Chromosomal rearrangements of NTRK genes are oncogenic driver mutations in thyroid cancer (TC). This study aimed to identify NTRK fusion-positive thyroid tumors and to correlate them with clinical and pathological data and determine their prognostic significance. The cohort consisted of 989 different TC samples. Based on the detected mutation, samples were triaged, and those that were positive for a BRAF, HRAS, KRAS, NRAS, RET, RET/PTC or PAX8/PPARγ mutation were excluded from further analyses. NTRK fusion gene testing was performed in 259 cases, including 126 cases using next-generation sequencing. NTRK fusion genes were detected in 57 of 846 (6.7%) papillary thyroid carcinomas and in 2 of 10 (20.0%) poorly differentiated thyroid carcinomas. A total of eight types of NTRK fusions were found, including ETV6/NTRK3, EML4/NTRK3, RBPMS/NTRK3, SQSTM1/NTRK3, TPM3/NTRK1, IRF2BP2/NTRK1, SQSTM1/NTRK1 and TPR/NTRK1.NTRK fusion-positive carcinomas were associated with the follicular growth pattern, chronic lymphocytic thyroiditis and lymph node metastases. NTRK1-rearranged carcinomas showed a higher frequency of multifocality and aggressivity than NTRK3-rearranged carcinomas. Tumor size, presence of metastases, positivity for the NTRK3 or NTRK1 fusion gene and a late mutation event (TERT or TP53 mutation) were determined as factors affecting patient prognosis. NTRK fusion genes are valuable diagnostic and prognostic markers.

• Klíčová slova
• NTRK, clinicopathological feature, follow-up, fusion gene, outcome, papillary thyroid carcinoma, poorly differentiated thyroid carcinoma, prognosis,
• Publikační typ
• časopisecké články MeSH

Alterations in kinase genes such as NTRK1/2/3, RET, and BRAF underlie infantile fibrosarcoma (IFS), the emerging entity 'NTRK-rearranged spindle cell neoplasms' included in the latest WHO classification, and a growing set of tumors with overlapping clinical and pathological features. In this study, we conducted a comprehensive clinicopathological and molecular analysis of 22 cases of IFS and other kinase gene-altered spindle cell neoplasms affecting both pediatric and adult patients. Follow-up periods for 16 patients ranged in length from 10 to 130 months (mean 38 months). Six patients were treated with targeted therapy, achieving a partial or complete response in five cases. Overall, three cases recurred and one metastasized. Eight patients were free of disease, five were alive with disease, and two patients died. All cases showed previously reported morphological patterns. Based on the cellularity and level of atypia, cases were divided into three morphological grade groups. S100 protein and CD34 were at least focally positive in 12/22 and 14/22 cases, respectively. Novel PWWP2A::RET, NUMA1::RET, ITSN1::RAF1, and CAPZA2::MET fusions, which we report herein in mesenchymal tumors for the first time, were detected by RNA sequencing. Additionally, the first uterine case with BRAF and EGFR mutations and CD34 and S100 co-expression is described. DNA sequencing performed in 13 cases uncovered very rare additional genetic aberrations. The CNV profiles showed that high-grade tumors demonstrate a significantly higher percentage of copy number gains and losses across the genome compared with low- and intermediate-grade tumors. Unsupervised clustering of the tumors' methylation profiles revealed that in 8/9 cases, the methylation profiles clustered with the IFS methylation class, irrespective of their clinicopathological or molecular features. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

• Klíčová slova
• BRAF mutation, CDKN2A, NTRK‐rearranged spindle cell neoplasms, entrectinib, infantile fibrosarcoma, kinase gene fusion, larotrectinib, methylation profiling, selpercatinib,
• MeSH
• dítě MeSH
• dospělí MeSH
• fibrosarkom * genetika   patologie   MeSH
• fúzní onkogenní proteiny genetika   MeSH
• lidé MeSH
• lokální recidiva nádoru genetika   MeSH
• nádorové biomarkery genetika   analýza   MeSH
• nádory měkkých tkání * genetika   MeSH
• nádory z pojivové a měkké tkáně * MeSH
• protoonkogenní proteiny B-Raf genetika   MeSH
• receptor trkA genetika   MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• fúzní onkogenní proteiny MeSH
• nádorové biomarkery MeSH
• protoonkogenní proteiny B-Raf MeSH
• receptor trkA MeSH

NTRK-rearranged spindle cell neoplasm represents an emerging entity included in the latest 5th edition of WHO classification of both soft tissue and female genital tumors. By immunohistochemistry, they are commonly positive for CD34, S100 protein, and CD30 and typically harbor fusions of kinase genes such as NTRK1/2/3, RET, and BRAF. In the gynecological tract, they typically affect the uterine cervix or uterine body. Most of the reported cases had fibrosarcoma-like morphology, occasionally showing perivascular and stromal hyalinization with only a few cases showing a less cellular spindle cell proliferation. Except for one case with RET fusion, all other gynecological cases harbored exclusively NTRK1/2/3 fusions. Besides kinase gene fusions, the analogous tumors in soft tissues may also harbor activating EGFR or BRAF point mutations, but no such case has been described in the uterus. Herein we are reporting two cases from the uterine cervix showing morphology and molecular features previously unreported at this anatomic site. The patients were 46 and 34 years old and clinically presented with unremarkable cervical polyps each measuring 8 mm in diameter. Histologically, both cases had a rounded polypoid outline and were composed of hypocellular proliferation of bland spindle cells lacking mitotic activity and growing in a fibrotic stroma which was punctuated by prominent small vessels with thick hyalinized walls. Immunohistochemically, both showed a diffuse expression of CD34, CD30, and S100 protein, whereas SOX10 was negative. Both cases harbored exon 20 EGFR mutation and did not reveal any fusions or significant copy number changes. The patient in case 1 was treated by hysterectomy with salpingectomy with no other residual tumor detected, and she was alive and well 27 months after the diagnosis. The patient in case 2 had no other known tumors at the time of diagnosis, but no follow-up is available. We believe the reported cases represent a hitherto unrecognized variant of "NTRK-rearranged spindle cell neoplasms" of the uterine cervix with novel EGFR mutations.

• Klíčová slova
• EGFR mutation, NTRK-rearranged spindle cell neoplasms, Perivascular and stromal hyalinization, S100 and CD34 co-expression, Soft tissues, Uterine cervix,
• Publikační typ
• časopisecké články MeSH

Infant gliomas have paradoxical clinical behavior compared to those in children and adults: low-grade tumors have a higher mortality rate, while high-grade tumors have a better outcome. However, we have little understanding of their biology and therefore cannot explain this behavior nor what constitutes optimal clinical management. Here we report a comprehensive genetic analysis of an international cohort of clinically annotated infant gliomas, revealing 3 clinical subgroups. Group 1 tumors arise in the cerebral hemispheres and harbor alterations in the receptor tyrosine kinases ALK, ROS1, NTRK and MET. These are typically single-events and confer an intermediate outcome. Groups 2 and 3 gliomas harbor RAS/MAPK pathway mutations and arise in the hemispheres and midline, respectively. Group 2 tumors have excellent long-term survival, while group 3 tumors progress rapidly and do not respond well to chemoradiation. We conclude that infant gliomas comprise 3 subgroups, justifying the need for specialized therapeutic strategies.

• MeSH
• analýza přežití MeSH
• anaplastická lymfomová kináza genetika   metabolismus   MeSH
• epigenomika metody   MeSH
• gliom klasifikace   genetika   metabolismus   MeSH
• kojenec MeSH
• lidé MeSH
• metylace DNA * MeSH
• nádory mozku klasifikace   genetika   metabolismus   MeSH
• novorozenec MeSH
• protoonkogenní proteiny c-met genetika   metabolismus   MeSH
• protoonkogenní proteiny genetika   metabolismus   MeSH
• receptor trkA genetika   metabolismus   MeSH
• regulace genové exprese u nádorů * MeSH
• sekvenování exomu metody   MeSH
• tyrosinkinasové receptory genetika   metabolismus   MeSH
• tyrosinkinasy genetika   metabolismus   MeSH
• Check Tag
• kojenec MeSH
• lidé MeSH
• mužské pohlaví MeSH
• novorozenec MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• anaplastická lymfomová kináza MeSH
• MET protein, human MeSH Prohlížeč
• protoonkogenní proteiny c-met MeSH
• protoonkogenní proteiny MeSH
• receptor trkA MeSH
• ROS1 protein, human MeSH Prohlížeč
• tyrosinkinasové receptory MeSH
• tyrosinkinasy MeSH

BACKGROUND: Tropomyosin receptor kinase inhibitors (TRKi) have been shown to produce a dramatic and long-lasting effect on tumours harbouring fusions of neurotrophic receptor tyrosine kinase (NTRK) genes. Due to the low incidence of these molecular aberrations in common types of solid adult tumours, the identification of patients eligible for the treatment with TRK inhibitors in routine clinical practice is a major challenge. The current methods for NTRK gene fusion testing include immunohistochemistry (IHC), fluorescence in situ hybridization (FISH), and several genomic assays using next-generation sequencing (NGS). After considering the characteristics of these tests, we recommend two-step testing for clinical practice in tumours with a low incidence of NTRK gene fusions. In the first step, a fresh or archival formalin fixed paraffin embedded (FFPE) sample is tested using a validated IHC method. If the IHC result is positive, verification using RNA-based should follow, preferably using fresh tissue sample. If fresh tissue bio-psy cannot be obtained, e.g. due to a disproportionate risk or discomfort for the patient, an archival FFPE sample may be used for testing. For tumours with high incidence of NTRK gene fusions, we recommend upfront NGS sequencing. Larotrektinib is currently the only TRK inhibitor registered in the EU. Although entrektinib, another TRK inhibitor, is not yet registered in the EU, it is currently available in the Czech Republic within an Early Access Programme. PURPOSE: The aim of this paper is to provide concise and clear guidance on testing for the presence of NTRK gene fusions and indications for the treatment with TRK inhibitors in the routine clinical oncology practice.

• Klíčová slova
• neurotrophic receptor kinase – targeted molecular therapy – entrektinib – larotrektinib – neoplasms,
• MeSH
• antitumorózní látky terapeutické užití   MeSH
• dospělí MeSH
• fúze genů MeSH
• inhibitory proteinkinas terapeutické užití   MeSH
• lidé MeSH
• nádory farmakoterapie   genetika   MeSH
• sirotčí receptory podobné receptoru tyrosinkinasy genetika   MeSH
• směrnice pro lékařskou praxi jako téma MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• antitumorózní látky MeSH
• inhibitory proteinkinas MeSH
• sirotčí receptory podobné receptoru tyrosinkinasy 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

PURPOSE: Tropomyosin receptor kinase (TRK) fusions are detected in less than 2% of central nervous system tumors. There are limited data on the clinical course of affected patients. EXPERIMENTAL DESIGN: We conducted an international retrospective cohort study of patients with TRK fusion-driven central nervous system tumors. RESULTS: A total of 119 patients were identified. The median age at the time of diagnosis was 4.5 years. The majority were reported to have a histology consistent with a diagnosis of high-grade glioma (HGG; 57.1%) followed by low-grade glioma (LGG; 27.7%). Pediatric patients had a better prognosis, with a median overall survival of 185.5 months compared with 24.8 months in adults (P < 0.0001). Patients with LGG also had a better outcome when compared with HGG (P = 0.0012). The objective response was 68.8% with larotrectinib compared with 38.1% for nontargeted treatment. CONCLUSIONS: Children with LGG had a favorable outcome compared with adult glioma and HGG. TRK inhibitors seem to improve tumor control.

• MeSH
• dítě MeSH
• dospělí MeSH
• fúze genů MeSH
• fúzní onkogenní proteiny * genetika   MeSH
• gliom * genetika   patologie   mortalita   terapie   MeSH
• inhibitory proteinkinas terapeutické užití   MeSH
• kojenec MeSH
• lidé středního věku MeSH
• lidé MeSH
• membránové glykoproteiny MeSH
• mladiství MeSH
• mladý dospělý MeSH
• nádory centrálního nervového systému * genetika   terapie   mortalita   patologie   MeSH
• předškolní dítě MeSH
• prognóza MeSH
• pyrazoly terapeutické užití   MeSH
• pyrimidiny terapeutické užití   MeSH
• receptor trkA * genetika   antagonisté a inhibitory   MeSH
• receptor trkB genetika   antagonisté a inhibitory   MeSH
• receptor trkC genetika   antagonisté a inhibitory   MeSH
• retrospektivní studie MeSH
• senioři MeSH
• stupeň nádoru MeSH
• výsledek terapie MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• kojenec MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• fúzní onkogenní proteiny * MeSH
• inhibitory proteinkinas MeSH
• larotrectinib MeSH Prohlížeč
• membránové glykoproteiny MeSH
• NTRK1 protein, human MeSH Prohlížeč
• NTRK3 protein, human MeSH Prohlížeč
• pyrazoly MeSH
• pyrimidiny MeSH
• receptor trkA * MeSH
• receptor trkB MeSH
• receptor trkC MeSH
• tropomyosin-related kinase-B, human MeSH Prohlížeč

Background: Pediatric papillary thyroid carcinoma (PTC) is a rare malignancy, but with increasing incidence. Pediatric PTCs have distinct clinical and pathological features and even the molecular profile differs from adult PTCs. Somatic point mutations in pediatric PTCs have been previously described and studied, but complex information about fusion genes is lacking. The aim of this study was to identify different fusion genes in a large cohort of pediatric PTCs and to correlate them with clinical and pathological data of patients. Methods: The cohort consisted of 93 pediatric PTC patients (6-20 years old). DNA and RNA were extracted from fresh frozen tissue samples, followed by DNA and RNA-targeted next-generation sequencing analyses. Fusion gene-positive samples were verified by real-time polymerase chain reaction. Results: A genetic alteration was found in 72/93 (77.4%) pediatric PTC cases. In 52/93 (55.9%) pediatric PTC patients, a fusion gene was detected. Twenty different types of RET, NTRK3, ALK, NTRK1, BRAF, and MET fusions were found, of which five novel, TPR/RET, IKBKG/RET, BBIP1/RET, OPTN/BRAF, and EML4/MET, rearrangements were identified and a CUL1/BRAF rearrangement that has not been previously described in thyroid cancer. Fusion gene-positive PTCs were significantly associated with the mixture of classical and follicular variants of PTC, extrathyroidal extension, higher T classification, lymph node and distant metastases, chronic lymphocytic thyroiditis, and frequent occurrence of psammoma bodies compared with fusion gene-negative PTCs. Fusion-positive patients also received more doses of radioiodine therapy. The most common fusion genes were the RET fusions, followed by NTRK3 fusions. RET fusions were associated with more frequent lymph node and distant metastases and psammoma bodies, and NTRK3 fusions were associated with the follicular variant of PTC. Conclusions: Fusion genes were the most common genetic alterations in pediatric PTCs. Fusion gene-positive PTCs were associated with more aggressive disease than fusion gene-negative PTCs.

• Klíčová slova
• RNA targeted sequencing, fusion genes, papillary thyroid carcinoma, pediatric, rearrangements,
• MeSH
• bodová mutace MeSH
• dítě MeSH
• fenotyp MeSH
• fúze genů * MeSH
• genetická predispozice k nemoci MeSH
• genová přestavba MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• nádorové biomarkery genetika   MeSH
• nádory štítné žlázy genetika   patologie   terapie   MeSH
• papilární karcinom štítné žlázy genetika   patologie   terapie   MeSH
• prognóza MeSH
• protoonkogenní proteiny B-Raf genetika   MeSH
• protoonkogenní proteiny c-met genetika   MeSH
• protoonkogenní proteiny c-ret genetika   MeSH
• receptor trkA genetika   MeSH
• receptor trkC genetika   MeSH
• věkové faktory MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• BRAF protein, human MeSH Prohlížeč
• MET protein, human MeSH Prohlížeč
• nádorové biomarkery MeSH
• NTRK1 protein, human MeSH Prohlížeč
• NTRK3 protein, human MeSH Prohlížeč
• protoonkogenní proteiny B-Raf MeSH
• protoonkogenní proteiny c-met MeSH
• protoonkogenní proteiny c-ret MeSH
• receptor trkA MeSH
• receptor trkC MeSH
• RET protein, human MeSH Prohlížeč

• MeSH
• fúze genů MeSH
• lidé MeSH
• membránové proteiny MeSH
• nádory dělohy * MeSH
• nádory z pojivové a měkké tkáně * MeSH
• proteiny nervové tkáně MeSH
• proteiny vázající kalmodulin MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• dopisy MeSH
• komentáře MeSH
• Názvy látek
• membránové proteiny MeSH
• proteiny nervové tkáně MeSH
• proteiny vázající kalmodulin MeSH
• STRN protein, human MeSH Prohlížeč

The section on mesenchymal tumors in the 5th edition of WHO classification of skin tumors has undergone several changes, the most important of which is the inclusion of newly identified tumor entities, which will be the main focus of this review article. These specifically include three novel cutaneous mesenchymal tumors with melanocytic differentiation, and rearrangements of the CRTC1::TRIM11, ACTIN::MITF, and MITF::CREM genes as well as EWSR1::SMAD3-rearranged fibroblastic tumors, superficial CD34-positive fibroblastic tumors, and NTRK-rearranged spindle cell neoplasms. Some of the other most important changes will be briefly mentioned as well.

• Klíčová slova
• ACTIN::MITF, CRTC1::TRIM11 cutaneous tumor, EWSR1::SMAD3-rearranged fibroblastic tumor, MITF pathway–activated melanocytic tumors, MITF::CREM fusion, NTRK-rearranged spindle cell neoplasm, Superficial CD34+ fibroblastic tumor,
• MeSH
• fúzní onkogenní proteiny genetika   MeSH
• lidé MeSH
• nádory kůže * genetika   patologie   klasifikace   MeSH
• Světová zdravotnická organizace MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• fúzní onkogenní proteiny MeSH