IgG4-related Inflammatory Abdominal Aortic Aneurysm, Spectrum of IgG4-related Chronic Periaortitis

Abstract

Inflammatory abdominal aortic aneurysm (IAAA) is a subtype of abdominal aortic aneurysm (AAA) showing aortic wall thickening and inflammatory cell infiltration.1–5) Idiopathic retroperitoneal fibrosis (IRF) is characterized by fibrous tissue proliferation with an unclear boundary surrounding the aorta and ureter,6–9) and its association with systemic sclerosing disease has been reported.6–8) Because of similar histological features, IAAA is considered to be closely IRF. In the inclusion of these diseases, the spectrum of chronic periaortitis (CP) has been suggested since the initial reports of IAAA.1,7–9) Immunoglobulin G4-related sclerosing disease (IgG4-SD) is a disease group characterized by high serum IgG4 levels, and histological infiltration by many IgG4-positive plasma cells with dense fibrous proliferation.10–12) In 2001, Hamano et al. described that patients with autoimmune pancreatitis have a high serum concentration of IgG4.10) Since then, IgG4-SD has been attracting a lot of attention and has been expanded to general organs.13–17) Now, IgG4-SD is recognized as a systemic sclerosing disease.12) Recently, several cases of IRF have been reported to belong to IgG4-SD,11, 14) thus, we focused on the relationship between IRF and IAAA, and elucidated that IAAA is also partially an IgG4-SD.18, 19) Here, we firstly review the clinicopathological features of IAAA, compare it with atherosclerotic AAA (aAAA), and explain the general concept of IgG4-SD. Next, we describe the differences in subgroups of IgG4-related and non-related cases of IAAA. Next, we mention that IgG4-SD can occur with other vascular lesions. Finally, we discuss that etiopathogenisis of IgG4-related vascular lesions with regard to CP. 1. Disease concept of IAAA There is no doubt that atherosclerotic features are involved in the pathogenesis of AAA, but atherosclerotic features alone are insufficient to induce aneurysm formation, and hemodynamics and factors destroying the wall structures have been investigated. In this report, in order to compare with IAAA, AAA other than IAAA is simply designated as aAAA. Clinically, IAAA accounts for 3–10% of all cases of AAA.3, 5) IAAA often occurs in the 50–60s, and this is 5–10 years younger than that of aAAA. The incidence is higher in men, with a male: female ratio of 7–9:1.1, 3, 5) Many aAAA cases are asymptomatic, whereas IAAA cases often manifest subjective symptoms, such as fever, dull pain and weight loss.2, 3) When pain is acute and severe, differentiation from an impending rupture is necessary.2) IAAA is frequently located in the abdominal aorta lower than the renal artery and may extend to the thoracic aorta and iliac arteries.2) The ureter is frequently involved, and the complication rates with hydronephrosis and urethral disorders are high. Serologically, inflammatory features are observed, such as a high erythrocyte sedimentation rate (ESR) value, and elevation of C-reactive protein (CRP) and white blood cell count (WBC).1, 3) In terms of fever and serological inflammatory findings, it is sometimes difficult to distinguish IAAA from infectious aneurysms (bacterial, fungus, syphilitic and tuberculosis). IAAA and infectious AAA should be very carefully differentiated referring to blood culture examination and the serum procalcitonin level.20) Many IAAA cases are followed for a prolonged period because the tumor size slowly increases, but infectious AAA progresses rapidly and tends to develop multiple aneurysms. Radiologically, IAAA is detected as a dilated aorta with a periaortic mantle and adhesions to adjacent organs. Enhanced computed tomography (CT) revealed a ‘mantle sign’, which is composed of an enhanced inner lumen, a non-enhanced thrombus layer, and an enhanced thickening of the tunica adventitia and surrounding fibrous tissue. Positron emission tomography and computed tomography (PET/CT) are useful to identify inflammatory changes in the aneurismal wall. Imaging has a major role in the diagnosis of IAAA and FDG-PET/CT is regarded as a promising technique to detect the degree of inflammation of the aneurismal wall. As for treatment, strong fibrous adherence with the periaortic organs in IAAA frequently causes surgical difficulties with a high fatality rate.1, 2) Steroid treatment may be recommended when the tumor is small and symptoms are severe. The macroscopic appearance of white glistening perianeurysmal fibrosis with tumorous lesions is characteristic.1–3) Histologically, IAAA is defined by severe thickening of the aortic wall, particularly fibrous proliferation of the tunica adventitia, and lymphocyte and plasma cell infiltration.1) The tunica adventitia thicknesses of the normal aorta and aAAA are thinner than 0.1 mm,18) but this increases to about 5 mm or thicker in IAAA, and the overall aortic wall thickness exceeds 10 mm in many cases.18) The pathogenesis of IAAA remains to be clarified. It was previously considered to be a simple terminal phase of aAAA, that is, some researchers thought that IAAA could not be designated as a subtype because of the absence of significant clinicopathological differences from aAAA.4) However, since IAAA cases complicated by autoimmune diseases and a high antinuclear antibody-positive rate were reported, an association with systemic autoimmune abnormalities has been considered most likely. Familial incidence also occurred at a rate of 6–15%, and an association with human leukocyte antigen-DRB1*15 (HLA-DRB1*15 ) and HLA-DRB1*0404 has been reported.7) Further, an association with local chronic infection has been attracting attention.