Gynecologic malignancies in older women.

The aging of the population is a social phenomenon that will present a challenge to clinical practice in the 21st century. Women constitute a majority of the elderly population as they outlive males by 5 to 7 years. Ovarian, endometrial, and vulvar cancers are diseases seen more commonly in postmenopausal and elderly women. Cervical cancer continues to be a significant problem in the elderly and is usually detected at a later stage in that population than in younger patients. Accordingly, primary care clinicians ought to possess a thorough knowledge of gynecologic malignancies and should refer women who present with these disorders to a gynecologic oncologist. Ovarian cancer patients treated by a gynecologic oncologist are more likely to undergo proper surgical staging, leading to optimal debulking surgery and improved survival. Age, by itself, should not alter the diagnostic and therapeutic approach to gynecologic malignancy. Elderly patients can safely undergo radical pelvic surgery. Multiagent chemotherapy is also possible in the elderly without excess morbidity, and without compromise of response rates. Radiation therapy for cervical cancer appears to be as effective and is generally well tolerated. The Papanicolaou (Pap) test continues to be the primary screening tool for cervical cancer. Although transvaginal ultrasound seems to be useful in detecting early-stage ovarian cancer, its cost effectiveness for screening the general population remains to be demonstrated. The main considerations in the treatment of ovarian, endometrial, cervical, and vulvar cancer are discussed.

Low colorectal anastomosis after radical pelvic surgery: a risk factor analysis.

OBJECTIVE: This study was conducted to analyze our experience with low (8-12 cm above the anal verge) and very low (<6 cm above the anal verge) colorectal resection and primary anastomosis at the time of radical en bloc resection of pelvic malignancies. STUDY DESIGN: A retrospective review of 77 patients undergoing supralevator pelvic exenteration with low colorectal resection and primary anastomosis in our gynecologic oncology service was carried out. Data were obtained from patient medical records and from the tumor registry. Univariate statistical analysis of the data was used. RESULTS: The distribution of primary malignancies in this cohort was as follows: 33 (43%) recurrent or primary cervical carcinomas, 27 (35%) primary or recurrent ovarian carcinomas, 7 (9%) recurrent vaginal carcinomas, 4 (5%) endometrial carcinomas, 3 (4%) colon carcinomas, and 3 (4%) cases of stage IV endometriosis. Forty patients underwent total pelvic exenteration, and 37 patients underwent posterior exenteration. Thirty-six patients in the total pelvic exenteration group had a history of pelvic irradiation. Twelve (30%) of these patients had development of breakdown or fistulas of the anastomosis. Six of the 12 patients (50%) had undergone protective colostomy. Thirty-seven patients underwent posterior exenteration with primary anastomosis for ovarian cancer, endometrial cancer, colon cancer, or endometriosis, and only 1 of these had received pelvic irradiation. This patient did not have a protective colostomy, and a rectovaginal fistula developed. In addition, there were 3 other breakdowns in the posterior exenteration group. Finally, the presence of preoperative ascites did not appear to alter the breakdown rate of the anastomosis among the patients with ovarian cancer who underwent cytoreductive surgery. CONCLUSION: Radical resection of pelvic tissue remains a crucial part of the armamentarium of the gynecologic oncologist. Previous pelvic irradiation appears to be a major risk factor (35% vs 7.5%) for anastomotic breakdown and fistulas, independent of the presence of a protective colostomy. The overall results appear to be better for patients undergoing this procedure as part of a posterior exenteration.

Antitumor activity of a novel glyco-nitric oxide conjugate in ovarian carcinoma.

BACKGROUND: Several studies have shown that nitric oxide (NO)-releasing agents can kill tumor cells. Unfortunately, currently available NO delivery molecules do not target tumor cells preferentially. To exploit the overexpression of glucose transport proteins and the high level of glucose transport characteristics of tumor cells, glucose was conjugated to S-nitroso-N-acetyl-penicillamine (2-gluSNAP) and evaluated for cytotoxicity in human ovarian carcinoma cells. METHODS: The cytotoxicity of 2-gluSNAP and SNAP was assessed by clonogenic cell survival assays performed in A2780S (cisplatin sensitive) and A2780cP (cisplatin-resistant) ovarian carcinoma cells in vitro. Immunoblotting and immunohistochemistry were used to assess the expression of Glut-1 hexose transport protein in the cell lines as well as in paraffin blocks from 28 surgical specimens of epithelial ovarian carcinoma. Apoptosis was assessed by an end-labeling assay. RESULTS: The ovarian carcinoma cell lines consistently were more sensitive to 2-gluSNAP than SNAP alone. The median effective doses (MEDs) for 2-gluSNAP and SNAP in the A2780s cell line were 0.0042 microM and 20.4 microM, respectively. Therefore, 2-GluSNAP was nearly 5000-fold more potent than the NO-donating moiety (SNAP) alone. In the A2780cP cells, the MED for 2-gluSNAP (0.38 microM) was 250-fold lower than that for SNAP alone (100 microM). Immunoblotting and immunohistochemistry studies showed overexpression of Glut-1 in the cell lines and in 23 of 28 epithelial ovarian carcinoma specimens. CONCLUSIONS: The novel glyco-NO conjugate 2-gluSNAP exhibits a much greater cytotoxicity than the parent NO donor without the hexose moiety. These agents have the potential to target tumor cells preferentially, that overexpress Glut-1. This transporter is expressed highly in epithelial ovarian carcinoma.

The impact of intraoperative autologous blood transfusion during type III radical hysterectomy for early-stage cervical cancer.

OBJECTIVE: The aim of this study was to determine the effects on transfusion rates, perioperative complications, and survival of using intraoperative autologous blood transfusions for patients undergoing type III radical hysterectomy and lymphadenectomy. STUDY DESIGN: A retrospective analysis was conducted on 156 patients treated with type III radical hysterectomy and lymphadenectomy at the University of Miami School of Medicine from 1990 to 1997. One group of patients (n = 50) had intraoperative autologous blood transfusions and the other (n = 106) did not. RESULTS: The group that received intraoperative autologous blood transfusion had a significant reduction in homologous blood transfusions (12% vs 30%; P =.02). Patient demographic data, histologic parameters, and operative factors were similar between the 2 groups. There was a higher percentage of patients with positive pelvic lymph nodes in the group that did not receive intraoperative autologous blood transfusion (10% vs 30%; P =.02). Seven patients in the intraoperative autologous blood transfusion group (14%) died with disease present and all the recurrences in this group were local. CONCLUSION: The use of intraoperative autologous blood transfusions during type III radical hysterectomy and lymphadenectomy appears to be safe and effective without compromising rates and patterns of recurrence.

Separation of sperm and vaginal cells with flow cytometry for DNA typing after sexual assault.

BACKGROUND: Successful DNA typing after rape is limited when only a few sperm and numerous vaginal cells are recovered from a swab, resulting in an extremely unfavorable ratio of male to female DNA. The goal of this study was to develop a protocol involving sperm cell sorting with flow cytometry based on differences in ploidy, major histocompatibility class I, CD45, and cytokeratin expression. METHOD: Vaginal lavages were mixed with serially diluted ejaculate. After immunostaining and stoichiometric nuclear staining, spermatocytes were isolated by fluorescence-activated cell sorting. All sorted cells were used for DNA extraction and subsequent quantitative fluorescent multiplex polymerase chain reaction. The preferential lysis was performed for comparison. EXPERIENCE: The sorting procedure was superior to the preferential lysis method within all tested conditions. In unfavorable dilutions, the male DNA could be identified only after cell sorting with flow cytometry. CONCLUSION: We were able to show that separation of sperm and vaginal cells using cell sorting with flow cytometry may be crucial when there are only microtraces of sperm detectable after rape.

Generation of tumor-specific cytotoxic T lymphocytes by stimulation with HPV type 16 E7 peptide-pulsed dendritic cells: an approach to immunotherapy of cervical cancer.

OBJECTIVE: The aim of this study was to generate HPV-16 E7 peptide-specific cytotoxic T lymphocytes (CTLs) in vitro for future adoptive immunotherapy of cervical cancer. METHODS: Peripheral blood mononuclear cells (PBMC) were isolated from HLA-A2+ healthy donors. The PBMCs were incubated with HPV-16 E7(11-20) peptide and varying cytokines in the primary culture. Restimulation was performed weekly with peptide-pulsed, irradiated autologous PBMCs. Alternatively, the PBMCs were depleted of abundant CD4+ cells and stimulated with HPV-16 E7(11-20) peptide-pulsed dendritic cells. Cytolytic activity was determined by a standard 4-h (51)Cr-release assay. RESULTS: After 6 weeks in culture, we were able to establish peptide-specific CTL lines in one of seven donors by incubating PBMCs with HPV-16 E7(11-20) peptide. When we employed autologous peptide-pulsed dendritic cells to stimulate CD8+ cell-enriched PBMCs, we obtained CTL lines in four of seven donors. The primed CTLs were able to lyse the HLA-A2+ and HPV-16+ cervical cancer cell line Caski. SiHa, an HLA-A2-, but HPV 16+, cervical cancer cell line could be lysed only after transfection with HLA-A2. In addition, a high cytotoxicity (>80%) was obtained against peptide-pulsed, but not unpulsed, targets such as autologous Ebstein-Barr virus-immortalized B cells or allogeneic lipopolysaccaride-stimulated PBMCs. DCs were clearly the most potent of all tested antigen presenting cells to stimulate a CTL response in a proliferation assay. CONCLUSION: HPV-16 E7 peptide-specific CTLs could be generated in vitro. A practical protocol to expand the CTLs to a sufficient number for an application in a clinical trial is in progress.

Separation of sperm and vaginal cells based on ploidy, MHC class I-, CD45-, and cytokeratin expression for enhancement of DNA typing after sexual assault.

BACKGROUND: Successful DNA typing after rape is limited when only a few sperm and numerous vaginal cells are recovered from a swab, resulting in an extremely unfavorable ratio of male to female DNA. The goal of this study was to develop a protocol involving sperm cell sorting with flow cytometry based on differences in ploidy, major histocompatibility (MHC) class I, CD45 and cytokeratin expression. METHODS: Vaginal lavages were mixed with serially diluted ejaculate. After immunostaining and stoichiometric nuclear staining, spermatocytes were isolated by fluorescence-activated cell sorting. All sorted cells were used for DNA extraction and subsequent quantitative fluorescent multiplex polymerase chain reaction. The preferential lysis was performed for comparison. RESULTS: The sorting procedure was superior to the preferential lysis method within all tested dilutions. One documented case of rape was examined with both procedures and only after cell sorting with flow cytometry was the male DNA identified. CONCLUSIONS: We were able to show that separation of sperm and vaginal cells using cell sorting with flow cytometry may be crucial when there is only a few sperm detectable after rape.

Epidemiology and biology of cervical cancer.

Worldwide, cancer of the cervix is the second leading cause of cancer death in women: each year, an estimated 500,000 cases are newly diagnosed. Among populations, there are large differences in incidence rates of invasive cervical cancer: these reflect the influence of environmental factors, screening Papanicolaou (Pap) tests, and treatment of pre-invasive lesions. The high-risk human papillomavirus (HPV) subtypes 16, 18, 31, 33, and 51 have been recovered from more than 95% of cervical cancers. We have made great strides in understanding the molecular mechanism of oncogenesis of this virus, focusing on the action of the E6 and E7 viral oncoproteins. These oncoproteins function by inactivating cell cycle regulators p53 and retinoblastoma (Rb), thus providing the initial event in progression to malignancy. Cervical cancers develop from precursor lesions, which are termed squamous intraepithelial lesions (SIL) and are graded as high or low, depending on the degree of disruption of epithelial differentiation. Viral production occurs in low-grade lesions and is restricted to basal cells. In carcinomas, viral DNA is found integrated into the host genome, but no viral production is seen. The well-defined pre-invasive stages, as well as the viral factors involved at the molecular level, make cervical carcinoma a good model for investigating immune therapeutic alternatives or adjuvants to standard treatments.

Critical care issues in cervical cancer management.

Radical pelvic surgery in gynecologic oncology patients poses a challenge to the surgeon and the ancillary team in charge of the peri-operative care. The high frequency of medical problems observed in this patient population, in conjunction with the stresses of radical surgery, necessitates careful monitoring of patients' medical status. A comprehensive team approach in the perioperative period is critical to patient care. Early intervention and anticipation of potential problems for the patient at risk in the postoperative period minimizes morbidity and mortality. This article will review the essentials of critical care as it relates to patients undergoing radical pelvic operations.

Radical hysterectomy for cervical cancer: hysterectomy before pelvic lymphadenectomy or vice versa?

The technique for radical abdominal hysterectomy (RAH) and lymphadenectomy (LND) for patients with cervical cancer has been well described. Whether RAH should be performed before or after pelvic lymph node dissection (PLND) is a controversial issue. This study compared the two procedures performed at the same institution. Patients treated with type III RAH for cervical cancer stage IB-IIA at our institution between 1987 and 1995 were included in this study. Only patients who underwent para-aortic lymph node dissection (PALND) first, followed by PLND and then RAH (Group A) or RAH and then PLND (Group B) were included. Clinical and surgical information including intraoperative and postoperative complications was collected. Operative reports were used to identify the patients who had RAH performed before PLND or vice versa. Data analysis was obtained using unpaired t-test with significance set at P < 0.05. Complete information was obtained for 314 patients. The results of Group A (157 patients) and Group B (157 patients) were as follows: mean age = 45.3 and 44.8 (P = 0.73); mean weight = 149 and 149 lb.; mean length of stay = 10 and 8 days (P < 0.0001); mean operative time = 230 and 172 mins (P = 0.004); mean estimated blood loss (EBL) = 1,238 and 1098 cc (P = 0.21); mean number of PALN removed = 7 and 6 (P = 0.06); mean number of PLN removed = 28 and 26 (P = 0.24). No statistical difference in major intraoperative and postoperative complications was observed. The most common complication was postoperative fever (53/157 in Group A and 49/157 in Group B). Radical hysterectomy can be safely performed either before or after PLND. The number of pelvic lymph nodes removed, as well as the EBL and the intraoperative complications are similar and are not affected by the operative time. The surgeon should decide the sequence of the procedures accordingly to his/her personal preference.

Evaluation of the Pfannenstiel incision for radical abdominal hysterectomy with pelvic and para-aortic lymphadenectomy.

Radical abdominal hysterectomy with pelvic and para-aortic lymphadenectomy (RAH/P + PAL) has classically been described through a low midline vertical incision. Transverse incisions have been used with good results for various pelvic surgical procedures. Hesitancy has been encountered when utilizing these transverse incisions in gynecologic oncology patients. In most studies, muscle-splitting transverse incisions seem to be of equal efficacy as midline vertical incisions in regards to surgical exposure and clinicopathologic data obtained and are known to be superior in cosmesis and postoperative morbidity. A retrospective chart review was performed to identify 25 patients who underwent RAH/P + PAL for stage I carcinoma of the cervix from 1990 to 1998 through a nonmuscle splitting (Pfannenstiel) abdominal incision. All patients were seen and had follow-up in the Division of Gynecologic Oncology, University of Miami School of Medicine/Jackson Memorial Medical Center (Miami, FL). Data were collected on various clinical and surgical parameters including height/weight, operative time, blood loss, number of lymph nodes obtained, length of hospital stay, and postoperative complications. Analysis of the data revealed that operative time and average blood loss were within acceptable parameters. The yield at lymphadenectomy for pelvic and para-aortic lymph nodes was also respectable. Postoperative complications were minimal and there were no wound complications reported. Therefore, the Pfannenstiel incision can be safely utilized in a select group of patients undergoing RAH/P + PAL.

Urinary complications of Miami pouch: trend of conservative management.

OBJECTIVE: Continent urinary diversions have become popular among gynecologic oncologists. Much information has been gained concerning the complications and current management of patients with continent ileocolonic reservoirs. The high mortality rate associated with reoperation has led clinicians to adopt a trend toward conservative means of management. The purpose of this study was to evaluate the applicability of conservative management of complications related to the creation of the continent ileocolonic reservoir Miami pouch. STUDY DESIGN: Patients who underwent creation of the Miami pouch at the Division of Gynecologic Oncology, University of Miami School of Medicine, since 1988 have been included in this study. Management of complications, with particular emphasis on the conservative treatment, has been reviewed in detail for each patient. Open surgery and conservative treatment have been compared. RESULTS: Seventy-seven patients underwent creation of the Miami pouch from February 1988 to September 1997. Sixty (77.9%) patients were affected by recurrent cervical cancer; 72 (93.5%) were previously radiated. The perioperative mortality rate was 11.7% (9 patients). Six of these patients died as a result of sepsis; all of them underwent reoperation at least once. The most common urinary complications were ureteral stricture or obstruction (22.1%), difficult catheterization (19.5%), and pyelonephritis (13%). Conservative management strategies used for these complications included percutaneous nephrostomy, stent placement, balloon dilatation, radiologically (ultrasonography, fluoroscopy, computed tomography) guided placement of catheters, and antibiotic treatment. Eighty percent of the complications associated with the ileocolonic reservoir were resolved with conservative treatment, whereas 16.9% required surgical revision. CONCLUSION: On the basis of these findings, conservative management of urinary reservoir complications should always be considered before surgical intervention is attempted. The exact time to engage in open revision should be individualized on the basis of the clinical condition of each patient. It is our belief that the conservative approach should be instituted whenever possible but surgical intervention not be delayed when absolutely indicated.

Predicting risk of complications with gynecologic laparoscopic surgery.

OBJECTIVE: To determine the incidence and predictors of risk for operative complications, conversions to laparotomy, and postoperative admissions after laparoscopic procedures. METHODS: We obtained demographic information on and medical histories of a consecutive series of 843 women who underwent laparoscopic surgery for all procedures other than tubal ligation at Brigham and Women's Hospital during 1994. All major complications after surgery were recorded. Major operative complications were defined as bowel, bladder, ureter, or vascular injuries or significant abdominal wall or other internal bleeding. Categorical analysis was used to compare differences in the rates of operative complications, conversions to laparotomy, and postoperative admissions after laparoscopy. We also estimated the influence of medical history and specific laparoscopic procedures on the risk of adverse complications after surgery. RESULTS: Operative complications and conversion to laparotomy occurred in 1.9% and 4.7% of laparoscopic procedures, respectively. Complications included four bowel, two bladder, one ureteral, two vascular, and five abdominal wall injuries. There were 165 patients (19.6%) admitted postoperatively. Aside from the type of operative procedure, increasing age was the most important predictor of complications. Relative to all other operative procedures, women treated for endometriosis or ovarian cystectomy had generally low rates of operative complications, conversions to laparotomy, and postoperative admissions. In contrast, 12.5% of women undergoing laparoscopically assisted vaginal hysterectomy experienced operative injuries or abdominal bleeding and 90% were hospitalized postoperatively. CONCLUSION: Serious operative complications after gynecologic laparoscopy were rare in this patient population. The more complex laparoscopic procedures resulted in proportionately greater rates of operative complications, conversions to laparotomy, and postoperative admissions to the hospital.

Management of early and late complications of ileocolonic continent urinary reservoir (Miami pouch).

PURPOSE: The object of this study is to review our experience and formulate a plan for early recognition and effective management of early and late complications seen in patients who have undergone construction of the ileocolonic continent urinary reservoir. METHOD: Charts of patients who underwent continent urinary diversion at the Division of Gynecologic Oncology, University of Miami School of Medicine, from 1988 to 1996 were reviewed. We analyzed our data in terms of early and late (beyond 6 weeks) complications resulting directly from the operation or from this form of urinary diversion. RESULTS: Urinary diversion via the continent ileocolonic reservoir has been performed at our institution since February 1988. Sixty-six women have undergone construction of the Miami pouch over the past 81 years. Sixty-three of 66 patients needed a reservoir as a part of total pelvic exenteration for persistent or recurrent gynecologic malignancy. Three patients underwent reservoir construction for repair of vesicovaginal fistula. Sixty-two of 66 patients (95%) have a history of prior pelvic radiation. A total of 35 patients (53%) suffered early complications resulting in an operative mortality rate of 9% (6 of 66 patients). Early complications related to the construction of the reservoir included ureteral stricture/obstruction [10], anastomotic leak [4], reservoir-cutaneous fistula [4], difficulty in catheterization [5], pyelonephritis [10], sepsis [6], DIC [2], and ARDS [1]. Nonsurgical management strategies used for reservoir-related complications in these cases included percutaneous nephrostomy, peripheral hyperalimentation, intravenous antibiotics, and ultrasound-guided catheter placement. Eighty-four percent (16/19) of functional complications of the reservoir resolved with conservative management, whereas 3/19 patients needed surgical revision. One or more late complications (beyond 6 weeks) occurred in 25 patients (37%). Late complications seen included ureteral stricture/obstructions [6], incontinence [8], difficulty in catheterization [7], and urinary stones [4]. Nonsurgical management strategies used included percutaneous nephrostomy, balloon dilation, scheduled catheterization, ultrasound-guided catheter placement, and endoscopic/percutaneous lithotripsy. Four of 25 patients needed reoperation, whereas in 84% (21/25) of patients problems resolved with initial conservative management. CONCLUSION: Successful conservative therapy constitutes establishment of drainage, adequate nutrition, avoidance of sepsis, close observation, and patience. This article reviews the complications of the continent ileocolonic form of urinary diversion and formulates a treatment outline emphasizing an initial conservative approach that offers optimal management of early and late complications seen in this patient group.

Vaginal small cell carcinoma mimicking a Bartholin's gland abscess: a case report.

We report a case of a 32-year-old woman with a lesion in the vagina which clinically mimicked a Bartholin's gland abscess, but was demonstrated to be a small cell carcinoma by light microscopy. This tumor is very rare and to our knowledge there are 13 reported cases of primary vaginal small cell carcinoma in the English literature. The mean age of presentation of this neoplasm in the 13 reported cases is 61 with a median survival of 12 months. This case stresses the importance of considering this unusual diagnosis when confronted with a large or recurrent "Bartholin's gland lesion," and underlines the need for careful pathological examination of such specimens.

Risk of complications following gynecological laparoscopic surgery.

Objective: To determine the incidence and predictors of risk for operative complications, conversions to laparotomy, and postoperative admissions following laparoscopic procedures.Methods: We obtained demographic information and medical history on all 843 women who underwent laparoscopic procedures at the Brigham and Women's Hospital between January and December 1994. All major complications following surgery were recorded. Major operative complications were defined as bowel, bladder, ureter, or vascular injuries, or significant abdominal wall or other internal bleeding. Categorical analysis was used to compare differences in the rates of operative complications, conversions to laparotomy, and postoperative admissions following laparoscopy. We also estimated the influence of specific laparoscopic procedures on the risk of adverse complications following surgery.Results: Operative complications and conversion to laparotomy occurred at rates of 19.0 and 47.4 per 1,000 laparoscopic procedures, respectively. Of 843 women studied, complications included 4 bowel, 2 bladder, 1 ureteral, 2 vascular, and 5 abdominal wall injuries. There were 165 (19.6%) patients admitted postoperatively. Aside from the type of operative procedure, age was the single most important predictor of complications. Women with government or HMO insurance were somewhat more likely to have their laparoscopy converted to a laparotomy than women with private insurance. Relative to all other operative procedures, women receiving laparoscopic-assisted treatment of endometriosis and women undergoing ovarian cystectomy had generally low rates of operative complications, conversions to laparotomy, and postoperative admissions. In contrast, 12.5% of women receiving laparoscopic-assisted vaginal hysterectomy experienced operative injuries or abdominal bleeding and 90.0% were hospitalized postoperatively.Conclusion: Serious operative complications after major gynecologic laparoscopy were rare in this data set. The complexity of the laparoscopic procedure is directly proportional to the rate of operative complications, conversions to laparotomy, and postoperative admissions to the hospital.