Age at diagnosis predicts local recurrence in women treated with breast-conserving surgery and postoperative radiation therapy for ductal carcinoma in situ: a population-based outcomes analysis.

PURPOSE: The main goal of treating ductal carcinoma in situ (dcis) is to prevent the development of invasive breast cancer. Most women are treated with breast-conserving surgery (bcs) and radiotherapy. Age at diagnosis may be a risk factor for recurrence, leading to concerns that additional treatment may be necessary for younger women. We report a population-based study of women with dcis treated with bcs and radiotherapy and an evaluation of the effect of age on local recurrence (lr). METHODS: All women diagnosed with dcis in Ontario from 1994 to 2003 were identified. Treatments and outcomes were collected through administrative databases and validated by chart review. Women treated with bcs and radiotherapy were included. Survival analyses were performed to evaluate the effect of age on outcomes. RESULTS: We identified 5752 cases of dcis; 1607 women received bcs and radiotherapy. The median follow-up was 10.0 years. The 10-year cumulative lr rate was 27% for women younger than 45 years, 14% for women 45-50 years, and 11% for women more than 50 years of age (p < 0.0001). The 10-year cumulative invasive lr rate was 22% for women younger than 45 years, 10% for women 45-50 years, and 7% for women more than 50 years of age (p < 0.0001). On multivariate analyses, young age (<45 years) was significantly associated with lr and invasive lr [hazard ratio (hr) for lr: 2.6; 95% confidence interval (ci): 1.9 to 3.7; p < 0.0001; hr for invasive lr: 3.0; 95% ci: 2.0 to 4.4; p < 0.0001]. An age of 45-50 years was also significantly associated with invasive lr (hr: 1.6; 95% ci: 1.0 to 2.4; p = 0.04). CONCLUSIONS: Age at diagnosis is a strong predictor of lr in women with dcis after treatment with bcs and radiotherapy.

Testing for her2 in breast cancer: current pathology challenges faced in Canada.

This review is designed to highlight several key challenges in the diagnosis of human epidermal growth factor receptor 2 (her2)-positive breast cancer currently faced by pathologists in Canada: Pre-analysis issues affecting the accuracy of her2 testing in non-excision sample types: core-needle biopsies, effusion samples, fine-needle aspirates, and bone metastasesher2 testing of core-needle biopsies compared with surgical specimensCriteria for retesting her2 status upon disease recurrenceLiterature searches for each topic were carried out using the medline, Embase, International Pharmaceutical Abstracts, and biosis databases. In addition, the congress databases of the American Society of Clinical Oncology (2005-2011) and the San Antonio Breast Cancer Symposium (2007-2011) were searched for relevant abstracts.All authors are expert breast pathologists with extensive experience of her2 testing, and several participated in the development of Canadian her2 testing guidelines. For each topic, the authors present an evaluation of the current data available for the guidance of pathology practice, with recommendations for the optimization or improvement of her2 testing practice.

Immunolocalization of matrix metalloproteinases and their inhibitors in clinical specimens of bone metastasis from breast carcinoma.

Matrix metalloproteinases (MMPs) are essential in several stages of the metastatic process, and in normal bone development and remodeling. We explored whether the interaction between tumor cells and bone leads to changes in MMP and tissue inhibitor of MMP (TIMP) expression thus affecting osteolysis in metastatic bone disease. Using immunohistochemistry we have investigated the MMP/TIMP expression in tumor cells, fibroblasts, osteoblasts and osteoclasts. Thirty one specimens of bone metastasis from breast carcinoma were stained for MMP-1, -2, -9, MT1-MMP and TIMP-1, and -2 and compared with staining in normal breast tissue, primary breast carcinoma and normal bone. Specimens came from patients in three clinical scenarios: from open biopsies without or with pathological fracture, or bone marrow biopsies containing tumor from patients with pancytopenia but without clinical evidence of osteolysis. By bone histomorphometry the latter group showed a heavy tumor load not different from the open biopsy groups but displayed little active bone resorption and low numbers of osteoclasts. Cell type-specific MMP/TIMP expression was observed and the staining patterns were comparable between the three groups of patients. Though no major differences in the MMP/TIMP staining of tumor cells and fibroblasts were observed between bone metastasis and primary tumor, we showed that tumor cells do express MMPs capable of degrading bone matrix collagen. The number and activity of osteoclasts and osteoblasts was increased dramatically in bone metastases, their MMP/TIMP profiles, however, were not different from normal bone, suggesting that the mechanism of bone degradation by osteoclasts is not different from normal bone remodelling.

The pathogenesis of venous limb gangrene associated with heparin-induced thrombocytopenia.

BACKGROUND: Platelet-mediated arterial occlusion is a well-recognized cause of limb loss in patients with heparin-induced thrombocytopenia. However, the syndrome of distal ischemic necrosis complicating the deep venous thrombosis (venous limb gangrene) sometimes associated with heparin-induced thrombocytopenia has not been well characterized. OBJECTIVE: To study the pathogenesis of venous limb gangrene associated with heparin-induced thrombocytopenia. DESIGN: Characterization (based on descriptive and case-control studies) of a novel syndrome of limb loss and hypothesis testing by analysis of plasma samples. SETTING: Five university-associated hospitals in one medical community. PATIENTS: Clinical and laboratory records of 158 patients with heparin-induced thrombocytopenia were reviewed to identify patients with venous limb gangrene (n = 8), limb arterial thrombosis (n = 10), and uncomplicated deep venous thrombosis (n = 58). MEASUREMENTS: Clinical and laboratory factors associated with venous limb gangrene, including thrombin-antithrombin complexes and vitamin K-dependent procoagulant and anticoagulant factors. RESULTS: Warfarin treatment was more frequently associated with venous limb gangrene than with limb arterial thrombosis (8 of 8 patients compared with 3 of 10 patients; P = 0.004). The anticoagulant effect of warfarin seemed greater in the 8 patients with venous limb gangrene than in the 58 patients who did not develop gangrene (median International normalized ratio, 5.8 compared with 3.1; P < 0.001). Compared with plasma from controls, plasma from patients with venous limb gangrene had a higher ratio of thrombin-antithrombin complex to protein C activity during warfarin treatment. No hereditable abnormalities of the protein C anticoagulant pathway were seen in any patient. CONCLUSIONS: Warfarin treatment of deep venous thrombosis associated with heparin-induced thrombocytopenia is a possible cause of venous limb gangrene, perhaps because of acquired failure of the protein C anticoagulant pathway to regulate thrombin generation.

Reproducibility of DNA ploidy and S-phase values from paraffin-embedded tissue.

OBJECTIVE: To determine the degree of variability of DNA flow cytometric results between two types of flow cytometers. STUDY DESIGN: Single-cell suspensions were made from 40 paraffin blocks of ovarian carcinoma using a modified Hedley procedure. These samples were consecutively analyzed in both Coulter's Profile II and Elite Flow cytometers. Gated and ungated data were collected and analyzed using Phoenix flow system's multicycle software. RESULTS: There were 16 (40%) DNA diploid, 23 (58%) DNA aneuploid and 1 DNA tetraploid tumor. The degree of variability in the DNA index coefficient of variation of the G0/G1 diploid peak, percentage of S phase, percentage of G2M, percentage of debris plus percentage of clumps were compared. Excellent correlations of the results were obtained in the DNA index (r = .999) and in percentage of S phase (r = .946). CONCLUSION: It is feasible to standardize variables of flow cytometric instruments to obtain reproducible results.

Prognostic value of DNA ploidy as assessed with flow cytometry in uveal melanoma.

OBJECTIVE: To investigate the prognostic value of tumour cell DNA content, as determined with flow cytometry, in formalin-fixed paraffin-embedded tissue from patients with uveal melanoma. DESIGN: Case series. SETTING: Pathology Laboratory, Vancouver General Hospital. PATIENTS: Ninety patients with primary uveal (choroid) malignant melanoma diagnosed between 1975 and 1984 followed for at least 60 months. OUTCOME MEASURES: Tumour cell DNA content, 5-year and 10-year disease-specific survival rates. RESULTS: The DNA histograms were classifiable as diploid (67 cases) or aneuploid (18 cases) in 85 cases. On univariate analysis DNA content, age at diagnosis, histologic type of tumour, largest single tumour dimension and tumour volume were predictors of 10-year survival. Multivariate analysis with the stepwise Cox proportional hazards regression model did not confirm cellular DNA content as an independent prognostic factor. However, age at diagnosis, largest tumour dimension and presence of spindle vs. mixed or epithelioid cell pattern were significant predictors of death from uveal melanoma. CONCLUSIONS: DNA ploidy of uveal melanoma is not a statistically significant predictor of survival.

Epstein-Barr virus in non-Hodgkin's lymphomas and lymphoid tissue in children.

In developed countries the majority of adolescent children show serological evidence of past Epstein-Barr virus (EBV) infection. This virus is associated with non-Hodgkin's lymphomas in immunocompromised children, but the relationship of EBV DNA to these tumors in children without documented immunodeficiency has not been investigated by the polymerase chain reaction (PCR). We used a PCR method with primers from the Bam W and Bam HI regions to study non-Hodgkin's lymphomas in children, with tonsillar tissue of age-matched children as controls for the presence of EBV DNA. Six of the 20 tonsils were positive using the Bam W primers; another four showed this DNA with Bam HI primers. EBV DNA was detected in only one tumor (a lymphoblastic lymphoma) by both primer sets. The demonstration of EBV DNA in the tonsils reflects past infections and the incidence is in accordance with that expected from serologic epidemiological studies. The absence of demonstrable EBV DNA in 19 lymphomas suggests that this virus is of little consequence in the pathogenesis of non-Hodgkin's lymphomas in children who are not known to be immunocompromised. The lymphoblastic lymphoma had a mixed cell population, and the virus was not necessarily related to the malignancy.

Primary multilobulated B-cell lymphoma of the breast.

Malignant lymphomas with multilobulated nuclei are recently recognized neoplasms. We report a case of multilobulated B-cell lymphoma arising in the breast. The light microscopic, electron microscopic, and immunohistochemical features are described and compared with those of previously reported T- and B-cell multilobulated lymphomas from other sites. A follicular center cell origin of this lymphoma is postulated. To our knowledge, this is the first report of a primary multilobulated lymphoma of the breast.

Aspiration biopsy cytology of lymph nodes in malignant lymphoma.

The cytologic findings of needle aspiration biopsy of lymph nodes in malignant lymphoma are presented. In 42 of 49 cases, a correct cytologic diagnosis was rendered. There was one false-positive diagnosis. The diagnostic accuracy of needle aspiration cytology is high. It helps to select patients for further investigation and treatment, thereby avoiding unnecessary surgery in patients who present with lymphadenopathy. The technique is also useful in the staging work-up of patients with lymphoma and the diagnosis of recurrent disease during the follow-up period.