Peptide Receptor Radionuclide Therapy–Induced Hypercortisolemic Crisis in Ectopic Cushing Syndrome

Abstract

A woman in her fourth decade of life with metastatic ectopic Cushing syndrome due to a thymic neuroendocrine tumor developed an acute adrenocorticotropin (ACTH)-mediated hypercortisolemic crisis 5 days after initiating lutetium-177-labeled DOTA-[Tyr³]-octreotate (¹⁷⁷Lu-DOTATATE) peptide receptor radionuclide therapy (PRRT). She presented with hypertension, rapid weight gain (8 kg in a week), psychosis, and biochemical evidence of severe hypercortisolism: serum cortisol: 141 µg/dL (SI: 3889.7 nmol/L) (reference range, 5-25 µg/dL [SI: 137.9-689.7 nmol/L]), plasma ACTH greater than 2000 pg/mL (SI >440.4 pmol/L) (reference range, 10-60 pg/mL [SI: 2.2-13.3 pmol/L]), potassium: 3.4 mEq/L (reference range, 3.5-5.0 mEq/L). Low-dose intravenous etomidate (0.02 mg/kg/h) was administered as a bridge to bilateral adrenalectomy. On etomidate infusion, she developed clinical evidence of adrenal insufficiency (hypotension) despite persistently high cortisol levels (25 µg/dL [SI: 689.7 nmol/L]) on chemiluminescence assay due to steroid precursor accumulation and assay interference, necessitating liquid chromatography–tandem mass spectrometry (LC-MS/MS) analysis for accurate diagnosis. Post adrenalectomy, the patient tolerated subsequent PRRT cycles. This case highlights PRRT-induced ACTH-mediated hypercortisolemic crisis treated with etomidate infusion for acute cortisol control and the need for LC-MS/MS for accurate biochemical monitoring.

Introduction

Ectopic Cushing syndrome (ECS) is a form of adrenocorticotropin (ACTH)-dependent endogenous hypercortisolism caused by neuroendocrine tumors (NETs), and it constitutes 12% to 17% of cases of Cushing syndrome [1]. This condition usually presents with moderate to severe hypercortisolemia that demands early localization and surgical excision to prevent morbidity and mortality [2]. Peptide receptor radionuclide therapy (PRRT) with lutetium-177 (¹⁷⁷Lu)-labeled somatostatin analogues is a targeted treatment for advanced (inoperable or metastatic) somatostatin receptor (SSTR)-expressing NETs, with demonstrated efficacy in tumor control and symptomatic relief [3, 4].

Herein, we describe a case of an ECS due to metastatic NET that developed an acute exacerbation of hypercortisolemia post PRRT and posed substantial therapeutic and monitoring challenges. Management of a hypercortisolemic crisis requires the use of rapidly acting cortisol-lowering agents such as etomidate, which inhibits steroidogenesis at multiple enzymatic levels (11β-hydroxylase, aldosterone synthase, and side-chain cleavage enzyme) with a predominant effect on 11β-hydroxylase (CYP11B1) [5]. However, cautious use of etomidate is advised due to the need for continuous intravenous infusion and its inherent potential to cause sedation, necessitating admission to an intensive care unit.

Case Presentation

A woman in her fourth decade of life presented with cushingoid features, hyperpigmentation, and new-onset hyperglycemia. Hormonal evaluation confirmed endogenous ACTH-dependent Cushing syndrome (Table 1). A contrast-enhanced computed tomography (CECT) of the thorax demonstrated a thymic lesion measuring 2.9 × 2.4 cm (Fig. 1A). Gallium-68-labeled DOTA-[Tyr³]-octreotate (⁶⁸Ga-DOTATATE) positron emission tomography-computed tomography (PET-CT) showed SSTR expression in the lesion (maximum standardized uptake value 8.0), with no evidence of local lymph node or distant metastases, consistent with ECS due to thymic NET, cT1aN0M0 (stage I, as per the American Joint Committee on Cancer [AJCC] version 9) [6] (Fig. 1B). There was no history of any multiple endocrine neoplasia type 1–related tumors in first- or second-degree relatives. The patient then underwent video-assisted thoracoscopic surgery with resection of the thymic NET and regional lymphadenectomy. Histopathology confirmed a well-differentiated typical thymic carcinoid tumor with no necrosis, and occasional mitosis (<2/2 mm²), suggesting a World Health Organization grade 1 NET. It involved surgical margins, and metastases were found in all 5 resected prevascular lymph nodes. On immunohistochemistry, tumor cells were positive for synaptophysin and chromogranin, and the Mib-1 index (Ki-67) was 0% to 1%. The pathological stage of the tumor was pT1aN1M0 (stage IVA, AJCC version 9). Postoperatively, serum cortisol and ACTH levels decreased significantly (see Table 1), and the 1-mg overnight dexamethasone suppression test (ONDST) cortisol normalized to 1.17 μg/dL (SI: 32.3 nmol/L) (reference range, <1.8 μg/dL [SI: <50 nmol/L]) 6 months later. Three years later, the patient presented with clinical and biochemical recurrence of Cushing syndrome. A CECT thorax and ⁶⁸Ga-DOTATATE PET-CT showed multiple SSTR-expressing lesions involving the pleura, pericardium, and paratracheal lymph nodes, consistent with metastatic NET (Fig. 1C and 1D). A biopsy from the pleura-based metastatic deposits showed a grade 1 well-differentiated NET. Mitosis or necrosis was not seen. Mib-1 index (Ki-67) was 8% to 10% (increased from 1%-2% at baseline). She was initiated on PRRT with ¹⁷⁷Lu-DOTATATE, receiving a dose of 164 mCi during the first treatment cycle. Five days post PRRT, she developed exertional breathlessness, rapid weight gain (8 kg), pedal edema, insomnia, excessive irritability, and hypertension (blood pressure, 150/100 mm Hg).

Table 1.

Hormonal investigations at baseline, post surgery, at recurrence, and post first peptide receptor radionuclide therapy cycle in our patient with ectopic Cushing syndrome

	Reference range	Baseline	Post surgery	Recurrence	Post 1st PRRT cycle
Cortisol, serum	5-25 µg/dL (138-690 nmol/L)	>60 µg/dL (>1655.4 nmol/L)	17.9 µg/dL (493.0 nmol/L)	>60.0 µg/dL (>1655.4 nmol/L)	141.0 µg/dL (3889.7 nmol/L)
ACTH, plasma	10-60 pg/mL (2.2-13.3 pmol/L)	174.8 pg/mL (38.5 pmol/L)	43.1 pg/mL (9.5 pmol/L)	143.0 pg/mL (31.5 pmol/L)	>2000 pg/mL (>440.4 pmol/L)
ONDST cortisol, serum	<1.8 µg/dL (<50 nmol/L)	39 µg/dL (1076.0 nmol/L)	1.17 µg/dL (32.3 nmol/L)	2.5 µg/dL (69.0 nmol/L)	ND
LDDST cortisol, serum	<1.8 µg/dL (<50 nmol/L)	58.65 µg/dL (1618.0 nmol/L)	ND	3.75 µg/dL (103.5 nmol/L)	ND

Values in parentheses are International System of Units (SI).

Abbreviations: ACTH, adrenocorticotropin; LDDST, low-dose dexamethasone suppression test; ND, not detected; ONDST, overnight dexamethasone suppression test; PRRT, peptide receptor radionuclide therapy.

Figure 1.

A and C, Axial contrast-enhanced computed tomography (CECT) and B and D, ⁶⁸Ga-DOTATATE PET-CT scans of our patient with ectopic Cushing syndrome demonstrating lesions of thymic neuroendocrine tumor (NET). A, CECT showed an enhancing mediastinal thymic mass (white arrow). B, DOTATATE PET-CT image showed intense somatostatin receptor (SSTR) expression in the thymic mass. C, Multiple pleura-based nodules visible on CECT (white arrows), suggestive of metastatic disease (detected at recurrence). D, SSTR-expressing pulmonary nodules, indicative of metastases from NET.

Diagnostic Assessment

Investigations suggested an acute hypercortisolemic crisis, which included serum cortisol: 141 µg/dL (SI: 3889.7 nmol/L) (reference range, 5-25 µg/dL [SI: 137.9-689.7 nmol/L]), plasma ACTH greater than 2000 pg/mL (SI: >440.4 pmol/L) (reference range, 10-60 pg/mL [SI: 2.2-13.3 pmol/L]), and potassium: 3.4 mEq/L (reference range, 3.5-5.0 mEq/L).

Treatment

The patient was scheduled for bilateral adrenalectomy and was initiated on low-dose intravenous etomidate infusion (0.02 mg/kg/h) as a bridge therapy for cortisol control in a nonintensive care setting. Hypertension was managed with spironolactone 100 mg per day. Serum cortisol and electrolytes were monitored daily, and potassium was supplemented as needed. By day 3 of the etomidate infusion, there was an improvement in clinical and biochemical parameters (Fig. 2); cortisol decreased to 31.2 μg/dL (SI: 860.7 nmol/L), measured by the Siemens Advia Centaur XP chemiluminescence assay (CLIA). On day 5 of etomidate infusion, she developed signs of cortisol insufficiency, which included anorexia, vomiting, and hypotension (90/60 mm Hg). Etomidate was discontinued, and intravenous hydrocortisone was administered, given the clinical suspicion of adrenal insufficiency. Serum cortisol measured by CLIA before hydrocortisone administration was falsely high at 25 µg/dL (SI: 689.7 nmol/L), and reanalysis of the same blood sample using liquid chromatography–tandem mass spectrometry (LC-MS/MS) confirmed an actual cortisol level of 6.84 µg/dL (SI: 188.7 nmol/L), with elevated 11-deoxycorticosterone: 4160.6 ng/dL (SI: 125.9 nmol/L) (reference range, 0-16 ng/dL [SI: 0-0.48 nmol/L]), 11-deoxycortisol: 27.6 µg/dL (SI: 796.54 nmol/L) (reference range, 0-1 µg/dL [SI: 0-28.86 nmol/L]), and 17-hydroxyprogesterone: 4 ng/mL (SI: 1.2 nmol/L) (reference range, 0.2-2.2 ng/mL [SI: 0.06-0.66 nmol/L]), consistent with 11β-hydroxylase inhibition by etomidate. Hypercortisolism recurred 2 days later, with laboratory evaluation demonstrating a cortisol concentration exceeding 75 µg/dL (SI: >2069 nmol/L) as measured by CLIA. This necessitated the resumption of low-dose etomidate infusion at 0.02 mg/kg/hour. The patient then underwent bilateral adrenalectomy, with excellent postoperative recovery.

Figure 2.

Cortisol and adrenocorticotropin (ACTH) levels post first cycle of peptide receptor radionuclide therapy (PRRT). The panel below the graph shows time points for etomidate infusion and adrenalectomy. POD5, postoperative day 5.

Outcome and Follow-up

Bilateral adrenalectomy was followed by regression of manifestations of Cushing syndrome. The patient tolerated 2 further cycles of PRRT well with no adverse events (acute kidney injury or bone marrow suppression) on subsequent follow-up of 3 years. The disease, however, progressed with recurrent pleural effusions, which were treated with pleurodesis and monthly octreotide long-acting release 20 mg for 6 months, followed by 1 cycle of capecitabine-temozolomide chemotherapy. ACTH levels remained elevated post adrenalectomy: 382 pg/mL (SI: 84.1 pmol/L) and 794 pg/mL (SI: 174.9 pmol/L), 5 months and 20 months after adrenalectomy, respectively. The patient remains alive 6 years after her diagnosis, albeit with a substantial disease burden, and is planned for further chemotherapy cycles.

Discussion

To the best of our knowledge, we report the first case of ACTH-mediated hypercortisolemic crisis following PRRT in metastatic ECS and describe the challenges in managing and monitoring with etomidate infusion in a nonintensive care setting.

We used PRRT as second-line therapy in our case, considering the good response rates and tolerability observed with targeted PRRT in other NETs at our institute. Pusceddu et al [7] stated that treatment with PRRT in patients with entero-pancreatic NETs was associated with significantly improved progression-free survival compared with chemotherapy (2.2 vs 0.6 years; hazard ratio, 0.37; P < .001). PRRT has been associated with risks such as acute kidney injury and myelosuppression [3]. In our patient, the initiation of PRRT was followed by a rapid and severe ACTH-mediated hypercortisolemic crisis, with highly elevated cortisol (increased from 60 µg/dL [SI: 1655.4 nmol/L] to 141 µg/dL [SI: 3889.7 nmol/L]) and ACTH levels (increased from 143.0 pg/mL [SI: 31.5 pmol/L] to >2000 pg/mL [SI: >440.4 pmol/L]). The pathophysiology of acute ACTH-mediated hypercortisolemic crisis likely parallels that of carcinoid crisis occurring after ¹⁷⁷Lu-DOTATATE PRRT, mediated by a sudden surge of more than 40 hormones (mainly serotonin, histamine, and catecholamines) resulting from massive tumor lysis [8]. PRRT-induced lysis of ACTH-secreting neuroendocrine cells in our case resulted in a massive release of ACTH that caused adrenal overproduction of cortisol, culminating in a severe hypercortisolemic crisis. Higher tumor burden and the presence of metastases have been described as risk factors for developing carcinoid crisis [8]. These factors presumably played a role in our case. The crisis was managed with a low-dose intravenous etomidate infusion. Although metyrapone and osilodrostat are effective and rapidly acting oral cortisol-lowering agents, these could not be used due to their unavailability in our setup in India. Etomidate infusion was considered based on our institute's prior experience using it to manage severe hypercortisolemia in patients with Cushing disease.

Boehm et al [4] described a series of 7 patients with ECS due to metastatic gastro-entero-pancreatic neuroendocrine neoplasms (GEPNEN) who were treated with PRRT. Five out of these 7 patients had a flare of Cushing within 1 week of the first cycle of PRRT. None of the patients had documented ACTH levels during the flare, except one whose baseline ACTH levels were 597.6 pg/mL (SI: 131.6 pmol/L) before PRRT, and maximum levels post PRRT were 1596.6 pg/mL (SI: 351.6 pmol/L), which increased to 1316.9 pg/mL (SI: 290 pmol/L) 3 months later due to disease progression. Four of these patients with a flare of Cushing post PRRT were managed with oral metyrapone, and none received intravenous etomidate [4]. Keizer et al [9] described a series of 6 patients (out of 476 patients) who developed varied hormonal crises post ¹⁷⁷Lu-DOTATATE PRRT that included 3 patients with carcinoid crises, 2 with vasoactive intestinal peptide crises, and 1 with catecholamine crises. Makis et al [10] described 2 patients with catecholamine crisis following PRRT for paragangliomas. Acute complications post PRRT are not limited only to acute hormonal crises but may also include tumor lysis syndrome, as showcased by Huang et al [11].

Etomidate effectively controls acute hypercortisolemia by acting on 11β-hydroxylase [5]. We used a dose of 0.02 mg/kg/hour in our patient, which effectively lowered cortisol levels and resulted in symptomatic improvement. Recent studies indicate that low-dose etomidate infusion (0.02-0.04 mg/kg/h) can control hypercortisolemia and may not necessitate admission to an intensive care unit [12]. It allows for precise dosage titration, enabling maintenance of cortisol levels in the high-normal range and potentially reducing the need for hydrocortisone replacement. After the administration of etomidate, subsequent reanalysis of cortisol revealed discrepancies between CLIA and LC-MS/MS measurements, indicating interference due to the inhibition of cortisol synthesis and build-up of precursor steroid metabolites. Falsely elevated cortisol levels due to cross-reactivity with steroid precursors have been previously described with various CLIA-based assays [13-15], and this finding may be generalized to other CYP11B1 inhibitors, such as metyrapone, as demonstrated by Monaghan et al [16]. Etomidate bridge therapy allowed bilateral adrenalectomy to be performed in our patient. While not implemented in our case, given the risk of PRRT-induced tumor lysis and subsequent sudden hormone release, preemptive medical management may be considered in certain high-risk patients, particularly those with biochemical/clinical evidence of severe hypercortisolemia, high tumor burden, or metastases.

Learning Points

• The potential for hypercortisolemic crises should be considered in patients with ECS who develop florid manifestations of Cushing following PRRT.

• Etomidate effectively controls cortisol levels and provides a bridge to definitive treatment with adrenalectomy, but it requires close monitoring due to its potential to interfere with cortisol measurements by CLIA.

• High clinical suspicion is needed to identify an adrenal crisis in the setting of normal-to-high CLIA-based cortisol levels during etomidate infusion. Blood pressure and potassium levels need frequent monitoring.

• Treatment of an ACTH-secreting NET requires a lifelong multimodality approach, including experts from the fields of endocrinology, medical, radiation, and surgical oncology, endocrine pathology, and nuclear medicine from high-volume centers, considering the rarity of these tumors.

Contributors

R.P. and C.Y. were involved in the patient's diagnosis and clinical management and drafted the initial version of the manuscript. A.L., S.M., M.K., and T.B. supervised the patient's clinical care and provided critical input throughout the case. T.B., M.K., S.M., and A.L. reviewed and revised the manuscript for intellectual content. R.P. was responsible for manuscript submission. All authors reviewed and approved the final version of the manuscript.

Abbreviations

⁶⁸Ga-DOTATATE

gallium-68-labeled DOTA-[Tyr3]-octreotate

¹⁷⁷Lu-DOTATATE

lutetium-177-labeled DOTA-[Tyr3]-octreotate

ACTH

adrenocorticotropin

AJCC

American Joint Committee on Cancer

CECT

contrast-enhanced computed tomography

CLIA

chemiluminescence assay

ECS

ectopic Cushing syndrome

LC-MS/MS

liquid chromatography–tandem mass spectrometry

LDDST

low-dose dexamethasone suppression test

NET

neuroendocrine tumor

ONDST

overnight dexamethasone suppression test

PET-CT

positron emission tomography–computed tomography

PRRT

peptide receptor radionuclide therapy

SSTR

somatostatin receptor

Funding

No public or commercial funding.

Disclosures

The authors have no financial disclosures or conflicts of interest.

Informed Patient Consent for Publication

Signed informed consent obtained directly from the patient.

Data Availability Statement

Data sharing is not applicable to this article as no data sets were generated or analyzed during the current study.