HPV E6 oncoproteins and nucleic acids in neck lymph node fine needle aspirates and oral samples from patients with oropharyngeal squamous cell carcinoma.

Commercial assays measuring HPV E6 viral oncoproteins, E6/E7 mRNA or DNA were used to test neck lymph node fine needle aspirates (FNA) and oropharyngeal samples (saliva and oral swabs) from 59 Canadian patients with oropharyngeal squamous cell carcinomas (OPSCC). Overall agreements of p16 antigen staining of tumors to FNA tested for OncoE6™, Aptima HPV E6/E7 mRNA and cobas HPV DNA were 81.4% (k 0.53), 94.9% (k 0.83) and 91.1% (k 0.73) respectively. Using HPV presence in a subset of 25 tumors as the comparator, overall agreement was 64.0% (k 0.08) with OncoE6™, 88.0% (k 0.65) with Aptima HPV E6/E7 mRNA and 91.7% (k 0.70) with cobas HPV DNA. HPV testing of oropharyngeal samples yielded lower agreements with tumor markers; 23.7-24.0% (k 0.02), 55.9-68.0% (k 0.24-0.37) and 78.9-86.9% (k 0.49-0.58) in the 3 respective tests. HPV 16 was present in 93.7-100% of the samples tested and showed 100% genotype agreement between FNA and tumors. The high rates for HPV E6 oncoproteins and E6/E7 mRNA suggests most patients were experiencing transcriptionally active HPV-related OPSCC. Results from these commercial assays performed on FNA but not oropharyngeal samples showed moderate to very good agreements with p16 and HPV testing of tumors.

The organization of colposcopy services in Ontario: recommended framework.

OBJECTIVE: The purpose of this guideline is to help ensure the provision of high-quality colposcopy practices in the province of Ontario, including those conducted as diagnostic procedures in follow-up to an abnormal cervical screening test. METHODS: This document updates the recommendations published in the 2008 colposcopy guideline from Cancer Care Ontario, The Optimum Organization for the Delivery of Colposcopy Service in Ontario. A systematic review of guidelines was conducted to evaluate the existing evidence and recommendations concerning these key aspects of colposcopy: □ Training, qualification, accreditation, and maintenance of competence□ Practice setting requirements□ Operational practice□ Quality indicators and outcomes. RESULTS: This guideline provides recommendations on training and maintenance of competence for colposcopists in the practice settings in which colposcopic evaluation and treatments are conducted. It also provides recommendations on operational issues and quality indicators for colposcopy. CONCLUSIONS: This updated guideline is intended to support quality improvement for colposcopy for all indications, including the follow-up of an abnormal cervical screening test and work-up for lower genital tract lesions that are not clearly malignant. The recommendations contained in this document are intended for clinicians and institutions performing colposcopy in Ontario, and for policymakers and program planners involved in the delivery of colposcopy services.

Giving patients information on abnormal cytology and human papillomavirus: survey of health providers.

OBJECTIVES: Knowledge of the link between HPV and cervical cancer is low among women. Health providers may be required to give information and counseling on HPV. This study surveyed health providers' comfort in counseling women about HPV. METHODS: Physicians, nurses and midwives attending a lecture on HPV completed a questionnaire (before the lecture) on their comfort level answering questions that a woman with an abnormal Pap may ask her health provider. Comfort level with knowledge was assessed on a 7-point Likert scale, with seven being very comfortable. RESULTS: Of the 96 attendees, 57.3% (55/96) were eligible and completed the questionnaire. Two-thirds of respondents were physicians (61.8%; 34/55), 38.2% were nurses or midwives (21/55). Telling a partner about HPV infection was the question about which the most respondents were very comfortable (69.1% answering 6 or 7) and chances of developing cervical cancer was the item about which the fewest respondents reported being very comfortable (36.4%). CONCLUSIONS: Less than one-half to two-thirds of health providers self-reported being very comfortable answering HPV-related questions that a woman may ask. More information is needed regarding health providers' actual knowledge of HPV and women's wishes for information.

Endometrial evaluation with transvaginal US and hysterosonography in asymptomatic postmenopausal women with breast cancer receiving tamoxifen.

PURPOSE: To determine performance characteristics of transvaginal ultrasonography (US) and hysterosonography for diagnosing endometrial abnormality in asymptomatic postmenopausal women with breast cancer receiving tamoxifen. MATERIALS AND METHODS: The authors prospectively examined 138 women receiving tamoxifen by using transvaginal US, hysterosonography, and office hysteroscopy. The combined hysteroscopic-histopathologic diagnosis was the reference standard. Sensitivity, specificity, positive and negative predictive values, and likelihood ratios of transvaginal US and hysterosonography were calculated. RESULTS: All 138 women underwent transvaginal US; 104, successful hysterosonography; and 117, successful hysteroscopy. Uterine abnormality was present in 47 (40.2%) of 117 women: 45 with polyps and two with submucosal fibroids. Receiver operating characteristic curve analysis revealed 6 mm to be the optimal endometrial thickness cutoff for diagnosing endometrial abnormalities. When a thickness greater than 6 mm or a focal endometrial finding was considered abnormal, transvaginal US had a sensitivity of 85.1% and a specificity of 55.7%. In 92 women who completed transvaginal US, hysterosonography, and hysteroscopy, hysterosonography was more specific (79.2%; P =.008) but not significantly more sensitive (89.7%; P =.508) than transvaginal US. When women with abnormal transvaginal US findings were further examined with hysterosonography, the sequential combination of transvaginal US and hysterosonography was more specific (77.1%) than transvaginal US alone (P <.001), without a significant decrease in sensitivity (78.7%; P =.25). CONCLUSION: In asymptomatic postmenopausal women receiving tamoxifen, 6 mm is the optimal endometrial thickness cutoff for diagnosing endometrial abnormalities with transvaginal US. Further examination with hysterosonography can improve specificity by reducing the high false-positive rate of transvaginal US.

Comparison of human papillomavirus DNA testing and repeat Papanicolaou test in women with low-grade cervical cytologic abnormalities: a randomized trial. HPV Effectiveness in Lowgrade Paps (HELP) Study No. 1 Group.

BACKGROUND: Results of cervical cytology screening showing atypical squamous cells of undetermined significance (ASCUS) or low-grade squamous intraepithelial lesions (LSIL) indicate risk for high-grade cervical intraepithelial neoplasia (CIN 2 or 3). In a community-based randomized trial we compared the test performance of human papillomavirus (HPV) DNA testing with that of 6-month repeat Papanicolaou (Pap) test in detecting histologically confirmed CIN 2 or 3. METHODS: We randomly assigned 212 women aged 16-50 years with ASCUS or LSIL on cervical cytology screening to undergo either immediate HPV DNA testing or a repeat Pap test in 6 months. Cervical swabs for the HPV DNA testing and the Pap smears were obtained by their family physicians. We tested the swabs for oncogenic HPV using the Hybrid Capture II assay (Digene Corp., Beltsville, Md.). Community-based pathologists examined the Pap smears. All women were referred for colposcopy by their family physicians. Two gynecological pathologists assessed the histology findings. We calculated test performance in women who completed the trial using CIN 2 or 3 as the reference standard. RESULTS: A total of 159 women completed the study. Compared with HPV DNA testing, which detected 87.5% (7/8) of the cases of CIN 2 or 3, repeat Pap smear showing high-grade intraepithelial neoplasia (HSIL) detected 11.1% (1/9) of cases (p = 0.004), and repeat Pap smear showing ASCUS, LSIL or HSIL detected 55.6% (5/9) (p = 0.16). Corresponding specificities were 50.6%, 95.2% (p = 0.002) and 55.6% (p = 0.61). Loss to follow-up was 17.1% in the HPV test group and 32.7% in the repeat Pap group (p = 0.009). Given the 7 cases of CIN 2 or 3 detected by HPV testing and the 5 cases detected by the repeat Pap smear, the incremental cost of HPV testing was calculated to be $3003 per additional case of CIN identified. INTERPRETATION: HPV DNA testing was more costly but was associated with significantly less loss to follow-up. It may detect more cases of CIN 2 or 3 in women with low-grade cytologic abnormalities.

Prevalence and predictors of human papillomavirus infection in women in Ontario, Canada. Survey of HPV in Ontario Women (SHOW) Group.

BACKGROUND: Human papillomavirus (HPV) is thought to be the primary cause of cervical intraepithelial neoplasia and cervical cancer. We determined the age-specific prevalence of HPV infection and its risk factors in Ontario women. METHODS: We obtained 2 cervical specimens from randomly selected women (in 5-year age categories, from 15 to 49 years) who were being seen in 32 family practices for cytologic screening. The specimens were tested for carcinogenic HPV by the hybrid capture II assay (Digene Corp., Silver Spring, Md.) and by polymerase chain reaction (PCR) and genotyping. RESULTS: Of 1004 women eligible to participate, samples were obtained from 955 (95.1%). The prevalence of HPV (as determined by the hybrid capture II method) was highest, at 24.0% (95% confidence interval [CI] 16.5% to 31.5%), among women 20 to 24 years of age and was progressively lower in older age groups, reaching 3.4% (95% CI 0.1% to 6.7%) in women 45 to 49 years old. The prevalence of HPV (any type) as determined by PCR showed a similar pattern but was significantly higher (p = 0.01) among women 45 to 49 years old than among those 40 to 44 years old (13.0% [95% CI 6.4% to 19.6%] v. 3.3% [95% CI 0.1% to 6.5%]). Risk factors for positivity with the hybrid capture II method were never-married status, divorced or separated status, more than 3 lifetime partners, more than 1 partner in the preceding year, cigarette smoking and current use of oral contraceptives. The presence of squamous intraepithelial lesions on cytologic examination was strongly associated with positivity with the hybrid capture II assay (odds ratio 96.0, 95% CI 22.3 to 413.4; p < 0.01). INTERPRETATION: The highest prevalence of HPV was 24.0%, in women 20 to 24 years old. Risk factors supported a sexual mode of transmission, and there was a strong association between HPV and abnormal cervical cytologic results.

Comparison of self-collected vaginal, vulvar and urine samples with physician-collected cervical samples for human papillomavirus testing to detect high-grade squamous intraepithelial lesions.

BACKGROUND: Certain types of human papillomavirus (HPV) in cervical samples are strongly associated with squamous intraepithelial lesions (SIL) and invasive cervical carcinoma. We determined and compared the test characteristics of testing for HPV with samples obtained by patients and with samples obtained by their physicians. METHODS: In a consecutive series of women referred to a colposcopy clinic at a teaching hospital because of abnormalities on cervical cytologic screening, 200 agreed to collect vulvar, vaginal and urine samples for HPV testing. The physician then collected cervical samples for HPV testing, and colposcopy, with biopsy as indicated, was performed. Presence of HPV was evaluated using the hybrid capture II assay (Digene Corp., Silver Spring, Md.) with a probe cocktail for 13 carcinogenic types. Cervical specimens were also tested for HPV by polymerase chain reaction and hybridization with type-specific probes. Cervical smears for cytologic examination were obtained from all women. RESULTS: High-grade lesions (high-grade squamous intraepithelial lesions [HSIL], equivalent to cervical intraepithelial neoplasia [CIN] grade 2 or 3, and adenocarcinoma) were found in 58 (29.0%) of the 200 women. Carcinogenic types of HPV were detected in the self-collected vaginal samples of 50 (86.2%) of these 58 women, in the self-collected vulvar samples of 36 (62.1%) and in the self-collected urine samples of 26 (44.8%). Carcinogenic types of HPV were detected in the cervical samples collected by physicians for 57 (98.3%) of these 58 women. The remaining 142 women (71.0%) had normal findings or low-grade squamous intraepithelial lesions (LSIL, CIN grade 1). Test results were negative or noncarcinogenic types of HPV were detected in the self-collected vaginal samples of 76 (53.5%) of these 142 women, in the self-collected vulvar samples of 89 (62.7%) and in the self-collected urine samples of 99 (69.7%). The sensitivity for self-collected samples ranged from 44.8% to 86.2%, and the specificity from 53.5% to 69.7%. For the samples collected by physicians, the sensitivity was 98.3% and the specificity 52.1%. The self-sampling methods were generally acceptable to the women: 98.4% of respondents (126/128) deemed urine sampling acceptable, 92.9% (118/127) found vulvar sampling acceptable, and 88.2% (112/127) found vaginal sampling acceptable. INTERPRETATION: Self-collection of samples for HPV testing was acceptable to women attending a colposcopy clinic for investigation of suspected cervical lesions and shows sufficient sensitivity to warrant further evaluation as a screening test for cervical cancer prevention programs.

Bilateral lymphangiomas of the ovary: an immunohistochemical characterization and review of the literature.

Lymphangiomas of the ovary are rare tumors, with only 13 cases reported. The diagnoses of these tumors have been based on histologic findings without immunohistochemical confirmation of endothelial cell origin. It is uncertain if these tumors are true neoplasms or if some represent reactive lesions. In this report, the literature is reviewed, and a 53-year-old woman with bilateral ovarian lymphangiomas is described. The ovarian masses were composed of numerous, thin-walled, cystic spaces containing a proteinaceous fluid, mature lymphocytes, and occasional erythrocytes. The cyst walls were lined by flat, benign-appearing cells that were immunoreactive for factor VIII-related antigen, CD34, and CD31. Further examination of the specimen showed absent fallopian tube fimbriae, tuboovarian adhesions, and chronic follicular salpingitis, suggesting that the lymphatic proliferation in the ovaries was a reactive change secondary to impaired regional lymphatic drainage.

Economic evaluation of hybrid capture human papillomavirus testing in women with low-grade papanicolaou smear abnormalities.

OBJECTIVES: Our aim was to determine the cost-effectiveness of three strategies for detecting cervical intraepithelial neoplasia 2 and 3 after a determination of atypical squamous cells of undetermined significance or low-grade squamous intraepithelial lesion on screening Papanicolaou (Pap) smear. METHODS: Single repeat Pap smear. Hybrid Capture testing for human papillomavirus, and immediate colposcopy were compared. A theoretical decision analysis model was constructed with 10,000 women in each group. Costs and outcomes are those of diagnosis and treatment of cervical intraepithelial neoplasia (CIN) 2 or 3. Outcome probabilities and utilization data were obtained from a literature review and expert opinion. RESULTS: Repeat smear detected 1,125 cases, Hybrid Capture, 1,350 cases, and colposcopy, 1,482 cases of CIN2 or CIN3, costing $1,490,000, $1,980,000, and $2,420,000, respectively. Incremental cost per high-grade dysplasia was $2,178 for Hybrid Capture and $3,333 for colposcopy. Sensitivity analyses that test management efficiencies are reported. CONCLUSIONS: More effective strategies are more costly. However, if costs saved by preventing invasive cancers are included, all three strategies may be cost-saving.

Takayasu arteritis with acute interstitial pneumonia and coronary vasculitis: expanding the spectrum. Report of a case.

We describe the first reported case of Takayasu arteritis presenting as idiopathic adult respiratory distress syndrome, with a pathologic diagnosis of acute interstitial pneumonia. In the same patient, rarely occurring, diffuse coronary vasculitis developed. This case vividly illustrates the extensive, clinically significant vascular involvement that can occur in Takayasu arteritis, as well as the potential extravascular, multisystemic nature of the disease.

Trabecular and solid-cribriform types of basal cell adenoma. A morphologic study of two cases of an unusual variant of monomorphic adenoma.

Monomorphic adenomas are a morphologically complex group of salivary gland tumors. Two unusual examples, one a trabecular and the other a solid form of basal cell adenoma, reveal the development of a cribriform growth pattern focally in the former example and diffusely in the latter. They illustrate the potential for cellular differentiation within this subgroup, organization of synthetic products by the tumor cells, and the histologic criteria useful for the distinction of basal cell adenoma from adenoid cystic carcinoma.

Thrombin activation rate constant: one-stage chromogenic assay for the extrinsic system.

Some properties of a one-stage, chromogenic clotting assay using tissue thromboplastin as an activator are described. The chromogenic assay uses S-2238 as substrate and estimates thrombin by the rate of absorbance produced. Under assay conditions, it was observed that the log (thrombin or absorbance/min) is linear with time. The linearity appeared to extend from zero thrombin up to maximum thrombin concentration for all concentrations of each plasma type examined including factor V and factor VII deficient plasmas. Since the linear slope, b, appears to be a measure of the rate of thrombin production, it was called the Thrombin Activation Rate Constant (TARC). For dilutions of normal plasma log (b) appears to be linearly related to log (plasma concentration) and to log (PT) where PT is the standard one stage clotting time. For plasmas deficient in extrinsic clotting factors, b was linearly related to log (factor concentrations). The chromogenic assay was most sensitive to changes in prothrombin; least sensitive to changes in factor VII; and unaffected by changes in concentration of factors VIII and IX. The standard PT was least sensitive to prothrombin and more sensitive to factors X and VII. For oral anticoagulated plasmas log b and log PT were linearly correlated with a regression slope which was more negative than that from normal plasma. From theses results it was concluded that TARC is a chromogenic assay sensitive to all factors in the extrinsic pathway; that TARC might be used as both a screening assay for extrinsic deficiencies and a monitoring assay for anticoagulants; and that TARC may be more sensitive than the standard PT to the defects from oral anticoagulation.

Effect of sera on thrombin activation rate constants: a one-stage assay for the extrinsic system.

A one-stage chromogenic assay sensitive to all factors of the extrinsic system has been developed. Diluted plasma is combined with tissue thromboplastin in the presence of S-2238, a thrombin-sensitive substrate. After a lag phase, log (A405/min) is linear with time up to the maximal thrombin concentration. The linear slope, b, is called the thrombin activation rate constant (TARC). Log b, or b, is linearly related to log transformations of plasma dilutions, of factor concentrations, of dicumarolized plasmas, and of one-stage prothrombin times. Since the lag phase can vary from 2 to more than 10 minutes, it is difficult to perform the assay on current automated equipment. Results show that factors VII and X affect the lag phase, while factors V and II do not. Small amounts of sera or thrombin, to a lesser extent, can shorten the lag phase to near zero without altering the relationships between TARC and plasma dilutions and between TARC and prothrombin times for dicumarolized plasmas and for dilutions of factor-deficient plasmas. The only effects of some sera are to increase b by approximately 20 percent. Successful sera can be made from clotted whole blood or supernatants of sera from citrated plasma clotted with tissue of partial thromboplastins. These sera appear to have minimal amounts of factor X, undetectable prothrombin, and undetectable free thrombin. The sera contain excesses of factor VII and/or factor VIIa and nearly 20 percent of factor V. If the sera activity arises from the extrinsic system, it is probably due to factor VIIa.

Spectrum of anomalies in the Meckel syndrome, or: "Maybe there is a malformation syndrome with at least one constant anomaly".

The Meckel syndrome comprises a variety of defects including the classical triad of occipital encephalocele, cystic kidneys, and polydactyly. The frequencies of the various defects are more accurately represented in the affected sibs of probands than in the probands themselves, since the latter are selected according to severity and preconceived notions of what constitutes the syndrome. In a series of 38 such sibs, all had cystic dysplasia of the kidney, 63% had an occipital meningocele, 55% had polydactyly, and 18% had no reported brain malformation. In families in which the proband had the classical triad, only 68% of the affected sibs had it. It is concluded that the diagnosis of Meckel syndrome may not be valid in the absence of cystic kidney dysplasia. In babies with encephalocele or anencephaly, pathologic examination, particularly of the kidneys, is important in determining risk of recurrence. This approach to estimating the variability of a syndrome might profitably be extended to other genetically determined pleiotropic conditions.