Granulomatous prostatitis following Bacillus Calmette–Guérin therapy

Clinical presentation

The patient is a 70-year-old male with medical history of low-grade bladder cancer (non-invasive low-grade papillary urothelial carcinoma) treated with intravesical BCG therapy (#12 cycles), last cycle administered 12 years before current presentation. On a regular follow-up visit, his prostate-specific agent (PSA) was elevated to 6.4 ng/mL. The patient denies a family history of prostate or urothelial cancer. The patient is a former smoker with eight pack years with smoking cessation following the diagnosis of bladder cancer.

Imaging

Multiparametric prostate MRI (mpMRI) with and without contrast was performed, which showed multifocal lesions in the peripheral zone, the largest lesion in right base measured 14 mm in largest dimension, and most compatible with prostate imaging–reporting and data system (PI-RADS) 4 (High-clinically significant prostate cancer is likely to be present).^[17-20] The smaller bilateral lesions (≤5 mm) demonstrate imaging features most compatible with a PIRADS 3 (Intermediate – the presence of clinically significant prostate cancer is equivocal) [Figures 1-3]. The lesions were assigned PI-RADS scores; however, GP was offered as an alternative diagnosis given the prior history of BCG therapy and multifocal, nodular distribution. Targeted tissue sampling was recommended.

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Figure 1:

A 70-year-old male with bacillus Calmette–Guérin granulomatous prostatitis who presented with elevated prostate-specific agent. (a) Magnetic resonance imaging of the prostate with and without contrast, coronal T2-weighted image shows right prostate base 14 mm lesion (yellow arrow). (b) Axial T2-weighted image shows the lesion (yellow arrow) with low-signal intensity.

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Figure 2:

A 70-year-old male with bacillus Calmette–Guérin granulomatous prostatitis who presented with elevated prostate-specific agent. (a) Magnetic resonance imaging (MRI) of the prostate, axial T2-weighted imaging: By prostate imaging–reporting and data system (PI-RADS) criteria, the lesion’s (yellow arrow) imaging features are most compatible with PI-RADS 4 (High-clinically significant prostate cancer is likely to be present). (b) MRI of the prostate, axial apparent diffusion coefficient: The right prostate base lesion (yellow arrow) restricts diffusion and demonstrates non-enhancing core. (c) MRI of the prostate, post contrast T1: By PI-RADS criteria, the lesion’s (yellow arrow) imaging features are most compatible with PI-RADS 4 (High-clinically significant prostate cancer is likely to be present).

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Figure 3:

A 70-year-old male with bacillus Calmette–Guérin granulomatous prostatitis who presented with elevated prostate-specific agent. (a) Magnetic resonance imaging of the prostate with and without contrast, axial T2-weighted image shows additional multifocal lesions (yellow arrows) in the peripheral zone, measuring 5 mm or less. No abnormal enhancement. (b) Apparent diffusion coefficient image shows imaging features most compatible with a Prostate Imaging-Reporting and Data System 3 (intermediate - the presence of clinically significant prostate cancer is equivocal) and the peripheral zone multifocal lesions (yellow arrows) seen in (a).

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On transrectal ultrasound, the prostate measured 41.7 mm × 48.9 mm × 27.7 mm (length, width, and height) with a calculated volume of 29.5 cubic cm. No hyperechoic or hypoechoic areas were visualized within.

Biopsy

Six random biopsies were obtained from the right and left portions of anteromedial, anterolateral, posteromedial, posterolateral, medial base, and lateral base of the prostate gland. Three additional biopsies were taken from the MRI-targeted lesions in the right base, left mid, and right anterior lobe. PSA density was 0.22. Patient tolerated the procedure without any complications. Targeted biopsy of the MRI lesion from right base, left mid, and right anterior lobe was reported as chronic prostatitis with granulomas, with atrophy and fibrosis, compatible with GP [Figure 4]. All submitted biopsy samples were negative for prostatic adenocarcinoma. In addition, random biopsies from different areas also revealed evidence of chronic prostatitis with granulomas and atrophy.

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Figure 4:

A 70-year-old male with bacillus Calmette–Guérin granulomatous prostatitis who presented with elevated prostate-specific agent. (a) Hematoxylin and eosin (H&E) image at ×200 magnification shows well-formed epithelioid granulomas (red arrows) with a background of chronic inflammation. (b) H&E image at ×400 magnification shows epithelioid granuloma (red arrow) with multinucleated giant cells in a background of chronic inflammation.

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Pathologic features

The pathogenic mechanisms of GP are thought to be either direct infection or inflammation.^[26] Intraprostatic reflux of BCG-contaminated urine from the bladder establishes the prostatic nidus and initiates the chronic inflammatory response, resulting in the formation of non-caseating or caseating granulomas within the prostate or periprostatic tissue, including the prostatic urethra.^[27] Several micro-organisms including tuberculosis, syphilis, brucellosis, viral, and fungal entities can cause GP. However, the infectious cause of BCG-induced GP is Mycobacterium tuberculosis.

Prostatic adenocarcinoma, non-specific GP, post-biopsy hemorrhage, benign prostatic hyperplasia nodules, and acute and chronic prostatitis can all mimic BCG-related GP.^[24] Rarely, adenocarcinoma may coexist with GP.^[26] Asymptomatic individuals do not require any specific treatment as GP is self-limited but tuberculostatic drugs may be initiated and systemic disease warrants the addition of anti-inflammatory drugs like prednisone.^[26]

Histologically, epithelioid cell granulomas with Langhans giant cells may be seen. A prominence of epithelioid histiocytes or the appearance of a xanthogranulomatous pattern may require a follow-up immunohistochemical examination since this mimics adenocarcinoma. In cases of GP, immunohistochemistry reveals antibodies to CD68 (histiocyte marker) and in prostatic cancer, antibodies to cytokeratin 5/6 (basal cells) or cytokeratin AE1/AE3 (epithelial cells).^[9] Acid-fast bacteria (AFB) staining may reveal M. tuberculosis or may be negative. Other special stains commonly do not detect any microorganisms.

Radiologic features

Multiparametric MRI has become a commonly utilized imaging tool to assess the presence of clinically significant prostate cancer (Gleason 7 or greater). The typical mpMRI findings of GP are: (i) low-intensity signal on T2-weighted images, (ii) hyperintense signal on DWI, (iii) low-signal/values on ADC maps, and (iv) peripheral rim enhancement on contrast.^[22,28,29]

A way to discern the diagnoses was proposed by Lee et al. by describing three different mpMRI patterns: A, B, or C.^[13] Peripheral zone lesions with diffusion restriction and moderate to marked homogeneous enhancement on dynamic contrast-enhanced images were classified as type A. This pattern is indicative of highly cellular non-necrotic granulomas. The lesions with diffusion restriction and a poorly enhancing component were classified as type B. These are seen in necrotic GP with the central necrosis having a high-signal density on T2-weighted images and focal hyperintensity on high b-value images. A low-signal intensity on high b-value DWI (b = 1000 s/mm²) is considered characteristic of type C. The suggested protocol is to use these findings alongside other diagnostic modalities and sequential monitoring on follow-up.^[27,30]

Another study identified three main patterns on MRI-diffuse, nodular, and cystic with mural nodule.^[31] A notched polygonal prostatic nodule is a diagnostic feature of GP. Sarkis et al. established the set of the prostatic imaging changes seen before and after BCG administration.^[32] A comparative study with pre-operative PSA and prostate MRI can help rule out prostate carcinoma.^[33] Gottlieb et al. recognized two-phased patterns of GP, acute and chronic, based on the temporal distribution of prostatic changes on mpMRI using the high-b-value sequence.^[29]

Transrectal prostatic sonography may demonstrate nodular/diffuse hypoechoic areas in the prostrate, which is a non-specific finding. Ultrasound examination only serves to complement the digital rectal examination and suspicious findings in the peripheral zone of the prostate must be followed by histological examination on biopsy.^[21,23,34] Increased focal prostatic uptake on 2-deoxy-2-(fluoro-¹⁸F)-D-glucose positron-emission tomography–computed tomography (PET-CT) can be indicative of malignancy but in patients with a high degree of suspicion for GP, it is considered a benign finding.^[35,36] PET-CT merely indicates hypermetabolic state of the tissue in GP.^[37]

Based on MRI alone, GP and prostate cancer cannot be definitively distinguished since they share common imaging features. Due to their overlapping features, biopsy is necessary for histologic confirmation, although the MRI findings can be suggestive in the setting of prior BCG administration. Therefore, if the biopsy and MRI findings are concordant, the information is critically useful in the event of future MRI examinations to avoid unnecessary re-targeting and re-biopsy of known foci of GP.