Oncocytic adrenocortical tumour presenting as an incidentaloma: a diagnostic challenge
Carol D Cardona Attard ®,1 Zachary Gauci,1 Noel Gatt,2 Warren Scicluna,3 Mario J Cachia1
1Diabetes and Endocrine Centre, Mater Dei Hospital, Msida, Malta
2Pathology Department, Mater Dei Hospital, Msida, Malta 3Medical Imaging Department, Mater Dei Hospital, Msida, Malta
Correspondence to
Dr Carol D Cardona Attard; carolcharm18@yahoo.com
Accepted 29 August 2022
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C BMJ Publishing Group Limited 2022. No commercial re-use. See rights and permissions. Published by BMJ.
To cite: Cardona Attard CD, Gauci Z, Gatt N, et al. BMJ Case Rep 2022; 15:e250900. doi: 10.1136/bcr-2022- 250900
SUMMARY
Oncocytic adrenocortical neoplasms are a rare histopathological subtype of adrenal tumours which are usually benign and, if malignant, are less likely to metastasise. We report a case of a non-functioning oncocytic adrenocortical tumour, identified incidentally in a middle-aged woman. It was initially reported as a left-sided 3.5x3.4×5.6 cm adrenal adenoma. It however increased in size to 5.4×4.0×4.3 cm on follow-up scans. Subsequent review of the scans revealed an indeterminate lesion with a precontrast density of 30 Hounsfield units, an absolute washout of 42.6% and a relative washout of 28.6%. As a result, laparoscopic left adrenalectomy was performed. Histology confirmed oncocytic adrenocortical carcinoma when using the Lin- Weiss-Bisceglia system, though it was deemed benign when using the Helsinki scoring system. There has been no evidence of recurrence to date. This case highlights the potential pitfalls in the diagnosis of oncocytic neoplasms and the increased specificity of the Helsinki score in assessing metastatic potential.
BACKGROUND
Oncocytic adrenocortical neoplasms (OAN) are a rare histopathological subtype of adrenocortical tumours, accounting for around 10% of adrenocor- tical neoplasms.1 An incidence of 0.72 per million population annually has been reported for onco- cytic adrenocortical carcinoma (ACC).2 They are usually large, yellow-tan tumours with focal fatty areas. Histologically, they consist of a minimum of 90% oncocytes, which are epithelial cells with copious oeosinophilic and granular cytoplasm and numerous mitochondria, mostly arranged in a diffuse sheet-like pattern.3 4
Here we report a case of an OAN, first identified on imaging as an adrenal incidentaloma. Histology was consistent with malignancy when using the Lin-Weiss-Bisceglia (LWB) criteria but not when using the Helsinki scoring system. Despite meeting the criteria for malignancy when using the LWB system, this tumour exhibited an indolent course without any local recurrence or distant metastases throughout her follow-up of more than 10 years.
CASE PRESENTATION
A woman in her 40s was initially referred to the endocrine clinic for further evaluation of a left adrenal incidentaloma. The left adrenal lesion was first identified on a CT scan of the abdomen and pelvis, which was performed as the patient devel- oped lower abdominal pain 2 weeks following a
total abdominal hysterectomy. It was first described as a 3.5 cm heterogeneous lesion in the left adrenal gland. The patient had no symptoms or signs of adrenal hormonal excess. Blood pressure was 110/70 mmHg, and the rest of the examination was unremarkable.
INVESTIGATIONS
Initial blood investigations included a normal renal profile with a serum potassium level of 4.8 mmol/L (3.5-5.1 mmol/L) and a serum sodium level of 135 mmol/L (135-145 mmol/L). Investiga- tions for adrenal hormonal excess revealed normal consecutive 24-hour urinary cortisol levels with values of 95 nmol/24 hours, 83 nmol/24 hours, 104 nmol/24 hours and 94 nmol/24 hours, respectively (55-276 nmol/24 hours) and 540 nmol/24 hours, 491 nmol/24 hours, 449 nmol/24 hours and 549 nmol/24 hours (57.7-806.8 nmol/24 hours) during the first 5 years of follow-up. Subsequently, the patient however had two consecutively high 24-hour urinary cortisol levels of 1189 nmol/24 hours and 2263 nmol/24 hours (57.7-806.8 nmol/24 hours). Consequently, an overnight dexamethasone suppression test was carried out, which was normal as serum cortisol was successfully suppressed to 35 nmol/L (<50 nmol/L). Serum adrenocortico- tropic hormone level was 11 pg/mL (10-48 pg/mL). Serial serum metanephrine and catecholamine levels were consistently within normal limits. An aldoste- rone/renin ratio was not done since the patient was normotensive and normokalaemic.
A repeat CT scan of the abdomen and pelvis was performed 5 months following the initial scan. The adrenal lesion was reported as a 3.5x3.4×5.6 cm inhomogeneous mass arising from the anterior limb of the left adrenal gland, with hypodense areas in the precontrast scan suggestive of lipid-rich foci. The findings were reported as being indicative of an adrenal myelolipoma. No delayed contrast- enhanced imaging was available at the time, and therefore, contrast washout could not be calculated.
A follow-up CT scan of the adrenals was done 1 year later. This was reported as showing no interval change in the size of the left adrenal lesion, which had an absolute enhancement washout of 60% and a relative washout of 40%, suggestive of an adenoma (figure 1). This is the lowest washout threshold for diagnosing an adenoma. A repeat CT scan of the adrenals 2 and 4 years later was also reported as not showing any interval change in size.
BMJ
Case report
A
pre-contrast phase
Min: - 14 Max: 84
Avg: 32
Std: 19
A: 1.79 cm2
R
L
B
portal venous phase
Min: 2
Max: 169
Avg: 91
Std: 27
A: 2.47 cm2
R
L
C
delayed phase
Min: 8
Max: 138
Avg: 63
Std: 22
A: 2.19 cm2
R
L
On CT adrenals 5 years following the original scan, an increase in the size of the left adrenal mass was described (dimensions now measuring 5.4x4.0×4.3 cm). In this scan, the density of the adrenal mass was calculated to be 20 Hounsfield units (HU) precontrast phase, 65 HU in the portal venous phase and 45 HU in the delayed phase, giving an absolute washout value of 44.4% (benign >60%) and a relative washout of 30.8% (benign >40%) (figures 2 and 3).
A
pre-contrast phase
Min: - 50 Max: 95 Avg: 19 Std: 22 A: 3.55 cm2
R
L
-
B portal venous phase
Min: - 55
Max: 116 Avg: 38 Std: 25
A: 3.10 cm2
R
L
C delayed phase
Min: - 32
Max: 114
Avg: 46
Std: 26
A: 2.88 cm2
R
L
The increase in the size of the adrenal lesion prompted discussion of the initial CT scans with an experienced consul- tant radiologist, who calculated a density of 30 HU precon- trast phase, 91 HU in the portal venous phase and 65 HU in the delayed phase, giving an absolute washout of 42.6% and a relative washout of 28.6% (figure 1). There was also a signifi- cant increase in the size of the adrenal mass from 3.4x3.5x4.9 cm in the original scans to 4.3×5.9×5.8 cm 5 years later (figures 2 and 3). The adrenal lesion was thus deemed to be indeterminate.
A
coronal view
0
R
L
W:360 C:60.0
CA.
BP:113.1 ST. 25
B
sagittal view
A
P
W:360
C:60.0
CA:
F
BP:54.4
ST. 2.5
DIFFERENTIAL DIAGNOSIS
The precontrast density of >10HU effectively excluded a benign lipid-rich adenoma. Myelolipomas, although heterogenous, are char- acterised by the presence of macroscopic fat within the lesion often with a density of ← 30 HU.56 Therefore, the major differential diag- noses included atypical benign lesions, such as lipid-poor adenomas, and malignant lesions. However, the low absolute and relative wash- outs made a diagnosis of a benign lipid-poor adenoma unlikely.7 A malignant lesion was thus thought to be more probable, with differ- entials including primary ACC, primary adrenal lymphoma (or more rarely adrenal angiosarcoma or leiomyosarcoma) and a secondary metastatic lesion. In view of the absence of evidence of malignant disease at other sites on cross-sectional imaging, a primary adrenal malignancy was thought to be more likely. Phaeochromocytoma, which could be benign or malignant, is another important differen- tial to consider in an indeterminate adrenal neoplasm. However, the normal biochemical analysis for serum metanephrine levels would make a diagnosis of a phaeochromocytoma less likely. Other rare differential diagnoses of an indeterminate adrenal mass include benign haemangiomas, ganglioneuromas and OAN, the latter of which can be benign or malignant.6 8-11
TREATMENT
Due to the increase in size and imaging features that were not consistent with a benign adenoma, the patient was referred for surgery and underwent laparoscopic left adrenalectomy almost 6 years after her first review at the endocrine clinic.
OUTCOME AND FOLLOW-UP
Histology revealed an encapsulated mass measuring 7.5 x4.0×4.2 cm attached to a portion of an unremarkable adrenal gland measuring 5.5×3.5×0.5 cm. It weighed 92 g. On sectioning, the tumour had a variegated, yellow myxoid surface with foci
A
the oncocytic adrenocortical tumour with hematoxylin and eosin stain
B atypical mitotic figures
S
D
9
0
3
E
50
C
Ki-67 proliferation index of 3-5%
of haemorrhagic and cystic degeneration. The capsule appeared to be intact, and the tumour was continuous with the adrenal gland. Microscopically, a diffusely oncocytic tumour was noted to occupy most of the adrenal cortex, obliterating the adrenal medulla. The tumour displayed oncocytic cells with well- demarcated cell borders and predominantly sheet-like architec- ture, but with occasional nested architecture (figure 4). Severe nuclear pleomorphism and multinucleated forms were noted. Numerous atypical mitoses were identified focally with no areas of necrosis. Mitoses averaged 7/50 high-power fields (HPF).
| Table 1 Lin-Weiss-Bisceglia system | |
| Major criteria | Venous invasion |
| Mitotic rate >5 mitoses per 50 high-power fields | |
| Atypical mitoses | |
| Minor criteria | Size >10 cm and/or weight >200 g |
| Tumour necrosis | |
| Invasion of sinusoidal structures | |
| Capsular invasion | |
Malignant: any major criteria.
Uncertain malignant potential: only minor criteria.
Benign: no major and no minor criteria.
There was evidence of vascular invasion but no perineural inva- sion. The tumour exhibited diffuse melan-A expression, patchy inhibin and cytokeratin expression and no expression of S-100. Ki-67 was calculated to be between 3% and 5% (figure 4). It was reported as consistent with an oncocytic ACC.
A staging CT scan was thus performed which showed no evidence of metastases. This was confirmed on an 18F-fluorodeoxyglucose positron emission tomography-CT (18F-FDG PET-CT) scan. The patient was reviewed by an oncologist, and a decision was taken to observe the patient. No adjuvant therapy was administered. On serial imaging to date, the patient has remained well with no evidence of local disease recurrence or metastases.
DISCUSSION
Oncocytic ACCs are rare adrenocortical neoplasms, which may be larger, though are less likely to have metastasised at presen- tation compared with conventional ACCs. They often do not exhibit direct organ invasion but sometimes extend into the surrounding adipose tissue.12 In a systematic review, although OAN occurred predominantly in women (66%), male gender was associated with an increased likelihood of having a malignant OAN. Mean age at diagnosis was 47 years for oncocytic ACCs compared with 38 years for benign OAN.13 These tumours tend to have a predilection for the left adrenal gland,413-18 as was also demonstrated in this case, though laterality was not associated with malignant potential.13
In a systematic review by Mearini et al, only 17% of OAN were reported to be functional.8 However, they did not use the LWB (table 1) histological criteria for assessment of malignant potential in their analysis. Other reports have described them as being symptomatic and hormonally active.4 12 19 In these studies, hormone production was recorded in 30%-34% of OAN,4 13 and in up to 54% and 66% of benign and malignant OAN, respectively, with no significant difference in hormone secretion between benign and malignant lesions.14
It is important to highlight the fact that the most recent guide- line on management of adrenal incidentalomas by the Euro- pean Society of Endocrinology recommends against repeated hormonal testing if the initial hormonal work-up is normal unless the patient exhibits new clinical signs indicative of hormonal excess.7 Serial hormonal testing was performed in this case since the work-up predated the publication of this guideline.
CT and MRI findings may be non-specific, and differentia- tion between benign and malignant OAN may be difficult.8 17 This is because benign OAN have an unenhanced attenuation of >10 HU on CT similar to that of lipid-poor adenomas, onco- cytic and conventional ACCs. However, benign oncocytic adre- nocortical tumours were reported to exhibit a greater percentage enhancement washout than oncocytic ACCs (mean 72% vs 12%, respectively). The latter has similar washout characteristics to
that of conventional ACCs, that is, an absolute washout of <60% and a relative washout of <40%, may exhibit internal necrosis and tend to be larger in size.2º On the other hand, benign oncocytomas are often homogeneous, devoid of haem- orrhage and calcifications, and without any associated aggres- sive features such as venous invasion or lymphadenopathy.21 The adrenal lesion described in this case did not demonstrate enhancement washouts in keeping with a benign OAN.
MRI of the adrenals was not performed as initially the tumour was reported to have benign imaging features. Once subsequent review of imaging revealed an increase in size and an indeterminate lesion, the patient was referred immediately for surgery. 18F-FDG PET-CT may be positive in both benign and malignant oncocytic adrenal tumours in view of abundant intracellular mitochondria.22 23 Low fluorode- oxyglucose uptake has also been reported in oncocytic ACCs with absent GLUT1 expression.18 Therefore, 18F-FDG PET-CT may not be a useful imaging tool for initial diagnosis, though may help to identify metastases in oncocytic ACCs.
Most OAN stain positive to synaptophysin, melan-A, inhibin and calretinin but are negative to S-1004 as was seen in this case. Oncocytic ACCs are more likely to stain positive for vimentin than benign oncocytic neoplasms13 and are immunoreactive for cytokeratins (AE1/AE3 and CAM5.2).3 Although the LWB was developed specifically for OAN in preference to the stan- dard Weiss score used for conventional ACC, the LWB may also overestimate the malignant potential of OAN, though to a lesser extent than the Weiss score.14 This is because of the high-grade nuclear features and diffuse architecture that both benign and malignant OAN contain.12 Using the LWB, the adrenal inciden- taloma described in this case was in-keeping with an oncocytic ACC as it satisfied all three major criteria: atypical mitoses, mitotic rate of >5/50 HPF and vascular invasion.
The Helsinki score is a more novel scoring system first reported in 2014. It has been described as the most specific (99.4%) and predictive of aggressive tumours since it incorporates the Ki-67 proliferation index (PI), which may be used to estimate the potential for metastasis in ACC, and thus can be used as an indicator of prognosis and survival.14 24 It is calculated using two of the histological parameters from the Weiss scoring system, namely mitotic rate and the presence of necrosis. The formula used is 3xmitoticrate greater than 5/50 HPF + 5xpresence of necrosis + PI. A score of >8.5 correlates with malignancy, while a score of >17 indicates a more aggressive tumour with a higher risk of metastasis and thus reduced survival.24 When using the Helsinki score, the oncocytic tumour described in our case obtained a score of 8, which would be consistent with a benign rather than a malignant tumour. This would explain why, although there was an increase in size, there was no evidence of local invasion or distant metastases throughout her 12-year follow-up period. Of note, the size is not pathognomonic of their aggressive behaviour14 nor is hormonal function. 13 14
The standard of care for oncocytic ACCs remains adrenalec- tomy. Whether this is to be carried out via an open or laparo- scopic approach remains controversial.13 Laparoscopic removal of large (up to 15 cm) oncocytic ACCs has been described.17 25 A 6-monthly CT or MRI for 2-3 years postoperatively and then annually for a total of 5 years has been proposed by Kanitra et al.13 There are no guidelines or standardised protocols on when to give adjuvant or neoadjuvant therapy in oncocytic ACCs, which are often administered in a similar manner as conventional ACCs. European Society of Endocrinology Clin- ical Practice Guidelines on the management of ACCs in adults, in collaboration with the European Network for the Study of Adrenal Tumours, suggest adjuvant mitotane in tumours at high
risk of recurrence with Ki-67>10%, microscopic positive resec- tion margins and stage III tumours.26
A better prognosis and overall survival of oncocytic ACCs compared with conventional ACCs have been described,12 with oncocytic ACCs having a median overall survival of 58 months compared with 14-32 months for conventional ACCs4 and a 2-year survival rate of 92% compared with 61%, respectively.14 A systematic review reported a 5-year survival rate of 47% for oncocytic ACCs, with a recurrence rate of 16% (often within 5 years) and a median time to recurrence of 18 months. The most common reported sites for metastases to develop were in the liver and lungs.13
In conclusion, this case highlights the potential pitfalls in diag- nosis and the need to re-review imaging and discuss such cases at a multidisciplinary team meeting, especially in the presence of tumour growth, large tumours >4cm, inconsistency in imaging reports or indeterminate adrenal lesions. If imaging features are indeterminate, alternative imaging in the form of MRI adrenals or even 18F-FDG PET-CT may be performed, unless the patient undergoes adrenalectomy.7 The Helsinki score is the most specific score to diagnose oncocytic ACCs as scores like LWB can overdiagnose such tumours and do not correlate as well with the risk of recurrence or metastases. 14
Learning points
Oncocytic adrenocortical carcinoma (ACC) is a rare subtype of ACC, which is usually more indolent with a lower risk of recurrence and metastases and a better prognosis compared with conventional ACC, though it may be difficult to distinguish benign from malignant lesions, especially on imaging.
The Helsinki scoring system is more specific for assessing malignant potential in oncocytic adrenocortical tumours when compared with the Lin-Weiss-Bisceglia criteria, the latter of which tends to overestimate metastatic potential and mortality in this histopathological subtype.
All imaging revealing an adrenal incidentaloma should be evaluated by an expert to assess the risk of malignancy, and if precontrast density on CT is >10 HU, contrast-enhanced washout values should be calculated.
All indeterminate adrenal lesions on CT should be discussed at a multidisciplinary team meeting and considered for surgery or alternative imaging.
An increase in size of an adrenal lesion noted on imaging should prompt re-evaluation of the original and current imaging and discussion in a multidisciplinary team meeting.
Acknowledgements We would like to thank Mr Alexander Attard and his team, who performed the laparoscopic adrenalectomy for the patient, and Dr Nick Refalo, who is the oncologist involved in the care of the patient.
Contributors All authors have made a significant contribution to the write-up of the paper, and all were involved in the conception, design, acquisition and interpretation of data. CDCA and ZG drafted the initial version of the manuscript, while NG, WS and MJC have revised it critically. All authors approved the final version of the manuscript.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests None declared.
Patient consent for publication Consent obtained directly from patient(s).
Provenance and peer review Not commissioned; externally peer reviewed.
Case reports provide a valuable learning resource for the scientific community and can indicate areas of interest for future research. They should not be used in isolation to guide treatment choices or public health policy.
ORCID İD Carol D Cardona Attard http://orcid.org/0000-0002-0947-8153
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