Concomitant Existence of Bilateral Adrenal Adenomas. To Operate or Not?

Abstract

Nowadays, through the wide use of both magnetic resonance imaging and computed tomography, the diagnosis of adrenal incidentaloma is becoming increasingly frequent. Pheochromocytomas are neuroendocrine tumors which produce catecholamine, and they are characterized by headaches, palpitations, sweating and hypertension. Aldosterone-secreting adrenal cortical adenomas can cause various metabolic and cardiovascular diseases due to aldosterone excess. Our aim is to present a rare case of a concomitant existence of pheochromocytoma in the right adrenal and a functioning adrenal cortical adenoma in the left, worthwhile mentioning since the appearance of these two entities in different location in the same patient is unprecedented. The treatment remains challenging.

Keywords:adrenal incidentaloma, pheochromocytoma, non-functioning adenoma, primary aldosteronism, aldosterïnoma.

INTRODUCTION

A random radiological finding of an adrenal lesion greater than 1cm in diameter, conducted for other medical purpose, defines adrenal incidentaloma (AI) (1). It is of paramount importance to check patients with AI for pheochromocytoma, hyperaldosteronism (if hypertension exists), hypercortisolism and malignancy (2). The most common etiology of an AI is the non-functioning adenoma, and its prevalence is estimated at 80% (3). The incidence of pheochromocytoma itself is estimated to approximately 1:100.000 (4). The prevalence of primary aldosteronism in hypertensive patients is about 4% and it constitutes as the most common etiology of secondary hypertension (5). Bilateral adrenal hyperplasia is the main cause of primary aldosteronism, followed by other causes such as aldosteronoma (6). Concerning resistant hypertension, the prevalence of primary aldosteronism increases to 14-21% (7). The definition of resistant hypertension includes the elevation of systolic and diastolic blood pressure above the levels of 140 mm Hg and 90 mm Hg, respectively, which is not improved using three different antihypertensive drugs of different classes (8).

Herein, we describe the rare case of two distinct adrenal masses in location, defined as a left aldosteronoma and a histopathologically proven right pheochromocytoma.

CASE PRESENTATION

A 57-year-old Caucasian female patient with hypertension, headaches, flushing, palm sweating and palpitations, which lasted a few hours and regressed with orally administrated nifedipine (calcium channel blocker) 10 mg, referred to the emergency department. Three months before, an abdominal ultrasound (US) was conducted for annual precautionary purposes. US showed a compact, round, right adrenal mass. Subsequently, a computed tomography (CT) and Magnetic resonance imaging (MRI) of lower abdomen took place, which confirmed the existence of a well bordered lesion measuring 9 x 6.7 x 2.5 cm in the right adrenal. There was neither extension of the lesion to adjacent organs nor the surrounding fatty tissue was depicted as abnormal. The mass presented internal cystic degeneration and intense enhancement of compacts after intravenous administration of contrast media. The CT also demonstrated a lesion above the left kidney, with dimensions of 3.11 x 1.7 x 1cm. The lesion was homogenous, round-shaped not consistent to malignancy. An AI was revealed. A 123I-metaiodobenzylguanidine (MIBG) scintigraphy revealed a large, circumscribed uptake region in the anatomical position of the right adrenal gland. These findings were consistent with pheochromocytoma, and the patient was admitted to hospital for further examination. Her whole medical history contained diabetes type 2, osteoporosis and there were no hormonal symptoms. The vitals were normal except for blood pressure 150/90 mm Hg and the clinical findings on physical examination did not reveal any abnormality. The 24-hour urine metanephrine levels were elevated (4.700 mcg/day – normal <350 mcg/24 hours). Aldosterone/renin ratio was normal, and the 1 mg overnight dexamethasone suppression test were also normal. The patient was treated with phenoxybenzamine as well as atenolol in order to block á-1 vascular receptors and to prepare for surgical treatment. The patient underwent right laparoscopic adrenalectomy with clear surgical margins (R0) (Figure 1A). The surgical specimen measured 10.5 x 7.1 x 2.7 cm and weighed 103 g (Figure 1B). The histological examination demonstrated an encapsulated yellowish and brownish-hemorrhagic tumor of a soft composition. The cells varied in shape and size and were arranged in nests. They were polygonal, with eosinophilic cytoplasm and hyperchromasia was also noticed. Fibrous tissue was observed between the nests. The immunohistochemical staining was positive for Synaptophysin (+), Chromogranin (+), NSE (+) and negative for S-100 (-), Melan-A (-), HMB-45 (-), Inhibin (-). The cell proliferation index was below 1% in tumor cells. The pathologist confirmed the clinical diagnosis, and this lesion was characterized as pheochromocytoma (Figure 2).

Four days postoperatively symptoms disappeared and the levels of urinary catecholamines returned to normal. Blood pressure levels were normal (138/85 mm/Hg) and a follow-up program in the endocrinology department was recommended to the patient. The patient showed clinical improvement in blood pressure levels and all other above-mentioned symptoms disappeared. Also, the laboratory examinations of catecholamine levels remained normal. Imaging follow-up did not reveal any changes in left adrenal lesion measurements (Figures 3, 4 A, B). Unfortunately, the patient was lost to follow-up after two years.

Eleven years later, the patient reappeared due to the presence of edemas, weight gain, muscular cramps, and fatigue. The history of the left adrenal mass was already known. As a result, further evaluation was done. Regarding the vitals, only blood pressure was elevated at about 153/81 mm Hg. On physical examination, the patient had central obesity (BMI 30.8) with neither moon face nor abdominal cutaneous striae. Her personal history revealed type 2 diabetes mellitus (T2DM) and osteoporosis started more than 10 years ago. Firstly, urine and blood samples were obtained in order to check the functional status of the mass. Serum cortisol and adrenocorticotropic hormone (ACTH) were normal. Potassium levels were low (2.7 mMol/L), even though she did not receive any medication causing hypokalemia. After normalization of potassium levels, aldosterone concentration in plasma was 50 ng/dL and plasma rennin activity less than 0.5 ng/mL/h. Aldosterone/renin ratio was above limits and arterial gases demonstrated metabolic alkalosis. All findings were compatible to primary aldosteronism. Plasma- (43 pg/mL – normal 20-65 pg/mL) and 24-hour urinary (270 mcg/day – normal <350 mcg/24 hours) metanephrines fluctuated within the normal range. Similarly, normetanephrine levels were 60 pg/mL (normal 35-120 pg/mL) in plasma and 310 mcg/day (normal < 450 mcg/24 hours) in urine. Additionally, there were no abnormalities detected in serum creatinine, urea, electrolytes, and thyroid profile. Examinations revealed levels of urine free cortisol within normal limits and normal diurnal variation of serum cortisol levels. The levels of ACTH were between the normal ranges. Suppression of cortisol was observed after the 1 mg overnight dexamethasone suppression test. Triple antihypertensive therapy was administrated to the patient, including spironolactone, nifedipine and captopril. No surgery was performed and a follow-up every three months was decided to monitor any change in the lesion and clinical response to antihypertensive treatment. After one year, the patient was healthy, her blood pressure was controlled within limits, no symptoms have been referred and no enlargement of the remaining adrenal has been observed (Figure 4 C, D).

DISCUSSION

Some authors have described cases of bilateral adrenal adenomas coexistence, or adenomas found in the same gland (9-16). Our case is worthwhile mentioning since the second lesion was clinically initially non-secreting. We should highlight that the use of new imaging techniques, including CT or US, render the adrenal masses a more frequent finding (17). The use of CT-guided or US-guided biopsy would both discover more of these cases and improve patients’ clinical outcome since bilateral adrenalectomy and adrenal insufficiency would be prevented (18, 19).

The primary diagnostic objectives of an AI are either the definition of a malignancy or the existence of hormone secreting adrenal tumor (20). Imaging features in favor of benign adrenal lesion are less than 10 Hounsfield Units (HU) attenuation, fast washout of contrast medium in 10 to 15 minutes (20). Furthermore, round shape, size less than 4 cm, unilateral location and homogeneous density are all factors consistent with benign adenomas (21, 22). As far as our patient is concerned, the possibility of malignancy seems remote since it is homogenous, small in size and round shaped. In addition, the absence of tumor development for one year minimizes the possibility of malignancy.

Pheochromocytoma usually appears to individuals between 40- to 60-year-old and it has an equal incidence in both sexes (24). It is associated to von Hippel Lindau (VHL) syndrome, multiple endocrine neoplasia type 2 (MEN2) and neurofibromatosis type 1 (NF1) or it appears sporadically (25). Familial pheochromocytomas occur in younger ages and adrenals are not the only affected organ (26). Genetic tests are required for the diagnosis (27). In our case, we cannot exclude the presence of familial pheochromocytoma. However, the older age of the patient and the location of the lesion only in the adrenals do not constitute the typical clinical presentation of this medical entity. Furthermore, the cost of genetic tests was another problem for the patient. The classic clinical presentation of pheochromocytoma includes anxiety, diaphoresis, paroxysmal headaches, and palpitations (28). The measurement of blood and urine catecholamines and their metabolites are used for the preoperative diagnosis (29). Computed tomography remains the primary imaging tool for pheochromocytoma, as in our case. It can be demonstrated as heterogeneous, homogeneous, necrotic, cystic, or even solid with attenuation on contrast CT more than 10 HU (30). Magnetic resonance imaging (MRI) is used in patients with metastatic disease (29). We used the 123I-MIBG due to the big size of the primary lesion and its high risk for malignancy and possible metastasis; MIBG can be also useful for determining the exact location of the lesion, especially in the bigger ones (31, 32). In the microscope, cells could be polyhedral with dark granular cells with rounded nucleus (17). Preoperatively, it is of paramount importance to control blood pressure firstly with an a-adrenergic antagonist and subsequently use b-blockers. Last but not least important, removal of the entire gland after anti-hypertensive preoperative management is the primary treatment approach against pheochromocytoma. Follow-up requires yearly surveillance at least by lifetime measuring catecholamines and metanephrines in both plasma and urine for lifetime. Unfortunately, our patient was lost to follow- up until the re-appearance of symptoms. The use of CT or MRI is necessary during the follow-up period when laboratory tests reveal an abnormality (21).

The functional status of the tumor should be tested and evaluated as negative in order to diagnose a cortical adrenal lesion as non-functioning (33). The functional status is determined by the ratio of plasma aldosterone to plasma renin, urinary and plasma metanephrines, ACTH levels and dexamethasone suppression test. In individuals with AI in observation, a CT should be conducted in between three to six months and afterwards annually for two continuous years (3). Changes in the size of the lesion more than 0.8 cm or in the hormonal assessment during follow-up render surgery as an option (34). Non-functioning and unilateral tumors less than 4 cm with benign characteristics do not require surgical removal (35).

Our case was initially a non-secreting cortical adenoma, which turned into aldosteronoma. Hypokalemia with poor control of hypertension should raise suspicion for the diagnosis. However, it should be noted that normal levels of potassium are a frequent laboratory finding in this disease (36). A ratio of plasma aldosterone concentration to plasma rennin activity more than 30 is suggestive to primary aldosteronism (37). The main differential diagnosis is between bilateral adrenal hyperplasia and unilateral adenoma (6). The best way to diagnose it is the use of adrenal venous sampling. However, it is an invasive technique with various complications such as venous rupture (38). Its use is limited only to cases in which CT does not offer adequate information. Computed tomography is the initial radiological method used to examine the possibility of malignancy. For a unilateral adenoma, the treatment consists of surgical removal. However, drugs can be used for patients who are either unwilling or not appropriate for surgery (36). These drugs include mineralocorticoid receptor antagonists such as eprenelone or spironolactone. In our case, there is a therapeutic dilemma since there is only one adrenal left. Thus, its resection will cause adrenal insufficiency. Furthermore, its imaging characteristics show no elements of malignancy. Since there are no precise guidelines about two concomitant secreting adrenal adenomas, it was decided to proceed to pharmaceutical treatment and not to surgery. We preferred a pharmaceutical approach with more than one antihypertensive drug, including spironolactone, in order to achieve a better pressure control and minimize adverse events. This will prevent adrenal insufficiency and lifetime oral administration of hydrocortisone to the patient. However, any change to the imaging characteristics compatible to malignancy or resistance to antihypertensive treatment will lead to adrenalectomy.

CONCLUSION

In conclusion, this report is noteworthy as the patient develops two different histological types of adrenal masses in a different location and time, a treated pheochromocytoma and a concomitant non-functioning cortical adrenal adenoma, which turned into aldosteronoma. The clinical elements of this case highlight the need of thorough preoperative search of hormone secretion and radiological findings of the adrenal mass, due to the possibility of malignancy and the side-effects of a possible hormone-secreting lesion. Adrenal insufficiency, with the need of continuous glucocorticoid replacement caused by adrenalectomy of both glands, is another issue that should be examined. Thus, we believe that all patients with adrenal mass should be evaluated according to the guidelines for the management of AI (2).

Conflict of interests: none declared.

Financial support: none declared.

Patient’s written informed consent for the publication of this case report and any accompanying images was obtained.

FIGURE 1.

Surgical operation. A: Laparoscopic right adrenalectomy; B: Surgical specimen

FIGURE 2.

Histopathological findings. A: Pheochomocytoma consisting of small nests (zellballen) and solid sheets of polygonal shaped cells in a rich vascular network, with capsular and adipose tissue invasion and a compressed rim of adrenal cortex on the upper right (hematoxylin-eosin, original magnification x20); B: Pheochromocytoma composed of cells of various nuclear pleomorphism, with finely granular basophilic cytoplasm and round oval nuclei with prominent nucleolus (hematoxylin-eosin, original magnification x200); C, D: Strong positive cytoplasmic staining of pheochromocytoma cells for chromogranin and synaptophysin, respectively (immunohistochemistry, original magnification x100); E: Ki67 proliferation index shows a low proliferative activity (approximately 1%) (immunohistochemistry, original magnification x400)

FIGURE 3.

Postoperative imaging two years after right laparoscopic adrenalectomy. Follow-up magnetic resonance imaging indicated absence of right adrenal lesion measurements and no changes in left adrenal ones (T1 weighting)

FIGURE 4.

Postoperative imaging after right laparoscopic adrenalectomy. Follow-up computed tomography indicated absence of right adrenal lesion measurements and no changes in left adrenal ones. A: two years postoperatively; B: 14 years postoperatively