title: Loss of heterozygosity analysis shows monoclonal evolution with frequent genetic progression and divergence in esophageal carcinosarcoma.
abstract: Carcinosarcoma (spindle cell carcinoma) of the esophagus is a rare neoplasm that shows squamous cell carcinoma (SCC) with a variable component of spindle cell sarcoma. Clinical and pathologic features of this neoplasm have been well documented, but the histogenesis has long been a matter of speculation and dispute. In an attempt to clarify the clonality and genetic relationships in the evolution of this neoplasm, we microdissected a total of 36 carcinomatous and sarcomatous foci from six esophageal carcinosarcoma (CS) and analyzed the allelic status with 25 microsatellite markers on chromosomal arms 3p, 5q, 6q, 8p, 9p, 11q, 13q, 17p, and 18q. In all cases, we found multiple and homogenous allelic losses in both the carcinomatous and sarcomatous components, strongly supporting the concept of monoclonal origin for this neoplasm. Homogeneous allelic losses were detected most frequently on 17p (5 cases), a chromosomal arm that included the p53 locus, followed by 3p, 11q, and 13q (3 cases); 9p (2 cases); and 8p and 18q (1 case). Moreover, five of the six cases showed additional or divergent allelic losses at more than one chromosomal locus at some of the microdissected foci, indicating genetic progression (2 cases) or genetic progression and divergence (3 cases). In four cases, the genetic changes indicated that an original clone of a pure SCC apparently acquired carcinosarcomatous or sarcomatous phenotype by successive genetic changes. On the other hand, we saw no evidence for tumors in which a sarcoma appeared to give rise to a carcinosarcomatous or carcinomatous subclone in the examined cases. In conclusion, our data support the concept that esophageal CS is derived from a single clone originating from a SCC. Furthermore, we showed genetic heterogeneity to accompany the phenotypic divergence, with patterns of genetic alterations that are consistent with both progression and divergence within individual tumors.
authors.affiliation: First Department of Pathology, Juntendo University, School of Medicine, Tokyo, Japan.
authors.forename: Toshiharu
authors.initials: T
authors.lastname: Matsumoto
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Fujii
authors.forename: Atsushi
authors.initials: A
authors.lastname: Arakawa
authors.forename: Shigetaka
authors.initials: S
authors.lastname: Yamasaki
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Sonoue
authors.forename: Kimiaki
authors.initials: K
authors.lastname: Hattori
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Kajiyama
authors.forename: Sachiko
authors.initials: S
authors.lastname: Hirose
authors.forename: Masahiko
authors.initials: M
authors.lastname: Tsurumaru
mesh_terms: D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000378:metabolism; D002277:Carcinoma / Q000235:genetics / Q000378:metabolism / Q000556:secondary; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism / Q000556:secondary; D002296:Carcinosarcoma / Q000235:genetics* / Q000378:metabolism / Q000556:secondary; D002999:Clone Cells / Q000473:pathology; D017931:DNA Primers / Q000737:chemistry; D004273:DNA, Neoplasm / Q000032:analysis; D018450:Disease Progression; D004938:Esophageal Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D019143:Evolution, Molecular; D005260:Female; D005819:Genetic Markers; D014644:Genetic Variation / Q000235:genetics*; D006801:Humans; D019656:Loss of Heterozygosity; D008297:Male; D042282:Microdissection; D018895:Microsatellite Repeats; D008875:Middle Aged; D016133:Polymerase Chain Reaction
chemical_list: D014408:Biomarkers, Tumor; D017931:DNA Primers; D004273:DNA, Neoplasm; D005819:Genetic Markers