Dimorphic cells: a common feature throughout the low nuclear grade breast neoplasia spectrum

Columnar cell lesions (CCLs) are recognized precursor lesions of the low nuclear grade breast neoplasia family. CCLs are cystic enlarged terminal duct lobular units with monotonous (monoclonal) columnar-type luminal cells. CCLs without atypia are regarded as benign and CCLs with atypia as true precursor lesions with clonal molecular changes, a certain progression risk, and an association with more advanced lesions. However, reproducibility of designating atypia in CCL is not optimal, and no objective markers of atypia have been identified, although 16q loss seems to be associated with atypical CCLs. Dimorphic ("pale") cell populations have been described in low nuclear grade ductal carcinoma in situ (DCIS) but not in CCLs and atypical ductal hyperplasia (ADH). Therefore, we searched for pale cells in CCL (N = 60), ADH (N = 41), and DCIS grade 1 (N = 84). Diagnostic criteria were derived from the WHO, and atypia was designated according to the Schnitt criteria. Pale cells occurred in 0% (0/30), 73% (22/30), 56% (23/41), and 76% (64/84) of CCLs without atypia, CCLs with atypia, ADH, and DCIS grade 1, respectively. Pale cells expressed ERα, E-cadherin and p120 and variably cyclin D1, and lacked expression of CK5 and p63. In conclusion, dimorphic "pale" cells occur throughout the low nuclear grade progression spectrum, increasing in frequency with progression. Interestingly, CCL lesions without atypia do not seem to bear showed pale cells, indicating that the presence of pale cells may serve as a diagnostic morphological feature of atypia in CCLs

Blunt duct adenosis: A separate entity from columnar cell lesions?

Blunt duct adenosis (BDA) is a breast lesion first described by Foote and Stewart in 1945 as a proliferative benign lesion of the terminal duct lobular unit. Throughout recent decades, further literature descriptions of BDA have been confusing. Some consider BDA to be a separate entity, some a growth pattern of columnar cell changes. The WHO 2012 considered BDA and columnar cell changes to be synonyms, while columnar cell lesions, especially those with atypia, are part of a spectrum of early precursors of the low nuclear grade breast neoplasia family. In the updated WHO 2019 version, BDA is mentioned as € not recommended' terminology for columnar cell lesions without further discussing it, leaving the question open if BDA should be considered a separate entity. Good diagnostic criteria for BDA have however largely been lacking, and its biological background has not yet been unravelled. In this paper, we point out that BDA is mainly associated with benign breast lesions and not with other recognised precursor lesions. Further, 16q loss, which is the hallmark molecular event in the low nuclear grade breast neoplasia family, is lacking in BDA. We therefore hypothesise that BDA may not be a true precursor lesion but a benign polyclonal lesion, and propose morphological diagnostic criteria to better differentiate it from columnar cell lesions

Expression of hypoxia-induced proteins in ductal carcinoma in situ and invasive cancer of the male breast

AIMS: The aim of this study was to determine the role of hypoxia in male breast carcinogenesis by evaluating the expression of the hypoxia-related proteins, hypoxia-inducible factor-1α (HIF-1α), carbonic anhydrase IX (CAIX) and glucose transporter-1 (Glut-1), in ductal carcinoma in situ (DCIS) of the male breast in relation to invasive cancer (IC). METHODS: Tumour tissue blocks of 18 cases of pure DCIS, 58 DCIS cases adjacent to IC (DCIS-AIC) and the 58 IC cases were stained by immunohistochemistry for HIF-1α, CAIX and Glut-1, and expression frequencies and patterns (diffuse and/or perinecrotic) were noted. RESULTS: HIF-1α overexpression was observed in 61.1% (11/18) of pure DCIS, in 37.9% (22/58) of DCIS-AIC and in 36.2% (21/58) of IC cases (not significant (n.s.)). CAIX overexpression was observed in 16.7% (3/18) of pure DCIS, in 37.9% (22/58) of DCIS-AIC and in 24.1% (14/58) of IC cases (n.s.). Glut-1 overexpression was observed in 61.1% (11/18) of pure DCIS, in 75.9% (44/58) of DCIS-AIC and in 62.1% (36/58) of IC cases (n.s.). Expression of hypoxia-related proteins was seen around necrosis in a little over one-third of DCIS cases, and often coincided with expression in adjacent IC when present. All these observations indicate that the hypoxia response is already at its maximum in the preinvasive DCIS stage. CONCLUSIONS: In conclusion, male DCIS frequently shows activated hypoxia response, comparable to male IC. This indicates that the activated hypoxia response previously seen in male IC is not a late bystander but likely a genuine carcinogenetic event

HER-2/neu Testing and Therapy in Gastroesophageal Adenocarcinoma

Despite ongoing advances in the treatment of gastroesophageal cancer, prognosis remains poor. The best promise to improve this poor survival is provided by new targeted agents. Of these, human epidermal growth factor receptor 2 (HER2) is currently in the spotlight. In this review, we provide an overview of recent developments in HER2 testing and results of clinical trials targeting HER2 in gastroesophageal adenocarcinoma. Based on the encouraging ToGA trial findings it is now expected that routine HER2 testing will be included in the diagnostic work-up of patients with advanced gastric cancer. With regard to this testing, overexpression of the HER2 protein seems to possess the best predictive properties. However, HER2 immunohistochemistry (IHC) is subject to assay and interobserver variability, so standardization and internal and external proficiency testing is an absolute prerequisite, especially as the IHC scoring system in gastric cancer is different from that of breast cancer. Further study is needed to investigate the clinical meaning of the significant heterogeneity observed in both gene amplification and protein overexpression in gastroesophageal cancer. Highly effective therapies for gastroesophageal cancer can only be accomplished by a multi-targeted approach, considering crosstalk between pathways and continuing to optimize chemotherapy

Hypoxia-Inducible Factor-1 as a Therapeutic Target in Endometrial Cancer Management

In the Western world, endometrial cancer (EC) is the most common malignant tumor of the female genital tract. Solid tumors like EC outgrow their vasculature resulting in hypoxia. Tumor hypoxia is important because it renders an aggressive phenotype and leads to radio- and chemo-therapy resistance. Hypoxia-inducible factor-1α (HIF-1α) plays an essential role in the adaptive cellular response to hypoxia and is associated with poor clinical outcome in EC. Therefore, HIF-1 could be an attractive therapeutic target. Selective HIF-1 inhibitors have not been identified. A number of nonselective inhibitors which target signaling pathways upstream or downstream HIF-1 are known to decrease HIF-1α protein levels. In clinical trials for the treatment of advanced and/or recurrent EC are the topoisomerase I inhibitor Topotecan, mTOR-inhibitor Rapamycin, and angiogenesis inhibitor Bevacizumab. Preliminary data shows encouraging results for these agents. Further work is needed to identify selective HIF-1 inhibitors and to translate these into clinical trials

Nuclear morphometric features in benign breast tissue and risk of subsequent breast cancer

Certain nuclear morphometric features measured in breast tumor tissue have been shown to predict the prognosis of breast cancer patients. However, the application of these features to predicting risk of breast cancer development has received little attention. We conducted a case-control study to evaluate nuclear morphometric features in benign breast tissue in association with subsequent breast cancer risk. The study was nested within a cohort of 4,888 women with a histopathologic diagnosis of benign breast disease (BBD) and involved 61 cases and 71 controls, amongst whom there were 53 matched case-control sets. Conditional logistic regression models were fitted to assess various measurements of nuclear size and nuclear shape factors in relation to subsequent breast cancer risk. In multivariate analysis, subsequent breast cancer risk was positively associated with a nuclear shape factor that takes the shortest nuclear axis and the longest nuclear axis into consideration simultaneously (highest quartile versus lowest 3 quartiles: odds ratio = 3.07, 95% confidence limits = 1.61, 5.84). In contrast, there was no alteration in subsequent breast cancer risk in association with nuclear size features and other shape factors. In conclusion, our study results suggest that the shape factor that takes both the shortest nuclear axis and the longest nuclear axis into consideration might be of value to predict subsequent development of breast cancer among women with BBD

Male breast cancer

Review on Male breast cancer, with data on clinics, and the genes involved

Nuclear DDX3 expression predicts poor outcome in colorectal and breast cancer

Purpose: DEAD box protein 3 (DDX3) is an RNA helicase with oncogenic properties that shuttles between the cytoplasm and nucleus. The majority of DDX3 is found in the cytoplasm, but a subset of tumors has distinct nuclear DDX3 localization of yet unknown biological significance. This study aimed to evaluate the significance of and mechanisms behind nuclear DDX3 expression in colorectal and breast cancer. Methods: Expression of nuclear DDX3 and the nuclear exporter chromosome region maintenance 1 (CRM1) was evaluated by immunohistochemistry in 304 colorectal and 292 breast cancer patient samples. Correlations between the subcellular localization of DDX3 and CRM1 and the difference in overall survival between patients with and without nuclear DDX3 were studied. In addition, DDX3 mutants were created for in vitro evaluation of the mechanism behind nuclear retention of DDX3. Results: DDX3 was present in the nucleus of 35% of colorectal and 48% of breast cancer patient samples and was particularly strong in the nucleolus. Nuclear DDX3 correlated with worse overall survival in both colorectal (hazard ratio [HR] 2.34, P<0.001) and breast cancer (HR 2.39, P=0.004) patients. Colorectal cancers with nuclear DDX3 expression more often had cytoplasmic expression of the nuclear exporter CRM1 (relative risk 1.67, P=0.04). In vitro analysis of DDX3 deletion mutants demonstrated that CRM1-mediated export was most dependent on the N-terminal nuclear export signal. Conclusion: Overall, we conclude that nuclear DDX3 is partially CRM1-mediated and predicts worse survival in colorectal and breast cancer patients, putting it forward as a target for therapeutic intervention with DDX3 inhibitors under development in these cancer types

The correlation between clinical, nuclear and histologic findings in a patient with Von Recklinghausen's disease

<p>Abstract</p> <p>Background</p> <p>Malignant peripheral nerve sheath tumours (MPNST) are known to develop in patients with Neurofibromatosis type I (NF1) resulting in a decreased overall survival. The association between NF1 and the development of such MPNST has been investigated in detail. The biological behaviour however of multiple disseminated neurofibromas in patients with NF1 and the risk factors for malignant transformation remain unknown. Clinical signs are unreliable and additional imaging techniques are therefore required. Of such, positron emission tomography using [¹⁸F]-2-fluoro-2-deoxy-D-glucose (¹⁸FDG PET) is used to detect malignant changes in neurofibromas.</p> <p>Case presentation</p> <p>A case is presented of a patient suffering from NF1 with clinical signs of malignant change and accumulation of ¹⁸FDG in multiple neurofibromas. Histopathological examination of 20 lesions however, did not reveal any malignant features. There was no statistically significant relation between¹⁸FDG accumulation and malignant change, but rather with pain, size and growth.</p> <p>Conclusion</p> <p>This case adds to the knowledge of the diverse biological behaviour of neurofibromas in patients with NF1</p