A puzzling malignant adrenal tumor

ARTICLE INFO

Keywords: Malignant adrenal tumor Adrenocortical carcinoma Pheochromocytoma

ABSTRACT

A previously healthy 49-year-old male presented with abdominal pain, constitutional syndrome, parox- ysmal palpitations and diaphoresis. Full-body CT scan showed a large malignant adrenal mass with abdominal lymph node and pulmonary metastasis. Biochemical studies revealed hypersecretion of catecholamines, cortisol, sexual steroids and steroid precursors; ACTH was not suppressed, and chro- mogranin A was negative. 18F-fluorodeoxyglucose PET/CT showed intense tracer uptake in the adrenal mass and abdominal lymph nodes. He was placed under adrenergic blockade and offered cytoreductive surgery, but his evolution was unfavorable with rapid clinical deterioration due to compressive abdom- inal symptoms, uncontrolled pain, peripheral oedema, cachexia and severe dilated cardiomyopathy. 123I-metaiodobenzylguanidine scintigraphy was negative. Poor clinical status precluded any surgical or systemic treatments. A biopsy of the adrenal mass suggested adrenocortical carcinoma. Two weeks later he developed recurrent level 3 non-insulin mediated hypoglycemias, with suppressed levels of insulin, C-peptide, IGF-1 and IGF-BP3. He responded poorly to palliative measures and died within a week, four months after the initial diagnosis. We present a puzzling case of an aggressive stage IV adrenal malignancy with bizarre secretory profile. Although we could not obtain a surgical specimen, combined available data suggested adrenocortical carcinoma. The pathophysiology is uncertain, and we explored exceed- ingly rare scenarios, including adrenocortical carcinoma masquerading as pseudo-pheochromocytoma; synchronous adrenocortical carcinoma and pheochromocytoma; adrenal mixed corticomedullary tumor; and ACTH-producing pheochromocytoma. The presence of ectopic ACTH-dependent hypercortisolism, discordant plasma and urinary metanephrine levels and IGF-2 mediated hypoglycemias were also quite perplexing. To our knowledge, this is the first report of a malignant adrenal tumor co-secreting steroid hormones with ACTH-dependent hypercortisolism, catecholamines and IGF-2. We faced obvious diag- nostic and therapeutic challenges and encourage future studies to explore the complex interactions between cortical and chromaffin cells of the adrenal gland, that may have bidirectionally contributed to this patient’s condition.

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A previously healthy 49-year-old male presented to his general practitioner with a 5-month history of left-sided diffuse abdominal pain, fatigue, involuntary weight loss, paroxysmal palpitations and nocturnal diaphoresis. He had no relevant family history. A thoraco-abdominopelvic computed tomography (CT) scan was ordered and showed a large (17.0 x 11.8 x 16.8 cm) heteroge- neous left adrenal mass highly suspicious for malignancy, and abdominal lymph node and pulmonary lesions suggestive of metastasis. The patient was urgently referred to our center. On physical examination, he was very pale and thin, with low-normal blood pressure and abdominal distension and discomfort. No clinical endocrine stigmata such as signs of hypercortisolism or feminization were noted. Biochemical studies were performed to address the hormonal status of the adrenal mass. Catecholamin- ergic activity was assessed by liquid chromatography coupled to tandem mass spectrometry on repeated assessments with- out drug or dietetic interferences, and revealed normal plasma free metanephrine (MN) and normetanephrine (NMN), elevated

plasma noradrenaline 2.0 times the upper reference limit (URL) [5479 pmol/L (470-2950)], and normal adrenaline. In contrast, 24-hour urinary fractionated metanephrines were elevated: 3-methoxytyramine at a maximum 12,291 nmol/d (0-1830), 6.7 times the URL; NMN 5,563 nmol/d (480-2424), 2.3 times the URL; and MN 7541 nmol/d (264-1729), 4.4 times the URL]. Urinary noradrenaline and dopamine were also elevated: maximum 6413 nmol/d (89-473), 13.6 times the URL, and 7,662 nmol/d (424-2,612), 2.9 times the URL, respectively; adrenaline level was normal. Additional laboratory tests documented hypercortisolism [serum morning cortisol 24.4 and 23.0 µg/dL after 1 mg dexam- ethasone; late-night salivary cortisol 0.495 µg/dL (0.000-0.208); 24-hour urinary free cortisol 102.4 µg/24h (4.3-176.0) with non-suppressed ACTH [84.5 and 47.8 pg/mL (9.0-52.0)]; and elevated sexual steroids and steroid precursors: estradiol [51.30 pg/mL (7.63-42.60)], dehydroepiandrosterone-sulfate [972 and 883 µg/dL (80-560)], delta-4 androstenedione [16.80 ng/ml (0.75-2.05)], 11-deoxycortisol [3.41 ng/ml (0.00-0.50)] and

21-deoxycortisol [0.64 µg/L (0.00-0.05)]. Primary hyperaldos- teronism was excluded; serum potassium was low-normal [3.28-4.88 nmol/L (3.50-5.00)]; and chromogranin A was nega- tive [<16.1 ng/ml (0-100)]. Full-body CT showed no additional lesions. Functional imaging was also performed, with 18F- fluorodeoxyglucose (FDG) PET/CT showing intense tracer uptake in the adrenal mass and abdominal lymph nodes. The patient was placed under adrenergic blockade and offered cytoreductive surgery for diagnostic and symptom management purposes. How- ever, progression was unfavorable, with rapid clinical deterioration requiring hospitalization. He exhibited compressive abdominal symptoms with uncontrolled pain, constipation and peripheral edema, cachexia, and hemodynamic instability with hypotension and tachycardia. The investigation continued with abdominal CT, excluding mechanical bowel occlusion, and a transthoracic echocardiogram documenting severe dilated cardiomyopathy. With potential intent of palliative treatment, he also underwent 123I-metaiodobenzylguanidine (123I-MIBG) scintigraphy, which was negative. A biopsy of the adrenal mass was finally per- formed; morphology and immunohistochemical profile revealed a malignant epithelioid neoplasm, notably with calretinin and CAM 5.2 positivity, chromogranin A negativity and Weiss score > 3 (Fuhrman nuclear grade III, > 5 mitotic figures/50 high power fields, presence of atypical mitotic figures and necrosis). These findings suggested adrenocortical carcinoma in this specific context. However, poor clinical status precluded any surgical or systemic treatment. Once stable, the patient was discharged under adren- ergic blockade, nutritional supplementation, opioid therapy and anti-edema measures, and referred to palliative care in addition to the usual endocrinology, medical and surgical oncology appoint- ments. Two weeks later, however, he was found unconscious, and was re-admitted to the emergency room. Severe hypoglycemia of 11 mg/dL was corrected with intravenous dextrose administration. He had no prior history of hypoglycemia. Level 3 hypoglycemia episodes recurred, and further biochemical tests suggested non- insulin-mediated hypoglycemia, with suppressed plasma insulin [<0.4pU/mL (2.6-24.9)] and C-peptide [0.13 ng/ml (1.10-4.40)]. IGF-2 assay was not promptly available, but IGF-1 and IGF-BP3 were also suppressed [<15.0 ng/ml (53.3-215)] and <0.500 mg/L (3.30-6-70), respectively]. He was placed under continuous con- centrated dextrose intravenous infusion, but responded poorly. It was decided to add subcutaneous octreotide 50 µg every 8 hours and prednisolone 40 mg/day, slightly reducing the severity of the hypoglycemia. Within a week, the patient died, 4 months after initial diagnosis. Clinical autopsy was not performed, as his family did not consent.

This was a puzzling case of aggressive stage IV adrenal malignancy, with a bizarre secretory profile of cortical and medullary hormones and possibly IGF-2. Based on clinical, imag- ing and biochemical data, we considered differential diagnoses of secretory malignant primary adrenal tumor an adrenocortical car- cinoma (ACC) masquerading as pseudo-pheochromocytoma and pheochromocytoma with ectopic ACTH secretion. Pathophysiology was uncertain, and we explored exceedingly rare scenarios. Clini- cally, paroxysms suggested pheochromocytoma, but the absence of hypertension argued against this. The compressive and con- stitutional symptoms argued for ACC. While ACC typically shows clinical evidence of hormone excess, particularly for cortisol, our patient did not have classical signs or symptoms of hyper- cortisolism or feminization; rapid onset and relative inefficient steroidogenesis could partially explain this [1]. Imaging alone is not discriminatory; yet the tumor’s huge size and irregular margins on conventional imaging, 18F-FDG positivity and 123I- MIBG negativity argued for ACC. The laboratory results were puzzling. Steroid excess with co-secretion of cortisol, estradiol and steroid precursors indicated a tumor of adrenocortical origin,

highly suspicious for ACC, while concurrent catecholamine excess suggested adrenomedullary hypersecretion by a pheochromocy- toma; and increased 3-methoxytyramine and dopamine levels, along with distant metastasis, suggested malignancy. Slightly ele- vated metanephrine levels, especially when inconsistent with a large tumor, might be non-specific and can be observed in ACC [2]. In the few reported cases, ACC presented as pheochromocy- toma primarily in clinical terms, and most catecholamine levels were ≤2 times the URL [3,4]. Our case stands out for its overt hor- monal production. We were also quite intrigued to find discordant plasma and urinary metanephrine levels, and would suggest that plasma free metanephrines have short half-life associated with rapid sulfate conjugation within the tumor and peripheral tissues, overstimulated by active hypercortisolism [5]. For histological eval- uation, unfortunately we could not obtain a surgical specimen; additional immunohistochemical markers and thorough tumor and capsule examination screening for high-grade components and capsular or vascular invasion would be necessary [1]. However, the combination of biopsy, clinical, imaging and laboratory data suggested ACC. Particularly, the absence of chromogranin A and presence of calretinin on immunohistochemistry favored adreno- cortical differentiation [2]. Adrenocortical neoplasms may in rare cases present as pseudo-pheochromocytoma preoperatively, with typical signs and symptoms and catecholamine elevation [3,4]. This could be explained by medullary hyperplasia secondary to environmental distortion by the cortical mass, or by immunohisto- chemical neuroendocrine features such as neuron-specific enolase and synaptophysin positivity, which correlate with catecholamine secretion in tumors with proven adrenocortical differentiation, including ACC. Chromogranin negativity might reflect fewer neu- rosecretory granules than in pheochromocytoma [2]. Synchronous ACC and pheochromocytoma in the same gland could be hypothe- sized, requiring both cellular components to be clearly demarcated [6]. Explanations for simultaneous tumors include incidental occur- rence, genetic predisposition syndrome, or paracrine stimulation of adrenocortical hyperfunction/proliferation by pheochromocytoma hormones with cortical neoplastic transformation and develop- ment of ACC [6]. Adrenal mixed corticomedullary tumor is also ultrarare, characterized by random admixture of both cortical and medullary cells in a single tumor, with varied ratios of histologi- cal components [7]. It produces catecholamines, steroid hormones (especially cortisol) and sometimes ectopic ACTH, with corre- sponding clinical syndromes. Metastatic cases have components of both ACC and pheochromocytoma, are very large and mainly pro- duce cortical hormones; pathogenesis could imply collision tumors, gene mutations and stemness factors [7]. ACTH-independent hypercortisolism accompanied by ACTH levels <10 pg/mL is the norm in ACC [1,2]. Surprisingly, we documented non-suppressed ACTH levels, suggesting ACTH-dependent hypercortisolism. This could be due to subclinical hypercortisolism with rapid onset or ectopic ACTH production by adrenocortical tumor cells, as recently suggested [8]. Although no specific tests to differentiate pituitary versus ectopic sources were performed, the anatomical and func- tional imaging exams were negative for other primary tumors. Also, subclinical hypercortisolism and unsuppressed ACTH lev- els were observed in adrenal mixed cortico-medullary tumors, along with bizarre medullary cells immunoreactive for ACTH, indicating ectopic ACTH production [7]. Another rare scenario suggesting concomitant ACTH-dependent hypercortisolism and catecholamine excess is an ACTH-producing pheochromocytoma; this could involve activation of steroid synthesis through cortical paracrine control by chromaffin cells and glucocorticoid-regulated positive feedback loops [9]. Nonetheless, our patient’s biopsy data, with absence of chromogranin, negative serum chromo- granin A assay and overt excess of other cortical steroids, argue against this. Finally, non-insulin-mediated hypoglycemia could be

explained by IGF-2 production by the large adrenal malignancy, which is an exceptionally rare occurrence reported in some cases of ACC and pheochromocytoma [1,8,10], with a contribution of severe malnutrition. To our knowledge, this is the first report of a malignant adrenal tumor co-secreting steroid hormones with ACTH-dependent hypercortisolism, catecholamines and, presum- ably, IGF-2. We faced obvious diagnostic and therapeutic challenges due to the tumor’s aberrant multihormonal nature, aggressive behavior and rapid progression, refractoriness to palliative mea- sures and severe clinical frailty. Although both ACC and malignant pheochromocytoma could explain most of the findings, the data taken together argues for ACC. This case proves that adrenal tumors have heterogeneous biology and behavior, and the interrelation- ship between hormone regulations should be further investigated. Cortical-chromaffin cell interactions may have contributed bidirec- tionally to this patient’s condition, and we encourage future studies to explore this intricate intra-adrenal crosstalk, which is yet to be fully elucidated.

Disclosure of interest

The authors declare that they have no competing interest.

Percovich-Hualpa J. “Metanephrin-producing adrenocortical carcinoma: a case report”. Revista Latinoamericana De Hipertensión [Internet] 2021;16(2) [Available from: https://www.redalyc.org/journal/1702/ 170269310012/170269310012.pdf].

[4] Alsabeh R, Mazoujian G, Goates J, Jeffrey Medeiros L, Weiss LM. “Adrenal cortical tumors clinically mimicking pheochromocytoma.”. Am J Clin Pathol 1995;104(4):382-90.

[5] Graeme E, Huynh T, Mayumi Hiroi, Karel Pacák. Understanding catecholamine metabolism as a guide to the biochemical diagnosis of pheochromocytoma. Rev Endocr Metab Disord 2001;2(3):297-311.

[6] Fassina A, Cappellesso R, Schiavi F, Fassan M. Concurrent pheochromocy- toma and cortical carcinoma of the adrenal gland. J Surg Oncol [Inter- net] 2011;103(1):103-4 [Available from: https://pubmed.ncbi.nlm.nih.gov/ 21031430/].

[7] Kimura N, Motoyama T, Saito J, Nishikawa T. Mixed corticomedullary tumor of the adrenal gland. Front Endocrinol [Internet] 2022; 13(16):1026918 [https://pubmed.ncbi.nlm.nih.gov/36187098/].

[8] Dilrukshi MDSA, Wickramarachchi AW, Abeyaratne DDK, Shine B, Bahram Jafar-Mohammadi, Somasundaram NP. An Adrenocortical Carcinoma Associ- ated with Non-Islet Cell Tumor Hypoglycemia and Aberrant ACTH Production. Case reports in endocrinology [Internet] 2020;(9):1-6 [Available from: https://doi.org/10.1155%2F2020%2F2025631].

[9] Elliott PF, Berhane T, Ragnarsson O, Falhammar H. Ectopic ACTH- and/or CRH-Producing Pheochromocytomas. J Clin Endocrinol Metab [Internet] 2021;106(2):598-608 [Available from: https://pubmed.ncbi.nlm.nih.gov/32710791/].

[10] Martínez García M, Trincado Aznar P, López Alaminos ME, González Fernández M, Alvarado Rosas A, Laclaustra Gimeno M. Persistent hypoglycemia due to an IGF-II-secreting malignant pheochromocytoma: a case report and literature review. Clin Case Rep 2020;8(12):2433-5.

Credit author statement

Francisca de Brito Marques performed: conceptualization;	Francisca de Brito Marques ª,* Lia Ferreirab
writing-original draft; writing-review and editing.	Henrique Reguengoc
Lia Ferreira performed: writing-review and editing.	Isabel Palma b
Henrique Reguengo performed: writing-review and editing.	a Department of Endocrinology, Pedro Hispano Hospital, Matosinhos Local Health Unit, Rua Dr. Eduardo Torres, Senhora da Hora, 4464-513 Matosinhos, Portugal
Isabel Palma performed: supervision; writing-review and edit- ing.
Ethical statement	b Department of Endocrinology, Santo António Local Health Unit, Largo Professor Abel Salazar, 4099-001
Written informed consent for publication was obtained.	Porto, Portugal " Department of Clinical Chemistry, Santo António Local Health Unit, Largo Professor Abel Salazar, 4099-001 Porto, Portugal
The publication of the manuscript was approved by the Local
Ethical Committee.
References
[1] Else T, Kim AC, Sabolch A, Raymond VM, Kandathil A, Caoili EM, et al. Adreno- cortical Carcinoma. Endocr Rev 2014;35(2):282-326.	* Corresponding author at: Serviço de Endocrinologia do Departamento de Medicina, Hospital Pedro Hispano, Rua Dr. Eduardo Torres,
[2] Fassnacht M, Dekkers OM, Else T, Baudin E, Berruti A, de Krijger RR, et al.
European Society of Endocrinology Clinical Practice Guidelines on the manage-	Senhora da Hora, 4464-513 Matosinhos, Portugal. E-mail address: franciscadbmm@gmail.com (F. de Brito Marques)
ment of adrenocortical carcinoma in adults, in collaboration with the European Network for the Study of Adrenal Tumors. Eur J Endocrinol 2018; 179(4):G1-46. [3] Latinoamericana De Hipertensión R, Latinoamericana S, Venezuela H, González-Fernández L, Añez-Ramos R, Rivas-Montenegro A, Moreno D,

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A puzzling malignant adrenal tumor

ABSTRACT

Disclosure of interest

Credit author statement

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