REVIEW ARTICLE
ANZJSurg.com
Management of adrenocortical carcinoma in Western Australia: a perspective over 14 years
David Leong ®,* Munyaradzi Nyantoro,t Hira Shedzad,* Peter Robins,# David Henley,* Simon Ryan,* Hieu Nguyen* and Dean Lisewskis
*Department of Endocrine Surgery, Sir Charles Gairdner Hospital, Perth, Western Australia, Australia
tDepartment of General Surgery, Fiona Stanley Hospital, Perth, Western Australia, Australia
Department of Nuclear Medicine, Sir Charles Gairdner Hospital, Perth, Western Australia, Australia and
§Department of Endocrine Surgery, Fiona Stanley Hospital, Perth, Western Australia, Australia
Key words
adrenal cancer, adrenocortical carcinoma, endocrine malignancy, long-term outcomes, recurrence.
Correspondence
Dr David Leong, Department of Endocrine Surgery, Sir Charles Gairdner Hospital, 1 Hospital Avenue, Nedlands, WA 6009, Australia. Email: dleong87@gmail.com
D. Leong MBBS, FRACS; M. Nyantoro MBBS; H. Shedzad MBBS; P. Robins MBBS, FRANZCR, FAANMS; D. Henley MBBS, FRACP, PhD; S. Ryan MBBS, FRACS; H. Nguyen MBBS, FRACS; D. Lisewski MBBS, FRACS.
Accepted for publication 7 June 2020. doi: 10.1111/ans.16111
Abstract
Background: Adrenocortical carcinoma is a rare but aggressive form of endocrine neo- plasm that confers a poor prognosis. To date, the only Australian data published is from New South Wales. This paper describes our experience in Western Australia with a focus on surgical approach and outcomes.
Methods: A retrospective study of patients treated for adrenocortical carcinoma in Western Australia over 14 years was performed.
Results: Over the 14-year period, a total of 33 patients underwent surgery for adrenocorti- cal carcinoma. Resection outcomes were superior in an open en bloc approach with an 85% R0 margin (P = 0.007). Local recurrence rates were lowest in an open en bloc approach (11%) compared to laparoscopic (75%). Multivariate analysis showed that an en bloc resec- tion is highly correlated with an R0 resection (P < 0.05) and significantly associated with lower (odds ratio = 0.06) local recurrence (P = 0.009). Higher volume surgeons (>5 cases) had lower operative times and blood loss. Compliance with mitotane was significantly improved with close monitoring of levels. The European Network for the Study of Adrenal Tumours (ENSAT) stage at presentation was most predictive of long-term survival with 100% of stage I patients alive compared to 53% of stage II, 25% of stage III and 17% of stage IV patients at the end of the follow-up period.
Conclusion: An open en bloc approach with a low threshold for multi-visceral resection performed by high volume surgeons have improved outcomes in local recurrence, operative times and blood loss.
Introduction
Adrenocortical carcinoma (ACC) is a rare but aggressive form of endocrine neoplasm that has an incidence of approximately 1 per million.1 The overall prognosis for ACC is poor, with 5-year over- all survival (OS) at 38.6%.2 The only cure is surgical resection with prognosis directly related to completeness of surgical resection and stage of disease at presentation.3 There is some debate with regards to the ideal surgical approach.4 However, recent guidelines by the European Society of Endocrinology have recommended an open en bloc approach as the standard of care.5 Post resection local recur- rence rates have been reported up to 65%.6-8 Nonetheless, there is little debate that achieving an R0 resection confers the best outcome in terms of recurrence and survival. To date, the only Australian
data published is from New South Wales (NSW).9,10 This paper describes our experience in Western Australia, focusing on surgical approach and outcomes.
Methods
All patients who underwent surgery for ACC from 2004 to 2018 in Western Australia were retrospectively analysed from a state based registry. This multicentre study was conducted across three tertiary Western Australian hospitals. Ethics was obtained through site-spe- cific approval from each hospital, respectively. A cohort of 33 patients was identified. Relevant clinical and outcome data were collected from hospital records and independently recorded by three
investigators (DL, HS and MN) to ensure accuracy. All data were entered into a database sheet using Microsoft Excel 2016.
Data available in the observational period was collected and analysed. Data on age, sex, body mass index, size of tumour, opera- tion time, blood loss, blood transfusion, surgical approach (open en bloc, open non en bloc, laparoscopic), resection margins (R0, R1, R2), histology, biochemical functional tests (cortisol/dehydroepian- drosterone sulfate (DHEAS)/aldosterone) and imaging characteris- tics were recorded. Post-operative adjuvant use of mitotane and therapy duration was also recorded. Outcomes of interest were local recurrence, distant metastasis, blood loss, transfusion rates and OS. Local recurrence was defined as positron emission tomography- computed tomography (PET-CT), or CT scans demonstrating recur- rence in the post resection bed during follow-up. Survival times were determined from the date of surgery until death and censored if lost to follow-up. Follow up of patients were validated using hos- pital records. An en bloc procedure was defined as including the retroperitoneal and perinephric fat with selective sacrifice of the dis- tal pancreas, spleen or kidney on the left and kidney or portion of liver on the right.
Statistical analysis
Descriptive statistics were presented as mean ± standard deviation, median and interquartile range or as counts (%), depending on the distribution. The relationships between local recurrence and other factors were evaluated with univariable and multivariable logistic analysis. Covariates with a P < 0.2 in the univariable analysis were included in the final analysis for the multivariable logistic regres- sion model. A P-value of <0.05 was considered statistically signifi- cant. All analysis was performed with IBM SPSS Software.
Results
Patient characteristics
Over the 14-year period, a total of 33 patients underwent surgery for ACC. This included 17 females and 16 males. The mean age at presentation was 56 ± 15.5. There were 20 left-sided tumours and 13 right. The average body mass index was 26.6 ± 3.9 and tumour size 98 mm ± 51 mm. The patient clinical characteristics are sum- marized in Table 1. Of note, seven patients presented with local invasion and four with distant metastases on imaging. There were two (6%) patients with ENSAT stage I disease, 17 (52%) stage II, eight (24%) stage III and six (18%) with stage IV disease. Median follow-up was 48 months (range 4-145 months).
In 32 out of 33 patients, the pre-operative diagnosis of ACC was suspected based on pre-operative biochemical and imaging charac- teristics. One patient diagnosed retrospectively, had CT imaging showing heterogeneity with moderate fluorodeoxyglucose PET avidity only. In terms of hormonal activity, 65% of tumours had cortisol hypersecretion, 25% elevated DHEAS and 12% a combina- tion. Three patients with distant metastases at presentation with a hormonally active tumour and low volume metastases underwent surgery with palliative intent.
The majority of patients had a pre-operative working diagnosis of ACC based on PET-CT SUV uptakes and CT characteristics. All
| Demographic characteristics | |
| Male:female | 16:17 |
| Age (years), mean ± SD | 56 ± 15.5 |
| BMI, mean ± SD | 26.6 ± 3.9 |
| Imaging characteristics, n (%) | |
| Side (left) | 20 (13) |
| Imaging size (mm), mean ± SD | 9.8 ±58 |
| Metastatic disease on imaging | 4 (12.1) |
| Local invasion on imaging | 7 (21.2) |
| Heterogeneity | 30 (90.9) |
| Irregular margins | 20 (60.6) |
| PET avid | 22 (66.7) |
| Hormone secretion, n (%) | |
| Cortisol | 20 (60.6) |
| Sex hormones | 7 (21.2) |
| Multiple | 5 (15.1) |
| Operation characteristics | |
| Approach, n (%) | |
| Laparoscopic | 4 (12.2) |
| Conversion | 0 |
| Open anterior | 28 (84.8) |
| Open lateral | 1 (3) |
| En bloc | 27 (81.8) |
| Multivisceral resection | 23 (69.7) |
| Splenectomy | 18 (78.3) |
| Distal pancreatectomy | 16 (69.6) |
| Nephrectomy | 21 (63.6) |
| Partial hepatectomy | 2 (8.7) |
| Margin status, n (%) | |
| R0 | 25 (75.8) |
| R1 | 8 (24.2) |
| R2 | 0 |
| Pathology | |
| Maximum tumour dimension (mm), mean ± SD | 98 ± 5.1 |
| Evidence of histological invasion | 17 |
| Weiss score, median (IQR) | 6 (3-9) |
| ENSAT staging, n (%) | |
| I | 2 (6) |
| II | 17 (52) |
| III | 8 (24) |
| IV | 6 (18) |
| Medical therapy, n (%) | |
| Radiotherapy | 7 (21) |
| Chemotherapy | 6 (18) |
| Mitotane | 18 (55) |
| Mitotane levels measured | 11 (61.1) |
BMI, body mass index; IQR, interquartile range; PET, positron emission tomography; SD, standard deviation.
patients underwent pre-operative CT scans with 90% demonstrating heterogeneity characteristic of necrosis and 60% of tumours irregu- lar margins. Twenty-four (72%) patients had a pre-operative PET- CT. All PET-CT scans were retrospectively analysed by an expert radiologist for tumour SUVmax and liver SUVmax values. Among the 24 PET-CT scans, 22 (91%) of tumours demonstrated high SUV uptake with one equivocal where uptake in the tumour was only marginally higher than liver SUVmax. Mean tumour SUVmax was 16.2 (range 3.9-39.8). When tumour SUVmax:liver SUVmax were compared, 22 tumours (91%) had a ratio >1.5 with a mean ratio of 5.36.
Treatment
The operative approach for 29 of the 33 (87.8%) patients was via laparotomy, with the remaining four (12.2%) patients a
laparoscopic approach. An en bloc approach was performed in 27 out of the 29 open approaches. A total of 85% (23) of open approaches involved multivisceral resection. In the laparoscopic group, two were retrospectively diagnosed as ACC histologically, one a suspected ACC attempted laparoscopically and one per- formed as a radical laparoscopic hand-assisted procedure due to the age (82) and comorbidity of the patient. An R0 resection was achieved in 25 of the 33 patients with the remaining 8 R1 resection. There were no R2 resections. Three of the 33 patients required infe- rior vena cava exclusion with tumour thrombus identified pre-oper- atively on imaging. There were seven treating surgeons in this cohort, with four performing the majority of the procedures. Two surgeons had performed more than 10 cases, two between 5 and 10 cases and the remaining surgeons one case each.
Adjuvant therapy
Mitotane was the most common adjuvant therapy offered to patients. Mitotane was offered to all ENSAT stage III and IV patients and selected stage II patients based on high-risk histologi- cal features. A total of 18 (54.5%) out of 33 patients were com- menced on mitotane with a target level of 14-20 µg/L. A total of 18 (55%) patients received mitotane in our series, 11 (61.1%) with monitored levels. The mean duration on mitotane was 14 months with the longest duration 120 months. A single endocrinologist was predominantly responsible for mitotane administration. Measure- ment of levels significantly improved compliance with duration on mitotane 29 ± 24.7 months compared to 16.5 ± 13.2 months (mean ± SD) (P<0.05). The mean levels were 14.2±3.4 ug/L (mean ± SD). A total of seven (38.9%) patients ceased mitotane prematurely due to intolerance. Radiotherapy as adjuvant therapy was administered at the post resection bed to three patients, with no difference in local recurrence (Table 2), while four others received radiotherapy to metastases only. Five patients received adjuvant chemotherapy; the regimes were cisplatin, Adriamycin and etoposide, mebendazole only, capecitabine only and one unac- counted for.
Outcomes (recurrence, blood loss and overall survival)
Overall, 25 out of 33 patients had an R0 resection with the remaining 8 an R1 resection. R1 positive margins were associated with laparoscopic and non-en bloc approaches with disruption of the tumour capsule. Resection outcomes were superior in an open en bloc approach with an 85% (n = 20) R0 margin achieved versus 50% (n = 2) in open non-en bloc and 25% (n = 4) laparoscopic (P < 0.007). Local recurrence rates were lowest in an open en bloc approach (11%) compared to non-en bloc (50%) and laparoscopic (75%). Univariate and multivariate analysis showed that an en bloc resection was highly correlated with an R0 resection and signifi- cantly associated with lower (odds ratio = 0.06) local recurrence (P = 0.009) (Table 2).
The mean blood loss was 991 mL in an open approach. Patients who underwent an open en bloc approach, however, had lower mean blood loss compared to a non-en bloc approach (734 mL ver- sus 1250 mL). The mean blood loss in laparoscopic cases was 500 mL; this was due to an outlier, a laparoscopic hand-assisted radical procedure with total blood loss of 800 mL. When the outlier was excluded, mean laparoscopic blood loss was 40 mL. A total of 11 (33%) out of 33 patients required a blood transfusion with mean units transfused 2 ± 0.5. Higher volume surgeons had less blood loss and shorter operative times Table 3.
Average open en bloc operating times were lower (209 ± 98 min) compared to non-en bloc (295 ± 92 min). Laparo- scopic cases averaged (161 ± 114 min) (mean ± SD).
While local recurrence rates were lower, there was no difference in distant metastasis or survival based on approach. The ENSAT stage at presentation was more predictive of long-term survival with 100% of stage I patients alive at the end of the period compared to 53% of stage II, 25% of stage III and 17% of stage IV patients (Figure 1).
Discussion
ACC remains a rare tumour with a poor prognosis despite signifi- cant advancement in the understanding of its pathophysiology. An
| Variable | Response | n (%) | Univariable OR (95% CI) | P-value | Multivariable OR (95% CI) | P-value |
|---|---|---|---|---|---|---|
| En bloc | Yes | 25 (80.6) | 0.06 (0.01, 0.5) | 0.009 | 0.05 (0.002, 0.89) | 0.041 |
| No | 6 (19.4) | 1.00 (Ref) | 1.00 (Ref) | |||
| Mitotane | Yes | 18 (58.1) | 0.25 (0.04, 1.54) | 0.136 | 0.41 (0.03, 5.65) | 0.508 |
| No | 13 (41.9) | 1.00 (Ref) | ||||
| Radiotherapy | Yes | 7 (21.2) | 2.8 (0.36, 21.49) | 0.322 | 3.96 (0.29, 53.49) | 0.300 |
| No | 26 (78.8) | 1.00 (Ref) | 1.00 (Ref) | |||
| Lymphovascular | Yes | 14 (45.2) | 0.88 (0.16, 4.71) | 0.876 | 0.74 (0.06, 9.23) | 0.812 |
| No | 17 (54.8) | 1.00 (Ref) | ||||
| Blood loss+,# | 727 ± 664 | 0.85 (0.45, 1.63) | 0.632 | 1.41 (0.55, 3.65) | 0.477 | |
| Tumour size1 | 101 ± 51 | 0.99 (0.97, 1.01) | 0.513 | 0.99 (0.95, 1.03) | 0.470 |
1.00 (Ref) = Reference level.
*Continuous variable, mean + standard deviation are presented.
*Variable was log-transformed.
CI, confidence interval; OR, odds ratio.
| Volume of surgery | Blood loss (mL) | Op time (min) |
|---|---|---|
| >10 | 765 | 175 |
| 5-10 | 895 | 245 |
| <5 | 925 | 250 |
Kaplan-Meier survival estimates by stage
1.00
Proportion of Patients alive
0.75
0.50
0.25
0.00
0
50
Months
100
150
R0 resection margin remains the key factor in local recurrence (LR) and OS.2,5,8 R0 resection rates are associated with increased 5-year survival rates compared to R1 or R2 resections.3,8,9 R1 and R2 resection margins are associated with higher local recurrence rates with reported rates between 36% and 85%.10-12
Our current surgical practice is to perform an open en bloc approach with two consultants present when possible for suspected ACC cases with a very low threshold for multivisceral resection. The presence of two consultants increases operative experience in these rare tumours. The key operative principle is avoiding any dis- ruption of the tumour capsule which is often difficult to achieve in a laparoscopic approach. Apart from minimizing inadvertent capsu- lar breach, en bloc multivisceral resection also potentially reduces blood loss by devascularizing the tumour.
An open en bloc approach with a low threshold for multivisceral resection is critical in avoiding inadvertent capsular rupture, tumour seeding and positive margins.5 Multivisceral resection including nephrectomy, however, can be performed selectively where possi- ble, with no evidence for improved survival with potential increased morbidity or compromising adjuvant chemotherapy.13,14 In our series, an 85% R0 resection margin rate was obtained in an open en bloc approach with local recurrence rates of 11%. While there is conflicting data on outcomes, laparoscopic surgery is asso- ciated with higher recurrence rates in larger tumours.15-17 A laparo- scopic approach can be considered according to the European Society of Endocrinology guidelines in smaller tumours (<6 cm) if performed by high-volume surgeons.5,16 In our series, however, 66% of patients developed local recurrence when a laparoscopic approach was attempted. Other benefits of multivisceral resection are devascularization of the tumour with potential lower blood loss. Higher blood loss and transfusion rates are associated with higher
recurrence rates and lower OS.18 In our series, an open en bloc approach with multivisceral resection had lower average blood loss compared to a non-en bloc approach with only 33% requiring a blood transfusion.
When a large Australian series from NSW was analysed, volume of surgery (n > 10) was associated with better R0 resection margins and outcomes.9 We found that higher volume surgeons (>10 cases) achieved similar R0 resection margins compared to medium vol- ume surgeons (5-10 cases), but lower volume surgeons (<5 cases) had longer operative times and higher blood loss.
Hormonal hypersecretion is described in up to 75% of ACCs.3 Cortisol hypersecretion is most common, ranging from 23% to 50%, followed by DHEAS 9-19%, a combination and rarely aldo- sterone secreting only.10,19,20 A total of 65% of patients in our series presented with hypercortisolism, 25% with androgen excess and 12% a combination of both. The majority of patients had a pre- operative working diagnosis of ACC based on high PET SUV uptakes and CT characteristics. All patients had pre-operative CT scans with 90% of tumours having heterogeneity characteristic of necrosis with 60% irregular margins. PET-CT is advocated as a useful tool in differentiating malignant and benign adrenal lesions with a reported SUV max criteria of 2.3-4.04 and tumour SUVmax:liver SUVmax ratios >1.5.21-25 A pitfall is functional ade- nomas, however, where higher SUVmax values have been reported, particularly with cortisol producing adenomas.26,27 The majority of patients in our series with a pre-operative PET-CT scan (91%) had high SUV rates.
Despite a low local recurrence rate, many patients developed dis- tant metastasis and succumbed to their disease without local recur- rence. This dismal prognosis is due to the lack of effective adjuvant therapy despite significant advances in the genomics of ACC.28-33 Radiotherapy has been shown to reduce local recurrence34,35 but not OS and disease free survival and is recommended in R1 resec- tions or Rx resections with a high risk of recurrence.5 We found no effect on local recurrence in our series; however, the numbers treated with radiotherapy were small.
Mitotane, a derivative of dichlorodiphenyldichloroethane with adrenolytic and cytotoxic activity towards adrenal fasciculata and reticularis, remains a key adjuvant therapy.3º Mitotane is adminis- tered with a therapeutic target between 14 and 20 µg/L36 with close monitoring associated with improved compliance from 25% to 55%.37-40 In our series a single endocrinologist administered mitotane with regular monitoring, enhancing both local experience and treatment compliance. One patient of note has been on mitotane for 120 months. There is conflicting evidence, however, whether mitotane improves OS and recurrence free survival due to the qual- ity of studies and heterogeneity of data.38-41 Mitotane in our series improved OS by 5 months in stage III patients only.
Chemotherapy consisting of etoposide, doxorubicin and cisplatin with mitotane as demonstrated in the FIRM-ACT trial had better response rates than streptozocin and mitotane, but no significant differences in OS.42 A few stage IV patients in our series received a variety of chemotherapy regimens with mitotane without signifi- cant improvement in OS.
Recent biological advances in the understanding of microRNA dysregulation in ACC32 has identified this as a potential target for
anti-cancer therapy. This is reported being used in an experimental nanocell (EnGeneIC Delivery Vehicles), treatment in NSW.10 While further trials are necessary, survival in advanced ACC was reported up to 55 months from index operation. Other described novel therapies include targeted therapy such as insulin like growth
nists,45 gene therapy33 and monoclonal antibodies.46,47 Most of these novel therapies, however, have had disappointing results.
This paper is limited in its retrospective nature and small cohort of patients. The patients were also sourced retrospectively from a registry which relies on reporting by clinicians and pathologists where omissions and misclassifications can occur.
Conclusion
In summary, an R0 resection confers optimal outcome in avoiding local recurrence, which is best achieved by an open en bloc approach with a low threshold for multivisceral resection. Adjuvant therapy with mitotane should be administered with close monitor- ing of levels. Further studies are required for effective adjuvant therapy in ACC.
Acknowledgements
The authors thank respective clinicians for access to their files and data as well as Johnny Lo for assistance in statistical analysis.
Conflicts of interest
None declared.
References
1. Brennan MF. Adrenocortical carcinoma. CA Cancer J. Clin. 1987; 37: 348-65.
2. Bilimoria KY, Shen WT, Elaraj D et al. Adrenocortical carcinoma in the United States: treatment utilisation and prognostic factors. Cancer 2008; 113: 3130-6.
3. Sturgeon C. Endocrine Neoplasia. New York: Springer, 2010.
4. Datta J, Roses RE. Surgical management of adrenocortical carcinoma: an evidence-based approach. Surg. Oncol. Clin. N. Am. 2016; 25: 153-70.
5. Fassnacht M, Dekkers O, Else T et al. European Society of Endocrinol- ogy clinical practice guidelines on the management of adrenocortical carcinoma in adults, in collaboration with the European Network for the Study of Adrenal Tumors. Eur. J. Endocrinol. 2018; 4: 179: pii: EJE- 18-0608.
6. Fassnacht M, Hahner S, Polat B et al. Efficacy of adjuvant radiotherapy of the tumour bed on local recurrence of adrenocortical carcinoma. J. Clin. Endocrinol. Metab. 2006; 91: 4501-4.
7. Kendrick ML, Lloyd R, Erickson L et al. Adrenocortical carcinoma: surgical progress or status quo? Arch. Surg. 2001; 136: 543-9.
8. Schulick RD, Brennan MF. Long-term survival after complete resection and repeat resection in patients with adrenocortical carcinoma. Ann. Surg. Oncol. 1999; 6: 719-26.
9. Ip JC, Pang TC, Glover AR et al. Improving outcomes in adrenocortical cancer: an Australian perspective. Ann. Surg. Oncol. 2015; 22: 2309-16.
10. Kwok GTY, Zhao JT, Glover AR et al. Treatment and management of adrenal cancer in a specialised Australian endocrine surgical unit: approaches, outcomes and lessons learnt. ANZ J. Surg. 2019; 89: 48-52.
11. Pommier RF, Brennan MF. An eleven-year experience with adrenocor- tical carcinoma. Surgery 1992; 112: 963-70.
12. Amini N, Margonis GA, Kim Y et al. Curative resection of adrenocorti- cal carcinoma: rates and patterns of postoperative recurrence. Ann. Surg. Oncol. 2016; 23: 126-33.
13. Bellantone R, Ferrante A, Boscherini M et al. Role of reoperation in recurrence of adrenal cortical carcinoma: results from 188 cases col- lected in the Italian National Registry for adrenal cortical carcinoma. Surgery 1997; 122: 1212-8.
14. Marincola Smith P, Kiernan CM, Tran TB et al. Role of additional organ resection in adrenocortical carcinoma: analysis of 167 patients from the U.S. adrenocortical carcinoma database. Ann. Surg. Oncol. 2018; 25: 2308-15.
15. Miller BS, Gauger PG, Hammer GD, Doherty GM. Resection of adre- nocortical carcinoma is less complete and local recurrence occurs sooner and more often after laparoscopic adrenalectomy than after open adrenalectomy. Surgery 2012; 152: 1150-7.
16. Autorino R, Bove P, De Sio M et al. Open versus laparoscopic adrenal- ectomy for adrenocortical carcinoma: a meta-analysis surgical and oncological outcomes. Ann. Surg. Oncol. 2016; 23: 1195-202.
17. Huynh KT, Lee DY, Lau BJ, Flaherty DC, Lee JH, Goldfarb M. Impact of laparoscopic adrenalectomy on overall survival in patients with non- metastatic adrenocortical carcinoma. J. Am. Coll. Surg. 2016; 223: 485-92.
18. Poorman CE, Postlewait LM, Ethun CG et al. Blood transfusion and survival for resected adrenocortical carcinoma: a study from the United States adrenocortical carcinoma group. Am. Surg. 2017; 83: 761-8.
19. Kostiainen I, Hakaste L, Kejo P et al. Adrenocortical carcinoma: pre- sentation and outcome of a contemporary patient series. Endocrine 2019; 65: 166-74.
20. Poirier J, Alguire C, Olney HJ et al. 1 - A large retrospective series of adrenocortical carcinoma (ACC) in a Canadian referral Centre: ACC is frequently diagnosed in Young adults and at late stages. Can. J. Diabe- tes 2019; 43: S2-2.
21. Blake MA, Slattery JM, Kalra MK et al. Adrenal lesions: characterisa- tion with fused PET/CT image in patients with proved or suspected malignancy - initial experience. Radiology 2006; 238: 970-7.
22. Boland GW, Blake MA, Holalkere NS, Hahn PF. PET/CT for the char- acterisation of adrenal masses in patients with cancer: qualitative versus quantitative accuracy in 150 consecutive patients. AJR Am. J. Roentgenol. 2009; 192: 956-96.
23. Metser U, Miller E, Lerman H et al. 18F-FDG PET/CT in the evalua- tion of adrenal masses. J. Nucl. Med. 2006; 47: 32-7.
24. Guerin C, Pattou F, Brunaud L et al. Performance of 18F-FDG PET/CT in the characterisation of adrenal masses in noncancer patients: a pro- spective study. J. Clin. Endocrinol. Metab. 2017; 102: 2465-247.
25. Gust L, Taieb D, Beliard A et al. Preoperative 18F-FDG uptake is strongly correlated with malignancy, Weiss score, and molecular markers of aggressiveness in adrenal cortical tumors. World J. Surg. 2012; 36: 1406-10.
26. Akkus G, Güney IB, Ok F et al. Diagnostic efficacy of 18F-FDG PET/CT in patients with adrenal incidentaloma. Endocr. Connect. 2019; 8: 838-45.
27. Leboulleux S, Dromain C, Bonniaud G et al. Diagnostic and prognostic value of18-fluorodeoxyglucose positron emission tomography in adre- nocortical carcinoma: a prospective comparison with computed tomog- raphy. J. Clin. Endocrinol. Metab. 2006; 91: 920-5.
28. Assie G, Jouinot A, Bertherat J. The ‘omics’ of adrenocortical tumours for personalised medicine. Nat. Rev. Endocrinol. 2014; 10: 215-28.
29. Stigliano A, Cerquetti L, Lardo P, Petrangeli E, Toscano V. New insights and future perspectives in the therapeutic strategy of adrenocor- tical carcinoma (Review). Oncol. Rep. 2017; 37: 1301-11.
30. Soon PSH, Mcdonald KL, Robinson BG, Sidhu SB. Molecular markers and the pathogenesis of adrenocortical cancer. Oncologist 2008; 13: 548-61.
31. Sidhu S, Gicquel C, Bambach CP et al. Clinical and molecular aspects of adrenocortical tumourigenesis. ANZ J. Surg. 2003; 73: 727-38.
32. Glover AR, Ip J, Ting Zhao J et al. Current management options for recurrent adrenocortical carcinoma. Onco. Targets. Ther. 2013; 6: 635-43.
33. Tacon LJ, Prichard RS, Soon PSH, Robinson BG, Clifton-Bligh RJ, Sidhu SB. Current and emerging therapies for advanced adrenocortical carcinoma. Oncologist 2011; 16: 36-48.
34. Tierney JF, Chivukula SV, Poirier J et al. National treatment practice for adrenocortical carcinoma: have they changed and have we made any progress? J. Clin. Endocrinol. Metab. 2019; 104: 5948-56.
35. Gharzai LA, Green MD, Griffith KA et al. Adjuvant radiation improves recurrence-free survival and overall survival in adrenocortical carci- noma. J. Clin. Endocrinol. Metab. 2019; 104: 3743-50.
36. Sabolch A, Feng M, Griffith K, Hammer G, Doherty G, Ben-Josef E. Adjuvant and definitive radiotherapy for adrenocortical carcinoma. Int. J. Radiat. Oncol. Biol. Phys. 2011; 80: 1477-84.
37. Hermsen IG, Fassnacht M, Terzolo M et al. Plasma concentrations of o, p’DDD, o,p’DDA, and o,p’DDE as predictors of tumor response to mitotane in adrenocortical carcinoma: results of a retrospective ENS@T multicenter study. J. Clin. Endocrinol. Metab. 2011; 96: 1844-51.
38. Kerkhofs TM, Baudin E, Terzolo M et al. Comparison of two mitotane starting dose regimens in patients with advanced adrenocortical carci- noma. J. Clin. Endocrinol. Metab. 2013; 98: 4759-67.
39. Terzolo M, Baudin AE, Ardito A et al. Mitotane levels predict the out- come of patients with adrenocortical carcinoma treated adjuvantly fol- lowing radical resection. Eur. J. Endocrinol. 2013; 169: 263-70.
40. Baudin E, Pellegriti G, Bonnay M et al. Impact of monitoring plasma 1,1-dichlorodiphenildichloroethane (o,p’ddd) levels on the treatment of patients with adrenocortical carcinoma. Cancer 2001; 92: 1385-92.
41. Postlewait LM, Ethun CG, Tran TB et al. Outcomes of adjuvant mitotane after resection of adrenocortical carcinoma: a 13-institution study by the US adrenocortical carcinoma group. J. Am. Coll. Surg. 2016; 222: 480-90.
42. Fassnacht M, Terzolo M, Allolio B et al. Combination chemotherapy in advanced adrenocortical carcinoma. N. Engl. J. Med. 2012; 366: 2189-97.
43. Fassnacht M, Berruti A, Baudin E et al. Linsitinib (OSI-906) versus placebo for patients with locally advanced or metastatic adrenocortical carcinoma: a double- blind, randomised, phase 3 study. Lancet Oncol. 2015; 16: 426-35.
44. Samnotra V, Vassilopoulou-Sellin R, Fojo AT. A phase II trial of gefitinib monotherapy in patients with unresectable adrenocortical carci- noma (ACC). J. Clin. Oncol. 2007; 25: 20.
45. Betz MJ, Shapiro I, Fassnacht M et al. German and Austrian adrenal network: peroxisome proliferator-activated receptor-y agonists suppress adrenocortical tumor cell proliferation and induce differentiation. J. Clin. Endocrinol. Metab. 2005; 90: 3886-96.
46. Haluska P, Worden F, Olmos D et al. Safety, tolerability, and pharma- cokinetics of the anti-IGF-1R monoclonal antibody figitumumab in patients with refractory adrenocortical carcinoma. Cancer Chemother. Pharmacol. 2010; 65: 765-73.
47. Habra MA, Stephen B, Campbell M et al. Phase II clinical trial of pembrolizumab efficacy and safety in advanced adrenocortical carci- noma. J. Immunother. Cancer 2019; 7: 253.
Supporting information
Additional Supporting Information may be found in the online ver- sion of this article at the publisher’s web-site:
Appendix S1. Supporting information