Microcystic Adnexal Carcinoma Workup

CT scanning may be used to map out local invasion into nerves, muscle, cartilage, or bone, and it may also be used to help define metastatic disease, if suspected. MRI has also been used to assess tumor extent.^{[11, 13]} However, imaging is not necessary in most cases of microcystic adnexal carcinoma (MAC).

A deep incisional or excisional biopsy is required. Superficial biopsies lead to misdiagnosis because deep extension and perineural invasion are key features of the tumor.

Note the images below.

Hematoxylin and eosin

Hematoxylin and eosin of deep biopsy specimens (preferably to subcutaneous fat) still remains the criterion standard in diagnosing microcystic adnexal carcinoma. Overall, microcystic adnexal carcinoma is a poorly circumscribed, deeply infiltrative, asymmetric tumor composed of variable proportions of keratocysts, squamoid or basaloid nests, infiltrating cords, and ductular structures set in a variably hyalinized but usually paucicellular desmoplastic stroma. In a minority of cases, microcystic adnexal carcinoma shows attachment to the epidermis or the follicles, but generally, a striking zonal separation is noted between the tumor and the epidermis.

In the superficial aspects of the tumor, small-to-medium keratinizing cysts lined by squamous epithelium can be seen. Atypia and mitoses are sparse. Nests of small basaloid or squamoid cells, sometimes showing a whorled-appearing infiltrate between the cysts with depth, are present. These may be solid, show central keratinization, can rarely be calcified or demonstrate central lumen formation, and have a tadpole or paisley-tie appearance.

In deeper sections, variable numbers of small ducts lined by 1-2 layers of cuboidal cells are present throughout the tumor. Narrow cords of cuboidal cells usually characterize the deepest portion of the tumor. Some of the nests and ducts show tail-like cellular extensions reminiscent of syringoma. Glycogen-rich, clear-cell change, foci of decapitation secretion, and sebaceous cell or duct differentiation may be present. The nuclei of all the components are mainly small, slightly irregular, and hyperchromatic, but little pleomorphism or mitotic activity occurs. Perineural infiltration is common. Lymphoid aggregates are common, particularly at the dermal-subcutaneous junction.

With regard to histologic subtype, tumors displaying the architectural features of microcystic adnexal carcinoma but with increased nuclear pleomorphism, hyperchromasia, vascular invasion, and necrosis may be suggestive of a more aggressive subtype. Clinically, these can demonstrate rapid growth, carcinosarcomatous metaplastic transformation with relapse, and suspected metastases.^[16]

Toluidine blue

Special staining with toluidine blue has been shown to highlight infiltrating tumor strands with a distinctive pink halo and perineural invasion with a maroon tint.^[31] This stain may be of benefit in Mohs micrographic surgery (MMS).

Immunohistochemistry

Definitive immunostaining to differentiate microcystic adnexal carcinoma from other sclerosing neoplasms, especially in superficial samples, is lacking. However, a few stains can be of some assistance.

p63, a member of the p53 gene family highly expressed in the basal cells and adnexa of human epithelial tissues, was compared with microcystic adnexal carcinoma, sclerosing basal cell carcinoma (SBCC), and desmoplastic trichoepithelioma (DTE) in one study. All tumors were stained with p63, but the nuclear staining pattern was more complete and diffuse in SBCC (20 of 20 cases) and DTE (10 of 10 cases). Individual microcystic adnexal carcinoma tumor islands had selective "scattered" positivity mostly confined to the periphery (5 of 5 cases) and even extinguished with tumor depth. The disadvantage is that the scattered pattern was most obvious in deeper portions of microcystic adnexal carcinoma and may not be of help in superficial biopsies.^[32]

CK (cytokeratin)–15 was found in a study using a battery of immunomarkers (ie, CK15, CK7, CK20, CK903, carcinoembryonic antigen (CEA), CD10, CD15, BerEP4) to stain microcystic adnexal carcinoma (92% of 13 cases) and DTE (100% of 8 cases), but not infiltrative basal carcinomas (10 cases) or squamous cell carcinomas (8 cases, 5 with ductal differentiation). Although the other stains were not reliably distinguishing, CK15 may be of help to exclude microcystic adnexal carcinoma and DTE from the latter 2 enities.^[33]

BerEP4, a basal cell marker, was reported to differentiate basal cell carcinoma from microcystic adnexal carcinoma,^[34] but reappraisal found that 38% of microcystic adnexal carcinomas revealed positivity.^[33]

CD5, a lymphoid tumor marker, was found to stain microcystic adnexal carcinomas 71% of the time, particularly in deeper portions of the tumor, which may help differentiate them from desmoplastic trichoepitheliomas and morpheaform basal cell carcinomas.^[35] This, again, may not facilitate diagnosis in superficial samples.

CK20 staining for the presence of Merkel cells in the tumor was negative in one case report.^[34] Its utility was suggested to help differentiate microcystic adnexal carcinoma from other benign adnexal tumors that typically carry scattered Merkel cells throughout. More studies are needed to validate this concept in microcystic adnexal carcinoma.

Other stains of interest but of little utility in diagnostic distinction include pancytokeratin, AE1/AE3, and cytokeratin-1; these all positively highlight tumor cells. Reactivity to hard keratin subclasses AE13 and AE14 has been demonstrated and suggests pilar differentiation.^[36] Epithelial membrane antigen and CEA highlight ductal structures or intracytoplasmic lumen formation and suggest a sudoriferous origin, but ductal differentiation can be seen in other mimicking tumors. At times, microcystic adnexal carcinoma can also be negative for CEA.^[33] Additionally, Leu-M1 is positive and S-100 is negative.^[36]

A suggested immunohistochemistry panel may include the following:

• Superficial biopsies: p63 may be of assistance if the peripheral pattern is seen, but this is best visualized in deeper portions of the dermis. CK15 may help exclude other malignancies, such as basal cell and squamous cell carcinomas, but DTE remains in the differential.
• Deep (midreticular dermis or deeper) biopsies: p63 with a scattered peripheral pattern within in each tumor island, or extinction with depth, may help confirm a diagnosis of microcystic adnexal carcinoma. CK15 can be used, as above. CD5 could also be used to verify microcystic adnexal carcinoma but may be less reliable.

Histologic differential diagnosis

With hematoxylin and eosin staining, attention to the infiltrative growth pattern and, if present, perineural invasion, usually easily discriminates microcystic adnexal carcinoma from the other tumors in suitable biopsy specimens. Rendering a definitive diagnosis from a shave or superficial punch biopsy specimen is often impossible. Duct formation, if present, would favor microcystic adnexal carcinoma over desmoplastic trichoepithelioma. Keratocysts, slight atypia, and few mitoses would favor microcystic adnexal carcinoma over syringoma.

Distinction from a morpheaform basal cell carcinoma can be made by the demonstration of duct and intracytoplasmic lumen formation and with zonation of the tumor from the epidermis, which is typically seen with microcystic adnexal carcinoma. Ductal formation is rare in basal cell carcinoma. If seen, it is usually in nodular subtypes. Subtle features, if seen, consistent with basal cell carcinoma (retraction artifact, fibromyxoid stroma, necrosis en mass) in basaloid islands may be supportive. CD5 positivity, CK15 positivity, or distinct p63 staining in deeper sections would also favor microcystic adnexal carcinoma over morpheaform basal cell carcinoma, whereas Ber-EP4 positivity favors basal cell carcinoma.

Desmoplastic squamous cell carcinoma or adenosquamous carcinoma generally lacks zonation from the epidermis, ductal structures, or intracytoplasmic lumen formation. CK15 positivity would favor microcystic adnexal carcinoma.

Desmoplastic melanoma also typically lacks zonation, ductal structures, and keratocyst formation, and it is reliably S-100 positive. Lymphoid aggregates are usually situated throughout the tumor, as opposed to the dermal-subcutaneous junction, as is seen in microcystic adnexal carcinoma.

Trichoadenomas tend to be more well-defined tumors with larger keratin cysts surrounded by a fibrovascular stroma. Typically, they lack deep invasion and do not show perineural invasion.

Metastatic adenocarcinomas (most commonly breast and colon) demonstrate more pleomorphism and cytologic atypia, and they lack keratocyst formation. p63 positivity may also help in differentiating a primary adnexal tumor over metastatic disease.^[37]

Most authorities distinguish microcystic adnexal carcinoma from similar low-grade sweat gland carcinomas that have previously been termed syringomatous carcinoma, eccrine epithelioma, or group 2 sclerosing sweat duct carcinoma, largely on the basis of the presence of keratocysts or other evidence of follicular differentiation. However, some have suggested that these tumors could be variations of the same entity.

Likewise, squamoid eccrine ductal carcinoma, a sweat gland carcinoma consisting of stranded epithelium with ductal differentiation and prominent squamoid features, is considered by some authorities to be a monophasic eccrine version of microcystic adnexal carcinoma (lacking follicular differentiation), similar to eccrine epithelioma. Although one case report described follicular features in a squamoid eccrine ductal carcinoma, this tends to be minimal, if present, and differs from eccrine carcinoma (and microcystic adnexal carcinoma) due to its conspicuous squamoid or syringosquamous metaplasialike qualities.^[38]