Extensive and divergent chromosomal losses in squamous and spindle-cell components of esophageal sarcomatoid carcinoma

Abstract

Sarcomatoid carcinoma of the esophagus is an unusual type of squamous cell carcinoma (SCC) with a variable component of sarcomatoid spindle cells (SA). The loss of heterozygosity (LOH) involving multiple cancer-associated chromosomal arms has been reported to have a concerted, rather than an individual, effect on tumor progression. In order to delineate the role of LOH in the evolution of a biphasic tumor, the carcinoma in situ (CIS), invasive squamous cell carcinoma (ISCC), and SA components from a sarcomatoid carcinoma of the esophagus were compared for their clonality and extent of LOH. Forty microsatellite markers on the cancer-associated chromosomes, 3p, 4p, 5q, 8p, 9p, 13q, 17p, and 18q, were used for the polymerase chain reaction-based LOH analysis. All eight sarcomatoid carcinomas tested revealed extensive LOHs, involving an average of seven chromosomal arms. All CIS, ISCC, and SA components carried not only a high-level primary LOH (mean chromosomal involvement, 5.3) in common but also a low-level secondary LOH (mean chromosomal involvement, 1.8) in disparity. Interestingly, more secondary LOHs were always burdened in the CIS (four cases) rather than the matched ISCC. SA had a greater (four cases), equal (one case), or fewer (one case) number of secondary LOHs than ISCC. Given that excessive chromosomal losses may confer a disadvantage for tumor growth or a benefit for a metaplastic transformation, these results suggest that the multidirectional differentiation of a SCC precursor is stimulated by extensive and divergent LOHs acquired at the initial or early stages, and a precursor burdened with excessive LOH either remains in CIS or expands as a SA component.

Relationship Between the Extent of Chromosomal Losses and the Pattern of CpG Methylation in Gastric Carcinomas

“…It should be noted that multidirectionally differentiated mixed cancers such as a sarcomatoid carcinoma (30) and a glandular-neuroendocrine carcinoma (31) as well as heterogeneous tumor sites of a gastric carcinoma commonly have divergent losses involving different alleles on the same chromosome. Considering that epigenetic changes occur only in dividing cells (32), the divergent losses bifurcated in mixed tumors suggest that a genome dosage reduction results in the gradual and heterogeneous hypomethylation during carcinogenesis, which give rise to the expansion of dissimilar subclones driven by the same chromosomal loss.…”

Preoperative genetic diagnosis of gastric carcinoma based on chromosomal loss and microsatellite instability

“…Therefore, it appears that the chromosomal losses in gastric carcinomas are unstable within the limited extent. Previous multifocal LOH analyses using similar microsatellite markers on multidirectionally differentiated cancers such as a sarcomatoid carcinoma 33 and a glandular neuroendocrine carcinoma, 31 both of which are rare tumors, described the highly heterogeneous extent of chromosomal losses that are classified into the different genotypes. This suggests that in rare cases, the chromosomal losses are unstable to the extent that they are associated with multidirectional differentiation.…”

“…29,30 A minimum number of PCR artifacts have been confirmed in previous studies using a similar set of chromosomal markers on 3p, 4p, 5q, 8p, 9p, 13q, 17p and 18q. 16,23,[31][32][33] Five or 6 markers per chromosome were selected for the high yield of heterozygous alleles on each chromosome. The "multiplex hot-start" method was applied to the reproducible PCR results using a small amount of paraffin-embedded biopsy tissues.…”

Diagnosis of primary esophageal synovial sarcoma by demonstration of t(X;18) translocation: a case report

“…Cytogenetic analysis is a powerful method allowing for differentiation between esophageal SS and esophageal sarcomatoid carcinoma [3,11,13]. The distinction of these two different tumors has therapeutic implications, as SS may respond to adjuvant chemotherapy with regimens including high-dose ifosfamide [19].…”

“…However, these different criteria for diagnosis are not specific of SS and can be demonstrated in other malignant tumors. Particularly in the esophageal location, these different features can be observed both in SS and in sarcomatoid carcinoma (carcinosarcoma) [3,11,13,16]. The recognition of SS in this unexpected site is probably often mistaken.…”