Microcystic Adnexal Carcinoma

I. Palamaras ( )• R.J. Barlow

St. John’s Institute of Dermatology, St. Thomas’ Hospital, London, UK

e-mail: drioulios@hotmail.com

Summary: Introduction

•Microcystic adnexal carcinoma (MAC) is a rare skin tumor and was firstly described in 1982. Slow growth, as well as subtle clinical and histological signs, may delay the diagnosis. Similarly, tumor size may be underestimated, and a standard excision may be incomplete.

20.1Introduction

Microcystic adnexal carcinoma (MAC) is an uncommon, locally invasive adnexal skin tumor which usually presents on the head and neck. It was described in 1982 by Goldstein et al., who considered it to be of follicular or eccrine origin and possibly to derive from a pluripotential adnexal cell [1]. Other authors have favored at least partial sebaceous or apocrine lineage [2]. The current consensus seems to be that MAC is a separate clinicopathologic entity, probably synonymous with at least some of the low-grade sweat gland carcinomas reported variously as eccrine epithelioma, syringomatous carcinoma, malignant syringoma, syringoid eccrine carcinoma, aggressive trichofolliculoma, and also as the sclerosing sweat gland carcinomas [3, 4].

MAC is a rare tumor but is associated with high morbidity. It can infiltrate subcutaneous fat as well as along fascial planes and nerves, perichondrium, and periosteum [5–8].

Summary: Epidemiology

•Most cases seem to occur in whites, though Asians and African Americans have also been affected. There is no significant sexual predilection, and most cases present between 40 and 60 years of age.

20.2Epidemiology

Only about 300 microcystic adnexal carcinomas have been reported in the literature [9], most in the white population. Other ethnic groups may also be affected, and at least 50 Japanese [10] and 7 African American patients have been reported in the literature [9, 11–15].

Most affected individuals are 40–60 years of age, although the reported age range is very wide (10– 102 years) [16–18]. Although there is no significant sexual predilection, it is possible that among affected individuals, there is a female preponderance [8, 16, 18–20].

Summary: Pathogenesis

•The pathogenesis of MAC is unknown. Loss of a tumor suppressor gene on the long arm of chromosome 6 may play a role. Although not confirmed, other possible risk factors include UV exposure, radiotherapy, and immune compromise.

20.3Pathogenesis

The molecular pathophysiology of MAC is unknown. Unlike other more common skin tumors, a p53 gene mutation seems not to play a role [2, 21]. Abbate et al. reported MAC in two sisters and, on this basis, suggested a genetic predisposition [22]. Cytogenetic analysis in another affected individual showed a chromosome deletion on arm 6q [23]. The same deletion has also been documented in all major types of malignant salivary gland tumors, prompting some authors to postulate the loss of a tumor suppressor gene on that locus [24, 25].

Although their relative significance has not yet been established, potential risk factors associated with MAC may include UV exposure, radiotherapy, and being immunocompromised. A role for UV exposure was raised in a review of 48 North American patients in which 24 out of 48 patients had MAC on the left side of the head and neck region, compared with nine on the right side and nine on the midline [16]. The author postulated that this may be a consequence of driving on the left side of the road [16]. The opposite would be expected to apply to patients in two Australian studies, though comparative data are not available [17, 19]. Whatever the role of UV exposure, MAC also occurs in unexposed areas, such as the tongue, axilla, vulva, buttocks, and perianal skin [26].

A history of radiation therapy was noted in five out of ten patients in one study [22] and in two out of ten patients in a second [27]. In a third study [28], there was a history of radiotherapy in 2 out of 13 patients, of whom one was also a renal transplant patient on immunosuppression. In a review [29] of 274 published cases of MAC, a history of radiation exposure is reported to have preceded development of the tumor in 14 of 84 patients in whom a history was available, an incidence of 19.5%.

Three cases of MAC have been reported in immunosuppressed patients – two in renal transplant recipients [28, 30] and one in a patient with chronic lymphocytic leukemia [31].

Summary: Clinical Features and Diagnosis

•MAC characteristically presents as a poorly defined, yellowish or slightly erythematous, and indurated plaque. Nerve involvement may cause paresthesia or dysesthesia. The tumor may extend for several centimeters beyond the clinical margins.

Fig. 20.1 Photograph of a patient with MAC on the philtrum, illustrating the difficulty in determining the clinical margins of the tumor

20.4Clinical Features and Diagnosis

An indolent growth history is a characteristic feature and may contribute to delayed diagnosis, which is common [32]. In one patient, MAC was diagnosed as the cause of asymptomatic and gradually expanding alopecia which had been present for 31 years [13]. Also, a review of 50 Japanese patients included a patient who was considered to have had an undiagnosed MAC for 50 years [10].

MAC has a predilection for the head and neck, accounting for 74% of cases in a review of all patients with MAC reported between 1973 and 2004 in the Surveillance, Epidemiology, and End Results database of the National Cancer Institute of the USA [18]. This was followed by the trunk (9%), the arms (8.5%), and legs (5.4%). Two tumors were present on the labia majora [18].

MAC is often mistaken for morpheaform basal-cell carcinoma (BCC), which it can resemble clinically. Like this, MAC usually presents as a nontender, poorly defined, indurated plaque (Fig. 20.1) which is yellowish or faintly erythematous in color. Ulceration is uncommon, and subcutaneous extension may result in deeper, nodular swelling.

The true size of the tumor can be considerably underestimated because of subclinical extension which can sometimes extend to several centimeters. Different case series have measured a 3- to 14.4-fold discrepancy between the presumed clinical size and the wound

Fig. 20.2 Photograph after Mohs micrographic surgery, illustrating the extent of subclinical spread

after Mohs micrographic surgery (MMS) (Fig. 20.2) [16, 20, 28, 33, 34].

Symptoms such as numbness, burning, stinging, or paresthesia may be present and should alert the examiner to the possibility of perineural infiltration [8].

Summary: Histopathological Features

•An adequately sized biopsy is needed to assess the architectural pattern of the tumor and its perineural involvement. MAC has a superficial component consisting of keratin cysts lined with eosinophilic squamous epithelium and a deeper component comprising nests and cords of basaloid cells. The associated inflammatory infiltrate is characteristically scanty.

20.5Histopathological Features

An adequately sized biopsy is critical both for diagnosis and for assessment of perineural involvement. Interpretation of the histology may be particularly difficult in a small shave or superficial punch biopsy in which it is not possible to assess the architectural pattern. In the largest published case series, the diagnosis of MAC was made in only 70% of initial biopsy specimens [10, 16, 17]. In periocular skin, this figure seems to be even lower, applying to only 19% of all 35 periocular MAC reported in the English language literature [35]. It is possible that this is because smaller biopsies are taken at this site, making a correct diagnosis more challenging.

These are aggressive tumors which can infiltrate subcutaneous tissue. The cytology is often bland, with little pleomorphism and mitotic activity (Fig. 20.3). The relative proportions of the cellular components differ, the first consisting of keratin cysts lined with eosinophilic squamous epithelium. Deeper in the tumor are nests and cords of usually basaloid epithelial cells. Some of these show central keratinization or calcification, and some show duct formation and a tadpole appearance that may cause diagnostic confusion with syringomas [1, 3]. Perineural invasion is charac-

teristic [5]. The tumor cells frequently elicit a desmoplastic stromal response [1, 2, 5, 6]. It is possible that a variant characterized by nuclear pleomorphism, hyperchromasia, vascular invasion, and necrosis behaves more aggressively and may metastasize [36].

Toluidine blue is the preferred staining technique of many Mohs surgeons and may be useful in this context because it stains tumor strands with a distinctive pink halo. Where tumor is present around nerves, a maroon tint is seen [37].

The differential diagnosis includes syringoma and desmoplastic trichoepithelioma, though these do not extend deeply into the dermis or subcutis and do not show perineural invasion [1, 3, 38].

A morphoeic basal-cell carcinoma is likely to show epidermal contiguity and can be excluded by the presence of ductal differentiation in MAC (though this can sometimes occur in nodular BCC) and by the presence of intracytoplasmic lumen formation. Likewise, a desmoplastic squamous cell carcinoma can usually be excluded on the basis of epidermal involvement and the absence of ductal structures.

There is no specific immunohistochemical stain for MAC, but immunohistochemistry may nevertheless be helpful in making a diagnosis. Of particular use is p63, the nuclear staining pattern of which is highly expressed