Predictive factors of preoperative sentinel lymph node detection in intermediate and high-risk endometrial cancer.

BACKGROUND: In endometrial cancer (EC), sentinel lymph node (SLN) mapping has emerged as an alternative to systematic lymphadenectomy. Little is known about factors that might influence SLN preoperative detection. The aim of our study was to evaluate the clinical and technical variables that may influence on the success of SLN detection in preoperative lymphatic mapping in patients with intermediate and high-risk EC when performing transvaginal ultrasound-guided myometrial injection of radiotracer (TUMIR). METHODS: Between March 2006 and March 2017, we prospectively enrolled patients with histologically confirmed EC with intermediate or high-risk of lymphatic involvement. All women underwent SLN detection by using TUMIR approach. After radiotracer injection, pelvic and abdominal planar and SPECT/CT images were acquired to obtain a preoperative lymphoscintigraphic mapping. Pattern of drainage was registered and analyzed to identify the factors directly involved in drainage. Sonographer learning curves to perform TUMIR approach were created following Cumulative Sum and Wright methods. Univariate and multivariate analyses were performed using logistic regression. RESULTS: During study period, 123 patients were included. SLN preoperative detection rate was 70.7%. Age under 75 years at diagnosis (P<0.01), radiotracer injection above 4 mL -high-volume- (P<0.01), and tumoral size below 2 cm (P=0.04) were associated with higher SLN preoperative detection rate. Twenty-five procedures were necessary to attain an adequate performance in TUMIR approach. CONCLUSIONS: The higher SLN preoperative detection rate in women with intermediate and high-risk endometrial cancer after TUMIR approach was related with younger age, smaller tumors and high-volume injection of radiotracer. Sonographers are required to perform 25 procedures before acquiring an expertise in radiotracer injection.

Evaluation of patients with advanced epithelial ovarian cancer before primary treatment: correlation between tumour burden assessed by [18F]FDG PET/CT volumetric parameters and tumour markers HE4 and CA125.

OBJECTIVES: Accurate assessment of disease extent is required to select the best primary treatment for advanced epithelial ovarian cancer patients. Estimation of tumour burden is challenging and it is usually performed by means of a surgical procedure. Imaging techniques and tumour markers can help to estimate tumour burden non-invasively. 2-[18F]FDG PET/CT allows the evaluation of the whole-body disease. This study aimed to correlate HE4 and CA125 serum concentrations with tumour burden evaluated by volumetric 2-[18F]FDG PET/CT parameters in advanced high-grade epithelial ovarian cancer. METHODS: We included 66 patients who underwent 2-[18F]FDG PET/CT and serum tumour markers determination before primary treatment. Volumes of interest were delimited in every pathological uptake. Whole-body metabolic tumour volume (wb_MTV) and total lesion glycolysis (wb_TLG) were calculated summing up every VOI's MTV value. SUVmax thresholds were set at 40% (MTV40 and TLG40) and 50% (MTV50 and TLG50). In addition, four VOI subgroups were defined: peritoneal carcinomatosis, retroperitoneal nodes, supradiaphragmatic nodes, and distant metastases. MTV and TLG were calculated for each group by adding up the corresponding MTV values. TLG was calculated likewise. RESULTS: wb_MTV and wb_TLG were found to be significantly correlated with serum CA125 and HE4 concentrations. The strongest correlation was observed between HE4 and wb_MTV40 (r = 0.62, p < 0.001). Pearson's correlation coefficients between peritoneal carcinomatosis MTV40 and tumour markers were 0.61 (p < 0.0001) and 0.29 (p = 0.02) for HE4 and CA125 respectively. None of these tumour markers showed a positive correlation with tumour load outside the abdominal cavity assessed by volumetric parameters. CONCLUSION: HE4 performs better than CA125 to predict metabolic tumour burden in high-grade epithelial ovarian cancer before primary treatment. 2-[18F]FDG PET/CT volumetric parameters arise as feasible tools for the objective assessment of tumour load and its anatomical distribution. These results support the usefulness of HE4 and PET/CT to improve the stratification of these patients in clinical practice. KEY POINTS: • In patients with high-grade advanced ovarian epithelial carcinoma, both CA125 and HE4 correlate to whole-body tumour burden assessed by PET/CT before primary treatment. • HE4 estimates peritoneal disease much better than CA125. • PET/CT volumetric parameters arise as feasible tools for the objective assessment of tumour load and its anatomical distribution.

Intraoperative electron radiation therapy after salvage surgery in gynecological cancers and retroperitoneal sarcomas: outcomes and adverse effects.

Background: Salvage surgery is considered an option for isolated recurrences of retroperitoneal and pelvic tumors, in patients who have undergone previous radiotherapy. In order to increase local control intra operative electron radiation therapy (IOERT) can be used in these patients to administer additional radiation dose. We evaluated the outcomes and adverse effects in patients with retroperitoneal sarcoma and gynecologic tumors after salvage surgery and IOERT. Materials and methods: Twenty patients were retrospectively analyzed. Twenty-three IOERT treatments were performed after surgery. Six (30%) were sarcoma and 14 (70%) were gynecological carcinoma. Administered dose depended on previous dose received with external beam radiotherapy (EBRT) and proximity to critical structures. The toxicities were scored using the Common Terminology Criteria for Adverse Events version 4.0. Results: The median age of the patients was 51 years (range 34-70). After a median follow-up of 32 months (range 1-68), in the sarcoma group the local control rate was 66.6%; while in the gynecological group the local control rate was 64.3%. In relation to late toxicity, one patient had a Grade 2 vesicovaginal fistula, and one patient presented Grade 4 enterocolitis and enteric intestinal fistula. Conclusions: IOERT could have a role in the treatment of retroperitoneal sarcomas in primary tumors after EBRT, as it may suggest a benefit in local control or recurrences after surgical resection in those at high risk of microscopic residual disease. The addition of IOERT to salvage resection for isolated recurrence of gynecologic cancers suggest favorable local control in cases with concern for residual microscopic disease.

Prognostic implications of genotyping and p16 immunostaining in HPV-positive tumors of the uterine cervix.

Human papillomaviruses (HPVs) are the causative agents of carcinoma of the uterine cervix. A number of HPV genotypes have been associated with cervical cancer and almost all tumors associated with HPV show strong p16 expression. However, there is little information on the possible impact of the HPV genotype and p16 immunostaining on the clinicopathological features or their prognostic value in cervical carcinoma. We evaluated a series of 194 patients with HPV-positive cervical cancers treated at our institution, focusing on the clinicopathological features and the relationship of the HPV genotypes and p16 immunostaining with the prognosis. A single HPV type was identified in 149 (77%) tumors, multiple HPV infection was detected in 30 cases (15%), and undetermined HPV type/s were identified in 15 (8%) carcinomas. HPV 16 and/or 18 were detected in 156 (80%) tumors. p16 was positive in 186 (96%) carcinomas, but eight tumors (4%) were negative for p16 (seven squamous cell carcinomas, one adenocarcinoma); 5/8 caused by HPV 16 and/or 18. Patients with HPV 16 and/or 18 were younger (49 ± 15 vs. 57 ± 17 years, p < 0.01) and more frequently had nonsquamous tumors than patients with other HPV types (24% [37/156] vs. 0% [0/38]; p = 0.01). Neither the HPV type nor multiple infection showed any prognostic impact. Patients with p16-negative tumors showed a significantly worse overall survival than women with p16-positive carcinomas (45 vs. 156 months, p = 0.03), although no significant differences in disease-free survival were observed. In the multivariate analysis, negative p16 immunostaining was associated with a worse overall survival together with advanced FIGO stage and lymph node metastases. In conclusion, the HPV genotype has limited clinical utility and does not seem to have prognostic value in cervical cancer. In contrast, a negative p16 result in patients with HPV-positive tumors is a prognostic marker associated with a poor overall survival.

Role of ICG-99mTc-nanocolloid for sentinel lymph node detection in cervical cancer: a pilot study.

PURPOSE: Sentinel lymph node biopsy (SLNB) can be used for nodal staging in early cervical cancer. For this purpose, the tracers most commonly used are radiotracers based on technetium. For the last decade, indocyanine green (ICG) has been used as a tracer for SLNB in other malignancies with excellent results and, more recently, a combination of ICG and a radiotracer has been shown to have the advantages of both tracers. The aim of this study was to evaluate the role of ICG-99mTc-nanocolloid in SLN detection in patients with cervical cancer. METHODS: This prospective study included 16 patients with cervical cancer. The hybrid tracer was injected the day (19-21 h) before surgery for planar and SPECT/CT lymphoscintigraphy. Blue dye was administered periorificially in 14 patients. SLNs were removed according to their distribution on lymphoscintigraphy and when radioactive, fluorescent and/or stained with blue dye. Nodal specimens were pathologically analysed for metastases including by immunochemistry. RESULTS: Lymphoscintigraphy and SPECT/CT showed drainage in all patients. A total of 69 SLNs were removed, of which 66 were detected by their radioactivity signal and 67 by their fluorescence signal. Blue dye identified only 35 SLNs in 12 of the 14 patients (85.7%). All patients showed bilateral pelvic drainage. Micrometastases were diagnosed in two patients, and were the only lymphatic nodes involved. CONCLUSIONS: SLNB with ICG-99mTc-nanocolloid is feasible and safe in patients with early cervical cancer. This hybrid tracer provided bilateral SLN detection in all patients and a higher detection rate than blue dye, so it could become an alternative to the combined technique.

Preoperative Assessment of Myometrial Invasion in Endometrial Cancer by 3D Ultrasound and Diffusion-Weighted Magnetic Resonance Imaging: A Comparative Study.

OBJECTIVE: The prognosis of endometrial cancer depends on the correct surgical staging. In early stages, 18% to 30% rate of positive lymph nodes is reported with a myometrial invasion of 50% or more. According to this, patients with International Federation of Gynecology and Obstetrics stage Ib would benefit from staging lymphadenectomy. Therefore, it is important to classify these patients preoperatively to plan the surgery. In the recent years, 3-dimensional (3D) ultrasound and diffusion-weighted magnetic resonance imaging (DW-MRI) have been incorporated in the preoperative management of these patients. The aim of this study was to assess the usefulness of 3D ultrasound and DW-MRI as predictor of myometrial invasion in endometrial cancer. MATERIAL AND METHODS: We retrospectively compared the assessment of myometrial invasion by 3D ultrasound and DW-MRI with final pathologic evaluation on hysterectomy specimens, in 98 patients diagnosed of early-stage endometrial cancer, who underwent surgery at the Hospital Clinic of Barcelona between 2012 and 2015. RESULTS: Evaluation of the depth of myometrial invasion with 3D ultrasound had a sensitivity, specificity, and accuracy of 77%, 83% and 81%, respectively. Evaluation of the depth of myometrial invasion with DW-MRI had a sensitivity, specificity, and accuracy of 69%, 86%, and 81%, respectively. Association of both techniques improved all the values, showing a sensitivity, specificity, and accuracy of 87%, 93%, and 91%, respectively. In both 3D ultrasound and DW-MRI, the presence of leiomyomas was the first detectable cause of false negative (3% and 4%, respectively) and false-positive (3% and 1%, respectively). CONCLUSIONS: We conclude that the implementation of the 2 studies in early-stage endometrial cancer provides low false-negatives and false-positives rates. In cases of patients with leiomyomas, adenomiosis, or intrauterine fluid collection, definitive evaluation of myometrial invasion could be better deferred to intraoperative biopsy in an attempt to reduce false-negatives and false-positives rates.

Is sphere assay useful for the identification of cancer initiating cells of the ovary?

OBJECTIVE: Current evidence suggests that the presence of tumor-initiating cells (TICs) in epithelial ovarian cancer (EOC) has a role in chemoresistance and relapse. Surface markers such as CD44(+)/CD24(-), CD117(+), and CD133(+) expression have been reported as potential markers for TICs related to ovarian cancer and tumorigenic cell lines. In this study, we have investigated if spheroid forms are TIC specific or whether they can also be produced by somatic stem cells from healthy tissue in vitro. In addition, we also investigated the specificity of surface markers to identify TICs from papillary serous EOC patients. METHODS: Cells were obtained from fresh tumors from 10 chemotherapy-naive patients with EOC, and cells from ovarian and tubal epithelium were obtained from 5 healthy menopausal women undergoing surgery for benign pathology and cultured in standard and in selective medium. Cells forming nonadherent spheroids were considered TICs, and the adherent cells were considered as non-TIC-like. Percentages of CD24(+), CD44(+), CD117(+), CD133(+), and vascular endothelial growth factor receptor (VEGF-R)(+) cell surface markers were analyzed by flow cytometry. RESULTS: Four of 10 EOC cell tissues were excluded from the study. Tumor cells cultured in selective medium developed spheroid forms after 1 to 7 weeks in 5 of 6 EOC patients. No spheroid forms were observed in cultures of cells from healthy women. Unlike previously published data, low levels of CD24(+), CD44(+), CD117(+), and VEGF-R(+) expression were observed in spheroid cells, whereas expression of CD133(+) was moderate but higher in adherent cells from papillary serous EOC cells in comparison with adherent cells from controls. CONCLUSIONS: Papillary serous EOC contains TICs that form spheroids with low expression of CD44(+), CD24(+), CD117(+) and VEGF-R(+). Further research is required to find specific surface markers to identify papillary serous TICs.

Intestinal surgery performed by gynecologists.

INTRODUCTION: Our objective was to compare the feasibility and safety of surgical procedures to treat gynecological pathologies with intestinal involvement performed by skilled gynecological surgeons and by a multidisciplinary team of gynecologists plus colorectal surgeons. MATERIAL AND METHODS: We performed a comparative, observational, prospective study at a tertiary referral center. The population included all women undergoing bowel surgery for gynecological pathologies over a 3-year period. Cases were analyzed by the specialty of the main surgeon performing the intestinal procedure. The main outcome measures were surgical procedure characteristics and postoperative outcomes and complications. RESULTS: A total of 65 women were included. Surgery was exclusively performed by a subspecialized gynecologist in 30.8% of the women, and undertaken by a multidisciplinary team (colorectal surgeons and gynecologists) in 69.2%. The main demographic and clinical characteristics were comparable in both groups. Main indications for bowel resection in gynecological surgery were advanced ovarian cancer and deep infiltrating endometriosis. In addition to the standard gynecological surgical procedures, a total of 135 intestinal segments were resected, with sigmoid colon the most frequent intestinal segment resected in both groups (53% in the gynecologist group and in 60% in the multidisciplinary group). No significant differences were observed between the two groups in the distribution and frequency of surgical techniques used, rate of complications, mean hospitalization time or frequency of re-intervention. CONCLUSION: Skilled gynecological surgeons appear to be equally good at handling common intestinal problems as a team of gynecologist and colorectal surgeons.

The EANM clinical and technical guidelines for lymphoscintigraphy and sentinel node localization in gynaecological cancers.

The accurate harvesting of a sentinel node in gynaecological cancer (i.e. vaginal, vulvar, cervical, endometrial or ovarian cancer) includes a sequence of procedures with components from different medical specialities (nuclear medicine, radiology, surgical oncology and pathology). These guidelines are divided into sectione entitled: Purpose, Background information and definitions, Clinical indications and contraindications for SLN detection, Procedures (in the nuclear medicine department, in the surgical suite, and for radiation dosimetry), and Issues requiring further clarification. The guidelines were prepared for nuclear medicine physicians. The intention is to offer assistance in optimizing the diagnostic information that can currently be obtained from sentinel lymph node procedures. If specific recommendations given cannot be based on evidence from original scientific studies, referral is made to "general consensus" and similar expressions. The recommendations are designed to assist in the practice of referral to, and the performance, interpretation and reporting of all steps of the sentinel node procedure in the hope of setting state-of-the-art standards for high-quality evaluation of possible metastatic spread to the lymphatic system in gynaecological cancer. The final result has been discussed by a group of distinguished experts from the EANM Oncology Committee and the European Society of Gynaecological Oncology (ESGO). The document has been endorsed by the SNMMI Board.

Undifferentiated uterine sarcoma: a rare, not well known and aggressive disease: report of 13 cases.

PURPOSE: Undifferentiated uterine sarcomas (UUS) are rare and aggressive tumor with scarce data on the outcome and best treatment. We aimed to describe the behavior among patients with UUS at our institution. MATERIALS AND METHODS: Thirteen patients with UUS treated in our centre from 1979 to 2010 were analyzed. STATISTICS: descriptive analysis for frequencies and Kaplan-Meier actuarial method for overall survival (OS). RESULTS: Patients mean age was 66 years. Three had FIGO 2009 stage IA, five IB, two IIB, and three IVB. Ten patients underwent surgery and eight received postoperative radiotherapy. Three patients received adjuvant chemotherapy. The median follow-up was 16 months (2-276 months). Stage I patients developed two local relapses and three distant metastases (DM). DM was also observed in stage II patients and in 61.5 % of the entire series. Fifty percent of patients receiving radiotherapy remain alive without relapse. The median OS was 16 months, being 17 months for stage I and 9 for the remainder. CONCLUSIONS: Poor outcome of UUS was associated with a high incidence of DM. Stage I had the best outcome. Radiotherapy seems to have benefited patients, with 100 % of local control and 50 % of long-term survivors. The high incidence of metastasis suggests the need for more accurate initial assessment.

Pathologic prognostic factors in stage I-III uterine carcinosarcoma treated with postoperative radiotherapy.

PURPOSE: To analyse the impact of prognostic factors on specific overall survival (SOS) after postoperative radiotherapy (P-RT) in carcinosarcomas. METHODS: We retrospectively analysed 81 patients who received P-RT from 1977 to 2010 after the diagnosis of carcinosarcomas. 2009 FIGO stage: 25-IA, 20-IB, 6-II, 9-IIIA, 11-IIIC. Age, stage, vascular and lymphatic space invasion (VLSI), myometrial invasion, grade, mitotic index, sarcomatous/epithelial components, tumour size and necrosis were considered for the analysis. STATISTICS: we used the Kaplan-Meier method for survival analysis and the Cox model for risk factor evaluation. RESULTS: The mean follow-up of the series was 78.86 months (range 7-381). The median age was 72 years (range 51-89). 30 out 81 (37 %) patients relapsed and died (22.2 % pelvic and abdominal, 13.5 % exclusive distant metastasis). On univariate and multivariate analysis only stage had a significant impact on SOS. At 5 years, stage I-II had a SOS of 66 % in comparison with stage III with 30 %. CONCLUSIONS: Two groups of patients showing different outcome were found after P-RT in uterine carcinosarcomas: stage I-II patients had a life expectancy 2.5-fold longer compared to stage III patients. New therapeutic strategies are warranted in carcinosarcomas considering the high incidence of distant metastasis.

Transvaginal ultrasound-guided myometrial injection of radiotracer (TUMIR): a new method for sentinel lymph node detection in endometrial cancer.

OBJECTIVE: The objective of this prospective study was to determine the feasibility, safety and performance of a new method for sentinel lymph node (SLN) detection in endometrial cancer (EC) using transvaginal ultrasound-guided myometrial injection of radiotracer (TUMIR). METHODS: From 2006 to 2011, 74 patients with high-risk EC were included in the study. Twenty-four hours before surgery 148MBq of (99m)Tc-nanocolloid (8mL) was injected into two spots in the anterior and posterior myometrium using an ultrasound-guided transvaginal puncture. SLN was localized preoperatively by lymphoscintigraphy and intraoperatively with gamma probe. After SLN biopsy the patients underwent a complete laparoscopic pelvic and paraaortic lymphadenectomy. RESULTS: The TUMIR method was successfully achieved in 67/74 patients (90.5%). SLN was identified in 55 women (74.3%). No adverse effects were observed. Pelvic drainage was observed in 87.2% of women and paraaortic SLN was identified in 45.4%, with 12.8% of the patients draining only in this area. The mean number of SLN retrieved was 2.8 per patient (range 1 to 9). Metastatic disease was found in 13 (23.6%) patients. Metastatic involvement of the paraaortic lymph nodes was observed in 4 (30.7%) cases. All were identified by TUMIR. The sensitivity and negative predictive value of SLN detected by TUMIR to detect metastasis were 92.3% (95% CI 22.9-100) and 97.7% (95% CI 82.0-100), respectively. CONCLUSIONS: TUMIR is a safe, feasible method to detect SLN in patients with EC, has a good detection rate and provides representative information of the lymphatic drainage of EC.

Laparoscopic lymphadenectomy in advanced cervical cancer: prognostic and therapeutic value.

OBJECTIVE: Clinical benefit of surgical staging in locally advanced cervical cancer has not yet been proved. The goal of this study was to analyze the prognostic and therapeutic value of laparoscopic para-aortic lymphadenectomy with selective excision of suspicious pelvic nodes in patients with locally advanced cervical cancer. METHODS: This is a retrospective study including 109 women treated in a single institution from 2000 to 2009. The International Federation of Gynecology and Obstetrics stage was IB2 in 12 women, IIB in 58 women, and IIIB in 39 women. None had suspicious para-aortic nodes by presurgical imaging evaluation. All patients underwent extraperitoneal para-aortic laparoscopic lymphadenectomy with selective excision of enlarged pelvic nodes and received pelvic radiotherapy with concomitant chemotherapy. Extended lumboaortic radiation therapy was added to patients with metastatic para-aortic nodes. The mean ± SD follow-up time was 43.1 ± 33.7 months. RESULTS: Metastatic lymph nodes were identified in 23 (21.1%) of 109 patients in the para-aortic area and in 24 (53.3%) of 45 patients who underwent selective excision of pelvic nodes. Patients with nodal metastases had increased risk of mortality than those with negative nodes independently of the location (pelvic and/or para-aortic) of the metastases (hazard ratio, 4.07; 95% confidence interval, 1.36-12.16 for patients with pelvic metastases [P = 0.012]; and 3.73; 95% confidence interval, 1.38-10.09 for patients with para-aortic metastases [P = 0.010]). In the subset of women with para-aortic metastases treated by extended lumboaortic radiation therapy, neither the number of lymph nodes removed nor the number of positive nodes were associated with survival (P = 0.556 and P = 0.195, respectively). CONCLUSION: Para-aortic and pelvic lymphadenectomy provides valuable information about mortality risk in patients with locally advanced cervical cancer.

Correlation between clinical findings and magnetic resonance imaging for the assessment of local response after standard treatment in cervical cancer.

BACKGROUND: The aim of our study is to evaluate the correlation between gynecological examination and magnetic resonance (MRI) findings for the assessment of local response in cervical cancer patients treated with radiotherapy/chemotherapy (RT/ChT). PATIENTS AND METHODS: This study is a retrospective review of 75 consecutive cervical cancer patients from April 2004 to November 2009 treated with RT/ChT. Clinical and radiological data were subsequently analyzed. Patient's median age was 51 with a FIGO stage from Ib to IVb. Individualized RT/ChT was administered with a median dose of 45 Gy. Sixty-three patients received a complementary brachytherapy. Seventy-one patients received chemotherapy on a weekly basis. Gynecological exam was performed 3 months and 6 months after treatment and these findings were compared to MRI results at the same time. STATISTIC ANALYSIS: We used the Spearman's Rho test to determine the correlation level between the clinical and radiological methods. RESULTS: A correlation of 0.68 (60%) was observed between the clinical and MRI findings at 3 months with a further increase of up to 0.86 (82.6%) at 6 months. In the few cases with a poor correlation, the subsequent assessment and the natural history of the disease showed a greater value of the clinical exam as compared with the MRI findings. CONCLUSIONS: Physical exam remains an essential tool to evaluate the local response to RT/ChT for cervical cancer. The optimal clinical radiological correlation found at 6 months after treatment suggests that the combination of gynecological examination and MRI are probably adequate in patient monitoring.

Human papillomavirus as a favorable prognostic biomarker in squamous cell carcinomas of the vagina.

OBJECTIVE: Recent evidence has confirmed two independent pathways in the development of vaginal squamous cell carcinoma (VaSCC): one related to and the other independent of human papillomavirus (HPV). The aim of our study was to evaluate whether HPV status has prognostic significance in this neoplasm. METHODS: All confirmed primary VaSCCs diagnosed and treated from 1995 to 2009 in two institutions were retrospectively evaluated (n=57). HPV infection was detected by PCR using SPF-10 primers and typed with the INNO-LIPA HPV assay and p16(INK4a) expression by immunohistochemistry. Disease-free and overall survival (DFS and OS) were analyzed by Kaplan-Meier analysis with the log-rank test and a multivariate Cox proportional hazard's model. RESULTS: HR-HPV DNA was detected in 70.2% patients. HPV16 was the most prevalent genotype (67.5% of cases). p16(INK4a) was positive in 97.5% HPV-positive and 17.6% HPV-negative tumors (p<.001). FIGO stage was associated with DFS (p=.042) and OS (p=.008). HPV-positive tumors showed better DFS (p=.042) and OS (p=.035) than HPV-negative tumors. Multivariate analysis confirmed better DFS and OS of HPV-positive patients independent of age and stage. This reduced risk of progression and mortality in HPV-positive patients was limited to women with FIGO stages I and II tumors (HR=0.26; 95% CI 0.10-0.69; p=0.006). CONCLUSIONS: HPV-positive early stage (FIGO I and II) VaSCCs have a better prognosis than early HPV-negative tumors. HPV detection and/or p16(INK4a) immunostaining can be easily implemented in routine pathology and should be considered as valuable prognostic biomarkers in the study of patients with VaSCC.

Comparison of HE4, CA125, ROMA and CPH-I for Preoperative Assessment of Adnexal Tumors.

(1) OBJECTIVE: To assess the performance of CA125, HE4, ROMA index and CPH-I index to preoperatively identify epithelial ovarian cancer (EOC) or metastatic cancer in the ovary (MCO). (2) METHODS: single center retrospective study, including women with a diagnosis of adnexal mass. We obtained the AUC, sensitivity, specificity and predictive values were of HE4, CA125, ROMA and CPH-I for the diagnosis of EOC and MCO. Subgroup analysis for women harboring adnexal masses with inconclusive diagnosis of malignancy by ultrasound features and Stage I EOC was performed. (3) RESULTS: 1071 patients were included, 852 (79.6%) presented benign/borderline tumors and 219 (20.4%) presented EOC/MCO. AUC for HE4 was higher than for CA125 (0.91 vs. 0.87). No differences were seen between AUC of ROMA and CPH-I, but they were both higher than HE4 AUC. None of the tumor markers alone achieved a sensitivity of 90%; HE4 was highly specific (93.5%). ROMA showed a sensitivity and specificity of 91.1% and 84.6% respectively, while CPH-I showed a sensitivity of 91.1% with 79.2% specificity. For patients with inconclusive diagnosis of malignancy by ultrasound features and with Stage I EOC, ROMA showed the best diagnostic performance (4) CONCLUSIONS: ROMA and CPH-I perform better than tumor markers alone to identify patients harboring EOC or MCO. They can be helpful to assess the risk of malignancy of adnexal masses, especially in cases where ultrasonographic diagnosis is challenging (stage I EOC, inconclusive diagnosis of malignancy by ultrasound features).

Comparison of serum human epididymis protein 4 with cancer antigen 125 as a tumor marker in patients with malignant and nonmalignant diseases.

BACKGROUND: Human epididymis protein 4 (HE4), a precursor of human epididymis protein, has been proposed as a tumor marker for ovarian cancer. We evaluated HE4 in comparison with cancer antigen 125 (CA 125) in healthy individuals and in patients with benign and malignant diseases. METHODS: CA 125 and HE4 serum concentrations were determined in 101 healthy individuals, 535 patients with benign pathologies (292 with benign gynecologic diseases) and 423 patients with malignant diseases (127 with ovarian cancers). CA 125 and HE4 cutoffs were 35 kU/L and 140 pmol/L, respectively. RESULTS: HE4 and CA 125 results were abnormal in 1.1% and 9.9% of healthy individuals and in 12.3% and 37% of patients with benign diseases, respectively. Renal failure was the most common cause of increased HE4 in patients with benign disease, who had significantly higher HE4 concentrations (P = 0.001) than patients with other benign diseases. HE4 showed a higher specificity than CA 125 in patients with benign gynecologic diseases, with abnormal concentrations in 1.3% and 33.2% of the patients, respectively. HE-4 concentrations were abnormal primarily in gynecologic cancer and lung cancer. By contrast, CA 125 was increased in many different nonovarian malignancies, including nonepithelial tumors. A significantly higher area under the ROC curve was obtained with HE4 than with CA 125 for differentiating benign from malignant diseases (0.755 vs 0.643) and in the differential diagnosis of gynecologic diseases (0.874 vs 0.722). CONCLUSIONS: HE4 has significantly higher diagnostic specificity than CA 125, and the combination of CA 125 and HE4 improved the detection of ovarian cancer in all stages and histological types.

HE4 a novel tumour marker for ovarian cancer: comparison with CA 125 and ROMA algorithm in patients with gynaecological diseases.

The aim of this study is to evaluate a new tumour marker, HE4, in comparison with CA 125 and the Risk of Ovarian Malignancy Algorithm (ROMA) in healthy women and in patients with benign and malignant gynaecological diseases. CA 125 and HE4 serum levels were determined in 66 healthy women, 285 patients with benign gynaecological diseases (68 endometriosis, 56 myomas, 137 ovarian cysts and 24 with other diseases), 33 patients with non-active gynaecological cancer and 143 with active gynaecological cancer (111 ovarian cancers). CA 125 and HE4 cut-offs were 35 U/mL and 150 pmol/L, respectively. ROMA algorithm cut-off was 13.1 and 27.7 for premenopausal or postmenopausal women, respectively. HE4, CA 125 and ROMA results were abnormal in 1.5%, 13.6% and 25.8% of healthy women and in 1.1%, 30.2% and 12.3% of patients with benign diseases, respectively. Among patients with cancer, HE4 (in contrast to CA 125) had significantly higher concentrations in ovarian cancer than in other malignancies (p < 0.001). Tumour marker sensitivity in ovarian cancer was 79.3% for HE4, 82.9% for CA 125 and 90.1% for ROMA. Both tumour markers, HE4 and CA 125 were related to tumour stage and histological type, with the lowest concentrations in mucinous tumours. A significantly higher area under the ROC curve was obtained with ROMA and HE4 than with CA 125 in the differential diagnosis of benign gynaecological diseases versus malignant ovarian cancer (0.952, 0.936 and 0.853, respectively). Data from our population indicate that ROMA algorithm might be further improved if it is used only in patients with normal HE4 and abnormal CA 125 serum levels (cancer risk for this profile is 44.4%). ROMA algorithm in HE4 positive had a similar sensitivity and only increases the specificity by 3.2% compared to HE4 alone.

Does human papillomavirus infection imply a different prognosis in vulvar squamous cell carcinoma?

BACKGROUND: Two independent pathways in the development of vulvar squamous cell carcinoma (VSCC) have been described, one related to and the other independent of high-risk human papillomavirus (HR-HPV). The aim of our study was to evaluate whether the HPV status has a prognostic significance or can predict response to radiotherapy. METHODS: All VSCC diagnosed from 1995 to 2009 were retrospectively evaluated (n=98). HPV infection was detected by amplification of HPV DNA by PCR using SPF-10 primers and typed by the INNO-LIPA HPV research assay. p16(INK4a) expression was determined by immunohistochemistry. Disease-free and overall survival (DFS and OS) were estimated by Kaplan-Meier analysis with the log-rank test and a multivariate Cox proportional hazard's model. RESULTS: HR-HPV DNA was detected in 19.4% of patients. HPV16 was the most prevalent genotype (73.7% of cases). p16(INK4a) stained 100% HPV-positive and 1.3% HPV-negative tumors (p<.001). No differences were found between HPV-positive and -negative tumors in terms of either DFS (39.8% vs. 49.8% at 5 years; p=.831), or OS (67.2% vs. 71.4% at 5 years; p=.791). No differences in survival were observed between HPV-positive and -negative patients requiring radiotherapy (hazard ratio [HR] 1.04, 95% confidence interval [CI] .45 to 2.41). FIGO stages III-IV (p=.002), lymph node metastasis (p=.030), size ≥ 20 mm (p=.023), invasion depth (p=.020) and ulceration (p=.032) were associated with increased mortality but in multivariated only lymph node metastasis retained the association (HR 13.28, 95% CI 1.19 to 148.61). CONCLUSIONS: HPV-positive and -negative VSCCs have a similar prognosis. Radiotherapy does not increase survival in HPV-positive women.

Paraaortic sentinel lymph node detection in intermediate and high-risk endometrial cancer by transvaginal ultrasound-guided myometrial injection of radiotracer (TUMIR).

OBJECTIVE: We aimed to evaluate the accuracy of sentinel lymph node (SLN) mapping with transvaginal ultrasound-guided myometrial injection of radiotracer (TUMIR) to detect lymph node (LN) metastases, in patients with intermediate and high-risk endometrial cancer (EC), focusing on its performance to detect paraaortic involvement. METHODS: Prospective study including women with preoperative intermediate or high-risk EC, according to ESMO-ESGO-ESTRO consensus, who underwent SLN mapping using the TUMIR approach. SLNs were preoperatively localized by planar and single photon emission computed tomography/computed tomography images, and intraoperatively by gamma-probe. Immediately after SLN excision, all women underwent systematic pelvic and paraaortic lymphadenectomy by laparoscopy. RESULTS: The study included 102 patients. The intraoperative SLN detection rate was 79.4% (81/102). Pelvic and paraaortic drainage was observed in 92.6% (75/81) and 45.7% (37/81) women, respectively, being exclusively paraaortic in 7.4% (6/81). After systematic lymphadenectomy, LN metastases were identified in 19.6% (20/102) patients, with 45.0% (9/20) showing paraaortic involvement, which was exclusive in 15.0% (3/20). The overall sensitivity and negative predictive value (NPV) of SLNs by the TUMIR approach to detect lymphatic involvement were 87.5% and 97.0%, respectively; and 83.3% and 96.9%, for paraaortic metastases. After applying the MSKCC SLN mapping algorithm, the sensitivity and NPV were 93.8% and 98.5%, respectively. CONCLUSION: The TUMIR method provides valuable information of endometrial drainage in patients at higher risk of paraaortic LN involvement. The TUMIR approach showed a detection rate of paraaortic SLNs greater than 45% and a high sensitivity and NPV for paraaortic metastases in women with intermediate and high-risk EC.