Conjunctival epithelium neoplasms

From EyeWiki


Conjunctival Epithelial Neoplasms


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.


The conjunctiva is formed by epithelium and stroma.


Near to the limbus there is columnar epithelium and closer to the fornix is a squamous epithelium. A fibrovascular connective tissue composes the stroma. It is thickens in the fornix and thinner at the limbus. The epithelium is nonkeratinized. Five layers form it.  The goblet cells are in the inner layer and there are more numerous in the inferior and medial portion of the bulbar conjunctiva and in the fornix.


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. In the middle of the stroma, the Krause and Wolfring’s glands are located. These glands and the goblet cells secrete the oily part of the tear.

Mucosa-associated lymphoid tissue (MALT)

Lymphocytes and plasmatic cells that are between the epithelial cells form it.

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 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 familiar medical and ophthalmologic history, including high sunlight expose. The clinician must describe the lesion: color, form, size, mobility, vascularization, elevation, characteristic aspect and associations; this can let him to a presumptive diagnosis.

A diagnostic biopsy can be skipped in cases of smaller tumors than appear benign: < 4 clock hours in a limbal tumor, or <15 mm of the basal dimension. In this case it is better to proceed removing the entire lesion in an excisional biopsy.

For larger tumors it is preferable to perform an incisional biopsy to obtain a histopathologic diagnosis.

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


Table 1. Classification of conjunctiveal epithelial neoplasms




  • 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


  • Conjunctival intraepithelial neoplasia
  • Conjunctival keratotic plaque
  • Actinic keratosis
  • Conjunctival intraepithelial neoplasia


  • Conjunctival invasive squamous cell carcinoma
  • Conjunctival invasive squamous cell carcinoma
  • Mucoepidermoid carcinoma
  • Spindle cells 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 to human papillomavirus (HPV), usually types 6 to 11. Shields et al. reported in a clinical series of 1,643 conjunctival tumors, that there were 5 childhood papillomas, accounting for 13% of being 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.


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


  • 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, Alfa-interferon, dinitrochlorobenzene immunotherapy, topical mitomycin chemotherapy 0.02% and oral cimetidine.

Conjunctival Papilloma in Adults

The conjunctival papilloma is a lesion that is associated to the HPV. It  is more frequent in young to elder adults and is more common in immunosuppressed patients. It has a 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 to the corneal limbus and the bulbar conjunctiva or the caruncle. In aggressive cases it can cover the entire cornea.


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


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

Papilloma of caruncle

Santos-Gómez Leal 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 call pseudocarcinomatous hyperplasia, it can arise from chronic inflammation of the conjunctiva, like a pterygium or a pingeculum.

Clinical features

The pseudoepitheliomatous hyperplasia is a lesion of rapid progression, its is elevated with hyperkeratosis. It is important to rule out a squamous cell malignancy because they are alike. 


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


  • Surgical excision with supplementary cryotherapy.
    • This is the treatment because of the similarity with squamous cell malignancies.


The Keratoacanthoma is a variant of the 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

The 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

The 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. The most of the time they are asymptomatic or have a foreign body sensation.


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


  • Lubricant: If the patient is symptomatic you can use them, and some times short periods of steroids.
  • 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 can has a salmon-like color.


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.


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

Epithelial inclusion cyst

The epithelial inclusion cyst could be spontaneous or occur after inflammation, surgery or trauma. It has round form 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. at their clinical series of 1663 conjunctival tumors have four conjunctival keratotic plaque and four actinic keratosis, each representing less than 1% of the entire conjunctival tumor.

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 a lot similar to the conjunctival intraepithelial neoplasia (CIN).


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

The actinic keratosis also calls senile keratosis shows a similar histopathologic aspect with prominent keratosis and usually appears over a chronic inflammation like a pingueculum or pterygium.


  • Excision and supplementary cryotherapy: Because of the clinical similarity with CIN, the finding of leukoplakia in the conjunctiva is a relative indication of 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 do not have the potential of the metastasize, unlike the invasive squamous carcinoma. Some authors are talking about an 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 considerate the main predisposing factors for the conjunctival intraepithelial neoplasia. But nevertheless, in some CIN there is not be found the HPV with the polymerase chain reaction.

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

Clinical features

CIN is more common in elderly and immunosuppressed patients with with skin and considerable sunlight exposure, but children can develop it.

Conjunctival intraepithelial neoplasia could be a fleshy, sessile or minimally elevated lesion that frequently appears perilimbal in the interpalpebral zone or less commonly begins 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 it can have fine vascularization.


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


  • Excision with adequate margins: this is the first approach. Incomplete removal increases the recurrences.
  • Growth removal with alcohol corneal epitheliectomy, partial lamellar sclerokeratoconjunctivectomy and double freeze thaw cryotherapy: this is for more localized lesions.
  • Low dose irradiation with strontium-90
  • Chemotherapy: with topical mitomycin C for recurrent or persistent cases. Also interferon alpha-2b and 5-flourouracil are used.
  • Cidofovir

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 the underlying tissues.

The incidence of the conjunctival invasive squamous cell carcinoma varies from 0.02 to 3.5 per 100,000, it is less frequent than the 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 the HPV type 16.

Clinical features

Conjunctival invasive squamous cell carcinoma cannot be differentiated clinically from CIN. It occurs frequently in the interpalpebral region of Caucasian elderly or immunosuppresed 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 be necessary an enucleation. 


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


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.


  • Excision with adequate margins and double freeze thaw cryotherapy: this is the first approach. Incomplete removal increases the recurrences. If the lesion is large, adjuvent amniotic membrane grafting can be used.
  • Growth removal with alcohol corneal epitheliectomy, partial lamellar sclerokeratoconjunctivectomy and double freeze thaw cryotherapy.
  • Chemotherapy: with topical mitomycin C for recurrent or persistent cases. Also interferon alpha-2b and 5-flourouracil are used.
  • Cidofovir
  • Enucleation
  • Eyelid-sparing exenteration


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 this 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 presented in the caruncle and then it 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.


The histopathology of mucoepidermoid carcinoma shows an epidermoid component, mucin and a goblet cells with signet cells.  The pseudoadenomatous hyperplasia also have a goblet cells and mucin that why this is a differential diagnosis of the mucoepidermoid carcinoma. Other differential diagnosis is a primary mucoepidermoid carcinoma of the paranasal sinuses.

Spindle cell carcinoma

The 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.


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