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  • Conjunctival Melanoma: Rare but Deadly

    Oculoplastics/Orbit
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    Conjunctival melanoma is a rare but potentially deadly ocular malignancy.1,2 It is well known to masquerade for months or years as a red spot on the eye or as focal conjunctivitis that is resistant to topical medications. It can be clinically confused with more common conditions, such as conjunctival nevus or primary acquired melanosis.3 Conjunctival melanoma arises from the mucous membrane that lines the surface of the eye. Recent evidence indicates that its incidence is rising. According to a study published in the American Journal of Ophthalmology in June 2003, conjunctival melanoma incidence increased by 5.5% biannually from 1973 to 1999, and this increase was particularly pronounced in white men and patients age 60 and older. The study's authors suggested that the change in incidence of conjunctival melanoma paralleled that of cutaneous melanoma and had a possible etiology of exposure to sunlight.4

    Most patients with conjunctival melanoma report symptoms of a painless brown or pink lesion on the surface of the eye for months or years. They typically seek medical care after the appearance of the lesion changes, thickens, or develops enlarged blood vessels.

    Predisposing Factors

    Malignant melanoma of the conjunctiva can arise from a conjunctival nevus, primary acquired melanosis (PAM), or de novo (without a pre-existing lesion) (Figure 1). A conjunctival nevus is a pigmented or nonpigmented elevated mass usually detected in children and often with intralesional cysts. An analysis of 410 patients with conjunctival nevus who were followed for a mean of seven years showed that 1% of the patients were eventually diagnosed with melanoma.5 Conjunctival PAM is a flat pigmented lesion without cysts that is detected primarily in adults. PAM can involve a small spot on the conjunctiva or extend to cover the conjunctiva's entire surface, including the bulbar, forniceal, and palpebral conjunvtiva, as well as the cornea. Occasionally PAM extends onto the skin and is labeled lentigo maligna. Conjunctival PAM poses a substantial risk for evolving into melanoma, with an estimated overall risk ranging from 9%, according to Wills Eye Institute research, to 32%, as observed by the Armed Forces Institute of Pathology.6,7 Greater extent of PAM increases the risk of transformation to melanoma, and each additional clock hour of involvement increases the relative risk of developing melanoma by 1.7.6 PAM patients at greatest risk of evolution to melanoma are those that show histopathologic evidence of severe atypia. Their risk ranges up to 13% in a clinic-based study and from 75% to 90% in a pathology-based study.6,7

    Courtesy of Carol L. Shields, MD
    Figure 1. Conjunctival nevus (A) and primary acquired melanosis (B)

    Clinical Features

    Conjunctival melanoma shows considerable clinical variability.1-3,8 It is generally a painless, pigmented or tan, elevated lesion located on the limbal, bulbar, forniceal, or palpebral conjunctiva. Often prominent feeder vessels and surrounding flat PAM are present (Figure 2). Conjunctival melanoma can range from a tiny lesion measuring less than 1 mm in diameter to a huge neglected mass encompassing the entire surface of the eye and measuring over 40 mm in diameter. Invasion into the orbit is particularly ominous. Local tumor recurrence afflicts around half of conjunctivae melanoma patients and distant metastasis approximately one in four (Table 1). Multiple recurrences, especially those that occur within the orbit, necessitate orbital exenteration. The most common sites of metastases are ipsilateral preauricular or submandibular lymph nodes, the brain, lung, and liver.8,9

    Courtesy of Carol L. Shields, MD
    Figure 2. Small (A) and large (B) conjunctival melanoma.

    Table 1. Risks for local tumor recurrence, exenteration, metastasis, and death in patients with conjunctival melanoma.8

    Diagnostic Testing

    The diagnosis of conjunctival melanoma is suspected particularly in an adult patient who notes the onset of a new pigmented lesion on the surface of the eye. There are several pigmented conjunctival tumors, including nevus, racial melanosis, primary acquired melanosis, and melanoma. In most instances, a clinical examination can differentiate these conditions. Nevi are generally present since childhood and often display subtle intrinsic cysts. Racial melanosis is flat bilateral pigment in dark complected races, classically manifesting in the perilimbal region. Primary acquired melanosis is unilateral flat pigmentation in light complected races and haphazard in distribution. Melanoma tends to display feeder vessels, measurable thickness, and irregular shape. Complete surgical excision of conjunctival melanoma with histopathology confirmation is critical. Occasionally ultrasound biomicroscopy is necessary to exclude intraocular invasion. Magnetic resonance imaging is useful for those patients suspected of having orbital extension and to rule out brain metastasis. There is interest in using sentinel lymph node biopsy to track micrometastatic disease, but its long-term benefit has not yet been established.9

    Current Treatments

    The management of conjunctival melanoma varies with the extent of the lesion.10 In general, this malignancy is particularly difficult to treat. Despite excellent microscopic excision of the mass, further disease can develop from associated PAM in 26% of patients within five years and 65% of patients within 15 years.8 

    While there have been no randomized controlled trials for the treatment of conjunctival melanoma, I describe the following treatments based on more than three decades of experience. Classic melanoma at the corneoscleral limbus is removed under the operating microscope with precision. The flat corneal component is removed with absolute alcohol treatment of the involved cornea. Then an epitheliectomy under totally dry conditions is used to scroll off the epithelium. The conjunctival component is removed with the wide "no touch" surgical technique of partial lamellar scleroconjunctivectomy, achieving tumor-free margins of 4 mm, and followed by double freeze-thaw cryotherapy. It is important to avoid partial excision as this can seed the tumor and lead to conjunctival or orbital recurrence. Larger lesions that extend into the forniceal region or orbit can require more extensive excision, always completed with tumor-free margins surrounding the tumor and no touch, dry technique. Closure is achieved by primary apposition of conjunctiva or with conjunctival rotational flaps, a mucous membrane graft from the opposite eye or the buccal mucosa, or amniotic membrane transplantation. Tissue glues have been used to place and secure grafts, particularly amniotic membrane. Often, fornix-deepening sutures or a symblepharon ring is required to re-form the fornix. Lesions that extend into the globe typically require modified enucleation, and those that extend into the orbit require orbital exenteration. If a patient with known conjunctival melanoma develops recurrent PAM, it is advisable to treat the melanosis promptly before melanoma develops using methods of excision, cryotherapy, or topical mitomycin C or interferon alpha-2b.

    Systemic Monitoring

    Patients with conjunctival melanoma should be monitored two or three times a year for metastatic disease. Metastases most often appear in the preauricular or submandibular lymph nodes, lung, and brain. Physical examination should include palpation of the head and neck lymph nodes. Annual chest X-rays and brain magnetic resonance imaging are recommended. Sentinel lymph node biopsy is recommended for the detection of micrometastases to the regional lymph nodes. It is hoped that this will improve a patient's chances of survival,9 but there is no evidence to date that it will do so.

    Prognosis

    Local recurrence of conjunctival melanoma and metastatic disease is most often found in patients with large multifocal or recurrent tumors, particularly those whose tumors are in the conjunctival fornix, caruncle, or tarsal region and those in whom histopathology indicates positive margins.8 This latter group of patients with positive margins on histopathology showed a 5.7 relative risk of succumbing to metastatic disease. To improve their prognosis, patients with conjunctival melanoma should be monitored by experienced ocular oncologists at four to six month intervals to detect even minimal disease recurrence or precursor PAM that might require treatment.

    References

    1. Shields JA, Shields CL. Conjunctival melanocytic lesions. Atlas of Eyelid and Conjunctival Tumors. Philadelphia, Pa: Lippincott Williams & Wilkins.; 2008;307-48.

    2. Seregard S. Conjunctival melanoma. Surv Ophthalmol. 1998;42:321-350.

    3. Shields CL, Demirci H, Karatza E, Shields JA. Clinical survey of 1643 melanocytic and nonmelanocytic tumors of the conjunctiva. Ophthalmology. 2004;111:1747-1754.

    4. Yu GP, Hu DN, McCormick S, Finger PT. Conjunctival melanoma: Is it increasing in the United States? Am J Ophthalmol. 2003;135:800-806.

    5. Shields CL, Fasiudden A, Mashayekhi A, Shields JA. Conjunctival nevi: clinical features and natural course in 410 consecutive patients. Arch Ophthalmol. 2004;122:167-175.

    6. Shields JA, Shields CL, Mashayekhi A, et al. Primary acquired melanosis of the conjunctiva: risks for progression to melanoma in 311 eyes. The 2006 Lorenz E. Zimmerman lecture. Ophthalmology. 2008;115:511-519.

    7. Folberg R, McLean IW, Zimmerman LE. Primary acquired melanosis of the conjunctiva. Hum Pathol. 1985;16:136-43.

    8. Shields CL, Shields JA, Gunduz K, et al: Conjunctival melanoma: risk factors for recurrence, exenteration, metastasis, and death in 150 consecutive patients. Arch Ophthalmol. 2000;118:1497-1507.

    9. Esmaeli B, Eicher S, Popp J, Delpassand E, Prieto VG, Gershenwald JE. Sentinel lymph node biopsy for conjunctival melanoma. Ophthal Plast Reconstr Surg. 2001;17:436-442.

    10. Shields CL. Conjunctival melanoma. Br J Ophthalmol. 2002;86:127.

    11. Shields CL, Demirci H, Shields JA, Spanich C. Dramatic regression of conjunctival and corneal acquired melanosis with topical mitomycin C. Br J Ophthalmol. 2002;86:244-245.

    Author Disclosure

    Support provided by the Eye Tumor Research Foundation of Philadelphia, the Macula Foundation of New York, and the Rosenthal Award of The Macula Society of Cleveland, Ohio.