title: A mosaic pattern of INI1/SMARCB1 protein expression distinguishes Schwannomatosis and NF2-associated peripheral schwannomas from solitary peripheral schwannomas and NF2-associated vestibular schwannomas.
abstract: BACKGROUND
  The INI1/SMARCB1 gene protein product has been implicated in the direct pathogenesis of schwannomas from patients with one form of schwannomatosis [SWNTS1; MIM # 162091] showing a mosaic pattern of loss of protein expression by immunohistochemistry [93% in familial vs. 55% in sporadic cases].
  
  
  OBJECTIVE
  To verify whether such INI1/SMARCB1 mosaic pattern could be extended to all schwannomas arising in the sporadic and familial schwannomatoses [i.e. to SMARCB1-related (SWNTS1) or LZTR1-related (SWNTS2) schwannomatosis or to SMARCB1/LZTR1-negative schwannomatosis] and whether it could be involved in classical NF2 or solitary peripheral schwannomas METHODS: We blindly analysed schwannoma samples obtained from a total of 22 patients including (a) 2 patients (2 males; aged 38 and 55 years) affected by non-familial SMARCB1-associated schwannomatosis (SWTNS1); (b) 1 patient (1 female; aged 33 years) affected by familial schwannomatosis (SWTNS1/ SMARCB1 germ line mutations); (c) 5 patients (3 males, 2 females; aged 33 to 35 years) affected by non-familial (sporadic) LZTR1-associated schwannomatosis (SWNTS2); (d) 3 patients (3 males; aged 35 to 47 years) affected by familial schwannomatosis (SWTNS2/ LZTR1 germ line mutations); (e) 2 patients (1 male, 1 female; aged 63 and 49 years, respectively) affected by non-familial schwannomatosis (SWTNS, negative for SMARCB1, LZTR1 and NF2 gene mutations); (f) 4 patients (3 males, 1 females; aged 15 to 24 years) affected by classical NF2 (NF2: harbouring NF2 germ line mutations; and (g) 5 patients (3 males, 2 females; aged 33 to 68 years) who had solitary schwannomas. [follow-up = 15-30 years; negative for constitutional/somatic mutation analysis for the SMARCB1, LZTR1 and NF2 genes] were (blindly) analyzed. The INI1/SMARCB1 immunostaining pattern was regarded as (1) diffuse positive nuclear staining [= retained expression] or (2) mosaic pattern [mixed positive/negative nuclei = loss of expression in a subset of tumour cells].
  
  
  RESULTS
  All solitary peripheral schwannomas and NF2-associated vestibular schwannomas showed diffuse nuclear INI1/SMARCB1 staining in 97-100% of neoplastic cells; schwannomas obtained from all cases of non-familial and familial schwannomatosis and NF2-associated non-vestibular schwannomas showed a mosaic pattern ranging from 10 to 70% of INI1/SMARCB1-positive expression. We did not record a complete lack of nuclear staining.
  
  
  CONCLUSIONS
  The present data suggests that (a) mosaic loss of immunohistochemical INI1/SMARCB1 expression, despite the interlesional variability, is a reliable marker of schwannomatosis regardless of the involved gene and it might help in the differential diagnosis of schwannomatosis vs. solitary schwannomas and (b) INI1/SMARCB1 expression is not useful in the differential with mosaic NF2, since NF2-associated peripheral schwannomas show the same immunohistochemical pattern.
authors.affiliation: Department of Medical and Surgical Sciences and Advanced Technologies "G. F. Ingrassia", Section of Anatomic Pathology, University of Catania, Catania, Italy.
authors.forename: Rosario
authors.initials: R
authors.lastname: Caltabiano
authors.affiliation: Department of Medical and Surgical Sciences and Advanced Technologies "G. F. Ingrassia", Section of Anatomic Pathology, University of Catania, Catania, Italy.
authors.forename: Gaetano
authors.initials: G
authors.lastname: Magro
authors.affiliation: National Centre for Rare Diseases, Istituto Superiore di Sanità, Rome, Italy.|Institute of Neurological Sciences, National Research Council, Catania, Italy.
authors.forename: Agata
authors.initials: A
authors.lastname: Polizzi
authors.affiliation: Unit of Rare Diseases of the Nervous System in Childhood, Department of Clinical and Experimental Medicine, Section of Pediatrics and Child Neuropsychiatry, University of Catania, AOU "Policlinico-Vittorio Emanuele", Via S. Sofia, 78, 95124, Catania, Italy.|Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy.
authors.forename: Andrea Domenico
authors.initials: AD
authors.lastname: Praticò
authors.affiliation: Unit of General Microsurgery and Hand Surgery, University of Rome "La Sapienza" and Hospital "Fabia Mater", Rome, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Ortensi
authors.affiliation: Unit of General Microsurgery and Hand Surgery, University of Rome "La Sapienza" and Hospital "Fabia Mater", Rome, Italy.
authors.forename: Valerio
authors.initials: V
authors.lastname: D'Orazi
authors.affiliation: Unit of General Microsurgery and Hand Surgery, University of Rome "La Sapienza" and Hospital "Fabia Mater", Rome, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Panunzi
authors.affiliation: Department of Medical and Surgical Sciences and Advanced Technologies "G. Ingrassia", Section of Radiology, University of Catania, Catania, Italy.
authors.forename: Pietro
authors.initials: P
authors.lastname: Milone
authors.affiliation: Department of Medical and Surgical Sciences and Advanced Technologies "G. Ingrassia", Section of Otolaryngology, University of Catania, Catania, Italy.
authors.forename: Luigi
authors.initials: L
authors.lastname: Maiolino
authors.affiliation: Department of Paediatrics and Child Neuropsychiatry, Section of Paediatric Neurology, Sapienza University of Rome, Rome, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Nicita
authors.affiliation: Department of Biomedical, Experimental and Clinical Sciences "Mario Serio", Section of Medical Genetics, University of Florence, Florence, Italy.
authors.forename: Gabriele Lorenzo
authors.initials: GL
authors.lastname: Capone
authors.affiliation: Department of Biomedical, Experimental and Clinical Sciences "Mario Serio", Section of Medical Genetics, University of Florence, Florence, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Sestini
authors.affiliation: Department of Biomedical, Experimental and Clinical Sciences "Mario Serio", Section of Medical Genetics, University of Florence, Florence, Italy.
authors.forename: Irene
authors.initials: I
authors.lastname: Paganini
authors.affiliation: 11 Unit of Molecular Genetics, Institute of Neurological Sciences, National Research Council, Cosenza, Italy.
authors.forename: Mariella
authors.initials: M
authors.lastname: Muglia
authors.affiliation: 11 Unit of Molecular Genetics, Institute of Neurological Sciences, National Research Council, Cosenza, Italy.
authors.forename: Sebastiano
authors.initials: S
authors.lastname: Cavallaro
authors.affiliation: Department of Medical and Surgical Sciences and Advanced Technologies "G. F. Ingrassia", Section of Anatomic Pathology, University of Catania, Catania, Italy.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Lanzafame
authors.affiliation: Department of Biomedical, Experimental and Clinical Sciences "Mario Serio", Section of Medical Genetics, University of Florence, Florence, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Papi
authors.affiliation: Unit of Rare Diseases of the Nervous System in Childhood, Department of Clinical and Experimental Medicine, Section of Pediatrics and Child Neuropsychiatry, University of Catania, AOU "Policlinico-Vittorio Emanuele", Via S. Sofia, 78, 95124, Catania, Italy. m.ruggieri@unict.it.
authors.forename: Martino
authors.initials: M
authors.lastname: Ruggieri
mesh_terms: D000293:Adolescent; D000328:Adult; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D016515:Genes, Neurofibromatosis 2 / Q000502:physiology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009442:Neurilemmoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009464:Neuroma, Acoustic / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D000071796:SMARCB1 Protein / Q000096:biosynthesis* / Q000235:genetics*; D055815:Young Adult
chemical_list: D000071796:SMARCB1 Protein; C513266:SMARCB1 protein, human
keywords: Histology; INI1; Immunohistochemistry; LZTR1; Mosaicism; NF2; Neurofibromatosis; Neurofibromatosis type 2; SMARCB1; SWNTS; Schwannomatosis