Intraductal Tubulopapillary Neoplasm Research Articles

Intraductal tubulopapillary neoplasm of the pancreas: a clinicopathologic study of 6 cases

To study the pathologic features, diagnosis, differential diagnosis and molecular characteristics of intraductal tubulopapillary neoplasm of the pancreas (ITPN). The clinical findings, morphologic features, immunophenotype (by EnVision method) and KRAS gene alterations (by reverse transcriptase-polymerase chain reaction) of 6 cases of ITPN encountered during the period from January, 2001 to June, 2010 were analyzed. There were altogether 2 males and 4 females. The mean age of the patients was 64 years. Gross examination showed that the tumors were located in large pancreatic ducts and appeared as polypoid nodules with ductal obstruction. Solid tumor nodules associated with adjoining dilated ducts were identified in one case. Histologically, the tumors were characterized by tubulopapillary growth pattern without luminal mucin. The tumor cells showed high-grade nuclear atypia with scanty intracytoplasmic mucin. Intraductal necrotic foci were frequently observed. Immunohistochemical study showed that the tumor cells expressed CK7 and CK19. Focal positivity for MUC5AC was demonstrated. Two cases expressed MUC1. The staining for MUC2 was negative. KRAS gene mutations were identified in 2 cases, with a single-amino-acid substitution in codon 12 (35G > A and 35G > T/34G > A). ITPN is a newly described pancreatic intraductal neoplasm and different from intraductal papillary mucinous neoplasm. ITPN is characterized by intraductal tubulopapillary growth pattern, severe cytologic atypia and scanty mucin secretion.

Intraductal Tubulopapillary Neoplasms of the Pancreas: Case Report and Review of the Literature

A 69-year-old woman was referred to our hospital after incidental identification of a pancreatic mass during follow-up for diabetes mellitus. Various imaging examinations showed a tumor in the main pancreatic duct, without apparent hypersecretion of mucin. Brush cytologic examination revealed class V disease (adenocarcinoma). Because preoperative examination suggested an intraductal neoplasm with associated invasive cancer, total pancreatectomy was performed. Histological examination, based on current World Health Organization classifications, suggested a diagnosis of intraductal tubulopapillary neoplasm. A small cystic lesion adjacent to the intraductal tubulopapillary neoplasm was incidentally diagnosed as serous cystadenoma. The patient has remained well without recurrence as of 24 months postoperatively. Computed tomography and magnetic resonance imaging of the intraductal tubulopapillary neoplasm suggested ductal cell carcinoma of the pancreas rather than intraductal papillary mucinous neoplasm. Distinguishing intraductal tubulopapillary neoplasm from ductal cell carcinoma is clinically important, as intraductal tubulopapillary neoplasm has a favorable prognosis after curative resection.

術前診断が困難であったITPNの1例

術前診断が困難であったITPNの1例

Acute Pancreatitis Associated with Intraductal Tubulopapillary Neoplasm of the Pancreas

Eun Young Kim, Jae Uk Shin, Yeon Ho Joo, Jue Yong Lee, Ji Hun Kim, Yun Jung Park, Myeng Nam Bae, Sang Mook Bae Department of Internal Medicine, The Catholic University of Korea College of Medicine, Seoul, Division of Gastroenterology, Department of Internal Medicine, Changwon Fatima Hospital, Changwon, Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea

膵管内腫瘍との鑑別を要し，内視鏡的治療で軽快した膵蛋白栓の1例

膵管内腫瘍との鑑別を要し，内視鏡的治療で軽快した膵蛋白栓の1例

Intraductal tubulopapillary neoplasm of the pancreas with somatic BRAF mutation.

Intraductal tubulopapillary neoplasm (ITPN) is a rare pancreatic tumor belonging to a newly recognized entity that is coined in the 2010 WHO classification. We present a case of ITPN-associated microinvasive adenocarcinoma that developed in an asymptomatic 78-year-old patient. The tumor demonstrated all the clinical, radiological, and pathological characteristics of ITPN, but it differs from other reported cases of ITPN in molecular analysis, which revealed a somatic mutation in BRAF (c.1799T>A; p.V600E) but no mutation in PIK3CA. Post-operative recurrence was discovered 34months after tumor resection with negative margins and a 6-month course of adjuvant chemotherapy. To the best of our knowledge, this is the first case of ITPN with BRAF mutation. This case suggests that an activation of RAS-mitogen-activated protein kinase signaling pathway may play a role in development of some of ITPNs. A possible mechanism of tumor recurrence in ITPN is also discussed. Further case series with molecular study are awaited to delineate the clinicopathological and molecular characteristics of ITPN.

Intraductal Tubular Neoplasms of the Bile Ducts

Although most tumors of the bile ducts are predominantly invasive, some have an exophytic pattern within the bile ducts; these intraductal papillary neoplasms usually have well-formed papillae at the microscopic level. In this study, however, we describe a novel type of intraductal neoplasm of the bile ducts with a predominantly tubular growth pattern and other distinctive features. Ten cases of biliary intraductal neoplasms with a predominantly tubular architecture were identified in the files of the Pathology Department at Memorial Sloan-Kettering Cancer Center from 1983 to 2006. For each of these cases we studied the clinical presentation, histologic and immunohistochemical features (9 cases only), and the clinical follow-up of the patients. Three male and 7 female patients (38 to 78 y) presented with obstructive jaundice or abdominal pain. Eight of the patients underwent a partial hepatectomy; 2 underwent a laparoscopic bile duct excision, followed by a pancreatoduodenectomy in one of them. The tumors range in size from 0.6 to 8.0 cm. The intraductal portions of the tumors (8 intrahepatic, 1 extrahepatic hilar, 1 common bile duct) were densely cellular and composed of back-to-back tubular glands and solid sheets with minimal papillary architecture. The cells were cuboidal to columnar with mild to moderate cytologic atypia. Foci of necrosis were present in the intraductal component in 6 cases. An extraductal invasive carcinoma component was present in 7 cases, composing <25% of the tumor in 4 cases, and >75% in 1 case. It was observed by immunohistochemical analysis that the tumor cells expressed CK19, CA19-9, MUC1, and MUC6 in most cases and that SMAD4 expression was retained. MUC2, MUC5AC, HepPar1, synaptophysin, chromogranin, p53, and CA125 were negative in all cases and most were negative for CEA-M and B72.3. Four patients were free of tumor recurrence after 7 to 85 months (average, 27 mo). Four patients with an invasive carcinoma component suffered metastases, 1 after local intraductal recurrence. However, the occurrence of metastasis in 3 of these patients was quite late (average, 52 mo). Intraductal tubular neoplasm of the bile ducts is a biliary intraductal neoplasm with a distinctive histologic pattern resembling the recently described intraductal tubulopapillary neoplasm of the pancreas. Immunohistochemical features are similar to those of other pancreatobiliary-type carcinomas. However, this tumor may be hard to recognize as intraductal because of its complex architecture. When the tumor is entirely intraductal, the outcome appears to be favorable, but metastases can occur when invasive carcinoma is present, even after many years.

Diagnostic challenge: Intraductal neoplasms of the pancreatobiliary system

To help pathologists avoid misdiagnosis of intraductal neoplasms arising from the pancreatobiliary system, we report two cases that illustrate diagnostic pitfalls. The first is of a 66-year-old man who complained of appetite loss. An early examination led to a diagnosis of intraductal papillary mucinous neoplasm. Macroscopically, a multilocular cyst without visible mucin was identified. Histologically, the compartments consisted of complex fusion of tubular glands surrounded by dilated pancreatic duct. The neoplasm resembled an acinar cell cystadenocarcinoma. However, the neoplastic cells were negative for trypsin. Thus, the final histopathologic diagnosis was an unusual cystic variant of intraductal tubulopapillary neoplasm (ITPN) of the pancreas. The second case is of a 71-year-old man who complained of right upper quadrant pain. Although bile duct stone was suspected, a polypoid nodule was extracted. Histologically, the nodule was composed of tubular glands, with some complex fusion and focal dysplasia, consistent with carcinoma. In addition, lack of MUC-5AC expression led to an initial impression of ITPN of the bile duct. However, the neoplasm showed dysplastic cells based on the columnar cells resembling pyloric glands, indicating the sequential progression. Thus, the final histopathological diagnosis was intraductal papillary neoplasm of the bile duct with high-grade intraepithelial neoplasia. Because phenotypic variants of intraductal neoplasms of the pancreatobiliary system exist, ITPN and ITPN-mimicking tumor must be carefully differentiated from other intraductal neoplasms.

Intracholecystic Papillary-Tubular Neoplasms (ICPN) of the Gallbladder (Neoplastic Polyps, Adenomas, and Papillary Neoplasms That Are ≥1.0 cm)

The literature on the clinicopathologic characteristics of tumoral intraepithelial neoplasms (neoplastic polyps) of the gallbladder (GB) is fairly limited, due in part to the variability in definition and terminology. Most reported adenomas (pyloric gland type and others) were microscopic and thus regarded as clinically inconsequential, whereas papillary in situ carcinomas have been largely considered a type of invasive adenocarcinoma under the heading of "papillary adenocarcinomas." In this study, 123 GB cases that have a well-defined exophytic preinvasive neoplasm measuring ≥1 cm were analyzed. The patients were predominantly female (F/M=2:1) with a mean age of 61 y and a median tumor size of 2.2 cm. Half of the patients presented with pain, and in the other half the neoplasm was detected incidentally. Other neoplasms, most being gastrointestinal tract malignancies, were present in 22% of cases. Gallstones were identified in only 20% of cases. Radiologically, almost half were diagnosed as "cancer," roughly half with polypoid tumor, and in 10% the lesion was missed. Pathologic findings: (1) The predominant configuration was papillary in 43%, tubulopapillary in 31%, tubular in 26%. (2) Each case was assigned a final lineage type on the basis of the predominant pattern (>75% of the lesion) on morphology, and supported with specific immunohistochemical cell lineage markers. The predominant cell lineage could be identified as biliary in 50% (66% of which were MUC1), gastric foveolar in 16% (all were MUC5AC), gastric pyloric in 20% (92% MUC6), intestinal in 8% (100% CK20; 75% CDX2; 50%, MUC2), and oncocytic in 6% (17% HepPar and 17% MUC6); however, 90% of cases had some amount of secondary or unclassifiable pattern and hybrid immunophenotypes. (3) Of the cases that would have qualified as "pyloric gland adenoma," 21/24 (88%) had at least focal high-grade dysplasia and 18% had associated invasive carcinoma. Conversely, 8 of 47 "papillary adenocarcinoma"-type cases displayed some foci of low-grade dysplasia, and 15/47 (32%) had no identifiable invasion. (4) Overall, 55% of the cases had an associated invasive carcinoma (pancreatobiliary type, 58; others, 10). Factors associated significantly with invasion were the extent of high-grade dysplasia, cell type (biliary or foveolar), and papilla formation. Among systematically analyzed invasive carcinomas, tumoral intraepithelial neoplasia was detected in 6.4% (39/606). (5) The 3-year actuarial survival was 90% for cases without invasion and 60% for those associated with invasion. In contrast, those associated with invasion had a far better clinical outcome compared with pancreatobiliary-type GB carcinomas (3-yr survival, 27%), and this survival advantage persisted even with stage-matched comparison. Death occurred in long-term follow-up even in a few noninvasive cases (4/55; median 73.5 mo) emphasizing the importance of long-term follow-up. In conclusion, tumoral preinvasive neoplasms (≥1 cm) in the GB are analogous to their pancreatic and biliary counterparts (biliary intraductal papillary neoplasms, pancreatic intraductal papillary mucinous neoplasms, and intraductal tubulopapillary neoplasms). They show variable cellular lineages, a spectrum of dysplasia, and a mixture of papillary or tubular growth patterns, often with significant overlap, warranting their classification under 1 unified parallel category, intracholecystic papillary-tubular neoplasm. Intracholecystic papillary-tubular neoplasms are relatively indolent neoplasia with significantly better prognosis compared with pancreatobiliary-type GB carcinomas. In contrast, even seemingly innocuous examples such as those referred to as "pyloric gland adenomas" can progress to carcinoma and be associated with invasion and fatal outcome.

Intraductal tubulopapillary neoplasm of the pancreas on fine needle aspiration: Case Report with Differential Diagnosis

Intraductal tubulopapillary neoplasm (ITPN) is a rare primary pancreatic neoplasm accounting for less than 1% of all pancreatic exocrine neoplasms and 3% of intraductal neoplasms of the pancreas. Data on this entity are still limited. Here, we report a case of ITPN with cytopathologic and histopathologic findings. A 41-year-old woman with a 2.2 cm cyst in the head of the pancreas for five years was referred to our institution. The endoscopic ultrasound-guided fine-needle aspiration produced cytospins were moderately cellular with a few fragments of markedly atypical epithelium. The neoplastic cells displayed high-grade nuclear atypia with enlarged, eccentric nuclei, anisonucleosis and prominent nucleoli, irregular nuclear membranes, high nucleus to cytoplasmic (N/C) ratios, and a moderate amount of cytoplasm with no intracytoplasmic mucin. Histologically, the lesion was found to be an ITPN with focal high-grade dysplasia. No invasive carcinoma was identified. The neoplastic cells exhibited luminal immunolabeling for MUC-1, but were negative for MUC-2, trypsin, chymotrypsin, and P53. Approximately 5% of the neoplastic cells showed Ki-67 immunoreactivity. ITPN of pancreas may be a source of markedly atypical epithelial cells in pancreatic cystic aspiration. Clinical and radiographic findings, molecular mutational analysis, in combination with cytological features are essential to differentiate it from other disease entities.

Intraductal tubulopapillary neoplasm of pancreas with stromal osseous and cartilaginous metaplasia; a case report

Recently, a surgically resected case of intraductal tubulopapillary neoplasm (ITPN) with stromal osseous and cartilaginous metaplasia was encountered. A CT scan showed calcification at the tail of the pancreas two years before the operation. In the resected specimen, macroscopically, the main pancreatic duct was dilated and filled with a whitish solid mass without mucinous material. The tumor showed mainly a solid and papillary growth pattern. The tumor cells had no evidence of acinar differentiation. The tumor cells, at the tail of the pancreas, invaded focally to surrounding pancreatic parenchyma with stromal desmoplastic and fibrosclerotic reaction and also formed nodular stromal osseous and cartilaginous metaplasia. The tumor did not invade extrapancreatic tissue and showed no lymph node metastasis. As there were no signs of chronic calcifying pancreatitis, it is hypothesized that the metaplastic stroma was formed by a stromal reaction due to the tumor growth. It is thought, therefore, that the intraducal component of the tumor had existed at least for two years. This case suggests that ITPN is a relatively indolent tumor with a better prognosis than that of other types of invasive ductal adenocarcinoma of the pancreas.

Imaging Studies of Intraductal Tubulopapillary Neoplasms of the Pancreas

The objective of this study was to describe the imaging findings for intraductal tubulopapillary neoplasms of the pancreas. Eleven pancreatic tumors pathologically confirmed as intraductal tubulopapillary neoplasm were retrospectively collected. The dynamic contrast-enhanced computed tomography (CT), magnetic resonance (MR) imaging including MR cholangiopancreatography (MRCP), ultrasound, and endoscopic retrograde cholangiopancreatography (ERCP) results were reviewed. The 2-tone duct sign and cork-of-wine-bottle sign were reviewed as indicators of intraductal tumor growth on CT/MR and MRCP/ERCP images, respectively. A 2-tone duct sign was noted on the dynamic CT images (7/10, 70%) and on the MR imaging (5/8, 63%). The distal main pancreatic duct was dilated in all the patients except one, who had a branch duct lesion. A cork-of-wine-bottle sign was observed on the MRCP image (3/8, 38%) and on the ERCP image (3/6, 50%). Intraductal tubulopapillary neoplasms are rare tumors showing characteristic imaging findings such as the 2-tone duct sign and the cork-of-wine-bottle sign that represent their intraductal growth.

Reporting precursors to invasive pancreatic cancer: pancreatic intraepithelial neoplasia, intraductal neoplasms and mucinous cystic neoplasm

Invasive ductal adenocarcinoma of the pancreas remains an almost universally lethal disease. Despite strenuous research efforts, the prognosis of the disease has not improved in the past decades. However, knowledge of pancreatic tumorigenesis and the identification and characterization of the precursor lesions that give rise to invasive pancreatic cancer have dramatically improved. This, coupled with the finding that it takes almost two decades for a pancreatic cell with an initial mutation to develop into a metastatic pancreatic cancer provides hope for the early detection of curable pancreatic neoplasms. We present a review of established precursor lesions of pancreatic cancer, including pancreatic intraepithelial neoplasia, intraductal papillary mucinous neoplasms (including intraductal oncocytic papillary neoplasm and intraductal tubulopapillary neoplasm), and mucinous cystic neoplasm.

膵全摘にて根治した膵intraductal tubulopapillary neoplasmの1例

症例は61歳，男性．糖尿病の増悪を機に施行された腹部USで膵腫瘍を認めた．腹部CT，MRIで膵全域におよぶ膵管拡張と膵実質の菲薄化を指摘され，ERCPで著明に拡張した主膵管内に充満する腫瘍が疑われた．特異な膵管内進展を伴う膵全体癌と診断し膵全摘術を施行した．腫瘍は病理学的に乳頭状・管状発育形態を併せ持つ腺癌で，T3N0M0 stage IIIであった．免疫組織学的にmucin core protein（MUC）-1，cytokeratin-7陽性であったが，MUC-2，MUC-5AC，chromogranin A，synaptophysin，trypsinが陰性であり，最終的にintraductal tubulopapillary neoplasm（ITPN）と診断した．ITPNは比較的新しい疾患概念であり，これまで報告されてきた膵管内腫瘍との関係性を含め考察を加え報告する．

Somatic Mutations in PIK3CA and Activation of AKT in Intraductal Tubulopapillary Neoplasms of the Pancreas

Intraductal tubulopapillary neoplasm (ITPN) is a recently recognized rare variant of intraductal neoplasms of the pancreas. Molecular aberrations underlying the neoplasm remain unknown. We investigated somatic mutations in PIK3CA, PTEN, AKT1, KRAS, and BRAF. We also investigated aberrant expressions of phosphorylated AKT, phosphatase and tensin homolog (PTEN), tumor protein 53 (TP53), SMAD4, and CTNNB1 in 11 cases of ITPNs and compared these data with those of 50 cases of intraductal papillary mucinous neoplasm (IPMN), another distinct variant of pancreatic intraductal neoplasms. Mutations in PIK3CA were found in 3 of 11 ITPNs but not in IPMNs (P = 0.005; Fisher exact test). In contrast, mutations in KRAS were found in none of the ITPNs but were found in 26 of the 50 IPMNs (P = 0.001; Fisher exact test). PIK3CA mutations were associated with strong expression of phosphorylated AKT (P < 0.001; the Mann-Whitney U test). Moreover, the expression of phosphorylated AKT was apparent in most ITPNs but only in a few IPMNs (P < 0.001; the Mann-Whitney U test). Aberrant expressions of TP53, SMAD4, and CTNNB1 were not statistically different between these neoplasms. Mutations in PIK3CA and the expression of phosphorylated AKT were not associated with age, sex, tissue invasion, and patients' prognosis in ITPNs. These results indicate that activation of the phosphatidylinositol 3-kinase pathway may play a crucial role in ITPNs but not in IPMNs. In contrast, the mutation in KRAS seems to play a major role in IPMNs but not in ITPNs. The activated phosphatidylinositol 3-kinase pathway may be a potential target for molecular diagnosis and therapy of ITPNs.

Intraductal tubulopapillary neoplasm of the bile duct: potential origin from peribiliary cysts

We report two patients with unique biliary tumors histologically similar to pancreatic intraductal tubulopapillary neoplasm (ITPN). One patient underwent right hepatectomy for a partly cystic mass in the hepatic hilum. The other patient had liver transplantation for cryptogenic cirrhosis and multiple hilar cysts detected in the explanted liver, some obliterated by papillary nodules. Histologically both tumors consisted of intracystic non-invasive and well differentiated adenocarcinoma with a papillary and tubular architecture. Associated cysts were peribiliary cysts partly lined by carcinoma cells that were continuous with the intracystic papillotubular masses. Both tumors shared the same immunophenotype: K7(+)/K20(-)/MUC1(+)/MUC2(-)/MUC5AC(-)/MUC6(+). Genetic analysis of KRAS and BRAF revealed wild type genotypes. These pathological and genetic features are similar to those of pancreatic ITPNs. This report suggested that ITPNs may rarely develop in the bile duct seemingly in association with peribiliary cysts.

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.

Intraductal Papillary Mucinous Carcinoma With No Overt Mucin Production

A 62-year-old man presented with a solid and cystic mass in the tail of the pancreas detected on computed tomography during a workup for nausea and vomiting. A distal pancreatectomy, along with a partial gastrectomy and splenectomy, was performed. The mass invaded the stomach wall and did not have copious mucin typical of many intraductal neoplasms. Microscopically, a neoplasm containing epithelium with pleomorphism, frequent mitotic figures, and a blunt pattern of invasion was present, best classified as a pancreatobiliary-type intraductal papillary mucinous carcinoma. An intraductal papillary mucinous neoplasm (IPMN) is a grossly or radiographically detectable proliferation of the main pancreatic duct or one of its major branches, typically larger than 1.0 cm. Intraductal papillary mucinous neoplasms are categorized as intestinal, gastric, or pancreatobiliary based on the epithelium in the papillary component. They may be associated with various degrees of dysplasia and even invasive carcinoma. Mucin glycoprotein and CDX2 immunohistochemistry can be useful in distinguishing epithelial types. Differential diagnostic considerations include retention cysts, pancreatic intraepithelial neoplasia, mucinous cystic neoplasms, serous cystic neoplasms, intraductal tubulopapillary neoplasms, acinar cell carcinoma, and intraductal oncocytic papillary neoplasms. Intraductal papillary mucinous neoplasms exhibit a spectrum of gross and microscopic features, differential diagnostic considerations, ancillary techniques available for IPMN characterization, and genetic associations; awareness of these characteristics are important to those who are studying IPMN and who are considering IPMN in their diagnosis of a pancreatic neoplasm.

A potential case of intraductal tubulopapillary neoplasms of the bile duct

Intraductal tubulopapillary neoplasm (ITPN) has been recently reported in pancreas. We experienced an unusual intraductal growing bile duct tumor, which showed the same histopathologic and immunostaining profiles as ITPN of pancreas. A 72-year-old female patient visited hospital due to intrahepatic stone. The hilar bile duct tumor was detected and incidental lung mass was found in systemic evaluation. The histopathologic finding of the two biopsy lesions was different. The lung tumor was an adenocarcinoma, and the bile duct tumor showed poorly differentiated carcinoma with eosinophilic cytoplasm. Lung lobectomy and hemihepatectomy were performed under the impression of double primary neoplasms of the lung adenocarcinoma and oncocytic variant of the biliary papillary tumor. However the histopathologic findings and immunostaining profiles of the two resected tumors were the same. Both the lung and bile duct tumors showed a tubulopapillary pattern with high-grade nuclear atypia. Pathologic findings were the same as a recently reported ITPN of the pancreas. Eosinophilic cytoplasm of the bile duct tumor was not oncocytic cytoplasm but pyknotic change due to necrosis. Here, we report the first case of ITPN of the bile duct with lung metastasis. The tumor in this case does not fit with any categories in the current biliary tumor classification. We speculate that this may be the first case of biliary ITPN.

Intraductal Tubulopapillary Neoplasms of the Pancreas Distinct From Pancreatic Intraepithelial Neoplasia and Intraductal Papillary Mucinous Neoplasms

We have encountered cases of unusual intraductal pancreatic neoplasms with predominant tubulopapillary growth. We collected data on 10 similar cases of "intraductal tubulopapillary neoplasms (ITPNs)" and analyzed their clinicopathologic and molecular features. Tumor specimens were obtained from 5 men and 5 women with a mean age of 58 years. ITPNs were solid and nodular tumors obstructing dilated pancreatic ducts and did not contain any visible mucin. The tumor cells formed tubulopapillae and contained little cytoplasmic mucin. The tumors exhibited uniform high-grade atypia. Necrotic foci were frequently observed, and invasion was observed in some cases. The ITPNs were immunohistochemically positive for cytokeratin 7 and/or cytokeratin 19 and negative for trypsin, MUC2, MUC5AC, and fascin. Molecular studies revealed abnormal expressions of TP53 and SMAD4 in 1 case, but aberrant expression of beta-catenin was not observed. No mutations in KRAS and BRAF were observed in the 8 cases that were examined. Eight patients are alive without recurrence, 1 patient died of liver metastases, and 1 patient is alive but had a recurrence and underwent additional pancreatectomy. The mitotic count and Ki-67 labeling index were significantly associated with invasion. All the features of ITPN were distinct from those of other known intraductal pancreatic neoplasms, including pancreatic intraepithelial neoplasia, intraductal papillary mucinous neoplasm, and the intraductal variant of acinar cell carcinoma. Intraductal tubular carcinomas showed several features that were similar to those of ITPN, except for the tubulopapillary growth pattern. In conclusion, ITPNs can be considered to represent a new disease entity encompassing intraductal tubular carcinoma as a morphologic variant.