Exploring conservative management for cervical intraepithelial neoplasia grade 2 in organised cervical cancer screening programmes: a multicentre study in Italy.

Cervical intraepithelial neoplasia grade 2 (CIN2) lesions may regress spontaneously, offering an alternative to immediate treatment, especially for women of childbearing age (15-45 years).We conducted a prospective multicentre study on conservative CIN2 management, with semiannual follow-up visits over 24 months, biomarkers' investigation and treatment for progression to CIN3+ or CIN2 persistence for more than 12 months. Here, we assess women's willingness to participate and adherence to the study protocol.The study was set in population-based organised cervical cancer screening.From April 2019 to October 2021, 640 CIN2 cases were diagnosed in women aged 25-64 participating in the screening programmes.According to our predefined inclusion and exclusion criteria, 228 (35.6%) women were not eligible; 93 (22.6%) of the 412 eligible refused, and 319 (77.4%) were enrolled. Refusal for personal reasons (ie, desire to become pregnant, anxiety, difficulty in complying with the study protocol) and external barriers (ie, residence elsewhere and language problems) accounted for 71% and 17%, respectively. Only 9% expressed a preference for treatment. The primary ineligibility factor was the upper age limit of 45 years. After enrolment, 12 (4%) women without evidence of progression requested treatment, 125 (39%) were lost to follow-up (mostly after 6-12 months) and 182 (57%) remained compliant. Remarkably, 40% of enrolees did not fully adhere to the protocol, whereas only 5% (20/412) of the eligible women desired treatment.Our study demonstrates a good acceptance of conservative management for CIN2 lesions by the women, supporting its implementation within cervical screening programmes.

Risk of CIN2 or more severe lesions after negative HPV-mRNA E6/E7 overexpression assay and after negative HPV-DNA test: Concurrent cohorts with a 5-year follow-up.

Aim of this study was to compare the 5-year risk of cervical intraepithelial neoplasia grade 2+ (CIN2+)/CIN3+ and the performance parameters at 3-year rescreening of a negative E6/E7 mRNA-human papillomavirus (HPV) test with those of a HPV-DNA-negative test. We studied a cohort of HPV-negative women tested with the Aptima HPV-mRNA Assay ("HPV-mRNA cohort") versus a cohort of HPV negatives tested with the Hybrid Capture 2 (HC2) DNA test living in neighboring areas. Both cohorts were rescreened after 3 years by a HPV-DNA test (HC2 or Cobas 4800 HPV test). HPV test positivity, referral to colposcopy and detection of CIN2+ at 3-year rescreening were computed. The Veneto Cancer Registry was checked to search for invasive cancers and CIN3 diagnosed up to 5 years from the negative baseline test. Some 22,338 HPV-mRNA and 68,695 HPV-DNA-negative women were invited to 3-year rescreening, and, respectively, 16,641 (74.5%) and 54,630 (79.6%) complied with the invitation. The proportion of HPV-positive tests, referral to colposcopy and detection of CIN2+ in the HPV-mRNA and HPV-DNA cohorts were, respectively. 4.0 and 3.9% (ratio 1.08; 95% confidence interval [CI] 0.99-1.17), 2.6 and 2.5% (ratio 1.06, 95% CI 0.95-1.18) and 1.4 and 1.7‰ (ratio 0.85, 95% CI 0.54-1.33). The relative 5-year cumulative risk of cancer and of CIN2+ in the HPV-mRNA and HPV-DNA cohorts were 4.5 and 8.7/100,000 (ratio 0.51; 95%CI 0.01-4.22) and 1.1 and 1.5/1,000 (ratio 0.74; 95%CI 0.45-1.16), respectively. A negative HPV-mRNA test confers a risk of invasive cervical carcinoma and of CIN2+ at 5 years comparable to that of a negative HPV-DNA test.

Pregnancy-associated cancers: frequency and temporal trends in Italy.

OBJECTIVE: Limited data are available on the frequency and time trends of pregnancy-associated cancers, particularly from Southern European countries. The aim of this study was to analyze the frequency and time trends of pregnancy-associated cancer in Italy. METHODS: This was a population-based linkage study using the regional hospital discharge forms database of four Italian regions with more than 17 million inhabitants. All resident women with a hospital discharge form reporting a birth or abortion in the time period under consideration were identified. The time period of the study was 2003-2015 for the Piemonte and Puglia region, 2006-2015 for the Tuscany region, and 2005-2015 for the Veneto region. Risk of developing a pregnancy-associated cancer was calculated as the ratio of the number of pregnancy-related cancers to the total number of pregnancies. RESULTS: A total of 2 297 648 pregnancies were identified. Overall, the pregnancy-associated cancer frequency was 134.8 per 100 000 pregnancies: the frequency ranged from 127.1 in Puglia to 157.3 in Tuscany. The frequency for 100 000 pregnancies was 66.4 in women aged <30 years; the risk increased with age, with a frequency of 275.6 among women aged 40+ years. Approximately two-thirds of cancers were associated with pregnancies resulting in a delivery and one-third with pregnancies resulting in a termination of pregnancy or spontaneous pregnancy loss. No clear trend emerged in the risk of pregnancy-associated cancer per 100 000 pregnancies and calendar year. CONCLUSION: No clear time trend was observed in the frequency of pregnancy-associated cancers in Italy during the last 10 years, the rates being 104, 164, and 130 per 100 000 pregnancies, respectively, in 2003, 2010, and 2015.

Neoadjuvant Platinum-based Chemotherapy Followed by Radical Hysterectomy for Stage Ib2-IIb Adenocarcinoma of the Uterine Cervix - An Italian Multicenter Retrospective Study.

AIM: To assess the patterns of recurrence and clinical outcomes of patients with cervical adenocarcinoma who underwent neoadjuvant platinum-based chemotherapy (NACT) followed by radical hysterectomy. PATIENTS AND METHODS: Data were retrospectively analyzed for 82 patients with International Federation of Gynecology and Obstetrics stage Ib2-IIb cervical adenocarcinoma who underwent this chemo-surgical treatment. The median follow-up of survivors was 89 months (range=5-208 months). RESULTS: Pathological complete response, optimal response and suboptimal response with intra-cervical residual disease were obtained in five (6%), 10 (12%) and 36 (44%) patients, respectively. Adjuvant external-beam radiotherapy with or without concurrent chemotherapy was administered to 47 patients. Nineteen (23%) out of the 82 patients experienced recurrence after a median of 12 months (range=5.3-86.8 months). Recurrent disease was pelvic in 12 (63%) patients, extra-pelvic in five (26%), and both pelvic and extra-pelvic in two (10%). According to pathological response, tumor relapsed in 10% of optimal responders, 14% of sub-optimal responders with intra-cervical residual disease, and 36% of sub-optimal responders with extra-cervical residual disease or non-responders. Five-year recurrence-free and overall survival were 77% and 84%, respectively. Patients who achieved an optimal response or sub-optimal response with intra-cervical residual disease had better 5-year recurrence-free (87% vs. 64%, p=0.017) and overall (92% vs. 74%, p=0.012) survival than those who had sub-optimal response with extra-cervical residual disease or no response. The latter had a 1.441-fold higher risk of recurrence and a 1.652-fold higher risk of death than those who obtained an optimal response or a sub-optimal response with intra-cervical residual disease. CONCLUSION: NACT followed by radical hysterectomy may be an option for patients with stage Ib2-IIb adenocarcinoma of the uterine cervix.

Screening women for cervical cancer carcinoma with a HPV mRNA test: first results from the Venice pilot program.

BACKGROUND: HPV DNA-based screening is more effective than a Pap test in preventing cervical cancer, but the test is less specific. New HPV tests have been proposed for primary screening. The HPV mRNA test showed a similar or slightly lower sensitivity than the HPV DNA tests but with a higher specificity. We report the results of an organised HPV mRNA-based screening pilot program in Venice, Italy. METHODS: From October 2011 to May 2014, women aged 25-64 years were invited to undergo a HPV mRNA test (Aptima). Those testing positive underwent cytological triage. Women with positive cytology were referred to colposcopy, whereas those with negative cytology were referred to repeat the HPV mRNA test 1 year later. The results of the HPV mRNA test program were compared with both the local historical cytology-based program and with four neighbouring DNA HPV-based pilot projects. RESULTS: Overall, 23 211 women underwent a HPV mRNA test. The age-standardised positivity rate was 7.0%, higher than in HPV DNA programs (6.8%; relative rate (RR) 1.11, 95% confidence interval (CI) 1.05-1.17). The total colposcopy referral was 5.1%, double than with cytology (2.6%; RR 2.02, 95% CI 1.82-2.25) but similar to the HPV DNA programs (4.8%; RR 1.02; 95% CI 0.96-1.08). The cervical intraepithelial neoplasia grade 2+ detection rate with HPV mRNA was greater than in the HPV DNA programs at baseline (RR 1.50; 95% CI 1.19-1.88) and not significantly lower at the 1-year repeat (RR 0.70; 95% CI 0.40-1.16). The overall RR was 1.29 (95% CI 1.05-1.59), which was much higher than with cytology (detection rate 5.5‰ vs 2.1‰; RR 2.50, 95% CI 1.76-3.62). CONCLUSIONS: A screening programme based on the HPV mRNA obtained results similar to those observed with the HPV DNA test. In routine screening programmes, even a limited increase in HPV prevalence may conceal the advantage represented by the higher specificity of HPV mRNA.

HE4, CA125 and risk of ovarian malignancy algorithm (ROMA) as diagnostic tools for ovarian cancer in patients with a pelvic mass: An Italian multicenter study.

OBJECTIVE: This multicenter study aims to evaluate HE4, CA125 and risk of ovarian malignancy algorithm (ROMA) performance in the differential diagnosis of epithelial ovarian cancer (EOC). METHODS: A total of 405 patients referred to gynecological oncologist with suspicious pelvic mass requiring a surgery for identification of EOC were consecutively enrolled; 387 patients satisfied inclusion criteria: 290 benign diseases; 15 borderline neoplasia and 82 tumors (73 EOC). RESULTS: Good diagnostic performance in discriminating benign from EOC patients was obtained for CA125, HE4 and ROMA when calculating optimal cut-off values: premenopause, specificity (SP) >86.6, sensitivity (SN) >82.6, area under the curves (AUC)≥0.894; postmenopause, SP>93.2, SN>82, AUC≥0.928. Fixing SP at 98%, performance indicators obtained for benign vs EOC patients were: premenopause, SN:65.2%, positive predictive value (+PV): 75%, positive likelihood ratio (+LR): 26.4 for CA125; SN:69.6%, +PV:76.2%, +LR:28.1 for HE4; SN:69.6%, +PV: 80%; +LR:35.1 for ROMA; postmenopause, SN:88%, +PV: 95.7%, +LR:38.7 for CA125; SN:78%, +PV:95.1%, +LR:34.3 for HE4; SN:88%, +PV:97.8%, +LR:77.4 for ROMA. When using routine cut-off thresholds, ROMA showed better well-balanced values of both SP and SN (premenopause, SN:87%, SP:86.1%; postmenopause, SN:90%; SP:94.3%). CONCLUSIONS: Overall, ROMA showed well balanced diagnostic performance to differentiate EOC from benign diseases. Meaningful differences of +PVs and +LRs between HE4 and CA125 suggest that the two markers may play at least in part different roles in EOC diagnosis, with HE4 seeming to be more efficient than CA125 in ruling in EOC patients in the disease group, also in early stages tumors, both in pre and postmenopause.

Follow-up in Gynecological Malignancies: A State of Art.

OBJECTIVE: The main purpose of this article is to explore the current practice for follow-up of gynecological cancer, pointing out the different procedures, to determine the most clinically and cost-effective surveillance strategies after the primary treatment. MATERIALS AND METHODS: We analyzed the follow up strategies for ovarian, endometrial, and cervical cancer. All of the topics discussed below arose from the "ESGO State of Art Conference-Follow-up in gynaecological malignancies" in Turin, (September 11-13, 2014; http://torino2014.esgo.org/). RESULTS: Physical but these practices should be integrated with biomarkers or imaging strategies. Currently, most recommendations about follow-up are based on retrospective studies and expert opinion, and there is some disagreement on surveillance strategies due to lack of evidence-based knowledge. CONCLUSIONS: All surveillance procedures should be evidence-based with a clearly defined purpose: there is a need for prospective studies to compare the effectiveness of different follow-up regimens measuring overall survival, detection of recurrence, quality of life (QoL), and costs as outcomes.

The role of HE4 in ovarian cancer follow-up: a review.

OBJECTIVE: The aim of this review was to analyze the state of the art about HE4 and follow-up in patients treated for ovarian cancer. METHODS: A literature search was conducted in the MEDLINE database using the key words "HE4" and "ovarian cancer" and "recurrence" or "relapse" or "follow up." RESULTS: Seven of 28 clinical studies were selected. Four studies were prospective, and all of them were based on a small number of patients (8-73 women). A failure of HE4 levels to normalize at completion of standard therapy may indicate a poor prognosis, thus suggesting the need of a closer follow-up. Moreover, HE4 showed better sensibility and specificity in the diagnosis of ovarian cancer recurrence with respect to CA-125, being also an earlier indicator of the relapse with a lead time of 5 to 8 months. HE4 showed a better performance in this setting if performed in association with other markers (CA-125, CA-72.4). HE4 seems to be an independent predictive factor for the surgical outcome at secondary cytoreductive surgery and to maintain its prognostic role even after the recurrence. CONCLUSIONS: These preliminary data start to suggest a superiority of HE4 over CA-125 in the detection of ovarian cancer recurrence. Moreover, the prognostic role of HE4 could help clinicians to personalize the follow-up program, whereas its predictive role could be useful to plan the treatment of the relapse. The role of HE4 in ovarian cancer follow-up deserves to be further investigated in prospective randomized multicentric studies.

Cancer antigen 125, human epididymis 4, kallikrein 6, osteopontin and soluble mesothelin-related peptide immunocomplexed with immunoglobulin M in epithelial ovarian cancer diagnosis.

BACKGROUND: Human epididymis protein 4 (HE4), kallikrein 6 (KLK6), osteopontin (OPN) and soluble mesothelin-related peptide (SMRP) are new promising biomarkers that could integrate CA125 in epithelial ovarian cancer (EOC) diagnosis. The autoantibody response to tumor antigens is a potential tool for improving the diagnostic performances of biomarkers. The aim of this study was to assess the diagnostic potential of these biomarkers in the form of free markers and immunocomplexed with immunoglobulin M (IgM). Moreover, we analyzed the association between these markers and clinico-pathological characteristics of EOC patients. METHODS: Serum and plasma samples of 60 healthy controls, 60 ovarian benign cysts, 60 endometriosis and 60 EOCs, collected before any treatment, were tested for CICs and free antigens by immunoassays. RESULTS: Immunocomplexes were characterized by poor sensitivity and specificity, since they allowed the detection only of a small number of EOC patients and were increased in patients with benign gynecological pathologies. However, the markers in the form of free antigens showed good diagnostic performances. Of note, CA125 and HE4 showed high sensitivity in the detection of the malignancy and HE4 emerged as a useful biomarker in differential diagnosis between EOC and endometriosis. Finally, elevated KLK6 and OPN, were associated with advanced FIGO stage, high grade disease, suboptimally debulked tumor and ascites. CONCLUSIONS: This study confirms the diagnostic role of CA125, HE4, KLK6, OPN and SMRP, and for the first time showed that CA125, HE4, KLK6, OPN and SMRP immunocomplexed with IgM are not a potential tool for EOC diagnosis.

Analysis of treatment failures and survival of patients with uterine papillary serous carcinoma: a Cooperation Task Force (CTF) Study.

OBJECTIVE: To assess the pattern of failures and the survival of patients with uterine papillary serous carcinoma (UPSC). METHODS: The hospital records of 119 women with UPSC were reviewed. Surgery was the initial therapy for all the cases. The median follow-up of survivors was 133 months (range, 3-216 months). RESULTS: Postoperative treatment was used in 98 patients (82.4%). Adjuvant treatment was radiotherapy in 25 women, chemotherapy in 61 women, and chemotherapy plus radiotherapy in 12 women. Tumor recurred in 44 (37.0%) of the 119 patients, after a median time of 15.1 months. Relapse was symptomatic in 15 patients (34.1%), and recurrent disease involved peritoneum or distant sites in 26 (66.7%) of the 39 patients for whom the site of failure was known. Five- and 10-year survival rates were 61.8% and 54.6%, respectively. Survival was related to disease stage (P < 0.0001). Among patients with advanced tumor, 5-year survival was lower in women who had macroscopic residual disease after surgery than in those who had not (15.4% vs 37.5%; P = 0.08). Distant failures were higher in women with histologically proven positive nodes than in those with negative nodes (28.6% vs 9.1%; P = 0.048). There was a trend to better survival for patients with stage I to stage II disease who underwent chemotherapy when compared with those who did not. CONCLUSIONS: Uterine papillary serous carcinoma has an aggressive clinical behavior with a great tendency to recur especially in peritoneal and distant sites. Tumor stage is a strong prognostic factor, whereas the role of adjuvant treatment is still uncertain.

Could different follow-up modalities play a role in the diagnosis of asymptomatic endometrial cancer relapses?: an Italian multicentric retrospective analysis.

OBJECTIVE: To determine current practice and to assess the value of routine follow-up procedures for endometrial cancer surveillance. To discuss whether such procedures are feasible and effective to identify asymptomatic recurrences and describe the pattern of relapse detected by procedures. METHODS: The records of 282 consecutive women with recurrent endometrial cancer treated from 1986 to 2005 were retrospectively collected in 8 Italian institutions. Primary disease, clinical history, and recurrence features and data were analyzed. RESULTS: Thirty-five (12.4%) of 282 patients had recurrence in vaginal vault, 51 patients (18.0%) had recurrence in central pelvis, 14 patients (4.9%) had recurrence in pelvic wall, and 39 patients (13.8%) had recurrence in lymph nodes. One-hundred twenty-eight patients (45.3%) showed a distant relapse, whereas 15 patients (5.3%) developed both distant relapse and local relapse. The site of relapse influenced survival because the patients with vaginal vault recurrences lived significantly longer than the patients with recurrences in other sites. Eighty (28.4%) of the 282 patients became symptomatic and anticipated the scheduled visit, 37 (13.1 %) of the patients reported their symptoms during the follow-up meeting, and 165 (58.5 %) of the patients were asymptomatic and the diagnostic path was introduced by a planned visit or examination. Among the asymptomatic patients, the first procedure that led to further examinations was clinical visit alone for 60 (36.4%) of 165 patients, imaging for 103 patients (62.4%), and cytologic examination for 2 patients (1.2%). Symptoms at recurrence can predict survival: patients with an asymptomatic recurrence had a median survival time from relapse of 35 months versus 13 months if they had a symptomatic repetition (P = 0.0001). CONCLUSIONS: Follow-up after endometrial cancer treatment varies in Italy. In this retrospective study, women with asymptomatic recurrence have shown a better clinical outcome compared with those with symptomatic relapse. The optimal approach is actually unknown, and guidelines comparing follow-up protocols have not been established. Prospective cost-effectiveness studies are needed.

Surveillance procedures for patients treated for endometrial cancer: a review of the literature.

OBJECTIVES: The aim of this review was to analyze the role of follow-up in patients treated for endometrial cancer and to provide some compelling issues that may contribute to improve daily practice while waiting for evidence-based guidelines. METHODS/MATERIALS: A literature search has been conducted in MEDLINE database using key words "endometrial neoplasms" and "follow up". RESULTS: Endometrial cancer represents the most common gynecologic malignancy after breast cancer. The overall recurrence rate is 13% and correlates with prognostic factors of the primary tumor. The anatomic sites of endometrial cancer relapse are mostly equivalently distributed between local (pelvic) and distant (abdominal and chest). Most endometrial cancer recurrences are symptomatic, even if vaginal vault relapses represent a particular setting of a more frequently asymptomatic disease. Most of endometrial cancer recurrences occur within 3 years since diagnosis of primary tumor. Long-term surveillance programs are mainly addressed to the early detection of recurrence, the rationale of follow-up being that an earlier diagnosis of relapse correlates with lower morbidity and mortality rates. Adjunctive objectives of routine follow-up are identification of treatment complications and detection of possible second tumors associated with endometrial cancer. CONCLUSIONS: No rationale (examination sensitivity/sensibility, cost-effectiveness, or patient's survival benefit) is available today for any particular follow-up protocol; follow-up procedures should probably be tailored according to different prognostic factors; only physical examination, including pelvic-rectal examination, showed some utility in detecting recurrence. In this uncertain setting, follow-up interval should be defined with the consideration of the patient's will.

Surveillance procedures for patients for cervical carcinoma: a review of the literature.

Cervical cancer is still one of the most common malignancies in women. Treatment for cervical cancer is very successful, especially in early stage. However, some patients will experience recurrence. Primary purpose of follow-up programs is early detection of recurrence disease that should be more likely to be amenable to treatment, thereby improving the clinical outcome. Although, in the literature, most studies have shown that the surveillance programs did not improve the clinical outcome of patients with diagnosis of recurrence, this clinical practice is regarded as traditional management. The use of Papanicolaou tests to detect recurrent cervical cancer is not sufficiently justified. The assessment of tumor markers such as squamous cell carcinoma antigen could be useful. Imaging techniques are important for the detection and assessment of recurrent disease. The role of chest radiographs to detect asymptomatic recurrence in patients treated for cervical carcinoma remains controversial. Detection of a new abnormal mass or the changes in the size of a known lesion caused by cancer growth and the determination of the extent of recurrence with computed tomography and magnetic resonance imaging may provide clinical assistance in selection of optimal therapy. The fluoro-2-deoxy-glucose-positron emission tomography for surveillance only shows 80% of specificity and accuracy with negative predictive value of 100%. Integrated fluoro-2-deoxy-glucose-positron emission tomography/computed tomography provides precise anatomic localization of suspicious areas and therefore a better diagnostic interpretation with a possible impact on disease-free survival as well. In conclusion, our review confirms the need of prospective studies to compare the effectiveness of different follow-up regimens measuring as outcome overall survival and quality of life parameters.

Are surveillance procedures of clinical benefit for patients treated for ovarian cancer?: A retrospective Italian multicentric study.

The aim of this retrospective investigation was to assess the pattern of failures of 412 patients with recurrent ovarian cancer followed up with different surveillance protocols.Time to recurrence was less than 6 months in 98 women (23.8%), 6 to 12 months in 102 women (24.7%), and more than 12 months in 212 women (51.5%). Symptoms at relapse were referred by 81 women (19.7%). Among the 331 asymptomatic patients, the surveillance procedure that raised the suspect of recurrent disease was clinical examination in 49 (14.8%), imaging technique in 90 (27.2%), serum CA 125 in 77 (23.3%), and both serum CA 125 and imaging technique in 115 (34.7%). At univariate analysis, survival from initial diagnosis was related to stage (P = 0.004), residual disease after initial surgery (P < 0.0001), time to recurrence (P < 0.0001), site of relapse (P = 0.04), and treatment at recurrence (P < 0.0001), and survival after recurrence was related to stage (P = 0.01), residual disease (P < 0.0001), time to recurrence (P < 0.0001), and treatment at recurrence (P < 0.0001). Conversely, symptoms at recurrence had no prognostic relevance. Cox proportional hazards model showed that residual disease and time to recurrence were the only independent prognostic variables for both survival from initial diagnosis (P < 0.0001) and survival after recurrence (P < 0.0001). In conclusion, there was no survival difference between asymptomatic and symptomatic patients at the time of relapse, and therefore, the diagnostic anticipation allowed by a scheduled follow-up protocol did not seem to improve the clinical outcome of patients who ultimately developed recurrent disease.

Surveillance procedures for patients with cervical carcinoma: a review of the literature.

Cervical cancer is still one of the most common malignancies in women. Treatment of cervical cancer is very successful, especially in the early stage. However, some patients will experience recurrence. The primary purpose of follow-up programs is early detection of recurrence disease that should be more likely to be amenable to treatment, thereby improving the clinical outcome. Although, in the literature, most studies have shown that the surveillance programs did not improve the clinical outcome of patients with diagnosis of recurrence, this clinical practice is regarded as traditional management. The use of Papanicolaou tests to detect recurrent cervical cancer is not sufficiently justified. The assessment of tumor markers such as the squamous cell carcinoma antigen could be useful. Imaging techniques are important for the detection and assessment of recurrent disease. The role of chest x-rays in detecting asymptomatic recurrence in patients treated for cervical carcinoma remains controversial. Detection of a new abnormal mass or the changes in the size of a known lesion caused by cancer growth and the determination of the extent of recurrence with computed tomography and magnetic resonance imaging may provide clinical assistance in the selection of optimal therapy. The fluoro-2-deoxy-glucose-positron emission tomography for surveillance only show 80% of specificity and accuracy with negative predictive value of 100%. Integrated fluoro-2-deoxy-glucose-positron emission tomography/computed tomography provides precise anatomic localization of suspicious areas and, therefore, a better diagnostic interpretation with a possible impact on disease-free survival as well. In conclusion, our review confirms the need for prospective studies to compare the effectiveness of different follow-up regimens measuring overall survival and quality of life parameters as outcomes.

Expression and prognostic relevance of endothelin-B receptor in vulvar cancer.

Overexpression of endothelin (ET)-1 and its receptors, ETAR and ETBR, commonly referred to as the 'ET-axis', has been demonstrated to play a role in cancer progression for various human tumours. Based on these results we propose a similar role of the expression of the ET-axis in vulvar cancer. Expression of the ET-axis was investigated immunohistochemically using tissue microarrays with tumour samples of 68 vulvar cancer patients. Samples were obtained from patients undergoing local excision or radical vulvectomy. ET-1 expression of tumour cells correlated highly significantly with early stages of vulvar cancer (p=0.004), whereas neither ETAR nor ETBR expression showed any association with TNM stages. High staining levels of ETBR in the tumour tissue were significantly related to tumour progression (p=0.01) and early metastases (p=0.09); low ETBR staining intensity correlated with longer relapse-free survival (p=0.019). In patients with ETBR overexpressing low-stage tumours (pT1-2) we observed a significantly reduced overall survival and disease-free survival (p=0.036 and 0.021, respectively). ETAR expression and ETBR expression were significantly correlative (p=0.018). Accordingly, co-expression of both receptors was related to tumour progression (p=0.022) and an increased risk for local recurrence (p=0.005). These results suggest that, in addition to established histological and clinical prognostic factors, analysis of ET-receptor and, in particular, of ETBR expression by means of simple immunohistochemical analysis might improve prediction of the prognosis for patients with vulvar squamous cell carcinoma.

Management of borderline ovarian tumors: results of an Italian multicenter study.

OBJECTIVE: A rising number of patients affected by ovarian masses suspected of borderline ovarian tumor are operated on primary laparoscopic procedure. METHODS: From January 1992 to June 2004, 113 patients affected by low malignant ovarian tumor were followed at the Gynecologic Departments of five Italian Institutions. Fifty-two (46.0%) patients were operated on laparoscopic surgery, whereas traditional laparotomic approach was preferred in 61 cases (54%). In 53 patients (46.9%), a fertility-sparing surgical treatment was chosen. RESULTS: The diameter of the ovarian cysts ranged between 20 and 300 mm; in 20 out 113 patients (17.7%), the borderline tumor was bilateral. In 22/113 (19.5%) cases, we observed tumor rupture or spilling during surgery, and this incidence was greater in the group of patients treated by laparoscopy compared to laparotomy, and this difference is statistically significative. In 13/113 (11.5%) patients, we observed a relapse; the incidence of relapse, however, is not dependent on the type of surgical approach. The progression-free survival is higher for stages IA-IC if compared to stages more than Ist and the difference is statistically significant. Type of surgical approach, laparoscopic versus laparotomic, does not seem to influence the PFS; when cystectomy is performed, the PFS is significantly lower if compared with demolitive surgery or monolateral annessectomy. Eight pregnancies were obtained: in one case, miscarriage was observed, whereas 7 healthy babies were born all but two by vaginal delivery. CONCLUSIONS: Conservative laparoscopic surgery may be the treatment of choice; an attractive option is that this surgery should be performed by an oncologist surgeon to obtain correct surgical staging and better results in terms of both relapse-free survival and pregnancies.

Preservation of ovarian function, reproductive ability and emotional attitudes in patients with malignant ovarian tumors.

OBJECTIVES: Although cancer is predominantly a disease of aging, an increasing number of women survive malignancies before or during their reproductive years, which may interfere with their fertility potential. Although a variety of studies have tried to document the impact of conservative treatment aimed at preserving ovarian function and reproductive ability, little information has been available regarding survivors' attitudes, emotions, and choices to have children. The aim of this study is to evaluate the reproductive history, experiences, attitudes, and emotions with regard to having children in conservatively treated patients with Stage I epithelial ovarian cancer, any stage LMP tumors, malignant ovarian germ cell tumors (MOGCTs) and Stage I sex cord-stromal tumors (SCSTs). STUDY DESIGN: Between 1986 and 2000, a total of 75 patients with primary malignant ovarian tumors underwent conservative treatment. Out of 75 patients in the study, 14 women (19%) presented Stage I epithelial ovarian cancer, 23 (31%) LMP tumors, 33 (43%) MOGCTs, and five (7%) SCSTs. Information was obtained from medical records and from a questionnaire mailed to all patients who were at least 15 years old at the time of the diagnosis (68 subjects). Median time of follow-up was 102 months (35-192 months). There were four (5.2%) clinical recurrences within 35 months. Only 20 patients (49%) had tried to conceive after the completion of their treatment; of these, 15 women (75%) succeeded and delivered 19 healthy children. Seventy percent (32/41) of the respondents claimed that their disease did not have any impact on their desire to have children. Whereas 51% (21/41) fear that their ovarian disease could have damaged their reproductive potential, 76% (31/41) are not concerned about the effects of the treatment they received on offspring. The impact of the disease on the patients' attitudes toward life was reported as positive. CONCLUSION: The results from our study, in agreement with the data from the literature, confirm that management of Stage I (grade 1, grade 2) epithelial ovarian cancer, any stage LMP tumors, MOGCTs and Stage I SCSTs with fertility-sparing surgery is a safe, practicable treatment option. Though preliminary, this survey provides insight into the attitudes and experiences of young women ovarian cancer survivors regarding fertility.