32 Chapter 2 response (>10% vital tumour); IIB, less than 10% vital tumour and grade III for complete response. We divided their grade IIA in 2 separate grades, i.e., one for more than 50% vital tumour and one for 10-50% vital tumour. This 4-tiered grading system is similar to the one used by Dworak for colorectal cancers33. We examined whether this 4-tiered approach was associated with prognosis. This turned out not to be the case. Our data support a slight modification of the Junker classification by combining grade I and IIA into one group, which is associated with a poorer prognosis, the group with <10% vital tumour cells (=Junker IIB) and those with pCR (Junker grade III). The prognostically relevant 10% threshold has also been reported for esophageal cancer39. Interestingly, residual vital tumour was found significantly more often at the periphery of the pathologic lesion in the resection specimen. Although the center of the solid tumour is more likely to be sensitive to hypoperfused and hypoxic, a microenvironment associated with an increased chance for development of resistance to radiotherapy and anticancer chemotherapy40, prolonged hypoxia of the tumour tissue may also lead to necrosis, a frequent finding in larger solid tumours41. In patients without pCR the margins of the surgical resection were more likely to contain vital tumour cells. The limitations of this study include the following: (a) the total number of cases is relatively small, (b) only the available slides could be studied and (c) it is a retrospective study; therefore, the tumour lesions, for example, were sampled for reporting purposes and not more systematically for research, and in daily practice more samples may be taken from the periphery of tumour lesions than from its centre or from necrotic appearing areas. For future studies, we advocate sampling more blocks from the resected tumour mass in order to more reliably determine the absence or presence of vital tumour cells. In addition, it should be noted that the presence of histologically vital tumour cells does not necessarily predict their biological capacity to metastasize. Finally, (d) we acknowledge that there was variation in the time between pre- and postinduction CRT imaging, and the end of CRT and surgery. In future studies of patients with neo-adjuvant CRT and surgery, we propose taking the post-CRT fraction of vital tumour cells into account. Although the IASLC Staging Manual in Thoracic Oncology advises categorization of ypT, the extent of tumour actually present at the time of pathology examination32 35, detailed information on how to evaluate vital tumour cells with relevant portions of necrotic and reactive changes is not provided. For better comparison, in future studies, we suggest the following approach: firstly, record gross size of pathological lesion (including reactive changes such as fibrosis and necrosis, and if present vital tumour) to determine the size of pT. This will also allow comparison with the RECIST data with the size on the resection specimen. Secondly, for the vital tumour component, the adjunct VT is used with ranges as shown in table 7, comparable to the regression system proposed by Becker et al for gastric cancer 42. For example, a pathologic tumour mass at gross examination of 4 cm with no vital tumor cells, less than 10% and more than 50% vital tumour cells would then be
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