Nasreen A. Syed, MD F.C. Blodi Eye Pathology Laboratory University of Iowa

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1 Nasreen A. Syed, MD F.C. Blodi Eye Pathology Laboratory University of Iowa

2 No financial disclosures No discussion of off-label use of medications or unapproved devices

3 67 year old male referred to Oculoplastics service for cicatricial ectropion of the left upper eyelid Has been present for years Also diagnosed with ocular rosacea and episcleritis Visual acuity: Right: 20/20 Left: 20/40

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7 Clinical impression Consistent with ocular cicatricial pemphigoid (OCP) Conjunctival biopsy performed on the left 1 piece for permanent sections 1 piece for direct immunofluorescence

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11 Sebaceous glands Holocrine gland Produces sebum fat, fatty acids, cholesterol Ocular adnexal sebaceous glands Meibomian glands Glands of Zeis sebaceous glands associated with eyelashes Eyelid skin vellus pilosebaceous units Caruncle pilosebaceous units Eyebrow large number of large pilosebaceous units

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16 Clinically sebaceous carcinoma is often mistaken for other pathology Chalazion Blepharitis Ocular cicatricial pemphigoid due to symblepharon (scarring of conjunctiva resulting in fusion of eyelid to globe) Other type of malignancy Loss of eyelashes (madarosis) can be a clue May take months to years to make an accurate diagnosis Requires an index of suspicion

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22 Sebaceous carcinoma can arise in any of the sebaceous glands in the ocular adnexa Origin from meibomian glands is slightly more common Lipid peroxidation has been postulated to play a role in carcinogenesis Unknown if ultraviolet exposure plays a role in carcinogenesis More commonly occurs in the upper eyelid More meibomian glands in upper eyelid May be present in Muir-Torre syndrome

23 Though arising from the sebaceous gland, sebaceous malignancies do not often demonstrate adenomatous differentiation Can be well-differentiated but often have the appearance of a poorly differentiated carcinoma Can masquerade as a SCCA Cells often have pleomorphic hyperchromatic nuclei Variable sebaceous differentiation Foamy cytoplasm similar to a mature sebocyte May have nuclear vacuoles of lipid

24 Sebaceous carcinoma has a predilection for spreading in a pagetoid or in situ fashion Often spreads throughout conjunctival epithelium from palpebral to bulbar conjunctiva Often, there are skip areas areas of malignancy separated by normal epithelium Can occasionally spread into the nasolacrimal drainage system The propensity of sebaceous CA to spread intraepithelially may lead to multifocal invasive foci of tumor

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28 Pagetoid spread

29 In situ spread

30 Oil-red-O can be done if wet tissue is available to demonstrate lipid in tumor Can set aside a small amount of wet tissue if there is a clinical suspicion

31 Use of immunohistochemistry to aid in the diagnosis of sebaceous carcinoma 1999, Sinard, Arch Ophthalmol Compared antigenic characteristics of eyelid carcinomas: Sebaceous CA 11 cases Basal cell CA 16 cases Squamous cell CA 14 cases Antibodies used: Cytokeratins AE1/AE3 Epithelial membrane antigen (EMA) CAM5.2 (CK8) BRST-1

32 Use of immunohistochemistry to aid in the diagnosis of sebaceous carcinoma (Sinard) Results: Cytokeratins AE1/AE3 positive in all tumors EMA positive in 10/11 (91%) seb CA, 11/14 (79%) SCCA, 1/16 (6%) BCCA CAM5.2 (CK8) positive in 8/11 (73%) seb CA, 0/14 SCCA, 7/16 (44%) BCCA BRST-1 positive in 7/11 (64%) seb CA, 5/14 (36%) SCCA, 0/16 BCCA

33 Use of immunohistochemistry to aid in the diagnosis of sebaceous carcinoma (Sinard) Conclusions EMA + CAM5.2 (CK8) are helpful in distinguishing seb CA from BCCA and SCCA OR BRST-1 + CAM5.2 (CK8) are helpful in distinguishing seb CA from BCCA and SCCA EMA may be helpful in identifying pagetoid areas of intraepithelial tumor

34 Use of immunohistochemistry to aid in the diagnosis of sebaceous carcinoma Univ. of Iowa experience Cases of Seb CA, BCCA and SCCA with pathology between 1997 and 2007 Seb CA: n = 20 BCCA: n = 22 SCCA: n = 15

35 Use of immunohistochemistry to aid in the diagnosis of sebaceous carcinoma UI Antibodies used: BerEP4 BRST2 (GCDFP) CEA CK7 CK8 (CAM5.2) CK20 EMA Her-2 (C-erb-2) HMFG-1 HMFG-2

36 Use of immunohistochemistry to aid in the diagnosis of sebaceous carcinoma UI Results:

37 Use of immunohistochemistry to aid in the diagnosis of sebaceous carcinoma UI Conclusions Statistically, Her-2 (C-erb-2) and HMFG-2 are more often positive in Seb CA than in BCCA or SCCA. Seb CA vs. SCCA: Seb CA = BerEP4 + / CK7 + / CK8 + / Her-2 + / HMFG-1 + Seb CA vs. BCCA: Seb CA = EMA + / Her-2 + / HMFG-1 + / HMFG-2 +

38 Adipophilin (2014, Milman, et al) is positive in 100% of sebaceous carcinomas (primary tumor) Androgen receptor Has been shown by multiple groups as an immunohistochemical marker that is specific for sebaceous CA (when compared to BCCA and cutaneous SCCA) Use as part of a panel including Ber-EP4, EMA & adipophilin May play a role in prognosis in sebaceous CA (2014, Mulay et al)

39 Oil-red-O is a messy stain that can be difficult to read CK7 is not useful in the conjunctival epithelium since normal epithelium is CK7 positive (unlike epidermis) HMFG-2 is not readily available commercially Adipophilin requires grading of staining intensity and percentage of cells (compared to BCCA, cutaneous SCCA) to determine positivity Adipophilin will not always be positive in conjunctival intraepithelial sebaceous CA

40 Initial biopsy Conjunctival/skin map biopsies Evaluation of any suspicious lymph nodes Sentinel lymph node biopsy Oncology evaluation for other sites of metastasis lung, liver, bone marrow

41 Conjunctival map biopsies:

42 Retrospective analysis of map biopsies for sebaceous carcinoma of the ocular adnexa (2015, Univ. of Iowa) 45 patients 429 conjunctival map biopsies 30% of biopsies were positive No statistical relationship between location of primary mass and positivity of map biopsies In nodular (solitary mass) tumors, clinical diagnosis of conjunctival intraepithelial involvement was incorrect in 44% of biopsies

43 Conjunctival map biopsies:

44 Sebaceous carcinoma can be a challenging diagnosis both clinically and histopathologically There is no perfect stain to make the diagnosis The conjunctiva is very often involved in sebaceous carcinoma Map biopsy of the conjunctiva is essential for staging of the tumor