Aurora-A kinase is differentially expressed in the nucleus and cytoplasm in normal Müllerian epithelium and benign, borderline and malignant serous ovarian neoplasms

Background Aurora-A kinase is important for cellular proliferation and is implicated in the tumorigenesis of several malignancies, including of the ovary. Information regarding the expression patterns of Aurora-A in normal Müllerian epithelium as well as benign, borderline and malignant epithelial ovarian neoplasms is limited. Methods We investigated Aurora-A expression by immunohistochemistry in 15 benign, 19 borderline and 17 malignant ovarian serous tumors, and 16 benign, 8 borderline, and 2 malignant ovarian mucinous tumors. Twelve fimbriae from seven patients served as normal Müllerian epithelium controls. We also examined Aurora-A protein expression by western blot in normal fimbriae and tumor specimens. Results All normal fimbriae (n = 12) showed nuclear but not cytoplasmic Aurora-A immunoreactivity by immunohistochemistry. Benign ovarian tumors also showed strong nuclear Aurora-A immunoreactivity. Forty-eight percent (13/27) of borderline tumors demonstrated nuclear Aurora-A immunoreactivity, while the remainder (52%, 14/27) lacked Aurora-A staining. Nuclear Aurora-A immunoreactivity was absent in all malignant serous tumors, however, 47% (8/17) demonstrated perinuclear cytoplasmic staining. These results were statistically significant when tumor class (benign/borderline/malignant) was compared to immunoreactivity localization or intensity (Fisher Exact Test, p < 0.01). Western blot analysis confirmed the greater nuclear Aurora-A expression in control Müllerian epithelium compared to borderline and malignant tumors. Conclusion Aurora-A kinase is differentially expressed across normal Müllerian epithelium, benign and borderline serous and mucinous ovarian epithelial neoplasms and malignant serous ovarian tumors., with nuclear expression of unphosphorylated Aurora-A being present in normal and benign neoplastic epithelium, and lost in malignant serous neoplasms. Further studies of the possible biological and clinical implications of the loss of nuclear Aurora-A expression in ovarian tumors, and its role in ovarian carcinogenesis are warranted.

Diagnosis of Ovarian Neoplasms Using Nomogram in Combination With Ultrasound Image-Based Radiomics Signature and Clinical Factors

Objectives: To establish and validate a nomogram integrating radiomics signatures from ultrasound and clinical factors to discriminate between benign, borderline, and malignant serous ovarian tumors.Materials and methods: In this study, a total of 279 pathology-confirmed serous ovarian tumors collected from 265 patients between March 2013 and December 2016 were used. The training cohort was generated by randomly selecting 70% of each of the three types (benign, borderline, and malignant) of tumors, while the remaining 30% was included in the validation cohort. From the transabdominal ultrasound scanning of ovarian tumors, the radiomics features were extracted, and a score was calculated. The ability of radiomics to differentiate between the grades of ovarian tumors was tested by comparing benign vs borderline and malignant (task 1) and borderline vs malignant (task 2). These results were compared with the diagnostic performance and subjective assessment by junior and senior sonographers. Finally, a clinical-feature alone model and a combined clinical-radiomics (CCR) model were built using predictive nomograms for the two tasks. Receiver operating characteristic (ROC) analysis, calibration curve, and decision curve analysis (DCA) were performed to evaluate the model performance.Results: The US-based radiomics models performed satisfactorily in both the tasks, showing especially higher accuracy in the second task by successfully discriminating borderline and malignant ovarian serous tumors compared to the evaluations by senior sonographers (AUC = 0.789 for seniors and 0.877 for radiomics models in task one; AUC = 0.612 for senior and 0.839 for radiomics model in task 2). We showed that the CCR model, comprising CA125 level, lesion location, ascites, and radiomics signatures, performed the best (AUC = 0.937, 95%CI 0.905–0.969 in task 1, AUC = 0.924, 95%CI 0.876–0.971 in task 2) in the training as well as in the validation cohorts (AUC = 0.914, 95%CI 0.851–0.976 in task 1, AUC = 0.890, 95%CI 0.794–0.987 in task 2). The calibration curve and DCA analysis of the CCR model more accurately predicted the classification of the tumors than the clinical features alone.Conclusion: This study integrates novel radiomics signatures from ultrasound and clinical factors to create a nomogram to provide preoperative diagnostic information for differentiating between benign, borderline, and malignant ovarian serous tumors, thereby reducing unnecessary and risky biopsies and surgeries.

Expression of the Laminin-5γ2 Chain Is Associated With Acquisition of Malignant Traits in Ovarian Serous and Mucinous Tumors.

BackgroundOvarian tumors are predominantly of epithelial origin and are currently divided into three groups: Adenoma, borderline tumor, and adenocarcinoma by the presence or absence of invasion and cellular atypia. However, it is difficult to assess invasion, so a more objective biomarker would be desirable. Laminin-5 (Lam5) is a protein that constitutes the extracellular matrix of the basement membrane, and it is composed of three short-chain subunits. One of them, the Lam5γ2 chain (Lam5γ2), has been reported to be expressed in some malignant tumors and is suggested to be related to tumor cell invasion. Against this background, we investigated immunohistologically whether the Lam5γ2 would be useful as a marker to predict invasion in ovarian serous and mucinous tumors.MethodsImmunohistochemistry for Lam5γ2 was performed on a total of 80 cases of serous and mucinous tumor adenomas, borderline tumors, and adenocarcinomas, and the differences in the localization of Lam5γ2 expression were observed.ResultsThe basement membrane expression of Lam5γ2 tended to be preserved or had disappeared in half of the adenomas and borderline serous tumors. In all cases of adenocarcinoma, the expression on the basement membrane had disappeared. The frequency of expression in tumor cells increased in the order of adenoma, borderline tumor, adenocarcinoma. In particular, in most adenocarcinoma cases a cytoplasmic expression was observed. The same tendency was noted in mucinous tumors, and the basement membrane expression tended to disappear in the order of adenoma, borderline tumor and adenocarcinoma. Many cases of adenocarcinoma were observed among the tumor cells. In adenocarcinoma cases of both types of tumor, many tumor cells showed prominent cytoplasmic expression particularly in the microinvasive foci and in the invasive front.ConclusionsThe disappearance of Lam5γ2 from the basement membrane and its aberrant expression in serous and mucinous tumor cells may serve as a phenotype for invasiveness.

Spectrum of BRAF Mutations and Gene Rearrangements in Ovarian Serous Carcinoma

PURPOSE Low-grade serous carcinoma (LGSC) is a rare type of ovarian cancer, which commonly arises from serous borderline tumor (SBT) and is characterized by frequent activating mutations in the mitogen-activated protein kinase pathway, including BRAF. The BRAFV600E mutation is associated with improved prognosis in SBT and LGSC, and responses to BRAF inhibitor therapy have been reported. We sought to characterize the clinicopathologic and molecular features of BRAF-driven tubo-ovarian and primary peritoneal serous tumors. METHODS Retrospective analysis of our institutional cohort of SBTs (n = 22), LGSCs (n = 119) and high-grade serous carcinomas (HGSCs, n = 1,290) subjected to targeted massively parallel sequencing was performed to identify cases with BRAF genetic alterations. Putative BRAF rearrangements were confirmed using targeted RNA sequencing and/or fluorescence in situ hybridization (FISH). BRAFV600E oncoprotein expression was assessed by immunohistochemistry on selected cases. RESULTS BRAF somatic genetic alterations were identified in 29 of 1,431 (2%) serous tumors and included mutations (n = 24), gene rearrangements (n = 3), and amplification (n = 2). BRAF mutations were more frequent in SBTs (7 of 22; 32%) compared with LGSCs (11 of 119; 9%, P = .009) and HGSCs (6 of 1,290; 0.5%; P < .0001, SBT/LGSC v HGSC). The BRAFV600E hotspot mutation was most common (n = 16); however, other BRAF driver mutations were also detected (n = 8). BRAF mutations were often clonal or truncal in SBTs and LGSCs, but subclonal in most HGSCs. Pathogenic BRAF gene fusions were identified in LGSCs (n = 2) and HGSC (n = 1) and involved distinct fusion partners ( AGK, MKRN1, and AGAP3). Three patients with BRAF-mutant LGSC were treated with targeted mitogen-activated protein kinase inhibitors, one of whom was maintained on therapy for over 3 years with clinical benefit. CONCLUSION Recognition of BRAF alterations beyond V600E mutation in LGSC may have clinical implications for appropriate targeted therapy selection.

Cytology of peritoneal implants of borderline serous tumor of ovaries in ascitic fluid

Objectives: Peritoneal fluid cytology is done routinely in cases with serous carcinoma of ovary. However, morphologic features of borderline serous tumors (BSTs) of ovary in ascitic fluid have been rarely described. The aim of our study was to evaluate the morphologic features of BST with and without ascitic fluid involvement (BST+ and BST-, respectively) and compare with those of serous carcinomas, both in conventional and liquid-based cytology (LBC) smears. Material and Methods: Out of 30 BST cases reported in 3 years, seven cases had BST+. We compared the cytomorphology of seven cases of BST+, seven cases of BST-, and seven cases of serous adenocarcinoma with positive ascitic fluid cytology. Both conventional and LBC smears were studied in all cases and compared. Histopathology of omentum in these cases was also studied. Results: Most cases with BST+ had regular papillary fragment borders with nuclei showing mild-to-moderate pleomorphism, fine nuclear chromatin with small nucleoli as compared with serous carcinomas all of which had irregular borders with moderate-to-severe nuclear pleomorphism, coarse chromatin, and macronucleoli. Conclusion: A combination of cytoarchitectural and nuclear features can help in suspecting BST in ascitic fluid. Ascitic fluid cytology together with tissue histology can increase the rate of the detection of peritoneal implants.

Histomorphological Spectrum of Ovarian Masses in a Tertiary Centre of Eastern Nepal

Aims: To analyze the trends of ovarian masses in a tertiary centre in eastern Nepal. Methods: This was a retrospective cross sectional study conducted in Department of Pathology at Nobel Medical College and teaching hospital, Biratnagar, Nepal. Database of two years from April 2019 to April 2021 was searched. Gross and microscopic findings of cases including demographic details of patients with ovarian mass were analyzed and presented by descriptive parameters. Results: Out of 127 cases of ovarian masses studied, 95 (74.8%) were neoplastic. The common types were Germ cell tumors were (47; 37%), epithelial tumors (43; 33.9%) and endometriotic cyst (23; 18.1%). Mean age was 38.1 (range: 17-77) years in benign, 47.1 (30 – 70) years in malignant and 36.9 (21-53) years in non-neoplastic tumors; 11 cases were malignant and 63.6% were solid; and 23.8% of serous tumors were bilateral. Conclusions: Benign neoplastic lesions were the most common lesions and presented earlier than borderline and malignant lesions. Endometriotic cysts comprised the most common non- neoplastic lesions. The non-neoplastic lesions were predominantly cystic and the malignant lesions were predominantly solid. Most of the benign lesions were solid-cystic. Most mucinous tumors and all the sex-cord stromal tumors were unilateral while the seromucinous tumor and a significant number of serous tumors were bilateral.

A mini-review regarding the carcinogenesis and morphology of serous tumors of the ovary, fallopian tube and peritoneum

Similar to the already well-recognized adenoma-carcinoma sequence in colorectal cancer pathogenesis, it has been believed for many decades that the progression of ovarian epithelial tumors occurs from benign serous cystadenomas to borderline tumors, to well-differentiated carcinomas, and ultimately, to poorly differentiated carcinomas. However, it is currently accepted that low-grade serous carcinoma (LGSC) and high-grade serous carcinoma (HGSC) are fundamentally different tumor types and, consequently, different diseases. In fact, whereas the benign-borderline-malignant sequence seems to apply quite well to low-grade serous carcinoma, the sequence of genetic alterations in high-grade serous carcinoma is substantially different. In this mini-review, we included the current consensus regarding the morphological and etiopathogenic results regarding serous tumors of the ovary, fallopian tube and peritoneum. It also briefly describes the history of benign, borderline and malignant serous tumors, discussing multiple types of dichotomies in serous carcinomas of the female genital tract and summarizing the current molecular classification.

Borderline Ovarian Tumors

Borderline ovarian tumors (BOTs) are a specific subgroup of ovarian tumors and are characterized by cell proliferation and nuclear atypia without invasion or stromal invasion. They are usually more present in younger people than the invasive ovarian cancer and are diagnosed at an early stage and thus have a better prognosis. Histologically, borderline tumors are divided into serous (50%), mucosal (46%), and mixed (4%). The serous tumors are bilateral in 30% of the cases and are accompanied by infiltrations outside the ovary in 35% of the cases. These infiltrations may be non-invasive or invasive depending on their microscopic appearance and may affect treatment. Surgery is the approach of choice, and laparoscopic surgery, with the undeniable advantages it offers today, is the “gold standard.” All the surgical steps required to properly treat borderline tumors, at both diagnostic and therapeutic levels, can be safely and successfully be applied laparoscopically. Manipulations during surgery should be limited, and biopsies for rapid biopsy should be done within an endoscopic bag.