TNM Stages Inversely Correlate With the Age at Diagnosis in ALK-Positive Lung Cancer

Wenfang Tang; Yuanyuan Lei; Jian Su; Chao Zhang; Rui Fu; Jin Kang; Honghong Yan; Xuening Yang; Haiyan Tu; Yilong Wu; Wenzhao Zhong


Transl Lung Cancer Res. 2019;8(2) 

In This Article


The rearrangements of ALK defined a molecular subset of NSCLC with distinct clinical and pathological features. The included patients shared similar clinical features, including never/light smoking history, adenocarcinoma, and young age.[4,6,13] However, few large-scale studies have clearly explored the correlations between the age, TNM stage and frequency of ALK-positive lung cancer.

In the most recent decade, several small-scale studies of this subgroup described the frequency of ALK-positive lung cancer in young patients or groups of patients stratified by age. In addition, some surgeons also explored the proportion of ALK rearrangements among the surgical population. These studies are summarized in Table 4.[4,5,8–19] As shown in Table 4, the frequency of ALK-positive lung cancer in the younger group ranged from 10.1% to 40.7% and was much higher than that of the older group, which ranged from 0.9% to 4.2%. Tanaka et al.[11] and Sacher et al.[12] demonstrated that the likelihood of exhibiting ALK translocations steadily decreased with age. In this study, we also identified this downtrend in a large-scale population. Regarding the difference in frequencies between TNM stage groups, few studies have focused on the proportion of ALK mutations in advanced lung cancer. However, the ALK rearrangements were more frequent in stage IV disease, with a high rate that ranged from 9.7–28.0%,[7,8,14] than in the unselected population,[3] which had a rate that ranged from 3–7%. In contrast, the frequency of ALK-positive lung cancer varied from 1.0% to 9.0% in the surgical patients with relatively early-stage disease. Yip et al. performed genotyping profiles of resected tissues from 204 patients with stage IB primary lung adenocarcinoma and found that only 2 (1%) patients exhibited ALK rearrangements.[9] However, Zhou et al. reported that the frequency of EML4-ALK fusions was 9.0% in 134 stage IA NSCLC cases;[10] Blackhall et al. compared the difference between detecting for ALK with IHC and Fish in 1,281 European surgical patients with stage I to III adenocarcinoma, and reported two distinct frequencies of 6.2% and 2.2%, respectively.[5] The various results may be attributed to multiple confounding factors, including small-scale patient samples, differing diagnosis technology, selected patients with a young age and nonsmoker. In our hospital, testing for ALK is a routine examination for patients treated with surgery. Our results demonstrated that the frequency of ALK mutation was 3.4% (127/3,782) in stage I–IIIa patients. However, in our results, the ALK-positive patients had a 79% increased likelihood of exhibiting stage IIIb–IV disease at the initial diagnosis, whereas, the KRAS-mutant patients did not demonstrate these special characteristics.

Of note, we identified with the Spearman correlation test that the TNM stages exhibited an inverse correlation with age at diagnosis, which suggested that patients who were younger at the initial diagnosis had a greater likelihood of being diagnosed with a more advanced diseases than patients who were older. A retrospective study by Liu et al. analyzed the clinicopathological features of ALK fusion in 200 advanced NSCLC patients. The median age was 48 years in the ALK-positive group.[14] Nevertheless, the ALK-positive patients with early-stage disease exhibited an older median age of 55–59 years than the patients with late-stage patients.[5,13,17,18] In fact, previous studies have indicated that young patients have a high proportion of stage III–IV disease in unselected NSCLC that ranges from 74% to 97%,[8,11,12,20–23] which suggests that younger NSCLC patients exhibit more progressive biology than older patients. The correlation between age and TNM stages could be explained by the steady downward trend of frequencies with age and the high incidence of stage IIIb–IV disease in ALK-positive lung cancer.

In fact, we hypothesized that ALK rearrangements are involved in different biological activities at the early and advanced stages in the course of the tumor evolution, which features a period of rapid growth from the early stage into the advanced stage. Therefore, most patients with ALK mutations were diagnosed with advanced disease at the initial diagnosis. This process could explain the low incidence of ALKrearrangements in patients with ground-glass opacity (GGO),[13] but patients with GGO tended to present with more lymph node metastases than patients with ALK-negative lung cancer[17] and have a shorter recurrence-free survival (RFS) than EGFR-mutant patients.[24] Furthermore, it has been supported that EML4-ALK-positive patients were observed to have more extrathoracic metastases including brain metastases at the initial diagnosis than EGFR-mutant patients[25] and patients with ROS1 gene rearrangements.[26]

The realization that NSCLC in young patients is a genetically unique disease naturally[11,27] lends itself to the question of whether the natural history and underlying disease biology of NSCLC is also distinct in this subgroup. Similarly, the difference in disease biology between younger and older patients in ALK-positive lung cancer was previously unknown. Our study found that patients aged 60 or older were associated with a trend toward improved prognosis compared with the other younger groups. Therefore, age may be an independent factor to predict the frequency of ALK-positive lung cancer, disease biology and prognosis of patients with ALK-positive lung cancer.

In interpreting these findings, some inherent limitations in this study must be considered. The patients included our study were drawn from a single institution and the duration of follow-up was short. Additionally, the screening methods for detecting the ALK gene varied, and included IHC, Fish, and NGS, which led to false positives.