In our case, general histological findings of indium lung, such as emphysema and fibrosis with deposition of particles and cholesterol granulomas, were observed throughout the patient’s lung. In particular, a characteristic histological feature of our case was a mixture of severe distal acinar emphysema and UIP-like patterns, including honeycomb changes. Nakano et al. reported an indium lung patient who had a smoking history and underwent bilateral LTX eight years after the nine-year ITO exposure ended [6, 7]. That patient’s lung also showed severe emphysema and interstitial fibrosis, including fibroblastic foci [6]. They described panlobular cystic changes in the emphysematous area but did not mention the subtype of emphysema and a histological pattern of the fibrosis in the report. Therefore, severe emphysema and fibrosis might be common histological features of indium lung, especially with long-term history, but to elucidate more precise histological features of long-term indium lung, including the subtype of emphysema and the pattern of interstitial fibrosis, further accumulation of cases is needed. The exact mechanism of pathogenesis of distal acinar emphysema remains unclear, but the connection between the pleura and the alveoli may be fragile due to the low distribution of capillaries and elastic fibres [8]. Neutrophilic inflammation is reported to be significantly associated with distal acinar emphysema in chronic obstructive pulmonary disease patients [9]. Indium can activate the NLR family pyrin domain containing 3 inflammasome, which might induce persistent neutrophilic inflammation [10, 11]. Hence, indium could cause persistent neutrophilic inflammation, which might damage the connection between the pleura and the alveoli and result in distal acinar emphysema. In our case, a UIP-like pattern was observed with/without peribronchial involvement. Asbestosis, a famous occupational lung disease showing a UIP pattern, was once believed to start in the respiratory bronchiole and gradually extend outwards to the peripheral lobules, but now a UIP pattern in asbestosis is known to occur regardless of the degree of peribronchial fibrosis [12]. Further examinations are needed to elucidate the pathogenesis of a UIP-like pattern and distal acinar emphysema in the indium lung.
Cummings et al. reported two cases of indium lung that showed pulmonary alveolar proteinosis (PAP) [13]. In a review of 10 cases of indium lung, diagnoses of interstitial lung disease (ILD) were made 4–13 years after the first exposure, and those of PAP were made 1–2 years after the first exposure [14]. Only one case of PAP had serum GM-CSF autoantibody. Cholesterol is a well-known component of pulmonary surfactant, but interestingly, cholesterol clefts were pathologically observed in both indium lung patients with/without PAP. In the surveillance of ITO workers in Japan, localized PAP-like findings were observed, but elevations in serum GM-CSF autoantibodies were undetected [15]. In animal models, PAP is a common feature caused by exposure to ITO. PAP appeared in the early phase after exposure of rats to indium [10, 11]. PAP and acute inflammation were followed by lung fibrosis and emphysema, and the severity of these lesions worsened in a dose- and time-dependent manner [10]. However, autoantibodies against GM-CSF were undetected in the indium treatment group [11]. Therefore, PAP might appear in the very early phase of indium lung in a manner independent of GM-CSF antibodies. In our case, we detected little surfactant in the entrapped airspace, but the surface of the cholesterol clefts was positive for SP-A, which might indicate that the cholesterol clefts were derived from surfactants. In a case report of autoimmune PAP with fibrosis, the fibrotic area contained less surfactant than other areas [16]. Therefore, our case may have presented PAP before the first VATs.
Previous reports using animal models demonstrated that ITO particles resided and injured the lung tissue for weeks or months, and only a small amount of ITO was transferred to other organs [17, 18]. There are few reports about the long-term influence of ITO on humans. Amata et al. showed that high levels of indium exposure were related to progressive emphysematous changes through examinations of 84 workers from 2002 to 2010 [19]. They also reported that the biological half-life of serum indium in humans was estimated to be 8.09 years. ITO is now considered to be a risk factor for lung cancer because an ex-ITO worker without a smoking history was diagnosed with primary lung cancer 17 years after the exposure stopped [5]. Recently, surveillance of a cohort with low-dose exposure to asbestos revealed that it was a risk factor for interstitial lung abnormalities. In the cohort with interstitial lung abnormalities, the median estimated cumulative asbestos exposure was 0.7 fibre/mL-year, and the mean time since first asbestos exposure was 53.5 years [19]. In our case, the decline in respiratory function clinically progressed approximately 20 years after exposure to ITO ended. Pathologically, emphysema and fibrosis significantly progressed, and cholesterol granulomas increased in the recipient lung of LTX compared to VATS specimens. Particles containing In and Sn remained deposited in the recipient lung tissue of our case and the case of the previous report [7]. Therefore, ITO may reside in the lung for a long time and continue to injure the tissue, which may result in a progressive decline in respiratory function. In this case, the patient-derived left lung remained, and it needed to be monitored for further development of emphysema, interstitial pneumonia, pneumothorax, and lung cancer. Asymptomatic workers with a history of exposure to ITO also need regular medical follow-ups.
We herein first reported the histopathology of an indium lung without smoking history, which progressed 20 years after cessation of exposure. The lung tissue showed severe subpleural destruction, such as distal acinar emphysema and honeycomb changes. These histological findings might contribute to the histological evaluation of the severity of indium lung. Because of the progressive nature of indium lung, careful follow-up is recommended for workers exposed to ITO even if they are asymptomatic.