IgG4-related Retroperitoneal Fibrosis Research Articles

Testicular Inflammation as a New Manifestation of IgG4-associated Disease

IgG4-related disease has properties of a systemic disorder but simultaneously is associated with a growing list of organ-specific manifestations including autoimmune pancreatitis, IgG4-associated cholangitis, IgG4-related kidney disease, and IgG4-associated prostatitis. In this study, we present, to the best of our knowledge, the first case of a patient with multiorgan IgG4-related disease who lost his testes because of IgG4-related testicular inflammation. We postulate that IgG4-related disease in the urogenital tract is not restricted to IgG4-related kidney disease and prostatitis, but that this rare disorder may also affect the testis.

Rethinking Ormond’s Disease

Idiopathic retroperitoneal fibrosis (RPF) is a periaortic sclerotic disease that encases adjacent retroperitoneal structures, particularly the ureters. A subset of idiopathic RPF cases can be associated with IgG4-related disease, but the frequency of this association is not clear. We selected 23 cases of idiopathic RPF and identified IgG4-related RPF cases based on the presence of IgG4+ plasma cells in the tissue, using an IgG4/IgG ratio cutoff of >40%. We then compared the IgG4-related RPF patients and the non-IgG4-related RPF patients in terms of both the presence of histopathologic features typical of IgG4-related disease and the simultaneous occurrence (or history) of other organ manifestations typical of IgG4-related disease. The IgG4-related RPF and non-IgG4-related RPF groups were also analyzed in terms of clinical, laboratory, and radiologic features and treatment review.We identified 13 cases of IgG4-related RPF (57% of the total cohort). The distinguishing features of IgG4-related RPF were histopathologic and extra-organ manifestations of IgG4-related disease. The IgG4-related RPF patients were statistically more likely than non-IgG4-related RPF patients to have retroperitoneal biopsies showing lymphoplasmacytic infiltrate (p = 0.006), storiform fibrosis (p = 0.006), or tissue eosinophilia (p = 0.0002). Demographics of the 2 groups, including a middle-aged, male predominance (mean age, 58 yr; 73% male), were similar.IgG4-related disease accounts for a substantial percentage of patients with “idiopathic” RPF. Histopathologic features such as storiform fibrosis, obliterative phlebitis, and tissue eosinophilia are critical to identifying this disease association. Extraretroperitoneal manifestations of IgG4-related disease are also often present among patients with IgG4-related RPF. Elevated IgG4/total IgG ratios in tissue biopsies are more useful than the number of IgG4+ plasma cells per high-power field in cases of RPF that are highly fibrotic.

Clinical Features of 10 Patients with IgG4-related Retroperitoneal Fibrosis

To elucidate the clinical characteristics of IgG4-related retroperitoneal fibrosis (RF). IgG4-related RF was diagnosed when all of the following three criteria were fulfilled: retroperitoneal soft tissue masses surrounding the aorta and/or adjacent tissues, elevation of the serum IgG4 levels, and abundant infiltration of IgG4-positive plasma cells in at least one organ or site. Ten patients were diagnosed as having IgG4-related RF. The mean age at diagnosis was 70.1 years, and the male-to-female ratio was 1:0.6. Only two patients had initial symptoms predominantly related to RF (back pain and edema of the lower extremities), while the remaining eight patients reported initial symptoms due to associated diseases. On laboratory examination, a severe inflammatory reaction was observed in one patient. Elevation of the levels of serum IgG and IgE, eosinophilia and positivity of antinuclear antibodies were detected in seven, five, two and seven patients, respectively. The retroperitoneal masses were detected primarily in the left renal hilus in four patients, in the periaortic region in five patients and in both regions in one patient. Hydronephrosis was present in five patients. The histological diagnosis was confirmed in the retroperitoneal masses (resection, n=1 biopsy, n=2) and extraretroperitoneal lesions (n=7). Twenty-four other IgG4-related diseases were found to be associated with IgG4-related RF in nine patients (autoimmune pancreatitis (n=2), sialadenitis (n=4), dacryoadenitis (n=5), lymphadenopathy (n=9), pulmonary pseudotumor (n=1) and pituitary pseudotumor (n=1)). Seven patients underwent steroid therapy, all of whom responded well and showed no instances relapse. IgG4-related RF has several clinical characteristic features. Our diagnostic criteria may be helpful in obtaining a correct diagnosis.

Retroperitoneal fibrosis associated with immunoglobulin G4-related disease

Retroperitoneal fibrosis is a rare disease characterized by the development of inflammation and fibrosis in the soft tissues of the retroperitoneum and other abdominal organs. Retroperitoneal fibrosis can be of 2 types: idiopathic and secondary. The recently advocated concept and diagnostic criteria of immunoglobulin G4 (IgG4)-related disease, derived from research on autoimmune pancreatitis (AIP), has led to widespread recognition of retroperitoneal fibrosis as a condition caused by IgG4-related disease. We now know that previously diagnosed idiopathic retroperitoneal fibrosis includes IgG4-related disease; however, the actual prevalence is unclear. Conversely, some reports on AIP suggest that retroperitoneal fibrosis is concurrently found in about 10% of IgG4-related disease. Because retroperitoneal fibrosis has no specific symptoms, diagnosis is primarily based on diagnostic imaging (computed tomography and magnetic resonance imaging), which is also useful in evaluating the effect of therapy. Idiopathic retroperitoneal fibrosis can occur at different times with other lesions of IgG4-related disease including AIP. Thus, the IgG4 assay is recommended to diagnose idiopathic retroperitoneal fibrosis. High serum IgG4 levels should be treated and monitored as a symptom of IgG4-related disease. The first line of treatment for retroperitoneal fibrosis is steroid therapy regardless of its cause. For patients with concurrent AIP, i.e., IgG4-related retroperitoneal fibrosis, the starting dose of steroid is usually 30-40 mg/d. The response to steroid therapy is generally favorable. In most cases, the pancreatic lesion and retroperitoneal fibrosis improve after the initial treatment. However, the epidemiology, treatment for recurring retroperitoneal fibrosis, and long-term prognosis are still largely unknown. Further analysis of such cases and research are necessary.

Two Siblings with Type 1 Autoimmune Pancreatitis

Type 1 autoimmune pancreatitis (AIP) is characterized by a high serum IgG4 concentration and is closely associated with the HLA-DRB1(*)04:05-DQB1(*)04:01 haplotype, for which family studies may disclose its immunogenetic significance. In the present study, we encountered two male siblings with type 1 AIP who exhibited diffuse pancreatic swelling with a capsule-like rim and diffuse pancreatic duct stricture. The younger brother also displayed characteristic IgG4-related sialadenitis and retroperitoneal fibrosis. Contrary to our expectations, the siblings showed only normal or slightly elevated values of serum IgG4 and no HLA DRB1(*)04:05-DQB1(*)04:01 haplotype, suggesting that type 1 autoimmune pancreatitis is associated with multiple immunogenetic factors.

Efficacy of Laparoendoscopic Single-Site Biopsy for Diagnosis of Retroperitoneal Tumor of Unknown Origin

Background and Purpose: When percutaneous image-guided biopsies are not possible for retroperitoneal tumor of unknown origin (RTUO), surgical tissue diagnosis becomes necessary. Laparotomy and laparoscopic surgery are current standard treatments; however, the laparoendoscopic single-site (LESS) approach offers many potential benefits. We describe our technique for LESS biopsy of RTUO. Patients and Methods: Five patients underwent LESS biopsy for diagnosis of RTUO. A multichannel port was inserted into the peritoneal or retroperitoneal space through a 3-cm skin incision, which adequately exposed the retroperitoneal tumor. The specimen was grasped and isolated circumferentially from the surrounding tissue. Results: LESS surgery was performed successfully without any complications such as open conversion. Mean operative time was 183 min and estimated blood loss was negligible. The diagnoses were IgG4-related retroperitoneal fibrosis (n = 4) and lymphoma (n = 1). Sufficient specimens were safely obtained not only for pathological diagnosis but also for further examinations such as immunophenotyping or DNA analysis. Convalescence was satisfactory. All patients were treated appropriately according to the resulting diagnosis. Conclusions: LESS biopsy for RTUO is a safe and effective alternative to open surgical and standard laparoscopic biopsies. Further studies of clinical experiences are needed to confirm the benefits of this new technique.

Prevalence of IgG4-Related Disease in Japan Based on Nationwide Survey in 2009

The number of patients with autoimmune pancreatitis who visited hospitals in Japan in 2007 was approximately 2709 (95% confidence interval; range 2540–3040). Because IgG4-related disease is a new clinical entity, there are no data with regard to its prevalence. To estimate the number of patients with IgG4-related disease in Japan, we randomly selected hospitals using stratification and asked them how many patients they had with IgG4-related disease in 2009. The number of patients with Mikulicz's disease, IgG4-related retroperitoneal fibrosis, IgG4-related renal disease, IgG4-related pulmonary disease, and IgG4-related lymphadenopathy who visited hospitals in Japan in 2009 was approximately 4304 (95% confidence interval; range 3360–5048), 272 (95% confidence interval; range 264–306), 57 (95% confidence interval; range 47–66), 354 (95% confidence interval; range 283–424), and 203 (95% confidence interval; range 187–240), respectively. The total number of patients with IgG4-related disease without autoimmune pancreatitis in Japan was approximately 5190 (95% confidence interval; range 4141–6084). The male : female ratio was 1 : 0.77, and the average of age of disease onset was 58.8 years. The total number of patients with IgG4-related disease in Japan in 2009, including autoimmune pancreatitis, was approximately 8000.

Improvement of a Compressed Inferior Vena Cava due to IgG4-related Retroperitoneal Fibrosis with Steroid Therapy

A 79-year-old man had a 3.5-year history of edema of the lower extremities of unknown etiology. Abdominal computed tomography showed a soft tissue mass around the abdominal aorta, and the biopsy revealed dense fibrosis with abundant infiltration of IgG4-positive plasma cells. His serum IgG4 level was increased to 188 mg/dL. His lower extremity edema was induced by stenosis of the inferior vena cava (IVC) due to the mass. With a diagnosis of IgG4-related retroperitoneal fibrosis, he was treated with steroid, and the leg edema decreased with improvement of patency of the IVC and reduction of the soft tissue mass.

S状結腸癌傍大動脈リンパ節転移を疑ったIgG4関連後腹膜線維症の1例

症例は74歳，男性．平成21年8月，右下腹部痛が出現したため近医を受診した．腹部CTでS状結腸の肥厚と口側腸管の拡張，大動脈と下腸間膜動脈周囲軟部組織の肥厚および左水腎症を認めた．9月に当科に紹介された．精査の結果，S状結腸癌とリンパ節転移または後腹膜線維症による左尿管狭窄と診断した．S状結腸切除D2郭清術を行った．術中所見で，腹部大動脈から下腸間膜動脈周囲に非常に硬い結合織を認め，下腸間膜動脈周囲組織の剥離に難渋した．病理診断は，S，Type3，SS，N0，Stage II．下腸間膜動脈周囲の結合織はIgG4関連線維症に矛盾しない所見であった．術後の経過は良好で15病日に退院．泌尿器科で左尿管狭窄に対してダブルJステントを挿入後，線維症の治療としてプレドニンの内服を開始した．水腎症は消失し，ダブルJステントは抜去され，画像上線維症は縮小した．

Proteinase 3 Anti-Neutrophil Cytoplasmic Antibody (PR3-ANCA) Positive IgG4-Related Retroperitoneal Fibrosis: Utility of PET-CT with <sup>18</sup>F-Fluorodeoxy Glucose (FDG)

A 55-year-old man showed a serum creatinine level of 1.51 mg/dL, CRP of 0.79 mg/dL, and proteinase 3 anti-neutrophil cytoplasmic antibody (PR3-ANCA) of 43.9 EU (normal range: below 10). The serum levels and ratios of IgG1, IgG2, IgG3, and IgG4 to total IgG were 1,570 mg/dL (49%), 1,190 mg/dL (37%), 82 mg/dL (3%), and 351 mg/dL (11%), respectively. Positron emission tomography and CT with (18)F-fluorodeoxyglucose (PET-CT) demonstrated retroperitoneal fibrosis. After a diagnosis of IgG4-related retroperitoneal fibrosis with PR3-ANCA was made, oral prednisolone improved serum creatinine and the titer of PR3-ANCA to normal levels, with no abnormal findings on PET-CT.

Acute Renal Failure due to IgG4-related Retroperitoneal Fibrosis

Acute Renal Failure due to IgG4-related Retroperitoneal Fibrosis

IJU this issue

Shiro Baba md phdAssociate Editor In Nagoya, negotiators at COP10 reported progress toward an international agreement on access to genetic resources and establishing biodiversity preservation targets over the next decade. It is a very important issue for all on this planet. For urologists, it is essential to know the basics of tissue engineering and stem cell research. Shokeir and Shehab El-Din (Mansoura, Egypt) reviewed recent publications on basic principles and application of this technology in the genitourinary tract. Techniques to establish embryonal stem cells and generate pluripotent stem cells are reviewed. Interestingly, bone marrow stem cells from chronic renal failure rats had no capacity for in vitro proliferation and bone marrow cells obtained from renal chronic failure patients might not be useful for autologous cell transplantation. Stem cell injection therapy has been attempted for stress urinary incontinence, erectile dysfunction, interstitial cystitis, and ureteral and bladder reconstruction. It is crucial for urologists to follow the advances in this field. Diagnosis of benign prostatic enlargement (BPE) can be aided with simple non-invasive abdominal ultrasonography. Foo (Singapore) reviewed clinical evaluations of patients with BPE. Intravesical prostatic protrusion (IPP) can distort the normal funneling bladder neck, which is shown on abdominal ultrasonography, causing benign prostatic obstruction and is a useful non-invasive predictor for clinical progression in BPE. Kamba et al. (Kyoto, Japan) reported a retrospective multi-institutional study on the oncological outcome of stage 1 seminoma with a mean follow up of 4.5 years, according to different post-orchiectomy management. Tumor invasion into the rete testis was, as reported previously, an independent predictive factor for relapse of this tumor. The follow up should include regular abdominopelvic computed tomography scan described in European Association Urology(EAU) guidelines. The issue of higher drop-out rate in the follow up among Japanese patients is discussed by Brassell (Washington DC, USA) in the Editorial Comment. Hayashi et al. (Osaka, Japan) investigated the protective effects of carvedilol, a β-adrenoreceptor agonist with potent anti-oxidant properties in a rat renal ischemia-reperfusion injury (IRI) model, resulting in lower plasma creatinine levels accompanied by a significant increase in the expression levels of Cu/Zn superoxide dismutase and the reduction of 8-hydroxydeoxyguanosine. It was shown that rats treated with carvedilol before and after IRI significantly sustained improved renal function up to 1 week after IRI. Okamoto et al. (Wakayama, Japan) used 8-week-old male Otsuka Long-Evans Tokushima fatty (OLETF) rats as an animal metabolic syndrome model. Molecules such as osteopontin (OPN) and monocyte chemoattractant protein-1 are known to play an important role in the development of insulin resistance, a main feature of metabolic syndrome. Higher protein expression of OPN in ethylene-glycol treated OLETF might be responsible for increased crystal retention in the tubular lumen. Further study on the causal link between the metabolic syndrome and kidney stone formation, however, is warranted. Polyuria after the excision of adrenal pheochromocytoma is extremely rare, and the case reported by Tobe et al. (Saitama, Japan) is the second case report to date. Despite oral administration of doxazosin (4 mg) for 2 months before surgery, polyuria started just after the adrenalectomy; urine output of more than 8 L/day continued for more than 2 weeks. A rapid decline in cAMP concentration in the collecting tubules after removal of the tumor is suspected in the mechanism. Suzuki et al. (Tokyo, Japan) examined sex-hormone profiles in eight sexually mature Japanese male patients with Down syndrome. Elevated luteinizing hormone and follicle stimulating hormone levels, and smaller testes suggest various amounts of testicular damage that can affect both germinal and Leydig cell elements. Kikuno et al. (Saitama, Japan) reported a patient with an IgG4-related retroperitoneal fibrosis with concomitant rheumatoid arthritis. High serum IgG4 concentration has been also reported in Mikulicz's disease, sclerosing pancreatitis and retroperitoneal fibrosis. It has to be mentioned that hydronephrosis caused by the same pathology was already reported in 2002.1

IgG4‐related retroperitoneal fibrosis: the first reported case in a Chinese population

Immunoglobulin G4 (IgG4)-related sclerosing disease is a newly recognized clinicopathological entity characterized by lymphoplasmacytic infiltration and varying degrees of fibrosis in various organs, with abundant IgG4-positive plasma cells in tissues. Patients usually exhibit multisystem involvement and often respond well to steroid and immunosuppressive therapy. However, this disease has been rarely reported in a Chinese population. We herein report a case of IgG4-related sclerosing disease solely presenting with retroperitoneal fibrosis that was effectively treated with systemic steroid therapy. To the best of our knowledge, this is the first reported case of IgG4-related retroperitoneal fibrosis in a Chinese population.

Retroperitoneal Fibrosis: A Clinicopathologic Study With Respect to Immunoglobulin G4

The possible involvement of immunoglobulin G4 (IgG4) in the pathogenesis of idiopathic sclerosing lesions has been suggested. In this study, a clinicopathologic analysis was performed to reveal characteristics of retroperitoneal fibrosis relating to IgG4. The study involved 17 patients with retroperitoneal fibrosis. Immunohistochemistry revealed numerous IgG4-positive plasma cell infiltrates in 10 cases (IgG4-related), but only a few positive cells in 7 cases (non-IgG4-related). All patients with IgG4-related retroperitoneal fibrosis were male, whereas all except 1 with unrelated lesions were female. Histologically, eosinophilic infiltration (>5 cells per high-power field) and obliterative phlebitis were commonly observed in IgG4-related lesions. Serologically, serum IgG and IgG4 concentrations were significantly higher in the IgG4-related cases, with the IgG4 concentrations all over 135 mg/dL (the upper limit of the normal range). Steroid therapy was performed in 13 cases, and was effective irrespective of IgG4. Three patients had recurrence during the follow up. Five of 10 IgG4-related cases had sclerosing lesions at other sites. The only tests that reliably distinguish the 2 groups were serum IgG4 levels or IgG4/IgG ratio in the plasma cells in a tissue biopsy. The only major clinical difference was the striking male predominance in IgG4-related cases. In conclusion, this study revealed that retroperitoneal fibrosis could be classified as IgG4-related or not. This distinction seems important to help better characterize the biology/pathogenesis of both groups and better predict the possibility of other IgG4-related processes at other anatomic sites.