Volpe C, Höög A, Ogishima T, et al.
Immunohistochemistry improves histopathologic diagnosis in primary aldosteronism.
J Clin Pathol. 2013; 66(4):351-4 [PubMed]

BACKGROUND: In primary aldosteronism (PA) the main source of aldosterone hypersecretion is an aldosterone-producing adenoma (APA) or a bilateral hyperplasia. Histopathology of the adrenal gland from patients with PA has been difficult, as there are no morphological criteria to ascertain which are the cells that produce aldosterone. We therefore applied new specific antibodies to explore which cells in the adrenal contain the enzymes for aldosterone and cortisol production, respectively.
METHODS: Adrenals from 24 patients with PA were studied. After routine preparation, consecutive sections were stained with antibodies for CYP11B1 (cortisol) and CYP11B2 (aldosterone) enzymes.
RESULTS: APA had a strong immunoreactivity for CYB11B2. In adrenals from seven patients, we found no APA, but several nodules with strong CYB11B2 immunoreactivity, indicating aldosterone-producing nodular hyperplasia.
CONCLUSIONS: Immunohistochemistry of adrenal steroidogenic enzymes provides novel diagnostic information. This may become an important part of routine histopathology, and contribute to improved clinical management in PA.

Strosberg JR
Update on the management of unusual neuroendocrine tumors: pheochromocytoma and paraganglioma, medullary thyroid cancer and adrenocortical carcinoma.
Semin Oncol. 2013; 40(1):120-33 [PubMed]

Pheochromocytomas, paragangliomas, and medullary thyroid carcinomas (MTCs) originate in cells that share a common neuroectodermal origin. Like other neuroendocrine neoplasms, they are characterized by a propensity to secrete amines (epinephrine and norepinephrine) and peptide hormones (calcitonin). Improved understanding of underlying molecular pathways, such as mutations of the RET (rearranged during transfection) proto-oncogene, has led to new rational targeted therapies. Adrenocortical carcinomas (ACCs) originate in the steroid hormone-producing adrenal cortex. While tumors of the adrenal cortex are not, strictly speaking, part the "diffuse neuroendocrine system," they are often included in neuroendocrine tumor guidelines due to their orphan status. In this update on management of unusual neuroendocrine tumors, we review the biology and treatment of these rare neoplasms.

Tripto-Shkolnik L, Blumenfeld Z, Bronshtein M, et al.
Pregnancy in a patient with adrenal carcinoma treated with mitotane: a case report and review of literature.
J Clin Endocrinol Metab. 2013; 98(2):443-7 [PubMed]

CONTEXT: Adrenocortical carcinoma (ACC) affects patients in a broad age group, including young women. Mitotane, an adrenolytic agent, is the mainstay of treatment after surgical removal of the tumor. There is extreme paucity of information regarding the effect of mitotane on childbearing potential and pregnancy outcome.
OBJECTIVE: The aim of the study was to describe and discuss the case of an ACC patient who conceived while on mitotane treatment. Current literature is reviewed.
PATIENT AND METHODS: A 33-year-old woman received mitotane treatment for 4 years due to metastatic ACC. Despite nearly therapeutic blood levels of the drug, the patient had regular menstruation and was able to conceive. Mitotane was stopped at gestation week 6. Although the drug continued to be detected in considerable amounts, the fetus developed normally, including morphologically intact adrenal glands. At gestation week 21, pregnancy was terminated due to ACC recurrence. Mitotane levels were undetectable in fetal cord blood and amniotic fluid.
CONCLUSION: Our report suggests that mitotane, despite its action as an endocrine disruptor, does not affect normal gonadal function or an ability to conceive. The concern of placental transfer by this hydrophobic compound is not supported by our findings. However, we do not recommend drawing conclusions regarding the safety of mitotane in pregnancy, based on 1 or several case reports. Until more data are available, pregnancy should be avoided in women being treated with mitotane for ACC.

Huyghe E, Crenn G, Duly-Bouhanick B, et al.
Retroperitoneoscopic adrenalectomy: comparison of retrograde and antegrade approach among a series of 279 cases.
Urology. 2013; 81(1):85-91 [PubMed]

OBJECTIVE: To compare the results of retroperitoneal laparoscopic adrenalectomy using the antegrade and retrograde approach.
MATERIALS AND METHODS: We performed an analysis of a single-center series of 279 retroperitoneal laparoscopic adrenalectomies from 1996 to 2010. We compared 172 cases performed with an antegrade approach and 107 with a retrograde approach without dissection of the renal hilum and initial control of the adrenal vein in comparable populations.
RESULTS: The operative time was shorter in the group treated with the retrograde technique, 101±51 vs 140±40 minutes, respectively (Student's t test, P<.001). Blood loss was similar in both groups, 85±224 vs 80±126 mL, respectively (P=NS). Hemodynamic instability was defined as the maximal systolic blood pressure minus the minimal systolic blood pressure divided the maximal systolic blood pressure. It was lower in the group who underwent the retrograde technique (32.7 vs 37.6 mL; Student's t test, P=.005) with a lower perioperative consumption of ephedrine (2.2 vs 5.1 mg, P=.004) and atropine (0.09 vs 0.22 mg, P=.026). No difference was found between the 2 groups in the frequency of perioperative complications or postoperative mortality (1 death in each group of causes unrelated to the surgery).
CONCLUSION: Retroperitoneal laparoscopic adrenalectomy using a retrograde approach is a safe and reproducible technique. It makes it possible to perform adrenalectomy without dissection of the renal hilum, with a reduction in the operative time. The good hemodynamic stability observed with this technique makes it very attractive for the treatment of pheochromocytoma.

Rossitto G, Regolisti G, Rossi E, et al.
Elevation of angiotensin-II type-1-receptor autoantibodies titer in primary aldosteronism as a result of aldosterone-producing adenoma.
Hypertension. 2013; 61(2):526-33 [PubMed]

The mechanisms of excess aldosterone secretion in primary aldosteronism (PA) remain poorly understood, although a role for circulating factors has been hypothesized for decades. Agonistic autoantibodies against type-1 angiotensin-II receptor (AT1AA) are detectable in malignant hypertension and preeclampsia and might play a role in PA. Moreover, if they were elevated in aldosterone-producing adenoma (APA) and not in idiopathic hyperaldosteronism (IHA), they might be useful for discriminating between these conditions. To test these hypotheses, we measured the titer of AT1AA in serum of 46 patients with PA (26 with APA, 20 with IHA), 62 with primary hypertension (PH), 13 preeclamptic women, and 45 healthy normotensive blood donors.We found that the AT1AA titer was higher (P<0.05) in both PA and PH patients (2.65 ± 1.55 and 1.86 ± 0.63, respectively) than in normotensive subjects (1.00 ± 0.20). In APA, it was 2-fold higher than in IHA patients (3.43 ± 1.20 versus 1.64 ± 1.39, respectively, P<0.001), despite similar blood pressure values. Of note, it allowed effective discrimination of APA from either PH or IHA, as shown by Receiver Operator Characteristics curve analysis. Moreover, after captopril challenge, plasma aldosterone concentration fell more in AT1AA-positive than in AT1AA-negative PA patients (-32.4% [21.1-42.9] versus 0.0% [0.0-22.6], P=0.015), suggesting an agonistic role for these autoantibodies. Thus, a higher serum AT1AA titer in patients with APA than in IHA and PH patients can be useful in differentiating APA patients from either PH or IHA, and thus in selecting PA patients to be submitted to adrenal vein sampling.

Raymond VM, Else T, Everett JN, et al.
Prevalence of germline TP53 mutations in a prospective series of unselected patients with adrenocortical carcinoma.
J Clin Endocrinol Metab. 2013; 98(1):E119-25 [PubMed] Article available free on PMC after 01/01/2014

PURPOSE: Adrenocortical carcinoma (ACC) is a hallmark cancer in families with Li Fraumeni syndrome (LFS) caused by mutations in the TP53 gene. The prevalence of germline TP53 mutations in children diagnosed with ACC ranges from 50-97%. Although existing criteria advocate for TP53 testing in all patients with ACC regardless of age at diagnosis, the overall prevalence of germline mutations in patients diagnosed with ACC has not been well studied.
PATIENTS AND METHODS: A total of 114 patients with confirmed ACC evaluated in the University of Michigan Endocrine Oncology Clinic were prospectively offered genetic counseling and TP53 genetic testing, regardless of age at diagnosis or family history. Ninety-four of the 114 patients met with a genetic counselor (82.5%), with 53 of 94 (56.4%) completing TP53 testing; 9.6% (nine of 94) declined testing. The remainder (32 of 94; 34%) expressed interest in testing but did not pursue it for various reasons.
RESULTS: Four of 53 patients in this prospective, unselected series were found to have a TP53 mutation (7.5%). The prevalence of mutations in those diagnosed over age 18 was 5.8% (three of 52). There were insufficient data to estimate the prevalence in those diagnosed under age 18. None of these patients met clinical diagnostic criteria for classic LFS. Three of the families met criteria for Li Fraumeni-like syndrome; one patient met no existing clinical criteria for LFS or Li Fraumeni-like syndrome. Three of the four patients with mutations were diagnosed with ACC after age 45.
CONCLUSIONS: Genetic counseling and germline testing for TP53 should be offered to all patients with ACC. Restriction on age at diagnosis or strength of the family history would fail to identify mutation carriers.

Ganeshan D, Bhosale P, Kundra V
Current update on cytogenetics, taxonomy, diagnosis, and management of adrenocortical carcinoma: what radiologists should know.
AJR Am J Roentgenol. 2012; 199(6):1283-93 [PubMed]

OBJECTIVE: A multimodality imaging spectrum of adrenocortical carcinoma, with an emphasis on both anatomic and functional imaging, will be reviewed. Recent advances in the molecular cytogenetics of this tumor and its impact on diagnosis, prognosis, and development of newer targeted therapy will be discussed in this article.
CONCLUSION: Adrenocortical carcinomas are rare aggressive tumors associated with a poor prognosis. Awareness of the molecular behavior and spectrum of imaging features of this tumor can help in appropriate patient treatment.

Chortis V, Taylor AE, Schneider P, et al.
Mitotane therapy in adrenocortical cancer induces CYP3A4 and inhibits 5α-reductase, explaining the need for personalized glucocorticoid and androgen replacement.
J Clin Endocrinol Metab. 2013; 98(1):161-71 [PubMed]

CONTEXT: Mitotane [1-(2-chlorophenyl)-1-(4-chlorophenyl)-2,2-dichloroethane] is the first-line treatment for metastatic adrenocortical carcinoma (ACC) and is also regularly used in the adjuvant setting after presumed complete removal of the primary tumor. Mitotane is considered an adrenolytic substance, but there is limited information on distinct effects on steroidogenesis. However, adrenal insufficiency and male hypogonadism are widely recognized side effects of mitotane treatment.
OBJECTIVE: Our objective was to define the impact of mitotane treatment on in vivo steroidogenesis in patients with ACC.
SETTING AND DESIGN: At seven European specialist referral centers for adrenal tumors, we analyzed 24-h urine samples (n = 127) collected from patients with ACC before and during mitotane therapy in the adjuvant setting (n = 23) or for metastatic ACC (n = 104). Urinary steroid metabolite excretion was profiled by gas chromatography/mass spectrometry in comparison with healthy controls (n = 88).
RESULTS: We found a sharp increase in the excretion of 6β-hydroxycortisol over cortisol (P < 0.001), indicative of a strong induction of the major drug-metabolizing enzyme cytochrome P450 3A4. The contribution of 6β-hydroxycortisol to total glucocorticoid metabolites increased from 2% (median, interquartile range 1-4%) to 56% (39-71%) during mitotane treatment. Furthermore, we documented strong inhibition of systemic 5α-reductase activity, indicated by a significant decrease in 5α-reduced steroids, including 5α-tetrahydrocortisol, 5α-tetrahydrocorticosterone, and androsterone (all P < 0.001). The degree of inhibition was similar to that in patients with inactivating 5α-reductase type 2 mutations (n = 23) and patients receiving finasteride (n = 5), but cluster analysis of steroid data revealed a pattern of inhibition distinct from these two groups. Longitudinal data showed rapid onset and long-lasting duration of the observed effects.
CONCLUSIONS: Cytochrome P450 3A4 induction by mitotane results in rapid inactivation of more than 50% of administered hydrocortisone, explaining the need for doubling hydrocortisone replacement in mitotane-treated patients. Strong inhibition of 5α-reductase activity is in line with the clinical observation of relative inefficiency of testosterone replacement in mitotane-treated men, calling for replacement by 5α-reduced androgens.

Miller BS, Gauger PG, Hammer GD, Doherty GM
Resection of adrenocortical carcinoma is less complete and local recurrence occurs sooner and more often after laparoscopic adrenalectomy than after open adrenalectomy.
Surgery. 2012; 152(6):1150-7 [PubMed]

BACKGROUND: Controversy surrounds the use of laparoscopy for resection of adrenocortical carcinoma. We evaluated the hypothesis that outcome is equivalent in patients undergoing laparoscopic adrenalectomy versus open adrenalectomy.
METHODS: This is a retrospective review of 217 patients (156 patients with stage I-III cancer) with adrenocortical carcinoma referred to a single institution between 2005 and 2011. Outcome and operative data were assessed for the subset undergoing resection with curative intent. Student t and Fisher exact tests and the Kaplan-Meier method were used to compare data (P ≤ .05 was considered statistically significant).
RESULTS: One hundred fifty-six patients (64% female; median age, 47 years [range, 18-80]; median follow-up, 26.5 months [range, 1-188]) were identified. Forty-six patients underwent laparoscopic adrenalectomy, and 110 underwent open adrenalectomy. Twenty-seven percent of laparoscopic adrenalectomy patients had stage III cancer. After laparoscopic adrenalectomy, 30% had positive margins or intraoperative tumor spill compared to 16% of the open adrenalectomy patients (P = .04). Overall survival for patients with stage II cancer was longer in those undergoing open adrenalectomy (P = .002). Time to visible tumor bed recurrence or peritoneal recurrence in stage II patients was shorter in laparoscopic adrenalectomy patients (P = .002).
CONCLUSION: Open adrenalectomy is superior to laparoscopic adrenalectomy for adrenocortical carcinoma based on completeness of resection, site and timing of initial tumor recurrence, and survival in stage II patients. Intraoperative evaluation is insensitive for the detection of stage III tumors.

Iacobone M, Citton M, Viel G, et al.
Adrenalectomy may improve cardiovascular and metabolic impairment and ameliorate quality of life in patients with adrenal incidentalomas and subclinical Cushing's syndrome.
Surgery. 2012; 152(6):991-7 [PubMed]

BACKGROUND: Adrenalectomy represents the definitive treatment in clinically evident Cushing's syndrome; however, the most appropriate treatment for patients with subclinical Cushing's syndrome (SCS) with an adrenal incidentaloma remains controversial. This study was aimed to assess whether adrenalectomy may improve cardiovascular and metabolic impairment and quality of life compared with conservative management.
METHODS: Twenty patients with adrenal incidentaloma underwent laparoscopic adrenalectomy for SCS, whereas 15 were managed conservatively. Hormonal laboratory parameters of corticosteroid secretion, arterial blood pressure (BP), glycometabolic profile, and quality of life (by the SF-36 questionnaire) were compared at baseline and the end of follow-up.
RESULTS: The 2 groups were equivalent concerning all the examined parameters at baseline. In the operative group, laboratory corticosteroid parameters normalized in all patients but not in the conservative-management group (P < .001). In operated patients, a decrease in BP occurred in 53% of patients, glycometabolic control improved in 50%, and body mass index decreased; in contrast, no improvement or some worsening occurred in the conservative-management group (P < .01). SF-36 evaluation improved in the operative group (P < .05).
CONCLUSION: Adrenalectomy can be more beneficial than conservative management in SCS and may achieve remission of laboratory hormonal abnormalities and improve BP, glycemic control, body mass index, and quality of life.

Erdogan I, Deutschbein T, Jurowich C, et al.
The role of surgery in the management of recurrent adrenocortical carcinoma.
J Clin Endocrinol Metab. 2013; 98(1):181-91 [PubMed]

CONTEXT: Surgery is the standard of care for localized adrenocortical carcinomas, but its role for recurrent disease is not well defined.
OBJECTIVE: Our objective was to evaluate clinical outcome after surgery for recurrence.
DESIGN: We conducted a retrospective analysis in 154 patients with first recurrence after initial radical resection from the German Adrenocortical Carcinoma Registry.
MAIN OUTCOME MEASURES: We evaluated progression-free survival (PFS) and overall survival (OS) by Kaplan-Meier method and identified prognostic factors by Cox regression analysis.
RESULT: A total of 101 patients underwent repeated surgery (radical resection, n = 78), and 99 received (additional) nonsurgical therapy. After a median of 6 (1-221) months, 144 patients (94%) experienced progression. Multivariate analysis adjusted for age, sex, tumor burden, time to first recurrence (TTFR), surgery for recurrence (including resection status), and additional therapy indicated that only two factors were significantly associated with shorter PFS [hazard ratio for progression: for TTFR ≤ 12 months, 1.8 (95% confidence interval = 1.3-2.6) vs. TTFR > 12 months; for macroscopically incomplete resection, 3.4 (1.5-7.9), and for no surgery, 3.4 (1.6-7.0) vs. microscopically complete (R0)-resection and OS [hazard ratio for death: for TTFR > 12 months, 3.1 (2.0-4.7) vs. TTFR ≤ 12 months; for macroscopically incomplete resection, 2.7 (1.1-6.9), and no surgery, 4.2 (1.8-9.6) vs. R0-resection]. Patients who had both TTFR over 12 months and R0-resection of recurrent tumors (n = 22) had the best prognosis (median PFS, 24 months; median OS, >60 months).
CONCLUSIONS: The best predictors of prolonged survival after first recurrence are TTFR over 12 months and R0-resection. Our data suggest that patients with longer TTFR and tumors amenable to radical resection should be operated, whereas individualized treatment decisions are needed for patients with short TTFR or with not completely resectable tumors.

Habra MA, Ejaz S, Feng L, et al.
A retrospective cohort analysis of the efficacy of adjuvant radiotherapy after primary surgical resection in patients with adrenocortical carcinoma.
J Clin Endocrinol Metab. 2013; 98(1):192-7 [PubMed] Article available free on PMC after 01/01/2014

CONTEXT: Adrenocortical carcinoma (ACC) is a rare malignancy with high recurrence and mortality rates. The role of adjuvant radiation therapy (RT) to improve outcome remains unclear.
OBJECTIVE: The aim of this study was to evaluate the impact of adjuvant RT on overall survival and recurrence rates of ACC patients.
DESIGN: We conducted a retrospective cohort study of select ACC patients who were seen at The University of Texas MD Anderson Cancer Center (MDACC) between 1998 and 2011. All patients in this study underwent primary tumor resection and received adjuvant RT within 3 months of primary surgical resection prior to referral to the MDACC. We compared patients who had surgery and adjuvant RT with patients who had surgery alone.
RESULTS: Baseline characteristics and adjuvant mitotane use were not significantly different between the adjuvant RT group (n = 16) and the non-RT group (n = 32). Local recurrence occurred in seven patients (43.8%) who received RT and 10 patients (31.3%) in the control group. At 5 yr, the estimated local recurrence-free rate (95% confidence interval) was 53% (32-87%) in the RT group and 67% (52-86%) in the non-RT group (P = 0.53). The distributions of time to distant recurrence and recurrence-free survival were not significantly different between the two groups. Using a multivariate Cox proportional hazards model for overall survival, the hazard ratio for RT use was 1.593 (95% confidence interval, 0.707-3.589; P = 0.26) after adjusting for stage and adjuvant mitotane therapy.
CONCLUSIONS: ACC has high rates of recurrence. In our study, RT did not improve clinical outcomes in patients who received their initial care in the community. We believe there is a need for a collaborative, multicenter, prospective randomized trial to evaluate the role of adjuvant treatments (both mitotane and RT) to assess their impact on recurrence patterns and survival.

Redlich A, Boxberger N, Strugala D, et al.
Systemic treatment of adrenocortical carcinoma in children: data from the German GPOH-MET 97 trial.
Klin Padiatr. 2012; 224(6):366-71 [PubMed]

BACKGROUND: Adrenocortical cancer (ACC) in childhood is a rare disease with poor prognosis. Complete surgical resection, systemic chemotherapy, and mitotane therapy are important curative treatment options for patients with advanced-stage tumors. Since 1997, pediatric ACC patients in Germany have been treated according to the non-randomized, single arm study GPOH-MET-97.
PATIENTS AND METHODS: Data regarding disease course, treatment, and survival rates of 60 patients (age 0.24-17.8 years) with ACC treated according to the GPOH-MET-97 protocol were collected and analyzed to determine outcome, with a focus on examining the effectiveness of mitotane therapy.
RESULTS: Among all patients, event-free survival and overall survival were found to be 43.3% and 64.8%, respectively. Chemotherapy with VCR, IFO, ADR, CARBO, and VP16 had been provided to 34 patients (56.6%) in different settings (neoadjuvant, adjuvant, and salvage) and mitotane therapy to 32 patients (53.3%). Duration of mitotane treatment longer than 6 months and mitotane levels greater than 14 mg/l were found to be associated with significantly better survival. Local relapse was found to be associated with a worse prognosis compared to distant metastasis only.
CONCLUSIONS: Systemic chemotherapy and mitotane therapy are important therapeutic options in the treatment of advanced pediatric ACC patients. Neoadjuvant therapy should be considered for patients with primarily incomplete resectable or inoperable tumors, and tumor spillage is an indication for adjuvant chemo- and mitotane therapy. All pediatric ACC patients should be treated in pediatric oncological centers according to a consistent protocol in a highly interdisciplinary setting.

Sidhu A, Debelenko L, Misra VK
Infantile adrenocortical tumor with an activating GNAS1 mutation.
J Clin Endocrinol Metab. 2013; 98(1):E115-8 [PubMed]

CONTEXT: Pediatric adrenocortical tumors (ACTs) are rare and are frequently associated with tumor predisposition syndromes. Somatic GNAS1 mutations are associated with adrenocortical hyperplasia, but have not typically been reported in ACTs.
OBJECTIVE: We report on genetic and histopathological findings in a 3-month-old infant presenting with a unilateral cortisol-producing ACT with malignant features.
METHODS: We performed a detailed clinical evaluation of the patient along with molecular genetic testing of genes associated with ACTs in both tumor tissue and peripheral lymphocytes. We also performed a histopathological analysis of the tumor tissue.
RESULTS: The patient was found to have a p.R201C-activating mutation in exon 8 of the GNAS1 gene in adrenocortical tumor tissue but not peripheral lymphocytes. This mutation is the characteristic genetic change in McCune-Albright syndrome. In contrast to previously reported GNAS1-positive tumors characterized by bimodal diffuse and nodular adrenocortical hypertrophy, our patient had a single adrenocortical mass that showed features of malignancy, including areas of necrosis, microcystic degeneration, and venous and capsular microinvasion-changes that have been seen previously in Beckwith-Wiedemann syndrome. However, our patient did not have clinical features of Beckwith-Wiedemann syndrome. Further analysis revealed abnormal allele-specific hypomethylation of the KCNQ1OT1 gene in the tumor sample but not peripheral lymphocytes.
CONCLUSION: This is a novel case of an activating GNAS1 mutation associated with an epigenetic alteration that may be related to adrenocortical tumorigenesis. Our findings may have implications in the molecular pathogenesis of pediatric ACTs.

Lin CI, Whang EE, Moalem J, Ruan DT
Strategic combination therapy overcomes tyrosine kinase coactivation in adrenocortical carcinoma.
Surgery. 2012; 152(6):1045-50 [PubMed]

BACKGROUND: Coactivation of tyrosine kinase limits the efficacy of tyrosine kinase inhibitors. We hypothesized that a strategic combination therapy could overcome tyrosine kinase coactivation and compensatory oncogenic signaling in patients with adrenocortical carcinoma (ACC).
METHODS: We profiled 88 tyrosine kinases before and after treatment with sunitinib in H295R and SW13 ACC cells. The effects of monotherapy and strategic combination regimens were determined by the 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (ie, MTS) assay.
RESULTS: The minimum inhibitory concentrations (IC(min)) of sunitinib quenched its primary targets: FLT-3, VEGFR-2, and RET. In contrast, ERK, HCK, Chk2, YES, CREB, MEK, MSK, p38, FGR, and AXL were hyperactivated. Monotherapy with sunitinib or PD98059 at their IC(min) reduced proliferation by 23% and 19%, respectively, in H295R cells and by 25% and 24%, respectively, in SW13 cells. Sunitinib and PD98059 in combination decreased proliferation by 68% and 64% in H295R and in SW13 cells, respectively (P < .05 versus monotherapy). The effects of combination treatment exceeded the sum of the effects observed with each individual agent alone.
CONCLUSION: We describe the first preclinical model to develop strategic combination therapy to overcome tyrosine kinase coactivation in ACC. Because many tyrosine kinase inhibitors are readily available, this model can be immediately tested in clinical trials for patients with advanced ACC.

Barreau O, Assié G, Wilmot-Roussel H, et al.
Identification of a CpG island methylator phenotype in adrenocortical carcinomas.
J Clin Endocrinol Metab. 2013; 98(1):E174-84 [PubMed]

PURPOSE: DNA methylation is a mechanism for gene expression silencing in cancer. Limited information is available for adrenocortical tumors. Abnormal methylation at the IGF2/H19 locus is common in adrenocortical carcinomas. Our aim was to characterize the methylation in adrenocortical carcinomas at a whole-genome scale and to assess its clinical significance and its impact on gene expression.
EXPERIMENTAL DESIGN: Methylation patterns of CpG islands in promoter regions of 51 adrenocortical carcinomas and 84 adenomas were studied by the Infinium HumanMethylation27 Beadchip (Illumina, San Diego, CA). Methylation of 33 genes was studied by methylation-specific multiplex ligation-dependent probe amplification (MRC-Holland, Amsterdam, The Netherlands) in 15 carcinomas. Gene expression data were available for 87 tumors from a previous study (HG-U133Plus2.0 AffymetrixGeneChip; Affymetrix, Santa Clara, CA). Clinical information, including patient features and survival, were available for all tumors.
RESULTS: Methylation was higher in carcinomas than in adenomas (t test P = 3.1 × 10(-9)). Unsupervised clustering of DNA methylation profiles identified two groups of carcinomas, one with an elevated methylation level, evoking a CpG island methylator phenotype (CIMP). The subgroup of hypermethylated carcinomas was further divided in two subgroups, with different levels of methylation (CIMP-high and CIMP-low). This classification could be confirmed by methylation-specific multiplex ligation-dependent probe amplification. Hypermethylation was associated with a poor survival (Cox model P = 0.02). The transcriptome/methylation correlation showed 1741 genes (of 12,250) negatively correlated; among the top genes were H19 and other tumor suppressors (PLAGL-1, G0S2, and NDRG2).
CONCLUSIONS: This genome-wide methylation analysis reveals the existence of hypermethylated adrenocortical carcinomas, with a poorer prognosis. Hypermethylation in these tumors is important for silencing specific tumor suppressor genes.

Sirianni R, Zolea F, Chimento A, et al.
Targeting estrogen receptor-α reduces adrenocortical cancer (ACC) cell growth in vitro and in vivo: potential therapeutic role of selective estrogen receptor modulators (SERMs) for ACC treatment.
J Clin Endocrinol Metab. 2012; 97(12):E2238-50 [PubMed]

CONTEXT: Adrenocortical carcinoma (ACC) is a rare tumor with a very poor prognosis and no effective treatment. ACC is characterized by an increased production of IGF-II and by estrogen receptor (ER)-α up-regulation.
OBJECTIVE: The objective of this study was to define the role played by ERα in 17β-estradiol (E2)- and IGF-II-dependent ACC growth and evaluate whether selective estrogen receptor modulators are effective in controlling ACC growth in vivo.
EXPERIMENTAL DESIGN: The human adrenocortical cell line H295R was used as an in vitro model and to generate xenograft tumors in athymic nude mice.
RESULTS: In H295R cells IGF-II controlled expression of steroidogenic factor-1 that, in turn, increased aromatase transcription and, consequently, estrogen production, inducing cell proliferation. ERα silencing significantly blocked E2- and IGF-II-dependent cell proliferation. This effect was dependent on the regulation of cyclin D1 expression by ERα, activated in response to both E2 and IGF-II. In fact, IGF-II induced ERα activation by phosphorylating serine 118 and 167. Furthermore, we demonstrated that ERα mediated E2-induced nongenomic signaling that stimulated IGF-I receptor (IGF1R), ERK1/2, and AKT phosphorylation, resulting in a ligand-independent activation of the IGF1R-induced pathway. In addition, E2 potentiated this pathway by up-regulating IGF1R expression as a consequence of increased cAMP-responsive element binding protein activation and binding to IGF1R promoter. The estrogen antagonist, hydroxytamoxifen, the active metabolite of tamoxifen, reduced IGF1R protein levels and both E2- and IGF-II-induced cell proliferation. Moreover, H295R xenograft growth was strongly reduced by tamoxifen.
CONCLUSION: These findings establish a critical role for ERα in E2- and IGF-II-dependent ACC proliferation and provide a rationale for targeting ERα to control the proliferation of ACC.

Lombardi CP, Raffaelli M, De Crea C, et al.
Open versus endoscopic adrenalectomy in the treatment of localized (stage I/II) adrenocortical carcinoma: results of a multiinstitutional Italian survey.
Surgery. 2012; 152(6):1158-64 [PubMed]

BACKGROUND: We compared the oncologic effectiveness of open adrenalectomy and endoscopic adrenalectomy in the treatment of patients with localized adrenocortical carcinoma.
METHODS: One hundred fifty-six patients with localized adrenocortical carcinoma (stage I/II) who underwent R0 resection were included in an Italian multiinstitutional surgical survey. They were divided into 2 groups based on the operative approach (either conventional or endoscopic).
RESULTS: One hundred twenty-six patients underwent open adrenalectomy and 30 patients underwent endoscopic adrenalectomy. The 2 groups were well matched for age, sex, lesion size, and stage (P = NS). The mean follow-up time was similar for the 2 groups (P = NS). The local recurrence rate was 19% for open adrenalectomy and 21% for endoscopic adrenalectomy, whereas distant metastases were recorded in 31% of patients in the conventional adrenalectomy group and 17% in the endoscopic adrenalectomy group (P = NS). The mean time to recurrence was 27 ± 27 months in the conventional open adrenalectomy group and 29 ± 33 months in the endoscopic adrenalectomy group (P = NS). No significant differences were found between the 2 groups in terms of 5-year disease-free survival (38.3% vs 58.2%) and 5-year overall survival rates (48% vs 67%; P = NS).
CONCLUSION: The operative approach does not affect the oncologic outcome of patients with localized adrenocortical carcinoma, if the principles of surgical oncology are respected.

Hofland J, de Herder WW, Derks L, et al.
Regulation of steroidogenesis in a primary pigmented nodular adrenocortical disease-associated adenoma leading to virilization and subclinical Cushing's syndrome.
Eur J Endocrinol. 2013; 168(1):67-74 [PubMed]

CONTEXT: Primary pigmented nodular adrenocortical disease (PPNAD) can lead to steroid hormone overproduction. Mutations in the cAMP protein kinase A regulatory subunit type 1A (PRKAR1A) are causative of PPNAD. Steroidogenesis in PPNAD can be modified through a local glucocorticoid feed-forward loop.
OBJECTIVE: Investigation of regulation of steroidogenesis in a case of PPNAD with virilization.
MATERIALS AND METHODS: A 33-year-old woman presented with primary infertility due to hyperandrogenism. Elevated levels of testosterone and subclinical ACTH-independent Cushing's syndrome led to the discovery of an adrenal tumor, which was diagnosed as PPNAD. In vivo evaluation of aberrantly expressed hormone receptors showed no steroid response to known stimuli. Genetic analysis revealed a PRKAR1A protein-truncating Q28X mutation. After adrenalectomy, steroid levels normalized. Tumor cells were cultured and steroidogenic responses to ACTH and dexamethasone were measured and compared with those in normal adrenal and adrenocortical carcinoma cells. Expression levels of 17β-hydroxysteroid dehydrogenase (17β-HSD) types 3 and 5 and steroid receptors were quantified in PPNAD, normal adrenal, and adrenal adenoma tissues.
RESULTS: Isolated PPNAD cells, analogous to normal adrenal cells, showed both increased steroidogenic enzyme expression and steroid secretion in response to ACTH. Dexamethasone did not affect steroid production in the investigated types of adrenal cells. 17β-HSD type 5 was expressed at a higher level in the PPNAD-associated adenoma compared with control adrenal tissue.
CONCLUSION: PPNAD-associated adenomas can cause virilization and infertility by adrenal androgen overproduction. This may be due to steroidogenic control mechanisms that differ from those described for PPNAD without large adenomas.

Ronchi CL, Sbiera S, Leich E, et al.
Low SGK1 expression in human adrenocortical tumors is associated with ACTH-independent glucocorticoid secretion and poor prognosis.
J Clin Endocrinol Metab. 2012; 97(12):E2251-60 [PubMed] Article available free on PMC after 01/01/2014

CONTEXT: Using single-nucleotide polymorphism analysis, we observed allelic loss of the gene for serum glucocorticoid (GC) kinase 1 (SGK1), a GC-responsive kinase involved in multiple cellular functions, in a subset of cortisol-secreting adenomas.
OBJECTIVE: Our objective was to analyze SGK1 expression in adrenocortical tumors and to further characterize its role in ACTH-independent cortisol secretion, tumor progression, and prognosis.
DESIGN AND SETTING: Gene expression levels of SGK1, SGK3, and CTNNB1 (coding for β-catenin) and protein expression levels of SGK1, nuclear β-catenin, and phosphorylated AKT were determined in adrenocortical tumors and normal adrenal glands.
PATIENTS: A total of 227 adrenocortical tumors (40 adenomas and 187 carcinomas) and 25 normal adrenal tissues were included. Among them, 62 frozen tumor samples were used for mRNA analysis and 203 tumors were investigated on tissue microarrays or full standard slides by immunohistochemistry.
MAIN OUTCOME MEASURES: We evaluated the relationship between SGK1 mRNA and/or protein levels and clinical parameters.
RESULTS: SGK1 mRNA levels were lower in cortisol-secreting than in nonsecreting tumors (P < 0.005). Nonsecreting neoplasias showed a significant correlation between SGK1 and CTNNB1 mRNA levels (P < 0.001; r = 0.57). Low SGK1 protein levels, but not nuclear β-catenin and phosphorylated AKT, were associated with poor overall survival in patients with adrenocortical carcinoma (P < 0.005; hazard ratio = 2.0; 95% confidence interval = 1.24-3.24), independent of tumor stage and GC secretion.
CONCLUSION: Low SGK1 expression is related to ACTH-independent cortisol secretion in adrenocortical tumors and is a new prognostic factor in adrenocortical carcinoma.

Sampaoli C, Cerquetti L, Gawhary RE, et al.
p53 Stabilization induces cell growth inhibition and affects IGF2 pathway in response to radiotherapy in adrenocortical cancer cells.
PLoS One. 2012; 7(9):e45129 [PubMed] Article available free on PMC after 01/01/2014

Adrenocortical carcinoma (ACC) is a very rare endocrine tumour, with variable prognosis, depending on tumour stage and time of diagnosis. However, it is generally fatal, with an overall survival of 5 years from detection. Radiotherapy usefulness for ACC treatment has been widely debated and seems to be dependent on molecular alterations, which in turn lead to increased radio-resistance. Many studies have shown that p53 loss is an important risk factor for malignant adrenocortical tumour onset and it has been reported that somatic mutations in TP53 gene occur in 27 to 70% of adult sporadic ACCs. In this study, we investigated the role of somatic mutations of the TP53 gene in response to ionizing radiation (IR). We studied the status of p53 in two adrenocortical cell lines, H295R and SW-13, harbouring non-functioning forms of this protein, owing to the lack of exons 8 and 9 and a point mutation in exon 6, respectively. Moreover, these cell lines show high levels of p-Akt and IGF2, especially H295R. We noticed that restoration of p53 activity led to inhibition of growth after transient transfection of cells with wild type p53. Evaluation of their response to IR in terms of cell proliferation and viability was determined by means of cell count and TUNEL assay.(wt)p53 over-expression also increased cell death by apoptosis following radiation in both cell lines. Moreover, RT-PCR and Western blotting analysis of some p53 target genes, such as BCL2, IGF2 and Akt demonstrated that p53 activation following IR led to a decrease in IGF2 expression. This was associated with a reduction in the active form of Akt. Taken together, these results highlight the role of p53 in response to radiation of ACC cell lines, suggesting its importance as a predictive factor for radiotherapy in malignant adrenocortical tumours cases.

Perrino CM, Prall DN, Calomeni EP, et al.
Ultrastructural findings in adrenal cortical adenomas clinically mimicking pheochromocytoma: a comparison with other adrenal tumors and tissue preparation techniques.
Ultrastruct Pathol. 2012; 36(5):287-93 [PubMed]

Adrenal cortical tumors clinically mimicking pheochromocytomas are extremely rare, with 14 cases in the literature. The authors describe 2 patients with adrenal cortical adenoma (ACA) and catecholamine elevations. The impact of tissue preparation methods on electron microscopy (EM) images was assessed in ACA mimicking pheochromocytoma, pheochromocytoma, and ACA lacking pheochromocytoma-like symptoms. Ten adrenal cortical tumors were examined using EM after a variety of tissue preparation techniques, including fixation with glutaraldehyde, formalin for varying lengths of time followed by glutaraldehyde, and/or formalin followed by paraffin embedding. Electron micrographs were assessed for image quality and the presence of dense secretory granules and eccentric, norepinephrine (NE)-type granules. Images created from tissue fixed in glutaraldehyde and/or formalin and embedded in resin were of good quality, while those derived from paraffin-embedded specimens were poor with disrupted cellular architecture. When pheochromocytoma was fixed in glutaraldehyde for 24 h or in formalin for 8 days, eccentric granules were identified. These granules were absent when tissue was fixed in formalin for 20 days or was obtained from a paraffin block. ACA without pheochromocytoma-like symptoms and ACA mimicking pheochromocytoma both had noneccentric dense-core granules on EM regardless of tissue preparation, and eccentric NE-type granules were absent. ACA is a rare cause of pheochromocytoma-like symptoms. These tumors lack eccentric, NE-type dense-core granules present in pheochromocytoma. Glutaraldehyde alone or formalin fixation followed by glutaraldehyde produces electron micrographs that may aid in the diagnosis of adrenal cortical tumors, whereas formalin-fixed, paraffin-embedded tissue results in images that are inadequate.

Ippersiel V, Rosière A, Michel L, Donckier J
Misleading diagnosis of renal artery stenosis by magnetic resonance angiography in a patient with primary aldosteronism.
Acta Chir Belg. 2012 Jul-Aug; 112(4):302-6 [PubMed]

A 24-year-old woman presented with severe hypertension. A diagnostic evaluation for secondary hypertension was undertaken. A duplex ultrasonography followed by a magnetic angiography suspected fibromuscular dysplasia. Unexpectedly, a contrast-enhanced angiography performed for renal angioplasty showed normal renal arteries. Primary aldosteronism was then evoked on the basis of decreased plasma renin and increased plasma aldosterone and aldosterone/renin ratio. After a CT-scan disclosed a left adrenal tumour, the patient underwent a left laparoscopic adrenalectomy. Pathological findings confirmed a benign adrenocortical adenoma. Blood pressure and aldosterone levels were normalized after surgery. Thus, clinicians should be aware of false-positive results of magnetic resonance angiography that could hide other causes of secondary hypertension.

Kotteas E, Ioachim E, Pavlidis N
A pregnant patient with adrenocortical carcinoma: case report.
Onkologie. 2012; 35(9):517-9 [PubMed]

BACKGROUND: Coexistence of an adrenocortical carcinoma and pregnancy is extremely rare with only 25 described cases so far, and has a poor prognosis.
CASE REPORT: We report the case of a 28-year-old patient with adrenocortical carcinoma initially presenting with Cushing's syndrome and pre-eclampsia in the 22nd week of gestation, treated in our department. She underwent adrenalectomy, but eventually died from metastatic disease. We focus on existing treatment options and concerns for this rare malignancy during pregnancy.
CONCLUSION: Early diagnosis and surgery are the cornerstones for better outcome.

Nilubol N, Zhang L, Shen M, et al.
Four clinically utilized drugs were identified and validated for treatment of adrenocortical cancer using quantitative high-throughput screening.
J Transl Med. 2012; 10:198 [PubMed] Article available free on PMC after 01/01/2014

BACKGROUND: Drug repurposing for cancer treatment is an emerging approach to discover clinically approved drugs that demonstrate antineoplastic effect. The effective therapeutics for patients with advanced adrenocortical carcinoma(ACC) are greatly needed. The objective of this study was to identify and validate drugs with antineoplastic effect in ACC cells using a novel quantitative high-throughput drug screening (qHTS) technique.
METHODS: A quantitative high-throughput proliferation assay of 2,816 clinically approved drugs was performed in the NCI-H295R ACC cell line. We validated the antiproliferative effect of candidate compounds in NCI-H295R cells. Further validation was performed in 3-dimensional multicellular aggregates (MCA) of NCI-H295R and SW-13 cell lines.
RESULTS: We identified 79 active compounds against ACC cells; 21 had an efficacy ≥ 60% and IC50 <1 μM. The top drug categories enriched were cardiotonic, antiseptic, and antineoplastic. We selected Bortezomib, ouabain, Methotrexate, pyrimethamine for validation. All had an antiproliferative effect in monolayer culture of NCI-H295R cells at clinical achievable serum level. Bortezomib and ouabain inhibited growth of MCA in both cell lines at a low concentration (10 fold below IC50). Methotrexate inhibited growth and caused disintegration of MCA in both cell lines at concentrations well below the maximum serum level (10 to 100 fold of IC50). Pyrimethamine caused growth inhibition in both cell lines at 10 fold of IC50 concentration.
CONCLUSIONS: qHTS of previously approved compounds is an effective and efficient method to identify anticancer drugs for a rare cancer such as ACC. We have validated the antineoplastic effect of Bortezomib, ouabain, Methotrexate and pyrimethamine, which could be translated into clinical trials in patients with locally advanced and/or metastatic ACC.

Dutta D, Jain R, Maisnam I, et al.
Isolated Cushing's syndrome in early infancy due to left adrenal adenoma: an unusual aetiology.
J Clin Res Pediatr Endocrinol. 2012; 4(3):164-8 [PubMed] Article available free on PMC after 01/01/2014

Bilateral macronodular adrenocortical disease as a part of McCune Albright Syndrome (MAS) is the most common cause of endogenous Cushing's syndrome (CS) in infancy. Adrenocortical tumors causing CS in infancy are extremely rare. We report the case of a girl with CS who presented at age 4 months with obesity and growth retardation. Her 8 am paired cortisol and adrenocorticotropic hormone levels were 49.3 µg/dL and <1 pg/mL, respectively with non-suppressed serum cortisol (41 µg/dL) on high-dose dexamethasone suppression test. Abdominal computed tomography scan demonstrated a 5.3x4.8x3.7 cm homogenous left adrenal mass with distinct borders. Laparotomy following pre-operative stabilization with ketoconazole 200 mg/day, revealed a 7.5x5x4 cm lobulated left adrenal mass with intact capsule and weighing 115 grams. Histopathology showed small round adrenal tumor cells with increased nucleo-cytoplasmic ratio and prominent nucleoli. The cells were separated by fibrous septae without any evidence of vascular or capsular invasion- findings consistent with adrenal adenoma. On the 8th post-operative day, after withholding hydrocortisone supplementation, the 8 am cortisol level was <1 µg/dL, suggestive of biochemical remission of CS. The patient improved clinically with a 7.5 kg weight loss over the next 3.5 months. This is perhaps the youngest ever reported infant with CS due to adrenal adenoma. Lack of clinical and biochemical evidence of hyperandrogenism as well as the benign histology in spite of the large tumor size (>7 cm diameter; 115 g) are some of the unique features of our patient.

Ndossi DG, Frizzell C, Tremoen NH, et al.
An in vitro investigation of endocrine disrupting effects of trichothecenes deoxynivalenol (DON), T-2 and HT-2 toxins.
Toxicol Lett. 2012; 214(3):268-78 [PubMed]

Trichothecenes are a large family of chemically related mycotoxins. Deoxynivalenol (DON), T-2 and HT-2 toxins belong to this family and are produced by various species of Fusarium. The H295R steroidogenesis assay, regulation of steroidogenic gene expression and reporter gene assays (RGAs) for the detection of androgen, estrogen, progestagen and glucocorticoid (ant)agonist responses, have been used to assess the endocrine disrupting activity of DON, T-2 and HT-2 toxins. H295R cells were used as a model for steroidogenesis and gene expression studies and exposed with either DON (0.1-1000ng/ml), T-2 toxin (0.0005-5ng/ml) or HT-2 toxin (0.005-50ng/ml) for 48h. We observed a reduction in hormone levels in media of exposed cells following radioimmunoassay. Cell viability was determined by four colorimetric assays and we observed reduced cell viability with increasing toxin concentrations partly explaining the significant reduction in hormone levels at the highest toxin concentration of all three trichothecenes. Thirteen of the 16 steroidogenic genes analyzed by quantitative real time PCR (RT-qPCR) were significantly regulated (P<0.05) by DON (100ng/ml), T-2 toxin (0.5ng/ml) and HT-2 toxin (5ng/ml) compared to the control, with reference genes (B2M, ATP5B and ACTB). Whereas HMGR and CYP19 were down-regulated, CYP1A1 and CYP21 were up-regulated by all three trichothecenes. DON further up-regulated CYP17, HSD3B2, CYP11B2 and CYP11B1 and down-regulated NR5A1. T-2 toxin caused down-regulation of NR0B1 and NR5A1 whereas HT-2 toxin induced up-regulation of EPHX and HSD17B1 and down-regulation of CYP11A and CYP17. The expressions of MC2R, StAR and HSD17B4 genes were not significantly affected by any of the trichothecenes in the present study. Although the results indicate that there is no evidence to suggest that DON, T-2 and HT-2 toxins directly interact with the steroid hormone receptors to cause endocrine disruption, the present findings indicate that exposure to DON, T-2 toxin and HT-2 toxin have effects on cell viability, steroidogenesis and alteration in gene expression indicating their potential as endocrine disruptors.

Zsippai A, Szabó DR, Tömböl Z, et al.
Effects of mitotane on gene expression in the adrenocortical cell line NCI-H295R: a microarray study.
Pharmacogenomics. 2012; 13(12):1351-61 [PubMed]

AIM: The adrenolytic agent mitotane is widely used in the treatment of adrenocortical cancer; however, its mechanism of action is poorly elucidated. We have studied mitotane-induced mRNA expression changes in the NCI-H295R adrenocortical cancer cell line.
MATERIALS & METHODS: Cell viability and hormone assays were used to select the optimal mitotane concentration effectively inhibiting hormone secretion without affecting cell viability. RNA isolated from cultures treated for 48 and 72 h was subjected to Agilent 4×44K microarray platforms. Microarray results were validated by quantitative reverse-transcription PCR.
RESULTS: Altogether, 117 significantly differentially expressed genes were detected at 48 h and 72 h (p < 0.05) in mitotane-treated samples relative to controls. Three significantly underexpressed genes involved in steroid hormone biosynthesis (HSD3B1, HSD3B2 and CYP21A2) and four significantly overexpressed genes (GDF15, ALDH1L2, TRIB3 and SERPINE2) have been validated.
CONCLUSION: Gene-expression changes might be involved in the adrenal action of mitotane and in the inhibition of hormone secretion.

Doghman M, Lalli E
Efficacy of the novel dual PI3-kinase/mTOR inhibitor NVP-BEZ235 in a preclinical model of adrenocortical carcinoma.
Mol Cell Endocrinol. 2012; 364(1-2):101-4 [PubMed]

Adrenocortical cancer is a rare malignancy for which current pharmacological therapies are still insufficient. We tested the effect of a novel PI3 kinase - mammalian target of rapamycin dual inhibitor (NVP-BEZ235) on proliferation of the H295R adrenocortical cancer cell line in vitro and grown as xenografts in immunodeficient mice. NVP-BEZ235 was able to significantly inhibit phosporylation of Akt kinase and S6 ribosomal protein in H295R cells and to significantly reduce their proliferation in vitro and xenograft growth in vivo. The drug also induced activation of Erk phosphorylation, which could be inhibited by simultaneous treatment with the Erk inhibitor FR180204. This latter drug synergized with NVP-BEZ235 in the inhibition of H295R proliferation in vitro. Our data suggest that dual PI3K/mTOR inhibitors may represent a useful pharmacological tool in the therapy of advanced adrenocortical cancer and that simultaneous inhibition of both Erk and PI3K - mTOR pathways may be required to obtain a higher antiproliferative effect in this type of tumor.

Gaujoux S, Bertherat J, Dousset B, Groussin L
Laparoscopic adrenalectomy for adrenocortical carcinoma: a medico-surgical perspective.
Ann Endocrinol (Paris). 2012; 73(5):441-7 [PubMed]

BACKGROUND: Adrenocortical carcinoma (ACC) is a rare tumor carrying a dismal prognosis. The only hope for cure is a complete surgical resection. Whether this can be achieved by laparoscopic adrenalectomy (LA) remains questionable, and is now a "hot topic" for the medical and surgical community. The aim of this article was to review the result of LA for ACC in the view of the recent and highly controversial literature.
METHODS: Electronic searches in MEDLINE via PubMed regarding relevant English language studies published through February 2012 were reviewed.
RESULTS: Initially, LA for ACC has only been reported as case report or short series. This initial experience emphasized the potential deleterious effect of LA, especially in case of tumor spillage during the procedure. Recently, larger studies comparing laparoscopic and open approach for ACC have been published. These retrospective studies reported conflicting results, either equivalent results or an increased risk of tumor spillage and peritoneal carcinomatosis, and are all limited by several bias.
CONCLUSION: Overall, no definitive answer regarding the equivalence of LA for ACC can be drawn from the available literature. Even if it is likely that for well-selected cases the same procedure performed by laparoscopic or open approach may provide equivalent results, we believe that in face of a modest benefit, the risk of tumor spillage during LA should be an important consideration. Even if it is tenting, laparoscopic approach for ACC should be avoided, at least until a clear standard of surgical care has been achieved and established for the open approach.