Keywords

1 Introduction

Hamano et al. [1] first reported the presence of elevated serum IgG4 concentrations in autoimmune pancreatitis (AIP) patients as a prototype of IgG4-RD in 2001, and Kamisawa et al. [2] proposed the existence of IgG4-related systemic disease as a new clinicopathologic entity affecting a wide variety of organs in 2003. Increased serum IgG4 levels (>135 mg/dl), the presence of IgG4-positive cells in affected organs, and response to treatment with glucocorticoids are typical features of IgG4-RD, regardless of the organ affected.

In some organs affected by IgG4-RD, however, distinctive forms of pathology can emerge. As an example, IgG4-related kidney disease encompasses renal and renal pelvic lesions, and tubulointerstitial nephritis in the renal cortex is a major, well-described manifestation of the disease. However, the glomeruli (discussed elsewhere), renal pelvis, and ureter can also be affected in IgG4-related renal diseases – the latter primarily in association with retroperitoneal fibrosis. Moreover, pseudotumor-like nodular lesions mimicking urothelial carcinoma can also form in the renal pelvis and ureter. Most reported cases of IgG4-related kidney diseases have a history of prior IgG4-related pancreatitis or sialoadenitis, but cases of patients with IgG4-related urinary tract disease in the absence of other organ involvement have also been reported. In this chapter, renal pelvic and ureteral lesions in IgG4-related diseases have been described.

2 Clinical Features of Renal Pelvic and Ureteral Lesions

Involvement of the renal pelvis and ureter in IgG4-RD appears to be a relatively uncommon disease manifestation, but the extent to which it is underdiagnosed is not clear. Our review of the literature using the search engines for Japanese and English medical articles, ICHUSHI (Web. Japana Centra Revuo Medicina) and PubMed, respectively, revealed a total of 35 reported cases of such involvement [3–30], including a renal pelvic case that was experienced by our group (Case 12). These cases are summarized in Table 13.1. In addition, a review article on IgG4-related renal disease has recently been reported [31]. The age of patients ranged from 39 to 84 years, and older patients as well as males constituted the majority. Most of the cases consisted of isolated renal pelvic or ureter involvement. However, continuous distributions from the renal pelvis to the ureter as well as inflammatory pseudotumors were also observed in some cases. Moreover, synchronous and metachronous involvement was found in bilateral pelvises and ureters.

Table 13.1 Clinical summary of reported cases of IgG4-related pelvic and uretheral lesions
Full size table

3 Renal Pelvic Lesions

The renal pelvic lesions of IgG4-RD are visualized radiologically as thickening of the renal pelvic wall without luminal irregularity or tumorous lesions in the renal hilum. As shown in Figs. 13.1, 13.2, and 13.3, unlike renal pelvic mucosal lesions, the lesions in IgG4-related kidney diseases are recognizable as nonspecific nodular lesions within the fibroadipose tissue of the renal hilum. The histology shows dense lymphoplasmacytic infiltration with lymphoid follicles and loss of adipose tissue within the renal hilum. Fibrosis with hyalinization and storiform fibrosis are found (Fig. 13.3f). However, the degree of sclerosing changes is comparatively milder than that observed in autoimmune pancreatitis, a prototypical form of IgG4-RD; furthermore, some cases show only a prominent inflammatory change with relatively few fibrotic changes (Case 11 in Table 13.1) [13]. Similar to the histological characteristics of other affected organs in IgG4-RD, eosinophilic infiltration, obliterative phlebitis (Fig. 13.1e), and perineural inflammatory infiltration (Fig. 13.3d) are also observed in some cases. This infiltration extends beyond the subepithelial layer of the renal pelvic urothelial mucosa; however, involvement of the urinary epithelial layer and epithelial injury are not prominent. Similar to IgG4-related autoimmune pancreatitis and sclerosing cholangitis, therefore, the epithelial layer is well-preserved without any erosive changes. This lack of epithelial layer involvement underlies the general difficulties in obtaining valuable pathological information from superficial mucosal specimens by renal pelvic biopsy procedures. However, specimens from most of the patients show an absence of inflammation extending into the renal parenchyma, with a clear border between the renal pelvic pathology and renal parenchyma. Exceptions to the rule occur, however, as some cases of inflammatory invasion of the renal parenchyma (Fig. 13.3) and interstitinal nephritis were observed (Case 3 in Table 13.1) [5].

Fig. 13.1
figure 1

IgG4-related renal pelvic disease (Case 2 in Table 13.1). (a) Macroscopic image of the cut surface of the resected kidney. A whitish mass was found in the renal hilum. (b) Low-power image. Asterisk denotes an inflammatory nodular lesion resembling a lymphoid organ with a clear border in the renal parenchyma. Arrow denotes renal pelvic mucosa. (c) Inflammatory lesion containing several lymphoid follicles and marked inflammatory cells. Note that the renal pelvic epithelium is well-preserved (arrow). (d) Fibrotic area (*) and inflammatory invasion into the adipose tissue of the renal pelvis (lower side). (e) Asterisk denotes obliterative phlebitis using elastica van Gieson staining. (f) Numerous IgG4-positive cells dispersed throughout the interfollicular area, as determined by immunohistochemical staining for IgG4

Full size image
Fig. 13.2
figure 2

IgG4-related renal pelvic disease (Case 12 in Table 13.1). (a) Computed tomography showing the presence of a mass within the renal pelvis (arrow). (b) Low-power image of the resected kidney. Lymphoid follicle-like inflammatory nodular lesions were found in the renal hilum. The renal pelvic mucosa was slit-like indicating stenosis (arrow). (c) Renal pelvic mucosa, albeit stenotic, was well-preserved with the absence of inflammation (arrow). Fibrosis was not prominent. (d) Inflammation consisting mostly of lymphocytes and plasma cells. (e) Immunohistochemical staining for IgG4. Many IgG4-positive cells were found in the interfollicular area. (f) Semi-serial sectioning of the area shown in (e). Immunohistochemical staining for IgG1. Several IgG1-positive cells were observed, albeit in smaller numbers than those of the IgG4-positive cells observed in (e)

Full size image
Fig. 13.3
figure 3

IgG4-related renal pelvic disease (Case 1 in Table 13.1). (a) Macroscopic image of the cut surface of the resected kidney. Whitish sclerotic changes were found in the adipose tissue of the renal hilum (arrows). (b) Low-power image of the resected kidney. Scar-like, broad fibrosis (*) was prominent, and lymphoid follicles were scattered in the periphery facing the renal parenchyma. (c) Fibrosis and inflammation extend from the adipose tissue of the renal hilum into the renal parenchyma (*). (d) Nerve bundles are intact (arrows). Note the perineural inflammation. (e) Inflammation and hyalinized fibrosis are shown. (f) Note the mild inflammation but prominent fibrosis

Full size image

Immunohistochemical staining for IgG4 has revealed substantial numbers of IgG4-positive plasma cells within inflammatory lesions, even though IgG4 normally comprises only 3–6 % of the total circulating IgG in adults [1]. In cases with prominent lymphoid follicle formation, IgG4-positive cells tend to be localized in the interfollicular area, with several IgG4-positive cells scattered in the germinal centers of lymphoid follicles. As expected, these cases fulfill the comprehensive pathological diagnostic criteria for IgG4-RD [32], based on an IgG4:total IgG ratio >0.40 and the presence of >10 cells/high powered field in the biopsy sample. The predominance of IgG4-positive cells instead of IgG1-positive cells also supports the diagnosis of IgG4-related diseases (Fig. 13.2e, f).

4 Ureteral Diseases

Ureteral involvement in IgG4-RD has been found in 42 % of the IgG4-related retroperitoneal fibrosis cases [13]. In some patients, either renal pelvic involvement or ureteral lesions (either unilateral or bilateral) are also observed. Regardless of the involvement of other organs, IgG4-RD of the ureter is characterized by the thickening of ureteral wall or the presence of nodular lesions involving the affected ureter. These are usually associated with hydronephrosis resulting from ureteral stenosis of the affected portion. Therefore, in most cases of IgG4-related ureteral disease, the initial presentation is hydronephrosis associated with retroperitoneal fibrosis or renal dysfunction with unknown etiology. The diagnosis of IgG4-RD may be suspected on the basis of an increased serum IgG4 concentration and/or hypocomplementemia, the latter of which is often observed with intrinsic renal involvement by IgG4-RD [33]. The diagnosis must be established by biopsy of an affected organ.

IgG4-related ureteral disease displays the common pathological features of other IgG4-RD manifestations: in addition to marked lymphoplasmacytic infiltration, eosinophilic infiltration and storiform fibrosis are also observed in the lesions. Advanced fibrosis eventually results in ureteral sclerosis that in turn induces ureteral stenosis and obstruction. Lymphoid follicle formation can also be detected, albeit to a lesser extent than that observed in renal pelvic lesions. The extension of the inflammatory reaction into the adipose tissue around affected organs is an important feature of IgG4-RD, including autoimmune pancreatitis, reflecting their characteristic radiological findings. Similarly, periureteral fibroadipose tissue as well as the ureteral wall harbor inflammatory and fibrosclerotic reactions (Fig. 13.4a). In some cases, these reactions extend into the lesions of retroperitoneal fibrosis. Immunohistochemical staining for IgG1 and IgG4 reveals a predominantly IgG4-positive plasma cell infiltration in this disease (Fig. 13.4d, e).

Fig. 13.4
figure 4

IgG4-related ureteral disease (Case 15 in Table 13.1). (a) Low-power image of the cross-section of the resected ureter. Distinct areas of prominent inflammation and fibrotic areas were found in the ureteral wall. Inflammation partially invades into adipose tissue of renal hilum (arrow). (b) In inflammatory areas, a follicle-like inflammatory formation and extension of inflammation into the adipose tissue were found. (c) Fibrosis was prominent, and sclerotic change was present; however, the inflammatory foci remained. (d) Immunohistochemical staining for IgG4. Many IgG4-positive cells were found around the inflammatory area. (e) Semi-serial section of the area shown in (d). Immunohistochemical staining for IgG1. Several scattered IgG1-positive cells, albeit in smaller numbers than those of the IgG4-positive cells, were seen

Full size image

5 Diagnosis

The diagnosis of IgG4-related renal pelvic and ureteral diseases is relatively easy and is based on the common clinicopathological features of IgG4-RD in cases where there is either a concurrent or preceding diagnosis of IgG4-RD in other organs, such as the pancreas or the salivary glands. However, if the initial lesions are within the renal pelvis or ureters with no overt involvement of other organs, differentiation of the lesions from malignant masses or stenosis in the affected area is crucial. Moreover, inflammatory pseudotumors not related to IgG4, inflammatory myofibroblastic tumors [15], and Cattleman’s disease in cases with limited fibrosclerosis [13] should also be considered in the differential diagnosis.

Increased serum IgG4 levels and infiltration of IgG4-positive plasma cells are important in the diagnosis of IgG4-related renal pelvic and ureteral diseases. According to the current comprehensive diagnostic criteria for IgG4-RD [32], elevated serum levels of IgG4 (≥135 mg/dl) and predominantly IgG4-positive plasma cell infiltration (≥10 cells/high-power field with an IgG4-positive:total IgG-positive plasma cell ratio of ≥40 %) are essential to securing the IgG4-RD diagnosis. However, as mentioned above, biopsy specimens from the surface of the renal pelvis or the ureteral mucosa usually fail to demonstrate the characteristic features of IgG4-RD. Although the number of IgG4-positive cells that can be detected in small renal pelvic and ureteral specimens is not known, the biopsy of stenotic lesions is recommended, as demonstrated in Case 13 in Table 13.1 where the IgG4-related ureteral disease was diagnosed by ureteral biopsy [14].

To complicate matters, IgG4-related ureteral disease in association with carcinoma in situ (urothelial carcinoma) [18], as seen with Case 21 in Table 13.1, raises the possibility of ureteral cancer preceding IgG4-RD. Although the infiltration of numerous IgG4-bearing plasma cells is important for the pathogenesis of IgG4-RD, patients with pancreatic adenocarcinomas accompanied by IgG4 infiltration into the cancerous area and/or elevated serum IgG4 levels [33–37], as well as patients with pancreatic or biliary malignancies arising in the setting of IgG4-RD [35, 38, 39], have been reported. However, no cause-and-effect relationship between IgG4-RD and cancer has been demonstrated. It is imperative to examine the role of IgG4 in renal pelvic and ureteral cancers. Further, potential malignancies must be excluded rigorously in patient undergoing evaluation for possible IgG4-RD. Renal pelvic and ureteral biopsies and cytological examinations are essential to the exclusion of malignancies.

6 Conclusion

Renal pelvic and ureteral lesions are part of the IgG4-RD spectrum and are essential to distinguish from malignancy. In this chapter, we reviewed IgG4-related renal pelvic and ureteral diseases in the light of previous reports. Consequently, these manifestations are often associated with IgG4-RD in other organs, elevations of serum IgG4 concentrations, and substantial numbers of IgG4-positive plasma cells in the affected tissues.