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Case report
eISSN 2799-8010 J Yeungnam Med Sci 2024;41(4):306-311 https://doi.org/10.12701/jyms.2024.00626
JYMS JOURNAL OF YEUNGNAM MEDICAL SCIENCE
Ruptured triple hormone-secreting adrenal cortical carcinoma with hyperaldosteronism, hypercortisolism, and elevated normetanephrine: a case report
Sin Yung Woo*, Seongji Park*, Kun Young Kwon, Dong-Mee Lim, Keun-Young Park, Jong-Dai Kim Division of Endocrinology, Department of Internal Medicine, Konyang University College of Medicine, Daejeon, Korea
We report a case of a ruptured triple hormone-secreting adrenal mass with hyperaldosteronism, hypercortisolism, and elevated normetanephrine levels, diagnosed as adrenal cortical carcinoma (ACC) by histology. A 53-year-old male patient who initially present- ed with abdominal pain was referred to our hospital for angiocoagulation of an adrenal mass rupture. Abdominal computed tomogra- phy revealed a heterogeneous 19 x 11 x 15 cm right adrenal mass with invasion into the right lobe of the liver, inferior vena cava, ret- rocaval lymph nodes, and aortocaval lymph nodes. Angiocoagulation was performed. Laboratory evaluation revealed excess cortisol via a positive 1-mg overnight dexamethasone suppression test, primary hyperaldosteronism via a positive saline infusion test, and plasma normetanephrine levels three times higher than normal. An adrenal mass biopsy was performed for pathological confirmation to com- mence palliative chemotherapy because surgical management was not deemed appropriate considering the extent of the tumor. Pathological examination revealed stage T4N1M1 ACC. The patient started the first cycle of adjuvant mitotane therapy along with ad- juvant treatment with doxorubicin, cisplatin, and etoposide, and was discharged. Clinical cases of dual cortisol- and aldosterone-se- creting ACCs or ACCs presenting as pheochromocytomas have occasionally been reported; however, both are rare. Moreover, to the best of our knowledge, a triple hormone-secreting ACC has not yet been reported. Here, we report a rare case and its management. This case report underscores the necessity of performing comprehensive clinical and biochemical hormone evaluations in patients with adrenal masses because ACC can present with multiple hormone elevations.
Keywords: Adrenocortical carcinoma; Adrenal mass rupture; Hyperaldosteronism; Hypercortisolism; Metanephrine; Pheochromocyto- ma
Introduction
Adrenal cortical carcinoma (ACC) is an uncommon tumor that originates in the adrenal cortex and accounts for ≤ 10% of adrenal incidentalomas [1-5]. Its incidence is approximately one case to two cases per million individuals annually, with biochemical evi-
dence of adrenocortical hormone production in approximately 45% to 70% of cases. Most patients presenting with hormone ex- cess commonly exhibit hypercortisolism as their primary symp- tom, which is observed in as many as 50% to 80% of hormone-se- creting ACCs, with 24% exhibiting concurrent virilization [6,7]. A few of these tumors primarily release aldosterone, with only 2.5%
Received: June 20, 2024 . Revised: July 31, 2024 . Accepted: August 2, 2024 . Published online: September 6, 2024
Corresponding author: Jong-Dai Kim, MD
Division of Endocrinology, Department of Internal Medicine, Konyang University College of Medicine, 158 Gwanjeodong-ro, Seo-gu, Daejeon 35365, Korea Tel: +82-42-600-9169 · Fax: +82-42-600-9090 · E-mail: jdkim78@nate.com
*These authors contributed equally to this work as co-first authors.
of all ACCs exclusively producing aldosterone [8]. Pheochromo- cytomas are catecholamine-secreting paragangliomas that develop in adrenal or extra-adrenal locations [9]. Cases of pheochromocy- toma concurrent with ACC have been documented, yet it is un- common for ACCs to manifest clinically as pheochromocytomas [10]. This case underscores an uncommon occurrence of ACC that clinically and biochemically mimics pheochromocytoma with cosecretion of aldosterone and cortisol.
Case
Ethics statement: This study was reviewed by the Institu- tional Review Board (IRB) of Konyang University Hospital (IRB No: 2024-05-002-003). Written informed consent was obtained from the patient to participate in the study. Informed consent for publication of the patient’s clinical details and im- ages was also obtained from the patient.
A 53-year-old man presented to the Emergency Department with a referral from another hospital for embolization of a ruptured right adrenal mass with retroperitoneal hematoma. The patient had been evaluated for a sudden-onset sharp, stabbing right abdomen pain that started 5 hours earlier after lifting a heavy object. His medical
history was significant for hypertension diagnosed 1 year earlier, which was not treated, and a 5 cm-sized adrenal adenoma diag- nosed 7 years earlier. Laboratory tests conducted 7 years ago to eval- uate the adrenal incidentaloma indicated potential primary hyperal- dosteronism with aldosterone levels at 20.2 ng/dL, which were at the high end of normal (range, 6.7-33.5 ng/dl), and suppressed plasma renin activity of 0.82 ng/ml/hr (range, 1-30.0 ng/ml/hr). Further testing 7 years ago confirmed excess cortisol production in- dependent of adrenocorticotropic hormone (ACTH), with an ACTH level of 2.17 pg/mL (range, 7.2-63.3 pg/mL), and a 1-mg overnight dexamethasone suppression test revealed a cortisol level of 11.63 µg/dL (range, <1.8 µg/dL) (Table 1). The last follow-up appointment at another hospital 2 years earlier did not reveal any change in tumor size or hormone work-up. There was no family his- tory of genetic syndromes that predisposed the patient to ACC. The patient had an elevated blood pressure of 130/100 mmHg, consistent with untreated hypertension.
Other vital signs were normal. Physical examination revealed pale conjunctiva and tenderness in the right upper quadrant and epigas- trium. No signs of hypertensive urgency, excess cortisol levels, or bruising were observed. No abdominal striae, central obesity, or ab- normal fat distribution was observed. Intravenous access was estab- lished through the right jugular vein, and a basic metabolic panel in- dicated normal creatinine levels. However, mild hypokalemia was
| Variable | 7 years ago | At present | At follow-up (3 months) | Reference range |
|---|---|---|---|---|
| Plasma | ||||
| Basal cortisol (µg/dL) | 14.9 | 10.9 | 9.31 | 5-27 |
| Basal ACTH (pg/mL) | 9.71 | 5.92 | <1.5 | 10-60 |
| Midnight cortisol (µg/dL) | 12.32 | 14.1 | NA | <7.5 |
| Plasma cortisol after ODST (µg/dL) | 11.63 | 18.3 | NA | <1.8 |
| Metanephrine (nmol/L) | NA | 0.08 | 0.07 | <0.35 |
| Normetanephrine (nmol/L) | NA | 2.98 | 0.82 | <0.64 |
| 17-a-OH progesterone (ng/ml) | 2.54 | NA | NA | 0.5-3.4 |
| Aldosterone (ng/dL) | 20.2 | 11.2 | 13.2 | 1-16 |
| Aldosterone after saline infusion test (ng/dL) | NA | 8.5 | NA | <6 |
| Plasma renin activity (ng/ml/hr) | 0.18 | 7.96 | 2.02 | 0.1-2.3 |
| 24-hr urine | ||||
| Free cortisol (µg/day) | 183.3 | NA | NA | 6-75 |
| VMA (mg/day) | 2.75 | NA | NA | <80 |
| Metanephrine (mg/day) | 0.15 | 0.09 | NA | <0.8 |
| Normetanephrine (mg/day) | 0.19 | 0.65 | NA | <0.5 |
| Epinephrine (ug/day) | 5.64 | NA | NA | <40 |
| Norepinephrine (µg/day) | 50.26 | NA | NA | <80 |
| 17-Ketosteroid (mg/day) | 10.6 | NA | NA | 10-20 |
ACTH, adrenocorticotropic hormone; NA, not applicable; ODST, overnight dexamethasone suppression test; VMA, vanillylmandelic acid.
observed with a potassium level of 3.46 mmol/L (3.0 mEq/L; range, 3.5-5.1 mmol/L), along with elevated liver enzymes at 166/108 IU/L (40/41 IU/L). Abdominal computed tomography (CT) revealed a heterogeneous 19x 11 x 15 cm right adrenal mass invading the right lobe of the liver, inferior vena cava, retrocaval
lymph nodes, and aortocaval lymph nodes (Fig. 1). The left adrenal gland was normal. The patient was referred to the Radiology De- partment for angioembolization, which was performed without complications. Antihypertensive medication (intravenous nicardip- ine) was initiated because of an elevated blood pressure of 160/120
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Because of the presence of hypertension and hypokalemia, serum aldosterone levels and plasma renin activity were evaluated, which revealed normal aldosterone at 11.2 ng/dL (range, 6.7-33.5 ng/dL) and non-suppressed plasma renin activity of 7.96 ng/ml/hr (range, 1-30.0 ng/ml/hr). A saline infusion test suggested primary hyper- aldosteronism with a post-infusion aldosterone level of 8.5 ng/dL (range, <6 ng/dL seated). Additional laboratory testing confirmed excessive cortisol production unrelated to ACTH, with an ACTH level of 2.17 pg/mL (range, 7.2-63.3 pg/mL). Furthermore, results from a 1-mg overnight dexamethasone suppression test indicated a cortisol level of 18.3 µg/dL (range, < 1.8 µg/dL). Plasma normeta- nephrine levels were elevated to 2.98 nmol/L (range, <0.64 nmol/ L). No further hormonal testing was performed.
Due to the presence of triple hormone hypersecretion and imag- ing findings suggestive of malignancy, adrenalectomy was consid- ered. However, given the severity of the local invasion, which would make clear margin resection difficult, and considering the low risk of rupture or rebleeding after embolization of all adrenal arterial inflows, palliative surgical resection was not performed. A biopsy of the right adrenal mass was performed for pathological confirmation to initiate palliative chemotherapy. The results showed tumor necrosis and positivity for inhibin a and vimentin, which was consistent with the diagnosed condition. Ki-67 staining revealed markedly increased proliferation (59.9% positive in 50 high-power fields) (Fig. 2). Next-generation sequencing (Cancer- SCAN [solid tumor L2]) revealed mutations in TP53 and CTN- NB1. Therefore, the patient was diagnosed with stage T4N1M1
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ACC, and the first cycle of adjuvant mitotane therapy was started, which was titrated to 500 mg four times per day. Adjuvant treat- ment with doxorubicin, cisplatin, and etoposide was also initiated because of the aggressive nature and rapid progression of the high- grade disease. The patient’s blood pressure remained within nor- mal range and the hypokalemia resolved without subsequent hy- perkalemia or decline in kidney function. The patient recovered smoothly and experienced an uncomplicated clinical course after embolization. The patient was discharged on antihypertensive therapy, mitotane, and codeine for pain control. His 3-month fol- low-up CT scan showed decreased sizes of the right adrenal gland, right para-aortic lymph nodes, and metastatic nodules in the right lobe of the liver. The patient is still alive (after 4 months). This case emphasizes the importance of maintaining a high level of suspicion of ACC in adrenal incidentalomas that mimic pheochromocyto- mas or present with elevated levels of multiple cortical hormones (aldosterone and cortisol).
Discussion
ACC is an infrequent yet markedly aggressive cancer, occurring at a rate of 0.7 to 2.0 cases per million people annually [1]. Approxi- mately 60% of these tumors are functional, with hypercortisolism being the most prevalent, affecting approximately half of all func- tional cases [11,12]. The remaining subtypes consist of mixed hor- mone-secreting tumors (25%), tumors secreting isolated sex hor- mones (20%), and tumors secreting isolated aldosterone (7.9%) [13]. According to a cohort study, patients with functional tumors experienced poorer long-term survival outcomes [13]. Currently, there are no available data indicating whether multiple hormone secretion affects the likelihood of malignancy [14].
Current guidelines advise screening all adrenal masses for bio- chemical excess, particularly hyperaldosteronism in cases of hyper- tension and/or hypokalemia, hypercortisolism, or catecholamine excess [4]. Additionally, patients with an abnormal aldoste- rone-to-renin ratio should undergo further confirmatory testing, which may include a saline challenge, oral salt loading, captopril challenge, or fludrocortisone suppression test. If spontaneous hy- pokalemia is present along with undetectable renin and a plasma aldosterone concentration >20 ng/dL (550 pmol/L), further confirmatory testing may be unnecessary [15]. In the current case, confirmatory testing was performed because of hypertension and hypokalemia; however, adrenal vein sampling was not possible due to rupture. In addition to aldosterone, it is essential to measure plasma or urinary metanephrines and conduct a 1-mg overnight dexamethasone suppression test (using a serum cortisol cutoff of ≤ 1.8 µg/dL [ ≤ 50 nmol/L]) in all patients with an adrenal mass
since as many as 50% of patients with adrenal incidentalomas show laboratory evidence of mild autonomous cortisol secretion (MACS) [4,16]. In the present case, the serum cortisol level after the overnight dexamethasone suppression test indicated MACS, with a value of 18.3 ug/dL, which is ten times the serum cortisol cutoff of ≤ 1.8 µg/dL.
This case revealed a functional tumor with hypercortisolism, hy- peraldosteronism, and elevated normetanephrine levels. There are only three reported instances of ACC producing metanephrine and five cases of dual hormone-secreting ACC with a combination of aldosterone and steroid hormones documented in the literature [14,17]. However, to the best of our knowledge, this is the first re- ported case of triple hormone-secreting ruptured ACC with hyper- cortisolism, hyperaldosteronism, and elevated normetanephrine levels. Six cases of ACC with dual secretion of aldosterone and cor- tisol have been reported. The proposed mechanism is believed to arise from genetic overlap between the genes responsible for cod- ing 11ß-hydroxylase and aldosterone synthase. This overlap may lead to the formation of a hybrid gene, resulting in heightened se- cretion of both enzymes, and consequently, both hormones [14].
Regarding metanephrine-producing ACC, only four cases have been documented in the literature. In one of these cases, an elevat- ed urine metanephrine level was observed, although it was not double the normal value [17-19]. In all four documented cases, metanephrine-producing ACC displayed histological characteris- tics typical of ACC, as observed in the present case. However, none of these patients had concomitant hyperaldosteronism. Three reported cases of mixed corticomedullary carcinoma in- volved solitary neoplasms comprising adrenocortical and chromaf- fin cells. Preoperatively, laboratory tests in one case confirmed both cortical and medullary hypersecretion, whereas only cortical hypersecretion was confirmed in the other two cases [20]. Conse- quently, it is evident that clinical and biochemical findings do not consistently match histological findings.
This case report highlights the importance of thorough clinical and biochemical hormone assessments in patients with adrenal masses because ACC can manifest with various hormone eleva- tions.
Article information
Conflicts of interest
No potential conflict of interest relevant to this article was report- ed.
Funding
None.
Author contributions
Conceptualization: all authors; Data curation: SYW, KYK; Formal analysis: KYK, DML, KYP, JDK; Validation: DML, KYP; Investi- gation: SYW, JDK; Resources: KYK; Supervision: DML, KYP, JDK; Writing-original draft: SYW, JDK; Writing-review & editing: SYW, SP
ORCID
Sin Yung Woo, https://orcid.org/0000-0001-6643-9751 Seongji Park, https://orcid.org/0000-0002-6876-5689 Dong-Mee Lim, https://orcid.org/0000-0001-9073-0872 Jong-Dai Kim, https://orcid.org/0000-0002-2606-3646
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