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Intraductal papillary neoplasms of the bile duct are still poorly characterized regarding (1) their molecular alterations during the development to invasive carcinomas, (2) their subtype stratification and (3) their biological behavior. We performed a multicenter study that analyzed these issues in a large European cohort. Intraductal papillary neoplasms of the bile duct from 45 patients were graded and subtyped using mucin markers and CDX2. In addition, tumors were analyzed for common oncogenic pathways, and the findings were correlated with subtype and grade. Data were compared with those from 22 extra- and intrahepatic cholangiocarcinomas. Intraductal papillary neoplasms showed a development from preinvasive low- to high-grade intraepithelial neoplasia to invasive carcinoma. Molecular and immunohistochemical analysis revealed mutated KRAS, overexpression of TP53 and loss of p16 in low-grade intraepithelial neoplasia, whereas loss of SMAD4 was found in late phases of tumor development. Alterations of HER2, EGFR, β-catenin and GNAS were rare events. Among the subtypes, pancreato-biliary (36%) and intestinal (29%) were the most common, followed by gastric (18%) and oncocytic (13%) subtypes. Patients with intraductal papillary neoplasm of the bile duct showed a slightly better overall survival than patients with cholangiocarcinoma (hazard ratio (cholangiocarcinoma versus intraductal papillary neoplasm of the bile duct): 1.40; 95% confidence interval: 0.46–4.30; P=0.552). The development of biliary intraductal papillary neoplasms of the bile duct follows an adenoma-carcinoma sequence that correlates with the stepwise activation of common oncogenic pathways. Further large trials are needed to investigate and verify the finding of a better prognosis of intraductal papillary neoplasms compared with conventional cholangiocarcinoma.

Background Expression of periostin is an indicator of epithelial-mesenchymal transition in cancer but a detailed analysis of periostin expression in prostate cancer has not been conducted so far. Methods Here, we evaluated periostin expression in prostate cancer cells and peritumoural stroma immunohistochemically in two independent prostate cancer cohorts, including a training cohort (n = 93) and a test cohort (n = 325). Metastatic prostate cancers (n = 20), hormone refractory prostate cancers (n = 19) and benign prostatic tissues (n = 38) were also analyzed. Results In total, strong epithelial periostin expression was detectable in 142 of 418 (34.0%) of prostate carcinomas and in 11 of 38 benign prostate glands (28.9%). Increased periostin expression in carcinoma cells was significantly associated with high Gleason score (p < 0.01) and advanced tumour stage (p < 0.05) in the test cohort. Whereas periostin expression was weak or absent in the stroma around normal prostate glands, strong periostin expression in tumour stroma was found in most primary and metastatic prostate cancers. High stromal periostin expression was associated with higher Gleason scores (p < 0.001). There was a relationship between stromal periostin expression and shortened PSA relapse free survival times in the training cohort (p < 0.05). Conclusions Our data indicate that periostin up-regulation is related to increased tumour aggressiveness in prostate cancer and might be a promising target for therapeutical interventions in primary and metastatic prostate cancer.

The transforming growth factor-β (TGF-β) signalling pathway is a key mediator of fibroblast activation that drives the aberrant synthesis of extracellular matrix in fibrotic diseases. Here we demonstrate a novel link between transforming growth factor-β and the canonical Wnt pathway. TGF-β stimulates canonical Wnt signalling in a p38-dependent manner by decreasing the expression of the Wnt antagonist Dickkopf-1. Tissue samples from human fibrotic diseases show enhanced expression of Wnt proteins and decreased expression of Dickkopf-1. Activation of the canonical Wnt pathway stimulates fibroblasts in vitro and induces fibrosis in vivo . Transgenic overexpression of Dickkopf-1 ameliorates skin fibrosis induced by constitutively active TGF-β receptor type I signalling and also prevents fibrosis in other TGF-β-dependent animal models. These findings demonstrate that canonical Wnt signalling is necessary for TGF-β-mediated fibrosis and highlight a key role for the interaction of both pathways in the pathogenesis of fibrotic diseases. Aberrant activation of the TGF-β pathway leads to fibrotic disease. Distler and colleagues show that TGF-β-mediated fibrosis requires the decrease of Dickkopf-1, an antagonist of canonical Wnt signalling, suggesting that the two pathways interact for the manifestation of this disease.

Biliary tract cancer (BTC) is a fatal cancer originating from epithelial cells of the intra- and extra-hepatic biliary duct system and the gallbladder. Genes and pathways regulating stem and progenitor cells as well as cell-fate decisions are increasingly recognized in tumorigenesis. We evaluated the expression of Notch1, Notch2, and HES1 (hairy and enhancer of split 1), as well as the biliary cell-fate regulators SOX9 (SRY (sex determining region Y)-box 9) and HNF1β (hepatocyte nuclear factor 1β), in BTC for correlation with clinicopathological parameters. Tissue microarrays including normal bile ducts and 111 BTCs consisting of 17 intrahepatic cholangiocarcinomas, 58 extrahepatic cholangiocarcinomas, and 36 gallbladder carcinomas were analyzed using immunohistochemistry. Lack of cytoplasmic SOX9 expression was associated with a higher tumor grade (P=0.010) and a significantly reduced overall survival (P=0.002; median 6 months vs. 24 months) in univariate survival analysis, whereas lack of nuclear SOX9 expression was associated with a higher tumor stage (P=0.003). Notch pathway members showed high expression in BTC. However, no correlation was found between cytoplasmic or nuclear Notch1, Notch2, and HES1, as well as HNF1β expression, and any of the clinicopathological parameters. In multivariate analysis, cytoplasmic SOX9 expression was an independent prognostic factor for overall survival (P=0.031, relative risk=0.571). We show strong Notch pathway activation and identify SOX9 as a prognostic marker in BTC. These results substantiate diagnostic and therapeutic approaches targeting developmentally active genes and pathways.

Paget disease of the breast, in most cases, represents intraepidermal spread of ductal carcinoma in situ. Molecular subtypes of invasive carcinoma of the breast have prognostic and therapeutic significance and show characteristic distribution. Little is known about the distribution of molecular subtypes in Paget disease of the breast. To examine the distribution of molecular subtypes in Paget disease of the breast and to compare them to concurrent invasive carcinoma of the breast, if present. We examined 48 cases of Paget disease of the breast with immunohistochemistry and antibodies against estrogen and progesterone receptors, human epidermal growth factor receptor 2 (HER2), and Ki-67, as well as HER2 chromogenic in situ hybridization, to classify the cases into molecular subtypes. Then, we compared the results to the molecular subtypes of associated invasive carcinoma of the breast, if present. The HER2 subtype was the most common found in Paget disease of the breast, followed by the luminal B subtype and 2 cases of the triple-negative subtype. The associated invasive carcinoma cases were most often of the luminal B subtype, followed by the HER2 subtype and the triple-negative subtype. The molecular subtype of Paget disease and invasive carcinoma was congruent in most of the cases. Molecular subtypes of invasive carcinoma of the breast can already be detected in Paget disease. The distribution of molecular subtypes of Paget disease and of Paget disease-associated invasive carcinoma differs from invasive carcinoma without associated Paget disease, with the HER2 subtype overrepresented in Paget disease and associated invasive carcinoma and the luminal and triple-negative subtypes underrepresented.

Background Decreased expression of the interferon-stimulated, putative tumour suppressor gene XAF1 has been shown to play a role during the onset, progression and treatment failure in various malignancies. However, little is yet known about its potential implication in the tumour biology of clear-cell renal cell cancer (ccRCC). Methods This study assessed the expression of XAF1 protein in tumour tissue obtained from 291 ccRCC patients and 68 normal renal tissue samples, utilizing immunohistochemistry on a tissue-micro-array. XAF1 expression was correlated to clinico-pathological tumour features and prognosis. Results Nuclear XAF1 expression was commonly detected in normal renal- (94.1%) and ccRCC (91.8%) samples, without significant differences of expression levels. Low XAF1 expression in ccRCC tissue, however, was associated with progression of tumour stage (p = 0.040) and grade (p < 0.001). Low XAF1 tumour levels were also prognostic of significantly shortened overall survival times in univariate analysis (p = 0.018), but did not provide independent prognostic information. Conclusion These data suggest down-regulation of XAF1 expression to be implicated in ccRCC progression and implies that its re-induction may provide a therapeutic approach. Although the prognostic value of XAF1 in ccRCC appears to be limited, its predictive value remains to be determined, especially in patients with metastatic disease undergoing novel combination therapies of targeted agents with Interferon-alpha.

Background GOLPH2 (Golgi phosphoprotein 2) is a novel Golgi membrane protein. Despite its unknown physiologic function, however, it has been proposed as a biomarker for hepatocellular and prostate carcinoma due to its upregulation in those cancer entities. Whether the overexpression of GOLPH2 is tumour specific or a generic parameter of malignancy and whether this finding is true for additional carcinomas has not been determined. In this study, we aimed to evaluate the expression pattern of GOLPH2 in testicular seminomas, the most common histologic subtype of testicular neoplasm. Methods GOLPH2 protein expression was assessed by immunohistochemistry in 69 testicular seminomas and compared to the expression rates in matching normal testicular tissue and intratubular germ cell neoplasia of unclassified type (IGCNU). In addition, a subset of Leydig cell tumours was analyzed accordingly. Results GOLPH2 was consistently overexpressed (89.9%) in seminomas. Matching non-neoplastic tissue showed weak or negative staining. The observed differences between non-neoplastic and neoplastic tissue were statistically highly significant (p < 0.001). There were no significant associations with tumour status. Interestingly, GOLPH2 was also highly expressed in the intertubular Leydig cells as well as in Leydig cell tumours. Conclusions GOLPH2 protein is highly expressed in seminomas and in Leydig cell tumours. This study fosters the association of GOLPH2 with malignant neoplastic processes. The staining pattern is easily assessable and consistent which is a favourable property especially in clinical settings. GOLPH2 could be a novel immunohistochemical marker for the assessment of testicular neoplasms, especially against the background that in analogy to hepatocellular carcinomas complementary GOLPH2 serum levels might be helpful in detecting metastases or recurrent tumour. Therefore serum studies and analyses of GOLPH2 expression in non-seminomatous germ cell tumours are strongly warranted.

Expression of p16 has been established as a good surrogate marker for high-risk human papillomavirus (HPV) infection in oropharyngeal squamous cell carcinoma (OPSCC) patients, and it has been associated with an improved prognosis, irrespective of the actual HPV status. Conversely, the human insulin-like growth factor II mRNA binding protein 3 (IMP3) has been related to aggressiveness in several types of tumors. The aim of the present study was to investigate and compare p16 and IMP3 as markers of favorable and unfavorable behavior, respectively, in head and neck SCC (HNSCC), with particular reference to the HPV status. Both markers were analyzed by immunohistochemical analysis of 156 HNSCC samples originating from the oropharynx (n=81), oral cavity (n=44), larynx (n=15), hypopharynx (n=10) and nasopharynx (n=6). The HPV status was examined in a randomly selected representative subcohort (n=38) using polymerase chain reaction. Of the 156 HNSCC samples, 81 (51.9%) and 54 (34.6%) were positive for IMP3 and p16, respectively. IMP3 expression (P=0.022), p16 expression (P<0.001) and the combination of these markers (P<0.001) were significantly associated with tumor site. In particular, 69/81 (85%) OPSCC samples were positive for either one or both markers compared with 36/75 (48%) SCC samples from other sites. p16 expression was significantly associated with HPV infection (P=0.017) and a trend towards a negative association between IMP3 expression and HPV infection was observed (P=0.053). The results of the present study suggested that IMP3 and p16 are more frequently expressed in OPSCC compared with other HNSCCs. The prognostic impact of IMP3 on OPSCC remains to be investigated in a larger series with an extended follow-up period.

Carcinomas of the Vaterian system are rare and presumably arise from preexisting adenomas (adenoma-carcinoma-sequence). Usually, biopsies are obtained to confirm and specify endoscopic findings, but differentiating reactive atypia from dysplasia or dysplasia from invasive carcinoma can sometimes be difficult or even impossible on morphological criteria alone. In case of invasive carcinoma, furthermore, the precise classification of carcinoma subtypes needs to be established since the distinct subtypes differ significantly in terms of clinical outcome. The cell adhesion proteins CD24, P-cadherin and S100A4 were shown to be expressed in several carcinomas and in dysplastic epithelium but only rarely in normal mucosa. We therefore investigated their expression in 177 carcinoma, 114 adenoma and 152 normal mucosa specimens of the ampulla of Vater. Although the expression of the cell adhesion proteins did not differ between the carcinoma subtypes, marked differences between normal mucosa, adenoma and carcinoma samples were observed. All marker proteins were expressed in less than 7% of normal mucosa samples (S100A4 in only 1% of cases) and showed an increasing expression from adenoma to invasive carcinoma. Our findings suggest that P-cadherin and S100A4 are helpful in discriminating normal mucosa or reactive atypia from neoplastic lesions. CD24 and S100A4, furthermore, can assist in the differential diagnosis of dysplasia vs invasive carcinoma.