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in morphoeic BCC and desmoplastic trichoepitheliomas [39]. In MAC, staining is scattered and peripheral, particularly in deeper parts of the tumor. Epithelial membrane antigen is positive in MAC and helps differentiate from morphoeic BCC [40]. Staining for cytokeratin 15 may be useful in excluding basal-cell and squamous cell carcinoma but not desmoplastic trichoepithelioma [41].
Summary: Treatment
•Surgery is the mainstay of treatment. Mohs micrographic surgery (MMS) is associated with fewer complications and a lower recurrence rate than standard surgical excision (SSE). When perineural infiltration is noted on the diagnostic biopsy or when MAC persists after previous treatment, it is possible that MMS using formalin-fixed, paraffin-embedded sections should be considered as an alternative to the frozen section technique. Otherwise, the fresh tissue technique can be used until tumorfree margins are achieved, followed by an additional layer for paraffin sections.
•Primary or adjuvant radiotherapy and chemotherapy have been attempted with ambivalent results.
20.6Treatment
Surgery is the treatment of choice, though radiotherapy has been attempted as either primary or adjuvant therapy in a small number of patients. These have usually had extensive locoregional disease, and treatment has usually been unsuccessful [29]. In one patient, the tumor is even thought to have recurred in a more extensive and aggressive form 6 months after primary radiotherapy [42]. Furthermore, previous radiation exposure has been implicated as a possible risk factor for MAC.
There have been no randomized controlled studies comparing Mohs micrographic surgery (MMS) with standard surgical excision (SSE). The rationale for using the former would be the characteristic poorly defined clinical margins of this tumor and its predilection for perineural spread.
For the purposes of writing this chapter, we have assessed all of the 13 reported case series consisting of five patients or more (Table 20.1). MMS was used to
treat MAC in six of these, with a total of 113 patients and an average follow-up of 4.3 years (range, 3 months–13.3 years) [17, 20, 27, 28, 33, 34]. Of these, 5.8% of tumors persisted (exact 95%; CI, 1.9– 13). On the other hand, SSE was used in four studies, with a total of 95 cases and an average follow-up of 6.9 years (range, 4 months–29 years) [5, 10, 19, 43]. Among these, 32.2% persisted (exact 95%; CI, 22.75–42.9).
The remaining three studies employed either MMS or SSE in 72 patients (MMS, n = 39 and SSE, n = 33), with a mean follow-up of 2 years in the MMS group and 2.7 years in the SSE group [2, 16, 22]. The percentage of tumors persisting in the MMS and SSE groups was 5.4% (exact 95%; CI, 0.6–18.2) and 12.9% (exact 95%; CI, 3.6–29.8), respectively. There was no true randomization in these studies, and all three series contained patients in whom SSE had resulted in incomplete excision and as a result of which, they were referred for MMS.
A second disadvantage of SSE over MMS would seem to be higher morbidity. In the studies reviewed, incomplete SSE was reported in 17.6–58% of patients subjected to SSE [2, 16, 19, 22, 43]. In one study [43], a mean of 1.6 non-Mohs excisions was required to achieve clear surgical margins in primary tumors, and a mean of 2.5 excisions in recurrent MAC. Others reported a mean of 2.75 [16] and 1.5 [2] non-Mohs excisions to obtain clear margins in mixed primary and persistent tumors.
MMS can be undertaken with either the frozen tissue technique or using formalin-fixed, paraffin-embedded sections (“Slow Mohs”). Frozen sections seem reliable for treating primary MAC not associated with perineural and/or intraneural infiltration [20]. However, involvement of nerves is often present and may not be readily apparent on frozen sections stained with hematoxylin and eosin (H&E) (Fig. 20.4) [20, 44]. Adding to this difficulty are the characteristic absence of a marked inflammatory infiltrate and the difficulty in distinguishing between small strands of tumor and adnexal tissue (Fig. 20.5) [20, 44]. As a consequence, some authors have recommended that the fresh tissue technique is used until tumor margins appear clear on frozen sections and that an additional layer is then sent for paraffin sections [35, 45]. An alternative to this may be the use of toluidine blue, possibly together with H&E stains on the same tissue blocks [37]. As noted above, toluidine blue stains the tumor stroma with a pink halo, owing to
Table 20.1 Results of comparison of MMS and SSE for MAC
|
Pretreatment MAC |
|
|
Recurrent MAC (posttreatment) |
|
|
Study |
Comments |
No. of cases |
Patients lost to |
No. of recurrent |
Recurrence rate |
Exact 95% CI (%) |
|
|
|
follow-up |
patients |
(%) |
– recurrence rate |
Only Mohs micrographic surgery (MMS) |
|
|
|
|
|
|
Palamaras et al. [20] |
|
9 |
2 |
1 |
14.3 |
0.36–57.9 |
Thomas CJ et al. [34] |
|
26 |
1 |
3 |
12 |
2.55–31.22 |
Leibovitch et al. [17] |
|
44 |
24 |
1 |
5 |
0.13–24.9 |
Snow et al. [28] |
|
13 |
– |
0 |
0 |
0–20.5 |
Friedman et al. [27] |
|
11 |
– |
0 |
0 |
0–23.8 |
Burns et al. [33] |
|
10 |
– |
0 |
0 |
0–25.9 |
Recurrence rate, mean |
|
|
|
|
5.8 (5/86) |
1.9–13 |
|
|
|
|
|
||
Average follow-up: 4.3 years (range, 3 months–13.3 years) |
|
|
|
|
||
|
|
|
|
|
|
|
Only standard surgical excision (SSE) |
|
|
|
|
|
|
Gabillot-Carre et al. [43] |
3 patients had adjuvant |
7 |
– |
4 |
57.14 |
18.4–90.1 |
|
Rx |
|
|
|
|
|
Salerno et al. [19] |
|
17 |
– |
2 |
11.8 |
1.46–36.45 |
Ohtsuka et al. [10] |
|
51 |
– |
16 |
31.4 |
19.1–45.9 |
Cooper et al. [5] |
|
20 |
5 |
7 |
46.6 |
21.3–73.4 |
Recurrence rate, mean |
|
|
|
|
32.2 (29/90) |
22.75–42.9 |
|
|
|
|
|
|
|
Average follow-up: 6.9 years (range, 4 months–29 years) |
|
|
|
|
|
|
MMS or SSE |
|
|
|
|
|
|
Abbate et al. [22] |
MMS |
6 |
– |
0 |
0 |
0–39.3 |
|
SSE |
4 |
– |
1 |
25 |
0.63–80.6 |
Chiller et al. [16] |
MMS |
25 |
– |
2 |
8 |
0.98–26 |
|
SSE |
20 |
– |
1 |
5 |
0.13–24.8 |
Le Boit et al. [2] |
MMS |
8 |
2 |
0 |
0 |
0–39.3 |
|
SSE |
9 |
2 |
2 |
28.6 |
3.6–71 |
Recurrence rate, mean |
MMS |
|
|
|
5.4 (2/37) |
0.6–18.2 |
Recurrence rate, mean |
SSE |
|
|
|
12.9 (4/31) |
3.6–29.8 |
Average follow-up: MMS 2.07; SSE 2.7 years (range, 0 months–11.1 years)
MMS Mohs micrographic surgery, SSE standard surgical excision, MAC microcystic adnexal carcinoma, Recurrence rate total number of recurrences divided by the total number of patients observed during follow-up, Rx radiotherapy
248
Barlow .J.R and Palamaras .I
20 Microcystic Adnexal Carcinoma |
249 |
|
|
Fig. 20.4 Photomicrograph of a frozen section made during the Mohs excision of the tumor in Fig. 20.1. There are nests of epithelioid cells infiltrating the dermis. There is no associated inflammation, a characteristic feature of MAC which can contribute to small isolated islands of tumor being mistaken for normal eccrine apparatus (hematoxylin and eosin stain; original magnification ×40)
Fig. 20.5 Photomicrograph of a frozen section made during the Mohs excision of the tumor in Fig. 20.1. This shows a nerve, deep to muscle, invaded by epithelioid tumor strands without an associated inflammatory infiltrate (hematoxylin and eosin stain; original magnification × 40)
mucopolysaccharides, and stains the perineural and intraneural involvement magenta.
Persistence of MAC seems to be more likely after previous incomplete excision when periocular skin is involved and when there is perineural infiltration. A previous incomplete excision will also reduce the likelihood of obtaining tumor-free margins when MMS is attempted subsequently [20, 34]. As in other situations,
conventional excisions can fragment the tumor during attempted excision and during reconstruction [20]. One study reported that one of two recurrent tumors persisted despite MMS [16]. Two more studies reported persisting tumors following MMS in two out of six cases [34] and in two out of three cases [20], respectively.
Perineural invasion has also been linked with persistence of MAC following treatment. In three case
250 |
I. Palamaras and R.J. Barlow |
|
|
series, the first reported perineural infiltration in six out of seven patients with persistent disease [17]; another, in three out of four [43]; and a third, in two out of three recurrent tumors [20].
Periocular MAC associated with perineural involvement is particularly likely to persist, including after MMS [20]. One possible reason for this is frequent failure to make an early correct diagnosis [35]. In a review study of 35 reported cases with periocular MAC, 5 out of 16 persisted after MMS, and 4 out of 10 after SSE. In the remaining nine patients, there was no available information on subsequent treatment [35]. Follow-up ranged from 2 months to 30 years. Two out of the three reported deaths directly related to MAC have occurred in periocular tumors with perineural infiltration. In view of the difficulty of tumor clearance at this site, some authors have suggested that enucleation should be considered in the management of this group of patients [35, 46]. Others disagree given the implications of this procedure [9, 20, 29, 47, 48].
Chemotherapy has been used as an adjuvant measure in two patients with complex MAC, both unsuccessfully. The first was administered cisplatinum and 5-fluorouracil, after several attempts at radiotherapy and then surgery for a lip tumor with local metastasis [47]. The second had a persistent lesion on the right nasolabial fold following surgery together with lung metastases which were treated with lobectomy. Chemotherapy with cisplatinum and 5-fluorouracil was attempted when further surgery was declined [43].
Summary: Prognosis and Follow-Up
•This is an indolent tumor, and the prognosis seems good, even in a number of inoperable cases reported in the literature. There have only been three reports in the literature of death directly attributable to MAC. A metaanalysis of 223 cases showed a 10-year overall survival rate of 86.4%.
20.7Prognosis and Follow-Up
It is worth noting that two patients judged to have tumors too extensive for surgical intervention have been observed for several years without deterioration.
One patient had involvement of the dura mater [47], and one had extensive facial infiltration [29].
MAC is an indolent and slow-growing tumor and the prognosis is usually good. Metastases are rare, and only five patients are reported to have had local spread (in-transit and lymph node) [47, 49–51] and three patients to have had distant metastases [43, 52, 53]. It is possible that in two of the patients reported to have had regional metastases, lymph node involvement may actually have been caused by occult contiguous infiltration along the neurovascular bundles [50, 51].
There are only three reports of death directly attributable to MAC [20, 53, 54]. One is thought to have been due to mediastinal metastases [53], and two others to intracranial extension of tumors on the face [20, 54]. In a meta-analysis of 223 patients with MAC from the database of the National Cancer Institute of the USA, the 10-year overall patient survival was calculated to be 86.4% (95% CI, 78–92%; standard error [SE], 3.3%) and 97.7% (SE, 5.2%) when matched with the US census population in 2000 [18].
Acknowledgments The authors would like to thank Dr. Alistair Robson, Consultant Dermatopathologist at St. John’s Institute of Dermatology, for providing the photomicrograph of a diagnostic paraffin section and for photographing the frozen sections obtained during a Mohs excision.
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