Localized Adrenocortical Carcinoma Research Articles

8180 Rare Variants Of Adrenocortical Carcinoma: A Retrospective Cohort Study

Abstract Disclosure: C.A. Villavicencio Torres: None. I. Bancos: None. Background: Adrenocortical carcinoma (ACC) is a rare malignancy with an estimated annual incidence of 0.7-2 cases per million per year. Scarce data are available on rare histological variants of ACC. Objective: To describe the clinical presentation and outcomes of patients diagnosed with oncocytic, sarcomatoid and myxoid ACC variants. Methods: Retrospective single center cohort study, 1992-2021 of patients with rare histological ACC variant. Results: A total of 20 patients were diagnosed with oncocytic (17, 85%), sarcomatoid (2, 10%), or myxoid (1, 5%) ACC. Median age of diagnosis was 47 years (range 17-80), and 14 (70%) were women. All patients had unilateral ACC (12, 60% left) with a median tumor size of 11 cm (range 4-29). Adrenal hormone excess was documented in 10 (50%) patients, mostly with either glucocorticoid or androgen excess. ENSAT stage I, II, III, and IV was documented in 2 (10%), 10 (50%), 6 (30%), and 2 (10%) patients, respectively. All patients were treated with adrenalectomy (laparoscopic in 5 and open in 15). In addition, patients were treated with mitotane (10, 50%), radiation (7, 35%), and chemotherapy (5,25%). Mitotane was administered for a median of 12 months (range 4-31) and was discontinued mainly due to side effects in 9 (90%) patients. Patients were followed for a median follow up of 6.5 years (range 0.4-12). In addition to 2 patients who presented with ENSAT stage IV metastatic disease, metastatic disease developed in additional 6 (30%) patients who initially presented with localized ACC (3 stage 2, 3 stage 3, 5 oncocytic, 1 sarcomatoid). Metastatic sites included lung (n=2), omentum (n=1), duodenum (n=1), liver (n=4), and bones (n=1). At the end of follow up, 11 (55%) patients remained disease free (53% oncocytic, 50% sarcomatoid, 100% myxoid), 5 (25%) patients were alive with metastatic ACC (23% oncocytic, 50% sarcomatoid), and 4 patients died of ACC (median time to death 21 months (range 10-50) post-adrenalectomy). Conclusions: Patients with oncocytic, sarcomatoid, and myxoid ACC may have a better prognosis than in reported literature. Larger multicenter studies are needed to identify patient and tumor-specific factors that guide management to assure improved outcomes in these very rare patients. Presentation: 6/2/2024

Efficacy and safety of adjuvant radiation therapy in localized adrenocortical carcinoma.

Adrenocortical carcinoma (ACC) is rare and have high rates of recurrence and mortality. The role of adjuvant radiation therapy (RT) in localized ACC was controversial. We conducted a retrospective study in our center between 2015 and 2021 to evaluate the efficacy and safety of adjuvant RT in localized ACC. Overall survival (OS) and disease-free survival (DFS) were estimated using the Kaplan-Meier method. Cox proportional hazards regression models were used to estimate the independent risk factors. Adverse events associated with RT were documented according to the toxicity criteria of the radiation therapy oncology group (RTOG) and the common terminology criteria for adverse events (CTCAE v5.0). Of 105 patients with localized ACC, 46 (43.8%) received adjuvant RT after surgery. The median radiation dose was 45.0Gy (range:30.0-50.4) and median follow up time was 36.5 (IQR: 19.7-51.8) months. In comparison to the no adjuvant RT group, patients with adjuvant RT had better 3-year OS (87.9% vs 79.5%, P=0.039), especially for patients with ENSAT I/II stage (P=0.004). Adjuvant RT also improved the median DFS time from 16.5months (95%CI, 12.0-20.9) to 34.6months (95%CI, 16.1-53.0). Toxicity of RT was generally mild and moderate with six grade 3 events. Postoperative adjuvant RT significantly improved OS and DFS compared with the use of surgery alone in resected ACC patients. Although this retrospective study on RT in localized ACC indicates that RT is effective in ACC, its findings need to be prospectively confirmed.

STUDY TO DETERMINE MULTIMODAL THERAPY IMPACT ON ADRENALECTOMY FOR LOCALIZED ADRENOCORTICAL CARCINOMA AND OVERALL SURVIVAL OF PATIENTS

This study aimed to determine the impact of multimodal therapy on adrenalectomy for localized adrenocortical carcinoma (ACC) and the overall survival of patients. The study included 200 patients. A retrospective analysis was conducted on 200 patients diagnosed with localized ACC who underwent adrenalectomy at a medical center. The patients were divided into the multimodal therapy group (n=100) and the adrenalectomy alone group (n=100). Patient characteristics, treatment modalities, pathological findings, and follow-up data were analyzed. The primary outcome measures included recurrence rates, overall survival rates, and treatment-related complications. The 5-year overall survival rate was significantly higher in Group B (68%) compared to Group A (45%) (p < 0.001). Group B also had a higher 5-year disease-free survival rate (54%) compared to Group A (32%) (p = 0.023). The local recurrence rate was lower in Group B (18%) compared to Group A (32%). Treatment-related adverse events occurred slightly more frequently in Group B (22%) than in Group A (15%) but did not significantly impact patient outcomes. Subgroup analyses consistently showed improved overall survival in Group B across different age groups, tumor stages, and histology. Adding multimodal therapy to adrenalectomy for localized ACC significantly improved overall survival, disease-free survival, and reduced local recurrence rates. Multimodal therapy should be considered a potential treatment approach for improving outcomes in ACC patients. Further studies with larger cohorts and prospective designs are needed to confirm these findings and optimize treatment strategies.

Laparoscopic or Open Adrenalectomy for Stage I-II Adrenocortical Carcinoma: A Retrospective Study.

Surgical resection of adrenocortical carcinoma (ACC) is the only curative treatment. Even in localized (I-II) stages, open adrenalectomy (OA) is the gold standard, though laparoscopic adrenalectomy (LA) can be proposed in selected patients. Despite the postoperative benefits of LA, its role in the surgical management of patients with ACC remains controversial regarding oncologic outcomes. The aim of this retrospective study was to compare the outcomes of patients with localized ACC submitted to LA or OA in a referral center from 1995 to 2020. Among 180 consecutive patients operated on for ACC, 49 presented with localized ACC (19 LA and 30 OA). Baseline characteristics were similar between groups, except for tumor size. Kaplan-Meier estimates of 5-year overall survival were similar in both groups (p = 0.166) but 3-year disease-free survival was in favor of OA (p = 0.020). Though LA could be proposed in highly selected patients, OA should still be considered the standard approach in patients with known or suspected localized ACC.

Impact of Multimodal Therapy on Margin Status on Overall Survival for Patients Undergoing Adrenalectomy for Localized Adrenocortical Carcinoma

Introduction: Adrenocortical carcinoma (ACC) is a rare and aggressive malignancy that arises from the adrenal cortex. It is a challenging disease to manage due to its rarity, variable presentation, and lack of effective systemic therapy options. Objectives: The main objective of the study is to find the impact of multimodal therapy on margin status on overall survival for patients undergoing adrenalectomy for localized adrenocortical carcinoma. Material and methods: The aim of this study was to investigate the impact of multimodal therapy on margin status and overall survival in patients who underwent adrenalectomy for localized adrenocortical carcinoma (ACC) between March 2022 till November 2022 at a single tertiary care center. Results: Based on the analysis of 300 patients who underwent adrenalectomy for localized adrenocortical carcinoma (ACC) between 2000 and 2022 at a single tertiary care center, the study found that multimodal therapy may improve margin status and overall survival in this patient population. Of the 300 patients included in the study, 150 received multimodal therapy (adjuvant radiation therapy and/or chemotherapy) and 150 received observation after surgery. The median follow-up time was 48 months. Conclusion: In conclusion, the findings of this study suggest that multimodal therapy may be an effective treatment option for patients undergoing adrenalectomy for localized adrenocortical carcinoma. Multimodal therapy was found to be associated with a significantly higher overall survival rate compared to observation alone.

Impact of multimodal therapy on margin status on overall survival for patients undergoing adrenalectomy for localized adrenocortical carcinoma.

Adrenocortical carcinoma is a rare malignancy that typically presents with advanced features and carries a poor prognosis. Complete surgical resection offers patients the best survival outcomes, but this is not always achievable and many require additional therapy for advanced features. Some literature has explored the role of chemotherapy and radiation, but little has been conducted to explore the effects of multimodal therapy. We retrospectively reviewed the National Cancer Database for adults with primary nonmetastatic adrenocortical carcinoma (ACC) who underwent either partial or radical adrenalectomy. Excluded patients included those with metastatic disease and those with primary tumor >30 cm. Patients were categorized based on adjuvant treatment; chemotherapy, radiation therapy (RT), RT + chemotherapy, or no adjuvant therapy. Overall survival (OS) was compared using survival curves, log rank tests, and multivariate survival analysis. We identified 1644 patients with localized ACC treated with adrenalectomy. The median tumor size was 10.6 cm. A total of 278 patients had positive margin status (R1), and 416 patients had nodal (pN+) disease. Out of all patients, a minority (39.4%) received adjuvant therapy, which was most commonly given as chemotherapy only. Statistically significant increase in OS was noted with the use of RT + chemotherapy in the node-negative, margins-positive (pN0/pNx; R1) subgroup versus patients who did not receive adjuvant therapy (5-year OS 60.5% and 28.2%, respectively [P = 0.002]). This held true on multivariate analysis with significant improvement in OS in the pN0/pNx; R1 population with RT + chemotherapy compared to those who received no treatment (hazard ratio: 0.40 [95% confidence interval: 0.2-0.9], P = 0.02). Our findings support the use of adjuvant chemotherapy plus RT in patients with positive surgical margins and no nodal disease. Additional studies are required to confirm these findings, clarify the objective benefit of multimodal therapy, and to determine the optimal chemotherapy/RT combination.

Impact of Lymphadenectomy on the Oncologic Outcome of Patients with Adrenocortical Carcinoma-A Systematic Review and Meta-Analysis.

Simple SummaryThe concept of locoregional lymphadenectomy (LND) in adrenocortical cancer (ACC) has gained interest in recent years, but its definite prognostic and therapeutic significance remains to be established. We undertook a systematic review and meta-analysis to determine the oncologic value of LND in ACC, focusing on overall survival as the primary endpoint. Eleven studies were identified and five were included in the meta-analysis, all of them were retrospective studies. Three studies reported the impact of LND on disease-specific survival in patients with stage I–III ACC and revealed a survival benefit of LND, whereas studies including patients with stage I–IV ACC (N = 2) did not show a survival benefit of LND. In summary, our results demonstrate an oncologic benefit of LND in patients undergoing curative-intended surgery for at least localized ACC (stage I–III).(1) Background: Locoregional lymphadenectomy (LND) in adrenocortical carcinoma (ACC) may impact oncological outcome, but the findings from individual studies are conflicting. The aim of this systematic review and meta-analysis was to determine the oncological value of LND in ACC by summarizing the available literature. (2) Methods: A systematic search on studies published until December 2020 was performed according to the PRISMA statement. The primary outcome was the impact of lymphadenectomy on overall survival (OS). Two separate meta-analyses were performed for studies including patients with localized ACC (stage I–III) and those including all tumor stages (I–IV). Secondary endpoints included postoperative mortality and length of hospital stay (LOS). (3) Results: 11 publications were identified for inclusion. All studies were retrospective studies, published between 2001–2020, and 5 were included in the meta-analysis. Three studies (N = 807 patients) reported the impact of LND on disease-specific survival in patients with stage I–III ACC and revealed a survival benefit of LND (hazard ratio (HR) = 0.42, 95% confidence interval (95% CI): 0.26–0.68). Based on results of studies including patients with ACC stage I–IV (2 studies, N = 3934 patients), LND was not associated with a survival benefit (HR = 1.00, 95% CI: 0.70–1.42). None of the included studies showed an association between LND and postoperative mortality or LOS. (4) Conclusion: Locoregional lymphadenectomy seems to offer an oncologic benefit in patients undergoing curative-intended surgery for localized ACC (stage I–III).

Survival characteristics of localized pediatric adrenocortical carcinoma managed with adenectomy: A national cancer center database analysis

Pediatric adrenocortical carcinoma (ACC) is a rare malignancy, encompassing less than 0.2% of all childhood malignancies. Due to the scarcity of this diagnosis, it is often managed according to guidelines established for adults, as there is a lack of reliable evidence regarding optimal adjuvant treatment options for pediatric patients. It is our aim to identify recent treatment trends as well as clinical and tumor characteristics and their impact on overall survival. Using the National Cancer Data Base (NCDB), this study identified 49 patients under 18 years old with localized ACC (M0) undergoing adrenalectomy from 2004 to 2017. Kaplan-Meier analysis was performed to determine overall survival (OS) from patient characteristics and treatments received. Comparison of survival was performed using the log rank test. The median age of our cohort was 3 years old with a slight female predominance of 61%. The median tumor size was 9.4cm, and patients older than 4 years were significantly (p=0.03) more likely to present with larger tumors (11.33cm vs 8.76cm). Adjuvant treatment in the form of systemic therapy was administered in 20 of 49 (41%) patients and radiation therapy in 2 of 49 (4%) patients. Three-year OS for patients 4 years old and younger was 92.6% vs 61.8% for those older than 4 years (p=0.002). Patients presenting with tumor size ≥9cm had worse three-year OS compared to those with tumors <9cm (95.24% vs 67.1% respectively, p=0.02, Fig. 1). In patients with tumors≥9cm, younger children age 0-4 years had significantly (p=0.04) higher OS rates than older children age 5-17 years. ACC is a rare pediatric malignancy with a female predominance. Those older than 4 years and those with presenting tumor size ≥9cm have decreased overall survival rates after adrenalectomy for localized disease. Additionally, children older than 4 have poorer prognosis, even after controlling for larger tumor size. This is the largest contemporary series of localized pediatric ACC to date. However, multi-institutional prospective cohort or randomized-controlled trials are necessary to better evaluate relevant prognostic factors and the role of adjuvant therapies following adrenalectomy.

Analysis of adjuvant chemotherapy in patients undergoing curative-intent resection of localized adrenocortical carcinoma

BackgroundStudies evaluating the role of adjuvant chemotherapy (ACT) in Adrenocortical Carcinoma (ACC) are limited due to its rarity. The objective of this study was to evaluate if ACT provides a survival benefit in patients who underwent curative-intent resection of localized ACC and to determine factors associated with receipt of ACT. MethodsThe National Cancer Data Base was queried to identify patients (2010–2016) with curative-intent resection of localized ACC (T1-T3, N0, M0). ResultsOf 577 patients with adrenalectomy, 389 (67%) had adrenalectomy alone, and 188 (33%) received ACT. Private insurance, lymphovascular invasion, stage II, and radiotherapy were predictors of ACT (P < 0.05). Advanced (T3) stage lymphovascular invasion, and being uninsured were associated with decreased OS (P < 0.05). There was no association between ACT and OS. ConclusionsFor patient who underwent curative-intent resection of localized ACC, there was no association between ACT and OS. Private insurance, lymphovascular invasion, stage II disease, and radiotherapy were associated with receipt of ACT.

Open vs laparoscopic adrenalectomy for localized adrenocortical carcinoma.

The purpose of the study was to compare the long-term outcomes of patients with localized adrenocortical carcinoma (ACC) subjected to open vs laparoscopic surgery. Retrospective study. This retrospective study included 46 patients with the ACC ENSAT stage I-stage III of whom 23 underwent open surgery (OA group), whereas 23 were subjected to laparoscopic adrenalectomy (LA group). The main outcomes analysed in the study were differences between the OA and LA groups in recurrence-free survival (RFS) and overall survival (OS). Patients in OA group had larger tumours (120 [70-250] mm vs 75 [26-110] mm; P<.001), higher Ki-67 index (16 [1-65] % vs 10 [1-25] %; P=.04) and higher disease stage (P=.01) compared with the patients in the LA group. The median duration of follow-up for patients underwent OA and LA was 51 (12-174) and 53 (5-127) months, respectively. Eight patients (5 OA and 3 LA) experienced recurrent disease, whereas six patients (3 OA and 3 LA) died during follow-up. No differences in RFS and OS were found between patients who underwent open or laparoscopic surgery. The study demonstrated that in patients with localized ACC and without invasion of extra-adrenal tissues, LA is a plausible treatment option in terms of RFS and OS. However, our results are limited to referral centres with large experience in the management of patients with ACC and may not necessarily apply to nonspecialized centres.

Value of Molecular Classification for Prognostic Assessment of Adrenocortical Carcinoma

The risk stratification of adrenocortical carcinoma (ACC) based on tumor proliferation index and stage is limited. Adjuvant therapy after surgery is recommended for most patients. Pan-genomic studies have identified distinct molecular groups closely associated with outcome. To compare the molecular classification for prognostic assessment of ACC with other known prognostic factors. In this retrospective biomarker analysis, ACC tumor samples from 368 patients who had undergone surgical tumor removal were collected from March 1, 2005, to September 30, 2015 (144 in the training cohort and 224 in the validation cohort) at 21 referral centers with a median follow-up of 35 months (interquartile range, 18-74 months). Data were analyzed from March 2016 to March 2018. Meta-analysis of pan-genomic studies (transcriptome, methylome, chromosome alteration, and mutational profiles) was performed on the training cohort. Targeted biomarker analysis, including targeted gene expression (BUB1B and PINK1), targeted methylation (PAX5, GSTP1, PYCARD, and PAX6), and targeted next-generation sequencing, was performed on the training and validation cohorts. Disease-free survival. Cox proportional hazards regression and C indexes were used to assess the prognostic value of each model. Of the 368 patients (mean [SD] age, 49 [16] years), 144 were in the training cohort (100 [69.4%] female) and 224 were in the validation cohort (142 [63.4%] female). In the training cohort, pan-genomic measures classified ACC into 3 molecular groups (A1, A2, and A3-B), with 5-year survival of 9% for group A1, 45% for group A2, and 82% for group A3-B (log-rank P < .001). Molecular class was an independent prognostic factor of recurrence in stage I to III ACC after complete surgery (hazard ratio, 55.91; 95% CI, 8.55-365.40; P < .001). The combination of European Network for the Study of Adrenal Tumors (ENSAT) stage, tumor proliferation index, and molecular class provided the most discriminant prognostic model (C index, 0.88). In the validation cohort, the molecular classification, determined by targeted biomarker measures, was confirmed as an independent prognostic factor of recurrence (hazard ratio, 5.96 [95% CI, 1.81-19.58], P = .003 for the targeted classifier combining expression, methylation, and chromosome alterations; and 2.61 [95% CI, 1.31-5.19], P = .006 for the targeted classifier combining methylation, chromosome alterations, and mutational profile). The prognostic value of the molecular markers was limited for patients with stage IV ACC. The findings suggest that in localized ACC, targeted classifiers may be used as independent markers of recurrence. The determination of molecular class may improve individual prognostic assessment and thus may spare unnecessary adjuvant treatment.

Management of Adrenocortical Carcinoma.

Adrenocortical carcinoma (ACC) is a rare endocrine malignancy typically with poor prognosis. This review aims to summarize the current knowledge regarding the clinical management of ACC. Surgery remains the cornerstone for localized ACC management. In more advanced cases, debulking surgery when feasible can help with hormonal control and may allow the initiation of systemic therapy. Over the last few years, our understanding of ACC molecular pathogenesis has expanded with no significant change in treatment options. Platinum-based chemotherapy is the gold standard in metastatic ACC despite suboptimal efficacy. Tyrosine kinase inhibitor use did not result in meaningful benefit in ACC patients. Multiple clinical trials are currently exploring the role of immunotherapy in ACC. Despite the remarkable improvement in our understanding of the molecular signature and pathways in ACC, this knowledge did not yield a major breakthrough in management of advanced ACC. Multi-institutional and international collaborations are needed to identify promising treatments and new therapeutic targets to improve the care of ACC patients.

Improvement in Recurrence-free Survival with Adjuvant Radiation in Adrenocortical Carcinoma

Adrenocortical carcinoma (ACC) is a rare malignancy with high rates of local recurrence and poor prognosis. Given high propensity to metastasize, the role of post-operative radiation therapy (RT) in localized ACC has been controversial. We sought to evaluate the benefit of adjuvant RT to local control in our updated institutional ACC database. From 424 patients in our ACC database, we retrospectively identified patients who underwent adjuvant RT at our institution from 1999 to 2017. Patients that were treated with surgery followed by adjuvant RT were matched to patients who only underwent resection on the basis of stage, surgical margin status, tumor grade, and adjuvant mitotane use. Local recurrence was defined as adrenal bed or abdominal failure. Overall and recurrence-free survival probabilities were estimated using the Kaplan-Meier method. Distributions were compared between cases and controls using the log-rank test statistic. Cox proportional hazards regression models were used to estimate the hazard ratio for time-to-event endpoints comparing controls to cases after adjustment for age at event and gender. Of 424 patients, 78 patients with ACC were selected, half who underwent adjuvant radiation. Patients were matched 1:1 without significant differences with respect to stage, margin status, grade, or mitotane use, although there were more females than males in the matched group (52.8% females with RT, 82% without RT). Median radiation dose was 55 Gy (range 45-60 Gy). Local recurrence was less common with adjuvant RT (13 vs 26 local failures in those treated with and without RT, respectively, (p = 0.038, hazard ratio [HR] 2.20; 95% confidence interval [CI] 1.04-4.63)). Five-year recurrence-free survival for patients with RT was 46.7% and 16.9% for patients without (p = 0.016; HR 2.32, 95% CI 1.14-4.57). There was numerically better overall survival in patients that received RT (72.1% versus 55.1%), although this was not statistically significant (p = 0.424, HR 1.46, 95% CI 0.58-3.68). Adjuvant RT following gross resection of ACC significantly improves recurrence free-survival in this retrospective case-matched cohort analysis. Even though, this represents the largest series to date on adjuvant RT for ACC, prospective confirmation of this data is needed.

Laparoscopic versus open adrenalectomy for localized (stage 1/2) adrenocortical carcinoma: Experience at a single, high-volumecenter

Open adrenalectomy is considered a standard operative approach for adrenocortical carcinoma, and laparoscopic adrenalectomy remains controversial. We analyzed our outcomes of laparoscopic adrenalectomy and open adrenalectomy for localized (stage 1/2) adrenocortical carcinoma in our hospital. This study retrospectively reviewed all patients with stage 1/2 adrenocortical carcinoma and a tumor size < 10 cm who underwent radical resection in our hospital between 2009 and 2017. These patients were divided into laparoscopic adrenalectomy and open adrenalectomy groups. Demographics, operative data, and follow-up outcomes were collected. The 5-year overall survival and recurrence-free survival were calculated with the Kaplan-Meier method and compared between laparoscopic adrenalectomy and open adrenalectomy group. A total of 23 patients operated by an open adrenalectomy and 21 patients operated with a laparoscopic adrenalectomy were included. Baseline patient characteristics (age, sex, tumor size, hormonal secretion) were similar between 2 groups. The mean postoperative stay was less in the laparoscopic adrenalectomy group (P = .003). The mean follow-up time was similar for the two groups (33 ± 24 vs 35 ± 25 months; P = NS). The local and peritoneal recurrence rates were 42% for laparoscopic adrenalectomy and 22% for open adrenalectomy (P = .035). Time to local and peritoneal recurrence was less in the laparoscopic adrenalectomy than in the open adrenalectomy (P = .048). The 5-year overall survival and recurrence-free survival for open adrenalectomy versus laparoscopic adrenalectomy were 43% vs 47% (P = .635) and 36% vs 39% (P = .802), respectively. We believe that open adrenalectomy should still be considered the standard operative management of adrenocortical carcinoma. Laparoscopic adrenalectomy may not provide patients with localized adrenocortical carcinoma with an equivalent oncologic outcome based on site and timing of initial tumor recurrence.

Update on adrenocortical carcinoma management and future directions.

To present an update on the management of and future directions in adrenocortical carcinoma (ACC). ACC is a rare malignancy with high morbidity and mortality. Surgery remains the mainstay treatment for localized disease, but it is often not feasible in more advanced cases. There is an ongoing controversy about the routine use of adjuvant treatments after surgery. Hormonal overproduction can complicate the management and worsen the prognosis of the disease. Systemic therapy with multiple cytotoxic drugs is often combined with the adrenolytic agent mitotane. Genomic analyses of ACC revealed numerous signal transduction pathway aberrations (insulin-like growth factor 2 overexpression, TP53 mutations and Wnt/β-catenin pathway activation), but so far, there has been no clinically meaningful breakthrough in targeting these genes. Immunotherapy offers hope for altering the orthodox management of cancer, and its role in ACC is being explored in multiple ongoing trials. Surgery by experienced team is the key treatment for localized ACC, whereas currently used chemotherapy has limited efficacy in advanced ACC. The improved understanding of the molecular pathways involved in ACC has not been translated into effective therapy. The development of new therapies requires collaborative effort to fight this disease.

Lymphadenectomy for Adrenocortical Carcinoma: Is There a Therapeutic Benefit?

Lymph node metastasis is an established predictor of poor outcome for adrenocortical carcinoma (ACC); however, routine lymphadenectomy during surgical resection of ACC is not widely performed and its therapeutic role remains unclear. Patients undergoing margin-negative resection for localized ACC were identified from a multi-institutional database. Patients were stratified into 2 groups based on the surgeon's effort or not to perform a lymphadenectomy as documented in the operative note. Clinical, pathologic, and outcome data were compared between the 2 groups. Of 120 patients who met inclusion criteria from 1993 to 2014, 32 (27%) underwent lymphadenectomy. Factors associated with lymphadenectomy were tumor size (12 vs. 9.5cm; p=.007), palpable mass at presentation (26 vs. 12%; p=.07), suspicious lymph nodes on preoperative imaging (44 vs. 7%; p<.001), and need for multivisceral resection (78 vs. 36%; p<.001). Median number of lymph nodes harvested was higher in the lymphadenectomy group (5.5 vs. 0; p<.001). In-hospital mortality (0 vs. 1.3%; p=.72) and grade 3/4 complication rates (0 vs. 12%; p=.061) were not significantly different. Patients who underwent lymphadenectomy had improved overall survival (5-year 76 vs. 59%; p=.041). The benefit of lymphadenectomy on overall survival persisted on multivariate analysis (HR=0.17; p=.006) controlling for adverse preoperative and intraoperative factors associated with lymphadenectomy, such as tumor size, palpable mass, irregular tumor edges, suspicious nodes on imaging, and multivisceral resection. In this multicenter study of adrenocortical carcinoma patients undergoing R0 resection, the surgeon's effort to dissect peritumoral lymph nodes was independently associated with improved overall survival.

Mitotane Revisited: A New Target for an Old Drug

Adrenocortical carcinoma (ACC) is among the deadliest endocrine malignancies. Radical surgical resection of a localized tumor is the only curative option for ACC, but in many patients cancer is diagnosed already at an advanced stage, needing pharmacological treatment. The mainstay of the medical therapy for metastatic ACC is mitotane (o,p -DDD), a derivative of the insecticide dichlorodiphenyl-trichloroethane, which is also used as an adjuvant treatment in patients resected for localized ACC but at a high risk of relapse. Mitotane is an old drug. More than 60 years ago, Nelson and Woodard showed that technical-grade dichlorodiphenildichloroethane caused selective atrophy of the adrenal cortex in the dog (1). Subsequent studies demonstrated that the active substance was o,p -DDD, an impurity in the technical-grade product, which was then introduced in the treatment of ACC (2). Today mitotane is the only approved drug for ACC treatment, even if controversies remain concerning its long-term efficacy (reviewed in reference 3). Mitotane has both an adrenolytic action on ACC cells and inhibits steroid hormone synthesis, with beneficial effects in patients with Cushing’s syndrome. However, mitotane therapy often has important side effects that limit its use in the clinic. Furthermore, for many patients it is difficult to attain and maintain the therapeutic levels of plasma mitotane (between 14 and 20 mg/L) (4). A better knowledge of the mechanism of action of mitotane is then required to develop new drugs that are more efficient and better tolerated by ACC patients. Recent studies showed that mitotane treatment negatively affects mitochondrial respiratory chain activity (5) and induces mitochondrial morphofunctional changes in ACC cells (6), but the mechanisms of those effects remained elusive. A breakthrough in our understanding of how mitotane works as a selective toxic agent for adrenal cells is represented by the study of Sbiera et al (7) published in this issue of Endocrinology. Here the authors show compelling evidence that mitotane treatment rapidly induces endoplasmic reticulum (ER) stress in ACC cells but not in cancer cell lines from tissues other than the adrenal. ER stress generates protein misfolding in the ER, which is sensed by several signaling cascades and triggers a response targeted to limit the effects of ER stress. Collectively this phenomenon is termed the unfolded protein response (UPR) (8). Mitotane-induced ER stress is correlated with the accumulation of toxic lipids inside ACC cells. In particular, increase in free cholesterol and decrease of cholesteryl esters pinpointed the inhibition of sterol-Oacyl-transferase (SOAT) (also known as acyl-coenzyme A cholesterol acyltransferase) activity as a potential mechanism of action of mitotane. In the adrenal, this enzyme has the role to produce stores of esterified cholesterol protecting cells from the damaging effects of free cholesterol. Cholesterol esters can be rapidly made available as substrates for steroidogenesis after ACTH stimulation by the action of hormone-sensitive lipase (9). Consistently with its important role in steroidogenesis, SOAT1 has been shown to be a target for steroidogenic factor-1, an essential transcriptional regulator of steroidogenic genes (10). Based on those results, Sbiera et al (7) show that mitotane indeed inhibits SOAT1 activity in vitro and that its effect correlates with

Major prognostic role of Ki67 in localized adrenocortical carcinoma after complete resection.

Recurrence of adrenocortical carcinoma (ACC) even after complete (R0) resection occurs frequently. The aim of this study was to identify markers with prognostic value for patients in this clinical setting. From the German ACC registry, 319 patients with the European Network for the Study of Adrenal Tumors stage I-III were identified. As an independent validation cohort, 250 patients from three European countries were included. Clinical, histological, and immunohistochemical markers were correlated with recurrence-free (RFS) and overall survival (OS). Although univariable analysis within the German cohort suggested several factors with potential prognostic power, upon multivariable adjustment only a few including age, tumor size, venous tumor thrombus (VTT), and the proliferation marker Ki67 retained significance. Among these, Ki67 provided the single best prognostic value for RFS (hazard ratio [HR] for recurrence, 1.042 per 1% increase; P < .0001) and OS (HR for death, 1.051; P < .0001) which was confirmed in the validation cohort. Accordingly, clinical outcome differed significantly between patients with Ki67 <10%, 10-19%, and ≥20% (for the German cohort: median RFS, 53.2 vs 31.6 vs 9.4 mo; median OS, 180.5 vs 113.5 vs 42.0 mo). Using the combined cohort prognostic scores including tumor size, VTT, and Ki67 were established. Although these scores discriminated slightly better between subgroups, there was no clinically meaningful advantage in comparison with Ki67 alone. This largest study on prognostic markers in localized ACC identified Ki67 as the single most important factor predicting recurrence in patients following R0 resection. Thus, evaluation of Ki67 indices should be introduced as standard grading in all pathology reports of patients with ACC.

EJE PRIZE 2014: Current and evolving treatment options in adrenocortical carcinoma: where do we stand and where do we want to go?

Adrenocortical carcinoma (ACC) is not only a rare and heterogeneous disease but also one of the most aggressive endocrine tumors. Despite significant advances in the last decade, its pathogenesis is still only incompletely understood and overall therapeutic means are unsatisfactory. Herein, we provide our personal view of the currently available treatment options and suggest the following research efforts that we consider timely and necessary to improve therapy: i) for better outcome in localized ACCs, surgery should be restricted to experienced centers, which should then collaborate closely to address the key surgical questions (e.g. best approach and extent of surgery) in a multicenter manner. ii) For the development of better systemic therapies, it is crucial to elucidate the exact molecular mechanisms of action of mitotane. iii) A prospective trial is needed to address the role of cytotoxic drugs in the adjuvant setting in aggressive ACCs (e.g. mitotane vs mitotane+cisplatin). iv) For metastatic ACCs, new regimens should be investigated as first-line therapy. v) Several other issues (e.g. the role of radiotherapy and salvage therapies) might be answered - at least in a first step - by large retrospective multicenter studies. In conclusion, although it is unrealistic to expect that the majority of ACCs can be cured within the next decade, international collaborative efforts (including multiple translational and clinical studies) should allow significant improvement of clinical outcome of this disease. To this end, it might be reasonable to expand the European Network for the Study of Adrenal Tumors (ENSAT) to a truly worldwide international network - INSAT.

Prognostic value of histological markers in localized adrenocortical carcinoma after complete resection

Prognostic value of histological markers in localized adrenocortical carcinoma after complete resection