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Molecular Genetics of Adrenocortical Cancer
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MeSH term: Adrenal Cortex Neoplasms
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Feminizing Adrenocortical Carcinoma with Distinct Histopathological Findings.
Intern Med. 2016; 55(22):3301-3307 [PubMed] Free Access to Full Article Related Publications
Investigating the Chemokine Receptor 4 as Potential Theranostic Target in Adrenocortical Cancer Patients.
Clin Nucl Med. 2017; 42(1):e29-e34 [PubMed] Related Publications
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.
Peritoneal metastases from adrenal cortical carcinoma treated by cytoreductive surgery and hyperthermic intraperitoneal chemotherapy.
Tumori. 2016; 102(6):588-592 [PubMed] Related Publications
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.
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
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.
Multi-Target Approach to Metastatic Adrenal Cell Carcinoma.
Arch Iran Med. 2016; 19(9):671-3 [PubMed] Related Publications
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
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.
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
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.
Prognosis of Patients with Metastatic Spinal Cord Compression from Adrenocortical Carcinoma.
In Vivo. 2016 09-10; 30(5):717-9 [PubMed] Related Publications
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.
Ectopic adrenocortical carcinoma located in the ovary.
Eur J Endocrinol. 2016; 175(4):K17-23 [PubMed] Related Publications
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.
Investigation of N-cadherin/β-catenin expression in adrenocortical tumors.
Tumour Biol. 2016; 37(10):13545-13555 [PubMed] Related Publications
Disorganized Steroidogenesis in Adrenocortical Carcinoma, a Case Study.
Endocr Pathol. 2017; 28(1):27-35 [PubMed] Related Publications
Comparison of radiofrequency ablation versus laparoscopic adrenalectomy for benign aldosterone-producing adenoma.
Radiol Med. 2016; 121(10):811-9 [PubMed] Related Publications
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.
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
Investigation of biochemical composition of adrenal gland tumors by means of FTIR.
Pol J Pathol. 2016; 67(1):60-8 [PubMed] Related Publications
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
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.
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
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.
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
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
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.
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
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
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.
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 Woman with Normotensive Primary Hyperaldosteronism.
Acta Med Iran. 2016; 54(2):156-8 [PubMed] Related Publications
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
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.
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
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.
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
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
Robotic assisted adrenalectomy: Surgical techniques, feasibility, indications, oncological outcome and safety.
Int J Surg. 2016; 28:169-72 [PubMed] Related Publications
Assessment and management of advanced adrenocortical carcinoma using a precision oncology care model.
Discov Med. 2016; 21(113):49-56 [PubMed] Related Publications
Myxoid adrenal cortical adenoma in an infant: An unusual morphology.
J Cancer Res Ther. 2015 Oct-Dec; 11(4):1040 [PubMed] Related Publications