Int Urol Nephrol DOI 10.1007/s11255-015-1189-4

UROLOGY - REVIEW

IgG4‑related disease: what urologists should know Daniele Bianchi1 

Received: 11 November 2015 / Accepted: 13 December 2015 © Springer Science+Business Media Dordrecht 2015

Abstract  Introduction  IgG4-related disease (IgG4-RD) is a recent nosological entity defined as a chronic immune-mediated fibro-inflammatory condition characterized by a tendency to form tumefactive, tissue-destructive lesions or by organ failure. Urologic involvement in IgG4-RD has been described in some short series of patients and in isolated case reports. Aim  The aim of the present study was to review urologic involvement in IgG4-RD with the purpose of providing urologists with the proper background necessary for a preliminary assessment of possible urologic localization of this recent clinical entity. Indeed, patients are typically referred for immunologic management, often right after a differential diagnosis of urologic disease. Materials and methods  A systematic search of PubMed® for both original and review articles published up until October 2015 was performed using keywords relating to IgG4 and to single specific urologic organs, structures, or anatomic sites. The search was then extended to Google® using the same search criteria in order to identify articles not indexed in PubMed®. Results  IgG4-RD is a systemic condition potentially involving every urologic site. It can mimic malignancies and is often misdiagnosed due to its rarity. Conclusions  A multidisciplinary approach to IgG4-RD should be required because it occasionally mimics other urologic diseases, including malignancies. Therefore,

* Daniele Bianchi [email protected] 1



Department of Urology, Policlinico Tor Vergata, Viale Oxford, 81, 00133 Rome, Italy

urologists should perform preliminary assessments to avoid inappropriate urologic treatments. Keywords  IgG4-related disease · Pseudotumors · Membranous glomerulonephritis · Tubulointerstitial nephritis · Autoimmune pancreatitis · Urology

Introduction IgG4-related disease (IgG4-RD) is a recent nosological entity defined as a chronic immune-mediated fibro-inflammatory condition [1] that potentially involves nearly every anatomic site [2, 3] and that is characterized by a tendency to form tumefactive, tissue-destructive lesions or by organ failure [4]. Its typical histopathologic features include a lymphoplasmacytic infiltrate rich in IgG4 plasma cells, obliterative phlebitis, and storiform fibrosis, while the main laboratory finding is an inconsistently elevated serum IgG4 concentration [5]. From pancreatic to extra‑pancreatic disease The concept of autoimmune pancreatitis (AIP) was first proposed by Yoshida et al. [6] in 1995, AIP type I was associated with elevated IgG4 serum levels [7], and in 2003 IgG4-RD was suggested as the basic systemic condition responsible for AIP type I, along with extra-pancreatic lesions [8]. Over the last decade, extra-pancreatic manifestations of the disease involving several organs have been reported in the literature [1, 3, 9]. Many studies have concentrated on urologic involvement, with the kidney being examined first before other urologic sites. Several different names for the disease were proposed before two independent teams headed by Hisanori Umehara and Kazuichi Okazaki agreed on IgG4-RD [10].

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The disease remains difficult to diagnose because of a lack of confidence on the part of clinicians, pathologists, and radiologists [2].

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criteria in order to identify articles not indexed in PubMed®. Based on the aim of the paper, the research particularly focused on diagnostic features and critical urologic sites affected by IgG4-RD.

An overview of the epidemiologic, clinical, and histopathologic features of IgG4‑RD

Results Epidemiologic data of IgG4-RD are sparse, with most large-scale studies reporting on autoimmune pancreatitis, which is more frequent in elderly men, with a male/female ratio of 5:1 [11]. In the case of head and neck involvement, the male/female ratio seems to be more balanced [9]. IgG4-RD usually presents subacutely, coming to attention because of organ swelling or damage or sometimes because of radiologic or pathologic findings [11]. More aggressive clinical symptoms can be seen, such as destructive bone lesions or tumors in the head and neck organs [9]. Serum IgG4 levels above 135 mg/dL [10] are important in the preliminary evaluation but do not constitute a necessary or sufficient condition for diagnosis [4]. Nevertheless, high IgG4 serum levels have been shown to be related to the number of organs involved or the disease extension [4]. Histopathologic features include a dense lymphoplasmacytic infiltrate rich in IgG4 plasma cells upon immunostaining [3], storiform-type fibrosis, and obliterative phlebitis [3, 5]. Other histopathologic features related to the disease are phlebitis without lumen obliteration or an increased amount of IgE [5]. For detailed information about cut-off values and further histopathologic aspects, including methods for semi-quantitative analysis of IgG4 immunostaining, see, for example, Deshpande et al. [5].

Aim The aim of the present study was to review urologic involvement in IgG4-RD with the purpose of providing urologists with the proper background necessary for a preliminary assessment of possible urologic localization of this recent clinical entity, which is often misdiagnosed. Indeed, patients are typically referred for immunologic management, often right after a differential diagnosis of urologic disease, to rule out malignancies.

Materials and methods A systematic search of PubMed® for both original and review articles published up until October 2015 was performed using keywords relating to IgG4 and to single specific urologic organs, structures, or anatomic sites. The search was then extended to Google® using the same search

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IgG4‑related kidney disease In 2004, the first cases of IgG4-related kidney disease (IgG4-RKD) were reported in Japan as an extra-pancreatic manifestation of this novel systemic entity, and renal dysfunction or proteinuria was recognized as the hallmark of renal involvement in patients with AIP [12, 13]. Upon examination of biopsy specimens, the condition was found to be similar to the more commonly occurring tubulointerstitial nephritis (TIN), from which IgG4-RKD must be differentiated. For a detailed analysis of the immunohistochemical characteristics of IgG4-related TIN, see, for example, Kawano et al. [14] and Raissian et al. [15]. IgG4-RKD is most common among the urologic manifestations of IgG4-RD and usually presents in the form of TIN [16–18], although some cases of membranous glomerulonephritis (MGN) have been described [15, 18, 19]. Patients with TIN have presented with mild proteinuria and microscopic hematuria, while those with MGN had heavy proteinuria or nephrotic syndrome [20]. For further details beyond the purpose of the present paper, see Cornell [20]. Later cases of IgG4-RKD have been incidentally detected by computed tomography (CT) in patients diagnosed with chronic sclerosing sialadenitis and dacryoadenitis, along with cases of isolated IgG4-RKD [17, 21]. Japanese and American researchers have provided different diagnostic algorithms. Kawano et al. [22] studied a series of 41 patients in Japanese hospitals between 2004 and 2011 who presented with histopathologic findings consistent with IgG4-RKD. The aim of that paper was to sort out a diagnostic algorithm and thus to devise diagnostic criteria for IgG4-RKD, which have since been accepted as the standard criteria of the Japanese Society of Nephrology [22]. The main laboratory features included urinalysis; checking serum total IgG, IgG4, and IgE levels; and testing for complementemia and creatininemia (see Table 1). IgG4 levels were elevated in all patients, and hypocomplementemia was found in about half. Imaging evaluation was performed using CT in 29 patients. The most common radiologic findings were multiple low-density lesions, with other less frequent signs being diffuse bilateral renal swelling and diffuse thickening of the renal pelvis. A solitary hypovascular parenchymal nodule was detected in only one patient in this study;

Int Urol Nephrol Table 1  Diagnostic criteria for IgG4-related kidney disease (IgG4RKD) proposed by Kawano et al. [22] 1. The presence of some kidney damage, as manifested by abnormal urinalysis or urine marker(s) or decreased kidney function with either elevated serum IgG level, hypocomplementemia, or elevated serum IgE level 2. Abnormal renal radiologic findings  (a) Multiple low-density lesions on enhanced computed tomography  (b) Diffuse kidney enlargement  (c) Hypovascular solitary mass in the kidney  (d) Hypertrophic lesion of renal pelvic wall without irregularity of the renal pelvic surface 3. Elevated serum IgG4 level (IgG4 ≥ 135 mg/dl) 4. Histologic findings in the kidney  (a) Dense lymphoplasmacytic infiltration with infiltrating IgG4positive plasma cells >10/HPF power field (HPF) and/or IgG4/ IgG-positive plasma cells >40 %  (b) Characteristics fibrosis surrounding nests of lymphocytes and/or plasma cells 5. Histologic findings in extra-renal organ(s) Dense lymphoplasmacytic infiltration with infiltrating IgG4-positive plasma cells >10/HPF and/or IgG4/IgG-positive plasma cells >40 % in extra-renal organ(s) Definite (1) + (3) + (4) a, b (2) + (3) + (4) a, b

Probable

Possible

(2) + (3) + (5) (1) + (3) + (4) a + (5) (1) + (4) a, b (2) + (4) a, b (2) + (5) (3) + (4) a, b (1) + (3) (2) + (3) (1) + (4) a (2) + (4) a

Appendix  Clinically and histologically, the following diseases should be excluded: Wegener’s granulomatosis, Churg–Strauss syndrome, extramedullary plasmacytoma  Radiologically, the following diseases should be excluded: malignant lymphoma, urinary tract carcinomas, renal infarction, and pyelonephritis (rarely, Wegener’s granulomatosis, sarcoidosis, and metastatic carcinoma)  Cases with suspected disease according to the diagnostic algorithm are classified into probable or possible IgG4-RKD according to these criteria

another patient probably had a unilateral renal mass causing renal swelling, but contrast-enhanced CT was not feasible because of decreased renal function. Twenty-eight patients underwent a renal biopsy, and upon histologic and immunostaining evaluation all showed marked IgG4-positive plasma cell infiltration. Thirty-eight

patients were prescribed corticosteroid therapy, 35 of which had a favorable response. The diagnostic algorithm proposed by the authors [22] was based on urinalysis, radiologic findings, function tests, serum IgG elevation, hypocomplementemia or serum IgE elevation, IgG4 levels, characteristic renal radiologic findings, and histopathologic examinations. All these things were investigated to determine a diagnosis of IgG4-RKD and to rule out lymphomas or other malignancies. Overall, a definite diagnosis of IgG4 was achieved for 39 of the 41 patients, while the two remaining patients were classified as probably and possibly having IgG4-RKD. It is worth noting that the authors discussed the levels of serum IgG4, which is an essential marker in their criteria, and that a previous case of IgG4-RKD with low serum IgG4 levels was reported in the literature [23]. For a review on IgG4-RKD, see Saeki and Kawano [24, 25]. The Northern American group of Raissian et al. [15] investigated 35 patients affected by IgG4-TIN and proposed a new set of diagnostic criteria. They consider IgG4 plasma cell-rich TIN upon histologic evaluation a mandatory criterion and consider renal imaging, serology, and involvement of other organs as other important criteria (see Table 2). The sensitivity and specificity achieved by immunohistochemical analysis were 100 and 92 %, respectively. The clinical management of IgG4-RD is usually referred to rheumatologists and is beyond the scope of this paper. For the clinical course of patients with IgG4-RKD, see, for example, Saeki et al. [26] or the recent prospective study by Nada et al. [27] that reports on 11 patients with IgG4-TIN who were followed for a minimum of 1 year or until endstage renal disease. A recent comprehensive review about IgG4-RKD, including the imaging spectrum and mimickers, has been published by Seo et al. [28]. IgG4‑related retroperitoneal fibrosis Although the true incidence of retroperitoneal fibrosis is unknown, estimates range from one case per 200,000 to 500,000 individuals per year. Idiopathic disease—accounting for over 70 % of cases—most commonly occurs in individuals 40–60 years of age [29]. In the literature, the history of idiopathic retroperitoneal fibrosis dates back to 1905, reported by Albarrán in French language [30], although this clinical entity took its name of Ormond disease from the first author describing it in English [31, 32]. Since then, Ormond disease has become synonymous with idiopathic retroperitoneal fibrosis, a condition affecting most frequently people above 50 years, 2–3 times more common in male than female [33].

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Table 2  Diagnostic criteria for IgG4-related tubulointerstitial nephritis (TIN) proposed by Raissian et al. [15] Histology

Plasma cell-rich tubulointerstitial nephritis with >10 IgG4 + plasma cells/hpf field in the most concentrated fielda Tubular basement membrane immune complex deposits by immunofluorescence, immunohistochemistry, and/or electron microscopyb

Imaging

Small peripheral low-attenuation cortical nodules, round or wedge-shaped lesions, or diffuse patchy involvement Diffuse marked enlargement of kidneys Elevated serum IgG4 or total IgG level

Serology

Other organ Includes autoimmune pancreatitis, sclerosing involvement cholangitis, inflammatory masses in any organ, sialadenitis, inflammatory aortic aneurysm, lung involvement, retroperitoneal fibrosis Diagnosis of IgG4-TIN requires the histologic feature of plasma cell-rich TIN with increased IgG4 + plasma cells and at least one other feature from the categories of “imaging,” “serology,” or “other organ involvement” a

  Mandatory criterion

b

  Supportive criterion, present in >80 % of cases

On the other hand, secondary retroperitoneal fibrosis can result from primary or metastatic neoplasms in the retroperitoneal space, infections (including tuberculosis, histoplasmosis, and actinomycosis), and drugs (including ergotamine, methysergide, methyldopa, pergolide, betablockers, hydralazine, phenacetin, and biological agents), although many aspects are still debated [34]. Retroperitoneal fibrosis secondary to malignancy is estimated to account for 8 % of cases and is of particular importance because of its poor prognosis [35]. Other potential causes of retroperitoneal fibrosis include major abdominal surgery, radiotherapy, trauma, or histiocytoses [34]. According to Zen et al. [32], IgG4-RD affecting the retroperitoneum and aorta can be classified as (1) retroperitoneal fibrosis; (2) inflammatory abdominal aortic aneurism; (3) a combination of retroperitoneal and aortic involvement; or (4) thoracic aortitis. The authors stated that clinical entities previously classified as idiopathic retroperitoneal fibrosis could be reassessed in terms of IgG4 infiltrate. Moreover, they noticed that retroperitoneal biopsies could be affected by spatial and temporal heterogeneity of the condition and thus have a high probability of sampling error, which can be emphasized by the presence of acellular, non-diagnostic fibrotic tissue after steroid therapy [32]. Nevertheless, steroid therapy can be effective in treating both IgG4-related and non-related disease, although it has not been validated yet [32]. What is also of concern is that a radiologic comparison between IgG4-related and non-related retroperitoneal fibrosis has not been performed, thus preventing radiologic features being used to facilitate the diagnosis [32]. In the same vein, Fujimori et al. [33] confirmed that the prevalence of retroperitoneal IgG4-RD is not clear and that there have likely been some misdiagnoses. Some reports on autoimmune pancreatitis have suggested that retroperitoneal fibrosis is detected in about 10 % of IgG4RD cases [33]. It is worth noting that most studies about

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retroperitoneal fibrosis have been conducted in patients with autoimmune pancreatitis, and in some cases it can be heterochronic to the onset of AIP [33]. No standardized diagnostic criteria for retroperitoneal IgG4-RD have been proposed. Therefore, Chiba et al. [36] studied 10 patients with retroperitoneal IgG4-RD and created special diagnostic criteria based on more general IgG4-RD ones. The mean age of the patients at diagnosis was 70.1, with a male/female ratio of 1:0.6 and with some cases of IgG4-related aortitis and periaortitis [36]. In a retrospective paper by Koo et al. [37], among 41 patients with retroperitoneal fibrosis, 19 underwent biopsy or surgery, and for nine of them, a pathologic review identified IgG4-RD features. The median ages were 59.4 ± 8.8 and 51.3 ± 10.5 years for patients with retroperitoneal IgG4-RD and idiopathic retroperitoneal fibrosis, respectively. The authors observed that retroperitoneal IgG4-RD may require a more aggressive maintenance immunosuppressive treatment over a longer period [37]. In the differential diagnosis, malignant lymphoma of the retroperitoneum should be taken into account [38]. Concerning therapy, although the efficacy of azathioprine and tamoxifen has been described in Europe and in the USA, a randomized controlled trial reported the significantly higher efficacy of steroids compared to tamoxifen in preventing retroperitoneal fibrosis recurrence [39]. Recent papers have reported the efficacy of rituximab, infliximab, and tocilizumab in patients resistant to conventional therapy [34]. Cases of acute kidney injury and severe bilateral hydronephrosis require a surgical approach, such as retrograde ureteral stenting, nephrostomy tube positioning, or surgical/laparoscopic ureterolysis [34]. Ureteral localization of IgG4‑related disease In 2013, Marando et al. [40] reported on two cases of IgG4RD with ureteral localization in an 82-year-old woman and

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in a 77-year-old man who underwent nephroureterectomy upon suspicion of malignancy. The authors performed a review of the literature, retrospectively identifying 18 pseudotumors of the ureter that appeared suggestive of ureteral localization of IgG4-RD, although IgG4 immunochemistry was available in only four cases [40]. The first case of ureteral IgG4-RD was reported in 2011 by Kim et al. [41]. Inflammatory pseudotumors of the ureter have not been classified uniformly. In addition to the typical classification into the three categories of myxoid/vascular pattern, compact spindle cell pattern, and fibromatosis-like pattern, some authors have proposed different subtypes, such as the cellular type, the plasma cell-rich type (lymphoplasmacytic type), and the fibrohistiocytic type [41]. Two further cases of IgG4-RD of the ureter have been subsequently published, one associated with kidney involvement [42] and the other with isolated ureteral involvement [43]. Thus, IgG4-RD of the ureter fits in the category of inflammatory pseudotumors, which actually raises the possibility that a significant number of cases of IgG4-RD of the ureter have been misdiagnosed as common pseudotumors [41]. Bladder localization of IgG4‑RD In 2013, Park et al. [44] reported the first case of an IgG4associated inflammatory pseudotumor of the urinary bladder in a 72-year-old woman who presented with gross painless hematuria, anemia, and elevated serum total IgG (the IgG4 subpopulation was not initially quantified). Urinalysis showed bacteriuria, hematuria, fecaluria, and proteinuria, and a contrast-enhanced CT revealed a mass arising from the left lateral bladder wall with adhesion to the sigmoid colon. Thus, the patient underwent a partial cystectomy with segmental resection of the adherent sigmoid colon. The histopathologic examination confirmed the diagnosis of IgG4 disease, with the average number of IgG4positive plasma cells per high power field equal to 57 and a IgG4/IgG ratio more than 40 %. The authors found more than 180 cases of inflammatory pseudotumors of the urinary bladder in the literature, but none were defined as IgG4-related. Therefore, they recommended IgG4 and IgG immunostaining in cases of elevated plasma cells in combination with inflammatory lesions in order to properly recognize potential IgG4-RD. Two further cases have recently been published [45, 46]. Urachal localization of IgG4‑RD In 2014, Dum et al. [47] published the first case of a urachal mass that proved to be a localization of IgG4RD upon histopathologic evaluation performed after a

partial cystectomy with umbilectomy. The 26-year-old male patient complained of recurrent urinary tract infections, and an abdominal ultrasound revealed a 6 cm mass at the bladder dome, consistent with a urachal tumor. Upon CT, a right lung lesion suspected of being metastatic was detected, and given the increased metabolic activity of both urachal and lung masses and two mediastinal lymph nodes, malignancy was suspected. A fine needle aspiration of the lung lesion and a transurethral resection of the urachal tumor revealed inflammation but no evidence of malignancy. Although the clinical features were consistent with urachal adenocarcinoma, histopathologic examination subsequent to the partial cystectomy with umbilectomy revealed a dense lymphoplasmacytic infiltration with IgG4-positive cells, storiform fibrosis, and obliterative phlebitis, which eventually led to the diagnosis of IgG4-RD. Serum IgG4 levels were 227 mg/dL. To our knowledge, this is a unique case of urachal localization of IgG4-RD in the literature. IgG4‑RD of the urethra In 2012, Choi et al. [48] reported the first case of IgG4RD of the urethra, which was revealed on a CT performed on a 72-year-old woman due to acute abdominal pain. An ultrasound-guided biopsy of the urethra ruled out malignancy and revealed a histologic picture compatible with IgG4-RD. The patient had been diagnosed with autoimmune pancreatitis 17 years before. Steroid-based therapy was prescribed, with symptoms improvement. Other researchers reported four cases of urethral caruncles with IgG4-RD features upon histopathologic examination, thus raising the possibility that some instances of urethral caruncles (11 % in their study) could be IgG4-related [49]. IgG4‑RD‑related epididymo‑orchitis The first case of IgG4-related epididymo-orchitis was reported in 2012 [50] in a 74-year-old man affected with bilateral swelling of the submandibular glands and a left paratesticular mass. The patient had a previous history of bladder cancer treated by transurethral resection and a subsequent cystectomy because of disease recurrence 2 years before the latest events. At the time of this new hospital admission, a left semicastration was performed, as mycobacterial infection was suspected. His serum IgG4 level was 505 mg/dL, and immunohistochemical analysis showed that the testis and epididymis were replaced by massive infiltration of plasma and lymphoid cells expressing IgG4. The IgG4/IgG ratio was greater than 85 %. A retrospective analysis [50] conducted on bladder and prostate specimens revealed features of IgG4-RD of

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the prostate with no bladder involvement. Moreover, the authors found that in addition to high serum IgG4 concentrations, B cell-activating factor family (BAFF) was elevated with an infiltration of BAFF receptor-expressing B cells and BAFF-expressing lymphoid cells. Therefore, the authors considered the possibility that BAFF/BAFF receptors could play a role in ectopic foci in IgG4-related disease with urogenital localization. This feature is consistent with other results for patients with AIP [51]. In 2013, de Buy Wenniger et al. [52] reported the case of a male patient who had undergone Whipple surgery at the age of 57 because of suspected pancreatic malignancy, which was not confirmed upon histologic assessment. Later, the patient was diagnosed with IgG4-related disease and required double-J catheter placement because IgG4-related fibrosis caused left kidney hydronephrosis. Seven years after pancreatic surgery, the man underwent left orchidectomy upon suspicion of malignancy, with no histologic confirmation. Six months later, because of right-sided orchitis complicated by abscess formation, the patient underwent right orchidectomy. A histologic evaluation showed an IgG4-related condition affecting both testicles. IgG4‑RD‑related paratesticular pseudotumors Approximately 200 cases of paratesticular fibrous pseudotumors (PFPs) have been described over the past decades, but an in-depth pathologic definition has not been achieved [53]. In 2010, Bösmüller et al. [54] reported three cases of paratesticular lesions in patients aged between 23 and 52 who were finally diagnosed with scrotal localization of IgG4 disease, given the plasma cell infiltration and an IgG4/IgG ratio of greater than 44 %. In two cases, there were multiple lesions arising from the tunica vaginalis. No serum IgG4 sampling was available. Dieckmann et al. [53] presented two cases of painless paratesticular masses in two young men aged 19 and 28. Both had storiform fibrotic tissue with tiny calcifications and lymphofollicular infiltrates upon histologic examination. Immunohistochemistry was performed only for the 19-year-old patient and revealed 10–15 positive cells on average per high power field, corresponding to approximately 40 % IgG-positive cells. Venulitis was found sporadically. The serum IgG4 level was not measured. In the discussion, the authors suggested that PFPs could be underreported and misrecognized due to their differential diagnoses with other benign scrotal conditions. Therefore, they hoped that targeted immunohistochemistry will be performed in future cases for a proper evaluation [53]. Karashima et al. [55] recently reported a case of IgG4RD of the paratestis in a 33-year-old man diagnosed with

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Wells syndrome—a rare dermatosis also known as eosinophilic cellulitis—5 years before. An ultrasound examination revealed a solid mass of the left epididymis, and the patient underwent radical left orchidectomy. A histopathologic evaluation revealed 50 % IgG4-positive cells and storiform fibrosis. An accumulation of 18F-fluorodeoxyglucose (18F-FDG) in the left lung was detected on a postoperative FDG-positron emission tomography/computed tomography (PET/CT), but it disappeared by the 24-month follow-up [55]. Preoperative serum IgG4 levels showed a value of 31.8 mg/dL, although the authors considered the possibility that prolonged corticosteroid therapy for the Wells syndrome could have decreased the value to within normal limits. As the authors themselves declared in the discussion [55], the case they reported should be considered “probable,” as the two diagnostic criteria of multiorgan involvement and histopathologic features described by Umehara et al. [3] were met. In 2012, Hart et al. [56] published the case of a 67-yearold man with a previous history of AIP and retroperitoneal fibrosis who underwent radical orchiectomy because of a scrotal mass suspected of being malignant. A histopathologic examination eventually showed scrotal localization of IgG4-RD. The serum IgG4 level was 391 mg/dL. The authors addressed the issue of a high index of suspicion for IgG4-RD in patients with a history of AIP presenting with any tumors. With particular regard to patients affected by IgG4-RD presenting with a scrotal mass, they proposed those patients should meet with a urologic surgeon to discuss conservative versus operative management. Nevertheless, the authors cited the risk of metastatic seeding in cases of trans-scrotal biopsies [56]. IgG4‑related prostatitis The first case of histologically confirmed IgG4-related prostatitis was described by Yoshimura et al. [57]. Later, Uehara et al. [58] analyzed a series of six patients with prostatitis associated with AIP and low urinary tract symptoms aged between 55 and 73. A control group of 10 patients was used. Upon histopathologic examination of prostate biopsies, the specimens of IgG4-RD patients showed significantly higher IgG4 plasma cells compared with those of control patients and had serum IgG4 levels ranging from 499 to 1550 mg/dL. Three patients with normal prostate-specific antigen (PSA) levels were prescribed corticosteroid therapy. Of these three patients with high PSA, two were found to have prostate cancer. The authors noted that all the examined patients had a previous history of AIP, and thus further studies were advocated to evaluate the presence of IgG4-related prostatitis in patients not affected with AIP.

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The largest case series of IgG4-related prostatitis was published in 2014 by Buijs et al. [59], with nine cases similar to the further ten cases reported in the literature [57, 58, 60, 61]. Only the patient reported by Bourlon et al. [62] had normal serum IgG4 levels, which the authors believed might fluctuate according to the state of disease activity. In addition, Bourlon et al. [62] observed that prostatic involvement in IgG4-RD should be considered in order to avoid unnecessary treatments, although some patients have undergone trans-urethral resection of the prostate with a favorable outcome. For an overview, see Bourlon et al. [62]. Cases of IgG4-related prostatitis have been reported

Table 3  Main findings concerning IgG4-related disease involving urologic sites

Kidney

Retroperitoneum

Ureter

Bladder

in patients affected with IgG4-related epididymo-orchitis [50] or with retroperitoneal fibrosis [63]. Penile involvement To date, penile involvement in IgG4-RD has not been confirmed [64]. Six cases of balanitis with increased IgG4 plasma cells have been reported in the literature, with an IgG4/IgG ratio of >40 %, at least focally, in two of these cases [64]. The main findings of our research are summarized in Table 3.

Takeda et al. [13] Uchiyama-Tanaka et al. [12] Kawano et al. [22] Raissian et al. [15] Zen et al. [32] Chiba et al. [36] Koo et al. [37] Kim et al. [41] Marando et al. [40]

Karashima et al. [55] Hart et al. [56] Yoshimura et al. [57] Uehara et al. [58] Buijs et al. [59] Hart et al. [60] Nishimori et al. [61] Bourlon et al. [62] Nakai et al. [63] Migita et al. [50]

First cases First cases 41 Cases 35 Cases Retrospective, difficult to estimate 10 Patients 9 Cases 3 Cases 2 Cases + retrospective review (18 cases suggestive for IgG4, with only 4 immunochemical analyses available) 1 Case 1 Case 1 Case + review (180 cases of inflammatory pseudotumor, with no immunochemical analysis available) 1 Case 1 Case 1 Case 1 Case 4 Cases (urethral caruncle) 1 Case 1 Case 3 Cases 1 Case + 1 Case suggestive for IgG4 (immunochemistry not available) 1 Case “probable” 1 Case 1 Case 6 Cases 9 Cases 1 Case 2 Cases 1 Case 1 Case 1 Case

Aggarwal et al. [64]

Not confirmed

Kim et al. [42] Moriarty et al. [43] Park et al. [44]

Montironi et al. [45] Dropkin et al. [46] Urachus Dum et al. [47] Urethra Choi [48] Williamson et al. [49] Epididymis-testis Migita et al. [50] de Buy Wenniger [52] Paratesticular region Bösmüller et al. [54] Dieckmann et al. [53]

Prostate

Penis

Note that kidney localization is quite common and thus difficult to estimate

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Discussion IgG4-RD is a recent clinical entity that remains difficult to diagnose because of a lack of confidence on the part of most clinicians, pathologists, and radiologists [2]. Accordingly, adequate knowledge of IgG4-RD even by non-rheumatologists is recommended, given the possible localization of IgG4 in any organ or at any anatomic site. At the present, diagnostic criteria have been formulated for IgG4-RD, and a consensus has been reached on two diagnostic criteria for IgG4-RD: serum IgG4 concentration >135 mg/dl and >40 % of IgG-positive plasma cells being IgG4-positive [3]. A potential role of proteinase-3 anti-neutrophil cytoplasmic antibody (PR3-ANCA) has been discussed [65]. Unfortunately, there are no specific urologic diagnostic criteria, except for IgG4-RKD [15, 22] and IgG4-related retroperitoneal fibrosis. This highlights the importance of both a prompt diagnosis and appropriate treatment in order to avoid unnecessary surgical procedures. Urologic surgical treatments Based on urologic articles, we found that differential diagnoses between IgG4-RD and malignancies are rarely formulated during preoperative evaluations but are more typically made after radical surgery. Of course, understanding of the disease is limited due to its rarity. It is difficult to judge whether the reported cases of orchidectomy could have been treated earlier on with drugs and whether the secondary effects could have been treated with prolonged high-dose steroids. In our opinion, such cases deserve to be discussed by a multidisciplinary team in order to achieve a whole patient evaluation, mainly because of the potential localization of the disease at multiple sites. Even when a surgical option is chosen, a proper diagnosis could be of help in surgical planning, including the possibility of avoiding surgery [53], and in terms of patient counseling. It is important to note that trans-scrotal biopsies are considered risky in terms of metastatic seeding [56]. Regarding PFPs, approximately 200 cases have been reported in the literature [53]; the median age in some case series is 42 [66], which is rather young. The two cases reported by Dieckmann et al. [53] were 19 and 28 years old. An observation about a possible concealed state of IgG4-RD has been formulated [67]. In our opinion, this theory should be investigated for a better etiologic assessment, as also reported by Dieckmann et al. [53]. In addition, the role of serum IgG4 levels should be better investigated, as Bourlon et al. [62] reported a case of IgG4-related

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Int Urol Nephrol

prostatitis with normal IgG4 serum levels. They state there could be a fluctuation in this parameter according to the disease activity state and thus consider the option of a systematic measurement instead of periodic measurements. On the other hand, serum IgG4 elevation is aspecific and can be observed in many other diseases [5]. An IgG4/IgG plasma cell ratio greater than 40 % has been proposed as a more accurate measure, specific to IgG4-RD, although it is not considered sufficient pathological evidence of disease [5]. Imaging There are no large-scale studies about the best imaging techniques for IgG4-RD, but it has been reported that conventional imaging, such as ultrasound, CT, and magnetic resonance imaging, has proven to be of limited aid in determining IgG4-RD [68]. On the other hand, 18F-FDG-PET/ CT can provide metabolic information about the whole body, thus allowing for a better comprehensive evaluation [69]. In 2014, Zhang et al. [69] presented a prospective study of 35 patients with IgG4-RD, mainly represented by Mikulicz’s disease, AIP, and retroperitoneal fibrosis. Upon an 18 F-FDG-PET evaluation, 34 patients had lesions in more than one organ and 24 had lesions in three or more organs. Of the 12 patients with retroperitoneal fibrosis, five had acute ureteral obstruction, which could be either complete and characterized by hydronephrosis and no radioactivity in the urine or partial [69]. The main limitation of the paper, as reported by the authors themselves, is that only previously diagnosed cases of IgG4-RD were included in the study. Therefore, further studies that include different patient characteristics are advocated [69]. Moreover, 18 F-FDG-PET could be an efficient tool in both guiding biopsies and evaluating the treatment response [69, 70]. 18 F-FDG-PET is a sensitive tool to evaluate the metabolic activity of retroperitoneal disease; however, it lacks specificity and does not allow the distinction between benign and malignant causes. Nevertheless, 18F-FDG-PET has been proposed to evaluate recurrent disease activity during follow-up, thus tailoring future conservative or surgical management [71]. The lack of imaging criteria in screening the disease is significant in routine clinical practice because they could be critical in facilitating differential diagnoses. A look at the medical therapy Over the last years, Japanese and American consensus statements have suggested steroids as the drugs of choice for first-line treatment [9]. Different treatment options have been proposed, with Japanese researchers suggesting

Int Urol Nephrol

prednisolone at a dose of 0.6 mg/Kg−1 of body weight per day for 2–4 weeks, tapering over a period of 3–6 months, and a maintenance dose of 2.5–5.0 mg/day for up to 3 years [4, 9]. The Mayo Clinic has suggested initial treatment with 40 mg/day of prednisone for 4 weeks, followed by tapering to 5 mg/week over 7 weeks [9]. According to this model, the patient should complete the treatment by the end of 11 weeks [9]. Second-line therapies for resistant or refractory cases have also been described, including azathioprine, mycophenolate mofetil, rituximab, and bortezomib [4, 9]. For a recent update on therapeutic options and clinical trials, see the latest International Consensus Guidance Statement on the Management and Treatment of IgG4-Related Disease [4]. Malignancies in IgG4‑RD There have been a few papers on the incidence and risk of malignancies in patients with IgG4-RD, and it is critical that clinicians be in close touch with patients with IgG4-RD. Hirano et al. [67] published a prospective study, reporting on a more than 6-month follow-up of 113 patients with IgG4-RD, most of whom had autoimmune pancreatitis. In their series, 15 malignancies were detected, represented by lung cancer (five patients), pancreatic cancer (two patients), gastric cancer (two patients), bile duct cancer, renal cancer, breast cancer, tongue cancer, melanoma, and acute myeloid leukemia (one patient each). Among the exclusion criteria, the authors accounted for malignancy diagnosed

IgG4-related disease: what urologists should know.

IgG4-related disease (IgG4-RD) is a recent nosological entity defined as a chronic immune-mediated fibro-inflammatory condition characterized by a ten...
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