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A case report of subclinical hypercortisolism due to adrenal incidentaloma complicated by myasthenia gravis after adrenalectomy

Abstract

A 62-year-old woman was admitted for evaluation of an incidentally discovered adrenal mass and hypertension. CT scan revealed a 7 cm mass in the right adrenal gland. After careful examination, the patient was diagnosed with subclinical hypercortisolism (SH). Adrenalectomy was performed. Histopathological examination showed an adrenocortical adenoma. Symptoms and signs of myasthenia gravis appeared 5 months later. CT of the chest showed a solid tissue mass in the mediastinum. The patient underwent a sternotomy with excision of the tumor, which histologically proved to be a type 2B thymoma. We describe a rare case of SH due to an incidentally discovered adrenocortical adenoma in a patient who manifested myasthenia gravis after surgical remission of the cortisol excess.

Tumori 2016; 102(Suppl. 2): e35 - e39

Article Type: CASE REPORT

DOI:10.5301/tj.5000503

Authors

Luigi Petramala, Cristiano Marinelli, Anna Teresa Giallonardo, Antonio Concistrè, Piernatale Lucia, Federico Venuta, Bruna Cerbelli, Antonio Ciardi, Giorgio De Toma, Claudio Letizia

Article History

Disclosures

Conflict of interest: None.
Financial support: None.

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Introduction

Cushing’s syndrome (CS) results from a chronic glucocorticoid excess with clinical signs and symptoms. Autonomous glucocorticoid excess without specific signs and symptoms of CS is termed subclinical hypercortisolism (SH) and is present in 5%-30% of adrenal incidentalomas (1). Endogenous hypercortisolism, similar to the use of exogenous glucocorticoids, induces a reversible state of immunosuppression, and this effect may determine the new onset of autoimmune diseases after remission of hypercortisolism. Recently, da Mota and coworkers (2) reported in a series of 66 consecutive cases of confirmed overt CS that the incidence of autoimmune disease was 16.7%.

We describe a rare case of SH due to an incidentally discovered adrenocortical adenoma in which the patient developed myasthenia gravis after surgical remission of the cortisol excess. To the best of our knowledge this is the first documented case of SH associated with myasthenia gravis.

Case report

A 61-year-old woman presented to our Specialized Center of Secondary Hypertension for evaluation of a 7 cm right adrenal mass that was discovered by ultrasonography performed for abdominal pain and arterial hypertension. On the computed tomography (CT) scan of the abdomen the adrenal mass appeared round shaped and homogeneous, with slight enhancement after intravenous administration of contrast medium. Her past medical history was remarkable for euthyroid multinodular goiter and polyglobulia with a negative JAK2 (V617F) test result on genetic analysis.

The patient was overweight (BMI 28 kg/m2, waist circumference 95 cm) and had mild arterial hypertension (150/100 mmHg). No physical signs of overt hypercortisolism or neuromyopathy were found at clinical examination. In particular, she had no cushingoid features such as purple striae, centripetal obesity, supraclavicular fat pad accumulation and buffalo hump, proximal weakness or plethora.

Laboratory analysis showed normal electrolytes, creatinine and glucose, and an altered hemogram and lipid profile (Tab. I). Measurements of plasma aldosterone (11.8 ng/dL), plasma renin activity (1.5 ng/mL/h), plasma DHEA-S (5 ng/dL) and total urinary metanephrines (107 µg/24h) were all normal. Urinary free cortisol excretion was 373 nmol/24 hours, while plasma cortisol am was 28 µg/dL and was not suppressible by 1 mg and 8 mg dexamethasone (DXM) overnight test (13.4 µg/dL and 10.2µg/dL, respectively); plasma adrenocorticotropic hormone (ACTH) am was 9.4 pg/mL (Tab. II). A bone mineral density test revealed marked osteoporosis (lumbar total T score: -4.2; femoral neck T score: -3.5).

General laboratory data

Values Normal range
Peripheral blood
 Red blood cells 5.36 (×1012/L) (3.5-5.10)
 White blood cells 6.71 (×109/L) (4.4-11.3)
 Hemoglobin 16.6 (g/dL) (12-15.30)
 Hematocrit 48.7 (%) (35-47)
 Platelets 266 (×109/L) (150-450)
Blood biochemistry
 Total protein 6.3 g/dL (6.3-8.4)
 Albumin 58.4% (55.8-66.1)
 Lactate dehydrogenase 167 U/L (80-200)
 Aspartate aminotransferase 28 U/L (8-38)
 Alanine aminotransferase 30 U/L (4-44)
 Gamma glutamyl transferase 32 U/L (6-42)
 Total bilirubin 0.3 mg/dL (0.2-1.2)
 Total cholesterol 287 mg/dL (81-235)
 HDL-cholesterol 54 mg/dL (45-65)
 LDL-cholesterol 193 mg/dL (70-130)
 Triglycerides 202 mg/dL (45-165)
 Creatinine 0.8 mg/dL (0.50-0.90)
 Uric acid 4.2 mg/dL (2.4-5.7)
 Sodium 142 mEq/L (136-145)
 Chloride 111 mEq/L (90-120)
 Potassium 3.4 mEq/L (3.4-5.5)
 Calcium 8.9 mg/dL (8.4-10)
 Fasting plasma glucose 100 mg/dL (70-100)
 Microalbuminuria 13 mg/L (0-28)

Preoperative hormonal examination of the adrenal incidentaloma and postoperative examination after adrenalectomy

Hormonal parameters (morning values) Values Reference range
Preoperatively Postoperatively
Adrenocorticotropin 9.4 15.3 (10-62 pg/mL)
Plasma cortisol 28 10.7 (4.6-22 µg/dL)
Plasma renin activity (PRA) 1.5 1.2 (0.2-2.8 ng/mL/h)
Plasma aldosterone (PAC) 11.8 10.7 (3-16 ng/dL)
PAC/PRA ratio 7.8 8.9 (<30 ng/dL:ng/mL/h)
Dehydroepiandrosterone sulfate 40 32 (30-260 µg/dL)
Thyroid stimulating hormone 2.5 2.6 (0.3-4 mU/L)
Urinary free cortisol 373 173 (38-208 mmol/24h)
Urinary aldosterone 18 20 (2.8-34 µg/24h)
Urinary total metanephrines 80 78 (52-341 µg/24h)
Urinary vanillylmandelic acid 7 5 (2-10 mg/24h)
Overnight dexamethasone suppression test
 1 mg: Plasma cortisol 13.4 (<1.8 μg/dL)
 8 mg: Plasma cortisol 10.2 (<1.8 μg/dL)

These data were consistent with a diagnosis of SH due to a large right adrenal mass. After appropriate information and discussion with the patient, open surgery under general anesthesia was planned based on a multidisciplinary approach. We first performed an exploratory laparotomy through a midline incision with appropriate antihypertensive therapy (amlodipine 10 mg and bisoprolol 2.5 mg) resulting in good control of blood pressure. Exploration of the abdomen revealed a 7 × 5 cm lesion originating from the right adrenal gland, which was completely excised with a total adrenalectomy. Macroscopic examination of the lesion showed an ocher-colored mass with gray areas, measuring 7 cm in diameter. Histological examination revealed nodular proliferation with a trabecular architecture, consisting of a dual cell population with clear vacuolated cytoplasm and eosinophilic granular cytoplasm, and many areas with hemorrhage and fibrosis. The final diagnosis was benign adrenocortical adenoma. Postoperative glucocorticoid therapy consisted of intravenous hydrocortisone hemisuccinate (200 mg to 30 mg per day) for 6 days and oral hydrocortisone 20 mg per day tapered to 10 mg one day after the operation.

After surgery, she started reporting weakness in the upper legs. Five months later, the cortisol excess had improved (Tab. II) but she developed worsening bilateral ptosis and double vision. On admission to our center, neurological examination showed bilateral ptosis (more evident on the right) and horizontal diplopia (suggesting bilateral rectus medialis weakness, predominant in the right eye) and proximal muscle weakness in the arms bilaterally (residual strength: 3/5, MRC score). Sensation was normal. Magnetic resonance imaging of the brain showed a small ischemic lesion in the left midbrain. An ice pack test was positive (increased palpebral fissure for at least 3 minutes after the application of an ice pack on the closed ptotic eyelid). Electromyography with single-fiber analysis of the left extensor carpi, right deltoid, right trapezius, right supraspinatus and left corrugator muscles showed abnormal jitter (>80 ms) in the left corrugator. Acetylcholine receptor (AChR) binding antibodies were positive (12.70 mmol/L; normal range <0.45 mmol/L).

A chest CT scan showed a solid tissue mass in the anterior mediastinum (Fig. 1A). Myasthenia gravis and thymoma were suspected. The patient was therefore started on pyridostigmine 180 mg/day and prednisone 25 mg/day, with no evident benefit. Subsequently, she underwent surgery for the anterior mediastinal mass with en bloc resection of the tumor and complete thymectomy. Microsopic histopathology showed moderate lymphocyte infiltration and plump epithelial cells with vesicular nuclei (Fig. 1B). These findings corresponded to the features of a type 2B thymoma according to the 2014 WHO classification.

(A) Chest computed tomography showing a solid tissue mass in the anterior mediastinum. (B) Type B2 thymoma (H&E, ×20). There is an even proportion of neoplastic epithelial cells and non-neoplastic lymphocytes (a). Neoplastic epithelial cells strongly immunoreactive for keratin 19 (b). Non-neoplastic epithelial immature thymocytes, immunoreactive for CD1a (c). Mature non-neoplastic T lymphocytes, immunoreactive for CD8 (d).

During the 1-year follow-up in our center, the patient did not experience any myasthenic symptoms and had normal electrodiagnostic tests. She remained well on pyridostigmine 120 mg/day and antihypertensive therapy (amlodipine and bisoprolol) with good control of blood pressure.

Discussion

The patient with an incidentally discovered large adrenal mass had no specific clinical manifestations of overt hypercortisolism, although she had hypertension and osteoporosis. The plasma and urinary cortisol levels were increased and the cortisol concentration was not suppressed (>1.8 µg/dL) during overnight 1 mg and 8 mg DXM suppression tests, while the plasma ACTH level was low. All findings indicated that the patient had SH. These abnormalities improved after resection of the right adrenocortical adenoma.

The routine use of abdominal procedures has significantly increased the incidental finding of adrenal lesions. The prevalence of these masses, commonly defined as adrenal incidentalomas, ranges from 2%-3% in autopsy series to 4% in radiological series, reaching 5%-8% in oncology studies and increasing with patients’ age (3).

Although clinically silent, 5%-30% of adrenal incidentalomas are responsible for a subtle cortisol overproduction, commonly defined as SH (3). SH is defined as ACTH-independent cortisol secretion by adrenal adenoma or hyperplasia in the absence of specific signs and symptoms of overt cortisol excess such as moon face, buffalo hump, purple striae, and central obesity. There is no consensus on the best treatment strategy nor on the gold standard test to diagnose and confirm SH.

With regard to diagnosis, the DXM test at various doses and protocols (1 mg, 2 days low dose and 8 mg high dose) has been proposed with various cutoff values, from 1.8 to 5 µg/dL (4). In addition to DXM, other tests have been used to diagnose or confirm SH; at present, serum ACTH level and urinary free cortisol level are used (4, 5). SH patients may experience metabolic and cardiovascular symptoms including hypertension, obesity, diabetes mellitus and osteoporosis due to continuous glucocorticoid excess (1).

With regard to treatment, laparoscopic adrenalectomy is a safe and effective procedure and has become the surgical technique of choice for benign adrenal masses. Controversy remains regarding the suitability of the laparoscopic approach for large lesions and lesions presumed to be malignant. Finally, there is general consensus that patients with SH require glucocorticoid replacement therapy to prevent the risk of adrenal insufficiency (5).

Glucocorticoid excess has an inhibitory effect on immune complex formation. In fact, patients with CS present lymphoid tissue involution and lymphopenia as well as increased susceptibility to infections. The opposite may occur in patients who are cured from CS. Indeed, development or exacerbation of autoimmune diseases has been reported in patients with cortisol secretion normalized after remission of CS (5). This appears to be related to improved activity of the immune system, which was suppressed by endogenous hypercortisolism during the active phase of the disease. It should therefore be borne in mind that an immune disease which is silent during the active phase of hypercortisolism may appear or reappear after complete remission of the chronic exposure to high glucocorticoid levels (6, 7).

In our patient, the hypercortisolism improved after resection of the right large adrenal mass but she developed clinical signs of myasthenia gravis associated with positive AChR antibodies and a type 2B thymoma. Despite an extensive literature search, we could not identify any published reports on patients who had SH due to adrenal incidentaloma and myasthenia gravis with thymoma. The occurrence of myasthenia gravis and thymoma before improvement of the cortisol excess in SH might be due to an autoimmune mechanism (8). Myasthenia gravis caused by a defect in the transmission of nerve impulses to muscle is a chronic autoimmune neuromuscular disease characterized by muscle weakness that increases during periods of activity and improves after periods of rest (9).

An interesting feature of myasthenia gravis is that 15%-20% of patients have an abnormality in their thymus: many patients have a hyperplastic thymus with germinal centers, while others have thymic tumors (10). Thymoma is the most common tumor of thymic epithelial cells; it arises within the thymus and accounts for 50% of anterior mediastinal masses (9). Nevertheless, thymomas are rare in humans, representing less than 0.5% of all cancers, and they are typically slow growing tumors that spread locally. They are relatively benign and are classified into 5 WHO histopathological subtypes. Surgery is the cornerstone of the management of thymomas for histopathological diagnosis and staging (11).

The high rate of association of thymoma with anti-AChrR antibodies strongly suggests a cause-effect relationship. In particular, thymoma patients who have clinical symptoms of myasthenia gravis invariably present anti-AChR antibodies. This demonstrates that thymoma plays an important role in the initiation of the autoimmune response to AChR (12).

In conclusion, we reported a single case of a patient with SH due to an adrenal incidentaloma who manifested signs and symptoms of myasthenia gravis associated with thymoma, before the cortisol excess improved with right adrenalectomy.

Disclosures

Conflict of interest: None.
Financial support: None.
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Authors

Affiliations

  • Department of Internal Medicine and Medical Specialties, La Sapienza University, Rome - Italy
  • Department of Neurological Sciences, La Sapienza University, Rome - Italy
  • Department of Thoracic Surgery, Policlinico Umberto I, La Sapienza University, Rome - Italy
  • Department of Surgery “Pietro Valdoni”, La Sapienza University, Rome - Italy

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