Ectopic Cushing Syndrome in Metastatic Castration‑Resistant Prostate Cancer

Posted on August 14, 2024 by MaryO

Abstract

Cushing’s syndrome (CS), as a result of ectopic adrenocorticotropic hormone (ACTH) production, constitutes a common paraneoplastic manifestation of various malignancies, with the most common being small cell lung carcinoma. In the literature, fewer than fifty cases associating ectopic CS with prostate cancer have been documented. In the present study, the case of a 76‑year old man suffering from castration‑resistant prostate adenocarcinoma that had been treated with enzalutamide and luteinizing hormone‑releasing hormone (LHRH) analogue for the last four years is presented. The patient presented to the emergency department with lower extremity muscle weakness, bradypsychia and hypokalemia. Following a thorough diagnostic evaluation, hypercortisolemia was identified. No suppression after low‑ and high‑dose dexamethasone challenge, increased cortisol 24 h excretion and normal pituitary magnetic resonance imaging led to the diagnosis of ectopic CS. Immediate targeted therapy was initiated with adrenal steroidogenesis inhibitors, including metyrapone and ketoconazole along with chemotherapy with docetaxel and prednisolone. There was a remarkable decrease in cortisol levels within days and hospitalization was no longer required. The patient managed to complete three cycles of chemotherapy; unfortunately, he succumbed within three months of the diagnosis of ectopic CS. In the present study, all existing cases of paraneoplastic CS related to prostate cancer are reviewed. The aim of the current study was to highlight the need of early diagnosis and treatment of this entity as it may present with atypical clinical findings and potentially evolve to a life‑threatening condition.

Introduction

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

Case report

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

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

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

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

Discussion

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

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

The first case reports of ectopic ACTH production in patients with prostatic carcinoma date back to the 1960s written by Webster et al (38) and Jarett et al (56). However, either tissue staining for ACTH was not available (38) or the primary tumor displayed no staining with the fluorescent anti-ACTH (56). The first well-documented case report of a patient with prostatic adenocarcinoma producing ACTH was presented by Newmark et al (37). Since then, several other cases of ectopic CS related to prostate cancer have been reported and are summarized in Table II. CS is a result of the ectopic production of ACTH in all of the cases except for two cases where corticotropin-releasing hormone (CRH) produced by the prostatic tumor is the driving cause (13,14). Indeed, CRH production from prostate cancer implicates 14% of the cases and is considered as an extremely rare source of ectopic ACTH (1–3%) (59). Histologically, CS emerged from small cell carcinoma of the prostate in 18 cases (11,13–15,20–22,24,25,27,29–31,33,34,47,50,51), neuroendocrine carcinoma of the prostate in five cases (17,21,26,28,32), prostate adenocarcinoma usually poorly differentiated/undifferentiated in 16 cases (16,18,19,23,35–39,41,42,44–46,49,52), anaplastic carcinoma in two cases (12,19) and carcinoid tumor of the prostate in another two cases (40,43). In the vast majority of the cases disease was metastatic with distant visceral metastases except for 11 cases (11,18,19,22,30,33,40,41,47,49,51) where disease was either locally advanced or metastatic only to lymph nodes.

Interestingly, the typical clinical manifestations of CS with centripetal obesity, moon facies, purple striae, buffalo hump and skin hyperpigmentation are rarely present (12,17,23,31,36,47). In most cases, muscle weakness, mental changes mild hypertension and edema are the presenting symptoms along with hypokalemic alkalosis and elevated glucose levels from laboratory tests (11,13–16,18–22,24–30,32–35,37–41,43–46,49–52). In the present case, the main clinical feature was limb muscle weakness combined with severe hypokalemic alkalosis. This comes in agreement with the existing literature which identifies hypokalemic alkalosis as often the only initial manifestation of the syndrome. This clinical picture reflects the rapid onset and aggressiveness of the syndrome. Most patients die early because of the underlying malignancy before the development of typical Cushing’s symptoms. Indeed, typical Cushing’s signs and symptoms develop under the condition of long-term hypercortisolism, so ectopic CS tends to present with less dramatic features, but higher blood pressure and more profound electrolyte abnormalities. Laboratory findings typically include hypokalemic alkalosis, elevated plasma glucose along with elevated plasma cortisol and ACTH levels and increased glucocorticoid excretion in urine as in the present case.

Initiation of supportive medication with oral or intravenous potassium supplements may be required. Treatment of CS is based on adrenal steroidogenesis inhibitors, including ketoconazole, metyrapone, mitotane or mifepristone (14,16–23,25–28,31–35,37,43–45,47,49–52) in over half of the cases (28/43; 65%) and more rarely etomidate (17,33) (2/43; 5%), as well as the newest therapeutic agent osilodrostat. Hypercortisolism may be controlled by blocking one or more adrenal enzymes, such as mitotane and metyrapone that inhibit 11β-hydroxylase or ketoconazole that inhibits both 17α-hydroxylase and 17,20-lyase. Interestingly, the somatostatin receptor ligand pasireotide is approved for patients with CS who have persistent or recurrent hypercortisolism and the dopamine agonist cabergoline facilitates initial normalization of urinary free cortisol levels and also improves the signs and symptoms of hypercortisolism. The cornerstone of treatment however remains the surgical removal of the tumor when is feasible. However, most of the ectopic ACTH-producing tumors are not resectable while patients may not be clinically fit enough for surgery. In these cases, supportive medication with antiglucocorticoid drugs is the preferred treatment option along with chemotherapy for the primary tumor. Chemotherapy was administered in one third of the cases (14/43) (13,17,19,21,22,24–27,31,35,47,52) and was mainly based on platinum-etoposide combinations. Whatever the treatment, prognosis is abysmal and median survival is as reported (Table II).

Neuroendocrine cells that lack androgen receptors are normally part of the normal prostate tissue and play a regulatory role in proliferation and secretion of the prostate epithelium (6,60). Neuroendocrine cells constitute only <1% of total epithelial cells found in prostate tissue and serve a paracrine or local regulatory role by secreting serotonin, calcitonin and other peptides (60). The inappropriate production of ACTH is attributed to these neuroendocrine cells that are part of the amine precursor uptake and decarboxylation (APUD) regulatory system (60). Neuroendocrine APUD cells are dispersed in numerous organs and systems in small concentrations such as gastrointestinal tract, lung and prostate and serve as one of the most important mechanisms of homeostasis. These cells have common biochemical and cytological properties as well as the ability to secrete polypeptides that include ACTH, neuron-specific enolase (NSE) and chromogranin A (CGA) (60). In vitro experiments have revealed that during androgen deprivation treatment (ADT), prostate adenocarcinoma cells have the capacity to transdifferentiate to a neuroendocrine (NE) phenotype, a process called neuroendocrine trans-differentiation. De novo prostate neuroendocrine carcinoma (small cell or large cell) is a rare entity (<2%), however treatment-emergent neuroendocrine neoplasms account for 10–17% of patients with metastatic CRPC (3). Indeed, a substantial population of pre-treated end-stage prostate cancer patients show salient features of de novo neuroendocrine small cell carcinomas, mostly with an aggressive behavior and often with visceral metastases. Radiotherapy and androgen deprivation therapy activate the process of neuroendocrine dedifferentiation through the following mechanisms: Either they induce malignant transformation of neuroendocrine cells within adenocarcinoma cells or they facilitate the growth of pre-existing neuroendocrine cells. In this manner, cancer cells lack androgen receptors and transform into castration-resistant prostate cancer cells resulting in disease progression. Although most patients are not routinely biopsied in end-stage disease, it has been estimated that at least 25% of the patients with advanced prostate cancer will develop neuroendocrine prostate cancer under androgen deprivation pressure (4). Neuroendocrine prostate carcinoma differs from the conventional adenocarcinoma of the prostate histologically by expressing neuroendocrine markers such as chromogranin A, SYP, CD56, and NSE instead of prostate adenocarcinoma markers like AR, P501S, PSMA, PSAP and PSA (61). Of note, the introduction of next generation antiandrogen agents like enzalutamide or abiraterone resulted in an increase of neuroendocrine prostate carcinomas from 6.3 to 13.3% after 2012 (3). Paraneoplastic syndromes associated with prostate cancer are rare. However, when they occur, they constitute the initial clinical manifestation of prostate cancer in up to 70% of cases and a sign of progression to castration-resistance in 20% of cases (62). Paraneoplastic syndromes often related to prostate cancer include endocrine syndromes (inappropriate antidiuretic hormone secretion, CS, hypercalcemia) as well as hematological disorders and neurological syndromes (62).

Pure carcinoids of the prostate are rare, while mixed carcinomas of prostate adenocarcinoma and carcinoid are more frequent. Small cell prostate carcinoma accounts for ~0.5–2% of prostate carcinoma cases (63). It is thought that small cell carcinoma of the prostate has a common origin with prostate adenocarcinoma as ~40–50% of men with small cell carcinoma of the prostate have a prior or concurrent history of prostatic adenocarcinoma (63). Based on the aforementioned information, ectopic ACTH production mainly emerges from the neuroendocrine transformation of the preexisting prostate adenocarcinoma. This raises the question of performing re-biopsy to histologically confirm the diagnosis. However, the imminent need to initiate treatment early may postpone the performance of a confirmatory re-biopsy. As known, the state of extreme hypercortisolism creates a fertile environment for infections. Therefore, the prompt initiation of targeted treatment with metyrapone or ketoconazole and potassium supplements to target hypercortisolism in combination with chemotherapy for the underlying malignancy may be deemed more urgent. This case was thoroughly discussed in multidisciplinary medical meetings focusing on the best therapeutic approach. In accordance with the present case, re-biopsy was not performed in most of the cases identified in the existing literature mainly due to the fast deterioration of the patient and the subsequent lack of time. Indeed, most patients die from sepsis secondary to uncontrolled CS. This is the reason that suppression of the hypercortisolism is urgent and should not be delayed to identify the source of CS.

In conclusion, the ectopic CS can be a clinical manifestation of prostate cancer. It requires timely diagnosis and aggressive treatment to avoid life-threatening complications of hypercortisolemia. The present case highlighted the necessity of multiple laboratory and imaging examinations required for the definitive diagnosis of CS, with the ultimate goal of initiating targeted therapy promptly.

Acknowledgements

Not applicable.

Funding

Funding: No funding was received.

Availability of data and materials

The data generated in the present study may be found in the PUBMED database at the following URL: https://pubmed.ncbi.nlm.nih.gov.

Authors’ contributions

FZ, MAD and SAP conceptualized the study. AA, KG and KS conducted the investigation. FZ, MAD and SAP supervised the study. AA, KG, SA and KS were involved in drafting the original manuscript and revised it critically for important intellectual content. SA also made a substantial contribution to the analysis and interpretation of the data, gave final approval for the manuscript to be published and agreed to be accountable for all aspects of the work. All authors read and approved the final manuscript. KG and AA confirm the authenticity of all the raw data.

Ethics approval and consent to participate

Not applicable.

Patient consent for publication

The patient provided written informed consent for this case study to be published.

Competing interests

MAD has received honoraria from participation in advisory boards from Amgen, Bristol-Myers-Squibb, Celgene, Janssen, Takeda. FZ has received honoraria for lectures and has served in an advisory role for Astra-Zeneca, Daiichi, Eli-Lilly, Merck, Novartis, Pfizer, and Roche. The remaining 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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Evaluating the usefulness of plasma chromogranin A measurement in cyclic ACTH-dependent Cushing’s syndrome

Posted on July 19, 2024 by MaryO
Abstract

Cushing’s syndrome, a clinical condition characterized by hypercortisolemia, exhibits distinct clinical signs and is associated with cyclic cortisol secretion in some patients. The clinical presentation of cyclic Cushing’s syndrome can be ambiguous and its diagnosis is often challenging.

We experienced a 72-year-old woman with cyclic ACTH-dependent Cushing’s syndrome caused by a pulmonary carcinoid tumor. Diagnosis was challenging because of the extended trough periods, and the responsible lesion was initially unidentified. A subsequent follow-up computed tomography revealed a pulmonary lesion, and ectopic ACTH secretion from this lesion was confirmed by pulmonary artery sampling. Despite the short peak secretion period of ACTH (approximately one week), immunostaining of the surgically removed tumor confirmed ACTH positivity. Interestingly, stored plasma chromogranin A levels were elevated during both peak and trough periods.

The experience in evaluating this patient prompted us to investigate the potential use of plasma chromogranin A as a diagnostic marker of ACTH-dependent Cushing’s syndrome. A retrospective study was conducted to determine the efficacy of plasma chromogranin A in three patients with ectopic ACTH syndrome (EAS), including the present case, and six patients with Cushing’s disease (CD) who visited our hospital between 2018 and 2021. Notably, plasma chromogranin A levels were higher in patients with EAS than in those with CD. Additionally, a chromogranin A level in the present case during the trough phase was lower than that in the peak phase, and was similar to those in CD patients. The measurement of plasma chromogranin A levels could aid in differentiating EAS from CD.

Keywords: ACTH-dependent Cushing’s syndrome, Cyclic, Carcinoid, Pulmonary arterial sampling, Chromogranin A

From https://www.jstage.jst.go.jp/article/endocrj/advpub/0/advpub_EJ24-0128/_article

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Unveiling the Uncommon: Cushing’s Syndrome (CS) Masquerading as Severe Hypokalemia

Posted on July 2, 2024 by MaryO

Abstract

Cushing’s syndrome (CS) arises from an excess of endogenous or exogenous cortisol, with Cushing’s disease specifically implicating a pituitary adenoma and exaggerated adrenocorticotropic hormone (ACTH) production. Typically, Cushing’s disease presents with characteristic symptoms such as weight gain, central obesity, moon face, and buffalo hump.

This case report presents an unusual manifestation of CS in a 48-year-old male with a history of hypertension, where severe hypokalemia was the primary presentation. Initial complaints included bilateral leg swelling, muscle weakness, occasional shortness of breath, and a general feeling of not feeling well. Subsequent investigations revealed hypokalemia, metabolic alkalosis, and an abnormal response to dexamethasone suppression, raising concerns about hypercortisolism. Further tests, including 24-hour urinary free cortisol and ACTH testing, confirmed significant elevations. Brain magnetic resonance imaging (MRI) identified a pituitary macroadenoma, necessitating neurosurgical intervention.

This case underscores the rarity of CS presenting with severe hypokalemia, highlighting the diagnostic challenges and the crucial role of a collaborative approach in managing such intricate cases.

Introduction

Cushing’s syndrome (CS), characterized by excessive cortisol production, is well-known for its diverse and often conspicuous clinical manifestations. Cushing’s disease is a subset of CS resulting from a pituitary adenoma overproducing adrenocorticotropic hormone (ACTH), leading to heightened cortisol secretion. The classic presentation involves a spectrum of symptoms such as weight gain, central obesity, muscle weakness, and mood alterations [1].

Despite its classic presentation, CS can demonstrate diverse and atypical features, challenging conventional diagnostic paradigms. This case report sheds light on a rare manifestation of CS, where severe hypokalemia was the primary clinical indicator. Notably, instances of CS prominently manifesting through severe hypokalemia are scarce in the literature [1,2].

Through this exploration, we aim to provide valuable insights into the diagnostic intricacies of atypical CS presentations, underscore the significance of a comprehensive workup, and emphasize the collaborative approach essential for managing such uncommon hormonal disorders.

Case Presentation

A 48-year-old male with a history of hypertension presented to his primary care physician with complaints of bilateral leg swelling, occasional shortness of breath, dizziness, and a general feeling of malaise persisting for 10 days. The patient reported increased water intake and urinary frequency without dysuria. The patient was diagnosed with hypertension eight months ago. He experienced progressive muscle weakness over two months, hindering his ability to perform daily activities, including using the bathroom. The primary care physician initiated a blood workup that revealed severe hypokalemia with a potassium level of 1.3 mmol/L (reference range: 3.6 to 5.2 mmol/L), prompting referral to the hospital.

Upon admission, the patient was hypertensive with a blood pressure of 180/103 mmHg, a heart rate of 71 beats/minute, a respiratory rate of 18 breaths/minute, and an oxygen saturation of 96% on room air. Physical examination revealed fine tremors, bilateral 2+ pitting edema in the lower extremities up to mid-shin, abdominal distension with normal bowel sounds, and bilateral reduced air entry in the bases of the lungs on auscultation. The blood work showed the following findings (Table 1).

Parameter Result Reference Range
Potassium (K) 1.8 mmol/L 3.5-5.0 mmol/L
Sodium (Na) 144 mmol/L 135-145 mmol/L
Magnesium (Mg) 1.3 mg/dL 1.7-2.2 mg/dL
Hemoglobin (Hb) 15.5 g/dL 13.8-17.2 g/dL
White blood cell count (WBC) 13,000 x 103/µL 4.5 to 11.0 × 109/L
Platelets 131,000 x 109/L 150-450 x 109/L
pH 7.57 7.35-7.45
Bicarbonate (HCO3) 46 mmol/L 22-26 mmol/L
Lactic acid 4.2 mmol/L 0.5-2.0 mmol/L
Table 1: Blood work findings

In order to correct the electrolyte imbalances, the patient received intravenous (IV) magnesium and potassium replacement and was later transitioned to oral. The patient was also started on normal saline at 100 cc per hour. To further investigate the complaint of shortness of breath, the patient underwent a chest X-ray, which revealed bilateral multilobar pneumonia (Figure 1). He was subsequently treated with ceftriaxone (1 g IV daily) and clarithromycin (500 mg twice daily) for seven days.

A-chest-X-ray-revealing-(arrows)-bilateral-multilobar-pneumonia
Figure 1: A chest X-ray revealing (arrows) bilateral multilobar pneumonia

With persistent abdominal pain and lactic acidosis, a computed tomography (CT) scan abdomen and pelvis with contrast was conducted, revealing a psoas muscle hematoma. Subsequent magnetic resonance imaging (MRI) depicted an 8×8 cm hematoma involving the left psoas and iliacus muscles. The interventional radiologist performed drainage of the hematoma involving the left psoas and iliacus muscles (Figure 2).

Magnetic-resonance-imaging-(MRI)-depicting-an-8x8-cm-hematoma-(arrow)-involving-the-left-psoas-and-iliacus-muscles
Figure 2: Magnetic resonance imaging (MRI) depicting an 8×8 cm hematoma (arrow) involving the left psoas and iliacus muscles

In light of the concurrent presence of hypokalemia, hypertension, and metabolic alkalosis, there arose concerns about Conn’s syndrome, prompting consultation with endocrinology. Their recommended workup for Conn’s syndrome included assessments of the aldosterone-renin ratio and random cortisol levels. The results unveiled an aldosterone level below 60 pmol/L (reference range: 190 to 830 pmol/L in SI units) and a plasma renin level of 0.2 pmol/L (reference range: 0.7 to 3.3 mcg/L/hr in SI units). Notably, the aldosterone-renin ratio was low, conclusively ruling out Conn’s syndrome. The random cortisol level was notably elevated at 1334 nmol/L (reference range: 140 to 690 nmol/L).

Furthermore, a low-dose dexamethasone suppression test was undertaken due to the high cortisol levels. Following the administration of 1 mg of dexamethasone at 10 p.m., cortisol levels were measured at 9 p.m., 3 a.m., and 9 a.m. the following day. The results unveiled a persistently elevated cortisol level surpassing 1655 nmol/L, signaling an abnormal response to dexamethasone suppression and raising concerns about a hypercortisolism disorder, such as CS.

In the intricate progression of this case, the investigation delved deeper with a 24-hour urinary free cortisol level, revealing a significant elevation at 521 mcg/day (reference range: 10 to 55 mcg/day). Subsequent testing of ACTH portrayed a markedly elevated level of 445 ng/L, distinctly exceeding the normal reference range of 7.2 to 63.3 ng/L. A high-dose 8 mg dexamethasone test was performed to ascertain the source of excess ACTH production. The baseline serum cortisol levels before the high-dose dexamethasone suppression test were 1404 nmol/L, which decreased to 612 nmol/L afterward, strongly suggesting the source of excess ACTH production to be in the pituitary gland.

A CT scan of the adrenal glands ruled out adrenal mass, while an MRI of the brain uncovered a 1.3×1.3×3.2 cm pituitary macroadenoma (Figure 3), leading to compression of adjacent structures. Neurosurgery was consulted, and they recommended surgical removal of the macroadenoma due to the tumor size and potential complications. The patient was referred to a tertiary care hospital for pituitary adenoma removal.

Magnetic-resonance-imaging-(MRI)-of-the-brain-depicting-a-1.3x1.3x3.2-cm-pituitary-macroadenoma-(star)
Figure 3: Magnetic resonance imaging (MRI) of the brain depicting a 1.3×1.3×3.2 cm pituitary macroadenoma (star)

Discussion

CS represents a complex endocrine disorder characterized by excessive cortisol production. While the classic presentation of CS includes weight gain, central obesity, and muscle weakness, our case highlights an uncommon initial manifestation: severe hypokalemia. This atypical presentation underscores the diverse clinical spectrum of CS and the challenges it poses in diagnosis and management [1,2].

While CS typically presents with the classic symptoms mentioned above, severe hypokalemia as the initial manifestation is exceedingly rare. Hypokalemia in CS often results from excess cortisol-mediated activation of mineralocorticoid receptors, leading to increased urinary potassium excretion and renal potassium wasting. Additionally, metabolic alkalosis secondary to cortisol excess further exacerbates hypokalemia [3,4].

Diagnosing a case of Cushing’s disease typically commences with a thorough examination of the patient’s medical history and a comprehensive physical assessment aimed at identifying characteristic manifestations such as central obesity, facial rounding, proximal muscle weakness, and increased susceptibility to bruising. Essential to confirming the diagnosis are laboratory examinations, which involve measuring cortisol levels through various tests, including 24-hour urinary free cortisol testing, late-night salivary cortisol testing, and dexamethasone suppression tests. Furthermore, assessing plasma ACTH levels aids in distinguishing between pituitary-dependent and non-pituitary causes of CS. Integral to the diagnostic process are imaging modalities such as MRI of the pituitary gland, which facilitate the visualization of adenomas and the determination of their size and precise location [1-4].

Treatment for Cushing’s disease primarily entails surgical removal of the pituitary adenoma via transsphenoidal surgery, with the aim of excising the tumor and restoring normal pituitary function. In cases where surgical intervention is unsuitable or unsuccessful, pharmacological therapies employing medications such as cabergoline (a dopamine receptor agonist) or pasireotide (a somatostatin analogue) may be considered to suppress ACTH secretion and regulate cortisol levels. Additionally, radiation therapy, whether conventional or stereotactic radiosurgery, serves as a supplementary or alternative treatment approach to reduce tumor dimensions and mitigate ACTH production [5,6]. To assess the effectiveness of treatment, manage any problem, and assure long-term illness remission, diligent long-term follow-up and monitoring are essential. Collaborative multidisciplinary care involving specialists such as endocrinologists, neurosurgeons, and other healthcare professionals is pivotal in optimizing patient outcomes and enhancing overall quality of life [2,4].

The prognosis of CS largely depends on the underlying cause, stage of the disease, and efficacy of treatment. Early recognition and prompt intervention are essential for improving outcomes and minimizing long-term complications. Surgical resection of the adrenal or pituitary tumor can lead to remission of CS in the majority of cases. However, recurrence rates vary depending on factors such as tumor size, invasiveness, and completeness of resection [2,3]. Long-term follow-up with endocrinologists is crucial for monitoring disease recurrence, assessing hormonal function, and managing comorbidities associated with CS.

Conclusions

In conclusion, our case report highlights the rarity of severe hypokalemia as the initial presentation of CS. This unique presentation underscores the diverse clinical manifestations of CS and emphasizes the diagnostic challenges encountered in clinical practice. A multidisciplinary approach involving endocrinologists, neurosurgeons, and radiologists is essential for the timely diagnosis and management of CS. Early recognition, prompt intervention, and long-term follow-up are essential for optimizing outcomes and improving the quality of life for patients with this endocrine disorder.

References

  1. Nieman LK, Biller BM, Findling JW, Newell-Price J, Savage MO, Stewart PM, Montori VM: The diagnosis of Cushing’s syndrome: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2008, 93:1526-40. 10.1210/jc.2008-0125
  2. Newell-Price J, Bertagna X, Grossman AB, Nieman LK: Cushing’s syndrome. Lancet. 2006, 367:1605-17. 10.1016/S0140-6736(06)68699-6
  3. Torpy DJ, Mullen N, Ilias I, Nieman LK: Association of hypertension and hypokalemia with Cushing’s syndrome caused by ectopic ACTH secretion: a series of 58 cases. Ann N Y Acad Sci. 2002, 970:134-44. 10.1111/j.1749-6632.2002.tb04419.x
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  5. Fleseriu M, Petersenn S: Medical therapy for Cushing’s disease: adrenal steroidogenesis inhibitors and glucocorticoid receptor blockers. Pituitary. 2015, 18:245-52. 10.1007/s11102-014-0627-0
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Is Cushing Syndrome More Common in the US Than We Think?

Posted on June 11, 2024 by MaryO

I think members of the Cushing’s Help boards have been saying this forever!  Cushing’s isn’t all that rare.  Just rarely diagnosed,

 

BOSTON — The prevalence of Cushing syndrome (CS) in the United States may be considerably higher than currently appreciated, new data from a single US institution suggest.

In contrast to estimates of 1 to 3 cases per million patient-years from population-based European studies, researchers at the University of Wisconsin, Milwaukee, estimated that the incidence of CS in Wisconsin is a minimum of 7.2 cases per million patient-years. What’s more, contrary to all previous studies, they found that adrenal Cushing syndrome was more common than pituitary adrenocorticotropic hormone (ACTH)– secreting tumors (Cushing disease), and that fewer than half of individuals with adrenal Cushing syndrome had classic physical features of hypercortisolism, such as weight gain, round face, excessive hair growth, and stretch marks.

“Cases are absolutely being missed…. Clinicians should realize that cortisol excess is not rare. It may not be common, but it needs to be considered in patients with any constellation of features that are seen in cortisol excess,” study investigator Ty B. Carroll, MD, Associate Professor of Medicine, Endocrinology and Molecular Medicine, and the Endocrine Fellowship Program Director at Medical College of Wisconsin in Milwaukee, told Medscape Medical News.

There are several contributing factors, he noted, “including the obesity and diabetes epidemics which make some clinical features of cortisol excess more common and less notable. Providers get used to seeing patients with some features of cortisol excess and don’t think to screen. The consequence of this is more difficult-to-control diabetes and hypertension, more advance metabolic bone disease, and likely more advanced cardiovascular disease, all resulting from extended exposure to cortisol excess,” he said.

Are Milder Cases the Ones Being Missed?

Asked to comment, session moderator Sharon L. Wardlaw, MD, professor of medicine at Columbia University College of Physicians and Surgeons, New York City, said “When we talk about Cushing [syndrome], we usually think of pituitary ACTH as more [common], followed by adrenal adenomas, and then ectopic. But they’re seeing more adrenal adenoma…we are probably diagnosing this a little more now.”

She also suggested that the Wisconsin group may have a lower threshold for diagnosing the milder cortisol elevation seen with adrenal Cushing syndrome. “If you screen for Cushing with a dexamethasone suppression test…[i]f you have autonomous secretion by the adrenal, you don’t suppress as much…. When you measure 24-hour urinary cortisol, it may be normal. So you’re in this in-between [state]…. Maybe in Wisconsin they’re diagnosing it more. Or, maybe it’s just being underdiagnosed in other places.”

She also pointed out that “you can’t diagnose it unless you think of it. I’m not so sure that with these mild cases it’s so much that it’s more common, but maybe it’s like thyroid nodules, where we didn’t know about it until everybody started getting all of these CT scans. We’re now seeing all these incidental thyroid nodules…I don’t think we’re missing florid Cushing.”

However, Wardlaw said, it’s probably worthwhile to detect even milder hypercortisolism because it could still have long-term damaging effects, including osteoporosis, muscle weakness, glucose intolerance, and frailty. “You could do something about it and normalize it if you found it. I think that would be the reason to do it.”

Is Wisconsin Representative of Cushing Everywhere?

Carroll presented the findings at the annual meeting of the Endocrine Society. He began by noting that most of the previous CS incidence studies, with estimates of 1.2-3.2 cases per million per year, come from European data published from 1994 to 2019 and collected as far back as 1955. The method of acquisition of patients and the definitions of confirmed cases varied widely in those studies, which reported CS etiologies of ACTH-secreting neoplasms (pituitary or ectopic) in 75%-85% and adrenal-dependent cortisol excess in 15%-20%.

The current study included data from clinic records between May 1, 2017, and December 31, 2022, of Wisconsin residents newly diagnosed with and treated for CS. The CS diagnosis was established with standard guideline-supported biochemical testing and appropriate imaging. Patients with exogenous and non-neoplastic hypercortisolism and those who did not receive therapy for CS were excluded.

A total of 185 patients (73% female, 27% male) were identified from 27 of the total 72 counties in Wisconsin, representing a population of 4.5 million. On the basis of the total 5.9 million population of Wisconsin, the incidence of CS in the state works out to 7.2 cases per million population per year, Carroll said.

However, data from the Wisconsin Hospital Association show that the University of Wisconsin’s Milwaukee facility treated just about half of patients in the state who are discharged from the hospital with a diagnosis of CS during 2019-2023. “So…that means that an actual or approximate incidence of 14-15 cases per million per year rather than the 7.2 cases that we produce,” he said.

Etiologies were 60% adrenal (111 patients), 36.8% pituitary (68 patients), and 3.2% ectopic (6 patients). Those proportions were similar between genders.

On biochemical testing, values for late-night salivary cortisol, dexamethasone suppression, and urinary free cortisol were highest for the ectopic group (3.189 µg/dL, 42.5 µg/dL, and 1514.2 µg/24 h, respectively) and lowest for the adrenal group (0.236 µg/dL, 6.5 µg/dL, and 64.2 µg/24 h, respectively). All differences between groups were highly statistically significant, at P < .0001, Carroll noted.

Classic physical features of CS were present in 91% of people with pituitary CS and 100% of those ectopic CS but just 44% of individuals with adrenal CS. “We found that adrenal-dependent disease was the most common form of Cushing syndrome. It frequently presented without classic physical features that may be due to the milder biochemical presentation,” he concluded.

Carroll reports consulting and investigator fees from Corcept Therapeutics. Wardlaw has no disclosures. 

Miriam E. Tucker is a freelance journalist based in the Washington DC area. She is a regular contributor to Medscape, with other work appearing in The Washington Post, NPR’s Shots blog, and Diatribe. She is on X (formerly Twitter) @MiriamETucker.

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Cite this: Is Cushing Syndrome More Common in the US Than We Think? – Medscape – June 07, 2024.

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