Conjunctival pigmented lesions

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Contents

Aetiology

Conjunctival pigmented lesions include a spectrum of benign, pre- malignant and malignant melanocytic conditions:

Melanosis

  • Hypermelanosis (i.e. melanin overproduction by normal melanocytes)
    • racial melanosis
    • secondary melanosis (variety of causes including: ocular disease [e.g. perilimbal pigmentation in vernal keratoconjunctivitis], particular systemic disorders or as an adverse drug reaction)
  • Primary acquired melanosis (PAM), also known as Conjunctival Melanocytic Intraepithelial Neoplasia (C-MIN)
    • with or without ‘atypia’ (cellular structural abnormalities), graded according to cytomorphology, melanocytic density and spread to superficial layers of epithelium. Severe disease amounts to Melanoma in situ (i.e., confined to epithelium)
  • Congenital melanocytosis
    • hyperpigmentation of episclera as a result of an overpopulation of melanocytes, also occurring in uvea and skin (i.e., Naevus of Ota). Predisposes to melanoma.

Naevus 

  • the most common conjunctival pigmented lesion: 52% of ocular pigmented lesions
  • congenital or acquired
  • cluster of naevus cells in the conjunctival epithelium, usually extending to substantia propria. Cysts are often present.

Melanoma

  • rare malignant tumour arising from melanocytes located among the basal cells of the conjunctival epithelium, in naevus, PAM with atypia, or arising spontaneously
  • 2-5% of ocular malignancies, age-adjusted incidence 0.2-0.8 per million in White populations (lower incidence in Black and Asian ethnicities)
  • may arise in both sun-exposed and non-sun-exposed parts of the conjunctiva (although UV light exposure is a well-documented risk factor for cutaneous melanoma, its role in ocular melanoma is unclear)
  • genetically similar to cutaneous and other mucosal melanomas
  • metastasises to regional lymph nodes and systemically, especially if involving caruncle and/or non-bulbar conjunctiva

Systemic disorders and drugs are linked rarely with acquired conjunctival pigmentation but include:

  • Addison’s disease (adrenal gland deficiency)
  • alcaptonuria (congenital enzyme deficiency)
  • drugs (chlorpromazine, topical epinephrine, etc)

Predisposing factors

Epithelial melanosis is common in dark-skinned ethnicities.
PAM typically affects older white-skinned patients (rarely in dark-skinned).
Melanoma is more common with fair skin and blue eyes, extremely rare in dark-skinned ethnicities. Presentation peaks in mid-fifties

Symptoms of conjunctival pigmented lesions

Asymptomatic except for cosmetic concern

Signs of conjunctival pigmented lesions

Ethnic melanosis

Bilateral, asymmetrical, flat, intra-epithelial (moves freely over sclera), patchy, brown pigmentation, most prominent in palpebral aperture especially at limbus or where anterior ciliary arteries perforate the sclera, develops in early years (static by adulthood)

PAM / C-MIN

Unilateral, any part of conjunctiva (including tarsal or forniceal), flat, intraepithelial (moves freely over sclera), single or multiple, indistinct areas, light to dark brown, no cystic spaces, often extensive, can be stable or may change (enlarge, shrink, darken or lighten)

Congenital Melanocytosis (Oculodermal Melanocytosis)

  • ocular
    Multifocal, slate-grey or blue grey, sub-epithelial (does not move freely over sclera)
  • dermal
    Mottled, blue to purple, discolouration of skin around the eye

Naevus

Solitary, sharply-demarcated, flat or slightly-elevated, intra-epithelial (moves freely over sclera). Confined to interpalpebral zone (very rare in palpebral or forniceal conjunctiva), most commonly adjacent to but not touching the limbus (less frequently at plica, caruncle, lid margin). NB: a pigmented lesion that straddles the peripheral cornea is highly suspicious and should be assumed to be a malignant melanoma. Presents in second or third decade when naevus becomes pigmented. Colour ranges from deep brown through pink to barely perceptible pigment. Often contains cystic spaces. Very rarely vascularised or inflamed

Melanoma

Any pigmented elevation of the conjunctiva, especially in association with PAM, should be considered to be a melanoma. Most commonly involves the bulbar conjunctiva (92% of cases), but can affect any part of the conjunctiva (bulbar, palpebral, forniceal or limbal) or caruncle. Nodular, well-vascularised mass with large conjunctival feeder vessels, fixed to underlying sclera (assess the degree of tethering, under topical anaesthesia). May be pigmented or non-pigmented (amelanotic or minimally pigmented lesions are seen in up to 19% of cases), and nodular, diffuse or mixed. Clinicopathological features significantly associated with a poor prognosis are extrabulbar location, involvement of adjacent tissue structures, tumour thickness exceeding 2 mm and local tumour recurrence

Differential diagnosis

Conjunctival intraepithelial squamous neoplasia (i.e. carcinoma in situ) can resemble an amelanotic melanoma
Blue naevus: a rare congenital deeply pigmented melanocytic lesion which can resemble PAM or melanoma

Management by optometrist

Practitioners should recognise their limitations and where necessary seek further advice or refer the patient elsewhere

GRADE* Level of evidence and strength of recommendation always relates to the statement(s) immediately above

Non pharmacological

General advice on ocular UV protection
(GRADE*: Level of evidence=low, Strength of recommendation=strong)

Ethnic melanosis
Has no malignancy potential and requires no treatment
(GRADE*: Level of evidence=low, Strength of recommendation=strong)

PAM / C-MIN
Sometimes has potential for malignancy (up to 13%) – refer for assessment, which requires biopsy to identify atypia
(GRADE*: Level of evidence=low, Strength of recommendation=strong)

Congenital Ocular Melanocytosis
Has potential for malignancy – refer.
Is associated with malignant melanoma of the affected skin, orbit and uveal tract (fundoscopy with papillary dilatation is required).
Also associated with hyperpigmentation elsewhere in the eye including the trabeculum (regular monitoring for glaucoma required)
(GRADE*: Level of evidence=low, Strength of recommendation=strong)

Naevus
Generally requires no treatment, but very rarely progresses to a malignant melanoma. Advise patient to report any increase in size, elevation or colour. Review after 6 months and then every 12 months if lesion unaltered. Photo-document if possible 
(GRADE*: Level of evidence=low, Strength of recommendation=strong)

Melanoma
Refer urgently (potentially sight - and life - threatening).
Disseminates by local extension and by spread via lymphatic system (check preauricular and submandibular lymph nodes)
(GRADE*: Level of evidence=low, Strength of recommendation=strong)

Pharmacological

None

Management category

B1: routine referral to ophthalmologist

  • PAM / C-MIN
  • Naevus, especially if non-bulbar conjunctiva is involved
  • Congenital Ocular Melanocytosis

B2 (modified): alleviation/palliation: normally no referral to ophthalmologist

  • Mild ethnic melanosis

A3: urgent (within one week) referral to ophthalmologist

  • Melanoma

Possible management by ophthalmologist

PAM requires multiple biopsies to detect the histopathological characteristics that predict invasive melanoma.
Tests for malignancy and excision where required

Melanoma is usually treated by en bloc surgical excision with adjuvant therapy such as: mitomycin C, radiotherapy, topical chemotherapy.

More than 50% develop local tumour recurrence with 20% requiring orbital exenteration and 20-30% developing fatal metastases.

Evidence base

*GRADE: Grading of Recommendations Assessment, Development and
Evaluation (see www.gradeworkinggroup.org)

Sources of evidence

Bresler SC, Simon C, Shields CL, McHugh JB, Stagner AM, Patel RM. Conjunctival pigmented lesions. Arch Pathol Lab Med. 2022;146(5):632-646.

Damato B, Coupland SE. Management of conjunctival melanoma. Expert Rev Anticancer Ther 2009;9:1227-1239

Grimes JM, Shah NV, Samie FH, Carvajal RD, Marr BP. Conjunctival Melanoma: Current Treatments and Future Options. Am J Clin Dermatol. 2020;21(3):371-381.

Harooni H, Schoenfield LR, Singh AD. Current appraisal of conjunctival melanocytic tumors: classification and treatment. Future Oncol. 2011;7(3):435-46

Larsen AC. Conjunctival malignant melanoma in Denmark: epidemiology, treatment and prognosis with special emphasis on tumorigenesis and genetic profile. Acta Ophthalmol. 2016;94 Thesis 1:1-27

Levecq L, De Potter P, Jamart J. Conjunctival Nevi, Clinical Features and Therapeutic Outcomes. Ophthalmology 2010;117(1):35-40 

Peil J, Bock F, Kiefer F, Schmidt R, Heindl LM, Cursiefen C, Schlereth SL. New Therapeutic Approaches for Conjunctival Melanoma-What We Know So Far and Where Therapy Is Potentially Heading: Focus on Lymphatic Vessels and Dendritic Cells. Int J Mol Sci. 2022;23(3):1478.

Rivolta C, Royer-Bertrand B, Rimoldi D et al. UV light signature in conjunctival melanoma; not only skin should be protected from solar radiation. J Hum Genet. 2016;61:361-2

Sayed-Ahmed I, Murillo JC, Monsalve P, Ulloa JP, Fernandez MP, Wong J, et al. Blue Nevi of the Ocular Surface: Clinical Characteristics, Pathologic Features, and Clinical Course. Ophthalmology. 2018;125(8):1189-1198

Shildkrot Y, Wilson MW. Conjunctival melanoma: pitfalls and dilemmas in
management. Curr Opin Ophthalmol. 2010 Sep;21(5):380-6

Plain language summary

The conjunctiva (the transparent skin over the white of the eye) sometimes develops brown discolouration. This is classified according to the cause:

Hypermelanosis: melanocytes (the cells of the body that produce the dark pigment melanin) go into overproduction. This may be a normal characteristic , or it may be caused by disease elsewhere in the body.

Primary Acquired Melanosis: unusually large numbers of melanocytes develop. This is rare in dark-skinned races and tends to affect older white-skinned people.

Congenital Melanocytosis: similar, except present from birth.

A Naevus, that is a brown spot on the conjunctiva, may be present from birth or may arise later. This is the commonest of all the conjunctival pigmented lesions. Usually it does not grow or spread.

Sometimes, a naevus changes into an Invasive Melanoma, also known as a Malignant Melanoma, which can spread to other parts of the body. This particularly affects people with fair complexions and is seen only very rarely in dark-skinned people.

There are also some uncommon generalised diseases that may produce discolouration of the conjunctiva. Some prescription drugs may also cause a similar effect.

Depending on the nature of the pigmented lesion, optometrists may monitor the condition themselves, or refer to an ophthalmologist routinely or urgently. Mild ethnic melanosis does not need to be referred.

The ophthalmologist will carry out tests to identify which condition the patient has. Melanoma is usually treated with surgery and additional drug therapy. Careful follow-up is required due to high rates of recurrence.

Conjunctival pigmented lesions
Version 10
Date of search 30.09.22
Date of revision 20.12.22
Date of publication 09.01.23
Date for review 29.09.24