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

Nikiforova, Marina N.; Khalid, Asif; Fasanella, Kenneth E.; McGrath, Kevin; Brand, Randall E.; Chennat, Jennifer; Slivka, Adam; Zeh, Herbert J.; Zureikat, Amer H.; Krasinskas, Alyssa M.; Ohori, N. Paul; Schoedel, Karen E.; Navina, Sarah; Mantha, Geeta S.; Pai, Reetesh K.; Singhi, Aatur D.

doi:10.1038/modpathol.2013.91

Cited by 137 publications

(105 citation statements)

References 21 publications

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“…38 However, a recent study indicated KRAS mutations have a sensitivity of 14% detecting MCN lesions, which is significantly lower than its IPMN counterpart. 27 This finding was replicated again in 2014 where only 1/16 patients (6%) had a positive KRAS mutation in an MCN population. Multiple studies have ruled out GNAS as a potential marker for MCNs as this mutation has only been found in IPMN lesions.…”

Section: Mucinous Cystic Neoplasmsupporting

confidence: 65%

“…24 Various studies have shown that KRAS has excellent specificity (ranging from 96%-100%), but has limited sensitivity (ranging from 45%-65%) in detecting mucinous neoplasms. [25][26][27] When combining CEA and KRAS, one study noted an increase in identification in pre-malignant and malignant cysts. 26 On the other hand, GNAS causes downstream production of cAMP that ultimately results in uncontrolled growth.…”

Section: Intraductal Papillary Mucinous Neoplasmmentioning

confidence: 99%

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An appraisal of pancreatic cyst fluid molecular markers

Modi

Pavurala

Krishna

2017

Int J Gastrointest Interv

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Pancreatic malignancy is the third leading cause of cancer related death in the United States with limited viable screening options. By the end of this decade, cancers are poised to become the leading cause of death with pancreatic cancer projected to be the second leading cause of cancer related mortality. Pancreatic cystic lesions (PCLs) are found in approximately 5%-14% of patients due to the increased utilization of cross-sectional imaging, with approximately 8%-10% of pancreatic cancers originating as PCLs. Current screening guidelines have shown discrepancies between morphologic characteristics of PCLs and identifying advanced pancreatic disease. Molecular analysis has emerged as a novel technology to aid in adequate diagnosis and management decisions of PCLs. Mucinous cysts including intraductal papillary mucinous neoplasms (IPMNs) or mucinous cystic neoplasms have similar oncogenic mutations including KRAS, TP53, SMAD4, PIK3CA, PTEN, or CKDN2A, while GNAS and RNF43 mutations are specific only to IPMNs. Serous cystadenomas have been associated with a loss of tumor suppressor gene VHL, while solid-psuedopapillary neoplasms have an oncogenic mutation CTNNB1. A specific molecular marker to diagnose existing high-grade dysplasia or impending malignant transformation is yet to be identified. Moving forward it is important to advance technology in isolating and identifying high-risk molecular markers from cyst fluid while considering their increased utilization in the evaluation of PCLs.

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Section: Mucinous Cystic Neoplasmsupporting

confidence: 65%

Section: Intraductal Papillary Mucinous Neoplasmmentioning

confidence: 99%

An appraisal of pancreatic cyst fluid molecular markers

Modi

Pavurala

Krishna

2017

Int J Gastrointest Interv

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“…Interestingly, the frequency of mutated KRAS remains consistent as IPMN progresses (i.e., from adenoma to carcinoma) [13]. However, KRAS mutations have been shown to have high specificity, but low sensitivity for mucinous differentiation (100-96% and 54-45%, respectively) [14,15].…”

Section: Expert Commentary and Five-year Viewmentioning

confidence: 99%

Activating mutations ofGNASandKRASin cystic fluid can help detect intraductal papillary mucinous neoplasms of the pancreas

Frampton

Stebbing

Gall

et al. 2015

Expert Review of Molecular Diagnostics

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Evaluation of: Singhi AD, Nikiforova MN, Fasanella KE, et al. Preoperative GNAS and KRAS testing in the diagnosis of pancreatic mucinous cysts. Clin. Cancer Res. 20(16), 4381-9 (2014).Intraductal papillary mucinous neoplasms (IPMNs) of the pancreas have a risk of malignant transformation following an adenoma-carcinoma sequence. Surgical resection is often required, especially for main pancreatic duct IPMNs (MD-IPMNs). There is an urgent need for novel biomarkers to reliably differentiate IPMNs from more benign pancreatic cysts and therefore avoid unnecessary surgery. DNA sequencing has demonstrated that guanine nucleotide binding protein alpha stimulating (GNAS) activity polypeptide 1 mutations play a driving role in IPMN development. GNAS mutations have been shown to be highly specific for IPMNs, whereas oncogenic KRAS mutations have been associated with mucinous differentiation. The evaluated article by Singhi et al. helps to define the role of these mutations as biomarkers in preoperative endoscopic ultrasound fine-needle aspiration samples for detecting IPMNs. They found that the presence of a GNAS and/or a KRAS mutation was highly specific and sensitive for IPMNs. Cystic lesions of the pancreas can either be inflammatory or proliferative [1]. Differentiating between low-and high-risk pre-malignant tumors can be difficult and the consequences of missing the chance for a curative resection in patients who are suitable can be devastating. To prevent this, many centers recommend routine excision of all suspicious pancreatic cystic tumors (PCTs), potentially exposing patients with benign disease to the unjustifiable risks of major surgery. PCTs can be classified into non-mucinous tumors with negligible malignant potential, such as the serous cystadenomas (SCA), and those with significant malignant potential, such as intraductal papillary mucinous neoplasms (IPMNs) and mucinous cystic neoplasms (MCNs). The mucinous cysts have the potential to give rise to in situ or invasive carcinoma, via an adenoma-carcinoma sequence. Thus, a correct pre-operative diagnosis and evaluation of a PCT is crucial for clinical decision-making.Endoscopic ultrasound fine-needle aspiration (EUS-FNA) has become an essential tool for cytopathologic confirmation of pancreatic lesions, and pre-operative planning. Recent meta-analysis has shown that pooled specificity for cytology is 93% (95% CI: 90-95) with a sensitivity of 54% (95% CI: 49-59) for a mucinous cyst [2]. Carcinoembryonic antigen (CEA) levels are raised in mucinous cyst fluid while low in non-mucinous lesions, and the optimum threshold of 192 ng/ml has high discriminatory accuracy [3]. Pooled specificity for CEA measurement is 88% (95% CI: 83-91), with a sensitivity of only 63% (95% CI: 59-67) for mucinous differentiation [ [4][5][6]. Of note, these experiments have revealed frequent activating mutations of GNAS and KRAS in IPMNs. Indeed, GNAS mutations appear to be a hallmark molecular alteration of IPMNs (prevalencẽ 66%) [6]. However, the ability and clinical usefulness of i...

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“…Pancreatic cyst fluids tested obtained by EUS-FNA were consecutively accrued for routine KRAS mutational analysis between January 2006 and December 2013 at the University of Pittsburgh Medical Center (Pittsburgh, PA; ref. 7). In all cases, cyst fluid was submitted for molecular analysis by the endoscopist because of uncertainty as to whether a pancreatic cyst represented a cystic neoplasm.…”

Section: Casesmentioning

confidence: 99%

“…Previously, we reported the results of our institution's clinical experience with DNA testing for KRAS mutations from pancreatic cyst fluid obtained by EUS-FNA (7). KRAS mutations had a specificity of 100% but a sensitivity of 54% for mucinous differentiation.…”

Section: Introductionmentioning

confidence: 99%

PreoperativeGNASandKRASTesting in the Diagnosis of Pancreatic Mucinous Cysts

Singhi¹,

Nikiforova²,

Fasanella

et al. 2014

Clinical Cancer Research

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172

134

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Purpose: Management guidelines for pancreatic intraductal papillary mucinous neoplasms (IPMN) and mucinous cystic neoplasms (MCN) are based on the assumption that mucinous cysts can be accurately distinguished from other pancreatic cystic lesions. Previous studies using surgical material have identified recurrent mutations in GNAS and KRAS in pancreatic mucinous neoplasms. Yet, the diagnostic utility of testing for both genes in pancreatic cyst fluid obtained by endoscopic ultrasound-fine-needle aspiration (EUS-FNA) remains unclear.Experimental Design: GNAS and KRAS testing was performed on EUS-FNA pancreatic cyst fluid from 91 pancreatic cysts: 41 IPMNs, 9 IPMNs with adenocarcinoma, 16 MCNs, 10 cystic pancreatic neuroendocrine tumors (PanNET), 9 serous cystadenomas (SCA), 3 retention cysts, 2 pseudocysts, and 1 lymphoepithelial cyst.Results: Mutations in GNAS were detected in 16 (39%) IPMNs and 2 (22%) IPMNs with adenocarcinoma. KRAS mutations were identified in 28 (68%) IPMNs, 7 (78%) IPMNs with adenocarcinoma, and 1 (6%) MCN. Mutations in either gene were present in 34 (83%) IPMNs, 8 (89%) IPMNs with adenocarcinoma, and 1 (6%) MCN. No mutations were found in cystic PanNETs, SCAs, retention cysts, pseudocysts, and a lymphoepithelial cyst. GNAS and KRAS mutations had 100% specificity [95% confidence interval (CI), 0.83-1.00] but 65% sensitivity (95% CI, 0.52-0.76) for mucinous differentiation. Among IPMNs, mutations in either gene had 98% specificity (95% CI, 0.86-1.00) and 84% sensitivity (95% CI, 0.70-0.92).Conclusions: The combination of GNAS and KRAS testing was highly specific and sensitive for IPMNs; however, the lack of sensitivity for MCNs highlights the need for additional markers to improve the detection of pancreatic mucinous neoplasms.

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

Cited by 137 publications

References 21 publications

An appraisal of pancreatic cyst fluid molecular markers

An appraisal of pancreatic cyst fluid molecular markers

Activating mutations ofGNASandKRASin cystic fluid can help detect intraductal papillary mucinous neoplasms of the pancreas

PreoperativeGNASandKRASTesting in the Diagnosis of Pancreatic Mucinous Cysts

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