- Tumors arise from melanocytes located among the basal cells of the conjunctival epithelium (Wong, Nanji et al. 2014)
- Melanocytes arise from the neural crest (Yanoff,. Sasani. Ocular Pathology 6th ed).
- Mucosal melanocytes do not have the same UV protection role as cutaneous melanocytes.
- Mucosal melanocytes possess immune processing functions including phagocytosis and antigen presentation.
- Cutaneous melanomas have been found to prominently carry oncogenic mutations in BRAF (serine/threonine kinase). These mutations have been found, but less commonly, in mucosal melanomas including conjunctival melanomas (Mihajilovic, Vlajkovic 2012).
- The T1799A BRAF mutation was identified in two of five (40%) conjunctival melanomas in one study (Goldenberg-Cohen, Cohen 2005).
- BRAF mutations were found in 3 of 15 conjunctival melanomas in another study (Spendlove, Damato 2004).
- In a larger study of 22 patients, The T1799A BRAF mutation was detected by sequencing in 5 of 22 tumors and this mutation tended to be associated with larger tumor diameter and greater depth of invasion (Gear, Williams 2004).
- Using PCR amplification, a study in Copenhagen found BRAF mutations in 39 of 111 conjunctival melanomas (Larson, AC, Dahl, C. 2016).
- Uveal melanomas frequently carry somatic mutations in Codon 209 of the GNAQ gene as the first initiating events, evident in 30-50% of cases, but these are not found in conjunctival melanomas (Dravitman-Storobinsky, Cohen 2010).
- Conjunctival melanomas harbored overaction of the oncogenic mTOR pathway, a target of rapamycin, in a study of eight tumors (Populo, Soares 2010).
- Incidence of conjunctival melanoma 0.45–0.8/million (Shildkrot, Wilson 2010)
- There is a trend of increasing frequency among white men in the US (Shildkrot, Wilson 2010).
- Male:Female ratio is about equal.
Damato et al 2009 Liverpool Oncology Data Base 1992-2006
Werschnik et al 2002 Germany 1958-1993
Norregaard et al 1996 Denmark 1960-1980
Shields et al 2011 1970-2003 Wills Eye Hospital
- Incidence appears to be higher in Caucasians than in Asian, Hispanic, or Black patients. This is based on the 382 conjunctival melanomas treated at Wills only 6% of the patients were being Asian, Hispanic or Black - the remainder were Caucasian. (combined two bullet points) This is in addition to the study of 168 conjunctival melanomas from 1992-2003, identified through the National Cancer Institute’s Surveillance, Epidemiology and End Results (SEER) registries, the annual age adjusted incidence rates showed about 50% of the tumors in white patients (Hu, Yu 2008).
- African Americans are affected with 0.2/million more than would be expected based on incidences of skin/uveal melanoma in that group (Shildkrot, Wilson 2010).
- Mortality rate at 5-year 8% (Esmaeli, Roberts et al. 2012)<
- Risk of regional node metastasis at 10-year 11% (Esmaeli, Roberts et al. 2012)
- Risk of metastatic rate 10-year 19% (Esmaeli, Roberts et al. 2012)
- Risk factors not established except that 57%–76% of conjunctival melanoma arise from primary acquired melanosis (PAM, Figure 1).
- De novo or from nevi is much rarer. (Wong, Nanji et al. 2014)
- Data regarding association between UV light and conjunctival melanoma equivocal (Wong, Nanji et al. 2014)
Figure 1. Conjunctival melanoma arising from PAM.
- Typical presentation: elevated pigmented nodule affecting bulbar, palpebral, forniceal, or caruncle conjunctiva; latter 3 increase likelihood of malignancy
- “Conjunctival” melanomas can actually develop on and be limited to the corneal epithelium (Tuomaala, Aine 2002).
- Amelanotic/minimal pigmented in 19% of cases (Figure 2).
- Typically associated with PAM.
- Other clinical features: increased vascularity, immobility, and absence of cysts (Shildkrot, Wilson 2010)
- Most frequent locations bulbar and limbal > cornea > palpebral, forniceal and caruncular. (Oellers, Karp 2012)
- Should invert the upper lid and check lower lid fornix to ensure no "hidden" lesions.
Figure 2. Recurrent amelanotic conjunctival melanoma of the palpebral conjunctiva in a blind eye.
- Full history and physical exam including palpating for regional lymph nodes.
- Adjunctive imaging (OCT, ultrasound) can be useful. (Oellers, Karp 2012)
- OCT in pigmented lesions can demonstrate hyper-reflectivity of the basal epithelium in PAM and nevi cysts thereby reducing the likelihood of conjunctival melanoma (Oellers, Karp 2012)
- Photography to document lesion changes
- Literature has described use of dermoscope for clinical evaluation of conjunctival melanoma. Of limited benefit. (Li, Xin 2014)
- Mainstay of diagnosis is by histology using excisional biopsy techniques.
- In a series of 85 conjunctival melanomas treated in Helsinki, Finland, tumor thickness of 2mm or greater predisposed to metastatic disease (Tuomaala, Kivela 2004).
- Some case maybe indeterminate. These cases benefit from immunohistochemistry markers.
- S100 is sensitive but not specific for conjunctival melanoma. HMB-45 is less sensitive but more specific. Wilms tumor gene 1 protein expression useful to distinguish between benign and malignant. Others including Ki-67 and Bc1-2 recently shown to be consistent immunohistochemical marker for melanocytic conjunctival tumors. (Lim, Madigan et al. 2013)
- Fluorescence in situ hybridization (FISH) has been shown to be useful in equivocal cases for diagnostic purposes. (Mudhar, Smith et al. 2013)
- Amelanotic melanoma can be differentiated from squamous conjunctival neoplasia by demonstrating expression of MART-1 - melanocyte antigen marker (Betts, Espana 2015).
- Recent evidence looking at genetic alterations in conjunctival melanoma showed 47% of had presence of NRAS and BRAF mutations. Suggests conjunctival melanoma more related to cutaneous rather than uveal melanoma. May impact therapeutic options. (Griewank, Westekemper et al. 2013)
Testing for staging, fundamental impairment
- Staging based on the AJCC (American Joint Committee on Cancer) (Shields, Kaliki et al. 2012), (Yousef, Finger 2012), (Wong, Nanji et al. 2014)
- Tis melanoma confined to conjunctival epithelium (i.e., PAM with atypia)
- T1 conjunctival melanoma on bulbar conjunctiva
- T2 conjunctival melanoma on non-bulbar conjunctiva (palpebral, forniceal, caruncular)
- T3 conjunctival melanoma with local invasion including eye, eyelid, orbit, sinus)
- T4 invasion locally to the CNS
- N regional lymph nodes
- M distant metastasis
- PET scan has been reported to identify preauricular regional tumor extension (Damian, Gaudiano 2013).
Whole body PET/CT imaging was performed in fourteen patients with clinical stage T3 and greater disease and only one had evidence of systemic metastasis - to the liver, lung, peritoneum, and lumbar spine (Kurli, Chin 2008).