Case Presentation: A 63-year-old man with past medical history of hypertension and metastatic castration resistant prostate carcinoma (mCRPC) presented with polydipsia, polyuria, and lower extremity swelling. He was initially diagnosed with prostate cancer eight years prior with a high screening PSA and a transrectal ultrasound guided biopsy. He opted for holistic treatment with serial PSA measurements. Seven years later, a rising PSA with no evidence of metastatic spread on imaging prompted localized cyberknife treatment. Subsequent repeat imaging, however, showed metastatic spread to pelvic lymph nodes and bones. After four months of androgen deprivation therapy, his PSA continued to rise, and he was diagnosed with mCRPC. Treatment with abiraterone acetate and prednisone was discontinued due to progression of disease.Two weeks later, the patient presented to the ED with hypokalemia, polydipsia, polyuria and lower extremity swelling. His glucose was 508 mg/dL with hgba1c of 8.1% (6.3% 3 months prior). Given persistent hypokalemia off steroids, a morning cortisol level was checked and found to be elevated. A workup for Cushing’s syndrome showed high 24-hour urine cortisol and ACTH; MRI of the brain showed a normal pituitary, and an abnormal dexamethasone suppression test with both low and high doses were all consistent with a paraneoplastic ectopic ACTH syndrome. A left inguinal lymph node biopsy showed high-grade neuroendocrine prostate carcinoma (NEPC). The patient clinically improved with ketoconazole and was discharged home. He was planned to start enzalutamide in the oncology clinic. A month later, he died in inpatient hospice.

Discussion: NEPC is a treatment-emergent phenomenon seen in about 30-40% of mCRPC cases. Overall survival is less than one year from time of diagnosis. Clinically, patients often have treatment resistant, rapidly progressive visceral and bulky soft-tissue disease associated with a low PSA. Our case is unique in that the patient had a high PSA (515 ng/ml) and relatively limited metastatic disease. His left inguinal lymph node biopsy stained positive for chromogranin, synaptophysin, and CD56, which in conjunction with a high serum chromogranin A level, points to NEPC. NEPC treatment consists of carboplatin/etoposide-based chemotherapy. Cushing’s syndrome due to ectopic ACTH is rarely seen in prostate cancer with less than thirty published cases. Ketoconazole and metyrapone are the most commonly used agents.

Conclusions: It is imperative for physicians to have increased awareness of NEPC as a rare yet challenging variant of prostate cancer. Regardless of PSA levels and the extent of metastatic disease, there ought to be high suspicion of NEPC when patients with prostate cancer present with new symptoms or laboratory abnormalities suggestive of an endocrinopathy such as diabetes mellitus or Cushing’s syndrome.