Sebaceous Adenoma Workup

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.

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

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.

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 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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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 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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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.

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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 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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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]

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]