Fehm et al. (1) present important and very convincing data documenting that circulating epithelial cells regularly detectable in peripheral blood of patients with carcinoma are malignant. There are numerous reports showing that there are circulating cells of epithelial origin in patients with carcinoma, even in early stages, as detected by reverse transcriptase-PCR or immunocytochemistry; however, a formal proof that these cells are neoplastic, i.e., (sub)clones of the corresponding primary tumor, was lacking (2, 3). The method chosen by Fehm et al. to successfully show this clonal relation was FISH1. They compared the patterns of FISH-aneusomies in primary tumors and corresponding circulating epithelial cells, which matched well in the majority of cases.

A focus of our research has been a clinical application of the FISH method for sensitive detection of tumor cells in effusion fluids, where cytological diagnosis is sometimes difficult because of the background of reactive mesothelial cells (4). This was achieved by detection of tumor-associated aneusomies present above a background threshold of physiological nondisomy. Indeed, the combination of FISH and cytological evaluation led to a higher detection rate of malignancy in effusions. Furthermore, for the first time it was shown by FISH that there are matching patterns of aneusomy in primary breast cancer and the respective axillary lymph node metastasis (5) and, furthermore, in distant metastatic cells that occurred asynchronously in effusions (Ref. 4; Table 1). Interestingly, cytogenetic data are rare documenting a genotypic correlation between primary tumors and corresponding metastasis (6, 7, 8, 9).

We are pleased about additional evidence of a tight clonal relationship between primary tumors and their metastases, as provided in the excellent article by Fehm et al. Clonal relationship as a general rule is a prerequisite if FISH analysis is to be applied in the sensitive and specific diagnosis of distant metastasis and circulating tumor cells, respectively. Consequently, FISH genotyping of primary tumors in the initial diagnostic work-up with a panel of FISH probes would allow choosing the suitable probe(s) subsequently to be used for an efficient search of (micro)metastatic cells.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1

The abbreviation used is: FISH, fluorescence in situ hybridization.

Table 1

Comparison of aneusomies in primary breast carcinoma and corresponding metastatic effusion cells (Hum. Pathol., 31: 448–455, 2000, with permission)

CaseSpecimenAneusomy (chromosome copy number detected)a
Chromosome 7Chromosome 11Chromosome 17Chromosome 18
Primary tumor Below cutoff Below cutoff 1 Below cutoff 
 Effusion Below cutoff 31 Below cutoff 
Primary tumor 3 43 4 5 3 4 5 3
 Effusion Below cutoff 43 4 5 6 3 4 5 6 8 
Primary tumor 3 4 3 43 4 3 4 
 Effusion Below cutoff Below cutoff Below cutoff 3 4 5 
Primary tumor 3 4 3 Below cutoff 
 Effusion 3 433 3
Primary tumor 4 54 5 6 7 8 >8 NAb 4 5 6
 Effusion 4 5 6 8 >8 3 4 5 6 7 8 >8  3 4 5 6 7 >8 
Primary tumor 3 3 NA NA 
 Effusion 3 4 3 4 5   
Primary tumor 3 4 3 4 NA NA 
 Effusion 3 4 5 6 3 4 5 6 7 8 >8   
Primary tumor 3 4 NA NA 
 Effusion 3 4 5 6 7 8 3 4 5 6   
Primary tumor NA NA 3 3 
 Effusion   Below cutoff 3 
CaseSpecimenAneusomy (chromosome copy number detected)a
Chromosome 7Chromosome 11Chromosome 17Chromosome 18
Primary tumor Below cutoff Below cutoff 1 Below cutoff 
 Effusion Below cutoff 31 Below cutoff 
Primary tumor 3 43 4 5 3 4 5 3
 Effusion Below cutoff 43 4 5 6 3 4 5 6 8 
Primary tumor 3 4 3 43 4 3 4 
 Effusion Below cutoff Below cutoff Below cutoff 3 4 5 
Primary tumor 3 4 3 Below cutoff 
 Effusion 3 433 3
Primary tumor 4 54 5 6 7 8 >8 NAb 4 5 6
 Effusion 4 5 6 8 >8 3 4 5 6 7 8 >8  3 4 5 6 7 >8 
Primary tumor 3 3 NA NA 
 Effusion 3 4 3 4 5   
Primary tumor 3 4 3 4 NA NA 
 Effusion 3 4 5 6 3 4 5 6 7 8 >8   
Primary tumor 3 4 NA NA 
 Effusion 3 4 5 6 7 8 3 4 5 6   
Primary tumor NA NA 3 3 
 Effusion   Below cutoff 3 
a

The occurrence of cell populations with FISH-aneusomy above background cutoff in primary carcinomas and their corresponding metastatic effusions is listed. Numbers 1–8, >8: monosomy, trisomy, tetrasomy, and so on for the respective chromosome. The cell population with the predominant aneusomy (e.g., trisomy) is underlined.

b

NA, not available.

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