ABSTRACT
Conjunctival melanoma is a rare disease which makes up approximately 5% of ocular melanomas. The lesion may occur de novo or originate from a pre-existing nevus or primary acquired melanosis. Biomicroscopy is of paramount importance in diagnosis and follow-up of the disease, while other diagnostic modalities serve as supplementary tools. Many clinical and histopathological risk factors have been reported for prognosis. This review aims to address the clinical findings, differential diagnosis, diagnostic tools, prognostic factors, and staging of this disease.
Keywords:
Conjunctival melanoma, diagnosis, prognosis
Introduction
Primary melanoma of the eye can occur in four different anatomical compartments of the globe: the orbit, eyelids, conjunctiva, and uvea (subdivided as the iris, ciliary body, and choroid). Conjunctival melanoma (CM) is considered an ocular surface neoplasia and accounts for 1-7% of all ocular melanomas, with an incidence rate nearly one-tenth of that of uveal melanoma in whites.1 CM, which can arise from primary acquired melanosis (PAM), from an existing conjunctival nevus, or de novo, is derived from a malignant proliferation of melanocytes of neural crest origin that normally reside in the basal layer of the conjunctival epithelium.2
CM differs substantially in histopathology, genetic profile, and management from other ocular melanomas and is handled as a separate entity in clinical practice. Even so, in terms of histopathogenesis, molecular biology, and biological behavior such as distant metastatic pattern, CM lies biologically closer to mucosal and cutaneous melanomas than does a uveal melanoma.3 The pattern of metastasis usually presents with spread to the regional lymph nodes first in CM and cutaneous melanoma, while uveal melanoma primarily tends to cause hematogenous metastasis to the liver.4 Another common trait between CM and cutaneous melanoma is that they are derived from melanocytes of neural crest origin, which migrate toward epithelium, whereas the melanocytes that form uveal melanoma cells migrate into deep mesodermal tissue.
CM is a potentially sight- and life-threatening tumor if left untreated, with a 10-year mortality rate up to 30%.4 Spread of the uncontrolled disease can manifest as local recurrence, involvement of distant conjunctiva, or distant metastasis through regional lymph nodes via involvement of blood vessels or lymphatics located in the substantia propria of the conjunctiva.1 All considered, CM requires appropriate management in line with the recent advances in our understanding of this disease.
Conclusion
Even though CM is regarded as a rare entity, it can have a severe impact on overall survival. Notably, the incidence rates are reported to show an increasing trend in some series. Biomicroscopy is indispensable in diagnosis, determination of additional features, and follow-up of the disease, whereas other imaging modalities can be used with their own limitations as adjunct tools. Metastatic work-up and SLNB should be conducted for the indications proposed in the literature. Staging is still in progress as new prognostic factors are defined to develop more precise indicators for overall survival.
References
1Lim LA, Madigan MC, Conway RM. Conjunctival melanoma: a review of conceptual and treatment advances. Clin Ophthalmol. 2013;6:521-531.
2Shields CL, Markowitz JS, Belinsky I, Schwartzstein H, George NS, Lally SE, Mashayekhi A, Shields JA. Conjunctival melanoma: outcomes based on tumor origin in 382 consecutive cases. Ophthalmology. 2011;118:389-395.
3Larsen AC. Conjunctival malignant melanoma in Denmark. Epidemiology, treatment, and prognosis with special emphasis on tumorigenesis and genetic profile. Acta Ophthalmol. 2016;94:1-27.
4Seregard S. Conjunctival melanoma. Surv Ophthalmol. 1998;42:321-350.
5Yu GP, Hu DN, McCormic S, Finger PT. Conjunctival melanoma: is it increasing in the United States? Am J Ophthalmol. 2003;135:800-806.
6Shields CL, Alset AE, Boal NS, Casey MG, Knapp AN, Sugarman JA, Schoen MA, Gordon PS, Douglass AM, Sioufi K, Say EA, Shields JA. Conjunctival tumors in 5002 cases. Comparative analysis of benign versus malignant counterparts. The 2016 James D. Allen lecture. Am J Ophthalmol. 2017;173:106-133.
7Dalvin LA, Salomão DR, Patel SV. Population-based incidence of conjunctival tumours in Olmsted County, Minnesota. Br J Ophthalmol. 2018;102:1728-1734.
8Isager P, Østerlind A, Engholm G, Heegaard S, Lindegaard J, Overgaard J, Storm HH. Uveal and conjunctival malignant melanoma in Denmark, 1943-97: incidence and validation study. Ophthalmic Epidemiol. 2005;12:223-232.
9Missotten GS, Keijser S, De Keizer RJ, De Wolff-Rouendaal D. Conjunctival melanoma in the Netherlands: a nationwide study. Invest Ophthalmol Vis Sci. 2005;46:75-82.
10Tuomaala S, Eskelin S, Tarkkanen A, Kivelä T. Population-based assessment of clinical characteristics predicting outcome of conjunctival melanoma in whites. Invest Ophthalmol Vis Sci. 2002;43:3399-3408.
11Triay E, Bergman L, Nilsson B, All-Ericsson C, Seregard S. Time trends in the incidence of conjunctival melanoma in Sweden. Br J Ophthalmol. 2009;93:1524-1528.
12Ghazawi FM, Darwich R, Le M, Jfri A, Rahme E, Burnier JV, Sasseville D, Burnier MN Jr, Litvinov IV. Incidence trends of conjunctival malignant melanoma in Canada. Br J Ophthalmol. 2019;104:23-25.
13Brouwer NJ, Marinkovic M, Luyten GPM, Shields CL, Jager MJ. Pigmentation of conjunctival melanoma recurrences and outcome. Graefes Arch Clin Exp Ophthalmol. 2019;257:1783-1788.
14Yousef YA, Finger PT. Predictive value of the seventh edition American Joint Committee on Cancer staging system for conjunctival melanoma. Arch Ophthalmol. 2012;130:599-606.
15Brownstein S. Malignant melanoma of the conjunctiva. Cancer Control. 2004;11:310-316.
16Jakobiec FA, Folberg R, Iwamoto T. Clinicopathologic characteristics of premalignant and malignant melanocytic lesions of the conjunctiva. Ophthalmology. 1989;96:147-166.
17Folberg R, McLean IW, Zimmerman LE. Malignant melanoma of the conjunctiva. Hum Pathol. 1985;16:136-143.
18Zimmerman LE. Criteria for management of melanosis. Arch Ophthalmol. 1966;76:307-308.
19Kenawy N, Lake SL, Coupland SE, Damato BE. Conjunctival melanoma and melanocytic intra-epithelial neoplasia. Eye (Lond). 2013;27:142-152.
20Coupland SE, Barnhill R, Conway RM, Damato BE, Esmaeli B, Albert DM, Auw-Hädrich C, Chévez-Barrios P, Grossniklaus HE, Heegaard S, Holbach LM, Kivelä T, Pavlick AC, Pe’er C, Shields C, Singh AD, Wittekind CW, Williams MD, Prieto VG, Finger PT. Conjunctival melanoma. In: Amin MB, Edge SB, Greene FL, Byrd DR, Brookland RK, Washington MK, Gershenwald JE, Compton CC, Hess KR, Sullivan DC, Jessup JM, Birerley JD, Gaspar LE, Schilsky RL, Balch CM, Winchester DP, Asare EA, Madera M, Gress DM, Meyer LR, eds. AJCC Cancer Staging Manual (8th ed). Switzerland; Springer; 2017:795-803.
21Shields JA, Shields CL, Mashayekhi A, Marr BP, Benavides R, Thangappan A, Phan L, Eagle RC Jr. 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.
22Kocaoglu FA. Biopsy in ocular oncology. Turk J Ophthalmol. 2014;44:49-54.
23Damato B, Coupland SE. Clinical mapping of conjunctival melanomas. Br J Ophthalmol. 2008;92:1545-1549.
24Keijser S, van Luijk CM, Missotten GS, Veselic-Charvat M, de Wolff-Rouendaal D, de Keizer RJ. Predictive value of exfoliative cytology in pigmented conjunctival lesions. Acta Ophthalmol Scand. 2006;84:188-191.
25Paridaens AD, McCartney AC, Curling OM, Lyons CJ, Hungerford JL. Impression cytology of conjunctival melanosis and melanoma. Br J Ophthalmol. 1992;76:198-201.
26Cinotti E, La Rocca A, Labeille B, Grivet D, Tognetti L, Lambert V, Kaspi M, Nami N, Fimiani M, Perrot JL, Rubegni P. Dermoscopy for the diagnosis of conjunctival lesions. Dermatol Clin. 2018;36:439-449.
27Wilson JW, Vajzovic L, Robles FE, Cummings TJ, Mruthyunjaya P, Warren WS. Imaging microscopic pigment chemistry in conjunctival melanocytic lesions using pump-probe laser microscopy. Invest Ophthalmol Vis Sci. 2013;54:6867-6876.
28Robles FE, Wilson JW, Warren WS. Quantifying melanin spatial distribution using pump-probe microscopy and a 2-D morphological autocorrelation transformation for melanoma diagnosis. J Biomed Opt. 2013;18:120502.
29Nanji AA, Sayyad FE, Galor A, Dubovy S, Karp CL. High-resolution optical coherence tomography as an adjunctive tool in the diagnosis of corneal and conjunctival pathology. Ocul Surf. 2015;13:226-235.
30Cinotti E, Singer A, Labeille B, Grivet D, Rubegni P, Douchet C, Cambazard F, Thuret G, Gain P, Perrot JL. Handheld in vivo reflectance confocal microscopy for the diagnosis of eyelid margin and conjunctival tumors. JAMA Ophthalmol. 2017;135:845-851.
31Khattak S, Gupta N, Zhou X, Pires L, Wilson BC, Yucel YH. Non-invasive dynamic assessment of conjunctival melanomas by photoacoustic imaging. Exp Eye Res. 2019;179:157-167.
32Tuomaala S, Kivelä T. Metastatic pattern and survival in disseminated conjunctival melanoma: implications for sentinel lymph node biopsy. Opthalmology. 2004;111:816-821.
33Esmaeli B. Wang X. Youssef A, Gershenwald JE. Patterns of regional and distant metastasis in patients with conjunctival melanoma: experience at a cancer center over four decades. Ophthalmology. 2001;108:2101-2105.
34Missotten GS, de Wolff-Rouendaal D, de Keizer RJ. Screening for conjunctival melanoma metastasis: literature review. Bull Soc Belge Ophtalmol. 2007;306:23-30.
35Tuomaala S, Kivelä T. Sentinel lymph node biopsy guidelines for conjunctival melanoma. Melanoma Res. 2008;18:235.
36Aziz HA, Gastman BR, Singh AD. Management of conjunctival melanoma: critical assessment of sentinel lymph node biopsy. Ocul Oncol Pathol. 2015;1:266-273.
37Cohen VML, Tsimpida M, Hungerford JL, Jan H, Cerio R, Moir G. Prospective study of sentinel lymph node biopsy for conjunctival melanoma. Br J Ophthalmol. 2013;97:1525-1529.
38Esmaeli B, Rubin ML, Xu S, Goepfert RP, Curry JL, Prieto VG, Ning J, Tetzlaff MT. Greater tumor thickness, ulceration, and positive sentinel lymph node are associated with worse prognosis in patients with conjunctival melanoma: implications for future AJCC classifications. Am J Surg Pathol. 2019;43:1701-1710.
39Sheng X, Li S, Chi Z, Si L, Cui C, Mao L, Lian B, Tang B, Wang X, Yan X, Kong Y, Dai J, Guo J. Prognostic factors for conjunctival melanoma: a study in ethnic Chinese patients. Br J Ophthalmol. 2015;99:990-996.
40Anastassiou G, Heiligenhaus A, Bechrakis N, Bader E, Bornfeld N, Steuhl KP. Prognostic value of clinical and histopathological parameters in conjunctival melanomas: a retrospective study. Br J Ophthalmol. 2002;86:163-167.
41Tuomaala S, Toivonen P, Al-Jamal R, Kivelä T. Prognostic significance of histopathology of primary conjunctival melanoma in Caucasians. Curr Eye Res. 2007;32:939-952.
42Esmaeli B, Roberts D, Ross M, Fellman M, Cruz H, Kim SK, Prieto VG. Histologic features of conjunctival melanoma predictive of metastasis and death (an American Ophthalmological thesis). Trans Am Ophthalmol Soc. 2012;110:64-73.
43Damato B, Coupland SE. An audit of conjunctival melanoma treatment in Liverpool. Eye (Lond). 2009;23:801-809.
44Werschnik C, Lommatzsch PK. Long-term follow-up of patients with conjunctival melanoma. Am J Clin Oncol. 2002;25:248-255.
45Paridaens AD, Minassian DC, McCartney AC, Hungerford JL. Prognostic factors in primary malignant melanoma of the conjunctiva: a clinicopathological study of 256 cases. Br J Ophthalmol. 1994;78:252-259.
46Abt NB, Zhao J, Huang Y, Eghrari AO. Prognostic factors and survival for malignant conjunctival melanoma and squamous cell carcinoma over four decades. Am J Otolaryngol. 2019;40:577-582.
47Brouwer NJ, Marinkovic M, Luyten GPM, Shields CL, Jager MJ. Lack of tumour pigmentation in conjunctival melanoma is associated with light iris colour and worse prognosis. Br J Ophthalmol. 2019;103:332-337.
48van Ipenburg JA, de Waard NE, Naus NC, Jager MJ, Paridaens D, Verdijk RM. Chemokine receptor expression pattern correlates to progression of conjunctival melanocytic lesions. Invest Ophthalmol Vis Sci. 2019;60:2950-2957.
49Shields CL, Kaliki S, Al-Dahmash S, Lally SE, Shields JA. American Joint Committee on Cancer (AJCC) clinical classification predicts conjunctival melanoma outcomes. Ophthalmic Plast Reconstr Surg. 2012;5:313-323.
50Jain P, Finger PT, Damato B, Coupland SE, Heimann H, Kenawy N, Brouwer NJ, Marinkovic M, Van Duinen SG, Caujolle JP, Maschi C, Seregard S, Pelayes D, Folgar M, Yousef YA, Krema H, Gallie B, Calle-Vasquez A; American Joint Committee on Cancer Ophthalmic Oncology Task Force. Multicenter, international assessment of the eighth edition of the American Joint Committee on Cancer Cancer Staging Manual for conjunctival melanoma. JAMA Ophthalmol. 2019;137:905-911.
51Esmaeli B. Inclusion of histologic ulceration and tumor thickness in future American Joint Committee on Cancer T category definitions for conjunctival melanoma. JAMA Ophthalmol. 2019;137:912-913.
