Three-dimensional tumor visualization of invasive breast carcinomas using whole-mount serial section histopathology: implications for tumor size assessment.

PURPOSE: Linear tumor size (T-size) estimated with conventional histology informs breast cancer management. Previously we demonstrated significant differences in margin and focality estimates using conventional histology versus digital whole-mount serial sections (WMSS). Using WMSS we can measure T-size or volume. Here, we compare WMSS T-size with volume, and with T-size measured conventionally. We also compare the ellipsoid model for calculating tumor volume to direct, WMSS measurement. METHODS: Two pathologists contoured regions of invasive carcinoma and measured T-size from both WMSS and (simulated) conventional sections in 55 consecutive lumpectomy specimens. Volume was measured directly from the contours. Measurements were compared using the paired t-test or Spearman's rank-order correlation. A five-point 'border index' was devised and assigned to each case to parametrize tumor shape considering 'compactness' or cellularity. Tumor volumes calculated assuming ellipsoid geometry were compared with direct, WMSS measurements. RESULTS: WMSS reported significantly larger T-size than conventional histology in the majority of cases [61.8%, 34/55; means = (2.34 cm; 1.99 cm), p < 0.001], with a 16.4% (9/55) rate of 'upstaging'. The majority of discordances were due to undersampling. T-size and volume were strongly correlated (r = 0.838, p < 0.001). Significantly lower volume was obtained with WMSS versus ellipsoid modeling [means = (1.18 cm3; 1.45 cm3), p < 0.001]. CONCLUSIONS: Significantly larger T-size is measured with WMSS than conventionally, due primarily to undersampling in the latter. Volume and linear size are highly correlated. Diffuse tumors interspersed with normal or non-invasive elements may be sampled less extensively than more localized masses. The ellipsoid model overestimates tumor volume.

Factors influencing survival among patients with HER2-positive metastatic breast cancer treated with trastuzumab.

PURPOSE: We have limited capability to predict survival among patients treated for metastatic HER2-positive breast cancer. Further research is warranted to identify significant prognostic and predictive factors. METHODS: We identified all HER2-positive metastatic breast cancer patients receiving trastuzumab at the Sunnybrook Odette Cancer Centre (SOCC) from 1999 to 2013 through the Cancer Care Ontario (CCO) Registry (n = 256) and selected patients with available pathology reports (n = 154). A retrospective review was completed documenting clinical, pathologic, and laboratory characteristics at the time of first trastuzumab therapy and survival outcomes. Cox proportional hazards regression models were used to identify prognostic factors for overall survival (OS) (primary endpoint) and failure-free survival (FFS), adjusted for the known prognostic factors of the presence of CNS metastases and the presence of ≥ 2 distant metastatic sites. RESULTS: A multivariable model identified older age [hazard ratio (HR) 1.18/decade, 95% confidence interval (CI) 1.02-1.37)], increased platelet-to-lymphocyte ratio (PLR) (HR 1.75/log-unit, 95% CI 1.25-2.46), increased serum alkaline phosphatase (ALP) (HR 1.87/log-unit, 95% CI 1.41-2.49), and ER positivity (HR 0.63, 95% CI 0.42-0.96) as significant prognostic factors for OS after adjusting for the presence of CNS metastasis (HR 3.19, 95% CI 1.59-6.38) and the presence of ≥ 2 distant metastatic sites (HR 2.10, 95% CI 1.19-3.70). PLR (HR 1.54/log-unit, 95% CI 1.12-2.12) was the only prognostic factor associated with FFS after adjusting for CNS and ≥ 2 distant metastatic sites. CONCLUSION: Older age, increased PLR, and ALP were identified as poor prognostic factors and ER positivity as a favorable prognostic factor for OS after adjusting for the presence of CNS metastasis and the presence of number of ≥ 2 distant metastatic sites. Increased PLR was a poor prognostic factor for both OS and FFS, and warrants further investigation into its prognostic ability amongst patients with HER2-positive metastatic breast cancer.

Thyroid hormone receptor beta-1 expression in early breast cancer: a validation study.

PURPOSE: Preliminary data suggest that high expression of the TRß1 tumor suppressor is associated with longer survival among women with early breast cancer. We undertook this study to validate these findings. METHODS: In this prospective cohort study, we analyzed the prognostic significance of TRß1 protein expression in the breast tumors of 796 women who had undergone breast surgery in the Henrietta Banting Breast Cancer database. All women were recruited after undergoing primary surgical therapy at Women's College Hospital (Toronto, ON, Canada) between January 1987 and December 2000. Details regarding patient age at diagnosis, systemic, and local therapies, as well as pathological features of their tumor have been systematically recorded. Clinical outcomes including breast cancer recurrence and death have been updated at least once each year with a median follow-up of 9.6 years (range 0.1-21 years). RESULTS: High TRß1 expression (> 4 on the Allred score) was associated with a longer breast cancer-specific survival with a HR 0.45 (95% CI 0.33-0.61), p < 0.0001 in a univariable Cox regression model. This was maintained in a multivariable model adjusted for age, tumor size, nodal status, chemotherapy, hormone therapy, radiotherapy, surgery, and ER status with a HR of 0.61 (95% CI 0.44-0.85), p = 0.004. CONCLUSIONS: High expression of TRß1 is associated with longer breast cancer-specific survival independent of other prognostic factors. Given that low TRß expression is associated with chemotherapy resistance in-vitro, TRß1 may also serve as a predictive biomarker or even a therapeutic target given the availability of TRß agonists.

Refined estimates of local recurrence risks by DCIS score adjusting for clinicopathological features: a combined analysis of ECOG-ACRIN E5194 and Ontario DCIS cohort studies.

PURPOSE: Better tools are needed to estimate local recurrence (LR) risk after breast-conserving surgery (BCS) for DCIS. The DCIS score (DS) was validated as a predictor of LR in E5194 and Ontario DCIS cohort (ODC) after BCS. We combined data from E5194 and ODC adjusting for clinicopathological factors to provide refined estimates of the 10-year risk of LR after treatment by BCS alone. METHODS: Data from E5194 and ODC were combined. Patients with positive margins or multifocality were excluded. Identical Cox regression models were fit for each study. Patient-specific meta-analysis was used to calculate precision-weighted estimates of 10-year LR risk by DS, age, tumor size and year of diagnosis. RESULTS: The combined cohort includes 773 patients. The DS and age at diagnosis, tumor size and year of diagnosis provided independent prognostic information on the 10-year LR risk (p ≤ 0.009). Hazard ratios from E5194 and ODC cohorts were similar for the DS (2.48, 1.95 per 50 units), tumor size ≤ 1 versus  > 1-2.5 cm (1.45, 1.47), age ≥ 50 versus < 50 year (0.61, 0.84) and year ≥ 2000 (0.67, 0.49). Utilization of DS combined with tumor size and age at diagnosis predicted more women with very low (≤ 8%) or higher (> 15%) 10-year LR risk after BCS alone compared to utilization of DS alone or clinicopathological factors alone. CONCLUSIONS: The combined analysis provides refined estimates of 10-year LR risk after BCS for DCIS. Adding information on tumor size and age at diagnosis to the DS adjusting for year of diagnosis provides improved LR risk estimates to guide treatment decision making.

Budget impact analysis of a breast rapid diagnostic unit.

BACKGROUND: The Odette Cancer Centre's recent implementation of a rapid diagnostic unit (rdu) for breast lesions has significantly decreased wait times to diagnosis. However, the economic impact of the unit remains unknown. This project defined the development and implementation costs and the operational costs of a breast rdu in a tertiary care facility. METHODS: From an institutional perspective, a budget impact analysis identified the direct costs associated with the breast rdu. A base-case model was also used to calculate the cost per patient to achieve a diagnosis. Sensitivity analyses computed costs based on variations in key components. Costs are adjusted to 2015 valuations using health care-specific consumer price indices and are reported in Canadian dollars. RESULTS: Initiation cost for the rdu was $366,243. The annual operational cost for support staff was $111,803. The average per-patient clinical cost for achieving a diagnosis was $770. Sensitivity analyses revealed that, if running at maximal institutional capacity, the total annual clinical cost for achieving a diagnosis could range between $136,080 and $702,675. CONCLUSIONS: Establishment and maintenance of a breast rdu requires significant investment to achieve reductions in time to diagnosis. Expenditures ought to be interpreted in the context of institutional patient volumes and trade-offs in patient-centred outcomes, including lessened patient anxiety and possibly shorter times to definitive treatment. Our study can be used as a resource-planning tool for future rdus in health care systems wishing to improve diagnostic efficiency.

An International Multicenter Review of the Malignancy Rate of Excised Papillomatous Breast Lesions.

BACKGROUND: Papillary lesions of the breast are a relatively rare, but heterogeneous group ranging from benign to atypical and malignant. Debate exists regarding the optimal management of these lesions. In the absence of more accurate risk-stratification models, traditional management guidelines recommend surgical excision, despite the majority of lesions proving benign. This study sought to determine the rate of malignancy in excised breast papillomas and to elucidate whether there exists a population in which surgical excision may be unnecessary. METHODS: A multicenter international retrospective review of core biopsy diagnosed breast papillomas and papillary lesions was performed between 2009 and 2013, following institutional ethical approval. Patient demographics, histopathological, and radiological findings were recorded. All data was tabulated, and statistical analysis performed using Stata. RESULTS: A total of 238 patients were included in the final analysis. The age profile of those with benign pathology was significantly younger than those with malignant pathology (p < 0.001). Atypia on core needle biopsy was significantly associated with a final pathological diagnosis of malignancy (OR = 2.73). The upgrade rate from benign core needle biopsy to malignancy on the final pathological sample was 14.4 %; however, only 3.7 % had invasive cancer. CONCLUSIONS: This international dataset is one of the largest in the published literature relating to breast papillomas. The overall risk of malignancy is significantly associated with older age and the presence of atypia on core needle biopsy. It may be possible to stratify higher-risk patients according to age and core needle biopsy findings, thereby avoiding surgery on low-risk patients.

Assessment of endometrial sampling as a predictor of final surgical pathology in endometrial cancer.

BACKGROUND: The histology and grade of endometrial cancer are important predictors of disease outcome and of the likelihood of nodal involvement. In most centres, however, surgical staging decisions are based on a preoperative biopsy. The objective of this study was to assess the concordance between the preoperative histology and that of the hysterectomy specimen in endometrial cancer. METHODS: Patients treated for endometrial cancer during a 10-year period at a tertiary cancer centre were identified from a prospectively collected pathological database. All pathology reports were reviewed to confirm centralised reporting of the original sampling or biopsy specimens; patients whose biopsies were not reviewed by a dedicated gynaecological pathologist at the treating centre were excluded. Surgical pathology data including histology, grade, depth of myometrial invasion, cervical stromal involvement and lymphovascular space invasion (LVSI) as well as preoperative histology and grade were collected. Preoperative and final tumour cell type and grade were compared and the distribution of other high-risk features was analysed. RESULTS: A total of 1329 consecutive patients were identified; 653 patients had a centrally reviewed epithelial endometrial cancer on their original biopsy, and are included in this study. Of 255 patients whose biopsies were read as grade 1 (G1) adenocarcinoma, 45 (18%) were upgraded to grade 2 (G2) on final pathology, 6 (2%) were upgraded to grade 3 (G3) and 5 (2%) were read as a non-endometrioid high-grade histology. Overall, of 255 tumours classified as G1 endometrioid cancers on biopsy, 74 (29%) were either found to be low-grade (G1-2) tumours with deep myometrial invasion, or were reclassified as high-grade cancers (G3 or non-endometrioid histologies) on final surgical pathology. Despite these shifts, we calculate that omitting surgical staging in preoperatively diagnosed G1 endometrioid cancers without deep myometrial invasion would result in missing nodal involvement in only 1% of cases. CONCLUSIONS: Preoperative endometrial sampling is only a modest predictor of surgical pathology features in endometrial cancer and may underestimate the risk of disease spread and recurrence. In spite of frequent shifts in postoperative vs preoperative histological assessment, the predicted rate of missed nodal metastases with a selective staging policy remains low.

What is the burden of axillary disease after neoadjuvant therapy in women with locally advanced breast cancer?

BACKGROUND: The burden of axillary disease in patients with locally advanced breast cancer (labc) after neoadjuvant therapy (nat) has not been extensively described in a large modern cohort. Here, we describe the extent of nodal metastases after nat in patients with labc. METHODS: All patients with labc treated at a single institution during 2002-2007 were identified. Demographic, radiologic, and pathologic variables were extracted. To assess the extent of lymph node metastases after nat, patients were separated into two groups: those with and without clinical or radiologic evidence of lymph node metastases before nat. Axillary lymph nodes retrieved at surgery that had no evidence of metastases after hematoxylin and eosin (h&e) staining underwent further pathology evaluation. RESULTS: Of the 116 patients identified, 115 were female (median age: 48.5). Before nat, 26 patients were clinically and radiologically node-negative; of those 26, 14 were histologically negative on final pathology. After serial sectioning and immunohistochemistry, 9 of 26 (35%) were node-negative. Of the 90 patients who had clinical or radiologic evidence of lymph node metastases before nat, 23 (26%) had no evidence of lymph node metastases on h&e staining. After serial sectioning and immunohistochemistry, 19 (21%) had no further axillary lymph node metastases. Overall, 76% of patients had pathology evidence of lymph node metastases after nat. CONCLUSIONS: Most patients with labc have axillary metastases after nat. Our findings support axillary lymph node dissection and locoregional radiation in most patients with labc after nat.

HER2/neu and Ki-67 expression predict non-invasive recurrence following breast-conserving therapy for ductal carcinoma in situ.

BACKGROUND: Ductal carcinoma in situ (DCIS) is a non-invasive form of breast cancer that may progress to invasive cancer. Identification of factors that predict recurrence and distinguish DCIS from invasive recurrence would facilitate treatment recommendations. We examined the prognostic value of nine molecular markers on the risks of local recurrence (DCIS and invasive) among women treated with breast-conserving therapy. METHODS: A total of 213 women who were treated with breast-conserving therapy between 1982 and 2000 were included; 141 received breast-conserving surgery alone and 72 cases received radiotherapy. We performed immunohistochemical staining on the DCIS specimen for nine markers: oestrogen receptor, progesterone receptor, Ki-67, p53, p21, cyclinD1, HER2/neu, calgranulin and psoriasin. We performed univariable and multivariable survival analyses to identify markers associated with the recurrence. RESULTS: The rate of recurrence at 10 years was 36% for patients treated with breast-conserving surgery alone and 18% for women who received breast-conserving surgery and radiotherapy. HER2/neu+/Ki-67+ expression was associated with an increased risk of DCIS recurrence, independent of grade and age (HR=3.22; 95% CI: 1.47-7.03; P=0.003). None of the nine markers were predictive of invasive recurrence. CONCLUSION: Women with a HER2/neu/neu+/Ki67+ DCIS have a higher risk of developing DCIS local recurrence after breast-conserving surgery.

Tumour characteristics among women with very low-risk breast cancer.

It has been proposed that a proportion of non-palpable breast cancers that are diagnosed through mammography represents a very low-risk subgroup of cancers that may not affect survival (overdiagnosis). The salient pathologic features of cancers in this theoretical subgroup are not known, and therefore, it is not possible to predict which patients have a cancer of this type. We reviewed the clinical characteristics and survival experiences of 715 patients with an invasive breast cancer of 5.0 cm or less. The tumour from each patient was represented in triplicate on a tissue microarray. Cases were divided into low-risk and moderate-/high-risk categories based on lymph node status and palpability. Low-risk cancers were those that were non-palpable, node-negative and were only detected by mammographic screening. All other cancers were high/moderate risk. The two groups of cancer patients were compared for a number of tumour characteristics, based on immunohistochemistry. There were 79 low-risk cancers and 636 moderate-/high-risk cancers. The low-risk cancers were characterized by ER-positivity, PR-positivity, HER2-negativity, ck5/6-negativity, EGFR-negativity and p53-negativity. About 54 of the 79 low-risk cancers (68 %) were of the luminal A subtype versus 335 of 636 moderate-/high-risk cancers (53 %; p = 0.008). Among 42 women with a non-palpable, mammogram-detected PR+ HER2- cancer of 5.0 cm or less, the 15-year distant recurrence-free survival rate was 100 %. Small breast cancers that are PR+ and HER2- and that are detectable by mammogram alone have a very low risk of recurrence. A proportion of these may represent examples of overdiagnosis.

Insulin like growth factor binding protein-7 reduces growth of human breast cancer cells and xenografted tumors.

Previously, we have shown that insulin-like growth factor binding protein-7 (IGFBP-7) expression is inversely correlated with disease progression in breast cancer and is associated with poor outcome. To further investigate the role of IGFBP-7 in the growth and metastatic behavior of breast cancer, primary breast tumors and metastatic tumors derived from the same patients were analyzed for IGFBP-7 expression. Immunohistochemical analysis revealed that IGFBP-7 is downregulated in half of the human metastatic breast tumors tested. IGFBP-7 has been linked to suppression of oncogenic pathways and can directly restore cellular senescence in melanomas, leading to their regression. It is possible that breast tumors with metastatic potential have escaped from IGFBP-7-induced suppression by its down-regulation. Twenty-two human primary breast tumor specimens were transplanted into human-bone NOD/SCID mice. One of the two triple negative primary breast tumors was serially xenotransplanted more than five times. Each serial transplant resulted in increased tumor take and rate of growth. Expression of IGFBP-7 was downregulated upon each serial implantation. To investigate the role of IGFBP-7 in breast tumor suppression, IGFBP-7 was overexpressed in the triple negative MDA-MB-468 human breast cancer line by stable transfection of a pSec-tag2-IGFBP-7 vector. The parental MDA-MB-468 breast cancer cells expressed extremely low levels of endogenous IGFBP-7. The production of IGFBP-7 protein by the MDA-MB-468 cells stably transfected with IGFBP-7 was confirmed by immunoblotting with anti-IGFBP-7 antibody. Ectopic overexpression of IGFBP-7 significantly reduced the growth of the IGFBP-7 transfected MDA-MB-468 cells compared to the parental MDA-MB-468 cells. We also assessed the role of IGFBP-7 on cell migration, a key determinant of malignant progression and metastasis. When parental MDA-MB-468 cells were treated with various amounts of conditioned medium derived from the IGFBP-7 overexpressing cell line, a significant difference in cell migration rate was observed between untreated and treated cells. IGFBP-7 strongly suppressed the phosphorylation of the mitogen-activated protein kinases (MAPK) ERK-1/2, suggesting that IGFBP-7 mediates its anti-proliferative effects through negative feedback signaling. Levels of phospho-ERK-1/2 were higher in the parental MDA-MB-468 than in IGFBP-7-expressing cells derived from it. When injected subcutaneously into NOD/SCID mice, the increased expression of IGFBP-7 in the MDA-MB-468 transfected cells reduced the rate of tumor growth in comparison to the parental MDA-MB-468 controls. These results suggest that the growth of breast cancer could be prevented by the forced expression of IGFBP-7 protein.

Sentinel lymph node biopsy vs. pelvic lymphadenectomy in early stage cervical cancer: is it time to change the gold standard?

OBJECTIVE: To compare the incidence of pelvic lymph node metastases in early stage cervical cancer patients undergoing sentinel lymph node biopsy (SLN) to a matched cohort undergoing pelvic lymphadenectomy. METHODS: All patient data were entered prospectively into an ongoing cervical cancer database. Since April 2004, 87 patients with FIGO stage IA/B1 cervical cancer underwent SLN detection with identification of bilateral SLN. This cohort (cases) was compared to a matched group of patients who underwent complete pelvic lymphadenectomy (controls). The groups were matched 3:1 for tumour size (+/-5 mm), histology, depth of invasion (+/-2 mm), and presence of capillary lymphatic space invasion (CLS). Descriptive statistics were calculated for all variables of interest. The association between cases and controls and lymph node metastases was carried out using a conditional logistic regression analysis. RESULTS: 81 women in the SLN cohort were matched with 1 control, 72 cases with 2 controls, and 65 cases with 3 controls. Among cases, 14 (17%) had pelvic lymph nodes metastases vs. 15 (7%) in the controls (p=0.0059, odds ratio= 2.8, 95% CI=1.3-5.9). Among the 14 cases of SLN metastases, 11 were detected by frozen section and 3 were detected on final paraffin sectioning. All were detected by H and E stains. The size of the SLN metastases ranged from less than 1 mm to 8 mm. CONCLUSIONS: Sentinel lymph node biopsy in early cervical cancer is a more sensitive procedure in detecting pelvic lymph node metastases compared to complete lymphadenectomy.

Intraoperative margin assessment of the radical trachelectomy specimen.

OBJECTIVE: To summarize our experience in the frozen section (FS) assessment of the trachelectomy surgical margin. METHODS: All surgeries from 1994 to 2007 were performed by one surgeon. The FS examination was consistently carried out by a group of gynecologic pathologists according to the protocol described in details in this article. Cases were retrieved from the pathology files and the slides were reviewed by two pathologists. RESULTS: 132 patients were identified with complete pathology records. They ranged from 17 to 46 years old (median 31). Surgeries were performed for clinical Stages 1A (n=39) and 1B (n=93) tumors (63 adenocarcinoma, 59 squamous cell carcinoma, 7 adenosquamous and 3 others). In 78 cases, no residual tumor was seen in the trachelectomy specimens as it was resected by the preceding LEEP or cone. The margin was reported as negative in 123, suspicious in 3 and positive in 6 cases. It was revised in 16 cases (6 positive, 2 suspicious and 8 negative but <5 mm). Final margin assessment agreed with the FS diagnosis in 130 (98.5%) and showed interpretational overcall in 2 cases (1.5%); only one of which resulted in a revised margin. No false negative intraoperative assessment was found. CONCLUSIONS: We describe our FS protocol and summarize our data. This protocol is reliable since none of the patients was under-treated.

The transition module: a method for preventing overfitting in convolutional neural networks.

Digital pathology has advanced substantially over the last decade with the adoption of slide scanners in pathology labs. The use of digital slides to analyse diseases at the microscopic level is both cost-effective and efficient. Identifying complex tumour patterns in digital slides is a challenging problem but holds significant importance for tumour burden assessment, grading and many other pathological assessments in cancer research. The use of convolutional neural networks (CNNs) to analyse such complex images has been well adopted in digital pathology. However, in recent years, the architecture of CNNs has altered with the introduction of inception modules which have shown great promise for classification tasks. In this paper, we propose a modified 'transition' module which encourages generalisation in a deep learning framework with few training samples. In the transition module, filters of varying sizes are used to encourage class-specific filters at multiple spatial resolutions followed by global average pooling. We demonstrate the performance of the transition module in AlexNet and ZFNet, for classifying breast tumours in two independent data-sets of scanned histology sections; the inclusion of the transition module in these CNNs improved performance.

Tumor Infiltrating Lymphocytes in Breast Cancer Patients with Progressive Disease during Neoadjuvant Chemotherapy.

A minority of breast cancer (BC) patients progress during neoadjuvant chemotherapy (NCT). The aim of this study was to assess the value of Tumor infiltrating lymphocytes (TILs) in such a high-risk population where valid biomarkers are eagerly needed. A retrospective review identified BC patients who either progressed during NCT or achieved a pathologic complete response (pCR). An experienced BC pathologist semi-quantified stromal TILs in pre-treatment core biopsies using hematoxylin and eosin stained slides. The primary outcome was to compare the levels of TILs between the 2 groups as a continuous and categorical variable using the t-test and X2 test as appropriate. The secondary outcome was to compare survival outcomes between patients with high versus low TILs level using the log-rank test. Fifty patients were successfully identified and assessed for TILs: 21 progressed during NCT and 29 had a pCR. Patients with progressive disease were older with more advanced disease (p = 0.03, p = 0.0001 respectively). A significantly lower mean level of TILs was found in patients with progressive disease compared to patients with pCR: 14.3% (Standard Deviation (SD): 16.9) versus 32.8% (SD: 31), p = 0.01). The level of TILs was neither associated with baseline characteristics nor with survival outcomes. BC patients progressing during NCT have low TILs levels compared to patients with pCR. Prospective studies are needed to establish the utility of TILs as early biomarkers of tumor response, particularly in patients with disease progression who need novel treatment approaches.

Radical vaginal trachelectomy vs. radical hysterectomy for small early stage cervical cancer: a matched case-control study.

OBJECTIVE: To determine the efficacy and outcome from radical vaginal trachelectomy (RVT) compared to a matched group of patients undergoing radical hysterectomy for small early stage cervical cancer. METHODS: All patient data were entered prospectively. Patients wishing preservation of fertility with cervical cancer, tumor <2 cm, and not meeting the definition of microinvasive cancer were offered RVT. The outcomes were compared to a matched group of patients who underwent radical hysterectomy for stage IA/IB cervical cancer. Groups were matched 1:1 for age (+/-5 years), tumor size (+/-1 mm), histology, grade, depth of invasion (+/-1 mm), presence of capillary lymphatic space invasion, pelvic lymph node metastasis, and adjuvant radiotherapy. RESULTS: A total of 137 patients underwent RVT between 1994 and 2007. Of them, 90 patients were successfully matched. Median tumor size was microscopic. Moreover, 43% and 49% were squamous and had adeno/adenosquamous histology. Median depth of invasion was 3.1 mm. Capillary lymphatic space invasion was present in 68% of cases. Of the tumors, 60% were grade 1, 29% were grade 2, and 11% were grade 3. After a median follow-up of 51 and 58 months, 5 and 1 recurrences were diagnosed in the RVT and radical hysterectomy groups, respectively. Five-year recurrence-free survival rates were present in 95% and 100% of the groups, respectively (p=0.17). In addition, 3 and 1 deaths occurred in the RVT and radical hysterectomy groups, resulting in 5-year survival rates of 99% and 100%, respectively (p=0.55). CONCLUSIONS: RVT seems to be the procedure of choice for women with small early stage cervical cancers wishing to preserve fertility.

Hyperinsulinemia induces myocardial infarctions and arteriolar medial hypertrophy in spontaneously hypertensive rats.

To investigate the effects of hyperinsulinemia on the myocardial vessels, long acting insulin (mixtard, a combination of 30% regular human insulin and 70% NPH human insulin) was injected daily for 8 weeks, intraperitoneally, in two strains of rats, normotensive WKY and hypertensive SHR. There were four groups in all, a control group, and an insulin-injected group in each strain. The drinking water contained 10% glucose to prevent hypoglycemia in the insulin-injected rats. At the end of the 8 weeks experimental period, after measuring blood pressure and taking blood for the determination of glucose, urea, creatinine, and insulin, the rats were killed. The organs were fixed in formaldehyde. The blood glucose levels were higher at the end of the experiment, in both the placebo- (saline)-injected and the insulin-injected rats. Blood pressure rose significantly only in the insulin-injected SHR. The intramyocardial arterioles in the insulin-injected SHR had a significantly thicker vascular wall than the placebo-injected SHR, as represented by the vessel wall to lumen ratio, because of hypertrophy of the media. When compared with the placebo injected WKY rats, there was a higher wall/lumen ratio of the intramyocardial arterioles in the insulin-injected WKY, but the difference did not reach significance. Heart weights factored by body weights was significantly higher in insulin-injected as compared with placebo-injected SHR. Myocardial infarctions were observed in four of eight rats in the insulin-injected SHR group despite the fact that there were no signs of atherosclerosis or intimal thickening. It is possible that the increase in heart weight and the probable increase in metabolic activity resulting from hyperinsulinemia, together with the increased oxygen demand of the myocardium and the arteriolar narrowing, may have contributed to the occurence of myocardial infarctions in the absence of atherosclerotic coronary occlusion.

Cancer care Ontario guideline recommendations for hormone receptor testing in breast cancer.

Hormone receptor testing (oestrogen and progesterone) in breast cancer at the time of primary diagnosis is used to guide treatment decisions. Accurate and standardised testing methods are critical to ensure the proper classification of the patient's hormone receptor status. Recommendations were developed to improve the quality and accuracy of hormone receptor testing based on a systematic review conducted jointly by the American Society of Clinical Oncology/College of American Pathologists and Cancer Care Ontario's Program in Evidence-Based Care. Evidence-based recommendations were formulated to set standards for optimising immunohistochemistry in assessing hormone receptor status, as well as assuring quality and proficiency between and within laboratories. A formal external review was conducted to validate the relevance of these recommendations. It is anticipated that widespread adoption of these guidelines will further improve the accuracy of hormone receptor testing in Canada.

Interobserver agreement for endometrial cancer characteristics evaluated on biopsy material.

A shift toward a disease-based therapy designed according to patterns of failure and likelihood of nodal involvement predicted by pathologic determinants has recently led to considering a selective approach to lymphadenectomy for endometrial cancer. Therefore, it became critical to examine reproducibility of diagnosing the key determinants of risk, on preoperative endometrial tissue samples as well as the concordance between preoperative and postresection specimens. Six gynaecologic pathologists assessed 105 consecutive endometrial biopsies originally reported as positive for endometrial cancer for cell type (endometrioid versus nonendometrioid), tumor grade (FIGO 3-tiered and 2-tiered), nuclear grade, and risk category (low risk defined as endometrioid histology, grade 1 + 2 and nuclear grade <3). Interrater agreement levels were substantial for identification of nonendometrioid histology (κ = 0.63; SE = 0.025), high tumor grade (κ = 0.64; SE = 0.025), and risk category (κ = 0.66; SE = 0.025). The overall agreement was fair for nuclear grade (κ = 0.21; SE = 0.025). There is agreement amongst pathologists in identifying high-risk pathologic determinants on endometrial cancer biopsies, and these highly correlate with postresection specimens. This is ascertainment prerequisite adaptation of the paradigm shift in surgical staging of patients with endometrial cancer.

Expression of HER2neu in ductal carcinoma in situ is associated with local recurrence.

AIMS: Determination of the risk of recurrence after local excision of ductal carcinoma in situ (DCIS) remains a challenge. Molecular profiling based on immunohistochemical staining to oestrogen receptor (ER), progesterone receptor (PR) and HER2neu improved risk prediction in invasive breast cancer, but few studies have evaluated if molecular classification of DCIS predicts local recurrence. We evaluated the expression of ER, PR and HER2neu in DCIS to determine if molecular classification predicts local recurrence after breast-conserving therapy for DCIS. MATERIALS AND METHODS: We reviewed the records of patients with DCIS treated between 1987 and 2000, carried out a pathology review and immunohistochemical staining for ER, PR and HER2neu and categorised cases into four molecular phenotypes [luminal A (ER+ and/or PR+, HER2neu-), luminal B (ER+ and/or PR+, HER2neu+), HER2neu subtype (ER-, PR-, HER2neu+), triple negative (ER-, PR-, HER2neu-)]. We evaluated the association between the molecular subtype and the development of local recurrence. RESULTS: In total, 180 cases of DCIS were included in the study (luminal A, n=113; luminal B, n=25; HER2neu type, n=29; triple negative, n=13). The median follow-up time was 8.7 years. We observed higher rates of local recurrence among luminal B (40%) and HER2neu type (38%) DCIS compared with luminal A (21%) and triple negative (15%) DCIS. On multivariable analysis, HER2neu overexpression was associated with an increased risk of local recurrence (hazard ratio=1.98; 95% confidence interval: 1.11, 3.53, P=0.02). CONCLUSION: HER2neu expression in DCIS is a significant predictor of local recurrence, whereas luminal A and triple negative phenotypes are associated with relatively low risks of local recurrence.