Newly diagnosed and relapsed epithelial ovarian carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

Early detection and treatment of ovarian cancer: shifting from early stage to minimal volume of disease based on a new model of carcinogenesis

The results of conservative (fertility-sparing) treatment in borderline ovarian tumors vary depending on age and histological type.

The United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) recently reported a reduction in the average overall mortality among ovarian cancer patients screened with an annual sequential, multimodal strategy that tracked biomarker CA125 over time, where increasing serum CA125 levels prompted ultrasound. However, multiple cases were documented wherein serum CA125 levels were rising, but ultrasound screens were normal, thus delaying surgical intervention. A significant factor which could contribute to false negatives is that many aggressive ovarian cancers are believed to arise from epithelial cells on the fimbriae of the fallopian tubes, which are not readily imaged. Moreover, because only a fraction of metastatic tumors may reach a sonographically-detectable size before they metastasize, annual screening with ultrasound may fail to detect a large fraction of early-stage ovarian cancers. The ability to detect ovarian carcinomas before they metastasize is critical and future efforts towards improving screening should focus on identifying unique features specific to aggressive, early-stage tumors, as well as improving imaging sensitivity to allow for detection of tubal lesions. Implementation of a three-stage multimodal screening strategy in which a third modality is employed in cases where the first-line blood-based assay is positive and the second-line ultrasound exam is negative may also prove fruitful in detecting early-stage cases missed by ultrasound.

Over the past quarter of a century, several scientific developments have challenged traditional concepts in ovarian cancer. First, it was recognized that ovarian cancer is not a homogeneous disease, but rather a group of diseases-each with different morphology and biological behavior. Approximately 90% of ovarian cancers are carcinomas (malignant epithelial tumors) and, based on histopathology, immunohistochemistry, and molecular genetic analysis, at least five main types are currently distinguished: high-grade serous carcinoma (HGSC, 70%); endometrioid carcinoma (EC,10%); clear-cell carcinoma (CCC,10%); mucinous carcinoma (MC, 3%); and low-grade serous carcinoma (LGSC, <5%) [1,2]. These tumor types (which account for 98% of ovarian carcinomas) can be reproducibly diagnosed by light microscopy and are inherently different diseases, as indicated by differences in epidemiologic and genetic risk factors; precursor lesions; patterns of spread; and molecular events during oncogenesis, response to chemotherapy, and prognosis [2,3]. Much less common are malignant germ cell tumors and potentially malignant sex cord-stromal tumors. The biomarker expression profile within a given histotype is consistent across stages. Ovarian cancers differ primarily based on histologic type. In the era of personalized cancer medicine, reproducible histopathologic diagnosis of tumor cell type is a sine qua non for successful treatment. Different tumor histotypes respond differently to chemotherapy. The International Federation of Gynecology and Obstetrics (FIGO) Committee on Gynecologic Oncology unanimously agreed that histologic type should be designated at staging. The finding of high-grade serous tubal intraepithelial carcinoma (STIC), in patients with BRCA mutation undergoing risk-reducing salpingo-oophorectomy (RRSO)[4] also influenced the new FIGO staging. Although STIC is capable of metastasizing and, therefore, cannot be considered a true carcinoma in situ , compelling evidence for a tubal origin of BRCA-positive HGSC has accumulated over the past decade [5,6]. The relative proportion of HGSCs of ovarian and tubal derivation is unknown, mainly because tumor growth in advanced-stage cancers conceals the primary site. Even in cases involving BRCA mutation, evidence of a tubal origin of HGSCs is incomplete and a multicentric origin of these tumors cannot be excluded. The process of the proposed changes to the staging of ovarian, fallopian tube, and primary peritoneal cancer started three years ago under the leadership of the Chair of the FIGO Committee on Gynecologic Oncology, Professor Lynette Denny. The proposal was sent to all relevant gynecologic oncology organizations and societies worldwide. The new staging was reached by consensus of those participating in the FIGO meeting held in Rome, Italy, on October 7, 2012 and approved two weeks later. The following is the consensus agreement that resulted from these efforts and represents new criteria for staging of these gynecologic cancer (Table 1). Table 1 2014 FIGO ovarian, fallopian tube, and peritoneal cancer staging system and corresponding TNM

The treatment and long-term survival of patients with ovarian cancer varies by stage. At present, five-year survival for patients with early-stage disease ranges from 50 to 95 percent, while five-year survival for patients with advanced-stage disease is less than 25 percent. Several new drugs with significant activity in advanced-stage ovarian cancer offer hope for increased long-term survival in the future. This article reviews the current and experimental approaches to the treatment of all stages of ovarian cancer.

State of the art of surgery in advanced epithelial ovarian cancer

Background: Ovarian cancer (OC) is the most common cause of death among gynecologic cancers. A key reason for the high lethality of OC is that early detection of OC is uncommon, and the majority of OC patients have advanced stage disease at diagnosis. Current non-invasive tests do not adequately distinguish benign from malignant adnexal masses. Diagnostic tests that reliably distinguish early stage OC from benign conditions may lead to earlier diagnosis of OC and improved survival. Methods: We designed a cohort study of plasma biomarkers in ovarian cancer patients. Specimens were analyzed from 100 patients with advanced OC (AJCC Stage III and IV), 50 patients with early stage OC (Stage I and II), and 50 patients with benign surgical conditions from the Mayo Ovarian SPORE Biospecimens Core. Presurgical plasma samples were assayed for multiple toll-like receptor agonists, cytokines, and vascular growth factors by ELISA and electrochemiluminescence. Biomarkers that were reliably detected in plasma were analyzed for association with OC. Differences in plasma biomarker levels between benign, early, and advanced OC patient groups were assessed using plate-adjusted logistic regression models. Results: Out of 23 biomarkers tested, 7 were excluded due to unreliable plasma detection. Of the remaining 16 biomarkers, 6_including interferon gamma (IFNγ), interleukin 6 (IL-6), IL-8, IL-10, tumor necrosis factor alpha (TNFα), and placental growth factor (PlGF)_were univariately associated with OC (all p&amp;lt;0.005), and one_IL-6_was associated with early stage OC (p &amp;lt; 0.0001). Heat shock protein 90kDa beta member 1 (HSP90B1, gp96) was associated with OC and early stage OC with borderline statistical significance (p = 0.039 and p = 0.026, respectively). However, when adjusted for cancer antigen 125 (CA-125), only HSP90B1 independently predicted OC (p = 0.008), as well as early stage OC (p = 0.014). Conclusions: The plasma cytokines IFNγ, IL-6, IL-8, IL-10, TNFα, and PlGF are associated with OC. However, after adjusting for CA-125, only HSP90B1 independently predicts OC, including early stage OC. These data warrant further investigation to determine whether measuring plasma HSP90B1 can aid in patient evaluation. Citation Format: Matthew S. Block, Matthew J. Maurer, Krista Goergen, Kimberly R. Kalli, Courtney L. Erskine, Marshall D. Behrens, Keith L. Knutson. Plasma heat shock protein 90kDa beta member 1 levels predict both early stage and advanced stage ovarian cancer independently from cancer antigen 125 in patients with an indeterminate adnexal mass. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1873. doi:10.1158/1538-7445.AM2014-1873

Ovarian cancer: role of ultrasound in preoperative diagnosis and population screening

Patients with ovarian serous cancer are usually younger and survive longer than patients with high-grade serous cancer. Unfortunately, most low-grade serous cancer patients eventually die of the disease because recurrent low-grade serous carcinoma is relative chemoresistant. So far, the known mutations identified in low-grade ovarian serous carcinomas and their putative precursor ovarian serous borderline tumors are BRAF and KRAS mutations. BRAF and KRAS mutations together have been identified in approximately 60% of serous borderline tumors and early stage low-grade serous carcinomas. However, BRAF mutation is rare in advanced-stage low-grade serous carcinomas. To further investigate the molecular pathogenesis of low-grade serous carcinoma, mutation analyses of 409 cancer related genes were performed in 21 low-grade ovarian serous carcinoma, 8 ovarian serous borderline tumors and one ovarian cystadenoma using next generation sequencer. A total of nineteen missense mutations were identified in 20 samples but ten samples had no detectable mutations. BRAF mutation was detected in 3 serous borderline tumors and one low-grade serous carcinoma. KRAS mutations were detected in three low-grade serous carcinomas. Other than BRAF and KRAS mutations, we also detected other prevalent mutations: ATRX mutations were detected in 3 low-grade ovarian serous carcinomas and a cystadenoma; KMT2C mutations were detected in 3 low-grade ovarian serous carcinomas; ATM mutations were detected in 2 low-grade ovarian serous carcinomas. Interestingly, both ATRX and MLL3 genes are involved in the chromatin remodeling. Moreover, both ATRX and ATM are involved in DNA damaging response. Thus, the pathogenesis of low-grade serous carcinoma may involve de-regulation of chromatin remodeling pathway and DNA damaging response. Further analysis of a large cohort of low-grade serous carcinomas for these prevalent mutations is ongoing. Citation Format: Yvonne TM Tsang, Daisy Izaguirre, Suet-Yan Kwan, Samuel C. Mok, David Gershenson, Kwong-Kwok Wong. Ovarian low grade serous cancer: Mutation analysis with a comprehensive 409 cancer gene panel. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1529. doi:10.1158/1538-7445.AM2014-1529

BackgroundIMP2 and IMP3 are mRNA binding proteins involved in carcinogenesis. We examined a large cohort of ovarian tumors with the aim to assess the value of IMP2 and IMP3 for differential diagnosis, and to assess their prognostic significance.MethodsImmunohistochemical analyses with antibodies against IMP2 and IMP3 were performed on 554 primary ovarian tumors including 114 high grade serous carcinomas, 100 low grade serous carcinomas, 124 clear cell carcinomas, 54 endometrioid carcinomas, 34 mucinous carcinomas, 75 mucinous borderline tumors, and 41 serous borderline tumors (micropapillary variant). The associations of overall positivity with clinicopathological characteristics were evaluated using the chi-squared test or Fisher’s Exact test.ResultsWe found IMP2 expression (in more than 5% of tumor cells) in nearly all cases of all tumor types, so the prognostic meaning could not be analyzed. The positive IMP3 expression (in more than 5% of tumor cells) was most common in mucinous carcinomas (82%) and mucinous borderline tumors (81%), followed by high grade serous (67%) and clear cell carcinomas (67%). The expression was less frequent in endometrioid carcinomas (39%), low grade serous carcinomas (23%), and micropapillary variant of serous borderline tumors (20%). Prognostic significance of IMP3 could be evaluated only in low grade serous carcinomas in the case of relapse-free survival, where negative cases showed better RFS (p = 0.033).ConclusionConcerning differential diagnosis our results imply that despite the differences in expression in the different ovarian tumor types, the practical value for diagnostic purposes is limited. Contrary to other solid tumors, we did not find prognostic significance of IMP3 in ovarian cancer, with the exception of RFS in low grade serous carcinomas. However, the high expression of IMP2 and IMP3 could be of predictive value in ovarian carcinomas since IMP proteins are potential therapeutical targets.

Clinical value of human epididymis protein 4 and the Risk of Ovarian Malignancy Algorithm in differentiating borderline pelvic tumors from epithelial ovarian cancer in early stages

ObjectiveTranscriptional profiling of epithelial ovarian cancer has revealed molecular subtypes correlating to biological and clinical features. We aimed to determine gene expression differences between malignant, benign and borderline serous ovarian tumors, and investigate similarities with the well-established intrinsic molecular subtypes of breast cancer.MethodsGlobal gene expression profiling using Illumina's HT12 Bead Arrays was applied to 59 fresh-frozen serous ovarian malignant, benign and borderline tumors. Nearest centroid classification was performed applying previously published gene profiles for the ovarian and breast cancer subtypes. Correlations to gene expression modules representing key biological breast cancer features were also sought. Validation was performed using an independent, publicly available dataset.Results5,944 genes were significantly differentially expressed between benign and malignant serous ovarian tumors, with cell cycle processes enriched in the malignant subgroup. Borderline tumors were split between the two clusters. Significant correlations between the malignant serous tumors and the highly aggressive ovarian cancer signatures, and the basal-like breast cancer subtype were found. The benign and borderline serous tumors together were significantly correlated to the normal-like breast cancer subtype and the ovarian cancer signature derived from borderline tumors. The borderline tumors in the study dataset, in addition, also correlated significantly to the luminal A breast cancer subtype. These findings remained when analyzed in an independent dataset, supporting links between the molecular subtypes of ovarian cancer and breast cancer beyond those recently acknowledged.ConclusionsThese data link the transcriptional profiles of serous ovarian cancer to the intrinsic molecular subtypes of breast cancer, in line with the shared clinical and molecular features between high-grade serous ovarian cancer and basal-like breast cancer, and suggest that biomarkers and targeted therapies may overlap between these tumor subsets. The link between benign and borderline ovarian cancer and luminal breast cancer may indicate endocrine responsiveness in a subset of ovarian cancers.

In Brief Objectives: Extensive debulking is recommended for the primary operative management of advanced ovarian and peritoneal cancer. Patients with advanced ovarian and peritoneal cancer frequently develop intestinal obstruction and intestinal resection with anastomosis or colostomy often offers the only chance to restore gastrointestinal function and provide complete cytoreduction. The purpose of this study was to compare our results with outcomes of other institutions. Methods: The study was a retrospective review of 29 women who underwent bowel resection as a part of primary surgical debulking for advanced ovarian or peritoneal cancer from 1995 to 2003. Results: Twenty-seven patients had ovarian cancer and 2 patients had peritoneal cancer. The ages ranged from 49 to 93 years. According to the International Federation of Gynecology and Obstetrics (FIGO) staging system, 2 patients were in FIGO stage II, 16 patients were in FIGO stage III, and 11 patients were in FIGO stage IV. Twenty-six patients had optimal debulking with no gross residual tumor. The intestinal procedures performed included 14 sigmoid resections with colostomy, 9 sigmoid resections with reanastomosis, 4 transverse colon resections with reanastomosis, 1 right hemicolectomy with ileo-transverse colon reanastomosis, 1 total colectomy, 2 ileostomies, 5 partial small bowel resections with reanastomosis, and 1 gastrostomy. Eight patients had more than one intestinal procedure. There was one postoperative death on the fifth postoperative day due to respiratory failure. Postoperative complications included 1 anastomotic leak with peritonitis, 1 pelvic abscess, 1 intraluminal colonic anastomotic bleed, 3 wound infections, 2 urinary tract infections, and one case of pneumonia. One patient developed disseminated intravascular coagulopathy intraoperatively. The median operating time was 3 hours and 55 minutes (range 2 hours 23 minutes-6 hours 5 minutes). The mean blood loss was 1256 mL (range 200–7500). The hospital stay ranged from 6 to 36 days (mean 15). Despite aggressive postoperative chemotherapy, only 1 stage II patient and 4 stage III patients have survived (17.2%). The median survival for the whole group was 21 months (mean 25, range 1 to 78). Conclusions: Intestinal resection to relieve obstruction or optimally debulk patients with advanced ovarian or peritoneal cancer can prolong survival and be curative in some patients and palliative in others. Bowel resection at the time of primary cytoreductive surgery in patients with advanced ovarian or peritoneal cancer is associated with acceptable perioperative morbidity.

To evaluate the association between pre-operative tumor load, progression-free survival, and overall survival in patients with advanced epithelial ovarian cancer. Patients diagnosed with The International Federation of Gynecology and Obstetrics (FIGO) stage III to IV primary ovarian, tubal, or peritoneal carcinoma, who underwent intraoperative abdominal disease spread assessment using the laparoscopic predictive index value (PIV) at the Gynecologic Oncology Unit of the Policlinico-Agostino Gemelli University Hospital-IRCCS, Rome, from January 2018 to December 2020, were included. Patients were divided into 2 groups based on median laparoscopic PIV at diagnosis in our population: group A (low tumor load) with PIV from 0 to 6, group B (high tumor load), with PIV from 8 to 12, and/or with extensive miliary carcinomatosis and mesentery retraction. During the study period, 817 patients with newly diagnosed advanced epithelial ovarian cancer were included, with a median age of 60 years (range;18-87), a median CA125 level of 584 (range; 5-6262), and ascites presence in 436 cases (54.0%). With a median follow-up of 51.0 months (95% CI 49.5 to 52.5), 571 (69.9%) recurrences and 388 (47.5%) deaths were observed. The median progression-free and overall survival were 22.0 months (95% CI 19.8 to 24.2) and 53.0 months (95% CI 48.7 to 57.3), respectively. A statistically significant correlation between PIV and risk of recurrence or death was observed (p < .001). The median progression-free survival was 27 months for PIV < 8 versus 16 months for PIV ≥ 8 (p < .001). The 5-year survival rate was 54.8 % (95% CI 49.1 to 60.5) for PIV < 8 and 30.4% (95% CI 23.7 to 37.1) for PIV ≥ 8 (p < .001). This correlation was maintained in the subgroup analysis by stage. Specifically, for FIGO stage III, the 5-year survival rate was 57.2 % for the group with PIV < 8 and 26.3 % for the group with PIV ≥ 8; for FIGO stage IV, it was 47.9 % for the group with PIV < 8, and 32.8 % for the group with PIV ≥ 8. In multivariate analysis, PIV was confirmed as an independent prognostic factor for both progression-free and overall survival, along with BRCA status and residual tumor after surgery, as well as ascites for progression-free survival and age for overall survival. This study underscores tumor burden at diagnosis, quantified by PIV, as a key independent prognostic factor in advanced ovarian cancer, irrespective of FIGO stage or BRCA status, even in the era of maintenance therapies.

The prognostic value of cellular DNA content in ovarian cancer (malignant common epithelial tumors) was investigated by flow cytometric analysis of paraffin-embedded tumor blocks from 128 previously untreated patients with International Federation of Gynecology and Obstetrics (FIGO) stage III and IV ovarian cancer entered in a prospective clinical trial of combination v sequential therapy with chlorambucil and cisplatin. Seventy-three percent of tumors were aneuploid and 27% were diploid. Multivariate analysis using a Cox model showed that cellular DNA content (P less than .001) and FIGO stage (P less than .02) were the only significant independent prognostic variables. The median survival was 13 months for patients with aneuploid tumors and 60 months for patients with diploid tumors (P less than .0001). Further analysis indicated that the good prognosis associated with diploid tumors was limited to patients with stage III disease, all patients with stage IV (spread beyond the peritoneal cavity or liver metastases) disease having a poor prognosis irrespective of ploidy. On pathological review, nine borderline ovarian tumors (of low malignant potential) were identified, and seven of these were diploid. These tumors have an unusually favorable prognosis, despite apparent dissemination within the peritoneal cavity, a paradox which is often difficult to explain using conventional histological criteria. Although the vast majority of tumors in this study (93%) were classified as invasive epithelial ovarian cancers, it is possible that some of the patients with stage III diploid tumors may have had malignancies that were predominantly of low malignant potential, thus accounting in part for the prognostic significance of DNA content. By incorporating flow cytometric DNA analysis with careful histopathological assessment, it may be possible to better identify patients with an inherently good prognosis. This assumes particular importance, as the relatively favorable prognosis of patients with stage III diploid ovarian tumors appears to be independent of the type of treatment.