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Introduction

Prostate cancer is the second most common cancer in males accounting for more than 900,000 cases per year (1). Adenocarcinoma is by far the most common subtype and affects more than 95% of the patients (2). Androgen deprivation therapy (ADT) remains the cornerstone of treatment for metastatic prostatic adenocarcinoma. Despite the initial response to androgen blockade, castration resistance often occurs via multiple mechanisms through androgen receptor (AR) pathway or others. Neuroendocrine dedifferentiation is one of the AR-independent castration resistance mechanisms that lead to an aggressive phenotype (3,4). While neuroendocrine differentiation in prostate cancer (NEPC) is a rare phenomenon in primary prostate cancer (<2%), it is detected in up to 10–17% of metastatic castrate-resistant prostate cancer (3). In addition, NEPC is often observed among males who have been previously treated with ADT or radiotherapy for prostate cancer (4,5). These types of tumors express typical neuroendocrine markers such chromogranin, synaptophysin (SYP) and specific neuronal enolase (NSE) but lack the expression of AR and AR-mediated genes (3,5). These tumors may originate de novo from a small population of neuroendocrine cells present in the prostate but usually occur from a population of luminal-derived castration-resistant cells through a neuroendocrine differentiation (NED) or trans-differentiation process. This phenotypic change can lead to a more aggressive clinical presentation with atypical manifestations and fewer effective treatment options. Bioactive substances produced by these cells can lead to paraneoplastic syndromes, including ectopic adrenocorticotropic hormone (ACTH) secretion. In the present study, a case of paraneoplastic Cushing syndrome (CS) in a patient with metastatic prostate cancer is presented. A review of the literature on this rare clinical entity is also presented to improve characterization of the clinical features and prognosis.

Case report

A 76-year old patient with a four-year history of metastatic prostate adenocarcinoma presented to the emergency department due to rapid-onset lower extremity weakness. The patient was first diagnosed with de novo metastatic prostate cancer in 2019 and was under ADT with enzalutamide and luteinizing hormone-releasing hormone analogue for the last four years. Biopsy of the prostate was performed in 2019 and revealed an adenocarcinoma Gleason 8 (5+3) of the prostate. Prostate-specific antigen (PSA) at initial diagnosis was 12.5 ng/ml and declined progressively to 0.007 ng/ml in 2022 after the initiation of enzalutamide. The patient now presented with lumbar pain and thus a magnetic resonance imaging (MRI) of the lumbar spine was performed which revealed the presence of an intraspinal metastasis in front of the fourth lumbar vertebra causing spinal cord compression. CT scans of the chest and abdomen showed an additional soft tissue metastasis on the left iliac bone and regional lymph node metastases. The patient started palliative radiotherapy at the metastatic foci of the O4 lumbar vertebrae and left iliac bone and was about to initiate chemotherapy with docetaxel. Of note, baseline PSA at disease progression was 0.48 ng/ml before the administration of chemotherapy.

The patient presented at the Emergency Department on the 13th of June 2023 with lower extremity muscle weakness and hypokalemia (2 mEq/l). He was hemodynamically stable and on inspection he appeared pale. Neurologically, he was oriented but exhibited emotional lability with bradypsychia. There were no focal neurological deficits in the lower extremities. Laboratory findings showed marked hypokalemia with serum potassium level of 2 mEq/l (3,5-5,1 mEq/l), metabolic alkalosis (HCO3: 48,5 mEq/l) and an elevated lactate dehydrogenase level of 461 U/l (135–225 U/l). Electrocardiogram revealed a prolonged QT interval with a corrected QT interval of 473 ms. The patient received intravenous and oral potassium supplements to prevent life-threatening arrhythmias and further investigation of hypokalemic alkalosis was initiated. The laboratory findings of the initial assessment are demonstrated in Table I.

Table I. Laboratory results at initial assessment.

Table I.

Laboratory results at initial assessment.

Analyte	Result	Reference interval
Serum potassium	2 mEq/l	3,5-5,1mEq/l
Glucose	199 mg/dl	75–115 mg/dl
Lactate dehydrogenase	461 U/l	135–225 U/l
HbA1c	6.1%	4.5–6%
Serum cortisol (08:00)	>1,380 nmol/l	138–690 nmol/l
Serum bicarbonate	48,5 mEq/l	22–29 mEq/l
Arterial pH	7,66	7,35-7,45
Initial endocrine evaluation
Midnight cortisol	>1,380 nmol/l	138–690 nmol/l
1 mg overnight dexamethasone suppression test	>1,380 nmol/l	138–690 nmol/l
8 mg overnight dexamethasone suppression test	>1,380 nmol/l	138–690 nmol/l
24 h urinary free cortisol	20,600.00 µg/gCr	1.00–119.00 µg/gCr
Plasma ACTH	194 pg/ml	<46 pg/ml

[i] ACTH, adrenocorticotropic hormone.

No episodes of diarrhea or vomiting were reported from recent medical history, thus potassium loss from the gastrointestinal tract was excluded. Additionally, urine electrolytes were within normal limits, hence renal potassium loss was also excluded. Therefore, endocrinological causes of hypokalemia were investigated. An adrenal protocol CT scan was performed which revealed no pathologic findings. Based on the aforementioned findings, evaluation of renin, aldosterone, ACTH and cortisol levels was requested. Τhe aforementioned tests revealed normal renin and aldosterone levels but elevated plasma cortisol levels >1,380 nmol/l (138–690 nmol/l) along with elevated plasma ACTH levels 194 pg/ml (<46 pg/ml). Measurement of 24 h urinary free cortisol revealed a value of 20,600.00 µg/gCr (1.00–119.00 µg/gCr). There was no suppression after both low-dose and high-dose dexamethasone challenge. Pituitary MRI was performed but revealed no pathologic findings (Fig. 1). Consequently, the patient was diagnosed with CS and ectopic ACTH production was considered the most likely diagnosis associated with paraneoplastic syndrome in the context of metastatic prostate adenocarcinoma.

Figure 1. Pituitary magnetic resonance imaging T2 with no pathological findings.

Clinical deterioration was acute and thus both symptomatic treatment and chemotherapy were initiated. Symptomatic treatment included oral potassium supplements, potassium-sparing diuretics, along with mineralocorticoid blockade (spironolactone). Treatment with ketoconazole 200 mg and metyrapone 500 mg three times per day, which block the steroid biosynthetic pathway, was initiated. Additionally, anticoagulant therapy was administered due to increased risk of thromboembolism. The patient remained under close monitoring throughout the course of his treatment and did not experience any treatment-related adverse events, including hepatotoxicity, which is most commonly reported. On the 10th day of treatment with ketoconazole and metyrapone, lab tests revealed a decrease in serum cortisol levels (425 nmol/l) and ACTH levels (129 pg/ml) along with the stabilization of potassium levels (Fig. 2A and B). Following the clinical and laboratory stabilization of the patient, chemotherapy with docetaxel 75 mg/m2 and prednisolone 5 mg bid was initiated. The patient was discharged from hospital after one month of hospitalization and continued chemotherapy. PSA declined from 0.48 to 0.22 ng/ml after three cycles of docetaxel administration. However, the patient died three months after initial presentation despite his initial response to treatment.

Figure 2. (A) Response of ACTH levels with adrenal blockage therapy. ACTH reference interval: <46 pg/ml (B) Response of serum cortisol levels within 10 days of therapy with ketoconazole and metyrapone. Serum cortisol reference interval: 138–690 nmol/l. ACTH, adrenocorticotropic hormone.

Discussion

Ectopic CS constitutes a rare paraneoplastic entity in prostate cancer. Ectopic CS as a paraneoplastic syndrome accounts for only 10–15% of CS cases and is mostly related to small cell lung cancer, pancreatic, thymus or thyroid carcinoma (6). This case highlights the urgency of diagnosing this entity and the importance of initiating treatment promptly. A case of ectopic ACTH production in a patient with castration-resistant metastatic prostate cancer who had previously received enzalutamide plus ADT is presented in the current study. Despite prompt diagnosis of ectopic Cushing disease and immediate initiation of treatment with ketoconazole and metyrapone, the patient deteriorated and eventually succumbed at three months after initial presentation with CS.

The existing literature for cases of CS related to prostate cancer was reviewed. The search strategy consisted of the following keywords: ‘cushing syndrome’ AND ‘prostate cancer’ that was applied to PUBMED bibliographical database (https://pubmed.ncbi.nlm.nih.gov/). Overall, a total of 102 papers were retrieved from the search algorithm. After the removal of two review articles (7,8) as well as two non-English papers (9,10), a total of 26 articles were considered eligible for this review (11–36). An additional search of the literature cited in the aforementioned papers revealed 12 more eligible papers (37–48). Finally, a google research was performed that revealed three additional papers (49–52). The search algorithm is illustrated in Fig. 3 and all the cases identified are summarized in Table II. Papers reporting neuroendocrine differentiation of the prostate with positive ACTH staining without clinical manifestations of ACTH serum production were excluded (53–58).

Figure 3. Flowchart presenting the successive steps during the selection of studies.

Table II. Case reports of patients with ectopic Cushing disease associated with prostate cancer.

Table II.

Case reports of patients with ectopic Cushing disease associated with prostate cancer.

Year	Authors	Histology of prostate cancer	Disease extent	Clinical manifestations	Laboratory findings	Diagnostic criteria	Treatment	Clinical outcome	(Refs.)
1959	Webster et al	Poorly differentiated	Lung, spleen, liver,	Confusion, lethargy,	Elevated glucose	Elevated glucocorticoid	Estrogen, orchiectomy,	Death <1 week from	(38)
		adenocarcinoma	left kidney, adrenals,	anorexia, muscular	levels (305 mg/dl),	excretion in urine,	insulin, intravenous	Cushing's diagnosis
			pituitary and lumbar	weakness mild	hypokalemic	Hyperglycemia,	potassium chloride
			vertebrae metastases	hypertension	alkalosis (1.8 mEq/l),	glycosuria, adrenal
					glycosuria, elevated	hyperplasia at autopsy,
					glucocorticoid	normal pituitary,
					excretion in urine	elevated urine potassium
						excretion
1965	Wise Jr. et al	Prostatic	Metastatic	Not available	Not available	Not available	Bilateral	Not available	(42)
		adenocarcinoma					adrenalectomy
1968	Hall	Prostatic	Liver metastases	Mental changes	Hypokalemic alkalosis	Elevated glucocorticoid	Orchiectomy and oral	Death at 2 months	(46)
		adenocarcinoma		(hypomania,	(2 mEq/l), elevated	excretion in urine	diethylstilbestrol daily,	after Cushing's
				disorientation),	fasting plasma glucose		oral potassium	onset
				diabetes mellitus,	levels (214 mg/dl),		supplements
				peripheral edema,	glycosuria, diffuse
				hepatomegaly, weight	slowing on EEG
				loss, muscle
				weakness, no
				Cushing's features
1973	Newmark et al	Undifferentiated	Bone, liver, lung	Acute psychosis	Elevated glucose	Elevated plasma ACTH	Orchiectomy, mitotane,	Death on the 12th	(37)
		carcinoma	metastases	(mental changes),	levels (605 mg/dl),	(1,590 pg/ml), high	metyrapone,	hospital day
				bilateral pitting edema	hypokalemic alkalosis	ACTH tumor	spironolactone,
					(2.6 mEq/l),	concentration, no	dexamethasone
					hypernatremia	suppression after
					(156 mEq/l)	high-dose DMZ challenge
1975	Lovern et al	Prostatic	Bone, liver,	Bilateral lower	Elevated glucose	Elevated plasma	Bilateral adrenalectomy,	Death at	(39)
		adenocarcinoma	omentum, spleen,	extremity pitting	levels (576 mg/dl),	cortisol (3,972 nmol/l),	insulin, intravenous	3 months
			gallbladder	edema, muscle	hypertension,	elevated plasma	antibiotics
			metastases,	weakness	glycosuria	ACTH (1,188 pg/ml),
			abdominal lymph			no suppression after
			nodes metastases			low and high-dose
						DMZ challenge,
						elevated corticosteroid
						excretion in urine,
						adrenal hyperplasia
1977	Wenk et al	Poorly	Pelvic lymph nodes,	Generalized weakness,	Hypokalemic alkalosis	Elevated plasma ACTH	Insulin, furosemide,	Death on the 23rd	(11)
		differentiated, small	urinary bladder	Dysuria, mild	(2.9 mEq/l),	(133 pg/ml) and cortisol	antibiotics for UTI	day
		cell (‘oat-cell’)		hypertension, pedal	hypernatremia	(1,434 nmol/l), high
		carcinoma		edema, confusion	(162 mEq/l), diabetes	ACTH tumor
					mellitus,	concentration
					hyperosmolality	(4,010 pg/g tissue), no
					(345 mOm/kg),	suppression after
					elevated plasma	high-dose DMZ challenge
					ACTH and cortisol
1978	Molland	Poorly differentiated	No metastases	Mental changes	Elevated glucose	Elevated plasma cortisol	No treatment	Death at 4 weeks	(41)
		adenocarcinoma of		(hypomania), bilateral	levels (260 mg/dl),	levels (2,759 nmol/l),
		the prostate		lower extremity	glycosuria,	adrenal hyperplasia,
				edema, no Cushing's	hypokalemic alkalosis	Crooke's hyaline changes
				features	(2.4 mEq/l)	of the pituitary
1981	Statham et al	Poorly differentiated	Liver, lung, bone	Mental changes	Hypokalemic alkalosis	Elevated plasma cortisol	Metyrapone 750 mg	Death at 2 months	(45)
		adenocarcinoma of		(‘euphoric behavior’),	(1.7 mEq/l),	levels (>1,377 nmol/l),	four times per day	after Cushing's
		the prostate	metastases	polydipsia, ankle	hypernatremia	elevated plasma ACTH	Prednisolone	onset
				edema	(157 mEq/l), elevated	(1,589 pg/ml), bilateral	15 mg/day,
					plasma glucose levels	adrenal hyperplasia	orchidectomy
1981	Vuitch and	Anaplastic	Liver, bone,	Moon facies, central	Elevated plasma	Elevated plasma cortisol	Estrogen, orchidectomy,	Death at 2 months	(12)
	Mendelsohn	carcinoma of the	retroperitoneal	obesity	cortisol (>1,65×106	(>1,65×106 nmol/l),	radiation	of Cushing's onset
		prostate	lymph node		nmol/l)	bilateral adrenal
			metastases			hyperplasia, no
						suppression after
						high-dose DMZ
						challenge, high ACTH
						tumor staining (10 ng/mg
						tissue), Crooke's hyaline
						changes of the pituitary
1984	Carey et al	Small cell	Liver, lung,	Polyuria, polydipsia,	Diabetes insipidus,	Elevated plasma cortisol	Chemotherapy	Death on the 22nd	(13)
		carcinoma of the	mediastinal lymph	cachexia	deficiency of growth	levels, elevated urine		hospital day
		prostate	node, bone,		hormone and	cortisol excretion, No
			stomach, dura		thyroid-stimulating	suppression after low
			metastases, bone		hormone excretion,	and high-dose DMZ
			marrow invasion		low levels of LH,	challenge, elevated
					FSH, testosterone	plasma ACTH levels,
					(hypogonadotropic	positive tumor staining
					hypogonadism)	for CRH, hyperplasia of
						corticotrophs in anterior
						pituitary
1984	Ghali and	Well-differentiated	Lung, liver, spleen,	Fainting episodes,	Hypokalemic alkalosis	Elevated plasma cortisol	Mitotane	Death at 6 weeks	(43)
	Garcia	adenocarcinoma and	pelvic lymph node,	mental changes	(1.9 mEq/l),	levels (1,511 nmol/l),
		carcinoid of the	bone marrow,	(confusion, loss of	glycosuria,	elevated plasma ACTH
		prostate	adrenal metastases	consciousness),	hypernatremia,	(180 pg/ml), increased
				Hypertension, bilateral	diabetes mellitus	urine corticosteroid
				ankle edema, purpuric		excretion, no suppression
				areas on both hands,		after high-dose DMZ
				no Cushing's signs		challenge, bilateral
						adrenal hyperplasia,
						Crooke's hyaline changes
						of the pituitary, ACTH
						staining of primary tumor
						and metastases
1985	Slater	Primary carcinoid	Locally advanced	Oliguria, hematuria,	Hypokalemic alkalosis	Elevated plasma cortisol	Potassium supplements,	Death at 1 week	(40)
		tumor of the prostate		nocturia, no clinical	(2.2 mEq/l)	levels (1.2×109 nmol/l).	subcutaneous insulin,
				Cushing's signs		elevated plasma ACTH	antibiotics
						levels (340 pg/ml),
						increased urine
						corticosteroid excretion,
						no suppression after
						high-dose DMZ
						challenge, bilateral
						adrenal hyperplasia,
						elevated tumor ACTH
						concentration (20 µg/g)
1988	Fjellestad-	Small-cell	Multiple metastases	Muscle weakness,	Hypokalemia	Elevated plasma cortisol	Ketoconazole	Death at 6 days	(14)
	Paulsen et al	carcinoma of the		abdominal pain,		levels (1,131 nmol/l),
		prostate		weight loss,		elevated plasma ACTH
				hypertension, diabetes		levels (354 pg/ml),
				mellitus		hyperplasia of pituitary
						corticotropic cells, adrenal
						hyperplasia, tumor
						staining for CRH, TSH,
						calcitonin and
						somatostatin
1999	Haukaas et al	Small cell carcinoma	Bone, lung, liver,	Weight gain, leg	Elevated plasma	Elevated plasma ACTH	High-dose estrogen	Death at 2 months	(15)
		and moderately	adrenal metastases	edema	glucose (468 mg/dl),	levels (25 pg/ml),	treatment, insulin,	after treatment
		differentiated			hypokalemia	elevated plasma cortisol	aldosterone antagonist,	initiation
		prostate			(1.9 mEq/l)	levels (>1,500 nmol/l),	diuretics, potassium
		adenocarcinoma				increased urine cortisole
						excretion (573 nmol/24 h),
						elevated ACTH and
						deoxycortisole levels after
						suppression with
						metopiron
2001	Rickman et al	Prostatic	Liver, bone	Mental changes	Hypokalemic alkalosis	Elevated plasma cortisol	Ketoconazole	Discharged on 15th	(16)
		adenocarcinoma	metastases	(confusion), lower-	(2.2 mEq/l), diabetes	levels (3,724 nmol/l),	1,200 mg/d, Intravenous	hospital day-death
				extremity edema,	mellitus	elevated plasma ACTH	potassium replacement,	13 days after
				hypertension, weight		levels (13,87 pg/ml),	spironolactone	discharge
				loss, no Cushing's		elevated serum CRH
				signs		levels (69 pg/dl),
						increased urine cortisol
						excretion (16,276 µg/
						24 h), bilateral adrenal
						hyperplasia, no
						suppression after
						high-dose DMZ
						challenge
2002	Hussein et al	Poorly differentiated	Bone, liver, lymph	Left thigh pain,	Hypokalemic alkalosis	Elevated cortisol levels	Oral ketoconazole	Death at 2.5 months	(44)
		adenocarcinoma of	node metastases	generalized fatigue,	(2.5 mEq/l), elevated	(2,041 nmol/l), elevated	therapy (400 mg tid),	after Cushing onset
		the prostate		bilateral lower	plasma glucose levels	ACTH levels (610 pg/ml),	bilateral orchiectomy,
				extremity edema,	(188 mg/dl)	no suppression after	intravenous potassium
				pigmentation without		high-dose DMZ	supplementation,
				ecchymoses, mild		challenge, increased urine	insulin, nifedipine
				hypertension		cortisol excretion
						(9,715 µg/day), bilateral
						adrenal hyperplasia,
						positive ACTH staining
						of metastasis
2007	Johnson and	Neuroendocrine	Bone, liver	Muscle weakness,	Hypokalemia,	Elevated plasma cortisol	Oral metyrapone	Death five days	(17)
	Canada	carcinoma of the	metastases	moon facies, lower	hypocalcemia,	levels (1,594 nmol/l),	750 mg every 6 h	after ICU admission
		prostate		extremity edema,	hypophosphatemia,	elevated plasma ACTH	initially, intravenous
				hypertension,	hypertension, and	levels (249 pg/ml),	etomidate
				hyperglycemia	hepatic dysfunction	increased urine cortisol	(0.06 mg/kg/h),
						excretion (2,400 µg/day)	intravenous potassium,
							magnesium, calcium
							and phosphate
							replacement,
							chemotherapy with
							cisplatin 30 mg/m2 and
							etoposide 100 mg/m2
2007	Kataoka et al	Moderately	Locally advanced-no	Leg edema, mild	Hyperglycemia,	Elevated serum ACTH	Oral metyrapone	Death after two	(18)
		differentiated	metastases	hypertension	Hypokalemia	levels (181 pg/ml),	(3 g/day), potassium	weeks
		prostatic			(1.9 mEq/l)	elevated serum cortisol	supplements
		adenocarcinoma				levels (184,300 nmol/l),
		with neuroendocrine				increased urine cortisol
		differentiation				excretion (9,890 µg/day)
						and corticosteroids, no
						suppression after low-
						and high-dose DMZ
						challenge, no response to
						CRH testing, bilateral
						adrenal hyperplasia
2007	Nimalasena	Patient 1: Small cell	Locally advanced	Fatigue, leg and arm	Hypokalemia	Elevated serum ACTH	Ketoconazole,	Death at 3.5 months	(19)
	et al	carcinoma of the		oedema	(2.7 mEq/l)	levels (241 pg/ml),	Metyrapone	after Cushing's
		prostate (from de-				elevated serum cortisol		diagnosis
		differentiated				levels (2,370 nmol/l)
		prostatic
		adenocarcinoma)
2007	Nimalasena	Patient 2: Anaplastic	Bone, liver metastases	Muscle weakness,	Hypokalemia	Elevated serum ACTH	Ketoconazole,	Death at 1 month	(19)
	et al	small cell carcinoma		bilateral leg and arm	(1.7 mEq/l)	levels (1,064 pg/ml),	octreotide, flutamide,	after Cushing's
				edema		elevated serum cortisol	chemotherapy with	diagnosis
						levels (2,392 nmol/l)	epirubicin, carboplatin,
							5-fluorouracil
2009	Alwani et al	Small cell carcinoma	Lung, liver, kidney,	Weight gain,	Hypokalemic alkalosis	No suppression after	Mifepristone	Death at 3 weeks	(20)
		of the prostate	spleen, bone,	generalized edema,	(2.7 mmol/l), elevated	DMZ testing, elevated	(800 mg/day), bilateral	after
			peritoneal metastases	hyperpigmentation of	lactate dehydrogenase	serum ACTH levels	adrenalectomy	adrenalectomy
				the skin, no other	(798 U/l)	(39 pg/ml), increased
				Cushing's signs, mild		urinary free cortisol
				hypertensions		excretion, positive ACTH
						immunohistochemical
						staining at primary and
						metastatic tumors
2008	Rajec et al	Small cell	Bone marrow	Mental changes,	Hypernatremia,	Elevated plasma cortisol	Ketoconazole,	Death after surgery	(21)
		carcinoma of the	infiltration, bone, liver,	weakness of legs,	hypokalemic alkalosis,	level, no suppression after	chemotherapy with	for bowel
		prostate	retroperitoneal lymph	fatigue, mild	hyperglycemia	low and high-dose DMZ	cisplatin/etoposide	perforation
			node metastases	hypertension
2008	Rajec et al	Poorly differentiated	Bone, liver	Progressive fatigue,	Hypernatremia,	Elevated plasma cortisol	Chemotherapy with	Death within two	(21)
		neuroendocrine	metastases, urinary	dyspnea, hematuria,	hypokalemic alkalosis,	levels (1,340 nmol/l)	carboplatin/etoposide	weeks after
		carcinoma	bladder infiltration	peripheral edemas,	hyperglycemia			Cushing's
				mental changes				diagnosis
2010	Alshaikh et al	Small cell carcinoma	Bladder and rectum	Edema of the lower	Hypokalemic alkalosis	Elevated urine cortisol	Ketoconazole 400 mg	Death at 6 months	(22)
		of the prostate	invasion,	limbs, shortness of	(1.7 mEq/l)	excretion (6,214.5 µg/dl),	bid, metyrapone 750 mg	after prostate
			retroperitoneal	breath/orthopnea,		elevated serum ACTH	tid, chemotherapy with	cancer diagnosis
			lymph nodes	generalized		level (3,160 pg/ml),	cisplatin/etoposide
				weakness/proximal		positive tumor staining
				muscle weakness,		for ACTH, no suppression
				abdominal obesity,		after high-dose DMZ
				hypertension, congestive
				heart failure
2010	Lemoinne et al	Prostatic	No metastasis	Depression, severe	Hypokalemia	Elevated plasma	Mifepristone	Death at 11 days)	(49)
		adenocarcinoma		hypertension and		cortisol levels		after ICU admission
				diabetes mellitus		(1,564 nmol/l), increased		(within 1 month
						urine cortisol excretion		after diagnosis
						(20,200 nmol/day),
						elevated serum ACTH
						level (145 pg/ml), no
						suppression after
						low-dose DMZ, normal
						pituitary MRI, bilateral
						adrenal hyperplasia
2011	Ramon et al	Poorly differentiated	Bone metastases,	Bone pain, muscle	Hypokalemic alkalosis	Elevated plasma ACTH	Octreotide 500 mg tid,	Clinical	(23)
		adenocarcinoma of	para-aortic and	weakness, uncontrolled	(2.7 mEq/l), elevated	level (11.9 pg/ml),	ketoconazole 200 mg	improvement after
		the prostate with	para-iliac lymph	hypertension, moon	plasma glucose,	increased urine free	tid, bilateral	adrenalectomy-
		neuroendocrine	nodes	facies, red-purple	hypocalcemia,	cortisol excretion	adrenalectomy	resolution of
		component		striae, multiple	hypophosphatemia,	(30,534 nmol/day), no		Cushing's signs and
				ecchymoses, truncal	reduced calcitriol level	suppression after		symptoms
				obesity, proximal		high-dose DMZ, positive
				muscle atrophy,		tumor ACTH staining
				hypertension
2016	Rueda-Camino	Small cell carcinoma	Liver, bone, pelvic	Mental changes (loss	Hypokalemic alkalosis	Elevated plasma cortisol	Chemotherapy with	Death at 12 months	(24)
	et al	of the prostate	lymph node	of consciousness),	(2.2 mEq/l),	levels (1,489 nmol/l),	cisplatin/etoposide	after the diagnosis
			metastases	pitting pedal edema,	hyperglycemia,	elevated plasma ACTH		of prostate cancer
				hypertension	hypercortisolemia	levels (250 pg/ml),
						increased urine free
						cortisol excretion
						(9,360 µg/day), no
						suppression after low and
						high-dose DMZ, positive
						tumor ACTH staining
2016	Shrosbree et al	Neuroendocrine	Bone, pelvic lymph	Weight loss, mental	Diabetes,	Adrenal hyperplasia,	Metyrapone,	Clinical	(25)
		(small cell)	node, liver, adrenal	changes (delirium),	hypokalaemic alkalosis,	elevated plasma cortisol	chemotherapy with	improvement after
		carcinoma of the	metastases	peripheral edema,	liver dysfunction,	levels (2,050 nmol/l),	carboplatin/etoposide	metyrapone
		prostate		symmetrical proximal	secondary	Increased urine cortisol		initiation-radiologic
				myopathy, multiple	hypogonadism,	excretion (300,441 nmol/		response to
				ecchymoses,	secondary	day), increased plasma		chemotherapy
				hypertension	hypothyroidism	ACTH levels (14 pg/ml),
						no suppression after low
						and high-dose DMZ,
						positive tumor ACTH
						staining, weakly positive
						tumor staining for ACTH
2016	Ramalingam	Neuroendocrine	Bone, lung, spleen,	Skin	Hypokalaemic alkalosis	Elevated plasma cortisol	Spironolactone,	Death at 12 months	(26)
	et al	prostate carcinoma	chest wall, liver,	hyperpigmentation,	(1.9 mEq/l),	levels (1,544 nmol/l),	ketoconazole,	after diagnosis
			pelvic lymph node	hypertension, profound	hyperglycemia	elevated plasma ACTH	chemotherapy with
			metastases	weakness/fatigue	(227 mg/dl)	levels (206 pg/ml),	cisplatin/etoposide
						increased urine cortisol
						excretion (11,786 µg/day)
						Bilateral adrenal
						hyperplasia
2016	Balestrieri	Small cell carcinoma	Locally advanced	Mental confusion,	Hypokalemia	Elevated plasma cortisol	Ketoconazole 400 mg	Death at 3 months	(47)
	et al	of the prostate		muscle weakness,	(2.3 mEq/l)	levels (1,098 nmol/l),	bid, SC Octreotide
				hypertension, diabetes,		elevated plasma ACTH	0.1 mg tid, intravenous
				moon facies, thin arms		levels (155.4 pg/ml), no	potassium,
				and legs		suppression after	spironolactone,
						high-dose DMZ, normal	chemotherapy with
						pituitary MRI, positive	epirubicin and
						tumor staining for ACTH,	carboplatin
						bilateral adrenal
						hyperplasia
2017	Elston et al	Mixed small-cell	Bone, lung, lymph	Generalised edema,	Hypokalaemic	Elevated plasma cortisol	Ketoconazole 1.2 g	Death at 9 months	(27)
		neuroendocrine	node metastases	hypertension, weight	alkalosis (2.3 mEq/l),	levels (>1,655 nmol/l),	daily, metyrapone 6 g	after diagnosis
		carcinoma and		gain, proximal muscle	hyperglycemia	elevated plasma ACTH	daily, spironolactone,
		adenocarcinoma of		weakness, labile mood,		levels (19.6 pg/ml),	potassium
		the prostate		insomnia, multiple		increased urine cortisol	supplements,
				petechiae on the chest,		excretion (36,315 nmol/	chemotherapy with
				thin skin, no other		day), no suppression after	carboplatin and
				Cushing's signs		low and high-dose DMZ,	etoposide
						normal pituitary MRI,
						Weak positive tumor
						staining for ACTH
2018	Kleinig et al	Small cell	Lung, liver, adrenal	Fatigue/proximal	Hypokalemic	Elevated plasma cortisol	Not reported	Death at 9 weeks	(29)
		neuroendocrine	metastases	muscle weakness,	alkalosis,	levels (7,220 nmol/l) No		from sepsis
		carcinoma of the		depression, back pain,	hyperglycemia	suppression after
		prostate		anorexia, weight loss,		low-dose DMZ, increased
				hypertension		urine cortisol excretion
						(14,088 nmol/day),
						elevated plasma ACTH
						levels (23.7 pg/ml)
2019	Murphy et al	Neuroendocrine	Bone,	Polydipsia, polyuria,	Hyperglycemia	Elevated plasma cortisol	Ketoconazole	Death at 1 month	(28)
		prostate carcinoma	retroperitoneal,	lower extremity edema	(508 mg/dl),	levels (2,541 nmol/l),		after diagnosis
			inguinal and pelvic		hypokaliemia	elevated plasma ACTH
			lymph node		(3.1 mEq/l)	levels (1,250 pg/ml),
			metastases			increased urine cortisol
						excretion (3,002 µg/day),
						normal pituitary MRI, no
						suppression after low and
						high-dose DMZ
2019	Klomjit et al	Small cell	Pelvic lymph node	Resistant hypertension,	Hypokalemic alkalosis	Elevated plasma ACTH	Bilateral	Death at 1 month	(30)
		neuroendocrine	metastases	lower extremity edema,	(2.8 mEq/l)	levels (147 pg/ml),	adrenalectomy	after diagnosis
		carcinoma of the		easy bruising,		increased urine cortisol
		prostate		generalized weakness,		excretion, no suppression
				no Cushing's features		after low-dose DMZ,
						normal pituitary MRI
2019	Soundarrajan	Small cell carcinoma	Liver and bone	Lower extremity	Hypokalemic alkalosis	Elevated plasma ACTH	Ketoconazole 200 mg	Admitted to hospice	(31)
	et al	of the prostate	metastases	weakness, Cushing's	(2.9 mEq/l),	levels (241 pg/ml),	twice daily,	facility
				signs (diffuse	hyperglycemia	increased urine cortisol	metyrapone 300 mg
				ecchymoses, central		excretion (5,760 µg/day),	daily, mifepristone,
				obesity with pale		normal pituitary MRI,	300 mg daily and
				abdominal stretch		positive tumor staining for	spironolactone
				marks)		ACTH, low serum	300 mg, chemotherapy
						calcitonin level, Elevated	with carboplatin
						carcinoembryonic antigen	and etoposide
						level
2019	Takeuchi et al	Small cell carcinoma	Liver, bone and	Weight/appetite loss,	Hypokalemia	Elevated plasma ACTH	Metyrapone, potassium	Death at four days	(50)
		of the prostate with	lymph node	lower extremity edema,	(K 1.8 mEq/l),	levels (225.5 pg/ml),	supplements	after transfer to
		component of	metastases	hyperpigmentation,	hyperglycemia,	elevated plasma cortisol		palliative hospital
		prostatic		thinning of the skin,	leukocytosis	levels (1,509 nmol/l),
		adenocarcinoma		limb muscle weakness	(16,300/µl).	increased urine cortisol
						excretion (544.4 µg/day),
						no suppression after
						low-dose and high-dose
						DMZ, negative tumor
						staining for ACTH
2020	Schepers et al	Large cell	Paraortic lymph	Peripheral edema,	Hypokalemic alkalosis	Elevated cortisol in saliva	Spironolactone,	Death within weeks	(32)
		neuroendocrine	nodes and bone	hypertension, muscle	(2.7 mEq/l)	(340 nmol/l), increased	Ketoconazole 400 mg	after diagnosis
		carcinoma of the	metastases	weakness, emotional		urine cortisol excretion	bid
		prostate		lability		(16,000 nmol/day),
						elevated plasma ACTH
						levels (11 pg/ml), elevated
						plasma cortisol levels
						(1.750 nmol/l), no
						suppression after low-dose
						DMZ, normal pituitary
						MRI, bilateral adrenal
						hyperplasia, negative
						tumor staining for ACTH
2020	Atmaca et al	Small cell carcinoma	No metastasis	Hypokalemia, heart	Hypokalemia	Elevated plasma cortisol	Ketoconazole 600 mg/	Death at 1 month	(51)
		of the prostate		failure	(2.37 mEq/l)	levels (1,650 nmol/l),	day	after diagnosis
						increased urine cortisol
						excretion (3,218.5 µg/dl),
						elevated plasma ACTH
						levels (416 pg/ml), no
						suppression after high-
						dose DMZ, normal
						pituitary MRI, positive
						tumor staining for ACTH
2021	Fernandes	Small cell	Liver, bone, lymph	Pelvic pain, rectal	Hypokalemic alkalosis	Elevated plasma cortisol	Metyrapone 250 mg	Death within few	(34)
	et al	neuroendocrine	node metastases	tenesmus, fatigue,	(2.1 mEq/l)	levels (160 nmol/l),	daily, potassium	days
		carcinoma of the		uncontrolled		increased urine cortisol	supplements
		prostate		hypertension, no		excretion (12,333 µg/day),
				Cushing's signs		elevated plasma ACTH
						levels (253 pg/ml), no
						suppression after high-
						dose DMZ, normal
						pituitary MRI
2021	Riaza Montes	Small cell carcinoma	Pelvic lymph node	Urinary retention,	Hypokalemic alkalosis	Elevated plasma cortisol	Ketoconazole,	Death at 21 days	(33)
	et al	of the prostate	metastases	arterial hypertension,	(2.4 mEq/l)	levels (7,945 nmol/l),	intravenous etomidate	after admission
				lower extremity edema		elevated plasma ACTH		(~1 month after
						levels (479 pg/ml)		diagnosis)
2021	Bloomer et al	Not reported	Metastatic	Muscle weakness,	Hypokalemia	Elevated plasma ACTH	Metyrapone,	Not reported	(52)
		(possibly prostate		hypertension	(~2.5 mEq/l)	levels (>1,000 pg/ml),	chemotherapy with
		adenocarcinoma)				increased urine cortisol	cisplatin/irinotecan
						excretion (10,000 µg/day)
2022	Zeng Khoo	Prostate	Liver, lymph node	Lower extremity	Hypokalemic alkalosis	Elevated plasma cortisol	Ketoconazole 400 mg	Death at 3 months	(35)
		adenocarcinoma	and bone metastases	edema, proximal	(2.5 mEq/l)	levels (1,229nmol/l),	bid, intravenous	after diagnosis
				muscle weakness, no		normal plasma ACTH	octreotide 100 mcg tid,
				Cushing's signs		levels (57.4pg/ml),	Spironolactone 25 mg
						increased urine cortisol	once daily,
						excretion (20,475 nmol/	chemotherapy with
						day), no suppression	platinum and etoposide
						after low and high-dose
						DMZ, normal pituitary
						MRI, positive tumor
						staining for ACTH,
						suppressed plasma
						renin/aldosterone
						activity, central
						hypothyroidism
2022	Hassan et al	Prostate	Liver and bone	Cushingoid features	Not available	Not available	Not available	Not available	(36)
		adenocarcinoma	metastases
		with neuroendocrine
		differentiation

[i] EEG, electroencephalogram; ACTH, adrenocorticotropic hormone; DMZ, dexamethasone; UTI, urinary tract infection; CRH, corticotropin-releasing hormone; TSH, thyroid stimulating hormone; ICU, intensive care unit.