Conjunctival amelanotic melanoma presenting as a multifocal pink lesion

Abstract

Conjunctival amelanotic malignant melanoma is a rare form of melanoma, which lacks visible pigment and is commonly located underneath the eyelids in the bulbar conjunctiva. In this report, we described a case of a Caucasian women in her 70s who presented with unilateral irritation and tenderness following cataract surgery. On eversion of the eyelid, two elevated pink lesions were noted. Tumour - Node - Metastasis staging with the American Joint Committee on Cancer staging system eighth edition was T3C and required multiple excisions and reconstruction procedures. This case exemplified the diagnostic pitfall of conjunctival amelanotic malignant melanoma, which is a potentially life-threatening disease and the importance of histopathology in the diagnostic process.

Background

Conjunctival melanoma is rare, with an incidence of less than 1 per million and is commonly located underneath the eyelids in the bulbar conjunctiva. A Caucasian woman in her 70s presented with unilateral irritation and tenderness following recent cataract surgery. On eversion of the eyelid, two elevated pink lesions were noted. Following an incisional biopsy, a diagnosis of multifocal de novo conjunctival amelanotic malignant melanoma was made. This case highlights the importance of eyelid eversion during examination and consideration of conjunctival amelanotic malignant melanoma as a potential diagnosis.

Case presentation

A woman in her 70s presented with left eye irritation and tenderness following an uncomplicated phacoemulsification and intraocular lens insertion two weeks prior. Patient was a known case of polycythaemia rubra vera (with upper end transformation towards myelofibrosis), ischaemic heart disease (x1 third generation stent), chronic obstructive pulmonary disease (ex-smoker with a 40-pack year history on home oxygen) and recurrent pulmonary emboli (despite warfarin 4 years ago).

On examination, best-corrected visual acuity measured 6/9 right eye and 6/9 left eye. Corneas were clear in both eyes. The anterior chamber was deep with 0.5+ cells in the left eye, with an intraocular lens in the bag. The left eye conjunctiva was mildly injected. On eversion of the left upper eyelid, two separate conjunctival non-pigmented nodules were present (figure 1). The first was an 11 mm elevated, pink lesion located from 1 to 2 o’clock with extension into the fornix (figure 2). The second was located from 10 to 11 o’clock and was an elevated pink nodule approximately 6 mm in size (figure 3). Posterior segment examination was normal with a disc cup ratio of 0.5 bilaterally.

Figure 1.

Two elevated pink conjunctival lesions were present, one superior temporal and one superior nasal on initial presentation.

Figure 2.

The superior temporal lesion was approximately 11 mm, located from 1 to 2 o’clock with extension into the fornix.

Figure 3.

The superior nasal lesion was approximately 6 mm in size, elevated and pink in colour. (Photo taken 4 weeks post cataract surgery).

Investigations

An incisional biopsy was sent for molecular pathology and immunohistochemical staining. Microscopy showed a neoplasm formed by highly atypical epithelioid cells underneath the epithelium with markedly pleomorphic nuclei and irregular nuclear membranes with intranuclear pseudoinclusions (figures 4 and 5). No pigment or necrosis was seen. Prominent mitotic figures and apoptotic debris were identified.

Figure 4.

Low magnification slide through the bulk of the tumour. A small rim of epithelium is seen superiorly with the deeper tissues including stroma inferiorly. There is a small area of intact epithelium visible of the far left, with loss of epithelium and ulceration laterally. The main bulk of the tumour is located in the superior left quadrant which then infiltrates downwards into the deeper structures.

Figure 5.

Very high magnification slide. There are sheets of cells, variability of cell nuclei and irregular cellular boarders, tumour cells have a nucleus 10–20 times larger they the surrounding infiltration of plasma cells and lymphocytes.

CT orbit scan showed an isodense crescent-shaped soft tissue thickening of the subconjunctival space on the left side which was not visible on radiology imaging 6 months prior. There was no sign of local lymphadenopathy or orbital disease.

A positron emission tomography (PET) scan with fluorodeoxyglucose was unable to visualise the left conjunctival lesion and no fluorodeoxyglucose avid lymphadenopathy or metastatic disease were identified.

Differential diagnosis

Clinical diagnosis was obscure and relied on histopathology. Differential diagnosis included non-pigmented nevi, conjunctival melanocytic intraepithelial neoplasia (C-MIN), conjunctival amelanotic melanoma and lymphoma.

Conjunctival nevi are the most common conjunctival lesion and are benign. Nevi usually appear in those aged between 10 and 30 years old,¹ and typically present as an elevated pigmented lesion in the bulbar conjunctiva with intralesional cysts.² Nevi are rarely located in the fornix or tarsus and usually stop abruptly at the limbus. While most lesions are either brown or tan, approximately 16% of all conjunctival nevi are completely non-pigmented.² On histology, nevi typically consist of nests of nevus cells located in the junctional and subepithelial conjunctiva and are usually observed clinically. The overall risk of malignant transformation is less than 1%.³

C-MIN is an acquired conjunctival melanocytic disease, which typically presents as a flat, unilateral, patchy or diffuse non-cystic brown lesion. It can present as a single or multifocal lesion and in rare cases be amelanotic. It is usually found in fair skinned individuals over the age of 40 years and has a reported incidence of up to 36% in Caucasians.⁴ Previously referred to as primary acquired melanosis with or without atypia, C-MIN refers to a spectrum of neoplastic changes from a primary melanocytic disease with varying degrees of atypia through to melanoma in situ.⁵ Grading is based on the histopathology pattern of horizontal epithelial involvement, vertical depth of infiltration and degree of cellular atypia.⁵ Treatment options include monitoring or surgical excision with or without adjuvant chemotherapy. Regional reoccurrence has been reported up to 50% after treatment.⁶

Conjunctival amelanotic melanoma is diagnostically challenging and can present as an amelanotic vascularised nodule that may be fixed to the episcleral. On biopsy, various combinations of atypical spindle cells, epithelioid cells or polyhedral cells are characteristic of conjunctival melanoma.

In this case, immunohistochemical staining showed strong diffuse positivity for Sry-related HMg-Box gene 10 (SOX10) and MelnA in the malignant cells which confirmed melanocytic origin. There was no staining for cytokeratin AE1+ (which if present highlights residual mucosa). Molecular pathology was negative for BRAF and NRAS gene variants, which are casually associated with melanoma-type tumours.

Lymphoma characteristically presents as a slow growing, painless, fleshy or salmon-pink-coloured mobile lesion typically located in the fornices or epibulbar surface. The estimated incidence of conjunctival lymphoma is 2–4/1 000 000.⁷ Most primary conjunctival lymphomas are non-Hodgkin B-cell lymphoma of which extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma), follicular lymphoma and diffuse large B-cells lymphoma are the three most common. Histogenesis depends on the lymphoma subtype and associated differentiation pathway.

In this case, immunohistochemical staining lymphoid markers CD45, CD20, CD3 were negative and there was no expression of multiple myeloma oncogene 1 (MUM1) or activin A receptor like type 1 (ALK1).

Treatment

Recommendation for excision via exenteration was declined. The patient underwent surgical excision of their left multifocal conjunctival melanoma using a no touch technique, double freeze-thaw cryotherapy and amniotic membrane graft. The excision was sent for examination under microscopy and the patient referred to oncology.

Outcome and follow-up

Histopathology confirmed invasive conjunctival malignant melanoma arising from melanoma in situ with a maximum thickness of 1.8 mm, mitotic count of 1/mm². There was no vascular invasion, and surgical margins were not clear.

Five months postoperatively, the patient underwent re-excision of the left conjunctival melanoma and reconstruction of the left supper fornix with mucous membrane graft. Histology showed invasion into the orbital stroma. There was a maximum cumulative diameter of 4 mm. Oncology adopted surveillance for recurrences and a repeat PET scan at 5 months was negative for local or systemic involvement.

One year and 4 months postoperative, a repeat PET scan showed new highly fluorodeoxyglucose avid masses in the left eye, left orbit, liver and parotid gland consistent with local reoccurrence and metastasis, respectively. The patient was commenced on nivolumab (immunotherapy -human programmed death receptor-1 blocking antibody). Clinical photography at 18 months showed pigmented changes in the periorbital area likely from local dissemination of melanoma (figure 6).

Figure 6.

Periorbital pigmented changes at 18 months following initial presentation, likely from local dissemination of melanoma.

Discussion

One of the earliest descriptions involving the surgical removal of a conjunctival involving melanoma was in 1871 by Mr Demarquay who removed a cherry-sized lesion with a blackish tint from a 15-year-old girl, first mistaken for a pinecone.⁸ Nowadays, conjunctival melanoma is recognised as a rare condition with an incidence of less than 1 per million,⁹ which is slowly rising, likely secondary to ultraviolet light exposure.^{9 10} Conjunctival melanoma arises from either C-MIN (57%–60%), de novo (16%–25%) or a pre-existing nevus (1%–6%).^{9 11} While reported in all age groups and races, it is predominantly found in middle age fair-skinned adults.¹²

Conjunctival melanoma represents atypical melanocytes proliferation that originates from the conjunctival epithelium -and unlike malignant melanoma in situ which is confined to the epithelium-invades into the substantia propria. In addition to direct extension into the globe and orbit, dissemination can occur via lymphatic or hematogenous spread, with metastasis most frequently to the liver, lungs, bone and brain.^{13 14}

A large multinational retrospective study on conjunctival melanomas reported that overall the majority of tumours had a nodular component (83%) and were located in the bulbar conjunctiva (72%).¹⁴ Tumour pigmentation was dark brown (38.2%), light brown (21.9%), pink (18.7%), black (8.9%), red (6.5%), grey (2.4%), yellow (0.8%) or white (0.8%).¹⁴ Surface ulceration of the tumour was seen in 9.7% of eyes and local invasion was most common into the eyelid or orbit.¹⁴

Surgical staging uses the eighth edition of the Tumour- Node-Metastasis (TNM) American Joint Committee on Cancer staging system, of which T3 disease was reported to be associated with more than two times the risk of local recurrences compared with T1 disease.¹⁴ Clinical prognostic factors include tumour thickness (>2 mm), extrabulbar location and involvement of adjacent tissue structures.¹⁵ Conjunctival melanoma with low tumour pigmentation has been reported to be associated with a worse prognosis but is not included in the TNM staging system.¹⁵

Conjunctival melanoma is commonly treated with wide excision non-touch technique with double cryotherapy to margins and amniotic membrane transplant.¹⁶ The latter of which is to mitigate against symblepharon formation. Adjuvant therapy includes topical chemotherapy (mitomycin C or interferon alfa-2b), focal cryotherapy or re-excision for recurrent disease and radiotherapy (brachytherapy or teletherapy). Traditionally, surgical exenteration was recommended in those with extensive tumour recurrences or non-resectable tumours without metastasis,¹⁷ to address the risk of local reoccurrence; however, its use is a matter of conjecture as other studies have found that exenteration was not associated with an increased rate of overall survival.¹⁸ Follow-up includes monitoring for local recurrence and referral to oncology for systemic workup and ongoing treatment. Conjunctival melanoma has a 10-year mortality rate of approximately 30%^{12 14} and a reoccurrence rate of approximately between 36%-65%.^{8 15} Recently, successful use of systemic immunotherapy for recurrent local disease and metastasis was reported.^{19 20} This illustrates the potential efficacy of targeted drugs in the management of advanced conjunctival malignant melanoma, but further studies are needed to determine the role of immunotherapy and its effects in recurrent conjunctival malignant melanoma.

This case demonstrated several surgical challenges and pitfalls. The incisional biopsy had a risk of inadvertent tumour seeding. Surgical management with exenteration was initially proposed by the surgical team yet declined by the patient. The amelanotic conjunctival melanoma margins were not clinically distinguishable during surgical excision and only ascertained on examination of the resected specimen. On histology, multiple atypical melanotic cells confined to the epithelial layer distant from the main tumour bulk were present, which could have indicated more widespread premalignant ocular surface changes, particularly given the de novo nature of the multifocal lesion. While surgery assists in terms of local disease control, several studies have reported high rates of local recurrence, distant metastasis and disease-related survival rates in patients treated with excisional biopsy alone compared with excision in combination with adjuvant therapy.^{21 22}

Learning points.

• Eyelid eversion is an important part of ophthalmology examination and enables visualisation of pathology that otherwise may not be appreciated.

• Conjunctival amelanotic melanoma is an important differential for physicians to consider when presented with pink-elevated lesions of the conjunctiva, to promote early detection and wide margin excisional biopsy.

• Positive immunohistochemical staining for Sry-related HMg-Box gene 10 (SOX10)and MelnA confirmed cells of melanocytic origin.

• Surgical exenteration may prevent local reoccurrence at the surgical site, despite not improving overall survivability.

Ethics statements

Patient consent for publication

Consent obtained from next of kin.