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Conservative management of cervical intraepithelial neoplasia.

A brief review of cervical intraepithelial neoplasia has been presented. Attempts have been made to identify the high-risk patient, and etiologic considerations have been detailed. The conservative management of cervical intraepithelial neoplasia is available and applicable to many patients. Regardless of the definitive therapy used in CIN, it is absolutely mandatory that proper pretreatment evaluation be performed. This includes cytology, colposcopy, colposcopy-directed biopsies, and clinical examination to rule out invasive cancer. If this can be done according to the stated criteria, one may proceed with outpatient treatment. If performed accurately, such treatment can be very effective, saving the patient a major surgical procedure. This is of tremendous benefit to the patient in time and money saved, as well as to the saving of hospital bed space and operating-room time. For the young patient who has not yet completed her family or the patient who is pregnant, outpatient evaluation is probably the optimal method. If the techniques are unavailable or the physician managing the patient does not have the expertise to perform them, standard management by means of conization, which historically has been used in this disease, should continue to be used. The consequence of inadequate outpatient management of CIN can be catastrophic. If the procedures are properly followed, then the patient with CIN can be managed safely and effectively.

Adolescent↗

Papillary squamous cell carcinoma of the uterine cervix: a clinicopathologic study of nine cases.

Papillary squamous cell carcinoma (PSCC) of the uterine cervix is an infrequently described subtype of cervical malignancy. Nine cases of PSCC encountered at the University of Virginia Medical Center are reviewed. The clinical course of these patients, including a propensity for late metastases and recurrences, appears distinctive. The papillae of PSCC are lined by dysplastic cells, unlike verrucous carcinoma. PSCC may exist in an in situ state, and demonstration of invasion, when present, requires deep biopsies or cervical conization. Therapy for PSCC appears to be the same as for ordinary squamous cell carcinoma of equivalent clinical stage.

Adult↗

Adenocarcinoma in situ of the cervix. Clinicopathologic observations of 11 cases.

Adenocarcinomas in situ (AIS) of the cervix represent less than 1% of all primary adenocarcinomas of the cervix; 11 cases from the Magee-Women's Hospital (1969-1984) are described. The patients' ages ranged from 25 to 81 years (average 48.5 years). One patient was nulliparous and the others had one to five children. The most common presenting symptom was postmenopausal or other abnormal vaginal bleeding. The AIS were diagnosed as follows: a positive, suspicious, or dysplastic Pap smear in seven cases; in three, the AIS was an incidental finding during a hysterectomy; and one case was diagnosed in an endocervical curettage. Most of the AIS were in or near the transformation zone, having two distinct histologic glandular patterns with tall columnar or large ballooned cells (Types I and II respectively). In three cases an associated in situ squamous cell carcinoma or severe dysplasia of the cervix was seen. Two patients had associated well-differentiated adenocarcinoma of the endometrium and a third had endometrial hyperplasia. One lesion stained strongly positive for carcinoembryonic antigen and all others were negative. Eight patients underwent total abdominal hysterectomy and bilateral salpingo-oopherectomy (TAH-BSO), two had total abdominal hysterectomy (one with salpingo-oophorectomy), and one 25-year-old was treated by deep conization only. All patients, except one who died with associated adenocarcinoma of the cecum, were alive 8 to 127 months after treatment.

Adenocarcinoma↗

Human papillomavirus DNA in adenocarcinoma in situ, microinvasive adenocarcinoma of the uterine cervix, and coexisting cervical squamous intraepithelial neoplasia.

Previously, human papillomavirus (HPV) DNA, mainly HPV-18 DNA, was detected in more than 40% (17/40 cases) of invasive adenocarcinoma of the uterine cervix in our laboratory. In order to identify HPV DNA in the precursor lesions of adenocarcinoma of the cervix, 11 cases of adenocarcinoma in situ containing microinvasive adenocarcinoma and 10 cases of adenocarcinoma in situ were studied for the presence of HPV DNA by in situ hybridization using highly sensitive 3H-labeled HPV-16 and HPV-18 DNA probes. HPV types present in cervical squamous intraepithelial neoplasia (CIN) coexisting with adenocarcinoma in situ and microinvasive adenocarcinoma were also studied. Apart from the coexisting CIN II-III with glandular neoplasms, 48 cases of CIN III (severe dysplasia and squamous carcinoma in situ) removed by conization or hysterectomy and known to be free of adenocarcinoma were used for comparison. HPV DNA was detected in 64% of microinvasive adenocarcinoma, 70% of adenocarcinoma in situ, and 63% of the control CIN III. HPV-18 DNA was the preponderant type of HPV DNA found in adenocarcinoma in situ and microinvasive adenocarcinoma. All cases of HPV DNA-positive microinvasive adenocarcinoma contained the same type of HPV DNA as the lesions of coexisting adenocarcinoma in situ. CIN coexisting with microinvasive adenocarcinoma or adenocarcinoma in situ contained the same type of HPV as identified in the glandular lesions, whereas all of the HPV DNA-positive control CIN III cases contained HPV-16 DNA. These results suggest that adenocarcinoma in situ is a precursor lesion of adenocarcinoma of the cervix that contains HPV DNA, and that CIN coexisting with adenocarcinoma may be a result of a metaplastic process of adenocarcinoma or of bidirectional differentiation of the affected reserve cells.

Adenocarcinoma↗

Microglandular hyperplasia of the cervix: a true "pill" lesion?

For many years, it has been assumed that microglandular hyperplasia (MGH) of the cervix occurs almost exclusively in women with endogenous (pregnancy) or exogenous (oral contraceptives) progestational stimulation, but this relationship has never been subjected to rigorous epidemiologic study. All available cases of MGH in our 1990 surgical pathology files were reviewed and clinical histories obtained. For each case of MGH, a control was chosen, consisting of a case in the same time frame of a woman of similar age who had undergone the same procedure (biopsy, conization, hysterectomy) for the same indication. A documented history of current oral contraception or pregnancy within the past 6 months was obtained in 57.9% (22 of 38) of the MGH cases and 47.4% (18 of 38) of the controls. This difference was not statistically significant by McNemar's test for paired data. The histologic features of the MGH lesions (lesion size, cytologic atypia, prominence of inflammation, and presence of solid component and of squamous metaplasia) were evaluated blindly without knowledge of the hormonal history. There were no statistically significant differences by the chi 2 test of association between cases with and without hormonal histories. This study provides no support for considering MGH or any of its constituent features. This study provides no support for considering MGH or any of its constituent features as causally related to oral contraception or other known hormonal perturbations.

Case-Control Studies↗

Cervical squamous cell carcinoma in situ with intraepithelial extension to the upper genital tract and invasion of tubes and ovaries: report of a case with human papilloma virus analysis.

A 55-year-old woman, who was found to have malignant squamous cells on a routine cervical smear, underwent a conization biopsy, followed by hysterectomy with bilateral salpingo-oophorectomy. No gross tumor was present in the uterus, but both ovaries, which were of normal size, contained multiple cysts filled with light brown, soft material. Microscopic examination showed squamous cell carcinoma in situ of the cervix with contiguous spread to the endometrium, fallopian tubes, and ovaries; squamous cell carcinoma extensively replaced the endometrial and tubal epithelium, focally invaded the wall of the fallopian tubes, and involved the parenchyma of both ovaries. Although an invasive cervical carcinoma occasionally spreads to the ovary, this case illustrates that exceptionally an in situ tumor spreads along the epithelium of the upper genital tract and the ovarian surface and invades the ovary and tubes. The detection of human papillomavirus DNA in the cervical, endometrial, tubal, and ovarian tumors by the polymerase chain reaction suggests a role for human papilloma virus infection in this case.

Carcinoma in Situ↗

Prevention, diagnosis, and treatment of postoperative infections.

Discontinuation of routine use of plastic surgical adhesive drapes, the electrocautery surgical knife, routine preoperative shaving, and routine intraoperative placement of wound drains may reduce the incidence of postoperative wound infection. Other potentially helpful measures include hot conization of the cervix before hysterectomy, delayed wound closure, and minimization of preoperative hospitalization time. Microbiologic cultures and the standard temperature definition of morbidity help but little in diagnosing postoperative infection; needed is careful physical examination of the patient before antibiotics are given. Drainage of abscesses and delay of wound closure may help one avoid the use of antibiotics. To prevent infections, an appropriate antibiotic should be in the tissues within 3 hours after surgery; its use should end in the recovery room. Prospective comparison studies are needed to help physicians choose among today's antibiotics.

Animals↗

Contribution of endocervical curettage in evaluating abnormal cervical cytology.

A review of 540 patients evaluated by the Gynecologic Colposcopy Clinic for abnormal cervical cytology revealed that 372 (68.9%) had cervical intraepithelial neoplasia (CIN), microinvasive carcinoma, or frank invasive carcinoma. The repeat cytologic smear taken before biopsy was falsely negative in 26.4%. An endocervical curettage was obtained in 52.5% of patients with an adequate colposcopy who had a neo-plastic lesion and was positive in 17.9% of those sampled, including six patients with no lesion found on the ectocervix. An endocervical curettage was obtained in 88.5% of patients with an inadequate colposcopy who had a neoplastic lesion, and was positive in 48.7%. All patients with an inadequate colposcopy not having an endocervical curettage underwent conization of the cervix. Twelve patients (2.2%) were ultimately found to have invasive or microinvasive carcinoma. A positive endocervical curettage and an inadequate colposcopy were both correlated with a final diagnosis of invasion. The contribution of endocervical curettage to the outpatient work-up of abnormal cervical cytology is substantial and it should be performed in all patients in whom cone biopsy is not planned.

Adenocarcinoma↗

Cone cerclage in pregnancy.

We report a technique of cone cerclage and the results and outcome in 17 patients who required a diagnostic cone biopsy in pregnancy. The mean age of the patients was 30.6 years (range 21-41). The mean gestational age was 18.8 weeks (range 10-32) at the time of the procedure. There were no major complications and hemorrhage was not a significant problem. There were no second-trimester abortions. Two patients required beta-sympathomimetics to suppress uterine activity for longer than 24 hours after the procedure. Six patients had invasive carcinoma, nine had cervical intraepithelial neoplasia (CIN) III, and two had CIN II. In 14 cases, the endocervical and ectocervical margins were negative; two patients with CIN and one with multifocal microinvasion had positive margins. Cone cerclage is a safe and easy method for performing diagnostic cervical conization during pregnancy.

Adult↗

A trend toward more conservative surgery in gynecologic oncology.

A trend toward more conservative surgical intervention is evident in the current management of many gynecologic malignancies. The trend to manage vulvar carcinoma has moved away from the standard en bloc radical vulvectomy and bilateral lymphadenectomy and now consists of more limited excision of the primary tumor as well as of the regional lymph nodes. In preinvasive cervical carcinoma, conization is preferred instead of hysterectomy. The possibility for a more conservative surgical approach is also being explored for the treatment of selected early stage and advanced or recurrent cervical carcinomas. Although the primary surgical treatment of endometrial carcinoma remains unchanged, the necessity to perform (in all cases) the more extensive procedure required for staging purposes is being challenged. In early stage borderline ovarian tumors, not only adnexectomy but cystectomy alone is considered acceptable and reexploration for staging purposes may be unwarranted. In stage IA invasive carcinoma, adnexectomy of the involved side only is probably also sufficient. In advanced ovarian carcinoma, the more aggressive cytoreduction involving multiple organ resection is being restrained. Secondary debulking is performed only on a selective basis and the routine performance of second-look laparotomy has been given up.

Carcinoma↗

Clearance of cervical human papillomavirus infection by treatment for cervical dysplasia.

OBJECTIVES: The aim of this study was to investigate the prevalence of human papillomavirus (HPV) after treatment for cervical dysplasia. STUDY DESIGN: The presence of HPV was investigated in cervical scrapes of 91 patients, before and after treatment, using consensus primers in the polymerase chain reaction. RESULTS: Before treatment for cervical dysplasia, 89 of 91 patients (98%) were HPV-positive compared with 28 of 91 patients (31%) after treatment. The HPV type present before treatment was found in the scrapes of only 9 of 89 patients (10%). Detection of HPV after treatment was associated with human immunodeficiency virus infection and incomplete conization. CONCLUSION: The HPV type present before treatment was frequently cleared by treatment for cervical dysplasia.

Adult↗

Colposcopic management of abnormal cervical cytology during pregnancy.

A total of 104 pregnant patients with abnormal cervical cells were referred to the Dysplasia Clinic for evaluation and management by colposcopy. Seventy-one pregnant patients presenting with basal cell atypia on cytologic examination had colposcopically directed biopsy revealing 8.45% severe dysplasia and 1.41% carcinoma in situ. Cytologic study in 31 pregnant patients with basal cell dysplasia revealed severe dysplasia in 29% and carcinoma in situ in 12.9% of the colposcopic biopsies. Cervical cytology revealed carcinoma in situ in two patients. Directed biopsy in both cases revealed carcinoma in situ with one case of questionable microinvasion. Colposcopically observed normal and abnormal physiologic findings and the pregnant cervix, complications after conization during pregnancy, and the impact of colposcopy in the management of the cytologically abnormal cervix during pregnancy are discussed.

Adult↗

Investigation of laser cervical cone biopsies negative for premalignancy or malignancy.

OBJECTIVE: To measure the rate of carbon dioxide, laser cone biopsies negative for premalignancy or malignancy and determine whether the clinical indications were appropriate or the pathology evaluations were correct. MATERIALS AND METHODS: The patient charts of 95 negative cone biopsies were reviewed by one of the authors to determine the indications for the procedure. All of the slide reviews were done by two of the authors. Following a review of the cone biopsy slides, three deeper sections of the tissue blocks were examined in specimens that were still negative or equivocal for premalignancy. Thereafter, for those still negative the preconization, referral Pap tests, and colposcopic directed tissue samples were reviewed. RESULTS: The overall negative rate of laser cone biopsy was 28% (95/341) and 68% (65/95) were done to investigate high-grade squamous intraepithelial lesions (HGSIL) (cervical intraepithelial neoplasia [CIN] 2,3). There were 25 false negative cone biopsy specimens because of misinterpretation of the original slides or discovery of pathology in additional sections. False positive reporting of some preconization Pap tests or tissue specimens as premalignant when none were seen on review likely resulted in 11 unnecessary conizations. The number of negative cones would thereby be reduced by 36 for a rate of 17% (59/341). CONCLUSIONS: The negative rate could be reduced by 11% with routine deeper sectioning of the tissue blocks of the cone biopsy specimen and improved accuracy of pathological interpretation.

Journal Article↗

Presentation of endometriosis of the cervix in cervical smear: a case report and review of literature.

Endometriosis of the cervix is considered a rare lesion with a predilection in women with a previous history of cervical trauma, such as biopsy, conization, or laser vaporization. Description of endometriosis of the cervix in cytological literature is equally rare with most of the published reports dealing with the role of fine-needle aspiration in diagnosis and how the atypia in cases with cervical endometriosis poses differential diagnosis for other premalignant and malignant endocervical lesions. We present here a case depicting endometriosis of the cervix in a cervical/endocervical smear from a 48-year-old female with intermenstrual spotting. The purpose of this article is 2-fold: to report a case of endometriosis of the cervix in exfoliative cytology and to review pertinent cytological literature. In this article, cytological and histological presentation of cervical endometriosis is described, and the importance of considering cervical endometriosis in the differential diagnosis when dealing with endometrial shedding that is not part of the normal physiology in a cycling woman is emphasized.

Journal Article↗

ZYC101a for treatment of high-grade cervical intraepithelial neoplasia: a randomized controlled trial.

OBJECTIVE: The objective of this study was to assess the safety and efficacy of a novel therapeutic, ZYC101a, for the treatment of women with histologically confirmed cervical intraepithelial neoplasia (CIN) 2/3. ZYC101a contains plasmid-DNA-encoding fragments derived from the E6 and E7 proteins of human papillomavirus (HPV) 16 and 18, and is formulated within small biodegradable microparticles. METHODS: A multicenter, double-blind, randomized, placebo-controlled trial was conducted in a group of women with biopsy-confirmed CIN 2/3. Subjects were randomized to 3 intramuscular doses of either placebo or ZYC101a (100 or 200 microg). Six months after the first injection, subjects underwent cervical conization. The primary endpoint for this study was histologically confirmed resolution of CIN 2/3. A total of 161 subjects were randomized, dosed, and evaluated for safety. After central pathology review, 127 subjects were evaluable for efficacy. RESULTS: The most common adverse events were related to the injection site, were mild to moderate, and did not worsen at later treatments. The proportion of subjects who resolved was higher in the ZYC101a groups compared to placebo (43% versus 27%), but the difference was not statistically significant (P =.12). In a prospectively defined population of women younger than 25 years (n = 43), resolution was significantly higher in the combined ZYC101a groups compared to placebo (70% versus 23%; P =.007). ZYC101a activity was not restricted to HPV-16-or HPV-18-positive lesions. CONCLUSIONS: ZYC101a was shown to be well tolerated in all patients and to promote the resolution of CIN 2/3 in women younger than 25 years. LEVEL OF EVIDENCE: I

Adolescent↗

Langerhans cells in cervical intraepithelial neoplasia related to smoking habits.

OBJECTIVE: Compare the numerical densities of intraepithelial Langerhans cells of uterine cervix of women affected by cervical intraepithelial neoplasia grade 3 (CIN 3) with their smoking habits. MATERIALS AND METHODS: A total of 71 conization specimens of women affected by CIN 3 were separated in 3 groups according to their smoking habits (smokers, nonsmokers, and former smokers). The identification of the Langerhans cells was performed by immunohistochemical analysis using antibodies to S100 protein. The number of intraepithelial Langerhans cells was counted at x400 magnification under a light microscope, and a 10-field count was performed in areas of CIN 3 of each section. Results were expressed as number of cells per square millimeter of epithelium. RESULTS: There was no significant difference in the number of Langerhans cells per square millimeter of epithelium in areas affected by CIN 3 among the 3 groups (p = .5). There was also no significant difference in the number of cigarettes smoked per day (p = .09), duration of consumption (p = .34), total amount of cigarettes smoked during the whole life (p = .18), and duration of abstention (p = .2). CONCLUSIONS: It was not shown that smoking reduces the number of intraepithelial Langerhans cells in the cervix of women affected by CIN 3.

Adolescent↗

Atypical glandular cells: new Bethesda Terminology and Management Guidelines.

Although Pap tests have enabled early detection of premalignant lesions, the introduction of new collecting devices has significantly improved the detection of lesions hidden in the endocervical canal, such as adenocarcinoma in situ (AIS). The term "atypical glandular cells of undetermined significance" (AGUS) was introduced at the 1988 Bethesda Conference and defined as morphologic changes in glandular cells beyond those that are suggestive of the benign reactive process, but insufficient for the diagnosis of adenocarcinoma in situ (AIS). In the new 2001 Bethesda System, the term has been eliminated and replaced with the term "atypical glandular cells" (AGC), with the following subclassifications: not otherwise specified (NOS), favor neoplasia, endocervical AIS, and adenocarcinoma. The risks of premalignant or malignant disease associated with the AGC favor neoplasia category are substantially higher than in the AGC NOS category (96% vs. 9-41%, respectively). Patients diagnosed with AGC NOS or AGC favor neoplasia will require colposcopy, endocervical sampling, and, for patients over 35 years of age, endometrial biopsy. If all of these tests are negative, the Pap test should be repeated in 4-6 month intervals until 4 consecutive normal tests are obtained. Positive results in one of the tests will require management according to ASCCP guidelines. The AGC favor neoplasia diagnosis also requires cervical conization and/or other testing, as the incidence of premalignant or malignant lesions in patients with this diagnosis is high. The role of HPV testing in this setting is unknown at this time.

Adenocarcinoma↗