|Year : 2022 | Volume
| Issue : 2 | Page : 445-451
Anaplastic lymphoma kinase fusion protein expression is associated with a favorable prognosis in resected invasive mucinous lung adenocarcinoma: A retrospective study from two Chinese tertiary hospitals
Jian Wang1, Penghua Wei2, Jing Liu3, Peng Su4, Aiyan Xing4, Haiyan Jing5, Jing Hao1
1 Department of Medical Oncology, Qilu Hospital of Shandong University, Jinan, China
2 Department of Internal Medicine, Third Peoples Hospital of Liaocheng City, China
3 Department of Biostatistics, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan, China
4 Department of Pathology, Qilu Hospital of Shandong University, Jinan, China
5 Department of Pathology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
|Date of Submission||23-Dec-2021|
|Date of Decision||25-Jan-2022|
|Date of Acceptance||26-Jan-2022|
|Date of Web Publication||06-May-2022|
107 Wenhua Xilu, Jinan, Shandong 250012
Source of Support: None, Conflict of Interest: None
Background: Invasive mucinous adenocarcinoma (IMA) is a distinct variant of lung adenocarcinoma, which typically has a worse survival. However, its pathogenesis is potentially associated with a high degree of molecular heterogeneity, which might determine its different prognosis.
Methods: We retrospectively analyzed 2207 consecutive lung adenocarcinoma patients who underwent radical resection at Qilu Hospital of Shandong University and Shandong Provincial Hospital from 2013 to 2019. Anaplastic lymphoma kinase (ALK) fusion protein expression was routinely detected by immunohistochemistry. The clinicopathological characteristics and treatment outcomes of IMA patients were retrieved, and compared between ALK-positive and ALK-negative IMA patients as well as between pure IMA and mixed IMA patients. The last follow-up was on December 31, 2020, and the median follow-up was 42 months.
Results: A total of 98 patients (4.4%) were diagnosed with IMA. ALK protein expression was positive in 24.5% of IMAs, which was significantly higher than that of non-IMA lung adenocarcinomas (4.7%, P < 0.001). ALK-positive and ALK-negative IMA, as well as pure IMA and mixed IMA, showed similar distribution in terms of patients' age, gender and smoking history, stage, and primary tumor location, except for a higher rate of lymph node metastasis in mixed IMA (22.0% vs. 46.2%, P = 0.012). Five cases (20.8%) of ALK-positive IMAs and 28 cases (40.6%) of ALK-negative IMAs experienced recurrence. Multivariable-adjusted Cox regression analysis demonstrated that ALK expression was a favorable prognostic factor for both disease-free survival (hazard ratio [HR]: 0.354; 95% confidence interval [CI]: 0.131–0.960; P = 0.041) and overall survival (HR: 0.138; 95% CI: 0.029–0.658; P = 0.013) in resected IMA. No difference in disease-free survival (HR: 0.524; 95% CI: 0.237–1.157; P = 0.110) and OS (HR: 0.553; 95% CI: 0.199–1.537; P = 0.256) was observed between pure IMA and mixed IMA.
Conclusion: Invasive mucinous lung adenocarcinoma showed higher ALK protein expression, which was a favorable prognostic factor for survival in early resected patients.
Keywords: Anaplastic lymphoma kinase, invasive mucinous adenocarcinoma, mixed IMA, pure IMA, survival
|How to cite this article:|
Wang J, Wei P, Liu J, Su P, Xing A, Jing H, Hao J. Anaplastic lymphoma kinase fusion protein expression is associated with a favorable prognosis in resected invasive mucinous lung adenocarcinoma: A retrospective study from two Chinese tertiary hospitals. J Can Res Ther 2022;18:445-51
|How to cite this URL:|
Wang J, Wei P, Liu J, Su P, Xing A, Jing H, Hao J. Anaplastic lymphoma kinase fusion protein expression is associated with a favorable prognosis in resected invasive mucinous lung adenocarcinoma: A retrospective study from two Chinese tertiary hospitals. J Can Res Ther [serial online] 2022 [cited 2022 Jul 7];18:445-51. Available from: https://www.cancerjournal.net/text.asp?2022/18/2/445/344875
| > Introduction|| |
Invasive mucinous adenocarcinoma (IMA) is a variant of lung adenocarcinoma, accounting for 2%–10% of adenocarcinomas., It has been histologically characterized by goblet cells and high columnar epithelial cells with mucin production. Pulmonary IMA has varied clinical presentations with a propensity for multicentric and multilobar involvement, and conflicting results regarding its prognosis has been reported.,,
In terms of the unique driving somatic mutations in IMA, Epidermal Growth Factor Receptor (EGFR)is relatively low (undetectable to 6.8%),, while Kirsten rat sarcoma virus (KRAS) mutation rate is as high as 60% to 80%.,, Anaplastic lymphoma kinase (ALK) gene rearrangement can be detected in 2%–5% of non-small cell lung cancers, however, its frequency can reach 11% in IMA patients, which is significantly higher than that of the other subtypes of adenocarcinoma. However, the molecular profiles of IMA might vary in different races. When compared to the Caucasian IMAs, the most frequently altered driver genes in East-Asians were EGFR (16.1%–33.3%), ALK (18.29%–29%), KRAS (13.7%–20.2%), ERBB2 (11.8%–15.2%), and PIK3CA (11.8%).,,, Furthermore, the prognostic effects of these mutations in early resected IMA remain unclear. The Chinese cohort study showed that IMA patients with EGFR and PIK3CA mutations achieved prolonged survival, while KRAS mutations were associated with poor prognosis. The prognostic value of ALK mutation in resected IMA has not been reported.
Hence, this study retrospectively analyzed the clinicopathological data and survival of resected consecutive IMA Chinese patients, aiming to investigate whether ALK expression endowed the IMA patients with unique clinical characteristics and also affected their prognosis. In addition, we explored the differences in clinical features and ALK expression between pure IMA and mixed invasive mucinous/nonmucinous adenocarcinomas (mixed IMA), which was defined as tumors with more than 10% of mucinous and nonmucinous morphologies, respectively.
| > Methods|| |
A total of 2207 native Chinese patients diagnosed with primary lung invasive adenocarcinoma who underwent surgical treatment at Qilu Hospital of Shandong University and Shandong Provincial Hospital between July 2013 and May 2019 were included. Among them, 98 (4.4%) patients with more than 10% mucinous components were enrolled in the IMA group. Data from all cases were retrospectively and consecutively collected, and were reviewed by two pathologists according to the 2015 WHO classification of lung adenocarcinoma. IMA patients were further divided into two subgroups: pure IMA and mixed IMA (mixed mucinous/nonmucinous adenocarcinoma, at least 10% for each component) groups. Clinicopathological characteristics of all patients were retrieved from the medical record system. TNM staging was based on the 7th edition of the American Joint Committee on Cancer staging system. This study was approved by the Ethics Committee of Qilu Hospital of Shandong University (2015040) and Shandong Provincial Hospital (SZRJJ NO. 2021-23).
Detection of anaplastic lymphoma kinase rearrangement
Immunohistochemistry (IHC) was performed on 5-μm thick formalin-fixed paraffin-embedded surgical specimens from all patients with the fully automated Ventana IHC system, using the D5F3 anti-ALK rabbit monoclonal primary antibody from the BenchMark Special Stains system (Roche). A matched rabbit monoclonal negative Ig antibody was used as negative control staining. The ALK status was described as either ALK positive or ALK negative by a binary scoring system. Basically, all paraffin sections were heated to 62°C and then subjected to the fully automated IHC assay using the prediluted Ventana D5F3 anti-ALK rabbit monoclonal primary antibody, together with the Optiview Amplification Kit and Optiview DAB IHC Detection Kit. The presence of strong granular cytoplasmic staining in tumor cells was considered as ALK positive, whereas the presence of weak granular cytoplasmic staining in tumor cells was recognized as ALK negative [Figure 1].
|Figure 1: Anaplastic lymphoma kinase staining in resected pure invasive mucinous adenocarcinoma (a and b) and mixed invasive mucinous adenocarcinoma (c and d) original magnification, 200×; scale bar, 500 pixel|
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Clinical outcomes and statistical analysis
Clinical outcomes included overall survival (OS), defined as the time interval from the date of surgery to death from any cause, and disease-free survival (DFS), defined as the time from the date of surgery to disease recurrence or death from any cause. If recurrence or death was not observed, the censoring date was the last follow-up. Both OS and DFS were calculated in months. Statistical analyses were performed using SPSS®, version 26.0 (SPSS Inc., Chicago, IL, USA). Comparisons of ALK-positive expression between IMA and non-IMA and the clinicopathological characteristics between ALK-positive and ALK-negative IMA or between two subgroups (pure IMA and mixed IMA) were performed using Chi-square test. Survival was estimated by the Kaplan–Meier method and compared using the log-rank test. Cox proportional hazards regression analysis was used to calculate the hazard ratio (HR) and 95% confidence interval (CI). A two-tailed P < 0.05 was considered to be statistically significant.
The follow-up data of IMA patients were collected from hospital records or obtained by telephone interviews. Five (5.1%) patients were lost to follow-up after surgery. The other 93 patients underwent routine examination every 3–6 months in the first 5 years and then yearly after surgery. Thirty-five (35.7%) patients received adjuvant platinum-based chemotherapy. None of the ALK-positive IMA patients received adjuvant tyrosine kinase inhibitor (TKI) treatment. When relapse occurred, postrecurrence treatment was also given. Eleven cases (11/33, 33.3%) underwent further gene mutation analysis. The last follow-up was on December 31, 2020, and the median follow-up was 42 months.
| > Results|| |
Comparison of anaplastic lymphoma kinase expression between invasive mucinous adenocarcinoma and noninvasive mucinous adenocarcinoma, pure invasive mucinous adenocarcinoma, and mixed invasive mucinous adenocarcinoma
Between July 2013 and May 2019, a total of 2207 consecutive lung adenocarcinoma patients who underwent radical resection were enrolled. Among them, 1318 cases were diagnosed at Qilu Hospital of Shandong University, of which 54 (4.1%) cases were IMA, and 889 cases were diagnosed at Shandong Provincial Hospital, of which 44 (4.9%) cases were IMA (P = 0.340). In total, 98 (98/2207, 4.4%) patients were diagnosed as IMA in our combined cohort. All patients were tested for ALK protein expression by immunohistochemistry. As shown in [Figure 2], ALK expression was positive in 24.5% (24/98) of IMA, which was higher than that of non-IMA (4.7%, 100/2114, P < 0.001). No significant difference in ALK expression was observed either in IMA (20.4% vs. 29.5%, P = 0.293) or non-IMA (4.0% vs. 5.2%, P = 0.195) patients between the two hospitals.
|Figure 2: Comparison of anaplastic lymphoma kinase positive rate in resected Invasive mucinous adenocarcinoma and noninvasive mucinous adenocarcinoma from two tertiary hospitals (Qilu, Qilu Hospital of Shandong University and Provincial, Shandong Provincial Hospital) *** P < 0.001|
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Comparison of characteristics between anaplastic lymphoma kinase-positive and anaplastic lymphoma kinase-negative invasive mucinous adenocarcinoma and pure and mixed invasive mucinous adenocarcinoma patients
The clinicopathological characteristics of 98 completely resected stage I–III lung adenocarcinoma patients are shown in [Table 1]. The percentage of males and females was almost equal, accounting for 50 (51.0%) and 48 (49.0%), respectively. The median age was 57 years. A total of 63 (65.6%) cases were never smokers. Moreover, 62 (63.3%) primary tumors were located in the right lung. Meanwhile, 54 (55.1%) cases were categorized as pathological stage I, 20 (20.4%) cases were classified as stage II, and 24 (24.5%) cases were classified as stage III. Pleural invasion occurred in 16 (16.3%) patients, 31 (31.6%) patients had lymph node metastasis, 59 (60.2%) patients developed pure IMA, and locoregional lymph node metastasis was more commonly seen in patients with mixed IMA than pure IMA (46.2% vs. 22.0%, P = 0.012). ALK expression was positive in 23.7% of pure IMA cases and 25.6% of mixed IMA cases (P = 0.829). No clinicopathological factor was shown to be significantly associated with ALK expression in IMA cases [Table 1] and [Table 2].
|Table 1: Clinicopathological characteristics of resected ALK-positive and ALK-negative invasive mucinous adenocarcinoma and pure and mixed invasive mucinous adenocarcinoma|
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|Table 2: Clinicopathological characteristics of resected ALK-positive and ALK-negative invasive mucinous adenocarcinoma and pure and mixed invasive mucinous adenocarcinoma (continued)|
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Prognostic value of anaplastic lymphoma kinase expression in completely resected invasive mucinous adenocarcinoma
A total of 33 (35.5%) of 93 patients relapsed and 23 (24.7%) patients died in our IMA cohort. The median DFS was 63.3 (95% CI: 55.9–70.7) months and OS was 72.4 (95% CI: 66.1–78.7) months. As shown in [Table 3] and [Table 4], ALK-positive expression was significantly associated with better DFS (73.9 vs. 59.4 months, HR = 0.354, P = 0.041) and OS (83.0 vs. 68.6 months, HR = 0.138, P = 0.013) in patients with IMA. Lymph node metastasis other than tumor stage was an independent prognostic factor for both worse DFS (41.6 vs. 73.0 months, HR = 0.216, P < 0.001) and OS (54.3 vs. 80.5 months, HR = 0.154, P = 0.001). Besides, patients <60 years experienced longer DFS (67.9 vs. 53.6 months, HR = 0.496, P = 0.083) and OS (80.9 vs. 56.7 months, HR = 0.195, P = 0.005) than elderly patients. All the other factors included in the Cox model, such as gender, smoking status, tumor size, pleural invasion, pure IMA, or mixed IMA, were not prognostic factors for resected IMA patients. The Kaplan–Meier survival curves stratified according to ALK expression are shown in [Figure 3].
|Table 3: Univariate and multivariate analyses of the disease-free survival prognostic factors for invasive mucinous adenocarcinoma patients|
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|Table 4: Univariate and multivariate analyses of the overall survival prognostic factors for invasive mucinous adenocarcinoma patients|
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|Figure 3: Kaplan–Meier survival curves of disease-free survival (a) and overall survival (b) of resected invasive mucinous adenocarcinoma patients based on anaplastic lymphoma kinase status|
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Among the ALK-positive and ALK-negative IMA patients, 5 (5/24, 20.8%) and 28 (28/69, 40.6%) patients had relapsed disease, respectively [Table 5]. Three ALK-positive IMA patients underwent further polymerase chain reaction (PCR) analysis, and fusion mutation was confirmed. Two cases received crizotinib and one case received alectinib after recurrence. Among the ALK-negative IMA patients, nearly one-third were given cisplatin-based chemotherapy and one-fourth received radiotherapy after recurrence. Five cases who were confirmed to have EGFR mutation by PCR analysis were treated with TKIs.
|Table 5: Postrecurrence treatment of resected ALK-positive and ALK-negative invasive mucinous adenocarcinoma|
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| > Discussion|| |
To date, it is unclear whether the molecular profile in invasive mucinous lung adenocarcinoma patients affects their prognosis, which is mainly due to the low incidence of IMA and limited oncogenic mutation information. This study showed that ALK protein expression was positive in 24.5% of Chinese resected IMA patients, and was a favorable prognostic factor for DFS and OS.
The incidence of IMA in this cohort study involving two tertiary hospitals was 4.4% of lung adenocarcinomas, which was consistent with previously reported incidence of 2%–10%., The prevalence of ALK-positive patients in non-IMA was 4.7%, which was also similar to that reported in unselected lung adenocarcinoma or non-IMA patients from Chinese populations diagnosed with different detection methods.,,,,,, The prognostic value of ALK mutation in unselected lung adenocarcinomas remains controversial. ALK rearrangement was not an independent prognostic factor for stage I–IIIA unselected lung adenocarcinoma patients according to one study. In contrast, ALK-positive early-stage NSCLC was either associated with superior or inferior survival in other studies., In addition, patients with ALK rearrangements had a significantly worse DFS than those harboring EGFR mutations. However, since ALK mutation is an important and frequent molecular event in IMA, its prognostic role in resected IMA needs to be clarified. To the best of our knowledge, this was the first study to explore the prognostic role of ALK expression in resected IMA.
Unlike patients with ALK expression in unselected or non-IMA reported in the literature, ALK-positive IMA cases were not enriched in younger patients, light or never smokers, and females, suggesting that ALK-mutated IMA had a different tumorigenic pathway from nonmucinous adenocarcinoma. ALK expression was detected in 24.5% of IMA patients in our study, which was similar to that reported in the other Chinese IMA cohorts.,, Notably, EGFR mutation was detected in five ALK-negative IMA patients with relapsed disease after surgery in our study. Although the exact EGFR mutation prevalence remained unknown, it was previously reported to be as high as 20% in Japanese IMA patients or 33.3% in Chinese IMA patients. The high prevalence rates of ALK expression and EGFR mutation highlighted the necessity that ALK and EGFR should be routinely assayed in IMA patients.
To date, defining the prognostic impact of molecular drivers of early-stage IMA has been challenging due to its relative rarity. The prognostic roles of these molecular drivers of lung cancer might depend on different histological subtypes. In unselected lung adenocarcinomas, the prognostic value of ALK mutation is inconclusive. In our study, the IMA patients with ALK expression were shown to have better DFS and OS than ALK-negative IMA patients. Since we aimed to explore the prognostic role of ALK in IMA, we did not use ALK-positive non-IMA, or EGFR-mutated IMA as comparator. Besides, invasive pure mucinous adenocarcinomas and mixed invasive mucinous/nonmucinous adenocarcinomas were generally considered to have similar demographic and genetic profiles. In our study, mixed IMA had similar ALK expression and seemed to be more aggressive than pure IMA due to more lymph node metastasis, which might explain the trend of worse DFS and OS in mixed IMA patients in the univariate survival analysis.
The potential molecular mechanisms remain unclear regarding why the different driver gene mutations, such as EGFR, ALK, and KRAS, have distinct prognostic roles for resected lung cancer patients, which warrants further detailed research. One possible explanation is that lung cancer patients with EGFR and ALK mutation are more likely to have low tumor mutation burden and PD-L1 expression compared with patients with wild-type genes, while high tumor mutation burden (TMB) and PD-L1 expression are associated with worse OS of patients with resected NSCLCs., By contrast, lung cancer patients with KRAS mutation had high TMB and PD-L1 expression.
This study had a few limitations. First, this was a retrospective study. Molecular profiles of most of these IMA patients, except for ALK expression, were not available. In addition, most ALK expression detected by immunohistochemistry was not confirmed by FISH or other detection methods. To minimize this limitation, the overall concordance rate in earlier studies between ALK IHC and FISH was 0.950. Second, the sample size was relatively small. Large-scale prospective trials with more patients are needed to confirm the findings and explore more effective targeted treatments.
| > Conclusion|| |
Invasive mucinous lung adenocarcinoma was enriched for ALK protein expression, which was a favorable prognostic factor of better survival in early resected patients.
This work was funded by the technology development project of Jinan Science and Technology Bureau: 201805089 and the National Science Foundation for Young Scientists of China: 8160253.
Financial support and sponsorship
This work was funded by the technology development project of Jinan Science and Technology Bureau: 201805089 and the National Science Foundation for Young Scientists of China: 81602538.
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]