Unusual Visualization of an Adrenal Carcinoma on NP-59 Scintiscan
Fan-Fen Wang, Yen-Hwa Chang,1 Chin-Chen Pan,2 Dom-Gene Tu,3 Justin Ging-Shing Won4*
[Iodine-131]6-beta-iodomethylnorcholesterol (NP-59) visualization of adrenocortical carcinoma is unusual. We describe a 17-year-old female with virilization and elevated plasma testosterone, dehydroepiandrosterone sulfate (DHEAS) and aldosterone. Magnetic resonance imaging disclosed a 9-cm right adrenal mass. NP-59 adrenal scanning displayed unilateral uptake of tracer and no visualization of the contralateral adrenal gland. Exploratory laparotomy revealed adrenocortical carcinoma. Subsequent immunohistochemical studies confirmed that the tumor was capable of producing a mixture of steroids, including testosterone, DHEAS and aldosterone. Visualization of an adrenal tumor on NP-59 scintiscan is an unusual finding, which cannot exclude the possibility of malignancy. [J Formos Med Assoc 2006;105(4):340-345]
Key Words: adrenocortical carcinoma, NP-59 scan, virilization
Adrenocortical carcinoma (ACC) is a rare disorder, with an estimated incidence of 0.6-2.0 cases per million.1 In general, approximately half of these tumors are functioning, that is, secreting excess hormones and producing endocrinologic symp- toms and signs, which lead to their discovery.2 Among functioning ACCs, the most common hor- monal abnormality is hypersecretion of both glucocorticoids and androgens (42%), followed by hypersecretion of glucocorticoids alone (41%) and hypersecretion of androgens alone (10%).3 The prognosis of ACC is usually poor, and the life expectancy of afflicted patients depends large- ly on correct diagnosis leading to prompt treat- ment.2
Several diagnostic methods have been in- troduced to determine whether an adrenal mass is benign or malignant. NP-59 ([I-131]6-beta- iodomethylnorcholesterol) nuclear scintigraphy, a noninvasive diagnostic modality that can pro- vide information about the functional status of
the adrenal glands, has been utilized for this pur- pose. On NP-59 scintigraphy, benign adrenal adenomas typically exhibit a concordant imaging pattern, with uptake of the radiotracer on the side of the known adrenal mass and lack of visualiza- tion of the contralateral gland.4,5 However, ACCs are usually not visualized, as the amount of radio- tracer uptake by these tumors is usually insuffi- cient to permit adequate imaging.
In this report, we describe a virilizing ACC, which displayed a concordant imaging pattern on NP-59 scintigraphy. This tumor was found to be capable of producing dehydroepiandrosterone sulfate (DHEAS), testosterone and aldosterone both in vivo and in vitro.
Case Report
A 17-year-old female was referred for evaluation of primary amenorrhea. She had been a good ath-
@2006 Elsevier & Formosan Medical Association
Division of Endocrinology and Metabolism, Taipei Municipal Yang-Ming Hospital; Departments of 1Surgery, 2Pathology and 4Medicine, Taipei Veterans General Hospital; and 3Department of Nuclear Medicine, Chai-I Christian Hospital and National Yang-Ming University, Taipei, Taiwan.
Received: March 17, 2005
*Correspondence to: Dr. Justin Ging-Shing Won, Department of Medicine, Taipei Veterans General Hospital, 201, Section 2, Shih-Pai Road, Taipei 112, Taiwan.
Revised: May 3, 2005
Accepted: June 7, 2005
E-mail: gswon@vghtpe.gov.tw
lete since childhood and had no major medical disorders. On physical examination, she was tall and lean, with clinical evidence of virilism, includ- ing hirsutism of the face and back, clitoromegaly, and deep voice. Breast development was Tanner stage 1 and Cushingoid features were not evident. Blood pressure was 100/65 mmHg. Biochemical data were within normal limits and serum potas- sium was 4.7 mmol/L (normal, 3.4-4.7 mmol/L).
Endocrine tests revealed a plasma estradiol level of 110 pg/mL (normal, 25-120 pg/mL), fol- licle-stimulating hormone (FSH) of 1.81 mIU/mL (normal, 5-30 mIU/mL), luteinizing hormone (LH) of 15.72 mIU/mL (normal, 2-200 mIU/mL), and prolactin of 7.87 ng/ml (normal, 3.0-26.0 ng/ mL). Serum testosterone and DHEAS were both far above the detection limit of our laboratory (testosterone > 14.40 ng/ml, normal, 0.09-0.86
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ng/ml; DHEAS > 1105 µg/dL, normal, 40-394 ug/ dL). Serum aldosterone was also elevated (579 pg/mL; normal, 37.5-240 pg/mL), but plasma renin level was normal (13.21 pg/mL; normal, 2.5-21.4 pg/mL). Early morning cortisol was 6.4 ug/dL (normal, 5-25 µg/dL), which increased to 31.3 ug/dL 60 minutes after an intravenous injec- tion of 250 ug of adrenocorticotropic hormone (ACTH)-(1-24) (Synacthen; Novartis Pharma AG, Basle, Switzerland). Serum 17-hydroxyprogester- one level was 4.73 ng/mL, which increased to 8.64 ng/mL 60 minutes after intravenous 250 ug ACTH- (1-24), thereby excluding the possibility of atten- uated congenital adrenal hyperplasia.
Magnetic resonance imaging of the adrenal glands showed an oval-shaped multicystic tumor, 9 × 5 × 8.4 cm in size, in the right suprarenal re- gion. The tumor showed low signal intensity on T1-weighted scan, and mild enhancement on T2-weighted scan (Figure 1). On dexamethasone- modified NP-59 adrenal scintiscan, mildly in- creased activity in the right suprarenal area was noted at 48 hours, and significant accumulation of tracer together with complete lack of visuali- zation of the contralateral gland was noted at 72 hours (Figure 2), favoring a concordant pattern of tumor imaging.
Exploratory laparotomy was performed with removal of the right adrenal tumor. Pathologic ex- amination of the resected tumor confirmed ACC. The postoperative course was uneventful, and re- placement of hydrocortisone was not required. Six days postoperatively, plasma testosterone had de- creased to 0.21 ng/mL, plasma aldosterone to 306
pg/mL, and morning serum cortisol was 27.9 ug/dL (plasma DHEAS not available). Treatment with mitotane, 500 mg three times a day, was start- ed 1 week after surgery and continued thereafter. One month after surgery, the patient experienced menarche, and her menstrual periods were sub- sequently regular. At the 1-year follow-up, she was apparently healthy and hirsutism was much improved. There was no clinical evidence of meta- stasis. Hormone profiles were all within normal ranges (testosterone, 0.65 ng/ml; DHEAS, 200 ug/ dL; aldosterone, 128 pg/mL).
Histopathologic examination
The resected adrenal tumor measured 11 x 10 x 5 cm and weighed 265 g. Microscopic examination showed pleomorphic tumor cells, containing hy- perchromatic bizarre nuclei and intensely eosi- nophilic cytoplasm (Figure 3). The tumor exhibited three pathologic features of the Weiss criteria:7 high nuclear grade; > 75% eosinophilic cytoplasm; and
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diffuse architecture of tumor structure. It was, therefore, classified as an ACC.
Immunohistochemical staining was per- formed using the labeled streptavidin-biotin method (LSAB 2 Kit; DAKO Corp, Carpinteria, CA, USA). Antibodies were diluted as follows: aldos- terone (1:50; Biogenesis, Poole, Dorset, UK); tes- tosterone (1:25; Biogenesis); and DHEAS (1:30; BiosPacific, Emeryville, CA, USA). On microscop- ic examination, the tumor showed focal immuno- reactivity (about 10%) to aldosterone. Well-stained cells tended to be arranged in thin trabeculae or ribbon patterns, and their nuclei were vesicular and uniform in size, whereas weakly-stained cells grew in sheets or in a pleomorphic sarcoma-like pattern (Figure 4A). In contrast to aldosterone, im- munoreactivity to both testosterone and DHEAS was diffuse and intense throughout the whole specimen (Figures 4B and 4C).
Discussion
This rare case of virilizing ACC showed concor- dant uptake on NP-59 scintiscan. Our review of the English literature revealed only 10 previous reports of primary ACC with a concordant NP-59 imaging pattern, including three patients with Cushing’s syndrome (one associated with hir- sutism),8-10 six patients with primary aldosteron- ism,11-14 and one patient with increased urinary excretion of androsterone and DHEA15 (Table).16 All of these tumors secreted excess hormones bio- chemically and produced clinical endocrinologic symptoms and signs, and some were also described as being well differentiated on histologic exami- nation of the resected tissues.9-11,15 Most (9/11) of these tumors were found at a lower stage (≤ stage 2), and most (7/11) of the patients remained free of recurrence during the follow-up period after tu- mor resection. Thus, both the functional status of the tumor and the degree of differentiation of tu- mor cells appear to be important factors in deter- mining visualization on NP-59 scintigraphy, with the degree of differentiation of tumor cells, i.e. grade of malignancy, probably being the more im-
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portant factor. The findings in this case, a pre- dominantly testosterone and DHEAS secreting virilizing ACC of relatively low grade malignancy (stage 2), which remained free of recurrence dur- ing 34 months of follow-up, support this hypo- thesis.
Hypertension and hypokalemia are the most common clinical features of primary aldosteron- ism. However, despite a high serum aldosterone level, our patient was normotensive and normo- kalemic, as has been reported in a previous case.17
Since hypertension is usually followed by hypo- kalemia in the evolving course of primary aldoster- onism, our patient might have been in the very early stage of primary aldosteronism, displaying no symptoms or signs of mineralocorticoid excess clinically, which is characteristic of the normoka- lemic type. 18
Steroidogenesis in human ACC is unique, and has been described either as low efficiency steroid production or abnormal steroidogenesis.19 In this case, extremely high plasma DHEAS and testo-
| Table. | NP-59 scan positive primary adrenocortical carcinomas reported in the English literature | ||||
|---|---|---|---|---|---|
| Age/Sex | Hypersecretory state | Tumor size (cm) | Staging at presentation* | Postoperative survival | Reference # |
| 30/F | Cushing's syndrome | 8 | 2 | Died at 9 mo | 8 |
| 66/F | Cushing's syndrome | 5 | 2 | Alive at 21 mo | 9 |
| 66/F | Cushing's syndrome (with hirsutism) | 5 | 2 | Alive at 66 mo | 10 |
| 47/F | Primary aldosteronism | 3 | 1 | Alive at 32 mo | 11 |
| 67/F | Primary aldosteronism | 7 | 2 | Alive at 17 mo | 12 |
| 43/M | Primary aldosteronism | 5 | 2 | Alive at 18 mo | 13 |
| 54/F | Primary aldosteronism | 11 | 3 | Alive at 6 mo | 13 |
| 42/M | Primary aldosteronism | 7 | 2 | Alive at 35 mo | 14 |
| 54/F | Primary aldosteronism | 11 | 3 | Alive at 2 mo | 14 |
| 43/F | Incidentaloma, with elevated androsterone & | 22 | 2 | 15 | |
| DHEA excretion in urine | Died at 11 mo | ||||
| 17/F | Virilism, with increased testosterone, | 11 | 2 | Alive at 34 mo | Present case |
| DHEAS & aldosterone secretion | |||||
*Staging: 1, < 5 cm; 2, > 5 cm and confined to the adrenal gland; 3, locoregional invasion or spread to local lymph nodes; and 4, distant meta- stasis.16
sterone levels were documented, which were ap- parently responsible for clinical virilization of the patient. DHEAS is a well-known adrenal androgen produced exclusively by the adrenals, whereas only a minimal amount of testosterone is produced in normal adrenals.20 It has been suggested that excess testosterone production in virilizing adre- nocortical tumors derives mainly from periphe- ral conversion of adrenal androgens, including DHEA, DHEAS, delta(5)-androstenediol, and del- ta(4)-androstenedione.21 In this case, immunohis- tochemical staining demonstrated that testoster- one could be produced directly from ACC cells. This finding is in accordance with a previous case report in which the ACC cells were capable of synthesizing testosterone.22 The activity of 17ß- hydroxysteroid dehydrogenase, the enzyme re- sponsible for converting androstenedione to tes- tosterone, has been shown to be 50-fold higher in virilizing adrenal adenomas than in normal adrenals.23 However, its activity in virilizing ACCs has not yet been studied; therefore, whether a similar mechanism exists and is responsible for the observed increased secretion of testosterone in virilizing ACCs remains to be determined. Fur- ther research regarding the activity or expression of 17ß-hydroxysteroid dehydrogenase on ACCs is needed to provide insight into the steroidogenic pathways of these tumors.
In this case, immunostaining to aldosterone appeared to be more intense in tumor cells with less nuclear atypia and with a trabecular or cord- like pattern. This histologic finding has been de- scribed as a characteristic of functioning ACCs.24 However, since there is much structural overlap between functioning and nonfunctioning tumors, tumor functionality cannot be predicted based on histology alone.24 In contrast to that of aldosterone, immunostaining to DHEAS and testosterone was diffuse and intense even in areas of nuclear pleo- morphism and of sarcoma-like pattern. This dis- crepancy may reflect the diversity and complexity of the steroidogenic pathways of ACCs.
In summary, this case of virilization due to a large ACC exhibited intense unilateral uptake on NP-59 adrenal scan. The tumor was shown to be
capable of producing a mixture of steroids, includ- ing testosterone, DHEAS and aldosterone, both in vivo and in vitro. This case illustrates the potential pitfall of assuming that all ACCs are unable to up- take sufficient radiotracer for imaging on NP-59 scanning. Visualization of an adrenal tumor on NP- 59 scintiscan cannot exclude the possibility of malignancy.
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