Nonfunctioning Adrenal Cortical Cancer and Analysis of the Steroidogenic Activity of the Tumor: A Case Report
Masaaki Morioka,1* Hiroyoshi Tanaka,1 Yozo Ohashi,2 Tie-Xiong Jin,2 Hironobu Watanabe,2 and Mutsuo Furihata3
1Department of Urology, Kawasaki Medical School, Kurashiki, Japan, and Departments of 2Urology and 3Pathology, Kochi Medical School, Nankoku, Japan
An adrenocortical cancer was detected by a CT scan in a 37-year-old woman, which did not have an excessive secretion of steroids or catecholamines. The tumor was enhanced inhomogeneously by the bolus injection of contrast medium, and magnetic resonance imaging (MRI) showed that the tumor was hypointense compared to the liver on a T1-weighted image and was diffusely hyperintense on a T2- weighted image. Histologically, the tumor consisted predominantly of compact cells with marked cellular and nuclear pleomorphism, but no capsular or vascular invasion were observed. An analysis of the steroidogenic activity of the tumor revealed that the activity of mitochondrial P450c118 was extremely reduced in the tumor.
Int J Urol 1998;5:170-173
Key words: adrenocortical cancer, MRI, tumor steroidogenic activity
INTRODUCTION
The incidence of adrenocortical cancer is rare, account- ing for only 0.2% of all malignant tumors, and is usually discovered as a large abdominal mass.1,2 Although recent advances in imaging methods contribute to the discovery of asymptomatic adrenal masses, adrenal cancer detected at an early stage is not yet widespread.2 However, plasma and tumor tissue endocrine studies were not accurately performed in most of the previous reports. We report a case of a nonfunctioning adrenal cancer which was detected by CT scan and examine the steroidogenic activity of the tumor.
CASE REPORT
A 37-year-old woman had been treated for hyperten- sion with several antihypertensive agents for 3 years, but her hypertension was not adequately controlled. Her blood pressure at presentation was 180/100 mm Hg, and her height and weight were 152 cm, and 52 kg, respectively. A complete blood count, serum electrolytes and creatinine, liver function tests and a fasting blood sugar were within normal limits. She underwent endo- crine examinations and an abdominal CT scan screen- ing for secondary hypertensive anomalies. The plasma renin activity (PRA), plasma aldosterone concentra-
tion (PAC) and serum kalium level were 0.7 ng/ml/hour, 5 ng/dl and 4.2 mEq/L, respectively. The basal level and circadian rhythm of plasma cortisol and adrenocor- ticotropic hormone were within normal limits, and plasma levels and the urinary excretion of catechola- mines were also within normal limits (Table 1). Al- though the endocrine studies were within the normal range, a CT scan revealed a right adrenal mass. The tumor was enhanced inhomogeneously by the injection of contrast medium (Fig. 1), and magnetic resonance imaging (MRI) disclosed that the tumor was hypointense compared to the liver on a T1-weighted image and diffuse hyperintense on a T2-weighted image (Fig. 2). This high signal intensity is typically suggestive of a malignant etiology or a pheochromocytoma. Therefore, stimulation tests using metoclopramide and 131I- metaiodobenzylguanidine scintigraphy were performed but both tests were negative. A transabdominal right adrenalectomy was performed due to the possibility of malignancy or an endocrine-inactive pheochromocy- toma. The tumor weighed 20 g and was encapsulated within thin fibrous tissues. The tumor was predomi- nantly composed of dark compact cells with marked nuclear pleomorphism and lesser numbers of large clear cells. Mitotic figures, including pathologic figure, were frequently observed (Fig. 3A). Immunohisto- chemical studies were performed using the streptavidin- biotin-peroxidase complex (ABC) method. The tumor cells were heterogeneously but strongly positive for anti- vimentin antibody (Fig. 3B), but other specific stains including Grimelius and Masson-Fontana were negative.
Endogenous steroid levels were measured both in the tumor and the adjacent nonmalignant adrenal tissue
| Study patient value | Normal range | ||
|---|---|---|---|
| Plasma renin activity | 0.7 | 0.2-2.7 ng/ml/h | |
| Plasma aldosterone | 5 | 3-16 ng/dL | |
| Plasma basal level (0800 h) | |||
| ACTH | 24 | 7.4-55.7 pg/mL | |
| Cortisol | 14.0 | 3.5-18.0 µg/dL | |
| Plasma cortisol after | |||
| dexamethasone suppression | 3.0 | < 4 ug/dL | |
| Urine | |||
| 17-OHCS | 6.1 | 1.9-6.1 mg/d | |
| 17-KS | 8.3 | 3.1-8.8 mg/d | |
| Plasma | |||
| Norepinephrine | 303.0 | 70-350 pg/mL | |
| Epinephrine | 19.3 | < 70 pg/mL | |
| Dopamine | < 30 | < 30 pg/mL | |
| Urine | |||
| Norepinephrine | 86.5 | 20-150 µg/d | |
| Epinephrine | 12.9 | < 28 µg/d | |
| Dopamine | 590.0 | 130-1200 µg/d | |
| VMA | 4.2 | 1.3-5.3 mg/d | |
| Normetanephrine | 0.12 | 0.05-0.36 mg/d | |
| Metanephrine | 0.07 | 0.01-0.30 mg/d | |
A
B
A
B
Fig. 2. Magnetic resonance imaging of the tumor. The tumor was hypointense on T1-weighted image compared to the liver (A), and diffuse hyperintense on T2-weighted image (B).
according to our previously reported method.3 The activities of the steroidogenic enzymes (cytochrome P450s) were evaluated only in the tumor itself due to a limited amount of nonmalignant adrenal tissue. The activities of P450c17 and P450c21 were evaluated in the presence of an NADPH-generating system using proges- terone and 17-hydroxyprogesterone as the substrates, respectively, while those of P450c118 and the aldoster- one-synthesizing enzymes (P450aldo) were evaluated in the presence of NADPH-generating and electron transport systems using 11-deoxycorticosterone (DOC) as a substrate.4,5 These procedures are the standard methods for evaluating the activities of mitochondrial P450c113, P450c18, and P450aldo. The levels of cor- ticosteroids and androgens, including cortisol, corticos- terone, DOC, and androstenedione were extremely low, whereas that of 11-deoxycortisol (S) was elevated in the tumor compared to that in the nontumorous portion. There was markedly reduced activity of mitochondrial P450c118, but minimal changes in the activity of mi- crosomal P450c17 and P450c21 in the tumor (Table 2). The activity of P450aldo, which is usually detectable in aldosterone-producing tumor, was not detected in the present case. From these clinicopathologic and endo-
B
| Endogenous steroid contents (ug/g wet tissue) | |||||||
|---|---|---|---|---|---|---|---|
| Cortisol | Corticosterone | S | DOC | A-dione | 17-OHP | Progesterone | |
| Tumor | 1.64 | 0.08 | 1.69 | UD | UD | 0.44 | UD |
| Adjacent tissue | 13.5 | 3.72 | 1.46 | 0.16 | 0.75 | 1.90 | 0.90 |
| Normal values | 12.36 ± 2.80ª | 4.05 ± 1.63 | 1.92 ± 0.47 | 0.16 ± 0.04 | 0.59 ± 0.24 | 1.39 ± 0.37 | 0.41 ± 0.21 |
Steroidogenic activity in the tumor (nmol/min/mg protein)
| P450c17 | P450c21 | P450c11B | P450aldo | |
|---|---|---|---|---|
| Activity | 2.63 | 2.68 | 0.28 | UD |
| Normal values | 4.29 ± 0.43 | 2.47 ± 0.56 | 4.38 ± 0.62 | UD |
| Substrate | Progesterone | 17-OHP | DOC | DOC |
S, 11-deoxycortisol; DOC, 11-deoxycorticosterone; A-dione, 4-4androstenedione; 17-OHP, 17-hydroxyprogesterone; UD, un- detectable; P450aldo, aldosterone-synthesizing enzymes. ªmean ± SD.
crine findings, we diagnosed the present tumor as an adrenocortical cancer.
The plasma levels of catecholamines, PAC, PRA, and cortisol in the postoperative period were also within the normal range. Her hypertension was controlled (150/90 mm Hg) postoperatively by combination therapy with a calcium antagonist and an angiotensin converting enzyme inhibitor. It was postulated that the poor control of her hypertension in the preoperative period was attributed to the insufficient dose of drugs.
DISCUSSION
Adrenal cancer often presents at an advanced stage with a large abdominal mass.2 Characteristic findings in imag- ing methods are described as large masses with necro- sis, invasion to adjacent organs and inhomogeneous
enhancement by contrast materials on CT scan.6,7 The high intensity signal on an MRI T2-weighted image is also considered to be characteristic for adrenal cancer, but MRI cannot distinguish a pheochromocytoma from adrenal cancer.6,7 We also could not differentiate this tumor from endocrine-inactive pheochromocytoma by the MRI findings alone. Histologically, the tumor cells showed nuclear pleomorphism and pathologic mitoses, with a predominance of pleomorphic, compact cells. According to the criteria of Weiss,8 these findings were compatible with a localized and nonmetastasizing adre- nal cancer. The heterogeneous but strongly positive staining with antibody to vimentin also suggested the malignant potential of this tumor.
Concerning the endocrine activity of the adrenal cancer, Cushing’s syndrome is the most frequent clini- cal presentation, and a nonfunctioning tumor is also
Nonfunctioning Adrenal Cancer
common,1 but an androgen-secreting tumor is rare.9 The term nonfunctioning usually refers to tumors that may produce detectable levels of several steroids, but are not sufficient to manifest clinically.6 From this point of view, the term nonhyperfunctioning tumor is more appropriate. The activities of the various P450 enzymes may change throughout the histologic differentiation process, and Papadopoulos et al. reported a markedly decreased activity of microsomal P450 in adrenal can- cer.10 Naganuma et al.11 also reported the reduced activ- ity of mitochondrial P450c1 1Bin adrenal cancers which produced androgens, but this report was not consid- ered reliable because they did not involve the electron transport system (adrenodoxin and NADPH-adrenodoxin reductase) in their experimental procedure. In the present case, the activities of the microsomal P450 enzymes were relatively preserved in the tumor, whereas that of mitochondrial P450c1 10 was markedly reduced to less than 10% of normal values.4,5 The activity of P450aldo was not detected in the tumor, which is consis- tent with our previous findings that tissue P450aldo activity was usually undetectable in adrenal tissues except in aldosterone-producing tumor, even if the activity of P450c118 was normal.5 These results may reflect low levels of cortisol and corticosterone, and a relatively elevated S level, but it was difficult to explain why the DOC level was reduced in this tumor. Although plasma DOC and S levels were not measured in the present case, it is possible that they might become elevated as the tumor enlarges. We previously reported a case of advanced adrenal cancer with mild virilization, and noted reduced activity of P450c17 and P450c11B and relatively elevated S levels.9 The reduced activity of P450 enzymes in adrenal tumors may suggest a func- tional immaturity of the tumor cells. The analysis of steroidogenic activity of the tumor tissue may contribute to a pathologic diagnosis of an adrenal cortical tumor. Also, in cases with abnormal findings on MRI, especially a diffuse high-intensity signal on a T2-weighted image, the tumor should be resected due to the possibility of malignancy even if the tumor is nonhyperfunctioning.
ACKNOWLEDGMENT
The authors thank Dr Fumiko Mitani of the Department of Biochemistry, Keio University for her kind donation of bo- vine adrenodoxin and NADPH-adrenodoxin reductase.
REFERENCES
1. Henley DJ, van Heerden JA, Grant GS, Carney JA, Car- penter PC. Adrenal cortical carcinoma-a continuing challenge. Surgery 1983;94:926-931.
2. Fishman EK, Deutsch BM, Hartman DS, Goldman SM, Zerhouni EA, Siegelman SS. Primary adrenocortical carcinoma: CT evaluation with clinical correlation. AJR 1987;148:531-535.
3. Morioka M, OhashiY, Sen Y, Komatsu F, Fujita Y, Konishi Y. Analysis of corticoids in adrenal glands by high per- formance liquid chromatography (HPLC) (in Japanese). Folia Endocrinol Jpn 1993;69:55-66.
4. Shibata H, Suzuki H, Ogishima T, Ishimura Y, Saruta T. Significance of steroidogenic enzymes in the pathogenesis of adrenal tumour. Acta Endocrinol 1993;128:235-242.
5. Morioka M, Ohashi Y, Watanabe H, Komatsu F, Jin T-X, Suyama B, Tanaka H. ACTH-independent macronodular adrenocortical hyperplasia (AIMAH): report of two cases and the analysis of steroidogenic activity in adrenal nod- ules. Endocrine J 1997;44:65-72.
6. Francis IR, Gross MD, Shapiro B, Korobkin M, Quint LE. Integrated imaging of adrenal disease. Radiol 1992; 184:1-13.
7. Dunnick NR. Adrenal carcinoma. Radiol Clin North Am 1994;32:99-108.
8. Weiss LM. Comparative histologic study of 43 metastasiz- ing and non-metastasizing adrenocortical tumors. Am J Surg Pathol 1984;8:163-169.
9. Inoue K, Komatsu F, Yamasaki I, Kamata M, Watanabe H, Ohashi Y, Morioka M, Fujita Y. Adrenocortical carci- noma with virilization (in Japanese). Nishinihon J Urol 1996;58:136-140.
10. Papadopoulos D, Grondal S, Rydstrom J, DePierre JW. Levels of cytochrome P450, steroidogenesis and micro- somal and cytosolic epoxide hydrolases in normal hu- man adrenal tissue and corresponding tumors. Cancer Biochem Biophys 1992;12:283-291.
11. Naganuma H, Ojima M, Sasano N. 11ß-hydroxylase in mitochondrial fractions of functioning and non-function- ing adrenocortical tumors. Tohoku J Exp Med 1988;155: 81-96.