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Adrenocortical Carcinoma: a Therapeutic Challenge - 44 Cases from a Single Tertiary Care Center in India
Shawn Sam Thomas1 . Arundhati Marathe1 . Anish Jacob Cherian1 . N Siddhartha1 . Gowri Mahasampath2 . Manipadam Marie Therese3 . Chandramohan Jagan3 . Hesarghatta Shyamasunder Asha4 . Nihal Thomas4 .
Ashish Singh5 . B Selvamani6 . Mazhuvanchary Jacob Paul1 . Deepak Thomas Abraham1
Received: 23 October 2020 / Accepted: 1 September 2021 /Published online: 13 September 2021 @ Indian Association of Surgical Oncology 2021
Abstract
This study was conducted among patients with adrenocortical carcinoma (ACC) to analyze their clinico-pathological profile, management outcomes, and risk factors for local recurrence, systemic metastasis, and survival. The data of patients with ACC who were managed at a single institution between January 2004 and December 2016 was retrospectively collected and analyzed using STATA 13.1. Forty-four patients with a diagnosis of ACC were included in the study. The mean age at presentation was 38.5±14.6 (9-74) with a male preponderance. Functioning tumors represented 59.1% (n=26), cortisol being the most common hormone secreted. Forty patients (90.9%) underwent surgery, 14 (35%) of whom required an en bloc resection of adjacent organs. Fifteen (37.5%) received radiation (RT) to the postoperative bed while chemotherapy and mitotane were administered in 12 (27.3%) and 9 (20.5%) respectively. The mean follow-up was 34.3 +32.7 months. Twelve (30%) patients developed local recurrence, 21 (55.3%) had systemic metastasis, and 15 (34.1%) expired. The mean 1-year and 5-year overall survival rates were 77% and 65.7% respectively. On multivariate analysis, patients with ENSAT stage III/IV were significantly associated with local recurrence (p=0.011) and metastasis (p=0.037). Age>50 (p=0.003) and ENSAT III/IV (p=0.017) were significantly associated with mortality on univariate analysis but not on multivariate analysis. In our study population, patients presented at a younger age with a male preponderance. Ninety percent underwent surgery, a subset (35%) requiring resection of adjacent organs to ensure R0 resection. Patients presenting at ENSAT stage I/II have better outcomes.
Keywords Adrenocortical carcinoma (ACC) . Surgery for ACC . Mitotane in ACC . Chemotherapy in ACC . Radiation therapy (RT) in ACC
☒ Deepak Thomas Abraham abrahamdt@gmail.com
1 Department of Endocrine Surgery, Christian Medical College, Paul Brand Building, 2nd floor, Vellore, Tamil Nadu 632004, India
2 Department of Biostatistics, Christian Medical College, Vellore, Tamil Nadu, India
3 Department of General Pathology, Christian Medical College, Vellore, Tamil Nadu, India
4 Department of Endocrinology, Christian Medical College, Vellore, Tamil Nadu, India
5 Department of Medical Oncology, Christian Medical College, Vellore, Tamil Nadu, India
6 Department of Radiation Oncology, Christian Medical College, Vellore, Tamil Nadu, India
Introduction
Adrenocortical carcinoma (ACC) is a rare tumor with an incidence of 0.5-2 cases per million population per year and a prevalence of 4-12 cases per million per year [1-3]. There is a bimodal age presentation, peaks being described in early childhood and the fourth to fifth decade of life, women being more frequently affected (55-60%) [4, 5]. The majority (40-60%) present with symptoms secondary to an excess of adrenocortical hormone secretion, making them functional tumors, a subset (20-30%) present with symp- toms of abdominal mass effect while the minority (15-20%) are incidentally detected [6-8]. Contrast-enhanced comput- erized tomography (CECT) of the thorax, abdomen, and pelvis and positron emission tomography (PET) are utilized for the assessment of resectability as well as in the process
of staging the disease. Surgery is the only curative therapy for patients with nonmetastatic resectable tumors while adjuvant therapy if administered is targeted at decreasing the risk of recurrence. The treatment for unresectable or metastatic tumors is palliative. ACC’s are a highly aggres- sive malignancy with a reported 5-year overall survival rate under 40% in most series [9-12]. Though the clinical char- acteristics, treatment modalities, and survival outcomes for patients with ACC have been reported, there are only two academic institutional reports from India [13, 14]. Interest- ingly, the clinical presentation and the treatment outcomes in both these studies differ from other reports in terms of male preponderance, advanced stage at presentation, and a lower rate of overall survival. Therefore, we conducted this analysis to perceptionalize the clinico-pathological profile, surgical outcomes, and the risk factors for local recurrence and survival among patients being managed for ACC at a tertiary care hospital in India.
Materials and Methods
Patients who had been diagnosed with ACC and managed at our institution between January 2004 and December 2016 were analyzed retrospectively. Their demographics, clinical presentation, hormonal profile, details of surgical procedure, adjuvant therapy, and outcomes were obtained from the computerized hospital information system. The diagnosis of ACC was based on postoperative histopathol- ogy in patients who had undergone surgery while among those who had not been operated either a core biopsy from the adrenal lesion or from the metastatic site was performed to confirm the diagnosis. The histopathological criteria for the diagnosis of ACC were based on Aubert’s modification of Weiss scoring system, and a score of> 3 was considered to be malignant [1].
Protocol for Evaluation and Management of an Adrenal Lesion (Fig. 1)
The measurement of aldosterone and renin has been intro- duced in our protocol in the last 3-4 years, while DHEAS and cortisol measurement has been routine in evaluation of adrenal tumors through the study period. The Euro- pean Network for the Study of Adrenal Tumors (ENSAT) staging system was used to stage the disease. From 2004 to 2012, Cisplatin/Carboplatin + Etoposide regimen was used for chemotherapy and then changed to Etoposide, Doxorubicin, and Cisplatin (EDP) from 2013 onwards. The response to chemotherapy and mitotane was defined as regression, stable disease, or progression as per the CECT report following therapy compared to the pre-ther- apy CECT findings. Patients who had defaulted from their
regular follow-up were contacted telephonically to enquire about their current health status.
Statistical Analysis
The statistical analysis was performed using STATA 13.1. Frequencies and percentages were reported for categorical variables. Fisher’s exact test or chi2 test was used to evaluate the association between two categorical variables. A survival analysis was performed using the Kaplan-Meier method. The log-rank test was used to evaluate differences in the endpoints between patient groups. p values <0.05 were con- sidered significant.
Results
Forty-four patients were diagnosed and managed for ACC during the study period. Forty-one were adults while there were three children aged 9, 12, and 14 years (Table 1). The site of metastasis among six patients with stage IV disease at presentation was lung in five and bone in one. Forty (90.9%) patients underwent surgery among which 38 were non- met- astatic while two had oligometastatic disease. In view of dis- seminated disease, surgery was not offered to four patients.
Surgery and Histopathology (Table 2)
Laparoscopic attempt was converted to an open procedure in one as the tumor appeared highly vascular. Among the patients who underwent en bloc resection, the histopatho- logical examination revealed infiltration by the tumor into the adjacent organs in only one. Four patients presented to us after being operated at other centers; hence, their resec- tion status was not clear as their complete operative details were not available.
Adjuvant Treatment
Fifteen (37.5%) patients received RT to the operative bed. RT was administered as adjuvant therapy following surgery in ten, in view of R1 disease in three, for a recurrent tumor in one and for intraoperative tumor spillage in one patient. The techniques adapted were convention in six, 3D conformal RT in four, intensity modulated radiation therapy (IMRT) in three, and unknown in two as they received RT elsewhere. The dose planned was based on resection status and dose to organs at risk (OAR) ranging between 45 and 54 Gy. One patient defaulted treatment at 36 Gy while all the oth- ers completed the intended dose. Among the patients who received RT, three patients (20%) developed a local recur- rence on follow-up. Chemotherapy was administered in 12 (27.3%), five receiving chemotherapy as an adjuvant form of
Suspected adrenal pathology on history and examination
Imaging: for localization and assessment of operability
Functional assessment:
1. 24-hour urinary metanephrine and normetanephrine
CECT: modality of choice
2. 8 am serum cortisol
MRI: Patients in whom CECT detected a doubtful infiltration into the liver or IVC or in whom liver metastasis was suspected
3. 24-hour urinary cortisol
4. Overnight dexamethasone suppression test
5. Plasma adrenocorticotrophic hormones (ACTH)
6. Plasma renin and aldosterone
PET: considered for patients who were suspected to have an ACC
7. Serum dehydroepiandrosterone sulphate (DHEAS)
8. Serum sodium and potassium
Nonmetastatic/oligometastatic and resectable - primary resection
Metastatic disease- systemic therapy with three monthly re-assessment
The need for adjuvant treatment (RT to postoperative bed, adjuvant systemic therapy with mitotane and chemotherapy) was individualized through a multidisciplinary team meeting
Follow up: Three monthly intervals for the first year, six monthly intervals for the next two years and subsequently on an annual basis
therapy following surgery, in six, it was administered for the therapy of metastatic disease that was detected on follow- up while in the remaining patient, the intent was palliative as he had disseminated disease at presentation. Systemic disease progressed in four (33.3%) despite chemotherapy; however, regression was seen in three patients (25%) and the disease remained stable in five (41.7%). Targeted ther- apy with pazopanib was tried in two patients, both having metastatic disease; however, in both patients, the extent of the disease continued to worsen. Nine (20.5%) patients received mitotane among whom six were those who had received chemotherapy as well. Mitotane was administered as an adjuvant therapy in five, while in two patients, it was given for metastatic disease detected on follow-up. Mitotane was also given to two patients in whom surgery was not performed in view of disseminated metastasis at presenta- tion. Among the patients who received mitotane, six (66.7%) progressed, two (22.2%) had stable disease, and one (11.1%) regressed. The use of mitotane was limited in most cases because of the difficulty in procuring it since it is not freely available and also because of the high cost of mitotane. Each 500 mg of mitotane cost approximately INR 480/USD 6.4
and the daily dosage ranges from 9 to 16 g in divided doses - restricting its usage to the most affordable or the upper middle class.
Local Recurrence and Systemic Metastasis
Twelve (30%) patients developed a local recurrence on follow-up, five of whom had systemic disease as well and hence were given best palliative supportive care alone. Among the remaining seven patients, four were surgically managed while three received chemotherapy (EDP) along with mitotane. The mean time to local recurrence was 24.8 ±20.3 months (4-43 months). Patients with ENSAT stage III/IV were associated with local recurrence on univar- iate (p=0.015) as well as multivariate analysis (p=0.011) (Table 3 and Fig. 2).
Among the thirty-eight patients who were non meta- static at presentation, systemic metastasis was detected in 21 patients (55.3%) on follow-up. The site of metastasis included the lung (8), liver (6), omentum/peritoneum (2), bone (1), and multiple sites (4) in the remaining patients. Three patients underwent excision of a solitary metastasis,
| Characteristic | n (%) |
|---|---|
| 1. Age: mean (range) | 38.5±14.6 (9-74) |
| Excluding children: mean (range) | 40.5±13.1 (22-74) |
| 2. Gender (M:F) | 26:18 |
| 3. Presentation | |
| a. Functional | 26 (59.1%) |
| b. Abdominal pain/mass | 20 (45.5%) |
| c. Incidental | 4 (9.1%) |
| 4. Type of hyperfunction (n=26) | |
| a. Exclusively Cushing's | 14 (53.8%) |
| b. Androgen excess + Cushing's | 5 (19.2%) |
| c. Androgen excess | 4 (15.4%) |
| d. Hyperaldosteronism | 3 (11.5%) |
| 5. Duration of presenting symptom: mean (range) | 12.3 (2-72 months) |
| 6. Elevated DHEAS | 16 (36.5%) |
| 7. Laterality | |
| a. Left adrenal | 25 (57%) |
| b. Right adrenal | 19 (43%) |
| 8. Feature on CECT (n=38) | |
| a. Central necrosis | 16 (43%) |
| b. Central necrosis + vascularity | 15 (40.5%) |
| c. Vascular thrombus | 5 (12.5%) |
| d. Intra-tumoral calcification | 2 (4.5%) |
| 9. ENSAT staging | |
| a. Stage I | 2 (4.6%) |
| b. Stage II | 26 (59.1%) |
| c. Stage III | 10 (22.7%) |
| d. Stage IV | 6 (13.6%) |
one each from lung, ovary, and liver resulting in a survival of 18, 21, and 65 months respectively following excision. Significant risk factors for systemic metastasis on univari- ate analysis included male gender (p=0.05) and ENSAT stage III/IV (p=0.034); however, only ENSAT stage III/ IV persisted to be significant (p=0.037) on multivariate analysis (Table 4 and Fig. 3).
Survival
Seven patients defaulted from review while 15 (34.1%) expired during the study period. The mean duration of follow-up was 34.3 + 32.7 months. The median overall sur- vival was 29.5 months with 1- and 5-year overall survival rates of 76.9% and 65.7%. The 1- and 5-year disease-free survival rates were 91.9% and 52.1%. The longest surviv- ing patient is still alive after 120 months (Fig. 4). Age>50 (p=0.003), ENSAT stage III/IV (p=0.017), and resec- tion status (p=0.05) were significantly associated with
mortality on univariate analysis but not on multivariate analysis (Table 5).
Discussion
We report a series of 44 patients who were diagnosed and managed for ACC from a tertiary care center in India. In contrast to reports from high-income countries, we found a male preponderance with an earlier age at presentation [3, 5, 6, 15, 16]. In comparison with another Indian study, though the gender disparity was similar, the age at presentation in this cohort was earlier [14]. Being a tertiary referral center in a lower-middle income country, we attribute the male preponderance to be related to a referral bias and the health- seeking behavior of patients from this region. The clinical presentation was similar to that reported in literature with the majority (60%) being functional, with cortisol the most common hypersecreted hormone, while 9.1% presented as an adrenal incidentaloma [3, 7, 10, 13]. The prognosis of ACC depends on the stage of the disease at presentation, patients with metastatic disease performing poorly. Delayed presen- tation with advanced disease has been commonly reported from low-middle income countries; however, unlike the two other reports from India where the majority of patients (58% and 46%) presented at stage 4, only 13.6% of patients in this cohort presented with systemic metastasis [13, 14]. This was an encouraging finding as it depicted a trend towards earlier detection of tumors for whom treatment with a cura- tive intent may be offered and is keeping with rates reported from countries with better equipped healthcare systems [7, 12, 17, 18].
Surgery and Local Recurrence
Complete surgical excision is the only approach that has been found to be curative for localized disease [6, 7, 12, 16]. In up to 25%, en bloc excision of adja- cent organs may be required for suspected infiltration of adjacent organs or to avoid capsular damage so as to accomplish R0 resection [3, 18, 19]. In addition, a tumor thrombus in the adrenal vein, renal vein, or inferior vena cava (IVC) may be present in up to 25% of patients and multivisceral resection would permit safer vascular access as well as aid in thrombectomy [7, 16, 19]. En bloc excision was necessary in 35% in this cohort. Despite complete excision, local recurrence has been reported in 20-40% of patients on follow-up [17, 20-22]. The factors associated with a higher risk of local recurrence include tumor size, advanced ENSAT stage at presentation, positive surgical margin, intra- operative tumor spillage, Ki67 index, Weiss score, and laparoscopic approach [3, 12, 18, 19, 23-26]. As all
| Variable | n (%) |
|---|---|
| Surgical details | |
| 1. Surgical approach | 40 |
| a. Open trans-peritoneal | 39 (97.5%) |
| b. Laparoscopic trans-peritoneal-converted to an open | 1 (2.5%) |
| 2. En bloc resection | 14 (35%) |
| a. Compartment excision (adrenalectomy + nephrectomy + splenec- | 4 (28.6%) |
| tomy + excision of tail of pancreas) | |
| b. Nephrectomy | 7 (50%) |
| c. Splenectomy | 3 (21.4%) |
| 3. Resection status | 36 |
| a. R0 | 31 (86.1%) |
| b. R1 | 4 (11.1%) |
| c. R2 | 1 (2.8%) |
| 4. Intraoperative spillage | 8 (22.2%) |
| 5. Tumor thrombectomy (adrenal vein, renal vein, or inferior vena cava) | 6 (15%) |
| Histopathology | |
| 1. Mean tumor size (range) | 12.8±5.1 cm (3-25) |
| 2. Mean tumor weight (range) | 614.8±604.2 g(10-2800) |
| 3. Capsular invasion | 15 (45%) |
| 4. Vascular invasion | 8 (20%) |
| 5. Median modified Weiss score (range) | 4 (3-7) |
patients had undergone an open surgery and Ki67 was not performed in the majority, these two risk factors were not assessed in this study. Among the remain- ing factors that were evaluated, ENSAT stage III/IV was the only significant (p = 0.015) variable associ- ated with local recurrence. With regard to tumor size, it was interesting to note that though a 8-cm size cut off was not significant (p=0.369), when the risk was re-analyzed with a 10-cm size cut off, it reached near significance (0.05), indicating that large tumors may be at a greater risk for local recurrence.
Role of RT
Postoperative RT to the tumor bed provides no addi- tional survival benefit; however, its effect on local recurrence rates has been conflicting. Fassnacht and Polat et al. have depicted lower recurrence rates fol- lowing RT while Habra and Sabolch et al. have shown no such response in their patients [27-30]. The Ger- man study group recommends RT for patients who have undergone R1/R2 resection, in those patients in whom the resection margin status is unknown, patients with stage III disease, and those with tumors > 8 cm in size or with a Ki67 index > 10% even if they have under- gone a R0 resection [28]. Therefore, the role of RT in the management of ACC is debatable. Among the
15 patients who had received adjuvant RT to the post- operative bed in this cohort, only 3 (20%) developed local recurrence. Though this figure seems promising, univariate analysis revealed no significant decrease in local recurrence rates (p=0.23) among patients who received RT; however, the number of patients receiving
| Risk factor | Univariate analysis | Multivari- ate analysis p value | ||
|---|---|---|---|---|
| HR | 95% CI | p value | ||
| Male gender | 0.68 | 0.19, 2.34 | 0.54 | - |
| Functional tumors | 1.30 | 0.38, 4.45 | 0.68 | - |
| Tumor size> 10 cm | 0.31 | 0.09, 1.08 | 0.055 | 0.087 |
| ENSAT* stage III/IV | 7.14 | 1.46, 34.92 | 0.015 | 0.011 |
| Resection status R1/R2 | 1.05 | 0.13, 8.44 | 0.96 | - |
| Intra-op tumor spillage | 2.81 | 0.66, 11.97 | 0.16 | - |
| Presence of capsular inva- sion | 0.76 | 0.20, 2.89 | 0.69 | - |
| Presence of vascular inva- sion | 2.31 | 0.42, 12.67 | 0.34 | - |
| Modified Weiss score >4 | 2.45 | 0.53, 11.38 | 0.25 | - |
| Postoperative RT to tumor bed (yes vs no) | 0.45 | 0.12, 1.66 | 0.23 | - |
| Chemotherapy (yes vs no) | 1.44 | 0.44, 4.71 | 0.55 | - |
“European Network for the Study of Adrenal Tumors
1.00
.
0.75
0.50
0.25
0.00
0
50
analysis time
100
150
ENSAT Stage I/ II
ENSAT Stage III/ IV
RT was relatively small, thereby statistical significance may be difficult to conclusively establish.
Systemic Therapy
There has been progress world over with regard to sys- temic therapy for ACC. Currently, mitotane and multid- rug chemotherapy with EDP are the most commonly used agents. Although significant improvement in overall sur- vival as well as disease-free survival has been depicted with mitotane, there are reports that contest this [7, 31-37]. The reported partial response/stable disease rate
| Risk factor | Univariate analysis | Multivari- ate analysis p value | ||
|---|---|---|---|---|
| HR | 95% CI | p value | ||
| Age>50 years | 3.15 | 0.58, 17.03 | 0.18 | - |
| Male gender | 5.02 | 0.95, 26.5 | 0.05 | 0.67 |
| Functional tumors | 1.93 | 0.38, 9.67 | 0.42 | - |
| Tumor size > 10 cm | 2.81 | 0.56, 14.0 | 0.21 | - |
| ENSAT* stage III/IV | 10.46 | 1.19, 91.93 | 0.034 | 0.037 |
| Resection status R1/R2 | 2.13 | 0.23, 19.36 | 0.50 | - |
| Presence of capsular invasion | 3.99 | 0.86, 18.62 | 0.08 | - |
| Modified Weiss score >4 | 0.64 | 0.15, 2.63 | 0.53 | - |
| Postoperative RT to tumor bed (no vs yes) | 2.58 | 0.57, 11.74 | 0.22 | - |
| Chemotherapy (no vs yes) | 0.35 | 0.69, 1.77 | 0.20 | - |
European Network for the Study of Adrenal Tumors
following treatment with mitotane is 30% [6, 7]. In keep- ing with this finding, among the nine (20.5%) patients in whom mitotane was used in this cohort, stable disease/ regression was observed in 33.3%. The overall reported response to chemotherapy has been more encouraging with 20-30% showing regression while this rate improves to 50% when stable responders are included [7]. How- ever, this response has been shown to be short lived, 6-18 months [7]. In our cohort, chemotherapy was admin- istered in 12 (27.3%) patients, stable disease/regression being observed in 66.7%.
Systemic Metastasis and Overall Survival
ACC is an aggressive disease; systemic metastasis on fol- low-up is seen in 40-65% with most series reporting 35-40% mortality [12, 17, 18, 23, 25, 38]. The reported 5-year overall survival is 20-45% with patients in stage I and II surviving significantly longer [6, 12, 39, 40]. Similar outcomes were seen in this cohort, 55.3% developing systemic metastasis on follow-up with a mortality of 34%. Patients presenting in ENSAT stage III/IV were significantly associated (p=0.037) with the development of systemic metastasis. Reported fac- tors affecting overall survival include advanced stage at pres- entation, older age, functioning tumors, high Ki67 index, resection status, tumor size, and adjuvant treatment [6, 8, 12, 17, 18, 23, 25, 38, 41, 42]. In this cohort, only age> 50 (p=0.003) and ENSAT stage III/IV (p=0.017) were sig- nificantly associated with mortality on univariate analysis; however, these were not significant on multivariate analysis.
1.00
0.75
0.50
0.25
0.00
0
50
analysis time
100
150
ENSAT Stage I/ II
ENSAT Stage III/ IV
The higher 5-year overall survival rate (65.7%) seen in this cohort could be attributed to the majority (64%) presenting in stage I/II.
Limitation
We acknowledge the retrospective nature of this study with its inherent flaws as a limitation. The biochemical evalu- ation of adrenal tumors has evolved in the last few years and extensive bio-chemical evaluation including renin and aldosterone as being currently done was not performed for
the patients in the earlier part of the study. The number of patients who received adjuvant therapy was relatively small and may not be sufficient to establish significance.
Conclusion
Contrary to the reported clinical profile, we observed a younger age at presentation with a male preponderance in our population. A subset requires resection of adjacent organs to ensure R0 resection or to permit safer vascular
1.00
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analysis time
| Risk factor | Univariate analysis | Multivari- ate analysis p value | ||
|---|---|---|---|---|
| HR | 95% CI | p value | ||
| Age>50 | 5.05 | 1.75, 14.61 | 0.003 | 0.16 |
| Male gender | 1.68 | 0.61, 4.67 | 0.32 | - |
| Functional tumors | 1.44 | 0.47, 4.37 | 0.52 | - |
| Tumor size> 10 cm | 1.13 | 0.38, 3.38 | 0.83 | - |
| ENSAT* stage III/IV | 3.99 | 1.29, 12.39 | 0.017 | 0.56 |
| Resection status R1/R2 | 4.20 | 1.00, 17.67 | 0.05 | 0.09 |
| Intra-op tumor spillage | 2.13 | 0.50, 8.95 | 0.30 | - |
| Presence of capsular inva- sion | 2.40 | 0.75, 7.64 | 0.14 | - |
| Presence of vascular inva- sion | 2.92 | 0.78, 10.91 | 0.11 | - |
| Modified Weiss score >4 | 0.89 | 0.24, 3.25 | 0.86 | - |
| Postoperative RT to tumor bed (no vs yes) | 0.84 | 0.26, 2.68 | 0.77 | - |
| Chemotherapy (no vs yes) | 0.43 | 0.12, 1.61 | 0.21 | - |
| Mitotane (no vs yes) | 0.99 | 0.27, 3.6 | 0.99 | - |
*European Network for the Study of Adrenal Tumors
access and aid in tumor thrombectomy. Advanced stage at presentation (ENSAT stage III/IV) is significantly associated with the development of local recurrence (p=0.011) and systemic metastasis (p=0.037). In addition, a large tumor size (> 10 cm) may predispose to local recurrence. Neither RT to the operative bed nor chemotherapy showed a statisti- cal significance in reducing local recurrence in this study.
Declarations
Ethics Approval The study was approved by the institutional review board - IRB Min No. 13090 (retro) dated 24.06.2020.
Consent to Participate Informed consent was obtained from all indi- vidual participants included in the study.
Consent to Publish Consent was obtained from all participants to publish. All the authors have seen and approved the final version of the manuscript and all authors fulfill the COPE requirements for authorship.
Conflict of Interest The authors declare no competing interests.
References
1. Aubert S, Wacrenier A, Leroy X et al (2002) Weiss system revisited: a clinicopathologic and immunohistochemical study of 49 adrenocortical tumors. Am J Surg Pathol 26:1612-1619. https://doi.org/10.1097/00000478-200212000-00009
2. Wooten MD, King DK (1993) Adrenal cortical carcinoma. Epi- demiology and treatment with mitotane and a review of the
literature. Cancer 72:3145-3155. https://doi.org/10.1002/1097- 0142(19931201)72:11%3c3145 :: aid-cncr2820721105%3e3.0. co;2-n
3. Almeida MQ, Bezerra-Neto JE, Mendonça BB et al (2018) Primary malignant tumors of the adrenal glands. Clinics (Sao Paulo) 73:e756s. https://doi.org/10.6061/clinics/2018/e756s
4. Sharma E, Dahal S, Sharma P, et al (2018) The characteristics and trends in adrenocortical carcinoma: a United States popula- tion based study. J Clin Med Res 10:636-640. https://doi.org/ 10.14740/jocmr3503w
5. Kebebew E, Reiff E, Duh Q-Y et al (2006) Extent of disease at presentation and outcome for adrenocortical carcinoma: have we made progress? World J Surg 30:872-878. https://doi.org/ 10.1007/s00268-005-0329-x
6. Allolio B, Fassnacht M (2006) Clinical review: adrenocortical carcinoma: clinical update. J Clin Endocrinol Metab 91:2027- 2037. https://doi.org/10.1210/jc.2005-2639
7. Else T, Kim AC, Sabolch A et al (2014) Adrenocortical car- cinoma. Endocr Rev 35:282-326. https://doi.org/10.1210/er. 2013-1029
8. Libé R (2015) Adrenocortical carcinoma (ACC): diagnosis, prognosis, and treatment. Front Cell Dev Biol 3 :. https://doi. org/10.3389/fcell.2015.00045
9. Wängberg B, Khorram-Manesh A, Jansson S et al (2010) The long-term survival in adrenocortical carcinoma with active sur- gical management and use of monitored mitotane. Endocr Relat Cancer 17:265-272. https://doi.org/10.1677/ERC-09-0190
10. Jouinot A, Bertherat J (2018) Management of endocrine dis- ease: adrenocortical carcinoma: differentiating the good from the poor prognosis tumors. Eur J Endocrinol 178:R215-R230. https://doi.org/10.1530/EJE-18-0027
11. Icard P, Goudet P, Charpenay C et al (2001) Adrenocortical carcinomas: surgical trends and results of a 253-patient series from the French Association of Endocrine Surgeons study group. World J Surg 25:891-897. https://doi.org/10.1007/ s00268-001-0047-y
12. Ayala-Ramirez M, Jasim S, Feng L et al (2013) Adrenocortical carcinoma: clinical outcomes and prognosis of 330 patients at a tertiary care center. Eur J Endocrinol 169:891-899. https://doi. org/10.1530/EJE-13-0519
13. Sabaretnam M, Mishra A, Agarwal G et al (2016) Adrenocortical carcinoma in children and adults: two decades experience in a single institution. Indian J Cancer 53:317. https://doi.org/10.4103/ 0019-509X.197737
14. Nair LM, Jagathnath Krishna KM, Kumar A et al (2019) Clinico- pathological features and outcomes of adrenocortical carcinoma: a single institution experience. Indian J Urol 35:213-217. https:// doi.org/10.4103/iju.IJU_19_19
15. Choi YM, Kwon H, Jeon MJ et al (2016) Clinicopathological features associated with the prognosis of patients with adrenal cortical carcinoma: usefulness of the Ki-67 index. Medicine (Baltimore) 95:e3736. https://doi.org/10.1097/MD.0000000000 003736
16. Mihai R (2015) Diagnosis, treatment and outcome of adrenocor- tical cancer. Br J Surg 102:291-306. https://doi.org/10.1002/bjs. 9743
17. Guelho D, Paiva I, Vieira A, Carrilho F (2016) Adrenocortical carcinoma: retrospective analysis of the last 22 years. Endocrinol Nutr 63:212-219. https://doi.org/10.1016/j.endonu.2015.12.009
18. Kostiainen I, Hakaste L, Kejo P et al (2019) Adrenocorti- cal carcinoma: presentation and outcome of a contemporary patient series. Endocrine 65:166-174. https://doi.org/10.1007/ s12020-019-01918-9
19. Gaujoux S, Mihai R, joint working group of ESES and ENSAT (2017) European Society of Endocrine Surgeons (ESES) and
European Network for the Study of Adrenal Tumours (ENSAT) recommendations for the surgical management of adrenocortical carcinoma. Br J Surg 104:358-376. https://doi.org/10.1002/bjs. 10414
20. Gonzalez RJ, Tamm EP, Ng C, et al (2007) Response to mitotane predicts outcome in patients with recurrent adrenal cortical car- cinoma. Surgery 142:867-875; discussion 867-875. https://doi. org/10.1016/j.surg.2007.09.006
21. Bellantone R, Ferrante A, Boscherini M et al (1997) Role of reop- eration in recurrence of adrenal cortical carcinoma: results from 188 cases collected in the Italian National Registry for Adrenal Cortical Carcinoma. Surgery 122:1212-1218. https://doi.org/10. 1016/S0039-6060(97)90229-4
22. Icard P, Chapuis Y, Andreassian B et al (1992) Adrenocortical carcinoma in surgically treated patients: a retrospective study on 156 cases by the French Association of Endocrine Surgery. Sur- gery 112:972-979 (discussion 979-980)
23. Scollo C, Russo M, Trovato MA, et al (2016) Prognostic factors for adrenocortical carcinoma outcomes. Front Endocrinol (Laus- anne) 7 :. https://doi.org/10.3389/fendo.2016.00099
24. Fassnacht M, Kroiss M, Allolio B (2013) Update in adrenocortical carcinoma. J Clin Endocrinol Metab 98:4551-4564. https://doi. org/10.1210/jc.2013-3020
25. Kim Y, Margonis GA, Prescott JD et al (2016) Nomograms to pre- dict recurrence-free and overall survival after curative resection of adrenocortical carcinoma. JAMA Surg 151:365-373. https:// doi.org/10.1001/jamasurg.2015.4516
26. Beuschlein F, Weigel J, Saeger W et al (2015) Major prognostic role of Ki67 in localized adrenocortical carcinoma after complete resection. J Clin Endocrinol Metab 100:841-849. https://doi.org/ 10.1210/jc.2014-3182
27. Fassnacht M, Hahner S, Polat B et al (2006) Efficacy of adjuvant radiotherapy of the tumor bed on local recurrence of adrenocorti- cal carcinoma. J Clin Endocrinol Metab 91:4501-4504. https:// doi.org/10.1210/jc.2006-1007
28. Polat B, Fassnacht M, Pfreundner L et al (2009) Radiotherapy in adrenocortical carcinoma. Cancer 115:2816-2823. https://doi.org/ 10.1002/cncr.24331
29. Habra MA, Ejaz S, Feng L et al (2013) A retrospective cohort analysis of the efficacy of adjuvant radiotherapy after primary surgical resection in patients with adrenocortical carcinoma. J Clin Endocrinol Metab 98:192-197. https://doi.org/10.1210/jc. 2012-2367
30. Sabolch A, Feng M, Griffith K, et al (2011) Adjuvant and defini- tive radiotherapy for adrenocortical carcinoma. International Journal of Radiation Oncology*Biology*Physics 80:1477-1484. https://doi.org/10.1016/j.ijrobp.2010.04.030
31. Nowak KM, Samsel R, Cichocki A et al (2018) Prognostic factors in adrenocortical carcinoma: data from a large Polish series. Pol- ish Archives of Internal Medicine 128:371-378. https://doi.org/ 10.20452/pamw.4260
32. Terzolo M, Angeli A, Fassnacht M et al (2007) Adjuvant mitotane treatment for adrenocortical carcinoma. N Engl J Med 356:2372- 2380. https://doi.org/10.1056/NEJMoa063360
33. Strosberg JR (2013) Update on the management of unusual neu- roendocrine tumors: pheochromocytoma and paraganglioma, medullary thyroid cancer and adrenocortical carcinoma. Semin Oncol 40:120-133. https://doi.org/10.1053/j.seminoncol.2012.11. 009
34. Calabrese A, Basile V, Puglisi S et al (2019) Adjuvant mitotane therapy is beneficial in non-metastatic adrenocortical carcinoma at high risk of recurrence. Eur J Endocrinol 180:387-396. https:// doi.org/10.1530/EJE-18-0923
35. Postlewait LM, Ethun CG, Tran TB et al (2016) Outcomes of adjuvant mitotane after resection of adrenocortical carcinoma: a 13-institution study by the US Adrenocortical Carcinoma Group. J Am Coll Surg 222:480-490. https://doi.org/10.1016/j.jamcollsurg. 2015.12.013
36. Vassilopoulou-Sellin R, Guinee VF, Klein MJ et al (1993) Impact of adjuvant mitotane on the clinical course of patients with adren- ocortical cancer. Cancer 71:3119-3123. https://doi.org/10.1002/ 1097-0142(19930515)71:10%3c3119 :: aid-cncr2820711037% 3e3.0.co;2-8
37. Bodie B, Novick AC, Pontes JE et al (1989) The Cleveland Clinic experience with adrenal cortical carcinoma. J Urol 141:257-260. https://doi.org/10.1016/s0022-5347(17)40734-8
38. . Şişman P, Şahin AB, Peynirci H et al (2017) Adrenocortical carci- noma: single center experience. Turk J Urol 43:462-469. https:// doi.org/10.5152/tud.2017.81598
39. Icard P, Louvel A, Chapuis Y (1992) Survival rates and prognostic factors in adrenocortical carcinoma. World J Surg 16:753-758. https://doi.org/10.1007/BF02067377
40. McAteer JP, Huaco JA, Gow KW (2013) Predictors of survival in pediatric adrenocortical carcinoma: a Surveillance, Epidemi- ology, and End Results (SEER) program study. J Pediatr Surg 48:1025-1031. https://doi.org/10.1016/j.jpedsurg.2013.02.017
41. Kendrick ML, Lloyd R, Erickson L et al (2001) Adrenocortical carcinoma: surgical progress or status quo? Arch Surg 136:543- 549. https://doi.org/10.1001/archsurg.136.5.543
42. Erdogan I, Deutschbein T, Jurowich C et al (2013) The role of surgery in the management of recurrent adrenocortical carcinoma. J Clin Endocrinol Metab 98:181-191. https://doi.org/10.1210/jc. 2012-2559
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