Estrogen receptor expression and increased risk of lymphovascular space invasion in high-grade serous ovarian carcinoma.

OBJECTIVE: Recent studies have demonstrated that lymphovascular space invasion (LVSI) is associated with increased risk of hematogenous and lymphatic metastasis and poor clinical outcome of women with epithelial ovarian cancer. Given the suspected role of estrogen in promoting ovarian cancer metastasis, we examined potential links between estrogen receptor and LVSI in high-grade serous ovarian carcinoma. METHODS: Tumoral expression of ER, PR, p53, MDR1, EGFR, HER2, DNA ploidy, and S-phase fraction was examined for 121 cases of stage I-IV high-grade serous ovarian carcinoma samples obtained at primary cytoreductive surgery. Biomarker expression was correlated to LVSI and survival outcomes. RESULTS: LVSI was observed in 101 (83.5%) of all cases. Immunohistochemistry of tested biomarkers showed ER (86.7%) to be the most commonly expressed followed by p53 (71.4%), HER2 (68.3%), EGFR (52.1%), MDR-1 (14.3%), and PR (8.9%). ER expression was positively correlated to PR expression (r=0.31, p=0.001). LVSI was only correlated with ER (odds ratio 6.27, 95%CI 1.93-20.4, p=0.002) but not with other biomarkers. In multivariate analysis, ER remained significantly associated with LVSI (p=0.039). LVSI remained a significant prognostic factor for decreased progression-free survival (HR 3.01, 95%CI 1.54-5.88, p=0.001) and overall survival (HR 2.69, 95%CI 1.18-6.23, p=0.021) while ER-expression did not remain as a significant variable in multivariate analysis. CONCLUSION: Our data demonstrated that estrogen receptor was positively correlated with LVSI that was an independent prognostic indicator of poor survival outcomes of high-grade serous ovarian carcinoma. This study emphasizes the importance of estrogen pathway in promoting lymphatic or vascular spread of high-grade serous ovarian carcinoma.

Inferior vena cava filter placement and risk of hematogenous distant metastasis in ovarian cancer.

BACKGROUND: Recent studies have suggested that inferior vena cava (IVC) filter placement in cancer patients is associated with decreased survival time after insertion. Causality, however, is yet to be understood. This study evaluates (i) the patterns of recurrence or progression of disease; and (ii) survival outcomes of ovarian cancer patients who underwent IVC filter placement. METHODS: A total of 274 patients who underwent primary cytoreductive surgery for epithelial ovarian, fallopian tube, and primary peritoneal cancers were identified for analysis. Anatomic location of the first recurrence or progression of disease, progression-free survival, and overall survival were correlated to IVC filter placement status inserted during the perioperative period. RESULTS: Overall, 38 (13.9%) patients underwent perioperative IVC filter insertion, of which 37 (97.4%) were permanently placed. The most common indication was newly diagnosed venous thromboembolism (VTE) (52.6%). Patients with IVC filter placement for VTE were more likely to develop subsequent deep vein thrombosis (25% vs. 7.2%, odds ratio, 4.31, 95% confidence interval, 1.40-13.3, P = 0.019), have hematogenous distant metastasis as the site of first recurrence or progression of disease (12-mo hematogenous distant metastasis ratio, 45.2% vs. 13.6%, hazard ratio, 5.10, 95% confidence interval, 2.35-11.1, P < 0.001, multivariate analysis), and show decreased survival outcomes (median progression-free survival, 5.7 vs. 15.3 mo, P < 0.001: and median overall survival, 22.1 vs. 47.2 mo, P = 0.002, both multivariate analysis) when compared with patients without IVC filter placement. CONCLUSIONS: Our results suggested that IVC filter placement for VTE in the perioperative period of primary cytoreductive surgery for ovarian cancer may be associated with increased risk of hematogenous distant metastasis and resulted in decreased survival.

Significance of perioperative infection in survival of patients with ovarian cancer.

OBJECTIVES: Perioperative infectious diseases comprise some of the most common causes of surgical mortality in women with ovarian cancer. This study was aimed to evaluate the significance of perioperative infections in survival of patients with ovarian cancer. METHODS: Patients who underwent primary cytoreductive surgery were included in the analysis (n = 276). The enumeration and speciation of pathogens, antimicrobial agents used, and sensitivity assay results were culled from medical records and correlated to clinicopathologic demographics and survival outcomes. Perioperative infection was determined as a positive microbiology result obtained within a 6-week postoperative period. RESULTS: The incidence of perioperative infection was 15.9% (common sites: urinary tract, 57.3%, and surgical wound, 21.4%). Commonly isolated pathogens were Enterococcus species (22.4%) and Escherichia coli (19.4%) in urinary tract infection, and Bacteroides fragilis, E. coli, and Klebsiella pneumoniae (all, 16%) in surgical wound infection. Imipenem represents one of the least resistant antimicrobial agents commonly seen in urinary tract and surgical wound infections in our institution. Perioperative infection was associated with diabetes, serous histology, lymph node metastasis, bowel resection, decreased bicarbonate, and elevated serum urea nitrogen in multivariate analysis. Perioperative infections were associated with increased surgical mortality, delay in chemotherapy treatment, decreased chemotherapy response, shorter progression-free survival (median time, 8.4 vs 17.6 months; P < 0.001), and decreased overall survival (29.0 vs 51.8 months; P = 0.011). Multivariate analysis showed that perioperative infections other than urinary tract infection remained a significant risk factor for decreased survival (progression-free survival, P = 0.02; and overall survival, P = 0.019). CONCLUSION: Perioperative infectious disease comprises an independent risk factor for survival of patients with ovarian cancer.

Significance of lymphovascular space invasion in epithelial ovarian cancer.

While the prognostic significance of lymphovascular space invasion (LVSI) is well established in endometrial and cervical cancer, its role in ovarian cancer is not fully understood. First, a training cohort was conducted to explore whether the presence and quantity of LVSI within the ovarian tumor correlated with nodal metastasis and survival (n = 127). Next, the results of the training cohort were applied to a different study population (validation cohort, n = 93). In both cohorts, histopathology slides of epithelial ovarian cancer cases that underwent primary cytoreductive surgery including pelvic and/or aortic lymphadenectomy were examined. In a post hoc analysis, the significance of LVSI was evaluated in apparent stage I cases (n = 53). In the training cohort, the majority of patients had advanced-stage disease (82.7%). LVSI was observed in 79.5% of cases, and nodal metastasis was the strongest variable associated with the presence of LVSI (odds ratio [OR]: 7.99, 95% confidence interval [CI]: 1.98-32.1, P = 0.003) in multivariate analysis. The presence of LVSI correlated with a worsened progression-free survival on multivariate analysis (hazard ratio [HR]: 2.06, 95% CI: 1.01-4.24, P = 0.048). The significance of the presence of LVSI was reproduced in the validation cohort (majority, early stage 61.3%). In apparent stage I cases, the presence of LVSI was associated with a high negative predictive value for nodal metastasis (100%, likelihood ratio, P = 0.034) and with worsened progression-free survival (HR: 5.16, 95% CI: 1.00-26.6, P = 0.028). The presence of LVSI is an independent predictive indicator of nodal metastasis and is associated with worse clinical outcome of patients with epithelial ovarian cancer.

Patient-reported symptoms and survival in ovarian cancer.

OBJECTIVE: While the development of an index of clinical symptoms to use for the detection and diagnosis of ovarian cancer is under active investigation, the role of clinical symptoms in survival after the initial diagnosis is poorly understood. The aim of this study was to correlate the type and extent of clinical symptoms with survival outcomes in ovarian cancer. METHODS: Medical records of 276 cases of primary epithelial ovarian, fallopian tube, and peritoneal cancers were evaluated. Thirty-one symptoms in 5 categories were cataloged. The significance of clinical symptoms in progression-free survival (PFS) and overall survival (OS) was evaluated. RESULTS: Overall, 93.5% of ovarian cancer patients expressed at least 1 symptom at the time of initial diagnosis. The 3 most common symptoms were abdominal pain (40.6%), increased abdominal size (33.7%), and bloating (21.7%). In survival analysis, weight loss (16.3%), nausea/vomiting (13.4%), and lower extremity edema (6.5%) were significantly associated with both decreased PFS and OS (all, P < 0.05). In multivariate analysis, lower extremity edema remained the strongest significant symptom, associated with increased surgical mortality rate, decreased response rate to adjuvant chemotherapy after primary cytoreductive surgery, and diminished survival outcomes (median PFS, 4.9 vs 15.3 months, P < 0.0001; and median OS, 5.9 vs 49.1 months, P < 0.001). Multiple symptoms were associated with poor survival outcomes (individual number of symptom ≤1 vs 2 vs ≥3; median PFS, 26.8 vs 17.4 vs 11.7 months [P < 0.001]; and median OS, 70 vs 41.6 vs 37.2 months [P < 0.001]). CONCLUSIONS: Lower extremity edema at initial diagnosis is a strong prognostic indicator of ovarian cancer patient.

Multidrug resistance gene (MDR-1) and risk of brain metastasis in epithelial ovarian, fallopian tube, and peritoneal cancer.

BACKGROUND: To evaluate risk factors that predict brain metastasis in epithelial ovarian, fallopian tube, and peritoneal cancer. METHODS: All patients with FIGO stage I to IV who underwent initial cytoreductive surgery between January 1995 and January 2009 were evaluated. The tumor samples were evaluated for 7 markers including multidrug resistance gene (MDR-1), DNA aneuploidity and S-phase fraction, human epidermal growth factor receptor 2, estrogen receptor, progesterone receptor, p53 mutation, epidermal growth factor receptor, and CD31. Biomarker expression was evaluated as a predictor of hematogenous metastasis to the following locations: (i) liver and spleen, (ii) lung, and (iii) brain. RESULTS: There were 309 cases identified during the period. Of those, 5 (1.6%, 95% CI: 0.2%-3.0%) women developed brain metastasis. Time to onset of brain metastasis was significantly longer than that for other recurrent sites (median time to recurrence after initial cytoreduction, brain vs. lung vs. liver, 21.4 vs. 12.6 vs. 11.0 months, P< 0.05). Significantly increased expression of MDR-1 was seen in tumors from women who developed brain metastasis (brain vs. nonbrain sites, 80% vs. 4.2%-24.3%, P= 0.004). In multivariate analysis, MDR-1 was the only significant variable associated with the risk of brain metastasis. MDR-1 expression predicted brain metastasis (receiver-operator-characteristic curve analysis, AUC 0.808, P= 0.018), and with a 10% positive expression of MDR-1 as the cutoff value, sensitivity, specificity, positive predictive value, negative predictive value, accuracy of prediction of brain metastasis were 80%, 86.1%, 15.4%, 99.3%, and 85.9%, respectively (odds ratio: 24.7, 95% CI: 2.64-232, P= 0.002). CONCLUSIONS: Increased expression of MDR-1 in the tumor tissue obtained at initial cytoreduction is associated with increased risk of developing brain metastases in women with epithelial ovarian, fallopian tube, or peritoneal cancer.

Clinical relevance of extent of extreme drug resistance in epithelial ovarian carcinoma.

OBJECTIVE: The objective of this study was to evaluate the clinical significance of the extent of extreme drug resistance (EDR) in in vitro drug resistance assays in advanced epithelial ovarian, fallopian, and primary peritoneal cancers. METHODS: A retrospective study was conducted using the database for in vitro drug resistance assay (EDR Assay, Oncotech, Inc.) results for advanced stage ovarian cancer samples obtained at primary surgery between 1995 and 2009. In vitro drug resistance assay results were evaluated for thirteen drugs according to the following two groups: platinum and taxane (primary treatment group) vs remaining agents (secondary treatment group). Dual-resistance was then defined as at least one EDR in the primary and secondary treatment groups. Chemotherapy response and survival outcome were correlated with assay results. RESULTS: There were 253 cases identified. Dual-resistance (n=53, 20.9%) was not associated with chemotherapy response (p=0.62) or survival outcomes (PFS, p=0.52; OS, p=0.11). Only one (0.4%) case exhibited complete EDR to all tested drugs, and 74 (29.4%) cases showed no EDR. There was no statistical correlation between total number of drugs in the EDR range and chemotherapy response (p=0.55), progression-free survival (PFS) (p=0.18), and overall survival (OS) (p=0.87). Proportion of EDR, defined as the ratio of the number of EDR drugs divided by all drugs for an individual patient, was also not related to chemotherapy response (p=0.37), PFS (p=0.13), or OS (p=0.13). CONCLUSIONS: Presence of extreme drug resistance to multiple agents in the in vitro drug resistance assays was not associated with survival outcomes in advanced stage epithelial ovarian, fallopian, and primary peritoneal cancers.

Prediction of Chemotherapy Response With Platinum and Taxane in the Advanced Stage of Ovarian and Uterine Carcinosarcoma: A Clinical Implication of In vitro Drug Resistance Assay.

OBJECTIVES: To evaluate the role of an in vitro drug resistance assay to predict the response to platinum and taxane combination chemotherapy in advanced ovarian and uterine carcinosarcoma. METHODS: We evaluated all patients with FIGO stage II-IV ovarian and FIGO stage III-IV uterine carcinosarcoma, who received platinum and taxane chemotherapy after initial cytoreductive surgery between January 1, 1995 and March 31, 2008. Cases that received neoadjuvant chemotherapy were excluded. Patient demographics, clinicopathologic data, response to chemotherapy, and follow-up outcomes were abstracted from the medical records. In vitro drug resistance assay results (Extreme Drug Resistance [EDR] Assay, Oncotech Inc, Tustin, CA) were evaluated. Response to chemotherapy was then compared with the assay results. RESULTS: There were 51 cases in which in vitro drug resistance assay results were available, of which 17 (33.3%) received combination chemotherapy with platinum and taxane. For these 17 cases, the primary site of disease was ovary in 12 cases and uterus in the other 5 cases. Overall response rate for these 17 cases was 70.6%. Chemotherapy response in the presence of EDR to at least 1 of the 2 drugs (EDR-PT) was significantly lower than non-EDR-PT (37.5% vs. 100%, P = 0.009). Sensitivity, specificity, positive predictive value, and negative predictive value for chemotherapy response in non-EDR-PT were 75%, 100%, 100%, and 62.5%, respectively. EDR-PT showed a significantly lower progression-free survival (1-year progression-free survival rate, 28.6% vs. 100%, P = 0.01) and overall survival (5-year overall survival rate, 26.9% vs. 57.1%, P = 0.033). CONCLUSIONS: Use of an in vitro drug resistance assay was a feasible test to predict the chemotherapy response and survival outcome in advanced ovarian and uterine carcinosarcoma.

Chemotherapy time interval and development of platinum and taxane resistance in ovarian, fallopian, and peritoneal carcinomas.

OBJECTIVE: To evaluate drug resistance after exposure to neoadjuvant chemotherapy and to postoperative chemotherapy in epithelial ovarian, fallopian, and primary peritoneal carcinomas. METHODS: In vitro drug resistance assay results (EDR Assay, Oncotech, Inc.) for platinum and taxane were evaluated for the following three groups: (1) primary cytoreductive surgery without prior chemotherapy; (2) primary cytoreductive surgery after neoadjuvant chemotherapy with platinum and taxane; and (3) recurrent cases after postoperative chemotherapy with platinum and taxane. Proportions of extreme drug resistance (EDR) were analyzed with Fisher's exact test. RESULTS: There were 277 cases that underwent primary cytoreductive surgery without prior chemotherapy: 14 cases of primary cytoreductive surgery after neoadjuvant chemotherapy with platinum and taxane, and 65 recurrent cases. Primary cytoreductive cases following neoadjuvant chemotherapy displayed an increased proportion of EDR to platinum agents compared to primary cytoreductive surgery without prior chemotherapy: neoadjuvant versus non-neoadjuvant, cisplatin 30 versus 7.3%, OR 5.4, 95%CI 1.3-23.2, P=0.027; carboplatin 33.3 versus 9.2%, OR 4.9, 95%CI 1.4-17.6, P=0.038. There were no differences in the proportion of EDR to taxanes between the two groups. On the contrary, recurrent cases showed an increased proportion of EDR to paclitaxel compared to primary cytoreductive surgery without prior chemotherapy: recurrent versus primary, paclitaxel 33.3 versus 21.1%, OR 1.9, 95%CI 1.0-3.5, P=0.031. There were no differences in the proportion of EDR for platinum and docetaxel between the two groups. Among recurrent cases, there was statistical significance between proportion of paclitaxel EDR and time interval of initial and recurrent surgeries (R2 0.143, P=0.011). Recurrent surgery after 5 years from initial cytoreduction was significantly associated with increased proportion of EDR to paclitaxel: 61.5 versus 22.6%, OR 5.5, 95%CI 1.35-22.2, P=0.011. CONCLUSIONS: Platinum resistance was common after neoadjuvant chemotherapy, while paclitaxel resistance was common after postoperative chemotherapy.

Vulvar mucinous adenocarcinoma associated with Crohn's disease: report of two cases.

BACKGROUND: Rectovaginal fistula in long-standing Crohn's disease is possibly associated with malignant transformation to mucinous adenocarcinoma of the vagina. However, there have been no previously reported cases documenting vulvar cancer in association with rectovaginal fistula in Crohn's disease. We report 2 cases of vulvar mucinous adenocarcinoma associated with Crohn's disease. Both showed vulvar symptoms after the development of rectovaginal fistula. CASE 1: A 48-year-old woman, with a 30-year history of Crohn's disease including a rectovaginal fistula, developed persistent pyoderma gangrenosum. Further workup revealed metastatic vulvar mucinous adenocarcinoma. CASE 2: A 37-year-old woman with long-standing Crohn's disease including numerous episodes of perianal or rectovaginal fistulas complained of a vulvar mass suspicious for an abscess. Biopsy showed mucinous adenocarcinoma. CONCLUSION: Vulvar lesions or symptoms in the setting of rectovaginal fistula in Crohn's disease are an important clinical feature and the possible development of vulvar cancer should be considered.

Low drug resistance to both platinum and taxane chemotherapy on an in vitro drug resistance assay predicts improved survival in patients with advanced epithelial ovarian, fallopian and peritoneal cancer.

The objective of this study was to evaluate the role of an in vitro drug resistance assay to platinum and taxane in the management of advanced epithelial ovarian, fallopian and primary peritoneal cancer. All patients with FIGO Stage IIIc and IV who received postoperative chemotherapy with platinum and taxane for more than 4 courses after the initial cytoreductive surgery between 1995 and 2008 were evaluated. Patients who received neoadjuvant chemotherapy were not included. An in vitro drug resistance assay (EDR Assay, Oncotech, Tustin, CA) was used to determine drug resistance for each patient's tumor tissue. Level of drug resistance was described as extreme (EDR), intermediate (IDR), or low (LDR). Response to chemotherapy and survival were correlated to the EDR Assay. Of the 335 patients who underwent primary cytoreductive surgery, 173 cases met the criteria for statistical evaluation. The 58 patients (33.5%) whose tumors had LDR to both platinum and taxane had statistically improved progression-free survival and overall survival (OS) compared with the 115 patients (66.5%) who demonstrated IDR or EDR to platinum and/or taxane (5-year OS rates, 41.1% vs. 30.9%, p = 0.014). The 5-year OS rates for the 28 (16.2%) cases that had optimal cytoreduction with LDR to both platinum and taxane was significantly improved over the 62 (35.8%) cases that were suboptimally cytoreduced with IDR or EDR to platinum and/or taxane (54.1% vs. 20.4%, respectively, p < 0.001). In conclusion, LDR to both platinum and taxane chemotherapy, as determined by an in vitro drug resistance assay, independently predicts improved survival in patients with advanced epithelial ovarian, fallopian and peritoneal cancer, especially in those patients who undergo optimal primary cytoreduction.

Pregnancy and genital sarcoma: a systematic review of the literature.

We conducted a literature review to determine the clinical characteristics of genital sarcoma during pregnancy. The systematic literature search was conducted using the search engines PubMed and MEDLINE with keywords "sarcoma" and "pregnancy" and was limited to female genital organs such as ovary, uterus, cervix, vagina, vulva, and retroperitoneal sarcoma. Kaposi's sarcoma, metastatic sarcoma, history of sarcoma, bone sarcoma located in pelvis, and fetal sarcoma were excluded in this study. There were 40 cases of genital sarcoma during pregnancy between 1955 and 2007. The majority of the cases were uterine sarcoma (37.5%), followed by retroperitoneal sarcoma (27.5%), vulvar sarcoma (22.5%), and vaginal sarcoma (12.5%). Mean age of the patient was 27.8 +/- 7.0. The distribution in the onset of symptoms had two peaks: first trimester (27.5%) and third trimester (50.0%). Growing mass (42.5%), abdominal pain (30.0%), and vaginal bleeding (22.5%) were the three most common symptoms. Incidental diagnosis was made in 22.5% and included during cesarean section (12.5%) and routine pelvic exam (7.5%). The cases initially not suspicious for malignancy were 42.5%. Thirty-three (82.5%) cases had live-born infants with term delivery in 55.2%. Mean birth weight was 2843 +/- 791 g, and male infants were more common (66.7%). Intrauterine growth retardation was seen in 12.5% of cases. Preterm labor was a common complication. Median survival period was 2.5 years (95% confidence, 1.9 to 3.1). The 2-, 3-, and 5-year cumulative survival rates were 60%, 38%, and 17%, respectively. Genital sarcomas in pregnancy are rare. There is a delay in diagnosis due to low index of suspicion. A majority had live births, and the 5-year survival is similar to that of advanced-stage sarcoma in nonpregnant women.

Primary peritoneal clear cell adenocarcinoma arising in previous abdominal scar for endometriosis surgery.

BACKGROUND: Endometriosis-associated ovarian cancer arising from the surgical incision site is an unusual clinical entity. CASE: A 37-year-old woman presented with a chief complaint of progressive swelling of the mons pubis. The patient was status post laparotomy for endometrioma/endometriosis 10 years ago. MRI showed a heterogeneous multiseptated large cystic mass within the mons pubis measuring 14 x 13.4 x 10.6 cm. Initial cytoreductive surgery revealed no evidence of tumor in the peritoneal cavity. The surgery was suboptimal due to severe adhesions to the symphysis pubis. The secondary cytoreductive surgery performed after six cycles of taxotere and carboplatin was optimal. Macroscopically, the tumor was a dusky pink-purple and contained a dense white-gray to light yellow gelatinous area. The tumor was a malignant cystic and glandular neoplasm. Immunohistochemical stains included CK7(+), CK5/6(-), EMA(+), Ber-Ep4(+), Calretinin(-), ER(-), and PR(-). CONCLUSION: Primary peritoneal clear cell adenocarcinoma arising from an abdominal scar associated with prior endometrioma/endometriosis surgery was first reported.

Ultrasonic surgical aspiration for vaginal intraepithelial neoplasia.

OBJECTIVE: To determine the safety and efficacy of ultrasonic surgical aspiration (USA) in the treatment of vaginal intraepithelial neoplasia (VAIN). METHODS: Using the ICD code for VAIN, all patients who underwent USA were evaluated. Patient demographics, clinicopathologic data, and follow-up outcomes were abstracted from the medical records. RESULTS: Ninety-two patients underwent USA for VAIN. No surgical complications or postoperative scarring were recorded, and all patients were followed without further therapy after the procedure. Pathologic evaluation of the degree of VAIN in the aspirate obtained at the time of USA correlated with the preoperative biopsy results in all cases. With a median follow-up period of 4.5 years, the overall recurrence rate was 19.6%. The recurrence rate for high grade VAIN was significantly greater than that for low grade VAIN (32.3% vs 13.1%, P=0.044). CONCLUSION: Ultrasonic surgical aspiration is a safe and effective surgical option for VAIN, providing a histologic sample with minimal invasiveness.

Massive retroperitoneal cyst during pregnancy: case report managed conservatively by percutaneous aspiration and review of literature.

Retroperitoneal cyst is an extremely rare complication of pregnancy. The management of this rare clinical entity is not well understood. An 18-year-old primigravid woman at 11 weeks of gestation with twins presented with complaints of severe nausea and vomiting. Abdominal magnetic resonance imaging showed a 25 x 18 x 10-cm retroperitoneal cyst reaching up to the level of xiphoid processes. No solid component or ascites was seen. She underwent ultrasound-guided percutaneous aspiration of the cyst and 2 L of fluid was removed. The cytology was negative for malignant cells. There was no recurrence of retroperitoneal cyst during the subsequent pregnancy. At 37 (0)/ (7) weeks' gestation, the patient spontaneously delivered the female fetuses in cephalic and breech presentation. There were only seven cases reported in the literature of retroperitoneal cysts during pregnancy between 1955 and 2008. Retroperitoneal cyst during pregnancy is characterized by its extremely rare incidence and its massive cyst size. Because of the difficulty in surgery due to the gravid uterus and close proximity to major organs and blood vessels, percutaneous aspiration of cyst could be an option during pregnancy.