PLAG1 gene fusions were recently identified in a subset of uterine myxoid leiomyosarcomas (M-LMS). However, we have encountered cases of PLAG1-rearranged uterine sarcomas lacking M-LMS-like morphology and/or any expression of smooth muscle markers. To better characterize their clinicopathologic features, we performed a multiinstitutional search that yielded 11 cases. The patients ranged in age from 34 to 72 years (mean, 57 years). All tumors arose in the uterine corpus, ranging in size from 6.5 to 32 cm (mean, 15 cm). The most common stage at presentation was pT1b (n = 6), and 3 cases had stage pT1 (unspecified), and 1 case each presented in stages pT2a and pT3b. Most were treated only with hysterectomy and adnexectomy. The follow-up (range, 7-71 months; median, 39 months) was available for 7 patients. Three cases (7-21 months of follow-up) had no evidence of disease. Three of the 4 remaining patients died of disease within 55 to 71 months, while peritoneal spread developed in the last patient, and the patient was transferred for palliative care at 39 months. Morphologically, the tumors showed a high intertumoral and intratumoral heterogeneity. M-LMS-like and epithelioid leiomyosarcoma-like morphology were present in 3 and 5 primary tumors, respectively, the remaining mostly presented as nondescript ovoid or spindle cell sarcomas. Unusual morphologic findings included prominently hyalinized stroma (n = 3), adipocytic differentiation with areas mimicking myxoid liposarcoma (n = 2), osteosarcomatous differentiation (n = 1), and undifferentiated pleomorphic sarcoma-like areas (n = 1). The mitotic activity ranged from 3 to 24 mitoses per 10 high-power fields (mean, 9); 3 of 10 cases showed necrosis. In 3 of 11 cases, no expression of smooth muscle actin, h-caldesmon, or desmin was noted, whereas 5 of 5 cases expressed PLAG1. By RNA sequencing, the following fusion partners were identified: PUM1, CHCHD7 (each n = 2), C15orf29, CD44, MYOCD, FRMD6, PTK2, and TRPS1 (each n = 1). One case only showed PLAG1 gene break by fluorescence in situ hybridization. Our study documents a much broader morphologic spectrum of PLAG1-rearranged uterine sarcomas than previously reported, encompassing but not limited to M-LMS-like morphology with occasional heterologous (particularly adipocytic) differentiation. As it is currently difficult to precisely define their line of differentiation, for the time being, we suggest using a descriptive name "PLAG1-rearranged uterine sarcoma."

• Klíčová slova
• PLAG1 fusion, adipocytic differentiation, epithelioid, lipoleiomyosarcoma, myxoid leiomyosarcoma, uterine stromal sarcoma,
• 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

In addition to "classic" and eosinophilic subtype, chromophobe renal cell carcinoma (RCC) is well-known to demonstrate various morphological patterns including adenomatoid, microcystic, pigmented, multicystic, papillary, neuroendocrine-like, and small cell-like, all of which are important to appreciate for accurate diagnosis. Herein, we expand on a unique chromophobe RCC morphology not previously described consisting of tumor cells with extensive stromal retraction, mimicking upper urothelial tract micropapillary carcinoma (MPC). Twelve MPC-like chromophobe RCC nephrectomies were reviewed with clinicopathological features recorded; molecular testing was performed on 7 of 12 tumors. Patients were mostly men (n=10) with a mean age of 65 years. Mean tumor size was 6.4 cm with pathological stage distribution as follows: 4 (33%) T1a, 2 (17%) T1b, 1 (8%) T2b, and 3 (25%) T3a. The extent of MPC-like chromophobe RCC foci ranged from 10% to 40% (mean=26%; there was no correlation between the extent of MPC-like chromophobe RCC foci and tumor stage). Other chromophobe RCC morphological patterns were not identified. When performed, all (100%) tumors depicted prototypic chromophobe RCC staining pattern of KIT positivity/KRT7 positivity. Molecular showed 6 of 7 (86%) with multiple chromosomal losses. Clinically significant mutations were identified in NF1, TP53, FLCN (likely somatic), CHEK2, and ZFHX3 genes. Follow up available in 9 patients showed no evidence of disease (mean=23 months). Although the etiology behind the extensive stromal retraction in our tumors is unknown, this may likely be artifactual in nature. Nonetheless, it is important to include MPC-like chromophobe RCC in the spectrum of "variant" morphologies to avoid diagnostic pitfalls from micropapillary carcinoma.

• Klíčová slova
• artifact, chromophobe, micropapillary, renal cell carcinoma, retraction,
• Publikační typ
• časopisecké články MeSH

Pigmented wheat varieties (Triticum aestivum spp.) are getting increasingly popular in modern nutrition and thoroughly researched for their functional and nutraceutical value. The colour of these wheat grains is caused by the expression of natural pigments, including carotenoids and anthocyanins, that can be restricted to either the endosperm, pericarp and/or aleurone layers. While contrasts in phytochemical synthesis give rise to variations among purple, blue, dark and yellow grain's antioxidant and radical scavenging capacities, little is known about their influence on gluten proteins expression, digestibility and immunogenic potential in a Celiac Disease (CD) framework. Herein, it has been found that the expression profile and immunogenic properties of gliadin proteins in pigmented wheat grains might be affected by anthocyanins and carotenoids upregulation, and that the spectra of peptide released upon simulated gastrointestinal digestion is also significantly different. Interestingly, anthocyanin accumulation, as opposed to carotenoids, correlated with a lower immunogenicity and toxicity of gliadins at both protein and peptide levels. Altogether, this study provides first-level evidence on the impact modern breeding practices, seeking higher expression levels of health promoting phytochemicals at the grain level, may have on wheat crops functionality and CD tolerability.

• Klíčová slova
• Data-dependent acquisition, Gluten, Pigmented wheat, Protein expression profiling,
• MeSH
• anthokyaniny MeSH
• celiakie * MeSH
• gliadin * chemie   MeSH
• hmotnostní spektrometrie MeSH
• karotenoidy MeSH
• lidé MeSH
• peptidy chemie   MeSH
• pšenice chemie   MeSH
• šlechtění rostlin MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• anthokyaniny MeSH
• gliadin * MeSH
• karotenoidy MeSH
• peptidy MeSH

Cutaneous tumors with melanocytic differentiation represent a broad group of neoplasms of both melanocytic and non-melanocytic origin. Besides traditional members such as clear-cell sarcoma (CCS) and PEComa, the latter group has recently expanded to also include MITF::CREM fusion-associated tumors, but the available data are limited. Herein, we present a third case of this rare neoplasm which occurred in the temporal region in a 1-year-old girl. It was an infiltratively growing polypoid dermal-based lesion lacking an intraepidermal component. It consisted of cellular solid sheets or small nests of epithelioid to spindled cells with a predominantly eosinophilic and much less commonly clear cytoplasm. The nuclei had round to ovoid shape and exhibited moderate to high-grade atypia and prominent nucleoli. The mitotic activity was 11 mitoses per 10 high-power fields, and atypical mitotic figures were present. Immunohistochemically, the tumor was strongly positive with S100 protein, SOX10, and MITF, while HMB45, tyrosinase, and Melan A were negative. Extensive molecular analysis revealed only MITF::CREM gene fusion. There had no evidence of disease 9 months after the diagnosis. These tumors need to be distinguished from malignant tumors with melanocytic differentiation, primarily from melanoma. However, additional cases still need to be studied to precisely define their biological potential and establish their nosologic status.

• Klíčová slova
• Clear-cell sarcoma-like, Clear-cell tumor, Cutaneous, MITF::CREM fusion, Melanocytic differentiation, Melanoma-like, Skin,
• MeSH
• buněčná diferenciace MeSH
• kojenec MeSH
• lidé MeSH
• melanocyty patologie   MeSH
• melanom * diagnóza   MeSH
• modulátor elementu responzivního pro cyklický AMP metabolismus   MeSH
• nádorové biomarkery analýza   MeSH
• nádory kůže * patologie   MeSH
• sarkom z jasných buněk * genetika   MeSH
• transkripční faktor spojený s mikroftalmií genetika   metabolismus   MeSH
• Check Tag
• kojenec MeSH
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH
• Názvy látek
• CREM protein, human MeSH Prohlížeč
• MITF protein, human MeSH Prohlížeč
• modulátor elementu responzivního pro cyklický AMP MeSH
• nádorové biomarkery MeSH
• transkripční faktor spojený s mikroftalmií MeSH

Twelve pigmented wheat genotypes, one tritordeum, and one common wheat were grown in three field experiments under varying nitrogen (N) fertilization rates to investigate the contributions of genotype, environment, and fertilization on the levels of phenolic acids, anthocyanins, carotenoids and antioxidant capacity of the grains. Soluble phenolic acids increased significantly (+16%) in the environment with high soil N content, while bound phenolic acids and anthocyanins decreased (-16 and -57%). N fertilization affected the agronomic and qualitative traits but had limited effects on some bioactive compounds (bound phenolic acids and anthocyanins). The greatest differences appeared among the color groups and within the same color types, with the black group showing the most anthocyanins and phenolic acids (34.4 and 1207 mg·kg-1) and the highest antioxidant capacity. Some of the cultivars could be promising for the development of innovative supply chains and the production of functional foods, as they showed good yield and quality performances, and good antioxidant features.

• Klíčová slova
• Triticum aestivum, anthocyanins, antioxidant capacity, carotenoids, nitrogen, phenolic acids, pigmented cereals, technological quality, × Tritordeum martinii,
• MeSH
• anthokyaniny MeSH
• antioxidancia * MeSH
• genotyp MeSH
• lipnicovité MeSH
• pšenice * genetika   MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• anthokyaniny MeSH
• antioxidancia * MeSH
• phenolic acid MeSH Prohlížeč

Since the publication of the 2020 World Health Organization classification of soft tissue and bone tumors, the classification of "fibroblastic" tumors has expanded to include a novel subset of tumors characterized by PRRX1::NCOA1/2 gene fusions. These tumors defy conventional classification and are morphologically distinct, characterized by a multi-nodular growth of bland spindle cells suspended in a myxo-collagenous stroma with mild cytologic atypia, "staghorn-like" vessels, and variable perivascular hyalinization. Mitotic activity is rare, and necrosis is not identified. Herein, we present six additional cases of PRRX1-rearranged mesenchymal tumors, including five cases with PRRX1::NCOA1 fusion and one case with PRRX1::KMT2D fusion. Three cases (3/6, 50%) demonstrated focal co-expression of S100 protein and SOX10, thereby expanding the immunohistochemical profile of this emerging entity. Like prior reported cases, there was no evidence of malignant behavior on short-term follow-up. The novel fusion, PRRX1::KMT2D, further expands the molecular spectrum of this entity and leads to a proposed revision of the provisional nomenclature to "PRRX1-rearranged mesenchymal tumor" to both accommodate non-NCOA1/2 fusion partners and allow for the possibility of partial neural or neuroectodermal differentiation.

• Klíčová slova
• KMT2D, Mesenchymal tumor, NCOA1, PRRX1, Soft tissue, Spindle cell,
• MeSH
• fúze genů MeSH
• homeodoménové proteiny genetika   MeSH
• lidé MeSH
• nádorové biomarkery genetika   MeSH
• nádory kostí * MeSH
• nádory měkkých tkání * genetika   patologie   MeSH
• nádory z pojivové a měkké tkáně * MeSH
• proteiny S100 MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• homeodoménové proteiny MeSH
• nádorové biomarkery MeSH
• proteiny S100 MeSH
• PRRX1 protein, human MeSH Prohlížeč

Clear cell mesothelioma is uncommon and shows predominance of clear cells with resemblance to clear cell carcinomas. Clinicopathologic and molecular descriptions of clear cell mesothelioma remained limited. In this study, we identified an index patient with clear cell mesothelioma, confirmed by immunohistochemical and ultrastructural studies. Targeted next-generation sequencing revealed the presence of an inactivating VHL mutation. We then systematically searched for VHL-mutant mesotheliomas in a comprehensive genomic profiling database of 1532 mesotheliomas. Collectively, we identified a cohort of four VHL-mutant clear cell mesotheliomas, including three peritoneal and one pleural tumors from three females and one male, with age range of 47-68 (median 63) years. Histologically, each tumor showed a microcystic to tubulopapillary architecture with prominent clear cells. By next-generation DNA sequencing, each of the four clear cell mesotheliomas harbored inactivating VHL mutations, while lacking other alterations typical of mesotheliomas such as BAP1, NF2, SETD2, CDKN2A, CDKN2B, TP53, and PTEN. By using low-pass whole genome sequencing on the index case and targeted next-generation sequencing on the remaining three cases, we identified extensive loss of heterozygosity throughout the genome but consistently sparing chromosomes 5, 7, and 20, characteristic of genomic near-haploidization. In summary, clear cell mesotheliomas were characterized by inactivating VHL mutations and genomic near-haploidization and appeared to represent a distinct clinicopathologic and molecular category of mesotheliomas. Our findings implicate VHL in the pathogenesis of a subset of mesotheliomas, particularly those with clear cell morphology.

• Klíčová slova
• VHL, clear cell, genetics, genomic near haploidization, mesothelioma, near haploid,
• MeSH
• chromozomální aberace MeSH
• genomika MeSH
• haploidie MeSH
• lidé středního věku MeSH
• lidé MeSH
• maligní mezoteliom * MeSH
• mezoteliom * genetika   MeSH
• mutace MeSH
• nádorový supresorový protein VHL genetika   MeSH
• nádory plic * genetika   MeSH
• senioři MeSH
• thiolesterasa ubikvitinu genetika   MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• systematický přehled MeSH
• Názvy látek
• nádorový supresorový protein VHL MeSH
• thiolesterasa ubikvitinu MeSH
• VHL protein, human MeSH Prohlížeč

Methylation silencing of certain cellular genes is a sign of carcinogenesis progression and therefore tests that detect methylation could be used in the diagnosis or staging of malignant diseases. In the diagnosis of squamous cell carcinomas of the cervix which are almost 100% caused by long-term infection with highrisk human papillomavirus (HR-HPV), methylation silencing of certain cellular genes is a highly specific marker of advanced dysplastic lesions and appears to result from aberrant activation of the methyltransferase DNMT1 by viral oncoproteins E6 and E7. A methylation test performed on a cervicovaginal cytology specimen allows to increase the diagnostic value of this non-invasive test and to select patients with severe squamous cell lesions for follow-up. Other less frequent anogenital malignancies that are induced by HR-HPV to a lesser extent can also be detected by cytological examination - glandular lesions of various origins, most commonly cervical and endometrial adenocarcinomas and anal carcinoma. The aim of our pilot study was to evaluate the utility of a methylation test for the diagnosis of these malignancies in a cohort of 50 liquid-based cervicovaginal cytologies with glandular lesion and 74 liquid-based anal cytologies from HIV-positive men having sex with men who are at high risk for anal cancer development.

• Klíčová slova
• HR-HPV, Methylation, anal cancer, anal carcinoma, cytology, glandular lesions,
• MeSH
• cytodiagnostika MeSH
• infekce papilomavirem * komplikace   diagnóza   patologie   MeSH
• lidé MeSH
• metylace MeSH
• onkogenní proteiny virové * genetika   MeSH
• Papillomaviridae genetika   MeSH
• pilotní projekty MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• onkogenní proteiny virové * MeSH

The objective of this study was to examine the rheological and fermentation behavior of doughs prepared from five different colored wheat varieties (black AF Zora, yellow KM 111-18, purple AF Jumiko, blue AF Oxana and red Vanessa - chosen as a standard), which contain polyphenolics in the outer layers of grains. Three wholemeal flour fractions (fine, semi-coarse and coarse) were used for each variety. The flour fractions differed in the particle size of the bran, the ash content and thus the phenolic compound content. The baking trials, texture and sensory analyses of breads were performed, to assess their overall acceptability. The coarser granulation of flour fractions, average hardness (8.5<12.6<20.2 N) and chewiness (584<796<1053 N) of breads increased, while other parameters: springiness (90>87>77%), cohesiveness (78>75>70%) and resilience (35>32>27%) decreased. Moreover, the increase in off-flavors was detected with higher bran content. Regarding the flour granulation, the fine fraction seemed to be the most suitable due to its high gas-retention capacity. The best products in terms of both dough and bread quality reached blue AF Oxana and yellow KM 111-18. Utilization of colored wheat in bakery industry may present a good strategy of providing value-added products to the consumers.

• Klíčová slova
• Bread texture, Colored wheat bran, Dough behavior, Flour fractions, Leavening gas,
• Publikační typ
• časopisecké články MeSH