Virchows Archiv

, Volume 462, Issue 6, pp 673–678

IgG4-related disease of the ureter: report of two cases and review of the literature

Authors

    • Department of Surgical and Morphological SciencesUniversity of Insubria
  • Gioacchino D’Ambrosio
    • Surgical Pathology UnitIRCCS Multimedica
  • Francesco Catanzaro
    • Urology UnitIRCCS Multimedica
  • Stefano La Rosa
    • Department of PathologyOspedale di Circolo
  • Fausto Sessa
    • Department of Surgical and Morphological SciencesUniversity of Insubria
    • Surgical Pathology UnitIRCCS Multimedica
Case Report

DOI: 10.1007/s00428-013-1421-5

Cite this article as:
Marando, A., D’Ambrosio, G., Catanzaro, F. et al. Virchows Arch (2013) 462: 673. doi:10.1007/s00428-013-1421-5

Abstract

IgG4-related disease (IgG4-RD) is a recently recognized multi-organ fibro-inflammatory lesion characterized by elevated IgG4 serum levels and mass-forming lesions. This condition shows similar histological features independently of the site of origin including storiform fibrosis, obliterative phlebitis, and dense lymphoplasmacytic infiltrate with a conspicuous IgG4-positive plasma cell component. Since this disease has only recently been categorized as a single specific nosologic entity, lesions with these typical morphological features have previously been named in different ways, creating some confusion and making it difficult to identify cases published in the literature. Lesions with features suggesting IgG4-RDs have very rarely been reported in the ureter, and they have been named using the terms “inflammatory pseudotumor” and “idiopathic segmental ureteritis.” Herein, we describe the clinicopathological features of ureteral IgG4-RD found in two different patients. An 82-year-old female and a 77-year-old male underwent ureteral resection due to severe ureteral wall thickness and lumen stenosis suggestive of urothelial carcinoma. However, histological examinations showed transmural fibro-inflammatory lesions, with abundant IgG4 plasma cells intermixed with histiocytes, lymphocytes, fibroblasts, and scattered eosinophils. We have also accurately reviewed the literature in order to identify, among lesions diagnosed with different names, examples of ureteral IgG4-related lesions to give the reader a comprehensive overview of this relatively rare inflammatory disease. We suggest using the name “ureteral IgG4-RD” for those lesions showing the same morphological features as IgG4-RDs located elsewhere.

Keywords

IgG4UreterIgG4-related diseaseInflammatory pseudotumor

Introduction

IgG4-related disease (IgG4-RD) is a novel and recently recognized multi-organ systemic fibro-inflammatory lesion characterized by elevated IgG4 serum levels and mass-forming lesions [1, 2]. This condition has now been described in virtually every organ, and with the exception of some specific sites such as lymph nodes and lung and oral cavity, the histological features are similar regardless of the site of origin and include storiform fibrosis, obliterative phlebitis, and dense lymphoplasmacytic infiltrate with a conspicuous IgG4-positive plasma cell component [2]. Due to the fact that this disease has only recently been categorized as a single specific nosologic entity, lesions showing the typical clinicopathological features have been named in different ways in the past, creating some difficulty in identifying cases published in the literature [3]. The term “inflammatory pseudotumor (IPT),” which has been used to diagnose mass-forming lesions composed of myofibroblastic spindle cells together with lymphoplasmacytic inflammatory cells and eosinophils [4], is probably the term which was most often used in the literature to describe this entity before the introduction of the term “IgG4-related disease.”

Lesions with clinicopathological features suggesting IgG4-RDs have been reported in the urinary system, and most cases were localized in the kidney and urinary bladder [5]. However, rare cases involving ureters with the same morphology have also been described, and they have been labeled as “inflammatory pseudotumor” or “idiopathic segmental ureteritis” [6, 7]. The first description of such a lesion was published by Bissada et al. in 1978 [6], and since then, only 18 other cases have been reported [718]. From a clinical and therapeutic point of view, ureteral IgG4-RD represents a challenging entity with a difficult preoperative diagnosis. Indeed, radiological investigation is often misleading, frequently suggesting a diagnosis of urothelial carcinoma because of ureter segmental obstruction by wall thickening, followed by hydronephrosis [14].

Herein, we describe the clinicopathological features of ureteral IgG4-RD found in two different patients. In addition, we have accurately reviewed the literature in order to identify, among lesions diagnosed with different names, those that are ureteral IgG4-related lesions in order to give the reader a comprehensive overview of this relatively rare inflammatory disease.

Clinical history

Case 1

An 82-year-old woman with a history of hypertension had an abdominal computed tomography scan that showed left hydronephrosis and a mass involving the distal portion of the left ureter. Urinary cytology did not reveal any neoplastic cells. However, since the clinical and radiological diagnosis was consistent with a ureteral carcinoma, the patient underwent left nephroureterectomy. Intraoperative macroscopic examination revealed a 4-cm-long hardening of the lower third of the ureter, and a cystoscopy, performed at the same time, showed an extension of the lesion to the dome of the urinary bladder. After the operation, the patient had an incipient relapse of the disease in the contralateral ureter, and she underwent corticosteroid therapy with subsequent lesion regression. After 9 months of follow-up, she had not developed any relapse or any other IgG4-related disease. No IgG4 serum level was evaluated.

Case 2

A 77-year-old man with a known history of urothelial dysplasia and urinary cytology positive for cancer cells underwent transurethral resection of a bladder lesion histologically diagnosed as a high-grade urothelial carcinoma in situ. Subsequently, total cystectomy was performed. During this operation, the intraoperative examination was consistent with an invasive cancer because of the increased consistency of the fat tissue around the urinary bladder also causing stenosis of the left ureter. No hydronephrosis of the ipsilateral kidney was observed. No IgG4 serum level was evaluated before surgery.

Materials and methods

Tissue samples were fixed in buffered formalin (formaldehyde 4 % w/v and acetate buffer 0.05 M) and routinely processed to paraffin wax. For morphological evaluation, sections were stained with hematoxylin and eosin (H&E), Weigert, and trichrome stains. For immunohistochemistry, the Ventana Medical System Benchmark XT Ultra (Ventana, Tucson, AZ) was employed using the following antibodies: anti-CD138 (monoclonal, clone B-A38, Ventana), anti-k chain (polyclonal, Covance), anti-λ chain (polyclonal, Covance), anti-IgG (polyclonal, Covance), anti-IgA (polyclonal, Thermoscientific), anti-IgM (polyclonal, Covance), and anti-IgG4 (monoclonal, clone HP6025, Invitrogen-Zymed).

Results

Microscopic evaluation of ureters in both cases revealed that ureteral stenotic lesions were characterized by severe fibrosclerosis with focal areas of storiform appearance involving the full thickness of the ureteral wall and extended into the periureteral fat tissue, without any evidence of urothelial carcinoma (Fig. 1a and b). A dense infiltration of inflammatory cells with an abundant plasma cell component (Fig. 1c), together with a mixed population of lymphocytes, histiocytes, and eosinophils, was observed in both cases. Phlebitis was observed in both cases (Fig. 1d and e), but it was obliterative only in case 1. In both cases, plasma cells were represented by IgG plasma cells showing immunoreactivity for both kappa and lambda light chains (Fig. 1f). Importantly, the majority of plasma cells were positive for the antibody directed against IgG4 (Fig. 1g). In case 1, the average IgG4 plasma cell count was 123 per high power field (HPF), and the IgG4+/IgG+ ratio was 80 %. In case 2, the average IgG4 plasma cell count was 142 per HPF, and the IgG4+/IgG+ ratio was 60 %. The count of IgG4 plasma cells was done according to the “Consensus statement on the pathology of IgG4-related disease” [2].
https://static-content.springer.com/image/art%3A10.1007%2Fs00428-013-1421-5/MediaObjects/428_2013_1421_Fig1_HTML.gif
Fig. 1

The ureters of both cases showed narrowed lumens (a hematoxylin–eosin) and thickened walls due to a fibro-inflammatory lesion which extended into the periureteral fat tissue (b hematoxylin–eosin). The inflammatory component consisted of a dense infiltration of plasma cells, together with a mixed population of lymphocytes, histiocytes, and eosinophils (c hematoxylin–eosin). Obliterative phlebitis was also observed in one case (d hematoxylin–eosin, e Weigert). Typically, plasma cells were represented by IgG plasma cells (f immunohistochemistry), and most of them were immunoreactive for IgG4 (g immunohistochemistry)

Discussion

IgG4-RD is the term recently proposed by a group of Japanese investigators to encompass a large variety of clinical and pathological entities, involving virtually every organ, which had previously been considered as separate diseases. This disease has been more frequently observed and described in the pancreas, where it was first described, but it has now also been reported in the lungs, salivary glands, periorbital tissue, lymph nodes, breast, prostate, thyroid, and skin [2]. IgG4-RD has rarely been described in the urinary tract, mainly in the kidney and bladder, whereas ureteral cases are extremely rare [3].

Recently, a consensus statement has established the diagnostic criteria and proposed a three-tiered classification of IgG4-RD. The three major histological features are: (1) dense lymphoplasmacytic infiltrate, (2) fibrosis at least focally arranged in a storiform pattern, and (3) obliterative phlebitis. Two other possible histopathological features are phlebitis without lumen obliteration and an increased number of eosinophils. The IgG4 count is a hallmark of the lesion, and in surgical specimens, the finding of more than 30 IgG4-positive plasma cells per HPF has been considered specific, as has a IgG4+/IgG+ ratio >40 % [2]. The proposed diagnostic terminology includes the following three categories: (1) lesion with histology highly suggestive of IgG4-RD, with the presence of at least two of the characteristic histological features stated above; (2) lesion with histology that probably suggests a IgG4-RD, but cases may either lack the full histological spectrum or the typical immunohistochemical profile; and (3) lesion with insufficient histopathological evidence of IgG4-RD, but there is a suspicion of the disease [2].

In terms of these recently proposed diagnostic criteria, our two cases of ureteral IgG4-RD belong to the first diagnostic category and for this reason were classified as histologically highly suggestive of IgG4-RD.

In our review of the English literature, we identified 13 papers that described lesions morphologically suggestive of ureteral IgG4-RD in 18 patients, although IgG4 immunohistochemistry was performed in only four studies (Table 1). The morphological descriptions reported were used to reclassify all the cases following the diagnostic criteria and terminology recently proposed by Deshpande et al. [2]. Since at least two major diagnostic criteria were described in all reported cases (i.e., fibrosis, sometimes with a storiform pattern, and dense lymphoplasmacytic infiltrate), all fibro-inflammatory diseases could be reclassified as lesions histologically highly suggestive of IgG4-RD. The mean age of patients was 62 years, spanning a very wide range (35–84 years), with a male prevalence. The lesions were more frequently localized in the left ureter (14 cases) than in the right one (5 cases) and were characterized by lumen stenosis 1.5 to 4 cm long (average, 2.6 cm). In one case, the disease was bilateral [16]. Interestingly, with the exception of our case 2 where the preoperative radiological and clinical diagnosis was that of an invasive urothelial bladder carcinoma, in all the other cases, the reported preoperative clinical diagnosis was that of ureteral carcinoma, because the radiological features of ureteral IgG4-RD overlap with those of ureteral urothelial carcinoma [15]. These observations underline the difficult preoperative diagnosis that has important clinical and therapeutic implications. Indeed, surgery is mandatory for ureteral cancer, while IgG4-RD needs pharmacological therapy with glucocorticoids, leaving the surgical approach only for those lesions causing kidney complications [1921]. The evaluation of IgG4 serum level may be of help in identifying ureteral IgG4-RD before surgery. However, it is worth noting that increased IgG4 serum level (>135 mg/dl) is considered helpful but not essential for the diagnosis, also because it can be found in other diseases including atopic dermatitis, parasitic diseases, pemphigus vulgaris, pemphigus foliaceus, and even pancreatic cancer [22]. In addition to fibrosis and dense lymphoplasmacytic infiltrate, another characteristic histological feature is phlebitis, with or without obliteration [2]. It was evaluated in nine reported cases and was found in five of them. Four of these five cases showed the typical features of obliterative phlebitis.
Table 1

Review of the English literature on ureteral IgG4-related disease

Case

Author

Age

Sex

Clinical diagnosis

Location

Side

Diameter (cm)

Dense lymphoplasmacytic infiltrate

Storiform fibrosis

Obliterative phlebitis

Phlebitis without obliteration

Increased eosinophils

IgG4/IgG ratio

Original diagnosis

Diagnostic categorya

Relapse (months)

1

Bissada et al. [6]

35

F

Nk

Nk

Lt

Nk

+

+

Nk

Nk

Nk

Nk

ISU

Suggestive

Yes (16)

2

Horn et al. [8]

64

M

Cancer

Lower

Lt

2.5

+

+

Nk

Nk

Nk

Nk

IPT

Suggestive

Nk

3

Nozawa et al. [9]

54

M

Cancer

Upper

Lt

3.0

+

+

Nk

Nk

Nk

Nk

IPT

Suggestive

No

4

Tripp et al. [7]

66

M

Nk

Mid

Rt

Nk

+

+

Nk

Nk

Nk

Nk

ISU

Suggestive

Nk

5

Buyl et al. [10]

65

M

Nk

Lower

Lt

Nk

+

+

Nk

Nk

Nk

Nk

RPF

Suggestive

No

6

Hamano et al. (a) [11]

60

M

Cancer

Nk

Lt

Nk

+

+

Nk

Nk

Nk

High

RPF

Suggestive

Yes (12)

7

Hamano et al. (b) [11]

74

M

Cancer

Nk

Rt

Nk

+

+

Nk

Nk

Nk

High

RPF

Suggestive

Yes (12)

8

Hamano et al. (c) [11]

63

M

Cancer

Nk

Lt

Nk

+

+

Nk

Nk

+

High

RPF

Suggestive

Nk

9

Kamisawa et al. [12]

75

M

Cancer

Lower

Lt

Nk

+

+

+

+

Nk

Nk

RPF

Suggestive

Yes (10)

10

Montgomery et al. [13]

70

M

Nk

Upper

Rt

3.0

+

+

Nk

Nk

+

Nk

IMT

Suggestive

Yes (1–4)

11

Hosokawa et al. [14]

66

M

Cancer

Upper

Lt

3.0

+

+

Nk

Nk

Nk

Nk

IPT

Suggestive

Nk

12

Joo et al. [15]

53

M

Cancer

Lower

Rt

3.0

+

+

+

Nk

+

Low

ISU

Suggestive

Nk

13

Kojima et al. (a) [16]

47

F

Nk

Nk

Bi

1.5

+

+

Nk

High

PCCD

Suggestive

No

14

Kojima et al. (b) [16]

73

M

Nk

Nk

Lt

3.5

+

+

Nk

High

PCCD

Suggestive

No

15

Abe et al. [17]

39

M

Cancer

Lower

Lt

3.0

+

+

Nk

Nk

+

86 %

IgG4-RPF

Suggestive

No

16

Kim et al. (a) [18]

45

M

Cancer

Mid

Lt

1.5

+

+

Nk

+

Nk

IPT

Suggestive

Yes (9)

17

Kim et al. (b) [18]

47

M

Cancer

Lower

Lt

1.5

+

+

+

Nk

+

Nk

IPT

Suggestive

Yes (8)

18

Kim et al. (c) [18]

84

F

Cancer

Upper

Rt

2.0

+

+

Nk

+

Nk

IPT

Suggestive

No

19

Present case 1

82

F

Cancer

Lower

Lt

4.0

+

+

+

+

+

80 %

IPT

Suggestive

Yes (1)

20

Present case 2

77

M

Incidental

Lower

Lt

2.0

+

+

+

+

60 %

IPT

Suggestive

No

F female, M male, Nk not known, Lt left, Rt right, Bi bilateral, IMT inflammatory myofibroblastic tumor, IPT inflammatory pseudotumor, ISU idiopathic segmental ureteritis, RPF retroperitoneal periureteral fibrosis, PCCD plasma cell type of Castleman's disease

aAccording to Consensus statement on the pathology of IgG4-related disease [2]

Kojima et al. have recently described three cases diagnosed as ureteral Castleman's disease [16]. In two of them (case 13 and 14 of Table 1), both increased IgG4 serum levels and dense plasma cell infiltration with >50 % IgG4-positive plasma cells strongly suggest that they represent two examples of ureteral IgG4-RD. Interestingly, Kojima et al. also suggested that most of retroperitoneal diseases showing morphological features of plasma cell type of Castleman's disease are to be considered as IgG4-RDs.

In addition to the morphological features, the immunohistochemical assessment of IgG4-positive plasma cells and the IgG4+/IgG+ ratio are important diagnostic criteria. Unfortunately, these findings have only been reported in more recent papers and are lacking in studies published before 2010, with the exception of the paper by Hamano et al. [11]. Following the criteria proposed by Deshpande et al. [2], three cases showed the diagnostic IgG4+/IgG+ ratio of 86, 80, and 60 %.

It has been demonstrated by several authors that patients with IgG4-RD have a significant risk of recurrent disease, and there is a high probability of developing related pathologies including autoimmune pancreatitis [11], Mikulicz's disease [23], hypophysitis, Riedel thyroiditis, interstitial pneumonitis, interstitial nephritis, prostatitis, lymphoadenopathy, retroperitoneal fibrosis, inflammatory aortic aneurysm, and other IPT [1]. Seven of the 14 patients for whom follow-up information was available developed relapse of disease after a mean time of 9.7 months (range, 1–16 months), and for this reason, patients with IgG4-RD need to be strictly monitored, as suggested by several authors [9, 19, 20].

In conclusion, we have described two cases of ureteral IgG4-RD, and we have reviewed the English literature on this topic. We have reclassified the cases reported in the literature according to the recently proposed Consensus statement on the pathology of IgG4-related disease [2]. Since these lesions have been called by several different names in the past and they represent different aspects of the same multi-organ disease, we suggest that it is important to unify the nomenclature. Moreover, we observed that ureteral lesions show similar features to IgG4-RDs of other sites, and for this reason, we propose the use of the name “ureteral IgG4-RD.”

Conflict of interest

The authors declare that they have no conflict of interest.

Copyright information

© Springer-Verlag Berlin Heidelberg 2013