Newly developed hypertension as an early marker of recurrence of adrenocortical carcinoma with high renin expression


Jin-Shuen Chen md phd, Division of Nephrology, Department of Internal Medicine, Tri-Service General Hospital, No. 325, Section 2, Cheng-Kung Road, Neihu 114, Taipei, Taiwan. Email:


Abstract:  Adrenocortical carcinoma can recur frequently after successful surgery but no adequate markers can detect this recurrence. Here, we present a recurrence of adrenocortical carcinoma with a high renin expression, after successful surgery, where hypertension has developed again. Tumor recurrence was observed via 18F-fluorodeoxyglucose positron emission tomography and coregistered computed tomography. Based on our findings, follow-up blood pressure assessment may effectively predict the recurrence of adrenocortical carcinoma.


Adrenocortical carcinoma is an extremely rare tumor with an estimated incidence of just 0.023% of all malignancies.1 The incidence density rate is one to two cases per million persons per year.2 More than half (59.3–60%3,4) of adrenocortical carcinomas secrete hormones, most commonly cortisol, followed by androgens, estrogen, and aldosterone.5 Nevertheless, renin-producing carcinoma of the adrenal cortex is extremely rare, with only two cases described to date.6,7

Regarding treatment of adrenocortical carcinoma, surgical removal has been the only effective method until now.8 However, there is a high rate of locoregional or metastatic recurrence after curative resection,2 and no adequate markers indicate the recurrence of adrenocortical carcinoma. Here, we report the third case of renin-producing adrenocortical carcinoma with a clinical picture of hypertension with pure hyperreninism and hyperaldosteronism. After successful surgery, unilateral adrenalectomy, plasma renin activity (PRA), serum aldosterone and hypertension all returned to normal. Four months later, the patient detected newly accelerated hypertension, followed by a recurrence of adrenocortical carcinoma identified via 18F-fluorodeoxyglucose positron emission tomography and coregistered computed tomography (FDG PET-CT). Newly developed hypertension may be the early marker of the recurrence of renin-producing adrenocortical carcinoma.

Case report

A 60-year-old woman was referred to our hospital complaining about progressive dyspnea on exertion and the swelling of bilateral lower legs for 2 weeks.

Six months before admission, hypertension was diagnosed accidentally after the patient visited another hospital for menopausal syndrome. She has continued taking amlodipine 5 mg and losartan 50 mg daily to control hypertension since then. She had also gained 5 kg over the previous 6 months. On physical examination, the weight of the patient was 65 kg and her height was 160 cm. Her mean arterial pressure (MAP) was 109 mmHg, and the pulse was 98 beats per minute; other vital signs were normal. There was no hypertrichosis in her cheeks, no androgenic or cushingoid appearance. The thyroid was normal in size, with no palpable nodules. There was no increase in supraclavicular or dorsal adipose tissue, hirsutism, or evidence of bruising. There were crackles over the bilateral basal region of the chest. The abdomen was flat, non-tender, and without striae. There was peripheral edema over the bilateral lower limbs.

Her serum sodium level (Na+) was 148 mEq/L (normal range: 136–145 mEq/L) and serum potassium level (K+) was 1.5 mEq/L (normal range: 3.5–5.1 mEq/L). Hormonal studies demonstrated increased PRA (64 ng/mL/h; normal range: 0.8–2.5 ng/mL/h) and serum aldosterone (1076 pg/mL; normal range: 35.7–240 pg/mL; Fig. 1). While cortisol was in the normal range (14.2 μg/dL; normal range: 4.3–22.4 μg/dL), adrenocorticotropic hormone (ACTH) was suppressed (9.8 pg/mL; normal range: 0.1–46 pg/mL) during this status. Her vanillylmandelic acid level was 2.4 mg per day (normal range: 1–7.5 mg per day). Because of increased PRA and serum aldosterone with suppressed ACTH, autonomous renin secretion may be suggested. Abdominal magnetic resonance imaging (MRI) revealed an 8-cm mass in the region of the left adrenal gland (Fig. 2), but no metastasis. The antihypertensive drugs were ceased after her left adrenal mass was surgically removed by unilateral adrenalectomy.

Figure 1.

Clinical course of serum plasma renin activity (PRA; the first panel), serum aldosterone (the second panel), serum potassium (K+ the third panel), and mean arterial pressure (MAP; the forth panel) were displayed, including four different time points; A: on admission, B: on the day after the unilateral adrenalectomy, C: 1 month after the unilateral adrenalectomy, D: 4 months after the unilateral adrenalectomy. As our data show, PRA, aldosterone, and MAP were higher on ‘A’ compared with that on ‘B’. After adrenalectomy, ‘C’ displays the similar data with ‘B’; however, ‘D’ shows PRA, aldosterone, and MAP higher than ‘B’, but the serum potassium level didn't show a significant change.

Figure 2.

Abdominal magnetic resonance imaging shows an 8-cm mass in the region of the left adrenal gland (arrow head).

Histopathological diagnosis of renin-producing adrenocortical carcinoma was done as well (Fig. 3a,b). The method of immunohistochemistry for renin staining is described below. Formalin-fixed and paraffin-embedded specimens for immunohistochemistry were cut into 3 μm-thick sections in serial form and mounted on glass slides. After deparaffinization the serial sections were covered with trypsin working solution (0.05% trypsin, 0.1% calcium chloride, pH 7.8) and incubated for 20 min at 37°C in a humidified chamber. Following blockades of bovine serum albumin for 30 min, the sections were incubated with the primary antibodies overnight at 4°C, that is, renin (sc-22752, Santa Cruz Biotechnology, CA, USA) rabbit polyclonal antibody at a dilution of 1:100. Thereafter, the sections were reacted with the secondary antibody 1:500 anti rabbit (NB 730-H, Novus, Littleton, CO, USA) for 1 h at room temperature. The antigen–antibody complexes were visualized by immersion in 3,3′-diaminobenizidine solution. Sections were counterstained with hematoxylin. For negative control, tissue sections were incubated with normal rabbit IgG and no specific immunoreactivity was detected in these sections.

Figure 3.

(a) Immunohistochemistry photo (×400) shows a picture of adrenocortical carcinoma characterized by solid and thickened trabecular arrangements of proliferative tumor cells with renin-positive cytoplasm, pleomorphic nuclei and prominent nucleoli. (b) Negative control (×400) doesn't show any staining intensity.

After unilateral adrenalectomy, the level of her MAP was much lower than the period when she still took amlodipine and losartan before having the operation. Her levels of PRA and aldosterone decreased (PRA: 4.8 ng/mL/h; aldosterone: 38.6 pg/mL). She didn't undergo adjuvant chemotherapy after the operation. One month after the surgery, follow-up assessment of her MAP, K+, PRA and aldosterone were still in the normal range without any drugs taken (MAP: 83 mmHg; K+: 4.6 mEq/L; PRA: 1.1 ng/mL/h; aldosterone: 92.6 pg/mL; Fig. 1). The patient was evaluated with FDG PET-CT. Neither residual tumor nor distal metastasis was revealed (Fig. 4a).

Figure 4.

One month after the unilateral adrenalectomy, (A) 18F-fluorodeoxyglucose positron emission tomography and coregistered computed tomography (FDG PET-CT) demonstrates no evidence of definitely abnormal FDG activity. Figure B shows FDG PET-CT 4 months after the unilateral adrenalectomy. It reveals FDG-avid soft tissue nodular lesions (white circle area) over the upper pole of the left peri-renal space (the highest maximum standardized uptake value [SUVmax]: 6.0).

Four months after the surgery, the patient detected accelerated hypertension, and she came to our outpatient department for postoperation follow up. Her MAP exceeded the normal range (MAP: 110 mmHg), but the K+ level was still within normal range (4.2 mEq/L). PRA and aldosterone were also examined, both data (PRA: 7.2 ng/mL/h, aldosterone: 453 pg/mL) revealed an increase when compared to those of ‘1 day’ and ‘1 month’ after operation (Fig. 1). Thus, the FDG PET-CT was performed. The study revealed FDG-avid soft tissue nodular lesions over the upper pole of the left peri-renal space (Fig. 4b). It suggested a recurrence of renin-producing adrenocortical carcinoma in the aforementioned regions.


To date, renin-producing tumors are very rare, and most of them are of renal origin. Of these, the juxtaglomerular cell tumor was the most frequent. An extrarenal renin-producing tumor is extremely rare.6 Non-renal renin-producing tumors include carcinoma of the lung, pancreas, urinary bladder and ovary.7 To the best of our knowledge, there have been only two cases of renin-producing adrenal tumor reported before. Our case is the third such case reported but it is different to the case reported by Iimura et al. in the steroid synthetic pattern (tumor produced corticosteroids and sex steroids) and to the case of K. Yamanaka et al. in the characteristics of Cushing's syndrome. Our case only exhibited hyperreninism, hyperaldosteronism and hypertension, but Cushing's syndrome or steroid overproduction were not observed. Maybe the huge adrenal tumor could compress the renal artery, which might elevate the PRA. After immunohistochemical staining, the diagnosis of renin-producing adrenocortical carcinoma was established (Fig. 3A,B), and the etiology of compression of the renal artery by the huge adrenal tumor was less likely.

Up to present, there is a high rate of locoregional or metastatic recurrence after curative resection. So far in the medical reports, no indicators to predict the recurrence of adrenocortical carcinoma have been found. In our experience, the recurrence of adrenocortical carcinoma developed 4 months after surgery. As Figure 1 shows, MAP elevation was the first sign, and was observed prior to the alteration of K+ in the recurrence of renin-producing adrenocortical carcinoma. The reason for a rise in MAP prior to a change in K+ might be because the PRA was not high enough to make the alteration of the Na+ and K+, but enough to make the change in blood pressure.

FDG PET-CT was performed on our patient to detect the recurrence of adrenocortical carcinoma. Why did we perform this method in this case? In one study of 175 adrenal masses in 150 patients, FDG PET data alone yielded a sensitivity, specificity, and accuracy of 99% (67 of 68 nodules), 92% (98 of 107), and 94% (165 of 175), respectively, and combined FDG PET-CT data yielded corresponding values of 100% (68 of 68 nodules), 98% (105 of 107), and 99% (173 of 175). FDG PET–CT is better able to help differentiate benign from malignant adrenal lesions compared with FDG PET alone. Therefore, specificity was significantly higher for PET-CT,9,10 and it may be an ideal method for early detection of recurrence of adrenocortical carcinoma.

In summary, newly developed hypertension may be the early indicator of recurrence of adrenocortical carcinoma with high renin expression, and FDG PET–CT is a very sensitive method with high specificity to confirm the diagnosis of its recurrence. Close monitoring of blood pressure after successful surgery for renin-producing adrenocortical carcinoma is crucial.