Cytogenetic profile of unknown primary tumors: clues for their pathogenesis and clinical management

Abstract

Unknown primary tumors (UPTs) represent an entity of great clinical and biological interest, whose origin cannot be determined even after medical workup. To better understand their pathogenesis by outlining their genetic composition, 20 UPTs were investigated by G-banding, supplemented with Fluorescence In Situ Hybridization and Comparative Genomic Hybridization analyses. The data obtained were sufficient to reach a diagnosis in five cases-four lymphomas and one Ewing sarcoma-demonstrating that in a subset of UPTs, cytogenetics can be an adjunct for differential diagnosis. In the remaining 15 UPTs, an aggressive cytogenetic pattern was revealed. The most frequently rearranged chromosome regions were 1q21, 3p13, 6q15-23, 7q22, 11p12-5, and 11q14-24, pinpointing gene loci probably associated with the peculiar pathogenesis of UPTs. The preferential involvement of 4q31, 6q15, 10q25, and 13q22 in adenocarcinomas (whereas 11q22 is involved in the rest of the carcinomas)-in addition to the marked divergence in the mean average of chromosomal changes, 16 and 3, respectively-demonstrates genotypic differences between the two histologic subgroups. Furthermore, the significantly shorter survival in cases displaying massive chromosome changes compared with those having a few changes indicates that the cytogenetic pattern might be used as a tool to assess prognosis in UPTs, even without the detection of their primary site.

Figure 1

A graphic illustration of the breakpoint distribution along the autosomal chromosomes (from 1p36 to 22q13) identified by G-banding analysis in the 15 tumors, in which a final diagnosis was not reached. In the total series of tumors (black, thick line), the highest frequency was found at 6q15, followed by 3p13 and 7q22. When, however, the tumors were divided according to their histologic type, the highest frequency was observed at 6q15, followed by 4q31, 10q15, and 13q22 in adenocarcinomas (black, thin line), whereas 11q22 showed the highest frequency in carcinomas (white line).

Figure 2

A histogram illustrating the imbalances identified by the combination approach (G-banding and CGH), along the autosomal chromosomes (from 1p36 to 22q13) in the 15 tumors, in which a final diagnosis was not reached. Gains appear as positive values while losses appear as negative values. The most frequent gains were those of 1q21, 7q22, and 11p12-15, whereas the most frequent losses were those of 6q21-23 and 11q14-24.

Figure 3

A G-banding karyogram from case 13 showing, among other aberrations, the rearranged chromosomes 21 and 22, which established an Ewing sarcoma diagnosis. See Table 2 for a detailed description of the tumor karyotype.

Figure 4

A G-banding karyogram from case 1 showing a representative adenocarcinoma karyotype with multiple complex chromosome aberrations. See Table 2 for a detailed description of the tumor karyotype.

Figure 5

IgH breakapart signals in interphase nuclei from case 16, demonstrating IgH rearrangements.

Figure 6

Kaplan-Meier survival curves for the two groups of patients — one with tumors displaying 1 to 5 changes (solid line), and the other with tumors having 18 to 51 changes (square dot line). The difference in survival time between the two groups was statistically significant (P=0.003).