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Introduction: Despite advances in the understanding of the molecular pathogenesis of cutaneous melanoma, relatively little is known about the genetic changes that occur in the progression of conjunctival melanocytic intraepithelial lesions to invasive conjunctival melanoma. Methods: We exposed 4 exenteration specimens that each contained varying grades of intraepithelial conjunctival melanocytic neoplasia and invasive neoplasia to a combination of various techniques, including array comparative genomic hybridization (aCGH), ribonucleic acid sequencing (RNA-seq), fluorescence in situ hybridization (FISH), and immunohistochemistry. Results: Three out of 4 of the invasive melanomas showed gains in 11q13 (CCND1 locus) by aCGH. FISH demonstrated CCND1 gain in invasive melanoma and in conjunctival melanocytic intraepithelial lesions (CMILs) of all grades (low-grade CMILs and in situ melanoma), and this was paralleled by increased expression of Cyclin D1 protein within the atypical melanocytes by immunohistochemistry, using a double-staining method with a red end point for Melan A cytoplasmic staining and a brown end point for nuclear Cyclin D1 expression. Higher grades of melanocytic intraepithelial lesions showed more cells expressing Cyclin D1 than lower grade melanocytic intraepithelial lesions. The Cyclin D1 protein expression was in the same location as the amplified CCND1 signal by FISH. One out of 3 of these cases also showed the amplification of the 12q13-15 locus corresponding to MDM2 and FISH confirmed gains in the conjunctival melanocytic intraepithelial neoplasia and invasive melanoma. The remaining fourth case showed a homozygous deletion of 9p21 (CDKN2A) by aCGH only, with immunohistochemistry showing clonal loss of p16 protein expression in the invasive and conjunctival melanocytic intraepithelial lesion. Two out of 4 of the invasive melanomas harboured classical driver mutations in NRAS and NF-1, respectively. None of the cases showed mutations in BRAF, KIT, and TERT mutations. RNA-seq data showed secondary mutations in ARAF, PLCB4, MET, EZH2, MAP2K2, CTNNB1, CIITA, NF2, TP53, and MEN1, some of which are implicated in the MAPK pathway. Conclusion: CMILs harbour amplifications of CCND1 (3 cases), MDM2 (1 case), and loss of CDKN2A (1 case), which are also present when the lesion progresses to invasive melanoma, implicating these amplifications in the early pathogenesis of CMILs. This study represents the first attempt to capture the mutational landscape of all stages of conjunctival melanoma in a single tissue excision.

We report a case of conjunctival intraepithelial neoplasia (CIN) in a patient presenting with the pigmented conjunctival lesion.This study involved a 56-year-old woman that presented with right eye irritation for 1 month. She noticed brownish pigmentation arising from her right nasal conjunctiva and growing slowly over time. Biomicroscopic examination showed a gelatinous pigmented conjunctival mass with feeder vessels. Conjunctival impression cytology (CIC) was done and reported as CIN. Treatment was started with 0.02% mitomycin-C eye drops. The conjunctival lesion responded well to medication. This report shows that CIN can manifest as a pigmented tumor, resembling melanoma. CIC plays a role in the diagnosis of this condition. This tumor responded well with 0.02% mitomycin-C eye drops.

Aim: The aim of this study was to discuss and illustrate the role age-conditional probability has in communicating risk of developing ocular and ocular adnexal malignancies. Methods: Cross-sectional incidence for retinoblastoma, uveal melanoma, conjunctival melanoma, and lacrimal gland carcinomas from 2000 to 2017 were obtained from the Surveillance, Epidemiology and End Results (SEER) database. Incidence rates were age-adjusted to the 2000 United States population. Age-adjusted incidence was converted to age-interval and cumulative risks. Outcomes were examined in 20-year intervals and cumulatively for adult cancers and yearly for retinoblastoma. Results: The risk of each malignancy displayed age-dependent variation. For adult malignancies, men were at higher risk at most age intervals. Uveal melanoma had the greatest cumulative lifetime risk. The probability of developing retinoblastoma declines precipitously after age 3 years. Conclusions: Age-conditional probability of developing cancer is a conceptually friendly means of understanding and communicating risk. It is particularly useful in comparing the risks of uncommon or rare cancers, such as those found in and around the eye. The assessment of risk in terms of age-conditional probability is a versatile and an underutilized pedagogical tool.

Purpose: To report a case of local metastasis of conjunctival melanoma, which may occur via extravascular migratory metastasis (EVMM), and discuss its clinical relevance in conjunctival melanoma tumor staging and possible management implications. Methods: Retrospective chart review of a single clinical case with clinicopathologic correlation. Results: A 65-year-old male referred due to local recurrence of conjunctival melanoma at the caruncle was successfully treated after two excisional procedures with negative sentinel lymph node biopsies. Forty-eight months after initial presentation, the patient developed a nodular lesion representing local recurrence in the ipsilateral upper tarsal conjunctiva, distant from the primary tumor site. Histopathology showed nodules in the substantia propria in the absence of primary acquired melanosis. The tumor cells were found along the extravascular surface without intralymphatic or intravascular tumor cells consistent with local metastasis. One possible mechanism is angiotropic microsatellitosis leading to local EVMM. Additional neck CT imaging showed no lymphadenopathy. Conclusion: EVMM via angiotropic microsatellitosis is another possible mechanism of noncontiguous local recurrence of conjunctival melanoma. Angiotropic microsatellitosis may represent a high-risk finding possibly related to increased melanoma-related mortality.

Background: Melanocytoma (magnocellular nevus) is a jet-black benign lesion histologically composed of polygonal tumor cells with small, inconspicuous nuclei and abundant cytoplasm. Melanocytomas in general are rare. Most cases occur in the optic nerve head. Conjunctival melanocytoma (magnocellular nevus) is extremely rare, and only 3 lesions of the ocular surface have been reported. Objectives: To describe the clinical and histological spectrum of conjunctival melanocytoma and discuss differential diagnoses of this rare lesion. Method: Four heavily pigmented conjunctival lesions were excised for slight tumor growth and histologically processed. The specimens were routinely stained with hematoxylin and eosin and periodic acid-Schiff. Sections were bleached and immunohistochemical stains were performed for CD68, HMB-45, S100, melanin, and Ki-67. Results: Histological examination revealed findings of a conjunctival melanocytoma in 3 cases. The fourth case was diagnosed histologically as a combined melanocytic lesion with a compound nevus and an inverted type A nevus. None of the lesions exhibited transition towards malignancy. The differential diagnoses included conjunctival melanoma, granular cell nevus, compound nevus with reactive changes, and blue nevus. Conclusions: Conjunctival melanocytic lesions suspicious for melanocytoma should be bleached to evaluate their cytologic features. CD68 can be helpful in identifying heavily pigmented melanomacrophages which may mimic a melanocytoma. As conjunctival melanocytomas are extremely rare, their pathogenesis may be different from that of other conjunctival nevi.

Background: Conjunctival melanoma is rare in adults and rarer in children. We systematically reviewed the presentation, diagnostic and management strategies as well as outcomes for conjunctival melanoma in children and adolescents. Methods: The following databases were searched: Medline, Embase, Web of Science and Scopus for cases of conjunctival melanoma occurring in children and adolescents < 18 years of age. Results: Seventeen studies with 32 patients (18 males) were identified. The median age at presentation was 11 years (range 4–18 years). Most patients were white. Most patients presented with a conjunctival mass or naevus with a recent history of growth or change. Excision biopsy provided diagnosis and management for all cases. Adjuvant chemotherapy and radiotherapy were also used. One patient had metastatic disease at diagnosis and 3 developed metastatic disease (range 1–10 months). Two patients died from disease and one was alive with metastatic disease. Two patients had disease recurrence. Outcomes were observed to be better where diagnosis was made earlier and “no-touch” excision biopsy was performed in an appropriate specialist setting. Conclusions: Conjunctival melanoma occurs rarely in children and adolescents. Surgery is the mainstay of management. The prognosis is guarded in metastatic disease due to the small sample size and limited follow-up.

Purpose: To evaluate local control and functional and cosmetic outcomes of postoperative high-dose-rate interventional radiotherapy (HDR-IRT) in patients affected by conjunctival melanoma with orbit invasion. Methods: A retrospective study was conducted in 2 patients affected by conjunctival melanoma infiltrating the orbit, treated with surgical excision and HDR-IRT. The treatment procedures consisted of surgical excision of the orbital infiltrating nodule followed, 1 month after surgery, by adjuvant HDR-IRT. A target dose of 34 Gy was delivered in 10 twice-a-day fractions over 5 consecutive days. Data analysis included local tumor control and metastatic rate, acute and late toxicity, functional and aesthetic results. Results: In both patients, treatment was well tolerated, and there was no orbital recurrence at a median follow-up of 37–40 months. There was an excellent functional outcome, without no significant acute or late side effects. Conclusions: HDR-IRT could be considered a promising, feasible, successful, and well-tolerated option for selected patients affected by ocular tumors with orbital invasion.

While the majority of cases of conjunctival melanoma (CM) involve the bulbar conjunctiva, concurrent pigmentation of the ipsilateral eyelid can be seen in up to 15% of cases. Although extension of conjunctival melanoma into the eyelid (AJCC cT3b) occurs in 1% of cases, non-contiguous lesions are very rare with only 5 clearly documented reports in the English literature. Several pathophysiological mechanisms have been proposed, including separate primary melanomas, patchy involvement from primary acquired melanosis (which may be sine pigmento) and exfoliation of malignant tumour cells into the tear film. Herein we present a case of eyelid melanoma arising in a patient previously treated for CM at a non-contiguous site and provide a comprehensive review of the relevant literature.

Background: Ocular melanomas threaten patients with early death, visual handicap, and loss of the eye. The aims of this study were to identify aspects of care that patients with ocular melanoma considered most important and to determine whether patients felt their needs had been adequately addressed. Methods: A cross-sectional study including US ocular melanoma patients and their caregivers. An online survey of US ocular melanoma patients was designed and conducted by the Ocular Melanoma Foundation. Results: The cohort included 180 patients with uveal melanoma and 4 with conjunctival melanoma. Median follow-up was 3 years. A third of patients reported that their uveal melanoma had initially been diagnosed as a nevus. Most uveal melanomas were treated with brachytherapy. Almost 50% of patients had no genetic tumor analysis. Screening methods reported most commonly were computed tomography and liver function tests. Metastatic disease developed in 11% of patients. Few patients (13.3%) reported an offer of psychological support. Most dissatisfaction was with lack of advice on financial aspects of care and lack of psychological counseling, with women tending to express more dissatisfaction with care. Many patients complained about the way ophthalmologists delivered bad news to them. Conclusions: This patients' perspective highlights directions for research, education, and other measures to improve the care of patients with ocular melanoma in the US and elsewhere.

A 60-year-old, South-Asian male patient presented with a dark brown lesion on his left conjunctiva surface near the limbus for 2 years. Examination showed a globular, dark brown-coloured mass near the temporal limbus at 4 to 5 o’clock position, measuring 3 × 3 × 2 mm. There were a few scattered flat pigmented lesions near the mass and also a few prominent vessels. The mass underwent wide local excision, with a clear margin, followed by double freeze cryotherapy of the conjunctival margins along with the application of Mitomycin C. The bare sclera was covered by amniotic membrane. Histology surprisingly revealed a nodular basal cell carcinoma (BCC) containing melanin. The melanin was present in the tumour cell cytoplasm, within melanophages and within dendritic, Melan A-positive melanocytes. The BCC was immunohistochemically positive for BerEP4 and negative for EMA. The clinically observed smaller nodules flanking the main pigmented BCC corresponded histologically to pigmented superficial growth pattern BCC connected to the under surface of the conjunctival epithelium. This is the first report of a pigmented BCC of the conjunctiva, mimicking a conjunctival melanoma. Pigmented BCC should be considered in the differential diagnosis of pigmented tumours of the conjunctiva.

Background: Conjunctival melanoma is a potentially lethal malignancy of the ocular surface. There have been no therapeutic advancements made in the past several decades despite increasing prevalence of the disease. Methods: The authors report the case of a 52-year-old Caucasian male with unresectable, recurrent conjunctival melanoma with V600 BRAF mutation who was treated with systemic BRAF/MEK inhibition. Results: There was complete regression of local disease within the first 9 months. The patient remains without local recurrence or systemic metastasis at 1 year. Conclusion: This is the first reported case of conjunctival melanoma with complete response to BRAF/MEK inhibition. As long as targeted therapy remains an option, patients with conjunctival melanoma should undergo mutational profiling of their tumor.

Purpose: To describe the clinical and histopathological features of a conjunctival melanoma (CM) during early pregnancy. Procedures: A 37-year-old, 20-week pregnant primigravida was referred to the Sheffield Ocular Oncology Service with a rapidly growing lesion arising from the right superior conjunctival fornix, noted from the first trimester of pregnancy. This was associated with pain and bloody discharge. Incisional biopsy confirmed the clinical suspicion of invasive CM. She was treated by primary surgical excision and cryotherapy under local anaesthesia. Results: Histology of the excised specimen showed an invasive malignant melanoma with surrounding in situ conjunctival changes arising from a naevus. The melanoma was 10.5 mm thick, focally necrotic, and had a mitotic count of 11/mm2 focally. The patient responded well to surgical treatment. She gave birth to a healthy boy, and the placenta showed no evidence of metastatic melanoma. There has been no recurrence or distant metastasis during 5 years of follow-up. Conclusion: CM during pregnancy is extremely rare. Because of possible transformation to malignant melanoma, we recommend close monitoring of females known to have pigmented conjunctival lesions of the conjunctiva during pregnancy.

The management of patients with diffuse invasive conjunctival melanoma focuses on local tumor control and screening for metastasis. Despite the lack of consensus on the benefit of sentinel lymph node biopsy for these neoplasms, the information obtained by histopathology is useful for tumor staging and treatment planning. Due to the lack of evidence of survival improvement, orbital exenteration is being performed with diminishing frequency. We describe a patient with diffuse invasive conjunctival melanoma and lymph node involvement treated by tumor debulking, brachytherapy (custom unshielded radioactive device), and adjuvant ipilimumab who has had a favorable outcome without emergence of local tumor relapse or distant metastasis during 16 months of follow up.

Conjunctival melanoma (CoM) is a rare and aggressive form of melanoma. There is a lack of consensus on a unified management plan for this disease. Recently, a few centers have adopted the regional sentinel lymph node biopsy into the staging process of CoM. This study presents a critical assessment of the role of sentinel lymph node biopsy in CoM and presents a simplified management algorithm based on high-risk clinical and pathological features.

Aim: In this review, we outline similarities between conjunctival and skin melanoma as well as the effectiveness of combined BRAF/MEK inhibition in melanoma, and discuss the applicability of these agents in conjunctival melanoma. Methods: The study provides a PubMed literature review. Results: Conjunctival melanoma and skin melanoma are genetically and phenotypically related. Both tumors typically harbor BRAF mutations in more than 50% of cases. New targeted therapies in metastatic skin melanoma include selective inhibition of BRAF and MEK. Combined BRAF/MEK inhibition has revolutionized the treatment of metastatic skin melanoma, significantly improving patients' prognoses. While these new substances have been investigated extensively in the treatment of skin melanoma, comparable studies in conjunctival melanoma do not exist owing to the rarity of the malignancy. Conclusions: The application of combined BRAF/MEK inhibition in metastatic or unresectable conjunctival melanoma shows great potential for improving patients' prognoses. Future studies are needed to investigate the assumed benefit.

Purpose: We report a patient with previous in situ melanoma of the forehead skin who was referred for treatment of a bulbar conjunctival melanoma and a separate superficially invasive melanoma of the eyelid skin, and we offer a review of the biological and clinical implications of patients who have multiple primary melanomas. Methods: This article offers a clinicopathological correlation with a review of the relevant literature. Results: An 80-year-old white man was referred for evaluation of a suspicious conjunctival tumor and a lower-eyelid lesion. Excisional biopsies revealed that both were primary melanomas arising within in situ disease. Over the span of 25 years, the patient had three separate foci of in situ melanoma, two of which spawned invasive melanoma. Conclusion: Separate melanomas arising from the bulbar conjunctiva and eyelid skin have rarely been reported. Multiple primary melanomas of the skin, however, are not uncommon. Based on studies of persons with multiple cutaneous melanomas, the prognosis is best predicted by the tumor with the greatest depth of invasion. Patients with multiple melanomas should be examined for dysplastic nevi, additional cutaneous melanomas, and screened periodically for future lesions. Ongoing studies enrolling patients with multiple primary melanomas are attempting to generate insights into low-penetrance susceptibility genes.