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Cardiac sarcoidosis: infiltrating under cover
SHORT CASE
Cardiac sarcoidosis: infiltrating under cover
block. The features were those of granulomatous myocarditis, consistent with sarcoidosis. The patient was reviewed with this in mind, but no evidence of sarcoidosis was found in other organ systems.
Stephen D Preston
Discussion Sarcoidosis is a multisystem disease of unknown aetiology characterised by compact non-necrotising granulomas. In patients with known sarcoidosis, only 5e10% have signs and symptoms of cardiac involvement. However, detailed questioning and investigation may demonstrate cardiac involvement in up to 40%. Signs and symptoms include sudden cardiac death, arrhythmia (atrial, ventricular or due to conduction system disease), and heart failure.1 Involvement of the heart is a serious complication, with approximately half of deaths due to sarcoidosis being a result of cardiac rather than other organ disease.1 Sarcoidosis is found in 0.17e3% of native hearts at transplantation and was considered a relative contraindication to heart transplantation as there was concern that the disease may recur in the xenograft.2e5 However, registry data showed that survival after cardiac transplantation for sarcoidosis was as good as, or better than, for patients without sarcoidosis. In this study, 65 patients with cardiac sarcoidosis had 88% 1-year survival (compared to 85% 1-year survival in patients transplanted for other conditions) with 80% still alive at 5 years.2 In a smaller, more recent, series of 12 cardiac sarcoidosis patients, posttransplant survival of 92% at 1 year and 83% at 5 years was achieved. No recurrent cardiac sarcoidosis or progressive extracardiac sarcoidosis was seen in any patient over a combined follow-up period of 1001 months (range: 5e288 months).4 Thus, whilst recurrent sarcoidosis may occur, it does not appear to adversely affect outcome from transplantation, and recurrent disease is rare. The majority of patients do not receive a diagnosis of cardiac sarcoidosis until pathological examination of the explant, with a preoperative diagnosis only being made in 0e33% of cases.4,5
Abstract This article describes a case of a heart explanted at transplantation for a clinical diagnosis of dilated cardiomyopathy associated with heart block. Pathological examination of the heart demonstrated nonnecrotising granulomas with replacement fibrosis, consistent with sarcoidosis. Cardiac involvement in sarcoidosis may cause chronic cardiac failure, arrhythmia, or sudden cardiac death, and may occur in patients without clinical involvement of other organ systems. Most cases of cardiac sarcoidosis treated by heart transplantation are unsuspected until the explanted heart is examined, with most cases thought to be dilated cardiomyopathy on clinical grounds.
Keywords heart block; heart failure; heart transplantation; sarcoidosis
Case report History This patient presented with 2:1 second degree heart block, treated by pacemaker. This progressed to severe left ventricular failure over the following 3 years. Coronary angiography demonstrated patent coronary arteries. A diagnosis of dilated cardiomyopathy was made. Whilst no relevant family history was present, Lamin A/C mutation related dilated cardiomyopathy was suggested by the combination of atrioventricular conduction delay and cardiomyopathy. The patient was listed for heart transplantation. A heart became available and was transplanted. The postoperative period was uneventful, and the patient was discharged just over 2 weeks postoperatively. The patient is now back at work and able to undertake some exercise. Pathology The heart weighed 480 g, with biventricular dilatation. The coronary arteries were widely patent, and there was no primary valvular disease. The myocardium had white patches of fibrosis in the septum and in the free walls of both ventricles (Figure 1). These did not have the regional distribution or thinning of the wall seen in myocardial infarction. Multiple tissue blocks from both ventricles and septum were sampled for histology. Histology demonstrated scattered, compact, non-necrotising granulomas within the myocardium and epicardium (Figure 2a and b). The pale lesions seen on gross inspection were areas of dense replacement fibrosis (Figure 2c). Granulomas were sparse within the fibrosis. Special stains for fungi and mycobacteria were negative. Increased fibrous tissue was seen in the atrioventricular node and bundle of His, which could explain heart
Stephen D Preston BSc(Hons) BM(Hons) MRCS(Eng) FRCPath Consultant Histopathologist, Papworth Hospital, Sims Woodhead Laboratory, Papworth Hospital, Cambridge, UK. Conflicts of interest: none.
DIAGNOSTIC HISTOPATHOLOGY --:-
Figure 1 Transverse sections through the ventricles showing biventricular dilatation with patchy white fibrosis. The grid lines are 1 cm apart.
1
Ó 2017 Published by Elsevier Ltd.
Please cite this article in press as: Preston SD, Cardiac sarcoidosis: infiltrating under cover, Diagnostic Histopathology (2017), https://doi.org/ 10.1016/j.mpdhp.2017.09.006
SHORT CASE
Figure 2 On histology, there were granulomas in (a) myocardium and (b) epicardium, with (c) areas of replacement fibrosis (a and b: Haematoxylin and eosin stain, c: elastic-van Gieson stain).
This is partly due to case selection, as patients with significant multi-organ sarcoidosis may not be selected for transplantation.4 However, some studies have suggested that patients with severe cardiac sarcoidosis tend to have less severe disease in other organ systems.3 It has been proposed that endomyocardial biopsy could improve pre-transplant diagnosis but the sensitivity of endomyocardial biopsy for sarcoidosis is only 19e25%.5,6 Some heart failure patients are supported before transplantation with a ventricular assist device and examination of the core of myocardium removed during this procedure provides another diagnostic opportunity.3 The frequency of granulomas is variable in cardiac sarcoidosis explants. Some hearts have granulomas in almost every high power field, whereas others have very few. The cases with fewest granulomas tend to have most fibrosis. The fibrosis is focal and is either transmural or subepicardial, and have a variable distribution.3 What is the relevance of the diagnosis to the patient? Earlier diagnosis might have permitted immunosuppressive therapy to slow the progress of the disease. Diagnosis at the time of transplantation changes the management of both the patient and their family. For the patient, the immunosuppressive regimen is modified. Corticosteroids are continued long term rather than tapered and stopped, to avoid recurrent sarcoidosis.4 For the family, this lifts the threat of a potentially heritable cardiomyopathy. A
DIAGNOSTIC HISTOPATHOLOGY --:-
Practice points C
C
C
Cardiac sarcoidosis should be considered in the differential diagnosis of a wide variety of cardiac symptoms and signs. Cardiac sarcoidosis may be found without other organ involvement. Granulomas may be sparse in long standing cardiac sarcoidosis, and widespread sampling may be required to find them.
REFERENCES 1 Lagana SM, Parwani AV, Nichols LC. Cardiac sarcoidosis: a pathology-focused review. Arch Pathol Lab Med 2010; 134: 1039e46. 2 Zaidi AR, Zaidi A, Vaitkus PT. Outcome of heart transplantation in patients with sarcoid cardiomyopathy. J Heart Lung Transpl 2007; 26: 704e7. 3 Roberts WC, Chung MS, Ko JM, Capehart JE, Hall SA. Morphological features of cardiac sarcoidosis in native hearts of patients having cardiac transplantation. Am J Cardiol 2014; 113: 706e12. 4 Theofilogiannakos EK, Pettit SJ, Ghazi A, Rassl D, Lewis C, Parameshwar J. Heart transplantation for advanced heart failure due to cardiac sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis 2015; 32: 208e14.
2
Ó 2017 Published by Elsevier Ltd.
Please cite this article in press as: Preston SD, Cardiac sarcoidosis: infiltrating under cover, Diagnostic Histopathology (2017), https://doi.org/ 10.1016/j.mpdhp.2017.09.006
SHORT CASE
6 Leone O, Veinot JP, Angelini A, et al. 2011 Consensus statement on endomyocardial biopsy from the Association for European Cardiovascular Pathology and the Society for Cardiovascular Pathology. Cardiovasc Pathol 2012; 21: 245e74.
5 Luk A, Metawee M, Ahn E, Gustafson F, Ross H, Butany J. Do clinical diagnoses correlate with pathological diagnoses in cardiac transplant patients? The importance of endomyocardial biopsy. Can J Cardiol 2009; 25: e48e54.
SELF-ASSESSMENT Questions 1. Compact granulomas and replacement fibrosis within myocardium are most in keeping with: a. b. c. d.
Giant cell myocarditis Sarcoidosis Tuberculosis Rheumatic fever
2. Anitschkow cells are pathognomonic of: a. b. c. d.
Dilated cardiomyopathy Acute rheumatic carditis Chronic ischaemic heart disease Sarcoidosis
3. Cardiac sarcoidosis may present as: a. b. c. d.
Cardiac failure Sudden cardiac death Heart block All of the above
1. The correct answer is b. Sarcoidosis. Giant cell myocarditis (GCM) is characterised by macrophage giant cells with lymphocytes, usually with prominent eosinophils. GCM will cause fibrosis in the chronic phase but is usually a florid inflammatory condition. Tuberculous myocarditis is typically characterised by necrotising, not compact, granulomas, and is very rare. Acute rheumatic fever is characterised Aschoff bodies surrounding fibrinoid material.1 2. The correct answer is b. Acute Rheumatic carditis. Anitshkow cells are plump macrophages in which the chromatin condenses to form a linear “caterpillar-like” stripe down the centre of the nucleus. They are pathognomonic of rheumatic fever, and are one cellular component of Aschoff bodies along with lymphocytes and plasma cells. Aschoff bodies may occur in any part of the heart. 3. The correct answer is d. All of the above. Sarcoidosis is well known to mimic many other disease processes, and the same is true in the heart.
Answers
SELF-ASSESSMENT DIAGNOSTIC HISTOPATHOLOGY --:-
3
Ó 2017 Published by Elsevier Ltd.
Please cite this article in press as: Preston SD, Cardiac sarcoidosis: infiltrating under cover, Diagnostic Histopathology (2017), https://doi.org/ 10.1016/j.mpdhp.2017.09.006
Cardiac sarcoidosis: infiltrating under cover
block. The features were those of granulomatous myocarditis, consistent with sarcoidosis. The patient was reviewed with this in mind, but no evidence of sarcoidosis was found in other organ systems.
Stephen D Preston
Discussion Sarcoidosis is a multisystem disease of unknown aetiology characterised by compact non-necrotising granulomas. In patients with known sarcoidosis, only 5e10% have signs and symptoms of cardiac involvement. However, detailed questioning and investigation may demonstrate cardiac involvement in up to 40%. Signs and symptoms include sudden cardiac death, arrhythmia (atrial, ventricular or due to conduction system disease), and heart failure.1 Involvement of the heart is a serious complication, with approximately half of deaths due to sarcoidosis being a result of cardiac rather than other organ disease.1 Sarcoidosis is found in 0.17e3% of native hearts at transplantation and was considered a relative contraindication to heart transplantation as there was concern that the disease may recur in the xenograft.2e5 However, registry data showed that survival after cardiac transplantation for sarcoidosis was as good as, or better than, for patients without sarcoidosis. In this study, 65 patients with cardiac sarcoidosis had 88% 1-year survival (compared to 85% 1-year survival in patients transplanted for other conditions) with 80% still alive at 5 years.2 In a smaller, more recent, series of 12 cardiac sarcoidosis patients, posttransplant survival of 92% at 1 year and 83% at 5 years was achieved. No recurrent cardiac sarcoidosis or progressive extracardiac sarcoidosis was seen in any patient over a combined follow-up period of 1001 months (range: 5e288 months).4 Thus, whilst recurrent sarcoidosis may occur, it does not appear to adversely affect outcome from transplantation, and recurrent disease is rare. The majority of patients do not receive a diagnosis of cardiac sarcoidosis until pathological examination of the explant, with a preoperative diagnosis only being made in 0e33% of cases.4,5
Abstract This article describes a case of a heart explanted at transplantation for a clinical diagnosis of dilated cardiomyopathy associated with heart block. Pathological examination of the heart demonstrated nonnecrotising granulomas with replacement fibrosis, consistent with sarcoidosis. Cardiac involvement in sarcoidosis may cause chronic cardiac failure, arrhythmia, or sudden cardiac death, and may occur in patients without clinical involvement of other organ systems. Most cases of cardiac sarcoidosis treated by heart transplantation are unsuspected until the explanted heart is examined, with most cases thought to be dilated cardiomyopathy on clinical grounds.
Keywords heart block; heart failure; heart transplantation; sarcoidosis
Case report History This patient presented with 2:1 second degree heart block, treated by pacemaker. This progressed to severe left ventricular failure over the following 3 years. Coronary angiography demonstrated patent coronary arteries. A diagnosis of dilated cardiomyopathy was made. Whilst no relevant family history was present, Lamin A/C mutation related dilated cardiomyopathy was suggested by the combination of atrioventricular conduction delay and cardiomyopathy. The patient was listed for heart transplantation. A heart became available and was transplanted. The postoperative period was uneventful, and the patient was discharged just over 2 weeks postoperatively. The patient is now back at work and able to undertake some exercise. Pathology The heart weighed 480 g, with biventricular dilatation. The coronary arteries were widely patent, and there was no primary valvular disease. The myocardium had white patches of fibrosis in the septum and in the free walls of both ventricles (Figure 1). These did not have the regional distribution or thinning of the wall seen in myocardial infarction. Multiple tissue blocks from both ventricles and septum were sampled for histology. Histology demonstrated scattered, compact, non-necrotising granulomas within the myocardium and epicardium (Figure 2a and b). The pale lesions seen on gross inspection were areas of dense replacement fibrosis (Figure 2c). Granulomas were sparse within the fibrosis. Special stains for fungi and mycobacteria were negative. Increased fibrous tissue was seen in the atrioventricular node and bundle of His, which could explain heart
Stephen D Preston BSc(Hons) BM(Hons) MRCS(Eng) FRCPath Consultant Histopathologist, Papworth Hospital, Sims Woodhead Laboratory, Papworth Hospital, Cambridge, UK. Conflicts of interest: none.
DIAGNOSTIC HISTOPATHOLOGY --:-
Figure 1 Transverse sections through the ventricles showing biventricular dilatation with patchy white fibrosis. The grid lines are 1 cm apart.
1
Ó 2017 Published by Elsevier Ltd.
Please cite this article in press as: Preston SD, Cardiac sarcoidosis: infiltrating under cover, Diagnostic Histopathology (2017), https://doi.org/ 10.1016/j.mpdhp.2017.09.006
SHORT CASE
Figure 2 On histology, there were granulomas in (a) myocardium and (b) epicardium, with (c) areas of replacement fibrosis (a and b: Haematoxylin and eosin stain, c: elastic-van Gieson stain).
This is partly due to case selection, as patients with significant multi-organ sarcoidosis may not be selected for transplantation.4 However, some studies have suggested that patients with severe cardiac sarcoidosis tend to have less severe disease in other organ systems.3 It has been proposed that endomyocardial biopsy could improve pre-transplant diagnosis but the sensitivity of endomyocardial biopsy for sarcoidosis is only 19e25%.5,6 Some heart failure patients are supported before transplantation with a ventricular assist device and examination of the core of myocardium removed during this procedure provides another diagnostic opportunity.3 The frequency of granulomas is variable in cardiac sarcoidosis explants. Some hearts have granulomas in almost every high power field, whereas others have very few. The cases with fewest granulomas tend to have most fibrosis. The fibrosis is focal and is either transmural or subepicardial, and have a variable distribution.3 What is the relevance of the diagnosis to the patient? Earlier diagnosis might have permitted immunosuppressive therapy to slow the progress of the disease. Diagnosis at the time of transplantation changes the management of both the patient and their family. For the patient, the immunosuppressive regimen is modified. Corticosteroids are continued long term rather than tapered and stopped, to avoid recurrent sarcoidosis.4 For the family, this lifts the threat of a potentially heritable cardiomyopathy. A
DIAGNOSTIC HISTOPATHOLOGY --:-
Practice points C
C
C
Cardiac sarcoidosis should be considered in the differential diagnosis of a wide variety of cardiac symptoms and signs. Cardiac sarcoidosis may be found without other organ involvement. Granulomas may be sparse in long standing cardiac sarcoidosis, and widespread sampling may be required to find them.
REFERENCES 1 Lagana SM, Parwani AV, Nichols LC. Cardiac sarcoidosis: a pathology-focused review. Arch Pathol Lab Med 2010; 134: 1039e46. 2 Zaidi AR, Zaidi A, Vaitkus PT. Outcome of heart transplantation in patients with sarcoid cardiomyopathy. J Heart Lung Transpl 2007; 26: 704e7. 3 Roberts WC, Chung MS, Ko JM, Capehart JE, Hall SA. Morphological features of cardiac sarcoidosis in native hearts of patients having cardiac transplantation. Am J Cardiol 2014; 113: 706e12. 4 Theofilogiannakos EK, Pettit SJ, Ghazi A, Rassl D, Lewis C, Parameshwar J. Heart transplantation for advanced heart failure due to cardiac sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis 2015; 32: 208e14.
2
Ó 2017 Published by Elsevier Ltd.
Please cite this article in press as: Preston SD, Cardiac sarcoidosis: infiltrating under cover, Diagnostic Histopathology (2017), https://doi.org/ 10.1016/j.mpdhp.2017.09.006
SHORT CASE
6 Leone O, Veinot JP, Angelini A, et al. 2011 Consensus statement on endomyocardial biopsy from the Association for European Cardiovascular Pathology and the Society for Cardiovascular Pathology. Cardiovasc Pathol 2012; 21: 245e74.
5 Luk A, Metawee M, Ahn E, Gustafson F, Ross H, Butany J. Do clinical diagnoses correlate with pathological diagnoses in cardiac transplant patients? The importance of endomyocardial biopsy. Can J Cardiol 2009; 25: e48e54.
SELF-ASSESSMENT Questions 1. Compact granulomas and replacement fibrosis within myocardium are most in keeping with: a. b. c. d.
Giant cell myocarditis Sarcoidosis Tuberculosis Rheumatic fever
2. Anitschkow cells are pathognomonic of: a. b. c. d.
Dilated cardiomyopathy Acute rheumatic carditis Chronic ischaemic heart disease Sarcoidosis
3. Cardiac sarcoidosis may present as: a. b. c. d.
Cardiac failure Sudden cardiac death Heart block All of the above
1. The correct answer is b. Sarcoidosis. Giant cell myocarditis (GCM) is characterised by macrophage giant cells with lymphocytes, usually with prominent eosinophils. GCM will cause fibrosis in the chronic phase but is usually a florid inflammatory condition. Tuberculous myocarditis is typically characterised by necrotising, not compact, granulomas, and is very rare. Acute rheumatic fever is characterised Aschoff bodies surrounding fibrinoid material.1 2. The correct answer is b. Acute Rheumatic carditis. Anitshkow cells are plump macrophages in which the chromatin condenses to form a linear “caterpillar-like” stripe down the centre of the nucleus. They are pathognomonic of rheumatic fever, and are one cellular component of Aschoff bodies along with lymphocytes and plasma cells. Aschoff bodies may occur in any part of the heart. 3. The correct answer is d. All of the above. Sarcoidosis is well known to mimic many other disease processes, and the same is true in the heart.
Answers
SELF-ASSESSMENT DIAGNOSTIC HISTOPATHOLOGY --:-
3
Ó 2017 Published by Elsevier Ltd.
Please cite this article in press as: Preston SD, Cardiac sarcoidosis: infiltrating under cover, Diagnostic Histopathology (2017), https://doi.org/ 10.1016/j.mpdhp.2017.09.006