The performance of human papillomavirus high-risk DNA testing in the screening and diagnostic settings.

OBJECTIVE: We sought to evaluate the performance of the human papillomavirus high-risk DNA test in patients 30 years and older. MATERIALS AND METHODS: Screening (n=835) and diagnosis (n=518) groups were defined based on prior Papanicolaou smear results as part of a clinical trial for cervical cancer detection. We compared the Hybrid Capture II (HCII) test result with the worst histologic report. We used cervical intraepithelial neoplasia (CIN) 2/3 or worse as the reference of disease. We calculated sensitivities, specificities, positive and negative likelihood ratios (LR+ and LR-), receiver operating characteristic (ROC) curves, and areas under the ROC curves for the HCII test. We also considered alternative strategies, including Papanicolaou smear, a combination of Papanicolaou smear and the HCII test, a sequence of Papanicolaou smear followed by the HCII test, and a sequence of the HCII test followed by Papanicolaou smear. RESULTS: For the screening group, the sensitivity was 0.69 and the specificity was 0.93; the area under the ROC curve was 0.81. The LR+ and LR- were 10.24 and 0.34, respectively. For the diagnosis group, the sensitivity was 0.88 and the specificity was 0.78; the area under the ROC curve was 0.83. The LR+ and LR- were 4.06 and 0.14, respectively. Sequential testing showed little or no improvement over the combination testing. CONCLUSIONS: The HCII test in the screening group had a greater LR+ for the detection of CIN 2/3 or worse. HCII testing may be an additional screening tool for cervical cancer in women 30 years and older.

Accuracy of colposcopy in the diagnostic setting compared with the screening setting.

OBJECTIVE: To estimate the accuracy of colposcopy to identify cervical precancer in screening and diagnostic settings. METHODS: As part of a larger clinical trial to evaluate the diagnostic accuracy of optical spectroscopy, we recruited 1,850 patients into a diagnostic or a screening group depending on their history of abnormal findings on Papanicolaou tests. Colposcopic examinations were performed and biopsies specimens obtained from abnormal and normal colposcopic sites for all patients. The criterion standard of test accuracy was the histologic report of biopsies. We calculated sensitivities, specificities, likelihood ratios, receiver operating characteristic curves, and areas under the receiver operating characteristic curves. RESULTS: The prevalence of high-grade squamous intraepithelial lesions (HSIL) or cancer was 29.0% for the diagnostic group and 2.2% for the screening group. Using a disease threshold of HSIL, colposcopy had a sensitivity of 0.983 and a specificity of 0.451 in the diagnostic group when the test threshold was low-grade squamous intraepithelial lesions (LSIL), and a sensitivity of 0.714 and a specificity of 0.813 when the test threshold was HSIL. Using the same HSIL disease threshold, in the screening group, colposcopy had a sensitivity of 0.286 and a specificity of 0.877 when the test threshold was LSIL, and a sensitivity of 0.191 and a specificity of 0.961 when the threshold was HSIL. The colposcopy area under the receiver operating characteristic curve was 0.821 (95% confidence interval 0.79-0.85) in the diagnostic setting compared with 0.587 (95% confidence interval 0.56-0.62) in the screening setting. Changing the disease threshold to LSIL demonstrated similar patterns in the tradeoff of sensitivity and specificity and measure of accuracy. CONCLUSION: Colposcopy performs well in the diagnostic setting and poorly in the screening setting. Colposcopy should not be used to screen for cervical intraepithelial neoplasia. LEVEL OF EVIDENCE: II.

The accuracy of the Papanicolaou smear in the screening and diagnostic settings.

OBJECTIVE: We evaluated the performance of the Papanicolaou smear in screening and diagnostic settings. STUDY DESIGN: We analyzed Papanicolaou smear results of 1,850 women recruited into a clinical trial to evaluate an emerging technology for the detection of cervical cancer. Screening and diagnosis groups were based on the history of previous Papanicolaou smear results. We calculated sensitivities, specificities, positive and negative likelihood ratios (LR+ and LR-), receiver operating characteristic curves, and areas under the receiver operating characteristic curve (AUC). RESULTS: In the screening group, by defining disease as cervical intraepithelial neoplasia (CIN) 2,3/cancer or worse and using high-grade squamous intraepithelial lesion (HSIL) as the test cutpoint, the AUC was 0.689, and the LR+ and LR- were 39.25 and 0.67, respectively. In the diagnosis group, the AUC was 0.764, and the LR+ and LR- were 3.79 and 0.56, respectively. By defining disease as human papillomavirus/CIN 1 or worse and HSIL as the test cutpoint, the AUC was 0.586, and the LR+ and LR- were 17.01 and 0.92 in the screening group; in the diagnosis group, the AUC was 0.686, and the LR+ and LR- were 2.77 and 0.75, respectively. CONCLUSIONS: In a screening setting, a Papanicolaou smear result of HSIL or worse is 39 times more likely in a patient with CIN 2,3/cancer than in a patient without it. This compares to 4 times more likely in the diagnostic setting. The magnitude of the positive likelihood ratio observed in the screening group indicated that abnormal Papanicolaou smear results obtained in the screening setting should have more impact on clinical decision making than those from results obtained in the diagnostic setting.

Ten-year outcome of patients with advanced epithelial ovarian carcinoma treated with cisplatin-based multimodality therapy.

PURPOSE: At the end of the 1970s it was thought that advanced epithelial ovarian cancer (EOC) could be cured by multimodality treatment using surgery, cisplatin-based combination chemotherapy, and radiotherapy (RT). Such multimodality treatment was used as standard therapy at our institution. Our long-term results are reviewed. PATIENTS AND METHODS: One hundred ninety-five previously untreated patients with stage III or IV EOC were treated between April 1979 and December 1982. All patients were to have debulking surgery, when feasible, followed by the administration of doxorubicin and cisplatin at 50 mg/m2 every 3 weeks until a total dose of doxorubicin of 450 mg/m2 had been reached. RT was used in addition in patients with disease remaining after the chemotherapy. Maintenance chemotherapy with oral cyclophosphamide and hexamethylmelamine (altretamine) was administered to patients who did not have a documented histologic complete remission. RESULTS: The 10-year overall and failure-free survivals were 4% and 8%, respectively. The median overall survival was 2 years. The achievement of a histologic complete response (n = 32) did not equate to cure because 20 (63%) of the patients eventually relapsed. Multivariate analysis identified residual disease of greater or less than 2 cm as the only independent prognostic factor. CONCLUSIONS: Our multimodality treatment program was noncurative for the majority of the patients. Innovative therapies are needed before we can hope to cure such disease.

Natural history of cervical intraepithelial neoplasia: a meta-analysis.

OBJECTIVE: To determine the probabilities of transition of stages in the cervical cancer by conducting a meta-studies on the topic. STUDY DESIGN: We identified health states of interest in the natural history of cervical precancer, identified all possible papers that could meet selection criteria, developed relevance and acceptability criteria for inclusion, then thoroughly reviewed the selected studies. To determine the transition probability data we used a random effects model. We determined probabilities for 4 health state transitions. The 6-month mean predictive transition probability (95% confidence intervals with "prediction interval" in parentheses) for high grade squamous intraepithelial lesions (HSIL) to cancer was 0.0037 (0.00004, 0.03386), for low grade squamous intraepithelial lesions (LSIL) to HSIL was 0.0362 (0.00055, 0.23220), for HSIL to LSIL was 0.0282 (0.00027, 0.35782), and for LSIL to normal was 0.0740 (0.00119, 0.42672). CONCLUSION: The transition probabilities between cervical cancer health states for 6-month intervals are small; however, the cumulative risk of cervical cancer is significant. Markers to identify the cervical precursors that will lead to the transition to cervical cancer are needed.

Human papillomavirus infection of the uterine cervix. Tissue sampling and laboratory methods affect correlations between infection rates and dysplasia.

Two common tissue sampling techniques--colposcopic biopsy and cervical scrape--and two common human papillomavirus (HPV) detection techniques--Southern blot and dot blot (SB and ViraPap [VP])--were compared to determine whether differences in these techniques alter correlations between "oncogenic" HPVs and cervical neoplasia. In 87 women with persistently abnormal Papanicolaou (Pap) smears, concurrent biopsy and scrape specimens contained HPV in 21 (24%) and contained no HPV in 26 (30%); 30 scrape specimens (34.5%) tested positive when the biopsy tested negative and 10 (11.5%) scrape specimens tested negative when the biopsy tested positive (overall concordance, 54%). Concordance for the most prevalent HPVs (16/18) was 59%. In carcinoma in situ, HPV was found in biopsy samples significantly more frequently than in scrape specimens: 17 of 23 (75%) biopsy samples versus 9 of 23 (39%) scrape specimens (P = 0.018). Conversely, in mild or no dysplasia, 0 of 42 biopsy samples tested positive for HPV 16/18 compared with 12 of 42 scrape specimens (29%; P = 0.0001). Of 229 specimens analyzed by SB and VP, 43 (19%) tested positive and 148 (65%) tested negative for HPV by both methods (concordance, 84%). Corroborative results indicated that 29 of 35 (83%) VP-positive SB-negative results were truly positive compared with none of three SB-positive VP-negative results. Both the cervical sampling technique and the method for HPV detection can significantly affect statistical correlations between cervical dysplasia and HPV type.

Stage IA carcinoma of the cervix revisited.

OBJECTIVE: To examine some of the controversy that still exists regarding the definition and management of microinvasive or early invasive cervical carcinoma, in particular, the current concepts regarding the definition of these conditions and their inclusion into the staging system for cervical cancer. DATA SOURCES: A MEDLINE search was used to identify English-language reports of clinical and pathologic information on cervical cancer. Articles published during 1970-1993 were reviewed. METHODS OF STUDY SELECTION: Articles were selected for review if the information published contained data regarding measured depth of invasion, histologic examination of lymph nodes, and lymphatic vascular space status with these tumors. TABULATION, INTEGRATION, AND RESULTS: Results from the studies were pooled to determine the correlation between depth of invasion with the likelihood of nodal disease and recurrence, both with and without lymphatic vascular space involvement. These studies indicated that the likelihood of recurrence and death from cancer, together with the presence of nodal metastasis, appears to be directly related to the depth of tumor invasion. The relative importance of factors such as lymphatic space involvement will likely remain controversial because they may not be independent prognostic factors. CONCLUSION: Review of the literature suggests that although no uniform opinion exists as to how these conditions should be described or managed, the evidence indicates that some modifications to the 1985 staging system for cervical cancer could be made to better categorize patients with these conditions and also, perhaps, provide guidelines for management.

Colposcopic accuracy in the diagnosis of microinvasive and occult invasive carcinoma of the cervix.

One hundred eighty patients with microinvasive and occult invasive squamous cell carcinoma of the cervix who were examined by colposcopy during a ten-year period are reviewed. Forty-two percent of patients with microinvasive carcinoma and 28% of patients with occult invasive carcinoma had an unsatisfactory colposcopic examination. Colposcopy led to the correct management in 90% of patients with occult invasive cancer and in 84% of patients with microinvasive carcinoma. Colposcopy appeared to be less sensitive in detecting microinvasive lesions than in detecting occult carcinoma. Two-thirds of the errors made were colposcopist-related, either failure of interpretation or protocol violation. A small but definite group of patients will have lesions whose colposcopic appearance is not sufficiently distinct or characteristic to permit a diagnosis of early invasion.

Results of conservative management of cervical intraepithelial neoplasia.

Cryotherapy and laser surgery have been the most frequently used conservative methods to treat cervical intraepithelial neoplasia (CIN) in the past decade. This report documents our experience using these modalities to treat 2773 patients between the years 1984-1989. One thousand eight hundred eleven women received laser surgery and the remaining 962 were treated with cryotherapy. In the first 2 years of the study period, only 78 patients were treated with laser surgery. Conversely, only 69 of the 979 patients treated in 1988 and 1989 had cryotherapy. As greater experience was gained with laser surgery, the success rates rose from 58.3% in 1984 to 95.5% in 1988. The success rate was similar for all grades of CIN. Overall, 11.2% of all patients were lost to follow-up. Among patients treated with laser surgery, 4.8% had postoperative bleeding that required either packing or, in two instances, sutures for hemostasis. Success with these methods appeared to be related to the size of lesion and not to the degree of histologic abnormality. The shift toward increasing use of laser surgery in our clinic was due to its precision in destroying identified lesions in the transformation zone. Our results indicate that both cryotherapy and laser surgery are simple, effective methods for the treatment of CIN.

Colposcopy, conization, and hysterectomy practices: a current perspective.

Data from the provincial cytology program has shown a progressive increase in the number of cases of cervical carcinoma in situ detected in the general population and a doubling of disease rate in third decade women, with most of the cases now in the 25- to 29-year-old age group. The introduction of a colposcopy service has led to a significant decrease in the number of diagnostic conizations performed over a 5-year period. Conization was still used for therapy in a substantial number of women despite the availability of cryotherapy and laser surgery. Eighty-five percent of all patients undergoing cone biopsy had sever dysplasia or carcinoma in situ (CIN III) on pathological examination. In 25% of patients, the conization specimen revealed either dysplasia or carcinoma in situ extending to resection margins. During review of 2249 patients, 1174 were spared a conization and were treated by either hysterectomy, cryotherapy, or laser surgery. It would appear that, although colposcopy can reduce dramatically the number of diagnostic cone biopsies, conization will still be required for therapy in a substantial number of patients.

Cryotherapy in the treatment of cervical intraepithelial neoplasia.

Cryotherapy was used to treat 516 patients with various degrees of dysplasia and carcinoma in situ over a 7-year period. Seventy-one percent of patients had either severe dysplasia or carcinoma in situ. In 88% of the patients treated, a single treatment session was successful in eradicating the lesion. Treatment was defined as successful when cytologic and colposcopic findings were negative 1 year after treatment. Five percent of patients were lost to follow-up. The criteria for selection of patients and possible causes of treatment failure are discussed.

Invasive cancer of the cervix in British Columbia: a review of the demography and screening histories of 437 cases seen from 1985-1988.

The charts of 437 patients with newly diagnosed invasive cervical cancer seen in British Columbia during 1985-1988 were reviewed to determine the age at diagnosis, stage of disease, and histology of the lesions. The patient's immigration status and country of birth were also examined. Two hundred forty-two patients (55%) were age 50 or over and 149 (34%) had preclinical stage IB disease. One hundred seventy of these patients (39%) had never had a cytologic examination before presenting with clinical symptoms, and 45 additional patients had not had cytology for 5 or more years before presenting with invasive disease; thus, a total of 215 cases (49%) fell into the category of "no cytology or cytology longer than 5 years ago." All negative smears were reviewed and in 39 patients (15%) having previous cytology, abnormal cells had been missed or undercalled. Native Indian women made up 10% of the cases of invasive carcinoma, a disproportionately large number as they represent only 2% of the British Columbian population. Of the 27 Native Indian patients in this series, 16 (59%) had never had a cytologic examination. Eighty-five (30%) of 276 women born in Canada had never had a cytologic examination, compared with 34 (71%) of 48 immigrants resident in the country for fewer than 10 years. Twenty-four patients were over the age of 60 with a history of negative Papanicolaou smears. We conclude that, if further gains are to be made in the reduction of death rates from invasive cervical carcinoma, new means must be found to encourage women to participate in Papanicolaou smear screening programs. In particular, special efforts must be made to attract specific groups, such as the Native Indian population and older recent immigrants.

A quality-control program for colposcopic practice.

Quality control is accepted as an integral part of the cytology laboratory's activities. However, provision of similar safeguards for colposcopic practice in assessing patients with abnormal cervical cytology has been an elusive problem. This report describes the quality-control program for colposcopy that is used province-wide in British Columbia for 21 hospital-based clinics staffed by 35 colposcopists. Copies of the results of all colposcopic examinations performed are sent to the Central Cytology Laboratory where the program is coordinated and the data are collated, analyzed, and evaluated. These data are used to set standards against which each colposcopist's performance and activity can be measured. One of the quality-control indicators used is a comparison between the colposcopic impression of the lesion and the corresponding direct biopsy diagnosis. Correlation within one histologic degree occurred in 86% of patients examined; this information was used to set a performance standard of 80% as the quality-control index for this particular indicator. Three colposcopists had scores below this standard. Comparisons were also made between presenting cytology, directed biopsy results, initial colposcopic impression, and final colposcopic evaluation (the clinical working diagnosis). The other major aspect of the quality-control program consists of an analysis of all cases of diagnosed invasive cervical cancer in the province in a given year to determine whether any colposcopically related errors occurred in the investigation and management of these cases. This system helps to identify individuals who may benefit from additional training.

Basal cell carcinoma of the vulva: clinical features and treatment results in 28 patients.

OBJECTIVE: To review our experience and that in the recent literature regarding basal cell carcinoma of the vulva to see whether current management guidelines are appropriate. METHODS: Twenty-eight women with basal cell carcinoma of the vulva were seen over 25 years at the BC Cancer Agency. The clinical-pathologic features were tabulated and the outcome was analyzed. RESULTS: The mean age was 74 years, and almost two-thirds were over the age of 70 at diagnosis. Patients typically presented with an irritation or soreness, with a symptom duration ranging from a few months to several years. Most lesions were confined to the anterior half of the vulva, and 23 of the 28 patients had T1 lesions. Wide local excision was the treatment method used most commonly. Only one patient was known to have died from disease metastasis. Ten women had other basal cell carcinomas, either before or after the diagnosis of their vulvar lesions, and in ten patients 11 other malignancies were diagnosed. CONCLUSION: Basal cell carcinoma of the vulva is an extremely uncommon tumor that rarely metastasizes or spreads. Primary treatment should consist of wide local excision and continued follow-up.

Adenocarcinoma of the fallopian tube. Experience with 41 patients.

Forty-one cases of primary fallopian tube carcinoma treated at our institution over the years 1946 to 1976 are described. The overall 5-year survival rate was 34.4%, although patients with early tumors had a 72.7% survival rate. The single most important factor affecting survival appeared to be the extent of disease at the time of diagnosis. Past and present treatment modalities are discussed, and proposals for management of this disease are outlined.

Primary invasive carcinoma of the vagina.

Data are presented from 97 patients treated for invasive primary epithelial carcinoma of the vagina between 1950 and 1980. The disease is primarily one of the elderly as 63% were found to be older than 60 years of age. Eleven of the 97 patients either refused or were unable to complete treatment because of poor medical condition or advanced stage of disease. Combined external and intracavitary radiation was the most common form of treatment. The overall two-year survival rate was 47%, or 59% when corrected for deaths due to other causes. Patients with stages I and II disease had corrected survival rates of 75% and 68%, respectively. Our results indicate that stage of disease is the most significant prognostic factor. Optimal results will be obtained with early diagnosis and individualized treatment.

Granulosa cell tumors. A clinical review of 61 cases.

Sixty-one patients with granulosa cell tumors of the ovary were treated in the A.M. Evans Clinic of the British Columbia Cancer Control Agency between 1944 and 1974. Their treatment and follow-up are reviewed, and while the 5-year survival rate was 78%, the 15-year rate fell to 50%. The material suggests that the trend to total hysterectomy and bilateral salpingo-oophorectomy has improved the prognosis, but other explanations are, of course, possible as this is a historical comparison.

Complex karyotypic alterations in an endometrial stromal sarcoma.

Cytogenetic investigation of a low-grade endometrial stromal sarcoma (ESS) revealed structural rearrangements of chromosomes 3, 6, and 7. The karyotypic findings in the few cases of ESS reported reveal recurrent involvement of both homologues of chromosome 7, with less consistent changes affecting chromosomes 6 and 17. The cytogenetic and histologic features of these uterine stromal tumors require further study.

Progress in gynecologic cancer detection and treatment.

Slow but steady progress has been made in the earlier diagnosis and better treatment of gynecological cancers, particularly over the last 50 years. Cervical cytology screening programs, where implemented, have led to a remarkable reduction in both the incidence and mortality from clinically invasive cervical cancer. This relatively simple technology has been truly one of the major success stories of modern medicine, but unfortunately this technique has not been uniformly applied to all women in the world, particularly to women in developing countries. New research into cervical cancer etiology, the role of HPV, and the development of vaccines against this virus offer a great hope particularly for developing countries. In addition, the combination of radiotherapy and chemotherapy has resulted in a marked improvement in outcome results for women with advanced cervical cancer. Ovarian cancer has seen the development of effective chemotherapy strategies for this disease. Currently this disease remains one of the major scourges in industrialized countries but the continued evolution of knowledge with regard to optimum sequencing of chemotherapeutic agents and surgery offers the prospect for better outcomes, less morbidity and a better quality of life. Ongoing research into the development of newer chemotherapeutic agents and a better understanding of the actual mechanisms regarding the efficacy of chemotherapy and drug resistance offers great promise for the future. Endoscopic surgery for staging and also for therapy shows promise for improved quality of life as well as outcomes for patients in the future and offers the challenge of trying to make this technology readily available to all women in the world. As we gain a better understanding of the molecular basis of disease and health we will truly be able to intervene in a preventive mode in the new millennium.

Epidermal thickness and skin appendage involvement in vulvar intraepithelial neoplasia.

Colposcopically directed biopsies obtained from 165 women with vulvar intraepithelial neoplasia (VIN) were studied to determine both the thickness of the dysplastic epithelium and the depth of involved and noninvolved skin appendages and ultimately to provide a morphometric basis for laser therapy for the condition. Multiple measurements per section were made, and the mean epithelial thickness was calculated for each biopsy. The mean (+/- SD) thickness of the epithelium for all grades of VIN was 0.52 +/- 0.23 mm, with the lesions ranging in thickness from 0.10 to 1.90 mm. The thickness of the involved epithelium varied little, regardless of the location of the lesions. The study indicated that VIN frequently is a multifocal disease most commonly affecting the central vulvar structures, with the posterior half of the vulva the area affected most often. The difference in thickness between the various grades of VIN was not of practical clinical significance from a therapeutic point of view. The measurements suggest that laser vaporization to a depth of 1.0 mm, including the zone of thermal necrosis, should be sufficient to destroy most epidermal lesions without skin appendage involvement. If the initial biopsy showed involvement of adjacent hair follicles or sebaceous glands, deeper tissue destruction would be necessary to theoretically achieve greater than 90% elimination of the disease.