Neuroendocrine prostate cancer (NEPC) is a rare and aggressive form of prostate cancer, distinct from the more common prostate adenocarcinoma. It originates from neuroendocrine cells, which are specialized cells that produce hormones in response to signals from the nervous system. It is characterized by rapid progression and often presents a more challenging clinical course.
What is Neuroendocrine Prostate Cancer
Neuroendocrine prostate cancer (NEPC) differs significantly from prostate adenocarcinoma, which makes up almost all prostate cancer diagnoses. While adenocarcinoma cells generally rely on androgen hormones for growth, NEPC cells are less dependent on this signaling pathway, often showing low or absent androgen receptor (AR) expression. This difference means that NEPC does not respond to standard hormone therapies.
The aggressive nature of NEPC is reflected in its tendency for early and widespread metastasis, particularly to visceral organs like the liver and lungs, rather than predominantly to bone as seen in adenocarcinoma. Symptoms of NEPC can be non-specific, but may include frequent urination, a weak or interrupted urine flow, or discomfort when sitting. It can also present with atypical features, such as low prostate-specific antigen (PSA) levels, despite advanced disease.
How Neuroendocrine Prostate Cancer Develops
Neuroendocrine prostate cancer can arise in two distinct ways. In rare instances, it develops de novo, meaning it originates as NEPC from the very beginning, accounting for less than 2% of all prostate cancers. This initial development involves mutations in genes like TP53, RB1, and PTEN, which cause cells to replicate uncontrollably.
More commonly, NEPC develops as a transformation from existing prostate adenocarcinoma, a process often referred to as treatment-emergent neuroendocrine differentiation (t-NEPC). This transformation frequently occurs in patients undergoing prolonged androgen deprivation therapy (ADT) or other androgen receptor pathway inhibitors for castration-resistant prostate cancer. The cancer cells exhibit “lineage plasticity,” allowing them to switch from an androgen-dependent adenocarcinoma phenotype to an androgen-independent neuroendocrine phenotype as a mechanism to bypass therapy.
Diagnosing Neuroendocrine Prostate Cancer
Diagnosing neuroendocrine prostate cancer involves specialized approaches because typical prostate cancer markers, such as prostate-specific antigen (PSA), may not be elevated. Low PSA levels despite aggressive disease progression can be a characteristic feature of NEPC that develops after hormone therapy. A biopsy of metastatic tumor tissue is necessary to confirm NEPC histology, particularly in patients with aggressive disease, unusual spread patterns, or progression despite low or non-rising PSA levels.
Pathologists use specialized staining techniques, known as immunohistochemistry, on biopsy samples to identify neuroendocrine features. Markers like chromogranin A, synaptophysin, and CD56 are used to detect neuroendocrine features. Advanced imaging techniques also play a role in diagnosis and assessing disease spread; for example, a gallium-68 PSMA PET scan can show multiple lesions, while an FDG PET scan might evaluate disease characteristics.
Treating Neuroendocrine Prostate Cancer
Treating neuroendocrine prostate cancer (NEPC) requires different strategies compared to typical prostate adenocarcinoma due to its hormone-independent nature. The primary approach often involves platinum-based chemotherapy regimens, borrowed from small cell lung cancer protocols due to shared neuroendocrine features. A common regimen combines cisplatin or carboplatin with etoposide.
Other treatment modalities can include radiation therapy for localized control or in specific cases, and surgery, though their roles are more limited. Emerging therapies, such as targeted agents or immunotherapy, are also explored, but their effectiveness in NEPC is under investigation or limited.
A multidisciplinary team approach is generally recommended for managing NEPC, involving specialists in medical oncology, radiation oncology, and pathology. This collaborative care aims to tailor treatment plans to the individual patient. Despite initial responsiveness to platinum-based chemotherapy, the durability of these treatments can be short, highlighting the ongoing need for new therapeutic options and clinical trials.
Outlook and Prognosis
Neuroendocrine prostate cancer is recognized for its aggressive nature and generally carries a poorer outlook compared to the more common prostate adenocarcinoma. The median overall survival can vary, with pure small cell NEPC having a shorter survival than mixed histology tumors. The importance of early and accurate diagnosis is underscored by the rapid progression of this disease.
Aggressive treatment strategies are pursued to manage NEPC, though current therapies have limited long-term durability. Ongoing research and participation in clinical trials are valuable for improving outcomes and exploring novel treatment approaches. Access to specialized cancer centers with expertise in NEPC can also provide patients with current diagnostic and therapeutic options.