The classification of soft tissue tumors has evolved considerably in the last decade, largely due to advances in understanding the pathogenetic basis of many of these, sometimes rare, tumors. Deletion of Retinoblastoma 1 (RB1), a well-known tumor suppressor gene, has been implicated in the tumorigenesis of a particular group of soft tissue neoplasms. This group of so-called “RB1-deleted soft tissue tumors” has been rapidly expanding in recent years, currently consisting of spindle cell/pleomorphic lipoma, atypical spindle cell/pleomorphic lipomatous tumor, pleomorphic liposarcoma, myofibroblastoma, cellular angiofibroma, and acral fibromyxoma. Most of these neoplasms, except pleomorphic liposarcoma, are considered benign entities and are mainly described in the older adult population. This article will review the currently known morphological, immunohistochemical, and molecular features of this heterogeneous group of mesenchymal tumors with an emphasis on differential diagnosis.

Introduction. Lysosomal storage disorders (LSDs) are rare diseases with more than 50 different entities described today. The spectrum of phenotypes varies from severe to lethal and early-onset disease to mild and late onset. Recognition of the clinical signs and diagnostic workup is challenging and requires expertise. Diagnosis relies on finding abnormal metabolites in urine and serum followed by further enzymatic or molecular analysis. Routine histological examination of the foetal and placental tissues frequently shows vacuolisation, providing a readily available important clue to the diagnosis. Case Report. A third child of consanguineal parents showed several dysmorphic features and a complicated neonatal period with eventual demise in the early postneonatal period due to respiratory failure. An LSD was suspected based on clinical presentation, urine metabolite excretion, skeletal radiograph, and vacuolisation in lymphocytes and placental tissues on, respectively, blood smear and routine histological examination. Homozygosity mapping favoured galactosialidosis. The diagnosis was confirmed by massive parallel sequencing, revealing a single nucleotide variation in the CTSA gene (c.265A>C, p.Ser89Arg). Discussion. Histological placental examination may be either the first clue or complimentary evidence in recognizing LSDs. It is important to recognize these clues as it may prompt further investigation and facilitate earlier recognition of the disease.

Background and Objectives: Central Nervous System (CNS) pediatric tumors represent the most common solid tumors in children with a wide variability in terms of survival and therapeutic response. By contrast to their adult counterpart, the mutational landscape of pediatric CNS tumors is characterized by oncogenic fusions rather than multiple mutated genes. CNS pediatric tumors associated with oncogenic fusions represent a complex landscape of tumors with wide radiological, morphological and clinical heterogeneity. In the fifth CNS WHO classification, there are few pediatric CNS tumors for which diagnosis is based on a single oncogenic fusion. This work aims to provide an overview of the impact of rare oncogenic fusions (NTRK, ROS, ALK, MET, FGFR, RAF, MN1, BCOR and CIC genes) on pathogenesis, histological phenotype, diagnostics and theranostics in pediatric CNS tumors. We report four cases of pediatric CNS tumors associated with NTRK (n = 2), ROS (n = 1) and FGFR3 (n = 1) oncogenic fusion genes as a proof of concept. Cases presentation and literature review: The literature review and the cohort that we described here underline that most of these rare oncogenic fusions are not specific to a single morpho-molecular entity. Even within tumors harboring the same oncogenic fusions, a wide range of morphological, molecular and epigenetic entities can be observed. Conclusions: These findings highlight the need for caution when applying the fifth CNS WHO classification, as the vast majority of these fusions are not yet incorporated in the diagnosis, including grade evaluation and DNA methylation classification.

Moyamoya disease (MMD) is a rare cerebrovascular disorder characterized by progressive stenosis of large intracranial arteries and formation of fragile collateral vessels that can be triggered by a broad range of genetic and immune factors. Central to MMD pathology is excessive proliferation of vascular smooth muscle cells (VSMCs) in the intima of affected arteries associated with contractile-to-synthetic phenotypic switching, but the underlying molecular mechanisms remain unclear. To identify dysregulated pathways we studied a cohort of 12 patients with well-documented MMD, including one post-mortem autopsy case, using a multi-omics approach combining whole exome sequencing with plasma proteomics. In addition, we conducted an in-depth spatial proteomics analysis of an occluded artery retrieved post-mortem from one idiopathic patient, combining targeted antibody-based imaging with laser capture microdissection coupled to mass spectrometry. Genetic predispositions for MMD was found in 8 out of 12 patients (67%), including three patients with variants in the major susceptibility gene RNF213 and five with varying underlying genetic conditions (trisomy 21, pathogenic variants in ACTA2 , SAMHD1 , NFIA ). Artery spatial proteomics revealed phenotypic switching of vascular smooth muscle cells associated with infiltration of these cells in the intima, including loss of contractile and gain of synthetic marker proteins. Most notably, increased expression of cellular fibronectin in the occluded lesion was associated with increased levels in patients’ plasma, providing a rational for cellular fibronectin as potential tissue leakage biomarker for moyamoya disease. Finally, infiltration of macrophages and antigen-presenting cells in the intima pointed to a role for inflammatory signals in disease progression. Together, our data provide an unprecedented spatial view on protein changes in an occluded moyamoya artery, revealing intimal infiltration of synthetic vascular smooth muscle cells and antigen-presenting immune cells as key pathological findings, opening novel avenues for future diagnosis and research.