A case of adrenocortical carcinoma diagnosed 9 years after the discovery of adrenal incidentaloma

Abstract

Adrenocortical carcinoma (ACC) is an uncommon cause of adrenal incidentaloma (AI). ACCs generally occur in large sizes, >4 cm in diameter, at initial presentation and grow rapidly. Therefore, there have been few reports of cases with long-term follow-up with imaging before ACC was diagnosed. Herein, we present a case of an adrenal mass that had remained small and unchanged for 5 years but later grew rapidly and was finally diagnosed as ACC. A 77-year-old hypertensive woman was referred to our hospital for the examination of a 5.4-cm left adrenal mass. Upon reviewing her previous unenhanced computed tomography (CT) scan, a 1.6-cm and 30 Hounsfield units (HU), homogeneous, round, left adrenal mass was incidentally detected 9 years ago. This mass remained unchanged until 4 years ago. One year ago, the mass enlarged to 3.0-cm and changed into an irregular form with heterogeneous density. The hormonal evaluation during the 9 years from the discovery of the AI was inadequate. The present examination diagnosed this case as ACC with subclinical Cushing’s syndrome. The patient underwent laparoscopic left adrenalectomy, and a histological diagnosis of high-grade ACC was made. The resected tumor had the CTNNB1 gene mutation. High unenhanced CT attenuation values (>10 HU) are one of the findings that raise suspicion of malignancy. This case suggests that patients with findings atypical of adenomas on an initial unenhanced CT might be carefully followed up given the possibility of development of ACCs, even if the initial tumor size is small.

AN ADRENAL INCIDENTALOMA (AI) is defined as an adrenal mass >1 cm in diameter that is incidentally discovered by imaging procedures, such as ultrasonography, computed tomography (CT) scan, and magnetic resonance imaging (MRI), performed for non-adrenal-related reasons [1]. With the widespread use of imaging techniques, AIs are detected at a rate of 1–5% in abdominal CT scans [2]. When AIs are discovered, the possibility of malignancy is a major concern. Most AIs are benign, and the prevalence of adrenocortical carcinomas (ACCs) has been reported to be approximately 1.9–4.7% in AIs [1-3]. Clinicians must be careful not to overlook ACC, as many patients with ACC are diagnosed at an advanced stage disease and have a poor prognosis [4, 5]. Therefore, it is important to evaluate the possibility of malignancy, including ACCs, in the work-up of AIs.

Various guidelines for management of AIs recommend that an unenhanced CT scan should be performed as initial imaging evaluation for cases suspected to have malignant imaging features [1, 3, 6-8]. The unenhanced CT scan findings suggestive of ACCs include large tumor size (usually >4 cm in diameter), high unenhanced CT attenuation value (>10 Hounsfield units [HU]), irregular shape, and heterogeneous density [3]. In addition, ACCs generally show a rapid increase in size over a short period of time (usually >2 cm per year). The duration of imaging follow-up for patients with nonhormone-producing adrenal masses who have indeterminate imaging features varies between 3–12 months after the initial examination according to guidelines [1, 3, 6-8]. Adrenalectomy is considered if the adrenal masses exceed 4 cm in diameter, if they enlarge by ≥1 cm during the observation period, if they exhibit high-risk imaging features, or if they acquire hormonal secretory ability [3, 7]. Therefore, there have been few previous reports of cases in which long-term imaging follow-up was possible before the diagnosis of ACC after the discovery of AI [9, 10]. Herein, we report a rare case of ACC initially presenting as a small tumor with high unenhanced CT attenuation value but no change over 5 years, followed by rapid growth.

Case Description

A 77-year-old woman was referred and admitted to our hospital for examination of a 5.4-cm left adrenal mass. We retrospectively reviewed her previous abdominal imaging findings and endocrinological investigations. Around 32 years ago, she was diagnosed with hypertension and started antihypertensive medication. However, she was not examined for secondary hypertension. She was also diagnosed with rheumatoid arthritis (RA) 9 years ago. An unenhanced CT scan performed before the introduction of a biosimilar anti-TNF-α antibody (adalimumab) demonstrated a 1.5 × 1.6 × 1.5-cm, 30 HU, homogeneous left adrenal mass with a round shape, and no calcification (Fig. 1A). Steroid was not adminsitered as treatment for RA. Baseline hormone levels revealed a slightly elevated plasma adrenocorticotropic hormone (ACTH) level of 59.6 pg/mL and a serum cortisol level of 14.9 μg/dL (Table 1). Plasma renin activity, plasma aldosterone concentration, and aldosterone/renin ratio (ARR) were 0.7 ng/mL/h, 192 pg/mL, and 274, respectively, under telmisartan 40 mg and hydrochlorothiazide 12.5 mg/day. However, no further hormone tests were performed. Abdominal CT scans performed 6 and 4 years ago for the purpose of scrutiny of liver dysfunction showed no change in the left adrenal mass (Fig. 1B). When she was admitted for mitral regurgitation (MR) 1 year ago, a CT scan performed showed that the left adrenal mass with heterogeneous lesions was enlarged to 2.1 × 2.8 × 3.0 cm and had changed its form to an irregular shape similar to a gourd (Fig. 1C). However, no further examination was performed. After some time, she visited the Urology Department in our hospital for a ureteral stone, and a 3.5 × 4.1 × 5.4-cm and heterogeneous left adrenal mass (Fig. 1D) was detected on abdominal CT scan.

Fig. 1

Timeline of computed tomography (CT) scan findings of the left adrenal mass (arrows).

(A) A 1.5 × 1.6 × 1.5-cm, 30 HU, homogeneous, rounded, left adrenal mass on the imaging performed 9 years ago. (B) A 1.5 × 1.6 × 1.5-cm, 30 HU, homogeneous left adrenal mass on the imaging performed 4 years ago. (C) A 2.1 × 2.8 × 3.0-cm and heterogeneous left adrenal mass on the imaging performed 1 year ago. (D) A 3.5 × 4.1 × 5.4-cm and heterogeneous left adrenal mass seen at the time of referral to our department. The upper row shows the axial view and the lower row shows the coronal view.

Table 1 Hormonal test performed 9 years ago and at present

Laboratory test	9 years ago	At present	Reference values
Plasma ACTH	59.6	2.1	(<46 pg/mL)
Serum cortisol	14.9	10.9	(6.2–19.4 μg/dL)
Plasma renin activity	0.7	1.4	(0.2–2.7 ng/mL/h)
Plasma aldosterone concentration	192	148	(20–130 pg/mL)
Plasma adrenaline	<10	12	(<100 pg/mL)
Plasma noradrenaline	310	284	(100–500 pg/mL)
Plasma dopamine	<2	6	(<30 pg/mL)
Serum dehydroepiandrosterone sulfate	N/A	88	(7–177 μg/dL)
24 h-urine free cortisol	N/A	31.2	(11.2–80.3 μg/day)
24 h-aldosterone	N/A	5.4	(<5.4 μg/day)
24 h-androsterone	N/A	0.33	(0.2–2.8 mg/day)
24 h-etiocholanolone	N/A	0.62	(0.1–2.4 mg/day)
24 h-dehydroepiandrosterone	N/A	<0.05	(<1.5 mg/day)
24 h-11-keto-etiocholanolone	N/A	0.46	(<0.7 mg/day)
24 h-11-OH-androsterone	N/A	0.70	(0.1–1.2 mg/day)
24 h-11-OH-etiocholanolone	N/A	0.28	(<0.8 mg/day)
24 h-11-keto-androsterone	N/A	<0.05	(<0.5 mg/day)
24 h-urine adrenaline	N/A	6.7	(1–23 μg/day)
24 h-urine noradrenaline	N/A	119	(29–120 μg/day)
24 h-urine dopamine	N/A	690	(100–1,000 μg/day)
24 h-urine metanephrine	N/A	0.11	(0.05–0.20 mg/day)
24 h-urine normetanephrine	N/A	0.24	(0.10–0.28 mg/day)

Abbreviations: ACTH, adrenocorticotropic hormone; N/A, not available.

At the time of the current admission, she was obese with a body mass index of 25.5 kg/m² but had not lost or gained weight in the last 9 years. Her blood pressure was 103/59 mmHg and she was currently maintained on amlodipine 10 mg per day. Physical examination revealed no Cushing’s sign, systolic murmur due to MR, and no swollen or tender joints due to RA. Her laboratory data showed dyslipidemia (plasma low-density lipoprotein cholesterol [LDL] level of 145 mg/dL), normokalemia (serum potassium level of 4.0 mEq/L), and normoglycemia (fasting plasma glucose level of 94 mg/dL and HbA1c 5.3%). The level of plasma LDL remained at around 140 mg/dL with diet and exercise therapy in the last 8 years. Bisphosphonate therapy was started 9 years ago for secondary osteoporosis due to RA. An evaluation of hormone secretion showed a low plasma ACTH level (2.1 pg/mL), normal serum cortisol level (10.9 μg/dL), normal serum dehydroepiandrosterone sulfate (DHEA-S) (88 μg/dL), and normal urinary 17-ketosteroid (17-KS) (Table 1). Hormonal tests revealed a lack of ACTH/cortisol circadian rhythm and high serum cortisol (10.1 μg/dL) after a 1-mg dexamethasone suppression test (DST). Therefore, she was diagnosed with subclinical Cushing’s syndrome (SCS) [11]. Upon imaging evaluation, ACC was suspected because of a heterogeneous contrast effect and some internal cystic degeneration on contrast-enhanced CT scan (Fig. 2A), the lack of fatty component on MRI with chemical shift imaging (Fig. 2B, 2C), and remarkable fluorodeoxyglucose (FDG) uptake (standardized uptake value max 8.7) in the left adrenal mass on FDG-positron emission tomography (PET)-CT scan (Fig. 2D).

Fig. 2

Imaging evaluation of the left adrenal mass (arrows).

(A) The contrast-enhanced CT scan shows a heterogeneous contrast effect and some internal cystic degeneration. Chemical shift MRI did not demonstrate significant signal loss between the in-phase (B) and opposed-phase (C). (D) The FDG-PET-CT scan shows remarkable FDG uptake (standardized uptake value max 8.7) in the left adrenal mass.

She then underwent laparoscopic left adrenalectomy in the Urology Department in our hospital. The resected adrenal tumor measured 7.0 × 4.0 × 2.5 cm and weighed 80 g (Fig. 3A). Histology confirmed ACC (Weiss score, 4), with a mitotic rate of 25 mitoses/50 HPF, <25% clear cell component, tumor necrosis, and venous invasion (Fig. 3B, 3C) [12]. Immunohistochemically, Ki67 labeling index was 20% in hot spots (Fig. 3D). The ACC was found to be Stage II (T2N0M0) according to the European Network for the Study of Adrenal Tumors staging system [13]. Postoperatively, adjuvant chemotherapy with mitotane, a dichloro-diphenyl-trichloro-ethane derivative, was started as outpatient care because of histologically high-grade ACC (Ki67 index >10%) [14]. Unfortunately, this patient showed local recurrence of ACC at 1.5 years postoperatively. FoundationOne^® CDx Cancer Genome Profile, performed as a companion diagnosis to multiple molecular targeted drugs, showed CTNNB1 G34A mutation in the resected adrenal tumor. In addition, β-catenin immunohistochemical staining showed accumulation in the nucleus of the tumor (Fig. 3E). Multidisciplinary treatment, including stereotactic radiotherapy, was performed.

Fig. 3

Histopathological examination and immunohistochemical analysis of the resected adrenal mass.

(A) The resected adrenal tumor measured 7.0 × 4.0 × 2.5 cm and weighed 80 g. (B, C) The hematoxylin-eosin staining led to a diagnosis of ACC (Weiss score, 4), with high mitotic rate (C), <25% clear cell component, tumor necrosis (indicated by arrow, B), and venous invasion. magnification B (×100), C (×200). (D) Ki67-positive cells exhibited 20% hot spots (magnification ×200). (E) β-catenin immunohistochemical staining showed accumulation in the nucleus of the tumor (magnification ×400).

Discussion

We encountered a case of ACC initially presenting as a small tumor with no changes for 5 years, followed by rapid growth. Such a clinical course is extremely rare in ACCs.

Several different mechanisms may have triggered the rapid growth of the adrenal mass in the present case. First, there have been several reports of ACCs diagnosed over a year after the discovery of adrenal masses [9, 10], but the genetic mutations in those cases were not analyzed (Table 2). Our patient exhibited a mutation in CTNNB1 (the gene coding for β-catenin). The Wnt/β-catenin pathway can be dysregulated in ACC, with an activating mutation of CTNNB1 being present in 16% of cases [15]. The mutated β-catenin accumulates in the cytoplasm and translocates to the nucleus, where it activates the transcription of the transcription factor LEF/TCF, further stimulating the transcription of target genes associated with tumor growth [16]. This was shown by the positive β-catenin immunostaining in the nucleus of the resected adrenal tumor in the present case. In addition, transgenic mice with constitutive activation of the β-catenin localized to the adrenal cortex showed adrenocortical tumors with malignant characteristics [17]. Therefore, CTNNB1 mutation may be involved in the pathogenesis of ACC. Second, we searched the literature for an association between a similar anti-TNF-α antibody (adalimumab) and ACC. Treatment of RA with adalimumab did not increase the risk of malignancies [18, 19]. A causal relationship between the development of ACC and adalimumab cannot be definitively concluded given the rarity of ACC. However, based on these reports, it is unlikely that adalimumab induced the development of ACC.

Table 2 The initial adrenal CT findings in patients diagnosed with ACC more than a year after the discovery of adrenal masses

Case # [ref]	Sex	Age (year)	Initial CT			Time till ACC diagnosis (month)	Size at time of ACC diagnosis (cm)	Stage	Weiss score	Ki67 (%)	Gene mutation
			Size (cm)	HU	hom/het
1 [our case]	F	77	1.6	30	hom	105	5.4	2	4	20	CTNNB1
2 [9]	M	77	1.4	22	N/A	26	2.9	4	N/A	N/A	N/A
3 [9]	F	53	1.8	38	N/A	43	6.5	2	8	N/A	N/A
4 [9]	F	49	2.1	20	N/A	27	9	4	N/A	N/A	N/A
5 [9]	F	59	2.5	17	N/A	76	5.3	4	N/A	N/A	N/A
6 [9]	F	37	3	39	N/A	89	14	4	N/A	N/A	N/A
7 [9]	F	63	3	43	N/A	32	16	4	6	N/A	N/A
8 [9]	F	32	6	30	N/A	22	11.5	4	N/A	N/A	N/A
9 [9]	F	56	8.2	39	N/A	20	11	2	5	N/A	N/A
10 [10]	N/A	66	1.4	12	hom	84	3.9	1	N/A	N/A	N/A
11 [10]	N/A	37	1.8	35	hom	19	3.1	1	N/A	N/A	N/A
12 [10]	N/A	28	4.5	21	hom	96	16.5	3	N/A	N/A	N/A
13 [10]	N/A	12	4.1	67	hom	85	4.9	2	4	N/A	N/A
14 [10]	N/A	34	3.4	N/A	het	52	8.3	2	N/A	N/A	N/A
15 [10]	N/A	58	2.5	N/A	het	131	5.7	4	N/A	N/A	N/A
16 [10]	N/A	45	3.6	N/A	het	74	9.1	4	N/A	N/A	N/A
17 [10]	N/A	42	2.8	N/A	het	106	8.7	2	N/A	N/A	N/A
18 [10]	N/A	38	1.5	N/A	hom	23	9.8	4	N/A	N/A	N/A
19 [10]	N/A	49	1.3	N/A	hom	31	4.6	2	N/A	N/A	N/A
20 [10]	N/A	24	3.4	N/A	het	13	4.8	1	N/A	N/A	N/A
21 [10]	N/A	81	3.9	N/A	het	22	5.2	2	N/A	N/A	N/A

Abbreviations: ACC, adrenocortical carcinoma; CT, computed tomography; ref, reference; HU, Hounsfield unit; hom, homogeneous; het, heterogeneous; F, female; M, male; N/A, not available.

The tumor diameter and unenhanced CT attenuation value are useful in differentiating benign from malignant tumors. The tumor diameters of ACCs were significantly larger than those of non-functional adenomas (7.0 cm versus 2.6 cm) [2]. The larger the size of the adrenal tumor, the higher the risk of ACC (2% risk in AIs <4 cm, 6% in AIs 4.1–6.0 cm, and 25% in AIs >6 cm) [20]. The 4 cm cutoff size has a high sensitivity of 93% but a low specificity of 24% for the detection of ACC [21]. Therefore, an unenhanced CT attenuation value is important as an additional criterion. An unenhanced CT attenuation value ≤10 HU is suggestive of a lipid-rich benign adenoma if the adrenal mass is a homogeneous lesion [22]. The mean HU (±standard deviation [SD]) for adrenal adenomas/hyperplasia was significantly lower than for ACCs (16.2 ± 13.6 versus 36.9 ± 4.1). An unenhanced CT attenuation value ≤10 HU or a combination of adrenal tumor size ≤4 cm and ≤20 HU excluded non-adenomas in 100% of cases. Assessment of HU for heterogeneous lesions requires caution, given the possibility of missing malignant lesions. Several studies have analyzed the initial adrenal CT findings in patients diagnosed with ACC more than a year after the discovery of adrenal masses (Table 2). Ozsari et al. reported 8 patients with ACC (Cases #2–9) that had initially underwent CT imaging examination, none of whom exhibited features of benign lesions [9]. Nogueira et al. reported 12 patients (Cases #10–21), among which 10 had indeterminate imaging features, such as diameters >4 cm, high unenhanced CT attenuation values >10 HU, or heterogeneous lesions; and 2 (Case #18,19) had a homogenous mass <2 cm in size. However, unenhanced CT attenuation values were not evaluated in both groups of patients [10]. Our case (Case #1) exhibited a high unenhanced CT attenuation value (>10 HU) on the initial CT. Therefore, precursor lesions in patients with a diagnosis of ACCs might show atypical findings of adenoma on unenhanced CT.

If the unenhanced CT findings are not benign, ACC, pheochromocytoma, and metastatic tumors may be considered as differential diagnoses. Functional assessment is important to differentiate between these conditions. Imaging is useful in distinguishing benign from malignant adrenal masses but not in differentiating hyperfunctioning from non-hyperfunctioning adrenal masses. In fact, current guidelines recommend an initial biochemical evaluation of all AIs to exclude SCS, primary aldosteronism, and pheochromocytoma [1-3, 6-8]. Hormonal testing of ACC patients revealed hypersecretory tumors, consisting of cortisol and androgens (47%), cortisol only (27%), and androgens only (6%) [6]. High serum DHEA-S and high urinary 17-KS were common in patients with ACC [2]. This case was ultimately diagnosed as a cortisol-secreting ACC. Unfortunately, initial and follow-up hormone testing had not been adequately evaluated for the past 9 years. Since the high ACTH level 9 years ago may have been influenced by the active phase of RA, the basal ACTH-cortisol levels should have been retested, and 1-mg DST should have been performed during the stable phase of RA. The complication of obesity, hypertension, dyslipidemia, and low bone mass may have been some clues to cortisol hypersecretion.

In cases with indeterminate imaging or suspicion for malignancy, contrast-enhanced CT scan, MRI, and PET-CT scan may be required as a second-line imaging modality. On contrast-enhanced CT, adenomas typically show rapid contrast medium washout (≥50% in 10 min), whereas non-adenomas show delayed contrast medium washout (<50% in 10 min) [3, 7, 8]. Chemical shift-MRI is useful in distinguishing adenomas from non-adenomas based on their elevated amounts of intracytoplasmic fat [3, 6]. Furthermore, MRI is suitable for pregnant women and individuals aged <40 years because there is no radiation exposure [1]. PET-CT can be helpful in detecting extra-adrenal metastatic disease, but it should be noted that 16% of benign adrenal masses may have greater FDG-PET uptake than the background tissue [1, 3, 7, 8]. CT-guided fine-needle aspiration (FNA) cannot distinguish adenomas from ACCs, but it can distinguish between adrenal tumors and metastatic tumors [23]. Moreover, FNA for ACCs has the risk of peritoneal dissemination [24]. Therefore, if ACC is suspected, a comprehensive clinical diagnosis must be made based on the above imaging findings. However, it is inconclusive whether a combination of these imaging studies should be performed at an early stage, when the tumor size was small and stable, as noted in our case.

In conclusion, we reported a case of an adrenal mass that had remained small and unchanged for 5 years, but later grew rapidly and was finally diagnosed as ACC. Patients with atypical findings as adenomas on initial unenhanced CT might be carefully followed up given the possibility of developing ACCs. If there is a rapid increase in tumor sizes or a change in the nature of the tumors, it is necessary to combine second-line imaging methods other than unenhanced CT and functional evaluation to determine the appropriate diagnosis and treatment plan.

Acknowledgments

We would like to thank Editage (www.editage.com) for English language editing.

Disclosure

The authors have nothing to disclose.

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