Microcystic Adnexal Carcinoma 

Updated: Feb 20, 2019
Author: Nektarios I Lountzis, MD; Chief Editor: Dirk M Elston, MD 

Overview

Practice Essentials

Microcystic adnexal carcinoma (MAC) is a rare, malignant appendage tumor commonly classified as a low-grade sweat gland carcinoma that typically occurs on the head and neck, particularly the central face. Microcystic adnexal carcinoma shows aggressive local invasion with rare reports of lymph node metastases.[1] The image below depicts MAC on the left upper cutaneous lip.

Clinical photo of a microcystic adnexal carcinoma Clinical photo of a microcystic adnexal carcinoma on the left upper lip of an elderly woman. Note the close clinical resemblance to basal cell carcinoma. Courtesy of Dirk M. Elston, MD.

Background

Microcystic adnexal carcinoma (MAC) is a rare, malignant appendage tumor commonly classified as a low-grade sweat gland carcinoma that typically occurs on the head and neck, particularly the central face. Goldstein et al[2] described the first series in 1982, emphasizing the importance of its distinction from the benign histologic mimics, such as syringoma, desmoplastic trichoepithelioma, and trichoadenoma. 

Despite subsequent widespread recognition of MAC as a discrete clinicopathologic entity, its precise relationship to and histologic discrimination from other putative locally aggressive sweat gland carcinomas (reported under a variety of names, including sclerosing sweat duct carcinoma, syringoid eccrine carcinoma, syringomatous carcinoma, and eccrine epithelioma) remains unresolved and has provoked considerable nosologic and diagnostic confusion. The authors regard MAC as synonymous with group 1 sclerosing sweat duct carcinomas as described by Cooper et al.[3] In addition, the tumor described as syringomatous adenoma of the nipple or sclerosing MAC of the oral cavity (also known as MAC-like carcinomas arising in the mucosal head and neck) is regarded by some authorities as MAC.

Pathophysiology

Little information is available on the molecular pathophysiology of microcystic adnexal carcinoma (MAC), although a genetic role is plausible. A case of MAC occurring in siblings further supports this possibility.[4] In one report using cytogenetic and fluorescence in situ hybridization, a deletion on arm 6q (q23q25) was found, which is a deletion found in other malignant salivary gland tumors.[5] DNA sequencing techniques have also discovered mutations in TP53 (found on chromosome 17), chromosomal losses in cyclin-dependent kinase inhibitor 2A (CDKN2A) (found on chromosome 9), and cyclin-dependent kinase inhibitor 2B (CDKN2B) (also found on chromosome 9) in a case of metastatic MAC.[6]

Furthermore, the differentiation pathway of MAC has provoked considerable debate. Goldstein et al[2] initially suggested that it showed dual pilar (the superficially located keratocysts resembling follicular infundibula) and eccrine differentiation. Others have supported this notion, noting, in particular, that the keratocysts often expressed pilar-type keratins and that occasionally, trichohyalin granules are present. However, some authors have suggested that MAC shows only eccrine differentiation.[7]

More recently, based on the ontogenetic relationship between hair follicles and apocrine glands, MACs have been theorized to display folliculoapocrine or sometimes folliculosebaceous-apocrine differentiation rather than folliculoeccrine differentiation.[1] Support for this premise is provided by occasional cases showing focal apocrine decapitation secretion and the demonstration of sebaceous features in some tumors.[8]

Moreover, the term "sclerosing microcystic adenocarcinoma" or "MAC-like carcinomas arising in the mucosal head and neck" has also been proposed for MAC arising specifically on mucosal surfaces, owing to the lack of adnexal structures in these areas as a potential source of tumor derivation.[9] However, differences may be explained by a single-cell origin, likely found in all locations (ie, eccrine), capable of variable differentiation with a potential to display eccrine, follicular, and apocrine features. Alternatively, more than one cell line (ie, salivary, eccrine, apocrine, adnexal epithelium) could also be capable of developing into MAC, where each cell line may or may not display eccrine, follicular, or apocrine features, but uniformly demonstrates ductal differentiation common to all MACs.

In the end, there appears to be a spectrum of histopathologic presentations of MAC, in which derivation could arise from various glandular and/or adnexal origins and differentiation being influenced by endogenous/genetic factors that have yet to be definitively determined.

Etiology

Therapeutic radiation (radiation therapy)

Approximately 19.5% (14 of 84) to 50% (5 of 10) of microcystic adnexal carcinoma (MAC) patients have had treatment with radiation therapy for a previous condition.[1, 4, 10, 11, 12] The average latency period is 30 years.

UV radiation

Long-term UV exposure has also been postulated as a predisposing factor for MAC, especially in view of its predilection for sun-exposed sites (ie, favoring the left side of the face, owing to suspected sun exposure while driving) and the skin of white persons.[13]

In persons of African American origin, in whom UV sun damage already plays a lesser role in cutaneous malignancy, one lesion occurred on the vulva of an African American woman[14] and multiple lesions arose on the trunk and extremities (with sparing of the face) of an African American man.[15] However, other reported cases in African Americans have occurred on the scalp[16, 17, 18] and upper cutaneous lip,[19] where sun exposure is expected. One case in a 6-year-old African American girl occurred on the left preauricular area, an area of known sun exposure,[20] but the age of onset would not suggest long-term UV light as a cause.

Its occurrence in sun-protected areas of whites[21] also suggests that UV exposure may not be the ultimate cause of MAC, but its predominant emergence on sun-exposed areas may indeed suggest a role.

Epidemiology

Frequency

Microcystic adnexal carcinoma (MAC) is a rare tumor, with only slightly more than 300 cases reported worldwide.[15] Thomas et al[22] reported a mean number of 1.63 cases per year in a rural northeastern area of the United States.

Race

Most cases (90%) of microcystic adnexal carcinoma (MAC) occur in whites, but it may occur in persons of other races such as Latinos and Asians.[23, 21, 24] Fifty-two cases have been reported in Japan.[25, 26] In African Americans, 10 cases in total have been reported in 9 patients.[14, 15, 16, 17, 18, 19, 20, 23] The overall clinical behavior of MAC appears to be similar in all races.

Sex

No significant sexual predilection is reported, although some studies suggest a slight female predominance.[4, 13, 21, 27]

Age

The age range is broad and has been reported from birth[28, 29] to age 90 years.[30] Most lesions manifest in the fifth to seventh decade of life.[4, 22, 21, 30] Median age is 68 years.[21]

Prognosis

Overall, the prognosis is good, especially when margin-control techniques such as Mohs micrographic surgery (MMS) are used, with a modest tendency for recurrence and a very low rate of metastases. Ten-year survival of patients with microcystic adnexal carcinoma (MAC) is equivalent to other patients of similar age without MAC.[21]

The largest series of cases reports an overall (combining results from simple excision and MMS) 10-year recurrence rate of 18%. Others have reported a 12% recurrence rate at mean follow-up of 39 months.[22] Recurrence in one case occurred 30 years after initial resection, making routine clinical follow up necessary.[31]

Although microcystic adnexal carcinoma is considered a nonmetastasizing tumor, rare reports detail histologically confirmed lymphatic spread. Of the more than 300 reported cases of MAC, only 10 have been metastatic.[6, 32, 33, 34, 35, 36, 37, 38, 39, 40]

Two deaths have been attributed to metastatic MAC. One patient presented with mediastinal lymphadenopathy and later died of the disease. However, no histologic evidence from the lymph nodes confirmed the cause of death.[38] The other death occurred from a MAC of the right-upper eyebrow that led to perineural spread though the orbit with central nervous system dissemination.[37] In another reported case of distant metastatic disease, the patient eventually died of aspiration pneumonia, not from the MAC itself.[39]

Mortality/morbidity

Morbidity is high because of the deeply infiltrating nature of the tumor, which can invade into bone, muscle, blood vessels, cartilage, and nerves. In one study, the mean clinical lesion size was 3 cm2, but the final defect size was 18 cm2, highlighting its occult extension.[22] Exquisitely rare orbital extension can occur, and a primary orbital presentation has also been reported.[41]

Mortality from metastatic disease is rare, with only six local[32, 33, 34, 35, 36, 37] and four distant metastases reported.[6, 38, 39, 40] Local metastatic disease, in most cases, may be occult contiguous extension along neurovasculature bundles.[35, 36, 37] Considering that more than 300 cases have been reported in the medical literature worldwide,[15] only two deaths have been attributed to MAC,[19, 37] both due to metastatic disease.

Of possible relation, Fernandez-Figueras et al reported a case of a high-grade carcinosarcoma with an architectural pattern similar to MAC but also exhibiting nuclear pleomorphism, hyperchromasia, and large nucleoli histologically. The patient developed metastatic lung disease from the tumor and died within 6 months.[42] The authors further noted histologic high-grade features in their case that were similar to other cases reported with metastatic disease,[19, 36, 39] and they suggested this may be an indicator for more aggressive disease. Whether the carcinomatous portion of this particular tumor represents an aggressive undefined adnexal carcinoma with an architectural pattern similar to MAC, a morphological variant of MAC with high-grade histologic features or even a squamous cell carcinoma with MAC-like differentiation, remains unknown.

 

Presentation

History

Microcystic adnexal carcinoma (MAC) has an indolent onset, manifesting as an indurated plaque or nodule, often present for many years. MAC is usually asymptomatic, but it may be painful. Numbness, pruritus, paresthesia, or recalcitrant facial nerve palsy may be present in patients with perineural infiltration.[43]

Physical Examination

Note the possible physical findings for microcystic adnexal carcinoma (MAC) and the images below.

Appearance

MACs are skin colored, yellow, or pink. The most common forms are indurated plaques or nodules. Cystlike tumors have also been reported. The skin surface is usually smooth, but it may show some hyperkeratosis. It can also be atrophic and ill-defined.

Location

It is most commonly found in the head and neck region (85%), with a predilection for the nasolabial area (especially the upper lip) and the periorbital skin.[22] A left-sided facial preponderance was noted in a large US study, considered to be the result of uneven UV exposure while driving (US steering wheels are placed on the left). MAC has been found to occur in other locations, such as the upper extremity (8%), trunk (4%), and lower extremity (4%).[22] Involvement of the axillae, buttocks, scalp, nipple,[44] vulva,[14, 45] or genitalia[13, 46] is rare but has been reported. Lesions in non–sun-exposed sites may occur more often in persons of nonwhite ethic origin. One case of multiple primary MACs (21 total) of the trunk and extremities in sun- and non–sun-exposed areas, with sparing of the face, has been reported.[15]

Size

The average size range is 1-3 cm in diameter,[22] and median size is about 1.5-2 cm.[1, 21] One case series reported a pretreatment lesion size range of 0.03-16 cm.[1, 10] Actual clinical size determination can be difficult because of the tendency for extensive subclinical involvement.

Clinical photo of a microcystic adnexal carcinoma Clinical photo of a microcystic adnexal carcinoma on the left upper lip of an elderly woman. Note the close clinical resemblance to basal cell carcinoma. Courtesy of Dirk M. Elston, MD.
Note the subtle pink plaque on the left mid temple Note the subtle pink plaque on the left mid temple.
 

DDx

Diagnostic Considerations

Also consider the following:

  • Squamous cell carcinoma with microcystic adnexal carcinoma (MAC)–like features
  • Adenosquamous carcinoma
  • Eccrine epithelioma
  • Squamoid eccrine ductal carcinoma
  • Trichoadenoma
  • Cutaneous metastases of breast carcinoma
  • Cutaneous metastases of microcystic squamous cell carcinoma of the lung [47]
  • Other metastatic adenocarcinomas
  • Sweat duct proliferation associated with atrophoderma vermiculata [48]
  • Sclerosing microcystic adenocarcinoma/MAC-like carcinomas arising in the mucosal head and neck (some consider this entity as MAC on mucosal surfaces) [9]

Differential Diagnoses

 

Workup

Imaging Studies

MRI or CT scanning may be used to assess tumor extent and map out local invasion into nerves, muscle, cartilage, or bone.[28, 29, 37, 39, 49] Lesions on MRI tend to have a low T2-signal intensity, given its low cellularity and fibrosing nature.[49] Imaging may also be used to help define metastatic disease, if suspected. However, imaging is not necessary in most cases of microcystic adnexal carcinoma (MAC).

Other Tests

Dermoscopy can be used but known specific features are limited and are rarely described in the literature. Some notable dermatoscopic features include dense, white, structureless areas centrally with white clods of variable diameter peripherally and a brown-pigmented outer rim; white clods may represent keratin retention cysts also common to other mimicking tumors, such as trichoepithelioma.[50, 51, 52]

Optical coherence tomography is a biomedical tissue-imaging technique used to obtain high-resolution subsurface images similar to a low-power microscope. The process is similar to confocal microscopy. In one instance, this technique was used to diagnose microcystic adnexal carcinoma (MAC) that was subsequently confirmed by histologic evaluation.[53] Similarly, reflectance confocal microscopy can be used in defining MAC in vivo.[54] The availability of these devices is limited, but their potential use as a noninvasive means of diagnosing subtle tumors and outlining ill-defined malignancies (eg, MAC) could prove to be an invaluable tool, particularly on cosmetically sensitive areas.

Procedures

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. Fine-needle aspiration has been attempted,[55] but its use is not standardized.

Ensuring that the biopsy specimen is adequate for diagnosis and that the histopathologist is aware of this entity is important because as many as 30-85% of cases of microcystic adnexal carcinoma (MAC) are misdiagnosed.[40, 56]

Histologic Findings

Note the images below.

A low-power view of microcystic adnexal carcinoma A low-power view of microcystic adnexal carcinoma demonstrates superficially located keratocysts and variably sized tumor nests and ducts. Note the diminution in size of the nests and cysts with the depth of dermal invasion. Courtesy of Dirk M. Elston, MD
Small ductular structures lined by 2-3 cell layers Small ductular structures lined by 2-3 cell layers of small eosinophilic cells showing little pleomorphism set in a dense fibrous stroma. Courtesy of Dirk M. Elston, MD.
A high-power view of small, irregularly shaped nes A high-power view of small, irregularly shaped nests and strands of small tumor cells without obvious ductal formation. Courtesy of Dirk M. Elston, MD.

Hematoxylin and eosin

Hematoxylin and eosin of deep biopsy specimens (preferably to subcutaneous fat) still remain the criterion standard in diagnosing microcystic adnexal carcinoma (MAC). Overall, MAC 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, MAC 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 (80%).[57] The presence of eosinophils, particularly with the presence of lesional clear-cell change, can be seen.[58, 59] Lymphoid aggregates are common, particularly at the dermal-subcutaneous junction.

With regard to histologic subtype, tumors displaying the architectural features of MAC but with increased nuclear pleomorphism, hyperchromasia, vascular invasion, and necrosis may be suggestive of a more aggressive subtype.[42, 57] Clinically, these can demonstrate rapid growth, possible carcinosarcomatous metaplastic transformation with relapse, and possible metastases.[42] Careful examination of sections would also be needed to completely exclude a cutaneous squamous cell carcinoma with MAC-like differentiation in this setting, as this entity can be identical to MAC but has higher-grade features, and adequate sampling often reveals an in situ or keratinizing invasive squamous cell carcinoma component (see Histologic differential diagnosis below).[43, 60] Sebaceous[8, 59] and trichoepitheliomatous[61] differentiation has been reported, which is of no prognostic significance. Monophasic eccrine variants are also seen. Solid carcinoma, also known as syringomatous carcinoma, is considered a solid variant of MAC found mostly on the scalp of elderly men.[62] This variant tends to have large nodular cords and islands of infiltrative neoplastic cells that reveal the typical ductal differentiation and perineural invasion of MAC.

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.[63] This stain may be of benefit in Mohs micrographic surgery (MMS).

Immunohistochemistry

Definitive immunostaining to differentiate MAC from other sclerosing neoplasms, especially in superficial samples, is lacking. However, a few immunostains 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 MAC, 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 MAC 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 MAC and may not be of help in superficial biopsy specimens.[64]

p75 neurotrophin receptor has been found to play a role in hair follicle biology, and one study[65] extrapolated its use in differentiating morpheaform basal cell carcinoma (14% positive with < 30% cells staining) and desmoplastic trichoepitheliomas (100% positive with >80% cells staining). MAC was not used in the study, but it was used in another study in which 4 (44%) of 9 MACs stained for p75 neurotrophin receptor.[66] DTEs and infiltrative basal cell carcinoma stained 94% and 36%, respectively, in this particular study.

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 MAC (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 MAC and DTE from the latter two entities.[67]

BerEP4, a basal cell marker, was reported to differentiate basal cell carcinoma from MAC,[68] but reappraisal found that 38% of MACs revealed positivity.[67]

CD5, a lymphoid tumor marker, was found to stain MACs 71% of the time, particularly in deeper portions of the tumor, which may help differentiate them from DTEs and morpheaform basal cell carcinomas.[69] 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.[68] Its utility was suggested to help differentiate MAC from other benign adnexal tumors that typically carry scattered Merkel cells throughout. Some studies appear to support this concept,[67, 70] but the variable presence of Merkel cells within sections makes its use less predictable.[65]

SOX-10 may also be of future diagnostic assistance. In one study, staining was seen in the majority of sweat gland tumors with the exception of syringoma and MAC.[52]

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.[71] 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, MAC can also be negative for CEA.[67] Additionally, Leu-M1 is positive and S-100 is negative.[71]

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. Presence of tumoral CK20 cells may support a benign process, but lack of CK20 cells may not exclude a malignant process. Multiple step sections should be considered.

  • 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 MAC. CK15 and CK20 can be used, as noted above. CD5 could also be used to verify MAC 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 MAC from the other tumors in suitable biopsy specimens. Rendering a definitive diagnosis from a shave or superficial punch biopsy specimen is often impossible. In this context, duct formation, if present, would favor MAC over DTE, but perineural invasion can be seen in both. DTE tends to be more circumscribed and contain stromal calcification and rudimentary papillary mesenchymal bodies, but an eosinophilic infiltrate, particularly with lesional clear-cell change, has been postulated to favor MAC.[58, 59] In the case of syringoma, the presence of keratocysts, slight atypia, and few mitoses would favor MAC.

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 MAC. 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 MAC 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 MAC.

Cutaneous squamous cell carcinoma with MAC-like differentiation, also known as MAC-like squamous cell carcinoma, has identical features to MAC, including ductal differentiation with a similar immunostaining pattern.[43, 60] Distinction is made by the presence of high-grade atypia with frequent mitoses and identifying an in situ or invasive squamous cell carcinoma component. Adequate sampling and multiple step-sectioning are critical at finding these features for an accurate diagnosis.

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 MAC.

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 help in differentiating a primary adnexal tumor over metastatic adenocarcinoma.[72] Furthermore, an immunoprofile of CK5, C14, CK17, and p63 positivity and Mammaglobin negativity may favor a primary adnexal carcinoma, such as MAC, over metastatic breast carcinoma to the skin.[73] Moreover, newly described microcystic squamous cell carcinoma of the lung has distinct features similar to MAC. Although none has metastasized to the skin, the potential is there and could be discerned from MAC via thyroid transcription factor 1 expression.

Unusual presentation of childhood onset diffuse atrophoderma vermiculata of the head and neck with histologic features of small keratocysts in the superficial dermis and sclerotic syringomatous proliferations in the mid dermis to subcutaneous fascia may mimic MAC.[48] The proliferations differed from MAC in that they lacked obvious perineural involvement, were diffuse across body surface areas, and did not progress over time. Ductal epithelial strands were also embedded in concentric fibrotic rings, and distinct ball-like papillary dermal elastin aggregates were present. These patients were thought to have possible syndromic relationship to Nicolau-Balus syndrome, Rombo syndrome, and the so-called multiple eccrine-pilar hamartoma syndrome.

Most authorities distinguish MAC from similar low-grade sweat gland carcinomas that have previously been termed syringomatous carcinoma (solid carcinoma), eccrine epithelioma, or group 2 sclerosing sweat duct carcinoma, largely based on the presence of biphasic differentiation evidenced by keratocysts or other signs of follicular differentiation typically seen in MAC.[3, 57] They may also lack the sclerosing stroma of MAC. However, some have suggested that these tumors could be variations of the same entity. Of note, some of these subtypes tend to occur in younger patients.[3, 71]

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 MAC (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 MAC) owing to its conspicuous squamoid or syringosquamous metaplasialike qualities.[74]

 

Treatment

Medical Care

Surgery is the mainstay of treatment (see Surgical Care). However, in one report of metastatic microcystic adnexal carcinoma (MAC), a systemic antineoplastic chemotherapy regimen of carboplatin and paclitaxel revealed a therapeutic response supported by imaging studies.[6] Oral S1 therapy, a fluoropyrimidine-derived treatment regimen that consists of tegafur, 5-chloro-2, 4-dihydroxypyridine (CDHP), and potassium oxonate, also successfully treated MAC on the philtrum.[75] Chromosomal aberrations have also been noted in MAC (deletion on arm 6q (q23q25), mutations in TP53 (chromosome 17), and chromosomal losses in cyclin-dependent kinase inhibitor 2A (CDKN2A) (chromosome 9) and cyclin-dependent kinase inhibitor 2B (CDKN2B) (chromosome 9),[5, 6] and these genetic mutations could serve as potential targets for future inhibitor chemotherapy.

Radiation therapy has also been used with some success as either primary therapy[76] or as an adjuvant to surgery in approximately 30 cases to date.[37, 77, 78, 79, 80, 81, 82] However, radiation alone often results in recurrence. One case of a lesion of the upper lip received radiation monotherapy with recurrence in 48 months. Reirradiation revealed remission at 15-month follow-up. Only one case report of a sweat gland carcinoma of the lower lip, suspected of being a MAC, described success with radiation monotherapy but with only a 6-month follow-up period.[83]

Of note, some tumors also are radioresistant,[76] and, as a caveat, radiation therapy/exposure is also implicated as a cause of MAC.[27, 84, 85] In two studies, a prior history of radiation exposure was found in 19.5% (14 of 84) to 50% (5 of 10) of patients with MAC.[4, 10]

Overall, the use of radiation therapy, as either primary or adjuvant, is inconclusive but may have a role in complicated or nonoperable cases. If considered, doses of 66-70 Gy in standard fractionation is typically recommended, extrapolating from the squamous cell head and neck literature, with target volume of the clinically apparent lesion plus 3-cm margins where possible.[79]

Surgical Care

Mohs micrographic surgery (MMS) is the current treatment of choice for microcystic adnexal carcinoma (MAC). Clinical margins are difficult to define, and MMS offers an excellent way of following the infiltrating nature of the tumor and tracing perineural involvement. The discrepancy between clinical and histologic extent can be marked, in that the size of the defect after complete tumor removal following MMS can be as much as four[13] to six[22] times that of the clinically apparent size. Therefore, standardized, predictable, predetermined surgical margins cannot be used in the treatment of MAC.

MMS versus simple excision

In the largest series to date (48 patients), Chiller et al[13] found little difference in the overall recurrence rate between tumors treated with MMS (2.4% per person-year) versus standard surgical excision (1.5% per person-year) at a mean follow-up of 3.2 years. However, MMS exhibited a clear benefit over simple excision in that 30% of tumors treated with simple excision required at least another office visit to clear the patient of histological tumor findings, with one patient still not tumor free after four simple excisions. This rate was compared with 0% if treated by MMS. A study by Abbate et al[4] reported similar findings (MMS with 0 recurrences out of 4 cases vs excision with 1 recurrence out of 6 cases).

In a large prospective study of patients with MAC, only one case of recurrence was reported out of 20 (5%) at a 5-year follow-up period after MMS.[56] A similar recurrence rate, 4.7%, was noted in a study by Tolkachjov.[86] A study by Friedman et al,[27] with a mean follow-up period of 5-years, had no noted recurrences in 11 patients treated with MMS (0%). Thomas et al[22] found a 12% recurrence rate with a mean follow-up of 3.3 years in their study. This was similar to the 10.3% recurrence rate noted in a 2-year follow up study by Snow et al.[87] In all, the overall recurrence rates for MMS appear to range from 0-12%.

Local recurrence rates of up to 30-47% have been reported with standard surgical excision. Recurrences have also been noted from 5 months to 30 years after excision; thus, longer follow-up is necessary to fully assess both treatment modalities.

Some have suggested the use of an additional layer after complete clearance of margins with MMS for further histologic control.[25, 88] No outcome data exist on this technique.

Staged excision or delayed-closure MMS (slow MMS)

Problems can also be encountered in interpreting frozen sections during MMS, when microscopic invasion can be elusive. Barlow et al[89] proposed that delayed-closure MMS using formalin-fixed, paraffin-embedded specimens improves the histologic assessment and decreases the risk of missing a strand of tumor. Some advocate the use of tangential frozen sections with MMS plus formalin-fixed paraffin sections for the final layer, and this is a workable compromise. Moreover, other reports advocate the use of toluidine-blue staining on frozen sections to highlight MAC extension. Tumor stroma has a pink halo, owing to the presence of mucopolysaccharide and hyaluronic acid, and perineural involvement has a magenta hue, thereby augmenting visualization and clearance with MMS.[63]

Complications

Local recurrence is a complication if it is not properly excised. Additionally, because of the deep penetration of the tumor, destruction of underlying tissue (eg, bone, cartilage, muscle) can lead to structural changes and increased morbidity.

Prevention

Sun avoidance minimizes UV exposure, which may be a predisposing factor.

Long-Term Monitoring

The longest latent period for microcystic adnexal carcinoma (MAC) recurrence following simple excision is 30 years. This particular patient underwent a simple excision for adnexal adenoma in 1953. When he presented again 30 years later, the initial slides were reviewed, and a retrospective diagnosis of MAC was made. This case illustrates the indolent nature of MAC and supports the view that simple excision may not be adequate and long-term follow-up care is required.