Grand RoundsGrand Rounds

Amir R. Hajrasouliha, M.D.Amir R. Hajrasouliha, M.D.

University of LouisvilleUniversity of Louisville

Department of Ophthalmology and Visual Department of Ophthalmology and Visual SciencesSciences

Friday, August 15th, 2014Friday, August 15th, 2014

Patient PresentationPatient Presentation

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

Patient PresentationPatient Presentation POHPOH: :

Conjuctival melonoma arising from primary acquired Conjuctival melonoma arising from primary acquired melanosis OD s/p resection 2009melanosis OD s/p resection 2009

PMHPMH: : HTNHTN

MedsMeds: : HCTZHCTZ

ROS:ROS: Negative (No headaches, weight loss or night sweats)Negative (No headaches, weight loss or night sweats)

Allergy:Allergy: NKDANKDA

ExamExam

BCVA cc PBCVA cc P T TTPTP

EOM: FULL OU CVF: FULL OUEOM: FULL OU CVF: FULL OU

20/20

32mm

32mm

14

15(-) RAPD

20/20

ODOD OSOS

ExtExt WNLWNL WNLWNLL/LL/L WNLWNL WNLWNLConjConj pigmented nestspigmented nests WNLWNL

at superior limbusat superior limbusKK ClearClear ClearClearACAC FormedFormed Formed Formed

IrisIris WNLWNL WNLWNLLensLens 1+NS1+NS 1+NS 1+NS

ExamExam

PlanPlan

Excisional biopsyExcisional biopsy

melanosis of basal cell

Nest of cells

Atypical cells

Assessment Assessment

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

Plan/Follow upPlan/Follow up

Excision with topical Mitomycin-C 0.04% Excision with topical Mitomycin-C 0.04% four times a day for 4 cycles of 7 days on four times a day for 4 cycles of 7 days on drop and 7 days off.drop and 7 days off.

Systemic workup was negative (including Systemic workup was negative (including whole body CT-PET)whole body CT-PET)

Conjuctival MelanomaConjuctival Melanoma Malignant melanoma of Malignant melanoma of

the conjunctiva presents the conjunctiva presents as a raised, pigmented or as a raised, pigmented or nonpigmented lesion that nonpigmented lesion that appears most commonly appears most commonly in white patients in their in white patients in their early 50s.early 50s.

May arise from acquired May arise from acquired nevi (2%), from PAM (50-nevi (2%), from PAM (50-75%), or de novo(10%).75%), or de novo(10%).

Accounts for only 2% of Accounts for only 2% of all ocular malignancies.all ocular malignancies.

Clinical FindingClinical Finding

Poor prognosis indicatorsPoor prognosis indicators Location in palpebral conjunctiva, caruncle or fornixLocation in palpebral conjunctiva, caruncle or fornix Invasion into deeper tissueInvasion into deeper tissue Thickness > 1.8mmThickness > 1.8mm Pagetoid or full-thickness intraepithelial spreadPagetoid or full-thickness intraepithelial spread Lymphatic invasionLymphatic invasion Involvement of eyelid marginInvolvement of eyelid margin

ManagementManagement

Excisional biopsy should be considered for any Excisional biopsy should be considered for any suspicious pigmented epibulbar lesions.suspicious pigmented epibulbar lesions.

Excision is recommended 4mm beyond clinically Excision is recommended 4mm beyond clinically apparent margins of the tumor along with thin apparent margins of the tumor along with thin lamellar scleral flap beneath the tumor and lamellar scleral flap beneath the tumor and cryotherapy applied to the conjuctival margins.cryotherapy applied to the conjuctival margins.

Topical mitomycin has been used to treat Topical mitomycin has been used to treat residual diseases.residual diseases.

ManagementManagement

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

JAMA Ophthalmol. 2014 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 nodeThe 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 with distant metastases without prior or concurrent regional lymph node involvement (skipping metastases). lymph node involvement (skipping metastases).

A few studies show supporting evidence for the use of SLNB A few studies show supporting evidence for the use of SLNB for tumors thicker than 2 mm, as well as for tumors greater for tumors thicker than 2 mm, as well as for tumors greater than 10 mm in diameter with increasing tumor diameter than 10 mm in diameter with increasing tumor diameter associated with a higher risk of distant recurrence. 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 Sentinel Lymph Node BiopsyBiopsy

Gene mutation and Gene mutation and diagnosisdiagnosis

The application of gene mutation analysis to conjunctival The application of gene mutation analysis to conjunctival melanomas (CMs) has also not been definitive in melanomas (CMs) has also not been definitive in classifying lesions. However, recent work using multiplex classifying lesions. However, recent work using multiplex ligation-dependent probe amplification identified a BRAF ligation-dependent probe amplification identified a BRAF V600E mutation in approximately 50% of a small cohort V600E mutation in approximately 50% of a small cohort of primary CMs, and more than 50% of metastatic of primary CMs, and more than 50% of metastatic specimens, supporting results of earlier studies.specimens, supporting results of earlier studies.

It has been proposed that the BRAF inhibitor PLX4023 It has been proposed that the BRAF inhibitor PLX4023 (vemurafenib), specific for the V600E mutation, could be (vemurafenib), specific for the V600E mutation, could be used for the treatment of CM, similar to the situation for used for the treatment of CM, similar to the situation for cutaneous melanoma with BRAF V600E mutation.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 There is every possibility that blood testing for the presence of methylated DNA will become an integral part of the clinical follow-up methylated DNA will become an integral part of the clinical follow-up of patients with melanoma. The ability to identify patients with of patients with melanoma. The ability to identify patients with subclinical (asymptomatic) metastatic melanoma, combined with subclinical (asymptomatic) metastatic melanoma, combined with new, highly active targeted and immunomodulatory agents, may lead new, highly active targeted and immunomodulatory agents, may lead to further improvements in outcomes for this patient population.to further improvements in outcomes for this patient population.

Built on Digital Sequencing, Guardant360 provides high-fidelity Built on Digital Sequencing, Guardant360 provides high-fidelity tumor sequencing information at the single-molecule level. Digital tumor sequencing information at the single-molecule level. Digital Sequencing is a proprietary method of capturing and genetically Sequencing is a proprietary method of capturing and genetically profiling trace fragments of tumor DNA that are shed into the blood profiling trace fragments of tumor DNA that are shed into the blood stream (cell-free DNA).stream (cell-free DNA).

Identification of multiple informative genomic mutations by deep sequencing of circulating cell-free 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 tumor DNA in plasma of metastatic melanoma patients. J Clin Oncol 32:5s, 2014 (suppl; abstr 90189018

DiagnosisDiagnosis

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