Adenocarcinomatous-predominant subtype associated with a better prognosis in adenosquamous lung carcinoma

Adenosquamous Carcinoma (ASC) is an uncommon type of lung cancer, accounting for 0.4–4% of all lung carcinomas [1, 2]. According to the 2015 WHO lung tumor classification criteria, it is defined as “a carcinoma showing components of both squamous cell carcinoma (SCC) and adenocarcinoma (AC), with each comprising to at least 10% of the tumor” [3]. However, ASC lung tumors were much more complex than simple mixes of AC and SCC components which were classified as intermediate between the AC and SCC when classifying the histological subtypes using genetic or molecular method [4]. ASC was reported to have more aggressive behavior and worse prognosis than “pure” AC and SCC with more frequent lymph-node metastasis at diagnosis [5].

Morphological features of AC and SCC were well described, AC being with acinar, lepidic, micropapillary, or papillary structures while SCC with identifiable keratinization, pearl formation, and/or intercellular bridges [3]. According to the proportion of glandular and squamous components, ASC could be divided into AC and SCC predominant subtypes. A few study reported that predominant subtype to be associated with prognosis of ASC [6, 7]. However, due to its rarity, no definitive clinical conclusion have been reached and to the best of our knowledge, there has been no report regarding radiologic findings of ASC with different predominant subtypes. Therefore, in this study we further explored the impact of different subtypes on the clinical features, radiologic findings and prognosis characteristics of ASC.

As far as we could establish, this is the first study to investigate the clinical, radiographic as well as prognostic characteristics of patients with the two different pathological subtypes of ASC. Our findings observed that: (1) ASC tended to have clinical characteristics of both adenocarcinoma and squamous cell carcinoma with poorer prognosis; (2) ASC could be divided into AC-predominant and SCC-predominant according to pathological subtypes, AC-predominant ASC were more commonly presented with air bronchogram and were with a better prognosis than SCC-predominant ASC; (3) Peripheral location of ASC served as an independent good prognostic factor.

Similar to previous reports, ASC tended to have the clinical characteristics of both adenocarcinoma and squamous cell carcinoma. On the one hand, imaging examination showed that most of the tumors were peripherally located, consistent with the characteristics of adenocarcinoma; On the other hand, most of the patients were males and smokers in their sixth decade of life, similar to squamous cell carcinoma. In this study, 73.5% (50/68) of the patients presented with peripherally located tumor, 67.6% (46/68) of the patients had a history of smoking, and the most common group was male smokers about 60 years old, which was consistent with previous studies [7, 9]. Our study also confirmed the invasive biological behavior of of ASC. The 3- and 5-year survival rates (53.5% at 3 years and 25.6% at 5 years) of all patients with stage I,II,IIIA were lower than those with AC or SCC. Even in Stage I and after complete surgical removal, the 5-year survival rate was only 33.6%. These were consistent with other reports [5, 10]: Maeda H [10] reported that the 5-year survival rates for all stage (I,II,IIIA) cases were 23.3% for ASC, 58.0% for AC (p < 0.0001), and 40.8% for SCC (p < 0.0001). The invasive biological behavior of ASC was also demonstrated by the high percentage of lymph node metastasis. We observed 50 (73.5%) of the 68 tumors had lymph node metastasis (N1 ~ 2).

To determine whether the predominant component affect clinical and radiographic characteristics, ASC cases were subdivided according to the predominance of AC or SCC, and differences between groups were evaluated. In our study, no significant differences were found between the two groups in age, gender, smoking history, CEA level and TNM stage. When it comes to CT findings in the subgroups, no literature has been reported. Here, we reported for the first time that AC-predominant ASC were more commonly presented with air bronchogram, which might be explained by previous report that the prevalence of air bronchograms on CT could predict the invasiveness of lung adenocarcinoma [11] since air bronchogram sign was formed when tumor cells lined the alveolar walls and alveolar septa, spreaded from one lobule to another through lymphatic, airways or direct infiltration, leaving the bronchi patent with mucosa intact [12]. This finding suggested that air bronchogram might be one of the predictive marker of AC-predominant ASC. When it is difficult for patients to take re-biopsy or when the biopsy specimens are insufficient for further pathological examination, the CT findings might be helpful in the differential diagnosis for pathological types, which may affect subsequent treatment.

Previous studies on the prognosis of ASC based on the proportion of adenomatous or squamous components have shown conflicting results. Takamori [13], Shimizu [14] and Filosso PL [15] suggested that the amount of adenocarcinoma component did not affect the survival rate, although the histological features of metastatic lymph nodes were to some extent affected by the histological type of the primary tumor. However, Gawrychowski [9], Mordant [16] and Zhao H [6] observed that patients who maintained a balance between the two ASC histological components had a better prognosis than those with one predominant component. These conflicting results may be due to the low incidence of ASC and the different pathological grouping criteria, for example some studies divided ASC to 3 groups with the cutoff of 40 and 60% components [6, 9], others divided ASC to 2 or 3 groups with the cutoff of 50% components [13, 15, 16], so definitive clinical conclusions can only be reached through more prospective multicenter studies. In our present study, multivariate analysis using the Cox’s proportional hazards model adjusted for age, gender, smoking status and tumor stage revealed that structural components (P = 0.022) was significantly correlated with prognosis. Patients with AC-predominant ASC had a better prognosis than with SCC-predominant ASC (median OS time 35 months vs. 24 months and 5-year OS rates 25.6% vs. 5.6%). Previous studies have shown that the squamous cell and adenocarcinomatous components might be derived from the same cells [17], and then monoclonal squamous cell carcinoma transformed to adenocarcinoma in ASC [18]. And we hypothesized that AC-predominant ASC might be in a later, better-differentiated phase in this transition and thus be with a better prognosis. However, recent data suggested that Asian pulmonary ASC might originate from adenocarcinoma and that squamous cell carcinoma components might be transformed from adenocarcinoma components [19]. Thus, further research is needed to explore this issue.

Few reports have described the relationship between CT findings and prognosis of ASC. Lee Y [20] evaluated 26 patients with ASC and found that the central ASC was larger than the peripheral ASC but except for tumor size, they found no significant difference in pathology, FDG PET, and survival data. Watanabe Y [7] analyzed 52 patients with ASC and reported that CT findings of inflammatory changes surrounding the tumor rather than tumor location (peripheral or central) were strong predictors of poor prognosis. Interestingly, they did find that centrally located ASC tended to have more inflammatory changes surrounding the tumor. In this study with the largest population focused on CT findings of ASC, we found that peripheral location of ASC served as an independent good prognostic factor (P = 0.009). Further research is needed to explore the differences between the central and peripheral ASC and why peripheral location predicts better survival.

There are several limitations in our study such as the limited number of patients with ASC, the retrospective design, different chemotherapy regiments, and unknown driver gene mutation status, which might influence the prognosis data [21, 22]. Therefore, further studies are warranted.

In conclusion, our study showed that the two different pathological subtypes of ASC were with different radiologic findings and prognosis characteristics. AC-predominant ASC were more commonly presented with air bronchogram, and were with a better prognosis than SCC-predominant ASC. Studies with a much larger sample size and longer duration of follow-up are still necessary to confirm these results.