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Conjunctival melanocytic lesions: referral refinement part 2: course code: C-16011 O/D.

Pigmentation of the conjunctiva can be found in a wide range of ocular diagnoses. Whilst secondary conjunctival pigmentation maybe seen following trauma or surgery, primary pigmentation may range from benign conjunctival melanosis to a malignant conjunctival melanoma. This article discusses the aetiology of primary pigmentation, looking at factors that can lead to correct diagnosis and appropriate referral of cases to ocular oncology services.

Conjunctival naevus

Epidemiology

Conjunctival naevi are the most common discrete melanocytic lesions observed. (1,2) A conjunctival naevus typically appears in the first decade of life as a solitary flat pigmented lesion. There is no sex predilection but naevi are more common in Caucasian populations and may be associated with the familial atypical mole and melanoma (FAM-M) (dysplastic naevus) syndrome. The FAM-M syndrome is an autosomal dominant entity that is characterized by numerous cutaneous dysplastic naevi and an increased incidence of cutaneous and ocular melanoma. (3,4) These patients often have a family history of melanoma and require monitoring by a dermatologist.

Clinical features

Conjunctival naevi are not always pigmented, with approximately 16% of cases found to be clinically amelanotic. The most common location (67-72%) is the bulbar conjunctiva, especially the inter-palpebral area (Figure 1). The second most common location is the caruncle (15%-22%) (Figure 2) and most unusual is the tarsus (0.7%); (3) tarsal melanocytic lesions should be regarded as highly suspicious for malignancy until proven otherwise. (3,5-6)

The lesion is discrete and mobile and over time can become more pigmented, a feature that could raise concern from the patient. However, increase in size or pigmentation can sometimes normally occur in young children, especially after puberty, without being indicative of malignant transformation. (7) A pathognomonic feature of conjunctival naevi is the presence of clear cysts, which are more evident if the lesion is non-pigmented.

Variants of the typical conjunctival naevus are "speckled" and "blue" naevus. The speckled naevus is less well defined and appears as a patchy area of pigmentation. The blue naevus ranges in colour from blue to black, is congenital and its appearance could vary from well circumscribed to less defined. It represents melanocytes that migrate into the sclera, the episclera or the substantia propria but do not reach the epithelium. (8) This kind of lesion can be multifocal (9) and has been shown to recur when excised. (8)

[FIGURE 1 OMITTED]

Diagnosis

Diagnosis can be achieved with slit lamp biomicroscopy. Anterior segment OCT has been advocated for the location of intra-lesional cysts that cannot be detected clinically. (10) For lesions without a clinical diagnosis, immunohistochemical markers can be used although melanoma specific antigen (HMB-45) can show a positive reaction with both naevi and melanomas. Other immunohistochemical markers such as MCSP (melanoma chondroitin sulphate proteoglycan) or PRAME (preferentially expressed antigen of melanoma) are under investigation as they have been shown to discriminate a conjunctival naevus from a melanoma (11) because of significantly higher expression in the latter.

Differential diagnosis

Differential diagnosis includes other conjunctival melanocytic lesions such as primary acquired melanosis (PAM), conjunctival melanoma or secondary pigmentation in conjunctival intraepithelial neoplasia (CIN III), and squamous cell carcinoma. A speckled naevus could resemble PAM. Amelanotic conjunctival naevi may mimic lymphoma, papilloma, CIN III, squamous cell carcinoma or amelanotic melanoma. Of note the aforementioned lesions do not have cysts. The only lesion that does have cysts is lymphangioma, which could resemble a diffuse amelanotic naevus. (2) Conjunctival naevi in children (juvenile conjunctival naevi) sometimes have atypical clinical presentation, and they are frequently associated with chronic inflammation mimicking conjunctivitis, leukaemia, lymphoma or conjunctival sarcoidosis. (12)

Prognosis

Malignant transformation occurs in less than 1% of cases as indicated after assessment of 753 patients from two independent reports. (3,13)

Management

Conjunctival naevi are benign but should be observed with serial slit lamp photographs. If growth is documented the patient should be referred to the ocular oncology service.

Incisional biopsy is contraindicated unless the lesion is so diffuse that it cannot be resected all at once. Controversial management includes argon laser photoablation. (14)

Racial Melanosis

Clinical features

Racial melanosis is a benign, bilateral condition with a predilection for dark-skinned individuals. It becomes apparent during the first few years of life. It is characterized by areas of flat pigmentation, scattered throughout the conjunctiva but concentrated at the limbus. On slit-lamp examination the pigmentation appears to be superficial and therefore can be moved freely with a cotton-tipped applicator.

Differential diagnosis

1. PAM--if the lesion appears asymmetrical and more pronounced in one eye (2)

2. Conjunctival freckle

3. Ocular melanocytosis--located sub-conjunctivally and therefore cannot be moved freely

4. Mascara deposits usually located in the inferior fornix

5. Adenochrome deposits--pigment clumps on the forniceal and (occasionally) tarsal conjunctiva related to the use of adrenaline anti-glaucoma drops. (15)

Management

No treatment is required for racial melanosis, as this is a benign condition with no tendency to undergo malignant transformation. Typical cases do not need to be referred to ophthalmology but asymmetric cases should have PAM excluded and so referral to ophthalmology is recommended.

Congenital Ocular Melanocytosis

This is a unilateral, melanocytic hyperplasia that is characterized by hyperpigmentation of the episclera, sclera, uveal tract, orbital tissues and the meninges. (16) It can be divided clinically into ocular melanocytosis and oculodermal melanocytosis (Naevus of Ota), the latter referring to when the periocular skin is also affected (unilaterally), most commonly in the distribution of the first and second divisions of the trigeminal nerve. (2,16,17) Both clinical entities are usually non-hereditary and are estimated to affect about 0.04% of Caucasians. (18)

Clinical features

Ocular surface lesions appear as multifocal patches of scleral and episcleral slate-grey pigmentation that cannot be moved. (17) The pigmentation can have either a diffuse or sectorial distribution. Occasionally, the peripheral cornea may be involved. Iris heterochromia is common with part of or the entire iris being darker than the iris in the contralateral eye. Iris mammillations, which are tiny, numerous, villiform, brown nodules occupying the iris stroma, are also common.19 The background fundus pigmentation is more pronounced compared to the opposite eye, giving rise to a darker red reflex. Fundus hyperpigmentation with sectorial distribution has also been reported.

[FIGURE 2 OMITTED]

Congenital ocular melanocytosis predisposes to uveal melanoma, as well as melanoma of the ipsilateral skin, orbit, optic nerve head and brain. It has been reported that about 1 in 400 individuals with this condition will develop uveal melanoma. (20,21) Elevated intraocular pressure (IOP) or glaucoma associated with hyperpigmentation of the anterior chamber angle, develops in about 10% of cases. (22,23)

Diagnosis

Diagnosis is based on external ocular and slit-lamp examination. One can move the conjunctiva with a cotton-tipped applicator and will find that in ocular melanocytosis the pigmented lesion cannot be moved freely, as it is located sub-conjunctivally, whereas in cases of racial melanosis or PAM, the superficially located lesions can be moved easily.

Management

Patients should be referred to the ocular Oncology service for annual review, as there is a risk of uveal, orbital and meningeal malignant melanomas. Periodic IOP measurements are also advised.

Primary Acquired Melanosis (PAM)

PAM is a unilateral condition that affects middle-aged, Caucasian individuals. (24) Although its aetiology is uncertain, it has been related to sunlight exposure and systemic conditions such as FAM-M syndrome and neurofibromatosis. (25) Histologically, two types of PAM exist (a) PAM without atypia (a benign proliferation of normal melanocytes) and (b) PAM with atypia (a pre-malignant condition characterized by proliferation of cytologically atypical melanocytes and significant chance of evolving to conjunctival melanoma). (26)

[FIGURE 3 OMITTED]

Clinical features

The lesions appear as unilateral, unifocal or multifocal patches of flat pigmentation in the superficial layers of any portion of the conjunctiva (Figure 3). (24,27,28) The peripheral cornea can also be involved. As the pigmented lesions may occupy the bulbar as well as palpebral conjunctiva, inversion of the upper eyelid for inspection of the tarsal conjunctiva is advised. The clinical features of PAM with and without atypia are the same and differentiation can only be achieved histopathologically. As both types occupy the superficial layers of the conjunctiva, the lesions can be freely moved with a cotton-tipped applicator.

Management

Small patches of PAM are common in the population. (29) Certain signs that require urgent referral to ophthalmology however, include: (2)

1. Lesion diameter [greater than or equal to]5mm

2. Presence of distinct nodule arising in an otherwise flat lesion

3. Documented progression of the lesion

4. Corneal involvement

5. Involvement of the forniceal or tarsal conjunctiva

6. Presence of dilated feeder vessels

Conjunctival melanoma

Epidemiology

Conjunctival melanoma accounts for 1-2 % of all ocular melanomas. (30) The incidence has increased by 5.5% bi-annually from 1973 to 1999. (31) There is no gender predilection but it most commonly appears in middle aged or elderly Caucasian individuals. It occurs in African or African-American individuals to a lesser extent, with occurrence in various ethnic groups being similar to uveal melanoma. (32)

Pathogenesis

The molecular pathogenesis of conjunctival melanoma is poorly understood. Associations have been made in the past with mutations of the BRAF gene. (7) Conjunctival melanoma could arise from a pre-existing melanocytic lesion, most commonly from PAM (75%), a conjunctival naevus (20%) or de novo (5%). (33) It has been associated with systemic conditions such as FAM-M syndrome, xeroderma pigmentosum and neurofibromatosis. In the latter condition it could occur in younger individuals. Exposure to solar radiation is considered an important risk factor. (32)

Clinical features

Conjunctival melanoma appears as a fleshy, elevated lesion of variable pigmentation (Figure 4a) commonly located in the nasal or temporal bulbar conjunctiva. Amelanotic or minimally pigmented conjunctival melanomas occur in 19% of cases. (34) The lesion can be well circumscribed or diffuse if it arises from PAM. The lesion can extend towards the eyelid margin or be contiguous to an eyelid margin melanoma (Figure 4b), towards the globe or towards the orbit. Aggressive conjunctival tumours with extension to the orbit can lead to peri-neural invasion too. (35) Otherwise it can extend to the lacrimal drainage system or the nose following tumour seeding at the time of surgery. There have been reports of cases with involvement of the lacrimal sac. (30,34) Therefore, epistaxis or epiphora could be a sign of distal recurrence. (36)

Pathology

It is composed of variably pigmented malignant melanocytes. Their morphology can range from low grade spindle cells to anaplastic epithelioid cells. It occasionally invades the stroma where it gains access to the lymphatic channels. Conjunctival malignant melanoma has been shown to locally induce the formation of new lymphatic vessels not only within the lesion but also in its close vicinity. (37)

Differential diagnosis

Full examination of the bulbar and tarsal conjunctivae is required. In addition, examination of the orbital rim is important because of the high rate of recurrence. All patients suspicious of the diagnosis and those being followed-up after treatment need to be examined for regional lymphadenopathy. Extension of the lesion to the lymph nodes has been assessed with various approaches including lymphoscintigraphy, whole body PET/CT scan, (38) MRI, ultrasonography with FNA biopsy of suspicious lymph nodes, (39) or sentinel node biopsy.

An amelanotic melanoma appears similar to lymphoma, squamous cell carcinoma or other non-pigmented conditions, such as pyogenic granuloma, a conjunctival haematoma, a foreign body or argyrosis. (2) However, although identifiable in the clinical setting, definitive diagnosis is done histopathologically. In difficult cases immunohistochemical studies has indicated the expression of various markers.

Management

All suspected conjunctival melanoma should be urgently referred to the ocular oncology service. Management is through surgical excision. Techniques can vary depending on the clinical features of the lesion. For example, if located in the limbal area, alcohol epitheliectomy, partial sclerokeratoconjunctiventomy and double freeze-thaw cryotherapy have been proposed. (2) All measures aim to avoid iatrogenic seeding. (30)

If the lesion is located in the forniceal area or is more diffuse, a larger excision needs to be performed and graft reconstruction may be required. This graft can be amniotic membrane, buccal mucosa or from the opposite conjunctiva. If the lesion extends into the globe a modified enucleation might be required. If there is an extension into the orbit, orbital exenteration may be required. In cases of advanced extension or recurrent lesions, plaque brachytherapy is an option. (40) Proton beam radiotherapy has also been used. (41)

If the lesion extends to the lymph nodes, prophylactic resection is controversial. Extensive lymph node resection can be avoided with sentinel lymph node biopsy. The technique involves pre-operative mapping of the afferent lymphatics using radionuclide imaging (lymphoscintigraphy), (42) followed by intra-operative localization of the sentinel node by methylene blue dye and radioactive tracer detection. (43)

The selected sentinel nodes are dissected and submitted for histopathologic evaluation. In cases with positive sentinel lymph node biopsies, further regional lymphadenectomy is performed. Indications for the use of this technique include tumours of non-limbal location, tumours with a thickness of more than 2mm and cases of local recurrences. (44)

[FIGURE 4 OMITTED]

Prognosis

Early detection and complete excision of the lesion offers the best prognosis. However, the prognosis also depends on the stage of conjunctival melanoma progression. T-I lesions are those where only the bulbar conjunctiva is involved, T-II if there is corneal involvement, T-III for involvement of the fornix, caruncle or tarsal conjunctiva, and T-IV for tumours invading the eyelid, intraocular, orbit, skin or sinuses involvement. (30,45) A favourable prognostic sign is the presence of peri-tumoural inflammation on histopathological examination. This is an indicator of an active immune response against the tumour. (36,46) The overall 10-year survival rate of patients is 70%-75%; mortality rate increases with involvement of non-bulbar conjunctiva regions, especially the caruncle, (5,30,47) or if there is local recurrence, especially in the medial bulbar conjunctiva, (30) or multifocal tumours, increased tumour thickness, high mitotic rate and lymphatic invasion. (34,45,46) PAM-related melanoma has a survival rate of 75%, whilst this is 74% in naevus-related melanoma and 65% in de novo-related melanoma. (34)

Melanoma can metastasize to the pre-auricular and sub-mandibular lymph nodes in 45-80% of cases. (48) Melanomas of the nasal conjunctiva tend to metastasize in the sub-mandibular lymph nodes whilst those in the temporal conjunctiva metastasize to the pre-auricular lymph nodes. (49) Conjunctival melanoma can also metastasize to the brain, liver, skin and bone. Systemic metastases have a less than 10% cumulative incidence if the lesion is less than 2 mm thick. (48) Incidence doubles with thickness more than 2mm. Another study has reported that 26% of patients develop systemic metastases without lymph node involvement. (49)

Conclusion

Conjunctival and other anterior segment pigmentation are often benign but can lead to malignancy and/or metastatic disease. Correct identification is required in order to refer appropriate cases to ophthalmology for treatment and better prognosis.

References

See http://www.optometry.co.uk clinical/index. Click on the article title and then download "references".

For the module questions to this article, please turn to page 52.

About the author

Victoria Cohen is a consultant ophthalmic surgeon and is director of the Ocular Oncology Service at Moorfields and St Bartholomew's Hospital in London. Ms Cohen is a member of the International Eye Cancer Network and the European Ocular Oncology Group. Vasilios Papastefanou is a fellow in ocular oncology who works in the London Ocular Oncology Service. Maria Tsimpida is currently an ocular oncology fellow at St. Bartholomew's Hospital and Moorfields Eye Hospital.

Victoria Cohen MA MB BChir FRCOphth, Vasilios P Papastefanou MD PhD, Maria Tsimpida MD PhD
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Title Annotation:CET: CONTINUING EDUCATION & TRAINING
Author:Cohen, Victoria; Papastefanou, Vasilios P.; Tsimpida, Maria
Publication:Optometry Today
Article Type:Disease/Disorder overview
Geographic Code:4EUUK
Date:Apr 22, 2011
Words:2570
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