Low-grade serous carcinoma (LGSC) may develop from serous borderline tumor (SBT) tissue, where the micropapillary type (mSBT) presents the highest risk for progression. The sensitivity of LGSC to standard chemotherapy is limited, so alternative therapeutic approaches, including targeted treatment, are needed. However, knowledge about the molecular landscape of LGSC and mSBT is limited. A sample set of 137 pathologically well-defined cases (LGSC, 97; mSBT, 40) was analyzed using capture DNA next-generation sequencing (727 genes) and RNA next-generation sequencing (147 genes) to show the landscape of somatic mutations, gene fusions, expression pattern, and prognostic and predictive relevance. Class 4/5 mutations in the main driver genes (KRAS, BRAF, NRAS, ERBB2, USP9X) were detected in 48% (14/29) of mSBT cases and 63% (47/75) of LGSC cases. The USP9X mutation was detected in only 17% of LGSC cases. RNA next-generation sequencing revealed gene fusions in 6 of 64 LGSC cases (9%) and 2 of 33 mSBT cases (9%), and a heterogeneous expression profile across LGSC and mSBT. No molecular characteristics were associated with greater survival. The somatic genomic and transcriptomic profiles of 35 mSBT and 85 LGSC cases are compared for the first time. Candidate oncogenic gene fusions involving BRAF, FGFR2, or NF1 as a fusion partner were identified. Molecular testing of LGSC may be used in clinical practice to reveal therapeutically significant targets.

• MeSH
• azosloučeniny * MeSH
• genomika MeSH
• lidé MeSH
• mutace MeSH
• nádory vaječníků * diagnóza   genetika   MeSH
• protoonkogenní proteiny B-Raf genetika   MeSH
• RNA MeSH
• serózní cystadenokarcinom * diagnóza   genetika   MeSH
• stanovení celkové genové exprese MeSH
• stupeň nádoru MeSH
• thiolesterasa ubikvitinu genetika   MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• azosloučeniny * MeSH
• Martius scarlet blue trichrome MeSH Prohlížeč
• protoonkogenní proteiny B-Raf MeSH
• RNA MeSH
• thiolesterasa ubikvitinu MeSH
• USP9X protein, human MeSH Prohlížeč

Using immunohistochemistry, we examined a large cohort of 135 ovarian tumors, made up of 96 low-grade serous carcinomas (LGSCs) and 39 serous borderline tumors (micropapillary variant, mSBT), with the aim of exploring their HER2 status (overexpression). We followed with comprehensive genomic analyses on this sample set from our previous study, which revealed HER2 mutation in 5% (4/75) of LGSC and 10% (3/29) of mSBT. No cases were evaluated as HER2-positive, but 6 LGSCs and 1 mSBT were scored as HER2 1+, and 2 LGSCs and 1 mSBT showed the so-called HER2 "ultra-low" phenotype. This could be of clinical value as a potential therapeutical target concerning emerging therapeutic treatments (antibody conjugates). However, the clinical significance of this expression still needs to be established.

• Publikační typ
• časopisecké články MeSH

BACKGROUND: We examined a large cohort of serous tubo-ovarian tumors with 26 immunohistochemical markers, with the aim to assess their value for differential diagnosis and prognosis. METHODS: Immunohistochemical analyses with 26 immunomarkers were performed on 250 primary tubo-ovarian tumors including 114 high grade serous carcinomas (HGSC), 97 low grade serous carcinomas (LGSC), and 39 serous borderline tumors (micropapillary variant, mSBT). The associations of overall positivity with clinicopathological characteristics were evaluated using the chi-squared test or Fisher's Exact test. RESULTS: We found significantly different expression of p53, p16, ER, PR, PTEN, PAX2, Mammaglobin, RB1, Cyclin E1, stathmin, LMP2, L1CAM, CD44, and Ki67 in HGSCs compared to LGSCs. No significant differences were found between LGSC and mSBT. None of the other included markers (PAX8, ARID1A, HNF1B, Napsin A, CDX2, SATB2, MUC4, BRG1, AMACR, TTF1, BCOR, NTRK) showed any differences between the investigated serous tumors. Regarding the prognosis, only PR and stathmin showed a statistically significant prognostic meaning in LGSCs, with better overall survival (OS) and recurrence-free survival (RFS) in cases positive for PR, and worse outcome (RFS) for stathmin. None of the study markers showed prognostic significance in HGSCs. CONCLUSION: We provided an extensive immunohistochemical analysis of serous ovarian/tubo-ovarian tumors. Although we found some differences in the expression of some markers in HGSCs compared to LGSCs, only p53, p16, and Ki67 seem to be useful in real diagnostic practice. We also suggested the best discriminative cut-off for Ki67 (10% of positive tumor cells) for distinguishing HGSC from LGSC. We found prognostic significance of PR and stathmin in LGSCs. Moreover, the high expression of stathmin could also be of predictive value in ovarian carcinomas as target-specific anti-stathmin effectors are potential therapeutic targets.

• Klíčová slova
• High grade serous carcinoma, Immunohistochemistry, Low grade serous carcinoma, Ovarian tumors, Tubo-ovarian tumors,
• MeSH
• antigen Ki-67 MeSH
• lidé MeSH
• nádorový supresorový protein p53 MeSH
• nádory vaječníků * diagnóza   MeSH
• serózní cystadenokarcinom * diagnóza   MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antigen Ki-67 MeSH
• Martius scarlet blue trichrome MeSH Prohlížeč
• nádorový supresorový protein p53 MeSH

BACKGROUND: High-grade serous ovarian carcinoma (HGSOC) is the most common and aggressive subtype of epithelial ovarian carcinoma. It is primarily diagnosed at stage III or IV when the 5-year survival rate ranges between 20% and 40%. Here, we aimed to validate the hypothesis, based on HGSOC cell lines, that proposed the existence of two distinct groups of HGSOC cells with high and low oxidative phosphorylation (OXPHOS) metabolism, respectively, which are associated with their responses to glucose and glutamine withdrawal. METHODS: We isolated and cultivated primary cancer cell cultures from HGSOC and nontransformed ovarian fibroblasts from the surrounding ovarium of 45 HGSOC patients. We tested the metabolic flexibility of the primary cells, particularly in response to glucose and glutamine depletion, analyzed and modulated endoplasmic reticulum stress, and searched for indices of the existence of previously reported groups of HGSOC cells with high and low OXPHOS metabolism. RESULTS: The primary HGSOC cells did not form two groups with high and low OXPHOS that responded differently to glucose and glutamine availabilities in the cell culture medium. Instead, they exhibited a continuum of OXPHOS phenotypes. In most tumor cell isolates, the responses to glucose or glutamine withdrawal were mild and surprisingly correlated with those of nontransformed ovarian fibroblasts from the same patients. The growth of tumor-derived cells in the absence of glucose was positively correlated with the lipid trafficking regulator FABP4 and was negatively correlated with the expression levels of HK2 and HK1. The correlations between the expression of electron transport chain (ETC) proteins and the oxygen consumption rates or extracellular acidification rates were weak. ER stress markers were strongly expressed in all the analyzed tumors. ER stress was further potentiated by tunicamycin but not by the recently proposed ER stress inducers based on copper(II)-phenanthroline complexes. ER stress modulation increased autophagy in tumor cell isolates but not in nontransformed ovarian fibroblasts. CONCLUSIONS: Analysis of the metabolism of primary HGSOC cells rejects the previously proposed hypothesis that there are distinct groups of HGSOC cells with high and low OXPHOS metabolism that respond differently to glutamine or glucose withdrawal and are characterized by ETC protein levels.

• Klíčová slova
• Epithelial ovarian carcinoma, Metabolism reprogramming, Ovarian fibroblasts, Oxidative phosphorylation, Patient-derived cells, Unfolded protein response,
• Publikační typ
• časopisecké články MeSH

PURPOSE: Low-grade serous ovarian carcinomas (LGSOCs) have historically low chemotherapy responses. Alterations affecting the MAPK pathway, most commonly KRAS/BRAF, are present in 30%-60% of LGSOCs. The purpose of this study was to evaluate binimetinib, a potent MEK1/2 inhibitor with demonstrated activity across multiple cancers, in LGSOC. METHODS: This was a 2:1 randomized study of binimetinib (45 mg twice daily) versus physician's choice chemotherapy (PCC). Eligible patients had recurrent measurable LGSOC after ≥ 1 prior platinum-based chemotherapy but ≤ 3 prior chemotherapy lines. The primary end point was progression-free survival (PFS) by blinded independent central review (BICR); additional assessments included overall survival (OS), overall response rate (ORR), duration of response (DOR), clinical-benefit rate, biomarkers, and safety. RESULTS: A total of 303 patients were randomly assigned to an arm of the study at the time of interim analysis (January 20, 2016). Median PFS by BICR was 9.1 months (95% CI, 7.3 to 11.3) for binimetinib and 10.6 months (95% CI, 9.2 to 14.5) for PCC (hazard ratio,1.21; 95%CI, 0.79 to 1.86), resulting in early study closure according to a prespecified futility boundary after 341 patients had enrolled. Secondary efficacy end points were similar in the two groups: ORR 16% (complete response [CR]/partial responses[PRs], 32) versus 13% (CR/PRs, 13); median DOR, 8.1 months (range, 0.03 to ≥ 12.0 months) versus 6.7 months (0.03 to ≥ 9.7 months); and median OS, 25.3 versus 20.8 months for binimetinib and PCC, respectively. Safety results were consistent with the known safety profile of binimetinib; the most common grade ≥ 3 event was increased blood creatine kinase level (26%). Post hoc analysis suggests a possible association between KRAS mutation and response to binimetinib. Results from an updated analysis (n = 341; January 2019) were consistent. CONCLUSION: Although the MEK Inhibitor in Low-Grade Serous Ovarian Cancer Study did not meet its primary end point, binimetinib showed activity in LGSOC across the efficacy end points evaluated. A higher response to chemotherapy than expected was observed and KRAS mutation might predict response to binimetinib.

• MeSH
• benzimidazoly škodlivé účinky   terapeutické užití   MeSH
• doba přežití bez progrese choroby MeSH
• dospělí MeSH
• doxorubicin analogy a deriváty   terapeutické užití   MeSH
• inhibitory proteinkinas škodlivé účinky   terapeutické užití   MeSH
• lidé středního věku MeSH
• lidé MeSH
• lokální recidiva nádoru farmakoterapie   MeSH
• MAP kinasa-kinasa 1 antagonisté a inhibitory   MeSH
• MAP kinasa-kinasa 2 antagonisté a inhibitory   MeSH
• mladý dospělý MeSH
• nádory vaječníků farmakoterapie   enzymologie   patologie   MeSH
• nádory vejcovodů farmakoterapie   enzymologie   patologie   MeSH
• paclitaxel terapeutické užití   MeSH
• peritoneální nádory farmakoterapie   enzymologie   patologie   MeSH
• polyethylenglykoly terapeutické užití   MeSH
• senioři MeSH
• serózní cystadenokarcinom farmakoterapie   enzymologie   patologie   MeSH
• stupeň nádoru MeSH
• topotekan terapeutické užití   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladý dospělý MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze III MeSH
• multicentrická studie MeSH
• práce podpořená grantem MeSH
• randomizované kontrolované studie MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• benzimidazoly MeSH
• binimetinib MeSH Prohlížeč
• doxorubicin MeSH
• inhibitory proteinkinas MeSH
• liposomal doxorubicin MeSH Prohlížeč
• MAP kinasa-kinasa 1 MeSH
• MAP kinasa-kinasa 2 MeSH
• MAP2K1 protein, human MeSH Prohlížeč
• MAP2K2 protein, human MeSH Prohlížeč
• paclitaxel MeSH
• polyethylenglykoly MeSH
• topotekan MeSH

Respiratory epithelial adenomatoid hamartoma (REAH) and seromucinous hamartoma (SH) are rare tumor-like lesions of the nasal cavity, paranasal sinuses, and nasopharynx. The pathogenesis of REAH/SH is still unclear. Neoplastic proliferation, chronic mechanical irritation, inflammation, or possible embryological tissue misplacement are speculated as possible mechanisms of their development. Low-grade tubulopapillary adenocarcinoma (LGTA) is a rare variant of nonsalivary, nonintestinal type sinonasal adenocarcinoma. The aim of this study was to evaluate the immunohistochemical and genetic profiles of 10 cases of REAH/SH, with serous, mucinous, and respiratory components evaluated separately and to compare these findings with the features of 9 cases of LGTA. All cases of REAH/SH and LGTA were analyzed immunohistochemically with a cocktail of mucin antigens (MUC1, MUC2, MUC4, MUC5AC, MUC6) and with epithelial (CK7, CK20, CDX2, SATB2) and myoepithelial markers (S100 protein, p63, SOX10). The next-generation sequencing assay was performed using FusionPlex Solid Tumor Kit (ArcherDx) in 10 cases of REAH/SH, and the EGFR-ZNF267 gene fusion was detected in 1 of them. Two female REAH/SH cases were assessed for the presence of clonality. Using the human androgen receptor assay, 1 case was proved to be clonal. The serous component of REAH/SH was positive for CK7/MUC1 and SOX10 similarly to LGTA. Although REAH/SH and LGTA are histopathologically and clinically separate entities, the overlap in their morphological and immunohistochemical profiles suggests that REAH/SH might be a precursor lesion of LGTA.

• Klíčová slova
• Low-grade tubulopapillary adenocarcinoma, Nasal cavity, REAH, Respiratory epithelial adenomatoid hamartoma, Seromucinous hamartoma, Sinonasal tract,
• MeSH
• adenokarcinom chemie   diagnóza   genetika   patologie   MeSH
• diagnostické techniky molekulární * MeSH
• diferenciální diagnóza MeSH
• dítě MeSH
• dospělí MeSH
• hamartom chemie   diagnóza   genetika   patologie   MeSH
• imunohistochemie * MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladý dospělý MeSH
• nádorové biomarkery * analýza   genetika   MeSH
• nádory nosu chemie   diagnóza   genetika   patologie   MeSH
• nemoci nosohltanu diagnóza   genetika   metabolismus   patologie   MeSH
• nemoci nosu diagnóza   genetika   metabolismus   patologie   MeSH
• nosní sliznice chemie   patologie   MeSH
• prediktivní hodnota testů MeSH
• prekancerózy diagnóza   genetika   metabolismus   patologie   MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• stupeň nádoru MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• srovnávací studie MeSH
• Názvy látek
• nádorové biomarkery * MeSH

In comparison to malignant tumors of vulva, vagina, cervix and uterine corpus, clear morphologic and molecular genetic features of precursor lesions of ovarian carcinoma have not been defined yet. We can see an effort to describe preinvasive lesions to allow dia-gnostics and treatment prior to development of invasive ovarian cancer. This tendency is magnified by the fact that ovarian carcinomas have the highest mortality from all gynecological malignancies. Currently, reports confirming different morphology, pathogenesis and molecular alterations in heterogeneous group of ovarian carcinomas have been described. There is a tendency to divide epithelial malignant tumors into two groups. Low grade ovarian serous carcinoma, low grade endometrioid, clear cell, mucinous ovarian cancers and Brenner tumors of ovary are categorized as type I ovarian tumors. Highgrade serous carcinoma, undifferentiated carcinomas and malignant mixed mesodermal tumors of the ovary (MMMTs) belong to type II tumors. A potential precursor lesion of highgrade serous ovarian cancer has been defined - serous tubal intraepithelial carcinoma.

• Klíčová slova
• preinvasive lesion -  ovarian cancer -  serous tubal intraepithelial carcinoma (STIC),
• MeSH
• karcinom diagnóza   patologie   terapie   MeSH
• lidé MeSH
• nádory vaječníků diagnóza   patologie   terapie   MeSH
• prekancerózy diagnóza   patologie   terapie   MeSH
• stupeň nádoru MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• anglický abstrakt MeSH
• časopisecké články MeSH
• přehledy MeSH

This is a review of the clinical and histopathological published data on very rare heterotopic acinic cell carcinomas (AcCCs) with suggested optimal management. Extrasalivary AcCCs originate primarily in parotid lymph nodes. They present at low clinical stage, show mostly low-grade histopathology and are circumscribed with a complete nodal capsule. Extracapsular dissection was advocated as adequate therapy. In rare cases with positive surgical margins, a completion parotidectomy or adjuvant radiotherapy should follow. Heterotopic high-grade AcCCs are rare, necessitating radical surgery including neck dissection and adjuvant radiotherapy. The short term prognosis is excellent, long term outcomes are not known. Longer term follow-up is essential.

• Klíčová slova
• acinic cell carcinoma, heterotopia, lymph node, salivary gland,
• MeSH
• acinární karcinom * diagnóza   terapie   MeSH
• lidé MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

High-grade transformation of acinic cell carcinoma (AciCC) (previously referred to as dedifferentiation) is a rare phenomenon characterized by histologic progression of low-grade AciCC to high-grade adenocarcinoma or undifferentiated carcinoma. We report 9 new cases with immunohistochemical analysis and examination of HER-2/neu and p53 genes to further define the profile of this tumor. Histologically, the high-grade component was composed of polymorphic cells with a high mitotic rate arranged in glandular and solid growth patterns with comedonecrosis. The MIB-1 labeling indices were elevated in the high-grade component, as compared with the low grade conventional AciCC. The high-grade component of AciCC was characterized by strong membrane staining for CK18 and beta-catenin, and nuclear staining for cyclin-D1. HER-2/neu, androgen receptor, C-kit, and epidermal growth factor receptor were absent from both low-grade and high-grade components. In contrast, S-100 protein, alpha-1-antitrypsin, and lysozyme were lost only in high-grade foci of transformed AciCC. The median age was 61 years (with range from 43 to 76 y). Lymph node (LN) metastases were found in 5 of 9 cases (56%). Distant metastases to the lungs (n=4), pleura (n=2), brain (n=3), and peritoneum (n=1), and paraaortic, paratracheal, and mediastinal LNs (n=2) were observed. Six of 9 patients (66%) died from tumor dissemination, all with a median overall survival of 4.3 years (range: 1 to 9 y). The high propensity for LN metastases indicates the need for neck dissection at the time of diagnosis.

• MeSH
• acinární karcinom genetika   metabolismus   patologie   MeSH
• dospělí MeSH
• geny erbB-2 * MeSH
• geny p53 * MeSH
• hybridizace in situ fluorescenční MeSH
• imunohistochemie MeSH
• lidé středního věku MeSH
• lidé MeSH
• mutační analýza DNA MeSH
• nádorová transformace buněk genetika   MeSH
• nádorové biomarkery analýza   MeSH
• nádorový supresorový protein p53 genetika   metabolismus   MeSH
• nádory příušní žlázy genetika   patologie   MeSH
• receptor erbB-2 genetika   MeSH
• senioři MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• nádorové biomarkery MeSH
• nádorový supresorový protein p53 MeSH
• receptor erbB-2 MeSH

AIMS: Secretory carcinoma (SC) (synonym: mammary analogue secretory carcinoma) is a low-grade salivary gland tumour that occurs in both major and minor salivary glands. SC is known for its wide morphological, architectural and immunohistochemical spectrum, which overlaps with those of several salivary gland neoplasms, including acinic cell carcinoma (AciCC) and intercalated duct-type intraductal carcinoma (IDC) in major salivary glands, and polymorphous adenocarcinoma (PAC) in minor salivary glands. These tumours share with SC some morphological features and SOX10 immunoreactivity; also, with the exception of AciCC, they all coexpress S100 and mammaglobin. METHODS AND RESULTS: We compared MUC4 and mammaglobin expression in 125 salivary gland carcinomas (54 genetically confirmed SCs, 20 AciCCs, 21 PACs, and 30 IDCs) to evaluate the potential of these two markers to differentiate these entities. Moderate to strong diffuse MUC4 positivity was detected in 49 SCs (90.7%), as compared with none of the IDCs and PACs. In contrast, mammaglobin was frequently expressed in SCs (30 of 36 cases; 83.3%), IDCs (24/28; 85.7%), and PACs (7/19; 36.8%). Two of three high-grade SCs lost MUC4 expression in the high-grade tumour component. No significant correlation was found between MUC4 expression and the fusion variant in SC (ETV6-NTRK versus non-ETV6-NTRK). CONCLUSION: The results of our study identify MUC4 as a sensitive (90.7%) and specific (100%) marker for SC, with high positive (100%) and negative (93.4%) predictive values. Thus, MUC4 may be used as a surrogate for SC in limited biopsy material and in cases with equivocal morphology.

• Klíčová slova
• MUC4, acinic cell carcinoma, immunohistochemistry, intraductal carcinoma, mammaglobin, polymorphous adenocarcinoma, secretory carcinoma,
• MeSH
• acinární karcinom diagnóza   patologie   MeSH
• diferenciální diagnóza * MeSH
• karcinom diagnóza   patologie   MeSH
• lidé MeSH
• mammaglobin A metabolismus   MeSH
• mucin 4 analýza   MeSH
• nádorové biomarkery analýza   MeSH
• nádory slinných žláz * diagnóza   metabolismus   patologie   MeSH
• sekreční karcinom mamárního typu diagnóza   metabolismus   patologie   MeSH
• slinné žlázy patologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• mammaglobin A MeSH
• MUC4 protein, human MeSH Prohlížeč
• mucin 4 MeSH
• nádorové biomarkery MeSH