An 82-year-old woman with COPD presented to the emergency department with cough, increasing sputum production, wheezing, and worsening shortness of breath for two weeks. On imaging studies, the patient was found to have a right upper lobe spiculated nodule and an endobronchial lesion with near total occlusion of the right lower lobe bronchus with sub-segmental atelectasis. Bronchoscopy with EBUS-TBNA of subcarinal and right hilar lymph nodes revealed lung cancer with clear cell phenotype. Given the predominance of clear cell morphology, the diagnosis of metastatic renal or ovarian cancer was entertained. However, there was no evidence of renal or ovarian lesions on the PET-CT scan, ruling out the possibility. Salivary gland type lung cancer (STLC), which is responsible for less than 1% of all lung cancer cases in adults, was also considered. The two distinct STLCs that may have similar morphologic appearances are hyalinizing clear cell carcinoma (HCCC) and mucoepidermoid carcinoma (MEC). The other type of tumour in the lung that demonstrates a clear cell phenotype is perivascular epithelioid cell neoplasms or PEComa, which are mesenchymal in origin. Immunohistochemical staining was strongly positive for p63, CK5/6, CK7, CK-LMW, and negative for TTF-1, Napsin A, p16, and CK20. Additional staining, including HMB-45, S-100, and mucicarmine, were also negative. Next-generation sequencing for the salivary gland fusion panel, including EWSR1-ATF1 fusion and EWSR1 gene rearrangement for HCCC and MAML2 gene rearrangements for MEC, was negative. She was diagnosed with non-small cell lung cancer favouring squamous cell carcinoma with clear cell phenotype, a rare entity.
- MeSH
- adenokarcinom z jasných buněk diagnóza patologie genetika MeSH
- bronchoskopie MeSH
- diferenciální diagnóza MeSH
- lidé MeSH
- nádory plic * diagnóza patologie genetika MeSH
- senioři nad 80 let MeSH
- Check Tag
- lidé MeSH
- senioři nad 80 let MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- kazuistiky MeSH
BACKGROUND: Molecular aberrations occurring in primary ovarian clear cell carcinoma (OCCC) can be of diagnostic, predictive, and prognostic significance. However, a complex molecular study including genomic and transcriptomic analysis of large number of OCCC has been lacking. METHODS: 113 pathologically confirmed primary OCCCs were analyzed using capture DNA NGS (100 cases; 727 solid cancer related genes) and RNA-Seq (105 cases; 147 genes) in order to describe spectra and frequency of genomic and transcriptomic alterations, as well as their prognostic and predictive significance. RESULTS: The most frequent mutations were detected in genes ARID1A, PIK3CA, TERTp, KRAS, TP53, ATM, PPP2R1A, NF1, PTEN, and POLE (51,47,27,18,13,10,7,6,6, and 4%, respectively). TMB-High cases were detected in 9% of cases. Cases with POLEmut and/or MSI-High had better relapse-free survival. RNA-Seq revealed gene fusions in 14/105 (13%) cases, and heterogeneous expression pattern. The majority of gene fusions affected tyrosine kinase receptors (6/14; four of those were MET fusions) or DNA repair genes (2/14). Based on the mRNA expression pattern, a cluster of 12 OCCCs characterized by overexpression of tyrosine kinase receptors (TKRs) AKT3, CTNNB1, DDR2, JAK2, KIT, or PDGFRA (p < 0.00001) was identified. CONCLUSIONS: The current work has elucidated the complex genomic and transcriptomic molecular hallmarks of primary OCCCs. Our results confirmed the favorable outcomes of POLEmut and MSI-High OCCC. Moreover, the molecular landscape of OCCC revealed several potential therapeutical targets. Molecular testing can provide the potential for targeted therapy in patients with recurrent or metastatic tumors.
- MeSH
- adenokarcinom z jasných buněk * genetika MeSH
- fúze genů MeSH
- genomika MeSH
- lidé MeSH
- lokální recidiva nádoru * MeSH
- stanovení celkové genové exprese MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
BACKGROUND AND OBJECTIVES: Utilisation of the one-step nucleic acid amplification (OSNA) molecular biology method for the detection of the metastatic involvement of sentinel lymph nodes (SLNs) in endometrial cancer (EC) patients. A comparison with histopathological ultrastaging and a description of the clinical consequences. METHODS: Surgically treated EC patients underwent detection of SLNs. Nodes greater than 5 mm were cut into sections 2-mm thick parallel to the short axis of the node. Odd sections were examined according to the OSNA method, while even ones according to an appropriate ultrastaging protocol. Nodes less than or equal to 5 mm were cut into halves along the longitudinal axis with one half examined according to the OSNA method and the other half by ultrastaging. RESULTS: Fifty-eight patients were included and 135 SLNs were acquired. Both ultrastaging and OSNA agreed on 116 results. According to the OSNA method, 20.69% more patients were classified into International Federation of Gynecology and Obstetrics (FIGO) stage III. When comparing the results of the OSNA method to the conclusions of ultrastaging as a reference method, sensitivity of 90.9%, specificity of 85.5% and concordance of 85.9% were attained. CONCLUSIONS: The results of the OSNA method showed a higher frequency of detection of micrometastases and included 20.69% more patients into FIGO stage III.
- MeSH
- adenokarcinom z jasných buněk genetika sekundární chirurgie MeSH
- biopsie sentinelové lymfatické uzliny MeSH
- dospělí MeSH
- keratin-19 genetika MeSH
- lidé středního věku MeSH
- lidé MeSH
- lymfatické metastázy MeSH
- mikrometastázy MeSH
- míra přežití MeSH
- nádorové biomarkery genetika MeSH
- nádory endometria genetika patologie chirurgie MeSH
- následné studie MeSH
- nukleové kyseliny analýza genetika MeSH
- peroperační doba MeSH
- prognóza MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- sentinelová uzlina patologie chirurgie MeSH
- serózní cystadenokarcinom genetika sekundární chirurgie MeSH
- techniky amplifikace nukleových kyselin metody MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- srovnávací studie MeSH
We describe a novel gene fusion, EWSR1-CREM, identified in 3 cases of clear cell carcinoma (CCC) using anchored multiplex polymerase chain reaction, a next-generation sequencing-based technique. CCC is a low-grade salivary tumor recently characterized to have EWSR1-ATF1 fusions in the majority of cases. Three cases of malignant tumor presenting in the base of tongue, lung, and nasopharynx were studied. All cases shared a clear cell morphology with hyalinized stroma, presence of mucin and p63 positivity and were initially diagnosed as mucoepidermoid carcinoma but were negative for evidence of any of the expected gene fusions. Anchored multiplex polymerase chain reaction demonstrated a EWSR1-CREM fusion in all 3 cases to confirm a diagnosis of CCC. This finding is biologically justified as CREM and ATF1 both belong to the CREB family of transcription factors. EWSR1-CREM fusions have not been previously reported in CCC and have only rarely been reported in other tumors. We show that the ability to discover novel gene variants with next-generation sequencing-based assays has clinical utility in the pathologic classification of fusion gene-associated tumors.
- MeSH
- adenokarcinom z jasných buněk genetika patologie MeSH
- lidé středního věku MeSH
- lidé MeSH
- modulátor elementu responzivního pro cyklický AMP genetika MeSH
- nádory jazyka genetika patologie MeSH
- nádory nosohltanu genetika MeSH
- nádory plic genetika patologie MeSH
- onkogenní fúze MeSH
- protein EWS vázající RNA genetika MeSH
- senioři MeSH
- stanovení celkové genové exprese MeSH
- transkriptom MeSH
- vysoce účinné nukleotidové sekvenování MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- kazuistiky MeSH
PURPOSE: Vav3 is a guanine nucleotide exchange factor that regulates the activity of Rho/Rac family GTPases. In a study on ovarian cancer, we recently demonstrated pronounced prognostic and predictive value of Vav3.1, a specific truncation variant of the parental Vav3 gene. Here, we sought to investigate the role of Vav3.1 in the most prevalent gynecological tumor entity, endometrial cancer. METHODS: Vav3.1 transcript levels were determined in a large cohort of endometrial cancer patients using variant-specific PCR (n = 239), and non-malignant endometrial tissue served as control (n = 26). Expression levels of Vav3.1 were stratified according to established clinicopathological characteristics and correlated to long-term patient survival (average follow-up of > 7.5 years). Type 1 and type 2 cancers were separately investigated. RESULTS: While Vav3.1 was markedly overexpressed in endometrial cancer tissue, we could not detect associations with clinical parameters related to prognosis, such as FIGO stage and tumor grade. Kaplan-Meier estimators of different measures of survival failed to show prognostic significance of Vav3.1 in endometrial cancer. Lack of prognostic value was observed for both type 1 and type 2 cancers. CONCLUSIONS: Our study shows that Vav3.1 is not suited as a marker of cancer progression and/or treatment response in endometrial cancer. Feasibility and potential benefit of targeting Vav3.1 in endometrial cancer needs to be evaluated in future studies, proceeding from its clear, roughly ten-fold, induction in the malignant endometrium.
- MeSH
- adenokarcinom z jasných buněk genetika patologie terapie MeSH
- dospělí MeSH
- kombinovaná terapie MeSH
- lidé středního věku MeSH
- lidé MeSH
- míra přežití MeSH
- nádorové biomarkery genetika MeSH
- nádory endometria genetika patologie terapie MeSH
- následné studie MeSH
- prognóza MeSH
- protein - isoformy MeSH
- protoonkogenní proteiny c-vav genetika MeSH
- retrospektivní studie MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- serózní cystadenokarcinom genetika patologie terapie MeSH
- studie případů a kontrol MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
Hepatocyte nuclear factor 1-beta (HNF-1-beta) is a transcription factor involved in cancerogenesis of various tumors, including endometrioid carcinoma. We performed comprehensive analysis of HNF-1-beta in lesions of the endometrium, including protein expression and genetic and epigenetic changes. Expression of HNF-1-beta was analyzed immunohistochemically in 320 cases including both tumor and non-tumor endometrial lesions. Promoter methylation and genetic variants were evaluated, using bisulphite and direct sequencing, in 30 (18 fresh frozen, 12 FFPE tumors) endometrioid carcinomas (ECs) and 15 ovarian clear cell carcinomas (OCCCs) as a control group. We detected expression of HNF-1-beta in 28 % of ECs (51/180 cases), 26 % of serous carcinoma (7/27 cases), 83 % of endometrial clear cell carcinoma (15/18 cases), 93 % of hyperplastic polyps with atypias (13/14 cases), 100 % of hyperplastic polyps without atypias (16/16 cases), 88 % of hyperplasias with atypias (14/16 cases), 91 % of hyperplasias without atypias (10/11 cases), and in ≥80 % of different normal endometrium samples. The control group of OCCCs showed HNF-1-beta expression in 95 % (18/19 cases). Methylation in promoter region was detected in 13.3 % (4/30) of ECs, but not in corresponding normal tissue where available, nor in OCCCs (0/15 cases). Mutation analysis revealed truncating variant c.454C > T (p.Gln152X) in one EC and missense variant c.848C > T (p.Ala283Val) was detected in one OCCC. In conclusion, expression of HNF-1-beta was detected in various extents in all types of lesions analyzed, nevertheless its strong expression was mostly limited to clear cell carcinomas. Biological significance of genetic and epigenetic changes needs further investigation.
- MeSH
- adenokarcinom z jasných buněk genetika patologie MeSH
- endometroidní karcinom genetika patologie MeSH
- epigeneze genetická genetika MeSH
- epigenomika metody MeSH
- genetická variace genetika MeSH
- hepatocytární jaderný faktor 1-beta genetika MeSH
- imunohistochemie metody MeSH
- lidé MeSH
- metylace DNA genetika MeSH
- nádorové biomarkery genetika MeSH
- nádory endometria genetika patologie MeSH
- promotorové oblasti (genetika) genetika MeSH
- serózní cystadenokarcinom genetika patologie MeSH
- Check Tag
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
Objevy translokací a fúzních onkogenů, které jsou jejich produktem, změnily přístup ke klasifikaci salivárních karcinomů a do značné míry i diagnostické a interpretační postupy. Metody molekulární diagnostiky mají v patologii slinných žláz jak diferenciálně diagnostický význam, tak slouží v klasifikaci některých karcinomů, protože mnohé translokace jsou specifické pro určitou nádorovou jednotku. Průkaz fúzního transkriptu může mít také prognostický význam. V tomto přehledovém článku budou představeny 4 salivární karcinomy, u nichž byly dosud identifikovány onkogenní translokace, a to mukoepidermoidní karcinom, adenoidně cystický karcinom, sekreční karcinom mamárního typu, a hyalinizující světlobuněčný karcinom malých slinných žláz.
In recent years the discovery of translocations and the fusion oncogenes that they result in has changed the way diagnoses are made in salivary gland pathology. These genetic aberrations are recurrent; and at the very least serve as powerful diagnostic tools in salivary gland tumors diagnosis and classification. They also show promise as prognostic markers and hopefully as targets of therapy. In this review the 4 carcinomas currently known to harbor translocations will be discussed, namely mucoepidermoid carcinoma, adenoid cystic carcinoma, mammary analogue secretory carcinoma, and hyalinizing clear cell carcinoma. The discovery and implications of each fusion will be highlighted and how they have helped to reshape the current classification of salivary gland tumors.
- Klíčová slova
- hyalinizující světlobuněčný karcinom,
- MeSH
- adenoidně cystický karcinom genetika patologie MeSH
- adenokarcinom z jasných buněk genetika patologie MeSH
- DNA vazebné proteiny genetika MeSH
- fúzní onkogenní proteiny * genetika MeSH
- hybridizace in situ fluorescenční MeSH
- jaderné proteiny genetika MeSH
- lidé MeSH
- mukoepidermoidní karcinom genetika patologie MeSH
- nádory slinných žláz * genetika metabolismus patologie MeSH
- onkogenní fúze MeSH
- onkogenní proteiny v-myb genetika MeSH
- polymerázová řetězová reakce s reverzní transkripcí MeSH
- proteiny vázající kalmodulin genetika MeSH
- proteiny vázající RNA genetika MeSH
- sekreční karcinom mamárního typu genetika patologie MeSH
- transkripční faktor ATF1 genetika MeSH
- transkripční faktory genetika MeSH
- translokace genetická MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- přehledy MeSH
