Early detection of pancreatic cancer

Abstract

The diagnosis of pancreatic cancer associates an appalling significance. Detection of preinvasive stage of pancreatic cancer will ameliorate the survival of this deadly disease. Premalignant lesions such as Intraductal Papillary Mucinous Neoplasms or Mucinous Cystic Neoplasms of the pancreas are detectable on imaging exams and this permits their management prior their invasive development. Pancreatic intraepithelial neoplasms (PanIN) are the most frequent precursors of pancreatic adenocarcinoma (PDAC), and its particular type PanIN high-grade represents the malignant non-invasive form of PDAC. Unfortunately, PanINs are not detectable on radiologic exams. Nevertheless, they can associate indirect imaging signs which would rise the diagnostic suspicion. When this suspicion is established, the patient will be enrolled in a follow-up strategy that includes performing of blood test and serial imaging test such as computed tomography or magnetic resonance imaging, which will cost in the best-case scenario a burden of healthcare systems, and potential mortality in the worst-case scenario when the patient underwent resection surgery, worthless when there is no moderate or high grade dysplasia in the final histopathology. This issue will be avoid having at its disposal a diagnostic technique capable of detecting high-grade PanIN lesions, such is the cytology of pancreatic juice obtained by nasopancreatic intubation. Herein, we review the possibility of detection of early malignant lesions before they become invasive PADC.

Key Words: Early pancreatic cancer; Pancreatic adenocarcinoma precursor lesions; Pancreatic juice analysis; PanIN; High-grade pancreatic intraepithelial neoplasm; Magnetic resonance cholangiopancreatography

Core Tip: High-grade pancreatic intraepithelial neoplasia can be diagnosed by cytology of pancreatic juice before they become invasive carcinoma. Candidates to this diagnostic procedure are patients with disturbed anatomy in pancreatic imaging without evident tumor such as segmental atrophy of parenchyma, main pancreatic duct (MPD) stenosis/dilatation, focal blurred MPD or local parenchymal fatty changes.

INTRODUCTION

Pancreatic cancer continuous to be a dismal disease. Patients diagnosed with pancreatic ductal adenocarcinoma (PDAC) stage I resectable disease show 26-month median cancer-specific survival versus 4.8-month median survival in patients with unresectable stage IV disease[1]. Furthermore, the Japan Pancreatic Cancer Registry revealed that the 5-year survival rates of patients categorized with the Union Internationale Contre le Cancer stage 0 (in situ), and stage 1 TS1a (invasive carcinoma with tumor diameter of < 10 mm and absence of regional lymph node metastasis or distant metastasis) were 85.8%, and 80.4%, respectively[2]. Another study from Japan showed an estimated overall survival rates at 10 years after resection for stage 0, stage 1 TS1a, and stage 1 TS1b, i.e. tumor diameter 11-20 mm, of 94.7%, 93.8%, and 78.9%, respectively[3]. A logical conclusion is that early-detection strategies that can identify cases of PDAC before the spread of the disease will improve the outcomes.

The recognized precursors of PDAC encompass a spectrum lesions such as pancreatic intraepithelial neoplasms (PanINs), intraductal papillary mucinous neoplasms (IPMN), intraductal tubulopapillary neoplasms, intraductal oncocytic papillary neoplasms, and mucinous cystic neoplasms (MCN)[4]. Grossly the most frequent and higher-risk for malignancy precursor lesions are PanIN high-grade (before PanIN 3), IPMN main-duct or mixed-type, and in less proportion the MCN with diameter of 4cm or larger.

Finding of PanIN or premalignant pancreatic cystic lesions constitutes an opportunity for patient management to minimize the risk of progression to invasive carcinoma.

Cystic pancreatic lesions are common incidental findings in cross-sectional imaging[5]. Diagnosis and management of these lesions has been established and revised in international guidelines[5-8]. Unlike the other precursor lesions, PanINs are lesions that cannot be detected by imaging [computed tomography (CT) or magnetic resonance imaging (MRI)] because of their microscopic identity[9] and lack of characterized associated indirect radiological signs. The PanIN lesions occur in the small pancreatic duct, are less of 5 mm in extension, and the tumor cannot be directly detected, therefore pancreatic tumors derived from PanIN lesions are seldom diagnosed by imaging modalities in stage 0 cases[3].

Nevertheless, main pancreatic duct strictures and dilations observed on imaging modalities (CT, MRI, and endoscopic ultrasound), additional partial pancreatic parenchymal atrophy[10] (Figure 1), and subtle or blurred parenchymal abnormalities related to secondary glandular disturbances from the PanIN can suggest the presence of early pancreatic lesions. In a retrospective multicenter study of early pancreatic cancer in Japan, Kanno et al[3] detected local fatty changes of the pancreatic parenchyma in 21/50 (42%) stage 0 and 61/146 (41.8%) stage I cases of the series.

Figure 1 A 75 year-old female patient with incidental changes in abdominal computed tomography scan and final histopathology of pancreatic adenocarcinoma of 10 mm. A: Blurred main pancreatic duct (MPD) and parenchyma without visible mass; B: T1 magnetic resonance imaging (MRI) showing hypervascular nodule at the body of the pancreas, C: T2 MRI depicted moderate dilation of the MPD.

In this editorial, we comment on another unspecific subtle abnormality report by Furuya et al[11]. The authors described a female patient with an incidental finding of pancreatic cyst. The magnetic resonance cholangiopancreatography showed signs of benign cyst but an ill-defined main pancreatic duct at the 20-mm length of the pancreatic tail without upstream dilation. Atypical cells were obtained by serial pancreatic juice aspiration cytology and distal pancreatectomy was performed and the histopathology revealed a high-grade PanIN.

Surveillance of the patients with blurred focal distortion and unspecific signs by regular blood test and imaging exams, or pancreatic resection in patients with suspect images may lead to unnecessary burden of healthcare systems (Figure 2) and avoidable morbimortality.

Figure 2 A 80 year-old woman with recurrent acute pancreatitis, cholelithiasis, and dilation of main pancreatic duct at the body and tail of the pancreas suspicious of intraductal papillary mucinous neoplasms. A: Enlarged main pancreatic duct (MPD) on contrast-enhanced computed tomography slice (arrow); B: Coronal T2 magnetic resonance imaging slice (arrow); C: Cholangio-magnetic resonance reconstruction. Enlarged MPD pointed with arrow (arrow). Final histopathology revealed absence of intraductal papillary mucinous neoplasms and reported chronic pancreatitis.

Endoscopic ultrasound-fine needle aspiration is not useful for the preoperative diagnosis of malignancy in stage 0 cases. Nevertheless, stage 0 patients can be diagnosed using pancreatic juice cytology obtained by endoscopic nasopancreatic drainage (ENPD), as it has been comment early before in the case by Furuya et al[11]. Moreover, it was shown in the study by Iiboshi et al[12] were 7 of 15 patients presenting with focal stenosis and distal dilatation of the main pancreatic duct and included in the ENPD placement group were diagnosed with carcinoma in situ. The cytology of pancreatic juice is a procedure which has attracted the attention in the eastern groups, particularly in Japan centers[13-15], however its practice is not extended in the western countries. Only one study from a western institution has been published focusing in the DNA methylation analysis in isolated but non-multiple samples of pancreatic juice obtained in intraoperative pancreatic resections or by ERCP intubation in non-operated on patients[16], still it only has reached a research interest and has not been expanded in clinical practice.

CONCLUSION

In conclusion, the detection of pancreatic adenocarcinoma before it has reached an invasive stage (i.e. high-grade PanIN before PDAC) will provide a survival rate far superior to the overall survival associated with patients diagnosed with this deadly disease. This detection can be achieved using the analysis of cytology of pancreatic juice, a technique employed in eastern countries but not extended in western groups.