Publications by authors named "Elise Bekers"

21 Publications

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Case of the month from the Netherlands Cancer Institute, Amsterdam: how to differentiate between benign and malignant prostatic cysts.

BJU Int 2020 08;126(2):240-244

Department of Urology, Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands.

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http://dx.doi.org/10.1111/bju.15156DOI Listing
August 2020

Cribriform architecture in radical prostatectomies predicts oncological outcome in Gleason score 8 prostate cancer patients.

Mod Pathol 2021 01 20;34(1):184-193. Epub 2020 Jul 20.

Department of Pathology, Erasmus MC, University Medical Center, Rotterdam, The Netherlands.

The Gleason score is an important parameter for clinical outcome in prostate cancer patients. Gleason score 8 is a heterogeneous disease including Gleason score 3 + 5, 4 + 4, and 5 + 3 tumors, and encompasses a broad range of tumor growth patterns. Our objective was to characterize individual growth patterns and identify prognostic parameters in Gleason score 8 prostate cancer patients. We reviewed 1064 radical prostatectomy specimens, recorded individual Gleason 4 and 5 growth patterns as well as presence of intraductal carcinoma, and evaluated biochemical recurrence- and metastasis-free survival. Gleason score 8 disease was identified in 140 (13%) patients, of whom 76 (54%) had Gleason score 3 + 5, 46 (33%) 4 + 4, and 18 (13%) 5 + 3 disease. Invasive cribriform and/or intraductal carcinoma (n = 87, 62%) was observed more frequently in Gleason score 4 + 4 (93%) than 3 + 5 (47%; P < 0.001) and 5 + 3 (44%; P < 0.001) patients. Gleason pattern 5 was present in 110 (79%) men: as single cells and/or cords in 99 (90%) and solid fields in 32 (29%) cases. Solid field pattern 5 coexisted with cribriform architecture (23/32, 72%) more frequently than nonsolid pattern 5 cases (36/78, 46%, P = 0.02). In multivariable analysis including age, prostate-specific antigen, pT-stage, surgical margin status, and lymph node metastases, presence of cribriform architecture was an independent parameter for biochemical recurrence-free (hazard ratio (HR) 2.0, 95% confidence interval (CI) 1.0-3.7; P = 0.04) and metastasis-free (HR 3.5, 95% CI 1.0-12.3; P = 0.05) survival. In conclusion, invasive cribriform and/or intraductal carcinoma occurs more frequently in Gleason score 4 + 4 prostate cancer patients than in Gleason score 3 + 5 and 5 + 3, and is an independent parameter for biochemical recurrence and metastasis. Therefore, cribriform architecture has added value in risk stratification of Gleason score 8 prostate cancer patients.
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http://dx.doi.org/10.1038/s41379-020-0625-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7806505PMC
January 2021

H3K27me3 expression and methylation status in histological variants of malignant peripheral nerve sheath tumours.

J Pathol 2020 10 1;252(2):151-164. Epub 2020 Sep 1.

Research Department of Pathology, University College London, London, UK.

Diagnosing MPNST can be challenging, but genetic alterations recently identified in polycomb repressive complex 2 (PRC2) core component genes, EED and SUZ12, resulting in global loss of the histone 3 lysine 27 trimethylation (H3K27me3) epigenetic mark, represent drivers of malignancy and a valuable diagnostic tool. However, the reported loss of H3K27me3 expression ranges from 35% to 84%. We show that advances in molecular pathology now allow many MPNST mimics to be classified confidently. We confirm that MPNSTs harbouring mutations in PRC2 core components are associated with loss of H3K27me3 expression; whole-genome doubling was detected in 68%, and SSTR2 was amplified in 32% of MPNSTs. We demonstrate that loss of H3K27me3 expression occurs overall in 38% of MPNSTs, but is lost in 76% of histologically classical cases, whereas loss was detected in only 23% cases with heterologous elements and 14% where the diagnosis could not be provided on morphology alone. H3K27me3 loss is rarely seen in other high-grade sarcomas and was not found to be associated with an inferior outcome in MPNST. We show that DNA methylation profiling distinguishes MPNST from its histological mimics, was unrelated to anatomical site, and formed two main clusters, MeGroups 4 and 5. MeGroup 4 represents classical MPNSTs lacking H3K27me3 expression in the majority of cases, whereas MeGroup 5 comprises MPNSTs exhibiting non-classical histology and expressing H3K27me3 and cluster with undifferentiated sarcomas. The two MeGroups are distinguished by differentially methylated PRC2-associated genes, the majority of which are hypermethylated in the promoter regions in MeGroup 4, indicating that the PRC2 target genes are not expressed in these tumours. The methylation profiles of MPNSTs with retention of H3K27me3 in MeGroups 4 and 5 are independent of mutations in PRC2 core components and the driver(s) in these groups remain to be identified. Our results open new avenues of investigation. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.
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http://dx.doi.org/10.1002/path.5507DOI Listing
October 2020

Ga-PSMA Cerenkov luminescence imaging in primary prostate cancer: first-in-man series.

Eur J Nucl Med Mol Imaging 2020 10 2;47(11):2624-2632. Epub 2020 Apr 2.

Department of Nuclear Medicine, Netherlands Cancer Institute-Antoni van Leeuwenhoek, Amsterdam, The Netherlands.

Purpose: Currently, approximately 11-38% of prostate cancer (PCa) patients undergoing radical prostatectomy have a positive surgical margin (PSM) on histopathology. Cerenkov luminescence imaging (CLI) using Ga-prostate-specific membrane antigen (Ga-PSMA) is a novel technique for intraoperative margin assessment. The aim of this first-in-man study was to investigate the feasibility of intraoperative Ga-PSMA CLI. In this study, feasibility was defined as the ability to distinguish between a positive and negative surgical margin, imaging within 45 min and low radiation exposure to staff.

Methods: Six patients were included in this ongoing study. Following perioperative i.v. injection of ~ 100 MBq Ga-PSMA, the prostate was excised and immediately imaged ex vivo. Different acquisition protocols were tested, and hotspots on CLI images from the intact prostate were marked for comparison with histopathology.

Results: By using an acquisition protocol with 150 s exposure time, 8 × 8 binning and a 550 nm shortpass filter, PSMs and negative surgical margins (NSMs) were visually correctly identified on CLI in 3 of the 5 patients. Two patients had a hotspot on CLI from cancer < 0.1 mm from the excision margin.

Conclusion: Overall, the study showed that Ga-PSMA CLI is a feasible and low-risk technique for intraoperative margin assessment in PCa. The remaining patients in this ongoing study will be used to assess the diagnostic accuracy of the technique.

Trial Registration: NL8256 registered at www.trialregister.nl on 04/11/20109.
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http://dx.doi.org/10.1007/s00259-020-04783-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7515945PMC
October 2020

Clinicopathological characteristics of glomeruloid architecture in prostate cancer.

Mod Pathol 2020 08 20;33(8):1618-1625. Epub 2020 Feb 20.

Department of Pathology, Erasmus MC, University Medical Center, P.O. Box 2040, 3000, Rotterdam, The Netherlands.

Glomeruloid architecture is the least common Gleason 4 growth pattern in prostate adenocarcinoma. Its clinicopathological features and relation with cribriform architecture, which has been recognized as an adverse feature, remains to be established. Our objective was to investigate clinicopathological features of glomeruloid architecture in radical prostatectomies. We reviewed 1064 radical prostatectomy specimens and recorded Grade Group, pT-stage, margin status, Gleason pattern percentages, and growth patterns. Simple and complex glomerulations were distinguished by gland size and intraluminal cribriform protrusions. Clinical endpoint was biochemical recurrence-free survival. Glomerulations were identified in 365 (34%) specimens. In 472 Grade Group 2 patients, 210 (44%) had simple and 92 (19%) complex glomerulations. Complex glomerulations coincided with cribriform architecture more often than simple glomerulations (67% versus 52%; P = 0.01). Men with simple glomerulations had significantly lower prostate specific antigen (PSA) levels (9.7 versus 12.1 ng/ml; P = 0.03), percentage Gleason pattern 4 (19% versus 25%; P = 0.001), extra-prostatic extension (34% versus 50%; P = 0.01), and positive surgical margins (25% versus 39%; P = 0.04) than those with cribriform architecture. Extra-prostatic extension (37%) and positive surgical margins (30%) in men with complex glomerulations resembled those with simple glomeruloid rather than those with cribriform architecture. In multivariate Cox regression analysis adjusted for PSA, pT-stage, margin status, and lymph node metastases, cribriform architecture had independent predictive value for biochemical recurrence-free survival (hazard ratio (HR)) 1.9; 95% confidence interval (CI) 1.2-2.9; P = 0.004), while simple (HR 0.8; 95% CI 0.5-1.2; P = 0.26) and complex (HR 0.9; 95% CI 0.5-1.6; P = 0.67) glomerulations did not. Both simple and complex glomeruloid architecture are associated with better outcome than cribriform architecture in Grade Group 2 prostate cancer patients. Therefore, glomeruloid pattern and particularly complex glomerulations should not be classified as a cribriform growth pattern variant in radical prostatectomy specimens.
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http://dx.doi.org/10.1038/s41379-020-0507-2DOI Listing
August 2020

Diagnostic Laparoscopy and Abdominal Cytology Reliably Detect Peritoneal Metastases in Patients with Urachal Adenocarcinoma.

Ann Surg Oncol 2020 Jul 12;27(7):2468-2475. Epub 2020 Feb 12.

Department of Surgical Oncology (Urology), The Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands.

Background: Urachal adenocarcinoma (UrAC) is a rare malignancy that can cause peritoneal metastases (PM). Analogous to other enteric malignancies, selected patients with limited PM of UrAC can be treated by cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS/HIPEC).

Objective: The aim of this study was to address the value of diagnostic laparoscopy (DLS) and abdominal cytology (ACyt) for the detection and evaluation of the extent of PM in patients with UrAC.

Methods: A consecutive series of cN0M0 patients with UrAC who underwent DLS with or without ACyt at a tertiary referral center between 2000 and 2018 was assessed. Patients were staged with computed tomography (CT) and/or positron emission tomography (PET)/CT or bone scan. DLS was performed to rule out PM and to evaluate the extent and resectability of PM if seen on imaging. Sensitivity and specificity values were calculated for imaging, DLS, ACyt, and the combination of DLS and ACyt.

Results: Thirty-two patients with UrAC underwent DLS. ACyt was obtained in 19 patients. Four patients had suspicion of PM on imaging. In the 28 patients who were PM-negative on imaging, DLS and ACyt revealed PM in 6 (21%) patients, of whom 5 had macroscopically visible PM; 1 patient had positive ACyt without visible PM. Sensitivity of combined DLS/ACyt for the detection of PM was 91%, with a specificity of 100%, whereas sensitivity of imaging was 36%. DLS correctly predicted resectability in all patients.

Conclusion: Combined DLS/ACyt proved an effective tool to detect occult PM and to evaluate the extent of PM to select UrAC patients for possible treatment with CRS/HIPEC.
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http://dx.doi.org/10.1245/s10434-020-08206-1DOI Listing
July 2020

TLE3 loss confers AR inhibitor resistance by facilitating GR-mediated human prostate cancer cell growth.

Elife 2019 12 19;8. Epub 2019 Dec 19.

Division of Molecular Carcinogenesis, Netherlands Cancer Institute, Amsterdam, Netherlands.

Androgen receptor (AR) inhibitors represent the mainstay of prostate cancer treatment. In a genome-wide CRISPR-Cas9 screen using LNCaP prostate cancer cells, loss of co-repressor conferred resistance to AR antagonists apalutamide and enzalutamide. Genes differentially expressed upon loss share AR as the top transcriptional regulator, and loss rescued the expression of a subset of androgen-responsive genes upon enzalutamide treatment. GR expression was strongly upregulated upon AR inhibition in a -negative background. This was consistent with binding of TLE3 and AR at the locus. Furthermore, GR binding was observed proximal to TLE3/AR-shared genes. GR inhibition resensitized cells to enzalutamide. Analyses of patient samples revealed an association between TLE3 and GR levels that reflected our findings in LNCaP cells, of which the clinical relevance is yet to be determined. Together, our findings reveal a mechanistic link between TLE3 and GR-mediated resistance to AR inhibitors in human prostate cancer.
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http://dx.doi.org/10.7554/eLife.47430DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6968917PMC
December 2019

Risk Factors and Clinical Outcomes of Head and Neck Cancer in Inflammatory Bowel Disease: A Nationwide Cohort Study.

Inflamm Bowel Dis 2018 08;24(9):2015-2026

Inflammatory Bowel Disease Centre, Department of Gastroenterology and Hepatology.

Background: Immunosuppressed inflammatory bowel disease (IBD) patients are at increased risk to develop extra-intestinal malignancies. Immunosuppressed transplant patients show increased incidence of head and neck cancer with impaired survival. This study aims to identify risk factors for oral cavity (OCC) and pharyngeal carcinoma (PC) development in IBD, to compare clinical characteristics in IBD with the general population, and to assess the influence of immunosuppressive medication on survival.

Methods: We retrospectively searched the Dutch Pathology Database to identify all IBD patients with OCC and PC between 1993 and 2011. Two case-control studies were performed: We compared cases with the general IBD population to identify risk factors, and we compared cases with non-IBD cancer patients for outcome analyses.

Results: We included 66 IBD patients and 2141 controls with OCC, 31 IBD patients and 1552 controls with PC, and 1800 IBD controls. Age at IBD diagnosis was a risk factor for OCC development, Crohn's disease (CD; odds ratio [OR], 1.04; 95% confidence interval [CI], 1.02-1.07), and ulcerative colitis (UC; OR, 1.03; 95% CI, 1.01-1.06). For PC, this applied to UC (OR, 1.05; 95% CI, 1.01-1.06). IBD OCC cases showed impaired survival (P = 0.018); in PC, survival was similar. There was no effect of immunosuppression on survival. Human papillomavirus (HPV) testing of IBD cases revealed 52.2% (12/23) HPV-positive oropharyngeal carcinomas (OPCs).

Conclusion: This study shows that IBD is associated with impaired OCC survival. Higher age at IBD diagnosis is a risk factor for OCC development. We found no influence of immunosuppression on survival; 52.2% of OPC in IBD contained HPV.
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http://dx.doi.org/10.1093/ibd/izy096DOI Listing
August 2018

Identification of novel GNAS mutations in intramuscular myxoma using next-generation sequencing with single-molecule tagged molecular inversion probes.

Diagn Pathol 2019 Feb 8;14(1):15. Epub 2019 Feb 8.

Department of Pathology, Radboud University Medical Center, Geert Grooteplein Zuid 10, 6525, GA, Nijmegen, The Netherlands.

Background: Intramuscular myxoma (IM) is a hypocellular benign soft tissue neoplasm characterized by abundant myxoid stroma and occasional hypercellular areas. These tumors can, especially on biopsy material, be difficult to distinguish from low-grade fibromyxoid sarcoma or low-grade myxofibrosarcoma. GNAS mutations are frequently involved in IM, in contrast to these other malignant tumors. Therefore, sensitive molecular techniques for detection of GNAS aberrations in IM, which frequently yield low amounts of DNA due to poor cellularity, will be beneficial for differential diagnosis.

Methods: In our study, a total of 34 IM samples from 33 patients were analyzed for the presence of GNAS mutations, of which 29 samples were analyzed using a gene-specific TaqMan genotyping assay for the detection of GNAS hotspot mutations c.601C > T and c602G > A in IM, and 32 samples using a novel next generation sequencing (NGS)-based approach employing single-molecule tagged molecular inversion probes (smMIP) to identify mutations in exon 8 and 9 of GNAS. Results between the two assays were compared for their ability to detect GNAS mutations with high confidence.

Results: In total, 23 of 34 samples were successfully analyzed with both techniques showing GNAS mutations in 12 out of 23 (52%) samples. The remaining 11 samples were analyzed with either TaqMan assay or smMIP assay only. The TaqMan assay revealed GNAS mutations in 16 out of 29 samples (55%), with six samples c.601C > T (p.R201C; 38%) and ten samples c.602G > A (p.R201H; 62%) missense mutations. The smMIP assay identified mutations in 16 out of 28 samples (57%), with five samples c.601C > T (p.R201C; 31%) and seven samples c.602G > A (p.R201H; 44%) missense mutations. In addition, four samples (25%) revealed novel IM-associated mutations, including c.601C > A (p.R201S), c.602G > T (p.R201L), c.602G > C (p.R201P) and c.680A > G (p.Q227R). Combining the results of both tests, 23 out of 34 sporadic IM samples (68%) showed a GNAS mutation.

Conclusions: Both the TaqMan and the smMIP assay a show a high degree of concordance in detecting GNAS hotspot mutations in IM with comparable sensitivity. However, since the NGS-based smMIP assay permits mutation detection in whole exons of GNAS, a broader range of GNAS mutations can be identified by the smMIP approach.
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http://dx.doi.org/10.1186/s13000-019-0787-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6368757PMC
February 2019

Frequent clonal relations between metastases and non-index prostate cancer lesions.

JCI Insight 2019 Jan 24;4(2). Epub 2019 Jan 24.

Division of Oncogenomics, Netherlands Cancer Institute, Amsterdam, Netherlands.

Primary prostate cancer lesions are clonally heterogeneous and often arise independently. In contrast, metastases were reported to share a monoclonal background. Because prostate cancer mortality is the consequence of distant metastases, prevention of metastatic outgrowth by primary tumor ablation is the main focus of treatment for localized disease. Focal therapy is targeted ablation of the primary index lesion, but it is unclear whether remaining primary lesions metastasize at a later stage. In this study, we compared copy number aberration profiles of primary prostate cancer lesions with matching pelvic lymph node metastases of 30 patients to establish clonality between a lymph node metastasis and multiple primary lesions within the same patient. Interestingly, in 23.3% of the cases, the regional metastasis was not clonally linked to the index primary lesion. These findings suggest that focal ablation of only the index lesion is potentially an undertreatment of a significant proportion of prostate cancer patients.
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http://dx.doi.org/10.1172/jci.insight.124756DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6413780PMC
January 2019

MRI as a tool to assess surgical margins and pseudocapsule features directly following partial nephrectomy for small renal masses.

Eur Radiol 2019 Feb 24;29(2):509-516. Epub 2018 Jul 24.

Department of Radiology and Nuclear Medicine, Radboud University Medical Center, Nijmegen, The Netherlands.

Purpose: To evaluate the feasibility of ex vivo 7T MRI to assess surgical margins (SMs) and pseudocapsule (PC) features after partial nephrectomy (PN).

Materials And Methods: In this prospective, IRB-approved study, seven patients undergoing a PN for nine tumours between November 2014 and July 2015 were included for analysis after obtaining informed consent. MRI of the specimen was acquired using a 7T small bore scanner. The imaging protocol consisted of anatomical T1-, T2- and diffusion-weighted imaging. After formalin fixation, specimens were cut for pathology work-up in the same orientation as the MR images were obtained. The entire specimen was processed into H&E slides that were digitally scanned, annotated and correlated with radiological findings for negative SMs, PC presence, PC continuity and extra-PC-extension (EPCE). Sensitivity and specificity of MRI for assessment of these endpoints were calculated.

Results: The sensitivity and specificity for assessment of the SM were 100% and 75%, respectively. Two false-positive outcomes were reported, both in case of EPCE and a SM ≤0.5 mm. For the presence of a PC, sensitivity and specificity were 100% and 33%, respectively. Two false-positive scans with anatomical structures mimicking the presence of a PC occurred. If a PC was present, continuity and EPCE were assessed with a sensitivity and specificity of 75% and 100% and 67% and 100%, respectively.

Conclusion: Ex vivo 7T MRI is a feasible tool for perioperative evaluation of SMs, and if present, PC features after PN. This may facilitate maximal sparing of renal parenchyma without compromising oncological outcomes.

Key Points: • Ex vivo MRI may contribute to improvement of negative surgical margins during partial nephrectomy. • Due to the assessment of surgical margins within a limited time span from obtaining the partial nephrectomy specimen, surgery for more complex tumours is possible with maximum sparing of healthy renal parenchyma without compromising oncological outcomes. • The intra operative assessment of pseudocapsule continuity along the resection margin enables maximal sparing of healthy renal parenchyma without delayed diagnosis of incomplete resection.
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http://dx.doi.org/10.1007/s00330-018-5630-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6302880PMC
February 2019

COL1A1 is a fusionpartner of USP6 in myositis ossificans - FISH analysis of six cases.

Ann Diagn Pathol 2018 10 30;36:61-62. Epub 2018 Jun 30.

Department of Pathology (Pathologie-DNA), Diakonessenhuis Utrecht, Utrecht, the Netherlands.

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http://dx.doi.org/10.1016/j.anndiagpath.2018.06.009DOI Listing
October 2018

Fibro-osseous pseudotumor of digits - Expanding the spectrum of clonal transient neoplasms harboring USP6 rearrangement.

Ann Diagn Pathol 2018 Aug 12;35:53-55. Epub 2018 May 12.

Department of Pathology (Pathologie-DNA), Diakonessenhuis Utrecht, Utrecht, The Netherlands.

Fibro-osseous pseudotumors of the digits (FOPD) is a rare self-limiting lesion composed of bland looking hypercellular fibrous tissue and bone. USP6 rearrangement is a consistent genetic finding in aneurysmal bone cyst, nodular fasciitis, myositis ossificans and giant cell lesions of small bones. We report herein the occurrence of USP6 rearrangement in fibro-osseous pseudotumors of the digits using fluorescence in situ hybridization analysis (FISH). Of the five patients included, three were female and two were male. The age ranged from 33 to 72 years (mean 48 years). Lesions arose in the palm (n = 2), thenar (n = 1), middle finger (n = 1) and great toe (n = 1). All patients underwent resection. Four cases (80%) harbored USP6 rearrangements showing that fibro-osseous pseudotumors of digits belongs to the spectrum of clonal transient neoplasms including aneurysmal bone cyst, nodular fasciitis, myositis ossificans and giant cell lesion of small bones.
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http://dx.doi.org/10.1016/j.anndiagpath.2018.05.003DOI Listing
August 2018

Multifocal occurrence of extra-abdominal desmoid type fibromatosis - A rare manifestation. A clinicopathological study of 6 sporadic cases and 1 hereditary case.

Ann Diagn Pathol 2018 Aug 21;35:38-41. Epub 2018 Apr 21.

Department of Pathology, Radboud University Medical Center, Nijmegen, The Netherlands. Electronic address:

Desmoid-type fibromatosis, also called desmoid tumor, is a locally aggressive myofibroblastic neoplasm that usually arises in deep soft tissue with significant potential for local recurrence. It displays an unpredictable clinical course. β-Catenin, the genetic key player of desmoid tumors shows nuclear accumulation due to mutations that prevent its degradation leading to activation of Wnt signaling and myofibroblastic cell proliferation. The corresponding hot spot mutations are located in exon 3 of the CTNNB1 gene or alternatively, in the APC tumor suppressor gene, most often as a germline mutation. Multifocal desmoid tumors are very rare and clinical characteristics are poorly understood. Here we present six sporadic and one familial case of multifocal desmoid tumors. Four female and three male patients, aged between 7 and 30 years (mean 18.4 years) were identified in a cohort of 1392 cases. Tumors were located in (distal) extremities, thorax, breast, abdominal wall, shoulder, and neck. Four cases showed a CTNNB1 mutation and one an APC germline mutation. In two sporadic cases no CTNNB1 mutation was identified. Four patients showed (multiple) recurrences and one patient was lost to follow-up. In conclusion, multifocal desmoid tumors are a very rare disease and may occur in sporadic cases that are characterized by recurrent CTNNB1 mutations. However, the underlying pathogenesis of multifocal desmoid tumors remains poorly understood with often aggressive clinical behavior and challenging therapeutical management.
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http://dx.doi.org/10.1016/j.anndiagpath.2018.04.001DOI Listing
August 2018

Myositis ossificans - Another condition with USP6 rearrangement, providing evidence of a relationship with nodular fasciitis and aneurysmal bone cyst.

Ann Diagn Pathol 2018 Jun 12;34:56-59. Epub 2018 Jan 12.

Department of Pathology, Radboud University Medical Center, Nijmegen, The Netherlands. Electronic address:

Myositis ossificans is defined as a self-limiting pseudotumor composed of reactive hypercellular fibrous tissue and bone. USP6 rearrangements have been identified as a consistent genetic driving event in aneurysmal bone cyst and nodular fasciitis. It is therefore an integral part of the diagnostic workup when dealing with (myo)fibroblastic lesions of soft tissue and bone. Two cases of myositis ossificans with USP6 rearrangement were published so far. We determine herein the incidence of USP6 rearrangement in myositis ossificans using USP6 fluorescence in situ hybridization analysis (FISH). Of the 11 cases included, seven patients were female and four were male. Age ranged from 6 to 56 years (mean 27 years). Lesions were located in the thigh (n = 5), knee (n = 1), lower leg (n = 1), lower arm (n = 1), perineum (n = 1), gluteal (n = 1) and thoracic wall (n = 1). All assessable cases except one (8/9) showed rearrangement of USP6 providing evidence that myositis ossificans is genetically related to nodular fasciitis and aneurysmal bone cyst.
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http://dx.doi.org/10.1016/j.anndiagpath.2018.01.006DOI Listing
June 2018

Mutational analysis using Sanger and next generation sequencing in sporadic spindle cell hemangiomas: A study of 19 cases.

Genes Chromosomes Cancer 2017 12 23;56(12):855-860. Epub 2017 Sep 23.

Department of Pathology, Radboud University Medical Centre, Nijmegen, The Netherlands.

Spindle cell hemangioma (SCH) is a distinct vascular soft-tissue lesion characterized by cavernous blood vessels and a spindle cell component mainly occurring in the distal extremities of young adults. The majority of cases harbor heterozygous mutations in IDH1/2 sporadically or rarely in association with Maffucci syndrome. However, based on mosaicism and accordingly a low percentage of lesional cells harboring a mutant allele, detection can be challenging. We tested 19 sporadic SCHs by Sanger sequencing, multiplex ligation-dependent probe amplification (MLPA), conventional next generation sequencing (NGS), and NGS using a single molecule molecular inversion probes (smMIP)-based library preparation to compare their diagnostic value. Out of 10 cases tested by Sanger sequencing and 2 analyzed using MLPA, 4 and 1, respectively, revealed a mutation in IDH1 (p.R132C). The 7 remaining negative cases and additional 6 cases were investigated using smMIP/NGS, showing hot spot mutations in IDH1 (p.R132C) (8 cases) and IDH2 (3 cases; twice p.R172S and once p.R172G, respectively). One case was negative. Owing to insufficient DNA quality and insufficient coverage, 2 cases were excluded. In total, in 16 out of 17 cases successfully tested, an IDH1/2 mutation was found. Given that IDH1/2 mutations were absent in 161 other vascular lesions tested by smMIP/NGS, the mutation can be considered as highly specific for SCH.
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http://dx.doi.org/10.1002/gcc.22501DOI Listing
December 2017

Soft tissue angiofibroma: Clinicopathologic, immunohistochemical and molecular analysis of 14 cases.

Genes Chromosomes Cancer 2017 10 25;56(10):750-757. Epub 2017 Jul 25.

Department of Pathology, Radboud University Medical Center, Nijmegen, The Netherlands.

Soft tissue angiofibroma is rare and has characteristic histomorphological and genetic features. For diagnostic purposes, there are no specific antibodies available. Fourteen lesions (6 females, 8 males; age range 7-67 years) of the lower extremities (12) and trunk (2) were investigated by immunohistochemistry, including for the first time NCOA2. NCOA2 was also tested in a control group of other spindle cell lesions. The known fusion-genes (AHRR-NCOA2 and GTF2I-NCOA2) were examined using RT-PCR in order to evaluate their diagnostic value. Cases in which no fusion gene was detected were additionally analysed by RNA sequencing. All cases tested showed nuclear expression of NCOA2. However, this was not specific since other spindle cell neoplasms also expressed this marker in a high percentage of cases. Other variably positive markers were EMA, SMA, desmin and CD34. STAT6 was negative in the cases tested. By RT-PCR for the most frequently observed fusions, an AHRR-NCOA2 fusion transcript was found in 9/14 cases. GTF2I-NCOA2 was not detected in the remaining cases (n = 3). RNA sequencing revealed three additional positive cases; two harbored a AHRR-NCOA2 fusion and one case a novel GAB1-ABL1 fusion. Two cases failed molecular analysis due to poor RNA quality. In conclusion, the AHRR-NCOA2 fusion is a frequent finding in soft tissue angiofibroma, while GTF2I-NCOA2 seems to be a rare genetic event. For the first time, we report a GAB1-ABL1 fusion in a soft tissue angiofibroma of a child. Nuclear expression of NCOA2 is not discriminating when compared with other spindle cell neoplasms.
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http://dx.doi.org/10.1002/gcc.22478DOI Listing
October 2017

Evaluation of tongue squamous cell carcinoma resection margins using ex-vivo MR.

Int J Comput Assist Radiol Surg 2017 May 27;12(5):821-828. Epub 2017 Jan 27.

Department of Otorhinolaryngology and Head and Neck Surgery, Radboud University Medical Center, Nijmegen, The Netherlands.

Purpose: Purpose of this feasibility study was (1) to evaluate whether application of ex-vivo 7T MR of the resected tongue specimen containing squamous cell carcinoma may provide information on the resection margin status and (2) to evaluate the research and developmental issues that have to be solved for this technique to have the beneficial impact on clinical outcome that we expect: better oncologic and functional outcomes, better quality of life, and lower costs.

Methods: We performed a non-blinded validation of ex-vivo 7T MR to detect the tongue squamous cell carcinoma and resection margin in 10 fresh tongue specimens using histopathology as gold standard.

Results: In six of seven specimens with a histopathologically determined invasion depth of the tumor of [Formula: see text] mm, the tumor could be recognized on MR, with a resection margin within a 2 mm range as compared to histopathology. In three specimens with an invasion depth of [Formula: see text] mm, the tumor was not visible on MR. Technical limitations mainly included scan time, image resolution, and the fact that we used a less available small-bore 7T MR machine.

Conclusion: Ex-vivo 7T probably will have a low negative predictive value but a high positive predictive value, meaning that in tumors thicker than a few millimeters we expect to be able to predict whether the resection margin is too small. A randomized controlled trial needs to be performed to show our hypothesis: better oncologic and functional outcomes, better quality of life, and lower costs.
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http://dx.doi.org/10.1007/s11548-017-1524-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5420007PMC
May 2017

Myxoid liposarcoma of the foot: a study of 8 cases.

Ann Diagn Pathol 2016 Dec 17;25:37-41. Epub 2016 Sep 17.

Department of Pathology, Radboud University Medical Center, Nijmegen, the Netherlands.

Introduction: Myxoid liposarcoma is the only translocation-associated liposarcoma subtype. It classically originates in the deep soft tissues of the thigh. At distal sites of the extremities, this tumor is exceedingly rare. We present a series of 8 cases occurring in the foot/ankle.

Results: Two female and 6 male patients, aged between 32 and 77 years (mean, 54.3 years), were identified. Tumor size ranged from 1.1 to 10 cm (mean, 6.8 cm). Two lesions eroded bone. All tumors were treated by excision and 7 by (neo)adjuvant radiotherapy. R0 status was reached in 2 cases with 1 case followed by metastasis in the groin. All other cases were documented with R1 (n=2) or R2 (n=4) resection status. In 1 patient, the follow-up status was unknown. All other patients were alive 15-135 (mean, 55.8) months after initial diagnosis. We conclude that myxoid liposarcoma at acral sites are exceedingly rare, and in this series, prognosis was good irrespective of resection status. Clinicians and pathologists have to be aware because this sarcoma type shows a peculiar clinical behavior with high radio- and chemosensitivity and metastatic spread to extrapulmonary sites.
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http://dx.doi.org/10.1016/j.anndiagpath.2016.09.003DOI Listing
December 2016

Solitary fibrous tumor - clinicopathologic, immunohistochemical and molecular analysis of 28 cases.

Diagn Pathol 2014 Nov 29;9:224. Epub 2014 Nov 29.

Department of Pathology, Radboud University Medical Center, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands.

Background: Solitary fibrous tumor is a mesenchymal tumor of fibroblastic type, which can affect any region of the body. Recently, a recurrent gene fusion NAB2-STAT6 has been identified as molecular hallmark. The NAB2-STAT6 fusion leads to EGR1 activation and transcriptional deregulation of EGR1-dependent target genes and is a driving event in initiation of SFT. In this study, we report the clinicopathologic and RT-PCR findings and evaluated expression of STAT6 and EGR1 protein in a cohort of 28 SFTs.

Methods: 28 patients with a median age of 54 years were included with SFTs originating at different sites, most occurring in the lung and pleura (9, 32%), 5 in soft tissues of the lower extremities (18%) and 5 in the head and neck (18%). For detection of the NAB2-STAT6 fusion gene, RT-PCR was performed using RNA extracted from formalin-fixed and paraffin-embedded tissues. Immunohistochemistry was performed on all cases with antibodies against STAT6 and EGR1.

Results: All patients were treated by surgery, 3 with adjuvant chemo- or radiotherapy. Follow-up data of 18 patients could be obtained of which 2 patients died of metastatic disease 13 months and 52 years after first diagnosis. Sixteen patients have no evidence of disease with a median follow up of 29.5 months (range 7 - 120 months). NAB2-STAT6 fusion transcripts were found in 19/28 cases (68%). The most common fusion was between NAB2 exon 4 and STAT6 exon 3 (11/19, 58%), mainly occurring in pleuropulmonary lesions. All cases showed strong nuclear expression of STAT6 (28/28, 100%) while EGR1 showed low-level variable nuclear expression in all samples, comparable with the EGR1 expression results of the control group.

Conclusions: The identification of the NAB2-STAT6 fusion in SFTs can provide important diagnostic information, especially in cases with aberrant morphology or when biopsy material is limited. STAT6 immunohistochemistry is another useful tool in diagnosing SFT. EGR1 immunohistochemistry indicates low-level protein expression in accordance with EGR1 activation due to distorted NAB2 activity.

Virtual Slides: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/13000_2014_224.
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http://dx.doi.org/10.1186/s13000-014-0224-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4264260PMC
November 2014

Metastatic melanoma mimicking solitary fibrous tumor: report of two cases.

Virchows Arch 2014 Feb 24;464(2):247-51. Epub 2014 Jan 24.

Department of Pathology, Radboud University Medical Centre, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands,

Malignant melanomas are known for their remarkable morphological variation and aberrant immunophenotype with loss of lineage-specific markers, especially in recurrences and metastases. Hot spot mutations in BRAF, NRAS, GNAQ, and GNA11 and mutations in KIT are oncogenic events in melanomas. Therefore, genotyping can be a useful ancillary diagnostic tool. We present one case each of recurrent and metastatic melanoma, both showing histological and immunohistochemical features of solitary fibrous tumor (SFT). Mutational analysis detected BRAF and NRAS mutations in the primary and secondary lesions, respectively. This result confirmed the diagnosis of recurrent/metastastic melanoma.
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http://dx.doi.org/10.1007/s00428-014-1542-5DOI Listing
February 2014