Conjunctival Epithelium Neoplasms

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Article initiated by:

Jocelyn Rivera, MD

All contributors:

Vatinee Y. Bunya, MD, MSCE, Maria A. Woodward, MD, Jocelyn Rivera, MD, Colleen Halfpenny, M.D., Jill Wells, MD, Justin Grassmeyer, M.D., Ph.D.

Assigned editor:

Erica Renee Alvarez, MD, Maria D. Bernal, MD

Review:

Assigned status Update Pending

 by Colleen Halfpenny, M.D. on January 14, 2023.

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Contributing Editors:	add

Conjunctival Epithelial Neoplasms

Anatomy

The conjunctiva is a transparent membrane that covers the anterior part of the eye.

Portions of the conjunctiva

• Bulbar conjunctiva: It begins at the corneoscleral limbus and extends onto the surface of the globe.
• Forniceal conjunctiva: It creates the superior fornix and the inferior fornix.
• Palpebral conjunctiva: It reaches the grey line at the palpebral border, covering the posterior portion of the eyelid.
• Special regions:
  • Plica semilunaris: It represents a remnant of the nictitating membrane found in inferior animals like amphibians. The plica semilunaris is a fold of the conjunctiva that is vertically oriented in the medial portion of the bulbar conjunctiva.
  • Caruncle: It is located in the middle of the upper and lower punctum. The caruncle contains conjunctival and cutaneous structure: nonkeratinized stratified squamous epithelium, stroma, melanocytes, sebaceous glands, hair follicles and striated muscle fibers.

Histology

The conjunctiva is formed by epithelium and stroma.

Epithelium

There is columnar epithelium near the limbus and squamous epithelium closer to the fornix. A fibrovascular connective tissue composes the stroma. It is thicker in the fornix and thinner at the limbus. The epithelium is nonkeratinized and is formed by five layers.  The goblet cells are in the inner layer and they are more numerous in the inferior and medial portion of the bulbar conjunctiva and in the fornix. Goblet cells secrete the innermost, mucoid component of the tear film.

Stroma

The stroma is formed by a vascularized lax connective tissue. The adenoid superficial layer develops at the age of three months; this is why a newborn can’t generate a follicular reaction. The deeper fibrous layer is attached to the posterior portion of the tarsus. Krause and Wolfring’s accessory tear glands are located in the middle of the stroma. These glands, along with the lacrimal gland, secrete the aqueous component of the tear film.

Mucosa-associated lymphoid tissue (MALT)

Formed by lymphocytes and plasmatic cells that are between the epithelial cells.

General considerations

Even though the conjunctiva is like other membranes of the body, it has a unique position that allows exposure to sunlight which is a risk factor for the development of some neoplasms. These neoplasms can develop from the epithelium or the stroma. Also, the caruncle has a special composition that generates tumors from the mucous membrane and cutaneous structures.

Diagnostic approaches

Usually the conjunctival lesions are visible at the slit lamp. This fact allows the clinician, or even the patient, to detect the neoplasm in its early stage. The physician has to carefully examine the entire globe including the cornea because some conjunctival neoplasms are related to the corneal ones. The ophthalmologist has to interrogate the patient about the time of evolution, symptoms, change of the size and personal and familial medical and ophthalmologic history, including high sunlight expose. The clinician must describe the lesion: color, form, size, mobility, vascularization, elevation, characteristic aspects and associations.

A diagnostic biopsy can be skipped in cases of smaller tumors that appear benign. If a lesion is less than 4 clock hours in a limbal tumor or less than 15 mm of the basal dimension, an excisional biopsy should be done to remove the entire lesion.

For larger tumors it is preferable to perform an incisional biopsy to obtain a histopathologic diagnosis as the initial step before proceeding with more extensive surgery.

Some times, exfoliative cytology and fine-needle aspiration biopsy can provide some useful information.

Classification

Table 1. Classification of conjunctival epithelial neoplasms

	Child	Adult
Benign	Conjunctival papilloma Conjunctival hereditary benign intraepithelial dyskeratosis	Conjunctival papilloma Papilloma of caruncle Conjunctival pseudoepitheliomatous hyperplasia Keratoacanthoma Conjunctival hereditary benign intraepithelial dyskeratosis Conjunctival dacryoadenoma Epithelial inclusion cyst
Premalignant	Conjunctival intraepithelial neoplasia	Conjunctival keratotic plaque Actinic keratosis Conjunctival intraepithelial neoplasia
Malignant	Conjunctival invasive squamous cell carcinoma

Conjunctival Benign Epithelial Neoplasms

Conjunctival Papilloma in Children

This neoplasm occurs between the first year of life and the age of 26. It is associated with human papillomavirus (HPV), usually types 6 to 11. Shields et al. reported in a clinical series of 1,643 conjunctival tumors of which 5 were childhood papillomas, accounting for 13% of benign epithelial lesions (<1%).

Clinical features

The conjunctival papilloma is an elevated lesion that usually has a fleshy red appearance, and it can be solitary or multiple. This neoplasm can have a sessile or pedunculated configuration and sometimes it can be pigmented (simulating melanoma). If multiple lesions collimate, they can produce a massive papillomatosis.

This benign lesion can be located in the inferior fornix or the bulbar conjunctiva, and rarely near to the cornea.

Histopathology

The histopathology shows a vascularized papillary fronds lined by acanthotic epithelium with almost no keratinization.

Treatment

• Surgical excision: It is not recommended because if the excision is incomplete, the virus can be liberated into the surrounding tissues and the lesion can recur more aggressively.
• Cryotherapy: The entire lesion is lifted and frozen. Immediately the lesion and the surrounding normal conjunctiva are cut with a “No-touch” technique and the defect is closed with absorbable sutures or an amniotic graft.
• Alternative therapy: laser treatment, Alpha-interferon, dinitrochlorobenzene immunotherapy, topical mitomycin chemotherapy 0.02% and oral cimetidine.

Conjunctival Papilloma in Adults

The conjunctival papilloma is a lesion that is associated with HPV. It  is more frequent in immunosuppressed patients. It has low malignant potential.

Clinical features

The conjunctival papilloma is an elevated lesion, that usually has a lighter pink appearance, but in adults it can be pigmented. Frequently, it can be a unilateral and a solitary lesion, and most often it begins near the corneal limbus, the bulbar conjunctiva or the caruncle. In aggressive cases, it can cover the entire cornea.

Histopathology

The histopathology shows vascularized papillary fronds lined by acanthotic epithelium, and a mild hyperkeratosis is sometimes present. Some papillomas have melanocytes that make them darker lesions.

Treatment

• Surgical excision with supplementary cryotherapy.
  • The surgeon has to evaluate very carefully the lesions that are near or above the cornea to ensure there is not invasion into the cornea.

Papilloma of caruncle

Santos-Gómez Leal et.al. reported in their series that this lesion has a prevalence of 25.66% of the tumors of the caruncle, with a mean age of 27 years (3-65 years old). It was more common in women 1.2:1. The characteristics are the same of the papilloma of conjunctiva in adults, with the same treatment. 

Conjunctival pseudoepitheliomatous hyperplasia

Also called pseudocarcinomatous hyperplasia, it can arise from chronic inflammation of the conjunctiva, like a pterygium or a pingueculum.

Clinical features

Pseudoepitheliomatous hyperplasia is a lesion of rapid progression. It is elevated with hyperkeratosis, and because of its similarity is important to rule out a squamous cell malignancy. 

Histopathology

The histopathology shows massive acanthosis, hyperkeratosis and parakeratosis of the conjunctival epithelium. There is not cytologic atypia, but sometimes mitotic figures are present.

Treatment

• Surgical excision with supplementary cryotherapy.

Keratoacanthoma

The Keratoacanthoma is a variant of conjunctival pseudoepitheliomatous hyperplasia.

Clinical features

This lesion has a gelatinous or leukoplakic appearance, similar to the squamous cell malignancies of the conjunctiva. It has a rapid progression and sometimes it can have an umbilicated center with elevated margins.  

Conjunctival hereditary benign intraepithelial dyskeratosis

This benign neoplasm is an autosomal-dominant lesion developed mostly in the Haliwa Indians, some African-Americans and almost never in Caucasians. It is occurs in the first decade of life. It has no known malignant potential.

Clinical features

Conjunctival hereditary benign intraepithelial dyskeratosis is a bilateral elevated lesion with fleshy plaques, generally in the nasal or the perilimbal conjunctiva. It usually has a V-shape. The patients can also present buccal lesions in the mucosa. Most of the time they are asymptomatic or may have a mild foreign body sensation.

Histopathology

The histopathology shows intact basement membrane with an engorged stroma and foci of acanthotic and hyperkeratotic conjunctiva.

Treatment

• Medical: If the patient is symptomatic you can use lubricants and some times short periods of steroids.
• Surgical: Resection with an amniotic membrane graft if the lesion is large.

Conjunctival dacryoadenoma

Jakobic et al. report this rare lesion in children and young adults.

Clinical features

The dacryoadenoma is a pinky and fleshy lesion that appears in the bulbar or palpebral conjunctiva. In adults it has a salmon-like color.

Histopathology

The histopathology of dacryoadenoma shows a lesion that originates from the surface epithelium and proliferates inward into the stroma. The dacryoadenoma develops glandular lobules that are alike to the lacrimal gland, but they do not have goblet cells.

Treatment

• Excision: The clinical diagnosis is difficult, so most lesions have had excisional biopsy before diagnosis.

Epithelial inclusion cyst

The epithelial inclusion cyst could be spontaneous or occur after inflammation, surgery or trauma. It is round and lined by conjunctival epithelium with clear fluid inside. If the fluid has epithelial cells, they can go to the bottom of the cyst and form a pseudohypopyon. If they are asymptomatic they can be observed, but if it is too large it can be excised completely with primary closure of the conjunctiva.

Conjunctival Premalignant Epithelial Neoplasms

Conjunctival keratotic plaque and Actinic keratosis

The conjunctival keratotic plaque and actinic keratosis are two lesions that cannot be clinically differentiated from each other. Shields et al. and their clinical series of 1663 conjunctival tumors, showed four conjunctival keratotic plaque and four actinic keratosis, each representing less than 1% of the entire case series.

Clinical features

The two lesions develop on the limbal or the bulbar conjunctiva in the interpalpebral region. They are a flat and white plaque that appear gradually. They are similar in presentation to conjunctival intraepithelial neoplasia (CIN).

Histopathology

The histopathology of the keratotic plaque shows acanthosis of the epithelium and keratinization of the conjunctival epithelium and parakeratosis.

The actinic keratosis also called senile keratosis shows similar histopathology with prominent keratosis and usually appears over an area of chronic inflammation like a pingueculum or pterygium.

Treatment

• Excision and supplementary cryotherapy: Because of the clinical similarity with CIN, the finding of leukoplakia in the conjunctiva is a relative indication for excision and cryotherapy.
• Document and observe: Some ophthalmologists prefer to document the lesion and follow it, particularly in elderly patients, because the prognosis is excellent.

Conjunctival intraepithelial neoplasia

The conjunctival intraepithelial neoplasia is a squamous neoplasia confined to the conjunctival epithelium that sometimes transgresses the basement membrane but strictly does not have the potential to metastasize, unlike the invasive squamous carcinoma. Some authors refer to the entire spectrum of epithelial neoplasia called “ocular surface squamous neoplasia”, that includes dysplasia, CIN and invasive squamous cell carcinoma.

The human papilloma virus (HPV) and sunlight are considered to be the main predisposing factors for conjunctival intraepithelial neoplasia. However, HPV with polymerase chain reaction is absent in some cases of CIN.

Shields et.al found in their series that CIN corresponded to 39% of all premalignant and malignant lesions and to 4% of all the conjunctival lesions.  

Clinical features

CIN is more common in elderly and immunosuppressed patients with fair skin and considerable sunlight exposure.

Conjunctival intraepithelial neoplasia could be a fleshy, sessile or minimally elevated lesion that frequently appears perilimbal in the interpalpebral zone, or less commonly in the inferior fornix or palpebral conjunctiva.

CIN can extend into the adjacent corneal epithelium. It appears like a gray superficial opacity that can be avascular or have fine vascularization.

Histopathology

The histopathology of mild CIN shows a partial replacement of the surface epithelium by abnormal epithelial cells that do not have normal maturation. In severe CIN, the histopathology is characterized by a total replacement of epithelium by abnormal epithelial cells with no maturation.

Treatment

• Surgical removal: The conjunctival lesion removal is carried out following the Shields’ “no touch” technique to avoid the potential risk of seeding. This technique incorporates large macroscopically tumor-free margins (at least 4 mm) in a single piece to increase the likelihood of clear margins. Cryotherapy is then applied to the conjunctival and limbal margins in a “double freeze slow thaw” technique, which achieves the rupture of tumor cell membranes and the occlusion of the blood vessels. Depending on the size of the wound defect, the conjunctiva is either closed primarily or with a graft (amniotic membrane or autoconjunctival graft).
• Topical Chemotherapy: Can be used as primary treatment or as adjuvant treatment (chemoreduction or chemoprevention). Often used in conjunction with surgery, especially in the case of positive margins.
  • Interferon alpha-2b (topically or subconjunctival injection).
    • Less toxic and well tolerated, but usually more expensive than other topical options. Studies have shown that most corneal specialists choose this as first line therapy over other agents, but this has become less commercially available and other topical options should be considered.
  • Mitomycin C
  • 5-flourouracil
  • Cidofovir
• Corneal components are removed through alcohol keratoepitheliectomy leaving at least 2-mm tumor-free margins, while scleral invasion is addressed with partial lamellar sclerectomy.

Conjunctival Malignant Epithelial Neoplasms

Conjunctival invasive squamous cell carcinoma

Conjunctival invasive squamous cell carcinoma is when CIN breaks the basement membrane of the conjunctival epithelium and invades the stroma and underlying tissues.

The incidence of conjunctival invasive squamous cell carcinoma varies from 0.02 to 3.5 per 100,000, it is less frequent than CIN, with a frequency of 60% of all conjunctival malignant epithelial tumors and 7% of all the conjunctival neoplasms. It is more common in men (75%) and elderly patients (75%>60 years old). Conjunctival invasive squamous cell carcinoma most commonly begins at the limbus (75%).

Conjunctival invasive squamous cell carcinoma tends to occur in patients with xeroderma pigmentosum and atopic eczema. It is associated to the dysfunction of T lymphocytes and type 16 HPV.

Clinical features

Conjunctival invasive squamous cell carcinoma cannot be differentiated clinically from CIN. It occurs frequently in the interpalpebral region of Caucasian elderly or immunosuppressed patients. The lesion can be a sessile, gelatinous, circumscribed or papillomatous mass with leukoplakia. Some lesions are diffuse, flat and poorly delineated that can be confused with a chronic conjunctivitis, scleritis or pagetoid invasion of sebaceous carcinoma.

The lesion is invasive to the local structures (orbit, cornea and the globe), but with a low range of metastasis (1-2%). If the invasion causes glaucoma, and the intraocular pressure is uncontrollable, that may necessitate an enucleation. 

Diagnosis

• Excisional biopsy: if the lesion is localized and small.
• Impression cytology: If the lesion is diffuse.
• Ultrasound biomicroscopy: to determinate limbal invasion.

Histopathology

The histopathology of conjunctival invasive squamous cell is well-differentiated neoplasm with abnormal epithelial cells that have mitotic activity and keratinic production. Some lesions can be poorly differentiated with pleomorphic cells, giant cells and a lot of mitotic figures with acanthosis and dyskeratosis.

Treatment

• Surgical removal: The conjunctival lesion removal is carried out following the Shields’ “no touch” technique to avoid the potential risk of seeding. This technique incorporates large macroscopically tumor-free margins (at least 4 mm) in the bioptic piece to increase the likelihood of clear margins. Cryotherapy is then applied to the conjunctival and limbal margins in a “double freeze slow thaw” technique, which achieves the rupture of tumor cell membranes and the occlusion of the blood vessels. . If the lesion is large, adjuvant amniotic membrane grafting can be used.
• Corneal components are removed with absolute alcohol for 1 minute in area at least 1-mm beyond the visible tumor margin.
• Scleral invasion is addressed with partial lamellar sclerectomy.
• Topical Chemotherapy: Can be used as primary treatment or as adjuvant treatment (chemoreduction or chemoprevention). Often used in conjunction with surgery, especially in the case of positive margins. These agents are corneal and conjunctival toxic so are often administered in a 1 week on, 1 week off fashion.
  • Interferon alpha-2b (topically or subconjunctival injection).
    • Less toxic and well tolerated, but usually more expensive than other topical options. Studies have showed that most corneal specialists choose this as first line therapy over other agents. Unfortunately, this is no longer commercially available in the United States.
  • Mitomycin C
  • 5-flourouracil
  • Cidofovir
• Enucleation or orbital exenteration is reserved for cases with intraocular or periocular invasion, respectively
• Low dose irradiation with strontium-90

Prognosis

The prognosis is good, with a local recurrence rate of 5% and regional lymph node metastasis of 2%.

Mucoepidermoid carcinoma

Mucoepidermoid carcinoma is an aggressive variation of the conjunctival invasive squamous cell carcinoma, that is less than 5% of these lesions.

Clinical features

Mucoepidermoid  carcinoma is more frequent in elderly men (>70 years old). It can be in the bulbar conjunctiva but can also be present in the caruncle and then can invade the orbit and paranasal sinuses. It can have a yellow, globular and cystic appearance. This neoplasm tends to invade the globe or the orbit. In the intraocular space, the mucoepidermoid can produce a mucinous cyst in the suprauveal space. The mucin production is more frequent in the intraocular space than in the bulbar conjunctiva.

Histopathology

The histopathology of mucoepidermoid carcinoma shows an epidermoid component, mucin and a goblet cells with signet cells.  Pseudoadenomatous hyperplasia can also have goblet cells and mucin and should be included in the differential diagnosis. Another differential diagnosis is primary mucoepidermoid carcinoma of the paranasal sinuses.

Spindle cell carcinoma

Spindle cell carcinoma is a more aggressive type of conjunctival invasive squamous cell carcinoma that is very rare with only 20 cases reported in the literature. It has a worst prognosis because of the tendency for intraocular invasion and metastasis to the the lung and bone.

Histopathology

The histopathology of spindle cell carcinoma shows pleomorphic spindle cells that look like fibroblasts. This can be misdiagnosed as fibrosarcoma, therefore the diagnosis must be confirmed with immunohistochemistry and electron microscopy.