Ovarian Cancer
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Cancer of the ovaries are the second most common group of gynaecologic cancers, and account for about 5% of all women's cancers. There are two main types; (i) epithelial tumours (carcinomas) which account for 90% of ovarian cancers, and (ii) non-epithelial tumours (eg. Stroma cell and germ cell tumours of the ovary). The epithelial ovarian cancers are usually found in women aged over 40, while the non-epithelial tumours are more common in girls and young women. Epithelial ovarian cancer has few early symptoms, a risk factor is having a family history of the disease. Taking the contraceptive pill is known to be protective against ovarian cancer.

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Information for Patients and the Public
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Latest Research Publications

Information Patients and the Public (21 links)

Information for Health Professionals / Researchers (12 links)

Latest Research Publications

This list of publications is regularly updated (Source: PubMed).

Abid N, Mnif H, Mellouli M, et al.
Uterine tumour resembling ovarian sex cord tumours presenting as multiple endometrial and cervical uterine polyps: a case report.
Pathologica. 2014; 106(2):73-6 [PubMed] Related Publications
BACKGROUND: Uterine tumours resembling ovarian sex-cord tumours (UTROSCT) are very rare, benign uterine tumours, composed solely of sex cord elements. These tumours have a polyphenotypic immunophentype that favours a derivation from uterine mesenchymal stem cells.
CASE REPORT: A 43-year-old female presented with recurrent vaginal bleeding. On hysteroscopy, she had multiple endometrial and cervical polyps that were removed endoscopically. Histologically, the specimen contained epithelioid cells arranged in tubules, trabeculae and anastomosing cords, without significant cellular atypia or mitotic activity. Immunohistochemical studies were performed. The tumour was found to be diffusely positive for vimentin, calretinin and desmin, focally positive for cytokeratin, CD99 and inhibin and negative for chromogranin and CD10. A subsequent total hysterectomy was performed and revealed neoplastic infiltration of the myometrium.
CONCLUSION: A polyphenotypic immunophenotype is a characteristic feature of UTROSCT, and may be helpful in diagnosis and in exclusion of other lesions. Familiarity with this tumour by gynaecologists and pathologists is essential to avoid misdiagnosis:correct diagnosis of this neoplasm is important in patient management.

Related: Endometrial (Uterus) Cancer Endometrial Cancer Cervical Cancer

Takeshita T, Ninoi T, Maebayashi T, et al.
Diffusion-weighted magnetic resonance imaging findings in a patient with struma ovarii.
Osaka City Med J. 2014; 60(1):45-52 [PubMed] Related Publications
In this report, the magnetic resonance imaging (MRI) appearance of struma ovarii (SO) in a patient who underwent diffusion-weighted imaging (DWI) of the pelvis and subsequent histological analysis is described. The solid portion of SO showed a high apparent diffusion coefficient (ADC) value, indicating unrestricted diffusion, and each loculus of SO showed different ADC values due to the different viscosity of the cyst contents in each loculus. These unique and characteristic DWI findings may serve as a helpful sign in making the correct diagnosis of SO when DWI findings are interpreted in conjunction with conventional MRI findings.

Hannan A, Awan UE, Siddiqui N, Muzaffar N
Malignant transformations in ovarian teratomas: a report of four cases.
J Pak Med Assoc. 2014; 64(8):946-8 [PubMed] Related Publications
Mature cystic teratoma (MCT) is a common ovarian neoplasm in young females. A secondary malignant transformation occurs rarely in cystic teratomas at an older age. These secondary malignant neoplasms most commonly are squamous cell carcinomas (SCCs). Various mechanisms are reported, but the exact aetiology is unknown. We report three cases of SCC arising in cystic teratoma and one case of papillary thyroid neoplasm as secondary transformation. The SCCs were arising from the cyst wall, while the papillary thyroid malignancy arose from the normal-looking thyroid epithelium. Histologically, all SCC cases were poorly differentiated. Poor prognostic features for secondary transformations include size more than 10 cm, older age and rapid growth. Data is scarce regarding their appropriate treatment. However, surgical debulking is necessary. Platinum-based adjuvant regimens and taxanes are recommended in cases of advanced disease. In this paper we review and share our experience with this rare disorder.

Teng FF, Kalloger SE, Brotto L, McAlpine JN
Determinants of quality of life in ovarian cancer survivors: a pilot study.
J Obstet Gynaecol Can. 2014; 36(8):708-15 [PubMed] Related Publications
OBJECTIVE: Ovarian cancer treatments and outcomes vary substantially, yielding a diverse group of survivors. Few data exist on quality of life (QoL) concerns and the foremost needs of these patients. Our goal was to conduct a pilot study to determine the QoL needs of ovarian cancer survivors to establish priorities for future interventions.
METHODS: In this cross-sectional study, the European Organization for Research and Treatment of Cancer Quality of Life Questionnaires (EORTC QLQ-C30 and OV28) QoL questionnaires and one investigator-derived questionnaire were administered in an outpatient setting. Clinical parameters were abstracted and tested for associations with QoL measures.
RESULTS: A total of 102 women consented to participate and completed all components. Their mean age was 58 years (range 29 to 85), with 80% having epithelial ovarian carcinoma and 66% high-grade serous carcinoma. Women with stage I (28%), II (15%), III (47%), and IV (10%) lesions were represented in the primary treatment (25%), surveillance (46%), recurrent (23%), and palliative (7%) phases of the survivorship continuum. Fifty-one percent characterized their disease burden as "quite a bit" or "very much," and this did not vary by histology or diagnoses. Global QoL did not vary by clinico-pathologic parameters. Cardiovascular and respiratory comorbidities were associated with EORTC scores in physical functioning (P=0.027 for cardiovascular and P=0.041 for respiratory), global QoL (P=0.03 for cardiovascular and P=0.039 for respiratory), and sexual health (P=0.025 for cardiovascular). Task completion/memory/concentration, anxiety, and fatigue were the distress categories given highest priority by respondents.
CONCLUSION: In women with ovarian cancer, clinical factors such as age, stage, and histology did not have a significant impact on QoL. Psychosocial factors have a larger impact on global QoL than physical symptoms.

Zhang L, Xue Y, Jiang B, et al.
Multiscale agent-based modelling of ovarian cancer progression under the stimulation of the STAT 3 pathway.
Int J Data Min Bioinform. 2014; 9(3):235-53 [PubMed] Related Publications
This research is developed to simulate ovarian cancer progression with signal transducers and activators of the transcription 3 (STAT 3) pathway. The main focus is on studying how the STAT 3 pathway affects the cancer cells' biomechanical phenotype under the stimulation of the interleukin-6 (IL-6) cytokine and various well-known microscopic factors. The simulated results agreed with recent experimental evidence that ovarian cancer cells with a stimulated STAT 3 pathway have high survival rates and drug resistance. And we discussed how the IL6 and these well-known microscopic factors impacted the cancer progression.

Related: Apoptosis

Chao WR, Lee MY, Lin WL, et al.
Assessing the HER2 status in mucinous epithelial ovarian cancer on the basis of the 2013 ASCO/CAP guideline update.
Am J Surg Pathol. 2014; 38(9):1227-34 [PubMed] Related Publications
Her2 gene amplification and protein overexpression are important factors in predicting clinical sensitivity to anti-HER2 monoclonal antibody therapy in breast, gastric, or gastro-esophageal junction cancer patients. The purpose of this study was to evaluate the HER2 status in the mucinous epithelial ovarian cancer (EOC). Adopting the 2013 American Society for Clinical Oncology and the College of American Pathologists guideline update for HER2 testing, 49 tissue microarray samples of mucinous EOC were analyzed by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) tests. The prevalence of HER2 positivity in Asian mucinous EOC was 9 of 49 Asian women (18.37%). The overall concordance was 100% between IHC and FISH results. Her2 gene copies before chromosome-17 correction increased significantly in a stepwise order through the negative, equivocal, and positive IHC result categories (P<0.001), as did the Her2 gene copies after chromosome-17 correction (P<0.001). Of the Taiwanese cohort (n=21), HER2 heterogeneity was 4.76% (1/21) in all but 14.26% (1/7) in HER2-positive cancer. In conclusion, we demonstrated that the prevalence of HER2 positivity in both Asian and white women was comparable; complete HER2 concordance existed between IHC and FISH tests for the Her2 gene copies per tumor cell either before or after correction of chromosome-17, and this can be applied as a potentially valuable tool to analyze the HER2 status. Polysomy-17 was absent under the CEP17 cutoff ≥3. The existence of HER2 heterogeneity can be discerned in certain HER2-expressed primary mucinous EOC in Taiwanese women.

Related: Chromosome 17 FISH

Saito S, Kajiyama H, Miwa Y, et al.
Unexpected ovarian malignancy found after laparoscopic surgery in patients with adnexal masses--a single institutional experience.
Nagoya J Med Sci. 2014; 76(1-2):83-90 [PubMed] Related Publications
Laparoscopy has become the standard surgery for the treatment of benign ovarian tumors. The aim of this study was to evaluate the appropriateness of laparoscopy for ovarian tumors, including those with malignant potential. A total of 487 patients with adnexal masses underwent laparoscopic surgery in Social Insurance Chukyo Hospital from January 2000 to December 2012. We reviewed 471 cases that fulfilled the criteria set for this study, and examined 10 cases with unexpected ovarian malignancy to analyze their preoperative diagnosis, second surgery, postoperative chemotherapy, and prognosis. The ages of the 471 patients ranged from 13 to 50 years, with a median of 31. Nulliparous patients numbered 321(68.1%). Of all, 436 patients mostly consisted of those with endometrioma, benign ovarian neoplasm or functional cyst. In all, we histologically identified 10 women with malignancy: 6 with borderline ovarian tumors (BOT), 2 with ovarian cancer, and 2 with histologically rare tumors (immature teratoma and granulosa cell tumor). All patients with BOT were diagnosed with a mucinous histology. Two patients underwent both second radical surgery (hysterectomy and contra- or bilateral salpingo-oophorectomy) and chemotherapies that consisted of CBDCA and PTX or DTX. Thus, 2 patients underwent staging procedures, but the remaining 8 cases did not. None of them had evidence of recurrences. With accurate staging and careful postoperative follow-up, laparoscopic surgery could be a feasible initial operation for patients with adnexal masses including early-stage ovarian malignancy.

Fernandez-Vega I, Santos-Juanes J, García-Pravia C
Bilateral Sertoli cell adenoma in gonads, associated with serous cystadenoma.
Pol J Pathol. 2014; 65(2):154-6 [PubMed] Related Publications
Complete androgen insensitivity syndrome is an extremely infrequent disease. The patients exhibit female phenotype because of insensitivity to the androgen receptor and may develop tumors, especially in their undescended gonads. We report a case of bilateral Sertoli cell adenoma in gonads with unilateral serous cystadenoma, in an elderly phenotypic woman with primary amenorrhea. We also provide radiological and pathological studies.

Park CM, Kim SY
Rupture of an endometrioma with extremely high serum CA-125 level (> 10,000 IU/ml) and ascites resembling ovarian cancer.
Eur J Gynaecol Oncol. 2014; 35(4):469-72 [PubMed] Related Publications
Carbohydate antigen 125 (CA-125) is a type of cell surface glycoproteins present in more than 80% of non-mucinous epithelial ovarian carcinomas; however, benign gynecologic conditions commonly cause a smaller increase in CA-125 level. This report presents the details regarding a 44-year-old woman with extremely high serum CA-125 level and ascites. She complained of having abdominal pain and abdominal distension. Her serum CA-125 level had been markedly elevated (> 10,000 IU!ml) and computed tomograpgy (CT) revealed an ovarian tumor and massive ascites. The cytological analysis showed no evidence of malignancy, however, the positron emission CT (PET-CT) scan suggested ovarian malignancy with peritoneal carcinomatosis. Under the impression that the patient had ovarian cancer, the present surgical team carried out an explorative laparotomy and discovered the ruptured bilateral ovarian endometriomas. In this study, it is suggested that clinicians carrying out differential diagnosis of pelvic mass with high serum CA-125 level and ascites should consider not only ovarian cancer but also ruptured endometrioma.

Seki T, Yanaihara N, Hirata Y, et al.
Uterine endometrial carcinoma with trophoblastic differentiation: a case report with literature review.
Eur J Gynaecol Oncol. 2014; 35(4):461-4 [PubMed] Related Publications
Choriocarcinoma is categorized as either gestational or nongestational depending on its origin. Nongestational choriocarcinoma originated in the trophoblastic differentiation is a rare but an aggressive tumor. This article reports a nongestational case of a uterine endometrial carcinoma with trophoblastic differentiation. A 54-year-old woman with a history of atypical genital bleeding that underwent semi-radical hysterectomy, bilateral salpingo-oophrectomy, and pelvic lymph nodes dissection. Pathological investigation showed that the tumor had endometrioid adenocarcinoma and choriocarcinomatous components. Although a series of multimodality treatments including craniotomy were performed, she died of aggressive lung and brain metastases one year after the primary surgery.

Related: Endometrial (Uterus) Cancer Endometrial Cancer

Ishikawa M, Nakayama K, Rahman MT, et al.
Therapy-related myelodysplastic syndrome and acute myeloid leukemia following chemotherapy (paclitaxel and carboplatin) and radiation therapy in ovarian cancer: a case report.
Eur J Gynaecol Oncol. 2014; 35(4):443-8 [PubMed] Related Publications
In recent years, the incidence of therapy-related myelodysplastic syndrome (t-MDS) and therapy-related acute myeloid leukemia (t-AML) that occur during chemotherapy for ovarian cancer has increased. While alkylating agents and topoisomerase II inhibitors are particularly mutagenic and have strong leukemogenic potential, paclitaxel and combination chemotherapy/radiation therapy also appear to induce t-MDS. The present authors report a case of t-MDS that developed during chemotherapy and radiation therapy for ovarian cancer. The patient was a 75-year-old woman who received six courses of cyclophosphamide/doxorubicin/cisplatin (CAP) therapy after initial surgery for Stage IIIc grade ovarian cancer in 1995. Beginning in February 2005, the patient experienced multiple recurrences due to sternal metastasis. Chemotherapy, including paclitaxel and carboplatin (TC), was administered intermittently and was combined with radiation therapy to a sternal metastatic lesion. Pancytopenia was observed in December 2008, and she was diagnosed with t-MDS (WHO subtype, refractory cytopenias with multilineage dysplasia [RCMD]): the time from first chemotherapy to t-MDS onset was 106 months. Without evidence of blast crisis, the recurrent lesions continued to grow and caused multiple cerebral infarctions, from which she eventually died. The cumulative doses of paclitaxel and carboplatin administered to this patient were 1,968 mg and 6,480 mg, respectively.

Related: Carboplatin Acute Myeloid Leukemia (AML) Paclitaxel

Yin Z, Sun J
Curcumin induces human SKOV3 cell apoptosis via the activation of Rho-kinase.
Eur J Gynaecol Oncol. 2014; 35(4):433-7 [PubMed] Related Publications
OBJECTIVE: Curcumin has been showed anti-inflammation and anti-cancer effect in various cancer cells such as lung cancer, breast cancer, and so on. However the pro-apoptosis effect and the mechanism of curcumin in ovarian cell is still not very clear. In this study, the authors demonstrated that curcumin induced human SKOV3 cell apoptosis and explored the underlying mechanism concerning Rho A/Rho-kinase pathway.
MATERIALS AND METHODS: Human SKOV3 cell was performed with MTT assay to measure the cell viability with curcumin. The cell was treatment with 15 microM or 30 microM curcumin and flow cytometry. Cell apoptosis analysis was performed to measure the cell apoptosis level. In order to explore the mechanism concerning pro-apoptosis activity of curcumin, the cells were pre-treatment with Y-27632, a specific Rho-kinase inhibitor, before curcumin was added. Then the expression of activated caspase-3 and Rho A, Rho-kinase was detected by western blot.
RESULTS: Treatment with 15 microM or 30 microM curcumin significantly promoted the apoptosis of SKOV3 cell (p < 0.05) and the apoptosis rate is dose-dependent. Curcumin also activated the expression of Rho A and Rho-kinase in a dose-dependent effect. When pre-treatment with Y-27632, the expression of activated caspase-3 was significantly decreased compared to the group without Y-27632 pre-treatment (p < 0.05).
CONCLUSIONS: Curcumin induced human SKOV3 cell apoptosis in a dose-dependent effect. The pro-apoptosis effect of curcumin is partly mediated via the activation of Rho A/Rho-kinase signal pathway. This may help to further clarify the mechanisms of curcumin in ovarian cancer therapy.

Related: Apoptosis Signal Transduction

Rossi A, Forzano L, Romanello I, et al.
Comparison of pelvic masses score (PMS) and Risk of Malignancy Index (RMI 3) in the evaluation of pelvic masses.
Eur J Gynaecol Oncol. 2014; 35(4):421-4 [PubMed] Related Publications
PURPOSE: Ovarian cancer is the fourth cause of death from cancer in women worldwide and the majority of its diagnoses is made in an advanced stage of the disease. Several sonographic scoring systems have been created for a better preoperative discrimination between benign and malignant pelvic masses. The aim of this study was to evaluate the performances of the Risk of the Malignancy Index 3 (RMI 3) and the Pelvic Masses Score (PMS).
MATERIALS AND METHODS: This retrospective study was performed in 55 women admitted to the department of Obstetrics and Gynecology of University of Udine for surgical exploration of pelvic masses between 2009 and 2012. Sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) were calculated for both the scores.
RESULTS: PMS showed a sensitivity of 100%, a specificity of 93.8%, a PPV of 70%, and a NPV of 100%, while RMI 3 yielded a sensitivity of 85%, a specificity of 91%, a PPV of 60%, and a NPV of 97.8%.
CONCLUSION: The authors found that, in discriminating between benign and malignant pelvic disease, the PMS method was more reliable than RMI3. PMS is a simple scoring system which can be used in clinical practice.

Yildirim Y, Ertas IE, Nayki U, et al.
En-bloc pelvic resection with concomitant rectosigmoid colectomy and immediate anastomosis as part of primary cytoreductive surgery for patients with advanced ovarian cancer.
Eur J Gynaecol Oncol. 2014; 35(4):400-7 [PubMed] Related Publications
OBJECTIVE: To assess the authors' experiences in en bloc pelvic resection with concomitant rectosigmoid colectomy and primary anastomosis as a part of primary cytoreductive surgery for patients with advanced ovarian cancer.
MATERIALS AND METHODS: Atotal of 22 patients with FIGO Stage IIB-IV epithelial ovarian cancer who underwent en bloc pelvic resection with anastomosis were retrospectively reviewed. Data analyses were carried out using SPSS 10.0 and descriptive statistics, Kaplan-Meier survival curves, and Log Rank (Mantel-Cox) test were used for statistical estimations.
RESULTS: Median age was 58.8 years. FIGO stage distribution of the patients was; one (4.5%) IIB, three (13.7%) IIC, three (13.7%) IIIA, six (27.3%) IIIB, and nine (40.9%) IIIC. Median peritoneal cancer index (PCI) was 8 (range 5-22) and optimal cytoreduction was achieved in 18 patients (81.8%) of whom 13 (59.1%) had no macroscopic residual disease (complete cytoreduction). There was no perioperative mortality. A total of nine complications occurred in seven (31.8%) patients. Anastomotic leakage was observed in one (4.5%) patient. There was no re-laparotomy. Mean follow-up time was 60 months. There were 15 (68.2%) recurrences of which 12 (80%) presented in extra-pelvic localizations. Mean disease-free survival (DFS) and overall survival (OVS) were estimated as 43.6 and 50.5 months, respectively. Patients with complete cytoreduction had a better DFS (p = 0.006) and OVS (p = 0.003) than those with incomplete cytoreduction.
CONCLUSION: En bloc pelvic resection, as a part of surgical cytoreduction, seems to be a safe and effective procedure in many patients with advanced ovarian cancer if required. Despite relatively high general complication rate, anastomosis-related morbidity of this procedure is low as 0.8%. Nevertheless, surgical plan and perioperative care should be personalized according to medical and surgical conditions of the patient.

Li Y, Gu YJ, Liu CN, Yue TF
An in vivo model for the study of ovarian cancer and the persistence of characteristic mutations in xenografts.
Eur J Gynaecol Oncol. 2014; 35(4):387-92 [PubMed] Related Publications
OBJECTIVE: To identify factors affecting xenograft growth of epithelial ovarian cancer (EOC) cells in nude mice and to detect characteristic mutations occurring in the xenografts following serial passage.
MATERIALS AND METHODS: A total of 64 human EOCs were subcutaneously inoculated in Balb/c nude mice in order to obtain a series of xenografts. Whole-exome sequencing was analyzed with Agilent SureSelect targeted enrichment capture system and Illumina Solexa Hiseq 2000 sequencing platform. Mutations were confirmed by comparison against the reference genome build 37.3.
RESULTS: The tumor take rate was 50% (32/64). TP53 mutation was detected in nine often Type II tumors. BRAF and CTNNB1 were not mutated in any of the samples, and PTEN mutation occurred in only one sample. The present data indicate that advanced stage serous EOCs and early stage non-serous EOCs were easy to grow in nude mice, and xenografts maintained the characteristic mutations.
CONCLUSIONS: Advanced stage serous EOCs and early stage non-serous EOCs were easy to grow in nude mice, and xenografts maintained the characteristic mutations. Xenografts in nude mice are useful in vivo models for the study of human EOCs.

Related: PTEN BRAF gene TP53 KRAS gene

Tanouye S, Gada R, Famuyide A, Coddington C
A rare granulosa cell tumor presentation with virilization and cystic adnexal mass on three-dimensional ultrasound: a case report.
J Reprod Med. 2014 Jul-Aug; 59(7-8):421-4 [PubMed] Related Publications
BACKGROUND: Androgen-producing granulosa cell tumors (GCTs) are rare but should be suspected in patients presenting with rapid onset virilization and a large cystic adnexal mass. Preoperative diagnosis is difficult. By ultrasound, completely cystic, estrogen-producing GCTs are uncommon, while 39% of reported androgenic GCTs are completely cystic. We report a case of a GCT presenting with virilization and initially characterized on 3-dimensional (3-D) ultrasound.
CASE: A 32-year-old woman, gravida 1 para 0010, presented with amenorrhea, rapid onset hirsutism, acne, a 15-lb (6,803 g) weight gain, and an 8.7-cm cystic adnexal mass. The mass was evaluated with 2-D ultrasound and characteristics were confirmed on 3-D ultrasound. No abnormal Doppler flow was noted. Initial laboratory values confirmed hyperandrogenemia. A laparoscopic right salpingo-oophorectomy was performed after thorough counseling, and pathology demonstrated an adult granulosa cell tumor. Postoperatively her androgen levels normalized and symptoms resolved within 6 weeks. She continues to pursue pregnancy.
CONCLUSION: Presentations of androgen-producing ovarian masses are rare; however, the possibility of an androgenic GCT should be considered in the presentation of a large, virilizing, cystic adnexal mass to facilitate appropriate counseling and management.

Günyeli I, Bozkurt KK, Yalçın Y, et al.
Granulosa cell tumor and concurrent endometrial cancer with (18)F-FDG uptake.
Hell J Nucl Med. 2014 May-Aug; 17(2):153-5 [PubMed] Related Publications
The findings and the role of fluorine-18-fluorodeoxyglucose positron emission tomography/computed tomography ((18)F-FDG PET/CT) for the diagnosis of ovarian granulosa cell tumor (OG) are described. We present the pre-operative findings of (18)F-FDG PET/CT scan of a case of OG concurrent with endometrium cancer and endometrial hyperplasia, which revealed a 48mm mass demonstrating mild increased metabolic activity on the right ovary. Total abdominal hysterectomy and bilateral salpingo-oophorectomy was performed. Frozen and paraffin-enbeded sections showed an encapsulated OG. There were few mitoses. There was concurrent atypical endometrial hyperplasia. In conclusion, we reported a case of an encapsulated OG, which showed mild uptake of the (18)F-FDG with concurrent endometrial cancer. There has been only one report of (18)F-FDG findings in primary ovarian granulosa cell tumor, similar to ours.

Related: Endometrial (Uterus) Cancer Endometrial Cancer

Zhang R, Yang J, Sima M, et al.
Sequential combination therapy of ovarian cancer with degradable N-(2-hydroxypropyl)methacrylamide copolymer paclitaxel and gemcitabine conjugates.
Proc Natl Acad Sci U S A. 2014; 111(33):12181-6 [PubMed] Article available free on PMC after 19/02/2015 Related Publications
For rapid and effective clinical translation, polymer-based anticancer therapeutics need long circulating conjugates that produce a sustained concentration gradient between the vasculature and solid tumor. To this end, we designed second-generation backbone-degradable diblock N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer carriers and evaluated sequential combination therapy of HPMA copolymer-paclitaxel and HPMA copolymer-gemcitabine conjugates against A2780 human ovarian carcinoma xenografts. First, extensive in vitro assessment of administration sequence impact on cell cycle, viability, apoptosis, migration, and invasion revealed that treatment with paclitaxel conjugate followed by gemcitabine conjugate was the most effective scheduling strategy. Second, in an in vivo comparison with first-generation (nondegradable, molecular weight below the renal threshold) conjugates and free drugs, the second-generation degradable high-molecular weight conjugates showed distinct advantages, such as favorable pharmacokinetics (three- to five-times half-life compared with the first generation), dramatically enhanced inhibition of tumor growth (complete tumor regression) by paclitaxel and gemcitabine conjugate combination, and absence of adverse effects. In addition, multimodality imaging studies of dual-labeled model conjugates confirmed the efficacy of second-generation conjugates by visualizing more than five-times enhanced tumor accumulation, rapid conjugate internalization, and effective intracellular release of payload. Taken together, the results indicate that the second-generation degradable HPMA copolymer carrier can provide an ideal platform for the delivery of a range of antitumor compounds, which makes it one of the most attractive candidates for potential clinical application.

Related: Paclitaxel Gemcitabine

Ghosh J, Thulkar S, Kumar R, et al.
Role of FDG PET-CT in asymptomatic epithelial ovarian cancer with rising serum CA-125: a pilot study.
Natl Med J India. 2013 Nov-Dec; 26(6):327-31 [PubMed] Related Publications
BACKGROUND: We evaluated the role of ¹⁸F-fluorodeoxy glucose (FDG) PET-CT scan in the diagnosis of early relapse in patients with epithelial ovarian cancer (EOC) who were asymptomatic but had a rising serum CA-125 level.
METHODS: Between May 2006 and July 2008, 16 patients with advanced EOC (stages III and IV) who had achieved complete response after cytoreductive surgery and platinum-based chemotherapy were included. These patients were asymptomatic but had a rising serum CA-125 level with normal physical examination and contrast-enhanced CT scan of the abdomen and pelvis. Patients were evaluated with (18)F-FDG PET-CT scan. Written informed consent was taken. Patients with a positive PET-CT scan were advised ultrasound-guided fine-needle aspiration cytology (FNAC) from the area showing increased uptake. Patients in whom FNAC was negative or inconclusive or those with negative PET-CT scan were followed up closely for the next 6 months with repeat clinical evaluation and CT scan.
RESULTS: Fifteen patients (15/16) had a positive PET-CT scan. In 9 patients the positive PET lesion was confirmed on FNAC, while in 5 patients this was confirmed on follow-up CT scan after 6 months. One patient who had a single positive lesion in the pelvis on PET-CT was initially considered false-positive because a follow-up CT scan at 6 months did not show the lesion. However, on regular follow-up after 2 years, she was detected to have an isolated lesion in the PET-positive area which was confirmed on secondary cytoreduction. This patient was considered as true-positive in the current analysis. One patient, who had a negative PET-CT scan and a negative CT scan at 6 months' follow-up was considered true-negative. The sensitivity and specificity of PET-CT scan was 100%. We could confirm positivity on histopathology/FNAC in 10 of the 15 (66.7%) true-positive cases.
CONCLUSION: ¹⁸F-FDG PET-CT scan is a sensitive and specific technique for early diagnosis of relapse in asymptomatic EOC patients with rising CA-125. However, its role in the management of recurrent ovarian cancers needs further evaluation.

Related: Transitional Cell Cancer of the Renal Pelvis and Ureter

Janavičius R, Rudaitis V, Mickys U, et al.
Comprehensive BRCA1 and BRCA2 mutational profile in Lithuania.
Cancer Genet. 2014; 207(5):195-205 [PubMed] Related Publications
There is limited knowledge about the BRCA1/2 mutational profile in Lithuania. We aimed to define the full BRCA1 and BRCA2 mutational spectrum and the clinically relevant prevalence of these gene mutations in Lithuania. A data set of 753 unrelated probands, recruited through a clinical setting, was used and consisted of 380 female breast cancer cases, 213 epithelial ovarian cancer cases, 20 breast and ovarian cancer cases, and 140 probands with positive family history of breast or ovarian cancer. A comprehensive mutation analysis of the BRCA1/2 genes by high resolution melting analysis coupled with Sanger sequencing and multiplex ligation-dependent probe amplification analysis was performed. Genetic analysis revealed 32 different pathogenic germline BRCA1/2 mutations: 20 in the BRCA1 gene and 12 in the BRCA2 gene, including four different large genomic rearrangements in the BRCA1 gene. In all, 10 novel BRCA1/2 mutations were found. Nine different recurrent BRCA1 mutations and two recurrent BRCA2 mutations were identified, which comprised 90.4% of all BRCA1/2 mutations. BRCA1 exon 1-3 deletion and BRCA2 c.658_659del are reported for the first time as recurrent mutations, pointing to a possible Baltic founder effect. Approximately 7% of breast cancer and 22% of ovarian cancer patients without family history and an estimated 0.5-0.6% of all Lithuanian women were found to be carriers of mutations in the BRCA1 or BRCA2 gene.

Related: Breast Cancer

Cosentino M, Algaba F, Saldaña L, et al.
Juvenile granulosa cell tumor of the testis: a bilateral and synchronous case. Should testis-sparing surgery be mandatory?
Urology. 2014; 84(3):694-6 [PubMed] Related Publications
Granulosa cell tumor of the testis is an infrequent stromal cell tumor that can be distinguished into adult and juvenile, the latter being more common. Juvenile granulosa cell tumor of the testis is a rare pathologic finding, accounting for 1.2%-3.9% of prepubertal testicular tumors. It is considered as a benign stromal sex cord tumor and is usually unilateral. Although radical surgery was previously considered the treatment of choice, testis-sparing surgery is now recommended in all cases where applicable. We report a bilateral synchronous juvenile granulosa cell tumor in a 6-month-old child treated with testis-sparing surgery and provide a review of the literature.

Related: Testicular Cancer

Suidan RS, St Clair CM, Lee SJ, et al.
A comparison of primary intraperitoneal chemotherapy to consolidation intraperitoneal chemotherapy in optimally resected advanced ovarian cancer.
Gynecol Oncol. 2014; 134(3):468-72 [PubMed] Related Publications
OBJECTIVE: To compare survival outcomes for patients with advanced epithelial ovarian cancer (EOC) who received primary intravenous/intraperitoneal (IV/IP) chemotherapy to those who received IV followed by consolidation (treatment given to patients in remission) IP chemotherapy.
METHODS: Data were analyzed and compared for all patients with stage III-IV EOC who underwent optimal primary cytoreduction (residual disease ≤ 1 cm) followed by cisplatin-based consolidation IP chemotherapy (1/2001-12/2005) or primary IV/IP chemotherapy (1/2005-7/2011).
RESULTS: We identified 224 patients; 62 (28%) received IV followed by consolidation IP chemotherapy and 162 (72%) received primary IV/IP chemotherapy. The primary IP group had significantly more patients with serous tumors. The consolidation IP group had a significantly greater median preoperative platelet count, CA-125, and amount of ascites. There were no differences in residual disease at the end of cytoreduction between both groups. The median progression-free survival (PFS) was greater for the primary IP group; however, this did not reach statistical significance (23.7 months vs 19.7 months; HR 0.78; 95% CI, 0.57-1.06; p=0.11). The median overall survival (OS) was significantly greater for the primary IP group (78.8 months vs 57.5 months; HR 0.56; 95% CI, 0.38-0.83; p=0.004). On multivariate analysis, after adjusting for confounders, the difference in PFS was not significant (HR 0.78; 95% CI, 0.56-1.11; p=0.17), while the difference in OS remained significant (HR 0.59; 95% CI, 0.39-0.89; p=0.01).
CONCLUSIONS: In our study, primary IV/IP chemotherapy was associated with improved OS compared to IV followed by consolidation IP chemotherapy in patients with optimally cytoreduced advanced EOC.

Zakharia Y, Rahma O, Khleif SN
Ovarian cancer from an immune perspective.
Radiat Res. 2014; 182(2):239-51 [PubMed] Related Publications
Despite major advances in the treatment of ovarian cancer over the past two decades, it is still an incurable disease and requires the development of better treatment strategies. In recent years, we have developed a greater understanding of tumor immunology and the interactions between tumors and the immune system. This has led to the emergence of cancer immunotherapy as the fourth treatment modality in cancer. In this article, we address the principles of immunotherapy and different approaches that have been investigated over the past decade and discuss the future of immune therapy in ovarian cancer.

Lorusso D, Ratti M, Ditto A, Raspagliesi F
High-risk borderline ovarian tumors: analysis of clinicopathological features and prognostic impact of different follow-up strategies.
Oncology. 2014; 87(3):183-92 [PubMed] Related Publications
OBJECTIVES: Borderline ovarian tumors (BOTs) represent 10-20% of all epithelial ovarian malignancies. Most of them are comparable to benign cysts but a high-risk group has been recognized. The aim of the study was to analyze different follow-up strategies in high-risk patients.
METHOD: Patients with BOT treated at our institution from 1992 to 2011 were retrospectively reviewed. Clinicopathological features influencing prognosis were analyzed and two different follow-up strategies compared [6-month laparoscopic look (LPS-look): group A vs. ultrasound/CA-125 evaluation: group B].
RESULTS: 70 patients with high-risk BOTs were identified. After a median progression-free survival (PFS) of 43 months, 27% of patients experienced recurrences. Six months after diagnosis, 26 high-risk patients were submitted to LPS-look: at surgery, 6 out of 10 patients presenting evidence of disease were optimally debulked while in the remaining 4, only biopsies were performed. No difference in PFS was registered between group A and B patients, nevertheless a significant increase in PFS was registered among completely versus incompletely debulked patients with evidence of disease at laparoscopy.
CONCLUSION: Clinical follow-up remains the gold standard for BOTs. These very preliminary data seem to suggest that LPS-look may have an impact on the secondary PFS in a subgroup of high-risk patients.

Related: Endometrial (Uterus) Cancer Endometrial Cancer

Saatli B, Yildirim N, Ozay AC, et al.
Synchronous tumors of the female genital tract: a 20-year experience in a single center.
Ginekol Pol. 2014; 85(6):441-5 [PubMed] Related Publications
OBJECTIVE: To evaluate the clinicopathological characteristics and the clinical outcome of synchronous malignant neoplasms of the female reproductive tract.
MATERIAL AND METHODS: Patients who were operated and diagnosed with synchronous malignant tumor of the genital system (n = 25) at the Dokuz Eylul University Department of Obstetrics and Gynecology Gynecologic Oncology Unit between 1992 and 2012 were included into this study. Recurrent, metastatic and metachronously detected tumors were not included. Age at diagnosis, parity menopausal status, hormone use, presenting sign or symptoms and the clinical outcomes were evaluated.
RESULTS: 20 of 25 patients had endometrial-ovarian cancer. The mean age at diagnosis was 53,6 years. The most common presenting symptom was abnormal uterine bleeding. The median follow-up duration for all patients was 69 months. Overall survival for all patients was 87 months and 81 months for patients with endometrial-ovarian cancer 5-year survival rate was 73% for all patients and 68% for patients with endometrial-ovarian cancer.
CONCLUSIONS: Endometrial-ovarian cancer togetherness is the most common in synchronous gynecologic malignancies. They occur at a younger age and have more favorable prognosis than metastatic primary gynecologic tumors.

Related: Endometrial (Uterus) Cancer Endometrial Cancer Gynacological Cancers

Rosen B, Laframboise S, Ferguson S, et al.
The impacts of neoadjuvant chemotherapy and of debulking surgery on survival from advanced ovarian cancer.
Gynecol Oncol. 2014; 134(3):462-7 [PubMed] Related Publications
OBJECTIVES: Women with advanced ovarian cancer are treated with chemotherapy either before (neoadjuvant) or after surgery (primary debulking). The goal is to leave no residual disease post-surgery; for women treated with primary debulking surgery this has been associated with an improvement in survival. It has not been shown that the survival advantage conferred by having no residual disease post-surgery is present for women who receive neoadjuvant chemotherapy.
METHODS: We reviewed the records of 326 women with stage IIIc or IV serous ovarian cancer. We determined if they received neoadjuvant chemotherapy or primary debulking surgery and we measured the extent of residual disease post-surgery. We estimated seven-year survival rates for women after various treatments.
RESULTS: Women who had neoadjuvant chemotherapy were more likely to have no residual disease than women who had primary debulking surgery (50.1% versus 41.5%; p=0.03) but they experienced inferior seven-year survival (8.6% versus 41%; p<0.0001). Among women who had primary debulking surgery, those with no residual disease had much better seven-year survival than women who had any residual disease (73.6% versus 21.0%; p<0.0001). Women who had no residual disease after debulking surgery and who received intraperitoneal chemotherapy had a seven-year survival of 90%.
CONCLUSIONS: Neoadjuvant chemotherapy should be reserved for ovarian cancer patients who are not candidates for primary debulking surgery. Among women with no residual disease after primary debulking surgery, intraperitoneal chemotherapy extends survival.

Pradeep S, Kim SW, Wu SY, et al.
Hematogenous metastasis of ovarian cancer: rethinking mode of spread.
Cancer Cell. 2014; 26(1):77-91 [PubMed] Article available free on PMC after 14/07/2015 Related Publications
Ovarian cancer has a clear predilection for metastasis to the omentum, but the underlying mechanisms involved in ovarian cancer spread are not well understood. Here, we used a parabiosis model that demonstrates preferential hematogenous metastasis of ovarian cancer to the omentum. Our studies revealed that the ErbB3-neuregulin 1 (NRG1) axis is a dominant pathway responsible for hematogenous omental metastasis. Elevated levels of ErbB3 in ovarian cancer cells and NRG1 in the omentum allowed for tumor cell localization and growth in the omentum. Depletion of ErbB3 in ovarian cancer impaired omental metastasis. Our results highlight hematogenous metastasis as an important mode of ovarian cancer metastasis. These findings have implications for designing alternative strategies aimed at preventing and treating ovarian cancer metastasis.

Related: ERBB3 Signal Transduction

Del Conte G, Sessa C, von Moos R, et al.
Phase I study of olaparib in combination with liposomal doxorubicin in patients with advanced solid tumours.
Br J Cancer. 2014; 111(4):651-9 [PubMed] Article available free on PMC after 12/08/2015 Related Publications
BACKGROUND: Olaparib, an oral PARP inhibitor, has shown antitumour activity as monotherapy in patients with germline BRCA1/2 (gBRCA)-mutated breast and ovarian cancer. This study evaluated olaparib capsules in combination with liposomal doxorubicin (PLD) in patients with advanced solid tumours (NCT00819221).
METHODS: Patients received 28-day cycles of olaparib, continuously (days 1-28) or intermittently (days 1-7), plus PLD (40 mg m(-2), day 1); seven olaparib dose cohorts (50-400 mg bid) were explored to determine the recommended dose. Assessments included safety, pharmacokinetics, pharmacodynamics and preliminary efficacy (objective response rate (ORR)).
RESULTS: Of 44 patients treated (ovarian, n=28; breast, n=13; other/unknown, n=3), two experienced dose-limiting toxicities (grade 3 stomatitis and fatal pneumonia/pneumonitis (200 mg per 28-day cycle); grade 4 thrombocytopenia (400 mg per 7-day cycle)). The maximum tolerated dose was not reached using continuous olaparib 400 mg bid plus PLD. Grade ≥3 and serious AEs were reported for 27 (61%) and 12 (27%) patients, respectively. No major pharmacokinetic interference was observed between olaparib and PLD. The ORR was 33% (n=14 out of 42; complete response, n=3). A total of 13 responders had ovarian cancer: 10 were platinum-sensitive, 11 had a gBRCA mutation.
CONCLUSIONS: Continuous/intermittent olaparib (up to 400 mg bid) combined with PLD (40 mg m(-2)) was generally tolerated and showed evidence of antitumour activity in ovarian cancer.

Related: Breast Cancer Doxorubicin Liposomal Doxorubicin

Chui MH, Ryan P, Radigan J, et al.
The histomorphology of Lynch syndrome-associated ovarian carcinomas: toward a subtype-specific screening strategy.
Am J Surg Pathol. 2014; 38(9):1173-81 [PubMed] Related Publications
Women with Lynch syndrome (LS) are at increased risk for the development of epithelial ovarian cancer (OC). Analogous to previous studies on BRCA1/2 mutation carriers, there is evidence to suggest a histotype-specific association in LS-associated OCs (LS-OC). Whereas the diagnosis of high-grade serous carcinoma is an indication for BRCA1/2 germline testing, in contrast, there are no screening guidelines in place for triaging OC patients for LS testing based on histotype. We performed a centralized pathology review of tumor subtype on 20 germline mutation-confirmed LS-OCs, on the basis of morphologic assessment of hematoxylin and eosin-stained slides, with confirmation by immunohistochemistry when necessary. Results from mismatch-repair immunohistochemistry (MMR-IHC) and microsatellite instability (MSI) phenotype status were documented, and detailed pedigrees were analyzed to determine whether previously proposed clinical criteria would have selected these patients for genetic testing. Review of pathology revealed all LS-OCs to be either pure endometrioid carcinoma (14 cases), mixed carcinoma with an endometrioid component (4 cases), or clear cell carcinoma (2 cases). No high-grade or low-grade serous carcinomas or mucinous carcinomas of intestinal type were identified. Tumor-infiltrating lymphocytes were prominent (≥40 per 10 high-powered fields) in 2 cases only. With the exception of 1 case, all tumors tested for MMR-IHC or MSI had an MMR-deficient phenotype. Within this cohort, 50%, 55%, 65%, and 85% of patients would have been selected for genetic workup by Amsterdam II, revised Bethesda Guidelines, SGO 10% to 25%, and SGO 5% to 10% criteria, respectively, with <60% of index or sentinel cases detected by any of these schemas. To further support a subtype-driven screening strategy, MMR-IHC reflex testing was performed on all consecutive non-serous OCs diagnosed at 1 academic hospital over a 2-year period; MMR deficiency was identified in 10/48 (21%) cases, all with endometrioid or clear cell histology. We conclude that there is a strong association between endometrioid and clear cell ovarian carcinomas and hereditary predisposition due to MMR gene mutation. These findings have implications for the role of tumor subtype in screening patients with OC for further genetic testing and support reflex MMR-IHC and/or MSI testing for newly diagnosed cases of endometrioid or clear cell ovarian carcinoma.

Related: Canada Cancer Screening and Early Detection

Burandt E, Young RH
Thecoma of the ovary: a report of 70 cases emphasizing aspects of its histopathology different from those often portrayed and its differential diagnosis.
Am J Surg Pathol. 2014; 38(8):1023-32 [PubMed] Related Publications
Seventy thecomas of the ovary were evaluated to ascertain their histopathologic spectrum. The tumors occurred over a wide age range (average 49.6 y). Presentation in the form of pelvic or abdominal pain was uncommon, but postmenopausal bleeding was relatively frequent. All the tumors were unilateral, ranging up to 22.5 cm (average 4.9 cm) in greatest dimension. They were typically intact, uniformly solid, and yellow. Microscopic examination usually showed a predominant diffuse growth but was altered to varying degrees by hyaline plaques (37 cases), nodular growth (20 cases), calcification (20 cases), and keloid-like sclerosis (12 cases). Forty percent of the tumors had a minor component of fibroma. Reticulin stains typically showed an investment of single cells. The tumor cells characteristically had ill-defined cytoplasmic membranes and distinctive pale gray cytoplasm. Two tumors had degenerative so-called bizarre atypia. Fifteen tumors had nuclear grooves, but they were rarely conspicuous. The differential diagnosis is primarily with other sex cord-stromal neoplasms, particularly sclerosing stromal tumor, microcystic stromal tumor, steroid cell tumor, and adult granulosa cell tumor. The nodules of the first have a more heterogenous morphology than the uniform cell type of thecomas, and microcystic stromal tumors are distinguished because of microcysts and differing character of the tumor cells. Steroid cell tumors also have contrasting cytoplasmic features. Granulosa cell tumor with a prominent thecomatous component is the most clinically important differential and is largely solved by thorough sampling. Our experience indicates a relatively distinctive appearance of thecomas, which contrasts with the lipid-rich character often emphasized in the literature. Awareness of this and a spectrum of other findings should enable accurate interpretation of an almost invariably benign tumor.

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