Wxu

Pleomorphic Adenoma Cell Block
Fig. 5.51 Pleomorphic adenoma. A Squamous differentiation. B Chondroid differentiation. C Osseous differentiation. D Lipomatous differentiation.

typically is positive with stains for elastin. This material can push apart epithelial elements to give a cylindromatous or cribriform appearance that is readily mistaken for adenoid cystic carcinoma. Some longstanding tumours show increasing hyalin-isation and the epithelial component is progressively effaced. It is important, however, to scrutinise the residual epithelial elements of such old, scarred pleo-morphic adenomas as there is a significant risk of malignant progression in such tumours {85}. Tumours that have a lipomatous stromal component of 90% or more have been called lipomatous pleo-morphic adenomas {1881, 2299}. More extensive inflammation and necrosis can be seen following spontaneous infarction or fine needle aspiration. In such tumours there may be an increase in mitotic figures and some cellular atyp-ia {361,1495}. In addition, squamous metaplasia may be present and these changes can be mistaken for malignancy. Some tumours show cystic degener ation with the neoplastic elements forming a rim around a central cavity. Occasionally tumour cells can be seen within vascular spaces {475}. These are usually within the body of the tumour or at the periphery and this is assumed to be a peroperative phenomenon. Sometimes this is seen in vessels distant from the main tumour mass. However, this finding does not appear to have any significance in terms of tumour behaviour and, in particular, the risk of metastasis.

Immunoprofile

The inner ductal cells in the tubulo-glan-dular structures are positive for cytoker-atin 3, 6, 10, 11, 13, and 16, whereas the neoplastic myoepithelial cells are irregularly positive for cytokeratin 13, 16, and 14 {311}. The neoplastic myoepithelial cells co-express vimentin and pan-cytok-eratin and are variably positive for S-100 protein, a-smooth muscle actin, GFAP, calponin, CD10 and muscle-specific actin (HHF-35) {545}. Modified myoep-

ithelial cells in these tumours are also reactive for p63 {214}. The non-lacunar cells in the chondroid areas are positive for both vimentin and pan- cytokeratin, whereas the lacunar cells are positive only for vimentin {1776}. The spindle-shaped neoplastic myoep-ithelial cells around the chondroid areas express bone morphogenetic protein (BMP) {1083} whereas the inner ductal cells in the tubulo-glandular structures and the lacuna cell in the chondroid areas express BMP-6 {1397}. Type II collagen and chondromodulin-I is present in the chondroid matrix {1396}. Aggrecan is present not only in the chondroid matrix but also in the myxoid stroma and in the inter-cellular spaces of the tubulo-glan-dular structures {2898}.

Genetics

Cytogenetics

Extensive cytogenetic studies of pleomorphic adenomas have shown that approximately 70% of the tumours are karyotypically abnormal {306,1639, 2239}. Four major cytogenetic subgroups may be discerned:

> Tumours with rearrangements involving 8q12 (39%)

> Tumours with rearrangements of 12q13-15 (8%)

> Tumours with sporadic, clonal changes not involving 8q12 or 12q13-15 (23%)

> Tumours with an apparently normal karyotype (30%).

Whereas t(3;8)(p21;q12) and t(5;8)(p13;q12) are the most frequently observed translocations in the first subgroup, a t(9;12)(p24;q14-15) or an ins(9;12)(p24;q12q15) are the most frequent rearrangements seen in the second subgroup. In addition, many variant translocations have been identified in which a number of other chromosome segments are found as translocation partners of both 8q12 and 12q13-15. Secondary chromosome changes, including trisomies, dicentrics, rings and double minutes, are found in about one-third of the cases with abnormal kary-otypes. Previous studies have also indicated that patients with karyotypically normal adenomas are significantly older than those with rearrangements of 8q12 (51.1 years versus 39.3 years, p < 0.001) and that adenomas with normal kary-otypes are often more stroma rich than tumours with 8q12 abnormalities {306}.

Molecular genetics

The target gene in pleomorphic adenomas with 8q12 abnormalities is PLAG1, a developmentally regulated zinc finger gene {82,1279,2701}. Translocations involving 8q12 commonly result in promoter swapping/substitution between PLAG1 and a ubiquitously expressed translocation partner gene, leading to activation of PLAG1 expression. The breakpoints invariably occur in the 5'-noncoding regions of both the target gene and the promoter donor genes. The most commonly observed fusions are CTNNB1-PLAG1 and LIFR-PLAG1, resulting from t(3;8)(p21 ;q12) and t(5;8)(p13;q12) translocations, respectively {1279,2701}. Recently, cryptic gene fusions involving CTNNB1-PLAG1 and SII-PLAG1 were also found in kary-otypically normal adenomas {82}. The PLAG1 protein is a nuclear oncoprotein that functions as a DNA-binding transcription factor. Deregulation of PLAG1 target genes, including IGF2, is likely to

Was this article helpful?

0 0
Delicious Diabetic Recipes

Delicious Diabetic Recipes

This brilliant guide will teach you how to cook all those delicious recipes for people who have diabetes.

Get My Free Ebook


Post a comment