Adrenal Carcinoma
Joel Handler, MD
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 (nor- mal range: 3.5-5.0). Atenolol 50 mg q.d. was pre- scribed for her hypertension.
Due to persistent back pain, a physical therapy eval- uation 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 ug/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
From Kaiser Permanente, Anaheim, CA Address for correspondence: Joel Handler, MD, Kaiser Permanente, 411 Lakeview Avenue, Anaheim, CA 92807
ID: 2833
involving both upper thighs and mild bilateral lower extremity pitting edema.
Magnetic resonance imaging/magnetic reso- nance 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 mcg (normal range: 0-135), human chorionic gonadotropin level was <5 mIU/mL (<6.2), a 24-hour urine-free cortisol read- ing was 1575 µg/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 adeno- ma 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 dif- ferentiated, malignant neoplasm consistent with adrenal cortical carcinoma. With synaptophysin staining, a protein involved in neurotransmitter exo- cytosis and a neuroendocrine marker1 was positive (Figure 2). Mitotane with adjunctive chemotherapy was advised upon postoperative recovery.
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, includ- ing hypertension, which is diastolic in 82% of affected individuals.2 Causes of Cushing’s syn- drome (Table II) often require extensive metabolic
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DATE 9/12/02
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Anaheim
testing to diagnose, but initial imaging studies revealing metastatic lung disease and a large adre- nal mass readily forecasted the diagnosis of adre- nal carcinoma.
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 dexam- ethasone at midnight would have been an alternative initial diag- nostic test. Due to episodic secretion from adenomas and incorrect collections, 8%-15% of urinary cortisol collec- tions are normal in Cushing’s syndrome, and intermediate eleva- tions need to be con- firmed by follow-up testing.2 With a less dra- matic presentation, the next algorithmic step would have been low- dose dexamethasone suppression to establish the diagnosis of Cush- ing’s syndrome. In pitu- itary-dependent Cushing’s disease, 50% of 9 a.m. ACTH levels are in the normal range, and an expect- ed 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 carci- noma patient, is com- mon in patients with ectopic ACTH syn- drome (>95%), but uncommon with pri- mary pituitary disease (<10%)2 or adrenal car- cinoma, occurring in only two out of 34 indi- viduals in one series.3
Imaging features tending to separate pri- mary adrenal carcino- mas from adenomas are greater than 4-6 cm with an irregular mar- gin and inhomogeneity by CT scanning. Belldegrun et al.4 noted that 92% of adrenal
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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 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
carcinomas were larger than 6 cm and advised sur- gical 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 throm- bosis, 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 pheochromocy- tomas from primary malignant adrenocortical tumors.5 As this case highlights, fine needle aspira- tion 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 man- ifestations of cortisol excess with 38% nonfunction- al.5 Twenty-four percent of patients in this series had
| 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
the combination of Cushing’s syndrome and viriliza- tion (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 com- pression by the tumor.8,9 Blood pressures usually improve following tumor resection.3
Because malignant cells synthesize steroids inef- ficiently, a large mass is required to elevate sys- temic steroid levels,10 accounting for the fact that presentation with hormonally mediated symptoms
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usually occurs with large tumors and metastatic disease. Size and weight of the tumor are charac- teristics used to distinguish benign from malignant adrenal tumors because differentiation may be dif- ficult. 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, calcifica- tions, and venous invasion are macroscopic fea- tures 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, immunohis- tologic markers (i.e., synaptophysin) are of little use in making this distinction or deciding progno- sis.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 metas- tases 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 sur- vival. Surgical resection even in patients with exten- sive metastatic disease is considered the initial thera- peutic approach.7,11 While some authors claim some survival benefit with nonresectable local tumor debulking6,11 and others do not,3 surgical results fol- lowing removal of the primary tumor in the presence of metastatic disease generally have not shown bene- fit.11 Mitotane is a toxin to adrenocortical cell mito- chondria and therefore, in addition to blocking adre- nal 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 diarrhea3; others will experience neurologic sequelae including ataxia, speech difficulty, vertigo, and somnolence.7 Mitotane may help to transiently alleviate endocrine sympto- matology, 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 sug- gested that the cortical mass was not a pheochromocytoma, which is usually a benign lesion.
REFERENCES
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3 Wajchenberg BL, Pereira MAA, Medonca BB, et al. Adrenocortical carcinoma. Cancer. 2000;88:711-736.
4 Belldegrun A, Hussain S, Seltzer S, et al. Incidentally dis- covered mass of the adrenal gland. Surg Gynecol Obstet. 1986;163:203-207.
5 Ng L, Libertino JM. Adrenocortical carcinoma: diagnosis, evaluation, and treatment. J Urol. 2003;169:5-11.
6 Thompson NW, Cheung PSY. Diagnosis and treatment of functioning and nonfunctioning including adrenocortical neoplasms incidentalomas. Surg Clin North Am. 1987; 67(2):423-436.
7 Luton JP, Cerdas S, Billaud L, et al. Clinical features of adrenocortical carcinoma, prognostic factors, and the effect of mitotane therapy. N Engl J Med. 1990;322:1195-1201.
8 Hutter AM, Kayhoe DE. Adrenal cortical carcinoma: clini- cal features of 138 patients. Am J Med. 1966;41:572-580.
9 Zografos GC, Driscoll DL, Karakousis CP, et al. Adrenal carcinoma: a review of 53 cases. J Surg Oncol. 1994;55: 160-164.
10 Soreide JA, Braband K, Thoreson SO. Adrenal cortical car- cinoma in Norway, 1970-1984. World J Surg. 1992;16: 663-668.
11 Grondal S, Cedermark B, Eriksson B, et al. Adrenocortical carcinoma. A retrospective study of a rare tumor with a poor prognosis. Eur J Surg Oncol. 1990;16:500-506.