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Conjunctival Nevus

Conjunctival nevus (pigmented lesion) on the sclera (white part of the eye)

A conjunctival nevus (plural: conjunctival nevi), commonly known as an eye freckle or mole, is a benign pigmented lesion on the conjunctiva. It typically appears during adolescence and can develop throughout puberty. It varies in pigment distribution, elevation, and size but does not have blood vessels feeding it. Conjunctival nevi are mainly caused by melanocytes' proliferation and genetic mutations, but their specific mechanisms are still under investigation. Factors like hormonal change, sun exposure, genetic predisposition, and age can influence their appearance and formation. While they are generally harmless and rarely develop into melanoma, there is still a slight risk of complications, including conjunctival melanoma and inflamed juvenile conjunctival nevi. Therefore, proper diagnosis and monitoring via slit lamp biomicroscopy and anterior segment optical coherence tomography (AS-OCT) are essential, with further testing and surgical excision if malignancy is suspected.

Signs and symptoms

A schematic diagram illustrating the cornea, conjunctiva, sclera, as well as other structural components of the eye.

A conjunctival nevus is a benign, painless lesion that appears on the outer layer of the eye's surface, known as the conjunctiva. This thin and transparent mucous membrane covers the inside of eyelids and the sclera, including the fornix– the junction between the eyelid and the eyeball; it also extends over the sclera and to the corneoscleral limbus, where it meets the cornea. These lesions can be found in different zones of the conjunctiva, most frequently found on the bulbar conjunctiva (ocular conjunctiva), which covers the anterior sclera of the eye, but also arise on the caruncular, plica semilunaris, and fornical conjunctiva.

Conjunctival nevi often appear as a small dot with cyst-like characteristics, displaying uneven shadowing and nonuniform color distribution. Their coloration can range from pale yellow to dark brown, with the spots potentially darkening over time. These nevi range in size and can be either flat or slightly raised. Notably, nevi in children often exhibit less pigmentation compared to the darker brown hues typically observed in adults; due to their variable appearance depending on the stage of development and time of occurrence, conjunctival nevi can be hard to spot.

Classification

Conjunctival nevi are primarily not cancerous and asymptomatic. They are classified based on their histological characteristics and the distribution of pigment-producing cells (melanocytes) in the conjunctiva. The main subtypes of conjunctival nevi include junctional and compound nevi. When first observed during childhood, the appearance of the nevi should remain relatively unchanged and stable, with only slight lightening or darkening over time.

Junctional Nevi

Junctional nevi are most common among children. They are found specifically within the conjunctival epithelium, appearing as a nest of pigmentation. Its flat appearance with light pigmentation resembles that of other forms of cancerous nevi, therefore making it difficult to detect.

Compound Nevi

Compound nevi accounts for 70-78% of all conjunctival nevi. They originate from a junctional nevus and form over time as nevus cells migrate from the epithelium into a tissue layer within the conjunctiva known as superficial substantia propria, where they are commonly found. These nevi typically have a thick and convex appearance.

Causes

The definitive cause of conjunctival nevus development is not fully explained, but based on present evidence, there are two main pathogenic mechanisms:

Melanocytic Proliferation

Melanocytes are specialized cells that secrete a pigment called melanin, which gives coloration to the skin, hair, and eyes. While these cells are typically dispersed evenly, they can occasionally clump abnormally in the conjunctival epithelium, resulting in the formation of lesions and nevi. Although these growths are benign, such proliferation can potentially dysregulate mechanisms of melanocyte migration or survival; however, the specific initiation factor of the mechanisms is unknown.

Genetic Mutations

Conjunctival nevi are associated with specific gene mutations similar to those found in cutaneous nevi, or skin nevi. The primary mutations identified in conjunctival nevi are:

BRAF Mutations

• BRAFV600E mutation is common where valine is substituted with glutamic acid in the BRAF gene.
• More frequently found in acquired nevi with little difference between children and adults.

NRAS mutations

• Occur in a mutually exclusive manner with BRAF mutations.
• Common in larger lesions and congenital lesions (appear earlier in life).

Risk factors

Several factors can affect the appearance and development of conjunctival nevi.

Hormonal changes

• Conjunctival cells express progesterone receptors and estrogen receptors.
• Hormonal fluctuations during pregnancy or puberty can affect the pigmentation and size of the lesions.

Sun exposure:

• UV radiation may increase melanocyte numbers by inducing genetic mutations in conjunctival cells.
• Individuals with fair skin and light-colored eyes are more susceptible due to reduced melanin.

Genetic predisposition:

• A family history of nevi or melanocytic lesions elevates the risk.

Diagnosis

A slit lamp biomicroscopy is used during eye examinations to examine various structures within the eye.

Slit Lamp Biomicroscopy

Conjunctival nevi are commonly diagnosed by slit lamp biomicroscopy, also called slit lamp examination. It allows accurate visualization of the characteristic features of the lesion. On a magnified ocular vision, ophthalmologists look for well-circumscribed, variably pigmented lesions, and intrinsic cystic structures would be generally discernible. However, detection by slit lamp biomicroscopy cannot always be relied upon since visibility can vary depending on the lesion’s characteristics.

An example of a scan image of the eye generated using anterior segment optical coherence tomography (AS-OCT).

Anterior Segment Optical Coherence Tomography (AS-OCT)

Anterior segment optical coherence tomography (AS-OCT) is an imaging tool that can supplement slit lamp biomicroscopy by providing insights into other features of conjunctival nevi, such as the presence of internal cysts that may not be clinically evident, as well as information about the depth of lesion. However, AS-OCT has limitations with darker lesions, as shadowing can obscure the observation of the underlying structure. Thus, the overall efficacy of AS-OCT compared to slit lamp biomicroscopy remains uncertain.

Excisional Biopsy and Histopathology

The most definitive diagnosis of conjunctival nevus is excisional biopsy and histopathologic examination, where the lesion is removed entirely for examination under a microscope. These methods can confirm the different classifications of conjunctival nevi.

Biopsy is typically recommended in cases where there are concerns about malignant transformation of lesions, such as tumor growth or abnormal features observed during slit lamp biomicroscopy. Other associated factors that may increase the likelihood of performing a biopsy include:

• Older age
• Larger lesion diameter
• Certain lesion locations (e.g., superior bulbar conjunctiva, caruncle, or plica)
• Absence of clear cysts
• Minimal or prominent intrinsic vasculature
• Presence of feeder vessels
• Corneal involvement
• At the patient’s request, due to concerns of cancer, irritation, or cosmetic reasons

Monitoring and treatment

Monitoring

Since conjunctival nevus has a low risk of malignancy, patients with conjunctival nevi are typically monitored regularly rather than undergoing immediate intervention. Routine observation happens every 6 to 12 months and involves slit lamp examinations and serial anterior segment photography to detect any changes in size and pigmentation. Although the overall risk of malignant transformation is less than 1%,, specific signs such as growth, darkening, inflammation, new vascularization, or presenting in atypical areas such as the forniceal or tarsal conjunctiva, may indicate malignant transformation and require surgical excision for further evaluation. Additionally, studies suggest a higher risk in children, with up to 8% of benign nevi that may become cancerous, often observed in the latter half of the first decade of life.

Surgical Excision

Surgical removal of conjunctival nevi is considered for symptomatic lesions, those affecting vision, or those showing potential malignancy. The procedure involves a meticulous no-touch technique, removing the lesion with a 4mm safety margin to avoid directly contacting the lesion and to prevent the spread of potentially malignant cells. If the lesions are located at the cornea or the sclera, additional techniques like alcohol epitheliectomy (photorefractive keratectomy (PRK)) and superficial sclerectomy (glaucoma surgery) are used to ensure clear margins. Following excision, the specimen undergoes histopathologic examination to confirm the diagnosis and malignancy. If malignancy is confirmed, double-freeze, slow-thaw cryotherapy is applied to prevent recurrence.

When the surgical excision of a conjunctival nevi creates a defect too large to close directly, reconstructive techniques are used to restore the ocular surface, promoting wound healing and preventing scar and symblepharon formation that can restrict eye mobility.

Amniotic membrane transplant (AMT) and conjunctival autograft (CAG) are common methods used:

• AMT uses a thin, transparent membrane from the innermost layer of the placenta and is helpful for large defects or for preserving the conjunctiva for future surgeries.
• CAG transplants a portion of the patient’s healthy conjunctiva to cover the defect and is generally more effective than AMT in reducing recurrence and inflammation.

Associated conditions/ complications

Conjunctival Melanoma (CM)

Conjunctival melanoma (CM) arises when conjunctival nevi undergo malignant transformation into conjunctival melanoma. Though rare, it is a serious form of eye cancer caused by melanocytes in the conjunctiva. It accounts for approximately 1-7% of all eye melanomas and is more prevalent among older adults and individuals of European descent. This cancer can develop through the transformation from a pre-existing conjunctival nevus or appear spontaneously (de novo).

Clinical features

Indicators of a conjunctival melanoma include changes in size, shape, or pigment level of a conjunctival nevus. It typically appears as a thick, raised, dark lump on the eye, with varying shades of pigmentation, as well as blood vessels feeding into the lesion. It predominantly affects one eye and is more common among adults. While some cases are reported to be painless, due to the aggressive nature of this eye cancer type, conjunctival melanoma poses a significant risk to vision, in more severe cases being sight-threatening.

Location and treatment

Conjunctival melanoma is more commonly found on the bulbar conjunctiva or near the limbus in areas directly exposed to sunlight. Sunlight exposure, which involves UV radiation, is a mutagenic factor that increases the risk of melanoma formation, similar to the way it contributes to the formation of skin melanoma. The primary treatment for conjunctival melanoma is surgical removal. However, due to its aggressive nature, it has a tendency to recur after surgery and potentially spread to larger areas of the conjunctiva or the body through the lymphatic system.

Inflamed Juvenile Conjunctival Nevi (IJCN)

Inflamed juvenile conjunctival nevi (IJCN) are non-cancerous, pigmented lump growths that occur on the bulbar conjunctiva, typically near the corneal limbus in children and adolescents. These irregularly shaped pigmented lesions can grow rapidly and form new blood vessels, often resembling the appearance of malignant melanoma.

Causation and characteristics

The exact cause of IJCN is not fully understood, but they are more frequently observed in boys with a history of allergic reactions. It is likely to be caused by the adherence of eosinophils to the nevi, triggering an allergic response that results in inflammation of the nevus. The pigmentation seen in IJCNs may also be related to the conjunctival cells’ response to the allergic stimuli.

Clinical features and treatment

IJCN can be present from birth or develop later during childhood, but all cases share the characteristic of its rapid growth in size. Key indicators that differentiate IJCN from malignant lesions include the formation of feeding blood vessels into the lesion's irregular margins or pigmentation changes. Treatment for IJCN often involves anti-allergy medications; however, surgical excision may be necessary if it is suspected to be under malignant transformation.

Other Conditions that Resemble Conjunctival Nevus

Several other conditions can resemble conjunctival nevus and should be distinguished during diagnosis.

Primary Acquired Melanosis (PAM)

Primary acquired melanosis (PAM) is a flat, diffuse pigmented lesion, usually with a dust-like pigmentation. It is more common in older individuals and typically affects one eye. PAM differs from CN in that it lacks cystic components and is non-circumscribed.

Complexion-associated Melanosis (CAM)

Complexion-associated melanosis (CAM), also known as racial melanosis, is a flat, diffuse, uncircumscribed patch-shaped lesion typically found on both eyes (bilateral presentations), often symmetrically around the limbus, and in individuals with darker skin complexion. It is differentiated from PAM and CN and is generally benign with a lower risk of malignancy.

Ocular melanocytosis

Ocular melanocytosis appears as brown or blue-grey pigmented lesions, predominantly on the episclera. It may be mistaken for a CN as its pigmentation is visible through the conjunctiva. While ocular melanocytosis has a low risk of developing into uveal melanoma, it is not associated with the risk of conjunctival melanoma development.