Functioning metastasis from adrenocortical carcinoma

Abstract

Recurrence of Cushing’s syndrome due to functional metastasis from adrenocortical carcinoma (ACC) after adrenalectomy is extremely rare. We describe a case of a 56-year-old woman who presented with Cushing’s syndrome due to an ACC. Abdominal CT showed a heterogeneous left adrenal tumour of 8 cm as well as a right adrenal nodule with 3 cm. An 18F-fluorodeoxyglucose positron emission tomography-CT (18F-FDG/CT PET) revealed an increased uptake of both adrenal lesions (maximum standardised uptake values, 17.7 and 10.4 for left and right adrenal lesions, respectively). Patient underwent bilateral adrenalectomy with R0 resection. Pathological examination revealed a left ACC with a Weiss’ score of 7, Ki67 10%, stage II European Network for the Study of Adrenal Tumours and a right adrenal adenoma. After surgery, clinical improvement was noted. Two months later, she noticed recurrence of hypercortisolism and multiple liver and lung metastasis were demonstrable, without evidence of local recurrence on the 18F-FDG/CT PET and abdominal MRI.

Background

Adrenocortical carcinoma (ACC) is a rare and aggressive endocrine neoplasm with an incidence of 0.7–2 cases per million persons per year.¹ ACC can develop at any age with a peak incidence between 40 and 60 years, and a female preponderance (female: male 1.5–2.5:1).² In adults, ACC is mostly sporadic, although, it can be diagnosed in the context of hereditary syndromes, such as Li-Fraumeni syndrome, Lynch syndrome, familial adenomatous polyposis and multiple endocrine neoplasia type 1.¹ The prognosis of patients with ACC is generally poor, partly due to the advanced stage at diagnosis, with a median overall survival about 4 years.^{3 4} Most common sites of metastasis are lymph nodes, lungs, liver and bone.³ The standard treatment of ACC consists in complete surgical resection for localised tumour and systemic therapy with mitotane alone or in association with etoposide, doxorubicin and cisplatin (EDP) for advanced ACC.⁴

Approximately 60% of ACCs are functional, most commonly presenting with rapid onset Cushing’s syndrome or mixed Cushing’s and virilising syndromes. Hyperandrogenism (30%) and rarely hyperestrogenism (5%) and hyperaldosteronism (2.5%) can be seen in patients with ACC.¹ Although hormone secretion by the primary tumour is common, there are only a few cases reported in which a late metastatic lesion is hormonally active.³

We describe a rare case of a cortisol-secreting ACC, European Network for the Study of Adrenal Tumours (ENSAT) stage II, that recurred 2 months after R0 adrenalectomy with functional secreting-cortisol metastasis, without evidence of recurrence of the primary tumour.

Case presentation

A 56-year-old woman presented with weight gain of approximately 27 kg (body height, 165 cm; body weight, 107 kg; body mass index, 39.3 kg/m²), easy bruising, proximal muscle weakness and refractory hypertension over the past 6 months. Her medical history included hypertension, pre-diabetes, hypercholesterolaemia, depressive syndrome and nephrolithiasis. On physical examination, she had a blood pressure of 206/112 mm Hg, a plethoric face, supraclavicular fat pads, a buffalo hump, central obesity, abdominal violaceous striae and scattered ecchymoses.

Investigations

Laboratory results (table 1) were compatible with hypokalaemia (3 mmol/L) (normal range 3.5–5 mmol/L) and endogenous hypercortisolism: elevated midnight salivary cortisol (17.8 ng/mL (reference range <2.08 ng/mL) and urinary free-cortisol levels (745 µg/day and 830.4, reference range: 36–137 µg/day), unsuppressed cortisol after 48 hour 2 mg/day dexamethasone test (cortisol 27.4 µg/dL, cut-off point <1.8 µg/dL) and the absence of cortisol circadian rhythm: serum cortisol 26.7 µg/dL at 08:00 (5–25 µg/dL) and 28.9 µg/dL at 23:00. The ACTH level was undetectable (<5.0 pg/mL), suggesting ACTH-independent Cushing’s syndrome.

Table 1.

Laboratory evaluation

Parameters	Value	Reference range
Potassium (mmol/L)	3	3.5–5
Urinary free-cortisol (μg/24 hours)	830.4	36–137
Urinary metanephrine (mg/24 hours)	0.04	<0.8
Urinary normetanephrine (mg/24 hours)	0.1	<0.4
Aldosterone (ng/dL)	9.02	7–30
Plasma renin activity (ng/mL)	0.53	0.03–0.27
Aldosterone/renin ratio	17.02	<30
Total testosterone (ng/d)	64	<70
DHEAS (μg/dL)	147.4	19–205
Androstenedione (ng/mL)	3.24	0.4–3.4
17-hydroxyprogesterone (ng/mL)	1.38	0.2–1.72

Abdominal CT revealed a heterogeneous left adrenal mass with internal necrosis that measured 8 cm with 45 Hounsfield Units and a right adrenal, hypodense, well-defined, nodule with 3 cm and 17 Hounsfield Units. Adrenal androgens, aldosterone/renin ratio and metanephrines were normal (table 1). Staging was performed with 18F-FDG/CT PET scan (figure 1) and abdominal MRI (figure 2). The first revealed a large left adrenal mass (8 cm) with a maximum standardised uptake value (SUVmax) of 17.7 and a right adrenal nodule (3 cm) with a SUVmax of 10.4, without abnormal uptake in extra-adrenal regions. Abdominal MRI showed a large heterogeneous left adrenal mass measuring 8.2×6.9 cm and a right adrenal nodule with 2.9×1.5 cm, without signs of adjacent organs invasion.

Figure 1.

18F-fluorodeoxyglucose (FDG) positron emission tomography-CT (PET) scan revealed a large left adrenal mass (8 cm) with a maximum standardised uptake value (SUVmax) of 17.7 and a right adrenal mass (3 cm) with a SUVmax of 10.4, without abnormal FDG uptake in extra-adrenal regions.

Figure 2.

Abdominal MRI showed a large heterogeneous left adrenal mass measuring 8.2×6.9 cm (arrow) and a right adrenal nodule with 2.9×1.5 cm (arrowhead), without signs of adjacent organs invasion.

Treatment

The patient underwent bilateral adrenalectomy and pathology was compatible with left ACC and right adrenocortical adenoma. Histopathological examination of the left ACC showed a solid and trabecular pattern, with high mitotic rate (20 mitoses/50 HPF), multiple atypical mitoses and marked nuclear pleomorphism. The clear cells comprised less than 25% of the tumour. There were areas of focal necrosis with vascular and tumour capsular invasion. The Weiss score was 7 and resection was classified as R0.

Outcome and follow-up

Postoperatively, Cushing’s syndrome improved and the patient was maintained on hydrocortisone and fludrocortisone supplementation. Her blood pressure was controlled, potassium levels normalised and she lost 8 kg in 1 month.

Two months after surgery, the patient noticed recurrence of Cushing’s symptoms with poorly controlled hypertension, central weight gain, easy bruising and peripheral oedema. Corticosteroid replacement was discontinued, and recurrent ACTH-independent Cushing’s syndrome was confirmed biochemically. Her 24-hour urine free cortisol was markedly elevated (1814 µg/day, reference range: 36–137 µg/day), with a suppressed ACTH (<5.0 pg/mL). She underwent an 18FDG-PET/CT that revealed multiple liver and lung lesions, without any evidence of recurrence of the primary adrenal lesion (figure 3). Abdominal MRI confirmed multiple liver metastasis, with no evidence of recurrence in the adrenal bed (figure 4).

Figure 3.

PET scan 2 months after surgery demonstrates multiple liver and lung metastases.

Figure 4.

Abdominal MRI 2 months after surgery showed multiple liver metastasis, with no evidence of recurrence within the adrenal bed.

She was started on mitotane 1.5 g daily as adjuvant therapy which was gradually titrated to 3 g daily. During mitotane treatment, she developed diarrhoea, increased γ-glutamyl transferase levels (232 UI/L, reference range 9–36) and central hypothyroidism: TSH 0.47 µUI/mL (reference range 0.3–4.20) with a fT4 0.7 ng/dL (reference range 0.9–1.7) and levothyroxine 25 mcg was initiated. To control hypercortisolism, metyrapone 250 mg three times daily was started and then titrated up to 2.75 g daily with clinical improvement. Spironolactone and potassium supplements were associated with improvement of blood pressure and potassium levels. She started Pneumocystis jirovecii prophylaxis with oral cotrimoxazole. Mitotane was discontinued after 1 month of therapy due to development of haemorrhagic cystitis. Treatment options were discussed on multidisciplinary meeting with the patient, and it was decided to perform chemotherapy with etoposide 100 mg/m² and cisplatin 40 mg/m2 (EP) due to tolerance issues. However, after one cycle of EP, the patient condition deteriorated significantly, she refused further aggressive treatment and was subsequently referred to palliative care under metyrapone treatment for hypercortisolism control. She died 2 months after chemotherapy due to hypercortisolism related septicaemia.

Discussion

We report a case of a woman who presented with M0 cortisol secreting ACC and developed functional cortisol secreting metastases within 2 months after surgery. Our case is also noteworthy because it highlights the capacity for advanced and metastatic cancers to maintain their hormonal secretion capacity.

Advanced ACC is a rare and very aggressive neoplasm with poor prognosis.⁵ Approximately 60% of ACCs are functional, and glucocorticoids and/or androgens are the most commonly oversecreted steroids.¹ Currently, the only curative therapy for ACCs remains complete tumour resection which is indicated for localised ACCs (European Network for the Study of Adrenal Tumours—ENSAT stages I–III). However, even with an R0 resection, 50%–80% of patients develop recurrent or metastatic disease, as seen in our patient.³ Frequently, very high cortisol levels in ACC saturate the renal HSD11B2 (11beta-hydroxysteroid dehydrogenase type 2), enzyme in the distal nephron that converts biologically active cortisol into inactive cortisone. As a result, there is glucocorticoid-mediated mineralocorticoid receptor activation. Therefore, hypokalaemia and hypertension can be observed in patients with hypercortisolism, like our patient.² Metyrapone is a first-line agent for suppressing steroidogenesis in Cushing’s syndrome. It inhibits 11-β hydroxylase, which catalyses the conversion of 11-deoxycortisol to cortisol. Metyrapone has a quick onset of action and controls hypercortisolaemia in 50%–75% of patients with Cushing syndrome.⁶ Mitotane therapy inhibits steroid synthesis although at a much slower pace than metyrapone. It inhibits the action of CYP11A1 and CYP11B1 and destroys adrenocortical cells via mitochondrial toxicity. Due to a slower onset of action, it should be used in combination with other drugs, like metyrapone, to control significant cortisol overproduction.⁶ Serum levels of mitotane must be monitored and target levels are 14–20 µg/mL.^{1 4} Mitotane is a lipophilic molecule with a long half-life and high doses of mitotane might lead to significant adverse reactions: nausea, vomiting, diarrhoea, adrenal insufficiency, increase of hepatic enzymes, hypercholesterolemia and hypothyroidism. Haemorrhagic cystitis is an unusual side effect of mitotane therapy.¹

EDP-mitotane regimen is considered the standard chemotherapy in advanced ACC.^{6 7} Chemotherapy with EDP-mitotane was associated with longer progression-free survival compared with the combination of streptozocin plus mitotane (5.5 months vs 2.1 months, respectively).⁸

Prognosis of patients with ACC is generally poor with a median overall survival about 4 years. Established prognostic factors are age, tumour stage, extent of surgical resection (R0, R1, R2), mitotic rate and hormone secretion.⁹ Cortisol-secreting ACC is associated with poor prognosis, higher recurrence rates and worse survival compared with non-cortisol-producing ACCs.¹ A recent ENSAT Multicentre Study (Elhassan Y, Altieri B, Berhane S 2021), evaluating 942 patients with ACC from 14 ENSAT centres, documented an improved prognostic stratification with modified GRAS Score (Grade, R status, Age and Symptoms) compared with ENSAT staging and Ki67, suggesting its potential to guide personalised patient care in ACC.¹⁰

This case demonstrates some interesting features of ACC that pose challenges to its management, including the explosive metastatic growth 2 months after surgery and the potential for fully functional steroidogenesis in late metastases of ACC.

In conclusion, we present a rare case of recurrent Cushing’s syndrome after bilateral adrenalectomy due to functional metastasis. Clinicians should consider this possibility if symptoms of hypercortisolism recur after adrenalectomy for ACC and no evidence of local recurrence is found.

Learning points.

• Advanced adrenocortical carcinoma (ACC) is a rare endocrine malignancy with a poor prognosis.

• Recurrence of Cushing’s Syndrome associated with ACC after adrenalectomy is mainly due to local recurrence or from postsurgical remnants, and only rarely is caused by de novo functional metastasis from ACC.

• Clinicians should consider the diagnosis of cortisol-secreting metastasis from ACC if patients present with hypercortisolism recurrence after adrenalectomy and no evidence of loco-regional disease is found.

• This case highlights the potential for fully functional steroidogenesis in late metastases from ACC.

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