Letters to the Editor
Sudden Cardiac Death Due To IgG4-Related Disease To the Editor.—We read with interest the recently published case report by Patel et al1 describing a patient who died suddenly and for whom immunohistochemistry of the autopsy sample demonstrated marked immunoglobulin G4 (IgG4)–positive lymphocytic infiltration in the coronary artery wall and other organs, including the kidney, pancreas, and lymph nodes. Coronary artery involvement of IgG4-related disease has been demonstrated in several previous case reports: coronary artery luminal narrowing, presumably of an atherosclerotic nature, may occur at the site of a coronary artery surrounded by thickened or tumefactive adventitia with IgG4-positve lymphocytic infiltration,2 as in the case described by Patel et al.1 On the other hand, several case reports have demonstrated only mild coronary artery luminal narrowing, regardless of the marked adventitial IgG4-positive cell infiltration.3,4 The condition that was documented by Patel et al might be termed IgG4related coronary artery disease; on the other hand, it should be noted that there have been no specific criteria for diagnosing IgG4-related coronary artery disease or IgG4-related cardiac disease until now. Histologic findings are an important and indispensable requirement for the diagnosis of IgG4related diseases; however, there are several organs, such as the pancreas, in which IgG4-related disease does exist but for which the acquisition of antemortem tissue is difficult and/or impractical. Diagnostic criteria for IgG4-related disease in such organs are advocated; however, diagnostic criteria for IgG4-related cardiovascular disease have not been defined as yet. According to a previous report by Tanigawa et al2 and the report by Patel et al,1 there is no doubt that the cardiovascular system is a target of the multiorgan involvement of IgG4related disease, and IgG4-related coronary artery disease may lead to a fatal outcome. On the other hand, considering that IgG4 may counteract the overactivated inflammatory process and that the severe IgG4-related pericoronary phenomenon is not necArch Pathol Lab Med—Vol 139, May 2015
essarily accompanied by coronary artery stenosis or occlusion, we may need to further assess whether IgG4related pathological conditions enhanced or, in reverse, ameliorated the coronary artery luminal stenosis and occlusion observed in their case. It is possible that the IgG4-positive cell infiltrate in the pericoronary artery may have, conversely, reduced the severity of the coronary artery disease. Nevertheless, whether IgG4-positive lymphocytic infiltrates promote or suppress coronary artery disease, such a histology, or elevated serum IgG4, may indicate a higher possibility of the presence of coronary artery lesions. In terms of the role of IgG4-positive lymphocytes in coronary atherogenesis, it would be of relevance to determine whether the thickened intima was positive for infiltration of such cells in the case of Patel et al.1 In general, B and T cells may reside in adventitial regions, but T cells (but not B cells), as well as monocytes/macrophages, infiltrate the inflamed intimal lesions.5 Although Patel et al1 demonstrated immunostaining of the wall of a coronary artery, we would be interested in IgG4 staining in specific parts of the coronary artery wall, including the adventitia, media, and intima, and would welcome comment on this point from the authors. We think that the case report by Patel et al1 has two important messages: first, coronary artery involvement can occur as a component of multiorgan IgG4-related disease; and second, IgG4-related coronary artery disease may be associated with a sudden fatal outcome, although whether IgG4-positive lymphocytes promote the coronary artery atherogenic process remains unclear. NOBUKAZU ISHIZAKA, MD JUN TANIGAWA, MD SHUJI SUZUKI, MD Department of Cardiology Osaka Medical College Osaka, Japan 1. Patel NR, Anzalone ML, Buja LM, Elghetany MT. Sudden cardiac death due to coronary artery involvement by IgG4-related disease: a rare, serious complication of a rare disease. Arch Pathol Lab Med. 2014;138(6):833–836. 2. 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(10): 1131–1134. 3. 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. 4. Urabe Y, Fujii T, Kurushima S, Tsujiyama S, Kihara Y. Pigs-in-a-blanket coronary arteries: a case of immunoglobulin G4-related coronary periarteritis assessed by computed tomography coronary angiography, intravascular ultrasound, and positron emission tomography. Circ Cardiovasc Imaging. 2012;5(5):685–687. 5. Grabner R, Lotzer K, Dopping S, et al. Lymphotoxin beta receptor signaling promotes tertiary lymphoid organogenesis in the aorta adventitia of aged ApoE-/- mice. J Exp Med. 2009;206(1): 233–248.
doi: 10.5858/arpa.2014-0325-LE
In Reply.—We thank Drs Ishizaka, Tanigawa, and Suzuki for their interest in our recent article describing a case of sudden cardiac death in a man with concomitant coronary artery disease and IgG4-related disease (IgG4-RD).1 The authors raise several concerns, and we thank them for the opportunity to further explain our findings. First, the authors of the letter state, ‘‘The condition that was documented by Patel et al might be termed IgG4related coronary artery disease.’’ In contrast, we have described our findings as ‘‘coronary artery involvement by IgG4-related disease.’’ 1 This distinction is crucial because no conclusion can be drawn about the biological relationship between the fibrosis with infiltration by IgG4-positive lymphocytes and the coronary artery atherosclerosis. The authors go on to say that ‘‘. . .we may need to further assess whether IgG4-related pathological conditions had enhanced or, in reverse, ameliorated the coronary artery luminal stenosis and occlusion observed in their case.’’ We interpreted the findings in our case as ‘‘. . .fatal outcome due to sudden cardiac death in a patient with IgG4-RD.’’ 1 To clarify, we believe that this patient exhibited 2 distinct processes that simultaneously involved the coronary arteries. Indeed, it would be difficult to make any claims about whether a causal relationship between the processes of IgG4-RD and atherogenesis even exists. Instead, 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, leading to cardiac hypoperfusion and sudden cardiac death. Letters to the Editor 571
Letters to the Editor
Figure 1. Immunohistochemical staining for IgG4 shows an extensive, dense infiltrate of IgG4-positive plasma cells throughout the coronary artery wall, including the adventitia, media, and intima (original magnification 340). The overall wall is thickened by the lymphoplasmacytic infiltrate and fibrosis. In addition, there are concomitant atherosclerotic changes. Figure 2. High-power view of the thickened intima, which shows an infiltrate of IgG4positive plasma cells (original magnification 3400).
Drs Ishizaka, Tanigawa, and Suzuki raise an important point regarding the intima. We previously mentioned in our report that there was involvement of each portion of the coronary arterial wall, including the intima. Figures 1 and 2 herein provide further immunohistochemical evidence of the extensive infiltration by IgG4-positive cells, highlighting involvement of the adventitia and media and to a lesser extent the intima. Nevertheless, again, this distribution alone cannot support any conclusions about causal relationships between the IgG4-RD and atherosclerosis, precluding any speculation about such a connection. While it is true that no specific criteria have been suggested for diagnosing IgG4-RD in the coronary arteries, this is an exceedingly rare phenomenon. In light of this, we relied on criteria established in other organs. Subsequently, a consensus statement on pathologic findings in IgG4-RD was released by experts.2 Although the coronary arteries were not mentioned, our case showed 572 Arch Pathol Lab Med—Vol 139, May 2015
fibrosis with a dense lymphoplasmacytic infiltrate, which met even the most conservative of pathologic criteria. Microscopic images highlighted the overwhelming infiltrate of IgG4positive cells. In addition, we saw involvement of the adventitial microvasculature, similar to the adventitial venulitis described in a case of IgG4related aortitis,3 as well as involvement of several other organs. Unfortunately, because of the nature of presentation, serum IgG4 levels were not obtained. As a result, we relied strictly on pathologic criteria. In summary, we would like to reiterate that we have identified a case of multiorgan involvement by IgG4RD. The patient showed concomitant involvement of the coronary arteries by IgG4-RD and atherosclerosis, and there is no evidence to determine whether or not any causal relationship between these findings exists. Still, this case adds to the growing body of literature describing cardiovascular involvement by IgG4-RD. NIMESH R. PATEL, MD Department of Pathology & Immunology Baylor College of Medicine Houston, TX 77030 MARY L. ANZALONE, MD Medical Examiner Service Harris County Institute of Forensic Sciences Houston, TX 77054 L. MAXIMILIAN BUJA, MD Department of Pathology & Laboratory Medicine The University of Texas Health Science Center at Houston Houston, TX 77030 M. TAREK ELGHETANY, MD Department of Pathology & Immunology Baylor College of Medicine Houston, TX 77030 Department of Pathology Texas Children’s Hospital Houston, TX 77030 1. Patel NR, Anzalone ML, Buja LM, Elghetany MT. Sudden cardiac death due to coronary artery involvement by IgG4-related disease: a rare, serious complication of a rare disease. Arch Pathol Lab Med. 2014;138(6):833–836. 2. Deshpande V, Zen Y, Chan JK, et al. Consensus statement on the pathology of IgG4-related disease. Mod Pathol. 2012;25(9):1181–1192. 3. Stone JH, Patel VI, Oliveira GR, Stone JR. Case records of the Massachusetts General Hospital: case 38–2012: a 60-year-old man with abdominal pain
and aortic aneurysms. N Engl J Med. 2012;367(12): 2335–2346.
doi: 10.5858/arpa.2014-0467-LE
b-Catenin as a Morphoimmunohistochemical Marker for the Diagnosis of Papillary Thyroid Carcinoma To the Editor.—One of the strategies used to improve the diagnosis of papillary thyroid carcinoma (PTC) involves the identification of its morphologic characteristics through immunohistochemical (IHC) staining. As reported by Fischer et al,1 the identification of the biochemical and structural basis of nuclear irregularities could improve the subjective interpretation of the features of PTC. In this field of research, lamin2 and emerin3 have been described as very promising stains. Both of these markers show a specific nuclear membrane affinity, allowing them to identify grooves, pseudoinclusions, and garlandlike nuclei (Figure, A and B). Ultimately, they could potentially lead to a sensitive and reliable identification of malignant lesions. A tissue microarray (TMA) series of 109 PTCs (51 follicular variants [FvPTCs], 19 conventional variants [CvPTCs], and 39 cases with mixed conventional and follicular features), 2 uncertain malignant potential (UMP) tumors, and 50 benign lesions (38 follicular adenomas and 12 hyperplastic nodules) was analyzed. In our IHC test, emerin (FL-254, Santa Cruz Biotechnology, Santa Cruz, California) led to false-positive results, significantly enhancing minimal nuclear membrane irregularities (in 26 of 50 benign nodules). Emerin also complicated the final diagnosis of some benign lesions (Figure, C and D) that were easily diagnosed using hematoxylin-eosin. Nevertheless, the entire series of PTCs was correctly identified, suggesting that emerin shows high sensitivity for PTCs but low specificity for benign cases. To improve the diagnostic process from an alternative point of view, bcatenin was evaluated. The aim was to ascertain an IHC antibody capable of identifying the most specific feature of PTC: nuclear pseudoinclusions. Our hypothesis is based on the pathomorLetters to the Editor
Copyright of Archives of Pathology & Laboratory Medicine is the property of College of American Pathologists and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
Sudden Cardiac Death Due To IgG4-Related Disease To the Editor.—We read with interest the recently published case report by Patel et al1 describing a patient who died suddenly and for whom immunohistochemistry of the autopsy sample demonstrated marked immunoglobulin G4 (IgG4)–positive lymphocytic infiltration in the coronary artery wall and other organs, including the kidney, pancreas, and lymph nodes. Coronary artery involvement of IgG4-related disease has been demonstrated in several previous case reports: coronary artery luminal narrowing, presumably of an atherosclerotic nature, may occur at the site of a coronary artery surrounded by thickened or tumefactive adventitia with IgG4-positve lymphocytic infiltration,2 as in the case described by Patel et al.1 On the other hand, several case reports have demonstrated only mild coronary artery luminal narrowing, regardless of the marked adventitial IgG4-positive cell infiltration.3,4 The condition that was documented by Patel et al might be termed IgG4related coronary artery disease; on the other hand, it should be noted that there have been no specific criteria for diagnosing IgG4-related coronary artery disease or IgG4-related cardiac disease until now. Histologic findings are an important and indispensable requirement for the diagnosis of IgG4related diseases; however, there are several organs, such as the pancreas, in which IgG4-related disease does exist but for which the acquisition of antemortem tissue is difficult and/or impractical. Diagnostic criteria for IgG4-related disease in such organs are advocated; however, diagnostic criteria for IgG4-related cardiovascular disease have not been defined as yet. According to a previous report by Tanigawa et al2 and the report by Patel et al,1 there is no doubt that the cardiovascular system is a target of the multiorgan involvement of IgG4related disease, and IgG4-related coronary artery disease may lead to a fatal outcome. On the other hand, considering that IgG4 may counteract the overactivated inflammatory process and that the severe IgG4-related pericoronary phenomenon is not necArch Pathol Lab Med—Vol 139, May 2015
essarily accompanied by coronary artery stenosis or occlusion, we may need to further assess whether IgG4related pathological conditions enhanced or, in reverse, ameliorated the coronary artery luminal stenosis and occlusion observed in their case. It is possible that the IgG4-positive cell infiltrate in the pericoronary artery may have, conversely, reduced the severity of the coronary artery disease. Nevertheless, whether IgG4-positive lymphocytic infiltrates promote or suppress coronary artery disease, such a histology, or elevated serum IgG4, may indicate a higher possibility of the presence of coronary artery lesions. In terms of the role of IgG4-positive lymphocytes in coronary atherogenesis, it would be of relevance to determine whether the thickened intima was positive for infiltration of such cells in the case of Patel et al.1 In general, B and T cells may reside in adventitial regions, but T cells (but not B cells), as well as monocytes/macrophages, infiltrate the inflamed intimal lesions.5 Although Patel et al1 demonstrated immunostaining of the wall of a coronary artery, we would be interested in IgG4 staining in specific parts of the coronary artery wall, including the adventitia, media, and intima, and would welcome comment on this point from the authors. We think that the case report by Patel et al1 has two important messages: first, coronary artery involvement can occur as a component of multiorgan IgG4-related disease; and second, IgG4-related coronary artery disease may be associated with a sudden fatal outcome, although whether IgG4-positive lymphocytes promote the coronary artery atherogenic process remains unclear. NOBUKAZU ISHIZAKA, MD JUN TANIGAWA, MD SHUJI SUZUKI, MD Department of Cardiology Osaka Medical College Osaka, Japan 1. Patel NR, Anzalone ML, Buja LM, Elghetany MT. Sudden cardiac death due to coronary artery involvement by IgG4-related disease: a rare, serious complication of a rare disease. Arch Pathol Lab Med. 2014;138(6):833–836. 2. 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(10): 1131–1134. 3. 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. 4. Urabe Y, Fujii T, Kurushima S, Tsujiyama S, Kihara Y. Pigs-in-a-blanket coronary arteries: a case of immunoglobulin G4-related coronary periarteritis assessed by computed tomography coronary angiography, intravascular ultrasound, and positron emission tomography. Circ Cardiovasc Imaging. 2012;5(5):685–687. 5. Grabner R, Lotzer K, Dopping S, et al. Lymphotoxin beta receptor signaling promotes tertiary lymphoid organogenesis in the aorta adventitia of aged ApoE-/- mice. J Exp Med. 2009;206(1): 233–248.
doi: 10.5858/arpa.2014-0325-LE
In Reply.—We thank Drs Ishizaka, Tanigawa, and Suzuki for their interest in our recent article describing a case of sudden cardiac death in a man with concomitant coronary artery disease and IgG4-related disease (IgG4-RD).1 The authors raise several concerns, and we thank them for the opportunity to further explain our findings. First, the authors of the letter state, ‘‘The condition that was documented by Patel et al might be termed IgG4related coronary artery disease.’’ In contrast, we have described our findings as ‘‘coronary artery involvement by IgG4-related disease.’’ 1 This distinction is crucial because no conclusion can be drawn about the biological relationship between the fibrosis with infiltration by IgG4-positive lymphocytes and the coronary artery atherosclerosis. The authors go on to say that ‘‘. . .we may need to further assess whether IgG4-related pathological conditions had enhanced or, in reverse, ameliorated the coronary artery luminal stenosis and occlusion observed in their case.’’ We interpreted the findings in our case as ‘‘. . .fatal outcome due to sudden cardiac death in a patient with IgG4-RD.’’ 1 To clarify, we believe that this patient exhibited 2 distinct processes that simultaneously involved the coronary arteries. Indeed, it would be difficult to make any claims about whether a causal relationship between the processes of IgG4-RD and atherogenesis even exists. Instead, 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, leading to cardiac hypoperfusion and sudden cardiac death. Letters to the Editor 571
Letters to the Editor
Figure 1. Immunohistochemical staining for IgG4 shows an extensive, dense infiltrate of IgG4-positive plasma cells throughout the coronary artery wall, including the adventitia, media, and intima (original magnification 340). The overall wall is thickened by the lymphoplasmacytic infiltrate and fibrosis. In addition, there are concomitant atherosclerotic changes. Figure 2. High-power view of the thickened intima, which shows an infiltrate of IgG4positive plasma cells (original magnification 3400).
Drs Ishizaka, Tanigawa, and Suzuki raise an important point regarding the intima. We previously mentioned in our report that there was involvement of each portion of the coronary arterial wall, including the intima. Figures 1 and 2 herein provide further immunohistochemical evidence of the extensive infiltration by IgG4-positive cells, highlighting involvement of the adventitia and media and to a lesser extent the intima. Nevertheless, again, this distribution alone cannot support any conclusions about causal relationships between the IgG4-RD and atherosclerosis, precluding any speculation about such a connection. While it is true that no specific criteria have been suggested for diagnosing IgG4-RD in the coronary arteries, this is an exceedingly rare phenomenon. In light of this, we relied on criteria established in other organs. Subsequently, a consensus statement on pathologic findings in IgG4-RD was released by experts.2 Although the coronary arteries were not mentioned, our case showed 572 Arch Pathol Lab Med—Vol 139, May 2015
fibrosis with a dense lymphoplasmacytic infiltrate, which met even the most conservative of pathologic criteria. Microscopic images highlighted the overwhelming infiltrate of IgG4positive cells. In addition, we saw involvement of the adventitial microvasculature, similar to the adventitial venulitis described in a case of IgG4related aortitis,3 as well as involvement of several other organs. Unfortunately, because of the nature of presentation, serum IgG4 levels were not obtained. As a result, we relied strictly on pathologic criteria. In summary, we would like to reiterate that we have identified a case of multiorgan involvement by IgG4RD. The patient showed concomitant involvement of the coronary arteries by IgG4-RD and atherosclerosis, and there is no evidence to determine whether or not any causal relationship between these findings exists. Still, this case adds to the growing body of literature describing cardiovascular involvement by IgG4-RD. NIMESH R. PATEL, MD Department of Pathology & Immunology Baylor College of Medicine Houston, TX 77030 MARY L. ANZALONE, MD Medical Examiner Service Harris County Institute of Forensic Sciences Houston, TX 77054 L. MAXIMILIAN BUJA, MD Department of Pathology & Laboratory Medicine The University of Texas Health Science Center at Houston Houston, TX 77030 M. TAREK ELGHETANY, MD Department of Pathology & Immunology Baylor College of Medicine Houston, TX 77030 Department of Pathology Texas Children’s Hospital Houston, TX 77030 1. Patel NR, Anzalone ML, Buja LM, Elghetany MT. Sudden cardiac death due to coronary artery involvement by IgG4-related disease: a rare, serious complication of a rare disease. Arch Pathol Lab Med. 2014;138(6):833–836. 2. Deshpande V, Zen Y, Chan JK, et al. Consensus statement on the pathology of IgG4-related disease. Mod Pathol. 2012;25(9):1181–1192. 3. Stone JH, Patel VI, Oliveira GR, Stone JR. Case records of the Massachusetts General Hospital: case 38–2012: a 60-year-old man with abdominal pain
and aortic aneurysms. N Engl J Med. 2012;367(12): 2335–2346.
doi: 10.5858/arpa.2014-0467-LE
b-Catenin as a Morphoimmunohistochemical Marker for the Diagnosis of Papillary Thyroid Carcinoma To the Editor.—One of the strategies used to improve the diagnosis of papillary thyroid carcinoma (PTC) involves the identification of its morphologic characteristics through immunohistochemical (IHC) staining. As reported by Fischer et al,1 the identification of the biochemical and structural basis of nuclear irregularities could improve the subjective interpretation of the features of PTC. In this field of research, lamin2 and emerin3 have been described as very promising stains. Both of these markers show a specific nuclear membrane affinity, allowing them to identify grooves, pseudoinclusions, and garlandlike nuclei (Figure, A and B). Ultimately, they could potentially lead to a sensitive and reliable identification of malignant lesions. A tissue microarray (TMA) series of 109 PTCs (51 follicular variants [FvPTCs], 19 conventional variants [CvPTCs], and 39 cases with mixed conventional and follicular features), 2 uncertain malignant potential (UMP) tumors, and 50 benign lesions (38 follicular adenomas and 12 hyperplastic nodules) was analyzed. In our IHC test, emerin (FL-254, Santa Cruz Biotechnology, Santa Cruz, California) led to false-positive results, significantly enhancing minimal nuclear membrane irregularities (in 26 of 50 benign nodules). Emerin also complicated the final diagnosis of some benign lesions (Figure, C and D) that were easily diagnosed using hematoxylin-eosin. Nevertheless, the entire series of PTCs was correctly identified, suggesting that emerin shows high sensitivity for PTCs but low specificity for benign cases. To improve the diagnostic process from an alternative point of view, bcatenin was evaluated. The aim was to ascertain an IHC antibody capable of identifying the most specific feature of PTC: nuclear pseudoinclusions. Our hypothesis is based on the pathomorLetters to the Editor
Copyright of Archives of Pathology & Laboratory Medicine is the property of College of American Pathologists and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
