Defining Nodal Tumor Burden

Pathologically detected tumor may range from as small as a single cell to 1 or 2 cm with the average metastatic focus measuring 6.0 mm (19). Thus, the dynamic range of proven nodal tumor burden is 0.01 mm (single cells) to about 20 mm, a 2000-fold difference in maximum size. Prognostic segregation of the smallest from largest metastases was a logical improvement for classification. In 1971, Huvos et al. (2) observed that breast cancer patients with metastases no larger than 2.0 mm experienced no survival disadvantage when compared to patients with no nodal metastases detected. These smaller metastases were called micrometastases. Accordingly, metastases larger than 2.0 mm were referred to as macrometastases. Following this study, a footnote was added to the AJCC staging manuals indicating the relatively favorable prognosis when only micrometastases were detected. With the advent of sentinel node biopsy, it became easier to detect micrometastases. Compared to non-sentinel axillary nodes, metastases are four times more likely to be detected in sentinel nodes and occult micrometastases are 12 times more likely to be detected in sentinel nodes when similar detection strategies are employed for both sentinel and nonsentinel nodes (20). Hermanek et al. (21) suggested a new category of detectable tumor cell deposits that were extremely small and lacked the biological features typically associated with invasive tumors or metastases. They referred to these deposits as isolated tumor cells and cell clusters (or ITCs). The proposed biological features could not be reliably detected even in larger lymph node metastases and AJCC and UICC ultimately adopted a size criterion, 0.2 mm, to define the lower limit of micrometastases. Thus, nodal tumor deposits were divided into three logical categories: foci no larger than 0.2 mm (ITCs); foci larger than 0.2 mm but no larger than 2.0 mm (micrometastases); and foci larger than 2.0 mm (macrometastases). Note that there is approximately a 10-fold difference in maximum measurable dimension between the smallest and largest metastases in each category, whereas all three categories combined span a dynamic range from 0.02 mm (one to two cells) to 20 mm (a relatively large metastasis). The difference in tumor volume is even more profound as volume is proportional to the radius raised to the third power. For example, a single 0.2 mm tumor deposit occupies the same volume as 1000 cells each 0.02 mm in greatest dimension. Similarly, it would take 1000 deposits measuring 0.2 mm to equal the volume of a single 2.0 mm micrometastasis.

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