Section 2 -

Conjunctival Tumors Maria A. Saornil Ocular Oncology & Pathology Ocular Registry of Pathology "Miguel N Burnier Jr" Instituto Universitario de Oftalmobiología Aplicada Universidad de Valladolid Spain

1. Anatomy & Histology Conjunctiva is a mucous membrane that covers the anterior portion of the eye. It is composed of a non-keratinized stratified squamous epithelium with goblet cells, melanocytes and a stroma rich in vessels, lymphatic channels and contains associated lymphoid tissue (CALT). The junction between the conjunctiva and sclera is called limbus and contains stem cells that are capable to differentiate into conjunctival or corneal epithelium. There are special areas as plica semilunaris and caruncle containing epidermal appendages (hair follicles, sebaceous and sweat glands) where tumors from these structures can occur. Functions include contribution to the lacrimal film (mucinous component), a barrier to foreign bodies and infections, maintenance and healing of corneal epithelium (libel stem cells) and immune response (CALT). [1, 2, 3] 2. Epidemiology & Classification Conjunctival tumors are the most frequent ocular and adnexal tumors with eyelid tumors. They have a large spectrum of conditions ranging from benign lesions such as papilloma to visual- or life-threatening malignancies such as carcinoma or melanoma. [4, 5] They can arise from any conjunctival component although the most frequent are epithelial and melanocytic origin. Epithelial tumors are 30-50% of total showing higher prevalence in countries with high solar exposure. Pigmented tumors are about 40% and most of them are benign and affect white patients. [4, 5] In most of the cases clinical differential diagnosis among benign, premalignant and malignant lesions is difficult being the biopsy essential for accurate diagnosis and treatment. Conjuntival tumors classification Benign Premalignant Malignant Epithelial *Papiloma *Pseudoepiteliomatous Hyperplasia *Keratoacanthoma *Hereditary Benign Intrapithelial Dyskeratosis * Actinic Keratosis *CIN: Intraepithelial Neoplasia * Squamous Ca *Mucoepidermoid Ca *Basal cell Ca Melanocytic * Nevus without atypia * Racial Melanosis * Ocular Melanocytosis * Secondary Melanosis * Nevus with atypia * Primary adquired melanosis * Melanoma Adnexal * Oncocytoma * Pleomórphic Adenoma * Apocrine Adenoma * Sebaceous Adenoma/hyperplasia * Sebaceous Ca Soft Tissue * Pyogenic Granuloma * Hemangioma * Lymphangioma * Fibroma * Myxoma * Neurofibroma * Kaposi's Sarcoma * Fibrous histiocitoma * Rhabdomyosarcoma * Liposarcoma Lymphoid * Reactive Lymphoid hyperplasia * Lymphoma * Leukemia * Plasmacytoma 3. Epithelial Tumors Benign Squamous papilloma appears as a pink fibrovascular frond of tissue in a sessile or pedunculated configuration. It has been documented to be associated with human papillomavirus (subtypes 6,11,16 and 18).They can grow and often extend over the corneal surface. Histopathologically the lesion is composed of vascularized papillary fronds covered by acanthotic epithelium. [6] Pseudoepitheliomatous hyperplasia is an epithelial response to chronic conjunctival irritation or inflammation. Clinical and histologically can mimic a squamous cell carcinoma. It appears as a pinkish mass with leukoplakia. Histologically the lack of nuclear atypia accompanied by stromal inflammation differenciate the lesion from squamous cell carcinoma. [4, 5] Hereditary Benign Intraepithelial dyskeratosis is a rare condition, consistent with benign acanthosis of conjunctiva and oral mucous membranes with epithelial diskeratosis seen in African-American and native American (Haliwa Indians). It is an autosomal dominant disorder characterized by bilateral plaques on perilimbal conjunctiva. Histopathologically is characterized by acanthosis, dyskeratosis on surface and deep in the epithelium however basal membrane is intact and there is not nuclear atypia. [1, 5] Premalignant Actinic Keratosis is believed to be related to solar exposure. Usually develops slowly in the interpalpebral area overlying a preexisting pinguecula or pterygium. They are leukoplakic elevated plaques. Histologically are sharply demarcated plaques of acanthotic epithelium with parakeratosis and cytologic atypia over an elastotic degeneration in the stroma. [4, 7] Intraepithelial Neoplasia CIN (Dysplasia/carcinoma in situ) are one of the most frequent tumors of the ocular surface with an incidence 2 cases/100000 per year. It used to appear in older people but may appear in young immunosupressed patients and be bilateral. Clinically they are gelatinous interpalpebral lesions with tendency to superficial spread usually in the limbus and invading the cornea. [5, 8, 9]C linical appearance is the result of histologic changes consistent with variable hyperplasia with atypical cells that may replace the epithelium partially (dysplasia mild, moderate or severe) or totally (carcinoma in situ). [4, 7, 8] The risk of developing squamous carcinoma is low, but recurrences over the ocular surface and repeated surgeries and adyuvant therapies may damage the visual function. [10, 11, 12, 13] Malignant Squamous carcinoma is thedysplastic conjunctival epithelium that penetrates the basement membrane. The morphologic characteristics are similar to the skin squamous carcinoma and usually, it is a well-differentiated carcinoma with individual cell keratinisation. They used to appear as exophytic slow growing lesions at the limbus and tend to be only superficially invasive. Intraocular invasion may occur but is infrequent. Metastatic disease is rare. [7, 14] Spindle Cell carcinoma is a rare and more aggressive variant presenting as flat lesions simulating peripheral ulcers or pterigium. They are characteristically composed of spindle cell that resembles a sarcoma histopathologically. However, the cells show a transition between squamous to spindle shape, and small foci of individual keratinization are usually found within the neoplastic cells. Immunohistochemistry for cytokeratin can confirm the epithelial origin of this neoplasm. [4, 15] Mucoepidermoid carcinoma is anothertype composed of dfierent proportions of mucus secreting cells and squamous cells intermixed and sometimes resembles adenocarcinomas. They are uncommon, usually affect elderly individuals, and tend to be more aggressive invading the eye and the orbit. [1, 4] 4. Melanocytic Tumors Pigmented tumors arise from melanocytes of the epithelium and stroma. The most important ones include nevus, primary adquired melanosis and malignant melanoma. Clinical and histopathologic early identification are essential for diagnosis, treatment and to improve the prognosis of the patient. [16, 17, 18, 19, 20] Benign Nevus is the most common melanocytic tumor of the conjunctiva. It usually becomes clinically apparent in the first or second decade of life as a circumscribed flat interpalpebral lesion lightly pigmented containing cysts. Histopathologically is composed of nest of benign melanocytes located at the junction of the epithelial and subepithelial layers at birth or early infancy (junctional nevus). At the next stage of maduration nevus cells are present both within the epithelium as well as beneath the subepithelial space (compound nevus). This lesion may characteristically darken and enlarge with the onset of puberty and numerous cysts can be seen within the pigmented patch. Later the cells finish maduration process and completely abandoned the conjunctival epithelium (subepithelial nevus). [6, 18] Mature nevus use to remain stable during the adult life, and any change make the lesion suspicious of malignant transformation into melanoma (<1%). [1, 5, 18] Racial melanosis is a relatively common bilateral bulbar conjunctival pigmentation found in darkly pigmented individuals. Histopathologically, it is characterized by proliferation of benign appearing melanocytes in the basal layer of the epithelium. [1, 5, 18] Premalignant Primary Adquired Melanosis (PAM) is a benign lesion, but is the most frequent precursor for the development of conjunctival malignant melanoma. It is a proliferation of epithelial melanocytes usually unilateral, flat and multicentric and occurs in Caucasians patients in the fourth or fifth decade. The clinical course can last years, or even decades, which leads to a delay in diagnosis. Conjunctival biopsy is the only accurate method to categorize PAM. It can be classified in PAM without (low-risk to malignant transformation) or with (high-risk to malignant transformation) atypia. [16] The classification is histopathological (cannot be assessed clinically) and is based on the nuclear features of the melanocytes: PAM without atypia: histopathologically, there is proliferation of generally uniform dentritic normal appearing melanocytes confined to the basal epithelial layer. The risk of progressing to malignant melanoma is < 20%. PAM with atypia , however, presents with proliferating atypical melanocytes that assume a variety of cellular forms: polyhedral, spindle, large dendritic, and epithelioid cells. The cells percolate towards the conjunctival surface. The epithelial basement membrane remains intact. PAM with atypia carries a nearly 50% risk for ultimate evolution into malignant melanoma. If the lesion is too extensive to be excised, map biopsies are recommended: one biopsy at the transition between normal conjunctiva and PAM; one biopsy in the thickness area; and one biopsy elsewhere. Any area suspicious for melanoma should be excised. Periodic surveillance with conjunctival biopsies have been advocated as a preventive measure. Malignant Melanoma of the conjunctiva is a rare tumor (0.2 to 0.8 per million in white population) that can arise from preexisting primary acquired melanosis (75% of the cases), de novo without any apparent preexisting lesion, or from preexisting conjunctival nevi. [16, 20, 21] Malignant tumor cells penetrate the epithelial basement membrane and extend into the subepithelial layers, thus creating an enlarging painless nodule that can extend into the eye and orbit. Recurrence is very common and distant metastases are more frequent to ipsilateral facial lymph nodes, brain, lungs and liver. [21, 22, 23] Mortality due to metastatic spread of conjunctival malignant melanoma exceeds 25% after 10 years. [21, 22, 23] Factors that correlate with a poorer prognosis include: palpebral or fornical location, preexistent PAM with atypia featuring pagetoid extension, predominance of epithelioid cells, and tumor invasion deeper than 0.8mm. Treatment includes surgical excision with or without cryotherapy, radiotherapy, and exenteration. Adjuvant treatment with topical chemotherapeutic agents such as mitomycin C has been used successfully. [24, 25, 26, 27] 5. Lymphoid Tumors Lymphomas of the eye and ocular adnexa are rare and represents 2-8% of extranodal lymphomas. Patients with conjunctival involvement show a lower incidence of systemic lymphoma (20%) compared to those with orbit (35%) or eyelid (70%) infiltration, and they are bilateral in almost 40% of the cases. [28, 29] . Clinically lesions appears as a diffuse, pink subconjunctival mass ("salmon patch"), flat and slow growing, usually close to the fornix. It is imposible to differenciate clinically between a benign and malignant lymphoid tumor and a biopsy is necessary to stablish the diagnosis. Systemic work up should be done in all patients to rule out systemic disease. They are usually low-grade B-cell no-Hodking Lymphoma of mucosa-associated lymphoid tissue type (MALT). These lesions frequently are challenging to diagnose because biopsies are small and sometimes is difficult to distinguish between malignant and reactive processes and required experienced pathologists. [30] There are ancillary histopathological techniques to make the correct diagnosis, such as immunohistochemistry and flow cytometry Treatment include chemotheraphy if the patient has systemic lymphoma. In case of localized lesion low dose external beam irradiation, local interferon or observation can be considered. 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