Commentary on Adrenal wash-out CT: moderate diagnostic value in distinguishing benign from malignant masses

in European Journal of Endocrinology
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  • 1 Department of Surgical Sciences, Radiology & Molecular Imaging, Uppsala University, Uppsala University Hospital, Uppsala, Sweden

Correspondence should be addressed to A Sundin; Email: anders.sundin@radiol.uu.se
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The increasing use of cross-sectional imaging, mainly CT, results in an accelerating number of incidental findings, for instance of adrenal tumours. Although most ‘adrenal incidentalomas’ are benign, it is important to identify the malignant and the hormone producing (functional) tumours. For a small fraction of adrenal incidentalomas, the diagnosis is apparent on imaging, but the large majority requires radiological characterisation. To this end, a previous joint European Society of Endocrinology and European Network for the Study of Adrenal Tumours publication in this jounal, recommends CT measurements of the native (non-contrast) tumour attenuation ≤10 Hounsfield units, consistent with a lipid-rich benign adrenocortical adenoma, and imaging at least 6 months apart, on which unchanged tumour size implies a benign tumour. Because of weak evidence, calculation of CT contrast medium washout was not recommended as a means for tumour characterisation, but this technique has nevertheless still been applied in several countries. The recent article by Schloetelburg et al. in this journal is important because, in the largest study to date, the authors confirm that calculation of CT contrast medium washout with established thresholds is insufficient to reliably characterise adrenal tumours. Their results are therefore expected to impact the management of these patients.

Abstract

The increasing use of cross-sectional imaging, mainly CT, results in an accelerating number of incidental findings, for instance of adrenal tumours. Although most ‘adrenal incidentalomas’ are benign, it is important to identify the malignant and the hormone producing (functional) tumours. For a small fraction of adrenal incidentalomas, the diagnosis is apparent on imaging, but the large majority requires radiological characterisation. To this end, a previous joint European Society of Endocrinology and European Network for the Study of Adrenal Tumours publication in this jounal, recommends CT measurements of the native (non-contrast) tumour attenuation ≤10 Hounsfield units, consistent with a lipid-rich benign adrenocortical adenoma, and imaging at least 6 months apart, on which unchanged tumour size implies a benign tumour. Because of weak evidence, calculation of CT contrast medium washout was not recommended as a means for tumour characterisation, but this technique has nevertheless still been applied in several countries. The recent article by Schloetelburg et al. in this journal is important because, in the largest study to date, the authors confirm that calculation of CT contrast medium washout with established thresholds is insufficient to reliably characterise adrenal tumours. Their results are therefore expected to impact the management of these patients.

With the escalating radiological imaging in medicine, especially by CT, follows an increasing number of incidental imaging findings that need to be managed. So-called adrenal ‘incidentalomas’, defined as an adrenal tumour depicted on imaging performed for other reasons than adrenal disease, are found in approximately 5% of CT examinations, that is about every 20th scan that includes the adrenals in the field of view (1). CT of the abdomen always includes the adrenals and, in most protocols, CT of the thorax also includes the adrenals in the field of view. By way of illustration, according to the British National Health Service statistics, approximately 5 400 000 CT scans are performed each year and about 600 000 of those (12%) comprise CT examinations of the abdomen and thorax. This means that each year an adrenal incidentaloma is detected in about 30 000 examinations (5%). By applying the same percentages to the annual number of CT scans performed in the USA (80 000 000), adrenal incidentalomas are detected in roughly 500 000 examinations each year. This imposes a significant additional workload on healthcare because these adrenal incidentalomas need to be characterised as benign or malignant (radiology) and the patients require biochemical testing to establish whether the tumour is functioning or not, that is screening for mineralocorticoid, glucocorticoid, and catecholamine secretion (endocrinology, internal medicine). The vast majority of adrenal incidentalomas are benign. Also, in patients with a cancer history diagnosis adrenal incidentalomas are benign in approximately three-quarters of the patients (2), although the finding of an adrenal tumour in a cancer patient is suspicious of an adrenal metastasis, and requires work-up accordingly.

There are some tumour diagnoses that are apparent on CT and MRI, for which the patient management of their adrenal incidentaloma therefore does not pose a problem, such as myelolipomas comprising varying proportions of myeloid tissue and macroscopic fat, which is easily identified on CT and MRI (3), and simple cysts, that are water-attenuating and without contrast enhancement, and adrenal hematomas, typically with characteristic imaging presentation on trauma-CT, but an adrenal bleed may also be unrelated to trauma. Further, large malignant tumours are easily recognised as such on CT and MRI because of their irregular-lobulated less well-defined margin, heterogeneous internal structure and contrast enhancement, consistent with tumour necrosis, and the patients have to be managed accordingly. However, adrenal incidentalomas with an apparent diagnosis, and those which clearly are malignant, and for which the subsequent patient management is clear, comprise a minor fraction and the vast majority of adrenal incidentalomas are morphologically uncharacteristic in their imaging appearance and require further characterisation.

Because older patients, in whom adrenal incidentalomas are most frequent, may have undergone previous imaging, a CT examination or MRI at least 6 months old, in which the tumour’s size and morphological appearance are similar, will suffice to establish that the incidentaloma is benign, and these patients need no imaging follow-up. In lack of previous radiology, CT measurements of the tumours’ attenuation on native (pre-contrast) examination applying ≤10 Hounsfield units (HU) as the upper limit (cut-off) is well established to diagnose lipid-rich adrenocortical adenomas, showing approximately 70% sensitivity and almost 100% specificity (4). Notably, because most CT examinations of the abdomen and thorax are performed during intravenous contrast enhancement, a native CT examination of the adrenals has to be scheduled. Thus, an additional CT examination is required in a large number of patients. To avoid unnecessary radiation exposure to young patients (<40 years), alternatively, an MRI of the adrenals with sequences of in-phase and out-of-phase may be scheduled, for follow-up. Except for size measurements and evaluation of tumour morphology, MRI of the adrenals with most protocols allows for detection of ‘chemical shift’, that is a decrease in the tumour signal in sequences out-of-phase in comparison with in-phase, which is consistent with intracellular fat in a benign adrenocortical adenoma (5), in which case no further imaging is needed.

The finding that the ‘washout’ rate of iodine-based CT contrast media from the adrenal tumours could be applied as a means to characterize incidentalomas as benign was later incorporated into the radiological routine, especially valuable for incidentalomas with >10 HU native attenuation, and when a native examination was lacking. The contrast medium washout was calculated based on the tumour’s CT attenuation (HU) measured in the venous phase and in the delayed phase, typically 10–15 min after contrast medium injection start (relative washout) and, when available, also incorporating the native tumour attenuation into the equation (absolute washout). A relative washout >40% and an absolute washout >60% were found to indicate a benign tumour (6, 7).

However, because of the results of subsequent studies, showing benign washout characteristics for pheochromocytomas (8), and a meta-analysis reporting weak evidence for CT with contrast washout for incidentaloma characterisation (9), the accuracy of adrenal washout calculations was questioned. Based on the findings in this meta-analysis, the European Society of Endocrinology (ESE) and the European Network for the Study of Adrenal Tumours (ENSAT) published a joint guideline paper in this journal recommending that characterisation of adrenal incidentalomas should be based on native attenuation measurements and, when inconclusive, measurements of lesion size on examinations at least 6 months apart (10). Consequently, the radiological practice in several European countries changed, and CT with contrast medium washout calculations as a means to characterise adrenal incidentalomas was more or less abandoned, whereas other countries continued to apply this technique (11), and still are, as reflected in a recent review paper (12).

A recent paper from the Würzburg group by Schloetelburg et al. published in this journal (13) is therefore imperative, with high impact on the management of patients with adrenal incidentalomas, because it reports the diagnostic yield of relative and absolute washout in the largest study to date, assessing the technique in 216 patients with 252 adrenal incidentalomas, and with confirmation of the tumour diagnosis by histopathology and radiological and clinical long-term follow-up. Consistent with the results of the previous meta-analysis (9) the authors demonstrate failure of adrenal contrast medium washout calculations (relative washout >40%, absolute washout >60%) to characterise adrenal incidentalomas. Importantly, relative and absolute washout calculations misclassified 35% and 36% of the adrenal tumours, respectively. The imaging characterisation of pheochromocytomas is generally not crucial, because they are usually diagnosed as such, based on biochemistry, and only a small fraction (approximately 10%) of pheochromocytomas are malignant. The authors included the pheochromocytomas in their analysis of potentially malignant adrenal tumours, and found that the absolute washout calculations indicated that 22% were benign, whereas conversely 36% of all benign lesions were indicated as malignant. In the latter situation, misdiagnosis of benign adrenal lesions as malignant can lead to unnecessary surgical resection and, except for the surgical risks and costs, also with undesirable consequences for the patient’s mental well-being. In the former situation, misdiagnosis will delay the resection of a malignant tumour, with the risk for a more complicated surgical procedure, or even the development of a non-curative situation.

Established prerequisites to use native CT attenuation measurements for tumour characterisation, are benign morphological imaging characteristics including harmonic rounded shape, homogenous internal structure and sharp borders, and this also applies to tumours suitable for calculations of contrast medium washout. Therefore, another important finding by the Würtsburg group in their current paper is that homogeneity of adrenal tumours was not helpful as a means to identify benign lesions. Notably, the classical benign imaging features (homogenous internal structure, sharp delineation and harmonic rounded-oval form) were fulfilled in merely 63% of the adrenocortical adenomas. Conversely, 66% of the adrenocortical cancers and 68% of the metastases showed benign morphological features on imaging.

Except for the study by Schloetelburg et al., (13) there are two additional recent reports which also are likely to impact future guidelines, and therefore are appropriate to mention (14, 15). In these two studies, the authors have assessed an increased threshold, set to 20 HU, on native CT for adrenal tumour characterisation, the results of which however lie outside the scope of this commentary report.

To conclude, the results in the study by Schloetelburg et al. (13) have high impact on the management of patients with adrenal incidentalomas and support the previous ESE and ENSAT recommendations to base CT measurements for tumour characterisation on native CT and for tumours >10 HU on size and morphology comparison on imaging at least 6 months apart.

Declaration of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of this commentary.

Funding

This work did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.

References

  • 1

    Song JH, Chaudhry FS, Mayo-Smith WW. The incidental adrenal mass on CT: prevalence of adrenal disease in 1049 consecutive adrenal masses in patients with no known malignancy. American Journal of Roentgenology 2008 190 11631168. (https://doi.org/10.2214/AJR.07.2799)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 2

    Hammarstedt L, Muth A, Sigurjonsdottir , Almqvist E, Wängberg B, Hellström M & Adrenal Study Group of Western Sweden. Adrenal lesions in patients with extra-adrenal malignancy: benign or malignant? Acta Oncologica 2012 51 215221. (https://doi.org/10.3109/0284186X.2011.608084)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 3

    Calissendorff J, Juhlin CC, Sundin A, Bancos I, Falhammar H. Adrenal myelolipomas. Lancet: Diabetes and Endocrinology 2021 9 767775. (https://doi.org/10.1016/S2213-8587(2100178-9)

    • Search Google Scholar
    • Export Citation
  • 4

    Boland GW, Lee MJ, Gazelle GS, Halpern EF, McNicholas MM, Mueller PR. Characterization of adrenalmasses using unenhanced CT: an analysis of the CT literature. American Journal of Roentgenology 1998 171 201204. (https://doi.org/10.2214/ajr.171.1.9648789)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 5

    Mayo-Smith WW, Lee MJ, McNicholas MM, Hahn PF, Boland GW, Saini S. Characterization of adrenal masses (< 5 cm) by use of chemical shift MR imaging: observer performance versus quantitative measures. American Journal of Roentgenology 1995 165 9195. (https://doi.org/10.2214/ajr.165.1.7785642)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 6

    Korobkin M, Brodeur FJ, Francis IR, Quint LE, Dunnick NR, Londy F. CT time-attenuation washout curves of adrenal adenomas and nonadenomas. American Journal of Roentgenology 1998 170 747752. (https://doi.org/10.2214/ajr.170.3.9490968)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 7

    Caoili EM, Korobkin M, Francis IR, Cohan RH, Dunnick NR. Delayed enhanced CT of lipid-poor adrenal adenomas. American Journal of Roentgenology 2000 175 14111415. (https://doi.org/10.2214/ajr.175.5.1751411)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 8

    Woo S, Suh CH, Kim SY, Cho JY, Kim SH. Pheochromocytoma as a frequent false positive in adrenal washout CT: a systematic review and meta-analysis. European Radiology 2018 28 10271036. (https://doi.org/10.1007/s00330-017-5076-5)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 9

    Dinnes J, Bancos I, Ferrante di Ruffano L, Chortis V, Davenport C, Bayliss S, Sahdev A, Guest P, Fassnacht M & Deeks JJ et al.Management of endocrine disease: imaging for the diagnosis of malignancy in incidentally discovered adrenal masses: a systematic review and meta-analysis. European Journal of Endocrinology 2016 175 R51R64. (https://doi.org/10.1530/EJE-16-0461)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 10

    Fassnacht M, Arlt W, Bancos I, Dralle H, Newell-Price J, Sahdev A, Tabarin A, Terzolo M, Tsagarakis S, Dekkers OM. Management of adrenal incidentalomas: European Society of Endocrinology Clinical Practice Guideline in collaboration with the European Network for the study of adrenal tumors. European Journal of Endocrinology 2016 175 G1G34. (https://doi.org/10.1530/EJE-16-0467)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 11

    Mayo-Smith WW, Song JH, Boland GL, Francis IR, Israel GM, Mazzaglia PJ, Berland LL, Pandharipande PV. Management of incidental adrenal masses: a white paper of the ACR Incidental Findings Committee. Journal of the American College of Radiology 2017 14 10381044. (https://doi.org/10.1016/j.jacr.2017.05.001)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 12

    Sundin A, Hindié E, Avram AM, Tabarin A, Pacak K, Taïeb D. A clinical challenge: endocrine and imaging investigations of adrenal masses. Journal of Nuclear Medicine 2021 62 (Supplement 2) 26S33S. (https://doi.org/10.2967/jnumed.120.246066)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 13

    Schloetelburg W, Ebert I, Petritsch B, Weng AM, Dischinger U, Kircher S, Buck AK, Bley TA, Deutschbein T & & Fassnacht M. Adrenal wash-out CT: moderate diagnostic value in distinguishing benign from malignant adrenal masses. European Journal of Endocrinology 2022 186 183193. (https://doi.org/10.1530/EJE-21-0650)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 14

    Bancos I, Taylor AE, Chortis V, Sitch AJ, Jenkinson C, Davidge-Pitts CJ, Lang K, Tsagarakis S, Macech M & Riester A et al.Urine steroid metabolomics for the differential diagnosis of adrenal incidentalomas in the EURINE-ACT study: a prospective test validation study. Lancet: Diabetes and Endocrinology 2020 8 773781. (https://doi.org/10.1016/S2213-8587(2030218-7)

    • Search Google Scholar
    • Export Citation
  • 15

    Kahramangil B, Kose E, Remer EM, Reynolds JP, Stein R, Rini B, Siperstein A, Berber E. A modern assessment of cancer risk in adrenal incidentalomas: analysis of 2219 patients. Annals of Surgery 2022 275 e238e244. (https://doi.org/10.1097/SLA.0000000000004048)

    • Crossref
    • Search Google Scholar
    • Export Citation

 

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  • 1

    Song JH, Chaudhry FS, Mayo-Smith WW. The incidental adrenal mass on CT: prevalence of adrenal disease in 1049 consecutive adrenal masses in patients with no known malignancy. American Journal of Roentgenology 2008 190 11631168. (https://doi.org/10.2214/AJR.07.2799)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 2

    Hammarstedt L, Muth A, Sigurjonsdottir , Almqvist E, Wängberg B, Hellström M & Adrenal Study Group of Western Sweden. Adrenal lesions in patients with extra-adrenal malignancy: benign or malignant? Acta Oncologica 2012 51 215221. (https://doi.org/10.3109/0284186X.2011.608084)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 3

    Calissendorff J, Juhlin CC, Sundin A, Bancos I, Falhammar H. Adrenal myelolipomas. Lancet: Diabetes and Endocrinology 2021 9 767775. (https://doi.org/10.1016/S2213-8587(2100178-9)

    • Search Google Scholar
    • Export Citation
  • 4

    Boland GW, Lee MJ, Gazelle GS, Halpern EF, McNicholas MM, Mueller PR. Characterization of adrenalmasses using unenhanced CT: an analysis of the CT literature. American Journal of Roentgenology 1998 171 201204. (https://doi.org/10.2214/ajr.171.1.9648789)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 5

    Mayo-Smith WW, Lee MJ, McNicholas MM, Hahn PF, Boland GW, Saini S. Characterization of adrenal masses (< 5 cm) by use of chemical shift MR imaging: observer performance versus quantitative measures. American Journal of Roentgenology 1995 165 9195. (https://doi.org/10.2214/ajr.165.1.7785642)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 6

    Korobkin M, Brodeur FJ, Francis IR, Quint LE, Dunnick NR, Londy F. CT time-attenuation washout curves of adrenal adenomas and nonadenomas. American Journal of Roentgenology 1998 170 747752. (https://doi.org/10.2214/ajr.170.3.9490968)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 7

    Caoili EM, Korobkin M, Francis IR, Cohan RH, Dunnick NR. Delayed enhanced CT of lipid-poor adrenal adenomas. American Journal of Roentgenology 2000 175 14111415. (https://doi.org/10.2214/ajr.175.5.1751411)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 8

    Woo S, Suh CH, Kim SY, Cho JY, Kim SH. Pheochromocytoma as a frequent false positive in adrenal washout CT: a systematic review and meta-analysis. European Radiology 2018 28 10271036. (https://doi.org/10.1007/s00330-017-5076-5)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 9

    Dinnes J, Bancos I, Ferrante di Ruffano L, Chortis V, Davenport C, Bayliss S, Sahdev A, Guest P, Fassnacht M & Deeks JJ et al.Management of endocrine disease: imaging for the diagnosis of malignancy in incidentally discovered adrenal masses: a systematic review and meta-analysis. European Journal of Endocrinology 2016 175 R51R64. (https://doi.org/10.1530/EJE-16-0461)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 10

    Fassnacht M, Arlt W, Bancos I, Dralle H, Newell-Price J, Sahdev A, Tabarin A, Terzolo M, Tsagarakis S, Dekkers OM. Management of adrenal incidentalomas: European Society of Endocrinology Clinical Practice Guideline in collaboration with the European Network for the study of adrenal tumors. European Journal of Endocrinology 2016 175 G1G34. (https://doi.org/10.1530/EJE-16-0467)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 11

    Mayo-Smith WW, Song JH, Boland GL, Francis IR, Israel GM, Mazzaglia PJ, Berland LL, Pandharipande PV. Management of incidental adrenal masses: a white paper of the ACR Incidental Findings Committee. Journal of the American College of Radiology 2017 14 10381044. (https://doi.org/10.1016/j.jacr.2017.05.001)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 12

    Sundin A, Hindié E, Avram AM, Tabarin A, Pacak K, Taïeb D. A clinical challenge: endocrine and imaging investigations of adrenal masses. Journal of Nuclear Medicine 2021 62 (Supplement 2) 26S33S. (https://doi.org/10.2967/jnumed.120.246066)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 13

    Schloetelburg W, Ebert I, Petritsch B, Weng AM, Dischinger U, Kircher S, Buck AK, Bley TA, Deutschbein T & & Fassnacht M. Adrenal wash-out CT: moderate diagnostic value in distinguishing benign from malignant adrenal masses. European Journal of Endocrinology 2022 186 183193. (https://doi.org/10.1530/EJE-21-0650)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 14

    Bancos I, Taylor AE, Chortis V, Sitch AJ, Jenkinson C, Davidge-Pitts CJ, Lang K, Tsagarakis S, Macech M & Riester A et al.Urine steroid metabolomics for the differential diagnosis of adrenal incidentalomas in the EURINE-ACT study: a prospective test validation study. Lancet: Diabetes and Endocrinology 2020 8 773781. (https://doi.org/10.1016/S2213-8587(2030218-7)

    • Search Google Scholar
    • Export Citation
  • 15

    Kahramangil B, Kose E, Remer EM, Reynolds JP, Stein R, Rini B, Siperstein A, Berber E. A modern assessment of cancer risk in adrenal incidentalomas: analysis of 2219 patients. Annals of Surgery 2022 275 e238e244. (https://doi.org/10.1097/SLA.0000000000004048)

    • Crossref
    • Search Google Scholar
    • Export Citation