Cancer may complicate the course of any interstitial lung disease, including idiopathic pulmonary fibrosis, sarcoidosis, progressive systemic sclerosis (scleroderma), Langer- hans cell granulomatosis, asbestosis, and tuberculosis. Nevertheless, how the previous injury in interstitial lung disease predisposes to lung cancer remains a mystery. Bron- chiolar and epithelial hyperplasia, undifferentiated scar, and cuboidal transformation of the alveolar epithelium may predispose to malignant transformation. Inflammation, injury, repair, and fibrosis in interstitial diseases may cause genetic damage leading to cancer.
Alveolar cell hyperplasia, related to chronic pulmonary damage, is found in both animals and men, being frequently seen in scleroderma and idiopathic pulmonary fibrosis. When malignant it is called alveolar cell carcinoma. Certain patients with pul- monary fibrosis, particularly those with scleroderma, have an increased incidence of lung cancer (Figure 37.1). A third of the patients with idiopathic pulmonary fibrosis may develop lung cancer (Figure 37.2a, b). The incidence tends to be lower in nonsmokers because smoking is a risk factor for the development of lung cancer in patients with pul- monary fibrosis. In this group of patients, lung carcinomas tend to be peripheral and in the lower lobes. Squamous cell carcinoma occurs in male patients, whereas adenocarci- noma predominates in females. The distribution of the histologic type of lung cancer in interstitial lung disease is similar to that found in lung cancer patients without pul- monary fibrosis; however, it is dissimilar to the distribution observed in scar carcinoma.
Finger clubbing is more common in patients with idiopathic pulmonary fibrosis and lung cancer than in those with IPF but no lung cancer.
The pathogenetic mechanisms responsible for the development of lung cancer in patients with interstitial pulmonary fibrosis are not known. A chronic scar may cause localized lymphatic obstruction resulting in an increase of potential carcinogens. The local accumulation of cancerous substances may then induce hyperplasia of alveolar lining that, in turn, under the influence of genes, cytokines, and chemokines, may become the site of inflammation, destruction, fibrosis, disorganization, and malignant transformation of the alveolar lining. Genes p53 and p21 are overexpressed in the hyper- plastic bronchial and alveolar epithelial cells in patients with IPF and play a role in inhibiting cellular proliferation and promoting the repair of tissue injury. The chronic course of IPF may result in DNA damage that might lead to p53 mutations. The p53 muta- tion may be one of the reasons behind the high incidence of lung cancer in idiopathic pulmonary fibrosis patients.
Is there an increase in the incidence of lung cancer in patients with sarcoidosis? In a 10-year study of 2544 patients with pulmonary sarcoidosis, 48 developed malignant tumor, whereas only 33.8 cases were expected if sarcoidosis had the same rate as the general population. Romer et al. failed to demonstrate a high risk of malignancy and lymphoma in patients with sarcoidosis. Sarcoidosis patients develop breast cancer at the expected frequency. Because physical examination and mammograms are unable to dis- tinguish between sarcoidosis and malignancy, biopsy of all suspicious lesions in patients with sarcoidosis is recommended.
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Figure 37.1. The increased incidence of cancer in ILD is not limited only to IPF but also occurs in patients with systemic sclerosis (SSc). How previous injury in interstitial fibrosis predisposes to lung cancer remains a mystery. The bronchoscopy reveals precancer- ous mucosal lesions in a patient with SSc.
Figure 37.2. Lung cancer in a patient with idiopathic pulmonary fibrosis (IPF). Radiograph of the chest shows typical parenchymal lower lung changes of IPF with overall volume loss and no visible mass (a). CT of the chest shows a left lower lobe lung mass located peripherally and surrounded by subpleural parenchymal fibrosis, honeycomb change, and trac- tion bronchiectasis. The cytoanalysis revealed squamous cell carcinoma (b).
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Malignant disease may produce a local sarcoid reaction or mimic manifestations of systemic sarcoidosis. Testicular and renal cell carcinomas can cause hilar and mediasti- nal adenopathy. These sarcoid reaction or sarcoid-like granulomas may be found in regional lymph nodes draining a carcinoma or a lymphoma. Granulomas have also been found among the tumor cells at the site of the primary neoplasm; rarely, epithelioid cell granuloma may occur intermingled with the primary lung tumor. This occurs mostly in patients with adenocarcinoma. Sarcoid reactions may also occur in spleen in patients with gastric cancers. These local nonspecific “sarcoid” reactions should be distinguished from systemic sarcoidosis (Table 37.1).
Thus, we know neither the exact incidence of carcinoma complicating interstitial lung disease and sarcoidosis nor the reasons of such an association when present. The physi- cian, however, should remain alert to the possibility of carcinoma occurring in patients with diffuse interstitial lung disease. Once the diagnosis is entertained, it should be confirmed by obtaining a biopsy. An early diagnosis assures therapeutic success.
Various other malignancies have higher incidence in certain ILDs. For instance, malig- nant pleural mesothelioma is much more frequent in patients with asbestosis (Figure 37.3). When we contemplate the problem of ILD and malignancies, we have to mention that lymphangitic carcinomatosis has to be considered in differential diagnosis of ILDs (Figure 37.4a, b, c).
Figure 37.3. Malignant mesothelioma in a patient with asbestosis. The tumor spreads locally and grows along needle tracks. The scar due to diagnostic video-assisted thoracoscopy is seen. The thoracoscopic talc pleurodesis has also been performed.
Table 37.1. Differences between a nonspecific local sarcoid reaction and multisystem sarcoidosis.
Local Sarcoid Multisystem
Features Reaction Sarcoidosis
Organ involved One More than one
Age (years) Any 20–50
Chest x-ray Normal Abnormal in 90%
Delayed hypersensitivity Normal Depressed
Elevated serum ACE Less than 5% More than 60%
Kveim-Siltzbach test Negative Positive
BAL lymphocytosis Absent Present
Slit-lamp examination Normal Positive 15–20%
Hypercalcemia Absent Present in 13%
Gallium body scan Localized uptake Multisystem uptake ACE, angiotensin converting enzyme; BAL, bronchoalveolar lavage.
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Figure 37.4. Lymphangitic carcinomatosis by plain radiograph showing reticular pattern (Kerley B-lines) (a) and HRCT scanning showing the interlobular, septal thickening (b) in a patient with breast carcinoma. Nests of neoplastic cells fill perivascular lymphatics (c).
