CASE REPORT
Adrenocortical carcinoma with Cushing’s syndrome presenting unusual urinary 17-ketosteroid fractionation
H. Watanobe, K. Kannari, K. Kimura, and K. Takebe Third Department of Internal Medicine, Hirosaki University School of Medicine, 5 Zaifu-cho, Hirosaki-shi, Aomori-ken, 036 Japan
ABSTRACT. A case of adrenal carcinoma with Cushing’s syndrome was presented: Endocrinolog- ical and morphological investigations disclosed the presence of a functional adrenal carcinoma. This case was characterized by its unusual urinary 17-ketosteroid (17-KS) fractionation, i.e. a marked elevation of 17-KS was accompanied by the increments of etiocholanolone, but not of dehydroepiandrosterone (DHEA) or androsterone. Measurements of the plasma adrenocorticos- teroids revealed normal DHEA and DHEA-S (sulfate) levels, moderately increased 17-OH-preg- nenolone, and markedly increased (< 100 times the normal) 11-deoxycortisol (cpd S). Therefore, it seems plausible that the normal urinary DHEA level in this patient would have occurred as a result of remarkably low C17-20 lyase activity sufficient to hamper DHEA production, and that markedly increased etiocholanolone might possibly have been converted from cpd S as well as from DHEA and androstenedione through 53-reduction.
INTRODUCTION
A marked elevation of 17-ketosteroids (17-KS) asso- ciated with increased 17-hydroxycorticosteroids (17- OHCS) in the urine strongly suggests the presence of adrenal carcinoma as a pathology of Cushing’s syn- drome (1). It is, however, not merely the increased total excretions of 17-KS but also its unique fractionation, i.e. the prominent ratio of dehydroepiandrosterone (DHEA), that characterize Cushing type adrenal carci- nomas in a sufficient number of cases (2, 3).
We, however, recently experienced a case of adrenal carcinoma of which markedly increased 17-KS was accompanied by proportional increments of etiocho- lanolone, but not of DHEA or androsterone. There have been reported only two cases of adrenal carcinoma presenting a similar 17-KS fractionation to ours (4, 5). On the basis of the plasma adrenocorticosteroid pro- files in this patient, we have considered several possi- bilities to explain this unusual finding.
CASE REPORT
History A 38-year-old man, with one year history of diabetes
mellitus and two months of general lassitude and body weight loss, was transferred to our hospital from a nearby clinic. Investigations performed at that clinic revealed that his diabetic condition was insulin-requiring and probably secondary to Cushing’s syndrome, since increased levels of plasma cortisol and urinary 17- OHCS were concomitantly observed.
His physical status on admission to our hospital was characterized by central obesity, round face, general eruption of acne vulgaris, easy bruisability and promi- nent muscle weakness of the upper and lower extremi- ties. Blood pressure was 146/96 mmHg. Laboratory studies revealed: marked neutrophilia (89%) and eosin- openia (0%); Na, 152 mEq/L; K, 1.9 mEq/L; CI, 92 mEq/L; triglyceride, 198 mg/dl; total cholesterol, 291 mg/dl. Fasting blood glucose ranged from 205 to 240 mg/dl while on no insulin therapy. Arterial blood gas analysis showed the presence of metabolic alkalosis.
Endocrinological examination
Among extensive endocrinological investigations, the followings seem to deserve description. The baseline plasma concentration of cortisol was markedly elevat- ed, and diurnal rhythms of both cortisol and aldoste- rone were proven to be disturbed. Basal urinary excre- tions of 17-OHCS and 17-KS while on no test therapy were 85-105 mg/day and 55-75 mg/ day, respectively. On standard metyrapone test (4.5 g/day, in 6 divided doses) a significant reduction of the urinary 17-OHCS was observed, and it was compatible with an impaired secretory reserve of pituitary ACTH simultaneously
Key-words: Adrenal carcinoma, Cushing’s syndrome, 17-ketosteroid, etiocholano- lone, dehydroepiandrosterone, androsterone, androstenedione, 11-deoxycortisol.
Correspondence: Hajime Watanobe, M.D., Third Department of Internal Medicine, Hirosaki University School of Medicine, 5 Zaifu-cho, Hirosaki-shi, Aomori-ken, 036 Japan.
| Androsterone | 1.49-2.25 | + *(1.03-4.58) | |
| Etiocholanolone | 9.18-15.54 | 111 (0.61-3.91) | |
| DHEA | 0.72-1.35 | - (0.05-2.54) | |
| 11-K androsterone | 0.05-0.06 | - (less than 0.06) | |
| 11-K etiocholanolone | 1.07-2.40 | 1 (0.05-0.62) | |
| 11-OH androsterone | 2.25-3.65 | t (0.30-1.68) | |
| 11-OH etiocholanolone | 4.14-6.15 | ttt | (0.01-0.48) |
*( ) : normal range (mg/day)
demonstrated by this procedure. As regards the dexa- methasone suppressibility, even a high dose (8mg/day, in 4 divided doses for two days) failed to produce significant reductions of both 17-OHCS and 17-KS. Additionally, no significant adrenocortical responses were observed by either rapid ACTH test or ACTH-Z (zinc) test.
These findings strongly suggested that the patient was suffering not from pituitary-dependent Cushing’s dis- ease but from Cushing’s syndrome. And that, an ad- renal carcinoma was most likely as its underlying etiol- ogy.
Table 1 depicts the urinary 17-KS fractionation of this
patient analyzed several times. Basal increased excre- tion was demonstrated for 11-K etiocholanolone, 11- OH androsterone and 11-OH etiocholanolone, all of which are urinary metabolites of cortisol (6). Increased urinary excretion of etiocholanolone was noteworthy, but it was not accompanied by elevations of either DHEA or androsterone.
Table 2 shows the levels of several adrenocorticoste- roids in this patient’s plasma obtained on early days of his admission. Mineralocorticoids, except corticoste- rone, were unanimously elevated, and especially more than 30 times the normal value of 11-deoxycorticoste- rone (DOC) was to be noted.
Among the universally elevated plasma glucocorti- coids, 11-deoxycortisol (cpd S) was extraordinarily high to the extent of more than 100-fold excess of the normal.
As regards androgens, DHEA and DHEA-S (sulfate) fell within the normal range. Testosterone, however, was below normal. The urinary 17-OHCS was determined by the method of Silber and Porter (7). Measurement of 17-KS was done by Zimmerman reaction (8) and its subfractions were analyzed by gas-liquid chromato- graphy described elsewhere (9). Determinations of the plasma ACTH, cortisol and aldosterone were performed by radioimmunoassay (RIA) using commercial kits.
17 a-OH lase
C 17-20 lyase
442.9 11 *(30-198)
DHEA-S 2980 (500-3000) 250- (120-750)
pregnenolone
17-OH-pregnenolone
250.01
+ DHEA
(25-154)
36-OH-steroid dehydrogenase
progesterone
158.111
17-OH-progesterone
androstenedione
104.11
(12.2-58.6)
(18.6-65.9)
21-OH-lase
DOC
330 111 (2.1-8.9)
11-deoxycortisol
4796 111
testosterone
340
(20.0-42.4)
(420-1200)
11ß-OH-lase
corticosterone
cortisol
414 - (100-1000)
32.9 11
(3.7-13.0)
18-OH-lase
18-OH-corticosterone
18-OH-steroid dehydrogenase
aldosterone
8.11
(1.1-6.3)
*( ) : normal range.
unit: cortisol (ug/dl); DHEA-S (ng/ml); others (ng/dl).
MAT 51 IM1 51
The plasma adrenocorticosteroids were kindly mea- sured by Dr. Motoko Ojima (Fukushima Prefectural Medical College, Fukushima, Japan) using RIA.
Clinical course
Preoperative diagnosis of adrenal carcinoma was strengthened radiologically as well.
On abdominal CT scanning, a partially calcified huge tumor of right adrenal origin was demonstrated (Fig. 1). The pituitary gland, however, appeared normal on CT scan. On adrenal venography, a marked dilatation of the right adrenal vein and the ipsilateral bizarre abnor- mal blood vessels were shown.
Simultaneously performed adrenal venous samplings revealed around 8-fold greater the concentration of cortisol in the right than in the left. On adrenal scinti- grams with use of 75Se-scintadren, radioactivity was detected slightly in the left but not in the right.
Laparotomy was performed on the 64th day of hospital-
ization. A huge tumor of right adrenal origin was easily localized and it displaced the right kidney strongly downward. Since the tumor was tightly adhesive to liver, duodenum and inferior vena cava, the operative maneuver could not proceed further and ended in ex- cising a superficial specimen for histopathological ex- aminations. Specimen of the right adrenal tumor re- vealed a medullary growth of carcinoma cells with uneven-sized nuclei and/ or intranuclear inclusion bod- ies (Fig. 2).
Administration of 9 g/ day of op’-DDD was started post- operatively. Urinary excretions of 17-OHCS, being around 100 mg/ day prior to medication, decreased to less than 60 mg/ day on the third week of treatment, but remained the same level thereafter.
The patient’s general condition worsened progressive- ly due to widespread tumor metastases and he died on the 38th week of hospitalization. A necropsy could not be performed unfortunately.
DISCUSSION
As is generally accepted, marked elevations of the urinary 17-KS in patients with clinically evident Cush- ing’s syndrome make one assume an adrenal carci- noma as its underlying etiology (1). It is, however, not merely the total urinary amount of 17-KS but its pecul- iar fractionation that characterize Cushing type adrenal carcinomas, That is, the metabolites of C19 steroids (DHEA, etiocholanolone and androsterone) are ex- creted into the urine in large quantities in a major pro- portion of the cases (2, 3).
Our case seems to be characterized by an extremely unique 17-KS fractionation as was already described. Although etiocholanolone was markedly high, DHEA and androsterone remained normal throughout his clin- ical course.
Perusal of the literature revealed only two cases of adrenal carcinoma presenting a similar 17-KS fraction- ation to ours (4, 5), which then underlies the rarity of our patient. Several possibilities were considered as fol- lows to explain this unusual finding.
The first possibility concerns the metabolism of C19 steroids. Etiocholanolone and androsterone are con- verted from both DHEA and androstenedione in rough- ly equal proportions in normal subjects, and thus a urinary E/A (etiocholanolone/androsterone) ratio ap- pears as around 1.0 (10). Whereas in Cushing’s syn- drome irrespective of its underlying etiology, the uri- nary E/A ratio was reported high in most cases (11, 12). It is most likely to be due to a greater reduction rate in the liver of C19 steroids for 50 (etiocholanolone) than for 5 a (androsterone) isomers as a result of high glu- cocorticoid concentrations (11, 12). The E/A ratio of our patient was also high, ranging from 6.2 to 7.4. Therefore, this preferential 50-reduction could have been a partial contribution. However, this could never be a sole explanation for the queer 17-KS fractionation
of this case, since such a metabolism occurs in most cases of Cushing’s syndrome (11, 12).
Another contributing factor would possibly have been cpd S, whose concentration in plasma was extraordi- narily high in our patient. It is because cpd S undergoes metabolism in the liver not only to tertrahydro S but also to etiocholanolone and androsterone with a much greater conversion rate for etiocholanolone (10). In normal subjets, the plasma level of cpd S is negligibly small compared with that of DHEA-S, the predominant form of DHEA (13).
However, in cases of adrenal carcinoma where cpd S is produced in high quantities, such a metabolic path- way should not be dismissed. This possible role of cpd S as a precursor of etiocholanolone was also consid- ered by Vande Wiele et al. (5) in evaluating their unusu- al case of adrenal carcinoma.
Ojima et al. (14) reported that an impaired activity of 3ß-hydroxysteroid dehydrogenase was found in all of the three types (Cushing type, mineralocorticoid ex- cess type and adrenogenital syndrome type) of func- tional adrenal carcinoma, and that an additional derangement of C17-20 lyase activity was observed very often in the former two types. In the majority of Cushing type adrenal carcinomas, an enormous production of 17-OH-pregnenolone could overcome a diminished C17-20 lyase activity, and thus a high DHEA production would still be observed (14).
Therefore, an unusual urinary 17-KS fractionation ob- served in this patient would have been a result of com- bination of the remarkably low C17-20 lyase activity re- sulting in normal DHEA concentration and a high eti- ocholanolone production derived from DHEA, andros- tenedione and cpd S.
ACKNOWLEDGMENTS
We would like to thank Dr. Motoko Ojima (Fukushima Prefectural Medical College, Fukushima, Japan) for measuring the plasma adre- nocorticosteroid concentrations using RIA.
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