Microcystic adnexal carcinoma

INTRODUCTION — 

Microcystic adnexal carcinoma (MAC) is a rare, infiltrative cutaneous tumor that most often presents as a scar-like papule or plaque on the head and neck [1]. Historical terms that have been used to refer to this tumor include "sclerosing sweat duct carcinoma," "malignant syringoma," and "syringoid carcinoma." Although metastasis and death from MAC are rare events, the tumor is locally invasive and may result in significant morbidity. Thus, surgical treatment for complete removal of the tumor is recommended.

The clinical presentation, diagnosis, and management of MAC will be discussed here. Other cutaneous adnexal tumors are reviewed separately. (See "Cutaneous adnexal tumors".)

EPIDEMIOLOGY — 

MAC is a rare tumor. An analysis of data from the Surveillance, Epidemiology, and End Results (SEER) database collected between 2000 and 2015 found an incidence rate of 0.5 per million individuals, with 83 percent occurring in White individuals [2]. However, MAC can also occur in other populations [3-8]. Some studies indicate a slight female predominance [2,6,8-11].

MAC most commonly affects middle-aged and older adults [6,9]. In the SEER database analysis, 55 percent of cases occurred in individuals older than 65 years [2]. Rare cases have been reported in children [12-14]. Congenital MAC has been described in a few neonates [15,16].

RISK FACTORS — 

The rarity of MAC makes it difficult to draw definitive conclusions on risk factors for the disease [2]. Ultraviolet (UV) radiation, ionizing radiation, and immunosuppression have been proposed as potential contributory factors.

●UV radiation – The common localization of tumors to the head and neck and the elevated frequency in White individuals suggests that exposure to UV radiation may contribute to the development of MAC [9,10,17,18]. However, the pathogenetic role of UV radiation was not confirmed by molecular studies, as mutations detected in MAC lack the so-called "UV signature" [18,19].

●Ionizing radiation – The development of tumors in sites of previous radiation therapy has been reported in multiple patients [6,20-25]. These case reports raise the question of whether ionizing radiation increases the risk for MAC.

●Immunosuppression – Although immunosuppression increases the risk for cutaneous squamous cell carcinoma and basal cell carcinoma, the effect of immunosuppression on the risk for development of MAC is unclear. However, four cases of MAC have been reported in transplant patients [26] (see "Epidemiology and risk factors for skin cancer in solid organ transplant recipients"). Aggressive tumor behavior has been reported in immunosuppressed patients [27,28].

●Other – MAC arising within a nevus sebaceous has been reported in at least four patients [29-32] and in association with multiple benign syringomas in at least two patients [33]. (See "Nevus sebaceus and nevus sebaceus syndromes".)

HISTOGENESIS — 

Histologic studies strongly suggest that MAC derives from pluripotent cells that exhibit differentiation toward both eccrine structures and hair follicles [34-39]. Immunohistochemical stains that demonstrate hard keratins in the superficial cystic component of MAC support the presence of follicular differentiation [35,36,40], and the often positive stains for carcinoembryonic antigen (CEA) in MAC tumors indicate the presence of eccrine differentiation (table 1) [30,36,38,41].

Of note, sebaceous differentiation has also been detected in several cases of MAC [42,43], and germinative follicular differentiation has been detected in another case (supporting apocrine differentiation) [44], findings that further support pluripotent cells as the cells of origin. In a rare case of MAC occurring in the tongue, the cell of origin appeared to be derived from the salivary gland [45].

Few data are available on the cytogenetic analysis of MAC [46,47]. One study found a clonal chromosome 6q deletion similar to that seen in salivary tumors, suggesting a histogenetic relationship between these tumors [46]. There is a single case report of a metastatic MAC with deoxyribonucleic acid (DNA) sequencing that demonstrated a mutation of TP53 and chromosomal losses in the cyclin-dependant kinase inhibitor 2A (CDKN2A) and cyclin-dependant kinase inhibitor 2B (CDKN2B) genes [48].

In a study of 18 tumors, DNA next-generation sequencing of over 400 cancer-related genes revealed that the most recurrent mutation was TP53 inactivation (22 percent), followed by insertions in the kinase domain of JAK1 (17 percent) [19]. In contrast with cutaneous squamous cell carcinoma, mutations in TP53 did not show ultraviolet (UV) signature.

Hedgehog signaling (HH) expression was not associated with MAC in one small study, differentiating it from basal cell carcinoma [49].

CLINICAL FEATURES

●Lesion characteristics – MAC most frequently manifests as a fairly unremarkable, white or yellowish papule or plaque with or without overlying telangiectasias (picture 1 and picture 2 and picture 3 and picture 4). Individuals with darkly pigmented skin may present with only an ill-defined papule or nodule that lacks surface or pigmentary changes.

MAC usually presents as a solitary tumor. However, multiple primary tumors have occurred in at least one patient [3].

The tumor margins are often indistinct, a feature consistent with the common discrepancy between the clinical size of the tumor and the more extensive tumor invasion regularly detected on histopathologic examination. Early tumors are often only slightly elevated; a more nodular quality tends to develop over time. Tumors that seem fixed to underlying tissues may have invaded underlying structures, such as muscle, cartilage, and bone. Ulceration and necrosis are rare findings.

●Location – The vast majority of tumors occur on the head and neck, in most cases on the central face [50]. In a 2021 analysis of Surveillance, Epidemiology, and End Results (SEER) data on 708 patients with MAC, tumors were located on the head and neck in 75 percent of patients [2]. However, tumors may develop in any cutaneous site.

A literature review found 38 cases of orbital tumors, with seven patients having orbit exenteration required [51]. There are multiple reports of orbital MAC extending into the brain through the optic nerve or the nerves superior to the orbit [52-56]. Examples of additional reported sites of MAC include the trunk and extremities, breast, nipple, vulva, auditory canal, axilla, perineum, hands, feet, and scalp [3,4,6,8,14,40,57-59].

●Extracutaneous MAC – Rarely, MAC develops in extracutaneous locations. MAC involving the tongue, oral cavity, or maxillary sinus has been documented in a few patients [9,60]. Most patients with MAC do not experience associated symptoms. Occasionally, symptoms related to perineural invasion, such as burning, pain, hyperesthesia, or paresthesia, are present [61].

●Growth pattern – Tumor development is usually characterized by slow, gradual growth over years; periods of stability and more rapid growth may be observed [50].

DIAGNOSIS — 

The histopathologic examination of the lesion biopsy is usually sufficient for the diagnosis of MAC (see 'Biopsy' below and 'Pathology' below). Despite the relative ease of skin biopsy procedures, the undramatic clinical appearance and insidious growth of MAC can lead to a delay in biopsy and diagnosis for several years [20,30,61].

Dermoscopy may also provide clues to diagnosis, particularly the presence of scar-like, white, structureless areas [62,63]. However, dermoscopy does not provide a consistent pattern, and at least one author found dermoscopy not helpful [64]. Confocal microscopy and optical coherence tomography have been used in single case reports to assist in the clinical diagnosis [65,66].

Biopsy — For the diagnosis of MAC, the depth of the biopsy should extend into the deep dermis and subcutaneous fat. Thus, punch biopsies, incisional or excisional biopsies, or deep (saucerization) shave biopsies are preferred. (See "Skin biopsy techniques", section on 'Biopsy techniques'.)

Superficial shave biopsies are not recommended, since the recognition of the architecture of this deeply infiltrative tumor and the detection of perineural invasion are useful for diagnosis.

Pathology — MAC is a deeply infiltrative tumor composed of small nests and cords of bland-appearing cells. Rare cases of tumors displaying architectural features of MAC with high-grade cytologic atypia have been reported [67,68].

Common histologic features of MAC include [52]:

●Small, keratin-filled cysts in the upper dermis (picture 5).

●Nests and cords of epithelial cells within a hyalinized stroma that seem to form ductal structures; these structures decrease in size at greater depths (picture 6A-B).

●Little, if any, cytologic atypia and few mitoses.

●Perineural invasion (picture 7).

●Deep infiltration within the dermis (infiltration into the subcutaneous fat, muscle, or deeper structures may also be present) (picture 8).

When MAC encounters bone or cartilage, the tumor may grow laterally along the periosteal or perichondrial plane or may directly invade these structures [61].

Although not typically seen, amyloid deposition [39] and an inflammatory infiltrate with eosinophils [35,69] have been detected in specimens of MAC. There are reports of sebaceous or follicular differentiation or xanthomatous reaction [37,42-44,70]. Findings of necrosis and ulceration are uncommon.

Immunohistochemistry — Immunohistochemical studies are occasionally utilized to support the diagnosis of MAC and rule out other disorders when the diagnosis is uncertain [18,36,71-76]. (See 'Histologic differential diagnosis' below.)

The immunohistochemical characteristics of MAC and several disorders that may be mistaken for MAC are provided in the table (table 1). Of note, the carcinoembryonic antigen (CEA) stain, which is positive in one-half of MAC specimens, is useful for distinguishing MAC from basal cell carcinoma and squamous cell carcinoma (picture 9) [50]. The addition of androgen receptor stain will help distinguish MAC from infiltrating basal cell carcinoma and desmoplastic trichoepithelioma [77].

DIFFERENTIAL DIAGNOSIS

Clinical — The indurated papules, plaques, or nodules of MAC may clinically resemble:

●Morpheaform basal cell carcinoma (picture 10)

●Desmoplastic squamous cell carcinoma

●Scars

●Syringomas (picture 11)

●Cysts

Histopathologic examination distinguishes MAC from these disorders. (See 'Pathology' above and 'Histologic differential diagnosis' below.)

Histologic differential diagnosis — Several other cutaneous tumors share pathologic features with MAC. Careful assessment of the histologic features is essential for obtaining the correct diagnosis (table 2) [10,35,78].

The histologic differential diagnosis for MAC primarily includes:

●Trichoepithelioma and trichoadenoma – The recognition of ductal features in MAC distinguishes it from desmoplastic trichoepithelioma and trichoadenoma [79], which are benign adnexal tumors of follicular origin. (See "Cutaneous adnexal tumors", section on 'Trichoblastoma and trichoepithelioma' and "Cutaneous adnexal tumors", section on 'Trichoadenoma'.)

●Syringoma – The asymmetrical architecture, single-cell strands, and the perineural and deep invasion of MAC differentiate MAC from syringoma, a benign eccrine tumor [79]. (See "Cutaneous adnexal tumors", section on 'Syringoma'.)

●Morpheaform basal cell carcinoma. (See "Basal cell carcinoma: Epidemiology, pathogenesis, clinical features, and diagnosis", section on 'Morpheaform/infiltrative'.)

●Desmoplastic squamous cell carcinoma.

EVALUATION AND STAGING

●Physical examination – Patients diagnosed with MAC should receive a full skin examination with careful inspection of the tumor site to assess the clinical extent of the tumor. While nodal spread is rare, palpation of the regional lymph nodes should also be performed to assess for enlarged lymph nodes that may indicate regional metastasis. If enlarged lymph nodes are detected, lymph node biopsy via fine needle aspiration or surgical removal of the enlarged lymph node is indicated [80].

●Imaging – Radiologic studies are not necessary in most patients diagnosed with MAC. However, if the physical examination suggests that the tumor is fixed to the underlying structures, is large (≥2 cm), is in the periorbital area, or there is evidence of node involvement, computed tomography (CT) or magnetic resonance imaging (MRI) of the site is useful [2]. It can confirm bone invasion, involvement of deep structures, deep orbit involvement, or node involvement [53,81-83]. Radiologic imaging of other body sites is not indicated in the absence of signs or symptoms suggestive of distant disease.

●Staging – The staging of MAC correlates with the staging system for cutaneous squamous cell carcinoma outlined by the American Joint Committee on Cancer (AJCC) staging (table 3) [84].

TREATMENT — 

Surgery is the primary treatment modality utilized for the management of MAC. Radiation therapy has been employed in select cases.

Local disease — Surgery that results in complete tumor removal is the treatment of choice for locally invasive MAC [85]. The surgical techniques most commonly utilized for MAC include Mohs, a procedure that involves histologic assessment of the complete tissue margin, and wide local excision (WLE) with postoperative margin assessment. (See "Mohs surgery".)

Mohs surgery — We suggest Mohs surgery, rather than conventional surgical excision with postoperative margin assessment, for the treatment of MAC [86]. The infiltrative quality and often extensive subclinical extension of the tumor can make complete removal by other surgical procedures challenging [10,11,87].

Mohs surgery allows for intraoperative assessment of 100 percent of the excised tumor margin while sparing the maximum amount of healthy tissue. This enables the surgeon to confirm the complete removal of the tumor on the day of surgery prior to wound closure. (See "Mohs surgery".)

Mohs surgery may reduce the need for subsequent surgical procedures compared with conventional surgical excision. However, due to the subclinical extent of the tumor, Mohs surgery may result in defect sizes up to six times larger than the size of the clinically apparent tumor [11].

No high-quality trials have compared Mohs surgery with WLE for the treatment of MAC, and the relative efficacy of these procedures in improving patient outcomes remains uncertain.

●In a retrospective study of 69 patients with MAC, clear margins were achieved within a single treatment session in all 34 patients who were treated with Mohs surgery [87]. In contrast, 21 of 35 patients (60 percent) treated with conventional surgical excision had positive margins after the procedure.

●In a retrospective study of six patients with periocular MAC (three with extensive perineural invasion), tumor clearance was achieved in five of the six patients after one to nine Mohs stages [88].

●In another retrospective study of 67 patients treated with Mohs surgery, the mean number of stages was two for primary MAC and increased to four for recurrent tumors [89].

Modified Mohs surgery — Several authors have suggested modifications to the standard Mohs surgery in attempts to improve surgical outcomes.

●Toluidine blue stain – One example is the use of a toluidine blue stain, which may facilitate the identification of isolated tumor nests and perineural invasion [90,91].

●Permanent sections – Because the histologic detection of small islands or strands of tumor cells may be easier in permanent sections than in the frozen sections, an additional layer of tissue for permanent sections can be obtained after apparent tumor clearance via Mohs surgery.

●"Slow Mohs" – Alternatively, a staged Mohs-like procedure utilizing permanent, rather than frozen, sections ("slow Mohs") can be performed [55,61,92].

The effects of these procedure modifications on patient outcomes have not been evaluated in formal studies.

Wide local excision — WLE to the deep fascia is an alternative to Mohs surgery for the treatment of MAC.

●Margins – The often extensive subclinical extension of MAC makes it difficult to identify the true clinical margins. It has been estimated that 2 cm peripheral margins with a minimum deep margin to the fascia can completely excise 99 percent of tumors [85].

Techniques that allow complete evaluation of margins, such as complete circumferential peripheral and deep margin assessment (CCPDMA; also called excision with peripheral and deep en face margin assessment [PDEMA]), increase the likelihood of complete tumor clearance.

●Intraoperative frozen sections – When feasible, intraoperative frozen sections can guide the extent of excision. Although the impact of adding intraoperative frozen sections to traditional surgical excision in MAC has not been specifically studied, the author's experience suggests that this intervention may help surgeons more closely approximate the amount of tissue removal necessary for complete tumor excision during surgery. Frozen sections may be particularly useful in sites on the head and neck where tissue sparing is a significant concern.

●Re-excision – Re-excision is performed if postoperative histologic examination reveals that a tumor is not completely removed [10]. In an analysis of data from the United States National Cancer Database that included 406 cases of MAC, the overall rate of surgical margin positivity after standard local excision was 10.8 percent [93].

Radiation therapy — The role of radiation therapy in the treatment of MAC is uncertain, and there is insufficient evidence to recommend its routine use.

●Definitive radiation therapy – There are only a few case reports documenting the use of radiation therapy as definitive treatment for MAC [2,85,94-96]. Radiation doses of 60 to 74 Gy have been used, but no standard dose has been determined given the limited number of cases reported. Recurrence occurred 6 to 48 months following initial clearance in nearly all cases.

●Postoperative (adjuvant) radiation therapy – We reserve postoperative radiation therapy for cases in which complete surgical removal is not possible. Some experts suggest doses of 60 Gy or greater with a margin of 3 to 5 cm [85]. In a retrospective study of 14 patients with MAC (11 of whom had positive surgical margins) who were followed for a median of five years, 13 of 14 patients achieved local control [17].

●Chemoradiation – Radiation therapy in combination with platinum-based agents and taxanes has been used in few patients with recurrent or metastatic tumors. There is a single case report of chemoradiation as first-line treatment for MAC [97]. A patient with a 12-year history of untreated MAC on the nasal philtrum and extensive involvement of the lower face was treated with 70 Gy of intensity-modulated radiation therapy combined with four cycles of carboplatin and paclitaxel (as radiosensitizers) and remained asymptomatic and progression free at six years [97].

Recurrent tumors — If feasible, recurrent MAC (picture 12) should be excised with surgical techniques that allow complete margin control (eg, Mohs micrographic surgery or CCPDMA) (see 'Mohs surgery' above). Radiation therapy and chemoradiation with platinum-based agents and taxanes are treatment options for patients with recurrent disease who are not candidates for surgery and for those with recurrent tumors in critical locations (eg, periorbital areas), for which clear margins cannot be achieved surgically. (See 'Radiation therapy' above.)

In a single case report, a patient with a recurrent MAC of the scalp was treated with docetaxel plus cisplatin followed by 66 Gy of radiation and was disease free at 18 months [98].

Therapeutic targeting of p53 or the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway may be indicated in advanced tumors [19].

Metastatic disease — Locoregional or distant metastasis of MAC is a rare event, and standards for the approach to such patients are lacking. The management of the individual patient requires multidisciplinary consultation including surgical oncology, medical oncology, and radiation oncology.

In single case reports, radiation therapy and chemoradiation with platinum-based agents and taxanes have been used with variable response [28,48,54,59,80,81,99].

PROGNOSIS — 

MAC is primarily a locally aggressive tumor. Metastasis to the lymph nodes or other sites is uncommon. In a 2021 analysis of Surveillance, Epidemiology, and End Results (SEER) data on 708 cases of MAC, regional involvement and distant metastasis occurred in 18.5 and 1 percent of patients, respectively [2].

Tumor recurrence is the major prognostic concern in MAC. The time to tumor recurrence varies widely. Most cases recur within two to three years [50]. However, recurrence up to 29 years after surgery has been reported [6].

Risk factors for tumor recurrence have not been definitively established. In one series of 67 patients with MAC, the risk of recurrence increased by 11 percent for every 1 cm² increase in tumor size, and tumors >5 cm² had a 13-fold higher recurrence rate [89]. Some authors propose that tumors that demonstrate perineural invasion may be more likely to recur after Mohs surgery [55]. This may be due to tumor "skip" areas along involved nerves that lead to failures to detect residual tumor.

There are multiple reports of MAC extending into the orbit, leading to tumor invasion into the brain through the optic nerve or the nerves superior to the orbit [52-56]. This suggests that this location is associated with increased risk for morbidity and that treatment should be followed with close long-term monitoring.

A few cases of death related to local tumor extension into vital areas (eg, intracranial invasion) have been reported [55,82,100]. Only one death directly attributable to metastatic MAC has been documented [100].

FOLLOW-UP — 

Guidelines for the follow-up of patients with MAC have not been established. The potential for delayed recurrence after years indicates that long-term follow-up is necessary. We typically follow patients every 6 to 12 months and perform a full skin examination and lymph node palpation at each visit. Patients with histories of tumors invading deep, vital, or conduit structures (eg, the orbit) need to be followed more closely. The optimal frequency of follow-up of these patients depends on the individual clinical scenario.

We usually perform radiologic imaging only if signs or symptoms suggestive of extracutaneous involvement are present. Radiologic studies (CT or MRI) are used to follow patients with deeply invasive tumors in which physical examination is not adequate for assessing signs of tumor recurrence.

SUMMARY AND RECOMMENDATIONS

●Definition and epidemiology – Microcystic adnexal carcinoma (MAC) is a rare, infiltrative cutaneous tumor that is most often found on the head and neck. MAC occurs predominantly in White, older adults. (See 'Epidemiology' above and 'Risk factors' above.)

●Clinical presentation – MAC most commonly presents as a nonulcerated, white or yellow papule, plaque, or nodule on the skin (picture 2 and picture 4). The head and neck are frequent sites for involvement. Tumors usually grow slowly over the course of years. (See 'Clinical features' above.)

●Diagnosis – The diagnosis of MAC is based upon the detection of consistent pathologic findings. Characteristic features include small, keratin-filled cysts; nest and cords of cells that resemble ductal structures; and an infiltrative growth pattern. Perineural invasion is common. Immunohistochemical studies (table 1) are occasionally used to distinguish MAC from other disorders. (See 'Diagnosis' above.)

●Evaluation and staging – The evaluation of the patient with MAC should include a complete skin examination with careful attention to the tumor site and lymph node palpation. Most patients do not require radiologic studies. The staging system for cutaneous squamous cell carcinoma of the American Joint Committee on Cancer (AJCC) is used for MAC (table 3). (See 'Evaluation and staging' above.)

●Treatment

•Local disease

-Surgery – We suggest Mohs surgery rather than wide local excision (WLE) for the treatment of MAC (Grade 2C) (see 'Mohs surgery' above). If Mohs surgery is not available, WLE to the deep fascia with 2 cm peripheral margins is an alternative option. (See 'Wide local excision' above.)

-Radiation therapy – There is very limited evidence to support the use of definitive radiation therapy for MAC. We reserve postoperative adjuvant radiation therapy for tumors for which complete excision is not possible. (See 'Radiation therapy' above.)

•Recurrent tumors – For recurrent MAC, we suggest excision with surgical techniques that allow complete margin control, if feasible, rather than radiation therapy (Grade 2C). Radiation therapy is an option for patients who are not surgical candidates and for those with recurrent tumors in critical locations (eg, periorbital area). (See 'Recurrent tumors' above.)

●Prognosis and follow-up – MAC is primarily a locally aggressive tumor. Local recurrence is the major prognostic concern. As recurrence of MAC may occur after many years, patients should be routinely followed for signs of disease recurrence every 6 to 12 months and have a full skin examination and lymph node palpation at each visit. (See 'Prognosis' above and 'Follow-up' above.)