To the Editor:
Isolated tumor cells (ITCs) are defined as very low volume nodal (or systemic) involvement and are not considered metastases for staging purposes.1 When found in the sentinel lymph nodes (SLNs) of breast cancer, no systemic or regional treatment has been suggested for this finding alone.2 In contrast to this consensus statement, recently published data from the European Institute of Oncology (EIO)3 suggest that further nodal involvement beyond the SLNs may be encountered in up to 15% of the cases if the SLN contains only ITC, and on this basis the authors mandate axillary treatment even in the event of SLN ITCs.
By reviewing and meta-analyzing data on further nodal involvement associated with SLN micrometastasis and ITCs, we found a similar proportion of second echelon lymph node metastasis for the whole group4 and around 10% for SLN metastases detected by cytokeratin immunohistochemistry (IHC) alone. However, we were unable to separate the data according to SLN metastasis size because the definitions of ITC varied, and several authors reported results only in relation to the method of detection of the SLN involvement: IHC versus hematoxylin and eosin staining. ITCs are differently interpreted by pathologists,5 and this category of SLN involvement seems suboptimally reproducible.6 This is why the EIO data are important and of high impact, as they were generated in a single institution, with a systematic approach to SLNs involving compete step sectioning of the lymph nodes.
However, before making a general recommendation on the basis of their data, I would like to draw attention to one specific methodologic issue that weakens their strong data on ITCs. The histopathologic workup of SLNs is based on frozen sections and hematoxylin and eosin staining of the SLNs, and IHC is used only in doubtful cases. The EIO has rejected the routine use of IHC (consistently with several current recommendations) on the basis of only a few cases. Although I agree that the role of IHC decreases as the distance between levels of step sectioning decreases,7 IHC still increases the rate of detecting ITCs as it is more sensitive. Detecting ITCs is a statistically random event8 and should not be considered the aim of SLN histology.9 Considering that both frozen sections (with their generally lower quality than paraffin embedded material) and the lack of routinely performing IHC allow more single cells or small clusters to remain undetected, I suggest that a number of ITCs have remained undetected at the levels sectioned. Therefore, ITC may be more frequent and be associated with a somewhat lower rate of non-SLN involvement in departments where complete step sectioning of the SLNs and IHC are used in conjunction.5
Despite this minor criticism, I congratulate the authors for the very important message of their paper, ie, metastasis size is a continuous variable, and the category of micrometastasis is not homogeneous as concerns the risks of further nodal involvement.
Gabor Cserni, MD, PhD
Bacs-Kiskun County Teaching Hospital
Kecskemet, Hungary
cserni@freemail.hu
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