ACTH-secreting metastatic prostate cancer with neuroendocrine differentiation
- 1 Faculty of Medicine, American University of Beirut, Beirut, Lebanon
- 2 Division of Endocrinology, Department of Internal Medicine, American University of Beirut Medical Center, Beirut, Lebanon
- 3 Division of Hematology and Oncology, Department of Internal Medicine, American University of Beirut Medical Center, Beirut, Lebanon
- Correspondence to Professor Arafat Tfayli; at35@aub.edu.lb
Abstract
Cushing’s syndrome (CS) due to ectopic adrenocorticotropic hormone (ACTH) secretion (EAS) can result from a variety of tumours and rarely from those of prostatic origin. We present a male patient in his early 60s with ACTH-secreting metastatic prostate adenocarcinoma with neuroendocrine differentiation (ICD-O code 8574/3) years after prostatectomy and androgen-deprivation therapy, initially presenting with Cushingoid features. After open radical prostatectomy and bilateral orchiectomy for disease recurrence, the patient was found to have metastatic liver and bone lesions highly suggestive of metastatic prostatic cancer. About 10% of cells on liver biopsy expressed ACTH, a finding consistent with EAS as the cause of CS. His stay was complicated with multiple infections and ultimate death. Hence, we report a case of metastatic prostate adenocarcinoma with neuroendocrine differentiation who presented with CS. We also emphasize the importance of adequate and timely treatment.
Background
Cushing’s syndrome (CS) can result from a paraneoplastic syndrome due to ectopic adrenocorticotropic secretion, which accounts for 10%–20% of cases of excess adrenocorticotropic hormone (ACTH).1 Because of the severity and rapid progression, patients with ectopic ACTH secretion (EAS) rarely have the typical Cushingoid phenotype.2 3 In fact, they typically present with severe hypertension, hyperglycemia, hypokalemic metabolic alkalosis, and increased susceptibility to infections, bruises and bone fractures.1 The non-pituitary tumours, which are most commonly associated with ectopic ACTH production, are bronchial carcinoid tumours, small cell lung cancers, medullary thyroid cancers, pheochromocytomas and rarely prostate cancers, among others.4
Prostate cancer is the second most common cancer and the third leading cause of cancer-related death in men worldwide.5 Although rare, prostate cancer can differentiate into neuroendocrine, small cell and adenocarcinomas with ectopic ACTH secretion.6–15 Neuroendocrine differentiation has been documented to be induced by radiotherapy, chemotherapy and androgen-deprivation therapy and has been associated with prostate cancer progression and poor prognosis.16
Case presentation
A male patient, in his early 60s, presented to us 2 years ago. Ten years prior to his presentation, he was treated for prostatic adenocarcinoma with radical prostatectomy. Five years prior to his presentation, he had disease recurrence with bone metastasis. Consequently, the patient underwent bilateral orchiectomy and took 6 cycles of docetaxel with poor response and disease progression. As a result, the patient was started on Enzalutamide 3 years prior to his presentation. The patient also had osteoporosis (treated with denosumab), hypertension, obstructive sleep apnea and chronic hypocalcemia of unclear aetiology, likely due to denosumab administration.
On presentation to our institution, the patient had abdominal distention, facial and bilateral upper and lower limb edema. Physical examination was notable for ascites and severe hypertension of 192/100 mm Hg, as well as the previously mentioned increased abdominal girth, facial puffiness and bilateral pitting edema of the four limbs.
Investigations and differential diagnosis
Laboratory test results on presentation are shown in table 1.
Laboratory results of the patient on presentation
| Reference range | Patient’s results | |
| Calcium | 8.5–10.5 mg/dL | 6.0 |
| Phosphate | 2.7–4.8 mg/dL | 2.7 |
| Parathyroid hormone | 15.0–76.0 pg/mL | 659.0 |
| Vitamin D 25(OH) | Desirable >25 ng/mL | 22.9 |
| 1,25-Dihydroxyvitamin D serum | 19.9–79.3 pg/mL | 118.0 |
| Plasma glucose | 76–110 mg/dL | 151 |
| Serum potassium | 3.5–5.1 mmol/L | 2.5 |
| Urine albumin-to-creatinine ratio | <30 mg/g | 172 |
| Albuminuria | <20 mg/L | 250 |
Management included cessation of enzalutamide, increase in amlodipine dosage to 10 mg (daily) for blood pressure control and initiation of 600 mg of calcium carbonate (Caltrate) and 0.5 mcg of alfacalcidol (One-alpha) (two times per day, each) for hypocalcemia. Abdominal CT scan showed innumerable hypo-enhancing lesions involving all liver segments with peripheral rim enhancement consistent with metastatic lesions (figure 1), as well as a right adrenal nodule. CT scan of the chest done later was negative for any primary malignant features in the lungs and thorax, further confirming the prostatic origin of the metastasis.
Abdominal CT illustrating liver hypo-enhancing lesions with peripheral rim enhancement indicating metastasis.
Liver biopsy and proper immunostaining were done a week after initial presentation. Synaptophysin, thyroid transcription factor-1 (TTF-1) and alpha-methylacyl-CoA racemase (AMACR/P504S) stains were positive, while prostate-specific antigen (PSA) was negative (figure 2A,B). ACTH stain was not done yet. The biopsy findings thus represented high-grade prostate adenocarcinoma with neuroendocrine differentiation (ICD-O code 8574/3), especially when put in the proper context of metastatic prostate cancer to bones. Accordingly, he was scheduled to receive cisplatin-etoposide a week later.
Liver biopsies (A–C) showing positive staining for synaptophysin, thyroid transcription factor-1 and ectopic adrenocorticotropic hormone, respectively.
One day before his scheduled first chemotherapy session, the patient was readmitted for low calcium levels. His hypocalcemia was managed with intravenous calcium, 600 mcg of oral calcium tablets (three times daily) and 0.5 mcg of One-alpha tablets (two times per day). The patient remained hyperglycemic (273 mg/dL) and thrombocytopenic (platelets 75 000; reference range (ref) 1 50 000–400 000), most likely from bone marrow involvement. He also had mildly elevated total bilirubin (1.3 mg/dL; ref 0.0–1.2 mg/dL) and direct bilirubin (0.7 mg/dL; ref 0.0–0.3 mg/dL). Due to elevated bilirubin levels, abdominal ultrasound was done showing no evidence of gallbladder disease, but innumerable liver lesions. He was started on cisplatin-etoposide for his metastatic lesions the day after.
Workup of the right adrenal nodule is shown in table 2.
Workup of the secretory adrenal nodule including that of hypercortisolism
| Test | Day A | Day B | Day C | Day D |
| Cortisol level | 98.00 µg/dL | 105.00 µg/dL | 106.80 µg/dL | 106.00 µg/dL |
| Dexamethasone suppression tests | 1 mg at 23:00 | 2 mg at 23:00 | 2 mg every 6 hours for 48 hours | – |
| ACTH | 1334 pg/mL (ref 11–60) |
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| Cortisol, 24-hour Ur | 4362 µg/24 hours (ref 11–73) |
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| DHEA-S | 2864 ng/mL (ref 517–2950) |
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| Aldosterone, 24-hour Ur | 2.69 µg/24 hours. (ref 1.19–28.1 µg/24 hours) |
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| Serum metanephrines | <0.10 nmol/L (ref <0.37) |
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Letters are used to refer to days, instead of dates/numbers, for the sake of patient deidentification. Days A, B, C and D are each separated by 1 day.
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ACTH, adrenocorticotropic hormone; DHEA-S, dehydroepiandrosterone sulfate.
Baseline cortisol level was measured and found to be 98.00 µg/dL (ref 5.0–25.0 µg/dL). Afterwards, ACTH level was measured and was also found to be as high as 1334 pg/mL (ref 11–60 pg/mL), confirming a diagnosis of ACTH-dependent CS. To investigate the source of ACTH, workup included a normal MRI of the sella which ruled out a pituitary tumour and three consecutive suppression tests which showed lack of suppression. First, dexamethasone suppression test with 1 mg was performed on Day A, and cortisol level was taken the following day at 08:00 (Day B). Second, dexamethasone suppression test with 2 mg was performed on Day B, and cortisol level was taken the day after at 08:00 (Day C). Lastly, dexamethasone 2 mg was given every 6 hours for 48 hours (Day C), and cortisol level was taken the day after at 08:00 (Day D). A significantly high cortisol level was found on 24-hour urine collection: 4362 μg/24 hours (ref 11–73 μg/24 hours). Finally, a normal to high dehydroepiandrosterone sulfate (DHEA-S) level of 2864 ng/mL (ref 517–2950 ng/mL) indicated an ACTH-dependent hypercortisolism (table 2).
See figure 3 for a schematic review of the workup done to establish the cause of the patient’s CS.
Test to establish the cause of Cushing’s syndrome. Figure prepared by Yara Yazbeck, MD, and Vanessa Akiki, MD. HDDST, high-dose dexamethasone suppression test.
Afterwards, the patient was immediately started on Aldactone 25 mg (daily). Nonetheless, treatment with inhibitors of adrenal steroidogenesis (ketoconazole/metyrapone) or mitotane could not be immediately executed as these drugs were not available in the country, due to an economic crisis at that time. Securing treatment from abroad took a week. Two days after the patient finished his chemotherapy session, he complained of left leg swelling, ecchymosis and pain that were suggestive of cellulitis. CT scan of the left lower limb was done to rule out necrotising fasciitis. Although there was no evidence of the latter, CT scan showed an avulsion injury in the calcaneus. On further investigation, the patient was found to have febrile neutropenia with cellulitis and Klebsiella pneumoniae bacteremia. The pathology slide for the liver biopsy was re-examined and ACTH staining was positive in 10% of the cells (figure 2C).
Treatment
For the treatment of the patient’s hypercortisolism, mitotane, ketoconazole or mifepristone was recommended. A delay in the start of the medication was experienced due to unavailability in the country at that time. When made available, oral mitotane 500 mg (three times per day) was started. Table 3 shows electrolyte changes before and after mitotane initiation.
Sodium and potassium levels before and after mitotane initiation
| Reference range | Day X (9 days before mitotane initiation) |
Day Y (11 days after mitotane initiation) |
|
| Sodium | 135–145 mmol/L | 148 | 140 |
| Potassium | 3.5–5.1 mmol/L | 3.3 | 4.0 |
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Letters are used to refer to days, instead of dates/numbers, for the sake of patient deidentification. Days D and X are separated by 5 days.
Outcome and follow-up
The patient had a deteriorating mental status, and a nasogastric tube was inserted. Mitotane could not be crushed. Because he was a poor surgical candidate, bilateral adrenalectomy could not be done. The patient then had multiple infections and eventually passed away.
Discussion
The patient we report in this paper is a case of CS due to ectopic ACTH secretion from metastatic prostatic adenocarcinoma with neuroendocrine differentiation (ICD-O code 8574/3).
It was concluded that our patient’s metastatic hepatic tumour was prostatic in origin, mainly based on biopsy findings including AMACR/P504S and TTF-1 positivity. The AMACR/P504S is a marker used for the immunodetection of prostate adenocarcinoma, with 97% sensitivity and 92% specificity.17 Additionally, TTF-1 was reported to be expressed in metastatic prostate adenocarcinoma after excluding primary lung or thorax malignancy, which we also did using CT scans.18 Furthermore, the primary prostatic origin of the hepatic lesions was inferred from the positive personal history of prostatic adenocarcinoma metastatic to the bones. Immunohistochemistry showing positivity for synaptophysin also favoured a diagnosis of metastatic adenocarcinoma of the prostate with neuroendocrine differentiation (ICD-O code 8574/3).19 The likelihood of this diagnosis was also due to the metastasis and neuroendocrine differentiation of our patient’s tumour after docetaxel12 15 16 and enzalutamide therapy.
Studies have shown variable response to docetaxel in the treatment of prostate cancer, including many patients who do not respond to treatment.20 There is current evidence showing the effect of docetaxel in reducing tumour metastasis, on one hand, and increasing its resistance to treatment, contributing to metastasis, on the other hand.20 Although docetaxel has been shown to trigger neuroendocrine differentiation of prostate cancer, and thus treatment resistance and disease progression, it has also been shown to have a synergistic effect with octreotide in the treatment of castration-resistant prostate cancer with neuroendocrine differentiation and somatostatin receptor scintigraphy.16 21 These variable outcomes of docetaxel treatment can be clinically predicted by chromogranin A (CgA) response.21 Favourable response to docetaxel treatment in castration-resistant prostate cancer is associated with decreasing CgA, while rising CgA may be associated with poor prognosis.21 Nonetheless, CgA was not measured in our patient.
The management of CS due to ectopic ACTH secretion from a neuroendocrine tumour is complex and should focus on two levels: CS and neuroendocrine tumour treatment.22 Ectopic ACTH syndrome is often considered an endocrine emergency due to the excessive hypercortisolism and its consequences.22 Although the most optimal treatment of ACTH-secreting tumours is complete tumour resection, few available options remain when the tumour is metastatic, as is the case in our patient post-radical prostatectomy.22 Aside from symptomatic management, available treatment options include androgen-deprivation therapy or adrenalectomy, when medical treatment fails.22 However, the former has been linked to treatment resistance, disease progression, and poor prognosis, which also might have been the case in our patient.16 This signifies the need for new treatment modalities in the setting of metastatic neuroendocrine tumours, in general, and ACTH-secreting neuroendocrine tumours metastatic from the prostate, in particular. So far, ketoconazole remains the most used agent for the treatment of CS due to EAS, as it both suppresses the response to high cortisol and has antiandrogenic effect.
Learning points
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Cushing’s syndrome (CS) is possible due to metastatic prostate cancer with neuroendocrine differentiation, even years after prostatectomy.
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Ectopic adrenocorticotropic hormone (ACTH) secretion (EAS) should be kept on the differential as an etiology for CS in a patient presenting with Cushingoid features with history of prostate cancer.
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The timely workup for metastasis and EAS in such patients is important.
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New treatment regimens are needed to better manage metastatic prostate cancer, with less induction of neuroendocrine differentiation, currently a well-recognized mechanism of treatment resistance and disease progression.
Ethics statements
Patient consent for publication
Footnotes
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Contributors BH drafted the paper. BH, YY, and VA designed the figures and tables. All authors contributed to patient care and editing the final manuscript.
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Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
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Case reports provide a valuable learning resource for the scientific community and can indicate areas of interest for future research. They should not be used in isolation to guide treatment choices or public health policy.
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Competing interests None declared.
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Provenance and peer review Not commissioned; externally peer reviewed.
- © BMJ Publishing Group Limited 2022. No commercial re-use. See rights and permissions. Published by BMJ.
References
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