Small cell osteosarcoma (SCOS), a variant of conventional high-grade osteosarcoma (COS), may mimic fusion-driven round cell sarcomas (FDRCS) by overlapping clinico-radiological and... Show moreSmall cell osteosarcoma (SCOS), a variant of conventional high-grade osteosarcoma (COS), may mimic fusion-driven round cell sarcomas (FDRCS) by overlapping clinico-radiological and histomorphological/immunohistochemical characteristics, hampering accurate diagnosis and consequently proper therapy. We retrospectively analyzed decalcifed formalin-fxed parafn-embedded (FFPE) samples of 18 bone tumors primarily diagnosed as SCOS by methylation profling, fusion gene analysis, and immunohistochemistry. In eight cases, the diagnosis of SCOS was maintained, and in 10 cases it was changed into FDRCS, including three Ewing sarcomas (EWSR1::FLI1 in two cases and no identifed fusion gene in the third case), two sarcomas with BCOR alterations (KMT2D::BCOR, CCNB3::BCOR, respectively), three mesenchymal chondrosarcomas (HEY1::NCOA2 in two cases and one case with insufcient RNA quality), and two sclerosing epithelioid fbrosarcomas (FUS::CREBL3 and EWSR1 rearrangement, respectively). Histologically, SCOS usually possessed more pleomorphic cells in contrast to the FDRCS showing mainly monomorphic cellular features. However, osteoid was seen in the latter tumors as well, often associated with slight pleomorphism. Also, the immunohistochemical profle (CD99, SATB2, and BCOR) overlapped. Clinically and radiologically, similarities between SCOS and FDRCS were observed, with by imaging only minimal presence or lack of (mineralized) osteoid in most of the SCOSs. In conclusion, discrimination of SCOS, epigenetically related to COS, versus FDRCS of bone can be challenging but is important due to diferent biology and therefore therapeutic strategies. Methylation profling is a reliable and robust diagnostic test especially on decalcifed FFPE material. Subsequent fusion gene analysis and/or use of specifc immunohistochemical surrogate markers can be used to substantiate the diagnosis. Show less
Steeg, A.F.W. van der; Jans, M.; Tytgat, G.; Fiocco, M.F.; Ven, C. van de; Scheltinga, C.E.J.T. van; ... ; Wijnen, M.H.W.A. 2023
Introduction. In the Netherlands pediatric oncological care for solid tumours is concentrated in one centre since November 2014. One of the most frequently diagnosed solid non-brain tumours in... Show moreIntroduction. In the Netherlands pediatric oncological care for solid tumours is concentrated in one centre since November 2014. One of the most frequently diagnosed solid non-brain tumours in children is the neuroblastoma. Results of surgical treatment of neuroblastoma since the start of this centralization are presented and compared to a historic cohort. Methods. The new national cohort of neuroblastoma (n = 111) consists of all consecutive patients treated be-tween January 1st, 2015 and April 1st, 2021. The historic neuroblastoma cohort consists of all operated neuroblastoma patients in the Netherlands between 1998 and 2014 (n = 244). Intra-operative compli-cations and surgical outcome were registered. Post-operative complications were divided in short (<30 days after surgery) and long term (>30 days). The severity of complications was graded using the Clavien Dindo Classification (CDC) system. Results. Intraoperative outcomes showed significant differences in favour of the new cohort with less blood loss (p < 0.001), fewer vascular complications (p < 0.001) and shorter duration of surgery (p < 0.001). Short term complications were comparable in numbers, but significantly more patients had CDC grade 3/ 4/5 complications in the historic cohort (p = 0.005). Long term complications did not differ. Estimated overall survival showed a better survival in the new cohort (log rank 0.022). Conclusion. Centralization of care for neuroblastoma patients has led to a significant improvement of both intraoperative outcomes and short term complications. (c) 2022 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Show less
Samim, A.; Blom, T.; Poot, A.J.; Windhorst, A.D.; Fiocco, M.; Tolboom, N.; ... ; Keizer, B. de 2022
Purpose: Meta-[F-18]fluorobenzylguanidine ([F-18]mFBG) is a positron emission tomography (PET) radiotracer that allows for fast and high-resolution imaging of tumours expressing the norepinephrine... Show morePurpose: Meta-[F-18]fluorobenzylguanidine ([F-18]mFBG) is a positron emission tomography (PET) radiotracer that allows for fast and high-resolution imaging of tumours expressing the norepinephrine transporter. This pilot study investigates the feasibility of [F-18]mFBG PET-CT for imaging in neuroblastoma. Methods: In a prospective, single-centre study, we recruited children with neuroblastoma, referred for meta-[I-123]iodobenzylguanidine ([I-123]mIBG) scanning, consisting of total body planar scintigraphy in combination with single-photon emission computed tomography-CT (SPECT-CT). Within two weeks of [I-123]mIBG scanning, total body PET-CTs were performed at 1 h and 2 h after injection of [F-18]mFBG (2 MBq/kg). Detected tumour localisations on scan pairs were compared. Soft tissue disease was quantified by number of lesions and skeletal disease by SIOPEN score. Results: Twenty paired [I-123]mIBG and [F-18]mFBG scans were performed in 14 patients (median age 4.9 years, n = 13 stage 4 disease and n = 1 stage 4S). [F-18]mFBG injection was well tolerated and no related adverse events occurred in any of the patients. Mean scan time for [F-18]mFBG PET-CT (9.0 min, SD 1.9) was significantly shorter than for [I-123]mIBG scanning (84.5 min, SD 10.5), p < 0.01. Most tumour localisations were detected on the 1 h versus 2 h post-injection [F-18]mFBG PET-CT. Compared to [I-123]mIBG scanning, [F-18]mFBG PET-CT detected a higher, equal, and lower number of soft tissue lesions in 40%, 55%, and 5% of scan pairs, respectively, and a higher, equal, and lower SIOPEN score in 55%, 30%, and 15% of scan pairs, respectively. On average, two more soft tissue lesions and a 6-point higher SIOPEN score were detected per patient on [F-18]mFBG PET-CT compared to [I-123]mIBG scanning. Conclusion: Results of this study demonstrate feasibility of [F-18]mFBG PET-CT for neuroblastoma imaging. More neuroblastoma localisations were detected on [F-18]mFBG PET-CT compared to [I-123]mIBG scanning. [F-18]mFBG PET-CT shows promise for future staging and response assessment in neuroblastoma. Show less
Samim, A.; Blom, T.; Poot, A.J.; Windhorst, A.D., Fiocco, M.; Tolboom, N.; Braat, A.J.A.T.; ... ; Keizer, B. de 2022
Purpose Meta-[F-18]fluorobenzylguanidine ([F-18]mFBG) is a positron emission tomography (PET) radiotracer that allows for fast and high-resolution imaging of tumours expressing the norepinephrine... Show morePurpose Meta-[F-18]fluorobenzylguanidine ([F-18]mFBG) is a positron emission tomography (PET) radiotracer that allows for fast and high-resolution imaging of tumours expressing the norepinephrine transporter. This pilot study investigates the feasibility of [F-18]mFBG PET-CT for imaging in neuroblastoma. Methods In a prospective, single-centre study, we recruited children with neuroblastoma, referred for meta-[I-123]iodobenzylguanidine ([I-123]mIBG) scanning, consisting of total body planar scintigraphy in combination with single-photon emission computed tomography-CT (SPECT-CT). Within two weeks of [I-123]mIBG scanning, total body PET-CTs were performed at 1 h and 2 h after injection of [F-18]mFBG (2 MBq/kg). Detected tumour localisations on scan pairs were compared. Soft tissue disease was quantified by number of lesions and skeletal disease by SIOPEN score. Results Twenty paired [I-123]mIBG and [F-18]mFBG scans were performed in 14 patients (median age 4.9 years, n = 13 stage 4 disease and n = 1 stage 4S). [F-18]mFBG injection was well tolerated and no related adverse events occurred in any of the patients. Mean scan time for [F-18]mFBG PET-CT (9.0 min, SD 1.9) was significantly shorter than for [I-123]mIBG scanning (84.5 min, SD 10.5), p < 0.01. Most tumour localisations were detected on the 1 h versus 2 h post-injection [F-18]mFBG PET-CT. Compared to [I-123]mIBG scanning, [F-18]mFBG PET-CT detected a higher, equal, and lower number of soft tissue lesions in 40%, 55%, and 5% of scan pairs, respectively, and a higher, equal, and lower SIOPEN score in 55%, 30%, and 15% of scan pairs, respectively. On average, two more soft tissue lesions and a 6-point higher SIOPEN score were detected per patient on [F-18]mFBG PET-CT compared to [I-123]mIBG scanning. Conclusion Results of this study demonstrate feasibility of [F-18]mFBG PET-CT for neuroblastoma imaging. More neuroblastoma localisations were detected on [F-18]mFBG PET-CT compared to [I-123]mIBG scanning. [F-18]mFBG PET-CT shows promise for future staging and response assessment in neuroblastoma. Show less
Infantile fibrosarcoma (IFS) and congenital mesoblastic nephroma (CMN) are locally aggressive tumors primarily occurring in infants. Both IFS and the cellular subtype of CMN show overlapping... Show moreInfantile fibrosarcoma (IFS) and congenital mesoblastic nephroma (CMN) are locally aggressive tumors primarily occurring in infants. Both IFS and the cellular subtype of CMN show overlapping morphological features and an ETV6-NTRK3 fusion, suggesting a close relationship. An activating alteration of EGFR, based on an EGFR kinase domain duplication (KDD), occurs in a subset of CMNs lacking an NTRK3 rearrangement, especially in the classic and mixed type. So far no EGFR-KDDs have been detected in IFS.We describe four pediatric tumors at the extremities (leg, n = 2; foot and arm n = 1) with histological features of IFS/CMN. Two cases showed classic IFS morphology while two were similar to classic/mixed type CMN. In all cases, an EGFR-KDD was identified without detection of a fusion gene. There were no abnormalities of the kidneys in any of the patients.This is the first description of IFS with an EGFR-KDD as driver mutation, supporting that IFS and CMN are similar lesions with the same morphological and genetic spectrum. Pathologists should be aware of the more fibrous variant of IFS, similar to classic/mixed type CMN. Molecular analyses are crucial to treat these lesions adequately, especially with regard to the administration of tyrosine kinase inhibitors. Show less
Lak, N.S.M.; Voormanns, T.L.; Zappeij-Kannegieter, L.; Zogchel, L.M.J. van; Fiocco, M.; Noesel, M.M. van; ... ; Stutterheim, J. 2021
Purpose: Survival of children with rhabdomyosarcoma that suffer from recurrent or progressive disease is poor. Identifying these patients upfront remains challenging, indicating a need for... Show morePurpose: Survival of children with rhabdomyosarcoma that suffer from recurrent or progressive disease is poor. Identifying these patients upfront remains challenging, indicating a need for improvement of risk stratification. Detection of tumor-derived mRNA in bone marrow (BM) and peripheral blood (PB) using reverse-transcriptase qPCR (RT-qPCR) is a more sensitive method to detect disseminated disease. We identified a panel of genes to optimize risk stratification by RT-qPCR.Experimental Design: Candidate genes were selected using gene expression data from rhabdomyosarcoma and healthy hematologic tissues, and a multiplexed RT-qPCR was developed. Significance of molecular disease was determined in a cohort of 99 Dutch patients with rhabdomyosarcoma (72 localized and 27 metastasized) treated according to the European pediatric Soft tissue sarcoma Study Group (EpSSG) RMS2005 protocol.Results: We identified the following 11 rhabdomyosarcoma markers: ZIC1, ACTC1, MEGF10, PDLIM3, SNAI2, CDH11, TMEM47, MYOD1, MYOG, and PAX3/7-FOXO1. RT-qPCR was performed for this 11-marker panel on BM and PB samples from the patient cohort. Five-year event-free survival (EFS) was 35.5% [95% confidence interval (CI), 17.5%-53.5%] for the 33/99 RNA positive patients, versus 88.0% (95% CI, 78.9%-97.2%) for the 66/ 99 RNA-negative patients ( P < 0.0001). Five-year overall survival (OS) was 54.8% (95% CI, 36.2%-73.4%) and 93.7% (95% CI, 86.6%-100.0%), respectively (P < 0.0001). RNA panel positivity was negatively associated with EFS (Hazard Ratio = 9.52; 95% CI, 3.23-28.02), whereas the RMS2005 risk group stratification was not, in the multivariate Cox regression model.Conclusions: This study shows a strong association between PCR-based detection of disseminated disease at diagnosis with clinical outcome in pediatric patients with rhabdomyosarcoma, also compared with conventional risk stratification. This warrants further validation in prospective trials as additional technique for risk stratification. Show less
Tas, M.L.; Dootjes, L.W.; Fiocco, M.; Krijger, R.R. de; Dierselhuis, M.P.; Eijkelenburg, N.K.A. van; ... ; Noesel, M.M. van 2021
High-risk neuroblastoma accounts for 4% of newly diagnosed pediatric malignancies, but for 9-10% of pediatric cancer mortality. To reduce the number of (late) recurrences and subsequently improve... Show moreHigh-risk neuroblastoma accounts for 4% of newly diagnosed pediatric malignancies, but for 9-10% of pediatric cancer mortality. To reduce the number of (late) recurrences and subsequently improve survival, anti-GD2 monoclonal antibody based immunotherapy has been added to the maintenance phase of treatment. The first randomized study (ANBL0032) was ground breaking, showing a 20% improved event free survival. Subsequently immunotherapy was included in all international high-risk treatment regimens. Randomization will never be repeated. In this article we present additional data from our retrospective cohort to corroborate the ANBL0032 study. Our cohort contains 84 Dutch high-risk neuroblastoma patients. They were treated with GPOH or POG induction, followed by immunotherapy according to original ANBL0032 protocol (immunotherapy group) or single-agent isotretinoin (historical control group). In the complete cohort, 5 year OS was 64 +/- 7% and 49 +/- 8% for the immunotherapy group and the control group, respectively (p = 0.16). Five year EFS was 57 +/- 7% and 41 +/- 8%, respectively (p = 0.16). In the subgroup of patients +/- 18 months, 5-yr OS was 63 +/- 8% and 39 +/- 9, respectively (p = 0.04) and EFS 54 +/- 8% and 29 +/- 8%, respectively (p = 0.05). Our five year data suggest a role for the immunotherapy in preventing late events, especially in patients >= 18 months old.Background: Anti-GD2 based immunotherapy has improved overall (OS) and event free survival (EFS) for high-risk neuroblastoma (HR-NBL) patients. Here, we evaluate the longterm efficacy of anti-GD2 immunotherapy in combination with isotretinoin, GM-CSF, and IL-2. Methods: Dutch HR-NBL patients treated with immunotherapy according to the COG-ANBL0032 protocol (n = 47) were included and compared to historical controls (n = 37) treated with singleagent isotretinoin maintenance therapy. Survival time was calculated from start of the maintenance therapy.Results: The study and control group were similar concerning baseline characteristics. In the complete cohort, 5 year OS was 64 +/- 7% and 49 +/- 8% for the immunotherapy group and the control group, respectively (p = 0.16). Five year EFS was 57 +/- 7% and 41 +/- 8%, respectively (p = 0.16). In the subgroup of patients >= 18 months, 5-yr OS was 63 +/- 8% and 39 +/- 9, respectively (p = 0.04) and EFS 54 +/- 8% and 29 +/- 8%, respectively (p = 0.05). Landmark analysis for EFS with landmark point at 6 months after start of maintenance suggests a larger effect on the prevention of late than early events.Conclusions: This study is the first to confirm the results of the COG-ANBL0032 study in a cohort treated with a different induction regimen. Anti-GD2 immunotherapy prevents late events, most significantly in patients older than 18 months of age at diagnosis. Show less
IJzerman, N.S.; Drabbe, C.; Hollander, D. den; Mohammadi, M.; H. van boven; Desar, I.M.E.; ... ; Graaf, W.T.A. van der 2020
Gastrointestinal stromal tumour (GIST) is a disease of older adults and is dominated by KIT/PDGFR mutations. In children, GIST is rare, predominantly occurs in girls, has a stomach location and... Show moreGastrointestinal stromal tumour (GIST) is a disease of older adults and is dominated by KIT/PDGFR mutations. In children, GIST is rare, predominantly occurs in girls, has a stomach location and generally lacks KIT/PDGFR mutations. For young adults (YA), aged 18 to 40 years, the typical phenotypic and genotypic patterns are unknown. We therefore aimed to describe the clinical, pathological and molecular characteristics of GIST in in YA. YA GIST patients registered in the Dutch GIST Registry (DGR) were included, and data were compared to those of older adults (OA). From 1010 patients in the DGR, 52 patients were YA (54% male). Main tumour locations were stomach (46%) and small intestine (46%). GIST genetic profiles were mutations in KIT (69%), PDGFRA (6%), SDH deficient (8%), NF1 associated (4%), ETV6-NTRK3 gene fusion (2%) or wildtype (10%). Statistically significant differences were found between the OA and YA patients (localisation, syndromic and mutational status). YA presented more often than OA in an emergency setting (18% vs. 9%). The overall five-year survival rate was 85%. In conclusion, YA GISTs are not similar to typical adult GISTs and also differ from paediatric GISTs, as described in the literature. In this series, we found a relatively high percentage of small intestine GIST, emergency presentation, 25% non-KIT/PDGFRA mutations and a relatively good survival. Show less
Martin, E.; Coert, J.H.; Flucke, U.E.; Slooff, W.B.M.; Sande, M.A. van de; Noesel, M.M. van; ... ; Verhoef, C. 2019
Background Malignant peripheral nerve sheath tumors (MPNST) are rare and aggressive non-rhabdomyoblastic soft-tissue sarcomas (NRSTS) in children. This study set out to investigate clinical... Show moreBackground Malignant peripheral nerve sheath tumors (MPNST) are rare and aggressive non-rhabdomyoblastic soft-tissue sarcomas (NRSTS) in children. This study set out to investigate clinical presentation, treatment modalities, and factors associated with survival in pediatric MPNST using Dutch nationwide databases. Methods Data were obtained from the Netherlands Cancer Registry (NCR) and the Dutch Pathology Database (PALGA) from 1989 to 2017. All primary MPNSTs were collected. Demographic differences were analyzed between adult and pediatric (age <= 18 years) MPNST. In children, demographic and treatment differences between neurofibromatosis type 1 (NF1) and non-NF1 were analyzed. A Cox proportional hazard model was constructed for localized pediatric MPNSTs. Results A total of 70/784 MPNST patients were children (37.1% NF1). Children did not present differently from adults. In NF1 children, tumor size was more commonly large (> 5 cm, 92.3% vs 59.1%). Localized disease was primarily resected in 90.6%, and radiotherapy was administered in 37.5%. Non-NF1 children tended to receive chemotherapy more commonly (39.5% vs 26.9%). Overall, estimated five-year survival rates of localized NF1-MPNST was 52.4% (SE: 10.1%) compared with 75.8% (SE: 7.1%) in non-NF1 patients. The multivariate model showed worse survival in NF1 patients (HR: 2.98; 95% CI, 1.17-7.60, P = 0.02) and increased survival in patients diagnosed after 2005 (HR: 0.20; 95% CI, 0.06-0.69, P = 0.01). No treatment factors were independently associated with survival. Conclusion Pediatric MPNSTs have presentations similar to adult MPNSTs. In children, NF1 patients present with larger tumors, but are treated similarly to non-NF1 MPNSTs. In localized pediatric MPNST, NF1 is associated with worse survival. Promisingly, survival has increased for pediatric MPNSTs after 2005. Show less
Kraal, K.C.J.M.; Timmerman, I.; Kansen, H.M.; Bos, C. van den; Zsiros, J.; Berg, H. van den; ... ; Tytgat, G.A.M. 2019
