Case Report
Deoxycorticosterone-secreting Adrenocortical Carcinoma
Akihiro Yamamoto, Takushi Naroda, Susumu Kagawa, Yoshihumi Umaki, Yasumi Shintani, Toshiaki Sano, and Hironobu Sasano
Abstract
A case of DOC-secreting adrenocortical carcinoma in a 66-year-old man is reported. He had hypertension, hypokalemia, suppressed PRA, and excessive serum levels of DOC. His serum aldosterone level was normal. The resected adrenal mass weighed 230 g. Histologically, the tumor was mainly composed of compact cells associated with necrosis and atypical mitoses. Invasion of venous structure, sinusoids, and capsule was also present. Immunohistochemically, P450 C21(21-hydroxylase) was positive in many tumor cells, and P450 C17(17 a-hydroxylase) was intensely positive in a relatively small number of tumor cells. The patient died 9 months after operation due to rupture of metastatic liver tumor. Endocr Pathol 4:165-168, 1993.
Department of Urology (AY, TN, SK), First De- partment of Internal Medi- cine (YU, YS), First De- partment of Pathology (TS), School of Medicine, The University of Tokushima, Tokushima; and Second Department of Pathology (HS), Tohoku University, School of Medi- cine, Sendai, Japan.
Address correspondence to Dr. Akihiro Yamamoto, Departument of Urology, School of Medicine, The University of Tokushima, Kuramoto-cho 2, Tokushima City 770, Ja- pan.
@ 1993 Blackwell Scientific Publications, Inc.
Deoxycorticosterone (DOC)-producing ad- renal tumors are rare and usually malignant [2,7]. Such tumors do not always result in symptoms of mineralocorticoid excess due to its weak mineralocorticoid activity. Docu- mented cases of carcinoma with excessive mineralocorticoid activity are mostly large [1,6,7]. The patient presented herein, with clinical hypermineralocorticoidism, had a relatively large number of tumor cells posi- tive for 21-hydroxylase, which was consis- tent with DOC-producing adrenocortical carcinoma.
Case Report
A 66-year-old man was referred to our hospital for evaluation of a left adrenal tumor. He had been hypertensive for 4 months. His blood pressure was 160/104 mm Hg with no medication. He had hypokalemia (2.6 mEq/L) and suppressed plasma renin activity (PRA) (<0.1 ng/ml/
hr). Laboratory findings showed an excess of aldosterone precursors, especially DOC, and slightly elevated levels of glucocorti- coids: plasma aldosterone, 47 pg/mL (35.7- 240); serum DOC, 17.10 ng/ml (0.08- 0.278); 18-OH DOC, 0.23 ng/ml (0.01- 0.07); pregnenolone, 0.2 ng/ml (0.1-1.0); progesterone, 1.7 ng/ml (<0.7); corticosterone, 1.02 ng/ml (0.38-8.42); cortisol, 18.9 µg/dL (4.9-19.0); and urine 17-OHCS, 15.8 mg/day (3.4-12.0). Urine excretion levels of 17-KS, adrenaline, and noradrenaline were normal.
Abdominal computed tomography re- vealed a large heterogenous left adrenal mass (Fig. 1). Magnetic resonance imaging demonstrated that the tumor had isoin- tensity by T1-weighted imaging (WI) and hyperintensity by T2-WI, compared with the liver. There were some small areas that had hyperintensity by T1-WI and hypoin- tensity by T2-WI, suggesting bleeding.
With a preoperative diagnosis of adre- nocortical carcinoma, left adrenalectomy
3.
R
F
was performed using a flank approach. There was no adhesion to the surrounding tissue.
Pathological Findings
The resected tumor weighed 230 g and measured 10.0 × 8.0 × 4.5 cm in diameter. The tumor was soft and surrounded by a thin capsule. On the cut surface, the tumor
2
Figure 2. Cut surface of the tumor revealed a red-brown, partly grayish white mass associated with hemorrhage and necrosis.
was red-brown, partly grayish white, and associated with hemorrhage and necrosis (Fig. 2).
Microscopically, the tumor was mainly composed of compact cells showing diffuse architecture and was associated with necro- sis and collagenous bands (Fig. 3). Tumor cells showed pleomorphism with atypical mitoses. Invasion of venous structures, sinusoids, and the capsule of the tumor was also present. Thus, except for a mitotic rate, this tumor fulfilled 8 of the 9 criteria was advocated by Weiss [8]. On the basis of these findings, this tumor was diagnosed as an adrenocortical carcinoma.
Immunohistochemical study was done using antibodies against steroidogenic en- zymes of cytochrome P450 [7]. P450 C21 (21-hydroxylase) was positive in approxi- mately 50% of tumor cells, mainly to a moderate degree (Fig. 4A), whereas P450 C11(11ß-hydroxylase) and P450 C17(17 @- hydroxylase) were intensely positive in 5-10% of tumor cells (Fig. 4B). P450 SCC (cholesterol side-chain cleavage) and 3ßHSD (3ß-OH dehydrogenase) were in- tensely positive in a few cells, but the number of immunoreactive cells differed from area to area. These immunohisto- chemical findings are consistent with DOC excess and slightly elevated levels of glucocorticoids.
Liver metastasis and multiple lung me- tastasis were detected 1 month after opera- tion. These metastatic lesions grew rapidly despite administration of o,p’-DDD. The patient became hypertensive again and had mental changes. Results of laboratory find- ings 7 months after operation showed marked hypermineralocorticoidism and hy- perglucocorticoidism; plasma aldosterone, 100 pg/mL; serum DOC, 24.6 ng/ml; 18- OH DOC, 0.66 ng/ml; progesterone, 4.58 ng/ml; cortisol, 61.88 ug/dL; and urine 17-OHCS, 34.7 mg/day.
The patient died 9 months after opera- tion due to rupture of a metastic liver tumor.
Discussion
Hypertension, hypokalemia, and sup- pressed PRA are the major clinical findings of hypermineralocorticoidism. Although
DOC is not as potent as aldosterone when the levels of DOC are greatly elevated, the same conditions can occur [4]. DOC- producing adrenocortical tumors are rare, and only sporadic case reports have been documented [1-6]. Cases of adrenal carci- noma with hypermineralocorticoidism are usually associated with concomitant hyper- secretion of the other adrenocortical hor- mones, such as glucocorticoids and andro-
gens [2], including our patient, who had increased urinary excretion of 17-OHCS. Therefore, in these cases, there was a preponderance of the mineralocorticoid syn- thetic pathway as far as DOC relative to the later steps and relative to glucocorticoid levels, without a diminution in these steps.
In histopathological evaluation of adrenocortical tumors, distinction between benign and malignancy may be difficult, and the diagnosis is usually made after consideration of a combination of clinical, gross, and microscopic appearances. The combination of 9 histological criteria was proposed by Weiss [8] and has been used as an effective predictor of carcinoma. In our patient, the resected tumor met 8 of the 9 criteria and is considered highly malig- nant. The patient followed a fulminant clinical course with extensive hemato- genous metastases.
The functional state of adrenocortical tumors may be revealed by immunohisto- chemical demonstration of steroidogenic enzymes of cytochrome P450 [7] (Fig. 5). Progesterone in mineralocorticoid synthe- sis is hydroxylated at position 21 by microsomal cytochrome P450 (P450 C21), yielding DOC. In contrast, progesterone is mostly hydroxylated at the 17 a- position by another specific microsomal cytochrome P450 (P450 C17), yielding 17 a-hydroxyprogesterone, which is the pre- cursor of cortisol. In our patient, P450
17a-hydroxylase (P 450 C17)
17, 20 lyase (P 450 C17)
Cholesterol
Pregnenolone
17-OH Pregnenolone
DHEA
3₿-OH dehydrogenase (3₿ HSD)
Progesterone
17-OH Progesterone
4A andro- stenedione
21-hydroxylase (P 450 C21)
DOC
11-deoxy Cortisol
11ß-hydroxylase (P 450 C11)
Corticosterone
Cortisol
Corticosterone methyl oxidase (P 450 C11)
Aldosterone
C21 was positive in many tumor cells, and P450 C17 was intensely positive in 5-10% of tumor cells, suggesting a mineralocorti- coid excess associated with production of glucocorticoid. These findings were com- patible with the patient’s preoperative clinical and biochemical manifestations. 3BHSD, which converts pregnenolone to progesterone, was positive in a few cells showing heterogenous staining. Concern- ing P450 SCC and 3ßHSD, this result showed that the tumor was mainly com- posed of cells negative for these enzymes intermingled with sporadic positive cells. These results, together with immunolocal- ization of P450 C21, may indicate inef- fective steroidogenesis of adrenocortical malignancy. P450 specific for 11ß-hydroxy- lation (P450 C11) converts DOC to corticosterone. This P450 C11 is also known to catalyze the 2 final reactions of aldosterone biosynthesis (i.e., corticoster- one methyl oxidase I and II activities) [7]. In our patient, P450 C11 was intensely positive in a relatively small number of
tumor cells, with normal serum levels of corticosterone and aldosterone. This find- ing indicates that the tumor described herein could produce aldosterone but not excessively. Immunolocalization of steroid- ogenic enzymes can demonstrate the sites of steroidogenesis in surgical pathology specimens and is also of value in retrospec- tive analysis of steroidogenesis in adreno- cortical neoplasms, including carcinomas.
References
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