Synchronous skull base and spinal metastases in a patient with treatment-resistant, high-grade serous adenocarcinoma of tubo-ovarian origin.

Brain metastases (BMs) arising from ovarian cancer remain rare. Spinal cord metastases are even rarer, accounting for just 0.4% of total metastatic spinal cord compressions. In this report, we describe a case of a woman in her 70s who developed sequential brain and spinal cord metastases during her treatment for high-grade serous ovarian cancer, without a germline or somatic BRCA mutation. Following completion of neoadjuvant chemotherapy, interval debulking surgery and adjuvant chemotherapy, relapsed disease was ultimately identified as a single BM, curiously mimicking an acoustic neuroma. Subsequently, spinal cord metastases rapidly developed. Throughout, multidisciplinary team meetings guided decisions on patient management. In this report, we highlight the rarity of such a presentation and discuss the possible role of disease pathophysiology, associated systemic anticancer therapy resistance, and treatment possibilities for both cerebral and spinal metastases.

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.

Metastasis of serous ovarian carcinoma to the breast: a case report and review of the literature.

BACKGROUND: Breast metastasis from primary ovarian cancer is rare, with an estimated frequency of 0.07%. More than 110 cases are reported in the literature of metastatic spread of ovarian cancer to the breast and axilla. This entity usually represents aggressive late disease characterized by multi-drug chemoresistance and a poor prognosis with a median survival time of 16 months. Currently no standardized treatment protocol exists for this condition. CASE PRESENTATION: We present a case of a 59-year-old Caucasian female with recurrent high-grade serous ovarian cancer who was diagnosed with symptomatic unilateral breast metastasis while on fourth line chemotherapy with weekly paclitaxel. She was treated with local radiation with 2300 cGy to the right breast with a complete response. She then had a subsequent recurrence in the ipsilateral breast 8 months after completion of post treatment imaging. She remains alive to date approximately 2 years after her initial diagnosis of breast metastasis on seventh line treatment. CONCLUSIONS: Breast metastasis from primary ovarian cancer is rare and represents advanced disease characterized by multi-drug chemoresistance and a poor prognosis. This case describes radiation therapy as a safe, effective treatment option to improve local control and quality of life in these patients, but with limited durability of response.

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.

Metastatic spread of serous ovarian carcinoma to the bilateral breasts: a rare presentation.

A woman presented with a mass in her right breast. She had previously been treated with carboplatin, paclitaxel and bevacizumab for serous ovarian carcinoma diagnosed 5 years previously and was currently on maintenance olaparib. A right breast mammogram demonstrated periareolar skin thickening and the physical examination revealed an erythematous, non-blanching cutaneous lesion. A punch biopsy revealed high-grade serous carcinoma of ovarian origin, positive for PAX-8, WT-1 and p53. Positron emission tomogram-CT scan showed diffusely increased fluorodeoxyglucose uptake in the right breast. She was treated with external beam radiation therapy to the right breast and regional lymphatics and received 5200 cGy in 20 fractions to the right breast and supraclavicular region with good response. Two weeks after completing radiation therapy, she presented with a new lesion inferior to her left areola, concerning for metastasis to the contralateral breast. Subsequent biopsy of the left breast identified metastatic serous ovarian carcinoma for which she received an additional 5200 cGy in 20 fractions to the breast.

Carcinosarcoma arising from high-grade serous carcinoma of the ovary without estrogen receptor, WT-1, and PAX8 immunoreactivity.

OBJECTIVE: We encountered a case of high-grade serous carcinoma (HGSC) of the ovary which recurred as carcinosarcoma of the sigmoid colon. Tumor cells of both the primary carcinoma and the secondary carcinosarcoma were negative for estrogen receptor (ER), WT-1, and PAX8. It is well known that most ovarian carcinomas arising from the Müllerian duct are immunoreactive for these biologic parameters. To our knowledge, this is the first case report that provides the results of immunohistochemical analysis of WT-1 and PAX8 for a primary carcinoma and recurrent carcinosarcoma. CASE REPORT: A 61-year-old woman had an advanced right ovarian HGSC. After a primary debulking surgery (hysterectomy, bilateral salpingo-oophorectomy and omentectomy) and adjuvant chemotherapy, complete remission was achieved. However, four and a half years later, a tumor arising beside the sigmoid colon was detected. A tumorectomy was performed through combined partial resection of the ileum and sigmoid colon. Microscopically, the tumor was diagnosed as carcinosarcoma of the sigmoid colon, which had originated from HGSC of the ovary. Interestingly, the malignant cells of the primary carcinoma and epithelial components of the recurrent carcinosarcoma were negative for ER, WT-1, and PAX8. These immunohistochemical features were unusual. Three cycles of chemotherapy with the previously used regimen and three additional cycles of doxorubicin and ifosfamide combination chemotherapy were administered. Currently, 3 years after the final chemotherapy was administered, the patient remains healthy. CONCLUSION: HGSC of the ovary can recur as carcinosarcoma. Tumor cells of the primary HGSC without ER, WT-1, and PAX8 expression may have dedifferentiated and recurred as carcinosarcoma.

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.

Cardiophrenic Lymph Node Metastasis of Ovarian High-grade Serous Carcinoma Showing Wild-type p53 Immunostaining Pattern and Aberrant CD56 Expression.

Patterns of p53 immunostaining are used as a surrogate marker for tumor protein 53 (TP53) mutations in the diagnosis of ovarian high-grade serous carcinoma (HGSC). We present a rare case of ovarian HGSC that metastasized to the diaphragm and cardiophrenic lymph nodes and showed the immunostaining pattern of wild-type p53 and aberrant neural cell adhesion molecule (CD56) expression. A 63-year-old woman developed multifocal metastases in the diaphragmatic pleura and cardiophrenic lymph nodes. Because she had a history of ovarian HGSC and pulmonary adenocarcinoma, we considered the possibility that the metastatic carcinoma was of either ovarian or pulmonary origin. Immunostaining revealed that the tumor cells were negative for thyroid transcription factor 1 but positive for Wilms tumor 1. The tumor additionally exhibited strong membranous CD56 expression and patchy p53 expression, both of which were inconsistent with the characteristics of ovarian HGSC. However, targeted sequencing analysis revealed that the tumor harbored a pathogenic mutation at the splice acceptor site of TP53 intron 9 (c.994-1G>C).

Rare clinical manifestations of primary peritoneal serous carcinoma presenting as colorectal cancer: A report of two cases.

OBJECTIVE: To report two cases of for primary peritoneal serous carcinoma (PPSC) to present with gastrointestinal manifestations that mimic colorectal cancer. CASE REPORT: There were two patients with initial presentations of fatigue with iron deficiency anemia, and tenesmus with bloody stool. Tumors of the ascending colon and rectum were detected by colonofiberoscope, and pathologic reports of tumor biopsies revealed adenocarcinoma of suspected gynecologic origin. Both patients underwent optimal debulking surgery without macroscopic residual tumor, and then received adjuvant carboplatin and paclitaxel chemotherapy with bevacizumab. CONCLUSIONS: PPSC can clinically present like primary colorectal carcinoma. The differential diagnosis requires special staining of several markers for tumor tissues.

Metastatic ovarian cancer spreading into mammary ducts mimicking an in situ component of primary breast cancer: a case report.

BACKGROUND: Accurate diagnosis of metastatic tumors in the breast is crucial because the therapeutic approach is essentially different from primary tumors. A key morphological feature of metastatic tumors is their lack of an in situ carcinoma component. Here, we present a unique case of metastatic ovarian carcinoma spreading into mammary ducts and mimicked an in situ component of primary carcinoma. To our knowledge, this is the second case (and the first adult case) confirming the in situ-mimicking growth pattern of a metastatic tumor using immunohistochemistry. CASE PRESENTATION: A 69-year-old Japanese woman was found to have a breast mass with microcalcifications. She had a known history of ovarian mixed serous and endocervical-type mucinous (seromucinous) carcinoma. Needle biopsy specimen of the breast tumor revealed adenocarcinoma displaying an in situ-looking tubular architecture in addition to invasive micropapillary and papillary architectures with psammoma bodies. From these morphological features, metastatic serous carcinoma and invasive micropapillary carcinoma of breast origin were both suspected. In immunohistochemistry, the cancer cells were immunoreactive for WT1, PAX8, and CA125, and negative for GATA3, mammaglobin, and gross cystic disease fluid protein-15. Therefore, the breast tumor was diagnosed to be metastatic ovarian serous carcinoma. The in situ-looking architecture showed the same immunophenotype, but was surrounded by myoepithelium confirmed by immunohistochemistry (e.g. p63, cytokeratin 14, CD10). Thus, the histogenesis of the in situ-like tubular foci was could be explained by the spread of metastatic ovarian cancer cells into existing mammary ducts. CONCLUSION: Metastatic tumors may spread into mammary duct units and mimic an in situ carcinoma component of primary breast cancer. This in situ-mimicking growth pattern can be a potential pitfall in establishing a correct diagnosis of metastasis to the breast. A panel of breast-related and extramammary organ/tumor-specific immunohistochemical markers may be helpful in distinguishing metastatic tumors from primary tumors.

Atypical Cells in Peritoneal Cleft: A Pitfall in Diagnosis of Colorectal Adenocarcinoma.

Atypical cells in peritoneal clefts are usually either reactive mesothelial cells or pT4 colonic adenocarcinoma in colon specimen removed for primary colon cancer. However, rarely if ever are these atypical cells metastasis from other primary visceral malignancy due to "sac-like" anatomic structure of this area. We present a case where these atypical cells were determined to be metastasis of gynecological origin by judicious use of immunohistochemical stains. A final diagnosis of serous tubal intraepithelial carcinoma of right fallopian tube was diagnosed only after total abdominal hysterectomy bilateral salpingo-oophorectomy. To our knowledge, this is the first report of a serous tubal intraepithelial carcinoma presenting as stage 4 colonic adenocarcinoma. The importance of this interesting case is 2-fold. It highlights the peritoneal cleft as an anatomic region not often recognized or discussed as well as tumor presentation in this region. In addition, this example stresses the need for additional mesothelial markers in addition to WT-1 workup of atypical mesothelial proliferation.

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.

Primary mixed large cell neuroendocrine and high grade serous carcinoma of the endometrium.

Endometrial large-cell neuroendocrine carcinoma admixed with a high-grade serous (HGS) adenocarcinoma is extremely rare with only one reported case in the literature. We present the second reported case in a 47-year-old woman who presented with abdominal pain, distension and loss of weight. On examination she had a fixed pelvic mass and vascular left vaginal mass. Imaging confirmed a 13 cm solid cystic rectouterine pelvic mass, omental disease and retroperitoneal lymphadenopathy. She underwent a modified posterior exenteration, partial posterior vaginectomy, omentectomy and Hartmanns procedure with suboptimal debulking. Histopathology revealed a stage 4B mixed carcinoma with large cell neuroendocrine (70%) and HGS carcinoma (30%). Eight cycles of adjuvant cisplatin and paclitaxel were given with a complete radiological and biochemical response after 7 months. Unfortunately, she developed widespread recurrence at 9 month and was offered second line chemotherapy.

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.

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.