Background
Sebaceous glands are holocrine, oil-producing glands present in the dermis of mammalian skin. Sebaceous glands are usually attached to hair follicles and are part of a complex skin-adnexal unit known as the folliculoapocrine (sweat) apparatus. The glands are present over the entire body, with the exception of the palms of the hands and the soles of the feet. They are most abundant on the scalp and central face.
Skin adnexal tumors with sebaceous differentiation are uncommon, difficult to classify, and may be controversial. The main controversy concerns the microscopic features, which vary from well-to-poorly differentiated and sometimes undifferentiated varieties. A spectrum of morphologic features can be encountered within the same neoplasm. Most reports include few cases. Large series of cases for comparison and follow-up have not been published.
Because of the intimate association of sebaceous glands with other adnexal structures in the folliculosebaceous-apocrine unit, many sebaceous neoplasms show complex histopathologic features with mixed sebaceous, pilar (hair), and apocrine (sweat) gland differentiations. Therefore, the term sebaceous neoplasm is necessary to include these complex skin adnexal tumors with varying degrees of sebaceous differentiation. The term sebaceous neoplasm includes benign and malignant tumors with different degrees of sebaceous differentiation. The following terms are recognized within this category: sebaceous adenoma, sebaceous epithelioma (sebaceoma), sebaceous carcinoma, basal cell carcinoma with sebaceous differentiation, sebocrine adenoma, and sebomatricoma.
Skin lesions containing benign sebaceous gland proliferation (eg, sebaceous hyperplasia), congenital hamartomas (eg, nevus sebaceus), and lesions with ectopic sebaceous structures (eg, Fordyce spot, Montgomery tubercles) are generally not considered to be true sebaceous neoplasms. [1] True sebaceous neoplasms are relatively rare, while sebaceous hyperplasia is a frequent finding in individuals with chronically sun-exposed skin.
When patients with numerous sebaceous adenomas and/or other neoplasms with sebaceous differentiation have an associated internal malignancy, the clinical condition is known as Muir-Torre syndrome, a subtype of familial nonpolyposis gut carcinoma syndrome, or Lynch syndrome. [2]
Pathophysiology
The sebaceous gland is a secretory structure consisting of sebaceous lobules and ducts. Although the sebaceous gland is a glandular adnexal structure, it is topographically and ontogenetically related to the hair sheath. Therefore, antigenic similarities exist between the isthmus of the outer hair sheath and the germinative basaloid cells of the sebaceous gland. Sebaceous glands are most abundant in the skin of the head and neck regions, particularly in the central face, but they are also present throughout the hair-bearing areas of the body and the mucocutaneous junction, including the labium minus. The eyelids have modified sebaceous glands (ie, Zeis glands of cilia associated with eyelashes, meibomian glands within the tarsal plates of the upper and lower eyelids). [3] Ectopic sebaceous glands, known as the Fordyce condition, commonly occur on the vermilion border of the lips and on the buccal mucosa of adults; these structures are not considered sebaceous neoplasias.
Using transmission electron microscopy, a small number of melanocytes can be identified that synthesize melanin-containing organelles (melanin granules) in the ducts and acini of human sebaceous glands. [4]
As one of the skin's adnexal structures, the sebaceous gland is intimately associated with hair (pilar) and arrector pili muscle. Because of the intimate association of sebaceous glands with hair and apocrine ducts, many sebaceous neoplasms show complex histopathologic features with various elements of pilar and sweat gland differentiation.
Pilar and sebaceous neoplasms share a common expression for both high and low molecular weight cytokeratin that is not seen in most eccrine or apocrine tumors, pointing to similar cellular differentiation patterns of hair and sebaceous structures. Furthermore, the architectural features of sebaceous tumors resemble those of pilar neoplasms, and not those of sweat gland tumors. Many antigens associated with sweat gland neoplasms, including S-100 protein, CA72.4, gross cystic disease fluid protein 15 (GCDFP-15), and carcinoembryonic antigen (CEA), are absent in sebaceous tumors. [5]
Mature sebocytes express antigenicity for epithelial membrane antigen (EMA) and related substances. Some studies have reported selective labeling of sebocytes and their neoplasms for nuclear androgen receptor protein (ARP), but with some contradictory results. Reactivity for immunoglobulin A, lipase, milk fat globule–associated (ovarian carcinoma–associated) sebaceous antigen OV-2, and OKM5 (CD36) antigen may be selective for sebaceous lesions. [6, 7, 8] In addition, studies from 2016 suggest that mature sebocytes have strong nuclear staining for factor XIIIa. [9, 10]
Any sebaceous gland in the body has the potential to develop into sebaceous neoplasms. These tumors are cutaneous adnexal tumors that show varying degrees of sebaceous differentiation. Sebaceous adenoma is defined as a benign epithelial neoplasm composed of sebaceous gland–like structures or tumors with well-recognized sebaceous differentiation by microscopic examination. In most cases of Muir-Torre syndrome, the sebaceous neoplasms and associated viscera malignancies are due to abnormalities of mismatch repair proteins (MSH2, MSH6, MLH1, PMS2) and microsatellite instability. In contrast, sporadic sebaceous neoplasms are usually due to derangements in the Wnt/beta-catenin signaling pathway. Lymphoid enhancer–binding factor (LEF-1) gene mutations are typical of sebaceomas and sebaceous adenomas, while sebaceous carcinomas may have complete silencing of the LEF1 gene. [11]
Etiology
The identification of a truncating germline mutation in the mismatch repair gene, hMLH1 or hMSH2, by DNA molecular genetic study in some patients having cystic sebaceous tumors with Muir-Torre syndrome highlights the value of recognizing cutaneous markers of internal malignancy. [12]
In 1999, Rütten et al [13] studied 19 patients with Muir-Torre syndrome using DNA molecular genetic analysis and reported that 8 (42%) of these patients presented with a cystic variant of sebaceous tumors (including sebaceous adenomas). They concluded that the cystic sebaceous neoplasm is a marker for the mismatch repair–deficient subtype of Muir-Torre syndrome and is associated with a high risk for developing internal malignancies later in life.
Muir-Torre syndrome is an autosomal dominant inherited germline mutation in one of the DNA mismatch repair genes, most commonly hMSH2. [14] It is inherited with a high degree of penetrance and variable expression, with a male-to-female ratio of 3:2. Children of an individual with Muir-Torre syndrome, therefore, may have a 50% risk of inheriting the cancer predisposition. In families in which the germline mutation can be identified, those individuals who have inherited the mutation should undergo regular screening examinations, particularly of the gastrointestinal tract, colorectum, genitourinary tract, and female genital tract.
Epidemiology
Frequency
United States
The exact incidence of sebaceous neoplasms is unknown. Prior to 1967, sebaceous neoplasms were regarded as rare solitary tumors, with only a few published reports of them. However, in 1967, Muir and his colleagues [15] first described the association of multiple sebaceous tumors and carcinoma of the larynx and the intestine. Torre [16] noted that a patient with multiple skin neoplasms showing sebaceous differentiation later developed carcinoma of the ampulla of Vater in the duodenum and in the colon. Multiple sebaceous neoplasms in a patient may be associated with the clinical Muir-Torre syndrome.
International
No reported increased incidence of sebaceous adenoma has occurred in any particular geographical location.
Race
No reported predisposition is reported for any particular race.
Sex
Sebaceous adenomas affect men and women equally.
Age
Sebaceous adenomas frequently appear on the face or scalp of middle-aged and older individuals, after age 50 years. The mean age at onset is 60 years.
Prognosis
Sebaceous adenomas are benign tumor growths that derive from sebaceous glands. Solitary tumors are treated by complete surgical removal with a 100% cure rate. Incomplete removal has occasionally resulted in local recurrence.
When multiple sebaceous adenomas are associated with Muir-Torre syndrome, visceral carcinomas, including adenocarcinomas of the colon, stomach, duodenum, hematologic system, genitourinary tract, endometrium, and larynx (in decreasing order of frequency) may also be present. The most significant feature of Muir-Torre syndrome is the favorable prognosis of each of the associated carcinomas. [17]
However, some of these malignancies have metastatic potential; deaths due to internal malignancies have been reported. The Mayo clinic has established a scoring system to determine the risk of associated disease. The scoring system includes age at presentation of the initial sebaceous neoplasm, the total number of sebaceous neoplasms, any personal history of a Lynch-related cancer, and family history of Lynch-related cancers. Patients with a score of 3 or more were more likely to have Muir-Torre syndrome. [18]
Patient Education
Advise older patients (>60 y) of the potential existence of an internal malignancy when multiple sebaceous neoplasms are present.
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A biopsy-proven sebaceous adenoma on the forehead of a 64-year-old man. The tumor appeared as a dome-shaped, elevated nodule with a circumscribed margin. It measured 8 mm in diameter, with a smooth, shiny, yellow, and speckled appearance. The tumor had a history of slow growth, and the patient had noticed it for more than a year. Note the pearly appearance and the presence of a few capillaries traversing the tumor surface, a feature closely mimicking the clinical appearance of that of a basal cell carcinoma. The total surgical removal of this tumor was uneventful. The patient has not experienced a recurrence.
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Low-power view of a photomicrograph of sebaceous adenoma. Note the dome-shaped elevation of the epidermal surface, the sharp circumscription from the adjacent dermal tissue, and the slight central cystic appearance with eosinophilic secretory material. Patients with sebaceous tumors showing more prominent cystic change have been found to have DNA abnormalities that are linked to a higher risk of the development of internal malignancies at a later date.
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A medium-power view of the well-differentiated SA on the forehead of a 64-year-old man, showing proliferation of well-differentiated sebaceous lobules with central, larger, mature sebocytes and peripheral, smaller, less-differentiated, basaloid, germinative cells. Note that the sebaceous lobules are connected to the overlying epidermis and are slightly off-center in this field; a collection of eosinophilic, pink-colored, keratinous material is present in a dilated follicular ostium within the tumor (hematoxylin and eosin, original magnification X75). In contrast to a sebaceous hyperplasia, a sebaceous adenoma such as seen in this microscopic field contains sebaceous lobules with a 2-cell type and not a single-cell type of sebocytes as seen in the former. The neoplasm was completely removed, with no known recurrences to date.
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Higher-power view of a photomicrograph of a sebaceous adenoma. Note the intermingled 2 cell types, ie, well-differentiated pale-staining sebocytes containing vacuolated (bubbly) cytoplasm and smaller, darkly stained, basaloid, less-differentiated matrix cells. An occasional mitotic figure (arrow) was present. The tumor was completely excised, and no recurrence was noted in this patient after 5 years of follow-up (hematoxylin and eosin, original magnification X200).
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A close-up, higher-power view of the same sebaceous adenoma. The cytologic details are evident. Notice the predominant, larger sebocytes (arrow) containing pale-staining, bubbly cytoplasm (intracytoplasmic compartmentalization) and a few smaller, basaloid, germinative cells of pilosebaceous structures. The nuclei are vesicular without overt pleomorphism or mitotic activity (hematoxylin and eosin, original magnification X300).
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Multiple sebaceous neoplasms on the skin of the chest and the trunk of a 62-year-old man. The tumors were biopsy-proven sebaceous tumors with varying degrees of sebaceous differentiation. The patient was found to have a well-differentiated adenocarcinoma of the colon by subsequent colonoscopy, CT scan, and MRI examination.
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Sebaceous adenoma. Multilobulated and similar in organization to a normal sebaceous gland. Characterized by multiple layers of basaloid germinative cells located peripherally with mature sebocytes comprising the lobule center.
