Pancreatic adenocarcinoma: update on the surgical pathology of carcinomas of ductal origin and PanINs

Hruban, Ralph H.; Fukushima, Noriyoshi

doi:10.1038/modpathol.3800685

Cited by 101 publications

(72 citation statements)

References 45 publications

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“…PanINs arise in the smaller pancreatic ducts and are classified morphologically into three grades, according to nuclear polarity, nuclear size (pleomorphism) and hyper-chromatic staining [28]. Despite complex interactions between tumor cells and PanINs, histological and molecular evidence suggests that PanINs can gradually progress to PDACbearing genetic traits such as K-ras mutation, Cyclin D1 over-expression and loss of p16 expression [29,30]. Since CP is also an independent risk factor for the development of PDAC [31], the high proportion of RNF13 expression in CP and PanINs suggests that RNF13 might be involved in the earliest stages of pathogenesis of PDAC and could potentially be used as a biomarker for diagnosis of PDAC at a non-invasive stage.…”

Section: Discussionmentioning

confidence: 99%

RNF13: a novel RING-type ubiquitin ligase over-expressed in pancreatic cancer

et al. 2008

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Protein ubiquitination by E3 ubiquitin ligases plays an important role in cancer development. In this study, we provide experimental evidence that a RING-finger-containing protein RNF13 is an ER/Golgi membrane-associated E3 ubiquitin ligase and its RING finger domain is required for the ubiquitin ligase activity. Immunohistochemical analysis of pancreatic ductal adenocarcinoma (PDAC) and paracancerous normal tissues from 72 patients documented RNF13 over-expression in 30 tumor samples (41.7%, 30/72), and its expression was significantly associated with histological grading (P = 0.024). In addition, RNF13 was detected in precancerous lesions: tubular complexes in chronic pancreatitis (CP) and pancreatic intraepithelial neoplasia (PanIN) (79.3%, 23/29 and 62.8%, 22/35, respectively). Moreover, RNF13 staining was significantly correlated with Tenascin-C expression (P = 0.004) in PDAC samples, further supporting the role of RNF13 in cancer progression. Over-expression of wild type but not RING domain-mutant RNF13 in pancreatic MiaPaca-2 cancer cells increased invasive potential and gelatinolytic activity by matrix metalloproteinase-9. Taken together, these findings reveal that RNF13 is a novel E3 ubiquitin ligase involved in pancreatic carcinogenesis; ubiquitin-mediated modification of proteins by RNF13 may participate in pancreatic cancer development.

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Section: Discussionmentioning

confidence: 99%

RNF13: a novel RING-type ubiquitin ligase over-expressed in pancreatic cancer

et al. 2008

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“…Cases with either microscopic or gross viable residual tumor were staged based on the AJCC Cancer Staging Manual, 7 th edition. The grading of PanIN lesions were based on the previously published criteria [16][17][18][19]. The study was approved by the Institutional Review Board of The University of Texas M. D. Anderson Cancer Center.…”

Section: Study Population and Histologic Evaluationmentioning

confidence: 99%

Pathologic complete response to neoadjuvant therapy in patients with pancreatic ductal adenocarcinoma is associated with better prognosis

Wang¹,

Zhao²

2012

Annals of Diagnostic Pathology

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In patients with pancreatic ductal adenocarcinoma (PDA) who received neoadjuvant therapy and pancreatectomy, pathologic complete response (pCR) is rarely observed and the prognostic significance of pCR is not clear. In this study, we reported 11 patients with pCR (2.5%) from 442 patients with PDA who received neoadjuvant treatment and pancreatectomy from 1995 to 2010. There were 6 men and 5 women with median age of 61 years. Four patients had either synchronous or prior history of extra-pancreatic cancer. Five patients received neoadjuvant chemotherapy followed by chemoradiation, and 6 received chemoradiation alone. Ten patients had pancreaticoduodenectomy and one had distal pancreatectomy. Scar and chronic pancreatitis consistent with therapy effect were present in all cases (100%). Pancreatic intraepithelial neoplasia 3 (Pan IN3)/carcinoma in situ was present in 5 cases, PanIN1 and PanIN2 in 5 cases. However, no residual invasive carcinoma or lymph node metastasis was identified in all cases. Follow-up information was available in 10 patients. Follow-up time ranges from 6 to 194 months (median, 63 months). During follow-up, three patients died of other causes and one developed a second primary PDA in the tail of pancreas at 84 months after initial pancreaticoduodenectomy and died at 105 months after the initial diagnosis of PDA. The other 6 patients were alive with no evidence of disease. Patients with pCR had better survival than those who had post-therapy stage I or IIA

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“…The reported genetic alterations in PanINs include activating point mutations in the KRAS2 oncogene 4 and inactivation of p16/CDKN2A, 5 TP53, 6 SMAD4/DPC4, 6,7 and BRCA2. 2,8,9 Most of these genetic alterations have been detected in the histologically more advanced PanIN lesions (PanIN-2 and PanIN-3), and the initiating events in neoplastic progression within the pancreatic ducts remains unknown. In addition, telomere shortening is a common genetic abnormality observed in all stages of PanINs including the vast majority of earliest lesions (PanIN-1A).…”

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confidence: 99%

CpG island methylation profile of pancreatic intraepithelial neoplasia

et al. 2008

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Infiltrating adenocarcinoma of the pancreas is thought to develop through well-defined precursor lesions called pancreatic intraductal neoplasia (PanIN). Despite the exponential growth in our understanding of genetic events that characterize the progression of PanINs to invasive carcinoma, little is known about the role of epigenetic alterations in these precursor lesions. To define the timing and prevalence of methylation abnormalities during early pancreatic carcinogenesis, we investigated the CpG island methylation profile in the various grades of PanINs. Using methylation-specific PCR, we analyzed DNA samples from 65 PanIN lesions for methylation status of eight genes recently identified by microarray approach as aberrantly hypermethylated in invasive pancreatic cancer. Aberrant methylation at any of the eight genes was identified in 68% of all the PanIN lesions examined, and, notably, aberrant methylation was identified in more than 70% of the earliest lesions (PanIN-1A). The average number of methylated loci was 1.1 in PanIN-1A, 0.8 in PanIN-1B, 1.1 in PanIN-2, and 2.9 in PanIN-3 lesions (P ¼ 0.01 for PanIN -3 vs earlier PanINs). Among the genes analyzed, NPTX2 demonstrated an increase in methylation prevalence from PanIN-1 to PanIN-2 (P ¼ 0.0008), and from PanIN-2 to PanIN-3 for SARP2 (P ¼ 0.001), Reprimo (P ¼ 0.01), and LHX1 (P ¼ 0.03). These results suggest that aberrant CpG island hypermethylation begins in early stages of PanINs, and its prevalence progressively increases during neoplastic progression. Keywords: PanIN; pancreatic cancer; methylation specific PCR; DNA methylation Accumulating evidence supports the hypothesis that infiltrating adenocarcinoma of the pancreas develops from noninvasive precursor lesions in the small ducts and ductules, called pancreatic intraductal neoplasia (PanIN). 1,2 Characterization of molecular basis for these precursor lesions may refine our understanding of pancreatic ductal carcinogenesis and also provide important insight into early pancreatic cancer detection strategies and novel targets for chemoprevention. 3 Many of the genetic abnormalities observed in invasive pancreatic cancer have also been observed in PanIN lesions. The reported genetic alterations in PanINs include activating point mutations in the KRAS2 oncogene 4 and inactivation of p16/CDKN2A, 5 TP53, 6 SMAD4/DPC4, 6,7 and BRCA2. 2,8,9 Most of these genetic alterations have been detected in the histologically more advanced PanIN lesions (PanIN-2 and PanIN-3), and the initiating events in neoplastic progression within the pancreatic ducts remains unknown. In addition, telomere shortening is a common genetic abnormality observed in all stages of PanINs including the vast majority of earliest lesions (PanIN-1A). 10 PanIN lesions may be particularly important in patients with a strong family history of pancreatic cancer. [11][12][13] Pancreata in patients with a strong family history of pancreatic cancer are remarkable for the presence of multifocal PanIN lesions, and these PanIN lesions are characteristi...

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Pancreatic adenocarcinoma: update on the surgical pathology of carcinomas of ductal origin and PanINs

Cited by 101 publications

References 45 publications

RNF13: a novel RING-type ubiquitin ligase over-expressed in pancreatic cancer

RNF13: a novel RING-type ubiquitin ligase over-expressed in pancreatic cancer

Pathologic complete response to neoadjuvant therapy in patients with pancreatic ductal adenocarcinoma is associated with better prognosis

CpG island methylation profile of pancreatic intraepithelial neoplasia

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