Are bilateral breast cancers and breast cancers coexisting with ovarian cancer different from solitary tumors? A pair‐matched immunohistochemical analysis aimed at intrinsic tumor phenotype

Patients with bilateral breast cancer (BBC) and breast‐ovarian cancer syndrome (BOCS) constitute populations potentially enriched for molecular defects involved in the pathomechanisms of these malignancies. The aim of our study was to compare tumor morphology and expression of estrogen and progesterone receptor, HER2, Ki67, cytokeratin 5/6, E‐cadherin, vimentin and epidermal growth factor receptor in tissue microarrays from 199 tumors from BBC or BOCS patients and 199 age‐matched solitary tumors. Compared to controls, BBC and BOCS considered jointly had lower incidence of DCIS, lower expression of PgR and HER2, and higher expression of Ki67 and vimentin. BOCS tumors were of higher grade, had lower expression of ER and PgR and higher expression of Ki67, CK5/6, vimentin and EGFR. BBC had less DCIS component, lower HER2 expression and higher Ki67 expression. Metachronous BBC (mBBC) had lower expression of ER, PgR and HER2, and higher expression of Ki67 and vimentin. Synchronous BBC (sBBC) had less DCIS component, higher expression of ER, and lower expression of CK5/6, EGFR and E‐cadherin. BBC and breast cancers in BOCS differ in many aspects from solitary tumors. BBC are a heterogeneous group of tumors, differing between sBBC and mBBC. mBBC phenotype shares many features with BOCS tumors.     

How do women at increased risk of breast cancer make sense of their risk? An interpretative phenomenological analysis

Objectives

Offering breast cancer risk prediction for all women of screening age is being considered globally. For women who have received a clinically derived estimate, risk appraisals are often inaccurate. This study aimed to gain an in-depth understanding of women's lived experiences of receiving an increased breast cancer risk.

Design

One-to-one semi-structured telephone interviews.

Methods

Eight women informed that they were at a 10-year above-average (moderate) or high risk in a breast cancer risk study (BC-Predict) were interviewed about their views on breast cancer, personal breast cancer risk and risk prevention. Interviews lasted between 40 and 70 min. Data were analysed using Interpretative Phenomenological Analysis.

Results

Four themes were generated: (i) encounters with breast cancer and perceived personal significance, where the nature of women's lived experiences of others with breast cancer impacted their views on the significance of the disease, (ii) ‘It's random really’: difficulty in seeking causal attributions, where women encountered contradictions and confusion in attributing causes to breast cancer, (iii) believing versus identifying with a clinically-derived breast cancer risk, where personal risk appraisals and expectations influenced women's ability to internalize their clinically derived risk and pursue preventative action and (iv) perceived utility of breast cancer risk notification, where women reflected on the usefulness of knowing their risk.

Conclusions

Providing (numerical) risk estimates appear to have little impact on stable yet internally contradictory beliefs about breast cancer risk. Given this, discussions with healthcare professionals are needed to help women form more accurate appraisals and make informed decisions.     

Erdheim-Chester disease: evidence for a disease entity different from Langerhans cell histiocytosis? Three cases with detailed radiological and immunohistochemical analysis

Erdheim-Chester (EC) disease is a rare pathological entity with a highly specific and characteristic pattern of radiographic bone changes. Histologically it resembles Langerhans cell histiocytosis (LCH), and it is still a matter of discussion whether EC disease is a distinct entity or a type of LCH. In this study, 3 cases of Erdheim-Chester disease were followed up over years and examined in detail both radiologically and immunohistochemically. All 3 cases showed the pathognomonic skeletal features for EC disease as well as an identical immunohistochemical phenotype quite different from LCH. Macrophages and Touton cells reacted strongly positive with the histiocytic marker CD 68, whereas staining with S100 and CD1a, markers for Langerhans cells, were negative. Both the immunohistochemical phenotype and the bone changes were clearly distinct from LCH.     

Metronomic chemotherapy and anti‐angiogenesis: can upgraded pre‐clinical assays improve clinical trials aimed at controlling tumor growth?

Metronomic chemotherapy, which is continuously administered systemically at close to non‐toxic doses, targets the endothelial cells (ECs) that are proliferating during tumor angiogenesis. This leads to harmful effects of an even greatly increased number contiguous tumor cells. Although pre‐clinical studies of angiogenesis‐related EC features in vitro and of the anti‐angiogenic and anti‐tumor effects in vivo of metronomic chemotherapy have provided valuable insights, clinical trials with this type of therapy have been less successful in inhibiting tumor growth. One possible reason for the apparent disconnect between the pre‐clinical and clinical outcomes is that most of the currently used experimental angiogenesis assays and tumor models are incapable of yielding data that can be translated readily into the clinical setting. Many of the assays used suffer from unintentional artifactual effects, e.g., oxidative stress in vitro, and inflammation in vivo, which reduces the sensitivity and discriminatory power of the assays. Co‐treatment with an antioxidant or the inclusion of antioxidants in the vehicle often significantly affects the angiogenesis‐modulating outcome of metronomic mono‐chemotherapy in vivo. This ‘metronomic chemotherapy vehicle factor’ merits further study, as do the observations of antagonistic effects following metronomic treatment with a combination of standard chemotherapeutic drugs in vivo.     

Are endometrial polyps from pre-menopausal women similar to post-menopausal women? An immunohistochemical comparison of endometrial polyps from pre- and post-menopausal women

OBJECTIVE: Do endometrial polyps from pre- and post-menopausal women have similar immunohistochemical expression of oestrogen and progesterone receptors (ER, PR) and markers of cellular proliferation/apoptosis (Ki67 and Bcl-2). DESIGN: Prospective cohort study. Non-parametric statistical analysis was used. SETTING: Polyps recruited from women attending an out-patient hysteroscopy clinic in a UK district general hospital. PATIENTS: Fourteen pre-menopausal and 16 post-menopausal women who presented with abnormal bleeding with endometrial polyps. INTERVENTIONS: Immunohistochemical staining was performed on endometrial polyps. MAIN OUTCOME MEASURES: Significant differences or correlations between hormone receptor expression (oestrogen and progesterone) and cell growth indices (Ki67 and Bcl-2). RESULTS: Endometrial polyps from pre- and post-menopausal women had significant differences in their expression of hormone receptors and Ki67. However, polyps from both groups of women had similarly increased levels of Bcl-2, an inhibitor of apoptosis. CONCLUSIONS: Pre- and post-menopausal polyps exhibit differing hormone receptor and proliferation markers, presumably a result of their hormonal milieu. However, both groups appear to have lost the usual control mechanisms for apoptotic regulation, this appears to be responsible for their growth.     

Are alterations of tight junctions at molecular and ultrastructural level different in duodenal biopsies of patients with celiac disease and Crohn's disease?

Abnormalities of transmembrane and cytoplasmic proteins of tight junctions (TJ) have been implicated in pathogenesis of both celiac (CeD) and Crohn’s diseases (CD). Since disease pathogenesis in CeD and CD are different, we planned to study if there is any differential expression pattern of TJ marker proteins and ultrastructural changes, respectively, in duodenal villi vs crypts. Endoscopic duodenal biopsies from treatment naïve patients with CeD (n?=?24), active CD (n?=?28), and functional dyspepsia (as controls, n?=?15), both at baseline and 6 months after treatment, were subjected to light microscopic analysis (modified Marsh grading); immune-histochemical staining and Western blot analysis to see the expression of key TJ proteins [trans-membrane proteins (claudin-2, claudin-3, claudin-4, occludin, and JAM) and cytoplasmic protein (ZO-1)]. Transmission electron microscopy and image analysis of the TJs were also performed. There was significant overexpression of claudin-2 (pore-forming) and occludin (protein maintaining cell polarity) with under-expression of claudin-3 and claudin-4 (pore-sealing proteins) in treatment naïve CeD and active CD with simultaneous alteration in ultrastructure of TJs such as loss of penta-laminar structure and TJ dilatation. Normalization of some of these TJ proteins was noted 6 months after treatment. These changes were not disease specific and were not different in duodenal villi and crypts. Overexpression of pore-forming and under-expression of pore-sealing TJ proteins lead to dilatation of TJ. These changes are neither disease specific nor site specific and the end result of mucosal inflammation.     

Does family history predict the age at onset of new breast cancers in BRCA1 and BRCA2 mutation‐positive families?

Panchal S, Bordeleau L, Poll A, Llacuachaqui M, Shachar O, Ainsworth P, Armel S, Eisen A, Sun P, Narod SA. Does family history predict the age at onset of new breast cancers in BRCA1 and BRCA2 mutation‐positive families? Women who carry BRCA mutations are advised to begin breast cancer screening based on the age‐specific risks of breast cancer development. It is not clear to what extent the family history of breast cancer influences age of onset. We evaluated the use of family history to predict the age of breast cancer onset in BRCA mutation carriers. Pedigrees from an Ontario‐based registry were reviewed to identify the index case of breast cancer (most recent diagnosis) and other family cases of breast cancer. The youngest age of breast cancer diagnosis and mean age at breast cancer diagnosis in the other family cases were compared to the age of onset in the index case. The 260 BRCA1 and 213 BRCA2 pedigrees were reviewed. In BRCA2 families, the index case was diagnosed on average at 44.4 years when the youngest reported family case was less than or equal to 35 years, compared to 51.9 years when the earliest cases were diagnosed after age 50 (p = 0.04). A modest trend was seen for BRCA1 carriers, but this was not statistically significant. To a small extent, the onset of breast cancer in a BRCA2 mutation carrier can be predicted from her family history of cancer, however, the trend is modest and should not alter clinical recommendations regarding initiation of screening.     

Lipomatous hemangiopericytoma: a fat-containing variant of solitary fibrous tumor? Clinicopathologic, immunohistochemical, and ultrastructural analysis of a series in favor of a unifying concept

The dinicopathologic, immunohistochemical and ultrastructural features of 13 lipomatous hemangiopericytomas are presented. There were 6 male and 7 female patients whose ages at diagnosis ranged from 27 to 75 years (median 48) all presenting with a mass of variable duration. The tumor sizes ranged from 1.7 cm to 19 cm (median 5.5 cm). The locations included the orbit (1), neck (1), mediastinum (1), epicardium (1), retroperitoneum (3), right iliac fossa (1), and upper (1) and lower (4) extremity. Histologically, the lesions were composed of a varying admixture of spindle-shaped to round cells, variably collagenous stroma, adipose tissue, and branched, often thick-walled, hemangiopericytoma-like vessels. For 11 tumors, the mitotic activity ranged from 1 to 3 mitoses per 10 high-power fields (HPF). One tumor which contained hypercellular areas showed 13 mitoses per 10 HPF, and another hypercellular lesion showed up to 43 mitoses per 10 HPF, abnormal mitoses, and necrosis. Immunohistochemically, tumor cells were invariably positive for vimentin and CD99, and mostly for CD34 but negative for desmin, keratin, CD31, CD117 (c-kit), and inhibin. About half of the tumors showed reactivity for bcl-2. Occasionally, focal reactivity was also observed for smooth muscle actin, muscle-specific actin, S100 protein, and epithelial membrane antigen. Ultrastructural examination of seven cases showed features in keeping with fibroblastic, myofibroblastic, or pericytic differentiation. Treatment consisted of simple tumorectomy in 10 cases and wide excision in 3. Follow-up information on 10 patients (range: 6 to 77 months; median: 18 months) showed no recurrence. Lipomatous hemangiopericytoma which share the clinical, pathologic, immunohistochemical, and ultrastructural features of solitary fibrous tumor (SFT) is likely to represent, in most cases, a fat-containing variant of SFT.     

Which breast carcinomas need HER‐2/neu gene study after immunohistochemical analysis? Results of combined use of antibodies against different c‐erbB2 protein domains

AIMS: Evaluation of HER2 gene amplification in breast cancers is a compelling, routine procedure. The aim of this work was to evaluate which breast carcinomas would really benefit from HER-2/neu gene analysis. METHODS AND RESULTS: We studied 130 invasive breast carcinomas by immunohistochemistry (IHC) using CB11 and TAB250 MAbs directed against different domains of the c-erbB2 molecule. From this series, we selected 106 cases (32 G1, 36 G2, and 38 G3) in which HER-2/neu gene analysis, using chromogenic in-situ hybridization (CISH), was successful. IHC results were scored using the FDA approved system with three score values: 0/1+ (negative), 2+, 3+ (positive). In addition, we developed a double scoring system with six score values (0/1+ 2+ negative, 3+, 4+, 5+, 6+ positive) obtained by summating the individual scoring values obtained with each MAb. All double scoring negative cases were non-amplified (100% sensitivity), whereas all cases scored 6+ were amplified. Double scoring values and CISH results were then correlated with grade and histological type. G1 ductal carcinomas and carcinomas of lobular and of special histological type did not show HER-2/neu amplification even in the presence of protein over-expression. CONCLUSIONS: The combined results of IHC analysis (double scoring values) obtained using MAbs directed against different c-erbB2 domains correctly indicates the HER-2/neu gene status in 57.5% of cases. In addition, simple morphological features such as low grade and special histological type are good predictors of the non-amplification of the HER-2/neu gene in breast carcinoma.     

Are there any more ovarian tumor suppressor genes? A new perspective using ultra high‐resolution copy number and loss of heterozygosity analysis

Ovarian cancer is characterized by complex genetic alterations, including copy number loss and copy number‐neutral loss of heterozygosity (LOH). These alterations are assumed to represent the “second hit” of the underlying tumor suppressor gene (TSG), however, relative to the number of LOH hotspots reported, few ovarian TSGs have been identified. We conducted a high‐resolution LOH analysis using SNP arrays (500K and SNP6.0) of 106 primary ovarian tumors of various histological subtypes together with matching normal DNA. LOH was detected in at least 35% of samples on chromosomes 17, 19p, 22q, Xp, 13q, 8p, 6q, 4q, 5q, 1p, 16q, and 9q with a median minimal region of overlap of only 300 kb. Subtype‐specific differences in LOH frequency were noted, particularly for mucinous cases. We also identified 192 somatic homozygous deletions (HDs). Recurrent HDs targeted known TSGs such as CDKN2A (eight samples), RB1 (five samples), and PTEN (three samples). Additional recurrent HDs targeted 16 candidate TSGs near minimal regions of LOH on chromosomes 17, 13, 8p, 5q, and X. Given the importance of HDs in inactivating known genes, these candidates are highly likely to be ovarian TSGs. Our data suggest that the poor success of previous LOH studies was due to the inability of previous technology to resolve complex genomic alterations and distinguish true LOH from allelic imbalance. This study shows that recurrent regions of LOH and HD frequently align with known TSGs suggesting that LOH analysis remains a valid approach to discovering new candidates. © 2009 Wiley‐Liss, Inc.     

Are recent increases in deliberate self-harm associated with changes in socio-economic conditions? An ecological analysis of patterns of deliberate self-harm in bristol 1972-3 and 1995-6

BACKGROUND: The incidence of deliberate self-harm (DSH) in Britain has increased markedly over the last 30 years. Reasons for this rise are not clear. We have investigated whether changes in the social and economic environment underlie any of the recent increase in DSH incidence. METHODS: An ecological analysis was used to assess associations between changes in census-based measures of the social and economic environment--the Townsend Deprivation Index and a three-factor social fragmentation index--and changes in age- and sex-specific hospital attendance rates for DSH for the 28 wards of the city of Bristol between 1972-3 and 1995-6. RESULTS: There were significant cross-sectional associations between the Townsend Index and rates of DSH in both males and females in both time periods. Increases in Townsend Index were also associated with increases in DSH. This association was statistically significant at the 5% level in 25-34 year-old females. Associations with the social fragmentation index were weak, although our index was based on rather limited data. CONCLUSIONS: This analysis suggests that changes in levels of socio-economic deprivation may influence area-specific patterns of DSH and such changes may have contributed to recent rises in DSH.