[Pre-surgical diagnosis of neuroendocrine carcinoma of the extrahepatic bile duct: a case study].

A 70-year-old woman presented to our hospital with jaundice. Abdominal ultrasonography showed biliary duct dilatation. Blood tests revealed elevated total bilirubin and hepatobiliary enzyme levels. A contrast-enhanced computed tomography of the abdomen showed bile duct thickening with wall enhancement. Transpapillary bile duct biopsy showed an invasive carcinoma proliferating in a follicular pattern. Pathology revealed positive synaptophysin and chromogranin A and a Ki67 index >40%, consistent with a diagnosis of neuroendocrine carcinoma (NEC). After confirming the absence of distant metastases, a subtotal stomach-preserving pancreaticoduodenectomy was performed. The result of the postoperative pathology was the same as the preoperative biopsy. According to previous reports, 7 out of 28 cases with NEC/mixed adenoneuroendocrine carcinoma could be diagnosed as NEC before surgery. However, biliary cytology and bile duct scraping cytology were used in many cases;only 11 cases underwent bile duct biopsy. For the latter, 5 out of 11 cases could be diagnosed preoperatively. NEC of the extrahepatic duct often exhibits a submucosal tumor-like morphology, which may result in a false negative result with biliary cytology or bile duct scraping cytology. In our case, the transpapillary bile duct biopsy sample was sufficient to diagnose NEC. This method could be an attractive option for the diagnosis of these tumors.

A novel somatic FGFR3 mutation in primary lung cancer.

The recent discovery of mutations and fusions of oncokinase genes in a subset of lung cancers (LCs) is of considerable clinical interest, since LCs containing such mutations or fusion transcripts are reportedly sensitive to kinase inhibitors. To better understand the role of the recently identified fibroblast growth factor receptor 3 (FGFR3) mutations and fusions in pulmonary carcinogenesis, we examined 214 LCs for mutations in the mutation cluster region of the FGFR3 gene using sequencing analysis. We also examined 190 LCs for the FGFR3-TACC3 and FGFR3-BAIAP2L1 fusion transcripts using reverse transcription-polymerase chain reaction (RT-PCR) analysis. Although the expression of FGFR3-TACC3 and FGFR3-BAIAP2L1 fusion transcripts was not detected in any of the carcinomas, somatic FGFR3 mutations were detected in two (0.9%) LCs. The two mutations were the same, i.e., p.R248H. That was a novel mutation occurring in the same codon as p.R248C, for which an oncogenic potential has previously been shown. Increased FGFR3 expression was shown in the two LCs containing the FGFR3 p.R248H mutation using qPCR. Histologically, both carcinomas were squamous cell carcinomas, therefore the incidence of the FGFR3 mutation among the squamous cell carcinoma cases was calculated as 3.2% (2/63). When we examined other co-occurring genetic abnormalities, one case exhibited a p53 p.R273C mutation, while the other case exhibited PIK3CA and SOX2 amplifications. The above results suggest that an FGFR3 p.R248H mutation is involved in the carcinogenesis of a subset of LCs and may contribute to the elucidation of the characteristics of FGFR3 mutation-positive LCs in the future.

CD74-ROS1 fusion transcripts in resected non-small cell lung carcinoma.

The recent discovery of fusion oncokinases in a subset of non-small cell lung carcinomas (NSCLCs) is of considerable clinical interest, since NSCLCs that express such fusion oncokinases are reportedly sensitive to kinase inhibitors. To better understand the role of recently identified ROS1 and RET fusion oncokinases in pulmonary carcinogenesis, we examined 114 NSCLCs for SLC34A2-ROS1, EZR-ROS1, CD74-ROS1 and KIF5B-RET fusion transcripts using RT-polymerase chain reaction and subsequent sequencing analyses. Although the expression of SLC34A2-ROS1, EZR-ROS1, or KIF5B-RET fusion transcripts was not detected in any of the cases, the expression of CD74-ROS1 fusion transcripts was detected in one (0.9%) of the 114 NSCLCs. The fusion occurred between exon 6 of CD74 and exon 34 of ROS1 and was an in-frame alteration. The mutation was detected in a woman without a history of smoking. Histologically, the carcinoma was an adenocarcinoma with a predominant acinar pattern; notably, a mucinous cribriform pattern and a solid signet-ring cell pattern were also observed in part of the adenocarcinoma. ROS1 protein overexpression was immunohistochemically detected in a cancer-specific manner in both the primary cancer and the lymph node metastatic cancer. No somatic mutations were detected in the mutation cluster regions of the KRAS, EGFR, BRAF and PIK3CA genes and the entire coding region of p53 in the carcinoma, and the expression of ALK fusion was negative. The above results suggest that CD74-ROS1 fusion is involved in the carcinogenesis of a subset of NSCLCs and may contribute to the elucidation of the characteristics of ROS1 fusion-positive NSCLC in the future.

Aberrant expression and mutation-inducing activity of AID in human lung cancer.

BACKGROUND: Activation-induced cytidine deaminase (AID) is expressed in B lymphocytes and triggers antibody diversification. Recent reports have indicated that the constitutive expression of AID in mice causes not only lymphomas, but also cancers of some organs including the lung, prompting us to investigate the expression and effect of AID on human lung cancer. MATERIALS AND METHODS: We examined AID mRNA expression in 17 lung cancer cell lines and 51 primary lung cancers using a quantitative RT-PCR analysis. Next, we established H1299 lung cancer cells stably overexpressing AID and performed a supF forward mutation assay. We then examined AID protein expression and p53 mutation in 129 primary lung cancers by an immunohistochemical analysis and PCR-SSCP and sequencing analyses, respectively. RESULTS: Aberrant mRNA expression of AID was detected in 29% (5 of 17) of the lung cancer cell lines and 31% (16 of 51) of the primary lung cancers. AID-overexpressing H1299 clones showed a 5.0- to 6.1-fold higher mutation frequency than an empty vector-transfected H1299 clone, and about half of the AID-induced mutations were base substitutions, indicating that AID induces gene mutations in lung cancer cells. Furthermore, an association was found between the AID protein expression level and the p53 mutation status in an analysis of 129 primary lung cancers. A further expression analysis revealed that a portion of AID is localized at the centrosomes. CONCLUSION: Our current findings suggest that the aberrant expression of AID may be involved in a subset of human lung cancers as a result of its mutation-inducing activity.