Introduction
In general, papilloma is a histopathological
term describing tumours with specific morphology. They take on a classic fingerlike or cauliflowerlike appearance. Papillomatous lesions often are lobulated with a central vascular core. Irrelevant of its cytology, a neoplasm of epithelial origin with this form of growth also is called papilloma. Papillomas can be benign or malignant and can be found in numerous anatomical locations (e.g., skin, conjunctiva, cervix, breast duct). Specifically, conjunctival papillomas are benign squamous epithelial tumours with minimal propensity toward malignancy.
Conjunctival papillomas are categorized into infectious (viral), squamous cell, limbal, and inverted (histological description) based on appearance, location, patient’s age, propensity to recur after excision, and histopathology. They demonstrate an exophytic growth pattern. Interestingly, inverted papillomas exhibit both exophytic and endophytic growth patterns.
Conjunctival papilloma also can be classified based on gross clinical appearance, as either pedunculated or sessile. The pedunculated type is synonymous with infectious conjunctival papilloma and squamous cell papilloma. The limbal conjunctival papilloma often is referred to as the noninfectious conjunctival papilloma because it is believed that limbal papillomas arise from UV radiation exposure. Because of its gross appearance, limbal papillomas are typed as sessile. Although rare, inverted conjunctival papillomas sometimes are referred to as mucoepidermoid papillomas because these lesions possess both a mucous and an epidermoid component.
A strong association exists between human papilloma virus (HPV) types 6 and 11 and the development of conjunctival papillomas. Infectious conjunctival papillomas also are known as squamous cell papillomas. This term arises from its histopathological appearance (i.e., the lesion is confined to the epithelial layer, which is acanthotic).
Pathophysiology
HPV and polyomavirus are members of the Papovavirus family. These viruses are small (55 nm), naked, and icosahedral with circular double-stranded DNA. Papilloma viruses exhibit site and cell-type specificity, as follows:
- HPV 6 and 11 – Benign skin warts or condylomas of the female genital tract and conjunctival papilloma
and conjunctival papilloma
- HPV 16 and 18 – Cervical carcinoma
Transmission is via direct human contact. Proliferation of dermal connective tissue is followed by acanthosis and hyperkeratosis. HPV is tumorigenic, and it commonly produces benign tumours with low potential for malignancy. In general, prolonged proliferation may lead to cellular atypia and dysplasia.
Frequency
Literature reviewed yielded no published study outlining the prevalence of conjunctival papillomas in a cross section of a population. Interestingly, studies are numerous for extraocular sites. Prevalence of conjunctival papillomas ranged from 4-12%. A strong association exists between HPV and squamous cell papilloma. Moreover, the HPV genome is identifiable in most conjunctival papillomas and in 85% of conjunctival dysplasias and carcinomas.
Although no cross-section epidemiological studies are available, evidence suggests that people without overt clinical presentation may harbour the virus, and HPV DNA can be identified in asymptomatic conjunctiva. HPV types 6 and 11 are the most frequently found in conjunctival papilloma. A recently published paper reported that HPV type 33 is another source in the pathogenesis of conjunctival papilloma. HPV types 16 and 18 commonly are associated with not only high-grade cervical intraepithelial neoplasia and invasive carcinoma but also squamous cell dysplasia and carcinoma of the conjunctiva. The recurrence rate for infectious papillomas is high. Limbal papillomas have a recurrent rate of 40%.
Prognosis
Conjunctival papillomas (squamous cell, limbal, or inverted) are not life threatening. Conjunctival papillomas may be large enough to be displeasing or cosmetically disfiguring. HPV types 6 and 11 may be transferred to the child during parturition from an infected birth canal resulting in ocular symptoms.
Squamous cell papilloma, which has an infectious viral aetiology, has the propensity to recur after medical and surgical treatment. New and multiple lesions may arise after excision. Recurrent conjunctival papillomas may extend into the nasolacrimal duct causing obstruction. Lauer et al and Migliori reported a case of nasolacrimal duct obstruction after extension of the papillomas into the lacrimal sac. Most papillomas are benign. Rarely, they can undergo malignant transformation, signs of which include inflammation, keratinization, and symblepharon formation.
Age
Squamous cell papillomas (i.e., infective papilloma, viral conjunctival papilloma) are seen commonly in children and young adults, usually younger than 20 years. Because HPV is associated strongly with this form of papilloma, siblings, including twins, also may be affected. Limbal papillomas are seen commonly in older adults. A slight association exists between UV radiation and limbal conjunctival papilloma.
Case Report
A 9 year male child came with history of swelling and redness foreign body in left eye since 6 month. There was no history of any injury, diminution of vision. No history of any systemic illness. No history of similar complaints in sibling. No history of similar complaints in past. Birth history was full term normal vaginal delivery.
On examination best corrected visual acuities in both eyes were 6/6, right eye was normal, left eye lids were normal. A solitary, greyish red colour lesion seen on temporal area of conjunctiva. It was situated 2 mm away from limbus with irregular surface, about 2 x 1 mm in size, with well defined margin, mass was soft in consistency. Cornea was clear and IOP and EOM was normal fundus was also normal. A patient had taken conservative medical treatment in private hospital but lesion was not regressed so excision biopsy was done. Histopathological report confirmed squamous cell papilloma on 3 month follow up there was no signs of recurrence.
Discussion
History
General approach
- A good ocular history is not only essential but also critical in making the correct diagnosis.
- Knowing the patient’s age and the anatomical location of the tumour or tumourlike lesion (e.g., inverted papillomas [Schneiderian or mucoepidermoid papillomas] typically involve the mucous membrane of the nose, paranasal sinuses, and lacrimal sac) is helpful for the ophthalmologist. The conjunctiva rarely is affected.
- A change in size and shape should raise the index of suspicion for a possible neoplastic proliferation. However, other reasons may contribute to the change in size. Cystic lesions may increase in size secondary to accumulation of fluids and/or acellular debris. An inflammatory response may cause a benign lesion to increase in size.
- Most conjunctival tumours are isolated lesions. However, in a small percentage, conjunctival lesions may be an extension of systemic disease (i.e., Lhermitte-Duclos disease, Cowden syndrome).
- A history of congenital, bilateral, or multifocal conjunctival lesions strongly suggests an underlying systemic disease. Therefore, a profound systemic workup is warranted.
History associated with conjunctival papilloma
- Squamous cell papilloma
- Usually seen in younger patients
- History of maternal HPV infection at the time of parturition
- A past history of tumour excision with recurrence
- Refractive to past medical and surgical treatments
- No decrease or loss of visual acuity
- A history of a sibling with the same condition
- A history of cutaneous warts at extraocular sites
- Limbal papilloma
- Seen in older adults
- History of UV exposure
- Possible decrease or loss of visual acuity
- Recurrence after excision, not common
- History of chronic conjunctivitis refractive to medications
Physical
Key features to assist an ophthalmologist in examining a surface tumour include the following:
Tumour location: Knowing the probability of finding a tumour in a specific anatomical location greatly assists the ophthalmologist not only in making the diagnosis but also, and more importantly, in prioritizing the differential diagnosis.
- Approximately 25% of all lesions involving the caruncle are papillomas.
- Squamous cell carcinoma is seen commonly in the interpalpebral zone adjacent to the limbus and rarely appears elsewhere. Although possible, a diagnosis of squamous cell carcinoma would be questionable if remote from the limbus.
Tumour colour:Tumour colour provides important clues and clinical judgement based on the following
- Pigmented lesions suggest a melanocytic origin.
- Salmon-coloured lesions are associated with lymphoid tumours.
- Pale or dull yellow lesions are associated with xanthomas.
Tumour topography : In evaluating, attention should be made to the tumour’s surface, to include the tumour’s texture and edge.
- The conjunctiva surface appearance is altered predictably in epithelial tumours (i.e., the surface epithelium is raised, cobblestone, and/or acanthotic).
- In differentiating from epithelial tumours, tumours arising from the substantia propria tend to have a smooth epithelial surface.
- Tumour edges between normal and diseased conjunctiva may appear abrupt, as seen in conjunctival papilloma or conjunctival intraepithelial neoplasia (CIN).
- In cases where the edges are ill defined, lymphoid tumours should be considered.
Tumour growth pattern : The pattern of growth may be described as solitary, diffuse, or multifocal.
- Solitary growth is seen in conjunctival papilloma.
- Diffuse growth, although rare, is associated with conjunctival intraepithelial neoplasia, sebaceous carcinoma (pagetoid spread), lymphoma, and reactive lymphoid hyperplasia.
Tumour consistency : The tumour consistency can be described as solid, soft, or cystic.
- Tumour consistency is established by palpation, which is useful in evaluating and diagnosing subepithelial tumours.
- Palpation is performed under topical anaesthesia during the slit lamp examination, using a cotton-tip applicator.
- This technique is beneficial in determining whether an epithelial tumour has invaded the underlying supporting tissue. Most papillomas are freely mobile over the sclera. An epithelial tumour that has already invaded the underlying connective tissue will feel fastened to the globe when tenderly pushed from side to side.
Clinical signs associated with squamous cell papilloma (infectious papilloma) are as follows:
- This is a benign and self-limiting lesion.
- It is seen commonly in children and young adults.
- Most lesions are asymptomatic without associated conjunctivitis or folliculitis.
- Anatomically, it commonly is located in the inferior fornix, but it also may arise in the limbus, caruncle, and palpebral region.
- The lesion may be bilateral and multiple.
- Grossly, squamous cell papilloma appears as a grayish red, fleshy, soft, pedunculated mass with an irregular surface (cauliflowerlike).
Clinical signs associated with limbal papilloma are as follows:
- Typically, this is a benign lesion.
- It is seen commonly in older adults.
- Anatomically, the lesion commonly occurs at the limbus or the bulbar conjunctiva.
- These lesions may spread centrally toward the cornea or laterally toward the conjunctiva.
- Visual acuity may be affected if the lesion grows centrally.
- These lesions almost always are unilateral and single.
- They tend to have variable proliferation potential with a tendency to slowly enlarge in size.
Clinical signs associated with inverted conjunctival papilloma are as follows:
- l This lesion is slow growing and is seen commonly in the nose, paranasal sinuses, or both. The lacrimal sac and the conjunctiva are uncommon sites.
- The lesion is unilateral, unifocal, and does not recur after surgical excision.
Differentials Diagnosis
- Ichthyosis
- Sebaceous Gland Carcinoma
- Squamous Cell Carcinoma, Conjunctival
Other Problems to be Considered
- Conjunctival intraepithelial neoplasia
- Amelanotic melanoma
- Lhermitte-Duclos disease
- Cowden syndrome
Management
Observation
Some squamous cell papilloma may regress
Medical Treatment
- Steroid
- Sub conjunctival interferon a, topical mitomycin C for recurrence
- Oral cimetidine
Surgical treatment :
- Cryotherapy
- Excision biopsy
Procedures
Biopsy (incisional or excisional) is a reasonable and safe method that aids in obtaining a definitive diagnosis. Indications for a biopsy are as follows:
- To rule in or to rule out the possibility of malignancy
- For lesions not obviously benign (symptomatic and/or show growth)
- For neoplasm suggestive of malignancy (HIV-positive patients or chronic unilateral conjunctivitis unresponsive to therapy)
- Therapeutic decision
- To determine the surgical margin in ill-defined lesions
- To exclude the possibility of recurrent neoplastic changes
- To harvest tissue for special studies (i.e., flow cytometry)
Frozen section
- The most common indication for a frozen section is to determine whether surgical margins are free of tumour (i.e., to assess the adequacy of tissue excision).
- A frozen section should not be used for “on-the-spot” diagnosis, since frozen tissue rendered tissue morphology is less optimal for microscopic examination.
- Invasive disease can be excluded, but intraepithelial lesions may not.
- Conjunctival tissue tends to curl after excision; therefore, it is best to examine after fixation and inking the borders. After obtaining the biopsy, place the tissue flat on a piece of firm paper/cardboard before placing in fixation medium.
Surface tissue sampling
- Exfoliative cytology (tissue scraping)
- This technique is used commonly to aid in the diagnosis of cervical disease. However, this technique and its role in aiding the ophthalmologist in diagnosing ocular surface lesions are less well defined.
- Major limitations include the possibility of false-negative results and its inability to determine the depth of invasion.
- Most benign and inflammatory lesions cannot be identified precisely by cytologic methods.
- It is useful as a guide for where to do biopsy or resect ill-defined conjunctival lesions.
- Impression cytology
- Another technique for collecting surface cells, impression cytology uses a cellulose acetate filter paper. When the filter paper is placed in direct contact with the surface cells, the cells adhere to the paper.
- Impression cytology is less traumatic than exfoliative cytology.
- Intracellular structures are better preserved than with exfoliative cytology.
Limitations are similar to exfoliative cytology; both are not appropriate for identifying intraepithelial tumours (Fig. 1).
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| Fig.1 : Conjunctival Papilloma |
References
- John W. Gittinger Jr. Manual of clinical problems in Ophthalmology. Little Brown and Co. Boston Toronto 1996: 10-12.
- Crausford J, Brooks. Conjunctival tumour in Ophthalmology. Ed Thomas D\Buabe 1982; 4 : 10.
- Lauer SA. Human Papilloma virus type 18 in conjunctival. Neoplasia. Am J Ophthalmology 1990; 110 : 23-7.
- Odnch MGA. Spectrum of bilateral squamous conjunctival tumour associated with human papilloma virus. Type 16, Ophthalmology 1991; 98 : 628-35.
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