, an uncommon form of ocular melanoma, shares some molecular characteristics with cutaneous melanoma and some with mucosal melanoma. Treatment of cases where it becomes advanced or metastatic raises unique treatment challenges. Nivolumab/relatlimab (Opdualag) recently received FDA approval for metastatic melanoma based on the phase 2/3 RELATIVITY-047 trial, which showed better median progression-free survival (PFS) in the first-line setting without new safety signals. The efficacy of this drug in conjunctival melanoma has not been reported yet. Case presentation: An 87-year-old woman with a history of mild dementia was admitted to the oncology department with a large, exophytic tumor protruding from her left eye, diagnosed as conjunctival melanoma two years previously. This tumor was secreting a whitish fluid and obstructing her vision. Immunotherapy with Opdualag was started, with a near clinical complete response after the 1st cycle. The patient was treated with only four cycles due to worsening of her dementia. Conclusion: Nivolumab/relatlimab (Opdualag) is a promising treatment alternative in conjunctival melanoma when surgery is not viable. [ABSTRACT FROM AUTHOR]

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. 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. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the clinical features and prognosis of conjunctival melanoma in Japanese patients. Study design: Retrospective observational case series. Methods: Twenty patients (8 men and 12 women) diagnosed with conjunctival melanoma at a singlehospital between 2003 and 2017 were analyzed. Data on clinical presentation, sex, age, the affected eye, tumor location, tumor origin, tumor stage according to the American Joint Committee on Cancer staging system (eighth edition), treatment, outcomes, local recurrence, metastasis, and survival were extracted from the patients' medical records and reviewed. Results: The mean age at diagnosis was 64.2 ± 14.8 years. Tumor locations at the first examination included the bulbar conjunctiva (n = 19), plica (n = 13), and fornix (n = 12). The tumor stage was T1 in 5 cases (25%), T2 in 12 cases (60%), T3 in 3 cases (15%), and T4 in none. The mean follow-up duration was 91.7 ± 46.0 months. The local recurrence rates at 1, 5, and 10 years were 5.0%, 18.8%, and 31.5%, respectively, whilst the metastasis rates were 5.0%, 25.6%, and 32.4%, respectively. Four of the 6 patients who experienced metastasis died; duration from metastasis to death was 17.5 months (range, 7–25). The 5-year survival rate for conjunctival melanoma was 78.8%. Tumor thickness was significantly associated with survival duration on univariate Cox regression analyses. Conclusion: The mortality rate for conjunctival melanoma in the Japanese population was lower and higher than that reported in the Chinese and United States populations, respectively. Tumor thickness was a prognostic factor for survival in patients with conjunctival melanoma. [ABSTRACT FROM AUTHOR]

Introduction: Conjunctival melanoma (CM) is a rare but potentially lethal ocular malignancy that arises from melanocytes in the conjunctiva. Its clinical presentation can mimic other more common conjunctival lesions, such as squamous cell carcinoma (SCC), leading to diagnostic challenges. Case Presentation: We present a case of CM initially misdiagnosed as conjunctival SCC due to overlapping clinical features. Conclusion: CM presenting as nonpigmented, conjunctival tumor is a diagnostic challenge. Clinicians should maintain a high index of suspicion for conjunctival melanocytic or amelanotic lesions, particularly those with atypical features.

Uveal and conjunctival melanomas are relatively rare tumors; nonetheless, they pose a significant risk of mortality for a large number of affected individuals. The pathogenesis of melanoma at different sites is very similar, however, the prognosis for patients with ocular melanoma remains unfavourable, primarily due to its distinctive genetic profile and tumor microenvironment. Regardless of considerable advances in understanding the genetic characteristics and biological behaviour, the treatment of uveal and conjunctival melanoma remains a formidable challenge. To enhance the prospect of success, collaborative efforts involving medical professionals and researchers in the fields of ocular biology and oncology are essential. Current data show a lack of well-designed randomized clinical trials and limited benefits in current forms of treatment for these tumors. Despite advancements in the development of effective melanoma therapeutic strategies, all current treatments for uveal melanoma (UM) and conjunctival melanoma (CoM) remain unsatisfactory, resulting in a poor long-term prognosis. Ongoing trials offer hope for positive outcomes in advanced and metastatic tumors. A more comprehensive understanding of the genetic and molecular abnormalities involved in the development and progression of ocular melanomas opens the way for the development of personalized therapy, with various potential therapeutic targets currently under consideration. Increased comprehension of the molecular pathogenesis of UM and CoM and their specificities may aid in the development of new and more effective systemic therapeutic agents, with the hope of improving the prognosis for patients with metastatic disease. Graphic Abstract [ABSTRACT FROM AUTHOR]

Purpose: To identify high‐risk histopathologic and molecular features of local recurrence, nodal metastasis, distant metastasis (DM) and disease‐specific death (DSD) in conjunctival melanoma (CoM). Methods: Ninety patients with pathologically diagnosed CoM between 2008 and 2023 were enrolled. Immunohistochemistry staining of BRAFV600E, NRASQ61R, CD117, PD‐1 and PD‐L1 was performed in 65 and 45 patients, respectively. Cox regression and Kaplan–Meier survival analysis were conducted to identify risk factors for local recurrence, nodal metastasis, DM and DSD. Results: Pathologically, ulceration (hazard ratio [HR]: 3.170; 95% CI: 1.312–7.659; p = 0.01) and regression (HR: 3.196; 95% CI: 1.094–9.335; p = 0.034) were risk factors for DM. Tumour thickness ≥ 4 mm (HR: 4.889; 95% CI: 1.846–12.946; p = 0.001) and regression (HR: 4.011; 95% CI: 1.464–10.991; p = 0.007) were risk factors for DSD. For patients with tumour thickness < 4 mm, the presence of ulceration indicated a higher risk of nodal metastasis (log‐rank p = 0.0011), DM (log‐rank p = 0.00051) and DSD (log‐rank p = 0.02). Patients with regression (+)/tumour‐infiltrating lymphocytes (TILs) (+) had a higher risk for DM (log‐rank p = 0.011) and DSD (log‐rank p = 0.0032). Molecularly, the positive rate of BRAFV600E, NRASQ61R, CD117, PD‐1 and PD‐L1 was 40.00% (26/65), 43.08% (28/65), 70.77% (46/65), 46.67% (21/45) and 28.89% (13/45), respectively. Positive BRAFV600E was identified as an independent risk factor for DM (HR: 2.533; 95% CI: 1.046–6.136, p = 0.039). The expression level of BRAFV600E was positively correlated with vascular invasion (p = 0.01), as well as the expression levels of PD‐1 (p = 0.038) and PD‐L1 (p = 0.049). Conclusions: Tumour thickness ≥ 4 mm, ulceration, the coexistence of regression and TILs, and positive BRAFV600E were risk factors for poor prognosis of CoM patients. Besides, expression level of BRAFV600E was positively correlated with the expression levels of PD‐1 and PD‐L1. [ABSTRACT FROM AUTHOR]

Conjunctival melanoma, an uncommon form of ocular melanoma, shares some molecular characteristics with cutaneous melanoma and some with mucosal melanoma. Treatment of cases where it becomes advanced or metastatic raises unique treatment challenges. Nivolumab/relatlimab (Opdualag) recently received FDA approval for metastatic melanoma based on the phase 2/3 RELATIVITY-047 trial, which showed better median progression-free survival (PFS) in the first-line setting without new safety signals. The efficacy of this drug in conjunctival melanoma has not been reported yet.Case presentationAn 87-year-old woman with a history of mild dementia was admitted to the oncology department with a large, exophytic tumor protruding from her left eye, diagnosed as conjunctival melanoma two years previously. This tumor was secreting a whitish fluid and obstructing her vision. Immunotherapy with Opdualag was started, with a near clinical complete response after the 1st cycle. The patient was treated with only four cycles due to worsening of her dementia.ConclusionNivolumab/relatlimab (Opdualag) is a promising treatment alternative in conjunctival melanoma when surgery is not viable.

Purpose: To explore the role of ultraviolet radiation (UVR) in the occurrence and development of various ocular malignancies. Methods: In this article, we retrieved ocular malignancy data from the Global Cancer Observatory (GCO) and performed correlation analysis with the global UV index and sunshine duration. We searched for associated studies using the following databases: Embase, Pubmed, Cochrane Library, and Google Scholar. We conducted the literature by searching the Mesh terms denoting an exposure of interest (''UV radiation'', ''ultraviolet rays'', and ''ocular malignancies'', All studies included are published until December 30, 2023 without language restrictions. Results: The mechanisms and epidemiological statistics of UVR on the onset and progression of eyelid malignancies are the most studied and clear. The role of UVR in conjunctival melanoma is similar to that in eyelid melanoma. The relationship between uveal melanoma and UVR is controversial, however, it may have at least a certain impact on its prognosis. UVR causes ocular surface squamous neoplasia by further activating HPV infection. Conclusions: UVR is a decisive risk factor for ocular malignancies, but the incidence of ultraviolet-induced tumors is also affected by many other factors. A correct and comprehensive understanding of the mechanisms of UVR in the pathogenesis of ocular malignant tumors can provide patients with more effective and selective immune regulation strategies.

Purpose: Conjunctival melanoma with large corneal involvement is a rarity. We here present a case of conjunctival melanoma with pronounced central corneal involvement. Observation: A 69-year-old fair white male presented with a visual axis impeding corneal nodular lesion with associated conjunctival melanosis. Tumor excision with intraoperative mitomycin c (0.02 %) application for 180 seconds and amniotic membrane transplantation for defect coverage was performed in retrobulbar anesthesia. Histopathological evaluation revealed the nodular lesion to be a conjunctival melanoma (pT1a) with associated conjunctival melanocytic intraepithelial lesion (C-MIL). Conclusion and importance: Most conjunctival melanomas with corneal affection reach a radial corneal involvement of 1 mm. The here reported case accounted for 4 mm, which is seldom and therefore an important report. Surgical excision followed by intraoperative and postoperative mitomycin c exposure was a successful primary treatment. Currently there are no signs of tumor relapse in any part of the eye or the organism 12 months after excision. However, the long-term follow-up needs to be awaited.

Purpose: Conjunctival melanoma is a rare neoplasm with high rates of recurrence and metastasis. Traditional management includes surgical excision and cryotherapy, followed by adjuvant therapy as needed. Immune checkpoint inhibitors, including nivolumab, are a targeted treatment option with improved survival rates. However, various immune-related adverse effects have been reported with these drugs. While systemic granulomatous inflammation is a documented systemic side effect, it has rarely been reported in the conjunctiva and ocular adnexa. Observation: A patient with a history of recurrent metastatic conjunctival melanoma presented with both a left sub-conjunctival and upper eyelid lesion after the commencement of treatment with nivolumab. The lesions were excised with a clinical suspicion for metastasis and consisted of noncaseating granulomatous inflammation with no evidence of malignancy on histopathologic examination. Infectious and primary autoimmune etiologies were ruled out. Conclusion and importance: This is a biopsy-proven case of periocular immune checkpoint inhibitor-associated granulomatous inflammation.

Conjunctival melanoma (CM) has genetic characteristics that are similar to primary cutaneous melanoma (PCM). The management of advanced CM with orbital metastasis was limited until the adoption of novel immunotherapy agents that significantly improved the survival of metastatic PCM. To review and compare the immune checkpoint inhibitor (ICI) treatment response in cases reported in the English literature with orbital involvement secondary to CM versus PCM. In addition, we report a case of local recurrence of CM in a young female after successful treatment with ICI. In addition to reviewing the chart of one patient who presented to our clinic, we conducted a comprehensive literature review to identify CM cases and cases with orbital metastasis secondary to advanced CM and PCM. Outcomes included patient demographics, response to ICI, and associated adverse effects. There were ten cases with orbital involvement, four were secondary to CM, and six were metastasis from PCM. Orbital metastasis from PCM regressed following treatment with ICI agents, whereas those secondary to CM resolved completely. There were 19 cases of CM without orbital invasion. Of the 29 cases identified, complete resolution of ocular melanoma was achieved in 15 patients, representing 52% of the cases collectively, and none of them reported recurrence except in our case. CM with orbital invasion responds well to ICIs, with manageable toxic effects. Despite the complete resolution, close observation is needed as the recurrence risk remains. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate clinical and demographic characteristics and factors affecting recurrence, metastasis, and survival in conjunctival melanoma (CM). Methods: The clinical records of 45 patients who were treated for CM between October 1998 and June 2022 were retrospectively evaluated. Age, gender, presence of underlying conjunctival nevus-primary acquired melanosis (PAM), tumor stage according to the 8th edition of the American Joint Committee on Cancer (AJCC) staging system, tumor basal diameter, tumor thickness, lymph node (LN) involvement, metastasis, presence of tumor at the surgical margin, treatment method, need for adjuvant therapy, local tumor control, recurrence, and survival were recorded. Results: Twenty-one (46.7%) patients were female and 24 (53.3%) patients were male. The mean age at diagnosis was 53.2 ± 16.1 years. Median follow up time was 12 (1–300) months. Fifteen (33.3%) patients had conjunctival PAM; 2 (4.4%) patients had conjunctival nevus. The tumor stage was T1 in 24 (55.8%), T2 in 13 (30.2%), and T3 in 6 (14.0%) of the cases. The T stage in 2 cases could not be determined. For stage T1 and T2 CM, in addition to excisional biopsy (EB) and cryotherapy, alcohol epitheliectomy (AE) was performed in 17 cases (37.8%), superficial sclerectomy (SS) was performed in 7 (15.6%), and amnion membrane transplantation (AMT) due to a large conjunctival defect in 9 (20.0%). Six (14.0%) T3 cases underwent primary exenteration. Positive surgical margins were observed in 23 (51.1%) of the excised tumors at histopathologic examination. Adjuvant topical mitomycin-C (MMC) was used in 7 (30.4%) and strontium-90 episcleral brachytherapy in 4 (17.4%) of the 23 cases with tumor-positive borders. During the follow-up, recurrence was seen in 14 (31.1%) cases. According to Kaplan Meier analysis, the mean time to recurrence development was 90.5 ± 16.1 months and the 5-year recurrence free rate was 52.0%. Fourteen of the recurrent cases underwent EB + cryotherapy, 3 underwent AE + SS, and 3 underwent secondary exenteration. Metastasis and LN involvement occurred in 11 (24.4%) and 8 (17.8%) of the cases, respectively. Four (8.9%) cases expired during follow-up. According to Kaplan–Meier analysis, the mean time to metastasis was 106.2 ± 17.3 months and the 5-year metastasis free rate was 52.0%. While recurrence was more frequent in CM developing from PAM/nevus, metastasis was more frequent in men and those with LN involvement. Conclusion: Conjunctival melanoma was a malignant tumor with high recurrence and metastasis rates. Precursor nevus/PAM is a risk factor for recurrence, while male gender and regional LN involvement were risk factors for metastasis in this study. [ABSTRACT FROM AUTHOR]

Conjunctival melanoma (CM) is a rare but aggressive cancer. Over the past decade, molecular studies using rapidly advancing technologies have increasingly improved our understanding of CM genetics. CMs are mainly characterized by dysregulated MAPK and PI3K/AKT/mTOR pathways, driven by commonly mutated (BRAF, NRAS, NF1) or less commonly mutated (KIT, PTEN) genes. Another group of genes frequently mutated in CMs include TERT and ATRX, with known roles in telomere maintenance and chromatin remodeling/epigenetic regulation. Uveal melanoma-related genes (BAP1, SF3B1, GNAQ/11) can also be mutated in CMs, albeit infrequently. Additional CM-related mutated genes have increasingly been identified using more comprehensive genetic analyses, awaiting further confirmation in additional/larger studies. As a tumor arising in a partly sun-exposed mucosal tissue, CM exhibits a distinct genomic profile, including the frequent presence of an ultraviolet (UV) signature (and high mutational load) and also the common occurrence of large structural variations (distributed across the genome) in addition to specific gene mutations. The knowledge gained from CM genetic studies to date has led to new therapeutic avenues, including the use of targeted and/or immuno-therapies with promising outcomes in several cases. Accordingly, the implementation of tumor genetic testing into the routine clinical care of CM patients holds promise to further improve and personalize their treatments. Likewise, a growing knowledge of poor prognosis-associated genetic changes in CMs (NRAS, TERT, and uveal melanoma signature mutations and chromosome 10q deletions) may ultimately guide future strategies for prognostic testing to further improve clinical outcomes (by tailoring surveillance and considering prophylactic treatments in patients with high-risk primary tumors). [ABSTRACT FROM AUTHOR]

A study published in the International Journal of Dermatology examines the impact of sex on the presentation and survival of conjunctival melanoma. The study analyzed data from the Surveillance, Epidemiology, and End Results (SEER) database and found that male patients had a higher incidence of the disease compared to females. Female patients, however, had higher rates of advanced disease stages and thicker tumors at the time of diagnosis. Despite this, male patients had a 45% increased risk of disease-specific mortality compared to females. The study suggests that the higher systemic availability of estrogen in females and differences in health-seeking behaviors may contribute to the survival disparities. However, the study acknowledges limitations in the database and reporting practices. [Extracted from the article]

Metastatic disease is linked to TERT promoter mutations in conjunctival melanomas (CM). Both TERT promoter and ATRX mutations are associated with faulty telomere maintenance. This study aimed to determine the prognostic value of ATRX loss in conjunctival melanocytic lesions. Eighty-six conjunctival melanocytic lesions from the Rotterdam Ocular Melanoma Study group were collected. ATRX status and TERT promoter status were determined using immunohistochemical staining and molecular diagnostics, respectively. None of the nevi (n = 16) and primary acquired melanosis (PAM) without atypia (n = 6) showed ATRX loss. ATRX loss was found in 2/5 PAM with atypia without CM and in 8/59 CM. No cases with a TERT promoter mutation (n = 26) showed ATRX loss. Eight/eleven metastatic CM harbored a TERT promoter mutation, two other metastatic CM showed ATRX loss and one metastatic case showed no TERT promoter/ATRX alterations. In conclusion ATRX loss and TERT promoter mutations are only found in (pre)malignant conjunctival melanocytic lesions, with most metastatic cases harboring one of these alterations, suggesting that both alterations are associated with adverse behavior. Similar to TERT promoter mutations, ATRX loss may be used as a diagnostic tool in determining whether a conjunctival melanocytic lesion is prone to having an adverse course. [ABSTRACT FROM AUTHOR]

Simple Summary: Ocular malignancies encompass a broad range of disorders that affect the eyelids, orbit, and eye and have significant impacts for national healthcare systems. Due to its exposure to various stressors, the eye is an anatomical site susceptible to cellular toxicity and tissue damage, which can result in significant vision loss. In this context, similar to other tissue types, p53 plays a crucial role in maintaining ocular homeostasis. However, few in vitro experimentation and clinical trials of p53 pathway modulators have been conducted. The aim of this review is to discuss the potential of pharmacological p53 activators as a novel targeted therapy for managing ocular tumors. The pivotal role of p53 in the regulation of a vast array of cellular functions has been the subject of extensive research. The biological activity of p53 is not strictly limited to cell cycle arrest but also includes the regulation of homeostasis, DNA repair, apoptosis, and senescence. Thus, mutations in the p53 gene with loss of function represent one of the major mechanisms for cancer development. As expected, due to its key role, p53 is expressed throughout the human body including the eye. Specifically, altered p53 signaling pathways have been implicated in the development of conjunctival and corneal tumors, retinoblastoma, uveal melanoma, and intraocular melanoma. As non-selective cancer chemotherapies as well as ionizing radiation can be associated with either poor efficacy or dose-limiting toxicities in the eye, reconstitution of the p53 signaling pathway currently represents an attractive target for cancer therapy. The present review discusses the role of p53 in the pathogenesis of these ocular tumors and outlines the various pharmacological activators of p53 that are currently under investigation for the treatment of ocular malignancies. [ABSTRACT FROM AUTHOR]

Conjunctival melanoma (CM) is a rare and fatal malignant eye tumor. In this study, we deciphered a novel anti-CM mechanism of a natural tetracyclic compound named as cucurbitacin B (CuB). We found that CuB remarkably inhibited the proliferation of CM cells including CM-AS16, CRMM1, CRMM2 and CM2005.1, without toxicity to normal cells. CuB can also induce CM cells G2/M cell cycle arrest. RNA-seq screening identified KIF20A, a key downstream effector of FOXM1 pathway, was abolished by CuB treatment. Further target identification by activity-based protein profiling chemoproteomic approach revealed that GRP78 is a potential target of CuB. Several lines of evidence demonstrated that CuB interacted with GRP78 and bound with a Kd value of 0.11 μmol/L. Furthermore, ATPase activity evaluation showed that CuB suppressed GRP78 both in human recombinant GRP78 protein and cellular lysates. Knockdown of the GRP78 gene significantly induced the downregulation of FOXM1 and related pathway proteins including KIF20A, underlying an interesting therapeutic perspective. Finally, CuB significantly inhibited tumor progression in NCG mice without causing obvious side effects in vivo. Taken together, our current work proved that GRP78–FOXM1–KIF20A as a promising pathway for CM therapy, and the traditional medicine CuB as a candidate drug to hinder this pathway.

Purpose: We herein compare topical interferon alpha 2b (IFN-α2b) to topical mitomycin C (MMC) in the adjuvant management after excision of primary acquired melanosis with atypia (PAM) and melanoma of the conjunctiva/cornea (CM). Methods: We included 25 tumors from 25 patients (six with PAM and 19 with CM). After surgical excision, four patients started with adjuvant IFN-α2b (two in combination with radiotherapy), 19 with MMC, and two with radiotherapy alone. Five patients were switched from initial MMC/radiotherapy to IFN-α2b during follow-up. Efficacy was assessed via time to tumor recurrence and initial therapy response. Results: With initial IFN-α2b, three patients (3/4, two with additional radiotherapy) showed complete remission (follow-up: 1478–1750 days) and one recurrence (1/4) was noted after 492 days. With initial MMC, no recurrence was recorded in 15 of the 19 patients (follow-up: 99–4732 days). Five patients were switched from MMC or radiotherapy to IFN-α2b: two patients showed complete remission (2/5), while another two (2/5) experienced recurrences and remained without recurrence after repeated courses of IFN-α2b (follow-up: 1798 and 1973 days). Only one patient showed incomplete response. Adverse effects were recorded in five patients, all received MMC. Conclusion: Topical IFN-α2b (arguably together with radiotherapy) may be a viable alternative to MMC in PAM and CM. We observed fewer side effects at similar response rates. However, when response to MMC was poor, IFN-α2b may also be of limited utility. [ABSTRACT FROM AUTHOR]

Conjunctival melanoma is an uncommon and malignant tumor of the ocular surface with the propensity for metastasis and death. Despite the grim outlook, the factors predicting poor prognosis are slowly being uncovered given the rarity of the disease. Here, we present a rare and surprising case of a long standing, extensive, and invasive conjunctival melanoma that, despite multiple factors predicting a poor prognosis, had no systemic metastatic disease. We hope that by reviewing in depth the various factors that may explain our patient's unusual course of illness we can add to our growing understanding of conjunctival melanoma.

Background We aimed to determine the effect of clinicopathologic features on overall survival among Caucasian ocular melanoma patients in the Central Anatolia region of Turkey. Methods This single-center study included conjunctival (n = 12) and uveal (n = 19) melanoma patients diagnosed between January 2008 and March 2020. Clinicopathologic features and outcomes were reviewed retrospectively. Five cases were tested for BRAF V600 mutations with real-time polymerase chain reaction, and one case was tested with next-generation sequencing. Survival was calculated using the Kaplan-Meier method. Results Thirty-one patients had a mean initial age of 58.32 years (median, 61 years; range 25 to 78 years). There were 13 male and 18 female patients. The median follow-up time was 43.5 months (range, 6 to 155 months) for conjunctival melanoma and 35 months (range, 8 to 151 months) for uveal melanoma. When this study ended, eight of the 12 conjunctival melanoma patients (66.7%) and nine of the 19 uveal melanoma patients (47.4%) had died. The presence of tumor-infiltrating lymphocytes was related to improved overall survival in conjunctival melanoma (p = .014), whereas the presence of ulceration (p = .030), lymphovascular invasion (p = .051), tumor in the left eye (p = .012), tumor thickness of > 2 mm (p = .012), and mitotic count of >1/mm2 (p = .012) reduced the overall survival in conjunctival melanoma. Uveal melanoma tumors with the largest diameter of 9.1–15 mm led to the lowest overall survival among subgroups (p = .035). Involvement of the conjunctiva (p=.005) and lens (p = .003) diminished overall survival in uveal melanoma. BRAF V600 mutation was present in one case of conjunctival melanoma, GNAQ R183Q mutation was present in one case of uveal melanoma. Patients with uveal melanoma presented with an advanced pathological tumor stage compared to those with conjunctival melanoma (p = .019). Conclusions This study confirmed the presence of tumor-infiltrating lymphocytes as a favorable factor in conjunctival melanoma and conjunctival and lens involvement as unfavorable prognostic factors in uveal melanoma for overall survival, respectively.

Background: Conjunctival melanoma (CM) is associated with a high rate of local recurrence and poor survival rate. Novel therapeutic options are needed to reduce recurrence rate. The objective of the study was to demonstrate the improved effectiveness of electrochemotherapy (ECT) on CM using repetitive application. Methods: Tumor spheroids of three CM cell lines (CRMM1, CRMM2, CM2005.1) were treated repetitively with ECT using the chemotherapeutic agent bleomycin on days 3, 5, and 7 of culture. Application of bleomycin alone and electroporation alone served as controls. The cytotoxic effect was analyzed on day 10 compared to untreated control using an independent t-test. The spheroid outgrowth rate was measured. Result: CM tumor spheroid size (median value: 78%, SD: 32%) and viability (median value: 11%, SD: 11%) were dramatically reduced after repetitive ECT treatment (p-value < 0.001). Decreased proliferation capacity (down to 8%) and an increase of apoptotic cells were observed. In most repetitive ECT-treated spheroids, no viable or proliferating cells were detected. Only 33–40% of repetitive ECT-treated spheroids exhibited single outgrowing cells with a delay of time up to 38 days. Conclusion: Repetitive ECT application effectively induces cytotoxic effects in CM spheroids by inducing apoptosis, inhibiting proliferation and decreasing the percentage of surviving tumor cells. Thus, repetitive ECT results in improved antitumor effectiveness in CM and could be an alternative therapy option. [ABSTRACT FROM AUTHOR]

Conjunctival melanoma (CM) is a rare and fatal malignant eye tumor. In this study, we deciphered a novel anti-CM mechanism of a natural tetracyclic compound named as cucurbitacin B (CuB). We found that CuB remarkably inhibited the proliferation of CM cells including CM-AS16, CRMM1, CRMM2 and CM2005.1, without toxicity to normal cells. CuB can also induce CM cells G2/M cell cycle arrest. RNA-seq screening identified KIF20A, a key downstream effector of FOXM1 pathway, was abolished by CuB treatment. Further target identification by activity-based protein profiling chemoproteomic approach revealed that GRP78 is a potential target of CuB. Several lines of evidence demonstrated that CuB interacted with GRP78 and bound with a K d value of 0.11 μmol/L. Furthermore, ATPase activity evaluation showed that CuB suppressed GRP78 both in human recombinant GRP78 protein and cellular lysates. Knockdown of the GRP78 gene significantly induced the downregulation of FOXM1 and related pathway proteins including KIF20A, underlying an interesting therapeutic perspective. Finally, CuB significantly inhibited tumor progression in NCG mice without causing obvious side effects in vivo. Taken together, our current work proved that GRP78–FOXM1–KIF20A as a promising pathway for CM therapy, and the traditional medicine CuB as a candidate drug to hinder this pathway. GRP78 was found to be one of potential targets of cucurbitacin B. Downregulating GRP78–FOXM1–KIF20A pathway represented an alternative strategy for treatment of the rare ocular tumor named conjunctival melanoma. [Display omitted] [ABSTRACT FROM AUTHOR]

This study investigates the demographic and clinical features of conjunctival tumours. Conjunctival tumours include a large spectrum of conditions ranging from benign lesions to aggressive, life-threatening malignancies. Knowing the distribution of conjunctival tumours by age and gender is important for reducing cancer morbidity. The clinical records of 375 patients (410 eyes) diagnosed with a conjunctival mass at a tertiary referral centre between February 1999 and November 2020 were retrospectively evaluated. Two-hundred-seventeen (57.9%) patients were male and 158 (42.1%) were female. Of 410 conjunctival tumours, 159 (38.8%) were benign, 106 (25.9%) premalignant, and 145 (35.4%) malignant. Overall, the 3 most common diagnoses were squamous cell carcinoma (SCC, 19.5%), conjunctival intraepithelial neoplasia (CIN, 18.3%), and naevus (17.8%). The most common benign, premalignant, and malignant tumours were naevus (n = 73/159, 45.9%), CIN (n = 75/106, 70.8%), and SCC (n = 80/145, 55.2%) respectively. Naevus was the most common tumour in ≤20 years and > 20-40 years old patient groups (56.2% and 25.4% respectively). CIN was the most frequent tumour in patients aged > 40-60 years (25.7%). SCC was the most common tumour in > 60-80 years and > 80 years old patient groups (44.3% and 80.0% respectively). The median patient age was greater in patients with malignant tumours (64.5 years) compared to patients with premalignant (55.5 years, p = 0.011) and benign tumours (22.0 years, p < 0.001). Malignant tumours displayed larger base diameter, greater thickness, and intrinsic vessels compared to premalignant or benign lesions (p < 0.001 for each parameter). Malignant tumours also displayed more amelanotic vs melanotic appearance (p < 0.001) and limbal vs extralimbal bulbar location compared to benign lesions (p < 0.001). Premalignant and malignant tumours comprised 61.2% of all conjunctival tumours and were usually detected in patients > 40 years of age in this study. [ABSTRACT FROM AUTHOR]

Uveal melanoma is the most common malignant neoplasm of the eyeball, developing from melanocytes of the uveal membrane of the eye, which is significantly different from melanoma of the conjunctiva, mucous membranes and skin. The management of this disease is therefore different from that of other forms of melanoma. The disease is most often confined to the eye and its local treatment includes radiation therapy and surgery. Some patients, despite successful local treatment, develop distant metastases, most often located in the liver. The guidelines presented here cover the principles of diagnosis, prognostic evaluation and treatment of both the disease confined to the eyeball and the disease at the metastatic stage. The principles of management of conjunctival melanoma are also discussed. The recommen)dations are based on a review of the literature and expert opinion, and are accompanied by an assessment of their strength and reliability [ABSTRACT FROM AUTHOR]

Primary acquired melanosis (PAM) is acquired conjunctival pigmentation that can give rise to conjunctival melanoma (CM), a malignant tumor of the bulbar and palpebral conjunctiva or the caruncle. Surgical excision is the treatment of choice for this neoplasm. Topical chemotherapy is also used for patients with PAM with atypia or CM and, in patients with recurrent or extensive disease, this may be an important option. Of the several chemotherapeutic drugs used, topical interferon alpha 2b (IFN-α2b) has become popular because of its low toxicity. Clinical evidence from case reports and case series supports the efficacy of IFN-α2b as the preferred adjuvant treatment for PAM and CM. In addition, topical IFN-α2b has been successfully applied to melanocytic tumors refractory to other treatments, such as cryotherapy and topical mitomycin C. In patients with locally advanced CM, the combination of IFN-α2b and systemic immunotherapy may serve as an alternative to exenteration. Given the low frequency of CM, long-term multicenter studies are needed to demonstrate the efficacy of IFN-α2b for preventing local recurrence and distant metastasis. [ABSTRACT FROM AUTHOR]

Purpose: To determine the prevalence, clinical characteristics, and demographic factors of melanocytic lesions of the ocular surface, such as racial melanosis, primarily acquired melanosis, conjunctival nevus, and conjunctival melanoma in a Hispanic population. Materials and methods: A cross-sectional and observational study was undertaken in a tertiary referral ophthalmological center in northern Mexico from December 2020 to April 2021. All patients attending an ophthalmology specialty clinic were screened during their first visit in order to detect melanocytic lesions of the ocular surface. Demographic factors, clinical characteristics, and diagnosis and treatment were recorded. Results: 227 patients were screened for melanocytic lesions. Melanocytic lesions were identified in 114 patients (50.2%). The prevalence of the different melanocytic lesions in the screened population was racial melanosis, 45.3%; primary acquired melanosis, 3.5%, and conjunctival nevus 1.3%. No conjunctival melanoma was identified in the screened population. Primary acquired melanosis was more common in the fifth to sixth decade of life and in females. Racial melanosis showed no gender predilection and was also more common in the fifth to sixth decade of life. Only 1 melanocytic lesion (a primary acquired melanosis) required medical treatment with excisional biopsy and cryotherapy. Conclusion: The prevalence of racial melanosis is remarkably high in the Hispanic population. While less prevalent, primary acquired melanosis is also present in a considerable percentage of Hispanic patients. Both melanocytic lesions exhibit demographic characteristics that match those previously reported in the medical literature. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the surveillance value of circulating tumor DNA (ctDNA) for detecting distant metastasis and indicating systemic therapeutic efficacy in conjunctival melanoma (CoM)., Design: Retrospective, observational case series., Methods: From July 2021 to June 2023, 30 CoM patients in our center underwent plasma ctDNA assessment, out of which 12 individuals presented with distant metastases. We employed a 437-gene panel containing common mutations in CoM and common drug-sensitive mutations using next-generation sequencing (NGS) technology to analyze ctDNA mutations in plasma. Clinical and radiological records were used to assess tumor status. The relationship between ctDNA characteristics, tissue gene mutations, and clinical manifestations were explored., Results: CoM-related driver mutations were detected in ctDNA of 11 patients with distant metastasis. The ctDNA were highly consistent with tissue sequencing, mutual driver mutation including BRAF, NRAS, KRAS, NF1, CTNNB1, and TP53 mutation. those with a higher VAF had shorter progression-free survival (PFS, p=0.0475) and overall survival (OS, p=0.0043). The ctDNA variant allele fraction (VAF) was not correlated with the sum of the longest diameters (SLD, p=0.8192) in distant metastasis patients., Conclusions: Positive plasma ctDNA reflected the presence of metastases. The ctDNA could be used as a complement or alternative to tissue sequencing. High VAF ctDNA might indicate rapid disease progression in distant metastasis patients., Competing Interests: Competing Interests The authors declare no competing financial interests., (Copyright © 2024. Published by Elsevier Inc.)

Introduction: Local recurrence of conjunctival melanoma (CM) is common after excision. Local radiotherapy is an effective adjuvant treatment option, and brachytherapy with ruthenium-106 ( 106 Ru) is one such option. Thus, herein, we aimed to describe our experience with and the clinical results of post-excision adjuvant 106 Ru plaque brachytherapy in patients with CM., Methods: Nineteen patients (8 men and 11 women) received adjuvant brachytherapy with a 106 Ru plaque after tumor excision. The mean adjuvant dose administered was 109 Gy (range, 80-134 Gy), and a depth of only 2.2 mm was targeted because the tumor had been excised. A full ophthalmological examination including visual acuity testing, slit-lamp examination, and indirect ophthalmoscopy was performed before therapy and at every postoperative follow-up. The mean follow-up period was 62 months (range, 2-144 months)., Results: Three patients developed a recurrence in a nontreated area, at either the conjunctiva bulbi or the conjunctiva tarsi. None of the patients developed a recurrence in the treated area. The local control rate was 84% (16/19)., Conclusion: 106 Ru plaque brachytherapy is an effective adjuvant treatment to minimize the risk of local recurrence after excision of a CM. Patients have to be followed up regularly and carefully for the early detection of recurrence., Competing Interests: The authors have no conflicts of interest to declare., (© 2024 S. Karger AG, Basel.)

Abstract Background Imaging mass cytometry (IMC) combines the principles of flow cytometry and mass spectrometry (MS) with laser scanning spatial resolution and offers unique advantages for the analysis of tissue samples in unprecedented detail. In contrast to conventional immunohistochemistry, which is limited in its application by the number of possible fluorochrome combinations, IMC uses isoptope-coupled antibodies that allow multiplex analysis of up to 40 markers in the same tissue section simultaneously. Methods In this report we use IMC to analyze formalin-fixed, paraffin-embedded conjunctival tissue. We performed a 18-biomarkers IMC analysis of conjunctival tissue to determine and summarize the possibilities, relevance and limitations of IMC for deciphering the biology and pathology of ocular diseases. Results Without modifying the manufacturer’s protocol, we observed positive and plausible staining for 12 of 18 biomarkers. Subsequent bioinformatical single-cell analysis and phenograph clustering identified 24 different cellular clusters with distinct expression profiles with respect to the markers used. Conclusions IMC enables highly multiplexed imaging of ocular samples at subcellular resolution. IMC is an innovative and feasible method, providing new insights into ocular disease pathogenesis that will be valuable for basic research, drug discovery and clinical diagnostics.

Metastatic disease is linked to TERT promoter mutations in conjunctival melanomas (CM). Both TERT promoter and ATRX mutations are associated with faulty telomere maintenance. This study aimed to determine the prognostic value of ATRX loss in conjunctival melanocytic lesions. Eighty-six conjunctival melanocytic lesions from the Rotterdam Ocular Melanoma Study group were collected. ATRX status and TERT promoter status were determined using immunohistochemical staining and molecular diagnostics, respectively. None of the nevi (n = 16) and primary acquired melanosis (PAM) without atypia (n = 6) showed ATRX loss. ATRX loss was found in 2/5 PAM with atypia without CM and in 8/59 CM. No cases with a TERT promoter mutation (n = 26) showed ATRX loss. Eight/eleven metastatic CM harbored a TERT promoter mutation, two other metastatic CM showed ATRX loss and one metastatic case showed no TERT promoter/ATRX alterations. In conclusion ATRX loss and TERT promoter mutations are only found in (pre)malignant conjunctival melanocytic lesions, with most metastatic cases harboring one of these alterations, suggesting that both alterations are associated with adverse behavior. Similar to TERT promoter mutations, ATRX loss may be used as a diagnostic tool in determining whether a conjunctival melanocytic lesion is prone to having an adverse course.

Background: Conjunctival melanoma (CM) is a life-threatening ocular tumor with a high rate of local recurrence and metastasis. Our objective is to analyze research trends in CM field and compare contributions from different countries, institutions and authors. Methods: We extracted all CM-related publications published from 1997 to 2022 from the Web of Science database and applied Microsoft Excel and VOSviewer to review publication data, analyze publication trends, and visualize relevant data. Results: A total of 708 publications were identified. The United States contributed the most publications (280) and citations (8,781 times) with the highest H-index value (47). The Ophthalmic Plastic and Reconstructive Surgery, British Journal of Ophthalmology, American Journal of Ophthalmology and Cornea were the most productive journal concerning CM, and Shields CL, Shields JA, Jager MJ as well as Finger PT had published the most papers in the field. Keywords were classified into three clusters: clinical research, management-related research and genetic research. The keywords "primary acquired melanosis", "metastasis" and "BRAF mutations" were most frequently emerged. According to the average appearing year (AAY), targeted therapy (AAY of 2019.0) and nivolumab (AAY of 2018.7) were identified as the main focuses of the field in the near future. Conclusion: In the past 25 years, the United States, Germany, England and the Netherlands held the leading position in the CM research. A group of scholars made important contributions to CM research and will continue to guide cutting-edge research. Treatments that have been shown to be effective for advanced cutaneous melanoma, such as targeted therapy and immunotherapy, are potential focuses for future CM research. [ABSTRACT FROM AUTHOR]

To assess the predictive value of the tumor staging system in the AJCC Cancer Staging Manual, Eighth Edition , and histologic features for outcomes and metastasis patterns in conjunctival melanoma (CM). Retrospective, single-center cohort study. Eighty-three patients with CM were treated at Shanghai Ninth People's Hospital between 2000 and 2021. We reviewed the clinical and histologic parameters and used Kaplan–Meier survival curves and Cox proportional hazards regression models for risk factor analyses. Time to nodal/distant metastasis, disease-specific survival, metastatic pattern, and metastatic site. At presentation, 5 patients (6%) had clinical tumor (cT)1 disease, 34 patients (41%) had cT2 disease, and 44 patients (53%) had cT3 disease. Four patients (5%) had nodal metastasis (N1), and none had distant metastasis (M1). During follow-up, 12 patients (14%) developed nodal metastasis, 29 patients (35%) developed distant metastasis, and 26 patients (31%) died of disease. The brain, liver, and lung were common distant metastasis sites. Higher cT category was associated with increased risks of distant metastasis (P < 0.001) and disease-specific death (P = 0.002). The separate analysis of primary and recurrent tumors at presentation showed that the patients with cT3 tumors had a higher risk of distant metastasis than those with cT2 tumors. Greater tumor thickness, ulceration, and the presence of regression were correlated with distant metastasis. Previously unreported mutations were detected in the tumor suppressor genes FAT atypical cadherin 4 (FAT4) and spleen associated tyrosine kinase (SYK). Among the 29 patients who developed distant metastasis, we analyzed 2 patterns of metastasis: Eleven patients (38%) developed nodal metastasis before distant metastasis, and 18 patients (62%) developed distant metastasis without previously known nodal metastasis. The patients with cT3 tumors were more likely to follow the latter metastasis pattern (P = 0.02). Conjunctival melanoma presented with mostly advanced stages and high rates of distant metastasis in the current Chinese cohort. This study confirmed the prognostic value of the tumor staging system in the AJCC Cancer Staging Manual, Eighth Edition, for Chinese patients. Histologic features, such as tumor thickness and ulceration, should be emphasized when assessing prognosis and guiding the treatment of CM. Prognostic value of AJCC T category was associated with increased risks of distant metastasis and disease-specific death, Greater tumor thickness, and, ulceration, and the presence of regression were correlated with distant metastasis. Patients with cT3 tumors were more likely to develop distant metastasis without prior nodal metastasis. [ABSTRACT FROM AUTHOR]

Aims: Conjunctival and cutaneous melanoma partially share similar clinical and molecular backgrounds. As 5-hydroxymethylcytosine (5-hmC) loss has been demonstrated in cutaneous melanoma, we decided to assess if similar changes were occurring in conjunctival melanoma. Methods: 5-methylcytosine (5-mC), 5-hmC and TET2 were respectively identified by immunohistochemistry and RNA ISH in 40 conjunctival nevi and 37 conjunctival melanomas. Clinicopathological correlations were established. Results: 5-mC, TET2 and 5-hmC were respectively identified in 67.5%, 95% and 100% of conjunctival nevi and in 81.1%, 35.1% and 54% of conjunctival melanomas. A significant 5-hmC and TET2 loss was identified in conjunctival melanoma comparing to nevus, as well as a significant correlation between TET2 and 5-hmC expression. In the melanomas, 5-hmC expression was only significantly associated with local lymphatic invasion, but not with other clinicopathological parameters. There was a correlation between TET2 expression and the localization of the tumors. 5-mC expression was not associated with any clinicopathological parameters. Conclusions: We identified a significant 5-hmC loss in conjunctival melanoma similar to cutaneous melanoma. This loss may possibly be attributed to TET2 loss or IDH1 mutations. 5-hmC loss in conjunctival melanoma may help in the differential diagnosis between atypical conjunctival nevus and conjunctival melanoma.

Purpose: To report successful ring-shaped iodine-125 plaque brachytherapy for conjunctival melanoma. Observations: Eye Physics (EP) plaque brachytherapy, designed with Plaque Simulator software, proved to be an effective treatment modality with some corneal irritation and no recurrence at 12-months post radiation. Conclusion and importance: Management of conjunctival melanoma is complicated by the lack of gold standard adjuvant treatments. I-125 EP plaque brachytherapy represents a viable option for these malignancies. Specifically, ring-shaped plaque geometries allow for targeted radiotherapy.

Hironobu Jimura,1 Yuuki Mishima,1 Chie Sotozono,2 Akihide Watanabe,2 Jun Asai,3 Chiho Ohbayashi,4 Nahoko Ogata1 1Department of Ophthalmology, Nara Medical University, Nara, Japan; 2Department of Ophthalmology, Kyoto Prefectural University of Medicine, Kyoto, Japan; 3Department of Dermatology, Kyoto Prefectural University of Medicine, Kyoto, Japan; 4Department of Diagnostic Pathology, Nara Medical University, Nara, JapanCorrespondence: Nahoko OgataDepartment of Ophthalmology, Nara Medical University, Nara, JapanTel +81-744-29-8884 (ext.3432)Fax +81-744-23-8032Email ogata@naramed-u.ac.jpAbstract: Primary acquired melanosis (PAM) of the conjunctiva is a potentially serious melanocytic lesion that can lead to the development of a melanoma. A 60-year-old woman noticed pigmentation of the conjunctiva of her left eye for more than 10 years. She underwent excisional biopsy combined with cryotherapy and was diagnosed with PAM without atypia by intraoperative consultation. She was followed for 7 years, and no changes were observed. Fourteen years after the initial biopsy, she noted a growing conjunctival tumor, and a melanoma was suspected. She underwent orbital exenteration and skin grafting procedures. Histopathological examination of the specimen led to a diagnosis of conjunctival malignant melanoma. Re-examination of the initial biopsy specimen revealed that there was a proliferation of melanocytes that partially expanded over the basal layer of the conjunctiva which had been diagnosed as PAM with moderate atypia. We conclude that this case of conjunctival PAM had progressed to a conjunctival malignant melanoma after 14 years. Pathological evaluation of intraepithelial lesions has its limitations; thus, cases of PAM, even in the absence of obvious atypia, require careful follow-up.Keywords: primary acquired melanosis, conjunctival malignant melanoma, malignant melanoma, conjunctival melanoma, conjunctival tumor

The present study reported a rare case of persistent bleeding caused by conjunctival melanoma containing abundant vascular channels. A 44-year-old Japanese woman presented with a left upper eyelid nodule in February 2023. A pigmented conjunctival mass was present in the upper palpebral conjunctiva. Enhanced computed tomography demonstrated marked enhancement in the left eyelid in the artery phase, indicating hemangioma. The patient suffered blunt trauma to the face in May 2023 and continuous bleeding occurred. Doctors in the emergency room attempted hemostasis by diathermy and suture, but the bleeding could not be stopped. The patient eventually underwent emergent orbital exenteration of the left eye. At high magnification of the histology sample of the bleeding site, small-to-large vascular channels with various vascular lumens made up of endothelial cells within the conjunctival melanoma tissue could be observed. The tumor cells were positive for SOX10, Melan A, S100 and HMB45. We herein propose a novel variant of conjunctival melanoma with rich vascularization, clinically causing persistent bleeding. [ABSTRACT FROM AUTHOR]

Conjunctival melanoma is a rare type of ocular melanoma, which is prone to local recurrence and metastasis and can lead to patient death. Novel therapeutic strategies have revolutionized cutaneous melanoma management. The efficacy of these therapies in conjunctival melanoma, however, has not been evaluated in larger patient cohorts. In this multi-center retrospective cohort study with additional screening of the ADOREG database, data were collected from 34 patients with metastatic conjunctival melanoma who received targeted therapy (TT) (BRAF ± MEK inhibitors) or immune checkpoint inhibitors (ICI) (anti-PD-1 ± anti-CTLA4). In 15 cases, tissue was available for targeted next-generation-sequencing (611 genes) and RNA sequencing. Driver mutations, tumor mutational burden, copy number variations and inflammatory/IFNγ gene expression signatures were determined. Genetic characterization identified frequent BRAF (46.7%, 7/15), NRAS (26.7%, 4/15), NF1 (20%, 3/15), and TERT promoter (46.7%, 7/15) mutations. UV associated C>T and CC>TT mutations were common. Median follow-up time after start of first TT or ICI therapy was 13.2 months. In 26 patients receiving first-line ICI, estimated one-year progression-free survival (PFS) rate was 42.0%, PFS and overall survival (OS) 6.2 and 18.0 months, respectively. First-line TT was given to 8 patients, estimated one-year PFS rate was 54.7%, median PFS and OS 12.6 and 29.1 months, respectively. Our findings support the role of UV irradiation in conjunctival melanoma and the genetic similarity with cutaneous melanoma. Conjunctival melanoma patients with advanced disease benefit from both targeted therapies (BRAF ± MEK inhibitors) and immune checkpoint inhibitors. • Our findings support the role of UV irradiation in conjunctival melanoma. • Oncogene mutation patterns are similar to cutaneous melanoma. • In contrast to uveal melanoma, lymph node metastasis is common. • Response to immune checkpoint inhibition (ICI) is better than in uveal melanoma. • Targeted therapy (TT) should be considered in BRAF mutated conjunctival melanoma. [ABSTRACT FROM AUTHOR]

Simple Summary: We determined the sensitivity of several conjunctival melanoma cell lines to kinase inhibitors as well as a few other inhibitors using an image-based high throughput drug screening assay with 542 compounds. All cell lines demonstrated sensitivity to cell cycle inhibition, especially with polo-like inhibitors. The response to MAPK pathway inhibition was better in the presence of BRAFV600E mutations, while the response to PI3k/mTOR inhibition was better in the presence of the NRASQ61L mutation. Our study uncovers a large panel of new vulnerabilities in conjunctival melanoma and establishes the background for the expansion of therapeutic options in the management of this tumor. Recent evidence suggests that numerous similarities exist between the genomic landscapes of both conjunctival and cutaneous melanoma. Since alterations of several components of the MAP kinases, PI3K/mTOR, and cell cycle pathways have been reported in conjunctival melanoma, we decided to assess the sensitivity of conjunctival melanoma to targeted inhibition mostly of kinase inhibitors. A high content drug screening assay based on automated fluorescence microscopy was performed in three conjunctival melanoma cell lines with different genomic backgrounds with 489 kinase inhibitors and 53 other inhibitors. IC50 and apoptosis induction were respectively assessed for 53 and 48 compounds. The genomic background influenced the response to MAK and PI3K/mTOR inhibition, more specifically cell lines with BRAF V600E mutations were more sensitive to BRAF/MEK inhibition, while CRMM2 bearing the NRASQ61L mutation was more sensitive to PI3k/mTOR inhibition. All cell lines demonstrated sensitivity to cell cycle inhibition, being more pronounced in CRMM2, especially with polo-like inhibitors. Our data also revealed new vulnerabilities to Hsp90 and Src inhibition. This study demonstrates that the genomic background partially influences the response to targeted therapy and uncovers a large panel of potential vulnerabilities in conjunctival melanoma that may expand available options for the management of this tumor. [ABSTRACT FROM AUTHOR]