Post-treated prostate cancer: normal findings and signs of local relapse on multiparametric magnetic resonance imaging
The use of multiparametric magnetic resonance imaging (mp-MRI) for prostate cancer has increased over recent years, mainly for detection, staging, and active surveillance. However, suspicion of recurrence in the set of biochemical failure is becoming a significant reason for clinicians to request mp-MRI. Radiologists should be able to recognize the normal post-treatment MRI findings. Fibrosis and atrophic remnant seminal vesicles after prostatectomy are often found and must be differentiated from local relapse. Moreover, brachytherapy, external beam radiotherapy, cryosurgery, and hormonal therapy tend to diffusely decrease the signal intensity of the peripheral zone on T2-weighted images (T2WI) due to the loss of water content, consequently mimicking tumor and hemorrhage. The combination of T2WI and functional studies like diffusion-weighted imaging and dynamic contrast-enhanced improves the identification of local relapse. Tumor recurrence tends to restrict on diffusion images and avidly enhances after contrast administration either within or outside the gland. The authors provide a pictorial review of the normal findings and the signs of local tumor relapse after radical prostatectomy, external beam radiotherapy, brachytherapy, cryosurgery, and hormonal therapy.
KeywordsProstate cancer Multiparametric resonance imaging Recurrence
Multiparametric magnetic resonance imaging (mp-MRI) has been used for detection, localization, and staging of prostate cancer (PCa) over the last few years. It combines T1 and T2-weighted images (WI) with at least two functional techniques such as dynamic contrast-enhanced MR imaging (DCE-MRI), diffusion-weighted imaging (DWI), and MR spectroscopy (MRS) . The role of mp-MRI on PCa has, however, been extended to cases of active surveillance, patients who refused biopsy, MRI-guided or MRI-Ultrasound fusion biopsy, post-treatment surveillance, and diagnosis of recurrence [1, 2, 3, 4].
Radical prostatectomy (RP) and radiotherapy (RT), either by external beam radiotherapy (EBRT) or brachytherapy (BT), have curative intent in patients with localized PCa. Other alternative treatment options like cryosurgery and high-intensity focused ultrasound (HIFU) are minimally invasive procedures with reduced toxicity. However, they are not completely established yet .
This manuscript provides a pictorial review of the normal findings and signs of local tumor relapse after RP, EBRT, BT, cryosurgery, and hormonal therapy (HT).
Imaging approach to biochemical failure
Recurrence after curative intent treatment is not uncommon. Among patients undergoing RP or RT, 27% to 53% develop biochemical failure (BF), which is defined as a rise in prostate-specific antigen (PSA) level, and 16% to 35% need second-line treatment. PSA level remains the basis of follow-up after curative treatment, but the definition of BF differs between RP and RT. After RP, it is defined by two consecutive PSA values of >0.2 ng/mL. After RT, with or without short-term hormonal manipulation, it is defined by a PSA increase >2 ng/mL higher than the initial PSA nadir value. We should emphasize that PSA recurrence tends to precede clinical recurrence after RP or RT, in some cases by several years [5, 6, 7, 8, 9, 10].
PSA is also a good marker for following the course of metastatic PCa, usually treated with HT. However, it must be stressed that some poorly differentiated tumors do not secrete PSA and laboratorial follow-up should not constitute an isolated parameter in these patients. Clinical progression, commonly with bone pain, should also be considered .
After identifying a BF, it should be defined whether the recurrence has developed at local or distant sites. Patients with local-only disease should be distinguished and guided toward salvage local treatments. These treatments are associated with considerable morbidity and should be avoided in patients with distant metastases, who have a lower chance of benefiting from them and should undergo systemic therapies .
In the assessment of distant metastases, bone scans for bone metastases and abdominopelvic computed tomography (CT) for lymph node disease are usually requested. Positron emission tomography with CT (PET/CT) and diffusion-weighted whole-body MRI, both more sensitive than bone scan and targeted radiographs in the detection of bone metastases in patients with high-risk PCa, may also be used [11, 12, 13, 14, 15, 16, 17, 18]. According to the European Society of Urogenital Radiology (ESUR) , an MRI protocol based on T1WI and short tau inversion recovery (STIR) sequences for axial and pelvic skeleton is also recommended for bone metastasis assessment.
In local recurrence assessment, transrectal ultrasound (TRUS) is neither sensitive nor specific in both post-RP and RT cases. Due to its high contrast resolution, MRI has been increasingly used in cases of suspicion of PCa local relapse after RP or RT . Conventional morphological sequences may be untrustworthy and accuracy levels have increased with combined use of functional techniques, namely DCE-MRI and DWI .
Radical prostatectomy implies removal of the entire prostate gland and both seminal vesicles, along with some of the fat surrounding tissue, with the goal of getting negative margins. The procedure should be accompanied by extended pelvic lymphadenectomy in patients with intermediate- and high-risk PCa. In men with low-risk PCa and <50% positive biopsy cores, both the need and the extent of lymphadenectomy remain controversial as the risk of lymph node involvement is low [5, 20].
Radical retropubic prostatectomy (RRP) and perineal prostatectomy are performed through open incisions. Minimally invasive laparoscopic radical prostatectomy (LRP) and robot-assisted laparoscopic prostatectomy (RALP) have been recently developed and are being increasingly used in many centers. RALP is apparently associated with less blood loss and transfusion need, when compared to RRP. Negligible differences regarding the remaining post-operative complications were found [21, 22].
According to the European Association of Urology (EAU) , RP is indicated in patients with low- and intermediate-risk localized PCa (cT1a-T2b and Gleason Score [GS] 2–7 and PSA < 20 ng/mL) and life expectancy higher than 10 years. Some selected patients with low-volume, high-risk localized PCa (cT3a or GS 8–10 or PSA > 20 ng/mL) and very high-risk localized PCa (cT3b-T4 N0 or any T N1) may also undergo RP, but always in a multimodality setting. The goal of RP is to eradicate the disease, conserving continence and potency [23, 24].
Over the last decade, the diagnosis of PCa has been established in younger men, so the preservation of sexual function has gained greater importance. Nerve-sparing RP may be attempted in patients with low risk for extracapsular disease (T1c, GS < 7 and PSA < 10 ng/mL). The recognition of neurovascular bundle involvement on initial staging MRI is crucial [5, 25, 26].
A persistently elevated post-RP PSA level (6 weeks after) is usually related to residual tumor, either due to distant micrometastases or residual pelvic disease. Rarely, a stable and low PSA level may be caused by residual benign glands . If PSA level increases promptly after surgery, distant metastases are more likely to be the cause. On the other hand, a later and slower rise probably indicates local disease recurrence. pT2-3a N0 tumors are more associated with local recurrence, particularly when margins are negative, while pT3b-4 and/or pN1 cancers are more likely to relapse at distant sites. GS in the prostatectomy specimen also has prognostic implications: when <8, local relapse is more probable; when ≥8, systemic recurrence and cancer-related death are more likely to happen [10, 27].
In the majority of centers, post-RP recurrent cancer is defined as two consecutive PSA values of 0.2 ng/mL or more, despite some authors considering a higher cut-off of 0.4 ng/mL [7, 8, 10, 28]. When a post-RP BF is recognized, salvage RT is generally performed without histological confirmation of local relapse, since TRUS is neither sensitive nor specific and a negative biopsy does not rule out a local recurrence [7, 8]. MRI is very useful in cases of suspicion of PCa local relapse after RP . Several studies have been published over the last few years reporting higher accuracy rates for the combined use of morphological and functional sequences comparing to morphological sequences alone. Cirillo et al.  showed that contrast-enhanced sequences improve diagnostic performance when added to T2WI. In another study, Sciarra et al.  reported a sensitivity of 87% and specificity of 94% for the combined use of MRS and DCE-MRI in the detection of local PCa recurrence in patients with BF after RP.
External beam radiotherapy
External beam radiotherapy (EBRT) remains a valid alternative to surgery for curative therapy. It is recommended for localized PCa (T1c-T2c N0 M0), even in young patients who reject surgical intervention. In high-risk patients with locally advanced PCa (T3-4 N0 M0), long-term androgen deprivation therapy (ADT) before and during RT is recommended and leads to increased overall survival. EBRT may also be used after RP in T3 N0 M0 tumors, improving biochemical and clinical disease-free survival. This combination is particularly effective in cases with post-surgical positive margins. In very high-risk prostate cancer (c-pN1 M0), RT alone is inadequate. These patients, if no severe comorbidity is found, should undergo EBRT and immediate long-term adjuvant hormonal treatment [5, 33].
The current definition of BF after radiation is a PSA rise of more than 2 ng/mL above the post-treatment nadir . In contrast to post-RP local relapse, it is necessary to obtain histological confirmation of the local recurrence after radiation therapy, taking into account the high morbidity of salvage options .
Fibrosis and changes of parenchymal vascularization after RT modify the biological behavior of tumors and normal tissue, and may consequently limit the use of functional techniques like DCE-MRI or DWI. Even though, some manuscripts with promising results have been published. According to a study of Haider et al. , DCE-MRI performs better than T2WI in the detection of tumor relapse in the peripheral zone after EBRT. The authors reported sensitivity and specificity levels of 72% and 85%, respectively. The enhancement of post-radiation fibrosis is low and slowly progressive, whereas recurrent cancer is typically hypervascular . Kim et al.  concluded that the use of combined T2WI and DWI demonstrates better diagnostic performance when compared to T2WI alone for predicting locally recurrent PCa after radiation therapy. In another study, Morgan et al.  also emphasized the added vale of DWI, concluding that ADC measurement is useful for detecting local tumor relapse larger than 0.4 cm2 within the prostate. In a more recent study, Donati et al.  concluded that the combination of T2WI and DWI achieves the best overall diagnostic accuracy and the highest inter-reader agreement in the detection of recurrent PCa after RT. In other studies, Arumainayagam et al.  and Akin et al.  demonstrated that mp-MRI using T2WI, DCE-MRI, and DWI is an accurate test for detecting radio-recurrent PCa. The former achieved accuracy levels of 80%–90%.
Some studies were also developed regarding the utility of MRS. Pucar et al.  showed that MRS might be more sensitive than TRUS and digital rectal examination for localization of post-EBRT cancer recurrence.
Transperineal BT is a secure and effective treatment for low-risk PCa. According to the EAU, it is recommended in patients with cT1-T2a N0 M0, GS < 7 (or 3 + 4), PSA ≤ 10 ng/mL, ≤50% of biopsy cores involved with cancer, prostate volume <50 mL, without a previous transurethral resection of the prostate (TURP), and an International Prostatic Symptom Score ≤12 [5, 21].
This transperineal technique is performed with TRUS. The patient is positioned in a dorsal decubitus gynecological position and seeds’ implantation is performed under general anesthesia or spinal block .
There is no consensus on BF after BT. A PSA bounce, defined as a temporary increase of the PSA level followed by a further decrease, occurs in 30%–60% of patients 12–24 months after implantation, without clinical relevance. PSA bounce typically persists for about 12 months and PSA levels usually do not increase more than 1.0 ng/mL .
In cryosurgery, freezing of the prostate gland is guaranteed by the placement of cryoneedles under TRUS guidance, thermosensors at the level of the external sphincter and bladder neck, and insertion of a urethral warmer. A −40°C temperature is achieved in the mid-gland and at the neurovascular bundle, generally after two freeze–thaw cycles, inducing cell death. Cellular dehydration, rupture of cellular membranes, vascular stasis, and microthrombi are the underlying mechanisms [42, 43, 44, 45].
Potential candidates for cryosurgery are those with low- or intermediate-risk PCa and comorbidities that contraindicate RT or RP. At the time of therapy, prostate gland should be <40 mL, so prior hormonal downsize may be needed [43, 44].
Prostate cells undergo apoptosis when deprived of androgenic stimulation. Testosterone is crucial for growth and perpetuation of tumor cells, so androgen deprivation therapy (ADT) constitutes one of the therapeutic options for PCa. ADT aims to suppress the secretion of testicular androgens (castration) or inhibit the action of circulating androgens at the receptor level (anti-androgens) [10, 47].
Hormonal therapy (HT) is the standard option in metastatic PCa, becoming mandatory if patients are symptomatic. In N + M0, HT also constitutes the standard treatment after extended node dissection if more than 2 positive nodes are found. Symptomatic patients with extensive T3–T4 and high PSA level (>25–50 ng/mL) may also benefit with HT, but not as monotherapy, unless patients are unfit for RT. The use of HT in T1a–T2c localized PCa is limited and only indicated in symptomatic patients who need symptom palliation or are unfit for curative treatment .
Once a post-treatment BF is detected, local or distant recurrence should be recognized. Several studies have already demonstrated the value of mp-MRI in the detection of post-RP and EBRT tumor relapse. The combination of morphological sequences with functional techniques like DCE-MRI and DWI has improved diagnostic accuracy levels and is now widely accepted and used.
Susceptibility magnetic artifacts after BT appear to significantly hamper tumor foci detection within the gland. However, in some non-artifact-hampered exams, mp-MRI might be useful to distinguish between clinically irrelevant PSA bounce and true BF. This issue remains controversial and surely implies further research. Moreover, other studies are also needed to validate the use of mp-MRI in the detection of recurrent PCa after less widespread therapies, like cryosurgery or HIFU.
Even in the assessment of distant metastases, MRI may be used. Despite bone scans and abdominopelvic CT being typically the first choices, both bone and lymph node metastases may be identified on MRI. Particularly in high-risk patients, an MRI protocol including T1WI and STIR sequences is already set as an alternative to bone scans.
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