Grand Rounds Amir R. Hajrasouliha, M.D. University of Louisville Department of Ophthalmology and Visual Sciences Friday, August 15th, 2014

Patient Presentation HPI: 80 y/o white male is presenting for yearly checkup s/p excisional biopsy of conjunctival melanoma in his right eye 4 yrs ago. He had no recurrence of disease for the past two years on examination. No other complaint. HPI: 80 y/o white male is presenting for yearly checkup s/p excisional biopsy of conjunctival melanoma in his right eye 4 yrs ago. He had no recurrence of disease for the past two years on examination. No other complaint.

Patient Presentation POH: POH: Conjuctival melonoma arising from primary acquired melanosis OD s/p resection 2009 Conjuctival melonoma arising from primary acquired melanosis OD s/p resection 2009 PMH: PMH: HTN HTN Meds: Meds: HCTZ HCTZ ROS: ROS: Negative (No headaches, weight loss or night sweats) Negative (No headaches, weight loss or night sweats) Allergy: Allergy: NKDA NKDA

Exam BCVA cc P T TP BCVA cc P T TP EOM: FULL OU CVF: FULL OU 20/20 3  2mm (-) RAPD 20/20

ODOS ExtWNLWNL L/LWNLWNL Conjpigmented nestsWNL at superior limbus KClearClear ACFormed Formed IrisWNLWNL Lens1+NS 1+NS Exam

Plan Excisional biopsy

melanosis of basal cell

Nest of cells

Atypical cells

Assessment 80 year old male with recurrent conjuctival melanoma OD 80 year old male with recurrent conjuctival melanoma OD

Plan/Follow up Excision with topical Mitomycin-C 0.04% four times a day for 4 cycles of 7 days on drop and 7 days off. Excision with topical Mitomycin-C 0.04% four times a day for 4 cycles of 7 days on drop and 7 days off. Systemic workup was negative (including whole body CT-PET) Systemic workup was negative (including whole body CT-PET)

Conjuctival Melanoma Malignant melanoma of the conjunctiva presents as a raised, pigmented or nonpigmented lesion that appears most commonly in white patients in their early 50s. Malignant melanoma of the conjunctiva presents as a raised, pigmented or nonpigmented lesion that appears most commonly in white patients in their early 50s. May arise from acquired nevi (2%), from PAM (50- 75%), or de novo(10%). May arise from acquired nevi (2%), from PAM (50- 75%), or de novo(10%). Accounts for only 2% of all ocular malignancies. Accounts for only 2% of all ocular malignancies.

Clinical Finding Poor prognosis indicators Poor prognosis indicators Location in palpebral conjunctiva, caruncle or fornix Location in palpebral conjunctiva, caruncle or fornix Invasion into deeper tissue Invasion into deeper tissue Thickness > 1.8mm Thickness > 1.8mm Pagetoid or full-thickness intraepithelial spread Pagetoid or full-thickness intraepithelial spread Lymphatic invasion Lymphatic invasion Involvement of eyelid margin Involvement of eyelid margin

Management Excisional biopsy should be considered for any suspicious pigmented epibulbar lesions. Excisional biopsy should be considered for any suspicious pigmented epibulbar lesions. Excision is recommended 4mm beyond clinically apparent margins of the tumor along with thin lamellar scleral flap beneath the tumor and cryotherapy applied to the conjuctival margins. Excision is recommended 4mm beyond clinically apparent margins of the tumor along with thin lamellar scleral flap beneath the tumor and cryotherapy applied to the conjuctival margins. Topical mitomycin has been used to treat residual diseases. Topical mitomycin has been used to treat residual diseases.

Management Orbital exentration is performed for advanced disease when local excision or enucleation would be insufficient. Orbital exentration is performed for advanced disease when local excision or enucleation would be insufficient.

JAMA Ophthalmol May;132(5):622-9.Usefulness of a red chromagen in the diagnosis of melanocytic lesions of the conjunctiva.

The role of SLNB remains controversial. The role of SLNB remains controversial. The frequency of regional lymph node The frequency of regional lymph node metastases is reported to be between 26% metastases is reported to be between 26% and 40%. and 40%. Two studies reported that 17/194 patients Two studies reported that 17/194 patients (8.7%) and 7/27 patients (26%) presented (8.7%) and 7/27 patients (26%) presented with distant metastases without prior or concurrent regional lymph node involvement (skipping metastases). with distant metastases without prior or concurrent regional lymph node involvement (skipping metastases). A few studies show supporting evidence for the use of SLNB for tumors thicker than 2 mm, as well as for tumors greater than 10 mm in diameter with increasing tumor diameter associated with a higher risk of distant recurrence. A few studies show supporting evidence for the use of SLNB for tumors thicker than 2 mm, as well as for tumors greater than 10 mm in diameter with increasing tumor diameter associated with a higher risk of distant recurrence. Conjunctival melanoma: a review of conceptual and treatment advances. Clin Ophthalmol. 2013; 7: 521– 531. Sentinel Lymph Node Biopsy

Gene mutation and diagnosis The application of gene mutation analysis to conjunctival melanomas (CMs) has also not been definitive in classifying lesions. However, recent work using multiplex ligation-dependent probe amplification identified a BRAF V600E mutation in approximately 50% of a small cohort of primary CMs, and more than 50% of metastatic specimens, supporting results of earlier studies. The application of gene mutation analysis to conjunctival melanomas (CMs) has also not been definitive in classifying lesions. However, recent work using multiplex ligation-dependent probe amplification identified a BRAF V600E mutation in approximately 50% of a small cohort of primary CMs, and more than 50% of metastatic specimens, supporting results of earlier studies. It has been proposed that the BRAF inhibitor PLX4023 (vemurafenib), specific for the V600E mutation, could be used for the treatment of CM, similar to the situation for cutaneous melanoma with BRAF V600E mutation. It has been proposed that the BRAF inhibitor PLX4023 (vemurafenib), specific for the V600E mutation, could be used for the treatment of CM, similar to the situation for cutaneous melanoma with BRAF V600E mutation. Lake SL et al. Multiplex ligation-dependent probe amplification of conjunctival melanoma reveals common BRAF V600E gene mutation and gene copy number changes. Invest Ophthalmol Vis Sci. 2011;52(8):5598–5604.

There is every possibility that blood testing for the presence of methylated DNA will become an integral part of the clinical follow-up of patients with melanoma. The ability to identify patients with subclinical (asymptomatic) metastatic melanoma, combined with new, highly active targeted and immunomodulatory agents, may lead to further improvements in outcomes for this patient population. There is every possibility that blood testing for the presence of methylated DNA will become an integral part of the clinical follow-up of patients with melanoma. The ability to identify patients with subclinical (asymptomatic) metastatic melanoma, combined with new, highly active targeted and immunomodulatory agents, may lead to further improvements in outcomes for this patient population. Built on Digital Sequencing, Guardant360 provides high-fidelity tumor sequencing information at the single-molecule level. Digital Sequencing is a proprietary method of capturing and genetically profiling trace fragments of tumor DNA that are shed into the blood stream (cell-free DNA). Built on Digital Sequencing, Guardant360 provides high-fidelity tumor sequencing information at the single-molecule level. Digital Sequencing is a proprietary method of capturing and genetically profiling trace fragments of tumor DNA that are shed into the blood stream (cell-free DNA). Identification of multiple informative genomic mutations by deep sequencing of circulating cell-free tumor DNA in plasma of metastatic melanoma patients. J Clin Oncol 32:5s, 2014 (suppl; abstr 9018 Diagnosis

Thank You