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Predictive value of cone margins and post-cone endocervical curettage with residual disease in subsequent hysterectomy.

In 51 of 106 patients (48%) residual disease was identified in hysterectomy specimens performed following cervical conization. Invasive squamous cell carcinoma was found in one patient in spite of clear cone margins. Thirty-nine of sixty-three patients (62%) with cervical intraepithelial neoplasia (CIN) involving the inner (endocervical) margin of the cone biopsy had residual disease. When both the inner margin and post-cone endocervical curettage (ECC) were involved, residual disease was present in 24 of 30 (80%) hysterectomy specimens. When the inner margins of the cone were involved with CIN-III and the post-cone ECC was negative, 36% of hysterectomy specimens contained residual disease compared to 88% when post-cone ECC was positive. These findings indicate that post-cone endocervical curettage has significant predictive value with respect to the presence or absence of residual disease in patients with CIN involving the inner margins of the cervical cone.

Adult↗

Interferon gamma treatment for cervical intraepithelial neoplasia.

Eight patients with cervical intraepithelial neoplasia (CIN) were administered perilesional injections of human recombinant interferon gamma (IFN-gamma), and the response was evaluated by colposcopy and exfoliative cytology and then by histopathology. In all patients, colposcopic and cytologic findings improved after two to four injections of IFN-gamma and the cytologic findings reverted to normal in five of these eight patients. All five were free of dysplastic lesions. The other three patients with positive cytology and positive colposcopy after completion of IFN-gamma treatment underwent hysterectomy or laser conization, and histopathologic examination revealed residual dysplastic lesions. On the other hand, a control study revealed that only one of eight patients showed spontaneous regression during the 3-month observation period. During the course of these treatments, keratinizing cells were often present in the cervical smears and isolated cell keratinization was often evident in the residual dysplastic lesions of the surgical specimens. These observations suggest that IFN-gamma treatment is an effective therapeutic method for CIN lesions and that IFN-gamma has the potential to differentiate nonkeratinizing squamous cells into keratinizing cells.

Adult↗

Systemic alpha-interferon (Wellferon) treatment of genital human papillomavirus (HPV) type 6, 11, 16, and 18 infections: double-blind, placebo-controlled trial.

The efficacy of systemic interferon-alpha (IFN-alpha n1; Wellferon) treatment on genital human papillomavirus (HPV) infections was studied in a double-blind, placebo-controlled trial. A total of 120 women were randomly allocated to receive either interferon (IFN, n = 60) or placebo (n = 60). In both treatment groups, 15 patients with lesions induced by each of the four HPV types (HPV 6, 11, 16, and 18) were included. The dose of IFN was 1.5 x 10(6) IU subcutaneously three times for the first week followed by 3 x 10(6) IU three times weekly for a further 6 weeks. The control patients received matching placebo injections. Ten patients (three IFN-treated and seven placebo-treated) were lost to follow-up. As determined by colposcopy, cytological and histological examinations, and HPV typing (in situ hybridization, ISH), 8 IFN-treated patients (14%) and 11 placebo-treated patients (18%) showed complete response (CR) at the 8th week. The corresponding figures were 22 (37%) and 25 (43%) at the 24th week and 28 (49%) and 25 (49%) at the 52nd week, respectively. The total number of HPV DNA negative patients at Week 8 was 29 (49%) in the IFN group and 24 (40%) in the placebo group (statistically nonsignificant). At Week 24, 37 (63%) of the IFN-treated patients and 39 (67%) of the placebo-treated patients were HPV DNA negative. In 2 placebo-treated cases, cervical lesions progressed to CIN III and were treated by conization after the 24th week. There were 4 recurrences (7%) in the IFN group and no recurrences in the placebo group at the 24th week, corresponding figures at the 52nd week being 6 (11%) and 4 (7%), respectively. When the clinical efficacy was evaluated in relation to the histological grade of lesion and four different HPV types, there were no differences in CR or in the number of HPV DNA negative patients between the two study groups. In conclusion, systemic IFN-alpha therapy did not show any significant therapeutic effect on genital HPV infections (by HPV types 6, 11, 16, and 18) compared to placebo.

Adult↗

Invasive carcinoma after cone biopsy for cervical intraepithelial neoplasia.

A retrospective review of 578 patients with invasive cervical cancer identified 8 patients with a history of one or more cone biopsies for treatment of cervical intraepithelial neoplasia. The cone biopsy and hysterectomy specimens were reviewed to identify factors predictive of the subsequent development of invasive cancer. The mean interval from cone biopsy to diagnosis of invasive carcinoma was 6.7 years (range 1.5-16.5 years). High-grade intraepithelial neoplasia is a potentially invasive lesion. Adenocarcinoma in situ was identified as a high-risk lesion that may be inadequately treated by cone biopsy. Four patients developed invasive squamous cancer in spite of complete excision of the initial lesion. Patients who have high-grade intraepithelial neoplasia treated with cone biopsy require long-term follow-up, and conization may hamper the subsequent diagnosis of preinvasive lesions.

Adenocarcinoma↗

Diagnostic value of endocervical curettage during colposcopy.

A retrospective study including patients with cytology, colposcopy and endocervical curettage (ECC) was carried out to compare ECC outcomes to final diagnosis. ECC was performed in 68 cases for a discordance between cytology and colposcopy and in 85 cases because the lesion was incompletely visible. Complete concordance between ECC and final diagnosis was obtained in 123 cases. ECC overestimated diagnosis in eight cases (5 true false positives) and underestimated it in 20 cases (6 true false negatives). Among the latter, ECC failed to recognize invasion in seven cases. Sensitivity, specificity, positive and negative predictive values of ECC to diagnose high grade cervical intraepithelial neoplasia (CIN) and invasive lesions together were 84%, 97%, 95% and 90%, respectively. Outcomes to diagnose invasive lesions were 22%, 100%, 100% and 95%, respectively. ECC sensitivity to diagnose endocervical lesions is satisfactory but its sensitivity to establish the diagnosis of invasion is very low. Consequently, a conization is advisable when ECC has diagnosed an endocervical lesion, especially a high grade CIN.

Adult↗

Cervical intraepithelial neoplasia in pregnant intravenous drug users infected with human immunodeficiency virus type 1.

OBJECTIVE: The purpose of this study was to evaluate the frequency and natural history of cervical intraepithelial neoplasia (CIN) during pregnancy in past or current intravenous drug users infected with human immunodeficiency virus type 1 (HIV-1). STUDY DESIGN: We prospectively evaluated 48 pregnant HIV-1 seropositive patients and 38 HIV seronegative controls. All the subjects were current or past intravenous drug users. Follow-up visits were carried out each trimester of pregnancy and 8-12 weeks post-partum with Papanicolau smears, colposcopic examinations and, when necessary, colposcopically directed cervical biopsies. RESULTS: Thirteen of 48 HIV-seropositive women (27.1%) and three of 38 HIV-seronegative controls (7.9%) (P = 0.027 by Fisher exact test) had biopsy-proven CIN at the beginning of pregnancy. High-grade CIN was detected in 10 cases (20.8%) and in two (5.3%) controls (P = 0.058 by Fisher exact test). None of the cervical squamous intraepithelial lesions progressed throughout pregnancy, in both cases and controls. Post-partum cold-knife cervical conization was performed on seven patients with CIN III and examination of the cone biopsy specimens demonstrated persistence of CIN III. CONCLUSIONS: HIV-infected intravenous drug users are at high risk of CIN during pregnancy, thus requiring adequate screening programs. Our preliminary data suggest that the progression rate of CIN during gestation is low in this high-risk group.

Adult↗

The utility of HPV DNA triage in the management of cytological AGC.

OBJECTIVE: Given the demonstrated utility of human papilloma virus DNA triage in the management of atypical squamous cells of undetermined significance, this study sought to evaluate the potential role of human papilloma virus DNA testing in the evaluation and management of cytological atypical glandular cells. STUDY DESIGN: Following institutional review board approval, 28 women presenting with cytological atypical glandular cells underwent repeat thin-prep cytology, Hybrid Capture 2 human papilloma virus DNA testing, colposcopic evaluation, Fisher electrosurgical conization, and endometrial sampling. Human papilloma virus test results in each patient were then correlated with histologic lesions, if present. RESULTS: Sixteen of the 28 study patients had pathologic lesions (11/28 high-grade squamous intraepithelial lesion, 3/28 low-grade squamous intraepithelial lesion, 1/28 adenocarcinoma in situ, 1/28 simple endometrial hyperplasia). Human papilloma virus DNA testing was available in 24 of 28 subjects (86%). The sensitivity of human papilloma virus positivity to predict the presence of cervical intraepithelial neoplasia was 100% (confidence interval 77% to 100%), specificity 64% (confidence interval 35% to 85%), positive predictive value 76%, and negative predictive value 100%. Women who tested human papilloma virus positive were 12 times more likely to have cervical intraepithelial neoplasia than women who were human papilloma virus negative (Fisher P<.001). Human papilloma virus positivity was not predictive of endometrial pathology; women who were human papilloma virus positive were less likely to have endometrial pathology than were women who were human papilloma virus negative (risk ratio 1.6, 95% confidence interval 0.01-1.7). CONCLUSION: Atypical glandular cells can represent a variety of lesions. The majority of the lesions will be squamous intraepithelial lesions of the cervix (50%), with high-grade squamous intraepithelial lesion present in 40% of subjects. Human papilloma virus DNA testing is a sensitive test for the presence of squamous intraepithelial lesion, with excellent negative predictive value for the absence of squamous intraepithelial lesion. The results of this study suggest human papilloma virus DNA testing might be an effective screening test in the initial evaluation and management of cytological atypical glandular cells.

Adult↗

Cervical neoplasia during pregnancy: diagnosis, management and prognosis.

Pregnancy represents an exceptional opportunity for the early diagnosis of cervical cancer since visual inspection, cytological examination and bimanual palpation are considered to be part of routine antenatal care. An abnormal cervical smear should generally be managed as in the non-pregnant state. However, colposcopy and biopsies are mainly intended to exclude invasive disease because a conservative approach is preferred in cases of pre-invasive disease. The only absolute indication for conization in pregnancy is to rule out (micro-)invasive disease or make the diagnosis of invasive carcinoma when such a diagnosis will alter the timing or mode of delivery. Overall, earlier stages of cervical cancer are encountered during pregnancy compared with the general population. Although stage of disease and gestational age will largely influence the timing of the interventions, treatment of invasive cervical cancer is similar to the non-pregnant state. In strongly desired pregnancies, the use of neo-adjuvant chemotherapy in order to obtain fetal maturity should be considered and discussed with the patient. Although good evidence supports short-term safety, long-term data regarding the in-utero exposure of cytotoxic drugs need to be consolidated. After stratifying for stage, the outcome is similar to the non-pregnant state.

Biopsy↗

Management of multicentric lesions of the lower genital tract.

OBJECTIVES: To report management and outcome of multicentric lesions of the lower genital tract. To define risk factors of recurrence. STUDY DESIGN: Retrospective review of multicentric dysplasias treated in our colposcopic clinic between 1996 and 2003. Multicentric dysplasias included CIN with VAIN and/or VIN. After primary treatment, follow-up was colposcopic, cytologic and virologic. RESULTS: Forty-four patients presented multicentric lesions out of 998 patients referred for CIN (4.4%). The average age was 36.8 years. Immunologic disorders were present in 20.4%. Ninety-one percent had cervicovaginal or cervicovulvar lesions, only 9% had three sites of genital dysplasia. 53.3% of lesions were concomitant. 79.5% of CIN were high grade, 62.5% of VAIN low grade and 62.5% of VIN high grade. Therapeutic modalities were as follows: conization for CIN (70.4%), CO2 laser for VAIN (33.3%) and surgery for VIN (41.7%). Forty patients were followed and had at least one post-treatment cytologic control; 55% of them had residual disease. Out of the 23 patients with at least two negative controls after treatment, 43.5% presented recurrence. Risk of recurrence was not statistically bound to such parameters as tabagism, immunologic disorder, high grade lesions, non-surgical treatment, and persistence of HPV infection after treatment. CONCLUSION: Multicentric dysplasias are associated with high rate of residual lesion and recurrence. Management of these lesions require long term follow-up.

Adolescent↗

In situ adenocarcinoma and squamous carcinoma of uterine cervix. Pathological and immunohistochemical analysis with cytokeratin 13.

OBJECTIVES: The aim of the study was the pathological and immunohistochemical analysis of cytokeratin 13 (CK13) in intraepithelial cervical tumors. STUDY DESIGN: We studied 415 in situ squamous carcinomas and 13 in situ mucinous cervical type adenocarcinomas of the uterine cervix. All patients underwent laser cervical conization and had a follow-up ranging 12-135 months. RESULTS: 3% of the squamous carcinoma patients recurred during the follow-up period, while the percentage of recurrence of in situ adenocarcinoma patients was 7.6%. We observed positive surgical edges in 46.1% of glandular tumors, and in 5% of squamous tumors. The percentage of recurrence was high among the cases with positive borders independently from their histopathologic type (14.3% in the squamous carcinomas versus 50% in the adenocarcinomas), compared to cases with negative edges (2.3% in the squamous carcinomas versus 0% in the adenocarcinomas). We observed CK13 positive staining in cervical squamous tumors and in mucinous cervical type adenocarcinomas, while there was no positive staining in non-neoplastic cervical glandular elements. CONCLUSION: CK13 positive immunostaining among in situ squamous and in situ mucinous cervical type adenocarcinoma cases adds additional evidence to data supporting a common origin of the two lesions.

Adenocarcinoma, Mucinous↗

[Colposcopy: the value of HPV testing in clinical practice].

The indications for colposcopy have changed recently because of the new Bethesda terminology, the introduction of HPV testing in clinical practice, and the latest consensus guidelines on management of patients with an abnormal cervical cytological test. Colposcopy remains the reference technique to assess patients with abnormal cytological test results, especially those with ASC-H, LSIL, HSIL, and AGC. In women with an ASC-US result, colposcopic examination of only those who test positive for high-risk HPV increases the specificity of the technique. When liquid-based cytology is used, HPV DNA testing is the preferred approach in these women. In primary screening using combined cytology and HPV DNA testing in women over the age of 30, colposcopy is indicated in patients with normal cytology and two HR HPV DNA positive tests performed at a nine month interval. For the follow up of untreated patients with ASC-US/LSIL and CIN I, colposcopy carried out at one year after a single HR HPV DNA positive test is as sensitive as colposcopy after two or three abnormal cytology tests. After excision or conization in patients with high-grade CIN, colposcopy after a single HR HPV DNA positive test is as sensitive as cytology testing and colposcopy at six months. Therapeutic decisions must not be based solely on the results of HPV DNA testing except in specific cases.

Adult↗

DNA recovery from Hybrid Capture II samples stored in specimen transport medium with denaturing reagent, for the detection of human papillomavirus by PCR.

The purpose of this study was to examine the quality of DNA recovered for human papillomavirus (HPV) detection using polymerase chain reaction (PCR) in samples that had been collected for Hybrid Capture II (HCII), testing and stored in specimen transport medium (STM) with denaturing reagent at -20 degrees C for 18 months. Endocervical tissue was collected from 92 women for HCII assay using the Digene STM, and a Papanicolaou smear was carried out in all cases. Seven women had normal colposcopy results. The remaining 85 patients underwent colposcopy-directed biopsy or cervical conization for histological investigation. Of the 92 samples tested, 84 were HCII-positive and 8 were negative. Quality control for amplification was carried out with beta-globin primers G73 and G74, and HPV was tested using PGMY09 and PGMY11. DNA was recovered from 83 of the 92 samples (90%). Among the 84 samples HCII-positive initially, HPV was detected by PCR in 56 (67%). PCR did not detect HPV DNA in the eight samples that were HCII-negative, although five of them were positive for beta-globin. This paper describes a novel DNA extraction technique that may permit exact HPV typing in stored samples collected originally for HCII testing, making it possible to carry out retrospective investigations to retrieve information on specific HPV types in large HCII series.

Cervix Uteri↗

Clinicopathologic features of villoglandular papillary adenocarcinoma of the uterine cervix.

OBJECTIVES: The objectives of this study are to analyze the clinicopathologic features of villoglandular papillary adenocarcinoma (VGPA) of the uterine cervix and to discuss the management thereof. We examined 13 patients with VGPA. METHODS: Clinical profiles, including patient age, clinical stage, surgical procedure, and outcome, were recorded. Pathologically, macroscopic features, polypoid tumor size, horizontal spread and depth of endophytic tumor, nuclear atypicality, mitotic count, lymph capillary space invasion, and lymph node metastasis were investigated. RESULTS: The median age of 13 patients was 45 years, with 10 and 3 patients staged Ib and IIb, respectively. All the patients underwent hysterectomy and pelvic lymphadenectomy and are alive without recurrence. Macroscopically, the tumor showed a polypoid pattern in 8 patients and a flat pattern in the remaining 5 patients. Polypoid tumor size ranged between 4 x 2 and 20 x 15 mm. Horizontal spread and depth of endophytic tumor ranged between 8 and 30 mm and between 3 and 11 mm, respectively. The tumor in all the 13 patients except 1 showed moderate nuclear atypicality. The mean mitotic count was 43/10 high-power fields. Lymph capillary space invasion was present in 4 patients, 1 of whom also had bulky lymph node metastases. CONCLUSIONS: VGPA has been reported to rarely involve lymph capillary space invasion or lymph node metastasis, leading some surgeons to conduct less radical surgeries such as conization. Nevertheless, we encountered patients with these pathologic risk factors. Much caution should be exercised in managing patients with VGPA.

Adenocarcinoma, Papillary↗

Is electrosurgical loop excision with negative margins sufficient treatment for cervical ACIS?

OBJECTIVES: A recent clinical practice guideline supports the conservative management of adenocarcinoma in situ of the cervix (ACIS) diagnosed or suspected before treatment. However, patients may be diagnosed with unsuspected ACIS found in a loop electrosurgical excisional procedure (LEEP) specimen done for squamous dysplasia. To assess the outcome in this group of patients, we retrospectively analyzed all our cases of cervical ACIS and endocervical glandular dysplasia (EGD) to determine if LEEP was sufficient treatment. STUDY METHOD: A retrospective review of all patients treated for ACIS-EGD from 1990 to 2003 at Kingston General Hospital Colposcopy Clinic was undertaken. Sixty patients were identified. RESULTS: Of the 60 patients, 31 were diagnosed with ACIS-EGD only from the LEEP specimen. Twenty-two patients had ACIS and nine had EGD. Seven had further surgical procedures (five hysterectomies and two cold knife cone biopsies CKC) for positive LEEP margins. All seven of these specimens were disease free. Three of 31 LEEP patients were not compliant with colposcopic follow up. The remaining 28 patients were followed in our colposcopy clinic or by their family doctor for 6-107 months (median: 42; mean: 51) and have remained free of persistent or recurrent ACIS-EGD. CONCLUSION: Colposcopic follow-up with cytology and endocervical curettage (ECC) is acceptable for patients with ACIS-EGD found unexpectantly in LEEP specimens with negative margins. This is an alternative to proceeding to repeat LEEP, cold-knife conization, or simple hysterectomy, especially in patients desiring conservative management or preservation of fertility. Patients with positive margins, however, require further histologic evaluation.

Adenocarcinoma↗

Immune responses to human papillomavirus in genital tract of women with cervical cancer.

OBJECTIVES: To address a question whether immune responses to HPV infection play a role in control of cervical cancer, we analyzed systemic and mucosal immune responses to HPV in women who underwent radical hysterectomy for cervical cancer (HCC) or loop conization due to cervical dysplasia (LOOP), or had hysterectomy for other reasons (HNN). METHODS: HPV-specific antibodies in sera and vaginal washes were determined by ELISA using recombinant HPV 16 E7 oncoprotein. Cytokines in vaginal washes were assayed by Linco cytokine multiplex method using Luminex technology. Differential gene expression profiling in cervical tumor was determined by microarray analysis and Real-time RT-PCR. RESULTS: While levels of HPV-16 E7-specific IgG in vaginal wash were significantly higher in women undergoing HCC and HNN, the levels of the HPV-16 E7-specific IgA in vaginal wash of women with cervical cancer and cervical dysplasia were lower as compared to patients in HNN. Proinflammatory cytokines, such as IL-6 and IL-8, were dominant in vaginal washes of all subjects studied. However, no pattern of Th1-type and Th2-type cytokine induction was observed as demonstrated by protein analysis as well as differential gene expression profiling in cervical tumor. CONCLUSIONS: These results suggest a selective down-regulation of local HPV-specific IgA responses in women with cervical cancer.

Adult↗

Laparoscopic modified radical hysterectomy: a strategy for a clinical dilemma.

OBJECTIVE: To investigate the role of laparoscopic modified radical (type 2) hysterectomy when cervical cancer cannot be excluded or documented preoperatively. METHODS: Between 1996 and 2004, 50 patients with cervical intraepithelial neoplasia (CIN III) or adenocarcinoma in situ (AIS) involvement of cone endocervical margins and/or endocervical curettings, who were not candidates for observation or repeat conization, underwent laparoscopy to perform a modified radical hysterectomy. RESULTS: Forty-nine (98.0%) modified radical hysterectomies were completed laparoscopically and one (2.0%) patient required a laparotomy. Of the overall group, 35 (70.0%) had residual pathology; 26 (52.0%) were precancerous lesions, and 9 (18.0%) had invasive disease (5 adenocarcinomas, 3 squamous lesions, and 1 adenosquamous carcinoma). Of the nine with cancer, one had stage IA1 disease, three had stage IA2 disease, and five had stage IB1 disease. Five (55.6%) invasive lesions were diagnosed intraoperatively (frozen section), and a laparoscopic pelvic and lower aortic lymph node dissection was performed. The median operative time was 96 min (range 58-185), blood loss 100 ml (50-450), and postoperative hospital stay 2.5 days (range 1-14). There were no incidences of prolonged urinary retention fistulas, or other serious complications. All patients with cancer remain disease-free (median follow-up 44.2 months, range 1-88.7 months). CONCLUSIONS: Laparoscopic modified radical hysterectomy is a treatment option for patients for whom cervical cancer cannot be definitively excluded, and can be completed with acceptable operative time, blood loss, and hospitalization.

Adenocarcinoma↗

Widespread lymph node metastases in a young woman with FIGO stage IA1 squamous cervical cancer.

BACKGROUND: Lymphatic and hematologic metastases are rare in microinvasive cervical cancers (FIGO stage IA1), supporting a role for conservative treatment. Cervical conization followed by prolonged surveillance is an accepted treatment in patients with low-risk features and negative surgical margins. This option is particularly appealing for younger or nulliparous patients, in whom fertility may be highly desired. CASE: We report a case of a 22-year-old, HIV-negative female with stage IA1 squamous cell cervical carcinoma who was found to have bilateral lymph node metastases in both pelvic and para-aortic distributions after electing to undergo hysterectomy. CONCLUSION: Clinicians treating patients with microinvasive cervical cancer conservatively must be aware of the possibility of lymph node involvement and should consider radiological imaging to look for metastatic disease.

Adult↗

Langerhans' cells and smoking in intraepithelial neoplasia of the cervix.

OBJECTIVE: To compare the intraepithelial population of Langerhans' cells (LC) in normal cervix epithelium adjacent to cervical intraepithelial neoplasia grade 3 (CIN 3) and correlate to smoking habit. METHODS: Cases in this study included conization specimens from 48 women affected by CIN 3. The LC count was performed in areas without histopathologic alteration adjacent to CIN 3. The control group is compound by normal cervix from 46 hysterectomy specimens. The identification of LC was done by immunohistochemical study demonstrating immunoreactivity to S-100 protein. The number of intraepithelial LC was determined using 400x magnification light microscope in 10 high-power fields, and results were expressed in number of cells per square millimeter (LC/mm(2)). RESULTS: In the control group, there was lower number of Langerhans' cells in smokers than in non-smokers (P = 0.045). There was lower number of Langerhans' cells in normal areas adjacent to CIN 3 than in normal cervix control group (P = 0.004). There was no significant difference in the number of Langerhans' cells in normal areas of the cervix with CIN 3 between smokers and non-smokers (P = 0.991). The number of cigarettes consumed daily, time of consume, total number of cigarettes consumed showed a reduced LC count, yet was not statistically significant. CONCLUSIONS: It was revealed that smoking reduces the number of intraepithelial Langerhans' cells in the uterine cervix. In women with CIN 3, the LC count was lower, despite the habit of smoking.

Adult↗