Conjunctival Melanoma: Symptoms, Types, Causes and Treatment

Conjunctival melanoma is a rare but potentially life-threatening cancer of the eye's conjunctiva—the clear, thin membrane covering the white part of the eye and lining the inside of the eyelids. While uncommon, this disease carries significant risk due to its ability to recur locally and metastasize to distant sites, making early recognition and appropriate management critical. In this article, we will explore the symptoms, types, causes, and treatment options for conjunctival melanoma, drawing on the latest scientific research and international clinical experience.

Symptoms of Conjunctival Melanoma

Early detection of conjunctival melanoma can be challenging because the initial symptoms are often subtle or may overlap with benign eye conditions. Nonetheless, recognizing the warning signs is vital for timely diagnosis and improved outcomes.

Symptom	Description	Importance	Source(s)
Pigmented lesion	Dark spot or patch on the conjunctiva	Most common initial sign	1 5 11
Growth/Thickening	Noticeable increase in size, nodularity	Suggests malignancy	1 11
Bleeding	Bloody tears or hemorrhage from lesion	Rare, may signal necrosis	1
Redness/Inflammation	Local irritation or swelling	May mimic benign conditions	1 11
Recurrence	Return of tumor in same or nearby location	Indicates aggressive behavior	10 14

Table 1: Key Symptoms

Common Presenting Features

Most often, patients notice a new or changing pigmented spot on the eye. This lesion may be flat or raised and is typically located on the exposed (bulbar) conjunctiva, though it can also appear in hidden areas such as the fornix or under the eyelids 1 5 11. Over time, the lesion may increase in size, become nodular, or develop irregular borders.

Bleeding and Other Alarming Signs

Although uncommon, bleeding from the tumor—manifesting as bloody tears—may occur, particularly in advanced cases where tumor tissue has become necrotic 1. This symptom can be alarming and is more often seen in large, ulcerated, or rapidly growing tumors.

Inflammatory and Recurrence Symptoms

Some patients experience redness, irritation, or swelling around the lesion, symptoms that can be mistaken for conjunctivitis or other benign conditions 1 11. A critical sign to watch for is tumor recurrence after primary treatment, as this is associated with a higher risk of metastasis and poorer prognosis 10 14.

Types of Conjunctival Melanoma

Understanding the different types of conjunctival melanoma is essential for accurate diagnosis, prognosis, and planning effective treatment strategies. Classification is based on both clinical appearance and histopathological features.

Type	Main Feature	Prognosis/Implication	Source(s)
Lentigo Maligna	Flat, slowly spreading lesion	Generally better prognosis	5
Superficial Spreading	Irregular, spreads across surface	Intermediate risk	5
Nodular	Raised, rapidly growing nodule	Worse prognosis	5
Mixed Cell	Combination of cell types	Higher mortality	2
Multifocal	Multiple lesions in one eye	Increased risk (location-dependent)	2

Table 2: Main Types

Classic Subtypes

The three main forms of conjunctival melanoma mirror those seen in skin melanoma:

• Lentigo Maligna Melanoma: Appears as a flat, slow-growing patch, often associated with long-term sun exposure. Generally, it has a better outcome than other types 5.
• Superficial Spreading Melanoma: Characterized by irregular, spreading growth across the conjunctival surface, with intermediate risk 5.
• Nodular Melanoma: Presents as a rapidly enlarging, raised nodule; this type is associated with a more aggressive course and poorer prognosis 5.

Histopathological Variants

Histological analysis can reveal further distinctions, such as pure spindle cell or mixed cell types. Mixed cell tumors carry a significantly higher risk of mortality than pure spindle cell melanomas 2.

Special Considerations

• Multifocal Tumors: When multiple melanomas are present within the same eye, the risk of mortality increases significantly, especially in favorable locations (such as the bulbar conjunctiva) 2.
• Pedunculated Lesions: Some melanomas, particularly those in the fornix, can develop a stalk-like (pedunculated) appearance due to eyelid movement and gravity 1.

Causes of Conjunctival Melanoma

The development of conjunctival melanoma involves a complex interplay of genetic, environmental, and possibly precursor lesion factors. Recent genomic studies have revealed critical insights into its origins.

Cause/Factor	Description	Key Insights	Source(s)
UV Exposure	Sunlight-induced DNA damage	Significant but debated	6 7 9 8
Genetic Mutations	BRAF, NRAS, NF1, TERT, ACSS3	Drive tumorigenesis	3 4 6 7 9
Precursor Lesions	Primary acquired melanosis, nevus	Sites of transformation	1 5 7
MicroRNA Changes	Altered gene regulation	Linked to progression	7

Table 3: Key Causes

The Role of Sunlight (UV Exposure)

Like cutaneous melanoma, conjunctival melanoma frequently arises in sun-exposed areas of the eye, suggesting ultraviolet (UV) radiation as a potential risk factor. Recent large-scale genomic studies show a high mutational burden and a UV mutational signature in many cases, supporting the role of sunlight in pathogenesis 6 7 9. However, some studies have not detected UV-induced mutations in all tumors, indicating that other factors are also at play 8.

Key Genetic Drivers

Multiple gene mutations have been identified as central drivers in conjunctival melanoma, notably:

• BRAF Mutations: Present in about 25–47% of cases 3 4 6 7 9. These are especially common in younger patients, males, and tumors arising in sun-exposed (bulbar) locations 7.
• NRAS and NF1 Mutations: NRAS mutations occur in 18–27% and NF1 in up to 33% of tumors, with these mutations being mutually exclusive with BRAF 3 4 6 9. The presence of these mutations groups conjunctival melanomas into four genetic classes: BRAF-mutated, RAS-mutated, NF1-mutated, and triple wild-type 4 6.
• TERT Promoter Mutations and ACSS3: Also frequently found and may contribute to tumor growth and progression 6 9.

Precursor Lesions

Many conjunctival melanomas develop from pre-existing conditions:

• Primary Acquired Melanosis (PAM): Flat, pigmented lesions that may undergo malignant transformation 1 5 7.
• Conjunctival Nevus: Benign pigmented growths that rarely become malignant, but some cases of melanoma arise from nevi 1 7.

MicroRNAs and Epigenetics

Recent research has identified specific microRNAs that are upregulated in conjunctival melanoma, reflecting changes in gene regulation and possible new therapeutic targets 7.

Treatment of Conjunctival Melanoma

Managing conjunctival melanoma is challenging due to the tumor’s potential for local recurrence and metastasis. Over the past decade, significant advances have been made, offering new hope for patients.

Treatment	Description	Outcome/Notes	Source(s)
Surgical Excision	Removal of tumor with clear margins	Primary treatment	10 11 14
Adjuvant Therapy	Cryotherapy, topical chemotherapy, radiation	Reduces recurrence	10 11 12 14
Targeted Therapy	BRAF/MEK inhibitors for metastatic disease	Effective in BRAF-mutated	3 9 12
Immunotherapy	Immune checkpoint inhibitors (PD-1, CTLA-4)	Promising for advanced cases	9 13
Sentinel Node Biopsy	Detects early metastasis	Experimental, early promise	11

Table 4: Main Treatments

Surgery and Local Management

• Surgical excision with wide, tumor-free margins remains the mainstay of treatment for localized conjunctival melanoma 10 11.
• Simple excision alone, however, has a high recurrence rate and is now considered obsolete; adjuvant therapies are essential for optimal outcomes 10 14.
• Cryotherapy (freezing of tumor bed), topical chemotherapy (mitomycin C, interferon), and radiation therapy (brachytherapy, proton beam, EBRT) are commonly used as adjuncts to reduce risk of local recurrence 10 11 14.

Advances in Systemic Therapy

• Targeted Therapy: For tumors with BRAF mutations, targeted agents such as BRAF and MEK inhibitors have shown encouraging results in controlling metastatic conjunctival melanoma 3 9 12.
• Tumors with NRAS mutations may be less responsive to these drugs, emphasizing the importance of genetic testing 12.
• Immunotherapy: Immune checkpoint inhibitors (PD-1 and CTLA-4 antagonists) used in cutaneous melanoma are also effective in metastatic conjunctival melanoma, offering durable responses in some patients 9 13.

Specialized Approaches

• Sentinel Lymph Node Biopsy: A technique to detect microscopic metastasis; may improve early detection but remains experimental 11.
• Referral to Specialized Centers: Outcomes are significantly better when patients are managed at large, experienced ocular oncology centers 10.

Follow-up and Surveillance

• Long-term follow-up is essential due to the high risk of local and distant recurrence, often requiring systemic surveillance 11 14.

Conclusion

Conjunctival melanoma, though rare, poses significant challenges due to its aggressive potential and the delicate anatomical location it affects. Recent advances in genetic understanding and treatment options offer new hope for patients. Here’s a summary of the main points covered:

• Key symptoms include a new or growing pigmented lesion, nodularity, bleeding, and recurrence, often requiring vigilance for early detection.
• Types of conjunctival melanoma mirror those found in skin, with lentigo maligna, superficial spreading, and nodular variants, as well as distinct histopathological subtypes that influence prognosis.
• Causes are multifactorial, involving sun exposure (UV light), key genetic mutations (BRAF, NRAS, NF1, TERT), and precursor lesions like PAM and nevus.
• Treatment strategies are multidisciplinary, combining surgery, adjuvant local therapies, and advanced systemic options such as targeted therapy and immunotherapy, ideally guided by expert centers and genetic profiling.

By understanding the nuances of conjunctival melanoma, both patients and clinicians can work toward earlier diagnosis, personalized care, and improved outcomes in this rare but impactful disease.