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Sebaceous Carcinoma of the Eyelid Carlos Prieto-Granada, MD, and Paul Rodriguez-Waitkus, MD, Phd

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Sebaceous Carcinoma of the Eyelid Carlos Prieto-Granada, MD, and Paul Rodriguez-Waitkus, MD, Phd Helpful immunostains for the differential diagnosis of PSC include EMA, Ber-Ep4, AR, and adipophilin. Photo courtesy of Lynn E. Harman, MD. Half Dome From Glacier Point. Sebaceous Carcinoma of the Eyelid Carlos Prieto-Granada, MD, and Paul Rodriguez-Waitkus, MD, PhD Background: Periocular sebaceous carcinoma (PSC) is a rare but aggressive neoplasm that tends to clinically and histopathologically mimic other conditions. PSC can be challenging to diagnose using histomorphology alone given its overlap with 2 more common tumors that occur in this area (basal cell carcinoma [BCC] and squamous cell carcinoma [SCC]). Use of immunohistochemistry can help resolve this differential diagnosis. Methods: A review of the literature was performed, focusing on the epidemiology, morphology, and immu- nohistochemical features of PSC. Results: The most useful immunostains in the differential diagnosis of PSC are epithelial membrane antigen, Ber-Ep4, androgen receptor (AR), and adipophilin. To discern PSC from BCC, one should use EMA, Ber-Ep4, AR, and adipophilin, whereas discerning PSC from SCC can be achieved by evaluating AR and adipophilin. In addition, p53 and ERBB2 (formally known as HER2/neu) are other potentially useful immunohistochemi- cal markers for the differential diagnosis of PSC. Conclusions: Use of new immunohistochemical techniques, as well as the elucidation of molecular alterations, such as the presence of ERBB2 amplification, will advance our understanding of PSC. Introduction 5% of all malignant neoplasms arising in the periocu- Cutaneous sebaceous carcinoma is a rare disease that lar region, followed basal cell carcinoma (BCC), which makes up an estimated 0.05% of all cutaneous malig- makes up 90% of eyelid malignancies.4-6 nancies.1,2 However, because the eyelid and periocular In general, periocular sebaceous carcinoma (PSC) regions harbor a high density of sebaceous glands ei- presents in the elderly (average of 70 years of age).1-3 ther associated with eyelashes (Zeis) or the tarsal plate Predisposing factors, such as immunosuppression, pri- (meibomian), it is not surprising that, when consider- or history of radiotherapy to the head and neck, and ing all cutaneous sebaceous carcinomas, up to 40% of Muir–Torre syndrome, occur in a minority of patients.7 these tumors arise in this particular anatomical site.3 PSC can clinically present as a diffuse thickening of the In the United States, sebaceous carcinoma represents eyelid, often exhibiting inflammatory features. More advanced cases are characterized as a discrete, palpe- bral mass. The clinical presentation of early-stage PSC From the Departments of Dermatology & Cutaneous Surgery (CP- has the potential of mimicking non-neoplastic lesions, G, PR-W) and Pathology & Cell Biology (PR-W), Morsani College of Medicine, University of South Florida, Tampa, Florida. notably chalazion, keratoconjunctivitis, and other in- 5,8,9 Address correspondence to Carlos Prieto-Granada, MD, Universi- flammatory, non-neoplastic processes. Thus, those ty of South Florida, 13330 USF Laurel Drive, Fourth floor, Tampa, with PSC are at an increased risk for delayed diagnosis. FL 33612. E-mail: [email protected] Historically, a diagnosis of PSC was associ- Submitted August 15, 2015; accepted December 17, 2015. ated with a poor prognosis and a mortality rate that No significant relationships exist between the authors and the 10,11 companies/organizations whose products or services may be ref- reached 50%. However, with increased disease erenced in this article. awareness and the introduction of better diagnostic 126 Cancer Control April 2016, Vol. 23, No. 2 techniques, rates of survival have improved (mortal- In a similar fashion to cutaneous sebaceous carci- ity rates of 2%–11%).4,11,12 Early identification is crucial noma, cytologically PSC tumors are composed of 3 ba- and relies on a high level of clinical suspicion, together sic cell types: basaloid, sebaceous/vacuolated cells, and with an accurate histopathological diagnosis that often intermediate forms. These cell types are usually inter- depends on small or limited specimens on biopsy. mixed at varying ratios, which will determine the level of differentiation of a given tumor, among other factors Histomorphology (see Figs 2D, 2E, and 2G). Broadly speaking, the per- When examining the invasive component of PSC at centage of basaloid cells will be inversely correlated low magnification, 4 basic morphological patterns with the level of differentiation, which ranges from well- can be recognized: trabecular, lobular, papillary, and differentiated tumors to poorly differentiated and ana- BCC-like (Figs 1 and 2).7 Similar to BCC, a mixture of plastic/de-differentiated tumors. 2 or more of these patterns can be seen in a single le- Another factor to consider when grading a lesion is sion. However, all of the classic features of BCC are the architecture of the tumor. Well-differentiated PSC tu- not found, such as peripheral palisading, tumor–stro- mors are often nodular, whereas poorly differentiated mal cleft artifacts, and mucinous/myxoid spindle cell tumors are more infiltrative. Taking into account all of stroma. The trabecular pattern of PSC has a tendency these features, including grading, architecture, presence to reveal areas of central comedo-like necrosis. An in or absence of an in situ component/pagetoid spread, as situ component of PSC may be encountered, either as a well as presence of spread to distant sites, the following standalone lesion as well as adjacent or overlying an in- 4-tiered classification has been proposed13: PSC in situ, vasive lesion (see Figs 1C–F). The intraepithelial lesions low-grade, high-grade infiltrating PSC with or without are often bowenoid in appearance and can exhibit exu- pagetoid spread, and PSC with extraocular/extracutane- berant pagetoid spread (see Figs 1D and 1E). They can ous spread, including distant metastases. also radially spread by undermining the normal con- In addition to its ability to clinically mimic other le- junctival epithelium (see Fig 1F). Keratinization is not sions, PSC can also overlap the histopathology of several usually a feature of PSC. The presence of changing ke- benign and malignant entities encountered in the peri- ratinization should prompt the health care professional ocular region. Among the benign processes, the health to consider squamous cell carcinoma (SCC) with seba- care professional should consider sebaceous adenoma,14 ceous differentiation rather than PSC.7 follicular adnexal tumors (eg, desmoplastic trichoepithe- A B C D E F Fig 1A–F. Composite demonstrating different morphological patterns of PSC. (A) Basal cell carcinoma–like type of configuration. H & E, ×40. (B) Complete with superficial ulceration with the presence of vacuolated cells. H & E, ×200. (C, D) Usual presentation of PSC with extensive intraepi- dermal involvement exhibiting pagetoid spread. A subjacent main tumor mass is present with tumor cells expanding into the epidermis through the follicular structures. C: H & E, ×20. D: H & E, ×100 (E) High-power imaging shows the nuclear features of PSC: vesicular chromatin with prominent yet small nucleoli. H & E, ×200. (F) The radial extension of PSC cells through normal epithelium reveals conjunctival mucosa undermined by tumor cells. H & E, ×40. H & E = hematoxylin and eosin, PSC = periocular sebaceous carcinoma. April 2016, Vol. 23, No. 2 Cancer Control 127 A B C D E F G H I Fig 2A–I. — Panel exhibiting immunohistochemical staining patterns of 3 markers useful for the differential diagnosis of PSC. (A–C) Epithelial membrane antigen often exhibits patchy but intense membranous and cytoplasmic positivity in PSC. An internal control is present and represented by normal sebaceous glands (C, arrow). A: H & E, ×20. B: H & E, ×20. C: H & E, ×200. (A, D, E) Although this case exhibits a basal cell carcinoma–like pattern (D and E: H & E, ×200), (F) Ber-Ep4 is completely negative. F: H & E, ×200. An internal control is present in the germinative portion of an adjacent follicular structure (arrow). (G) The presence of intermediate cells with lipid vacuoles (arrows) is highlighted with adipophilin. G: H & E, ×400. (H, I) A “vacuolar-type” staining pattern is seen. H: H & E, ×200. I: H & E, ×400. H & E = hematoxylin and eosin, PSC = periocular sebaceous carcinoma. lioma),15 trichoadenoma,16 and squamous papilloma.17-19 Merkel cell carcinoma, which have washed-out, neu- When considering malignancies, the 2 main possibilities roendocrine-type chromatin. By contrast, melanoma are BCC — particularly with sebaceous differentiation cells often display large nuclei with vesicular chroma- — and SCC with sebaceous differentiation (rare). The tin and macronucleoli. In a proportion of poorly dif- latter also includes a basaloid variant. A rare but plau- ferentiated types of PSC (approximately 23%–77%), sible differential diagnostic possibility — particularly morphological assessment will be hampered by the for poorly differentiated types of PSC — is Merkel cell presence of overlapping features with other entities carcinoma, which is a malignant neoplasm with a predi- included the differential diagnosis.4,22,23 In such situa- lection to arise in the head and neck area.20,21 When con- tions, immunohistochemical stains may be helpful. fronted with in situ PSC with abundant pagetoid spread, other pagetoid malignancies such as pagetoid SCC in Immunohistochemistry situ, melanoma in situ, and intraepidermal Merkel cell Among the malignant tumors that arise in the perioc- carcinoma should be considered. ular region, the 3 most common are BCC, squamous Morphologically, the nuclear features in PSC tu- cell carcinoma (SCC), and PSC.5,6 Several immunohis- mor cells have a distinctive shape — namely, they tochemical markers are useful in the differential diag- are round, oval, or indented — and contain fine, ink- nosis, including epithelial antigens, as are hormonal drop, or smudgy chromatin with 1 or 2 small nucleoli markers and other markers highlighting fat vacuole (see Figs 1E and 2G).7 These features are not found in production. Immunohistochemical stains will also re- 128 Cancer Control April 2016, Vol. 23, No. 2 flect subjacent molecular al- terations.
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