Section 1 -

Tumors of the Eyelid Skin Adnexae Alexandre Nakao Odashiro Lac – Pathology Laboratory, Campo Grande , MS , Brazil Universidade para o Desenvolvimento do Estado e Região do Pantanal – UNIDERP Campo Grande, MS, Brazil Abelardo A. Rodríguez-Reyes, M.D Ophthalmic Pathology Service, Asociacion Para Evitar la Ceguera en Mexico' I.A.P. Hospital ''Dr Luis Sanchez Bulnes'', Mexico

Eyelid The eyelid is composed of skin externally and mucosa (the conjunctiva) on the inner surface apposed to the eye. Eccrine, apocrine glands (glands of Moll) and sebaceous glands (Zeis glands associated with the eyelash and the Meibomian glands embedded within the eyelid fibrous tarsus) populate the eyelid (Kumar et al., 2005). The most common malignancy of the eyelid is basal cell carcinoma followed by sebaceous carcinoma (Pereira et al., 2005b) . Squamous cell carcinoma, contrary to skin elsewhere, is only the third most common malignant lesion. Melanoma is rare in the eyelid (Cook and Bartley, 1999). We will address here the most important eyelid lesions. Lesions that affect the region of the face characterize some syndromes. In Cowden's syndrome, there are multiple trichilemmomas, follicular infundibular hyperplasia and keratoses (Ruhoy et al., 2004), which can all be found in the eyelids. Gorlin-Goltz syndrome (Basal cell nevus) affects 1 in 60.000 people in the 1st-3rd decade of life, and is characterized by multiple odontogenic keratocysts, basal cell nevi and basal cell carcinomoas, sebaceous cysts and skeletal abnormalities (Manfredi et al., 2004). Squamous Cell Carcinoma , unlike skin elsewhere, is the third most common malignant neoplasm of the eyelid, after basal cell and sebaceous carcinoma. Basal Cell Carcinoma (BCC) is the most common malignant neoplasm of the eyelid (90%) (Loeffler and Hornblass, 1990). The most important differential diagnosis is Sebaceous Carcinoma. The latter can mimic BCC clinically and histopathologically (see below). Sebaceous Adenoma is a rare benign neoplasm. It appears as a single, firm, yellowish nodule with a predilection for the eyebrow and eyelid. This neoplasm is associated with Muir-Torre syndrome, which is characterized by multiple sebaceous neoplasms, keratoacanthoma, and visceral carcinoma, especially of the colon (Rishi and Font, 2004). Histopathologically, lobules of sebaceous glands vary in size and shape and are composed of mature and immature sebocytes. It is reported that Muir-Torre syndrome is associated with the expression of DNA mismatch repair genes MSH2 & MLH1. The use of immunohistochemical and in situ hybridization techniques to diagnose these genes in Muir-Torre syndrome has been reported. The results are very encouraging but further evaluation is needed (Mathiak et al., 2002, Ponti et al., 2005). Sebaceous Carcinoma (SC) is the most important malignant neoplasm of the eyelid and the second most common eyelid malignant tumor (Pereira et al., 2005b). SC is very rare in the skin elsewhere. SC affects old patients and can affect immunosuppressed individuals (Stockl et al., 1995). It is a notorious masquerader that exhibits several clinical presentations and histological growth patterns, often delaying diagnosis for months to years (Pereira et al., 2005b). Clinical Features: It is more common in the upper lid and may simulate a chalazion or a cutaneous horn. Also, it may present as u nilateral conjunctivitis, blepharitis, meibomitis, or blepharoconjunctivitis – masquerade syndrome. From 1060 patients with clinical diagnosis of chalazion, there were 17 cases of malignant neoplasm, 14 of them were SC (Ozdal et al., 2004). Some cases of SC occurring in Muir-Torre syndrome have been reported. Histopathological Findings: Most of tumors are undifferentiated lesions, simulating basal cell carcinomas or squamous cell carcinomas. Pereira (Pereira et al., 2005b) reported the histopathological features of 44 cases of SC. Only 18% of the cases had a prominent sebaceous differentiation. 75% could be misdiagnosed as a squamous carcinoma and 15% had features similar to basal cell carcinoma. 32% of the tumors presented comedocarcinoma pattern of necrosis, similar to breast tumors. However, cytoplasmatic vacuoles were seen in 100% of the lesions, at least focally. Well-differentiated tumors are characterized by bizarre cells with vacuolated cytoplasm, showing invasiveness. Types of Spread: Other characteristic of this tumor is that the malignant epithelial cells may invade the epidermis, producing an overlying change that resembles Paget's disease – the intraepithelial mode of spread. It is necessary to obtain multiple biopsy specimens from the lid margin, as well as the palpebral and bulbar conjunctivas to determine the extent of intraepithelial involvement. Also, SC can spread as carcinoma in situ, simulating squamous carcinoma in situ. In such cases, bizarre cells with atypical mitosis, as well as vacuolated cells are helpful to make the correct diagnosis. Frozen sections stained with oil red O (lipid stain) is very helpful. However, in most cases, SC is only suspected after a preliminary histopathological examination, where red oil O is difficult to utilize. Immunohistochemistry Immunohistochemistry can be helpful to establish the diagnosis of SC, especially in the poorly differentiated lesions. Most of the SC is characteristically positive for BRST-1, CAM 5.2 and EMA. Basal cell carcinoma are negative for EMA, while squamous carcinoma is negative for CAM 5.2 (Sinard, 1999). BRST-2 is also positive in SC (Rodrigues et al., 1999). Proliferative markers, such as PCNA and P53, are also helpful as SC is a highly proliferative lesion. Prognosis: A worse prognosis is observed with a duration of symptoms more than 6 months, upper eyelid, and a maximal diameter 10 mm or more. Others factors include origin from the meibomian glands, infiltrative growth pattern, moderate to poor sebaceous differentiation, and invasion of lymphatic channels, vascular structures, and the orbit (Rao et al., 1982). The mortality rate associated with this tumor is about 14%. In summary, regarding SC, biopsies from elderly patients with upper eyelid lesions and/or recurrent chalazion should be carefully interpreted to rule out SC; SC should be considered in cases of non-classical basal cell carcinoma or squamous carcinoma in situ of the eyelid; immunohistochemical markers including BRST-1, EMA and CAM 5.2 are helpful in the differential diagnosis. Neurofibromas: cutaneous neurofibromas can occur in the eyelid, orbit and adjacent structures, as a manifestation of neurofibromatosis (NF) . Neurofibromas arise from the peripheral nerve sheaths and are composed by Schwann cells, endoneural fibroblasts, neurons, mast cells, and vascular elements (Sippel, 2001). Capillary Hemangioma: they are the most common soft tissue tumors of infancy and those involving the eyelid and orbit are a distinct clinical entity. The incidence in the general newborn population is between 1.0% and 2.6% (O'Keefe et al., 2003). Histopathological findings are similar to those found in the skin elsewhere. For large tumors, new therapeutic options include laser, intralesional and systemic corticosteroids. On the other hand, Cavernous Hemangioma occurs in adults . Kaposi Sarcoma (KS) : KS is the most common malignancy seen in HIV-infected patients. Ocular involvement is common, and may be seen in up to 1 in 5 patients with KS (Brun and Jakobiec, 1997). Ophthalmic lesions may be the initial clinical manifestation of KS. It c an affect the eyelid or the conjunctiva. Clinically, eyelid KS may mimic a hordeolum unresponsive to conventional therapy (Shuler et al., 1989). The histopathological findings are similar to KS in the skin elsewhere. Myxoma: is a rare tumor of the eyelid, and when multiple, a clinicians should raise the possibility of Carney's complex, a rare autosomal dominant disorder characterized by multiple cutaneous myxomas, mammary myxoma, cardiac myxoma, lentigines, endocrine overactivity, and psammomatous melanotic schwannomas (Yuen et al., 2005). Congenital Oculodermal Melanocytosis (Nevus of Ota) is a benign lesion that comprises dermal melanocytes, and is congenital or acquired during adolescence (Turnbull et al., 2004). It affects skin innervated by the first or second branch of the trigeminal nerve, hence, can be considered a type of blue nevus of the skin around the orbit, lids, and brow, usually associated with an ipsilateral blue nevus of the conjunctiva and a diffuse nevus of the uvea. It is common in blacks and Orientals (incidence of 0.2% to 1% in the Japanese population) and is rare in Caucasians (Turnbull et al., 2004). Although rare, this lesion can be the source for a melanoma (Odashiro et al., 2005a, Hartmann et al., 1989). Of the reported cases of oculodermal melanocytosis, 4.6 % underwent malignant transformation (Baroody and Holds, 2004). Malignant Melanoma m ay arise from a junctional, compound, or cellular blue nevus or may arise de novo. However, it is a rare neoplasm in the eyelid. The histopathological features are similar to skin melanoma elsewhere.