High-resolution computed tomography findings for patients with drug-induced pulmonary toxicity, with special reference to hypersensitivity pneumonitis-like patterns in gemcitabine-induced cases

Abstract

Background: Gemcitabine (GEM) is widely used as a chemotherapeutic agent. However, pulmonary toxicity has been rarely observed with GEM use. This article aims to determine the incidence and causes of drug-induced pulmonary toxicity, and to classify the high-resolution computed tomography (HRCT) findings for antitumor therapy-associated pulmonary toxicity based on characteristic patterns and pathological considerations, with a special focus on GEM-associated pulmonary toxicity (GAPT).

Methods: Medical records of all patients with drug-induced pulmonary toxicity seen at Kyorin University hospital between April 2006 and December 2011 were retrospectively reviewed. The study examined correlations between HRCT and the assessed pathological or clinical findings, with a specific focus on antitumor drugs.

Results: We identified 66 patients with drug-induced pulmonary toxicity. Among the antitumor drugs, GEM was the primary offending agent (n = 8) for pulmonary toxicity followed by docetaxel and gefitinib. HRCT patterns for the eight GAPT patients included the non-specific interstitial pneumonia (NSIP; n = 5) and the hypersensitivity pneumonitis (HP)-like pattern (n = 3). In contrast, four patients in the study were found to have the HP-like pattern, with three cases associated with GEM and one case associated with imatinib mesylate. The transbronchial lung biopsy or video-assisted thoracic surgery specimens for these patients showed granuloma or organizing tissue with a random distribution that was independent of the respiratory bronchiole. These results appeared to correspond to the HRCT-determined centrilobular nodules.

Conclusion: GEM was the leading cause of drug-induced pulmonary toxicity in the patients examined in this study. This toxicity appears as NSIP or an HP-like pattern during HRCT examinations. This HP-like pattern may be useful for diagnosing GEM-induced pulmonary toxicity, as well as demonstrating granuloma or organizing tissue during lung pathology examinations.

Figure 1.

Relevance between the total score of the affected lung area and the laboratory findings in patients with antitumor-associated pulmonary toxicity. Although serum C-reactive protein (CRP) and lactate dehydrogenase (LDH) appeared to have a positive coefficient of correlation, the results were not statistically significant (CRP: r = 0.44, p = .059, LDH: r = 0.427, p = .069). All other data exhibited no correlation with the total score. Abbreviations: A-aDO2, alveolar-arterial oxygen difference; Alb, albumin; CRP, C-reactive protein; KL-6, Krebs von den Lungen-6; LDH, lactate dehydrogenase; SP-D, surfactant protein-D.

Figure 2.

High-resolution computed tomography (HRCT) patterns for the 28 patients were classified into four patterns, which included (A) diffuse alveolar damage (case 12), (B) nonspecific interstitial pneumonia (case 5), (C) organizing pneumonia (case 27), and (D) hypersensitivity pneumonitis-like pattern (case 26). HRCT pattern definitions were as follows: (A): Diffuse hazy increased opacity of the lung, with preservation of bronchial and vascular margins. (B): Ground-glass opacities with reticulation, traction bronchiectasis, or bronchiolectasis, with little or no honeycombing. (C): Consolidation appears as a homogeneous increase in the pulmonary parenchymal attenuation that obscures the margins of the vessels and airway walls. (D): Random distribution of tiny centrilobular nodules.

Figure 3.

Transbronchial lung biopsy pathology evaluation in patients with the hypersensitivity pneumonitis-like pattern determined by high-resolution computed tomography. Staining by hematoxylin and eosin (A) or by Elastica-Masson (B) in case 1 demonstrated alveolar air spaces that were filled with an exudative fluid and which contained mild inflammatory cells with desquamated tracheal epithelial cells. In case 3, both hematoxylin and eosin (C) and the Elastica-Masson stain (D) showed exudative fluid in the alveolar air spaces, along with an abundant accumulation of alveolar macrophages.