The impact of predominant histopathological pattern and other histopathological factors on survival in pulmonary adenocarcinomas

Abstract

Background

Adenocarcinoma is the most common subtype of lung cancer. Histopathologically, lung adenocarcinoma is classified into five distinct patterns: lepidic, acinar, papillary, solid, and micropapillary. In 80-90% of cases, heterogeneous histopathological patterns are observed. This study aimed to evaluate the impact of predominant histological patterns on survival in surgically treated patients, as well as to identify other clinical, demographic, and histopathological factors affecting prognosis.

Methods

In this retrospective cohort study, 499 patients who underwent surgery for primary lung adenocarcinoma were evaluated. Survival data were obtained from electronic medical records. Demographic, clinical, and histopathological parameters were analyzed for both surviving and deceased patient groups. Univariate and multivariate Cox regression analyses were conducted to determine independent predictors of mortality.

Results

A total of 499 patients who underwent anatomical resection for primary lung adenocarcinoma and had complete medical data were retrospectively analyzed. The mean age was 61±8.1 years, and 77.6% of patients were male. The median tumor size was 3.5 cm (range: 2.30-5.20 cm), and the median Charlson comorbidity index was 3 (range: 2-4). The 5-year overall survival (OS) rate was found to be 64.5%. The 5-year OS was 59.8% in males and 77.7% in females (p=0.001). Regarding the side of surgery, the 5-year OS was 57.8% for left-sided resections and 67.9% for right-sided resections (p=0.024). The presence of a micropapillary pattern and acinar predominance were both identified as negative prognostic factors for survival (p=0.017, p=0.024, respectively). Additionally, lymphatic invasion and postoperative complications were found to be independent prognostic factors adversely affecting survival in multivariate analysis (p=0.014, p=0.011).

Conclusion

This study demonstrates that predominant histological patterns significantly influence survival in lung adenocarcinoma. The presence of a micropapillary component and acinar predominance were identified as negative predictive factors in multivariate analysis. We believe that relying solely on the TNM staging system may be insufficient for survival prediction; factors such as predominant histological pattern, lymphatic invasion, gender, Charlson comorbidity index, and postoperative complications should also be taken into account. These criteria may also be considered in planning oncological treatment strategies.

Lung adenocarcinoma is the most common histological subtype of lung cancer.^[1] The prognosis of lung cancer primarily depends on pathological type, stage, degree of tumor differentiation, and presence of microvascular invasion.^[2] Among these, staging remains the most reliable prognostic factor, taking into account tumor size, lymph node involvement, and the presence of distant metastases. Since lung cancer is often asymptomatic in its early stages, many patients are diagnosed at advanced stages when curative treatment is no longer feasible.^[3] The observation that patients with identical TNM stages may exhibit varying prognoses has emphasized the importance of factors beyond staging in treatment decision-making.^[2]

Histopathologically, lung adenocarcinoma is classified into five major subtypes: Lepidic, acinar, papillary, solid, and micropapillary (MP).^[4] In 80-90% of lung adenocarcinoma cases, a heterogeneous histopathological pattern is observed.^[5] The 2021 World Health Organization (WHO) classification recommends documenting the percentages of each histological pattern in invasive non-mucinous lung adenocarcinomas and highlights the need for a formal grading system.^[6]

The aim of this study is to investigate the impact of predominant histological patterns—along with other potential prognostic factors—on overall survival (OS) in patients with lung adenocarcinoma, with the broader goal of contributing to improved survival outcomes.

Methods

This retrospective study included 499 patients who underwent surgery for primary lung adenocarcinoma between 2014 and 2018. Ethical committee approval was obtained the University of Health Sciences Türkiye, Yedikule Chest Diseases and Thoracic Surgery Training and Research Hospital (approval number: 2023-399). Demographic, clinical, and histopathological parameters were retrieved and analyzed using the national patient database and the institutional hospital records system. Patient survival data were obtained from electronic medical records.

Patients were excluded if they had incomplete data, a history of another malignancy, preoperative metastasis, received neoadjuvant therapy, did not undergo anatomical resection, had positive surgical margins, or experienced postoperative surgical mortality (defined as death within 30 days after surgery). OS was defined as the time interval from the date of surgical intervention to the date of death from any cause.

Preoperative and Postoperative Assessment

The routine preoperative evaluation of all patients included medical history, physical examination, complete blood count, biochemical analysis, pulmonary function testing, arterial blood gas analysis, thoracic computed tomography (CT), brain magnetic resonance imaging, and positron emission tomography/CT. When indicated, additional tests such as diffusing capacity for carbon monoxide and cardiopulmonary exercise testing were performed. Informed consent form was obtained from all patients. Comorbid conditions were scored using the Charlson comorbidity index (CCI). The CCI was used to assess the comorbidity burden of patients. This index assigns weighted scores to specific comorbid conditions associated with mortality, generating a total score. All existing systemic diseases of each patient were recorded, and the CCI score was calculated. A higher score indicates a greater comorbidity burden and, consequently, a potentially increased risk of morbidity and mortality. Scoring was based on the original system defined by Charlson et al.^[7] and verified according to the ICD-compatible version updated by Quan et al.^[8] Each patient’s comorbid conditions were evaluated according to the table, and a total score was obtained (Table 1).

Table 1. CCI parameters and scoring system.

Comorbidity	Score
Myocardial infarction	1
Congestive heartfailure	1
Peripheral vascular disease	1
Cerebrovascular disease (stroke, TIA, etc.)	1
Dementia	1
Chronic pulmonary disease	1
Connective tissue disease (e.g., rheumatoidarthritis)	1
Peptic ulcer disease	1
Mild liver disease	1
Diabetes without end-organ damage	1
Diabetes with end-organ damage	2
Hemiplegia	2
Moderateor severe renal disease	2
Any malignancy (excluding skin cancers, <5 years after diagnosis)	2
Leukemia	2
Lymphoma	2
Moderateor severe liverdisease	3
Metastatic solidtumor	6
AIDS/HIV infection	6

CCI: Charlson comorbidity index; TIA: Transient ischaemic attack; AIDS: Acquired immunodeficiency syndrome; HIV: Human immunodeficiency virus.

In post-operative period air leak persisting for 7 days or more after surgery was defined as prolonged air leak. Tumor staging was performed according to the 9^th edition of the TNM staging system.

Statistical Analysis

Statistical analyses were performed using SPSS version 22.0 (Statistical Package for the Social Sciences). For descriptive statistics, data with a normal distribution were expressed as mean ± standard deviation, while non-normally distributed data were reported as median and interquartile range (IQR). Categorical variables were presented as frequencies and percentages.

Survival analysis was conducted using the Kaplan-Meier method. Differences in survival between groups were assessed using the Kaplan-Meier estimator and compared using the log-rank test. For each covariate, a separate Cox regression model was constructed including an interaction term with the natural logarithm of survival time (covariate × ln(time)). Based on Schoenfeld residual tests, no significant time-dependent effects were observed, indicating that the proportional hazards assumption was satisfied for all variables and for the model as a whole.

Results

A total of 499 patients who underwent anatomical resection for primary lung adenocarcinoma were retrospectively evaluated. The mean follow-up duration was 64.8±33.1 months. Ten patients (2%) were excluded from the study due to surgical mortality (defined as death within the first 30 days postoperatively).

The majority of patients were male (77.6%; n=387), with a mean age of 61±8.1 years. The median tumor size was 3.5 cm (IQR: 2.3-5.2 cm) (Table 2). The median CCI score was 3 (IQR: 2-4). Of the patients, 288 (57.7%) underwent right-sided surgery and 211 (42.3%) left-sided surgery. Thoracotomy was performed in 428 patients (85.8%), while 71 patients (14.2%) underwent video-assisted thoracoscopic surgery (VATS).

Table 2. Demographic, clinical, and histopathological characteristics of the patients (n=499).

Variable	-	N	%
Age (mean ± standard deviation)	-	61±8.1 year
Gender	Male	387	77.6
	Female	112	22.4
Charlson comorbidity index (median, IQR)	-	3 (2-4)
Side of surgery	Right	288	57.7
	Left	211	42.3
Surgical approach	Thoracotomy	428	85.8
	VATS	71	14.2
Type of resection	Lobectomy	448	89.8
	Pneumonectomy	41	8.2
	Segmentectomy	10	2
Extended resections	Chest wall resection	40	8
	Sleeve resection	9	1.8
	Intrapericardial resection	13	2.6
TNM stage	I	212	42.7
	II	154	30.8
	III	132	26.5
Postoperative complications	-	145	29.1
Predominant histological pattern	Lepidic predominant	46	9.2
	Acinar predominant	284	56.9
	Papillary predominant	31	6.2
	Solid predominant	138	27.7
Presence of micropapillary pattern	-	43	8.6
WHO 2021 grade classification	Grade 1	40	8
	Grade 2	223	44.7
	Grade 3	236	47.3
Stromal parameters	Stromal desmoplasia	277	55.5
	Inflammatory stromal reaction	296	59.3
Pleural invasion	Present	194	38.9
	Absent	305	61.1
STAS	Present	35	7
	Absent	91	18.2
Types of invasion	Vascular invasion	187	37.6
	Lymphatic invasion	236	47.3
	Perineural invasion	40	8

VATS: Video-assisted thoracoscopic surgery; IQR: Interquartile range; STAS: Spread through air spaces.

All patients received anatomical resections: lobectomy in 448 cases (89.8%), pneumonectomy in 41 cases (8.2%), and segmentectomy in 10 cases (2%). Extended resections were performed in 62 patients (12.4%), including chest wall resection in 40 (8%), sleeve resection in 9 (1.8%), and intrapericardial resection in 13 (2.6%).

According to the 9^th edition of the TNM staging system, 212 patients (42.7%) were classified as stage I, 154 patients (30.8%) as stage II, and 132 patients (26.5%) as stage III. Postoperative complications occurred in 145 patients (29.1%).

The demographic and histopathological characteristics of the entire cohort are summarized in Table 2.

Survival Analysis

The mean OS time for the entire cohort was 82.38±2.04 months, and the 5-year OS rate was 64.5%.

When stratified by sex, female patients demonstrated significantly higher 5-year OS compared to male patients (77.7% vs. 59.8%, p=0.001) (Table 3). Among female patients, the lepidic-predominant subtype was observed in 23 cases (20.5%), whereas among male patients, it was identified in 23 cases (5.9%) (p<0.001) (Table 4).

Table 3. Univariate and multivariate analysis of factors associated with overall survival.

Variable	Univariate p-value	Multivariate p-value	Hazard ratio (95% CI)
Male sex	0.001	0.001	1.91 (1.31-2.80)
Charlson comorbidity index	0.001	0.001	1.26 (1.10-1.44)
Left-sided surgery	0.001	0.024	1.37 (1.04-1.80)
Extended resection	<0.001	0.950	1.01 (0.68-1.49)
Pneumonectomy	0.001	0.890	1.03 (0.65-1.64)
TNM stage	<0.001	<0.001	1.76 (1.47-2.11)
Acinar predominant pattern	0.030	0.024	1.39 (1.04-1.86)
Presence of micropapillary pattern	<0.001	0.017	1.65 (1.09-2.50)
Pleural invasion	<0.001	0.650	1.32 (0.98-1.78)
Vascular invasion	0.001	0.717	1.05 (0.78-1.42)
Lymphatic invasion	<0.001	0.014	1.45 (1.07-1.95)
Perineural invasion	0.001	0.321	1.25 (0.80-1.96)
Stromal desmoplasia	0.023	0.134	1.24 (0.93-1.64)
Postoperative complication	0.010	0.011	1.45 (1.09-1.95)

CI: Confidence interval.

Table 4. Relationship between gender and predominant histological patterns.

Gender	Lepidic N (%)	Acinary N (%)	Papillary N (%)	Solid N (%)
Female	23 (20.5%)	66 (58.9%)	6 (5.4%)	17 (15.2%)
Male	23 (5.9%)	218 (56.3%)	25 (6.5%)	121 (31.3%)

Patients who underwent left-sided surgery had lower survival rates than those who underwent right-sided surgery (57.8% vs. 67.9%, p=0.010) (Table 3). Among patients operated on the left side, 27 cases (12.9%) underwent pneumonectomy, whereas 14 cases (4.9%) who were operated on the right side underwent pneumonectomy (p=0.001). Additionally, N1 lymph node involvement was present in 54 patients (25.6%) operated on the left side and in 34 patients (11.8%) operated on the right side, which was statistically significant (p<0.001).

A significant association was found between the CCI and 5-year OS (p=0.001) (Figure 1). The most frequent CCI score among the cases was 2. A total of 213 patients had a CCI value of 2, with a 5-year survival rate of 70%. The index scores and corresponding 5-year survival rates are presented in Table 5.

Figure 1.

Charlson comorbidity index survival analysis.

Table 5. Charlson comorbidity index scores, case numbers, and 5-year survival rates.

Charlson comorbidity index scores	N %	5-year survival rates
2	213	70%
3	155	63.9%
4	89	53.9%
5	33	60.6%
6	6	33.3%
7	2	0%

Patients who experienced postoperative complications also had significantly lower 5-year OS (55.9% vs. 67.0%, p=0.010) (Figure 2). Postoperative complications were reported in detail (Table 6). Prolonged air leak was observed in 53 patients (36.5%) and was the most common postoperative complication.

Figure 2.

Survival analysis based on postoperative complications.

Table 6. Types of postoperative complications and 5-year survival rates.

Postoperative complications	N	Survival rates (%)
Prolonged air leak	53	66%
Respiratory failure	10	30%
Pneumonia	12	50%
Hematoma	14	29%
Expnasion defect	6	16%
Wound infection/dehiscence	15	53%
Tachycardia/arrhythmia	16	50%
Chylothorax	3	0%
Bronchopleural fistula	3	33%
Hepatized lung	1	100%
Hoarseness	3	33%
Others	9	45%

Among the 41 patients who underwent pneumonectomy, the 5-year OS rate was only 36.6% (p<0.001). Similarly, extended resections performed in 62 patients (12.4%) were associated with reduced survival (p<0.001).

According to the 9^th edition of the TNM staging system, the 5-year OS rates were 78.2% for stage I, 64.1% for stage II, and 40.9% for stage III (p<0.001). When analyzed by nodal status, 5-year OS was 74.5% in N0 cases, 44.3% in N1, and 28.2% in N2 patients (p<0.001).

In the classification based on predominant histologic pattern, the most common subtype was acinar predominant. The 5-year OS for acinar predominant patients was 59.9%, indicating a negative impact on survival (p=0.030) (Table 7, Figure 3). While 48.4% of patients with acinar-predominant pattern received adjuvant therapy, this rate was 72.5% in those with solid-predominant pattern, which was statistically significant (p<0.001).

Table 7. Five-year survival rates according to predominant histopathological patterns.

Predominant histopathological pattern	N	Five-year survival rates %
Lepidic	46	69.6%
Acinary	284	59.9%
Papillary	31	71%
Solid	138	69.9%

Figure 3.

Survival analysis based on predominant histopathological pattern.

Although no patients had a MP pattern as the predominant subtype, 43 patients (8.6%) exhibited MP components, and their 5-year OS was significantly lower at 41.9% (p<0.001) (Figure 4). The MP pattern was observed in 16.7% of patients with N2 lymph node involvement compared to 7.5% of those without, in 13.4% of patients with pleural invasion compared to 5.6% without, and in 31.4% of STAS-positive cases compared to 5.5% of STAS-negative cases. These differences were statistically significant (p=0.018, p=0.002, and p<0.001, respectively).

Figure 4.

Survival analysis based on the presence of micropapillary pattern.

Stromal desmoplasia was present in 277 patients (55.5%), and these patients had reduced survival compared to those without desmoplasia (60.5% vs. 68.0%, p=0.023). Vascular invasion was observed in 47.3% of patients, and their 5-year OS was 54.8%, compared to 69.2% in those without vascular invasion (p=0.001). Perineural invasion, found in 40 patients (8.0%), was also associated with poorer survival (45.0% vs. 65.5%, p=0.001). Lymphatic invasion was present in 47.3% of patients and significantly reduced 5-year OS (56.4% vs. 70.6%, p<0.001). Among patients without lymph node involvement, lymphatic invasion was present in 38.9%, whereas it was positive in 70.5% of those with N1 lymph node involvement and in 63.3% of those with N2 lymph node involvement (p<0.001) (p<0.001). Pleural invasion was detected in 38.2% of cases and was similarly associated with reduced survival (53.9% vs. 69.8%, p<0.001).

No statistically significant impact on survival was observed for spread through air spaces (STAS), surgical approach (VATS vs. thoracotomy), age, stromal inflammatory response, or WHO 2021 tumor grade (p=0.602, p=0.062, p=0.068, p=0.207, and p=0.065, respectively).

Multivariate Analysis

In multivariate Cox regression analysis, the following factors were identified as independent predictors of decreased survival: Male sex, left-sided surgery, higher CCI score, acinar predominant pattern, presence of a MP component, lymphatic invasion, and occurrence of postoperative complications (Table 3).

Discussion

The association between male sex and poorer survival outcomes is a significant finding consistent with current literature. Sex-related survival differences have been frequently reported, particularly in patients with non-small cell lung cancer (NSCLC). In a study by Cerfolio et al.^[9] involving stage I-III NSCLC patients, female patients demonstrated significantly better prognoses compared to males.

Similarly, in a study by Yoshida et al.^[10] investigating postoperative prognostic indicators stratified by sex, female sex emerged as one of the most important independent predictors of survival, and this effect persisted even when controlled for pathological stage. In our study, the higher prevalence of lepidic-predominant pattern among female patients may partially explain their superior survival. The lepidic pattern is known to represent a more well-differentiated and indolent subtype of adenocarcinoma and has been associated with better survival in the literature. Therefore, the combination of biological and histopathological advantages in female patients may reinforce the observed prognostic differences between sexes.

Our findings also revealed that left-sided resections were associated with worse survival compared to right-sided surgeries. One possible explanation is that left-sided surgeries, particularly pneumonectomies, were more common among patients with more advanced-stage disease, necessitating more aggressive procedures. Furthermore, the higher incidence of lymph node involvement in left-sided cases may also contribute to the poorer outcomes.

Both acinar-predominant and MP components were found to negatively affect survival in our cohort. In particular, the presence of MP components was strongly associated with reduced survival, aligning well with prior studies. Wart et al.^[11] identified MP and solid patterns as negative prognostic factors in their analysis, correlating their presence with shorter survival. Similarly, in the study by Watanabe et al.,^[12] the MP-predominant subtype was found to be closely associated with poor prognosis, with an HR of 1.525. In our study, the HR was determined to be 1.65.

In the study by Zhang et al.,^[13] the adverse impact of the MP pattern on survival was attributed to its aggressive dissemination characteristics, such as lymph node metastasis, visceral pleural invasion, and STAS. The same finding was observed in our study.The strong link between this histopathological subtype and increased metastatic potential as well as treatment resistance highlights the importance of incorporating this variable into therapeutic decision-making.

However, our finding that the acinar-predominant pattern also negatively affects survival is only partially supported by the literature and may be related to indirect factors. The significantly higher proportion of solid-predominant patterns among patients who received adjuvant therapy compared to those with acinar-predominant patterns may have contributed to the poorer-than-expected survival outcomes in the acinar-predominant group. In the study by Wart et al.^[11], it was found that patients with solid-predominant patterns responded significantly better to adjuvant therapy. This suggests that, in addition to tumor biology, patient-specific systemic factors may also influence prognosis.

In our study, a statistically significant association was observed between the CCI and 5-year survival, consistent with prior research. The CCI is a well-established scoring system that quantifies comorbidity burden and is widely used to predict long-term mortality.^[14] In this context, the study conducted by Birim et al.^[15] also reported that the CCI can serve as a significant predictive factor for survival in patients diagnosed with lung cancer. They found that survival decreased by 2.2-fold in patients with a CCI score ≥3. The study further indicated that individuals with higher CCI scores had markedly shorter survival times, which may be attributed not only to increased mortality from non-tumor-related causes due to comorbidities but also to the limitation of available oncological treatment options.^[15] Therefore, preoperative assessment of objective comorbidity scores such as the CCI can offer valuable guidance in determining individualized treatment strategies and refining prognostic assessments.

In our study, the presence of lymphatic invasion was identified as a strong negative prognostic factor. Lymphatic invasion indicates the tumor’s capacity for dissemination via lymphatic vessels and has been consistently associated with poor survival. In a study by Okiror et al.^[16] involving surgically treated NSCLC patients, lymphatic invasion was similarly linked to significantly worse survival HR (2.58). This finding suggests that lymphatic invasion serves not only as a marker of tumor aggressiveness but also as an independent prognostic factor.

Furthermore, the same study reported that patients with lymphatic invasion had a significantly higher likelihood of lymph node involvement (N positivity), which is consistent with our findings.^[16] This suggests that lymphatic invasion may serve as a predictive parameter for regional dissemination. Therefore, careful assessment of lymphatic invasion in surgical specimens may provide clinically valuable insights, both for prognostic evaluation and for guiding adjuvant treatment decisions.

Postoperative complications were also significantly associated with poorer survival in our study, in agreement with prior findings. In the study by Shinohara et al.,^[17] patients experiencing postoperative complications had significantly worse survival than those without complications. This supports the notion that postoperative complications may adversely affect not only short-term outcomes but also long-term survival.

This study has several limitations. First, due to its retrospective design, there is a potential risk of selection and information bias. Additionally, being conducted at a single center limits the generalizability of the findings. The relatively small sample size may have reduced the statistical power, particularly in subgroup analyses. Moreover, heterogeneity in adjuvant treatment protocols and follow-up durations may also have influenced the results. Despite these limitations, the findings of this study are considered to contribute meaningfully to the existing literature.

This study demonstrated that predominant histological patterns have a significant impact on survival in lung adenocarcinoma. The presence of a MP or acinar-predominant pattern was identified as a negative predictive factor. Additionally, male sex, lymphatic invasion, a higher CCI, and the occurrence of postoperative complications were also found to be adverse prognostic indicators. These findings suggest that relying solely on the TNM staging system may be insufficient for accurate survival prediction and oncological treatment planning. Therefore, these additional parameters should be incorporated into a comprehensive prognostic evaluation. Multicenter, large-scale, prospective, and meta-analytic studies are needed to further validate these results.

Ethics

Ethics Committee Approval: Ethical committee approval was obtained the University of Health Sciences Türkiye, Yedikule Chest Diseases and Thoracic Surgery Training and Research Hospital (approval number: 2023-399).

Informed Consent: Informed consent form was obtained from all patients.