title: Evolution of Dermatofibrosarcoma Protuberans to DFSP-Derived Fibrosarcoma: An Event Marked by Epithelial-Mesenchymal Transition-like Process and 22q Loss.
abstract: Dermatofibrosarcoma protuberans (DFSP) is a rare and indolent cutaneous sarcoma. At times, a fibrosarcomatous transformation marked by a more aggressive clinical behavior may be present. We investigated the natural history and the molecular bases of progression from classic DFSP to the fibrosarcomatous form (FS-DFSP), looking, retrospectively, at the outcome of all patients affected by primary DFSP treated at our institution from 1993 to 2012 and analyzing the molecular profile of 5 DFSPs and 5 FS-DFSPs by an integrated genomics approach (whole transcriptome sequencing, copy number analysis, FISH, qRT-PCR, IHC). The presence of fibrosarcomatous features was identified in 20 (7.6%) patients out of 263 DFSP. All cases were treated with macroscopic complete surgery. A local relapse occurred in 4 of 23 patients who received a microscopic marginal surgery (2 classic DFSP, 2 FS-DFSP), while metastasis affected 2 patients, both FS-DFSP (10% of FS-DFSP), being the first event. DFSP evolution to FS-DFSP was paralleled by a transcriptional reprogramming. The recurrent loss of chromosome 22q appeared to contribute to this phenomenon by promoting the expression of epigenetic regulators, such as EZH2. Loss of the p16/CDKN2A/INK4A locus at 9p was also observed in two FS-DFSP metastatic cases.
  
  
  
  FS-DFSP is a rare subgroup among DFSP, with a 10% metastatic risk, that was independent from local recurrence and that was not observed in DFSP, that were all cured by wide surgery. Chromosome 22q deletion might play a role in FS-DFSP, and p16 loss may convey a poor outcome. EZH2 dysregulation was also found and represents a druggable target. Mol Cancer Res; 14(9); 820-9. ©2016 AACR.
authors.affiliation: Adult Mesenchymal Tumour and Rare Cancer Medical Oncology Unit, Cancer Medicine Department, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Stacchiotti
authors.affiliation: Centro Interdipartimentale di Ricerche sul Cancro G. Prodi, Università di Bologna, Bologna, Italy.
authors.forename: Annalisa
authors.initials: A
authors.lastname: Astolfi
authors.affiliation: Melanoma and Sarcoma Unit, Department of Surgery, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Gronchi
authors.affiliation: Melanoma and Sarcoma Unit, Department of Surgery, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Fontana
authors.affiliation: Dipartimento di Medicina Sperimentale, Specialistica e Diagnostica, Università di Bologna, Bologna, Italy.
authors.forename: Maria A
authors.initials: MA
authors.lastname: Pantaleo
authors.affiliation: Department of Diagnostic Pathology and Laboratory, Laboratory of Experimental Molecular Pathology, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.
authors.forename: Tiziana
authors.initials: T
authors.lastname: Negri
authors.affiliation: Unit of Experimental Oncology 1, CRO Aviano National Cancer Institute, Aviano, Italy.
authors.forename: Monica
authors.initials: M
authors.lastname: Brenca
authors.affiliation: Unit of Immunotherapy of Human Tumors, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.
authors.forename: Marcella
authors.initials: M
authors.lastname: Tazzari
authors.affiliation: Centro Interdipartimentale di Ricerche sul Cancro G. Prodi, Università di Bologna, Bologna, Italy.
authors.forename: Milena
authors.initials: M
authors.lastname: Urbini
authors.affiliation: Centro Interdipartimentale di Ricerche sul Cancro G. Prodi, Università di Bologna, Bologna, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Indio
authors.affiliation: Melanoma and Sarcoma Unit, Department of Surgery, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Colombo
authors.affiliation: Melanoma and Sarcoma Unit, Department of Surgery, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Radaelli
authors.affiliation: Department of Diagnostic Pathology and Laboratory, Laboratory of Experimental Molecular Pathology, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy. silvia.stacchiotti@istitutotumori.mi.it.
authors.forename: Silvia
authors.initials: S
authors.lastname: Brich
authors.affiliation: Department of Anatomic Pathology, General Hospital of Treviso, Treviso, Italy.
authors.forename: Angelo P
authors.initials: AP
authors.lastname: Dei Tos
authors.affiliation: Adult Mesenchymal Tumour and Rare Cancer Medical Oncology Unit, Cancer Medicine Department, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.
authors.forename: Paolo G
authors.initials: PG
authors.lastname: Casali
authors.affiliation: Unit of Immunotherapy of Human Tumors, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Castelli
authors.affiliation: Department of Diagnostic Pathology and Laboratory, Laboratory of Experimental Molecular Pathology, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.
authors.forename: Gian Paolo
authors.initials: GP
authors.lastname: Dagrada
authors.affiliation: Department of Diagnostic Pathology and Laboratory, Laboratory of Experimental Molecular Pathology, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.
authors.forename: Silvana
authors.initials: S
authors.lastname: Pilotti
authors.affiliation: Unit of Experimental Oncology 1, CRO Aviano National Cancer Institute, Aviano, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Maestro
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002892:Chromosomes, Human, Pair 22; D018223:Dermatofibrosarcoma / Q000235:genetics* / Q000473:pathology*; D018450:Disease Progression; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D012878:Skin Neoplasms / Q000235:genetics* / Q000473:pathology*; D055815:Young Adult