Biomarkers in Sebaceous Gland Carcinomas

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Sander R. Dubovy, MD Professor of Ophthalmology and Pathology Victor T. Curtin Chair in Ophthalmology Florida Lions Ocular Pathology Laboratory Bascom Palmer Eye Institute University of Miami Miller School of Medicine

Biomarkers in Sebaceous Gland Carcinomas

Disclosure of Relevant Disclosure of Relevant Financial Relationships Financial Relationships

USCAP requires that all planners (Education Committee) in a position to Dr. Sander R. Dubovy declares he has no conflict(s) of interest influence or control the content of CME disclose any relevant financial to disclose. relationship WITH COMMERCIAL INTERESTS which they or their spouse/partner have, or have had, within the past 12 months, which relates to the content of this educational activity and creates a conflict of interest.

Biomarkers in Sebaceous Gland Carcinomas

Outline Introduction • Sebaceous carcinoma (SC) is a malignant neoplasm that arises from • Introduction to sebaceous cell carcinoma the sebaceous glands, most commonly in the periocular areas. • Incidence, demographics, risk factors • Clinical manifestations are often mistaken for benign conditions and • Ocular origins thus proper diagnosis and management is delayed. • Gross pathology • Metastases to regional lymph nodes and other sites are common. • Microscopic pathology • Immunohistochemistry • Management • Cases

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Introduction Sebaceous Gland • Pathologists should be aware of the varied clinical • Composed of two types of cells: manifestations, histopathological morphology and • Peripheral basophilic cells various biomarkers used for accurate diagnosis. • Sebocytes: Central foamy/vacuolated cytoplasm • Overview of the most important factors in periocular sebaceous carcinomas and biomarkers.

Biomarkers in Sebaceous Gland Carcinomas Biomarkers in Sebaceous Gland Carcinomas

Definitions Extraorbital primary locations • Sebaceous carcinoma (sebaceous gland carcinoma, • 75% of the cases arise in the ocular adnexae. sebaceous cell carcinoma) is a malignant neoplasm that • Approximately 25% of sebaceous carcinomas arise from an arises from the sebaceous glands. extraocular region • Parotid gland is the most common location. • Glands in these areas are named: • Meibomian glands (eyelid) • These tumors arise from two possible cells: pluripotent cells with • Zeis glands (cilia) capacity for sebaceous differentiation or from ectopic sebaceous cells that developed during embryogenesis • Sebocytes: • Foamy cells within the gland • Produce sebum to regulate tear evaporation • Precursor cell of sebaceous carcinoma Shields JA, Demirci H, Marr BP, Eagle RC, Shields CL. Sebaceous carcinoma of the ocular region: a review. Surv Ophthalmol. Biomarkers in Sebaceous Gland Carcinomas Biomarkers in Sebaceous Gland Carcinomas 2005;50(2):103 -22.

Extraorbital primary locations Incidence • Other reported locations include: • Periocular skin neoplasms account for 5-10% of all skin • submandibular glands malignancies in the United States. • extremities • Basal cell carcinoma - 90% of malignant eyelid tumors • toes • Sebaceous cell carcinoma - 5% of eyelid tumors • penis • Squamous cell carcinoma - 4% of eyelid tumors • chest • Melanoma - 1% of eyelid tumors • sole of foot • external auditory canal • ear • anterior neck region • Wide variety of anatomical locations of this neoplasm.

Ghosh, Sudip Kumar; Bandyopadhyay, Debabrata; Gupta, Sandipan; Chatterjee, Gobinda; & Ghosh, Arghyaprasun. (2008). Rapidly growing extraocular sebaceous carcinoma occurring during pregnancy: A case report. Dermatology Online Journal, 14(8). Biomarkers in Sebaceous Gland Carcinomas Biomarkers in Sebaceous Gland Carcinomas

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Incidence Demographics and Risk Factors • Incidence of sebaceous carcinoma is 0.5/million in the Caucasian population older than 20-years-old in the US. • Reports from China, India and other Asian countries indicate incidence of 31.2% - 39% of eyelid malignancies

• Age: Mean age at diagnosis has ranged from 57 years to 72 years. • Sung details a case of one of the youngest patient on the literature to develop sebaceous carcinoma without syndromic disease at age 32. • Sex: Approximately 70% of the sebaceous carcinomas occur in females.

Biomarkers in Sebaceous Gland Carcinomas Mulay K, Aggarwal E, White VA. Periocular sebaceous gland carcinoma: A Biomarkers in Sebaceous Gland Carcinomas comprehensive review. Saudi J Ophthalmol. 2013;27(3):159-65.

Demographics and Risk Factors • Irradiation: Several reports of patients with prior history of irradiation due to hereditary retinoblastoma treatment, acne, cutaneous hemangioma and eczema. • Rundle details a case in which a patient developed sebaceous gland carcinoma after being subject to irradiation for bilateral retinoblastoma.

• The carcinogenic effects of irradiation are well documented.

• The irradiation could affect the remaining RB gene and thus predispose the patient for secondary malignancies. • Osteosarcoma • Cutaneous melanoma • Sebaceous gland carcinoma

Biomarkers in Sebaceous Glandhttps://www.cancer.gov/types/retinoblastoma/patient/retinoblastoma-treatment-pdq Carcinomas Biomarkers in Sebaceous Gland Carcinomas http://iopscience.iop.org/article/10.1088/0031-9155/57/22/7741

Ocular origins • Meibomian glands: Most common origin • Upper eyelid is affected in 75% • Lower eyelid 22% • Conjunctiva 2% • Caruncle 2%

• Retrospective study of 104 cases of sebaceous carcinoma of the ocular adnexa with at least 5 years’ follow-up • Various clinicopathologic features that indicate poor prognosis were identified

http://www.pathologyoutlines.com/topic/eyeeyelidanatomy.html Biomarkers in Sebaceous GlandShields JA, Carcinomas et al. Sebaceous Carcinoma of the Eyelids: Personal Experience with 60 Cases. Ophthalmology 2004;111:2151-2157. Biomarkers in Sebaceous Gland Carcinomas

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Biomarkers in Sebaceous Gland Carcinomas Biomarkers in Sebaceous Gland Carcinomas

Ocular origins • Zeis glands: Glands associated with cilia: 10% of SC of the eyelid. • Caruncle: 5-10% of all SC (abundant sebaceous glands). • Conjunctiva: SC of the conjunctiva with no involvement of the nearby skin structures (rare).

Biomarkers in Sebaceous Gland Carcinomas Biomarkers in Sebaceous Gland Carcinomas

Clinical Features • Commonly can masquerade as a benign condition, Clinical Presentation blepharitis/chalazion (“masquerade syndrome”) • Resulting in a delay in diagnosis. • Solitary nodule • Increases the chance of local recurrence, metastasis, and death. • Diffuse pseudoinflammatory pattern

• Pedunculated lesion

• Caruncular mass

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Clinical Features • Solitary eyelid nodule: Most common clinical Clinical Presentation manifestation • Painless, firm, sessile to round, subcutaneous • Solitary nodule nodule in the eyelid. • Yellow color due to the presence of lipid. • Loss of cilia (madarosis). • Diffuse pseudoinflammatory pattern

• Pedunculated lesion

• Caruncular mass

Biomarkers in Sebaceous Gland Carcinomas Biomarkers in Sebaceous Gland Carcinomas

Clinical Features • Diffuse pseudo-inflammatory pattern: The second most Clinical Presentation common presentation. • Diffuse unilateral thickening of the eyelid. • Solitary nodule • Most likely to extend to the epithelium • SC must be ruled out in an older patient with unilateral blepharitis that does not respond to standard treatment. • Diffuse pseudoinflammatory pattern

• Pedunculated lesion

• Caruncular mass

Case initially diagnosed as a chronic blepharoconjunctivitis Biomarkers in Sebaceous Gland Carcinomas Biomarkers in Sebaceous Gland Carcinomas https://www.reviewofophthalmology.com/article/eyelid-lesions-diagnosis-and- tt t

Clinical Features • Pedunculated lesion: SC may become pedunculated with Clinical Presentation keratinization and possess a cutaneous horn appearance. • Most common ocular location is the eyelid margin, from the gland of Zeis. • Solitary nodule

• Diffuse pseudoinflammatory pattern

• Pedunculated lesion

• Caruncular mass

Pedunculated lesion of the axilla

Biomarkers in Sebaceous Gland Carcinomas Biomarkers in Sebaceous Gland Carcinomas http://www.actasdermo.org/en/extraocular-sebaceous-carcinoma-a-report/articulo/S1578219012003113/

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Clinical Features Gross Pathology • Yellow color due to the lipid deposition. Caruncular mass: Irregular, yellow mass in the medial canthal lesion. May replace the entire eyelid and involve the orbit. • Specimens may show origin in the tarsal plate.

Biomarkers in Sebaceous Gland Carcinomas Biomarkers in Sebaceous Gland Carcinomas http://www.aaopt.org/optometry-and-vision-science-ovs-announces-preview-march- 2014

Gross Pathology

Biomarkers in Sebaceous Gland Carcinomas Biomarkers in Sebaceous Gland Carcinomas

Microscopic Pathology • Cells with finely vacuolated, frothy cytoplasm • Pleomorphism and high nuclear mitotic rate are frequent features • Tumor cells often have hyperchromatic, atypical nuclei with foamy cytoplasm

Involvement of Biomarkers in Sebaceous Gland Carcinomas Biomarkers in Sebaceous Gland Carcinomas sebaceous glands

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• Vacuolated Microscopic Pathology cytoplasm • A characteristic feature of SC is its ability to exhibit intraepithelial spread into conjunctival, eyelid and corneal epithelium, this occurs in 44-80% of the cases (pagetoid spread).

• Mitotic figures

• Pleomorphic nuclei

Biomarkers in Sebaceous Gland Carcinomas Biomarkers in Sebaceous Gland Carcinomas Jakobiec FA, Mendoza PR. Eyelid sebaceous carcinoma: clinicopathologic and multiparametric immunohistochemical analysis that includes adipophilin. Am J Ophthalmol. 2014;157(1):186-208.e2.

Microscopic Pathology • Lobular pattern: Occurs more frequently and looks like a Microscopic Pathology normal sebaceous gland with undifferentiated cells in the • Comedocarcinoma: Lobules show large necrotic central core periphery, and well-differentiated lipid producing cells with peripheral viable cells. centrally.

Biomarkers in Sebaceous Gland Carcinomas Biomarkers in Sebaceous Gland Carcinomas

Microscopic Pathology Microscopic Pathology • Papillary: Occurs in conjunctiva SC, with papillary projections • Papillary: Occurs in conjunctiva SC, with papillary projections and sebaceous differentiation. and sebaceous differentiation.

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Methods of Spread • Epithelial involvement: SC has been shown to exhibit flat, superficial involvement of the eyelid or conjunctival epithelium. • Pagetoid spread because of the morphological similarity of pagetoid spread of intraductal breast carcinoma.

Pagetoid spread 

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• Pagetoid spread of malignant cells is common

Full‐thickness Pagetoid involvement of epithelium

Involvement of sebaceous glands

Biomarkers in Sebaceous Gland Carcinomas Biomarkers in Sebaceous Gland Carcinomas

Methods of Spread Methods of Spread • Regional metastasis: Most common route of metastasis is via lymphatic channels to regional lymph nodes. • Corneal invasion: Sebaceous carcinoma with pagetoid • SC of the upper eyelid tends to invade the preauricular and parotid spread from the bulbar conjunctiva to the corneal nodes. epithelium and stroma • SC of the lower eyelids tend to metastasize to the submandibular and cervical nodes. • Distant metastasis: Organs most commonly involved are lung, liver, bone, and brain.

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Methods of Spread Perineural invasion AJCC Cancer Staging

• Pathological classification • Tumor type • Differentiation (grade) • Completeness of tumor removal • Greatest tumor dimension • Tumor margins

Biomarkers in Sebaceous Gland Carcinomas Biomarkers in Sebaceous Gland Carcinomas

AJCC Cancer Staging - 8th edition AJCC Cancer Staging - 8th edition

• Size < 10 mm, 20 mm • Size < 10 mm, 20 mm • Tarsal plate • Tarsal plate • Eyelid margin • Eyelid margin • Invasion of ocular or orbital • Invasion of ocular or orbital structures structures

Biomarkers in Sebaceous Gland Carcinomas Biomarkers in Sebaceous Gland Carcinomas

AJCC Staging - 8th edition AJCC Staging – 8th edition

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Biomarkers in Sebaceous Gland Carcinomas Biomarkers in Sebaceous GlandGrade Carcinomas I Grade II Grade III

Grading Grade IV

• Retrospective, clinicopathologic study • Evaluated cytopathologic features and immunohistochemistry of eyelid sebaceous carcinoma in 12 patients • EMA, Ber-EP4, p53, Ki-67, and adipophilin • Cytoplasmic and nuclear characteristics correlated with immunohistochemical results

Biomarkers in Sebaceous Gland Carcinomas Biomarkers in SebaceousJakobiec FA, Gland Mendoza PR. EyelidCarcinomas sebaceous carcinoma: clinicopathologic and multiparametric immunohistochemical analysis that includes adipophilin. Am J Ophthalmol. 2014;157(1):186-208.e2.

Recommended Approach • Microscopic examination raises the prospect of SC

• Immunostaining for both EMA and p53

• If either EMA or p53 is positive then confirm with adipophilin EMA p53 staining

• A negative androgen receptor adipophilin result can be used to rule out SC in a poorly differentiated tumor

Biomarkers in SebaceousJakobiec FA, Gland Mendoza PR. EyelidCarcinomas sebaceous carcinoma: clinicopathologic and multiparametric immunohistochemical analysis that includes adipophilin. Am J Ophthalmol. 2014;157(1):186-208.e2. Biomarkers in SebaceousJakobiec FA, Gland Mendoza PR. EyelidCarcinomas sebaceous carcinoma: clinicopathologic and multiparametric immunohistochemical analysis that includes adipophilin. Am J Ophthalmol. 2014;157(1):186-208.e2.

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Immunohistochemistry • Plaza et al. studied 27 cases of SC • Tissue microarray technique.

• Compared IHC results to 21 control cases of basal cell carcinoma (BCC) and 22 control cases of squamous cell carcinoma (SCC). •EMA • A large variation of biomarkers exists with questionable •CK7 utility. • Ber-EP4 • Factor XIIIA • Androgen receptor • Experienced pathologists can usually confirm the • p53 diagnosis using morphology and • Adipophilin • Progesterone receptor membrane component 1 (PGRMC1) immunohistochemistry is not necessary. • Squalene synthase (SQS) • Alpha/beta hydrolase domain-containing protein 5 (ABHD5)

Biomarkers in Sebaceous Gland Carcinomas Biomarkers in Sebaceous Gland Carcinomas

Epithelial membrane antigen EMA • EMA – Glycoprotein with • Commonly used as a extensive O-linked marker to evaluate: glycosylation of its extracellular domain. • Epithelial carcinomas • Product of MUC1 gene • Meningioma • Paget disease • Overexpression of the • Systemic anaplastic MUC1 gene is often large cell lymphoma associated with colon, vs cutaneous breast, ovarian, lung and pancreatic cancers. anaplastic large cell lymphoma

• Membrane staining Optic nerve sheath meningioma

Jakobiec FA, Mendoza PR. Eyelid Sebaceous Carcinoma: Biomarkers in Sebaceous Gland Carcinomas Clinicopathologic and Multiparametric Immunohistochemical Analysis Biomarkers in Sebaceous Gland Carcinomas That Includes Adipophilin. Am J Ophthalmol. 2014 http://www.pathologyoutlines.com/topic/stainsema.html

Sebaceous Carcinoma - EMA EMA in Sebaceous Carcinoma • In the series by Plaza et al., 27/27 SCs were EMA-positive (100%).

• In 4 cases of SC, EMA was only focally and irregularly positive because these cases represented poorly differentiated lesions.

• All cases of BCC (21/21, 100%) were negative.

• SCC expressed EMA in 16/22 (72.72%) of cases.

Biomarkers in Sebaceous GlandJakobiec Carcinomas FA, Mendoza PR. Eyelid Sebaceous Carcinoma: Clinicopathologic and Biomarkers in Sebaceous Gland Carcinomas Multiparametric Immunohistochemical Analysis That Includes Adipophilin. Am J Ohthl l2014

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EMA EMA in Sebaceous Carcinoma • EMA is useful in differentiating SC from BCC.

• EMA alone is not useful in differentiating SC from SCC.

Biomarkers in Sebaceous GlandPlaza JA etCarcinomas al. Role of ImmunoSebaceous Carcinoma: A Clinicopathologic and histochemistry in the Diagnosis ofImmunohistochemical Study. Am J Dermatopathol 2015;37:809–821. Biomarkers in Sebaceous Gland Carcinomas Plaza JA et al. Role of ImmunoSebaceous Carcinoma: A Clinicopathologic and histochemistry in the Diagnosis ofImmunohistochemical Study. Am J Dermatopathol 2015;37:809–821.

EMA CK7 • Cytokeratin 7 is an intermediate filament protein

• Low molecular cytokeratin (54 kDa)

• Found in breast, lung, ovary, and urothelium but usually not in the GI tract or in stratified squamous epithelium

Cytokeratin 7 shows cytoplasmic • It is often used in conjunction with positivity in epithelial cell nests in a cytokeratin 20 in distinguishing ovarian, Brenner tumor. pulmonary, and breast carcinomas (CK7+) from colon carcinomas (CK7-).

Biomarkers in Sebaceous Gland Carcinomas Biomarkers in Sebaceous GlandKriplani D,Carcinomas Patel MM. Immunohistochemistry: A diagnostic aid in differentiating primary epithelial ovarian tumors and tumors metastatic to the ovary. South Asian J Cancer. 2013 Oct-Dec; 2(4): 254–258.

CK7 in Sebaceous Carcinoma CK7 - SC • Plaza et al. found that • 24/27 (88.8%) of cases of SC • 2/22 (9%) of SCC • 6/21 (28.5%) of BCC expressed CK7.

• May be valuable in differentiating SC from SCC in most instances.

• CK7 is not a reliable marker to separate SC from BCC.

Biomarkers in Sebaceous Gland Carcinomas Biomarkers in Sebaceous GlandPlaza JA etCarcinomas al. Role of ImmunoSebaceous Carcinoma: A Clinicopathologic and histochemistry in the Diagnosis ofImmunohistochemical Plaza JA et al. Role of ImmunoSebaceous Carcinoma: A Clinicopathologic and histochemistry in the Diagnosis ofImmunohistochemical Study. Am J Dermatopathol 2015;37:809–821. Study. Am J Dermatopathol 2015;37:809–821.

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CK7- BCC CK7 - SCC CK7

Ber-EP4 Ber-EP4 • EpCam (CD326) is a • Membranous staining transmembrane epithelial adhesion • Sensitive and specific for lung molecule present on adenocarcinoma (positive) vs. all non-squamous mesothelioma (negative) epithelial cells.

• Distinguishes metastatic • Ber-EP4 targets adenocarcinoma to liver or EpCam cholangiocarcinoma (positive) from hepatocellular carcinoma (usually negative) EpCAM staining in breast carcinoma Membrane reactivity in lung adenocarcinoma

Biomarkers in Sebaceous Gland Carcinomas Biomarkers in Sebaceous GlandCarella Carcinomas R et al. Immunohistochemical Panels for Differentiating Epithelial Malignant Mesothelioma From Lung Adenocarcinoma. Am J Surg Path. 2001. http://www.abcam.com/epcam-antibody-ber-ep4-ab7504.html#description_images_1

Ber-EP4 in Sebaceous Carcinoma Ber-EP4 in Sebaceous Carcinoma • Plaza et al. showed: • 7/27 (25.9%) of SC expressed Ber-EP4 • 21/21 (100%) of BCC cases are positive (diffusely and strongly positive) • 22/22 (100%) of SCC are negative • This suggests that Ber-EP4 is a reliable marker in differentiating SC (EMA+/Ber-EP4 +/-) from BCC (EMA- /Ber-EP4+) and SCC (EMA+/- /Ber- EP4-) • When used with other markers.

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Ber-EP4 Factor XIIIA

• Component of the final stages of the clotting cascade.

• Acts on fibrin to form cross links between fibrin molecules to form an insoluble clot. https://upload.wikimedia.org/wikipedia/commons/thumb/3/31/Stabilisation_de_la_fibrine_par_le_factor_XIII.png/260px-Stabilisation_de_la_fibrine_par_le_factor_XIII.png

Biomarkers in Sebaceous Gland Carcinomas Biomarkers in Sebaceous Gland Carcinomas

Factor XIIIA • Nuclear staining • Positive staining in: • Soft tissue: benign fibrous histiocytoma and variants, malignant fibrous histiocytoma • Calcifying fibrous tumor • Clark et al. found consistent, strong nuclear • Verruciform xanthoma staining in normal, hyperplastic and neoplastic • Atypical fibroxanthoma, hemangiopericytoma, sebocytes myofibroblastoma in lymph nodes, pleomorphic hyalinizing angiectatic tumor, storiform collagenoma • He concluded: Useful marker to differentiate • Cervix: angiomyxoma sebaceous from squamous carcinoma analyzing staining pattern. • CNS: Erdheim-Chester disease

Biomarkers in Sebaceous Gland Carcinomas Biomarkers in Sebaceous Gland Carcinomas

Factor XIIIA Factor XIIIA

Biomarkers in Sebaceous Gland Carcinomas Biomarkers in Sebaceous Gland Carcinomas Clark LN et al. Nuclear factor XIIIa staining (clone AC-1A1 mouse monoclonal) is a highly sensitive marker of sebaceous differentiation in normal and neoplastic sebocytes. J Cutan Pathol. 2016. Clark LN et al. Nuclear factor XIIIa staining (clone AC-1A1 mouse monoclonal) is a highly sensitive marker of sebaceous differentiation in normal and neoplastic sebocytes. J Cutan Pathol. 2016.

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Factor XIIIA Factor XIIIA • Plaza et al. found that none of the SC (0/27), BCC (0/21), or SCC (0/22) expressed Factor XIIIA. • Discrepancy in these findings may be attributed to the clone or dilution of the antibody used.

Plaza JA et al. Role of ImmunoSebaceous Carcinoma: A Clinicopathologic and histochemistry in the Diagnosis ofImmunohistochemical Study. Am J Dermatopathol 2015;37:809–821.

Biomarkers in Sebaceous Gland Carcinomas Biomarkers in Sebaceous Gland Carcinomas

Androgen Receptor • The androgen receptor dimer binds to a specific sequence of DNA.

• Sensitive marker for sebaceous carcinoma • Results in up- or • AR positive in 19/19 (100%) cases of SC down-regulation of • AR positive in 6/18 (33.3%) cases of BCC specific gene • AR positive in 0/18 (0%) cases of squamous cell carcinoma transcription. • Insulin-like growth • Along with other markers and morphology, AR can factor I receptor be helpful in the differentiation of SC from SCC and (IGF-1R). BCC.

Biomarkers in Sebaceous Gland Carcinomas Biomarkers in Sebaceous Gland Carcinomas

Androgen Receptor on Sebaceous Carcinoma Androgen Receptor

• Plaza et al. found different results compared to other studies • 9/27 (33.3%) of the SC cases were positive. • 3/21 (14.2%) of BCC cases were positive. • 0/22 (0%) of SCC were positive.

• They concluded that nuclear expression of androgen receptor can be seen in BCC cases in a similar percentage. • Not a valuable marker to differentiate SC from BCC.

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p53 as a marker p53 in Sebaceous Carcinoma • Tumor suppressor gene • Plaza et al. found that: • Induces cell cycle arrest • SC cases 12/27 (44.4%) expressed p53 • DNA repair or to force the cell to undergo apoptosis. • BCC cases 4/21 (19%) expressed p53 • Differentiate malignant conditions (p53+) • Carcinoma in situ • SCC cases 3/22 (13.6%) expressed p53 • Invasive carcinoma • Not a recommended diagnostic marker in the • Others differential diagnosis of SC, BCC, and SCC.

• Reactive and metaplastic conditions (p53-)

Biomarkers in Sebaceous Gland Carcinomas Biomarkers in Sebaceous Gland Carcinomas

p53

(Ophthal Plast Reconstr Surg 2014;30:392–395) • Retrospective case series. Fourteen specimens were analyzed for p53 gene mutations with PCR and Sequencher.

• Seven of 14 (50%) sebaceous carcinoma samples were found to have p53 gene mutations.

• None of the samples had tandem mutations, which are caused by UV exposure. Therefore it is consistent with the belief that the development of SC is a UV-independent process.

• No statistically significant trend was found between the presence of p53 mutations and metastasis, recurrence, tumor size, TNM stage, and pagetoid spread.

Biomarkers in Sebaceous Gland Carcinomas Biomarkers in Sebaceous Gland Carcinomas

Adipophilin Adipophilin

• Plaza et al. found • Assists with the storage of neutral lipids within the lipid droplet adipophilin expression in: • Expressed in sebocytes and sebaceous lesions • 27/27 (100%) in cases of SC • Membranous labeling of intracytoplasmic lipid globules • Also expressed in: • Lactating mammary epithelium • BCC 16/21 (76.19%) • Adrenal cortex • Steatotic hepatocytes in alcoholic cirrhosis • Renal cell carcinoma • SCC 11/22 (50%) showed a • Hepatocellular carcinomas granular uptake in the • Pancreatic carcinomas cytoplasm. • Prostatic carcinomas • Liposarcomas

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Adipophilin • The pattern of adipophilin expression can be useful in distinguishing SC from other periocular • Retrospective, histopathologic study neoplasms. • Evaluated the efficacy of adipophilin immunohistochemistry in the diagnosis of sebaceous cell carcinoma of the ocular adnexal region • No cases of BCC or SCC • 25 patients with sebaceous carcinoma, 21 with basal cell showed membranous carcinoma, 22 with conjunctival squamous cell carcinoma, 9 with labeling of intracytoplasmic cutaneous squamous cell carcinoma, and 5 with conjunctival lipid globules. mucoepidermoid carcinoma.

Results - SC • Significantly stronger adipophilin expression, a greater number of intracytoplasmic vacuoles, and larger vacuoles.

• The specificity and sensitivity of adipophilin immunostaining were both 100% when more than 5% of the staining occurred in vacuoles (<95% granular staining). • Conclusions: • Histology remains the gold standard for diagnosis of sebaceous carcinoma. E, F, Moderately differentiated sebaceous carcinoma cells infiltrate the epidermis in a • Immunohistochemical assessment for adipophilin is a helpful diagnostic adjunct in the pagetoid pattern and demonstrate strong, diffuse immunoreactivity for adipophilin as assessment of ocular adnexa neoplasms confluent medium-sized intracytoplasmic vacuoles (red arrows) and small vacuoles and presumed to be sebaceous carcinoma. granules (black arrow).

Biomarkers in Sebaceous Gland Carcinomas Biomarkers in Sebaceous Gland Carcinomas Milman T, Schear MJ, Eagle RC. Diagnostic utility of adipophilin immunostain in periocular carcinomas. Ophthalmology. 2014;121(4):964-71. Milman T, Schear MJ, Eagle RC. Diagnostic utility of adipophilin immunostain in periocular carcinomas. Ophthalmology. 2014;121(4):964-71.

Other lipid droplet proteins Other lipid droplet proteins • Plaza et al. found: • Alpha/beta hydrolase domain-containing protein 5 (ABHDC5) • PGRMC1 was expressed in 22/27 • The protein encoded by this gene belongs to a large family of proteins defined by an alpha/beta hydrolase fold (81.4%) of SC • SQS in 14/27 (51.8%) of SC • ABHD5 in 19/27 (70.3%) of SC. • PGRMC1: Protein which co-purifies with progesterone binding proteins in the liver and ovary. • BCC 0/21 (0%) or SCC 0/22 (0%) expressed none of these markers. • PGRMC1, SQS, and ABHD5 are therefore very specific but not very • Squalene synthase (SQS) or farnesyl-diphosphate: farnesyl-diphosphate sensitive markers for the diagnosis of farnesyl transferase • Enzyme localized to the membrane of the endoplasmic reticulum. SC.

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Immuno Panel that May be Helpful in Differentiating Sebaceous Cell • Perforin stained strongly in 9/11 (81%) of Saudi Journal of Ophthalmology (2013) 27, 159–165 the sebaceous neoplasms Acta Ophthalmol. 2016 Aug;94(5):e325-30 Sebacous Carcinoma Basal Cell Carcinoma Squamous Carcinoma • 7/9 (77.7%) of the SC •CEA +/- - - • 2/2 (100%) of sebaceous adenoma •ADP + - - • The speciﬁcity of perforin in identifying •AR + +/- - sebaceous neoplasms versus SCC and BCC was 100% (95% CI 69–100). •EMA + - + • Perforin better highlighted the intraepithelial • BerEP4 - + - spread of SC than EMA. • CA19-9 +/- +/- - • The expression pattern of perforin in • CA 15-3 + - +/- sebaceous neoplasms allows the use of •BRST-1 + +/- - perforin as a new immunohistochemical •CAM 5.2 + - +/- marker for sebaceous neoplasms.

Biomarkers in Sebaceous Gland Carcinomas Biomarkers in Sebaceous Gland Carcinomas

Summary of Immunohistochemistry Differential Diagnosis

• Chalazion: Painful, tender, circumscribed nodule, without • Jakobiec et al - EMA, p53, adipophilin, androgen receptor are diffuse involvement that has similar appearance to SC. useful adjuncts for diagnosis of SC • Any patient with recurrent chalazia, especially in older individuals must undergo biopsy to rule out SC. • Plaza et al – adipophilin, ABHD5, PGRMC1, and SQS are novel markers specific for SC • Adipophilin is the most sensitive

• Millman et al - pattern and intensity of adipophilin immunostaining are helpful in distinguishing sebaceous carcinoma from other neoplasms with overlapping histology.

Biomarkers in Sebaceous Gland Carcinomas Biomarkers in Sebaceous Glandhttp://www.emedicinehealth.com/chalazion_lump_in_eyelid/page4_em.htm Carcinomas http://eyepath.org.uk/atlas/chalazion/

Differential Diagnosis Differential Diagnosis • Blepharitis: Common; diffuse inflammation of the eyelids • Conjunctivitis: Diffuse SC involvement of the palpebral, • Often SC is misdiagnosed as blepharitis. forniceal and bulbar conjunctiva can appear as a • No madarosis conjunctivitis. Bilateral conjunctivitis is less likely to be SC.

Biomarkers in Sebaceous Gland Carcinomas Biomarkers in Sebaceous Glandhttps://www.flickr.com/photos/jian-hua_qiao_md/11873430274 Carcinomas https://en.wikipedia.org/wiki/Blepharitis

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Differential Diagnosis: Differential Diagnosis • Basal cell carcinoma: Nodular form of BCC presents as a solitary nodule. • Keratoconjunctivitis: As SC progresses it may involve the Generally white, with vascular elevated margins with likely ulceration. corneal epithelium. It causes reactive inflammation around • Most commonly involves the lower eyelid the neoplasms and thus it may resemble keratoconjunctivitis.

Biomarkers in Sebaceous Gland Carcinomas Biomarkers in Sebaceous Gland Carcinomas

Differential Diagnosis Differential Diagnosis:

• Squamous cell carcinoma: Most common in upper lid. Associated with actinic keratosis. Conjunctival intraepithelial neoplasia (CIN) can be similar to diffuse epithelial invasion of SC. Actinic keratosis

The diffuse sclerosing or morpheaform forms of BC most closely resembles SC, with unlikely involvement of the conjunctiva.

Biomarkers in Sebaceous Glandhttp://www.pathologyoutlines.com/topic/skintumornonmelanocyticbcc.html Carcinomas Biomarkers in Sebaceous Glandhttp://www.humpath.com/spip. Carcinomas php?article3854 http://cursoenarm.net/UPTODATE/contents/mobipreview.htm?29/47/30451

Differential diagnosis Differential Diagnosis: • Squamous cell carcinoma : Arises in epithelium, infiltrates in sheets, nests • Melanoma: Nodular or diffuse growth pattern. Generally and islands. pigmented with brown appearance, rather than the • Eosinophilic tumor with keratinization characteristic SC yellow. Amelanotic melanoma may of cells and formation of keratin pearls. resemble SC.

• Pleomorphism and mitotic figures are common

Biomarkers in Sebaceous Gland Carcinomas Biomarkers in Sebaceous Glandhttp://www.oculist.net/downaton502/prof/ebook/duanes/pages/v4/v4c003.html Carcinomas http://www.visionaryeyespecialists.com.au/common-eyelid-problems/ http://www.mussenhealth.us/cell-carcinoma/lentigo-maligna.html

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Differential Diagnosis: Differential Diagnosis:

• Merkel cell carcinoma: Solitary subcutaneous nodule in the • Lymphoma: More common than SC. In the eyelid area, it is upper eyelid of older individuals, with red or red-blue color. usually deep to the epidermis and the skin moves freely over the lesion. Conjunctival lymphoma has characteristic “salmon patch” with no inflammatory signs that are present in SC.

Biomarkers in Sebaceous Glandhttp://webeye.ophth.uiowa.e Carcinomasdu/eyeforum/cases/217-Merkel-Cell-Carcinoma-Eyelid.htm Biomarkers in Sebaceous Glandhttp://emedicine.medscape.com/article/ Carcinomas 1219134-overview http://www.pathologyoutlines.com/topic/skintumornonmelanocyticmerkelcell.ht http://www.pathologyoutlines.com/caseofweek/case281.htm l

Muir-Torre Syndrome Muir-Torre Syndrome

• Variant of autosomal dominant hereditary nonpolyposis • MMR genes: colorectal cancer (HNPCC) syndrome or Lynch syndrome. • Mutator S Homologue (MSH)2 • Incidence: HNPCC occurs in about 1/350 individuals in the • Mutator L Homologue (MLH)1 general population •MSH6 • Postmeiotic Segregation Increased (PMS)2 • Muir-Torre syndrome is evident in 9.2% of the cases and in 28% of families with HNPCC.

Biomarkers in Sebaceous Gland Carcinomas Biomarkers in Sebaceous Gland Carcinomas

Muir-Torre Syndrome: Sebaceous Adenoma • Benign growth that presents as a small, usually less than 0.5 cm in diameter (2-4 mm), smooth, yellow, speckled papules with central umbilication on the skin of the face or scalp over several months. • Most common cutaneous manifestation of Muir-Torre (68%).

• To diagnose Muir-Torre:

• One characteristic from Group A and B or • Multilobulated tumor sharply demarcated from the surrounding tissue. • Three characteristics from Group C Central cells contain frothy and vacuolated cytoplasm.

Biomarkers in Sebaceous Gland Carcinomas Biomarkers in Sebaceous Glandhttp://www.regi Carcinomasonalderm.com/Regional_Derm/Sfiles/sebaceous_adenoma.html

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Sebaceous Muir Torre: Sebaceoma hyperplasia A papule is an area of abnormal skin tissue that is less than 1 cm around. Usually a papule has distinct borders, and it can appear in Distinction between sebaceous adenoma and sebaceoma may be difficult and there is an a variety of shapes increasing tendency to regard these two tumors as part of a continuum of benign tumors • No malignant Basaloid undifferentiated sebocytes admixed with potential single or small clusters of mature vacuolated • Risk factors: Sun sebocytes. exposure and old Irregular shaped cell masses in which more than age 50 percent cells are undifferentiated, basaloid cells together with significant aggregates of sebaceous cells and transitional cells

Biomarkers in Sebaceous Gland Carcinomas Biomarkers in Sebaceous Glandhttp://www.pathologyoutlines.com/topic/skintumor Carcinomas nonmelanocyticsenilesebaceoushyperplasia.html

Sebaceous Adenoma Sebaceous Adenoma vs. Sebaceous Carcinoma • 94 sebaceous tumors from 92 patients • Tumors with strong p53 staining were significantly associated with the diagnosis of sebaceous carcinoma vs benign sebaceous lesions • Nuclear mismatch repair protein expression was intact in all lesions showing p53 alterations • Suggests p53 dysfunction may represent a divergent pathway in these tumors • ShalinSC, Sakharpe A, Lyle S, Lev D, Calanje, Lazar AJ P53 Staining Correlates with Tumor Type and Location in Sebaceous Neoplasms. The American Journal of Dermatopathology. 2012; 34(2): 129=138.

Biomarkers in Sebaceous Gland Carcinomas Biomarkers in Sebaceous Gland Carcinomas

Signalling Signalling • Beta-catenin: coordination of cell-cell adhesion and gene transcription WNT-catenin overexpression is associated with increased tumor size invasion and metastasis • Androgen receptor: regulation of gene expression; increased activity inhibits p53 expression • P53: overexpression associated with tumor type and location • E-cadherin: suppressor of invasion and growth of epithelial • P21: cyclin dependent kinase inhibitor; down regulation has cancers association with lymph node metastasis • Lower expression-poor differentiation, high proliferation rate • Shh ABCG2: maintenance of stem cells in adult tissues; sonic • Promoter methylation-reduced survival, size >2 cm, lymph node mets, poor differentiation hedgehog pathway; overexpression associated with aggressiveness and metastasis

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Management Management • The first step is to establish the diagnosis and determine the • Primary excisional biopsy extent of the disease • It is generally preferred to perform a complete surgical •Skin excision of the lesion when the diagnosis is suspected. • Conjunctiva • Cornea • Caruncle • Periocular tissue

• Palpation of head and neck nodes is advisable. • Cosmetic appearance is an issue to consider if the diagnosis is unclear • Management options include: surgical excision, surgical excision • Incisional biopsy to confirm combined with cryotherapy, topical chemotherapy, radiotherapy, • Excisional biopsy afterward amniotic membrane grafting and other techniques.

Biomarkers in Sebaceous Gland Carcinomas Biomarkers in Sebaceous Gland Carcinomas

Management Map Biopsy • Full-thickness, pentagonal, eyelid resection is favorable. • Determines extent of disease. • Margins are 5.0 mm on the nasal and • Usually 10-15 biopsies are taken. temporal sides. • The most common method involves: • Eversion of the eyelids and taking four specimens from the palpebral conjunctiva • Six specimens from the bulbar conjunctiva.

Biomarkers in Sebaceous Gland Carcinomas Biomarkers in Sebaceous Gland Carcinomas

Management Orbital Exenteration • Cryotherapy • Widely believed to be the best option for SC that diffusely involves the conjunctiva and with invasion into the orbit. • Useful in cases of SC with pagetoid spread to the conjunctival surface. It is used during map biopsies and during definitive surgical excision.

• Appropriate for orbital invasion cases of SC with no evidence of distant metastasis. • Lid-sparing exenteration is an option that must be considered if the eyelid contains no tumor • Faster healing • Better fitting prosthesis • Topical chemotherapy • Has been used in select cases of pagetoid spread involving the conjunctival epithelium.

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Case 1 An 87-year-old female presented for evaluation of left eyelid Case redness for a couple of weeks.

Biomarkers in Sebaceous Gland Carcinomas Biomarkers in Sebaceous Gland Carcinomas

Incisional Biopsy Incisional Biopsy

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Map Biopsy Map Biopsy

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Pathology report:

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Biomarkers in Sebaceous Gland Carcinomas Biomarkers in Sebaceous Gland Carcinomas

Case 2 • 74-year-old female who presents with recurrent chalazion of the left eye. Map Biopsy

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Biomarkers in Sebaceous Gland Carcinomas Biomarkers in Sebaceous Gland Carcinomas

• Sebaceous carcinoma on the eyelids, palpebral conjunctiva, forniceal conjunctival and corneal epithelium

• Marked amount of pagetoid spread.

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EMA EMA

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CK7 CK7

Biomarkers in Sebaceous Gland Carcinomas Biomarkers in Sebaceous Gland Carcinomas

Ber-EP4 Ber-EP4 – stains epithelium

Biomarkers in Sebaceous Gland Carcinomas Biomarkers in Sebaceous Gland Carcinomas

p53 p53

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Androgen Androgen Receptor Receptor

Biomarkers in Sebaceous Gland Carcinomas Biomarkers in Sebaceous Gland Carcinomas

Factor XIIIA Factor XIIIA

Biomarkers in Sebaceous Gland Carcinomas Biomarkers in Sebaceous Gland Carcinomas

IHC Summary Summary IHC Result • Sebaceous cell carcinoma has high morbidity/mortality and may be misdiagnosed as squamous cell and basal cell EMA +++ carcinoma CK7 ++ • Morphology remains most important for the diagnosis of Ber-EP4 0 sebaceous cell carcinoma Androgen Receptor + • Immunohistochemical stains including EMA, p53, adipophilin, and perforin; as well as CEA may be useful Factor XIIIA 0 adjuncts in diagnosis p53 ++

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References

• Plaza JA, Mackinnon A, Carrillo L, Prieto VG, Sangueza M, Suster S. Role of immunohistochemistry in the diagnosis of sebaceous carcinoma: a clinicopathologic and immunohistochemical study. Am J Dermatopathol. 2015;37(11):809-21. References • Mulay K, White VA, Shah SJ, Honavar SG. Sebaceous carcinoma: clinicopathologic features and diagnostic • Chen WS, Chen PL, Li J, Lind AC, Lu D. Lipid synthesis and processing proteins ABHD5, PGRMC1 and squalene synthase can role of immunohistochemistry (including androgen receptor). Can J Ophthalmol. 2014;49(4):326-32. serve as novel immunohistochemical markers for sebaceous neoplasms and differentiate sebaceous carcinoma from sebaceoma and basal cell carcinoma with clear cell features. J Cutan Pathol. 2013;40(7):631-8. • Jakobiec FA, Werdich X. Androgen receptor identification in the diagnosis of eyelid sebaceous carcinomas. Am • Asadi-amoli F, Khoshnevis F, Haeri H, Jahanzad I, Pazira R, Shahsiah R. Comparative examination of androgen receptor J Ophthalmol. 2014;157(3):687-96.e1-2. reactivity for differential diagnosis of sebaceous carcinoma from squamous cell and basal cell carcinoma. Am J Clin Pathol. 2010;134(1):22-6. • Boussahmain C, Mochel MC, Hoang MP. Perilipin and adipophilin expression in sebaceous carcinoma and • Jakobiec FA, Mendoza PR. Eyelid sebaceous carcinoma: clinicopathologic and multiparametric immunohistochemical analysis mimics. Hum Pathol. 2013;44(9):1811-6. that includes adipophilin. Am J Ophthalmol. 2014;157(1):186-208.e2. • Milman T, Schear MJ, Eagle RC. Diagnostic utility of adipophilin immunostain in periocular carcinomas. • Mulay K, White VA, Shah SJ, Honavar SG. Sebaceous carcinoma: clinicopathologic features and diagnostic role of Ophthalmology. 2014;121(4):964-71 immunohistochemistry (including androgen receptor). Can J Ophthalmol. 2014;49(4):326-32. • Ansai S, Takeichi H, Arase S, Kawana S, Kimura T. Sebaceous carcinoma: an immunohistochemical reappraisal. Am J • Shields JA, Demirci H, Marr BP, Eagle RC, Shields CL. Sebaceous carcinoma of the ocular region: a review. Dermatopathol. 2011;33(6):579-87. Surv Ophthalmol. 2005;50(2):103-22. • Ansai S, Arase S, Kawana S, Kimura T. Immunohistochemical findings of sebaceous carcinoma and sebaceoma: retrieval of • Deprez M, Uffer S. Clinicopathological features of eyelid skin tumors. A retrospective study of 5504 cases and cytokeratin expression by a panel of anti-cytokeratin monoclonal antibodies. J Dermatol. 2011;38(10):951-8. review of literature. Am J Dermatopathol. 2009;31(3):256-62. • Sramek B, Lisle A, Loy T. Immunohistochemistry in ocular carcinomas. J Cutan Pathol. 2008;35(7):641-6. • Dasgupta T, Wilson LD, Yu JB. A retrospective review of 1349 cases of sebaceous carcinoma. Cancer. • Mittal R, Araujo I, Czanner G, Coupland SE. Perforin expression in eyelid sebaceous carcinomas: a useful and specific 2009;115(1):158-65. immunomarker for the differential diagnosis of eyelid carcinomas. Acta Ophthalmol. 2016;94(5):e325-30. • Uhlenhake EE, Clark LN, Smoller BR, Shalin SC, Gardner JM. Nuclear factor XIIIa staining (clone AC-1A1 mouse monoclonal) is • Izumi M, Mukai K, Nagai T, et al. Sebaceous carcinoma of the eyelids: thirty cases from Japan. Pathol Int. a sensitive and specific marker to discriminate sebaceous proliferations from other cutaneous clear cell neoplasms. J Cutan 2008;58(8):483-8. Pathol. 2016;43(8):649-56. • Fan YS, Carr RA, Sanders DS, Smith AP, Lazar AJ, Calonje E. Characteristic Ber-EP4 and EMA expression in sebaceoma is immunohistochemically distinct from basal cell carcinoma. Histopathology. 2007;51(1):80-6. • Bayer-garner IB, Givens V, Smoller B. Immunohistochemical staining for androgen receptors: a sensitive marker of sebaceous differentiation. Am J Dermatopathol. 1999;21(5):426-31.

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References

• Ostler DA, Prieto VG, Reed JA, Deavers MT, Lazar AJ, Ivan D. Adipophilin expression in sebaceous tumors References and other cutaneous lesions with clear cell histology: an immunohistochemical study of 117 cases. Mod Pathol. 2010;23(4):567-73. • Rangel J, Mccalmont TH. Intracytoplasmic adipophilin immunopositivity: a pitfall in the distinction of metastatic • Poniecka AW, Alexis JB. An immunohistochemical study of basal cell carcinoma and trichoepithelioma. Am J renal carcinoma from sebaceous carcinoma. J Cutan Pathol. 2010;37(12):1193-5. Dermatopathol. 1999;21(4):332-6. • Muthusamy K, Halbert G, Roberts F. Immunohistochemical staining for adipophilin, perilipin and TIP47. J Clin • Metze D, Soyer HP, Zelger B, et al. Expression of a glycoprotein of the carcinoembryonic antigen family in Pathol. 2006;59(11):1166-70. normal and neoplastic sebaceous glands. Limited role of carcinoembryonic antigen as a sweat gland marker. J Am Acad Dermatol. 1996;34(5 Pt 1):735-44. • Kass LG, Hornblass A. Sebaceous carcinoma of the ocular adnexa. Surv Ophthalmol. 1989;33(6):477-90. • Heyderman E, Graham RM, Chapman DV, Richardson TC, Mckee PH. Epithelial markers in primary skin • Hayashi N, Furihata M, Ohtsuki Y, Ueno H. Search for accumulation of p53 protein and detection of human cancer: an immunoperoxidase study of the distribution of epithelial membrane antigen (EMA) and carcinoembryonic antigen (CEA) in 65 primary skin carcinomas. Histopathology. 1984;8(3):423-34. papillomavirus genomes in sebaceous gland carcinoma of the eyelid. Virchows Arch. 1994;424(5):503-9. • Beer TW, Shepherd P, Theaker JM. Ber EP4 and epithelial membrane antigen aid distinction of basal cell, • Rao NA, Hidayat AA, Mclean IW, Zimmerman LE. Sebaceous carcinomas of the ocular adnexa: A squamous cell and basosquamous carcinomas of the skin. Histopathology. 2000;37(3):218-23. clinicopathologic study of 104 cases, with five-year follow-up data. Hum Pathol. 1982;13(2):113-22. • Clark LN, Elwood HR, Uhlenhake EE, Smoller BR, Shalin SC, Gardner JM. Nuclear factor XIIIa staining (clone AC-1A1 mouse monoclonal) is a highly sensitive marker of sebaceous differentiation in normal and neoplastic sebocytes. J Cutan Pathol. 2016;43(8):657-62. • Khandelwal P, Liu S, Sullivan DA. Androgen regulation of gene expression in human meibomian gland and conjunctival epithelial cells. Mol Vis. 2012;18:1055-67. • Kiyosaki K, Nakada C, Hijiya N, et al. Analysis of p53 mutations and the expression of p53 and p21WAF1/CIP1 protein in 15 cases of sebaceous carcinoma of the eyelid. Invest Ophthalmol Vis Sci. 2010;51(1):7-11.

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Biomarkers in Sebaceous Gland Carcinomas Biomarkers in Sebaceous Gland Carcinomas