Journal of Forensic and Legal Medicine 32 (2015) 73e76
Contents lists available at ScienceDirect
Journal of Forensic and Legal Medicine j o u r n a l h o m e p a g e : w w w . e l s e v i e r . c o m / l o c a t e / j fl m
Case review
Pseudotumour formation in atheromatous coronary arteries Ann D. Treacy a, *, Katsuya Norita a, Peter J. Ingram b, Mary N. Sheppard a a b
Department of Histopathology, The National Heart and Lung Institute at the Royal Brompton Hospital, London, UK State Pathologist's Department, Institute of Forensic Medicine, Belfast, Northern Ireland, UK
a r t i c l e i n f o
a b s t r a c t
Article history: Received 11 August 2014 Received in revised form 14 October 2014 Accepted 7 February 2015 Available online 6 March 2015
Three cases with mass like lesions (pseudotumours) surrounding atheromatous coronary arteries were referred to the Royal Brompton Hospital for expert pathology review. All were males with mean age 74 years (range 55e91). In all cases, coronial autopsies were carried out for sudden deaths in the community. Past medical histories of note were hypertension (N ¼ 2) and ischaemic heart disease (N ¼ 1), with one patient having a past history of aortic aneurysm repair. At autopsy, firm, white and whorled masses surrounded both right and left coronary arteries ranging in size from 9 to 25 mm in diameter. Each coronary artery had intimal atheroma with associated stenosis ranging from moderate to severe. A thrombus was identified in one case. Histological sections showed a mixed inflammatory infiltrate extending from the media into the adventitia of each coronary artery, composed predominantly of plasma cells and lymphocytes with rare neutrophils and eosinophils. There was accompanying dense fibrosis accounting for approximately 50% of the mass size on microscopic examination of slides. The presence of intimal circumferential atheroma was confirmed in all cases. Immunohistochemical studies showed staining with IgG4 in two of three cases. Atheroma may be associated with mild chronic inflammation present in the intima or associated with plaques and adventitia. The differential diagnosis for coronary artery inflammatory masses would include vasculitis, syphilis, inflammatory pseudotumor and IgG4 associated disease. This is the first report of isolated coronary artery IgG4 related disease in association with atheroma. © 2015 Elsevier Ltd and Faculty of Forensic and Legal Medicine. All rights reserved.
Keywords: IgG4 associated disease Pseudotumor Atheroma Coronary artery atheroma
1. Introduction Coronary artery atheroma accounts for the vast majority of sudden cardiac deaths in the community.1 In most cases autopsy examination yields atheromatous coronary arteries and occasionally a thrombus.2 The pathogenesis of atheroma is due to endothelial damage and lipid accumulation in foamy macrophages3 and consequently these lesions are often associated with chronic inflammatory cells. Coronary artery vasculitis accounts for a rare number of deaths.4 Similarly mass lesions associated with coronary arteries are
infrequent findings at autopsy. Possible aetiologies include aneurysm, pseudo aneurysm or malignancy such as lymphoma. We report a series of atheromatous coronary arteries with masses seen grossly and histologically confirmed florid lymphoplasmacytic inflammation, the differential diagnosis for which would include vasculitis, syphilis, inflammatory pseudotumor and IgG4 associated disease. We discuss the histological and immunohistochemical findings and report for the first time isolated coronary IgG4 disease in the setting of atheroma.
2. Case histories
Abbreviations: CRY, cardiac risk in the young; SLE, systemic lupus erythematosus; LAD, left anterior descending; RCA, right coronary artery. * Corresponding author. Present address: Department of Histopathology, Mater Private Hospital, Eccles St., Dublin 7, Ireland. Tel.: þ353 (87) 8076849. E-mail addresses: [email protected] (A.D. Treacy), Peter.Ingram@statepathni. org.uk (P.J. Ingram), [email protected] (M.N. Sheppard).
Three cases with mass like lesions surrounding atheromatous coronary arteries were referred to the CRY Cardiac Pathology Unit at Royal Brompton Hospital, a tertiary cardiac pathology referral centre. All cases were referred for an expert opinion, from the State Pathologist's Department at the Institute of Forensic Medicine, Belfast, which carried out 1132 autopsies that year. Routine autopsy
http://dx.doi.org/10.1016/j.jflm.2015.02.004 1752-928X/© 2015 Elsevier Ltd and Faculty of Forensic and Legal Medicine. All rights reserved.
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A.D. Treacy et al. / Journal of Forensic and Legal Medicine 32 (2015) 73e76
examination involved review of prior medical history and circumstances of death, detailed external examination, internal examination and dissection of all organs and histological assessment of all major organs (heart, lungs, liver, kidneys) as well as examination of any macroscopic abnormalities seen. Slides and blocks from the coronary arteries and myocardium were referred for review. Immunohistochemical studies were carried out using 4 mm thick formalin fixed, paraffin embedded tissue sections with the antibodies against CD3, CD20, ALK-1, CD68, IgG4 and IgG. The slides were prepared using heat induced epitope retrieval (CD3, CD20, CD68 & ALK-1) and enzyme retrieval (IgG & IgG4) and stained on a Ventana Benchmark platform. Slides for IgG4 and IgG were reviewed and areas of highest concentration of staining cells identified. Three high power fields (40x) were counted and an average calculated along with the IgG4 to IgG ratio. The three cases were all males with mean age 74 years (range 55e91 years). In all cases coronial autopsies were carried out for sudden deaths in the community. Past medical histories of note were hypertension (N ¼ 2) and ischaemic heart disease (N ¼ 1), with one patient having a past history of aortic aneurysm repair. No history of left heart catheterization, coronary artery angioplasty, and/or stenting was noted. At autopsy, firm, white and whorled masses were described surrounding atheromatous left and right coronary arteries ranging in size from 9 to 25 mm in diameter (Fig. 1). These extended from the ostia of the vessels all along the route of each to the distal aspect of the vessel. In one case masses were present around both right and left arteries. The other cases involved the main branches of a single coronary artery (right ¼ 1, left ¼ 1). They were surrounding and intimately involved with the wall of the coronary artery. Each coronary artery had intimal atheroma with narrowing of the lumen ranging from moderate (50% stenosis) to severe (>75% stenosis). A thrombus was identified in one case (Fig. 2). No gross infiltration of the myocardium was seen. No vascular abnormalities or lesions were identified elsewhere in two of the cases. No masses were identified elsewhere on gross examination. One of the cases had repair of an abdominal aortic aneurysm five years prior to death, however this was on a background of severe atheromatous aortic disease and hypertension. At autopsy the Dacron graft was patent and there was evidence of extensive atheroma but no inflammatory masses.
Fig. 1. Macroscopic image of coronary artery showing concentric atheroma with associated fibrotic mass extending into surrounding fat.
Fig. 2. Macroscopic image of coronary artery with concentric atheroma, plaque rupture with thrombus formation. Surrounding the artery there is fibrosis which shows extension into fat.
Histological sections of coronary arteries showed a mixed inflammatory infiltrate extending from the media into the adventitia, composed predominantly of plasma cells and lymphocytes with rare neutrophils and eosinophils. No giant cells or epithelioid cells were noted. No necrosis was present. Inflammation extended into the surrounding epicardial fat with associated lymphoid aggregate formation at the edge along with focal infiltration of the myocardium by these lymphoid aggregates (Fig. 3). There was accompanying dense fibrosis accounting for 50% of the mass size on microscopic examination of slides (Fig. 4). The presence of intimal circumferential atheroma was confirmed in all cases. Thrombosis associated with rupture was seen in one case. All the intramural vessels were free of atheroma and did not contain this inflammatory infiltrate. Myocardial fibrosis was identified in one case. Besides the focal lymphoid aggregates described, no inflammatory infiltrate was present in the rest of the myocardium. No vasculitis or lymphoplasmacytic inflammation was seen on histological sections of other organs sampled at autopsy. Histological assessment of the pancreas was carried out in two of three cases and showed no evidence of IgG4 related disease. No histological examination of the aorta was carried out.
Fig. 3. Low power (4X) microscopic image of coronary artery with mild concentric atheroma and surrounding fibrosis with inflammation including multiple lymphoid aggregates. The inflammation shows infiltration into surrounding fat.
A.D. Treacy et al. / Journal of Forensic and Legal Medicine 32 (2015) 73e76
Fig. 4. High power (20X) microscopic image showing an area of central fibrosis and adjacent areas of mixed fibrosis and lymphoplasmacytic inflammation.
Immunohistochemical studies showed staining of inflammatory cells with CD68 (a histiocyte marker) and CD3 (a T lymphocyte marker). No staining was seen with ALK 1. Positive staining with IgG4 was identified in two of three cases, with a mean count of >50 IgG4 positive cells in a high power field and a IgG4 to IgG ratio >50% (Fig. 5). Causes of death were head injury, thrombosis of right coronary artery and critical stenosis of the left anterior descending coronary artery respectively. 3. Discussion Coronary artery atheroma is a common finding at autopsy and is the leading cause of death in 60% of sudden cardiac deaths.5,6 Atheroma may be associated with mild chronic inflammation present in the intima, within plaques and also in the adventitia. Atheroma has been described as a chronic inflammatory response process7 with the atheromatous artery producing enzymes, adhesion molecules and cytokines seen in chronic inflammation with a corresponding rise in CRP (C reactive protein) levels.8 Whilst some of the inflammatory process may be reflected in increased blood levels of inflammatory cytokines or other acute phase reactants,8 much of the inflammatory response is a local one but many cases show adventitial chronic inflammatory cells with lymphoid follicles are also seen with atheroma.9 However atheroma is rarely associated with a coronary artery inflammatory mass, raising a differential diagnosis, which includes
vasculitis, syphilis, inflammatory pseudotumor and IgG4 associated disease. Coronary artery vasculitis is a rare cause of sudden cardiac death. In many cases it may be a manifestation of systemic conditions such as collagen vascular diseases (systemic lupus erythematosus SLE),5,10 rheumatoid arthritis, Behçet's disease, hypersensitivity arteritis, Churg-Strauss syndrome and Wegener's granulomatosis.4,6 In children, Takayasu's arteritis and Kawasaki disease are the most common forms of coronary artery vasculitis. The inflammatory cell infiltrate varies depending on the aetiological cause with neutrophilic infiltrates commonly seen with Wegner's granulomatosis7,11 and eosinophils or plasma cells more commonly seen in cases associated with ChurgeStrauss syndrome, rheumatoid arteritis or SLE. In all cases of vasculitis the coronary arteries show little or no evidence of atheroma.4,8 None of our cases showed systemic vasculitis or had a past medical history to suggest it as an aetiological factor. The presence of a lymphoplasmacytic infiltrate as we have described, raises the differential diagnosis of tertiary syphilis, however tertiary syphilis is associated with saccular aneurysms and with aortic disease,12,13 with isolated coronary artery involvement reported in a single case report only.14 In the absence of serological and clinical evidence to support syphilis, along with the absence of aortic disease we chose to exclude it in these three cases. In recent times lymphoplasmacytic inflammation raises the possibility of IgG4 associated disease, a fibro-inflammatory condition which has been reported in various organs singly or in multiple sites as a systemic disorder.8,15e17 Histological features associated with IgG4 related disease include a dense lymphoplasmacytic infiltrate arranged in a storiform pattern with variable numbers of eosinophils.9,18,19 The inflammatory infiltrate may be associated with a mass lesion. The inflammatory cells are usually a mix of B and T lymphocytes. The presence of IgG4 bearing plasma cells is necessary for diagnosis of IgG4 related disease.15,20 Analysis of IgG4 immunohistochemistry has been a contentious issue with a range of cut-off points reported,21,22 however a recent consensus statement proposes different cut-off points depending on organ sites, along with careful correlation with histological appearances, clinical details and radiological appearances.23,24 The IgG to IgG4 ratio is another important consideration with a ratio of >40% deemed mandatory for a histological diagnosis of IgG4 related disease irrespective of site.24,25 IgG4 related disease of the cardiovascular system is rare. Cases of IgG4 related inflammatory abdominal aortic aneurysms account for a subset of inflammatory abdominal aortic aneurysms26 and one case series has reported IgG4 related sclerosing disease in 4% of all thoracic aortic lesions.27 Similarly case reports reporting involvement of popliteal and femoral arteries28 have been published. These cases were not associated with atheromatous disease. The case series we report share morphological features and histology descriptions of mass like lesion around the coronary arteries.25,29,30 Our cases were not associated with IgG4 related disease elsewhere. Serum concentrations of IgG4 are increased in patients with angiographically-proven coronary artery disease, suggesting that IgG4-related immuno-inflammation may also have a role in the development and/or progression of coronary artery atherosclerosis.23 Yet the association of florid IgG4 inflammation and pseudotumor formation in coronary arteries is rare in the setting of atheroma, which is such a common disease. Conflicts of interest The authors report no conflicts of interest.
Fig. 5. High power (20X) view of IgG4 immunohistochemical stain showing positive staining of numerous plasma cells.
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Funding None.
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Ethical approval None declared. References 1. Thomas AC, Knapman PA, Krikler DM, Davies MJ. Community study of the causes of “natural” sudden death. BMJ 1988 Dec 3;297(6661):1453e6. 2. Davies MJ. Anatomic features in victims of sudden coronary death. Coronary artery pathology. Circulation 1992 Jan;85(Suppl. 1):I19e24. 3. Ross R. The pathogenesis of atherosclerosisean update. N Engl J Med 1986 Feb 20;314(8):488e500. 4. Norita K, Noronha SV, Sheppard MN. Sudden cardiac death caused by coronary vasculitis. Virchows Arch 2012 Feb 4;460(3):309e18. 5. Bowker TJ, Wood DA, Davies MJ, Sheppard MN, Cary NRB, Burton JDK, et al. Sudden, unexpected cardiac or unexplained death in England: a national survey. QJM 2003 Apr;96(4):269e79. 6. Gallagher PJ. The pathological investigation of sudden cardiac death. Curr Diagn Pathol 2007 Oct;13(5):366e74. 7. Galle J. Atherosclerosis and arteriitis: implications for therapy of cardiovascular disease. Herz 2004 Feb 1;29(1):4e11. 8. Hansson GK. Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med 2005 Apr 21;352(16):1685e95. 9. Watanabe M, Sangawa A, Sasaki Y, Yamashita M, Tanaka-Shintani M, Shintaku M, et al. Distribution of inflammatory cells in adventitia changed with advancing atherosclerosis of human coronary artery. J Atheroscler Thromb 2007 Dec;14(6):325e31. 10. Abdellatif AA, Waris S, Lakhani A, Kadikoy H, Haque W, Truong LD. True vasculitis in lupus nephritis. Clin Nephrol 2010 Aug;74(2):106e12. 11. Aubry M-C. Necrotizing granulomatous inflammation: what does it mean if your special stains are negative? Mod Pathol 2012 Jan;25:S31e8. Nature Publishing Group. 12. Miller DV, Maleszewski JJ. The pathology of large-vessel vasculitides. Clin Exp Rheumatol 2011 Jan;29(1 Suppl. 64):S92e8. 13. Morphet J. Cardiovascular syphilis. Can J Cardiol 2008 Dec 1;24(12):886. Pulsus Group. 14. Kennedy JLW, Barnard JJ, Prahlow JA. Syphilitic coronary artery ostial stenosis resulting in acute myocardial infarction and death. Cardiology 2006;105(1):25e9. 15. Stone JH, Zen Y, Deshpande V. IgG4-related disease. N Engl J Med 2012 Feb 9;366(6):539e51. 16. Deshpande V, Chicano S, Chiocca S, Finkelberg D, Selig MK, Mino-Kenudson M, et al. Autoimmune pancreatitis: a systemic immune complex mediated disease. Am J Surg Pathol 2006 Dec;30(12):1537e45.
17. Divatia M, Kim SA, Ro JY. IgG4-Related sclerosing disease, an emerging entity: a review of a multi-system disease. Yonsei Med J 2012;53(1):15. 18. Deshpande V, Gupta R, Sainani N, Sahani DV, Virk R, Ferrone C, et al. Subclassification of autoimmune pancreatitis: a histologic classification with clinical significance. Am J Surg Pathol 2011 Jan;35(1):26e35. 19. Zen Y, Nakanuma Y. IgG4-Related disease: a cross-sectional study of 114 cases. Am J Surg Pathol 2010 Dec 1;34(12):1812. 20. Higuchi ML, Gutierrez PS, Bezerra HG, Palomino SA, Aiello VD, Silvestre JML, et al. Comparison between adventitial and intimal inflammation of ruptured and nonruptured atherosclerotic plaques in human coronary arteries. Arq Bras Cardiol 2002 Jul;79(1):20e4. 21. Tanigawa J, Daimon M, Murai M, Katsumata T, Tsuji M, Ishizaka N. Immunoglobulin G4-related coronary periarteritis in a patient presenting with myocardial ischemia. Hum Pathol 2012 Jul;43(7):1131e4. 22. Dhall D, Suriawinata AA, Tang LH, Shia J, Klimstra DS. Use of immunohistochemistry for IgG4 in the distinction of autoimmune pancreatitis from peritumoral pancreatitis. Hum Pathol 2010 May;41(5):643e52. 23. Sakamoto A, Ishizaka N, Saito K, Imai Y, Morita H, Koike K, et al. Serum levels of IgG4 and soluble interleukin-2 receptor in patients with coronary artery disease. Clin Chim Acta 2012 Mar 22;413(5e6):577e81. 24. Deshpande V, Zen Y, Chan JK, Yi EE, Sato Y, Yoshino T, et al. Consensus statement on the pathology of IgG4-related disease. Mod Pathol 2012 May 18;25(9): 1181e92. 25. Matsumoto Y, Kasashima S, Kawashima A, Sasaki H, Endo M, Kawakami K, et al. A case of multiple immunoglobulin G4-related periarteritis: a tumorous lesion of the coronary artery and abdominal aortic aneurysm. Hum Pathol 2008 Jun;39(6):975e80. Elsevier. 26. Kasashima S, Zen Y. IgG4-related inflammatory abdominal aortic aneurysm. Curr Opin Rheumatol 2011 Jan;23(1):18e23. 27. Kasashima S. A clinicopathologic study of immunoglobulin G4-related sclerosing disease of the thoracic aorta. J Vasc Surg 2010 Dec 1;52(6):1587e95. Elsevier Inc. 28. Kasashima S, Kawashima A, Endo M, Matsumoto Y, Kasashima F, Zen Y, et al. A clinicopathologic study of immunoglobulin G4-related disease of the femoral and popliteal arteries in the spectrum of immunoglobulin G4-related periarteritis. J Vasc Surg 2012 Nov 15:1e7. 29. Ikutomi M, Matsumura T, Iwata H, Nishimura G, Ishizaka N, Hirata Y, et al. Giant tumorous lesions (correction of legions) surrounding the right coronary artery associated with immunoglobulin-G4-related systemic disease. Cardiology 2011;120(1):22e6. 30. Tajima M, Nagai R, Hiroi Y. IgG4-Related cardiovascular disorders. Int Heart J 2014 Jul 10;55(4):287e95.
Contents lists available at ScienceDirect
Journal of Forensic and Legal Medicine j o u r n a l h o m e p a g e : w w w . e l s e v i e r . c o m / l o c a t e / j fl m
Case review
Pseudotumour formation in atheromatous coronary arteries Ann D. Treacy a, *, Katsuya Norita a, Peter J. Ingram b, Mary N. Sheppard a a b
Department of Histopathology, The National Heart and Lung Institute at the Royal Brompton Hospital, London, UK State Pathologist's Department, Institute of Forensic Medicine, Belfast, Northern Ireland, UK
a r t i c l e i n f o
a b s t r a c t
Article history: Received 11 August 2014 Received in revised form 14 October 2014 Accepted 7 February 2015 Available online 6 March 2015
Three cases with mass like lesions (pseudotumours) surrounding atheromatous coronary arteries were referred to the Royal Brompton Hospital for expert pathology review. All were males with mean age 74 years (range 55e91). In all cases, coronial autopsies were carried out for sudden deaths in the community. Past medical histories of note were hypertension (N ¼ 2) and ischaemic heart disease (N ¼ 1), with one patient having a past history of aortic aneurysm repair. At autopsy, firm, white and whorled masses surrounded both right and left coronary arteries ranging in size from 9 to 25 mm in diameter. Each coronary artery had intimal atheroma with associated stenosis ranging from moderate to severe. A thrombus was identified in one case. Histological sections showed a mixed inflammatory infiltrate extending from the media into the adventitia of each coronary artery, composed predominantly of plasma cells and lymphocytes with rare neutrophils and eosinophils. There was accompanying dense fibrosis accounting for approximately 50% of the mass size on microscopic examination of slides. The presence of intimal circumferential atheroma was confirmed in all cases. Immunohistochemical studies showed staining with IgG4 in two of three cases. Atheroma may be associated with mild chronic inflammation present in the intima or associated with plaques and adventitia. The differential diagnosis for coronary artery inflammatory masses would include vasculitis, syphilis, inflammatory pseudotumor and IgG4 associated disease. This is the first report of isolated coronary artery IgG4 related disease in association with atheroma. © 2015 Elsevier Ltd and Faculty of Forensic and Legal Medicine. All rights reserved.
Keywords: IgG4 associated disease Pseudotumor Atheroma Coronary artery atheroma
1. Introduction Coronary artery atheroma accounts for the vast majority of sudden cardiac deaths in the community.1 In most cases autopsy examination yields atheromatous coronary arteries and occasionally a thrombus.2 The pathogenesis of atheroma is due to endothelial damage and lipid accumulation in foamy macrophages3 and consequently these lesions are often associated with chronic inflammatory cells. Coronary artery vasculitis accounts for a rare number of deaths.4 Similarly mass lesions associated with coronary arteries are
infrequent findings at autopsy. Possible aetiologies include aneurysm, pseudo aneurysm or malignancy such as lymphoma. We report a series of atheromatous coronary arteries with masses seen grossly and histologically confirmed florid lymphoplasmacytic inflammation, the differential diagnosis for which would include vasculitis, syphilis, inflammatory pseudotumor and IgG4 associated disease. We discuss the histological and immunohistochemical findings and report for the first time isolated coronary IgG4 disease in the setting of atheroma.
2. Case histories
Abbreviations: CRY, cardiac risk in the young; SLE, systemic lupus erythematosus; LAD, left anterior descending; RCA, right coronary artery. * Corresponding author. Present address: Department of Histopathology, Mater Private Hospital, Eccles St., Dublin 7, Ireland. Tel.: þ353 (87) 8076849. E-mail addresses: [email protected] (A.D. Treacy), Peter.Ingram@statepathni. org.uk (P.J. Ingram), [email protected] (M.N. Sheppard).
Three cases with mass like lesions surrounding atheromatous coronary arteries were referred to the CRY Cardiac Pathology Unit at Royal Brompton Hospital, a tertiary cardiac pathology referral centre. All cases were referred for an expert opinion, from the State Pathologist's Department at the Institute of Forensic Medicine, Belfast, which carried out 1132 autopsies that year. Routine autopsy
http://dx.doi.org/10.1016/j.jflm.2015.02.004 1752-928X/© 2015 Elsevier Ltd and Faculty of Forensic and Legal Medicine. All rights reserved.
74
A.D. Treacy et al. / Journal of Forensic and Legal Medicine 32 (2015) 73e76
examination involved review of prior medical history and circumstances of death, detailed external examination, internal examination and dissection of all organs and histological assessment of all major organs (heart, lungs, liver, kidneys) as well as examination of any macroscopic abnormalities seen. Slides and blocks from the coronary arteries and myocardium were referred for review. Immunohistochemical studies were carried out using 4 mm thick formalin fixed, paraffin embedded tissue sections with the antibodies against CD3, CD20, ALK-1, CD68, IgG4 and IgG. The slides were prepared using heat induced epitope retrieval (CD3, CD20, CD68 & ALK-1) and enzyme retrieval (IgG & IgG4) and stained on a Ventana Benchmark platform. Slides for IgG4 and IgG were reviewed and areas of highest concentration of staining cells identified. Three high power fields (40x) were counted and an average calculated along with the IgG4 to IgG ratio. The three cases were all males with mean age 74 years (range 55e91 years). In all cases coronial autopsies were carried out for sudden deaths in the community. Past medical histories of note were hypertension (N ¼ 2) and ischaemic heart disease (N ¼ 1), with one patient having a past history of aortic aneurysm repair. No history of left heart catheterization, coronary artery angioplasty, and/or stenting was noted. At autopsy, firm, white and whorled masses were described surrounding atheromatous left and right coronary arteries ranging in size from 9 to 25 mm in diameter (Fig. 1). These extended from the ostia of the vessels all along the route of each to the distal aspect of the vessel. In one case masses were present around both right and left arteries. The other cases involved the main branches of a single coronary artery (right ¼ 1, left ¼ 1). They were surrounding and intimately involved with the wall of the coronary artery. Each coronary artery had intimal atheroma with narrowing of the lumen ranging from moderate (50% stenosis) to severe (>75% stenosis). A thrombus was identified in one case (Fig. 2). No gross infiltration of the myocardium was seen. No vascular abnormalities or lesions were identified elsewhere in two of the cases. No masses were identified elsewhere on gross examination. One of the cases had repair of an abdominal aortic aneurysm five years prior to death, however this was on a background of severe atheromatous aortic disease and hypertension. At autopsy the Dacron graft was patent and there was evidence of extensive atheroma but no inflammatory masses.
Fig. 1. Macroscopic image of coronary artery showing concentric atheroma with associated fibrotic mass extending into surrounding fat.
Fig. 2. Macroscopic image of coronary artery with concentric atheroma, plaque rupture with thrombus formation. Surrounding the artery there is fibrosis which shows extension into fat.
Histological sections of coronary arteries showed a mixed inflammatory infiltrate extending from the media into the adventitia, composed predominantly of plasma cells and lymphocytes with rare neutrophils and eosinophils. No giant cells or epithelioid cells were noted. No necrosis was present. Inflammation extended into the surrounding epicardial fat with associated lymphoid aggregate formation at the edge along with focal infiltration of the myocardium by these lymphoid aggregates (Fig. 3). There was accompanying dense fibrosis accounting for 50% of the mass size on microscopic examination of slides (Fig. 4). The presence of intimal circumferential atheroma was confirmed in all cases. Thrombosis associated with rupture was seen in one case. All the intramural vessels were free of atheroma and did not contain this inflammatory infiltrate. Myocardial fibrosis was identified in one case. Besides the focal lymphoid aggregates described, no inflammatory infiltrate was present in the rest of the myocardium. No vasculitis or lymphoplasmacytic inflammation was seen on histological sections of other organs sampled at autopsy. Histological assessment of the pancreas was carried out in two of three cases and showed no evidence of IgG4 related disease. No histological examination of the aorta was carried out.
Fig. 3. Low power (4X) microscopic image of coronary artery with mild concentric atheroma and surrounding fibrosis with inflammation including multiple lymphoid aggregates. The inflammation shows infiltration into surrounding fat.
A.D. Treacy et al. / Journal of Forensic and Legal Medicine 32 (2015) 73e76
Fig. 4. High power (20X) microscopic image showing an area of central fibrosis and adjacent areas of mixed fibrosis and lymphoplasmacytic inflammation.
Immunohistochemical studies showed staining of inflammatory cells with CD68 (a histiocyte marker) and CD3 (a T lymphocyte marker). No staining was seen with ALK 1. Positive staining with IgG4 was identified in two of three cases, with a mean count of >50 IgG4 positive cells in a high power field and a IgG4 to IgG ratio >50% (Fig. 5). Causes of death were head injury, thrombosis of right coronary artery and critical stenosis of the left anterior descending coronary artery respectively. 3. Discussion Coronary artery atheroma is a common finding at autopsy and is the leading cause of death in 60% of sudden cardiac deaths.5,6 Atheroma may be associated with mild chronic inflammation present in the intima, within plaques and also in the adventitia. Atheroma has been described as a chronic inflammatory response process7 with the atheromatous artery producing enzymes, adhesion molecules and cytokines seen in chronic inflammation with a corresponding rise in CRP (C reactive protein) levels.8 Whilst some of the inflammatory process may be reflected in increased blood levels of inflammatory cytokines or other acute phase reactants,8 much of the inflammatory response is a local one but many cases show adventitial chronic inflammatory cells with lymphoid follicles are also seen with atheroma.9 However atheroma is rarely associated with a coronary artery inflammatory mass, raising a differential diagnosis, which includes
vasculitis, syphilis, inflammatory pseudotumor and IgG4 associated disease. Coronary artery vasculitis is a rare cause of sudden cardiac death. In many cases it may be a manifestation of systemic conditions such as collagen vascular diseases (systemic lupus erythematosus SLE),5,10 rheumatoid arthritis, Behçet's disease, hypersensitivity arteritis, Churg-Strauss syndrome and Wegener's granulomatosis.4,6 In children, Takayasu's arteritis and Kawasaki disease are the most common forms of coronary artery vasculitis. The inflammatory cell infiltrate varies depending on the aetiological cause with neutrophilic infiltrates commonly seen with Wegner's granulomatosis7,11 and eosinophils or plasma cells more commonly seen in cases associated with ChurgeStrauss syndrome, rheumatoid arteritis or SLE. In all cases of vasculitis the coronary arteries show little or no evidence of atheroma.4,8 None of our cases showed systemic vasculitis or had a past medical history to suggest it as an aetiological factor. The presence of a lymphoplasmacytic infiltrate as we have described, raises the differential diagnosis of tertiary syphilis, however tertiary syphilis is associated with saccular aneurysms and with aortic disease,12,13 with isolated coronary artery involvement reported in a single case report only.14 In the absence of serological and clinical evidence to support syphilis, along with the absence of aortic disease we chose to exclude it in these three cases. In recent times lymphoplasmacytic inflammation raises the possibility of IgG4 associated disease, a fibro-inflammatory condition which has been reported in various organs singly or in multiple sites as a systemic disorder.8,15e17 Histological features associated with IgG4 related disease include a dense lymphoplasmacytic infiltrate arranged in a storiform pattern with variable numbers of eosinophils.9,18,19 The inflammatory infiltrate may be associated with a mass lesion. The inflammatory cells are usually a mix of B and T lymphocytes. The presence of IgG4 bearing plasma cells is necessary for diagnosis of IgG4 related disease.15,20 Analysis of IgG4 immunohistochemistry has been a contentious issue with a range of cut-off points reported,21,22 however a recent consensus statement proposes different cut-off points depending on organ sites, along with careful correlation with histological appearances, clinical details and radiological appearances.23,24 The IgG to IgG4 ratio is another important consideration with a ratio of >40% deemed mandatory for a histological diagnosis of IgG4 related disease irrespective of site.24,25 IgG4 related disease of the cardiovascular system is rare. Cases of IgG4 related inflammatory abdominal aortic aneurysms account for a subset of inflammatory abdominal aortic aneurysms26 and one case series has reported IgG4 related sclerosing disease in 4% of all thoracic aortic lesions.27 Similarly case reports reporting involvement of popliteal and femoral arteries28 have been published. These cases were not associated with atheromatous disease. The case series we report share morphological features and histology descriptions of mass like lesion around the coronary arteries.25,29,30 Our cases were not associated with IgG4 related disease elsewhere. Serum concentrations of IgG4 are increased in patients with angiographically-proven coronary artery disease, suggesting that IgG4-related immuno-inflammation may also have a role in the development and/or progression of coronary artery atherosclerosis.23 Yet the association of florid IgG4 inflammation and pseudotumor formation in coronary arteries is rare in the setting of atheroma, which is such a common disease. Conflicts of interest The authors report no conflicts of interest.
Fig. 5. High power (20X) view of IgG4 immunohistochemical stain showing positive staining of numerous plasma cells.
75
Funding None.
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