Risk factors for lymph node metastasis in apparent early-stage epithelial ovarian cancer: implications for surgical staging

Objectives

The extent of lymphadenectomy to be performed in apparent early-stage epithelial ovarian cancer (EOC) is not well defined. We evaluated the patterns of lymphatic spread in apparent early-stage EOC and risk factors for lymph node metastasis, as these have potential implications for clinical decision making.

Methods

All cases of apparent early-stage EOC diagnosed at our institution between January 1994 and December 2003 were retrospectively identified. Apparent early-stage EOC was defined as gross disease that appeared confined to the pelvis without abdominal spread at the time of initial exploration. Demographics, pathologic findings, staging procedures performed, and clinical impression at surgery were analyzed. Patterns of lymph node positivity and risk factors associated with upstaging were assessed.

Results

One hundred and ninety patients with apparent early-stage EOC undergoing primary surgical staging met criteria for inclusion. All patients had at least some pathologic assessment of lymph nodes, with 115 having both bilateral pelvic and paraaortic lymphadenectomy performed. After review of pathology and operative reports, the final FIGO staging within the cohort was 54 IA (28.4%), 10 IB (5.3%), 51 IC (26.8%), 1 IIA (0.5%), 4 IIB (2.1%), 37 IIC (19.5%), 8 IIIA (4.2%), 25 IIIC (13.2%). Overall 25/190 (13%) had lymph nodes metastasis as follows: 8 (32%) had positive pelvic nodes, 12 (48%) had positive paraaortic nodes, and 5 (20%) had both positive pelvic and paraaortic lymph nodes. Significant risk factors for lymph node metastasis included bilateral vs. unilateral primary lesion (26.8% vs. 7.5%, p < 0.001), positive cytologic washings vs. negative (22.4% vs. 9.1%, p = 0.012), ascites vs. no ascites (28.2% vs. 9.3%, p = 0.002), serous vs. other histology (28% vs. 9%, p = 0.001), grade 1 vs. grade 2 vs. grade 3 disease (2.7% vs. 1.9% vs. 23.2%, p < 0.001), and preoperative CA 125 levels of > 35 vs. ≤ 35 U/ml (22.4% vs.0% p = 0.006). No patients with mucinous cancers (n = 29) had lymph node metastases. Patterns of LN metastases were largely independent of laterality of primary lesions: among those with unilateral lesions and positive nodes (n = 10), 5 (50%) had ipsilateral lymph node involvement, 4 (40%) had bilateral involvement, and 1 (10%) had isolated contralateral lymph nodes positive.

Conclusions

Complete surgical staging in EOC patients with gross disease confined to the ovaries and pelvis should include bilateral pelvic and paraaortic lymphadenectomy.Even in patients with unilateral lesions, lymph node metastases are commonly bilateral. Bilateral ovarian lesions, positive cytology, presence of ascites, high grade histology, and serous histology are risk factors for lymph node involvement. This information may be helpful in counseling patients presenting for consideration of re-staging after unexpected findings of malignancy.     

Preoperative 18F-FDG PET/CT in the management of advanced epithelial ovarian cancer

Objective

The introduction of 18-FDG-PET/CT during preoperative evaluation of patients with epithelial ovarian cancer (EOC) has led to an increase of the detection of extra-abdominal metastases. However, the clinical impact of this upstage remains unclear.

Methods

Patients with suspected advanced EOC underwent 18-FDG-PET/CT within two weeks prior to debulking surgery.

Results

Between 2006 and 2011 95 patients met the inclusion criteria. Based on the concordance or the discrepancy of clinical and PET/CT stage, patients were divided into 3 groups (A: clinical and PET III; B: clinical III and PET IV; C: clinical and PET IV). Twenty-five patients were upstaged from FIGO stage III to stage IV by PET/CT. The proportion of patients who achieved a residual tumor < 1 cm in group B and C was similar, whereas it was significantly lower compared to group A. Similarly, complete response to adjuvant chemotherapy was achieved more frequently in patients in group A. PFS was similar in the three groups (17, 17 and 12 months in group A, B and C), as well as OS (51, 41 and 35 months).

Conclusions

PET/CT is able to detect distant metastases in EOC patients. The presence of extra-abdominal disease probably indicates a more aggressive disease which also shows a lower response to standard chemotherapy. However, upstaged patients have a similar prognosis compared to stage III patients, probably because intra-abdominal disease is more likely to lead patients to death. This might also explain why residual tumor is the most important prognostic factor for advanced EOC patients.     

Polymorphisms in the CASP8 gene and the risk of epithelial ovarian cancer

Objective

The CASP8 gene plays a central role in the apoptotic pathway and is therefore a plausible cancer susceptibility gene. However, the precise role of the CASP8 gene in epithelial ovarian cancer carcinogenesis is unclear. Therefore, we analyzed the correlation between single nucleotide polymorphisms (SNPs) and haplotypes in CASP8 and the risk and clinical characteristics of epithelial ovarian cancer (EOC) in the Chinese population.

Subjects and methods

Eight tag SNPs were identified using the MassARRAY system to genotype 37 genetic polymorphisms around and in the CASP8 gene in 100 unrelated, healthy females. Then, a case-control study of 218 EOC patients and 285 controls who were matched on residence, age and race was conducted using these 8 tag SNPs.

Results

The risk of developing EOC was significantly decreased in association with CASP8 rs3834129 ins > del (odds ratio (OR)_del/del = 0.129, 95% confidence interval (95% CI): 0.038-0.439; OR_ins/del = 0.769, 95% CI, 0.534-1.108), rs3769827 T > C (OR_C/C = 0.187, 95% CI: 0.070-0.500; OR_T/C = 0.729, 95% CI: 0.505-1.052), rs6704688 C > T (OR_T/T = 0.344, 95% CI, 0.168-0.707; OR_C/T = 0.802, 95% CI, 0.552-1.166), and with the del-C-T haplotype of these 3 SNPs (OR = 0.615, 95% CI: 0.453-0.8363). Moreover, a notably later onset was significantly associated with the rs3834129 ins/del + del/del and the rs3769827 T/C + C/C genotypes (p < 0.0001).

Conclusions

Genetic variants of the CASP8 gene protect against EOC carcinogenesis and delay the age of EOC onset. Furthermore, these protective effects may be due to the dysfunctional expression of caspase-8 caused by the − 652 6 N del variant in the promoter.     

A prospective comparison of integrated FDG-PET/contrast-enhanced CT and contrast-enhanced CT for pretreatment imaging of advanced epithelial ovarian cancer

Objective

The use of tumor debulking surgery in the management of epithelial ovarian cancer (EOC), which is often disseminated in the peritoneal cavity at the time of diagnosis, has a significant impact on prognosis. We compared ¹⁸F-fluorodeoxyglucose (FDG) positron emission tomography/contrast-enhanced computed tomography (PET/CT) to contrast-enhanced CT for the detection of dissemination into the abdominal cavity preventing successful primary debulking surgery.

Methods

Forty-one women with EOC underwent preoperative whole-body low-dose FDG-PET/CT followed by diagnostic high dose contrast-enhanced CT scan, and the results were compared with systematically recorded surgical findings as a reference standard. Both site-based and patient-based analyses were conducted.

Results

FDG-PET/CT was superior to conventional CT for the detection of carcinomatosis in subdiaphragmatic peritoneal surfaces (p = 0.020) and in the bowel mesentery (p = 0.001). Patient-based analysis of upper abdominal areas requiring extensive surgical procedures showed no significant differences between the two imaging methods. The sensitivity of PET/CT and CT was poor in certain areas of the peritoneal cavity (64% vs. 27% in the small bowel mesentery and 65% vs. 55% in the right upper abdomen). Extra-abdominal disease spread was detected by PET/CT in 32 patients and by CT in 25 patients.

Conclusions

PET/CT was not superior to CT for the detection of intra-abdominal disease spread. Patients with suspected EOC should be referred for upfront radical surgery regardless of the results of preoperative imaging studies. PET/CT is more effective for the detection of extra-abdominal disease than CT, but the clinical significance of this finding is unclear.     

Prognosis of ovarian clear cell carcinoma compared to other histological subtypes: a meta-analysis

Objective

To compare the survival outcome between clear cell carcinoma (CCC) and other histological subtypes in epithelial ovarian carcinoma (EOC).

Methods

From January 1974 to February 2011, we identified a total of 31,800 (CCC; 2152, non-CCC; 29648) patients from 12 studies meeting the inclusion criteria.

Results

Heterogeneity tests demonstrated significant between-study variation (I² = 92.1%) with no significant difference in hazard ratio (HR) for death between CCC and non-CCC (HR; 1.16, 95% CI; 0.85-1.57, random-effects model). Comparing the HR based on stage I + II, and stage III + IV, between CCC and non-CCC, showed that CCC patients had a higher hazard rate for death than those with non-CCC of the ovary (stage I + II; HR; 1.17, 95% CI; 1.01-1.36, stage III + IV; HR; 1.65, 95% CI; 1.52-1.79). In a comparison of CCC and serous EOC, advanced stage (III and IV) CCC only showed a poorer hazard rate for death than serous EOC (HR; 1.71, 95% CI; 1.57-1.86).

Conclusion

This analysis suggests that ovarian CCC patients had poorer prognosis than those with other histological subtypes of EOC, especially in advanced EOC stages. Different treatment strategies may be needed for patients with ovarian CCC.     

Expression of 67-kDa laminin receptor was associated with tumor progression and poor prognosis in epithelial ovarian cancer

Objective

67-kDa laminin receptor (67LR) has been identified as a prognostic biomarker for a variety of human cancers. We investigated the clinical significance of 67LR expression and its functional role in epithelial ovarian cancer (EOC).

Methods

67LR expression was evaluated by immunohistochemistry in 62 patients with EOC. We assessed the correlation of 67LR expression with clinical characteristics. In vitro experiment was performed for 67LR with inhibition using siRNA to evaluate its role in cell survival, apoptosis, and invasion in EOC cells.

Results

67LR was predominantly expressed on the cell membrane in the majority of EOC samples (45/62, 73%). 67LR expression was significantly correlated with advanced stage (P = 0.001). Patients with 67LR expression had shorter progression-free survival among all the patients (P = 0.010) and in particular among patients with advanced stages (P = 0.046). When 67LR expression was inhibited by siRNA in EOC cells (HeyA8 and A2780), there was a significant decrease of cell proliferation and invasion as well as increase of apoptosis.

Conclusion

These findings suggest that 67LR expression may play an important role in tumor progression into advanced stage with poor prognosis in EOC and down-regulation of 67LR on tumor cells may be a therapeutic target in those patients.     

Changes in serum CA-125 can predict optimal cytoreduction to no gross residual disease in patients with advanced stage ovarian cancer treated with neoadjuvant chemotherapy

Objective

To evaluate the predictive power of serum CA-125 changes in the management of patients undergoing neoadjuvant chemotherapy followed by interval debulking surgery (NACT-IDS) for a new diagnosis of epithelial ovarian carcinoma (EOC).

Methods

Using the Cancer Registry databases from our institutions, a retrospective review of patients with FIGO stage IIIC and IV EOC who were treated with platinum-based NACT-IDS between January 2006 and December 2009 was conducted. Demographic data, CA-125 levels, radiographic data, chemotherapy, and surgical-pathologic information were obtained. Continuous variables were evaluated by Student's t test or Wilcoxon-Mann-Whitney test.

Results

One hundred-three patients with stage IIIC or IV EOC met study criteria. Median number of neoadjuvant cycles was 3. Ninety-nine patients (96.1%) were optimally cytoreduced. Forty-seven patients (47.5%) had resection to no residual disease (NRD). The median CA-125 at diagnosis and before interval debulking was 1749 U/mL and 161 U/mL, respectively. Comparing patients with NRD v. optimal macroscopic disease (OMD), there was no statistical difference in the mean CA-125 at diagnosis (1566 U/mL v. 2077 U/mL, p = 0.1). There was a significant difference in the mean CA-125 prior to interval debulking, 92 v. 233 U/mL (p = 0.001). In the NRD group, 38 patients (80%) had preoperative CA-125 ≤ 100 U/mL compared to 33 patients (63.4%) in the OMD group (p = 0.04).

Conclusions

Patients who undergo NACT-IDS achieve a high rate of optimal cytoreduction. In our series, after treatment with taxane and platinum-based chemotherapy, patients with a preoperative CA-125 of ≤ 100 U/mL were highly likely to be cytoreduced to no residual disease.     

Therapy-related myeloid leukemia after treatment for epithelial ovarian carcinoma: an epidemiological analysis

Objective

Therapy related acute myeloid leukemia (t-AML) is a potential late complication of cytotoxic therapy, and it is of particular concern in the treatment of patients with epithelial ovarian carcinoma (EOC) exposed to multiple courses of chemotherapy during the course of their disease. This study examines the incidence, characteristics and clinical outcomes of patients who developed secondary myeloid-type leukemia after a diagnosis of EOC.

Methods

National Cancer Institute's Surveillance, Epidemiology and End Results database was pooled for diagnosis of secondary myeloid leukemia after an initial diagnosis of EOC. This group of patients was compared to patients with de novo AML, and to EOC patients who did not develop secondary myeloid leukemia. Demographic, cytopathological and survival data were recorded. Cox Proportional Hazards model was used to calculate hazard ratios (HR) for developing secondary leukemia and to determine the statistically significant variables impacting survival. Kaplan-Meier estimates of survival were obtained and comparisons between the groups were performed using log-rank test.

Results

One hundred and nine myeloid leukemia cases were identified among 63,359 patients with a prior diagnosis of EOC for an overall incidence of 0.17%. The median latency to development of leukemia was 4 years (range 0-27 years). Median survival from the time of secondary leukemia diagnosis was 3 months and significantly worse than the 6 month median survival in patients with de novo AML (p < 0.001). Age at leukemia diagnosis greater than 65 and development of secondary vs. de novo leukemia had a statistically worse prognosis on multivariate analysis (HR of 2.69, 95%CI 2.60-2.78 and 1.81, 95%CI 1.49-2.20 respectively). The development of secondary leukemia was more common with EOC diagnosis made prior to the platinum/taxane era (HR 6.70, 95%CI 3.69-12.18). There was no difference in median survival between EOC patients who developed AML and those who did not.

Conclusion

Development of t-AML is a rare but lethal event among EOC patients, and its incidence has decreased significantly since the use of platinum/taxane-based chemotherapy became the standard of care.     

The impact of disease distribution on survival in patients with stage III epithelial ovarian cancer cytoreduced to microscopic residual: a Gynecologic Oncology Group study

Objective

To assess the survival impact of initial disease distribution on patients with stage III epithelial ovarian cancer (EOC) cytoreduced to microscopic residual.

Methods

We reviewed data from 417 stage III EOC patients cytoreduced to microscopic disease and given adjuvant intravenous platinum/paclitaxel on one of three randomized Gynecologic Oncology Group (GOG) trials. We subdivided patients into three groups based on preoperative disease burden: (1) minimal disease (MD) defined by pelvic tumor and retroperitoneal metastasis (2) abdominal peritoneal disease (APD) with disease limited to the pelvis, retroperitoneum, lower abdomen and omentum; and (3) upper abdominal disease (UAD) with disease affecting the diaphragm, spleen, liver or pancreas. We assessed the survival impact of potential prognostic factors, focusing on initial disease distribution using a proportional hazards model and estimated Kaplan-Meier survival curves.

Results

The study groups had similar clinicopathologic characteristics. Median overall survival (OS) was not reached in MD patients compared to 80 and 56 months in the APD and UAD groups (P < 0.05). The five-year survival percentages for MD, APD, and UAD were 67%, 63%, and 45%. In multivariate analysis, the UAD group had a significantly worse prognosis than MD and APD both individually and combined (Progression Free Survival (PFS) Hazards Ratio (HR) 1.44; P = 0.008 and OS HR 1.77; P = 0.0004 compared to MD + APD).

Conclusion

Stage III EOC patients with initial disease in the upper abdomen have a worse prognosis despite cytoreductive surgery to microscopic residual implying that factors beyond cytoreductive effort are important in predicting survival.     

Para-aortic lymphadenectomy for primary fallopian tube cancer

Objective

To investigate the topography of lymph node spread and the need for para-aortic lymphadenectomy in primary fallopian tube cancer (PFTC).

Methods

Twenty-six women were diagnosed with PFTC at Cheil General Hospital and Women's Healthcare Center, Seoul, Korea, between March 1992 and November 2009. Of the 26 patients, we retrospectively analyzed 15 patients who underwent complete staging surgery, including bilateral pelvic and para-aortic lymphadenectomy.

Results

The median follow-up period was 57.9 months (range, 3-185 months) and the 5-year survival rate was 86.3%. Five (33.3%) patients were diagnosed with FIGO stage I, 1 (6.7%) with stage II, and 9 (60%) with stage III cancer. The median number of lymph nodes removed was 53.8 (range, 18-106 nodes). Four (26.7%) patients had nodal involvement: 2 patients with para-aortic lymph node involvement and 2 patients with both pelvic and para-aortic lymph node involvement. None of the patients was positive for pelvic lymph nodes alone.

Conclusion

A comprehensive para-aortic lymphadenectomy was necessary for accurate staging in PFTC.     

Surgical staging of early stage epithelial ovarian cancer: results from the CDC-NPCR ovarian patterns of care study

Objectives

The objectives of this study were to determine the adequacy of surgical staging performed on surgically treated epithelial ovarian cancer (EOC) patients with apparent early stage disease and to determine if receipt of surgical staging had an influence on survival.

Methods

Detailed surgical staging information was collected from medical records for 721 patients diagnosed between 1998 and 2000 with EOC. Patients resided in California or New York and were identified through population-based cancer registries.

Results

Nearly 90% of patients had removal of the omentum and evaluation of bowel serosa and mesentery but only 72% had assessment of retroperitoneal lymph nodes and the majority of patients did not receive biopsies of other peritoneal locations. Only lymph node assessment (as well as node assessment combined with washings and omentectomy) had a statistically significant association with improved survival. The 5-year survival for women with node sampling was 84.2% versus 69.6% for those without this surgical procedure, and patients who did not have lymph node assessment had nearly twice the risk of death as those who did. When patients were stratified by receipt of chemotherapy, lack of node sampling had an effect only on patients who also had no chemotherapy (adjusted HR = 2.2, CI = 1.0-4.5).

Conclusions

The results of this population-based study confirm the prognostic importance of surgical staging for women with EOC, and the important role of gynecologic oncologists in treating these patients. Adjuvant chemotherapy does not appear to further improve survival for those women who receive adequate surgical staging.     

Differentiation of metastatic from non-metastatic lymph nodes in patients with uterine cervical cancer using diffusion-weighted imaging

Objective

This study aims to determine the diagnostic value of diffusion-weighted imaging (DWI) in the differentiation of metastatic lymph nodes from non-metastatic lymph nodes in uterine cervical cancer.

Methods

In 42 patients who underwent lymph node dissection for uterine cervical cancer, conventional MRI and DWI examinations were performed before surgery. Of the 1109 total dissected pelvic lymph nodes, 188 enlarged nodes with a short-axis diameter of 5 mm or greater were included for further analysis. Each of the size-based criteria (i.e., short-axis diameter and long-axis diameter) and ADC-based criteria (i.e., mean ADC, minimum ADC, mean rADC (relative ADC) and minimum rADC) were compared between metastatic lymph nodes and non-metastatic lymph nodes.

Results

There were statistically significant differences between metastatic and non-metastatic lymph nodes in the short-axis diameter, long-axis diameter, mean ADC, minimum ADC, mean rADC and minimum rADC (P < 0.001). The Az of the minimum ADC (0.990) was greater than that of the other ADC-based criteria (0.974, 0.939, 0.976 for mean ADC, mean rADC and minimum rADC, respectively) and all size-based criteria (0.878 for short-axis diameter and 0.858 for long-axis diameter) (P < 0.05). Using the minimum ADC criteria (≤ 0.881 × 10^− 3mm²/s), the sensitivity and specificity for differentiating metastatic from non-metastatic lymph nodes were 95.7% and 96.5%, respectively.

Conclusions

DWI is feasible for differentiating metastatic from non-metastatic pelvic lymph nodes in patients with uterine cervical cancer and minimum ADC could be served as a representative marker.     

Addition of bevacizumab to weekly paclitaxel significantly improves progression-free survival in heavily pretreated recurrent epithelial ovarian cancer

Objective

Weekly paclitaxel has been shown to be an effective cytotoxic regimen for recurrent epithelial ovarian cancer (EOC), and may act through inhibition of angiogenesis. Bevacizumab, a potent angiogenesis inhibitor, has also been shown to have activity in patients with EOC. Therefore, we sought to determine if the addition of bevacizumab to weekly paclitaxel led to an increased survival compared to weekly paclitaxel alone.

Methods

A single institutional review was conducted for patients with recurrent EOC treated with weekly paclitaxel (60-70 mg/m²) on days 1, 8, 15, and 22 of a 28 day cycle and those treated with weekly paclitaxel and bevacizumab (10-15 mg/kg on day 1 and 15). Response rates (RR) were calculated, and progression-free survival (PFS), and overall survival (OS) were compared using Kaplan-Meier survival analysis.

Results

Twenty-nine patients treated with weekly paclitaxel and 41 patients treated with paclitaxel/bevacizumab were identified. The groups were similar in demographics, initial optimal cytoreduction, stage, histology, grade, platinum sensitivity, and median number of previous regimens (4 vs. 4, p = 0.69).The overall response rate (ORR) was 63% (complete response (CR) 34% and partial response (PR) 29%) for paclitaxel/bevacizumab and 48% (CR 17% and PR 31%) for weekly paclitaxel (p = 0.23). Improvement in PFS was seen in those treated with paclitaxel/bevacizumab in comparison to weekly paclitaxel alone (median PFS 13.2 vs. 6.2 months, p < .01). There was a trend towards improved OS for paclitaxel/bevacizumab (median OS 20.6 vs. 9.1 months; p = 0.12). Toxicities were similar between the two regimens although more bowel perforations (2 vs. 0) were seen in the paclitaxel/bevacizumab group.

Conclusion

A significant increase in PFS with a trend towards improved OS was demonstrated in this heavily pretreated population treated with paclitaxel/bevacizumab as compared to weekly paclitaxel alone. This data should be helpful in guiding future trials to determine the optimal care for women with recurrent EOC.     

nm23 gene polymorphisms are associated with survival of patients with epithelial ovarian cancer but not with susceptibility to disease

Objective

nm23, a tumor metastasis suppressor gene, has been linked to protection against tumorigenesis and tumor metastasis. This study evaluated whether genetic variants in the nm23 gene were associated with susceptibility to epithelial ovarian cancer (EOC) or the clinical outcome of patients.

Methods

A case-control study was performed with 302 patients with epithelial ovarian cancer and 302 control women. According to the genotypes, the outcome in 213 EOC patients was compared. Progression-free survival (PFS) and overall survival (OS) were analyzed with Kaplan-Meier plots and Cox models adjusted for clinical factors.

Results

The case-control analysis showed that the rs16949649 and rs2302254 polymorphisms in the nm23 gene promoter were not associated with the risk of developing EOC. In contrast, survival analysis showed that the rs2302254 C/T polymorphism was related to the prognosis of EOC patients. Compared with patients carrying the C/C genotype, patients carrying the T/T genotype had a shorter median PFS and median OS by Kaplan-Meier plots and Cox models adjusted for clinical factors. For rs16949649 T/C polymorphisms, Kaplan-Meier analysis indicated that patients carrying the homozygous C/C genotype had shorter PFS and OS than those carrying the T allele (T/T + T/C genotype). The Cox proportional hazard model analysis suggested that this relationship was only retained in OS when adjusted for clinical factors.

Conclusion

Our studies suggest that rs16949649 and rs2302254 polymorphisms in the nm23 gene promoter may influence the prognosis of patients with epithelial ovarian cancer.     

Androgen receptor expression is a biological marker for androgen sensitivity in high grade serous epithelial ovarian cancer

Objectives

In the present study we explore the effects of androgens and anti-androgens on primary cultures of EOC cells. We also investigate the effects of chemotherapy on AR expression. Epithelial ovarian cancer (EOC) arises from ovarian surface epithelial cells (OSE), which express the androgen receptor (AR). Androgen stimulation of OSE cells results in increased proliferation and protection from apoptosis. Nevertheless, in clinical trials anti-androgens have had a low objective response rate in relapsed ovarian cancer.

Methods

1. Androgen receptor (AR) expression and response to androgenic stimulation were correlated in primary ovarian cancer cells derived from ascitic fluid from patients with advanced ovarian cancer,2. AR expression in primary epithelial ovarian cancer was investigated before and after chemotherapy using paired histological samples which had been incorporated into a tissue microarray.

Results

Eleven primary ovarian cancer cultures were established from ascitic fluid. There was wide variation of expression of androgen receptor mRNA between cultures. Cell division increased after dihydro-testosterone (DHT) stimulation in 6 out of 11 primary cultures. The fraction of cells in S-phase increased from 4.4% in cells grown in serum-free medium to 8.3% in cells stimulated with 100 nM of DHT (P < 0.001). The increase in S-phase fraction was abrogated after treatment with the anti-androgen, bicalutamide in 4 out of 5 responsive cultures. There was a strong correlation (r² = 0.7) between nuclear AR expression by immunohistochemistry and S-phase fraction changes in primary cultures.Paired pre- and post-chemotherapy histological samples from 29 patients were incorporated into a tissue microarray (TMA). Nuclear and cytoplasmic AR expression by immunohistochemistry (IHC) decreased significantly after chemotherapy (P < 0.01).

Conclusion

AR expression correlates with increased S-phase fraction in response to androgenic stimulation. Immunohistochemical analysis of AR expression needs to be further tested in clinical trials to select AR positive EOC for anti-androgen therapy. Anti-androgen use early in the course of ovarian cancer is more likely to be effective as these data suggest that androgen receptor expression decreases with exposure to chemotherapy and this may explain the low response rates seen in clinical trials of patients heavily pre-treated with multiple courses of chemotherapy.     

Should stage IIIC ovarian cancer be further stratified by intraperitoneal vs. retroperitoneal only disease?: a Gynecologic Oncology Group study

Objective

To examine whether clinical outcomes varied with intraperitoneal (IP) and/or retroperitoneal (RP) involvement in stage IIIC epithelial ovarian cancer (EOC) patients with microscopic residual disease after cytoreduction.

Methods

Retrospective review was performed for EOC patients enrolled in Gynecologic Oncology Group (GOG)-182 who underwent primary cytoreduction to microscopic residual disease. Patients were divided into 3 groups: stage IIIC by lymphadenopathy with < 2 cm IP spread (RP); > 2 cm IP spread and negative nodes (IP/RP−); and > 2 cm IP dissemination and positive lymphadenopathy (IP/RP+). Product-limit and multivariate proportional hazards modeling were used.

Results

Analyses included 417 stage IIIC women who underwent primary cytoreduction with lymphadenectomy to microscopic residual. There were 203, 123, and 91 in the RP, IP/RP−, and IP/RP+ groups, respectively. IP/RP+ and IP/RP− were associated with worse progression-free survival (PFS) (Hazard Ratio (HR) 1.68, 95% confidence interval (CI) 1.23-2.30; HR 1.38, 95% CI 1.04-1.84) vs. RP only. IP/RP+ was associated with worse overall survival (OS) (HR 1.79, 95% CI 1.24-2.57) while IP/RP− trended towards worse OS (HR 1.21, 95% CI 0.85-1.73) vs. RP only. Median PFS for IP/RP+ and IP/RP− groups was 21 and 29 months, respectively, vs. 48 months in the RP group (p = 0.0007) and median OS of 63 and 79 months vs. “not reached,” respectively (p = 0.0038).

Conclusions

Among EOC patients surgically cytoreduced to microscopic residual disease, those upstaged to IIIC by retroperitoneal involvement demonstrated significant improvement in PFS and OS compared to patients with intraperitoneal tumor, suggesting that these women may represent a unique subset of FIGO stage IIIC patients.     

Patterns of first recurrence following adjuvant intraperitoneal chemotherapy for stage IIIC ovarian cancer

Objective

Adjuvant intraperitoneal (IP) platinum-based chemotherapy has been shown to improve outcome for patients with advanced ovarian cancer. We hypothesize that patients who have received adjuvant IP chemotherapy more commonly recur first at extraperitoneal sites than patients who have received adjuvant intravenous (IV) chemotherapy.

Methods

Patients with newly diagnosed stage IIIC optimally debulked serous ovarian cancer were identified from institutional databases. Patterns of recurrence were compared between patients who received IV and IP chemotherapy using standard two-sided statistical tests.

Results

Of the 104 patients who met inclusion criteria, 60 received IV chemotherapy and 44 received IP chemotherapy. Patients in the IV group had a first recurrence more commonly in the lower abdomen or pelvis than the IP group. Patients in the IP group more commonly recurred in the upper abdomen and extra-abdominal lymph nodes. More patients in the IP group than the IV group recurred at extra-abdominal sites (45.5% versus 23.3%, P = 0.018).

Conclusions

Patients receiving adjuvant IP chemotherapy are less likely to first recur in the lower abdomen or pelvis and more likely to recur outside of the abdominal cavity. The data suggest that IP chemotherapy is highly effective in the anatomic areas of peritoneal distribution.     

Progranulin is a potential prognostic biomarker in advanced epithelial ovarian cancers

Objective

There are few validated relapse prediction biomarkers for epithelial ovarian cancer (EOC). We have shown progranulin (PGRN) and secretory leukocyte protease inhibitor (SLPI) are up regulated, overexpressed survival factors in EOC. We hypothesized they would predict presence of occult EOC.

Method

PGRN, SLPI, and the known biomarker HE4 were measured in EOC patient plasma samples, prospectively collected every 3 months from initial remission until relapse. Clinical data and CA125 results were incorporated into statistical analyses. Exploratory Kaplan-Meier estimates, dividing markers at median values, evaluated association with progression-free survival (PFS) and overall survival (OS). Area-under-the-curve (AUC) statistics were computed from receiver operating characteristic (ROC) curves to evaluate discrimination ability. A Cox proportional hazards model assessed the association between PFS, OS, and biomarkers, adjusting for clinical prognostic factors.

Results

Samples from 23 advanced stage EOC patients were evaluated. PGRN at 3 months was the only biomarker independently associated with PFS (P < 0.0001) and OS (P < 0.003). When used to predict progression by 18 months, sensitivity and specificity were 93% and 100%, respectively, with AUC = 0.944. The Cox model hazard ratio for PFS, divided at 59 ng/ml by ROC analysis and adjusted for clinical factors, was 23.5 (95% CI: 2.49-220). Combinations with SLPI, HE4, and/or CA125 did not improve the model.

Conclusions

We report pilot data indicating a potential independent association of PGRN on EOC patient PFS and OS. A validation study will be required to confirm this finding and to inform whether PGRN warrants evaluation as a potential screening biomarker.     

Micropapillary pattern in serous borderline ovarian tumors: does it matter?

Objective

To evaluate the clinical and prognostic impact of micropapillary pattern in patients with serous borderline ovarian tumors (SBOT).

Methods

We retrospectively assessed 130 consecutive patients with typical (n = 97, 74.6%) or micropapillary (n = 33, 25.4%) SBOT. Clinicopathologic factors and outcomes were compared between these two groups.

Results

There were no significant between-group differences in age, menopausal status, parity, body mass index, cancer antigen 125 concentration, tumor size, tumor rupture, positive cytology, ovarian surface involvement, retrieved lymph nodes, use of laparoscopy, fertility-sparing and ovary-sparing procedures, complete staging and restaging, and adjuvant chemotherapy. However, the incidences of advanced stage (II-III) tumors (10.3% vs 36.4%, P = 0.001), microinvasion (2.1% vs 15.2%, P = 0.012), peritoneal implants (8.3% vs 33.4%, P < 0.001), and lymph node involvement (0% vs 21.2%, P < 0.001) were significantly higher in patients with micropapillary than with typical SBOT. Five patients with typical (5.2%) and three with micropapillary (9.1%) SBOT had recurrent disease (P = 0.418), and one patient (3%) in micropapillary SBOT group died due to the disease (P = 0.254). The 5-year disease-free survival (DFS) rates for patients with typical and micropapillary SBOT were 96% and 86%, respectively (P = 0.148). All three patients with micropapillary SBOT who had recurrence had peritoneal implants (one noninvasive and two invasive). Multivariate analysis showed that peritoneal implant was the only significant factor related to DFS (P = 0.002).

Conclusions

Because micropapillary SBOT was significantly associated with peritoneal implants, especially invasive implants, and lymph node involvement, complete staging procedures, including lymph node dissection, are recommended. However, micropapillary SBOT itself was not significantly associated with DFS. Peritoneal implant was the only factor independently associated with tumor recurrence.     

Pelvic lymph node dissection in early ovarian cancer: success of retrieval of lymph nodes by individual lymph node groups in respect to pelvic laterality

Objective

To evaluate the differences in number of harvested retroperitoneal pelvic lymph nodes by specific lymph node regions in respect to pelvic laterality.

Study design

We extracted cases of early ovarian cancer (EOC) with lymphadenectomy from the medical database which were treated at our institution in the period between 1994 and 2008. Recommendations of FIGO and EGSOC (European Guidelines for Staging in Ovarian Cancer) for staging of ovarian malignancies were followed. Stage of the disease was established on the basis of intra-abdominal condition which we found during surgery and histopathologic status of retroperitoneal lymph nodes (LN). For each case and every LN group, we subtracted the number of dissected lymph nodes on the left side from the number of dissected lymph nodes on the right side of the pelvis. The result would represent the difference between number of removed LN on each side of the pelvis for specific LN group. A negative difference means that a greater number of LN was extracted from the left side and a positive difference that the greater number of LN was extracted from the right side of the pelvis. We used Wilcoxon signed-rank test for statistical analysis of differences.

Results

48 cases with EOC underwent lymphadenectomy. In three cases, metastatic retroperitoneal pelvic lymph nodes were found. There were 79.1%, 50.0%, 45.8%, 93.8%, 52.1%, 60.4% and 70.8% of cases with left-right difference in number of removed lymph nodes in external iliac region, common iliac region, presacralic, above obturator nerve, under obturator nerve, lateral from the external ilac vessels and lateral from the common iliac vessels nodal group, respectively. The mean differences between left and right groups were in the range from 2 to 4 lymph nodes. There was no identifiable bias toward either side of the pelvis for any of the analyzed lymph node groups.

Conclusion

There is a right and left prevalence of retrieved LN by individual LN regions in the pelvis that could be influenced by asymmetry in right-left pelvic LN distribution. However, we did not find any evidence that the observed imbalance is, on average, directed toward either side of the pelvis.