Cílem následujícího sdělení je podat přehled využití imunohistochemických metod v diagnostice mezenchymálních nádorů dělohy. Diskutována je zejména problematika týkající se stanovení hladkosvalové diferenciace, diferenciální diagnostiky mezi hladkosvalovými a endometriálními stromálními nádory adiagnostika zánětlivého myofibroblastického nádoru. Kromě toho je zmíněn význam imunohistochemických vyšetření v diagnostice poměrně recentně definovaných jednotek, jako je YWHAE alterovaný high grade endometriální stromální sarkom (HG-ESS), BCOR alterovaný HG-ESS, nádory s NTRK fúzí a SMARCA4 deficientní sarkomy. Posledním aspektem je rozbor významu imunohistochemických metod při stanovení biologické povahy leiomyocelulárních nádorů. U jednotek s výskytem rekurentních molekulárních aberací je také zmíněna problematika jejich molekulární klasifikace.

The goal of this manuscript is to provide a comprehensive overview of the use of immunohistochemical methods in diagnosing mesenchymal tumours of the uterus. The main points discussed include, especially, the issue of determining smooth muscle differentiation, the differential diagnosis between smooth muscle and endometrial stromal tumours, and the diagnosis of inflammatory myofibroblastic tumour. The role of immunohistochemical examination in the diagnosis of some of the only recently definedentities such as YWHAE-altered high grade endometrial stromal sarcoma (HG-ESS), BCOR-altered HG-ESS, tumours with NTRK fusion, and SMARCA4-deficient sarcomas is also discussed. The last aspect of this work is an analysis of the significance of immunohistochemical methods in the determination of the biological behaviour of leiomyocellular tumours. The issue of their molecular classification for those lesions associated with the presence of recurrent molecular aberrations is also discussed.

• MeSH
• diferenciální diagnóza MeSH
• endometriální stromální sarkom diagnóza   genetika   MeSH
• imunohistochemie MeSH
• leiomyosarkom diagnóza   genetika   MeSH
• lidé MeSH
• nádory dělohy * diagnóza   genetika   MeSH
• nádory ze svalové tkáně * diagnóza   genetika   MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• práce podpořená grantem MeSH
• přehledy MeSH

• Klíčová slova
• pembrolizumab,
• MeSH
• endometroidní karcinom farmakoterapie   genetika   imunologie   MeSH
• inhibitory kontrolních bodů * terapeutické užití   MeSH
• kolorektální nádory farmakoterapie   genetika   imunologie   MeSH
• lidé MeSH
• mikrosatelitní nestabilita * účinky léků   MeSH
• nádory dělohy farmakoterapie   genetika   imunologie   MeSH
• přežití po terapii bez příznaků nemoci MeSH
• výsledek terapie MeSH
• Check Tag
• lidé MeSH

Leiomyoma with bizarre nuclei (LBN) is an uncommon variant of uterine smooth muscle neoplasm. Involvement of fumarate hydratase (FH) has been suggested in the pathogenesis of a subset of LBN. The goal of our study is to assess the clinicopathological, morphological, immunohistochemical and molecular findings focusing on FH in LBNs (n = 108) and compare it with the findings in usual leiomyomas (UL; n = 50) and leiomyosarcomas (LMS; n = 42). Immunohistochemically, loss of FH expression was found in 67/108 of LBN, 1/50 of UL and in no LMS. Class 4/5 FH mutations were detected in 15/53 LBN with sufficient DNA quality for molecular analysis. Pathogenic variants of the FH gene were detected in neither UL nor LMS. Local recurrence after surgery was present in 18/92 of LBN patients, 7 of which were histologically verified and 2 of which were found to be LBN. Our results confirmed that LBN behave in a benign fashion, although they may relapse. FH gene mutations were a common finding only in LBN, but not in UL and LMS. Immunohistochemistry with an antibody against FH seems to have a good sensitivity (87%) and moderate specificity (58%) with regard to predicting FH gene mutations and could be used as a screening method in tumors with features suggestive of FH alterations to identify patients who are at risk for the FH aberrations.

• MeSH
• buněčné jádro patologie   MeSH
• dospělí MeSH
• fumarasa genetika   MeSH
• leiomyom genetika   patologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mutace MeSH
• nádorové biomarkery genetika   MeSH
• nádory dělohy genetika   patologie   MeSH
• senioři MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

• Klíčová slova
• syndrom hereditární leiomyomatózy a renálního karcinomu, syndrom mnohočetné kožní a děložní leiomyomatózy,
• MeSH
• dědičné nádorové syndromy diagnóza   genetika   komplikace   MeSH
• fumarasa genetika   MeSH
• karcinom z renálních buněk etiologie   genetika   patologie   MeSH
• leiomyom * diagnóza   etiologie   patologie   MeSH
• leiomyomatóza * diagnóza   patologie   vrozené   MeSH
• lidé MeSH
• nádory dělohy genetika   MeSH
• nádory kůže diagnóza   etiologie   genetika   MeSH
• senioři MeSH
• Check Tag
• lidé MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• kazuistiky MeSH

Uterine leiomyosarcomas (uLMS) are rare, aggressive malignancies for which limited treatment options are available. To gain novel molecular insights into uLMS and identify potential novel therapeutic targets, we characterized 84 uLMS samples for genome-wide somatic copy number alterations, mutations, gene fusions and gene expression and performed a data integration analysis. We found that alterations affecting TP53, RB1, PTEN, MED12, YWHAE and VIPR2 were present in the majority of uLMS. Pathway analyses additionally revealed that the PI3K/AKT/mTOR, estrogen-mediated S-phase entry and DNA damage response signaling pathways, for which inhibitors have already been developed and approved, frequently harbored genetic changes. Furthermore, a significant proportion of uLMS was characterized by amplifications and overexpression of known oncogenes (CCNE1, TDO2), as well as deletions and reduced expression of tumor suppressor genes (PTEN, PRDM16). Overall, it emerged that the most frequently affected gene in our uLMS samples was VIPR2 (96%). Interestingly, VIPR2 deletion also correlated with unfavorable survival in uLMS patients (multivariate analysis; HR = 4.5, CI = 1.4-14.3, p = 1.2E-02), while VIPR2 protein expression was reduced in uLMS vs. normal myometrium. Moreover, stimulation of VIPR2 with its natural agonist VIP decreased SK-UT-1 uLMS cell proliferation in a dose-dependent manner. These data suggest that VIPR2, which is a negative regulator of smooth muscle cell proliferation, might be a novel tumor suppressor gene in uLMS. Our work further highlights the importance of integrative molecular analyses, through which we were able to uncover the genes and pathways most frequently affected by somatic alterations in uLMS.

• MeSH
• dospělí MeSH
• genomika metody   MeSH
• Kaplanův-Meierův odhad MeSH
• karcinogeneze genetika   MeSH
• leiomyosarkom genetika   mortalita   patologie   terapie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• myometrium patologie   MeSH
• nádory dělohy genetika   mortalita   patologie   terapie   MeSH
• onkogeny genetika   MeSH
• proliferace buněk genetika   MeSH
• receptory vazoaktivního intestinálního peptidu typu II genetika   MeSH
• regulace genové exprese u nádorů genetika   MeSH
• sekvenční analýza RNA metody   MeSH
• sekvenování celého genomu metody   MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• signální transdukce genetika   MeSH
• tumor supresorové geny MeSH
• vysoce účinné nukleotidové sekvenování 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
• práce podpořená grantem MeSH

We examined the value of targeted molecular screening for the identification of uterine anaplastic lymphoma kinase (ALK)-rearranged mesenchymal tumors, including ALK immunohistochemistry followed by molecular genetic testing, in all uterine leiomyosarcomas and STUMPs (smooth muscle tumors of uncertain malignant potential). All leiomyosarcoma and STUMP cases diagnosed in a 10-year period (2006-2016) at Charles University Faculty of Medicine in Pilsen were retrieved and reviewed. Of 23 cases, one case (LMS [leiomyosarcoma]) was positive for ALK rearrangement, namely, PPP1CB-ALK fusion gene. No specific histologic features (i.e., lymphocytic infiltrate and stromal edema) were observed in this case. This suggests that inflammatory myofibroblastic tumor (IMT)-like histologic features may not be an initial reliable screening tool in identifying uterine IMT cases. Thus, we proposed a two-step IHC and molecular genetic testing (as a reflex test) for IMT in all uterine LMS and STUMP cases. This will enhance the proper detection of such tumors at the population level and ultimately offer patients available targeted therapies.

• MeSH
• anaplastická lymfomová kináza MeSH
• genetické testování metody   MeSH
• genová přestavba * MeSH
• imunohistochemie MeSH
• leiomyosarkom diagnóza   genetika   metabolismus   MeSH
• lidé MeSH
• nádor z hladké svalové tkáně diagnóza   genetika   metabolismus   MeSH
• nádorové biomarkery genetika   metabolismus   MeSH
• nádory dělohy diagnóza   genetika   metabolismus   MeSH
• retrospektivní studie MeSH
• tyrosinkinasové receptory genetika   metabolismus   MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

Cieľ štúdie: Cieľom článku je sumarizovať známe faktory podmieňujúce vznik sarkómov tela maternice a limitácie ich klinickej diagnostiky. Typ štúdie: Prehľadový článok. Názov a sídlo pracoviska: Divízia molekulová medicína, Martinské centrum pre biomedicínu, JLF UK Martin, Slovenská republika; Gynekologicko-pôrodnícka klinika JLF UK a UNM Martin, Slovenská republika; Divízia onkológia, Martinské centrum pre biomedicínu JLF UK Martin, Slovenská republika. Metodika: Analýza a sumarizácia poznatkov o etiológii, abnormálne pôsobiacich faktoroch a možnostiach diagnostiky sarkómov tela maternice na základe publikovaných štúdií. Výsledky a záver: Sarkómy maternice predstavujú veľmi heterogénne, malígne tumorové typy mezenchymalného pôvodu, ktorých výskyt je veľmi zriedkavý. Na druhej strane ide o veľmi agresívne tumory s veľmi zlou prognózou a celkovo nízkym intervalom prežívania. Najčastejším typom sarkómov sú leiomyosarkómy, nasledované v percentuálnom zastúpení endometriálnymi stromálnymi sarkómami a adenosarkómami. Patogenéza týchto tumorov zostáva doposiaľ relatívne neobjasnená. Sú známe určité skupiny predispozičných faktorov ako aj konkrétnych geneticko-molekulárnych zmien asociovaných s ich výskytom. Najväčšie riziko predstavuje pri invazivných diagnostických metódach možnosť rozrušenia malígnej vrstvy a pri využití zobrazovacích metód sú najväčšou limitáciou obmedzené možnosti v odlíšení medzi malígnymi a benígnymi variantmi, obzvlášť v prípade leiomyosarkómov.

Objective: The main goal of this article is to summarize the known factors underlying the tumorigenesis of sarcomas and to present the limitations of clinical diagnosis. Design: A review article. Settings: Division of Molecular Medicine, Biomedical Center, JLF UK Martin, Slovakia; Department of Gynaecology and Obstetrics JLF UK and UNM Martin, Slovakia; Division of Oncology, Biomedical Center in Martin, JLF UK, Martin, Slovakia. Methods: An analysis and summarisation of published studies about etiology, aberrant factors and limmitations of clinical diagnosis of uterne sarcomas. Results and conclusions: Uterine sarcomas are heterogenous, malignant tumour types of mesenchymal origin with a very low incidence. On the other hand, sarcomas are very aggressive tumours with a poor prognosis, and a very low chance of surviving in general. The most common types of sarcomas are leiomyosarcomas, followed in percentage occurrence by endometrial stromal sarcomas and adenosarcomas. This tumour pathogenesis remains still relatively unknown. There are recognized only several predisposition factor types, and the limitated molecular-genetic aberrations associated with their occurrence. Importantly, the potential perturbation of the malignant mass during the implementation of invasive methods can be considered as the most serious risk factor. In regards to the visualization methods application, there are still limited ways of distinguishing between malignant and benign forms, especially in the case of leiomyosarcomas.

• Klíčová slova
• mezenchymální tumory,
• MeSH
• diagnostické techniky a postupy MeSH
• diagnostické zobrazování metody   MeSH
• gynekologické vyšetření metody   MeSH
• leiomyosarkom diagnóza   etiologie   MeSH
• lidé MeSH
• nádory dělohy * diagnóza   etiologie   genetika   MeSH
• rizikové faktory MeSH
• sarkom diagnóza   etiologie   MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• práce podpořená grantem MeSH
• přehledy MeSH

The diagnosis of a uterine smooth muscle lesion is, in the majority of cases, straightforward. However, in a small number of cases, the morphological criteria used in such lesions cannot differentiate with certainty a benign from a malignant lesion and a diagnosis of smooth muscle tumor with uncertain malignant potential (STUMP) is made. Uterine leiomyosarcomas are often easy to diagnose but it is difficult or even impossible to identify a prognostic factor at the moment of the diagnosis with the exception of the stage. We hypothesize, for uterine smooth muscle lesions, that there is a gradient of genomic complexity that correlates to outcome. We first tested this hypothesis on STUMP lesions in a previous study and demonstrated that this 'gray category' could be split according to genomic index into two groups. A benign group, with a low to moderate alteration rate without recurrence and a malignant group, with a highly rearranged profile akin to uterine leiomyosarcomas. Here, we analyzed a large series of 77 uterine smooth muscle lesions (from 76 patients) morphologically classified as 19 leiomyomas, 14 STUMP and 44 leiomyosarcomas with clinicopathological and genomic correlations. We confirmed that genomic index with a cut-off=10 is a predictor of recurrence (P<0.0001) and with a cut-off=35 is a marker for poor overall survival (P=0.035). For the tumors confined to the uterus, stage as a prognostic factor was not useful in survival prediction. At stage I, among the tumors reclassified as molecular leiomyosarcomas (ie, genomic index ≥10), the poor prognostic markers were: 5p gain (overall survival P=0.0008), genomic index at cut-off=35 (overall survival P=0.0193), 13p loss including RB1 (overall survival P=0.0096) and 17p gain including MYOCD gain (overall survival P=0.0425). Based on these findings (and the feasibility of genomic profiling by array-comparative genomic hybridization), genomic index, 5p and 17p gains prognostic value could be evaluated in future prospective chemotherapy trials.

• MeSH
• analýza přežití MeSH
• dospělí MeSH
• leiomyom diagnóza   genetika   patologie   MeSH
• leiomyosarkom diagnóza   genetika   patologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• lidské chromozomy, pár 13 genetika   MeSH
• lidské chromozomy, pár 17 genetika   MeSH
• lidské chromozomy, pár 5 genetika   MeSH
• lokální recidiva nádoru MeSH
• nádor z hladké svalové tkáně diagnóza   genetika   patologie   MeSH
• nádory dělohy diagnóza   genetika   patologie   MeSH
• prognóza MeSH
• sekvenční analýza hybridizací s uspořádaným souborem oligonukleotidů * MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• stanovení celkové genové exprese * 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
• práce podpořená grantem MeSH

Purpose: Uterine sarcomas are rare and heterogeneous tumors characterized by an aggressive clinical behavior. Their high rates of recurrence and mortality point to the urgent need for novel targeted therapies and alternative treatment strategies. However, no molecular prognostic or predictive biomarkers are available so far to guide choice and modality of treatment.Experimental Design:We investigated the expression of several druggable targets (phospho-S6S240ribosomal protein, PTEN, PDGFR-α, ERBB2, and EGFR) in a large cohort of human uterine sarcoma samples (288), including leiomyosarcomas, low-grade and high-grade endometrial stromal sarcomas, undifferentiated uterine sarcomas, and adenosarcomas, together with 15 smooth muscle tumors of uncertain malignant potential (STUMP), 52 benign uterine stromal tumors, and 41 normal uterine tissues. The potential therapeutic value of the most promising target, p-S6S240, was tested in patient-derived xenograft (PDX) leiomyosarcoma models.Results:In uterine sarcomas and STUMPs, S6S240phosphorylation (reflecting mTOR pathway activation) was associated with higher grade (P= 0.001) and recurrence (P= 0.019), as shown by logistic regression. In addition, p-S6S240correlated with shorter progression-free survival (P= 0.034). Treatment with a dual PI3K/mTOR inhibitor significantly reduced tumor growth in 4 of 5 leiomyosarcoma PDX models (with tumor shrinkage in 2 models). Remarkably, the 4 responding models showed basal p-S6S240expression, whereas the nonresponding model was scored as negative, suggesting a role for p-S6S240in response prediction to PI3K/mTOR inhibition.Conclusions:Dual PI3K/mTOR inhibition represents an effective therapeutic strategy in uterine leiomyosarcoma, and p-S6S240expression is a potential predictive biomarker for response to treatment.Clin Cancer Res; 23(5); 1274-85. ©2017 AACR.

• MeSH
• cílená molekulární terapie MeSH
• fosfatidylinositol-3-kinasy genetika   MeSH
• fosforylace MeSH
• inhibitory fosfoinositid-3-kinasy MeSH
• leiomyosarkom farmakoterapie   genetika   patologie   MeSH
• lidé MeSH
• myši MeSH
• nádorové biomarkery genetika   MeSH
• nádory dělohy farmakoterapie   genetika   patologie   MeSH
• přežití po terapii bez příznaků nemoci MeSH
• prognóza MeSH
• regulace genové exprese u nádorů účinky léků   MeSH
• ribozomální protein S6 genetika   MeSH
• signální transdukce účinky léků   MeSH
• TOR serin-threoninkinasy antagonisté a inhibitory   genetika   MeSH
• xenogenní modely - testy antitumorózní aktivity MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Hereditary leiomyomatosis and renal cell carcinoma syndrome-associated renal cell carcinomas (RCC) are difficult to diagnose prospectively. We used immunohistochemistry (IHC) to identify fumarate hydratase (FH)-deficient tumors (defined as FH negative, 2-succinocysteine [2SC] positive) in cases diagnosed as "unclassified RCC, high grade or with papillary pattern," or "papillary RCC type 2," from multiple institutions. A total of 124 tumors (from 118 patients) were evaluated by IHC for FH and 2SC. An FH deficiency was found in 24/124 (19%) cases. An indeterminate result (only 1 marker abnormal) was found in 27/124 (22%) cases. In a tissue microarray of 776 RCCs of different types, only 2 (0.5%) tumors, initially considered papillary type 2, were FH deficient. FH mutations were found in 19/21 FH-deficient tumors (with confirmed germline mutations in 9 of 9 tumors in which germline status could be assessed) and in 1/26 FH-indeterminate tumors identified by IHC. No FH mutations were found in 2/21 FH-deficient RCCs, 25/26 FH-indeterminate RCCs, and 10/10 RCCs demonstrating FH expression by IHC. Patients with FH-deficient RCC had a median age of 44 years (range, 21 to 65 y). Average tumor size was 8.2 cm (range, 0.9 to 18 cm). FH-deficient RCCs were characterized by at least focal macronucleoli and demonstrated 2 or more growth patterns in 93% cases. Papillary was the most common (74%) and dominant (59%) pattern, whereas other common patterns included: solid (44%), tubulocystic (41%), cribriform (41%), and cystic (33%). At presentation, 57% were stage ≥pT3, 52% had positive nodes, and 19% had distant metastases. After a mean follow-up of 27 months (range, 1 to 114 mo), 39% of patients were dead of disease, and 26% had disease progression. We conclude that FH and 2SC are useful IHC ancillary tools, which allow recognition of FH-deficient RCC.

• MeSH
• čipová analýza tkání MeSH
• cystein analogy a deriváty   analýza   biosyntéza   MeSH
• dědičné nádorové syndromy diagnóza   genetika   patologie   MeSH
• dospělí MeSH
• fumarasa nedostatek   genetika   MeSH
• imunohistochemie MeSH
• karcinom z renálních buněk diagnóza   etiologie   MeSH
• leiomyomatóza diagnóza   genetika   patologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladý dospělý MeSH
• nádory dělohy diagnóza   genetika   patologie   MeSH
• nádory kůže diagnóza   genetika   patologie   MeSH
• nádory ledvin diagnóza   etiologie   MeSH
• psychomotorické poruchy komplikace   MeSH
• senioři MeSH
• svalová hypotonie komplikace   MeSH
• vrozené poruchy metabolismu komplikace   MeSH
• zárodečné mutace 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