P ediatric and D e ve lo p m e n ta l P a th o lo g y 17, 231-239, 2014 DOI: 10.2350/13-12-1414-CR.1 © 2014 Society fo r P ediatric P a th o lo g y
Inflammatory Myofibroblastic Tumor of the Aortic Valves Causing Sudden Cardiac Death: A Case Report and Review of the Literature Bin X u, 1 R ichard S. Fraser, 1 C laudia R enaud, 2 Sameh Y oussef, 1 Ronald D. G ottesman, 2 C hantal B ernard1*
and
’ Department of Pathology, Montreal Children's Hospital, McGill University Health Centre, Montreal, QC H3H 1P3, Canada d e p a rtm e n t of Pediatric Critical Care, Montreal Children's Hospital, McGill University Health Centre, Montreal, QC H3H 1P3, Canada
Received December 16, 2013; accepted March 20, 2014; published online March 20, 2014.
ABSTRACT Cardiac inflammatory myofibroblastic tumor (IMT) is a rare entity affecting predominantly infants, children, and young adults. Although most tumors have a benign clinical course after complete surgical resection, some have significant clinical effects. We report the case of a 9year-old girl who had sudden cardiac death as a result of occlusion of the left circumflex coronary artery. A review of 57 cases of cardiac IMTs reported in the literature in terms of epidemiology, clinical presentation, histologic and immunohistologic features, and outcome is presented. Recognition of this rare abnormality is important in order to initiate prompt surgical intervention. Key words: autopsy, cardiac inflammatory myofibro blastic tumor, pediatric, sudden cardiac death
INTRODUCTION Inflammatory myofibroblastic tumor (IMT) is a distinct neoplasm characterized by a proliferation of fibroblast like cells, usually with an interspersed inflammatory cell infiltrate [1-3]. It may occur throughout the body and at any age, but the majority of the cases have been reported in the abdominal or pelvic cavity of children and young adults [1-3]. Inflammatory myofibroblastic tumor of the heart is rare, with fewer than 60 cases being reported in the literature under various designations, including IMT, plasma cell granuloma, inflammatory pseudotumor, and inflammatory fibrosarcoma [1,4— 47]. It typically presents as an endocardium-based polypoid mass and may arise in the atrium, ventricle, and/or cardiac valve. Although the majority of cardiac tumors followed a benign clinical course after surgical resection, sudden death has been documented in 5 patients, including 2 as a result of tumor occluding a coronary artery [7,29,36]. We present the *Corresponding author, e-mail: [email protected]
case of a 9-year-old girl with IMT of the posterior cusp of the aortic valve causing near-complete occlusion of the left circumflex artery and sudden death.
CLINICAL SUMMARY A 9-year-old Asian female with no significant past medical history briefly lost consciousness at school. She was back to her usual clinical state with normal vital signs upon arrival of the ambulance, as well as in the emergency department. However, she experienced retro sternal chest pain, followed by acute cardiovascular collapse soon after her arrival, for which prolonged resuscitation attempts were unsuccessful. The surface electrocardiogram was significant for diffuse severe ischemic S-T segment abnormalities. The estimated time interval from the syncope to the cardiorespiratory arrest was less than an hour. An autopsy was requested to identify the cause of the sudden unexpected death.
AUTOPSY FINDINGS External examination revealed a well-developed female child with no dysmorphic features. The heart was situated in the midline with the apex pointing towards the left. It weighed 241 g and had normal cardiac chamber dimensions. All valves are normal except for the posterior cusp of the aortic valve, on which a polypoid, white tumor measuring 1.5 cm was attached on its free edge (Fig. 1A,B). The tumor consisted of several slender papillary fronds that had numerous nodular enlargements resembling beads on a string. Most fronds seemed to be free floating in the ascending aorta; however, 1 extended into the left main coronary artery and completely blocked the left circumflex coronary artery (Figs. 1A, 2). Histologic examination showed a near complete occlusion of the proximal left circumflex artery by tumor frond with surrounding organiz ing thromboemboli and acute fibrin thrombi (Fig. 2). Serial sectioning of the left anterior descending and the right coronary arteries revealed no significant pathologic changes.
Figure 1. A complex polypoid mass was attached at the edge of the posterior cusp of the aortic valves (A,B). One of the papillary frond extended into the left circumflex coronary artery (arrow), causing complete obstruction. Transmural fibrosis was noted in the free wall of the left ventricle representing remote myocardial infarct (A,C; arrow heads). Scale bar: 1 cm.
An area of transmural fibrosis measuring 2 cm was identified macroscopically and on histologic examination within the lateral free wall of the left ventricle, representing a remote myocardial infarct in the territory of left circumflex artery (Fig. 1C). Despite extensive sampling, there was no evidence of acute myocardial ischemia or infarction, which may be explained by the short time interval between the time of onset (syncope) and cardiac arrest. Histologically, the tumor had 2 distinct appearances. The distal portion of the tumor was densely fibrotic and hypocellular with overlying fibrin (Fig. 3A,B), while the proximal part was relatively cellular and composed of loosely arranged fascicles of plump and spindle cells admixed with predominantly lymphocytes and scattered plasma cells in a collagenized background (Fig. 3C,D). Mitotic figures and necrosis were absent. No elastin was observed on elastica van Gieson stain. Immunohistochemical (IHC) studies showed that the spindle cells were positive for vimentin and smooth muscle actin. CD34 highlighted the endothelial cell lining at the surface of the tumor and fine vasculature within the proximal portion of the tumor. The tumor was negative for desmin and anaplastic lymphoma kinase-1 (ALK-1). A fluorescent in situ hybridization (FISH) analysis using Vysis ALK break-apart FISH probe (Vysis, Downers Grove, IL, USA) was performed and confirmed the absence of ALK-1 translocation. The count of IgG4-positive plasma cells ranges from 0 to 2 per high-power field. No abnormalities were found in other organs. Postmortem bacterial cultures, virology, and toxicology were negative. DISCUSSION Pediatric cardiac tumors are rare. The majority are hamartomas and benign neoplasms, such as rhabdomyoma,
232
B. Xu
ET AL.
myxoma, teratoma, and fibroma [48]. The current case is presented as an endocardium-based tumor with multiple papillary projections, which raises the possibility of a papillary fibroelastoma. However, the diagnosis is exclud ed in the absence of elastic fibers on histology and van Gieson stain. The tumor is focally fibrotic and paucicellular, histologically resembling fibroma. Cardiac fibromas occur almost exclusively in myocardium, while the lesion of this case is valve based, which makes a diagnosis of cardiac fibroma unlikely. On histologic examination, the tumor contains plump or spindle fibroblasts and myofi broblasts admixed with a predominant lymphocytic infiltrate. The major differential diagnoses of this histo logic appearance are cardiac IMT and IgG4-related disease. IgG4-related disease is a chronic inflamma tory condition characterized histologically by storiform fibrosis, obliterative phlebitis, and/or prominent lymphoplasmacytic infiltrate with an increased number of IgG4positive plasma cells [49-52], It may rarely affect the heart, with a handful of cases being reported in the literature in the forms of periarteritis, myocardial disease, and pericar ditis [53-56], The endocardium-location of this tumor, the lack of typical histological features, and a low count of IgG4-positive plasma cells exclude such diagnosis in the current case. Cardiac IMTs account for less than 5% of primary cardiac tumors, with a total of 57 cases reported to date (Table 1). It occurs predominantly in children and young adults, with a mean age of presentation of about 17 years. Among the reported cases, 21 of 57 patients (37%) were 1 year of age or less and 20 (35%) were between 1 and 20 years of age. The majority were endocardium-based polypoid lesions protruding into the cardiac cavity. About 60% arise in the right atrial or ventricular endocardium,
Figure 2. Serial se ction in g o f th e co ro na ry arteries revealed th a t th e p ro xim a l le ft circu m flex co ro na ry a rte ry (LCX) was o b structed by one o f th e p o ly p o id fro n d s (A, w h ite a rro w head). Scale bar: 0.5 cm. B. H istologic e xa m in a tio n show ed nearco m p le te occlusion o f th e p ro xim a l LCX w ith fib ro tic tu m o r fro n d (TF) associated w ith o rg a n izin g th ro m b o e m b o lu s and cholesterol clefts (h e m a to xylin p h lo xin e sa ffro n stain, m a g n ific a tio n X25). C. There was also evidence o f acute th ro m b u s (black a rro w head) w ith fib rin dep osit adjace nt to th e fib ro tic tu m o u r fro n d (m a g n ific a tio n X100). D. Im m unohistochem istry show ed th a t th e spindle cells w ith in th e tu m o r fro n d w ere positive fo r sm ooth muscle actin (m a g n ific a tio n X100).
about 50% in a valve, and 12% with aortic valve involvement (Table 1). The typical IHC profile supports myofibroblastic differentiation, with positive staining for smooth muscle actin and vimentin, and negative reactions for desmin, C'D31, CD34, and S-100 [1,2,4-47], Forty to sixty percent of extracadiac IMTs and 10% of cardiac IMTs also show ALK-1 overexpression on IHC. Over the past decade, our understanding about the pathogenesis of 1MT has changed substantially with the
clinical demonstration of recurrence and the discovery of cytogenetic abnormalities [2,3]. The tumor initially was thought to represent an abnormal and exaggerated inflammatory response to injuries and infections, and hence the name inflammatory pseudotumor with which it has often been associated [1-3,57]. It is now known that 50%-70% of tumors harbor a rearrangement of the ALK-1 gene on chromosome 2 with various partner genes, including TMP3, TMP4, RANBP2, and A TIC [2,3], In IMT C ausing S udden C ardiac D eath
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Inflammatory Myofibroblastic Tumor of the Aortic Valves Causing Sudden Cardiac Death: A Case Report and Review of the Literature Bin X u, 1 R ichard S. Fraser, 1 C laudia R enaud, 2 Sameh Y oussef, 1 Ronald D. G ottesman, 2 C hantal B ernard1*
and
’ Department of Pathology, Montreal Children's Hospital, McGill University Health Centre, Montreal, QC H3H 1P3, Canada d e p a rtm e n t of Pediatric Critical Care, Montreal Children's Hospital, McGill University Health Centre, Montreal, QC H3H 1P3, Canada
Received December 16, 2013; accepted March 20, 2014; published online March 20, 2014.
ABSTRACT Cardiac inflammatory myofibroblastic tumor (IMT) is a rare entity affecting predominantly infants, children, and young adults. Although most tumors have a benign clinical course after complete surgical resection, some have significant clinical effects. We report the case of a 9year-old girl who had sudden cardiac death as a result of occlusion of the left circumflex coronary artery. A review of 57 cases of cardiac IMTs reported in the literature in terms of epidemiology, clinical presentation, histologic and immunohistologic features, and outcome is presented. Recognition of this rare abnormality is important in order to initiate prompt surgical intervention. Key words: autopsy, cardiac inflammatory myofibro blastic tumor, pediatric, sudden cardiac death
INTRODUCTION Inflammatory myofibroblastic tumor (IMT) is a distinct neoplasm characterized by a proliferation of fibroblast like cells, usually with an interspersed inflammatory cell infiltrate [1-3]. It may occur throughout the body and at any age, but the majority of the cases have been reported in the abdominal or pelvic cavity of children and young adults [1-3]. Inflammatory myofibroblastic tumor of the heart is rare, with fewer than 60 cases being reported in the literature under various designations, including IMT, plasma cell granuloma, inflammatory pseudotumor, and inflammatory fibrosarcoma [1,4— 47]. It typically presents as an endocardium-based polypoid mass and may arise in the atrium, ventricle, and/or cardiac valve. Although the majority of cardiac tumors followed a benign clinical course after surgical resection, sudden death has been documented in 5 patients, including 2 as a result of tumor occluding a coronary artery [7,29,36]. We present the *Corresponding author, e-mail: [email protected]
case of a 9-year-old girl with IMT of the posterior cusp of the aortic valve causing near-complete occlusion of the left circumflex artery and sudden death.
CLINICAL SUMMARY A 9-year-old Asian female with no significant past medical history briefly lost consciousness at school. She was back to her usual clinical state with normal vital signs upon arrival of the ambulance, as well as in the emergency department. However, she experienced retro sternal chest pain, followed by acute cardiovascular collapse soon after her arrival, for which prolonged resuscitation attempts were unsuccessful. The surface electrocardiogram was significant for diffuse severe ischemic S-T segment abnormalities. The estimated time interval from the syncope to the cardiorespiratory arrest was less than an hour. An autopsy was requested to identify the cause of the sudden unexpected death.
AUTOPSY FINDINGS External examination revealed a well-developed female child with no dysmorphic features. The heart was situated in the midline with the apex pointing towards the left. It weighed 241 g and had normal cardiac chamber dimensions. All valves are normal except for the posterior cusp of the aortic valve, on which a polypoid, white tumor measuring 1.5 cm was attached on its free edge (Fig. 1A,B). The tumor consisted of several slender papillary fronds that had numerous nodular enlargements resembling beads on a string. Most fronds seemed to be free floating in the ascending aorta; however, 1 extended into the left main coronary artery and completely blocked the left circumflex coronary artery (Figs. 1A, 2). Histologic examination showed a near complete occlusion of the proximal left circumflex artery by tumor frond with surrounding organiz ing thromboemboli and acute fibrin thrombi (Fig. 2). Serial sectioning of the left anterior descending and the right coronary arteries revealed no significant pathologic changes.
Figure 1. A complex polypoid mass was attached at the edge of the posterior cusp of the aortic valves (A,B). One of the papillary frond extended into the left circumflex coronary artery (arrow), causing complete obstruction. Transmural fibrosis was noted in the free wall of the left ventricle representing remote myocardial infarct (A,C; arrow heads). Scale bar: 1 cm.
An area of transmural fibrosis measuring 2 cm was identified macroscopically and on histologic examination within the lateral free wall of the left ventricle, representing a remote myocardial infarct in the territory of left circumflex artery (Fig. 1C). Despite extensive sampling, there was no evidence of acute myocardial ischemia or infarction, which may be explained by the short time interval between the time of onset (syncope) and cardiac arrest. Histologically, the tumor had 2 distinct appearances. The distal portion of the tumor was densely fibrotic and hypocellular with overlying fibrin (Fig. 3A,B), while the proximal part was relatively cellular and composed of loosely arranged fascicles of plump and spindle cells admixed with predominantly lymphocytes and scattered plasma cells in a collagenized background (Fig. 3C,D). Mitotic figures and necrosis were absent. No elastin was observed on elastica van Gieson stain. Immunohistochemical (IHC) studies showed that the spindle cells were positive for vimentin and smooth muscle actin. CD34 highlighted the endothelial cell lining at the surface of the tumor and fine vasculature within the proximal portion of the tumor. The tumor was negative for desmin and anaplastic lymphoma kinase-1 (ALK-1). A fluorescent in situ hybridization (FISH) analysis using Vysis ALK break-apart FISH probe (Vysis, Downers Grove, IL, USA) was performed and confirmed the absence of ALK-1 translocation. The count of IgG4-positive plasma cells ranges from 0 to 2 per high-power field. No abnormalities were found in other organs. Postmortem bacterial cultures, virology, and toxicology were negative. DISCUSSION Pediatric cardiac tumors are rare. The majority are hamartomas and benign neoplasms, such as rhabdomyoma,
232
B. Xu
ET AL.
myxoma, teratoma, and fibroma [48]. The current case is presented as an endocardium-based tumor with multiple papillary projections, which raises the possibility of a papillary fibroelastoma. However, the diagnosis is exclud ed in the absence of elastic fibers on histology and van Gieson stain. The tumor is focally fibrotic and paucicellular, histologically resembling fibroma. Cardiac fibromas occur almost exclusively in myocardium, while the lesion of this case is valve based, which makes a diagnosis of cardiac fibroma unlikely. On histologic examination, the tumor contains plump or spindle fibroblasts and myofi broblasts admixed with a predominant lymphocytic infiltrate. The major differential diagnoses of this histo logic appearance are cardiac IMT and IgG4-related disease. IgG4-related disease is a chronic inflamma tory condition characterized histologically by storiform fibrosis, obliterative phlebitis, and/or prominent lymphoplasmacytic infiltrate with an increased number of IgG4positive plasma cells [49-52], It may rarely affect the heart, with a handful of cases being reported in the literature in the forms of periarteritis, myocardial disease, and pericar ditis [53-56], The endocardium-location of this tumor, the lack of typical histological features, and a low count of IgG4-positive plasma cells exclude such diagnosis in the current case. Cardiac IMTs account for less than 5% of primary cardiac tumors, with a total of 57 cases reported to date (Table 1). It occurs predominantly in children and young adults, with a mean age of presentation of about 17 years. Among the reported cases, 21 of 57 patients (37%) were 1 year of age or less and 20 (35%) were between 1 and 20 years of age. The majority were endocardium-based polypoid lesions protruding into the cardiac cavity. About 60% arise in the right atrial or ventricular endocardium,
Figure 2. Serial se ction in g o f th e co ro na ry arteries revealed th a t th e p ro xim a l le ft circu m flex co ro na ry a rte ry (LCX) was o b structed by one o f th e p o ly p o id fro n d s (A, w h ite a rro w head). Scale bar: 0.5 cm. B. H istologic e xa m in a tio n show ed nearco m p le te occlusion o f th e p ro xim a l LCX w ith fib ro tic tu m o r fro n d (TF) associated w ith o rg a n izin g th ro m b o e m b o lu s and cholesterol clefts (h e m a to xylin p h lo xin e sa ffro n stain, m a g n ific a tio n X25). C. There was also evidence o f acute th ro m b u s (black a rro w head) w ith fib rin dep osit adjace nt to th e fib ro tic tu m o u r fro n d (m a g n ific a tio n X100). D. Im m unohistochem istry show ed th a t th e spindle cells w ith in th e tu m o r fro n d w ere positive fo r sm ooth muscle actin (m a g n ific a tio n X100).
about 50% in a valve, and 12% with aortic valve involvement (Table 1). The typical IHC profile supports myofibroblastic differentiation, with positive staining for smooth muscle actin and vimentin, and negative reactions for desmin, C'D31, CD34, and S-100 [1,2,4-47], Forty to sixty percent of extracadiac IMTs and 10% of cardiac IMTs also show ALK-1 overexpression on IHC. Over the past decade, our understanding about the pathogenesis of 1MT has changed substantially with the
clinical demonstration of recurrence and the discovery of cytogenetic abnormalities [2,3]. The tumor initially was thought to represent an abnormal and exaggerated inflammatory response to injuries and infections, and hence the name inflammatory pseudotumor with which it has often been associated [1-3,57]. It is now known that 50%-70% of tumors harbor a rearrangement of the ALK-1 gene on chromosome 2 with various partner genes, including TMP3, TMP4, RANBP2, and A TIC [2,3], In IMT C ausing S udden C ardiac D eath
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