title: Pancreatic undifferentiated rhabdoid carcinoma: KRAS alterations and SMARCB1 expression status define two subtypes.
abstract: Pancreatic undifferentiated carcinoma is a heterogeneous group of neoplasms, including pleomorphic giant cell, sarcomatoid, round cell, and rhabdoid carcinomas, the molecular profiles of which have so far been insufficiently characterized. We studied 14 undifferentiated carcinomas with prominent rhabdoid cells, occurring as advanced tumors in seven females and seven males aged 44-96 years (mean: 65 years). Histologically, 10 tumors qualified as pleomorphic giant cell and 4 as monomorphic anaplastic carcinomas. A glandular component, either in the primary or in the metastases, was seen in 5 out of 14 tumors (4 out of 10 pleomorphic giant cell and 1 out of 4 monomorphic anaplastic subtypes, respectively). Osteoclast-like giant cells were absent. Immunohistochemistry revealed coexpression of cytokeratin and vimentin, and loss of membranous β-catenin and E-cadherin staining in the majority of cases. Nuclear SMARCB1 (INI1) expression was lost in 4 out of 14 cases (28%), representing all 4 tumors of the monomorphic anaplastic subtype. FISH and mutation testing of KRAS revealed KRAS amplification in 5 out of 13 (38%) and exon 2 mutations in 6 out of 11 (54%) successfully analyzed cases. A strong correlation was found between KRAS alterations (mutation and/or copy number changes) and intact SMARCB1 expression (7 out of 8; 87%). On the other hand, loss of SMARCB1 expression correlated with the absence of KRAS alterations (3 out of 5 cases; 60%). The results suggest that rhabdoid phenotype in pancreatic undifferentiated rhabdoid carcinomas has a heterogeneous genetic background. SMARCB1 loss is restricted to the anaplastic monomorphic subtype and correlates with the absence of KRAS alterations, whereas the pleomorphic giant cell subtype is characterized by KRAS alterations and intact SMARCB1 expression. Recognition and appropriate subtyping of these rare variants might become necessary for future therapeutic strategies.
authors.affiliation: Institute of Pathology, University Hospital of Erlangen, Erlangen, Germany.
authors.forename: Abbas
authors.initials: A
authors.lastname: Agaimy
authors.affiliation: Institute of Pathology, University Hospital of Erlangen, Erlangen, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Haller
authors.affiliation: Institute of Pathology, University Hospital of Erlangen, Erlangen, Germany.
authors.forename: Judith
authors.initials: J
authors.lastname: Frohnauer
authors.affiliation: 1] Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA [2] Institute of Pathology, University Medical Center, Göttingen, Germany.
authors.forename: Inga-Marie
authors.initials: IM
authors.lastname: Schaefer
authors.affiliation: Institute of Pathology, University Medical Center, Göttingen, Germany.
authors.forename: Philipp
authors.initials: P
authors.lastname: Ströbel
authors.affiliation: Institute of Pathology, University Hospital of Erlangen, Erlangen, Germany.
authors.forename: Arndt
authors.initials: A
authors.lastname: Hartmann
authors.affiliation: Institute of Pathology, University Hospital of Erlangen, Erlangen, Germany.
authors.forename: Robert
authors.initials: R
authors.lastname: Stoehr
authors.affiliation: Department of Pathology, Technical University of München, München, Germany.
authors.forename: Günter
authors.initials: G
authors.lastname: Klöppel
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000032:analysis; D002868:Chromosomal Proteins, Non-Histone / Q000096:biosynthesis*; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000096:biosynthesis*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D008875:Middle Aged; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras); D018335:Rhabdoid Tumor / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D000071796:SMARCB1 Protein; D014157:Transcription Factors / Q000096:biosynthesis*; D018631:ras Proteins / Q000235:genetics*
chemical_list: D014408:Biomarkers, Tumor; D002868:Chromosomal Proteins, Non-Histone; D004268:DNA-Binding Proteins; C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; D000071796:SMARCB1 Protein; C513266:SMARCB1 protein, human; D014157:Transcription Factors; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins
references.citation: JOP. 2004 Nov 10;5(6):512-5
references.pmid: 15536293
references.citation: Diagn Cytopathol. 2008 Apr;36(4):238-44
references.pmid: 18335561
references.citation: Pathol Int. 1999 Feb;49(2):160-3
references.pmid: 10355971
references.citation: AMA Arch Pathol. 1954 Aug;58(2):101-11
references.pmid: 13170907
references.citation: Pediatr Hematol Oncol. 2013 Oct;30(7):587-604
references.pmid: 23848359
references.citation: Pathol Int. 2000 Jan;50(1):57-62
references.pmid: 10692179
references.citation: Mod Pathol. 2005 Jul;18(7):951-8
references.pmid: 15761491
references.citation: JOP. 2007 May 09;8(3):330-4
references.pmid: 17495363
references.citation: Cancer. 1977 May;39(5):2114-26
references.pmid: 870168
references.citation: Recent Results Cancer Res. 1996;142:19-50
references.pmid: 8893333
references.citation: Cancer Res. 1999 Jan 1;59(1):74-9
references.pmid: 9892189
references.citation: Hum Pathol. 2007 Jun;38(6):935-9
references.pmid: 17376508
references.citation: Adv Anat Pathol. 2007 Sep;14(5):335-9
references.pmid: 17717433
references.citation: Arch Pathol Lab Med. 1997 Oct;121(10):1104-7
references.pmid: 9341593
references.citation: Histopathology. 1992 Feb;20(2):167-70
references.pmid: 1313783
references.citation: Cancer. 1977 Mar;39(3):1181-9
references.pmid: 912652
references.citation: Am J Surg Pathol. 1997 Feb;21(2):130-46
references.pmid: 9042279
references.citation: Semin Diagn Pathol. 1995 Aug;12(3):233-48
references.pmid: 8545590
references.citation: Mod Pathol. 2013 Mar;26(3):385-92
references.pmid: 23060122
references.citation: Cancer. 1968 Jun;21(6):1072-9
references.pmid: 5648045
references.citation: Am J Surg Pathol. 2014 Sep;38(9):1274-81
references.pmid: 24832165
references.citation: Mod Pathol. 2013 Oct;26(10):1346-54
references.pmid: 23599154
references.citation: Ann Diagn Pathol. 1998 Dec;2(6):351-62
references.pmid: 9930572
references.citation: Pathol Int. 2006 Nov;56(11):702-6
references.pmid: 17040295
references.citation: PLoS One. 2010 Jan 21;5(1):e8802
references.pmid: 20098682
references.citation: J Med Case Rep. 2008 Dec 17;2:391
references.pmid: 19091098
references.citation: J Pathol. 1998 May;185(1):53-60
references.pmid: 9713360
references.citation: Med Mol Morphol. 2007 Sep;40(3):168-71
references.pmid: 17874050
references.citation: Diagn Pathol. 2013 Feb 20;8:31
references.pmid: 23425390
references.citation: Am J Clin Pathol. 2013 Feb;139(2):167-76
references.pmid: 23355201
references.citation: Diagn Mol Pathol. 2010 Dec;19(4):236-42
references.pmid: 21051996
references.citation: Am J Pathol. 1998 Jun;152(6):1501-7
references.pmid: 9626054
references.citation: Am J Surg Pathol. 2011 Oct;35(10):e47-63
references.pmid: 21934399
references.citation: Clin Cancer Res. 2002 Nov;8(11):3461-7
references.pmid: 12429635
references.citation: J Surg Oncol. 1980;15(4):345-8
references.pmid: 7453183
references.citation: Am J Surg Pathol. 2014 Jul;38(7):910-20
references.pmid: 24503755