docOphthalmic Pathology Specialty Conference USCAP 2015
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Ophthalmic Pathology Specialty Conference USCAP 2015
Ophthalmic Pathology Specialty Conference USCAP 2015 Fausto J. Rodriguez M.D. Department of Pathology & Sidney Kimmel Comprehensive Cancer Center Johns Hopkins University Nothing relevant to disclose Case History • 24 year-old male from Catania, Italy presenting with recurrent conjunctival abnormalities • The first set of biopsies were obtained from a "keratotic plate" in the limbal conjunctiva between 3 and 6 o'clock, as well as a separate lesion focally extending into the left cornea Diagnosis • Hereditary Benign Intraepithelial Dyskeratosis (HBID) Follow-up • Subsequent biopsies obtained from the right eye demonstrated identical histologic features Hereditary Benign Intraepithelial Dyskeratosis Hereditary Benign Intraepithelial Dyskeratosis • Also known as Witkop-von Sallmann syndrome, and ‘red eye disease’ • Presents with bilateral plaques involving the bulbar conjunctiva and oral cavity, usually with ocular injection • Leukoplakic quality and movable on physical examination • The ocular injection is secondary to hyperemic epibulbar blood vessels • Extent of involvement is variable, but may be prominent Hereditary Benign Intraepithelial Dyskeratosis • The lesions usually recur but have no malignant potential • Visual loss is rare, but may occur when there is extension to the corneal epithelium • Histologically, there is a recognizable keratin plaque composed of packed parakeratotic layers containing dyskeratotic keratinocytes • Round keratinocytes with eosinophilic cytoplasm and pyknotic nuclei are typical Hereditary Benign Intraepithelial Dyskeratosis • Subepithelial chronic inflammation may be present • Pathologic findings in the context of the clinical and family history are essentially diagnostic Hereditary Benign Intraepithelial Dyskeratosis • Inherited in an autosomal dominant fashion • Almost all cases have been described in Native Americans from North Carolina belonging to the Haliwa-Saponi tribe • Rare reports of HBID in patients without this background exist Affected • Genetic linkage analysis of two native American families • Locus for the putative gene located in chromosome region 4q35 • Altered in the form of a duplication Hereditary Benign Intraepithelial Dyskeratosis • 4q35 duplication also identified in an affected Caucasian boy • In a French Caucasian family with two individuals afflicted with HBID, there was a lack of 4q35 duplication • Rather a missense mutation in the NLRP1 gene (17p13.2) – Encodes for a member of the Ced-4 family of apoptosis proteins Hereditary Benign Intraepithelial Dyskeratosis Differential Diagnosis • The differential diagnosis of HBID, includes other squamous epithelial lesions, including actinic keratosis, pterygium, papilloma and conjunctival intraepithelial neoplasia (CIN) Differential Diagnosis Conjunctival Papilloma • Usually affects adults • Children may be affected, may be multiple • Strong association with HPV virus (~80%) • Predominantly low risk (6 and 11) HPV types Conjunctival Papilloma HPV 6/11 ISH Differential Diagnosis Conjunctival Papilloma Differential Diagnosis Pterigyum • Represents an ingrowth of conjunctiva into the corneal periphery • Often bilateral • Related to sun exposure • Usually benign, but may cause visual loss if it extends to the pupil • Dysplastic changes may develop rarely Differential Diagnosis Pterigyum Pterigyum Atypia Differential Diagnosis Genetic disorders • Xeroderma pigmentosum is an inherited syndrome associated with germline mutations in genes encoding for proteins involved in nucleotide excision repair • Develop a variety of cancers and intraepithelial lesions in sun exposed areas, including skin and conjunctiva • Oral lesions similar to HBID may occur in the context of other genetic disorders (Darier-White disease and the white sponge nevus of Canon) • Ocular involvement appears to be unique to HBID Differential Diagnosis Xeroderma Pigmentosum • Exposure to sunlight leads to an increased incidence of skin and mucous membrane cancer (BCC, SCC, melanoma) • Defects in DNA repair: Nucleotide Excision Repair (NER) mechanism Differential Diagnosis Xeroderma Pigmentosum XPD XP-D XP-C XP-C XP-D XP XP TTD XP DiGiovanna JJ and Kraemer KH. J Inv Dermatol (2012) Differential Diagnosis Conjunctival intraepithelial neoplasia • Main differential diagnosis of HBID involves conjunctival intraepithelial neoplasia (CIN) • Spectrum of disease ranging from mild dysplasia to squamous cell carcinoma • Usually sporadic and associated with increased sun exposure Conjunctival intraepithelial neoplasia Mild Dysplasia Conjunctival intraepithelial neoplasia Moderate Dysplasia Conjunctival intraepithelial neoplasia Severe Dysplasia asi Conclusions • HBID is a unique genetic disorder associated with pseudoneoplastic squamous lesions affecting the eye and oral mucosa • Strong association with specific ethnic group (HaliwaSaponi tribe), but may occur rarely in other populations • Prominent dyskeratosis typical histologic finding • Main differential diagnosis is conjunctival intraepithelial neoplasia (CIN) Questions?
