Subgrading of G2 Pancreatic Neuroendocrine Tumors as 2A (Ki67 3% to < 10%) Versus 2B (10% to ≤ 20%) Identifies Behaviorally Distinct Subsets in Keeping with the Evolving Management Protocols.

BACKGROUND: Grade 1/2 PanNETs are mostly managed similarly, typically without any adjunct treatment with the belief that their overall metastasis rate is low. In oncology literature, Ki67-index of 10% is increasingly being used as the cutoff in stratifying patients to different protocols, although there are no systematic pathology-based studies supporting this approach. METHODS: Ki67-index was correlated with clinicopathologic parameters in 190 resected PanNETs. A validation cohort (n = 145) was separately analyzed. RESULTS: In initial cohort, maximally selected rank statistics method revealed 12% to be the discriminatory cutoff (close to 10% rule of thumb). G2b cases had liver/distant metastasis rate of almost threefold higher than that of G2a and showed significantly higher frequency of all histopathologic signs of aggressiveness (tumor size, perineural/vascular invasion, infiltrative growth pattern, lymph node metastasis). In validation cohort, these figures were as striking. When all cases were analyzed together, compared with G1, the G2b category had nine times higher liver/distant metastasis rate (6.1 vs. 58.5%; p < 0.001) and three times higher lymph node metastasis rate (20.5 vs. 65.1%; p < 0.001). CONCLUSIONS: G2b PanNETs act very similar to G3, supporting management protocols that regard them as potential therapy candidates. Concerning local management, metastatic behavior in G2b cases indicate they may not be as amenable for conservative approaches, such as watchful waiting or enucleation. This substaging should be considered into diagnostic guidelines, and clinical trials need to be devised to determine the more appropriate management protocols for G2b (10% to ≤ 20%) group, which shows liver/distant metastasis in more than half of the cases, which at minimum warrants closer follow-up.

Dataset for the reporting of carcinoma of the exocrine pancreas: recommendations from the International Collaboration on Cancer Reporting (ICCR).

AIMS: Current guidelines for pathology reporting on pancreatic cancer differ in certain aspects, resulting in divergent reporting practices and a lack of comparability of data. Here, we report on a new international dataset for pathology reporting on resection specimens with cancer of the exocrine pancreas (ductal adenocarcinoma and acinar cell carcinoma). The dataset was produced under the auspices of the International Collaboration on Cancer Reporting (ICCR), which is a global alliance of major (inter)national pathology and cancer organisations. METHODS AND RESULTS: According to the ICCR's rigorous process for dataset development, an international expert panel consisting of pancreatic pathologists, a pancreatic surgeon and an oncologist produced a set of core and non-core data items based on a critical review and discussion of current evidence. Commentary was provided for each data item to explain the rationale for selecting it as a core or non-core element and its clinical relevance, and to highlight potential areas of disagreement or lack of evidence, in which case a consensus position was formulated. Following international public consultation, the document was finalised and ratified, and the dataset, which includes a synoptic reporting guide, was published on the ICCR website. CONCLUSIONS: This first international dataset for cancer of the exocrine pancreas is intended to promote high-quality, standardised pathology reporting. Its widespread adoption will improve the consistency of reporting, facilitate multidisciplinary communication, and enhance the comparability of data, all of which will help to improve the management of pancreatic cancer patients.

Rosai-Dorfman disease of the pancreas: Cytologic analysis of three cases presenting as pancreatic masses.

Rosai-Dorfman Disease (RDD), or sinus histiocytosis with massive lymphadenopathy, is a rare entity characterized by proliferating S100-positive histiocytes. It is most commonly found in lymph nodes with extranodal involvement usually occurring in the head and neck. Pancreatic involvement is extremely rare. The pathology department archives were searched for fine needle aspirations and pancreatic resections showing evidence of RDD. Clinicopathologic features, cytologic smears, cell blocks, immunocytochemical stains and surgical resections were reviewed. Three cases were identified. They were all females, aged 65, 69 and 75, with involvement of the pancreatic tail or head by solid masses of median size 2.3 cm (range 2.1-4.5 cm). Cytologic findings on smears included multiple histiocyte clusters resembling loosely cohesive epithelioid granulomas, singly dispersed histiocytes with moderate to marked nuclear atypia and characteristic emperipolesis. These atypical histiocytes stained positively for CD68, CD163 and S100. Smear background contained variable mixed inflammatory cells, necrotic debris and stromal fragments. The RDD diagnosis was further confirmed on pancreatic resection in two patients and core biopsy in one. The latter patient required three separate procedures before a definitive diagnosis was made. RDD of pancreas is a rare benign inflammatory condition that is diagnostically challenging on cytology. This can cause delays in cytologic diagnosis and/or misdiagnosis. Identification of characteristic cytologic features, primarily histiocytes with emperipolesis, and matching immunocytochemical profile can ensure accurate diagnosis and distinction from mimics.

Development of a Plasma Screening Panel for Pediatric Nonalcoholic Fatty Liver Disease Using Metabolomics.

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in children, but diagnosis is challenging due to limited availability of noninvasive biomarkers. Machine learning applied to high-resolution metabolomics and clinical phenotype data offers a novel framework for developing a NAFLD screening panel in youth. Here, untargeted metabolomics by liquid chromatography-mass spectrometry was performed on plasma samples from a combined cross-sectional sample of children and adolescents ages 2-25 years old with NAFLD (n = 222) and without NAFLD (n = 337), confirmed by liver biopsy or magnetic resonance imaging. Anthropometrics, blood lipids, liver enzymes, and glucose and insulin metabolism were also assessed. A machine learning approach was applied to the metabolomics and clinical phenotype data sets, which were split into training and test sets, and included dimension reduction, feature selection, and classification model development. The selected metabolite features were the amino acids serine, leucine/isoleucine, and tryptophan; three putatively annotated compounds (dihydrothymine and two phospholipids); and two unknowns. The selected clinical phenotype variables were waist circumference, whole-body insulin sensitivity index (WBISI) based on the oral glucose tolerance test, and blood triglycerides. The highest performing classification model was random forest, which had an area under the receiver operating characteristic curve (AUROC) of 0.94, sensitivity of 73%, and specificity of 97% for detecting NAFLD cases. A second classification model was developed using the homeostasis model assessment of insulin resistance substituted for the WBISI. Similarly, the highest performing classification model was random forest, which had an AUROC of 0.92, sensitivity of 73%, and specificity of 94%. Conclusion: The identified screening panel consisting of both metabolomics and clinical features has promising potential for screening for NAFLD in youth. Further development of this panel and independent validation testing in other cohorts are warranted.

Bile duct involvement by hepatocellular carcinoma: A rare occurrence and poor prognostic indicator in bile duct brushing samples.

BACKGROUND: Hepatocellular carcinoma (HCC) rarely involves the biliary tree and may be inadvertently sampled on bile duct brushings (BDBs). METHODS: The pathology archives of 5 institutions were searched for BDBs with HCC involvement. RESULTS: A total of 17 BDBs from 14 patients were obtained. There was a male:female ratio of 6:1; the median age of the patients was 59.5 years (range, 22-80 years). The median hepatic tumor size was 6.2 cm (range, 2.2-13.0 cm). HCC risk factors included viral hepatitis (5 patients), cirrhosis (5 patients), hemochromatosis (1 patient), and alcoholic steatohepatitis (1 patient). Jaundice with elevated bilirubin, liver enzymes, and α-fetoprotein was common. Endoscopic retrograde cholangiopancreatography demonstrated bile duct dilatation, polypoid intraductal masses (5 samples), clots/debris (2 samples), or strictures (4 samples). All BDBs had single and clustered large cells with naked atypical nuclei, granular cytoplasm, high nuclear/cytoplasmic ratios, and nuclei with prominent macronucleoli. Less common findings included clear/microvesicular cytoplasm (35%), papillae (29%), and anisonucleosis (35%). Classic HCC features (widened trabeculae [35%], endothelial wrapping [24%], multinucleation [24%], and cytoplasmic bile pigment [35%]) were uncommon. A total of 11 BDBs were diagnosed as malignant (10 with HCC and 1 with cholangiocarcinoma), 2 were diagnosed as atypical, and 1 BDB was diagnosed as negative; approximately two-thirds were found to have polysomy on fluorescence in situ hybridization. Approximately 71% of patients died of disease at a median of 3.5 months. CONCLUSIONS: HCC may extend into the intrahepatic and/or extrahepatic biliary tree, causing masses and/or strictures that may be sampled on BDB. Although cytologically malignant, the classic features of HCC are uncommon, which can cause misdiagnosis. Cytopathologists should be mindful of this differential when evaluating BDBs, particularly when concomitant liver masses and/or HCC risk factors are present. Because of the associated high mortality and rapid rate of death, its presence should be conveyed clearly in pathology reports.

Rosai-Dorfman Disease of the Pancreas Shows Significant Histologic Overlap With IgG4-related Disease.

Rosai-Dorfman disease (RDD) is a rare entity characterized by proliferating S100-positive histiocytes. Originally described in lymph nodes, it can involve extranodal sites. Pancreatic involvement is rare, with <10 cases previously reported. Recent studies demonstrate a possible overlap between RDD and the more common IgG4-related disease (IRD), which could further complicate pathologic diagnosis. We describe distinct morphologic characteristics as well as overlapping histologic features of IRD in 5 cases of pancreatic RDD at our institution and compare these to a cohort of nonpancreatic extranodal RDD cases. All pancreatic cases were mass forming and had spindled patterns of elongated histiocytes with smaller areas of more classical appearing RDD; all cases had areas of storiform fibrosis and dense lymphoplasmacytic infiltrates with no increase in IgG4-positive plasma cells, and all cases had some degree of vasculitis (4 cases had obliterative vasculitis). Thirteen nonpancreatic extranodal RDD cases had dense lymphoplasmacytic infiltrates; most (85%) had some fibrosis with 46% showing storiform fibrosis, 85% had vasculitis with 31% demonstrating obliterative vasculitis and 2 cases had increased IgG4 staining. Extranodal (pancreatic and nonpancreatic) RDD often shows overlapping morphologic features with IRD, including lymphoplasmacytic inflammation, storiform fibrosis with elongated histiocytes and vasculitis. This can create a diagnostic challenge in the pancreas where IRD is more commonly encountered. Pathologists need to be aware that RDD can occur in the pancreas and should include RDD in the differential of any mass forming pancreatic lesion in which morphologic features of IRD are present.

Cholangiocarcinoma.

This article focuses on cholangiocarcinoma, both intrahepatic and extrahepatic. The various classification schemes based on anatomic location, macroscopic growth pattern, microscopic features, and cell of origin are outlined. The clinicopathologic, immunohistochemical and molecular differences between intrahepatic cholangiocarcinoma and extrahepatic cholangiocarcinoma, as well as differences in the 2 subtypes of intrahepatic cholangiocarcinoma, are discussed. Finally, precursor lesions, prognosis, treatment, and promising new potential targeted therapies are reviewed.

Infiltrative Hepatocellular Carcinoma With Portal Vein Tumor Thrombosis Treated With a Single High-Dose Y90 Radioembolization and Subsequent Liver Transplantation Without a Recurrence.

BACKGROUND: Infiltrative hepatocellular carcinoma with macrovascular invasion is a relatively rare presentation and usually fatal disease. METHODS: Both patients exceeded Milan and University of California-San Francisco (UCSF) criteria, and per Barcelona Clinic Liver Cancer group guidelines, they were enrolled in a prospective open-label radioembolization phase II trial that gave them optimized lobar doses of Yttrium-90 as solely the first-line therapy without concomitant or additional pharmacological or locoregional therapies. RESULTS: Three months after radioembolization, the patients demonstrated no residual viable disease on surveillance imaging. The patients were then followed up with serial imaging for 2 years in 3-month intervals, without documenting recurrence or extrahepatic disease. Finally, both patients underwent transplantation and after more than 20 months of imaging surveillance, no locoregional or systemic recurrence have been observed. CONCLUSIONS: We present, to our knowledge, the first 2 reports of transplantation after successfully downstaging infiltrative disease with portal vein tumoral thrombosis, which traditionally poses as a relative contraindication for resection or transplantation.

Adenosquamous Carcinoma of the Esophagus: An NCDB-Based Investigation on Comparative Features and Overall Survival in a Rare Tumor.

OBJECTIVES: Esophageal adenosquamous carcinoma (ASC) is a rare tumor with characteristics of adenocarcinoma (AC) and squamous cell carcinoma (SCC), the two most common esophageal cancers. Its behavior is aggressive but poorly understood. Using the National Cancer Database (NCDB), the clinical features and overall survival of ASC were compared with AC and SCC. METHODS: The NCDB was queried for patients with esophageal ASC, AC, and SCC. Univariate association of histology with patient characteristics and overall survival were analyzed and socioeconomic characteristics were balanced. RESULTS: Clinical M stage was 0 in a significantly lower proportion of ASC (69.0%) than in AC (70.9%) or SCC (75.6%) (p < 0.001). Median survival was lower in patients with ASC (9.6 months) than with AC (13.5) or SCC (9.7) and 2-year OS was lower in patients with ASC (23.8%) than with AC (34.6%) or SCC (26.5%) (p < 0.001). The OS hazard ratio for ASC was 1.14 when compared to AC (95% CI = 1.016-1.267, p = 0.025) and 1.10 when compared to SCC, but the latter was not significant (95% CI = 0.980-1.222, p = 0.111). CONCLUSION: ASC is a rare tumor among esophageal carcinomas with a greater burden of metastatic disease than AC or SCC and worse OS than AC.

Cytologic predictors of malignancy in bile duct brushings: a multi-reviewer analysis of 60 cases.

Diagnosing malignancy in bile duct brushings is highly challenging. Seven reviewers of variable backgrounds and levels of participation in bile duct brushing sign out blindly reviewed 60 specimens (30 malignant with histologic confirmation and 30 benign (15 stented) with resection or ≥18 months of uneventful follow-up), testing the utility of 14 malignant characteristics. Eleven characteristics were statistically significantly associated with malignancy including 3-dimensional clusters (63% in malignant vs 3% in benign, odds ratio 50, P=0.0003), pleomorphism (62 vs 3, odds ratio 48, P=0.0004), 2-cell population (60% vs 3, odds ratio 44, P=0.0005), chromatin pattern (hypo/hyperchromasia) changes (70% vs 7%, odds ratio 33, P<0.0001), high nuclear-to-cytoplasmic ratio (48 vs 3%, odds ratio 27, P=0.0023), cytoplasmic vacuoles (43 vs 3%, odds ratio 22, P=0.0042), nuclear irregularity (70 vs 10%, odds ratio 21, P<0.0001), cellular discohesion (38 vs 3%, odds ratio 18, P=0.0082), hypercellularity (23% vs 0), nuclear molding (20% vs 0) and prominent nucleoli (21% vs 0). Necrosis and infiltrating inflammation were not helpful in identifying malignancy ('neutrophil cannibalism' was noted in 43% malignant); 21/30 (70%) malignant brushings had ≥3 malignant characteristics, while 23 (77%) benign brushings had none. Of 20 brushings with ≥4 characteristics, 1(5%) proved benign and showed detachment atypia, a close malignant mimicker in brushings. Identification of 3 characteristics maximized the combined sensitivity (70%), specificity (97%) and accuracy (83%), but sensitivity dropped as number of characteristics increased. Identification of 3/11 characteristics (3-dimensional clusters, pleomorphism, high nuclear-to-cytoplasmic ratio, nuclear irregularity, hypercellularity, discohesion, chromatin changes, vacuoles, prominent nucleoli, molding and 2-cell population) improves pathologists' overall performance greatly.

Immunohistochemical Classification of Ampullary Carcinomas: Critical Reappraisal Fails to Confirm Prognostic Relevance for Recently Proposed Panels, and Highlights MUC5AC as a Strong Prognosticator.

Recently, immunohistochemistry-based classifications of ampullary carcinomas have been proposed (Ang and colleagues [PMID: 24832159]; Chang and colleagues [PMID: 23439753]). In this study, the prognostic value of Ang/Chang panel markers (CK20, MUC1, MUC2, CDX2) as well as other markers (CK7, MUC5AC, and MUC6) were tested on full-faced sections of 136 ampullary carcinoma resections with substantial (>5 mm) invasion. Immunohistochemistry was correlated with both histologic classification (intestinal [INT], pancreatobiliary [PB], or nontubular based on ≥3/5 observer agreement) and clinical outcome. No prognostic correlation was found with MUC1, CDX2, MUC2 or CK20 despite testing with different quantitative cutoffs. CK7 and CK20 were nonspecific. Ang classification had reasonable correlation with histologic subclassification of tubular cases as INT versus PB with high specificity but low sensitivity and ambiguous category was large (29%) and included also some classical cases. Prognostically, Ang classification approached but did not reach statistical significance, even when their large "ambiguous" group was eliminated and only tubular cases were analyzed (Ang-INT vs. Ang-PB; P=0.08). The Chang panel, in which the definition of the INT subcategory is not clearly defined, only marginally reached prognostic significance when tested as MUC1+/CDX2- versus MUC1-/CDX2+ and only by Wilcoxon test (P=0.0485) but 31% of the cases were "unclassifiable." The only individual marker that was found to have direct and strong correlation with the clinical outcome was MUC5AC (not used in the Ang or Chang panels), with statistically significant survival differences found with various cutoffs tested (for 20% cutoff, 5-y survival, 68% vs. 31%; P=0.0002). In addition, MUC5AC significantly stratified the histologically PB and INT cases (P=0.01 and 0.03, respectively), as well as Ang's ambiguous and Chang's unclassified cases (P=0.006 and 0.007, respectively). In conclusion, the widely used putative lineage markers, MUC1/MUC2/CK7/CK20/CDX2, do not seem to have direct/significant prognostic correlation either individually or in combination of Ang and Chang panels. Ang panel is helpful as an adjunct in determining the cell lineage with a few caveats. MUC5AC proves to be a significant independent prognosticator and should be incorporated into evaluation of ampullary carcinomas.

The Use of Ancillary Stains in the Diagnosis of Barrett Esophagus and Barrett Esophagus-associated Dysplasia: Recommendations From the Rodger C. Haggitt Gastrointestinal Pathology Society.

Barrett esophagus (BE) is a known risk factor for the development of esophageal adenocarcinoma. Pathologists play a critical role in confirming the diagnosis of BE and BE-associated dysplasia. As these diagnoses are not always straightforward on routine hematoxylin and eosin-stained slides, numerous ancillary stains have been used in an attempt to help pathologists confirm the diagnosis. On the basis of an in-depth review of the literature, the Rodger C. Haggitt Gastrointestinal Pathology Society provides recommendations regarding the use of ancillary stains in the diagnosis of BE and BE-associated dysplasia. Because goblet cells are almost always identifiable on routine hematoxylin and eosin-stained sections, there is insufficient evidence to justify reflexive use of Alcian blue (at pH 2.5) and/or periodic-acid Schiff stains on all esophageal biopsies to diagnose BE. In addition, the use of mucin glycoprotein immunostains and markers of intestinal phenotype (CDX2, Das-1, villin, Hep Par 1, and SOX9) are not indicated to aid in the diagnosis of BE at this time. A diagnosis of dysplasia in BE remains a morphologic diagnosis, and hence, ancillary stains are not recommended for diagnosing dysplasia. Although p53 is a promising marker for identifying high-risk BE patients, it is not recommended for routine use at present; additional studies are needed to address questions regarding case selection, interpretation, integration with morphologic diagnosis, and impact on clinical outcome. We hope that this review and our recommendations will provide helpful information to pathologists, gastroenterologists, and others involved in the evaluation of patients with BE and BE-associated dysplasia.

Massive Gastric Juvenile Polyposis: A Clinicopathologic Study Using SMAD4 Immunohistochemistry.

OBJECTIVES: Juvenile polyps involving the stomach are uncommon. Massive gastric juvenile polyposis is even rarer. METHODS: We describe the clinicopathologic features of nine cases of massive gastric juvenile polyposis. RESULTS: All patients had anemia; four had hypoalbuminemia. The polyps were composed predominantly of dilated crypts lined by columnar epithelium and abundant edematous stroma with mixed inflammatory infiltrates. One patient had a poorly differentiated adenocarcinoma, arising in juvenile polyp-associated intraepithelial neoplasia. A second patient had a well-differentiated intramucosal adenocarcinoma arising in a juvenile polyp with high-grade dysplasia. Three of our cases had polyposis restricted to the stomach. Six (66.6%) had loss of SMAD4 immunoreactivity, making them subject to severe bleeding and hypoproteinemia, as well as developing severe dysplasia or adenocarcinoma. CONCLUSIONS: SMAD4 immunohistochemstry is a helpful ancillary diagnostic test in cases of suspected juvenile polyposis syndrome involving the stomach.

Massive gastric juvenile-type polyposis: a clinicopathological analysis of 22 cases.

AIMS: Massive gastric polyposis is a rare entity that is often associated with juvenile polyposis syndrome (JPS). The aim of this study was to evaluate the clinicopathological features of 22 patients with abundant gastric juvenile-type or hyperplastic-like polyps. METHODS AND RESULTS: The study included 12 males and 10 females with a median age of 48 years (range: 13-79 years). Fourteen (64%) patients carried a diagnosis of JPS, and three had prior gastrointestinal adenocarcinomas. Patients without known JPS presented at an older median age (60 years versus 40 years; P = 0.0068). Clinical symptoms included nausea, vomiting, and abdominal pain; 23% of patients were asymptomatic. Eighteen cases showed complete or near-complete carpeting of the gastric mucosa by innumerable polyps, ranging from a few millimetres to ~100 mm. Most polyps formed long, bulbous projections and had characteristic histological features, including a smooth outer contour, prominent stromal oedema, and widely spaced, often cystically dilated glands lined by foveolar epithelium; some polyps had less stroma and more hyperplastic foveolar epithelium. All had normal underlying or adjacent mucosa. Four (18%) cases harboured adenocarcinoma, and seven (32%) others showed dysplasia. SMAD4 immunohistochemical staining showed patchy loss in polyps from 19 of 20 cases tested. Five of six (84%) patients tested had a germline SMAD4 mutation. CONCLUSIONS: Massive gastric juvenile-type polyposis can occur in patients with and without known JPS, and may mimic different conditions, such as other polyposis syndromes and Ménétrier disease. Pathologists play an important role in disease classification, as some patients lack a family or personal history of JPS, have few if any colonic polyps, and may not harbour diagnostic germline mutations.

"Simple Mucinous Cyst" of the Pancreas: A Clinicopathologic Analysis of 39 Examples of a Diagnostically Challenging Entity Distinct From Intraductal Papillary Mucinous Neoplasms and Mucinous Cystic Neoplasms.

Pancreatic cysts >1 cm lined by nonpapillary mucinous epithelium without ovarian-type stroma pose diagnostic challenges. The term "simple mucinous cyst" was recently proposed for this entity. Our goal was to determine the clinicopathologic characteristics of these cysts, as they have not been previously described. Of the 39 patients with pancreatic resections included in this study, the mean age was 65 years and the female-to-male ratio was 4:1. The characteristics of the cysts are as follows: 82% had elevated cyst fluid carcinoembryonic antigen levels, 67% were unilocular, 69% occurred in the body/tail, 92% did not communicate with pancreatic ducts, the mean size was 2.4 cm (range, 1.0 to 5.5 cm), the cyst contents tended to be serous (48%) or viscous (28%), all had a smooth lining (only 1 had focal excrescences) composed of bland columnar mucinous epithelium (low-grade dysplasia) in 92% with focal high-grade dysplasia in 8%, and 65% had degenerative changes (granulation-like tissue, hemorrhage, and myxoid stroma). The cyst lining was CK7+ and 97% had a MUC5AC+ and/or MUC6+ gastric phenotype; overt intestinal features were absent. In total, 55% of cysts tested (fluid and/or resections) harbored KRAS mutations. The term "simple mucinous cyst" is useful to apply to >1 cm mucinous cysts that do not have characteristic features of intraductal papillary mucinous neoplasms or mucinous cystic neoplasms. KRAS mutations can be detected in these typically bland cysts, and in rare instances, focal high-grade dysplasia may be present. Hence, these cysts should be viewed as neoplastic and treated similarly to other mucinous pancreatic cysts.

Nonmucinous Biliary Epithelium Is a Frequent Finding and Is Often the Predominant Epithelial Type in Mucinous Cystic Neoplasms of the Pancreas and Liver.

Mucinous cystic neoplasms (MCNs) can occur in the pancreas and liver. Classically, these cystic lesions are lined by columnar mucinous epithelium with underlying ovarian-type stroma. It has been proposed that cysts with ovarian-type stroma and nonmucinous epithelium be considered separate entities in both the pancreas and liver. Using a series of 104 pancreatic and 32 hepatic cases, we aimed to further characterize the epithelium present in MCNs. Mucinous epithelium was defined as pancreatic intraepithelial neoplasia-like columnar cells with pale pink/clear apical mucin. Epithelial cells ranging from flat to cuboidal to short columnar without obvious mucin or goblet cells were classified as nonmucinous/biliary epithelium. A mixture (at least 5%) of mucinous and nonmucinous/biliary epithelium was noted in 81%. Almost half (47%) of the cases had abundant (>50%) nonmucinous/biliary epithelium. Of the 71 cases with ≤50% nonmucinous/biliary epithelium, 8 cases demonstrated high-grade dysplasia (7 pancreas, 1 liver) and 14 demonstrated invasive adenocarcinoma (11 pancreas, 3 liver). Conversely, of the 58 cases with >50% nonmucinous/biliary epithelium, not a single case of high-grade dysplasia (P=0.007) or invasive carcinoma (P<0.001) was identified. In summary, nonmucinous/biliary epithelium frequently occurs in MCNs of the pancreas and liver. As mucinous and nonmucinous/biliary epithelia often occur together, there does not appear to be enough evidence to regard cases with predominantly nonmucinous/biliary epithelium as separate entities. Our findings suggest that mucinous change is a "progression" phenomenon in MCNs of the pancreas and liver, and only when abundant mucinous epithelium is present is there a risk of progression to malignancy.