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Tumors of conjunctiva and cornea Dr. Aric Vaidya BPKIHS, Dharan, Nepal Introduction • Ocular surface composed of conjunctiva and cornea • Conjunctiva -mucous membrane which covers globe and inner part of eyelids • Nonkeratinized stratified epithelia • Goblet cells - 10% of basal cells of conjunctival epithelium Introduction • Cornea -transparent, avascular tissue • Corneal epithelium -stratified squamous epithelial cells • Corneal epithelial stem cells give rise tosuperficial cells • Regulation of cell growth and metabolism are critical Conjunctiva Cornea Introduction • Primary tumors of conjunctiva and cornea grouped into: 1. Congenital 2. Acquired Classification 1)Tumors of epithelial origin 2)Glandular tumors of conjunctiva 3) Tumors of Neuroectodermal origin 4)Vascular and Mesenchymal tumors 5)Lymphatic and lymphocytic tumors 6)Metastatic tumors Classification 1)Tumors of epithelial origin: • Benign: – Papilloma – Inclusion cysts – Pseudoepitheliomatous hyperplasia – Benign hereditary intraepithelial dyskeratosis • Preinvasive: – Conjunctival and corneal intraepithelial neoplasia • Malignant: – Squamous cell carcinoma – Mucoepidermoid carcinoma 2)Glandular tumors of conjunctiva: – Oncocytoma – Sebaceous gland carcinoma 3) Tumors of Neuroectodermal origin: • Benign pigmented lesions: – Congenital epithelial melanosis – Benign melanosis – Ocular melanocytosis – Nevus • Preinvasive pigmented lesions: – Primary acquired melanosis(PAM) • Malignant pigmented lesions: – Melanoma Classification 4)Vascular and Mesenchymal tumors: • Benign: – Hemangioma – Inflammatory vascular tumors • Malignant: – Kaposi sarcoma 5)Lymphatic and lymphocytic tumors: – Lymphagiectasia and lymphangioma – Lymphoid hyperplasia – Lymphoma 6)Metastatic tumors Ocular Surface Squamous Neoplasia(OSSN) Classification of Ocular Surface Squamous Neoplasia(OSSN) Benign Preinvasive Malignant Papilloma Conjunctival and corneal intraepithelial neoplasia grades I-III Squamous cell carcinoma Pseudoepitheliomatous hyperplasia Benign hereditary intraepithelial dyskeratosis Mucoepidermoid carcinoma Introduction • Lee & Hirst, 1995 -term “Ocular surface squamous neoplasia” (OSSN) • Denote a spectrum of neoplasm originating from squamous epithelium • Relatively high recurrence after treatment and may metastasize • Considered as a low grade malignancy but invasive lesion can spread to globe or orbit Epidemiology • Uncommon disease with geographic incidences vary from 0.2 to 3.5 per 100,000 • Greater frequency near the equator (Lee & Hirst 1995) • Predominantly in elderly - third most common oculo-orbital tumor • Rare in the United States, with an incidence rate of 0.03 per 100,000 persons • Approximately 5-fold higher in males and Caucasians (Sun et al. 1997) Pathogenesis • Specific etiologic factors yet to be known • Main associated factors – exposure to ultraviolet (UV) radiation – human papilloma virus infection and – human immunodeficiency virus (HIV) seropositivity – immunosuppression Pathogenesis • Ultraviolet (UV) B radiation: – incidence rate -increased with proximity to equator – incidence of squamous cell carcinoma(SCC) declined by 49% for each 10 degree increase in latitude – SCC decreased by 29% per unit reduction in UV exposure. (Newton et al. 1996) – Lesions - often found at corneal limbus in interpalpebral area Pathogenesis • Ultraviolet (UV) B radiation: – role of limbal stem cells in development of OSSNcontroversial – mutations in the P53 tumor suppressor gene (TP53 gene) – Stimulates expression of some proteolytic enzymes, such as MMPs and their tissue inhibitors (TIMPs) Pathogenesis Human Papilloma Virus: – role not clear – low risk HPV type 6 and 11 • a/w conjunctival papilloma – high risk HPV type 16 and 18 • commonly found in high grade dysplasia, or invasive squamous cell carcinoma – several studies have failed to demonstrate HPV in malignant conjunctival epithelial tumors Pathogenesis Human Immunodeficiency virus: – OSSN- now recognized as an AIDS-related cancer – occurred earlier in HIV-infected individuals – increased prevalence of HIV among patients with CIN -younger than 50 years – tissue analysis in HIV patients identified multiple oncogenic viruses Pathogenesis • Immunosuppression : – localized immune suppression of skin from sun damage may lead to • increased susceptibility to HPV infection – immunosuppressed cancer patients and organ transplant patients – after corneal graft • due to local immunosuppression, HPV, or possibly that neoplastic cells in donor corneal epithelia • Other factors: – old age, male sex , and fair skin pigmentation – heavy cigarette smoking, exposure to petroleum products – genetic conditions like xeroderma pigmentosum Clinical manifestations • Conjunctival papilloma • Conjunctival intraepithelial neoplasia (CIN) • Squamous cell carcinoma Conjunctival papilloma • Pedunculated: – HPV, type 6 or 11 – Fleshy, exophytic growth with fibrovascular core – Originates from a stalk with multilobulated appearance – Smooth, clear epithelium and small corkscrew vessels – Inferior fornix, tarsal or bulbar conjunctiva – May be multiple –more in HIV pts Conjunctival papilloma • Sessile – HPV, type 16 or 18 – More likely dysplastic or carcinomatous – Limbus – Flat base with glistening surface and numerous red dots Conjunctival papilloma • Signs of dysplasia: – Keratinization – Symblepharon formation – Inflammation – Invasion Treatment Pedunculated: – – – – – – Most regress spontaneously Observation Cryotherapy alone Excision with cryotherapy to base Excision with adjunctive application of IFN-alpha 2b Frequent recurrences • Sessile: – Observed closely or excised – Excisional biopsy with adjunctive cryotherapy Conjunctival intraepithelial neoplasia(CIN) 3 clinical variants: – Papilliform –sessile papilloma harboring dysplastic cells – Gelatinous –result of acanthosis and dysplasia – Leukoplakic –hyperkeratosis, parakeratosis, and dyskeratosis CIN CIN • Mild inflammation and abnormal vascularization • Classification: – Mild dysplasia or CIN 1 – Moderate dysplasia or CIN 2 – Severe dysplasia or CIN 3 – Carcinoma-in-situ • Slow growing tumors • Potential to spread to other ocular surfaces Management Management Squamous cell carcinoma(SCC) • Final stage of this tumour • Dysplastic epithelium invade beyond basement membrane • Larger and more elevated than CIN • Pathogenesis: – Risk factors: UV radiation, viral, genetic – More common and aggressive in: • HIV • Xeroderma pigmentosa scc Clinical features • Broad based lesion at or near limbus in interpalpebral fissure • Grow outward with sharp borders • Can be leukoplakic • Usually remains superficial rarely penetrating sclera or Bowman’s layer Clinical features • • • • Pigmentation in dark-skinned patients Engorged conjunctival vessels feeding tumor Locally invasive and can metastasize Intraocular invasion a/w – iritis, glaucoma, retinal detachment, or rupture of the globe • Regional lymph nodes Investigations and diagnosis • Clinical feature of lesion • Assessment of extension of lesions : – Intraocular invasion – Orbital invasion- CT scan or MRI – Regional lymph node spread • Pathologic diagnosis: – Gold standard for definite diagnosis -tissue histology – Incisional or excisional biopsy • Cytology Histology Management • Complete local excision – 4 mm beyond clinically apparent margins – Thin lamellar scleral flap beneath tumor • • • • Absolute alcohol to remaining underlying sclera Adjunctive cryotherapy to margins Risk of recurrence related to surgical margins Extensive external spread – Orbital exenteration and possible radiation therapy Nevus • • • • • Most common melanocytic conjunctival tumor Malignant transformation - 1% Presentaion- 1st to 2nd decades Most common site- juxtalimbal area Histology- similar to cutaneous nevi except no dermis • Types– Junctional – Compound – Subepithelial Nevus Nevus • Flat near limbus, elevated elsewhere • Pigmentation variable • Signs of malignancy • Rapid enlargement at puberty • Management : – Excision of suspicious lesions – Excise nevi on palpebral or forniceal conjunctiva Dermoid Epibulbar Dermoid Tumor: • 1 in 10,000 individuals • Pathogenesis – Displaced embryonic skin tissue – Composed of fibrous tissue, hair with sebaceous glands – Covered by conjunctival epithelium Dermoid • Clinical features: – Well-circumscribed, solid, smooth, porcelain white – Round to oval elevated lesion embedded in superficial sclera or cornea – Most common in infertemporal limbus – Arcus-like deposit of lipid along anterior corneal border – Corneal astigmatism –anisometropic amblyopia Treatment • No malignant potential • Lesion often extends deep into underlying tissues • Elevated portion may be excised • Relaxing incision • For cosmetic appearance • Amblyopia treatment Lipodermoid: • Found at limbus or outer canthus • Appears as soft, yellowish white, movable subconjunctival mass • Consists of fatty tissue and surrounding dermis-like connective tissue • May be a/w accessory auricles and other congenital defects (Goldenhar's syndrome) Pyogenic granuloma • Common reactive hemangioma • Misnamed –not suppurative, no giant cells • May occur – Over chalazion – Minor trauma – Post op granulation tissue • Rapidly growing red, pedunculated, smooth lesion • Bleeds easily and stains with fluorescein dye Pyogenic granuloma • Management: – Topical steroids – Resistant cases- surgical excision Kaposi sarcoma • Malignant neoplasm of vascular endothelium • Involves skin, mucous membrane and internal organs • Pathogenesis: – Infection with HHV-8 – Occurs in setting of AIDS Kaposi sarcoma • Clinical findings: – Reddish, highly vascular subconjunctival lesion – Can be mistaken for subconjunctival hemorrhage – Orbital involvement –lid and conjunctival edema – Inferior fornix most common – Nodular or diffuse Kaposi sarcoma Management : • Treatment may not be curative • Nodular lesions less responsive to therapy • Surgical debulking • Cryotherapy • Radiotherapy • Local or systemic chemotherapy • Intralesional interferon alpha-2a - effective Primary Acquired Melanosis(PAM) • Preinvasive intraepidermal lesion of sun-exposed skin • Flat, brown noncystic lesions of conjunctival epithelium • PAM associated with cellular atypia – progress to melanoma in ~ 46% Primary Acquired Melanosis(PAM) • Pathogenesis: – Abnormal melanocytes proliferate in basal conjunctival epithelium – Malignant transformation • nodularity, enlargement or increased vascularity • Management : – Excisional biopsy – All palpebral pigmented lesions should be excised – Lesions that show atypia • Adjunctive cryotherapy • Mitomycin-C – Check regional lymph nodes Melanoma • 2% of all ocular malignancies • Prevalence: – ~ 1 per 2 million in population of European ancestry – Rare in blacks and Asians • Better prognosis than cutaneous melanoma Melanoma Pathogenesis : – Arise from acquired nevi, PAM, or normal conjunctiva – Malignant transformation of congenital conjunctival nevus -rare – Intralymphatic spread increases risk of metastasis – Underlying ciliary body melanoma can extend through sclera – Cutaneous melanoma -rarely metastasize to conjunctiva Melanoma Clinical features: • Most common on bulbar conjunctiva or at limbus • Variable pigmentation • Highly vascularized –bleed easily • Grow in nodular fashion • Can invade globe or orbit Melanoma Melanoma • Outcome: – Bulbar melanomas -better prognosis than those on palpebral conjunctiva, fornix, or caruncle – Metastasis in ~ 26% • Cytologic risk factors for metastasis: – Large size, multicentricity, – Epithelioid cell type, lymphatic invasion • Can metastasize to regional lymph nodes, brain, and other sites Melanoma Management: – Excisional biopsy – Excision of conjunctiva 4mm beyond clinically apparent margins – Excision of thin lamellar scleral flap beneath tumor – Treat remaining sclera with absolute alcohol – Cryotherapy to conjunctival margins – Primary closure or conjunctival/amniotic membrane graft – Topical MMC –for residual disease – Orbital exenteration–advanced disease or palliative Rx Melanoma • Prognosis : – Overall mortality 12% at 5 years and 25% at 10 years – Poor prognostic factors: • • • • • • • Invasion into deeper tissues Multifocal tumors Extralimbal tumors Thickness >1.8 mm Involvement of eyelid margin Recurrence Lymphatic or orbital spread Summary • Ocular surface composed of conjunctiva and cornea • Various benign and malignant tumors involving ocular surface • OSSN denotes a spectrum of neoplasms originating from squamous epithelium • Nevus -most common melanocytic conjunctival tumor • Surgical excision along with various adjuvant therapies are modalities of management Bibliography • American Academy of Ophthalmology, BCSC, section 8, 2013-2014 • Albert Jakobiec’s Principles and Practice of Ophthalmology Third edition. Part2: Volume 1, Section 6- cornea and conjunctiva • Clinical Ophthalmology A Systematic Approach Jack J Kanski ,7th edition • Myron Yanoff & Jay Duker Ophthalmology,3rd edition,2009. Thank you