Early diagnosis of pancreatic cancer: Current trends and concerns

Abstract Early detection of pancreatic cancer (PC) is essential for a better prognosis. Some recent studies have demonstrated that a slight dilatation of the main pancreatic duct (MPD) and small cystic lesions were detected initially in most cases diagnosed at an early stage. Detecting these abnormal findings in cases with high risk factors through an effective screening system including image diagnosis, some biological markers, or familial cancer registrations should contribute to early diagnosis of PC. It has been reported that endoscopic ultrasonography (EUS) is essential for detecting tumors <10 mm with a favorable prognosis. Additionally, EUS‐guided fine‐needle aspiration biopsy is useful for confirming final histological diagnosis. For the diagnosis of stage 0 PC, local irregular stenosis of MPD should be an important initial abnormal sign detected by EUS or magnetic resonance cholangiopancreatography. Cytodiagnosis multiple times using pancreatic juice obtained by endoscopic nasopancreatic drainage should be essential for the final diagnosis. Recently, activities of regional networks between specialist doctors in medical centers and general practitioners for early diagnosis of PC have been reported in Japan. In the future, these activities may play an important role in the early diagnosis of PC.


| INTRODUCTION
Many patients with pancreatic cancer (PC) with a poor prognosis are diagnosed at an advanced stage. This is attributed to the difficulty of early diagnosis of PC. 1,2 According to the recent Japan Pancreatic Cancer Registry (JPCR) analyzed by Japan Pancreas Society (JPS), the 5-year survival rate of cases with tumors ≤10 mm (TS1a) reached 80.4%, and the 5-year survival rate of cases with Stage 0 reached 85.8%. 3 These data suggest that early diagnosis should play an important role in improving the prognosis of PC. In this manuscript, we would like to review the current trends and concerns of early diagnosis of PC. to PC. 4 According to their progressions, the extent of atypia was classified as PanIN-1 (low-grade dysplasia), PanIn-2 (moderate-grade dysplasia), and PanIN-3 (high-grade dysplasia). Cases with PC in situ (PCIS) are classified into PanIN-3. It has been reported that K-ras mutations in PanIN-1, p16 inactivating mutations in PanIN-2, TP53 These observations should support a genetic progression model of pancreatic carcinogenesis leading to invasive cancer. [5][6][7][8][9][10] Recently, the estimated lifetime of clonal evolution during PC development and progression based on a computational model using many autopsy cases has been reported. 11,12 This model suggested an average of 11.7 years from the initiating carcinogenesis until development of the parental clone, an average of 6.8 years to the development of metastatic subclones within the primary PC, and an average of 2.7 years until death of the case (Figure 1). Most cases with PC were diagnosed toward the end of this lifetime span, suggesting that the poor prognosis was a result of late diagnosis in the natural history of PC. These results suggest that we should have a golden opportunity of 2 or 3 years to diagnose 'early pancreatic cancer' including Stage 0 or I.  (Table 2). [17][18][19][20][21][22][23][24][25][26][27][28][29][30] These studies demonstrated that the frequency of PC concomitant with IPMN ranged from 1.1% to 11.2%. As for branch duct IPMN, two working groups of JPS reported that seven PC cases were detected in 349 branch duct IPMN cases during the follow-up period, 17 and that PC concomitant with IPMN may be diagnosed earlier than ordinary PC. 18 These observations suggest that patients with IPMN or pancreatic cysts should be carefully observed as having premalignant disease of PC.

| Family history and hereditary PC syndrome
According to the registry of the National Familial Pancreas Tumor Registry (NFPTR), the risk of PC was 6.8-fold higher in the relatives of cases with familial PC, and 2.4-fold higher in relatives of cases with sporadic PC. 31 It has been reported that BRCA2, PALB2, and ataxia telangiectasia mutated germ-line mutations are most frequently identified in familial PC cases. 32    As a result, 399 out of 6475 cases were histologically diagnosed as PC. Of these cases, 16 were finally diagnosed as PCIS. 56 As the concept of the Onomichi project spreads, some Japanese medical associations have tried to establish the regional network for early diagnosis of PC. In the future, regional networks between SPC and GP in medical associations for early diagnosis of PC should be established in other rural areas in Japan.

| DIAGNOSIS OF PCIS
According to a recent JPCR by JPS, the 5-year survival rate of cases with UICC Stage 0 is 85.8%, which is a satisfactory prognosis. 3  fatty infiltration around PCIS as a slightly low echoic lesion. 56,66 Further examinations will be needed to confirm these possibilities in the future ( Figure 6).
For pathological diagnosis of PCIS, cytodiagnosis using pancreatic juice (PJ) during ERCP has been reported to be useful. Recently, there have been some reports of cytodiagnosis multiple times using PJ obtained by ENPD. The sensitivity and accuracy for diagnosis of PCIS using this method was 100%, and 95%, respectively. 64,70,71 Current Japanese CGL for PC recommends cytodiagnosis multiple times using PJ during ERCP when localized stenosis of MPD is observed by MRCP, EUS, or ERCP. 14

ACKNOWLEDGMENTS
The authors are grateful to all members of Onomichi Medical Association for their assistance.

CONF LICTS OF INTEREST
Hanada K. has the following financial relationships to disclose: Honoraria (lecture and manuscript fee) from: Eisai Co. Ltd. The other authors declare no conflicts of interest for this article.