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Histologic reconstruction of bronchiolar lesions in lung transplant patients with bronchiolitis obliterans syndrome.

To the Editor: In lung transplantation, bronchiolitis obliterans syndrome (BOS), which is thought to represent chronic airway rejection, is the major limiting factor for long-term graft survival. It is defined as a progressive irreversible airflow obstruction graded in 5 stages on the basis of its severity. According to International Society of Heart and Lung Transplantation registry, the incidence of BOS is 9.5%, 38.9%, and 61.6% at 1 year, 5 years, and 10 years, respectively.2 The underlying histologic lesion is constrictive bronchiolitis with submucosal deposition of fibrous tissue in bronchioles resulting in narrowing of their lumen.3,4 In the more advanced forms, it leads to scarred areas that may be easily overlooked.3,4 Of particular importance, these changes are reported to be patchy, and consequently the diagnosis can be missed if the lung is inadequately sampled. Up to now, no obvious explanation has been proposed in the literature to gain insights into the apparent discrepancy between the number of involved bronchioles on histologic sections and the severity of respiratory function impairment. We have made the assumption that bronchiolar stenotic lesions may be segmental. To test this hypothesis, we have analyzed serial sections of lung tissue samples from patients who have developed BOS. Among the 514 patients who underwent lung transplantation in Foch hospital between 1988 and 2012, 10 underwent bilateral retransplantation for BOS. Of them, 3 were excluded because of pathologic confounding conditions or insufficient histologic material. Two patients with BOS in whom an autopsy had been performed were added to the study. Overall, the lung samples of 9 patients (5 male and 4 female patients aged 23 to 66 y) with BOS stage III (mean FEV1 35% of predicted) formed the basis of the present study. None of the patients included in the present study had concomitant restrictive allograft syndrome. All tissue samples were fixed in 10% formalin and were routinely processed. Five tissue samples retrieved from the archives were included in conventional cassettes (40 26 7mm), whereas the 4 others were included in megacassettes (70 50 15mm) designed to provide a larger tissue section. For each case, a paraffin block was selected, and serial sectioning was performed to obtain 4-mm-thick sections until the block was exhausted. Every 100 mm, a section was stained by hematoxylin and eosin for examination. A total of 50 to 100 sections per case were collected. Thus, the whole thickness of the examined tissue ranged approximately from 5 to 10mm. Light microscopic examination showed that the airway lesions mainly involved terminal bronchioles and larger bronchioles, whereas respiratory bronchioles (characterized by interspersed alveoli in their walls) were spared. In 4 of 9 cases, we also observed that the lesions extended into small bronchi. The airway lesions consisted of a fibrous and inflammatory process responsible for partial to complete luminal narrowing (Fig. 1). Although the ratio inflammation to fibrosis varied from one case to another, fibrosis predominated over inflammation in general. The inflammatory infiltrate was mild to moderate and mainly consisted of lymphocytes, plasma cells, and macrophages. However, we observed in 1 case, in addition to fibrous bronchiolar stenosis, occlusion of bronchioles related to the accumulation of numerous foamy macrophages in the lumen. The percentage of stenotic bronchioles ranged from 19% to 54% (mean 39%). Analysis of serial sections revealed that the narrowing of the airways was segmental (Figs. 2A, B). The stenoses measured about 0.5 to 10mm in length. Multilevel stenoses of the airways were not found. In summary, the present study demonstrates the segmental pattern of bronchiolar obstruction involving terminal bronchioles, whereas respiratory bronchioles remain intact in lung recipients with BOS. Using microcomputed tomography of isolated lung samples, very similar results have been obtained by Verleden et al5 that have been presented at the