Genome-Derived Ampullary Adenocarcinoma Classifier and Postresection Prognostication.

Importance: Ampullary adenocarcinoma (AA) is characterized by clinical and genomic heterogeneity. A previously developed genomic classifier defined biologically distinct phenotypes with greater accuracy than standard histologic classification. External validation is needed before routine clinical use. Objective: To test external validity of the prognostic value of the hidden genome classifier of AA. Design, Setting, and Participants: This retrospective cohort study took place at 6 international academic institutions. Consecutive patients (n = 192) who underwent curative-intent resection of histologically confirmed AA were included. The data were analyzed from January 2005 through July 2020. Exposures: The multilevel meta-feature regression model previously trained on a prospectively sequenced cohort of 3411 patients (1001 pancreatic adenocarcinoma, 165 distal bile duct adenocarcinoma, and 2245 colorectal adenocarcinoma) was applied to AA sequencing data to quantify the relative proportions of parental cell of origin. Main Outcome and Measures: Genomic classification was correlated with immunohistologic subtype (intestinal [INT] or pancreatobiliary [PB]) and with overall survival (OS), using the log-rank test and Cox proportional hazard models. Results: Among 192 patients with AA (median age, 69.0 [IQR, 60.0-74.0] years and 134 were male [64%]), concordance between immunohistologic and genomic subtypes was 55%. Most INT subtype tumors were categorized into the colorectal genomic subtype (43 of 57 [72.9%]). Of the 114 PB subtype tumors, 29 had a pancreatic genomic profile (25.4%) and 24 had a distal bile duct genomic profile (21.1%). Whereas the standard immunohistologic subtypes were not associated with survival (log rank P = .26), predicted genomic probabilities were correlated with survival probability. Genomic scores with higher colorectal probability were associated with higher survival probability; higher pancreatic and distal bile duct probabilities were associated with lower survival probability. Conclusions and Relevance: The AA genomic classifier is reproducible with available molecular testing in a diverse international cohort of patients and improves stratification of the divergent clinical outcomes beyond standard immunohistologic classification. These data provide a molecular classification that may be incorporated into clinical trials for prospective validation.

Pancreatic cancer: Cutaneous metastases, clinical descriptors and outcomes.

BACKGROUND: Cutaneous metastases in pancreatic cancer (PC) are rare. Herein, we evaluate the clinical, genomic, and other descriptors of patients with PC and cutaneous metastases. METHODS: Institutional databases were queried, and clinical history, demographics, PC cutaneous metastasis details, and overall survival (OS) from cutaneous metastasis diagnosis were abstracted. OS was estimated using Kaplan-Meier methods. RESULTS: Forty patients were identified, and median age (Q1-Q3, IQR) of PC diagnosis was 66.0 (59.3-72.3, 12.9) years. Most patients had Stage IV disease at diagnosis (n = 26, 65%). The most common location of the primary tumor was the tail of the pancreas (n = 17, 43%). The most common cutaneous metastasis site was the abdomen (n = 31, 78%), with umbilical lesions occurring in 74% (n = 23) of abdominal lesions. The median OS (95% CI) was 11.4 months (7.0, 20.4). Twenty-three patients had umbilical metastases (58%), and 17 patients had non-umbilical metastases (43%). The median OS (95% CI) was 13.7 (7.0, 28.7) months in patients with umbilical metastases and 8.9 (4.1, Not reached) months in patients with non-umbilical metastases (p = 0.1). Sixteen of 40 (40%) patients underwent somatic testing, and findings were consistent with known profiles. Germline testing in 12 (30%) patients identified pathogenic variants in patients: CHEK2, BRCA1, and ATM. CONCLUSION: Cutaneous metastases from PC most frequently arise from a pancreas tail primary site and most frequently occur in the umbilicus. Cutaneous metastases may generally be categorized as umbilical or non-umbilical metastases.

Prognostic Impact of Tumor Budding in Intrahepatic Cholangiocellular Carcinoma.

BACKGROUND: Intrahepatic cholangiocarcinoma (ICC) represents an aggressive carcinoma with a dismal prognosis. For resection specimens, histopathological prognosticators are limited to standard AJCC parameters. Tumor budding (TB), a quantitative leviable parameter for tumor cell separation and infiltration is a promising prognostic factor for several cancers. This retrospective study investigated the prognostic impact of tumor budding in ICC, using a semi-automated approach. METHOD: From the Memorial Sloan-Kettering Cancer Center pathology archives, tissue specimens from ICC patients were HE stained and digitized. Tumor budding was analyzed according to the International Tumor Budding Consensus Conference 2016 via QuPath in ten 0.785 mm² vision fields within the tumor center and the tumor-host interface. Within each field, automated QuPath cell detection was conducted and manually reviewed. Tumor budding was correlated with clinico-pathological parameters including AJCC 8th edition classification, hepatitis status, age, ethnicity, treatment, sex, patient overall (OS) and recurrence free survival (RFS) via uni- and multivariate analyses. RESULTS: From 89 patients, 1780 Vision fields comprising 6006 tumor buds were analyzed and correlated with patients' OS and RFS. The median value for tumor budding in tumor budding hot spots was five within the tumor-host interface and six within the tumor center. Tumor budding correlated significantly with patient OS and RFS in uni- and multivariate analyses (p<0.001). CONCLUSION: Our data supports tumor budding, assessed using a digitally enhanced technique, as an independent prognosticator in ICCs for patient's OS and RFS.

Genome-Derived Classification Signature for Ampullary Adenocarcinoma to Improve Clinical Cancer Care.

PURPOSE: The clinical behavior of ampullary adenocarcinoma varies widely. Targeted tumor sequencing may better define biologically distinct subtypes to improve diagnosis and management. EXPERIMENTAL DESIGN: The hidden-genome algorithm, a multilevel meta-feature regression model, was trained on a prospectively sequenced cohort of 3,411 patients (1,001 pancreatic adenocarcinoma, 165 distal bile-duct adenocarcinoma, 2,245 colorectal adenocarcinoma) and subsequently applied to targeted panel DNA-sequencing data from ampullary adenocarcinomas. Genomic classification (i.e., colorectal vs. pancreatic) was correlated with standard histologic classification [i.e., intestinal (INT) vs. pancreatobiliary (PB)] and clinical outcome. RESULTS: Colorectal genomic subtype prediction was primarily influenced by mutations in APC and PIK3CA, tumor mutational burden, and DNA mismatch repair (MMR)-deficiency signature. Pancreatic genomic-subtype prediction was dictated by KRAS gene alterations, particularly KRAS G12D, KRAS G12R, and KRAS G12V. Distal bile-duct adenocarcinoma genomic subtype was most influenced by copy-number gains in the MDM2 gene. Despite high (73%) concordance between immunomorphologic subtype and genomic category, there was significant genomic heterogeneity within both histologic subtypes. Genomic scores with higher colorectal probability were associated with greater survival compared with those with a higher pancreatic probability. CONCLUSIONS: The genomic classifier provides insight into the heterogeneity of ampullary adenocarcinoma and improves stratification, which is dictated by the proportion of colorectal and pancreatic genomic alterations. This approach is reproducible with available molecular testing and obviates subjective histologic interpretation.

Integrated digital pathology at scale: A solution for clinical diagnostics and cancer research at a large academic medical center.

OBJECTIVE: Broad adoption of digital pathology (DP) is still lacking, and examples for DP connecting diagnostic, research, and educational use cases are missing. We blueprint a holistic DP solution at a large academic medical center ubiquitously integrated into clinical workflows; researchapplications including molecular, genetic, and tissue databases; and educational processes. MATERIALS AND METHODS: We built a vendor-agnostic, integrated viewer for reviewing, annotating, sharing, and quality assurance of digital slides in a clinical or research context. It is the first homegrown viewer cleared by New York State provisional approval in 2020 for primary diagnosis and remote sign-out during the COVID-19 (coronavirus disease 2019) pandemic. We further introduce an interconnected Honest Broker for BioInformatics Technology (HoBBIT) to systematically compile and share large-scale DP research datasets including anonymized images, redacted pathology reports, and clinical data of patients with consent. RESULTS: The solution has been operationally used over 3 years by 926 pathologists and researchers evaluating 288 903 digital slides. A total of 51% of these were reviewed within 1 month after scanning. Seamless integration of the viewer into 4 hospital systems clearly increases the adoption of DP. HoBBIT directly impacts the translation of knowledge in pathology into effective new health measures, including artificial intelligence-driven detection models for prostate cancer, basal cell carcinoma, and breast cancer metastases, developed and validated on thousands of cases. CONCLUSIONS: We highlight major challenges and lessons learned when going digital to provide orientation for other pathologists. Building interconnected solutions will not only increase adoption of DP, but also facilitate next-generation computational pathology at scale for enhanced cancer research.

Genetic Determinants of Outcome in Intrahepatic Cholangiocarcinoma.

BACKGROUND AND AIM: Genetic alterations in intrahepatic cholangiocarcinoma (iCCA) are increasingly well characterized, but their impact on outcome and prognosis remains unknown. APPROACH AND RESULTS: This bi-institutional study of patients with confirmed iCCA (n = 412) used targeted next-generation sequencing of primary tumors to define associations among genetic alterations, clinicopathological variables, and outcome. The most common oncogenic alterations were isocitrate dehydrogenase 1 (IDH1; 20%), AT-rich interactive domain-containing protein 1A (20%), tumor protein P53 (TP53; 17%), cyclin-dependent kinase inhibitor 2A (CDKN2A; 15%), breast cancer 1-associated protein 1 (15%), FGFR2 (15%), polybromo 1 (12%), and KRAS (10%). IDH1/2 mutations (mut) were mutually exclusive with FGFR2 fusions, but neither was associated with outcome. For all patients, TP53 (P < 0.0001), KRAS (P = 0.0001), and CDKN2A (P < 0.0001) alterations predicted worse overall survival (OS). These high-risk alterations were enriched in advanced disease but adversely impacted survival across all stages, even when controlling for known correlates of outcome (multifocal disease, lymph node involvement, bile duct type, periductal infiltration). In resected patients (n = 209), TP53mut (HR, 1.82; 95% CI, 1.08-3.06; P = 0.03) and CDKN2A deletions (del; HR, 3.40; 95% CI, 1.95-5.94; P < 0.001) independently predicted shorter OS, as did high-risk clinical variables (multifocal liver disease [P < 0.001]; regional lymph node metastases [P < 0.001]), whereas KRASmut (HR, 1.69; 95% CI, 0.97-2.93; P = 0.06) trended toward statistical significance. The presence of both or neither high-risk clinical or genetic factors represented outcome extremes (median OS, 18.3 vs. 74.2 months; P < 0.001), with high-risk genetic alterations alone (median OS, 38.6 months; 95% CI, 28.8-73.5) or high-risk clinical variables alone (median OS, 37.0 months; 95% CI, 27.6-not available) associated with intermediate outcome. TP53mut, KRASmut, and CDKN2Adel similarly predicted worse outcome in patients with unresectable iCCA. CDKN2Adel tumors with high-risk clinical features were notable for limited survival and no benefit of resection over chemotherapy. CONCLUSIONS: TP53, KRAS, and CDKN2A alterations were independent prognostic factors in iCCA when controlling for clinical and pathologic variables, disease stage, and treatment. Because genetic profiling can be integrated into pretreatment therapeutic decision-making, combining clinical variables with targeted tumor sequencing may identify patient subgroups with poor outcome irrespective of treatment strategy.

Simple mucinous cysts of the pancreas have heterogeneous somatic mutations.

Simple mucinous cysts of the pancreas have an epithelial lining resembling pancreatic intraepithelial neoplasia but may have a clinical presentation similar to premalignant mucinous neoplasms such as intraductal papillary mucinous neoplasms. Whether the epithelial lining shares genomic alterations with other pancreatic preinvasive neoplasms such as PanIN and intraductal papillary mucinous neoplasm has not been determined. We performed targeted sequencing analysis using a custom-designed MiSeq panel including the full coding regions of 18 pancreatic cancer genes on 13 clinically and pathologically well-characterized simple mucinous cysts. We detected 59 mutations in 15 genes in the cohort, with a median of 4 mutations per cyst (range = 0-16 mutations per cyst). The mutated genes and rate of detected mutations were as follows: KMT2C (MLL3) (62%), KRAS (15%), BRAF (8%), RNF43 (8%), CDKN2a (8%), TP53 (15%), and SMAD4 (8%). No GNAS mutations were detected. Four cases (31%) had no mutations detected. These findings place the majority of simple mucinous cysts of the pancreas in the spectrum of early, low-grade mucinous neoplasia, albeit with a different spectrum of genomic alterations compared with PanIN and intraductal papillary mucinous neoplasm.

Pancreatoblastoma: Cytologic and histologic analysis of 12 adult cases reveals helpful criteria in their diagnosis and distinction from common mimics.

BACKGROUND: Pancreatoblastoma (PBL) is a rare malignant pancreatic tumor seen predominantly in childhood, and its cytologic diagnosis remains challenging. METHODS: Twelve fine-needle-aspirations from 11 adults were analyzed. RESULTS: In total, 6 men and 5 women (median age, 45 years; age range, 32-60 years) had tumors measuring a median 5.6 cm (range, 2.5-12 cm) located in the pancreatic head (n = 7) or tail (n = 4), including 3 with familial adenomatous polyposis (FAP)/FAP-related syndromes and 4 with metastasis at diagnosis. The median follow-up was 39.8 months (range, 0.8-348 months), and 5 patients died of disease. The original cytology diagnoses were: PBL (n = 2), neuroendocrine neoplasm (n = 2), poorly differentiated neuroendocrine carcinoma (n = 2), well differentiated neuroendocrine tumor (n = 1), poorly differentiated carcinoma (n = 2), "positive for malignancy" (n = 1), acinar cell carcinoma (n = 1), and epithelioid neoplasm with endocrine and acinar differentiation versus PBL (n = 1). Universal cytopathologic findings included hypercellularity; 3-dimensional clusters; and single, monotonous, blast-like cells that were from 1.5 to 2.0 times the size of red blood cells with high nuclear-to-cytoplasmic ratio, fine chromatin, small, distinct nucleoli, and a resemblance to well differentiated neuroendocrine tumor and poorly differentiated neuroendocrine carcinoma. Branching pseudopapillae (n = 7) and grooved nuclei (n = 3) raised the differential diagnosis of solid-pseudopapillary neoplasm, but with more atypia. Uncommon features included pleomorphism (n = 4) and numerous mitoses (n = 1). Squamoid morules were seen on smears (n = 5) or cell blocks (n = 6) in 70% of patients and were characterized by epithelioid cells with elongated, streaming nuclei, fine chromatin, absent nucleoli, and positive nuclear ß-catenin (n = 6 of 8). The median Ki-67 index was 21% (range, 2%-70%), and neuroendocrine marker expression was common (100%), but acinar markers were variable (63%). CONCLUSIONS: A combination of cytologic findings in PBL, including a predominant population of primitive blast-like cells, subtle squamoid morules, frequent neuroendocrine and variable acinar phenotype, should facilitate accurate cytologic diagnosis and distinction from common mimics.

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.

Distinct histomorphological features are associated with IDH1 mutation in intrahepatic cholangiocarcinoma.

Intrahepatic cholangiocarcinoma has known histological heterogeneity. Mutations in IDH1 (mIDH1) define a molecular subclass of intrahepatic cholangiocarcinoma and IDH-targeted therapies are in development. Characterizing mIDH1 ICC histomorphology is of clinical interest for efficient identification. Resected ICCs with targeted next-generation sequencing by MSK-IMPACT were selected. Clinical data were obtained. By slide review, blinded to IDH status, data were collected for histology type, mucin production, necrosis, fibrosis, cytoplasm cell shape (low cuboidal, plump cuboidal/polygonal, and columnar), and architectural pattern (anastomosing, tubular, compact tubular, and solid). A tumor was considered architecturally heterogeneous if no dominant pattern represented ≥75% of the tumor. Parameters were compared between mIDH1and IDH wild-type controls. In the examined cohort (113 ICC: 29 mIDH1 and 84 IDH wild-type), all IDH1-mutant tumors were of small duct-type histology, thus analysis was limited to 101 small duct-type tumors. mIDH1cases were more likely to have plump cuboidal/polygonal shape (P = .014) and geographic-type fibrosis (P = .005), while IDH1 wild-type were more likely to have low cuboidal shape (P = .005). Both groups were predominantly architecturally heterogeneous with no significant difference in the distribution of architectural patterns. Plump cuboidal/polygonal cell shape and a geographic-type pattern of intra-tumoral fibrosis are more often seen in mIDH1compared to IDH wild-type tumors; however, IDH1 mutation is not associated with a distinct histoarchitectural pattern.

Risk of Invasive Anal Cancer in HIV-Infected Patients With High-Grade Anal Dysplasia: A Population-Based Cohort Study.

BACKGROUND: The progression rate and predictors of anal dysplastic lesions to squamous cell carcinoma of the anus remain unclear. Characterizing these parameters may help refine anal cancer screening guidelines. OBJECTIVE: This study aimed to determine the rate of progression of high-grade anal dysplasia to invasive carcinoma in HIV-infected persons. DESIGN: Using the Surveillance, Epidemiology, and End Results database linked to Medicare claims from 2000 to 2011, we identified HIV-infected subjects with incident anal intraepithelial neoplasia III. To estimate the rate of progression of anal intraepithelial neoplasia III to invasive cancer, we calculated the cumulative incidence of anal cancer in this cohort. We then fitted Poisson models to evaluate the potential risk factors for incident anal cancer. SETTINGS: This is a population-based study. PATIENTS: Included were 592 HIV-infected subjects with incident anal intraepithelial neoplasia III. MAIN OUTCOME MEASURES: The primary outcome measured was incident squamous cell carcinoma of the anus. RESULTS: Study subjects were largely male (95%) with a median age of 45.7 years. Within the median follow-up period of 69 months, 33 subjects progressed to anal cancer. The incidence of anal cancer was 1.2% (95% CI, 0.7%-2.5%) and 5.7% (95% CI, 4.0%-8.1%) at 1 and 5 years, following a diagnosis of anal intraepithelial neoplasia III. Risk of progression did not differ by anal intraepithelial neoplasia III treatment status. On unadjusted analysis, black race (p = 0.02) and a history of anogenital condylomata (p = 0.03) were associated with an increased risk of anal cancer incidence, whereas prior anal cytology screening was associated with a decreased risk (p = 0.04). LIMITATIONS: The identification of some incident cancer episodes used surrogate measures. CONCLUSIONS: In our population-based cohort of HIV-infected subjects with long-term follow-up, the risk of progression from anal intraepithelial neoplasia III to anal squamous cell carcinoma was higher than reported in other studies and was not associated with the receipt of anal intraepithelial neoplasia III treatment. See Video Abstract at http://links.lww.com/DCR/A933.

Advances in the cytologic diagnosis of gastroenteropancreatic neuroendocrine neoplasms.

Two-thirds of neuroendocrine neoplasms arising in the human body originate from the gastrointestinal system or pancreas. Gastroenteropancreatic neuroendocrine neoplasms are heterogeneous, comprising both well differentiated neuroendocrine tumors (NETs) and poorly differentiated neuroendocrine carcinomas (NECs). The clinical presentation, molecular characteristics, and behavior are distinct for NETs and NECs. Fine-needle aspiration is an important modality for the primary diagnosis and staging of these neoplasms and can provide information of prognostic and therapeutic significance. Our evolving understanding of neuroendocrine neoplasm biology has led to several iterations of classification. In this review, new concepts and issues most relevant to cytology diagnosis of gastroenteropancreatic neuroendocrine neoplasms are discussed, such as newer detection methods that aid in diagnosis and staging, recent changes in World Health Organization classification, practical issues related to grading these neoplasms on cytology, guidelines for diagnostic reporting, and panels of immunohistochemical stains for the diagnosis of metastasis. The current understanding of genetic and epigenetic events related to tumor development and potential applications for cytology also are presented as they relate to prognostication and recent therapeutic advances.

Intrahepatic Cholangiocarcinomas Have Histologically and Immunophenotypically Distinct Small and Large Duct Patterns.

Intrahepatic cholangiocarcinomas are histologically heterogenous. Using a cohort of 184 clinically defined, resected intrahepatic cholangiocarcinomas, we retrospectively classified the histology into 4 subtypes: large duct (LD), small duct (SD) (predominantly tubular [SD1] or predominantly anastomosing/cholangiolar, [SD2]), or indeterminate. Then, we tested the 4 subtypes for associations with risk factors, patient outcomes, histology, and immunophenotypic characteristics. SD was the most common (84%; 24% SD1 and 60% SD2) with lower proportions of LD (8%), and indeterminate (8%). Primary sclerosing cholangitis was rare (2%), but correlated with LD (P=0.005). Chronic hepatitis, frequent alcohol use, smoking, and steatosis had no histologic association. LD was associated with mucin production (P<0.001), perineural invasion (P=0.002), CA19-9 staining (P<0.001), CK7, CK19, CD56 immunophenotype (P=0.005), and negative albumin RNA in situ hybridization (P<0.001). SD was histologically nodular (P=0.019), sclerotic (P<0.001), hepatoid (P=0.042), and infiltrative at the interface with hepatocytes (P<0.001). Albumin was positive in 71% of SD and 18% of LD (P=0.0021). Most albumin positive tumors (85%) lacked extracellular mucin (P<0.001). S100P expression did not associate with subtype (P>0.05). There was no difference in disease-specific or recurrence-free survival among the subtypes. Periductal infiltration and American Joint Committee on Cancer eighth edition pT stage predicted survival by multivariable analysis accounting for gross configuration, pT stage, and histologic type. pT2 had worse outcome relative to other pT stages. Significant differences in histology and albumin expression distinguish LD from SD, but there is insufficient evidence to support further subclassification of SD.

Well differentiated grade 3 pancreatic neuroendocrine tumors compared with related neoplasms: A morphologic study.

BACKGROUND: Pancreatic neuroendocrine neoplasms with a Ki-67 labeling index greater than 20% were reclassified in 2017 by the World Health Organization into well differentiated (WD) and poorly differentiated grade 3 neuroendocrine carcinoma (NEC). The authors describe the cytologic features of grade 3 WD pancreatic neuroendocrine neoplasms compared with grade 2 neoplasms and NEC. METHODS: Fine-needle aspirates from 65 pancreatic neuroendocrine neoplasms were reviewed, and their cytomorphologic features were compared across grade 2, WD grade 3, and PD small cell type (PD-S), large cell type (PD-L), and type not otherwise specified (PD-NOS) neoplasms. RESULTS: The 65 aspirates consisted of 19 grade 2 neoplasms, 32 WD grade 3 neoplasms, and 14 NECs (6 PD-S, 5 PD-L, and 3 PD-NOS). The medians Ki-67 proliferation index was 11% (range, 3.2%-17%) in grade 2 neoplasms, 40% (range, 21%-89%) in WD grade 3 neoplasms, 80% (range, 63%-95%) in PD-S neoplasms, 39% (range, 25%-61%) in PD-L neoplasms, and 70% (range, 30%-80%) in PD-NOS neoplasms. Both grade 2 and WD grade 3 neoplasms were associated with plasmacytoid morphology and smooth nuclear contours, but WD grade 3 neoplasms had significant increases in abundant cytoplasm (72% vs 17%; P = .007), nuclear tangles (75% vs 42%; P = .006), and apoptosis (86% vs 58%; P = .005). Compared with NECs, WD grade 3 neoplasms had increased plasmacytoid morphology (75% vs 7%; P < .001), smooth nuclear contours (94% vs 64%; P = .02), round nuclei (59% vs 21%; P = .01), and less pleomorphism (13% vs 50%; P = .004), molding (9% vs 79%; P < .001), and necrosis (13% vs 43%; P = .003). WD grade 3 neoplasms had less pleomorphism (13% vs 50%; P = .04), less necrosis (13% vs 60%; P = .04), and more plasmacytoid morphology (75% vs 20%; P = .03) than PD-L. CONCLUSIONS: The prevalence of cytologic features differs in WD grade 3 pancreatic neuroendocrine neoplasms compared with grade 2 neoplasms and NECs, and these differences assist in the recognition of this newly classified entity. Cancer Cytopathol 2018;126:326-35. © 2018 American Cancer Society.

Assessment of cytologic differentiation in high-grade pancreatic neuroendocrine neoplasms: A multi-institutional study.

BACKGROUND: Well-differentiated (WD) and poorly differentiated (PD) pancreatic neuroendocrine neoplasms are biologically distinct entities with different therapies and prognoses. WD neoplasms with elevated proliferation (Ki-67 > 20%) have been shown to have an overlapping histology with PD neuroendocrine carcinomas. This study compared expert cytomorphologic assessments of differentiation in pancreatic neuroendocrine neoplasms in a multi-institutional study. METHODS: Fine-needle aspiration specimens from pancreatic neuroendocrine neoplasms (grade 2 [G2] and grade 3 [G3] according to the 2017 World Health Organization classification; n = 72) were diagnosed independently by 3 cytopathologists as WD or PD (poorly differentiated large cell type [PD-L] or poorly differentiated small cell type [PD-S]) purely on the basis of cytomorphology. Their diagnoses were compared with a final classification supported by immunohistochemistry (retinoblastoma (RB), death domain- associated protein (DAXX), and α thalassemia/mental retardation syndrome X-linked (ATRX) protein expression), targeted mutation analysis (Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets), prior history of G1/G2 histology, and consensus. RESULTS: The rate of agreement on differentiation was 38% (15 WD cases and 12 PD cases) for the 70 cases included (55 WD cases [n = 19 G2, n = 31 G3, and n = 5 could not be graded] and 15 PD cases [n = 6 PD-S, n = 6 PD-L, and n = 3 PD, not otherwise specified). Two cases could not be classified by the employed methods. PD carcinomas had a higher rate of agreement (10 of 15 [67%]) than WD neoplasms (15 of 55 [27%]). Round nuclei and plasmacytoid cells were associated with agreement for WD cases, whereas apoptosis and angulated nuclei were associated with disagreement. Necrosis was associated with agreement for PD cases. CONCLUSIONS: A purely morphologic approach to the distinction between G2 and G3 pancreatic neuroendocrine neoplasms based on cytology can be challenging, with disagreement found among experienced cytopathologists. Cancer Cytopathol 2018;126:44-53. © 2017 American Cancer Society.

Subclinical focal Cholangitis mimicking liver metastasis in asymptomatic patients with history of pancreatic Ductal Adenocarcinoma and Biliary tree intervention.

BACKGROUND: Cholangitis is an inflammatory process of the biliary tract with a wide range of clinical manifestations and it is not always considered in the differential diagnosis in asymptomatic patients. To the best of our knowledge there is no previous report in the English literature of focal cholangitis manifesting exclusively as liver parenchymal changes mimicking liver metastasis in asymptomatic patients with pancreatic ductal adenocarcinoma (PDAC) and history of manipulation of the biliary tree. The purpose of this article is to present six cases of subclinical focal cholangitis mimicking liver metastasis in asymptomatic patients with history of PDAC and biliary tree intervention. CASE PRESENTATION: There are six cases with new hepatic lesions detected on follow-up scans in asymptomatic patients with history of PDAC and manipulation of biliary tree. Overall seven lesions were detected, all of them were on the liver periphery, five were hypovascular and two were hypervascular. None of those patients had elevation of CA 19.9 compared with the previous exams. The three patients that had magnetic resonance imaging presented restriction on diffusion weighted imaging and high signal intensity on T2-weighted image. Two patients underwent liver biopsy, which showed only inflammatory changes. All patients were treated with antibiotics and underwent imaging follow-up, which demonstrated resolution of the lesions. None of the patients showed imaging or clinical signs of disease progression during this interval. CONCLUSION: Radiologists and oncologists need to be aware of the possibility of focal cholangitis causing hepatic lesions mimicking neoplasia in patients with history of biliary tree intervention, even in the absence of clinical symptoms.

Cytology assessment can predict survival for patients with metastatic pancreatic neuroendocrine neoplasms.

BACKGROUND: Histological features and Ki-67 index have known usefulness in predicting prognosis and guiding therapy among patients with metastatic pancreatic neuroendocrine neoplasms. Fine-needle aspiration may offer advantages for Ki-67 assessment because the technique obtains highly cellular, well-preserved specimens with the potential for broader tumor sampling. In the current study, the authors evaluated concordance for grade and differentiation between concurrent core needle biopsy and cytology preparations. Cytological features and grade then were correlated with survival. METHODS: Differentiation, grade by Ki-67 index, and correlation of these features with survival were compared between concurrent core needle biopsy and cytology specimens from 44 patients with metastatic pancreatic neuroendocrine neoplasms. RESULTS: Differentiation by cytology smear resulted in 38 cases of well (86%) and 6 cases of poor (14%) differentiation. Agreement for differentiation between smear and cell block, smear and core needle biopsy, and cell block and core needle biopsy was 88%, 94%, and 83%, respectively, and agreement for grade was 68%, 54%, and 22%, respectively. Cytology differentiation and cytology grade were found to be strong predictors of outcome with respective hazard ratios of 8.3 (95% confidence interval [95% CI], 3.1-22.1; P<.001) and 1.9 (95% CI, 1.2-2.9) for each ascending grade. The median disease-specific survival cytology projections were 121 months (95% CI, 57-185 months [estimated]) for grade 1, 45 months (95% CI, 29-87 months) for grade 2, and 19 months (95% CI, 1-44 months) for grade 3, with median survivals of 45 months and 3 months, respectively, for patients with well-differentiated and poorly differentiated neuroendocrine tumors (P<.001). CONCLUSIONS: Grading of pancreatic neuroendocrine neoplasms on cytology may not correlate exactly with concurrent core needle biopsy, but cytology differentiation and grade are predictive of survival based on stage-adjusted analysis. Cancer Cytopathol 2017;125:188-196. © 2016 American Cancer Society.

EBV-associated lymphoepithelioma-like carcinoma of the pancreas: Case report with targeted sequencing analysis.

Lymphoepithelioma-like carcinomas are distinctive epithelial derived malignant neoplasms that have a syncytial growth pattern and lymphoid stroma. The majority of tumors with this appearance are Epstein Barr virus (EBV)-associated. We report a patient with a clinical presentation concerning for lymphoma who was diagnosed with an EBV-associated pancreatic carcinoma with a lymphoepithelioma-like pattern. Targeted sequencing analysis showed a molecular profile distinct from conventional ductal adenocarcinoma of the pancreas.

Low interobserver agreement in cytology grading of mucinous pancreatic neoplasms.

BACKGROUND: Identifying high-grade features in patients with pancreatic mucinous neoplasms (MNs) is important for patient management. The reproducibility of MN cytology grading has been evaluated to a limited extent. In the current study, the authors evaluated interobserver variability in grading MNs and the identification of neoplastic mucin in endoscopic ultrasound-guided fine-needle aspiration specimens. METHODS: A 54-case grading set was created from histologically confirmed MNs (44 MNs) and nonmucinous lesions with abundant gastrointestinal contamination (10 nonmucinous lesions). Six observers received a tutorial, reviewed prescreened slides, and recorded: 1) a diagnosis according to a 6-tiered system (TS) (nondiagnostic, atypical [ATP], mucinous cyst low grade [MCLG], mucinous cyst high grade, suspicious for adenocarcinoma, and positive for adenocarcinoma); 2) the cyst fluid carcinoembryonic antigen diagnosis (CEADX); and 3) the presence of neoplastic musin. Interobserver agreement (IOA) was evaluated by calculation of kappa coefficients (Kappa). Diagnostic accuracy was not evaluated. RESULTS: The IOA was lowest for the 6-TS (Kappa, 0.13; P<.001). The CEADX was available for 18 cases (33%), including 6 of 24 MCLG cases (25%). CEADX modestly improved IOA for combined tiers of the 6-TS with ATP and MCLG as separate categories. The highest IOA was noted with a 3-TS (nondiagnostic, ATP/MCLG, and mucinous cyst high grade/suspicious for adenocarcinoma/positive for adenocarcinoma [Kappa, 0.28; P<.001]) and various 4-TS (Kappa, 0.22-0.23). IOA was found to be low for neoplastic mucin (Kappa = 0.15; P<.001). CONCLUSIONS: In a study using simulated cytology practice, observers demonstrated fair IOA for grading MNs and low IOA for identifying neoplastic mucin. Knowledge of the cyst fluid CEA level was found to modestly improve the IOA for low-grade lesions.

Cytomorphologic and immunophenotypical features of acinar cell neoplasms of the pancreas.

BACKGROUND: Acinar cell neoplasms of the pancreas are rare but when encountered, the diagnosis is often established based on cytology specimens. Diagnostic accuracy is important because acinar cell carcinomas are aggressive yet may mimic tumors with different outcomes and management. METHODS: The authors identified all patients with a diagnosis of acinar cell neoplasm in the institutional database; assessed cytomorphology and immunocytochemistry for trypsin, chymotrypsin, synaptophysin, chromogranin A, and MIB-1; and compared all cytology and final histological diagnoses for diagnostic discrepancies. RESULTS: Cytological features were described for 16 histologically proven malignant acinar cell neoplasms: acinar cell carcinoma (8 cases), mixed acinar-neuroendocrine carcinoma (6 cases), mixed acinar-ductal carcinoma (1 case), and pancreatoblastoma (1 case).The majority of aspirates from acinar cell cystadenomas were nondiagnostic or negative (5 of 6 cases; 83%). Acinar and neuroendocrine differentiation that was detected by immunocytochemistry in >20% of tumor cells was found to be correlated with mixed acinar-neuroendocrine carcinoma histology. Cytohistological correlation included 32 patients with 17 discordant diagnoses (53%). The following preoperative cytology diagnoses proved to be acinar cell neoplasms on resection: neuroendocrine tumor (5 cases), adenocarcinoma (5 cases), atypical ductal cells (2 cases), solid pseudopapillary neoplasm, and hepatocellular carcinoma. Three aspirates diagnosed as acinar cell carcinoma by cytology proved to be chronic pancreatitis (2 cases) and ductal adenocarcinoma (1 case). CONCLUSIONS: Acinar cell carcinoma has a distinctive cytological appearance but is frequently misdiagnosed on cytology. Immunocytochemistry is useful for identifying acinar differentiation.