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Ovarian mucinous tumors with sarcomatous mural nodules are rare. Sarcomatous nodules have a bad prognosis. Its diagnosis and treatment are controversial.It is still controversial whether malignant mural nodules represent a dedifferentiated form of mucinous tumors or collisional tumors. This is a case report of a 32-year-old female diagnosed with ovarian mucinous tumor recurred as a mucinous carcinoma combined with sarcomatoid and undifferentiated sarcoma mural nodules after surgery and chemotherapy. The primary lesion did not have a sarcomatous component after comprehensive sampling and repeated review, while the recurrent lesion had a predominantly sarcomatous component. The patient received a second operation and postoperative chemotherapy plus Anlotinib with no progression at 16 months of follow-up. Primary mucinous carcinoma and sarcomatous mural nodules revealed the same K-RAS mutation(c.35G>T, pG12V), TP53 mutation (c.817C>T, p.R273C), MLL2 mutation(c.13450C>T, p.R4484) and NF1 mutation(c.7876A>G, p.S2626G). We present a comprehensive analysis on morphologic characteristics, molecular detection results, clinical management, and prognosis of ovarian mucinous tumors with mural nodules of sarcomatoid and undifferentiated sarcoma. Mutation sharing between primary mucinous carcinoma and recurrent sarcomatous nodules supports monoclonal origin of primary and recurrent tumors, suggesting a tendency for sarcomatous differentiation during the progression of epithelial tumors. Malignant mural nodules represent dedifferentiation in mucinous ovarian tumors rather than collision of two different tumor types. Therefore, it is imperative to conduct comprehensive sampling, rigorous clinical examination, and postoperative follow-up in order to thoroughly evaluate all mural nodules of ovarian mucinous tumors due to their potential for malignancy and sarcomatous differentiation.
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Primary mucinous ovarian carcinoma (PMOC) is a rare tumor, accounting for approximately 3% of all epithelial ovarian cancers (EOCs), with clinical risk factors and biologic features distinct from that of EOC. The prognosis for women with recurrent and high-grade PMOC remains poor, likely related to a poor response to conventional chemotherapy for EOC. A 27-year-old Chinese woman sought medical attention in January 2021 for abdominal distention from a large pelvic mass. After extensive investigations and workup, she was diagnosed with PMOC of the right ovary. Following multidisciplinary team (MDT) discussions, the patient underwent fertility-sparing surgery (FSS) (abdominal left adnexectomy, right partial oophorectomy, pelvic lymph node dissection, para-aortic lymph node dissection, omentectomy) as she yearned to preserve her fertility and the contralateral ovary appeared normal. Deep genetic analyses revealed ERBB2 co-amplification with CDK12 and chromosome 11q13.3 amplicon. Treatment with fertility-sparing surgery and adjuvant chemotherapy with trastuzumab results in complete remission. This novel strategy utilizing precise diagnostics and characterization of the histo-type of rare tumors allowed personalized targeting with optimum drug response for women who yearn fertility preservation and remission from the disease, especially when there is very limited clinical experience on management of such rare ovarian tumors.
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Preservación de la Fertilidad , Neoplasias Ováricas , Receptor ErbB-2 , Trastuzumab , Humanos , Femenino , Adulto , Quimioterapia Adyuvante , Trastuzumab/uso terapéutico , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/genética , Neoplasias Ováricas/cirugía , Preservación de la Fertilidad/métodos , Adenocarcinoma Mucinoso/genética , Adenocarcinoma Mucinoso/tratamiento farmacológico , Adenocarcinoma Mucinoso/cirugía , Cromosomas Humanos Par 11/genética , Antineoplásicos Inmunológicos/uso terapéutico , Respuesta Patológica Completa , Quinasas Ciclina-DependientesRESUMEN
INTRODUCTION: The aim of this study was to assess the safety of fertility-sparing surgery (FSS) in stage I endometrioid epithelial cancer (EEOC) and mucinous ovarian cancer (MOC). METHODS: A retrospective caseâcontrolled study was conducted using the Surveillance, Epidemiology, and End Results (SEER) database, focusing on stage I EEOC and MOC between 2000 and 2016. The effects of FSS on overall survival (OS) were compared using log-rank tests. Univariate and multivariate Cox analyses were performed to control for confounders. RESULTS: The study identified 970 patients with FIGO stage I EEOC and 810 with stage I MOC. Of these patients, 116 (12.0%) EEOC and 268 (33.1%) MOC patients underwent fertility-sparing surgery. The results showed that patients with G3 EEOC had a worse 5-year OS than patients with G1 EEOC (96.1% vs. 90.1%, p = 0.020). IC stage MOC patients had a worse prognosis than IA and IB stage patients (94.9% vs. 88.7%, p = 0.001). FSS did not significantly affect the 5-year OS of patients with EEOC (94.8% vs. 95.4%, p = 0.687) or MOC (95.9% vs. 92.3%, p = 0.071). Further subgroup analysis according to tumor stage and histological grade did not show a worse OS with FSS in stage I EEOC or MOC patients, even with high-risk types such as G3 histology and IC phase. In a multivariable analysis, the application of FSS was not associated with inferior OS in EEOC or MOC. CONCLUSIONS: FSS for patients with stage I EEOC or MOC does not lead to worse outcomes than radical surgery, making it a viable option for young patients with early-stage disease wishing to preserve fertility.
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Preservación de la Fertilidad , Neoplasias Ováricas , Humanos , Femenino , Neoplasias Ováricas/patología , Estudios Retrospectivos , Preservación de la Fertilidad/efectos adversos , Preservación de la Fertilidad/métodos , Carcinoma Epitelial de Ovario/cirugía , Carcinoma Epitelial de Ovario/patología , Tratamientos Conservadores del Órgano/métodos , Estadificación de NeoplasiasRESUMEN
Objective: To evaluate the clinicopathological characteristics of primary mucinous ovarian carcinoma (MOC) and define oncologic outcomes. Material and Methods: This retrospective study reviewed patients diagnosed with primary MOC at a single institution and underwent primary treatment between 1990 and 2019. The clinicopathological factors affecting oncological outcomes and treatment response were evaluated. The Kaplan-Meier method was used to evaluate survival outcomes. Survival curves were compared using the log-rank test. Results: The cohort's (n=92) median (range) age was 48 (15-82) years. Seventy-five (81.5%) patients were in the International Federation of Gynecology and Obstetrics stage I-II. Forty patients received platinum-based adjuvant chemotherapy. The 5-year progression-free survival was 98% in stage I-II and 17% for stage III-IV (p<0.001). In multivariate analysis, the only independent risk factor for disease failure was stage (hazard ratio: 6.838, 95% confidence interval: 1,358-34,415; p=0.020). Conclusion: Advanced stage was an independent poor prognostic factor for recurrence in patient with MOC.
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Mucinous ovarian carcinoma (MOC) is a rare histological type of epithelial ovarian cancer. It has poor response to conventional platinum-based chemotherapy regimens and PARPi-based maintenance treatment, resulting in short survival and poor prognosis in advanced-disease patients. MOC is characterized by mucus that is mainly composed of mucin in the cystic cavity. Our review discusses in detail the role of mucins in MOC. Mucins are correlated with MOC development. Furthermore, they are valuable in the differential diagnosis of primary and secondary ovarian mucinous tumors. Some types of mucins have been studied in the context of chemoresistance and targeted therapy for ovarian cancer. This review may provide a new direction for the diagnosis and treatment of advanced MOC.
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Epithelial ovarian neoplasms (EON) constitute the majority of ovarian cancers. Among EON, high-grade serous carcinoma (HGSC) is the most common and most likely to present at an advanced stage. Radiologists should recognize the imaging features associated with HGSC, particularly at ultrasound and MR imaging. Computed tomography is used for staging and to direct care pathways. Peritoneal carcinomatosis is common and does not preclude surgical resection. Other less common malignant EON have varied appearances, but share a common correlation between the amount of vascularized solid tissue and the likelihood of malignancy.
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Carcinoma , Neoplasias Ováricas , Femenino , Humanos , Neoplasias Ováricas/diagnóstico por imagen , Neoplasias Ováricas/metabolismo , Neoplasias Ováricas/patologíaRESUMEN
OBJECTIVE: Mucinous ovarian carcinoma (MOC) is a rare histotype of ovarian cancer, with low response rates to standard chemotherapy, and very poor survival for patients diagnosed at advanced stage. There is a limited understanding of the MOC immune landscape, and consequently whether immune checkpoint inhibitors could be considered for a subset of patients. METHODS: We performed multicolor immunohistochemistry (IHC) and immunofluorescence (IF) on tissue microarrays in a cohort of 126 MOC patients. Cell densities were calculated in the epithelial and stromal components for tumor-associated macrophages (CD68+/PD-L1+, CD68+/PD-L1-), T cells (CD3+/CD8-, CD3+/CD8+), putative T-regulatory cells (Tregs, FOXP3+), B cells (CD20+/CD79A+), plasma cells (CD20-/CD79a+), and PD-L1+ and PD-1+ cells, and compared these values with clinical factors. Univariate and multivariable Cox Proportional Hazards assessed overall survival. Unsupervised k-means clustering identified patient subsets with common patterns of immune cell infiltration. RESULTS: Mean densities of PD1+ cells, PD-L1- macrophages, CD4+ and CD8+ T cells, and FOXP3+ Tregs were higher in the stroma compared to the epithelium. Tumors from advanced (Stage III/IV) MOC had greater epithelial infiltration of PD-L1- macrophages, and fewer PD-L1+ macrophages compared with Stage I/II cancers (p = 0.004 and p = 0.014 respectively). Patients with high epithelial density of FOXP3+ cells, CD8+/FOXP3+ cells, or PD-L1- macrophages, had poorer survival, and high epithelial CD79a + plasma cells conferred better survival, all upon univariate analysis only. Clustering showed that most MOC (86%) had an immune depleted (cold) phenotype, with only a small proportion (11/76,14%) considered immune inflamed (hot) based on T cell and PD-L1 infiltrates. CONCLUSION: In summary, MOCs are mostly immunogenically 'cold', suggesting they may have limited response to current immunotherapies.
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Antígeno B7-H1 , Neoplasias Ováricas , Humanos , Femenino , Antígeno B7-H1/genética , Carcinoma Epitelial de Ovario/patología , Neoplasias Ováricas/tratamiento farmacológico , Linfocitos T CD8-positivos , Factores de Transcripción Forkhead/uso terapéutico , Linfocitos Infiltrantes de Tumor , Microambiente TumoralRESUMEN
Objective: The aim of the present study was to evaluate evolution and prognosis of mucinous ovarian carcinomas (mOC), with respect to the two invasive patterns: expansile and infiltrative invasion. Methods: This was a descriptive, retrospective, multicenter study conducted in 13 French centres from 1 January 2001 to 31 December 2019. All patients operated on for epithelial ovarian neoplasia of the mucinous type (infiltrative/expansile) were included, whether the surgery was performed immediately or after neoadjuvant chemotherapy. Results: A total of 94 women with mucinous carcinomas were included in the present study. Mucinous tumours were divided into 35 expansile (37%) and 59 infiltrative (63%) mOC. There was a statistically significant difference in early and late stages at initial diagnosis between expansile and infiltrative mOC. None of the expansile mOC showed metastatic lymph nodes, whereas almost a quarter of the infiltrative mOC were metastatic to the pelvic/para-aortic region. There was a clear difference in RFS, in favour of expansile mOC, with 90% survival at 5 years, compared with 60% for infiltrative mOC. Conclusions: Although infiltrative and expansile mOC belong to the same histological family, they present many distinctions in clinical presentation, histological invasion, and disease course.
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Mucinous ovarian carcinoma is a less-prevalent subtype of epithelial tumors. We present a case of giant mucinous ovarian carcinoma weighing 41.1 kg in a 24-year-old Indian girl. Benign mucinous tumors have the potential to reach an enormous size but such a huge malignant mucinous tumor is very rare in literature and its occurrence in a young female is even rarer.
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INTRODUCTION: Though ovarian malignancies are common, mucinous ovarian carcinomas of high grade are rare. They usually occur in a young female under 40 years of age. Here, we present a case of mucinous ovarian carcinoma (stage III), with omental involvement and incidental hydronephrosis in a 67-year-old female patient. CASE PRESENTATION: A 67-year-old female patient presented to us with a history of lower abdominal pain for 2 months and per-vaginal discharge for the last 6 days. On deep palpation of the abdomen, a nodular mass occupying the suprapubic region was found. Bimanual palpation revealed a mass on the right and left adnexa. After visualization of septate cystic mass bilaterally on CECT, she was planned for staging laparotomy with bilateral salpingo-oophorectomy (BSO) with infra-colic omentectomy with peritoneal cytology. Incidentally, a horseshoe-shaped kidney with right mild hydronephrosis was found. After surgery and histopathologic examination, mucinous ovarian carcinoma (stage III), with omental involvement was confirmed. DISCUSSION: Mucinous ovarian carcinomas are rare malignancies, with different natural history, molecular profile, and prognosis as compared to other epithelial tumors of the ovary. These carcinomas can be either primary or secondary (those metastasized to the ovary from elsewhere), and this differentiation is essential. The therapeutic approach to the patients depends upon the stage at which these carcinomas are diagnosed. CONCLUSION: Mucinous ovarian carcinomas are rare and have unique features among the epithelial ovarian carcinomas. Appreciation of these features will surely make a positive impact in improving the management and thus the prognosis of these carcinomas.
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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.
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Adenocarcinoma Mucinoso , Neoplasias Ováricas , Complejo Represivo Polycomb 1 , Adenocarcinoma Mucinoso/tratamiento farmacológico , Adenocarcinoma Mucinoso/genética , Índice de Masa Corporal , Carcinoma Epitelial de Ovario/tratamiento farmacológico , Carcinoma Epitelial de Ovario/genética , Femenino , Humanos , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/genética , Complejo Represivo Polycomb 1/genéticaRESUMEN
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.
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Adenocarcinoma Mucinoso , Neoplasias de la Mama , Neoplasias Ováricas , Biomarcadores de Tumor , Neoplasias de la Mama/patología , Carcinoma Epitelial de Ovario , Femenino , Humanos , Inmunohistoquímica , Hibridación Fluorescente in Situ/métodos , Receptor ErbB-2/genéticaRESUMEN
Advanced or recurrent mucinous carcinoma of the ovary minimally responds to current cytotoxic treatments and has a poor prognosis. Despite multimodal treatment with chemotherapy and surgery, most patients ultimately progress and require palliative systemic therapy. Anti-HER2 therapy has been demonstrated to be an effective strategy for the treatment of HER2-positive breast cancer. However, the role of anti-HER2 therapy in ovarian cancer remains largely unknown. Here, we report the case of a young woman with FIGO Stage IIIc recurrent mucinous ovarian carcinoma (MOC) who developed trastuzumab resistance and disease progression following cross-treatment with trastuzumab combined with pertuzumab. HER2 amplification was discovered using next-generation sequencing (NGS). The patient then received bevacizumab, and pyrotinib (an irreversible HER2 antagonist) plus capecitabine treatment, and achieved a long-term clinical benefit for 22 months. Pyrotinib combined with bevacizumab is a potential treatment for MOC patients who are heavily pretreated and harbor a HER2 amplification. Our case may provide valuable treatment information for patients with advanced or recurrent MOC.
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Introduction: Ovarian cancer (OC) is the leading cause of gynecological cancer-related death. Of the main OC histologic subtypes, invasive mucinous carcinomas (MC) account for only 3% of OC cases and are frequently associated with favorable prognosis. Nevertheless, MCs differ greatly from the other OC histotypes in clinical, pathological, and biological behavior. However, the origin and molecular pathogenesis of MC are not yet fully understood. Therefore, identification of novel diagnostic markers could potentially facilitate early diagnosis of OC, particularly the MC histotype, thereby leading to the development of histotype-specific treatment regimens and improved survival rates. Methods: In the present study, Trefoil factor gene family members (TFF1, TFF2 and TFF3) were identified as MC histotype-specific biomarkers using RNA sequencing (RNA-seq) data for 95 stage I-II OCs. The diagnostic value of TFF1, TFF2 and TFF3 was then evaluated by immunohistochemistry on 206 stage I-II OCs stratified by histotype (high-grade serous carcinoma [HGSC], endometrioid carcinoma [EC], clear cell carcinoma [CCC], and MC). Results: We showed significantly elevated intracytoplasmic protein expression levels for TFF1, TFF2 and TFF3 in MC samples, thereby revealing an association between expression of Trefoil factor gene family members and the MC histotype. Taken together, these findings suggest that the TFF proteins may play a pivotal role in tumor initiation and progression for the MC histotype. Conclusion: Taken together, these findings suggest that the TFF proteins may play a pivotal role in tumor initiation and progression for the MC histotype. Moreover, these novel histotype-specific diagnostic biomarkers may not only improve patient stratification of early-stage ovarian carcinomas but may also be candidates for the development of molecular targeted therapies.
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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.
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Adenocarcinoma Mucinoso/etnología , Carcinoma Epitelial de Ovario/etnología , Neoplasias Ováricas/etnología , Proteínas Proto-Oncogénicas B-raf/genética , Adenocarcinoma Mucinoso/tratamiento farmacológico , Adenocarcinoma Mucinoso/genética , Adulto , Carcinoma Epitelial de Ovario/tratamiento farmacológico , Carcinoma Epitelial de Ovario/genética , Femenino , Humanos , Quinasas de Proteína Quinasa Activadas por Mitógenos , Mutación , Recurrencia Local de Neoplasia , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/genética , Proteínas Proto-Oncogénicas p21(ras) , Taiwán/epidemiologíaRESUMEN
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.
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Adenocarcinoma Mucinoso/terapia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Procedimientos Quirúrgicos de Citorreducción , Escisión del Ganglio Linfático , Neoplasias Ováricas/terapia , Radioterapia , Salpingooforectomía , Adenocarcinoma Mucinoso/patología , Apendicectomía , Femenino , Humanos , Terapia Molecular Dirigida , Estadificación de Neoplasias , Neoplasias Ováricas/patología , Peritoneo/cirugíaRESUMEN
Early-stage (I and II) ovarian carcinoma patients generally have good prognosis. Yet, some patients die earlier than expected. Thus, it is important to stratify early-stage patients into risk groups to identify those in need of more aggressive treatment regimens. The prognostic value of 29 histotype-specific biomarkers identified using RNA sequencing was evaluated for early-stage clear-cell (CCC), endometrioid (EC) and mucinous (MC) ovarian carcinomas (n = 112) using immunohistochemistry on tissue microarrays. Biomarkers with prognostic significance were further evaluated in an external ovarian carcinoma data set using the web-based Kaplan-Meier plotter tool. Here, we provide evidence of aberrant protein expression patterns and prognostic significance of 17 novel histotype-specific prognostic biomarkers [10 for CCC (ARPC2, CCT5, GNB1, KCTD10, NUP155, RPL13A, RPL37, SETD3, SMYD2, TRIO), three for EC (CECR1, KIF26B, PIK3CA), and four for MC (CHEK1, FOXM1, KIF23, PARPBP)], suggesting biological heterogeneity within the histotypes. Combined predictive models comprising the protein expression status of the validated CCC, EC and MC biomarkers together with established clinical markers (age, stage, CA125, ploidy) improved the predictive power in comparison with models containing established clinical markers alone, further strengthening the importance of the biomarkers in ovarian carcinoma. Further, even improved predictive powers were demonstrated when combining these models with our previously identified prognostic biomarkers PITHD1 (CCC) and GPR158 (MC). Moreover, the proteins demonstrated improved risk prediction of CCC-, EC-, and MC-associated ovarian carcinoma survival. The novel histotype-specific prognostic biomarkers may not only improve prognostication and patient stratification of early-stage ovarian carcinomas, but may also guide future clinical therapy decisions.
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Mucinous epithelial ovarian cancer (mEOC) is a rare subset of epithelial ovarian cancer. When diagnosed at a late stage, its prognosis is very poor, as it is quite chemo-resistant. To find new therapeutic options for mEOC, we performed high-throughput screening using a siRNA library directed against human protein kinases in a mEOC cell line, and polo-like kinase1 (PLK1) was identified as the kinase whose downregulation interfered with cell proliferation. Both PLK1 siRNA and two specific PLK1 inhibitors (onvansertib and volasertib) were able to inhibit cell growth, induce apoptosis and block cells in the G2/M phase of the cell cycle. We evaluated, in vitro, the combinations of PLK1 inhibitors and different chemotherapeutic drugs currently used in the treatment of mEOC, and we observed a synergistic effect of PLK1 inhibitors and antimitotic drugs. When translated into an in vivo xenograft model, the combination of onvansertib and paclitaxel resulted in stronger tumor regressions and in a longer mice survival than the single treatments. These effects were associated with a higher induction of mitotic block and induction of apoptosis, similarly to what was observed in vitro. These data suggest that the combination onvansertib/paclitaxel could represent a new active therapeutic option in mEOC.
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Mucinous ovarian cancer (MOC) is a rare subtype of epithelial ovarian carcinoma (EOC). Whereas all EOC subtypes are addressed in the same way, MOC is a distinct entity. Appreciating the pathological features and genomic profile of MOC may result in the improvement in management and, hence, the prognosis. Distinguishing primary MOC from metastatic mucinous carcinoma can be challenging but is essential. Early-stage MOC carries an excellent prognosis, with advanced disease having a poor outcome. Surgical management plays an essential role in the early stage and in metastatic disease. Chemotherapy is usually administered for stage II MOC and beyond. The standard gynecology protocol is frequently used, but gastrointestinal regimens have also been administered. As MOC is associated with multiple molecular alterations, targeted therapy could be the answer to treat this disease.
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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.