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Fig. 5.43. Basal cell adenocarcinoma. In spite of the lack of significant cellular atypia, the infiltrative pattern is diagnostic of malignancy. Courtesy of Prof. J.W. Eveson, Bristol, UK

Fig. 5.44. Myoepithelial carcinoma. Multiple nodules infiltrate dense fibrous tissue amount of basement membrane material varies, but can be marked, especially in the membranous variant. Occasional cases show cytological pleomorphism, but generally this is absent, and mitotic figures are usually sparse. The most reliable indicator of malignancy is infiltration of the surrounding gland, and less frequently of blood vessels and nerves (Fig. 5.43) [16]. In addition, the Ki-67 proliferation index is usually higher in basal cell adenocarcinoma than its benign counterpart (>5% vs. <2.7%) [152]. More than half the carcinomas in one study expressed p53, and 3 out of 11 cases were positive for epidermal growth factor receptor (EGFR); in contrast, all the adenomas were negative [152]. The differential diagnosis of basal cell adenocarcinoma includes solid forms of adenoid cystic carcinoma (see Sect. 5.9.3), which are much more aggressive neoplasms with cytological pleomorphism and plentiful mitotic figures; these are generally associated with other growth patterns such as small luminal structures. The behaviour of most basal cell adenocarcinomas is low grade. A review found an incidence of local recurrence of 37%, cervical lymph node metastasis of 8%, distant metastases of 4% and one patient died of disseminated disease [144].

5.9.8 Myoepithelial Carcinoma

(Malignant Myoepithelioma)

Fig. 5.44. Myoepithelial carcinoma. Multiple nodules infiltrate dense fibrous tissue in patients over 50 years of age, and there is an equal sex incidence [16]. The usual site is the parotid gland, but they have been described in the submandibular [131, 144], sublingual [139] and minor glands [111]. They can arise de novo, but about 25% develop in a preexisting basal cell adenoma [144], usually of the membranous type [16] (see Sect. 5.8.3). Microscopically, the general morphological and cytological appearances are almost identical to basal cell adenoma and likewise, four growth patterns are recognised - solid, tubular, trabecular and membranous - although these are not thought to have prognostic significance. The tumour islands contain a mixture of large, paler and small ba-saloid cells, with the latter usually demonstrating peripheral palisading, though this is less marked than in the benign counterpart. The large cells sometimes form eddies, and the tumour islands may also contain small tubules and foci of squamous metaplasia. The

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Myoepithelial carcinoma is defined as a malignant epithelial neoplasm in which the predominant differentiation of the tumour cells is myoepithelial [171]. The average age of patients at presentation is about 55 years (range 14-86), and the sex incidence is approximately equal. Most cases arise in the parotid, but they also occur in the submandibular and minor glands [62, 168]. They may arise de novo, but at least 50% develop in a pre-existing pleomorphic adenoma or benign myoepi-thelioma [2, 54, 149, 168].

Macroscopically, malignant myoepitheliomas are uncircumscribed masses usually 20-50 mm in diameter (maximum 250 mm). The microscopic architecture is often multinodular with infiltration into adjacent tissues. The nodules comprise solid and sheet-like growths of tumour cells often with plentiful myxoid or hyaline material, and sometimes displaying central necrosis (Figs. 5.44, 5.45). The range of cell types reflects that seen in benign myoepitheliomas and includes epi-thelioid cells (the most frequent) often arranged in tra-becular or pseudo-acinar structures with cleft-like spaces. Cells with clear cytoplasm or vacuolation (resembling lipoblasts) and cells with hyaline (plasmacytoid) and spindle to stellate forms are also seen (Fig. 5.46). In most malignant myoepitheliomas one cell type predom-

Fig. 5.45. Myoepithelial carcinoma, solid growth pattern with central necrosis in one of the nodules. This finding may mimic salivary duct carcinoma with comedo-like necrosis
Fig. 5.47. Myoepithelial carcinoma: focal squamous metaplasia with keratin pearl formation
Fig. 5.46. Myoepithelial carcinoma. The spindle cell component shows nuclear pleomorphism resembling a soft tissue sarcoma. A helpful diagnostic pointer is that other types of myoepithelial cell are usually identified elsewhere

inates, but there is usually a minor component of other cell types. No true glands or lumina are seen in pure, malignant myoepitheliomas, but as with their benign counterparts, occasional small ducts in a neoplasm with otherwise typical features should not preclude the diagnosis [183]. The nuclei can vary from relatively uniform, small with finely distributed chromatin, lacking obvious nucleoli, to markedly enlarged and pleomorphic, showing chromatin clumping and large nucleoli. Mitotic figures may be plentiful (range 3 to 51 per 10 high power fields) and include atypical forms [168]. Multinucleate [33] and bizarre tumour giant cells may occasionally be present. The tumour-related matrix is generally prominent and is hyalinised or myxoid.

Special stains in tumours without any ductal differentiation show no mucicarmine-positive mucus, but plentiful glycogen is found in clear cells and the myxoid matrix is positive with Alcian Blue. Metaplas-tic changes are frequent and include areas showing squamous differentiation, often with keratinisation (Fig. 5.47). Perineural invasion is seen in 44% and vascular invasion in 16%. In one series, 40% of tumours were categorised as high grade and 60% as low grade [168]. All tumours show some positivity for S-100 protein, vimentin and broad-spectrum cytokeratin (e.g. AE1-AE3 or MNF116). Other cytokeratin antisera (CAM 5.2 and LP34) show some reactivity in most tumours, and about half display some expression of cytokeratin [13]. Of the more specific myoepithelial markers, approximately 75% of tumours including those composed of plasmacytoid cells, express calponin and about 50% are positive with aSMA; p63 was positive in 60% [166]. Amongst other markers, glial fibrillary acidic protein (GFAP) is positive in 31% and epithelial membrane antigen (EMA) in 20%, in addition to highlighting any true small ducts, but carcino-embry-onic antigen (CEA) is usually negative. CD117 (c-kit) was positive in the few cases studied [112]. The mean MIB1 (Ki-67) index in one series was 35% (range 1565), with any count above 10% said to be diagnostic of malignancy in a myoepithelial neoplasm [151].

Electron microscopy shows that some tumour cells contain small desmosomes, but actin filaments are few [168]. It has been shown that malignant myoepithelio-mas secrete matrix-degrading proteinases, as well as proteinase inhibitors [215], and this appears to be associated with demonstrated inhibition of angiogenesis. These features indicate an anti-invasive effect, and although as yet poorly understood, this is likely to have

Table 5.3. Classification of clear cell tumours and tumour-like conditions of the salivary glands [174]

Benign

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