CushieBlog

Introduction

Cushing Syndrome (CS) is rare, with an estimated incidence of 0.2-5.0 per million people per year, and prevalence of 39-79 per million ⁽¹⁾. Ectopic ACTH Syndrome (EAS), a type of CS originating from extra-pituitary ACTH-secreting tumors, is uncommon. The prevalence of CS due to ACTH-secreting adrenal medullary lesions is not well established. However, EAS is observed in approximately 1.3% of all identified cases of pheochromocytoma ⁽²⁾. Recognizing EAS can be challenging due to its rarity, leading to delayed diagnosis.

Neuroendocrine neoplasms can produce CRH, which can lead to the secretion of ACTH by the pituitary. In certain cases, co-secretion of ACTH and CRH by an adrenal neoplasm has been observed. Only two published cases have provided definitive biochemical and immunohistochemical evidence of exclusive CRH secretion ⁽³⁾.

Case Report

A 57-year-old woman with a history of well-controlled hypertension sought care due to a two-month history of 60 lb weight gain, facial rounding, easy bruising, muscle weakness, lower extremity edema and acne. Her blood pressure control had worsened, and laboratory tests showed a markedly low serum potassium level of 1.8 mmol/L while taking hydrochlorothiazide. To manage her blood pressure, she was prescribed a calcium channel blocker, an angiotensin receptor blocker, and potassium supplements. However, her symptoms worsened, and she was referred to our emergency department. Blood pressure at presentation to our hospital was 176/86 mmHg. She had characteristic features of CS, including face rounding, supraclavicular fullness, dorsocervical fat accumulation, pedal edema, oral candidiasis, multiple forearm ecchymoses, and acneiform skin eruptions. No visible abdominal striae were present. She had no family history of pheochromocytoma, or multiple endocrine neoplasia type 2.

Serum cortisol level was 128 mcg/dL (normal range: 4.6-23.4) at 5 PM, with an ACTH level of 1055 pg/mL (normal range: 6-50); serum DHEA-S level was elevated at 445 mcg/dL (normal range: 8-188). Her 24-hour urine cortisol was at 12,566 mcg (normal range: 4.0-50.0). Plasma metanephrines were normal at <25 pg/mL (normal range: <57), and plasma normetanephrine was 44 (normal range: <148). A second plasma metanephrine measurement showed similar results. Serum aldosterone level and plasma renin activity were low at 2 ng/dL (normal range: 3-16) and 0.11 ng/mL/h (normal range: 0.25-5.82), respectively. Dopamine and methoxytyramine levels were not measured. An abdominal CT revealed a 4.8 x 4.5 x 5 cm right heterogeneously enhancing adrenal mass with a mean Hounsfield Unit of 68 in the non-contrast phase, and an absolute percentage washout of 30% (Fig 1A). The left adrenal gland appeared hyperplastic (Fig 1B). An Octreoscan, which was the in-hospital available nuclear medicine imaging modality, confirmed a 5.1 cm adrenal mass that was mild to moderately avid, with diffuse bilateral thickening of the adrenal glands and no other focal radiotracer avidity. A pituitary MRI did not show an adenoma, and EAS was suspected. Further evaluation with 68Ga-DOTATATE PET/CT (Fig 2) performed after her admission demonstrated an avid right adrenal mass consistent with a somatostatin receptor-positive lesion. No other suspicious tracer uptake was detected. These findings were consistent with a neuroendocrine tumor, such as pheochromocytoma.

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Fig. 1. Preoperative abdominal computed tomography scan showing a 4.8 x 4.5 x 5 cm right heterogeneously enhancing adrenal mass with irregular borders (A) and a hyperplastic left adrenal gland (B).

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Fig 2. 68Ga-DOTATATE PET/CT showing an avid right adrenal mass.

To control her symptoms while undergoing workup, the patient received oral metyrapone 500 mg thrice daily and oral ketoconazole 200 mg twice daily. Ketoconazole was stopped due to an increase in transaminases. The dosage of metyrapone was increased to 500 mg four times daily and later decreased to alternating doses of 250 mg and 500 mg four times daily. Within 3 weeks of starting medical therapy, serum cortisol level normalized at 20 mcg/dL. The 24-hour UFC improved to 246.3 mcg/24h. She experienced gradual improvement in facial fullness, acne, and blood pressure control.

The possibility of a silent pheochromocytoma was considered, and a-adrenergic blockade with doxazosin 1 mg daily was started 1 month prior surgery. She underwent surgery after two months of metyrapone therapy. With an unclear diagnosis and a large, heterogeneous adrenal mass, the surgical team elected to perform open adrenalectomy for en bloc resection due to concerns for an adrenal malignancy. The tumor was well-demarcated and did not invade surrounding structures (Figure 3A). H&E-stained sections showed classic morphologic features of a pheochromocytoma (Figure 3B), with immunohistochemistry demonstrating strong immunoreactivity for synaptophysin and chromogranin, and negative SF- I and inhibin stains excluding an adrenal cortical lesion. The sections analyzed by QuPath ⁽⁴⁾ revealed that approximately 4% of ce11s were ACTH cells, often found in isolation, and had a clear, high signal-to-noise staining (Figure 3C). CRH cells were less prevalent, comprising about 2.4% of the total analyzed cells, and tended to cluster together (Figure 3D). These cells had more background staining, resulting in a lower signal- to-noise ratio.

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Figure 3. Gross and Histopathological analysis of the patient’s pheochromocytoma. (A) Image of the gross excised specimen. (B) H&E staining (200x final magnification) demonstrates prominent vascularity and cells with finely granular, eosinophilic cytoplasm and salt-and-pepper chromatin. (C) ACTH staining (200x final magnification) shows clear and isolated positive cells, representing about 4.0% of the section analyzed by QuPath. (D) CRH staining (200x final magnification) reveals tight clusters of positive cells, accounting for 2.4% of the total cells. Positive (human placenta and hypothalamus) and negative (thyroid gland) control tissues performed as expected (data not shown).

The patient’s postoperative recovery was uneventful, with a short course of hydrocortisone which was stopped 1 week after surgery after HPA axis evaluation showed normal results. After one month, hypercortisolism had resolved, as shown by a normal 24-hour UFC at 28 mcg.

Administration of dexamethasone at 11 PM resulted in suppression of morning cortisol to 0.8 and 0.6 mcg/dL 1 and 7 months after surgery, respectively. Her liver function tests normalized, and blood pressure was well-controlled with amlodipine 10 mg daily and losartan 100 mg daily. Genetic testing for pheochromocytoma predisposition syndromes is currently planned.

Discussion

EAS accounts for 10-20% of cases of ACTH-dependent CS (5). This condition can be caused by several neuroendocrine neoplasms that produce bioactive ACTH (6) In the literature, we have found 99 documented cases of EAS caused by a pheochromocytoma. Of these, 93% showed ACTH expression. Only two cases have been reported with dual staining of ACTH and CRH (7). Exclusive CRH production has only been reported in two cases (8:9). However, the true prevalence of CRH-producing pheochromocytomas might be underestimated, as most cases testing for CRH expression was not performed.

Although the clinical presentation of EAS may be highly variable, there is often a rapid onset of hypercortisolism accompanied by severe catabolic symptoms. The diagnostic process should focus on identifying the location of a potential neuroendocrine neoplasm responsible for the ACTH secretion. Sometimes the peripheral origin of ACTH must be confirmed by inferior petrosal sinus sampling (IPSS). In this case, given the clinical presentation consistent with EAS, negative pituitary MRI, and the presence of an adrenal mass that needed to be removed independently, IPSS was not performed.

Neuroendocrine neoplasms express somatostatin receptors on their surface, which allow functional imaging using [11 lln]-pentetreotide (Octreoscan). However, Octreoscan has a low sensitivity in detecting occult EAS. In cases where the tumor is in the abdomen and pelvis, Octreoscan has limited utility in locating the source of ACTH (10). This increased risk of false negatives is caused by physiological tracer uptake by the liver, spleen, urinary tract, bowel, and gallbladder. The use of Gallium-68 labeled somatostatin receptor ligands (PET/CT 68Ga-DOTATATE) is more effective in detecting somatostatin receptors (SSTR2) than [11lln]-pentetreotide due to its higher spatial resolution and affinity (11)_ This test was performed after discharge form the hospital to rule out the presence of a second, smaller neuroendocrine tumor that the Octreoscan might have missed. A new molecular imaging technique targeting CRH receptors (68Ga CRH PET/CT) has shown potential in identifying tumors expressing CRH, but its availability remains limited (12). In our patient’s case, both the Octreoscan and 68Ga- DOTATATE successfully identified the adrenal tumor as a potential ACTH/CRH secretion source.

According to relevant guidelines, presurgical adrenergic blockade is recommended for patients with biochemical evidence of catecholamine excess ⁽13, 14⁾. Conversely, silent pheochromocytomas can generally be operated without alpha blockade ⁽¹⁵⁾. Despite this, we opted to administer pre-operative alpha blockade as a precautionary measure for this patient.

Pathology examination confirmed the diagnosis of pheochromocytoma. ACTH and CRH staining demonstrated that clear and significant populations of two separate ACTH and CRH positive cells were present in the excised pheochromocytoma. ACTH/CRH cells were dispersed throughout various regions of the pheochromocytoma rather than being well-defined, separate histological entities. As a result, there is no indication that this resulted from collision tumors, but rather random mutation and expansion of tumor cells into ACTH or CRH secreting cells. These results have limitations, including variation in ACTH and CRH expressing regions due to tumor heterogeneity, nonspecific binding of polyclonal antibodies, and normal low-rate false negative/positive detection using QuPath.

Post-surgical normal HPA activity was likely due to the de-suppression of the HPA axis by medical therapy, but it may also be explained by chronic stimulation of corticotroph cells induced by ectopic CRH secretion.

The standard approach to managing EAS involves surgical intervention. However, surgery may not be a viable option in cases where the source of ACTH production is unknown. Medical therapy to reduce or block excess cortisol can be used in such circumstances.

Conclusions

In conclusion, a pheochromocytoma causing EAS should be considered even in the absence of elevated plasma metanephrines. These tumors may simultaneously express ACTH and CRH.CRH.