title: Sarcomatoid adrenocortical carcinoma: a comprehensive pathological, immunohistochemical, and targeted next-generation sequencing analysis.
abstract: Adrenocortical carcinomas (ACCs) with sarcomatous areas represent an extremely rare type of highly aggressive malignancy of unknown molecular pathogenesis. The current study was planned to gain insight into its molecular genetics using a targeted next-generation sequencing approach and to explore the status of epithelial-mesenchymal transition (EMT)-associated markers (E-/P-/N-cadherins, MMP-2/-9 and caveolin-1), downstream transcriptional regulators of EMT-related signaling pathways (ZEB-1/-2, Slug), stem cell factors (Oct3/4, LIN28, SOX2, SO17, NANOG, CD133, nestin), and markers of adrenocortical origin/tumorigenesis (SF-1, β-catenin, p53) in phenotypically diverse tumor components of 6 cases. Thirteen pathogenic variants of ACC-associated TP53 and CTNNB1 genes were detected in epithelial and/or nonepithelial components in 4 out of 6 tumors. Three cases had identical mutations in distinct components, 1 of which contained TP53/CTNNB1 in 3 out of 5 components, whereas 1 harbored a single TP53 mutation only in the nonepithelial component. By immunohistochemistry, SF-1 and E-/P-/N-cadherins were found positive only in the epithelial component of all cases, whereas the nonepithelial components were mainly enriched for nestin, ZEB-1, and MMP-2/-9. β-Catenin demonstrated an aberrant nuclear localization in the sarcomatoid component of 5 cases, whereas p53 was strongly positive in nonepithelial constituent in 4 of 6 cases. In summary, we have shown that Wnt/β-catenin signaling pathway dysregulation and mutational inactivation of TP53 are common genetic events in sarcomatoid ACCs, a subset of which being monoclonal in origin. These tumors are enriched for EMT-related markers and stem cell factors, potentially conferring a poor prognosis, which might be exploited as novel therapeutic targets.
authors: Department of Pathology, Erasmus MC Cancer Institute, University Medical Center Rotterdam, Rotterdam 3015 GE, The Netherlands; Department of Histopathology, King's College Hospital, London SE5 9RS, UK. Electronic address: t.papathomas@erasmusmc.nl.
authors: Thomas G
authors: TG
authors: Papathomas
authors: Department of Oncology, University of Turin, 10043 Turin, Italy. Electronic address: eleonora.duregon@unito.it.
authors: Eleonora
authors: E
authors: Duregon
authors: Department of Pathology, Erasmus MC Cancer Institute, University Medical Center Rotterdam, Rotterdam 3015 GE, The Netherlands. Electronic address: e.korpershoek.1@erasmusmc.nl.
authors: Esther
authors: E
authors: Korpershoek
authors: Department of Pathology, Erasmus MC Cancer Institute, University Medical Center Rotterdam, Rotterdam 3015 GE, The Netherlands. Electronic address: restuccia.david@gmail.com.
authors: David F
authors: DF
authors: Restuccia
authors: Department of Pathology, Erasmus MC Cancer Institute, University Medical Center Rotterdam, Rotterdam 3015 GE, The Netherlands. Electronic address: r.vanmarion@erasmusmc.nl.
authors: Ronald
authors: R
authors: van Marion
authors: Department of Diagnostic Medical Sciences and Special Therapies, Surgical Pathology and Cytopathology Unit, University of Padova, Padova 35121, Italy. Electronic address: rocco.cappellesso@gmail.com.
authors: Rocco
authors: R
authors: Cappellesso
authors: Department of Pathology, CHU Albert Michallon, Grenoble 38043, France. Electronic address: NSturm@chu-grenoble.fr.
authors: Nathalie
authors: N
authors: Sturm
authors: Division of Pathology, University of Modena, Modena 41100, Italy. Electronic address: rossi.giulio@policlinico.mo.it.
authors: Giulio
authors: G
authors: Rossi
authors: Division of Pathology, Policlinico Universitario Gemelli, Rome 00168, Italy. Electronic address: antonella.coli@rm.unicatt.it.
authors: Antonella
authors: A
authors: Coli
authors: Division of Pathology, San Gerardo Hospital, Monza 20900, Italy. Electronic address: n.zucchini@hsgerardo.org.
authors: Nicola
authors: N
authors: Zucchini
authors: Department of Pathology, Erasmus MC Cancer Institute, University Medical Center Rotterdam, Rotterdam 3015 GE, The Netherlands. Electronic address: j.stoop@erasmusmc.nl.
authors: Hans
authors: H
authors: Stoop
authors: Department of Pathology, Erasmus MC Cancer Institute, University Medical Center Rotterdam, Rotterdam 3015 GE, The Netherlands. Electronic address: j.w.oosterhuis@erasmusmc.nl.
authors: Wolter
authors: W
authors: Oosterhuis
authors: Department of Statistical Sciences, University of Padova, Padova 35121, Italy. Electronic address: laura.ventura@unipd.it.
authors: Laura
authors: L
authors: Ventura
authors: Department of Oncology, University of Turin, 10043 Turin, Italy. Electronic address: marco.volante@unito.it.
authors: Marco
authors: M
authors: Volante
authors: Department of Diagnostic Medical Sciences and Special Therapies, Surgical Pathology and Cytopathology Unit, University of Padova, Padova 35121, Italy. Electronic address: ambrogio.fassina@unipd.it.
authors: Ambrogio
authors: A
authors: Fassina
authors: Department of Pathology, Erasmus MC Cancer Institute, University Medical Center Rotterdam, Rotterdam 3015 GE, The Netherlands. Electronic address: w.dinjens@erasmusmc.nl.
authors: Winand N M
authors: WN
authors: Dinjens
authors: Department of Oncology, University of Turin, 10043 Turin, Italy. Electronic address: mauro.papotti@unito.it.
authors: Mauro
authors: M
authors: Papotti
authors: Department of Pathology, Erasmus MC Cancer Institute, University Medical Center Rotterdam, Rotterdam 3015 GE, The Netherlands; Department of Pathology, Reinier de Graaf Hospital, Delft 2625, AD, The Netherlands. Electronic address: r.dekrijger@erasmusmc.nl.
authors: Ronald R
authors: RR
authors: de Krijger
mesh_terms: D000306:Adrenal Cortex Neoplasms / Q000737:chemistry / Q000175:diagnosis* / Q000235:genetics / Q000473:pathology; D018268:Adrenocortical Carcinoma / Q000737:chemistry / Q000175:diagnosis* / Q000235:genetics / Q000473:pathology; D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000032:analysis* / Q000235:genetics*; D001706:Biopsy; D002296:Carcinosarcoma / Q000737:chemistry / Q000175:diagnosis* / Q000235:genetics / Q000473:pathology; D004252:DNA Mutational Analysis; D004847:Epithelial Cells / Q000737:chemistry / Q000473:pathology; D058750:Epithelial-Mesenchymal Transition; D005060:Europe; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D009154:Mutation; D014411:Neoplastic Stem Cells / Q000737:chemistry / Q000473:pathology; D014157:Transcription Factors / Q000032:analysis / Q000235:genetics; D060449:Wnt Signaling Pathway; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor; D014157:Transcription Factors
keywords: Adrenocortical carcinoma; Epithelial-mesenchymal transition; Mutations; Nestin; Sarcomatoid