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The successful experiences of HER2 inhibitors in patients with HER2 ( +) breast cancer (BC) and advanced gastroesophageal adenocarcinoma (GEA) have encouraged us to continuously explore the HER2 status and its potential as a therapeutic target in primary mucinous ovarian carcinoma (mOC). Using 49 primary mOC samples, we compared the assay characteristics of HER2 status between both 2017 American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) for GEA and 2018 ASCO/CAP for BC guideline recommendations. We demonstrated moderate to strong agreement between their HER2 IHC results (Weighted Kappa = 0.78) and perfect agreement between their HER2 FISH results (Kappa = 1.00). The overall concordance of non-equivocal HER2 IHC and HER2 FISH results was 97.56% (kappa = 0.93) by 2017 ASCO/CAP for GEA criteria and 100% (kappa = 1.00) by 2018 ASCO/CAP for BC criteria. The number (n = 8; 16.32%) of HER2 IHC equivocal (score + 2) by 2017 ASCO/CAP for GEA criteria was twofold higher than that (n = 4; 8.16%) by 2018 ASCO/CAP for BC criteria. Additionally, we identified one false-positive (FP) case (n = 1; 2.04%) that was HER2 IHC positive (score + 3), but HER2 FISH non-amplified result by the 2017 ASCO/CAP for GEA criteria. In conclusion, owing to the absence of FP/ FN and fewer equivocal cases of HER2 IHC, we recommend that the 2018 ASCO/CAP for BC are more appropriate than 2017 ASCO/CAP for GEA criteria in appraising the HER2 status in mOC and justifying the inclusion of eligible subjects for basket clinical trials of the newly developmental anti-HER2 treatments., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background/aim: Mucinous ovarian carcinoma (mOC) is a rare subtype with distinct clinical characteristics and biological behavior that differentiate them from other epithelial ovarian cancers. This study aimed to evaluate BMI-1 expression as a potential target for therapeutic approaches in advanced stage mOC., Materials and Methods: We performed gene set, as well as transcription factor enrichment analysis and immunohistochemistry assessing of the BMI-1 protein levels in tissue specimens of eighteen mucinous ovarian cancer patients. To validate the clinical relevance of the findings, we performed cell viability assays and western blot analysis utilizing high-grade serous (HGSC) and mOC cell lines., Results: BMI1 expression was not significantly associated with patient age, FIGO stage, lymph node status, and family history. With regard to progression-free survival, there was also no significant association (p=0.418). Cell viability was significant decreased in response to carboplatin in HGSC cells TYK-nu and OVHASO, and in mOC cell lines COV644 and EFO-27. Western blot analysis demonstrated various expression levels across all cell lines., Conclusion: BMI-1 could be a useful potential therapeutic target in some ovarian cancer patients, including mOC patients., (Copyright © 2022 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Opinion Statement: Complete surgical resection is the gold-standard treatment for all mucinous ovarian carcinoma (MOC) cases. Advanced-stage disease is often additionally treated with adjuvant platinum-based chemotherapy; however, these were developed largely against the more common high-grade serous ovarian carcinoma and have low efficacy in treating MOC. More effective therapeutics are needed to treat late-stage and platinum-resistant tumors; however, traditional drug development and clinical trial paradigms are a major challenge for such a rare disease. New approaches to support evidence-based treatment decisions are required, such as registry trials. Recently, a number of targeted therapies have emerged as viable treatment options in other cancer types, and for some of these, the actionable tumor mutations are also seen in MOC. Thus, a promising alternative approach to provide benefit to current MOC patients involves DNA sequencing to identify a tumor's unique mutational profile and allow matching to available targeted agents. Such a pipeline can involve special approval to administer a drug already approved for clinical use in other cancer types to a given MOC patient, or their inclusion in existing ongoing clinical trials, such as basket trials encompassing patients with tumors from a range of anatomical sites. Implementation of such personalized medicine can be boosted using improved pre-clinical models, where through a clinical research collaboration a patient's own tumor cells can be used to a test a range of putative therapies prior to administration in the clinic, enabling selection of the available pharmaceutical/s that give any given patient the best possible chance of cancer remission., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objective: Considering the clinical evidence of BRAF inhibitors that can treat melanoma patients successfully, we aimed to investigate the status of BRAF mutations of primary mucinous ovarian carcinomas (MOC) in Taiwanese women, and apply the emerging paradigm classification of BRAF mutation groups., Materials and Methods: 20 archived primary MOC samples were analyzed. The BRAF mutations of activation segment (exon 15), CR3 (conserved regions 3), kinase domain of the BRAF gene were analyzed using the highly sensitive BRAF mutant enriched kit (FemtoPath®) with Sanger sequencing method. Additionally, we extended our prior reported data of HER2 aberrations and KRAS mutation into this study in order to compare with the status of BRAF mutation., Results: Of them (n = 20), 16 (80%) harbored BRAF missense mutations. Their mutation profile and case number (n) were categorized as (1) class I: V600E (n=1), V600M (n = 1); (2) class II: A598V (n = 1), T599I (n = 10); (3) class III: none (n = 0); and (4) unclassified variants: S602F (n = 2), T599I/S602F (n = 1). The BRAF S602F is novel. The prevalence of BRAF mutation is significantly higher than either HER2 mutation (80% vs. 35%; p = 0.022) or HER2 amplification (80% vs. 35%; p = 0.022). However, the mutation rates of BRAF and KRAS were not significantly different (80% vs. 60%; p = 0.289)., Conclusion: Activating BRAF mutation, HER2 amplification, HER2 mutation and KRAS mutation were not mutually exclusive. However, they may even have a synergistic effect in tumorigenesis. BRAF mutation is not uncommon in primary MOC of Taiwanese. The BRAF mutant (T599I) stands the majority. We suggested that there was a lower potential response to the existing V600 BRAF inhibitors, but may be responsive to dual BRAF plus MEK inhibitors or single MEK inhibitor. Further studies are warranted to investigate the clinical benefits of newly targeted therapy in recurrent or advanced stage primary MOC patients carrying different classes of BRAF mutation., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2021. Published by Elsevier B.V.)

Primary mucinous ovarian carcinomas (MOC) are notoriously difficult to distinguish from mucinous carcinomas metastatic to the ovary (mMC). Studies performed on small cohorts reported algorithms based on tumor size and laterality to aid in distinguishing MOC from mMC. We evaluated and improved these by performing a large-scale, nationwide search in the Dutch Pathology Registry. All registered pathology reports fulfilling our search criteria concerning MOC in the Netherlands from 2000 to 2011 were collected. Age, histology, laterality, and size were extracted. An existing database covering the same timeline containing tumors metastatic to the ovary was used, extracting all mMC, age, size, laterality, and primary tumor location. Existing algorithms were applied to our cohort. Subsequently, an algorithm based on tumor histology, laterality, and a nomogram based on age and size was created for differentiating MOC and mMC. We identified 735 MOC and 1018 mMC. Patients with MOC were significantly younger and MOC were significantly larger and more often unilateral than mMC. Signet ring cell carcinomas were rarely primary. Our algorithm used signet ring cell histology, bilaterality, and a nomogram integrating patient age and tumor size to diagnose mMC. Sensitivity and specificity for mMC was 90.1% and 59.0%, respectively. Applying existing algorithms on our cohort yielded a far lower sensitivity. The algorithm described here using tumor histology, laterality, size, and patient age has higher sensitivity but lower specificity compared to earlier algorithms and aids in indicating tumor origin, but for conclusive diagnosis, careful integration of morphology, immunohistochemistry, and clinical and imaging data is recommended.

Mucinous type of epithelial ovarian cancer (MuOC) is a unique subtype with a poor survival outcome in recurrent and advanced stages. The role of type-specific epigenomics and its clinical significance remains uncertain. We analyzed the methylomic profiles of 6 benign mucinous adenomas, 24 MuOCs, 103 serous type of epithelial ovarian cancers (SeOCs) and 337 nonepithelial ovarian cancers. MuOC and SeOC exhibited distinct DNA methylation profiles comprising 101 genes, 81 of which exhibited low methylation in MuOC and were associated with the response to glucocorticoid, ATP hydrolysis-coupled proton transport, proteolysis involved in the cellular protein catabolic process and ion transmembrane transport. Hierarchical clustering analysis showed that the profiles of MuOC were similar to colorectal adenocarcinoma and stomach adenocarcinoma. Genetic interaction network analysis of differentially methylated genes in MuOC showed a dominant network module is the proteasome subunit beta (PSMB) family. Combined functional module and methylation analysis identified PSMB8 as a candidate marker for MuOC. Immunohistochemical staining of PSMB8 used to validate in 94 samples of ovarian tumors (mucinous adenoma, MuOC or SeOC) and 62 samples of gastrointestinal cancer. PSMB8 was commonly expressed in MuOC and gastrointestinal cancer samples, predominantly as strong cytoplasmic and occasionally weak nuclei staining, but was not expressed in SeOC samples. Carfilzomib, a second-generation proteasome inhibitor, suppressed MuOC cell growth in vitro. This study unveiled a mucinous-type-specific methylation profile and suggests the potential use of a proteasome inhibitor to treat MuOC., (© 2018 The Authors International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Objective: Mucinous ovarian carcinoma (MOC) is an uncommon subtype of epithelial ovarian cancers, and the pathogenesis is still poorly understood because of its rarity. We conducted a gene set-based analysis to investigate the pathogenesis of MOC by integrating microarray gene expression datasets based on the regularity of functions defined by gene ontology or canonical pathway databases., Materials and Methods: Forty-five pairs of MOC and normal ovarian tissue sample gene expression profiles were downloaded from the National Center for Biotechnology Information Gene Expression Omnibus database. The gene expression profiles were converted to the gene set regularity indexes by measuring the change of gene expression ordering in a gene set. Then the pathogenesis of MOC was investigated with the differences of function regularity with the gene set regularity indexes between the MOC and normal control samples., Results: The informativeness of the gene set regularity indexes was sufficient for machine learning to accurately recognize and classify the functional regulation patterns with an accuracy of 99.44%. The statistical analysis revealed that the GTPase regulators and receptor tyrosine kinase erbB-2 (ERBB2) were the most important aberrations; the exploratory factor analysis revealed phosphoinositide 3-kinase-activating kinase, G-protein coupled receptor pathway, oxidoreductase activity, immune response, peptidase activity, regulation of translation, and transport and channel activity were also involved in the pathogenesis of MOC., Conclusion: Investigating the pathogenesis of MOC with the functionome provided a comprehensive view of the deregulated functions of this disease. In addition to GTPase regulators and ERBB2, a plenty of deregulated functions such as phosphoinositide 3-kinase, G-protein coupled receptor pathway, and immune response also participated in the interaction network of MOC pathogenesis., (Copyright © 2017. Published by Elsevier B.V.)

Background: The proportion of women with mucinous ovarian carcinoma in whom nodal metastases are identified during staging remains unclear., Objectives: To review the literature on surgical lymph node assessment during staging of women diagnosed with mucinous ovarian carcinoma., Search Strategy: A systematic search using synonyms of 'mucinous ovarian carcinoma' and 'lymph node assessment' was conducted in PubMed, Scopus, Embase and the Cochrane Library., Selection Criteria: When they covered ten or more mucinous ovarian carcinoma cases, staging surgery and minimally one of the following outcomes: prevalence of metastases, stage shift or survival data., Data Collection and Analysis: Studies were quality evaluated with the Cochrane risk-of-bias assessment tool for non-randomised studies of interventions. Outcomes were pooled using an inverse variance weighted random effects model., Main Results: Sixteen studies were included. In 278 women with mucinous ovarian cancer suspected to be stage I-II, a pooled proportion of 0.8% (95% CI <0.1-2.9%) had lymph node metastases and were upstaged. In those suspected of stage I (n = 184), this proportion was 0.7% (95% CI <0.1-3.8%). No difference (P = 0.287) was found in metastases between sampling at 0.0% (95% CI 0.0-3.3%) and complete pelvic and/or para-aortic lymph node dissection at 1.2% (95% CI <0.1-4.2%). One study directly compared the survival of patients staged with and without lymph node dissection and reported no significant difference., Conclusions: Surgical lymph node assessment in women suspected of stage I-II mucinous ovarian carcinoma rarely identifies nodal metastases and consequently has no significant impact on staging., Tweetable Abstract: Surgical lymph node assessment in women with stage I-II mucinous ovarian cancer rarely has staging consequences., (© 2016 Royal College of Obstetricians and Gynaecologists.)

Objective: The use of lymph node sampling during staging procedures in clinical early-stage mucinous ovarian carcinoma (MOC) is an ongoing matter of debate. Furthermore, the incidence of lymph node metastases (LNM) in MOC in relation to tumour grade (G) is unknown. We aimed to determine the incidence of LNM in clinical early-stage MOC per tumour grade., Design: Retrospective study with data from the Dutch Pathology Registry (PALGA)., Setting: The Netherlands, 2002-2012., Population or Sample: Patients with MOC., Methods: Histology reports on patients with MOC diagnosed in the Netherlands between 2002 and 2012 were obtained from PALGA. Reports were reviewed for diagnosis, tumour grade and presence of LNM. Clinical data, surgery reports and radiology reports of patients with LNM were retrieved from hospital files., Main Outcome Measures: Incidence of LNM, disease-free survival (DFS)., Results: Of 915 patients with MOC, 426 underwent lymph node sampling. Cytoreductive surgery was performed in 267 patients. The other 222 patients received staging without lymph node sampling. In eight of 426 patients, LNM were discovered by sampling. In four of 190 (2.1%) patients with G1 MOC, LNM were present, compared with one of 115 (0.9%) patients with G2 MOC and three of 22 (13.6%) patients with G3 MOC. Tumour grade was not specified in 99 patients. Patients with clinical early-stage MOC had no DFS benefit from lymph node sampling., Conclusions: LNM are rare in early-stage G1 and G2 MOC without clinical suspicion of LNM. Therefore, lymph node sampling can be omitted in these patients., Tweetable Abstract: Lymph node sampling can be omitted in clinical early-stage G1 and G2 mucinous ovarian cancer., (© 2016 Royal College of Obstetricians and Gynaecologists.)

Ovarian cancer is the most common cause of gynecologic cancer death. Both morphologically and immunohistochemically, metastatic mucinous tumors are the best mimickers of mucinous ovarian tumors; its pathogenesis still remains a mystery. PAX2 and PAX8 immunohisyochemistries are useful for differentiating numerous primary tumour types from metastatic ones. There are few studies in literature about PAX expressions in mucinous and seromucinous tumors. None of these are takes into account the histologic type (whether it is seromucinous or mucinous) or the metastatic origin. With this purpose hematoxylin and eosine slides of ovarian mucinous and seromucinous tumors were re-evaluated and one block was chosen for each case. The study included 76 ovarian mucinous and seromucinous tumors of the ovary reported in Hacettepe University department of pathology between 2000 and 2013. Tissue microarray (TMA) was designed from the chosen blocks, PAX2, PAX8, CDX2 immunostains was preformed to the TMA slides. As a result, most of the metastatic cases were negative for PAX2 (91.2 %) and PAX8 (86.3 %), many were diffusely and strongly positive for CDX2 (68.2 %). Seromucinous tumors were devoid of CDX2 expression; but all cases (except one) displayed strong and diffuse positivity with PAX8. In other words differing from mucinous tumors, seromucinous tumors show strong PAX8 positivity-similar to serous tumors. This study shows that PAX8 and CDX2 could be useful in differentiating primary mucinous from metastatic tumor. Furthermore unlike the homogeneity in seromucinous tumors for PAX8 and CDX2 mucinous tumors shows heterogeneity with different expression patterns.