Incidence and Geographical Distribution of Adrenocortical Carcinoma: Retrospective Analysis of a State Cancer Registry.

OBJECTIVE: Adrenocortical carcinoma (ACC) is a rare malignancy without established association with environmental risk factors. ACC incidence is stable based on large surgical databases while referral centers data reported increasing number of cases seen. We studied ACC incidence and distribution at a county level to find potential ACC "hot spots" that could be linked to environmental exposures. METHODS: A retrospective analysis of Texas Cancer Registry that included ACC patients diagnosed between 2000 and 2018. County-level heatmaps were created and compared with breast, prostate, and lung cancer. RESULTS: We identified 448 ACC cases during the study period. Cases were registered in 110 of the 254 counties (43.3%) in Texas, representing 92.74% of the total population. The median incidence was 23 new cases/y (range 14-33). The mean population-adjusted ACC incidence rate was 0.104 per 100 000 per year (standard deviation 0.005; 95% CI, 0.092-0.116). Seven counties (6.3%) accounted for 215 (48.0%) cases, with more than 10 cases each and median standardized incidence ratio (SIR) of 0.1 (range, 0.0-0.9). One hundred three counties (93.7%) accounted for the remaining 233 cases (52%), with fewer than 10 cases per county. The highest standardized incidence ratios were found in counties with a median population of fewer than 14 000 residents and with only one reported case. CONCLUSION: Our analysis is the first report to create ACC heatmap and could not detect any geographic clustering of ACC in Texas. The incidence of ACC remained stable and consistent with data from other large databases.

Regional differences in stage distribution and rates of treatment for adrenocortical carcinoma across United States SEER registries.

BACKGROUND: We tested for regional differences across United States (US) in rates of adrenalectomy, systemic therapy, and adrenalectomy and systemic therapy combination for adrenocortical carcinoma (ACC) patients. We hypothesized that no differences exist, especially after accounting for baseline patient and tumor characteristics. METHODS: Within Surveillance, Epidemiology, and End Results (SEER) database (2004-2018), 1275 ACC patients were identified. Distribution of patient age, tumor size, ENSAT (European Network for the Study of Adrenal Tumors) stages, and treatments were tabulated and graphically displayed, according to nine geographical registries, corresponding to the population of specific states, cities or macro areas of the US on which the data are based on. Multinomial models predicted treatment probability for each patient according to registries. RESULTS: Patients count according to registries ranged from 62 to 509. Differences across registries existed for age (range 54-59 years; P=0.4), tumor size (8.5-11.0 cm; P=0.2), ENSAT stage (1-11% vs. 17-35% vs. 18-32% vs. 24-44%, in respectively ENSAT stage I, II, III, and IV), and treatment distribution (35-53% vs. 5-21% vs. 23-42%, in respectively adrenalectomy, systemic therapy, and adrenalectomy and systemic therapy combination; P=0.039). After adjustment for age, stage and year of diagnosis, clinically meaningful residual differences across registries remained for adrenalectomy (33-54%), systemic therapy (4-19%), and adrenalectomy and systemic therapy combination (20-38%). However, most variability originated from registries with smallest sample sizes. CONCLUSIONS: We identified important variability in ACC treatment according to SEER geographical registries, even after considering baseline patient and tumor characteristics. These findings may be indicative of differences in quality of care or expertise in ACC management.

New Findings on Presentation and Outcome of Patients With Adrenocortical Cancer: Results From a National Cohort Study.

CONTEXT: Because of the rarity of adrenocortical cancer (ACC), only a few population-based studies are available, and they reported limited details in the characterization of patients and their treatment. OBJECTIVE: To describe in a nationwide cohort the presentation of patients with ACC, treatment strategies, and potential prognostic factors. METHODS: Retrospective analysis of 512 patients with ACC, diagnosed in 12 referral centers in Italy from January 1990 to June 2018. RESULTS: ACC diagnosed as incidentalomas accounted for overall 38.1% of cases, with a frequency that increases with age and with less aggressive pathological features than symptomatic tumors. Women (60.2%) were younger than men and had smaller tumors, which more frequently secreted hormones. Surgery was mainly done with an open approach (72%), and after surgical resection, 62.7% of patients started adjuvant mitotane therapy. Recurrence after tumor resection occurred in 56.2% of patients. In patients with localized disease, cortisol secretion, ENSAT stage III, Ki67%, and Weiss score were associated with an increased risk of recurrence, whereas margin-free resection, open surgery, and adjuvant mitotane treatment were associated with reduced risk. Death occurred in 38.1% of patients and recurrence-free survival (RFS) predicted overall survival (OS). In localized disease, age, cortisol secretion, Ki67%, ENSAT stage III, and recurrence were associated with increased risk of mortality. ACCs presenting as adrenal incidentalomas showed prolonged RFS and OS. CONCLUSION: Our study shows that ACC is a sex-related disease and demonstrates that an incidental presentation is associated with a better outcome. Given the correlation between RFS and OS, RFS may be used as a surrogate endpoint in clinical studies.

Clinicopathological features of adrenal malignancies: Analysis of hospital-based cancer registry data in Japan.

OBJECTIVE: To identify the clinicopathological features of adrenal malignancies and analyze the prognoses of patients with adrenal cortical carcinoma (ACC) and malignant pheochromocytoma (MPCC). PATIENTS AND METHODS: We used a hospital-based cancer registry data in Japan to extract cases of adrenal malignancies that were histologically confirmed, diagnosed, and initially treated from 2012-2015. For survival analysis, we used data from the 2008-2009 cohort to estimate 5-year overall survival (OS) by the Kaplan-Meier method. RESULTS: A total of 989 adrenal malignancies were identified in the 2012-2015 cohort. The most common histologies were ACC (26.4%), diffuse large B-cell lymphoma (DLBCL; 25.4%), neuroblastoma (22.2%), and MPCC (11.9%). While most ACC and MPCC patients were in their 60s, DLBCL patients accounted for 61.5% of adrenal malignancies in the over-70 cohort. Among ACC patients with clinical staging data, 46.3% of patients were stage IV. Although surgery was a chief strategy for all stages, younger patients tended to receive combination therapy, including surgery and chemotherapy or hormone therapy. In the 2008-2009 cohort, the 5-year OS rates of ACC (n = 49) and MPCC (n = 23) patients were 56.2% and 86.4% while ACC patients without surgery had 1- and 2-year OS rates of 25.0% and 12.5%. CONCLUSION: In Japan, DLBCL accounted for the majority of adrenal malignancies in older patients. Despite advanced staging, ACC patients were mainly treated with surgery and their prognosis was not satisfactory. Such epidemiological data may be useful in considering initial management strategies.

Revisiting the AJCC staging system of adrenocortical carcinoma.

OBJECTIVE: To evaluate the performance characteristics of AJCC 7th and 8th staging systems among patients with adrenal cortical carcinoma. METHODS: Surveillance, Epidemiology, and End Results (SEER) 18-registry was accessed and patients with adrenocortical carcinoma who were diagnosed 2010-2015 with complete information about AJCC 7th staging system were included. AJCC 8th staging system information was then reconstructed for each patient using available TNM staging variables. Kaplan-Meier overall survival estimates, multivariable Cox regression analysis, and concordance index (C-statistic) were used to examine the performance characteristics of both staging systems. RESULTS: A total of 574 patients with a diagnosis of adrenocortical carcinoma were included in the current analysis. Using Kaplan-Meier survival estimates, overall survival was compared among different AJCC stages for both versions; and the P value was significant (< 0.001) for both comparisons. C-statistic was then calculated for both staging systems and the results were as follows: for AJCC 7th version: 0.726 (95% CI 0.683-0.769); and for AJCC 8th version: 0.745 (95% CI 0.704-0.786). Patients with M1 disease (stage IV according to AJCC 8th edition) were then divided according to the extent of distant metastases into single versus multiple sites of metastases. Using Kaplan-Meier survival estimates, patients with a single site of metastases have better overall survival (P = 0.006). A C-statistic for a hypothetical modification of AJCC 8th staging system subdividing stage IV patients into IVA and IVB based on the number of metastatic sites was: 0.753 (95% CI 0.713-0.794). CONCLUSIONS: There is a minimal difference in the prognostic performance between both versions of the AJCC staging system. Subdivision of stage IV cancer into stage IVA and IVB (according to the number of organs with metastatic deposits) should be considered in subsequent versions of adrenocortical carcinoma staging.

Positive Lymph Nodes in Adrenocortical Carcinoma: What Does It Mean?

BACKGROUND: The role of lymphadenectomy in adrenocortical carcinoma resection is controversial. Therefore, we conducted a population-based study to assess the association between positive lymph nodes (LN) and survival. METHODS: The Surveillance, Epidemiology, and End Results set of cancer registries were utilized. The associations between positive lymph nodes and tumor size, grade and laterality were assessed. Cancer specific survival (CSS) trends and factors affecting survival were analyzed. RESULTS: A total of 2170 adult patients were identified; 60% underwent resection. Among those resected, LN were examined in 23% and were positive in 25% of patients with LN examined. Patients with positive LN tended to have smaller tumors compared to those with negative LN (12 ± 5 vs 15 ± 11 cm, p = 0.02). The rate of positive LN was higher in right ACC, p = 0.03. Median overall CSS was 21 months, with significant differences between resection (42 months) and no resection (4 months), p < 0.01. Median CSS did not change over time when comparing ACC patients who underwent surgery before 2000, 2000-2009, and 2010-2016. On multivariable analysis including resection group, advanced age, grades III and IV, regional and distant stage, in addition to positive LN were associated with worse survival, p < 0.05. CONCLUSION: Lymphadenectomy is infrequently performed during ACC resection, and when performed, regional LN involvement tends to be associated with worse survival. Neoplasm size and grade were not associated with LN involvement and therefore, do not inform lymphadenectomy need. Further studies are needed to assess the indications for, and value of lymphadenectomy in ACC.

Management of adrenocortical carcinoma in Western Australia: a perspective over 14 years.

BACKGROUND: Adrenocortical carcinoma is a rare but aggressive form of endocrine neoplasm 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 adrenocortical 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 resection 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.

ENSAT registry-based randomized clinical trials for adrenocortical carcinoma.

Adrenocortical carcinoma (ACC) is an orphan disease lacking effective systemic treatment options. The low incidence of the disease and high cost of clinical trials are major obstacles in the search for improved treatment strategies. As a novel approach, registry-based clinical trials have been introduced in clinical research, so allowing for significant cost reduction, but without compromising scientific benefit. Herein, we describe how the European Network for the Study of Adrenal Tumours (ENSAT) could transform its current registry into one fit for a clinical trial infrastructure. The rationale to perform randomized registry-based trials in ACC is outlined including an analysis of relevant limitations and challenges. We summarize a survey on this concept among ENSAT members who expressed a strong interest in the concept and rated its scientific potential as high. Legal aspects, including ethical approval of registry-based randomization were identified as potential obstacles. Finally, we describe three potential randomized registry-based clinical trials in an adjuvant setting and for advanced disease with a high potential to be executed within the framework of an advanced ENSAT registry. Thus we, therefore, provide the basis for future registry-based trials for ACC patients. This could ultimately provide proof-of-principle of how to perform more effective randomized trials for an orphan disease.

Metastatic and recurrent adrenocortical cancer is not defined by its genomic landscape.

BACKGROUND: Adrenocortical carcinoma (ACC) is a rare, often-aggressive neoplasm of the adrenal cortex, with a 14-17 month median overall survival. We asked whether tumors from patients with advanced or metastatic ACC would offer clues as to putative genes that might have critical roles in disease progression or in more aggressive disease biology. METHODS: We conducted comprehensive genomic and expression analyses of ACCs from 43 patients, 30 female, and 42 from metastatic sites, including deep sequencing, copy number analysis, mRNA expression and microRNA arrays. RESULTS: Copy number gains and losses were similar to that previously reported for ACC. We identified a median mutation rate of 3.38 per megabase (Mb). The mutational signature was characterized by a predominance of C > T, C > A and T > C transitions. Only cancer genes TP53 (26%) and beta-catenin (CTNNB1, 14%) were mutated in more than 10% of samples. The TCGA-identified putative cancer genes MEN1 and PRKAR1A were found in low frequency-4.7 and 2.3%, respectively. The majority of the mutations were in genes not implicated in the etiology or maintenance of cancer. Specifically, amongst the 38 genes that were mutated in more than 9% of samples, only four were represented in Tier 1 of the 576 COSMIC Cancer Gene Census (CCGC). Thus, 82% of genes found to have mutations likely have no role in the etiology or biology of ACC; while the role of the other 18%, if any, remains to be proven. Finally, the transcript length for the 38 most frequently mutated genes in ACC is statistically longer than the average of all coding genes, raising the question of whether transcript length in part determined mutation probability. CONCLUSIONS: We conclude that the mutational and expression profiles of advanced and metastatic tumors are very similar to those from newly diagnosed patients-with very little in the way of genomic aberration to explain differences in biology. With relatively low mutation rates, few major oncogenic drivers, and loss of function mutations in several epigenetic regulators, an epigenetic basis for ACC may be postulated and serve as the basis for future studies.

Pediatric adrenocortical tumor - review and management update.

PURPOSE OF REVIEW: Adrenocortical tumor (ACT) is a rare disease with an annual worldwide incidence of 0.3-0.38/million children below 15 years old, and Brazilian population presents the highest incidence because of germline mutation in the TP53. Pediatric ACT is associated with virilizing features and hypercortisolism in most cases. Malignancy is defined when local invasion or metastasis is found, and it is associated with a poor prognosis. However, the correct and early diagnosis and treatment may impact on overall and disease-free survival. RECENT FINDINGS: A complete understanding of the disease and its singularities facilitates the assistance to the pediatric patient with ACT. The new insights about adrenal tumorigenesis have provided a better understanding of this disease. In this scenario, the era of molecular studies is leading to the refinement of the taxonomy, and it is offering the opportunity to discover new biomarkers and pathways of tumorigenesis, beyond the knowing ß-catenin, Insulin-like growth factor-II/IGF-IR, and the p53/Rb signaling. SUMMARY: The rarity of this disease makes it a real challenge. Here, we present a review focusing on clinical practice. A methodic approach aiming to clarify the diagnosis and a follow-up are suggested to guide physicians in the assistance of pediatrics patients, improving the prognosis.

A common polymorphism in the retinoic acid pathway modifies adrenocortical carcinoma age-dependent incidence.

BACKGROUND: Genome-wide association studies (GWASs) have enriched the fields of genomics and drug development. Adrenocortical carcinoma (ACC) is a rare cancer with a bimodal age distribution and inadequate treatment options. Paediatric ACC is frequently associated with TP53 mutations, with particularly high incidence in Southern Brazil due to the TP53 p.R337H (R337H) germline mutation. The heterogeneous risk among carriers suggests other genetic modifiers could exist. METHODS: We analysed clinical, genotype and gene expression data derived from paediatric ACC, R337H carriers, and adult ACC patients. We restricted our analyses to single nucleotide polymorphisms (SNPs) previously identified in GWASs to associate with disease or human traits. RESULTS: A SNP, rs971074, in the alcohol dehydrogenase 7 gene significantly and reproducibly associated with allelic differences in ACC age-of-onset in both cohorts. Patients homozygous for the minor allele were diagnosed up to 16 years earlier. This SNP resides in a gene involved in the retinoic acid (RA) pathway and patients with differing levels of RA pathway gene expression in their tumours associate with differential ACC progression. CONCLUSIONS: These results identify a novel genetic component to ACC development that resides in the retinoic acid pathway, thereby informing strategies to develop management, preventive and therapeutic treatments for ACC.

Objective Response and Prolonged Disease Control of Advanced Adrenocortical Carcinoma with Cabozantinib.

BACKGROUND: Objective response of advanced adrenocortical carcinoma (ACC) to mitotane and cytotoxic chemotherapy regimen is only ~20% and early tumor progression is frequent. Previous clinical trials with oral multikinase inhibitors were negative, which has been attributed in part to inadvertent drug interaction with mitotane. Cabozantinib (CABO) is an inhibitor of c-MET, vascular endothelial growth factor receptor 2, AXL, and RET and approved for advanced kidney cancer, liver carcinoma after previous sorafenib, and medullary thyroid carcinoma. OBJECTIVE: To investigate the clinical efficacy and safety of CABO monotherapy in ACC patients. DESIGN: Retrospective cohort study. SETTING: Three referral centers for ACC (Germany, United States). RESULTS: Sixteen patients (13 female) with progressive ACC received CABO after previous mitotane in 15/16 and 3 (median, range 0-8) further systemic treatments. Prior CABO therapy, mitotane was discontinued in all patients. Mitotane plasma concentration was <2 mg/L in 7/16 patients and discontinued >12 months in 6 additional patients before CABO use. In 4/5 cases with available plasma samples, CABO concentration was in the expected steady-state range. Adverse events of grade 1/2 and 3 were observed in 13 and 3 patients, respectively, and consistent with the known safety profile of CABO. Best response was partial response in 3, stable disease in 5, and progressive disease in 8 patients. Median progression-free and overall survival was 16 and 58 weeks, respectively. CONCLUSION: CABO monotherapy appears to be safe and effective as a monotherapy in advanced ACC after failing prior treatments. Therefore, prospective investigation of CABO in ACC patients is warranted.

Epidemiological risk factors for adrenocortical carcinoma: A hospital-based case-control study.

Adrenocortical carcinoma (ACC) is a rare malignancy whose risk factors are unclear. We explored the association of ACC risk with exposure to selected environmental factors, with a focus on cigarette smoking. We conducted a hospital-based case-control study at The University of Texas MD Anderson Cancer Center. Cases (n = 432) patients with ACC treated at MD Anderson, and controls (n = 1,204) were healthy and genetically unrelated spouses of patients at MD Anderson who had cancers not associated with smoking. Information on the subjects' demographic features and selected risk factors was collected using a structured, validated questionnaire and medical records review. Unconditional logistic regression was used to calculate adjusted odds ratios (AORs) via the maximum-likelihood method. Cases had a younger mean (± standard deviation) age than did controls (47.0 ± 0.7 and 60.0 ± 0.3 years, respectively), and the majority of cases were female (60.6%) and non-Hispanic white (82.4%). We found a markedly increased risk of ACC among male cigarette smokers, with an AOR = 1.8 (95% confidence interval [CI] =1.2-2.9), but not among female smokers (AOR = 1.1, 95% CI = 0.7-1.6). Family history of cancer was associated with increased risk of ACC (AOR = 2.8, 95% CI 1.9-4.3) and in both men and women, whereas alcohol consumption was associated with reduced risk in men (AOR = 0.2, 95% CI = 0.1-0.3) but not women (AOR = 0.7, 95% CI = 0.5-1.1). Understanding these risk factors and their underlying mechanisms may help prevent ACC in susceptible individuals and eventually identify new therapeutic options for ACC.

A nationwide survey of adrenal incidentalomas in Japan: the first report of clinical and epidemiological features.

The aim of this study was to reveal clear epidemiologic and clinical characteristics of incidentally discovered adrenal masses, termed adrenal incidentalomas (AIs), and to establish appropriate managemental and therapeutic regimens in Japan. This study had been originally carried out as a project of a research proposed on behalf of the Japanese Ministry of Health, Labour and Welfare, from 1999 to 2004. This nationwide multicenter study on AIs included 3,672 cases with clinically diagnosed AIs, involving 1,874 males and 1,738 females, with mean age 58.1 ± 13.0 years (mean ± SD). In the present study, we focused on the investigation of the real prevalence of various adrenal disorders with AI. The mean nodule size of AI based on computed tomography was 3.0 ± 2.0 cm. Compared to non-functioning adenomas (NFAs), tumor diameters were significantly larger in adrenocortical carcinomas (ACCs), pheochromocytomas, cortisol-producing adenomas (CPAs), myelolipomas, metastatic tumors, cysts, and ganglioneuromas (p < 0.01). Endocrinological evaluations demonstrated that 50.8% of total AIs were non-functioning adenomas, while 10.5%, including 3.6% with subclinical Cushing's syndrome, were reported as CPAs, 8.5% as pheochromocytomas, and 5.1% as aldosterone-producing adenomas. ACCs were accounted for 1.4% (50 cases) among our series of AIs. In conclusion, while almost 50 % of AIs are non-functional adenomas, we must be particularly careful as AIs include pheochromocytomas or adrenal carcinomas, because they may be asymptomatic. To our knowledge, this is the first and the largest investigation of AI, thus providing basic information for the establishment of clinical guidelines for the management of AI.

The incidence of endogenous Cushing's syndrome in the modern era.

INTRODUCTION: Epidemiological studies on the incidence of Cushing's syndrome (CS) are few and most often includes only patients with the most common form, that is Cushing's disease (CD). OBJECTIVE: To analyse the incidence of endogenous CS in an unselected cohort of patients from western Sweden between 2002 and 2017. METHODS: Medical records from patients who had received a diagnostic code for CS and adrenocortical carcinoma in the Västra Götaland County between 2002 and 2017 were reviewed. Eighty-two patients had been diagnosed with endogenous CS in the region during the study period and were included in this analysis. RESULTS: Thirty-nine patients (48%) had CD, 21 (26%) had ectopic ACTH-producing tumour, 17 (21%) had a benign adrenal CS, and 5 (6%) had cortisol-producing adrenocortical carcinoma. Nine of 21 (43%) patients with ectopic CS had an ACTH-producing lung tumour, 4 had a neuroendocrine pancreas tumour, and 5 had an occult tumour. The annual incidence of endogenous CS was 3.2 cases per million/y; 1.5 for CD, 0.8 for ectopic CS, 0.7 for benign adrenal CS and 0.2 for adrenocortical carcinoma. CONCLUSIONS: Approximately three new cases of endogenous CS, per one million inhabitants, were diagnosed annually between 2002 and 2017. Compared with previous reports, proportionally more patients had ectopic CS. The reason for this is unclear although increased awareness of hypercortisolism in patients with malignant tumours in the modern era is a possible explanation.

Adrenocortical carcinoma: presentation and outcome of a contemporary patient series.

BACKGROUND: Adrenocortical carcinoma (ACC) is a rare endocrine carcinoma with poor 5-year survival rates of < 40%. According to the literature, ACC is rarely an incidental imaging finding. However, presentation, treatment and outcome may differ in modern series. DESIGN AND METHODS: We studied all patients (n = 47, four children) from a single centre during years 2002-2018. We re-evaluated radiologic and histopathological findings and assessed treatments and outcome. We searched for possible TP53 gene defects and assessed nationwide incidence of ACC. RESULTS: In adults, incidental radiologic finding led to diagnosis in 79% at median age of 61 years. ENSAT stage I, II, III and IV was 19%, 40%, 19% and 21%, respectively. Nonenhanced CT demonstrated > 20 Hounsfield Units (HU) for all tumours (median 34 (21-45)), median size 92 mm (20-196), Ki67 17% (1-40%), Weiss score 7 (4-9) and Helsinki score 24 (4-48). ACC was more often found in the left than the right adrenal (p < 0.05). One child had Beckwith-Wiedemann and one a TP53 mutation. In adults, the primary tumour was resected in 88 and 79% received adjuvant mitotane therapy. Median hospital stay was significantly shorter in the laparoscopic vs. open surgery group (4 (3-7) vs. 8 (5-38) days, respectively; p < 0.001). In 3/4 patients, prolonged remission of > 5 to > 10 years was achieved after repeated surgery of metastases. Overall 5-year survival was 67%, and 96% vs. 26% for ENSAT stage I-II vs. III-IV (p < 0.0001). ENSAT stage and Ki67 predicted survival, type of surgery did not. Mitotane associated with better survival. CONCLUSIONS: Contemporary ACC predominantly presents as an incidental imaging finding, characterised by HU > 20 on nonenhanced CT but variable tumour size (20-196 mm). Malignancy cannot be ruled out by small tumour size only. The 5-year survival of 96% in ENSAT stage I-III compares favourably to previous studies.

The who, when, and why of primary adrenal malignancies: Insights into the epidemiology of a rare clinical entity.

BACKGROUND: Primary malignancies of the adrenal glands are rare. Epidemiologic assessment of primary adrenal malignancies is lacking and has been limited to case reports and series. Population-level data can provide a better understanding of the incidence, distribution, and prognostic factors associated with these rare malignancies. METHODS: The Surveillance, Epidemiology, and End Results database (1973-2013) was queried for all patients who were diagnosed with primary adrenal malignancies, categorized in 5 histologic groups: adrenocortical carcinoma (ACC), pheochromocytoma and paraganglioma (PH), neuroblastoma (NE), non-Hodgkin lymphoma (NHL), and sarcoma (SA). Age-adjusted incidence, distribution trends, and cancer-specific survival (CSS) for each group were analyzed. RESULTS: In total, 4695 patients with primary adrenal malignancies were identified, including 2057 with ACC, 512 with PH, 1863 with NE, 202 with NHL, and 61 with SA. The age-adjusted incidence of all 5 histologic subtypes was rising. Age at presentation differed substantially by histologic group: NE was the most prevalent during the first decade of life, whereas ACC predominated after age 30 years, and NHL outnumbered PH after age 70 years. Patient-specific factors were not associated with advanced disease at the time of presentation. The 5-year CSS rate for each histologic subtype was 38% for ACC, 69% for PH, 64% for NE, 38% for NHL, and 42% for SA. Survival outcomes for patients with ACC, NHL, PH and SA remained unchanged over the 40-year study period. Multimodal therapy was associated with higher CSS in patients with NE. CONCLUSIONS: This first population-level analysis of all primary adrenal malignancies provides important initial data regarding presentation and clinical outcomes. Notably, except for patients with NE, the survival of patients with these rare cancers has not improved over the past 40 years.