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Ocular Melanoma

Ocular melanoma (OM) is a general term referring to uveal melanoma, conjunctival melanoma, and possibly other types of eye cancer. The latter are very rare and mainly comprise orbital melanoma and secondary melanoma. Radiation and surgery are the mainstays of treatment but may be insufficient to prevent metastatic spread in the long term. About half of all patients are found to suffer from advanced-stage OM years after the initial diagnosis and eventually succumb to the disease.


Presentation

Uveal melanoma and conjunctival melanoma are the main subtypes of OM. These entities are associated with different symptoms, require distinct treatments, and differ in their outcomes. They have to be distinguished in every respect [1]:

  • Patients suffering from uveal may present with visual impairment including visual field defects, blurred vision, metamorphopsia, or photopsia. Irritation, redness, and pain may also occur. Still, about one-third of uveal melanomas are detected incidentally in asymptomatic patients.
  • Conjunctival melanoma most commonly arises from the bulbar conjunctiva and corresponds to a well visible, dark patch that is increasing in size. During the early stages of tumor development, conjunctival melanoma remains flat, and most lesions are indeed recognized and excised before reaching the advanced stages of nodular growth. This type of melanoma is usually supplied by prominent feeder vessels, which may be of particular importance in the rare cases of amelanotic melanoma. The latter are of light colors contrast less with the healthy conjunctiva. While some patients claim irritation and pain, most remain asymptomatic.
Supraclavicular Adenopathy
  • On physical examination, there was no supraclavicular adenopathy and no skin lesions were noted. There was a mass in the right upper quadrant. The total bilirubin was 4.8 mg/dL.[ncbi.nlm.nih.gov]
Axillary Mass
  • In female patients presenting with an isolated axillary mass, with a negative breast work up and known prior history of melanoma, the differential diagnosis should include possible metastatic melanoma.[ncbi.nlm.nih.gov]
Back Pain
  • Melanoma metastatic to the spine typically arises within the vertebral column, presents with back pain, and has a poor prognosis.[ncbi.nlm.nih.gov]
Photosensitivity
  • The latter requires the injection of a photosensitizer and the subsequent exposure to light of the corresponding wavelength. The localized release of free radicals results in oxidative stress and cell death.[symptoma.com]
Purpura
  • Unfortunately, the patient passed away due to involvement of thrombotic thrombocytopenic purpura 9 months after the initial consultation, however, aggravation of the liver metastatic focus was not observed.[ncbi.nlm.nih.gov]
Tonic-Clonic Seizure
  • We describe a case of 52-year-old man who presented with an episode of tonic-clonic seizures. He had right ocular melanoma 23 years ago with subsequent enucleation which was the standard treatment at that time.[ncbi.nlm.nih.gov]
Neglect
  • If neglected, orbital spread can become extensive enough to cause proptosis. Before the twentieth century, it was not uncommon for uveal melanoma to spread through the optic canal into the cranial cavity to involve the brain.[ncbi.nlm.nih.gov]
Hematuria
  • A 71-year-old man presented with gross hematuria. He had undergone left enucleation 20 years previously for ocular melanoma and had not required adjuvant therapy.[ncbi.nlm.nih.gov]

Workup

The vast majority of uveal melanomas is definitively diagnosed based on the results of a thorough ophthalmological examination. Imaging techniques such as A and B ultrasonography, fluorescein angiography, and optical coherence tomography may be employed to support the initial findings and to dispel remaining doubts, so biopsies are rarely necessary. Choroidal melanoma usually presents as a dome or mushroom-shaped subretinal mass that may provoke retinal detachment. Similarly, iris and ciliary body melanoma appear as mass lesions that may interfere with the function or alter the shape of surrounding tissues. Increased intraocular pressure may be noted, and lens displacement, localized cataract, or distortion of the pupil may also occur [2].

Conjunctival melanoma may evolve from primary acquired melanosis (about 60% of all cases), conjunctival nevus (up to 25%), or develop de novo (approximately 15%). They all present as flat, dark lesions of the conjunctival epithelium, and the distinction between them may pose a major challenge. Feeder vessels, signs of inflammation, and lesion growth should raise suspicion as to a malignant condition, but they are not exclusion criteria. In case of doubt, an excisional biopsy with security margins should be performed, and the diagnosis should be histopathologically be confirmed [3]. Conjunctival melanoma cells may be spindle-shaped or epitheliod and generally stain positive for melanoma markers HMB-45, melan-A/MART-1, and MITF. The expression of Ki-67 can provide valuable hints as to their proliferative activity, and the respective findings can be corroborated by an assessment of the mitotic rate and lymphatic invasion [4].

Mediastinal Mass
  • The mediastinum, however, is a rare site of these metastases, and metastatic melanoma presenting as a large mediastinal mass is quite unusual.[ncbi.nlm.nih.gov]
Posterior Mediastinal Mass
  • We report herein a peculiar case of a solitary, late metastasis of malignant ocular melanoma, manifesting as a sizable posterior mediastinal mass and presenting with paroxysmal atrial fibrillation.[ncbi.nlm.nih.gov]

Treatment

Radiation is the current standard of treatment for most small and medium-sized uveal melanomas. Distinct techniques may be employed, such as plaque radiation therapy, proton beam radiotherapy, and stereotactic radiotherapy, without any of them having been proven to be more effective than the others. They may be combined with transpupillary thermal therapy, which uses infrared radiation to destroy the tumor, or with photodynamic therapy. The latter requires the injection of a photosensitizer and the subsequent exposure to light of the corresponding wavelength. The localized release of free radicals results in oxidative stress and cell death [5] [6]. Surgery is preferred for neoplasms originating from the iris, for larger tumors, and in case of recurrent disease [7]. According to the properties of the tumor, the surgeon may choose between transscleral resection, transretinal endoresection, or en bloc resection, and thus spare the eye, or opt for enucleation. At present, enucleation, once the standard treatment for OM, is reserved for advanced-stage melanoma with high risks of local recurrence.

The primary treatment of conjunctival melanoma is the wide local excision of the tumor plus adjuvant brachytherapy, cryotherapy, or the topical application of chemotherapeutic agents such as mitomycin C, 5-fluorouracil, and interferon α. Adjuvant therapies are employed to prevent local recurrence and to improve the long-term control of the disease, but there's no consensus as to the selection of the most suitable therapy [8].

With the increasing knowledge about the molecular background of OM, treatment strategies are constantly evolving. Current research focuses on molecular-targeted therapies and immunotherapies, which are urgently needed to improve the long-term efficacy of present therapies, to avoid the development of metastases, and to treat patients with advanced-stage disease. Because mutations in the GNAQ or GNA11 genes can be confirmed in up to 80% of uveal melanomas, considerable efforts are directed towards the identification of inhibitors of downstream MAPK pathways [9]. Yet, clinical studies conducted to date did not yield promising results [10].

Prognosis

Mean survival times for OM patients have been reported to be about 15 years, with minor differences between uveal and conjunctival melanoma. The five-year cancer-specific survival rates amount to 70% in both cases [1]. Increasing tumor thickness and basal tumor diameter are unfavorable prognostic factors, as well as diffuse tumor growth [2].

Advanced-stage OM is associated with poor outcomes, and even though metastatic disease is rarely recognized at the time of diagnosis, up to half of all patients will eventually present with metastases [8]. Decades may pass between the initial diagnosis and the identification of metastatic melanoma, which explains the rather long survival of OM patients, but the systemic spread of the disease is associated with a poor prognosis and high mortality [7]. Conjunctival melanoma initially metastasizes to the regional lymph nodes, while uveal melanoma metastasizes hematogenously and directly spreads to the liver, lungs, and bones.

Etiology

The causes of OM development remain poorly understood. Notwithstanding, individual risk factors have been identified: Patients with congenital ocular or oculodermal melanocytosis have a lifetime risk of 1 in 400 to develop uveal melanoma [11]. Similarly, uveal nevi, particularly large ones, augment the risk of this type of cancer. Conjunctival melanoma has been related to primary acquired melanosis with severe atypia, which undergoes malignant transformation in up to 13% of affected patients. By contrast, mild atypia or the presence of conjunctival nevi don't significantly contribute to the individual risk of conjunctival melanoma as they rarely undergo malignant transformation [2] [12]. Fair eyes, fair skin, and the presence of cutaneous nevi may also be considered in the context of OM development, while data regarding a possible association between exposure to ultraviolet radiation and the risk of OM are inconclusive. Conjunctival melanoma has been suggested to be related to ultraviolet light exposure [13]. The incidence of uveal melanoma, however, was found to increase with higher geographic latitude, which has been attributed to the protective role of ocular pigmentation [14].

Epidemiology

OM comprises <5% of all melanomas and is the second most common type of melanoma after cutaneous malignant melanoma. The majority of cases corresponds to uveal melanoma, while conjunctival melanoma is rare. For the United States, the overall incidence of OM has been estimated at 6 in 1,000,000 people. There's Caucasian male predominance and most patients are of advanced age. OM is exceedingly rare in patients with dark skin [15].

Sex distribution
Age distribution

Pathophysiology

There are two major subtypes of OM. Uveal melanoma arises from the choroid, or, less frequently, the iris or ciliary body, whereas conjunctival melanoma is a type of mucosal melanoma developing from melanocytes located in the basal layer of the epithelium of the conjunctival membrane. They differ with regard to the genetic and molecular abnormalities displayed by tumor cells. Uveal melanoma, on the one hand, is characterized by the constitutive activation of mitogen-activated protein kinase pathways. Mutations in the GNAQ or GNA11 genes, which encode for closely related α subunits of Gq proteins, interfere with the activation of phospholipase Cβ and the downstream regulation of Ras/Raf/MEK/ERK signaling [8] [9]. Conjunctival melanoma, on the other hand, has been associated with BRAF and NRAS mutations [8].

These differences between uveal and conjunctival melanoma imply that targeted therapies have to be developed for and tested in both types of OM. What's more, the molecular divergence between OM and cutaneous malignant melanoma may explain why the low response rates of OM patients to systemic therapies applied in case of skin cancer [8].

Prevention

Patients with known risk factors for OM may be recommended to regular ophthalmological examinations. Otherwise, no recommendations can be given to prevent the development of OM.

Summary

Melanoma arises from melanocytes, which can be found in distinct ocular tissues. OM may develop from uveal melanocytes, from conjunctival or orbital ones. Accordingly, primary OM may refer to uveal melanoma, conjunctival melanoma, or orbital melanoma. The vast majority of cases corresponds to uveal melanoma. For the sake of completeness, the possibility of non-ocular melanoma metastasizing to the eye shall also be mentioned. All these types of OM develop as the result of unique pathophysiological cascades. Accordingly, the respective tumor cells vary in their molecular characteristics, in their growth behavior, and sensitivity to drugs and other types of treatment. For the same reason, knowledge obtained in studies on cutaneous malignant melanoma cannot be extrapolated to OM.

Notwithstanding, the single types of OM do have features in common. Both patients suffering from uveal melanoma and those diagnosed with conjunctival melanoma tend to respond well to primary treatments. More than two-thirds of them remain alive five years after the initial diagnosis. Late recurrence and metastatic spread are the major complications of either condition, and they are universally associated with a poor outcome. Additional research is required to offer more effective therapies to patients with advanced-stage OM, but studies have to be focused on a specific type of the disease.

Patient Information

Ocular melanoma (OM) is a general term referring to certain malignant tumors developing in the eye. Similar to the better known cutaneous malignant melanoma, OM arises from melanocytes, but the pathophysiological events leading to the development of skin cancer and OM are different. While sun exposure has long since been identified as a risk factor for cutaneous melanoma, it doesn't seem to play a major role in the case of eye cancer. Patients with congenital ocular or oculodermal melanocytosis or primary acquired melanosis are more likely to develop OM, and the presence of nevi may also contribute to the individual risk.

Melanocytes can be found in the middle layer of the eye, named uvea, and in the conjunctiva. Consequently, patients may develop uveal melanoma or conjunctival melanoma. Uveal melanoma may be recognized during an ophthalmological examination; conjunctival melanoma is generally observed by the patients themselves. The former manifests in visual impairment including visual field defects, blurred vision, the perception of flashes of light or floaters, and, less frequently, irritation, redness, and pain. By contrast, conjunctival melanoma typically presents as a pigmented, dark brown lesion of the ocular surface. It rarely causes additional complaints.

Uveal and conjunctival melanoma are also treated differently. The primary treatment for uveal melanoma is radiation. Distinct techniques may be employed to destroy tumor cells while preserving the eye and vision. On the other hand, conjunctival melanoma is treated surgically. In both cases, the outcome largely depends on the complete destruction or excision of the tumor. In order to prevent any local recurrence and to improve the long-term control of OM, adjuvant therapies may be applied.

The majority of patients responds well to therapy, and mean survival times amount to about 15 years. Unfortunately though, up to half of all patients eventually present with metastases. Several years may pass between the initial diagnosis and the recognition of tumor spread, but metastatic OM is associated with a poor prognosis.

References

Article

  1. Mahendraraj K, Shrestha S, Lau CS, Chamberlain RS. Ocular melanoma-when you have seen one, you have not seen them all: a clinical outcome study from the Surveillance, Epidemiology and End Results (SEER) database (1973-2012). Clin Ophthalmol. 2017; 11:153-160.
  2. Jovanovic P, Mihajlovic M, Djordjevic-Jocic J, Vlajkovic S, Cekic S, Stefanovic V. Ocular melanoma: an overview of the current status. Int J Clin Exp Pathol. 2013; 6(7):1230-1244.
  3. Pacheco GE, Garcia-Onrubia L, Garcia-Alvarez C, et al. A retrospective review of conjunctival melanoma: Presentation, treatment and evolution. Arch Soc Esp Oftalmol. 2019; 94(5):218-224.
  4. Damato B, Coupland SE. Management of conjunctival melanoma. Expert Rev Anticancer Ther. 2009; 9(9):1227-1239.
  5. Pereira PR, Odashiro AN, Lim LA, et al. Current and emerging treatment options for uveal melanoma. Clin Ophthalmol. 2013; 7:1669-1682.
  6. Souto EB, Zielinska A, Luis M, et al. Uveal melanoma: physiopathology and new in situ-specific therapies. Cancer Chemother Pharmacol. 2019; 84(1):15-32.
  7. Karde SR, Bhand PR, Ramesh N, Arockiam S. Metastatic melanoma after 23 years of primary ocular melanoma. BMJ Case Rep. 2016; 2016.
  8. Blum ES, Yang J, Komatsubara KM, Carvajal RD. Clinical Management of Uveal and Conjunctival Melanoma. Oncology (Williston Park). 2016; 30(1):29-32, 34-43, 48.
  9. Chen X, Wu Q, Depeille P, et al. RasGRP3 Mediates MAPK Pathway Activation in GNAQ Mutant Uveal Melanoma. Cancer Cell. 2017; 31(5):685-696.e686.
  10. Steeb T, Wessely A, Ruzicka T, Heppt MV, Berking C. How to MEK the best of uveal melanoma: A systematic review on the efficacy and safety of MEK inhibitors in metastatic or unresectable uveal melanoma. Eur J Cancer. 2018; 103:41-51.
  11. Singh AD, De Potter P, Fijal BA, Shields CL, Shields JA, Elston RC. Lifetime prevalence of uveal melanoma in white patients with oculo(dermal) melanocytosis. Ophthalmology. 1998; 105(1):195-198.
  12. 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 71-62.
  13. Rivolta C, Royer-Bertrand B, Rimoldi D, et al. UV light signature in conjunctival melanoma; not only skin should be protected from solar radiation. J Hum Genet. 2016; 61(4):361-362.
  14. Virgili G, Gatta G, Ciccolallo L, et al. Incidence of uveal melanoma in Europe. Ophthalmology. 2007; 114(12):2309-2315.
  15. McLaughlin CC, Wu XC, Jemal A, Martin HJ, Roche LM, Chen VW. Incidence of noncutaneous melanomas in the U.S. Cancer. 2005; 103(5):1000-1007.

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Last updated: 2019-07-11 21:54