original article Wien Klin Wochenschr DOI 10.1007/s00508-014-0647-9
Use of PET-CT for the assessment of treatment results in patients with sarcoidosis Aysun Yakar · Fatih Yakar · Murat Sezer · Mehmet Bayram · Ezgi Başak Erdoğan · Didem Özkan · Hatice K. Özçelik · Levent Tabak
Received: 11 January 2014 / Accepted: 15 October 2014 © Springer-Verlag Wien 2014
Summary Background and aim Sarcoidosis is a multisystem disease of unknown origin. Determining the involvement and the response to the treatment is important. The aim of this study was to identify the effects of methylprednisolone and indomethacine on metabolic activity and pulmonary function test parameters in patients with sarcoidosis. Material and methods A total of 24 pulmonary sarcoidosis patients were enrolled in the study. All the patients underwent spirometry and [18F]fluorodeoxyglucose positron emission tomography–computed tomography (FDG PET-CT) scan before treatment and were divided into two groups according to the necessity of corticosteroid treatment or not. Patients who did not have corticosteroid indication were treated with indomethacine. Symptomatic patients and patients who did not respond to indomethacine treatment received methylprednisolone. Patients were followed up on a monthly basis to determine the response. FDG uptakes as the disease activity were re-evaluated before ending the treatment at the sixth month.
Results Mean age of patients (16 male, 8 female) was 39.79 (9.3) years. Besides mediastinum and pulmonary parenchyma, extrapulmonary sites were also involved in patients with pulmonary sarcoidosis (distant lymph nodes (upper abdominal, supraclavicular, inguinal, and axillary), liver, and spleen). Although maximum standard uptake values of methylprednisolone group regressed significantly (p 0.005). Conclusion FDG PET-CT may be useful for determining activity and the efficacy of treatments. Methylprednisolone is effective in reducing metabolic activity but does not lead to improvement in functional parameters.
F. Yakar, MD () · M. Sezer, MD · M. Bayram, MD · D. Özkan, MD · H. K. Özçelik, MD Department of Pulmonary Medicine, Bezmialem Vakıf University, Fatih, Istanbul, Turkey e-mail: [email protected]
Zusammenfassung Hintergrund und Ziel Die Sarkoidose ist eine Multisystemerkrankung unbekannten Ursprungs. Die Bestimmung des Ausmaßes der Erkrankung und des Ansprechen auf Therapie ist wichtig. Das Ziel dieser Studie war es, die Wirkung von Methylprednisolon und Indomethacin auf die Stoffwechselaktivität und auf Lungenfunktionsparameter bei Patienten mit Sarkoidose zu erfassen. Material und Methoden Es wurden 24 Patienten mit Sarkoidose in die Studie aufgenommen. Bei allen Patienten wurde eine Spirometrie und ein FDG PET-CT vor der Therapie durchgeführt. Die Patienten wurden in zwei Gruppen je nach der Notwendigkeit einer Cortisontherapie geteilt. Die Patienten, bei denen keine Indikation für
A. Yakar, MD Forensic Science Institution, Ministry of Justice, Istanbul, Turkey E. B. Erdoğan, MD Department of Nuclear Medicine, Bezmialem Vakıf University, Istanbul, Turkey Prof. Dr. L. Tabak, MD Department of Pulmonary Medicine, American Hospital, Istanbul, Turkey
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Keywords PET-CT · Sarcoidosis · Methylprednisolone · Indomethacine · Spirometry
Einsatz von PET-CT bei der Erfassung von Behandlungsergebnissen bei Patienten mit Sarkoidose
Use of PET-CT for the assessment of treatment results in patients with sarcoidosis
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original article
eine Cortisontherapie bestand, wurden mit Indomethacin behandelt. Patienten mit Symptomen und Patienten, die nicht auf die Indomethacin-Therapie ansprachen, erhielten Cortison. Die Patienten wurden zur Erfassung des Ansprechens auf die Therapie monatlich kontrolliert. Als Parameter der Aktivität der Erkrankung wurden FDGUptakes vor Ende der 6-monatigen Therapie neuerlich erhoben. Ergebnisse Das mittlere Alter der Patienten (16 Männer, 8 Frauen) lag bei 39,79 (9,3) Jahren. Neben dem Mediastinum und Lungenparenchym waren auch extrapulmonale Organe befallen (Lymphknoten im Bereich des oberen Abdomens, der Supraclaviculargruben, der Leisten und der Axillae; Leber und Milz). Obwohl die SUV max Werte in der Gruppe mit Methylprednisolon signifikant (p 10 pack-years. The disease stages of the patients were as follows: 11 (45.8 %), 9 (37.5 %), 3 (12.5 %), and 1 (4.1 %) patients had stages 1, 2, 3, and 4 sarcoidosis, respectively. Although 11 patients had stage 1 sarcoidosis according to chest X-ray findings, PET-CT showed that 4 of them had parenchymal involvement, 5 had supraclavicular lymph node (LN) involvement, 1 had splenic involvement, 6 had upper abdominal involvement, and two had inguinal LN involvement. Of all 24 patients, PET-CT showed that 22 (91.6 %) had mediastinal involvement, 17 (70.8 %) had pulmonary parenchymal involvement, 11 (45.8 %) had upper abdominal LN involvement, 9 (37.5 %) had supraclavicular LN involvement, 7 (29.1 %) had inguinal LN involvement, 4 (16.6 %) had splenic involvement, 3 (12.5 %) had liver involvement, and 3 (12.5 %) had axillary LN involvement. Two patients with a suspicion of cutaneous involvement had no metabolic activity on PET-CT. The FDG uptake rates of organs and LNs on PETCT are presented in Table 2. The SUVmax of 22 patients with mediastinal LN involvement ranged from 3.8 to 30.5. Patients with currently diagnosed or relapsed stage 1 sarcoidosis had higher uptake values than did those with stage 2 sarcoidosis. This difference was statistically significant (p = 0.003). The pulmonary parenchymal involvement values of patients with stage 2 disease (SUVmax, 3.1–13.8) were lower than those of patients with stage 3 disease (SUVmax, 8.4–13). However, this difference was not statistically significant (p = 0.209). In total, 16 patients were treated with methylprednisolone, and 8 received indomethacin. The disease stages of the 16 patients who received methylprednisolone were as follows: 5 (31.3 %), 7 (43.8 %), 3 (18.8 %), and 1 (6.3 %) patients had stage 1, 2, 3, and 4 sarcoidosis, respectively. FDG uptake decreased in the majority (15 of 16, 93.8 %) of patients in the methylprednisolone group (Figs. 2 and 3). In addition, patients with stage 3 (Fig. 4) and stage 4 (Fig. 5) diseases showed metabolic regression after methylprednisolone therapy. The remaining one patient without FDG decrease had recurrent stage 2 sarcoidosis.
Use of PET-CT for the assessment of treatment results in patients with sarcoidosis
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original article Fig. 1 Flow chart of the study. FDG fluorodexyglucose, PETCT positron emission tomography–computed tomography
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Table 2 [18F]FDG uptake rates of organs and lymph nodes on PET-CT Stage
Mediastinum
Pulmonary parenchyma
Upper abdominal LN
Supraclavicular LN
Inguinal LN
Spleen
Axillary LN
Liver
1 (n = 11)
11
4
6
5
2
1
None
None
2 (n = 9)
9
9
3
3
3
1
2
1
3 (n = 3)
1
3
1
1
1
2
1
1
4 (n = 1)
1
1
1
None
1
None
None
1
Total: 24
22 (91.6 %)
17 (71 %)
11 (45.8 %)
9 (37.5 %)
7 (29 %)
4 (16.6 %)
3 (12.5 %)
3 (12.5 %)
PET-CT positron emission computerized tomography, LN lymph node, FDG fluorodeoxyglucose
Despite the evidence of a decrease in FDG uptakes, only three patients had an increased forced vital capacity (FVC) of > 15 %, and no patients had a > 15 % increase on DLCO. Absolute values of baseline and end-of-treatment PFT and FDG uptake values are given in Table 3. In the indomethacin group, six (75 %) patients had stage 1 disease and two (25 %) had stage 2 disease. FDG uptake regressed in only one patient with stage 1 sarcoidosis. Despite decreased glucose uptake after indometha-
cin treatment, no significant increase in FVC or DLCO was present in this patient. Patients who did not respond to indomethacin treatment were planned for methylprednisolone therapy. One patient refused steroids, and six received methylprednisolone. Of these six patients, four (66.7 %) had stage 1 sarcoidosis and two (33.3 %) had stage 2 sarcoidosis. Five patients had decreased FDG uptake and a slight increase ( 15 % in DLCO.
Use of PET-CT for the assessment of treatment results in patients with sarcoidosis
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original article
Fig. 5 PET- CT of a stage 4 patient before (a, c, d, and e) and after (b, f, g, and h) methylprednisolone treatment Table 3 Baseline and end-of-treatment FVC, DLCO, and FDG uptake values Patients 1
Drug
DLCO (%)
FDG uptake (SUVmax)
Baseline
End of treatment
Baseline
End of treatment
Baseline
End of treatment
83
83
80
80
7.0
1.1
2
68
72
83
75
12.0
10.9
3
85
97
83
89
11.2
1.8
4
128
129
85
83
5.8
1.1
5
73
93
80
85
13.0
4.2
6
103
98
89
86
12.1
7.7
7
51
54
80
72
12.9
6.3
8
66
80
115
120
11.6
4.2
9
101
111
77
71
7.8
4.1
10
75
83
65
72
10.2
4.1
11
104
105
85
87
8.1
2.0
12
86
99
90
90
18.0
2.0
13
73
80
68
70
23.9
4.9
14
106
115
72
69
6.6
0.5
15
10
104
94
102
11.5
4.1
16
95
99
84
78
13.8
5.0
1
Methylprednisolone
FVC (%)
95
99
98
86
30.3
2.0
2
Indomethacine
107
117
82
77
5.3
5.3
3
116
120
83
82
23.5
23.5
4
70
81
104
95
28.6
24.5
5
124
127
85
85
8.7
7.8
6
71
67
110
115
19.8
19.8
7
85
93
90
93
6.9
6.5
8
82
78
114
115
8.7
13.1
SUVmax values belong to the areas with the highest FDG uptakes FVC forced vital capacity, DLCO diffusing capacity of the lung for carbon monoxide, FDG fluorodeoxyglucose, SUVmax maximum standard uptake value
The decrease in SUVmax values in the methylprednisolone group after treatment was statistically significant; however, the decrease in the indomethacine group was not. The lack of significance in the indomethacine group may be due to the small number of patients. Inflammatory cells (neutrophils, lymphocytes, macrophages, etc.) have increased FDG uptake, leading to significant tracer accumulation in inflammatory and infectious areas. Based on this information, whole-body
FDG PET is an important tool to assess disease activity, extent, and distribution, to identify occult sites of disease for diagnostic biopsy, and to follow the response to treatment in patients with sarcoidosis. The mediastinal (91.7 %) and lung parenchymal (70.8 %) involvement rates in our study were consistent with those in the literature [15]. Although, glucose uptake was seen in subcutaneous nodules, bone, muscle, and lacrimal/ parotid glands in the studies by Teirstein et al. [22] and
6 Use of PET-CT for the assessment of treatment results in patients with sarcoidosis
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original article Fig. 6 Median SUVmax values of indomethacin and methylprednisolone groups before and after treatment
Braun et al. [8], we did not identify any glucose uptake in the cutaneous or sinonasal sites. In our institute, we use both chest X-ray and CT for diagnosis, staging, and assessment of sarcoidosis patients, as recommended [1]. In the classical staging method, only mediastinal involvement should be present in stage 1 sarcoidosis; in our study, however, FDG PETCT revealed hypermetabolism in the lung parenchyma (36 %), upper abdominal LNs (54 %), and spleen (9 %) of patients with stage 1 sarcoidosis. This finding was consistent with findings of Braun et al. [8] and raises suspicion about the accuracy of the classical staging method and supports the notion that PET-CT may identify undetected pulmonary and extrapulmonary disease processes. However, we do not use PET-CT for the diagnosis and staging of these patients, in routine clinical practice. Usually, as the disease progresses, the involvement of the mediastinum decreases, while the involvement of the parenchyma increases. Our findings support this notion, showing lower uptake in the mediastinum of patients with stage 2 relative to stage 1 disease. The SUVmax values of the mediastinum in patients with currently diagnosed and relapsed stage 1 sarcoidosis were higher than those in patients with stage 2 sarcoidosis (p = 0.003). Also, Milman et al. [20] showed a significant decrease in the FDG uptake in the hilum and mediastinum and an unchanged or slightly increased uptake in the lung parenchyma following treatment with inhaled corticosteroids, consistent with a shift from stage 1 to stage 2 disease, as in our study. The FDG uptake values of the lungs in patients with stage 3 sarcoidosis ranged from 8.4 to 13.0, whereas only four patients with stage 2 sarcoidosis had uptake values > 8.0. However, our results were not statistically significant, probably due to the limited number of patients in the study. Patients with stage 3 and 4 diseases also
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showed metabolic regression after methylprednisolone therapy, which may indicate that metabolic processes continue even in the late stages of the disease. The FDG uptake for mediastinal LNs ranged from 3.8 to 30.3. To our knowledge, such a high SUVmax value (30.3) has not been previously reported in patients with sarcoidosis. FDG PET showed increased uptake in supraclavicular LNs in 9 of 24 patients (37.5 %). Supraclavicular LN biopsy, which is not a frequent technique for diagnosis, can yield a diagnosis in one-third of patients suspected to have sarcoidosis. Indications for corticosteroid treatment include worsening pulmonary symptoms, deteriorating lung function, progressive radiographic changes, ocular, neurologic, or cardiac involvement, and hypercalcemia. In this study, 16 patients received oral corticosteroids, and 15 of them showed regression on FDG PET-CT. In a study by Teirstein et al. [22], 36 patients received corticosteroids, and 11 of them exhibited therapy-related decreases in SUVmax. Moreover, when Braun et al. [8] treated five patients with corticosteroids, complete regression occurred in two patients, improvement but incomplete regression occurred in another two, and disease progression occurred in the fifth patient. Some case reports have also demonstrated the efficacy of corticosteroid treatment as evidenced by FDG PET [20, 21, 23]. The use of anti-inflammatory agents is recommended in patients with early-stage sarcoidosis, but there are a limited number of studies on this topic [16–19]. Türktaş et al. [18] reported disease regression with anti-inflammatory treatment. Whether the improvement was therapy-related or spontaneous is controversial. In our study, however, seven of eight patients did not show regression with indomethacin therapy. In contrast, decrease
Use of PET-CT for the assessment of treatment results in patients with sarcoidosis
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original article
of uptake was shown in 15 of the 16 patients treated with oral corticosteroids. Furthermore, decrease of uptake occurred with oral corticosteroids in five of the six patients who did not respond to indomethacin. This finding indicates failure to respond to indomethacin. In addition, there was no improvement in PFT or DLCO after indomethacin treatment. Although, there was a significant FDG uptake decrease in 1 patient after indomethacine treatment, we cannot exclude the possibility of spontaneous resolution of the disease. Three patients treated with corticosteroids had a > 15 % increase in FVC, but the remaining patients did not. None of the responders had a significant increase in DLCO. Treatment may decrease the activity of disease, but it does not improve functional parameters. The disparity between PFT results and PET-CT results raises suspicion about the efficacy of PFT as a determinant of the disease. There are several limitations of this study. First, the number of patients was small. Increasing the number of participants may increase the accuracy and reduce the errors of the study. Second, PET-CT is an expensive technique with which to diagnose sarcoidosis. Third, the inequality between the corticosteroid and nonsteroidal anti-inflammatory drug groups caused randomization error despite the fact that we included all eligible patients. Fourth, patient number in indomethacine group was too small to identify a statistical significance. Fifth, these data are only consistent for patients with untreated pulmonary sarcoidosis, and we cannot assume the treatment effects and value of PET-CT in the excluded patients. Finally, there were more patients with early rather than advanced disease, which was probably due to our selection criteria for untreated patients. In summary, whole-body FDG PET-CT may be useful to detect occult diagnostic biopsy sites, determine the efficacy of treatment, and evaluate disease activity in patients with sarcoidosis. Corticosteroid treatment is effective for reducing metabolic activity. Despite metabolic regression, corticosteroid treatment does not improve functional parameters. Further studies are needed to clarify the role of FDG PET-CT in the staging, treatment, and follow-up of patients with sarcoidosis. Acknowledgments The English in this document has been checked by at least two professional editors, both native speakers of English. For a certificate, please see: http://www.textcheck.com/ certificate/DxY8pE. Conflict of interest None of the authors declares any conflicts of interest.
References 1. Statement on sarcoidosis. Joint Statement of the American Thoracic Society (ATS), the European Respiratory Society (ERS) and the World Association of Sarcoidosis and Other Granulomatous Disorders (WASOG) adopted by the ATS Board of Directors and by the ERS Executive Committee, February 1999. Am J Respir Crit Care Med. 1999;160(2):736–55. 2. Beaumont D, Herry JY, Sapene M, Bourguet P, Larzul JJ, de Labarthe B. Gallium-67 in the evaluation of sarcoidosis: correlations with serum angiotensin-converting enzyme and bronchoalveolar lavage. Thorax. 1982;37(1):11–8. 3. Israel HL, Albertine KH, Park CH, Patrick H. Whole-body gallium 67 scans. Role in diagnosis of sarcoidosis. Am Rev Respir Dis. 1991;144(5):1182–6. 4. Klech H, Kohn H, Kummer F, Mostbeck A. Assessment of activity in sarcoidosis. Sensitivity and specificity of 67Gallium scintigraphy, serum ACE levels, chest roentgenography, and blood lymphocyte subpopulations. Chest. 1982;82(6):732–8. 5. Line BR, Hunninghake GW, Keogh BA, Jones AE, Johnston GS, Crystal RG. Gallium-67 scanning to stage the alveolitis of sarcoidosis: correlation with clinical studies, pulmonary function studies, and bronchoalveolar lavage. Am Rev Respir Dis. 1981;123(4 Pt. 1):440–6. 6. Niden AH, Mishkin FS, Salem F, Thomas AV, Jr., Kamdar V. Prognostic significance of gallium lung scans in sarcoidosis. Ann N Y Acad Sci. 1986;465:435–43. 7. Nosal A, Schleissner LA, Mishkin FS, Lieberman J. Angiotensin-I-converting enzyme and gallium scan in noninvasive evaluation of sarcoidosis. Ann Intern Med. 1979;90(3):328–31. 8. Braun JJ, Kessler R, Constantinesco A, Imperiale A. 18F-FDG PET/CT in sarcoidosis management: review and report of 20 cases. Eur J Nucl Med Mol Imaging. 2008;35(8):1537–43. 9. Glaudemans AW, de Vries EF, Galli F, Dierckx RA, Slart RH, Signore A. The use of (18)F-FDG-PET/CT for diagnosis and treatment monitoring of inflammatory and infectious diseases. Clin Dev Immunol. 2013;2013:623036. 10. Morgenthau AS, Iannuzzi MC. Recent advances in sarcoidosis. Chest. 2011;139(1):174–82. 11. Gottlieb JE, Israel HL, Steiner RM, Triolo J, Patrick H. Outcome in sarcoidosis. The relationship of relapse to corticosteroid therapy. Chest. 1997;111(3):623–31. 12. Baughman RP, Lower EE. Treatment of sarcoidosis with corticosteroids: who is going to relapse and why? Sarcoidosis Vasc Diffuse Lung Dis. 1998;15(1):19–20. 13. Hunninghake GW, Gilbert S, Pueringer R, Dayton C, Floerchinger C, Helmers R, et al. Outcome of the treatment for sarcoidosis. Am J Respir Crit Care Med. 1994;149(4 Pt. 1):893–8. 14. Baughman RP, Nunes H, Sweiss NJ, Lower EE. Established and experimental medical therapy of pulmonary sarcoidosis. Eur Respir J. 2013;41(6):1424–38. 15. Cottin V, Muller-Quernheim J. Sarcoidosis from bench to bedside: a state-of-the-art series for the clinician. Eur Respir J. 2012;40(1):14–6. 16. Tabak L. Sarkoidoz olgularında uzun dönem izlem sonuçları. Solunum. 2001;3:86–90. 17. Zabel P, Entzian P, Dalhoff K, Schlaak M. Pentoxifylline in treatment of sarcoidosis. Am J Respir Crit Care Med. 1997;155(5):1665–9.
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original article 18. Türktaş H, Oğuzülgen İ, Gürsel G. Effects of pentoxifylline and methylprednisolone combined therapy on sarcoidosis. Turkish Respir J. 2000;1:15–20. 19. James DG, Carstairs LS, Trowell J, Sharma OP. Treatment of sarcoidosis. Report of a controlled therapeutic trial. Lancet. 1967;2(7515):526–8. 20. Milman N, Mortensen J, Sloth C. Fluorodeoxyglucose PET scan in pulmonary sarcoidosis during treatment with inhaled and oral corticosteroids. Respiration. 2003;70(4):408–13. 21. Kaira K, Ishizuka T, Yanagitani N, Sunaga N, Hisada T, Mori M. Value of FDG positron emission tomography in monitoring the effects of therapy in progressive pulmonary sarcoidosis. Clin Nucl Med. 2007;32(2):114–6.
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22. Teirstein AS, Machac J, Almeida O, Lu P, Padilla ML, Iannuzzi MC. Results of 188 whole-body fluorodeoxyglucose positron emission tomography scans in 137 patients with sarcoidosis. Chest. 2007;132(6):1949–53. 23. Brudin LH, Valind SO, Rhodes CG, Pantin CF, Sweatman M, Jones T, et al. Fluorine-18 deoxyglucose uptake in sarcoidosis measured with positron emission tomography. Eur J Nucl Med. 1994;21(4):297–305. 24. Miller MR, Crapo R, Hankinson J, Brusasco V, Burgos F, Casaburi R, et al. General considerations for lung function testing. Eur Respir J. 2005;26(1):153–61.
Use of PET-CT for the assessment of treatment results in patients with sarcoidosis
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Use of PET-CT for the assessment of treatment results in patients with sarcoidosis Aysun Yakar · Fatih Yakar · Murat Sezer · Mehmet Bayram · Ezgi Başak Erdoğan · Didem Özkan · Hatice K. Özçelik · Levent Tabak
Received: 11 January 2014 / Accepted: 15 October 2014 © Springer-Verlag Wien 2014
Summary Background and aim Sarcoidosis is a multisystem disease of unknown origin. Determining the involvement and the response to the treatment is important. The aim of this study was to identify the effects of methylprednisolone and indomethacine on metabolic activity and pulmonary function test parameters in patients with sarcoidosis. Material and methods A total of 24 pulmonary sarcoidosis patients were enrolled in the study. All the patients underwent spirometry and [18F]fluorodeoxyglucose positron emission tomography–computed tomography (FDG PET-CT) scan before treatment and were divided into two groups according to the necessity of corticosteroid treatment or not. Patients who did not have corticosteroid indication were treated with indomethacine. Symptomatic patients and patients who did not respond to indomethacine treatment received methylprednisolone. Patients were followed up on a monthly basis to determine the response. FDG uptakes as the disease activity were re-evaluated before ending the treatment at the sixth month.
Results Mean age of patients (16 male, 8 female) was 39.79 (9.3) years. Besides mediastinum and pulmonary parenchyma, extrapulmonary sites were also involved in patients with pulmonary sarcoidosis (distant lymph nodes (upper abdominal, supraclavicular, inguinal, and axillary), liver, and spleen). Although maximum standard uptake values of methylprednisolone group regressed significantly (p 0.005). Conclusion FDG PET-CT may be useful for determining activity and the efficacy of treatments. Methylprednisolone is effective in reducing metabolic activity but does not lead to improvement in functional parameters.
F. Yakar, MD () · M. Sezer, MD · M. Bayram, MD · D. Özkan, MD · H. K. Özçelik, MD Department of Pulmonary Medicine, Bezmialem Vakıf University, Fatih, Istanbul, Turkey e-mail: [email protected]
Zusammenfassung Hintergrund und Ziel Die Sarkoidose ist eine Multisystemerkrankung unbekannten Ursprungs. Die Bestimmung des Ausmaßes der Erkrankung und des Ansprechen auf Therapie ist wichtig. Das Ziel dieser Studie war es, die Wirkung von Methylprednisolon und Indomethacin auf die Stoffwechselaktivität und auf Lungenfunktionsparameter bei Patienten mit Sarkoidose zu erfassen. Material und Methoden Es wurden 24 Patienten mit Sarkoidose in die Studie aufgenommen. Bei allen Patienten wurde eine Spirometrie und ein FDG PET-CT vor der Therapie durchgeführt. Die Patienten wurden in zwei Gruppen je nach der Notwendigkeit einer Cortisontherapie geteilt. Die Patienten, bei denen keine Indikation für
A. Yakar, MD Forensic Science Institution, Ministry of Justice, Istanbul, Turkey E. B. Erdoğan, MD Department of Nuclear Medicine, Bezmialem Vakıf University, Istanbul, Turkey Prof. Dr. L. Tabak, MD Department of Pulmonary Medicine, American Hospital, Istanbul, Turkey
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Keywords PET-CT · Sarcoidosis · Methylprednisolone · Indomethacine · Spirometry
Einsatz von PET-CT bei der Erfassung von Behandlungsergebnissen bei Patienten mit Sarkoidose
Use of PET-CT for the assessment of treatment results in patients with sarcoidosis
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original article
eine Cortisontherapie bestand, wurden mit Indomethacin behandelt. Patienten mit Symptomen und Patienten, die nicht auf die Indomethacin-Therapie ansprachen, erhielten Cortison. Die Patienten wurden zur Erfassung des Ansprechens auf die Therapie monatlich kontrolliert. Als Parameter der Aktivität der Erkrankung wurden FDGUptakes vor Ende der 6-monatigen Therapie neuerlich erhoben. Ergebnisse Das mittlere Alter der Patienten (16 Männer, 8 Frauen) lag bei 39,79 (9,3) Jahren. Neben dem Mediastinum und Lungenparenchym waren auch extrapulmonale Organe befallen (Lymphknoten im Bereich des oberen Abdomens, der Supraclaviculargruben, der Leisten und der Axillae; Leber und Milz). Obwohl die SUV max Werte in der Gruppe mit Methylprednisolon signifikant (p 10 pack-years. The disease stages of the patients were as follows: 11 (45.8 %), 9 (37.5 %), 3 (12.5 %), and 1 (4.1 %) patients had stages 1, 2, 3, and 4 sarcoidosis, respectively. Although 11 patients had stage 1 sarcoidosis according to chest X-ray findings, PET-CT showed that 4 of them had parenchymal involvement, 5 had supraclavicular lymph node (LN) involvement, 1 had splenic involvement, 6 had upper abdominal involvement, and two had inguinal LN involvement. Of all 24 patients, PET-CT showed that 22 (91.6 %) had mediastinal involvement, 17 (70.8 %) had pulmonary parenchymal involvement, 11 (45.8 %) had upper abdominal LN involvement, 9 (37.5 %) had supraclavicular LN involvement, 7 (29.1 %) had inguinal LN involvement, 4 (16.6 %) had splenic involvement, 3 (12.5 %) had liver involvement, and 3 (12.5 %) had axillary LN involvement. Two patients with a suspicion of cutaneous involvement had no metabolic activity on PET-CT. The FDG uptake rates of organs and LNs on PETCT are presented in Table 2. The SUVmax of 22 patients with mediastinal LN involvement ranged from 3.8 to 30.5. Patients with currently diagnosed or relapsed stage 1 sarcoidosis had higher uptake values than did those with stage 2 sarcoidosis. This difference was statistically significant (p = 0.003). The pulmonary parenchymal involvement values of patients with stage 2 disease (SUVmax, 3.1–13.8) were lower than those of patients with stage 3 disease (SUVmax, 8.4–13). However, this difference was not statistically significant (p = 0.209). In total, 16 patients were treated with methylprednisolone, and 8 received indomethacin. The disease stages of the 16 patients who received methylprednisolone were as follows: 5 (31.3 %), 7 (43.8 %), 3 (18.8 %), and 1 (6.3 %) patients had stage 1, 2, 3, and 4 sarcoidosis, respectively. FDG uptake decreased in the majority (15 of 16, 93.8 %) of patients in the methylprednisolone group (Figs. 2 and 3). In addition, patients with stage 3 (Fig. 4) and stage 4 (Fig. 5) diseases showed metabolic regression after methylprednisolone therapy. The remaining one patient without FDG decrease had recurrent stage 2 sarcoidosis.
Use of PET-CT for the assessment of treatment results in patients with sarcoidosis
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original article Fig. 1 Flow chart of the study. FDG fluorodexyglucose, PETCT positron emission tomography–computed tomography
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Table 2 [18F]FDG uptake rates of organs and lymph nodes on PET-CT Stage
Mediastinum
Pulmonary parenchyma
Upper abdominal LN
Supraclavicular LN
Inguinal LN
Spleen
Axillary LN
Liver
1 (n = 11)
11
4
6
5
2
1
None
None
2 (n = 9)
9
9
3
3
3
1
2
1
3 (n = 3)
1
3
1
1
1
2
1
1
4 (n = 1)
1
1
1
None
1
None
None
1
Total: 24
22 (91.6 %)
17 (71 %)
11 (45.8 %)
9 (37.5 %)
7 (29 %)
4 (16.6 %)
3 (12.5 %)
3 (12.5 %)
PET-CT positron emission computerized tomography, LN lymph node, FDG fluorodeoxyglucose
Despite the evidence of a decrease in FDG uptakes, only three patients had an increased forced vital capacity (FVC) of > 15 %, and no patients had a > 15 % increase on DLCO. Absolute values of baseline and end-of-treatment PFT and FDG uptake values are given in Table 3. In the indomethacin group, six (75 %) patients had stage 1 disease and two (25 %) had stage 2 disease. FDG uptake regressed in only one patient with stage 1 sarcoidosis. Despite decreased glucose uptake after indometha-
cin treatment, no significant increase in FVC or DLCO was present in this patient. Patients who did not respond to indomethacin treatment were planned for methylprednisolone therapy. One patient refused steroids, and six received methylprednisolone. Of these six patients, four (66.7 %) had stage 1 sarcoidosis and two (33.3 %) had stage 2 sarcoidosis. Five patients had decreased FDG uptake and a slight increase ( 15 % in DLCO.
Use of PET-CT for the assessment of treatment results in patients with sarcoidosis
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original article
Fig. 5 PET- CT of a stage 4 patient before (a, c, d, and e) and after (b, f, g, and h) methylprednisolone treatment Table 3 Baseline and end-of-treatment FVC, DLCO, and FDG uptake values Patients 1
Drug
DLCO (%)
FDG uptake (SUVmax)
Baseline
End of treatment
Baseline
End of treatment
Baseline
End of treatment
83
83
80
80
7.0
1.1
2
68
72
83
75
12.0
10.9
3
85
97
83
89
11.2
1.8
4
128
129
85
83
5.8
1.1
5
73
93
80
85
13.0
4.2
6
103
98
89
86
12.1
7.7
7
51
54
80
72
12.9
6.3
8
66
80
115
120
11.6
4.2
9
101
111
77
71
7.8
4.1
10
75
83
65
72
10.2
4.1
11
104
105
85
87
8.1
2.0
12
86
99
90
90
18.0
2.0
13
73
80
68
70
23.9
4.9
14
106
115
72
69
6.6
0.5
15
10
104
94
102
11.5
4.1
16
95
99
84
78
13.8
5.0
1
Methylprednisolone
FVC (%)
95
99
98
86
30.3
2.0
2
Indomethacine
107
117
82
77
5.3
5.3
3
116
120
83
82
23.5
23.5
4
70
81
104
95
28.6
24.5
5
124
127
85
85
8.7
7.8
6
71
67
110
115
19.8
19.8
7
85
93
90
93
6.9
6.5
8
82
78
114
115
8.7
13.1
SUVmax values belong to the areas with the highest FDG uptakes FVC forced vital capacity, DLCO diffusing capacity of the lung for carbon monoxide, FDG fluorodeoxyglucose, SUVmax maximum standard uptake value
The decrease in SUVmax values in the methylprednisolone group after treatment was statistically significant; however, the decrease in the indomethacine group was not. The lack of significance in the indomethacine group may be due to the small number of patients. Inflammatory cells (neutrophils, lymphocytes, macrophages, etc.) have increased FDG uptake, leading to significant tracer accumulation in inflammatory and infectious areas. Based on this information, whole-body
FDG PET is an important tool to assess disease activity, extent, and distribution, to identify occult sites of disease for diagnostic biopsy, and to follow the response to treatment in patients with sarcoidosis. The mediastinal (91.7 %) and lung parenchymal (70.8 %) involvement rates in our study were consistent with those in the literature [15]. Although, glucose uptake was seen in subcutaneous nodules, bone, muscle, and lacrimal/ parotid glands in the studies by Teirstein et al. [22] and
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original article Fig. 6 Median SUVmax values of indomethacin and methylprednisolone groups before and after treatment
Braun et al. [8], we did not identify any glucose uptake in the cutaneous or sinonasal sites. In our institute, we use both chest X-ray and CT for diagnosis, staging, and assessment of sarcoidosis patients, as recommended [1]. In the classical staging method, only mediastinal involvement should be present in stage 1 sarcoidosis; in our study, however, FDG PETCT revealed hypermetabolism in the lung parenchyma (36 %), upper abdominal LNs (54 %), and spleen (9 %) of patients with stage 1 sarcoidosis. This finding was consistent with findings of Braun et al. [8] and raises suspicion about the accuracy of the classical staging method and supports the notion that PET-CT may identify undetected pulmonary and extrapulmonary disease processes. However, we do not use PET-CT for the diagnosis and staging of these patients, in routine clinical practice. Usually, as the disease progresses, the involvement of the mediastinum decreases, while the involvement of the parenchyma increases. Our findings support this notion, showing lower uptake in the mediastinum of patients with stage 2 relative to stage 1 disease. The SUVmax values of the mediastinum in patients with currently diagnosed and relapsed stage 1 sarcoidosis were higher than those in patients with stage 2 sarcoidosis (p = 0.003). Also, Milman et al. [20] showed a significant decrease in the FDG uptake in the hilum and mediastinum and an unchanged or slightly increased uptake in the lung parenchyma following treatment with inhaled corticosteroids, consistent with a shift from stage 1 to stage 2 disease, as in our study. The FDG uptake values of the lungs in patients with stage 3 sarcoidosis ranged from 8.4 to 13.0, whereas only four patients with stage 2 sarcoidosis had uptake values > 8.0. However, our results were not statistically significant, probably due to the limited number of patients in the study. Patients with stage 3 and 4 diseases also
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showed metabolic regression after methylprednisolone therapy, which may indicate that metabolic processes continue even in the late stages of the disease. The FDG uptake for mediastinal LNs ranged from 3.8 to 30.3. To our knowledge, such a high SUVmax value (30.3) has not been previously reported in patients with sarcoidosis. FDG PET showed increased uptake in supraclavicular LNs in 9 of 24 patients (37.5 %). Supraclavicular LN biopsy, which is not a frequent technique for diagnosis, can yield a diagnosis in one-third of patients suspected to have sarcoidosis. Indications for corticosteroid treatment include worsening pulmonary symptoms, deteriorating lung function, progressive radiographic changes, ocular, neurologic, or cardiac involvement, and hypercalcemia. In this study, 16 patients received oral corticosteroids, and 15 of them showed regression on FDG PET-CT. In a study by Teirstein et al. [22], 36 patients received corticosteroids, and 11 of them exhibited therapy-related decreases in SUVmax. Moreover, when Braun et al. [8] treated five patients with corticosteroids, complete regression occurred in two patients, improvement but incomplete regression occurred in another two, and disease progression occurred in the fifth patient. Some case reports have also demonstrated the efficacy of corticosteroid treatment as evidenced by FDG PET [20, 21, 23]. The use of anti-inflammatory agents is recommended in patients with early-stage sarcoidosis, but there are a limited number of studies on this topic [16–19]. Türktaş et al. [18] reported disease regression with anti-inflammatory treatment. Whether the improvement was therapy-related or spontaneous is controversial. In our study, however, seven of eight patients did not show regression with indomethacin therapy. In contrast, decrease
Use of PET-CT for the assessment of treatment results in patients with sarcoidosis
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original article
of uptake was shown in 15 of the 16 patients treated with oral corticosteroids. Furthermore, decrease of uptake occurred with oral corticosteroids in five of the six patients who did not respond to indomethacin. This finding indicates failure to respond to indomethacin. In addition, there was no improvement in PFT or DLCO after indomethacin treatment. Although, there was a significant FDG uptake decrease in 1 patient after indomethacine treatment, we cannot exclude the possibility of spontaneous resolution of the disease. Three patients treated with corticosteroids had a > 15 % increase in FVC, but the remaining patients did not. None of the responders had a significant increase in DLCO. Treatment may decrease the activity of disease, but it does not improve functional parameters. The disparity between PFT results and PET-CT results raises suspicion about the efficacy of PFT as a determinant of the disease. There are several limitations of this study. First, the number of patients was small. Increasing the number of participants may increase the accuracy and reduce the errors of the study. Second, PET-CT is an expensive technique with which to diagnose sarcoidosis. Third, the inequality between the corticosteroid and nonsteroidal anti-inflammatory drug groups caused randomization error despite the fact that we included all eligible patients. Fourth, patient number in indomethacine group was too small to identify a statistical significance. Fifth, these data are only consistent for patients with untreated pulmonary sarcoidosis, and we cannot assume the treatment effects and value of PET-CT in the excluded patients. Finally, there were more patients with early rather than advanced disease, which was probably due to our selection criteria for untreated patients. In summary, whole-body FDG PET-CT may be useful to detect occult diagnostic biopsy sites, determine the efficacy of treatment, and evaluate disease activity in patients with sarcoidosis. Corticosteroid treatment is effective for reducing metabolic activity. Despite metabolic regression, corticosteroid treatment does not improve functional parameters. Further studies are needed to clarify the role of FDG PET-CT in the staging, treatment, and follow-up of patients with sarcoidosis. Acknowledgments The English in this document has been checked by at least two professional editors, both native speakers of English. For a certificate, please see: http://www.textcheck.com/ certificate/DxY8pE. Conflict of interest None of the authors declares any conflicts of interest.
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