The prognostic value of Ki67 in systemically untreated patients with node-negative breast cancer.

AIM: To evaluate the utility of Ki67 as a prognostic marker in a series of patients with node-negative breast cancer untreated with adjuvant systemic therapy. METHODS: The cohort consisted of 203 cases treated with breast conserving surgery and radiation only; median follow-up was 183 months (range 156-277 months). An immunohistochemical panel of oestrogen receptor (ER), progesterone receptor (PR), cytokeratin (CK)5/6 and Ki67 and human epidermal growth factor 2 in situ hybridization (HER2-ISH) was performed on the tumour samples. Ki67 scores were evaluable in 193/203 patients (95.1%). The primary outcome was breast cancer specific survival (BCSS). RESULTS: Of the cohort, 29 (14.2%) died of breast cancer. A cut off of 10% separated tumours into a 'Ki67-low' (n=70) or 'Ki67-high' group (n=123). The breast cancer specific survival was 97.1% and 77.6% for Ki67-low and Ki67-high groups, respectively. Univariate analysis showed that in this lymph node-negative cohort, the predictors for BCSS were tumour size, Ki67, LVI, age and histological grade 3. Multivariable analysis showed that Ki67 index and lymphovascular space invasion were independent predictors of breast cancer death. To examine the utility of Ki67 in assignment of immunohistochemically molecular subtypes, cases were assigned into Luminal A (ER-positive, HER2-negative, Ki67 ≤14%), Luminal B (ER-positive, HER2-negative, Ki67 >14%) and triple negative (ER/PR-negative and HER2-negative, any Ki67). The 15-year breast cancer specific survival was 91.7%, 79.4% and 75.8%, respectively. CONCLUSIONS: A statistically significant difference in breast cancer specific survival is seen in groups defined using Ki67 and receptor status, whereas histological grading was not a significant predictor of survival. Ki67 immunostaining provides prognostic information beyond traditionally assessed clinicopathological variables.

HER2 testing in breast cancer: an overview of current techniques and recent developments.

Testing for HER2 positivity in breast cancer carries implications for prognosis and therapeutic response in patients. In recent times there have been numerous developments and refinements in the available technologies for HER2 testing. In addition to this, guidelines have been developed and modified in an attempt to improve reliability and accuracy of testing. Immunohistochemistry and FISH testing have been the most widely used methodology, and the technique which has the largest knowledge base. Some of the inherent disadvantages have prompted the development of newer brightfield techniques which overcome some of these issues. There is gathering experience with these emerging technologies. Despite efforts to optimise and standardise procedures there remains a small percentage of cases that continue to be unresolved, whether this be due to issues of polysomy of chromosome 17, other complex genetic changes or analytical/interpretative issues. An ideal method for the resolution of these equivocal results should be considered in a specialised testing/referral centre, and this may include karyotyping studies of chromosome 17 or multiple probes for chromosome 17 using fluorescence in situ hybridisation or multiplex ligation-dependent probe amplification.It is timely to review of some of the newer techniques available for routine testing and approaches for cases which prove difficult to resolve using conventional testing methodology.

Characteristics of HER2-positive breast cancer diagnosed following the introduction of universal HER2 testing.

The aim of this study was to determine the impact of universal HER2 testing on the clinico-pathologic profile of HER2+ breast cancer. Data were extracted from breast cancer pathology reports spanning two periods: before (2003/4, n = 379), and after (2008/9, n = 560) the introduction of universal testing. In 2003/4, 43.3% of breast cancers were tested for HER2 with 16% of tested cases HER2+. In 2008/9, 98.4% of cases were tested with 14.7% HER2+. In 2008/9, HER2+ status was associated with younger age, higher grade, increased tumour size, lymph node involvement, negative oestrogen and/or progesterone receptor status. HER2+ cases diagnosed in 2003/4 were not significantly different in respect of these features. The rate of HER2+ breast cancer amongst screen detected cases in 2008/9 was 8.3%. The phenotype of HER2+ breast cancer was stable following the introduction of universal testing. The overall rate of HER2+ breast cancer was influenced by screen detection.

Familial concordance of breast cancer pathology as an indicator of genotype in multiple-case families.

The heterogeneity of multiple case breast cancer families that do not carry mutations in BRCA1 or BRCA2 (non-BRCA1/2 families) poses a challenge to the identification of breast cancer susceptibility genes. The aim of this study was to determine whether intrafamilial concordance in breast cancer pathology could identify subgroups of non-BRCA1/2 families with consistent genotypic features. Invasive breast cancers were reviewed from 84 individuals belonging to 30 multiple-case families; BRCA1 (n = 9), BRCA2 (n = 10), and non-BRCA1/2 (n = 11). Hierarchical cluster analysis based on histopathology and age at first diagnosis was then used to specify three subgroups designated Clusters 1-3. The genomic features of non-BRCA1/2 families were examined by genome wide linkage and FGFR2 SNP genotyping, according to whether they showed cluster-concordant or cluster-mixed familial pathology. The majority of pathogenic BRCA1 mutation carriers (80%) fell into a single cluster. In contrast pathogenic BRCA2 mutation carriers were distributed across all three clusters and within families, cluster groups were also generally mixed. Most non-BRCA1/2 mutation carriers belonged to Cluster 3 (71%). Genome wide linkage data from five non-BRCA1/2 Cluster 3-concordant families were compared with four mixed cluster non-BRCA1/2 families. This revealed a number of distinct linkage peaks, including some regions previously associated with breast cancer susceptibility. The distribution of low risk alleles in FGFR2 was not different between these two subgroups (P = 0.237). The pattern of breast cancer pathology concordance amongst family members may assist the investigation of breast cancer susceptibility in multiple case families.

Diagnostic evaluation of papillary lesions of the breast on core biopsy.

The management of asymptomatic intraductal papillary lesions of the breast diagnosed on core biopsy poses a challenge for patients and clinicians, as the distinction between common benign lesions and atypical or malignant varieties may be difficult without formal excision. The aim of this study was to determine whether a combination of histopathologic and biomarker features could be used to accurately identify benign papillary lesions on core biopsy. An inclusive group of 127 excised papillary lesions was characterized by detailed histopathologic review and immunohistochemical staining for the basal markers cytokeratin 5/6 (CK5/6) and P63 and the proliferation marker Ki67. Comparison of benign, atypical, and malignant lesions revealed that the combination of broad, sclerotic fibrovascular cores, and epithelial CK5/6 staining was most commonly seen in benign papillomas. Ki67 staining revealed striking intralesional heterogeneity, but there was no difference between the high scores of benign, atypical, or malignant lesions (P=0.173). In a non-overlapping set of 42 cases, a binary classifier specifying benign lesions on the basis of thick fibrovascular cores and epithelial CK5/6 staining on core biopsy gave an overall misclassification rate of 4/42 (10%) when compared with the final excision diagnosis. Misclassified cases included 2/27 lesions ultimately diagnosed as benign and 2/2 atypical papillomas. All malignant lesions (n=13) were correctly assigned. The combined assessment of fibrovascular core thickness and CK5/6 staining on core biopsy distinguished benign from malignant papillary lesions, but did not separate benign from atypical cases. This approach may form a useful addition to the clinicopathologic evaluation of papillary lesions of the breast.

A class discovery and class prediction approach to histopathological classification of mammographic screen detected columnar cell lesions of the breast.

AIMS: Columnar cell lesions (CCLs) of the breast have been increasingly recognised in biopsies taken to investigate mammographic screen detected microcalcification. The aim of this study was to identify distinct CCL subtypes by systematic analysis of histopathology. METHODS: Hierarchical cluster analysis was performed based on the profile of histopathological features in 102 screen detected CCLs. Features assessed included nuclear morphology, acinar dilatation, epithelial cell hyperplasia, cell crowding, apical snout formation and intraluminal secretion. The stability of this classification was tested in an independent cohort of 32 cases. RESULTS: The histopathology of screen detected CCLs was extremely variable. Hierarchical cluster analysis identified two subclasses: Class 1 (34/102, 33%) characterised by absence of nuclear atypia and less pronounced hyperplasia; and Class 2 (68/102, 67%) that were generally more atypical. Ki-67 scores were significantly lower for Class 1 CCLs (p < 0.001). In the independent cohort of 32 cases, Class 1 cases were clearly distinguished from Class 2, indicating that these were stable phenotypes amongst screen detected CCLs. CONCLUSIONS: The histopathological features of CCLs diagnosed at screening are extremely heterogeneous. Using a systematic approach, we have devised a broad classification system that delineates a category of less atypical CCLs that could form a basis for future studies.

Is survival from infiltrating lobular carcinoma of the breast different from that of infiltrating ductal carcinoma?

Previous studies of patients with breast cancer have compared survival of invasive ductal carcinoma (IDC) and invasive lobular carcinoma (ILC) with contradictory results. This study examines the effect of the diagnosis of IDC or ILC in conjunction with age at diagnosis, pathologic tumor size, pathologic stage, histologic grade, and lymph node status of 307 women with IDC or ILC in 1992 in the Greater Western region of Sydney in Australia. Survival analysis was conducted using the Kaplan-Meier method. Relative risks associated with IDC or ILC and other important prognostic factors and adjusted for each other were computed using Cox proportional hazard regression. The proportion of grade I tumors was significantly higher in ILC (41%) than in IDC (16%). Conversely, the proportion of grade III tumors was only 18% in ILC as against 41% in IDC (p = 0.020). The 10-year survival of women with IDC was 69%, compared to 84% for ILC (p = 0.073). However, the 15 percentile point difference between overall survival of IDC and ILC was markedly reduced after adjustment for nodal status. The difference was eight percentile points for node-negative patients (p = 0.361) and five percentile points for node-positive patients (p = 0.464). Age at diagnosis, tumor size, pathologic stage, and lymph node status were independent prognostic indicators for 10-year survival. There was no prognostic difference between IDC and ILC. The result shows the importance of adjusting for other important clinicopathologic characteristics before comparing the overall survival of IDC and ILC.

Supporting the implementation of breast pathology recommendations: feasibility of a feedback mechanism to pathologists.

AIMS: The aims of the study were to explore the feasibility, acceptability, impact and cost of a feedback program to pathologists reporting on breast specimens through a BreastScreen Service. METHODS: The study was conducted at a single BreastScreen NSW Screening and Assessment Service. Pathology reports were audited against the ACN recommendations about pathology reporting [Australian Cancer Network Pathology Working Party. The Pathology Reporting of Breast Cancer: a guide for pathologists, surgeons and radiologists. Sydney: Australian Cancer Network, 1997] during two consecutive periods. Feedback was provided to pathologists at the completion of each audit. A comparison of completeness of pathology reports between audits was undertaken. The Screening and Assessment Service staff and participating pathologists were interviewed to assess acceptability and information about resource allocation. RESULTS: The study demonstrated that the feedback mechanism was acceptable to pathologists and staff at the BreastScreen Screening and Assessment Service, and that participation in the study resulted in some improvements in pathology reporting. CONCLUSIONS: The study demonstrated the feasibility of providing feedback to pathologists about their reporting of breast specimens. However, there were costs to the Service of participating. A way of managing these costs would need to be explored if the feedback mechanism was made a routine BreastScreen procedure.

Prognostic importance of tumor size for localized conventional (clear cell) renal cell carcinoma: assessment of TNM T1 and T2 tumor categories and comparison with other prognostic parameters.

BACKGROUND: The T1 and T2 classifications of the International Union Against Cancer TNM classification system for renal cell carcinoma are based on primary tumor size, and in various editions of the classification, the cut points between T1 and T2 have been amended to provide clinical utility. In the current edition, the T1/T2 cut point is less than or equal to and greater than 7 cm. and more recently a subdivision of the T1 classification (less than or equal to and < 4 cm) has been proposed to identify patients suitable for partial nephrectomy. This study investigates the prognostic significance of tumor size in a series of organ-confined clear cell renal cell carcinomas. METHODS: One hundred thirty cases of organ-confined clear cell renal cell carcinomas, with a minimum of 5 years' follow-up, were identified from the New South Wales Cancer Registry. Tumor size was compared with survival using the method of Kaplan and Meier for TNM size categories, and proportional hazards regression was used for assessing size as a continuous variable. Proportional hazards regression also was used for multivariable comparisons of size and other prognostic parameters (Fuhrman grade, AgNOR score, and Ki-67 index) against survival. RESULTS: Of 116 cases for which tumor dimension was recorded, 25 patients had died of cancer-related causes. Primary tumor size ranged from 12 to 140 mm (mean, 57.3 mm). The association between survival and size was significant irrespective of the TNM classification and was also significant when size was modeled continuously (P = 0.000125, hazard of death increased by 3.51 times for each doubling of tumor size). On univariate analysis, Fuhrman grade (P = 0.04) and AgNOR score (P = 0.015) were associated with survival; however, on multivariate analysis only tumor size retained significance. CONCLUSIONS: Although the cut point of T1 and T2 TNM categories and the proposed T1 subdivision cut point correlate with survival, our finding that size is a continuous variable indicates that as a prognostic parameter for clear cell renal cell carcinoma, primary tumor size is relative rather than indicative.