Pancreatic ductal adenocarcinoma progression is restrained by stromal matrix.

Desmoplasia describes the deposition of extensive extracellular matrix and defines primary pancreatic ductal adenocarcinoma (PDA). The acellular component of this stroma has been implicated in PDA pathogenesis and is being targeted therapeutically in clinical trials. By analyzing the stromal content of PDA samples from numerous annotated PDA data sets and correlating stromal content with both anatomic site and clinical outcome, we found PDA metastases in the liver, the primary cause of mortality to have less stroma, have higher tumor cellularity than primary tumors. Experimentally manipulating stromal matrix with an anti-lysyl oxidase like-2 (anti-LOXL2) antibody in syngeneic orthotopic PDA mouse models significantly decreased matrix content, led to lower tissue stiffness, lower contrast retention on computed tomography, and accelerated tumor growth, resulting in diminished overall survival. These studies suggest an important protective role of stroma in PDA and urge caution in clinically deploying stromal depletion strategies.

Evaluating the Adoption of Laboratory Practice Guidelines.

CONTEXT.­: To date, the College of American Pathologists (CAP) has developed 17 laboratory practice guidelines (LPGs) including updates. In 2013, the CAP was awarded a 5-year cooperative agreement grant from the United States Centers for Disease Control and Prevention to increase the effectiveness of LPGs. OBJECTIVE.­: To assess the awareness and adoption of 2 CAP LPGs: immunohistochemical (IHC) assay validation and initial workup of acute leukemia. DESIGN.­: Baseline surveys for each LPG were conducted in 2010 and 2015, respectively. To measure the adoption of guideline recommendations and inform future updates, a follow-up study consisting of surveys, telephone interviews, and focus group sessions was conducted in laboratories that indicated they perform IHC testing. A follow-up study for the acute leukemia LPG is planned. RESULTS.­: For the IHC Validation LPG, a total of 1624 survey responses, 40 telephone interviews, and discussions with 5 focus group participants were analyzed. The response rate for the aforementioned 3 modalities was 46%, 13%, and 3%, respectively. All modalities indicated most respondents were aware of the LPG and had adopted most or all of its recommendations. Respondents expressed needs for continued communication, increased specificity, and more prescriptive recommendations when the guideline is updated. CONCLUSIONS.­: While data-driven development of evidence-based LPGs requires significant resources, active data collection to identify gaps and assess adoption contributes to improved laboratory testing practices in support of patient care. The CAP identified sustainable modalities to track metrics and developed multiple tools that should improve guideline development, adoption, and implementation. Of these modalities, written or electronic surveys were the most logistically feasible and had the highest response rate.

Purity Independent Subtyping of Tumors (PurIST), A Clinically Robust, Single-sample Classifier for Tumor Subtyping in Pancreatic Cancer.

PURPOSE: Molecular subtyping for pancreatic cancer has made substantial progress in recent years, facilitating the optimization of existing therapeutic approaches to improve clinical outcomes in pancreatic cancer. With advances in treatment combinations and choices, it is becoming increasingly important to determine ways to place patients on the best therapies upfront. Although various molecular subtyping systems for pancreatic cancer have been proposed, consensus regarding proposed subtypes, as well as their relative clinical utility, remains largely unknown and presents a natural barrier to wider clinical adoption. EXPERIMENTAL DESIGN: We assess three major subtype classification schemas in the context of results from two clinical trials and by meta-analysis of publicly available expression data to assess statistical criteria of subtype robustness and overall clinical relevance. We then developed a single-sample classifier (SSC) using penalized logistic regression based on the most robust and replicable schema. RESULTS: We demonstrate that a tumor-intrinsic two-subtype schema is most robust, replicable, and clinically relevant. We developed Purity Independent Subtyping of Tumors (PurIST), a SSC with robust and highly replicable performance on a wide range of platforms and sample types. We show that PurIST subtypes have meaningful associations with patient prognosis and have significant implications for treatment response to FOLIFIRNOX. CONCLUSIONS: The flexibility and utility of PurIST on low-input samples such as tumor biopsies allows it to be used at the time of diagnosis to facilitate the choice of effective therapies for patients with pancreatic ductal adenocarcinoma and should be considered in the context of future clinical trials.

De novo compartment deconvolution and weight estimation of tumor samples using DECODER.

Tumors are mixtures of different compartments. While global gene expression analysis profiles the average expression of all compartments in a sample, identifying the specific contribution of each compartment remains a challenge. With the increasing recognition of the importance of non-neoplastic components, the ability to breakdown the gene expression contribution of each is critical. Here, we develop DECODER, an integrated framework which performs de novo deconvolution and single-sample compartment weight estimation. We use DECODER to deconvolve 33 TCGA tumor RNA-seq data sets and show that it may be applied to other data types including ATAC-seq. We demonstrate that it can be utilized to reproducibly estimate cellular compartment weights in pancreatic cancer that are clinically meaningful. Application of DECODER across cancer types advances the capability of identifying cellular compartments in an unknown sample and may have implications for identifying the tumor of origin for cancers of unknown primary.

Prolonged Remission of Cancer of Unknown Primary following Initiation of Eculizumab Therapy for Paroxysmal Nocturnal Hemoglobinuria.

We report the case of a 64-year-old woman who presented with cancer of unknown primary treated with carboplatin and paclitaxel, followed by maintenance erlotinib. Her chemotherapy regimen was discontinued due to the development of profound hemolysis that was later identified to be due to paroxysmal nocturnal hemoglobinuria (PNH). She was started on a complement inhibitory antibody, eculizumab 900 mg every 2 weeks, with marked suppression of hemolysis. Eight years after diagnosis of cancer, the patient remains on eculizumab with no signs of cancer recurrence on regular imaging. Regardless of whether the co-occurrence of cancer and PNH was any more than coincidental in this patient, the uniqueness of the case is emphasized by the remarkable and sustained response of not only PNH but also possibly the associated cancer to eculizumab.

Stromal Content Is Correlated With Tissue Site, Contrast Retention, and Survival in Pancreatic Adenocarcinoma.

PURPOSE: Desmoplastic stroma is a cardinal feature of primary pancreatic ductal adenocarcinoma (PDAC), but its effects on the biology, prognosis and therapeutic outcomes are not known. We developed an automated method to assess tumor stroma density (TSD) and investigated computed tomography (CT)-correlates of stroma in PDAC. PATIENTS AND METHODS: We collected PDAC samples from rapid autopsy and resection series and digitally annotated samples to quantify TSD. A series of resected patients also underwent preoperative multiphasic CT. RESULTS: Automated and manual assessments of TSD were highly correlated (ρ= 0.65, P < 0.001). Solid organ metastases had a lower median TSD than primary tumors (P < 0.001). Patients with high TSD enjoyed prolonged recurrence free survival (RFS) (P = 0.003; HR = 0.51) and overall survival (P = 0.008, HR = 0.57). In another independent dataset, patients with high TSD had decreased risk for recurrence (P = 0.003, HR = 0.03) and death (P = 0.003, HR = 0.03) at time of resection, however the protective effect diminished over time. Patients with normalized portovenous phase CT tumor enhancement ratio ≥0.40 had a longer RFS following resection (P = 0.020). Normalized portovenous phase CT tumor enhancement ratio was significantly correlated with TSD (P = 0.003). CONCLUSIONS: Objective quantitative assessment of stroma in PDAC revealed several clinically relevant observations. Firstly, stroma was less abundant in metastatic PDAC, the cause of most PDAC mortality. Secondly, high stromal content correlates with favorable outcome in resected cases, implying a protective effect of stroma and suggesting careful consideration of active stromal depletion therapies. Finally, standard multiphase CT imaging correlates with stroma content as well as clinical outcome, indicating that non-invasive assessment of stroma is a feasible sensitivity enrichment approach in PDAC.

Interpathologist Diagnostic Agreement for Non-Small Cell Lung Carcinomas Using Current and Recent Classifications.

CONTEXT.­: Measurement of interpathologist diagnostic agreement (IPDA) should allow pathologists to improve current diagnostic criteria and disease classifications. OBJECTIVES.­: To determine how IPDA for pathologists' diagnoses of non-small cell lung carcinoma (NSCLC) is affected by the addition of a set of mucin and immunohistochemical (IHC) stains to hematoxylin-eosin (H&E) alone, by recent NSCLC reclassifications, by simplification of these classifications, and by pathologists' practice location, pulmonary pathology expertise, practice duration, and lung carcinoma case exposure. DESIGN.­: We used a Web-based survey to present core images of 54 NSCLC cases to 22 practicing pathologists for diagnosis, initially as H&E only, then as H&E plus mucin and 4 IHC stains. Each case was diagnosed according to published 2004, 2011, and 2015 NSCLC classifications. Cohen's kappa was calculated for the 231 pathologist pairs as a measure of IPDA. RESULTS.­: Twenty-two pathologists diagnosed 54 NSCLC cases by using 4 published classifications. IPDA is significantly higher for H&E/mucin/IHC diagnoses than for H&E-only diagnoses. IPDA for H&E/mucin/IHC diagnoses is highest with the 2015 classification. IPDA is estimated higher after collapse of stated diagnoses into subhead or dichotomized classes. IPDA for H&E/mucin/IHC diagnoses with the 2015 World Health Organization classification is similar for community and academic pathologists, and is higher when pathologists have pulmonary pathology expertise, have more than 6 years of practice experience, or diagnose more than 100 new lung carcinoma cases per year. CONCLUSIONS.­: Higher IPDA is associated with use of mucin and IHC stains, with the 2015 NSCLC classification, and with pathologists' pulmonary pathology expertise, practice duration, and frequency of lung carcinoma cases.

Virtual microdissection identifies distinct tumor- and stroma-specific subtypes of pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) remains a lethal disease with a 5-year survival rate of 4%. A key hallmark of PDAC is extensive stromal involvement, which makes capturing precise tumor-specific molecular information difficult. Here we have overcome this problem by applying blind source separation to a diverse collection of PDAC gene expression microarray data, including data from primary tumor, metastatic and normal samples. By digitally separating tumor, stromal and normal gene expression, we have identified and validated two tumor subtypes, including a 'basal-like' subtype that has worse outcome and is molecularly similar to basal tumors in bladder and breast cancers. Furthermore, we define 'normal' and 'activated' stromal subtypes, which are independently prognostic. Our results provide new insights into the molecular composition of PDAC, which may be used to tailor therapies or provide decision support in a clinical setting where the choice and timing of therapies are critical.

Molecular Testing in Anatomic Pathology and Adherence to Guidelines: A College of American Pathologists Q-Probes Study of 2230 Testing Events Reported by 26 Institutions.

CONTEXT: The appropriate and timely performance of molecular testing in anatomic pathology is an indicator of quality. The National Comprehensive Cancer Network (NCCN) publishes a comprehensive treatment guideline that includes recommendations for ancillary testing. OBJECTIVE: To establish benchmarks for rates of adherence to NCCN testing recommendations through a multi-institutional study. DESIGN: Participants in a 2013 Q-Probes study of the College of American Pathologists reported data from molecular testing on anatomic pathology cases, excluding hematolymphoid neoplasms, breast primary carcinomas, and gynecologic cytology. RESULTS: Twenty-six institutions reported data from 2230 molecular testing events. In a retrospective study limited to colon, lung, and melanoma, there was strict adherence to guidelines in a median 71% (10th to 90th percentile range, 33%-90%) and there was at least loose adherence in a median 95% (10th to 90th percentile range, 57%-100%). There was adequate tissue to complete testing in a median 98% (10th to 90th percentile range, 86%-100%); in aggregate the adequacy rate for cell blocks was lower (84%, P < .001). Median test turnaround time was 8 days (10th to 90th percentile range, 4-13 days). In a prospective collection of all organ sites, there was strict adherence to guidelines in a median 53% (10th to 90th percentile range, 20%-71%), and there was at least loose adherence in a median 94% (10th to 90th percentile range, 75%-100%). Adherence to guidelines was higher for lung specimens and in institutions with more multidisciplinary conferences. CONCLUSIONS: This multi-institutional study provides benchmarking data on appropriateness and timeliness of molecular testing in anatomic pathology.

Turnaround time for large or complex specimens in surgical pathology: a College of American Pathologists Q-Probes study of 56 institutions.

CONTEXT: Turnaround time (TAT) for large or complex surgical pathology specimens is an indicator of efficiency in anatomic pathology and may affect coordination of patient care. OBJECTIVE: To establish benchmarks for TAT and to identify practice characteristics that may influence TAT. DESIGN: Participants in a 2012 Q-Probes quality improvement program of the College of American Pathologists retrospectively reviewed all surgical pathology cases from the prior 6 months to identify up to 50 cases coded as Current Procedural Terminology (CPT) code 88307 (excluding biopsies) or 88309. Participants reported the times and dates of accessioning and final sign-out. RESULTS: A total of 56 institutions reported on 2763 large or complex cases, which included 70% with CPT code 88307 and 30% with CPT code 88309. Cases requiring special handling comprised 51.5%, and 48.5% were routine. Among all institutions the median TAT was 2.72 calendar days (10th-90th percentile range, 6.23-1.22 days). Longer TAT occurred in governmental institutions (median, 6.06 versus 2.13 days; P < .001) and in institutions that mandate overnight fixation for some specimen types (median, 3.83 versus 2.07 days; P = .03). Longer TAT was associated with CPT code 88309 (median, 3.99 versus 2.82 days; P < .001), special handling (median, 4.13 versus 1.94 days; P < .001), frozen section (median, 3.38 versus 2.92 days; P < .001), radical cancer resection (P < .001), and malignant cases (P < .001). Turnaround time was not significantly affected by either pathology training programs or routine weekend sign-out. CONCLUSIONS: This study provides benchmark data for TAT in large or complex surgical pathology specimens. Turnaround time was good overall, but the range among participating institutions was wide.

Surgical pathology report defects: a College of American Pathologists Q-Probes study of 73 institutions.

CONTEXT: The rate of surgical pathology report defects is an indicator of quality and it affects clinician satisfaction. OBJECTIVE: To establish benchmarks for defect rates and defect fractions through a large, multi-institutional prospective application of standard taxonomy. DESIGN: Participants in a 2011 Q-Probes study of the College of American Pathologists prospectively reviewed all surgical pathology reports that underwent changes to correct defects and reported details regarding the defects. RESULTS: Seventy-three institutions reported 1688 report defects discovered in 360,218 accessioned cases, for an aggregate defect rate of 4.7 per 1000 cases. Median institutional defect rate was 5.7 per 1000 (10th to 90th percentile range, 13.5-0.9). Defect rates were higher in institutions with a pathology training program (8.5 versus 5.0 per 1000, P = .01) and when a set percentage of cases were reviewed after sign-out (median, 6.7 versus 3.8 per 1000, P = .10). Defect types were as follows: 14.6% misinterpretations, 13.3% misidentifications, 13.7% specimen defects, and 58.4% other report defects. Overall, defects were most often detected by pathologists (47.4%), followed by clinicians (22.0%). Misinterpretations and specimen defects were most often detected by pathologists (73.5% and 82.7% respectively, P < .001), while misidentifications were most often discovered by clinicians (44.6%, P < .001). Misidentification rates were lower when all malignancies were reviewed by a second pathologist before sign-out (0.0 versus 0.6 per 1000, P < .001), and specimen defect rates were lower when intradepartmental review of difficult cases was conducted after sign-out (0.0 versus 0.4 per 1000, P = .02). CONCLUSION: This study provides benchmarking data on report defects and defect fractions using standardized taxonomy.

A six-gene signature predicts survival of patients with localized pancreatic ductal adenocarcinoma.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) remains a lethal disease. For patients with localized PDAC, surgery is the best option, but with a median survival of less than 2 years and a difficult and prolonged postoperative course for most, there is an urgent need to better identify patients who have the most aggressive disease. METHODS AND FINDINGS: We analyzed the gene expression profiles of primary tumors from patients with localized compared to metastatic disease and identified a six-gene signature associated with metastatic disease. We evaluated the prognostic potential of this signature in a training set of 34 patients with localized and resected PDAC and selected a cut-point associated with outcome using X-tile. We then applied this cut-point to an independent test set of 67 patients with localized and resected PDAC and found that our signature was independently predictive of survival and superior to established clinical prognostic factors such as grade, tumor size, and nodal status, with a hazard ratio of 4.1 (95% confidence interval [CI] 1.7-10.0). Patients defined to be high-risk patients by the six-gene signature had a 1-year survival rate of 55% compared to 91% in the low-risk group. CONCLUSIONS: Our six-gene signature may be used to better stage PDAC patients and assist in the difficult treatment decisions of surgery and to select patients whose tumor biology may benefit most from neoadjuvant therapy. The use of this six-gene signature should be investigated in prospective patient cohorts, and if confirmed, in future PDAC clinical trials, its potential as a biomarker should be investigated. Genes in this signature, or the pathways that they fall into, may represent new therapeutic targets. Please see later in the article for the Editors' Summary.

Isoform-specific upregulation of palladin in human and murine pancreas tumors.

Pancreatic ductal adenocarcinoma (PDA) is a lethal disease with a characteristic pattern of early metastasis, which is driving a search for biomarkers that can be used to detect the cancer at an early stage. Recently, the actin-associated protein palladin was identified as a candidate biomarker when it was shown that palladin is mutated in a rare inherited form of PDA, and overexpressed in many sporadic pancreas tumors and premalignant precursors. In this study, we analyzed the expression of palladin isoforms in murine and human PDA and explored palladin's potential use in diagnosing PDA. We performed immunohistochemistry and immunoblot analyses on patient samples and tumor-derived cells using an isoform-selective monoclonal antibody and a pan-palladin polyclonal antibody. Immunoblot and real-time quantitative reverse transcription-PCR were used to quantify palladin mRNA levels in human samples. We show that there are two major palladin isoforms expressed in pancreas: 65 and 85-90 kDa. The 65 kDa isoform is expressed in both normal and neoplastic ductal epithelial cells. The 85-90 kDa palladin isoform is highly overexpressed in tumor-associated fibroblasts (TAFs) in both primary and metastatic tumors compared to normal pancreas, in samples obtained from either human patients or genetically engineered mice. In tumor-derived cultured cells, expression of palladin isoforms follows cell-type specific patterns, with the 85-90 kDa isoform in TAFs, and the 65 kDa isoform predominating in normal and neoplastic epithelial cells. These results suggest that upregulation of 85-90 kDa palladin isoform may play a role in the establishment of the TAF phenotype, and thus in the formation of a desmoplastic tumor microenvironment. Thus, palladin may have a potential use in the early diagnosis of PDA and may have much broader significance in understanding metastatic behavior.

Cushing Syndrome in a 6-Month-Old Infant due to Adrenocortical Tumor.

Cushing syndrome is rare in infancy and usually due to an adrenocortical tumor (ACT). We report an infant with Cushing syndrome due to adrenocortical carcinoma. The patient presented at six months of age with a three-month history of growth failure, rapid weight gain, acne, and irritability. Physical examination showed obesity, hypertension, and Cushingoid features. Biochemical evaluation showed very high serum cortisol, mildly elevated testosterone, and suppressed ACTH. Abdominal MRI revealed a heterogeneous right adrenal mass extending into the inferior vena cava. Evaluation for metastases was negative. The tumor was removed surgically en bloc. Pathologic examination demonstrated low mitotic rate, but capsular and vascular invasion. She received no adjuvant therapy. Her linear growth has improved and Cushingoid features resolved. Hormonal markers and quarterly PET scans have been negative for recurrence 24 months postoperatively. In conclusion, adrenocortical neoplasms in children are rare, but should be considered in the differential diagnosis of Cushing syndrome.

Use of the ThinPrep method in bile duct brushings: analysis of morphologic parameters associated with malignancy and determination of interobserver reliability.

Recent work suggests the ThinPrep method can improve diagnostic sensitivity and accuracy in bile duct brushings. However, the proportion of atypical and suspicious diagnoses remains high. The aim of this study was to identify the most useful morphologic features in ThinPrep bile duct cytology and evaluate interobserver reliability. We evaluated 100 bile duct brushings prepared by ThinPrep, all with either histology or long term clinical follow-up (55 malignant, 45 benign). Morphologic features were evaluated by four experienced cytopathologists blind to clinical information and follow-up diagnoses. These features included cellularity, blood or diathesis, mitoses, inflammation, three-dimensional groups, discohesive atypical cells, macronucleoli, well-defined cytoplasmic borders, and nuclear features of malignancy (nuclear membrance irregularity, chromatin clumping). The data were analyzed by intraclass correlation (ICC) and stepwise multiple logistic regression. Reviewers showed unanimous agreement in 29% of cases, one degree of disagreement in 58% of cases, and full disagreement in 13% of cases. Of benign cases, 38% were thought to be diagnostic of malignancy by at least one of the four reviewers. Sensitivity for the morphologic parameters varied from 18 to 67%; the highest sensitivity was for discohesive atypical cells, well-defined cytoplasmic borders, nuclear features of malignancy, and cellularity (67, 62, 51 and 46%, respectively). Specificity of parameters varied from 16 to 100%; the highest specificity was for mitoses, three-dimensional groups, nuclear features of malignancy, and macronucleoli (100, 98, 93, and 93%, respectively). Interobserver reliability (ICC) was very good for specimen cellularity (0.72) and nuclear features of malignancy (0.60). In logistic regression analysis, only nuclear features of malignancy and increasing patient age separated benign from malignant. On ThinPrep bile duct brushings, nuclear features of malignancy are most useful in distinguishing benign from malignant, and interobserver reliability for this parameter is very good. Discohesive atypical cells show moderate sensitivity and specificity, while three dimensional clusters and macronucleoli are specific but not sensitive for malignancy, and are not significant in multivariate logistic regression models. The relatively high proportion of benign cases thought to be diagnostic of malignancy by at least one reviewer argues for a consensus approach to this diagnosis.

Molecular diagnostic testing as an adjunct to morphologic evaluation of pancreatic ductal system brushings: potential augmentation for diagnostic sensitivity.

Malignancies arising from the pancreatic and biliary ductal systems present the gastroenterologist and pathologist with diagnostic challenges. Tumors of the pancreatic and/or biliary ductal system may present as either duct strictures or mass lesions. When lesions present as strictures without associated demonstrable masses, brushing cytology may represent the only reasonable diagnostic technique aside from open biopsy. Diagnostic sensitivities for brushing cytology have ranged from 18 to 90%. Positive diagnoses of malignancy are of great clinical value but a negative result is of relatively little clinical aid when the radiographic or clinical findings are suspicious for a malignancy.A variety of techniques have been used in an attempt to improve diagnostic sensitivity for brushing cytology. These have included immunohistochemistry and various molecular diagnostic techniques. Using the high resolution melting curve technique, we performed mutational analysis on 20 bile duct brushing specimens for mutations in p53, K-ras, BRAF, and EGFR genes. Eleven specimens had corresponding surgical specimens, which were similarly analyzed. Our series included twelve adenocarcinomas, one islet cell tumor, one case of dysplasia, and six benign cases. K-ras mutations were found in cytology specimens of 3 out of 12 malignancies. No EGFR or B-raf mutations were detected and only a single p53 mutation in an adenocarcinoma was detected in the corresponding cytology specimen. No mutations were detected in benign lesions or in the dysplasia. Only 8% of specimens from adenocarcinomas had p53 mutations and only 33% of cases had K-ras mutations. Mutational analysis did not appear to improve the cytologic detection of adenocarcinoma by bile duct brushings.

Fine needle aspiration of pancreatic cysts: Use of ancillary studies and difficulty in identifying surgical candidates.

OBJECTIVE: To evaluate ancillary biochemical testing after pancreatic cyst fine needle aspiration (FNA) in the clinical setting. STUDY DESIGN: Findings from 110 pancreatic guided FNA were reviewed cysts evaluated by image- and correlated with histology, clinical follow-up and biochemical analysis of cyst fluid and serum. Adequate followup was available for 95. RESULTS: In terms of identifying cysts requiring surgery, FNA showed 55.3% sensitivity, 95% specificity, 92.9% positive predictive value (PPV) and 64.4% negative predictive value (NPV). FNA showed only nonspecific cyst contents in 51% of cases, but 40% of those patients proved to be surgical candidates at follow-up. Overall, patients with lesions requiring surgery were younger (p = 0.14), more often presented with pain (p = 0.006), had larger cysts (p = 0.05) and less often had a history of chronic pancreatitis (p = 0.12). Among cases in which FNA showed only nonspecific cyst contents, patients with lesions requiring surgery were more often female (p = 0.08), were younger (p = 0.10), had larger cysts (p = 0.06) and had pain at presentation (p = 0.02). Differences in fluid and serum analytes were not statistically significant. CONCLUSION: FNA of pancreatic cysts shows high specificity but poor sensitivity, even with cyst fluid and serum biochemical analysis. FNA of cysts requiring surgery often yielded nonspecific cyst cytology and causing a misinterpretation as pseudocysts. Ancillary biochemical analysis of cyst fluid remains problematic in the clinical setting.

Cytomorphology of yolk sac tumor of the liver in fine-needle aspiration: a pediatric case.

Yolk sac tumors (YST) in extragonadal locations are rare. Cytologic diagnosis of YST on fine-needle aspiration (FNA) smears may be a challenge to the cytopathologist. Further neo-adjuvant therapy may be based on cytologic diagnosis making accuracy important. We studied FNA material from a hepatic mass in a pediatric patient to further define the cytomorphologic features of hepatic YST. Features include large pleomorphic balls of tumor cells with high nuclear to cytoplasmic ratios, papillary or microglandular pattern of growth, cytoplasmic and intranuclear vacuoles, and prominent nucleoli. Positive immunohistochemical studies included alpha-fetoprotein, cytokeratin AE1/AE3, and CAM 5.2, which are useful in supporting the diagnosis. We report a pediatric patient in whom the diagnosis of hepatic YST was made by cytologic, histologic, and immunohistochemical studies. The subsequent liver biopsy was consistent with the FNA diagnosis. Our findings may further help to characterize the cytomorphologic features of this rare lesion.

Pancreatic and bile duct brushing cytology in 1000 cases: review of findings and comparison of preparation methods.

BACKGROUND: Duct brushing cytology is an important tool in evaluation of the extrahepatic biliary tract and large pancreatic ducts. The emergence of neoadjuvant therapies underscores the importance of accurate preoperative diagnosis by noninvasive means. Liquid-based preparation methods, such as ThinPrep, have become popular for nongynecologic cytology specimens. METHODS: Findings from bile and pancreatic duct brushings were reviewed over the 10-year period of 1994-2003. Cytologic material, imaging reports, and clinical data were reviewed and pathologic and clinical follow-up data were obtained. The slides were prepared by direct smear only (18.8%), direct smear plus cytospin (14.4%), or direct smear plus ThinPrep (66.8%). RESULTS: A total of 1118 specimens were identified (1008 bile duct, 110 pancreatic duct) from 864 patients. The cytologic findings were: 53.5% negative, 16.5% malignant, 18.2% suspicious for malignancy, 11% atypical/inconclusive, 0.8% inadequate. Follow-up in the form of either histology or at least 6 months clinical observation was available for 82.2% of cases (n = 971). Overall operating characteristics were: 52.6% sensitivity, 99.4% specificity, 98.9% positive predictive value, 67.1% negative predictive value, and 75.7% accuracy. Diagnostic agreement between cytology and follow-up was the main variable analyzed. Agreement was significantly affected by characteristics of the sampled lesion, with ductal narrowing having the lowest rate of malignancy. In addition, the ThinPrep method showed superior sensitivity and accuracy compared with other preparation methods (P = .02). Nonsignificant associations were noted for patient age and gender, site of lesion, and the presence of either stones or prior stent. CONCLUSION: In a large dataset from a single institution, brushing cytology showed modest sensitivity and high specificity. Diagnostic agreement was considerably better for benign cases. The combination of direct smear and the ThinPrep method showed superior sensitivity and accuracy.

Urothelial carcinoma with rhabdoid features: report of 6 cases.

Extrarenal rhabdoid tumors have been described in a variety of primary sites with only rare case reports of urothelial carcinomas with rhabdoid features in the literature. In this report, we describe the clinicopathologic characteristics, including clinical follow-up on 6 cases of urothelial carcinoma with prominent rhabdoid features. Four cases were retrieved from the consultation files of one of the authors and 2 were retrieved from the surgical pathology files at our institution. The patients were all men, with ages ranging from 53 to 86 years (mean, 66.5 years). Patients initially presented with hematuria or obstructive symptoms. The sites included bladder (n = 4) and renal pelvis (n = 2). All cases had a prominent rhabdoid component (mean, 60%), ranging from 40% to 80%. In addition to the rhabdoid component, multiple coexistent histological components were seen, including in situ urothelial carcinoma (carcinoma in situ) and high-grade papillary urothelial carcinoma (n = 2), poorly differentiated carcinoma with small-cell features (n = 1), sarcomatoid (n = 2), and a myxoid component (n = 2). All cases in this series had focal or diffuse positive staining with one or more cytokeratin markers (epithelial membrane antigen, CAM 5.2, AE1/AE3). Of the 6 patients, 4 were treated initially with surgery (radical cystoprostatectomy, n = 2; radical nephrectomy, n = 2). Of 6 patients, 2 died within 1 month, whereas a third patient died within 4 months. The remaining 3 patients were alive at 3, 3, and 9 months after diagnosis. The histological and immunohistochemical findings in this study serve to broaden the morphological spectrum of urothelial carcinomas with prominent rhabdoid features and add further evidence as to their poor prognosis.