Myoepithelial neoplasms of the skin and soft tissue still represent a confusing and somewhat controversial field in pathology as it appears that this category includes several different entities. However, recent studies have suggested that both apocrine mixed tumors (AMT) and cutaneous myoepitheliomas (CM) harbor identical chromosomal rearrangements involving the PLAG1 gene and hence may represent a morphological spectrum. The aim of the present study was to share our institutional experience with these tumors and specifically focus on studying their immunohistochemical and molecular features to further assess their relatedness. Eleven cases of AMT and 7 cases of CM were collected and analyzed using immunohistochemistry (IHC), PLAG1 FISH, and Archer FusionPlex assay. There were 14 male and 4 female patients with ages ranging from 26 to 85 years (median 55.8 years, mean 58.5 years). AMTs were mainly located in the head and neck (n = 10), while CMs were mainly located in the acral sites (n = 5). PLAG1 IHC was diffusely strongly positive in 14/17 (82%) cases, whereas a single case of AMT diffusely expressed HMGA2. Both tumor groups showed PLAG1 gene fusions which were detected in 6/13 analyzable samples (AMT, n = 4 and CM, n = 2), and included TRPS1::PLAG1 (n = 3), NDRG1::PLAG1 (n = 1), CTNNB1::PLAG1 (n = 1) and a novel PXDNL::PLAG1 fusion (n = 1). The remaining 5 cases were negative, 5 were not analyzable and the single case positive for HMGA2 by IHC revealed a potential HMGA2 gene rearrangement. The cases were further studied by FISH, with 12/17 cases showing PLAG1 gene rearrangement (AMT, n = 8 and CM, n = 4). Altogether, 14/18 cases showed PLAG1 gene rearrangement by at least one of the methods. PLAG1 immunohistochemistry had a 92% specificity and sensitivity. Our study provided additional data to suggest that AMT and CM share overlapping morphological and immunohistochemical features as well as molecular background characterized by PLAG1 gene fusions and thus represent a morphological spectrum. In addition, we identified a novel PXDNL::PLAG1 fusion and suggested that rare cases may harbor HMGA2 gene alterations which seem to be mutually exclusive with PLAG1 gene fusions. The relatedness of these tumors to salivary gland myoepithelial neoplasms and distinctness from eccrine mixed tumors and other skin and soft tissue myoepithelial neoplasms with EWSR1/FUS fusions is discussed.

• MeSH
• DNA vazebné proteiny * genetika   MeSH
• dospělí MeSH
• genová přestavba * MeSH
• hybridizace in situ fluorescenční MeSH
• imunohistochemie * MeSH
• lidé středního věku MeSH
• lidé MeSH
• myoepiteliální nádor * genetika   patologie   MeSH
• nádorové biomarkery * genetika   analýza   MeSH
• nádory komplexní a smíšené genetika   patologie   chemie   MeSH
• nádory kůže * genetika   patologie   MeSH
• nádory potních žláz genetika   patologie   MeSH
• protein HMGA2 * genetika   MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• srovnávací studie MeSH

Most of salivary gland neoplasms (benign and malignant) are characterized by recurrent gene fusions. Pleomorphic adenoma (PA), the most frequent salivary gland tumor, is driven by chromosomal rearrangements involving PLAG1 mapped to 8q12 and HMGA2 mapped to 12q13-15 in most cases. Multiple fusion partners have been identified including CTNNB1, FGFR1, LIFR, CHCHD7 and TCEA for PLAG1 fusions and NFIB, WIF1 and FHIT for HMGA2 fusions. To date, no data exist on the morphology of the few reported HMGA2-WIF1-rearranged PAs. We present 28 major salivary gland adenomas displaying distinctive trabecular and canalicular morphology associated with recurrent genotype. Patients were 15 females and 13 males aged 43 to 87 (median: 65). All tumors originated from the parotid. Their size range was 1 to 4 cm (mean: 2.3). Histologically, all tumors showed elongated or columnar cells arranged into bilayered to multilayered communicating and branching strands and trabeculae in a manner similar to canalicular adenoma of minor salivary glands or trabecular myoepithelioma with variable solid confluent intercalated duct-like areas. Fifteen tumors were exclusively canalicular/trabecular while 13 had intermingled or well-demarcated conventional (chondromyxoid) PA component comprising 5 to >50% of the tumor. The monomorphic areas expressed uniformly CK7 (28/28), vimentin (21/21), S100 (24/24), SOX10 (16/17) and variably p63 (8/21) and mammaglobin (6/16) but were negative with p40 (0/24), smooth muscle actin (0/24) and MUC4 (0/16). Targeted RNA sequencing revealed HMGA2 fusions in 14/16 (87%) assessable cases. Fusion partner was WIF1 (12), RPSAP52 (1) and HELB (1). Separate testing of the 2 components in 1 hybrid tumor showed same HMGA2/WIF1 fusion. HMGA2 immunohistochemistry was homogeneously positive in all cases including the 2 fusion-negative cases. A control cohort of 12 genuine canalicular adenomas revealed no HMGA2 fusions (0/4) and lacked HMGA2 immunoreactivity (0/12). This study highlights a distinctive variant in the spectrum of PA characterized by prominent trabecular and canalicular adenoma-like morphology. Our data confirm that canalicular adenomas in major salivary glands (either monomorphic or part of hybrid tumors) are distinct from canalicular adenoma of minor salivary glands. Their uniform genotype irrespective of presence or absence of a conventional PA component argues for classifying those tumors lacking a conventional PA component as "monomorphic variants of PA" rather than canalicular/basal cell adenomas, intercalated duct adenoma, trabecular myoepithelioma or true hybrid tumors.

• MeSH
• adaptorové proteiny signální transdukční genetika   MeSH
• dospělí MeSH
• fúze genů * MeSH
• genová přestavba * MeSH
• lidé středního věku MeSH
• lidé MeSH
• nádorové biomarkery analýza   genetika   MeSH
• nádory slinných žláz chemie   genetika   patologie   MeSH
• pleomorfní adenom chemie   genetika   patologie   MeSH
• protein HMGA2 genetika   MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

Giant cell tumors of soft tissue (GCT-ST) are rare low-grade neoplasms that were at one time thought to represent the soft tissue counterparts of GCT of bone (GCT-B) but are now known to lack the H3F3 mutations characteristic of osseous GCT. We present six distinctive giant cell-rich soft tissue neoplasms that expressed keratins and carried a recurrent HMGA2-NCOR2 gene fusion. Patients were five females and one male aged 14-60 years (median, 29). All presented with superficial (subcutaneous) masses that were removed by conservative marginal (3) or wide (2) local excision. The tumors originated in the upper extremity (2), lower extremity (2), head/neck (1), and trunk (1). Five patients with follow-up (median, 21 months; range, 14-168) remained disease-free. Grossly, all tumors were well-demarcated but not encapsulated with variable lobulation. Histologically, they were composed of bland plump epithelioid or ovoid to spindled mononuclear cells admixed with evenly distributed multinucleated osteoclast-type giant cells. Foci of stromal hemorrhage and hemosiderin were seen in all cases. The mitotic activity ranged from 2 to 14/10 high power fields (median: 10). Foci of necrosis and vascular invasion were seen in one case each. The mononuclear cells were immunoreactive with the AE1/AE3 keratin cocktail and less frequently/less diffusely for K7 and K19 but lacked expression of other lineage-associated markers. RNA-based next-generation sequencing revealed an HMGA2-NCOR2 fusion in all tumors. None of the keratin-negative conventional GCT-ST showed the HMGA2-NCOR2 fusion (0/7). Metaplastic bone (4/9) and SATB2 expression (3/4) were frequent in keratin-negative conventional GCT-ST but were lacking in keratin-positive HMGA2-NCOR2 fusion-positive tumors. The distinctive immunophenotype and genotype of these tumors strongly suggest that they represent a discrete entity, differing from conventional GCT-ST and other osteoclast-rich morphologic mimics. Their natural history appears favorable, although a study of additional cases and longer follow-up are warranted.

• MeSH
• dítě MeSH
• dospělí MeSH
• keratiny MeSH
• korepresor 2 jaderného receptoru genetika   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• nádory měkkých tkání genetika   patologie   MeSH
• nádory obrovskobuněčné genetika   patologie   MeSH
• onkogenní fúze MeSH
• protein HMGA2 genetika   MeSH
• senioři MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Although the administration of retinoids represents an important part of treatment for children suffering from high-risk neuroblastomas, approximately 50% of these patients do not respond to this therapy or develop resistance to retinoids during treatment. Our study focused on the comparative analysis of the expression of five genes and corresponding proteins (DDX39A, HMGA1, HMGA2, HOXC9 and PBX1) that have recently been discussed as possible predictive biomarkers of clinical response to retinoid differentiation therapy. Expression of these five candidate biomarkers was evaluated at both the mRNA and protein level in the same subset of 8 neuroblastoma cell lines after treatment with natural or synthetic retinoids. We found that the cell lines that were HMGA2-positive and/or HOXC9-negative have a reduced sensitivity to retinoids. Furthermore, the experiments revealed that the retinoid-sensitive cell lines showed a uniform pattern of change after treatment with both natural and sensitive retinoids: increased DDX39A and decreased PBX1 protein levels. Our results showed that in NBL cells, these putative protein biomarkers are associated with sensitivity or resistance to retinoids, and their endogenous or induced expression can distinguish between these two phenotypes.

• MeSH
• bexaroten farmakologie   MeSH
• biomarkery farmakologické metabolismus   MeSH
• chemorezistence účinky léků   genetika   MeSH
• DEAD-box RNA-helikasy genetika   metabolismus   MeSH
• dítě MeSH
• fenretinid farmakologie   MeSH
• fixace tkání MeSH
• homeodoménové proteiny genetika   metabolismus   MeSH
• isotretinoin farmakologie   MeSH
• kojenec MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• nádorové buněčné linie MeSH
• nádory nervového systému genetika   metabolismus   patologie   chirurgie   MeSH
• neuroblastom genetika   metabolismus   patologie   chirurgie   MeSH
• novorozenec MeSH
• pre-B-buněčný leukemický transkripční faktor 1 genetika   metabolismus   MeSH
• předškolní dítě MeSH
• proliferace buněk účinky léků   MeSH
• protein HMGA1A genetika   metabolismus   MeSH
• protein HMGA2 genetika   metabolismus   MeSH
• protinádorové látky farmakologie   MeSH
• tretinoin analogy a deriváty   farmakologie   MeSH
• zalévání tkání do parafínu MeSH
• Check Tag
• dítě MeSH
• kojenec MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• novorozenec MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH