Adrenal Rest Tumor of the Liver Causing Cushing's Syndrome: Treatment withKetoconazole preceding an Apparent Surgical Cure*

Abstract

Ketoconazole, an imidazole derivative known to inhibit cytochrome P450-dependent adrenal enzymes was given to a patient with a functioning adrenal rest tumor of the liver in preparation for surgery. The drug was administered in a stepwise manner for 42 days starting with 400 mg and reaching 1 g the last 4 weeks of the trial. Clear clinical improvement was evident early in the trial and was associated with evidence of amelioration of her hypercortisolism and striking changes in serum and urinary levels of steroid hormones and metabolites. Sex steroids in serum and urine fell dramatically from the first day to the end of the trial. Urinary 17-ketosteroid excretion fell from a basal average of 139 mg/24 h to near normal levels within a week of therapy; serum testosterone fell from a basal level of 2.4 to 0.18 ng/ml; serum 17 beta-estradiol fell likewise from 1096 to 150 pg/ml. In contrast, cortisol levels in serum and urine increased in the first 2 weeks of the trial and subsequently fell to values below the basal levels. Similarly, serum 17 alpha-OH-progesterone levels increased 63% above the basal levels by day 6 of the trial and declined afterwards. Nine months after successful tumor resection the patient is apparently cured as judged by steroid hormone levels and physical appearance. We conclude that ketoconazole was effective in blocking tumoral steroidogenesis which resulted in clinical benefit.

Malignant Adrenal Rest Tumor of the Retroperitoneum Producing Adrenocortical Steroids

“…Whether these criteria can be applied to adrenal rest tumors has never been assessed. In the present case, supraclavicular lymph node metastasis was found from the time of first admission confirming malignancy, and the histopathologic findings including the MIB1 index (about 10%) were consistent with a malignant diagnosis according to Weiss. To our knowledge, only 11 cases of malignant adrenal rest tumors (with the exception of the present case) have been so far reported [2][3][4][5][6][7][8][9][10][11][12]. In these cases, the primary sites of malignant adrenal rest tumor were the testis, liver, retroperitoneum, kidney, and spinal cord, and seven cases showed hormonal symptoms.…”

“…The primary tumor in the three deceased cases was considered highly malignant arising in the testis. Three out of 11 tumors were consistent with the diagnosis of malignancy by only tumor size and weight [2,8,12], and malignancy in the other case appears to be determined only on the basis of extensive mitoses [11]. Moreover, in one case that arose from the testis, the authors themselves stated that the possibility of a malignant Leydig cell tumor with ectopic cortisol production could not be fully ruled out.…”

“…The adrenal rest rarely persists until adulthood as it generally undergoes atrophy and disappears within a few years after birth [2]; however, a neoplasm can arise from the adrenal rest. Their malignant counterpart, however, is extremely rare, and only a few sporadic cases have been reported [2][3][4][5][6][7][8][9][10][11][12].…”

Unusual causes of Cushing's syndrome

“…A non-ACTH-mediated development of a neoplasm in such tissues is uncommon and the clinical picture depends on the steroid producing profile of the tumour (Conn's syndrome, virilisation or Cushing's syndrome). So far only 9 cases of Cushing's syndrome caused by functional ectopic adrenal neoplasms have been reported (31)(32)(33)(34)(35)(36)(37)(38). The ectopic locations involved the vicinity of normal adrenals, the liver, the pararenal region, and the ovary.…”

Adrenal response to corticotropin during therapy with itraconazole

“…An increasing number of reports of adverse endocrine effects of ketoconazole being used to manage certain endocrinopathies and hormone-dependent neoplasia suggests that this imidazole derivative may prove to be more useful as an endocrine drug than as an antimicrobial agent (2,16 …”