Minute mixed ductal-endocrine carcinoma of the pancreas with predominant intraductal growth

We report a rare case of minute (5 mm x 4 mm) mixed ductal-endocrine carcinoma of the pancreas with predominant intraductal growth. A 34-year-old Japanese man was admitted because of elevated serum pancreatic enzymes. Endoscopic retrograde pancreatography revealed an unidentified material of 18 mm within the main pancreatic duct. Stone or parasite with acute pancreatitis was suspected clinically, and the biopsy revealed malignant cells positive for CA19-9, carcinoembryonic antigen (CEA) and synaptophysin. No apparent tumor was identified in the pancreas by various imaging techniques. Resection of pancreatic body and tail was performed. Grossly, the main pancreatic duct in the pancreatic body was occluded by as much as 20 mm. The pancreas had minute carcinoma of 5 mm x 4 mm just around the occluded main pancreatic duct. The tumor cells invaded the main pancreatic duct and spread within it as long as 20 mm. Histologically, the carcinoma had biphasic pattern; one was ductal carcinoma with tubular formations and another was carcinoma with neuroendocrine features. These two elements were admixed, and the ductal element comprised 30% while the endocrine element comprised 70%. The ductal element was immunoreactive for cytokeratins, CEA and CA19-9, while the endocrine element was immunoreactive for chromogranin A and synaptophysin. No immunoreactivity for pancreatic enzymes was noted. Ultrastructural observations showed dense core granules and no zymogen granules. Our case is unique clinically in that the tumor manifested as an intraductal material and no apparent tumor was found by imaging modalities, and pathologically in that the tumor was rare mixed ductal-endocrine carcinoma and the tumor was very small and mainly grew within the main pancreatic duct.     

Intraductal acinar cell carcinoma of the pancreas

We describe a purely intraductal acinar cell carcinoma involving branch ducts of the pancreas in a 74-year-old man, which presented as recurrent episodes of acute pancreatitis. Endoscopic ultrasound examination revealed an intraductal mass bulging into the main pancreatic duct suggesting, pre-operatively, an intraductal mucinous papillary tumour. Gross examination showed several dilated branch ducts that contained haemorrhagic tumour material without any solid or true cystic formation within the pancreatic parenchyma. Using histology, a purely intraductal acinar cell carcinoma was observed, involving branch ducts only, associated with foci of carcinoma in situ in adjacent exocrine parenchyma. The main pancreatic duct was free of disease except for its communication with a cancerous branch duct. A concomitant neuroendocrine microadenoma was incidentally found during slide screening. Immunohistochemistry performed on the intraductal proliferation confirmed zymogen secretion with positive staining for alpha-1 anti-chymotrypsin and anti-trypsin and the persistence of diastase-periodic acid-Schiff positive granules in the apical pole of the tumour cells. Neuroendocrine markers were negative in the acinar cell carcinoma and positive in the neuroendocrine microadenoma. To our knowledge, this is the first report of an intraductal acinar cell carcinoma of the pancreas involving branch ducts and sparing the main pancreatic duct.     

Intraductal proliferation in the pancreas and its relationship to human and experimental carcinogenesis

Summary In 21 patients who had undergone total pancreatectomy for pancreatic head carcinoma, the uninvolved pancreas was examined with regard to the type, incidence and regional distribution of duct epithelial proliferation. The results were compared with those in 37 operative specimens from patients with chronic pancreatitis, in 46 normal pancreases from autopsies and with findings in experimental pancreatic carcinogenesis.While the incidence of squamous metaplasia and non-papillary epithelial hypertrophy varied little in the different groups, papillary epithelial hyperplasia was found three times more often in cases of carcinoma, with associated mild duct obstruction. Atypical epithelial proliferation was only detected in the vicinity of carcinomas. Unequivocal transition from papillary hyperplasia to atypical proliferation was not observed. In hamsters treated with dihydroxy-di-n-propylnitrosamine (DHPN) for induction of pancreatic duct carcinomas, the early duct lesions closely resembled atypical epithelial proliferation of human pancreas.It is concluded that (1) papillary epithelial hyperplasia is probably only indicative of early duct obstruction and/or a general neoplastic stimulus, (2) intraductal epithelial proliferation with atypia is a true precursor of duct carcinoma, and (3) chronic pancreatitis lacks atypical duct lesions.     

Bone morphogenetic protein‐2 expression in an intraductal papillary mucinous neoplasm with marked ossification: A case report

Intratumoral ossification has been reported in a number of epithelial tumors, but its presence in intraductal papillary mucinous neoplasms (IPMNs) is very rare. Herein, we present a rare case of IPMN with marked ossification. A 56‐year‐old Japanese man was under follow‐up for a previously diagnosed IPMN. Seven years later, he was found to have dilatation of the main pancreatic duct and an enlarged solid mass, for which pancreaticoduodenectomy was performed. Macroscopically, multiple and cystically dilated pancreatic branch ducts, as well as a dilated main pancreatic duct, were identified. There was a solid, polypoid hard mass measuring 15 × 12 mm in the cystically dilated branch of the duct in the pancreatic head. Histological examination revealed papillary proliferation of atypical cuboidal or columnar epithelial cells in the dilated main and branch pancreatic ducts. The solid mass included an invasive adenocarcinoma component with a tubular or trabecular structure that showed pronounced ossification. We diagnosed the patient with invasive IPMN accompanied by marked ossification. Immunohistochemically, tumor cells in both the non‐invasive and invasive lesions expressed bone morphogenetic protein‐2 (BMP‐2). While the mechanism of intratumoral ossification is unclear, it may have involved BMP‐2 in the present case.     

Pancreatographic investigation of pancreatic duct system and pancreaticobiliary malformation

To clarify the anatomy of the pancreatic duct system and to investigate its embryology, we reviewed 256 pancreatograms with normal pancreatic head, 81 with pancreas divisum and 74 with pancreaticobiliary maljunction. Accessory pancreatograms were divided into two patterns. The long-type accessory pancreatic duct forms a straight line and joins the main pancreatic duct at the neck portion of the pancreas. The short-type accessory pancreatic duct joins the main pancreatic duct near its first inferior branch. The short-type accessory pancreatic duct is less likely to have a long inferior branch arising from the accessory pancreatic duct. The length of the accessory pancreatic duct from the orifice to the first long inferior branch was similar in the short- and long-type accessory pancreatic ducts. The first long inferior branch from the long-type accessory pancreatic duct passes though the main pancreatic duct near the origin of the inferior branch from the main pancreatic duct. Immunohistochemically, in the short-type accessory pancreatic duct, the main pancreatic duct between the junction with the short-type accessory pancreatic duct and the neck portion was located in the ventral pancreas. The long-type accessory pancreatic duct represents a continuation of the main duct of the dorsal pancreatic bud. The short-type accessory pancreatic duct is probably formed by the proximal main duct of the dorsal pancreatic bud and its long inferior branch.     

Pancreatographic investigation of the pancreatic duct system

Background Embryologically, the pancreatic duct system develops by the fusion between the dorsal and ventral pancreatic bud ducts. It has been suggested that the proximal part of the main dorsal pancreatic duct partially regresses to form the accessory pancreatic duct (APD). Aim of this study was to clarify the anatomy of the pancreatic duct system of the head of the pancreas and investigate the embryology of the normal pancreatic duct system. Methods We reviewed endoscopic retrograde pancreatography of normal pancreatic heads (n = 256) and pancreas divisum (n = 36), focusing on long inferior branches arising from the APD and the main pancreatic duct (MPD). The accessory pancreatograms were divided into two patterns of course and shape, the long type (171 cases) and the short type (85 cases) according to the length of the MPD from the orifice to the junction with the APD. The long-type APD formed a straight line and joined the MPD at the neck portion of the pancreas. The short-type APD joined the MPD near its first inferior branch. Results The shape of the long-type APD was quite similar to that of the dorsal pancreatic duct of pancreas divisum. The short-type APD was less likely to have a long inferior branch arising from the APD. The length of the APD from the orifice to the first long inferior branch was similar in the long-type APD (19.4 ± 4.0 mm) and in the short-type APD (18.8 ± 4.2 mm). The first long inferior branch from the long-type APD passed though the MPD near the origin of the inferior branch from the MPD, whereas the short-type APD joined the MPD near its inferior branch. Conclusions There are two types of APD. The long-type APD was quite similar to the shape of the dorsal pancreatic duct of pancreas divisum, and seems to represent a continuation of the main duct of the dorsal pancreatic bud. The short-type APD was less likely to have a long inferior branch, and seems to be formed by the most proximal part of the main duct of the dorsal pancreatic bud and its long inferior branch.     

Minute pancreatic adenocarcinoma presenting with stenosis of the main pancreatic duct

We describe a case of minute pancreatic ductal adenocarcinoma featuring stenosis of the main pancreatic duct (MPD) and associated with histological findings of periductal elastosis and fibroblast proliferation. A 53-year-old Japanese man with preoperative radiological evidence of MPD stricture and dilation of the distal MPD, and suspected of having pancreatic cancer, underwent successful resection. Neither radiological nor macroscopic examination directly disclosed any tumorous lesions, and a small focus of carcinoma (8 x 8 mm) was only revealed on microscopic examination. The tumor was a poorly differentiated, invasive ductal adenocarcinoma that had invaded the intrapancreatic nerves and veins. Interestingly, the MPD located at the edges of the tumor had not been destroyed by the carcinoma, but its wall had been thickened by elastic tissue and fibroblast proliferation, resulting in stenosis. The peripheral pancreas exhibited secondary obstructive pancreatitis. To date, the detection of small pancreatic tumor masses using imaging procedures remains difficult, and most patients are diagnosed on the basis of pancreatic ductal changes. However, the published work on small pancreatic cancers contains little information about the histological features of the affected MPD. The present findings suggest that MPD strictures are not always provoked by destruction or filling with cancer cells, and that they can be caused by periductal elastosis and fibroblast proliferation in a minute carcinoma. Such changes in the MPD may therefore be of clinical importance in the detection of early stage cancers.     

Intraductal Pancreatic Neuroendocrine Tumor

Intraductal lesions of the pancreas are usually due to intraductal papillary mucinous neoplasms and the less common intraductal tubular adenoma. Cases of acinar cell carcinoma within intraductal location have also been encountered recently. Pancreatic neuroendocrine tumors are rarely encountered within the main pancreatic duct. A 74-year-old male presented with non-specific abdominal symptoms and was found to have an obstructive lesion in the main pancreatic duct with associated chronic pancreatitis. A distal pancreatectomy was performed which revealed a solid and cystic tumor measuring 6 × 3 × 2 cm situated wholly within the main pancreatic duct. It formed an obstructing intraluminal polypoid lesion that resulted in surrounding chronic pancreatitis. Microscopic evaluation of the mass showed it to be a well-differentiated pancreatic neuroendocrine tumor with entrapped, non-malignant tubules. Intraductal pancreatic neuroendocrine tumors may occur in two settings. Firstly, and more commonly, there is a parenchymal-based tumor that then encroaches on and pushes into the main pancreatic duct. The less common scenario is of a primary intraductal location without a pancreatic parenchymal lesion. While an intraductal location of a pancreatic neuroendocrine tumor is rare, it should be borne in mind when confronted by an intraductal lesion in the pancreas.     

Xanthogranulomatous pancreatitis combined with intraductal papillary mucinous carcinoma in situ

Xanthogranulomatous lesion is a rare condition in which lipid-laden histiocytes are deposited at various locations in the body. Xanthogranulomatous pancreatitis (XGP) associated with an intraductal papillary mucinous tumor (IPMT) is extremely rare. In this study, we described a case of XGP associated with IPMT and include a review of the literature. A pancreatic cystic mass was detected in a 72-yr-old woman by abdominal computed tomography. Pylorus-preserving pancreaticoduodenectomy was performed and diagnosis of XGP combined with intraductal papillary mucinous carcinoma in situ was made. After 13 months of follow-up, the patient is in good health without any evidence of tumor recurrence. Although XGP associated with IPMT is rare, we suggest that such cases should be brought to the attention of clinical investigators, as it may produce clinical features that mimic pancreatic cancer.     

Fine-needle aspiration cytology of intraductal papillary-mucinous tumors: a retrospective analysis

Intraductal papillary-mucinous tumor (IPMT) of the pancreas has become the accepted terminology for a group of mucin-producing epithelial proliferations lying within ectatic segments of the main pancreatic duct or its large branches. These neoplasms generally are associated with an indolent course, characteristic endoscopic ultrasonographic (EUS) findings, and a variable histo- and cytomorphology ranging from hyperplasia to carcinoma. Cytological specimens obtained by endoscopic ultrasound-guided or percutaneous fine-needle aspiration (FNA) are characterized by a background containing abundant mucin in which are entrapped single or loosely cohesive clusters of neoplastic cells characteristically showing a goblet-cell morphology. The degree of nuclear atypia, cell crowding, and cell shape varies between smears within a single case and between cases. Cytomorphological examination, when coupled with EUS features, is accurate for the diagnosis of these lesions but often it underdiagnoses the grade of the neoplasm.     

Papillary hyperplasia of the pancreas

We report the first case of surgically resected pure papillary hyperplasia of the pancreas. Interestingly, it was not associated with chronic pancreatitis or pancreatic cancer. Histologic and immunohistochemical features are described, with a review of the literature on papillary hyperplasia of the pancreas.     

Intraductal papillary mucinous neoplasm

Intraductal papillary mucinous neoplasm (IPMN) is a grossly visible (≥1 cm), mucin-producing neoplasm that arises in the main pancreatic duct and/or its branches. Patients with intraductal papillary mucinous neoplasm can present with symptoms caused by obstruction of the pancreatic duct system, or they can be asymptomatic. There are 3 clinical subtypes of intraductal papillary mucinous neoplasm: main duct, branch duct, and mixed. Five histologic types of intraductal papillary mucinous neoplasm are recognized: gastric foveolar type, intestinal type, pancreatobiliary type, intraductal oncocytic papillary neoplasm, and intraductal tubulopapillary neoplasm. Noninvasive intraductal papillary mucinous neoplasms are classified into 3 grades based on the degree of cytoarchitectural atypia: low-, intermediate-, and high-grade dysplasia. The most important prognosticator, however, is the presence or absence of an associated invasive carcinoma. Some main duct-intraductal papillary mucinous neoplasms progress into invasive carcinoma, mainly tubular adenocarcinoma (conventional pancreatic ductal adenocarcinoma) and colloid carcinoma. Branch duct-intraductal papillary mucinous neoplasms have a low risk for malignant transformation. Preoperative prediction of the malignant potential of an intraductal papillary mucinous neoplasm is of growing importance because pancreatic surgery has its complications, and many small intraductal papillary mucinous neoplasms, especially branch duct-intraductal papillary mucinous neoplasms, have an extremely low risk of progressing to an invasive cancer. Although most clinical decision making relies on imaging, a better understanding of the molecular genetics of intraductal papillary mucinous neoplasm could help identify molecular markers of high-risk lesions. When surgery is performed, intraoperative frozen section assessment of the pancreatic resection margin can guide the extent of resection. Intraductal papillary mucinous neoplasms are often multifocal, and surgically resected patients should be followed for metachronous disease.     

The role of p21ras in pancreatic neoplasia and chronic pancreatitis.

K-ras mutations have been detected in both ductal cell carcinoma and intraductal papillary mucinous tumor (IPMT) of pancreas. The frequency of this mutation in ductal cell carcinoma is high, whereas in IPMT, it is variable. It has been suggested that the relatively high frequency of this mutation in ductal cell carcinomas compared with IPMT may account for the differences in biological behavior between these tumor types. More recently, the significance of K-ras mutations in pancreatic tissue has been questioned with the demonstration of this mutation in nonneoplastic pancreata. The current study aims to estimate the relative frequency and evaluate the biological significance of K-ras gene mutations in these neoplasms by performing polymerase chain reaction (PCR) assays of microdissected areas of IPMT, ductal cell carcinomas, and resected chronic pancreatitis. The study also investigates whether alterations of p21ras occur in K-ras mutation-negative cases by using immunohistochemical staining for K-, N- and H-ras. K-ras codon 12 mutations were found almost as frequently in IPMT (71%) as in ductal cell carcinomas (78%). They were also associated with the earliest morphological lesion, flat mucinous change. This mutation also was detected in 42% of cases of chronic pancreatitis. Expression of p21ras was found to correlate closely with K-ras mutation status in IPMT and ductal cell carcinoma. Negative staining for pan-ras, H-ras, and N-ras in cases with wild-type K-ras genes suggests that alternative routes of ras gene alteration are not operative in IPMT or ductal carcinoma. The findings suggest that K-ras activation is frequently associated with both IPMT and ductal cell carcinoma. Its high prevalence in nonneoplastic pancreata suggests that it is also associated with self-limited morphological lesions of the pancreas that do not progress to malignancy.     

Multicentric development of pancreatic intraductal carcinoma through atypical papillary hyperplasia.

We report a case of multiple intraductal carcinomas of the pancreas associated with diffuse atypical papillary hyperplasia. A 67-year-old Japanese man with a complaint of epigastric pain was examined by endoscopic retrograde pancreatography, which demonstrated multiple dilated branches of the pancreatic duct in the body and tail of the pancreas. Histologic examination on the resected pancreas showed diffuse atypical papillary hyperplasia in multiple dilated ducts associated with multiple intraductal carcinomas. Histologic features are described and multicentric carcinogenesis through atypical papillary hyperplasia is discussed.     

Paraduodenal pancreatitis: a clinico-pathologically distinct entity unifying "cystic dystrophy of heterotopic pancreas", "para-duodenal wall cyst", and "groove pancreatitis"

A distinct form of chronic pancreatitis occurring predominantly in and around the duodenal wall (near the minor papilla) has been reported under various names, including cystic dystrophy of heterotopic pancreas, pancreatic hamartoma of duodenum, para-duodenal wall cyst, myoadenomatosis, and groove pancreatitis. Our experience with these lesions and the review of the literature show that these lesions have the following common characteristics: (1) The duodenal wall contains dilated ducts, some with inspissated secretions, and pseudocystic changes as well as adjacent stromal reactions including hypercellular granulation tissue, foreign-body type giant cell reaction engulfing mucoprotein material, and myofibroblastic proliferation. (2) Brunner's gland hyperplasia is typically present. (3) Dense myoid stromal proliferation, with intervening rounded lobules of pancreatic acinar tissue, creates a histologic picture reminiscent of "myoadenomatosis," "pancreatic hamartoma," or even leiomyoma in some cases. (4) Spillover of fibrosis into the adjacent pancreas and soft tissue occurs, especially in the "groove" area (between the pancreas, common bile duct and duodenum), including the region around the common bile duct. (5) Clinically, these lesions often mimic "pancreas cancer" or periampullary tumors, because of marked scarring as well as the ill-defined borders of the process. Patients with these findings are predominantly males, 40-50 years old, with a history of alcohol abuse. That the process is often centered in the region of minor papilla (and the adjacent pancreas) suggests that an anatomic variation of the ductal system may render this area particularly susceptible to the effects of alcoholic injury, and the myo-adenomatoid and cystic changes on the duodenal wall may in turn represent changes related to a localized recurrent pancreatitis. In conclusion, these clinicopathologic findings characterize a distinctive process that can be referred to as paraduodenal pancreatitis.     

Uncommon types of chronic pancreatitis

Alcoholic chronic pancreatitis and obstructive chronic pancreatitis are the most frequent and the better characterized types of pancreatitis. Recent advances in biology and genetics have brought new insights into the understanding of rare forms of chronic pancreatitis such as tropical chronic pancreatitis, hereditary chronic pancreatitis and chronic pancreatitis in cystic fibrosis. Some other rare forms of chronic pancreatitis have been identified: eosinophilic chronic pancreatitis, chronic pancreatitis after radiotherapy or during hypercalcemia, minimal change chronic pancreatitis and chronic pancreatitis associated with gut diseases or connectivitis. Recently, a particular form of non alcoholic chronic pancreatitis with duct destruction has been described often presenting as a pancreatic mass, leading in some cases to surgical resection of the pancreas. New insights into the understanding of chronic pancreatitis lead to new physiopathological concepts, and many arguments suggest that combined factors may lead to chronic inflammatory lesions of the pancreas.     

Predominance of sialomucin secretion in malignant and premalignant pancreatic lesions.

Sialomucin and sulphomucin-secreting cells were studied in the normal and pathologic human pancreas with the high iron diamine-alcian blue technique which allows differentiation between the two types of mucin. In six normal autopsy pancreata, only sulphomucin was found. In benign lesions of either calcifying chronic pancreatitis (seven cases) or obstructed chronic pancreatitis (six cases), sulphomucins were widely predominant. In contrast, malignant lesions (pancreatic adenocarcinoma [12 cases], cystadenocarcinoma [two cases]) or premalignant lesions (mucinous cystadenoma [one case], ductectatic mucinous cystadenoma [four cases], villous adenoma of the main pancreatic duct [two cases]) showed a predominant sialomucin secretion, except for three poorly differentiated pancreatic carcinomas that did not show mucin staining. The sialomucin positivity was not observed at distance from the malignant lesions. In one case of benign enteroid cyst, sulphomucins predominated. These findings indicate a preponderance of sialomucin secretion in malignant or premalignant pancreatic lesions.     

Malignant biliary papillomatosis: analysis of p53 expression

Biliary papillomatosis is a papillary adenomatosis of the biliary mucosa of the extra- and the intrahepatic biliary tree. It is a rare neoplasm difficult to manage, characterized by extensive lesions and a great potential for malignant transformation. We report a case of a 75 year-old man, who presented with malignant papillomatosis of the common bile duct without involvement of the intrahepatic biliary ducts. Duodenopancreatectomy enabled the diagnosis of papillomatosis lined 5.5 cm of the common bile duct which displayed an invasive 1.5 cm papillary carcinoma located in the distal portion of the choledocus. Immunohistochemistry showed strong expression of p53 in the distally located invasive carcinoma and in distant dysplastic lesions. MUC5AC was exclusively detected in both malignant and dysplastic lesions without detection of MUC1 or MUC2. Detection of p53 expression on biliary brush samples could be interesting for the follow-up and the prediction of malignant progression in multifocal biliary papillomatosis.     

Intraductal papillary mucinous neoplasm of the pancreas presenting as acute pancreatitis

Intraductal papillary mucinous neoplasms are rare pancreatic exocrine tumors with distinct clinicopathologic features. They usually present with a long history of chronic pancreatitis-like symptoms, which are often associated with weight loss, diarrhea, and malabsorption. We report a case of benign intraductal papillary mucinous neoplasm with focal squamous metaplasia presenting as acute necrotizing pancreatitis. The clinicopathologic features are discussed in a brief review of the literature.     

Pseudointraductal papillary mucinous neoplasia caused by microscopic periductal endocrine tumors of the pancreas: a report of 3 cases

Intraductal papillary mucinous neoplasms constitute histologically distinctive pancreatic tumors characterized by cystically dilated pancreatic ducts lined by papillary epithelium, often with extensive mucin production. With increasing awareness of and vigilance for these tumors, there has been a surge in the incidence of intraductal papillary mucinous neoplasms in the last few decades. However, resections of presumed intraductal papillary mucinous neoplasms sometimes reveal other types of cystic lesions. Here we describe 3 cases of small, incidentally identified pancreatic endocrine tumors that focally compressed the main pancreatic duct and presented clinically, radiologically, and grossly as intraductal papillary mucinous neoplasm. The histology of the dilated ducts in all cases lacked convincing features of intraductal papillary mucinous neoplasm, prompting more careful examination of the specimens and eventual identification of small well-differentiated endocrine neoplasms. The constellation of findings represented by pancreatic endocrine neoplasm-associated duct stricture and dilatation can mimic intraductal papillary mucinous neoplasm clinically and pathologically. Awareness of this phenomenon can potentially avoid misdiagnosis of intraductal papillary mucinous neoplasm in such cases.