Early Detection of Neuroendocrine Prostate Cancer as Lineage Plasticity in Recurrent Prostate Cancer After Radiation and Androgen Deprivation Therapy: A Case Report

Background: Neuroendocrine prostate cancer is one of the most aggressive prostate cancers, with severely poor prognosis. However, its detection is dicult because no useful marker has been found so far. In addition, serum prostate-specic antigen (PSA) and prostate-specic membrane antigen (PSMA), and PSMA positron emission tomography/computed tomography don’t help in neuroendocrine prostate cancer. However, its early detection is necessary because its prognosis is poor. Case presentation: We described three cases of early neuroendocrine prostate cancer detection after initial external beam radiotherapy followed by salvage androgen deprivation therapy (ADT). We used Magnetic Resonance Imaging for three ADT-resistant patients, and it detected neuroendocrine prostate cancer in all three, although the PSA level was <2 ng/mL. Conclusions: Magnetic resonance imaging might be a better modality for neuroendocrine prostate cancer detection despite low serum prostate-specic-antigen levels.. Our ndings in these three cases will help establish better criteria or better follow-up for patients administered salvage androgen deprivation therapy for biochemical recurrence of prostate cancer after external beam radiotherapy. for early detection of lineage plasticity as recurrence after radiation and salvage ADT. The strategy for early NEPC detection is not established. Our report indicates the importance of MRI in early detection of BCR of prostate cancer with NEPC after initial EBRT followed by salvage ADT despite low serum PSA levels. Our ndings might help establish better criteria or better follow-up for patients administered salvage ADT for BCR of prostate cancer despite low serum PSA levels.


Background
The Prostate Cancer Clinical Trials Working Group 3 (PCWG3) de nes castration-resistant prostate cancer (CRPC) as a prostate-speci c antigen (PSA) level of > 1 ng /mL after androgen deprivation therapy (ADT) [1]. In addition, according to the Phoenix criteria published by the American Society for Radiation Oncology (ASTRO), biochemical recurrence of prostate cancer after external beam radiotherapy (EBRT) is de ned as a PSA rise of ≥ 2 ng/mL above the lowest level [2]. However, since there is no PSA criterion of prostate cancer recurrence after initial EBRT followed by salvage ADT for biochemical recurrence of prostate cancer, the CRPC de nition is often used instead. In this report, we described three cases of prostate cancer with neuroendocrine differentiation (neuroendocrine prostate cancer [NEPC]) that recurred with low serum PSA levels after initial EBRT followed by salvage ADT for biochemical recurrence of prostate cancer.
Case Presentation Case 1 In 2009, a 77-year-old man presented with a serum PSA level of 17.84 ng/mL, and prostate cancer was suspected. Transrectal prostate needle biopsy was performed, which gave a Gleason score of 4 + 3. The patient was diagnosed with cT3bN0M0 prostate cancer, and he was administered intensity-modulated radiation therapy (IMRT). Initially, he showed a good response to the treatment (lowest serum PSA level = 0.86 ng/mL). However, his serum PSA level gradually increased to 3.67 ng/mL in August 2013, and he was diagnosed with biochemical recurrence of prostate cancer according to the ASTRO Phoenix criteria.
Subsequently, he was administered salvage ADT. Initially, he showed a good response, and his serum PSA level decreased to 0.07 ng/mL in December 2014. However, in July 2019, his serum PSA level began to increase slightly and reached 0.30 ng/mL. Figure 1A shows the clinical course of salvage ADT and serum PSA levels. Despite low serum PSA levels, local recurrence was suspected because of continuous increase of serum PSA levels after salvage ADT. Therefore, the patient underwent pelvic magnetic resonance imaging (MRI), which detected recurrence of a suspicious lesion in the left lobe of the prostate. Transperineal prostate saturation needle biopsy detected adenocarcinoma partially accompanied by NEPC in the lesion (1 of 14 cores was positive). Figure 1B shows immunohistochemical (IHC) ndings of the tumor-positive specimen with positive chromogranin A (CgA) and synaptophysin (SYP) staining.

Case 2
In 2013, a 66-year-old man presented with a serum PSA level of 24.6 ng /mL, and prostate cancer was suspected. Transrectal prostate needle biopsy was performed, which gave a Gleason score of 4 + 3. The patient was diagnosed with cT1cN0M0 prostate cancer, and he was administered EBRT. Initially, he showed a good response to the treatment (lowest serum PSA level = 3.68 ng/mL). However, his serum PSA level gradually increased to 5.9 ng/mL in May 2015, and he was diagnosed with biochemical recurrence of prostate cancer according to the ASTRO Phoenix criteria. Subsequently, he was administered salvage ADT. Initially, he showed a good response with decreased serum PSA levels of < 0.01 ng/mL for ~ 3 years. However, in February 2020, his serum PSA level began to increase slightly and reached 0.10 ng/mL. Figure 2A shows the clinical course of salvage ADT and serum PSA levels. Despite low serum PSA levels, local recurrence was suspected because of continuous increase of serum PSA levels after salvage ADT. Therefore, the patient underwent pelvic MRI, which detected recurrence of a suspicious lesion in the left lobe of the prostate. Transperineal prostate saturation needle biopsy detected adenocarcinoma accompanied by NEPC in the lesion (2 of 14 cores were positive). Figure 2B shows IHC ndings of the tumor-positive specimen with partially positive CgA and SYP staining in the atypical glands.

Case 3
In 2008, a 67-year-old man presented with a serum PSA level of 7.06 ng/mL, and prostate cancer was suspected. Transrectal prostate needle biopsy was performed, which gave a Gleason score of 3 + 5. The patient was diagnosed with cT2bN0M0 prostate cancer, and he was administered IMRT with neoadjuvant hormone therapy. Initially, he showed a good response (lowest serum PSA level = 0.27 ng/mL). However, his serum PSA level gradually increased to 3.0 ng/mL in March 2016, and he was diagnosed with biochemical recurrence of prostate cancer according to the ASTRO Phoenix criteria. Subsequently, he was administered salvage ADT. Initially, he showed a good response, and his serum PSA level decreased to 0.61 ng/mL in December 2017. However, in July 2019, his serum PSA level began to increase slightly and reached 1.15 ng/mL. Figure 3A shows the clinical course of salvage ADT and serum PSA levels. Despite low serum PSA levels, local recurrence was suspected because of continuous increase of serum PSA levels after salvage ADT. Therefore, the patient underwent pelvic MRI, which detected recurrence of a suspicious lesion in the right lobe of the prostate. Transperineal prostate saturation needle biopsy detected adenocarcinoma accompanied by NEPC in the lesion (3 of 14 cores were positive). Figure 3B shows IHC ndings of the tumor-positive specimen with positive CgA and SYP staining.

Discussion And Conclusion
NEPC is one of most aggressive prostate cancers, with a median prognosis of only 7 months [3,4]. NEPC arises after salvage ADT as a result of (i) lineage plasticity, (ii) differentiation from adenocarcinoma to a neuroendocrine tumor, and (iii) escape from androgen receptor (AR) pathway inhibitation [5][6][7][8]. Therefore, early NEPC detection is necessary. However, NEPC detection is di cult because no useful marker has been found so far. SYP, CgA, and neuron-speci c enolase (NSE) are often used as neuroendocrine markers, but their sensitivity is low [9]. In addition, serum PSA and prostate-speci c membrane antigen (PSMA) don't help in NEPC. PSMA positron emission tomography/computed tomography (PET/CT) is useful for detecting small CRPC lesions but not NEPC [10]. NEPC is also resistant to both salvage androgen deprivation therapy (ADT) and AR-targeted therapy, so cisplatin-based chemotherapy is administered instead of AR-targeted therapy.
MRI detects small-size NEPC. Diffusion-weighted imaging (DWI) MRI detects small cell lung cancer (SCLC), which is a neuroendocrine cancer [11]. The apparent diffusion coe cient in SCLC is lower compared to benign lung tissue and non-small cell lung cancer (NSCLC) [12]. Similar to SCLC, MRI might be a better modality for NEPC detection compared to other types of imaging.
PSA-negative/PSA-low prostate cancer cells might be resistant to the stress related to antitumor therapy such as radiation, hormone therapy, and chemotherapy [13]. Therefore, PSA-negative/PSA-low prostate cancer cells might survive antitumor therapy through lineage plasticity, and serum PSA levels might not increase to > 1.0 ng/mL when recurrence is detected. This phenomenon should be considered for early detection of lineage plasticity as recurrence after radiation and salvage ADT.
The strategy for early NEPC detection is not established. Our report indicates the importance of MRI in early detection of BCR of prostate cancer with NEPC after initial EBRT followed by salvage ADT despite low serum PSA levels. Our ndings might help establish better criteria or better follow-up for patients administered salvage ADT for BCR of prostate cancer despite low serum PSA levels.