transforming-growth-factor-beta and Adenoma--Pleomorphic

PLAG1 rearrangements have been described as a molecular hallmark of salivary gland pleomorphic adenoma (PA), carcinoma ex pleomorphic adenoma (CEPA), and myoepithelial carcinoma (MECA). Several fusion partners have been described, however, commonly no further assignment to the aforementioned entities or a morphological prediction can be made based on the knowledge of the fusion partner alone. In contrast, TGFBR3-PLAG1 fusion has been specifically described and characterized as an oncogenic driver in MECA, and less common in MECA ex PA. Here, we describe the clinicopathological features of three TGFBR3-PLAG1 fusion-positive salivary gland neoplasms, all of which arose in the deep lobe of the parotid gland. Histopathology showed high morphological similarities, encompassing encapsulation, a polylobular growth pattern, bland basaloid and oncocytoid cells with myoepithelial differentiation, and a distinct sclerotic background. All cases showed at least limited, unusual foci of minimal invasion into adjacent salivary gland tissue, including one case with ERBB2 (Her2/neu) amplified, TP53 mutated high-grade transformation, and lymph node metastases. Of note, all cases illustrated focal ductal differentiation. Classification remains difficult, as morphological overlaps between myoepithelial-rich cellular PA, myoepithelioma, and MECA were observed. However, evidence of minimal invasion advocates classification as low-grade MECA. This case series further characterizes the spectrum of uncommon cellular myoepithelial neoplasms harboring TGFBR3-PLAG1 fusion, which show recurrent minimal invasion of the adjacent salivary gland tissue, a predilection to the deep lobe of the parotid gland, and potential high-grade transformation.

Topics: Adenoma, Pleomorphic; Adult; Aged; DNA-Binding Proteins; Gene Rearrangement; Humans; Male; Neoplasm Grading; Oncogene Proteins, Fusion; Parotid Gland; Proteoglycans; Receptors, Transforming Growth Factor beta; Salivary Gland Neoplasms; Transforming Growth Factor beta

Although pleomorphic adenoma is the most common type of salivary gland epithelial tumor, it frequently contains "mesenchymal"-like components, including myxoid or chondroid tissues. We reported previously that chondroid tissue formation in pleomorphic adenoma was associated with overexpression of bone morphogenetic proteins (BMPs) by neoplastic myoepithelial cells. BMPs belong to the transforming growth factor (TGF)-beta superfamily, so we hypothesized that pleomorphic adenoma may express TGF-betas and that these molecules may regulate mesenchymal-like tissue formation. To evaluate this hypothesis, we immunohistochemically examined TGF-beta1, -beta2 and -beta3 expression and localization in normal salivary glands and in 43 cases of pleomorphic adenomas. There was no evidence of TGF-beta1 expression in normal salivary glands or pleomorphic adenomas. Signals for TGF-beta2 in the normal salivary glands were observed in the intercalated ducts, while in pleomorphic adenomas they were observed in the inner ductal cells of the tubulo-glandular structures. Signals for TGF-beta3 in the normal salivary glands were observed in mucous cells, whereas in pleomorphic adenomas they were observed in the solid nests of neoplastic myoepithelial cells, in the portion showing squamous metaplasia, and in the inner ductal cells of tubulo-glandular structures. TGF-betas induce ectopic cartilage formation in vivo, but chondroid tissues in pleomorphic adenomas showed only weak TGF-beta3 expression. TGF-beta may be related to differentiation of the inner ductal cells and the neoplastic myoepithelial cells. In conclusion, pleomorphic adenomas expressed TGF-beta2 and -beta3, which may be associated with differentiation of the inner ductal cells and neoplastic myoepithelial cells.

Topics: Adenoma, Pleomorphic; Antibodies; Bone Morphogenetic Proteins; Cartilage; Cell Differentiation; Coloring Agents; Epithelial Cells; Humans; Immunoenzyme Techniques; Immunohistochemistry; Mesoderm; Metaplasia; Mucous Membrane; Salivary Ducts; Salivary Gland Neoplasms; Salivary Glands; Transforming Growth Factor beta; Transforming Growth Factor beta1; Transforming Growth Factor beta2; Transforming Growth Factor beta3

One important pathological character of pleomorphic adenomas is that there is chorndriod component in the epithelial tumors. It is well known that bone morphogenetic protein (BMPs) plays important roles in the morphogenesis of hard tissue by inducing mesenchymal cells to differentiate into osteoblasts and chondroblasts in vivo. So we examined the expression of BMP and BMP2 mRNA in pleomorphic adenomas to study the pathological mechanism of chorndriod tissue formation.. Using ABC immunohistochemistry method, 6 specimens of pleomorphic adenomas were examined with BMP antibody. Reverse transcriptase-polymerase chain reaction (RT-PCR) methods were developed for detecting BMP2 mRNA expression with special primers used to amplify the BMP2 cDNA mature domain fragment. The total RNA was extracted from frozen 6 specimens of pleomorphic adenoma and then reversed to cDNA by reverse transcription using AMV reverse transcriptase. PCR conditions were 94 degrees C for 20 seconds, 60 degrees C for 30 seconds, and 72 degrees C for 1 minute, 40 cycles, followed by extension for 30 minute at 72 degrees C. The reaction products were analyzed by electrophoresis.. BMP expression could be found in all of the specimens of pleomorphic adenoma examined by immunohistochemistry method. BMP2 RT-PCR product was detected in only 5 specimens that showed BMP2 mRNA existed in 5 specimens.. These results may be helpful to study the mechanism of pleomorphic adenoma. It is speculated that BMP secreted by tumor cells may play important roles in origin of osteoid tissue in pleomorphic adenoma by inducing neoplastic myoepithelial cells to differentiate to chondrocytes.

Topics: Adenoma, Pleomorphic; Bone Morphogenetic Protein 2; Bone Morphogenetic Proteins; Humans; Immunohistochemistry; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Salivary Gland Neoplasms; Transforming Growth Factor beta

This study investigated the immunolocalization of small and large proteoglycans (PGs), including decorin, biglycan, PG-M/versican and aggrecan, in salivary pleomorphic adenoma (PA) using monoclonal and polyclonal antibodies. In addition, a polyclonal antibody, A0082, recognizing blood vessels was also used to help identify truly mesenchymal tissues in PA. Decorin reactivity was detected only in tumor capsule and interstitial tissue of non-neoplastic salivary gland, but not in the tumor tissue. Biglycan was frequently revealed throughout the matrix of small chondroid regions and in the peripheral portion of larger chondroid regions. PG-M/versican was mainly localized to the truly mesenchymal tissues in PA and the innermost portion of tumor capsule. On the contrary, aggrecan was extensively expressed in the non-luminal epithelial areas as well as in the myxoid and chondroid areas, but not in the truly mesenchymal tissues. These findings suggest that aggrecan is the most widely distributed PG in PA and may be produced mainly by non-luminal tumor cells. The absence of aggrecan from the truly mesenchymal tissues argues against its origin from this source. Both aggrecan and biglycan may play important roles in the chondroid differentiation and morphogenesis of PA.

Topics: Adenoma, Pleomorphic; Aggrecans; Antibodies; Antibodies, Monoclonal; Biglycan; Cell Differentiation; Chondroitin Sulfate Proteoglycans; Decorin; Epithelium; Extracellular Matrix; Extracellular Matrix Proteins; Humans; Immunohistochemistry; Lectins; Lectins, C-Type; Mesoderm; Morphogenesis; Proteoglycans; Salivary Gland Neoplasms; Salivary Glands; Transforming Growth Factor beta; Versicans

Immunohistochemical investigation of bone morphogenetic protein-2 (BMP-2) and type II collagen, two cartilage-associated proteins, was undertaken using monoclonal antibodies in 20 cases of salivary pleomorphic adenoma (PA) in order to explore their possible roles in chondroid differentiation of this tumor. Other salivary gland tumors, including adenoid cystic carcinoma (17 cases), polymorphous low-grade adenocarcinoma (10 cases), basal cell adenoma (3 cases), basal cell adenocarcinoma (1 case), and epithelial-myoepithelial carcinoma (2 cases), were also examined for comparison. In PA, BMP-2 immunoreactivity was detected in the luminal and non-luminal cells of the tubulo-ductal structures, plasmacytoid cells, and other scattered tumor cells in solid areas. In addition, tumor cells in chondroid areas in most cases (14/15), and stellate cells in myxoid areas in many cases (7/19), were also intensely labeled for BMP-2. Furthermore, BMP-2 was also detected in the non-neoplastic ductal cells in salivary glands, whereas no other salivary gland tumors were positively stained for this protein. Type II collagen was localized in the intercellular matrix of chondroid areas and in a few chondroid differentiating cells in myxoid areas, confirming its cartilage-specificity. A proportional relationship was observed between BMP-2 expression and chondroid formation, although BMP-2 was also stained in occasional PAs without chondroid formation. It is speculated that BMP-2 might be secreted by tumor cells and play a role in chondroid formation in PA by inducing some tumor cells to produce type II collagen and other chondroid matrical substances, like glycosaminoglycans. The expression of BMP-2 is specific to PA and may possibly be used as a useful marker in differentiating PA from other salivary gland tumors.

Topics: Adenocarcinoma; Adenoma; Adenoma, Pleomorphic; Biomarkers, Tumor; Bone Morphogenetic Protein 2; Bone Morphogenetic Proteins; Carcinoma; Collagen; Humans; Immunohistochemistry; Salivary Gland Neoplasms; Transforming Growth Factor beta