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Expression of neuroendocrine (NE) markers in primary ovarian non-NE epithelial tumors has rarely been evaluated. The aim of our study was to evaluate the expression of the most widely used NE markers in these neoplasms and to determine any prognostic significance of NE marker expression. The cohort consisted of 551 primary ovarian tumors, including serous borderline tumors, low-grade serous carcinomas, high-grade serous carcinomas (HGSC), clear cell carcinomas, endometroid carcinomas, mucinous borderline tumors, and mucinous carcinomas. Immunohistochemical analysis was performed using antibodies against INSM1, synaptophysin, chromogranin, and CD56 on tissue microarray. Positivity for INSM1, synaptophysin, chromogranin, and CD56 was most frequently observed in mucinous tumors (48.7%, 26.0%, 41.5%, and 100%, respectively). The positivity for these NE markers was mostly restricted to nonmucinous elements distributed throughout the tumor. The mucinous borderline tumor and mucinous carcinomas groups had similar proportions of positivity (mucinous borderline tumor: 53%, mucinous carcinomas: 39%). In the other tumor types, except for HGSC, there was only focal expression (5%-10%) or negativity for NE markers. HGSC showed high CD56 expression (in 26% of cases). Survival analysis was only performed for CD56 in HGSC as this was the only group with sufficient positive cases, and it showed no prognostic significance. Except for mucinous tumors, expression of NE markers in non-NE ovarian epithelial tumors is low. CD56 expression in HGSC occurs frequently but is without diagnostic or prognostic value.
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Adenocarcinoma Mucinoso , Tumores Neuroendocrinos , Neoplasias Ováricas , Femenino , Humanos , Sinaptofisina/metabolismo , Biomarcadores de Tumor/metabolismo , Cromograninas , Tumores Neuroendocrinos/patología , Neoplasias Ováricas/patología , Adenocarcinoma Mucinoso/diagnóstico , Proteínas Represoras/metabolismoRESUMEN
Primary ovarian mucinous tumors represent a heterogeneous group of neoplasms, and their diagnosis may be challenging. We analyzed 124 primary ovarian mucinous tumors originally diagnosed as mucinous borderline tumors (MBTs) or mucinous carcinomas (MCs), with an emphasis on interobserver diagnostic agreement and the potential for diagnostic support by molecular profiling using a next-generation sequencing targeted panel of 727 DNA and 147 RNA genes. Fourteen experienced pathologists independently assigned a diagnosis from preset options, based on a review of a single digitized slide from each tumor. After excluding 1 outlier participant, there was a moderate agreement in diagnosing the 124 cases when divided into 3 categories (κ = 0.524, for mucinous cystadenoma vs MBT vs MC). A perfect agreement for the distinction between mucinous cystadenoma/MBT as a combined category and MC was found in only 36.3% of the cases. Differentiating between MBTs and MCs with expansile invasion was particularly problematic. After a reclassification of the tumors into near-consensus diagnostic categories on the basis of the initial participant results, a comparison of molecular findings between the MBT and MC groups did not show major and unequivocal differences between MBTs and MCs or between MCs with expansile vs infiltrative pattern of invasion. In contrast, HER2 overexpression or amplification was found only in 5.3% of MBTs and in 35.3% of all MCs and in 45% of MCs with expansile invasion. Overall, HER2 alterations, including mutations, were found in 42.2% of MCs. KRAS mutations were found in 65.5% and PIK3CA mutations in 6% of MCs. In summary, although the diagnostic criteria are well-described, diagnostic agreement among our large group of experienced gynecologic pathologists was only moderate. Diagnostic categories showed a molecular overlap. Nonetheless, molecular profiling may prove to be therapeutically beneficial in advanced-stage, recurrent, or metastatic MCs.
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Adenocarcinoma Mucinoso , Cistoadenoma Mucinoso , Neoplasias Quísticas, Mucinosas y Serosas , Neoplasias Ováricas , Humanos , Femenino , Cistoadenoma Mucinoso/patología , Reproducibilidad de los Resultados , Neoplasias Ováricas/diagnóstico , Neoplasias Ováricas/genética , Neoplasias Ováricas/patología , Adenocarcinoma Mucinoso/diagnóstico , Adenocarcinoma Mucinoso/genética , Adenocarcinoma Mucinoso/patologíaRESUMEN
The goal of this manuscript is to provide an overview of the significance of immunohistochemical methods in diagnosing endometrial carcinoma. The main points discussed include: the use of immunohistochemistry in the differential diagnosis of the main histological types of endometrial carcinoma, the difference between primary serous endometrial carcinoma and the involvement with high grade serous carcinoma of another primary source, the diagnosis of undifferentiated/dedifferentiated endometrial carcinoma, and diagnosing tumours with neuroendocrine differentiation. The role of p53 expression evaluation is also emphasized as a special area of interest, not only in the context of differential diagnosis, but also from the point of view of the prognosis and prediction of endometrial carcinoma as an ancillary marker for subtypization of these tumours.
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Carcinoma Endometrioide , Neoplasias Endometriales , Biomarcadores de Tumor , Carcinoma Endometrioide/diagnóstico , Diagnóstico Diferencial , Neoplasias Endometriales/diagnóstico , Femenino , Humanos , InmunohistoquímicaRESUMEN
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.
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Neoplasias Endometriales , Sarcoma Estromático Endometrial , Biomarcadores de Tumor , ADN Helicasas , Femenino , Humanos , Proteínas Nucleares , Factores de TranscripciónRESUMEN
Evaluation of tumor infiltrating lymphocytes (TIL) is gaining importance in many cancers not only because of their prognostic, but also predictive significance. One of the tumors in which the evaluation of TIL is of prognostic importance and has potential predictive impact on the modification of treatment procedures is breast cancer, especially its so-called triple negative, and HER2 positive variants.The aim of this review is to provide an overview of the issue of TIL evaluation in breast cancer, focusing not only on the clinical significance of this evaluation, but especially on the methodological aspects of evaluation and standardized reporting of the results.
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Neoplasias de la Mama , Neoplasias de la Mama Triple Negativas , Neoplasias de la Mama/diagnóstico , Femenino , Humanos , Linfocitos Infiltrantes de Tumor , Pronóstico , Receptor ErbB-2RESUMEN
Hereditary tumor syndromes with a possible manifestation in the female internal genital tract represent a heterogeneous group of diseases. The two most common entities are the hereditary breast and ovarian cancer syndrome, and the Lynch syndrome. The less common syndromes include the rhabdoid tumor predisposition syndrome, Cowden syndrome, tuberous sclerosis complex, DICER1 syndrome, nevoid basal cell carcinoma syndrome, Peutz-Jeghers syndrome, von Hippel-Lindau disease, and hereditary leiomyomatosis and renal cell cancer syndrome. The goal of this manuscript is to provide a comprehensive overview of those hereditary tumor syndromes which can manifest in the area of the female genital system, with an emphasis on their summary, the characteristics of the tumors which can develop in association with these syndromes, and the approach to the processing of prophylactically removed tissues and organs. The issue of Lynch syndrome screening is also discussed.
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Neoplasias Colorrectales Hereditarias sin Poliposis , Neoplasias Renales , Leiomiomatosis , Síndromes Neoplásicos Hereditarios , Neoplasias Colorrectales Hereditarias sin Poliposis/genética , ARN Helicasas DEAD-box , Femenino , Predisposición Genética a la Enfermedad , Humanos , Síndromes Neoplásicos Hereditarios/genética , Ribonucleasa IIIRESUMEN
We report a case of a 58-year-old female with microscopic extraovarian sex cord proliferations affecting both Fallopian tubes. Molecular analysis showed likely pathogenic germline missense mutations of the KDM5A and KMT2D genes. However, mutations of other genes, including FOXL2 and STK11, were not detected. Our case represents the 12th case of extraovarian sex cord proliferation reported in the literature to date. This is the first time that a molecular genetic analysis of the lesion has been performed, and it showed a wild-type FOXL2 gene, which represents another argument supporting the estimated benign nature of these rare lesions.
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Neoplasias Ováricas , Tumores de los Cordones Sexuales y Estroma de las Gónadas , Proliferación Celular , Trompas Uterinas , Femenino , Humanos , Persona de Mediana Edad , Mutación , Neoplasias Ováricas/genética , Tumores de los Cordones Sexuales y Estroma de las Gónadas/genéticaRESUMEN
We are reporting a case of endometrial lymphoepithelioma-like carcinoma (LELC) in a 63-year-old female. Microscopically, the tumor consisted of groups of tumor cells surrounded by dense lymphoplasmacytic infiltrate. Immunohistochemically, the tumour cells were positive for cytokeratins AE1/AE3, EMA, PAX8, p16, and estrogen receptors. Protein p53 showed an aberrant type of expression. Molecular genetic analysis revealed mutations in the TP53 and PIKP53CA genes. Based on our results, we believe that the tumor represents an unusual morphological variant of endometrial serous carcinoma.To the best of our knowledge, only six cases of LELC arising in endometrium have been reported in literature to date.
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Biomarcadores de Tumor/análisis , Biomarcadores de Tumor/genética , Carcinoma/química , Carcinoma/genética , Neoplasias Endometriales/química , Neoplasias Endometriales/genética , Inmunohistoquímica , Técnicas de Diagnóstico Molecular , Biopsia , Carcinoma/patología , Carcinoma/terapia , Fosfatidilinositol 3-Quinasa Clase I/genética , Neoplasias Endometriales/patología , Neoplasias Endometriales/terapia , Femenino , Humanos , Persona de Mediana Edad , Estadificación de Neoplasias , Valor Predictivo de las Pruebas , Resultado del Tratamiento , Proteína p53 Supresora de Tumor/análisis , Proteína p53 Supresora de Tumor/genéticaRESUMEN
The evaluation of inflammatory infiltrate (tumor infiltrating lymphocytes - TIL) should be a standard part of biopsy examination for malignant melanoma. Currently, the most commonly used assessment method according to Clark is not optimal and there have been attempts to find an alternative system. Here we present an overview of possible approaches involving five different evaluation methods based on hematoxylin-eosin staining, including the recent suggestion of unified TIL evaluation method for all solid tumors. The issue of methodology, prognostic and predictive significance of TIL determination as well as the importance of immunohistochemical subtyping of inflammatory infiltrate is discussed.
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Linfocitos Infiltrantes de Tumor , Melanoma , Neoplasias Cutáneas , Biopsia , Humanos , Melanoma/inmunología , Melanoma/terapia , Pronóstico , Neoplasias Cutáneas/inmunología , Neoplasias Cutáneas/terapiaRESUMEN
We report the case of a 54-year-old female with dedifferentiated carcinoma of the ovary. Grossly, both ovaries were affected by a tumor of up to 25 mm (right ovary) and 220 mm (left ovary) in diameter. Microscopically, the tumors of both ovaries showed features of well differentiated endometrioid carcinoma with mucinous differentiation. Moreover, in the left ovary there was an undifferentiated solid component consisting of larger cells. Immunohistochemically, the undifferentiated component showed diffuse vimentin positivity and focal expression of cytokeratin 18. Other markers examined including PAX8, estrogen receptors and progesterone receptors were all negative. Dedifferentiated carcinomas consist of an undifferentiated epithelial component and a component of endometrioid carcinoma of FIGO grade 1 or 2. Clinically, they represent aggressive tumors with unfavorable prognosis mostly occurring in the endometrium. To the best of our knowledge, thus far only 6 cases arising in the ovary have been reported in the literature.
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Carcinoma Endometrioide , Neoplasias Ováricas , Biomarcadores de Tumor , Carcinoma Endometrioide/diagnóstico , Carcinoma Endometrioide/cirugía , Femenino , Humanos , Inmunohistoquímica , Persona de Mediana Edad , Neoplasias Ováricas/diagnóstico , Neoplasias Ováricas/cirugíaRESUMEN
Here we report on the case of a 61-year-old female with an accidental finding of intravascular fasciitis (IVF) affecting the ascending aorta in a specimen resected due to an acute aortic dissection. No infiltrative process of the aorta or surrounding soft tissues was grossly apparent. Microscopically, the lesion had poorly defined margins and was composed of plump spindle- and oval-shaped cells set in an abundant myxoid stroma. Immunohistochemically, cytoplasmic positivity for ß-catenin was observed and about 25% of cells were positive for calponin. The Ki-67 index was approximately 25% (increasing to about 50% in hot spot areas). Occasional isolated cells also showed positivity for alpha actin. Other markers were all negative in the tumor cells including; smooth muscle actin, desmin, h-caldesmon, D2-40, DOG1, S100 protein, CD34, CD31, ERG, melan A, HMB45, IgG, IgG4, ALK, cytokeratin AE1/AE3, and LCA. Intravascular fasciitis is a benign myofibroblastic proliferation which most commonly occurs in subcutaneous tissues and may mimic malignancy. To the best of our knowledge this is only the 2nd ever reported case of IVF affecting the aorta. Keywords: intravascular fasciitis - nodular fasciitis - soft tissue lesions - myofibroblasts - aorta.
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Disección Aórtica , Fascitis , Disección Aórtica/etiología , Fascitis/complicaciones , Femenino , Humanos , Persona de Mediana EdadRESUMEN
Penile squamous cell carcinoma (pSCC) is a rare tumour with a variable prognosis. More prognostic markers linked to mutational signatures and the tumour immune microenvironment are needed. A cohort made up of 165 invasive pSCC was retrospectively analysed using formalin-fixed, paraffin-embedded tumour tissue, focusing on tumour mutational burden (TMB), programmed death ligand 1 (PD-L1) expression, microsatellite instability (MSI), the number of tumour infiltrating lymphocytes (TILs) expressing cytotoxic T-lymphocyte-associated protein 4 (CTLA4), HPV status determined by p16 immunohistochemistry, and several traditional histopathological variables. High TMB (>10 mut/Mb) was associated with high PD-L1 expression (TPS 50-100%), and HPV-negative status. High PD-L1 expression was linked to HPV negativity, a high number of intratumoural CTLA4+ cells, and brisk lymphocytic infiltrate. High TMB was a significant predictor of shorter overall survival (OS) in both univariate and multivariate analysis when using a median cut-off value of 4.3 mut/Mb, but not when using an arbitrary cut-off of 10 mut/Mb. Low CTLA4+ cell infiltration at the tumour invasion front was a marker of shorter OS and cancer-specific survival in both univariate and multivariate analysis. PD-L1 expression had no significant impact on prognosis. Only two cases were MSI high. The results support the hypothesis of two aetiological pathways in pSCC cancerogenesis: (1) SCC linked to HPV infection characterised by low TMB, less common PD-L1 expression, and a lower number of TILs; and (2) SCC linked to chronic inflammation leading to a high number of acquired mutations (high TMB), HPV negativity, increased neoantigen production (i.e., PD-L1), and high immune cell infiltration.
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Carcinoma de Células Escamosas , Infecciones por Papillomavirus , Neoplasias del Pene , Masculino , Humanos , Antígeno B7-H1/metabolismo , Antígeno CTLA-4 , Infecciones por Papillomavirus/complicaciones , Estudios Retrospectivos , Neoplasias del Pene/genética , Microambiente TumoralRESUMEN
CONTEXT.: Non-smooth muscle uterine sarcomas are mostly represented by low-grade endometrial stromal sarcoma. However, several other rare, distinct types of uterine sarcoma are recognized, including high-grade endometrial stromal sarcoma, tumors with kinase fusions, uterine tumors resembling ovarian sex cord tumors, soft tissue-type sarcoma, and emerging entities such as KAT6A/B-rearranged tumors. The landscape of uterine sarcomas has changed, mostly because of the increasing knowledge concerning their molecular aberrations. OBJECTIVE.: To offer a comprehensive review of the literature focusing on fusions occurring in other than smooth muscle mesenchymal uterine tumors with respect to their type, frequency, and overlap between diagnostic categories and entities. DATA SOURCES.: The data were mined from the PubMed/MEDLINE database covering the time period from January 1988 to June 2023. In total, 156 studies focusing on the problematics of fusions occurring in non-smooth muscle mesenchymal uterine tumors were selected, and thus became the basis for this review. CONCLUSIONS.: One hundred ten fusions were identified in 703 tumors. The diagnostic significance of the molecular aberrations occurring in these tumors can be unclear in some cases. This can be related to the rare aberrations with a limited number of reported cases. Additionally, even well-known aberrations considered as specific for a certain distinct entity can occur in more lesions, the biological behavior and clinical significance of which can differ substantially.
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The current knowledge about the immunohistochemical features of adult granulosa cell tumor (AGCT) is mostly limited to the "traditional" immunohistochemical markers of sex cord differentiation, such as inhibin, calretinin, FOXL2, SF1, and CD99. Knowledge about the immunohistochemical markers possibly used for predictive purpose is limited. In our study, we focused on the immunohistochemical examination of 290 cases of AGCT classified based on strict diagnostic criteria, including molecular testing. The antibodies used included 12 of the "diagnostic" antibodies already examined in previous studies, 10 antibodies whose expression has not yet been examined in AGCT, and 7 antibodies with possible predictive significance, including the expression of HER2, PD-L1, CTLA4, and 4 mismatch repair (MMR) proteins. The results of our study showed expression of FOXL2, SF1, CD99, inhibin A, calretinin, ER, PR, AR, CKAE1/3, and CAIX in 98%, 100%, 90%, 78%, 45%, 41%, 94%, 82%, 26%, and 9% of AGCT, respectively. GATA3, SATB2, napsin A, MUC4, TTF1, and CD44 were all negative. PTEN showed a loss of expression in 71% of cases and DPC4 in 4% of cases. The aberrant staining pattern (overexpression) of p53 was found in 1% (3/268) of cases, 2 primary tumors, and 1 recurrent case. Concerning the predictive markers, the results of our study showed that AGCT is microsatellite stable, do not express PD-L1, and are HER2 negative. The CTLA4 expression was found in almost 70% of AGCT tumor cells.
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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.
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Compuestos Azo , Cistadenocarcinoma Seroso , Neoplasias Ováricas , Femenino , Humanos , Proteínas Proto-Oncogénicas B-raf/genética , Cistadenocarcinoma Seroso/diagnóstico , Cistadenocarcinoma Seroso/genética , Neoplasias Ováricas/diagnóstico , Neoplasias Ováricas/genética , Mutación , Perfilación de la Expresión Génica , Genómica , ARN , Clasificación del Tumor , Ubiquitina Tiolesterasa/genéticaRESUMEN
BACKGROUND: Clear cell (hemangioblastoma-like) stromal tumor of the lung (CCSTL) is a rare pulmonary neoplasm. Recently, 9 cases of CCSTL harboring the YAP1-TFE3 gene fusion have been described, and it has been suggested that this aberration could be a characteristic feature of this tumor. CASE PRESENTATION: We here report another case of CCSTL in a 57-year-old male, which presented as a solitary lung nodule 45 mm in the greatest dimension. Microscopically, the tumor consisted of epithelioid to spindled cells with mild-to-moderate nuclear atypia, finely granular or vesicular chromatin, and small nucleoli. Nuclear indentations were a common finding. There were up to 3 mitoses per 10 HPF. The cytoplasm was slightly eosinophilic or clear. Scattered non-tumor large multinucleated cells were present. Immunohistochemically, the tumor cells showed diffuse positivity for TFE3, CD10, vimentin, and IFITM1. Other markers examined were negative, and the expression of lineage-specific markers was not found. NGS analysis revealed a fusion transcript of the YAP1 and TFE3 genes, and a pathogenic variant of the MUTYH gene. CONCLUSION: Our finding supports the recent data suggesting that CCSTL represents a distinct entity characterized by the recurrent YAP1-TFE3 fusion.
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Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice , Neoplasias Pulmonares , Masculino , Humanos , Persona de Mediana Edad , Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice/genética , Pulmón , Fusión Génica , Células Gigantes/química , Neoplasias Pulmonares/genética , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/análisisRESUMEN
Penile squamous cell carcinoma (pSCC) is a rare malignancy with a slowly increasing incidence and variable prognosis. Regional lymph node involvement signifies poor prognosis but represents a late sign, and more prognostic markers for effective patient risk stratification are urgently needed. In this retrospective study, 152 tumour samples with formalin-fixed, paraffin-embedded tissue were analysed for traditional pathological variables, tumour budding, p53, p16, and mismatch repair proteins (MMR) immunohistochemistry. The density of tumour lymphocytic infiltrate was also determined, using subjective evaluation by two pathologists (brisk/non-brisk/absent) and also using the immunoscore method, which categorised the cohort into five immunoscore groups according to the number of CD3+ and CD8+ T-cells in both the tumour centre and tumour invasion front. Only one case (0.6%) was MMR-deficient. Tumour budding count ≥5 tumour buds/20× power field and non-brisk/absent lymphocytic infiltrate were significant negative predictors of both the overall survival (OS) and cancer-specific survival (CSS), whereas a low immunoscore was a significant marker of shorter OS but not CSS. Advanced pT stage (3+4) was a significant marker of shorter CSS but not OS. In the multivariate analysis, high-grade budding was a significant parameter if adjusted for the patient's age and associated variables, except for the pN stage. The lymphocytic infiltrate retained its prognostic significance if adjusted for age and associated variables. The negative prognostic significance of the previously described parameters (lymphatic, venous, and perineural invasion, regional lymph node metastasis, and p53 mutated profile) were confirmed in our study. Grade, histological subtype, and HPV status (as determined by p16 immunohistochemistry) showed, surprisingly, little or no prognostic significance.
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Carcinoma de Células Escamosas , Neoplasias del Pene , Masculino , Humanos , Estudios Retrospectivos , Proteína p53 Supresora de Tumor/metabolismo , Carcinoma de Células Escamosas/patología , Pronóstico , Neoplasias del Pene/patología , InflamaciónRESUMEN
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.
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Cistadenocarcinoma Seroso , Neoplasias Ováricas , Humanos , Femenino , Antígeno Ki-67 , Proteína p53 Supresora de Tumor , Neoplasias Ováricas/diagnóstico , Cistadenocarcinoma Seroso/diagnósticoRESUMEN
Three main uterine leiomyoma molecular subtypes include tumors with MED12 mutation, molecular aberrations leading to HMGA2 overexpression, and biallelic loss of FH. These aberrations are mutually exclusive and can be found in approximately 80-90% of uterine leiomyoma, in which they seem to be a driver event. Approximately 10% of uterine leiomyoma, however, does not belong to any of these categories. Uterine leiomyoma with HMGA2 overexpression is the most common subtype in cellular and second most common category of usual leiomyoma. In some of these tumors, rearrangement of HMGA2 gene is present. The most common fusion partner of HMGA2 gene is RAD51B. Limited data suggests that RAD51B fusions with other genes may be present in uterine leiomyoma. In our study, we described two cases of uterine leiomyoma with RAD51B::NUDT3 fusion, which occur in one case of usual and one case of highly cellular leiomyoma. In both cases, no other driver molecular aberrations were found. The results of our study showed that RAD51::NUDT3 fusion can occur in both usual and cellular leiomyoma. RAD51B may be a fusion partner of multiple genes other than HMGA2 and HMGA1. In these cases, RAD51B fusion seems to be mutually exclusive with other driver aberrations defining molecular leiomyoma subtypes. RAD51B::NUDT3 fusion should be added to the spectrum of fusions which may occur in uterine leiomyoma, which can be of value especially in cellular leiomyoma in the context of differential diagnosis against endometrial stromal tumors.
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Ovarian clear cell carcinoma (OCCC) is a subtype of ovarian carcinoma characterized by unique biological features and highly malignant characteristics including low chemosensitivity. Therefore, new therapeutic targets are needed. These could include the downstream pathways of receptor tyrosine kinases, especially the human epidermal growth factor receptor 2 (HER2). Our main objective was to characterize the HER2 status using immunohistochemistry (IHC) and FISH on 118 OCCCs, also considering the novel paradigm of HER2-zero and HER2-low status. Other aims included determination of the association between HER2 status and survival, HER2 gene DNA and RNA NGS analysis, HER2 gene expression analysis, and correlation between IHC and gene expression in HER2-zero and HER2-low cases. Cases with HER2 overexpression/amplification accounted for 5.1% (6/118), with additional 3% harbouring HER2 gene mutation. The remaining 112 (94.9%) cases were HER2-negative. Of these, 75% were classified as HER2-zero and 25% as HER2-low. This percentage of HER2 aberrations is significant concerning their possible therapeutic influence. Cases from the HER2-zero group showed significantly better survival. Although this relationship lost statistical significance in multivariate analysis, the results have potential therapeutic significance. HER2 gene expression analysis showed a significant correlation with HER2 IHC status in the entire cohort (HER2-positive vs. HER2-negative), while in the cohort of only HER2-negative cases, the results did not reach statistical significance, suggesting that gene expression analysis would not be suitable to confirm the subdivision into HER2-low and HER2-zero. Our results also emphasize the need for standardized HER2 testing in OCCC to determine the best predictor of clinical response.