Publications by authors named "Alyaa Al-Ibraheemi"

54 Publications

Molecular Characterization of Inflammatory Tumors Facilitates Initiation of Effective Therapy.

Pediatrics 2021 Nov 12. Epub 2021 Nov 12.

Department of Pediatrics, Dana-Farber/Boston Children's Cancer and Blood Disorders Center and Harvard Medical School, Harvard University, Boston, Massachusetts.

Inflammatory myofibroblastic tumor (IMT) is a rare, mesenchymal tumor that has an increased incidence in childhood. Tumors are usually isolated to the chest, abdomen, and retroperitoneum, but metastatic presentations can be seen. Presenting symptoms are nonspecific and include fever, weight loss, pain, shortness of breath, and cough. Approximately 85% of IMTs harbor actionable kinase fusions. The diagnosis can be delayed because of overlapping features with inflammatory disorders, such as elevated inflammatory markers, increased immunoglobin G levels, fever, weight loss, and morphologic similarity with nonmalignant conditions. We present a girl aged 11 years with a TFG-ROS1 fusion-positive tumor of the lung that was initially diagnosed as an immunoglobin G4-related inflammatory pseudotumor. She underwent complete left-sided pneumonectomy and later recurred with widely metastatic disease. We then report the case of a boy aged 9 years with widely metastatic TFG-ROS1 fusion-positive IMT with rapid molecular diagnosis. In both children, there was an excellent response to oral targeted therapy. These cases reveal that rapid molecular testing of inflammatory tumors is not only important for diagnosis but also reveals therapeutic opportunities. Targeted inhibitors produce significant radiologic responses, enabling potentially curative treatment approaches for metastatic ROS1 fusion IMT with previously limited treatment options. Primary care pediatricians and pediatric subspecialists have a crucial role in the early consultation of a pediatric oncology center experienced in molecular diagnostics to facilitate a comprehensive evaluation for children with inflammatory tumors.
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http://dx.doi.org/10.1542/peds.2021-050990DOI Listing
November 2021

Bockenheimer Disease is Associated With a TEK Variant.

Cold Spring Harb Mol Case Stud 2021 Oct 14. Epub 2021 Oct 14.

Boston Children's Hospital, Harvard Medical School.

Bockenheimer disease is a venous malformation involving all tissues of an extremity. Patients have significant morbidity and treatment is palliative. The purpose of this study was to identify the cause of Bockenheimer disease to develop pharmacotherapy for the condition. Paraffin-embedded tissue from 9 individuals with Bockenheimer disease obtained during a clinically-indicated operation underwent DNA extraction. Droplet digital PCR (ddPCR) was used to screen for variants most commonly associated with sporadic venous malformations [TEK (NM_000459.5:c.2740C>T; p.Leu914Phe), PIK3CA (NM_006218.4:c.1624G>A; p.Glu542Lys and NM_006218.4:c.3140A>G; p.His1047Arg)]. ddPCR detected a TEK L914F variant in all 9 patients (variant allele fraction 2%-13%). PIK3CA E542K and H1047R variants were not identified in the specimens. Sanger sequencing and restriction enzyme digestion confirmed variants identified by ddPCR. A pathogenic variant in the endothelial cell tyrosine kinase receptor TEK is associated with Bockenheimer disease. Pharmacotherapy targeting the TEK signaling pathway might benefit patients with the condition.
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http://dx.doi.org/10.1101/mcs.a006119DOI Listing
October 2021

Assessment of BCOR Internal Tandem Duplications in Pediatric Cancers by Targeted RNA Sequencing.

J Mol Diagn 2021 10 27;23(10):1269-1278. Epub 2021 Jul 27.

Department of Pathology, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts. Electronic address:

Alterations in the BCOR gene, including internal tandem duplications (ITDs) of exon 15 have emerged as important oncogenic changes that define several diagnostic entities. In pediatric cancers, BCOR ITDs have recurrently been described in clear cell sarcoma of kidney (CCSK), primitive myxoid mesenchymal tumor of infancy (PMMTI), and central nervous system high-grade neuroepithelial tumor with BCOR ITD in exon 15 (HGNET-BCOR ITDex15). In adults, BCOR ITDs are also reported in endometrial and other sarcomas. The utility of multiplex targeted RNA sequencing for the identification of BCOR ITD in pediatric cancers was investigated. All available archival cases of CCSK, PMMTI, and HGNET-BCOR ITDex15 were collected. Each case underwent anchored multiplex PCR library preparation with a custom-designed panel, with BCOR targeted for both fusions and ITDs. BCOR ITD was detected in all cases across three histologic subtypes using the RNA panel, with no other fusions identified in any of the cases. All BCOR ITDs occurred in the final exon, within 16 codons from the stop sequence. Multiplex targeted RNA sequencing from formalin-fixed, paraffin-embedded tissue is successful at identifying BCOR internal tandem duplications. This analysis supports the use of anchored multiplex PCR targeted RNA next-generation sequencing panels for identification of BCOR ITDs in pediatric tumors. The use of post-analytic algorithms to improve the detection of BCOR ITD using DNA panels was also explored.
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http://dx.doi.org/10.1016/j.jmoldx.2021.07.006DOI Listing
October 2021

Undifferentiated Embryonal Sarcoma of the Liver With Rhabdoid Morphology Mimicking Carcinoma: Expanding the Morphologic Spectrum or a Distinct Variant?

Pediatr Dev Pathol 2021 Jun 14:10935266211018930. Epub 2021 Jun 14.

Department of Pathology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.

Undifferentiated embryonal sarcoma of the liver (UESL) is a rare aggressive neoplasm that occurs predominantly in children. Like mesenchymal hamartoma of the liver (MHL), UESL harbors recurrent rearrangements involving 19q13.3 and 19q13.4, a region of the genome that contains a primate-specific cluster of micro-RNAs. Here, we present a case of a high-grade neoplasm that arose in the left hepatic lobe of a 5-year-old male and gave rise to widespread lymph node, visceral, and soft tissue metastases. The tumor was composed of sheets, tubules, and papillae of epithelioid cells with rhabdoid morphology. INI1 and BRG1 expression were retained. Tumor cells diffusely expressed epithelial markers, including multiple keratins. While the morphologic and immunophenotypic features were suggestive of poorly differentiated carcinoma with rhabdoid features, the tumor was found to harbor the t(11;19)(q13;q13.3) translocation characteristic of UESL, as well as a mutation. Given the clinical presentation, imaging, clinical course, the tumor was classified as UESL with unusual, carcinoma-like histopathologic features. In the context of an unclassified high-grade hepatic tumor in a young child, molecular or cytogenetic testing for chromosome 19q13 alterations should be considered.
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http://dx.doi.org/10.1177/10935266211018930DOI Listing
June 2021

Verrucous Venous Malformation-Subcutaneous Variant.

Am J Dermatopathol 2021 Dec;43(12):e181-e184

Department of Pathology, Boston Children's Hospital and Harvard Medical School, Boston, MA.

Background: Verrucous venous malformation (VVM), previously called "verrucous hemangioma," typically involves the dermis and the subcutaneous fat. We have encountered patients with VVM confined to the hypodermis.

Materials And Methods: During a nearly 20-year period, 13 patients, aged 2-17 years, presented with a subcutaneous mass in the limb without clinically obvious epidermal alterations. Consequently, operative excisions did not include the skin.

Results: Histopathologically, the specimens were composed of blood-filled channels with morphologic characteristics of capillaries and veins that infiltrated adipose tissue. Aggregates often formed nodules with variable fibrosis and a component of large and radially oriented vessels. A diagnosis of VVM was supported by endothelial immunopositivity for GLUT-1 (25%-75% immunopositive channels in 16/16 specimens); D2-40 (1%-25% channels in 14/15 specimens); and Prox-1 (1%-50% of channels in 14/16 specimens). A MAP3K3 mutation was identified by droplet digital PCR in 3 of the 6 specimens.

Conclusions: Diagnosis of VVM in this uncommon location is challenging because of absence of epidermal changes and lack of dermal involvement. Imaging is not pathognomonic, and mimickers are many. Appropriate immunohistochemical stains and molecular analysis contribute to the correct diagnosis.
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http://dx.doi.org/10.1097/DAD.0000000000001963DOI Listing
December 2021

Novel BRAF gene fusions and activating point mutations in spindle cell sarcomas with histologic overlap with infantile fibrosarcoma.

Mod Pathol 2021 08 13;34(8):1530-1540. Epub 2021 Apr 13.

Department of Pathology, Oregon Health & Science University, Portland, OR, USA.

Infantile fibrosarcoma (IFS)/cellular congenital mesoblastic nephroma (cCMN) commonly harbors the classic ETV6-NTRK3 translocation. However, there are recent reports of mesenchymal tumors with IFS-like morphology harboring fusions of other receptor tyrosine kinases or downstream effectors, including NTRK1/2/3, MET, RET, and RAF1 fusions as well as one prior series with BRAF fusions. Discovery of these additional molecular drivers contributes to a more integrated diagnostic approach and presents important targets for therapy. Here we report the clinicopathologic and molecular features of 14 BRAF-altered tumors, of which 5 had BRAF point mutations and 10 harbored one or more BRAF fusions. Of the BRAF fusion-positive tumors, one harbored two BRAF fusions (FOXN3-BRAF, TRIP11-BRAF) and another harbored three unique alternative splice variants of EPB41L2-BRAF. Tumors occurred in ten males and four females, aged from birth to 32 years (median 6 months). Twelve were soft tissue based; two were visceral including one located in the kidney (cCMN). All neoplasms demonstrated ovoid to short spindle cells most frequently arranged haphazardly or in intersecting fascicles, often with collagenized stroma and a chronic inflammatory infiltrate. No specific immunophenotype was observed; expression of CD34, S100, and SMA was variable. To date, this is the largest cohort of BRAF-altered spindle cell neoplasms with IFS-like morphology, including not only seven novel BRAF fusion partners but also the first description of oncogenic BRAF point mutations in these tumors.
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http://dx.doi.org/10.1038/s41379-021-00806-wDOI Listing
August 2021

Liver Pathology, Including MOC31 Immunohistochemistry, in Congenital Tufting Enteropathy.

Am J Surg Pathol 2021 08;45(8):1091-1097

Departments of Pathology.

Congenital tufting enteropathy (CTE) is a rare heritable cause of intractable diarrhea due to EPCAM mutation. Pathologic findings include intestinal villous atrophy, tufted discohesive tear-drop-shaped epithelium, and a normal brush border. In affected patients, absent intestinal epithelial cell adhesion molecule (EpCAM) expression results in loss of MOC31 immunostaining. CTE liver pathology has not yet been described. We identified CTE patients with liver biopsies and reviewed clinicopathologic material including MOC31 immunohistochemistry. Three CTE patients had 4 liver core biopsies (at ages 1, 5, 7, and 16 y), 2 for preintestinal transplant evaluation, and 2 (from a single patient) for pretreatment assessment of chronic hepatitis C; all had received parenteral nutrition (PN). All samples showed loss of biliary epithelial polarization and mild portal and lobular inflammation. Only the hepatitis C patient demonstrated fibrosis. One patient each had lobular neutrophilic microabscesses and macrovesicular steatosis. Proliferative ductular reactions were absent in CTE patients but present in all controls on PN for other reasons. MOC31 was absent in biliary epithelium and hepatocytes of all CTE patients; controls showed consistent strong membranous biliary epithelial and patchy membranous periportal hepatocyte staining. Our data show that, histologically, hepatopathy in CTE can be difficult to separate from comorbid disease including PN effect; however, the absent ductular reaction may be characteristic. MOC31 localization in the biliary epithelium and zone 1 hepatocytes of controls suggests these compartments of the liver might be most susceptible to effects of EpCAM deficiency. In addition, we validate the liver as suitable tissue for CTE diagnosis using MOC31 immunohistochemistry.
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http://dx.doi.org/10.1097/PAS.0000000000001710DOI Listing
August 2021

Vascular Anomalies of the Head and Neck: A Pediatric Overview.

Head Neck Pathol 2021 Mar 15;15(1):59-70. Epub 2021 Mar 15.

Department of Pathology, Boston Children's Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, MA, 02115, USA.

Vascular anomalies, further classified into vascular tumors and malformations, often involve the head and neck region of children. These entities may raise diagnostic dilemmas, as they often demonstrate heterogenous and overlapping histologic features. The aim of this paper is to provide an overview of the common vascular anomalies in the head and neck region of children. Specific entities discussed include infantile hemangioma, congenital hemangioma, tufted angioma, kaposiform hemangioendothelioma, and various vascular malformations. Clinicopathologic features and associated molecular associations are reviewed.
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http://dx.doi.org/10.1007/s12105-020-01236-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8010067PMC
March 2021

Cytomorphologic Spectrum of SMARCB1-Deficient Soft Tissue Neoplasms.

Am J Clin Pathol 2021 07;156(2):229-245

Department of Pathology, Brigham and Women's Hospital.

Objectives: The SWI/SNF complex core subunit SMARCB1 is inactivated in a variety of neoplasms that share characteristic "rhabdoid" cytomorphology. The aim of this study was to evaluate SMARCB1-deficient soft tissue neoplasms on cytology to identify diagnostic clues.

Methods: Eleven SMARCB1-deficient tumors, including six epithelioid sarcomas, three malignant rhabdoid tumors, one epithelioid malignant peripheral nerve sheath tumor (MPNST), and one poorly differentiated chordoma with fine-needle aspiration (FNA), serous effusion, or touch prep (TP) from two institutions, were included. Targeted next-generation sequencing (NGS) was performed in two cases.

Results: Evaluation of FNA (n = 4), effusion (n = 4), and TP (n = 3) in nine adult and two pediatric patients demonstrated cellular samples (n = 11), epithelioid cells with rhabdoid morphology (n = 9), eccentrically located nuclei with prominent nucleoli (n = 7), and cytoplasmic bodies (n = 4); two patients were diagnosed on FNA with cell block. Immunohistochemistry (IHC) demonstrated SMARCB1 loss in all cases and keratin and/or EMA expression in all but the epithelioid MPNST; NGS identified SMARCB1 inactivation in both cases.

Conclusions: SMARCB1-deficient soft tissue neoplasms comprise a variety of tumors with epithelioid morphology and frequent expression of keratin and/or EMA. Recognition of characteristic rhabdoid morphology on cytology can prompt IHC and/or NGS testing for SMARCB1 deficiency and help establish the diagnosis.
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http://dx.doi.org/10.1093/ajcp/aqaa223DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8259500PMC
July 2021

Novel variants in the stem cell niche factor WNT2B define the disease phenotype as a congenital enteropathy with ocular dysgenesis.

Eur J Hum Genet 2021 06 1;29(6):998-1007. Epub 2021 Feb 1.

Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA.

WNT2B is a member of the Wnt family, a group of signal transduction proteins involved in embryologic development and stem cell renewal and maintenance. We recently reported homozygous nonsense variants in WNT2B in three individuals with severe, neonatal-onset diarrhea, and intestinal failure. Here we present a fourth case, from a separate family, with neonatal diarrhea associated with novel compound heterozygous WNT2B variants. One of the two variants was a frameshift variant (c.423del [p.Phe141fs]), while the other was a missense change (c.722 G > A [p.G241D]) that we predict through homology modeling to be deleterious, disrupting post-translational acylation. This patient presented as a neonate with severe diet-induced (osmotic) diarrhea and growth failure resulting in dependence on parenteral nutrition. Her gastrointestinal histology revealed abnormal cellular architecture particularly in the stomach and colon, including oxyntic atrophy, abnormal distribution of enteroendocrine cells, and a paucity of colonic crypt glands. In addition to her gastrointestinal findings, she had bilateral corneal clouding and atypical genital development later identified as a testicular 46,XX difference/disorder of sexual development. Upon review of the previously reported cases, two others also had anterior segment ocular anomalies though none had atypical genital development. This growing case series suggests that variants in WNT2B are associated with an oculo-intestinal (and possibly gonadal) syndrome, due to the protein's putative involvement in multiple developmental and stem cell maintenance pathways.
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http://dx.doi.org/10.1038/s41431-021-00812-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8187348PMC
June 2021

Newcomers in Vascular Anomalies.

Surg Pathol Clin 2020 Dec;13(4):719-728

Department of Pathology, Boston Children's Hospital, 300 Longwood Avenue, BCH 3027, Boston, MA 02115, USA. Electronic address:

Vascular anomalies are composed of tumors and malformations and with overlapping histologies, thus are often misdiagnosed or labeled with imprecise terminology. Lesions are common and usually diagnosed during infancy or childhood; the estimated prevalence is 4.5%. Vascular tumors rapidly enlarge postnatally and demonstrate endothelial proliferation. Malformations are errors in vascular development with stable endothelial turnover; they are typically named based on the primary vessel that is malformed (capillary, arterial, venous, lymphatic). This article reviews the pathologic and molecular genetic characteristics for select recently described vascular anomalies.
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http://dx.doi.org/10.1016/j.path.2020.08.008DOI Listing
December 2020

Lipoblastoma phenotype contains a somatic PIK3CA mutation.

Pediatr Dermatol 2021 Jan 9;38(1):299-300. Epub 2020 Oct 9.

Department of Plastic and Oral Surgery, Harvard Medical School, Boston Children's Hospital, Boston, MA, USA.

Lipoblastoma typically occurs in childhood and is associated with rearrangements of the PLAG1 gene. We present a patient with an isolated mass thought to be a lipoblastoma clinically, radiographically, and histologically. The lesion was diagnosed as a PIK3CA-adipose lesion after the tissue was negative for PLAG1 rearrangement and contained a somatic PIK3CA mutation (H1047R). Although PIK3CA variants are associated with PROS (PIK3CA-related overgrowth spectrum), this report illustrates a non-syndromic, lipoblastoma phenotype caused by a PIK3CA mutation.
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http://dx.doi.org/10.1111/pde.14406DOI Listing
January 2021

Calcifying synovial sarcoma of the tongue with SS18 rearrangement: a rare variant in a rare location.

Oral Surg Oral Med Oral Pathol Oral Radiol 2021 11 20;132(5):e186-e189. Epub 2020 Aug 20.

Department of Oral Medicine Infection and Immunity, Harvard School of Dental Medicine, Boston, MA, USA; Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.

Synovial sarcoma is a soft tissue malignancy harboring t(X;18) resulting in fusion of two genes SS8 (at 18q11) and SSX (1, 2 or 4 at Xp11) forming the gene fusion product SS18-SSX. It affects adults in their 3rd-4th decades, most frequently in the para-articular regions of the extremities. Less than 10% of the cases occur within the head and neck region and of these, 60% occur in the neck and only 10% occur in the oral cavity. We report a synovial sarcoma of the tongue in a 14-year-old female patient with unusual histology. The patient presented with a mass occupying most of the tongue with extension into the floor of mouth and the lingual gingiva of the anterior mandibular teeth. The tumor was composed of a highly cellular proliferation of spindle cells in a herringbone pattern with many small vessels but without glandular structures, and with extensive calcifications throughout the tumor. Tumor cells were positive for epithelial membrane antigen and transducin-like enhancer of split-1, and fluorescence in situ hybridization studies identified SS18 gene rearrangement. The patient was managed with two debulking procedures followed by chemoradiation and is currently alive with disease.
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http://dx.doi.org/10.1016/j.oooo.2020.08.016DOI Listing
November 2021

Arteriovenous malformation phenotype resembling congenital hemangioma contains KRAS mutations.

Clin Genet 2020 12 2;98(6):595-597. Epub 2020 Sep 2.

Department of Plastic and Oral Surgery, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.

Extracranial arteriovenous malformation (AVM) is most commonly caused by a somatic mutation in MAP2K1. We report two patients with vascular anomalies that had an unclear clinical diagnosis most consistent with either an AVM or congenital hemangioma. Lesions were cutaneous, reddish-purple with telangiectasias, present at birth, and had defined borders. Histopathology indicated AVM and both lesions contained somatic KRAS mutations. A rare AVM phenotype exists that shares clinical features with congenital hemangioma.
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http://dx.doi.org/10.1111/cge.13833DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7955771PMC
December 2020

Making the most of small samples: Optimization of tissue allocation of pediatric solid tumors for clinical and research use.

Pediatr Blood Cancer 2020 09 15;67(9):e28326. Epub 2020 Jul 15.

Department of Pathology, Boston Children's Hospital, Boston, Massachusetts.

Introduction: Tissue from pediatric solid tumors is in high demand for use in high-impact research studies, making the allocation of tissue from an anatomic pathology laboratory challenging. We designed, implemented, and assessed an interdepartmental process to optimize tissue allocation of pediatric solid tumors for both clinical care and research.

Methods: Oncologists, pathologists, surgeons, interventional radiologists, pathology technical staff, and clinical research coordinators participated in the workflow design. Procedures were created to address patient identification and consent, prioritization of protocols, electronic communication of requests, tissue preparation, and distribution. Pathologists were surveyed about the value of the new workflow.

Results: Over a 5-year period, 644 pediatric solid tumor patients consented to one or more studies requesting archival or fresh tissue. Patients had a variety of tumor types, with many rare and singular diagnoses. Sixty-seven percent of 1768 research requests were fulfilled. Requests for archival tissue were fulfilled at a significantly higher rate than those for fresh tissue (P > .001), and requests from resection specimens were fulfilled at a significantly higher rate than those from biopsies (P > .0001). In an anonymous survey, seven of seven pathologists reported that the process had improved since the introduction of the electronic communication model.

Conclusions: A collaborative and informed model for tissue allocation is successful in distributing archival and fresh tissue for clinical research studies. Our workflows and policies have gained pathologists' approval and streamlined our processes. As clinical and research programs evolve, a thoughtful tissue allocation process will facilitate ongoing research.
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http://dx.doi.org/10.1002/pbc.28326DOI Listing
September 2020

Plexiform Myofibroblastoma: Clinicopathologic Analysis of 36 Cases of a Distinctive Benign Tumor of Soft Tissue Affecting Mainly Children and Young Adults.

Am J Surg Pathol 2020 11;44(11):1469-1478

Department of Pathology, Brigham and Women's Hospital.

The spectrum of benign superficial fibroblastic/myofibroblastic tumors continues to expand and includes entities such as plexiform fibrohistiocytic tumor, dermatomyofibroma and fibroblastic connective tissue nevus. Here, we describe a seemingly distinctive group of lesions which we have labeled "plexiform myofibroblastoma" (PM). PM is a rare superficial mesenchymal tumor of fibroblastic/myofibroblastic lineage that predominantly occurs in children and young adults. Thirty-six cases from the consultation archives of one of the authors have been studied to characterize the clinicopathologic characteristics of PM. 19 patients (53%) were female and 17 were male, with age at presentation ranging from congenital (2 cases) to 50 years of age (median: 9.5 y). Three patients had multiple lesions. Males tended to develop tumors during childhood (median: 2 y; range: congenital-37 y), while in females the age distribution was relatively uniform from childhood through adulthood (median age: 25 y; range: 4 mo to 50 y). Most tumors occurred in truncal locations (25/40), including the back (11), anterolateral chest wall (4), axilla (4), abdominal wall (4), perineum (1) and suprapubic region (1). Other tumor sites were the neck (10/40), occiput (2), lower extremity (2) and breast (1). The average greatest dimension was 2.7±1.7 cm (range: 0.6 to 8 cm). Three male patients, 2 of whom were brothers, presented between 6 months and 1 year of age with multiple lesions variably involving the back, occiput and axillae; these lesions spontaneously regressed after being present for about 2 years, with no evidence of recurrence at a mean follow-up of 11.4±3.2 years. Histologically, PM was composed of plexiform fascicles of fibroblastic/myofibroblastic spindle cells that ramify through the subcutis and reticular dermis. The bland neoplastic cells had indistinct cell borders, palely eosinophilic cytoplasm and ovoid or tapered nuclei. There was no histiocytoid component in any case, and no cases contained osteoclast-like giant cells. Twelve of thirty-four (35%) reviewed cases showed at least focal keloidal hyalinization, 6/34 (18%) contained somewhat fasciitis-like areas and 6/34 (18%) contained focal myxoid stroma. Immunohistochemical studies were positive for SMA (27/32 cases), desmin (9/21) and CD34 (13/24) and negative for β-catenin (0/14) and S-100 (0/22). EMA was weakly positive in 2/15 cases. An FGFR2 M535L tyrosine kinase domain variant of unknown significance was detected in 1/7 sequenced cases, and no somatic alterations, copy number alterations or gene fusions were detected in the other 6. Clinical follow-up data were available for 16/36 patients (44%; median duration: 5.5 y). Although most excisions had positive margins (11/16), only 1 patient developed a local recurrence 4 years after initial excision. No tumors metastasized. PM is a benign tumor with characteristic histology, epidemiology and anatomic site distribution. Because PM rarely recurs, a watchful waiting approach would be reasonable for lesions excised with positive margins.
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http://dx.doi.org/10.1097/PAS.0000000000001534DOI Listing
November 2020

Genomics of MPNST (GeM) Consortium: Rationale and Study Design for Multi-Omic Characterization of NF1-Associated and Sporadic MPNSTs.

Genes (Basel) 2020 04 2;11(4). Epub 2020 Apr 2.

Department of Pathology, University College London Cancer Institute, Bloomsbury, London WC1E 6BT, UK.

The Genomics of Malignant Peripheral Nerve Sheath Tumor (GeM) Consortium is an international collaboration focusing on multi-omic analysis of malignant peripheral nerve sheath tumors (MPNSTs), the most aggressive tumor associated with neurofibromatosis type 1 (NF1). Here we present a summary of current knowledge gaps, a description of our consortium and the cohort we have assembled, and an overview of our plans for multi-omic analysis of these tumors. We propose that our analysis will lead to a better understanding of the order and timing of genetic events related to MPNST initiation and progression. Our ten institutions have assembled 96 fresh frozen NF1-related (63%) and sporadic MPNST specimens from 86 subjects with corresponding clinical and pathological data. Clinical data have been collected as part of the International MPNST Registry. We will characterize these tumors with bulk whole genome sequencing, RNAseq, and DNA methylation profiling. In addition, we will perform multiregional analysis and temporal sampling, with the same methodologies, on a subset of nine subjects with NF1-related MPNSTs to assess tumor heterogeneity and cancer evolution. Subsequent multi-omic analyses of additional archival specimens will include deep exome sequencing (500×) and high density copy number arrays for both validation of results based on fresh frozen tumors, and to assess further tumor heterogeneity and evolution. Digital pathology images are being collected in a cloud-based platform for consensus review. The result of these efforts will be the largest MPNST multi-omic dataset with correlated clinical and pathological information ever assembled.
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http://dx.doi.org/10.3390/genes11040387DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7231181PMC
April 2020

Arteriovenous Malformation MAP2K1 Mutation Causes Local Cartilage Overgrowth by a Cell-Non Autonomous Mechanism.

Sci Rep 2020 03 10;10(1):4428. Epub 2020 Mar 10.

Department of Plastic & Oral Surgery, Boston Children's Hospital, Harvard Medical School, Boston, USA.

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).
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http://dx.doi.org/10.1038/s41598-020-61444-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7064492PMC
March 2020

Genomic and Immunologic Characterization of INI1-Deficient Pediatric Cancers.

Clin Cancer Res 2020 06 2;26(12):2882-2890. Epub 2020 Mar 2.

Department of Pediatric Hematology/Oncology, Dana-Farber/Boston Children's Cancer and Blood Disorders Center and Harvard Medical School, Boston, Massachusetts.

Purpose: Several aggressive pediatric cancers harbor alterations in , including rhabdoid tumors, epithelioid sarcoma, and chordoma. As tumor profiling has become more routine in clinical care, we investigated the relationship between genetic variants identified by next-generation sequencing (NGS) and INI1 protein expression. Therapeutic approaches for INI1-deficient tumors are limited. Early reports suggest a potential role for immune checkpoint inhibition in these patients. Thus, we also investigated PD-L1 and CD8 expression in INI1-negative pediatric brain and solid tumors.

Experimental Design: We performed immunohistochemistry (IHC) for INI1 and immune markers (PD-L1, CD8, and CD163) and NGS on tumor samples from 43 pediatric patients who had tumors with INI1 loss on previous IHC or genomic alterations on prior somatic sequencing.

Results: two-copy deletions and inactivating mutations on NGS were associated with loss of INI1 protein expression. Single-copy deletion of was not predictive of INI1 loss in tumor histologies not known to be INI1-deficient. In the 27 cases with INI1 loss and successful tumor sequencing, 24 (89%) had a alteration detected. In addition, 47% (14/30) of the patients with INI1-negative tumors had a tumor specimen that was PD-L1 positive and 60% (18/30) had positive or rare CD8 staining. We report on 3 patients with INI1-negative tumors with evidence of disease control on immune checkpoint inhibitors.

Conclusions: A significant proportion of the INI1-negative tumors express PD-L1, and PD-L1 positivity was associated with extracranial tumor site. These results suggest that clinical trials of immune checkpoint inhibitors are warranted in INI1-negative pediatric cancers.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-3089DOI Listing
June 2020

Recurrent RET gene fusions in paediatric spindle mesenchymal neoplasms.

Histopathology 2020 Jun 15;76(7):1032-1041. Epub 2020 May 15.

Department of Pathology, Boston Children's Hospital, Boston, MA, USA.

Aims: The classification of paediatric spindle mesenchymal tumours is evolving, and the spectrum of so-called 'infantile fibrosarcoma' has expanded to include tumours with NTRK, BRAF and MET gene fusions. RET-rearranged paediatric spindle cell neoplasms are an emerging group; there is sparse literature on their clinical, pathological and genetic features, and their nosological place in the canon of soft tissue tumours is uncertain. In this study, we report five RET-rearranged paediatric spindle cell tumours with fusion partners MYH10, KIAA1217 and CLIP2.

Methods And Results: The tumours occurred in the pelvic region, paraspinal region, kidney and subcutaneous tissue of hand and abdomen. The patients' ages ranged from 6 months to 13 years (median 1 year). The tumours were composed of monomorphic spindle cells arranged in a fascicular pattern. Lesional cells had minimally atypical ovoid or tapered nuclei and pale cytoplasm with indistinct borders. Necrosis was not identified. Mitoses numbered three to 12 per 10 high-power field. Cases showed inconsistent and variable expression of S100, CD34 and SMA. Clinical behaviour ranged from small lesions potentially cured by simple resection to large lesions exhibiting metastasis, but responsive to kinase inhibitor therapy.

Conclusions: Our findings help to define RET-rearranged spindle cell tumours. Although it is likely that these tumours comprise part of the morphological and clinical spectrum of infantile fibrosarcoma (IFS), identification of RET gene alteration is important for its unique therapeutic implications.
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http://dx.doi.org/10.1111/his.14082DOI Listing
June 2020

Recurrent and novel USP6 fusions in cranial fasciitis identified by targeted RNA sequencing.

Mod Pathol 2020 05 11;33(5):775-780. Epub 2019 Dec 11.

Department of Pathology, Boston Children's Hospital, Boston, MA, USA.

Cranial fasciitis is a benign myofibroproliferative lesion of the scalp and underlying bones typically occurring in the pediatric population. Histologically, it is characterized by loose fascicles of stellate cells in a fibromyxoid background, findings similar to those described in the closely related variant nodular fasciitis. Previously characterized as a reactive process, the identification of USP6 translocations in over 90% of nodular fasciitis cases prompted their reclassification as a clonal neoplastic process. Unlike nodular fasciitis, the molecular underpinnings of cranial fasciitis are less clear. While a subset of cranial fasciitis has been associated with Wnt/β-catenin pathway dysregulation, recent case reports suggest that this entity may also harbor USP6 fusions, a finding we sought to further investigate. We identified fifteen archival cases of cranial fasciitis, five females and ten males ranging in age from 3 months to 9 years (median 11 months), composed of formalin-fixed paraffin-embedded and fresh frozen tissues (11 and 4 cases respectively). Samples were evaluated on an RNA-based targeted sequencing panel targeting genes recurrently rearranged in neoplasia, including USP6. Five of fifteen cases (33%) were positive for USP6 rearrangements predicted to result in the fusion of the entire USP6 coding region to the promoter of the 5' partner, (three of which were novel):  two SERPINH1-USP6 (novel) and one each of COL3A1-USP6 (novel), SPARC-USP6, and MYH9-USP6. These results demonstrate the recurrent nature of USP6 rearrangements in cranial fasciitis, and highlight the success of targeted RNA sequencing in identifying known and novel fusion partners. The identification of USP6 promoter-swapping rearrangements is helpful in understanding the underlying biology of cranial fasciitis, and reinforces its biologic relationship to nodular fasciitis. Targeted RNA sequencing is a helpful tool in diagnosing this pseudosarcomatous lesion.
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http://dx.doi.org/10.1038/s41379-019-0422-6DOI Listing
May 2020

Clinical characterization and long-term outcomes in pediatric epithelioid hemangioendothelioma.

Pediatr Blood Cancer 2020 02 14;67(2):e28045. Epub 2019 Nov 14.

Department of Hematology/Oncology, Vascular Anomalies Center, Boston Children's Hospital, Boston, Massachusetts.

There is a paucity of information about the clinical characteristics and long-term outcomes of pediatric epithelioid hemangioendothelioma (EHE), a rare vascular neoplasm commonly presenting in adulthood. In our case series of 24 patients with EHE aged 2-26 years, the majority presented with multi-organ disease. Progression was seen in 63% of patients with a mean time to progression of 18.4 months (range: 0-72). Three patients treated with sirolimus achieved stable disease or partial response for >2.5 years. Longitudinal prospective pediatric studies are needed to develop standardized approaches to surgical and medical management.
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http://dx.doi.org/10.1002/pbc.28045DOI Listing
February 2020

Arteriovenous malformation associated with a HRAS mutation.

Hum Genet 2019 Dec 21;138(11-12):1419-1421. Epub 2019 Oct 21.

Department of Plastic and Oral Surgery, Harvard Medical School, Boston Children's Hospital, 300 Longwood Ave, Boston, MA, 02115, USA.

The majority of extracranial arteriovenous malformations (AVMs) are caused by somatic mutations in MAP2K1. We report a somatic HRAS mutation in a patient who has a facial AVM associated with subcutaneous adipose overgrowth. We performed whole exome sequencing on DNA from the affected tissue and found a HRAS mutation (p.Thr58_Ala59delinsValLeuAspVal). Mutant allelic frequency was 5% in whole tissue and 31% in isolated endothelial cells (ECs); the mutation was not present in blood DNA or non-ECs. Somatic mutations in HRAS can cause AVM.
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http://dx.doi.org/10.1007/s00439-019-02072-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6874881PMC
December 2019

A Distinctive Genomic and Immunohistochemical Profile for NOTCH3 and PDGFRB in Myofibroma With Diagnostic and Therapeutic Implications.

Int J Surg Pathol 2020 Apr 29;28(2):128-137. Epub 2019 Sep 29.

Boston Children's Hospital, Boston, MA, USA.

. 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 . The relationship of myofibroma and PDGFRB to the NOTCH pathway has not yet been described. . 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). . Alterations identified by next-generation sequencing included sequence variants in 8/10 cases (80%), a variant in 1/10 cases (10%), and a 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 and . 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. . Our findings suggest a common pathway of PDGFRB/NOTCH3 activation in myofibromas, even in cases that lack 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.
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http://dx.doi.org/10.1177/1066896919876703DOI Listing
April 2020

Intramuscular fast-flow vascular anomaly contains somatic MAP2K1 and KRAS mutations.

Angiogenesis 2019 11 5;22(4):547-552. Epub 2019 Sep 5.

Department of Plastic & Oral Surgery, Boston Children's Hospital, Harvard Medical School, 300 Longwood Ave, Boston, MA, 02115, USA.

Background: The term "intramuscular hemangioma capillary type" (IHCT) refers to a fast-flow vascular lesion that is classified as a tumor, although its phenotype overlaps with arteriovenous malformation (AVM). The purpose of this study was to identify somatic mutations in IHCT.

Methods: Affected tissue specimens were obtained during a clinically indicated procedure. The diagnosis of IHCT was based on history, physical examination, imaging and histopathology. Because somatic mutations in cancer-associated genes can cause vascular malformations, we sequenced exons from 446 cancer-related genes in DNA from 7 IHCT specimens. We then performed mutation-specific droplet digital PCR (ddPCR) to independently test for the presence of a somatic mutation found by sequencing and to screen one additional IHCT sample.

Results: We detected somatic mutations in 6 of 8 IHCT specimens. Four specimens had a mutation in MAP2K1 (p.Q58_E62del, p.P105_I107delinsL, p.Q56P) and 2 specimens had mutations in KRAS (p.K5E and p.G12D, p.G12D and p.Q22R). Mutant allele frequencies detected by sequencing and confirmed by ddPCR ranged from 2 to 15%.

Conclusions: IHCT lesions are phenotypically similar to AVMs and contain the same somatic MAP2K1 or KRAS mutations, suggesting that IHCT is on the AVM spectrum. We propose calling this lesion "intramuscular fast-flow vascular anomaly."
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http://dx.doi.org/10.1007/s10456-019-09678-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6868332PMC
November 2019

Atypical lipomatous tumour/well-differentiated liposarcoma and de-differentiated liposarcoma in patients aged ≤ 40 years: a study of 116 patients.

Histopathology 2019 Dec 13;75(6):833-842. Epub 2019 Oct 13.

Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.

Aims: Limited data exist on atypical lipomatous tumour (ALT)/well-differentiated liposarcoma (WDL) and de-differentiated liposarcoma (DDLPS) in children and young adults.

Methods And Results: Cases of ALT/WDL/DDLPS arising in patients aged ≤ 40 years were collected from multiple institutional and consultation archives. A total of 116 cases of ALT/WDL (75) and DDLPS (41) were identified, representing fewer than 5% of these tumours seen at our institutions during this time-period. The patients (59 male/57 female) ranged in age from 8 to 40 years. Sites included deep central (abdomen/retroperitoneum/pelvis/groin) (n = 60), extremity (n = 42), trunk (n = 5), head/neck (n = 8) and mediastinum (n = 1). De-differentiated patterns included: high-grade pleomorphic sarcoma, myxofibrosarcoma-like, heterologous rhabdomyoblastic differentiation, low-grade spindle cell sarcoma and homologous lipoblastic differentiation. Forty-one patients experienced a local recurrence and 11 patients with DDLPS developed metastasis. ALT arising in the extremities had lower recurrence rates than deep central WDL (5-year recurrence-free survival 88.9% versus 59.0%; P = 0.002), while patients with deep central DDLPS experienced significantly more adverse events compared to WDL at this site (5-year event-free survival 11.9% versus 59.0%) (P < 0.0001). Seven (of eight) head/neck tumours had follow-up available; five recurred, and one patient (DDLPS) with recurrence also experienced a metastasis. The single mediastinal tumour (DDLPS) recurred and metastasised.

Conclusion: ALT/WDL and DDLPS occurring in patients aged ≤ 40 years is rare, but exhibits similar morphological features to its counterparts in older adults, including potential for heterologous and homologous de-differentiation in the latter. Although case numbers are limited, tumours arising in the head and neck exhibit high rates of adverse events, suggesting that classification as WDL rather than ALT is more appropriate.
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http://dx.doi.org/10.1111/his.13957DOI Listing
December 2019

Fibroadipose Vascular Anomaly in the Upper Extremity: A Distinct Entity With Characteristic Clinical, Radiological, and Histopathological Findings.

J Hand Surg Am 2020 Jan 3;45(1):68.e1-68.e13. Epub 2019 Jul 3.

Department of Plastic and Oral Surgery, Vascular Anomalies Center, Boston Children's Hospital, Harvard University, Boston, MA.

Purpose: Fibroadipose vascular anomaly (FAVA) is an intramuscular vascular malformation that has been recently described as a distinct clinical entity. The clinical, radiological, and histopathological characteristics of FAVA in the upper extremity are reviewed.

Methods: This was a retrospective case series of upper-extremity FAVA lesions.

Results: We reviewed 19 patients with FAVA of the upper limb. Pain, stiffness, swelling, and flexion contractures were the most common presentations. Except for one lesion confined to the hand, all lesions either presented with or developed a contracture within 10 years. Ten patients underwent surgical debulking. Six required tendon transfer reconstruction and 3 necessitated a free functional muscle transfer.

Conclusions: Fibroadipose vascular anomaly in the upper extremity requires an accurate diagnosis and may benefit from early referral to a multidisciplinary vascular anomaly center with experienced hand surgeons. Compression garments, propranolol, and sclerotherapy seem to be ineffective. Surgical resection focused on symptomatic regions with appropriate reconstruction may have benefit in salvage of limbs with compromised function.

Type Of Study/level Of Evidence: Therapeutic IV.
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http://dx.doi.org/10.1016/j.jhsa.2019.05.008DOI Listing
January 2020

Imaging findings in epithelioid hemangioendothelioma.

Clin Imaging 2019 Nov - Dec;58:59-65. Epub 2019 Jun 12.

Division of Vascular and Interventional Radiology, Boston Children's Hospital and Harvard Medical School, United States of America; Vascular Anomalies Center, Boston Children's Hospital and Harvard Medical School, United States of America. Electronic address:

Purpose-objective: Epithelioid hemangioendothelioma (EHE) is a rare vascular malignancy with varying biologic behavior. The purpose of this study was to identify imaging findings most characteristic of EHE.

Methods: Retrospective review of clinical and imaging records in patients referred to our Vascular Anomalies Center over a 17 year period with biopsy proven EHE.

Results: We evaluated 29 patients (17 F) with median age of 16 years (range 2-76 y). The most common presenting symptoms were pain (n = 13) and palpable mass (n = 7). 22 (70%) had multifocal disease. Most common sites of involvement were lung (n = 25), liver (n = 16), bone (n = 12), soft tissue (n = 3) and lymph nodes (n = 1). Of patients with single site disease, 3 had lung, 3 liver, and 1 had bone lesions. In 18/25 with lung disease, there were multiple nodules of varying sizes and characteristics. In 14/16 with hepatic disease there were multiple nodules with predominantly peripheral distribution. Subcapsular retraction was seen in 10/16 and a "lollipop" sign (hepatic or portal vein tapering at the edge of a well-defined hypoenhancing lesion) identified in 5/16. Of 12 osseous lesions, 11 were lytic, 8 involved vertebrae and 9 involved the axial skeleton.

Conclusion: EHE has varied imaging findings. The most common sites are lungs, liver, and bone, with multi-organ involvement seen in most. Lung disease is most commonly characterized by multiple nodules. Hepatic lesions demonstrate the most distinctive findings, with peripheral distribution, lack of early enhancement, subcapsular retraction and "lollipop" sign. Osseous lesions are commonly lytic and more prevalent in the axial skeleton.
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http://dx.doi.org/10.1016/j.clinimag.2019.06.002DOI Listing
March 2020

Surgical Management of Fibroadipose Vascular Anomaly of the Lower Extremities.

J Pediatr Orthop 2020 Mar;40(3):e227-e236

Departments of Orthopedic Surgery.

Background: Fibroadipose vascular anomaly (FAVA) is a recently-defined vascular malformation often involving the extremities and presenting in childhood. Patients may present to orthopaedic surgeons with pain, swelling, joint contractures, and leg length discrepancy. There is no established therapy or treatment paradigm. We report on outcomes following surgical excision for patients with this condition.

Methods: Between 2007 and 2016, all 35 patients that underwent excision of lower-extremity FAVA were retrospectively reviewed using a combination of medical records, radiologic findings, and telemedicine reviews.

Results: Mean age at initial presentation was 12.3±6.8 years. Mean follow-up from time of definitive diagnosis at our institution was 66 months (range: 12 to 161 mo). Mean follow-up after surgery was 35 months (range: 6 to 138 mo). Females were affected more than males (71% vs. 29%). The most common location of FAVA was in the calf (49%), followed by the thigh (40%). The most commonly involved muscle was gastrocnemius (29%), followed by the quadriceps (26%). At latest follow-up after surgery, there was an improvement in the proportion of patients with pain at rest (63% vs. 29%), pain with activity (100% vs. 60%), as well as analgesia use (94% vs. 37%). Fourteen patients (40%) had symptomatic residual disease or recurrence of FAVA requiring further treatment. Six patients (17%) required further surgery and 6 (17%) required further interventional radiologic procedures. Three patients (9%) required eventual amputation for intractable pain and loss of function. Lesions with direct nerve involvement were associated with persistent neuropathic symptoms at latest follow-up (P=0.002) as well as symptomatic residual disease and/or recurrence requiring further treatment (P=0.01). Seventeen patients (49%) had 19 preoperative joint contractures. Eighteen of the 19 contractures (95%) had sustained improvement at latest follow-up.

Conclusions: In carefully selected patients, surgical excision of FAVA results in improvement of symptoms. However, symptomatic residual disease and/or recurrence are not uncommon. Direct nerve involvement is associated with a worse outcome.

Level Of Evidence: Level IV-case series.
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http://dx.doi.org/10.1097/BPO.0000000000001406DOI Listing
March 2020

Adipocytic tumors in Children: A contemporary review.

Semin Diagn Pathol 2019 Mar 28;36(2):95-104. Epub 2019 Feb 28.

Department of Pathology, Children's Hospital Boston and Harvard Medical School, Boston Children's Hospital, 300 Longwood Avenue, Boston, MA 02115, United States. Electronic address:

Adipocytic neoplasms in the pediatric population demonstrate a different histologic spectrum and frequency than in adults. The vast majority of these tumors are benign, with lipoma being the most common entity. The identification of signature cytogenetic and molecular alterations for certain lesions, such as PLAG1 gene rearrangement in lipoblastoma and FUS-DDIT3 fusion in myxoid liposarcoma, has been helpful in approaching these neoplasms and aiding in confirming the diagnosis. Furthermore, it is important for pathologists to recognize that adipocytic neoplasms may be associated with different syndromes with potential impact in managing such patients. This review provides a summary of the clinical pictures, histologic characteristics, molecular alterations, differential diagnoses, and syndromic associations of the commonly encountered fatty tumors in children.
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http://dx.doi.org/10.1053/j.semdp.2019.02.004DOI Listing
March 2019
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