Fibrotic focus and hypoxia in male breast cancer

Abstract

Fibrotic focus is a scar-like lesion near the center of a carcinoma and has been associated with high-grade, lymph node metastases and poor survival in female breast cancers. Hypoxia is suggested to be the crucial link between fibrotic focus and aggressive tumor phenotype and is also itself a poor prognostic marker. We here set out to study fibrotic focus and hypoxia in male breast cancer for the first time. In a group of 134 male breast cancer patients, the presence and size of a fibrotic focus and the expression of three hypoxia-related immunohistochemical stainings, hypoxia-inducible factor-1a, carbonic anhydrase IX and Glut-1 were studied in correlation with clinicopathological features and prognosis. Fibrotic focus was seen in 25% of the male breast cancer cases and was correlated with hypoxia-inducible factor-1a overexpression (P ¼ 0.023), high grade (P ¼ 0.005), high mitotic activity (P ¼ 0.005) and lymph node metastases (P ¼ 0.037). Hypoxia-inducible factor-1a-positive tumors were more often high grade (P ¼ 0.003) and HER2 amplified (P ¼ 0.005). Glut-1 expression was also more common in grade 3 tumors (P ¼ 0.038), but no association between carbonic anhydrase IX and any clinicopathological feature was found. Fibrotic focus 48 mm and hypoxia-inducible factor-1a overexpression were correlated with decreased patients' outcome (P ¼ 0.035 and 0.008, respectively). Hypoxia-inducible factor1a overexpression was an independent and the most powerful predictor of survival in multivariate analysis (P ¼ 0.029; hazard ratio 2.5). In conclusion, the presence of a fibrotic focus is associated with hypoxia-inducible factor-1a overexpression, and both are associated with aggressive tumor phenotype and poor survival in male breast cancer. These markers seem to have similar clinical importance as previously reported in female breast cancer. Modern Pathology (2012) 25, 1397-1404; doi:10.1038/modpathol.2012.101; published online 8 June 2012Keywords: fibrotic focus; hypoxia; male breast cancer; prognosis Male breast cancer is uncommon and represents o1% of all breast cancers. 1 Large series in male breast cancer are lacking and much of the knowledge is generalized from breast cancer in female subjects. The limited data published on male breast cancer indicate that there are genetic and phenotypic differences between male and female breast cancer. [2][3][4][5][6] Initially, prognosis in men was claimed to be poor with higher incidence of lymph node metastases at the time of discovery, but more recent studies showed that prognosis of male and female breast cancers corrected for stage and age is similar. [7][8][9] Although tumor size and lymph node status are independent prognosticators in male breast cancer, 9,10 there still is a need for more accurate outcome predictors of male breast cancer.A fibrotic focus is a scar-like lesion consisting of an area of mainly collagen and fibroblasts, often located near the center of a carcinoma. Fibrotic focus is associated with poor survival in female breast cancer and with high grade, hig...

Nuclear HIF1A expression is strongly prognostic in sporadic but not familial male breast cancer

“…Similarly, sporadic female breast cancers 6 showed a higher frequency of HIF1A positive tumors (50%) compared with sporadic male breast cancers in our study (28%), and comparable to the study by Kornegoor et al 18 (27%). A similar but less extreme difference is seen when comparing CA9 expression in male breast cancer and female breast cancer, 6,26 again in keeping with the findings of Kornegoor et al 18 We also only found seven cases (3%) that expressed both HIF1A and CA9. Although this is below the range seen in female breast cancer (11-23%), 6,27 it is not unexpected given the decreased staining of either marker when compared with female breast cancer and the known variability in HIF1A and CA9 half-lives.…”

“…Similarly, expression of the carbonic anhydrase IX (CA9) in female breast cancer has also been correlated with higher grade and poorer survival and is also overexpressed in triple negative (estrogen receptor negative, progesterone receptor negative, HER2 negative) tumors and associated with somatic loss of the BRCA1 protein. 17 There is only one study of hypoxic markers in male breast cancer, 18 comprising of 134 cases, which showed that 27% (34/ 125) and 7% (9/132) of cases demonstrated HIF1A and CA9 expression with HIF1A also associated with prognosis. 18 The study was not stratified into sporadic and familial cancers, and currently there are no data in familial male breast cancer, or whether similar changes of the hypoxic pathway are present in particular intrinsic phenotypes as shown in female breast cancer.…”

“…17 There is only one study of hypoxic markers in male breast cancer, 18 comprising of 134 cases, which showed that 27% (34/ 125) and 7% (9/132) of cases demonstrated HIF1A and CA9 expression with HIF1A also associated with prognosis. 18 The study was not stratified into sporadic and familial cancers, and currently there are no data in familial male breast cancer, or whether similar changes of the hypoxic pathway are present in particular intrinsic phenotypes as shown in female breast cancer. 6 As both sporadic and familial male breast cancer patients also appear to have an increased predisposition to develop second malignancies, the effect or intrinsic response to hypoxia in these individuals may also be significant and has not been described in any study to date.…”

Prognostic value of automatically extracted nuclear morphometric features in whole slide images of male breast cancer

“…Tumor size and MAI were dichotomized using previously defined cutoff values. 15 Univariate survival analysis was done by plotting the Kaplan-Meier survival curves and performing the logrank test.…”

“…This group of patients was previously used to analyze the molecular sub-typing, fibrotic focus and hypoxia in male breast cancer. 14,15 The patients for whom survival data was not available were excluded in the current study. Age, tumor size and lymph node status were extracted from the pathology reports.…”