What is the best course of treatment for a patient with a history of prostate cancer who now presents with poorly differentiated retroperitoneal cancer that is synaptophysin positive?

Poorly Differentiated Retroperitoneal Cancer with Synaptophysin Positivity After Prostate Cancer Treatment

Primary Diagnosis: Treatment-Emergent Neuroendocrine Prostate Cancer

This synaptophysin-positive retroperitoneal mass represents treatment-emergent neuroendocrine prostate cancer (NEPC), a lethal transformation that occurs in response to androgen receptor signaling inhibition, and requires immediate platinum-based chemotherapy rather than continued hormonal therapy. 1, 2

Diagnostic Confirmation

• Obtain immunohistochemistry panel including synaptophysin, chromogranin A, PSA, and prostate markers (NKX3.1, PSMA) to confirm neuroendocrine differentiation 1, 3
• Synaptophysin positivity with negative or weak prostate markers confirms NEPC transformation 1, 4
• Check serum PSA level, which is characteristically low or disproportionately low relative to tumor burden in NEPC 4
• Neuroendocrine differentiation occurs in approximately 14.9% of prostate adenocarcinomas and represents aggressive disease behavior 3

Staging Workup

• Perform CT chest/abdomen/pelvis to assess extent of retroperitoneal disease and identify visceral metastases 5, 6
• Obtain bone scan to evaluate for skeletal metastases, as bone involvement would classify this as M1b disease 6
• Measure serum LDH, AFP, and beta-hCG to assess prognosis using IGCCCG criteria if germ cell tumor remains in differential 5
• Brain MRI is indicated if high beta-hCG levels or neurological symptoms are present 5

Treatment Approach

First-Line Chemotherapy

Initiate platinum-based chemotherapy with cisplatin plus etoposide (EP regimen), which is the standard treatment for small-cell/neuroendocrine carcinomas 4:

• Cisplatin 20 mg/m² IV days 1-5 plus etoposide 100 mg/m² IV days 1-5, repeated every 21 days 5
• Alternative: Carboplatin AUC 5-6 plus etoposide if cisplatin contraindicated 4
• Plan for 4-6 cycles based on response 4, 2

Why Not Hormonal Therapy

• NEPC is androgen receptor-independent and does not respond to continued androgen deprivation therapy 2
• The transformation to neuroendocrine phenotype specifically occurs as an escape mechanism from hormonal therapy 2
• Continuing hormonal approaches will result in disease progression and death 4, 2

Prognosis and Response Assessment

• Survival is poor with median overall survival of 12-24 months even with chemotherapy 2
• Repeat imaging after 2-3 cycles to assess response 5
• Rising LDH or progression on imaging indicates chemotherapy resistance 5
• Consider clinical trial enrollment given limited effective treatment options 2

Critical Pitfalls to Avoid

• Do not continue androgen deprivation therapy alone, as this will not control NEPC 2
• Do not treat as conventional prostate adenocarcinoma with taxane-based chemotherapy (docetaxel/cabazitaxel) as first-line, as platinum-based regimens are more appropriate for neuroendocrine histology 4, 2
• Do not delay treatment waiting for PSA to rise, as PSA is an unreliable marker in NEPC 4
• Do not assume this is a germ cell tumor despite retroperitoneal location and synaptophysin positivity; the history of prostate cancer and negative prostate markers distinguish NEPC from primary germ cell tumors 1, 3

Alternative Consideration: Primary Germ Cell Tumor

If immunohistochemistry shows negative prostate markers (PSA, NKX3.1, PSMA) and elevated AFP/beta-hCG, consider primary retroperitoneal germ cell tumor 5:

• Treat with BEP chemotherapy (bleomycin, etoposide, cisplatin) for 3-4 cycles based on IGCCCG risk classification 5
• Retroperitoneal primary with non-pulmonary visceral metastases would classify as intermediate or poor prognosis 5
• Surgical resection of residual masses after chemotherapy if markers normalize 5

However, the history of prostate cancer treatment makes NEPC transformation far more likely than coincidental germ cell tumor 1, 2.