- Email: [email protected]
Radiologic and Functional Analysis of Compensatory Lung Growth After Living-Donor Lobectomy
Radiologic and Functional Analysis of Compensatory Lung Growth After Living-Donor Lobectomy Kei Shikuma, MD, Toyofumi F. Chen-Yoshikawa, MD, PhD, Tsuyoshi Oguma, MD, PhD, Takeshi Kubo, MD, PhD, Keiji Ohata, MD, Masatsugu Hamaji, MD, PhD, Atsushi Kawaguchi, PhD, Hideki Motoyama, MD, PhD, Kyoko Hijiya, MD, PhD, Akihiro Aoyama, MD, PhD, Hisako Matsumoto, MD, PhD, Shigeo Muro, MD, PhD, and Hiroshi Date, MD, PhD Departments of Thoracic Surgery, Respiratory Medicine, and Diagnostic Imaging and Nuclear Medicine, Kyoto University Graduate School of Medicine, Kyoto; and Section of Clinical Cooperation System, Center for Comprehensive Community Medicine, Faculty of Medicine, Saga University, Saga, Japan
Background. Whether compensatory lung growth occurs in adult humans is controversial. The aim of this study was to confirm compensatory lung growth by analyzing ipsilateral residual lung after lower lobectomy in living lung transplant donors with quantitative and qualitative computed tomography assessments. Methods. Chest computed tomography and pulmonary function tests were performed in 31 eligible donors before and 1 year after donor lobectomy. Ipsilateral residual lung volume was measured with three-dimensional computed tomography volumetry. The computed tomographyestimated volumes of low, middle, and high attenuations in the lung were calculated. Assessment of the D value, a coefficient of the cumulative size distribution of lowdensity area clusters, was performed to evaluate the structural quality of the residual lung. Results. Postoperative pulmonary function test values were significantly larger than preoperative estimated
values. Although postoperative total volume, low attenuation volume, middle attenuation volume, and high attenuation volume of the ipsilateral residual lung were significantly larger than the preoperative volumes, with 50.2%, 50.0%, 41.5%, and 43.1% increase in the median values, respectively (all p < 0.0001), the differences in D values before and after donor lobectomy were not significant (p [ 0.848). The total volume of ipsilateral residual lung was increased by more than 600 mL (50%). Conclusions. The volume of ipsilateral residual lung increased, but its structural quality did not change before and after donor lobectomy. The existence of compensatory lung growth in adult humans was suggested by quantitative and qualitative computed tomography assessments.
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Various studies have reported radiologic increases in the volume of the residual lung and postoperative pulmonary functional restoration in lung cancer patients with heterogeneous backgrounds [6, 7]. In contrast to such studies, we previously reported functional restoration after lower lobe resection of living lung transplantation (LLT) donors who were considered homogeneous, healthy subjects by pulmonary function test (PFT) results, quantitative three-dimensional (3D) computed tomography (CT), and radiologic Hounsfield unit (HU) evaluations [8, 9]. In the present study, other CT imaging parameters, the percentile of low attenuation volume (%LAV) within the lung, and D-value assessments were used to evaluate the structural quality of the residual lung after lower lobectomy. Several reports noted that increased %LAV reflects the loss of lung tissue associated with emphysematous change [10, 11]. The cumulative size distribution of low attenuation area clusters follows a power law characterized by the exponent D [12]. The D-value measurement reflects the fractal dimension of terminal air space geometry and has also been widely
ompensatory lung growth (CLG) is defined by an absolute increase in the quantity of functioning lung tissue in response to injury or disease, or both [1]. Whether CLG occurs in adult humans and large mammals is still controversial. In particular, an experimental pneumonectomy model has been studied as a useful model of CLG because of advantages related to ease of defining loss of functional lung tissue and of evaluating the compensatory responses in the residual lung [2–4]. Increases in lung volume after lung resection in adult humans have been widely considered to be alveolar dilatation, not CLG [2]. However, Butler and colleagues [5] reported a case of lung regeneration in the contralateral residual lung after pneumonectomy in an adult patient.
Accepted for publication Sept 11, 2017. Address correspondence to Dr Date, Department of Thoracic Surgery, Kyoto University Graduate School of Medicine, 54 Kawaharacho, Shogoin, Sakyo-ku Kyoto 606-8507, Japan; email: [email protected].
Ó 2017 by The Society of Thoracic Surgeons Published by Elsevier Inc.
(Ann Thorac Surg 2017;-:-–-) Ó 2017 by The Society of Thoracic Surgeons
0003-4975/$36.00 https://doi.org/10.1016/j.athoracsur.2017.09.060
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SHIKUMA ET AL COMPENSATORY LUNG GROWTH AFTER LOBECTOMY
Abbreviations and Acronyms CLG CT DLCO
= compensatory lung growth = computed tomography = diffusing capacity of the lung for carbon monoxide FEV1 = forced expiratory volume in 1 second HAV = high attenuation volume HU = Hounsfield units L = lower lobe LAV = low attenuation volume LLT = living lung transplantation M = middle lobe MAV = middle attenuation volume PFT = pulmonary function test U = upper lobe VA = alveolar ventilation VC = vital capacity %HAV = percentile of high attenuation volume within the lung %LAV = percentile of low attenuation volume within the lung %MAV = percentile of middle attenuation volume within the lung 3D = three-dimensional
used for early emphysema detection [10–13] because the D value can sensitively detect alveolar tissue destruction and provide additional information about the morphologic features of emphysema [11–13]. The aim of this study was to evaluate the presence of CLG of the ipsilateral residual lung after lower lobectomy in LLT donors, which could be considered healthy and mature subjects, by PFTs and quantitative and qualitative CT assessments. In this study, PFTs and CT images were prospectively obtained at specified times, and CT images were analyzed retrospectively.
Material and Methods The Kyoto University Graduate School and Faculty of Medicine Ethics Committee approved this study (approval No. E 2336).
Donors From November 2010 to December 2012, 34 living donors (for 19 consecutive LLTs) were evaluated in our institute. The criteria for donor selection are reported elsewhere [9]. The living donors underwent chest CT before and 1 year after donor lobectomies. Included were 31 donors who underwent lower lobe resection and were monitored for 1 year; of these, 3 donors were excluded because thinslice CT images were not available before or after donor lobectomies. PFTs, including vital capacity (VC), forced expiratory volume in 1 second (FEV1), diffusing capacity of the lung for carbon monoxide (DLCO), and the ratio of DLCO to alveolar ventilation (DLCO/VA) were prospectively evaluated in enrolled donors before and after donor lobectomies. The estimated values for the PFTs (VC, FEV1,
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and DLCO) after lung resection were calculated from preoperative values, as previously reported [14]. In detail, there were 19 segments in total in a donor’s lungs, 5 segments in the right lower lobe, and 4 segments in the left lower lobe. Thus, to calculate the estimated postoperative PFT values, the preoperative PFT values for right-sided and left-sided lower lobectomy were multiplied by 14/19 and 15/19, respectively, taking into account the number of segments removed in a donor. In the present study, chest CT and PFT assessments of 31 donors who underwent right or left lower lobectomy and were monitored for 1 year were retrospectively reviewed using several quantitative and qualitative assessments. The requirement for informed consent from each donor was waived for the retrospective part of the study design. Informed consent was obtained from each donor before the prospective part of the study.
CT Image Analysis The CT images were analyzed retrospectively. Enrolled donors underwent noncontrast-enhanced chest CT (Aquilion 64; Toshiba Medical Systems, Tochigi, Japan). In addition to routine calibration using an air and water phantom, HU values of all images were corrected using tracheal air densities to eliminate the influence of X-ray tube aging, as previously reported [8, 11, 13]. The entire chest was scanned during one breath-hold with 0.5-mm collimation and a gantry rotation time of 500 ms, using automatic exposure control at 120 kVp. Thin-slice images (1 mm) were reconstructed with a lung kernel. The processes were supervised by a board-certified diagnostic radiologist (T.K). The acquired CT data were then analyzed by AZE Virtual Place (AZE Ltd, Tokyo, Japan), and the volume of ipsilateral residual lung (right upper and middle lobes of right-sided donors, or left upper lobe of left-sided donors) evaluated before and 1 year after donor lobectomies was calculated semiautomatically (Fig 1). Thresholds of –950 and –700 HU were applied to the acquired lung CT data according to previous reports [15]. The volume between each HU threshold range was automatically calculated. The volume under –951 HU was defined and calculated as LAV, between –701 and –950 HU volume was defined and calculated as middle attenuation volume (MAV), and–700 HU and over was defined and calculated as high attenuation volume (HAV; Fig 2). The percentile of each volume of the lung was defined as %LAV, %MAV, and %HAV. The values of %LAV, % MAV, and %HAV were compared before and after donor lobectomy. The D-value measurement is a power law analysis of a low attenuation area cluster [12, 16]. The size distribution of low attenuation area clusters follows a power law, and their analysis is useful for revealing the pattern of progression of emphysema [11–13]. The formula, Y ¼ K X–D, represents the concept of low attenuation area cluster analysis, with Y indicating the cumulative frequency distribution of low attenuation cluster size, K is the constant, and X is the low attenuation cluster size. Y can be described by a power law of X [12, 16]. The threshold of – 960 HU was used to detect low attenuation clusters,
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Fig 1. Ipsilateral residual lung volume was measured by three-dimensional computed tomography preoperatively and at 1 year after resection. Upper (U) and middle (M) lobes are stretched and fit in the thorax in the postoperative state. Representative images are shown. (L ¼ lower lobe.)
according to previous reports [11–13]. The values of D were obtained by linear regression and calculated as the slope of the straight line on log-log plots. The D value was examined by custom-made software, calculated as the average of all chest two-dimensional axial CT images, according to previous reports, and was compared before and after donor lobectomy.
Statistical Analysis Descriptive statistics for categoric variables are reported as frequencies and percentages, and continuous variables are reported as medians (25th to75th percentile), as appropriate. Not all data were normally distributed. Continuous variables were compared by the MannWhitney U test. All statistical tests were two-sided with p of less than 0.05 defined as significant. Statistical analyses were performed by JMP 11 software (SAS Institute Inc, Cary, NC).
Results Donor Characteristics and Outcomes The preoperative characteristics of the donors are summarized in Table 1. No donors showed significant findings on chest CT. None of the donors died. Postoperative complications were observed in 10 donors: prolonged pleural effusions in 7, pneumothorax in 2, prolonged air leakage for more
than 7 days in 1, and empyema in 1. All donors returned to normal life by 1 year after lobectomy. Preoperative PFTs of the donors are reported in Table 1. Postoperative PFT values of the donors were significantly higher than the values estimated from preoperative values based on the number of resected segments: estimated VC, 3,039 mL (2629 to 3,692 mL); FEV1, 2,487 mL (2,226 to 3,063 mL); and DLCO, 19.5 mL $ min–1 $ mm Hg–1 (15.6 to 23.2 19.5 mL $ min–1 $ mm Hg–1); postoperative values: VC, 3550 mL (2890 to 4230 mL; p < 0.0001); FEV1, 2910 mL (2,520 to 3,400 mL; p < 0.0001); and DLCO, 21.5 19.5 mL $ min–1 $ mm Hg–1 (17.1 to 24.2 19.5 mL $ min–1 $ mm Hg–1; p ¼ 0.006).
Ipsilateral Residual Lung CT Analysis Quantitative lung changes were examined by analyzing the total volume, LAV, MAV, and HAV of the ipsilateral residual lung estimated by 3D-CT in the preoperative and postoperative states. Significant differences were noted in the values of total volume, LAV, MAV, and HAV of the ipsilateral residual lung before and after the operation (all p < 0.0001; Table 2). Postoperative total volume of the ipsilateral residual lung measured by 3D-CT was increased by more than 600 mL (50%). Qualitative lung changes analyzed by %LAV, %MAV, % HAV, and D values of the ipsilateral residual lung estimated by 3D-CT in the preoperative and postoperative states. No significant differences were found in %LAV, % HAV, and D between before and after the operation
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Fig 2. A representative computed tomography (CT) imaging mapping of high attenuation volume (HAV), middle attenuation volume (MAV), and low attenuation volume (LAV). The green area shows the HAV area ( –700 Hounsfield units [HU]). The red area shows the MAV area ( –701 to –950 HU). The blue area shows the LAV area (< –951 HU). The percentiles of these volumes were measured as %HAV, %MAV, and %LAV on three-dimensional CT.
(Table 2). Although %MAV was significantly decreased (p ¼ 0.037) in the postoperative state, the difference in the median value was only 0.3% (Table 2). Representative images of the D-value analysis are shown in Figure 3.
Comment The present study found postoperative PFTs and ipsilateral residual lung volumes were significantly larger after donor lobectomy than the preoperatively estimated values; however, there were no differences in the D value before and after donor lobectomy. This result indicated that the volume of the ipsilateral residual lung increased considerably but that its structural quality did not change from before to after donor lobectomy. These findings supported the occurrence of CLG in adult humans. We previously reported the restoration of pulmonary function and radiologic lung volume after lobectomy in donors [8, 17]; however, we could not further investigate the possibility of CLG in that study because of the limitations of the analytic methods. Analysis of a lung biopsy specimen is one of the most reliable options to confirm structural change, such as CLG, in the residual lung of the donors, but it is not possible due to ethical issues. We therefore conducted the present study to confirm CLG by analyzing the ipsilateral residual lung after lower lobectomy with quantitative and qualitative CT assessments. Because of the severe donor shortage, LLT has become one of the viable options for the treatment of patients with end-stage respiratory diseases in Japan [17, 18]. Monitoring living donors after lobar resection is not only clinically important but also becomes promising research, because the changes after lobar resection in healthy subjects might be a suitable model to observe CLG after lung resection [2, 4]. Various studies have been reported to prove postoperative pulmonary functional restoration or radiologic enlargement of residual lung after lobectomy in lung cancer patients [6, 7]; however, such studies included
heterogeneous patients with a variety of backgrounds, including elderly patients with pulmonary complications. In contrast to those studies, the current study included a homogeneous cohort of healthy subjects, which might be more suitable for observing CLG after lung resection. Advances in radiologic technology, such as 3D-CT evaluations, have disclosed a variety of new findings in Table 1. Preoperative Clinical Features of the Enrolled Donors
Variables Age, y Sex Male Female Body mass index, kg/m2 Smoking history Never Former or current Smoking pack-years Lobectomy Left side Right side VC, mL %VC, % FEV1 , mL %FEV1, % DLCO, mL , min–1 , mm Hg–1 DLCO/VA , mL , min–1 , mm Hg–1
No. or Median (25th–75th percentile) (N ¼ 31) 38 (30–47) 20 11 23.9 (20.9–25.5) 19 12 10 (6.5–15.5)
3960 116.8 3370 103.9 26.0
13 18 (3450–4830) (101.5–122.3) (2820–4020) (94.4–111.9) (20.6–30.0)
5.38 (4.67–6.5)
DLCO ¼ diffusing capacity of the lung for carbon monoxide; DLCO/VA ¼ ratio of diffusing capacity of the lung for carbon monoxide to alveolar ventilation; FEV1 ¼ forced expiratory volume in 1 second; VC ¼ vital capacity; %VC and % FEV1 ¼ the percentage of the predicted values of VC and FEV1.
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Table 2. The Preoperative and Postoperative Imaging Variables of Ipsilateral Residual Lung Variablea Total lung volume, mL LAV, mL MAV, mL HAV, mL %LAV (%) %MAV (%) %HAV (%) Db
Preoperative (n ¼ 31) 1343 350 783 209 24.1 59.5 15.0 2.088
a Values are reported as medians (25th–75th percentile). clusters, which follows a power law.
HAV ¼ high attenuation volume;
(1,144–1,629) (264–405) (662–940) (184–232) (21.7–29.3) (56.6–62.9) (14.4–16.7) (1.958–2.373) b
Postoperative (n ¼ 31) 2017 525 1108 299 25.9 59.2 15.4 2.136
(1,604–2,342) (365–743) (937–1,326) (263–351) (20.9–35.1) (50.6–61.3) (14.1–16.6) (1.765–2.481)
p Value <0.0001 <0.0001 <0.0001 <0.0001 0.408 0.037 0.408 0.848
The value of D is the exponent of the cumulative size distribution of low attenuation area
LAV ¼ low attenuation volume;
lung diseases such as emphysema, lung cancer, and interstitial pneumonia [15, 19–22]. In particular, a stereologic imaging approach has become more prevalent to evaluate CLG to eliminate the bias of histologic sections, such as geometric shapes or shrinkage during tissue fixation of alveoli [2, 22]. In the present study, HUdependent volumetric and D-value assessments were used to evaluate the structural quality of the lung before and after the operation. The imaging value of %LAV, using thresholds of 950 HU to distinguish between normal lung and emphysematous lesions, is considered a standard index of emphysematous change that reflects pathologic lung destruction and hyperinflation [10]. Some reports noted that the imaging value of %HAV, using thresholds of 700 HU to distinguish between normal lung and interstitial lung disease lesions, is useful for characterization and quantification of interstitial lung disease lesions [15, 23]. In the present study, –700 and –950 HU thresholds, according to a previous report that noted their strong correlation to PFT, were used to evaluate the radiologic quality of the residual lung [15]. Power law analysis was developed to quantitatively describe the random variations in size and shape seen in natural objects, such as the distributions of the sizes of cities, earthquakes, solar flares, and moon craters [16].
MAV ¼ middle attenuation volume.
Mishima and colleagues [12] previously reported that low attenuation area cluster size and its cumulative size distributions follow a power law and that the D value, a coefficient of cumulative size distribution of low-density area clusters, is useful for showing the pattern of progression of emphysema. The concept of the D value, which is less affected by lung hyperinflation than %LAV, is now widely used to evaluate lung destruction [11–13]. An unchanged D value indicates that the fractal dimension of the terminal airspace in tissue structure is unchanged, whereas a decreased D value means an increased prevalence of large size, low attenuation clusters that indicate destruction of alveolar tissue [13]. Tanabe and colleagues [11] reported that the D value was significantly correlated with FEV1, %FEV1, and DLCO/VA in patients with emphysema [11]. Thus, this imaging variable is useful for qualitative assessment of the lung. CLG is defined by an absolute increase in the quantity of functioning lung tissue in response to injury or disease, or both [1]. The occurrence of CLG in adult humans or large mammals after lung resection remains controversial [2, 24]. Lungs possess a large amount of reserve capacity for exercise or resection. One of the explanations for this restoration after lung resection is the unfolding of alveolar epithelium that is not used before lung resection [2]. Thus, CLG should be distinguished from lung regeneration, Fig 3. Representative images are shown of the D value measured preoperatively and at 1 year postoperatively. The D-value measurement is a power law analysis of low attenuation area clusters. The D value was examined by custommade software and calculated as the average of all two-dimensional axial chest computed tomography images. Each of the colored areas indicates clusters of low attenuation areas. The images were obtained from the same donor.
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which means regeneration of alveoli and bronchi. However, Butler and colleagues [5] reported an instance of lung regeneration in an adult patient and suggested that regeneration of alveoli, rather than alveolar hyperexpansion alone, was occurring. The current study showed an increase of more than 40% in the volume of ipsilateral residual lung, although the D value did not change between preoperatively and postoperatively. These results indicated that neither lung destruction nor hyperinflation was observed, despite the volume increasing. However, whether unfolding of alveolar epithelium or regeneration of alveoli is responsible for this compensatory response in the present study is difficult to determine. Some reports mentioned that stretch or distension of the remaining lung after lung resection is considered the major factor in CLG, because intrathoracic negative pressure between the thorax and remaining lung creates chronic lung stress, which leads to alveolar hypoxia, microvascular perfusion, and hormone secretion [2, 3, 25]. As a limitation, the variable of %MAV was significantly decreased in the postoperative state; however, the difference in the median value was only 0.3%, and there were no differences in the other imaging indicators. This result could be induced by partial hyperexpansion related to patient backgrounds, such as smoking status or body mass index. Further studies, with more subjects, of the structural quality of the residual lung after lobectomy and the effects on postoperative PFTs in individual cases are needed. Histologic confirmation of structural change in the residual lung of the donors was not obtained. Whether regeneration of alveoli or remodeling is responsible for this compensatory response after lung resection remains unknown. Histologic and molecular biological confirmation is needed in clinical settings and animal models in the future. The analysis of the structure of terminal bronchioles by micro-CT or immune stains of epithelial, endothelial, and mesenchymal cells, which are assumed to participate in alveolar regeneration in the tissue samples in animal models, will be helpful for assessing CLG and lung regeneration in future research [26–28]. Alveolar tissue restoration is not clearly confirmed in patients with emphysema and pulmonary fibrosis but may offer a novel therapeutic approach for such lung diseases [27, 28]. This study did not demonstrate actual regeneration of the lung; however, if it were observed in the healthy human after lung resection, and if some factors related to restoration were identified, it would be helpful for patients with emphysema or pulmonary fibrosis in the future. In conclusion, the present study provided supportive evidence with quantitative and qualitative CT assessments for the occurrence of CLG in healthy adults, not in diseased lungs, after lobectomy.
References 1. Hsia CC. Quantitative morphology of compensatory lung growth. Eur Respir Rev 2006;15:148–56. 2. Paisley D, Bevan L, Choy KJ, Gross C. The pneumonectomy model of compensatory lung growth: insights into lung regeneration. Pharmacol Ther 2014;142:196–205.
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3. Hsia CC. Signals and mechanisms of compensatory lung growth. J Appl Physiol (1985) 2004;97:1992–8. 4. Thane K, Ingenito EP, Hoffman AM. Lung regeneration and translational implications of the postpneumonectomy model. Transl Res 2014;163:363–76. 5. Butler JP, Loring SH, Patz S, Tsuda A, Yablonskiy DA, Mentzer SJ. Evidence for adult lung growth in humans. N Engl J Med 2012;367:244–7. 6. Ohno Y, Koyama H, Nogami M, et al. Postoperative lung function in lung cancer patients: comparative analysis of predictive capability of MRI, CT, and SPECT. AJR Am J Roentgenol 2007;189:400–8. 7. Ueda K, Tanaka T, Hayashi M, et al. Compensation of pulmonary function after upper lobectomy versus lower lobectomy. J Thorac Cardiovasc Surg 2011;142:762–7. 8. Mizobuchi T, Chen F, Yoshino I, et al. Radiologic evaluation for volume and weight of remnant lung in living lung donors. J Thorac Cardiovasc Surg 2013;146:1253–8. 9. Chen F, Yamada T, Sato M, et al. Postoperative pulmonary function and complications in living-donor lobectomy. J Heart Lung Transplant 2015;34:1089–94. 10. Coxson HO, Mayo J, Lam S, Santyr G, Parraga G, Sin DD. New and current clinical imaging techniques to study chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2009;180:588–97. 11. Tanabe N, Muro S, Hirai T, et al. Impact of exacerbations on emphysema progression in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2011;183:1653–9. 12. Mishima M, Hirai T, Itoh H, et al. Complexity of terminal airspace geometry assessed by lung computed tomography in normal subjects and patients with chronic obstructive pulmonary disease. Proc Natl Acad Sci U S A 1999;96:8829–34. 13. Tanabe N, Muro S, Oguma T, et al. Computed tomography assessment of pharmacological lung volume reduction induced by bronchodilators in COPD. COPD 2012;9:401–8. 14. Chen F, Fujinaga T, Shoji T, et al. Outcomes and pulmonary function in living lobar lung transplant donors. Transpl Int 2012;25:153–7. 15. Shin KE, Chung MJ, Jung MP, Choe BK, Lee KS. Quantitative computed tomographic indexes in diffuse interstitial lung disease: correlation with physiologic tests and computed tomography visual scores. J Comput Assist Tomogr 2011;35:266–71. 16. Newman ME. Power laws, Pareto distributions and Zipf’s law. Contemp Physics 2005;46:323–51. 17. Chen F, Kubo T, Shoji T, Fujinaga T, Bando T, Date H. Comparison of pulmonary function test and computed tomography volumetry in living lung donors. J Heart Lung Transplant 2011;30:572–5. 18. Miyoshi R, Chen-Yoshikawa TF, Hijiya K, et al. Significance of single lung transplantation in the current situation of severe donor shortage in Japan. Gen Thorac Cardiovasc Surg 2016;64:93–7. 19. Horeweg N, van der Aalst CM, Thunnissen E, et al. Characteristics of lung cancers detected by computer tomography screening in the randomized NELSON trial. Am J Respir Crit Care Med 2013;187:848–54. 20. Park KJ, Bergin CJ, Clausen JL. Quantitation of emphysema with three-dimensional CT densitometry: comparison with two-dimensional analysis, visual emphysema scores, and pulmonary function test results. Radiology 1999;211:541–7. 21. Shikuma K, Menju T, Chen F, et al. Is volumetric 3-dimensional computed tomography useful to predict histological tumour invasiveness? Analysis of 211 lesions of cT1N0M0 lung adenocarcinoma. Interact Cardiovasc Thorac Surg 2016;22:831–8. 22. Hsia CC, Hyde DM, Ochs M, Weibel ER. ATS/ERS Joint Task Force on Quantitative Assessment of Lung Structure. An official research policy statement of the American Thoracic Society/European Respiratory Society: standards for quantitative assessment of lung structure. Am J Respir Crit Care Med 2010;181:394–418. 23. Salaffi F, Carotti M, Bosello S, et al. Computer-aided quantification of interstitial lung disease from high resolution
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computed tomography images in systemic sclerosis: correlation with visual reader-based score and physiologic tests. Biomed Res Int 2015;2015:834262. 24. Merkus PJ, ten Have-Opbroek AA, Quanjer PH. Human lung growth: a review. Pediatr Pulmonol 1996;21:383–97. 25. Ravikumar P, Yilmaz C, Bellotto DJ, Dane DM, Estrera AS, Hsia CC. Separating in vivo mechanical stimuli for postpneumonectomy compensation: imaging and ultrastructural assessment. J Appl Physiol (1985) 2013;114:961–70.
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26. Boon M, Verleden SE, Bosch B, et al. Morphometric analysis of explant lungs in cystic fibrosis. Am J Respir Crit Care Med 2016;193:516–26. 27. Plantier L, Boczkowski J, Crestani B. Defect of alveolar regeneration in pulmonary emphysema: role of lung fibroblasts. Int J Chron Obstruct Pulmon Dis 2007;2:463–9. 28. Beers MF, Morrisey EE. The three R’s of lung health and disease: repair, remodeling, and regeneration. J Clin Invest 2011;121:2065–73.
Background. Whether compensatory lung growth occurs in adult humans is controversial. The aim of this study was to confirm compensatory lung growth by analyzing ipsilateral residual lung after lower lobectomy in living lung transplant donors with quantitative and qualitative computed tomography assessments. Methods. Chest computed tomography and pulmonary function tests were performed in 31 eligible donors before and 1 year after donor lobectomy. Ipsilateral residual lung volume was measured with three-dimensional computed tomography volumetry. The computed tomographyestimated volumes of low, middle, and high attenuations in the lung were calculated. Assessment of the D value, a coefficient of the cumulative size distribution of lowdensity area clusters, was performed to evaluate the structural quality of the residual lung. Results. Postoperative pulmonary function test values were significantly larger than preoperative estimated
values. Although postoperative total volume, low attenuation volume, middle attenuation volume, and high attenuation volume of the ipsilateral residual lung were significantly larger than the preoperative volumes, with 50.2%, 50.0%, 41.5%, and 43.1% increase in the median values, respectively (all p < 0.0001), the differences in D values before and after donor lobectomy were not significant (p [ 0.848). The total volume of ipsilateral residual lung was increased by more than 600 mL (50%). Conclusions. The volume of ipsilateral residual lung increased, but its structural quality did not change before and after donor lobectomy. The existence of compensatory lung growth in adult humans was suggested by quantitative and qualitative computed tomography assessments.
C
Various studies have reported radiologic increases in the volume of the residual lung and postoperative pulmonary functional restoration in lung cancer patients with heterogeneous backgrounds [6, 7]. In contrast to such studies, we previously reported functional restoration after lower lobe resection of living lung transplantation (LLT) donors who were considered homogeneous, healthy subjects by pulmonary function test (PFT) results, quantitative three-dimensional (3D) computed tomography (CT), and radiologic Hounsfield unit (HU) evaluations [8, 9]. In the present study, other CT imaging parameters, the percentile of low attenuation volume (%LAV) within the lung, and D-value assessments were used to evaluate the structural quality of the residual lung after lower lobectomy. Several reports noted that increased %LAV reflects the loss of lung tissue associated with emphysematous change [10, 11]. The cumulative size distribution of low attenuation area clusters follows a power law characterized by the exponent D [12]. The D-value measurement reflects the fractal dimension of terminal air space geometry and has also been widely
ompensatory lung growth (CLG) is defined by an absolute increase in the quantity of functioning lung tissue in response to injury or disease, or both [1]. Whether CLG occurs in adult humans and large mammals is still controversial. In particular, an experimental pneumonectomy model has been studied as a useful model of CLG because of advantages related to ease of defining loss of functional lung tissue and of evaluating the compensatory responses in the residual lung [2–4]. Increases in lung volume after lung resection in adult humans have been widely considered to be alveolar dilatation, not CLG [2]. However, Butler and colleagues [5] reported a case of lung regeneration in the contralateral residual lung after pneumonectomy in an adult patient.
Accepted for publication Sept 11, 2017. Address correspondence to Dr Date, Department of Thoracic Surgery, Kyoto University Graduate School of Medicine, 54 Kawaharacho, Shogoin, Sakyo-ku Kyoto 606-8507, Japan; email: [email protected].
Ó 2017 by The Society of Thoracic Surgeons Published by Elsevier Inc.
(Ann Thorac Surg 2017;-:-–-) Ó 2017 by The Society of Thoracic Surgeons
0003-4975/$36.00 https://doi.org/10.1016/j.athoracsur.2017.09.060
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SHIKUMA ET AL COMPENSATORY LUNG GROWTH AFTER LOBECTOMY
Abbreviations and Acronyms CLG CT DLCO
= compensatory lung growth = computed tomography = diffusing capacity of the lung for carbon monoxide FEV1 = forced expiratory volume in 1 second HAV = high attenuation volume HU = Hounsfield units L = lower lobe LAV = low attenuation volume LLT = living lung transplantation M = middle lobe MAV = middle attenuation volume PFT = pulmonary function test U = upper lobe VA = alveolar ventilation VC = vital capacity %HAV = percentile of high attenuation volume within the lung %LAV = percentile of low attenuation volume within the lung %MAV = percentile of middle attenuation volume within the lung 3D = three-dimensional
used for early emphysema detection [10–13] because the D value can sensitively detect alveolar tissue destruction and provide additional information about the morphologic features of emphysema [11–13]. The aim of this study was to evaluate the presence of CLG of the ipsilateral residual lung after lower lobectomy in LLT donors, which could be considered healthy and mature subjects, by PFTs and quantitative and qualitative CT assessments. In this study, PFTs and CT images were prospectively obtained at specified times, and CT images were analyzed retrospectively.
Material and Methods The Kyoto University Graduate School and Faculty of Medicine Ethics Committee approved this study (approval No. E 2336).
Donors From November 2010 to December 2012, 34 living donors (for 19 consecutive LLTs) were evaluated in our institute. The criteria for donor selection are reported elsewhere [9]. The living donors underwent chest CT before and 1 year after donor lobectomies. Included were 31 donors who underwent lower lobe resection and were monitored for 1 year; of these, 3 donors were excluded because thinslice CT images were not available before or after donor lobectomies. PFTs, including vital capacity (VC), forced expiratory volume in 1 second (FEV1), diffusing capacity of the lung for carbon monoxide (DLCO), and the ratio of DLCO to alveolar ventilation (DLCO/VA) were prospectively evaluated in enrolled donors before and after donor lobectomies. The estimated values for the PFTs (VC, FEV1,
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and DLCO) after lung resection were calculated from preoperative values, as previously reported [14]. In detail, there were 19 segments in total in a donor’s lungs, 5 segments in the right lower lobe, and 4 segments in the left lower lobe. Thus, to calculate the estimated postoperative PFT values, the preoperative PFT values for right-sided and left-sided lower lobectomy were multiplied by 14/19 and 15/19, respectively, taking into account the number of segments removed in a donor. In the present study, chest CT and PFT assessments of 31 donors who underwent right or left lower lobectomy and were monitored for 1 year were retrospectively reviewed using several quantitative and qualitative assessments. The requirement for informed consent from each donor was waived for the retrospective part of the study design. Informed consent was obtained from each donor before the prospective part of the study.
CT Image Analysis The CT images were analyzed retrospectively. Enrolled donors underwent noncontrast-enhanced chest CT (Aquilion 64; Toshiba Medical Systems, Tochigi, Japan). In addition to routine calibration using an air and water phantom, HU values of all images were corrected using tracheal air densities to eliminate the influence of X-ray tube aging, as previously reported [8, 11, 13]. The entire chest was scanned during one breath-hold with 0.5-mm collimation and a gantry rotation time of 500 ms, using automatic exposure control at 120 kVp. Thin-slice images (1 mm) were reconstructed with a lung kernel. The processes were supervised by a board-certified diagnostic radiologist (T.K). The acquired CT data were then analyzed by AZE Virtual Place (AZE Ltd, Tokyo, Japan), and the volume of ipsilateral residual lung (right upper and middle lobes of right-sided donors, or left upper lobe of left-sided donors) evaluated before and 1 year after donor lobectomies was calculated semiautomatically (Fig 1). Thresholds of –950 and –700 HU were applied to the acquired lung CT data according to previous reports [15]. The volume between each HU threshold range was automatically calculated. The volume under –951 HU was defined and calculated as LAV, between –701 and –950 HU volume was defined and calculated as middle attenuation volume (MAV), and–700 HU and over was defined and calculated as high attenuation volume (HAV; Fig 2). The percentile of each volume of the lung was defined as %LAV, %MAV, and %HAV. The values of %LAV, % MAV, and %HAV were compared before and after donor lobectomy. The D-value measurement is a power law analysis of a low attenuation area cluster [12, 16]. The size distribution of low attenuation area clusters follows a power law, and their analysis is useful for revealing the pattern of progression of emphysema [11–13]. The formula, Y ¼ K X–D, represents the concept of low attenuation area cluster analysis, with Y indicating the cumulative frequency distribution of low attenuation cluster size, K is the constant, and X is the low attenuation cluster size. Y can be described by a power law of X [12, 16]. The threshold of – 960 HU was used to detect low attenuation clusters,
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Fig 1. Ipsilateral residual lung volume was measured by three-dimensional computed tomography preoperatively and at 1 year after resection. Upper (U) and middle (M) lobes are stretched and fit in the thorax in the postoperative state. Representative images are shown. (L ¼ lower lobe.)
according to previous reports [11–13]. The values of D were obtained by linear regression and calculated as the slope of the straight line on log-log plots. The D value was examined by custom-made software, calculated as the average of all chest two-dimensional axial CT images, according to previous reports, and was compared before and after donor lobectomy.
Statistical Analysis Descriptive statistics for categoric variables are reported as frequencies and percentages, and continuous variables are reported as medians (25th to75th percentile), as appropriate. Not all data were normally distributed. Continuous variables were compared by the MannWhitney U test. All statistical tests were two-sided with p of less than 0.05 defined as significant. Statistical analyses were performed by JMP 11 software (SAS Institute Inc, Cary, NC).
Results Donor Characteristics and Outcomes The preoperative characteristics of the donors are summarized in Table 1. No donors showed significant findings on chest CT. None of the donors died. Postoperative complications were observed in 10 donors: prolonged pleural effusions in 7, pneumothorax in 2, prolonged air leakage for more
than 7 days in 1, and empyema in 1. All donors returned to normal life by 1 year after lobectomy. Preoperative PFTs of the donors are reported in Table 1. Postoperative PFT values of the donors were significantly higher than the values estimated from preoperative values based on the number of resected segments: estimated VC, 3,039 mL (2629 to 3,692 mL); FEV1, 2,487 mL (2,226 to 3,063 mL); and DLCO, 19.5 mL $ min–1 $ mm Hg–1 (15.6 to 23.2 19.5 mL $ min–1 $ mm Hg–1); postoperative values: VC, 3550 mL (2890 to 4230 mL; p < 0.0001); FEV1, 2910 mL (2,520 to 3,400 mL; p < 0.0001); and DLCO, 21.5 19.5 mL $ min–1 $ mm Hg–1 (17.1 to 24.2 19.5 mL $ min–1 $ mm Hg–1; p ¼ 0.006).
Ipsilateral Residual Lung CT Analysis Quantitative lung changes were examined by analyzing the total volume, LAV, MAV, and HAV of the ipsilateral residual lung estimated by 3D-CT in the preoperative and postoperative states. Significant differences were noted in the values of total volume, LAV, MAV, and HAV of the ipsilateral residual lung before and after the operation (all p < 0.0001; Table 2). Postoperative total volume of the ipsilateral residual lung measured by 3D-CT was increased by more than 600 mL (50%). Qualitative lung changes analyzed by %LAV, %MAV, % HAV, and D values of the ipsilateral residual lung estimated by 3D-CT in the preoperative and postoperative states. No significant differences were found in %LAV, % HAV, and D between before and after the operation
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Fig 2. A representative computed tomography (CT) imaging mapping of high attenuation volume (HAV), middle attenuation volume (MAV), and low attenuation volume (LAV). The green area shows the HAV area ( –700 Hounsfield units [HU]). The red area shows the MAV area ( –701 to –950 HU). The blue area shows the LAV area (< –951 HU). The percentiles of these volumes were measured as %HAV, %MAV, and %LAV on three-dimensional CT.
(Table 2). Although %MAV was significantly decreased (p ¼ 0.037) in the postoperative state, the difference in the median value was only 0.3% (Table 2). Representative images of the D-value analysis are shown in Figure 3.
Comment The present study found postoperative PFTs and ipsilateral residual lung volumes were significantly larger after donor lobectomy than the preoperatively estimated values; however, there were no differences in the D value before and after donor lobectomy. This result indicated that the volume of the ipsilateral residual lung increased considerably but that its structural quality did not change from before to after donor lobectomy. These findings supported the occurrence of CLG in adult humans. We previously reported the restoration of pulmonary function and radiologic lung volume after lobectomy in donors [8, 17]; however, we could not further investigate the possibility of CLG in that study because of the limitations of the analytic methods. Analysis of a lung biopsy specimen is one of the most reliable options to confirm structural change, such as CLG, in the residual lung of the donors, but it is not possible due to ethical issues. We therefore conducted the present study to confirm CLG by analyzing the ipsilateral residual lung after lower lobectomy with quantitative and qualitative CT assessments. Because of the severe donor shortage, LLT has become one of the viable options for the treatment of patients with end-stage respiratory diseases in Japan [17, 18]. Monitoring living donors after lobar resection is not only clinically important but also becomes promising research, because the changes after lobar resection in healthy subjects might be a suitable model to observe CLG after lung resection [2, 4]. Various studies have been reported to prove postoperative pulmonary functional restoration or radiologic enlargement of residual lung after lobectomy in lung cancer patients [6, 7]; however, such studies included
heterogeneous patients with a variety of backgrounds, including elderly patients with pulmonary complications. In contrast to those studies, the current study included a homogeneous cohort of healthy subjects, which might be more suitable for observing CLG after lung resection. Advances in radiologic technology, such as 3D-CT evaluations, have disclosed a variety of new findings in Table 1. Preoperative Clinical Features of the Enrolled Donors
Variables Age, y Sex Male Female Body mass index, kg/m2 Smoking history Never Former or current Smoking pack-years Lobectomy Left side Right side VC, mL %VC, % FEV1 , mL %FEV1, % DLCO, mL , min–1 , mm Hg–1 DLCO/VA , mL , min–1 , mm Hg–1
No. or Median (25th–75th percentile) (N ¼ 31) 38 (30–47) 20 11 23.9 (20.9–25.5) 19 12 10 (6.5–15.5)
3960 116.8 3370 103.9 26.0
13 18 (3450–4830) (101.5–122.3) (2820–4020) (94.4–111.9) (20.6–30.0)
5.38 (4.67–6.5)
DLCO ¼ diffusing capacity of the lung for carbon monoxide; DLCO/VA ¼ ratio of diffusing capacity of the lung for carbon monoxide to alveolar ventilation; FEV1 ¼ forced expiratory volume in 1 second; VC ¼ vital capacity; %VC and % FEV1 ¼ the percentage of the predicted values of VC and FEV1.
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Table 2. The Preoperative and Postoperative Imaging Variables of Ipsilateral Residual Lung Variablea Total lung volume, mL LAV, mL MAV, mL HAV, mL %LAV (%) %MAV (%) %HAV (%) Db
Preoperative (n ¼ 31) 1343 350 783 209 24.1 59.5 15.0 2.088
a Values are reported as medians (25th–75th percentile). clusters, which follows a power law.
HAV ¼ high attenuation volume;
(1,144–1,629) (264–405) (662–940) (184–232) (21.7–29.3) (56.6–62.9) (14.4–16.7) (1.958–2.373) b
Postoperative (n ¼ 31) 2017 525 1108 299 25.9 59.2 15.4 2.136
(1,604–2,342) (365–743) (937–1,326) (263–351) (20.9–35.1) (50.6–61.3) (14.1–16.6) (1.765–2.481)
p Value <0.0001 <0.0001 <0.0001 <0.0001 0.408 0.037 0.408 0.848
The value of D is the exponent of the cumulative size distribution of low attenuation area
LAV ¼ low attenuation volume;
lung diseases such as emphysema, lung cancer, and interstitial pneumonia [15, 19–22]. In particular, a stereologic imaging approach has become more prevalent to evaluate CLG to eliminate the bias of histologic sections, such as geometric shapes or shrinkage during tissue fixation of alveoli [2, 22]. In the present study, HUdependent volumetric and D-value assessments were used to evaluate the structural quality of the lung before and after the operation. The imaging value of %LAV, using thresholds of 950 HU to distinguish between normal lung and emphysematous lesions, is considered a standard index of emphysematous change that reflects pathologic lung destruction and hyperinflation [10]. Some reports noted that the imaging value of %HAV, using thresholds of 700 HU to distinguish between normal lung and interstitial lung disease lesions, is useful for characterization and quantification of interstitial lung disease lesions [15, 23]. In the present study, –700 and –950 HU thresholds, according to a previous report that noted their strong correlation to PFT, were used to evaluate the radiologic quality of the residual lung [15]. Power law analysis was developed to quantitatively describe the random variations in size and shape seen in natural objects, such as the distributions of the sizes of cities, earthquakes, solar flares, and moon craters [16].
MAV ¼ middle attenuation volume.
Mishima and colleagues [12] previously reported that low attenuation area cluster size and its cumulative size distributions follow a power law and that the D value, a coefficient of cumulative size distribution of low-density area clusters, is useful for showing the pattern of progression of emphysema. The concept of the D value, which is less affected by lung hyperinflation than %LAV, is now widely used to evaluate lung destruction [11–13]. An unchanged D value indicates that the fractal dimension of the terminal airspace in tissue structure is unchanged, whereas a decreased D value means an increased prevalence of large size, low attenuation clusters that indicate destruction of alveolar tissue [13]. Tanabe and colleagues [11] reported that the D value was significantly correlated with FEV1, %FEV1, and DLCO/VA in patients with emphysema [11]. Thus, this imaging variable is useful for qualitative assessment of the lung. CLG is defined by an absolute increase in the quantity of functioning lung tissue in response to injury or disease, or both [1]. The occurrence of CLG in adult humans or large mammals after lung resection remains controversial [2, 24]. Lungs possess a large amount of reserve capacity for exercise or resection. One of the explanations for this restoration after lung resection is the unfolding of alveolar epithelium that is not used before lung resection [2]. Thus, CLG should be distinguished from lung regeneration, Fig 3. Representative images are shown of the D value measured preoperatively and at 1 year postoperatively. The D-value measurement is a power law analysis of low attenuation area clusters. The D value was examined by custommade software and calculated as the average of all two-dimensional axial chest computed tomography images. Each of the colored areas indicates clusters of low attenuation areas. The images were obtained from the same donor.
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which means regeneration of alveoli and bronchi. However, Butler and colleagues [5] reported an instance of lung regeneration in an adult patient and suggested that regeneration of alveoli, rather than alveolar hyperexpansion alone, was occurring. The current study showed an increase of more than 40% in the volume of ipsilateral residual lung, although the D value did not change between preoperatively and postoperatively. These results indicated that neither lung destruction nor hyperinflation was observed, despite the volume increasing. However, whether unfolding of alveolar epithelium or regeneration of alveoli is responsible for this compensatory response in the present study is difficult to determine. Some reports mentioned that stretch or distension of the remaining lung after lung resection is considered the major factor in CLG, because intrathoracic negative pressure between the thorax and remaining lung creates chronic lung stress, which leads to alveolar hypoxia, microvascular perfusion, and hormone secretion [2, 3, 25]. As a limitation, the variable of %MAV was significantly decreased in the postoperative state; however, the difference in the median value was only 0.3%, and there were no differences in the other imaging indicators. This result could be induced by partial hyperexpansion related to patient backgrounds, such as smoking status or body mass index. Further studies, with more subjects, of the structural quality of the residual lung after lobectomy and the effects on postoperative PFTs in individual cases are needed. Histologic confirmation of structural change in the residual lung of the donors was not obtained. Whether regeneration of alveoli or remodeling is responsible for this compensatory response after lung resection remains unknown. Histologic and molecular biological confirmation is needed in clinical settings and animal models in the future. The analysis of the structure of terminal bronchioles by micro-CT or immune stains of epithelial, endothelial, and mesenchymal cells, which are assumed to participate in alveolar regeneration in the tissue samples in animal models, will be helpful for assessing CLG and lung regeneration in future research [26–28]. Alveolar tissue restoration is not clearly confirmed in patients with emphysema and pulmonary fibrosis but may offer a novel therapeutic approach for such lung diseases [27, 28]. This study did not demonstrate actual regeneration of the lung; however, if it were observed in the healthy human after lung resection, and if some factors related to restoration were identified, it would be helpful for patients with emphysema or pulmonary fibrosis in the future. In conclusion, the present study provided supportive evidence with quantitative and qualitative CT assessments for the occurrence of CLG in healthy adults, not in diseased lungs, after lobectomy.
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