Cushing Syndrome as a Manifestation of Neuroendocrine Prostate Cancer: A Rare Presentation Within a Rare Tumor

Neuroendocrine prostate cancer (NEPC) is a rare entity representing 1% of all prostate malignancies, associated with poor prognosis and often concomitant with paraneoplastic syndromes such as Cushing's syndrome (CS) with ectopic adrenocorticotropic hormone (ACTH) production. We present a case of a 56-year-old man with recent lower urinary tract symptoms hospitalized for pelvic pain, rectal tenesmus, and fatigue. A CT scan documented a large prostatic mass, adenomegalies, and hepatic lesions. Bone scintigraphy showed dispersed osteoblastic metastization. The patient had uncontrolled hypertension and hypokalemia that lead to the diagnosis of paraneoplastic ACTH-dependent CS. Prostate biopsy confirmed small cell NEPC. Potassium supplementation, anti-hypertensive medication, and metyrapone were initiated. The patient was proposed for palliative chemotherapy but died within a few days from a urinary tract infection. The authors aim to draw attention to a case of paraneoplastic CS, a rare manifestation, within the rarity that is NEPC.


Introduction
Prostate cancer (PC) is the second most frequent malignancy in men worldwide. In 2018, 1,276,106 new cases were diagnosed, causing 358,989 deaths (3.8% of all deaths caused by cancer in men) [1,2].
The majority of PC is adenocarcinoma, originating from glandular cells. Neuroendocrine prostate cancer (NEPC) is a rare aggressive variant of PC derived from the neuroendocrine component of the prostate, consisting of a small subset of cells, randomly scattered within the epithelium of the prostate glands [3].
The 2016 World Health Organization classification consensus distinguishes adenocarcinoma with neuroendocrine differentiation from well-differentiated neuroendocrine tumors and high-grade neuroendocrine tumors that include small cell neuroendocrine carcinoma (SCC) and large cell neuroendocrine carcinoma [4][5][6].
Histologic features of prostate SCC include small cells with minimum cytoplasm, fine "salt-and-pepper" chromatin, lack of prominent nucleoli, extensive tumor necrosis, apoptosis, and high mitotic rate. Immunohistochemically, these tumors show chromogranin and synaptophysin positive expression in 61% and 89% of cases, respectively; and 17% of cases are positive for prostate-specific antigen (PSA) and 24% and 35% of cases are positive for p63 and high molecular weight cytokeratin, respectively [7].
Paraneoplastic manifestations -symptoms related to the production of bioactive substances from cancer cells, or occasionally related to immune cross-reactivity to cancer neo-antigens -can occur at any stage [6,7].
Paraneoplastic Cushing's syndrome (CS) accounts for 10%-20% of CS and develops secondary to neoplastic adrenocorticotropic hormone (ACTH) production, leading to hypercortisolism and its wide range of clinical manifestations including increased mortality. It is mainly derived from the lung, thymus, pancreas, thyroid, chromaffin cell tumors, and rarely from the ovary or prostate [8][9][10].

Case Presentation
A 56-year-old man presented to the emergency department with pelvic pain, rectal tenesmus, and fatigue. In the past four months, he experienced some episodes of low urinary tract symptoms and initiated treatment for hypertension.
Computed tomography (CT) documented a large heterogenic prostatic mass (59 x 35 x 33 mm) with loss of cleavage planes, numerous adenomegalies, multiple pericentimetric hepatic hypocaptating lesions, suggestive of secondary lesions, and evidence of bone involvement (Figures 1, 2). A urinary catheter was placed due to urinary retention. PSA was elevated with 223 ng/ml (normal <4 ng/ml) and the patient was admitted for pain control and investigation.
At admission, the patient was hypertensive (165/89 mmHg). Laboratory tests evidenced metabolic alkalosis (pH 7.58; HCO3 42 mEq/L), normal sodium of 140 mEq/L, and severe hypokalemia (2.1 mEq/L; normal 3.5-4.5 mEq/L), that showed to be refractory to adequate replacement measures. Hypokalemia investigation showed high levels of morning plasma cortisol (58 g/L; normal 3.7-19.4 g/L), high levels of 24 h urinary cortisol (12,333 g/24 h; normal range 4.3-176) with a negative overnight 8 mg dexamethasone suppression test (81 g/L; normal <19 g/L) and elevated levels of plasma ACTH (253 pg/mL; normal 7.2-63.3 pg/mL). A diagnosis of paraneoplastic ACTH-dependent CS was made. The patient was initiated on 250 mg metyrapone daily. The patient's potassium levels increased and 24 h urinary cortisol, after one week on metyrapone, decreased to 3254 g/24 h. A brain magnetic resonance imaging confirmed the absence of any pituitary abnormality and CT excluded nodules on the thyroid or adrenal gland, confirming ectopic ACTH production.
A prostatic biopsy revealed a small cell neuroendocrine carcinoma, positive for synaptophysin and focally for CAM5.2 and PSA, and negative for chromogranin A with a very high Ki67 expression (90%-100%) (Figures 3-5).