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Adrenocortical Cancer

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Molecular Genetics of Adrenocortical Cancer

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Latest Research Publications

This list of publications is regularly updated (Source: PubMed).

Hatano M, Takenaka Y, Inoue I, et al.
Feminizing Adrenocortical Carcinoma with Distinct Histopathological Findings.
Intern Med. 2016; 55(22):3301-3307 [PubMed] Free Access to Full Article Related Publications
We herein present a 60-year-old man with adrenocortical carcinoma who had gynecomastia. An endocrinological examination revealed increased levels of serum estradiol and dehydroepiandrosterone-sulfate (DHEA-S) and reduced levels of free testosterone. Magnetic resonance imaging showed an adrenal tumor with heterogeneous intensity. Iodine-131 adosterol scintigraphy showed an increased uptake at the same site. Because feminizing adrenocortical carcinoma was suspected, right adrenalectomy was performed; the pathological diagnosis was adrenocortical carcinoma. The results of immunostaining indicated a virilizing tumor. Aromatase activity was identified on RT-PCR. As disorganized steroidogenesis is pathologically present in adrenocortical carcinoma, this diagnosis should be made with caution.

Bluemel C, Hahner S, Heinze B, et al.
Investigating the Chemokine Receptor 4 as Potential Theranostic Target in Adrenocortical Cancer Patients.
Clin Nucl Med. 2017; 42(1):e29-e34 [PubMed] Related Publications
PURPOSE: Adrenocortical carcinoma (ACC) is a rare but aggressive endocrine tumor with limited treatment options. Preclinical studies confirmed overexpression of the chemokine receptor 4 (CXCR4) in this cancer type. This study aimed to analyze the role of CXCR4 imaging using Ga-pentixafor for ACC staging and selection of patients for CXCR4-directed endoradiotherapy.
METHODS: Thirty patients with histologically proven advanced, metastasized ACC underwent F-FDG PET/CT and Ga-pentixafor PET/CT within a time interval of 3 ± 4 days to evaluate suitability for CXCR4-directed endoradiotherapy. Scans were analyzed retrospectively for visual extent of ACC and SUVmax/mean of the tumor lesions. Ga-pentixafor PET was compared with F-FDG PET, the reference imaging standard. All patients were rated for suitability of CXCR4-directed endoradiotherapy considering patient's history, previous treatment, and CXCR4 expression of FDG-positive lesions compared with background activity within the same organ.
RESULTS: All patients had lesions that were positive for both F-FDG and Ga-pentixafor PET and were rated as positive for disease. In 2 patients (7%), Ga-pentixafor PET identified more lesions compared with F-FDG PET. In 5 patients (17%) and 10 patients (33%), complementary and comparable information, respectively, was provided by dual-tracer imaging. In 13 patients (43%), more tumor lesions were identified by F-FDG PET compared with Ga-pentixafor PET. The F-FDG uptake of the malignant lesions was significantly higher (P < 0.01) than the SUVmax/mean for Ga-pentixafor. Overall, 70% of the patients were rated as suitable or potentially suitable for CXCR4-directed treatment.
CONCLUSIONS: Ga-pentixafor allows in vivo imaging of CXCR4 expression in patients with advanced ACC and may serve as companion diagnostic tool in selecting patients for potential CXCR4-directed endoradiotherapy. Seventy percent of the patients with advanced, metastasized ACC may be suitable for a CXCR4-directed treatment after failure of standard treatment options.

Sugarbaker PH
Peritoneal metastases from adrenal cortical carcinoma treated by cytoreductive surgery and hyperthermic intraperitoneal chemotherapy.
Tumori. 2016; 102(6):588-592 [PubMed] Related Publications
PURPOSE: Adrenal cortical carcinoma is a rare cancer that often presents in an advanced stage. Not only systemic metastases but also local recurrence and peritoneal metastases prevent long-term survival in these patients.
METHODS: A profoundly symptomatic patient with extensive peritoneal metastases and local recurrence was treated using cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) with melphalan as the chemotherapy agent.
RESULTS: Relative sparing of the small bowel within the abdomen and pelvis allowed a visible complete resection of all cancer. The HIPEC with melphalan was used to control microscopic residual disease. Similar surgical technology used in this patient could be used to prevent local recurrence and peritoneal metastases in patients at the time of resection of the primary adrenal cortical carcinoma.
CONCLUSIONS: Rare diseases may have peritoneal metastases as a component of disease progression and profit from treatment with CRS plus HIPEC. The clinical features suggesting a favorable outcome from this combined treatment are relative sparing of small bowel and its mesentery, absence of disease outside the abdomen, low-grade disease, or limited extent of high-grade disease.

Tran TB, Postlewait LM, Maithel SK, et al.
Actual 10-year survivors following resection of adrenocortical carcinoma.
J Surg Oncol. 2016; 114(8):971-976 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Adrenocortical carcinoma (ACC) is a rare and aggressive malignancy with limited therapeutic options beyond surgical resection. The characteristics of actual long-term survivors following surgical resection for ACC have not been previously reported.
METHOD: Patients who underwent resection for ACC at one of 13 academic institutions participating in the US Adrenocortical Carcinoma Group from 1993 to 2014 were analyzed. Patients were stratified into four groups: early mortality (died within 2 years), late mortality (died within 2-5 years), actual 5-year survivor (survived at least 5 years), and actual 10-year survivor (survived at least 10 years). Patients with less than 5 years of follow-up were excluded.
RESULTS: Among the 180 patients available for analysis, there were 49 actual 5-year survivors (27%) and 12 actual 10-year survivors (7%). Patients who experienced early mortality had higher rates of cortisol-secreting tumors, nodal metastasis, synchronous distant metastasis, and R1 or R2 resections (all P < 0.05). The need for multi-visceral resection, perioperative blood transfusion, and adjuvant therapy correlated with early mortality. However, nodal involvement, distant metastasis, and R1 resection did not preclude patients from becoming actual 10-year survivors. Ten of twelve actual 10-year survivors were women, and of the seven 10-year survivors who experienced disease recurrence, five had undergone repeat surgery to resect the recurrence.
CONCLUSION: Surgery for ACC can offer a 1 in 4 chance of actual 5-year survival and a 1 in 15 chance of actual 10-year survival. Long-term survival was often achieved with repeat resection for local or distant recurrence, further underscoring the important role of surgery in managing patients with ACC. J. Surg. Oncol. 2016;114:971-976. © 2016 Wiley Periodicals, Inc.

Wahab NA, Zainudin S, AbAziz A, et al.
Multi-Target Approach to Metastatic Adrenal Cell Carcinoma.
Arch Iran Med. 2016; 19(9):671-3 [PubMed] Related Publications
Adrenal cell carcinoma is a rare tumor and more than 70% of patients present with advanced stages. Adrenal cell carcinoma is an aggressive tumor with a poor prognosis. Surgical intervention is the gold standard treatment and mitotane is the only drug approved for the treatment of adrenal cell carcinoma. Until recently in 2012, the etoposide, doxorubicin, cisplatin plus mitotane are approved as first-line therapy based on response rate and progression-free survival. This case illustrates a case of advanced adrenal cell carcinoma in a young girl who presented with huge adrenal mass with inferior vena cava thrombosis and pulmonary embolism. Multi-approach of therapy was used to control the tumor size and metastasis. Therefore, it may prolong her survival rate for up to 5 years and 4 months.

El Ghorayeb N, Grunenwald S, Nolet S, et al.
First case report of an adrenocortical carcinoma caused by a BRCA2 mutation.
Medicine (Baltimore). 2016; 95(36):e4756 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Adrenocortical carcinoma (ACC) may rarely be a component of inherited cancer syndromes such as Li-Fraumeni syndrome and Beckwith-Wiedemann syndrome. ACC caused by a BRCA2 mutation has never been reported.
METHODS: Nucleotide sequencing of BRCA2 in lymphocyte and tumoral DNA of a 50-year-old male who presented with an androgen-secreting ACC and a strong family history of breast, ovarian, and pancreatic cancers.
RESULTS: A germline BRCA2 2 bp heterozygous deletion at nucleotide 8765 (8765delAG) leading to a frameshift mutation (p.Glu2846GlyfsX23) was detected. Only the BRCA2 deleted allele was retained in the ACC tumoral DNA compared with the control DNA supporting a loss of heterozygosity in the tumor.
CONCLUSION: This is the first reported case of a patient with ACC associated with a BRCA2 germline mutation. Loss of heterozygosity in ACC DNA suggests a causal link with the BRCA2 8765delAG mutation.

Das S, Sengupta M, Islam N, et al.
Weineke criteria, Ki-67 index and p53 status to study pediatric adrenocortical tumors: Is there a correlation?
J Pediatr Surg. 2016; 51(11):1795-1800 [PubMed] Related Publications
PURPOSE: Adrenocortical tumors (ACTs) are rare in pediatric age group. Pediatric ACTs behave differently from their histologically similar adult counterparts and Weiss criteria often cannot accurately predict their clinical behavior. Wieneke et al. proposed a set of 9 macroscopic and microscopic criteria for diagnosis of malignancy in pediatric ACTs. The aim of the present study was to validate the Wieneke criteria in pediatric ACTs and to correlate Ki-67 labeling index and p53 expression with the Wieneke score.
METHODS: Our study comprised 17 cases of pediatric ACTs more than 11years, from January 2005 to December 2015. Relevant clinical features were obtained from records. Comprehensive analysis of gross and microscopic features was performed, according to the criteria proposed by Wieneke et al. Each tumor was categorized as benign, intermediate for malignancy or malignant. Ki-67 and p53 immunostaining was done in all cases. The patients were followed-up over a period of 6months to 60months.
RESULTS: Applying Wieneke criteria, there were 9 benign and 7 malignant cases, and 1 case was assigned as intermediate for malignancy. The most significant markers in favor of malignancy were capsular and venous invasion, followed by the presence of mitotic figures >15/20 HPF. p53 was over-expressed in 86% of the carcinomas. We found a significant correlation between Ki-67 index and Wieneke scoring system. All cases of adenoma achieved complete remission, while 3 patients with carcinoma died.
CONCLUSION: Our study validates the utility of Wieneke criteria in differentiating adrenocortical carcinomas from adenomas in pediatric age group. Moreover, Ki-67 index and p53 status can be used as supplementary tools in distinguishing adrenocortical carcinomas from adenomas.

Janssen S, Bartscht T, Rades D
Prognosis of Patients with Metastatic Spinal Cord Compression from Adrenocortical Carcinoma.
In Vivo. 2016 09-10; 30(5):717-9 [PubMed] Related Publications
BACKGROUND/AIM: Adrenocortical cancer is a rare aggressive type of cancer. The prognosis is poor, particularly for metastatic disease. This study focused on metastatic spinal cord compression (MSCC) from adrenocortical carcinoma.
PATIENTS AND METHODS: Data of three patients who received palliative irradiation of MSCC from adrenocortical carcinoma were retrospectively analyzed for motor function, ambulatory status and survival.
RESULTS: One patient died before completion of radiotherapy. The other two patients died two weeks and four weeks, respectively, following irradiation. In these patients, pre-radiotherapy pain scores were 9 and 10 points. In both patients, partial pain relief was achieved (scores of 5 and 4 points). All three patients were non-ambulatory before irradiation. In assessable patients, motor function remained unchanged following irradiation.
CONCLUSION: Palliative irradiation resulted in considerable pain relief, whereas motor function did not improve. Considering the extremely poor survival, supportive care alone may be considered if pain relief is achieved without irradiation.

Chentli F, Terki N, Azzoug S
Ectopic adrenocortical carcinoma located in the ovary.
Eur J Endocrinol. 2016; 175(4):K17-23 [PubMed] Related Publications
AIM: Ovarian corticosteroid-producing tumors are exquisitely rare. Our aim was to describe the first case observed in our practice.
CASE HISTORY: A 34-year-old female was referred for Cushing's syndrome (CS) occurring in the postpartum period. Clinical examination showed severe CS with diabetes mellitus, hypertension, and a large mass in the right lower abdomen. Biochemistry demonstrated corticotropin (ACTH)-independent CS (cortisol=1900ng/mL (n=50-250), ACTH<10pg/mL (n=20-46)) with estradiol and testosterone overproduction.
INVESTIGATIONS: Abdomen CT scan revealed a 14cm right ovarian mass and small adrenal glands. Surgical exploration found the ovarian tumor with hemoperitoneum and enlarged lymph nodes. Histological study confirmed adrenocortical tumor located in the ovary with a Weiss score >5, associated with peritoneal and lymph node metastases. Immunohistochemical staining was positive for inhibin-α, melan-A, and SF1, demonstrating tissue of adrenal origin. After surgery, plasma glucose level spontaneously returned to normal. However, the patient died on the second post-surgical day due to catastrophic pulmonary embolism.
CONCLUSION: In this reported case, clinical, hormonal, histological, and immunohistochemical findings confirmed a cortisol and sex hormone-producing ovarian tumor with peritoneal and lymph node metastases, a very rare but important condition to recognize.

Rubin B, Regazzo D, Redaelli M, et al.
Investigation of N-cadherin/β-catenin expression in adrenocortical tumors.
Tumour Biol. 2016; 37(10):13545-13555 [PubMed] Related Publications
β-catenin is a multifunctional protein; it is a key component of the Wnt signaling, and it plays a central role in cadherin-based adhesions. Cadherin loss promotes tumorigenesis by releasing membrane-bound β-catenin, hence stimulating Wnt signaling. Cadherins seem to be involved in tumor development, but these findings are limited in adrenocortical tumors (ACTs). The objective of this study was to evaluate alterations in key components of cadherin/catenin adhesion system and of Wnt pathway. This study included eight normal adrenal samples (NA) and 95 ACT: 24 adrenocortical carcinomas (ACCs) and 71 adrenocortical adenomas (ACAs). β-catenin mutations were evaluated by sequencing, and β-catenin and cadherin (E-cadherin and N-cadherin) expression was analyzed by quantitative reverse transcription PCR (qRT-PCR) and by immunohistochemistry (IHC). We identified 18 genetic alterations in β-catenin gene. qRT-PCR showed overexpression of β-catenin in 50 % of ACC (12/24) and in 48 % of ACA (21/44). IHC data were in accordance with qRT-PCR results: 47 % of ACC (7/15) and 33 % of ACA (11/33) showed increased cytoplasmic or nuclear β-catenin accumulation. N-cadherin downregulation has been found in 83 % of ACC (20/24) and in 59 % of ACA (26/44). Similar results were obtained by IHC: N-cadherin downregulation was observed in 100 % (15/15) of ACC and in 55 % (18/33) of ACA. β-catenin overexpression together with the aberrant expression of N-cadherin may play important role in ACT tumorigenesis. The study of differentially expressed genes (such as N-cadherin and β-catenin) may enhance our understanding of the biology of ACT and may contribute to the discovery of new diagnostic and prognostic tools.

Uchida T, Nishimoto K, Fukumura Y, et al.
Disorganized Steroidogenesis in Adrenocortical Carcinoma, a Case Study.
Endocr Pathol. 2017; 28(1):27-35 [PubMed] Related Publications
Most adrenocortical carcinomas (ACCs) produce excessive amounts of steroid hormones including aldosterone, cortisol, and steroid precursors. However, aldosterone- and cortisol-producing cells in ACCs have not yet been immunohistochemically described. We present a case of ACC causing mild primary aldosteronism and subclinical Cushing's syndrome. Removal of the tumor cured both conditions. In order to examine the expression patterns of the steroidogenic enzymes responsible for adrenocortical hormone production, 10 tumor portions were immunohistochemically analyzed for aldosterone synthase (CYP11B2), 11β-hydroxylase (CYP11B1, cortisol-synthesizing enzyme), 3β-hydroxysteroid dehydrogenase (3βHSD, upstream enzyme for both CYP11B2 and CYP11B1), and 17α-hydroxylase/C17-20 lyase (CYP17, upstream enzyme for CYP11B1, but not for CYP11B1). CYP11B2, CYP11B1, and 3βHSD were expressed sporadically, and their expression patterns varied significantly among the different tumor portions examined. The expression of these enzymes was random and not associated with each other. CYP17 was expressed throughout the tumor, even in CYP11B2-positive cells. Small tumor cell populations were aldosterone- or cortisol-producing cells, as judged by 3βHSD coinciding with either CYP11B2 or CYP11B1, respectively. These results suggest that the tumor produced limited amounts of aldosterone and cortisol due to the lack of the coordinated expression of steroidogenic enzymes, which led to mild clinical expression in this case. We delineated the expression patterns of steroidogenic enzymes in ACC. The coordinated expression of steroidogenic enzymes in normal and adenoma cells was disturbed in ACC cells, resulting in the inefficient production of steroid hormones in relation to the large tumor volume.

Yang MH, Tyan YS, Huang YH, et al.
Comparison of radiofrequency ablation versus laparoscopic adrenalectomy for benign aldosterone-producing adenoma.
Radiol Med. 2016; 121(10):811-9 [PubMed] Related Publications
PURPOSE: To retrospectively compare the safety and efficacy of radiofrequency ablation (RFA) with laparoscopic adrenalectomy (LA) in treating aldosterone-producing adenoma (APA) of the adrenal gland.
MATERIALS AND METHODS: From September 2009 to September 2013, seven patients, diagnosed with unilateral adrenal APA and underwent computed tomography (CT)-guided percutaneous RFA, were recruited in this retrospective study. Eighteen unilateral adrenal APA with the same tumor size (<25 mm) who underwent LA during the same interval were enrolled as control group. Treatment success was defined as complete tumor ablation on follow-up CT scan and normalization of serum aldosterone-to-renin ratio. We also compared "normalization ability" between RFA group and LA group. Normalization ability was defined as reduction in blood pressure, decrease in number of antihypertensive medicine use, reduction in serum aldosterone, and increase in serum potassium level.
RESULTS: There was no statistically significant demographic difference in both groups. The mean tumor size was 18 (8-25) mm in RFA and 19 (11-25) mm in LA groups, respectively. There was only one intra-procedure hypertensive crisis in the RFA group. No other complications needed further management in both groups. During an interval of 3-6 months of follow-up, the treatment success rate reached 100 % in the RFA group versus 94.4 % in the LA group. Normalization ability was statistically equivalent in the RFA and the LA group. Comparing with LA group, RFA group demonstrated with less post-operative pain (visual analog scale, 2.0 ± 1.16 vs. 4.22 ± 1.44, p < 0.001) and shorter operative time (105 ± 34 vs. 194 ± 58 min, p < 0.001).
CONCLUSIONS: CT-guided percutaneous RFA is effective, safe and is a justifiable alternative for patients who are reluctant or unfit for laparoscopic surgery for the treatment of APA.

Choi YM, Kwon H, Jeon MJ, et al.
Clinicopathological Features Associated With the Prognosis of Patients With Adrenal Cortical Carcinoma: Usefulness of the Ki-67 Index.
Medicine (Baltimore). 2016; 95(21):e3736 [PubMed] Free Access to Full Article Related Publications
Adrenocortical carcinoma (ACC) is a rare tumor with a poor prognosis. Identification of clinicopathological features and molecular prognostic markers is important for the treatment of ACC. The aim of this study was to evaluate the clinical and histopathological features of ACC for prognostic prediction.This retrospective cohort study included 86 patients pathologically confirmed with ACC in a single center. Ki-67 index was evaluated by immunohistochemical staining of paraffin-embedded samples.The median age of the 86 (46 male and 40 female) patients with ACC was 49 years old (range 21-78), and the mean primary tumor size was 12.2 ± 5.2 cm. ACCs were incidentally found in 29 patients (34%). Three patients (3%) had bilateral ACC, and 59 patients (69%) had distant metastasis (37 synchronous and 22 metachronous). Twenty-four patients (28%) had symptoms from hormone excess or mass effects, and 25 patients (29%) had nonspecific symptoms. The 5-year survival rate for ACC was 28%. Sixty patients underwent surgical treatment, including 37 patients with an R0 resection. Tumor size, Ki-67 index, stage, and resection status were independently associated with overall survival by multivariate analysis. In patients with R0 resection, recurrence was significantly associated with larger tumor size and functional tumor.Tumor size, Ki-67 index, stage, and resection status are important prognostic indicators of survival in ACC patients.

Dudala J, Białas MB, Szczerbowska-Boruchowska M, et al.
Investigation of biochemical composition of adrenal gland tumors by means of FTIR.
Pol J Pathol. 2016; 67(1):60-8 [PubMed] Related Publications
The application of Fourier transform infrared (FTIR) microspectroscopy for the analysis of biomolecular composition of adrenal gland tumors is described. Samples were taken intraoperatively from three types of adrenal lesions: adrenal adenoma (ACA), adrenal cortical hyperplasia (ACH), both derived from adrenal cortical cells, and pheochromocytoma (Ph) derived from chromaffin cells of the adrenal medulla. The specimens were cryo-sectioned and freeze-dried. Since the investigated lesions originated from different cell types, it was predictable that they might differ in biomolecular composition. The experimental results were used to determine which absorption bands differentiate the analyzed samples the most. The main difference was observed in the lipid functional groups. The experimental results indicated that the level of lipids was higher in both the adenoma and the hyperplasia samples compared to pheochromocytomas. In contrast, the level of proteins was higher in the pheochromocytomas. Furthermore, differences within the range of nucleic acids and carbohydrates were observed in the studied adrenal gland tumor types.

Nanba K, Omata K, Tomlins SA, et al.
Double adrenocortical adenomas harboring independent KCNJ5 and PRKACA somatic mutations.
Eur J Endocrinol. 2016; 175(2):K1-6 [PubMed] Article available free on PMC after 01/08/2017 Related Publications
OBJECTIVE: Co-secretion of cortisol and aldosterone can be observed in adrenal adenomas. The aim of this study was to investigate the molecular characteristics of a co-existing aldosterone- and a cortisol-producing adenoma (CPA) in the same patient.
DESIGN AND METHODS: Two different adenomas within the same adrenal gland from a 49-year-old female patient with primary aldosteronism (PA) and Cushing's syndrome (CS) were studied. Multiple formalin-fixed paraffin-embedded tumor blocks were used for the analysis. Immunohistochemistry (IHC) was performed using a specific antibody against aldosterone synthase (CYP11B2). DNA and RNA were isolated separately from CYP11B2-positive and -negative tumor regions based on CYP11B2 IHC results.
RESULTS: CYP11B2 IHC clearly demonstrated that three pieces from one adenoma were positive for CYP11B2 and the remaining three from the other adenoma were negative for CYP11B2. In quantitative real-time RT-PCR, CYP11B2 mRNA was upregulated in CYP11B2-positive tumor specimens (219-fold vs CYP11B2-negative tumor specimens). Targeted next-generation sequencing (NGS) detected novel KCNJ5 gene mutations (p.T148I/T149S, present in the same reads) and a PRKACA gene hotspot mutation (p.L206R) in the CYP11B2-positive and -negative tumors, respectively. Sanger sequencing of DNA from each tumor specimen (CYP11B2-positive tumor, n=3; CYP11B2-negative tumor, n=3) showed concordant results with targeted NGS.
CONCLUSION: Our findings illustrate the co-existence of two different adrenocortical adenomas causing the concurrent diagnosis of PA and CS in the same patient. Molecular analysis was able to demonstrate that the two diseases resulted from independent somatic mutations seen in double adrenocortical adenomas.

Liu Y, Jiang YF, Wang YL, et al.
Ectopic adrenocortical adenoma in the renal hilum: a case report and literature review.
Diagn Pathol. 2016; 11:40 [PubMed] Article available free on PMC after 01/08/2017 Related Publications
BACKGROUND: Ectopic (accessory) adrenocortical tissue, also known as adrenal rests, is a developmental abnormality of the adrenal gland. The most common ectopic site is in close proximity to the adrenal glands and along the path of descent or migration of the gonads because of the close spatial relationship between the adrenocortical primordium and gonadal blastema during embryogenesis. Ectopic rests may undergo marked hyperplasia, and occasionally induce ectopic adrenocortical adenomas or carcinomas.
CASE PRESENTATION: A 27-year-old Chinese female patient who presented with amenorrhea of 3 months duration underwent computed tomography urography after ultrasound revealed a solitary mass in the left renal hilum. Histologically, the prominent eosinophilic tumor cells formed an alveolar- or acinar-like configuration. The immunohistochemical profile (alpha-inhibin+, Melan-A+, synaptophysin+) indicated the adrenocortical origin of the tumor, diagnosed as ectopic adrenocortical adenoma. The patient was alive with no tumor recurrence or metastasis at the 3-month follow-up examination.
CONCLUSIONS: The unusual histological appearance of ectopic adrenocortical adenoma may result in its misdiagnosis as oncocytoma or clear cell renal cell carcinoma, especially if the specimen is limited. This case provides a reminder to pathologists to be aware of atypical cases of this benign tumor. Although uncommon, an ectopic adrenal lesion should be included in the differential diagnosis of tumors involving the renal hilum. A misdiagnosis of this benign condition as a malignant renal tumor may have severe consequences for the patient, including unnecessary radical nephrectomy. Preoperative biopsy and appropriate immunohistochemical staining will assist in determining the origin and nature of the tumor and in avoiding intraoperative uncertainty.

Háhn J, Szoboszlay S, Krifaton C, et al.
Development of a combined method to assess the complex effect of atrazine on sex steroid synthesis in H295R cells.
Chemosphere. 2016; 154:507-14 [PubMed] Related Publications
The aim of the study was to develop a rapid, cost-effective combined testing method to assess the indirect effect of compounds interfering with sex steroid synthesis and to determine complex effects of atrazine on estrogen and androgen synthesis in vitro on H295R human cell line. Steroidogenic assay was performed on H295R human adrenocortical carcinoma cell line. Instead of standard analytical methods, bioluminescence bioreporter assays (Saccharomyces cerevisiae BLYES and BLYAS) were used to measure estrogenic and androgenic effects of sex steroid hormones released by human cells in response to atrazine. Atrazine resulted in elevated estrogen production presumably due to its well documented inductive effect on aromatase on H295R cell line, detected by BLYES. Interestingly, results of BLYAS test showed concentration-dependent increase of androgen production in H295R cells. That indicates that atrazine can not only increase estrogen level via aromatase induction, but may interfere in androgen synthesis as well. The combined method allows us to assess the androgenic and estrogenic effect of sex steroids produced by human cells in increased or decreased quantity as a result of the different chemicals, without determining specific analytical measurement endpoints, by using the yeast based bioluminescent bioreporter test.

Maiter D, Bex M, Vroonen L, et al.
Efficacy and safety of mitotane in the treatment of adrenocortical carcinoma: A retrospective study in 34 Belgian patients.
Ann Endocrinol (Paris). 2016; 77(5):578-585 [PubMed] Related Publications
OBJECTIVES: Evaluation of patient characteristics and mitotane use in the treatment of adrenocortical carcinoma (ACC) over a 4-year period in Belgium.
MATERIAL AND METHODS: This was a multicentre retrospective review of the outcome of 34 patients treated with mitotane for ACC during the period [01/2008-12/2011] (12 diagnosed before and 22 diagnosed during the study period) and evaluated up to 06/2013.
RESULTS: Patient and tumour characteristics were consistent with those generally described for ACC. Mean age at diagnosis was 46.5 years, most patients were female (62%), had functioning ACC (65%) and advanced tumours (ENSAT stages III or IV: 82%). Therapeutic mitotane plasma levels (14-20 mg/L) were achieved at least once in 70% of the cohort, after a median of 4 months, and were maintained for more than 2 months in 61% of evaluable patients. Mitotane-related adverse effects were observed in 66% of patients, were never serious, and included gastrointestinal, neurological, neuropsychological, hormonal, dermatologic and metabolic effects. Most patients (88%) discontinued mitotane, mainly due to tumour progression. Multivariate analysis showed that ENSAT stage was a prognostic factor for overall (OS) and disease-free survival (DFS); OS was also influenced independently by achievement of therapeutic mitotane plasma levels for at least two consecutive months.
CONCLUSION: Patient and tumour characteristics were consistent with previously published data. OS and DFS were mostly influenced by ENSAT stage at diagnosis. Achieving therapeutic levels of mitotane for at least two consecutive months seemed to positively influence OS, but such levels were not reached or sustained in some patients.

El Ghorayeb N, Rondeau G, Latour M, et al.
Rapid and Complete Remission of Metastatic Adrenocortical Carcinoma Persisting 10 Years After Treatment With Mitotane Monotherapy: Case Report and Review of the Literature.
Medicine (Baltimore). 2016; 95(13):e3180 [PubMed] Article available free on PMC after 01/08/2017 Related Publications
Mitotane has been used for more than 5 decades as therapy for adrenocortical carcinoma (ACC). However its mechanism of action and the extent of tumor response remain incompletely understood. To date no cases of rapid and complete remission of metastatic ACC with mitotane monotherapy has been reported. A 52-year-old French Canadian man presented with metastatic disease 2 years following a right adrenalectomy for stage III nonsecreting ACC. He was started on mitotane which was well tolerated despite rapid escalation of the dose. The patient course was exceptional as he responded to mitotane monotherapy after only few months of treatment. Initiation of chemotherapy was not needed and he remained disease-free with good quality of life on low maintenance dose of mitotane during the following 10 years. A germline heterozygous TP53 exon 4 polymorphism c.215C>G (p. Pro72Arg) was found. Immunohistochemical stainings for IGF-2 and cytoplasmic β-catenin were positive. Advanced ACC is an aggressive disease with poor prognosis and the current therapeutic options remain limited. These findings suggest that mitotane is a good option for the treatment of metastatic ACC and might result in rapid complete remission in selected patients.

Qin L, Xu T, Xia L, et al.
Chloroquine enhances the efficacy of cisplatin by suppressing autophagy in human adrenocortical carcinoma treatment.
Drug Des Devel Ther. 2016; 10:1035-45 [PubMed] Article available free on PMC after 01/08/2017 Related Publications
BACKGROUND: It has been demonstrated that chloroquine (CQ) enhances the efficacy of chemotherapy. However, little is known about whether CQ could enhance the efficacy of cisplatin (DDP) in the treatment of adrenocortical carcinoma (ACC). In this study, we explore the efficacy and mechanism by which CQ affects DDP sensitivity in human ACC in vitro and in vivo.
METHODS: The autophagic gene Beclin-1 expression was detected by immunohistochemistry, and the protein levels were analyzed using immunoblotting assays of ACC tissues and normal adrenal cortex tissues. The ACC SW13 cells were treated with DDP and/or CQ. The cell viability assay was performed using the MTT method. Qualitative autophagy detection was performed by monodansylcadaverine staining of autophagic vacuoles. Annexin V-fluorescein isothiocyanate/propidium iodide double staining was used to count cell apoptosis by flow cytometry. The autophagy-related protein (Beclin-1, LC3, and p62) and apoptosis relative protein (Bax and Bcl-2) levels were evaluated with Western blot analysis. Furthermore, a murine model of nude BALB/c mice bearing SW13 cell xenografts was established to evaluate the efficacy of concomitant therapy.
RESULTS: The expression of the autophagic gene Beclin-1 was significantly downregulated in ACC tissues compared to normal adrenal cortex tissues. The Beclin-1 protein level in ACC tissues was lower than that in normal adrenal cortex tissues (P<0.05). In vitro concomitant therapy (DDP and CQ) was more effective in restraining SW13 cell proliferation. DDP could promote cell apoptosis and induce autophagy in SW13 cells. Concomitant therapy further promoted cell apoptosis by inhibiting autophagy. In vivo, we found that concomitant therapy was more potent than DDP monotherapy in inhibiting the growth of xenografted tumors and prolonging the survival of tumor-bearing mice.
CONCLUSION: The antitumor ability of DDP was related to autophagy activity, and the concomitant therapy (DDP and CQ) could be an optimal strategy for treating ACC.

Kaslow AM, Riquier-Brison A, Peti-Peterdi J, et al.
An ectopic renin-secreting adrenal corticoadenoma in a child with malignant hypertension.
Physiol Rep. 2016; 4(5) [PubMed] Article available free on PMC after 01/08/2017 Related Publications
A previously healthy 7-year-old male presented with hypertensive emergency, hypokalemia, and elevated plasma renin activity and aldosterone levels. There was no evidence of virilization or cushingoid features. MRI of the abdomen revealed a large (5 × 5 × 3 cm) peripherally enhancing, heterogeneous mass arising from the left adrenal gland. The patient was treated for a suspected pheochromocytoma. However, his blood pressure was not responsive to alpha-blockade. Blood pressure was controlled with a calcium channel blocker and an angiotensin-converting enzyme (ACE) inhibitor. A complete surgical resection of the mass was performed. Postoperatively, his blood pressure normalized and he did not require antihypertensives. On pathological examination, the tumor tissue stained negative for chromogranin and positive for renin. The final diagnosis was renin-secreting adrenal corticoadenoma, an extremely rare adrenal tumor not previously reported in a pediatric patient. Malignant hypertension due to a renin-secreting tumor may need to be distinguished from a pheochromocytoma if alpha-adrenergic blockade is ineffective.

Moradi S, Shafiepour M, Amirbaigloo A
A Woman with Normotensive Primary Hyperaldosteronism.
Acta Med Iran. 2016; 54(2):156-8 [PubMed] Related Publications
Normotensive hyperaldosteronism is a rare disorder. It is usually diagnosed with hypokalemia or an adrenal mass. Our patient was a 27-year-old female presented with weakness. She had normal blood pressure, hypokalemia, high plasma aldosterone level and suppressed plasma renin activity. After the saline load, test aldosterone didn't show suppression. Adrenal computed tomography revealed a left adrenal mass. The patient was treated with spironolactone and potassium supplement. Surgical adrenalectomy was done. Final pathologic diagnosis was benign adrenocortical adenoma without capsular invasion. In postoperative course serum, potassium was normal.

Calissendorff J, Calissendorff F, Falhammar H
Adrenocortical cancer: mortality, hormone secretion, proliferation and urine steroids - experience from a single centre spanning three decades.
BMC Endocr Disord. 2016; 16:15 [PubMed] Article available free on PMC after 01/08/2017 Related Publications
BACKGROUND: Adrenocortical carcinoma (ACC) is a rare malignant disease with a poor prognosis. Our aims were to study survival and to explore prognostic markers.
METHODS: We retrospectively investigated the medical records of all 50 ACC patients at a single centre diagnosed between 1985 and 2012 and followed them up until 31/12/2014.
RESULTS: Of this cohort, twenty six (52 %) were females. Adrenalectomy was performed in 48 patients (96 %), and twenty seven (54 %) were treated with adjuvant cytotoxic agents. The tumor sizes ranged from 6 to 20 cm. Overall survival time was 5.5 years (0.3-19.8), the two and five-year survival was 64 and 40 %, respectively. In ENSAT stage II 25/48 patients had a median survival of 7.0 years (0.7-15.5), in stage III 8/48 this was 1.9 (0.4 - 19.8), and in stage IV 15/48 it was 1.2 (0.3-3.6) years. Seventeen patients (34 %) were still alive at the end of 2014. The total follow-up time was 8.4 (0.3-19.8) years. Cell proliferation measured with Ki-67 had a median value of 15 % (2-80) and the urinary steroid profile was clearly pathologic in 29 of 43 (67 %) tested patients. The proliferation index did not significantly predict mortality (Ki-67 ≤ 10 vs. >10 %, 9.0 vs. 3.2 years, P = 0.0833), but resection margins did (R1 vs. R2, P = 0.0066; R0 vs. R2, P < 0.0001). The urinary steroid profile did not predict mortality (normal vs. pathologic urine profile: median survival 6.6 vs. 3.3 years, P = 0.261).
CONCLUSIONS: The prognosis was generally poor and macroscopically positive resection margins resulted in a worse prognosis. However, some patients were still alive many years following primary surgery with no sign of residual disease.

Legendre CR, Demeure MJ, Whitsett TG, et al.
Pathway Implications of Aberrant Global Methylation in Adrenocortical Cancer.
PLoS One. 2016; 11(3):e0150629 [PubMed] Article available free on PMC after 01/08/2017 Related Publications
CONTEXT: Adrenocortical carcinomas (ACC) are a rare tumor type with a poor five-year survival rate and limited treatment options.
OBJECTIVE: Understanding of the molecular pathogenesis of this disease has been aided by genomic analyses highlighting alterations in TP53, WNT, and IGF signaling pathways. Further elucidation is needed to reveal therapeutically actionable targets in ACC.
DESIGN: In this study, global DNA methylation levels were assessed by the Infinium HumanMethylation450 BeadChip Array on 18 ACC tumors and 6 normal adrenal tissues. A new, non-linear correlation approach, the discretization method, assessed the relationship between DNA methylation/gene expression across ACC tumors.
RESULTS: This correlation analysis revealed epigenetic regulation of genes known to modulate TP53, WNT, and IGF signaling, as well as silencing of the tumor suppressor MARCKS, previously unreported in ACC.
CONCLUSIONS: DNA methylation may regulate genes known to play a role in ACC pathogenesis as well as known tumor suppressors.

Asakawa M, Yoshimoto T, Ota M, et al.
A Case of Cushing's Syndrome with Multiple Adrenocortical Adenomas Composed of Compact Cells and Clear Cells.
Endocr Pathol. 2016; 27(2):136-41 [PubMed] Related Publications
A 58-year-old woman was referred to our hospital for Cushingoid features and diagnosed as adrenal Cushing's syndrome due to a right adrenocortical mass (60 × 55 mm). The mass was composed of three different tumors; the first one was homogeneously lipid-poor neoplasm measuring 20 × 13 mm located at the most dorsal region, the second one was heterogeneous and lipid-rich tumor containing multiple foci of calcification measuring 50 × 32 mm located at the central region, and the last one was heterogeneous harboring dilated and tortuous vessels and lipid-poor one measuring 35 × 18 mm at the most ventral region of the adrenal gland. A right adrenalectomy was subsequently performed by open surgery. Macroscopic and microscopic analyses revealed that all three tumors were adrenocortical adenomas; the first one represents a pigmented adrenocortical adenoma, the second one adrenocortical adenoma associated with degeneration, and the third one adrenocortical adenoma harboring extensive degeneration. Immunohistochemical analysis of the steroidogenic enzymes also revealed that all of the tumors had the capacity of synthesizing cortisol. This is a very rare case of Cushing's syndrome caused by multiple adrenocortical adenomas including a pigmented adenoma. Immunohistochemical analysis of steroidogenic enzymes contributed to understanding of steroidogenesis in each of these three different adrenocortical adenomas in this case.

Fujisawa Y, Sakaguchi K, Ono H, et al.
Combined steroidogenic characters of fetal adrenal and Leydig cells in childhood adrenocortical carcinoma.
J Steroid Biochem Mol Biol. 2016; 159:86-93 [PubMed] Related Publications
Although childhood adrenocortical carcinomas (c-ACCs) with a TP53 mutation are known to produce androgens, detailed steroidogenic characters have not been clarified. Here, we examined steroid metabolite profiles and expression patterns of steroidogenic genes in a c-ACC removed from the left adrenal position of a 2-year-old Brazilian boy with precocious puberty, using an atrophic left adrenal gland removed at the time of tumorectomy as a control. The c-ACC produced not only abundant dehydroepiandrosterone-sulfate but also a large amount of testosterone via the Δ5 pathway with Δ5-androstenediol rather than Δ4-androstenedione as the primary intermediate metabolite. Furthermore, the c-ACC was associated with elevated expressions of CYP11A1, CYP17A1, POR, HSD17B3, and SULT2A1, a low but similar expression of CYB5A, and reduced expressions of AKR1C3 (HSD17B5) and HSD3B2. Notably, a Leydig cell marker INSL3 was expressed at a low but detectable level in the c-ACC. Furthermore, molecular studies revealed a maternally inherited heterozygous germline TP53 mutation, and several post-zygotic genetic aberrations in the c-ACC including loss of paternally derived chromosome 17 with a wildtype TP53 and loss of maternally inherited chromosome 11 and resultant marked hyperexpression of paternally expressed growth promoting gene IGF2 and drastic hypoexpression of maternally expressed growth suppressing gene CDKN1C. These results imply the presence of combined steroidogenic properties of fetal adrenal and Leydig cells in this patient's c-ACC with a germline TP53 mutation and several postzygotic carcinogenic events.

Yiannakopoulou E
Robotic assisted adrenalectomy: Surgical techniques, feasibility, indications, oncological outcome and safety.
Int J Surg. 2016; 28:169-72 [PubMed] Related Publications
Nowadays robotic assisted adrenalectomy has become an alternative to conventional laparoscopic adrenalectomy. However, evidence on the possible advantages and drawbacks of robotic assisted adrenalectomy remains still limited. This manuscript aimed to review evidence on robotic assisted adrenalectomy in terms of surgical technique, feasibility, indications, oncological outcome and safety. Existing evidence, although limited, suggests that robotic assisted adrenalectomy is feasible and safe. However, the number of patients submitted to robotic assisted adrenalectomy is limited with the majority of them being operated for benign disease. There are only a few case reports of robotic assisted adrenalectomy performed for adrenocortical carcinoma, oncocytoma or metastasis. Partial adrenalectomy seems to be a promising application of robotic assisted adrenalectomy especially for the treatment of hereditary pheocromocytomas. Robotic assisted adrenalectomy overcoming the technical limitations of laparoscopic surgery could possibly elicit a mild surgical response instead of the well described surgical response. Surgical response affects surgical morbidity and mortality as well as oncological outcome of malignant disease. If this hypothesis is proved correct, robotic assisted adrenalectomy could be possibly indicated in the treatment of disease. In conclusion, robotic assisted adrenalectomy is feasible and safe. Further research is needed on the oncological outcome of this minimally invasive technique as well as on its effect on surgical stress response.

Fox C
A curious case of paralysis.
JAAPA. 2016; 29(3):1-3 [PubMed] Related Publications
Primary hyperaldosteronism is found in up to 13% of patients with hypertension. This article describes a patient with hypokalemia, hypertension, and periodic paralysis that were caused by primary hyperaldosteronism. Plasma aldosterone concentration to plasma renin activity ratio is a common screening test, and adrenal vein sampling can be performed to determine which gland is overproducing aldosterone. Treatment with mineralocorticoid receptor antagonists or adrenalectomy gives similar reductions in BP.

Elfiky AA, Krishnan Nair HK
Assessment and management of advanced adrenocortical carcinoma using a precision oncology care model.
Discov Med. 2016; 21(113):49-56 [PubMed] Related Publications
Within the category of orphan diseases and rare malignancies, adrenocortical carcinoma (ACC) represents an aggressive entity with high mortality and morbidity. While localized tumors which are diagnosed early can be cured with surgical intervention, there are prognostic factors which predict for micrometastases and consequent recurrent and advanced disease. In such cases, cytotoxic chemotherapy and mitotane have been utilized with a very modest degree of benefit. The poor prognosis of recurrent and advanced ACC has underscored the interest in nuanced characterization of ACC cases using next-generation sequencing (NGS)-based genomic and other '-omic' profiling to guide the precision medicine approach and personalized use of targeted and novel therapies.

Chatterjee G, Dasgupta S, Bhattacharya K, et al.
Myxoid adrenal cortical adenoma in an infant: An unusual morphology.
J Cancer Res Ther. 2015 Oct-Dec; 11(4):1040 [PubMed] Related Publications
Myxoid adrenal cortical neoplasms are rare. To the best of our knowledge, no such case has been reported in pediatric or infantile age group till now. Here we report a case of non-functional myxoid adrenocortical adenoma (ACA) in a 7-month-old girl, who presented with a large mass in the abdomen. Microscopically, the tumor was composed of alveolar clusters of cells with focal pseudoglandular architecture in a background of abundant alcian blue positive myxoid matrix. Compressed rim of adrenal tissue was identified at periphery. The patient was put on a close follow-up in view of scarce literature on the subject. She has been doing fine without any recurrences. Myxoid adrenal cortical tumors expand the differential diagnoses of a myxoid neoplasm in retroperitoneum.

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