In 2020, the International Agency for Research on cancer reported 1,414,259 new cases of prostate cancer, becoming the second most frequent type of neoplasia in males. Localized and metastatic adenocarcinoma of the prostate are well managed with several treatment options available. However, other variants such as neuroendocrine differentiation of prostate cell lines have increasingly become a clinical challenge. This aggressive variant of prostate cancer is characterized by hormone refractoriness, low or absent androgen receptors and is associated with low serum levels of prostate specific antigen (PSA).¹ The aim of this report is to present a rare case of a neuroendocrine prostate cancer case.

Case Presentation

A 45-year-old male was awakened by an intense pain in the perineum. During the following 4 days the patient used paracetamol and ibuprofen (self-medication) with no improvement. No other symptoms were reported, and the patient had no history of previous cancer or chronic pathology. The patient received medical attention from a urology surgeon. During the rectal digital examination, the prostate gland was solid and fixed. Serum levels of PSA were 2.8 ng/ml. A transrectal ultrasound biopsy was performed reporting small cell neuroendocrine carcinoma.

An open radical prostatectomy and pelvic lymph node dissection was performed with no intraoperative complications. The diagnosis of the pathology report was small cell neuroendocrine carcinoma (WHO 2016) in 95% of the neoplasia with tumor necrosis of 60% and a mitotic index >20/2 mm² and a Gleason score 9 acinar adenocarcinoma (4+5) ISUP 5 (2019) in 5% of the neoplasia. The capsule, urethral and seminal vesicals were reported as infiltrated by the tumor. Bilateral lymphatics were reported as negative for neoplasia. Figures 1–4 show microscopic features of the neoplasia.

Figure 1. Mixed neoplasia pattern including small round cells with scarce eosinophilic to clear cytoplasm. Nuclei show discrete variation in size with granular chromatin. Cells form small nests and, in some areas, rosette pattern with extensive necrosis and apoptosis is visible.

Figure 2. Microscopic features compatible with mixed small cell neuroendocrine carcinoma negative for CD45 and AE1/AE3 cytokeratin and positive chromogranin with a proliferative index (ki67) of 60%.

Figure 3. A mixed neoplasia pattern including small round cells with scarce eosinophilic to clear cytoplasm. The nuclei show discrete variation in size with granular chromatin. The cells form small nests and, in some areas, a rosette pattern with extensive necrosis and apoptosis is visible.

Figure 4. Microscopic features compatible with mixed small cell neuroendocrine carcinoma negative for CD45 and AE1/AE3 cytokeratin and positive chromogranin with proliferative index (ki67) of 60%.

Figures 1 and 2 show a mixed neoplasia pattern including small round cells with scarce eosinophilic to clear cytoplasm. The nuclei show discrete variation in size with granular chromatin. The cells form small nests and, in some areas, a rosette pattern with extensive necrosis and apoptosis is visible.

Figures 3 and 4 show microscopic features compatible with mixed small cell neuroendocrine carcinoma negative for CD45 and AE1/AE3 cytokeratin and positive chromogranin with a proliferative index (ki67) of 60%.

At 6 months following surgery, the patient is under observation by oncology and urology. Continence is preserved and managed with 5-phospodiesterase inhibitors, which have shown partial results.

Positron emission tomography (PET) scan reported local tumor and bone metastatic activity. Therefore, the patient received adjuvant chemotherapy management with 6 cycles of paclitaxel and carboplatin. Four weeks after finishing chemotherapy, the patient reported pelvic pain. A new PET scan showed local tumor activity and the patient is now under treatment with topotecan.

Discussion

Neuroendocrine carcinoma of the prostate may develop in patients with previous acinar adenocarcinoma in later stages of castration-resistant prostate cancer owing to lineage plasticity as an adaptative mechanism to targeted therapy.^2,3 Adenocarcinoma of the prostate cells may acquire neuroendocrine differentiation and in extreme cases a complete transformation of small cell carcinoma.² Some molecules have been shown to trigger neuroendocrine differentiation. Androgen-deprivation management might affect the expression of epithelial markers, such as a decrease in E-cadherin and an increased expression of mesenchymal markers (N-cadherin, vimentin, Zeb1, Twist1 and Snail2) undergoing an epithelial and mesenchymal transition.² Neuroendocrine differentiation, apoptosis and angiogenesis in prostate cancer cells under blocking androgen receptor treatment have been related to beta adrenergic signaling. Zhao and Li reported the role of beta-adrenergic signaling as a regulator of several cellular processes affecting development of aggressive prostate cancer by regulating neuroendocrine differentiation.⁴ Other biological markers are associated with neuroendocrine differentiation such as IL-8 and IL-6 in association with STAT3.⁵ The FOXA1 transcription factor is a necessary molecule for the development and differentiation of epithelial cells in the prostate. This transcription factor recruits the androgen receptor to lineage-specific genomic loci to turn on prostate gene expression, and is expressed at high levels in the prostate. Kim et al reported that FOXA1 was significantly down-regulated in neuroendocrine prostate cancer.⁵ This neoplasia stage-dependent expression of FOXA12 is probably associated with its dual roles in promoting cell growth but inhibiting neuroendocrine differentiation which are characteristics of castration-resistant prostate cancer and neuroendocrine prostate cancer.

While de novo cases are rare, it is assumed that these cases come from normal neuroendocrine cells or a multipotent stem cell located in the prostate, based on high expression of CD44 and other genes related to stemness such as OCT-3/4 and Bmi. Scientific information suggests that neuroendocrine cells help to sustain surrounding prostate adenocarcinoma cellular growth through a paracrine mechanism via their secretory products such as serotonin, neuron-specific enolase and others.²

Conclusion

Small cell neuroendocrine carcinoma of the prostate is a rare condition. Molecular mechanisms of cellular differentiation are not completely clear, especially in de novo cases. The present case is a good example of an atypical presentation of an aggressive variant prostate cancer in a 45-year-old male. Information about similar cases is necessary in order to provide an international consensus and to determine optimal management and prognosis.