PBPath Journal Watch Articles


Wellcome to the PBPath Journal Watch!

DOI

https://doi.org/10.5281/zenodo.3635440

https://osf.io/3d67y/

This bi-monthly journal watch features exciting recently published pancreas and biliary pathology articles that will provide up to date medical knowledge in our field. These articles will be showcased in several convenient categories, including surgical pathology, cytopathology, and molecular pathology among others. The articles in each category are in no particular order. See the list of journals we search regularly here. Previous months’ issues may be found in our archive and you may see drafts of the upcoming issue here.

We encourage members to actively participate by recommending new articles and providing feedback using the forms provided below.

We hope that you will enjoy the new PBPath Journal Watch!

Pancreas


- Pancreatic ductal adenocarcinoma: tumor regression grading following neoadjuvant FOLFIRINOX and Radiation

Histopathology 2020 Feb;():

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=32031712

INTRODUCTION: In the adjuvant setting, when compared to gemcitabine, patients with pancreatic ductal adenocarcinoma (PDAC) treated with FOLFIRINOX show superior survival. Herein, we quantitatively assess pathologic tumor response to chemoradiation in pancreatectomy specimen and reassess guidelines for tumor regression grading. METHODS: We evaluated 92 patients with borderline resectable/locally advanced PDAC following pancreatectomy and neoadjuvant treatment with FOLFIRINOX and radiation. Demographic data, CAP tumor regression grade (TRG), and overall survival (OS) was recorded. A quantitative analysis of residual tumor was performed on the slide with the highest tumor burden to derive a tumor to tumor bed ratio. RESULTS: On univariate analysis, only lymph node status (p=0.043), and CAP TRG (p=0.038) correlated with OS. Sixteen percent of patients showed complete pathologic response. The optimal tumor to tumor bed ratio cut point was 11.6% and on a multivariate model was the only pathologic parameter that correlated with OS (p=0.016) (Hazard Ratio 2.27). CONCLUSIONS: The high proportion of patients with PDAC showing complete and near complete pathologic response supports the use of FOLFIRINOX and radiation in the neoadjuvant setting. Several traditional pathology parameters fail to predict OS in patients treated with chemoradiation while a quantitative tumor to tumor bed ratio is a powerful predictor of OS. The data supports a two-tiered approach to TRG based on tumor to tumor bed ratio and quantitative analysis merits further consideration.

doi: https://doi.org/10.1111/his.14086



- Experience and future perspectives on the use of the Papanicolaou Society of Cytopathology Terminology System for reporting pancreaticobiliary cytology

Diagnostic cytopathology 2020 Feb;():

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=32031332

The Papanicolaou Society of Cytopathology developed a set of guidelines for reporting pancreaticobiliary cytology in 2014 (PB System), with a six-tiered system: Nondiagnostic, Negative, Atypical, Neoplastic (Benign or Other), Suspicious, and Positive. This proposed scheme incorporates ancillary testing such as biochemical testing of cyst fluids for diagnosis and provides terminology that standardizes the category of the various diseases of the pancreas, some of which are difficult to diagnose specifically by cytology alone. Since its initial publication five and half years ago, several groups have published their experiences on the use of the PB System and have shown that most objectives proposed by the original publication have been achieved. They have shown that there is a better understanding and definition of the diagnostic categories with an associated distribution and risk of malignancy. The diagnostic categories of Neoplastic: Other, Suspicious, and Malignant show a high sensitivity and specificity for the diagnosis of malignancy. The System also provides a multi-specialist view of pancreatic lesions, with biochemical and radiological findings being incorporated into the final pathological report. The present review summarizes these findings and discusses the future perspectives and foreseen changes that are to be incorporated to a second edition of the reporting System.

doi: https://doi.org/10.1002/dc.24393



- Pathology of Treated Pancreatic Ductal Adenocarcinoma and Its Clinical Implications

Archives of pathology & laboratory medicine 2020 Feb;():

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=32023088

CONTEXT.—: Preoperative neoadjuvant therapy has been increasingly used to treat patients with potentially resectable pancreatic ductal adenocarcinoma (PDAC). Neoadjuvant therapy often induces extensive fibrosis in tumor, adjacent pancreatic parenchyma, and peripancreatic tissue. Histopathologic evaluations and histologic tumor response grading (HTRG) of posttherapy pancreatectomy specimens are very difficult and challenging. Studies on prognostic significance of posttherapy pathologic staging, optimal system for HTRG, and other pathologic parameters in treated PDAC patients are limited. OBJECTIVE.—: This review is to provide a timely update of the prognostic values of posttherapy pathologic staging, HTRG, and other pathologic parameters in PDAC patients who received neoadjuvant therapy and pancreas resection. DATA SOURCES.—: Systemic review of major studies on pathologic evaluation and its clinicopathologic implications in treated PDAC patients. CONCLUSIONS.—: Systemic pathologic examination, histologic tumor regression grading, pathologic evaluation of the margins, tumor involvement of superior mesenteric vein/portal vein, accurate pathologic staging, and reporting of posttherapy pancreatectomy specimens provide highly valuable prognostic information for postoperative patient care. Our findings suggest for the first time that tumor size of 1.0 cm, instead of 2.0 cm, is a better cutoff for ypT2 in PDAC patients. The newly proposed 3-tier MD Anderson HTRG system not only has proved to be an independent prognostic marker for PDAC patients who received neoadjuvant therapy and pancreatectomy, but also improves interobserver agreement among pathologists in evaluation of tumor response. This grading system should be considered in future editions of the College of American Pathologists protocol for PDAC.

doi: https://doi.org/10.5858/arpa.2019-0477-RA



- A Comparison of the Pathological Types of Undifferentiated Carcinoma of the Pancreas

Pancreas 2020 Jan;():

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=32011534

OBJECTIVES: This study aimed to identify the detailed clinicopathological features of undifferentiated carcinoma of the pancreas (UCP). METHODS: We investigated clinical, imaging features and the prognoses of 261 patients; 8 were our patients, and the remainder were identified by searching English-language articles in PubMed. RESULTS: We classified patients with UCP into 3 types based on pathological findings: osteoclast-like giant cell-associated carcinoma, pleomorphic cell carcinoma (PLC), and spindle cell carcinoma. There were no remarkable differences in clinical, radiological features between these 3 types. However, PLCs were significantly more likely to be unresectable than were the other 2 types (P < 0.001). Patients with osteoclast-like giant cell-associated carcinoma achieved the best overall survival (OS) rates (P < 0.001), whereas those with spindle cell carcinoma had significantly longer OS rates than did those with PLC (P = 0.004). These OS patterns were maintained when considering only those patients who underwent resection. Patients with PLC had both lower curative resection and high lymph node metastasis rates (P = 0.029, P = 0.023). Patients who underwent resection had more favorable prognoses than did those who did not. CONCLUSIONS: Surgery is the first choice for resectable UCP. Pleomorphic cell carcinoma is particularly malignant; postoperative treatment should be introduced immediately.

doi: https://doi.org/10.1097/MPA.0000000000001483



- Radiological and Pathological Assessment of the 2017 Revised International Association of Pancreatology Consensus Guidelines for Intraductal Papillary Mucinous Neoplasm, With an Emphasis on the Gastric Pyloric Gland Type

Pancreas 2020 Jan;():

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=32011532

OBJECTIVES: This study aimed to assess the pitfalls of the current International Association of Pancreatology guidelines (IAPCG2017) for pancreatic intraductal papillary mucinous neoplasm (IPMN) and identify the criteria for future guidelines. METHODS: Eighty surgically resected, consecutive IPMN cases were analyzed. Data including tumor site, IPMN duct type, and surgery type were collected. Based on radiological data, cases were retrospectively classified as high-risk stigmata (HRS) and non-HRS. Pathological grades and histological subtypes of IPMN cases were determined. Severe stromal sclerosis of the IPMN septa/marked parenchymal atrophy in the upstream pancreas was investigated pathologically. Positive/negative predictive values of the IAPCG2017 were calculated. Clinicopathological features of HRS-benign cases (pathologically benign IPMN cases meeting the HRS criteria) were extracted. RESULTS: The positive/negative predictive values were 72.7%/64.0%, 70.0%/34.6%, and 54.0%/63.3% for IAPCG2017, HRS-main pancreatic duct, and HRS-nodule criteria, respectively. The 15 HRS-benign cases (18.8%) included 13 pancreatoduodenectomies and 10 cases of gastric pyloric (GP) gland subtype. Severe upstream atrophy was significantly related to IPMN malignancy, unlike the severe sclerosis of IPMN septa. CONCLUSIONS: Benign IPMNs of GP subtype are sometimes categorized as HRS with the IAPCG2017. Collecting data on the natural course of GP-IPMN is necessary. To evaluate upstream atrophy may be of value to predict IPMN malignancy.

doi: https://doi.org/10.1097/MPA.0000000000001487



- Intratumoral Fibrosis and Tumor Growth Pattern as Prognostic Factors in Optimally Resected Pancreatic Neuroendocrine Neoplasms: An Analysis of 168 Cases

Pancreas 2020 Jan;():

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=32011527

OBJECTIVES: Pancreatic neuroendocrine neoplasms (PanNENs) can recur after curative resection. We sought to establish the significance of tumor fibrosis and tumor growth pattern as predictors of recurrence-free survival and overall survival. METHODS: A retrospective query of an institutional surgical database was performed from 2000 to 2018 to identify optimally resected PanNENs. All eligible slides were reviewed by an experienced gastrointestinal pathologist for established histopathologic prognostic factors, as well as fibrosis and tumor growth pattern. We evaluated the effect of the interested variables through Cox proportional hazards models. RESULTS: One hundred sixty-eight cases were considered. The majority of patients (90%) had grade 1 or 2 tumors, 46% showed significant fibrosis, and 22% demonstrated an infiltrative growth pattern. Twenty-one percent of patients had a recurrence. In multivariable analysis, lymphovascular invasion with a hazard ratio (HR) of 5.1 and infiltrative growth pattern (HR, 2.8) were significantly associated with increased risk of recurrence and increased risk of death (HR, 3.6 and 2.7, respectively). There was a significant decrease in recurrence-free survival and overall survival for fibrosis and infiltrative growth pattern. CONCLUSIONS: In optimally resected PanNENs, the presence of fibrosis and infiltrative growth pattern are significant risk factors for recurrence and/or decreased survival.

doi: https://doi.org/10.1097/MPA.0000000000001478



- Prediction of the Probability of Malignancy in Mucinous Cystic Neoplasm of the Pancreas With Ovarian-Type Stroma: A Nationwide Multicenter Study in Japan

Pancreas 2020 Jan;():

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=32011526

OBJECTIVE: The aim of the study was to develop a formula for predicting the probability of malignancy of mucinous cystic neoplasm (MCN) of the pancreas with ovarian-type stroma. METHODS: A total of 364 patients were enrolled. A total score was calculated as the sum of the approximate integers of the odds ratios of the predictive factors identified by multivariate analysis. The relationship between the total score and pathological results was assessed. RESULTS: A total of 321 patients had benign MCN and 43 had malignant MCN. Five possible predictive factors were analyzed: 56 years or older, high serum carcinoembryonic antigen level, high carbohydrate antigen 19-9 level, tumor size of 51 mm or greater, and the presence of mural nodules. The total score was significantly higher in patients with malignant MCN (median = 24, range = 0-37) compared with benign MCN (median = 5, range = 0-33, P < 0.001). Receiver operating characteristic curve analysis demonstrated that the area under the curve was 0.86, and the sensitivity and specificity of the total score for discriminating malignant MCNs were 72% and 83%, respectively, using a cut-off value of 22. CONCLUSIONS: The current simple formula can predict the malignancy of MCN and may thus contribute to the adequate management of patients with MCN.

doi: https://doi.org/10.1097/MPA.0000000000001475



- CD109 promotes the tumorigenic ability and metastatic motility of pancreatic ductal adenocarcinoma cells

Pancreatology : official journal of the International Association of Pancreatology (IAP) … [et al.] 2020 Jan;():

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=32007357

BACKGROUND: Accumulating evidence indicates that CD109, a glycosylphosphatidylinositol-anchored glycoprotein, is highly expressed in human epithelial carcinomas of multiple organs including the pancreas, but its functional role in carcinoma development has not yet been fully clarified. The aim of this study was to investigate the role of CD109 in the malignancy of pancreatic ductal adenocarcinoma (PDAC). METHODS: PDAC specimens of 145 cases were immunostained for CD109, and correlations between CD109 expression and clinicopathological conditions were analyzed. CD109 expression in PANC-1 cells, a PDAC-derived cell line, was decreased by siRNA or shRNA and its effect on the malignancy of PANC-1 cells was examined. RESULTS: Suppression of CD109 expression in PANC-1 cells resulted in reduction of in vitro cell motility and tumorigenicity in xenografts. Based on these results, we investigated the relationship between CD109 expression and metastasis of PDAC using tumor tissue specimens. Among 106 recurrent cases of 145 PDAC, there was a tendency for CD109-positive cases to be accompanied by distant metastasis. CONCLUSIONS: CD109 plays a critical role in the promotion of tumorigenic ability and cellular motility relating to metastasis of PDAC cells.

doi: https://doi.org/10.1016/j.pan.2020.01.013



- Generation and characterization of a cell line from an intraductal tubulopapillary neoplasm of the pancreas

Laboratory investigation; a journal of technical methods and pathology 2020 Jan;():

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=32005909

Intraductal tubulopapillary neoplasm (ITPN) is a distinct precancerous lesion in the pancreas with unique clinical and molecular features. Although in vitro studies in two-dimensional culture have led to numerous important insights in pancreatic cancer, such models are currently lacking for precancerous lesions. In this study, we report the generation and characterization of a cell line from a human pancreatic ITPN. Neoplastic cells were initially cultured in a three-dimensional organoid system, followed by transfer to two-dimensional culture. RNA sequencing revealed a gene expression profile consistent with pancreatic ductal origin, and whole genome sequencing identified many somatic mutations (including in genes involved in DNA repair and Wnt signaling) and structural rearrangements. In vitro characterization of the tumorigenic potential demonstrated a phenotype between that of normal pancreatic ductal cells and cancer cell lines. This cell line represents a valuable resource for interrogation of unique ITPN biology, as well as precancerous pancreatic lesions more generally.

doi: https://doi.org/10.1038/s41374-020-0372-0



- PDAC-ANN: an artificial neural network to predict pancreatic ductal adenocarcinoma based on gene expression

BMC cancer 2020 Jan;20(1):82

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=32005189

BACKGROUND: Although the pancreatic ductal adenocarcinoma (PDAC) presents high mortality and metastatic potential, there is a lack of effective therapies and a low survival rate for this disease. This PDAC scenario urges new strategies for diagnosis, drug targets, and treatment. METHODS: We performed a gene expression microarray meta-analysis of the tumor against normal tissues in order to identify differentially expressed genes (DEG) shared among all datasets, named core-genes (CG). We confirmed the CG protein expression in pancreatic tissue through The Human Protein Atlas. It was selected five genes with the highest area under the curve (AUC) among these proteins with expression confirmed in the tumor group to train an artificial neural network (ANN) to classify samples. RESULTS: This microarray included 461 tumor and 187 normal samples. We identified a CG composed of 40 genes, 39 upregulated, and one downregulated. The upregulated CG included proteins and extracellular matrix receptors linked to actin cytoskeleton reorganization. With the Human Protein Atlas, we verified that fourteen genes of the CG are translated, with high or medium expression in most of the pancreatic tumor samples. To train our ANN, we selected the best genes (AHNAK2, KRT19, LAMB3, LAMC2, and S100P) to classify the samples based on AUC using mRNA expression. The network classified tumor samples with an f1-score of 0.83 for the normal samples and 0.88 for the PDAC samples, with an average of 0.86. The PDAC-ANN could classify the test samples with a sensitivity of 87.6 and specificity of 83.1. CONCLUSION: The gene expression meta-analysis and confirmation of the protein expression allow us to select five genes highly expressed PDAC samples. We could build a python script to classify the samples based on RNA expression. This software can be useful in the PDAC diagnosis.

doi: https://doi.org/10.1186/s12885-020-6533-0



- SUMO pathway inhibition targets an aggressive pancreatic cancer subtype

Gut 2020 Jan;():

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=32001555

OBJECTIVE: Pancreatic ductal adenocarcinoma (PDAC) still carries a dismal prognosis with an overall 5-year survival rate of 9%. Conventional combination chemotherapies are a clear advance in the treatment of PDAC; however, subtypes of the disease exist, which exhibit extensive resistance to such therapies. Genomic MYC amplifications represent a distinct subset of PDAC with an aggressive tumour biology. It is clear that hyperactivation of MYC generates dependencies that can be exploited therapeutically. The aim of the study was to find and to target MYC-associated dependencies. DESIGN: We analysed human PDAC gene expression datasets. Results were corroborated by the analysis of the small ubiquitin-like modifier (SUMO) pathway in a large PDAC cohort using immunohistochemistry. A SUMO inhibitor was used and characterised using human and murine two-dimensional, organoid and in vivo models of PDAC. RESULTS: We observed that MYC is connected to the SUMOylation machinery in PDAC. Components of the SUMO pathway characterise a PDAC subtype with a dismal prognosis and we provide evidence that hyperactivation of MYC is connected to an increased sensitivity to pharmacological SUMO inhibition. CONCLUSION: SUMO inhibitor-based therapies should be further developed for an aggressive PDAC subtype.

doi: https://doi.org/10.1136/gutjnl-2018-317856



- Prospective assessment of resection margin status following pancreaticoduodenectomy for pancreatic ductal adenocarcinoma after standardisation of margin definitions

Pancreatology : official journal of the International Association of Pancreatology (IAP) … [et al.] 2020 Jan;():

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31996296

BACKGROUND: Surgical resection remains the only curative treatment for pancreatic ductal adenocarcinoma (PDAC). The prognostic value of resection margin status following pancreatoduodenectomy (PD) remains controversial. Standardised pathological assessment increases positive margins but limited data is available on the significance of involved margins. We investigated the impact of resection margin status in PDAC on patient outcome. METHOD: We identified all patients with PD for PDAC at one pancreatic cancer centre between August 2008 and December 2014. Demographic, operative, adjuvant therapeutic and survival data was obtained. Pathology data including resection margin status of specific anatomic margins was collected and analysed. RESULTS: 107 patients were included, all pathologically staged as T3 with 102 N1. 87.9% of patients were R1 of which 53.3% showed direct extension to the resection margin. Median survival for R0 patients versus R1<1 mm and R1 = 0 mm was 28.4 versus 15.4 and 25.1 versus 13.4 months. R1 = 0 mm status remained a predictor of poor outcome on multivariate analysis. Evaluation of individual margins (R1<1 mm) showed the SMV and SMA margins were associated with poorer overall survival. Multiple involved margins impacted negatively on outcome. SMA margin patient outcome with R1 = 1-1.9 mm was similar to R1=>2 mm. CONCLUSION: Using an R1 definition of <1 mm and standardised pathology we demonstrate that R1 rates in PDAC can approach 90%. R1 = 0 mm remained an independent prognostic factor for overall survival. Using R1<1 mm we have shown that involvement of medial margins and multiple margins has significant negative impact on overall survival. We conclude that not all margin positivity has the same prognostic significance.

doi: https://doi.org/10.1016/j.pan.2020.01.004



- Predicted Prognosis of Pancreatic Cancer Patients by Machine Learning

Clinical cancer research : an official journal of the American Association for Cancer Research 2020 Jan;():

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31992588

PURPOSE: Pancreatic cancer remains a disease of high mortality despite advanced diagnostic techniques. Mucins (MUC) play crucial roles in carcinogenesis and tumor invasion in pancreatic cancers. MUC1 and MUC4 expression are related to the aggressive behavior of human neoplasms and a poor patient outcome. In contrast, MUC2 is a tumor suppressor, and we have previously reported that MUC2 is a favorable prognostic factor in pancreatic neoplasia. This study investigates whether the methylation status of three mucin genes from postoperative tissue specimens from patients with pancreatic neoplasms could serve as a predictive biomarker for outcome after surgery. EXPERIMENTAL DESIGN: We evaluated the methylation status of MUC1, MUC2, and MUC4 promoter regions in pancreatic tissue samples from 191 patients with various pancreatic lesions using methylation-specific electrophoresis. Then, integrating these results and clinicopathological features, we used support vector machine-, neural network-, and multinomial-based methods to develop a prognostic classifier. RESULTS: Significant differences were identified between the positive- and negative-prediction classifiers of patients in 5-year overall survival (OS) in the cross-validation test. Multivariate analysis revealed that these prognostic classifiers were independent prognostic factors analyzed by not only neoplastic tissues but also non-neoplastic tissues. These classifiers had higher predictive accuracy for OS than tumor size, lymph node metastasis, distant metastasis, and age and can complement the prognostic value of the TNM staging system. CONCLUSIONS: Analysis of epigenetic changes in mucin genes may be of diagnostic utility and one of the prognostic predictors for patients with pancreatic ductal adenocarcinoma.

doi: https://doi.org/10.1158/1078-0432.CCR-19-1247



- Insulinoma-associated protein 1 (INSM1) is a robust marker for identifying and grading pancreatic neuroendocrine tumors

Cancer cytopathology 2020 Jan;():

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31977134

BACKGROUND: Pancreatic neuroendocrine tumor (PNET) is a diagnostic challenge with limited samples in not only identification but grading. Prior studies have shown insulinoma-associated protein 1 (INSM1) to be a robust marker in identifying PNETs from other solid pancreatic tumors on resection specimens. In this study, we investigated the utility of INSM1 not only for identifying PNETs but also for grading in cell blocks (CBs) and surgical resections (SRs). METHODS: A search for PNET cases between 2000 and 2019 identified 55 samples (26 CBs and 29 SRs) that were further separated into high (2 CBs, 3 SRs), intermediate (4 CBs, 7 SRs), and low (20 CBs, 19 SRs) grades based on their final pathology report and Ki-67 level. Immunohistochemical (IHC) staining for INSM1 (C-8, Santa Cruz Biotechnology [1:100]) was performed and quantified using an H score of 0 to 300. Non-PNET solid pancreatic tumors were compared and included acinar cell carcinoma, solid pseudopapillary neoplasm, and ductal adenocarcinoma. RESULTS: All 55 cases of PNET demonstrated nuclear INSM1 staining. The average H scores for INSM1 staining of PNET were 254 and 252 in CB and SR, respectively. The H scores decreased with increasing tumor grade, with low-grade (G1), intermediate-grade (G2), and high-grade (G3) tumors showing average INSM1 H scores of 229 and 253, 266 and 253, and 30 and 33 in both CB and SR, respectively. CONCLUSION: IHC with INSM1 plays a role in identifying and potentially grading PNETs.

doi: https://doi.org/10.1002/cncy.22242



- Neuroendocrine carcinomas: Cytological mimics and diagnostic dilemmas

Diagnostic cytopathology 2020 Jan;():

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31976618

BACKGROUND: Neuroendocrine carcinomas (NEC) are rare tumours with multiple morphologic mimics. The cytologist may miss these cases if not aware. AIMS AND OBJECTS: We focused upon the clinical presentation, cytological features and problems in the diagnosis of NEC. MATERIALS AND METHODS: We studied the detailed cytomorphology of 19 cases of NEC (histopathology proved). RESULTS: Of these 19 cases of NEC, 15 cases constituted fine needle aspiration (FNA) specimens, one transbronchial needle aspiration specimen, two pleural fluid specimens and a single biliary brushing specimen. All of the FNA specimens were from extra-pulmonary sites (namely, breast, pancreas, liver and three lymph node FNAs). Eight of the 19 cases (42.1%) showed a significant disparity between cytological and histopathology diagnoses. The break-up of discordant diagnoses are of adenocarcinoma (three cases), Ewing’s sarcoma (one case), infiltrating ductal carcinoma (one case), lymphoma (one case), and squamous cell carcinoma (two cases). The cytology of NECs predominantly showed discrete, round to oval cells with a moderate amount of cytoplasm. The nuclei were pleomorphic, having prominent nucleoli. Occasional cases showed characteristic salt and pepper chromatin and were correctly diagnosed as a neuroendocrine group of tumours. CONCLUSION: The accurate diagnosis of NEC depends on clinical correlation, meticulous screening for any obvious neuroendocrine features and cell block morphology. Immunohistochemistry is essential for ruling out of tumours of neuroendocrine origin. A Ki67 index is mandatory for grading of all neuroendocrine tumours.

doi: https://doi.org/10.1002/dc.24386



- Microscopic Size Measurements Predict Outcomes in Post-Neoadjuvant Resections of Pancreatic Ductal Adenocarcinoma (PDAC)

Histopathology 2020 Jan;():

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31965618

BACKGROUND: Pancreatic ductal adenocarcinomas (PDACs) are increasingly treated with neoadjuvant therapy. However, the American Joint Committee on Cancer (AJCC) 8th Edition T staging based on tumor size does not reflect treatment effect, which often results in multiple, small foci of residual tumor in a background of mass-forming fibrosis. Thus, we evaluated the performance of AJCC 8th Edition T staging in predicting patient outcomes using a microscopic tumor size measurement method. METHODS AND RESULTS: 106 post-neoadjuvant therapy pancreatectomies were reviewed, and all individual tumor foci were measured. T stages based on gross size (GS) and the largest single microscopic focus size (MFS) were examined in association with clinicopathologic variables and patient outcomes. 63/106 (59%) were locally advanced; 78% received FOLFIRINOX treatment. Average GS and MFS were 2.5cm and 1.1cm, respectively; 9 cases each were classified as T0, 35 and 85 cases as T1, 42 and 12 cases as T2, and 20 and 0 cases as T3, based on the GS and MFS, respectively. Higher GS- and MFS-based T stages were significantly associated with higher tumor regression grade, lymphovascular and perineural invasion, and higher N stage. Furthermore, higher MFS-based T stage was significantly associated with shorter disease-free survival (DFS) (p<0.001) and shorter overall survival (OS) (p=0.002). GS was significantly associated with OS (p=0.046), but not with DFS. CONCLUSIONS: In post-neoadjuvant PDAC resections, MFS-based T staging is superior to GS-based T staging for predicting patient outcomes, suggesting that microscopic measurements have clinical utility beyond the conventional use of GS measurements alone.

doi: https://doi.org/10.1111/his.14067



- A four-chemokine signature is associated with a T cell-inflamed phenotype in primary and metastatic pancreatic cancer

Clinical cancer research : an official journal of the American Association for Cancer Research 2020 Jan;():

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31964786

PURPOSE: The molecular drivers of antitumor immunity in pancreatic ductal adenocarcinoma (PDAC) are poorly understood, posing a major obstacle for the identification of patients potentially amenable for immune checkpoint blockade or other novel strategies. Here, we explore the association of chemokine expression with effector T cell infiltration in PDAC. EXPERIMENTAL DESIGN: Discovery cohorts comprised 113 primary resected PDAC and 107 PDAC liver metastases. Validation cohorts comprised 182 PDAC from TCGA and 92 PDACs from the Australian ICGC. We explored associations between immune cell counts by immunohistochemistry, chemokine expression and transcriptional hallmarks of antitumor immunity by RNAseq, and mutational burden by whole genome sequencing. RESULTS: Among all known human chemokines, a coregulated set of four (CCL4, CCL5, CXCL9, CXCL10) was strongly associated with CD8+ T cell infiltration (p < 0.0001). Expression of this ‘4-chemokine signature’ positively correlated with transcriptional metrics of T cell activation (ZAP70, ITK, IL2RB), cytolytic activity (GZMA, PRF1), and immunosuppression (PD-L1, PD1, CTLA4, TIM3, TIGIT, LAG3, FASLG, IDO1). Furthermore, the 4-chemokine signature marked tumors with increased T cell activation scores (MHC I presentation, T cell/APC co-stimulation) and elevated expression of innate immune sensing pathways involved in T cell priming (STING and NLRP3 inflammasome pathways, BATF3-driven dendritic cells). Importantly, expression of this 4-chemokine signature was consistently indicative of a T cell-inflamed phenotype across primary PDAC and PDAC liver metastases. CONCLUSIONS: A conserved 4-chemokine signature marks resectable and metastatic PDAC tumors with an active antitumor phenotype. This could have implications for the appropriate selection of PDAC patients in immunotherapy trials.

doi: https://doi.org/10.1158/1078-0432.CCR-19-2803



- My approach to endoscopic ultrasound-guided fine-needle aspiration biopsy specimens of the pancreas

Journal of clinical pathology 2020 Jan;():

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31964682

Endoscopic ultrasound-guided fine-needle aspiration biopsy (EUS-FNAB) is the optimal method for sampling lesions of the pancreas. This procedure is being performed at increasing numbers of hospitals and therefore, more and more cellular pathology departments are having to process and report EUS-FNAB specimens. This article outlines the advantages of using tissue/cell block preparation to process these specimens. In particular, such preparation concentrates, conserves and preserves sampled material which is then available for a full array of further analyses. Tissue/cell block preparation also enables EUS-FNAB specimens to be assessed by a wider range of cellular pathologists. This article demonstrates how a tissue/cell block protocol permits the diagnosis of the full range of pancreatic pathologies sampled by EUS-FNAB. The protocol is identical for all these pathologies (including both solid and cystic lesions) and is simple at all stages of the specimen pathway, from collection to processing to assessment.

doi: https://doi.org/10.1136/jclinpath-2019-206331



- Spatial and phenotypic characterization of pancreatic cancer-associated fibroblasts after neoadjuvant treatment

Histology and histopathology 2020 Jan;():18201

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31960942

Pancreatic ductal adenocarcinoma (PC) is characterized by a highly fibrotic desmoplastic stroma. Subtypes of cancer-associated fibroblasts (CAFs) have been identified in chemotherapy-naïve PC (CTN-PC), but their precise functions are still unclear. Our knowledge regarding the properties of CAFs in the regressive stroma after neoadjuvant treatment (NAT) of PC (NAT-PC) is particularly limited. We aimed to examine the marker phenotypic properties of CAFs in the regressive stroma of PC. Surgical specimens from patients with CTN-PC (n=10) and NAT-PC (n=10) were included. Juxtatumoural, peripheral, lobular, septal, peripancreatic, and regressive stromal compartments were manually outlined using digital imaging analysis (DIA) for area quantification. The compartment-specific expression of CD271, cytoglobin, DOG-1, miR-21, osteonectin, PDGF-Rβ, and tenascin C was evaluated by immunohistochemistry or in situ hybridization, using manual scoring and automated DIA. The area fraction of the regressive stroma was significantly higher in NAT-PC than in CTN-PC (P=0.0002). CD271 (P<0.01), cytoglobin (P<0.05), DOG1 (P<0.05), miR-21 (P<0.05), and tenascin C (P<0.05) exhibited significant differences in their expression profiles between the juxtatumoural compared to the peripheral and regressive stroma. PDGF-Rβ expression was significantly higher in juxtatumoural than in peripheral CAFs (P<0.05). Our data provide further support of the concept of stromal heterogeneity and phenotypic different CAF subtypes in PC. CAFs in the regressive stroma of NAT-PC show a marker phenotype similar to some (namely, peripheral) and different from other (namely, juxtatumoural) previously defined CAF subtypes. It may be hypothesized that phenotypic CAF subtypes, at least in part, also may share functional properties. Studies examining the precise functional characteristics of CAF subtypes in PC are needed.

doi: https://doi.org/10.14670/HH-18-201



- Pancreatic Solid Pseudopapillary Neoplasm: Key Pathologic and Genetic Features

Archives of pathology & laboratory medicine 2020 Jan;():

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31958381

CONTEXT.—: Solid pseudopapillary neoplasm of the pancreas is a low-grade malignant tumor generally associated with a good prognosis. Solid pseudopapillary neoplasms show peculiar morphologic features, but sometimes the differential diagnosis with other pancreatic neoplasms (ie, pancreatic neuroendocrine tumors) can be a challenging task, especially in cytologic or biopsy specimens. In these cases immunohistochemistry is a useful tool, but the diagnostic utility of several proposed immunohistochemical markers is questionable. In recent years, despite several attempts to characterize the pathogenetic, molecular, and prognostic features of solid pseudopapillary neoplasms, they still remain unclear. OBJECTIVE.—: To give the reader a comprehensive update on this entity. DATA SOURCES.—: The PubMed database (US National Library of Medicine) was searched using the following string: pseudopapillary tumor [AND/OR] neoplasm [AND/OR] pancreas. All articles written in English were included. In addition, because a heterogeneous terminology has been used in the past to define solid pseudopapillary neoplasms, the reference lists of each paper selected in the PubMed database were also reviewed. CONCLUSIONS.—: This review gives a comprehensive update on the pathologic, clinical, and molecular features of SPNs, particularly addressing issues and challenges related to diagnosis. In addition, we have tried to correlate the molecular alterations with the morphologic and clinical features.

doi: https://doi.org/10.5858/arpa.2019-0473-RA



- miR-431 Promotes Metastasis of Pancreatic Neuroendocrine Tumors by Targeting DAB2 Interacting Protein, a Ras GTPase Activating Protein Tumor Suppressor

The American journal of pathology 2020 Jan;():

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31953039

The incidence of pancreatic neuroendocrine tumor (PNET) is increasing, and it presents with various clinical manifestations and an unfavorable survival rate. A better understanding of the drivers of PNET tumorigenesis is urgently needed. Distinct miRNA signatures have been identified for different stages of tumorigenesis in both human and mouse PNETs. The functions of these miRNAs are poorly understood. miR431 is the most up-regulated miRNA in the metastatic signature. However, it is unknown whether miR431 contributes to metastasis of PNETs. Herein, we show that miR431 overexpression activates Ras/extracellular signal-regulated kinase (Erk) signaling and promotes epithelial-mesenchymal transition, migration/invasion in vitro, and metastasis in both xenograft and spontaneous mouse models of PNET. Treatment of PNET cells with Erk inhibitor or locked nucleic acids sequestering miR431 inhibits invasion. Four target prediction modules and dual-luciferase reporter assays were used to identify potential mRNA targets of miR431. A Ras GTPase activating protein tumor suppressor, DAB2 interacting protein (DAB2IP), was discovered as an miR431 target. Overexpression of DAB2IP’s rat homolog DIP, but not its mutant defective in Ras GTPase activating protein activity, reverses miR431’s effect on promoting invasion, Erk phosphorylation, and epithelial-mesenchymal transition of PNETs. Taken together, miR431 silences DAB2IP to active Ras/Erk and promote metastasis of PNETs. miR431 may be targeted to manage metastatic PNETs.

doi: https://doi.org/10.1016/j.ajpath.2019.11.007



- Gene Expression Signatures Identify Novel Therapeutics for Metastatic Pancreatic Neuroendocrine Tumors

Clinical cancer research : an official journal of the American Association for Cancer Research 2020 Jan;():

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31937620

PURPOSE: Pancreatic neuroendocrine tumors (pNETs) are uncommon malignancies noted for their propensity to metastasize and comparatively favorable prognosis. Although both the treatment options and clinical outcomes have improved in the last decades, most patients will die of metastatic disease. New systemic therapies are needed. EXPERIMENTAL DESIGN: Tissues were obtained from 43 patients with well-differentiated pNETs undergoing surgery. Gene expression was compared between primary tumors versus liver and lymph node metastases using RNA-Seq. Genes that were selectively elevated at only one metastatic site were filtered out to reduce tissue-specific effects. Ingenuity Pathway Analysis (IPA) and the Connectivity Map (CMap) identified drugs likely to antagonize metastasis-specific targets. The biological activity of top identified agents was tested in vitro using two pNET cell lines (BON-1 and QGP-1). RESULTS: 902 genes were differentially expressed in pNET metastases compared to primary tumors, 626 of which remained in the common metastatic profile after filtering. Analysis with IPA and CMap revealed altered activity of factors involved in survival and proliferation, and identified drugs targeting those pathways, including inhibitors of mTOR, PI3K, MEK, TOP2A, PKC, NF-kB, CDK and HDAC. Inhibitors of MEK and TOP2A were consistently the most active compounds. CONCLUSIONS: We employed a complementary bioinformatics approach to identify novel therapeutics for pNETs by analyzing gene expression in metastatic tumors. The potential utility of these drugs was confirmed by in vitro cytotoxicity assays, suggesting drugs targeting MEK and TOP2A may be highly efficacious against metastatic pNETs. This is a promising strategy for discovering more effective treatments for pNET patients.

doi: https://doi.org/10.1158/1078-0432.CCR-19-2884



- P53, Somatostatin receptor 2a and Chromogranin A immunostaining as prognostic markers in high grade gastroenteropancreatic neuroendocrine neoplasms

BMC cancer 2020 Jan;20(1):27

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31924180

BACKGROUND: High grade gastroenteropancreatic (GEP) neuroendocrine neoplasms (NEN) with a Ki67 proliferation index > 20%, include well-differentiated tumours grade 3 (NET G3) and poorly differentiated (PD) neuroendocrine carcinomas (NEC). Abnormal p53-expression is a feature of PD tumours, while expression of chromogranin A (CgA) and somatostatin-receptor 2a (SSTR-2a) may be a feature of well-differentiated tumours. The aim of this study was to elucidate the expression and prognostic value of these three markers in 163 GEP-NEN patients with a Ki67-index > 20%. METHOD: Clinical data, histopathology and overall survival were analysed according to Kaplan-Meier’s method and Cox regression. The expression of SSTR-2a, CgA and synaptophysin was analysed in tumour specimens by immunohistochemistry, and semi-quantitatively scored as negative (< 5%), heterogeneously positive (5-30%) or strongly positive (> 30%). P53 was defined as normal when scored as heterogeneously positive (1-30%), and abnormal when negative (0%) or strongly positive (> 30%). RESULTS: In multivariate analysis, better survival was observed among patients with heterogeneously positive p53 compared to strongly positive (p < 0.001). When dichotomised, tumours with a heterogeneously positive p53 vs. negative and strongly positive p53 also showed a significantly better survival (p = 0.002). Survival was significantly worse for negative CgA compared to heterogeneously positive CgA (p = 0.02). Strongly positive SSTR-2a expression was found in 26% of the 163 included patients. Well-differentiated morphology correlated with strong expression of SSTR-2a and CgA, and heterogeneously positive p53-staining, and was more frequent in pancreatic primaries. In pancreatic primaries, strongly positive SSTR-2a was associated with longer survival (univariate analysis, p = 0.02). A significantly lower Ki67 proliferation index was found in patients with a heterogeneously positive p53, a positive SSTR-2a and CgA expression. CONCLUSION: Our results suggest that abnormal p53-expression is an independent negative prognostic marker in GEP-NEN with a Ki67-index > 20%. Patients with heterogeneously positive p53 had the best prognosis. SSTR-2a was a positive prognostic marker in pancreatic NEN. Negative CgA was associated with a significantly worse OS compared to heterogeneously positive CgA-expression in a multivariate sub-analysis. Lower Ki67 index correlated significantly with heterogeneously positive p53, positive SSTR-2a and CgA expression.

doi: https://doi.org/10.1186/s12885-019-6498-z



- Neuroendocrine carcinoma diagnosis from bile duct cytological specimens: A retrospective single-center study

Diagnostic cytopathology 2020 Feb;48(2):154-158

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31697402

Neuroendocrine carcinoma (NEC) in the extrahepatic bile duct is extremely rare and clinically aggressive. Cytological examination of bile and/or bile duct brushing specimens plays an important role in the diagnosis of carcinoma of the extrahepatic bile duct, but only a few articles have described the cytological features of NEC in this area. Thus, we retrospectively analyzed the cytological features of NEC in bile and/or bile duct brushing specimens. Patients with a histopathological diagnosis of NEC who underwent bile and/or bile duct brush cytological examination were enrolled in this study. The cytological features, including the background, arrangement, and shape of the neoplastic cells, and nuclear and cytoplasmic features were reviewed. Six patients with small cell NEC were enrolled, and two of them had pancreatic tumors directly invading the bile duct wall. The cytological specimens showed small and/or large neoplastic cell clusters with occasional single cells in all cases. The neoplastic cells had a high nuclear/cytoplasmic ratio and round-to-oval nuclei with powdery chromatin, inconspicuous nucleoli, and scant cytoplasm. Nuclear molding was a characteristic finding in all cases. One case had an adenocarcinoma component, which was also present in the cytological specimen. Cytological examination of bile and/or bile duct brushing specimens can be useful for the diagnosis of small cell NEC. This is an extremely rare but aggressive carcinoma, and its diagnosis by identifying characteristic cytological features may facilitate early detection and treatment.

doi: https://doi.org/10.1002/dc.24334



- Impact of CD36 on Chemoresistance in Pancreatic Ductal Adenocarcinoma

Annals of surgical oncology 2020 Feb;27(2):610-619

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31605325

BACKGROUND: CD36, a multi-ligand scavenger receptor, has been associated with several cancers. Many studies have revealed that CD36 contributed to cancer malignancy. This study aimed to reveal the function of CD36 expression in pancreatic ductal adenocarcinoma (PDAC). METHODS: CD36 expression was characterized using immunohistochemistry in 95 clinical specimens resected from patients with PDAC. We divided patients into two groups, with different CD36 expression levels, and analyzed and compared their prognoses. CD36 expression was also assessed in PDAC cell lines. Gemcitabine-resistant (GR) PDAC cell lines were transfected with small interfering RNA (siRNA) that specifically targeted CD36 to evaluate chemoresistance and apoptosis. RESULTS: In resected PDAC samples, CD36 expression was significantly correlated with microinvasion into the venous system (p = 0.0284). Patients with high CD36 expression had significantly lower overall survival (OS) and recurrence-free survival (RFS) rates than patients with low expression; thus, CD36 was an independent prognostic factor for OS and RFS. In subgroup analyses, CD36 was an independent risk factor for OS and RFS in 59 patients treated with gemcitabine adjuvant chemotherapy. CD36 expression was upregulated in PDAC-GR cell lines compared with the PDAC parent cell line. Transduction with siRNA downregulated CD36, which reduced PDAC cell resistance to gemcitabine and inhibited anti-apoptosis proteins. CONCLUSION: CD36 expression influenced gemcitabine resistance by regulating anti-apoptosis proteins. High CD36 expression was a significant, unfavorable prognostic factor in PDAC. Anti-CD36 treatment might serve as an optional treatment for lowering resistance to gemcitabine.

doi: https://doi.org/10.1245/s10434-019-07927-2



- Elucidating the roles of ASPM isoforms reveals a novel prognostic marker for pancreatic cancer

The Journal of pathology 2020 Feb;250(2):123-125

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31595972

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers worldwide. Late diagnosis, desmoplastic tissue and intrinsic resistance to therapy are among the main reasons for its aggressive phenotype. In addition, it is now appreciated that cancer stem cells - a rare subpopulation of tumor cells highly resistant to therapy - are crucial players in PDAC initiation, progression and resistance to therapy. In a recent article in The Journal of Pathology, Hsu et al elucidated the specific roles of abnormal spindle-like, microcephaly-associated protein (ASPM) isoforms in PDAC. The authors reported that ASPM isoform I (ASPM-iI) is mainly expressed in the cytoplasm of PDAC cells. Its expression is associated with the Wnt signaling pathway, which promotes stemness and maintains the cancer stem cell niche. Clinically, expression of ASPM-iI correlates with poor survival in PDAC patients. Thus, this study revealed a novel prognostic marker as well as a potential therapeutic target for PDAC. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

doi: https://doi.org/10.1002/path.5355



- Cell block processing is optimal for assessing endoscopic ultrasound fine needle aspiration specimens of pancreatic mucinous cysts

Journal of clinical pathology 2020 Feb;73(2):102-106

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31462450

AIMS: The cell block technique for assessing endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) specimens from pancreatic mucinous cystic lesions (MCLs) was systematically evaluated for the first time, including comparisons with three traditional methods of assessing such specimens. METHODS: The prospective arm comprised EUS-FNA specimens from EUS-suspected pancreatic MCLs. The retrospective arm comprised EUS-FNA specimens from pancreatic MCLs surgically resected before the study start. For each specimen, these data points were collected: macroscopic likelihood of mucin, cyst fluid carcinoembryonic antigen (CEA) level and presence of mucin in air-dried, direct smears and in cell block preparations. RESULTS: The prospective and retrospective arms of the study comprised 80 and 30 EUS-FNA specimens, respectively. Seven prospective cases led to surgical resections during the study, and therefore, 37 EUS-FNA specimens were confirmed to have originated from MCLs. In the prospective arm, macroscopic mucin was suspected, cyst fluid CEA level exceeded 192 ng/mL, mucin was detected in direct smears and cell block preparations in 78%, 30%, 39% and 73% of cases, respectively. Of the 37 specimens confirmed to originate from MCLs, macroscopic mucin assessment, cyst fluid CEA level, direct smear mucin assessment and cell block mucin assessment had sensitivities for diagnosing MCL of 87%, 45%, 45% and 81%, respectively. CONCLUSIONS: Cell block preparations are as likely to identify mucin from pancreatic MCLs as macroscopic assessment but are twice as likely to diagnose MCL than direct smears and fluid CEA biochemistry. The cell block technique is easy for sample collection and processing especially because these are identical for solid and cystic pancreatic lesions.

doi: https://doi.org/10.1136/jclinpath-2019-206079



- Morphological classification of pancreatic ductal adenocarcinoma that predicts molecular subtypes and correlates with clinical outcome

Gut 2020 02;69(2):317-328

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31201285

INTRODUCTION: Transcriptional analyses have identified several distinct molecular subtypes in pancreatic ductal adenocarcinoma (PDAC) that have prognostic and potential therapeutic significance. However, to date, an indepth, clinicomorphological correlation of these molecular subtypes has not been performed. We sought to identify specific morphological patterns to compare with known molecular subtypes, interrogate their biological significance, and furthermore reappraise the current grading system in PDAC. DESIGN: We first assessed 86 primary, chemotherapy-naive PDAC resection specimens with matched RNA-Seq data for specific, reproducible morphological patterns. Differential expression was applied to the gene expression data using the morphological features. We next compared the differentially expressed gene signatures with previously published molecular subtypes. Overall survival (OS) was correlated with the morphological and molecular subtypes. RESULTS: We identified four morphological patterns that segregated into two components (‘gland forming’ and ‘non-gland forming’) based on the presence/absence of well-formed glands. A morphological cut-off (≥40% ‘non-gland forming’) was established using RNA-Seq data, which identified two groups (A and B) with gene signatures that correlated with known molecular subtypes. There was a significant difference in OS between the groups. The morphological groups remained significantly prognostic within cancers that were moderately differentiated and classified as ‘classical’ using RNA-Seq. CONCLUSION: Our study has demonstrated that PDACs can be morphologically classified into distinct and biologically relevant categories which predict known molecular subtypes. These results provide the basis for an improved taxonomy of PDAC, which may lend itself to future treatment strategies and the development of deep learning models.

doi: https://doi.org/10.1136/gutjnl-2019-318217



- Endoscopic ultrasound-guided tissue acquisition of solid mass lesions of the pancreas: A retrospective comparison study of fine-needle aspiration and fine-needle biopsy

Diagnostic cytopathology 2020 Jan;():

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31903736

BACKGROUND: Although endoscopic ultrasound guided fine-needle biopsy (EUS-FNB) has emerged as an alternative to fine-needle aspiration (FNA) for the sampling of solid pancreatic mass lesions, it remains unclear which method is more effective. We compared the diagnostic yields of FNA, FNB, and combined FNA/FNB at a tertiary care institution. METHODS: Specimens from EUS-FNA (04/2014-08/2017) and EUS-FNB (10/2015-08/2017) with SharkCore needle of pancreatic solid mass lesions were retrieved. Clinical, radiologic, and pathologic data was recorded. Pathology results of malignancy/neoplasms with uncertain malignant potential were considered as true positive. The “negative” cases included were with ≥6 months of follow-up. Nondiagnostic cases showed unremarkable pancreatic tissue, nonpancreatic elements, atypia, or features suspicious for malignancy. Diagnostic yield was defined as percentage of lesions sampled in which a benign or malignant tissue diagnosis, as defined above, was obtained. Statistical comparisons were performed using Fisher’s exact test and univariable and multivariable logistic regression analysis. RESULTS: The study cohort included 76 FNA only cases, 88 FNB only cases, and 40 combined FNA/FNB cases. Diagnostic yields were 70% (FNA), 70% (FNB), and 83% (FNA/FNB), which were not statistically different. Increase in lesion size and presence of ROSE were significantly associated with a diagnostic outcome on both univariable and multivariable analysis, unlike the number of passes. CONCLUSION: Our results demonstrate that for solid pancreatic lesions, the diagnostic yields of FNA, FNB, and combined FNA and FNB are comparable. Presence of ROSE and increasing lesion size increased the diagnostic yield while the number of passes had no significant impact.

doi: https://doi.org/10.1002/dc.24377



- Metastatic leiomyosarcoma pancreas diagnosed on endoscopic ultrasound guided fine needle aspiration - A report of two cases with review of spindle cell lesions of pancreas

Cytopathology : official journal of the British Society for Clinical Cytology 2020 Jan;():

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31900985

Metastatic tumors of pancreas are rare accounting for 3-11% of all malignancies in pancreas seen at autopsy.1  The commonest metastatic tumors include renal cell carcinoma, malignant melanoma and colorectal carcinoma. Leiomyosarcomas (LMS) rarely metastasize to pancreas with few cases reported in literature.2  Majority of these reports are based on histopathologic diagnosis following surgical exploration. However, the role of endoscopic ultrasound guided fine needle aspiration (EUS FNA) in preoperative diagnosis of metastatic LMS in pancreas has not been fully elucidated. We report two cases of metastatic LMS diagnosed on EUS FNA. Moreover, spindle cell lesions (SCL) of pancreas are rare encompassing a wide variety of lesions. This article also reviews various SCL of pancreas reported in literature along with diagnostic features and pitfalls associated with them.

doi: https://doi.org/10.1111/cyt.12797



- Proposal for a definition of “Oligometastatic disease in pancreatic cancer”

BMC cancer 2019 Dec;19(1):1261

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31888547

BACKGROUND: To date, patients with metastasized pancreatic ductal adenocarcinoma (PDAC M1) are regarded as a uniform collective. We hypothesize the existence of oligometastatic disease (OMD): a state of PDAC M1 disease with better tumor biology, limited metastasis, and increased survival. METHODS: Data of 128 PDAC M1 patients treated at the University of Cologne between 2008 and 2018 was reviewed. Interdependence between clinical parameter was calculated using the Mann-Whitney U-Test. Survival curves were generated using the Kaplan-Meier method and analyzed using the log-rank test. RESULTS: Eighty-one (63%) patients had metastases confined to one organ (single organ metastasis, SOG) whereas the remaining 47 (37%) showed multiple metastatic sites (multi-organ metastasis, MOG). Survival analysis revealed a median overall survival (OS) of 12.2 months for SOG vs 4.5 months for MOG (95% CI 5.7-9.8; p < 0.001). We defined limited disease by the presence of ≤4 metastases in liver or lung. Limited disease together with CA 19-9 baseline < 1000 U/ml and response or stable disease after first-line chemotherapy defined OMD. We identified 8 patients with hepatic metastases and 2 with pulmonary metastases matching all OMD criteria. This group of 10 (7.8%) had a median overall survival of 19.4 vs 7.2 months compared to the remaining patients (95% CI 5.7-9.8; p = 0.009). CONCLUSION: We propose a definition of oligometastatic disease in PDAC including anatomical criteria and biological criteria reflecting better tumor biology. The 10 OMD patients (7.8%) survived significantly longer and might even benefit from surgical resection in the future.

doi: https://doi.org/10.1186/s12885-019-6448-9



- The North American Neuroendocrine Tumor Society Consensus Paper on the Surgical Management of Pancreatic Neuroendocrine Tumors

Pancreas 2020 Jan;49(1):1-33

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31856076

This manuscript is the result of the North American Neuroendocrine Tumor Society consensus conference on the surgical management of pancreatic neuroendocrine tumors from July 19 to 20, 2018. The group reviewed a series of questions of specific interest to surgeons taking care of patients with pancreatic neuroendocrine tumors, and for each, the available literature was reviewed. What follows are these reviews for each question followed by recommendations of the panel.

doi: https://doi.org/10.1097/MPA.0000000000001454



- Update on risk stratification in the Papanicolaou Society of Cytopathology System for Reporting Pancreaticobiliary Cytology categories: 3-Year, prospective, single-institution experience

Cancer cytopathology 2020 Jan;128(1):29-35

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31722125

BACKGROUND: Risk stratification is a critical element for the successful implementation of cytopathology reporting systems. To the authors’ knowledge, there are limited prior studies regarding risk stratification for The Papanicolaou Society of Cytopathology System for Reporting Pancreaticobiliary Cytology (PSCPC). In the current study, the authors reported on a single-institution experience on 3-year prospective PSCPC regarding risk of malignancy (ROM) and the overall risk of malignancy (OROM). METHODS: A computerized search was performed from August 2014 to December 2017 for all pancreatic fine-needle aspiration (FNA) samples. Pathology from surgical resections and biopsies and relevant radiologic and clinical follow-up data were collected. The ROM and the OROM were calculated. The OROM was based on the total number of FNA samples in each category. RESULTS: A total of 1017 pancreatic FNA cases were identified, with surgical and/or clinical follow-up data available for 548 cases. The cytopathologic diagnoses included 242 nondiagnostic (category I), 162 benign (category II), 142 atypical (category III), 20 neoplastic-benign (category IV: benign), 133 neoplastic-other (category IV: other), 28 suspicious (category V), and 290 malignant (category VI) cases. A total of 364 malignancies were documented in 11 cases, 4 cases, 36 cases, 0 cases, 36 cases, 21 cases, and 255 cases, respectively, from categories I, II, III, IV: benign, IV:other, V, and VI. The ROM was 25%, 17.4%, 41.8%, 0%, 34.3% (95.2%), 95.5%, and 99.6%, respectively, and the OROM was 4.5%, 2.5%, 25.3%, 0%, 27.1% (83.3%), 75%, and 87.9%, respectively, for categories I, II, III, IV: benign, IV: other (with high-grade dysplasia), V, and VI. CONCLUSIONS: The true ROM for PSCPC is likely between the ROM and OROM for the benign and indeterminate categories. In the neoplastic-other category (category IV: other), identifying high-grade dysplasia is important for its association with malignancy and a higher ROM.

doi: https://doi.org/10.1002/cncy.22199



- Cystic Lesions of the Pancreas: Differential Diagnosis and Cytologic-Histologic Correlation

Archives of pathology & laboratory medicine 2020 Jan;144(1):47-61

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31538798

CONTEXT.—: Pancreatic cystic lesions (PCLs) are very common, and their detection is increasing with the advances in imaging techniques. Because of the major implications for management, distinguishing between neoplastic and nonneoplastic PCLs is critical. Neoplastic cysts with potential to progress into cancer include mucinous PCLs (intraductal papillary mucinous neoplasms and mucinous cystic neoplasms) and nonmucinous cysts (solid pseudopapillary tumors, serous cystic neoplasms, and neuroendocrine tumors with cystic degeneration). Nonneoplastic cysts with no risk of malignant transformation include pseudocysts, retention cysts, lymphoepithelial cysts, cystic pancreatic lymphangioma, and duplication cyst/ciliated foregut cysts. The role of endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) cytology with cyst fluid analysis in the diagnosis of PCLs has evolved during the last decade; however, a definitive diagnosis on cytologic specimens is hampered by the sparse cellularity and can be challenging. EUS-FNA can play an important role to differentiate low-risk from high-risk pancreatic cysts and to distinguish between patients with cysts who need clinical follow-up versus those who require surgery. OBJECTIVE.—: To provide an integrative approach to diagnose pancreatic cystic lesions using EUS-FNA cytology and cyst fluid analysis, along with clinical, radiologic, histologic, genetic, and molecular characteristics. DATA SOURCES.—: The review and analysis of the latest literature describing pancreatic cystic lesions. CONCLUSIONS.—: Accurate diagnosis of PCLs requires a multidisciplinary and multimodal team approach, including the integration of clinical findings, imaging, cytology, cyst fluid analysis, and molecular testing.

doi: https://doi.org/10.5858/arpa.2019-0308-RA



- Role of Ancillary Testing on Endoscopic US-Guided Fine Needle Aspiration Samples from Cystic Pancreatic Neoplasms

Acta cytologica 2020 09;64(1-2):124-135

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31509835

Pancreatic cysts are increasingly detected on imaging studies. Accurate determination of the cyst type is important to provide appropriate care for the patients. It is also very clear that not one single modality can provide adequate diagnostic information. A multidisciplinary approach is the key to the diagnosis of pancreatic cysts. In this setting, the role of ancillary testing, which includes biochemical testing (carcinoembryonic antigen and amylase levels in the cyst), molecular testing (e.g., KRAS, GNAS, VHL, and CTNB1), and/or immunohistochemical tests are very important to obtain an accurate diagnosis. This review will discuss helpful ancillary tests in common pancreatic cyst neoplasms and how to approach the diagnosis of pancreatic cysts.

doi: https://doi.org/10.1159/000502372



- Grading Pancreatic Neuroendocrine Tumors by Ki-67 Index Evaluated on Fine-Needle Aspiration Cell Block Material

American journal of clinical pathology 2020 Jan;153(1):74-81

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31415691

OBJECTIVES: This study aimed to determine whether Ki-67 index evaluated on cytologic material could reliably grade pancreatic neuroendocrine tumors (PanNETs). METHODS: Cases with adequate cell block and available surgical specimens were included. Ki-67 index was calculated using “eyeballing,” “hot spot,” and “complete” counting methods. RESULTS: The overall concordance rates between cytology and surgical specimens were 71%, 73%, and 59%, respectively, by using eyeballing, hot spot, and complete counting approaches. All grade 1 tumors were correctly graded on cytology, but in grade 2 tumors concordance rates were only 36%, 41%, and 9%, respectively. All grade 2 tumors were undergraded when cell blocks contained fewer than 1,000 cells, while concordance rate increased to 57%, 64%, and 14%, respectively, in cases with 1,000 cells or more. CONCLUSIONS: Grade 2 PanNETs can be significantly undergraded when Ki-67 index is evaluated on cell block material. In cases with 1,000 or more cells, the hot spot counting method has better correlation with surgical specimens.

doi: https://doi.org/10.1093/ajcp/aqz110



- The expression of versican and its role in pancreatic neuroendocrine tumors

Pancreatology : official journal of the International Association of Pancreatology (IAP) … [et al.] 2020 Jan;20(1):142-147

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31771905

BACKGROUND: Pancreatic neuroendocrine tumors (pNET) are rare and heterogeneous. New biomarkers are needed for better predicting the prognosis and for providing individualized treatment. Versican (VCAN) plays an important role in tumorigenesis. Therefore, we plan to investigate the role of VCAN in pNET prognosis. METHOD: The clinical and pathological data of pNET patients who underwent surgery between 2005 and 2010 were collected and evaluated. Radiologic tumor assessments with contrast computed tomography or magnetic resonance imaging were performed at baseline and follow up. The radiologic response was classified according to the RECIST 1.1 criteria. VCAN expression was assessed by immunohistochemical staining (IHC). RESULT: Among 155 pNET patients, 112 (72.3%) pNET patients were VCAN positive, and 43 (27.7%) were negative. Positive expression of VCAN in pNET was significantly associated with a longer disease-free survival (DFS) compared with VCAN negative pNET (p = 0.038, HR 0.462, 95% CI 0.218-0.978). Subgroup analysis showed that VCAN positive expression was associated with a longer DFS in the G1 subgroup (p = 0.031, HR 0.124, 95% CI 0.013-1.193), the tumor size>2 cm subgroup (p = 0.047, HR 0.458, 95% CI 0.207-1.012) and the NF-pNET subgroup (p = 0.003, HR 0.274, 95% CI 0.112-0.673). Multivariable analysis showed that VCAN negative expression, G2 and tumor size>2 cm were independent factors of poor prognosis of pNET (p = 0.041, p < 0.001, p = 0.008, respectively). CONCLUSION: Our data indicate that VCAN positive expression may serve as an independent factor of predicting DFS in pNET; its expression in pNET tissues was correlated with a longer DFS.

doi: https://doi.org/10.1016/j.pan.2019.11.009



- Recurrent Rearrangements in PRKACA and PRKACB in Intraductal Oncocytic Papillary Neoplasms of the Pancreas and��Bile Duct

Gastroenterology 2020 Feb;158(3):573-582.e2

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31678302

BACKGROUND & AIMS: Intraductal oncocytic papillary neoplasms (IOPNs) of the pancreas and bile duct contain epithelial cells with numerous, large mitochondria and are cystic precursors to pancreatic ductal adenocarcinoma (PDAC) and cholangiocarcinoma (CCA), respectively. However, IOPNs do not have the genomic alterations found in other pancreatobiliary neoplasms. In fact, no recurrent genomic alterations have been described in IOPNs. PDACs without activating mutations in KRAS contain gene rearrangements, so we investigated whether IOPNs have recurrent fusions in genes. METHODS: We analyzed 20 resected pancreatic IOPNs and 3 resected biliary IOPNs using a broad RNA-based targeted sequencing panel to detect cancer-related fusion genes. Four invasive PDACs and 2 intrahepatic CCAs from the same patients as the IOPNs, were also available for analysis. Samples of pancreatic cyst fluid (n = 5, collected before surgery) and bile duct brushings (n = 2) were analyzed for translocations. For comparison, we analyzed pancreatobiliary lesions from 126 patients without IOPN (controls). RESULTS: All IOPNs evaluated were found to have recurring fusions of ATP1B1-PRKACB (n = 13), DNAJB1-PRKACA (n = 6), or ATP1B1-PRKACA (n = 4). These fusions also were found in corresponding invasive PDACs and intrahepatic CCAs, as well as in matched pancreatic cyst fluid and bile duct brushings. These gene rearrangements were absent from all 126 control pancreatobiliary lesions. CONCLUSIONS: We identified fusions in PRKACA and PRKACB genes in pancreatic and biliary IOPNs, as well as in PDACs and pancreatic cyst fluid and bile duct cells from the same patients. We did not identify these gene fusions in 126 control pancreatobiliary lesions. These fusions might be used to identify patients at risk for IOPNs and their associated invasive carcinomas.

doi: https://doi.org/10.1053/j.gastro.2019.10.028



- Pancreatic stone protein - sepsis and the riddles of the exocrine pancreas

Pancreatology : official journal of the International Association of Pancreatology (IAP) … [et al.] 2020 Feb;():

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=32037128

Pancreatic stone protein (PSP), discovered in the 1970ies, was first associated with stone formation during chronic pancreatitis. Later, the same protein was independently detected in islet preparations and named regenerating protein 1 (REG1). Additional isoforms of PSP, including pancreatitis-associated protein (PAP), belong to the same protein family. Although the names indicate a potential function in stone formation or islet regeneration, involvements in cellular processes were only suggestive and never unequivocally proven. We established an association between PSP levels in patient blood samples and the development of sepsis. In this review, written in connection with receiving the Lifetime Achievement Award of the European Pancreatic Club, the evolution of the sepsis aspect of PSP is described. We conclude that the true functional properties of this fascinating pancreatic protein still remain an enigma.

doi: https://doi.org/10.1016/j.pan.2020.01.016



- Long-term outcomes and significance of preoperative lymphocyte-to-monocyte ratio as a prognostic indicator in patients with invasive pancreatic neoplasms after repeat pancreatectomy

BMC cancer 2020 Feb;20(1):111

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=32041563

BACKGROUND: Invasive pancreatic neoplasms have a high propensity for recurrence even after curative resection. Recently, patients who underwent pancreatectomy have an opportunity of undergoing secondary pancreatic resection, so-called “repeat pancreatectomy” to achieve curative operation and prolong their survival. We evaluated the long-term clinical outcomes and identified the prognostic factors, including systemic inflammation markers and the lymphocyte-to-monocyte ratio (LMR) of patients who underwent repeat pancreatectomy for invasive pancreatic tumors. METHODS: Twenty-eight consecutive patients with invasive pancreatic neoplasms (22 pancreatic ductal adenocarcinomas, 2 pancreatic acinar cell carcinomas, and 4 invasive intra-papillary mucinous carcinomas) with isolated local recurrence only in the remnant pancreas were analyzed retrospectively. To identify factors for the selection of optimal patients who should undergo repeat pancreatectomy, perioperative clinical parameters were analyzed by Cox proportional regression models. RESULTS: Of 28 patients, 12 patients experienced recurrence within 3 years after repeat pancreatectomy. Kaplan-Meier analysis showed that the median cancer-specific overall survival time of patients with invasive pancreatic neoplasms was 61 months, showing favorable outcomes. High preoperative LMR (LMR ≥ 3.3) (p = 0.022), no portal vein resection (p = 0.021), no arterial resection (p = 0.037), and pathological lymph node negative (p = 0.0057) were identified as favorable prognostic parameters on univariate analysis, and LMR ≥ 3.3 (p = 0.0005), and pathological lymph node negative (p = 0.018) on multivariate analysis. CONCLUSIONS: Preoperative LMR is potentially a good indicator for selecting suitable patients to undergo repeat pancreatectomy in patients with isolated local recurrence of invasive pancreatic neoplasms.

doi: https://doi.org/10.1186/s12885-020-6602-4



- Proceedings of the 3rd International Conference for Cancer Metabolism and Therapy, October 12-14, 2018, Shanghai, China

Pancreas 2020 Feb;49(2):149-157

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=32049950

The 3 International Conference for Cancer Metabolism and Therapy was successfully held at the South Hospital Conference Center of Shanghai First People’s Hospital, nearly 200 international experts from the field of cancer metabolism and therapy and about two thousand local scientists attended the conference. The conference was sponsored by the Yangtze River Delta City Group Hospital Synergistic Development Strategic Alliance, the China Anti-Cancer Association Cancer Metabolism Professional Committee, the Chinese Association for Cancer Metabolism and Therapy under Chinese Medical Doctoral Association-Clinical Precision Medicine, and co-organized by the First People’s Hospital Affiliated to Shanghai Jiaotong University, and Shanghai Jiao Tong University School of Basic Medicine Undertake, Translational Medicine Network, Shanghai Anti-Cancer Association Youth Council, Fudan University Affiliated Tumor Hospital, University of California, Los Angeles, Agi Hirshberg Center for Pancreatic Diseases and Hirshberg Foundation for Pancreatic Cancer Research, Dalian University of Technology, New York-Presbyterian, American Cancer Research Association (AACR). The theme of the conference was ‘Inheritance, Innovation, Excellence, Leading’ and its aim is to create a high-end academic exchange platform to discuss new technologies, new methods, and new products in tumor metabolism, tumor immunity, tumor markers and other fields. The conference involves cancer metabolism reprogramming, metabolism and tumor microenvironment, lipid metabolism, non-metabolic function of metabolic enzymes, metabolism and epigenetics, clinical transformation, new technologies for tumor immunotherapy, clinical application of tumor immunotherapy, emerging targeted therapy, PD-1/PD-L1 technology, CAR-T technology, novel tumor protein markers, novel tumor methylation markers, ctDNA, CTC, etc. The meeting ended in a lively discussion among scientists from different levels who truly benefit from the sessions about cancer metabolism and treatment. The next meeting is planned to be held October 2 through October 6, 2019 in Los Angeles, Calif. The meeting venue will be announced accordingly in the meeting web site (www.cmt.org).

doi: https://doi.org/10.1097/MPA.0000000000001482



- Is Needle Knife Fistulotomy a Shortcut to Preventing Postendoscopic Retrograde Pancreatitis?

The American journal of gastroenterology 2020 Feb;():

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=32049681

Post-endoscopic retrograde cholangiopancreatography pancreatitis (PEP) remains a common and potentially severe adverse event, with continued research efforts to reduce PEP incidence. Robust evidence exists supporting the selective use of pancreatic duct stent placement, administration of rectal indomethacin, wire-guided cannulation technique, and aggressive fluid hydration using lactated Ringer solution. Jang et al. presented a randomized control trial describing primary needle-knife fistulotomy and its benefit for biliary access and reduced PEP incidence. Although these data are compelling, we discuss the key study limitations and the need for further studying the role of primary needle-knife fistulotomy.

doi: https://doi.org/10.14309/ajg.0000000000000553



- Dynamic ROS Regulation by TIGAR: Balancing Anti-cancer and Pro-metastasis Effects

Cancer cell 2020 Feb;37(2):141-142

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=32049042

The role of ROS in cancer is complex, with studies demonstrating both pro- and anti-tumor effects. In a pancreatic ductal adenocarcinoma model, ROS limitation through TIGAR has been shown to initially support cancer development but to later become a metabolic liability in metastasizing cells that is counteracted by decreased TIGAR expression.

doi: https://doi.org/10.1016/j.ccell.2020.01.009



- Islets and pancreatic ductal adenocarcinoma - An opportunity for translational research from the ‘Bench to the Bedside’

Pancreatology : official journal of the International Association of Pancreatology (IAP) … [et al.] 2020 Feb;():

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=32057682

The islet-acinar axis is of prime importance to the optimal functioning of the human pancreas. Not only is this inter-relationship important for normal physiological processes, it is also relevant in diseased states, including chronic pancreatitis and pancreatic ductal adenocarcinoma (PDAC). Early experiments, nearly 4 decades ago, explored the role of islets in the development and progression of PDAC. These led to further studies that provided compelling evidence to support the role of islets and their hormones in PDAC. This association presents oncologists with therapeutic options not only for managing, but potentially preventing PDAC, a cancer that is well known for its poor patient outcomes. This review will discuss the accumulated evidence regarding the role of islets and their hormones in PDAC and highlight areas for future research.

doi: https://doi.org/10.1016/j.pan.2020.02.001



- Systemic BK Virus Infection in a Pediatric Patient With Severe Combined Immunodeficiency

Pediatric and developmental pathology : the official journal of the Society for Pediatric Pathology and the Paediatric Pathology Society 2020 Feb;():1093526619892181

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=32056495

Human BK virus (BKV) infection is known to occur mostly during childhood with the establishment of latent infection with no tissue damage or clinical manifestations. However, conditions causing immunosuppression can lead to increased virus replication and tissue damage. Although the tissues most commonly involved are the kidneys, bladder, ureters and, to some extent, brain tissue, there are some reports that suggest that BKV may cause multisystemic infections. In this case, a 12-month-old child was seen to suffer from multiple gastrointestinal infections. This prompted a search for immunodeficiencies, which revealed the presence of severe combined immunodeficiency. The child was eventually hospitalized and continued showing recurrent bouts of gastroenteritis as well as lower respiratory infection. After multiple antibiotic courses, he developed acute kidney injury, a hemophagocytic syndrome, and eventually respiratory failure, which led to his death a year later. Autopsy findings revealed the presence of a disseminated BKV infection involving the kidneys, ureters, leptomeninges, and pancreas. Analysis of the literature failed to show any previous case of BKV pancreatitis. The present case suggests that BKV can damage more tissues than previously reported and may be responsible for systemic infections in immunosuppressed patients.

doi: https://doi.org/10.1177/1093526619892181



- Conditional Survival After Resection for Pancreatic Cancer: A Population-Based Study and Prediction Model

Annals of surgical oncology 2020 Feb;():

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=32052299

BACKGROUND: Conditional survival is the survival probability after already surviving a predefined time period. This may be informative during follow-up, especially when adjusted for tumor characteristics. Such prediction models for patients with resected pancreatic cancer are lacking and therefore conditional survival was assessed and a nomogram predicting 5-year survival at a predefined period after resection of pancreatic cancer was developed. METHODS: This population-based study included patients with resected pancreatic ductal adenocarcinoma from the Netherlands Cancer Registry (2005-2016). Conditional survival was calculated as the median, and the probability of surviving up to 8 years in patients who already survived 0-5 years after resection was calculated using the Kaplan-Meier method. A prediction model was constructed. RESULTS: Overall, 3082 patients were included, with a median age of 67 years. Median overall survival was 18 months (95% confidence interval 17-18 months), with a 5-year survival of 15%. The 1-year conditional survival (i.e. probability of surviving the next year) increased from 55 to 74 to 86% at 1, 3, and 5 years after surgery, respectively, while the median overall survival increased from 15 to 40 to 64 months at 1, 3, and 5 years after surgery, respectively. The prediction model demonstrated that the probability of achieving 5-year survival at 1 year after surgery varied from 1 to 58% depending on patient and tumor characteristics. CONCLUSIONS: This population-based study showed that 1-year conditional survival was 55% 1 year after resection and 74% 3 years after resection in patients with pancreatic cancer. The prediction model is available via www.pancreascalculator.com to inform patients and caregivers.

doi: https://doi.org/10.1245/s10434-020-08235-w



- Associations between metabolites and pancreatic cancer risk in a large prospective epidemiological study

Gut 2020 Feb;():

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=32060129

OBJECTIVE: To assess whether prediagnostic metabolites were associated with incident pancreatic ductal adenocarcinoma (PDAC) in a prospective cohort study. DESIGN: We conducted an untargeted analysis of 554 known metabolites measured in prediagnostic serum (up to 24 years) to determine their association with incident PDAC in a nested case-control study of male smokers (372 matched case-control sets) and an independent nested case-control study that included women and non-smokers (107 matched sets). Metabolites were measured using Orbitrap Elite or Q-Exactive high-resolution/accurate mass spectrometers. Controls were matched to cases by age, sex, race, date of blood draw, and follow-up time. We used conditional logistic regression adjusted for age to calculate ORs and 95% CIs for a 1 SD increase in log-metabolite level separately in each cohort and combined the two ORs using a fixed-effects meta-analysis. RESULTS: Thirty-one metabolites were significantly associated with PDAC at a false discovery rate <0.05 with 12 metabolites below the Bonferroni-corrected threshold (p<9.04×10-5). Similar associations were observed in both cohorts. The dipeptides glycylvaline, aspartylphenylalanine, pyroglutamylglycine, phenylalanylphenylalanine, phenylalanylleucine and tryptophylglutamate and amino acids aspartate and glutamate were positively while the dipeptides tyrosylglutamine and α-glutamyltyrosine, fibrinogen cleavage peptide DSGEGDFXAEGGGVR and glutathione-related amino acid cysteine-glutathione disulfide were inversely associated with PDAC after Bonferroni correction. Five top metabolites demonstrated significant time-varying associations (p<0.023) with the strongest associations observed 10-15 years after participants’ blood collection and attenuated thereafter. CONCLUSION: Our results suggest that prediagnostic metabolites related to subclinical disease, γ-glutamyl cycle metabolism and adiposity/insulin resistance are associated with PDAC.

doi: https://doi.org/10.1136/gutjnl-2019-319811



- Cellular and Molecular Probing of Intact Human Organs

Cell 2020 Feb;():

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=32059778

Optical tissue transparency permits scalable cellular and molecular investigation of complex tissues in 3D. Adult human organs are particularly challenging to render transparent because of the accumulation of dense and sturdy molecules in decades-aged tissues. To overcome these challenges, we developed SHANEL, a method based on a new tissue permeabilization approach to clear and label stiff human organs. We used SHANEL to render the intact adult human brain and kidney transparent and perform 3D histology with antibodies and dyes in centimeters-depth. Thereby, we revealed structural details of the intact human eye, human thyroid, human kidney, and transgenic pig pancreas at the cellular resolution. Furthermore, we developed a deep learning pipeline to analyze millions of cells in cleared human brain tissues within hours with standard lab computers. Overall, SHANEL is a robust and unbiased technology to chart the cellular and molecular architecture of large intact mammalian organs.

doi: https://doi.org/10.1016/j.cell.2020.01.030



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Gallbladder


- Germline alterations in patients with biliary tract cancers: A spectrum of significant and previously underappreciated findings

Cancer 2020 Feb;():

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=32012241

BACKGROUND: With limited information on germline mutations in biliary tract cancers, this study performed somatic and germline testing for patients at Memorial Sloan Kettering Cancer Center with known biliary tract carcinoma with the aim of determining the frequency and range of pathogenic germline alterations (PGAs). METHODS: Patients with biliary tract carcinoma were consented for somatic tumor and matched blood testing of up to 468 genes via the Memorial Sloan Kettering Cancer Center Integrated Mutation Profiling of Actionable Cancer Targets next-generation sequencing platform. A germline variant analysis was performed on a panel of up to 88 genes associated with an increased predisposition for cancer. Demographic and diagnostic details were collected. RESULTS: Germline mutations were tested in 131 patients. Intrahepatic cholangiocarcinoma was the most common cancer (63.4%), and it was followed by gallbladder adenocarcinoma (16.8%), extrahepatic cholangiocarcinoma (16%), and otherwise unspecified biliary tract cancer (3.8%). Known and likely PGAs were present in 21 patients (16.0%), with 9.9% harboring a PGA in a high/moderate-penetrance cancer predisposition gene. Among high-penetrance cancer susceptibility genes, PGAs were most commonly observed in BRCA1 and BRCA2 (33.3%), which made up 5.3% of the entire cohort, and they were followed by PALB2, BAP1, and PMS2. Mutations in ATM, MITF, and NBN, moderate-penetrance cancer susceptibility genes, were identified in 1 patient each. There was no observed difference in the types of mutations among the subtypes of biliary tract cancer. CONCLUSIONS: The frequency of PGAs found was comparable to existing data on the prevalence of germline mutations in other solid tumor types with matched tumor analysis. This provides support for the role of the BRCA1/2, ATM, and BAP1 genes in biliary tract cancer susceptibility.

doi: https://doi.org/10.1002/cncr.32740



- Smooth Muscle Distribution Patterns of Choledochal Cysts and Their Implications for Pathogenesis and Postoperative Complications

American journal of clinical pathology 2020 Feb;():

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=32010932

OBJECTIVES: Histopathologic characteristics of choledochal cysts and their clinical implications have not been previously comprehensively studied. METHODS: Smooth muscle distribution patterns and other histologic findings (inflammation, metaplasia, dysplasia, and heterotopia) in 233 surgically resected choledochal cysts were evaluated. RESULTS: Mean patient age was 23.3 ± 19.8 years, with male:female ratio of 0.3. Most cases were Todani type I (175 cases, 75.1%) or IVa (56 cases, 24.1%). Choledochal cysts with thin scattered/no muscle fiber (175 cases, 75.1%) were the predominant pattern and were associated with more frequent postoperative biliary stricture (P = .031), less frequent pyloric metaplasia (P = .016), and mucosal smooth muscle aggregates (P < .001) compared to cysts with thick muscle bundles. Severe chronic cholangitis (P = .049), pyloric metaplasia (P = .019), mucosal smooth muscle aggregates (P < .001), biliary intraepithelial neoplasia (P = .021), and associated bile duct (P = .021) and gallbladder carcinomas (P = .03) were more common in adults (age >20 years vs ≤20 years), suggesting that chronic irritation in association with developmental anomalies involves tumorigenesis from choledochal cysts. CONCLUSION: Smooth muscle distribution pattern of choledochal cyst may predict postoperative complication, raising clinical implications of smooth muscle patterns in postoperative management of choledochal cysts.

doi: https://doi.org/10.1093/ajcp/aqaa002



- Luschka Ducts of the Gallbladder in Adults: Case Series Report and Review of the Medical Literature

International journal of surgical pathology 2020 Jan;():1066896920901334

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31983263

Luschka ducts (LD) of the gallbladder (GB) are rare congenital lesions. They are defined as bile ducts that connect directly the hepatic bile duct system to the GB. We aimed to present the characteristics of 55 cases of GB LDs as diagnosed on cholecystectomy specimens. Surgically resected GBs (55) were analyzed for LD morphological features (length, morphological pattern, and epithelial lesions) as well as for immunohistochemical features. The age varied between 24 and 88 years. The gender ratio was 30:25 (female-male). The diagnosis was acute and subacute/chronic cholecystitis (21 and 34 cases, respectively). GB abnormalities of Rokitansky-Aschoff sinus, adenomyoma, septate, and subserosal-liver types were present in 36, 6, 22, and 12 GBs, respectively, while adenocarcinoma was present in 2 GBs. A history of renal cyst, pancreatitis, and colon diverticulosis was observed in 8, 11, and 4 cases, respectively. The LDs were detected at subserosal, resection, or both sites (25, 4, and 26 cases, respectively). The length varied between <1 and 36 mm. Duct-type LDs were observed in 17 cases, complex-type LDs in 5 cases, and mixed-type LDs in 33 cases. Mucosecretion was seen in 12 LDs and cystic dilatation in 8 cases. Epithelial atypia was observed in 2 cases and meganucleoli in 15 cases. Presence of LD-angulation correlated with chronic cholecystitis, while LD-nuclear atypia correlated with acute cholecystitis. In conclusion, LDs may harbor varied aspects, from duct-like or cystic, to nodular, biliary adenoma-like complexes. GB abnormalities of Rokitansky-Aschoff sinus, septa, or subserosal-liver types and extra-GB lesions such as renal cysts, pancreatitis, and colon diverticulosis were associated.

doi: https://doi.org/10.1177/1066896920901334



- Gallbladder Mixed Neuroendocrine-Non-neuroendocrine Neoplasm (MiNEN) Arising in Intracholecystic Papillary Neoplasm: Clinicopathologic and Molecular Analysis of a Case and Review of the Literature

Endocrine pathology 2020 Jan;():

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31981075

Mixed neuroendocrine-non-neuroendocrine neoplasms (MiNENs) of the gallbladder are generally composed of adenocarcinoma and neuroendocrine carcinoma (NEC). Rare cases associated with intracholecystic papillary neoplasm (ICPN) have been reported. Although recent molecular data suggest that the different components of digestive MiNENs originate from a common precursor stem cell, this aspect has been poorly investigated in gallbladder MiNENs. We describe the clinicopathologic and molecular features of a MiNEN composed of ICPN, adenocarcinoma, and NEC. A 66-year-old woman presented with severe abdominal pain. She underwent radical cholecystectomy and an intracholecystic mass was found. Histologically, it was composed of ICPN associated with adenocarcinoma and large cell neuroendocrine carcinoma (LCNEC). The three components were positive for DNA repair proteins and p53. EMA was positive in the ICPN and adenocarcinoma components, while it was negative in the LCNEC. Heterogeneous expression of Muc5AC, cytokeratin 20, and CDX2 was only observed in the ICPN component. Cytokeratin 7 was diffusely positive in both adenocarcinoma and LCNEC components, while it was heterogeneously expressed in the ICPN. The copy number variation analysis showed overlapping results between the adenocarcinoma and LCNEC components with some minor differences with the ICPN component. The three tumor components showed the same mutation profile including TP53 mutation c.700T > C (p. Tyr234His), without mutations in other 51 genes known to be frequently altered in cancer pathogenesis and growth. This finding may support the hypothesis of a monoclonal origin of the different tumor components. We have also performed a review of the literature on gallbladder MiNENs.

doi: https://doi.org/10.1007/s12022-020-09605-6



- Gallbladder and extrahepatic bile duct cancers in the Americas: Incidence and mortality patterns and trends

International journal of cancer 2020 Jan;():

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31922259

Trends in gallbladder cancer incidence and mortality in populations across the Americas can provide insight into shifting epidemiologic patterns and the current and potential impact of preventative and curative programs. Estimates of gallbladder and extrahepatic bile duct cancer incidence and mortality for the year 2018 were extracted from International Agency for Research on Cancer (IARC) GLOBOCAN database for 185 countries. Recorded registry-based incidence from 13 countries was extracted from IARCs Cancer Incidence in Five Continents series and corresponding national deaths from the WHO mortality database. Among females, the highest estimated incidence for gallbladder and extrahepatic bile duct cancer in the Americas were found in Bolivia (21.0 per 100,000), Chile (11.7) and Peru (6.0). In the US, the highest incidence rates were observed among Hispanics (1.8). In the Chilean population, gallbladder cancer rates declined in both females and males between 1998 and 2012. Rates dropped slightly in Canada, Costa Rica, US Whites and Hispanics in Los Angeles. Gallbladder cancer mortality rates also decreased across the studied countries, although rising trends were observed in Colombia and Canada after 2010. Countries within Southern and Central America tended to have a higher proportion of unspecified biliary tract cancers. In public health terms, the decline in gallbladder cancer incidence and mortality rates is encouraging. However, the slight increase in mortality rates during recent years in Colombia and Canada warrant further attention. Higher proportions of unspecified biliary tract cancers (with correspondingly higher mortality rates) suggest more rigorous pathology procedures may be needed after surgery.

doi: https://doi.org/10.1002/ijc.32863



- Long-term outcomes of surgical resection for T1b gallbladder cancer: an institutional evaluation

BMC cancer 2020 Jan;20(1):20

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31907021

BACKGROUND: There is no comprehensive agreement concerning the overall performance of radical resection for T1b gallbladder cancer (GBC). This research focused on addressing whether T1b GBC may spread loco-regionally and whether radical resection is necessary. METHODS: A retrospective analysis was conducted of 1032 patients with GBC who underwent surgical resection at our centre and its affiliated institutions between January 1982 and December 2018. A total of 47 patients with T1b GBC, 29 (62%) of whom underwent simple cholecystectomy and 18 (38%) of whom underwent radical resection with regional lymph node dissection, were enrolled in the study. RESULTS: GBC was diagnosed pre-operatively in 16 patients (34%), whereas 31 patients (66%) had incidental GBC. There was no blood venous or perineural invasion in any patient on histology evaluation, except for lymphatic vessel invasion in a single patient. There were no metastases in any analysed lymph nodes. The open surgical approach was more prevalent among the 18 patients who underwent radical resection (open in all 18 patients) than among the 29 patients who underwent simple cholecystectomy (open in 21; laparoscopic in 8) (P = 0.017). The cumulative 10- and 20-year overall survival rates were 65 and 25%, respectively. The outcome following simple cholecystectomy (10-year overall survival rate of 66%) was akin to that following radical resection (64%, P = 0.618). The cumulative 10- and 20-year disease-specific survival rates were 93 and 93%, respectively. The outcome following simple cholecystectomy (10-year disease-specific survival rate of 100%) was equivalent to that following radical resection (that of 86%, P = 0.151). While age (> 70 years, hazard ratio 5.285, P = 0.003) and gender (female, hazard ratio 0.272, P = 0.007) had a strong effect on patient overall survival, surgical procedure (simple cholecystectomy vs. radical resection) and surgical approach (open vs. laparoscopic) did not. CONCLUSIONS: Most T1b GBCs represent local disease. As pre-operative diagnosis, including tumour penetration of T1b GBC, is difficult, the decision of radical resection is justified. Additional radical resection is not required following simple cholecystectomy provided that the penetration depth is restricted towards the muscular layer and that surgical margins are uninvolved.

doi: https://doi.org/10.1186/s12885-019-6507-2



- Intracholecystic Papillary-Tubular Neoplasms (ICPN) of the Gallbladder: A Short Review of Literature

Applied immunohistochemistry & molecular morphology : AIMM 2020 Jan;28(1):57-61

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31815746

Increasing use of radiographic studies of the hepatobiliary system has led to a growing diagnostic rate of many asymptomatic polyps of the gallbladder which would have gone undiagnosed otherwise. Neoplastic polyps of the gallbladder are 5% of the total number of polyps of this organ. However, due to their malignant potential, the correct diagnosis and classification become of crucial importance. Lack of unified terminology and reporting criteria have led to a limited body of scientific evidence regarding their classification and management. Therefore in 2012 the novel and unified terminology, Intracholecystic papillary-tubular neoplasm was proposed for these lesions when they measure >1 cm. Smaller lesions are usually of no adverse outcome. Intracholecystic papillary-tubular neoplasms show 5 histologic subcategories: (1) pyloric gland subtype which is the most commonly encountered neoplastic polyp in the gallbladder and has the lowest rate of harboring high-grade dysplasia and invasive carcinoma and it shows diffuse cytoplasmic positivity with MUC6, a specific pyloric marker; (2) biliary subtype which is diffusely positive for MUC1 and has the highest risk of concurrent adenocarcinoma; (3) gastric foveolar subtype which is MUC5AC positive in all the cases. Most of the cases in this category are associated with some extent of high-grade dysplasia; (4) intestinal subtype which is the easiest one to recognize as it mimics tubular adenomas of the gastrointestinal tract and show MUC2 and CDX2 positivity; and (5) oncocytic subtype which is the least common.

doi: https://doi.org/10.1097/PAI.0000000000000711



- Clinicopathologic Characteristics of Gallbladder Adenomyomas and the Contribution of Macroscopic Sampling in Adenomyoma Diagnosis

Turk patoloji dergisi 2020 10;36(1):11-16

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31633192

OBJECTIVE: Adenomyoma, a reactive and hamartomatous lesion of the gallbladder, is included in the differential diagnosis of several benign and malignant lesions. Macroscopic sampling is very important in the determination of these lesions. The agreed macroscopy protocol in recent years has been prepared by the Hepatopancreatobiliary Pathology Working Group. We aimed to evaluate the clinicopathologic properties of adenomyoma cases in the gallbladder and the contribution of new macroscopy techniques to the diagnosis of adenomyoma in the pre-protocol and post-protocol parts of a one-year period. MATERIAL AND METHOD: Two institutes were included in the study. Adenomyoma cases diagnosed in the pre-protocol and post-protocol periods of one year duration were included in the study. Slides and demographic properties of the cases were reexamined. RESULTS: While adenomyoma was present in 22 of 1879 gallbladder before the protocol, it was observed in 32 of 1781 gallbladders in the post-protocol period. 17 of the cases were male and 37 were female. The mean age of the cases was 51.8. 52% of the lesions were located in the fundus. A gallstone was observed in 37 cases, and cholesterolosis in 14 cases. In the comparison of the two periods, the number of cases was lower in the post-protocol period but a 0.6% increase in the diagnosis of adenomyoma was found. CONCLUSION: Adenomyoma is one of the lesions of the gallbladder that should be recognized but can be easily overlooked macroscopically. When we conducted the sampling according to the last protocol, the increase in the diagnosis of adenomyoma showed that adequate and accurate sampling was very useful for the detection of adenomyoma in the gallbladder.

doi: https://doi.org/10.5146/tjpath.2019.01471



- Ultrastructural Characteristics of Gallbladder Epithelial Inclusions Mimicking Cystoisospora

American journal of clinical pathology 2020 Jan;153(1):88-93

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31600399

OBJECTIVES: There is recently reported increased prevalence of Isospora organisms in cholecystectomy specimens from immunocompetent patients, especially in acalculous cholecystectomies. We performed an ultrastructural and molecular evaluation of these specimens. METHODS: From 28 gallbladders with intraepithelial inclusions, two specimens with diffuse involvement of the gallbladder epithelium were analyzed by electron microscopy. Polymerase chain reaction was performed on five samples for the ITS2 region of C belli and eukaryotic 18S region. The 18S products were sequenced by next-generation sequencing. RESULTS: Electron microscopic analysis showed cytoplasmic condensations leading to vacuole formation. In contrast with true C belli, there were no identifiable organelles or organization. None of these cases showed amplified products other than human on molecular analysis. CONCLUSIONS: Electron microscopic analysis demonstrates that the inclusions are condensed cytoplasmic material and not true organisms.

doi: https://doi.org/10.1093/ajcp/aqz137



- Clinical Significance of CBS and CCL21 in Gallbladder Adenocarcinomas and Squamous Cell/Adenosquamous Carcinomas

Applied immunohistochemistry & molecular morphology : AIMM 2020 Feb;28(2):103-110

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=32044878

Gallbladder cancer (GBC) is a rare disease with high mortality. However, no biomarkers for the carcinogenesis, progression, prognosis, and early diagnosis are clinically available. This study investigated the expressions of cystathionine-β-synthase (CBS) and C-C chemokine receptor 7 (CCR7) protein and their clinical and pathologic significances in gallbladder squamous cell/adenosquamous carcinomas (SC/ASC) and adenocarcinomas (AC). CBS and chemokine ligand 21 (CCL21) expression was measured using immunohistochemistry in 69 SC/ASCs and 146 ACs. A significantly high percentage of patients with an age above 45 years, lymph node metastasis, and invasion was observed in the SCs/ASCs compared with ACs (P<0.05). Both AC and SC/ASC patients with positive CBS and CCL21 expression exhibited a high tumor-lymph node-metastasis stage, lymph node metastasis, and invasion compared with patients with negative CBS and CCL21 expression (P<0.05 or P<0.01). SC/ASC patients with positive CBS expression was prone to have a larger tumor size than those with negative expression (P<0.05). Positive CBS and CCL21 expression correlated with poor differentiation and larger tumor size in AC patients. Positive CBS and CCL21 are closely associated with a decreased overall survival in SC/ASC and AC patients (P<0.05 or P<0.01) and were independent factors for a poor-prognosis. Both CBS and CCL21 showed a good overall diagnostic performance for SC/ASC (AUC=0.742 and AUC=0.764, respectively) and AC (AUC=0.734 and AUC=0.718, respectively). In conclusion, positive CBS and CCL21 expression are closely associated with the clinical severity and poor prognosis in GBC, and can be a marker for the diagnosis of AC and SC/ASC type of GBC.

doi: https://doi.org/10.1097/PAI.0000000000000705



- Neoadjuvant chemotherapy with gemcitabine plus cisplatin followed by radical liver resection versus immediate radical liver resection alone with or without adjuvant chemotherapy in incidentally detected gallbladder carcinoma after simple cholecystectomy or in front of radical resection of BTC (ICC/ECC) - a phase III study of the German registry of incidental gallbladder carcinoma platform (GR)- the AIO/ CALGP/ ACO- GAIN-trial

BMC cancer 2020 Feb;20(1):122

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=32059704

BACKGROUND: Currently, complete surgical resection represents the only potentially curative treatment option for Biliary Tract Cancer (BTC) including Gallbladder Cancer (GBC). Even after curative resection, 5-year OS is only 20-40%. Gallbladder carcinoma is relatively rare, but still the fifth most common neoplasm of the digestive tract and even the most frequent cancer of the biliary system. Gallbladder carcinoma is suspected preoperatively in only 30% of all pts., while the majority of cases are discovered incidentally by the pathologist after cholecystectomy for a benign indication. For improving curative rates in BTC and GBC, early systemic therapy combined with radical resection seems to be a promising approach. The earliest moment to apply chemotherapy would be in front of radical surgery. The encouraging results of neoadjuvant/perioperative concepts in other malignancies provide an additional rationale to use this treatment in the early phase of GBC management and even ICC/ECC. Especially because data regarding pure adjuvant chemotherapy in BTC’s are conflicting. METHODS: This is a multicenter, randomized, controlled, open-label phase III study including pts. with incidentally discovered GBCs after simple cholecystectomy in front of radical liver resection and pts. with resectable/ borderline resectable cholangiocarcinomas (ICC/ ECC) scheduled to receive perioperative chemotherapy (Gemcitabine + Cisplatin 3 cycles pre- and post-surgery) or surgery alone followed by a therapy of investigator’s choice. Primary endpoint is OS; secondary endpoints are PFS, R0-resection rate, toxicity, perioperative morbidity, mortality and QoL. A total of N = 333 patients with GBC or BTC will be included. Recruitment has started in August 2019. DISCUSSION: The current proposed phase III GAIN study investigates whether induction chemotherapy followed by radical resection in ICC/ECC and re-resection in IGBC (and - if possible - postoperative chemotherapy) prolongs overall survival compared to radical surgery alone for incidental gallbladder carcinoma and primary resectable or borderline resectable cholangiocarcinoma. Utilizing a neoadjuvant approach including a second radical surgery will help to raise awareness for the necessity of radical surgery, especially second radical completion surgery in IGBC and improve the adherence to the guidelines. TRIAL REGISTRATION: ClinicalTrials.gov ID: NCT03673072 from 17.09.2018. EudraCT number: 2017-004444-38 from 02.11.2017.

doi: https://doi.org/10.1186/s12885-020-6610-4



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Bile Ducts


- Smooth Muscle Distribution Patterns of Choledochal Cysts and Their Implications for Pathogenesis and Postoperative Complications

American journal of clinical pathology 2020 Feb;():

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=32010932

OBJECTIVES: Histopathologic characteristics of choledochal cysts and their clinical implications have not been previously comprehensively studied. METHODS: Smooth muscle distribution patterns and other histologic findings (inflammation, metaplasia, dysplasia, and heterotopia) in 233 surgically resected choledochal cysts were evaluated. RESULTS: Mean patient age was 23.3 ± 19.8 years, with male:female ratio of 0.3. Most cases were Todani type I (175 cases, 75.1%) or IVa (56 cases, 24.1%). Choledochal cysts with thin scattered/no muscle fiber (175 cases, 75.1%) were the predominant pattern and were associated with more frequent postoperative biliary stricture (P = .031), less frequent pyloric metaplasia (P = .016), and mucosal smooth muscle aggregates (P < .001) compared to cysts with thick muscle bundles. Severe chronic cholangitis (P = .049), pyloric metaplasia (P = .019), mucosal smooth muscle aggregates (P < .001), biliary intraepithelial neoplasia (P = .021), and associated bile duct (P = .021) and gallbladder carcinomas (P = .03) were more common in adults (age >20 years vs ≤20 years), suggesting that chronic irritation in association with developmental anomalies involves tumorigenesis from choledochal cysts. CONCLUSION: Smooth muscle distribution pattern of choledochal cyst may predict postoperative complication, raising clinical implications of smooth muscle patterns in postoperative management of choledochal cysts.

doi: https://doi.org/10.1093/ajcp/aqaa002



- Innervation of the proximal human biliary tree

Virchows Archiv : an international journal of pathology 2020 Jan;():

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31993770

The autonomic nervous system plays a role in a variety of liver regenerative and metabolic functions, including modulating bile secretion and cholangiocyte and hepatobiliary progenitors of the canals of Hering. However, the nature and location of nerves which link to the proximal biliary tree have remained uncertain. We investigate the anatomic relationship of nerves to the proximal biliary tree including the putative stem/progenitor cell niche of the canal of Hering. Using double immunostaining (fluorescence, histochemistry) to highlight markers of cholangiocytes (biliary-type keratins), nerves (S100, neurofilament protein, PGP9.5, tyrosine hydroxylase), and stellate cells (CRBP-1), we examined sections from normal adult livers from autopsy or surgical resections. There is extensive contact between nerves and interlobular bile ducts, bile ductules, and canals of Hering (CoH). In multiple serial sections from 4 normal livers, biliary-nerve contacts were seen in all of these structures and were more common in the interlobular bile ducts (78/137; 57%) than in the ductules and CoH (95/294; 33%) (p < 0.001). Contacts appear to consist of nerves in juxtaposition to the biliary basement membrane, though crossing through basement membrane to interface directly with cholangiocytes is also present. These nerves are positive for tyrosine hydroxylase and are, thus, predominately adrenergic. Electron microscopy confirms nerves closely approximating ductules. Nerve fiber-hepatic stellate cell juxtaposition is observed but without stellate cell approximation to cholangiocytes. We present novel findings of biliary innervation, perhaps mediated in part, by direct cholangiocyte-nerve interactions. The implications of these findings are protean for studies of neuromodulation of biliary physiology and hepatic stem/progenitor cells.

doi: https://doi.org/10.1007/s00428-020-02761-4



- TGF-��2 silencing to target biliary-derived liver diseases

Gut 2020 Jan;():

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31992593

OBJECTIVE: TGF-β2 (TGF-β, transforming growth factor beta), the less-investigated sibling of TGF-β1, is deregulated in rodent and human liver diseases. Former data from bile duct ligated and MDR2 knockout (KO) mouse models for human cholestatic liver disease suggested an involvement of TGF-β2 in biliary-derived liver diseases. DESIGN: As we also found upregulated TGFB2 in liver tissue of patients with primary sclerosing cholangitis (PSC) and primary biliary cholangitis (PBC), we now fathomed the positive prospects of targeting TGF-β2 in early stage biliary liver disease using the MDR2-KO mice. Specifically, the influence of TgfB2 silencing on the fibrotic and inflammatory niche was analysed on molecular, cellular and tissue levels. RESULTS: TgfB2-induced expression of fibrotic genes in cholangiocytes and hepatic stellate cellswas detected. TgfB2 expression in MDR2-KO mice was blunted using TgfB2-directed antisense oligonucleotides (AON). Upon AON treatment, reduced collagen deposition, hydroxyproline content and αSMA expression as well as induced PparG expression reflected a significant reduction of fibrogenesis without adverse effects on healthy livers. Expression analyses of fibrotic and inflammatory genes revealed AON-specific regulatory effects on Ccl3, Ccl4, Ccl5, Mki67 and Notch3 expression. Further, AON treatment of MDR2-KO mice increased tissue infiltration by F4/80-positive cells including eosinophils, whereas the number of CD45-positive inflammatory cells decreased. In line, TGFB2 and CD45 expression correlated positively in PSC/PBC patients and localised in similar areas of the diseased liver tissue. CONCLUSIONS: Taken together, our data suggest a new mechanistic explanation for amelioration of fibrogenesis by TGF-β2 silencing and provide a direct rationale for TGF-β2-directed drug development.

doi: https://doi.org/10.1136/gutjnl-2019-319091



- Neuroendocrine carcinoma diagnosis from bile duct cytological specimens: A retrospective single-center study

Diagnostic cytopathology 2020 Feb;48(2):154-158

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31697402

Neuroendocrine carcinoma (NEC) in the extrahepatic bile duct is extremely rare and clinically aggressive. Cytological examination of bile and/or bile duct brushing specimens plays an important role in the diagnosis of carcinoma of the extrahepatic bile duct, but only a few articles have described the cytological features of NEC in this area. Thus, we retrospectively analyzed the cytological features of NEC in bile and/or bile duct brushing specimens. Patients with a histopathological diagnosis of NEC who underwent bile and/or bile duct brush cytological examination were enrolled in this study. The cytological features, including the background, arrangement, and shape of the neoplastic cells, and nuclear and cytoplasmic features were reviewed. Six patients with small cell NEC were enrolled, and two of them had pancreatic tumors directly invading the bile duct wall. The cytological specimens showed small and/or large neoplastic cell clusters with occasional single cells in all cases. The neoplastic cells had a high nuclear/cytoplasmic ratio and round-to-oval nuclei with powdery chromatin, inconspicuous nucleoli, and scant cytoplasm. Nuclear molding was a characteristic finding in all cases. One case had an adenocarcinoma component, which was also present in the cytological specimen. Cytological examination of bile and/or bile duct brushing specimens can be useful for the diagnosis of small cell NEC. This is an extremely rare but aggressive carcinoma, and its diagnosis by identifying characteristic cytological features may facilitate early detection and treatment.

doi: https://doi.org/10.1002/dc.24334



- Development of the Intrahepatic and Extrahepatic Biliary Tract: A Framework for Understanding Congenital Diseases

Annual review of pathology 2020 Jan;15():1-22

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31299162

The involvement of the biliary tract in the pathophysiology of liver diseases and the increased attention paid to bile ducts in the bioconstruction of liver tissue for regenerative therapy have fueled intense research into the fundamental mechanisms of biliary development. Here, I review the molecular, cellular and tissular mechanisms driving differentiation and morphogenesis of the intrahepatic and extrahepatic bile ducts. This review focuses on the dynamics of the transcriptional and signaling modules that promote biliary development in human and mouse liver and discusses studies in which the use of zebrafish uncovered unexplored processes in mammalian biliary development. The review concludes by providing a framework for interpreting the mechanisms that may help us understand the origin of congenital biliary diseases.

doi: https://doi.org/10.1146/annurev-pathmechdis-012418-013013



- Gallbladder and extrahepatic bile duct cancers in the Americas: Incidence and mortality patterns and trends

International journal of cancer 2020 Jan;():

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31922259

Trends in gallbladder cancer incidence and mortality in populations across the Americas can provide insight into shifting epidemiologic patterns and the current and potential impact of preventative and curative programs. Estimates of gallbladder and extrahepatic bile duct cancer incidence and mortality for the year 2018 were extracted from International Agency for Research on Cancer (IARC) GLOBOCAN database for 185 countries. Recorded registry-based incidence from 13 countries was extracted from IARCs Cancer Incidence in Five Continents series and corresponding national deaths from the WHO mortality database. Among females, the highest estimated incidence for gallbladder and extrahepatic bile duct cancer in the Americas were found in Bolivia (21.0 per 100,000), Chile (11.7) and Peru (6.0). In the US, the highest incidence rates were observed among Hispanics (1.8). In the Chilean population, gallbladder cancer rates declined in both females and males between 1998 and 2012. Rates dropped slightly in Canada, Costa Rica, US Whites and Hispanics in Los Angeles. Gallbladder cancer mortality rates also decreased across the studied countries, although rising trends were observed in Colombia and Canada after 2010. Countries within Southern and Central America tended to have a higher proportion of unspecified biliary tract cancers. In public health terms, the decline in gallbladder cancer incidence and mortality rates is encouraging. However, the slight increase in mortality rates during recent years in Colombia and Canada warrant further attention. Higher proportions of unspecified biliary tract cancers (with correspondingly higher mortality rates) suggest more rigorous pathology procedures may be needed after surgery.

doi: https://doi.org/10.1002/ijc.32863



- Exome sequencing of 22 genes using tissue from patients with biliary tract cancer

APMIS : acta pathologica, microbiologica, et immunologica Scandinavica 2020 Jan;128(1):3-9

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31628675

Biliary tract cancers (BTC) are a rare heterogeneous disease group with a dismal prognosis and limited treatment options. The mutational landscape consists of genetic aberrations both shared by and characteristic for anatomical location. Here, we present exome sequencing data on 22 genes from a phase 2 trial using a clinically validated panel used in patients with colorectal cancer. A total of 56 patients were included in a one-armed phase 2 trial investigating the treatment combination of capecitabine, gemcitabine, oxaliplatin, and cetuximab. Tissue DNA yield and quality allowed analysis of 30 patients on our panel including 22 genes. ARID1A (33%) and TP53 (33%) were found to be most frequently mutated followed by KRAS mutations found in 20% of the patients. Mutational aberrations in ARID1A were found more prevalent than expected, whereas TP53 and KRAS were in concordance with earlier reported data. Mutation in CTNNB1 was significantly associated with poor prognosis. Our panel is clinically validated and suitable for a high volume of samples to detect mutations in patients with BTC. However, it is reasonable to assume that the clinical utility could be optimized in this patient group by extending the panel to include BTC specific mutations with potential therapeutic consequences such as IDH1/2, FGFR fusions, ERBB3, and BRCA1/2.

doi: https://doi.org/10.1111/apm.13003



- Cholangiolar pattern and albumin in situ hybridisation enable a diagnosis of intrahepatic cholangiocarcinoma

Journal of clinical pathology 2020 Jan;73(1):23-29

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31422372

AIMS: The histological distinction of intrahepatic cholangiocarcinoma (ICC) from metastatic adenocarcinoma remains a challenge. The primary goal was to evaluate the diagnostic value of morphology and albumin expression in the diagnosis of ICC. METHODS: We evaluated morphological patterns in 120 ICCs and 677 non-hepatic adenocarcinomas and performed in situ hybridisation (ISH) stain for albumin in the former cohort (retrospective cohort). We also identified 119 samples from primary and metastatic lesions, the validation cohort, in which albumin ISH was performed as part of the diagnostic workup. Targeted sequencing was performed on selected cases. We also mined existing expression profiling data including cases from The Cancer Genome Atlas (TCGA) (41 760 unique samples). RESULTS: In the retrospective cohort, 45% of ICCs and <1% of non-hepatic adenocarcinomas showed a cholangiolar pattern; albumin ISH was positive in 93% of ICCs with significant intratumorous heterogeneity. In the validation cohort, 29% of ICCs showed a cholangiolar pattern and 88% expressed albumin, while all metastatic non-hepatic neoplasms were negative (n=37) (sensitivity 88% and specificity 100%). Targetable genetic alterations (IDH mutations and FGFR2 fusions) were identified in 31% of ICCs (10 of 32). An analysis of the TCGA data validated the specificity of the albumin assay. CONCLUSIONS: The cholangiolar pattern and albumin RNA ISH distinguishes ICC from metastatic adenocarcinoma with high specificity. Given the high prevalence of targetable mutations in ICC, albumin RNA ISH is an essential component in the workup of tumours of uncertain origin. A specific diagnosis of ICC could trigger molecular testing and uncover targetable genetic alterations.

doi: https://doi.org/10.1136/jclinpath-2019-206055



- Role of Ancillary Techniques in Biliary Cytopathology Specimens

Acta cytologica 2020 05;64(1-2):175-181

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31121596

Biliary brushing cytology has become the standard of practice for the investigation of strictures of the biliary and pancreatic duct systems. The methodology however has a limitation in that it has low diagnostic sensitivity when only cytologic evaluation is used. A number of testing methodologies have been applied to brushing specimens in an attempt to improve overall sensitivity without loss of specificity. These have included DNA ploidy analysis, immunocytochemistry, individual gene mutational analysis, fluorescence in-situ hybridization (FISH), and next generation sequencing (NGS). Currently, FISH coupled with routine cytology appears to be the method of choice for improving diagnostic sensitivity. NGS shows significant promise for improvement of diagnostic sensitivity.

doi: https://doi.org/10.1159/000498976



- Integrating next-generation sequencing to endoscopic retrograde cholangiopancreatography (ERCP)-obtained biliary specimens improves the detection and management of patients with malignant bile duct strictures

Gut 2020 01;69(1):52-61

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30971436

OBJECTIVE: Despite improvements in imaging, serum CA19-9 and pathological evaluation, differentiating between benign and malignant bile duct strictures remains a diagnostic conundrum. Recent developments in next-generation sequencing (NGS) have opened new opportunities for early detection and management of cancers but, to date, have not been rigorously applied to biliary specimens. DESIGN: We prospectively evaluated a 28-gene NGS panel (BiliSeq) using endoscopic retrograde cholangiopancreatography-obtained biliary specimens from patients with bile duct strictures. The diagnostic performance of serum CA19-9, pathological evaluation and BiliSeq was assessed on 252 patients (57 trainings and 195 validations) with 346 biliary specimens. RESULTS: The sensitivity and specificity of BiliSeq for malignant strictures was 73% and 100%, respectively. In comparison, an elevated serum CA19-9 and pathological evaluation had sensitivities of 76% and 48%, and specificities of 69% and 99%, respectively. The combination of BiliSeq and pathological evaluation increased the sensitivity to 83% and maintained a specificity of 99%. BiliSeq improved the sensitivity of pathological evaluation for malignancy from 35% to 77% for biliary brushings and from 52% to 83% for biliary biopsies. Among patients with primary sclerosing cholangitis (PSC), BiliSeq had an 83% sensitivity as compared with pathological evaluation with an 8% sensitivity. Therapeutically relevant genomic alterations were identified in 20 (8%) patients. Two patients with ERBB2-amplified cholangiocarcinoma received a trastuzumab-based regimen and had measurable clinicoradiographic response. CONCLUSIONS: The combination of BiliSeq and pathological evaluation of biliary specimens increased the detection of malignant strictures, particularly in patients with PSC. Additionally, BiliSeq identified alterations that may stratify patients for specific anticancer therapies.

doi: https://doi.org/10.1136/gutjnl-2018-317817



- Recurrent Rearrangements in PRKACA and PRKACB in Intraductal Oncocytic Papillary Neoplasms of the Pancreas and��Bile Duct

Gastroenterology 2020 Feb;158(3):573-582.e2

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31678302

BACKGROUND & AIMS: Intraductal oncocytic papillary neoplasms (IOPNs) of the pancreas and bile duct contain epithelial cells with numerous, large mitochondria and are cystic precursors to pancreatic ductal adenocarcinoma (PDAC) and cholangiocarcinoma (CCA), respectively. However, IOPNs do not have the genomic alterations found in other pancreatobiliary neoplasms. In fact, no recurrent genomic alterations have been described in IOPNs. PDACs without activating mutations in KRAS contain gene rearrangements, so we investigated whether IOPNs have recurrent fusions in genes. METHODS: We analyzed 20 resected pancreatic IOPNs and 3 resected biliary IOPNs using a broad RNA-based targeted sequencing panel to detect cancer-related fusion genes. Four invasive PDACs and 2 intrahepatic CCAs from the same patients as the IOPNs, were also available for analysis. Samples of pancreatic cyst fluid (n = 5, collected before surgery) and bile duct brushings (n = 2) were analyzed for translocations. For comparison, we analyzed pancreatobiliary lesions from 126 patients without IOPN (controls). RESULTS: All IOPNs evaluated were found to have recurring fusions of ATP1B1-PRKACB (n = 13), DNAJB1-PRKACA (n = 6), or ATP1B1-PRKACA (n = 4). These fusions also were found in corresponding invasive PDACs and intrahepatic CCAs, as well as in matched pancreatic cyst fluid and bile duct brushings. These gene rearrangements were absent from all 126 control pancreatobiliary lesions. CONCLUSIONS: We identified fusions in PRKACA and PRKACB genes in pancreatic and biliary IOPNs, as well as in PDACs and pancreatic cyst fluid and bile duct cells from the same patients. We did not identify these gene fusions in 126 control pancreatobiliary lesions. These fusions might be used to identify patients at risk for IOPNs and their associated invasive carcinomas.

doi: https://doi.org/10.1053/j.gastro.2019.10.028



- Is Endoscopic Balloon Dilation Still Associated With Higher Rates of Pancreatitis?: A Systematic Review and Meta-Analysis

Pancreas 2020 Feb;49(2):158-174

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=32049951

The objective of this study was to compare the efficacy and safety of endoscopic papillary balloon dilation (EPBD), endoscopic sphincterotomy (ES), and the combination of large balloon dilation and ES (ES + EPLBD) in the treatment of common bile duct stones, with a special focus on postendoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP). Individualized search strategies were developed in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. We included randomized controlled trials (RCTs) which evaluated at least one of the following outcomes: PEP, complete stone removal in the first ERCP, need for mechanical lithotripsy, recurrence of common bile duct stones, bleeding, and cholangitis. Twenty-five RCTs were selected for analysis. Pancreatitis rates were higher for EPBD than for ES (P = 0.003), as were severe pancreatitis rates (P = 0.04). However, in the 10-mm or greater balloon subgroup analysis, this difference was not shown (P = 0.82). Rates of PEP were higher in the subgroup of non-Asian subjects (P = 0.02), and the results were not robust when RCTs that used endoscopic nasobiliary drainage were omitted. The incidence of pancreatitis was comparable between EPLBD and ES + EPLBD. All 3 approaches were equally efficacious. Nevertheless, the results should be interpreted with caution, because pancreatitis is a multifactorial pathology, and RCTs can have limited generalizability.

doi: https://doi.org/10.1097/MPA.0000000000001489



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Ampulla


- Clinicopathological features of pyloric gland adenomas of the duodenum: a multicentre study of 57 cases

Histopathology 2020 Feb;76(3):404-410

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31529725

AIMS: To determine the clinicopathological features of pyloric gland adenomas (PGA) that arise in the duodenum. METHODS AND RESULTS: Fifty-seven cases of duodenal PGA were identified and analysed from 56 patients. Clinicopathological and immunohistochemical analyses were performed. PGA tend to occur in older individuals (median age = 73.5), with a slight female predominance (25 males, 31 females). PGA arise more commonly in the proximal duodenum (68.75% in D1, 25% in D2 and 6.25% in D3) and usually present as mucosal nodules (98.2%) or plaques (1.8%), with a mean size of 14.8 mm. There is associated gastric heterotopia in 22.8% of cases. PGA showing features of high-grade dysplasia were significantly larger in size than PGA, showing only low-grade dysplasia (23.1 versus 8.7 mm; P = 0.0001) and more likely to show a tubulovillous rather than a pure tubular architecture (P = 0.025). In our series, 10 of 56 patients had intramucosal or invasive carcinoma associated with the duodenal PGA (17.9%). Three of these carcinomas showed lymph node metastasis. Following definitive treatment, local recurrence occurred in only three patients. CONCLUSIONS: Duodenal PGA tend to occur in the proximal duodenum of older individuals. Larger size and tubulovillous architecture correlates with high-grade dysplasia and associated adenocarcinoma. The low recurrence rate of these lesions would suggest that endoscopic management is appropriate, provided that the lesion can be completely resected.

doi: https://doi.org/10.1111/his.13996



- Pathologic Evaluation of Endoscopically Resected Non-Ampullary Duodenal Lesions: A Single Center Experience

Turk patoloji dergisi 2019 Dec;():

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31825518

OBJECTIVE: Endoscopic resections are increasingly being used for superficial gastrointestinal lesions. However, application of these techniques in the duodenum remains challenging, due to the technical difficulties and high complication rates. This study projects a western tertiary center’s experience in the endoscopic treatment and diagnostic workup of 19 cases of non-ampullary duodenal lesions. MATERIAL AND METHOD: Specimens (12 endoscopic mucosal resections, 6 endoscopic submucosal dissections, and one endoscopic full-thickness resection) were processed following a strict protocol (photographed, mapped digitally and submitted totally) for histopathologic examination. Clinicopathologic characteristics, margin status and follow-up information were analyzed. RESULTS: The mean age of the 16 patients was 52 years (range: 22-81). Mean lesion size was 1.4 cm (range: 0.3-3.6 cm) for all cases, 2 cm for endoscopic submucosal dissections and 1.1 cm for endoscopic mucosal resections. Mean number of blocks submitted was 4/case. Seven neuroendocrine tumors, 3 tubulovillous adenomas were diagnosed along with nine benign lesions. For endoscopic submucosal dissections, en-bloc and R0 resection rates were 100% (n=6/6) and 83% (n=5/6); for endoscopic mucosal resections, they were 92% (n=11/12) and 83% (n=10/12), respectively. Only one patient had procedure-related late perforation that was managed endoscopically. No mortality was encountered. CONCLUSION: Duodenal endoscopic resections proved successful, safe and feasible methods in a tertiary center. The pathologist’s role is to designate the accurate diagnosis, related histopathologic parameters and margin status. The gross protocol was found to be essential in evaluating specimen margins and orientation, as well as in size measurement. We recommend following a standardized approach including gross photography and digital mapping when handling these specimens, for both diagnostic and data collection purposes.

doi: https://doi.org/10.5146/tjpath.2019.01474



- A PTPN11 mutation in a woman with Noonan syndrome and protein-losing enteropathy

BMC gastroenterology 2020 Feb;20(1):34

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=32054441

BACKGROUND: Noonan syndrome is an autosomal dominant, variably expressed multisystem disorder characterized by specific facial and cardiac defects, delayed growth, ectodermal abnormalities, and lymphatic dysplasias. Lymphedema and chylous pleural effusions are common in Noonan syndrome, but protein-losing enteropathy (PLE) has only rarely been described in the condition and little is known about its genetic associations. CASE PRESENTATION: We report the case of a 30-year-old Chinese woman who developed severe recurrent edema and hypoproteinemia. Gastroduodenoscopy showed a “snowflake” appearance of lymphangiectasia in the duodenum, and CT reconstruction of the small intestine showed segmental thickening of the intestinal wall with localized stenosis. Whole exome sequencing revealed that the patient harbored a pathogenic variant of PTPN11 (c.A922G p.N308D), which was unfortunately inherited by her 2.5-year-old daughter who had short stature and atrial septal defect but no hypoproteinemia. CONCLUSIONS: This case of Noonan syndrome with PLE was associated with a PTPN11 mutation. A comprehensive review of PLE in Noonan syndrome revealed that PLE often presents late in this context but there is no clear genotype-phenotype correlation. Genetic evaluation with next-generation sequencing can be useful for securing the diagnosis and planning early intervention and management.

doi: https://doi.org/10.1186/s12876-020-01187-1



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