From benign adrenal incidentaloma to adrenocortical carcinoma: an exceptional random event
Belmihoub I.1 Silvera S. MD 2, Sibony M.MD 3, Dousset B. MD4, Legmann P.PhD5, Bertagna X. MDPhD1, Bertherat J. MDPhD 1,6, Assié G, MDPhD 1,6
1- Center for Rare Adrenal Diseases, Department of Endocrinology, Hôpital Cochin, Assistance Publique Hôpitaux de Paris, France
2-Department of Radiology, Saint Joseph Hospital, Paris
3- Department of Pathology, Hôpital Cochin, Assistance Publique Hôpitaux de Paris, France 4- Department of Digestive and Endocrine Surgery, Hôpital Cochin, Assistance Publique Hôpitaux de Paris, France
5- Department of Radiology A, Hôpital Cochin, Assistance Publique Hôpitaux de Paris, France
6- Institut Cochin, Institut National de la Santé et de la Recherche Médicale U1016, Centre national de la recherche scientifique UMR8104, Université Paris Descartes, Sorbonne Paris Cité, Paris, France
Word count: 1512 words
Number of figures: 3.
Key words : adrenal incidentaloma, adrenocortical carcinoma, transformation, european
recommendations
Corresponding autor :
Assié Guillaume, PhD
Service des maladies endocriniennes et métaboliques, Hôpital Cochin, 27, rue du Faubourg- Saint-Jacques, 75014 Paris, France Mail : guillaume.assie@aphp.fr
Abstract :
New European guidelines for the management of adrenal incidentalomas were recently released (1). One of the most novel recommendations is to stop following patients when they present a typical, small and non-secreting adenoma. We report here the case of a 71-year-old man with such an adenoma, who developed an adrenocortical carcinoma (ACC) fourteen years later, with subsequent metastases and death. Clinically he had a normal blood pressure and no sign of hormonal hypersecretion. The hormonal work-up showed no hormone excess: urinary free cortisol level was normal, the diurnal cortisol rhythm was respected and urinary catecholamine metabolites levels were normal. Computed tomography (CT) scan showed a homogeneous lesion, with a low density. The lesion remained unchanged during the five years of follow-up. Eight years after the last CT, a large right heterogeneous adrenal mass was incidentally discovered during an ultrasound examination. On CT-scan it was a 6 cm heterogeneous tumor. On hormonal work-up there was no secretion. The patient was operated of an adrenalectomy and the histology described an ACC with a Weiss score at 8, with no benign contingent. To our knowledge this is the first case of an ACC occurring in a patient with prior adrenal imaging showing a typical benign adenoma.
Introduction
Adrenal incidentaloma is defined as an adrenal lesion, generally of 1cm or more, discovered on imaging performed for extra-adrenal disorders. In medical series, 80% of adrenal incidentalomas are adenomas and 8% are carcinomas, whereas in surgical series those rates are 55% and 11% respectively (2,3). Management of adrenal incidentaloma is aimed at ruling out malignancy and hormone secretion, based on proper imaging and appropriate hormonal exploration. The European Society of Endocrinology Clinical Practice Guideline published in collaboration with the European Network for the Study of Adrenal Tumors new guidelines in
2016 for the clinical management of patients with adrenal incidentalomas. One of the most important new recommendations is to stop the follow-up when the mass is described as a typical benign non secreting adrenal adenoma. Such an adenoma consists in a homogeneous mass smaller than 4 cm with low density on CT-scan and no hormone secretion. (1).
We report here the case of a patient with an adrenal incidentaloma characterized as a typical benign adenoma, without any hormone secretion, who presented thirteen years later an ACC, with subsequent metastases and a fatal evolution.
Methods
Hormones measurements were as follow: ACTH was assayed by immunoradiometric assays, plasma cortisol by competition assays and urinary metanephrines were assessed by high performance liquid chromatography.
Computed Tomography-scans (CT-scans) were performed during the five first years with unenhanced imagings to measure the largest diameter in millimeters and the basal density in Hounsfield Units (UH), and eight years after with enhanced and unenhanced acquisitions to calculate the wash out. Magnetic Resonance Imaging (MRI) was first performed on coronal T2-weighted imaging and fifteen years after with T2-weighted and out-of-phases images for the characterization of the adrenal lesion. MIBG scintigraphy, adrenal iodocholesterol scintigraphy and 18 fluorodeoxyglucose positron emission tomography/CT (PET/CT) were also performed.
Microscopic pathological examination was realized following the criteria of the Weiss score.
The case
A 71-year-old man was referred to the endocrinology’s department for characterization of a right adrenal incidentaloma, discovered on a in a prior abdominal ultrasound examination in the context of urinary tract infection.
He reported a medical history of myelodysplastic syndrome with anaemia and thrombocytopenia, and recurrent urinary tract infections. Clinically, the patient presented no hypertension, no clinical features of Cushing’s syndrome nor of catecholamine hypersecretion. Potassium level was 3.9 mmol/l (3.5- 5 mmol/l). The endocrine work-up revealed normal 24 hours urine cortisol excretion (46µg, normal range (NR): 25-90µg/24 h), normal plasma cortisol circadian rhythm, with a midnight cortisol at 31 ng/ml and an early- morning cortisol at 130 ng/mL. Urinary meta- and normetanephrins were also normal both reported to creatinin and to 24hours. No dexamethasone suppression test was performed at this time.
The adrenal CT-scan showed a right adrenal lesion measuring 17 mm of diameter, homogeneous. Three additional unenhanced adrenal CT-scans were performed during the five following years, showing a stable tumor of 21 mm, with low attenuations measured at 7.9, 13 and 9HU at 1, 3 and 5 years respectively. A MRI showed a 21 mm lesion, with a normal T2- weighted signal (Fig. 1), but no in and out-of-phase images were performed at that time. The monitoring of this non-secreting adrenocortical adenoma was stopped after 5 years of follow- up, without any clinical, biological or imaging change.
Despite the interrupted CT-scan surveillance, annual ultrasound examinations were pursued in the context of recurrent urinary tract infections. Eight years after the last CT-scan, a 6cm heterogeneous right adrenal mass was reported.
Clinically the patient presented no sign of hormone excess. Blood pressure was normal. Potassium level remained normal at 4.1 mmol/L (3.5-5 mmol/L). On hormonal work-up plasma cortisol was not suppressed on 1 mg overnight dexamethasone suppression test (84
ng/ml). Urinary free cortisol was normal at 46ug/24hours (NR: 25-90 µg/24h), urinary metanephrine level was 0.46 umol/24 hours (NR: 0.25-1.75 mol/24 h) and urinary normetanephrine level was slightly increased at 2.74 umol/24 h (NR: 0.5-2.4 umol/24 h). On CT-scan and MRI (Fig.2), the adrenal mass was measuring 6 cm. The lesion appeared heterogeneous, precluding any global density measurement. The tissular portion presented an unenhanced attenuation of 25 HU with an absolute washout of less than 50 % on CT, and insufficient signal loss on out-of-phase images as compared with in-phase images on MRI. MIBG scintigraphy and adrenal iodocholesterol scintigraphy showed no uptake on the right adrenal mass. Positron emission tomography/CT (PET/CT) images revealed a strong increased 18Fluorodeoxyglucose (FDG) uptake of the right adrenal mass, with a standardized uptake value (SUV) of 7.4. There was no other uptake.
Right adrenalectomy was performed for a suspicion of ACC. Histology confirmed the diagnosis of ACC with a Weiss score at 8 (Fig.3). Macroscopic and microscopic examination did not identify any benign area.
Five months later, a CT-scan revealed local and distal recurrence with liver, pulmonary and peritoneal metastases. The patient died 2 months later.
Discussion:
In this case the patient presented a typical benign adrenal adenoma: smaller than 4 cm, homogeneous, with a low density on CT-scan and without any hormone hypersecretion. In its consensus statement of 2008 the French Society of Endocrinology recommended for those typical adrenal masses repeat CT imaging at 6 months, 2 and 5 years (4). The aim of this approach was to avoid missing a malignant lesion. The new European recommendations published in 2016 suggest to stop follow-up for typical benign and non secreting adrenal adenomas. This strategy is justified, beyond the lack of malignant transformation reported so
far, by the financial and psychological costs (1), and by the risk related to radiation exposure when repeated CTs are proposed (5). Despite following the 2008 recommendations, including a prolonged follow-up, we were not able to detect early this ACC. Indeed this ACC appeared later than the 5-years surveillance we performed. Of course, following the new ESE recommendations, we would also have missed this ACC.
Several cases of ACC have been reported, with prior imaging -performed one year earlier or more- available. Oszari and al. studied 25 ACC with previous imaging (6). Twenty of them had preexisting adrenal masses described before ACC diagnosis. However, none of these cases showed any benign radiological features on these previous images: 70% were heterogeneous and, when performed, the pre-contrast density was > 10 HU. Nogueira and al. studied radiographic characteristics of 20 adrenal masses before ACC diagnosis (7). Only 2 of them had at least one morphological feature of benignancy, but unenhanced CT-scan density was available for these 2 cases. We may speculate that spontaneous density could have helped to classify these tumors as atypical adrenal masses. In contrast, our patient had a 5-years follow-up with a well characterized adrenal mass showing concordant features of benignancy. Therefore a missed diagnosis of ACC at that time is unlikely.
In this case, the tumor had only malignant component with no benign compartment, confirmed by a microscopic examination of the entire adrenal. From this observation, two hypotheses can be proposed. The first and most probable hypothesis is the independent occurrence of two events in a single adrenal, with initially a typical benign non secreting adenoma - as demonstrated by imaging- and several years after the occurrence of an ACC -as proven histologically. In such a setting, the absence of benign compartment could be explained by an invasion and destruction of benign structures. However, instances with both an ACC and a remaining benign compartment have been reported, referred as to collision tumors (8). Bernard and al. described an adrenocortical tumor with two different histological
components: one central malignant part surrounded by another part with benign tissue (9). A second hypothesis is a transformation of the adenoma into an ACC. Transformation of benign adrenal adenomas into ACC has been long debated. There are some evidences against, like the high prevalence of adenomas contrasting with the extremely low prevalence of ACC - though this does not preclude the hypothesis of exceptional transformation events-, or the lack of adenomatous areas in adrenals of ACC patients in most cases. On the other hand the adenoma-carcinoma sequence -similarly to the pathogenesis of colorectal cancer- is supported by some molecular evidences. First, many adenomas and ACC share common molecular alterations, such as beta-catenin mutations (10, 11). Furthermore, using mouse models, two studies showed that activating beta-catenin and Igf2 led to a sequence of benign adrenal proliferation, evolving into malignant proliferation at later stages (12, 13). Finally in human tumors, Ronchi and al. investigated 46 adrenal tumors- adenomas and carcinomas- and reported genes pathways -such as Wnt/beta-catenin but also Notch signaling- similarly altered in ACA and ACC, compatible with an adenoma-carcinoma sequence (14). Altogether these observations suggest that ACC may develop from adenomas, but this process is obviously rare and further studies are needed for a definite proof of the adenoma-carcinoma sequence in adrenal cortex.
To conclude, the case reported here of an ACC occurring several years after the diagnosis of a typical adrenal adenoma as highly exceptional. Should this single case alleviate the new ESE consensus defending the total absence of surveillance for typical adrenal adenomas? We do think that these new guidelines should not be modified based on a single case, especially considering the more than two thousands adenomas with no malignant transformation reported in literature.
Acknowledgements
The authors thank Brou de Lauriere foundation, COMETE-TACTIC (grant PRT-K 14079, grant INCA_DGOS 8663), and Carigest-promex for their support.
Disclosure:
The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.
Consent statement
We declare that consent has not been obtained because the patient is deceased.
References:
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FIG 1. Adrenal lesion during the first five years of follow-up.
The first image (A) is a T2-weighted image obtained during the first hospitalization, showing a well- limited right adrenal lesion (white arrow). The second image one year later is from an unenhanced CT (B) showing an adrenal lesion measured at 22mm, with attenuation in the region of interest of 8 UH, a finding indicative of a lipid-rich adenoma. Density values and size of the adrenal lesion remained stable three (C) and five (D) years later.
FIG 2. MR images of the adrenocortical carcinoma 15 years after the first evaluation. The right adrenal mass is hyperintense on T2-weighted sequence (A1). There is no loss of signal on out-of-phase image (C1), as compared with in-phase image (B1). The hypersignal observed in the middle of the lesion is part of an hemorrhage component (B1, C1, white thin arrows). On late contrast enhancement images -after 5 min- the mass appears heterogeneous and poorly enhanced (D1).
FIG 3. Histological findings after adrenal surgery.
The WEISS score was 8, with 1 point for the following items: nuclear grade, high mitotic rate (A, B), atypical mitotic figures, <25% or vacuolated cells, diffuse architecture, necrosis (B), veinous invasion (C), invasion of tumour capsule. There was no sinusoid invasion. Ki67-positive cells was elevated (30 %) (D). No benign component could be found on the adrenal.
A
B
C
D
AV 13.6
SD 19.6
AR 78
Q
AV
AV 7.9
9
SD 14.4
SD
AR 6
AR
FIG 1. Adrenal lesion during the first five years of follow-up.
The first image (A) is a T2-weighted image obtained during the first hospitalization, showing a well- limited right adrenal lesion (white arrow).
The second image one year later is from an unenhanced CT (B) showing an adrenal lesion measured at 22mm, with attenuation in the region of interest of 8 UH, a finding indicative of a lipid-rich adenoma. Density values and size of the adrenal lesion remained stable three (C) and five (D) years later.
.
A1
B1
C1
D1
FIG 2. MR images of the adrenocortical carcinoma 15 years after the first evaluation.
The right adrenal mass is hyperintense on T2-weighted sequence (A1). There is no loss of signal on out-of-phase image (C1), as compared with in-phase image (B1). The hypersignal observed in the middle of the lesion is part of an haemorrhage component (B1, C1, white thin arrows). On late contrast enhancement images -after 5 min- the mass appears heterogeneous and poorly enhanced (D1).
A
B
C
D
The WEISS score was 8, with 1 point for the following items: nuclear grade, high mitotic rate (A, B), atypical mitotic figures, <25% or vacuolated cells, diffuse architecture, necrosis (B), veinous invasion (C), invasion of tumour capsule. There was no sinusoid invasion. Ki67- positive cells was elevated (30 %) (D). No benign component could be found on the adrenal.