Chanjuan Shi

Gastroenteropancreatic neuroendocrine tumors (GEP-NETs), although curable when localized, frequently metastasize and require management with systemic therapies, including somatostatin analogues, peptide receptor radiotherapy, small-molecule targeted therapies, and chemotherapy. Although effective for disease control, these therapies eventually fail as a result of primary or secondary resistance. For small-molecule targeted therapies, the feedback activation of the targeted signaling pathways and activation of alternative pathways are prominent mechanisms, whereas the acquisition of additional genetic alterations only rarely occurs. For somatostatin receptor (SSTR)-targeted therapy, the heterogeneity of tumor SSTR expression and dedifferentiation with a downregulated expression of SSTR likely predominate. Hypoxia in the tumor microenvironment and stromal constituents contribute to resistance to all modalities. Current studies on mechanisms underlying therapeutic resistance and options for management in human GEP-NETs are scant; however, preclinical and early-phase human studies have suggested that combination therapy targeting multiple pathways or novel tyrosine kinase inhibitors with broader kinase inhibition may be promising.

Pancreatic myoepithelial hamartoma is a rare, benign solid and cystic lesion of the pancreas. We present the first case of an adult with a giant myoepithelial hamartoma extending throughout the pancreas in a patient with diabetes in 4 immediate family members. The patient is a 46-year-old man presented with recurrent acute pancreatitis. Computed tomographic imaging showed that the head and body of the pancreas were replaced by a solid-cystic mass with focal calcification. Medical history includes insulin-dependent diabetes mellitus (IDDM) diagnosed at age 30. Endoscopic ultrasound-guided fine-needle aspiration showed pancreatic acinar tissue and smooth muscle without evidence of malignancy. Total pancreatectomy was performed because of the diffuse nature of the cystic disease and preexisting IDDM. The histopathologic diagnosis was consistent with myoepithelial hamartoma. In addition, there was a family history of IDDM and hamartomatous cyst resection in the paternal grandmother. We report the first case of diffuse pancreatic myoepithelial hamartoma with near total replacement of the entire pancreatic parenchyma, and the first reported case associated with a family history of heritable IDDM. Improved knowledge of the genetics, development, and malignant potential of such rare diseases is critical to determine appropriate management for patients.

Pancreatic cancer is the fourth leading cause of cancer death in the United States, with an estimated 38,000 American deaths in 2013. Worldwide it causes approximately 227,000 deaths each year and is the eighth most common cause of cancer-related death. The major type, pancreatic ductal adenocarcinoma, is a nearly uniformly metastatic and fatal disease, and the mortality rate for pancreatic ductal adenocarcinoma closely follows that of the incidence. Pancreatic cancer presents clinically with pain, with symptoms related to obstruction of the biliary or pancreatic ducts, or with protean symptoms such as weight loss and cachexia. Pancreatic neuroendocrine tumor is a separate major category of pancreatic neoplasms, often has endocrine clinical sequelae, and is less frequently metastatic and fatal.Although most carcinomas of the pancreas appear to be sporadic, studies suggest that 3-10% of all cases of pancreatic ductal adenocarcinoma are hereditary. Some of the genes responsible for the familial aggregation of pancreatic cancer are known, and they most convincingly include germline mutations in the BRCA2, PALB2, CDKN2A, PRSS1, ATM, STK11/LKB1, and DNA mismatch-repair genes.The profile of somatic genetic mutations in pancreatic cancer is distinct from other neoplasms. The KRAS oncogene is commonly activated by somatic mutations in pancreatic cancer, whereas three tumor-suppressor genes are commonly inactivated. Ninety percent or more of pancreatic cancers harbor activating point mutations in codon 12 of KRAS. The CDKN2A tumor-suppressor gene is inactivated in 90-100% of pancreatic cancers, TP53 in 75%, and SMAD4 in 50%. In addition, recurrent somatic mutations of the MKK4, STK11/LKB1, TGFβ receptors, Smad and Fanconi anemia pathways, ATM, and ARID1A genes have also been reported. Various loci of gene amplifications each affect a minority of carcinomas.Inactivation of the SMAD4 gene may be rather specific for pancreatic ductal adenocarcinoma. SMAD4 is inactivated in as few as 15% of metastatic colorectal cancers and in less than 10% of other major cancer types. SMAD4 belongs to a class of proteins that mediate signals of the TGF-β superfamily.Microsatellite instability (RER+) is seen in a small minority (~ 4%) of pancreatic cancers. These RER+ cancers have a characteristic histologic appearance (medullary histology) and frequently have wild-type KRAS gene.The diagnosis of pancreatic cancer is suspected based on clinical findings, and often can be confirmed with radiologic and endoscopic techniques. Effective screening tests are not available yet. However, DNA-based testing appears promising.Recently, the exomes of the four most common cystic neoplasms of the pancreas have been sequenced, and each cyst type has its own unique mutational profile. Serous cystic neoplasms are characterized by VHL mutations, solid-pseudopapillary neoplasms harbor CTNNB1mutations, intraductal papillary mucinous neoplasms have GNAS, RNF43, KRAS, and, in advanced cases, TP53 and SMAD4 gene mutations, and mucinous cystic neoplasms have RNF43, KRAS, and, in advanced cases, TP53 and SMAD4 alterations.DAXX, ATRX, MEN-1 and mTOR pathway genes are mutated in pancreatic neuroendocrine tumors.

BACKGROUND: Most tumour response scoring systems for resected pancreatic cancer after neoadjuvant therapy score tumour regression. However, whether treatment-induced changes, including tumour regression, can be identified reliably on haematoxylin and eosin-stained slides remains unclear. Moreover, no large study of the interobserver agreement of current tumour response scoring systems for pancreatic cancer exists. This study aimed to investigate whether gastrointestinal/pancreatic pathologists can reliably identify treatment effect on tumour by histology, and to determine the interobserver agreement for current tumour response scoring systems. METHODS: Overall, 23 gastrointestinal/pancreatic pathologists reviewed digital haematoxylin and eosin-stained slides of pancreatic cancer or treated tumour bed. The accuracy in identifying the treatment effect was investigated in 60 patients (30 treatment-naive, 30 after neoadjuvant therapy (NAT)). The interobserver agreement for the College of American Pathologists (CAP) and MD Anderson Cancer Center (MDACC) tumour response scoring systems was assessed in 50 patients using intraclass correlation coefficients (ICCs). An ICC value below 0.50 indicated poor reliability, 0.50 or more and less than 0.75 indicated moderate reliability, 0.75 or more and below 0.90 indicated good reliability, and above 0.90 indicated excellent reliability. RESULTS: The sensitivity and specificity for identifying NAT effect were 76.2 and 49.0 per cent respectively. After NAT in 50 patients, ICC values for both tumour response scoring systems were moderate: 0.66 for CAP and 0.71 for MDACC. CONCLUSION: Identification of the effect of NAT in resected pancreatic cancer proved unreliable, and interobserver agreement for the current tumour response scoring systems was suboptimal. These findings support the recently published International Study Group of Pancreatic Pathologists recommendations to score residual tumour burden rather than tumour regression after NAT.