Conjunctival melanoma

The incidence is increasing.

Tumor related mortality is reported at 30%.

 

Conjunctival malignant melanoma, a rare but potentially life-threatening cancer.

 

 

Arises from melanocytes located among the basal cells of the conjunctival epithelium. 

 

 

Comprises about 2% of all eye tumors.

 

 

Comprises 5% of melanomas in the ocular region and 0.25% of all melanomas overall.

 

 

Cutaneous melanoma is 360 to 900 times more common than conjunctival melanoma.

 

 

Overall incidence is between 0.24 to 0.8 cases per million.

 

 

Its incidence is increasing.

 

 

There is a possible association between CMM and ultraviolet (UV) light exposure.

 

 

Risk factors for CMM are not yet established. 

 

 

Asians & Pacific Islanders are the least affected, while American Indians are 1.1 times more likely to be affected, Blacks 1.2 times, Hispanics 2.2 times, and White, non-Hispanics 3.3 times.

 

 

Most studies show no gender predilection.

 

 

Association between conjunctival melanoma  and primary acquired melanosis and nevi is well.

 

 

Fifty seven to seventy six percent of CMM arises from primary acquired melanosis.

 

 

Primary acquired melanosis with severe atypia can transform into a melanoma at a frequency of 13 to 50%.

 

 

Primary acquired melanosis

 

without atypia or mild atypia is unlikely to progress to melanoma.

 

 

It may arise de novo (16-25%) or from nevi (1-6%).

 

 

Commonly presents as a thickened, raised, pigmented lesion with prominent feeder vessels and surrounding areas of melanosis.

 

 

Conjunctival malignant melanoma is usually unilateral.

 

 

It presents in adulthood.

 

 

While typically melanotic, amelanotic CMM can occur 15-19% of cases.

 

 

The tumor is uncommonly associated with ocular pain and irritation.

 

 

Its most common location is

 

on the bulbar conjunctiva, comprising 60-92% of cases.

 

 

The bulbar conjunctiva, 

 

is directly exposed to sunlight. 

 

 

The limbus is involved in 48- 61% of cases of conjunctival melanoma.

 

 

No particular quadrant of involvement appears to be favored.

 

 

Less frequently, conjunctival melanoma may present on the palpebral and forniceal conjunctiva, plica semilunaris and caruncle. 

 

 

Conjunctival melanoma in these less frequent involved sites is associated with worse prognosis.

 

 

Multifocal conjunctival melanoma is present in 22-28% of patients and are also associated with increased mortality.

 

 

It may present with invasion in 1% of cases.

 

 

It usually spreads first through lymphatic drainage system.

 

 

Nasal conjunctiva tumors drain to the submandibular lymph nodes.

 

 

Tumors of the rest of the conjunctiva primarily drain to the preauricular and deep cervical lymph nodes.

 

 

Conjunctival melanomas may also invade other structures through direct extension or hematogenous spread, such as the orbit (2% of cases), eyelids (1%), the nasolacrimal duct, nasal cavity or paranasal sinuses (1-5% cases.

 

 

Conjunctival melanomas with limbal involvement may invade the cornea.

 

 

The Bowman’s membrane acts as an important natural barrier, restricting the tumor to superficial layers.

 

 

Diagnosis is usually made by clinical examination and slit lamp biomicroscopy. 

 

 

The presence of pigment, particularly on the tarsal conjunctiva should heighten suspicion for conjunctival melanoma.

 

 

Differential diagnosis: primary acquired melanosis, and conjunctival nevi. 

 

 

Primary acquired melanosis is typically unilateral but presents as a flat, asymmetric, noncystic, pigmented patch on the conjunctiva or cornea. 

 

 

Primary acquired melanosis

 

may be multifocal.

 

 

Conjunctival nevi are mostly stable, unilateral, focal pigmented lesions, and often have cystic spaces.

 

 

Differential diagnoses include: local extension of uveal melanoma or 

 

melanocytoma, and distant metastasis of cutaneous melanoma. 

 

 

When a biopsy is performed,

 

an excisional biopsy is preferred over concerns of tumor cell seeding.

 

 

Measurements of tumor thickness are performed.

 

 

There are four types of atypical melanocytes that exist in conjunctival melanoma lesions: spindle cells, balloon cells, small polyhedral cells, and round epithelioid cells.

 

 

Each of these cells can be found in a variety of other 

 

conditions, including primary acquired melanosis and conjunctival nevi.

 

 

Other histological features correlating with clinical findings in order to solidify the diagnosis of malignancy include: pagetoid spread, radial extension of the intraepithelial component, inflammation of the basal layer, mitotic activity, decreased maturation of basal cells, and invasion of sclera, or cornea past Bowman’s membrane.

 

 

Purely spindle cell type lesions are associated with a more favourable prognosis than mixed cell type lesions.

 

 

Pagetoid growth, mitotic figures greater than five per high powered field, and absence of inflammatory response may be associated with a worse prognosis.

 

 

The tumor thickness, and adequacy of lateral and deep margins should be addressed by the pathologist.

 

 

Other findings suggesting melanoma are pagetoid spread, radial extension of the intraepithelial component, bandlike inflammation of the basal layer, mitotic activity, decreased maturation of basal cells, and invasion of sclera, or cornea past Bowman’s membrane.

 

 

Histologic features may predict prognosis: spindle cell type lesions have been associated with a more favorable prognosis than mixed cell type lesions, while pagetoid growth, mitotic figures greater than five per high powered field, and absence of inflammatory response may be associated with a worse prognosis.

 

 

Ultrasound biomicroscopy (UB) uses high frequency sound waves generating an image based on the echo pattern. 

 

 

UB can penetrate pigmented tumors and estimate tumor thickness, making it useful for pre-surgical planning. 

 

 

Optical coherence tomography uses light, rather than sound waves to generate images.

 

 

In-vivo confocal microscopy, accomplishes excellent resolution, at the level of individual cells.

 

 

The rarity of this tumor has made it difficult to conduct clinical trials to determine the best therapy. 

 

 

The standard of care is wide local excision, followed by cryotherapy to the margins, which is often followed by a variety of adjuvant therapies in order to prevent recurrence and metastasis. 

 

 

Sentinel lymph node biopsy 

 

may be used to detect regional metastasis. 

 

 

Radical techniques such as enucleation and exenteration were considered for eradication of melanoma, but have been shown to provide no improvement in survival.

 

 

Such radical surgical techniques are only performed as palliation for tumors that invade the orbit or completely involve the conjunctiva.

 

 

The mainstay of treatment of conjunctival melanoma is wide local excision and biopsy with no-touch technique and cryotherapy to the margins. 

 

 

A wide excisional biopsy is preferred over incisional , but the latter may be performed in the case of extensive lesions.

 

 

With scleral invasion or corneal involvement, partial sclerectomy  to the cornea are performed. 

 

 

Cryotherapy is then delivered to the margins.

 

 

Adjuvant cryotherapy reduces recurrence in comparison to excision alone.

 

 

Amniotic or mucosal grafts help with cosmetic appearance by covering up large-sized defects. 

 

 

Outcomes of the surgical technique of wide excision with cryotherapy: Overall, 72% of cases experience complete resolution, 29% of cases experienced local recurrence, 19% of cases experienced metastasis, 10% of cases required exenteration, and 6% of cases were fatal, all over a mean follow-up time of 52 months.

 

 

 Complications from surgery include: symblepharon formation, non-healing epithelial defects, hyphema, limbal stem cell deficiency,corneal scarring, infection, and diplopia.

 

 

Possible adverse effects of cryotherapy include inadvertent damage to 

 

conjunctiva, cornea or iris, resulting in chemosis, subconjunctival hemorrhage, scleral and corneal tissue loss, corneal endothelial damage, iritis, hyphema, iris atrophy, and intraocular pressure alterations including hypotony may occur.

 

 

Less commonly, eyelid, uvea, and extraocular muscles may damage  may result in ectropion, uveitis, and possible paralysis of extraocular muscles.

 

 

 CMM are prone to recurrences.

 

 

Adjuvant treatment is especially recommended in cases of inexcisable disease, where histology reveals tumor presence at surgical margins. 

 

 

There is no preferred adjuvant therapy.

 

 

Adjuvant therapies include: cryotherapy, mitomycin C, interferon alpha-2b, brachytherapy, external beam radiotherapy and proton beam radiotherapy. 

 

 

Cryotherapy may also be used to manage local recurrent disease. 

 

 

Topical chemotherapy is valued for its ability to treat the entire ocular surface and include: mitomycin C and interferon alpha-2b.

 

 

Mitomycin C is currently the preferred adjuvant therapy.

 

 

Overall, 40% of cases experienced complete resolution, 20% of cases experienced partial resolution without recurrence or metastasis, 40% of cases experienced local recurrence, 10% cases experienced metastasis, and 20% required exenteration, all within a mean follow-up time of 19.4 months.

 

 

Mitomycin C is associated with poor results as primary therapy as it does not cross the basement membrane, limiting its activity to surface lesions.

 

 

Interferon alpha-2b (IFN-α2b) 

 

interferes with tumor cell proliferation by prolonging the length of the cell cycle, down-regulating oncogenes and promoting tumor suppressor genes: 

 

in ocular lesions, it acts by enhancing the immune response by increasing MHC class I cell surface antigen expression 

 

 

Interferon alpha-2b (IFN-α2b) has been applied both topically and in subconjunctival/perilesional injections, but data using IFN for CMM is limited.

 

 

It is not considered radiosensitive and radiotherapy should not be used as primary therapy.

 

 

It is used as adjuvant therapy following surgical excision.

 

 

Radiotherapy options consist of brachytherapy and external beam radiotherapy.

 

 

Brachytherapy reduces recurrence in comparison to excision alone, excision with cryotherapy, or excision with MMC.

 

 

Use of external beam radiation  has been minimal in CMM due to concerns about damage to other ocular structures. 

 

 

Proton beam radiotherapy (PBRT) is a form of EBRT which is able to concentrate ionizing radiation to the tumor site while minimizing its effects on surrounding tissues. 

 

  

 

A limitation of brachytherapy is its susceptibility to movement of the eye which may decrease the calculated dose of radiation to the target area.

 

 

Use of EBRT has been minimal in CMM due to concerns about damage to other ocular structures. 

 

 

Proton beam radiotherapy (PBRT), a form of EBRT which is able to concentrate ionizing radiation to the tumor site while minimizing its effects on surrounding tissues. 

 

 

Cryotherapy an adjuvant therapy that is typically administered at the time of excision to the surgical margins.

 

 

Theuse of sentinel lymph node biopsy remains highly debated: There is evidence demonstrating similarities in patterns of metastasis between  cutaneous and conjunctival melanoma.

 

 

Metastasis and recurrence are common for patients with CMM.

 

 

It has an overall average local recurrence of 40% over a mean interval of 2.4 years. 

 

 

5-and 10- year percentage estimates of recurrence following surgical excision ranged from 36-45%, and 31-59%, respectively.

 

 

Risk factors for recurrence include: 

 

 

thickness of primary tumor

 

 

subsequent local recurrences,

 

 

incomplete excision at the time of surgery

 

 

and non-limbal tumor location.

 

 

location of the tumor in plica semilunaris, or non-epibulbar locations such as the forniceal conjunctiva, caruncle, or eyelid margins.

 

 

Epibulbar tumors show a lower frequency of local recurrence and distant metastases.

 

 

Five large studies revealed an average frequency of lymph node metastasis of 19% over a mean interval of 3.4 years

 

 

When staged according to the American Joint Committee on Cancer (AJCC) guidelines, 5- and 10- year percentage estimates range from 17-52% and 27-57%, respectively.

 

 

Regional lymph nodes are the most common initial site of metastasis.

 

 

The most common lymph nodes affected are the preauricular, parotid, submandibular, and cervical nodes. 

 

 

Temporal conjunctival melanomas show a tendency to metastasize to preauricular lymph nodes.

 

 

Nasal conjunctival melanoma tends to metastasize to the submandibular lymph nodes.

 

 

Risk factors for lymph node metastasis include: tumor thickness, histologic ulceration, and mitotic figure count > 1/mm2.

 

 

Metastatic disease affects the liver, lungs, brain, and skin but has also been reported in the bones and gastrointestinal tract.

 

 

It can also spread directly towards the eyeball and orbit, and nasolacrimal system and sinuses.

 

 

Only 16-25% of conjunctival melanomas arise de novo.

 

 

De novo conjunctival melanomas are associated with the greatest risk for metastasis and death.

 

 

CMM originating de novo has estimated 10-year risk of orbital invasion, 10-year risk of metastasis, and 10-year mortality rates of 17%/49%/35%.

 

 

CMM from primary acquired melanosis: 16%/25%/9%, and from nevus: 9%/26%/9%.

 

 

Tumor Node Metastasis (TNM) staging system for conjunctival melanomas: 

 

 

T1 describes CMM affecting the bulbar conjunctiva 

 

 

T2 describes CMM affecting the palpebral and forniceal conjunctiva and the caruncle. 

 

 

T1 and T2 tumors are further subdivided by number of quadrants affected. 

 

 

T3 describes CMM that locally invades the globe, eyelid, orbit, or paranasal sinuses. 

 

 

T4 describes CMM with invasion of the central nervous system. 

 

 

Lymph node metastasis is subdivided into three general categories: unable to be assessed (Nx), no regional lymph node metastasis (N0), and positive lymph node metastasis (N1). 

 

 

There is a common genetic kinship between conjunctival and cutaneous melanoma, while also differentiating it from uveal melanoma.

 

 

KIT mutations have only rarely been found in CMM samples. 

 

 

NRAS I’d found in 16% of CMM samples.

 

 

BRAF has received the most attention, due to a high level of concordance in the BRAF mutation between cutaneous and conjunctival melanoma. 

 

 

BRAF is  found in 33% of primary CMM, 67% of CMM secondary to metastasis, and 22% of CMM of unknown origin. 

 

 

BRAF inhibitors are considered in cases of CMM with regional and systemic metastasis.

 

 

CMM appears to have a different genetic identity from that of uveal melanoma. 

 

 

Losses in 9p gene, gains in chromosome 7 or amplifications of CCND1 centromere proximal chromosomal areas of chromosome 11 are seen in CMM.

 

 

The most common mutation in CMM is BRAF

 

 

The frequency of local recurrence up to 45% in 5 years, lymph node metastasis up to 52%, systemic metastasis up to 42%, and mortality up to 23% during this time period.

 

 

The percentage of patients with local metastasis, distant metastasis, and melanoma-related death approach 52%, 42% and 23%, respectively within 5 years.

Diagnosis is generally by clinical examination and slit-lamp findings. However, high resolution imaging such as UHR OCT and confocal microscopy may offer assistance with making the diagnosis, and assisting in surgical planning.

 

 

Current management is wide local excision with cryotherapy to the margins. Adjuvant therapies include topical chemotherapy, cryotherapy, and radiotherapy.

 

 

Lumphoscintigraphy should be performed for tumors >2mm in thickness