Case Reports

Sudden Cardiac Death Due to Coronary Artery Involvement by IgG4-Related Disease A Rare, Serious Complication of a Rare Disease Nimesh R. Patel, MD; Mary L. Anzalone, MD; L. Maximilian Buja, MD; M. Tarek Elghetany, MD

 Immunoglobulin G4–related disease (IgG4-RD) is a systemic disorder characterized by multiorgan fibrosis with IgG4-producing plasma cells, increased IgG4 serum concentration, and responsiveness to steroid therapy. Involvement of the pancreas, salivary glands, orbit, aorta, and other sites has been well documented in the literature; however, there have been limited reports of cases involving the coronary arteries. We report the case of a 53-year-old Hispanic man who was brought to the emergency center and diagnosed with sudden cardiac death. Autopsy was subsequently performed, revealing multiorgan involvement by IgG4-RD, including involvement of the coronary arteries. The inflammation and fibrosis, in combination with concomitant atherosclerotic disease, resulted in severe stenosis of the coronary arteries. Two of the coronary arteries were further occluded by thrombosis. These factors led to cardiac hypoperfusion, myocardial infarction and, ultimately, sudden cardiac death. Fatal involvement of the coronary arteries has not been previously reported, raising a new concern for a severe complication of IgG4-RD. (Arch Pathol Lab Med. 2014;138:833–836; doi: 10.5858/ arpa.2012-0614-CR)



53-year-old Hispanic man with an unknown medical history was brought to the emergency center after he was found unresponsive on the floor of his apartment by his roommate. The patient had complained of chest pain earlier during the day, as well

Accepted for publication June 21, 2013. From the Department of Pathology & Immunology, Baylor College of Medicine, Houston, Texas (Drs Patel and Elghetany); Medical Examiner Service, Harris County Institute of Forensic Sciences, Houston, Texas (Dr Anzalone); the Department of Pathology & Laboratory Medicine, The University of Texas Health Science Center at Houston (Dr Buja); and the Department of Pathology, Texas Children’s Hospital, Houston (Dr Elghetany). The authors have no relevant financial interest in the products or companies described in this article. A prior version of the abstract was presented online in association with the 2012 Meeting of the Texas Society of Pathologists; January 13–14, 2012; Dallas, Texas. Reprints: Nimesh R. Patel, MD, Department of Pathology & Immunology, Baylor College of Medicine, One Baylor Plaza, BCM 315, Houston, TX 77030 (e-mail: [email protected]). Arch Pathol Lab Med—Vol 138, June 2014

as before the day of presentation. Cardiopulmonary resuscitation was attempted in the field and in the emergency center. The patient underwent intubation, advanced cardiovascular life support protocol was initiated, and the patient received epinephrine, atropine, and vasopressin. However, he remained asystolic and death was pronounced 5 minutes after presentation.

PATHOLOGIC FINDINGS Autopsy was performed and external examination revealed xanthelasma of the bilateral eyelids. Upon internal examination, a diffuse fibrous process involving multiple organ systems was seen. There was cardiomegaly (430 g) with left ventricular hypertrophy and severe 3-vessel coronary artery disease (Figure 1, A through C). The coronary arteries exhibited severe atherosclerosis involving the proximal left anterior descending artery (with near total luminal occlusion), as well as the proximal left circumflex and right coronary arteries (which appeared thrombosed). In addition, the proximal coronary arteries displayed conspicuously thick walls and were encased by pink-tan, fleshy tissue, raising the concern for an infiltrative process. This was associated with subacute myocardial infarction of the anterolateral left ventricular wall from the apex of the heart to the base. Microscopically, the proximal coronary arteries showed luminal stenosis due to encasement and transmural infiltration by lymphocytes and plasma cells with fibrosis and rare eosinophils. The infiltrate extensively involved the media and adventitia, but also involved the intima (Figure 2, A and B). Phlebitis of the vasa vasorum and perineural inflammation were identified within the adventitia. Immunohistochemical staining for immunoglobulin (Ig) G4 (rabbit monoclonal, 1:800; Epitomics, Inc, Burlingame, California) was performed on representative formalin-fixed paraffin-embedded sections of the coronary arteries (Figure 2, C). There was an average of 505 IgG4-positive plasma cells per high-power field (HPF; 3 fields examined in the most plasma cell–rich areas; 340 objective and 310 ocular). The coronary arteries also showed marked involvement by atherosclerosis, and 2 of the vessels displayed concomitant thrombosis, resulting in luminal occlusion. The myocardium demonstrated a transmural subacute infarct characterized by fibrovascular granulation tissue with siderophages and scattered plasma cells. Other cardiac findings included myocyte hypertrophy, patchy interstitial fibrosis, and a focal infiltrate of plasma cells within the epicardium.

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Figure 1. Gross images. The proximal left circumflex artery (A, in situ, indicated by arrow) and right coronary artery (B, serially sectioned) are encased by tan, fleshy tissue and display atherosclerotic changes with luminal thrombosis. The left anterior descending artery (C, serially sectioned) shows severe stenosis by an atherosclerotic plaque, as well as fibroinflammatory thickening of the adventitia. Figure 2. A, Examination of a coronary artery shows a lymphoplasmacytic infiltrate with increased fibrosis involving the adventitia, media, and intima. There is also concomitant atherosclerotic disease and thrombosis, resulting in luminal occlusion of the vessel. B, High-power view of the lymphoplasmacytic infiltrate within the wall of a coronary artery. C, Immunohistochemical staining for IgG4 shows an extensive, dense infiltrate of IgG4-positive plasma cells within the same area of the coronary artery wall seen in B (hematoxylin-eosin, original magnifications 320 [A] and 3400 [B]; original magnification 3400 [C]).

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The right and left kidneys weighed 250 g and 275 g, respectively. The cortices appeared mottled and were partially replaced by multiple tan, fleshy subcapsular nodules. Microscopically, the kidneys showed a diffuse lymphoplasmacytic infiltrate with eosinophils and exuberant fibrosis, as well as arterionephrosclerosis and arteriolonephrosclerosis. The pancreas was firm and adherent to the peripancreatic adipose tissue. Sectioning of the pancreas revealed extensive infiltration of the parenchyma by firm, tan, fleshy tissue. Microscopically, there was an extensive infiltrate of lymphocytes, plasma cells, and eosinophils with exuberant fibrosis. There were multiple enlarged bronchomediastinal, paraaortic, peripancreatic, and iliac lymph nodes measuring up to 4 cm in greatest dimension. The cut surface of representative lymph nodes consisted of tan, fleshy tissue. Microscopically, there were focal infiltrates of plasma cells with rare eosinophils and focal hemophagocytosis. The lymph node architecture was otherwise well preserved. The liver weighed 1600 g and was sectioned to reveal a dark red-brown, homogenous cut surface with no focal lesions. Sectioning of the lungs revealed a dark purple, congested, and edematous parenchyma without focal lesions. Microscopic examination of the portal tracts and sinusoidal spaces of the liver, as well as the bronchovascular structures of the lungs, revealed an infiltrate of plasma cells, lymphocytes, and eosinophils. Immunohistochemical staining for IgG4 was selectively performed on representative sections of kidney, pancreas, and lymph nodes, confirming markedly increased infiltrates of IgG4-positive plasma cells in each of these sites. In summary, the postmortem findings were consistent with multiorgan involvement by IgG4-related disease (IgG4-RD). The inflammation and sclerosis, in combination with concomitant atherosclerotic disease, resulted in severe stenosis of the coronary arteries. Two of the coronary arteries were further occluded by thrombosis. These factors led to cardiac hypoperfusion, myocardial infarction and, ultimately, sudden cardiac death. To our knowledge, this is the first reported case of fatal involvement of the coronary arteries by this disease. COMMENT IgG4-RD is an immune-mediated disease that can affect multiple organs and is characterized by a lymphoplasmacytic infiltrate with a distinctive population of IgG4-bearing plasma cells and sclerosis. In 2001, patients with autoimmune pancreatitis were found to have elevated serum concentrations of IgG4. Since then, involvement of numerous sites has been described, including the salivary glands, skin, periorbital tissue, lymph nodes, meninges, prostate, pericardium, and aorta.1 It is now thought that many diseases that were long viewed as unique entities are actually part of a single spectrum of disease. However, because of the relatively recent recognition of this spectrum, many names have been ascribed, including IgG4-related systemic disease, IgG4-related sclerosing disease, systemic IgG4 plasmacytic syndrome, and IgG4-related multiorgan lymphoproliferative syndrome.1,3 In 2010, the Umehara group in Japan reached a consensus to refer to this entity as IgG4-related disease in an effort to unify our understanding of the entity and its involvement with various sites in the body.2,4 Arch Pathol Lab Med—Vol 138, June 2014

Clinically, IgG4-RD usually affects middle-aged to elderly men. The incidence in Japan has been estimated to be 0.28 to 1.08 per 100 000 people.4 IgG4-RD commonly develops in organs with a ductal or glandular architecture,5 but this is not a consistent feature. In many cases, its clinical symptoms are relatively mild; however, some patients develop serious complications, including organ dysfunction due to the cellular infiltration and fibrosis, and symptoms of obstruction or compression as a result of organomegaly. Patients may have involvement of a single organ, or may have lesions in multiple organs, either synchronously or metachronously.4 Each of the involved organs shows an infiltrate of IgG4positive plasma cells in association with a variably elevated serum concentration of IgG4; however, the histopathologic features are dependent upon the organ involved.3,6 Therefore, Umehara and colleagues4 recently created a list of comprehensive diagnostic criteria, which includes the clinical finding of diffuse/localized swelling or masses in single or multiple organs; elevated serum IgG4 concentration (135 mg/dL); and histopathologic findings of fibrosis and a marked lymphoplasmacytic infiltrate, with IgG4positive plasma cells showing a ratio of greater than 40% IgG4þ/IgGþ cells and greater than 10 IgG4þ plasma cells per HPF. These are, of course, the minimal diagnostic criteria, and organ-specific criteria should still be used.4 In fact, different authors have used varying diagnostic cutoffs to alter the sensitivity and specificity3 of diagnosis. For example, Dhall et el7 used a cutoff of 50 IgG4þ cells per HPF (averaged over 3 fields in the most densely staining areas) in cases of pancreatitis and were able to distinguish type 1 autoimmune pancreatitis from other forms of pancreatitis with a sensitivity of 84% and a specificity of 100%. IgG4-RD usually responds significantly to glucocorticoid therapy, especially with early initiation of treatment; and some lesions have been reported to spontaneously regress. However, a lack of diagnosis may lead to long-term inflammatory processes that result in fibrosis and irreversible organ damage. Therefore, 18F-FDG-PET (18F-fluorodeoxyglucose positron emission tomography) scan can serve as a useful tool to discover organ involvement and help determine the therapeutic strategy.2 Vascular complications of IgG4-RD are uncommon but have been previously reported. In certain organs, involved veins can show segmental or transmural chronic inflammation and may show luminal occlusion by fibrous tissue (obliterative phlebitis)3; however, a vasculitic process per se is not seen, since the phlebitis does not show a significant component of neutrophils, fibrinoid necrosis, or karyorrhectic debris.6 On the other hand, in a subset of patients, periaortitis, true aortitis, and retroperitoneal fibrosis may represent either the sole manifestation or part of systemic involvement by IgG4-RD.8 In a 2011 meta-analysis, Stone8 showed that the arch is the most commonly involved portion of the thoracic aorta, with 3 of the 6 thoracic cases reported in the literature showing predominant involvement of the adventitia and the remaining 3 showing equivalent or predominant involvement of the media. In addition, there was variable obstructive phlebitis in the adventitia and storiform fibrosis. Kasashima and Zen5 found that aneurysmal dilatation is the principal feature in some cases, while wall thickening and severe inflammatory cell infiltration is predominant in others.

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Aortic aneurysms can be divided into inflammatory and atherosclerotic types. Inflammatory aortic aneurysms are usually seen within the infrarenal abdominal aorta.9 A subset of cases of inflammatory abdominal aortic aneurysm are due to IgG4-RD, although concomitant atherosclerotic changes can be seen in the media and intima.5 These cases also show fibrous adhesions extending into the surrounding soft tissue. The 7 reported cases of IgG4-related inflammatory abdominal aortic aneurysm8 were found to be comparable to the adventitia-predominant form of thoracic IgG4-related aortitis; however, the thoracic cases tended to show greater proportions of IgG4-positive plasma cells, increased frequency of involvement of the aortic media, and higher serum IgG4 levels. In general, inflammatory aortic aneurysm involving the ascending aorta or aortic arch is exceedingly rare, but IgG4-related inflammatory aneurysm of the aortic arch has been reported.9 IgG4-RD may also manifest as an inflammatory retroperitoneal lesion resulting from involvement of the abdominal aorta, kidneys, or ureters.8 In summary, all of these findings led Stone8 to conclude that adventitial involvement is a feature of IgG4related aortic lesions, while Kasashima and Zen5 emphasized that stricture and occlusive changes are not commonly seen. The concepts of inflammatory periarteritis and chronic coronary periarteritis have been previously discussed in the literature, including examples of patients without significant luminal stenosis, as well as patients with resulting ischemic heart disease.10 Furthermore, cases of inflammatory periaortitis or periarteritis of the superior mesenteric, inferior mesenteric, and splenic arteries have histologically proven to be consistent with IgG4-RD.10 However, to our knowledge, only a few cases of coronary periarteritis proven or presumed to be due to IgG4-RD have been thus far reported in the literature. In a retrospective analysis, Sakamoto et al11 described a patient with inflammatory coronary artery aneurysm, autoimmune pancreatitis, and markedly elevated serum IgG4 level. Matsumoto et al12 reported the case of a patient with IgG4related coronary periarteritis and abdominal aortic aneurysm. The right coronary artery (RCA) displayed a tumorous lesion consisting of severe inflammation and thickening of the adventitia with obliterative phlebitis of venous branches, sclerosing inflammation of the media, and an increased infiltrate of IgG4-positive plasma cells by immunohistochemistry. The aorta also showed predominant involvement of the adventitia. Takei et al13 reported the case of a patient with systemic IgG4-RD and associated abdominal aortic aneurysm, as well as multiple coronary aneurysms. This patient had dilatation and stenosis of the right and left coronary arteries; however, there was no clinical evidence of myocardial ischemia. Tanigawa et al14 reported the case of a patient with myocardial infarction who was found to have a periarterial mass with luminal narrowing of the left circumflex artery and increased serum IgG4 level. Biopsy of the mass showed lymphoid follicles as well as an increased infiltrate of IgG4positive plasma cells. This appears to be the first reported case of a patient with IgG4-related coronary periarteritis and active coronary ischemia. Subsequently, Ikutomi et al15 reported the case of a patient with IgG4-RD who presented with angina and was found to have stenotic lesions of the left anterior descending and left circumflex arteries with

1. Khosroshahi A, Stone JH. A clinical overview of IgG4-related systemic disease. Curr Opin Rheumatol. 2011;23(1):57–66. 2. Masaki Y, Kurose N, Umehara H. IgG4-related disease: a novel lymphoproliferative disorder discovered and established in Japan in the 21st century. J Clin Exp Hematop. 2011;51(1):13–20. 3. Cheuk W, Chan JKC. IgG4-related sclerosing disease: a critical appraisal of an evolving clinicopathologic entity. Adv Anat Pathol. 2010;17(5):303–332. 4. Umehara H, Okazaki K, Masaki Y, et al. Comprehensive diagnostic criteria for IgG4-related disease (IgG4-RD), 2011. Mod Rheumatol. 2012;22(1):21–30. 5. Kasashima S, Zen Y. IgG4-related inflammatory abdominal aortic aneurysm. Curr Opin Rheumatol. 2011;23(1):18–23. 6. Smyrk TC. Pathological features of IgG4-related sclerosing disease. Curr Opin Rheumatol. 2011;23(1):74–79. 7. 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;41(5):643–652. 8. Stone JR. Aortitis, periaortitis, and retroperitoneal fibrosis, as manifestations of IgG4-related systemic disease. Curr Opin Rheumatol. 2011;23(1):88–94. 9. Ishida M, Hotta M, Kushima R, Asai T, Okabe H. IgG4-related inflammatory aneurysm of the aortic arch. Pathol Int. 2009;59(4):269–273. 10. Ishizaka N, Sakamoto A, Imai Y, Terasaki F, Nagai R. Multifocal fibrosclerosis and IgG4-related disease involving the cardiovascular system. J Cardiol. 2012;59(2):132–138. 11. Sakamoto A, Nagai R, Saito K, et al. Idiopathic retroperitoneal fibrosis, inflammatory aortic aneurysm, and inflammatory pericarditis—retrospective analysis of 11 case histories. J Cardiol. 2012;59(2):139–146. 12. Matsumoto Y, Kasashima S, Kawashima A, et al. A case of multiple immunoglobulin G4–related periarteritis: a tumorous lesion of the coronary artery and abdominal aortic aneurysm. Hum Pathol. 2008;39(6):975–980. 13. Takei H, Nagasawa H, Sakai R, et al. A case of multiple giant coronary aneurysms and abdominal aortic aneurysm coexisting with IgG4-related disease. Intern Med. 2012;51(8):963–967. 14. 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;43(7):1131–1134. 15. Ikutomi M, Matsumura T, Iwata H, et al. Giant tumorous lesions surrounding the right coronary artery associated with immunoglobulin-G4related systemic disease. Cardiology. 2011;120(1):22–26.

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dilatation of the RCA. This patient also had increased wall thickness of the coronary arteries with tumorous lesions surrounding the RCA. Steroid therapy was minimally effective, and resection of the ectatic RCA revealed a pronounced infiltrate of IgG4-positive plasma cells within the wall. To our knowledge, we are presenting the first report of fatal outcome due to sudden cardiac death in a patient with IgG4-RD. Serum IgG4 level and imaging studies were not obtained owing to the patient’s sudden cardiac death. Nevertheless, the postmortem findings of extensive fibrosis and histologic evidence of dense infiltrates of IgG4-positive plasma cells within the coronary arteries, kidneys, pancreas, and lymph nodes are consistent with a diagnosis of IgG4RD. Of note, the present case shows involvement of the intima in addition to the media and adventitia, with concomitant atherosclerosis and thrombosis. Thus, the IgG4-RD directly contributed to luminal stenosis and occlusion, resulting in fatal myocardial infarction. In conclusion, this case raises the concern for a severe complication of IgG4-RD, making coronary artery evaluation prudent in cases of suspected IgG4-RD. In addition, evaluation for coronary periarteritis and arteritis should be considered in patients who present with either fibrous thickening or aneurysmal dilatation of the coronary arteries. Clinical diagnosis should rely on serum IgG4 level, examination of responsiveness to glucocorticoid therapy, and imaging studies to look for involvement of other organs that may be more amenable to biopsy.2 The authors thank Karen Prince for her help with the preparation of the images. References

Sudden cardiac death due to coronary artery involvement by IgG4-related disease: a rare, serious complication of a rare disease.

Immunoglobulin G4-related disease (IgG4-RD) is a systemic disorder characterized by multiorgan fibrosis with IgG4-producing plasma cells, increased Ig...
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