Rare Conjunctival Melanoma; Simulation Techniques to Help Empathize with Melanoma Patients

A Rare Conjunctival Melanoma Case

By Christopher Weyer, DO, Elizabeth Young, and Leslie Marshall, DO

Summary

Primary conjunctival melanomas (CM) are an exceedingly rare type of melanoma. They account for approximately five percent of all cases of ocular melanomas, with ocular melanomas representing only 3.7 percent of all melanoma cases.^1-3 The majority of primary ocular melanomas occur in the uvea, but interestingly, CM and uveal melanomas bare little genetic similarity to one another. CM has far greater mutation commonality with mucosal and cutaneous melanoma.^2,4-7

In this report, we describe a patient with a rare epitheloid cell type conjunctival malignant melanoma who was successfully treated with wide local excision.

Figure 1

Figure 2

Figure 3

Case

A 72-year-old Caucasian male presented for routine outpatient dermatologic examination following excision of a nodular basal cell carcinoma (BCC) on his trunk in 2010 and a superficial and nodular BCC on his right leg treated with electrodesiccation and curettage in 2011. On examination, he was noted to have a 0.4cm firm, black pedunculated nodule (Figure 1) on the right medial canthal conjunctiva. The patient was previously unaware of the lesion. A conjunctival biopsy was performed due to suspicion of malignant melanoma. Of note on the biopsy, the lesion was not fixed to the sclera. Histopathology revealed an epitheloid cell type conjunctival malignant melanoma with a Breslow thickness of 2.2mm involving the deep and lateral margins (Figure 2). In addition, an in-situ melanoma involving the adjacent conjunctival epithelium was also identified. Immunohistochemistry of the tumor revealed positive staining with S100, melan-A, and HMB-45. PHH3 staining showed rare invasive tumor cells consistent with rare mitotic activity. The patient was referred for treatment including wide local excision with cryotherapy to the margins and subsequent sentinel node biopsy. The patient had negative sentinel lymph node biopsy and has been disease free for more than two years (Figure 3).

Discussion

Primary conjunctival melanomas (CM) are an exceedingly rare type of melanoma. They account for approximately five percent of all cases of ocular melanomas, with ocular melanomas representing only 3.7 percent of all melanoma cases.^1-3 The majority of primary ocular melanomas occur in the uvea, but interestingly, CM and uveal melanomas bare little genetic similarity to one another. CM has far greater mutation commonality with mucosal and cutaneous melanoma, and theoretically would lend itself to similar treatment modalities.^2,4-7 CM is a disease mainly of 55- to 65-year-old Caucasians and lacks notable gender predilection. Rarely it has been reported in pediatric, Asian, and black populations.^8,9 Clinical presentation typically consists of an enlarging fixed pigmented nodule in the peri-limbal area with the presence of feeder vessels. Less frequently involved locations include the palpebral conjunctiva, fornix, tarsus, or caruncle. Locations outside of the limbus portend a poorer prognosis. Other poor prognostic factors include tumor thickness greater than 2mm, de novo origin, ulcerated or nodular tumors, involvement of adjacent tissue structures, older age, nonwhite race, male gender, and local recurrence. Local recurrence is estimated to be 45 and 59 percent at five and 10 years, respectively.^2,5,10-12

The conjunctiva consists of two or more layers of non-keratinized squamous or stratified columnar epithelium with interspersed goblet cells overlying the substantia propria. The substantia propria is the stromal component underlying the epithelium and is further divided into a superficial lymphoid and a deeper fibrous layer. Conjunctival melanocytes are located in the epithelium’s basal layer and substantia propria.^13,14 The conjunctival lymphatics drain to the preauricular, parotid, submandibular, and deep cervical nodes.¹⁴

CMs are thought to arise de novo in 16-26 percent of cases. These lesions portend a poorer prognosis than CM arising from a precursor lesion.^5,11,15 The risk factors for development of CM are largely unknown, but ultraviolet radiation is thought to play a role in pathogenesis, as the conjunctiva is the only mucosal surface with natural exposure to sunlight. Furthermore, NRAS (neuroblastoma RAS viral (v-ras) oncogene homologue) and BRAF (v-RAF murine sarcoma viral oncogene homologue B1) mutations may be found in CMs and are also found in sun exposure related cutaneous melanomas.^4,6,7,15

Primary acquired melanosis (PAM) and conjunctival nevi are the two melanocytic precursor lesions that can give rise to CM, and an estimated five to eight percent of CMs arise in a combination lesion of PAM and nevus.^11,13,16 PAM is the most common CM precursor and is reported in anywhere from 42-75 percent of newly diagnosed CMs.^10,16 PAM most commonly presents unilaterally with a poorly circumscribed macular “dusting” of golden yellow or brown pigment located in any area of the bulbar or palpebral conjunctiva. It can also extend onto the surrounding cornea or eyelid skin. In rare cases, PAM can be non-pigmented. PAM is so named to differentiate it from secondary acquired melanosis and congenital melanocytic lesions. PAM lesions most commonly occur in middle-aged Caucasians due to a neoplastic proliferation of epithelial melanocytes. It has been proposed that PAM should be renamed conjunctival melanocytic intraepithelial neoplasia (C-MIN) or hypermelanosis for more accurate nomenclature. Histologic examination for atypia categorizes it into PAM with atypia (designated PAM+) and PAM without atypia (PAM-). PAM- theoretically portends no risk of malignant transformation. PAM+ is considered analogous to a cutaneous lentigo maligna in that it is a preinvasive intraepidermal lesion. It has been estimated that up to 46 percent of PAM+ lesions progresses to CM, and several factors affect the likelihood of malignant progression; epitheliod cytology, atypical melanocytes vertically invading the epithelium, pagetoid spread, and areas of pigmentation and thickening of the lesion. If multiple CM lesions are present, PAM+ is almost always the precursor lesion, but it remains more common for PAM+ to give rise to a singular CM.^11,13,15,17 Due to the higher risk of progression to CM, PAM+ lesions occupying two to five clock hours should be excised with 4-5mm margins and cryotherapy to the edges, and PAM+ lesions occupying greater than five clock hours should have incisional map biopsies of all quadrants performed in addition to excision of the most thickened areas.^9,10

Conjunctival nevi are the reported precursor lesion in two to 40 percent of CMs. Conjunctival nevi are usually unilateral, but in stark contrast to PAM, nevi are usually formed in childhood and are often well circumscribed light brown or initially non-pigmented papules containing cysts. These lesions are most commonly found on the palpebral conjunctiva or peri-limbal area and usually present as a gradually darkening papule, with accelerations in pigmentation during puberty or pregnancy. Conjunctival nevi are categorized identically to cutaneous nevi as being junctional, compound, or subepithelial. They are most commonly junctional, and CM has been reported to arise from both junctional and compound nevi. Nevus cell descension into the substantia propria can cause descent of surface epithelium and goblet cells, which is thought to explain the cyst formation that is characteristic of compound or subepithelial conjunctival nevi. These nevi should be monitored annually and have a slit-lamp photo taken at baseline for comparison. An increase in vascularity, color variegation, or enlargement warrants an excisional biopsy. Cryotherapy to the edges should be used for highly suspicious nevi or following histopathological evaluation, if warranted.^13,17,18

Diagnosis of CM is made via histopathological evaluation showing sheets or nests of epitheliod, small polyhedral, spindle-shaped, balloon cells, or a combination of the aforementioned types of melanoma cells invading into the substantia propria from the epithelium. S-100, melan-A, and HMB-45 immunohistochemical stains would be expected to be positive. It is important to exclude cutaneous melanoma metastasis to the conjunctiva or extraocular extension of a uveal melanoma. Differentiation can be made by microRNA expression profiling. CM has had 25 tumor specific microRNAs identified with eight of the 25 being unique to CM and not previously reported in cutaneous melanomas. None of the 25 isolated microRNAs have been reported in uveal melanomas. Another differentiating factor is the finding of BRAF and NRAS mutations in CM, which would be expected to be absent in the majority of uveal melanomas. Neither the 25 identified microRNAs nor BRAF mutation have been consistently shown to have significant impact on prognosis.^2,6,11,15,19

Management of CM is debated, and consensus is lacking as to the optimal treatment strategy due to the scarcity of reported cases. Exenteration is no longer commonly recommended, except in extensive cases of orbital invasion.^20,21 The most common treatment modality utilized is excision with 3-6mm of tumor free conjunctival margin with double freeze slow thaw cryotherapy to the margins. Excision with adjunctive topical 0.02 percent or 0.04 percent mitomycin C chemotherapy, brachytherapy, or interferon alfa-2b has also been reported. Epithelialectomy or sclerectomy is utilized when the tumor is adherent to the cornea or sclera, respectively. Excision without adjunctive therapy is discouraged and has been reported to result in higher rates of local recurrence and increased mortality. All cases of CM with tumor thickness greater than 2mm, histologic ulceration, or non-limbal location carry higher risk of regional metastasis, thus sentinel node biopsy is recommended in these cases.^{11,12,16,22-25}

1. Chang AE, Karnell LH, Menck HR. The National Cancer Data Base report on cutaneous and noncutaneous melanoma: a summary of 84,836 cases from the past decade. The American College of Surgeons Commission on Cancer and the American Cancer Society. Cancer. 1998;83(8):1664-78.

2. 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(11):1295-303.

3. McLaughlin CC, Wu XC, Jemal A, Martin HJ, Roche LM, Chen VW. Incidence of noncutaneous melanomas in the U. S. Cancer. 2005;103:1000–7.

4. Griewank KG, Westekemper H, Murali R, et al. Conjunctival melanomas harbor BRAF and NRAS mutations and copy number changes similar to cutaneous and mucosal melanomas. Clin Cancer Res. 2013;19(12):3143-52.

5. Seregard S. Conjunctival melanoma. Surv Ophthalmol. 1998;42(4):321-50.

6. Gear H, Williams H, Kemp EG, Roberts F. BRAF mutations in conjunctival melanoma. Invest Ophthalmol Vis Sci. 2004;45(8):2484-8.

7. Maldonado JL, Fridlyand J, Patel H, et al. Determinants of BRAF mutations in primary melanomas. J Natl Cancer Inst. 2003;95(24):1878-90.

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 JA, Shields CL, Mashayekhi A, et al. Primary Acquired Melanosis of the Conjunctiva: Experience with 311 Eyes. Transactions of the American Ophthalmological Society. 2007;105:61-72.

10. Shields CL, Shields JA. Conjunctival primary acquired melanosis and melanoma: tales, fairy tales, and facts. Ophthal Plast Reconstr Surg. 2009;25(3):167-72.

11. Shields CL, Markowitz JS, Belinsky I, et al. Conjunctival melanoma: outcomes based on tumor origin in 382 consecutive cases. Ophthalmology. 2011;118(2):389-95.e1-2.

12. Tuomaala S, Toivonen P, Al-jamal R, Kivelä T. Prognostic significance of histopathology of primary conjunctival melanoma in Caucasians. Curr Eye Res. 2007;32(11):939-52.

13. Folberg R, Jakobiec FA, Bernardino VB, Iwamoto T. Benign conjunctival melanocytic lesions. Clinicopathologic features. Ophthalmology. 1989;96(4):436-61.

14. Seregard S, Blasi AB, Balestrazzi E. Chapter 2: Conjunctiva. In: Eye pathology: an illustrated guide. Springer. 2015; 41-42.

15. Anastassiou G, Heligenhaus A, Bechrakis N, Bader E, Bornfield N, Steuhl KP.Prognostic value of clinical and histopathological parameters in conjunctival melanomas: a retrospective study. British Journal of Ophthalmology. 2002;86(2):163.

16. Tuomaala 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(11):3399-408.

17. Levec L, De potter P, Jamart J. Conjunctival nevi clinical features and therapeutic outcomes. Ophthalmology. 2010;117(1):35-40.

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

19. Larsen AC, Mikkelsen LH, Borup R, et al. MicroRNA Expression Profile in Conjunctival Melanoma. Invest Ophthalmol Vis Sci. 2016;57(10):4205-12.

20. Paridaens AD, McCartney AC, Minassian DC, Hungerford JL. Orbital exenteration in 95 cases of primary conjunctival malignant melanoma. The British Journal of Ophthalmology. 1994;78(7):520-528.

21. Paridaens 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(4):252-9.

22. Maalouf TJ, Dolivet G, Angioi KS, Leroux A, Genin P, George JL. Sentinel lymph node biopsy in patients with conjunctival and eyelid cancers: experience in 17 patients. Ophthal Plast Reconstr Surg. 2012;28(1):30-4.

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

24. 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(2):244-5.

25. Shields JA, Shields CL, De potter P. Surgical management of circumscribed conjunctival melanomas. Ophthal Plast Reconstr Surg. 1998;14(3):208-15.