A patient with ectopic cortisol production derived from malignant testicular masses
Shilpa H Jain*, Peter M Sadow, Vania Nosé and Robert G Dluhy
SUMMARY
Background A 65-year-old man presented to an oncology clinic with bilateral testicular masses, lower extremity edema, and cushingoid appearance.
Investigations Measurements of serum cortisol and adrenocorticotropic hormone levels, testicular ultrasound and abdominal CT scans, and review of histopathology to identify the cellular origin of the ectopic cortisol production.
Diagnosis Cushing syndrome was diagnosed on the basis of a markedly elevated 24-hour urine free cortisol level and classic cushingoid features. The etiology of Cushing syndrome was determined to be an adrenocortical carcinoma arising from testicular adrenal rest cells. Nevertheless, the possibility of a malignant Leydig cell tumor with ectopic cortisol production could not be excluded.
Management Mitotane and metyrapone were used to decrease cortisol production. Excess mineralocorticoid activity was blocked with spironolactone; sodium retention was also managed with sodium restriction and diuretics. Despite initial success with this regimen, the patient died as a result of tumor progression and complications of poorly controlled hypercortisolism.
KEYWORDS adrenal rest cells, adrenocortical carcinoma, Cushing syndrome, Leydig cell tumor
CME
SH Jain is a Clinical and Research Fellow and RG Dluhy is a Professor of Medicine in the Division of Endocrinology, Diabetes, and Hypertension at Brigham and Women’s Hospital and Harvard Medical School. PM Sadow is an Assistant Pathologist at Massachusetts General Hospital and an Instructor in Pathology at Harvard Medical School. V Nosé is the Associate Director of Surgical Pathology at Brigham and Women’s Hospital and an Associate Professor of Pathology at Harvard Medical School, Boston, MA, USA.
Correspondence
*Division of Endocrinology, Diabetes, and Hypertension, Brigham and Women’s Hospital, 221 Longwood Avenue, Boston, MA 02115, USA
Received 18 July 2008 Accepted 3 September 2008 Published online 21 October 2008 www.nature.com/clinicalpractice doi:10.1038/ncpendmet0985
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Learning objectives
Upon completion of this activity, participants should be able to:
1 Describe the clinical features of Cushing’s syndrome.
2 Identify biochemical test criteria for the diagnosis of hypercortisolism.
3 Describe the causes of hypercortisolism.
4 List goals of treatment of adrenocorticotropic hormone-independent hypercortisolism.
5 Describe the types and mechanisms of action of agents acting to reduce cortisol levels.
Competing interests
The authors, the Journal Editor V Heath and the CME questions author D Lie declared no competing interests.
THE CASE
A 65-year-old man with chronic hypertension presented to an oncology clinic with enlarge- ment of his left testis. A testicular ultrasound scan revealed a 7×5×5.5 cm left testicular mass and a 3.1×2.3×1 cm right testicular mass. A left radical inguinal orchiectomy was performed. On pathological examination, the left testicular mass was presumed to be a malignant Leydig cell tumor, and measured 8.5x6.5×6.5 cm. CT scans of the chest, abdomen, and pelvis identified media- stinal lymphadenopathy and a large retroperito- neal mass. PET with fluorodeoxyglucose revealed metastases to supraclavicular, mediastinal, and retroperitoneal lymph nodes. Biopsy of the retro- peritoneal mass confirmed the diagnosis of a metastatic malignant Leydig cell tumor.
Two months after the orchiectomy, the patient reported leg swelling, increased dyspnea, and
| Table 1 Results of the patient's initial laboratory evaluation. | ||
|---|---|---|
| Test (units) | Result | Normal range |
| Cortisol (nmol/l) | 1,269 | 138-552 at 0800 h |
| Potassium (mmol/l) | 2.9 | 3.6-5.0 |
| Sodium (mmol/l) | 143 | 137-145 |
| Glucose (mmol/l) | 8.3 | 4.1-6.1 |
| Bicarbonate (mmol/l) | 39 | 22-31 |
| Testosterone (nmol/l) | 9.2 | 8.4-28.7 |
| Estradiol (pmol/l) | Undetectable | 73-275 |
| FSH (IU/l) | 7.3 | 3.1-12.2 |
| LH (IU/l) | 6.3 | 1.7-8.6 |
| Aldosterone (nmol/l) | 0.6 | 0.1-0.9 |
| Abbreviations: FSH, follicle-stimulating hormone; LH, luteinizing hormone. | ||
progressive muscle weakness. His hypertension had worsened despite having been treated with metoprolol (50 mg daily), hydrochlorothiazide (25 mg daily), amlodipine (2.5 mg daily), and clonidine (0.3 mg three times daily) for more than a year. The patient was referred to an endocrinology clinic, where physical examina- tion revealed blood pressure 164/90 mmHg, pulse 88 beats per minute, temperature 37.2℃, BMI 30 kg/m2, and an obvious cushingoid appearance with central obesity, supraclavicular fat pads, moon facies, facial plethora, and cutaneous ecchymoses. Bilateral pitting edema (degree of 2+) and decreased proximal strength were also noted. Initial laboratory evaluation of the patient’s blood samples revealed an elevated cortisol level (1,269 nmol/l; normal range 138- 552 nmol/l at 0800h), low potassium level (2.9 mmol/l; normal range 3.6-5.0 mmol/l), elevated sodium level (143 mmol/l; normal range 137-145 mmol/l), elevated glucose level (8.3 mmol/l; normal range 4.1-6.1 mmol/l), and metabolic alkalosis (bicarbonate level 39 mmol/l; normal range 22-31 mmol/l) (Table 1). Testo- sterone level was 9.2 nmol/l (normal range 8.4- 28.7 nmol/l), estradiol was undetectable, FSH was 7.3 IU/1 (normal range 3.1-12.2 IU/1), and LH was 6.3 IU/1 (normal range 1.7-8.6 IU/1). Serum aldosterone level was 0.6 nmol/l (normal range 0.1-0.9 nmol/l on a normal salt diet). On the basis of these findings, spironolactone (200 mg daily), furosemide (20 mg daily), potassium
chloride (20mEq daily), and lisinopril (10 mg daily) were added to treat edema and hypokalemia.
One week later, the patient developed hypo- xia, worsening of his peripheral edema, hyper- cortisolism (1,683 nmol/l), hypokalemia (2.0 mmol/l), and hyperglycemia (14.2 mmol/l). A CT scan of the chest and abdomen revealed pulmonary embolus, extensive mediastinal, supraclavicular, mesenteric, and retroperitoneal lymphadenopathy, and normal adrenal glands. Echocardiogram indicated normal ejection fraction and mild left ventricular hypertrophy. The patient was treated with the anticoagulant enoxaparin, furosemide (up to 120 mg intra- venously, twice per day), potassium supplemen- tation (up to 180 mEq/day), spironolactone (400 mg/day), insulin, and a salt-restricted diet. Within two weeks, hypoxia, hypokalemia, and edema improved with the intensive diuretic treatment, and hypokalemia resolved with increased mineralocorticoid blockade.
Cushing syndrome was diagnosed on the basis of a markedly elevated urine free cortisol level (3,216 nmol/day; normal range <138 nmol/day) and a persistently elevated serum cortisol level (1,159 nmol/l at 0700h and 1,324nmol/l at 1200h). Hypercortisolism was found to be independent of adrenocorticotropic hormone (ACTH), as serum ACTH was undetectable.
Histological examination of the left testis revealed considerable necrosis with extension through the tunica albuginea and approach- ing the overlying serosa. The prominent eosinophilic cytoplasm of tumor cells, which is often associated with a high concentration of mitochondria, indicated cells with active metabolism and steroid hormone production (Figure 1). The tumor cells had intranuclear pseudoinclusions (Figure 1), which are sugges- tive of neuroendocrine differentiation. Reinke’s crystals, which are a rare finding in Leydig cell tumors, were not identified by light or electron microscopy. Immunohistochemistry revealed positive staining for inhibin, a positive marker for either adrenocortical or steroidogenic tes- ticular tumors (Figure 2). Staining for ACTH was negative. These findings led to the conclu- sion that the patient’s hypercortisolism derived from ectopic cortisol production, either by malignant testicular adrenal rest cells or a malignant Leydig cell tumor.
Surgical removal of the source of ectopic corti- sol was not considered in this patient because of its unclear efficacy in a patient with widespread
metastasis. To reduce cortisol production, metyr- apone (250 mg every 8h) and mitotane (500 mg every 12h) were started 3 months after orchi- ectomy. Within one week of starting these medi- cations, both medications were increased to 750 mg every 6 h. Serum cortisol level decreased to 910 nmol/l. Mitotane treatment was stopped, however, after two weeks because of severe trans- aminitis (alanine aminotransferase level 810U/l, aspartate aminotransferase level 293 U/1). By the end of his one-month hospitalization, his hypercortisolism, hypertension, and hyper- glycemia were controlled on metyrapone (750 mg every 6h), spironolactone (400 mg daily), meto- prolol (25 mg three times daily), clonidine (0.3 mg three times daily), and insulin glargine (10 units daily). He was subsequently discharged to a rehabilitation center.
The outpatient treatment plan was to start the patient on the glucocorticoid antagonist mife- pristone. The patient’s retroperitoneal lympha- denopathy, however, progressed to encase the left ureter and compress the left renal artery and vein. One month after discharge the patient was admitted with acute renal failure and a thoracic vertebral compression fracture. One month later he developed episodes of delirium and died suddenly.
DISCUSSION OF DIAGNOSIS
Cushing syndrome results from prolonged expo- sure to glucocorticoid excess. Typical symp- toms, signs, and complications include truncal obesity, facial plethora, skin atrophy, proxi- mal myopathy, hyperglycemia, mood disor- ders, and fractures. Signs of mineralocorticoid excess, such as hypokalemia, sodium retention, hypertension, and metabolic alkalosis, can be observed when cortisol production is mark- edly elevated. At high concentrations, cortisol can escape its usual conversion to cortisone by the enzyme 11ß-hydroxysteroid dehydrogenase type 2. Cortisol, unlike cortisone, can bind to and activate mineralocorticoid receptors.
Once Cushing syndrome is suspected clinically, the diagnosis should be confirmed by biochemi- cal examinations. The three key biochemical fea- tures of Cushing syndrome are increased cortisol production, lack of diurnal variation in cortisol levels, and lack of negative feedback inhibition of cortisol production. Cushing syndrome can be diagnosed on the basis of 24-hour urine free cortisol levels, late night serum or salivary corti- sol levels, or dexamethasone suppression tests.1
Typically, two measurements of 24-hour urine free cortisol levels elevated to three times the upper limit of the normal range are diagnostic of Cushing syndrome. Late night serum or sali- vary cortisol levels are elevated in Cushing syn- drome because cortisol is not secreted in its usual diurnal pattern. Dexamethasone suppression tests can be used to prove autonomous secretion of cortisol.
The next step is to determine whether corti- sol production is ACTH dependent or indepen- dent. In ACTH-dependent cortisol production, ACTH from the pituitary gland or an ectopic source (i.e. the lungs or the thymus) stimulates the adrenal gland to secrete cortisol. In ACTH- independent hypercortisolism, cortisol is either taken exogenously or produced autonomously by an adrenal adenoma, adrenal carcinoma, or
Cholesterol
Cholesterol side-chain cleavage
Mitotane Ketoconazole Aminoglutethimide
–
Pregnenolone
17-OH Pregnenolone
3-Hydoxysteroid dehydrogenase
17-OH Progesterone
21-Hydroxylase
11-Deoxycortisol
11ß-Hydoxylase
Mitotane Ketoconazole Metyrapone Etomidate
–
Cortisol
bilateral adrenal hyperplasia (micronodular or macronodular).
The patient described had classic cushingoid features and marked elevations in urine free cortisol and serum cortisol levels. Given the high pre-test probability of Cushing syndrome, the 24-hour urine free cortisol measurement was not repeated nor was a dexamethasone suppression test performed. The undetectable ACTH level indicated that cortisol secretion was ACTH independent. Clinical findings of the patient suggested that ectopic cortisol pro- duction could either derive from a malignant Leydig cell tumor or from an adrenocorti- cal carcinoma arising from bilateral testicular adrenal rest cells.
Cortisol production by a metastatic Leydig cell tumor has been reported in two patients who presented with unilateral testicular masses and underwent unilateral orchiectomies.2,3 In these two patients, similarly to the patient described here, the tumors recurred and the patients then developed cushingoid features and sodium retention. Serum cortisol levels were elevated and ACTH levels were undetectable in both patients. Testosterone was low in one patient2 and normal in another patient.3 Unlike
in the patient described here, serum estradiol levels of these two patients were elevated to 2-10 times the upper limit of normal. In both patients, histological features of the testis were consistent with a Leydig cell tumor. The tumors were thought to arise in the testis proper and benign histological characteristics (specifi- cally no extensive necrosis or pleomorphism) were observed. In the patient described here, testicular histology revealed cells with histo- logical signs of malignancy and it was unclear whether the tumor arose within the testicular parenchyma or in the paratesticular soft tissue, subsequently invading the testis.
Adrenal rest cells, which are remnants in the paratesticular tissue arising from the embryonic urogenital ridge, can also produce cortisol.4 During embryonic development, adrenocortical cells can break away from the adrenal gland and migrate along with the gonads. Up to 15% of male infants have adrenocortical cells-termed adrenal rest cells-in their testes.5 Adrenal rest cells usually regress during infancy, and even when present in adults they do not usually cause any symptoms and are typically detected incidentally. In patients with congenital adrenal hyperplasia, however, high levels of ACTH can stimulate growth of adrenal rest cells in testes and lead to the development of bilateral tes- ticular masses.6 Malignant transformation of adrenal rest cells could theoretically result in ectopic cortisol production.
In the patient described, it could not be determined whether the tumor was an adreno- cortical carcinoma arising from bilateral tes- ticular adrenal rest cells or a malignant Leydig cell tumor with ectopic cortisol production. Leydig cells might be identified with light microscopy by the presence of Reinke’s crys- tals, although this finding is rare.7 Electron microscopy and immunohistochemistry can highlight key ultrastructural and steroidogenic features of Leydig cells, but differentiation of Leydig cells from adrenal rest cells can still be difficult.7,8 Tissue specimens suitable for these examinations, however, were not available from this patient. Liquid chromatography- tandem mass spectroscopy of urine or plasma steroid precursors might have been used to characterize the steroid secretion characteris- tics of the tumor,9 but this tool wasn’t readily available and delay of the patient’s treatment in order to do further diagnostic testing was not recommended.
The bilateral nature of the patient’s tumor suggested an adrenal rest cell malignancy, since bilateral adrenal rest cells are a common finding whereas bilateral Leydig cell tumors are rare. In addition, primary testicular tumors usually metastasize to the retroperitoneal lymph nodes, not to the contralateral testis. On the basis of these findings, we speculate that the patient described had Cushing syndrome due to a paratesticular adrenocortical carcinoma.
TREATMENT AND MANAGEMENT
Treatment goals in patients with ACTH-inde- pendent hypercortisolism are to antagonize the effects of mineralocorticoid and glucocorticoid excess and to reduce cortisol production.
Mineralocorticoid excess is treated with salt restriction, diuretics, mineralocorticoid antago- nists, and, if needed, potassium supplements. Despite treatment with high doses of the aldo- sterone antagonist spironolactone, several other antihypertensive medications were required to control the blood pressure of the patient described. Potassium supplements were no longer required after escalation of the spironolactone dose. Elevated cortisol level can be reduced with steroidogenic enzyme inhibitors, including metyrapone, ketoconazole, aminoglutethamide, and etomidate (Figure 3).10 Metyrapone, ketoconazole, and etomidate inhibit the 11ß- hydroxylase enzyme. Ketoconazole and amino- glutethamide inhibit the side-chain cleavage of cholesterol. These medications can rapidly decrease cortisol production, but their gastro- intestinal, hepatotoxic, and neurological adverse effects limit their use. The antineoplastic drug mitotane inhibits the 11ß-hydroxylase enzyme and the side-chain cleavage of cholesterol. Mitotane can cause adrenal atrophy and necrosis. As it takes several months before medical adrena- lectomy is achieved by mitotane treatment, it is important to use other steroidogenic inhibitors with quicker onset as adjunctive therapies.
For the patient described, the combination of metyrapone and mitotane was initially success- ful in lowering cortisol levels. This regimen was not successful, however, in the long-term because of the adverse effects of the medica- tions and the aggressive nature of the tumor. Mifepristone, which is a potent antagonist for glucocorticoid, progestin and androgen recep- tors, might have been a useful therapy for this patient. Mifepristone is not currently approved in the US for Cushing syndrome, but it can be
obtained for compassionate use. The effects of this drug, however, are difficult to assess. First, cortisol levels cannot be used to monitor the efficacy of mifepristone, as it inhibits cortisol’s activity, rather than its production. Second, there is no reliable biochemical assay available for assessing glucocorticoid activity. Clinical parameters of glucocorticoid activity (i.e. cushingoid features and elevated blood glucose level) are used instead to assess response to treatment with mifepristone. This drug has been successfully used to treat patients with Cushing syndrome due to adrenal cancer and ectopic ACTH production.11 Nevertheless, it is important to use a mineralocorticoid antago- nist in conjunction with mifepristone, as mife- pristone does not reduce cortisol levels and it does not prevent cortisol from binding to mineralocorticoid receptors.
Intravenous etomidate is another effective agent for immediate control of hypercortisolism.12 This medication, however, is preferably admini- stered in an intensive care unit, thus it was not considered to be safe for the patient described who was treated at a rehabilitation clinic.
The use of any of the above agents is associ- ated with the risk of adrenal insufficiency. The goal of the treatment for Cushing syndrome is to achieve eucortisolism, but in some cases hypocortisolism might occur. Concurrent gluco- corticoid, and in rare cases mineralocorticoid, replacement, should, therefore, be considered.
CONCLUSIONS
The patient described represents a rare case of Cushing syndrome that was attributable to a malignant testicular tumor, presumably an adreno- cortical carcinoma arising in the paratesticular tissue. This case highlights the importance of reviewing the pathology, embryology, and hor- monal profile when considering the origin of ectopic cortisol production. In all patients with ACTH-independent hypercortisolism, treatment should aim to antagonize the effects of mineralo- corticoid and glucocorticoid excess and to reduce cortisol production.
References
1 Nieman LK et al. (2008) The diagnosis of Cushing’s syndrome: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 93: 1526-1540
2 Papadimitris C et al. (2000) Cushing syndrome as the presenting feature of metastatic Leydig cell tumor of the testis. Urology 56: 153
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