1. Update Management of Adrenal Incidentaloma
Good morning seniors and colleagues. I am Sandy Leung from North District Hospital. Today I am going to talk about the update management of adrenal incidentaloma.
Joint Hospital Surgical Grand Round 21/10/2017
LEUNG Lai Ying, Sandy
North District Hospital

2. Outline What is an adrenal incidentaloma? How to manage them?
How should we follow-up?
First we will look at the definition and demographics of adrenal incidentaloma. Then we will specifically focus on The radiological investigation and how should we follow-up.

3. What is an adrenal incidentaloma?
Asymptomatic adrenal mass greater than 1 cm that is discovered incidentally on imaging performed for non-adrenal problem
Adrenal incidentaloma is defined as Asymptomatic adrenal mass greater than 1cm detected on imaging for non-adrenal problems
Thompson et al. “Adrenal incidentaloma.” Current Opinion in Oncology 2003, 15(1),

4. How common is it? Autopsy studies Radiological studies
From autopsy studies, the prevalence is around 2%
From radiological studies, the frequency Is increasing from around 0.5% in 1980s to up to 4.4% in the study in 2006
Radiological
studies
Luisa Barzon et al. “Prevalence and natural history of adrenal incidentalomas.” Eur J Endocrinol
S. Bovio et al. “Prevalence of adrenal incidentaloma in a contemporary computerized tomography series.” Journal of Endocrinological Investigation, Apr 2006, Vol 29, Issue 4, 298–302.
S. Bovio et al / %

5. What is an adrenal incidentaloma?
You may say adrenal incidentaloma is not very common from previous studies, however it is an important disease if it is malignant or be functionally active. From previous series, around 75% of cases are non-functioning benign adenoma.
Martin Fassnacht et al. “Management of adrenal incidentalomas: European Society of Endocrinology Clinical Practice Guideline in collaboration with the European Network for the Study of Adrenal Tumors.” Eur J Endocrinol. 2016 Aug;175(2):G1-G34.
Cho YY et al. “Clinical characteristics and follow-up of Korean
patients with adrenal incidentalomas.” Korean Journal of Internal
Medicine –564.

6. How to manage them? Clinical exam Biochemical workup
Radiological workup
So How to manage them? clinically we need to look for symptoms of hormonal excess or features of malignancy

7. Biochemical workup - Screening
Phaeochromocytoma
24-hour urine for metanephrines and catecholamines
Conn’s syndrome
Aldosterone-renin ratio
Cushing’s syndrome
1mg overnight dexamethasone suppression test
Our role in Biochemical workup mainly is the screening. 24-hour urine for metanephrines and catecholamines to screen phaeochromocytoma. Aldosterone-renin ratio to screen Conn syndrome. And 1mg overnight dexamethasone suppression test to screen Cushing syndrome.

8. Radiological workup – What modality?
Non-contrast CT
Contrast washout CT
Chemical-shift MRI
Sensitivity
Specificity
Israel et al. 2004 78 83
100
Byung et al. 2007 97 86 50
Hyun et al. 2014
92.0
67.6
53.7
Jung et al. 2014
80.0
75.7
60.0
Warda et al. 2016 95 81
How about radiological workup, what image modality should we use to detect malignant lesion. This is the table summarizing previous studies comparing different imaging modality. Contrast washout CT is the standard nowadays because of the high sensitivity and specificity. With the sensitivity more than 92% and specificity range from67 to 100%. And the equipment is more easily available.
Israel: 42 lesion, Hounsfield units, adrenal-to-spleen chemical shift ratio (100% 100%) signal intensity index (100% 67%). The final diagnosis of each mass was based on the available radiologic and pathologic data. The diagnosis of a lipid-rich adenoma was made if the mass measured equal to or less than 10 H on unenhanced CT [7], had an adrenal-to-spleen chemical shift ratio of less than 0.71 on MRI [5], and had a signal-intensity index of greater than 16.5% [8] or if the mass fulfilled two of the three preceding criteria and had greater than 6-month imaging follow-up without any interval change. If a mass did not meet the criteria of a lipid-rich adenoma but had imaging follow-up of 1 year or more without change, it was considered benign.
Byung: 43 lesions, contrast washout and adrenal-to-spleen ratio (ASR) or signal intensity index (SII).  follow-up imaging or pathologic review as the reference standard.
Hyun: 478 lesions for CT, 235 lesions for MRI, washout and signal intensity index (SII) and adrenal-to-spleen ratio,
Jung: 52 lesions, adrenal-to-spleen ratio (ASR) or signal intensity index (SII). Follow-up imaging or histologic diagnosis was used as the standard reference.
Warda: 45 lesion, ASR and SII. Follow-up or histopathology was used as standard reference.
Reference standard: follow-up imaging or histological diagnosis
Israel et al. “Comparison of unenhanced CT and chemical shift MRI in evaluating lipid-rich adrenal adenomas.” AJR:183, July 2004.
Byung et al. “Comparison of Delayed Enhanced CT and Chemical Shift MR for Evaluating Hyperattenuating Incidental Adrenal Masses.” RSNA Radiology June 2007 Vol 243, Issue 3.
Hyun et al. “The value of 15-minute delayed contrast-enhanced CT to differentiate hyperattenuating adrenal masses compared with chemical shift MR imaging.” Eur Radiol (2014) 24:1410–1420.
Jung et al. “Characterization of Lipid-Poor Adrenal Adenoma: Chemical-Shift MRI and Washout CT.” AJR:202, May 2014.
Warda et al. “Chemical-shift MRI versus washout CT for characterizing adrenal incidentalomas.” Clinical Imaging. Jul/Aug2016, Vol. 40 Issue 4, p p.
Ilias I et al. “The optimal imaging of adrenal tumours: a comparison of different methods.” Endocrine-Related Cancer –599.

9. Radiological features of malignancy
Gross Signs of Malignancy
Heterogeneity
Irregular margin
Peripheral invasion
Regional lymph node
Distant metastasis
Size
Hounsfield units (on plain scan)
Contrast washout value (on contrast scan)
Here are the radiological features tht we need to look for for suspected malignancy, Besides the features of gross invasion, heterogeneity tht usually represent internal hemorrhage, necrosis, and calcifications also count. The size, the hounsfield units on plain CT and contrast washout value on contrast CT are the things we also look for. Mri we would look for the chemical shift.

10. Radiological features of malignancy - Size
By the forest plot on left side, with 4cm cut off, the sensitivity is 91% and specificity is 71%.
The right hand side is the ROC curve. The summary operating point is just the point after balancing sensitivity and specificity, the point actually is representing 4cm size, therefore choosing 4cm is the best cut-off in patient with adrenal incidentaloma without prior history of malignancy. 6m
Receiver operating characteristic: graphical plot that illustrates the diagnostic ability of a binary classifier system as its discrimination threshold is varied. by plotting the true positive rate (TPR) (sensitivity) against the false positive rate (FPR) (1-specifivity) at various threshold settings. to select possibly optimal models and to discard suboptimal ones independently from (and prior to specifying) the cost context or the class distribution. ROC analysis is related in a direct and natural way to cost/benefit analysis of diagnostic decision making. The best possible prediction method would yield a point in the upper left corner
Sabet, Fatemeh Alsadat et al. “Likelihood Ratio of Computed Tomography Characteristics for Diagnosis of Malignancy in Adrenal Incidentaloma: Systematic Review and Meta-Analysis.” Journal of Diabetes and Metabolic Disorders 15 (2016): 12.

11. Radiological features of malignancy - Size
Likelihood Ratio of Malignancy for Size on CT
Cut-off
No of studies
Co-sensitivity (95 % CI)
Co-specificity (95 % CI)
I2 (95%CI)
Pooled positive LR
Pooled negative LR
3 cm 9
0.91 (0.83–0.95)
0.44 (0.28–0.62)
77 (50–100)
1.6 (1.2–2.2)
0.21 (0.10–0.42)
4 cm 11
0.91 (0.82–0.96)
0.71 (0.55–0.83)
77 (51–100)
3.1 (2–4.9)
0.13 (0.06–0.25)
5 cm 8
0.78 (0.67–0.87)
0.82 (0.65–0.91)
69 (32–100)
4.3 (2.1–8.9)
0.26 (0.16–0.44)
6 cm
0.74 (0.63–0.82)
0.85 (0.69–0.94)
94 (89–99)
5.0 (2.4–10.8)
0.31 (0.22–0.43)
So how large the lesion is suspicious of malignant? This is a meta analysis to look at the likelihood ratio of malignancy for size on CT. Different cutoff have been used. If the cut off is set at 4 cm, the sensitivity is 91% and the specificity is 71%.
Reference standard: operation, biopsy, FNA or follow up for more than 6 months
Sabet, Fatemeh Alsadat et al. “Likelihood Ratio of Computed Tomography Characteristics for Diagnosis of Malignancy in Adrenal Incidentaloma: Systematic Review and Meta-Analysis.” Journal of Diabetes and Metabolic Disorders 15 (2016): 12.

12. Radiological features of malignancy – Hounsfield units
Likelihood Ratio of Malignancy by Hounsfield units
Mass density cut-off
No of studies
Co-sensitivity (95 % CI)
Co-specificity (95 % CI)
Pooled positive LR
Pooled negative LR
10 HU 1
0.65
2.85
16 HU
0.95 ∞
0.05
20 HU
0.81
5.26
Another features to distinguish malignancy is by the hounsfield unit on plain CT. Again different cut off have been used in different study. Usually we are taking the 10HU as cut off in view of the high sensitivity
Reference standard: operation, biopsy, FNA or follow up for more than 6 months
Giles W. L. Boland et al. “Characterization of Adrenal Masses Using
Unenhanced CT: An Analysis of the CT Literature.” AJR 1998;171:
Sabet, Fatemeh Alsadat et al. “Likelihood Ratio of Computed Tomography Characteristics for Diagnosis of Malignancy in Adrenal Incidentaloma: Systematic Review and Meta-Analysis.” Journal of Diabetes and Metabolic Disorders 15 (2016): 12.

13. Radiological features of malignancy – Contrast washout value
Contrast washout value on CT
Malignant lesions
enhance rapidly
slower washout
Suspicious if
Relative washout <40%
Absolute washout <60%
How to Calculate washout:
Pre-contrast (HU0)
60s after contrast (HUmax)
15min after contrast (HU15)
Relative washout
(HUmax − HU15)/HUmax
Absolute washout
(HUmax − HU15)/(HUmax − HU0)
For contrast washout value on contrast CT. The theory behind is that malignant lesions enhance rapidly but demonstrate a slower washout. Therefore relative washout and absolute washout could be calculated after knowing the HU before and after contrast injection by the formula state on right side. Relative washout less than 40% or absolute washout less than 60% is suspicious of malignant.
Martin Fassnacht et al. “Management of adrenal incidentalomas: European Society of Endocrinology Clinical Practice Guideline in collaboration with the European Network for the Study of Adrenal Tumors.” Eur J Endocrinol. 2016 Aug;175(2):G1-G34.
Jacqueline Dinnes et al. “MANAGEMENT OF ENDOCRINE DISEASE: Imaging for the diagnosis of malignancy in incidentally discovered adrenal masses: a systematic review and meta-analysis.” Eur J Endocrinol Aug 1,  R51-R64.
Kebapci M et al. “Differentiation of adrenal adenomas (lipid rich and lipid poor) from nonadenomas by use of washout characteristics on delayed enhanced CT. “ Abdominal Imaging –715.

14. Shall we biopsy? Generally NO! Bleeding Tumor seeding (esp. ACC)
Hormonal fluctuations in functioning tumors
Only if suspect to be metastasis from other primary
Which then affects treatment plan
Shall we biopsy adrenal lesion? Generally No. As this could cause complication includes bleeding, tumor seeding especially in adrenal cortical carcinoma, and most horrifying complication would be hormonal fluctuation in functioning tumors. Therefor adrenal biopsy would be performed only if the lesion is suspect to be metastasis from other primary and biopsy result would affect the treatment plan.

15. Who should have surgery?
Functionally active lesions
Collaborate with endocrinologist for peri-operative care
Proven or suspected malignancy
> 4cm
Primary
? Secondary
After finish investigate the lesion, it comes to the topic who should have surgery. Those functionally active lesions should have adrenalectomy after collaborate with endocrinologist for peri-operative care.
For proven or suspected malignancy, lesion more than 4cm should be resected for histological diagnosis. For primary malignancy, Radical open surgical excision is the the only method by which long-term disease-free survival may be achieved. For adrenal metastasis, whether to resect is determined by any additional survival difference and should be based on the course of primary disease.

16. Follow-up for others?
To detect malignant transformation / development of overt hormone excess
AACE/AAES guideline in 2009
<4cm + benign: Imaging 3-6 months then annually 1-2 years
Blood test annually up to 5 years
So not every case need to have adrenalectomy, then we need to think about the follow up investigation for those non-functional benign adrenal lesion. The aim is to detect malignant transformation or the development of overt hormone excess. According to the old guidelines in 2009 from the AACE/ AAES , lesion less than 4cm with radiologically benign features were recommended to have imaging at 3-6 months time, then annually for 1-2 years. And blood test annually up to 5 years.
Martha Zeiger et al. “American Association of Clinical Endocrinologists and American Association of Endocrine Surgeons Medical Guidelines for the Management of Adrenal Incidentalomas: Executive Summary of Recommendations.” Endocrine Practice: Jul 2009, Vol. 15, No. 5,

17. Natural history of lipid-rich incidentalomas
A 5yr prospective follow up for lipid rich adrenal incidentaloma showed Overall tumor growth during 5 year follow up is 1mm. If we specifically look at the case with more than 2cm adrenal lesion, they have a larger growth during follow up, up to 2mm with statistical significant result. No cases found to have subclinical hypercortisolism after the 5 year follow-up. Therefore no patient in this study develop clinically relevant tumor growth or new subclinical hypercortisolism that require adrenalectomy.
Schalin-Jäntti C, et al. “A 5-Year Prospective Follow-Up Study of Lipid-Rich Adrenal Incidentalomas: No Tumor Growth or Development of Hormonal Hypersecretion.” Endocrinology & Metabolism. Dec2015, Vol. 30 Issue 4, p p.

18. Swedish study on incidentaloma FU
226 patients recruited over 18 months with incidentaloma on CT was assessed
6.2% patient had surgery after initial workup
At 2 years of FU assessment
No hypersecreting lesions
No primary adrenal malignancy
Muth A et al. “Cohort study of patients with adrenal lesions discovered incidentally.” British Journal of Surgery –1391.

19. New guidelines
Therefore the european society of endocrinology published their guideline in 2016

20. New guidelines <4cm + Benign + Indeterminate Non-functional Surgery
>4cm or
Suspicious of malignant or
Functional
Surgery
<4cm +
Benign +
Non-functional
No FU imaging
Blood test not needed unless new clinical features
Imaging 6-12 months
Indeterminate
Size enlarge >20% +
>5mm increase in diameter
Surgery
Below threshold
For lesions larger than 4cm or functional, then surgery is indicated. Less than 4cm and radiologically benign, no follow up imaging is needed. blood test is not needed unless new clinical features arise.
For indeterminate lesion, imaging at 6-12 month interval is advised to assess the lesion growth. If lesion enlarge by more than 20% and more than 5mm increase in the maximum diameter, then adrenalectomy is suggested. If the lesion growth is below the threshold, then additional imaging at 6-12 months later is suggested.
Martin Fassnacht et al. “Management of adrenal incidentalomas: European Society of Endocrinology Clinical Practice Guideline in collaboration with the European Network for the Study of Adrenal Tumors.” Eur J Endocrinol. 2016 Aug;175(2):G1-G34.

21. Conclusion Adrenal incidentaloma is common.
Both biochemical & specialized radiological investigations are mandatory.
Contrast CT with measurement of washout is the preferred radiological investigation.
Adrenal biopsy is usually not indicated.
Functional lesions or lesions of size 4cm or more should undergo surgery.
Follow-up monitoring is necessary for indeterminate lesions.

22. Thank you
15m

23. New guidelines details

24. This is the recap on the management of patients with adrenal incidentalomas. We need to assess the lesion whether is potentially malignant and whether is functionally active to aim at the establishment of a definitive daignosis. If it is a non-functioning benign lesion such as adenoma or lipoma then no further investigation is needed. If the lesion is clinically relevant hormone excess or malignant tumor then adrenalectomy is needed. While those staying in-between, additional investigation is needed.
Martin Fassnacht et al. “Management of adrenal incidentalomas: European Society of Endocrinology Clinical Practice Guideline in collaboration with the European Network for the Study of Adrenal Tumors.” Eur J Endocrinol. 2016 Aug;175(2):G1-G34.

25. Flowchart Fig 2
Martin Fassnacht et al. “Management of adrenal incidentalomas: European Society of Endocrinology Clinical Practice Guideline in collaboration with the European Network for the Study of Adrenal Tumors.” Eur J Endocrinol. 2016 Aug;175(2):G1-G34.

26. Martin Fassnacht et al. “Management of adrenal incidentalomas: European Society of Endocrinology Clinical Practice Guideline in collaboration with the European Network for the Study of Adrenal Tumors.” Eur J Endocrinol. 2016 Aug;175(2):G1-G34.

27. Flowchart Fig 4
Martin Fassnacht et al. “Management of adrenal incidentalomas: European Society of Endocrinology Clinical Practice Guideline in collaboration with the European Network for the Study of Adrenal Tumors.” Eur J Endocrinol. 2016 Aug;175(2):G1-G34.

28. Subclinical Hypercortisolism

30. MRI Features

31. Radiological features of malignancy - MRI
Chemical shift on MRI
Qualitative
Simple visual assessment of signal intensity loss
Quantitative
Adrenal-to-spleen signal ratio
Signal intensity index
Lipid-rich adenomas
Lose signal intensity on out-of-phase images compared with in-phase images
Malignant lesions / pheochromocytomas and lipid-poor adenomas (lack of intracellular lipid)
Remain unchanged
For the MRI features, we could look at the chemical shift. Adrenal adenoma with high content of intracellular lipid would lose the signal intensity on out of phase image compared with in phase image, while malignant lesion and pheochromocytomas and those lipid poor adrenal adenoma are lack of intracellular lipid will remain unchanged for signal intensity. So qualitatively, we could simply visually assess for any signal intensity loss. If we want quantitative analysis then adrenal to spleen signal ratio or signal intensity index could be used.
Martin Fassnacht et al. “Management of adrenal incidentalomas: European Society of Endocrinology Clinical Practice Guideline in collaboration with the European Network for the Study of Adrenal Tumors.” Eur J Endocrinol. 2016 Aug;175(2):G1-G34.
Marin D et al. “Effectiveness of a three-dimensional dual gradient echo two-point Dixon technique for the characterization of adrenal lesions at 3 Tesla.” European Radiology –268.

32. Radiological features of malignancy - MRI
Chemical shift on MRI
Studies (n/N)
Sensitivity (95% CI)
Specificity (95% CI)
MRI adrenal-spleen ratio (1.5Tesla only)
1 (12/49)
58% (28–85%)
86% (71–95%)
MRI loss of signal intensity (1.5Tesla only)
2 (20/75)
86% (31–99%)
85% (73–93%)
If we look back to the last meta analysis, (7m30s)
reference standards where i) at least 50% of participants with ACC or a malignant adrenal mass had a histologically proven reference standard diagnosis (obtained either through adrenalectomy or adrenal biopsy) and ii) at least 50% of those with a benign adrenal mass had their final diagnosis reached by either histology or imaging-based follow-up of any duration.
Reference standard: i) malignant adrenal mass by histological diagnosis, and
ii) benign adrenal mass by either histology or follow-up imaging
Jacqueline Dinnes et al. “MANAGEMENT OF ENDOCRINE DISEASE: Imaging for the diagnosis of malignancy in incidentally discovered adrenal masses: a systematic review and meta-analysis.” Eur J Endocrinol Aug 1,  R51-R64.

33. Adrenal biopsy

34. What if we did biopsied? Non-diagnostic rate
The pooled non-diagnostic rate derived from 30 studies (2013 adrenal biopsy procedures) was 8.7% with a statistical significant P value (CI: 6.2–11.2%; I 2=84%, P<0.001). No relationship between non-diagnostic rates and the number of adrenal biopsies performed in a year (reflecting center experience) was observed (R2=0.0175).
Correlation with needle gauge or number of passes used was not possible due to underreporting and variability of the techniques used.
Early major complication include adrenal hematoma, pancreatitis, pneumothorax requiring chest tube placement, hemothorax, perirenal hematoma, duodenal hematoma and hypertensive crisis, and minor complications (self-limiting/not in need of intervention or hospitalization) included pneumothorax (n=12), hematomas, self-resolved pain, hypertensive episodes, abdominal discomfort, asymptomatic self-limited hypotension and bradycardia, nausea, mild hematuria, hemothorax, and severe pain requiring analgesics. All three hypertensive events were described in patients with pheochromocytomas. Only one delayed-onset complication was noted which is needle track metastasis seeding). Again No relationship of the complication rate to the number of adrenal biopsies performed in a year was observed (R2=0.0055).
Non-diagnostic rate
Irina Bancos et al. “DIAGNOSIS OF ENDOCRINE DISEASE: The diagnostic performance of adrenal biopsy: a systematic review and meta-analysis.” Eur J Endocrinol Aug 1,  R65-R80.

35. What if we did biopsied? Complication rate
The pooled overall complication rate derived from 25 studies (1339 biopsies) was 2.5% (CI: 1.5–3.4%; I 2=19%, P=0.195) . 10m
5 studies done by the EUS-FNA technique, there were no complications related to the procedure. However, again the sample size was limited with a total of 300 biopsies
Early major complication include hematoma, pneumothorax, hypertensive episodes. All three hypertensive events were described in patients with pheochromocytomas. Only one delayed-onset complication was noted which is needle track metastasis seeding). Again No relationship of the complication rate to the number of adrenal biopsies performed in a year was observed (R2=0.0055).
Complication rate
Irina Bancos et al. “DIAGNOSIS OF ENDOCRINE DISEASE: The diagnostic performance of adrenal biopsy: a systematic review and meta-analysis.” Eur J Endocrinol Aug 1,  R65-R80.

36. Histological evaluation?
Diagnostic performance of adrenal biopsy
Diagnosis of malignancy
(7 studies, 217 patients)
Diagnosis of ACC 
(4 studies, 107 patients)
Diagnosis of metastasis
(5 studies, 131 patients)
Estimate
95% CI
Sensitivity
87%
78-93%
70%
42-88%
74-94%
Specificity
100%
76-100%
98%
86-100%
96%
89-98%
LR+
229.4
100.43
19.8
LR−
0.13
30.86
DOR
1775
0.31
151
41-560
So shall we biopsy the adrenal lesion. this meta analysis showed the overall sensitivity for adrenal biopsy in diagnosing malignancy is 87% and specificity is 100%.
Reference standard
includes either 1) histology following adrenalectomy or autopsy, 2) imaging follow up after 3-12 months, or 3) or clinical follow up for at least 2 years.
is reported for at least 50% of patients with malignant adrenal masses (disease positives) and at least 50% of patients with benign adrenal masses (disease negatives) undergoing adrenal biopsy
Reference standard: histology following adrenalectomy or autopsy, imaging after 3-12 months, or clinical follow up for at least 2 years
Irina Bancos et al. “DIAGNOSIS OF ENDOCRINE DISEASE: The diagnostic performance of adrenal biopsy: a systematic review and meta-analysis.” Eur J Endocrinol Aug 1,  R65-R80.

37. Others

38. Clinical exam Look for history or symptoms of functioning lesions
Signs of Cushing’s syndrome
Any hypertension (+/- hypokalemia)
Classic triad of phaeochromocytoma
Headaches, palpitations and sweating
Hirsuitism
Look for history suggestive of familial disease or syndromes
Clinically, we need to look for history or symptoms of functioning lesions including signs of Cushing syndrome, any hypertension, the classic triad of phaeochromocytoma: haedache, palpitation and sweating. And we should not forget to look for the features of sex hormone excess tht is hirsuitism which represent a high chance of malignant lesion. We also need to look for history suggestive of familial disease or syndromes like the multiple endocrine neoplasia

39. Primary adrenocortical carcinoma
Demographics from National Institutes of Health
Incidence: 0.72 per one million
30% cases confined to adrenal at time of diagnosis
Radical open surgical excision is the treatment of choice for patients with localized malignancies
Overall 5-year survival: 38-46%
5-year survival for patients with stage IV tumors: 20%
Larger clinical and surgical adrenal incidentaloma series report an ACC prevalence of 1.4–12% (2, 10, 11, 12), with variability mostly driven by referral bias
Boscaro M et al. “Adrenocortical carcinoma: epidemiology and natural history.” Minerva Endocrinol. 1995 Mar;20(1):89-94.
(63%) had metastases at diagnosis. Survival time ranged from 1 to 108 months. One-year survival rate was 60%, and 5-year survival rate was 10%
Adrenocortical carcinoma (ACC) is a rare tumor that affects only 0.72 persons per one million population
Historically, only about 30% of these malignancies are confined to the adrenal gland at the time of diagnosis
5-year survival for patients with stage IV tumors is usually less than 20%.
Radical open surgical excision is the treatment of choice for patients with localized malignancies and remains the only method by which long-term disease-free survival may be achieved.[4] Overall 5-year survival is approximately 38% to 46%.[1,2]
Bilimoria KY et al. “Adrenocortical carcinoma in the United States: treatment utilization and prognostic factors.” Cancer (2008) 113 (11):
Fassnacht M et al. “Epidemiology of adrenocortical carcinoma.” In: Hammer GD, Else T, eds.: Adrenocortical Carcinoma: Basic Science and Clinical Concepts. New York, Springer, 2010, 23-9.

40. Natural history of incidentalomas
This is a review paper on the natural history of adrenal incidentaloma with the follow up range from less than 1 year to 7 years. Overall 9% of the adrenal lesion would increase size, with 0.09% becoming malignant, and 1.7% become hyperfunctional. 12m
Luisa Barzon et al. “Prevalence and natural history of adrenal incidentalomas.” Eur J Endocrinol

41. Adrenal anatomy
R adrenal with more consistent position, but more dangerous as near inferior vena cava
L adrenal more variable position, but safer in dissection