Primary malignant melanoma of the conjunctiva (MMC) is the most common type of mucosal malignant melanoma. It frequently develops as a single, dark conjunctival patch that is increasing in size. It is well visible, and most patients are diagnosed during early stages of the disease, before tumor cells spread to the regional lymph nodes or distant organs. Accordingly, the prognosis of MMC patients is favorable. After the surgical resection of the entire tumor, affected individuals receive localized therapy to reduce the risk of recurrence. Large primary tumors and metastases can hardly be resected in their entirety and are associated with a poor outcome.
The vast majority of MMC patients presents with a single, dark conjunctival patch that becomes more extensive over time . Most MMC develop in the sun-exposed cornea or bulbar conjunctiva, often involving the limbus, but the disease may also affect the tarsal or forniceal conjunctiva or lacrimal caruncle  . In advanced-stages of the disease, local dissemination may occur and additional patches may develop in other parts of the conjunctiva. Dissemination may also have iatrogenic causes .
Most MMC are of dark brown, nearly black color, with amelanotic MMC being very rare occurrences . Amelanotic MMC may be of white, yellow, pink, or red color. Regardless of their pigmentation, they are usually supplied by clearly visible feeder vessels. Hemorrhages are rare. . During early stages, melanomas are flat or slightly elevated tumors. By contrast, nodular growth is characteristic of advanced-stage disease . The surface of the tumor may be ulcerated but not keratinized  .
To assess for lymphogenic spread, the parotid, preauricular, postauricular, submandibular, and cervical lymph nodes should be palpated. Lymphadenopathy may be noted if lymph node metastases are present .
- Conjunctival Disease
Mapping and clinical staging of conjunctival disease has improved. Adjunctive radiotherapy and topical chemotherapy have made tumour control more successful, with reduced morbidity. [nature.com]
Moreover, patients with multifocal conjunctival disease are more likely to have recurrences than patients with unifocal disease.5 Topical mitomycin chemotherapy is being used in the treatment of conjunctival neoplasia.13,14,22,23 Thus far, it has been [jamanetwork.com]
Other predisposing factors include irradiation, arsenic poisoning, Addison's disease, and chloasma of pregnancy. [ojoonline.org]
- Fair Complexion
The incidence is 1 in 2 millions in Fair complexion population with predisposing lesions primary acquired melanosis (75% of cases), preexisting conjunctival nevus (junctional or compound) (25%) or it may arise de novo (nodular melanoma).  Clinically [ojoonline.org]
The caruncle is a remnant of the anterior surface of the nictitating membrane, is covered by modified skin lined with conjunctival epithelium, and contains hair follicles, sebaceous glands, sweat glands and accessory lacrimal tissue (Seregard 1998; Levy [onlinelibrary.wiley.com]
After a detailed clinical history has been obtained and a thorough ophthalmological examination including the visual inspection of the entire conjunctiva has been performed, imaging techniques should be employed for tumor staging. Sonography, computed tomography, and magnetic resonance imaging may all be used to this end, but positron emission tomography is the more effective way to visualize metastases  .
While the histological examination of tissue samples largely supports the diagnosis of MMC, biopsies of MMC should be avoided due to increased risks of recurrence and metastatic spread . Instead of biopsies, surgical interventions carried out with curative intent should be used to obtain tumor samples for microscopic characterization. Such samples are densely populated by pleomorphic, most commonly epitheliod or spindle-shaped tumor cells, which are organized in a sheet or nest-like manner below the conjunctival epithelium. Pigmented granules are readily observed in the majority of these cells but are lacking in the rare amelanotic MMC. Tumor cells typically carry pleomorphic nuclei with irregular borders and prominent nucleoli . Moderate to severe nuclear atypia should be considered an indicator of malignancy but is not a reliable criterion for the differentiation of MMC and benign lesions. Furthermore, neither of the aforementioned features is specific for MMC, and it is highly recommended to assess the expression of melanocyte markers by means of immunohistochemical staining. Such an analysis may reveal the expression of HMB-45, Ki-67, melanoma antigen/MART-1, and S100 protein . Whereas MART-1 and S100 protein are expressed by both normal and degenerated melanocytes, benign lesions don't tend to stain positive for HMB-45 and Ki-67 .
The standard treatment of MMC consists in the surgical resection of the tumor and localized cryotherapy, brachytherapy, or chemotherapy. Before the excision of the tumor is performed, it may be treated with formalin to reduce the risk of tumor cell seeding . The necessity of wide surgical margins has repeatedly been discussed, with some studies suggesting that the outcome may not be affected by the width of surgical margins as long as the achievement of histopathologically tumor-cell-free margins is confirmed postoperatively . Others insist on surgical margins of at least 2 mm  . Given the importance of the complete resection of MMC, radical measures like exenteration may have to be taken in some cases. According to the results of preoperative tumor staging, lymph node dissection may be required or foregone. The usefulness of sentinel lymph-node biopsies has not yet been proven.
No consensus has been reached regarding the efficacy of the aforementioned adjuvant therapies. Cryotherapy has largely been replaced by chemotherapy with mitomycin-C. Mitomycin-C is applied during 2-4 cycles of 1-2 weeks. Periods of rest need to be considered to prevent conjunctival injection, tearing, inflammation, and pain, and to improve compliance . If necessary, corticosteroids may be applied to reduce the local inflammation . Elsewhere, ophthalmologists prefer iridium, ruthenium, or strontium-based brachytherapy after the excision of MMC .
Molecular-targeted therapy is becoming increasingly important, particularly in the treatment of advanced-stage MMC. The administration of molecular-targeted therapies should be based on a detailed genetic characterization of the tumor. Considering the molecular features of MMC, B-Raf kinase inhibitors, MEK inhibitors, and c-kit inhibitors may be applied  . Several compounds have been approved for the treatment of advanced-stage melanoma, including vemurafenib and dabrafenib, trametinib and cobimetinib, imatinib and other kinase inhibitors. Other drugs are currently on trial or under review.
The overall five-year survival rate of MMC patients has been estimated to be about 90% . Thus, the prognosis of MMC patients is significantly better than the prognosis of those who are diagnosed with other types of mucosal malignant melanoma . This is most likely due to the visible location of the tumor, which facilitates an early diagnosis. The size and thickness of the primary tumor and the presence of lymph node or distant metastases at the time of diagnosis are the most important prognostic factors, with advanced MMC being more likely to recur, to spread and metastasize to the liver, lungs, brain, or gastrointestinal tract, among others  . While local recurrence affects about a third of MMC patients, 12% are diagnosed with distant metastases within five years after the initial diagnosis.
Few patients experience a partial loss of visual acuity during treatment . Vision loss may be related to keratitis following surgery, chemotherapy or cryotherapy, hypotony and macular edema following cryotherapy, or radiation-induced cataract .
MMC originate from melanocytes, which are pigment-carrying cells that arise from neural crest cells which migrate along the peripheral nerves to invade the dermis and epidermis, the ocular mucous membranes, uvea, and retinal pigment epithelium, among others. In the skin, melanocytes protect from DNA damage induced by ultraviolet radiation, and they may fulfill related tasks in the conjunctiva. Exposure to sunlight is a well-known risk factor for the development of skin cancer and may play a similar role in MMC cancerogenesis: Exposure to ultraviolet light is assumed to be the main reason why most MMC develop in the epibulbar conjunctiva  . Furthermore, the incidence of conjunctival melanoma negatively correlates with the geographic latitude, and tumor cells carry the molecular signature of UV-induced DNA damage .
About 80% of MMC develop from pre-existing lesions, namely from a nevus (7%) or primary acquired melanosis (74%) . The triggers of their malignant transformation remain elusive, but it is generally accepted that the degree of cellular atypia is related to the likelihood of cancer development. Other features to be considered in this context are the pattern of melanocytic proliferation and the extent of vertical spread .
Mucosal malignant melanoma accounts for 1.3% of all melanomas, with MMC being the most common subtype  . MMC is usually diagnosed in the elderly and the incidence of MMC peaks during the sixth and seventh decade of life . The patients' mean age at the time of diagnosis is 58 years. The overall incidence of MMC has been estimated to be 5 per 10,000,000 inhabitants and year but seems to be rising in the Caucasian population . While males and females are affected equally, MMC is exceedingly rare in dark-skinned individuals .
Sunlight exposure is assumed to play a major role in the development of MMC. Ultraviolet radiation is known to induce DNA damage, to cause mutations of the BRAF gene. BRAF mutations are detected in up to 35% of MMC. The BRAF gene is considered a protooncogene and encodes for the B-Raf protein, a serine/threonine protein kinase. Mutations like V600E, the substitution of glutamic acid by valine at position 600, result in the constitutive activation of the B-Raf kinase. The enzyme is part of the MAP kinase pathway, which is involved in the regulation of cell growth, differentiation, and apoptosis. Similarly, a dysregulation of the MAP kinase pathway in MMC tumor cells may be caused by mutations of the protooncogenes KIT and NRAS. The triggers of these mutations remain unknown.
The identification of driver mutations affecting the BRAF, KIT, or NRAS genes in MMC paves the way towards molecular-targeted therapy: B-Raf inhibitors like vemurafenib, MEK inhibitors like trametinib, and c-kit inhibitors such as imatinib have been used to treat advanced-stage melanoma  . By contrast, NRAS mutations have not yet been targeted in MMC therapy.
Due to the role of ultraviolet radiation in the generation of driver mutations in melanocytes, MMC prevention should include the reduction of sun exposure . Sunscreen can't be applied to the conjunctiva, but people may avoid the full midday sun, may use sunglasses and wide-brimmed hats.
Malignant melanoma is best known as a type of skin cancer. However, melanocytes can be found in other tissues, and melanoma may develop in an extracutaneous manner. Besides uveal melanoma, the most common primary malignant intraocular neoplasm, melanocyte-derived malignancies may develop in mucous membranes. Among mucosal malignant melanoma, MMC has the highest incidence. MMC is a unilateral disorder, and affected individuals typically present with a single, dark brown conjunctival patch whose size is increasing. It may be difficult to distinguish MMC from primary acquired melanosis and benign nevi, which may be considered precursors of tumor development. While clinical and imaging data may suggest benignancy or malignancy, a reliable diagnosis of MMC requires the histological examination of tissue samples. However, any manipulation of MMC is known to increase the risk of tumor cell seeding, local dissemination, and metastasis. Excision biopsy with curative intent is the method of choice to obtain the necessary samples and to treat the disease. Adjuvant therapy is recommended to diminish the risk of recurrence .
Malignant melanoma is a well-known type of skin cancer. It originates from degenerated melanocytes, from cells that carry dark pigments and are responsible for the color of skin. Melanocytes can also be found elsewhere in the human body, e.g., in the conjunctiva, uvea, and retina of the eye. Accordingly, melanoma may also develop in these regions.
Primary malignant melanoma of the conjunctiva (MMC) is a rare disease, mainly affecting the elderly. MMC patients usually present with a single, dark conjunctival patch that becomes more extensive over time. Every part of the conjunctiva may be affected, but MMC most commonly develop in the sun-exposed cornea or bulbar conjunctiva, often involving the limbus. There may be well visible blood vessels supplying the tumor, which is initially flat or slightly elevated but may eventually protrude.
Treatment consists in the surgical excision of the entire tumor - something that is easier to achieve as long as the lesion is small - and adjuvant therapy to reduce the risk of local recurrence. Adjuvant therapy may consist in the local application of cold (cryotherapy), radiation (brachytherapy), or cytostatics (chemotherapy). Patients who are diagnosed early have a favorable prognosis. However, delays in the diagnosis of MMC augment the risk of metastasis. MMC may spread to the regional lymph nodes or distant organs like the liver and lungs. Metastatic disease is associated with a poor outcome.
The triggers of MMC development remain largely unknown. One of the few risk factors that have been identified so far is exposure to ultraviolet radiation. In this regard, MMC resembles skin cancer. Thus, patients may reduce their individual risks of developing MMC by avoiding the full midday sun, by using sunglasses and wide-brimmed hats. The application of sunscreen doesn't protect from MMC but is certainly useful to prevent malignant melanoma of the skin, so all these types of sun protection should be routinely used.
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