A prospective investigation of fluorescence imaging to detect sentinel lymph nodes at robotic-assisted endometrial cancer staging.

BACKGROUND: The accuracy of sentinel lymph node mapping has been shown in endometrial cancer, but studies to date have primarily focused on cohorts at low risk for nodal involvement. In our practice, we acknowledge the lack of benefit of lymphadenectomy in the low-risk subgroup and omit lymph node removal in these patients. Thus, our aim was to evaluate the feasibility and accuracy of sentinel node mapping in women at sufficient risk for nodal metastasis warranting lymphadenectomy and in whom the potential benefit of avoiding nodal procurement could be realized. OBJECTIVE: To evaluate the detection rate and accuracy of fluorescence-guided sentinel lymph node mapping in endometrial cancer patients undergoing robotic-assisted staging. STUDY DESIGN: One hundred twenty-three endometrial cancer patients undergoing sentinel lymph node sentinel node mapping using indocyanine green were prospectively evaluated. Two mL (1.0 mg/mL) of dye were injected into the cervical stroma divided between the 2-3 and 9-10 o'clock positions at the time of uterine manipulator placement. Before hysterectomy, the retroperitoneal spaces were developed and fluorescence imaging was used for sentinel node detection. Identified sentinel nodes were removed and submitted for touch prep intraoperatively, followed by permanent assessment with routine hematoxylin and eosin levels. Patients then underwent hysterectomy, bilateral salpingo-oophorectomy, and completion bilateral pelvic and periaortic lymphadenectomy based on intrauterine risk factors determined intraoperatively (tumor size >2 cm, >50% myometrial invasion, and grade 3 histology). RESULTS: Of 123 patients enrolled, at least 1 sentinel node was detected in 119 (96.7%). Ninety-nine patients (80%) had bilateral pelvic or periaortic sentinel nodes detected. A total of 85 patients met criteria warranting completion lymphadenectomy. In 14 patients (16%) periaortic lymphadenectomy was not feasible, and the mean number of pelvic nodes procured was 13 (6-22). Of the 71 patients undergoing pelvic and periaortic lymphadenectomy, the mean nodal count was 23.2 (8-51). Of patients undergoing lymphadenectomy, 10.6% had lymph node metastasis on final hematoxylin and eosin evaluation. Notably, the sentinel node was the only positive node in 44% of cases. There were no cases in which final pathology of the sentinel node was negative and metastatic disease was detected upon completion lymphadenectomy in the non-sentinel nodes (no false negatives), yielding a sensitivity of 100%. Of the 14 sentinel nodes ultimately found to harbor metastases, 3 were negative on touch prep, yielding a sensitivity of 78.6% for intraoperative detection of sentinel node involvement. In all 3 of the false-negative touch preps, final pathology detected a single micrometastasis (0.24 mm, 1.4 mm, 1.5 mm). As expected, there were no false-positive results, yielding a specificity of 100%. No complications related to sentinel node mapping or allergic reactions to the dye were encountered. CONCLUSION: Intraoperative sentinel node mapping using fluorescence imaging with indocyanine green in endometrial cancer patients is feasible and yields high detection rates. In our pilot study, sentinel node mapping identified all women with Stage IIIC disease. Low false-negative rates are encouraging, and if confirmed in multi-institutional trials, this approach would be anticipated to reduce the morbidity, operative times, and costs associated with complete pelvic and periaortic lymphadenectomy.

Combined weekly topotecan and biweekly bevacizumab in women with platinum-resistant ovarian, peritoneal, or fallopian tube cancer: results of a phase 2 study.

BACKGROUND: A phase 2 trial was conducted to determine the toxicity and efficacy of combined weekly topotecan and biweekly bevacizumab in patients with primary or secondary platinum-resistant ovarian, peritoneal, or fallopian tube cancer (OC). METHODS: Patients were treated with bevacizumab 10 mg/kg on days 1 and 15 and topotecan 4 mg/m(2) on days 1, 8, and 15 of a 28-day cycle until progressive disease (PD) or excessive toxicity. The primary endpoint was progression-free survival (PFS); secondary objectives included overall survival (OS), objective response, and toxicity. RESULTS: Patients (N = 40) received a median of 8 treatment cycles. Toxicity was generally mild or moderate, with neutropenia (18%), hypertension (20%), gastrointestinal toxicity (18%), pain (13%), metabolic toxicity (15%), bowel obstruction (10%), and cardiotoxicity (8%) being the most common grade 3 and 4 adverse events. No bowel perforations, febrile neutropenia, or treatment-related deaths occurred. Median PFS and OS were 7.8 (95% confidence interval [CI], 3.0-9.4) and 16.6 months (95% CI, 12.8-22.9), with 22 (55%) patients progression-free for ≥6 months. Ten (25%) patients had partial response (PR), 14 (35%) had stable disease (SD), and 16 (40%) had PD. Patients treated with 2 prior regimens received greater benefit than patients treated with 1: PR/SD, 78.9% versus 42.9% (P = .03); median PFS, 10.9 versus 2.8 months (P = .08); median OS, 22.9 versus 12.8 months (P = .02). CONCLUSIONS: A weekly topotecan and biweekly bevacizumab combination demonstrates acceptable toxicity and encouraging efficacy in patients with platinum-resistant OC; further study is warranted.

Surgical outcomes in gynecologic oncology in the era of robotics: analysis of first 1000 cases.

OBJECTIVE: We sought to examine outcomes in an expanding robotic surgery (RS) program. STUDY DESIGN: In all, 1000 women underwent RS from May 2006 through December 2009. We analyzed patient characteristics and outcomes. A total of 377 women undergoing RS for endometrial cancer staging (ECS) were compared with the historical data of 131 undergoing open ECS. RESULTS: For the entire RS cohort of 1000, the conversion rate was 2.9%. Body mass index increased over 3 time intervals: T1 = 26.2, T2 = 29.5, T3 = 30.1 (T1:T2, P = .01; T1:T3, P = .0001; T2:T3, P = .037). Increasing body mass index was not associated with increased major complications: T1 = 8.7%, T2 = 4.3%, T3 = 5.7%. In the ECS cohort, as compared with open ECS, women undergoing RS had lower blood loss (46.9 vs 197.6 mL, P < .0001), shorter hospitalization (1.4 vs 5.3 days, P < .0001), fewer major complications (6.4% vs 20.6%, P < .0001), with higher lymph node counts (15.5 vs 13.1, P = .007). CONCLUSION: RS is associated with favorable morbidity and conversion rates in an unselected cohort. Compared to laparotomy, robotic ECS results in improved outcomes.

Robotic surgery in gynecologic oncology: program initiation and outcomes after the first year with comparison with laparotomy for endometrial cancer staging.

OBJECTIVE: The objective of the study was to evaluate outcomes during the first year of a robotic surgery program in gynecologic oncology. STUDY DESIGN: We studied the initiation of a robotic surgery program with prospective data collection, including intraoperative times, estimated blood loss (EBL), length of stay (LOS), lymph node yields, and complications. Patients were compared with historical and contemporary open staging surgery for endometrial cancer. RESULTS: One hundred eighteen patients underwent robotic surgery (mean age 52.5 years, body mass index of 26.3 kg/m(2), hospital stay of 32.4 hours), with 8 major and 13 minor complications. Compared with open endometrial staging (n = 131), the robotic procedure (n = 25) was longer (283 vs 139 minutes, P < .0001), had less blood loss (66.6 vs 197.6 mL, P < .0001), and had shorter length of stay (40.3 vs 127 hours, P < .0001) with comparable node yields (17.5 vs 13.1, P = .1109). CONCLUSION: Robotic surgery is feasible in gynecologic oncology and facilitated a dramatic expansion in our minimally invasive surgical practice. Despite longer operative times, EBL and LOS are reduced and lymph node yields are comparable.

Clear cell adenocarcinoma of the vagina in a patient with vaginal endometriosis.

BACKGROUND: Malignant transformation of endometriosis is an infrequent complication of endometriosis. Extragonadal disease is uncommon. CASE: 55-year-old female presented with postmenopausal bleeding. Physical examination revealed a 2-cm polypoid lesion at the posterior vaginal apex, which was found to be a moderately differentiated invasive adenocarcinoma. Final pathology at the time of definitive surgery demonstrated a clear cell adenocarcinoma of the vagina arising in vaginal endometriosis. CONCLUSION: Vaginal endometriosis may lead to the development of cancer. Malignancy arising in endometriotic foci is rare, but most commonly occurs in the ovary. We report a case of clear cell malignancy arising in vaginal endometriosis, adding to only seven cases previously reported. Risk factors include unopposed estrogen and obesity, but it may occur in the absence of either.

Predictors of occult neoplasia in women undergoing risk-reducing salpingo-oophorectomy.

OBJECTIVE: The purpose of this study was to define the rate of neoplasia in prophylactic surgical specimens with the use of a careful surgical and pathologic protocol in a prospective study of high-risk women who were undergoing risk-reducing salpingo-oophorectomy. Outcomes of interest were neoplasia that was identified in surgical specimens and clinical outcomes of women who were undergoing risk-reducing salpingo-oophorectomy. We hypothesized that older age and having a BRCA1 mutation would be predictors for tubal or ovarian neoplasia and that a careful surgical and pathologic protocol would lead to a low rate of subsequent primary peritoneal cancer. STUDY DESIGN: A prospective tissue and research database enrolled patients who underwent risk-reducing salpingo-oophorectomy for prevention of ovarian cancer. Clinical and pathologic data were extracted for those patients after the initiation of a defined surgical and pathologic protocol in 1999. RESULTS: One hundred thirteen women met the high-risk criteria; 40 of the women (45%) who were tested had a deleterious mutation in BRCA1, and 22 women (25%) had a mutation in BRCA2. Seven women had ovarian or tubal neoplasia (6.2%). One woman had occult endometrial cancer. Age > or =45 years and having a BRCA1 or BRCA2 mutation were significant predictors of occult neoplasia. Two patients with neoplasia that was identified at risk-reducing salpingo-oophorectomy experienced recurrence. Three patients with BRCA1 mutations have subsequent new diagnoses of breast cancer. No patients had primary peritoneal cancer after risk-reducing salpingo-oophorectomy. CONCLUSION: Age > or =45 years and mutations in BRCA1 or BRCA2 predict occult neoplasia in women who undergo risk-reducing salpingo-oophorectomy. A thorough pathologic and surgical protocol at the time of risk-reducing salpingo-oophorectomy may improve the risk of subsequent primary peritoneal cancer.

A prospective, randomized study analyzing sartorius transposition following inguinal-femoral lymphadenectomy.

OBJECTIVES: Based on the reduced morbidity seen in our retrospective study, we undertook a prospective, randomized trial to determine whether transposition of the sartorius muscle improves post-operative morbidity in women with squamous cell carcinoma of the vulva undergoing inguinal-femoral lymphadenectomy. METHODS: Patients with squamous carcinoma of the vulva requiring inguinal-femoral lymphadenectomy were randomized to undergo sartorius transposition or not. All patients received perioperative antibiotics, DVT prophylaxis, and closed suction surgical site drainage. Outcomes assessed include wound cellulitis, wound breakdown, lymphocyst formation, lymphedema, and/or rehospitalization. Cohorts were compared using Fisher's exact test. Baseline characteristics were compared using Student's t test or Fischer's exact test as appropriate. Logistic regression was used to assess the impact of sartorius transposition, after adjusting for other factors. RESULTS: From June 1996 to December 2002, 61 patients underwent 99 inguinal-femoral lymphadenectomies, 28 with sartorius transposition, and 33 without. The mean (SD) age for controls and patients undergoing sartorius transposition was 63.5 (15.2) and 73.8 (13.7) years, respectively (P < 0.05). There were no statistically significant differences in BSA, tobacco use, co-morbid medical conditions, past surgical history, medication use, size of incision, duration of surgery, number of positive lymph nodes, pathologic stage, pathologic grade, pre- or postoperative hemoglobin, or length of hospitalization. There were no statistically significant differences in the incidence of wound cellulitis, wound breakdown, lymphedema, or rehospitalization. The incidence of lymphocyst formation was increased in the sartorius transposition group. After adjusting for age, however, the groups appeared similar. CONCLUSIONS: Sartorius transposition after inguinal-femoral lymphadenectomy does not reduce postoperative wound morbidity.

Serologic analysis of ovarian tumor antigens reveals a bias toward antigens encoded on 17q.

We utilized SEREX immunoscreening to identify a set of novel tumor antigens that are associated with human serous ovarian cancer and may prove useful for the early detection and treatment of this disease. Extensive screening with a panel of sera from 25 late-stage ovarian cancer patients against 3 independent cDNA libraries identified a set of 9 antigens that were immunogenic in more than 1 patient and not in a panel of 20-45 normal female serum donors. These antigens include p53, NY-ESO-1, UBQLN1, HOXB6, TOP2A, putative helicase-RUVBL (RUVBL), HMBA-inducible (HEXIM1), DDX5 and HDCMA. Ten of 25 ovarian cancer patients (40%) expressed serum IgG to at least 1 of these antigens, while 14% (4/25) had antibodies to 2 or more antigens. Unexpectedly, 4 antigens identified in this screen, DDX5, HEXIM1, TOP2A and HOXB6, are encoded within a region of 17q that also includes the genes for HER2/neu, Homeobox-B7 and BRCA1. Real-time RT-PCR analysis showed that mRNA for HER2/neu and 3 SEREX-defined antigens, TOP2A, HOXB6 and DDX5, was more abundant in ovarian tumors than most normal tissues, including normal and benign ovarian tissues, suggesting that elevated expression of genes encoded within this region of chromosome 17 is a common event in ovarian tumors. Thus, these abnormal expression patterns combined with the endogenous immune response suggests that these antigens represent potential targets for immunotherapy.

Evaluation of p27 in preinvasive and invasive malignancies of the cervix.

OBJECTIVE: p27 is a cell cycle inhibitor whose loss is commonly found in epithelial tumors. Low levels have been associated with poor prognosis. Our goal was to determine if p27 expression could be used to screen for dysplasia and if it is a prognostic factor for cervical malignancies. METHODS: Ten normal cervices, 51 consecutive cone biopsies for preinvasive disease, and 128 consecutive hysterectomies for invasive cervical cancer (1994-1999) were stained for p27 using standard immunocytochemical techniques. All of the cervical cancer patients were managed with radical hysterectomy and lymph node dissection, except for 14 women who underwent adjuvant hysterectomy and lymph node sampling after chemoradiation. RESULTS: There was no significant difference in p27 staining between normal cervices (all stained 4+) and preinvasive lesions (46/51 stained 4+ and 5/51 stained 3+). For the invasive lesions, 47 women had no residual disease in the hysterectomy specimen, due to prior cone biopsy (41) or radiation (6). All had 4+ p27 staining in the residual cervix. None of these women recurred. Eighty-one women had residual disease in the hysterectomy specimen; 25/81 (31%) had p27 staining of <50%. Loss of p27 was not significantly associated with invasion >50% (32 vs 27%), size >4 cm (20 vs 13%), or use of postoperative radiation (36 vs 20%). Loss of p27 was associated with lymphvascular space invasion (LVSI) (44 vs 20%, P = 0.04). Only 4 women had nodal metastasis; all 4 had p27 staining less than 50%; 6/81 (7%) women with residual disease developed recurrences and died. Of the women who died, 3/6 had p27 staining less than 50%. CONCLUSION: p27 is not lost in preinvasive cervical lesions and, therefore, cannot be used to screen for dysplasia. In cervical cancers p27 staining was <50% in 31% of cases, and is associated with increased risk of LVSI. Perhaps, because of the excellent overall survival of this group of women with Stage I cervical cancer, loss of p27 staining was not associated with poor prognosis.

Glassy cell carcinoma of the cervix revisited.

OBJECTIVE: Glassy cell carcinoma (GCC) of the cervix has traditionally been characterized as an aggressive histologic subtype with poor outcomes. An earlier series from our institution supported a grim prognostic outlook, demonstrating a survival rate of only 55% in women with stage I disease. We present a comparison of a contemporary series of patients with GCC. METHODS: All cases of GCC treated from 1993 to 1999 identified by our tumor registry were reviewed for a variety of clinicopathologic features, treatment strategies, and outcome. RESULTS: A total of 403 cases of invasive cancer of the cervix were identified. There were 22 patients with histologically confirmed GCC, representing only 5.4% of all cervical cancer diagnoses. Patients with GCC had an overall survival of 73% (16/22) and a disease-free survival of 64% (14/22). The incidence of stage I lesions was 64% (14/22). Overall survival of patients with stage I disease was 86% (12/14), with a disease-free survival of 71% (10/14) at a median follow-up of 28.5 months. Seven stage IB lesions were treated with surgery alone, whereas six received adjuvant radiation or chemoradiation following surgery. Two patients in each treatment group recurred, yielding an overall recurrence rate of 29% (4/14). However, of those who recurred with stage I disease, all 4 patients had two or more intermediate risk factors (lymph-vascular space invasion [LVSI], deep tumor invasion, or tumor size greater than 3 cm). CONCLUSIONS: Glassy cell carcinoma of the cervix appears to have a better prognosis than previously reported. We observed that intermediate risk histopathologic features identified in squamous cell cohorts are also predictive of a poorer outcome in patients with GCC. Thus, patients with LVSI, deep stromal invasion, and large tumor size are at the highest risk for pelvic relapse and should be candidates for adjuvant treatment.

Angiogenesis in ovarian cancer: molecular pathology and therapeutic strategies.

Ovarian cancer claims the lives of more women in North America each year than all other gynecologic malignancies combined. Despite the high initial response rates of patients with advanced ovarian cancer to aggressive primary surgical debulking followed by combination chemotherapy, the majority of patients will ultimately develop disease recurrence. The high risk of relapse and nearly guaranteed incurability after relapse is due to genetic instability and a high mutation rate of neoplastic cells that together allow for a high risk of selection for drug resistance. Given the seemingly insurmountable obstacle that acquired drug resistance presents in a setting of minimal, often undetectable, residual tumor burden in women with ovarian cancer, antiangiogenic-targeted therapies offer an attractive strategy for enhanced long-term disease-free survival. The past decade has witnessed a substantial proliferation in our knowledge regarding tumor angiogenesis, which has spurred interest in antiangiogenesis drug development. Current clinical trials are evaluating these agents in a variety of solid tumors, including ovarian cancer. Preliminary work has provided hope that the addition of antiangiogenic therapies may be incorporated into the treatment of women afflicted with ovarian cancer and may translate into enhanced survival.