Isolated left adrenal medullary hyperplasia

Abstract

A 44-year-old Japanese man was referred to our hospital for the evaluation of paroxysmal hypertension. ¹²³I-metaiodobenzylguanidine (MIBG) single-photon emission computed tomography (SPECT) revealed specific uptake in the left adrenal gland in addition to high levels of serum and urinary catecholamines although computed tomography and magnetic resonance imaging were not able to detect a definite adrenal mass. Left adrenalectomy was performed and he was diagnosed with adrenal medullary hyperplasia (AMH). A diagnosis of unilateral AMH is important because AMH resection can effectively treat hypertension.

<Learning objective: Isolated unilateral adrenal medullary hyperplasia (AMH) is a relatively rare disease that causes hypertension, and is generally diagnosed only after catecholaminergic symptoms mimicking pheochromocytoma. However, a diagnosis of unilateral AMH is important because AMH resection can effectively treat hypertension. ¹²³I-MIBG-SPECT is an important diagnostic modality for a diagnosis of unilateral AMH even though computed tomography and magnetic resonance imaging are not able to detect a definite adrenal mass.>

Introduction

Pheochromocytoma (PCC) is a catecholamine-producing tumor of the adrenal medulla that is composed of chromaffin cells. Up to 25% of PCC occurs in the context of hereditary cancer syndrome including multiple endocrine neoplasia type 2 (MEN2), von Hippel-Lindau disease, and neurofibromatosis type 1. Some patients with MEN2 have adrenal medullary hyperplasia (AMH) [1]. However, sporadic AMH, that is not associated with MEN2, is relatively rare and generally diagnosed only after presenting with catecholaminergic symptoms mimicking PCC [2].

We herein present a patient with sporadic AMH finally diagnosed by pathological examination of resected adrenal gland in addition to excessive catecholamine excretion and abnormal uptake in left adrenal gland by preoperative ¹²³I-metaiodobenzylguanidine (MIBG) single-photon emission computed tomography (SPECT) although computed tomography (CT) and magnetic resonance imaging (MRI) were not able to detect a definite adrenal mass.

Case report

A 44-year-old Japanese man was referred to our hospital for the evaluation of secondary hypertension. He had been diagnosed with mild hypertension when he was aged in his 20 s, and this had subsequently been treated with medication. He had presented at a local hospital with paroxysmal hypertension of up to 230/140 mmHg accompanied by a burning sensation and peripheral coldness six months previously. He was prescribed with amlodipine (10 mg/day), which did not control his paroxysmal blood pressure, which persistently reached 180/100 mmHg. Doxazosin (2 mg/day) was then added. During initial presentation at our hospital, his blood pressure was 168/100 mmHg under the above regimen and his pulse was 90 beats/min. Findings of a physical examination were all normal, and he did not have café-au-lait spots. He was 165 cm tall and weighed 65 kg. He had no medical or family history of PCC and AMH. However, both his mother and grandmother had hypertension which was controlled by anti-hypertensive agents.

Chest X-ray showed normal. Electrocardiography showed left ventricular hypertrophy. Transthoracic echocardiography demonstrated diffuse hypertrophy of the left ventricle, with a left ventricular ejection fraction of 60%.

The patient’s routine laboratory findings were as follows: white blood cell count, 5400/mm³; blood urea nitrogen, 13 mg/dL; creatinine, 0.9 mg/dL; sodium, 140 mEq/L; potassium, 3.6 mEq/L; calcium, 9.8 mg/dL; aspartate aminotransferase, 27 IU/L; alanine aminotransferase, 37 IU/L; lactate dehydrogenase, 167 IU/L; creatine kinase, 142 IU/L; plasma glucose, 97 mg/dL; hemoglobin A1c, 5.4%; negative urinary sugar and protein. His blood hormonal examination to evaluate the cause of hypertension showed normal except for serum norepinephrine and dopamine, and plasma aldosterone [epinephrine, 38 pg/mL (≤100); norepinephrine, 1205 pg/mL (100–450); dopamine, 30 pg/mL (≤20); cortisol, 10.39 μg/dL (6.24–18.0); adrenocorticotropic hormone, 20.4 pg/mL (7–56); aldosterone, 411 pg/mL (35–240); renin activity, 1.6 ng/mL/h (0.2–3.9); free T3, 3.66 pg/mL (2.37–3.91); free T4, 1.41 ng/dL (0.95–1.57); thyroid stimulating hormone, 2.3 μIU/mL (0.48–5.08); intact parathyroid hormone, 49.5 pg/mL (10.3–65.9)]. Captopril challenge test was performed and it was negative (aldosterone; time zero, 210 pg/mL, one hour, 154 pg/mL; renin activity; time zero, 5.3 ng/mL/h, one hour, 9.9 ng/mL/h).

Abdominal CT and MRI did not detect a distinct adrenal mass although the left adrenal gland appeared slightly enlarged (Fig. 1A, arrowhead) (Fig. 1B, arrow). However, ¹²³I-MIBG-SPECT revealed the significant uptake in the left adrenal gland (Fig. 1C–E). Urinary norepinephrine and dopamine were elevated >3-fold at 566.8 μg/day and 3839.9 μg/day, respectively and normetanephrine was elevated at 0.49 μg/day (Table 1). Head and neck MRI did not identify any abnormalities in the thyroid gland as well as head and neck paraganglioma.

Fig. 1.

Diagnostic imaging. Abdominal computed tomography (A) and magnetic resonance image (B) show a small nodule (5 mm in diameter) of the left adrenal gland (arrows). The strong uptake of the left adrenal gland is observed on ¹²³I-metaiodobenzylguanidine scintigraphy [C, planner image; D, single-photon emission computed tomography (SPECT) image, the left adrenal gland] (arrows) and the slight uptake was seen in the right adrenal gland (E, SPECT image, the right adrenal gland) (arrow).

Table 1.

Change of urine catecholamine before and after operation.

	Before	After	Normal range
Epinephrine	14.3	5.0	3.4–26.9 μg/day
Norepinephrine	566.8	117.1	48.6–168.4 μg/day
Dopamine	3839.9	797.8	365.0–961.0 μg/day
Vanillylmandelic acid	2.3	–	1.2–4.9 μg/mg·Cr
Metanephrine	0.14	0.09	0.04–0.18 mg/day
Normetanephrine	0.49	0.27	0.10–0.28 mg/day

As left AMH was suspected by the result of ¹²³I-MIBG-SPECT and significant increase of urine catecholamines, the dose of doxazocin was gradually increased to 10 mg/day, while that of amlodipine was reduced to 5 mg/day and this regimen decreased the patient’s blood pressure to 130/80 mmHg. Then, about two months later, he was admitted to the department of urology in our hospital, and the laparoscopic left adrenalectomy was successfully performed. A histological examination of the resected left adrenal gland revealed hyperplasia with the cortico-medullary ratio of around 1:1 (Fig. 2A), nests and funicular formations of large pleomorphic cells with eosinophilic materials and round nuclei (Fig. 2B). Those tumor cells were positive for chromogranin A (Fig. 2C and D). The final histopathological findings confirmed a diagnosis of AMH.

Fig. 2.

Histopathological findings of resected left adrenal gland. (A) Adrenal medullary hyperplasia in left adrenal medulla (arrows) (hematoxylin and eosin staining; bar, 500 μm). (B) Nests and trabecular formations of large pleomorphic cells with granular cytoplasm and round nuclei (hematoxylin and eosin staining; bar, 100 μm). (C and D) Large pleomorphic cells are positive for chromogranin A (arrows; bar, 500 μm: D; bar, 100 μm).

The patient’s urine catecholamine levels normalized soon after surgery (Table 1). His blood pressure decreased, but amlodipine, 5 mg was needed to control his blood pressure. Thus, we diagnosed essential hypertension with AMH because of his clinical course and his family history of hypertension without PCC or AMH.

Discussion

The proposed diagnosis of AMH is based on a clinical history of episodic attacks of hypertension and/or tachycardia suggesting PCC, increased catecholamine secretion, diffuse expansion of the adrenal medulla in the alae or tail of the adrenal gland with or without nodules, an adrenal medulla comprising enlarged cells with or without pleomorphism, and an adrenal corticomedullary ratio of <10:1 [3]. Furthermore, AMH is defined as a nodular and/or diffuse lesion of <1 cm in the adrenal medulla, where larger lesions are regarded as PCC. The diagnosis of AMH in our patient was consistent with all these criteria.

Nine patients with isolated unilateral AMH have been reported in Japan [4], [5], [6], [7], [8], [9], [10]. Three of them had AMH with size of >1 cm and one had no hypertension. Two patients were incidentally diagnosed with AMH at the time of surgery for renal tumors or adrenal cysts [6], [7]. Thus, only four Japanese patients including the patient described herein had hypertension with symptoms that mimicked PCC and suspected AMH before surgery. Routine diagnostic CT, MRI, and ultrasonographic imaging modalities usually cannot detect masses in adrenal glands. Thus, to preoperatively conclude a definitive diagnosis of AMH is often difficult [2].

Both AMH and PCC can be more sensitively and specifically identified and localized by ¹²³I-MIBG scintigraphy than by CT and ultrasonography [2]. In the present patient, ¹²³I-MIBG scintigraphy showed significant uptake of ¹²³I-MIBG in the left adrenal gland although CT and MRI were not able to detect any masses in the bilateral adrenal glands. After left adrenalectomy, urinary catecholamine levels became normalized and blood pressure was decreased in our patient. Thus, ¹²³I-MIBG scintigraphy can help to diagnose unilateral AMH based on significant uptake.

In conclusion, a diagnosis of unilateral AMH is important because AMH resection can effectively treat hypertension even though CT and MRI were not able to detect a definite adrenal mass. Thus, ¹²³I-MIBG-SPECT is an important diagnostic modality for discriminating unilateral AMH in patients with hypertension accompanied by elevated catecholamines values.