Ultrasound-guided tandem placement for low-dose-rate brachytherapy in advanced cervical cancer minimizes risk of intraoperative uterine perforation.

OBJECTIVES: Tandem placement as part of low-dose-rate (LDR) brachytherapy boost for cervical cancer may be complicated by uterine perforation. The objective of this study was to describe a 10-year experience of using intraoperative ultrasound guidance in an attempt to minimize the risk of uterine perforation. METHODS: Operative and inpatient records were reviewed to identify cases in which intraoperative ultrasound guidance was employed in order to assist tandem placement, and to determine whether clinical or radiographic findings subsequently suggested uterine perforation. Demographic factors were collected in order to determine the baseline risk of perforation within this population. RESULTS: Between 1998 and 2008, 71 patients underwent 110 ultrasound-guided placements of tandem applicators. The median age was 48 (range, 26-88) years, and 20% were older than 60 years. Disease stage was FIGO IB1 (n = 10), IB2 (n = 13), IIA (n = 4), IIB (n = 19), IIIA (n = 2), IIIB (n = 16), IVA (n = 5) and IVB (n = 2). The median gravidity was 3 (range 1-10) and median parity was 3 (range 0-10). Seven patients had a preimplant history of pelvic infection, four had a history of intrauterine contraceptive device use, and 10 had a prior history of Cesarean section delivery. Only one patient experienced infection that may have been attributable to tandem placement-associated uterine perforation. At median survivor follow-up of 34 months, 19 patients had died. The estimated 3-year disease-free and overall survival rates for the entire population were 60% and 66%, respectively. CONCLUSIONS: Within the present population, intraoperative ultrasound guidance of tandem placement was associated with no confirmed cases of uterine perforation.

Bowel resection at the time of primary cytoreduction for epithelial ovarian cancer.

BACKGROUND: The purpose of this study was to determine the morbidity and survival associated with bowel resection at the time of primary cytoreductive surgery for ovarian cancer. STUDY DESIGN: We reviewed all patients undergoing bowel resection by gynecologic oncology faculty at the time of primary cytoreduction for advanced epithelial ovarian cancer diagnosed between 1983 and 1995. RESULTS: There were 105 patients meeting the above criteria. The median age was 65 years (range 34 to 85 years). There were 76 stage III and 25 stage IV cancers. The primary indication for bowel resection was tumor debulking in 92% of the patients. Seventy patients had segmental resection of the colon only, and 22 patients underwent resections that included the large and small bowels. Mean operating time was 260 minutes and mean estimated blood loss was 1,447 mL. Thirty-three (31%) patients were optimally cytoreduced to less than 1 cm residual disease. Ten patients experienced major complications directly related to bowel resection, including bowel fistula (4 patients), early postoperative bowel obstruction (5 patients), and stomal hernia (1 patient). Other morbidity included ileus for more than 10 days (18 patients), cardiac complications (17 patients), pneumonia (8 patients), sepsis (5 patients), and thromboembolism (4 patients). Six patients died and five patients required reexploration within 30 days of operation. Patients with preoperative bowel obstruction and suboptimal residual disease were more likely to have postoperative morbidity. Median survival in the optimally debulked patients was 35 months compared with 18 months in patients suboptimally cytoreduced (p = 0.006). Multivariate analysis demonstrated that optimal debulking (p = 0.009) and platinum chemotherapy (p = 0.00006) were independently associated with improved survival. Age, International Federation of Gynecologia Oncologists stage, American Society of Anesthesiologists class, and paclitaxel chemotherapy did not influence survival. CONCLUSIONS: In patients undergoing bowel resection at the time of primary cytoreduction for ovarian cancer, optimal cytoreduction to less than 1 cm residual disease results in improved survival. Morbidity is common but is comparable to other published series of ovarian cancer patients undergoing primary cytoreductive surgery without bowel resection. Additionally, patients with preoperative bowel obstruction and suboptimal residual disease are more likely to have serious morbidity.

Pathologic variables and adjuvant therapy as predictors of recurrence and survival for patients with surgically evaluated carcinosarcoma of the uterus.

BACKGROUND: The purpose of this study was to determine clinicopathologic variables associated with extrauterine disease, recurrence, and survival in patients with carcinosarcoma (CS) of the uterus. METHODS: Patients believed to have disease confined to the uterine corpus who underwent primary surgical assessment were identified and data retrospectively reviewed. RESULTS: Occult metastases were found in 38 (61%) of 62 patients. At last follow-up, 31 (50%) had had recurrence, with an extrapelvic component in 43%, and 53% had died. Depth of myometrial invasion and lymph-vascular space invasion (LVSI) were associated with extrauterine disease. Five-year survival for patients with disease confined to the corpus (74%) was significantly greater than for those with more advanced disease (24%, P = 0.0013). Factors associated with recurrence and survival included depth of myometrial invasion, LVSI, adnexal and serosal involvement, positive cytology, and lymph node metastases. Of 24 patients with uterine disease only, 11 received no adjuvant therapy, yet 8 (73%) were free of disease at last follow-up. Neither adjuvant radiotherapy nor chemotherapy was identified as an independent prognostic variable for recurrence or survival. CONCLUSIONS: More than half of patients with CS clinically confined to the uterine corpus harbor occult metastases in a pattern similar to that found with endometrial carcinoma. Survival is significantly diminished for this group. Although the benefit of adjuvant therapy cannot be demonstrated by this study, a number of early stage patients survive without adjuvant therapy. This argues for extending the International Federation of Gynecology and Obstetrics endometrial carcinoma surgical staging system to include CS, and also for conducting prospective trials to examine the benefits of adjuvant therapy for patients with early stage disease.

Malignant germ cell tumors of the ovary.

OBJECTIVE: To evaluate the efficacy of adjuvant therapy for ovarian germ cell tumors. METHODS: We reviewed records of women who had malignant germ cell tumors of the ovary from 1977-1997. RESULTS: Seventy-two women had surgical resections of malignant ovarian germ cell tumors and most received adjuvant therapy. Fifty-six women (78%) presented with stage I disease, and 16 (22%) had more advanced disease. Tumor subtypes included dysgerminoma (n = 20), yolk sac tumor (n = 8), immature teratoma (n = 29) and mixed germ cell tumor (n = 15). Surgical management of the 56 with stage I disease consisted of total abdominal hysterectomy, bilateral salpingo-oophorectomy, and extensive surgical staging in ten women, whereas a conservative surgical approach, consisting of unilateral adnexectomy with or without comprehensive surgical staging, was adopted in later years (n = 46). Fifty-six women were treated with postoperative chemotherapy, predominantly platinum-based regimens. The 5-year actuarial survival rate was 93%. None of the 36 women who presented after 1984 have died of disease. CONCLUSION: These data confirmed that platinum-based adjuvant treatments allow most women with ovarian germ cell malignancies to have conservative surgery without compromising survival.

Interstitial brachytherapy for vaginal recurrences of endometrial carcinoma.

OBJECTIVE: The aim of this study was to evaluate the efficacy of interstitial brachytherapy in the management of vaginal recurrences of endometrial carcinoma. METHODS: Thirty patients received interstitial irradiation, with or without external beam radiotherapy. They were followed for a minimum of 5 years or until death. RESULTS: The median age was 66 years at initial diagnosis of endometrial cancer. FIGO stages included Stage I (n = 18), Stage II (n = 7), and Stage III (n = 5). All patients were treated originally by total abdominal hysterectomy and bilateral salpingo-oophorectomy, with or without lymphadenectomy, and 13 (43%) also received postoperative adjuvant whole pelvis radiotherapy as part of their primary treatment. Vaginal recurrences were diagnosed at a mean interval of 29 months after hysterectomy (range, 3-119 months). No patient had clinical evidence of pelvic sidewall extension or of distant metastatic disease. All patients were treated with interstitial brachytherapy; each implant delivered a mean maximal tumor dose of 25.5 Gy. Eighteen patients (60%) also received external beam radiotherapy (mean dose, 48 Gy) as part of their treatment for vaginal recurrence. Twenty-eight patients (93%) experienced a complete clinical response. Ten patients relapsed in the vagina (n = 5) or at distant sites (n = 5). Eleven patients are dead of disease. From the time of vaginal recurrence, the median overall survival was 60 months and the cause of death adjusted 5-year survival rate was 65%. Major morbidity included radiation proctitis (n = 2), fistula (n = 2), and radiation stricture (n = 1). CONCLUSION: Interstitial irradiation resulted in favorable local control as well as a 5-year survival rate and morbidity comparable to that reported previously for conventional brachytherapy.

Relapse of acute lymphoblastic leukemia in pregnancy: survival following chemoirradiation and autologous transfer of interleukin-2-activated stem cells.

Four cases of relapse of acute lymphoblastic leukemia (ALL) in pregnancy have been reported previously. During the past 2 decades, ALL has become curable in a majority of children, many of whom have entered their reproductive years. Thus, additional occurrences of relapsing ALL during pregnancy can be anticipated. We present the fifth case in the English-language medical literature of recurrent ALL in pregnancy. A 20-year-old woman with ALL experienced a relapse during the third trimester of her first pregnancy. Reinduction therapy was started with vincristine and prednisone and the baby was delivered 3 weeks later. Umbilical cord blood was collected and stored. The patient then received intensive chemotherapy with whole body radiotherapy and autologous peripheral blood stem cell rescue. The ALL has been in second remission for 22 months. Our patient is the only current survivor of a relapse of ALL during pregnancy. In addition, the collection of umbilical cord blood from a pregnant woman with leukemia has not been reported previously.

Management of ovarian cancer in patients older than 80 years of Age.

OBJECTIVE: The objective of this study was to examine the treatment, associated morbidity, and survival in very elderly patients with epithelial ovarian cancer. METHODS: A retrospective analysis of patients 80 years of age and older treated for epithelial ovarian cancer by the Gynecologic Oncology faculty at the University of California Irvine was performed. RESULTS: Eighteen patients were older than 80 years of age at the time of diagnosis of ovarian cancer. Median age was 83 years (range 80-86 years). There were 2 stage I, 10 stage IIIC, 4 stage VI, and 2 unstaged patients. One patient had a tumor of low malignant potential, 4 patients had grade II tumors, and 10 patients had tumors that were grade III. Eighty-three percent of patients had one or more preexisting medical illnesses. Cardiac disease, stroke, and hypertension were most common. Sixteen of 18 patients (88%) underwent primary debulking surgery. American Society of Anesthesiologists physical status classification was as follows: 7/16 (44%) class II, 6/16 (38%) class III, and 2/16 (13%) class IV. The procedures performed included 16 bilateral salpingo-oophorectomies, 11 total abdominal hysterectomies, 16 omentectomies, 3 lymph node dissections, and 7 bowel resections. Four (25%) patients were optimally cytoreduced to <1 cm of residual disease. Seventy-five percent of surgical patients received blood transfusions of 2 or more units PRBC. Mean EBL was 600 cc (range 200-4200 cc). Thirty-eight percent of patients experienced major postoperative morbidity. There were 7 patients with postoperative congestive heart failure, 3 with sepsis, 1 with aspiration pneumonia, and 2 postoperative deaths. Seventy-five percent of patients spent time in the intensive care unit. Median number of days was 3 (range 1-22 days). Mean postoperative stay was 8 days (range 6-57 days). Sixty-five percent of patients were discharged to home. The other patients were discharged to intermediate care facilities or nursing homes. Eighty-three percent of patients received chemotherapy. Of the 10 patients (63%) receiving adjuvant chemotherapy, the mean interval from surgery to initiation of therapy was 3 weeks (range 1-4 weeks). Overall median survival was 6 months (range 1-45 months). Median survival in patients with optimal debulking was 32.5 months (range 7-45 months) compared to 3.5 months (range 1-41 months) in patients suboptimally debulked. CONCLUSIONS: In patients older than 80 years of age who undergo debulking surgery for ovarian cancer, serious medical comorbidity and advanced ASA status are common. Despite aggressive surgical effort and frequent blood transfusions, optimal debulking to less than 1 cm is achieved in only 25% of patients. Impressive morbidity and mortality occurs in this group of patients, but most patients are discharged to home and are able to receive postoperative chemotherapy.

Neoadjuvant chemotherapy in the treatment of locally advanced cervical carcinoma in pregnancy: a report of two cases and review of issues specific to the management of cervical carcinoma in pregnancy including planned delay of therapy.

BACKGROUND: Women diagnosed with invasive cervical carcinoma during pregnancy are faced with difficult decisions regarding therapy and the fate of their unborn child. A modest treatment delay for International Federation of Gynecology and Obstetrics Stage I cervical lesions is considered acceptable in patients who wish to continue their pregnancy. METHODS: Two patients with locally advanced cervical carcinoma diagnosed early in the second trimester strongly desired continuation of their pregnancies. They were treated with neoadjuvant chemotherapy until the third trimester, and then underwent delivery and definitive surgical treatment. The patients were evaluated during pregnancy for evidence of a clinical response to chemotherapy. Intraoperative findings and pathologic analysis of the surgical material provided further objective data regarding disease status. RESULTS: Both patients experienced a dramatic reduction in tumor volume, rendering radical hysterectomy feasible at the time of cesarean section. In addition, both patients tolerated chemotherapy well and there were no adverse fetal effects. Favorable neonatal outcomes were achieved. One patient experienced recurrence within 5 months of surgery, whereas the other patient remained without evidence of disease for 2 years. CONCLUSIONS: To the authors' knowledge, these reports constitute the first description of the use of neoadjuvant chemotherapy for invasive squamous cell carcinoma of the cervix in pregnancy (MEDLINE 1966-1997). This therapeutic option should be considered in selected women with locally advanced cervical carcinoma who do not want termination of their pregnancy.

p53 overexpression in advanced-stage endometrial adenocarcinoma.

OBJECTIVES: Mutation and overexpression of the p53 tumor suppressor gene in endometrial cancers are associated with advanced stage and poor survival. We sought to determine whether p53 overexpression is an independent variable predictive of poor prognosis in advanced endometrial adenocarcinomas. STUDY DESIGN: Immunohistochemical evaluation was used to examine p53 expression in paraffin blocks from 179 endometrial adenocarcinomas. RESULTS: p53 overexpression was seen in 35% of cancers and was associated with higher stage (p = 0.004), black race (p < 0.001), higher grade (p = 0.02), lack of hormone replacement (p = 0.04), and older age (p = 0.05). In addition to a higher frequency of p53 overexpression (57% vs 26%), black women had a lower survival rate than white women (p = 0.001), but overexpression was associated with poor survival in both races. After we corrected for hormone use, multivariate analysis revealed that older age (p < 0.001), higher stage (p < 0.001), higher grade (p = 0.01), and p53 overexpression (p = 0.04) were predictive of poor survival. CONCLUSIONS: Overexpression of p53 in advanced-stage endometrial cancers is an independent variable that is associated with poor survival, occurs more frequently in black women, and may contribute to the racial disparity in survival.

Early ovarian cancer: a review of its genetic and biologic factors, detection, and treatment.

Early-stage ovarian carcinoma requires comprehensive surgical staging; reexploration for patients who had suboptimal initial surgery would indicate an apparent early ovarian carcinoma. After proper surgery, patients can be subdivided into a high- or low-risk group, and treatment options then can be discussed with the patient. Patients in the low-risk category can be followed up expectantly without any form of adjuvant therapy. Patients in the high-risk category, however, should be encouraged to participate in randomized clinical trials, because it is unclear at the current time which combination of chemotherapy and how many treatments should be used. A platinum-based paclitaxel regimen probably should be used, although the relative merits of carboplatin and cisplatin and the appropriate schedule for taxol (1 hour vs. 3 hours vs. 24 hours vs. 96 hours) are yet unknown. It is hoped that clinicians will continue to encourage patients to participate in randomized clinical trials so that optimal therapy for early ovarian cancer can be established.

Mutational analysis of the estrogen-receptor gene in endometrial carcinoma.

OBJECTIVE: To determine whether mutation in the DNA of the estrogen-receptor gene occurs in endometrial cancer. METHODS: Polymerase chain reaction amplification and single-stranded conformation polymorphism analysis of the entire coding region (exons 1-8) of the human estrogen-receptor gene, as well as an untranslated region (exon I*) in the gene, were performed on genomic DNA extracted from 56 snap-frozen endometrial cancers. All cancers demonstrating mobility shifts on single-stranded conformation polymorphism suggestive of DNA sequence alteration were subjected to definitive DNA sequencing of the relevant portion of the estrogen-receptor gene. RESULTS: In addition to detecting a frequent, previously described polymorphism in exon 1, single-stranded conformation polymorphism analysis of the 56 endometrial cancers identified seven cancers with mobility shifts. Three cancers shifted in exon 3, one cancer each shifted in exons 4 and 7, and two shifted in exon 8. Deoxyribonucleic acid sequencing revealed sequence alterations in all seven cases demonstrating mobility shifts. In six of these seven cases, these alterations were consistent with infrequent silent polymorphisms; in the seventh cancer, the sequence alteration proved to be a somatic missense mutation at codon 537 in the region of the estrogen-receptor gene encoding the hormone-binding domain of the receptor protein. CONCLUSION: The infrequent DNA mutation in the estrogen-receptor gene is unlikely to account for the variation in estrogen-receptor expression observed in endometrial cancer.

Malignant transformation of the human endometrium is associated with overexpression of lactoferrin messenger RNA and protein.

In the mouse uterus, lactoferrin is a major estrogen-inducible uterine secretory protein, and its expression correlates directly with the period of peak epithelial cell proliferation. In this study, we examine the expression of lactoferrin mRNA and protein in human endometrium, endometrial hyperplasias, and adenocarcinomas using immunohistochemistry, Western immunoblotting, and Northern and in situ RNA hybridization techniques. Our results reveal that lactoferrin is expressed in normal cycling endometrium by a restricted number of glandular epithelial cells located deep in the zona basalis. Two thirds (8 of 12) of the endometrial adenocarcinomas examined overexpress lactoferrin. This tumor-associated increase in lactoferrin expression includes an elevation in the mRNA and protein of individual cells and an increase in the number of cells expressing the protein. In comparison, only 1 of the 10 endometrial hyperplasia specimens examined demonstrates an increase in lactoferrin. We also observe distinct cytoplasmic and nuclear immunostaining patterns under different fixation conditions in both normal and malignant epithelial cells, similar to those previously reported in the mouse reproductive tract. Serial sections of malignant specimens show a good correlation between the localization of lactoferrin mRNA and protein in individual epithelial cells by in situ RNA hybridization and immunohistochemistry. Although the degree of lactoferrin expression in the adenocarcinomas did not correlate with the tumor stage, grade, or depth of invasion in these 12 patients, there was a striking inverse correlation between the presence of progesterone receptors and lactoferrin in all 8 lactoferrin-positive adenocarcinomas. In summary, lactoferrin is expressed in a region of normal endometrium known as the zona basalis which is not shed with menstruation and is frequently overexpressed by progesterone receptor-negative cells in endometrial adenocarcinomas.

Allelotype of endometrial carcinoma.

An allelotype analysis of endometrial carcinoma was undertaken to identify chromosomal loci that are relevant to this tumor type. A total of 70 highly polymorphic microsatellite markers, distributed among all nonacrocentric chromosome arms, were examined for evidence of loss of heterozygosity or allelic imbalance in DNA samples from matched normal and tumor tissues. An average of 21 informative tumor cases were obtained for each marker. Allelic deletions or imbalance were observed on 31 of 41 chromosome arms with no marker showing an allelic loss ratio of greater than 33%. Those chromosome arms most frequently involved were 3p, 8p, 9p, 14q, 16q and 18q. There was a strong correlation between loss of heterozygosity on chromosome 14q and death from disease. These data indicate that the molecular genetic character of endometrial carcinoma is complex and that a relatively large number of different chromosomal loci are likely to play a role in the etiology and progression of this tumor type.

Multivariable analysis of DNA ploidy, p53, and HER-2/neu as prognostic factors in endometrial cancer.

BACKGROUND: Several molecular-genetic alterations in endometrial cancers, including aneuploidy and aberrant expression of p53 and HER-2/neu, have been associated with poor prognosis. To determine the importance of molecular-genetic factors relative to more traditional surgical-pathologic prognostic factors, a multivariable analysis was performed. METHODS: Immunohistochemical staining for p53, HER-2/neu, estrogen receptor, progesterone receptor, and epidermal growth factor receptor was performed on frozen sections from 100 primary endometrial cancers. DNA ploidy was determined using computerized image analysis of Feulgen-stained touch preparations. In addition, information regarding surgical-pathologic features of the cancers was obtained. Univariable analysis was performed followed by multivariable analysis using Cox's proportional hazards model to identify variables predictive of poor prognosis. RESULTS: With univariable analysis, race, histologic type, stage, grade, myometrial invasion, estrogen receptor, progesterone receptor, ploidy, p53 and HER-2/neu were predictive of the presence of persistent or recurrent disease. In the multivariable analysis, only International Federation of Gynecology and Obstetrics stage (P = 0.005), grade (P = 0.005), myometrial invasion (P = 0.024), and ploidy (P = 0.028) were significant. CONCLUSIONS: Among molecular-genetic prognostic factors, DNA ploidy was the most strongly predictive of persistent or recurrent disease.

Mutations of the E-cadherin gene in human gynecologic cancers.

Expression of the E-cadherin cell adhesion molecule is reduced in several types of human carcinomas, and the protein serves as an invasion suppressor in vitro. To determine if mutations of the E-cadherin gene (on chromosome 16q22) contribute to epithelial tumorigenesis, 135 carcinomas of the endometrium and ovary were examined for alterations in the E-cadherin coding region. Four mutations were identified: one somatic nonsense and one somatic missense mutation, both with retention of the wild-type alleles, and two missense mutations with somatic loss of heterozygosity in the tumour tissue. These data support the classification of E-cadherin as a human tumour suppressor gene.

Overexpression of p53 is not a feature of benign and early-stage borderline epithelial ovarian tumors.

Since overexpression of mutant p53 protein is a common feature of invasive epithelial ovarian cancers, we investigated whether overexpression of the p53 tumor suppressor gene product occurs in benign and borderline epithelial ovarian tumors. Immunohistochemical staining for p53 was performed in frozen samples of 17 benign tumors and in 49 borderline tumors (4 frozen, 45 paraffin embedded). Overexpression of p53 was observed in 0/17 (0%) benign ovarian tumors and 2/49 (4%) borderline tumors. Overexpression of p53 in borderline tumors was only seen in advanced stage cases; overexpression was seen in 2/8 (25%) stage III cases, but not in any of 41 stage I/II cases. In conclusion, overexpression of p53 is not a feature of benign epithelial ovarian tumors or early-stage borderline ovarian tumors. Similar to invasive epithelial ovarian cancers, however, a fraction of metastatic borderline tumors also overexpress p53.

Mutation and overexpression of the p53 tumor suppressor gene frequently occurs in uterine and ovarian sarcomas.

OBJECTIVE: To determine the frequency of mutation and overexpression of the p53 tumor suppressor gene in female genital tract sarcomas. METHODS: Immunostaining for p53 was performed in frozen sections of 46 ovarian and uterine sarcomas. Single-stranded conformation polymorphism analysis of exons 4-9 of the p53 gene was performed in 33 sarcomas. We performed DNA sequencing of the p53 gene in 22 cases in which we found p53 protein overexpression and/or shifted bands on single-stranded conformation polymorphism analysis. RESULTS: Overexpression of p53 was seen in 27 of 46 sarcomas (59%), including 26 of 41 (63%) mixed mesodermal tumors, one of four (25%) leiomyosarcomas, and zero of one endometrial stromal sarcoma. Among the 33 sarcomas subjected to molecular analysis, 21 demonstrated mutations in the p53 gene (64%). Eighteen cancers had a single mutation, whereas three cases showed two mutations in the p53 gene. There was one mutation in exon 4, seven mutations in exon 5, three mutations in exon 6, six mutations in exon 7, six mutations in exon 8, and one mutation in exon 9. With the exception of one microdeletion, which predicted a truncated protein product, all of the mutations were missense point mutations. All but one of the point mutations resulted in changes in the predicted amino acid sequence. There were 18 transition mutations (75%), five transversions (21%), and one deletion (4%). CONCLUSIONS: Mutation of the p53 tumor suppressor gene, with resultant overexpression of p53 protein, frequently occurs in ovarian and uterine sarcomas. Because most of the mutations are transitions, p53 mutations in these cancers likely arise from spontaneous errors in DNA synthesis and repair rather than from exposure to carcinogens.