Sequential Accumulation of K-ras Mutations and p53 Overexpression in the Progression of Pancreatic Mucinous Cystic Neoplasms to Malignancy

Jimenez, Ramon E.; Warshaw, Andrew L.; Z’graggen, Kaspar; Hartwig, Werner; Taylor, Dolores Z.; Compton, Carolyn C.; Castillo, C. Fernandez-del

doi:10.1097/00000658-199910000-00006

Cited by 167 publications

(112 citation statements)

References 41 publications

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“…[18][19][20][21][22] Consistent with previous studies, the prevalence of KRAS mutations in IPMNs was 67%. In contrast, only 14% of MCNs harbored a KRAS mutation.…”

Section: Discussionsupporting

confidence: 89%

Integration of KRAS testing in the diagnosis of pancreatic cystic lesions: a clinical experience of 618 pancreatic cysts

et al. 2013

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With improvements in abdominal imaging, detection of incidental pancreatic cysts are becoming increasingly common. Analysis of pancreatic cyst fluid from fine-needle aspiration is particularly important in identifying intraductal papillary mucinous neoplasms (IPMNs) and mucinous cystic neoplasms (MCNs), which have significant implications in clinical intervention and follow-up. Previous controlled studies have shown that KRAS mutations in cyst fluid are highly specific for mucinous differentiation in pancreatic cysts; however, this has not been examined in the clinical setting. Over a 6-year study period, 618 pancreatic cyst fluids obtained by fine-needle aspiration at the time of endoscopic ultrasound were tested for KRAS mutations as part of routine evaluation for a cystic neoplasm. Of the 618 specimens, 603 (98%) from 546 patients were satisfactory for molecular analysis. Patients ranged in age from 17 to 90 years (mean, 63.9 years) and were predominantly female (68%). Pancreatic cysts were relatively evenly distributed throughout the pancreas and ranged in size from 0.6 to 11.0 cm (mean, 2.3 cm). Mutations in KRAS were detected in 232 of 603 (38%) aspirates. Although sufficient for molecular analysis, 320 of 603 (53%) specimens were either less than optimal (38%) or unsatisfactory (15%) for cytopathologic diagnosis. Surgical follow-up information was available for 142 (26%) patients and consisted of 53 KRAS-mutated and 89 KRAS-wild-type cysts. Overall, KRAS mutations had a specificity of 100%, but a sensitivity of 54% for mucinous differentiation. When stratified by cyst type, KRAS had a sensitivity of 67% and 14% for IPMNs and MCNs, respectively. In summary, KRAS mutations were highly specific for mucinous differentiation, but were inadequate in identifying MCNs. Future molecular studies and the combination of other fluid markers are required to improve the detection and classification of pancreatic mucinous neoplasms by endoscopic ultrasound fine-needle aspiration.

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“…[18][19][20][21][22] Consistent with previous studies, the prevalence of KRAS mutations in IPMNs was 67%. In contrast, only 14% of MCNs harbored a KRAS mutation.…”

Section: Discussionsupporting

confidence: 89%

Integration of KRAS testing in the diagnosis of pancreatic cystic lesions: a clinical experience of 618 pancreatic cysts

et al. 2013

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“…It was neither correlated to tumour stage since mutations were detected in plasma of patients with non metastatic tumours, which supports the hypothesis that KRAS2 mutations are early events in pancreatic carcinogenesis (Jimenez et al, 1999). Two studies in the literature are in agreement with this result (Yamada et al, 1998;Theodor et al, 2000), but another one found a statistically significant relation between circulating DNA KRAS2 mutations and poor prognosis (Castells et al, 1999).…”

Section: Molecular and Cellular Pathologysupporting

confidence: 55%

Differential diagnosis between chronic pancreatitis and pancreatic cancer: value of the detection of KRAS2 mutations in circulating DNA

et al. 2002

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KRAS2 mutations in codon 12 have been detected in about 80% of pancreatic cancers. The aim of this study was to evaluate the value of KRAS2 mutations detection in circulating deoxyribo nucleic acid to differentiate pancreatic cancer from chronic pancreatitis. Circulating deoxyribo nucleic acid was isolated from serum in 47 patients with histologically proven pancreatic adenocarcinomas (26 males, median age 65 years) and 31 controls with chronic pancreatitis (26 males, median age 48 years). Mutations at codon 12 of KRAS2 gene were searched for using polymerase chain reaction and allele specific amplification. Serum carbohydrate antigen 19.9 levels were also determined. KRAS2 mutations were found in 22 patients (47%) with pancreatic cancer and in four controls with chronic pancreatitis (13%) (P50.002). None of the latter developed a pancreatic cancer within the 36 months of median follow-up. The sensitivity, specificity, positive and negative predictive values of serum serum KRAS2 mutations for the diagnosis of pancreatic cancer were 47, 87, 85 and 52%, respectively. KRAS2 mutations were not related to age, gender, smoking habit, tumour stage, or survival. Among the 26 patients with normal or non-contributive (due to cholestasis) serum carbohydrate antigen 19.9 levels, 14 (54%) had KRAS2 mutations. The combination of KRAS2 and carbohydrate antigen 19.9 gave a sensitivity, specificity, positive and negative predictive values for the diagnosis of pancreatic cancer of 98, 77, 87 and 96%, respectively. Detection of KRAS2 mutations in circulating deoxyribo nucleic acid has a low sensitivity but a specificity about 90% for the diagnosis of pancreatic cancer. It seems particularly useful when serum carbohydrate antigen 19.9 levels are normal or inconclusive. A combined normal serum carbohydrate antigen 19.9 and absence of circulating KRAS2 mutations makes the diagnosis of pancreatic cancer extremely unlikely.

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“…Previous studies of KRAS mutations in MCNs have shown that the prevalence of mutations increases with the degree of dysplasia; indeed, KRAS mutations are less frequent in benign and borderline subtypes of MCNs and more common in MCNs with in situ carcinoma or invasive carcinoma (12,13). Jimenez et al reported KRAS mutations in 20% of benign, 33% of borderline, and 89% of malignant MCNs (13). The current study showed a similar tendency and additionally revealed a frequent association between KRAS mutation and mucinous MCN, regardless of the degree of dysplasia.…”

Section: Figure 3 Computed Tomography (A) and Pathological Findings mentioning

confidence: 99%

Mucinous Cystic Neoplasms Lined by Abundant Mucinous Epithelium Frequently Involve KRAS Mutations and Malignant Progression

Shibata

Ohike

Norose

et al. 2017

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Abstract. Background: Pancreatic and hepatic mucinous cyst neoplasms (MCNs) have a malignant potential, but indolent MCNs are not uncommon. Materials and Methods:The pathological and genetic characteristics of resected MCNs (n=15) Mucinous cystic neoplasm (MCN) of the pancreas was first described by Compagno and Oertel in 1978 (1). In the most recent World Health Organization (WHO) Classification of Tumours of the Digestive System (2010) (2), MCN was classified as a distinct entity of cystic neoplasms in both pancreas and liver, and it has been defined as "a cyst-forming epithelial neoplasm, usually showing no communication with the ductal system, composed of cuboidal to columnar, variably mucin-producing epithelium, and associated with ovarian-type subepithelial stroma" (3-5). MCNs tend to occur most often in middle-aged women and are regarded as pre-malignant lesions with significant potential for invasion and metastasis. Therefore, surgical resection is advocated as the primary treatment modality. However MCNs have a low prevalence of invasive carcinoma: indeed, in a recent large series, invasive carcinoma accounted for 3.9% to 16% of lesions in the pancreas (6, 7) and 10% of those in the liver (8). Recently, the term MCN has been challenged by 10), who favor dividing MCNs into two types: "pure MCNs" and "nonmucinous cystadenomas of the pancreas with pancreatobiliary phenotype and ovarian-like stroma". The latter is associated with ovarian-type stroma but is lined by a predominantly nonmucinous and non-dysplastic cuboidal epithelium that probably has no malignant potential. This advocacy may affect the treatment policy and surgical indications for pancreatic and hepatic MCNs. In the present study, we divided pancreatic and hepatic MCNs into mucinous and non-mucinous lesions based on the amount of mucin in the lining epithelium and examined whether or not there was any significant difference in the clinical behavior and biological characteristics between the two. Materials and MethodsFifteen cases of MCN of the pancreas or liver surgically resected between 1994 and 2016 at the Authors' Institutes were examined in the present study. A cystic neoplasm lined by cuboidal to columnar, variably mucin-producing epithelial cells and overlying ovarian-type subepithelial stroma, was regarded as MCN. Based on the findings of a light-microscopic examination of entire or multiple hematoxylin and eosin (H&E)-stained slides (at least five) including 7063 This Αrticle is freely accessible online.

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Sequential Accumulation of K-ras Mutations and p53 Overexpression in the Progression of Pancreatic Mucinous Cystic Neoplasms to Malignancy

Cited by 167 publications

References 41 publications

Integration of KRAS testing in the diagnosis of pancreatic cystic lesions: a clinical experience of 618 pancreatic cysts

Integration of KRAS testing in the diagnosis of pancreatic cystic lesions: a clinical experience of 618 pancreatic cysts

Differential diagnosis between chronic pancreatitis and pancreatic cancer: value of the detection of KRAS2 mutations in circulating DNA

Mucinous Cystic Neoplasms Lined by Abundant Mucinous Epithelium Frequently Involve KRAS Mutations and Malignant Progression

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