A Combination of Molecular Markers and Clinical Features Improve the Classification of Pancreatic Cysts

Abstract

Background & Aims The management of pancreatic cysts poses challenges to both patients and their physicians. We investigated whether a combination of molecular markers and clinical information could improve the classification of pancreatic cysts and management of patients. Methods We performed a multi-center, retrospective study of 130 patients with resected pancreatic cystic neoplasms (12 serous cystadenomas, 10 solid-pseudopapillary neoplasms, 12 mucinous cystic neoplasms, and 96 intraductal papillary mucinous neoplasms). Cyst fluid was analyzed to identify subtle mutations in genes known to be mutated in pancreatic cysts (BRAF, CDKN2A, CTNNB1, GNAS, KRAS, NRAS, PIK3CA, RNF43, SMAD4, TP53 and VHL); to identify loss of heterozygozity at CDKN2A, RNF43, SMAD4, TP53, and VHL tumor suppressor loci; and to identify aneuploidy. The analyses were performed using specialized technologies for implementing and interpreting massively parallel sequencing data acquisition. An algorithm was used to select markers that could classify cyst type and grade. The accuracy of the molecular markers were compared with that of clinical markers, and a combination of molecular and clinical markers. Results We identified molecular markers and clinical features that classified cyst type with 90%–100% sensitivity and 92%–98% specificity. The molecular marker panel correctly identified 67 of the 74 patients who did not require surgery, and could therefore reduce the number of unnecessary operations by 91%. Conclusions We identified a panel of molecular markers and clinical features that show promise for the accurate classification of cystic neoplasms of the pancreas and identification of cysts that require surgery.

Solid Pseudopapillary Tumor of the Pancreas: A Single-center Experience and Review of the Literature

“…SPTs are typically positive for vimentin, NSE, alpha-1-antitrypsin and alpha-1-antichymotrypsin and negative for CgA, epithelial membrane antigen and cytokeratine. The presence of the CTNNB1 molecular marker along the absence of KRAS, GNAS, RNF43 and LOH on chromosome 18 are reported to be a useful stand-alone diagnostic tool but also useful when used in conjunction with specific clinical markers (27). Most of the patients present with atypical symptoms, including abdominal discomfort, mild abdominal pain, increased abdominal girth, poor appetite and nausea, all related to tumor compression on the adjacent organs (23,28).…”

An appraisal of pancreatic cyst fluid molecular markers

“…42 Finally, it is important to note that in stark contrast to IPMNs or MCNs, these cysts do not have mutations of KRAS, GNAS, RNF43, TP53, SMAD4, PIK3CA, PTEN, or CKDN2A.…”

“…Additional associations with PIK3CA, PTEN, and CKDN2A have also been published. [40][41][42] However, the lack of sensitivity of KRAS portends the continued need for research to ensure accurate identification of MCNs. 15 …”

“…18 Molecularly, mutations seen in tumor suppressor gene VHL and LOH of chromosome 3 were both associated with SCAs. 41,42 The VHL gene is important as it encodes for an E3 ubiquitin ligase that inhibits activation of HIF1-a, an oncogene. In the absence of the E3 ubiquitin ligase, HIF1-a can promote cell proliferation and angiogenesis.…”

Endoscopic ultrasound-guided histological diagnosis of a mucinous non-neoplastic pancreatic cyst using a specially designed through-the-needle microforceps

“…Cystic fluid carcinoembryonic antigen (CEA) concentration and cytology have low sensitivity in distinguishing mucinous from non-mucinous cysts [1], leading to frequent misdiagnoses and unnecessary surgical interventions [2]. Recently evaluated molecular markers seem very accurate, but they are not widely available in clinical practice [3].…”