Prognostic significance using histologic subtype in stage I lung adenocarcinoma

Introduction

For the treatment of malignancy, we have to need the well-known standardization. In non-small cell lung cancer (NSCLC), the tumor-node-metastasis (TNM) staging classification is the golden standard for treatment (1). The TNM staging system is modified continuously. The current 8^th edition TNM staging slightly differs from the previous adenocarcinoma classification system. Adenocarcinoma is the most common histologic type of lung cancer (2). However, it has heterogeneous patterns in terms of histologic subtype and proportion. Ground-glass opacity (GGO) is commonly observed on computed tomography (CT) scan in early-stage adenocarcinoma. In 2011, the International Association for the Study of Lung Cancer (IASLC), the American Thoracic Society, and the European Respiratory Society have added a novel pathological subtype in the histological classification (3). This type of classification should be proposed because of it has a significantly different prognosis even at same stage according to the TNM staging. Regardless of tumor size, patients with GGO lesions present with excellent clinical outcomes (4), and their prognosis significantly differs according to the histologic subtype. The lepidic-predominant subtype is associated with a good prognosis (5). The micropapillary- and solid-predominant subtypes have a high malignant potential (6,7). The acinar- and papillary-predominant subtypes present with intermediate malignant grade (8,9). The Lung Cancer Study Committee has proposed a prognostic histologic subtype grading system for adenocarcinoma (10). However, high grade patterns are rare in early lung adenocarcinoma. This study aimed to identify the prognostic significance of histologic subtypes in stage I lung adenocarcinoma. We present this article in accordance with the STROBE reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-905/rc).

Methods

The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The Institutional Review Board of Catholic Medical Center approved this study (Republic of Korea) (HC23WADI0086). The need for a written informed consent was waived because of the retrospective nature of this study.

Study population

This study enrolled patients who underwent lobectomy or segmentectomy from January 2010 to April 2017 at Seoul and Bucheon St. Mary’s Hospital. In total, 1,445 patients underwent surgical resection. The electronic medical records of patients with pathologic stage I adenocarcinoma according to the 8^th edition of the TNM classification of lung cancer were evaluated. The exclusion criteria included patients with non-adenocarcinoma tumors and mucinous adenocarcinoma, those who underwent incomplete resection, those who died perioperatively, those with tumors measuring >4 cm, lymph node metastasis, chest wall or parietal pleural invasion based on the pathologic reports, those with adenocarcinoma in situ (AIS) and minimally invasive adenocarcinoma (MIA), those with pathologic reports that did not include the histologic subtypes, those with multifocal GGO and synchronous or metachronous lung cancer, and those who received neoadjuvant chemotherapy (Figure 1).

Figure 1 Study flow diagram.

Data collection

In total, 752 patients with pathologic stage I invasive adenocarcinoma were included in this analysis. Data on the characteristics of the patients including age, sex, underlying disease, and history of smoking and previous malignancy and surgical procedure were reviewed. The preoperative assessments included chest CT scan, positron emission tomography (PET)-CT scan, brain magnetic resonance imaging, bone scanning, and bronchoscopy. Imaging data including tumor location, presence of GGO features (pure or part-solid nodule), maximum standardized uptake value (SUVmax), and clinical stage were obtained. Information on pathologic results including tumor size and grade, predominant pattern, number of lymph node dissections, visceral pleural invasion, lymphatic vessel invasion (LVI), and blood vessel invasion (BVI) was collected. LVI was indicated the tumor cells floating in the lymphatic vessels on hematoxylin-eosin (HE) and anti-podoplanin antibody (D2-40) stained sample. BVI is the invasion to the vascular lumen on HE and Elastica van Gieson (EvG) stained sample.

Each histologic subtype size was assessed based on the pathologic data. The pathologic data included tumor size, tumor proportion, and proportion of each histologic subtype. The formula was calculated by multiplying the diameter of the whole tumor size by the proportion of non-fibrotic lesions or cancer cells and the proportion of histological subtype according to the proposal from the IASLC lung cancer staging project (11).

Statistical analysis

A more effective prognostic indicator was assessed. Based on the high malignant potential of the micropapillary and solid histologic subtypes, the cutoff value for acinar or papillary size in the best model was added. The prognostic ability was estimated by identifying the area under the receiver operating characteristic curve (AUC) for recurrence.

All patients were followed-up until recurrence and mortality or loss to follow-up. Cancer specific survival was defined as the interval from the date of surgery to the date of death due to lung cancer. Recurrence was defined as local or extra-thoracic metastasis based on clinical and pathological evidence. Disease-free survival was defined as the time from date of surgery to the date of recurrence.

All statistical analyses were performed using the Statistical Package for the Social Sciences software version 18 (SPSS Inc., Chicago, USA). Continuous variables were compared using the Kruskal-Wallis test, and categorical variables were compared using the chi-square test and the Fisher’s exact test.

Disease-free survival was estimated using the Kaplan-Meier method and log-rank test. Prognostic factors associated with recurrence and survival were determined using the Cox proportional hazards model after assessing the proportionality assumption. Variables with P values of <0.05 in the univariate analysis were included in the multivariate analysis using forward selection.

Results

Table 1 shows the baseline characteristics of the patients. The median age of the patients was 64 (range, 25–86) years, and female participants (57.4%) were predominant. Further, 200 (26.6%) patients were current or previous smokers. The median SUVmax was 2.5 (range, 0–18.5). In total, 431 (57.3%) patients presented with part-solid or pure GGO lesions on preoperative CT scan. Lobectomy (88.6%) was the most common procedure, and 652 (86.7%) patients underwent video-assisted thoracic surgery.

The median tumor size was 2 (range, 0.3–4) cm. In terms of differentiation, 68 (9%) patients presented with poor differentiation. Poorly differentiation indicated that the tumor cells lack any other recognizable patterns. In total, 193 (25.7%) patients presented with LVI, 60 (8%) with BVI, and 127 (16.9%) with visceral pleural invasion. The median number of dissected lymph nodes was 11 (range, 0–53). Mediastinal lymph node evaluation could be omitted in some cases such as pure GGO- or GGO-dominant lesions which was suspicious for AIS or MIA (17 patients) (12). None of the patients presented with margin positivity (Table 2).

According to the predominant histologic subtype, the acinar-predominant subtype (44.7%) was the most common, followed by the lepidic subtype (38.2%). However, the micropapillary and solid predominant subtypes were rare in patients with stage I lung adenocarcinoma (1.7% and 5.2%, respectively).

The patients were also classified according to the presence of histologic subtype component, more than 5% and including the predominant subtype. In total, 649 (86.3%) patients presented with the acinar component, 582 (77.4%) with the lepidic component, 122 (16.2%) with the micropapillary component, and 100 (13.3%) with the solid component.

Each histologic subtype was classified according to acinar size with a cutoff value of 1 cm (Figure 2). According to the survival curve (Figure 2A), patients with acinar subtype tumors measuring >1 and ≤2 cm as well as those with acinar subtype tumors measuring ≤1 cm and those with non-acinar subtype tumors significantly differed in terms of recurrence (P=0.005 and 0.003, respectively). However, there was no difference with the group of more than 2cm size of acinar subtype (P=0.38). According to the survival curve based on the micropapillary and solid subtype tumors with a cutoff size of 1 cm, patients with the presence of micropapillary and solid subtype component and those without these subtypes significantly differed in terms of recurrence (Figure 2B,2C). However, papillary subtype did not have any significance.

Figure 2 Survival curve for disease free interval according to acinar (A), micropapillary (B) and solid (C) subtype size.

Receiver operating characteristic curve analysis was conducted to identify a more valuable prognostic variable for predicting prognosis (Figure 3). The AUC for recurrence based on the predominant pattern of the micropapillary or solid subtype tumors was 0.597 (P=0.001). The AUC for recurrence in any tumors with ≥20% of the combined micropapillary or solid subtype tumors was 0.638 (P<0.001). The AUC for recurrence in the acinar subtype measuring >1 cm or the presence of micropapillary or solid subtype was 0.710 (P<0.001).

Figure 3 Receiver operating characteristic curve analysis for predicting prognosis. (A) The AUC for recurrence was 0.597 using a predominant pattern of micropapillary or solid subtype (P=0.001). (B) Using any tumor with 20% or more of combined micropapillary or solid subtype, the AUC for recurrence was 0.638 (P<0.001). (C) The AUC for recurrence was 0.710 by more than 1 cm size of acinar subtype or positive of micropapillary or solid subtype (P<0.001). AUC, area under the receiver operating characteristic curve.

Based on the survival analysis of recurrence (Table 3), multivariate analysis showed that non-GGO lesions (P<0.001), micropapillary-predominant subtype (P=0.01), solid-predominant subtype (P=0.006), visceral pleural invasion (P=0.005), LVI (P<0.001), and the presence of micropapillary or solid subtype or more than 1cm size of acinar subtype (P<0.001) had a significant prognostic impact on recurrence.

Based on the cancer-specific survival analysis (Table 4), age (P=0.04), SUVmax (P<0.001), the presence of micropapillary or solid subtype or more than 1cm size of acinar subtype (P=0.04) and LVI (P=0.003) were prognostic factors of survival.

Discussion

The incidence of lung cancer has been increasing, and lung cancer is the leading cause of mortality worldwide (13). Further, this condition is among the malignancies with the worst prognosis. Surgical resection is the best treatment modality for a full recovery (14). However, its therapeutic effect in lung cancer is unsatisfactory compared with that in other types of malignancies. The 5-year survival rate of patients with stage I lung cancer remains high at 70–80%. NSCLC accounts for >80% of all lung cancer cases (15). Adenocarcinoma is the most common histologic type, and it accounts for approximately 50% of all lung cancer cases. The most prominent feature of adenocarcinoma is histological heterogeneity and has various histological subtypes and proportion. Thus, adenocarcinoma is more unique than other types of lung cancer. In most cases, early-stage adenocarcinoma is characterized by GGO pattern on CT scan. However, patients with lung cancer with a non-adenocarcinoma histology presented with a solid mass. The clinical relevance between adenocarcinoma and TNM staging is less associated compared with other lung cancers. For example, pure GGO or GGO-dominant nodules in adenocarcinoma have favorable clinical outcomes regardless of its whole size (16). In 2011, a novel histological classification of lung adenocarcinoma was introduced based on the predominant histological pattern because of various histological subtypes and proportions. The micropapillary and solid-predominant subtypes have worse characteristics. Their biological characteristics, including association with driver genes, are considered to be different. For example, they have mitotic characteristics, a higher SUVmax, and LVI, which are associated with a worse prognosis (17,18). In this subtype, lymph node metastasis was more common even in patients with small lesions (19). It seems to be inappropriate to analyze them as the same group. Due to the unique features of adenocarcinoma, prognosis is more challenging to predict and is complicated. With advancements in imaging studies, pathophysiological examination, and molecular genetics, the characteristics of lung adenocarcinoma were identified. The IASLC has several proposals for lung adenocarcinoma (11). In part-solid nodules, central solid lesions with surrounding GGO on chest CT scan are associated with a central invasive area with surrounding lepidic lesions. However, this association is not always right, and several studies have shown that prognosis is more associated with invasive lesions than with the whole tumor size. Hence, Travis et al. proposed that the whole tumor size and invasive component size should be recorded in the clinical and pathological setting (11). However, to determine TNM stage, they proposed that the size of solid lesions on CT scan must be used for the clinical T category, and the invasive component size must be used for the pathologic T category. Several studies have supported this concept regarding the tumor size of adenocarcinoma for predicting prognosis (4,20). However, Hattori et al. recommend that pure GGO and part-solid nodules have a good prognosis regardless of their size (16). The grading system according to the histologic subtype is another major proposal of the IASLC (10). In their proposal, adenocarcinoma was classified into three groups according to the proportion of the micropapillary and solid subtypes. Data from previously reported articles revealed that the micropapillary and solid-predominant subtypes have a worse prognosis. This study indicated a cutoff value for the proportion. The high-risk group comprises any tumor with ≥20% high-grade patterns. However, the two abovementioned proposals might be in conflict with each other. We believe that size is more important than proportion because it represents tumor burden. We hypothesized that prognosis is based on tumor burden with tumor characteristics. Thus, larger micropapillary and solid subtype tumors can have a worse prognosis. Further, the prognostic impact of the size of each histologic subtype was investigated. Travis et al. recommend the measurement of the invasive size if the lesion is multi-focal (11). The formula is calculated by multiplying the percentage of invasive component area by the overall tumor size. This formula was adapted for each histologic subtype size. However, the measurement had some issues. For example, there was a solid area on CT scan, and the specimens included not only real tumor cells but also benign scars or fibrotic tissues. Therefore, it is important to identify the tumor cell proportion in the specimen. After the tumor cell proportion was identified, each histologic subtype size was calculated by multiplying the diameter of the tumor size by the proportion of cancer cells and the proportion of histological subtypes. Based on our previous data, we focused the prognostic role of acinar subtype size. The acinar subtype has an intermediate malignant potential. However, the acinar subtype is the most common in stage I lung adenocarcinoma, accounting for >50% of lung adenocarcinomas (21). Meanwhile, the percentage of micropapillary and solid subtypes was small. Hence, similar to micropapillary and solid subtype tumors, larger acinar subtype tumors may have a major prognostic role. However, several studies have underestimated the prognostic role of the acinar subtype as they only focused on the micropapillary and solid subtypes. If a supplement prognostic indicator was established, the micropapillary and solid subtypes were used as a basis because they have adverse prognostic effects even though not predominant. Based on our survival curve of the acinar subtype, there was a significant difference if the acinar size was >1 cm. The presence of the micropapillary or solid subtype with an acinar size of >1 cm had the best sensitivity and specificity to the AUC in our study. Multivariate analysis of recurrence also revealed that our indicator was a powerful prognostic factor.

The current study had several limitations. First, it was nonrandomized and retrospective in nature. Second, the sample size of patients based on different histologic subtypes was small. Hence, it was challenging to predict patient prognosis. In particular, the number of patients in the micropapillary group was limited. Third, the actual value of each subtype size was not presented. However, the formula for the size measurement from a previous study was used. Fourth, we included only micropapillary and solid pattern as a high grade pattern. However, it was not correct. It is micropapillary, solid or complex glandular. We could not assess for what proportion of acinar tumors have complex glandular patterns because of the retrospective design. In our study, BVI was not significant prognostic factor. However, recent study indicated vascular invasion was associated with poor outcome in early adenocarcinoma (22). Finally, this study was conducted at a single center; thus, selection bias might have existed.

Conclusions

Each histologic subtype size can be associated with patient prognosis. The micropapillary and solid subtypes have adverse effects. Further, a sizable acinar subtype has prognostic effects in stage I lung adenocarcinoma. This prognostic indicator can provide valuable information that can supplement the current classification.

Acknowledgments

This manuscript was edited by Enago.

Funding: None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-905/rc

Data Sharing Statement: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-905/dss

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-905/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-905/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The Institutional Review Board of Catholic Medical Center approved this study (Republic of Korea) (HC23WADI0086), and written informed consent from the patients was waived because of the retrospective design of the study.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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