Christine H. Holschneider

Ovarian cancer: epidemiology, biology, and prognostic factors.

Ovarian cancer varies widely in frequency among different geographic regions and ethnic groups, with a high incidence in Northern Europe and the United States, and a low incidence in Japan. The majority of cases are sporadic, and only 5% to 10% of ovarian cancers are familial. The etiology of ovarian cancer is poorly understood. Models of ovarian carcinogenesis include the theory of incessant ovulation, in which a persons age at ovulation, i.e., lifetime number of ovulatory cycles, is an index of her ovarian cancer risk. Excessive gonadotropin and androgen stimulation of the ovary have been postulated as contributing factors. Exposure of the ovaries to pelvic contaminants and carcinogens may play a role in the pathogenesis of ovarian cancer. Epidemiologic and molecular-genetic studies identify numerous risk and protective factors. The most significant risk factor is a family history of the disease. Recent advances in molecular genetics have found mutations in the BRCA1 and BRCA2 tumor suppressor genes responsible for the majority of hereditary ovarian cancer. Additional risk factors include nulliparity and refractory infertility. Protective factors include multiparity, oral contraceptives, and tubal ligation or hysterectomy. With five years of oral contraceptive use, women can cut their risk of ovarian cancer approximately in half; this also holds true for individuals with a family history. Stage at diagnosis, maximum residual disease following cytoreductive surgery, and performance status are the three major prognostic factors. Using a multimodality approach to treatment, including aggressive cytoreductive surgery and combination chemotherapy, five-year survival rates are as follows: Stage I (93%), Stage II (70%), Stage III (37%), and Stage IV (25%).

Posttreatment surveillance and diagnosis of recurrence in women with gynecologic malignancies: Society of Gynecologic Oncologists recommendations

Although gynecologic cancers account for only 10% of all new cancer cases in women, these cancers account for 20% of all female cancer survivors. Improvements in cancer care have resulted in almost 10 million cancer survivors, and this number is expected to grow. Therefore, determining the most cost-effective clinical surveillance for detection of recurrence is critical. Unfortunately, there has been a paucity of research in what are the most cost-effective strategies for surveillance once patients have achieved a complete response. Currently, most recommendations are based on retrospective studies and expert opinion. Taking a thorough history, performing a thorough examination, and educating cancer survivors about concerning symptoms is the most effective method for the detection of most gynecologic cancer recurrences. There is very little evidence that routine cytologic procedures or imaging improves the ability to detect gynecologic cancer recurrence at a stage that will impact cure or response rates to salvage therapy. This article will review the most recent data on surveillance for gynecologic cancer recurrence in women who have had a complete response to primary cancer therapy.

Multi-Institutional Reciprocal Validation Study of Computed Tomography Predictors of Suboptimal Primary Cytoreduction in Patients With Advanced Ovarian Cancer

PURPOSE Identify features on preoperative computed tomography (CT) scans to predict suboptimal primary cytoreduction in patients treated for advanced ovarian cancer in institution A. Reciprocally cross validate the predictors identified with those from two previously published cohorts from institutions B and C. PATIENTS AND METHODS Preoperative CT scans from patients with stage III/IV epithelial ovarian cancer who underwent primary cytoreduction in institution A between 1999 and 2005 were retrospectively reviewed by radiologists blinded to surgical outcome. Fourteen criteria were assessed. Crossvalidation was performed by applying predictive model A to the patients from cohorts B and C, and reciprocally applying predictive models B and C to cohort A. RESULTS Sixty-five patients from institution A were included. The rate of optimal cytoreduction ( 1 cm residual disease) was 78%. Diaphragm disease and large bowel mesentery implants were the only CT predictors of suboptimal cytoreduction on univariate (P < .02) and multivariate analysis (P < .02). In combination (model A), these predictors had a sensitivity of 79%, a specificity of 75%, and an accuracy of 77% for suboptimal cytoreduction. When model A was applied to cohorts B and C, accuracy rates dropped to 34% and 64%, respectively. Reciprocally, models B and C had accuracy rates of 93% and 79% in their original cohorts, which fell to 74% and 48% in cohort A. CONCLUSION The high accuracy rates of CT predictors of suboptimal cytoreduction in the original cohorts could not be confirmed in the cross validation. Preoperative CT predictors should be used with caution when deciding between surgical cytoreduction and neoadjuvant chemotherapy.

Coexisting ovarian malignancy in young women with endometrial cancer.

OBJECTIVE: In premenopausal women with endometrial cancer, ovarian preservation may be a consideration. Our objective was to examine the occurrence of coexisting ovarian malignancy and to identify predictors of adnexal involvement. METHODS: With institutional review board approval, a retrospective chart review was conducted of young women with endometrial cancer identified at 4 affiliated institutions from 1996 to 2004. RESULTS: Among 102 young women (aged 24–45 years) who underwent hysterectomy for endometrial cancer, 26 (25%) were found to have coexisting epithelial ovarian tumors: 23 were classified as synchronous primaries, and 3 as metastases. Ovarian cancer histology was endometrioid in 92% of cases. Among the 26 cases of coexisting ovarian involvement, 12 (46%) had grade 1 endometrial cancer on preoperative biopsy, 4 (15%) had normal preoperative imaging of the adnexa, and 4 (15%) had benign-appearing ovaries at the time of intraoperative assessment. On final pathology, 18 of 26 cases (69%) occurred in patients with grade 1 endometrial cancers, and 15 (58%) occurred with inner myometrial invasion. Our study further highlights the risk of conservative management with 1 case of ovarian cancer diagnosed 9 months after hysterectomy with ovarian conservation for a stage IA, grade 1 endometrial cancer and a case of advanced endometrial cancer metastatic to the ovaries developing 3 years after successful resolution of a grade 1 endometrial cancer treated with megestrol acetate (Megace). CONCLUSION: Careful preoperative and intraoperative assessment of the adnexa is mandatory in young women with endometrial cancer. Those who desire ovarian preservation should be counseled regarding the high rate of coexisting ovarian malignancy. LEVEL OF EVIDENCE: II-3

BRCA-mutation-associated fallopian tube carcinoma: a distinct clinical phenotype?

OBJECTIVE: To compare clinical and histologic features between fallopian tube cancers in women with germline BRCA mutations and sporadic cases. METHODS: Twenty-eight patients with fallopian tube cancer had BRCA mutation testing using multiplex polymerase chain reaction and protein truncation testing. Histologic slides were reviewed by 2 pathologists, and immunohistochemical staining for p53, ki67, estrogen receptor, and progesterone receptor was performed on carcinomas and dysplastic and benign tubal epithelia. RESULTS: Twelve of 28 (43%) women had BRCA mutations: 11 BRCA1, 1 BRCA2. Excluding 4 cases found at prophylactic surgery, the median age of diagnosis of BRCA mutation carriers was 57 years compared with 65 years among sporadic cases (P = .09). Patients with BRCA-associated fallopian tube cancer had a median survival time of 68 months compared with 37 months when compared with sporadic cases (P = .14). Both groups had predominantly advanced stage, high grade, serous fallopian tube cancers. No patient had exclusively proximal disease. Occult fallopian tube cancer diagnosed at prophylactic surgery in BRCA mutation carriers was exclusively distal. “Skip” areas of high-grade dysplasia were only seen in 2 patients, both of whom were BRCA mutation carriers. There were no differences in the immunohistochemical staining for p53, ki67, estrogen receptor or progesterone receptor in carcinomas and dysplastic or benign epithelia of patients with or without BRCA mutations. Overexpression of p53 was commonly seen in fallopian tube cancers and dysplastic epithelium, but rarely noted in benign epithelium. CONCLUSION: Fallopian tube cancer is part of the BRCA mutation phenotype and seems to share many clinical features with sporadic fallopian tube cancers, including no exclusively proximal disease. The presentation of BRCA-associated fallopian tube cancers may, however, occur at a younger age and have an improved survival. LEVEL OF EVIDENCE: III

Identification of patient groups at highest risk from traditional approach to ovarian cancer treatment

OBJECTIVE Define subgroups of patients at highest risk for major morbidity and mortality after a traditional approach of maximal surgical efforts followed by chemotherapy for advanced ovarian cancer (AOC). METHODS Preoperative health, intra-operative findings and outcomes were assessed in consecutive patients with primary AOC from 4 centers. Initial tumor dissemination was stratified into 3 groups based on volume of disease. Surgery was categorized using a previously described surgical complexity score (SCS). Statistical analysis was directed toward validating a multivariable risk-adjusted model. RESULTS 576 patients with stage IIIC (N=447, 77.6%) or IV AOC (N=129, 22.4%) were analyzed. Age (HR (per year): 1.02; 95%CI: 1.01-1.03), high tumor dissemination (HTD) (HR: 1.73; 95%CI: 1.19-2.56), residual disease (RD) >1 cm (HR: 2.46; 95%CI: 1.74-3.53), and stage IV (HR: 1.93; 95% CI: 1.51-2.45), independently correlated with OS. We identified a small subgroup of patients who comprised a high-risk group (N=38, 6.6%) characterized by all of the following characteristics: high initial tumor dissemination (HTD) or stage IV plus poor performance or nutritional status plus age ≥ 75. In this group, high SCS to achieve low RD was associated with morbidity of 63.6% and limited survival benefit. CONCLUSIONS Optimal management of AOC requires accurate, risk-adjusted predictors of outcomes allowing a tailored approach starting with primary therapy. Complex surgical procedures to render low RD improve survival, and in the majority of cases, the benefits of such surgery appear to outweigh the morbidity. However careful analysis identifies a subgroup of patients in whom an alternative approach may be the better strategy.

The modified pereyra procedure in recurrent stress urinary incontinence : a 15-year review

Objective: To assess the effectiveness and perioperative morbidity of the modified Pereyra procedure in the treatment of recurrent stress urinary incontinence. Methods: Data of 54 patients who underwent a modified Pereyra procedure for the treatment of recurrent stress urinary incontinence between January 1, 1978, and August 1, 1992, were analyzed retrospectively regarding presenting symptoms, preoperative evaluation, surgical procedure, complications, and cure and failure rates. The patients were divided into two groups depending on the preoperative absence (group I) or presence (group II) of risk factors for repeated failure (detrusor instability, low-pressure urethra, fibrotic urethra, negative Q-tip test, and neurogenic incontinence). Results: After a mean follow-up of 36.3 months, the cure rate of 81.6% in group I (N= 38) was significantly (P= .005) higher than that in group II (N= 16; 43.8% cured). The mean time of occurrence of failure was 11.9 months for group I and 6.8 months for group II. The incidence of intraoperative complications (Pereyra suture in bladder, hemorrhage) for both groups was 7.4%. Immediate postoperative complications were found in 25.9% of all patients; these were mainly infectious processes. Late postoperative complications occurred in 33.3%, with the most prevalent being new-onset urge incontinence and de novo detrusor instability (11.1%) and obstructive voiding dysfunction (9.3%). The rates of perioperative morbidity were not significantly different between the groups. Conclusion: The modified Pereyra procedure is well suited for the treatment of uncomplicated recurrent stress urinary incontinence, with a long-term cure rate of over 80%. However, success rates are significantly lower for recurrent stress incontinence in association with persistent risk factors for failure. In either instance, the procedure is associated with appreciable perioperative morbidity.(Obstet Gynecol 1994;83:573-8)

Neoadjuvant cisplatin and radical cesarean hysterectomy for cervical cancer in pregnancy.

Background A 28-year-old Hispanic gravida 1 was found to have a 4–5 cm cervical mass when she presented at 23 weeks gestation. On pelvic examination, the tumor was shown to encompass the entire circumference of the cervix without parametrial or vaginal involvement. A biopsy of the mass revealed a poorly differentiated squamous-cell carcinoma of the cervix. An MRI study of the abdomen and pelvis showed a 4 cm cervical mass that was suspicious for left parametrial and rectovaginal septal involvement. No hydronephrosis or lymphadenopathy was noted. The patient elected to proceed with her pregnancy.Investigations General physical and gynecological examinations, cervical biopsy, pelvic and obstetric ultrasound, histopathological examination, MRI of the abdomen and pelvis without and with gadolinium, neonatal hearing test and renal function studies.Diagnosis Poorly differentiated stage IB2 squamous-cell carcinoma of the cervix with MRI imaging suggestive of parametrial and rectovaginal septal involvement.Management Neoadjuvant chemotherapy using weekly cisplatin from 24 to 30 weeks, bed rest and oral terbutaline at 31 weeks because of premature contractions, and a course of antenatal steroids to promote fetal lung maturity. At 33 weeks radical cesarean hysterectomy, bilateral pelvic and para-aortic lymphadenectomy and bilateral ovarian transposition were carried out, followed by adjuvant pelvic radiation therapy with cisplatin chemosensitization 4 weeks postpartum.

Limited utility of conventional criteria for predicting unresectable disease in patients with advanced stage epithelial ovarian cancer

OBJECTIVE To evaluate the predictive value of conventional criteria for identifying surgically unresectable disease among patients with ovarian cancer undergoing initial operative intervention at tertiary referral centers employing a so-called aggressive approach to surgical cytoreduction. METHODS All patients with advanced epithelial ovarian cancer undergoing primary surgery between August 1997 and August 2006 were identified. Surgical/pathological documentation of disease extent pre/post-cytoreduction was extracted from the medical record retrospectively. All patients meeting conventional criteria for unresectable disease criteria (ascites >1000 mL, omental extension to spleen >1 cm, parenchymal liver disease >1 cm, porta hepatis involvement >1 cm, diaphragmatic disease >1 cm, carcinomatosis >1 cm, and suprarenal adenopathy >1 cm) were selected for further study. RESULTS A total of 180 consecutive patients had disease meeting conventional criteria for unresectability at =1 site(s). Optimal cytoreduction (residual disease=1 cm) was achieved in 166 patients (92.2%). Optimal resection rates according to the most common individual unresectable disease criteria were as follows: ascites >1000 mL=91.3% (116/127), carcinomatosis >1 cm=91.0% (81/89), and splenic involvement >1 cm=84.9% (45/53). For patients with ascites >1000 mL alone, optimal cytoreduction was achieved in 95.8% (46/48) of cases. Optimal resection rates according to the total number of unresectable disease sites were as follows: 1 site=95.0% (19/20), 2 sites=93.8% (61/65), 3 sites=81.5% (22/27), 4 sites=93.3% (14/15), and 5 sites=80.0% (4/5). CONCLUSIONS These data suggest that commonly accepted criteria of surgically unresectable disease for women with advanced ovarian cancer lack the necessary precision to guide clinical management. Pre-operative assessment of resectability should be made by an experienced surgical team prior to deferring the initial attempt at surgical cytoreduction.

The fragile histidine triad gene: a molecular link between cigarette smoking and cervical cancer.

Purpose: Smoking is an epidemiologic risk factor for cervical cancer. The fragile histidine triad (FHIT) gene is a tumor suppressor gene that is altered in 80% of tobacco-associated lung cancers. We hypothesized that reduced FHIT protein expression, homozygous deletions (HD) or hemizygous deletions (HemiD) and microsatellite alterations (MA) at the FHIT/FRA3B locus occur more commonly in cervical cancers of smokers than nonsmokers. Experimental Design: Archival tissues of 58 patients with stage IA1 to IB2 squamous cell carcinoma of the cervix were identified. FHIT protein expression was studied with immunohistochemistry. Laser capture microdissection was used to isolate tumor and normal DNA. HD/HemiD of FHIT exons 4 and 5 were analyzed by monoplex real-time PCR. MA at FHIT/FRA3B were studied with multiplex nested PCR with three fluorescently labeled microsatellite markers (D3S1300, D3S1312, and D3S1480). Results: Eighteen of 26 tumors from smokers (69%) and 13 of 32 nonsmokers (41%; P < 0.05) showed loss of FHIT protein expression. Thirty-seven stage IB tumors yielded sufficient DNA for analyses. HD or HemiD of both exons tested occurred in 8 of 17 smokers (47%) and 2 of 20 nonsmokers (10%; P < 0.05). MA at more than two sites were found in 11 of 17 tumors of smokers (65%) and 6 of 20 nonsmokers (30%; P < 0.05). Mean composite genomic FHIT alteration scores were significantly higher for tumors of smokers versus nonsmokers (0.67 versus 0.40; P < 0.02). Conclusion: Loss of FHIT expression, HD, HemiD, and MA at the FHIT/FRA3B locus occur significantly more commonly in cervical cancers of smokers. These findings suggest that the tumor suppressor gene FHIT may represent a molecular target in cigarette smoking–associated cervical carcinogenesis.