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Expression of cyclooxygenase-2 (COX-2) and Ki67 as related to disease severity and HPV detection in squamous lesions of the cervix.

OBJECTIVES: To assess the expression of cyclooxygenase (COX-2) and Ki67 in cervical squamous lesions in relation to disease severity and human papillomavirus (HPV) detection. SUBJECTS AND METHODS: For this cross-sectional study, 223 women subjected to diathermic conization of the cervix have been enrolled, between February 2001 and April 2004. All patients undertook pelvic examination, including colposcopy and collection of samples for Hybrid Capture II (HCII). Pathological assessment disclosed: 9 cases of normal epithelium/cervicitis, 33 CIN1, 28 CIN2, 146 CIN3 and 7 invasive squamous cell carcinomas. COX-2 and Ki67 protein expression was determined with immunohistochemistry. COX-2 immunoreactivity grading was based on the German ImmonoReactive score. The continuum percentage of positive cells was used for the assessment of nuclear Ki67 expression. RESULTS: Expression of COX-2 did not correlate with disease severity and with Ki67 expression. The HPV detection rates did not differ significantly across COX-2 protein expression strata, ranging from negative to strong expression. Ki67 expression, however, was higher in the CIN3 group (P = 0.001) as compared to the specimens rendered as normal/cervicitis. CONCLUSIONS: COX-2 protein expression did not correlate with disease severity or Ki67 expression.

Adult↗

Laparoscopic pelvic lymphadenectomy in the staging of early carcinoma of the cervix.

Laparoscopic pelvic lymphadenectomy was performed in 39 patients. An incision of the peritoneum between the round and infundibulo-pelvic ligament on each side gave access to the retroperitoneal space. Subsequently, laparoscopic surgery allowed precise dissection of external and internal iliac vessels, umbilical artery, and obturator nerve. The peritoneum was left open, and the lymph was drained into the peritoneal cavity. No lymphocele was observed. Three to 22 (mean, 8.7) nodes were removed, and there was no significant morbidity. Sensitivity and specificity were 100% in this preliminary experience. It is thus possible to remove the first-line regional lymph nodes of the cervix for pathologic examination. Because "skip" metastases are quite rare in early cervical carcinoma, the risk of missing a positive node is low. Brachytherapy alone, vaginal surgery, or, in microinvasive carcinoma, conization alone can be applied safely without the need of a staging laparotomy in cases with negative nodes.

Biopsy↗

Three-group metaphase as a morphologic criterion of progressive cervical intraepithelial neoplasia.

OBJECTIVE: The purpose of our study was to investigate the presence of three-group metaphase in progressive cervical intraepithelial neoplasia. STUDY DESIGN: This was a retrospective histologic study on the conization specimens of 41 women with microinvasive cervical carcinoma, 28 of whom were enrolled in the study. Three-group metaphase was scored in the invasive part of the lesion and in the adjacent cervical intraepithelial neoplasia. RESULTS: Three-group metaphase was found in 93% of cervical intraepithelial neoplasia adjacent to the invasive part of the lesion. However, three-group metaphase was found in 11% of the microinvasive cervical carcinoma cases with an infiltration depth of less than 2.5 mm and in 60% of the microinvasive cervical carcinoma cases with an infiltration depth of between 2.5 and 5.0 mm. CONCLUSION: The chance of finding three-group metaphase seems to be limited by the area of the lesion examined for three-group metaphase on the slide. Given the relation between three-group metaphase and aneuploid cervical intraepithelial neoplasia found in the literature and the occurrence of three-group metaphase in the cervical intraepithelial neoplasia adjacent to the microinvasive cervical carcinoma in this study, three-group metaphase can be considered a morphologic criterion for progressive cervical intraepithelial neoplasia and can be of value for practical use.

Cervix Uteri↗

Cone biopsy: an outpatient procedure.

In view of hospital costs, 108 cone biopsies performed on 104 women from 1974 to 1978 at the Shands Teaching Hospital were analyzed retrospectively in order to determine if cone biopsy could be done as an outpatient surgical procedure. No contraindications were found for the majority pf patients in eliminating overnight postoperative stay if there were no immediate complications at the time of operation or in the recovery room. Twenty-two subsequent outpatient conizations have confirmed these findings.

Adult↗

The anatomic distribution of cervical adenocarcinoma in situ: implications for treatment.

The anatomic distribution of cervical adenocarcinoma in situ was ascertained in 23 cases of adenocarcinoma in situ, 10 of which also had "early" invasive adenocarcinoma. The adenocarcinoma in situ involved both surface and gland epithelia in all cases, involved a variable number of quadrants, involved glands beneath the transformation zone in about two thirds of cases, was multifocal only occasionally, extended up the endocervical canal for a variable distance (up to 30 mm), and was associated with squamous dysplasia in about half of cases. From this topographic outline of adenocarcinoma in situ, it is recommended that if cervical conization is chosen as conservative therapy for adenocarcinoma in situ the "cone" be cylindrical in shape, to include the transformation zone and deep glands, and extend at least 25 mm up the endocervical canal.

Adenocarcinoma↗

A new approach to hysterectomy without colpotomy: pelviscopic intrafascial hysterectomy.

OBJECTIVE: Total abdominal and vaginal hysterectomies have been performed by extrafascial enucleation of the uterus with amputation of the upper vagina. Our new method, which is limited to an intrafascial cylindriform enucleation of the cervix, leaves intact the highly vascularized extrafascial cervical tissue, the corresponding nerves, and the topography of the ureters. STUDY DESIGN: From December 1991 to December 1992, 60 patients underwent an intrafascial hysterectomy by pelviscopy and two patients by laparotomy for leiomyomas, endometriosis, and other intractable bleeding disorders and for a variety of additional benign gynecologic diseases. Uterine extirpation was performed in the classic manner with grasping forceps, scissors, ligatures, and sutures. No electrosurgical equipment, stapling devices, or lasers were used. RESULTS: We analyzed our cases according to intraoperative, immediate postoperative, and late postoperative complications. We had no major complications. Average operating time is compatible with that of conventional total abdominal or vaginal and laparoscopy-assisted vaginal hysterectomy. Blood loss was minimal (average drop of hemoglobin 1.8 gm). Average hospitalization was 50.6 hours. CONCLUSION: There has never been an indication for the removal of the normal cervix at hysterectomy, other than for cancer prophylaxis. The synthesis of supracervical extirpation of the uterus, conization of the cervix, and operative laparoscopy (pelviscopy) enables us to perform a truly laparoscopic hysterectomy without colpotomy. Pelvic floor support is maintained and transvaginal sexual sensation is less likely to be impaired because of the preservation of the cardinal and uterosacral ligaments. With the serrated-edge macromorcellator, morcellated cylinders of cervical and uterine body tissue guarantee a thorough histologic examination and interpretation. Physical stress to the patient is minimized. There are no abdominal or vaginal incisions. The abdominal space remains practically unopened. Pelviscopic intrafascial hysterectomy equates with minimally invasive and organ-preserving surgery. It may be sufficient for cervical and endometrial cancer prophylaxis.

Adult↗

Diethylstilbestrol exposure in utero and endometriosis in infertile females.

Endometriosis was found in 39% and in utero diethylstilbestrol (DES) exposure in 5% of 397 infertile women who had undergone laparoscopy and/or laparotomy among 750 consecutively evaluated infertile couples. Fifty percent of the DES-exposed infertile women also had endometriosis, similar to the 39% with endometriosis among non-DES-exposed women. Cervical stenosis was found in 25% of all DES-exposed patients and in 83% of those who had undergone cryocautery or conization. However, 40% did not have endometriosis. Thus, while the frequency of endometriosis and cervical stenosis is extremely high in infertile women exposed in utero to DES, a significant association beyond that found in non-DES-exposed patients could not be established. Some of the infertility may be associated with cervical stenosis alone.

Abortion, Spontaneous↗

Loop electrosurgical excision procedure of the cervix and time of delivery in subsequent pregnancy.

OBJECTIVE: To study the effect of the loop electrosurgical excision procedure (LEEP) on gestational age at delivery in the subsequent pregnancy. METHOD: Identification of women with LEEP. Chart analysis and inquiry into gestational age at the subsequent delivery. Exclusion of first trimester abortions, multiple gestations, cold knife conizations and women over 40 years during LEEP. For comparison, 40 weeks was used as the mean date of delivery in a normal population. Wilcoxon signed rank test was used and P<0.05 was considered significant. RESULT: Fifty-six women delivered after LEEP. Seven delivered preterm of whom three were induced and one had a history of preterm delivery. Deliveries prior to 32 weeks of gestation did not occur. Mean gestational age at delivery was 39 2/7 weeks (95%CI: 38 5/7-39 6/7) which is significantly earlier (P=0.03) than the hypothetical 40 weeks. CONCLUSION: After LEEP, deliveries prior to 32 weeks did not occur. Gestational age at delivery was only 5 days earlier than expected. LEEP cannot be considered a risk for early preterm delivery.

Adult↗

Atypical glandular cells on cervical smears.

OBJECTIVES: A standardized propaedeutic research to determine the clinical significance of cervical smears with atypical glandular cells. METHODS: Of the 8,807 women seen at the Division of Lower Genital Tract Pathology and Colposcopy, São Paulo, Brazil, during a 5-year study, 57 (0.65%) had atypical glandular cells. Forty-two of them underwent colposcopy and hysteroscopy with 12-month follow-up. Conization and/or hysterectomy were performed if both exams were negative. The chi-square test and Fisher's exact test were used for statistical analysis. RESULTS: A clinically significant lesion of the cervix and endometrium was diagnosed in 59.5% of the cases. The lesion was restricted to the cervix in women younger than 40 years, but could also be located in the body of the uterus in women older than 40 years. CONCLUSIONS: Colposcopic evaluation in all women and study of the uterine cavity in women aged 40 years or older is necessary in the presence of this cytologic finding.

Adult↗

A randomized trial of the sleeved cytobrush and the endocervical curette.

OBJECTIVE: To compare endocervical specimens obtained with the endocervical curette to those obtained with the sleeved cytobrush. METHODS: All nonpregnant women undergoing either cervical conization or hysterectomy were eligible for this randomized, split-sample trial. Both endocervical curette and cytobrush sampling were performed on all 62 participants before surgery, with randomization designating the order of the sampling procedures. A pathologist blinded to sampling order reviewed study specimens. The endocervical canals of the surgical specimens were evaluated against endocervical curette and brush samples. Odds ratios (ORs), relative risks (RRs), and risk differences were used to compare the sensitivity and specificity of each procedure in unmatched and matched analyses. RESULTS: There was a significantly higher rate of inadequate specimens in the endocervical curette group (22% versus 2% in the brush group; 95% confidence interval [CI] for the difference: 9%, 31%). Unmatched analysis showed the two tests to be comparable in terms of sensitivity and specificity. Whereas the specificities of both tests were high (100% for the endocervical curette, 88% for the brush; RR 1.13, 95% CI 1.00, 1.28), the sensitivities were poor (44% for the sleeved brush and 32% for the endocervical curette; RR 1.38, 95% CI 0.65, 2.94). Matched analysis showed the sleeved endocervical brush to be a more sensitive sampling method compared with the curette (OR 2.04, 95% CI 0.98, 4.22). Sparse data prevented a matched analysis on the specificity of the two tests. CONCLUSION: Endocervical sampling with the sleeved cytobrush achieves similar sensitivity and specificity to that of traditional endocervical curettage. Given the much greater rate of inadequate specimens when using the endocervical curette, the sleeved cytobrush is a reasonable alternative to this technique.

Adult↗

Superiority of electrocautery over the suture method for achieving cervical cone bed hemostasis.

OBJECTIVE: To compare the efficacy of electrocautery with that of the suture method for achieving hemostasis of the cervical cone bed. METHODS: We performed a retrospective chart review of all patients who underwent cold-knife conization of the cervix over a 5-year period. Patients were categorized into two groups: the cautery group, in which the cone bed was electrocauterized with a hand-held electrocoagulation device; and the suture group, in which hemostasis was achieved by a continuous locking suture placed circumferentially around the cone bed. Outcome measures evaluated include estimated blood loss, operative time, and incidence of complications, including secondary hemorrhage, cervicitis, and cervical stenosis. Data were analyzed by Student t test, chi(2) test, linear regression, and multiple logistic regression where appropriate. RESULTS: There were 156 women in the cautery group and 35 in the suture group. The cautery group had significantly lower estimated blood loss (27 mL versus 101 mL; P <.01) and shorter operative time (34 versus 43 minutes; P <.01) than the suture group. The procedure-related complication rate was 6.4% in the cautery group, compared with 14.3% in the suture group (P = nonsignificant). A higher use of lateral sutures, vasopressors, and thrombotic agents was seen in the cautery group. However, even after adjusting for these variables, mean estimated blood loss (33 mL, P <.01) and mean operative time (34 minutes, P <.01) were significantly less in the cautery group than in the suture group. CONCLUSIONS: Cauterization of the cone bed is superior to suture as a method of achieving hemostasis, with significantly less blood loss and shorter operative time.

Adult↗

Laparoscopic ureteroneocystostomy.

BACKGROUND: In gynecologic surgery, there is always the possibility that ureteral injuries will occur intraoperatively. Traditionally, ureteral injuries are treated by laparotomy, which increases morbidity. This inspired us to develop a laparoscopic alternative to deal with accidental intraoperative ureteral injuries. CASE: A 49-year-old woman with stage Ia1 cervical cancer found after conization was to undergo a laparoscopic Piver class 2 hysterectomy. Because the ureters could not be effectively mobilized as a result of pelvic fibrosis, the left ureter was accidentally transected. The patient underwent a laparoscopic extravesical ureteroneocystostomy. CONCLUSION: Laparoscopic ureteral reimplantation is technically possible and is a viable alternative to open surgery.

Anastomosis, Surgical↗

Prevalence and histologic significance of cervical human papillomavirus DNA detected in women at low and high risk for cervical neoplasia.

OBJECTIVES: To determine and compare the prevalence and histologic significance of human papillomavirus (HPV) nucleic acids in cervical specimens from women at low (routine hysterectomy) and high (suspicion of cervical neoplasia) risk for cervical neoplasia. METHODS: Cervical brushings were taken from the cervices of hysterectomy and conization or loop electrical excision specimens and analyzed for HPV nucleic acids by polymerase chain reaction and restriction fragment length polymorphism analysis. Histopathology was confirmed by review of reports or, for HPV-positive results, re-review of the histopathology. Statistical analysis used Student t test or Fisher exact test. RESULTS: Four hundred seventeen and 43 low- and high-risk cervices, respectively, were studied. Statistically significant differences were observed in the index of HPV positivity between the low- and high-risk groups (1.7 versus 42%, P < .001) and the proportion of HPV being cancer-associated HPV types (14 versus 78%, P = .005). None of the 417 cervices from low-risk women contained HPV 16. In the high-risk group, histologically confirmed cervical intraepithelial neoplasia lesion was statistically more likely to be associated with HPV (59 versus 13%, P = .005). CONCLUSION: Cervices from routine, low-risk hysterectomies in predominately middle-aged women have an extremely low index of cancer-associated HPVs. Considering the strong association of HPV with histologically proven disease, prospective studies exploring the relationship of cancer-associated HPVs to neoplasia in middle-aged women merit consideration.

Adult↗

Angiogenesis in squamous cell carcinoma in situ and microinvasive carcinoma of the uterine cervix.

OBJECTIVE: To evaluate angiogenesis in squamous cell carcinoma in situ (CIS) and microinvasive squamous cell carcinoma of the uterine cervix and to investigate the relations among angiogenesis, stromal inflammation, and depth of invasion. METHODS: Three groups of women were studied: 22 controls who had undergone hysterectomy for benign conditions; 18 with squamous cell CIS of the cervix who underwent cone biopsy, hysterectomy, or both; and 14 with microinvasive squamous cell carcinoma who underwent conization of the cervix and subsequent surgical management according to depth of invasion. All specimens were stained immunohistochemically for factor VIII-related antigen. Areas below the basement membrane with the highest angiogenic density were selected. The degree of stromal inflammatory reaction was assessed. Statistical analyses included Kruskal-Wallis, analyses of variance and covariance, Scheffe and Bonferroni-Dunn post hoc procedures, and Pearson correlation analysis. P < .05 was considered statistically significant. RESULTS: Microvessel counts per high-power field (x 400) of microinvasive squamous cell carcinoma of the cervix differed significantly from those of controls and squamous cell CIS (median 34.5 per high-power field, range 9-76 versus median 17, range 7-47, and median 19, range 8-39, respectively; P < .005). Microvessel counts per high-power field in squamous cell CIS did not differ significantly from those of controls (P = .91). Among patients with microinvasive squamous cell carcinoma of the cervix, no significant correlation was found between microvessel counts per high-power field and the depth of invasion (r = 0.19, P = .51). Stromal inflammatory reaction (graded 0-3) differed significantly among controls, squamous cell CIS, and microinvasive carcinoma (mean 0.40, 0.83, and 1.64, respectively; P < .005). CONCLUSIONS: Microinvasive squamous cell carcinoma of the uterine cervix is angiogenic, but depth of invasion is not associated with increased angiogenicity. Squamous cell CIS is not angiogenic.

Adult↗

Influence of specialty on pathology resource use in evaluation of cervical dysplasia.

OBJECTIVE: Colposcopy is performed by different providers, including nurse practitioners, family physicians, and gynecologists. The training and experience of these providers vary. The fiscal impact of provider type is unknown. This study evaluates pathology resource use by gynecologists and nongynecologists at the time of colposcopy. METHODS: A retrospective cohort study was performed. Data were collected by review of pathology reports and records of all patients with cervical dysplasia treated with cervical excision by loop electrosurgical excision procedure or cold knife conization at our institution between January 1, 1996, and December 31, 1997. Data were analyzed according to type of provider performing the colposcopy before the cervical excision. RESULTS: Gynecologists obtained a total of 190 biopsy specimens in 127 patients, with a mean number of 1.5 +/- 0.75 per patient and a median of 1. Nongynecologists took a total of 148 biopsy specimens in 44 patients, with a mean of 3.4 +/- 1.14 per patient and a median of 3 (P < .001). These differences persisted irrespective of presenting cytology. Nongynecologists were more likely to do endocervical curettage than gynecologists (95% compared with 82%, respectively, P < .001). Cervical dysplasia was diagnosed equally well, even though fewer biopsies were taken by gynecologists. CONCLUSION: Both groups of providers were equally capable of identifying dysplastic lesions. Despite equivalent diagnostic accuracy, nongynecologists used two to three times more pathology resources. If this pattern of use of resources exists at other clinical sites, patients with cervical dysplasia and payers would be better served by gynecologic rather than nongynecologic care.

Adult↗

Changes in the topological expression of markers of differentiation and apoptosis in defined stages of human cervical dysplasia and carcinoma.

OBJECTIVE: We compared the capacity of cells in normal cervical epithelium, progressive stages of CIN, and invasive carcinoma to proliferate, differentiate, and undergo apoptosis. METHODS: We investigated 30 conizations showing regular squamous epithelium of the ectocervix, all stages of cervical preinvasive neoplastic lesions (CIN I to III), or invasive carcinoma. The expression of the cell proliferation and differentiation marker Ki67 and Mad-1, respectively, and of the apoptosis-related proteins bcl-2, active caspase-3, and DNase I was analyzed on paraffin sections by immunohistochemistry. The expression of DNase I or -like enzymes was also analyzed at the level of their gene transcripts by in situ hybridization. In addition, apoptotic events were identified by in situ end labeling of fragmented DNA (ISEL). RESULTS: Expression of Ki67 was restricted to suprabasal cells in normal cervical epithelium but increased with CIN severity and invasive carcinoma. ISEL demonstrated apoptosis in superficial layers of normal, CIN I, and CIN II epithelium, whereas in CIS (CIN III) and invasive carcinoma, ISEL-positive cells were additionally observed at varying epithelial locations. Bcl-2 immunostaining remained restricted to the basal layer of all preneoplastic and neoplastic stages. Active caspase-3 was present in the suprabasal layer and extended to all upper layers in normal epithelium and slightly decreased with increasing dysplasia. In invasive carcinoma it was restricted to few scattered cells. The differentiation marker Mad-1 extended from the spinous to the superficial layer in regular epithelium, but gradually shifted to more superficial layers with increasing CIN grade and invasive carcinoma. A similar topological change was observed for DNase I with increasing CIN grade. In CIS and invasive carcinoma, DNase I immunopositive cells were solely interspersed within neoplastic cells. In contrast, DNase I specific mRNA was present in all epithelial layers in CIN III and neoplasia, suggesting a translational block of the expression of DNase I or -like enzymes. CONCLUSION: Our data indicate that the elevated proliferation observed with increasing CIN severity and carcinoma was not paralleled by a similar increase in cell elimination. Most of the dysplastic and neoplastic cervical epithelial cells appeared incapable of entering terminal differentiation and complete it by apoptosis, possibly due to their failure to express or activate apoptosis executing enzymes.

Apoptosis↗

Cervical schistosomiasis, human papilloma virus (HPV), and human immunodeficiency virus (HIV): a dangerous coexistence or coincidence?

BACKGROUND: Female genitourinary schistosomiasis (FGS) is widespread in endemic areas causing significant morbidity and mortality. Recent data suggest that FGS of the cervix not only is considered a risk factor for contracting different sexually transmitted diseases (STD), but also plays a significant role in modifying the natural history and immunological response to those infections, in particular HIV and HPV. CASE REPORT: A 32-year-old female from Zambia, who was recently diagnosed with HIV and high-grade dysplasia with koilocytosis on cervical Pap smear, underwent cervical conization which confirmed moderate cervical dysplasia and also revealed the presence of viable and nonviable schistosoma eggs in cervical stroma. Four different HPV types were isolated by PCR, including one "low-risk" (type 6) and three "high-risk" types (types 45,56, and 58). CONCLUSION: The presence of HPV, HIV infection, and cervical schistosomiasis in our patient is likely more than coexistence of multiple agents in the same milieu as cervical schistosomiasis increase susceptibility for other STDs including HIV and HPV. Therefore, in patients with schistosomiasis, immediate treatment for schistosomiasis and additional testing for HIV and HPV is warranted.

Adult↗

Laser CO2 vaporization for high-grade cervical intraepithelial neoplasia: a long-term follow-up series.

OBJECTIVE: The goal of this study was to evaluate the effectiveness of laser CO(2) vaporization for conservative treatment of ectocervical high-grade cervical intraepithelial neoplasia (CIN) particularly by the evaluation of the reappearance risk of disease in long-term follow-up. METHODS: One hundred fifty-nine patients were submitted to CO(2) laser vaporization for high-grade CIN and followed up for a minimum of 5 years. Selection of cases, depth of ablation, complications, and cure rate (percentage of treated patients in whom there was no recurrent/persistent high-grade CIN at the 5-year follow-up examination) were retrospectively evaluated. RESULTS: Selected cases for colposcopy were submitted to a 6-mm mean depth of vaporization without intra- or postoperative complications. The cure rate for a single treatment was 97.5% and a satisfactory colposcopic follow-up was possible in 99.4% of treated patients. No case of invasive carcinoma occurred after a mean follow-up of 7.1 years. Four cases (2.5%) were high-grade CIN persistence observed after a mean time of 3.75 months, suggesting incomplete destruction of the deepest part of the lesion involving the glandular crypt base. CONCLUSIONS: Long-term follow-up proves that laser CO(2) vaporization still has a place in the treatment of CIN. In selected cases it represents a safe alternative for conization in the treatment of high-grade CIN, but colposcopic expertise is essential for adequate preoperative selection of cases.

Colposcopy↗