pancreatic intraepithelial neoplasia ( panin ) is a nomenclature for microscopic proliferative epithelial lesions of the pancreas which was proposed in 2001 by hruban et al . .
panin is assumed to be a precursor lesion of invasive ductal carcinoma ( idc ) .
precursor lesions of idc also include intraductal papillary mucinous neoplasm ( ipmn ) and mucinous cystic neoplasm .
panin is divided into three grades , panin-1 , -2 , and -3 , according to the cytological and architectural atypia .
panin-1 is further subdivided into flat ( panin-1a ) and papillary types ( panin-1b ) .
this hypothesis has arisen from the observation of the resected specimens , in which synchronous or metachronous occurrence of panin and idc were seen .
panin had been reported to be more common in the pancreas with idc than without [ 2 , 3 ] .
it has also been reported that idc occurred in the remnant pancreas several years after partial pancreatectomy for high - grade panin had been performed [ 4 , 5 ] .
several studies have demonstrated higher frequencies of genetic alterations such as k - ras mutation or dpc4 inactivation in higher - grade panin lesions [ 6 
 7 
 8 
 9 ] .
thus , it is hypothesized that pancreatic ductal lesions may progress from a histologically normal duct through flat lesion ( panin-1a ) , papillary lesion ( panin-1b ) , atypical lesion ( panin-2 ) to severely atypical lesion ( panin-3 ) .
panin-3 is likely to develop eventually into idc because panin-3 and idc share critical genetic abnormalities .
however , the histological evidence that panin-3 invades beyond the basement membrane of pancreatic ductal epithelium , that is , the moment panin-3 becomes idc , has not been captured yet . as defined by the consensus guideline
, panin is a microscopic papillary or flat , non - invasive epithelial neoplasia that is usually < 5 mm in diameter .
, panin-3 obstructed several branch pancreatic ducts and subsequently caused pancreatitis which developed clinical symptom and was detectable as a pancreatic mass on imaging studies . since pancreatic cancer was suspected , further examinations were performed .
histological examination of the resected specimens showed panin-3 slightly invading beyond the basement membrane of the ductal epithelia accompanied by fibrotic changes caused by occlusion of branch ducts .
a 65-year - old woman had been admitted to a former hospital for acute pancreatitis , which recurred 2 months thereafter .
she was referred to our center for further examination of her pancreas after the second pancreatitis had been relieved .
she was slightly thin , showing a body mass index of 20.2 , and had neither smoking nor drinking habits .
laboratory data showed no abnormalities including serum levels of amylase and tumor markers related to pancreatic diseases .
abdominal ultrasound revealed a low echoic mass of 13 mm in diameter in the pancreatic body without upstream dilatation of the main pancreatic duct ( mpd ) ( fig .
endoscopic ultrasound showed a low echoic mass of 20 mm in diameter in the pancreatic body ( fig .
since pancreatic cancer was suspected in the pancreatic body , she underwent endoscopic retrograde pancreatography , which showed a strictured segment of 2 mm in length in the mpd at the pancreatic body ( fig .
cytological examination of the pancreatic juice obtained during endoscopic retrograde pancreatography revealed adenocarcinoma ( fig .
1 g ) . the patient was diagnosed with pancreatic body cancer without obvious vascular involvement ( t3 , n0 , m0 , stage iia , according to the uicc classification ) and underwent distal pancreatectomy .
the resected specimens were fixed in formalin and cut at a slice thickness of 5 mm as shown in fig .
histological examination revealed papillary growth of intraductal epithelia with significant nuclear atypia which was classified as panin-3 according to the definition of the consensus guideline   mainly in the branch ducts ( fig .
panin-3s were located separately in branch ducts with normal epithelia in the mpd between them ( fig .
2b , h , i ) , indicating that they originated from different sites of the branch ducts .
histologically , this case was diagnosed as idc of the pancreatic body ( t1 , n0 , m0 , stage i ) .
high - grade panin ( panin-3 ) is recognized as a best - defined precursor lesion of idc based on genetic as well as histological observations .
panin-3 has been reported to share some genetic alterations with idc [ 6 
 7 
 8 
 9 ] and to be found usually in the pancreas with idc [ 2 
 3 
 4 
 5 ] .
however , the direct evidence of the moment when panin-3 invades beyond the basement membrane to become idc has not been captured yet .
this is the first case report in which microinvasion of panin-3 was histologically confirmed in the resected pancreatic specimens .
considerable ambiguities had existed in the distinction between panin and ipmn , therefore the definitions of these two lesions were revised at the consensus meeting held at johns hopkins hospital in 2003 . according to the revised definitions , panin is a microscopic , papillary or flat epithelial neoplasm arising in the pancreatic duct and differs from ipmn , which is defined as a grossly visible , mucin - producing , predominantly papillary epithelial neoplasm . in this case ,
pancreatic epithelial neoplasm itself was not identified in any radiological examinations , and mucin production was not evident in pancreatic ductal epithelia by microscopic observation .
a few reports had suggested that minimally invasive carcinoma should be distinguished from invasive ipmn because this subgroup of ipmn showed apparently better prognosis [ 11 , 12 
 13 ] .
however , the precise definition of minimally invasive carcinoma has not been established [ 14 , 15 ] and has been recently proposed by some studies [ 16 , 17 ] . in this case
, the patient has been alive without any signs of recurrence for more than 3 years .
since there has been no concept of minimally invasive panin to date , this case is classified as idc in spite of excellent outcome . a new notion that minimally invasive panin
should be distinguished from idc might be widely accepted in the future . in this case ,
panin-3 lesions were located separately in several branch ducts without involving the epithelia of the main duct between them .
this fact indicates that panin does not arise from one small portion of pancreatic ductal epithelium and spread creeping along the epithelia , but arises multicentric .
it is well known that ipmn , another precursor lesion of idc , occurs multicentric . as the whole pancreas may be involved in the genetic alteration which is related to carcinogenesis , it is not difficult to understand that panin occurs independently in different sites of the pancreas .
several cases dealing with multiple occurrence of idc have been reported as rare clinical manifestation [ 18 , 19 ] .
this observation could explain the rapid growth of pancreatic ductal carcinoma as follows : microinvasion initially occurs in several pancreatic ducts ; each invasion independently progresses and eventually makes a fusion mass .
this observation could also explain the multiple occurrence of idc when microinvasions occur independently distinct from each other .
unlike ipmn , panin-3 is hardly detected in clinical practice because panin-3 itself is not visible on imaging examination . in this case
, panin-3 was successfully detected due to pancreatitis caused by the intraductal growth of panin-3 and subsequent occlusion of the pancreatic ducts .
pancreatitis might be a candidate for the diagnostic clues to the early detection of pancreatic ductal carcinoma within the preinvasive stage .
there are other known diagnostic clues to early detection , such as pancreatic cysts or dilatation of the mpd . in this case , however , neither pancreatic cyst nor dilatation of the mpd was observed .
the detection of pancreatic ductal carcinoma in the preinvasive stage is the most promising way of improving patient survival .
we hope that our report will contribute to the further understanding of early development of pancreatic ductal carcinoma .
 high - grade pancreatic intraepithelial neoplasia ( panin-3 ) is recognized as a precursor lesion of invasive ductal carcinoma ( idc ) . 
 however , histological evidence that panin-3 invades beyond the basement membrane of pancreatic ductal epithelium , that is , the moment panin-3 becomes idc , has not been captured yet . 
 this may be because panins which are microscopic papillary or flat lesion rarely develop clinical symptoms and are not detectable on imaging examination . 
 on the other hand , most idcs were found in the advanced stage with massive invasion . in this report 
 , panin-3 obstructed several branch pancreatic ducts and subsequently caused pancreatitis which developed clinical symptom and was detectable as a pancreatic mass in imaging studies . 
 a 65-year - old woman was referred to our institution for further examination of her repeated pancreatitis . 
 abdominal ultrasound revealed a low echoic mass of 13 mm in diameter in the pancreatic body without upstream dilatation of the main pancreatic duct ( mpd ) . 
 endoscopic retrograde pancreatography showed a strictured segment of 2 mm in length in the mpd at the pancreatic body . 
 cytological examination of pancreatic juice revealed adenocarcinoma and distal pancreatectomy was performed . 
 a resected specimen revealed a whitish mass of 15 mm in diameter in the pancreatic body , which was identified as pancreatitis by histological examination . 
 papillary growth of panin-3 was seen mainly in the branch ducts . 
 each panin-3 was located separately in the branch ducts with normal epithelia in the mpd between them . in three adjacent branch ducts , 
 panin-3 was observed to be invading microscopically beyond the basement membrane . 
Introduction
Case Report
Discussion