Publications by authors named "Lodewijk A A Brosens"

86 Publications

A Parathyroid-Gut Axis: Hypercalcemia and the Pathogenesis of Gastrinoma in Multiple Endocrine Neoplasia 1.

Mol Cancer Res 2021 Mar 26. Epub 2021 Mar 26.

Pathology, UMC Utrecht.

Patients with multiple endocrine neoplasia 1 (MEN1) syndrome have a germline mutation in the MEN1 gene. Loss of the wildtype allele can initiate endocrine tumorigenesis. Microscopic and macroscopic pituitary, parathyroid, and pancreatic tumors (referred to as the 3 P's) show loss of the wildtype MEN1 allele up to 100%. In contrast, the duodenal gastrinoma pathogenesis in MEN1 syndrome follows a hyperplasia-to-neoplasia sequence. Gastrinomas have loss of heterozygosity of the MEN1 locus in <50%, and invariably coincide with linear, diffuse, or micronodular gastrin-cell hyperplasia. The factor initiating the gastrin-cell hyperplasia-to-neoplasia sequence is unknown. In this perspective, we argue that hypercalcemia may promote the gastrin-cell hyperplasia-to-neoplasia sequence through the calcium sensing receptor. Hypercalcemia is present in almost all patients with MEN1 syndrome due to parathyroid adenomas. We propose a parathyroid-gut axis, which could well explain why patients with MEN1 syndrome are regularly cured of duodenal gastrinoma after parathyroid surgery, and might cause MEN1 syndrome phenocopies in MEN1-mutation negative individuals with parathyroid adenomas. This perspective on the pathogenesis of the gastrin-cell hyperplasia and neoplasia sequence sheds new light on tumorigenic mechanisms in neuroendocrine tumors and might open up novel areas of gastrinoma research. It may also shift focus in the treatment of MEN1 syndrome related gastrinoma to biochemical prevention.
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http://dx.doi.org/10.1158/1541-7786.MCR-21-0073DOI Listing
March 2021

Preoperative misdiagnosis of pancreatic and periampullary cancer in patients undergoing pancreatoduodenectomy: A multicentre retrospective cohort study.

Eur J Surg Oncol 2021 Mar 15. Epub 2021 Mar 15.

Department of Surgery, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands. Electronic address:

Introduction: Whereas neoadjuvant chemo(radio)therapy is increasingly used in pancreatic cancer, it is currently not recommended for other periampullary (non-pancreatic) cancers. This has important implications for the relevance of the preoperative diagnosis for pancreatoduodenectomy. This retrospective multicentre cohort study aimed to determine the frequency of clinically relevant misdiagnoses in patients undergoing pancreatoduodenectomy for pancreatic or other periampullary cancer.

Methods: Data from all consecutive patients who underwent a pancreatoduodenectomy between 2014 and 2018 were obtained from the prospective Dutch Pancreatic Cancer Audit. The preoperative diagnosis as concluded by the multidisciplinary team (MDT) meeting was compared with the final postoperative diagnosis at pathology to determine the rate of clinically relevant misdiagnosis (defined as missed pancreatic cancer or incorrect diagnosis of pancreatic cancer).

Results: In total, 1244 patients underwent pancreatoduodenectomy of whom 203 (16%) had a clinically relevant misdiagnosis preoperatively. Of all patients with a final diagnosis of pancreatic cancer, 13% (87/679) were preoperatively misdiagnosed as distal cholangiocarcinoma (n = 41, 6.0%), ampullary cancer (n = 27, 4.0%) duodenal cancer (n = 16, 2.4%), or other (n = 3, 0.4%). Of all patients with a final diagnosis of periampullary (non-pancreatic) cancer, 21% (116/565) were preoperatively incorrectly diagnosed as pancreatic cancer. Accuracy of preoperative diagnosis was 84% for pancreatic cancer, 71% for distal cholangiocarcinoma, 73% for ampullary cancer and 73% for duodenal cancer. A prediction model for the preoperative likelihood of pancreatic cancer (versus other periampullary cancer) prior to pancreatoduodenectomy demonstrated an AUC of 0.88.

Discussion: This retrospective multicentre cohort study showed that 16% of patients have a clinically relevant misdiagnosis that could result in either missing the opportunity of neoadjuvant chemotherapy in patients with pancreatic cancer or inappropriate administration of neoadjuvant chemotherapy in patients with non-pancreatic periampullary cancer. A preoperative prediction model is available on www.pancreascalculator.com.
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http://dx.doi.org/10.1016/j.ejso.2021.03.228DOI Listing
March 2021

Human gastrointestinal epithelia of the esophagus, stomach, and duodenum resolved at single-cell resolution.

Cell Rep 2021 Mar;34(10):108819

Hubrecht Institute and Oncode Institute, Royal Netherlands Academy of Arts and Sciences (KNAW), Utrecht, the Netherlands; Princess Maxima Center for Pediatric Oncology, Utrecht, the Netherlands. Electronic address:

The upper gastrointestinal tract, consisting of the esophagus, stomach, and duodenum, controls food transport, digestion, nutrient uptake, and hormone production. By single-cell analysis of healthy epithelia of these human organs, we molecularly define their distinct cell types. We identify a quiescent COL17A1 KRT15 stem/progenitor cell population in the most basal cell layer of the esophagus and detect substantial gene expression differences between identical cell types of the human and mouse stomach. Selective expression of BEST4, CFTR, guanylin, and uroguanylin identifies a rare duodenal cell type, referred to as BCHE cell, which likely mediates high-volume fluid secretion because of continual activation of the CFTR channel by guanylin/uroguanylin-mediated autocrine signaling. Serotonin-producing enterochromaffin cells in the antral stomach significantly differ in gene expression from duodenal enterochromaffin cells. We, furthermore, discover that the histamine-producing enterochromaffin-like cells in the oxyntic stomach express the luteinizing hormone, yet another member of the enteroendocrine hormone family.
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http://dx.doi.org/10.1016/j.celrep.2021.108819DOI Listing
March 2021

The presence of metastatic thoracic duct lymph nodes in Western esophageal cancer patients.

Ann Thorac Surg 2021 Mar 4. Epub 2021 Mar 4.

Department of Surgery, University Medical Center Utrecht, The Netherlands.

Background: The thoracic lymphadenectomy during an esophagectomy for esophageal cancer includes resection of the thoracic duct (TD) compartment containing the thoracic duct lymph nodes (TDLN). However, the role of TD compartment resection is still a topic of debate since metastatic TDLNs have only been demonstrated in squamous cell carcinomas in Eastern esophageal cancer patients. Therefore, the aim of this study was to assess the presence and metastatic involvement of TDLNs in a Western population, in which adenocarcinoma is the predominant type of esophageal cancer.

Methods: From July 2017 to May 2020 all consecutive patients undergoing an open or robot-assisted transthoracic esophagectomy with concurrent lymphadenectomy and resection of the TD compartment in the University Medical Center Utrecht, The Netherlands and the Città della Salute e della Scienza University Hospital in Turin, Italy were included. The TD compartment was resected en bloc and was separated in the operation room by the operating surgeon after which it was macro- and microscopically assessed for (metastatic) TDLNs by the pathologist.

Results: A total of 117 patients with an adenocarcinoma (73%) or squamous cell carcinoma (27%) of the esophagus were included. In 61 (52%) patients TDLNs were found, containing metastasis in 9 (15%) patients. No major complications related to TD compartment resection were observed.

Conclusions: This is the first study to demonstrate the presence of metastatic TDLNs in adenocarcinomas of the esophagus. This result provides a valid argument to routinely extend the thoracic lymphadenectomy with resection of the TD compartment during an esophagectomy for esophageal cancer.
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http://dx.doi.org/10.1016/j.athoracsur.2021.02.041DOI Listing
March 2021

Individual risk calculator to predict lymph node metastases in patients with submucosal (T1b) esophageal adenocarcinoma: a multicenter cohort study.

Endoscopy 2021 Feb 24. Epub 2021 Feb 24.

Erasmus MC, Gastroenterology and Hepatology, Rotterdam, Netherlands.

There is a risk for lymph node metastases (LNM) after endoscopic resection of early esophageal adenocarcinoma (EAC). The aim of this study was to develop and internally validate a prediction model that estimates the individual metastases risk in patients with pT1b EAC. This is a nationwide, retrospective, multicenter cohort study. Patients with pT1b EAC and treated with endoscopic resection and/or surgery between 1989 and 2016 were included. Primary endpoint was the presence of LNM in surgical resection specimen or the detection of metastases during follow-up. All resection specimens were histologically reassessed by specialized gastrointestinal pathologists. Subdistribution hazard regression analysis was used to develop a prediction model. The discriminative ability of this model was assessed using the c-statistic. 248 patients with pT1b EAC were included. Metastases were seen in 78 patients, and the 5-year cumulative incidence was 30.9% (95% CI 25.1%-36.8%). The risk for metastases increased with submucosal invasion depth (subdistribution hazard ratio [SHR] 1.08, 95% CI 1.02-1.14, for every increase of 500 μm), for tumors with lymphovascular invasion (SHR 2.95, 95% CI 1.95-4.45) and for larger tumors (SHR 1.23, 95% CI 1.10-1.37, for every increase of 10 mm). The model demonstrated a good discriminative ability (c-statistic 0.81, 95% CI 0.75-0.86). One third of patients with pT1b EAC experienced metastases within 5 years. The probability for developing post resection metastases can be estimated with a personalized predicted risk score incorporating tumor invasion depth, tumor size and lymphovascular invasion. This model needs to be externally validated before implementation into clinical practice.
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http://dx.doi.org/10.1055/a-1399-4989DOI Listing
February 2021

Tumour-stroma ratio has poor prognostic value in nonpedunculated T1 colorectal cancer: A multicentre case-cohort study.

United European Gastroenterol J 2021 Feb 10. Epub 2021 Feb 10.

Department of Gastroenterology and Hepatology, Leiden University Medical Centre, Leiden, The Netherlands.

Background: Current risk stratification models for early invasive (T1) colorectal cancer are not able to discriminate accurately between prognostic favourable and unfavourable tumours, resulting in over-treatment of a large (>80%) proportion of T1 colorectal cancer patients. The tumour-stroma ratio (TSR), which is a measure for the relative amount of desmoplastic tumour stroma, is reported to be a strong independent prognostic factor in advanced-stage colorectal cancer, with a high stromal content being associated with worse prognosis and survival. We aimed to investigate whether the TSR predicts clinical outcome in patients with non-pedunculated T1 colorectal cancer.

Methods: Haematoxylin and eosin (H&E)-stained tumour tissue slides from a retrospective multicentre case cohort of patients with nonpedunculated surgically treated T1 colorectal cancer were assessed for TSR by two independent observers who were blinded for clinical outcomes. The primary end point was adverse outcome, which was defined as the presence of lymph node metastasis in the resection specimen or colorectal cancer recurrence during follow-up.

Results: All 261 patients in the case cohort had H&E slides available for TSR scoring. Of these, 183 were scored as stroma-low, and 78 were scored as stroma-high. There was moderate inter-observer agreement κ = 0.42). In total, 41 patients had lymph node metastasis, 17 patients had recurrent cancer and five had both. Stroma-high tumours were not associated with an increased risk for an adverse outcome (adjusted hazard ratio = 0.66, 95% confidence interval 0.37-1.18; p = 0.163).

Conclusions: Our study emphasises that existing prognosticators may not be simply extrapolated to T1 colorectal cancers, even though their prognostic value has been widely validated in more advanced-stage tumours.
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http://dx.doi.org/10.1177/2050640620975324DOI Listing
February 2021

Axial slicing versus bivalving in the pathological examination of pancreatoduodenectomy specimens (APOLLO): a multicentre randomized controlled trial.

HPB (Oxford) 2021 Jan 21. Epub 2021 Jan 21.

Department of Pathology, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, the Netherlands. Electronic address:

Background: In pancreatoduodenectomy specimens, dissection method may affect the assessment of primary tumour origin (i.e. pancreatic, distal bile duct or ampullary adenocarcinoma), which is primarily determined macroscopically. This is the first study to prospectively compare the two commonly used techniques, i.e. axial slicing and bivalving.

Methods: In four centres, a randomized controlled trial was performed in specimens of patients with a suspected (pre)malignant tumour in the pancreatic head. Primary outcome measure was the level of certainty (scale 0-100) regarding tumour origin by four independent gastrointestinal pathologists based on macroscopic assessment. Secondary outcomes were inter-observer agreement and R1 rate.

Results: In total, 128 pancreatoduodenectomy specimens were randomized. The level of certainty in determining the primary tumour origin did not differ between axial slicing and bivalving (mean score 72 [sd 13] vs. 68 [sd 16], p = 0.21), nor did inter-observer agreement, both being moderate (kappa 0.45 vs. 0.47). In pancreatic cancer specimens, R1 rate (60% vs. 55%, p = 0.71) and the number of harvested lymph nodes (median 16 vs. 17, p = 0.58) were similar.

Conclusion: This study demonstrated no differences in determining the tumour origin between axial slicing and bivalving. Both techniques performed similarly regarding inter-observer agreement, R1 rate, and lymph node harvest.
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http://dx.doi.org/10.1016/j.hpb.2021.01.005DOI Listing
January 2021

Surgical management of a perforated 'black oesophagus'.

ANZ J Surg 2021 Jan 8. Epub 2021 Jan 8.

Department of Surgery, University Medical Center Utrecht, Utrecht, The Netherlands.

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http://dx.doi.org/10.1111/ans.16565DOI Listing
January 2021

Genome Methylation Accurately Predicts Neuroendocrine Tumor Origin: An Online Tool.

Clin Cancer Res 2021 Mar 22;27(5):1341-1350. Epub 2020 Dec 22.

Department of Pathology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.

Purpose: The primary origin of neuroendocrine tumor metastases can be difficult to determine by histopathology alone, but is critical for therapeutic decision making. DNA methylation-based profiling is now routinely used in the diagnostic workup of brain tumors. This has been enabled by the availability of cost-efficient array-based platforms. We have extended these efforts to augment histopathologic diagnosis in neuroendocrine tumors.

Experimental Design: Methylation data was compiled for 69 small intestinal, pulmonary, and pancreatic neuroendocrine tumors. These data were used to build a ridge regression calibrated random forest classification algorithm (neuroendocrine neoplasm identifier, NEN-ID). The model was validated during 3 × 3 nested cross-validation and tested in a local and an external cohort ( = 198 cases).

Results: NEN-ID predicted the origin of tumor samples with high accuracy (>95%). In addition, the diagnostic approach was determined to be robust across a range of possible confounding experimental parameters, such as tumor purity and array quality. A software infrastructure and online user interface were built to make the model available to the scientific community.

Conclusions: This DNA methylation-based prediction model can be used in the workup for patients with neuroendocrine tumors of unknown primary. To facilitate validation and clinical implementation, we provide a user-friendly, publicly available web-based version of NEN-ID.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-3281DOI Listing
March 2021

The Impact of Clinical and Pathological Features on Intraductal Papillary Mucinous Neoplasm Recurrence After Surgical Resection: Long-Term Follow-Up Analysis.

Ann Surg 2020 Nov 17. Epub 2020 Nov 17.

Department of Surgery, Hepatobiliary and Pancreatic Surgery Section of the Division of Surgical Oncology, Johns Hopkins Hospital, Baltimore, MD.

Objective: This study aimed to identify risk factors for recurrence after pancreatic resection for intraductal papillary mucinous neoplasm (IPMN).

Summary Background Data: Long-term follow-up data on recurrence after surgical resection for IPMN are currently lacking. Previous studies have presented mixed results on the role of margin status in risk of recurrence after surgical resection.

Methods: A total of 126 patients that underwent resection for noninvasive IPMN were followed for a median of 9.5 years. Dedicated pathological and radiological reviews were performed to correlate clinical and pathological features (including detailed pathological features of the parenchymal margin) with recurrence after surgical resection. In addition, in a subset of 32 patients with positive margins, we determined the relationship between the margin and original IPMN using driver gene mutations identified by next-generation sequencing.

Results: Family history of pancreatic cancer and high-grade IPMN was identified as risk factors for recurrence in both uni- and multivariate analysis (adjusted hazard ratio 3.05 and 1.88, respectively). Although positive margin was not significantly associated with recurrence in our cohort, the size and grade of the dysplastic focus at the margin were significantly correlated with recurrence in margin-positive patients. Genetic analyses showed that the neoplastic epithelium at the margin was independent from the original IPMN in at least 9 of 32 cases (28%). The majority of recurrences (74%) occurred after 3 years, and a significant minority (32%) occurred after 5 years.

Conclusion: Sustained postoperative surveillance for all patients is indicated, particularly those with risk factors such has family history and high-grade dysplasia.
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http://dx.doi.org/10.1097/SLA.0000000000004427DOI Listing
November 2020

The Management of Neuroendocrine Tumors of the Lung in MEN1: Results From the Dutch MEN1 Study Group.

J Clin Endocrinol Metab 2021 Jan;106(2):e1014-e1027

Department of Endocrine Oncology, University Medical Center Utrecht, GA Utrecht, The Netherlands.

Introduction: Multiple endocrine neoplasia type 1 (MEN1)-related neuroendocrine tumors (NETs) of the lung are mostly indolent, with a good prognosis. Nevertheless, cases of aggressive lung NET do occur, and therefore the management of individual patients is challenging.

Aim: To assess tumor growth and the survival of patients with MEN1-related lung NETs at long-term follow-up.

Methods: The population-based Dutch MEN1 Study Group database (n = 446) was used to identify lung NETs by histopathological and radiological examinations. Tumor diameter was assessed. Linear mixed models and the Kaplan-Meier method were used for analyzing tumor growth and survival. Molecular analyses were performed on a lung NET showing particularly aggressive behavior.

Results: In 102 patients (22.9% of the total MEN1 cohort), 164 lesions suspected of lung NETs were identified and followed for a median of 6.6 years. Tumor diameter increased 6.0% per year. The overall 15-year survival rate was 78.0% (95% confidence interval: 64.6-94.2%) without lung NET-related death. No prognostic factors for tumor growth or survival could be identified. A somatic c.3127A > G (p.Met1043Val) PIK3CA driver mutation was found in a case of rapid growing lung NET after 6 years of indolent disease, presumably explaining the sudden change in course.

Conclusion: MEN1-related lung NETs are slow growing and have a good prognosis. No accurate risk factors for tumor growth could be identified. Lung NET screening should therefore be based on well-informed, shared decision-making, balancing between the low absolute risk of an aggressive tumor in individuals and the potential harms of frequent thoracic imaging.
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http://dx.doi.org/10.1210/clinem/dgaa800DOI Listing
January 2021

Amsterdam International Consensus Meeting: tumor response scoring in the pathology assessment of resected pancreatic cancer after neoadjuvant therapy.

Mod Pathol 2021 01 12;34(1):4-12. Epub 2020 Oct 12.

Department of Pathology, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.

Histopathologically scoring the response of pancreatic ductal adenocarcinoma (PDAC) to neoadjuvant treatment can guide the selection of adjuvant therapy and improve prognostic stratification. However, several tumor response scoring (TRS) systems exist, and consensus is lacking as to which system represents best practice. An international consensus meeting on TRS took place in November 2019 in Amsterdam, The Netherlands. Here, we provide an overview of the outcomes and consensus statements that originated from this meeting. Consensus (≥80% agreement) was reached on a total of seven statements: (1) TRS is important because it provides information about the effect of neoadjuvant treatment that is not provided by other histopathology-based descriptors. (2) TRS for resected PDAC following neoadjuvant therapy should assess residual (viable) tumor burden instead of tumor regression. (3) The CAP scoring system is considered the most adequate scoring system to date because it is based on the presence and amount of residual cancer cells instead of tumor regression. (4) The defining criteria of the categories in the CAP scoring system should be improved by replacing subjective terms including "minimal" or "extensive" with objective criteria to evaluate the extent of viable tumor. (5) The improved, consensus-based system should be validated retrospectively and prospectively. (6) Prospective studies should determine the extent of tissue sampling that is required to ensure adequate assessment of the residual cancer burden, taking into account the heterogeneity of tumor response. (7) In future scientific publications, the extent of tissue sampling should be described in detail in the "Materials and methods" section.
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http://dx.doi.org/10.1038/s41379-020-00683-9DOI Listing
January 2021

Minimally Invasive Resection of Large Gastric Gastrointestinal Stromal Tumors.

Dig Surg 2020 25;37(6):441-446. Epub 2020 Sep 25.

Department of Surgery, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands,

Introduction: Gastrointestinal stromal tumors (GISTs) frequently present as a large exophytically growing mass in the stomach, for which open partial gastrectomy is standard of care. The aim of this study was to evaluate the safety and feasibility of minimally invasive gastric resection (MIG) of large (>5 cm) GIST.

Methods: All patients who underwent MIG for a GIST in the University Medical Center Utrecht between 2011 and 2019 were included. Postoperative course and oncological outcomes were analyzed.

Results: Twenty-two patients with gastric GIST, median size 53 mm [20-175 mm], underwent MIG. In 4 patients, preoperative imatinib was given, aiming for tumor regression. Conversion from laparoscopic to open surgery occurred once (5%). An additional resection was performed in 3 patients (14%). In 2 patients (9%), an intraoperative complication occurred, consisting of tumor rupture in 1 patient (5%), and 6 patients (27%) developed postoperative complications. Median hospital stay was 5 days [3-7 days]. R0 resection was achieved in 96%. In 4 patients, adjuvant treatment was indicated. The median follow-up was 31 months, and 1-, 3- and 5-year disease-free survival were 94, 74 and 74%, respectively. One patient presented with local recurrence 2 years after the index resection.

Conclusion: MIG for large GIST up to 17.5 cm in diameter is safe, feasible, and oncologically sound, allowing for a controlled resection and reduced patient morbidity.
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http://dx.doi.org/10.1159/000510386DOI Listing
September 2020

The CARDIA-trial protocol: a multinational, prospective, randomized, clinical trial comparing transthoracic esophagectomy with transhiatal extended gastrectomy in adenocarcinoma of the gastroesophageal junction (GEJ) type II.

BMC Cancer 2020 Aug 20;20(1):781. Epub 2020 Aug 20.

Department of General, Visceral, Cancer and Transplantation Surgery, University of Cologne, Kerpener Str. 62, 50937, Cologne, Germany.

Background: Adenocarcinoma of the gastroesophageal junction (GEJ) Siewert type II can be resected by transthoracic esophagectomy or transhiatal extended gastrectomy. Both allow for a complete tumor resection, yet there is an ongoing controversy about which surgical approach is superior with regards to quality of life, oncological outcomes and survival. While some studies suggest a better oncological outcome after transthoracic esophagectomy, others favor transhiatal extended gastrectomy for a better postoperative quality of life. To date, only retrospective studies are available, showing ambiguous results.

Methods: This study is a multinational, multicenter, randomized, clinical superiority trial. Patients (n = 262) with a GEJ type II tumor resectable by both transthoracic esophagectomy and transhiatal extended gastrectomy will be enrolled in the trial. Type II tumors are defined as tumors with their midpoint between ≤1 cm proximal and ≤ 2 cm distal of the top of gastric folds on preoperative endoscopy. Patients will be included in one of the participating European sites and are randomized to either transthoracic esophagectomy or transhiatal extended gastrectomy. The trial is powered to show superiority for esophagectomy with regards to the primary efficacy endpoint overall survival. Key secondary endpoints are complete resection (R0), number and localization of tumor infiltrated lymph nodes at dissection, post-operative complications, disease-free survival, quality of life and cost-effectiveness. Postoperative survival and quality of life will be followed-up for 24 months after discharge. Further survival follow-up will be conducted as quarterly phone calls up to 60 months.

Discussion: To date, as level 1 evidence is lacking, there is no consensus on which surgery is superior and both surgeries are used to treat GEJ type II carcinoma worldwide. The CARDIA trial is the first randomized trial to compare transthoracic esophagectomy versus transhiatal extended gastrectomy in patients with GEJ type II tumors. Several quality control measures were implemented in the protocol to ensure data reliability and increase the trial's significance. It is hypothesized that esophagectomy allows for a higher rate of radical resections and a more complete mediastinal lymph node dissection, resulting in a longer overall survival, while still providing an acceptable quality of life and cost-effectiveness.

Trial Registration: The trial was registered on August 2nd 2019 at the German Clinical Trials Register under the trial-ID DRKS00016923 .
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http://dx.doi.org/10.1186/s12885-020-07152-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7439687PMC
August 2020

Genomic characterization of malignant progression in neoplastic pancreatic cysts.

Nat Commun 2020 08 14;11(1):4085. Epub 2020 Aug 14.

Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Intraductal papillary mucinous neoplasms (IPMNs) and mucinous cystic neoplasms (MCNs) are non-invasive neoplasms that are often observed in association with invasive pancreatic cancers, but their origins and evolutionary relationships are poorly understood. In this study, we analyze 148 samples from IPMNs, MCNs, and small associated invasive carcinomas from 18 patients using whole exome or targeted sequencing. Using evolutionary analyses, we establish that both IPMNs and MCNs are direct precursors to pancreatic cancer. Mutations in SMAD4 and TGFBR2 are frequently restricted to invasive carcinoma, while RNF43 alterations are largely in non-invasive lesions. Genomic analyses suggest an average window of over three years between the development of high-grade dysplasia and pancreatic cancer. Taken together, these data establish non-invasive IPMNs and MCNs as origins of invasive pancreatic cancer, identifying potential drivers of invasion, highlighting the complex clonal dynamics prior to malignant transformation, and providing opportunities for early detection and intervention.
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http://dx.doi.org/10.1038/s41467-020-17917-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7428044PMC
August 2020

Gastric Epithelial Polyps: When to Ponder, When to Panic.

Surg Pathol Clin 2020 Sep 11;13(3):431-452. Epub 2020 Jul 11.

Department of Pathology, Radboud University Medical Center, Geert Grooteplein Zuid 10, Nijmegen 6525 GA, The Netherlands; Department of Pathology, University Medical Center Utrecht, Utrecht University, Heidelberglaan 100, Utrecht 3584 CX, The Netherlands. Electronic address:

This review provides an overview of different types of gastric epithelial polyps. The polyps are classified based on their cell or epithelial compartment of origin. Some of these polyps can be considered reactive or nonneoplastic, whereas others are neoplastic in origin, are sometimes associated with a hereditary polyposis/cancer syndrome, and may have malignant potential. The aim of this review is to provide a pragmatic overview for the practicing pathologist about how to correctly diagnose and deal with gastric epithelial polyps and when (not) to ponder, and when (not) to panic.
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http://dx.doi.org/10.1016/j.path.2020.05.004DOI Listing
September 2020

Reliability and Agreement of Radiological and Pathological Tumor Size in patients with MEN1-Related Pancreatic Neuroendocrine Tumors: Results from a Population-Based Cohort.

Neuroendocrinology 2020 Jul 28. Epub 2020 Jul 28.

Background: Pancreatic neuroendocrine tumors (pNETs) have a high prevalence in patients with multiple endocrine neoplasia type 1 (MEN1) and are the leading cause of death. Tumor size is still regarded as the main prognostic factor and therefore used for surgical decision making. We assessed reliability and agreement of radiological and pathological tumor size in a population-based cohort of patients with MEN1-related pNETs.

Methods: Patients were selected from the Dutch MEN1 database if they had undergone a resection for a pNET between 2003 and 2018. Radiological (magnetic resonance imaging (MRI), computed tomography (CT) and endoscopic ultrasonography (EUS)) and pathological tumor size were collected from patient records. Measures of agreement (Bland-Altman plots with limits of agreement (LoA) and absolute agreement) and reliability (Intraclass Correlation Coefficients (ICC) and unweighted Kappa) were calculated for continuous and categorized (< or ≥ 2 cm) pNET size.

Results: In seventy-three included patients, the median radiological and pathological tumor size measured was 22 [3 - 160] and 21 [4 - 200] mm, respectively. Mean bias between radiological and pathological tumor size was -0.2mm and LoA ranged from -12.9 to 12.6mm. For the subgroups of MRI, CT and EUS, LoA of radiological and pathological tumor size ranged from -9.6 to 10.9, -15.9 to 15.8 and -13.9 to 11.0, respectively. ICCs for the overall cohort, MRI, CT and EUS were 0.80, 0.86, 0.75 and 0.76, respectively. Based on the 2 cm criterion, agreement was 81.5%, hence 12 patients (18.5%) were classified differently between imaging and pathology. Absolute agreement and kappa's of MRI, CT and EUS were 88.6%, 85.7%, 75.0% and 0.77, 0.71 and 0.50, respectively.

Conclusion: Within a population-based cohort, MEN1-related pNET size was not systematically over-, or underestimated on preoperative imaging. Based on agreement and reliability measures, MRI is the preferred imaging modality.
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http://dx.doi.org/10.1159/000510514DOI Listing
July 2020

The decisive role of molecular pathology in presumed somatic metastases of type II testicular germ cell tumors: report of 2 cases.

Diagn Pathol 2020 Jul 25;15(1):99. Epub 2020 Jul 25.

Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands.

Background: Molecular diagnostics can be decisive in the differential diagnosis between a somatic metastasis of type II testicular germ cell tumor (TGCT) or a second primary carcinoma. This is in line with recent recommendations from the International Society of Urological Pathology, based on an international survey which showed that molecular testing is currently only performed by a minority of urological pathologists.

Case Presentations: This case report illustrates the necessity of molecular testing in two patients with a history of type II TGCT and a metastatic (retro) peritoneal carcinoma years later. The genetic hallmark of type II TGCT, chromosome 12p gain, was studied by fluorescence in situ hybridization and whole genome methylation profiling in case 1, and by single nucleotide polymorphism (SNP)-array in case 2. Next generation sequencing (NGS) was used to further explore clonality between the primary TGCT and peritoneal metastasis in case 2. In case 1, chromosome 12p gain was found in the primary type II TGCT and in the acinar cell carcinoma of the metastatic malignancy. In case 2, SNP array showed 12p gain in the epithelial component of the primary teratomatous TGCT but not in the peritoneal adenocarcinoma. Furthermore, NGS showed no mutations in the primary teratomatous TGCT but a KRAS and GNAS mutation in the peritoneal adenocarcinoma, suggestive of an appendicular origin.

Conclusions: Without the molecular data, both cases would have been regarded as a metastatic TGCT with development of somatic-type malignancy, which appeared a wrong diagnosis for case 2. These cases demonstrate the importance of molecular methods as an adjunct in today's pathology practice.
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http://dx.doi.org/10.1186/s13000-020-01011-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7382836PMC
July 2020

Medullary Pancreatic Carcinoma Due to Somatic POLE Mutation: A Distinctive Pancreatic Carcinoma With Marked Long-Term Survival.

Pancreas 2020 08;49(7):999-1003

From the Department of Pathology, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Nijmegen.

Medullary pancreatic carcinoma (MPC) is a rare histological variant of pancreatic ductal adenocarcinoma (PDAC). Because of its rarity, data on the molecular background of MPC are limited. Previous studies have shown that a subset of MPCs is microsatellite instable due to mismatch repair deficiency. Here, we present a unique case of a female patient in her 60s who is a long-term survivor after surgery for pancreatic cancer. The patient had a microsatellite stable MPC with a somatic mutation of the polymerase epsilon gene (POLE). Both microsatellite instable and POLE-mutated cancers are usually associated with high tumor mutational burden and antigen load, resulting in a prominent antitumor immune response and overall better survival. The current case illustrates that, in addition to mismatch repair deficiency, MPC can develop because of a somatic POLE mutation, resulting in a tumor with a high tumor mutational burden and leading to a better prognosis compared with conventional PDAC. This new finding may have important implications in the management of patients with MPC and calls for further studies on the role of POLE in PDAC.
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http://dx.doi.org/10.1097/MPA.0000000000001588DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7368848PMC
August 2020

Associations of non-pedunculated T1 colorectal adenocarcinoma outcome with consensus molecular subtypes, immunoscore, and microsatellite status: a multicenter case-cohort study.

Mod Pathol 2020 12 24;33(12):2626-2636. Epub 2020 Jun 24.

Department of Pathology, University Medical Center Utrecht, Utrecht, the Netherlands.

Advanced colorectal cancer (CRC) consensus molecular subtype 4 (CMS4) or CRC with a low immunoscore is associated with shorter survival times. Non-metastatic CRC with microsatellite instability (MSI) is associated with a lower risk of recurrence. We evaluated outcome (lymph node metastases [LNM] or cancer recurrence) in these tumor subtypes in patients with surgically-removed non-pedunculated T1 CRC by performing a multicenter case-cohort study. We included all patients in 13 hospitals in the Netherlands from 2000-2014 (n = 651). We randomly selected a subgroup of patients (n = 223) and all patients with LNM or recurrence (n = 63), and median follow-up of 44 months. We centrally reviewed tumor-slides, and constructed and immunostained tissue microarrays determining MSI, CMS (MSI/CMS1, CMS2/3, or CMS4), and immunoscore (I-low/I-high). We used weighted Cox proportional hazard models to evaluate the association of MSI, CMS, and immunoscore with LNM or recurrence, adjusting for conventional histologic risk factors. In the randomly selected subgroup of patients, 7.1% of tumors were MSI/CMS1, 91.0% CMS2/3, 1.8% CMS4, and 25% I-low. In the case-cohort, patients with CMS4 tumors had an increased risk for LNM or recurrence compared with patients with tumors of other CMSs (adjusted hazard ratio [HR], 3.97; 95% CI, 1.12-14.06; P = 0.03). Albeit not significant, tumors with MSI had a lower risk for LNM or recurrence than other tumor subtypes (adjusted HR, 0.52; 95% CI, 0.12-2.30; P = 0.39), whereas tumors with a low immunoscore had an increased risk for LNM or recurrence (adjusted HR, 1.30; 95% CI, 0.68-2.48; P = 0.43). In conclusion, in a case-cohort study of patients with non-pedunculated T1 CRC, MSI, and immunoscore were not significantly associated with adverse outcome after surgery. CMS4 substantially increased the risk of adverse outcome. However, CMS4 is rare in T1 CRCs, limiting its value for determining the risk in patients.
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http://dx.doi.org/10.1038/s41379-020-0598-9DOI Listing
December 2020

Recurrent Loss of SMARCA4 in Sinonasal Teratocarcinosarcoma.

Am J Surg Pathol 2020 10;44(10):1331-1339

Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX.

Molecular analysis has reshaped the landscape of high grade sinonasal tumors by defining novel entities and identifying recurrent mutations in established tumor types. However, sinonasal teratocarcinosarcoma (TCS), a rare and aggressive tumor with intermixed teratomatous, carcinomatous, and sarcomatous elements, remains poorly understood. The multiphenotypic differentiation of TCS has engendered persistent controversy about its histogenesis and leads to diagnostic overlap with several other malignancies. In this study, we evaluated the molecular underpinnings of TCS to clarify its pathogenesis and diagnosis. We performed SMARCA4 immunohistochemistry (IHC) on 22 TCS and 153 other sinonasal tumors. We identified loss of SMARCA4 expression in 18 TCS (82%), including 15 (68%) with complete loss and 3 (14%) with partial loss. Although we also identified partial SMARCA4 loss in 1 of 8 SMARCB1-deficient sinonasal carcinomas (13%), SMARCA4 was intact in all other sinonasal carcinomas and neuroendocrine tumors. We then selected 3 TCS with complete SMARCA4 loss by IHC for a targeted next-generation sequencing panel that included 1425 cancer-related genes. We confirmed biallelic somatic inactivation of SMARCA4 without other known oncogenic mutations in these 3 cases. Overall, these findings suggest that SMARCA4 inactivation may be the dominant genetic event in TCS, expanding understanding of this gene's role in sinonasal tumorigenesis. They also raise the possibility that TCS is on a diagnostic spectrum with the newly described SMARCA4-deficient sinonasal carcinoma, blurring the lines between established and emerging sinonasal entities. In addition, SMARCA4 IHC may provide a useful adjunct for confirming a diagnosis of TCS in limited material.
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http://dx.doi.org/10.1097/PAS.0000000000001508DOI Listing
October 2020

Thirty-six-year-old woman with a liver mass: diagnosis hidden in history.

J Clin Pathol 2020 Dec 8;73(12):e7. Epub 2020 Jun 8.

Pathology, UMC Utrecht, Utrecht, The Netherlands.

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http://dx.doi.org/10.1136/jclinpath-2019-206271DOI Listing
December 2020

Surgical management and pathological assessment of pancreatoduodenectomy with venous resection: an international survey among surgeons and pathologists.

HPB (Oxford) 2021 Jan 20;23(1):80-89. Epub 2020 May 20.

Department of Surgery, Leiden University Medical Center, Leiden, the Netherlands. Electronic address:

Background: The aim of this survey was to gain insights in the current surgical management and pathological assessment of pancreatoduodenectomy with portal-superior mesenteric vein resection (VR).

Methods: A systematic literature search was performed to identify international expert surgeons (N = 150) and pathologists (N = 40) who published relevant studies between 2009 and 2019. These experts and Dutch surgeons (N = 17) and pathologists (N = 20) were approached to complete an online survey.

Results: Overall, 76 (46%) surgeons and 37 (62%) pathologists completed the survey. Most surgeons (71%) estimated that preoperative imaging corresponded correctly with intraoperative findings of venous involvement in 50-75% of patients. An increased complication risk following VR was expected by 55% of surgeons, mainly after Type 4 (segmental resection-venous conduit anastomosis). Most surgeons (61%) preferred Type 3 (segmental resection-primary anastomosis). Most surgeons (75%) always perform the VR themselves. Standard postoperative imaging for patency control was performed by 54% of surgeons and 39% adjusted thromboprophylaxis following VR. Most pathologists (76%) always assessed tumor infiltration in the resected vein and only 54% of pathologists always assess the resection margins of the vein itself. Variation in assessment of tumor infiltration depth was observed.

Conclusion: This international survey showed variation in the surgical management and pathological assessment of pancreatoduodenectomy with venous involvement. This highlights the lack of evidence and emphasizes the need for research on imaging modalities to improve patient selection for VR, surgical techniques, postoperative management and standardization of the pathological assessment.
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http://dx.doi.org/10.1016/j.hpb.2020.04.015DOI Listing
January 2021

Gastric- and intestinal-type IPMN: two of a kind?

Virchows Arch 2020 Jul 12;477(1):17-19. Epub 2020 May 12.

Department of Pathology, University Medical Center Utrecht, Utrecht University, Heidelberglaan 100, 3584, Utrecht, CX, Netherlands.

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http://dx.doi.org/10.1007/s00428-020-02827-3DOI Listing
July 2020

Comprehensive characterisation of pancreatic ductal adenocarcinoma with microsatellite instability: histology, molecular pathology and clinical implications.

Gut 2021 Jan 29;70(1):148-156. Epub 2020 Apr 29.

ARC-Net Research Center and Department of Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, Verona, Italy.

Objective: Recently, tumours with microsatellite instability (MSI)/defective DNA mismatch repair (dMMR) have gained considerable interest due to the success of immunotherapy in this molecular setting. Here, we aim to clarify clinical-pathological and/or molecular features of this tumour subgroup through a systematic review coupled with a comparative analysis with existing databases, also providing indications for a correct approach to the clinical identification of MSI/dMMR pancreatic ductal adenocarcinoma (PDAC).

Design: PubMed, SCOPUS and Embase were searched for studies reporting data on MSI/dMMR in PDAC up to 30 November 2019. Histological and molecular data of MSI/dMMR PDAC were compared with non-MSI/dMMR PDAC and with PDAC reference cohorts (including SEER database and The Cancer Genome Atlas Research Network - TCGA project).

Results: Overall, 34 studies with 8323 patients with PDAC were included in the systematic review. MSI/dMMR demonstrated a very low prevalence in PDAC (around 1%-2%). Compared with conventional PDAC, MSI/dMMR PDAC resulted strongly associated with medullary and mucinous/colloid histology (p<0.01) and with a / wild-type molecular background (p<0.01), with more common genes mutations. Data on survival are still unclear.

Conclusion: PDAC showing typical medullary or mucinous/colloid histology should be routinely examined for MSI/dMMR status using specific tests (immunohistochemistry, followed by MSI-PCR in cases with doubtful results). Next-generation sequencing (NGS) should be adopted either where there is limited tissue or as part of NGS tumour profiling in the context of precision oncology, acknowledging that conventional histology of PDAC may rarely harbour MSI/dMMR.
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http://dx.doi.org/10.1136/gutjnl-2020-320726DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7211065PMC
January 2021

Ex Vivo Assessment of Tumor-Targeting Fluorescent Tracers for Image-Guided Surgery.

Cancers (Basel) 2020 Apr 17;12(4). Epub 2020 Apr 17.

Department of Radiology, Nuclear Medicine and Anatomy, Radboud Institute for Health Sciences, Radboud University Medical Center, 6525GA Nijmegen, The Netherlands.

Image-guided surgery can aid in achieving complete tumor resection. The development and assessment of tumor-targeted imaging probes for near-infrared fluorescence image-guided surgery relies mainly on preclinical models, but the translation to clinical use remains challenging. In the current study, we introduce and evaluate the application of a dual-labelled tumor-targeting antibody for ex vivo incubation of freshly resected human tumor specimens and assessed the tumor-to-adjacent tissue ratio of the detectable signals. Immediately after surgical resection, peritoneal tumors of colorectal origin were placed in cold medium. Subsequently, tumors were incubated with In-DOTA-hMN-14-IRDye800CW, an anti-carcinoembryonic antigen (CEA) antibody with a fluorescent and radioactive label. Tumors were then washed, fixed, and analyzed for the presence and location of tumor cells, CEA expression, fluorescence, and radioactivity. Twenty-six of 29 tumor samples obtained from 10 patients contained malignant cells. Overall, fluorescence intensity was higher in tumor areas compared to adjacent non-tumor tissue parts ( < 0.001). The average fluorescence tumor-to-background ratio was 11.8 ± 9.1:1. A similar ratio was found in the autoradiographic analyses. Incubation with a non-specific control antibody confirmed that tumor targeting of our tracer was CEA-specific. Our results demonstrate the feasibility of this tracer for multimodal image-guided surgery. Furthermore, this ex vivo incubation method may help to bridge the gap between preclinical research and clinical application of new agents for radioactive, near infrared fluorescence or multimodal imaging studies.
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http://dx.doi.org/10.3390/cancers12040987DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7226456PMC
April 2020

Alternative Lengthening of Telomeres and Differential Expression of Endocrine Transcription Factors Distinguish Metastatic and Non-metastatic Insulinomas.

Endocr Pathol 2020 Jun;31(2):108-118

Department of Pathology, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX, Utrecht, The Netherlands.

Insulin-producing pancreatic neuroendocrine tumors (PanNETs)/insulinomas are generally considered to be indolent tumors with an excellent prognosis after complete resection. However, some insulinomas have a poor prognosis due to relapses and metastatic disease. Recently, studies in non-functional PanNETs indicated that behavior can be stratified according to alpha- and beta-cell differentiation, as defined by expression of the transcription factors ARX and PDX1, respectively. It is unknown whether similar mechanisms play a role in insulinomas. Therefore, we determined ARX and PDX1 expression in a cohort of 35 sporadic primary insulinomas and two liver metastases of inoperable primary insulinomas. In addition, WHO grade and loss of ATRX or DAXX were determined by immunohistochemistry, and alternative lengthening of telomeres (ALT) and CDKN2A status by fluorescence in situ hybridization. These findings were correlated with tumor characteristics and clinical follow-up data. In total, five out of 37 insulinoma patients developed metastatic disease. Metastatic insulinomas were all larger than 3 cm, whereas the indolent insulinomas were smaller (p value < 0.05). All three primary insulinomas that metastasized showed ARX expression, 2/3 showed ALT, and 1/3 had a homozygous deletion of CDKN2A as opposed to absence of ARX expression, ALT, or CDKN2A deletions in the 32 non-metastatic cases. The two liver metastases also showed ARX expression and ALT (2/2). The presence of ARX expression, which is usually absent in beta-cells, and genetic alterations not seen in indolent insulinomas strongly suggest a distinct tumorigenic mechanism in malignant insulinomas, with similarities to non-functional PanNETs. These observations may inform future follow-up strategies after insulinoma surgery.
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http://dx.doi.org/10.1007/s12022-020-09611-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7250793PMC
June 2020

Assessment of ARX expression, a novel biomarker for metastatic risk in pancreatic neuroendocrine tumors, in endoscopic ultrasound fine-needle aspiration.

Diagn Cytopathol 2020 Apr 17;48(4):308-315. Epub 2019 Dec 17.

Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands.

Background: The transcription factors ARX and PDX1, and alternative lengthening of telomeres (ALT) were recently described as prognostic markers for resected non-functional pancreatic neuroendocrine tumors (PanNETs). ALT positive tumors with ARX expression relapse most often. Currently, tumor size is the only preoperative marker used to decide whether or not to operate, thus additional preoperative prognostic markers are needed. Therefore, it is critical to assess the performance of these biomarkers on preoperative cytologic specimens.

Methods: Endoscopic fine-needle aspiration cellblock material and corresponding surgical specimens of 13 patients with PanNETs were assessed for histology, immunohistochemical staining of ARX, PDX1, Synaptophysin, Ki67, and telomere-specific fluorescence in situ hybridization to detect ALT, and then associated with clinicopathological features. Scoring for ARX and PDX1 was performed blinded by two independent observers.

Results: Of the 13 surgical specimens, 8 were ARX+/PDX1-, 2 ARX-/PDX1+, and 3 ARX+/PDX1+. Concordance between cytologic and surgical specimens for ARX protein expression was 100%, whereas concordance for PDX1, ALT, and WHO tumor grade was 85%, 91%, and 73%, respectively. There was a perfect inter-observer agreement in ARX and PDX1 scoring.

Conclusion: ARX can reliably be determined in cytologic specimens and has low inter-observer variability. For cytology, false-positive PDX1 expression was observed, possibly due to contamination or sampling, while ALT had a false-negative case due to incomplete sampling. As previously observed, tumor grade is underestimated in cytologic specimens. Thus, ARX and ALT are the most promising markers to predict metastatic behavior in PanNETs, thereby warranting further validation in larger studies.
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http://dx.doi.org/10.1002/dc.24368DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7079001PMC
April 2020

Optimal timing for prediction of pathologic complete response to neoadjuvant chemoradiotherapy with diffusion-weighted MRI in patients with esophageal cancer.

Eur Radiol 2020 Apr 10;30(4):1896-1907. Epub 2019 Dec 10.

Department of Radiation Oncology, University Medical Center Utrecht, Utrecht University, Heidelberglaan 100, 3584, CX, Utrecht, The Netherlands.

Objective: This study was conducted in order to determine the optimal timing of diffusion-weighted magnetic resonance imaging (DW-MRI) for prediction of pathologic complete response (pCR) to neoadjuvant chemoradiotherapy (nCRT) for esophageal cancer.

Methods: Patients with esophageal adenocarcinoma or squamous cell carcinoma who planned to undergo nCRT followed by surgery were enrolled in this prospective study. Patients underwent six DW-MRI scans: one baseline scan before the start of nCRT and weekly scans during 5 weeks of nCRT. Relative changes in mean apparent diffusion coefficient (ADC) values between the baseline scans and the scans during nCRT (ΔADC(%)) were compared between pathologic complete responders (pCR) and non-pCR (tumor regression grades 2-5). The discriminative ability of ΔADC(%) was determined based on the c-statistic.

Results: A total of 24 patients with 142 DW-MRI scans were included. pCR was observed in seven patients (29%). ΔADC(%) from baseline to week 2 was significantly higher in patients with pCR versus non-pCR (median [IQR], 36% [30%, 41%] for pCR versus 16% [14%, 29%] for non-pCR, p = 0.004). The ΔADC(%) of the second week in combination with histology resulted in the highest c-statistic for the prediction of pCR versus non-pCR (0.87). The c-statistic of this model increased to 0.97 after additional exclusion of patients with a small tumor volume (< 7 mL, n = 3) and tumor histology of the resection specimen other than adenocarcinoma or squamous cell carcinoma (n = 1).

Conclusion: The relative change in tumor ADC (ΔADC(%)) during the first 2 weeks of nCRT is the most predictive for pathologic complete response to nCRT in esophageal cancer patients.

Key Points: • DW-MRI during the second week of neoadjuvant chemoradiotherapy is most predictive for pathologic complete response in esophageal cancer. • A model including ΔADCwas able to discriminate between pathologic complete responders and non-pathologic complete responders in 87%. • Improvements in future MRI studies for esophageal cancer may be obtained by incorporating motion management techniques.
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http://dx.doi.org/10.1007/s00330-019-06513-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7062655PMC
April 2020