Tns

Fig. 5.55 Pleomorphic adenoma. A Schematic illustration of promoter swapping between PLAG1 and CTNNB1 in pleomorphic adenomas wit are indicated by filled boxes. Breakpoints are indicated by arrows. B Schematic illustration of the HMGA2 gene. Coding exons are indic Breakpoints are indicated by arrows.

breakpoint cl utltr

imas with t(3;8). Coding exons are indicated by filled boxes.

play a major role in the genesis of pleomorphic adenomas {2700}. The target gene in adenomas with rearrangements of 12q14-15 is the high mobility group protein gene, HMGA2 (a.k.a. HMGIC) {878,879,2269}. HMGA2 encodes an architectural transcription factor that promotes activation of gene expression by modulating the conformation of DNA. The protein contains three DNA-binding domains that bind to the minor groove of AT-rich DNA. The majority of breakpoints in HMGA2 occur within the third large intron, resulting in separation of the DNA-binding domains from the highly acidic, carboxy-terminal domain. Two fusion genes, HMGA2-NFIB and HMGA2-FHIT, have been identified in adenomas with ins(9;12) and t(3;12), respectively {878,879}. Since no common functional domain has been found among the translocation partners, the critical event seems to be the separation of the DNA-binding domains from potential mRNA destabilizing motifs in the 3'-UTR, leading to deregulation of HMGA2 oncoprotein expression. High-level expression of HMGA2 resulting from gene amplification was recently suggested to be of importance for malignant transformation of pleomorphic adenomas {2194}.

The five PLAG1- and HMGA2-containing fusion genes so far identified are all tumour specific and may therefore be used as diagnostic markers for pleomor-phic adenomas. The fusions may be detected either by RT-PCR or by interphase fluorescence in-situ hybridization {878,879,1279,2701}. Molecular studies of the RAS and ERBB2 oncogenes have shown that mutation and activation of RAS frequently occur in pleomorphic adenomas, particularly in tumours with PLAG1 activation {1727, 2198,2464,2465}, whereas amplification and/or overexpression of ERBB2 seem to be rare {2198,2465}. Similarly, TP53 alterations are infrequent in adenomas {1907, 2198,2734}. In contrast, mutation and overexpression of TP53 are found in a relatively high proportion of carcinoma ex pleomorphic adenomas {1491,1907, 2169}. In addition, recent studies have shown that the TP53-related genes TP63 and TP73, which are novel myoepithelial markers, are overexpressed in basal and myoepithelial cells in pleomorphic adenomas {214,2734}. The pathogenetic relevance of the latter observations is uncertain. Studies using the human androgen receptor gene assay have demonstrated that the stromal and epithelial cells in pleomorphic adenomas are clonal and derived from the same progenitor cell {1455}. Finally, it was recently demonstrated that pleomorphic adenomas contain Simian virus 40 (SV40) DNA sequences and express the SV40 large T antigen, suggesting that this oncogenic virus may be involved in the genesis and/or progression of this tumour {1643}.

Prognosis and predictive factors

Although pleomorphic adenoma is a benign tumour it can cause problems in clinical management due to its tendency to recur and the risk of malignant transformation. Recurrences are rare in the minor glands but in a meta-analysis of parotid tumours 3.4% of tumours recurred after 5 years and 6.8% after 10 years with a range of 1-50% {1083}. The variation of frequency of recurrence in this survey probably reflected the inclu sion of cases reported before superficial parotidectomy became a widely used treatment and the variability of long-term follow-up. Some single centre, long-term surveys however, have shown recurrence rates as low as 1.6% {2169}. Recurrences appear to be much more likely in younger patients {1436,1681}. The possible reasons for recurrences or persistence in pleomorphic adenoma include:

- The diffluent nature of predominantly mucoid tumours {2157}.

- The variability of the thickness of the capsule, together with the tendency of the tumour to invade the capsule {1065}.

- Tumour nodules bulging through the capsule.

- Intratumoural splitting beneath the capsule.

- It is probable that the tumour cells have low biological requirements and this enables them to survive when spilt into the operative site.

Many recurrent pleomorphic adenomas are multifocal and some are so widely distributed that surgical control becomes impossible.

A. Cardesa L. Alos

Table 5.03 Classification of clear cell tumours of the salivary glands.

Benign

Pleomorphic adenoma, myoepithelioma, sebaceous adenoma, oncocytoma and oncocytic hyperplasia Malignant, primary a). Carcinomas not usually characterized by clear cells, but with clear cell predominant areas;

e.g. mucoepidermoid and acinic cell carcinomas.

b). Carcinomas usually characterized by clear cells;

i. Dimorphic epithelial-myoepithelial carcinoma.

ii. Monomorphic clear cell carcinoma.

clear cell myoepithelial carcinoma.

iii. Sebaceous carcinoma.

Definition

Myoepithelioma is a benign salivary gland tumour composed almost exclusively of sheets, islands or cords of cells with myoepithelial differentiation that may exhibit spindle, plasmacytoid, epithelioid or clear cytoplasmic features.

ICD-O code 8982/0

Synonyms

Myoepithelial adenoma, benign myoep-ithelial tumour.

Epidemiology

Myoepitheliomas account for 1.5% of all tumours in the major and minor salivary glands and represent 2.2% and 5.7%, respectively of all benign major and minor salivary gland tumours {668}. Both sexes are affected with equal frequency {41,128,546,668,1647,2282,2367}. Most tumours occur in adults, but rare examples have been recorded in children {1527}. The age of patients with myoepithelioma ranges from 9-85, with an average of 44 years and the peak age of occurrence in the third decade {668}.

Localization

Myoepitheliomas develop preferentially in the parotid gland (40%) {668}. Minor salivary glands follow in frequency, especially in hard and soft palates {546,668, 2282,2367}. Other minor salivary gland sites can also be affected {41,1647}.

Clinical features

Myoepitheliomas usually present as slow growing painless masses {41,2282, 2367}.

Macroscopy

Myoepitheliomas are well-circumscribed, solid tumours that usually measure less than 3 cm in diameter {41,541,2367}. Myoepitheliomas have a solid, tan or yellow-tan, glistening cut surface {668}.

Histopathology

A variety of cell morphologies has been recognized, including spindle, plasma-

Malignant, metastatic

Carcinomas, especially kidney, thyroid, melanoma.

cytoid or hyaline, epithelioid, and clear {546}. Most are composed of a single cell type but combinations may occur. Spindle cells are arranged in interlacing fascicles with stroma-like appearance {1579}. Plasmacytoid cells are polygonal cells with eccentric nuclei and dense, nongranular or hyaline, abundant eosinophilic cytoplasm. Plasmacytoid cells are found more often in tumours arising in the minor salivary glands than in the parotid gland. These hyaline cells may simulate neoplastic plasma cells, skeletal muscle or "rhabdoid" cells {1575}. Epithelioid cells are arranged in nests or cords of round to polygonal cells, with centrally located nuclei and a variable amount of eosinophilic cytoplasm. The surrounding stroma may be either collagenous or mucoid. Some myoepitheliomas are composed predominantly of clear polygonal cells with abundant and optically clear cytoplasm, containing large amounts of glycogen but devoid of mucin or fat. These tumours may show intercellular micro-cystic spaces.

In other myoepitheliomas, occasional duct-like structures and intercellular microcystic spaces may be present. An unusual reticular variant of myoep-ithelioma characterized by netlike arrangements of interconnected cell cords, extending through a loose, vascu-larized stroma, has been reported {546}.

Immunoprofile

The cells of myoepithelioma are usually positive for cytokeratins, especially for CK7 and 14. The reactivity of the spindle cells is variable for a-smooth muscle actin, muscle specific actin (MSA), calponin, S-100, GFAP and smooth muscle myosin heavy chain. There is considerable variation of tumour expression of MSA. The spindle cells react strongly for MSA, the epithelioid cells react sporadically, and the plasmacytoid and clear cells are often nonreactive {805}.

Electron microscopy

Ultrastructural studies confirmed the epithelial and myoepithelial differentiation of myoepithelioma {538,541}.

Differential diagnoses

Distinction from pleomorphic adenoma is based on the relative lack of ducts and the absence of myxochondroid or chon-droid areas. Myoepitheliomas with clear cells, or mixed epithelioid and clear cells have to be separated from other salivary gland tumours with clear cells, such as: mucoepidermoid carcinoma, acinic cell carcinoma, epithelial-myoepithelial carcinoma, oncocytoma and clear cell carcinoma. All these tumours lack the characteristic immunoprofile of the myoepithelial cells. In contrast to carcinomas, myoepitheliomas have a non-infiltrative, well-circumscribed periphery.

Myoepithelioma 259

A isJSS

Myoepithelioma
Fig. 5.56 Myoepithelioma. A Spindle cell type. B Epithelioid cell type. C Plasmacytoid cell type. D Clear cell type.

Predominantly spindle cell myoepithe-liomas must be distinguished from benign and malignant mesenchymal tumours.

Genetics

Cytogenetic studies have demonstrated structural alterations of chromosomes 1, 9, 12, and 13: t(1 ; 12)(q25;q 12), del(9) (q22.1q22.3), del(13)(q12q22) in a parotid myoepithelioma {654}. Mutations of TP53 have been observed in 3 of 12 (25%) myoepitheliomas {2734}.

Prognosis and predictive factors

According to well-documented series myoepitheliomas are less prone to recur than pleomorphic adenomas {2282}. However, higher recurrence rates have been reported by others {41,646}. Recurrence is correlated with positive margins at the first excision {646}. The recommended treatment is complete surgical excision. Benign myoepithe-liomas can undergo malignant transformation, especially in long standing tumours or in tumours with multiple recurrences {41}.

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