OCULAR MELANOSIS

Signs and Symptoms

Ocular melanosis represents a pigmented discoloration of the superficial ocular tissues. Patients are not symptomatic with regard to discomfort or visual disturbance, but often present with cosmetic concerns, particularly when the condition is newly acquired. In some cases, patients will report that their eyes are chronically red, mistakenly interpreting the ocular pigmentation as hyperemia. Biomicroscopically, ocular melanosis appears as a brown to dark brown discoloration of the epi-bulbar conjunctiva. Depending upon the etiology, it may be unilateral or bilateral, flat to slightly elevated, and may take the form of irregular patches, streaks or circumlimbal darkening.

Racial melanosis—which has also been referred to as primary conjunctival hypermelanosis and complexion-related conjunctival pigmentation—is a congenitally acquired condition. According to some sources, it is seen in up to 92% of patients of African descent, but may also be encountered in those whose ancestors hail from the Caribbean, South America or southern Asia.1-4 This condition tends to be bilateral and symmetric, is most prominent circumlimbally, and remains relatively consistent throughout the patient’s life.

Aside from racial melanosis, nevi represent the most common type of conjunctival melanosis. They present as discrete, well-demarcated congenital lesions, located most often on the interpalpebral bulbar conjunctiva, but occasionally affecting the caruncle, plica or lid margin.5 Conjunctival nevi may be flat to slightly elevated with occasional cystic formations, and may vary significantly in pigment density. Caucasians are most likely to develop conjunctival nevi as compared to other races, accounting for 89% of cases according to one clinical series.6

Primary acquired melanosis (PAM) is less common than racial melanosis or conjunctival nevi, and tends to be encountered much more frequently in Caucasians than in those of African descent.5 It may be differentiated from racial melanosis in that PAM: (1) is typically unilateral and irregular in shape, (2) demonstrates increased growth over time and (3) involves widespread areas of conjunctiva, including the fornices.

Malignant conjunctival melanoma is a rare tumor of the ocular surface. It is typically encountered in middle-aged or elderly white individuals, though a small number of cases involving patients of African descent have been documented.1-4,7,8 Clinically, conjunctival melanomas are densely pigmented, elevated or nodular lesions with intrinsic vascularization (sometimes called “feeder vessels”) arising from the fornices. They are generally unilateral but often multicentric, and may concurrently involve areas of the bulbar and/or tarsal conjunctiva.

Pathophysiology

The word melanosis is a generic term referring to excessive darkening of a tissue due to a disturbance in melanin production or deposition. In cases where the eye is involved, the condition is sometimes called melanosis oculi or melanosis bulbi. In racial melanosis, there is an accumulation of benign melanocytes and melanin granules within the basilar layer of conjunctival epithelium, typically limited to the perilimbal tissues.1,9 Conjunctival nevi also represent benign proliferations of melanocytes within the basal layer of the epithelium. As the patient ages, however, these nevus cells can migrate deeper into the underlying stroma.5 Another common characteristic feature of conjunctival nevi is the presence of intralesional cysts.10

In contradistinction to racial melanosis and conjunctival nevi, PAM is characterized by the presence of abnormal melanocytes within or near the basal layer of the epithelium. Four types of cells—small polyhedral, epithelioid, spindle and dendritic—may be identified in these lesions.5 Additionally, PAM may display five distinct growth patterns: (1) basilar hyperplasia, (2) basilar nests, (3) intraepithelial nests, (4) pagetoid growth (i.e., cell invasion into the epithelium) and (5) melanoma-in-situ (i.e., replacement of normal epithelial cells with melanocytes).5

PAM is classified histopathologically based on the type of atypical cells and the extent of intraepithelial growth. Those lesions that show a propensity toward large atypical (e.g., epithelioid) cells and epithelial invasion constitute PAM with atypia; those lesions that are comprised primarily of small polyhedral cells and remain confined to the basal epithelial layer are referred to as PAM without atypia.5,11,12 These distinctions are important, because atypia has been shown to directly correlate with a lesion’s higher potential for malignant transformation.5,11-13 Because of this phenomenon, some have advocated abandoning the term primary acquired melanosis with atypia in favor of the more specific and straightforward melanoma-in-situ.2,3,14

Conjunctival melanoma may reflect malignant transformation of pre-existing nevi or PAM; less commonly, they arise de novo.4-6,11-13 These lesions often show prominent nesting of atypical melanocytes in the junctional region (i.e., between the epithelial and subepithelial tissues) as well as pagetoid extension of tumor cells into the overlying epithelium.5 The definitive diagnostic criterion for invasive melanoma is extension of atypical melanocytes into the underlying conjunctival stroma (substantia propria).11,12 Melanoma is a highly malignant tumor and has significant capacity for metastasis; spread to the ipsilateral facial lymph nodes, brain, lung and liver are most common.15-17

Management

Management strategies for ocular melanosis depend upon the nature of the condition. Racial melanosis is considered benign and warrants no intervention perhaps other than photodocumentation. Education and reassurance should be given for patients with cosmetic concerns. Only in those cases that are unilateral or seemingly progressive should the practitioner consider additional testing such as biopsy. Conjunctival nevi may require somewhat greater scrutiny. Physicians should inquire regarding any recent changes in lesional size, shape, elevation, color, firmness or irritation. Also, unusual features such as increased vascularization or unusual location should be considered. Suspicious lesions should be referred for excisional biopsy to rule out malignancy, but in most cases simple periodic observation constitutes adequate management for conjunctival nevi.6

PAM typically warrants greater concern and investigation. Since PAM may have a propensity for malignant transformation and is potentially life-threatening, practitioners should routinely arrange for excisional biopsy on these patients.18 Those cases that do not display atypia (or only mild atypia on histological evaluation) may be followed using the same guidelines as one would for a conjunctival nevus, as the risk of malignant conversion in these lesions is quite low.5,12 However, if PAM with moderate or severe atypia is noted, then prompt removal of the lesion is indicated. Management options depend on the size, disposition and location of the lesion, and may include surgical excision with or without cryotherapy, radiotherapy or topical chemotherapy with antimetabolites such as mitomycin-C.5,19 In those rare instances that demonstrate local or regional spread of malignant cells, enucleation or even exenteration may be indicated.5

Cases of suspected conjunctival melanoma should be referred promptly to an ocular oncologist or oculoplastics specialist for evaluation and excisional biopsy. Because of the high risk of metastasis, all patients with biopsy-proven melanoma need to be referred to a medical oncologist for sentinel node biopsy and full-body staging.17,20,21

The management of these lesions can be difficult and varies based upon the extent and severity of the presentation, although surgical removal is typically the treatment of first choice. Excision with wide margins and possible adjunctive cryotherapy or chemotherapy to ensure destruction of the malignant tissue is employed for isolated melanomas.20 Lesions that extend into the globe or orbit may unfortunately demand enucleation or orbital exenteration, respectively.9

Despite treatment, the risk of morbidity is high with conjunctival melanoma. One long-term study found the following results: the risk of local tumor recurrence is 26% at five years, 51% at 10 years, and 65% at 15 years; metastasis was present in 16% of patients at five years, 26% of patients at 10 years, and 32% of patients at 15 years; and tumor-related death occurred in 7% of patients at five years and 13% at eight years.15

Clinical Pearls

Racial melanosis is exceedingly prevalent in dark-skinned individuals, but pigmented lesions of the conjunctiva are otherwise relatively uncommon. In general, lesions that are unilateral, elevated or more prominent in the fornices or palpebral conjunctiva have a greater tendency toward malignancy, and warrant close scrutiny.

The transformation of conjunctival nevi to malignant melanoma occurs only in rare instances—on the order of 4% or less.6,15 Still, practitioners should consider changes in size, elevation, color or vascularization as suspicious and an indication for additional consultation or testing.

Primary acquired melanosis, as well as malignant melanoma, may sometimes be overlooked or dismissed in patients of color because of the similarity in appearance to racial melanosis.4,7,22,23 Eye care practitioners must remain diligent during examination, and obtain appropriate testing in all cases of atypical conjunctival melanosis, regardless of the patient’s race.

Both conjunctival nevi and melanomas may occasionally present as amelanotic lesions, i.e. devoid of melanin pigment. In such cases, they usually appear as pink, variably elevated, fleshy plaques or nodules. The prognosis for these lesions is the same as for the pigmented variety; however, definitive diagnosis is often delayed because of the atypical appearance.

1. Azari AA, Agapov J, Rezaei Kanavi M, et al. Racial melanosis: a striking presentation. JAMA Ophthalmol. 2014;132(1):76.

2. Damato B, Coupland SE. Conjunctival melanoma and melanosis: a reappraisal of terminology, classification and staging. Clin Experiment Ophthalmol. 2008;36(8):786-95.

3. Harooni H, Schoenfield LR, Singh AD. Current appraisal of conjunctival melanocytic tumors: classification and treatment. Future Oncol. 2011;7(3):435-46.

4. Colby KA, Nagel DS. Conjunctival melanoma arising from diffuse primary acquired melanosis in a young black woman. Cornea. 2005;24(3):352-5.

5. Lin SM, Ferrucci S. Primary acquired melanosis of the conjunctiva. Optometry. 2006;77(5):223-8.

6. Shields CL, Fasiuddin AF, Mashayekhi A, Shields JA. Conjunctival nevi: clinical features and natural course in 410 consecutive patients. Arch Ophthalmol. 2004;122(2):167-75.

7. Anonubi CC, Akinsola FB, Abdulkareem FB, et al. Conjunctival melanoma in a 55 year old male Nigerian: a case report. Niger Postgrad Med J. 2006;13(4):366-9.

8. Hu DN, Yu G, McCormick SA, Finger PT. Population-based incidence of conjunctival melanoma in various races and ethnic groups and comparison with other melanomas. Am J Ophthalmol. 2008;145(3):418-423.

9. Shields CL, Shields JA. Tumors of the conjunctiva and cornea. Surv Ophthalmol. 2004;49(1):3-24.

10. Zembowicz A, Mandal RV, Choopong P. Melanocytic lesions of the conjunctiva. Arch Pathol Lab Med. 2010;134(12):1785-92

11. Shields JA, Shields CL, Mashayekhi A, et al. Primary acquired melanosis of the conjunctiva: experience with 311 eyes. Trans Am Ophthalmol Soc. 2007;105:61-71; discussion 71-2.

12. 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(3):511-519.e2

13. Brownstein S. Malignant melanoma of the conjunctiva. Cancer Control. 2004;11(5):310-6.

14. Ackerman AB, Sood R, Koenig M. Primary acquired melanosis of the conjunctiva is melanoma in situ. Mod Pathol 1991;4(2):253-63.

15. 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(11):1497-507.

16. Köklü S, Gültuna S, Yüksel I, et al. Diffuse gastroduodenal metastasis of conjunctival malignant melanoma. Am J Gastroenterol. 2008;103(5):1321-3.

17. Savar A, Ross MI, Prieto VG, et al. Sentinel lymph node biopsy for ocular adnexal melanoma: experience in 30 patients. Ophthalmology. 2009;116(11):2217-23.

18. Corcoran KT, Marsich MM, Ward DC. Potentially life-threatening primary acquired melanosis. Clin Eye Vis Care. 2000;12(3-4):185-8.

19. Anandajeya WV, Corrêa ZM, Augsburger JJ. Primary acquired melanosis with atypia treated with mitomycin C. Int Ophthalmol. 2009;29(4):285-8.

20. Oellers P, Karp CL. Management of pigmented conjunctival lesions. Ocul Surf. 2012;10(4):251-63.

21. Shildkrot Y, Wilson MW. Conjunctival melanoma: pitfalls and dilemmas in management. Curr Opin Ophthalmol. 2010;21(5):380-6.

22. Kalski RS, Lomeo MD, Kirchgraber PR, Levine MR. Caruncular malignant melanoma in a black patient. Ophthalmic Surg. 1995;26(2):139-41.

23. Medina Mendez CA, Singh AD. Multifocal Melanoma of the Conjunctiva in an African American Patient With Neurofibromatosis Type 1. Cornea. 2014 Apr 2. [Epub ahead of print]