Ectopic Adrenocorticotrophic Hormone Syndrome in a 10-Year-Old Girl With a Thymic Neuroendocrine Tumor

Posted on November 29, 2024 by MaryO

Abstract

Background

Thymic neuroendocrine tumor as a cause of Cushing syndrome is extremely rare in children.

Case presentation

We report a case of a 10-year-old girl who presented with typical symptoms and signs of hypercortisolemia, including bone fractures, growth retardation, and kidney stones. The patient was managed with oral ketoconazole, during which she experienced adrenal insufficiency, possibly due to either cyclic adrenocorticotropic hormone (ACTH) secretion or concurrent COVID-19 infection. The patient underwent a diagnostic work-up which indicated the possibility of an ACTH-secreting pituitary neuroendocrine tumor. However, after a transsphenoidal surgery, the diagnosis was not confirmed on histopathological examination. Subsequent bilateral inferior petrosal sinus sampling showed strong indications of the presence of ectopic ACTH syndrome. Detailed rereading of functional imaging studies, including 18F-FDG PET/MRI and 68Ga DOTATOC PET/CT, ultimately identified a small lesion in the thymus. The patient underwent videothoracoscopic thymectomy that confirmed a neuroendocrine tumor with ACTH positivity on histopathological examination.

Conclusion

This case presents some unique challenges related to the diagnosis, management, and treatment of thymic neuroendocrine tumor in a child. We can conclude that ketoconazole treatment was effective in managing hypercortisolemia in our patient. Further, a combination of functional imaging studies can be a useful tool in locating the source of ectopic ACTH secretion. Lastly, in cases of discrepancy in the results of stimulation tests, bilateral inferior petrosal sinus sampling is highly recommended to differentiate between Cushing disease and ectopic ACTH syndrome.

Peer Review reports

Background

In children above seven years of age, the majority of pediatric Cushing syndrome (CS) cases are caused by a pituitary neuroendocrine tumors (PitNET). However, a differential diagnosis of hypercortisolemia in children is often challenging concerning the interpretation of stimulation tests and the fact that up to 50% of PitNET may not be detected on magnetic resonance imaging (MRI) [1]. An ectopic adrenocorticotropic hormone (ACTH) syndrome (EAS) is extremely rare in children. Its diagnosis is often missed or confused with Cushing disease (CD) [2]. Most ACTH-secreting tumors originate from bronchial or thymic neuroendocrine tumors (NETs), or less commonly, from NETs in other locations. To diagnose EAS, specific functional imaging studies are often indicated to elucidate the source of ACTH production.

Pharmacotherapy may be used before surgery to control hypercortisolemia and its symptoms/signs, or in patients in whom the source of hypercortisolism has not been found (e.g., EAS), or surgery failed. Ketoconazole or metyrapone, as adrenal steroidogenesis blockers, were found to be very efficient, although they exhibit side effects [3].

Furthermore, cyclic secretion of ACTH followed by fluctuating plasma cortisol levels is extremely rare in children, including those with EAS [4, 5]. Therefore, in cyclic EAS, the use of steroid inhibitors or acute illness or trauma can be associated with adrenal insufficiency, which can be life-threatening. Here we describe the clinical features, laboratory and radiological investigations, results, management, and clinical outcome of a 10-year-old girl with a thymic NET presenting with ACTH secretion.

Case presentation

A 10-year-old girl was acutely admitted to our university hospital for evaluation of facial edema and macroscopic hematuria in May 2021. A day before admission, she presented to the emergency room for dysuria, pollakiuria, nausea, and pain in her right lower back. Over the past year she had experienced excessive weight gain with increased appetite and growth retardation (Fig. 1). Her height over three years had shifted from the 34th to the 13th centile (Fig. 1). Her parents noticed facial changes, pubic hair development, increased irritability, and moodiness.

Fig. 1

figure 1

Body weight, body height, and body mass index development of the case patient. The black arrow indicates the first presentation, the blue arrow indicates the start of ketoconazole treatment and the yellow arrow indicates the time of thymectomy. Mid-parental height is indicated by the green line

At admission, she was found to have a moon face with a plethora, few acne spots on forehead, as well as facial puffiness. In contrast to slim extremities, an abnormal fat accumulation was observed in the abdomen. Purple striae were present on abdomen and thighs. She did not present with any bruising, proximal myopathy, or edema. On physical examination, she was prepubertal, height was 135 cm (13th centile), and weight was 37 kg (69th centile) with a BMI of 20.4 kg/m2 (90th centile). She developed persistent hypertension. Her past medical history was uneventful except for two fractures of her upper left extremity after minimal trips one and three years ago, both treated with a caste. Apart from hypothyroidism on the maternal side, there was no history of endocrine abnormalities or tumors in the family.

In the emergency room, the patient was started on sulfonamide, pain medication, and intravenous (IV) fluids. Her hypertensive crises were treated orally with angiotensin-converting enzyme inhibitor or with a combination of adrenergic antagonists and serotonin agonists administered IV. Hypokalemia had initially been treated with IV infusion and then with oral potassium supplements. A low serum phosphate concentration required IV management. The initial investigation carried out in the emergency room found hematuria with trace proteinuria. Kidney ultrasound showed a 5 mm stone in her right ureter with a 20 mm hydronephrosis. She did not pass any kidney stones, however, fine white sand urine analysis reported 100% brushite stone.

Hypercortisolemia was confirmed by repeatedly increased 24-hour urinary free cortisol (UFC), (5011.9 nmol/day, normal range 79.0-590.0 nmol/day). Her midnight cortisol levels were elevated (961 nmol/l, normal range 68.2–537 nmol/l). There was no suppression of serum cortisol after 1 mg overnight dexamethasone suppression test (DST) or after low-dose DST (LDDST). An increased morning plasma ACTH (30.9 pmol/l, normal range 1.6–13.9 pmol/) suggested ACTH-dependent hypercortisolemia. There was no evidence of a PitNET on a 1T contrast-enhanced MRI. The high-dose DST (HDDST) did not induce cortisol suppression (cortisol 1112 nmol/l at 23:00, cortisol 1338 nmol/l at 8:00). Apart from the kidney stone, a contrast-enhanced computed tomography (CT) of her neck, chest, and abdomen/pelvis did not detect any lesion. Various tumor markers were negative and the concentration of chromogranin A was also normal.

A corticotropin-releasing hormone (CRH) stimulation test induced an increase in serum cortisol by 32% at 30 min and ACTH concentration by 67% at 15 min (Table 1). A 3T contrast-enhanced MRI scan of the brain identified a 3 × 2 mm lesion in the lateral right side of the pituitary gland (Fig. 2). An investigation of other pituitary hormones was unremarkable. Apart from low serum potassium (minimal level of 2.8 mmol/l; normal range 3.3–4.7 mmol/l) and phosphate (0.94 mmol/l; normal range 1.28–1.82 mmol/l) concentrations, electrolytes were normal. The bone mineral density assessed by whole dual-energy X-ray absorptiometry was normal.

Fig. 2

figure 2

Coronal and sagittal 3T contrast-enhanced brain MRI scans. A suspected 3 × 2 mm lesion in the lateral right side of the pituitary gland (yellow arrows)

The patient was presented at the multidisciplinary tumor board and it was decided that she undergoes transsphenoidal surgery for the pituitary lesion. No PitNET was detected on histopathological examination and no favorable biochemical changes were noted after surgery. After the patient recovered from surgery, subsequent bilateral inferior petrosal sinus sampling (BIPSS) confirmed EAS as the maximum ratio of central to peripheral ACTH concentrations was only 1.7. During the investigation for tumor localization, she was started on ketoconazole treatment (300 mg/day) to alleviate symptoms and signs of hypercortisolism. Treatment with ketoconazole had a beneficial effect on patient health (Fig. 1). There was a weight loss of 2 kg in a month, a disappearance of facial plethora, and a decrease in vigorous appetite. Her liver function tests remained within the normal range.

Table 1 Result of corticotropin-releasing hormone stimulation test

The 24-hour UFC excretion normalized three weeks after ketoconazole initiation. However, six weeks after continuing ketoconazole therapy (400 mg/day), the patient complained of nausea, vomiting, and diarrhea. She was found to have adrenal insufficiency with a low morning serum cortisol of 10.70 nmol/l (normal range 68.2–537 nmol/l) and salivary cortisol concentrations < 1.5 nmol/l (normal range 1.7–29 nmol/l). She was also found to be positive for COVID-19 infection. Ketoconazole treatment was stopped and our patient was educated to take stress steroids in case of persisting or worsening symptoms. Her clinical status gradually improved and steroids were not required.

Meanwhile, whole-body fluorine-18 fluorodeoxyglucose positron emission tomography (18F-FDG PET)/MRI was performed with no obvious hypermetabolic lesion suspicious of a tumor. No obvious accumulation was detected on 68Ga-DOTATOC PET/CT images (Fig. 3). However, a subsequent careful and detailed re-review of the images detected a discrete lesion on 18F-FDG PET/MRI and 68Ga-DOTATOC PET/CT scans in the left anterior mediastinum, in the thymus (Fig. 4).

Fig. 3

figure 3

18F-FDG PET/MRI (A) and 68Ga-DOTATOC (B) PET/CT scans. Whole body MIP reconstructions. Subtle correspondent focal hyperactivity in the left mediastinum (black arrow). The 18F-FDG PET/MRI image courtesy of Prof. Jiri Ferda, MD, PhD, Clinic of the Imaging Methods, University Hospital Plzen, Czech Republic

Fig. 4

figure 4

Axial slices of PET/MRI (A–C) and 68Ga-DOTATOC (D–F) PET/CT scans. Subtle correspondent focal hyperactivity in the left mediastinum (white arrow). No obvious finding on MRI (C) and CT (F) scans. The FDG PET/MRI image courtesy of Prof. Jiri Ferda, MD, PhD, Clinic of the Imaging Methods, University Hospital Plzen, Czech Republic

Three weeks after the episode of adrenal insufficiency and being off ketoconazole treatment, our patient´s pre-surgery laboratory tests showed slightly low morning cortisol 132 nmol/l with surprisingly normal ACTH 2.96 pmol/l (normal range 1.6–13.9 pmol/). Given the upcoming surgery, she was initiated on a maintenance dose of hydrocortisone (15 mg daily = 12.5 mg/m2/day). Further improvement of cushingoid characteristics (improvement of facial plethora and moon face, weight loss) was noticed. Our patient underwent videothoracoscopic surgery, and a hyperplastic thymus of 80 × 70 × 15 mm with a 4 mm nodule was successfully removed. Tumor immunohistochemistry was positive for ACTH, chromogranin A, CD56, and synaptophysin. Histopathological findings were consistent with a well-differentiated NET grade 1. A subsequent genetic screening did not detect any pathogenic variant in the MEN1 gene.

After surgery, hydrocortisone was switched to a stress dose and gradually decreased to a maintenance dose. Antihypertensive medication was stopped and further weight loss was observed after thymectomy. Within a few weeks after the thoracic surgery, the patient entered puberty, her mood improved significantly, and potassium supplements were stopped. Finally, hydrocortisone treatment was stopped ten months after thymectomy.

Discussion and conclusions

The case presented here demonstrates a particularly challenging work-up of the pediatric patient with the diagnosis of CS caused by EAS due to thymic NET. Differentiating CD and EAS can sometimes be difficult, including the use of various laboratory and stimulation tests and their interpretation, as well as proper, often challenging, reading of functional imaging modalities, especially if a discrete lesion is present at an unusual location [1]. When using established criteria for Cushing disease (for the CRH test an increase of cortisol and/or ACTH by ≥ 20% or ≥ 35%, respectively, and a ≥ 50% suppression of cortisol for the HDDST) our patient presented discordant results. The CRH stimulation test induced an increase in cortisol by 32% and ACTH by 67% and the 3T MRI pointed to the right-side pituitary lesion, both to yield false positive results. The HDDST, on the other hand, did not induce cortisol suppression and was against characteristic findings for CD. We did not proceed with desmopressin testing, which also induces an excess ACTH and cortisol response in CD patients and has rarely been used in pediatric patients, except in those with extremely difficult venous access [6]. Recently published articles investigated the reliability of CRH stimulation tests and HDDST and both concluded that the CRH test has greater specificity than HDDST [7, 8]. Elenius et al. suggested optimal response criteria as a ≥ 40% increase of ACTH and/or cortisol (cortisol as the most specific measure of CD) during the CRH test and a ≥ 69% suppression of serum cortisol during HDDST [7]. Using these criteria, the CD would be excluded in our patient. To demonstrate that the proposed thresholds for the test interpretation widely differ, Detomas et al. proposed a ≥ 12% cortisol increase and ≥ 31% ACTH increase during the CRH test to confirm CD [8].

The fact that up to 50% of PitNET may not be detected on MRI [1] and that more than 20% of patients with EAS are reported to have pituitary incidentalomas [9] makes MRI somewhat unreliable in differentiating CD and EAS. However, finally, well-established and generally reliable BIPSS in our patient supported the diagnosis of EAS. Thus, BIPSS is considered a gold standard to differentiate between CD and EAS; however, it can still provide false negative results in cyclic CS if performed in the trough phase [10] or in vascular anomalies or false positive results as in a recent case of orbital EAS [11].

In children, the presence of thymus tissue may be misinterpreted as normal. Among other reports of thymic NET [12], Hanson et al. reported a case of a prepubertal boy in whom a small thymic NET was initially treated as normal thymus tissue on CT [13]. In our case, initially, the lesion was not detected on the 18F-FDG and 68Ga-DOTATOC PET scans. A small thymic NET was visible only after a detailed and careful re-reading of both PET scans. Although somatostatin receptor (SSR) PET imaging may be helpful in identifying ectopic CRH- or ACTH-producing tumors, there are still some limitations [13]. For example, in the study by Wannachalee et al., 68Ga-DOTATATE identified suspected primary lesions causing ECS in 65% of patients with previously occult tumors and was therefore concluded as a sensitive method for primary as well as metastatic tumors [14]. In our patient, the final correct diagnosis was based on the results of both PET scans. This is in full support of the article published by Liu et al. who concluded that 18F-FDG and SSR PET scans are complementary in determining the proper localization of ectopic ACTH production [15]. Additionally, it is worth noting that not all NETs stain positively for ACTH which may present a burden in its identification.

To control hypercortisolemia, both ketoconazole and metyrapone were considered in our patient. Due to the side effects of metyrapone on blood pressure, ketoconazole was started as a preferred option in our pediatric patient. A retrospective multicenter study concluded that ketoconazole treatment is effective with acceptable side effects, with no fatal hepatitis and adrenal insufficiency in 5.4% of patients [3]. During ketoconazole treatment, our patient developed adrenal insufficiency; however, it is impossible to conclude whether this was solely due to ketoconazole treatment or whether an ongoing COVID-19 infection contributed to the adrenal insufficiency or whether this was caused by a phase of lower or no ACTH secretion from the tumor often seen in patients with cyclic ACTH secretion. The patient’s cyclic ACTH secretion is highly probable since her morning cortisol was slightly lower and ACTH was normal, even after being off ketoconazole treatment for 3 weeks.

When retrospectively and carefully reviewing all approaches to the diagnostic and management care of our pediatric patient, it would be essential to proceed to BIPSS before any pituitary surgery, especially when obtaining discrepant results from stimulation tests, as well as detecting a discrete pituitary lesion (≤ 6 mm) as recommended by the current guidelines [16]. This was our first experience using ketoconazole in a young child, and although this treatment was associated with very good outcomes in treating hypercortisolemia, close monitoring, and family education on signs and symptoms of adrenal insufficiency are essential to recognizing adrenal insufficiency promptly in any patient with EAS, especially those presenting also with some other comorbidities or stress, here COVID-19 infection.

In conclusion, the pediatric patient here presenting with EAS caused by thymic NET needs very careful assessment including whether cyclic CS is present, the outline of a good management plan to use all tests appropriately and in the correct sequence, monitoring carefully for any signs or symptoms of adrenal insufficiency, and apply appropriate imaging studies, with experienced radiologists providing accurate readings. Furthermore, ketoconazole treatment was found to be effective in reducing the symptoms and signs of CS in this pediatric patient. Finally, due to the rarity of this disease and the challenging work-up, we suggest that a multidisciplinary team of experienced physicians in CS management is highly recommended.

Data availability

No datasets were generated or analysed during the current study.

Abbreviations

ACTH:
Adrenocorticotrophic hormone
BIPSS:
Bilateral inferior petrosal sinus sampling
CD:
Cushing disease
CRH:
Corticotropin-releasing hormone
CS:
Cushing syndrome
CT:
Computed tomography
DST:
Dexamethasone suppression test
EAS:
Ectopic adrenocorticotropic hormone syndrome
18F-FDG PET:
Fluorine-18 fluorodeoxyglucose positron emission tomography
HDDST:
High-dose dexamethasone suppression test
IV:
Intravenous
LDDST:
Low-dose dexamethasone suppression test
NET:
Neuroendocrine tumor
PitNET:
Pituitary neuroendocrine tumor
UFC:
Urinary free cortisol

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Acknowledgements

The authors thank all the colleagues from the Thomayer University Hospital and Military University Hospital who were involved in the inpatient care of this patient.

Funding

This work was supported by the Charles University research program Cooperatio Pediatrics, Charles University, Third Faculty of Medicine, Prague.

Author information

Authors and Affiliations

  1. Department of Children and Adolescents, Third Faculty of Medicine, Charles University, University Hospital Kralovske Vinohrady, Šrobárova 50, Prague, 100 34, Czech Republic

    Irena Aldhoon-Hainerová

  2. Department of Pediatrics, Thomayer University Hospital, Prague, Czech Republic

    Irena Aldhoon-Hainerová

  3. Department of Medicine, Military University Hospital, Prague, Czech Republic

    Mikuláš Kosák

  4. Third Department of Medicine, First Faculty of Medicine, Charles University, Prague, Czech Republic

    Michal Kršek

  5. Institute of Nuclear Medicine, First Faculty of Medicine, Charles University, General University Hospital, Prague, Czech Republic

    David Zogala

  6. Developmental Endocrinology, Metabolism, Genetics and Endocrine Oncology Affinity Group, Eunice Kennedy Shriver NICHD, NIH, Bethesda, MD, USA

    Karel Pacak

Contributions

All authors made individual contributions to the authorship. IAH, MK, MK, and DZ were involved in the diagnosis and management of this patient. DZ was responsible for the patient´s imaging studies. IAH wrote the first draft of the manuscript. KP revised the manuscript critically. All authors reviewed and approved the final draft.

Corresponding author

Correspondence to Irena Aldhoon-Hainerová.

Ethics declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Signed informed consent was obtained from the patient and the patient´s parents for the publication of this case report and accompanying images.

Competing interests

The authors declare no competing interests.

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A Challenging Case of Severe Cushing’s Syndrome in the Course of Metastatic Thymic Neuroendocrine Carcinoma with a Synchronous Adrenal Tumor

Posted on August 8, 2024 by MaryO

Ectopic ACTH syndrome (EAS) remains one of the most demanding diagnostic and therapeutic challenges for endocrinologists. Thymic neuroendocrine tumors account for 5%–10% of all EAS cases. We report a unique case of a 31-year-old woman with severe EAS caused by primary metastatic combined large-cell neuroendocrine carcinoma and atypical carcinoid of the thymus. The patient presented with severe hypercortisolemia, which was successfully controlled with continuous etomidate infusion. Complex imaging initially failed to detect thymic lesion; however, it revealed a large, inhomogeneous, metabolically active left adrenal mass infiltrating the diaphragm, suspected of primary disease origin. The patient underwent unilateral adrenalectomy, which resulted in hypercortisolemia resolve. The pathology report showed an adenoma with adrenal infarction and necrosis. The thymic tumor was eventually revealed a few weeks later on follow-up imaging studies. Due to local invasion and rapid progression, only partial resection of the thymic tumor was possible, and the patient was started on radio- and chemotherapy.

1 Introduction

Endogenous Cushing’s syndrome (CS) is a rare endocrine condition caused by excess cortisol production with an annual incidence of 0.2–5 cases per million people (1). Adrenocorticotropin (ACTH) hypersecretion of nonpituitary tumors leading to ectopic ACTH syndrome (EAS) accounts for 9%–18% of ACTH-dependent CS cases (1, 2) and represents one of the most common paraneoplastic syndromes (3, 4). Neuroendocrine tumors (NETs) of various locations, degrees of histological differentiation, and aggressiveness potential can lead to EAS; however, most frequently, they derive from the foregut, with the well-differentiated bronchial NET being the most common one in recent series (5, 6). NETs of the thymus (NETTs) represent up to 5% of all thymic tumors, with an incidence of 0.02 per 100,000 people per year in the Caucasian population (7, 8). Up to 50% of the hormonally active NETTs present with ACTH hypersecretion (8) that account for 5%–10% of EAS cases (5, 9). They usually behave aggressively with regional invasion and early distant metastases and lead to the rapid development of severe hypercortisolism (SH), which worsens the initial poor prognosis (8–11).

Herein, we present a unique case of a patient with EAS caused by a primary metastatic, ACTH-secreting thymic large-cell neuroendocrine carcinoma (LCNEC) with an atypical carcinoid (AC) component with rapid progression, which initially failed to be visualized in imaging studies. Moreover, the diagnostic process was even more difficult because of the co-presence of an adrenal lesion suspected of malignancy on imaging studies and to be the primary origin of the disease.

2 Case report

In April 2019, a 31-year-old previously healthy woman presented to the Emergency Department with a 3-week history of progressing fatigue, muscle weakness, exercise intolerance, headaches, progressive hypertension, generalized swelling, polyuria, polydipsia, and nycturia. Due to the reported symptoms, the patient had previously consulted a family doctor, who initiated oral potassium supplementation because of hypokalemia (2.8 mmol/L) found in basic laboratory tests. On physical examination, the patient presented with significant peripheral pitting edema, high blood pressure (170/100 mmHg), tachycardia (170 beats/minute), and acne lesions on the face, back, and chest. The initial laboratory tests at the Emergency Department showed the following: leukocytosis (13.95 × 109/L) with neutrophilia (12.98 × 109/L) and lymphopenia (0.27 × 109/L), hypochloremic metabolic alkalosis (pH 7.52; HCO3−, 38.3 mmol/L; and Cl−, 91 mmol/L), hyperglycemia (478 mg/dL), and profound hypokalemia (2.2 mmol/L). Initial laboratory findings are summarized in Table 1A.

Table 1a

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Table 1A Summary of initial laboratory test performed at Emergency Department.

Within the Emergency Department, the patient was considered as a patient with newly diagnosed diabetes and was referred to the Endocrinology Department, where she was started on insulin therapy along with aggressive hypokalemia repletion, antihypertensive treatment, and preventive heparin anticoagulation. Given the overall clinical presentation and resistance to initiated treatment, aggressive CS was quickly suspected. During the first days of hospitalization, the patient also developed agitation with paranoid symptoms; thus, the psychiatrist was consulted, and the patient was additionally started on antipsychotic treatment.

The hormonal evaluation revealed SH with high concentrations of morning (78.2 μg/dL; reference range, 3.7–19.4) and midnight (69.1 μg/dL; reference range, < 5.4) serum cortisol, 24 h urinary free cortisol (UFC) excretion exceeding 65 times the upper reference limit (11,587.5 μg/24 h; reference range, 4.6–176.0), and hyperandrogenemia (testosterone, 6.3 ng/mL; reference range, 0.06–0.8; DHEA-S, 853.2 μg/dL; reference range, 95.8–511.7). ACTH level was markedly elevated (963.7 pg/mL; reference range, 6.0–48.0), confirming ACTH-dependent CS. No dynamic hormonal testing was performed, considering the severe state of the patient. The hormonal findings are summarized in Table 1B.

Table 1b

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Table 1B Summary of initial hormonal assessment in presented patient.

To control SH, continuous etomidate infusion was initiated with significant improvement in the patient’s general condition, edema reduction and normalization of blood pressure, glycemia, and potassium level with a decrease in the need for antihypertensive and insulin treatment, mineralocorticoid receptor blockade, and potassium supplementation. Pituitary magnetic resonance imaging (MRI) revealed no lesion. ACTH-dependent SH with negative pituitary imaging and short duration with rapid progression of symptoms were highly suggestive of EAS. Computed tomography (CT) of the chest, abdomen, and pelvis was performed and revealed a left, inhomogeneous, solid adrenal mass measuring 80 mm ×56 mm ×39 mm of 25 Hounsfield units adjacent to/infiltrating the left dome of the diaphragm, hyperplasia of the right adrenal gland, and numerous sclerotic bone lesions concerning for metastases (Figure 1).

Figure 1

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Figure 1 Frontal (A) and axial (B) CT scans of the abdomen presenting a large lesion of the left adrenal gland. 18F-FDG-PET-CT presenting high metabolic activity of the left adrenal gland lesion (C1, C2) and metastatic bone lesions in the spine and sternum (D).

Plasma and urine metanephrines, renin, and aldosterone levels were within the reference range (Table 1B). However, an excessively elevated concentration of chromogranin A (CgA) was observed (13,835.0 ng/mL; reference range, < 100), which firmly suggested the presence of a NET. The patient underwent whole-body SPECT-CT somatostatin receptor scintigraphy (SRS) with 99mTc-octreotate, which showed no evidence of somatostatin receptor overexpression. Subsequently, whole-body 18F-fluorodeoxyglucose (FDG)-positron emission tomography (PET)-CT was performed and revealed that the left adrenal gland lesion previously found on CT scan is partially metabolically active [maximum standardized uptake value (SUVmax), 3.2] and suspicious of malignancy; the right adrenal gland presented diffused 18F-FDG uptake (SUVmax, 2.6) likely resulting from excessive ACTH overstimulation. 18FDG-PET-CT also showed multifocal metabolically active sclerotic bone lesions in the spine, ribs, clavicles, scapules, sternum, pelvis, femurs, and humerus. A SUVmax 2.1 area (not correlated with CT imaging) was also found in the anterior mediastinum, which has been considered primarily as a residual thymus with physiological FDG uptake (Figure 1).

The clinical presentation was highly suggestive of generalized malignancy with ectopic ACTH secretion with the potential origin in the left adrenal gland. The patient was discussed at a multidisciplinary team meeting and was decided to undergo left-sided open adrenalectomy. After the surgery, the symptoms of hypercortisolemia resolved, the etomidate infusion could have been stopped, and the patient did not require further use of antihypertensive and insulin treatment, mineralocorticoid receptor blockade, and potassium supplementation. Furthermore, postoperatively, a significant decline in cortisol levels was noted (4.08 μg/dL), and the patient was transitioned to oral hydrocortisone. ACTH level also dropped (312.0 pg/mL 2 h after morning dose of oral hydrocortisone); however, it still remained significantly elevated. While waiting for the histopathological result, the patient underwent additional colonoscopy, gastroscopy, and bronchoscopy, but no other potential cancer origin was found. We consulted with the oncologist, and active surveillance was recommended until the histopathological examination results were obtained. The patient was discharged after 5 weeks of hospitalization, awaiting the result of the histopathological examination, in good general condition, requiring only hydrocortisone substitution.

The histopathological examination revealed an adrenal adenoma with the domination of adrenal infarction and necrosis. Immunohistochemistry (IHC) showed the following: CgA (+), EMA (−), synaptophysin (−), S100 (−), CKAE1/AE3 (+), RCC (−), melan-A (−), Ki-67 positive in single adrenal cells. Although its diagnosis was unlikely, according to the histopathology and IHC, it was not possible to clearly exclude the adrenocortical cancer (ACC). However, given ACTH-dependent hypercortisolemia and significantly elevated CgA concentration, an undetected neuroendocrine tumor was considered first.

A follow-up 18F-FDG-PET-CT performed after 8 weeks revealed a metabolically active mass (SUVmax, 9.3) in the superior anterior mediastinum in the thymus location (Figure 2A). CT (Figure 2B) and the subsequently performed MRI (Figure 2C) of the chest confirmed mediastinal mass measuring 42 mm × 33 mm, adjacent to the trachea and superior vena cava, encircling the ascending aorta and aortic arch, most likely corresponding to the invasive thymic malignancy.

Figure 2

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Figure 2 Eight-week follow-up 18F-FDG-PET-CT presenting metabolically active lesion in the superior anterior mediastinum in the thymus location (A1, A2). Axial CT (B) and MRI (C) scans of the chest presenting mediastinal mass corresponding to the invasive thymic malignancy.

The patient was qualified for a thoracic surgery; however, due to the local invasion, it was only possible to perform a partial thymectomy (August 2019). After the procedure, the ACTH concentration dropped but not significantly (537.3 pg/mL before and 446.0 pg/mL after the surgery). A histopathology report revealed thymic LCNEC with AC component extensively infiltrating the surgical margins. On IHC, the tumor stained positive for CgA, synaptophysin, and CD56, and weakly for ACTH; the Ki-67 index was 40%, p53 expression was 70% (Figure 3). The final diagnosis was TNM stage IVB (pT2NxM1b), Masaoka–Koga stage III ACTH-secreting combined thymic LCNC and AC.

Figure 3

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Figure 3 Large-cell neuroendocrine carcinoma of the thymus with atypical carcinoid morphology, pathological diagnosis. (A) Microscopic image of the primary tumor, HE staining. (B) Weak positive IHC staining for ACTH. (C) Microscopic image of the brain metastasis, HE staining. (D) Weak positive IHC staining for ACTH of the brain metastasis. (E) Electron microscopic image of cancer cells; the material was taken from a paraffin block, which resulted in a poorly preserved ultrastructure. Visible neuroendocrine granules concentrated around the cell nucleus (×17,500). (F) Ultrastructural image of the neuroendocrine granules with a diameter of (×24,500).

As part of the cancer multidisciplinary team meeting, the patient was qualified for postoperative radiotherapy (RTH) for the thymus bed and residual mass of the mediastinal tumor. Between October and December 2019, the patient received 64 Gy/t in 2 Gy/t fraction doses. Unfortunately, the ACTH concentration increased during the RTH to the maximum observed value of 1,021.2 pg/mL, which suggested further progression of the disease. Follow-up 18F-FDG-PET-CT (January 2020) showed a thymic mass measuring 31 mm × 20 mm, less metabolically active (SUVmax, 4.3) than initially. It also revealed a new 18F-FDG-avid lesion in the pancreas tail in the left temporal lobe (SUVmax, 12.7). The brain MRI confirmed the presence of metastasis measuring 30 × 24 × 18 mm. The patient was qualified for postoperative chemotherapy (CTH) according to the ADOC regimen (cisplatin, doxorubicin, vincristine, and cyclophosphamide) for aggressive thymic tumors (January 2020–May 2020). CTH resulted in disease partial response, and ACTH concentration dropped to 192.0 pg/mL. In June 2020, the patient underwent a craniotomy with left non-radical temporal tumor resection and received additional RTH. The disease was stable for almost 10 months; however, the follow-up 18F-FDG-PET-CT on May 2021 showed new active lesions in the right lung, pancreas, left iliopsoas muscle, and left breast. ACTH level at that time increased to 655.5 pg/mL. The patient was introduced to the PE regimen CTH (cisplatin and etoposide, June 2021–September 2021) with a short-term partial response. Because of the further disease progression, the patient was started on palliative CTH. More than 3.5 years after the first hospitalization, in November 2022, the patient passed away.

3 Discussion

In this paper, we present a unique case of a patient with ACTH-secreting combined thymic LCNEC with AC component, primary manifested as severe CS. NETTs constitute approximately 2%–5% of thymic tumors (7–9), representing approximately 2% of all mediastinal tumors (8). NETTS are typically diagnosed with a mean age of 55, with a clear male predominance (male-to-female ratio, 3:1) (7). EAS with ACTH secretion occurs in up to 50% of hormonally active NETTS (8). NETTs associated with EAS appear in younger populations below age of 40 compared to overall NETTs and are also more prevalent in male individuals (albeit in a lower proportion when compared to non-EAS NETTs) (9). EAS-related NETTs have a worse outcome than biochemically inactive thymic tumors, since they usually have an aggressive course, with early regional invasion, distant metastasis, and high mortality (8–11). Patients with EAS typically present with rapid-onset, severe CS, including resistant hypertension, hyperglycemia, profound and refractory hypokalemia with metabolic alkalosis, generalized edema, and proximal muscle weakness (4–6). SH, which occurs in approximately 60% of patients with hormonally active NETTs secreting ACTH (and approximately 80% in the case of ACTH-secreting thymic carcinomas), significantly worsens the initial poor prognosis (9). In the systematic review by Guerrero Pérez et al., mortality in patients with advanced disease was approximately 55%, and the median time between diagnosis and death was 38 months (9). NETTs are typically large tumors that could manifest with neoplastic mass effect (11, 12); however, only up to 10% of patients with ACTH-secreting NETTs present with local compressive symptoms (9).

In EAS, the progression of hypercortisolemia is typically accelerated, and patients with very rapid SH onset may not present with typical cushingoid features. During the initial assessment at the Emergency Department, the patient was overlooked—the physician’s attention was captured by diabetes mellitus, but the clinical features have not been linked to CS. It highlights the need for a high CS clinical suspicion in case of SH. The presence of profound hypokalemia in combination with hyperglycemia and resistant hypertension with edema is a clue that should prompt diagnosis (4, 5).

In the Endocrinology Department, the patient was quickly suspected of aggressive CS. Serum cortisol, UFC, and ACTH were dramatically increased. The patient was started on etomidate infusion to control hypercortisolemia. Etomidate is considered the most potent and effective agent for rapidly inhibiting cortisol overproduction (13, 14). Indeed, the patient’s clinical condition notably improved after only a few days of etomidate therapy with edema reduction and normalization of blood pressure, glycemia, and kalemia.

In the presented patient, the severity of hypercortisolemia with negative pituitary MRI image and positive whole-body CT imaging were compatible with EAS. Whole-body CT and functional imaging highly suggested a generalized malignancy with a potential origin in the left adrenal gland. The possibility of metastatic pheochromocytoma was considered—the concentration of CgA was significantly elevated, but urine and plasma metanephrines were negative. The ACC was also taken into consideration. Nevertheless, only one case of ACC potentially related to EAS was reported (15).

However, it is puzzling how only one of the adrenal glands was ACTH overstimulated, and the function of the second one seemed to be inhibited. A significant decline in cortisol concentration after exclusive unilateral adrenalectomy indicated that the left adrenal gland tumor could indeed have been the primary origin of malignancy and CS itself. On the other hand, ACTH level remained significantly elevated, although it dropped more than twofold compared to baseline. It was considered that the persistently elevated (but markedly lower) ACTH concentration was associated with the presence of metastases or could (albeit partially) result from the pituitary response to a significant decrease in cortisol concentration. Of course, metastatic ectopic ACTH-secreting tumor of unknown origin was also considered at that time.

Surprisingly, the histopathology examination revealed an adrenal adenoma with the domination of necrosis due to the adrenal infarction. It cannot be ruled out that the patient had a previously undiagnosed adrenal adenoma, and even short-term but dramatic ACTH hyperstimulation led it to its significant growth and provoked an adrenal infarction, imitating a malignancy in the imagery evaluation. Differentiating benign and malignant adrenal lesions based on 18F-FDG-PET-CT has a high diagnostic accuracy (16–18); however, metabolically active adenomas may present with increased FDG uptake and mimic malignancy (19). In addition, adrenal hemorrhage and necrosis can present with increased activity on 18F-FDG-PET-CT (20). Thus, it seems that the increased 18F-FDG avidity of the left adrenal lesion with foci of intratumoral necrosis was directly related to dramatically elevated ACTH concentrations and adrenal overstimulation.

CT scan located the EAS-related NETTs in 97.8% of cases in the aforementioned systematic review by Guerrero Pérez et al. (9). In the presented patient, imagery diagnostic initially failed to visualize the thymic tumor. There are only few reports on non-diagnostic chest CT or MRI evaluation in patients with EAS NETTs (21–23); however, in the presented cases, NETTs were found on SRS, which is contrary to our report. The first 18F-FDG-PET-CT localized an area of 2.1 SUVmax in the anterior mediastinum, initially considered a residual thymus because of the physiological FDG uptake. It is also unique how the PET-CT scan, chest CT, and MRI revealed a highly 18F-FDG-avid, large, invasive mediastinal mass just a few weeks after the baseline assessment. Imagery and functional studies were additionally retrospectively assessed by independent radiologists and nuclear medics to exclude a possible oversight during the initial analysis. However, it was maintained that there was no clear evidence of a thymic neoplasm at baseline.

Thymic carcinomas present with high FDG uptake, typically with SUVmax > 7 (24), SUV max values <4 as being most consistent with benign thymic processes (25). On the other hand, there is a marked overlap in FDG uptake between physiological thymic FDG uptake and thymic neoplasia in the literature, indicating that 18F-FDG-PET-CT has a limited ability to assess the thymus and an equivocal role in the differentiation of a normal thymus from thymic neoplasia (26). Among all described cases of EAS-related NETTs in the literature in which 18F-FDG-PET-CT was indicated as one of the diagnostic step, the primary tumor was visualized in all of them (27–38). The primary NETT SUVmax was reported only in five of them ranging from 2.48 to 12.0 (27–31); in the remaining ones, 18F-FDG avidity was reported from mild to high. However, in all mentioned cases (besides one (31), where no information about radiological chest imaging was reported), the NETT was previously visualized on chest CT, and 18F-FDG-PET-CT was performed to assess the disease staging rather than to find EAS origin.

On IHC, the thymic tumor stained weekly positive for ACTH in contrast to dramatically elevated plasma ACTH concentration. There seems to be a negative correlation between ACTH immunoreactivity and the neuroendocrine tumor malignancy potential. Moreover, the diagnosis of EAS is not ruled out in the case of primary tumor negative ACTH IHC staining. Less differentiated neuroendocrine tumors are believed to secrete ACTH rapidly and might also lose the ability to store ACTH in the secretory granules, thus leaving for typical techniques insufficient ACTH amounts stored to be stained (39, 40). In addition, the tumor might secrete various biologically active ACTH precursors that are negative on IHC.

Complete NETT resection is the only curative option and the strongest factor for overall survival (7, 41, 42). In the case of a subtotal resected tumor, RTH and CTH are considered (42–44); however, there is no consensus and guidelines for the optimal postoperative strategy, mainly due to the rarity of the disease. Systematic therapies are also used as palliative treatment in case of unresectable, metastatic, and recurrent NETTs (42, 44). Besides the primary metastatic disease, the presented patient underwent a partial resection with macroscopic residual tumor (R2) and was then qualified for postoperative RTH and CTH. After the R2 resection, postoperative RTH may be combined sequentially or concurrently with CTH (45). RTH was not clearly effective, as the follow-up 18F-FDG-PET-CT showed new metastases, including an extensive metastasis to the left temporal lobe. Several CTH regimens have been used in patients with NETTs (42, 44, 45). CTH response rates in metastatic poorly differentiated NETTs are 30%–50%, with progression-free survival rates of 6–9 months (45). The presented patient was introduced to an ADOC regimen, which resulted in a partial response. However, the patient started second-line and later palliative CTH because of the further disease progression.

4 Conclusions

We present a unique and challenging case of malignant, primary metastatic NETT initially manifesting with severe EAS and not visible in initial imaging studies in a patient with coexisting adrenal tumor suspected of malignancy and primary disease origin. The presented case highlights that the diagnosis and management of EAS remain challenging; it requires a high clinical suspicion, rapid hypercortisolemia control with symptomatic treatment of cortisol-induced comorbidities, and simultaneously complex imaging studies to determine the primary source of the ACTH hypersecretion. The treatment of choice is resection of ACTH-secreting NET; however, it may not be possible in patients with initially occult or metastatic disease. Malignant NETTs with ectopic CS are extremely rare, and their management has to be individualized in every case, requiring a multidisciplinary approach. Regardless, the prognosis remains poor due to the aggressiveness of the disease.

Data availability statement

The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.

Ethics statement

The studies were conducted in accordance with the local legislation and institutional requirements. The patient gave an oral consent for publication while alive. Written informed consent for publication was obtained from the patient’s parents.

Author contributions

LD: Resources, Writing – review & editing, Writing – original draft, Methodology, Investigation, Formal analysis, Data curation, Conceptualization. AW-L: Writing – review & editing, Supervision, Resources, Methodology, Data curation, Conceptualization. MM: Writing – review & editing, Resources, Data curation, Conceptualization. PW: Writing – review & editing, Supervision, Resources, Methodology, Data curation.

Funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. The publication fee was covered by the Medical University of Warsaw.

Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Publisher’s note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

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Keywords: adrenal tumor, cortisol, ectopic ACTH syndrome, etomidate, thymic neuroendocrine carcinoma

Citation: Dzialach L, Wojciechowska-Luzniak A, Maksymowicz M and Witek P (2024) Case report: A challenging case of severe Cushing’s syndrome in the course of metastatic thymic neuroendocrine carcinoma with a synchronous adrenal tumor. Front. Endocrinol. 15:1399930. doi: 10.3389/fendo.2024.1399930

Received: 12 March 2024; Accepted: 24 May 2024;
Published: 14 June 2024.

Edited by:

Vincent Geenen, University of Liège, Belgium

Reviewed by:

Mara Carsote, Carol Davila University of Medicine and Pharmacy, Romania
Aleksandra Gilis-Januszewska, Jagiellonian University Medical College, Poland

Copyright © 2024 Dzialach, Wojciechowska-Luzniak, Maksymowicz and Witek. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Lukasz Dzialach, lukasz.dzialach@wum.edu.pl

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