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
• Child MeSH
• Adult MeSH
• Gene Fusion MeSH
• Oncogene Proteins, Fusion * genetics   MeSH
• Glioma * genetics   pathology   mortality   therapy   MeSH
• Protein Kinase Inhibitors therapeutic use   MeSH
• Infant MeSH
• Middle Aged MeSH
• Humans MeSH
• Membrane Glycoproteins MeSH
• Adolescent MeSH
• Young Adult MeSH
• Central Nervous System Neoplasms * genetics   therapy   mortality   pathology   MeSH
• Child, Preschool MeSH
• Prognosis MeSH
• Pyrazoles therapeutic use   MeSH
• Pyrimidines therapeutic use   MeSH
• Receptor, trkA * genetics   antagonists & inhibitors   MeSH
• Receptor, trkB genetics   antagonists & inhibitors   MeSH
• Receptor, trkC genetics   antagonists & inhibitors   MeSH
• Retrospective Studies MeSH
• Aged MeSH
• Neoplasm Grading MeSH
• Treatment Outcome MeSH
• Check Tag
• Child MeSH
• Adult MeSH
• Infant MeSH
• Middle Aged MeSH
• Humans MeSH
• Adolescent MeSH
• Young Adult MeSH
• Male MeSH
• Child, Preschool MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

Congenital mesoblastic nephroma (CMN), the most common renal tumor of infancy, is a mesenchymal neoplasm histologically classified into classic, cellular, or mixed types. Most cellular CMNs harbor a characteristic ETV6-NTRK3 fusion. Here, we report an unusual congenital mesoblastic nephroma presenting in a newborn boy with a novel EML4-ALK gene fusion revealed by Anchored Multiplex RNA Sequencing Assay. The EML4-ALK gene fusion expands the genetic spectrum implicated in the pathogenesis of congenital mesoblastic nephroma, with yet another example of kinase oncogenic activation through chromosomal rearrangement. The methylation profile of the tumor corresponds with infantile fibrosarcoma showing the biological similarity of these two entities.

• MeSH
• Fibrosarcoma diagnosis   genetics   pathology   MeSH
• Oncogene Proteins, Fusion genetics   MeSH
• In Situ Hybridization, Fluorescence MeSH
• Humans MeSH
• Nephroma, Mesoblastic diagnosis   genetics   pathology   MeSH
• Infant, Newborn MeSH
• Proto-Oncogene Proteins c-ets genetics   MeSH
• Receptor, trkC genetics   MeSH
• Repressor Proteins genetics   MeSH
• RNA-Seq MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Infant, Newborn MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't 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
• Adenocarcinoma diagnosis   genetics   pathology   MeSH
• Oncogene Proteins, Fusion genetics   metabolism   MeSH
• Immunohistochemistry MeSH
• Middle Aged MeSH
• Humans MeSH
• Membrane Glycoproteins genetics   metabolism   MeSH
• Biomarkers, Tumor genetics   metabolism   MeSH
• Colonic Neoplasms diagnosis   genetics   pathology   MeSH
• Follow-Up Studies MeSH
• Oncogene Fusion MeSH
• Receptor, trkA genetics   metabolism   MeSH
• Receptor, trkB genetics   metabolism   MeSH
• Receptor, trkC genetics   metabolism   MeSH
• Gene Expression Regulation, Neoplastic MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Neoplasm Staging MeSH
• Receptor Protein-Tyrosine Kinases genetics   metabolism   MeSH
• Check Tag
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

BACKGROUND: Metanephric adenoma (MA) is a rare benign renal neoplasm. On occasion, MA can be difficult to differentiate from renal malignancies such as papillary renal cell carcinoma in adults and Wilms̕ tumor in children. Despite recent advancements in tumor genomics, there is limited data available regarding the genetic alterations characteristic of MA. The purpose of this study is to determine the frequency of metanephric adenoma cases exhibiting cytogenetic aberration t (9;15)(p24;q24), and to investigate the association between t (9,15) and BRAF mutation in metanephric adenoma. METHODS: This study was conducted on 28 archival formalin fixed paraffin-embedded (FFPE) specimens from patients with pathologically confirmed MA. Tissue blocks were selected for BRAF sequencing and fluorescent in situ hybridization (FISH) analysis for chromosomal rearrangement between KANK1 on chromosome 9 (9p24.3) and NTRK3 on chromosome 15 (15q25.3), which was previously characterized and described in two MA cases. RESULTS: BRAFV600E mutation was identified in 62% of our cases, 9 (38%) cases were BRAFWT, and 4 cases were uninformative. Of the 20 tumors with FISH results, two (10%) were positive for KANK1-NTRK3 fusion. Both cases were BRAFWT suggesting mutual exclusivity of BRAFV600E and KANK1-NTRK3 fusion, the first such observation in the literature. CONCLUSIONS: Our data shows that BRAF mutation in MA may not be as frequent as suggested in the literature and KANK-NTRK3 fusions may account for a subset of BRAFWT cases in younger patients. FISH analysis for KANK1-NTRK3 fusion or conventional cytogenetic analysis may be warranted to establish the diagnosis of MA in morphologically and immunohistochemically ambiguous MA cases lacking BRAF mutations.

• MeSH
• Adaptor Proteins, Signal Transducing genetics   MeSH
• Adenoma genetics   pathology   MeSH
• Cytoskeletal Proteins genetics   MeSH
• Child MeSH
• Adult MeSH
• Oncogene Proteins, Fusion genetics   MeSH
• In Situ Hybridization, Fluorescence MeSH
• Middle Aged MeSH
• Humans MeSH
• Chromosomes, Human, Pair 15 genetics   MeSH
• Chromosomes, Human, Pair 9 genetics   MeSH
• Adolescent MeSH
• Young Adult MeSH
• Mutation * MeSH
• Kidney Neoplasms genetics   pathology   MeSH
• Proto-Oncogene Proteins B-raf genetics   MeSH
• Receptor, trkC genetics   MeSH
• Aged MeSH
• Translocation, Genetic MeSH
• Check Tag
• Child MeSH
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Adolescent MeSH
• Young Adult MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

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.

• MeSH
• Point Mutation MeSH
• Child MeSH
• Phenotype MeSH
• Gene Fusion * MeSH
• Genetic Predisposition to Disease MeSH
• Gene Rearrangement MeSH
• Humans MeSH
• Adolescent MeSH
• Young Adult MeSH
• Biomarkers, Tumor genetics   MeSH
• Thyroid Neoplasms genetics   pathology   therapy   MeSH
• Thyroid Cancer, Papillary genetics   pathology   therapy   MeSH
• Prognosis MeSH
• Proto-Oncogene Proteins B-raf genetics   MeSH
• Proto-Oncogene Proteins c-met genetics   MeSH
• Proto-Oncogene Proteins c-ret genetics   MeSH
• Receptor, trkA genetics   MeSH
• Receptor, trkC genetics   MeSH
• Age Factors MeSH
• Check Tag
• Child MeSH
• Humans MeSH
• Adolescent MeSH
• Young Adult MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

Larotrectinib je prvním registrovaným léčivým přípravkem protinádorové agnostické léčby pro tumory s fúzemi genů NTRK. Publikovaná analýza 159 dospělých i pediatrických pacientů se solidními tumory s fúzí NTRK léčených larotrectinibem prokázala medián trvání léčebné odpovědi 35,2 měsíce a medián doby do progrese onemocnění 28,3 měsíce. Jednalo se o značně heterogenní skupinu pokročilých předléčených nádorů. Larotrectinib má dobrý bezpečnostní profil; dávka byla redukována u 8 % nemocných a k přerušení terapie došlo u 2 % pacientů z důvodů nežádoucích účinků.

Larotrectinib is a registered anticancer drug for antitumor therapy for tumors with NTRK gene fusions. A published analysis of 159 adult and pediatric patients with solid NTRK fusion tumors treated with larotrectinib showed a median duration of response of 35.2 months and a median time to disease progression of 28.3 months. These were highly heterogeneous groups of advanced pretreated tumors. Larotrectinib has a good safety profile; the dose was reduced in 8% of patient, in 2% due to side effects.

• MeSH
• Gene Fusion MeSH
• Humans MeSH
• Mutation * MeSH
• Antineoplastic Agents, Immunological * adverse effects   therapeutic use   MeSH
• Receptor, trkA genetics   therapeutic use   MeSH
• Receptor, trkB genetics   therapeutic use   MeSH
• Receptor, trkC genetics   therapeutic use   MeSH
• Treatment Outcome MeSH
• Check Tag
• Humans MeSH

RNAscope® technology provided by Advanced Cell Diagnostics (ACD) allows the detection and evaluation of coinciding mRNA expression profiles in the same or adjacent cells in unprecedented quantitative detail using multicolor fluorescent in situ hybridization (FISH). While already extensively used in thinly sectioned material of various pathological tissues and, to a lesser extent, in some whole mounts, we provide here a detailed approach to use the fluorescent RNAscope method in the mouse inner ear and thick brain sections by modifying and adapting existing techniques of whole mount fluorescent in situ hybridization (WH-FISH). We show that RNAscope WH-FISH can be used to quantify local variation in overlaying mRNA expression intensity, such as neurotrophin receptors along the length of the mouse cochlea. We also show how RNAscope WH-FISH can be combined with immunofluorescence (IF) of some epitopes that remain after proteinase digestion and, to some extent, with fluorescent protein markers such as tdTomato. Our WH-FISH technique provides an approach to detect cell-specific quantitative differences in developing and mature adjacent cells, an emerging issue revealed by improved cellular expression profiling. Further, the presented technique may be useful in validating single-cell RNAseq data on expression profiles in a range of tissue known or suspected to have locally variable mRNA expression levels.

• MeSH
• Fluorescent Antibody Technique methods   MeSH
• In Situ Hybridization, Fluorescence MeSH
• Cochlea metabolism   MeSH
• RNA, Messenger genetics   metabolism   MeSH
• Mice, Inbred BALB C MeSH
• Mice, Inbred C57BL MeSH
• Neurotrophin 3 metabolism   MeSH
• Receptor, trkB genetics   metabolism   MeSH
• Receptor, trkC genetics   metabolism   MeSH
• Gene Expression Regulation MeSH
• Imaging, Three-Dimensional MeSH
• Animals MeSH
• Check Tag
• Animals MeSH
• Publication type
• Journal Article MeSH

Low-grade sinonasal adenocarcinomas (low-grade SNACs) of the sinonasal tract comprise a poorly characterized and histologically heterogeneous group of tumors. We describe three cases of a histologically distinct variant of low-grade SNAC characterized by ETV6 gene rearrangements. The patients included 2 women (aged 32 and 88 y) and a man (aged 75 y); all were initially treated with surgery alone. Follow-up ranged from 9 to 170 months with one patient having 2 local recurrences and none experiencing distant or regional metastases. Tumors were composed of cytologically bland columnar and cuboidal eosinophilic tumor cells with basally located nuclei arranged in tubular and tubulotrabecular patterns. Immunohistochemically, CK7, DOG1, GCDFP-15, and SOX10 were positive in all cases, and vimentin was positive in 2 cases. Scattered single cells or small groups of tumor cells were S-100 positive. Only one case had weak, focal expression of GATA3, and mammaglobin was consistently negative. Two cases had ETV6-NTRK3 gene fusions, whereas ETV6 had an unknown fusion partner gene in one case. The highly similar morphology, immunohistochemical profile, and genetics of the presented cases are suggestive of a specific disease. Although translocation-associated adenocarcinomas in the sinonasal tract have previously been described exclusively as salivary-type carcinomas, we present the first type of carcinoma characterized by recurrent genetic rearrangements and distinct phenotype occurring exclusively in the sinonasal tract with no known major salivary gland counterpart. We provisionally designate this tumor ETV6-rearranged low-grade SNAC. Identification of additional cases is necessary to fully appreciate the morphologic and biological spectrum of this disease.

• MeSH
• Adenocarcinoma chemistry   genetics   pathology   surgery   MeSH
• Biopsy MeSH
• Adult MeSH
• Phenotype MeSH
• Gene Fusion MeSH
• Genetic Predisposition to Disease MeSH
• Gene Rearrangement * MeSH
• In Situ Hybridization, Fluorescence MeSH
• Immunohistochemistry MeSH
• Real-Time Polymerase Chain Reaction MeSH
• Humans MeSH
• Neoplasm Recurrence, Local MeSH
• Magnetic Resonance Imaging MeSH
• Biomarkers, Tumor analysis   genetics   MeSH
• Paranasal Sinus Neoplasms chemistry   genetics   pathology   surgery   MeSH
• Proto-Oncogene Proteins c-ets genetics   MeSH
• Receptor, trkC genetics   MeSH
• Repressor Proteins genetics   MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Neoplasm Grading MeSH
• Treatment Outcome MeSH
• Check Tag
• Adult MeSH
• Humans MeSH
• Male MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

We present a salivary gland tumor of the parotid gland in a 54-year-old woman, which contained a minor mammary analogue secretory carcinoma (MASC) component (20%) intermixed with a morphologically entirely different mucinous adenocarcinomatous component that comprised 80% of the tumor mass and a morphologically nondescript low-grade intraductal carcinoma (in situ) component. On fluorescence in situ hybridization, a break in the ETV6 gene was documented in the mucinous adenocarcinomatous, the conventional MASC, and the intraductal (in situ) components. RT-PCR failed to reveal an ETV6-NTRK3 fusion. The entire conventional MASC and only rare mucinous adenocarcinoma tumor cells were mammaglobin positive, whereas the low-grade intraductal carcinoma (in-situ) component was negative. S-100 protein stained only the MASC component.

• MeSH
• In Situ Hybridization, Fluorescence MeSH
• Immunohistochemistry MeSH
• Middle Aged MeSH
• Humans MeSH
• Adenocarcinoma, Mucinous pathology   MeSH
• Reverse Transcriptase Polymerase Chain Reaction MeSH
• Proto-Oncogene Proteins c-ets genetics   MeSH
• Receptor, trkC genetics   MeSH
• Repressor Proteins genetics   MeSH
• Mammary Analogue Secretory Carcinoma pathology   MeSH
• Check Tag
• Middle Aged MeSH
• Humans MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Case Reports MeSH

• MeSH
• Research Support as Topic MeSH
• Brain-Derived Neurotrophic Factor genetics   MeSH
• Mice MeSH
• Nerve Growth Factor genetics   metabolism   MeSH
• Neurons, Afferent metabolism   MeSH
• Receptor, trkA genetics   metabolism   MeSH
• Receptor, trkC genetics   metabolism   MeSH
• Signal Transduction MeSH
• Pacinian Corpuscles growth & development   MeSH
• Animals MeSH
• Check Tag
• Mice MeSH
• Animals MeSH
• Publication type
• Comparative Study MeSH