Lung cancers are the leading cause of cancer-related deaths worldwide.¹ The most common type of lung cancer is adenocarcinoma (30%–50%). The incidence of lung adenocarcinomas is continually rising.²

Yesner and Carter³ long ago reported a 7% increase in lung adenocarcinomas, 4% decrease in squamous cell carcinoma, and a 3% decrease in small-cell cancers in second-decade male populations.

In 2011, it was reported that a total of 40% of lung cancers are adenocarcinomas; of the remaining lung cancers, 30% are squamous cell carcinomas, 20% are small-cell carcinomas, and 10% are large-cell carcinomas.⁴

Adenocarcinomas are heterogeneous in pathologic, clinical, radiologic, and surgical features and clinical prognosis. Adenocarcinomas were divided into 4 subtypes according to their predominant morphologic structure by the International Association for the Study of Lung Cancer (IASLC)/American Thoracic Society (ATS)/European Respiratory Society (ERS).⁴

1. Preinvasive lesions: atypical adenomatous hyperplasia; adenocarcinoma in situ (mixed, nonmucinous, mucinous)

2. Minimally invasive adenocarcinoma (nonmucinous, mucinous, mixed)

3. Invasive adenocarcinoma (lepidic, acinar, solid, papillary, micropapillary)

4. Variants (invasive mucinous, colloid, fetal, enteric)

According to the histologic classifications of adenocarcinomas according to dominant morphologic structure, the clinical prognoses of the subtypes are not clearly expressed in the literature. Providing the homogeneity within the subtypes with regard to clinical prognosis is important in approaches during presurgical, surgical, and postsurgical intervals.

Patients and Methods

Medical records were retrospectively assessed for adenocarcinoma patients between the years 2000 and 2010 who previously had neither preoperative neoadjuvant therapy nor adjuvant therapy and who had stages Ia, Ib, IIa, and IIb resection according to the revised seventh TNM classification. Between the years 2000 and 2010, resection was performed on 487 non–small-cell lung cancer patients, and 86 of these patients were found to have either stage I or II adenocarcinomas. Slides of the patients were reviewed and reevaluated according to the new histologic staging. Patients were evaluated according to age, sex, tumor size (T size), tumor localization, surgical procedure, subtypes, recurrence, and survival. Clinical outcomes were determined according to survival, disease-free survival, and recurrence period.

All patients underwent preoperative routine thorax–upper abdomen and brain computed tomography (CT), and bone scintigraphy. After clinical staging, endobronchial lesions were excluded via bronchoscopy in centrally located lesions. In patients with pathologic-size mediastinal lymphadenopathies in thorax positron emission tomography–CTs, N₂ was assessed from 3 to 4 mediastinal lymph node levels of upper and lower paratracheal, pretracheal, and anterior subcarinal nodes obtained by routine mediastinoscopy before resection.

During operation, 87.2% of the patients had lobectomies, a minimum of 3 to 4 lymph nodes were dissected from N₁ and N₂ stations for sampling, and median clinical follow-up was 4 years (range, 2–13.1 years).

Results

Adenocarcinoma subtypes were evaluated according to age, sex, localization, stage, size, nodal invasion, recurrence, and survival.

A total of 69.8% of the patients were older than 60 years, 83.7% were male, and 16.3% were female (Table 1).

Table 1  Clinical features and histologic distribution of the patients

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Histologically, 70 patients (81.4%) had invasive subtype, 11 patients (12.8%) had variant subtype, and 5 patients (5.8%) had preinvasive adenocarcinoma subtypes (Table 1).

1. Assessment of lung adenocarcinomas with regard to tumor localizations

A total of 57 of the adenocarcinomas (66.3%) were in the right hemithorax, and 29 (33.7%) were in the left hemithorax. There were no statistically significant differences with regard to right/left lung localization between adenocarcinoma histologic subtypes and invasive adenocarcinoma predominant subtypes. However, survival was found to be statistically longer in types with right hemithorax localization (P = 0.026; Table 2).

Table 2  Clinical-pathologic data influential on survival

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Invasive adenocarcinomas had a tendency to locate more in the superior lobe localizations compared with the other 2 subtypes, and this was found to be statistically significant (P = 0.008; Table 3). Although it was determined that superior lobe localization did not contribute to survival compared with other localizations, survival rate was significantly lower in left superior lobe lesions compared with right superior lobe lesions (P = 0.039; Table 2).

Table 3  Comparison of the invasive type with the other types

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2. Assessment of adenocarcinomas with regard to stage

In our series, 21 patients (24.4%) were stage Ia, 17 patients (19.8%) were stage Ib, 27 patients (31.4%) were stage IIa, and 21 patients (24.4%) were stage IIb. In 13 patients with stage II there was N₁ and in 4 patients there was 1 lymph node invasion, 3 patients had 2 invasions, and 2 patients had 4 to 5 invasions.

There was a statistically significant difference between the disease-free survival intervals of stages Ia and Ib (log-rank, P = 0.030; Table 2).

Stage Ia comprised a patient group that included 5 patients with preinvasive adenocarcinoma, 14 patients with invasive adenocarcinoma (2 lepidic, 5 acinar, 2 papillary, and 5 solid), and 2 patients with variant-type adenocarcinoma.

Stage Ib comprised 14 patients with invasive adenocarcinoma (1 lepidic, 6 acinar, 1 micropapillary, and 6 solid) and 3 patients with variant-type adenocarcinoma.

There was a statistically significant difference between the disease-free survival intervals of stages IIa and IIb as well (log-rank, P = 0.040; Table 2). The stage IIa group had 24 patients with invasive adenocarcinoma (14 acinar, 1 papillary, and 9 solid) and 3 patients with variant type. Stage IIb had 18 patients with invasive adenocarcinoma (2 lepidic, 8 acinar, 7 solid, and 1 micropapillary) and 3 patients with variant type.

Our series was classified according to the seventh TNM classification, and when the disease-free survival rates between stages Ia-Ib-IIa and IIb were compared it was seen that stage IIb had the shortest survival period and the difference was statistically significant (Table 2 and Fig. 1).

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There were no statistically significant differences between stages Ib and IIa when disease-free survivals were compared (log-rank, P = 0.4; data not shown).

3. Assessment of T size of adenocarcinoma cases

In 29 cases (33.7%) tumor sizes were ≥3 cm and <5 cm, in 21 cases (24.4%) tumor sizes were ≥2 cm and <3 cm, in 16 cases (18.6%) tumor sizes were ≥5 cm and <7 cm, and in 11 cases (12.8%) tumor sizes were ≤2 cm.

Of the adenocarcinomas, tumor size was smaller than 3 cm for 51 cases (59.3%), and 35 cases (40.7%) were larger than 3 cm. Tumor necrosis, lymph node invasion (N₁), and peritumoral lymphatic invasion were all found to be statistically higher in tumors larger than 3 cm (P = 0.003/0.039/0.04; Table 4).

Table 4  Comparison of the adenocarcinomas with T size more and less than 3 cm

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When cases with T size larger than 3 cm were compared with cases with a T size smaller than 3 cm, recurrence rate was found to be significantly higher (P = 0.001). Five-year disease-free survival rate was 54.9% in tumors larger than 3 cm, whereas it was 88.2% in tumors smaller than 3 cm (log-rank, P = 0.006; Table 4).

In invasive adenocarcinomas and solid predominant subtypes, T size was larger than 3 cm in most cases, and this ratio was found to be significantly high (P = 0.047/0.020; data not shown).

Assessment of peritumoral lymphovascular invasion

It was observed that peritumoral lymphovascular invasion affects disease-free survival. When 27 patients (31.4%) with lymphovascular invasion and 59 patients (68.6%) with no reports of lymphovascular invasion were compared with regard to disease-free survival, survival rate was found to be 51.9% in the group with lymphovascular invasion and 75.9% in the group without the invasion (log-rank, P = 0.018; Table 2 and Fig. 2). Recurrence rate was calculated to be significantly higher in the group with lymphovascular invasion (P = 0.014). A total of 13 of the 27 patients with lymphovascular invasion had N₁, whereas none of the 59 patients without lymphovascular invasion had N₁ (P = 0.000).

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Discussion

A total of 86 patients who underwent resection and systematic lymph node dissection because of stages I and II adenocarcinoma were separated into types and stages according to the seventh TNM classification and new lung adenocarcinoma histomorphologic classification. Five-year survival following resection in the preinvasive type was 100% and in accordance with literature data.⁵

In our series, adenocarcinoma types known as mixed adenocarcinomas were overly composed in number, but because the mixed types were considered to be an invasive adenocarcinoma group according to the new classification, our series ended up including mostly invasive adenocarcinomas.

In tumors larger than 3 cm, peritumoral lymphovascular invasion, lymph node involvement, recurrence rate, and necrosis rate were all higher compared with tumors smaller than 3 cm. It has been observed that a T size exceeding 3 cm is a marker of poor prognosis. In the literature, the number of reports dealing with tumors exceeding 3 cm is limited.

In the invasive adenocarcinoma type and especially in the solid predominant type, the tumor size was larger than 3 cm compared with other types. Rate of necrosis is significantly higher in solid invasive types compared with other types. Current literature data accept the presence of necrosis as a sign of poor prognosis, along with recurrence rate.⁶

In our series, necrosis did not have a significant effect on overall survival and disease-free survival. Solid predominant invasive type was assigned to the high-grade malignant potential group in the literature.^5,7–11

In our series, it was seen that malignity criteria and aggressivity were high in cases with a tumor size larger than 3 cm. Solid-type tumors had more necrosis and were mostly tumors exceeding 3 cm. Survival was also shorter in solid predominant type compared with other types. Taking all of these observations and the literature data into account, solid predominant type was assessed to be a high-grade invasive adenocarcinoma.

There were a lot of studies that reported a 5-year survival rate of close to 100% in the lepidic predominant type.^15,19–21 In our study, because the survival ratio of lepidic predominant invasive type was high, it was accepted as the type with the least malignant aggressivity potential.

Necrosis rate was statistically low in acinar predominant type compared with all other invasive predominant types, and the tumor size was not larger than 3 cm in these tumors, unlike in solid types. The survival rate was between 65.6% and 69%. For these reasons, this type of tumor was evaluated as predominant invasive type with moderate malignant aggressivity.

The number of papillary predominant invasive type was limited ın our study, and there was no reliable survival analysis. However, there are many reports in the literature that describe papillary predominant type as an adenocarcinoma with moderate malignant aggressivity.^6,16 Kadota et al¹⁶ have calculated the maximum standardized uptake values in a fluorodeoxyglucose–positron emission tomography study of 222 adenocarcinoma cases with stage I disease. From the highest to the lowest values, they were defined in this particular order: solid, micropapillary, acinar, papillary, lepidic, and predominant invasive adenocarcinoma types. The authors have stated that the relationship between histologic type and recurrence rate was correlated. Our clinical-pathologic data seem to be parallel (solid-acinar–lepidic) with the study data of Kadota et al.¹⁶

In our study group the number of micropapillary predominant invasive type was limited; therefore, a reliable survival analysis was not performed for this entity. In the literature, micropapillary predominant type is reported as predominant invasive tumor with high malignant aggressivity.^12,17–21

In another study, these tumors were classified into 3 grades depending on their clinical behavior and prognosis. Lepidic type was accepted as grade 1, acinar and papillary types were grade 2, and solid and micropapillary types were assessed to be grade 3.⁶ In our series, acinar predominant invasive type was statistically more prevalent in males. This finding is contrary to previous literature data. Male sex, along with solid predominant type, was regarded as a bad prognosis factor in some studies.⁷

Invasive adenocarcinomas tend to be in the superior lobes compared with the 2 other types, and the difference is statistically significant. Superior lobe localization did not have any impact on survival when survival rates for other localizations were taken into account. However, mortality rate was found to be significantly higher in adenocarcinomas with left hemithorax localization.

In invasive adenocarcinomas with stages I and II, the recurrence rate was higher than the other types, and the survival was lower in a significant fashion.

In our series, it was observed that peritumoral lymphovascular invasion had a negative effect on disease-free survival, in parallel with results of a study by Kato et al.²²

In a study conducted by Kato et al,²² the presence of angiolymphatic invasion was not found to have a major impact on patients with tumors larger than 3 cm, but angiolymphatic invasion was found to have a clinical impact in the same patient group if those patients also had accompanying pleural involvement. In our study group, peritumoral lymphovascular invasion was determined to be statistically higher in patients with tumors larger than 3 cm, contrary to the findings by Kato et al.²² On the other hand, peritumoral lymphovascular invasion was found to be significantly higher in patients with pleural involvement, similar to findings by Kato et al.²²

In the patient group with lymphovascular invasion, N₁ was found to be significantly high, and there were no patients with N₁ in the group without lymphovascular invasion. Presence of lymphovascular invasion in patients with pleural involvement and no pathologic lymph node involvement should lead the physician to think of the possibility of occult lymph node positivity. In such cases, early additional treatment plans should be considered.

There were no differences between invasive adenocarcinoma predominant types with regard to peritumoral lymphatic involvement.

Patients were staged according to the TNM classification revised by IASLC/ATS/ERS. In our series, it was determined that disease-free survival between stages Ia-Ib and IIa-IIb was different in a statistically significant fashion.

It is worth pointing out that disease-free survival was not homogeneous between stages I and II, but that there was not such a difference between stages Ib and IIa. In our series, disease-free survival rates between all stages (Ia-Ib–IIa-IIb) were evaluated with Kaplan-Meier and log-rank tests, and it was determined that survival ratio was significantly lower in stage IIb patients. The fact that these stages had different survival periods within themselves and were actually heterogeneous in this aspect was attributed to the notion that adenocarcinomas had biologic heterogeneity.^7–9

The reasons that survival periods were long in stage Ia were that they had 5 preinvasive lesions, they had an absence of micropapillary type, and solid and acinar types had the same ratio within the stage.

Kadota et al¹⁶ and Goldstraw et al²³ have reported the survival percentage to be 73% in stage Ia patients and 58% in stage Ib patients. The reason that the survival rate was higher in stage Ia was attributed to the fact that early-stage adenocarcinomas showed biologic heterogeneity. It was pointed out that adjuvant therapy protocols had to be applied to this subset of patients in whom recurrences could be seen.

Limitations

As a retrospective study and one with a small sample size, limitations are inevitable. However, this study had the inherent limitations of all observational studies.

As a result, the new histologic classification of adenocarcinomas has been a step forward in identifying groups with homogeneous prognosis. However, when the heterogeneity of the adenocarcinomas is taken into account, the authors believe that more entities that will affect the prognosis, such as peritumoral lymphatic invasion, left hemithorax localization, and tumor necrosis rate, should be considered in TNM classification.