Lung cancer in patients with idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) was thought to be associated with increased risk of lung cancer on the basis of two reasons. Firstly, autopsy studies showed that lung cancer was found simultaneously in patients with IPF 1. Secondly, there were several epidemiological reports of increased incidence of lung cancer during the follow-up of IPF 2–6. Recently, Hubbard et al. 7 reported increased incidence of lung cancer in IPF patients compared to age- and sex-matched control population in a large population-based cohort study. However, not all studies have shown an increased risk of lung cancer in IPF 8, 9. Assuming that IPF is associated with an increased risk of lung cancer, the mechanism is not certain. Because cigarette smoking itself is also an independent risk factor for IPF 10, smoking can be a confounding factor for the association of both diseases. There may also be other confounding factors for both conditions, like unknown occupational or environmental exposure 11, 12. Another possibility is that fibrosis itself may contribute to the development of cancer. It was proposed that fibrosis might be involved in the carcinogenesis by the occurrence of atypical or dysplastic epithelial changes in pulmonary fibrosis which progressed to invasive malignancy 1, 13, 14. In that situation, the cancer will develop in the region not far from the area of major fibrosis. However, there is no study focusing on the location of the cancer in relation to the fibrotic lesion. Nowadays, the concordance of two lesions can be easily examined by chest computed tomography (CT). Also, it may be helpful to know whether the histological types of the cancer in IPF are different from the cancer without fibrosis. This study was performed to investigate whether the fibrosis is directly related to cancer development by the analysis of the real concordance rate of the lesions on the chest CT, and to compare the histological types of lung cancer in 63 patients with lung cancer and IPF.

Material and methods

Results

Compared to the lone IPF patients, age, male sex, and proportion of smokers were significantly higher in IPF-CA by univariate (table 1⇓) and multivariate analysis (table 2⇓). Odds ratio of smoking for the development of lung cancer was 2.71. Furthermore, compared to the total lung cancer group, the age, male sex, and proportion of smokers were also significantly higher in IPF-CA (table 3⇓). In the IPF-CA group, squamous cell carcinoma was the most frequent cell type (35%), followed by adenocarcinoma, small cell carcinoma, and large cell carcinoma. In one double-primary cancer, both lesions (small cell and squamous cell carcinoma) were detected at the same time with IPF and located in the nonfibrotic area. There was no significant difference in the distribution of cell types between the total lung cancer group and IPF-CA group (table 3⇓). In contrast to previous reports, more cancers were found in the upper lung, i.e. 20 (31%) in right upper lobe, 13 (20%) in left upper lobe, 2 (3%) in right middle lobe, 19 (30%) in right lower lobe, and 8 (13%) in left lower lobe. Among the 63 IPF-CA, 40 patients (56%) had the cancers located in the periphery of the lung. In the peripheral lung cancer group, only 23 cancers (37% of all IPF-CA, 66% of peripheral cancer) showed as F-CA on the chest CT (table 4⇓). There was a higher tendency to develop adenocarcinoma (44%) in the F-CA compared to the NF-CA (23%) group, but the difference was not statistically significant (p=0.081). All the small cell carcinomas were located centrally and of the NF-CA type (table 4⇓). There were no significant differences in the stage of lung cancer, smoking history, age and sex between F-CA and NF-CA groups.

Discussion

The presented data show that despite the tendency for peripheral location of the cancer in IPF-CA, the real concordance rate of lung cancer with a fibrotic lesion in IPF was low (37%). Furthermore, the most frequent histological type of IPF-CA was squamous cell carcinoma, and age, male sex, and smoking were risk factors for lung cancer in IPF, similar to lung cancer in the general population.

In previous literature, IPF-CA was reported to be more frequent in the periphery of the lung and the lower lobe, where the fibrosis was predominant, suggesting a direct relationship 5, 6, 19. The peripheral location of the lung cancer was reported as 88% by Nagai and Chiyotani 5, 91% by Mizushima and Kobayashi 2 and 66% by Lee et al. 19. If fibrosis is directly related to the development of the cancer, cancer will develop inside or in close proximity to the area of major fibrosis. Having examined the real concordance of the cancer and the fibrosis by chest CT it was found that only 37% of lung cancers (66% of peripheral cancer) were located inside the fibrotic area. The frequency of the peripheral cancer in IPF-CA was 55% in the present study, which was lower than previously reported. The reason for this discrepancy was not certain, but there is a possibility that IPF was detected early by the cancer work-up (including chest CT) in this study's patients, especially in whom IPF was diagnosed at the same time as the cancer (concurrent detection group). In order to avoid bias, the frequency of peripheral and central cancer was compared between two groups (concurrent detection group and nonconcurrent detection group). No significant difference was found between these two groups (51% in concurrent group, 67% in nonconcurrent group), suggesting that the low frequency of peripheral cancer was not due to concurrent detection. Additionally, no significant differences were found in other parameters such as histological types, stage of the lung cancer or the concordance rate of cancer and fibrosis (33% in concurrent, 44% in nonconcurrent detection groups) between the two groups. Another possibility of bias was a misdiagnosis of usual interstitial pneumonia, because open or thoracoscopic lung biopsy was done in only one-third of the IPF patients. However, all of the patients had compatible clinical features and typical HRCT findings, which were proposed as diagnostic criteria of IPF without surgical lung biopsy by the American Thoracic Society/European Respiratory Society consensus statement 20.

There have been controversies on the most frequent cell types of the lung cancer in IPF-CA. Initially, adenocarcinoma was reported as the most frequent histological type, and some authors 6, 13 suggested that high frequency of adenocarcinoma in IPF-CA was related to the fibrotic scars. Other studies 3, 5, 19 however, showed that squamous cell carcinoma was the most frequent type. The presented study also found that squamous cell carcinoma was the most common type and the distribution of the histological types was similar to general lung cancer. The exception was small cell carcinoma, which is a central disease, and all the small cell carcinomas were located in the nonfibrotic area. Even though not statistically significant, there was a tendency for more adenocarcinoma in the F-CA group. However, this can be explained by the fact that adenocarcinoma is the most frequent cell type in peripheral lung cancers in general, and the fibrosis of IPF is characteristically present in the periphery of the lung.

Because smoking is a known risk factor for the development of IPF, it can be a serious confounding factor for IPF and lung cancer. Some of the previous studies have shown that smoking increased the risk of lung cancer even in patients with IPF 3, 5, 6. The presented data suggest that not only smoking, but also the male sex was a strong risk factor for lung cancer in patients with IPF. The odds ratio however, was unstable due to the small number of female patients with IPF-CA (only two patients). In Korea, smokers are predominantly male. According to the reports of the National Statistical Office of Korea in 1995, 62% of males were smokers compared to only 6% of females. Since most of the effect of male sex in the presented study may actually be due to smoking, this can explain the relatively low odds ratio for the smoking data (5.6 by univariate analysis and 2.71 by multivariate analysis). Other limitations in the present study include the following: total numbers of subjects were relatively small, and there is a possibility of incorrect information, because all the data were obtained from the medical records, even though the detailed smoking history was available for 98% of the subjects. The remote exposures to possible dusts which might cause both pulmonary fibrosis and lung cancer 10–12, an inherent limitation of all retrospective studies, could not be completely excluded in the subjects.

Despite these limitations, the results presented suggest that the features of lung cancer in idiopathic pulmonary fibrosis are similar to general lung cancer. However, further prospective controlled study using large numbers of pathologically proven idiopathic pulmonary fibrosis patients is required.