The vast majority of MMC patients presents with a single, dark conjunctival patch that becomes more extensive over time [1]. 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 [1] [2]. 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 [1].

Most MMC are of dark brown, nearly black color, with amelanotic MMC being very rare occurrences [3]. 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. [1]. During early stages, melanomas are flat or slightly elevated tumors. By contrast, nodular growth is characteristic of advanced-stage disease [4]. The surface of the tumor may be ulcerated but not keratinized [1] [4].

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 [1].

• Pain

  Ocular Therapeutix has resubmitted an NDA for post-surgical pain for its lead product candidate, DEXTENZA™ (dexamethasone insert), which has completed Phase 3 clinical development for the treatment of ocular pain and inflammation following ophthalmic [eei-biotechfinances.com]

  Cystitis (bladder infection) symptoms are easier to distinguish and include back pain, concentrated appearance, urgency, hematuria (presence of red blood cells in the urine), and suprapubic pain as well as increased frequency of urination and pyuria. [web.uconn.edu]

  Medical condition: painful polyneuropathy of different origin Disease: Population Age: Adults, Elderly Gender: Male, Female Trial protocol: DK (Ongoing) Trial results: (No results available) EudraCT Number: 2004-004633-33 Sponsor Protocol Number: bosex [clinicaltrialsregister.eu]

  Signs and symptoms of glaucoma may include eye pain and redness, as well as blurry vision. Vision loss. [mayoclinic.org]

  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. [symptoma.com]

• Inflammation

  DEXTENZA has completed Phase 3 evaluation for the treatment of ocular pain and inflammation following ophthalmic surgery. [eei-biotechfinances.com]

  Results of our study also show that the atrophy and inflammation noted on histopathologic examination were not clinically significant. [jamanetwork.com]

  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. [symptoma.com]

  inflammation, and fibrosis. [ojoonline.org]

  Malignant melanomas arising from nevi (they may arise from junctional and compound nevi) usually appear as a change (increasing nodularity, variegated pigmentation, bleeding, or inflammation) in known pigmented lesions of the conjunctiva, but it may be [emedicine.medscape.com]

• Surgical Procedure

  Surgical procedures. American Society of Ocularists. http://www.ocularist.org/resources_surgical_procedures.asp. Accessed July 8, 2018. Intraocular (uveal) melanoma symptoms, tests, prognosis, and stages (PDQ). [mayoclinic.org]

  The use of various surgical procedures were correlated with local recurrence and survival rates. [scinapse.io]

  Data on whether or not surgery and radiation were utilized were available in the SEER database; however, specific details pertaining to the surgical procedure, such as surgical margins and the drugs and dosages utilized for chemotherapy, were not reported [dovepress.com]

• Fever

  Symptoms for pneumonia include fever, chills, chest pain, rales, and cough. Prostatitis can occur as a result of P. mirabilis infection, causing fever, chills, and tender prostate in men. [web.uconn.edu]

  Anti-proliferative Anti-viral Topical 1 million IU/ml four times daily or intralesional 3 million IU/ml 10 million IU/ml subconjunctival injections administered weekly Superficial punctate keratopathy Follicular conjunctivitis Systemic flu-like syndrome Fever [healthdocbox.com]

  In this manner, the invasion level is incorporated only in the definitions of melanomas ≤1mm23 (Chart 1). 3) Clinical staging a) investigation for evidence of metastatic disease: fever, migraine, asthenia, weight loss, bone pain, neurological and respiratory [zdoc.site]

• Swelling

  The main clinical manifestations are a pigmented lesion, lump, or swelling in the conjunctiva in 83% of the cases. [oatext.com]

• Pneumonia

  This is the result of infected hospital breathing equipment and causes pneumonia. Symptoms for pneumonia include fever, chills, chest pain, rales, and cough. [web.uconn.edu]

  Detection of Chlamydia pneumoniae in a bilateral orbital mucosa-associated lymphoid tissue lymphoma. Am J Ophthalmol 2006;141:1162-3. 46. Chan CC, Smith JA, Shen DF, et al. [ojoonline.org]

• Cough

  Symptoms for pneumonia include fever, chills, chest pain, rales, and cough. Prostatitis can occur as a result of P. mirabilis infection, causing fever, chills, and tender prostate in men. [web.uconn.edu]

• Nausea

  Pyelonephritis is marked by nausea and vomiting. Proteus mirabilis can enter the bloodstream through wounds. This happens with contact between the wound and an infected surface. [web.uconn.edu]

  In the month before admission, she had noted generalized weakness, nausea and vomiting, and increasingly severe headaches induced by postural changes and associated with visual disturbances. [doctiktak.com]

  […] and Safety Profile Established in more than 490 participants in over 10 years. 20,993 ingestions in 412 study participants: • 97.3% detection rate of the ingestible sensor • 100% correct identification (no false positives) • 4 subjects (1%) reported nausea [proteus.com]

• Vomiting

  Pyelonephritis is marked by nausea and vomiting. Proteus mirabilis can enter the bloodstream through wounds. This happens with contact between the wound and an infected surface. [web.uconn.edu]

  In the month before admission, she had noted generalized weakness, nausea and vomiting, and increasingly severe headaches induced by postural changes and associated with visual disturbances. [doctiktak.com]

  Profile Established in more than 490 participants in over 10 years. 20,993 ingestions in 412 study participants: • 97.3% detection rate of the ingestible sensor • 100% correct identification (no false positives) • 4 subjects (1%) reported nausea or vomiting [proteus.com]

• Aphthous Stomatitis

  Dermatol Clin - PJ (Show Context) 5 Association between psychological disorders and the presence of Oral lichen planus, Burning mouth syndrome and Recurrent aphthous stomatitis. Med Oral - Soto-Araya, Rojas-Alcayaga, et al. [citeseerx.ist.psu.edu]

• Heart Disease

  In the U.S. around 75 million people have hypertension or high blood pressure 1 About half of patients are not at blood pressure (BP) goal 2 For every increase of 20 mm Hg in systolic BP or 10 mm Hg in diastolic BP, the risk of ischemic heart disease [proteus.com]

• Ulcer

  ∅ o ∅ < 1mmClark IV/V; ulcer 1,01-2mm ulcer ∅ o ∅ o ∅ 1,01-2mm ulcer 2,01-4mm ulcer ∅ o ∅ o ∅ o ∅ o ∅ IB IIA IIB 2,01-4mm ulcer > 4mm ulcer ∅ IIC > 4mm ulcer o ∅ IIIA < 1-> 4mm ulcer ∅ < 1-> 4mm ulcer ∅ ·mm ∅ ·mm ··to ···mm ∅ IIIB < 1-> 4mm ulcer or [zdoc.site]

  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. [practicaldermatology.com]

  Lesion origin is a critical factor: De novo melanomas tend to have the worst prognosis.5 Other factors predictive of poor survival include older age, male gender, nonwhite race, and tumors with nodularity or ulceration. [aao.org]

  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. [symptoma.com]

  In a previous study of over 500 metastatic skin cancers, early metastasis (<3 years after surgery) was found to be significantly associated with past history of non-melanoma skin cancer, thicker lesions (Breslow depth), and ulcerative melanomas (19). [frontiersin.org]

• Sweating

  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]

• Fear

  “I think that one of the greatest fears for any surgeon who is a comprehensive ophthalmologist is to operate on an eye that may harbor an unrecognized malignancy,” Dr. Murray said. [healio.com]

• Headache

  Case Report A 41-year-old Asian woman presented in January 1993 with a 6-month history of occipital headaches and increasing dizziness. [doctiktak.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 [2] [4].

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 [4]. 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 [1]. 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 [4]. 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 [5].

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 [2]. 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 [4]. Others insist on surgical margins of at least 2 mm [1] [2]. 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 [6]. If necessary, corticosteroids may be applied to reduce the local inflammation [1]. Elsewhere, ophthalmologists prefer iridium, ruthenium, or strontium-based brachytherapy after the excision of MMC [2].

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 [7] [8]. 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% [2]. Thus, the prognosis of MMC patients is significantly better than the prognosis of those who are diagnosed with other types of mucosal malignant melanoma [9]. 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 [2] [4]. 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 [2]. Vision loss may be related to keratitis following surgery, chemotherapy or cryotherapy, hypotony and macular edema following cryotherapy, or radiation-induced cataract [1].

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 [2] [4]. Furthermore, the incidence of conjunctival melanoma negatively correlates with the geographic latitude, and tumor cells carry the molecular signature of UV-induced DNA damage [10].

About 80% of MMC develop from pre-existing lesions, namely from a nevus (7%) or primary acquired melanosis (74%) [2]. 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 [1].

Mucosal malignant melanoma accounts for 1.3% of all melanomas, with MMC being the most common subtype [4] [9]. MMC is usually diagnosed in the elderly and the incidence of MMC peaks during the sixth and seventh decade of life [9]. 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 [2]. While males and females are affected equally, MMC is exceedingly rare in dark-skinned individuals [4].

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 [7] [8]. 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 [10]. 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 [2].

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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