IgG4-Related prostatitis, a difficult diagnosis in a tricky case

Immunoglobulin G4-related disease (IgG4-RD) is a recently described systemic disease that is characterized by multiorgan, inflammatory, mass-forming lesions with an increased number of IgG4-positive plasma cells.  Prostate involvement by the disease is very rare and diagnosis remains difficult. We herein report a case of a 64-year-old man who underwent a cephalic duodenopancreatectomy on a presumed diagnosis of cephalic pancreatic mass suggesting a cholagiocarcinoma. Pathological analysis showed an IgG4 postive lymphoplasmatic infiltration with diffuse fibrosis. Serum IgG4 level was significantly increased.

8 years later, he presented obstructive lower urinary tract symptoms resistant to α-blocker treatment. A transurethral resection of the prostate was performed, and the patient’s urinary function dramatically improved. Prostate samples showed again IgG4 postive lymphoplasmatic infiltration with diffuse fibrosis and the post operative diagnosis of IgG4-related prostatitis (IgG4-RP) was made. This case points out a potential diagnostic pitfall for physician as steroid therapy is effective in IgG4-RP. Thus accurate diagnosis is mandatory to avoid unnecessary surgeries.


IgG4-RD is an increasingly recognized condition in adults affecting a wide range of organ systems. Major clinical manifestations are heterogeneous and usually apparent in the organs. Pathologically, it induces a tissue fibrosis with lymphopasmatic infiltration and obliterative phlebitis.1 IgG4-related prostatitis is the prostatic manifestation of IgG4-RD. Obstructive urinary symptoms are very frequent, and leads often to surgery.  We describe here a case of a 72-year-old man who was operated twice in 8 years for misdiagnosis of IgG4-RD. Histopathological analysis revealed and confirmed afterwards the diagnosis of both IgG4-Related pancreatitis and IgG4 related prostatitis. This case highlights the need to have a precise diagnosis to avoid needless therapeutic consequences. Despite the age and the prostate enlargement, physicians should consider the diagnosis of IgG4-Related prostatitis in patients with auto immune pancreatitis history and should perform a prostate biopsy. The principal bases of treatment remain steroid therapy and a long term follow-up.

Case presentation:

A 72-year-old man presented to our office for a urological examination with the complaints of recent lower urinary tract symptoms. The patient has a long history of insulin-dependent diabetes mellitus. At the age of 64 years, he presented to gastroenterology department with a rapid-onset jaundice, weight loss without pain. Abdominal MRI and endoscopic retrograde cholangiopancreatography showed a hilar bile-duct stricture with wall thickening. Hilar cholangiocarcinoma was strongly suspected, and the patient underwent hilar resection with excision of caudate lobe. During surgery, the pancreatic segment of bile duct was seen to be sheathed in a pancreatic heterogeneous mass, and a cephalic duodenopancreatectomy was performed. Pathological analysis of the pancreatic and bile ducts did not show any neoplasic lesions but did reveal periductal lymphoplasmacytic infiltration, with diffuse fibrosis suggestive of auto immune pancreatitis (AIP). Numerous IgG4-positive plasma cells were identified on immunostaining. At that time, serum IgG4 level was greatly elevated (951mg/dl).  

Upon actual episode, the patient was complaining of dysuria, nocturia and urinary frequency for about two months. Physical examination was normal. Digital rectal examination demonstrated a smooth prostate gland of a low volume. Uroflowmetry revealed a fallen peak flow of 4 milliliters per second. Ultrasonography showed a homogenous prostate of 30 ml with no dilation of the upper urinary tract. Post void residual was around 200 ml. The patient was suspected of having benign prostatic hyperplasia (BPH), since then he had been under α-blocker treatment with no improvement of his voiding symptoms. Post void residual remained high. An ascending urethrogram and a voiding cystogram were performed, which demonstrated an isolated narrowing of the prostatic urethra despite the α-blocker treatment (Figure1). This supported the diagnosis of BPH. Laboratory examinations showed a PSA level of 0,12 ng/ml. Microbiological analysis of a mid-stream urine specimen was normal. 

Figure 1: Retrograde urethrocystogram showing an isolated narrowing of the prostatic urethra. 

The patient underwent a trans-urethral resection of the prostate. Postoperative follow-up was uneventful. The patient was discharged from the hospital after 48 hours. He was seen 6 weeks later, he presented a lasting frequency for several days then his symptoms completely resolved. Pathological analysis of the resected prostate samples showed a serious and disseminated inflammation, involving essentially the stroma but not the glands with many plasmacytes and lymphocytes. Also, a storiform fibrosis was seen without an obliterative phlebitis associated. An increased amount of eosinophils with some neutrophils was found without any sign of necrosis or granuloma. Immunostaining revealed a high account of CD138-positive plasmacytes. Glands were negative for the AMACR test excluding a neoplasic involvement. Additional immunostaining showed dense infiltration of IgG and IgG4-positive plasmacytes. IgG4/IgG ratio was 75% (Figure2). Diagnosis of IgG4 related prostatitis was retained and additional biological investigation was performed. Serum levels of IgG 4 were extremely high as it reached 1380 mg/dl, percentage of serum eosinophils was normal and test for autoantibodies Anti-LKM was negative. Serum IgA, IgM and IgE levels were all within the normal range.  Tests for anti-DNA antibodies, rheumatoid factor and antinuclear antibodies were negatives.

Figure 2: Tissue samples of prostate after transurethral resection showing the IgG4-related prostatitis. (a) Low-power view showing patchy lymphoplasmacytic inflammation. (b) Higher power view showing lymphoplasmacytic inflammation and plasma cells with increased eosinophils  (c,d) Numerous IgG4-positive plasma cells are identified on immunostaining.

A repeat uroflowmetry 3 months after surgery showed a big change in peak flow ( 20 ml/s) without any post void residual . To date, without steroid therapy, there hasn’t been any recurrence of voiding symptoms or appearance of lymphadenopathy.


For some years now has emerged this new clinicopathological entity named IgG4-related disease. Originally described as pancreatic then biliary tract disease, further investigations showed a wider involvement to several other organs.  It is characterized by a tendency to form tumefactive lesions at multiple sites; a dense lymphoplasmacytic infiltrate rich in IgG4+ plasma cells; storiform fibrosis; and often but not always—elevated serum IgG4 concentrations.1 This is a rare disease. It’s probably of an underestimated incidence due to the difficult diagnosis and the lack of knowledge of physicians about this entity.

The list of the affected organs by IgG4-RD is increasing day after day. This condition has now been described in virtually every organ system: the biliary tree, salivary glands, periorbital tissues, kidneys, lungs, lymph nodes, meninges, hypophisis, aorta, breast, prostate, thyroid, pericardium, and skin.1 The presentation is often systemic and do not necessary include the pancreas. The clinical aspects vary according to the affected organs.

The pathophysiological mechanisms involved in the onset of IgG4-RD are still largely misunderstood. Several hypotheses have been proposed to elucidate this riddle including: genetic susceptibility,2 allergy due to  hyper-IgE, and peripheral eosinophilia,3 autoimmunity with incrimination of several autoantibodies such as anti CA II4 and  PSTI,5 other studies have observed a resemblance between Helicobacter Pylori and constituents of epithelial pancreatic cells.6 More recently, the Th2 reaction has been suggested as predominant in IgG4 disease7 but none of these hypotheses was confirmed.

The diagnosis of IgG4-related disease requires both an appropriate histological findings and increased numbers of IgG4+ plasma cells (or an elevated IgG4:IgG ratio) in tissue.8 Other criteria were considered: high serum IgG4 concentration, favorable response to glucocorticoid therapy and a multiple organs involvement. The three major histopathological features are: dense lymphoplasmacytic infiltrate, fibrosis arranged at least focally in a storiform pattern and an obliterative phlebitis. An increased number of eosinophils can also be noticed.8

Genitourinary system involvement is infrequent. Paratesticular9 and uretereal pseudotumors10 have been reported to be IgG4 related but Kidney affection was the best described. It includes tubulointerstitial nephritis, low-density cortical lesions and hypovascular renal masses.11 Prostate involvement is newly described manifestation of IgG4 RD. Since the first confirmed case published by Yoshimura et al in 2006,12 around twenty cases of prostate affection have been reported. Most of them were associated to synchronic / methachronic autoimmune pancreatitis or IgG4-associated cholangitis.13-14 In one case, IgG4-related prostatitis progressed from localized IgG4-related lymphadenopathy.15 

Prostate involvement by IgG4 related disease may be mimicking a prostate cancer. Indeed, digital examination of the gland can be abnormal, finding a diffusely asymmetric prostate or even a unilateral, irregular nodule (16). PSA levels can also be increased in patients presenting an IgG4-related prostatitis without histological evidence of prostate cancer.13 However, both diseases may coexist at the same time. Uehara et al. series reported 2 observations of patients with elevated PSA levels and who had both IgG4-related prostatitis and prostate cancer.13  In the same series, the common finding between all the 6 cases, serum IgG4 levels was significantly elevated (almost all were over 1000 mg/dL) like in our case. This might be a feature of the prostatic involvement by the IgG4 disease. Nevertheless, serum IgG4 concentrations of this immunoglobulin are normal in up to 40% of patients with biopsy-proven IgG4-related disease with AIP.17

IgG4 related prostatitis remains a difficult diagnosis. Clinically, urinary symptoms are of rapid evolution. Buijs et al. gathered 9 of IgG4-related prostatitis among 117 men in the autoimmune pancreatitis and IgG4-associated cholangitis patient databases in 2 tertiary hospitals. All these patients presented with the aspecific sign of urinary retention.14 Histological findings were interesting in this biggest series, showing that fibrosis in at least a focally storiform pattern was rarely seen, and (obliterative) phlebitis was absent in all patients. Furthermore, eosinophil numbers were more often elevated in patients with IgG4-RD compared with controls.14 This suggests that prostatic histopathological findings are unconventional in comparison to what we encountered in the IgG4-RD consensus.8

The recurrent nature of IgG4-related disease, combined with the diversity of possible sites of involvement may mean multiple resections and potential loss of exocrine gland function.15 Treatment of this disease is generally successful with steroids and urinary symptoms may completely resolve.16 Transurethral resection of the prostate was widely considered as an unnecessary surgery but in one case report, patient’s urinary function dramatically improved after the operation and good functional results has been maintained for 3 years without additional treatment.18 A recent guideline recommends glucocorticoids as the first-line therapeutic agent, with 94% of interexpert agreement, with the use of prednisolone (0.6 mg/kg/d) for 4 weeks as induction therapy, then the glucocorticoid dose can be tapered gradually.19 In a wide review of the literature (62 studies that included a total of 3034 patients) focusing on the therapeutic approach of IgG4-RD, Brito-Zéron et al.20 showed that nearly 70% of reported IgG4-RD patients were treated with oral glucocorticoids in monotherapy. The efficacy of monotherapy with glucocorticoids was specified in 1220 patients, of whom 97% had a therapeutic response. Relapses, however, were reported in 464/1395 (33%) patients despite typically short follow-up periods. Therapeutic efficacy was reported in 219/231 (95%) of relapses when glucocorticoids were resumed, 56/69 (81%) of those treated with azathioprine, 16/22 (72%) of those treated with other immunosuppressive agents, and in the 9 cases treated with rituximab (100%). In 14 studies, the authors detailed the outcome of 159/246 patients with wait-and-see management; spontaneous improvement or resolution was reported in 68 (43%) cases.20 As the urinary symptoms often improve or resolve with steroid therapy, prostate biopsy is necessary to rule out synchronous malignancy in patients with suspected prostate cancer based on abnormal rectal examination or elevated PSA level.16

Written By: Ben Chehida Mohamed Ali, MD, Department of Urology, CHU Sart Tilman, Liège, Belgium; Mathantu Balombi, Department of Urology, CHR Huy, Belgium; Leclercq Philippe, MD, Gastroenterology Department, CHU Sart Tilman, Liège, Belgium; Thomas Alexandre, MD, Department of Urology, CHU Sart Tilman, Liège, Belgium

We have no specific financial interest to declare and no specific affiliation relevant to the subject matter or materials discussed in this manuscript.

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