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Although the skeleton is not a preferred site of overt metastasis in colorectal cancer, demonstration of tumour cells in bone marrow has to be seen as evidence of the general disseminative capability of an individual tumour.1 Other observations such as involuntary transmission of tumour by organ grafts directly supports the notion that very few quiescent cells lodging at improbable sites, such as the kidney or heart, suffice to generate de novo metastatic disease in the organ recipient.2 The TNM classification recommends mention of the presence of disseminated tumour cells as a facultative factor for metastatisation (M0 (i+) or M0 (mol+)) according to the immunological or molecular detection technique.3
However, the results of the one and only meta-analysis available to date show that the prognostic impact of epithelial cells in the bone marrow of colorectal cancer patients has to be substantiated by further studies under standardised conditions.4 To further investigate this question, bilateral crest aspiration is performed routinely in our institution for patients undergoing colorectal surgery for neoplastic diseases. From September 1997 until July 2000, we investigated 233 patients using this method: approximately 2 million mononuclear cells were analysed from each sample and divided into 10 cytospins. One half was stained with the A45-B/B3 antibody (supplied by U Karstens, PhD, Berlin, Germany) and the other half with Ber-EP4 (Dako, Hamburg, Germany). Staining was performed using the alkaline phosphatase anti-alkaline phosphatase technique. Histopathological staging showed that 15 of these patients suffered from an early adenocarcinoma (T1 category), and in seven patients no malignancy could be documented, in spite of complete analysis of the specimen.
Patients without cancer were of particular interest to us, for addressing the question of the early dissemination of epithelial cells in colorectal neoplasms. To our surprise, we observed the presence of disseminated epithelial cells in the bone marrow of three of these patients (table 1, fig 1).
In a previous study, we examined the clonality of disseminated tumour cells in the bone marrow of 51 colorectal cancer patients by determining the mutational pattern in codons 12 and 13 of the K-ras gene.5 Our results demonstrated that, at least for K-ras mutations, disseminated epithelial cells are not always clonal with the primary tumour. The type of mutations suggested also that cell dissemination might be an early event in the development of colorectal neoplasms5 as most bone marrow K-ras mutations were found in codon 13, a codon barely mutated in invasive colorectal cancer but frequently mutated in aberrant crypt foci.6,7
Obviously, epithelial cells can already disseminate in the polyp stage, in particular when so-called intraepithelial neoplasia is diagnosed. Indeed, dissemination of epithelial cells into the bone marrow in a stage defined as non-cancerous questions the carcinomatous nature of these cells, and in particular their micrometastatic nature. In contrast, should these cells be cancer cells—which we cannot exclude on the basis of our previous and present observations—then the benign nature of intraepithelial neoplasia should in turn be challenged.
We would be delighted to receive feedback from other researchers that would help us to interpret the present observation.
Conflict of interest: None declared.