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Localization of human papillomavirus type 16 DNA using the polymerase chain reaction in the cervix uteri of women with cervical intraepithelial neoplasia.

The localization of human papillomavirus type 16 (HPV-16) DNA throughout the cervix uteri of women with cervical intraepithelial neoplasia (CIN) was studied by utilizing the polymerase chain reaction technique directly on histologically defined sections of paraffin-embedded cervical tissue obtained by conizations. HPV-16 DNA was detected only in the sections that contained CIN lesions and/or koilocytes. No HPV-16 DNA was detected in sections that contained only normal epithelium. This is in accordance with HPV-16 playing a role in the development of CIN lesions.

Cervix Uteri↗

The risk of nodal metastasis in early adenocarcinoma of the uterine cervix.

A functional and widely accepted definition of microinvasive cervical adenocarcinoma remains elusive. The purpose of this study was to determine at which depth of invasion the likelihood of lymph node metastasis or disease recurrence was so small that conservative surgery could be considered appropriate. Charts of patients with adenocarcinoma of the cervix (ACC) who underwent radical hysterectomy and pelvic lymphadenectomy (n = 98) at Indiana University Medical Center from 1987 to 1998 were retrospectively reviewed. Patients with stage IA1-IB1 lesions were included in the study. Patients treated with preoperative radiotherapy were excluded. Pathologic parameters evaluated included histologic type, depth of stromal invasion (DOI), and the presence of lymphatic vascular space invasion, or lymph node metastases. The patient median age was 39 years (20-65). The median time of follow-up was 30 months (4-124). Lymph node metastases were found in ten patients and 11 developed recurrences. The precise DOI could be measured in 84 patients. Of the 48 patients with cancers with a DOI </= 5 mm, none had involved parametria or nodes; whereas eight of the 36 with a DOI > 5 mm had nodal metastases (P = 0.00069). None of these 48 patients with a tumor DOI </= 5 mm developed a recurrence whereas six of the 36 patients with a tumor DOI > 5 mm developed recurrent disease (P = 0.0048). The risk of nodal metastases and recurrence is so low in patients with ACC and DOI </= 5 mm that for patients with such depth documented on conization with negative margins pelvic lymphadenectomy may be omitted.

Adenocarcinoma↗

Cytological changes associated with tubo-endometrioid metaplasia of the uterine cervix.

Two women who had undergone previous cervical surgery for the treatment of glandular intraepithelial neoplasia (GIN) and cervical intraepithelial neoplasia (CIN), were found to have severely dyskaryotic cells of glandular and metaplastic type in follow-up cervical smears. A third patient was found to have similar abnormal cells in a routine screening smear. All of the patients were subjected to either hysterectomy or cervical conization and in all cases histological examination showed tubo-endometrioid glands in the endocervix, well away from the uterine isthmus, with no associated endometrial stromal tissue. All of the cervical smears were reviewed and cytological features that facilitate the distinction between tubo-endometrioid metaplasia and squamous or glandular dyskaryosis were identified. These features include the smaller size of affected cells, more marked nuclear hyperchromasia, inconspicuous nucleoli, the formation of glandular structures, the lack of discrete squamous dyskaryosis and the absence of the typical 'feathering' noted with GIN. The possibility of tubo-endometrioid metaplasia should be considered when atypical glandular or metaplastic cells are noted in cervical smears, particularly, but not exclusively, in women who have been treated for CIN or GIN. In the presence of these changes clinicians should rebiopsy the cervix before embarking on further unnecessary surgery which may adversely affect fertility and pregnancy, particularly in younger patients.

Adult↗

Atypical glandular cells: criteria to discriminate benign from neoplastic lesions and squamous from glandular neoplasia.

OBJECTIVE: To evaluate the presence of some criteria in cervical smears with atypical glandular cells and their correlation with histological patterns to identify pre-neoplastic and neoplastic lesions. METHODS: Seventy-three women referred with an atypical glandular cell smear, who had undergone conization or hysterectomy, were included in this study. Referral Pap smears were reviewed using the set of 27 cyto-morphological criteria that was correlated with the histological diagnosis. RESULTS: Histological results showed intraepithelial or invasive neoplasia in 35 (48%) cases and benign lesions in 38 (52%) cases. After logistic regression and decision tree analysis an increased nuclear/cytoplasmic ratio and the presence of dyskeratotic cells were strongly associated with intraepithelial or invasive neoplasia and the differential cyto-morphological criteria for glandular lesions were decreased cytoplasm, irregular nuclear membranes and the presence of nucleoli. CONCLUSION: The analysis of individual cyto-morphological criteria can better predict intraepithelial or invasive neoplasia and differentiate glandular from squamous lesions.

Adult↗

Colposcopic evaluation of pregnant patients with abnormal cervical smears.

Colposcopic examination and biopsy were used to assess 123 pregnant patients presenting with abnormal cervical smears. Eighty-seven per cent were 30 years of age or less and 95 (77 per cent) had had one or no previous children. Two patients were found to have microinvasive carcinoma and, in an additional 95 patients, either severe dysplasia or carcinoma in situ was present. Fifty-five patients (45 per cent) had subsequent conization or hysterectomy and in no instance was the histological diagnosis more serious than that anticipated from the colposcopic evaluation. Only three patients (1-6 per cent) had a cone biopsy during pregnancy; only one minor complication occurred. Colposcopic examination is the choice method of evaluating patients with abnormal cervical smears in pregnancy.

Adolescent↗

A study of cryosurgery for dysplasia and carcinoma in situ of the uterine cervix.

We studied 22 patients with a histopathological diagnosis of severe dysplasia and 89 patients with a diagnosis of carcinoma in situ of the uterine cervix. Twenty patients (18 per cent) had negative cervical smears for four to six years after diagnosis by biopsy of the cervix. The 91 patients with persistently abnormal smears were treated by cryosurgery, using a double freeze technique with nitrous oxide. Seventy-four (86 per cent) had persistently normal cervical smears after one treatment and eight after a second treatment while nine patients required conization for recurrently abnormal cervical smears. The duration of follow-up was five or six years in 48 patients (53 per cent). In a subsidiary study, material was obtained for histological examination from 72 patients with normal smears by endocervical curettage and multiple biopsies of the cervix; 8 showed slight atypia and 2 had residual carcinoma in situ.

Adolescent↗

Outcome of third trimester pregnancies after cryotherapy of the uterine cervix.

A retrospective study was undertaken to assess the effect of cryotherapy of the uterine cervix on the outcome of third trimester pregnancies. It was concluded that cryosurgery of the cervix had no effect on the onset or progress of labour, or on the infant, an important advantage compared with cold-knife conization as a therapy for young women with cervical intraepithelial neoplasia.

Adolescent↗

Factors associated with progression of cervical human papillomavirus (HPV) infections into carcinoma in situ during a long-term prospective follow-up.

In the course of a prospective study of 508 women with papillomavirus (HPV) lesions of the uterine cervix, 66 lesions that progressed into carcinoma in situ (CIS) were identified and treated by conization during a mean follow-up period of 35 months. The lesions were investigated with light microscopy and with in-situ DNA hybridization using 35S-labelled probes for HPV 6, 11, 16, 18, 31 and 33. After radical cone treatment, 11 of the 66 women (16.7%) have presented with a recurrent HPV infection. The recurrence rate increased with the duration of the follow-up period from less than 10% at the mean follow-up of 25 months to 16.7% at the most recent follow-up at 35 months. Most of these 66 HPV lesions (89%) presented with concomitant CIN in the first punch biopsy, but it is noteworthy that the other 11% presented without concomitant CIN. HPV DNA of at least one of the six types examined was found in 73% of the first biopsies and it is noteworthy that the so-called 'low-risk' types, HPV 6 and 11, were found as frequently as the 'high-risk' types, HPV 16 and 18 (18% and 17%, respectively). This would suggest a similarity in the biological behaviour of these two HPV groups. Although the concept of the 'high-risk' and 'low-risk' HPV types may remain at least partially valid, it is imperative to realize that infection by HPV 6 and 11 by no means excludes the possibility for clinical progression into CIS and eventually to an invasive carcinoma.

Adolescent↗

Large loop excision of the transformation zone (LLETZ). A new method of management for women with cervical intraepithelial neoplasia.

The paper describes the technique of 'LLETZ' (large loop excision of the transformation zone), a new method of management for women with an abnormal cervical smear which offers the advantages of conization with those of local destruction. A large loop of thin wire forms a diathermy electrode that allows deep excision of the transformation zone with minimal tissue damage. The tissue removed can be examined histologically. The technique was used to investigate and treat 111 women with abnormal smears referred to the Bristol Royal Infirmary during 1986. Microinvasive disease was revealed in one woman where it was not suspected by cytology or colposcopic examination. Of 102 women followed up for at least 1 year by cytology, colposcopy and, where appropriate, histology, two women were found to have residual/recurrent cervical intraepithelial neoplasia.

Cervix Uteri↗

Unsatisfactory colposcopy and the response to orally administered oestrogen: a randomized double blind placebo controlled trial.

Thirty-six women with dyskaryotic cervical smears and unsatisfactory colposcopy were randomly allocated to receive either 30 micrograms ethinyl oestradiol or placebo daily by mouth for 10 days. Thirty-four women were available for review (17 women in each of the two groups), full colposcopic inspection of the transformation zone was possible in a significantly greater proportion of the oestrogen treated group (70% versus 23%, P less than 0.01). As most diagnostic conizations are currently performed on the basis of unsatisfactory colposcopy, the use of oestrogen medication followed by colposcopic reassessment should permit a reduction in the number of patients subject to operation.

Adult↗

A clinicopathological study of adenocarcinoma in situ of the cervix. The influence of cervical HPV infection and other factors, and the role of conservative surgery.

Adenocarcinoma in situ (ACIS) of the uterine cervix is an increasingly recognized disease. Thirty-seven cases were reviewed to determine the effect of HPV, marital status, parity, smoking habit and age on the topography and behaviour of this lesion. Using a commercial probe, 25% of 28 lesions tested were positive for HPV 16/18. The presence of HPV and a history of smoking appeared to exert no significant influence upon the topography and behaviour of ACIS. Nulliparity and a history of never being married was associated with a significant reduction in the incidence of coexisting CIN lesions. Age less than 36 years was associated with a significant reduction in the proximal linear extent of ACIS. While hysterectomy is probably the definitive treatment for ACIS of the cervix, there is an important place for conservative management by conization alone. Patients younger than 36 years are most likely to be desirous of retained fertility and appear to have the lesions most amenable to conservative surgery.

Adenocarcinoma↗

Comparison of light microscopy, in situ hybridization and polymerase chain reaction for detection of human papillomavirus in histological tissue of cervical intraepithelial neoplasia.

The aims of the study were to estimate the prevalence of HPV infection in patients treated for high grade lesions of the cervix uteri (HG CIN), and to evaluate the validity of the histological criteria used for detection of HPV infection. The study comprised 203 women treated for HG CIN by laser conization. Forty-three preoperative biopsies and 160 cone specimens were examined for HPV infection using light microscopy (LM), in situ hybridization (ISH), and polymerase chain reaction (PCR). ISH was performed using commercial biotinylated probes for HPV types 6/11, 16/18, and 31/33/35 (Vira-Type In Situ Kits, Digene Diagnostics, Silver Spring, MD). HPV-PCR was performed with the L1 consensus primers Gp5+/6+. The prevalence of HPV detected by LM was 70%; by ISH 48% and by PCR 83%. Using PCR as the gold standard, LM had a sensitivity of 0.71 and specificity of 0.41. The corresponding results for ISH were 0.51 and 0.65, respectively. The positive predictive value for both tests reached over 80%, but the negative predictive value was less than 25%. This study demonstrates that morphology is an unspecific method of identifying HPV infections. LM identification of HPV infections has no clinical implications. Our analyses comparing test performances of LM, ISH and PCR show that PCR is the superior method.

Adult↗

Comparison between the Hybrid Capture II test and a PCR-based human papillomavirus detection method for diagnosis and posttreatment follow-up of cervical intraepithelial neoplasia.

Human papillomavirus (HPV) infection is the major cause of cervical cancer and its precursor, cervical intraepithelial neoplasia (CIN), and HPV testing has therefore been proposed for improved triaging and follow-up of women treated for CIN. We compared two common HPV DNA detection tests (Hybrid Capture II [HCII] and PCR-enzyme immunosorbent assay (EIA) using the primers GP5+/GP6+ followed by HPV typing with reverse dot blot hybridization) for sensitivity and specificity for detection of CIN and of CIN recurrence after treatment. Two hundred and thirty-nine women referred to the Department of Obstetrics and Gynaecology in Västerås, Sweden, were enrolled because of atypical Pap smears; 177 of these were later treated for dysplasia by conization or loop diathermy. Samples for HPV DNA testing were taken before and 4 to 6 months after treatment. There was substantial agreement between the HCII and PCR-EIA (kappa, 0.70 before treatment and 0.72 after treatment). The sensitivity for histopathologically confirmed CIN III was 100.0% for PCR-EIA and 95.6% for HCII. For patients with CIN II or worse (CIN II+), the sensitivities were 92.9% (PCR-EIA) and 91.8% (HCII). The specificities for CIN II+ in the pretreatment setting were 30.4% for PCR-EIA and 24.1% for HCII. After treatment, the sensitivities for CIN III in cytology were 100.0% by both methods, and for CIN II+, sensitivities were 80.0% by both methods. The specificities for CIN II+ in the posttreatment setting were 83.5% for PCR and 85.4% for HCII. In conclusion, the sensitivities of both PCR-EIA and HCII are high and almost equal, suggesting that both methods are suitable as tools for detection and posttreatment follow-up of CIN II-III.

DNA, Viral↗

-Coexistence of neural proliferations with early epithelial neoplasias and benign ectopias of the uterine cervix-.

OBJECTIVE: The study wanted to test the hypothesis that stromal systems can influence the development of the epithelium. METHOD: The stroma of specimens obtained by conizations of the cervix was histologically investigated. RESULTS: Neural proliferations such as neuromas, neurofibromas and vascular neurofibromatoses were found. They were common in the presence of epithelial lesions. CONCLUSION: Thus, the frequency of neural proliferations correlated with the nature of the epithelial abnormality. This association argues against the conventional concept that the growth of cervical intraepithelial neoplasias is absolutely autonomous.

Biopsy↗

CO2 laser vaporization in the treatment of cervical human papillomavirus infection in women with abnormal Papanicolaou smears.

In a randomized study, we have evaluated the treatment of cervical human papillomavirus (HPV) lesions by CO2 laser vaporization. Fifty patients with abnormal Papanicolaou smears and histological evidence of cervical HPV infection associated or not with cervical intraepithelial neoplasia (CIN) grade I were randomized to either a treatment or a control group. The cervical swabs were obtained every 3 months in both groups and examined for HPV type 16 DNA by the polymerase chain reaction. After a follow-up period of 12 months no significant differences were found between the laser treatment and the control groups in relation to the disappearance of the abnormal Papanicolaou smear. Two patients in the treatment group and 3 in the control group had a conization because of development of CIN I or aggravation of the concomitant CIN found at the initial visit. The percentage of women who demonstrated HPV in their cervical smears at 12 months' follow-up was identical in the two groups, supporting the hypothesis that HPV is a persistent infection during which the virus is widespread in the vaginal epithelium.

Biopsy↗

Colposcopy, cervicography, speculoscopy and endoscopy. International Academy of Cytology Task Force summary. Diagnostic Cytology Towards the 21st Century: An International Expert Conference and Tutorial.

ISSUES: The colposcope was developed in 1925 and is well established in clinical gynecologic practice for defining and delineating cytologically detected lesions mainly of the cervix but also the vagina and vulva. Additionally, various endoscopic procedures in gastroenterology, pulmonary and urologic lesions enhance the cytologic detection and histologic verification of precancerous and cancerous lesions. The cost-effectiveness of all these devices and their applicability, particularly in countries with a limited health budget, is a major issue. This task force considered aspects of the present state of the art and the challenges in the 21st century. CONSENSUS POSITION: Automated cytology can interface with colposcopic examination in a number of significant ways. Automated cytologic analysis of conventional cervical smears can potentially direct colposcopic examination by predicting the nature of a lesion, assist in determining which patients should receive colposcopy and, in some settings, thereby reduce the number of colposcopies. Potentially, various combinations of automated cytology and colposcopy may be used to generate screening protocols that might result in more effective and inexpensive screening. The role of cervicography, or high-resolution cervical photography, as a screening device remains to be defined. Sensitivity for high grade lesions is generally no greater than that in cytology, and specificity appears lower. The interpretation of cervical photographs in triage of mildly abnormal cytology may prove to be useful in countries with established cytology programs. In areas of the world where cytology screening programs are not in place, the interpretation of cervical photographs may have its most dramatic effect. Cost-effectiveness analyses are needed. There are, at present, insufficient data for the evaluation of speculoscopy, a procedure using chemiluminescent illumination of the cervix for visualization of acetowhite areas. Basic training in colposcopy should be integrated into the residency programs of obstetrics and gynecology. Criteria for the adequate training of colposcopists should be developed. Continuing education programs in colposcopy should be developed when they are not already in existence. The cost-effectiveness of integrating colposcopy as a primary screening technique should be evaluated. Following a high-grade squamous intraepithelial lesion (HSIL) cytology result, colposcopically directed punch biopsy should be taken with or without endocervical curettage. This generally should precede the loop electrosurgical excision procedure (LEEP); however, in certain circumstances direct LEEP may be indicated. LEEP under colposcopic vision is an efficient way to treat an HSIL lesion of the cervix because the histologic extent and margins can be determined, unlike with laser surgery or cryosurgery. It is also more cost-effective than cold knife conization because general anesthesia and an operating room are unnecessary. Following LEEP, the endocervical canal should be examined colposcopically for any evidence of involvement. Lesions in the endocervix can then be removed with a different-shaped loop. Further research into Raman spectroscopy as a diagnostic aid in cervical pathology is needed, as is the use of micrococolpohysteroscopy for in vivo cytologic analyses, especially of the endocervical canal and transformation zone. Hysteroscopy is the most direct method for the diagnosis and treatment of intrauterine diseases. Hysteroscopic endometrial biopsy is more accurate than conventional biopsy methods. Cervical invasion of endometrial cancer can be detected by hysteroscopy. The depth of invasion, however, is more accurately determined by magnetic resonance imaging or computed tomography. ONGOING ISSUES: Many topics for ongoing research and/or implementation are mentioned under "Consensus Position," above. (ABSTRACT TRUNCATED)

Automation↗

Quality control of the autopap screening system employed as a primary screening device: rapid review of smears coded as no further review.

AIMS AND BACKGROUND: Automated reading of smears is increasingly used in cervical screening, and quality control procedures to check its performance are required. The aim of the present study was to evaluate the usefulness of rapid review of all smears coded as "no further review" (NFR) by the AutoPap system as a quality control procedure. METHODS: From 2002-2005, 153,269 smears were processed by AutoPap at the Centro per lo Studio e la Prevenzione Oncologica of Florence, Italy, and 24,503 (15.9%) were coded as NFR. All NFR smears underwent immediate rapid review by expert readers. RESULTS: Sixty-five of 118 NFR cases reviewed as ASCUS-R complied to recommended 6 months cytology, and 25 of 30 NFR cases reviewed as ASCUS-SIL or more severe accepted immediate colposcopy. As a result of such assessment, one single case of microinvasive carcinoma was detected in a woman aged 34 years: NFR smear had been reviewed as AGCUS, was followed by repeat AGCUS cytology and repeat negative colposcopy, and finally underwent conization. CONCLUSIONS: NFR report at AutoPap was associated with an extremely high negative predictive value, which might suggest using AutoPap as a primary screening tool, with NFR report prompting a "return to screening" recommendation. Rapid review of NFR smears is not recommended as a quality control measure for the negligible yield of high-grade lesions detected.

Adult↗

Local impairment of immunoreactivity in HIV-infected women with HPV-related squamous intraepithelial lesions of the cervix.

AIMS AND BACKGROUND: The aim of this study was to compare the local immune response in two groups of patients with high-grade cervical intraepithelial squamous lesions (SIL): one with HIV infection and the other with HPV infection alone. MATERIALS AND METHODS: 16 conization specimens (8 from HIV-infected and 8 from non-HIV-infected patients) of HPV-related, high-grade SIL were selected. The specimens from non-HIV patients were considered as controls. The total number of Langerhans cells, CD4 and CD8 cells present in 10 field areas (3.120 mm2) was recorded in each case. In HIV patients CD4 and CD8 peripheral counts were performed immediately before surgery. RESULTS: The CD4/CD8 ratio never exceeded 0.71, whereas the lowest ratio in controls was 0.81: this difference was statistically significant (P = 0.0009). The mean number of Langerhans cells was markedly reduced in the high-grade SILs in the HIV patients in comparison with controls (P = 0.001). The number of CD4 cells and the CD4/CD8 ratio correlated with the peripheral CD4 count (P = 0.001 and 0.02). CONCLUSIONS: In our study a marked local impairment of cervical immunoreactivity was observed, which may play a major role in the progression of these lesions in HIV-infected women.

Adult↗