Particular Cases of Cushing’s Syndrome One with Adrenocortical Carcinoma and the Other with Double Adenomas
KIYOHIKO YOSHIKAWA, HAJIME YAMAGUCHI, MOTOKO OJIMA* TAKAYUKI MASUDAŤ and NOBUAKI SASANOŤ
Department of Internal Medicine, Iwaki-Kyoritsu General Hospital, Iwaki 973, *the Third Department of Internal Medicine, Fukushima Medical College, Fukushima 960 and t the Second Department of Pathology, Tohoku University School of Medicine, Sendai 980
YOSHIKAWA, K., YAMAGUCHI, H., OJIMA, M., MASUDA, T. and SASANO, N. Particular Cases of Cushing’s Syndrome - One with Adrenocortical Carcinoma and the Other with Double Adenomas -. Tohoku J. exp. Med., 1985, 146 (1), 73-82 - Two particular cases of adrenocortical tumors associated with Cushing’s syndrome were documented. In the first case, the steroid pattern suggested a malignancy, and the histology of the excised tumor confirmed it. In the second case, the left adrenal had two distinct tumors ; one dark-brown, and the other yellow in color. Recent trends in the diagnosis and treatment of Cushing’s syndrome were discussed. -_ Cushing’s syndrome ; adrenocortical car- cinoma ; steroid pattern ; double adenomas
Recent progress in computed tomography (CT) has improved greatly the diagnosis of adrenal tumors (Hauser et al. 1981; Copeland 1984). In rare cases, Cushing’s syndrome is caused by bilateral or multiple adrenocortical adenomas. However, the multiple adenomas are difficult to be differentiated from nodular hyperplasia of the adrenals. In equivocal cases, the diagnosis of adenoma is made if no evidence of hyperplasia is proved in the adrenocortical tissue except for the nodular or adenomatous lesions (Neville and O’Hare 1982). In other words, the adrenocortical adenoma is differentiated from the macronodular hyperplasia by atrophy of the attached and contralateral cortex (Flattet and Hedinger 1980; Neville and O’Hare 1982). Atrophy of the cortex harboring a nodule, even if a small adenoma, could be demonstrated by CT (Hauser et al. 1981).
In patients with Cushing’s syndrome, an adrenal tumor weighing over 100 g is usually malignant (Neville and O’Hare 1982). Diagnosis of carcinoma weigh-
ing less than 100 g is usually based on histological examinations. However, histological criteria for the diagnosis of malignancy have not been established. The diagnosis of adrenocortical malignancy in Cushing’s syndrome could also be made by endocrinological determinations ; blood levels of androgens and precur- sor steroids are far higher than those in adenoma (Gabrilove et al. 1983). Furthermore, analyses of steroids in plasma and tumor tissue provide evidence of abnormalities in the enzyme system of steroidogenesis and are helpful in the pathological diagnosis of malignancy (Sasano et al. 1980).
The present paper presents two cases of Cushing’s syndrome - one with well differentiated carcinoma and the other with double adenomas in the left adrenal. Discussion will be focused on the preoperative and in vitro evaluation of the tumor character.
CASE REPORT
Case 1 : A 35-year-old female was admitted to Iwaki-Kyoritsu General Hospital on 27 April, 1982. Following her first delivery in 1973, irregular menstruation, gradual gain of body weight and signs of hypertension up to 180- 200 mm Hg appeared. Excessive water intake, polyuria, fatigability and noctur- ia were added in 1981, and amenorrhea in January, 1982.
On admission blood pressure was 208/110 mm Hg and an appearance of Cushing’s syndrome was evident. The clitoris was slightly hypertrophied and hypertrichosis was evident.
| Cholesterol | ||
|---|---|---|
| 1 | -> 17-OH Pregnenolone | -> Dehydroepiandrosterone |
| Pregnenolone | ||
| 1 ☒ 6.05 ng/ml (0.2~1.5)} | 1 12.6 ng/ml (0.1~4.0) | 4 57.7 ng/ml (1.2~7.5) |
| Progesterone | -> 17-OH Progesterone | -> Androstenedione |
| Į 7.17 ng/ml | Į 10.20 ng/ml | 1 6.46 ng/ml (0.5~1.5) |
| 11-Deoxycorticosterone | -> 11-Deoxycortisol | Testosterone |
| 1.25 ng/ml (0.02~0.20) | V 4.42 ng/100 ml (0.2~1.2) | Į 211 ng/100 ml |
| Corticosterone | Cortisol | Estradiol |
| ↓ | 18.8 4g/100 ml | 20 pg/ml |
| 18-OH Corticosterone | ||
| 1 | ||
| Aldosterone | ||
| 39 ng/100 ml (2~12) |
t The normal range is in parentheses.
1
10
$ 57. 6.22
13361
2
5
10
11
Laboratory examinations revealed hypokalemia (2.6 mEq/liter) and high LDH levels (253 I.U./liter). Plasma concentrations of cortisol were high (18.8 ug/100 ml) and did not show diurnal changes. Levels of aldosterone, androgens and their precursors were also high as shown in Table 1. Urinary levels of free cortisol and 17-OHCS were elevated as well. They were not suppressed by the 8-mg dexamethasone suppression test, and the metyrapone test resulted in a decrease in urinary 17-OHCS. These results suggested the diagnosis of Cushing’s syndrome due to an adrenal tumor. Plasma concentrations of cortisol did not respond to a rapid ACTH test and the levels of urinary 17 KS and plasma DHEA
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and aldosterone were high. All of 6 fractions of urinary 17 KS except for DHEA were high. A discrepancy between urinary and plasma levels of DHEA was remarkable.
Supine CT scan of the abdomen demonstrated a large globular mass of different densities in the left retroperitoneum between the 11th thoracic and the 2nd lumbar vertebrae (Fig. 1). Isotope scanning with 131I-cholesterol revealed an incorporation of radioactivity in the left adrenal tumor area and it was not uniform as suggested by the CT scan. Total excision of the left adrenal was carried out on June 28.
Pathological examinations : The resected tumor weighing 284 g was nearly globular in shape measuring about 10×10×10 cm. The cut surface was yellow- ish and brown intermingled with foci of pink tissue and hemorrhagic necrosis. Nodular or lobular structure was partially observed (Fig. 2).
Histologically the yellow areas were composed of clear cells which were considerably well differentiated and arranged partly in a ribbon pattern. How- ever, aggregates of small cells were arranged in a sheet-like or coarse alveolar structure and occasionally contained pseudocysts, suggesting malignant nature of
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the tumor (Fig. 3). Malignant pattern was particularly evident near the foci of necrosis and fibrosis and occasionally associated with mitosis (Fig. 4). These characteristics of malignancy were confirmed in 3 of 15 blocks and suggested
multicentric malignancy.
Electronmicroscopically, tumor cells were generally divided into two types ; small compact cells and moderately clear cells of medium size. Small cells had numerous small mitochondria frequently elongated with well developed cristae. SER (smooth-surfaced endoplasmic reticulum) was indistinct and lipid droplets and lipofuscin granules were less (Fig. 5A). Medium-sized cells had numerous swollen mitochondria with a few cristae. Frequent dilation of well developed SER suggested degeneration. RER (rough-surfaced endoplasmic reticulum) was occasionally evident. Lipid-rich cells were scattered (Fig. 5B).
Tissue steroid concentrations : Immediately after the removal, 3 differently looking pieces of the tumor were cut out : yellow (I), brown (II) and pink (III) in color, and frozen at -20℃. The pink part (III) was mainly composed of fibrous tissue. A part of each piece was extracted and assayed for the steroids. The levels of pregnenolone was high in I and II and low in III compared to the normal adrenocortical tissue. The levels of progesterone, DOC, corticosterone, 17 OH-pregnenolone, 17 OH-progesterone, cortisol and DHEA were all low. The high pregnenolone/progesterone ratio and the low progesterone/deoxycorticoster- one ratio suggested a reduced activity of 36-hydroxysteroid dehydrogenase and an elevation of 21-hydroxylase activity (Table 2).
Case 2 : A 49-year-old female was admitted to Iwaki-Kyoritsu General Hospital on 15 May, 1974. She complained of irritability and excitability lasting about 5 years. Recently she noticed visual disturbance, moon face, and ec- chymosis in the lower extremeties.
On admission an appearance of Cushing’s syndrome was typical. X-ray examinations revealed severe osteoporosis with compression fractures of vertebrae of Th 11 and 12 and L 1 and 2.
Laboratory examinations revealed high total cholesterol and NEFA. Oral 100 g glucose loading test showed a distinct diabetic pattern, and secondary diabetes mellitus was suspected from an excessive reaction in blood IRI level and insulinogenic index of 1.32.
| I | II | III | Normal range | ||
|---|---|---|---|---|---|
| Pregnenolone | 0.88 | 0.7 | 0.40 | 0.67~1.72 | mg/g tissue |
| Progesterone | 0.06 | 0.04 | 0.08 | 0.94~1.75 | ug/g tissue |
| 11-Deoxycorticosterone | 291 | 276 | 142 | 330~880 | ng/g tissue |
| Corticosterone | 1.4 | 1.6 | 0.7 | 2.3 ~8.1 | ug/g tissue |
| 17-OH Pregnenolone | 0.43 | 0.35 | 0.12 | 1.53 | mg/g tissue |
| 17-OH Progesterone | 0.11 | 0.07 | 0.03 | 0.88 | mg/g tissue |
| Cortisol | 0.3 | 0.2 | 0.04 | 8.0 ~21.6 | mg/g tissue |
| Dehydroepiandrosterone | 110 | 83 | 41 | 380~760 | ng/g tissue |
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The urinary level of 17-OHCS was high but total and fraction levels of 17-KS were normal. DHEA was not detected. Plasma levels of catecholamine, aldos- terone, estrogenic steroids and hypophyseal gonadotropin were normal (Table 3). Oral administration of 2 mg, 6 mg, and even 12 mg of dexamethasone in 4 divided doses failed to suppress the steroid excretion. Metyrapone test failed to increase the urinary 17-OHCS. A delayed response to ACTH was observed.
Pneumoretroperitoneum and a scintigram using 131I-adosterol revealed a left adrenal tumor. Computed tomography was not available at that time. The possibility of adrenal carcinoma was negligible because of no increase of DHEA in 17-KS fractions. The left adrenal gland was removed on 19 November, 1974.
Pathological examinations : The resected mass weighed about 10 g in total and contained two separate spherical tumors ; a large dark brown one measuring 2 cm in the largest diameter and a small yellow one measuring 0.8 cm in diameter (Fig. 6).
Histologically, the large dark brown tumor was mostly composed of compact cells with slightly basophilic cytoplasm, arranging in an alveolar pattern with slight lymphocytic infiltration in the subcapsular area. Electron-microscopically most of the tumor cells had large mitochondria with well developed cristae. Numerous large spherical SER were remarkable and a few number of lipofuscin granules with medium electron density were interspersed (Fig. 7). Lipid droplets were few.
The small yellow tumor was mainly composed of large clear cells with small nuclei (Fig. 8). Electron-microscopically, mitochondria were usually small and sparse. A number of lipid droplets with high or low electron density were
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frequently found while SER was elongated with empty lumen.
The attached adrenal cortex was slightly atrophic and composed of clear cells. Tissue steroid analysis was not performed.
DISCUSSION
Recent progress in the CT diagnosis for adrenal mass has made it possible to biopsy the adrenal tissue to establish the diagnosis before the operation (Berkman et al. 1984). However, in some cases it is still difficult to interpret the histologic patterns of an adrenal tumor in terms of malignancy or of the functional state. Histological criteria for the diagnosis of malignancy of the functioning adrenocor- tical tumors have not been established. In Cushing’s syndrome, in vitro func- tional abnormalities of the removed tumor, such as secretions of precursor steroids and a blunted or absent response to ACTH, served as an additional parameter for the distinction of benign and malignant tumors (Neville and O’Hare 1978; O’ Hare et al. 1979). In case 1, malignancy was suggested by high levels of urinary 17 KS, increases in plasma DHEA and aldosterone, no response to synthetic ACTH infusion, and the large size of the tumor in CT. The tumor weight of 284 g and lesions of necrosis on the cut surface were of malignant sign. Histological examinations revealed that the greater part of the tumor was composed of well differentiated clear cells with no evidence of malignancy. However, lesions of unquestionable malignancy composed of small cells with sheet-like or coarse alveolar arrangements were evident in 3 of 15 paraffin blocks. These findings of histological malignancy which were corroborated by the result of tissue steroid analyses provided evidence of histological diagnosis of malignancy.
In case 2, closely located double adenomas in the unilateral gland, a unique finding in Cushing’s syndrome, were not diagnosed preoperatively. The distinc- tion of adenoma from nodular hyperplasia was evident in this case. Grossly detectable atrophy of the attached adrenal cortex supplies a clue to the diagnosis of adenoma associated with Cushing’s syndrome (Neville and O’Hare 1982). The two adenomas in the present case were quite different from each other in the histology. Takaki et al. (1980) reported a case of combined Cushing’s syndrome and primary aldosteronism caused by double adenomas in the unilateral gland. It was concluded that Cushing’s syndrome was induced by a black adenoma and primary aldosteronism by a yellow one. In our case 2, the dark-brown tumor was composed of compact cells suggesting a Cushing-type adenoma, and the small yellow one was composed of clear cells lacking any morphological evidence of hyperfunction. Unfortunately steroid analysis was not carried out. Sasano et al. (1980) emphasized that analysis of the tissue content and in vitro production of steroids by tumor tissue is the most direct method of analyzing adrenal tumor function.
In conclusion, adrenal CT and detailed steroid studies are recommended for the preoperative diagnosis of adrenal tumors. In cases of multiple adenomas, in
vitro steroid analyses of individual tumors are necessary for the evaluation of their functional state.
References
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