N6-Methyladenosine-Modified KREMEN2 Promotes Tumorigenesis and Malignant Progression of High-Grade Serous Ovarian Cancer.

High-grade serous ovarian cancer (HGSOC) remains the most lethal female cancer by far. Herein, clinical HGSOC samples had higher N6-methyladenosine (m6A) modification than normal ovarian tissue, and its dysregulation had been reported to drive aberrant transcription and translation programs. However, Kringle-containing transmembrane protein 2 (KREMEN2) and its m6A modification have not been fully elucidated in HGSOC. In this study, the data from the high-throughput messenger RNA (mRNA) sequencing of clinical samples were processed using the weighted correlation network analysis and functional enrichment analysis. Results revealed that KREMEN2 was a driver gene in the tumorigenesis of HGSOC and a potential target of m6A demethylase fat-mass and obesity-associated protein (FTO). KREMEN2 and FTO levels were upregulated and downregulated, respectively, and correlation analysis showed a significant negative correlation in HGSOC samples. Importantly, upregulated KREMEN2 was remarkably associated with lymph node metastasis, distant metastasis, peritoneal metastasis, and high International Federation of Gynecology and Obstetrics stage (Ⅲ/Ⅳ), independent of the age of patients. KREMEN2 promoted the growth of HGSOC in vitro and in vivo, which was dependent on FTO. The methylated RNA immunoprecipitation qPCR and RNA immunoprecipitation assays were performed to verify the m6A level and sites of KREMEN2. FTO overexpression significantly decreased m6A modification in the 3' and 5' untranslated regions of KREMEN2 mRNA and downregulated its expression. In addition, we found that FTO-mediated m6A modification of KREMEN2 mRNA was recognized and stabilized by the m6A reader IGF2BP1 rather than by IGF2BP2 or IGF2BP3. This study highlights the m6A modification of KREMEN2 and extends the importance of RNA epigenetics in HGSOC.

First Reported Histologically and Molecularly Confirmed Bilateral High-Grade Serous Ovarian Adenocarcinoma Metastasized to Placental Decidua of the Membranes.

A 43-year-old female presented with blood loss and persistent abdominal pain at 14 weeks of gestation. Ultrasound examination and subsequent magnetic resonance imaging (MRI) revealed bilateral multicystic uterine adnexa. Exploratory laparotomy was performed at 17 weeks of gestation and bilateral serous ovarian adenocarcinoma FIGO stage IIIC was diagnosed. Complete cytoreductive surgery (CRS) was not feasible at that moment. Nine days after the exploratory laparotomy, immature rupture of membranes and contractions occurred and she delivered a premature boy after 19 weeks of gestation. Pathological examination of the placenta revealed that her ovarian cancer metastasized to the membranes. We describe the first case of ovarian cancer metastasized to the decidua of the placental membranes with histological, immunohistochemical, and molecular confirmation. This case highlights the importance of conscientious evaluation of placenta and membranes in pregnant women with ovarian cancer.

In vivo modeling of metastatic human high-grade serous ovarian cancer in mice.

Metastasis is responsible for 90% of human cancer mortality, yet it remains a challenge to model human cancer metastasis in vivo. Here we describe mouse models of high-grade serous ovarian cancer, also known as high-grade serous carcinoma (HGSC), the most common and deadliest human ovarian cancer type. Mice genetically engineered to harbor Dicer1 and Pten inactivation and mutant p53 robustly replicate the peritoneal metastases of human HGSC with complete penetrance. Arising from the fallopian tube, tumors spread to the ovary and metastasize throughout the pelvic and peritoneal cavities, invariably inducing hemorrhagic ascites. Widespread and abundant peritoneal metastases ultimately cause mouse deaths (100%). Besides the phenotypic and histopathological similarities, mouse HGSCs also display marked chromosomal instability, impaired DNA repair, and chemosensitivity. Faithfully recapitulating the clinical metastases as well as molecular and genomic features of human HGSC, this murine model will be valuable for elucidating the mechanisms underlying the development and progression of metastatic ovarian cancer and also for evaluating potential therapies.

Can risk groups accurately predict non-sentinel lymph node metastasis in sentinel lymph node-positive endometrial cancer patients? A Turkish Gynecologic Oncology Group Study (TRSGO-SLN-004).

BACKGROUND AND OBJECTIVES: The purpose of this study was to find out the risk factors associated with non-sentinel lymph node metastasis and determine the incidence of non-sentinel lymph node metastasis according to risk groups in sentinel lymph node (SLN)-positive endometrial cancer patients. METHODS: Patients who underwent at least bilateral pelvic lymphadenectomy after SLN mapping were retrospectively analyzed. Patients were categorized into low, intermediate, high-intermediate, and high-risk groups defined by ESMO-ESGO-ESTRO. RESULTS: Out of 395 eligible patients, 42 patients had SLN metastasis and 16 (38.1%) of them also had non-SLN metastasis. Size of SLN metastasis was the only factor associated with non-SLN metastasis (p = .012) as 13/22 patients with macrometastasis, 2/10 with micrometastasis and 1/10 with isolated tumor cells (ITCs) had non-SLN metastasis. Although all 4 metastases (1.8%) among the low-risk group were limited to SLNs, the non-SLN involvement rate in the high-risk group was 42.9% and all of these were seen in patients with macrometastatic SLNs. CONCLUSIONS: Non-SLN metastasis was more frequent in higher-risk groups and the risk of non-SLN metastasis increased with the size of SLN metastasis. Proceeding to complete lymphadenectomy when SLN is metastatic should further be studied as the effect of leaving metastatic non-SLNs in-situ is not known.

Hypermethylation of Genes in New Long Noncoding RNA in Ovarian Tumors and Metastases: A Dual Effect.

The role of methylation in the regulation of genes of long noncoding RNA (lncRNA) is still poorly understood. We revealed new hypermethylated lncRNA genes in ovarian tumors and their effect on metastasis of ovarian cancer. A multiple and significant (p<0.001) increase in methylation of a group of lncRNA genes (MEG3, SEMA3B-AS1, ZNF667-AS1, and TINCR) was shown by quantitative methylation-specific PCR using the non-parametric Mann-Whitney test. Moreover, methylation of SEMA3B-AS1, ZNF667-AS1, and TINCR genes in ovarian cancer tumors was detected for the first time. Comparative analysis of 19 samples of peritoneal metastases and paired primary tumors showed a significant decrease in the methylation level of the same 4 genes: MEG3 (p=0.004), SEMA3B-AS1 (p=0.002), TINCR (p=0.002), and ZNF667-AS1 (p<0.001). Reduced methylation of suppressor lncRNA genes in peritoneal metastases is probably associated with the involvement of these lncRNA in the regulation of plastic reversion of the epithelial-mesenchymal transition to the mesenchymal-epithelial transition. Thus, the effect of lncRNA and their methylation on the development of tumors and metastases of ovarian cancer was demonstrated, which is important for understanding of the pathogenesis and mechanisms of metastasis of ovarian cancer. New properties of lncRNA can find application in the development of new approaches in the therapy of ovarian cancer.

The relationship between retroperitoneal lymphadenectomy and survival in advanced ovarian cancer patients.

BACKGROUND: Systematic retroperitoneal lymphadenectomy has been widely used in the surgical treatment of advanced ovarian cancer patients. Nevertheless, the corresponding therapeutic may not provide a survival benefit. The aim of this study was to assess the effect of systematic retroperitoneal lymphadenectomy in such patients. METHODS: Patients with advanced ovarian cancer (stage III-IV, according to the classification presented by the International Federation of Gynecology and Obstetrics) who were admitted and treated in Zhejiang Cancer Hospital from January 2004 to December 2013 were enrolled and reviewed retrospectively. All patients were optimally or suboptimally debulked (absent or residual tumor < 1 cm) and divided into two groups. Group A (no-lymphadenectomy group, n = 170): patients did not undergo lymph node resection; lymph nodes resection or biopsy were selective. Group B (n = 240): patients underwent systematic retroperitoneal lymphadenectomy. RESULTS: A total of 410 eligible patients were enrolled in the study. The patients' median age was 51 years old (range, 28-72 years old). The 5-year overall survival (OS) and 2-year progression-free survival (PFS) rates were 78 and 24% in the no-lymphadenectomy group and 76 and 26% in the lymphadenectomy group (P = 0.385 and 0.214, respectively). Subsequently, there was no significant difference in 5-year OS and 2-year PFS between the two groups stratified to histological types (serous type or non-serous type), the clinical evaluation of negative lymph nodes or with macroscopic peritoneal metastasis beyond pelvic (IIIB-IV). Multivariate Cox regression analysis indicated that systematic retroperitoneal lymphadenectomy was not a significant factor influencing the patients' survival. Patients in the lymphadenectomy group had a higher incidence of postoperative complications (incidence of infection treated with antibiotics was 21.7% vs. 12.9% [P = 0.027]; incidence of lymph cysts was 20.8% vs. 2.4% [P < 0.001]). CONCLUSIONS: Our study showed that systematic retroperitoneal lymphadenectomy did not significantly improve survival of advanced ovarian cancer patients with residual tumor < 1 cm or absent after cytoreductive surgery, and were associated with a higher incidence of postoperative complications.

Malignant peritoneal cytology and increased mortality risk in stage I non-endometrioid endometrial cancer.

OBJECTIVE: To examine the survival of women with stage I non-endometrioid endometrial cancer with malignant peritoneal cytology. METHODS: A retrospective observational cohort study was conducted to examine the National Cancer Institute's Surveillance, Epidemiology, and End Results Program from 2010 to 2016. Women with stage I serous, clear cell, carcinosarcoma, undifferentiated, and mixed endometrial cancer with known peritoneal cytology results at hysterectomy were examined (N = 4506). Propensity score inverse probability of treatment weighting was used to balance the measured covariates, and survival outcomes were assessed according to peritoneal cytology results. RESULTS: Malignant peritoneal cytology was reported in 401 (8.9%) women. In multivariable analysis, older age, serous histology, and large tumors were associated with an increased likelihood of malignant peritoneal cytology (all, P < 0.05). In a propensity score weighted model, malignant peritoneal cytology was associated with a nearly two-fold increase in all-cause mortality risk compared to negative peritoneal cytology (5-year rates, 63.4% versus 80.2%, hazard ratio 2.18, 95% confidence interval 1.78-2.66). In sensitivity analyses, malignant peritoneal cytology was associated with decreased overall survival in old and young age groups, serous, clear cell, carcinosarcoma, and mixed histology groups, stage T1a disease, and staged and unstaged cases, but not for stage T1b disease. Difference in 5-year overall survival rates between the malignant and negative peritoneal cytology groups was particularly large among those with clear cell histology (24.0%), stage T1a disease (19.4%), aged >78 years (18.2%), and serous tumors (17.6%). CONCLUSION: Malignant peritoneal cytology can be prevalent in stage I non-endometrioid endometrial cancer. Our study suggests that malignant peritoneal cytology is a prognostic factor for decreased survival in stage I non-endometrioid endometrial cancer.

Potential clinical application of tumor-infiltrating lymphocyte therapy for ovarian epithelial cancer prior or post-resistance to chemotherapy.

BACKGROUND: Immunotherapy has become a powerful treatment option for several solid tumor types. The presence of tumor-infiltrating lymphocytes (TIL) is correlated with better prognosis in ovarian cancer, pointing at the possibility to benefit from harnessing their anti-tumor activity. This preclinical study explores the feasibility of adoptive cell therapy (ACT) with TIL using an improved culture method. METHODS: TIL from high-grade serous ovarian cancer were cultured using a combination of IL-2 with agonistic antibodies targeting 4-1BB and CD3. The cells were phenotyped using flow cytometry in the fresh tissue and after expansion. Tumor reactivity was assessed against HLA-matched ovarian cancer cell lines via IFN-γ ELISPOT. RESULTS: Ovarian cancer is highly infiltrated with CD8+ TIL that are preferentially and robustly expanded with the addition of the agonistic antibodies. With a 95% success rate, the TIL are grown to ≥ 100 × 106 cells in 2-3 weeks without over differentiation. In addition, the CD8+ TIL grown with this method showed HLA-restricted tumor recognition. CONCLUSIONS: These results indicate the viability of TIL ACT for refractory ovarian cancer by allowing for the large expansion of anti-tumor TIL in a short time and consistent manner.

Expression profiles of VEGF-A, VEGF-D and VEGFR1 are higher in distant metastases than in matched primary high grade epithelial ovarian cancer.

BACKGROUND: In many malignancies including ovarian cancer, different angiogenic factors have been related to poor prognosis. However, data on their relations to each other or importance as a prognostic factor in ovarian cancer is missing. Therefore, we investigated the expressions of VEGF-A, VEGF-C, and VEGF-D, and the receptors VEGFR1, VEGFR2, and VEGFR3 in patients with malignant epithelial ovarian neoplasms. We further compared expression levels between primary tumors and related distant omental metastases. METHODS: This study included 86 patients with malignant ovarian epithelial tumors and 16 related distant metastases. Angiogenic factor expression was evaluated using immunohistochemistry (n = 102) and qRT-PCR (n = 29). RESULTS: Compared to primary high grade serous ovarian tumors, the related omental metastases showed higher expressions of VEGF-A (p = 0.022), VEGF-D (p = 0.010), and VEGFR1 (p = 0.046). In univariate survival analysis, low epithelial expression of VEGF-A in primary tumors was associated with poor prognosis (p = 0.024), and short progression-free survival was associated with high VEGF-C (p = 0.034) and low VEGFR3 (p = 0.002). The relative expressions of VEGF-D, VEGFR1, VEGFR2, and VEGFR3 mRNA determined by qRT-PCR analyses were significantly correlated with the immunohistochemically detected levels of these proteins in primary high grade serous ovarian cancer and metastases (p = 0.004, p = 0.009, p = 0.015, and p = 0.018, respectively). CONCLUSIONS: The expressions of VEGF receptors and their ligands significantly differed between malignant ovarian tumors and paired distant metastases. VEGF-A, VEGF-D, and VEGFR1 protein expressions seem to be higher in distant metastases than in the primary high grade serous ovarian cancer lesions.

Rare metastatic patterns after malignant transformation of serous borderline tumor of the ovary.

Serous borderline tumors are rare, benign ovarian neoplasms that may recur and undergo malignant transformation to low-grade serous carcinomas (LGSCs). In this report, a 50-year-old female with a remote history of a serous borderline ovarian tumor experienced a recurrence of LGSC, presenting as a large solitary subcutaneous mass anterior to the sternum after a 33-year disease-free interval. The described case highlights the unpredictable nature of this disease and the importance of implementing lifelong surveillance strategies.

One-step nucleic acid amplification vs ultrastaging in the detection of sentinel lymph node metastasis in endometrial cancer patients.

BACKGROUND AND OBJECTIVES: Utilisation of the one-step nucleic acid amplification (OSNA) molecular biology method for the detection of the metastatic involvement of sentinel lymph nodes (SLNs) in endometrial cancer (EC) patients. A comparison with histopathological ultrastaging and a description of the clinical consequences. METHODS: Surgically treated EC patients underwent detection of SLNs. Nodes greater than 5 mm were cut into sections 2-mm thick parallel to the short axis of the node. Odd sections were examined according to the OSNA method, while even ones according to an appropriate ultrastaging protocol. Nodes less than or equal to 5 mm were cut into halves along the longitudinal axis with one half examined according to the OSNA method and the other half by ultrastaging. RESULTS: Fifty-eight patients were included and 135 SLNs were acquired. Both ultrastaging and OSNA agreed on 116 results. According to the OSNA method, 20.69% more patients were classified into International Federation of Gynecology and Obstetrics (FIGO) stage III. When comparing the results of the OSNA method to the conclusions of ultrastaging as a reference method, sensitivity of 90.9%, specificity of 85.5% and concordance of 85.9% were attained. CONCLUSIONS: The results of the OSNA method showed a higher frequency of detection of micrometastases and included 20.69% more patients into FIGO stage III.

Knockdown of MALAT1 enhances chemosensitivity of ovarian cancer cells to cisplatin through inhibiting the Notch1 signaling pathway.

Long non-coding RNAs (lncRNAs) are critical regulators in chemoresistance of various tumors including ovarian cancer. Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) has been reported to be upregulated and contributed to ovarian cancer tumorigenesis. The aim of this study was to explore the roles of MALAT1 and the underlying molecular regulatory mechanism in the chemoresistance of ovarian cancer cells. Our data demonstrated that MALAT1 and Notch1 mRNA were upregulated in ovarian cancer tissues, as well as cisplatin (CDDP)-resistant ovarian cancer cells. A positive correlation between MALAT1 and Notch1 mRNA expression was observed. MALAT1 knockdown significantly attenuated CDDP resistance, and enhanced CDDP-induced apoptosis in CDDP-resistant ovarian cancer cells. MALAT1 knockdown enhanced CDDP-induced apoptosis in vivo, as indicated by upregulation of Bax protein expression and downregulation of Bcl-2 protein expression. Additionally, MALAT1 knockdown inhibited the Notch1 pathway and ABCC1 expression in CDDP-resistant ovarian cancer cells. MALAT1 was demonstrated to interact with Notch1. Notch1 knockdown attenuated CDDP resistance, and downregulated the protein expression of ABCC1 in ovarian cancer cells. Taken together, our findings suggested that knockdown of MALAT-1 enhanced chemosensitivity of ovarian cancer cells to CDDP through inhibiting Notch1 signaling pathway.

Cardiophrenic lymph node resection in cytoreduction for primary advanced or recurrent epithelial ovarian carcinoma: a cohort study.

OBJECTIVES: To evaluate the clinical outcomes of epithelial ovarian carcinoma patients who underwent cardiophrenic lymph node resection. METHODS: We retrospectively reviewed the records of all surgically treated patients with advanced epithelial ovarian carcinoma (stages IIIC-IV) who underwent cardiophrenic lymph node resection between 2002 and 2018. Only those in whom cardiophrenic lymph node involvement was the only detectable extra-abdominal disease were included. Patients with suspected cardiophrenic lymph node metastasis on staging images underwent a transdiaphragmatic incision to access the para-cardiac space after complete abdominal cytoreduction achievement. Data on disease-free survival, overall survival, and surgical procedures performed concurrently with cardiophrenic lymph node resection were collected. RESULTS: Of the total 456 patients, 29 underwent cardiophrenic lymph node resection; of these, 24 patients met the inclusion criteria. Twenty-two, one, and one patients had high grade serous epithelial ovarian carcinoma, low grade epithelial ovarian carcinoma, and ovarian carcinosarcoma, respectively. Ten patients had recurrent disease (recurrence group). Fourteen patients underwent cytoreduction during primary treatment (primary debulking group); four underwent cytoreduction after neoadjuvant chemotherapy. Cardiophrenic lymph node resection was performed on the right side in 19 patients, left side in three, and bilaterally in two. The average procedural duration was 28 minutes, with minimal blood loss and no severe complications. Twenty-one patients had cardiophrenic lymph node positivity. The median disease-free intervals were 17 and 12 months in the recurrent and primary debulking surgery groups, respectively. The mediastinum was the first recurrence site in 10 patients. Five patients developed brain metastases. Five patients had an overall survival beyond 50 months. CONCLUSIONS: Although rare, the cardiophrenic lymph nodes may be a site of metastasis of ovarian cancer. Although their presence might indicate future recurrence, some patients may achieve long-term survival. Resection should be considered in cases of suspicious involvement to confirm extra-abdominal disease and achieve complete cytoreduction.

Breast metastasis two years after pelvic surgery and adjuvant chemotherapy for serous ovarian cancer.

Ovarian cancer is considered the leading cause of death among gynecologic neoplasias. Breast metastases from primary ovarian cancer have been reported in only 0.03-0.6% of all breast cancers. A 38-year-old female, multipara, affected by advanced ovarian cancer and undergone a total abdominal hysterectomy with bilateral salpingo-oophorectomy, omentectomy, and pelvic peritonectomy two years earlier, was discovered to have a breast metastasis. She underwent a quadrantectomy (QSI) with an open biopsy of nodularity attached to the pectoral muscle fascia: on definitive histological characterization the breast lesions showed a high-grade invasive carcinoma, with papillary serum differentiation, and the immunohistochemistry study of breast lesion showed positivity for cytokeratin 7 and an extensive positivity for Wilm's tumor (WT)-1 and paired box 8 (PAX8). These aspects are indicative of mammary metastasis from carcinoma of ovarian origin. Despite their rarity, metastases to breast from ovarian cancer should be considered possible because their recognition and differentiation compared to primary tumors are crucial for prognosis. Future clinical studies on MOCB should be performed to discover new specific markers for a more accurate histopathological diagnosis and to establish the real need of surgical treatment.

Durable response by olaparib for a Japanese patient with primary peritoneal cancer with multiple brain metastases: A case report.

Brain metastases (BM) from epithelial ovarian cancer (EOC) or primary peritoneal cancer (PPC) are extremely rare, accounting for 1-2.5% of all cases. Although therapeutic options, such as surgery, irradiation and chemotherapy are proven to yield survival benefit, the overall prognosis of these patients remains unsatisfactory. Poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitor, olaparib is useful for patients with recurrent EOC or PPC. However, reports suggesting the efficacy of PARP inhibitors for patients with EOC or PPC with BM are limited. We report the case of a 58-year-old Japanese woman with recurrent PPC with multiple BM. After obtaining informed consent from the patient, we performed BRCA testing that detected a deleterious BRCA 1 mutation. At that time, olaparib was not yet approved in Japan, we learned about the compassionate use program of olaparib called Managed Access Program (MAP). Of note, we have established a system to enroll patients in MAP. After olaparib treatment, the patient exhibited a considerable decrease of BMs. Eighteen months since the initiation of olaparib treatment, the patient has reported no evidence of disease progression. Olaparib maintenance treatment could be effective for Japanese patients with PPC and multiple BMs.

Penetration in 3D tumor spheroids and explants: Adding a further dimension to the structure-activity relationship of cell-penetrating peptides.

Drug delivery into tumors and metastases is a major challenge in the eradication of cancers such as epithelial ovarian carcinoma. Cationic cell-penetrating peptides (CPPs) are a promising group of delivery vehicles to mediate cellular entry of molecules that otherwise poorly enter cells. However, little is known about their penetration behavior in tissues. Here, we investigated penetration of cationic CPPs in 3D ovarian cancer spheroids and patient-derived 3D tumor explants. Penetration kinetics and distribution after long-term incubation were imaged by confocal microscopy. In addition, spheroids and tumor explants were dissociated and cell-associated fluorescence determined by flow cytometry. CPPs with high uptake activity showed enhanced sequestration in the periphery of the spheroid, whereas less active CPPs were able to penetrate deeper into the tissue. CPPs consisting of d-amino acids were advantageous over l-amino acid CPPs as they showed less but long lasting cellular uptake activity, which benefitted penetration and retention over time. In primary tumor cultures, in contrast to nonaarginine, the amphipathic CPP penetratin was strongly sequestered by cell debris and matrix components pointing towards arginine-rich CPPs as a preferred choice. Overall, the data show that testing in 3D models leads to a different choice of the preferred peptide in comparison to a standard 2D cell culture.

Stage- and Histologic Subtype-Dependent Frequency of Lymph Node Metastases in Patients with Epithelial Ovarian Cancer Undergoing Systematic Pelvic and Paraaortic Lymphadenectomy.

PURPOSE: Tumor stage and distinct histological subtypes in epithelial ovarian cancer (EOC) show different prognostic outcome. The aim of this study is to evaluate whether the frequency of lymph node (LN) metastases in patients with different tumor stages and histological subtypes undergoing systematic pelvic and paraaortic lymphadenectomy is coincidentally divergent. METHODS: Patients with EOC treated with upfront staging or debulking surgery between January 2000 and December 2016 were included. Systematic lymphadenectomy was performed in all consecutive patients with optimal debulking and without medical contraindications. RESULTS: Seven hundred sixty-two patients including 27.2% with early-stage EOC were included. The median number of removed LNs was 69, and metastases to LNs were found in 54.7%. No LN metastases were found in patients with low-grade endometrioid carcinoma, independently of tumor stage. LN metastases in early-stage low-grade serous (N = 5), mucinous (N = 31), and clear cell (N = 28) EOC were found in one (20%), zero, and one (3.6%) patient, respectively. LN metastases were detected in more than 10% of patients with all other histological subtypes. On multivariate analyses, overall survival was significantly impaired in patients with LN metastases, as compared with patients without LN metastases (p = 0.001). CONCLUSIONS: The risk of LN metastases in patients with EOC is dependent on stage and histological subtype. Patients with incidental finding of early mucinous or low-grade endometrioid EOC are at very low risk of retroperitoneal lymph node metastases. Reoperation for lymph node staging only should be discussed individually with caution.

Disease Distribution in Low-stage Tubo-ovarian High-grade Serous Carcinoma (HGSC): Implications for Assigning Primary Site and FIGO Stage.

The latest FIGO and TNM (eighth edition) staging systems for ovarian, tubal, and peritoneal neoplasms require primary site assignment as tubal/ovarian/peritoneal, but provide no guidance or criteria. Fewer than 10% of extrauterine high-grade serous carcinoma (HGSC) cases present at low stage (stage I/II). Low-stage cases offer a unique opportunity to understand the pattern of disease early in its evolution prior to wide dissemination and provide valuable evidence for guiding specimen handling and tumor staging. This study aimed to examine disease distribution in low-stage tubo-ovarian HGSC. Anonymized pathology reports of 152 stage I/II extrauterine HGSCs from 6 teaching hospitals were analyzed: group 1 (n=67) comprised cases with complete tubal examination by Sectioning and Extensively Examining the FIMbriated end of the tube (SEE-FIM) and group 2 (n=85) consisted of cases without documentation of both tubes being fully examined by the SEE-FIM or a SEE-FIM-like protocol. The stage, site/pattern of involvement, site/size of largest tumor focus and laterality of tubal and ovarian involvement were recorded. Tubal mucosal involvement was present in 95% of optimally examined cases and many factors influenced detection of tubal disease. Bilateral involvement, suggestive of metastasis, was significantly more frequent in the ovaries (35%) than the tubes (9%) (P<0.0001, Fisher exact test). No case showed a complete absence of tubal/ovarian involvement, questioning the biological existence of primary peritoneal HGSC. Disease distribution in low-stage cases supports a tubal origin for most HGSCs. Detailed tubal sampling upstages some apparent stage I cases through detection of microscopic tubal involvement.

Atypical Proliferative (Borderline) Serous Tumor in the Brain: A Case Report.

A 59-year-old woman with a remote history of invasive ductal carcinoma of the breast was found on a follow-up computed tomography scan of her brain to have a 1-cm lesion in the right frontal lobe in 2008. In the ensuing years, before her current admission, multiple imaging studies of the brain revealed that the lesion was stable and it was, therefore, interpreted as a small area of encephalomalacia related to a thrombosed cortical vein, a cavernoma, or treated metastatic breast cancer. In 2013, the patient underwent a bilateral salpingo-oophorectomy for ovarian tumors that were diagnosed as bilateral serous cystadenofibromas. A partial omentectomy showed no evidence of implants. In June 2016, the brain lesion was completely excised and diagnosed as an atypical proliferative (borderline) serous tumor. Immunohistochemical staining demonstrated that the tumor cells were immunoreactive for Pax8, WT-1, ER, and CK-7 and negative for Gata-3, PR, TTF-1, CDX-2, Napsin A, and CK-20, which was consistent with that diagnosis. We present a brief review of possible mechanisms to account for this unusual presentation and speculate that the most likely one is exfoliation of fallopian tube epithelial cells into the peritoneal cavity, which then gain access to lymphatics resulting in cells implanting in the brain and subsequently progressing to an atypical proliferative (borderline) serous tumor.