Adenoid cystic carcinoma (AdCC) is one of the most common salivary gland malignancies and occurs in all major and minor salivary gland and seromucous gland sites. AdCCs of salivary gland origin have long been categorized as fusion-defined carcinomas owing to the almost consistent presence of fusion genes MYB::NFIB , or less commonly MYBL1::NFIB. We collected a cohort of 95 cases of AdCC, which were largely characterized by canonical fusions MYB::NFIB (49 cases) or MYBL1::NFIB (9 cases). In additional 11 cases of AdCC, rearrangements in MYB or NFIB genes were detected by FISH. In addition, NGS revealed novel noncanonical fusion transcripts EWSR1::MYB ; ACTB::MYB; ESRRG::DNM3, MYB::TULP4 , and ACTN4::MYB , each of them in 1 case. The tumors that showed noncanonical fusions had features of metatypical AdCC with a diverse architecture, lobulated multinodular growth pattern, and hypercellular peripheral palisading of nuclei (2 cases), tubular hypereosinophilia (2 cases), and pale eosinophilic to vacuolated (bubbly) cytoplasm (3 cases). Our study documented 3 cases of AdCC of salivary glands harboring novel gene fusions TULP4::MYB , ACTN4::MYB , and ACTB::MYB , in 1 case each, which have not been described before. A rare EWSR1::MYB fusion was detected in 1 case. Moreover, 1 case of sinonasal metatypical AdCC showed EWSR1 rearrangement detected by FISH. Also, 1 case with an ESRRG::DNM3 fusion of unknown significance is described in this study. These discoveries illustrate how broad molecular profiling will expand understanding of changes in known entities.

• Klíčová slova
• adenoid cystic carcinoma, salivary gland neoplasm, sinonasal,
• MeSH
• adenoidně cystický karcinom * genetika   patologie   MeSH
• dospělí MeSH
• fúze genů MeSH
• fúzní onkogenní proteiny * genetika   MeSH
• genetická predispozice k nemoci MeSH
• genová přestavba MeSH
• hybridizace in situ fluorescenční MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladý dospělý MeSH
• nádorové biomarkery * genetika   MeSH
• nádory slinných žláz * genetika   patologie   MeSH
• protein EWS vázající RNA * genetika   MeSH
• protoonkogenní proteiny c-myb genetika   MeSH
• senioři MeSH
• trans-aktivátory genetika   MeSH
• transkripční faktory NFI genetika   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• EWSR1 protein, human MeSH Prohlížeč
• fúzní onkogenní proteiny * MeSH
• MYB protein, human MeSH Prohlížeč
• MYBL1 protein, human MeSH Prohlížeč
• nádorové biomarkery * MeSH
• NFIB protein, human MeSH Prohlížeč
• protein EWS vázající RNA * MeSH
• protoonkogenní proteiny c-myb MeSH
• protoonkogenní proteiny MeSH
• trans-aktivátory MeSH
• transkripční faktory NFI MeSH

Classification of head and neck tumors has evolved in recent decades including a widespread application of molecular testing in tumors of the salivary glands, sinonasal tract, oropharynx, nasopharynx, and soft tissue. Availability of new molecular techniques allowed for the definition of multiple novel tumor types unique to head and neck sites. Moreover, the expanding spectrum of immunohistochemical markers facilitates a rapid identification of diagnostic molecular abnormalities. As such, it is currently possible for head and neck pathologists to benefit from a molecularly defined classifications, while making diagnoses that are still based largely on histopathology and immunohistochemistry. This review highlights some principal molecular alterations in head and neck neoplasms presently available to assist pathologists in the practice of diagnosis, prognostication and prediction of response to treatment.

• Klíčová slova
• Head and neck, Molecular diagnostics, Next-generation sequencing, Salivary gland, Sinonasal tumor, Soft tissue,
• MeSH
• imunohistochemie MeSH
• lidé MeSH
• molekulární patologie * MeSH
• nádory hlavy a krku * diagnóza   genetika   MeSH
• patologové MeSH
• slinné žlázy MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

We report 2 cases of high-grade sinonasal adenocarcinoma with a distinct morphological and immunohistochemical phenotype. Albeit histologically different from secretory carcinoma of the salivary glands, both tumors presented here share an ETV6::NTRK3 fusion. The highly cellular tumors were composed of solid and dense cribriform nests, often with comedo-like necroses in the center, and minor areas with papillary, microcystic, and trabecular formations without secretions, mostly located at the periphery of the lesion. The cells displayed high-grade features, with enlarged, crowded, and often vesicular nuclei with conspicuous nucleoli and brisk mitotic activity. The tumor cells were immunonegative for mammaglobin while showing immunopositivity for p40/p63, S100, SOX10, and GATA3, as well as for cytokeratins 7, 18, and 19. For the first time, we describe 2 cases of primary high-grade non-intestinal type adenocarcinomas of the nasal cavity, distinct from secretory carcinoma by morphology and immunoprofile, harboring the ETV6::NTRK3 fusion.

• Klíčová slova
• ETV6::NTRK3, Nasal cavity, Salivary duct carcinoma, Secretory carcinoma, Sinonasal, non-intestinal-type adenocarcinoma,
• MeSH
• adenokarcinom * genetika   patologie   MeSH
• fúzní onkogenní proteiny genetika   MeSH
• imunohistochemie MeSH
• karcinom * genetika   patologie   MeSH
• lidé MeSH
• nádorové biomarkery genetika   MeSH
• nádory prsu MeSH
• nádory slinných žláz * genetika   patologie   MeSH
• protein ETS, translokační varianta 6 MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH
• Názvy látek
• fúzní onkogenní proteiny MeSH
• nádorové biomarkery MeSH
• NTRK3 protein, human MeSH Prohlížeč

This review gives a brief history of the development of head and neck pathology in Europe from a humble beginning in the 1930s to the explosive activities the last 15 years. During the decades before the introduction of immunohistochemistry in the 1980s, head and neck pathology grew as a subspeciality in many European countries. In the late 1940s, the Institute of Laryngology and Otology with its own pathology laboratory was founded in London, and in 1964 the World Health Organization (WHO) International Reference Centre for the Histological Classification of Salivary Tumours was established at the Bland-Sutton Institute of Pathology, also in London. International collaboration, and very much so in Europe, led to the publication of the first WHO Classification of Salivary Gland Tumours in 1972. In the 1960s, a salivary gland register was organised in Hamburg and in Cologne the microlaryngoscopy was invented enabling microscopic endoscopic examination and rather shortly afterwards a carbon dioxide laser attached to the microscope became established and laryngeal lesions could be treated by laser vaporisation. During the last three decades, the use of immunohistochemistry supplemented with cytogenetic and refined molecular techniques has greatly facilitated the pathological diagnostics of head and neck lesions and has had a huge impact on research. Collaboration between different European centres has drastically increased partly due to establishment of scientific societies such as the Head and Neck Working Group (HNWG) within the European Society of Pathology and the International Head and Neck Scientific Group (IHNSG). A very large number of European pathologists have contributed to the 2nd, 3rd and 4th WHO books, and are involved in the upcoming 5th edition. Accredited educational meetings and courses are nowadays regularly arranged in Europe. Numerous textbooks on head and neck pathology have been written and edited by European pathologists. The increased collaboration has created larger series of tumours for research and new entities, mainly defined by their genetic abnormalities, are continuously emerging from Europe, particularly regarding salivary gland neoplasms and "undifferentiated" sinonasal tumours. These findings have led to a better and more precise classification and open the possibilities for new treatment strategies.

• Klíčová slova
• Cancer, Head and neck pathology, History of European head and neck pathology, Laryngeal neoplasms, Salivary neoplasms, Sinonasal neoplasms,
• MeSH
• lidé MeSH
• nádory hlavy a krku * diagnóza   MeSH
• nádory slinných žláz * MeSH
• slinné žlázy MeSH
• Světová zdravotnická organizace MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Geografické názvy
• Evropa MeSH

Salivary gland carcinomas represent a heterogeneous group of poorly characterized head and neck tumors. The purpose of this study was to evaluate ALK gene and protein aberrations in a large, well-characterized cohort of these tumors. A total of 182 salivary gland carcinomas were tested for anaplastic lymphoma kinase (ALK) positivity by immunohistochemistry (IHC) using the cut-off of 10% positive cells. ALK positive tumors were subjected to FISH analysis and followed by hybrid capture-based next generation sequencing (NGS). Of the 182 tumors, 8 were ALK positive by IHC. Further analysis using hybrid capture NGS analysis revealed a novel MYO18A (Exon1-40)-ALK (exon 20-29) gene fusion in one case of intraductal carcinoma. Additional genomic analyses resulted in the detection of inactivating mutations in BRAF and TP53, as well as amplifications of ERBB2 and ALK. ALK rearrangements are a rare entity in salivary gland carcinomas. We identified a potentially targetable novel ALK fusion in an intraductal carcinoma of minor salivary glands.

• Klíčová slova
• Anaplastic lymphoma kinase, FISH, Immunohistochemistry, Intraductal carcinoma, Next generation sequencing, Salivary gland carcinoma,
• MeSH
• amplifikace genu MeSH
• anaplastická lymfomová kináza genetika   MeSH
• dítě MeSH
• dospělí MeSH
• fúze genů MeSH
• hybridizace in situ fluorescenční MeSH
• imunohistochemie MeSH
• intraduktální neinfiltrující karcinom enzymologie   genetika   patologie   MeSH
• karcinom enzymologie   genetika   patologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• nádorové biomarkery genetika   MeSH
• nádory slinných žláz enzymologie   genetika   patologie   MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• vysoce účinné nukleotidové sekvenování MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• ALK protein, human MeSH Prohlížeč
• anaplastická lymfomová kináza MeSH
• nádorové biomarkery MeSH

Diagnosis of salivary gland neoplasms is often challenging due to their high morphological diversity and overlaps. Several recurrent molecular alterations have been described recently, which can serve as powerful diagnostic tools and potential therapeutic targets (e.g. NTRK or RET fusions). However, current sequential molecular testing can be expensive and time consuming. In order to facilitate the diagnosis of salivary gland neoplasms, we designed an all-in-one RNA-based next generation sequencing panel suitable for the detection of mutations, fusions and gene expression levels (including NR4A3) of 27 genes involved in salivary gland neoplasms. Here we present the validation of the "SalvGlandDx" panel on FFPE histological specimen including fine needle aspiration (FNA) cell block material, against the standard methods currently used at our institution. In a second part we describe selected unique cases in which the SalvGlandDx panel allowed proper diagnosis and new insights into special molecular characteristics of selected salivary gland tumors. We characterize a unique salivary gland adenocarcinoma harboring a ZCCHC7-NTRK2 fusion, a highly uncommon spindle cell and pseudoangiomatoid adenoid-cystic carcinoma with MYBL1-NFIB fusion, and a purely oncocytic mucoepidermoid carcinoma, whereas diagnosis could be made by detection of a CRTC3-MAML2 rearrangement on the cell block specimen of the FNA. Further, a rare case of a SS18-ZBTB7A rearranged low-grade adenocarcinoma previously described as potential spectrum of microsecretory adenocarcinoma, is reported. In addition, features of six cases within the spectrum of polymorphous adenocarcinoma / cribriform adenocarcinoma of salivary gland including PRKD1 p.E710D mutations and novel fusions involving PRKAR2A-PRKD1, SNX9-PRKD1 and ATL2-PRKD3, are described.

• Klíčová slova
• Biopsy, Comprehensive, FNA, Molecular, Salivary gland neoplasm, Testing,
• MeSH
• biopsie MeSH
• fúzní onkogenní proteiny genetika   metabolismus   MeSH
• hybridizace in situ fluorescenční MeSH
• imunohistochemie metody   MeSH
• lidé MeSH
• mutace MeSH
• nádorové biomarkery * MeSH
• nádorové buněčné linie MeSH
• nádory slinných žláz diagnóza   farmakoterapie   genetika   MeSH
• staging nádorů MeSH
• stanovení celkové genové exprese * metody   MeSH
• stupeň nádoru MeSH
• vysoce účinné nukleotidové sekvenování * metody   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• fúzní onkogenní proteiny MeSH
• nádorové biomarkery * MeSH

We present a 72 years old male with a left nasal cavity (mammary analogue) secretory carcinoma (SC) which exhibited classical morphological features on light microscopical examination, diffuse strong S100 and mammoglobin positivity on immunohistochemistry, and ETV6-NTRK3 gene fusion on next generation sequencing (NGS) analysis. Unusual features of this tumor are expression of p63 and DOG1 on immunohistochemistry and the atypical junction between Exon 4 of the ETV6 gene and Exon 14 of the NTRK3 gene.

• Klíčová slova
• ETV6-NTRK3 fusion protein, human, Immunohistochemistry, Mammary analogue secretory carcinoma, Nasal cavity,
• MeSH
• anoctamin 1 biosyntéza   MeSH
• exony genetika   MeSH
• fúzní onkogenní proteiny genetika   MeSH
• lidé MeSH
• membránové proteiny biosyntéza   MeSH
• nádorové biomarkery analýza   MeSH
• nádorové proteiny biosyntéza   MeSH
• nádory nosu genetika   patologie   MeSH
• nosní dutina patologie   MeSH
• sekreční karcinom mamárního typu genetika   patologie   MeSH
• sekvenční analýza DNA MeSH
• senioři MeSH
• vysoce účinné nukleotidové sekvenování MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH
• Názvy látek
• ANO1 protein, human MeSH Prohlížeč
• anoctamin 1 MeSH
• CKAP4 protein, human MeSH Prohlížeč
• ETV6-NTRK3 fusion protein, human MeSH Prohlížeč
• fúzní onkogenní proteiny MeSH
• membránové proteiny MeSH
• nádorové biomarkery MeSH
• nádorové proteiny MeSH

This study was undertaken to determine the frequency, and the clinicopathologic and genetic features, of colon cancers driven by neurotrophic receptor tyrosine kinase (NTRK) gene fusions. Of the 7008 tumors screened for NTRK expression using a pan-Trk antibody, 16 (0.23%) had Trk immunoreactivity. ArcherDx assay detected TPM3-NTRK1 (n=9), LMNA-NTRK1 (n=3), TPR-NTRK1 (n=2) and EML4-NTRK3 (n=1) fusion transcripts in 15 cases with sufficient RNA quality. Patients were predominantly women (median age: 63 y). The tumors involved the right (n=12) and left colon unequally and were either stage T3 (n=12) or T4. Local lymph node and distant metastases were seen at presentation in 6 and 1 patients, respectively. Lymphovascular invasion was present in all cases. Histologically, tumors showed moderate to poor (n=11) differentiation with a partly or entirely solid pattern (n=5) and mucinous component (n=10), including 1 case with sheets of signet ring cells. DNA mismatch repair-deficient phenotype was seen in 13 cases. Tumor-infiltrating CD4/CD8 lymphocytes were prominent in 9 cases. Programmed death-ligand 1 positive tumor-infiltrating immune cells and focal tumor cell positivity were seen in the majority of cases. CDX2 expression and loss of CK20 and MUC2 expression were frequent. CK7 was expressed in 5 cases. No mutations in BRAF, RAS, and PIK3CA were identified. However, other genes of the PI3K-AKT/MTOR pathway were mutated. In several cases, components of Wnt/β-catenin (APC, AMER1, CTNNB1), p53, and TGFβ (ACVR2A, TGFBR2) pathways were mutated. However, no SMAD4 mutations were found. Two tumors harbored FBXW7 tumor suppressor gene mutations. NTRK fusion tumors constitute a distinct but rare subgroup of colorectal carcinomas.

• MeSH
• adenokarcinom diagnóza   genetika   patologie   MeSH
• fúzní onkogenní proteiny genetika   metabolismus   MeSH
• imunohistochemie MeSH
• lidé středního věku MeSH
• lidé MeSH
• membránové glykoproteiny genetika   metabolismus   MeSH
• nádorové biomarkery genetika   metabolismus   MeSH
• nádory tračníku diagnóza   genetika   patologie   MeSH
• následné studie MeSH
• onkogenní fúze MeSH
• receptor trkA genetika   metabolismus   MeSH
• receptor trkB genetika   metabolismus   MeSH
• receptor trkC genetika   metabolismus   MeSH
• regulace genové exprese u nádorů MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• staging nádorů MeSH
• tyrosinkinasové receptory genetika   metabolismus   MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• fúzní onkogenní proteiny MeSH
• membránové glykoproteiny MeSH
• nádorové biomarkery MeSH
• receptor trkA MeSH
• receptor trkB MeSH
• receptor trkC MeSH
• tropomyosin-related kinase-B, human MeSH Prohlížeč
• tyrosinkinasové receptory MeSH

Adenoid cystic carcinoma (ACC) is among the most frequent malignancies of the salivary gland, and is notorious for its prolonged clinical course characterized by frequent recurrences often years after initial treatment. No molecular marker has been shown to have independent prognostic value in ACC, including characteristic gene fusions involving MYB, MYBL1, and NFIB. MicroRNA has been shown to be associated with clinical outcome in numerous malignancies, including one study of ACC, warranting further validation of this class of markers in this disease. Here, we investigate the prognostic value of microRNA in two ACC cohorts: a training cohort (n = 64) and a validation cohort (n = 120) with microarray and qPCR. In the training cohort, multivariate analysis of microarray data found high expression of hsa-miR-6835-3p to be associated with reduced recurrence-free survival (RFS) (p = 0.016). Measuring the highest ranking microRNAs identified in survival analysis in the same cohort, qPCR identified high expression of hsa-miR-4676 to be associated with reduced overall survival (OS) and high expression of hsa-mir-1180 to be associated with improved RFS. This was not confirmed in the validation cohort, in which qPCR identified high expression of hsa-mir-21, hsa-mir-181a-2, and hsa-mir-152 to be associated with reduced OS and high expression of hsa-miR-374c to be associated with improved RFS. Interestingly, two distinct subsets of ACC separated in microRNA expression irrespective of gene fusion status, but without significant difference in outcome. Collectively, qPCR identified several microRNAs associated with OS and RFS, and different subsets of ACC separated according to microRNA expression, suggestive of ACC being a heterogeneous group of malignancies in its microRNA profile.

• Klíčová slova
• Adenoid cystic carcinoma, MYB, MYBL1, Prognosis, Salivary gland, microRNA,
• MeSH
• adenoidně cystický karcinom genetika   mortalita   patologie   MeSH
• dospělí MeSH
• fúze genů * MeSH
• kohortové studie MeSH
• lidé středního věku MeSH
• lidé MeSH
• mikro RNA analýza   MeSH
• mladiství MeSH
• mladý dospělý MeSH
• nádory slinných žláz genetika   mortalita   patologie   MeSH
• prognóza MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• mikro RNA MeSH

Infantile fibrosarcoma and congenital mesoblastic nephroma are tumors of infancy traditionally associated with the ETV6-NTRK3 gene fusion. However, a number of case reports have identified variant fusions in these tumors. In order to assess the frequency of variant NTRK3 fusions, and in particular whether the recently identified EML4-NTRK3 fusion is recurrent, 63 archival cases of infantile fibrosarcoma, congenital mesoblastic nephroma, mammary analog secretory carcinoma and secretory breast carcinoma (tumor types that are known to carry recurrent ETV6-NTRK3 fusions) were tested with NTRK3 break-apart FISH, EML4-NTRK3 dual fusion FISH, and targeted RNA sequencing. The EML4-NTRK3 fusion was identified in two cases of infantile fibrosarcoma (one of which was previously described), and in one case of congenital mesoblastic nephroma, demonstrating that the EML4-NTRK3 fusion is a recurrent genetic event in these related tumors. The growing spectrum of gene fusions associated with infantile fibrosarcoma and congenital mesoblastic nephroma along with the recent availability of targeted therapies directed toward inhibition of NTRK signaling argue for alternate testing strategies beyond ETV6 break-apart FISH. The use of either NTRK3 FISH or next-generation sequencing will expand the number of cases in which an oncogenic fusion is identified and facilitate optimal diagnosis and treatment for patients.

• MeSH
• dospělí MeSH
• fibrosarkom diagnóza   genetika   MeSH
• fúzní onkogenní proteiny genetika   MeSH
• genetické testování MeSH
• hybridizace in situ fluorescenční MeSH
• karcinom genetika   MeSH
• kojenec MeSH
• lidé středního věku MeSH
• lidé MeSH
• lokální recidiva nádoru genetika   MeSH
• mezoblastický nefrom vrozené   diagnóza   genetika   MeSH
• mladiství MeSH
• nádory ledvin vrozené   diagnóza   genetika   MeSH
• nádory prsu genetika   MeSH
• novorozenec MeSH
• předškolní dítě MeSH
• protein ETS, translokační varianta 6 MeSH
• proteiny asociované s mikrotubuly genetika   MeSH
• proteiny buněčného cyklu genetika   MeSH
• protoonkogenní proteiny c-ets genetika   MeSH
• receptor DDR2 genetika   MeSH
• represorové proteiny genetika   MeSH
• sekvenční analýza RNA MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• serinové endopeptidasy genetika   MeSH
• Check Tag
• dospělí MeSH
• kojenec MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• novorozenec MeSH
• předškolní dítě MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• DDR2 protein, human MeSH Prohlížeč
• EML4 protein, human MeSH Prohlížeč
• fúzní onkogenní proteiny MeSH
• proteiny asociované s mikrotubuly MeSH
• proteiny buněčného cyklu MeSH
• protoonkogenní proteiny c-ets MeSH
• receptor DDR2 MeSH
• represorové proteiny MeSH
• serinové endopeptidasy MeSH