Conjunctival Melanoma Research Articles

Prospective study of sentinel lymph node biopsy for conjunctival melanoma

BackgroundTo report our experience with sentinel lymph node biopsy for staging patients with conjunctival melanoma.MethodsA prospective review of patients with conjunctival melanoma who underwent sentinel lymph node biopsy at St...

MiRNA and conjunctival melanoma migration

AbstractPurpose : In cutaneous melanoma, downregulation of miR‐211 has been implicated in migration and invasion. As we have previously demonstrated the downregulation of miR‐211 in conjunctival melanoma in vivo, we evaluated in vitro the role of miR‐211 in the migration of 4 conjunctival melanoma cell lines compared to a cutaneous melanoma cell line. Methods : Migration assays were performed using a cutaneous melanoma cell line and 4 conjunctival melanoma cell lines. Taqman RT‐PCR was performed to evaluate the level of miR‐211 in each cell line. Results : Compared to the cutaneous melanoma cell line with a high migration potential, 2 conjunctival melanoma cell lines demonstrated moderate migration abilities while 2 others no migration. The migration potential of the cell lines was significantly inversely correlated with Taqman evaluation of miR‐211 expression (p=0,0239). Conclusions : The migration ability of conjunctival melanoma cell lines is lower than a cutaneous melanoma cell line. The level of miR‐211 expression in conjunctival melanoma appears in vitro to inversely correlate with the migration potential of the cell lines, confirming the downregulation of miR‐211 observed in vivo in conjunctival melanoma.

Different assessments of immunohistochemically stained Ki‐67 ocular malignancies

AbstractPurpose To investigate a tumor proliferation marker Ki‐67 in conjunctival malignancies and to compare the results of different quantitative assessments.Methods This study was designed as a pilot study to assess nuclear proliferation protein (Ki 67) in conjunctival malignancies. Immunohistochemical staining of Ki‐67 was evaluated in 8 surgical samples of ocular surface neoplasias: 6 cases of invasive conjunctival squamous carcinoma and 2 of conjuntival melanoma. Ki‐67 counting and evaluation was assessed on selected areas using different methods: manual counting (MC) of >1500 cells;digital image analysis with Nuclear V9 algorithm and digital image analysis using stereology module for ImageScope of Aperio. Ki‐67 values from manual, stereoscopic and automated analyses were compared.Results The MC, the nuclear V9 algorithm analysis and stereologic method revealed positivity of Ki‐67 in invasive conjunctival squamous carcinoma from 22 to 60%, 21.5 to 43.5 % and from 30.1 to 51.5% respectively; in conjunctival melanomas from 20 to 30 %; from 17.8 to 18%, and from 7.17 to 29.1% respectively. The strongest correlation was observed between Aperio algorithm and stereologic method in conjunctival squamous carcinoma (0.87). Weaker correlation was found between Aperio/manual (0.6) and manual/stereological (0.83) methods.Conclusion Our data demonstrate that different methods of Ki‐67 evaluation may give dissimilar results, but results of this computer assisted nuclear V9 algorithm correlates strongly with stereoscopic analysis and can be helpful in accurate quantitative evaluation of imunochistochemically stained biomarkers.

C‐Kit SCF receptor (CD117) expression and KIT gene mutation in conjunctival pigmented lesions

AbstractPurpose to investigate the presence of KIT gene mutations and immunoreactivity in 85 conjunctival melanocytic tumors and clarify the role of KIT as a potential therapeutic target in this group of patients.Methods 85 conjunctival pigmented tumors (27 melanomas, 12 PAMs and 46 nevi) were immunostained for KIT. Intensity and pattern of expression were evaluated. Molecular analysis to identify KIT mutations was performed in 15 selected cases (tumor‐rich areas >50%). KIT immunostaining score and pattern were statistically related to patients’ age, sex, diagnostic category, presence of relapse, disease‐free survival, presence of metastases, metastasis‐free survival, limbal versus non‐limbal tumor location and thickness of melanomas.Results KIT stains was documented in 48% of melanomas, 50% of PAMs and 24% of nevi. The mean score of KIT staining in the melanomas/PAMs group was significantly different from nevi (p=0.0076). No statistically significant differences were detected between either c‐kit immunostaining score or pattern and each of the other clinico‐pathologic parameters considered. No KIT gene mutations were detected in melanomas and nevi. A silent mutation/polymorphism in KIT exon 13 was found in one PAM.Conclusion Despite the high level of KIT immunostains in conjunctival PAM and melanoma, this parameter seems not to be a good predictor for the presence of molecular mutations. KIT‐activating mutations should be considered an uncommon event in these tumors.

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PURPOSE The aim of this study was to evaluate conjunctival melanoma outcomes based on American Joint Committee on Cancer classification. The study design constituted a nonrandomized interventional case series. METHODS This was a retrospective chart review comprising 343 participants, and the main outcome measures were melanoma local recurrence, lymph node metastasis, distant metastasis, and death. RESULTS On the basis of the American Joint Committee on Cancer classification (seventh edition), conjunctival melanoma was classified as T1 (196 [57%]), T2 (110 [32%]), T3 (37 [11%]), and T4 (0). The mean tumor basal diameter increased with tumor staging with 8.5 mm for T1, 12.7 mm for T2 (p = 0.0003), and 16 mm for T3 (p < 0.0001). The melanoma arose from primary acquired melanosis (T1 = 71%; T2 = 84%; T3 = 81%), preexisting nevus (T1 = 8%; T2 = 5%; T3 = 3%), or de novo (T1 = 21%; T2 = 12%; T3 = 16%). Outcomes at 5 years (Kaplan-Meier) revealed melanoma local recurrence/new tumor in 44% T1, 78% T2 (p < 0.0001), and 76% T3 (P=0.0044); regional lymph node metastasis in 17% T1, 52% T2 (p < 0.0001), and 49% T3 (p = 0.0092); melanoma-related distant metastasis in 11% T1, 35% T2 (p < 0.0001), and 42% T3 (p = 0.0018); and melanoma-related death in 5% T1, 20% T2 (p = 0.0655), and 23% T3 (p = 0.0526). Based on American Joint Committee on Cancer classification, factors predictive of melanoma recurrence included T2 stage (p < 0.0001), and T3 stage (p = 0.0061). After adjusting for tumor origin, factors predictive of regional lymph node metastasis, melanoma-related distant metastasis, and melanoma-related death included melanoma arising de novo (p < 0.0001; p < 0.0001; p < 0.0001), T2 stage (p < 0.0001; p < 0.0001; p = 0.007), and T3 stage (p = 0.005; p = 0.0014; p = 0.0342). CONCLUSION The American Joint Committee on Cancer staging predicts prognosis of conjunctival melanoma. Melanoma classified as T2 and T3 (compared with T1) showed significantly higher rates of local recurrence, regional lymph node metastasis, distant metastasis, and death.

Giant Conjunctival Nevus

Conjunctival nevus is the most common tumor of the ocular surface and we selected the largest nevi to evaluate for clinical features and outcomes. To describe the clinical features and outcomes of giant (≥10 mm diameter) conjunctival nevus. Retrospective case series of 618 patients with conjunctival nevus, 32 of which had giant conjunctival nevus, treated at an ocular oncology service between July 1, 1974, and June 30, 2012. Observation, excisional biopsy, and cryotherapy. Management, nevus recurrence, and nevus transformation into melanoma. Of 618 patients with conjunctival nevus, 32 (5%) were classified as having giant conjunctival nevus. The mean patient age at diagnosis was 34 years. Of those with giant conjunctival nevus, a history of an increase in nevus base or thickness was noted in 15 cases (47%) and an increase in color intensity in 2 cases (6%). The giant nevus involved cornea in 11 cases (34%), limbus in 23 (72%), bulbar conjunctiva in 31 (97%), fornix in 9 (28%), tarsus in 3 (9%), semilunar fold in 10 (31%), and caruncle in 7 (22%). The nevi had mean diameter of 16 mm and mean thickness of 2 mm. On slitlamp examination, intrinsic cysts were identified in 25 cases (78%), intrinsic blood vessels in 26 (81%), and feeder vessels in 22 (69%). Management included excisional biopsy with cryotherapy in 23 cases (72%) and observation in 9 cases (28%). Amniotic membrane graft reconstruction was used following excision in 3 cases (13%). Malignant melanoma developed within the giant nevus in 1 case after 23 years of observation. Postexcisional biopsy, nevus recurrence was detected in 4 cases (17%), pseudopterygium in 1 (4%), dry eye in 1 (4%), and eyelid blepharoptosis in 1 (4%). In an ocular oncology practice, giant conjunctival nevus represents 5% of conjunctival nevi. This benign tumor rarely transforms into conjunctival melanoma. Management alternatives include observation or wide excisional biopsy, cryotherapy, and reconstruction, possibly with amniotic membrane graft.

Update and review of conjunctival melanoma treatment

Update and review of conjunctival melanoma treatment

TERT promoter mutations in ocular melanoma distinguish between conjunctival and uveal tumours

Background:Recently, activating mutations in the TERT promoter were identified in cutaneous melanoma. We tested a cohort of ocular melanoma samples for similar mutations.Methods:The TERT promoter region was analysed by Sanger sequencing in 47 uveal (ciliary body or choroidal) melanomas and 38 conjunctival melanomas.Results:Mutations of the TERT promoter were not identified in uveal melanomas, but were detected in 12 (32%) conjunctival melanomas. Mutations had a UV signature and were identical to those found in cutaneous melanoma.Conclusion:Mutations of TERT promoter with UV signatures are frequent in conjunctival melanomas and favour a pathogenetic kinship with cutaneous melanomas. Absence of these mutations in uveal melanomas emphasises their genetic distinction from cutaneous and conjunctival melanomas.

Conjunctival Melanomas Harbor BRAF and NRAS Mutations and Copy Number Changes Similar to Cutaneous and Mucosal Melanomas

Conjunctival melanoma is a rare but potentially deadly tumor of the eye. Despite effective local therapies, recurrence and metastasis remain frequent. Once the tumor has metastasized, treatment options are limited and the prognosis is poor. To date, little is known of the genetic alterations in conjunctival melanomas. We conducted genetic analysis of 78 conjunctival melanomas, to our knowledge the largest cohort reported to date. An oncogene hotspot array was run on 38 samples, screening for a panel of known cancer-relevant mutations. Thirty tumors were analyzed for genome-wide copy number alterations (CNA) using array-based comparative genomic hybridization. Sanger sequencing of selected target mutations was conducted in all samples. BRAF mutations were identified in 23 of 78 (29%) tumors. NRAS mutations, previously not recognized as relevant in conjunctival melanoma, were detected in 14 of 78 (18%) tumors. We found CNAs affecting various chromosomes distributed across the genome in a pattern reminiscent of cutaneous and mucosal melanoma but differing markedly from uveal melanoma. The presence of NRAS or BRAF mutations in a mutually exclusive pattern in roughly half (47%) of conjunctival melanomas and the pattern of CNAs argue for conjunctival melanoma being closely related to cutaneous and mucosal melanoma but entirely distinct from uveal melanoma. Patients with metastatic conjunctival melanoma should be considered for therapeutic modalities available for metastatic cutaneous and mucosal melanoma including clinical trials of novel agents.

C-Kit SCF receptor (CD117) expression andKITgene mutation in conjunctival pigmented lesions

To investigate the presence of KIT gene mutations and immunoreactivity in 85 conjunctival melanocytic tumours and to clarify the role of KIT as a potential therapeutic target in this group of patients. Eighty-five conjunctival pigmented tumours [27 melanomas, 12 primary acquired melanosis (PAMs) and 46 nevi] were immunostained for KIT. Intensity and pattern of expression were evaluated. Molecular analysis to identify KIT mutations was performed in 15 selected cases (tumour-rich areas >50%). KIT immunostaining score and pattern were statistically related to patients' age, sex, diagnostic category, presence of relapse, disease-free survival, presence of metastases, metastasis-free survival, limbal versus nonlimbal tumour location and thickness of melanomas. KIT stains were documented in 48% of melanomas, 50% of PAMs and 24% of nevi. The mean score of KIT staining in the melanomas/PAMs group was significantly different from nevi (p = 0.0076). No statistically significant differences were detected between either c-kit immunostaining score or pattern and each of the other clinico-pathologic parameters considered. No KIT gene mutations were detected in melanomas and nevi. A silent mutation/polymorphism in KIT exon 13 was found in one PAM. Despite the high level of KIT immunostains in PAMs and melanomas, this parameter seems not to be a good predictor of the presence of molecular mutations. KIT-activating mutations should be considered an uncommon event in this tumour.

SU‐E‐T‐355: A Novel Ophthalmic Applicator Design for Brachytherapy for Conjunctival Melanoma

Purpose: To design and construct a novel ophthalmic brachytherapy applicator for the treatment of conjunctival melanoma using I‐125 radioactive seed sources to overcome the dosimetric limitations of the commonly used standard Collaborative Ocular Melanoma Study (COMS) plaques. Methods: A commercially available polymethylmethacrylate conformer (Gulden Ophtalmics, Elkins Park, PA) was employed to hold a total of 12 low dose I‐125 seeds (model IAI‐125A, IsoAid, LLC, Port Richey, FL) distributed along the periphery of the conformer. Three dimensional dose distribution was calculated using the Plaque Simulator software (EyePhysics, LLC, Los Alamitos, CA) to optimize seed distribution pattern. The AAPM TG‐43 dose calculation formulism was utilized within the software. Results: The seed distribution pattern was designed in a way that dose would be delivered to the conjunctival tissue,while limiting the dose to the cornea and lens. Once the design was finalized, each slot for the seed was fabricated using a 6‐axis computer numerical control (CNC) machine available at our institution. The slots were milled into the convex side of the conformer to minimize any patient discomfort and to protect the cornea from direct contact with the seeds. Conclusion: The difficulty of treating conjunctival melanomas with COMS eyeplaques due to its unique anatomical distribution called for a custom design brachytherapy applicator. The applicator designed in the current study can effectively deliver radiation dose to affected area while minimizing the dose to the centrally located unaffected tissues.

Nevus melanocítico atípico limbar. A propósito de un caso

Case reportA 78-year-old-woman presented with a corneal non-pigmented vascularised tumour of her left eye, of 2 months onset, but with no previous ocular disorders. Surgical excision was performed, and the histopathological study showed the lesion to be an atypical melanocytic nevus of the limbus. DiscussionCorneal pigmented lesions tend to occur as a result of conjunctival or sclerocorneal limbus lesions spreading or arising de novo from melanocytic cells that have migrated following corneal injury. A biopsy should be carried out to type and distinguish benign lesions (nevus) from pre-malignant or malignant lesions (primary acquired melanosis or conjunctival melanoma).

Conjunctival melanoma with metastasis to the parotid gland in a 10 year-old boy: A case report and literature review

Abstract Conjunctival melanoma is a rare invasive neoplasm, usually seen in middle-aged and elderly persons. Its incidence in the adult population seems to be on the rise but it remains extremely rare in children with only few reported cases. Conjunctival melanoma metastasizing to the parotid has been reported in few cases in adults; whereas in the pediatric population only two cases of conjunctival melanoma metastasis have been reported from which only one is to the parotid gland. Methods : A case report of conjunctival melanoma and secondary metastasis to the ipsilateral parotid gland in 10 year-old boy and literature review. Case report : A 10 year-old boy, previously healthy, presented to the ophthalmology service for left conjunctival nevus that was surgically excised after a rapid increase in size. The histopathologic diagnosis came out as melanoma. He presented 1month after excision with left preauricular node. MRI study showed a parotid lymph node with a necrotic center that was also positive on PET scan. Fine needle aspiration cytology revealed metastatic melanoma. Following a complete negative workup for other metastatic disease, the patient underwent left total parotidectomy with facial nerve preservation and ipsilateral neck dissection. Plaque brachytherapy was given for local control of the conjunctival lesion. Post operatively he received systemic chemotherapy with interferon-α2b and left neck radiotherapy with no evidence of recurrence or metastasis after almost 1 year post-diagnosis. Conclusion : Malignant melanomas of the conjunctiva are extremely rare in children and even more rare to present with metastasis. We hereby present the second case of conjunctival melanoma metastatic to the parotid in a pediatric patient.

Dematiaceous Fungi Mimicking a Conjunctival Melanoma

An 85-year-old, immunocompetent man was referred to the authors due to the presence of an enlarging, pigmented mass of the conjunctiva concerning for a conjunctival melanoma. Wide excision of the mass revealed a pigmented or "dematiaceous" fungus. He was treated with topical natamycin, and the lesion healed well without any evidence of recurrence. Dematiaceous fungi should be considered in the differential for pigmented conjunctival lesions.

This issue of ACTA, printed and electronic

This issue of <i>ACTA</i>, printed and electronic

The Use of Strontium-90 Beta Radiotherapy as Adjuvant Treatment for Conjunctival Melanoma

Background/Aims. To report the safety and efficacy of strontium (Sr90) beta radiotherapy as adjuvant treatment for conjunctival melanoma. Methods. A retrospective cohort study was undertaken from 1999 to 2007 of all patients who underwent Sr90 beta radiotherapy for incompletely excised conjunctival melanoma. Failure of treatment was defined as recurrence of a conjunctival melanoma at the same location following beta radiotherapy. Results. Twenty patients underwent Sr90 beta radiotherapy for incompletely excised conjunctival melanoma. Median follow-up interval was 59 months (8–152). All patients had conjunctival melanoma involving the bulbar conjunctiva. Underlying diagnoses included PAM with atypia in 60% (12 of 20), PAM without atypia in 15% (3 of 20), and de novo conjunctival melanoma in 25% (5 of 20). Following Sr90 beta radiotherapy, in 90% (18 out of 20) local control was achieved and visual acuity was not affected in any patient. Three patients (15%) had dry eye symptoms, episcleritis, and descemetcoele, respectively. No cataract or secondary glaucoma was reported. Conclusions. Sr90 treatment is a very effective adjuvant treatment after excisional biopsy and cryotherapy for conjunctival melanoma with a local success rate of 90%. The treatment is not associated with significant side effects and visual acuity is not affected.

Conjunctival melanoma: a review of conceptual and treatment advances

The aim of this study was to review the available literature and identify recent advances in the classification and management of conjunctival melanoma (CM) for clinicians working in this field. English-based articles were identified using the MEDLINE® database, and additional cited works not detected in the initial search were also obtained. Articles were assessed according to the Australian National Health and Medical Research Council levels of evidence criteria. Review of the literature indicated that the current classification and management of CM is predominantly based upon primarily nonrandomized, single-institution, retrospective case series. While these studies provide the basis for the recent seventh edition of the tumor node metastasis staging classification, this classification more accurately reflects the current knowledge of prognostic factors for CM. Application of this revised classification system together with prospective trials will provide the opportunity for future consistent and comparable data collection across centers, and it will improve the quality of evidence upon which current classification and management of CM is based. Furthermore, the high risk of local recurrence with current standard management suggests that adjuvant therapy, particularly mitomycin C and/or brachytherapy, may improve outcomes regardless of clinical staging. Finally, the use of sentinel lymph node biopsy may have significant benefit for a select group of CM patients.

18F-FDG PET-CT for Staging of Conjunctival Melanoma

The value of F-18 fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET-CT) for the evaluation of cutaneous melanoma has been demonstrated previously. However, there are few reports regarding the use PET-CT for the staging of conjunctival melanoma (CM). We report here a case, a 34-year-old male with a six-month history of a pigmented nodule at the palpebral conjunctiva of the left eye, and a firm left preauricular lymph node detected on physical examination. Biopsy of the ocular lesion confirmed CM, and fine needle aspiration cytology of the preauricular node was positive for malignancy. CT showed three pulmonary nodules. An 18F-FDG PET-CT was performed to restage the patient. The study showed hypermetabolic lesions in the left eye, and in the left preauricular node. The scan was negative for metastasis. These findings were important in guiding management of the disease in this patient. Future prospective studies should further evaluate the role of 18F-FDG PET-CT for the staging of CM.

Sentinel Lymph Node Biopsy for Eyelid and Conjunctival Tumors

To describe current indications, methods, and outcomes of sentinel lymph node (SLN) biopsy for eyelid and conjunctival tumors. Review of experience to date and relevant articles published in PubMed in English. The use of SLN biopsy for conjunctival and eyelid tumors has evolved greatly in the past decade, and positive SLNs have been reported for conjunctival and eyelid melanoma, eyelid Merkel cell carcinoma, eyelid sebaceous carcinoma, and eyelid squamous cell carcinoma. Current indications for SLN biopsy of eyelid and conjunctival malignancies are the presence of conjunctival melanomas ≥2 mm in histologic thickness and/or histologic ulceration; cutaneous eyelid melanomas ≥1 mm thick, those with >1 mitotic figures per high-power field, and/or those with histologic ulceration; sebaceous carcinomas ≥10 mm in width; and Merkel cell carcinomas of any size. The frequency of false-negative biopsy results seems to be decreasing as more experience is gained with the technical nuances of the procedure and with the complex lymphatic drainage of the head and neck region. Given the emerging data published on feasibility and reported cases of microscopically positive SLNs identified in patients with otherwise normal examination of the regional lymph nodes and normal imaging studies, it seems appropriate to continue to further evaluate SLN biopsy for selected ocular tumors in future prospective studies. SLN biopsy is feasible for eyelid and conjunctival tumors, and continued use of the procedure is recommended. Future multi-institutional trials are needed to expand on currently available data, fine-tune patient selection criteria, and elucidate the relationships between SLN status and patient survival and tumor recurrence.

Therapy of melanocytic conjunctival tumors

Clinical experience of our single center in dealing with pigmented epibulbar lesions - melanocytic conjunctival tumors is presented. Since 2008 we use the topical treatment with mitomycin C (MMC) as an alternative or adjunctive method for excision in the treatment of melanocytic neoplasia of the conjunctiva. The retrospective case series of 85 patients with pigmented lesions of the conjunctiva - melanocytic conjunctival tumors, histopathologically examined in the period 2001-2010 is presented. Since 2008 we started to apply MMC in the treatment of primary acquired melanosis (PAM) and dysplastic nevi. We apply MMC topically directly after an excision as 2-times five minutes application. In 85 patients with pigmented lesions of the conjunctiva histopathological findings after excision of the lesion showed in 68 (80 %) cases melanocytic nevocelullar nevus, out of which 55 cases were combined and 13 cases were junctional nevi. In 60 (80 %) cases of melanocytic nevi atypia was found in 25 patients (42 %), nevus without atypia was present in 35 cases (58 %). PAM with atypia was found in 16 patients (classified since 2000). During the period of application of MMC we diagnosed only one patient with primary conjunctival melanoma. There was no presence of relapse of the pigmented lesion either after primary excision or after excision with MMC. Resection of more than one quadrant of bulbar conjunctiva in patients with pigmented lesions of the conjunctiva in cases of conjunctival nevus with atypia and PAM with atypia combined with topical MMC chemotherapy is an alternative therapy for residual pigmented lesions. There was no presence of relapse of pigmentation in area of excision with or without using MMC during the surgery in patients with PAM. The number of our patients is not sufficient yet to draw a conclusion (Fig. 6, Ref. 21).