Conjunctival Melanoma

Overview

Malignant melanoma of the conjunctiva presents as a raised pigmented or nonpigmented lesion.^[1]

This lesion is uncommon but potentially lethal. It can arise in previously unblemished and unpigmented regions (approximately 10% of cases), from a preexisting nevus (approximately 20% of cases), or from the flat, spreading pigmentation of primary acquired melanosis with atypia (60-70% of cases). Examples of the disease are seen below.

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Conjunctival melanomas may be associated with primary acquired melanosis (75%) or may arise from a preexisting nevus or de novo. Reprinted from Univer....

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Conjunctival melanoma. Courtesy of Peter Rubin, MD, Director, Eye Plastics Service, Massachusetts Eye & Ear Infirmary, Boston, MA.

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Conjunctival melanoma. Courtesy of Peter Rubin, MD, Director, Eye Plastics Service, Massachusetts Eye & Ear Infirmary, Boston, MA.

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Tarsal conjunctival melanoma. Courtesy of Peter Rubin, MD, Director, Eye Plastics Service, Massachusetts Eye & Ear Infirmary, Boston, MA.

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Invasive conjunctival melanoma. Courtesy of Peter Rubin, MD, Director, Eye Plastics Service, Massachusetts Eye & Ear Infirmary, Boston, MA.

In addition to spreading by lymphatics and the bloodstream, conjunctival melanoma can undergo direct extension to the eyeball and orbit.^[2]

The most frequent site of metastasis is the lung, followed by the liver, brain, and bone. In managing these patients, it is important to palpate the regional lymph nodes because spread to the ipsilateral preauricular, submandibular, and cervical nodes from the conjunctival sac is well recognized. Cohen et al reported an isolated gastric metastasis from a conjunctival melanoma.^[3]Gastric metastases are frequently seen in cutaneous melanoma.

Go to Ciliary Body Melanoma, Choroidal Melanoma, and Iris Melanoma for complete information on these topics.

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Etiology

Together with mucus-secreting goblet cells within the stratified epithelium, melanocytic cells are found in the basal layer of the conjunctiva. These melanocytic cells are of neuroectodermal origin, and melanocytic tumors may arise from these cells.

Theoretically, conjunctival melanoma may originate from primary acquired melanosis, from preexisting nevi, or as de novo lesions (that is, without any histologic or clinical evidence of a preexisting lesion). It may be difficult to determine the precursor lesion in many cases.^[4]

Primary acquired melanosis

Approximately 50-75% of cases of conjunctival melanoma arise in a setting of primary acquired melanosis. Typically, primary acquired melanosis is found in middle-aged whites; along with malignant melanomas, it is extremely rare in the younger population.

The natural history of primary acquired melanosis begins with the development of superficial epithelial pigmentation, with a typical peppered distribution of pigment. These lesions can slowly evolve over years, waxing and waning, extending in a radial manner over larger areas of conjunctiva and skin.

Nevus

Evidence indicates that approximately 20-25% of patients with conjunctival melanoma have a history or microscopic evidence of a benign conjunctival nevus. (See the image below.)

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Conjunctival nevus. Courtesy of Peter Rubin, MD, Director, Eye Plastics Service, Massachusetts Eye & Ear Infirmary, Boston, MA.

Malignant melanomas arising from nevi (they may arise from junctional and compound nevi) usually appear as a change (increasing nodularity, variegated pigmentation, bleeding, or inflammation) in known pigmented lesions of the conjunctiva, but it may be impossible to establish a clear clinical history of a preexisting history of nevus.

Occasional reports of cases showing the presence of both acquired melanosis and a nevus have been documented.

However, some uncertainty surrounds the role of nevi in the histogenesis of malignant melanoma. Previously, compressed cells at the melanoma base were considered to be nevi, but reports now suggest that these flattened cells are, in fact, compressed melanoma cells and not nevus cells.

De novo

Approximately 25% of cases of conjunctival melanoma come from de novo lesions. These lesions can be ulcerative, amelanotic, papillary, or fungating.

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Epidemiology

Incidence in the United States

Primary malignant melanoma of the conjunctiva is much less common than are intraocular or skin melanomas. Malignant melanoma of the conjunctiva accounts for only 2% of all ocular malignancies.

International Incidence

The incidence of primary acquired melanosis with atypia or with malignant melanoma of the conjunctiva has been estimated to be 0.052 cases a year per 100,000 population in Denmark.^[5]

In Sweden, only 2 new cases of primary malignant melanoma of the conjunctiva were diagnosed in 1987; the age-standardized incidence of conjunctival melanoma is 0.74 cases per 1 million population in men, and 0.45 cases per 1 million population in women. The incidence of conjunctival melanoma increased in Sweden between 1960 and 2005.^[6]

In Denmark, the overall incidence of conjunctival melanoma was 0.5 per million population per year.^[7]

Race, sex, and age predilections

Conjunctival melanoma occurs predominantly in whites and is rarely seen in blacks.

No clear sex predilection has been established.

Typically, conjunctival melanoma occurs in patients in their early 50s. It is rarely seen in people younger than 20 years, although Strempel and Kroll reported 3 cases of conjunctival malignant melanoma in children.^[8]

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Prognosis

The overall tumor-related mortality rate for conjunctival melanoma is 25-26%. This rate increases to 40-44% if the tumor has arisen from primary acquired melanosis with an intraepithelial pagetoid growth pattern. This tumor tends to spread first to the parotid or submandibular nodes.^[9]

In several studies, the 5-year survival rate for patients with conjunctival melanoma after surgery and/or radiotherapy was 83-84%, and the 10-year survival rate was 69-80%. The 5-year recurrence rate was 39%.

Paridaens et al listed the following prognostic factors in conjunctival melanoma (in increasing order of mortality risk):

Two-fold risk - Tumors in unfavorable locations (eg, palpebral conjunctiva, fornices, plica, caruncle, lid margins)
Three-fold risk - Mixed cell types, compared with pure spindle-cell types
Four-fold risk - Histologic evidence of lymphatic invasion; initial thickness greater than 4 mm for tumors in unfavorable locations only
Five-fold risk - Multifocal tumors in patients with lesions in favorable (epibulbar) locations only

Other poor prognostic features, as outlined by Jakobiec and associates, include moderate-to-severe atypia, a paucity of small polyhedral cells in the tumor, invasion of deeper ocular tissues, greater than 5 mitotic figures per 10 high-power fields, and lack of a tumor-induced inflammatory response.

Fifty-three cases involving pathologically confirmed conjunctival melanoma in ethnic Chinese patients were reviewed. Adjuvant therapy and tumor thickness correlated significantly with recurrence-free survival, and tumor stage was a significant predictor of overall survival.^[10]

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Patient History

Eliciting a good history of the growth characteristics of each lesion is important in patients with conjunctival melanomas. The well-informed patient often is aware of subtle changes that may be crucial in identifying these lesions.

Melanomas that arise without a preexisting conjunctival nevus are usually at the limbus and are believed to initially have a short horizontal growth phase followed by a rapid vertical growth phase.

Melanomas that arise in a preexisting nevus are often characterized by growth of the lesion or by increased vascularity.

Any nevus that has increased in vascularity, size, or solidity or that has become fixed to the underlying sclera (nevi are always freely movable over the sclera, except at the fixation point at the limbus) should be suspected of being a malignant melanoma.

In the case of primary acquired melanosis, the onset of malignant degeneration is often heralded by the development of nodular thickening in a previously flat area of pigmentation. Other noteworthy features of malignant degeneration include increased vascularity, fixation of the conjunctiva to the underlying sclera, and hemorrhage.

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Physical Examination

The clinical presentation of conjunctival melanoma can vary and depends on the antecedent status of the conjunctiva. A melanoma can be distinguished from primary acquired melanosis by its tendency to become fixed to the underlying tissues, which is not a feature of primary acquired melanosis.

In managing patients with conjunctival melanoma, it is important to palpate the regional lymph nodes, because spread to the ipsilateral preauricular, submandibular, and cervical nodes from the conjunctival sac is well recognized.

Conjunctival melanomas may extend onto the peripheral limbus. Most melanomatous nodules at the limbus affect the peripheral cornea; some grow circumferentially around the limbus. Rarely, a melanomatous nodule may be located more centrally in the cornea.

Pigmentation of the eyelid margins and skin occasionally accompanies primary conjunctival melanomas, particularly those located on the palpebral conjunctiva and fornix; this combined presentation discloses a poorer prognosis.

Other uncommon manifestations include poliosis.

Monitoring

Documentation by photography and observation for growth of conjunctival melanomas over regular intervals of time is recommended for small lesions.

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Differential Diagnosis

Not all conjunctival melanomas are pigmented; melanomas with little or no pigment can look like squamous and sebaceous gland carcinomas, papillomas, lymphoid hyperplasia, and even pterygia. Amelanotic melanomas can puzzle even the pathologist; staining with the S-100 protein stain and the more specific homatropine methylbromide (HMB-45) antibody stain can assist in diagnosis.

Differentials to consider include the following:

Choroidal Melanoma
Ciliary Body Melanoma
Iris Melanoma
Conjunctival squamous cell carcinoma
Conjunctival melanosis
Conjunctival mycosis
Conjunctival seborrheic keratosis
Acquired melanosis (primary or secondary)
Foreign body (eg, graphite)
Drug toxicity (eg, epinephrine)
Conjunctival pseudomelanoma - Iatrogenic secondary to scleral tunnel

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Ultrasonographic Biomicroscopy

Extrascleral extension of a ciliary body melanoma can simulate a conjunctival melanoma in some cases. Ultrasonographic biomicroscopy (UBM) of such eyes confirms the presence, character, and extent of the underlying ciliary body tumor and often reveals the route of access of the tumor to the surface by way of a scleral emissary canal.

UBM may serve as an additional diagnostic tool to estimate the tumor thickness before surgical resection of a conjunctival melanoma.^[11]

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Conjunctival Excision Biopsy

Because acquired melanosis, nevi, melanomas, and other pigmented lesions (eg, papillomas, adrenochrome deposits, foreign bodies, blood-filled cysts) may have comparable clinical features, biopsies of such lesions usually should be taken before more extensive therapy is considered. A biopsy of a malignant melanoma does not seem to augment its lethality and may prevent needless, mutilating surgery. Conjunctiva is an easily accessible tissue source for diagnostic biopsy.^{[12, 13, 14, 15]}

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Histopathology

Invasive melanoma cells may be small polyhedral, epithelioid, spindled, or ballooned. (See the images below.)

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Histologic findings of invasive melanoma cells may be small polyhedral, epithelioid, spindled, or ballooned. Courtesy of Peter Rubin, MD, Director, Ey....

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Histologic findings of invasive melanoma cells may be small polyhedral, epithelioid, spindled, or ballooned. Courtesy of Peter Rubin, MD, Director, Ey....

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Dysplastic melanocytes may invade beyond the epithelium into the substantia propria or into the globe or lids. Reprinted from University of Utah, Pete....

Melanoma cells are larger than nevus cells and grow as irregular nests or as individual cells in nodules that extend through all the layers of the epidermis and dermis. Typically, these cells have large nuclei with chromatin clumping at the periphery of the nuclear membrane and distinct eosinophilic nucleoli. The ascent of atypical melanocytes to the surface of the conjunctival epithelium is indicative of malignancy.^[16]

As previously mentioned, not all conjunctival melanomas are pigmented; melanomas with little or no pigment can look like squamous and sebaceous gland carcinomas, papillomas, lymphoid hyperplasia, and even pterygia. Staining with the S-100 protein stain and the more specific homatropine methylbromide (HMB-45) antibody stain can assist in diagnosis.^[17]

The Callender classification for melanoma does not apply to conjunctival melanomas.

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Staging

This classification applies only to melanoma. Histologic verification of the melanocytic lesion should occur.

The assessment of the cancer is based on inspection, slit lamp examination, palpation of the regional lymph nodes, and when indicated, radiologic (including computed tomography) and ultrasonographic examination of the orbit, paranasal sinuses, and chest.

Complete resection of the primary site is indicated. Histologic study of the margins and the deep aspect of resected tissues is necessary. Resection or needle biopsy of enlarged regional lymph nodes or orbital masses is desirable.^{[18, 19, 20]}

Clinical classification (cTNM)

A primary tumor (T) is classified as follows:

TX - Primary tumor cannot be assessed
TO - No evidence of primary tumor
T1 - Tumor(s) of bulbar conjunctiva occupying 1 quadrant or less
T2 - Tumor(s) of bulbar conjunctiva occupying more than 1 quadrant
T3 - Tumor(s) of conjunctival fornix and/or palpebral conjunctiva and/or caruncle
T4 - Tumor invades eyelid, cornea, and/or orbit (see the images below)

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An aggressive conjunctival melanoma with lid involvement. Courtesy of Peter Rubin, MD, Director, Eye Plastics Service, Massachusetts Eye & Ear Infirma....

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Large conjunctival melanoma that has invaded the orbit. Courtesy of Peter Rubin, MD, Director, Eye Plastics Service, Massachusetts Eye & Ear Infirmary....

Regional lymph nodes (N) are classified as follows:

NX - Regional lymph nodes cannot be assessed
N0 - No regional lymph node metastasis
N1 - Regional lymph node metastasis

Distant metastasis (M) is classified as follows:

MX - Distant metastasis cannot be assessed
M0 - No distant metastasis
M1 - Distant metastasis

Pathologic classification (pTNM)

Pathologic tumor (T) staging (extent of disease through completion of definitive surgery) for conjunctival melanoma is summarized as follows, where pT is primary tumor^{[21, 22]}:

pTX – Primary tumor cannot be assessed
pT0 - No evidence of primary tumor
pTis - Melanoma confined to the conjunctival epithelium; less than or equal to 1 quadrant*; melanoma confined to the conjunctival epithelium; melanoma in situ (includes the term primary acquired melanosis):
- Atypia replacing greater than 75% of normal epithelial thickness
- Epithelioid cytology including, (1) abundant cytoplasm, (2) vesicular nuclei or prominent nucleoli, and/or (3) the presence of intraepithelial nests of atypical cells (≤ 1 quadrant)
T1 - Conjunctival melanoma of the bulbar conjunctiva
pT1a - Thickness of 0.5 mm or less with invasion of the substantia propria; more than 1 but less than or equal to 2 quadrants*
pT1b - Thickness greater than 0.5 mm but at least 1.5 mm with invasion of the substantia propria; more than 2 but less than or equal to 3 quadrants*
pT1c – Thickness greater than 1.5 mm with invasion of the substantia propria; more than 3 quadrants*
T2 - Conjunctival melanoma of the nonbulbar conjunctiva (palpebral, forniceal, caruncular) region
pT2a - Thickness 0.5 mm or less with invasion of the substantia propria
pT2b - Thickness greater than 0.5 but at least 1.5 mm with invasion of the substantia propria
pT2c - Thickness greater than 1.5 mm with invasion of the substantia propria
pT3 - Melanoma invades the eye, eyelid, nasolacrimal system, sinuses, or orbit
pT4 - Melanoma invades the central nervous system

*Quadrants are defined by clock hour, starting at the limbus (eg, 3, 6, 9, 12) and extending from central cornea to and beyond the eyelid margins; this bisects the caruncle.

Stage group

No stage grouping is recommended at this time.

Histopathologic type

This categorization applies only to melanoma of the conjunctiva.

Histopathologic grade

The histopathologic grade, as follows, represents the origin of the primary tumor:

GX - Origin cannot be assessed
G0 - Primary acquired melanosis
G1 - Malignant melanoma arises from a nevus
G2 - Malignant melanoma arises from a primary acquired melanosis
G3 - Malignant melanoma arises de novo

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Medical and Radiologic Care

Mitomycin is an off-label drug that is used in ophthalmology. It is a potent chemotherapeutic agent that inhibits fibroblasts and, therefore, diminishes scarring after glaucoma filtering surgery. It has been used as an adjunct in pterygium surgery, photorefractive keratoplasty haze management, and conjunctival melanoma management. (Applied topically, however, mitomycin-C has reportedly resulted in an intumescent lens, requiring surgical intervention.)^{[23, 24]}

Outpatient radiotherapy is indicated as needed in patients with conjunctival melanoma.

Future Application

BRAF appeared in 35% of reported cases of conjunctival melanoma in Denmark.^[7]Ongoing clinical trials are evaluating the role of targeted therapies as both adjuvant and metastatic treatment in conjunctival melanoma. This is potentially useful for advanced nonresectable cases.

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Surgical Care

In an adult, all elevated or enlarged pigmented lesions with a history of change should be excised as suspected malignant melanoma.

Note that metastatic melanomas from anywhere in the body and extensions from ciliary body melanomas may first become apparent in the conjunctiva.

The treatment of conjunctival melanoma is surgical, with complete removal of the tumor, if possible. Cryotherapy to the normal-appearing conjunctiva surrounding the lesion is usually performed.

Damato and Coupland reported that high rates of local tumor control, with little ocular morbidity, resulted from excision of invasive melanoma with adjunctive brachytherapy and topical chemotherapy.^[25]This audit also noted that when no caruncular involvement had occurred, disease-specific mortality was rare, except in patients who were referred after a surgical procedure. The investigators’ results suggested that risks of local recurrence and metastatic death are increased by inadequate surgical intervention.

The suggestions of Shields in the surgical management of circumscribed conjunctival melanomas are advocated.

The "no touch" technique is essential throughout the procedure. No surgical instrument is used more than once in any area (addressing the concern of microscopically seeding tumor cells).

Treatment of primary conjunctival melanomas in the limbal region of the bulbar conjunctiva can usually be accomplished with initial, localized absolute alcohol epitheliectomy.

This treatment is followed by wide (2- to 3-mm clear zone), local excision by a partial lamellar scleroconjunctivectomy.

The bed of excision, as well as the adjacent conjunctiva or cornea away from the nodule, is treated with supplemental double freeze-thaw cryotherapy, using a specific technique (lifting the conjunctiva). Treat the entire area of the lesion, because untreated areas may lead to spread through local lymphatic channels. Laser therapy after excision has also been used.

Nodal involvement indicates extensive metastatic disease, but occasionally, cases in which lesions were limited to regional nodes and cured by node resection have occurred.

If the tumors are located in the fornical or palpebral conjunctiva, wide surgical resection with alcohol treatment to the scleral base and cryotherapy to the surrounding conjunctiva is performed.

Exenteration of the orbit

Exenteration of the orbit sometimes is necessary for large melanomas that have invaded the orbit, but this procedure does not improve the prognosis. It may be performed for patients in whom the objective is to do local debulking of a tumor, because this procedure is not linked to increased patient survival. The use of radical neck dissection at the period of exenteration is not without controversy.^[26]

The poor survival rate, despite orbital exenteration, suggests that metastasis has already occurred at the time of treatment and confirms that the extent of the disease at diagnosis is the most important factor in determining the outcome. Considerable orbital invasion indicates the necessity for exenteration; however, subtotal exenteration can be carried out if no evidence of radial extension of the lesion to the skin of the anterior lid exists.

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Consultations

Consultation with a radiation oncologist is appropriate.^[27]As previously stated, Damato and Coupland reported that high rates of local tumor control, with little ocular morbidity, resulted from excision of invasive melanoma with adjunctive brachytherapy and topical chemotherapy.^[25]

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Author

Manolette R Roque, MD, MBA, FPAO, Section Chief, Ocular Immunology and Uveitis, Department of Ophthalmology, Asian Hospital and Medical Center; Section Chief, Ocular Immunology and Uveitis, International Eye Institute, St Luke's Medical Center Global City; Senior Eye Surgeon, The LASIK Surgery Clinic; Director, AMC Eye Center, Alabang Medical Center