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Figs. 5.53, 5.54. Endodermal sinus tumour of the parotid gland. Positive staining for placental alkaline phosphatase (PLAP) is essential to confirm the diagnosis. Courtesy of Dr. Isabela Wernicke [211]

5.9.15 Higher Grade Change in Carcinomas lial-myoepithelial carcinomas showed myoepithelial features. The processes underlying dedifferentiation of salivary neoplasms remain to be established, but previous radiotherapy may have been important in some of the AdCCs [32] and PLGAs [160]. In general, no definite factors in the progression of low-grade to highgrade carcinomas have been identified at a molecular level [208]; for example, there is conflicting evidence regarding p53 mutations, which might have been involved in a single case of transformed AdCC [32], but was not a factor in dedifferentiated acinic cell carcinomas [51, 95].

5.9.16 Metastatic

Malignancies

Figs. 5.53, 5.54. Endodermal sinus tumour of the parotid gland. Positive staining for placental alkaline phosphatase (PLAP) is essential to confirm the diagnosis. Courtesy of Dr. Isabela Wernicke [211]

High-grade transformation is a rare but well-established event in several primary low-grade salivary carcinomas, and usually heralds a more aggressive clinical course. Examples have been described in acinic cell [51, 95, 154, 213], adenoid cystic [32, 140], epithelial-myoepithelial [2, 73, 186], mucoepidermoid [146] and polymorphous low-grade adenocarcinoma [160, 191], as well as malignant myoepithelioma [156]. In each case, the diagnoses of high-grade change were based on histopathological criteria, especially increased mi-totic and proliferation rates. Most of the transformed components were poorly differentiated adenocarcino-mas, but some of those in adenoid cystic and epithe

Metastases to the major glands and the intraparotid lymph nodes constitute approximately 10% of all salivary carcinomas [82]; the exact figure varies from study to study depending on local factors such as different incidences of particular cancers. For example, Bergensen et al. [18] in Australia reported that metastases constituted 72% of all malignancies, resulting from the high incidence of skin cancer. In an AFIP series and literature review in 1991 of 785 parotid metastases [82], 64% were found to have originated from the head and neck region (including the skin), 11% from distant sites and 25% from an unknown primary. Of the distant sites, lung, kidney and breast accounted for more than four-fifths (Table 5.4); only four cases were from the prostate, but it is perhaps under-recognised [195]. Metastases to the submandibular glands are less common than to the parotids, but are more likely to be from distant sites [226].

Microscopically, metastases in the salivary glands can resemble almost any primary tumour, so that for example, mammary duct carcinoma is morphologically identical (but immunohistochemically different) to salivary duct carcinoma (see Sect. 5.9.9). Similarly, renal cell carcinoma is part of the differential diagnosis of any clear cell tumour of the salivary glands, and examples of prostate carcinoma have been mistaken for acinic cell carcinoma [195]. Immunohistochemistry is of some value, and can identify prostate and thyroid primaries and melanoma with a reasonable degree of accuracy. Unlike most primary malignant salivary tumours, renal cell carcinomas are usually negative with cytokeratin 7; in contrast, CD10 stains most kidney carcinomas, but is only positive in salivary tumours with myoepithelial differentiation. However, the possibility of metastasis is still best confirmed or excluded by imaging techniques of the kidneys.

5.10 Hybrid

Carcinoma

Hybrid tumours are composed of two different types of tumour, each of which conforms to an exactly defined category of tumour. They are rare, comprising <0.1% of neoplasms in the Hamburg Salivary Tumour Registry [172]. Malignant examples demonstrate various combinations, e.g. epithelial-myoepithelial and adenoid cystic carcinomas [37].

5.11 Endodermal Sinus Tumour

ICD-O:9071/3

There are only two reports of primary endodermal sinus tumour (EST) of the parotid gland. One that recurred after chemotherapy occurred in a 2-year-old girl [227]; the other was seen in a 16-month-old girl, who is alive and well 2 years after chemotherapy [211]. The serum AFP was elevated and returned to normal levels after surgical resection of the EST. As for EST in other sites, several patterns can be recognised [211]. Diffuse positive staining for AFP and placental alkaline phosphatase (PLAP) by immunohistochemistry may be necessary to confirm the diagnosis (Figs. 5.53, 5.54) [211].

5.12 Sialoblastoma

ICD-O:8974/1

This rare tumour of the major glands arises in the perinatal period or in the first year of life [62]. It is well circumscribed, up to 150 mm in diameter and composed of numerous solid hypercellular islands of primitive basaloid cells, some with peripheral palisading, and often with small central ducts. The tumour cells have large round to ovoid vesicular nuclei and abundant eo-sinophilic cytoplasm, and immunohistochemistry and electron microscopy show both epithelial and myoepi-thelial cells [102]. Mitotic figures may be numerous, but none is atypical. Criteria for malignancy include invasion of nerves or vascular spaces, necrosis and marked cytological atypia [14]. Out of 15 reported cases, 4 had recurrences and another had metastases to regional lymph nodes.

5.13 Alterations in Gene Expression and Molecular Derangements in Salivary Gland Carcinoma

Present classifications contain at least 17 different salivary malignancies that can be broadly subdivided into carcinomas with myoepithelial differentiation and carcinomas with acinar/epithelial differentiation. Marker proteins including cell-proliferation antigens, myoepi-thelial proteins, matrix metalloproteinases, growth factors and their receptors, and steroid receptors have been introduced for diagnosis and prognostication of specific types of salivary gland carcinoma [171].

Despite advances, the genetic events associated with the development and progression of salivary gland neoplasia are largely unknown. There is a clear need for better understanding of such events, for defining new prognostic and diagnostic markers, and for designing targeted therapeutic interventions. The recent application of microarray technologies in the study of head and neck cancer, as well as other malignancies, has resulted in the generation of interesting new data [167, 216, 235]. Also, studies of microsatellite markers have identified losses of heterozygosity [212] and differences in chromosomal loci among various types of salivary gland carcinoma.

5.13.1 Predominantly Myoepithelial Malignancies

The commonest salivary gland malignancy expressing myoepithelial properties is the adenoid cystic carcinoma (AdCC). Abnormal gene expression of AdCC has been studied using oligonucleotide microarrays of 8,920 genes [79]. The most overexpressed genes coded for basement membrane and extracellular matrix proteins of myoepithelial differentiation, such as laminin-p1, versican, biglycan and type IV collagen-a.1. Other overexpressed genes included transcription factors SOX-4 and the AP-2 family, and members of the Wnt/ beta-catenin signalling pathway such as casein kinase 1, epsilon and frizzled-7. The most underexpressed genes included in particular those encoding for secretory proteins of acinar differentiation such as amylase, carbonic anhydrase and salivary proline-rich proteins. In AdCC, loss of heterozygosity frequently occurs in chromosome 6q23-25, correlating with prognostic parameters [212]. In addition, altered gene expression in pleomorphic adenomas has been recently studied in cDNA microarrays [78].

5.13.2 Predominantly

Epithelial Malignancies

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