DISCUSSION

Postoperative recurrence of NSCLC commonly occurs within 5 years after resection; thus, NSCLC is often declared to be cured if no recurrence appears within 5 years after resection. However, postoperative recurrence of NSCLC over 5 years after resection has also been recognized. Several studies have reported recurrence of NSCLC over 5–10 years after resection.

About 4%–10% of the cases who underwent complete resection for stage I–III NSCLC had recurrence 5–10 years after resection. Some studies have shown nonclinicopathological factors to be the prognostic factors for the development of postoperative recurrence after 5–10 years, whereas others have shown intratumoral vascular invasion and lymph node metastasis to be the prognostic factors for the development of postoperative recurrence after 5–10 years.1–3


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Ultra-late recurrence of NSCLC over 10 years after curative resection is rare, and we could find only a few case reports of ultra-late recurrence9–15 (Table 4). However, there was no study that analyzed the features of ultra-late recurrence. To the best of our knowledge, this is the first study analyzing the features of ultra-late recurrence in patients who underwent complete resection for NSCLC.

(To view a larger version of Table 4, click here.)

Differential diagnosis between recurrent lung cancer and metachronous lung cancer remains controversial because there are no formally established differential criteria.1 Multiple intrapulmonary nodules are often diagnosed as intrapulmonary metastasis when they appear synchronously. However, in case of a single nodule, it is difficult to judge whether the nodule is intrapulmonary metastasis or a second primary tumor. In the present study, recurrence was distinguished from a second primary tumor following the criteria of Martini and Melamed.19

Ultra-late recurrence cases were compared with non-recurrence cases, and it was observed that none of the examined factors significantly influenced ultra-late recurrence; however, lymphatic invasion was close to significantly influencing it. In addition, all cases that developed ultra-late recurrence had invasive carcinoma. Therefore, there is a possibility of ultra-late recurrence of any invasive NSCLC.

Furthermore, recurrence of NSCLC over 15 years after curative resection included adenocarcinoma with ALK rearrangement.

Adenocarcinoma with ALK rearrangement is usually found in younger patients and shows a favorable prognosis and clinical course after resection.20–22 However, there is a possibility of its recurrence even after a long interval. Studies have shown recurrence over 15 years after resection in cases with adenocarcinoma with ALK rearrangement.9,12–14 Therefore, a long follow-up period is recommended, particularly in patients with adenocarcinoma with ALK rearrangement.

This study has several limitations. First, we could not follow all the cases for 10 years or more; therefore, the cause of death is unclear in some cases. Of 835 deaths, the cause of death was not clear in 169 (20.2%) cases. Therefore, there is a possibility that recurrence developed in these cases and was overlooked. Second, the follow-up period was not the same for all cases; therefore, patient selection bias and time trend bias may exist. Third, differential diagnosis between recurrent lung cancer and metachronous lung cancer has not been clearly established. Moreover, histopathological diagnosis could not be confirmed in all cases of recurrence. Therefore, there is a possibility that the case we considered being recurrence was not completely excludable. Further large clinical prospective studies are needed to overcome these limitations.

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