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Knowing how to recognize and manage the various forms of conjunctival pigmented lesions can literally mean the difference between life and death in some cases.
Reviewed by Carol L. Shields, MD
When it comes to conjunctival pigmented lesions, knowing how to manage nevus, primary acquired melanosis (PAM), and melanoma can dramatically help to improve patient survival, said Carol L. Shields, MD. Conjunctival melanoma is relatively rare, at about 0.43 per million persons,1 and this tumor can be fatal.
Conjunctival nevus tends to be pigmented and asymptomatic with a low risk for transformation into melanoma, somewhere under 1%, said Dr. Shields, co-director, Oncology Service, Wills Eye Hospital, and professor of ophthalmology at Thomas Jefferson University in Philadelphia. PAM tends to occur in Caucasians, is nearly always unilateral, and carries a chance for melanoma somewhere between 10% and 30%.
“We like to clean that up-we don’t want to see melanoma,” she said.
Though conjunctival melanoma is relatively rare, this tumor can be fatal. Clinicians should look for molecular biomarkers in all patients to identify high-risk melanoma because there are medications for biomarkers. (Images courtesy of Carol L. Shields, MD)
PAM is considered a strong precursor to conjunctival melanoma. Once a patient has a melanoma, there is a risk for invasion posteriorly in the orbit, with a 60% to 70% chance for metastasis, and ultimately, death from melanoma, Dr. Shields noted.
“Do not ignore a pigmented lesion,” Dr. Shields advised.
In pediatric cases, the diagnosis is almost always a nevus.
However, in some middle-aged patients, a pigmented lesion could be nevus or something more suspicious, like PAM or melanoma. These patients should be referred to an ocular oncologist for management.
Conjunctival nevus starts at the junction of the epithelium and the stroma, generally as a congenital birthmark that becomes visible in the first decade of life.
“One of the hallmarks of conjunctival nevi is the presence of intralesional cysts seen in about 65% of cases,” Dr. Shields said. “Nevi can be pigmented or nonpigmented, and the nonpigmented lesions often masquerade as other conditions, like episcleritis, scleritis, and lymphoid tumors.
“Cysts are not pathognomonic for nevi,” she added. “They can be found with other tumors, such as mucoepidermoid squamous neoplasia or lymphangioma/lymphangiectasia.”
Most conjunctival nevi occur on the bulbar conjunctiva right at the limbus at 3 or 9 o’clock, according to Dr. Shields.
It is “pretty rare to see a nevus in the fornix or on the tarsus or on the cornea,” she said.
Consider PAM if there is a pigmented lesion in those areas, she advised.
About 15% of conjunctival nevi occur in the caruncle region, and these nevi have fine hairs from the pilosebaceous units emanating through the nevus.
“Keep in mind, melanoma in the caruncle can occur and that’s an ominous location because it tends to grow deep before it is discovered,” Dr. Shields said.
There are several types of nevi, including giant nevus and blue nevus. Giant nevi occupy at least one quadrant on the bulbar surface-and based on size alone, melanoma is considered. Ideally, these should be completely resected.
Blue nevus tends to be deep to Tenon’s fascia with a gray-black appearance.
“Even though it is benign, the dark color imparts a suspicious look and can resemble deep melanoma,” she said. "Flip the lid and check the tarsus to rule out tarsal PAM or melanoma.”
Overall, studies suggest 1 in 300 conjunctival nevi will evolve into melanoma.
PAM appears like a flat freckle, is usually unilateral, and starts in the basal layer of the epithelium as melanoma in situ. It can be occasionally found in non-Caucasians, also imparting a risk for melanoma in those patients.
PAM is flat and has no cysts, but the rate of PAM transformation into melanoma at 10 years is about 12%. In one retrospective chart review of 382 consecutive patients,2 melanoma arose from PAM in 74% of the cases.
“We need to beat PAM to prevent melanoma,” she said. There are clues for identifying which PAM case might turn into melanoma-the most important factor being the size of PAM.
“Every clock hour adds a 1.7-times greater risk for transformation into melanoma,” Dr. Shields said. For example, a patient with 7 clock hours has a 12-times greater risk for transformation than the patient with only 1 clock hour.
Conjunctival melanoma is increasing in the United States, Dr. Shields said.
“It’s increase is mostly related to the depletion of the ozone layer and excessive sun exposure,” she said. “The rate is highest in men.”
There are close to 200 cases in the United States per year, and the risk for metastasis is about 25% by 10 years. Melanoma generally appears pigmented, but can be nonpigmented and hide for months.
In one study, 5 years (10 years), melanoma-related death occurred in 5% (9%) in melanoma arising from PAM, 0% (9%) in melanoma arising from nevus, and was significantly worse in those arising de novo 17% (35%), p < 0.001).2
Melanoma management “is more than removing a lump on the surface of the eye,” she said.
It involves precise surgical resection to achieve clean margins and avoidance of direct tumor manipulation (“no-touch” technique), cryotherapy to surrounding PAM, and reconstruction with flaps and grafts.
The first surgery is unquestionably the most important to minimize tumor seeding. Patients with conjunctival melanoma should be managed at an experienced center to avoid tumor recurrence and metastasis, Dr. Shields suggested.
New information on conjunctival melanoma involves such tumor biomarkers as BRAF, TERT, and PTEN. These markers could be mutated in melanoma and provide information regarding risk for metastasis. Clinicians now have targeted antibiomarker therapies that can improve prognosis.3
“We look for molecular biomarkers in all patients to identify high-risk melanoma because we have medications for biomarkers,” she said. “It’s similar to skin melanoma management.”
One study found 40% of patients with conjunctival melanoma have BRAF mutation, and implies a poor prognosis.4,5
TERT is also a promoter mutation for melanoma and for melanoma survivorship, and patients with TERT mutations have poor survival rates.6
PTEN is seen in several kinds of cancers, and can be mutated in conjunctival melanoma.
On the upside, Dr. Shields noted that anti-BRAF medications are available, including vemurafenib and dabrafenib, that “hunt down BRAF mutations and wipe out the tumor.”
1. Yu GP, Hu DN, McCormick S, Finger PT. Conjunctival melanoma: Is it increasing in the United States? Am J Ophthalmol. 2003;135:800-806.
2. Shields CL, Markowitz JS, Belinsky I, et al. Conjunctival melanoma: Outcomes based on tumor origin in 382 consecutive cases. Ophthalmology. 2011;118:389-395.
3. Shields CL, Chien JL, Surakiatchanukul T, Sioufi K, Lally SE, Shields JA. Conjunctival tumors: Review of clinical features, risks, biomarkers, and outcomes--The 2017 J. Donald M. Gass Lecture. Asia-Pac J Ophthlamol. 2017;6:109-120.
4. Larsen AC, Dahmcke CM, Dahl C, et al. A retrospective review of conjunctival melanoma presentation, treatment, and outcome and an investigation of features associated with BRAF mutations. JAMA Ophthalmol. 2015;133:1295-1303.
5. Larsen AC, Dahl C, Dahmcke CM, et al. BRAF mutations in conjunctival melanoma: Investigation of incidence, clinicopathological features, prognosis, and paired premalignant lesions. Acta Ophthalmol. 2016;94:463-470.
6. Nagore E, Heidenreich B, Rachakonda S, et al. TERT promoter mutations in melanoma survival. Int J Cancer. 2016;139:75-84.
Carol L. Shields, MD
E: Oncology@willseye.org or email@example.com
This article was adapted from Dr. Shields’ presentation during Cornea Subspecialty Day at the 2016 meeting of the American Academy of Ophthalmologyy. Dr. Shields is a consultant to Aura Biosciences.