A Phase I Evaluation of Extended Field Radiation Therapy With Concomitant Cisplatin Chemotherapy Followed by Paclitaxel and Carboplatin Chemotherapy in Women With Cervical Carcinoma Metastatic to the Para-aortic Lymph Nodes: An NRG Oncology/Gynecologic Oncology Group Study.

BACKGROUND: Chemo-radiation (chemoRT) has improved the overall survival for locally advanced cervical cancer (LACC) though women whose disease involves the para-aortic nodes (PAN) experience recurrence rates and worse survival outcomes compared to those without PAN involvement. This Phase I study determined if additional cycles of systemic chemotherapy could be safely added to extended field chemoRT in this population of patients. METHODS: Women with LACC and documented positive PAN were eligible for treatment. All women were treated with extended field radiation and brachytherapy and concurrent cisplatin 40 mg/m2 weekly for six weeks. Four to six weeks after completion of chemoRT, patients were treated with four cycles of paclitaxel 135 mg/m2 and escalating doses of carboplatin (Dose Level (DL) 1 = AUC 4, DL2 = AUC 5). RESULTS: Eleven women were entered on study and 9 were evaluable for dose limiting toxicities (DLT). Two women (1 in each of 2 DLs) did not complete chemoRT and so were not evaluable for DLT. Three women completed all 10 cycles at DL 1 with no DLTs. Six women were then treated at DL 2. For the 10 patients evaluable for response, the ORR was 60% (CR + PR). PFS and OS at 12 months were 60% and 90%, respectively. The predominant grade 3 or 4 acute toxicities were hematologic. There were no grade 5 events. CONCLUSION: Extended field chemoRT followed by paclitaxel 135 mg/m2 and carboplatin AUC 5 is feasible in women with LACC and positive PAN.

Complications of Robotic Gynecologic Surgery in the Severely Morbidly Obese.

BACKGROUND: Surgeons are increasingly faced with the challenge of caring for obese patients. Advanced laparoscopic procedures have been shown to be safe in women with high BMI, but conversion rates remain high. Because robotics holds many potential advantages over traditional laparoscopic surgery, we sought to evaluate the outcome of robotic-assisted gynecologic surgery in obese patients. METHODS: A retrospective chart review of obese female patients undergoing robotic gynecologic surgery between January 2008 and August 2010 was done. Patients were divided into three groups based on BMI (group I, BMI 30-34.9 kg/m2; group II, BMI 35-39.9 kg/m2; and group III, BMI >40 kg/m2). Patients were assessed for baseline characteristics, comorbid conditions, and surgical outcomes and complications. RESULTS: A total of 128 obese patients were identified with 43 in group I, 30 in group II, and 55 in group III. There was an increased prevalence of diabetes and asthma in group III and younger age in group I. Of the 128, 117 (91 %) underwent hysterectomy and/or staging with the majority of patients having surgery for either endometrial cancer or fibroids. Conversion to laparotomy was more common in groups 2 and 3 with a positive correlation between increasing BMI and conversion. There was no difference in complications between the groups and only 1 major postoperative complication in the entire cohort. CONCLUSIONS: Robotic-assisted gynecologic surgery can be safely performed in severely morbidly obese patients. Although conversion rates are higher with increasing obesity, a majority of procedures can still be completed minimally invasively.

Distribution and case-fatality ratios by cell-type for ovarian carcinomas: a 22-year series of 562 patients with uniform current histological classification.

BACKGROUND: Ovarian carcinoma is comprised of several different cell types reflecting different clinicopathologic features. Pathologic criteria for distinguishing cell types have evolved, and therefore non-contemporary literature on ovarian cancer may have limited current relevance. A new dualistic model of pathogenesis that distinguishes type I (endometrioid, mucinous, clear cell and low grade serous carcinomas) from type II (high grade serous carcinomas and carcinosarcomas) tumors has become widely accepted. METHODS: A cohort of 562 patients with invasive ovarian carcinoma from a large community hospital practice was reviewed. Cell type, FIGO stage, mortality and interpathologist diagnostic reproducibility were analyzed. RESULTS: Advanced stage ovarian carcinomas were type II in 86% of cases while low stage tumors were most often type I. Only 1.7% of type II tumors were confirmed to be stage I with comprehensive surgical staging. Type II tumors accounted for 85% of deaths, and clear cell carcinomas, 5% of deaths. Cell type-specific case-fatality ratios for type II tumors were 62% and 79% for high grade serous carcinoma and carcinosarcoma, respectively. For type I tumors, case-fatality ratios were 38%, 36%, 27% and 13% for low grade serous, clear cell, endometrioid and mucinous carcinomas, respectively. The kappa value for diagnostic reproducibility among 3 gynecologic pathologists was 0.83. CONCLUSIONS: Current diagnostic criteria confirm that high grade serous carcinoma and carcinosarcoma account for the vast majority (85%) of ovarian cancer deaths. Cell type designation is highly reproducible among gynecologic pathologists. Type II tumors are rarely stage I (<2%) when comprehensively staged by a gynecologic oncologist.

Survival rates for international federation of gynecology and obstetrics stage III ovarian carcinoma by cell type: a study of 262 unselected patients with uniform pathologic review.

OBJECTIVE: Published data are conflicting on the influence of cell type on prognosis in ovarian cancer. The recent separation of low-grade serous carcinoma as a distinctive cell type of ovarian cancer with an indolent behavior, in retrospect, suggests that survival in studies that have not separated this group may be inaccurate. METHODS: An unselected series of 262 International Federation of Gynecology and Obstetrics stage III ovarian carcinomas was studied. Diagnostic classification of each tumor was made with particular attention to recent refinements in cell-type classification. Survival curves were constructed according to Kaplan-Meier and compared with the log-rank test. RESULTS: The 5-year survival for 207 high-grade serous carcinomas was 40%, as compared with 71% for 18 patients with low-grade serous carcinoma (P = 0.0113). Low-grade serous carcinoma was significantly more likely to be optimally debulked (P = 0.0039) and significantly less likely to be substage IIIC (P < 0.0001). The survival for carcinosarcoma was significantly inferior to all serous carcinomas (P = 0.0322). The significance of this latter comparison was lost when carcinosarcomas were compared with only high-grade serous carcinoma (P > 0.05). CONCLUSIONS: Low-grade serous carcinoma has a significantly better prognosis than high-grade serous carcinoma and also differs with regard to substage distribution and proportion of patients optimally debulked. Because of its excellent prognosis, failure to separate low-grade serous carcinomas, notwithstanding its infrequent occurrence, can change the results of survival analyses that do not make this separation.

Prophylactic Negative Pressure Wound Therapy After Laparotomy for Gynecologic Surgery: A Randomized Controlled Trial.

OBJECTIVE: To estimate the effectiveness of prophylactic negative pressure wound therapy in patients undergoing laparotomy for gynecologic surgery. METHODS: We conducted a randomized controlled trial. Eligible, consenting patients, regardless of body mass index (BMI), who were undergoing laparotomy for presumed gynecologic malignancy were randomly allocated to standard gauze or negative pressure wound therapy. Patients with BMIs of 40 or greater and benign disease also were eligible. Randomization, stratified by BMI, occurred after skin closure. The primary outcome was wound complication within 30 (±5) days of surgery. A sample size of 343 per group (N=686) was planned. RESULTS: From March 1, 2016, to August 20, 2019, we identified 663 potential patients; 289 were randomized to negative pressure wound therapy (254 evaluable participants) and 294 to standard gauze (251 evaluable participants), for a total of 505 evaluable patients. The median age of the entire cohort was 61 years (range 20-87). Four hundred ninety-five patients (98%) underwent laparotomy for malignancy. The trial was eventually stopped for futility after an interim analysis of 444 patients. The rate of wound complications was 17.3% in the negative pressure wound therapy (NPWT) group and 16.3% in the gauze group, absolute risk difference 1% (90% CI -4.5 to 6.5%; P=.77). Adjusted odds ratio controlling for estimated blood loss and diabetes was 0.99 (90% CI 0.62-1.60). Skin blistering occurred in 33 patients (13%) in the NPWT group and in three patients (1.2%) in the gauze group (P<.001). CONCLUSION: Negative pressure wound therapy after laparotomy for gynecologic surgery did not lower the wound complication rate but did increase skin blistering. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT02682316. FUNDING SOURCE: The protocol was supported in part by KCI/Acelity.

Upstaging pathologic stage I ovarian carcinoma based on dense adhesions is not warranted: a clinicopathologic study of 84 patients originally classified as FIGO stage II.

BACKGROUND: FIGO stage II ovarian cancer comprises 8% of ovarian cancers. It is a common but not universal practice to upstage densely adherent pathologic stage I tumors to stage II. FIGO guidelines are not clear, and data supporting this practice are sparse. METHODS: We retrospectively reviewed patients with stage II ovarian cancer and grouped them based upon histologic evidence of extraovarian extension. Tumors densely adherent to extraovarian structures but without histologic tumor outside the ovary were considered pathologic stage I. All others were considered surgical-pathologic stage II. Three histologic patterns of extraovarian tumor involvement were identified. RESULTS: Eighty-four patients were studied. Twenty-four patients had pathologic stage I disease and 60 had histologic evidence of extraovarian pelvic spread and were surgical-pathologic stage II. The 5-year survival for stage I was 100%, and the median survival was not reached. The 5-year survival for those with surgical-pathologic stage II disease was 56.8% and the median survival was 73 months. There were no differences observed based upon pattern of extraovarian spread. The survival difference between pathologic stage I and surgical-pathologic stage II was significant (p<0.001). There were no differences seen in 5-year survival among surgical-pathologic stage II patients with serous, endometrioid or clear cell histologies (64.5%, 64.8% and 64.3% respectively). CONCLUSION: These retrospective data suggest that the practice of upstaging densely adherent pathologic stage I tumors to stage II may not be warranted. Cell type is not a prognostic factor in stage II.

Prognostic factors for stage I ovarian carcinoma.

Stage I ovarian carcinoma is relatively uncommon, and data on prognostic factors are conflicting. The clinical and pathologic features of 51 International Federation of Gynecology and Obstetrics stage I ovarian carcinomas were analyzed. There were 22 stage IA, 1 stage IB, and 28 stage IC cases. The mean follow-up was 6.1 years. The 5-year and 10-year disease-specific survival rates for the entire cohort were 92% and 78%, respectively. Among 51 patients, there were 6 tumor deaths, and 1 patient died of unrelated causes. All patients who died of disease were stage IC. Significant adverse prognostic factors were serous histology [relative risk (RR) 5.4, 95% confidence interval (CI) 1.3-22.0] and stage IC (RR 1.3, 95% CI 1.1-1.5). Among factors associated with stage IC, only positive washings or ascites affected survival (RR 9.25, 95% CI 1.9-44.4). The 5-year survival rates for stages IA and IC were 100% and 83%, respectively (P<0.025, log rank test). For comprehensively staged patients, the 5-year survival rate was 96% as compared with 72% for all others (P<0.025, log rank test). Tumor rupture, surface involvement, histologic grade and clear cell histology were not of adverse prognostic significance. Serous histology and positive washings or ascites are adverse prognostic factors in stage I. The prognostic importance of tumor grade, rupture, surface involvement and clear cell histology remains unclear. Patients who are International Federation of Gynecology and Obstetrics stage I on the basis of comprehensive surgical staging have an excellent prognosis.

Endometriosis mimicking ovarian cancer in the setting of acquired immune deficiency syndrome.

BACKGROUND: With rising rates of human immunodeficiency virus (HIV) among women and resultant immunosuppression, clinicians face varying presentations of gynecologic pathologies. We report a case of endometriosis in a patient with acquired immunodeficiency syndrome (AIDS) presenting with a Sister Mary Joseph's nodule and mimicking carcinomatosis. CASE: A woman with AIDS and 2-month history of abdominal pain, distention, and weight loss was found to have periumbilical and pelvic masses, ascites, lymphadenopathy, and an elevated CA 125 level. Operative findings included chocolate-colored ascites and peritoneal seeding involving the ovaries, uterus, appendix, bowel, umbilicus, and omentum. The patient underwent total abdominal hysterectomy with bilateral salpingo-oophorectomy and resection of all gross disease. Pathologic diagnosis was endometriosis and AIDS-associated adenopathy. COMMENT: Immunodeficiency from AIDS can affect the progression of endometriosis to the point of mimicking ovarian malignancy.

Modulation of angiogenic phenotype alters tumorigenicity in rat ovarian epithelial cells.

Vascular endothelial growth factor (VEGF) expression correlates with microvessel density, stage, malignant ascites, metastasis, and survival in ovarian cancer. By transducing VEGF165 into a nontumorigenic rat ovarian surface epithelial cell line (ROSE199), we investigated the direct effect of an angiogenic phenotype on tumor development. The neu oncogene, which is overexpressed in >30% of ovarian cancers, was used in comparison. Neu-transfected ROSE199 cells showed phenotypic characteristics of transformation in vitro with an abundance of focus-forming units in monolayer cultures and anchorage-independent growth in soft agar. In contrast, VEGF-secreting ROSE199 cells (VR) retained normal morphology and in vitro growth characteristics (e.g., proliferation rate) compared with parental ROSE199 cells. Interestingly, injection of VR cells into athymic mice formed malignant ascites in 100% of the animals when injected into the peritoneum and developed vascularized tumors in 85% of the mice when injected s.c. Furthermore, blocking VEGF-mediated signaling by the Flk-1/KDR receptor kinase inhibitor SU5416 significantly inhibited the growth of VR tumors. To validate that the proangiogenic switch is responsible for tumor development, the angiogenic phenotype was balanced by the inducible coexpression of endostatin under the control of Tet-activated promoter. Coexpression of endostatin along with VEGF reversed the tumorigenic phenotype of VR cells. These studies show that alterations in the angiogenic characteristics of ovarian surface epithelium may play an important role in the etiology of ovarian cancer, and that inhibition of angiogenesis can be effective in the treatment of epithelial ovarian cancer.

The ability of endometrial biopsies with atypical complex hyperplasia to guide surgical management.

OBJECTIVE: This study was undertaken to determine the clinical relevance of "qualifying comments" on pathology reports of complex atypical endometrial hyperplasia. STUDY DESIGN: A retrospective review of endometrial biopsy specimens with atypical hyperplasia at our institutions was performed if subsequent hysterectomy results were available for review. Endometrial biopsy results were graded on an ordinal scale (complex atypical endometrial hyperplasia vs atypical endometrial hyperplasia "cannot rule out a more severe lesion") and compared with pathology obtained at hysterectomy. Data were analyzed by using Fisher's exact test. RESULTS: Endometrial biopsy specimens were associated with carcinoma in 37.5% (18/48) of complex atypical endometrial hyperplasia cases and in 60% (18/30) of atypical endometrial hyperplasia-cancer cases. Atypical endometrial hyperplasia-cancer on biopsy was associated with an increased risk of discovering a malignancy at intermediate/high-risk for lymph node involvement (odds ratio 4.71, P = .0256). CONCLUSION: Biopsy specimens that show atypical endometrial hyperplasia-cancer are associated with an increased risk of finding a cancer at intermediate or high risk for nodal metastasis.

Carcinomas of the female genital tract occurring after pelvic irradiation: a report of 15 cases.

The concept of postradiation sarcoma is widely appreciated, however carcinomas arising in previously irradiated fields, the putative "postradiation carcinoma," are less well understood. Fifteen patients who developed gynecological malignancies after pelvic radiation therapy were studied. Five of these patients had HPV-related tumors both pre- and post- irradiation. Ten were irradiated for cervical cancer, one for endometrial carcinoma, one for vulvar carcinoma, one for colon cancer and 2 for benign conditions. The mean and median latent periods from the initiation of radiation therapy to the development of the second malignancy were 22.8 and 19 years, respectively (22.4 and 19.5 years, respectively, for non-HPV-related cancers; 24 and 18 years for HPV-related cancers). The "postradiation" malignancies included 2 ovarian carcinomas, 5 vaginal carcinomas (3 invasive, 2 in situ), 4 endometrial carcinomas, one cervical carcinoma, one vulvar carcinoma, one distal urethral carcinoma, and one pelvic carcinoma of unclear primary site. Gynecological carcinomas may occur many years after pelvic irradiation. Although the evidence for a causative role is circumstantial, these tumors appear to have a similar latent period as postradiation sarcomas.

Testing of two binary grading systems for FIGO stage III serous carcinoma of the ovary and peritoneum.

OBJECTIVE: A variety of histologic grading systems for ovarian carcinoma have been used, but there is no widely accepted system. Binary grading systems are inherently superior to the more common three-grade systems because they are more reproducible and they correspond to the number of options in the binary treatment decision for which grade is considered important: the use of or withholding of chemotherapy. METHODS: One hundred thirteen unselected FIGO stage III serous carcinomas of the ovary and peritoneum were tested with two grading systems: a binary system recently proposed by investigators at MD Anderson Cancer Center (MDACC) and a new binary system we formulated at the Washington Hospital Center (WHC). Both of these systems are based on nuclear grade. The WHC system has a higher threshold of nuclear size for diagnosing high-grade tumors. RESULTS: The WHC system separated the cases into 89 high-grade and 24 low-grade tumors. The median survival rates were 30 and 49 months for high and low grade respectively, and the actuarial survival curves were not significantly different (P > 0.10). The MDACC system separated the cases into 103 high-grade and 10 low-grade tumors. With this system, low-grade tumors were significantly more likely than high grade to be stage IIIA (P < 0.05) and occurred at a mean age of 57 years compared to 65 years for high-grade tumors (P < 0.05). Low-grade tumors were suboptimally debulked in 10% of cases compared to 27% for high-grade tumors (P > 0.05). The median survival for high-grade tumors was 34 months, and the median for low grade has not been reached. The actuarial survival curves were not significantly different (P = 0.065). CONCLUSION: The MDACC grading system appears more promising than the WHC system. The MDACC system separates a small (9% of advanced stage serous carcinomas) but distinctive well-differentiated tumor which usually has the appearance of invasive low-grade (micropapillary) serous carcinoma. The rarity of this tumor, however, will require a larger series to demonstrate prognostic value. The WHC system, which was designed to enlarge the low-grade group to a size that would be more meaningful in clinical practice, did not demonstrate a survival difference. The failure of the WHC system suggests that attempts to enlarge the low-grade group using histologic features alone are unlikely to be successful. The potential for confounding of grade with substage, volume of residual disease and patient age are issues that may impede determination of the independence of tumor grade in prognosis, and more data, especially for low-grade tumors, are needed.

Vulvar cancer in human immunodeficiency virus-seropositive premenopausal women: a case series and review of the literature.

This review describes three cases of human immunodeficiency virus-infected women who were diagnosed with vulvar cancer before age 40 years. A retrospective chart review was performed for three patients who were younger than 40 years of age and who had histologically confirmed invasive squamous cell carcinoma of the vulva diagnosed between 1999 and 2002. Demographic, clinical, and laboratory data were recorded. Three human immunodeficiency virus-seropositive women were diagnosed with invasive squamous cell carcinoma of the vulva, stages IA, IB1, and III. All cases were characterized by extensive surrounding vulvar, vaginal, and cervical intraepithelial neoplasia. CD4 cell counts were 250, 330, and 900 cells/uL. Two patients experienced previous acquired immune deficiency syndrome-defining illnesses: toxoplasmosis and cervical cancer. Vulvar cancer in young human immunodeficiency virus-seropositive women may be associated with other human papillomavirus-related diseases and immunosuppression, as evidenced by low CD4 counts and the presence of antecedent acquired immune deficiency syndrome-defining illnesses.

Stage IV carcinoma of the Bartholin gland managed with primary chemoradiation.

BACKGROUND: Optimal management of carcinoma of the Bartholin gland is not yet defined. Patients with locally advanced disease have historically been managed by radical and, occasionally, exenterative surgery. Although the management of advanced vulvar cancer has shifted toward conservative management with primary chemoradiation, there is limited information on the similar approach to the management of advanced Bartholin's gland carcinoma. CASE: We present a woman with stage IVA basaloid squamous carcinoma of the Bartholin gland. She was managed with primary chemoradiation in an attempt to spare her the morbidity associated with exenterative surgery. We discuss a rationale for the use of chemoradiation in advanced Bartholin's gland carcinoma. CONCLUSION: Conservative management of advanced carcinoma of the Bartholin gland with primary chemoradiation may be appropriate while sparing patients the sequelae of exenterative surgery.

Phase II study of mitomycin, doxorubicin, and cisplatin in the treatment of advanced uterine leiomyosarcoma: a Gynecologic Oncology Group study.

OBJECTIVE: Because of preliminary observations favoring the use of mitomycin, doxorubicin, and cisplatin (MAP) chemotherapy in leiomyosarcomas, the Gynecologic Oncology Group (GOG) decided to conduct a phase II clinical trial of this combination regimen in patients with advanced disease. METHODS: Patients with histologically confirmed uterine leiomyosarcoma who had not previously received cytotoxic drugs were considered for participation in this clinical trial. Eligible patients had measurable disease, GOG performance status 0-2, and adequate bone marrow, renal, and hepatic function according to standard criteria. Mitomycin 8 mg/m(2) and doxorubicin 40 mg/m(2) were each given by iv injection followed immediately by cisplatin 60 mg/m(2) in 1 liter of 0.45% saline plus mannitol 25 g. Patients who remained free from tumor progression or intolerable toxicity received at least three, to a maximum of six, cycles of MAP. RESULTS: Forty-one patients were registered, of whom 4 were determined ineligible (wrong cell type, 2; wrong site of origin, 1; inadequate pathology material, 1). Thirty-five of the 37 were evaluable for response after receiving from one to six (median three) cycles of MAP. Three patients (9%) achieved a complete response and 5 (14%) exhibited a partial response. The most common adverse effects were leukopenia (33 patients) and thrombocytopenia (30 patients). Pulmonary toxicity was seen in 10 patients and was a factor in the clinical deterioration and death of 2. CONCLUSION: MAP is active against advanced uterine leiomyosarcomas, but not remarkably so. Despite its low therapeutic index, this novel, possibly interactive, combination may serve as a forerunner to regimens that more efficiently exploit the enhancement of sarcoma cell kill under hypoxic conditions.