ECTOPIC ADRENOCORTICOTROPIC HORMONE SYNDROME DUE TO METASTATIC PROSTATE CANCER WITH NEUROENDOCRINE DIFFERENTIATION

Abstract

Objective:

Neuroendocrine differentiation of prostate cancer can result in ectopic adrenocorticotropic hormone (ACTH) secretion (EAS) and Cushing syndrome. The aim of this report is to highlight this unusual mechanism of hypercortisolism and its management.

Methods:

We report a 73-year-old patient with a history of prostate adenocarcinoma who presented with severe weakness, hyperglycemia, and hypokalemia caused by EAS.

Results:

Diagnostic workup showed elevated 24-hour urine cortisol and ACTH levels consistent with EAS. Fluorodeoxyglucose positron emission tomography-computed tomography revealed a hypermetabolic mass in the prostate and metastatic lesions to the liver and bones. Liver biopsy was consistent with small cell carcinoma with positive immunostaining for ACTH. Pleural fluid analysis was consistent with high-grade neuroendocrine carcinoma. The patient underwent chemotherapy with carboplatin and etoposide. Hypercortisolism was treated with ketoconazole, metyrapone, mifepristone, and spironolactone. He suffered complications including opportunistic infections, deep venous thrombosis, and delirium. Given his poor prognosis and clinical decline, the patient opted for comfort measures only in a hospice facility.

Conclusion:

Treatment-related neuroendocrine differentiation of prostate cancer is an emerging entity that may be associated with paraneoplastic syndromes including EAS.

INTRODUCTION

Ectopic adrenocorticotropic (ACTH) syndrome (EAS) accounts for 10 to 20% of all cases of Cushing syndrome (CS) (1). Typical features include muscle weakness, increased body weight, hypertension, hyperglycemia, hypokalemia, infections, bruising, osteoporosis, and psychiatric disorders. When EAS develops rapidly, patients seldom present with the classical stigmata of CS (1). Pulmonary neuroendocrine (carcinoid) tumors and small cell lung cancers are most commonly associated with EAS, but medullary thyroid cancer, pheochromocytomas, thymomas, breast, and prostate cancer have also been found to be sources of paraneoplastic ectopic ACTH secretion (2,3).

While rare, prostate cancer variants including adenocarcinomas, small cell, and neuroendocrine prostate carcinomas can cause paraneoplastic syndromes and ectopic ACTH secretion (4–12). Recent studies suggest that the neuroendocrine differentiation of prostate cancer is associated with radiation and androgen deprivation therapy and correlates with poor prognosis (13). Here, we present a male with a history of prostate adenocarcinoma who subsequently developed metastatic, high-grade neuroendocrine carcinoma and EAS.

CASE REPORT

A 73-year-old, Caucasian male with a history of prostate adenocarcinoma, hypertension, and recently diagnosed type 2 diabetes mellitus was transferred to our institution for management of EAS. Nine weeks prior, he was admitted to a local hospital for pneumonia and lower extremity weakness. There, he was noted to have refractory hypokalemic metabolic alkalosis and hyperglycemia. Workup showed markedly elevated 24-hour urine cortisol of 5,760 μg (reference range is 58 to 403 μg), morning serum cortisol of 82 μg/dL (reference range is 5 to 25 μg/dL), and ACTH level of 241 pg/mL (reference range is 6 to 50 pg/mL). Prostate-specific antigen was elevated at 6.5 ng/mL (reference range is 0 to 4.0 ng/mL). Pituitary magnetic resonance imaging was normal. Abdominal computed tomography (CT) showed a 1.6-cm adrenal adenoma (unenhanced attenuation of 23 Hounsfield units, 74% absolute washout) and multiple liver lesions concerning for metastatic carcinoma. Liver biopsy was read as small cell carcinoma. He was started on ketoconazole and transferred to our institution for further management.

On admission to our institution, he reported progressive lower extremity weakness. He had a history of smoking 40 packs of cigarettes per year. Physical exam was notable for a blood pressure of 122/52 mm Hg on anti-hypertensive medication, diffuse ecchymoses, central obesity with pale abdominal stretch marks, and proximal upper and lower extremity weakness. Laboratory findings were remarkable for hypokalemia (potassium of 2.9 mEq/L), metabolic alkalosis (bicarbonate of 32 mEq/L), and elevated liver enzymes (aspartate transaminase of 115 U/L [reference range is 0 to 39 U/L], alanine transaminase of 246 U/L [reference range is 0 to 52 U/L], total bilirubin of 2.5 mg/dL [reference range is 0 to 1.0 mg/dL], alkaline phosphatase of 110 U/L [reference range is 34 to 104 U/L]). Hemoglobin A1c was 8.2%.

A chest CT scan showed a 1.9-cm, soft tissue lesion adjacent to the left first rib, scattered bilateral sub-centimeter pulmonary nodules, and a left thyroid nodule. Fluorodeoxyglucose (FDG) positron emission tomography coupled with CT demonstrated a hypermetabolic, 4.0 × 2.5-cm, prostatic mass as well as lesions in the liver and ribs (Fig. 1).

Fig. 1.

Fluorodeoxyglucose positron emission tomography coupled with computed tomography images demonstrating hypermetabolic regions in the prostate, liver, mediastinal, peripancreatic, and retroperitoneal lymph nodes consistent with widespread metastatic disease.

Serum calcitonin level was low at <2 pg/mL (reference range is <11 pg/mL) and the carcinoembryonic antigen level was elevated at 3,077 ng/dL (reference range is 0 to 3 ng/dL). The liver biopsy sample was reviewed at our institution and read as small cell carcinoma. Immunostaining was positive for ACTH and CD56, a neuroendocrine marker, but negative for calcitonin and prostate markers including prostate-specific antigen, ERG, NKX3.1, and p504s (Fig. 2). During hospitalization, the patient developed pleural effusions; pleural fluid cytology revealed high-grade neuroendocrine carcinoma with immunostaining positive for chromogranin and synaptophysin (Fig. 3).

Fig. 2.

Hematoxylin and eosin staining at ×100 (A) and ×400 (B) show clusters of oval cells with minimal cytoplasm, stippled chromatin, nuclear molding, and frequent mitotic figures. Immunohistochemistry at ×200 positive for CD56 (C) and adrenocorticotropic hormone (D).

Fig. 3.

Cytology and immunohistochemistry of the pleural fluid at ×200. Hematoxylin and eosin staining (A). Immunostaining shows diffuse positivity for chromogranin (B) and synaptophysin (C).

Eight years prior, the patient underwent radiation and androgen deprivation therapy for prostate adenocarcinoma. The hypermetabolic prostate mass on positron emission tomography coupled with CT scanning and pathology findings were suggestive of treatment-related neuroendocrine differentiation of prostate cancer. He was thus started on reduced doses of chemotherapy with carboplatin and etoposide.

Hypercortisolism was initially treated with ketoconazole at 200 mg twice daily but later discontinued due to rising liver enzymes. Instead, metyrapone at 250 mg every 6 hours was started with subsequent decline in morning serum cortisol levels (from 333.7 to 31.6 μg/dL in 5 days), insulin dose requirements, and liver enzymes (Table 1). Due to lack of insurance coverage of this medication, metyrapone was substituted with mifepristone at 300 mg daily. Potassium levels improved with addition of spironolactone at 300 mg to counteract worsening hypokalemia from mifepristone. Hypertension was well controlled on amlodipine and spironolactone. Glucose levels also improved, requiring minimal amounts of insulin.

Table 1.

Laboratory Tests During Hospitalization with Varying Treatments

	Day 1	Day 5	Day 7	Day 9	Day 11	Day 15	Day 19	Day 22	Day 26
	Ketoconazole (200 mg twice daily)	Metyrapone (250 mg every 6 hours)					Mifepristone (300 mg daily)
Serum cortisol (RR: 5–25 μg/dL)	71 (2:55 am)	334 (7:58 am)	92 (5:41 pm)	42a (10:44 am)	32 (7:48 am)	–	–	–	–
ACTH (RR: 6–50 pg/mL)	254 (3:53 am)	442 (8:00 am)	409 (1:54 pm)	298 (10:44 am)	–	–	–	–	–
ALT/AST (RR: 0-52/0-39 U/L)	180/98	300/107	214/86	–	96/57	106/59	38/16	27/19	22/19
Fasting glucose/maximum glucose (mg/dL)	130/273	125/225	93/171	207/309	184/258	212/254	190/269	138/195	61/200
Total insulin dose (U)	6	30	23	29	46	17	17	10	2
Corticosteroid treatment	–	DXMb	HCc	HCc	HCc	HCd	–	–	–
Potassiume (mEq/L)	4.3	4.0	3.9	4.8	4.1	3.7	3.6	2.4f	3.4
Morning blood pressureg (mm Hg)	122/52	125/64	147/69	105/50	128/47	135/68	112/55	179/91	125/51

Abbreviations: ACTH = adrenocorticotropic hormone; ALT = alanine transaminase; AST = aspartate transaminase; DXM = dexamethasone; HC = hydrocortisone; RR = reference range.

^aReceived hydrocortisone before blood was drawn;

^b20 mg given with etoposide and carboplatin therapy;

^chydrocortisone at 20 mg in morning and 10 mg in evening;

^dhydrocortisone at 40 mg in morning and 20 mg in evening;

^epotassium chloride supplementation;

^fspironolactone dose increased to 300 mg daily and potassium chloride to 80 mg daily;

^gon antihypertensive medication.

The clinical course was complicated by thrombocytopenia, extravasation from port sites, neutropenic fevers, numerous infections, and lower extremity deep vein thrombi. To prevent adrenal crisis during periods of active infection, he received stress doses of steroids. The patient's mental status worsened as he developed delirium and was unable to participate in meaningful conversations. Given significant clinical decline, the patient's family, in keeping with the patient's prior wishes, opted to pursue comfort measures only in a hospice facility.

DISCUSSION

We report a case of hypercortisolemia due to EAS secondary to metastatic neuroendocrine carcinoma thought to be of prostatic origin. The patient had features of hypercortisolism including hypokalemic alkalosis, which is more commonly seen in EAS compared to other causes of CS. While cortisol binds the mineralocorticoid receptor with similar affinity as aldosterone, renal 11β-hydroxysteroid dehydrogenase type 2 converts cortisol to cortisone, which does not bind the mineralocorticoid receptor. In instances of severe hypercortisolemia, saturation of 11β-hydroxysteroid dehydrogenase type 2 allows cortisol to inappropriately gain access to the miner-alocorticoid receptor, thereby inducing hypertension and hypokalemia (14).

The patient's history of prostate cancer, an FDG-avid mass, and pathology results raised suspicion for neuroendocrine transformation of the previous adenocarcinoma. This diagnosis was favored over small cell lung cancer since the lung nodules noted on CT were not FDG avid, whereas the prostate mass was intensely hypermetabolic. Prostate biopsy was not obtained due to the patient's poor clinical status; thus prostatic origin of the neuroendocrine tumor could not be formally confirmed. Immunostaining of the liver specimen was negative for PSA, which is consistent with prior reports that neuroendocrine prostatic carcinomas are often negative for this marker (15).

Small cell prostate carcinoma (SCPC) and prostate adenocarcinoma have a common clonal origin; in fact, 40 to 50% of men with SCPC also have a history of prostatic adenocarcinoma (12). Less than 30 cases of SCPC associated with CS have previously been reported and were summarized by Elston et al (10) in 2017. Since then, Murphy et al (11) described an additional case of a 63-year-old male with EAS with a history of prostate adenocarcinoma, who was treated with radiation, androgen deprivation therapy, and later developed metastatic disease with neuroendocrine prostate cancer verified by biopsy.

As in the case described here, there is emerging evidence for a distinct entity of treatment-related neuroendocrine prostate cancer, which refers to acquired neuroendocrine differentiation secondary to radiation, androgen-deprivation, and chemotherapy causing EAS. One study suggests radiation therapy can result in altered transcription of chromogranin A, a neuroendocrine tumor marker, in part through activation of the protein kinase A pathway and phosphorylation of the cAMP response element binding protein in prostate cancer cells (13). Further, long-term androgen deprivation and chemotherapy are associated with an increased risk for neuroendocrine differentiation, though the mechanism remains unclear (16). Not only do neuroendocrine-like cells release peptide hormones, they also lack androgen receptors and escape apoptosis; this confers resistance to available therapies and disease progression (17).

Definitive treatment with resection of the tumor producing ectopic ACTH is preferred; however, in cases of metastatic or occult disease where surgery may not be appropriate, bilateral adrenalectomy or medical therapy can be pursued. Steroidogenesis inhibitors, ketoconazole, metyrapone, the adrenolytic agent mitotane, or the glucocorticoid receptor antagonist mifepristone may be used. Intravenous etomidate can be used in critically ill patients and in those unable to tolerate oral medications (18,19). Treatment with these agents can result in hypoadrenalism and stress-doses of steroids may be necessary to prevent adrenal crisis.

CONCLUSION

In summary, this patient illustrates the diagnostic challenges and complications that arise from EAS and highlights that neuroendocrine prostate cancer, which tends to be refractory to further therapy and associated with a poor prognosis, is a rare but emerging cause of paraneoplastic ACTH secretion.

Abbreviations:

ACTH

adrenocorticotropic hormone

CS

Cushing syndrome

CT

computed tomography

EAS

ectopic adrenocorticotrophic hormone syndrome

FDG

fluorodeoxyglucose

SCPC

small cell prostate carcinoma