Squamous intraepithelial lesions in cervical tissue samples of limited adequacy and insufficient for grading as low or high grade: outcome, clinico-pathological correlates, and predictive role of p16INK4a and Ki67 biomarker staining.

OBJECTIVE: Cervical tissue samples of limited adequacy but with pathological features of squamous intraepithelial lesions (SIL) may not be gradable and result in a diagnosis of ungraded SIL (SILQ). SILQ outcome, clinico-pathological correlates, and the predictive role of biomarker staining are unknown. MATERIALS AND METHODS: Among 17,551 colposcopy attendees, 478 (2.7%) had SILQ. Glass slides of 472 were reviewed. Positive [high SIL (HSIL), adenocarcinoma in situ (AIS), or carcinoma] and negative [negative for intraepithelial lesion or malignancy (NILM) or low SIL (LSIL)] outcomes were based on the worst pathology in 24 months of follow-up. p16 and Ki67 immunohistochemistry of 80 random SILQ and 149 controls (44 NILM, 15 LSIL, 75 HSIL, and 15 AIS) was scored as unsatisfactory, positive, or negative. Biomarker and outcome status were correlated, and sensitivity, specificity positive predictive value (PPV), and negative predictive value (NPV) were calculated. RESULTS: Of the total cases, 332 (1.9%) were reviewed as SILQ, and follow-up for 329 was positive in 134 (41%). Atypical glandular cells, AIS, atypical squamous cells (cannot exclude HSIL), HSIL referral Pap test (70% vs. 47%, p < .001), and HSIL colposcopic impression (33% vs. 19%, p < .001) were more frequent among positive compared with negative outcomes. Best SILQ sensitivity (89%) and NPV (77%) occurred with combined biomarkers, and best specificity (52%) and PPV (58%) occurred with Ki67. All 4 performance metrics among the controls were high. CONCLUSIONS: The 2% frequency and 41% positive outcome highlight the clinical importance of SILQ. The referral Pap test and colposcopic impression could prioritize follow-up colposcopy for some SILQ, and negative staining with both biomarkers could eliminate further colposcopy in others.

The diagnostic utility of TP53 and CDKN2A to distinguish ovarian high-grade serous carcinoma from low-grade serous ovarian tumors.

Low-grade serous carcinomas and serous borderline tumors, combined herein and referred to as low-grade serous tumors, show distinct molecular alterations and clinical behaviors compared with high-grade serous carcinomas. The discrimination between low-grade serous tumors and high-grade serous carcinomas can be challenging on small tissue samples, such as cell blocks of paracentesis fluid or biopsies from omental disease. The purpose of this study was to test the ability of TP53 and CDKN2A immunohistochemistry to distinguish between high-grade serous carcinomas and low-grade serous tumors on small tissue samples. Tissue microarrays containing 582 high-grade serous carcinomas, 45 low-grade serous carcinomas, and 49 serous borderline tumors, confirmed by contemporary histopathological review, were stained for TP53 and CDKN2A (DO7 and E6H4 antibody clones, respectively). TP53 was scored as completely absent, wild-type pattern or overexpressed (>60%), and CDKN2A was scored as either negative/patchy (<90%) or block expression (>90%). The combination of the two markers, ie, the TP53 wild-type pattern and CDKN2A patchy expression, had sensitivity for low-grade serous tumors of 89%, a specificity of 93%, a positive predictive value of 68%, and a negative predictive value of 98%. These markers can, therefore, be used on small biopsies/cell blocks to refute a diagnosis of low-grade serous tumors. These findings may inform emerging neoadjuvant therapeutic strategies in advanced ovarian cancers and may be crucial for future clinical trials on molecular-based therapies.

Quantification of ER/PR expression in ovarian low-grade serous carcinoma.

OBJECTIVE: Case reports suggest that hormonal therapy may be a useful treatment option for low-grade serous carcinomas (LGSC) but the clinical value remains uncertain. We hypothesized that LGSCs show a constitutive high hormone receptor expression and that type diagnosis may be sufficient to initiate hormonal therapy. METHODS: We assessed ER and PR expression on 27 LGSC, 69 high-grade serous carcinomas (HGSC), 36 serous borderline tumors (SBOT), and five normal fallopian tubes using three different platforms/antibodies on tissue microarrays. Staining from the Leica Bond Max and DAKO PharmDx platforms was evaluated using the Allred score. Quantitative fluorescence immunohistochemistry was performed using the HistoRx AQUAnalysis platform. A second cohort of 12 LGSC and 183 HGSC was assessed using the HistoRx AQUAnalysis platform. Welch ANOVA or Fisher's Exact Test was used to compare differences in the histological types for each platform. Nonparametric bivariate density plots were used to graphically demonstrate the relationship between ER and PR for the various histological types. RESULTS: LGSC have higher ER and PR expression compared to HGSC but significantly less than FT and SBOT. Nonparametric bivariate density revealed two populations of LGSC: one fifth of LGSC are ER high/PR high expressers similar to SBOT but the majority show low ER/PR expression more like HGSC. CONCLUSIONS: Quantitative assessment of ER/PR expression using the HistoRx AQUAnalysis platform may be useful as a predictive diagnostic for hormonal therapy in LGSC, assuming that only the fraction of double high expressers benefit from hormonal treatment.

Comparative risk of high-grade histopathology diagnosis after a CIN 1 finding in endocervical curettage versus cervical biopsy.

OBJECTIVE: No evidence-based clinical management recommendations exist for women with an endocervical curettage (ECC) cervical intraepithelial neoplasia grade 1 (CIN 1) result when the concurrent cervical biopsy is not high-grade. For women with these pathologic findings, we assessed their short-term risk of high-grade histopathologic diagnosis in the Calgary Health Region where ECC was routinely performed. MATERIALS AND METHODS: We analyzed pathology and colposcopy reports from 1,902 referral colposcopies where both ECC and biopsies were normal or CIN 1. We calculated the short-term risk of CIN 2 or more severe (CIN 2+) detected 12 to 24 months after colposcopy. Pearson χ tests or Fisher exact tests were used to compare risks of a CIN 2+ diagnosis between combinations of test results and strata of risk factors. RESULTS: The short-term risk of CIN 2+ was the same after a CIN 1 biopsy and CIN 1 ECC (4.9% of 1,389 vs 5.0% of 359, respectively, p = .37). Compared with low-grade referral cytology, the risk of CIN 2+ after high-grade cytology was elevated significantly for CIN 1 ECC (13.3% vs 3.3%, p < .01) and nonsignificantly for CIN 1 biopsy (7.1% vs 4.6%, p = .12). CONCLUSIONS: After low-grade cytology, the short-term risk of a high-grade histologic diagnosis in women with either CIN 1 ECC or biopsy is equivalent, suggesting similar management. A CIN 1 ECC may warrant different management in the context of high-grade referral cytology.

Architectural patterns of ovarian/pelvic high-grade serous carcinoma.

We describe the architectural patterns of advanced ovarian/pelvic high-grade serous carcinomas that have been treated with upfront surgery, followed by adjuvant chemotherapy or neoadjuvant chemotherapy, followed by interval debulking to explore the association with the chemotherapeutic response. For 70 cases of advanced (i.e. stage III/IV) high-grade serous carcinomas (33 platinum resistant/intermediate, 37 platinum sensitive; 24 neoadjuvantly treated, 44 primary surgery), all tumor-containing histologic slides were reviewed by 1 of 3 pathologists. Histologic type was confirmed and the following features were assessed: major architectural pattern and the presence of any of 8 predefined minor architectural patterns (papillary, transitional cell carcinoma-like, micropapillary, microcystic, nested papillary, slit-like, glandular, solid). A semiquantitative assessment of psammoma bodies, histiocytic response, necrosis, nuclear atypia, and single-cell invasion was performed. Mitotic count was performed in 10 HPF and 1 HPF was counted for intraepithelial lymphocytes. The morphologic features were tested for an association with previous neoadjuvant chemotherapy and response to chemotherapy (resistant/intermediate versus chemotherapy-sensitive cases stratified by neoadjuvant chemotherapy), which was carried out using χ tests for categorical variables and analysis of variance for continuous data. Combinations of features were analyzed using unsupervised clustering (Wald). Although 8 of 18 features were significantly different when samples from neoadjuvantly treated patients were compared with those not previously treated, no individual histomorphologic feature or a combination of features was associated with response to chemotherapy. Further subtyping of high-grade serous carcinomas will likely need ancillary molecular markers that may have a greater potential to identify cases that will not respond to platinum-based chemotherapy.

The development of an instrument to assess clinical teaching with linkage to CanMEDS roles: A psychometric analysis.

BACKGROUND: Assessment of clinical teaching by learners is of value to teachers, department heads, and program directors, and must be comprehensive and feasible. AIMS: To review published evaluation instruments with psychometric evaluations and to develop and psychometrically evaluate an instrument for assessing clinical teaching with linkages to the CanMEDS roles. METHOD: We developed a 19-item questionnaire to reflect 10 domains relevant to teaching and the CanMEDS roles. A total of 317 medical learners assessed 170 instructors. Fourteen (4.4 %) clinical clerks, 229 (72.3%) residents, and 53 (16.7%) fellows assessed 170 instructors. Twenty-one (6.6%) did not specify their position. RESULTS: A mean number of eight raters assessed each instructor. The internal consistency reliability of the 19-item instrument was Cronbach's α = 0.95. The generalizability coefficient (Ep(2)) analysis indicated that the raters achieved Ep(2) of 0.95. The factor analysis showed three factors that accounted for 67.97% of the total variance. The three factors together, with the variance accounted for and their internal consistency reliability, are teaching skills (variance = 53.25s%; Cronbach's α = 0.92), Patient interaction (variance = 8.56%; Cronbach's α = 0.91), and professionalism (variance = 6.16%; Cronbach's α = 0.86). The three factors are intercorrelated (correlations = 0.48, 0.58, 0.46; p < 0.01). CONCLUSION: It is feasible to assess clinical teaching with the 19-item instrument that has demonstrated evidence of both validity and reliability.

Detection of cervical cancer and its precursors by endocervical curettage in 13,115 colposcopically guided biopsy examinations.

OBJECTIVE: Endocervical curettage (ECC) specimens obtained during colposcopy can detect cervical cancer and precursors otherwise missed by biopsy alone, but the procedure can be painful and reduce compliance with needed follow-up. ECC is routinely performed in the Calgary Health Region colposcopy clinics, permitting a look at its real-world utility. STUDY DESIGN: We analyzed pathology and colposcopy reports from 2003 to 2007. We calculated the added diagnostic utility of ECC compared with cervical biopsy alone. RESULTS: ECC increased the diagnostic yield of cervical intraepithelial neoplasia grade 2 or worse (cervical intraepithelial neoplasia [CIN]2+) in 1.01% of 13,115 colposcopically guided biopsy examinations. Therefore, 99 ECC specimens were taken to detect 1 additional CIN2+. ECC detected 5.4% of 2443 CIN2+ subjects otherwise missed by biopsy alone. Utility was greatest among women aged 46 years or older referred after a high-grade cytology. CONCLUSION: ECC is rarely informative when used routinely in colposcopic practice. Older women referred after high-risk cytology benefit most from ECC.

Controversy in colposcopic management: a Canadian survey.

OBJECTIVE: The substantial reduction in cervical cancer mortality over the last 40 years is attributed to the use of Papanicolaou cervical smear screening with subsequent colposcopic assessment and treatment. Although there is consensus regarding colposcopic management of high-grade intraepithelial cervical lesions, optimal management of patients with low-grade (LG) lesions is less clear. Our goal was to document the colposcopic management of the latter group in Canada. METHODS: A survey was mailed to 252 colposcopists in seven Canadian provinces who recommended management for colposcopy scenarios. Responses were reported in aggregate form. RESULTS: A total of 120/252 (48%) completed questionnaires. Most respondents were 41 to 50 years old, and 68% were male. For women found on colposcopy to have no evidence of a low-grade cervical LG lesion, 43% recommended discharge from colposcopy, and 53% recommended repeat colposcopy. For referrals with a biopsy-confirmed LG lesion, 13% recommended discharge to cytological follow-up, 65% recommended repeat colposcopy, and 16% recommended treatment. Following excisional treatment of LG lesions with negative margins, 13% recommended discharge to cytological follow-up, and 69% recommended further colposcopy. CONCLUSION: These results demonstrate wide variation in management of low-grade cervical lesions among Canadian colposcopists and highlight the need to establish evidence-based management protocols.

Primary carcinoma of the rectovaginal septum diagnosed as uterine prolapse.

BACKGROUND: Primary carcinoma of the rectovaginal septum is very rare. Most cases are associated with documented endometriosis, and patients will often present with vaginal or rectal bleeding. CASE: A 47-year-old woman presented to the emergency department complaining of urinary symptoms and "something falling out of the vagina." She was diagnosed initially as having uterine prolapse. However, further investigations and surgery showed that she had a primary papillary serous carcinoma of the rectovaginal septum, and the carcinoma later metastasized to the lymph nodes. No evidence of endometriosis was found. Assessment and subsequent treatment of this aggressive tumour was likely delayed because of its initial benign presentation. CONCLUSION: Our presentation of the case of a woman with primary carcinoma of the rectovaginal septum not associated with a focus of endometriosis shows that this rare aggressive cancer may present in a clinically benign fashion.

Surveys of Cancer Patients and Cancer Health Care Providers Regarding Complementary Therapy Use, Communication, and Information Needs.

BACKGROUND: Complementary therapies (CTs) are increasingly utilized by cancer patients. Nonetheless, patients report insufficient support from health care practitioners (HCPs) and there is a general lack of patient-practitioner communication about CT use. Best care practices suggest that HCPs should address the needs of patients, including CT use. This study examined current practices of patients and HCPs as well as their interactions relating to CTs. METHODS: A total of 481 cancer outpatients and 100 HCPs completed questionnaires. Patient questions addressed CT use and information needs; HCP questions addressed knowledge, opinions and beliefs about complementary and alternative medicine. Patient-practitioner communication around CT was also examined. RESULTS: 47% of patients reported using CTs since diagnosis. Many commenced CT use to improve quality of life (65%) based on recommendations from family or friends. Patients acknowledged the need for trusted sources of information and would attend a hospital-based education program (72%). HCPs reported limited training about CTs but most (90%) expressed interested in receiving more training. The majority of HCPs (>80%) reported limited knowledge about the role of CTs in cancer care or evidence to support CT use. Questions about communication and interactions revealed that 80% of patients reported not having had an HCP speak to them about CTs. However, 63% of HCPs reported addressing CT use. CONCLUSION: Results demonstrate a need for improved CT education and training for patients and HCPs. increasing HCP knowledge and clinical skills will ensure patients' information needs about CTs are acknowledged and attended to, thereby providing safer and comprehensive cancer care.