George H. Martin
Sebaceous neoplasms have long been a source of confusion to dermatologists and there are disagreements regarding nomenclature, classification, and best approaches to management. These lesions include hamartomas, hyperplasias, and benign tumors, as well as highly malignant neoplasms. Specific sebaceous lesions include sebaceous hyperplasia, nevus sebaceous of Jadassohn, sebaceous adenoma, seboacanthoma, sebaceous epithelioma, sebaceoma, mantleoma, basal cell carcinoma with sebaceous differentiation, sebomatricoma (sebomatrixoma), and sebaceous carcinoma (Eisen, 2009).
Sebaceous Gland Carcinoma (SGC)
SGC is an uncommon adnexal neoplasm with a well-documented capacity for regional and distant metastasis. Historically, SGC has been associated with high rates of recurrence after excision (Kyllo, 2015). This tumor is thought to arise from sebaceous glands in the skin and, thus, may occur anywhere on the body where these glands are present. About three-fourths of these tumors arise in the periocular region, an area rich in sebaceous glands (Wu, 2016).
This tumor accounts for 1-5% of eyelid malignancies, it occurs more frequently in women than men, and arises most often in the 6th-7th decade of life. It exhibits an aggressive clinical course, with a significant tendency for both local recurrence and distant metastasis. It usually appears as a painless, slowly enlarging nodule that is yellowish to pink/red color. Diagnosis of ocular SGC is often significantly delayed because it mimics several benign eye conditions, including chalazion, keratoconjunctivitis, blepharoconjunctivitis, and ocular pemphigoid (Wali, 2010).
Suspect SGC when you see:
- Non resolving chalazion:
- Inflammation of the Meibomian glands or glands of Zeis
- Painless granulomatous inflammation
- Most common misdiagnosis of sebaceous carcinoma
- Loss of cilia
- Yellow streaks on conjunctiva
- Increased vascularity
- Chronic unilateral inflammation
Despite the widespread anatomic distribution of sebaceous glands, extraorbital SGC is very rare comprising only 25% of all reported cases for these tumors (Mathur, 2010). Extraocular SGCs most commonly involve the head and neck region, in which sebaceous glands are most plentiful, followed by external genitalia, the parotid and submandibular glands, the external auditory canal, the trunk and upper extremity, sole, the dorsum of the great toe, and laryngeal or pharyngeal cavities (Mathur, 2010). The most frequent clinical presentation is a painless subcutaneous nodule, but it can also present as pedunculated lesions, an irregular mass, or diffuse thickening of the skin. This variable presentation often results in confusion with benign tumors or inflammatory conditions, including basal cell carcinoma (BCC), cutaneous cell carcinoma, squamous cell carcinoma, ceratoacanthoma, cornu cutaneum and Bowen’s disease, as well numerous other malignant and benign lesions thereby leading to delay in diagnosis, inappropriate treatment, increased morbidity, and mortality (Natarajan, 2011; Bolm, 2015).
Muir-Torre syndrome (MTS) is a rare autosomal dominant genodermatosis that predisposes individuals to skin tumors and visceral malignancies. MTS is very rare, with only about 200 cases reported. Males are more commonly affected, with a male to female ratio of 3:2, and individuals can present at any age. Sebaceous tumors precede visceral malignancy diagnosis in 22% of patients, occur simultaneously in 6%, and develop subsequently in 56% of reported MTS cases (Bhaijee, 2014). MTS-related sebaceous tumors include sebaceous adenoma, sebaceoma/sebaceous epithelioma, sebaceous carcinoma, keratoacanthoma with sebaceous differentiation, BCC with sebaceous differentiation, and cystic sebaceous neoplasms (Bhaijee, 2014).
This cancer is potentially very aggressive and close cancer surveillance is required in individuals with MTS and their families (John, 2016). The majority of MTS is caused by a mutation in one of the mismatch repair gene (MHL1, MLH2, or MHL3) (Bhaijee, 2014). However, a newly described subtype of MTS does not demonstrate microsatellite instability and may be inherited in an autosomal recessive pattern. In addition, MTS may be unmasked in transplant recipients taking specific immunosuppressant drugs or other immunosuppressed patients (John, 2016).
- Testing sebaceous lesions for microsatellite instability
- Immunohistochemical staining for mismatch repair genes
Merkel Cell Carcinoma
Merkel cell carcinoma (MCC) was originally described by Toker in 1972 as trabecular carcinoma of the skin. Other names for this malignancy include Toker tumor, primary small cell carcinoma of the skin, primary cutaneous neuroendocrine tumor, and malignant trichodiscoma (NCI, 2015). MCC is an aggressive neuroendocrine carcinoma arising in the dermo-epidermal junction. It was initially thought to be a sweat gland tumor until electron microscopic studies revealed cytoplasmic secretory granules in tumor cells (Munde, 2013). In Surveillance, Epidemiology and End Results Program data from 1986 to 2001, the age-adjusted United States annual incidence of MCC tripled from 0.15 to 0.44 per 100,000, an increase of 8.08% per year. This rate of increase is faster than any other skin cancer including melanoma and the reason for it is not known (NCI, 2015).
The etiology of MCC is not fully understood, but in 2008, a novel polyomavirus (Merkel cell polyoma virus, MCPyV) was first reported in MCC tumor specimens. High levels of viral DNA and clonal integration of the virus in MCC tumors have also been reported. It has been suggested that there may be two independent pathways for the development of MCC: one driven by the presence of MCPyV and the other driven primarily by sun damage (Saini, 2015; Tothill, 2015).
MCC lesions are blue or red, firm, non-tender, solitary, dome-shaped nodules.
Occasional plaque-like or subcutaneous masses may also be observed. Lesions are typically <2 cm, but they may reach 20 cm in size. MCC occurs most frequently in sun-exposed areas of skin, particularly the head and neck, followed by the extremities, and then the trunk with >25% of cases on the face (NCI, 2015). MCC can infiltrate locally via dermal lymphatics, resulting in multiple satellite lesions. Because of its nonspecific clinical appearance, MCC is rarely suspected prior to biopsy (NCI, 2015).
Histopathologically, monomorphic dermal and/or subcutaneous nodes are found consisting of round or oval medium sized cells with a vesicular nucleus and sparse cytoplasm. The neoplastic cells of MCC express cytokeratin (CK) 20 with a dot-like perinuclear accentuation. In addition, pan-CK, neuroendocrine markers (e.g., chromogranin A and synaptophysin), neurofilament proteins, CD56, CD57, Bcl-2, terminal deoxynucleotidyl transferase (TdT), and PAX-5 are immunohistochemically positive. CM2B4, an antibody against MCPyV is also positive in most tumors (Fried, 2014). Expression of p63 has been observed in some of the cases of MCC and has been associated with a poorer prognosis (Asioli, 2011). It has also been shown that Ki-67 staining predicts poor outcomes in patients with MCC (Vujic, 2015). In contrast, overall survival is higher in patients with Bcl-2-positive tumors vs those with negative tumors (Sahi, 2012)
Sentinel Lymph Node Biopsy (SLNB)
Sentinel lymph node positivity is strongly predictive of high short-term risk for recurrence or metastasis in patients with MCC. A study carried out about 15 years ago indicated that therapeutic lymph node dissection appears effective in preventing short-term regional nodal recurrence and aggressive adjuvant treatment should be considered for patients with positive sentinel lymph nodes (Mehrany, 2002). A more recent study that included 153 patients with localized MCC indicated that SLNB identifies occult nodal metastases in 29% of patients with localized MCC. Predictors of SLNB positivity are tumor size and presence of lymphovascular invasion (Fields, 2011). Most recently, a record review for 161 patients with MCC treated at a single institution indicated that SLNB identified micrometastases in 33% of 27 early-stage patients. Recurrence developed in 56% of SLNB-positive vs 39% of SLNB-negative patients (Santamaria-Barria, 2013).
Immunohistochemical assessment of SLNBs from 10 patients with MCC indicated that all micrometastatic foci stained strongly for CK-20. The authors of this study noted examination of hematoxylin and eosin (H&E) sections alone is insufficient for excluding micrometastatic MCC in sentinel lymph nodes and that staining for CK-20 has high sensitivity and specificity (Su, 2002).
Multidisciplinary treatment is essential to deliver optimal care to patients with MCC. Surgery involves a wide local excision with or without adjuvant therapy depending on the size of the primary lesion and stage of disease. There is controversy regarding the ideal margin width, and the National Comprehensive Cancer Network guidelines recommend 1–2 cm margins when feasible (NCCN, 2016). Mohs micrographic surgery has been employed as an alternative to wide local excision. Among the benefits of this approach are tissue conservation and identification of tumors that would otherwise require extremely wide excision margins (Boyer, 2002). Nevertheless, surgical resection of MCC with negative margins is the preferred primary modality of therapy when possible (Saini, 2015).
Radiation therapy can be considered for primary therapy in patients who are not surgical candidates. Postsurgical adjuvant radiation is often indicated in the treatment of MCC and is shown to improve outcomes (Saini, 2015). However, data are conflicting as to whether there is any survival benefit from adjuvant primary site or regional nodal irradiation, partly due to the lack of prospective clinical trials (Prewett, 2015). Chemotherapy is currently used in advanced stage MCC and as palliative therapy. There is no standard choice of chemotherapeutic agent (Saini, 2015).
Recent work also suggests that immunotherapy targeting the programmed cell death receptor 1/programmed cell death ligand 1 (PD-1/PD-L1) checkpoint holds great promise in treating advanced MCC and may provide durable responses in a portion of patients (Cassler, 2016). First-line therapy with pembrolizumab in 26 patients with advanced MCC was associated with an objective response rate of 56%. Responses were observed in patients with virus-positive and –negative tumors (Nghiem, 2016).
- Wide local excision (2 cm margins) or Mohs surgery
- Sentinel lymph node biopsy with anti-CK20 antibody if H&E eosin is negative
- For positive node:
- Therapeutic node dissection
- Adjuvant radiation and/or chemotherapy
- Consider immunotherapy in patients with advanced disease
Asioli S, Righi A, de Biase D, et al. Expression of p63 is the sole independent marker of aggressiveness in localised (stage I-II) Merkel cell carcinomas. Mod Pathol. 2011;24:1451-1461.
Bhaijee F, Brown AS. Muir-Torre syndrome. Arch Pathol Lab Med. 2014;138:1685-1689.
Bolm I, Babaryka G, Moergel M, Al-Nawas B, Kämmerer PW. Multifocal metastasizing extra-ocular facial sebaceous carcinoma as diagnostic challenge: case report and systematic review. J Maxillofac Oral Surg. 2015;14 (Suppl 1):331-337.
Boyer JD, Zitelli JA, Brodland DG, D’Angelo G. Local control of primary Merkel cell carcinoma: review of 45 cases treated with Mohs micrographic surgery with and without adjuvant radiation. J Am Acad Dermatol. 2002;47:885-892.
Cassler NM, Merrill D, Bichakjian CK, Brownell I. Merkel Cell Carcinoma Therapeutic Update. Curr Treat Options Oncol. 2016;17:36.
Eisen DB, Michael DJ. Sebaceous lesions and their associated syndromes: part I J Am Acad Dermatol. 2009;61:549-560.
Fields RC, Busam KJ, Chou JF, et al. Recurrence and survival in patients undergoing sentinel lymph node biopsy for Merkel cell carcinoma: analysis of 153 patients from a single institution. Ann Surg Oncol. 2011;18:2529-2537.
Fried I, Cerroni L. Merkel cell carcinoma. Pathologe. 2014;35:467-75.
John AM, Schwartz RA. Muir-Torre syndrome (MTS): An update and approach to diagnosis and management. J Am Acad Dermatol. 2016;74:558-566.
Kyllo RL, Brady KL, Hurst EA. Sebaceous carcinoma: review of the literature. Dermatol Surg. 2015;41:1-15.
Mathur SK, Singh S, Rajni Y, Amrita R, Rajeev S. Extraocular sebaceous carcinoma – a rare tumour at a rare site. Egypt Dermatol Online J. 2010;6:14.
Mehrany K, Otley CC, Weenig RH, Phillips PK, Roenigk RK, Nguyen TH. A meta-analysis of the prognostic significance of sentinel lymph node status in Merkel cell carcinoma. Dermatol Surg. 2002;28:113-117.
Munde PB, Khandekar SP, Dive AM, Sharma A. Pathophysiology of Merkel cell. J Oral Maxillofac Pathol. 2013;17:408-412.
Natarajan K, Rai R, Pillai SB. Extra ocular sebaceous carcinoma: a rare case report. Indian Dermatol Online J. 2011;2:91-93.
National Comprehensive Cancer Network. Merkel Cell Carcinoma. Version I. 2016. Available at: https://www.nccn.org/professionals/physician_gls/pdf/mcc.pdf.
National Cancer Institute. PDQ Adult Treatment Editorial Board. Merkel Cell Carcinoma Treatment (PDQ®): Health Professional Version. 2015 Apr 9. PDQ Cancer Information Summaries [Internet]. Bethesda (MD): National Cancer Institute (US); 2002-. Available at: http://www.ncbi.nlm.nih.gov/books/NBK65713/
Nghiem PT, Bhatia S, Lipson EJ, et al. PD-1 Blockade with Pembrolizumab in Advanced Merkel-Cell Carcinoma. N Engl J Med. 2016;374:2542-2552.
Prewett SL, Ajithkumar T. Merkel Cell Carcinoma: Current Management and Controversies. Clin Oncol (R Coll Radiol). 2015;27:436-444.
Sahi H, Koljonen V, Kavola H, et al. Bcl-2 expression indicates better prognosis of Merkel cell carcinoma regardless of the presence of Merkel cell polyomavirus. Virchows Arch. 2012;461:553-559.
Saini AT, Miles BA. Merkel cell carcinoma of the head and neck: pathogenesis, current and emerging treatment options. Onco Targets Ther. 2015;8:2157-2167.
Santamaria-Barria JA, Boland GM, Yeap BY, Nardi V, Dias-Santagata D, Cusack JC Jr. Merkel cell carcinoma: 30-year experience from a single institution. Ann Surg Oncol. 2013;20:1365-1373.
Tothill R, Estall V, Rischin D. Merkel cell carcinoma: emerging biology, current approaches, and future directions. Am Soc Clin Oncol Educ Book. 2015:e519-526.
Vujic I, Marker M, Posch C, et al. Merkel cell carcinoma: mitoses, expression of Ki-67 and bcl-2 correlate with disease progression. J Eur Acad Dermatol Venereol. 2015;29:542-548.
Wali UK, Al-Mujaini A. Sebaceous gland carcinoma of the eyelid. Oman J Ophthalmol. 2010;3:117-121.
Wu W. Dermatologic manifestations of sebaceous carcinoma. Medscape. 2016. http://reference.medscape.com/article/1101433-overview.