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Malignant, primary

(carcinomas not usually characterised by clear cells, but with rare clear cell variants)

Malignant, primary

(carcinomas usually characterised by clear cells)

Malignant, metastatic

Pleomorphic adenoma Myoepithelioma Sebaceous adenoma Oncocytoma

Multifocal nodular oncocytic hyperplasia (MNOH) Mucoepidermoid carcinoma Acinic cell carcinoma

Epithelial-myoepithelial carcinoma Hyalinising clear cell carcinoma

Clear cell malignant myoepithelioma (myoepithelial carcinoma) Sebaceous carcinoma

Carcinomas: especially kidney, thyroid. Also melanoma an effect on the biological aggressiveness of any particular tumour.

The variable appearance of malignant myoepitheli-oma, leads to a wide differential diagnosis, including other salivary carcinomas. Nodules with central necrosis mimic the comedocarcinoma structures in salivary duct carcinoma, but there is usually more stromal material in the myoepithelial neoplasm and in addition, S-100 and/or myoepithelial markers are usually positive. The clear cell variant resembles many other salivary neoplasms composed of clear cells, benign and malignant, primary and metastatic (Table 5.3) [132, 174] (see Sect. 5.9.5).

The prognosis of malignant myoepithelioma is variable, but approximately one-third of patients die of disease, another third have residual tumour and the remaining third are disease-free [62, 168]. When metastases occur, they can be found in neck lymph nodes and at distant sites, including lungs, kidney, brain and bones. Malignant myoepitheliomas arising in ordinary pleomorphic adenomas behave in the same way as those that arise de novo [168], but it has been suggested that neoplasms developing in multiply recurrent pleomor-phic adenomas may pursue a prolonged course [52]. A further suggestion is that malignant myoepitheliomas composed mainly of plasmacytoid cells may be more aggressive [53, 218]. However, Savera and Sloman in their series of 25 cases found only a weak statistical correlation for outcome with cytological atypia (high grade), but other parameters (tumour size, site, cell type, mitot-ic rate, presence of a benign tumour, necrosis, perineu-ral and vascular invasion) showed no relationship [168]. In practice with any particular case, the various histo-logical features should be listed, and an attempt made to describe the tumour as low- or high-grade, but adding a rider that histological grade is as yet a far from proven guide to clinical behaviour. Treatment is surgical, and no role for radio- and chemotherapy has yet been established.

5.9.9 Salivary Duct Carcinoma

ICD-O:8500/3

Salivary duct carcinoma (SDC) is probably not as uncommon as previously thought [87, 93]. Most patients are over 50 years old and there is at least a 3:1 male predominance. It arises mainly in the parotid, less often in the submandibular gland and only occasionally in the minor glands of the palate [47], buccal mucosa [162], maxilla [122] and larynx [69]. It can develop de novo or in a pre-existing pleomorphic adenoma [86, 87] or polymorphous low-grade adenocarcinoma [191]. The microscopic appearance of SDC bears a striking resemblance to ductal carcinoma of the breast, both in situ and invasive, where all of the features of the mammary equivalent can be reproduced (Fig. 5.48). Perineural and lymphovascular invasion are seen in many cases. Nuclear pleomorphism is usual, and is also apparent on FNA cytology [192]. Mitotic figures are often numerous, also reflected in a high Ki-67 proliferation index [93].

Although most cases of SDC can be diagnosed with HE alone, special stains can help in a few instances. Im-munohistochemistry shows expression of epithelial markers such as cytokeratins (including subtype 7, but not 20), EMA and GCDFP-15. S-100 protein is usually negative, as are myoepithelial markers, although they may highlight subtle in situ lesions [5]. Despite the morphological similarity to breast carcinoma, staining for oestrogen and progesterone receptors is almost always negative, in contrast to that for androgen receptors (AR), where >90% of SDCs react, even in women. AR positivity appears to be specific to SDC (including when it arises in a pleomorphic adenoma), and is not seen in for example, mucoepidermoid

Fig. 5.48. Salivary duct carcinoma: invasive irregular ducts and cribriform structures strongly resemble ductal carcinoma of the breast

Fig. 5.49. Salivary duct carcinoma, mucin-rich variant. This is composed of a mixture of usual-type salivary duct carcinoma and lakes of mucinous adenocarcinoma carcinoma [142]. Some studies have shown SDCs to express prostate specific antigen (PSA) or acid phosphatase [110, 120], but another failed to confirm this [185] and similarly, only 1 out of 40 cases in a Mayo Clinic series was PSA-positive [115]. More recently cases of SDC showing positive staining for HER-2/neu (c-erbB-2) protein on immunohistochemistry have been published [202], and the gene amplification has been demonstrated with FISH analysis [204].

Several rare morphological variants of SDC have been described, including cribriform [23], micropapil-lary [147], sarcomatoid [96], mucin-rich [190] and oncocytic (Figs. 5.49, 5.50) [184]. So-called low grade salivary duct carcinoma [46] is probably a separate entity (see below).

The differential diagnoses of SDC are high-grade mucoepidermoid carcinoma, oncocytic carcinoma and some metastases. The diagnosis of mucoepidermoid carcinoma requires the presence of squamous-like cells, mucus-producing cells and cells of intermediate type, and there is no expression of androgen receptors. Many salivary oncocytic carcinomas probably demonstrate other types of malignancy (including SDC) with plentiful oncocytic cells, but a true oncocytic carcinoma lacks any features of SDC and is AR-negative. At present, neither of these two differential diagnoses is clinically critical since the prognosis is similar. However, it is important to identify metastatic carcinoma, particularly from the prostate or breast. In most cases, metastases will be obvious from clinical investigation and imaging studies, but the usual immunoprofile of these tumours is different: prostatic carcinomas tend to be AR+, ER-, PSA+, CK 7+; breast carcinoma tend to be usually AR-, often ER +, PSA-, CK 7+; SDC is AR+, ER-, usually PSA-, and CK 7+.

Fig. 5.50. Salivary duct carcinoma with oncocytic differentiation. The cells have ample granular cytoplasm with vesicular nuclei and prominent nucleoli. A clear distinction between oncocyt-ic salivary duct carcinoma and true oncocytic carcinoma may not be possible, as they may not be separate entities

Fig. 5.50. Salivary duct carcinoma with oncocytic differentiation. The cells have ample granular cytoplasm with vesicular nuclei and prominent nucleoli. A clear distinction between oncocyt-ic salivary duct carcinoma and true oncocytic carcinoma may not be possible, as they may not be separate entities

The prognosis for SDC is poor, and most series have shown that more than 70% of patients die of disease, usually within 3 years. Nevertheless, Grenko et al. [86] alluded to a minority (about 25-30%) who do well, but their study was unable to identify any particular features of this group. Amongst possible prognostic indicators, tumour size is probably important, with lesions <30 mm in diameter having a better prognosis [103], but nevertheless several fatal lesions of 20 mm have been reported [23, 36, 87, 185]. Determination of tumour DNA ploi-dy has not been found to have prognostic significance [9, 86], but it is possible that MIB1 proliferative activity might do so [93]. At present, the best hope for long-term survival appears to be complete surgical excision

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