Occult axillary lymph node metastases in breast cancer do matter: results of 10-year survival analysis.

Axillary lymph node status is one of the most powerful prognostic factors for patients with breast cancer and is often critical in stratifying patients into adjuvant treatment regimens. In 203 apparently node-negative cases of breast cancer, a combination of immunohistochemical staining and step-sectioning identified occult metastases in 25% of cases. Ten-year follow-up information is available for these patients. Histologic features of the primary tumor and immunohistochemical staining for estrogen receptor, progesterone receptor, Her-2, and p53 were also evaluated. With multivariate analysis, both occult metastases and higher histologic grade of the primary tumor were independent predictors of disease-free survival. Histologic grade was the only significant independent predictor of overall survival. Estrogen receptor, progesterone receptor, Her-2, and p53 status did not predict the presence of metastases or survival when all tumor types were considered together. Metastases >0.5 mm significantly predicted a poorer disease-free survival when invasive ductal carcinomas were considered alone. Histologic grade was significantly associated with disease-free survival in the premenopausal and perimenopausal patients but not in the postmenopausal patients. The presence of occult metastases approached significance for overall survival in the premenopausal and perimenopausal patients but not in the postmenopausal patients.

Evaluation of thin-layer methods in urine cytology.

Conventional cytospin smears prepared from urinary tract specimens were compared with two new thin layer techniques, i.e. ThinPrep and AutoCyte PREP. Cellularity, cell preservation, background features, detection rate, screening time and ease of preparation were evaluated. Thin-layer techniques when applied to urine cytology were found to improve cell yield and cell preservation, and reduce background artefact. The reporting rate for abnormal urothelial cells was comparable to conventional cytospin smears, as was screening time. Laboratory staff found the methodologies to be practicable and easily incorporated into a large routine diagnostic service. We conclude that a one-slide thin-layer urine preparation is comparable to four cytospin slides in the detection of urothelial abnormalities, and that both ThinPrep and AutoCyte PREP have comparable features.

Cost-effectiveness studies on cervical cancer.

Cost-effectiveness analyses are an important source of information for the design and evaluation of policies to reduce cervical cancer. This paper describes the recommendations of a panel on cost-effectiveness studies convened as part of the International Consensus Conference on the Fight Against Cervical Cancer. Recommendations for cost-effectiveness studies include: (1) the use of reference case methods to support comparisons across studies, (2) the use of a consistent standard of evidence on the clinical effectiveness of different screening strategies, (3)further research into the costs and effectiveness of different screening and treatment strategies for cervical cancer, (4) further research into screening and treatment strategies in a wide range of countries, (5) easily accessible and detailed descriptions of the methods and supplementary analyses underlying published studies, (6) greater use of newly developed models of cervical cancer, and (7) greater revelation of potential conflict of interest by researchers.

Quality assurance and risk reduction guidelines.

Cervical cancer continues to be a major cause of death in women worldwide. The major problem facing most women is the unavailability of screening Pap tests in poor and underdeveloped countries. While rates of cancer deaths have decreased 60-80% in developed countries since the Pap test became available, the accuracy of Paps was challenged recently. In order to instill public confidence and promote optimal patient care, measures to improve the quality of the entire screening process should be undertaken. Continuous quality improvement processes are more appropriate than traditional quality assurance monitors. Although no standards can be defined that are applicable to all laboratory settings and nations, this document provides current views on universal quality procedures and risk reduction. Procedure/policy manuals, workload assessment, hierarchic/peer review, discrepancy analysis, rescreening studies and cytohistologic correlation are examples of universally applicable quality tools. The variability in practices in different parts of the world is also discussed.

Prospective study of PAPNET: review of 25,656 Pap smears negative on manual screening and rapid rescreening.

In this prospective study, 27,014 Pap smears were selected for PAPNET review on the request of the referring practitioner or patient. Smears that were negative on routine manual screening were submitted for rapid rescreening. Smears considered normal after these two manual screens (n = 25,656) were reviewed using the PAPNET testing system. Routine manual screening identified 1340 (4.96%) of the smears as abnormal, and a further 18 (0.07%) abnormalities were detected by rapid rescreening. PAPNET review identified an additional 102 (0.4%) abnormal smears, including 10 histologically confirmed high grade lesions. The use of PAPNET testing following routine manual screening and rapid rescreening in tandem, enables cytologists to detect additional diagnostically significant abnormalities and reduce the rate of false-negative smears.

Detection of false-negative Papanicolaou smears by rapid rescreening in a large routine cervical cytology laboratory.

Rapid rescreening was established in our laboratory in 1995, following the publication of several studies indicating improved sensitivity for the detection of abnormalities in cervical smears. During the study period, 285,841 negative smears (representing 89.09% of the total workload) were rapidly rescreened. A total of 7,650 (2.68%) were identified as abnormal or suspicious and selected for full rescreening. Of these, 228 cases were considered abnormal following pathologist review and resulted in the issue of an amended report. This represents an increased detection rate for all abnormalities of 0.08%. Of the cases with histological follow-up, a high grade epithelial abnormality (HGEA) was confirmed in 31% of cases and a low grade epithelial abnormality (LGEA) in 42%. We conclude that rapid rescreening is easily incorporated into the daily workflow of a large routine cervical cytology laboratory, Our results support conclusions from previous studies that rapid rescreening is an effective quality control technique resulting in the detection of increased numbers of abnormal smears.

Increased expression of cyclin-dependent kinase inhibitor 2 (CDKN2A) gene product P16INK4A in ovarian cancer is associated with progression and unfavourable prognosis.

Paraffin sections from 190 epithelial ovarian tumours, including 159 malignant and 31 benign epithelial tumours, were analysed immunohistochemically for expression of cyclin-dependent kinase inhibitor 2 (CDKN2A) gene product p16INK4A (p16). Most benign tumours showed no p16 expression in the tumour cells, whereas only 11% of malignant cancers were p16 negative. A high proportion of p16-positive tumour cells was associated with advanced stage and grade, and with poor prognosis in cancer patients. For FIGO stage I tumours, a high proportion of p16-positive tumour cells was associated with poorer survival, suggesting that accumulation of p16 is an early event of ovarian tumorigenesis. In contrast to tumour cells, high expression of p16 in the surrounding stromal cells was not associated with the stage and grade, but was associated with longer survival. When all parameters were combined in a multivariate analysis, high p16 expression in stromal cells was not an independent predictor for survival, indicating that low p16 expression in stromal cells is associated with other markers of tumour progression. High expression of p16 in the stromal cells of tumours from long-term survivors suggests that tumour growth is limited to some extent by factors associated with p16 expression in the matrix.

Quality assurance in cervical cytology screening. Comparison of rapid rescreening and the PAPNET Testing System.

OBJECTIVE: To assess the performance of the PAPNET Testing System and compare the sensitivity of this automated device with that of rapid rescreening. STUDY DESIGN: In this study, 1,000 cervical smears previously diagnosed by our laboratory as negative were seeded with 20 particularly "difficult" cases. We submitted this seeded set of smears for rapid rescreening and to PAPNET to determine cases that could be detected by rapid rescreening, PAPNET or both. RESULTS: Rapid rescreening detected 9 of the 20 cases (45%). The PAPNET system identified 19/20 (95%). This investigation found PAPNET rescreening to be more effective than rapid rescreening in detecting the seeded difficult cases. CONCLUSION: Use of the PAPNET Testing System in tandem with rapid rescreening can reduce the rate of false negatives in diagnostically difficult cervical cytologic smears.

Expression of MUC1 and MUC2 mucins in epithelial ovarian tumours.

This is the first study to describe the association between expression of MUC1 and MUC2 mucins and prognosis in ovarian cancer. Paraffin sections of epithelial ovarian tumours (n = 182: 29 benign, 21 low malignant potential, and 132 invasive tumours) were analysed immunohistochemically for expression of MUC1 and MUC2 mucin core proteins. Most benign, low malignant potential, and invasive tumours showed high MUC1 expression in the cytoplasm. Low cytoplasmic expression of MUC1 was a predictor for good prognosis, particularly within stage III tumours. A minority of benign epithelial tumours, but most low malignant potential and invasive non-mucinous tumours, showed high MUC1 expression on the cell membrane. High apical MUC1 reactivity was associated with non-mucinous tumours. Low expression of MUC1 in the apical membrane was associated with early stage and good outcome for invasive tumours. Most benign and low malignant potential tumours, but only a minority of invasive tumours, showed MUC2 expression. MUC2 was found in non-mucinous as well as in mucinous tumours. The presence of MUC2 was inversely associated with high tumour grade but was not associated with altered survival. These results support experimental evidence that MUC1 influences the metastatic ability of ovarian cancer.

Long-term results of trimming of the inferior turbinates.

The long-term benefit of trimming of the inferior turbinates for nasal obstruction is unclear and our aim was to assess this. Fourteen patients who had had pre-operative nasal symptom scores and anterior rhinomanometry prior to inferior turbinate resection were reassessed at least 7 years post-operatively. Both nasal symptom scores for obstruction and nasal resistance had increased significantly in the intervening time period. Nasal crusting and hypertrophy of the cut inferior turbinate are considered to be responsible for this. Patients should be warned some degree of nasal obstruction may recur postoperatively.

Immunocytochemical staining of cytologic specimens. How helpful is it?

The contribution of immunocytochemical (ICC) staining to the diagnosis of a range of cytologic specimens reported over a 20-month period was retrospectively assessed. A total of 194 cases (1.6% of total workload) were stained for diagnostic purposes in this period. Immunocytochemical staining was determined to be helpful in 75.8% of cases. In body fluid cases (105), staining was most often performed to assist with the discrimination of mesothelial cells and metastatic malignancy. Immunocytochemical staining was helpful in 82% of fluid specimens, with the preliminary diagnosis confirmed in 64%, refined in 8%, and revised in 10% of cases. In fine-needle aspiration (FNA) specimens, staining was helpful in 69%, resulting in a refinement of diagnosis in 55%, and confirming the preliminary diagnosis in 14%. The preliminary diagnosis was revised in a single FNA case. Immunocytochemical staining was particularly valuable in assisting the subclassification of poorly differentiated malignancies. A more precise diagnosis was possible following consideration of ICC results in 68% of cases with a preliminary diagnosis of poorly differentiated malignancy. Immunocytochemical staining was also helpful in identifying the primary site of metastatic carcinoma in six FNA cases. It is concluded that the selective use of well-chosen panels of antibodies can be very helpful in resolving diagnostic difficulties in cytologic specimens. In particular, ICC may be an invaluable aid to the diagnosis of difficult serous effusion specimens and in the sub-typing of poorly differentiated malignancy.

Occult axillary node metastases in breast cancer: their detection and prognostic significance.

Although the presence of axillary node metastases in breast cancer is a key prognostic indicator and may influence treatment decisions, a significant proportion of patients diagnosed as axillary node negative (ANN) using standard histopathological techniques may have occult nodal metastases (OMs). A combination of limited step-sectioning (4 x 100 microns intervals) and immunohistochemical staining (with cytokeratin (MNF.116) and MUC1 (BC2) antibodies) was used to detect OM in a retrospective series of 208 ANN patients. OMs were found in 53 patients (25%), and both step-sectioning and immunohistochemical detection significantly improved detection (P < 0.05). Detection using BC2 (25%) was superior to MNF.116 (18%) and haematoxylin and eosin (H&E) (8%). OMs were found in 51 patients using only the first and deepest sectioning levels and BC2 staining. OMs were more frequently found in lobular (38%) than ductal carcinoma (25%), and more frequently in women less than 50 years (41%) than in older women (19%). Univariate overall and disease-free survival analyses showed that the presence, size and number of OM had prognostic significance as did tumour size (disease-free only) and histological and nuclear grade (P > 0.05). Cox multivariate proportional hazard regression analyses showed that the presence and increasing size of OMs were significantly associated with poorer disease-free survival, independently of other prognostic factors (P < 0.05). However there was not a significant independent association of the presence of occult metastases with overall survival (P = 0.11). These findings have important implications with regard to selection of ANN patients for adjuvant therapy.

Prognostic significance of MUC1 epithelial mucin expression in breast cancer.

The epithelial mucin produced by the MUC1 gene is present in the apical cell membrane of normal breast epithelial cells and is highly expressed in many breast cancers. Several studies have provided conflicting evidence regarding the relationship between MUC1 expression and survival in breast cancer patients. In this study a detailed immunohistological analysis of MUC1 expression was performed using monoclonal antibody BC2 and was related to other tumor characteristics and patient survival. Patients whose tumors showed MUC1 expression in greater than 75% of tumor cells had significantly poorer disease-free and overall survival (P < .05). The proportion of cells showing cytoplasmic MUC1 expression was prognostically significant, but the proportion of cells that lined gland spaces showing apical membrane staining was of no prognostic significance. A high level of MUC1 expression was significantly associated with the presence of axillary node metastases and estrogen receptors but not with other tumor characteristics.

Notifying women of the results of their cervical smear tests by mail: does it result in a decreased loss to follow-up of abnormal smears?

We undertook a prospective randomised intervention study of the proportions of women with abnormal cytology results who were lost to follow-up in 42 general practices in urban and rural Queensland over 26 weeks. Practices in the intervention group were provided with a redesigned cervical smear request form that allowed patients to provide an address for direct notification from the laboratory by mail. Satisfaction questionnaires sent to the general practitioners in the intervention group showed that most made at least some use of direct notification, and most felt it was worthwhile. For women with an initial result of cervical intraepithelial neoplasia (CIN), there was a loss to follow-up of 23 per cent (95 per cent confidence interval (CI) 11 to 39) among the control group compared to none in the intervention group (upper CI 7 per cent), a highly significant difference (P < 0.001). Mailing cervical screening results to women may reduce the loss to follow-up of those with CIN findings.