Low-grade Serous Ovarian Carcinoma Research Articles

Heterogeneity of EpCAM-positive cells in low-grade serous ovarian carcinoma ascitic fluid: a clinical case

Ovarian cancer is one of the most malignant and aggressive tumors of the female reproductive system. Late diagnosis is one of the most significant problems: more than two-thirds of cases are detected only at stage III–IV. Ovarian cancer is characterized by a unique metastatic process. Implantation is the earliest and most common way of metastasis. It is often accompanied by fluid accumulation in the abdominal cavity, known as ascites. We report a case of low-grade serous ovarian carcinoma with a large heterogeneity of tumor cells in the ascitic fluid detected using multicolor flow cytometry. We demonstrated the advantages and benefits of this method in the diagnosis of ovarian cancer. Multicolor flow cytometry opens new horizons for liquid biopsy in oncology.

PROGNOSTIC CLINICAL, MORPHOLOGICAL AND IMMUNOHISTOCHEMICAL MARKERS OF LOW-GRADE SEROUS OVARIAN CARCINOMAS OF WOMEN WITH SEROUS BORDERLINE TUMORS IN ANAMNESIS

The problem of finding reliable clinical and morphological criteria for diagnosis and prognosis of serous borderline ovarian tumors, their relationship with the risk of developing of low-grade serous ovarian carcinomas (LGSC) in future is still relevant. This study is devoted to research and highlight of precursors that allow dividing women with serous borderline ovarian tumors (SBOT) into risk group for occurrence of LGSC within next 5 years. The study included 22 patients with FIGO stage I-II SBOT aged 24 to 46 years, 9 (39.13%) of whom were diagnosed with high-grade serous ovarian carcinoma next 5 years. Two study groups were formed: the control group (n = 13), which included patients with SBOT without further development of LGSC, and the main group (n = 9), which included women with emerging LGSCs. We studied expression of immunohistochemical markers Ki-67, MMP-9, p53, Bcl-2, E-cadherin, and also a diameter and localization of the tumor. As a result of the study, it was found that patients with diameter of the SBOT≥10 cm (χ² = 6.0, p <0.03), FIGO stage II (χ² = 4.7, p <0.03) and Ki-67 expression ≥10% (χ² = 9.03, p <0.03) have a high risk of developing LGSC within next 5 years. In the group of women who underwent LGSC development, there was a tendency to more pronounced expression of MMP-9 (χ² = 4.18, p <0.04) and moderate and pronounced expression of Bcl-2 (χ² = 9.66, p = 0.008). According to our data, markers Ki-67, MMP-9, Bcl-2 are prognostic and can be used as markers of LGSC risk in women with a history of SBOT. Tumor diameter ≥10 cm is also a predictor.

Recurrence of low-grade serous ovarian cancer successfully treated with Gemcitabine and Bevacizumab: a case report and literature review

Ovarian low-grade serous carcinoma (LGSC) is usually a slow growing tumor with a relatively good prognosis. However, LGSC that have relapsed are highly resistant to chemotherapy, and there is currently no established treatment for them in contrast to high-grade serous carcinoma (HGSC). Here, we first review the literature on this topic and then describe a case of LGSC that relapsed and responded to Gemcitabine and Bevacizumab. The patient was a 37-year-old nulliparous woman who had undergone three cycles of topotecan after initial surgery at age 28.5 years as well as three months later during a disease-free interval. Intraperitoneal dissemination was observed and laparoscopic biopsy was performed. Histopathological examination revealed LGSC, and genetic testing revealed mutations in the neurofibromatosis type 1 (NF1) and TP53 genes. The mass of the disseminated lesion subsequently increased overall, and subileus was observed. The patient was treated, but the operation was incomplete. Postoperatively, Gemcitabine and Bevacizumab therapy was started. After six cycles, tumor markers became negative and Positron Emission Tomography-CT (PET-CT) showed decreased tumor activity. There were 20 cycles without any symptoms. LGSC is often resistant to anticancer drugs, but Gemcitabine and Bevacizumab therapy was able to suppress the lesions and symptoms in this case. With these findings, future genomic testing may assist in the treatment strategy for cases of LGSC recurrence, which are considered to be less likely to respond to anticancer drugs. Comprehensive genetic analysis will hopefully lead to the molecular mechanism of carcinogenesis for more effective and targeted therapies.

Prescription of hormone replacement therapy in women with surgically induced menopause and borderline ovarian tumors: Should we be doing more?

Borderline Ovarian Tumors (BOT) are often diagnosed in premenopausal women and the likely precursors to ovarian low-grade serous carcinoma (LGSC), a hormonally sensitive malignancy. The safety of hormone replacement therapy (HRT) after surgical treatment of BOT is unknown. We aimed to describe the HRT prescribing and preventive services practice patterns in women with surgically induced menopause (SIM) after surgery for BOT. (See Table 1.)

Prognosis role of epitelial-mezenchimal transformation markers and surface stem tumor cells in the reccurence of serous low grade ovarian carcinomas

Ovarian cancer remains one of the most fatal pathologies among women around the world due to late diagnosis on the advanced stages of the tumor process. Serous ovarian carcinomas (SOC) often recur, which worsens the prognosis for patients’ recovery and survival. The identification of prognostic clinical and morphological factors that predict the appearance of recurrence remains an urgent problem.
 The aim of the research was studying relationships between the phenomenon of epithelial-mesenchymal transformation (EMT) and the expression of surface cancer stem cells (CSCS) markers to identify recurrence predictors among women with low grade serous ovarian carcinomas (LGSC).
 The material were paraffin blocks and slides of 43 patients with LGSC I-IV FIGO stage. The study included 30 cancers without recurrence and 13 tumors with it within 24 months. The expression of E-cadherin, Vimentin, CD44 and CD117 was studied using immunohistochemical (IHC) method.
 Results. Development of recurrence is typical for women with stage III-IV (p=0,01), the expression of Vimentin at level 51–100 % (p=0,001) and E-cadherin at 10–50 % (p=0.04). CD44 was expressed in 51.16 % of tumors and level didn`t depend on age, recurrence, but depended on disease stage (p=0.001). Recurrent LGSCs are characterized by the expression of CD117> 10 % (p=0.0001), its direct correlation with the stage (p=0.0001) and the recurrence (p=0.0001). A direct relationship was found between the CD117 and Vimentin expression.
 Conclusions. Prognostic markers of recurrence should be considered stage III-IV, levels of Vimentin 51–100 %, E-cadherin 10-50 % and CD117> 10 %. A correlation between CD117 and Vimentin expression indicates the commonality of EMT and CSCS in progression and recur. CD44 has no independent prognostic role.

Study on P53 Expression in Association with Histopathological Grading of Ovarian Serous Carcinoma

Background: Ovarian cancer is a disease of significant morbidity and mortality. It is the most common cancer among women worldwide. Early and accurate detection and grading of ovarian serous carcinoma is of utmost significance for prolongation of patient survival. Panels of immunomarkers have been tested to overcome limitation of histopathology. Immunomarker p53 is commonly used among them. This study was undertaken to evaluate the significance of p53 immunomarker in ovarian serous carcinoma. Objective: Objective of this study to see p53 expression and its association with different histopathological grading of ovarian serous carcinoma. Method: This cross-sectional study was conducted in the Department of Pathology, Rajshahi Medical College, over a period of two years from July 2017 to June 2019. A total of 32 clinically suspected cases of ovarian carcinoma admitted in the RMCH and later on histologically confirmed as ovarian serous carcinoma were included in the study. Histories of the patient were obtained from the hospital records. Tissue biopsy from the site of lesion or operated specimen of tissue was fixed with 10% formalin and was processed stained with haematoxyline and eosin stain and was examined. Result: Immunohistochemistry was done for p53 from significant paraffin embedded block. Of the 32 cases 20 were histologically confirmed as high grade and the rest 12 were low grade ovarian serous carcinoma. In this present study, age distribution showed that, about 60% of the patients were within 2nd to 5thdecades.The mean age of the patients was 41.34 years. The sensitivity of p53 was found high (80.2%) in case of serous ovarian carcinoma and its different grade. Conclusion: The study concluded that p53 is a highly sensitive immunomarker for detecting the grade of ovarian carcinoma specially serous ovarian carcinoma.

743P Real-world outcomes in patients treated with trametinib for low grade serous ovarian carcinoma

In the UK, trametinib (T) is recommended for the treatment of recurrent or progressive low grade serous ovarian cancer (LGSOC) following endocrine therapy (ET) and at least one platinum (Plat) based chemotherapy (ChT) regimen, as an alternative to cytotoxic ChT under interim COVID-19 arrangements.

Cytodiagnosis of bilateral abdominopelvic masses in a postmenopausal woman.

Cytologic diagnosis of ovarian low-grade serous carcinoma.

Characterization and clinical significance of the CADM1/HER2/STAT3 axis in serous ovarian tumors.

The subtypes of serous ovarian tumors (SOTs), including benign serous cystadenoma, serous borderline tumor (SBT), low-grade serous ovarian carcinoma (LGSC), and high-grade serous ovarian carcinoma (HGSC), remain poorly understood. Herein, we aimed to characterize the cell adhesion molecule 1 (CADM1)/signal transducer and activator of transcription 3 (STAT3)/human epidermal growth factor receptor 2 (HER2) axis and identify its clinical significance in patients with serous cystadenoma, SBT, LGSC, and HGSC.The immunohistochemical expression of CADM1, HER2, and STAT3 was assessed in 180 SOT specimens, and its association with clinical data was determined.High levels of CADM1 expression were detected in 100% of serous cystadenomas and 83.33% of SBTs, while a loss of CADM1 expression was observed in 44% of LGSCs and 72.5% of HGSCs. Relative to the levels in benign cystadenomas and SBTs, higher levels of HER2 and STAT3 expression were observed in LGSCs and aggressive HGSCs. Furthermore, the expression profile of the CADM1/HER2/STAT3 axis was significantly associated with histologic type, International Federation of Gynecology and Obstetrics stage, and lymph node metastasis in patients with SOT.Our study identified the changes in the CADM1/HER2/STAT3 axis that were closely associated with the clinical behavior of SOTs. These molecular data may provide new insights into SOT carcinogenesis and aid in the diagnosis and treatment of patients with SOT.

Immunologic factors involved in the malignant transformation of endometriosis to endometriosis-associated ovarian carcinoma.

Endometriosis is a risk factor for low-grade serous, clear cell, and endometroid ovarian carcinoma. In both endometriosis and ovarian carcinoma, immunological factors are associated with clinical outcome. Chronic inflammation in endometriosis may be linked to tumorigenesis, but exact processes contributing to endometriosis-associated ovarian carcinoma remain unknown. This review aims to describe potential immunological factors involved in the malignant transformation of endometriosis into ovarian carcinoma. PubMed and Embase were searched from inception up to October 2020 for studies comparing immunological processes in endometriosis and endometriosis-associated ovarian carcinoma. Detailed analysis of immune components in the malignant transformation of endometriosis into endometriosis-associated ovarian carcinoma is lacking. Altered levels of chemokines and cytokines as IL-6, IL-8, IL-10, and TNF-α are reported and the function, number and polarization of NK cells, dendritic cells, and monocytes differ between endometriosis and associated ovarian carcinoma compared to healthy tissue. In addition, altered inflammasome and complement systems, indicate a role for the immune system in the carcinogenesis of endometriosis. Chronic inflammation in endometriosis may potentially drive inflammation-induced carcinogenesis in endometriosis-associated ovarian carcinoma. Exact immunological pathways and cellular processes remain unknown and require more thorough investigation.

Differences in gynecologic tumor development in Amhr2-Cre mice with KRASG12D or KRASG12V mutations

How different KRAS variants impact tumor initiation and progression in vivo has not been thoroughly examined. We hypothesize that the ability of either KRASG12D or KRASG12V mutations to initiate tumor formation is context dependent. Amhr2-Cre mice express Cre recombinase in tissues that develop into the fallopian tubes, uterus, and ovaries. We used these mice to conditionally express either the KRASG12V/+or KRASG12D/+ mutation. Mice with the genotype Amhr2-Cre Pten(fl/fl) KrasG12D/+(G12D mice) had abnormal follicle structures and developed low-grade serous ovarian carcinomas with 100% penetrance within 18 weeks. In contrast, mice with the genotype Amhr2-Cre Pten(fl/fl) KrasG12V/+ (G12V mice) had normal follicle structures, and about 90% of them developed uterine tumors with diverse histological features resembling those of leiomyoma and leiomyosarcoma. Granulosa cell tumors also developed in G12V mice. Differences in cell-signaling pathways in the uterine tissues of G12D and G12V mice were identified using RNA sequencing and reverse-phase protein array analyses. We found that CTNNB1, IL1A, IL1B, TNF, TGFB1, APP, and IL6 had the higher activity in G12V mice than in G12D mice. These mouse models will be useful for studying the differences in signaling pathways driven by KrasG12V/+ or KrasG12D/+ mutations to aid development of targeted therapies for specific KRAS mutant variants. Our leiomyoma model driven by the KrasG12V/+ mutation will also be useful in deciphering the malignant progression from leiomyoma to leiomyosarcoma.

Clinical factors associated with prognosis in low-grade serous ovarian carcinoma: experiences at two large academic institutions in Korea and Taiwan

Low-grade ovarian serous carcinoma (LGSOC) has clinical features different from high-grade serous ovarian carcinoma (HGSOC) accounting for the majority of epithelial ovarian cancer. Because of its rarity, previous studies have only focused on the high-grade disease without considering the differences between the two subtypes. This study aimed to evaluate the effect of the clinical prognostic factors known for HGSOC on survival in patients with LGSOC. Based on the Federation of Gynecology and Obstetrics (FIGO) stage, progression-free survival (PFS) was markedly decreased in advanced disease compared with early disease. For stage I, patients with stage IC had poorer survival than those with stage IA and IB regardless of the number of cycles of adjuvant chemotherapy. For advanced disease, no gross residual disease after primary cytoreductive surgery was significantly associated with longer PFS when compared with gross residual disease. In multivariate analysis for PFS and overall survival (OS), age, preoperative CA-125, time interval from surgery to chemotherapy, and the number of cycles of adjuvant chemotherapy were not associated with prognosis. Complete cytoreduction was the only independent prognostic factor for PFS (HR 2.45, p = 0.045). Our study revealed that the known prognostic factors in HGSOC did not show any effect on the survival in LGSOC except for FIGO stage and complete cytoreduction.

A systematic review and meta-analysis of hormone receptor expression in low-grade serous ovarian carcinoma

ObjectiveSerous ovarian carcinoma is the most common histological type of ovarian cancer, with high-grade serous ovarian carcinoma (HGSOC) being more common than low-grade serous ovarian carcinoma (LGSOC). Despite pathogenic and clinical differences, both grades of serous ovarian carcinoma share the propensity to express receptors for the female hormones – oestrogen (ERs) and progesterone receptors (PRs) – albeit in differing frequencies. Study designSystematic review and meta-analysis of studies reporting the expression of hormone receptors in LGSOC, and comparison with expression in HGSOC. ResultsExpression of ERs is observed in 80.7 % of patients with LGSOC [95 % confidence interval (CI) 72.2–89.1 %] and 61.5 % of patients with HGSOC (95 % CI 38.8–84.1 %). Expression of PRs is observed in 54.4 % of patients with LGSOC (95 % CI 44.3–64.4 %) and 30.7 % of patients with HGSOC (95 % CI 15.7–45.7 %). ConclusionA higher percentage of LGSOCs are positive for ER expression compared with HGSOCs. Similarly, a higher percentage of LGSOCs are positive for PR expression, although PR expression is lower than ER expression. Expression of hormone receptors may represent a therapeutic opportunity for treatment with agents that block their activity, especially in LGSOC which is less responsive to chemotherapy and therapeutic options are limited.

Genomic analysis of low-grade serous ovarian carcinoma to identify key drivers and therapeutic vulnerabilities.

Low-grade serous ovarian carcinoma (LGSOC) is associated with a poor response to existing chemotherapy, highlighting the need to perform comprehensive genomic analysis and identify new therapeutic vulnerabilities. The data presented here represent the largest genetic study of LGSOCs to date (n = 71), analysing 127 candidate genes derived from whole exome sequencing cohorts to generate mutation and copy-number variation data. Additionally, immunohistochemistry was performed on our LGSOC cohort assessing oestrogen receptor, progesterone receptor, TP53, and CDKN2A status. Targeted sequencing identified 47% of cases with mutations in key RAS/RAF pathway genes (KRAS, BRAF, and NRAS), as well as mutations in putative novel driver genes including USP9X (27%), MACF1 (11%), ARID1A (9%), NF2 (4%), DOT1L (6%), and ASH1L (4%). Immunohistochemistry evaluation revealed frequent oestrogen/progesterone receptor positivity (85%), along with CDKN2A protein loss (10%) and CDKN2A protein overexpression (6%), which were linked to shorter disease outcomes. Indeed, 90% of LGSOC samples harboured at least one potentially actionable alteration, which in 19/71 (27%) cases were predictive of clinical benefit from a standard treatment, either in another cancer's indication or in LGSOC specifically. In addition, we validated ubiquitin-specific protease 9X (USP9X), which is a chromosome X-linked substrate-specific deubiquitinase and tumour suppressor, as a relevant therapeutic target for LGSOC. Our comprehensive genomic study highlighted that there is an addiction to a limited number of unique 'driver' aberrations that could be translated into improved therapeutic paths. © 2020 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Low-grade serous ovarian cancer: Prognostic impact of initial tumor load--A GINECO group and TMRG network study

Objective: Complete resection of disease is the most important prognostic factor for patients with low-grade serous ovarian carcinoma (LGSOC). However, the implication of carcinomatosis distribution and implant size according to their location is poorly investigated. Our objective was to assess the impact of peritoneal carcinomatosis quantitative and qualitative localizations on progression-free survival (PFS) and overall survival (OS) in patients with LGSOC after complete cytoreductive surgery.

MILO/ENGOT-ov11: Phase-3 Study of Binimetinib versus Physician’s Choice Chemotherapy in Recurrent or Persistent Low-grade Serous Carcinomas of the Ovary, Fallopian Tube, or Primary Peritoneum

Objective: Low-grade serous ovarian carcinomas (LGSOC) have historically low chemotherapy responses. Alterations affecting the MAPK pathway, most commonly KRAS/BRAF, are present in 30%–60% of LGSOC. A phase II study of the MEK inhibitor selumetinib showed promising response rate of 15% in LGSOC, and binimetinib, a potent MEK1/2 inhibitor, has demonstrated activity across multiple cancers.

Hur inhibition is a novel approach to treatment of chemotherapy-resistant low-grade serous ovarian carcinomas

Objective: Low-grade serous ovarian carcinoma (LGSO) is a subtype of ovarian cancer that affects women at a younger age and is associated with a more indolent course than high-grade serous ovarian cancer. It is generally poorly responsive to cytotoxic chemotherapy given slow doubling times and other molecular factors. Human antigen R (HuR) is an RNA-binding protein that binds to adenine- and uridine-rich elements (ARE) located in the 3′- or 5′-untranslated region of target mRNAs. HuR promotes the translation of several target mRNAs encoding proteins involved in treatment resistance, including class III b-tubulin (Figure 1a).

Genetic profiling characteristics of patients with low-grade serous carcinoma of the ovary in a racially diverse population

Objective: Low-grade serous ovarian carcinoma (LGSOC) commonly carries mutations in the MAP kinase pathway (KRAS, NRAS, BRAF). Penetrance of mutations in this pathway is reported to be approximately 50%. The role of other mutations in the pathogenesis of this disease is poorly understood. Our objective was to evaluate the penetrance of pathogenic mutations outside of this pathway in a racially diverse population.

Should we abandon systematic pelvic and paraaortic lymphadenectomy in low-grade serous ovarian cancer? A GINECO group and TMRG network study

Objective: Low-grade serous ovarian carcinoma (LGSOC) is a rare disease that accounts for 5% of all ovarian cancers. Complete resection of the carcinosis is an important prognostic factor in this disease. To date, the prognostic value of pelvic and paraaortic lymphadenectomy remains unclear.

Use of adjuvant chemotherapy for early-stage low-grade serous ovarian carcinoma

Objective: The aim of this study was to investigate patterns of use and the impact of adjuvant chemotherapy on overall survival (OS) of patients with stage IC and II low-grade serous ovarian carcinoma (LGSOC).