Cardiopulmonary Imaging Original Research

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1 Cardiopulmonary Imaging Original Research Song et al. CT After Stem Cell Transplant Cardiopulmonary Imaging Original Research Inyoung Song 1 Chin A Yi 1 Joungho Han 2 Dong Hwan Kim 3 Kyung Soo Lee 1 Tae Sung Kim 1 Myung Jin Chung 1 Song I, Yi CA, Han J, et al. Keywords: bronchiolitis obliterans, graft-versus-host disease, hematopoietic stem cell transplant, lung disease DOI: /AJR Received May 5, 2011; accepted after revision January 20, Department of Radiology and Center for Imaging Science, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50, Ilwon-dong, Gangnam-gu, Seoul , Korea. Address correspondence to C. A. Yi (cayi@skku.edu). 2 Department of Pathology of Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea. 3 Department of Medical Oncology and Hematology, Princess Margaret Hospital, University of Toronto, Toronto, ON, Canada. AJR 2012; 199: X/12/ American Roentgen Ray Society CT Findings of Late-Onset Noninfectious Pulmonary Complications in Patients With Pathologically Proven Graft-Versus- Host Disease After Allogeneic Stem Cell Transplant OBJECTIVE. We retrospectively analyzed the CT features of late-onset noninfectious pulmonary complications in patients with pathologically proven graft-versus-host disease (GVHD) after allogeneic stem cell transplant (SCT). MATERIALS AND METHODS. We analyzed the CT features of late-onset noninfectious pulmonary complications in 14 patients with pathologic diagnoses of GVHD who survived disease free for more than 3 months after SCT. Late-onset noninfectious pulmonary complications were diagnosed by excluding pulmonary infection in these patients with respiratory symptoms and signs. The presence, extent, and distribution of CT features were evaluated in terms of geographic hypoattenuation, expiratory airtrapping, ground-glass attenuation (GGA), reticulation, crazy paving pattern, bronchiectasis, nodules, and honeycombing. Further disease classification was made on the basis of clinical, radiologic, and pulmonary function test results and histologic findings. The longitudinal changes of late-onset noninfectious pulmonary complications were followed with CT. RESULTS. The 14 patients with late-onset were classified into subgroups with bronchiolitis obliterans (BO) (n = 7), nonclassifiable interstitial pneumonia (n = 5), and combined BO and nonclassifiable interstitial pneumonia (n = 2). The CT features of nonclassifiable interstitial pneumonia were GGA (5/7, 71%), reticulation (4/7, 57%), and crazy paving pattern (4/7, 57%) with a peribronchovascular distribution (6/7, 86%). All patients with nonclassifiable interstitial pneumonia had progression of disease with an increased extent of traction bronchiectasis, reticulation, and honeycombing on follow-up CT scans (median follow-up period, 22 months). CONCLUSION. Although not commonly encountered, nonclassifiable interstitial pneumonia as a pattern of chronic GVHD should be included in the differential diagnosis of unexplained peribronchial GGA or progressive traction bronchiectasis after SCT. T he widespread use of prophylactic antibiotics and various techniques to monitor infections has helped to decrease infectious complications in patients who undergo allogeneic stem cell transplant (SCT). However, clinically significant pulmonary complications occur in 40 60% of patients who undergo allogeneic SCT, and these complications cause 10 40% of all transplant-related deaths [1 5]. Pulmonary complications can be categorized as infectious and noninfectious according to cause and can be categorized as early and late by lapse of time after SCT. Late-onset noninfectious pulmonary complications include noninfectious pulmonary complications that occur more than 3 months after allogeneic SCT. They are now recognized as life-threatening complications because of the relative difficulty in diagnosis and treatment compared with infectious complications, the diagnosis and management of which have improved markedly [6, 7]. The pathophysiology of late-onset noninfectious pulmonary complications is not clearly understood, but graft-versus-host disease (GVHD) is inextricably linked with these complications. Chronic GVHD has proved to be the only important risk factor for the development of lateonset, and most patients with these complications have responded to treatment with corticosteroids and immunosuppressive drugs [6, 8]. Late-onset encompass a number of entities. Palmas et al. [7] proposed that these complications include bronchiolitis obliterans (BO), BO with organizing pneumonia (BOOP), diffuse alveolar damage (DAD), lympho- AJR:199, September

2 Song et al. cytic interstitial pneumonia, and nonclassifiable interstitial pneumonia. Afessa et al. [9] categorized late-onset noninfectious pulmonary complications as BO, BOOP, and idiopathic pneumonia syndrome. Although these subgroup diagnoses were made on the basis of clinical, radiologic, and pulmonary function test (PFT) results and histologic findings, pulmonary histologic confirmation is rarely performed for SCT patients, and clinical diagnoses are usually based on chest CT findings and PFT results [7, 9, 10]. To our knowledge, the CT features of lateonset in correlation with histologic findings have not been described. Although individual CT features of BO have been reported as areas of mosaic attenuation with expiratory airtrapping and BOOP as peribronchial consolidations [11 15], nonclassifiable interstitial pneumonia has not been systematically reviewed for CT features, and longitudinal changes have not been described, to our knowledge. In this study we describe the results of a retrospective analysis of the CT features of late-onset in patients with pathologically proven GVHD after allogeneic SCT so that the diagnosis can be made earlier and appropriate treatment chosen for these complications. Materials and Methods Patients and Criteria for Late-Onset Noninfectious Pulmonary Complications Between 1998 and 2008, the cases of 146 patients with a histologic diagnosis of GVHD after allogeneic SCT were identified by review of the medical records at our institution. GVHD was pathologically proved on the basis of the histologic findings from specimens obtained from the skin (n = 79), gastrointestinal tract (n = 43), liver (n = 18), and lung (n = 6). All cases of GVHD were confirmed by experienced pathologists. Ten patients who did not survive more than 3 months after allogeneic SCT were excluded from the study. Among the 136 patients (83 men, 53 woman; mean age, 33.1 ± 16.6 years), 67 patients underwent chest CT because of clinical or radiologic signs and symptoms of lung disease or abnormal results of PFTs. Routine PFTs were performed before SCT and when the patients had the clinical or radiologic signs and symptoms of lung disease 3 months after SCT. Standard culture and staining methods for bacterial, viral, and fungal pathogens were used to test the sputum, and bronchoalveolar lavage (n = 27), transbronchial lung (n = 15), percutaneous fine-needle aspiration (n = 2), and videoassisted thoracic surgical (n = 10) biopsy were performed to exclude pulmonary infection. Late-onset were confirmed in 14 patients (10 male patients, four female patients; mean age, 34.6 ± 15.9 years) by exclusion of pulmonary infection. The median time for the diagnosis of late-onset noninfectious pulmonary complications was 309 days after SCT (range, days). Once late-onset noninfectious pulmonary complications were identified, subclassification into BO and nonclassifiable interstitial pneumonia was performed on the basis of the clinical, radiologic, PFT, and histologic findings. BO was diagnosed in seven patients with the obstructive pattern of PFTs or any CT findings of geographic low attenuation or expiratory airtrapping. Nonclassifiable interstitial pneumonia was diagnosed in five patients with a restrictive pattern of PFT or an interstitial pattern on CT scans. Two patients had a combined obstructive and restrictive pattern of PFT and combined CT features of BO and nonclassifiable interstitial pneumonia. All five patients with nonclassifiable interstitial pneumonia and one patient with BO underwent lung biopsy, but six diagnoses of BO and two diagnoses of the combined pattern of BO and nonclassifiable interstitial pneumonia were based on the clinical, radiologic, and PFT findings. The ethical review boards of the institutions that contributed cases to this study did not require approval or informed consent from the subjects for a retrospective review of the patient records and images. Types of Transplant, Prophylaxis, and Treatment of Graft-Versus-Host Disease The demographic features of the patients are summarized in Table 1. The assessment and grading of acute and chronic GVHD was primarily based on the clinical findings and followed the commonly accepted diagnostic criteria [16, 17]. It was classified as limited (only localized skin or liver involvement) or extensive (generalized skin involvement or limited disease plus involvement of other organs). Extensive chronic GVHD was diagnosed on a clinical basis, supported by results from hematopoietic and chemical parameters, skin and liver biopsy findings, and a Shirmer test result. Patients with late-onset noninfectious pulmonary complications did not have a specific predominance in transplant source, conditioning regimen, GVHD prophylaxis, or history of acute GVHD, but most of the late-onset noninfectious pulmonary complications were diagnosed in patients with chronic extensive GVHD (93%, 13/14). Acquisition and Review of Thin-Section CT Images Thin-section CT images were obtained at endinspiration and end-expiration. A variety of CT scanners were used. The scanning protocol consisted of reconstruction of 1- to 3-mm collimation sections with a high-spatial-frequency algorithm at 1- or 2-cm intervals. Images were displayed at a PACS workstation with window settings appropriate for viewing the lung parenchyma (level, 600 to 700 HU; width, HU). Two radiologists blinded to the clinical and histologic information reviewed the images in consensus for evidence of late-onset noninfectious pulmonary complications. The observers evaluated the presence, extent, and distribution of the CT findings suggestive of late-onset noninfectious pulmonary complications in terms of geographic hypoattenuation, expiratory airtrapping, ground-glass attenuation (GGA), reticulation, crazy paving pattern, bronchiectasis, nodules, and honeycombing, as defined by the Fleischner Society Glossary of terms [18]. The lungs were divided into four zones (the upper and lower zones of each lung) to determine the extent of lung involvement of these findings. The upper zone was defined as the part of the lung above the level of the hilum; the lower zone was defined as the part of the lung below the level of the hilum. A score was assigned on the basis of the percentage of lung parenchyma with evidence of an abnormality, and this percentage was estimated to the nearest 10% of the parenchymal involvement in each lung zone. The overall percentage of involvement was calculated by averaging the scores of the four lung zones. The distribution was classified as being predominantly in the upper lung zone, lower lung zone, or random in the craniocaudal direction and as being predominantly subpleural, peribronchovascular, or random in the central to peripheral direction. Subpleural predominance was defined as findings that involved mainly the outer third of the lung. Peribronchovascular predominance was defined as findings located mainly around the bronchus and pulmonary arteries. Follow-up CT scans were obtained for all 14 patients with late-onset noninfectious pulmonary complications. The follow-up CT scans were used to evaluate changes in symptoms, and the CT protocols were the same as for the initial examination. The reviewers analyzed changes in the CT findings evaluated on the initial CT scans. Results High-Resolution CT Findings The CT findings of BO (n = 9) were geographic hypoattenuation (n = 9, 100%) and airtrapping (n = 5, 56%) with a subpleural predominance (n = 8, 89%) (Table 2). Three of the nine patients with BO had an increased extent of geographic hypoattenuation involving more than half of both lungs on follow-up CT scans. The median follow-up period was 22 months (range, months). 582 AJR:199, September 2012

3 CT After Stem Cell Transplant TABLE 1: Demographic Features of Patients With Late-Onset Noninfectious Pulmonary Complications (n = 14) Who Had Respiratory Symptoms or Signs 3 Months After Allogeneic Stem Cell Transplant Clinical Feature No. % Sex Male Female 4 29 Age (y) a 34.6 ± 15.9 (7 61) Diagnosis Acute myeloid leukemia 7 50 Acute lymphoblastic leukemia 2 14 Chronic myeloid leukemia 0 0 Myelodysplastic syndrome 1 7 Non-Hodgkin lymphoma 2 14 Hodgkin lymphoma 1 7 Aplastic anemia 0 0 Other 1 7 Transplant source Related donor Bone marrow 1 7 Peripheral blood stem cells 5 36 Unrelated donor Bone marrow 1 7 Peripheral blood stem cells 7 50 Cord blood 0 0 Conditioning regimen Total body irradiation, total lymphoid irradiation 6 43 Non total body irradiation and total lymphoid irradiation 8 57 GVHD prophylaxis Cyclosporin A with or without methotrexate 7 50 FK506 (tacrolimus) plus methotrexate 7 50 Acute GVHD Grade Grade Chronic GVHD None 1 7 Limited 0 0 Extensive Note GVHD = graft-versus-host disease. a Value is mean ± SD with range in parentheses. Nonclassifiable interstitial pneumonia (n = 7) was seen on CT scans as GGA (n = 5, 71%), reticulation (n = 4, 57%), and crazy paving pattern (n = 4, 57%) predominantly peribronchovascular in distribution (n = 6, 86%) (Table 3). In all patients with nonclassifiable interstitial pneumonia, the condition had progressed, evidenced at follow-up CT as increased extent of GGA, reticulation, crazy paving pattern, centrilobular nodules, and traction bronchiectasis. Traction bronchiectasis was seen in six of seven patients (86%) on initial CT scans and in all seven patients with nonclassifiable interstitial pneumonia on follow-up CT scans, and the extent of traction bronchiectasis had increased from a localized pattern to a diffuse pattern on follow-up images (Figs. 1 and 2). Honeycombing (n = 2, 29%) was seen on the follow-up images of patients with nonclassifiable interstitial pneumonia. The number of patients who had combined BO and nonclassifiable interstitial pneumonia had increased from two to five at follow-up. They had new or increased CT features of peribronchial GGA and traction bronchiectasis superimposed in the area of geographic hypoattenuation. They also had a combined obstructive and restrictive pattern of PFT results (Fig. 3). Lung Biopsies and Pulmonary Function Tests Lung biopsies (four transbronchial lung biopsies, two video-assisted thoracic surgical biopsies) were performed for six patients (one BO patient and five patients with nonclassifiable interstitial pneumonia). The pathologic findings of nonclassifiable interstitial pneumonia included bronchial wall thickening due to fibroblast proliferation with lymphocytic infiltration, denuded bronchiolar epithelium with regenerating atypical epithelial cells, or epithelial sloughing or total epithelial loss in the bronchioles associated with subepithelial fibroblast proliferation. These findings are compatible with GVHD [19, 20] (Fig. 4). The CT findings of peribronchial GGA and reticulation of nonclassifiable interstitial pneumonia correlated with areas of lymphoplasmacellular infiltration along the bronchioles and alveolar walls. Traction bronchiectasis on CT scans was seen as a consequence of peribronchial fibrosis and fibroblast at pathologic examination. Eleven patients with late-onset noninfectious pulmonary complications (five BO patients, four patients with nonclassifiable interstitial pneumonia, and two patients with the combined condition) underwent PFTs when lung disease developed. Four patients had an obstructive pattern, which was consistent with the criteria for BO. One patient with BO had a normal pattern at the onset of late-onset, but the ratio of forced expiratory volume in 1 second to forced vital capacity subsequently decreased to less than 70%. The PFT findings in the four patients with nonclassifiable interstitial pneumonia included restrictive change (three patients) and a normal range of findings (one patient). Two patients had a combined obstructive and restrictive pattern of PFTs. AJR:199, September

4 Song et al. Discussion In this study we systematically reviewed the CT findings of late-onset noninfectious pulmonary complications with a confirmed diagnosis of GVHD after allogeneic SCT. The term late-onset noninfectious pulmonary complication was first suggested by Palmas et al. [7] in 1998 to describe a lateonset pulmonary complication other than pulmonary infection that occurred more than 3 months after allogeneic SCT. Late-onset are a constellation of diagnoses that include BO, nonclassifiable interstitial pneumonia, BOOP, idiopathic pneumonia syndrome, and DAD [7, 9, 10, 21]. BO is a well-known pulmonary manifestation of chronic GVHD, and its CT features have been reported in some studies [11 13] to be geographic hypoattenuation and expiratory airtrapping, but other forms of late-onset noninfectious pulmonary complications were not reported about their CT features. In our study, the CT features of late-onset noninfectious pulmonary complications were subclassified as BO and nonclassifiable interstitial pneumonia. The CT features of BO were consistent with previous findings. Nonclassifiable interstitial pneumonia was characterized as having CT features of peribronchial GGA and reticulations, sometimes with a crazy paving pattern. Many of these lesions progressed with traction bronchiectasis and honeycombing on follow-up CT scans. The extent of lesion involvement had also increased from localized to diffuse involvement or from peribronchial to both peribronchial and subpleural lesions on follow-up CT scans. Although nonclassifiable interstitial pneumonia is not well known as a form of late-onset, the CT features were distinctive from those of BO and even atypical pneumonia. Knowledge of the CT features of nonclassifiable interstitial pneumonia may help radiologists make an earlier diagnosis of late-onset noninfectious pulmonary complications to guide earlier treatment. Other forms of these complications, such as BOOP and DAD, were not identified in our study. BOOP has not been consistently described as a form of late-onset noninfectious pulmonary complication and the incidence of BOOP is less than 2% [11, 21 23]. Therefore, the CT features might have been overlooked and regarded as nonclassifiable interstitial pneumonia in our study because the CT features of BOOP in immunocompromised patients who have undergone bone marrow TABLE 2: CT Features of Bronchiolitis Obliterans in Patients with Late-Onset Noninfectious Pulmonary Complications Bronchiolitis Obliterans (n = 9) Initial CT Follow-Up CT Geographic hypoattenuation (%) 9 (100) 9 (100) < > Airtrapping 5 (56) 4 (44) Craniocaudal distribution Upper 0 0 Lower 0 0 Random 9 9 Peripheral distribution Subpleural 8 8 Peribronchovascular 0 0 Random 1 1 Note Values are number of patients with percentages in parentheses. TABLE 3: CT Features of Interstitial Pneumonia in Patients with Late-Onset Noninfectious Pulmonary Complications Interstitial Pneumonia (n = 7) Initial CT Follow-Up CT Ground-glass attenuation (%) 5 (71) 6 (86) < > Reticulation (%) 4 (57) 6 (86) < > Crazy paving pattern (%) 4 (57) 5 (71) < > Centrilobular nodules 2 (29) 3 (43) Traction bronchiectasis 6 (86) 7 (100) Localized 5 2 Diffuse 1 5 Honeycombing 0 (0) 2 (29) Craniocaudal predominance Upper 2 3 Lower 2 1 Random 3 3 Peripheral distribution Peribronchovascular 4 3 Combined peribronchovascular and subpleural 2 4 Random 1 0 Note Values are number of patients with percentages in parentheses. 584 AJR:199, September 2012

5 CT After Stem Cell Transplant A Fig year-old man with liver graft-versus-host disease and dyspnea 6 months after allogeneic stem cell transplant for acute myeloid leukemia. A, Axial CT scan shows peribronchial ground-glass attenuation (GGA) (arrows). B, One-month follow-up CT scan shows progressed disease with increased extent of GGA and newly developed crazy paving pattern with reticulation. Also evident is progression of traction bronchiectasis (arrows). A C Fig year-old man with dyspnea and liver graft-versus-host disease after allogeneic stem cell transplant for acute myeloid leukemia. A, Initial axial CT scan shows peribronchial ground-glass attenuation and mild traction bronchiectasis. B, Photomicrograph of pathologic specimen obtained by video-assisted thoracic surgical biopsy shows findings of graft-versus-host disease with epithelial sloughing (arrow) and peribronchial fibrosis (arrowheads). C, Nine-month follow-up CT scan shows progressed disease with increased extent of reticulation and traction bronchiectasis, representing progressive fibrotic nature of interstitial pneumonia. B B AJR:199, September

6 Song et al. A B Fig year-old woman with dyspnea and abnormal pulmonary function test results and liver graft-versus-host disease after allogeneic stem cell transplant for non-hodgkin lymphoma. A, Axial CT scans show geographic hypoattenuation and airtrapping indicating bronchiolitis obliterans (BO). Small extent of peribronchial ground-glass attenuation (GGA) is evident in right middle lobe. B, Thirty-month follow-up CT scans show peribronchial GGA has increased in extent in right middle lobe and lingular division with new appearance of traction bronchiectasis (arrows), suggesting superimposed nonclassifiable interstitial pneumonia on underlying BO. Fig year-old man with liver graft-versus-host disease (GVHD) who underwent video-assisted thoracic surgical biopsy 7 months after allogeneic stem cell transplant for acute myeloid leukemia. Example of pathologic findings of lateonset. Photomicrograph shows widening of bronchial lumen (star) consistent with CT features of traction bronchiectasis. Bronchial walls are thickened with peribronchial fibroblast proliferation (straight arrows) and lymphocytic infiltration (arrowheads). Prominent feature of epithelial sloughing (curved arrows) is distinctive pathologic feature of GVHD. transplant were reported as GGAs and nodules in a more random distribution than is typical of peribronchial consolidations in immunocompetent hosts [22]. Some areas of DAD might have been combined with the area of GGA considered nonclassifiable interstitial pneumonia in our study. Chronic GVHD has been reported to be a major risk factor for the development of lateonset [7, 8, 10]. In our study, we retrospectively enrolled patients who had pathologically proven GVHD at any site. The incidence of late-onset in our GVHD patients was 10.3%, which overlaps with the incidence of 10 26% described in previous studies of patients who survived more than 3 months after allogeneic SCT regardless of proven GVHD [6, 7, 10, 21, 23, 24]. It is known that GVHD is initiated by activation of host T cells followed by donor T-cell activation in recognition of recipient alloantigens, so that various kinds of inflammatory cells release cytokines such as tumor necrosis factor α and interleukin 1, resulting in local tissue injury [25]. The pathologic features of epithelial sloughing and lymphocytic infiltration of the bronchial epithelium may reflect the pathogenesis of GVHD. In addition, varying degrees of fibrosis were present in areas of epithelial injury in our patients with lateonset who underwent video-assisted thoracic surgical biopsy. CT findings of peribronchial GGA and reticulation in nonclassifiable interstitial pneumonia correlated with areas of lymphoplasma cell infiltration along the bronchiolar and alveolar walls at pathologic examination, and traction bronchiectasis might have been a consequence of peribronchial fibrosis after epithelial injury at pathologic examination. Our study had several limitations. First, selection bias might have been involved owing to the retrospective enrollment of patients. Second, the CT protocols were not unified owing to the various section thicknesses. Third, some of our patients lacked pathologic results. Last, when evaluating follow-up images, the readers knew the initial CT findings. Conclusion It is important to differentiate late-onset noninfectious pulmonary complications from other pulmonary complications and to differentiate 586 AJR:199, September 2012

7 CT After Stem Cell Transplant the pattern of nonclassifiable interstitial pneumonia from the pattern of BO in patients with late-onset because BO has generally exhibited resistance to therapy and a progressive outcome, whereas patients with nonclassifiable interstitial pneumonia have often responded well to immunosuppressive treatment, especially in the early phase. We have reported the results of a single-center study on the radiologic findings, incidence, pathologic findings, and outcome of late-onset in patients with GVHD after allogeneic SCT. These complications are an important cause of posttransplant morbidity and mortality. Late-onset noninfectious pulmonary complications manifest themselves with characteristic CT features of BO and nonclassifiable interstitial pneumonia. Although the CT features of BO are well known, the CT features of nonclassifiable interstitial pneumonia have been rarely reported. 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