Background

Conjunctival melanoma is a rare but potentially aggressive form of cancer that affects the conjunctiva of the eye and lines inside of the eyelids. It arises from melanocytes, the pigment-producing cells in the conjunctiva. Conjunctival melanoma can occur in individuals of any age, but it is commonly diagnosed in adults, particularly those over 50 years old. The condition is associated with various risk factors, including fair skin, light eye color, chronic sun exposure, and a history of previous ocular melanocytic lesions.

Conjunctival melanoma requires early detection and prompt treatment due to its potential for local invasion, metastasis to nearby lymph nodes, and distant spread to other organs. The prognosis of conjunctival melanoma depends on factors such as tumor size, thickness, location, and involvement of adjacent structures. Prompt and appropriate management, including surgical excision and adjunctive therapies, is essential for optimal outcomes in patients with conjunctival melanoma.

Epidemiology

Incidence and Prevalence:

• Conjunctival melanoma is a rare malignancy, accounting for approximately 2%-5% of all ocular tumors and 5%-7% of all ocular melanomas.
• The exact incidence and prevalence of conjunctival melanoma are not well-defined due to its rarity.

Age and Gender:

• Conjunctival melanoma can occur at any age, but it is most diagnosed in adults.
• There is no significant gender predilection, with equal occurrence in males and females.

Ethnicity and Geographical Variation:

• Conjunctival melanoma can affect individuals of any ethnic background.
• Geographical variation in the incidence of conjunctival melanoma has been reported, with higher rates observed in certain regions with increased exposure to ultraviolet (UV) radiation, such as Australia.

Anatomy

Pathophysiology

Conjunctival melanoma arises from the malignant transformation of melanocytes in the conjunctiva, the thin, transparent membrane covering the front surface of the eye.

The exact pathophysiology of conjunctival melanoma is not fully understood, but it is involved in genetic combination, environmental, and immunological factors.

• Malignant Transformation: Conjunctival Melanoma arises from the uncontrolled growth and division of melanocytes in the conjunctiva. The exact cause of the malignant transformation is not fully understood, but genetic and environmental factors are believed to play a role.
• Invasion and Metastasis: Conjunctival Melanoma has the potential to invade tissues and spread to the distant sites through metastasis. It can invade deeper layers of the conjunctiva, the eyelid, and nearby structures such as the orbit and lymph nodes. Hematogenous spread can lead to metastasis in distant organs like liver, lungs, and bones.
• Lymphatic and Hematogenous Routes: The spread of Conjunctival Melanoma can occur through both lymphatic and hematogenous routes. Lymphatic metastasis commonly involves regional lymph nodes, while hematogenous metastasis occurs when cancer cells enter the bloodstream and disseminate to distant organs.
• Tumor Progression: Conjunctival Melanoma can exhibit various histopathological features, including the presence of melanocytic atypia, cellular pleomorphism, mitotic activity, and invasion of the epithelial basement membrane. These features determine the aggressiveness of the tumor and its potential for local recurrence and metastasis.

Etiology

Ultraviolet Radiation Exposure:

• Prolonged and cumulative exposure to ultraviolet (UV) radiation, primarily from sunlight, is a major risk factor for the development of conjunctival melanoma.
• UV radiation can induce DNA damage and genetic mutations in melanocytes, contributing to the initiation and progression of melanoma.

Genetic Factors:

• Genetic alterations play a role in the etiology of conjunctival melanoma.
• Mutations in genes such as NRAS, BRAF, and c-KIT have been identified in conjunctival melanoma tumors, leading to abnormal cell signalling and uncontrolled cell growth.

Fair Skin and Light Eye Color:

• Individuals with fair skin and light eye color, particularly those with blue or green eyes, are at an increased risk of developing conjunctival melanoma.
• These characteristics are associated with reduced melanin protection against UV radiation.

Personal and Family History:

• Individuals with a history of melanoma, including cutaneous or ocular melanoma, have an increased risk of developing conjunctival melanoma.

Immune System Dysfunction:

• Immune system dysfunction or impaired immune surveillance may contribute to the development of conjunctival melanoma.
• Conditions that suppress immune system, such as immunosuppressive therapy or human immunodeficiency virus (HIV) infection, may increase the risk.

Genetics

Prognostic Factors

Tumor Thickness and Invasion:

• The thickness and invasion of the conjunctival melanoma tumor are important prognostic factors.
• Thicker tumors and deeper invasion into the underlying tissues are associated with a poorer prognosis.

Tumor Location:

• The location of the tumor on the conjunctiva can influence the prognosis.
• Tumors located in the palpebral (eyelid) region or in the caruncle (small pinkish area near the inner corner of the eye) are associated with a worse prognosis compared to tumors located in the bulbar conjunctiva.

Tumor Margins and Extension:

• Incomplete surgical resection with positive tumor margins or extension of the tumor beyond the surgical margins with an increased risk of recurrence and poorer prognosis.

Lymph Node Involvement:

• Spread of conjunctival melanoma to regional lymph nodes is associated with a worse prognosis.
• Lymph node metastasis indicates a higher likelihood of distant metastasis and disease progression.

Genetic and Molecular Markers:

• Certain genetic and molecular markers, such as mutations in the BAP1 gene and loss of chromosome 3, have been associated with a worse prognosis in conjunctival melanoma.
• These markers may indicate a more aggressive tumor phenotype.

Clinical History

CLINICAL HISTORY

Age Group:

• Conjunctival melanoma can occur at any age, but it is more commonly diagnosed in adults.
• The peak incidence is typically in the fifth to seventh decade of life.

Physical Examination

PHYSICAL EXAMINATION

Visual Inspection:

• The affected eye is examined visually for any abnormal findings on the conjunctiva.
• The conjunctiva may appear pigmented, raised, or nodular in the melanoma.
• The lesion may vary in color, including brown, black, gray, or even amelanotic (without pigment).

Slit-Lamp Examination:

• A slit-lamp examination is performed to provide a detailed evaluation of the conjunctiva and anterior segment of the eye.
• The lesion is examined under high magnification to assess its size, shape, pigmentation, vascularity, and surface characteristics.
• The presence of any associated features, such as feeder vessels, intrinsic vascularity, or ulceration, is noted.

Gonioscopy:

• Gonioscopy may be performed to evaluate the involvement of the tumor in the angle structures of the eye.
• It helps assess the tumor’s extent and involvement of the anterior chamber angle, which can have implications for treatment and prognosis.

Fundoscopic Examination:

• A dilated fundoscopic examination is conducted to evaluate the posterior segment of eye, including the retina and optic nerve.
• This examination is important to assess for any intraocular involvement or metastasis of the conjunctival melanoma.

Lymph Node Examination:

• The regional lymph nodes, including preauricular, submandibular, and cervical lymph nodes, are palpated to check for enlargement or metastasis.

Age group

Associated comorbidity

Associated Comorbidity or Activity:

Conjunctival melanoma is not strongly associated with specific comorbidities. However, it has been reported to occur more frequently in individuals with fair skin, light eye color, and a history of sun exposure.

Associated activity

Acuity of presentation

Acuity of Presentation:

Conjunctival melanoma is often asymptomatic in the early stages.

As the tumor progresses, patients may experience various symptoms, such as:

• Changes in the appearance of the conjunctiva, such as pigmented or elevated lesions.
• Redness, irritation, or discomfort in the affected eye.
• Blurred vision or vision loss if the tumor affects the visual axis.
• Sensation of a foreign body or a mass in the eye.
• Excessive tearing or discharge from the eye.
• Enlargement of nearby lymph nodes if metastasis has occurred.

Differential Diagnoses

DIFFERENTIAL DIAGNOSIS

Conjunctival Nevus:

• Conjunctival nevus is a common benign pigmented lesion of the conjunctiva.
• It can resemble conjunctival melanoma in terms of pigmentation and location.
• However, conjunctival nevus typically has well-defined borders, uniform pigmentation, and shows no signs of growth or invasion.

Conjunctival Lymphoma:

• Conjunctival lymphoma is a rare malignant tumor that arises from lymphoid cells in the conjunctiva.
• It can present as a pigmented lesion on the conjunctiva, mimicking conjunctival melanoma.
• However, lymphoma typically exhibits a more diffuse, salmon-pink appearance and may be associated with systemic symptoms.

Conjunctival Squamous Cell Carcinoma:

• Conjunctival squamous cell carcinoma is a malignant tumor arising from the conjunctival epithelium.
• It can present as a pigmented lesion on the conjunctiva, which can be mistaken for melanoma.
• However, squamous cell carcinoma tends to have a more irregular surface, may be associated with surrounding inflammation, and is more commonly located at the limbus.

Conjunctival Hemangioma:

• Conjunctival hemangioma is a benign vascular tumor that can cause a pigmented appearance of the conjunctiva.
• It can sometimes be mistaken for melanoma due to its vascular nature and coloration.
• However, hemangioma typically has a more spongy or vascular appearance and can exhibit rapid growth during infancy.

Conjunctival Metastasis:

• Metastatic tumors from other primary sites can rarely involve the conjunctiva.
• These metastases can present as pigmented lesions, resembling conjunctival melanoma.
• An evaluation of medical history and systemic examination is crucial in identifying potential primary malignancies.

Laboratory Studies

Imaging Studies

Procedures

Histologic Findings

Staging

Treatment Paradigm

TREATMENT REGIMEN

Modification of Environment:

• Sun protection: Patients should be advised to protect their eyes from harmful UV radiation by wearing sunglasses and wide-brimmed hats.
• Avoidance of irritants: Patients should avoid exposure to irritants such as smoke, dust, and chemicals that can exacerbate symptoms or promote tumor growth.

Administration of Pharmaceutical Agents (Drugs):

• Topical chemotherapy: Mitomycin C or interferon-alpha can be used as adjuvant therapy to reduce the local recurrence risk.
• Immunotherapy: Immune checkpoint inhibitors, such as pembrolizumab and nivolumab, have shown promise in the treatment of advanced conjunctival melanoma.

Intervention with a Procedure:

• Surgical excision: Wide local excision with clear margins is the primary treatment for localized conjunctival melanoma.
• Cryotherapy: Cryotherapy may be used as an adjunct to surgical excision to destroy any residual tumor cells.
• Conjunctival mapping biopsy: This procedure involves mapping the entire conjunctival surface and taking multiple biopsies to ensure complete removal of the tumor.

Phase of Management:

• Surveillance: Regular follow-up visits with an ophthalmologist are necessary to monitor for recurrence or metastasis.
• Imaging studies: Imaging modalities such as ultrasound, CT scan, or MRI scan are used to assess for local or distant spread.
• Systemic evaluation: Evaluation for metastasis to regional lymph nodes and distant organs should be considered based on the tumor stage.

by Stage

by Modality

Chemotherapy

Radiation Therapy

Surgical Interventions

Hormone Therapy

Immunotherapy

Hyperthermia

Photodynamic Therapy

Stem Cell Transplant

Targeted Therapy

Palliative Care

Medication

Future Trends

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References

Management of conjunctival malignant melanoma: a review and update.ncbi.nlm.nih.gov