Immunoglobulin G4-related inflammatory pseudotumor of the right ventricle with right coronary artery occlusion

Abstract

Immunoglobulin G4-related inflammatory pseudotumors are usually benign. Such tumors of cardiac origin are extremely rare, with no primary cardiac tumors reported to date. We report a case of a 77-year-old woman, with a medical history of diabetes, hypertension, and hyperlipidemia, who was diagnosed with a malignant cardiac tumor on preoperative imaging and had a confirmed pathological diagnosis of immunoglobulin G4-related inflammatory pseudotumor. She was examined for atherosclerosis obliterans, and coronary computed tomography revealed obstruction of the right coronary artery and a cardiac tumor in the right atrium. A suspected malignant tumor measuring 40 mm (maximum standardized uptake value: 12.2) bordering the right atrium was detected using 18F-fluorodeoxyglucose positron emission tomography. Her tumor was in contact with the heart, making biopsy impossible. She was diagnosed with malignancy on preoperative imaging and underwent tumor resection, tricuspid valve replacement, right atrial and right ventricular plasty, coronary artery bypass, lung resection, and diaphragmatic repair. However, the final pathological diagnosis was immunoglobulin G4-related inflammatory pseudotumor. Preoperative diagnosis of immunoglobulin G4-related inflammatory pseudotumor is extremely difficult; however, if the condition is diagnosed preoperatively, chemotherapy or steroid therapy should be administered, and patients who do not respond to chemotherapy should be considered for surgical treatment.

Learning objective

Immunoglobulin G4-associated inflammatory pseudotumor is extremely rare. Preoperative imaging diagnosis of immunoglobulin G4-associated inflammatory pseudotumor is extremely difficult, and pathology with biopsy is the only definitive diagnosis. However, if we could make an accurate preoperative diagnosis, patients should be treated with chemotherapy or steroids, and surgical treatment should be considered for patients who do not respond to chemotherapy or steroids.

Introduction

Immunoglobulin G4-related disease (IgG4-RD) is a relatively rare immune-mediated fibroinflammatory disease characterized by elevated serum IgG4 levels, lymphoplasmacytic infiltration of multiple organs, and fibrosis, and it reportedly responds well to corticosteroid therapy [1]. Vascular involvement in IgG4-RD is more common among older male patients, and usually involves the aorta and great vessels [1]. It also affects cardiovascular tissues and causes myocardial ischemia owing to coronary artery lesions, which can be fatal; however, such cases are rare [2]. Conversely, while inflammatory pseudotumors (IPTs) tend to occur frequently in the lungs and orbit, IPTs of cardiac origin are extremely rare; to the best of our knowledge, there are no reports of such primary cardiac tumors [3]. We present a case of IgG4-RD and IgG4-related IPT in a 77-year-old-woman, in whom we diagnosed a right ventricular (RV) tumor with right coronary artery occlusion. The tumor was classified as malignant based on 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET), followed by tumor resection and extended surgery to resect the site of invasion from the pericardium to the diaphragm.

Case report

The study protocol was approved by the Ethics Approval Board of the Dokkyo Medical University Hospital Ethics Committee in Japan, and written informed consent was obtained from the patient.

A 77-year-old woman with a history of diabetes mellitus (DM), hypertension, hyperlipidemia, and stroke was admitted to the Department of Endocrinology & Metabolism for education. On close examination, electrocardiographic findings showed no ST changes, a negative T wave in induction III and aVf (Fig. 1a), and ankle-brachial pressure index value <0.8. She did not exhibit typical angina symptoms but did present with occasional chest discomfort on effort; therefore, she underwent a thorough examination. Preoperative blood tests revealed the following: amylase, 71 U/L; brain natriuretic hormone, 138.9 pg/mL; hemoglobin A1c (HbA1c), 8.5 %; IgG-4, 83.3 mg/dL, and soluble interleukin 2 receptor, 563 U/mL. Transthoracic echocardiography (TTE) showed hypokinesia of the inferior wall and enhanced positive echogenic images for the RV lateral pericardial lumen (Fig. 1b, c). There were no mass lesions in the right atrium (RA) or RV, and valvular disease was not diagnosed. Computed tomography showed a large parenchymal mass measuring 35 × 48 mm outside the RA, with no abnormal aortic or abdominal findings (Fig. 1d, e). Coronary angiography revealed a total occlusion of the proximal right coronary artery (RCA) caused by tumor invasion. There was no significant stenosis in left anterior descending artery (LAD) and left circumflex artery (LCX). Good collateral circulation from LAD and LCX to distal RCA was developed, and tumor blood vessels were also observed (Fig. 2a, b). Magnetic resonance imaging (MRI) revealed a substantial mass with cystic degeneration spilling over into the diaphragm, enlarged to 50 × 55 mm outside the RV, with the tumor penetrating the RCA (Fig. 2c). We suspected malignancy and performed 18F-FDG PET, which demonstrated FDG accumulation with a maximum standardized uptake value (SUVmax) of 12.2 in a 40-mm mass adjacent to the RA; no additional FDG accumulation was observed in other areas (Fig. 2d, e). Therefore, based on positive 18F-FDG PET and right heart system compression findings, we diagnosed a malignant tumor and scheduled tumor resection and coronary artery bypass grafting (CABG). The tumor extended into the pericardium, pleura, lungs, and diaphragm. However, there were no abnormal cardiac findings for the left coronary artery area. An incision in the RV revealed that the tumor extended into the posterior cusp of the tricuspid valve (Fig. 3a). The tumor tore the RCA; therefore, a new bypass was planned with sutures at the inflow and outflow sites. The tumor measured 60 × 80 mm (Fig. 3b). Frozen sections were prepared from multiple areas of the tumor. No malignant cells were noted, and numerous inflammatory cells (neutrophils and plasma cells) were found to infiltrate the tissue. However, we could not confidently differentiate it from an inflammatory myofibroblastic tumor (IMT), and the tumor was infiltrating the myocardium. Hence, we diagnosed the patient as being clinically malignant and performed an extended procedure that included tumor resection, tricuspid valve replacement (TVR), CABG, pneumonectomy, and diaphragmatic suture. For TVR, a St. Jude Medical Epic xenoartic bioprosthesis (St. Jude Medical, Saint Paul, MN, USA) 33 mm was used; for RV plasty, a collagen-impregnated double-weave Dacron patch (Hemashield; Maquet, Rastatt, Germany) (40 × 70 mm) and bovine pericardial patch (40 × 70 mm) were used for RA plasty. CABG was #4PD with saphenous vein graft and 200 × 200 mm GORE® DUALMESH® (W. L. Gore & Associates, Flagstaff, AZ, USA) was used for diaphragm sutures.

Fig. 1.

Preoperative images. (a) A 12‑lead electrocardiogram on admission. (b and c) Transthoracic echocardiography. Enhanced positive echogenic images of the right ventricular lateral pericardial lumen (white arrow: tumor). (d and e) Coronary computed tomography demonstrating the right coronary artery (RCA) outside the right atrium (RA) and inside the tumor (white arrow, tumor; red arrow, RCA). The pancreas is normal.

Ao, aorta; RV, right ventricle.

Fig. 2.

Preoperative images. (a and b) Catheter angiography demonstrating the right coronary artery occlusion (white arrow). No significant stenosis is observed in the left coronary artery. (c) Magnetic resonance imaging demonstrating the tumor outside the right atrium and invasion of the diaphragm (white arrow: tumor). (d and e) 18F-fluorodeoxyglucose positron emission tomography. Maximum intensity projection image (white arrow: tumor; maximum standardized uptake value up to 12.2).

Fig. 3.

Intraoperative and postoperative images. (a) Immediately after tumor resection (white arrow, tricuspid valve; red arrow, right coronary artery inflow, and outflow). (b) Cross section showing particolored tissues. (c) Hematoxylin and eosin staining showing massive infiltration of lymphocytes and plasma cells. (d) Elastica van Gieson staining showing obstructive phlebitis with vasa vasorum. (e) Masson's trichrome staining showing hyperplastic collagen fibers. (f) Immunohistochemistry for immunoglobulin G4 (IgG4) revealing IgG4-positive plasma cells.

RA, right atrium; RV, right ventricle.

The patient was extubated on postoperative day 1 and was transferred to the general ward on postoperative day 3. Right diaphragmatic elevation was noted owing to diaphragmatic nerve resection. However, postoperative TTE revealed no complications. After rehabilitation, the patient was discharged on postoperative day 30. The final diagnosis was IgG4-related IPT of the heart. Histologically, the tumor comprised fibrous tissue with massive inflammatory cell infiltration, which met the inclusion criteria for IgG4-RD [storiform fibrosis (+), IgG4/IgG-positive cell ratio of >40 %, and IgG4-positive plasma cell counts of >40/high-power field (HPF)]. Immunohistochemistry results for anaplastic lymphoma kinase (ALK) were negative; therefore, a diagnosis of IMT was ruled out (Fig. 3c–f).

Discussion

IgG4-related IPTs that target the heart are rare [4], and to our best knowledge, there are only a few reports of such primary cardiac tumors [3]. In 18F-FDG PET, the intensity and distribution of uptake vary depending on the organ, making it difficult to differentiate the malignancy [5]. The reported patient's MRI revealed a substantial mass with cystic degeneration spreading from the RA to the diaphragm, measuring 50 × 55 mm in size and penetrating the RCA. A 40-mm mass bordering the RA with an SUVmax of 12.2 was observed on 18F-FDG PET. Zhang et al. [6] reported that 18F-FDG PET findings in a patient with IgG4-RD were characterized by diffusely elevated 18F-FDG uptake in the exocrine organs (patchy 18F-FDG-avid hypermetabolic lesions, primarily involving the vascular walls, lungs, liver, and kidneys), and extensive distribution of multiple lesions that could not be interpreted as common metastasis of malignancies. However, our case did not exhibit any of these characteristics. IgG4-related IPT is organ-specific, and preoperative biopsies are said to be difficult to diagnose because the number of IgG4+ cells cannot be accurately counted in small tissues [3]. The patient presented here was diagnosed based on imaging because the tumor was in contact with the heart and, therefore, preoperative biopsy was associated with a high risk. Histopathological findings of IgG4-RD are diagnosed according to the comprehensive diagnostic criteria for IgG4-RD [7]. Here, the IgG4/IgG ratio was >40 %, and IgG4-positive plasma cells were >40/HPF. ALK positivity on staining is common in IMT, a borderline malignancy included in the IPT spectrum [8]. However, ALK staining was negative in this case.

Regarding the treatment of IgG4-related IPTs, according to Narla et al. [9], complete surgical resection is the treatment of choice for most IPTs, except orbital lesions when possible. Radiation therapy can be used in unresectable cases. In one study, the treatment of patients with IgG4-related IPT treated with corticosteroids resulted in 85.7 % resolution or significant reduction of lesions [3]. Moreover, Carbajal et al. [10] reported the use of a combination of cyclosporine chemotherapy and steroid therapy for IgG4-related heart disease because steroids induce a beneficial immune response to IgG4-related IPTs without inducing disease remission. In our case, postoperative 18F-FDG PET was negative; therefore, no additional treatment was administered.

IgG4-related IPT is organ-specific, and preoperative biopsies are said to be difficult to diagnose because the number of IgG4+ cells cannot be accurately counted in small tissues [3]. Our patient was diagnosed by imaging alone without a myocardial biopsy because the tumor was outside the heart on preoperative imaging and a preoperative biopsy would be associated with a high risk. Preoperative images revealed that the RCA was highly calcified, suggesting that the IgG4-induced RCA lesion had progressed to an IPT. Okuyama et al. [4] reported that coronary artery disease in IgG4-related disease is more frequent in older men and is characterized by the thickening of the coronary artery walls and the soft tissues surrounding several arteries and by mild stenosis of the vascular lumen. However, how coronary artery lesions with periarterial thickening and luminal narrowing lead to acute coronary syndromes remains unclear. In the present case, the RCA was torn by the tumor, and it was not an aneurysm but an IPT that invaded the right diaphragm, which has never been reported before. This patient did not present with typical angina despite RCA occlusion, probably because of a long history of DM (insulin usage, HbA1c 8.2 %), low activities of daily living due to arteriosclerosis obliterans, and a presence of good collateral circulation to RCA. Moreover, because the intraoperative findings indicated extensive RV involvement, the patient might have been diagnosed by a preoperative myocardial biopsy. IgG4-related IPT, if diagnosed preoperatively, should be treated with steroids and followed up with 18F-FDG PET to determine whether resolution or a shrinking trend is observed. If no resolution or shrinkage trend is observed following the use of steroids and other treatments, then surgical intervention should be considered.

Funding

None.

Declaration of competing interest

The authors declare that there is no conflict of interest.