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  • 1
    In: European Journal of Cancer, Elsevier BV, Vol. 173 ( 2022-09), p. 59-70
    Type of Medium: Online Resource
    ISSN: 0959-8049
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    Language: English
    Publisher: Elsevier BV
    Publication Date: 2022
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  • 2
    In: Genes, Chromosomes and Cancer, Wiley, Vol. 55, No. 8 ( 2016-08), p. 640-649
    Abstract: Nodular fasciitis (NF) is a clonal self‐limited neoplastic proliferation characterized by rearrangements of the USP6 locus in most examples. To our knowledge well‐documented malignant behavior has never been previously observed in NF. In this report we present an unusual case of NF with classical histologic features that showed a protracted clinical course characterized by multiple recurrences and eventual metastatic behavior over a period of 10 years. Molecular analyses revealed the presence and amplification of the novel PPPR6‐USP6 gene fusion, which resulted in USP6 mRNA transcriptional upregulation. These findings further support the oncogenic role of the USP6 protease in mesenchymal neoplasia and expand the biologic potential of NF. © 2016 Wiley Periodicals, Inc.
    Type of Medium: Online Resource
    ISSN: 1045-2257 , 1098-2264
    URL: Issue
    Language: English
    Publisher: Wiley
    Publication Date: 2016
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  • 3
    In: Genes, Chromosomes and Cancer, Wiley, Vol. 62, No. 11 ( 2023-11), p. 641-647
    Abstract: As the classification of kinase‐driven spindle cell tumors continues to evolve, we describe the first series of pediatric mesenchymal tumors harboring FGFR1 gene fusions that share histologic overlap with infantile fibrosarcoma and “ NTRK ‐rearranged” spindle cell neoplasms. Herein, we present three cases of FGFR1 ‐rearranged pediatric mesenchymal tumors, including one case with FGFR1 :: PARD6B gene fusion and two cases with FGFR1 :: EBF2 gene fusion. The tumors involved infants ranging from 3 to 9 months in age with a male‐to‐female ratio of 2:1. All tumors involved the deep soft tissue of the gluteal, pelvic, or perirectal region. Histologically, the tumors comprised a cellular spindle cell neoplasm with primitive stellate cells, focal myxoid stroma, focal epithelioid features, no necrosis, and occasional mitotic figures (2–6 per 10 high‐power field). By immunohistochemistry, the neoplastic cells focally expressed CD34 but lacked expression of S100 protein, SMA, desmin, myogenin, MyoD1, pan‐TRK, and ALK. These three cases, including a case with long‐term clinical follow‐up, demonstrate that FGFR1 fusions occur in a subset of newly described pediatric kinase‐driven mesenchymal tumors with locally aggressive behavior. Importantly, knowledge of these genetic alterations in this spectrum of pediatric tumors is key for diagnostic and targeted therapeutic purposes.
    Type of Medium: Online Resource
    ISSN: 1045-2257 , 1098-2264
    URL: Issue
    Language: English
    Publisher: Wiley
    Publication Date: 2023
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  • 4
    In: Scientific Reports, Springer Science and Business Media LLC, Vol. 10, No. 1 ( 2020-03-10)
    Abstract: Extracranial arteriovenous malformation (AVM) is most commonly caused by MAP2K1 mutations in the endothelial cell. The purpose of this study was to determine if local tissue overgrowth associated with AVM is caused by direct or indirect effects of the MAP2K1 mutation (i.e., cell-autonomous or cell-non autonomous). Because cartilage does not have blood vessels, we studied ear AVMs to determine if overgrown cartilage contained AVM-causing mutations. Cartilage was separated from its surrounding tissue and isolated by laser capture microdissection. Droplet digital PCR (ddPCR) was used to identify MAP2K1 mutations. MAP2K1 (p.K57N) variants were present in the tissue adjacent to the cartilage [mutant allele frequency (MAF) 6–8%], and were enriched in endothelial cells (MAF 51%) compared to non-endothelial cells (MAF 0%). MAP2K1 mutations were not identified in the overgrown cartilage, and thus local cartilage overgrowth likely results from the effects of adjacent mutant blood vessels (i.e., cell-non autonomous).
    Type of Medium: Online Resource
    ISSN: 2045-2322
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2020
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  • 5
    In: International Journal of Surgical Pathology, SAGE Publications, Vol. 28, No. 2 ( 2020-04), p. 128-137
    Abstract: Introduction. Myofibromas are rare tumors of pericytic lineage, typically affecting children, and are sometimes aggressive. A subset of sporadic and familial myofibromas have activating variants in PDGFRB. The relationship of myofibroma and PDGFRB to the NOTCH pathway has not yet been described. Methods. Ten myofibroma cases were sequenced with a targeted panel of 447 genes, including copy number variation and selected fusions. Immunohistochemical analysis of total NOTCH3 and activated NOTCH3 was assessed for all 10 myofibroma cases, and a series of histologic mimics (n = 20). Results. Alterations identified by next-generation sequencing included PDGFRB sequence variants in 8/10 cases (80%), a NOTCH3 variant in 1/10 cases (10%), and a NOTCH2 variant in 1/10 cases (10%). All 10 cases also showed a pattern of low-amplitude (1.5- to 2-fold) copy number alterations including gains in PDGFRB and NOTCH3. Ten of 10 myofibromas (100%) showed cytoplasmic staining for total NOTCH3 and 9 of 10 cases (90%) showed nuclear staining for activated NOTCH3. Within the control cohort of histologic mimics, 3 of 3 nodular fasciitis cases (100%) were positive for activated and total NOTCH3, and the remaining 17 cases were negative for pan NOTCH3, while 3 of 3 desmoid-type fibromatosis cases (100%) showed patchy weak nuclear staining for activated NOTCH3. Discussion. Our findings suggest a common pathway of PDGFRB/NOTCH3 activation in myofibromas, even in cases that lack PDGFRB sequence variants. These results support the pericytic lineage of myofibroma. Identification of the characteristic genomic alterations or immunohistochemical staining pattern may facilitate a difficult pathologic diagnosis, and support the use of targeted treatments.
    Type of Medium: Online Resource
    ISSN: 1066-8969 , 1940-2465
    Language: English
    Publisher: SAGE Publications
    Publication Date: 2020
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  • 6
    In: International Journal of Surgical Pathology, SAGE Publications, Vol. 27, No. 3 ( 2019-05), p. 236-243
    Abstract: Objectives. Desmoplastic small round cell tumor (DSRCT) is an aggressive round cell sarcoma that arises in the abdominal cavity/pelvis of young males. We sought to expand its clinicopathologic spectrum. Methods. Cases of DSRCT presenting in patients 〉 30 years of age or tumors arising outside of the abdominal cavity/pelvis were retrieved. Results. Thirty-four cases were identified. Sixteen tumors arose at atypical sites (head/neck, intracranial, thigh, axilla/shoulder, inguinal/paratesticular, intraosseous, and uterine corpus). The remaining 18 patients were older than 30 years, and their tumors involved the abdomen or pelvis. The majority of cases showed areas with classic histology, while 6 cases exhibited solid growth and 5 showed macronodular architecture. Cytologic appearance included round cell, rhabdoid, epithelioid, and small cell. Conclusion. DSRCT may arise at nonabdominal locations in both pediatric and adult populations, as well as intra-abdominally in older adults, and these tumors exhibit high rates of metastasis and morbidity.
    Type of Medium: Online Resource
    ISSN: 1066-8969 , 1940-2465
    Language: English
    Publisher: SAGE Publications
    Publication Date: 2019
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  • 7
    Online Resource
    Online Resource
    SAGE Publications ; 2016
    In:  International Journal of Surgical Pathology Vol. 24, No. 8 ( 2016-12), p. 685-691
    In: International Journal of Surgical Pathology, SAGE Publications, Vol. 24, No. 8 ( 2016-12), p. 685-691
    Abstract: The diagnosis of bone and soft tissue tumors in children is challenging. These lesions are especially difficult for general pathologists. We reviewed our experience with pediatric mesenchymal tumors sent in consultation to our service, with the goal of identifying issues that most often prompted second-opinion referral. Roughly 16 000 cases were seen in toto, of which 1601 occurred in children. These included 491 bone cases and 1110 soft tissue cases. The cases were referred by private practices/nonacademic medical centers (85%), academic medical centers (8%), and pediatric hospitals (7%). Reasons for referral were ( a) self-perceived lack of experience with pediatric mesenchymal tumors (n = 930), ( b) second opinion requested by the clinician or patient (n = 132), and ( c) perceived or real need for ancillary studies not available at the referring institution (n = 116). The referring pathologists suggested a diagnosis for 670 cases; of these, 476 (71%) were in essential agreement with our final diagnosis. Of the remaining, 139 (21%) were considered “minor disagreements” and 55 (8%) “major disagreements.” The “major disagreement” cases could be divided into ( a) malignant tumors submitted with benign diagnoses (58%), ( b) benign tumors submitted with malignant diagnoses (25%), ( c) nonneoplastic conditions submitted as representing neoplasms (11%), and ( d) neoplasm submitted as representing nonneoplastic conditions (6%). Pediatric mesenchymal tumors comprised 10% of cases sent to our mesenchymal tumor consultation practice. The rates of diagnostic disagreement found in this study are roughly in accordance with prior studies of mandatory and voluntary second opinion in adult soft tissue tumors. Given the rarity of these tumors, expert second opinion may be of value.
    Type of Medium: Online Resource
    ISSN: 1066-8969 , 1940-2465
    Language: English
    Publisher: SAGE Publications
    Publication Date: 2016
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  • 8
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 82, No. 12_Supplement ( 2022-06-15), p. 6084-6084
    Abstract: Neurofibromatosis type 1 (NF1) is the most common tumor predisposition syndrome, and is associated with an aggressive soft-tissue sarcoma, malignant peripheral nerve sheath tumours (MPNSTs), the greatest cause of mortality in people with NF1. The only potentially curative therapy involves en bloc resection with negative margins, which is not always appropriate. Even therapy with curative intent is associated with poor overall survival for both sporadic and NF1-related MPNSTs. The development of novel therapies has been largely hindered by a poor understanding of the molecular events underpinning MPNST pathogenesis. We report a comprehensive multi-omic study of MPNST evolution based on whole genome sequencing, transcriptomic and methylation profiling data on 95 tumors (64 NF1-related; 31 sporadic). In all cases, the early events in MPNST evolution involve biallelic inactivation of NF1 followed by inactivation of CDKN2A, as well as mutations in TP53 or PRC2 complex genes in a subset of cases. Analysis of the genomic architecture revealed distinct pathways of tumor evolution that can be identified through H3K27 trimethylation (H3K27me3) status. Integration of these data allows us to propose several mechanistic tumor evolution models. Tumors with H3K27me3 loss evolve through extensive copy number aberrations (CNAs) including haploidization followed by whole genome doubling and chromosome 8 amplifications, whereas tumors with H3K27me3 retention evolve through extensive chromosome instability and chromothripsis. Taken together, these genome-wide CNA profiles act as a surrogate for the loss of H3K27me3 status and correlate with prognosis, suggesting that CNA profiling of cell-free DNA could be incorporated in clinical decision-making. Citation Format: Isidro Cortes Ciriano, Chris D. Steele, Katherine Piculell, Alyaa Al-Ibraheemi, Vanessa Eulo, Marilyn M. Bui, Aikaterini Chatzipli, Brendan C. Dickson, Dana C. Borcherding, Alon Galor, Jesse Hart, Andrew Feber, Kevin B. Jones, Justin T. Jordan, Raymond H. Kim, Daniel Lindsay, Colin Miller, Yoshihiro Nishida, Jonathan Serrano, Nicole J. Ullrich, David Viskochil, Xia Wang, Matija Snuderl, Paula Proszek, Peter J. Park, Adrienne M. Flanagan, Angela C. Hirbe, Nischalan Pillay, David T. Miller, The Genomics of MPNST (GeM) Consortium. Recurrent genomic patterns of MPNST evolution correlate with clinical outcome [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6084.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2022
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  • 9
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 80, No. 14_Supplement ( 2020-07-15), p. A67-A67
    Abstract: Introduction: In pediatric cancer, there is an urgent need for research that can identify and validate new therapeutic modalities for pediatric cancers. Diagnostic biopsy samples remain the ideal tissue samples for research and must be collected from surplus biopsy material, which is often extremely limited. Here we describe our efforts to optimize tissue allocation for clinical care and research as a joint effort between Department of Pathology at Boston Children’s Hospital and the Pediatric Solid Tumor Program at the Dana-Farber/Boston Children’s Cancer and Blood Disorders Center. Methods: Oncologists, pathologists, surgeons, interventional radiologists, pathology technical staff, and clinical research coordinators participated in the workflow design. The group agreed to develop a formalized procedure to address these five steps: 1) patient identification and consent, 2) prioritization of research objectives, 3) advance communication of tissue requests to the pathology staff, 4) tissue preparation, and 5) tissue distribution. It was unanimously agreed that all tissue must flow through the pathology department. On or before the day of surgery, clinical research teams sent the pathologist a patient-specific electronic communication indicating research consent and detailing the prioritized disease-specific research requests, including the procedure planned, all tissue types and tissue volumes requested, and details of any special preparation needed, such as avoiding decalcification in bone tumors. The communication was optimized to be clear but brief, with the goal of minimizing the impact to the pathologist’s work load. Pathologists were surveyed about the change in process. Results: Over a five-year period (2013-2018), 662 pediatric DFCI/BCH solid tumor patients have consented to one or more trials that request FFPE, frozen, or fresh tissue. Tumor types represent a spectrum of cases, with many rare and singular diagnoses. Of 1,768 research tissue requests, 1,121 (63%) were fulfilled. Clinical study requests from resection specimens were the most likely to be fulfilled (95% of 390 requests fulfilled), while basic research requests from core biopsies were the least likely to be fulfilled (26% of 255 requests fulfilled). In an anonymous survey, 7 of 7 pathologists report that the process had improved since the introduction of the electronic communication. Conclusions: A collaborative and informed model for tissue allocation is successful in distributing tissue for clinical studies and basic research projects. Our workflows and policies have gained pathologist approval and streamlined our processes. As clinical and research programs evolve, a thoughtful tissue allocation process will facilitate ongoing research. Citation Format: R. Seth Pinches, Catherine Clinton, Abigail Ward, Stephanie C Meyer, Alyaa Al-Ibraheemi, Suzanne Forrest, Gianna R. Strand, Hillary Detert, Anne Piche-Schulman, Kristen Gil, Tamara Restrepo, Rosemarie Tavares-Proulx, Jeffrey Goldsmith, Raja Shaikh, Christopher Weldon, Sanda Alexandrescu, Allison F. O’Neill, Monica Hollowell, Marian H. Harris, Katherine A. Janeway, Brian D. Crompton, Alanna Church. Improving tissue allocation for research in pediatric solid tumors [abstract]. In: Proceedings of the AACR Special Conference on the Advances in Pediatric Cancer Research; 2019 Sep 17-20; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Res 2020;80(14 Suppl):Abstract nr A67.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2020
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  • 10
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 78, No. 19_Supplement ( 2018-10-01), p. A31-A31
    Abstract: Infantile myofibromas (IM) are rare benign neoplasms thought to derive from perivascular myoid cells. The prognosis is generally good, although about one-third of cases with multicentric involvement will also have visceral involvement, and the prognosis for these patients is poor. The use of combination cytotoxic chemotherapy (vincristine/dactinomycin and vinblastine/methotrexate) has proven effective in cases of multicentric disease with visceral involvement and in cases in which the disease has progressed and has threatened the life of the patient. The pathologic diagnosis of IM can be challenging, particularly with small biopsies, since IM exist on a morphologic spectrum with myopericytomas, glomangiopericytomas, and glomus tumors, and other spindle cell neoplasms are also on the histologic differential. Most families with autosomal dominant infantile myofibromatosis have germline variants in PDGFRB. In one case of autosomal dominant IM a NOTCH3 variant was identified in the absence of a PDGFRB variant. Most sporadic infantile myofibromas also have identifiable variants in PDGFRB. To date, however, there have been no genetic variants or immunohistochemical stains that are 100% sensitive or specific in diagnosing IM. Nine cases of infantile myofibroma/myofibromatosis were identified from the case archives of Boston Children’s Hospital. DNA was extracted from formalin-fixed, paraffin-embedded (FFPE) tissue sections and sequenced using a clinically validated targeted panel of 447 genes for 9 cases. Immunohistochemical stain for activated NOTCH3 was performed. The histopathology of each case was reviewed by two pediatric pathologists. Of the nine IM cases, 7 had one or more sequence variants in PDGFRB. One case had a NOTCH3 sequence variant and one had a NOTCH2 sequence variant. All nine cases (100%) had a distinctive pattern of copy alterations including gains of PDGFRB and NOTCH3. One case failed immunohistochemical staining; of the remaining 8 IM cases, all 8 showed nuclear staining for activated NOTCH3. We describe a distinctive pattern of genomic alterations in infantile myofibromatosis, including a high prevalence (7/9 cases) of alterations in PDGFRB, several of which are known to be activating, and copy number alterations including copy number gains of PDGFRB and NOTCH3 in all 9 cases. The p.N666K, p.D850V (both seen in this study), and p.R561C variants have been shown to result in constitutive activation of PDGFRB, transform cells and induce tumor formation, and render tumor sensitivity to tyrosine kinase inhibitors. In vascular smooth muscle cells, PDGFRB has been shown to be an immediate downstream target of NOTCH3 signaling. The consistent presence of activated NOTCH3, detected by immunohistochemistry in all IM cases, confirms that the genomic changes have functional effect. The NOTCH signaling pathway is the target of inhibitors including gamma-secretase inhibitors; some NOTCH-mutated leukemias have been shown to be sensitive to inhibition, suggesting that these inhibitors may also be useful in NOTCH-mutated myofibromas. Our findings suggest a common pathway of PDGFRB/NOTCH3 activation in infantile myofibromas. Identification of the characteristic genomic alterations or immunohistochemical staining pattern may facilitate a difficult pathologic diagnosis. Furthermore, targeted inhibitors are available for both PDGRFB and NOTCH, and may be of use in patients with visceral or multicentric disease. Citation Format: Selene C. Koo, Calicchio Monica, Benjamin Ferland, Marian H. Harris, Jon C. Aster, Katherine A. Janeway, Alyaa Al-Ibraheemi, Alanna J. Church. A distinctive genomic and immunohistochemical profile for NOTCH3 and PDGFRB in infantile myofibroma with diagnostic and therapeutic implications [abstract]. In: Proceedings of the AACR Special Conference: Pediatric Cancer Research: From Basic Science to the Clinic; 2017 Dec 3-6; Atlanta, Georgia. Philadelphia (PA): AACR; Cancer Res 2018;78(19 Suppl):Abstract nr A31.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2018
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