Sebaceous Adenoma 

Updated: Aug 05, 2019
Author: Nicole Ufkes; Chief Editor: William D James, MD 

Overview

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.

 

Presentation

History

Patients with sebaceous adenomas typically experience a gradual onset of small, usually less than 0.5 cm in diameter (2-4 mm), smooth, yellow, sometimes speckled papules that may feature crusting or central umbilication. Typically, they grow on the skin of the face or scalp over the course of a few months and are asymptomatic.

Identification of sebaceous adenomas is crucial because of their association with Muir-Torre syndrome. In Muir-Torre syndrome, germline mutations in mismatch repair genes result in regions of DNA microsatellite instability and subsequent increased risk of developing internal malignancies, commonly colorectal and genitourinary carcinomas.

Physical Examination

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.

Sebaceous adenomas range from less than 1 cm (usually 2-4 mm) to greater than 5 cm in maximum dimension. Tumors most frequently appear as a yellow, speckled, smooth-surfaced, circumscribed papule or nodule (see the image below). They can be tan or pink-to-red, and they may feature a polypoid appearance, crusting, and/or central umbilication.

A biopsy-proven sebaceous adenoma on the forehead 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.

Tumors are commonly located on the face, the scalp, and the neck. Occasionally, tumors may be seen at other sites, including the trunk and the legs. Sebaceous adenomas have been described on the caruncle of the eye,[19] eyelid,[20] bulbar conjunctiva,[21] and buccal mucosa.[22]

The clinical impression prior to the time of biopsy is usually that of basal cell carcinoma or a nondescript papule without definitive clinical diagnosis.

 

DDx

Differential Diagnoses

 

Workup

Laboratory Studies

Appropriate laboratory testing for possible occult internal malignancies, such as gastrointestinal tract, hematologic, or laryngeal carcinomas, is indicated. The following laboratory tests can be of diagnostic value if patients present with cutaneous signs of Muir-Torre syndrome:

  • Sigmoidoscopy may be performed to screen for colonic polyposis and colonic carcinoma.

  • Perform endoscopy to check for an occult gastric carcinoma.

  • Serum carcinoembryonic antigen values are frequently increased in patients with colonic carcinomas.

  • A complete blood cell count assists in detecting hematologic malignancies.

  • Bone marrow examination may be needed to further delineate a hematologic malignancy.

  • Laryngoscopy with biopsy examination of any suspicious lesions can rule out an occult laryngeal carcinoma.

Imaging Studies

Abdominal CT scanning and MRI assist in detecting an occult internal malignancy, such as kidney and urothelial cancers, in patients with Muir-Torre syndrome.

Procedures

A biopsy of skin tumors performed for histopathologic examination provides an accurate diagnosis of sebaceous neoplasms, including sebaceous adenomas.[23] Sebaceous adenoma and sebaceous hyperplasia are often physically and histologically similar in appearance. However, it is important to distinguish between the two, as sebaceous adenoma is the most common sebaceous tumor in Muir-Torre syndrome, whereas sebaceous hyperplasia is not associated with Muir-Torre syndrome and is a common occurrence in the general population.[11]

Histopathologic examination of specimens obtained from polypectomy and laryngoscopy of patients with suspected Muir-Torre syndrome confirms the presence or the absence of occult internal malignancy.[24] Peripheral blood smear, bone marrow examination, and lymph node biopsy may assist in detecting an associated hematologic malignancy in these patients.

Histologic Findings

Controversy surrounds the classification of sebaceous neoplasms. Some authors maintain that all lesions called sebaceous adenoma are, in fact, sebaceous carcinoma. Their arguments are largely based on histologic findings, rather than evidence concerning tumor biology or behavior. Until evidence suggests that these lesions are capable of behaving in a malignant fashion, classifying them separately from sebaceous carcinoma may be preferable. Complete excision of all sebaceous tumors is indicated.

Sebaceous adenomas are typically multilobulated tumors located in the upper dermis with frequent connections to the epidermis, and they often bear a strong resemblance to normal sebaceous glands. At a low-power view, sebaceous adenomas are well-circumscribed and sharply demarcated from the surrounding tissue (see first image below), with a proliferation of variously sized sebaceous lobules consisting of central, larger, mature sebaceous cells (sebocytes); peripheral, smaller, undifferentiated, germinative basaloid cells (see second and third images below); and transitional cells.

Low-power view of a photomicrograph of sebaceous a 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.
A medium-power view of the well-differentiated SA 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.
Higher-power view of a photomicrograph of a sebace 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).

The sebocytes contain pale-staining, foamy-to-bubbly cytoplasm, and central, crenated, hyperchromatic nuclei. The smaller, immature germinative sebocytes contain round-to-oval, vesicular nuclei and basophilic cytoplasm (see image below). The transitional cells show more eosinophilic cytoplasm.

A close-up, higher-power view of the same sebaceou 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).

 

Sebaceous adenoma. Multilobulated and similar in o 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.

Both sebaceous adenomas and hyperplasias present as well-circumscribed tumors composed of lobules of sebaceous cells. To distinguish between the two, the ratio of mature sebocytes to basaloid germ cells is used.[25] Sebaceous adenomas are characterized by greater numbers of germinative cells. Centrally located sebocytes are surrounded by two layers of germinative cells in the periphery of the lobules. Nuclear hyperchromatism, prominent nucleoli, cellular atypia, and high mitotic activity are rarely observed in sebaceous adenoma lesions.

In both benign and malignant sebaceous proliferations, the characteristic bubbly cytoplasmic profile of the mature sebocyte is maintained. The presence of tumor cells with sebaceous differentiation requires special histochemical techniques, such as oil red O or Sudan IV stains, on fresh tissue and epithelial membrane antigen (EMA) immunostains in paraffin-embedded tissue to highlight their presence. EMA staining in these tumors is comparable to that seen in non-neoplastic sebaceous epithelium, in that cytoplasmic lipid vesicles are rimmed by EMA reactivity.

The Muir-Torre variant of sebaceous adenoma tends to show more prominent cystic change, peripheral-disposed basaloid, germinative-type cells, often with mild nuclear pleomorphism, distinct nucleoli, and moderate mitotic activity. Note that patients with Muir-Torre syndrome (see image below) frequently present with sebaceous adenomas with classic histologic features of solitary tumors. No histologic features of sebaceous adenoma can reliably pinpoint an association with Muir-Torre syndrome, but loss of nuclear staining for MLH-1 or MSH-2 is highly suggestive of the syndrome. These tests are performed by the immunoperoxidase method.[26, 27, 28]

Multiple sebaceous neoplasms on the skin of the ch 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.

Neoplasms with sebaceous differentiation have many and disparate morphologic features because of different degrees of differentiation within the same tumor. Thus, the classification of these tumors can sometimes be difficult and confusing, which has resulted in the use of various histologic diagnostic terms in the literature. The differential features are listed below.

Sebaceous carcinomas differ from sebaceous adenomas by the presence of dermal aggregates of markedly atypical and poorly differentiated polyhedral tumor cells separated by fibrovascular stroma. The central portion of the cell nests frequently undergoes necrosis, resulting in a comedo pattern on scanning microscopy. The bubbly cytoplasm or intracellular compartmentalized vacuoles in sebaceous carcinoma are not as conspicuous as those seen in sebaceous adenomas.[29] As sebaceous adenomas are typically confined to the superficial dermis, any tumor that extends into the deep dermis with cytologic atypia and/or high mitotic activity should be evaluated as a well-differentiated sebaceous carcinoma.

Sebaceous carcinomas differ from Merkel cell carcinoma (another poorly differentiated skin cancer) in the negative expression of CK20 and neuron-specific enolase (NSE) and positive EMA on immunohistochemical examination.

Sebaceous epitheliomas share many histologic features of sebaceous adenomas, except for the presence of more than 50% of cells of the smaller, germinative, basaloid type. Some use the term basal cell carcinoma with sebaceous differentiation as a synonym for sebaceous epithelioma because the histologic features of these lesions can be difficult to distinguish; however, the former exhibits more of the histologic criteria of basal cell carcinoma.

Sebaceomas are benign cutaneous adnexal neoplasms with complex histologic differentiating features. They are typically circumscribed symmetrical neoplasms with smooth borders, composed of solid nodules of cells with variable cystic changes and the formation of ductlike structures.[30] Sebaceomas are classically differentiated from sebaceous adenomas by the presence of greater than 50% basaloid germinative cells. In addition, sebaceomas often lack the normal sebaceous lobule architecture (characterized by peripheral germinative cells and central mature sebocytes) that sebaceous adenomas maintain.[30] Mitotic activity may be high in sebaceomas; however, cellular atypia or necroses should not be present.[11]

Sebomatricoma is a term that has been suggested to include all benign tumors with sebaceous differentiation, including sebaceous hyperplasia, sebaceous adenoma, sebaceoma, and sebaceous epithelioma.[31]

Other Tests

To date, specific markers of sebaceous differentiation have not been described. However, use of an antibody panel directed at EMA, S-100 protein, and carcinoembryonic antigen (CEA) allows differentiation between sebaceous and sweat gland neoplasms in most instances. Sebaceous neoplasms typically stain positive for epithelial membrane antigen (EMA), while sweat gland epithelium stains for S-100 protein and CEA. Ber-Ep4, a marker for hair follicle differentiation, is typically negative in the sebocytes of sebaceous neoplasms, while basal cell carcinomas or trichoblastomas are typically positive for BerEp4.[32]

Cytokine 19 has also been useful for separating sebaceous tumors from basal cell carcinomas.[33] A 2017 study investigated the expression of terminal deoxynucleotidyl transferase (TdT) expression in sebaceous cell neoplasms and hyperplasia as compared with basal cell carcinomas.[34] While positive in the sebaceous neoplasms, TdT expression was consistently negative in basal cell carcinomas. More research is needed to determine the role of TdT in sebaceous cells.

GATA3 is positive in many epithelial tumors. It may help distinguish sebaceous adenoma from acrospiromas, but not from basal cell carcinoma or sebaceous carcinoma.[35]

In 2016, nuclear factor XIIIa (AC-1A1) staining was identified as a marker of sebaceous neoplasms.[9, 10] Factor XIIIa is a blood proenzyme found in fibroblasts and dermal dendritic cells, along with platelets, macrophages, and megakaryocytes. A study found that positive and strong staining for nuclear factor XIIIa was present in 100% of sebaceous neoplasms, while nonsebaceous clear-cell tumors were 95.5% negative or only weakly positive for factor XIIIa.[9] Furthermore, factor XIIIa shows increased sensitivity (87.3%) and specificity (95.1%) in the diagnosis of sebaceous neoplasms, as compared with adipophilin (83.2% sensitivity, 87.8% specificity) and GATA3 (80.9% sensitivity, 75.6% specificity).[36] Thus, factor XIIIa (AC‐1A1) may be a useful adjunct to the histologic evaluation of neoplasms with suspected sebaceous differentiation.

MLH-1 and MSH-2 immunostains can be applied to paraffin-embedded sections. Loss of mismatch repair protein expression suggests microsatellite instability and likely Muir-Torre syndrome. Immunohistochemical evaluation for the expression of mismatch repair proteins (MLH1, MSH2, MSH6, and PMS2) should be used in the initial diagnosis of sebaceous neoplasms in patients with suspected Muir-Torre syndrome.[37, 38]

The Muir-Torre variant of sebaceous adenoma tends to show more prominent cystic change, peripheral-disposed basaloid, germinative-type cells, often with mild nuclear pleomorphism, distinct nucleoli, and moderate mitotic activity. Note that patients with Muir-Torre syndrome (see image below) frequently present with sebaceous adenomas with classic histologic features of solitary tumors. Clinicopathological correlation is necessary to assess the risk of associated Muir-Torre syndrome. Loss of nuclear staining for MLH-1 or MSH-2 is common in sebaceous adenomas, and most of these patients do not have the syndrome. These tests are performed by the immunoperoxidase method. Testing for loss in sebaceous adenomas may make no more sense than testing for neurofibromin loss in a sporadic neurofibroma. The gene has to be mutated in order to grow the tumor, but a single neurofibroma does not correlate with germline mutation.[39]

 

Treatment

Medical Care

Recognizing the presence of sebaceous neoplasms can help identify patients with Muir-Torre syndrome; then, early treatment of an associated occult malignancy may be started. Except for the patients with Muir-Torre syndrome, no inpatient care is recommended for patients with sebaceous adenoma.

Surgical Care

The usual treatment of sebaceous adenoma is complete excision. Surgical treatment of sebaceous adenomas is aimed at completely removing the tumor and preventing regrowth of the tumorous tissue.

Consultations

Referring patients with cutaneous signs of Muir-Torre syndrome to a gastroenterologist, hematologist, or otolaryngologist is essential for dermatologists to rule out the presence of an occult malignant tumor.

Long-Term Monitoring

Completely remove sebaceous adenomas surgically to prevent local recurrences.