These 6 patients have shown at least 3 relapses or progression during their follow-up period, and have an overall survival median of 66 months (range, 42-89 months). This long-term survival is significantly higher than the previously reported extranodal NK/T-cell lymphoma overall survival median, which ranged from 19.6 months to less than 50 months [2
]. However, the clinical and laboratory characteristics of these patients themselves do not distinguish them from other extranodal NK/T-cell lymphomas patients (). All patients were categorized as low or low-intermediate risk because of low international prognostic index scores, which is similar to other extranodal NK/T-cell lymphoma patients. We then constructed an NK-prognostic index. Accordingly, 3 patients were categorized as group 1 (no risk), and the other 3 patients had 2 or 3 risk factors () [4
We reviewed the pathology of these patients in search of possible pathological observations that could explain the atypical clinical courses followed by these patients. However, their morphology and immunohistochemistry characteristics were similar to that of other NK/T-cell lymphoma patients, except for the relatively lower Ki-67 expression levels (<40-50%) observed in all patients, except in patient 4. These Ki-67 expression levels may indicate lower proliferative activity than that in aggressive cases, and they are consistent with a recent report on the prognostic power of Ki-67 expression [9
]. Therefore, these patients were grouped according to the atypical clinical behavior observed: (1) repeated relapses or progression (≥3 times) during their follow-up and (2) long-term survival for more than 40 months.
Clinically, the relapse characteristics of these patients can be detailed as described. First, 2 different relapse patterns were observed. Patients 1, 2, and 3 showed a wandering relapse pattern from nasal cavity to muscle. However, in patients 4, 5, and 6, the primary site of involvement and relapse lesions were confined to the head and neck region, such as oral and nasal cavities. The impact of these different relapse patterns on clinical outcomes such as survival, as well as the biological and pathological differences between these patterns is unclear. Further studies are needed to clarify these points.
Second, although the time interval between CR and initial relapse varied from 20 to 46 months, all patients showed a progression-free period of at least 20 months This is a relatively delayed relapse compared to relapses that commonly lead to a fatal clinical course. Relapsed extranodal NK/T-cell lymphomas are usually characterized by a rapid relapse or progression, during or immediately after treatment. They are also often followed by a fulminant aggressive course that results in resistance to treatment and death. Thus, delayed relapse as observed in these patients may influence the evaluation results of overall prognosis in extranodal NK/T-cell lymphoma. Previously, some delayed relapses similar to those observed in our patients have been reported. The longest delayed relapse case was observed in a sinonasal tract NK/T-cell lymphoma patient with a 12-year relapse after initial CR [10
]. A longer than 5-year relapse, after initial CR, was also reported in the retrospective analysis [2
The reasons behind the delayed relapse and indolent clinical course that allow long-term survival, despite repeated relapses, are unknown. However, one possible explanation is the presence of minimal residual lymphoma cells in a dormant state. NK/T-cell lymphoma usually runs an aggressive clinical course. Nevertheless, the relatively lower Ki-67 expression level (<40-50%) reported in most of our patients suggests the presence of lymphoma cells with biological characteristics similar to that of indolent lymphoma. This may explain the atypical clinical course observed in our patients, and It is supported by the fact that patients 4 and 5 lived with the disease for longer than 2 years without treatment (). Another possible hypothesis is the occurrence of a second NK/T-cell lymphoma. It has been reported that the Asian population is particularly affected by chronic active EBV infection [11
]. EBV-infected NK cells may evolve from a polyclonal to a monoclonal state, eventually leading to the development of overt NK-cell lymphoma. Thus, clonal evolution of residual EBV-infected NK-cells may result in a second NK/T-cell lymphoma, after initial lymphoma eradication. However, tumor specimens were unavailable for examination in order to confirm clonality. The clinicopathological features of NK/T-cell lymphoma patients with late relapses, some as late as 10-29 years after initial remission, were recently reported [6
]. These cases may support the possibility of second NK/T-cell lymphoma developing from premalignant EBV-infected NK cells. However, it has been reported that some patients also followed an aggressive clinical course after relapse, contradicting with the indolent clinical course observed in our cases after relapse. Thus, not all patients follow an indolent clinical course after late relapse, which hints at the possibility of selection bias.
Thus far, the proportion of patients showing this atypical clinical course among the total extranodal NK/T-cell lymphoma patient population is unclear. The patients selected in this study represented 4.29% of the 140 patients who were reviewed (90 patients from Samsung Medical Center; 50 from Korea University Medical Center). Therefore, a small group of patients (less than 5%) may follow this atypical clinical course. In conclusion, our experience suggests that some patients show a clinical behavior that diverges from the typical extranodal NK/T-cell lymphoma clinical course. Therefore, patients with indolent clinical courses, similar to the patients in this study, can be found among aggressive non-Hodgkin's lymphoma patients. Additional studies should be performed to evaluate the incidence and biological characteristics of such extranodal NK/T-cell lymphoma patients who follow an atypical clinical course.