Assessing the biological behavior of uterine inflammatory myofibroblastic tumors (IMTs) remains challenging. This study evaluated previously proposed risk schemes and features in 9 IMTs (6 indolent, 3 aggressive) by integrating clinicopathological features, immunohistochemistry, and next-generation sequencing (NGS). High-risk features (necrosis, infiltrative growth, nuclear atypia) were present in both groups, with LVSI in 1/3 of aggressive IMTs. Aberrant p16 expression and CDKN2A/2B deletions were noted in 2/3 aggressive cases. All cases harbored ALK fusions, wild-type p53, and lacked pathogenic gene mutations. Aggressive cases harbored arm-level and segmental copy number gains/losses at chr 1, 2, X, and had significantly reduced AR expression. The clinicopathological risk stratification score (CRSS) predicted the biological behavior correctly in cases with complete clinicopathological data (size, mitoses, age, infiltrative growth). Two morcellated cases (one indolent and one aggressive) would have been predicted as low risk based solely on the absence of pathogenic mutations. Hereby, the reliability of the proposed CRSS was confirmed. Aberrant p16 expression predicted malignant behavior in 2/3 aggressive cases. Absence of pathogenic mutations or presence of large scale CNVs does not seem to be a predictor of clinical behavior. Additional studies and NGS analyses of more cases may improve risk stratification for patients with incomplete clinicopathological information and may reveal additional risk stratifiers (such as the suggested large-scale CNVs or AR downregulation) for IMTs.
- Klíčová slova
- Biological behavior, IMT, Molecular testing,
- Publikační typ
- časopisecké články MeSH
The International Federation of Gynaecology and Obstetrics (FIGO) introduced a new staging system for endometrial carcinoma FIGO 2023 in June 2023. The new staging system differs significantly from previous versions by incorporating other non-anatomical parameters (histological type of tumour, tumour grade and the presence of massive lymphovascular space involvement as well as the molecular classification of the tumour). The FIGO 2023 staging system enhances the accuracy of prognostic assessments for patients at a specific stage with better options for targeted treatment. Another objective was to synchronise staging as much as possible with the European oncogynaecological ESGO/ESTRO/ESP guidelines for the management of patients with endometrial carcinoma established in 2021. However, several changes are controversial. Routine molecular classification of endometrial carcinomas is not yet commonly available in most countries of the world. Another limitation of the FIGO 2023 staging system of endometrial cancer is the inclusion of variables whose definitions are still evolving, as well as variables that are subject to considerable interobserver variability in their assessment. Advantages, controversies, and limitations for clinical practice of the new FIGO 2023 endometrial cancer staging system are discussed.
Im Juni 2023 hat die Internationale Vereinigung für Gynäkologie und Geburtshilfe (FIGO) ein neues Staging-System für das Endometriumkarzinom – FIGO 2023 – eingeführt. Das neue Staging-System unterscheidet sich signifikant von früheren Versionen, da nun auch andere nicht anatomische Parameter (z. B. histologischer Tumortyp, Tumorgrad, ausgedehnter Befall des lymphatischen Raums sowie die molekulare Klassifikation von Tumoren) einbezogen wurden. Das FIGO-2023-Staging-System verbessert die prognostische Genauigkeit bei Patientinnen in einem bestimmten Tumorstadium mit einer besseren Auswahl an gezielten Behandlungsmöglichkeiten. Zweck des neuen Systems ist es auch, das FIGO-Staging weitmöglichst mit dem Staging der gynäkologisch-onkologischen Europäischen Leitlinien der ESGO/ESTRO/ESP, die im Jahre 2021 für das Management von Patientinnen mit Endometriumkarzinom aufgestellt wurden, in Einklang zu bringen. Allerdings werden mehrere Änderungen immer noch kontrovers diskutiert. So ist in den meisten Ländern der Welt die routinemäßige molekulare Klassifikation von Endometriumkarzinomen nicht allgemein üblich oder erhältlich. Eine weitere Einschränkung des FIGO-2023-Staging-Systems für das Endometriumkarzinom ist die Einbeziehung von Variablen, deren Definitionen noch im Entstehen begriffen sind, bzw. von Variablen, die eine erhebliche Interobserver-Variabilität aufweisen. Die Vorteile, Kontroversen und Einschränkungen des neuen FIGO-2023-Staging-Systems in der klinischen Praxis werden hier diskutiert.
- Klíčová slova
- ESGO, ESP, ESTRO, FIGO 2023, controversies, endometrial cancer, molecular classification, staging, staging system,
- Publikační typ
- časopisecké články MeSH
Extrapulmonary small cell neuroendocrine carcinoma (EP-SCNC) is a rare malignancy with a poor prognosis. Most patients with EP-SCNC have metastatic disease upon presentation, and their average overall survival (OS) is less than 12 months. Our study aimed to conduct a complex analysis of EP-SCNC. One hundred eighty-one EP-SCNC tissue samples were subjected to a complex analysis. One hundred fifty-five tumors were pure EP-SCNC, whereas 26 were combined tumors. Immunohistochemistry for ASCL1, NEUROD1, YAP1, POU2F3, Rb1, p53, cyclin D1, p16, PTEN, DLL3, PD-L1, CD56, synaptophysin, chromogranin A, and INSM1 was performed, and 128 samples were analyzed molecularly using next-generation sequencing, comprising DNA and RNA analyses. Detailed results on immunohistochemical and molecular analyses were provided for each primary origin of EP-SCNC separately. Median survival for the whole cohort of patients was 8.94 months. Patient age (≥70 years), tumor mutational burden <15, and TP53 and BRCA2 mutations were negative prognostic factors. High expression of ASCL-1 was associated with shorter OS, whereas high expression of YAP1 was associated with longer OS. Patients with genitourinary tumors had significantly better OS than those with gastrointestinal tract EP-SCNC tumors. Rb1 expression loss was detected more often in genitourinary tract SCNCs. In contrast, p16 overexpression was found more often in genitourinary tract SCNCs. POU2F3 expression was detected more often in combined tumors, whereas NEUROD1 was detected more often in pure EP-SCNC. Regarding "druggable markers," DLL3 was expressed in 66% of tumors and PD-L1 in 17.4%. Detailed analyses of different prognostic and predictive markers are needed to better understand EP-SCNC biology and create more personalized therapy to improve patient prognosis.
- Klíčová slova
- POU class 2 homeobox 3, achaete-scute homolog 1, extrapulmonary neuroendocrine small cell carcinoma, neurogenic differentiation factor 1, tumor mutation burden, yes-associated protein 1,
- MeSH
- dospělí MeSH
- imunohistochemie MeSH
- lidé středního věku MeSH
- lidé MeSH
- malobuněčný karcinom * genetika patologie klasifikace metabolismus mortalita MeSH
- nádorové biomarkery * genetika metabolismus analýza MeSH
- neuroendokrinní karcinom * genetika patologie klasifikace mortalita metabolismus MeSH
- prognóza MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- nádorové biomarkery * MeSH
Uterine sarcomas with KAT6B/A::KANSL1 fusion represent a new entity characterized by bland morphology, commonly with hybrid features of low-grade endometrial stromal sarcoma (LG-ESS) and tumors with smooth muscle differentiation. In our study, we performed a detailed morphological, immunohistochemical, and molecular analysis of 9 cases of these tumors. Six of those had been originally diagnosed as LG-ESS, one as leiomyoma, one as leiomyosarcoma, and the remaining case as sarcoma with the KAT6B/A::KANSL1 fusion. Seven cases showed overlapping features between endometrial stromal and smooth muscle tumors, one case resembled cellular leiomyoma, and one case resembled high-grade endometrial stromal sarcoma. Immunohistochemically, the tumors showed a common expression of smooth muscle markers and endometrial stromal markers. Molecular findings showed the KAT6B/A::KANSL1 fusion in all cases (by NGS and FISH). In addition, mutations affecting genes such as TP53, PDGFRB, NF1, RB1, PTEN, ATM, RB1, FANCD2, and TSC1 were present in all 5 cases with aggressive behavior. One patient with no evidence of disease showed no additional mutations, while another harbored a mutation of a single gene (ERCC3). Of the 8 patients with available follow-up, two died of disease, 3 are currently alive with disease, and 3 have no evidence of disease. The correct recognition of tumors with the KAT6B/A::KANSL1 fusion is essential because despite the bland morphological features of most cases, these tumors have a propensity for aggressive behavior.
- Klíčová slova
- Endometrial stromal sarcoma, KAT6B/A::KANSL1 fusion, Next generation sequencing, Uterine tumor,
- MeSH
- dospělí MeSH
- endometriální stromální sarkom * genetika patologie MeSH
- fúze genů MeSH
- fúzní onkogenní proteiny * genetika MeSH
- histonacetyltransferasy * genetika MeSH
- imunohistochemie MeSH
- lidé středního věku MeSH
- lidé MeSH
- nádorové biomarkery * genetika analýza MeSH
- nádory dělohy * genetika patologie MeSH
- nádory endometria genetika patologie MeSH
- sarkom * 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
- Názvy látek
- fúzní onkogenní proteiny * MeSH
- histonacetyltransferasy * MeSH
- KAT6B protein, human MeSH Prohlížeč
- nádorové biomarkery * MeSH
Adult granulosa cell tumors (AGCTs) of the ovary are characterized by their propensity for late recurrences and are primarily managed surgically due to the limited efficacy of systemic treatment. The FOXL2 p.C134W somatic mutation has been identified in ∼95% of AGCT cases, and TERT promoter alterations have been linked to worse overall survival. This study highlights the potential prognostic significance of FOXO1 mutations, suggesting that they may be associated with poorer overall survival and shorter time to recurrence. A total of 183 primary AGCTs and 44 recurrences without corresponding primary tumors were analyzed. The primary AGCTs were categorized into 3 groups: 77 nonrecurrent tumors, 18 tumors that later recurred (including 9 cases with matched primary-recurrence pairs), and 88 tumors with unknown recurrence status. Targeted next-generation sequencing was conducted on 786 cancer-related genes to investigate their genetic profile. The study aimed to identify the molecular alterations associated with AGCT pathogenesis and recurrence rate, comparing primary versus recurrent tumors, and primary recurrent versus primary nonrecurrent cases. Our findings confirmed the high prevalence (99%) of the FOXL2 p.C134W mutation in AGCTs. Secondary truncating FOXL2 mutations were observed in 5% of cases. Two cases with typical AGCT morphology were FOXL2 wild-type, harboring mutations in KRAS or KMT2D instead, suggesting alternative genetic pathways. TERT promoter mutations were found in 43% of cases, more frequently in recurrences. Other recurrent mutations detected in the cohort included KMT2D (10%), FOXO1 (7%), CHEK2 (5%), TP53 (3.5%), PIK3CA (3.5%), and AKT1 (3%). Two recurrent, FOXL2-mutated cases also carried DICER1 mutations. One tumor exhibited MSI-high status and a tumor mutation burden of 19 mut/Mb.Our results indicate the need for further investigation into the role of FOXO1 as a potential prognostic marker in AGCTs.
- Klíčová slova
- DICER1, FOXL2, FOXO1, KMT2D, TERT promoter, adult-type granulosa cell tumor of the ovary,
- MeSH
- dospělí MeSH
- forkhead box protein O1 genetika MeSH
- lidé středního věku MeSH
- lidé MeSH
- lokální recidiva nádoru * genetika patologie MeSH
- mutace MeSH
- nádor z folikulárních buněk * genetika patologie mortalita MeSH
- nádory vaječníků * genetika patologie mortalita MeSH
- prognóza MeSH
- progrese nemoci MeSH
- protein FOXL2 genetika MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- telomerasa genetika 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
- Názvy látek
- forkhead box protein O1 MeSH
- FOXL2 protein, human MeSH Prohlížeč
- FOXO1 protein, human MeSH Prohlížeč
- protein FOXL2 MeSH
- telomerasa MeSH
- TERT protein, human MeSH Prohlížeč
Endometrial stromal tumors are rare lesions with a diverse morphology, which may make achieving the correct diagnosis challenging in some cases. We report a case of a uterine mesenchymal tumor diagnosed as endometrial stromal nodule with a peculiar whorled morphology and GREB1::CTNNB1 fusion confirmed by transcriptome RNA sequencing. The tumor was sharply demarcated, lacked invasive growth, and had benign behavior, as the patient remained without disease recurrence 15 years later. Immunohistochemically, the tumor cells showed diffuse nuclear expression of beta-catenin, confirming the activation of the beta-catenin pathway. Our case represents only the 4th reported case of CTNNB1-rearranged endometrial stromal tumor with extensive whorling. The biological nature of uterine tumors characterized by whorled morphology and rearrangement of CTNNB1 is not yet clear, which underscores the importance of genetic profiling for accurate diagnosis and potential targeted therapies in malignant cases.
- Klíčová slova
- ESN, Endometrial stromal tumors, GREB1, GREB1::CTNNB1 fusion, Uterine mesenchymal tumors,
- MeSH
- beta-katenin * genetika MeSH
- endometriální stromální nádory * genetika patologie MeSH
- fúze genů MeSH
- lidé středního věku MeSH
- lidé MeSH
- nádorové biomarkery * genetika analýza MeSH
- nádorové proteiny * genetika MeSH
- nádory endometria * genetika patologie MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- kazuistiky MeSH
- Názvy látek
- beta-katenin * MeSH
- CTNNB1 protein, human MeSH Prohlížeč
- GREB1 protein, human MeSH Prohlížeč
- nádorové biomarkery * MeSH
- nádorové proteiny * MeSH
The Rare Gynecologic Sarcoma study involved 23 institutions from 10 countries focusing on myxoid leiomyosarcoma and non-smooth muscle uterine sarcomas. Here, we present the main results of the study, including the comparison between the original and final diagnosis, the frequency and type of molecular aberrations, and the clinicopathologic outcomes. A total of 379 cases were included, with available results for next-generation sequencing (NGS) RNA in 338 of 379 cases and NGS DNA in 335 of 379 cases. According to the original diagnoses, the study included 204 cases of low-grade endometrial stromal sarcoma (LG-ESS), 75 cases of high-grade endometrial stromal sarcoma (HG-ESS), 74 cases of undifferentiated uterine sarcoma (UUS), 17 cases of myxoid leiomyosarcoma, and 9 cases of unclassifiable sarcoma. The results of our second reading showed that 29% (110/379) of all the tumors had been originally misdiagnosed. After the reclassification, the final diagnoses were 147 cases of LG-ESS, 69 cases of HG-ESS, 58 cases of UUS, 3 cases of LG-ESS with high-grade transformation, 7 cases of perivascular epithelioid cell tumor, 9 cases of uterine tumor resembling ovarian sex cord tumor, 8 cases of tumors with a KAT6B/A::KANSL1 fusion, 2 cases of tumors with an NTRK fusion, 29 cases of undifferentiated carcinoma, and 47 tumors with smooth muscle differentiation. The molecular testing showed that LG-ESS harbor a recurrent fusion in 75.9% and HG-ESS in 43.7% of cases. The results of our study emphasize the diagnostic, prognostic, and predictive significance of molecular testing in mesenchymal uterine tumors.
- Klíčová slova
- endometrial stromal sarcoma, next-generation sequencing, undifferentiated uterine sarcoma, uterine tumor,
- Publikační typ
- časopisecké články MeSH
The aim of this study was to determine whether the presence and extent of lymphovascular invasion (LVI) is prognostic in surgical stage I cervical squamous cell carcinoma (SCC). All available tumour slides and/or paraffin blocks from 426 patients with stage I cervical SCC treated surgically with curative intent were collected from 18 institutions and retrospectively analysed. Presence and extent of LVI (focal <5 spaces, extensive ≥5 spaces) were assessed on scanning magnification in large haematoxylin and eosin slide sets in 366 cases. Progression-free survival (PFS) was calculated as the time from surgery to first progression or death or last follow-up, whichever occurred first. Overall survival (OS) was defined as the time from surgery to death or last follow-up. Clinicopathological and statistical analyses were performed on 97 patients with the International Federation of Gynecology and Obstetrics (FIGO) 2018 stage IA and 329 patients with stage IB SCC of the cervix. LVI, both focal and extensive, was more frequent in stage IB than in stage IA (p<0.001). Patients with stage IB carcinomas with extensive LVI had worse PFS [hazard ratio (HR) 2.86; 95% confidence interval (CI) 1.49, 5.49; p=0.005] and OS (HR 2.88; 95% CI 1.38, 6.02; p=0.012) than those with focal or no LVI. In stage IA, in contrast, the presence and extent of LVI did not associate with PFS (p=0.926) or OS. Extensive LVI was not statistically correlated with PFS and OS in substages IA1, IA2 or IB2. PFS (HR 3.7; 95% CI 1.61, 8.46; p<0.001) and OS (HR 4.18; 95% CI 1.58, 11.04; p=0.002) in stage IB1, and PFS (HR 7.78; 95% CI 0.87, 69.82; p=0.039) in stage IB3 were diminished in the presence of extensive LVI. In conclusion, in patients with FIGO stage I cervical SCC, the presence and extent of LVI has prognostic significance in stage IB carcinoma, and quantifying LVI is recommended.
- Klíčová slova
- lymph node metastasis, lymphovascular invasion, prognosis, squamous cell carcinoma, stage,
- MeSH
- cervix uteri patologie chirurgie MeSH
- dospělí MeSH
- invazivní růst nádoru MeSH
- lidé středního věku MeSH
- lidé MeSH
- lymfatické metastázy patologie MeSH
- nádory děložního čípku * patologie chirurgie mortalita MeSH
- prognóza MeSH
- retrospektivní studie MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- spinocelulární karcinom * patologie chirurgie mortalita MeSH
- staging nádorů * 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
- multicentrická studie MeSH
Extrapulmonary small cell neuroendocrine carcinoma (EP-SCNC) is a rare malignancy with a poor prognosis. Despite its morphological similarity to lung small cell carcinomas, its oncogenesis remains uncertain. One hundred and seventy-one EP-SCNC were enrolled in a multicenter study, and all tissue samples underwent an immunohistochemical p53 analysis. One hundred twenty-five samples were molecularly analyzed using next-generation sequencing (NGS), comprising DNA and RNA analysis. p53 normal/wild type expression was detected in 68 cases (39.8%), whereas aberrant expression was detected in 103 cases (60.2%). Molecular TP53 alteration was detected in 92 out of 125 tumors (73.6%). The TP53 mutation was shown to be prognostic and associated with shorter overall survival (p = 0.041). The multivariate analysis of p53 and TP53 mutational status found that it impacted overall survival relative to distinct sites of tumor locations (p = 0.004 and p = 0.001, respectively). Age did not influenced survival in the multivariate analysis of p53 and TP53 (p = 0.002; p < 0.001 resp.). Among tumors with paired immunohistochemical and molecular results, 108 exhibited concordance between the immunohistochemical and molecular analysis, whereas 17 were discordant. Accordingly, p53 aberrant expression was tightly associated with a TP53 mutation (p < 0.001). In discordant cases, molecular analysis revealed no alteration in three tumors with p53 overexpression. In contrast, in 14 tumors with wild-type p53 expression, TP53 genetic alteration was detected. Possible causes of discordance are discussed in this manuscript. Furthermore, the incidence of aberrant p53 expression / TP53 molecular alteration was noticeably lower in EP-SCNC than in small-cell lung carcinomas. Therefore, in EP-SCNC, other driver mutations should be sought since personalized therapy can improve patient prognosis.
Low-grade endometrial stromal sarcoma (LG-ESS) can present diagnostic challenges, due to its overlapping morphological features with other uterine mesenchymal tumors. Misdiagnosis rates remain significant, and immunohistochemical data for LG-ESS are limited to small series and inconsistent antibody panels. This study aimed to refine the IHC profile of LG-ESS by analyzing a large, molecularly confirmed series of 147 cases using a panel of 24 antibodies, including newer markers like transgelin and smoothelin. CD10 and IFITM1, key endometrial stromal markers, were expressed in 86% (92% of those extensively) and 69% (60% of those extensively) of cases, with fusion-positive tumors showing significantly higher expression. Smooth muscle markers (α-SMA, desmin, h-caldesmon, calponin, transgelin) were variably expressed, predominantly in focal or low-intensity patterns, with α-SMA reaching the highest frequency of expression (44%). However, the intensity of smooth muscle marker expression was usually very low. Smoothelin was rarely expressed. Hormone receptors were frequently positive, with PR showing a higher frequency (92% vs. 83%) and intensity than ER. Markers like S-100, HMB45, and CD117 were largely negative; all tumors were p53 wild-type, with preserved SMARCB1/SMARCA4 expression and ALK and ROS1 negativity. This work represents the largest molecularly validated IHC study on LG-ESS, providing a robust diagnostic profile for routine pathology. By addressing key diagnostic limitations and examining newer markers, our study supports a more standardized approach to diagnosing LG-ESS and underscores the value of immunohistochemical panels, particularly in fusion-negative tumors where diagnosis relies on morphological and immunohistochemical interpretation. These findings contribute critical data for improving diagnostic accuracy.
- Klíčová slova
- Endometrial stromal markers, Immunohistochemistry, LG-ESS, Low-grade endometrial stromal sarcoma, Smoothelin,
- Publikační typ
- časopisecké články MeSH
