Adrenal Carcinoma

A 20‐year‐old, previously healthy female college track athlete noted that her sprint times were worsening in association with the development of bilateral lower extremity edema over a month's time. She sought medical attention. The edema was mild but repeated blood pressures were 150–155/100 mm Hg and a laboratory panel revealed an alanine aminotransferase level of 49 U/L (normal range: 5–35), random glucose of 152 mg/dL, and a potassium level of 3.1 mEq/L (normal range: 3.5–5.0). Atenolol 50 mg q.d. was prescribed for her hypertension.

Due to persistent back pain, a physical therapy evaluation was requested and thoracolumbar films revealed numerous pulmonary nodules. A follow‐up computerized tomography (CT) scan showed a 20‐cm mass apparently in the liver or adrenal gland along with multiple lung nodules ranging in size up to 1.7 cm. A previously ordered spot morning chemistry showed a 9 a.m. cortisol level of 40.3 μg/dL (normal range: 5–25) and an upright aldosterone level of 18.5 ng/dL (normal range: 4–31). Hospitalization followed.

The patient described frequent epistaxes, the appearance of stretch marks over the lower extremities, early satiety, abdominal bloating, a feeling of facial swelling, reduced spotty menses, and the onset of facial hair during the prior 2 months. Physical examination demonstrated a young female with facial fullness and darkened hair on the lips and chin. Blood pressure was 152/94 mm Hg. Nontender right upper quadrant fullness was noted along with purplish striae involving both upper thighs and mild bilateral lower extremity pitting edema.

Magnetic resonance imaging/magnetic resonance angiography (MRI/MRA) of the abdomen showed a right adrenal mass with invasion into and complete obliteration of the inferior vena cava (IVC) by thrombus along with multiple liver and lung metastases. A 24‐hour urine catecholamine collection was 85 meg (normal range: 0–135), human chorionic gonadotropin level was <5 mlU/mL (<6.2), a 24‐hour urine‐free cortisol reading was 1575 (μ/dL (normal range: 20–90), and blood adrenocorticotrophic hormone (ACTH) value was <1 pg/mL (normal range: 9–52).* Microscopic pathology of a CT‐guided biopsy of the adrenal mass revealed adrenal cortical adenoma or adrenal cortical neoplasm of undetermined malignant potential.

Laparotomy resulted in a right adrenalectomy and nephrectomy to remove a large adrenal tumor along with IVC thrombectomy. The maximal tumor dimension was 20 cm with a weight of 1500 mg (Figure 1). Pathology showed a necrotic, poorly differentiated, malignant neoplasm consistent with adrenal cortical carcinoma. With synaptophysin staining, a protein involved in neurotransmitter exocytosis and a neuroendocrine marker ¹ was positive (Figure 2). Mitotane with adjunctive chemotherapy was advised upon postoperative recovery.

Figure 1.

Right adrenalectomy and nephrectomy revealing a 20 cm 1500 g adrenal tumor with areas of hemorrhage

Figure 2.

Microscopic tumor specimen staining positive for synaptophysin, a generic neuroendocrine marker

DISCUSSION

This young woman presented with features of rapid‐onset Cushing's syndrome compatible with corticotrophin dependent or independent disease, and also had virilization characteristics. Features of Cushing's syndrome are listed in Table I, including hypertension, which is diastolic in 82% of affected individuals. ² Causes of Cushing's syndrome (Table II) often require extensive metabolic testing to diagnose, but initial imaging studies revealing metastatic lung disease and a large adrenal mass readily forecasted the diagnosis of adrenal carcinoma.

Table I.

Classification of Causes of Cushing's Syndrome

ACTH dependent

Cushing's disease (pituitary dependent)

Ectopic ACTH syndrome

Macronodular adrenal hyperplasia

ACTH independent

Adrenal adenoma and carcinoma

Primary pigmented nodular adrenal hyperplasia and Carney's syndrome

Primary pigmented nodular adrenal hyperplasia and Carney's syndrome

McCune‐Albright syndrome

Aberrant receptor expression (gastric inhibitory polypeptide, interleukin‐1B)

Iatrogenic (e.g., pharmacologic doses of prednisolone, dexamethasone)

Pseudo‐Cushing's syndromes

Alcoholism

Depression

Obesity

ACTH=adrenocorticotrophic hormone Adapted from Williams Textbook of Endocrinology. 10th ed. Philadelphia, PA: WB Saunders; 2003:508–525. 2

Table II.

Prevalence of Symptoms and Signs in Cushing's Syndrome

Findings	%
Symptoms
Weight gain	91
Menstrual irregularity	84
Hirsutism	81
Psychiatric dysfunction	62
Backache	43
Muscle weakness	29
Fractures	19
Loss of scalp hair	13
Signs
Obesity	97
Truncal	46
Generalized	55
Plethora	94
Moon face	88
Hypertension	74
Bruising	62
Red‐purple striae	56
Muscle weakness	56
Ankle edema	50
Pigmentation	4
Other findings
Hypertension	74
Diabetes	50
Overt	13
Impaired glucose tolerance test	37
Osteoporosis	50
Renal calculi	15
Adapted from Williams Textbook of Endocrinology. 10th ed. Philadelphia, PA: WB Saunders; 2003:508–525. 2

A very elevated, 24‐hour urine‐free cortisol level established the diagnosis in this patient. An 8 a.m. plasma cortisol >5 μg/dL following 1 mg dexamethasone at midnight would have been an alternative initial diagnostic test. Due to episodic secretion from adenomas and incorrect collections, 8%–15% of urinary cortisol collections are normal in Cushing's syndrome, and intermediate elevations need to be confirmed by follow‐up testing. ² With a less dramatic presentation, the next algorithmic step would have been low‐dose dexamethasone suppression to establish the diagnosis of Cushing's syndrome. In pituitary‐dependent Cushing's disease, 50% of 9 a.m. ACTH levels are in the normal range, and an expected nadir midnight ACTH level of >23 pg/mL is more discriminatory for ACTH‐dependent disease. ² An undetectable ACTH is the expected result for patients with adrenal tumor. Hypokalemic metabolic alkalosis, seen with this adrenal carcinoma patient, is common in patients with ectopic ACTH syndrome (>95%), but uncommon with primary pituitary disease (<10%) ² or adrenal carcinoma, occurring in only two out of 34 individuals in one series. ³

Imaging features tending to separate primary adrenal carcinomas from adenomas are greater than 4–6 cm with an irregular margin and inhomogeneity by CT scanning. Belldegrun et al. ⁴ noted that 92% of adrenal carcinomas were larger than 6 cm and advised surgical exploration for metabolically inactive lesions greater than 3.5 cm. One adrenal adenoma in this series measured 6.5 cm. In this patient, MRI had an advantage over CT in detecting large vessel thrombosis, particularly involving the inferior vena cava. ⁵ MRI/MRA information is important for surgical planning because IVC invasion is considered tumor extension rather than metastasis, and resection of tumor extension from the IVC to the right atrium has been accomplished. ⁶ Furthermore, the signal intensity of T1 and T2 weighted images on MRI may differentiate adenomas and pheochromocytomas from primary malignant adrenocortical tumors. ⁵ As this case highlights, fine needle aspiration does not facilitate distinction between benign and malignant adrenal tumors.

Adrenal carcinoma has been described as a rare tumor with a poor prognosis, with an incidence of approximately 0.5–2 cases/million/year. ⁷ It may appear from infancy into the eighth decade, but is described in a bimodal age distribution, appearing <5 years and in the fourth to fifth decade with a female predominance. ⁵ A series from France described presentation during pregnancy in 14 patients despite the common observation that Cushing's syndrome usually causes infertility. ⁷ The childhood adrenal carcinomas commonly present with virilization and have a better prognosis than the adult carcinomas. In a review of 602 patients, 95% were 40–50 years old and 62% exhibited manifestations of cortisol excess with 38% nonfunctional. ⁵ Twenty‐four percent of patients in this series had the combination of Cushing's syndrome and virilization (hirsutism and oligomenorrhea) seen with this case. In another series of adult adrenal carcinoma patients, the mixed Cushing's/virilization tumor was more common than either a pure Cushing's or pure virilization presentation. ³ Other manifestations of virilization may include cystic acne, voice deepening, temporal baldness, and clitoromegaly.

Adults with adrenal carcinoma generally present with hypertension, as did 36 out of 44 patients with functioning tumors in a Brazilian series. ³ Hypertension may be due to glucocorticoid and/or mineralocorticoid excess and possibly renin‐angiotensin system activation due to vascular compression by the tumor. ⁸ , ⁹ Blood pressures usually improve following tumor resection. ³

Because malignant cells synthesize steroids inefficiently, a large mass is required to elevate systemic steroid levels, ¹⁰ accounting for the fact that presentation with hormonally mediated symptoms usually occurs with large tumors and metastatic disease. Size and weight of the tumor are characteristics used to distinguish benign from malignant adrenal tumors because differentiation may be difficult. In the 602 cases reviewed by Ng and Libertino, ⁵ tumor diameter ranged from 4 to 25 cm (mean 9.8±4.1). Size >5 cm and wet weight >500 g as well as necrotic areas, hemorrhage, calcifications, and venous invasion are macroscopic features suggestive of malignancy. Three to 5 cm in greatest dimension tends to be a middle overlap area between adenomas and carcinomas, with some authors stating that >100 g in tumor weight generally distinguishes the carcinomas. ³ A Weiss histologic grading score of four or more out of nine criteria was highly specific for separating adrenal carcinoma from adenoma. ³ However, immunohistologic markers (i.e., synaptophysin) are of little use in making this distinction or deciding prognosis. ³ Local invasion most commonly involves the kidneys (26%) and inferior vena cava (9%–19%), whereas metastases affect the liver (48%), lung (45%), lymph nodes (29%), and bones (13%). ⁶ As described previously, tumor extension from the adrenal may fill the IVC to the right atrium and still be potentially resectable with the primary tumor. However, 30%–75% of the adult cases have metastases at the time of diagnosis, ⁶ , ⁷ and about 80% of the remainder will develop metastases. ⁷

Despite metastatic disease involving the lungs and liver, this young patient with a good functional level underwent surgical resection of the primary tumor with the belief that debulking might promote survival. Surgical resection even in patients with extensive metastatic disease is considered the initial therapeutic approach. ⁷ , ¹¹ While some authors claim some survival benefit with nonresectable local tumor debulking ⁶ , ¹¹ and others do not, ³ surgical results following removal of the primary tumor in the presence of metastatic disease generally have not shown benefit. ¹¹ Mitotane is a toxin to adrenocortical cell mitochondria and therefore, in addition to blocking adrenal steroid 11‐B hydroxylation, it is also a cytotoxin. It is the mainstay of therapy for metastatic or recurrent adrenocortical carcinoma, but >80% of patients will suffer severe nausea, vomiting, and diarrhea ³ ; others will experience neurologic sequelae including ataxia, speech difficulty, vertigo, and somnolence. ⁷ Mitotane may help to transiently alleviate endocrine symptomatology, but despite case reports describing improved survival, larger studies fail to confirm such benefit. ⁷ In one patient with mixed glucocorticoid and androgen excess, only cortisol secretion decreased following mitotane administration. ⁷ Most adult patients with advanced disease die within 2 years of diagnosis.

*Normal catecholamine levels as well as physical findings suggested that the cortical mass was not a pheochromocytoma, which is usually a benign lesion.