Value of Immunohistochemistry to Differentiate Digital Papillary Adenocarcinoma From Acral Hidradenoma With Papillary Structures.

ABSTRACT: Digital papillary adenocarcinoma is a malignant adnexal tumor with a predilection for acral sites. Hidradenoma is a benign solid and cystic sweat gland neoplasm with focal ductal and glandular differentiation and good outcomes. Hidradenomas can occur at acral sites and show papillary structures; for this reason, they are included in the differential diagnosis of digital papillary adenocarcinoma, and immunohistochemistry is a valuable tool in this scenario. We described a case of a 43-year-old man with an epithelial tumor showing papillary structures in the intermediate phalanx of the fourth finger. There was diffuse positivity for p63 and negativity for S100 protein, suggesting that this tumor was an acral hidradenoma with papillary structures.

Outcome of Ordinary Polymorphous Adenocarcinomas of the Salivary Glands in Comparison With Papillary and Cribriform Subtypes.

BACKGROUND/AIM: Polymorphous adenocarcinoma (PAC) is a low-grade salivary gland malignancy in contrast to variants with papillary (PAP) or cribriform (CASG) architecture and confers the second most common malignancy of minor salivary glands. Our study aimed to identify prognostic factors and to evaluate histomorphological and molecular diagnostic criteria of PACs. PATIENTS AND METHODS: A series of 155 PACs, including 10 PAPs and 12 CASGs from the population-based Cancer Registry of North Rhine-Westphalia (LKR-NRW) and the Hamburg Salivary Gland Reference Centre (HRC) were analyzed. RESULTS: One fifth of the tumors were located in the major salivary glands and PACS/CASGS invariably lacked p40 expression. Fifty-two percent of PACs showed a PRKD1 E710D mutation. Ordinary PACs had a disease-specific 10-year survival probability of 97% compared to 90% when combining PAPs and CASGs. T-stage at diagnosis was a prognostic factor with 98% for stages T1/T2 versus 75% for T3/T4. CONCLUSION: Diagnostic algorithms for the PAC/CASG spectrum of tumors need to be improved and should include molecular markers.

Cervical carcinomas with serous-like papillary and micropapillary components: illustrating the heterogeneity of primary cervical carcinomas.

Recent changes in the classification of cervical adenocarcinomas have re-categorized serous carcinoma as potentially nonexistent. However, clinical and pathological profiles of cervical adenocarcinomas with serous-like morphological features have not been systematically evaluated using the latest taxonomy and biomarkers. We studied 14 cases of primary cervical carcinomas with serous-like morphologies (papillary and micropapillary patterns). None of these cases exhibited evidence of serous carcinoma involving the upper tracts. Patient ages ranged between 34 and 86 years, most presented with abnormal uterine bleeding. Histologically, ten cases were classified as human papillomavirus (HPV)-associated carcinomas (eight usual-type endocervical adenocarcinomas and two adenosquamous carcinomas), of which six exhibited a papillary pattern and four had a micropapillary pattern. The four remaining cases were HPV-independent gastric-type adenocarcinomas, which displayed a papillary pattern in one case and a micropapillary pattern in three others. All ten HPV-associated carcinomas displayed block positive p16 and wild-type p53 by immunohistochemistry, with nine of them confirmed by HPV testing. Two of the four gastric-type adenocarcinomas had mutation-type p53, one of which also being p16 block positive. HER2 overexpression was demonstrated in 3/14 (21.4%) cases (2 HPV-associated and 1 HPV-independent). PD-L1 expression was identified in 4/10 (40%) cases, all HPV-associated. Targeted next-generation sequencing was performed in two cases with a micropapillary pattern, revealing a missense variant in ATM in an HPV-associated tumor and missense variants in TP53 and SMARCB1 in an HPV-independent tumor. The results demonstrated that primary endocervical adenocarcinomas can mimic the appearance of serous carcinoma, while not representing serous carcinoma. Serous-like papillary and micropapillary patterns may be present in both HPV-associated and HPV-independent cervical carcinomas, but none of the cases studied were unequivocally serous upon detailed analysis. Our findings support the exclusion of "cervical serous carcinoma" from existing classifications of cervical adenocarcinoma.

Clinicopathologic Characterization of Hidradenoma on Acral Sites: A Diagnostic Pitfall With Digital Papillary Adenocarcinoma.

Hidradenomas are benign sweat gland tumors that typically present as small nodules in adulthood. Their anatomic distribution is wide and rarely includes acral sites. In this setting, reliable separation from digital papillary adenocarcinoma is important, but notoriously difficult. Hematoxylin and eosin-stained sections of 25 hidradenomas on acral skin were retrieved. The clinical presenting features and morphologic findings were recorded, and follow-up was obtained. Immunohistochemistry was performed for AE1/3, CK5/6, EMA, CEA, SMA, S100, p40, and p63. The tumors presented as solitary nodules on the hands (n=17) and feet (n=8) of adults (age range: 20 to 81 y; median: 50 y), with an equal sex distribution. Histologically, the well-circumscribed tumors were lobular, with a solid and cystic growth within dermis. Duct and squamous differentiation and vascularized hyaline stroma were frequent. The majority (n=18) were poroid hidradenomas. Scattered cytologic atypia and mitotic activity (median: 2/10 HPF) were common, and a pseudoinfiltrative growth of strands in a hyaline to sclerotic matrix was noted in 5 tumors. No papillary structures, atypical mitoses, or tumor necrosis were present. Immunohistochemically, all tumors expressed AE1/3, CK5/6, p40, and p63 strongly and diffusely. Luminal differentiation was highlighted by epithelial membrane antigen and carcinoembryonic antigen staining. S100 and SMA staining was absent. Follow-up (1 to 288 mo; median: 61 mo), available for 20 patients, showed no local recurrences and no disease-related mortality. Acral hidradenomas and digital papillary adenocarcinomas share a well-circumscribed dermal growth pattern containing solid, cystic, and tubular areas with mitotic activity and at least focal cytologic atypia. Lack of papillary structures and the diffuse positivity for p40 and p63 in the absence of S100 and SMA expression are helpful features in favor of acral hidradenoma.

Adenocarcinoma papilar de nasofaringe de bajo grado "thyroid-like". Caso clínico y revisión de la literatura / Low-grade papillary adenocarcinoma of nasopharynx. Case report and review of the literatura

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Intracholecystic Papillary Neoplasms Are Distinct From Papillary Gallbladder Cancers: A Clinicopathologic and Exome-sequencing Study.

Although intracholecystic papillary neoplasms (ICPNs) have been increasingly recognized, their features remain unclear because of the lack of standardized definition. This study aimed to elucidate clinicopathologic and genetic features of ICPNs using stringent diagnostic criteria. On the basis of the recently proposed criteria, gallbladder neoplasms showing delicate papillary growth were diagnosed as ICPNs, while polypoid papillary adenocarcinomas arranged in a complex architecture were categorized as papillary gallbladder cancers (GBCs). Clinicopathologic features were compared among ICPNs (n=7), papillary GBCs (n=24), and nonpapillary GBCs (n=44). Whole-exome and validation Sanger sequencing was also conducted. Gross mucin hypersecretion was detected in 3/7 ICPNs (43%), 1/24 papillary GBCs (4%), and 1/44 nonpapillary GBCs (2%) (P<0.001). All patients with ICPN lacked lymphovascular invasion and nodal metastasis, while these features were occasionally observed in patients with papillary or nonpapillary GBC (13% to 59%). ICPNs were less advanced than papillary and nonpapillary GBCs (P<0.001) with all cases of ICPNs being recurrence-free. Whole-exome and Sanger sequencing identified somatic mutations in STK11 (a causative gene of Peutz-Jegher syndrome; n=3), CTNNB1 (n=2), and APC (a gene of familial adenomatous polyposis; n=1) in ICPNs, while those alterations were exceptional in papillary and nonpapillary GBCs. ICPNs more commonly showed cytoplasmic and/or nuclear expressions of ß-catenin than papillary and nonpapillary GBCs. In conclusion, the histology-based classification of gallbladder papillary neoplasms is useful for identifying ICPNs that share clinicopathologic features with the pancreatic counterpart. ICPNs meeting the criteria were genetically distinct from papillary and nonpapillary GBCs, with STK11, CTNNB1, and APC being identified as major driver genes for ICPNs.

Novel method for rapid identification of micropapillary or solid components in early-stage lung adenocarcinoma.

OBJECTIVE: Sublobar resection may be insufficient for early-stage lung adenocarcinoma with micropapillary or solid components because of the associated higher incidence of locoregional recurrence. This study sought to establish a novel method for rapidly identifying their presence to facilitate decision making for sublobar resection. METHODS: Antibody arrays of adhesion and apoptosis molecules were applied for adenocarcinomas with or without micropapillary/solid components to identify differentially expressed proteins. A semi-dry dot-blot system that visualizes the presence of target proteins was used to determine the presence of micropapillary or solid components in a prospective cohort of patients with clinical stage I who underwent operation. Sensitivity and specificity were calculated by comparing semi-dry dot-blot results with pathologic examinations. RESULTS: Insulin-like growth factor-binding protein 2 and P-cadherin were found more frequently in the micropapillary or solid positive group, and these were used as the target proteins in the semi-dry dot-blot system for detection of micropapillary or solid components. A total of 68 nodules with a mean size of 2.3 ± 0.7 cm, including 13 (19.1%) with a micropapillary and 20 (29.4%) with a solid pattern, were recruited. Micropapillary or solid (+) lesions were more likely to have lymph node upstaging, greater diameter, and higher maximum standardized uptake value. The specificity and sensitivity for detecting the minor presence of micropapillary or solid component using the semi-dry dot-blot method were 94.4% (95% confidence interval, 81.3-99.3) and 65.6% (95% confidence interval, 46.8-81.4), respectively. The average test duration was 26.9 ± 2.5 minutes. CONCLUSIONS: Detecting insulin-like growth factor-binding protein 2 and P-cadherin via the semi-dry dot-blot method could identify micropapillary or solid components in early-stage lung adenocarcinoma in a short processing time.

Thyroid-like low-grade nasopharyngeal papillary adenocarcinoma with squamous differentiation: a novel histological finding.

Thyroid-like low-grade nasopharyngeal papillary adenocarcinoma (TL-LGNPPA) is an extremely rare neoplasm originating from the nasopharyngeal surface epithelium. Histopathologically, TL-LGNPPA is characterized by cuboidal/columnar tumor cells forming papillary fronds and thyroid transcription factor-1 (TTF-1) expression resembling papillary thyroid carcinoma. To date, the recorded histological features of TL-LGNPPA have been almost uniform, and the range of histological variations in this tumor type has not been sufficiently understood. Here, we report on a 68-year-old man with TL-LGNPPA. Microscopic examination of the resected tumor revealed findings typical of papillary adenocarcinoma of this type, and moreover, this case showed scattered squamous cell foci as a hitherto unreported finding. The squamous cells showed no obvious nuclear atypia or proliferating activity, and their presence was similar to the "squamous metaplasia" of papillary thyroid carcinoma. Immunohistochemically, p40 and TTF-1 coexpression was observed in the squamous cell nuclei, indicating their origin from the glandular tumor cells of TL-LGNPPA.

Insulin-like growth factor II mRNA-binding protein 3 (IMP3) is a marker that predicts presence of invasion in papillary biliary tumors.

Biliary tumors showing intraductal papillary growth (Pap-BTs) include intraductal papillary neoplasm of the bile duct (IPNB) and papillary cholangiocarcinoma (CC). A differential diagnosis between IPNB and papillary CC currently remains challenging. The aim of the present study is to identify histological features and immunohistochemical markers of malignant potential such as tumor invasion in Pap-BTs. Subjects comprised 37 patients with Pap-BT (intrahepatic and perihilar [proximal], 27: 17 noninvasive and 10 invasive; distal, 10: all invasive). We examined histological features and the expression of p53, enhancer of zeste homolog 2, insulin-like growth factor II mRNA-binding protein 3 (IMP3), and DNA methyltransferase-1 in the intraductal area in Pap-BTs. Noninvasive Pap-BT was characterized by the presence of a low-grade dysplastic area, edematous stroma, and the absence of necrosis. The expression of p53, enhancer of zeste homolog 2, IMP3, and DNA methyltransferase-1 was significantly weaker in noninvasive Pap-BTs than in invasive Pap-BTs (P<.01). Diffuse cytoplasmic IMP3 expression was absent in noninvasive Pap-BTs. IMP3 showed the greatest specificity to predict a presence of invasion. A heatmap demonstrated that proximal noninvasive Pap-BTs and distal Pap-BTs may be completely different. In bile duct biopsies, the expression of IMP3 was the most precise predictor of invasion in Pap-BTs. In conclusion, Pap-BTs may be separated into 3 subgroups: (1) proximal noninvasive Pap-BT, corresponding to IPNB; (2) distal invasive Pap-BT, corresponding to papillary CC; and (3) the remaining Pap-BT including IPNB with associated adenocarcinomas, based on histological and immunohistochemical features. IMP3 may be a useful marker for predicting invasion in Pap-BT.

Aggressive Digital Papillary Adenocarcinoma With Multiple Organ Metastases: A Case Report and Review of the Literature.

Aggressive digital papillary adenocarcinoma (ADPA) is a rare sweat gland neoplasm with a high recurrence rate and metastatic potential. In this study, the authors describe a case that originally appeared to benign spiradenoma, but took an ominous course eventually resulting in the diagnosis of ADPA. A 73-year-old woman developed a gradually growing nodule on the second toe of her left foot, which she had first noticed 4 years previously. An excisional biopsy was performed followed by histological examination. The authors initially considered the tumor to be a benign spiradenoma and did not perform reexcision. However, she experienced local recurrence 24 months later, and multiple pulmonary metastasis 31 months later. On histological examination, both the primary and locally recurrent tumors were found to be composed of discrete and well-circumscribed solid nodules, lacking cystic space. All tumors (the primary tumor, locally recurrent tumor, and lung metastases) presented with a pattern of fused back-to-back tubular structures and myoepithelial differentiation confirmed by immunohistochemical examination. On the basis of these findings, the authors finally diagnosed ADPA with multiple pulmonary metastases. The patient underwent chemotherapy, but died of disease 49 months later. This case highlights the importance of high clinical suspicion of ADPA when digital lesions present.

Cystic micropapillary neoplasm of peribiliary glands with concomitant perihilar cholangiocarcinoma.

We report a case of a 75-year-old man with cystic micropapillary neoplasm of peribiliary glands detected preoperatively by radiologic examination. Enhanced computed tomography showed a low-density mass 2.2 cm in diameter in the right hepatic hilum and a cystic lesion around the common hepatic duct. Under a diagnosis of perihilar cholangiocarcinoma, right hepatectomy with caudate lobectomy and bile duct resection were performed. Pathological examination revealed perihilar cholangiocarcinoma mainly involving the right hepatic duct. The cystic lesion was multilocular and covered by columnar lining epithelia exhibiting increased proliferative activity and p53 nuclear expression; it also contained foci of micropapillary and glandular proliferation. Therefore, the lesion was diagnosed as a cystic micropapillary neoplasm of peribiliary glands and resembled flat branch-type intraductal papillary mucinous neoplasm of the pancreas. Histological examination showed the lesion was discontinuous with the perihilar cholangiocarcinoma. Immunohistochemistry showed the cystic neoplasm was strongly positive for MUC6 and that the cholangiocarcinoma was strongly positive for MUC5AC and S100P. These results suggest these two lesions have different origins. This case warrants further study on whether this type of neoplasm is associated with concomitant cholangiocarcinoma as observed in pancreatic intraductal papillary mucinous neoplasm with concomitant pancreatic duct adenocarcinoma.

Ciliated muconodular papillary tumor: a solitary peripheral lung nodule in a teenage girl.

Papillary tumors of the peripheral lung containing ciliated cells and extracellular mucin include solitary peripheral ciliated glandular papilloma, ciliated muconodular papillary tumor, and well-differentiated papillary adenocarcinoma with cilia formation. We report the case of a 19-year-old woman who was a nonsmoker and presented with an incidental small peripheral lung nodule. The resection specimen showed a soft grayish nodule. Histologic examination further revealed a relatively circumscribed mucinous nodule featuring a tubulopapillary tumor composed of ciliated columnar cells and goblet cells, accompanied with abundant extracellular mucin. No lepidic growth pattern was evident. The tumor cells were immunoreactive for cytokeratin 7, thyroid transcription factor-1, and carcinoembryonic antigen, whereas p63 and cytokeratin 5/6 highlighted the presence of basal cells. Next-generation sequencing did not identify any genetic alterations in targeted regions and mutational hotspots of a panel of 22 genes commonly implicated in lung and colon cancers. Taken together, our case was most likely a ciliated muconodular papillary tumor.

Intraductal papillary mucinous neoplasm involving pancreaticobiliary maljunction and an aberrant pancreatic duct draining into the stomach: A case report and review of the literature.

Intraductal papillary mucinous neoplasms (IPMN) are characterized by the growth of epithelial components with mucin production in the main pancreatic duct, or a large branch. We report a case of intraductal papillary mucinous carcinoma (IPMC) of the pancreatic head, complicated by pancreaticobiliary maljunction (PBM) and an aberrant pancreatic duct draining into the stomach. A 50-year-old man with malaise and jaundice was found to have a mass in the pancreatic head at a local hospital. He was clinically diagnosed with IPMC with invasion to the stomach and duodenum after extensive endoscopic and radiological evaluation and a pancreaticoduodenectomy was performed. Histologically, most of the lesion exhibited proliferation of atypical glands, with irregular papillary and villoglandular structures lined by mucinous columnar epithelium, which extended intraepithelially along the dilated pancreatic duct wall. Tumor cells spread into the duodenal wall formed mucous nodules. The pancreatic ducts of this lesion uniquely showed two malformations; PBM, and an aberrant pancreatic duct opening to the gastric wall. This case was rare in the sense that IPMC extended into such unique structures. We report a case of IPMC with rare localization. The pathogenesis of this type of tumor in an abnormal pancreatic duct will be discussed.

"Apocrine Hidrocystoma and Cystadenoma"-like Tumor of the Digits or Toes: A Potential Diagnostic Pitfall of Digital Papillary Adenocarcinoma.

Digital papillary carcinoma (DPC) is a rare, underreported, and often misdiagnosed malignant tumor of the sweat glands. It is often located on the digits and toes and most commonly occurs in male individuals in their fifties to seventies. Because of lack of pain, slow growth, and an inconspicuous appearance, clinical diagnosis is often missed or delayed. In contrast, apocrine hidrocystoma (AH) is a cystic adenoma that arises from the apocrine secretory coil, and it is extremely rare for AHs to develop on the digits. We report 7 cases of DPC, including clinical course, histopathologic and immunohistochemical findings, and therapeutic approach in which the initial histopathologic diagnosis in all cases was AH or cystadenoma. However, complete excision of the neoplasms led to a final diagnosis of DPC. After an adequate treatment, no recurrence or metastasis was found in any of the cases described. All the cases studied showed similar histopathologic and immunohistochemical findings. The initial incisional biopsy showed large unilocular or multilocular cystic spaces situated within the dermis, lined by a double layer of epithelial cells with tiny papillary structures. No cellular atypia, necrosis, or pleomorphism was observed. However, complete excision revealed neoplastic lesions involving the dermis and/or subcutis, with an infiltrative pattern and papillary projections into luminal spaces. Immunoperoxidase studies showed positivity for CK7, S-100 protein, CEA, p63, smooth muscle actin, and calponin. DPC is a rare but life-threatening malignancy, therefore it is important to be able to identify such a lesion both clinically and histopathologically, treat it, and monitor the patient for the tumor's potential recurrence and metastasis. Pathologists and dermatopathologists should be aware that a histopathologic diagnosis of AH or cystadenoma on the fingers and toes should be established with caution, because probably those lesions represent the superficial and cystic component of an underlying DPC, and a wider excision should be performed.

Intraductal papillary neoplasm of the bile ducts: A case report and literature review.

Intraductal papillary neoplasm of the bile duct (IPNB) is a rare bile duct neoplasm mostly found in far eastern nations where hepatolithiasis and clonorchiasis infections are endemic. In western countries, it is very rare and the etiology is unknown. In this article, we report the first IPNB patient we encountered in our clinic and a literature review. The patient is a 38-year-old female with a history of choledocholithiasis who presented with obstructive jaundice. She was found to have a papillary mass at the junction of the right hepatic duct and common hepatic duct with six masses in the liver parenchyma. The immunophenotypic and histologic features of the tumor are consistent with IPNB, gastric subtype. The patient had a partial hepatectomy and has been receiving palliative chemotherapy. In a search of PubMed database, we collected 354 IPNB patients reported in 22 articles. In these patients, 52.8% were from Japan and 27.7% were from western countries including the United States (11.0%). The age of the patients ranged from 35 to 80 years old with an average of 64.6. Male/female ratio was 1.5. Macroscopically, 57.5% of the tumors were in the left lobe and 29.5% were in the right lobe. The average size of the tumor were 4.2 cm at the time of diagnosis. Histologically, pancreato-biliary subtype accounted for 41.8%, intestinal 28.0%, gastric 13.5% and oncocytic 16%. An invasive component is most often present in the pancreato-biliary and gastric subtypes. Despite recent advanced technologies, diagnosis of IPNB is still challenging, especially in western countries due to its rarity. Defined clinico-pathologic features are in demand for the accurate diagnosis and proper treatment.

Pancreatic intraductal papillary mucinous neoplasm in a patient with Lynch syndrome.

Intraductal papillary mucinous neoplasm (IPMN) is a mucin-producing epithelial neoplasm that carries a risk of progression to invasive pancreatic ductal adenocarcinoma. Lynch syndrome is an autosomal dominant condition caused by germline mutations in mismatch repair genes such as MSH2 that lead to microsatellite instability and increased risk of tumor formation. Although families with Lynch syndrome have an increased risk of pancreatic cancer, a clear connection between Lynch syndrome and IPMN has not been drawn. We present a report of a 58 year-old Caucasian woman with multiple cancers and a germline mutation of MSH2 consistent with Lynch syndrome. A screening abdominal computed tomography scan revealed a dilated main pancreatic duct and cystic ductular structure in the uncinate process that were consistent with IPMN of the main pancreatic duct on excision. Immunohistochemistry and polymerase chain reaction of the patient's pancreas specimen did not reveal microsatellite instability or mismatch repair gene loss of expression or function. Our findings may be explained by the fact that loss of mismatch repair function and microsatellite instability is a late event in neoplastic transformation. Given the relative rarity of main duct IPMN, its appearance in the setting of somatic MSH2 mutation suggests that IPMN may fit into the constellation of Lynch syndrome related malignancies.

[Evaluation of immunohistochemistry HER2 results interpretation in invasive micropapillary carcinoma of the breast].

OBJECTIVE: To evaluate the standards of HER2 immunohistochemistry (IHC) interpretation in invasive micropapillary carcinoma of the breast (IMPC). METHODS: HER2 expression in 60 cases of IMPC was evaluated by IHC and fluorescence in situ hybridization (FISH) using TMA-based techniques. The characteristics between cases with HER2 IHC and HER2 gene amplification results were compared. RESULTS: Using 2007 American Society of Clinical Oncology/College of American Pathologist (ASCO/CAP) criteria, among the 52 cases that were successfully stained by IHC, 40 were HER2 IHC negative and 12 were equivocal (2+). Fifteen cases of HER2 IHC 0 were negative for amplification by FISH. Twenty-five cases with IHC 1+ were tested by FISH; and of these, one showed HER2 amplification, 2 were equivocal, and the others were not amplified. All cases of IHC 2+ showed HER2 amplification by FISH. IHC staining of HER2 was located at cell-cell membrane or basolateral membrane of micropapillary structure, but not in the cytoplasmic membrane facing the stroma in all 13 cases which were HER2 amplified, including 12 showing very strong staining and one showing moderate staining. Among the 37 non amplified HER2 cases, 22 showed IHC staining at cell-cell membrane or basolateral membrane (including 15 weak staining and 7 moderate staining). CONCLUSIONS: HER2 IHC detection in IMPC is characterized by staining at cell-cell membrane or basolateral membrane of the micropapillary structure, and absence of staining in the cytoplasmic membrane. It is suggested that interpretation of HER2 IHC staining should be based on membrane staining intensity, but not the completeness of the membrane staining in IMPC. It is suggested to determine the HER2 gene amplification status by using FISH when IHC staining shows moderate or strong intensity.

Epithelial-to-mesenchymal transition (EMT) in intraductal papillary mucinous neoplasm (IPMN) is associated with high tumor grade and adverse outcomes.

BACKGROUND: Epithelial-to-mesenchymal transition (EMT) is generally associated with increased tumor aggressiveness and poor prognosis. We evaluated EMT characteristics in intraductal papillary mucinous neoplasm (IPMN) tumor specimens and their potential role as biomarkers for malignancy, metastasis, and adverse patient outcomes. METHODS: IPMN surgical specimens were identified and reviewed by two gastrointestinal pathologists. Immunohistochemical analysis of E-cadherin, vimentin, and ZEB-1 was performed. Samples were linked to clinicopathologic and outcome data for these patients. Western blot test was used to evaluate ZEB-1 expression in IPMN samples; 846 human miRNAs were profiled, and EMT-related differentially expressed miRNAs were validated using quantitative real-time polymerase chain reaction. RESULTS: Fifty-eight IPMN specimens and five normal pancreatic tissue samples were immunohistochemically stained and scored. E-cadherin expression was significantly lower in malignant versus low-grade IPMN (p < 0.05). Vimentin expression was increased in malignant IPMN tumor samples (p < 0.05). EMT was associated with increased lymph node metastasis and decreased survival of malignant IPMN patients (p < 0.05). ZEB-1, an imperative EMT regulator, was exclusively expressed by malignant IPMN tumors. miRNA hierarchical clustering demonstrated grouping of two main IPMN subgroups: low-grade IPMN versus high-grade IPMN and carcinoma. Twenty-four miRNAs were differentially expressed (14 up-regulated, 10 down-regulated). The EMT-regulatory miRNAs, miR-200c and miR-141, were down-regulated (twofold and 1.8-fold decrease, respectively) in malignant versus low-grade IPMN (p < 0.05). CONCLUSIONS: EMT may play a role in IPMN tumorigenesis and metastasis. EMT molecular deregulations could be utilized as potential novel biomarkers for the identification of high-risk IPMN patients.