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ORIGINAL ARTICLE
Year : 2021  |  Volume : 17  |  Issue : 3  |  Page : 625-629

The role of prostate-specific antigen and multiparametric magnetic resonance imaging in the diagnosis of granulomatous prostatitis induced by intravesical Bacillus Calmette–Guérin vaccine therapy in patients with nonmuscle invasive bladder cancer


1 Department of Urology, Cheeloo College of Medicine, Shandong Provincial Hospital, Shandong University, Jinan, Shandong, China
2 Department of Urology, Cheeloo College of Medicine, Shandong Provincial Hospital, Shandong University; Department of Urology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China

Date of Submission24-Nov-2020
Date of Decision10-Jan-2021
Date of Acceptance15-Feb-2021
Date of Web Publication9-Jul-2021

Correspondence Address:
Muwen Wang
Department of Urology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250 021, Shandong
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jcrt.JCRT_1684_20

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 > Abstract 


Aims: This study aimed to evaluate the role of serum prostate-specific antigen (PSA) levels and multiparametric magnetic resonance imaging (mpMRI) in the diagnosis of granulomatous prostatitis (GP) induced by intravesical Bacillus Calmette–Guérin vaccine (BCG) therapy in patients with nonmuscle invasive bladder cancer (NMIBC).
Subjects and Methods: We retrospectively analyzed eight patients with bladder cancer who underwent intravesical BCG therapy after transurethral resection of bladder tumor (TURBt) cancer. All these eight patients received 12-core transrectal ultrasound-guided prostate systemic biopsies. Clinical data on PSA with T1-weighted imaging (T1WI), T2WI, diffusion-weighted imaging (DWI), and apparent diffusion coefficient (ADC) on mpMRI were enrolled in the study. H and E and acid-fast staining was performed to pathologically prove GP.
Results: Four of all eight cases were above 4 ng/ml total PSA (tPSA) levels and four cases were within normal ranges, while free PSA/tPSA levels decreased to lower than 16% in all patients. Every patient had hard prostatic nodules through digital rectal examination (DRE). All characters of prostate mpMRI did not show signal intensity (SI) of prostate cancer before BCG therapy but showed abnormal signals after BCG therapy. All nodular lesions showed equal SI on T1WI, lower SI on T2WI, higher SI on DWI, and lower SI on ADC after BCG therapy. Pathologic results were GP and acid-fast staining outcomes were positive in all biopsies.
Conclusions: Perioperative serum PSA levels, prostate magnetic resonance imaging, and DRE may help in the diagnosis of GP induced by intravesical BCG therapy. In general, male patients with middle- and high-risk NMIBC are recommended to undertake DRE, PSA, and prostate mpMRI, if possible, before and after TURBt.

Keywords: Bacillus Calmette–Guérin vaccine, granulomatous prostatitis, magnetic resonance imaging, prostate cancer, prostate-specific antigen


How to cite this article:
Wang Z, Han C, Xu Y, Yu X, Kang W, Xiang Y, Yuan Y, Li L, Wang M. The role of prostate-specific antigen and multiparametric magnetic resonance imaging in the diagnosis of granulomatous prostatitis induced by intravesical Bacillus Calmette–Guérin vaccine therapy in patients with nonmuscle invasive bladder cancer. J Can Res Ther 2021;17:625-9

How to cite this URL:
Wang Z, Han C, Xu Y, Yu X, Kang W, Xiang Y, Yuan Y, Li L, Wang M. The role of prostate-specific antigen and multiparametric magnetic resonance imaging in the diagnosis of granulomatous prostatitis induced by intravesical Bacillus Calmette–Guérin vaccine therapy in patients with nonmuscle invasive bladder cancer. J Can Res Ther [serial online] 2021 [cited 2021 Aug 5];17:625-9. Available from: https://www.cancerjournal.net/text.asp?2021/17/3/625/321016




 > Introduction Top


Intravesical Bacillus Calmette-Guérin (BCG) therapy has been an important adjuvant therapy after transurethral resection transurethral resection of bladder tumor (TURBt) of middle- and high-risk nonmuscle invasive bladder cancer (NMIBC), which decreases tumor recurrence and reduces the risk of progression of bladder cancer.[1] However, several complications have been reported, such as fever, hematuria, epididymitis, granulomatous cystitis, and granulomatous prostatitis (GP).[2] Among these complications induced by intravesical BCG therapy, the incidence of GP is approximately 0.3%–40%.[3]

GP is taken little consideration during the follow-up period of patients with NMIBC treated with BCG. While showing similar findings as prostate cancer on multiparametric magnetic resonance imaging (mpMRI), GP is a benign, focal inflammatory disease.[4],[5] Moreover, GP is featured as elevated serum prostate-specific antigen (PSA) levels and abnormal signals on prostate magnetic resonance imaging (MRI), which should be distinguished from prostate cancer.[6] Patients of GP induced by intravesical BCG therapy have more intense feelings about the worry of prostate cancer. The objective of this retrospective study is to evaluate the diagnostic roles of digital rectal examination (DRE), serum PSA levels, and prostate mpMRI findings in NMIBC patients with GP induced by intravesical BCG therapy during the perioperative periods of TURBt.


 > Subjects and Methods Top


Patients

Eight patients with pathologically proven GP in prostatic biopsy were enrolled in this study between January 2015 and June 2020. All eight patients had a medical history of intravesical BCG therapy after TURBt for middle- and high-risk NMIBC. All of them have received DRE, serum PSA levels and prostate MRI during the perioperative periods of TURBt, and prostate biopsy for abnormal lesions on prostate mpMRI. Serum PSA levels and T1-weighted imaging (T1WI), T2WI, diffusion-weighted imaging (DWI), and apparent diffusion coefficient (ADC) on mpMRI have been analyzed in this study.

Magnetic resonance imaging protocol

MRI was undergone by 3.0T MRI machine (Siemens, Germany). The MRI assay included T1WI, T2WI, DWI, and ADC. The results of mpMRI were for the analyzation of two experienced radiologists.

Prostate biopsy

All patients received transrectal ultrasound-guided prostate biopsy, 12-core prostate systemic biopsies. Routine pathological H and E (HE) staining and tissue acid-fast staining were performed on each core. The results were analyzed by two experienced pathologists in this hospital.

H and E staining

HE staining was conventional staining with the kit (Wuhan Sevier Biotechnology Company). The staining was performed according to the instructions: conventional xylene dewaxing and ethanol hydration with different concentration gradients. The samples were redyed by hematoxylin for 1 min and anti-blue by tap water. Eosin dye was dyed for 5 min and then washed with distilled water. Finally, gradient alcohol was dehydrated and neutral gum sealed the samples.

Acid-fast staining

Acid-fast staining was Ziehl–Neelsen staining with the kit (Beijing Solarbio Technology Company). The staining was conducted according to the instructions: conventional xylene dewaxing and ethanol hydration with different concentration gradients. The samples were stained with acid-proof dye for 5min on alcohol lamp. Then, the samples were rinsed with running water. Hydrochloric acid alcohol was differentiated them for 30 s. Hematoxylin redyed for 1 min, tap water anti-blue. Finally, gradient alcohol was dehydrated and neutral gum sealed the samples.


 > Results Top


[Table 1] lists the general characteristics of these eight cases (mean age 63.63 ± 9.47, ranged age 47–76). Serum PSA levels of all eight patients (mean [5.67 ± 4.10] ng/mL) became more elevated after intravesical BCG therapy. Meanwhile, the free PSA (fPSA)/total PSA (tPSA) levels of all patients were 12.16% ± 2.82%. The results of DRE were that every patient had a hard prostatic nodule in the peripheral zone. On mpMRI, the prostate signal intensity (SI) was normal before BCG therapy [Figure 1]a and [Figure 1]b. After intravesical BCG therapy, all lesions of peripheral zone showed lower SI than normal tissues of prostate on T2WI [Figure 1]c, higher SI on DWI [Figure 1]d, and lower SI on ADC map [Figure 1]e. All of these eight patients were pathologically proven of GP induced by intravesical BCG therapy [Figure 1]f. Moreover, the results of acid-fast staining were positive [Figure 1]g.
Table 1: The clinical paramaters of eight cases with granulomatous prostatitis induced by Bacillus Calmette–Guérin therapy

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Figure 1: The magnetic resonance imaging, H and E staining and anti-acid staining pictures of the patient with granulomatous prostatitis induced by Bacillus Calmette–Guérin therapy (Case 1). (a and b) The normal prostate SI on T1-weighted imaging and T2WI before transurethral resection of bladder tumor. (c) The lower SI of prostate peripheral zone on T2WI. (d) The higher SI of prostate peripheral zone on diffusion-weighted imaging. (e) The lower SI of prostate peripheral zone on apparent diffusion coefficient map. (f) H and E staining of pathologically proven granulomatous prostatitis induced by Bacillus Calmette–Guérin therapy. (g) Anti-acid staining of granulomatous prostatitis samples

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 > Discussion Top


Intravesical BCG therapy has been demonstrated to prevent recurrence of bladder cancer during the perioperative periods of TURBt for middle- and high-risk NMIBC, which is more valid than other antineoplastics.[7] However, several complications induced by intravesical BCG therapy have been reported, including fever, papules, pneumonia, hepatitis, joint pain, hematuria, renal abscess, orchitis, epididymitis, granulomatous cystitis, and GP.[2] Particularly, disseminated tuberculosis induced by BCG therapy has been found in the bilateral lungs and adrenal, cervical, mediastinal, and paraaortic lymph nodes.[8] Among these complications, the incidence of GP is approximately 0.3%–40%.[3] The features of GP are similar to prostate cancer, with elevated serum PSA levels and abnormal signals on prostate MRI, thereby misdiagnosed as prostate cancer.

BCG was first discovered as attenuated live vaccines against Mycobacterium tuberculosis by Calmette and Guérin. On account of motivation of inflammatory response and release of cytokines to recruit inflammatory cells after intravesical therapy, BCG stimulates adaptive immune response to recognize and eliminate tumor cells, thus preventing cancer recurrence.[9] It is reported that abnormal prostate signals on MRI are related to immune response caused by urine refluxing to prostate tissue after intravesical BCG therapy.[10] In this study, the signal intensities of central and peripheral zone are normal before intravesical BCG therapy. On the contrast, the signal intensities are lower on T2WI, higher on DWI, and lower on ADC after intravesical BCG therapy. It is referred that these abnormal prostate signals on mpMRI are attributed to immune response for BCG in urine refluxing into prostate tissue rather than prostate cancer or prostatic invasion of bladder cancer combined with biopsy and acid-fast staining results.

PSA, a kind of serine protease like kallikrein, which produced by prostate ducts and glandular epithelial cells through androgen stimulation, could only be secreted into prostate acinus through prostate ducts for structure integrity and tissue barriers of glandular epithelial cells. PSA leaks into the blood through impaired barriers between glandular epithelial cells and circulation, resulting in elevated serum PSA levels in prostate diseases. Combined PSA (cPSA) and fPSA are two forms of PSA in circulation. Studies have shown that a large number of proteins expressed by antichymotrypsin (ACT) are combined with fPSA to form cPSA in prostate cancer cells, thereby the ratio of fPSA to tPSA (f/t) is lower than normal tissue in prostate cancer.[11]

GP induced by intravesical BCG therapy has been reported to occur in approximately 0.3%–40% patients, without any clinical symptoms and treatments in 95% of cases.[12] However occasionally, GP might be misdiagnosed as malignant tumors including prostate cancer and prostatic invasion of bladder cancer.[13] The serum PSA levels became elevated after intravesical BCG therapy, which increases the difficulty in differentiating GP from prostate cancer. Previous reports have demonstrated that serum PSA levels in patients with GP induced by BCG therapy were 0.9–9.7 ng/mL (mean: 4.2 ng/mL).[14] In the present study, there was no specific difference in serum tPSA and fPSA levels after intravesical BCG therapy, but f/t decreased to 8.72%–15.96% (mean [12.16 ± 2.82]%) in all patients. All patients underwent prostate biopsy for filling the indication of biopsy that f/t levels less than 16%. Serum tPSA levels became more elevated after intravesical BCG therapy, which is probably related to impaired prostate tissue for the immune reaction of urine reflux. Meanwhile, serum f/t levels decreased to lower than 16%, but there was no conclusion whether BCG would elevate the expression of ACT transcription proteins.

The features of MRI after intravesical BCG therapy were nonspecificity. The MRI of GP in peripheral zone was similar to prostate cancer, with low SI on T2WI.[7] In the present study, the features of MRI were low SI on T2WI, in accordance with those of prostate cancer, which confirmed the report of Bour et al. [7] Therefore, mpMRI should be undergone to differentiate from prostate cancer combined with BCG therapy history. It is recommended that patients with middle- and high-risk NMIBC should undergo MRI to exclude prostate cancer during the perioperative period of TURBt.

Several studies have shown that the SIs of lesions were equal or even higher than those of the normal peripheral zone on DWI, which was related to the density of lymphocytes associated with caseous necrosis and acute inflammation because DWI reflected cell density of these lesions.[15] Due to signals intensity on T1WI in benign prostatic hyperplasia and prostate cancer were usually similar to those in muscle tissue, the results of T1WI on MRI, whose SI of lesions was equal, showed nonspecificity. The SI of GP with cystic lesions was lower on T2WI, thereby speculating that the contents of cystic lesions might be abscesses or protein fluid of inflammation. Although the etiology remains unclear, fibrosis, caseous necrosis, clot, or calcification might occur in those lesions judging from the lower SI on T2WI.[16]

Higher cellular density occurred in prostate cells after intravesical BCG therapy,[17] leading to restriction of diffusion.[18] Hence, the mean ADC maP value of GP might be lower than that reported in prostate cancer on mpMRI.[19] In this study, the mean ADC maP value appeared to be lower. In some specific clinical cases including patients with middle- and high-risk nonmuscle invasive bladder tumor after intravesical BCG therapy, lower ADC maP value on mpMRI might indicate GP instead of cancer. These results might recommend to dispute prostate biopsy because elevated serum PSA levels returned to baseline in 3–12 months in approximately 40% of patients.[20] Patients with elevated serum PSA levels and abnormal signals of peripheral zones on mpMRI after intravesical BCG therapy should be checked with their preoperative PSA and prostate MRI. If there are no abnormal results of preoperative PSA and prostate MRI, patients with elevated PSA and abnormal signals on prostate mpMRI may suffer from GP induced by intravesical BCG therapy.

This retrospective study had several limitations. First of all, the number of patients in this study was small, with only eight patients enrolled in this retrospective study. GP is an asymptomatic, benign, and focal inflammatory disease with similar findings as prostate cancer on mpMRI.[4],[5] As a result of this cause, GP is often ignored during the follow-up period of patients with NMIBC treated with BCG, so further studies are needed to confirm this conclusion of this retrospective study. Next, there were no accurate ADC maP values in these eight patients, which were beneficial to distinguish GP from prostate cancer, thereby further clinical and imaging studies are needed to verify the conclusion in this study. Ultimately, none of these eight patients underwent dynamic contrast-enhanced (DCE)-MRI examinations. In the present study, DCE persistent time of prostate lesions was longer than that of prostate cancer after intravesical BCG therapy due to increased blood supply for angiogenesis and fibrous tissue. Therefore, DCE is important to distinguish GP from prostate cancer.[21]


 > Conclusions Top


Perioperative DRE, serum PSA levels, and prostate mpMRI may help diagnosis of GP induced by intravesical BCG therapy. Patients with middle- and high-risk NMIBC are recommended to undergo DRE, serum PSA levels, and prostate MRI, if possible, before and after TURBt.

Financial support and sponsorship

This work was funded by a grant from Shandong Provincial Natural Science Foundation, China, (ZR2016HM32), Shandong Medical and Health Science and Technology Development Project (2016WS0444, 2019WS464), Shandong Key Research and Development Grogram (2018GSF118189, 2017GSF218078), and Traditional Chinese Medicine Science Foundation of Shandong Province (2019-0300).

Conflicts of interest

There are no conflicts of interest.



 
 > References Top

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Oppenheimer JR, Kahane H, Epstein JI. Granulomatous prostatitis on needle biopsy. Arch Pathol Lab Med 1997;121:724-9.  Back to cited text no. 13
    
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Suzuki T, Takeuchi M, Naiki T, Kawai N, Kohri K, Hara M, et al. MRI findings of granulomatous prostatitis developing after intravesical Bacillus Calmette-Guérin therapy. Clin Radiol 2013;68:595-9.  Back to cited text no. 14
    
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Qayyum A. Diffusion-weighted imaging in the abdomen and pelvis: Concepts and applications. Radiographics 2009;29:1797-810.  Back to cited text no. 15
    
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Lim J, Yu JS, Hong SW, Chung JJ, Kim JH, Kim KW. A case of mass-forming splenic tuberculosis: MRI findings with emphasis of diffusion-weighted imaging characteristics. J Korean Med Sci 2011;26:457-60.  Back to cited text no. 16
    
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