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1 Note: This copy is for your personal, non-commercial use only. To order presentation-ready copies for distribution to your colleagues or clients, contact us at Dai Inoue, MD Yoh Zen, MD Hitoshi Abo, MD Toshifumi Gabata, MD Hiroshi Demachi, MD Jyun Yoshikawa, MD Shiro Miyayama, MD Yasuni Nakanuma, MD Osamu Matsui, MD Immunoglobulin G4 related Periaortitis and Periarteritis : CT Findings in 17 Patients 1 Purpose: Materials and Methods: Results: To retrospectively evaluate computed tomographic (CT) findings of immunoglobulin G4 (IgG4)-related disease involving the vascular system. This study was approved by the institutional review board, and all patients included had consented to the use of their medical records for the purpose of research. The study consisted of 17 patients (16 men and one woman; age range, years). CT findings of IgG4-related periarterial lesions were retrospectively analyzed. Radiopathologic correlations were examined on the basis of surgically resected specimens. A total of 22 periarterial lesions were detected in 17 patients. The lesions were located in the thoracic aorta ( n = 4), abdominal aorta to iliac arteries ( n = 13), superior mesenteric artery ( n = 3), inferior mesenteric artery ( n = 1), and splenic artery ( n = 1). Radiologically, they were characterized by arterial wall thickening (mean thickness, 11 mm), relatively clear circumscription, possible association with luminal change (mostly dilated and rarely stenotic), exaggerated atherosclerotic change, and homogeneous enhancement at the late phase of contrast material enhanced CT. Twelve patients (71%) had IgG4-related disease in other organs. Pathologically, diffuse lymphoplasmacytic infiltration, numerous IgG4-positive plasma cells, and irregular fibrosis were noted in the thickened arterial wall, especially at the adventitia. Steroid therapy administered to eight patients rapidly diminished the arterial wall thickening. One patient who did not receive steroid therapy showed spontaneous improvement at follow-up CT. ORIGINAL RESEARCH n VASCULAR AND INTERVENTIONAL RADIOLOGY 1 From the Departments of Radiology (D.I., T.G., O.M.) and Human Pathology (Y.N.), Kanazawa University Graduate School of Medical Science, 13-1 Takaramachi, Kanazawa , Japan; Division of Pathology, Kanazawa University Hospital, Kanazawa, Japan (Y.Z.); Department of Radiology, Toyama Prefectural Central Hospital, Toyama, Japan (H.A., H.D.); Department of Radiology, Fukui Prefectural Hospital, Fukui, Japan (J.Y.); and Department of Radiology, Fukuiken Saiseikai Hospital, Fukui, Japan (S.M.). Received November 15, 2010; revision requested January 17, 2011; revision received April 21; accepted May 20; fi nal version accepted May 27. Address correspondence to D.I. ( d-inoue@lake.ocn.ne.jp ). Conclusion: IgG4-related arterial lesions occur mainly in the aorta and its main branches and are radiologically characterized by homogeneous arterial wall thickening corresponding to pathologic features of IgG4-related sclerosing inflammation in the adventitia. q RSNA, 2011 q RSNA, 2011 Radiology: Volume 261: Number 2 November 2011 n radiology.rsna.org 625

2 Immunoglobulin G4 (IgG4)-related disease is a newly designated entity that can be defined as idiopathic inflammatory and sclerosing lesions infiltrated by numerous IgG4-positive plasma cells. This disease occurs in systemic organs including the pancreas ( 1 ), bile duct ( 2 ), kidney ( 3 ), and salivary gland ( 4 ). Irrespective of the organ involved, IgG4-related disease is clinically characterized by a predilection for adult males, high serum IgG4 concentrations, favorable response to steroid therapy, and synchronous or metachronous association with IgG4-related disease in other organs ( 5,6 ). Pathologic characteristics are diffuse lymphoplasmacytic infiltrations, irregular fibrosis, obliterative phlebitis, and occasional infiltration of eosinophils ( 2 4,7 ). Numerous IgG4-positive plasma cells are noted in the affected organs with immunostaining ( 2 4,7 ). IgG4-related disease predominantly occurs in glandular tissues; however, it has recently been reported that the vascular system can also be affected ( 8 10 ). It is important to promptly diagnose IgG4-related disease, because this disease commonly manifests as swelling of the affected organs, which must be differentiated from true neoplasms. Of note, IgG4-related disease is treatable with a corticosteroid in contrast to neoplasms ( 5,6 ). Radiologic examinations and serologic analysis of IgG4 concentrations are key steps for the diagnosis. Autoimmune pancreatitis, a prototype of IgG4- related disease, is usually suspected by characteristic radiologic findings and is confirmed by subsequent serologic exam- Advances in Knowledge n Immunoglobulin G4 (IgG4)- related disease occurs in the aorta and its large branches. n The most characteristic radio- logic feature is arterial wall thickening, which shows homogeneous enhancement at the late phase of contrast-enhanced CT. n Radiologic abnormalities of this disease represent IgG4-related inflammation predominantly involving the adventitia, with attenuation or disruption of the media. ination of IgG4 ( 11 ). In this regard, it seems important to reveal the radiologic characteristics of IgG4-related disease in extrapancreatic organs. Indeed, some reports on the radiologic findings have already been published ( ); however, the radiologic characteristics of the vascular lesions are still unknown. In this study, we examined the computed tomographic (CT) findings of IgG4- related periaortic and periarterial lesions and radiopathologic correlations. The main purpose of this study was to retrospectively evaluate the CT findings of IgG4-related disease involving the vascular system. Materials and Methods Case Selection This study was approved by our institutional review board, and all patients included had consented to the use of their medical records for the purpose of research. This study consisted of 17 patients (16 men and one woman; mean age, 65 years; range, years) with IgG4-related disease involving the aorta or arteries. Patients with a pathologic diagnosis of IgG4-related disease and patients with typical radiologic features of autoimmune pancreatitis and high serum IgG4 concentrations were enrolled. All cases were selected from the pathology and radiology files of our hospitals (four cases from Kanazawa University Hospital, five cases from Toyama Prefectural Central Hospital, two cases from Fukui Prefectural Hospital, two cases from Fukuiken Saiseikai Hospital, two cases from National Hospital Organization Kanazawa Medical Center, one case from Kouseiren Takaoka Hospital, and one case from Toyama City Hospital) between November 2002 and April At these hospitals, clinical Implication for Patient Care n Recognizing CT findings and cor- responding histopathology is essential to correctly diagnose IgG4-related periaortitis and arteritis, which can be effectively treated with steroids. records of all patients are electronically preserved or manually documented. Subjective symptoms, laboratory data, and treatments were reviewed for 17 patients. Age, sex, clinical symptoms, and laboratory data that included serum IgG or IgG4 concentration and antinuclear antibody are summarized in Table 1. Diagnosis of IgG4-related Disease Periaortic or periarterial lesions were pathologically examined and diagnosed as IgG4-related disease in seven patients (cases 1, 3, 6, 13 16). In another seven patients (cases 5, 7, 8, 10 12, 17), IgG4-related disease was diagnosed by means of biopsy of nonvascular lesions. Those specimens showed histologic features consistent with IgG4-related disease, as described later. In three patients (cases 2, 4, 9), diagnosis of IgG4-related disease was based on the typical imaging features of the pancreas (autoimmune pancreatitis) and high serum IgG4 concentrations. Radiologic Examination CT images were available for all patients. Single, 4, 8, 16, and 64 detector row CT examinations were performed in four, one, five, five, and two patients, respectively. Abdominal CT images, including nonenhanced and contrast material enhanced images ( kvp and mas for single detector row scanners, kvp and mas for multi detector row scanners), were obtained in all cases. In Published online before print /radiol Content code: Radiology 2011; 261: Abbreviation: IgG = immunoglobulin Author contributions: Guarantors of integrity of entire study, D.I., Y.Z., H.A., T.G., H.D., J.Y., Y.N., O.M.; study concepts/study design or data acquisition or data analysis/interpretation, all authors; manuscript drafting or manuscript revision for important intellectual content, all authors; approval of fi nal version of submitted manuscript, all authors; literature research, D.I., Y.Z., H.A., T.G., H.D., Y.N.; clinical studies, all authors; and manuscript editing, D.I., Y.Z., T.G., H.D., Y.N., O.M. Potential confl icts of interest are listed at the end of this article. 626 radiology.rsna.org n Radiology: Volume 261: Number 2 November 2011

3 addition, 10 patients (cases 2 7, 12, 14 16) underwent chest CT. Precontrast and postcontrast CT images of the chest were available for nine patients (cases 3 7, 12, 14 16), and only nonenhanced images were available for the remaining patient (case 2). The interval between chest and abdominal CT was 0 7 days (mean, 2 days). Chest CT was not performed in seven patients (cases 1, 8 11, 13, 17). All CT scans were obtained with a section thickness of mm in 14 patients (cases 2 5, 7 15, 17) and 8 mm in three patients (cases 1, 6, 15). Postcontrast CT examinations were performed by using a dual-phase technique. The early phase images were obtained between 35- and 45-second delays after the administration of ml of nonionic contrast medium at the rate of 3 4 ml/sec with a power injector. After that, late phase images were obtained between 90- and 120-second delays after starting the injection. Because of the multiinstitutional retrospective nature of this study, the scanning protocols were not consistent. Image Analysis All CT images were reviewed by two radiologists (D.I. and H.A., with 9 and 18 years of vascular CT imaging experience, respectively), and decisions were reached by consensus. Location and number (single or multiple) of lesions were recorded in all cases. The following features were examined: the maximum thickness of the arterial wall, the length of the affected arterial segment, configurations of the border to the surrounding adipose tissue (smooth or irregular), luminal change of the affected vessels (not affected, stenotic, or dilated), presence or absence of calcifications or cystic portions in the arterial wall, and penetrating vessels within the lesions. The affected arterial segment was also evaluated for degree of atherosclerotic changes, including intimal calcification or mural thrombus compared with the unaffected segment (not significantly different, slightly, moderately, or severely exaggerated). Follow-up CT images available for 10 patients (cases 1, 3, 6, 7, 10, 11, 13 15, 17) were analyzed with regard to the change in maximum thickness of each lesion (not changed, decreased, or increased), the change in luminal diameters of the affected vessels (not changed, decreased, or increased), and the development of IgG4-related lesions in other sites. Radiopathologic Correlation Radiopathologic correlation was performed in seven cases (cases 1, 3, 6, 13 16). In four cases (cases 13 16), radiologic and pathologic features were compared by focusing on the location of inflammation and disruption of layer structures. This was performed by two radiologists (D.I. and H.A., with 9 and 18 years of vascular CT imaging experience, respectively) and a pathologist (Y.Z., with 12 years of experience), and decisions were reached by consensus. IgG4-related Disease at Other Sites IgG4-related disease in other organs was identified in 12 patients ( Table 2 ). Most of such lesions were detected at the same time as the vascular lesions, but three lesions (presacral retroperitoneal fibrosis in case 1, pulmonary ground-glass opacities in case 7, and autoimmune pancreatitis in case 14) had developed during the follow-up after the vascular lesions. Pathologic Examination Pathologic examinations were performed in 14 patients (cases 1, 3, 5 8, 10 17). Pathologic diagnoses of IgG4-related disease were made by using spec imens obtained from the aortic and/or arterial wall (surgical resection, cases 13 16; biopsy, cases 1, 3, 6), salivary gland (needle biopsy, cases 5, 17), pancreas (needle biopsy, case 10), paravertebral mass (needle biopsy, case 7), perirenal soft-tissue mass (needle biopsy, case 11), and ampulla of Vater (endoscopic biopsy, cases 8, 12). In four surgically treated cases ( ), three layers of the artery could be recognized in the pathologic specimens. The original resected specimens or those that underwent biopsy were available and reviewed by a pathologist (Y.Z, with 12 years of experience). All specimens were fixed in neutral formalin and embedded in paraffin. Sections were stained with hematoxylineosin or elastic van Gieson stain. The rest were used for immunohistochemical staining. Immunostaining of IgG and IgG4 was performed with an autostainer (HX System Benchmark; Ventana Medical Systems, Tucson, Ariz) according to the manufacturer s instructions. Primary antibodies used were a rabbit polyclonal antibody against human IgG (Dako Cytomation, Glostrup, Denmark) and a mouse monoclonal antibody for human IgG4 (Zymed Laboratory, San Francisco, Calif). Sections were pretreated with proteinase. IgG4-related disease was diagnosed on the basis of pathologic features such as diffuse lymphoplasmacytic infiltration, irregular fibrosis, obliterative phlebitis, occasional eosinophilic infiltration, numerous IgG4-positive plasma cell infiltration, and high ratios of IgG4/IgGpositive plasma cells (. 30%) ( 2 4,8 ). Results Clinical Presentation All but one (case 9) patient were adult men. The symptoms at the first presentation are summarized in Table 1. Seven (41%) patients (cases 1, 3, 6, 7, 10, 11, 15) had subjective symptoms presumably related to vascular or retroperitoneal lesions. The symptoms included back pain, edema in lower extremities, or hoarseness due to left recurrent laryngeal nerve palsy. Three patients (cases 5, 8, 17) had symptoms related to other IgG4-related disease: submandibular swelling and obstructive jaundice. One patient (case 2) presented with respiratory symptoms, but did not have any obvious lesions in the respiratory tract. The remaining six patients (cases 4, 9, 12 14, and 16) were asymptomatic. During CT examination for routine medical work-up or follow-up of other diseases, they were found to have vascular lesions ( Table 1 ). Radiologic Findings at Presentation Location of vascular lesions. A total of 22 vascular lesions were identified in Radiology: Volume 261: Number 2 November 2011 n radiology.rsna.org 627

4 Table 1 Clinical Characteristics and Laboratory Data Case/Age (y)/ Sex Clinical Symptom IgG (mg/dl)* IgG4 (mg/dl) ANA (titer) 1/79/M Edema in lower extremities /70/M Cough ,40 3/65/M Back pain ,40 4/54/M None (routine medical workup) /59/M Submandibular swelling /57/M Hoarseness 1234 NA NA 7/55/M Back pain /69/M Submandibular swelling ,40 9/60/F None (follow-up for lung cancer) ,40 10/76/M Edema in lower extremities /58/M Back pain NA NA NA 12/81/M None (evaluation for diabetes mellitus) /56/M None (preoperative evaluation for gastric cancer) NA 14/79/M None (evaluation for enteritis) /55/M Back pain NA 16/64/M None (routine medical workup) /72/M Jaundice ,40 * To convert to Systéme International (SI) units (grams per liter), multiply by Normal range, less than1600 mg/dl. To convert to SI units (grams per liter), multiply by Normal range, less than 135 mg/dl. ANA = antinuclear antibody, NA = not analyzed. 17 patients. The location of each lesion is noted in Table 3. Four patients (cases 3, 4, 7, 8) had multiple lesions in the aorta or large arteries ( Figs 1a, 1b, 2 ). All lesions were located in the aorta or its large branches. Thirteen patients (cases 5 17) had aortic lesions, of which the most common site was the infrarenal abdominal aorta, as seen in 11 patients (cases 7 17). Of 11 lesions involving the infrarenal abdominal aorta, eight lesions directly extended to the common iliac arteries (cases 10 16) or internal iliac arteries (case 17). Interestingly, no lesions involved the suprarenal abdominal aorta. Other aortic lesions were seen in the ascending aorta (case 5), the descending thoracic aorta (case 7), and the aortic arch (cases 6, 7). Of two lesions involving the aortic arch, one directly extended to the left common carotid and subclavian arteries (case 6) ( Fig 3 ). Aside from the aorta, similar lesions were observed in the superior mesenteric arteries (three cases), inferior mesenteric artery (one case), and splenic artery (one case). Characteristics of CT findings. The radiologic features are summarized in Table 3. On CT images, the affected arterial and/or aortic walls were all severely thickened, with an average maximum thickness of 5 22 mm (mean, 11 mm). The length of the involved segment ranged mm (mean, 72 mm). In 19 lesions, the arterial walls were circumferentially involved with almost equal ( n = 11) or uneven thickness ( n = 8). In the remaining three lesions, arteries were partly involved. Most lesions (19 of 22, 86%) were well circumscribed. In contrast, three lesions showed irregular extension into adjacent adipose tissue ( Fig 2c ). All lesions were homogeneously enhanced in the late phase of contrastenhanced CT. Atherosclerotic changes were exaggerated in the affected segment in 14 lesions (six cases, slightly; five cases, moderately; three cases, severely). Cystic change or calcification was not detected in any lesions. In the early phase of contrast enhanced CT, vessels such as lumbar artery or inferior mesenteric artery were detected within lesions, and all of them penetrated through thickened aortic and/or arterial walls without occlusion. Lymph node enlargement was not identified in the adjoining region. Table 2 Extravascular IgG4-related Lesions in 12 Cases Case IgG4-related Lesions at Extravascular Sites 1 Retroperitoneal fi brosis 2 Autoimmune pancreatitis 4 Autoimmune pancreatitis 5 Autoimmune pancreatitis, sialadenitis, dacryoadenitis 7 Paravertebral mass, lung lesions 8 Autoimmune pancreatitis, sialadenitis, a renal lesion 9 Autoimmune pancreatitis, a renal lesion 10 Autoimmune pancreatitis, paravertebral mass 11 Autoimmune pancreatitis, perirenal mass 12 Autoimmune pancreatitis, sclerosing cholangitis 14 Autoimmune pancreatitis 17 Autoimmune pancreatitis, sclerosing cholangitis, sialadenitis Of 22 lesions, seven (32%) were associated with luminal changes. Cases showed aortic dilatation, which had been originally diagnosed as inflammatory abdominal aortic aneurysm ( Fig 4a, 4b ). In case 13, luminal dilatation was continuously seen from the abdominal aorta to the right iliac artery. The superior mesenteric artery in case 2 also showed luminal dilatation ( Fig 5 ). Stenosis was rare and was only mildly noted in the splenic artery of case 4. Follow-up Images Follow-up CT images were available for 10 patients (cases 1, 3, 6, 7, 10, 11, 13 15, 17). The follow-up duration ranged 1 31 months, with a median follow-up period of 9 months. Of the 10 patients, six (cases 1, 3, 7, 10, 11, 17) were treated with a corticosteroid alone. Aortic and/or arterial wall thicknesses were considerably decreased in all cases because of therapy ( Fig 1c, 1d ). The luminal diameters of the affected vessels were not changed in any lesions, including the aneurysmal aorta in case 17, after steroid therapy. One patient (case 6) presented with hoarseness due to involvement of left recurrent laryngeal nerve palsy in the 628 radiology.rsna.org n Radiology: Volume 261: Number 2 November 2011

5 Table 3 Characteristics of Perivascular Lesions Case Affected Vessel Thickness (mm) Length (mm) Involvement Border Luminal Change Atherosclerotic Change * 1 Superior mesenteric artery Circumferential Smooth NS NS 2 Superior mesenteric artery 6 25 Circumferential Smooth Dilated NS 3 Superior mesenteric artery Circumferential Smooth NS NS 3 Left 9 45 Circumferential Irregular NS Slight 4 Splenic artery 6 59 Circumferential Smooth Stenotic NS 4 Right 7 45 Circumferential Smooth NS NS 5 Ascending aorta 7 35 Partial Smooth NS NS 6 Aortic arch to left common carotid and Circumferential Smooth NS NS subclavian arteries 7 Aortic arch Partial Smooth NS Slight 7 Descending thoracic aorta Circumferential Smooth NS Slight 7 Infrarenal abdominal aorta Circumferential Irregular NS Slight 8 Infrarenal abdominal aorta 5 30 Partial Smooth NS Moderate 8 Inferior mesenteric artery 5 45 Circumferential Smooth NS NS 9 Infrarenal abdominal aorta 7 55 Circumferential Smooth NS Moderate 10 Infrarenal abdominal aorta to bilateral Circumferential Smooth NS Slight 11 Infrarenal abdominal aorta to left Circumferential Irregular NS Slight 12 Infrarenal abdominal aorta to bilateral Circumferential Smooth NS Moderate 13 Infrarenal abdominal aorta to bilateral Circumferential Smooth Dilated Moderate 14 Infrarenal abdominal aorta to bilateral Circumferential Smooth Dilated Severe 15 Infrarenal abdominal aorta to bilateral Circumferential Smooth Dilated Severe 16 Infrarenal abdominal aorta to bilateral 6 84 Circumferential Smooth Dilated Severe 17 Infrarenal abdominal aorta to bilateral internal iliac artery Circumferential Smooth Dilated Moderate Note. NS = not signifi cant. * The degree of exaggeration compared with unaffected arterial segments. periaortic lesion. He did not receive any treatments because he did not consent to steroid therapy. Interestingly, the wall thickness of the aortic arch in this patient showed an increase at follow-up CT during the first 6 months. Then, it spontaneously decreased in the following 6 months without any treatment. This spontaneous regression also provided symptomatic relief. The remaining three patients (cases 13 15) were first treated with graft replacement, followed up by CT examinations. In case 13, there was no recurrence of perivascular lesions at postoperative follow-up. In case 14, a diffuse swelling of the pancreas was discovered, consistent with autoimmune pancreatitis at 5 months after surgery. After a 4-month treatment with a corticosteroid, CT depicted a considerable decrease in the aortic wall thickness along with improvement of the pancreatic swelling. In case 15, corticosteroid therapy (20 mg/day) was performed after graft replacement surgery because of left hydronephrosis due to the residual periaortic lesion. The periaortic lesion promptly responded to the steroid along with improvement of the hydronephrosis. Pathologic Features and Radiopathologic Correlation Pathologic features. Histologic examination of the arterial wall was performed in seven patients (cases 1, 3, 6, 13 16). Four patients (cases 13 16) underwent partial resection of aortic and/or arterial wall during graft replacement surgery. Transluminal examination of these specimens revealed severe inflammatory cell infiltration with irregular fibrosis in the arterial walls. Elastic van Gieson staining showed that the inflammation was mainly located in the adventitia ( Fig 4c, 4d ). The adventitia was severely thickened, which is associated with sclerosing inflammation. Inflammatory cells consisted of predominantly lymphocytes and plasma cells. In addition, eosinophilic infiltrations were easily identified. Obliterative phlebitis was noted in small venules in the adventitia with elastic van Gieson Radiology: Volume 261: Number 2 November 2011 n radiology.rsna.org 629

6 staining. In contrast to the substantial change in the adventitia, histologic change in the intima was mild, with only slight atherosclerotic changes such as cholesterol deposition or foam cell infiltration. Similar histologic features such as diffuse lymphoplasmacytic infiltration with irregular fibrosis were also noted in the specimens that underwent biopsy (cases 1, 3, 6), although transluminal examination was impossible because of the small size of the specimens. Necrosis, calcification, or atypical cells were not identified in any lesions. Immunostaining of IgG revealed numerous IgG-positive plasma cell infiltrates in all specimens. In addition, numerous IgG4-positive cells were diffusely observed within the inflamed areas at IgG4 immunostaining. The ratios of IgG4/IgG-positive plasma cells were all more than 40%. Radiopathologic correlation. When the radiologic and pathologic features were compared, arterial wall thickness on CT images corresponded to the adventitial thickening with sclerosing inflammation. Elastic fibers in the media were attenuated by sclerosing inflammation in the adventitia and completely disrupted in the aneurysmal aorta (case 16, Fig 6 ). At enhanced CT, an intima and media complex was detected as a highdensity thin layer between a thickened adventitia and enhanced lumen or mural thrombus in three cases (cases 13 15, Fig 4a, 4b ). In one case (case 16), calcification was noted in the intima between a thickened adventitia and the enhanced lumen. Homogeneous enhancement in the late phase of enhanced CT seemed to represent severe sclerosing inflammation in the adventitia. Discussion This study provided several parameters for diagnosing IgG4-related periaortitis and periarteritis based on the obtained results: Most patients with IgG4-related perivascular lesions were adult males, which is consistent with other IgG4- related diseases. Serologically, elevated serum IgG4 level is the most characteristic parameter. IgG4-related perivascular lesions could predominantly occur Figure 1 Figure 1: Contrast-enhanced CT scans (early phase) of IgG4-related perivascular lesion in 65-year-old man (case 3). The walls of (a) superior mesenteric artery (arrows) and (b) left (arrow) show severe thickening. Luminal change is not observed in either lesion. The borders of the lesions are smooth in a and irregular in b. (c, d) Steroid therapy reduced the wall thickness at both sites (arrows). in the aorta and its main branches. Radiologically, these lesions were characterized by arterial wall thickening, homogeneous enhancement at the late phase of contrast enhanced CT, relatively well circumscribed appearance, and possible association with luminal changes, including aneurysmal dilatation, focally exaggerated atherosclerotic change, and penetration of small vessels in the lesions. Other organ involvement is frequently (71%) seen. Histologically, the lesions consisted of sclerosing inflammation predominantly located in the adventitia, which seemed to correspond to homogeneous enhancement in the late phase of enhanced CT. Steroid therapy was effective like in IgG4-related disease at other sites. We speculate that radiologic features, elevated serum IgG4 levels, and other organ involvement are particularly important, and the presence of all of these three parameters would be enough for the clinical diagnosis. However, histologic examination is still necessary for the final diagnosis, especially for the precise differentiation from other type of socalled retroperitoneal fibrosis and/or inflammatory aneurysm of the aorta, as mentioned below. IgG4-related disease is a recently recognized disease entity, but is surmised to have existed unrecognized. It seems important to know how this disease has been diagnosed until now. We 630 radiology.rsna.org n Radiology: Volume 261: Number 2 November 2011

7 Figure 2 Figure 3 Figure 2: Contrast-enhanced CT scans (early phase) of IgG4-related perivascular lesion in 55-year-old man (case 7). Thickening of the aortic wall is shown in (a) aortic arch (arrow), (b) descending thoracic aorta (arrow), and (c) abdominal aorta (arrow). They are discontinuous lesions. Only abdominal aortic lesion has irregular border. (d) A paravertebral mass (arrow) was also diagnosed; at needle biopsy, it was diagnosed as IgG4-related disease. Figure 3: Contrast-enhanced CT scans (early phase) of IgG4-related perivascular lesion in 57-year-old man (case 6). (a) A perivascular lesion is observed in the aortic arch (arrows). (b) It extends to the left common carotid artery and subclavian artery (arrows). The border of the lesion is smooth. suppose that most of such cases were diagnosed as periaortitis, periarteritis, inflammatory aneurysm, or retroperitoneal fibrosis. Since the initial description of the inflammatory abdominal aortic aneurysm in 1972 ( 16 ), it has become clear that inflammatory abdominal aortic aneurysm is one member of a family of disorders often referred to as chronic periaortitis ( 17 ). This family comprises three members: inflammatory abdominal aortic aneurysm, idiopathic retroperitoneal fibrosis, and a combination of the two. Therefore, the term IgG4- related periaortitis and/or periarteritis may be appropriate to describe the pathologic condition of IgG4-related perivascular lesions, which includes perivascular mass lesions with or without aneurysmal change. Recent studies have revealed that retroperitoneal fibrosis can be classified as IgG4-related and nonrelated ( 18 ). Presumably, there is an overlap between IgG4-related periaortitis and retroperitoneal fibrosis, this discrimination is dependent on the predominant location of lesions. The term periaortitis seems appropriate to describe lesions with predominant periaortic involvement. Periureteral or plaque-like lesions should be referred to as retroperitoneal fibrosis. We consider the most important radiologic differential diagnosis of IgG4- related periaortitis and periarteritis to be malignant lymphoma. The presence or absence of IgG4-related disease at other organs seems most helpful for this discrimination because 71% of patients had such IgG4-related lesions in this study. Some reports have described the radiologic characteristics of IgG4-related disease, including autoimmune pancreatitis ( 12 ), renal lesions ( 13 ), and pulmonary lesions ( 14 ). If IgG4- related periaortitis or periarteritis is radiologically suspected, serologic examination of IgG4 would be helpful for the diagnosis. However, pathologic examination seems mandatory for patients with out typical IgG4-related disease in other organs or with normal IgG4 concentrations. Whether steroid therapy can exacerbate aneurysmal changes is an important issue. We now speculate that steroid therapy may increase the risk of aneurysmal rupture by promoting thinning of the arterial wall. In this study, we treated only one patient (case 17) Radiology: Volume 261: Number 2 November 2011 n radiology.rsna.org 631

8 Figure 4 Figure 5 Figure 4: (a, b) Contrast-enhanced CT scans (early phase) of IgG4-related perivascular lesion in 79-year-old-man (case 14) and (c, d) histologic features. There is marked thickening of abdominal aortic wall associated with luminal dilatation. The lesion border is smooth. Inferior mesenteric artery penetrates through the perivascular lesion (arrow). The lesion extends to the bilateral common iliac arteries in b. High-density thin layer is observed between thickened abdominal wall and mural thrombus (arrowheads). (c) Marked thickening of the adventitia with infl ammatory cell infi ltration and fi brosis. (Hematoxylin-eosin stain; original magnifi cation, 320.) (d) Elastic layer of the media is intact (arrow). (Elastic van Gieson stain; original magnifi cation, 320.) with an aneurysmal lesion with a steroid alone; whereas, the other patients with more extensive luminal dilatation (cases 13 16) were surgically treated because IgG4-related disease was not considered before surgery. We used a reduced dose of steroid (20 mg/day) to reduce the risk of aneurysmal rupture. This dose of steroid effectively diminished aortic wall thickening, as well as swelling of the pancreas and bile duct. The aneurysmal diameter was not affected during steroid therapy. However, we must pay attention to the risk of rupture when we treat aneurysmal IgG4-related periaortitis or periarteritis with a steroid. Indeed, ruptured abdominal aortic aneurysm related to IgG4-periaortisis was recently reported ( 19 ). Another important issue is the size of the artery involved by IgG4-related periarteritis. Until now, IgG4-related perivascular lesions have been found in abdominal aorta ( 8,9,20 ), thoracic aorta ( 10,21 ), and coronary artery ( 22 ). In this study, all lesions were located in the aorta or its main branches. Taken together, it is no wonder that IgG4- related vascular disease more commonly involves larger arteries and manifests as radiologically detectable lesions. Sim ilarly, most IgG4-related disease in parenchymal organs, including autoimmune pancreatitis or sialadenitis, Figure 5: (a, b) Contrast-enhanced CT scans (early phase) of IgG4-related perivascular lesion in 70-year-old man (case 2). The superior mesenteric artery shows circumferential perivascular lesion with smooth border (arrow). The lesion is associated with slight luminal dilatation. The pancreas shows diffuse swelling with capsule-like pancreatic rim, which is typical of autoimmune pancreatitis. is usually demonstrable radiologically. However, recently, some microscopic lesions, in cluding chronic active hepatitis, have been reported ( 23 ). The possibility exists that IgG4-related disease may also manifest as microscopic vascular involvement. This study had a few limitations. First, because of its retrospective and multi-institutional nature, the CT scanners and CT protocols were inconsistent, precluding examination of the detailed enhancement pattern of each lesion. Second, pathologic specimens of a vascular lesion and a serum marker such as serum IgG4 concentrations were not available in some cases. Last, not all patients underwent CT examinations in both chest and abdomen. If CT images had been obtained in both chest and 632 radiology.rsna.org n Radiology: Volume 261: Number 2 November 2011

9 Figure 6 Figure 6: Histologic fi ndings of aneurysmal IgG4-related perivascular lesion (case 16 ). (a, b) Sclerosing infl ammation in the adventitia partly involves the media. The elastic fi bers in the media are disrupted by the infl ammation (arrow). (Hematoxylin-eosin stain in a, Elastic van Gieson stain in b ; original magnifi cation, 340.) abdomen in all cases, more lesions might have been detected. In conclusion, this study revealed radiologic characteristics of IgG4-related periaortitis and periarteritis. IgG4-related arterial lesions occur mainly in the aorta and its main branches and are radiologically characterized by homogeneous arterial wall thickening and enhancement at the late phase of contrast-enhanced CT, which represents histologic features of IgG4-related sclerosing inflammation predominantly involving the adventitia. Recognizing the radiologic characteristics with pathologic correlation can be helpful to correctly diagnose IgG4-related periaortitis and periarteritis. Acknowledgments: The authors thank Yasuharu Kaizaki, MD (Fukui Prefectural Hospital, Fukui, Japan), for his help with the pathological studies. The authors also thank Masami Sugihara, MD (Toyama City Hospital, Toyama, Japan), Kiyohide Kitagawa, MD (Kouseiren Takaoka Hospital, Toyama, Japan), Akihiko Kobayashi (National Hospital Organization, Kanazawa Medical Center, Kanazawa, Japan), and Shuichi Choutoh, MD (Kanazawa Social Insurance Hospital, Kanazawa, Japan) for their help in radiological studies. Disclosures of Potential Conflicts of Interest: D.I. No potential conflicts of interest to disclose. Y.Z. No potential conflicts of interest to disclose. H.A. No potential conflicts of interest to disclose. T.G. No potential conflicts of interest to disclose. H.D. No potential conflicts of interest to disclose. J.Y. No potential conflicts of interest to disclose. S.M. No potential conflicts of interest to disclose. Y.N. No potential conflicts of interest to disclose. O.M. No potential conflicts of interest to disclose. References 1. Hamano H, Kawa S, Horiuchi A, et al. High serum IgG4 concentrations in patients with sclerosing pancreatitis. N Engl J Med 2001 ; 344 ( 10 ): Zen Y, Harada K, Sasaki M, et al. IgG4- related sclerosing cholangitis with and without hepatic inflammatory pseudotumor, and sclerosing pancreatitis-associated sclerosing cholangitis: do they belong to a spectrum of sclerosing pancreatitis? Am J Surg Pathol 2004 ; 28 ( 9 ): Cornell LD, Chicano SL, Deshpande V, et al. Pseudotumors due to IgG4 immune-complex tubulointerstitial nephritis associated with autoimmune pancreatocentric disease. Am J Surg Pathol 2007 ; 31 ( 10 ): Kitagawa S, Zen Y, Harada K, et al. Abundant IgG4-positive plasma cell infiltration characterizes chronic sclerosing sialadenitis (Küttner s tumor). 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