Abstract

Methods: A total of 2,203 patients (1,977 males, 226 females; mean age 57.8±34.9 years; range 22 to 86 years) operated for non-small cell lung cancer in our hospital between January 2002 and January 2011 were retrospectively analyzed for pathological diagnosis, survival, and tumor staging.

Results: As a result of pathological analysis, the diagnosis of adenosquamous cancer was confirmed in 46 out of 2,203 (2.1%) patients. The median survival time was 53.6 months (range 21.1 to 68.2 months) for adenocarcinoma, 48.1 months (range 24.4 to 66.9 months) for squamous cell cancer, and 27.9 months (range 10.7 to 44.6 months) for ASCL (p=0.026). The median survival time was 21.6 months in the group of patients with predominating adenocarcinoma, 21.4 months in the group of patients with predominating squamous cell carcinoma, and 37.8 months in the group of patients with codominant cell lines (p=0.007).

Conclusion: In our study, the survival rate of ASCL patients was lower than that of patients with squamous cell carcinoma or adenocarcinoma. Further clinical studies are needed to investigate whether adjuvant chemoradiotherapy following surgical resection improves overall survival rates.

There are several clinical reports suggesting that both components of ASCL possess similar biological features and behavioral characteristics,[8,9] while various reports indicate that the survival in ASCL is much worse than adenocarcinoma and SCC, with a five-years cumulative survival rate between 0 and 25%.[1-6] Despite the available reports on ASCL in the literature, the survival and prognosis in this malignancy still remain largely undetermined.

In this single-center study, we aimed to investigate whether a significant difference exits between the survival rates of patients operated for ASCL and patients operated for adenocarcinoma or SCC.

Methods

Standard diagnostic workup for each patient included plain chest X-ray, thoracic computed tomography (CT), abdominal CT, and cranial magnetic resonance imaging until 2007; thereafter, positron emission tomography (PET)-CT replaced abdominal CT. Fiberoptic bronchoscopy was performed in all patients, combined with transthoracic fine-needle aspiration biopsy in selected cases. Until PET-CT became available for diagnostic and staging procedures, all of the patients underwent preoperative standard cervical mediastinoscopy. Thereafter, preoperative mediastinoscopy was only performed in those patients with a mediastinal lymphadenopathy greater than 1 cm in diameter radiologically, and/or carrying a high suspicion for malignancy. Patients who underwent R₀ (resection with no residual macroscopic or microscopic tumor) resection were included and systematic lymphadenectomy was performed in all of these subjects. All patients except with stage 1 disease received adjuvant chemotherapy in the postoperative period. Radiotheraphy was added to the treatment of patients with postoperative N₂ disease.

Patients were followed-up every three months in the first year and every six months thereafter. The followups lasted until 2013 and the Turkish Republic Civil Registry Office database was utilized for patients who did not come to the outpatient clinic.

The seventh staging system announced in 2009 by International Association for the Study of Lung Cancer was applied for the pathological staging,[10] while histopathological type was identified according to the recommendations of the WHO in 2004.[7]

Statistical analysis
Statistical Package for the Social Sciences for Windows version 15.0 software program (SPSS Inc., Chicago, IL, USA) was utilized for the statistical analysis. Kaplan-Meier test was performed for the survival analysis and Wilcoxon log-rank test for the comparison of the study groups. Maximum type 1 error was accepted as 0.05 and a p value of <0.05 was considered to be statistically significant. The distribution of data was addressed with a confidence interval (CI) of 95%.

Results

Table 1: Comparison of demographical distribution, stage, and survival characteristics between groups

The groups demonstrated a homogenous distribution in regard to sex and tumor stages (p=0.102 and p=0.089, respectively). Of the patients, 41.5% operated for adenocarcinoma had stage 1 disease, whereas this ratio was 18% and 24% for patients operated for SCC and ASLC, respectively. The median survival time was 53.6 months (95% CI, 21.1 to 68.2) for adenocarcinoma patients, 48.1 months (95% CI, 24.4 to 66.9) for SCC patients, and 27.9 months (95% CI, 10.7 to 44.6) for ASCL patients, revealing a statistically significant difference in survival among these groups (p=0.026). The Wilcoxon, Gehan-Breslow statistical analysis revealed that this finding was a direct result of the survival difference between patients with stage 1 and stage 2 diseases.

The analysis of survival rates according to the various stages of different histopathologies demonstrated a significant difference between patients with stage 1 (p=0.026) and stage 2 (p=0.041) adenocarcinoma, SCC, and ASCL. The survival rate of stage 3A disease was similar in all groups (p=0.109) (Table 2).

Table 2: Stage-dependent survival rates in each group

The histopathological subtype analysis of the cases diagnosed with adenosquamous cancer revealed 18 patients with predominating adenocarcinoma (39%), 12 cases with predominating SCC (26%), and 16 patients exhibiting balance in these cell lines. The median overall survival time was recorded as 21.6 months (95% CI, 17.7 to 24.1) in the group of patients with predominating adenocarcinoma, 21.4 (95% CI, 16.9 to 26.6) months in the group of patients with predominating SCC, and 37.8 (95% CI, 29.7 to 44.8) months in the group of patients with codominant cell lines (p=0.007).

Discussion

There are several reports in the literature indicating that the postoperative survival of patients with ASCL does not differ significantly from patients with other types of lung cancer.[4,11] Nevertheless, it is generally accepted that this specific subtype is worse than others in terms of postoperative prognosis and survival. A study by Naruke et al.[12] supporting this approach revealed a five-year survival rate of 36.7% following surgical intervention in patients with small cell carcinoma of the lung and 18.9% in patients with ASCL. In the same study, the tumor node metastasis staging was also reported to be higher in ASCL patients. Studies conducted on this topic mostly suffer from the limited availability of patient series and the uncertainty of data on the characteristics and prognosis of the tumor. Our study has also demonstrated a similar result and the survival rate of ASCL patients was lower than that of patients diagnosed with adenocarcinoma and SCC.

In a study with 2,160 patients who have undergone resection for primary lung carcinoma, 56 patients (2.6%) were diagnosed with ASCL and among the patients with stage 1 and 2 disease the ASCL survival rate was lower than that of adenocarcinoma and SCC.[13] In a similar study by Cooke et al.,[14] the overall survival rates of ASCL and SCC were lower than that of adenocarcinoma. The five-year survival rate for stage 1 tumors was reported as 62.0% for ASCL, 69.2% for SCC, and 73.2% for adenocarcinoma. The survival analysis in our study demonstrated a striking difference between adenocarcinoma, SCC and ASCL, among patients with stage 1 and stage 2 tumors. Although the adenocarcinoma survival rate was higher in stage 3A tumors, the difference between the study groups was not statistically significant (p=0.109).

One of the largest studies on ASCL was conducted by Gawrychowski et al.[1] with 96 patients. In this study, the comparison of five-year survival among stage 1A patients revealed no significant difference between adenocarcinoma and ASCL. Nevertheless, the survival rate of ASCL was significantly lower in other stages.

The main reason for the significantly lower survival rate in stage 1 and 2 ASCL patients is the relatively more aggressive behavior of the tumor in comparison to the squamous cell and adenocarcinoma subtypes. In stage 3A, the survival clearly drops in all patient groups.[2]

Owing to the rapid spread of the tumor in ASCL patients, the diagnosis usually takes place at an advanced stage. In our study, only 24% of the patients with an operable ASCL were diagnosed on stage 1. The difficulty of diagnosis at an early stage and the relatively higher rate of administration of adjuvant chemoradiotherapy were held responsible for the difference in survival of these patients.[15]

It is still indefinite why ASCL tends to behave more aggressively than other types of lung cancer. Due to the heterogenic nature of the tumor, the identification of pathological features is difficult. Several authors have reported that the behavioral pattern of ASCL resembles adenocarcinoma more than SCC.[16] Various other reports have suggested a similarity in behavioral pattern and biological features of both ASCL components.[8,9]

A study with multivariate analysis demonstrated better survival in the presence of a balance between both components of ASCL; the loss of balance was noted as the main reason for lower survival.[1] Similar to various other studies in the literature, the survival of ASCL patients with balanced histopathological features in our study were better than the survival of patients with predominating adenocarcinoma or SCC component. The reason for this significant difference is not clear. Nevertheless, according to this finding, adjuvant chemoradiotherapy might be regarded as a treatment choice even for stage 1 patients, if a histopathological predominance of either adenocarcinoma or SCC is detected.

The first limitation of our study was that patients with stage 1 tumors did not receive adjuvant therapy; thus the survival analysis does not cover the influence of a possible adjuvant therapy on patients. Another limitation was related to the fact that stage 3A comprises a rather heterogeneous group of tumors. The prevalence of ASCL is already quite low, thus stage 3A ASCL cases are very rarely encountered. This restriction also interferes with the application of a statistically convincing comparison of subgroups in stage 3A tumors.

In conclusion, the prognosis of ASCL was shown to be worse than SCC and adenocarcinoma, in accordance with various reports in the literature. This finding was especially pronounced in patients with stage 1 and stage 2 tumors. In these patient groups, new clinical studies are needed to investigate whether adjuvant chemoradiotherapy following surgical resection improves overall survival rates.

Declaration of conflicting interests
The authors declared no conflicts of interest with respect to the authorship and/or publication of this article.

Funding
The authors received no financial support for the research and/or authorship of this article.

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