Neoadjuvant chemotherapy in cervical carcinoma: regulators of cell cycle, apoptosis, and proliferation as determinants of response to therapy and disease outcome.

To evaluate whether cellular markers predict the responsiveness to neoadjuvant chemotherapy (NAC) in cervical cancer, 21 patients with stages I and II cervical carcinomas treated by NAC before surgery were followed up for a mean of 52.3 months. Pre-NAC biopsy and operative specimens were subjected to counting of apoptotic (AI/V) and mitotic (MI/V) indices, detection of human papillomavirus (HPV) DNA, and immunohistochemical analysis of cell cycle and proliferation markers (p21, p53, pRb, proliferating cell nuclear antigen [PCNA], Ki-67) and multidrug resistance gene (MDR1), as related to NAC response (RAC), recurrence-free (RFS), and overall (OS) survival. Adenosquamous histology and lymph node involvement were significant determinants of nonsurvival. All carcinomas contained HPV DNA. In univariate analysis, p21, pRb, and MDRI in the biopsy specimen and PCNA, Ki-67, and pRb in the surgical sample significantly predicted RAC, while age, AI/V number of lymph nodes removed, and MI/V predicted RFS. Highly significant predictors of OS were AI/V number of lymph nodes removed, post-NAC MDR1 expression, MI/V and recurrence. Multivariate analysis confirmed the strong post-NAC effects of histologic type, AI/V, and MDR1 expression for RFS, and recurrence, age, and Ki-67 expression for OS. NAC responders with slightly decreased AI/V and increased MI/V had a poor prognosis.

Expression of cell-cycle-associated proteins pRB2/p130 and p27kip in vulvar squamous cell carcinomas.

Squamous cell vulvar carcinoma accounts for 4% of all gynecologic malignancies. The cause of vulvar cancer is still unclear. Identification of new biologic factors involved in vulvar carcinogenesis may be useful in clarifying the natural history of this malignancy. We investigated the immunohistochemical expression of the retinoblastoma-related proteins pRB2/p130 and CKI p27kip1 in a series of 51 invasive squamous cell carcinomas of the vulva (ISCCs) and in synchronous normal vulvar skin, non-neoplastic epithelial disorders (NNED) and vulvar intraepithelial neoplasia (VIN). Normal vulvar skin staining showed positivity for both pRB2/p130 and p27kip1. Loss of pRB2/p130 occurred in 29 (57%) of 51 specimens of ISCCs, and in 1 of 7 specimens with VIN (14%; P = .04). We also observed a significant decrease of pRB2/p130 expression from NNED to neoplastic tissues (VIN and ISCCs) (P = .004). Loss of p27kip1 expression was found in 16 of 51 specimens (31%) of invasive carcinomas, in 1 (14%) of 7 specimens of VIN, and in 2 of 18 specimens of NNED (11%). pRB2/p130 and p27(kip1) did not correlate significantly with any of the clinicopathologic parameters examined. Our data indicate that loss of pRB2/p130 and p27kip1 are frequent events in invasive vulvar carcinomas compared with synchronous premalignant lesions, non-neoplastic epithelial disorders, and normal vulvar skin. The significant progressive decrease of pRB2/p130 expression from non-neoplastic epithelial alterations through intraepithelial neoplasia to invasive vulvar carcinomas suggests a role for this tumor suppressor gene in vulvar carcinogenesis.

CD44 isoform 6 (CD44v6) is a prognostic indicator of the response to neoadjuvant chemotherapy in cervical carcinoma.

OBJECTIVE: Theclinical efficacy of neoadjuvant chemotherapy (NAC) in distinct groups of cervical cancer patients has been well documented, but parameters at the cellular level regulating the different responsiveness to this treatment have not been adequately explored. METHOD: A series of 21 patients with stage Ib and IIa bulky cervical carcinomas were treated by preoperative NAC with three courses of cisplatin, epirubicin, etoposide, and bleomycin prior to radical hysterectomy, and subsequently followed up for a mean of 52.3 months. Biopsies taken prior to NAC and operative specimens were subjected to immunohistochemical (IHC) staining for alpha-catenin, beta-catenin, E-cadherin, and CD44 isoform 6 (CD44v6), to uncover the role of adhesion molecules as determinants of the response to NAC and disease outcome. RESULTS: Seven of the twenty-one (33.3%) women died of the disease; adenosquamous (n = 4 cases) histology (RR 4.50, 95% CI 1.85-10.68) and lymph node involvement (RR 6.00, 95% CI 0.42-85.26) were significant determinants of nonsurvival. All 21 carcinomas were human papillomavirus DNA positive. The factors predicting the response to NAC in univariate analysis were: CD44v6 expression in the pre-NAC and post-NAC samples (P = 0.00056 and P = 0.00336, respectively). In multiple logistic regression analysis, the factors with independent predictive value for response to NAC were CD44v6 expression prior to (P = 0.0099) and after (P = 0.0470) NAC. In univariate survival analysis, the most significant (P < 0. 001) predictors of recurrence-free survival (RFS) were age and number of lymph nodes removed. In multivariate survival analysis, the independent predictor for RFS was only histological type (P = 0. 0064). Overall survival (OS) was predicted in a Cox model by recurrence (P = 0.0033), CD44v6 expression after NAC (P = 0.013), and patient's age (P = 0.039). CONCLUSIONS: These data indicate that CD44v6 is involved in the response to NAC, and eventually in disease outcome. This implicates that the assessment of CD44v6 expression might help in selecting patients who are likely to respond to NAC, i. e., women with significantly reduced CD44v6 expression in their tumors before treatment. Noteworthy, the response to NAC did not predict a favorable disease outcome.

Factors associated with cone margin involvement in CIN patients undergoing conization-equivalent electrosurgical procedure.

BACKGROUND: Most studies of cervical conization have considered the frequency of complications and the outcome of follow-up. The determinants of cone margin positivity have been inadequately described. In a series of CIN patients undergoing conization-equivalent electrosurgical procedure, we evaluated the factors associated with (i) any cone margin involvement, and (ii) endocervical margin involvement (with or without other locations) as contrasted with all other conditions. METHODS: Study population included 718 patients. Potential determinants of margin involvement were or were treated as categorical. Univariate analysis was based on the chi-square test. Multivariate associations were estimated by multiple logistic regression models. RESULTS: Cone margin involvement was observed in a total of 195 patients (27%). In univariate analysis, the frequency was positively related to histologic grade, time period, lesion size, and cone width and depth. In multivariate analysis, histology diagnosis and time period retained a strong association. The effect of lesion size was of borderline significance. The endocervical location emerged as a multivariate determinant of margin positivity. The effect of cone width and depth was not confirmed. Endocervical margin involvement was observed in 98 cases (14%). In univariate analysis, the frequency was positively associated with histologic grade, time period, and age, and inversely related to the visibility of the squamous-columnar junction. Multivariate analysis confirmed the strong effect of histology diagnosis and time period. The association with age and visibility of the squamous-columnar junction was weaker. CONCLUSIONS: Histology diagnosis and time period were the strongest determinants of cone margin involvement. Endocervical margin positivity was also related to patient age and visibility of the squamous-columnar junction. Cone width and depth had no protective effect.

Amniotic fluid index and labor length of pregnancies induced beyond 41 weeks of gestation with unfavorable cervix.

We evaluated if the response to prostaglandin E2 (PGE2) induction, in pregnancies completing 41 gestational weeks, is correlated to amniotic fluid index (AFI) values. A follow-up was performed from the time of the induction to the time of delivery of 63 pregnancies resulting in a spontaneous delivery showing unfavorable cervical examination at 41 weeks of gestation. This was induced by means of intracervical administration of PGE2 gel (Dinoprostone 0.5 mg). If the cervix was still unfavorable after 12 h, another gel administration followed. The number of PGE2 administration and AFI were both used as variables to correlate the time remaining before the delivery and the probability of delivery (Kaplan-Meier and Cox algorithms). Gestational age, parity, neonatal weight, and APGAR 5' were used as covariates. A cut-off of AFI > 6 better discriminates two groups regarding the probability of delivery at paired hours from the beginning of the induction. A statistically significant difference was demonstrated in only those patients which did not deliver within 12 h (44 cases). Multivariate analysis (Cox regression) yielded an adjusted odds ratio associated to the probability of delivery of 0.47 (0.23-0.95, 95% CI, p value = 0.0354) for AFI < or = 6 vs. AFI > 6.

Combined Pap smear, cervicography and HPV DNA testing in the detection of cervical intraepithelial neoplasia and cancer.

OBJECTIVE: The sensitivity of the Pap smear (PAP) continues to be the subject of debate. During the past several years, cervicography (CER) and HPV DNA testing have been suggested as optional tools in the screening of cervical cancer precursors. STUDY DESIGN: The performance characteristics of PAP, CER and HPV DNA testing (hybrid capture test [HCT]) in all potential combinations were evaluated in a series of 1,030 women (aged 16-70, median, 33), subjected to colposcopy (COLPO) as the reference tool. RESULTS: Of the 992 evaluable cases, 402/992 (41%) had positive COLPO (i.e., an abnormal transformation zone). Of them, 298 women underwent directed punch biopsy, while of the COLPO negative patients, 18/93 positive by at least one of the three tests had endocervical curettage. Of the 402 COLPO positive women, 146 (36%) remained negative on all tests, whereas 256 (64%) had at least one positive test. There were 84 cervical intraepithelial neoplasia (CIN) 2 and 3 lesions and 6 invasive carcinomas. Of the former, 10 were detected by PAP alone, 4 by CER alone and 3 by HCT alone. Three of the 6 carcinomas were HCT negative. The predictive value (PPV) of a positive test was 45% for PAP, 51% for CER and 48% for HCT. The combinations of PAP with CER (for PAP negative cases) and PAP with HCT were more sensitive for CIN 2 and 3 (95% and 94%, respectively) as compared with PAP alone but were associated with a significant decrease in specificity (44% and 46% vs. 57%, respectively). However, both combinations retained a PPV (43%) similar to that of PAP alone (45%). CONCLUSION: The potential combinations of PAP with CER and with HCT were more sensitive in detecting CIN 2 and 3 as compared with PAP alone and retained a PPV similar to that of PAP.

HPV testing: where are we now?

OBJECTIVES: 1) To assess if HPV (human papillomavirus)-DNA testing using the presently available technology offers any advantage over the utilization of the traditional Pap-smear as a screening tool for women at risk for cervical pre-cancers. 2) To assess if the HPV-DNA test is a valuable intermediate triage method for patients with Pap-smears demonstrating ASCUS (Abnormal Squamous Cells of Undetermined Significance) or LG-SIL (Low-Grade Squamous Intraepithelial Lesions) in order to better select those patients who would maximally benefit from colposcopy, thus, using clinical resources in an efficient way. MATERIAL AND METHODS: Review of the peer reviewed literature between 1992 and June 2000 regarding: 1) new and innovative approaches for cervical cancer screening and prevention; 2) advances in management protocols of ASCUS and LG-SIL with the introduction of HPV-DNA test. RESULTS: HPV-DNA testing in association with the Pap (Papanicolau) smear performed either conventionally or, preferably, with the new liquid based cytology is a valuable adjunct with high sensitivity and acceptable specificity rates in defining those patients most likely to demonstrate HG-SIL (High-Grade Squamous Intraepithelial Lesions) at the time of colposcopy. CONCLUSION: At present available evidence indicates that the best reason for performing HPV-DNA testing is the triage of selected patients with ASCUS and in specific settings with LG-SIL. Ongoing clinical studies may demonstrate additional advantages for this technology when used in a screening application.

Speculoscopy for Triage of Patients with an Abnormal Pap Smear: Data from the GISPE Study.

OBJECTIVE: This study evaluates the performance of Papanicolaou smear combined with speculoscopy in improving the predictive value of minor grade cervical cytological abnormalities. MATERIALS AND METHODS: A total of 3,300 asymptomatic women who had routine cervical smears were studied in 32 Italian centers. All these women underwent Pap smear and speculoscopy. The women positive at Pap smear or speculoscopy (n = 908) were referred for colposcopy and directed punch biopsy/endocervical curettage was performed when appropriate. RESULTS: Of the 908 patients referred for colposcopy, 538 underwent biopsy; 92 of these had a cervical lesion (cervical intraepithelial neoplasia [CIN]) confirmed on histology (67 CIN1 and 25 CIN2-3). Speculoscopy pointed out an area to biopsy in 84% of the CIN1 and in 75% of the CIN2-3 cases among women who showed minor (low-grade squamous intraepithelial lesion or less) cytological abnormalities. CONCLUSIONS: The potential combination of cytology and speculoscopy as an intermediate test in patients with minor grade cytologic (atypical squamous cells of undetermined significance or low-grade squamous intraepithelial lesion) cervical changes may decrease the number of recalls and directed biopsies in a cost-effective manner.

Ethnic differences in patterns of care of stage 1A(1) and stage 1A(2) cervical cancer: a SEER database study.

OBJECTIVE: The aim of this study was to evaluate patterns of care for women with Stage 1A(1) and 1A(2) cervical cancer utilizing the SEER database. METHODS: Review of SEER data from 11 registries from 1990 to 1995 was performed. Data from 2358 women were reviewed and stratified by substage, ethnicity, type of therapy, and age. RESULTS: Three remarkable differences among subgroups were identified. (1) Among women >/=35 years of age, whites were more likely to have Stage 1A(1) cancer than blacks or Hispanics; OR (95% CI) = 1.56 (1. 05, 2.31) and 1.41 (1.04, 1.91), respectively. (2) Patients >/=35 years of age were more likely to undergo hysterectomy than younger patients both for 1A(1) and 1A(2) stages; OR (95% CI) = 2.31 (1.68, 3.19) and 2.78 (2.21, 3.50), respectively, with Mantel-Haenszel test of independence chi(2) = 102.9943, P value < 0.001. (3) Black and Hispanic women >/=35 years of age with 1A(2) disease were less likely to have a hysterectomy than whites. Only 15% of Hispanic patients and 9% of blacks over the age of 35 and with Stage 1A(2) were treated via hysterectomy, compared to 76% of white women. Differences in hysterectomies for <35 years of age, 1A(1) patients approached but did not reach statistical significance: blacks 36% versus Hispanic/whites 59%, P value = 0.07. CONCLUSIONS: Older white women were more likely to have cervical carcinoma diagnosed at an earlier stage (1A(1)) than age-matched blacks or Hispanics. Older patients, across all ethnic groups analyzed, were also more likely to be treated for both Stage 1A(1) and 1A(2) disease via hysterectomy than younger patients. Ethnic differences in the management of women with Stage 1A(2) cervical cancer do exist: older minority women are less likely to have a hysterectomy and more likely to be treated via fertility-sparing, less definitive procedures than whites.

Management of the abnormal papanicolaou smear during pregnancy: lessons for quality improvement.

OBJECTIVE: Our goal in this study was to evaluate the management of pregnant patients with abnormal Papanicolaou smears. MATERIALS AND METHODS: We reviewed the records of 292 patients undergoing colposcopy to evaluate abnormal cervical cytology during pregnancy. RESULTS: A total of 32 (11%) of the subjects had Papanicolaou smears demonstrating atypical glandular cells of undetermined significance; 178 (61%) had low-grade squamous intraepithelial lesions; 69 (23.6%) had high-grade squamous intraepithelial lesions; and 2 (1%) had a malignancy. The first colposcopy was performed most commonly during gestational week 24. Colposcopy showed findings consistent with minor changes in 154 cases (53%) and with major changes in 61 (21%). Only 27 patients (9% of the total) underwent a colposcopically directed biopsy, and 51 (83.6%) of the 61 patients with a colposcopic impression of cervical intraepithelial neoplasia grade 2 or greater did not undergo biopsy. Only 24 (26%) of the 91 patients scheduled for follow-up colposcopy during pregnancy complied, and 123 of the 292 patients (42%) returned for follow-up examinations after delivery. Four patients had an invasive cervical carcinoma diagnosed in the 12 months immediately after delivery. Although the first intrapregnancy colposcopy in two of these patients noted findings consistent with cervical intraepithelial neoplasia grade 2 or greater, none of the four underwent biopsy during pregnancy. CONCLUSIONS: Evaluation of cytological abnormalities is frequently suboptimal during pregnancy. The threshold for colposcopically directed biopsy is often modified during pregnancy in a way that may be harmful to the patient. Extra effort is needed to tailor follow-up to the patient's need and to improve patient compliance.

[Outpatient diagnostic hysteroscopy: 14,000 cases]. / Isteroscopia diagnostica ambulatoriale: 14.000 casi.

Hysteroscopy is a technique which plays a fundamental diagnostic role in gynecological practice. The possibility of obtaining a direct intracavitary view and performing specific biopsies give it a greater level of diagnostic accuracy than intrauterine curettage. The authors' personal experience of 13,923 case enables the correct method of performing this procedure to be codified in order to avoid the inherent risks and complications. The main indication is abnormal uterine bleeding which is the most frequently observed pathology in gynecological practice. In cases of metrorrhagia in women of child-bearing age benign organic pathology accounts for 45% of patients and malignant pathology 0.3%. Post-menopausal patients reveal an increase in the incidence of organic pathology in general and neoplastic pathologies in particular (8.1%). Complications linked to this type of technique are extremely rare and in overall terms affect 1% of cases. The analysis of results shows that hysteroscopy today represents an extremely reliable and repeatable outpatient procedure. However, in spite of these advantages, including savings in health costs, it is not widely used at a capillary level given that if performed by persons who are not expert it may become traumatic and unreliable. The correct execution of hysteroscopy in fact calls for dexterity acquired over time which is not conditioned by the learning of previous techniques and requires an adequate period of training.

Transvaginal sonography vs. hysteroscopy in the preoperative staging of endometrial carcinoma.

The aim of this study was to evaluate the diagnostic accuracy of transvaginal sonography vs. hysteroscopy in the preoperative staging of endometrial carcinoma, in order to establish the most appropriate surgical therapy. Transvaginal sonography and hysteroscopy were used preoperatively in 67 women with histologically proven endometrial carcinoma. Deep myometrial invasion (> 50%) was present at postoperative pathology in 26/67 (39%) women and spread to the cervix occurred in 11/67 (16%) women. Transvaginal sonographic examination was initially directed at assessing myometrial invasion, which was correctly predicted in 52/67 (78%) women. Transvaginal sonography demonstrated a sensitivity of 88% (23/26) and a specificity of 71% (29/41) for deep invasion, with a positive predictive value (PPV) of 66% (23/35) and a negative predictive value (NPV) of 91% (29/32). The accuracy of transvaginal sonography in detecting cervical involvement was 82% (55/67), and that of hysteroscopy was 72% (48/67): transvaginal sonography was slightly less sensitive (54% vs. 64%), but more specific (87% vs. 73%) than hysteroscopy. When cervical invasion was present, the PPVs of transvaginal sonography and hysteroscopy were 46% (6/13) and 32% (7/22), respectively, while the NPV was 91% for both techniques (49/54; 41/45). Our data show that the accuracy of transvaginal sonography was comparable with that of hysteroscopy in detecting cervical involvement. Therefore, in the majority of cases, when both techniques showed that disease was limited, the appropriately limited type of surgery would be performed. Conversely, detection of a myometrial invasion of > 50% or an extension to the cervix would lead to an unnecessarily extensive operation if this was the sole criterion used for making the decision.

Hysteroscopic metroplasty.

Between February 1990 and June 1993 40 patients underwent hysteroscopic metroplasty for septate uterus. Twenty-six patients had previous miscarriages (65%) and fourteen were infertile (35%). Hysteroscopic section of uterine septa was performed by means of Hamou resectoscope with sorbitol-mannitol solution as distending medium. Surgical outcome was excellent without intraoperative and postoperative morbidity. After 40-60 days the uterine cavity was completely epithelialized without intrauterine adhesions in all the cases. One patient had incomplete septum section that required a second procedure. Postoperative reproductive outcome was evaluated in 26 patients: the cumulative pregnancy and birth rate was 73% and 86%, respectively. Five patients delivered by cesarean section (39%). In the infertile group the pregnancy and birth rate was much lower (44% and 75%, respectively) than in previous miscarriage group (88% and 91%, respectively). Infertile patients do not seem to be cured by hysteroscopic metroplasty; however, in these cases the endoscopic operation should be performed, because it may prevent subsequent miscarriage. Hysteroscopic metroplasty by means of Hamou resectoscope is a very successful, quick, simple and safe procedure that may replace abdominal metroplasty.