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Non-coding RNAs (ncRNAs) are a type of genetic material that do not encode proteins but regulate the gene expression at an epigenetic level, such as microRNAs (miRNAs) and long non-coding RNAs (lncRNAs). The role played by ncRNAs in many physiological and pathological processes has gained attention during the last few decades, as they might be useful in the diagnosis, treatment and management of several human disorders, including endocrine and oncological diseases. Adrenocortical carcinoma (ACC) is a rare and aggressive endocrine cancer, still characterized by high mortality and morbidity due to both endocrine and oncological complications. Despite the rarity of this disease, recently, the role of ncRNA has been quite extensively evaluated in ACC. In order to better explore the role of the ncRNA in human ACC, this review summarizes the current knowledge on ncRNA dysregulation in ACC and its potential role in the diagnosis, treatment, and management of this tumor.

Objective: Patients with primary aldosteronism (PA) can present with high PTH levels and negative calcium balance, with some studies speculating that aldosterone could directly stimulate PTH secretion. Either adrenalectomy or mineralocorticoid receptor blockers could reduce PTH levels in patients with PA. The aim of this study was to assess the relationship between aldosterone levels and parathyroid hormone (PTH)-vitamin D-calcium axis in a cohort of patients with PA, compared with patients with nonsecreting adrenocortical tumors in conditions of vitamin D sufficiency. Methods: We enrolled a series of 243 patients retrospectively, of whom 66 had PA and 177 had nonsecreting adrenal tumors, and selected those with full mineral metabolism evaluation and 25(OH) vitamin D levels >20 ng/mL at the time of initial endocrine screening. The final cohort was composed of 26 patients with PA and 39 patients, used as controls, with nonsecreting adrenal tumors. The relationships between aldosterone, PTH levels, and biochemistries of mineral metabolism were assessed. Results: Aldosterone was positively associated with PTH levels (r = 0.260, P < .05) in the whole cohort and in the PA cohort alone (r = 0.450; P = .02). In the multivariate analysis, both aldosterone concentrations and urinary calcium excretion were significantly related to PTH levels, with no effect of 25(OH) vitamin D or other parameters of bone metabolism. Conclusion: PTH level is associated with aldosterone, probably independent of 25(OH) vitamin D levels and urinary calcium. Whether aldosterone interacts directly with the parathyroid glands remains to be established.

Orientador: José Andrés Yunes Tese (doutorado) - Universidade Estadual de Campinas, Instituto de Biologia Resumo: O gene supressor de tumor TP53 é um dos mais bem caracterizados genes cujo papel na etiologia é conhecido tanto em tumores hereditários como esporádicos. Mutações germinativas neste gene normalmente estão associadas à Síndrome de Li-Fraumeni, uma síndrome de predisposição ao câncer cujos portadores apresentam alto risco de desenvolvimento de uma variedade de tumores ao longo da vida. Uma mutação específica deste gene é altamente prevalente na população brasileira, chegando a estar presente em 0.3% da população saudável. Esta mutação, a R337H, não foi descrita como uma mutação associada a um amplo espectro tumoral e, sim, como uma mutação tecido-específica associada somente ao desenvolvimento do tumor do córtex da adrenal (TCA). Entretanto, algumas evidências indicavam que ela poderia contribuir para a etiologia de outros tumores, além do TCA. A R337H foi encontrada em 06 famílias com Síndrome de Li- Fraumeni like e em 2.4% de pacientes diagnosticadas com câncer de mama. Com o objetivo de obter maiores evidências sobre a contribuição da R337H na etiologia de outros tumores além do TCA, investigamos a prevalência desta mutação em 493 pacientes diagnosticados com diferentes tumores pediátricos. Além disto, buscamos investigar alterações cromossômicas que poderiam estar associadas ao processo de tumorigênese em portadores desta mutação. Os resultados mostraram que além do TCA e câncer de mama, a R337H está fortemente associada ao carcinoma de plexo coroide (69%) e ao osteossarcoma (7%) na faixa etária pediátrica. Em nossa instituição, foi observado um aumento da incidência relativa do carcinoma de plexo coroide em relação ao papiloma de plexo coroide. Uma deleção do gene TP53 em células do sangue periférico sob a forma de um mosaico foi identificada nos pacientes portadores da R337H que desenvolveram o TCA. Os dados mostraram que se trata de uma deleção intersticial do cromossomo 17, a qual especula-se ter ocorrido durante o período embrionário. Os resultados sobre a prevalência desta mutação em diferentes tumores pediátricos poderão contribuir para um adequado aconselhamento genético das famílias em que a R337H está presente. Adicionalmente, o mosaicismo encontrado nos portadores da R337H que desenvolveram o TCA nos permitiu formular uma hipótese sobre a tumorigênese adrenocortical associada à R337H e talvez possa também contribuir para a futura compreensão do comportamento oncogênico desta mutação Abstract: The tumor suppressor gene TP53 is a well characterized gene whose role in the etiology of hereditary and sporadic cancer is well established. Germline mutations in this gene are usually associated with the Li-Fraumeni Syndrome (LFS), a cancer predisposition syndrome in which individuals are at a high risk to develop a wide spectrum of tumors during their lives. A specific mutation of TP53 gene is highly prevalent among the Brazilian population, reaching 0.3% of healthy individuals. This mutation, R337H, was not described as a mutation associated to a wide spectrum of tumors but as a tissue-specific mutation, predisposing individuals only to adrenocortical tumors (ACT). However, some evidences have indicated that it could contribute to the etiology of other tumors besides ACT. The R337H was found in six families diagnosed with LFS-like and also in 2.4% of patients diagnosed with breast cancer. In order to obtain more evidence regarding the role of R337H in the etiology of tumors besides ACT, we have investigated the prevalence of this mutation among 493 pediatric patients diagnosed with cancer. Moreover, we have looked for chromosomal changes potentially involved in tumorigenic process among R337H carriers. Our results demonstrated that, besides ACT and breast cancer, the R337H mutation is strongly associated to choroid plexus carcinoma (69%) and osteosarcoma (7%) in the pediatric age. At our institution it was observed a raise in the relative incidence of choroid plexus carcinoma to choroid plexus papilloma. It was identified a mosaic of cells presenting TP53 deletion in peripheral blood of R337H carriers who developed ACT. Our data showed that is an interstitial deletion affecting the short arm of chromosome 17 that may have occurred during the embryonic life. The results regarding the R337H prevalence among different pediatric tumors may potentially contribute to a more accurate genetic counseling of families bearing this mutation. Additionally, the TP53 deletion found in R337H carriers who developed ACT prompted us to formulate a hypothesis on the adrenocortical tumorigenesis associated to this mutation. Finally, our findings may be useful to better understand the oncogenic behavior of this mutation Doutorado Genética Animal e Evolução Doutor em Genética e Biologia Molecular

Background The main challenge in the management of indeterminate incidentally discovered adrenal tumours is to differentiate benign from malignant lesions. In the absence of clear signs of invasion or metastases, imaging techniques do not always precisely define the nature of the mass. The present pilot study aimed to determine whether radiomics may predict malignancy in adrenocortical tumours. Methods CT images in unenhanced, arterial, and venous phases from 19 patients who had undergone resection of adrenocortical tumours and a cohort who had undergone surveillance for at least 5 years for incidentalomas were reviewed. A volume of interest was drawn for each lesion using dedicated software, and, for each phase, first-order (histogram) and second-order (grey-level colour matrix and run-length matrix) radiological features were extracted. Data were revised by an unsupervised machine learning approach using the K-means clustering technique. Results Of operated patients, nine had non-functional adenoma and 10 carcinoma. There were 11 patients in the surveillance group. Two first-order features in unenhanced CT and one in arterial CT, and 14 second-order parameters in unenhanced and venous CT and 10 second-order features in arterial CT, were able to differentiate adrenocortical carcinoma from adenoma (P, The present pilot-study aimed to determine if Radiomics may predict malignancy in adrenocortical tumors. Two first-order features in unenhanced-CT and 1 in arterial-CT; 14 second-order parameters in unenhanced and venous-CT and 10 second-order features in arterial-CT were able to differentiate adrenocortical carcinoma from adenoma (p

BACKGROUND: Adrenocortical carcinoma (ACC) is a rare malignancy that is challenging to diagnose and has important implications for surgeons who approach this disease. Despite its rarity, it must always be in the differential diagnosis when investigating and treating large adrenal masses. We aim to demonstrate the complexities of this disease through a review of five recent patients at a single tertiary care center. METHODS: A series of five patients are described, each of whom presented to a single institution as referrals for “large adrenal mass” in the past sixteen months. Their pre-operative diagnosis, radiographic findings, the operative approach and the pathology results were examined. RESULTS: The first patient had a 12 cm high grade adrenocortical carcinoma. The second patient had pathology consistent with a 9 cm, high grade ACC. The third had a liposarcoma. The fourth patient had a myelolipoma. The fifth was diagnosed with a benign process. CONCLUSION: Although adrenocortical carcinoma is an uncommon cancer, it has significant implications for the patient’s prognosis and ultimately, their treatment algorithm. Therefore, when evaluating large adrenal masses, surgeons must remain vigilant of the possibility of adrenocortical carcinoma.

Patient: Male, 35 Final Diagnosis: Carney syndrome Symptoms: Pain at the spine Medication: — Clinical Procedure: Retroperitoneal adrenalectomy Specialty: Surgery Objective: Congenital defects/diseases Background: Carney complex (CNC) is a genetic disorder that presents as an adrenocorticotropic hormone (ACTH)-independent variant of endogenous Cushing syndrome. It was first reported in 1985 and was described as a form of multiple endocrine hyperplasia associated with mutations of the c-AMP-dependent protein kinase (PRKAR1A) gene that causes bilateral adrenal hyperplasia. We report a case of an incidentally found CNC in a 35-year-old male, and this case report focuses on the diagnostic scheme as well as the surgical treatment of this rare challenging condition. Case Report: A-35-year-old male presented with pathological thoracic spine fracture. The patient exhibited obesity, facial flushing, red-purplish streaks on the abdominal wall, multiple pigmented nevi of the trunk, and hypertension. Family history was positive for cardiac myxoma. Laboratory investigation showed ACTH-independent Cushing syndrome. Abdominal magnetic resonance imaging and computed tomography scan showed bilateral adrenal hyperplasia. The ensuing Liddle test revealed the characteristic paradox increase of 24-hours urine cortisol for CNC. After a bilateral retroperitoneoscopic adrenalectomy, histologic examination confirmed the presence of bilateral primary pigmented nodular adrenocortical disease (PPNAD). Genetic testing revealed a unique mutation of the responsible PRKAR1A gene. Conclusions: CNC presence was suspected due to the family history. Its characteristic pathologic manifestation called PPNAD, clinically presents as an ACTH-independent Cushing syndrome with paradoxical positive response of urinary glucocorticosteroid excretion after dexamethasone administration (Liddle’s test). Bilateral retroperitoneoscopic adrenalectomy constitutes an acceptable surgical option for PPNAD.

Recent advances in molecular genetics investigations of primary macronodular adrenal hyperplasia (PMAH) have been providing new insights for the research on this issue. The cAMP-dependent pathway is physiologically triggered by ACTH and its receptor, MC2-R, in adrenocortical cells. Different mechanisms of this cascade may be altered in some functioning adrenal cortical disorders. Activating somatic mutations of the GNAS gene (known as gsp oncogene) which encodes the stimulatory G protein alpha-subunit (Gsα) have been found in a small number of adrenocortical secreting adenomas and rarely in PMAH. Lately, ARMC5 was linked to the cyclic AMP signaling pathway, which could be implicated in all of mechanisms of cortisol-secreting by macronodules adrenal hyperplasia and the molecular defects in: G protein aberrant receptors; MC2R; GNAS; PRKAR1A; PDE11A; PDE8B. Around 50 % of patient's relatives with PMAH and 30 % of apparently sporadic hypercortisolism carried ARMC5 mutations. Therefore, PMAH is genetically determined more frequently than previously believed. This review summarizes the most important molecular mechanisms involved in PMAH.

Adrenocortical carcinoma (ACC) comprises approximately 0.02% of all malignant tumours, which are a very small fraction of a group of cancers that affect in 0.7 to 2 in 1 000 000 people per year. Recurrence is very common even after complete resection and prognosis is poor. We report a case of a sporadic form of ACC found in a 41-year-old Asian Bangladeshi man. His tumour was surgically excised completely with negative margins and he did not receive any adjuvant therapy. Four years later, adrenal adenoma was developed at his opposite side which was also excised. Then after a total duration of 7 years, he developed recurrence in both adrenal glands and extensive metastases to bilateral lungs, liver and abdominal wall. As per FIRM-ACT study, we started treatment with etoposide, doxorubicin, cisplatin plus mitotane (EDP-M), and the patient responded dramatically. He became symptom free and achieved radiological partial response just on completion of three cycles. To our knowledge, this is the first case of ACC in Bangladesh published in the literature. Managing rare cancers is always challenging due to the fact that clinicians lack practical experience in it. We believe that patient with a rare cancer with poor prognosis like ACC may also survive long, and extensive metastases can also be controlled.

Adrenocortical adenomas and carcinomas in other parenchyma are extremely rare, with few cases reported and because of the rarity of these tumors, they occasionally cause problems during diagnosis. Adrenal cortical neoplasms in liver parenchyma can be present in 3 forms, including direct invasion or adhesion to liver parenchyma, tumors arising in adrenohepatic fusion tissue or in ectopic adrenal gland tissue. We report 3 cases of adrenal cortical tumors that were misdiagnosed as hepatocellular carcinoma in the preoperative state. The first case involved an adrenocortical adenoma arising in adrenohepatic fusion tissue. The remaining 2 cases involved an adrenocortical carcinoma and an adrenocortical oncocytoma arising in ectopic adrenal tissue in the liver. We describe the clinical presentations, gross, microscopic findings, immunohistochemical findings with respect to each case, with emphasis on differential diagnosis from hepatocellular carcinoma.

This article links the understanding of developmental physiology of the adrenal cortex to adrenocortical tumor formation. Many molecular mechanisms that lead to formation of adrenocortical tumors have been discovered via next-generation sequencing approaches. The most frequently mutated genes in adrenocortical tumors are also factors in normal adrenal development and homeostasis, including those that alter the p53 and Wnt/β-catenin pathways. In addition, dysregulated protein kinase A signaling and ARMC5 mutations have been identified as key mediators of adrenocortical tumorigenesis. The growing understanding of genetic changes that orchestrate adrenocortical development and disease pave the way for potential targeted treatment strategies.

To review the current status of radiofrequency ablation as a primary treatment for hyperfunctioning adrenal nodules, predominantly aldosterone-producing adenomas (APAs).Radiofrequency ablation is an established treatment for focal benign and malignant lesions, including metastatic disease to the adrenal gland. Hyperaldosteronism is the leading cause of secondary hypertension with up to 80% due to APA, statistically the most common functioning adrenal nodule. Although surgery remains the recommended treatment of choice for confirmed unilateral functioning adrenal nodules, radiofrequency ablation offers a less-invasive approach, with results comparable with surgery.Radiofrequency ablation of functioning adrenal nodules is a newer application of a technology in use for almost 2 decades. Although limited, reports to date suggest that results are comparable with those of laparoscopic adrenalectomy, but with advantages including being a less-invasive outpatient procedure with lower morbidity, faster recovery, and lower cost. However, the current data are all retrospective, the number of patients treated is small, and reported long-term results are limited.

Primary adrenal angiosarcoma is an extremely rare vascular tumor. We report a case of a 63-year-old man with a collision tumor of epithelioid angiosarcoma and adrenocortical adenoma of the right adrenal gland. The adrenal tumor was incidentally observed by a preoperative computed tomography (CT) scan of penis squamous cell carcinoma. The patient underwent a right laparoscopic adrenalectomy, and the tumor size measured 34×34×15mm. Histological examination revealed two different tumor cell proliferations, namely epithelioid angiosarcoma and adrenocortical adenoma. He had no symptoms or abnormality in his endocrine studies, so the adrenocortical adenoma was considered non-functioning. Three months after the adrenalectomy, bilateral pleural metastasis was observed by CT scan and pleural biopsy. Paclitaxel monotherapy was performed, and the tumor retreated. The patient died one and a half years after the adrenalectomy, but the cause of death was believed to be another disease (metastatic penis squamous cell carcinoma). To the best of our knowledge, this is the fourth report of primary adrenal angiosarcoma combined with adrenocortical adenoma.

// Łukasz Koperski 1 , Marta Kotlarek 2 , Michal Świerniak 2, 3 , Monika Kolanowska 2, 3 , Anna Kubiak 2, 3 , Barbara Gornicka 1 , Krystian Jazdzewski 2, 3 and Anna Wojcicka 2, 3 1 Department of Pathology, Medical University of Warsaw, Warsaw, Poland 2 Laboratory of Human Cancer Genetics, Center of New Technologies, CENT, University of Warsaw, Warsaw, Poland 3 Genomic Medicine, Medical University of Warsaw, Warsaw, Poland Correspondence to: Anna Wojcicka, email: anna.wojcicka@uw.edu.pl Keywords: microRNA, adrenocortical carcinoma, cancer diagnostics, next-generation sequencing, NGS Abbreviations: AA, adrenocortical adenoma; ACC, adrenocortical carcinoma; NA, normal adrenal cortex; NGS, next-generation sequencing Received: May 03, 2016 Accepted: March 16, 2017 Published: April 03, 2017 ABSTRACT Background: Adrenocortical carcinoma is a rare finding among common adrenocortical tumors, but it is highly aggressive and requires early detection and treatment. Still, the differential diagnosis between benign and malignant lesions is difficult even for experienced pathologists and there is a significant need for novel diagnostic methods. In this study we aimed to reveal a complete set of microRNAs expressed in the adrenal gland and to identify easily detectable, stable and objective biomarkers of adrenocortical malignancy. Methods: We employed next-generation sequencing to analyze microRNA profiles in a unique set of 51 samples, assigned to either a learning dataset including 7 adrenocortical carcinomas (ACCs), 8 adrenocortical adenomas (AAs) and 8 control samples (NAs), or a validation dataset including 8 ACCs, 10 AAs and 10 NAs. The results were validated in real-time Q-PCR. Results: We detected 411 miRNAs expressed in 1763 length isoforms in the examined samples. Fifteen miRNAs differentiate between malignant (ACC) and non-malignant (AA + NA) tissue in the test set of independent samples. Expression levels of 6 microRNAs, miR-503-5p, miR-483-3p, miR-450a-5p, miR-210, miR-483-5p, miR-421, predict sample status (malignancy/non-malignancy) with at least 95% accuracy in both datasets. The best single-gene malignancy marker, miR-483-3p, has been validated by real-time RT PCR. Conclusions: As a result of the study we propose clinically valid and easily detectable biomarkers of adrenocortical malignancy that may significantly facilitate morphological examination. Since microRNAs can be detected in blood, the study brings tools for development of non-invasive diagnostics of adrenocortical carcinomas.

Adrenocortical carcinoma (ACC) is a rare, often fatal disease, that may be seen sporadically or with hereditary predisposition syndromes. Patients with ACC are usually girls under the age of seven who present signs of excess production of adrenal glucocorticoids and androgens, with the diagnosis being confirmed by imaging. Here we reproduce and examine what we believe to be the first autopsy case report of a child with ACC, reported by Dr. Henry Sampson in Philosophical Transactions, published by The Royal Society of London in 1697. The paper describes the autopsy of a girl with severe virilization and profound signs of Cushing syndrome who died at age six, strongly suggesting ACC. She apparently had extensive pulmonary metastases, and may have had liver involvement. The report indicates her disease arose from her left kidney and there is no indication of an adrenal origin, perhaps because the adrenal gland was not generally known as a separate organ at that time. This classic example of an early case report is particularly instructive in the context of medical knowledge and understanding in the 17th century compared to current knowledge.

Postoperative chylous ascites (PCA) is a rare clinical state that occurs during abdominal surgery. Despite its rarity, the need to diagnose and treat PCA is increasing in importance with the increased number of wide resections and lymph node dissections being performed and the serious consequences of treatment. Here we describe the PCA complications we observed after resection for treating a case of giant adrenocortical carcinoma and we have the brief review of the PCA complication.

We present here a case of metastatic adrenocortical carcinoma with bilateral lung nodules. The patient had been treated with mitotane therapy initially and then was later referred for chemotherapy. There was progression of disease noted on the F-FDG PET/CT. Ga prostate-specific membrane antigen (PSMA) PET/CT was planned to explore the possibility of future treatment with Lu-DKFZ-PSMA-617. It revealed peripheral increased uptake of Ga-HBED-CC-PSMA equal to liver uptake.

Adrenocortical carcinoma is a rare cancer with a poor but heterogeneous prognosis. These tumours are more frequently encountered in women, sometimes very young and may be diagnosed in women in their child bearing years or already pregnant. Several clinical data have indicated that the secretion and or proliferation of adrenocortical tumors may be affected by the hormonal context of pregnancy. In this review, we will examine the link between ACC and pregnancy in two main aspects. We will first consider the situation of a pregnant woman with a clinical suspicion of adrenocortical carcinoma: which diagnostic procedures will be useful and safe for the foetus? What are the therapeutic options? What is the prognosis if the diagnosis is confirmed? In a second part, we will examine the possible risk of mothering a child in a patient previously treated for an ACC. The data shown here were obtained from studies carried out in a tertiary reference medical centre in Paris (Hopital Cochin) and from the European Network for the Study of Adrenal Tumor (ENS@T) database of adrenocortical carcinoma.

We report spinal metastasis of adrenal cortical carcinoma (ACC) to the T12 vertebrae with epidural extension. ACC is a rare malignancy with poor prognosis and high rates of metastasis. However, spinal lesions of ACC are rare, and few have been reported in the literature. We discuss our management of this lesion and review the current understanding and treatment of ACC and spinal metastasis.

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.

Primary aldosteronism (PA) is caused by excessive production of aldosterone by the adrenal cortex and is determined by a benign aldosterone-producing adenoma (APA) in a significant proportion of cases. Local mechanisms, as opposed to circulatory ones, that control aldosterone production in the adrenal cortex are particularly relevant in the physiopathological setting and in the pathogenesis of PA. A breakthrough in our understanding of the pathogenetic mechanisms in APA has been the identification of somatic mutations in genes controlling membrane potential and intracellular calcium concentrations. However, recent data show that the processes of nodule formation and aldosterone hypersecretion can be dissociated in pathological adrenals and suggest a model envisaging different molecular events for the pathogenesis of APA.

Adrenocortical carcinoma frequently presents with sequelae of steroid precursor overproduction and has a proclivity for aggressive local growth, early metastasis, and recurrence. En bloc surgical resection with negative margins is the cornerstone of therapy for localized disease, and re-resection has a role in selected recurrent cases. Presence of occult micrometastatic disease at the time of presentation is confirmed by frequent distant failure after apparent negative margin resection. Data for many aspects of therapy are limited or nonexistent. This review critically considers existing evidence with a particular focus on surgical management.

The correct pathologic classification of adrenocortical carcinoma (ACC) is relevant to establish an early therapeutic strategy of this rare malignancy. The aim of the study was to assess the most frequent pitfalls in ACC diagnosis reviewing a large consecutive series of 300 cases with an original diagnosis or a clinical suspect of ACC, which were sent in consultation to our institution between 2004 and 2014. A major disagreement that significantly modified the clinical management of patients was recorded in 26 cases (9%). The most common pitfall (10 cases) was to distinguish ACC from pheochromocytoma and vice versa. Seven other cases diagnosed as ACC were reclassified as metastases from other primaries and primary adrenal soft tissue tumors (including 3 angiosarcomas). Finally, 5 adrenocortical adenomas were reclassified into carcinomas, and 4 ACCs were converted into adenomas. Minor disagreements were mostly related to the identification of ACC variants (up to 32% of cases of adrenocortical tumors in the present series). Moreover, more than 50% of ACC cases lacked Ki-67. In conclusion, our results indicate that, in the presence of a histologically suspected ACC, a special attention should be devoted to exclude metastatic and soft tissue tumors and pheochromocytoma (in this latter case with special reference to the oncocytic variant of adrenocortical tumors). Moreover, pathologists should be aware of the major role of Ki-67 in determining prognosis and in selecting patients to the most appropriate treatment.

Introduction Adrenal gland neoplasms are mostly benign. The differential diagnosis between adrenocortical adenoma and carcinoma relies on nine morphologic parameters (Weiss criteria) that are mostly subjective. Although rare, carcinomas represent an aggressive disease that require short time follow-up. For this reason, the diagnosis should be accurate. Neoplasms of the medulla are mostly represented by phaeochromocytomas, all potentially metastatic. Prognostic score systems (GAPP and PASS) have been implemented but not enough objective and useful in borderline cases. More objective parameters should be introduced. Little is known in literature on the inflammatory response in these tumors. Aim of our study was the definition (type, density and distribution) of inflammation in the adrenal neoplasms. Material and methods Immunohistochemistry for CD45 (inflammatory cells), CD20 (B cells) and CD3 (T cells) antibodies was performed in 15 adrenocortical neoplasms and 17 phaeochromocytomas. A manual count of the signal was set for each marker, to establish the cellular type, their density (cells/mm2) and location within the tumor. Fisher's exact test was applied to assess the correlation between the immunoscore and clinico-pathologic parameters. Results The difference of cellular density between the three markers was statistically significant (p value = 0.0028), with highest values for CD45 and CD3. No differences were detected between the periphery and the center of the lesions. The most relevant finding was the detection of a higher immunoscore in adrenocortical adenomas, compared to carcinomas. Moreover, most of phaeochromocytomas showed high expression of inflammation, except the only metastatic case. Conclusions The present study showed that inflammation could represent a valuable diagnostic and potential prognostic parameter, useful for the correct management of these lesions.

DNA methylation profiling has been suggested a reliable technique to distinguish between benign and malignant adrenocortical tumors, a process which with current diagnostic methods remains challenging and lacks diagnostic accuracy of borderline tumors. Accurate distinction between benign and malignant adrenal tumors is of the essence, since ACC is a rare but aggressive endocrine disease with an annual incidence of about 2.0 cases per million people per year. The estimated five-year overall survival rate for ACC patients is

Large adrenal masses pose a diagnostic dilemma. The purpose of this study was twofold: first, to assess the degree of interobserver agreement in evaluating the morphology of pathologically proven adrenal adenomas and adrenocortical carcinomas larger than 4 cm in diameter; and second, to identify morphologic characteristics that correlated with the pathologic diagnosis. For this blinded, retrospective study, we collected cases of 25 adrenal adenomas and 33 adrenocortical carcinomas measuring larger than 4 cm. Two radiologists evaluated morphologic characteristics of the lesions on CT. Interobserver agreement was evaluated using kappa statistics, and the correlation of imaging characteristics with the diagnosis was evaluated using a logistic regression model. We found the highest interobserver agreement in the assessment of precontrast attenuation (Κ = 0.81) as well as substantial agreement in determining the shape and the presence of calcifications (Κ = 0.69 and 0.74, respectively). Readers agreed less often regarding the presence of fat (Κ = 0.48), as well as regarding the presence of necrosis, heterogeneity, and the overall impression (Κ = 0.15, 0.24, and 0.26, respectively). CT characteristics correlated with benignity included round shape (p = 0.02), an overall radiologic impression of a benign lesion (p

Rationale: The development of rebound thymic hyperplasia (RTH) has been reported in patients who have recovered from stressful conditions such as surgery and steroid therapy. We report a case of RTH following the resolution of hypercortisolism after adrenalectomy for the treatment of adrenocortical adenoma in a patient with Cushing syndrome. Patient concerns: A 5-month-old female infant with a history of overeating, hirsutism, and excessive weight gain for the previous 2 months was referred to the hospital. The laboratory results revealed elevated 24-hour urinary free cortisol levels. An overnight dexamethasone suppression test showed no response. Abdominal imaging revealed a right-sided suprarenal mass measuring 4_3cm. Histology showed an adrenocortical adenoma. Thus, she underwent a right adrenalectomy. Diagnoses: The patient showed clinical improvement with weight loss and normal cortisol levels over the next 4 months. Six months after the operation, a chest computed tomography showed enlargement of the left thymic lobe, which was previously nonexistent. Interventions: A fine needle aspiration biopsy was performed, and histological examination revealed diffuse thymic hyperplasia. Outcomes: At the 1-year follow-up, the chest imaging studies showed resolution of the RTH. Lessions: An understanding of RTH after adrenalectomy as a treatment for cortisol-producing adrenocortical tumors is important for the prevention of unnecessary surgical intervention and therapy.

Careful morphological evaluation forms the basis of the workup of an adrenal cortical neoplasm. However, the adoption of immunohistochemical biomarkers has added tremendous value to enhance diagnostic accuracy. The authors provide a brief review of immunohistochemical biomarkers that have been used in the confirmation of adrenal cortical origin and in the detection of the source of functional adrenal cortical proliferations, as well as diagnostic, predictive, and prognostic biomarkers of adrenal cortical carcinoma. In addition, a brief section on potential novel theranostic biomarkers in the prediction of treatment response to mitotane and other relevant chemotherapeutic agents is also provided. In the era of precision and personalized medical practice, adoption of combined morphology and immunohistochemistry provides a new approach to the diagnostic workup of adrenal cortical neoplasms, reflecting the evolution of clinical responsibility of pathologists.

Background Adrenocortical carcinoma (ACC) is a rare, heterogeneous malignancy with a poor prognosis. ACCs are classified as functioning and non-functioning. The pathogenesis of ACC remains elusive, and diagnosis of ACC is currently based on pathology. In the absence of other effective approaches, surgical resection is the preferred treatment option. Case presentation Here, we report a case of ACC in the retroperitoneum. The patient underwent radical adrenalectomy and remained disease-free throughout a 6-month follow-up. Conclusions Radical surgical resection is an efficient therapy for ACC, and hydrocortisone can be used to alleviate symptoms of secondary acute adrenal hypofunction.

Hyperaldosteronism, caused by an aldosterone-producing adenoma (APA) or much less commonly unilateral adrenal hyperplasia, can be cured or improved in >95% of patients by unilateral laparoscopic adrenalectomy. Approximately 50% of these patients have a complete clinical remission, with blood pressure returning to normal levels without the need for antihypertensives. In the remaining ≈50%, blood pressure levels commonly fall but not into the normal range, despite biochemical cure: such patients require continuing but usually lower levels of antihypertensive therapy. The persistent hypertension is commonly attributed to vascular damage or underlying primary hypertension. APA/unilateral adrenal hyperplasia together account for ≈5% of hypertension,1 with the remainder of primary aldosteronism (PA) caused by bilateral adrenal hyperplasia. The prevalence of bilateral adrenal hyperplasia, commonly a less florid form of PA, seems currently to reflect the disparate cutoffs used. Reported levels are equal to or less than those of unilateral disease if strict cutoffs in screening and confirmatory testing are used, and approximately double when more relaxed cutoffs are in place. Such patients are not treated by adrenalectomy, except in a handful of cases of fulminant familial hypertension type III, but with mineralocorticoid receptor antagonists, amiloride, and other antihypertensive agents as required. A large, recent study has shown that a markedly elevated aldosterone-to-renin ratio accurately identified patients with an APA but not its location.2 In most jurisdictions, the advantages of laparoscopic adrenalectomy for unilateral disease are well recognized. These include total cure in half the patients lateralized who are relieved of the burden and cost of lifetime medication and lower levels of medication for blood pressure in the remainder. In addition, patients note a marked improvement in well-being and quality of life. For this reason, adrenal venous sampling (AVS) is recommended3,4 for confirmed PA patients, with some exceptions. Rarely are patients …

Background The systemic inflammatory response may be associated with tumor progression. We sought to analyze the impact of neutrophil-lymphocyte ratio (NLR) and platelet-lymphocyte ratio (PLR) on recurrence-free survival (RFS) and disease-specific survival (DSS) among patients who underwent surgery for adrenocortical carcinoma (ACC).

Adrenocortical carcinoma (ACC) is a malignant neoplasm often associated with an aggressive biological behavior. The histologic differentiation between ACC and adrenocortical adenoma (ACA) is largely determined by employing the Weiss criteria, although this classification may not apply to all the cases. Additionally, various genomic features of ACC could be an auxiliary mode to establish the diagnosis of ACC. Most ACC cases are hormonally functional, and immunohistochemical analysis of steroidogenic enzymes has provided pivotal information as to the analysis of intratumoral production of corticosteroids. This article summarizes the current status of the histopathological diagnosis, molecular pathogenesis, and hormonal features of ACC.

Adrenocortical carcinoma (ACC) is a heterogeneous and rare disease. At presentation or at the time of a recurrence, the disease commonly spreads to the liver, lungs, lymph nodes, and bones. The brain has only rarely been reported as a site of metastases.The aims of this report were to describe the clinical characteristics of patients with ACC who developed brain metastasis and were evaluated at the National Cancer Institute.We describe the history and clinical presentation of six patients with ACC and metastatic disease in the brain. Images of the six patients and pathology slides were reviewed when available.The median age at the time of the diagnosis of ACC was 42 years. The median time from the initial diagnosis until the presentation of brain metastasis was 43 months. As a group the patients had previously received multiples lines of chemotherapy (median of three), and they presented with one to three metastatic brain lesions. Four patients underwent metastasectomy, one had radiosurgery, and one had both modalities. Two patients are still alive, three died, between 2 and 14 months after the diagnosis of brain metastases, and one was lost to follow-up.Patients with advanced ACC can rarely present with metastasis to the brain, most often long after the initial diagnosis. Timely diagnosis of brain metastasis with appropriate intervention after discussion in a multidisciplinary meeting can improve the prognosis in this particular scenario.

SummaryObjective Unilateral primary aldosteronism (PA) should have a contralaterally normal and therefore suppressed adrenal zona glomerulosa. However, there is no validated definition of adrenal suppression. We created two biochemical hypotheses of adrenal suppression based upon measurements taken during adrenal vein sampling (AVS) to determine whether either proved useful for interpretation of AVS or prediction of hypertension outcome in operated cases. Design Retrospective database analysis. Patients Ninety-nine cases of PA from a tertiary hypertension unit. Measurements Hypothesis 1 was the proportional suppression of the uninvolved/lowest adrenalaldo/cortisol to IVCaldo/cortisol ratio pre- and post cosyntropin. Hypothesis 2 was the absolute decrease in the uninvolved adrenalaldo/cortisol ratio after cortrosyn injection. ROC analysis performed using lateralization and hypertension resolution as the outcomes of interest. Results Hypothesis 1 proved highly predictive of lateralization with a ROC AUC of 0·958, P

A 9-year-old, spayed female Chihuahua was presented with a 1-week history of lethargy and anorexia. Abdominal ultrasonography and computed tomography found bilateral adrenal masses without metastasis. Serum cortisol levels that were sampled before and after an adrenocorticotropic hormone stimulation test were within reference ranges. Lethargy and anorexia completely resolved after short-term fluid therapy; the clinical signs did not occur for approximately 8 months until her sudden death. A postmortem examination revealed bilateral adrenocortical carcinomas and liver metastasis. Primary adrenocortical carcinomas developed in the dog met the definition of bilateral incidental adrenal gland masses (IAGMs). This is the first case report to demonstrate based on histological identification that adrenocortical carcinomas cause bilateral IAGMs in dogs.

Pheochromocytoma with synchronous ipsilateral adrenal cortical adenoma (PSCA) may present with mixed clinical, biochemical, and radiological features characteristic to each neoplasm subtype. All patients with a pathological diagnosis of pheochromocytoma were evaluated for an ipsilateral cortical adenoma from 1994 through 2015. Retrospectively extracted data included indications for adrenalectomy, diagnostic workup (biochemical and radiographic), operative characteristics, pathological findings, and postoperative complications. Sixteen of 413 patients (4%) undergoing adrenalectomy for pheochromocytoma had a PSCA. Median patient age was 57.7 years (IQR 50.1, 63.1); 50% were male. On imaging, 75% of the adrenal neoplasms were found incidentally and only 50% were reported to have a synchronous ipsilateral neoplasm based on imaging findings. Clinically important cortical hormone secretion was diagnosed in 38% of these patients; 25% had glucocorticoid secretory autonomy; and 13% had primary aldosteronism. Physicians should be aware that adrenal neoplasms with mixed diagnostic findings may represent PSCA. Evaluation should be performed on this co-occurrence to prevent perioperative complications from resection of an unexpected secretory cortical neoplasm.

Adrenocortical carcinoma (ACC) is a rare disease with a poor prognosis. The presence of a mass syndrome or signs of hormonal hypersecretion often lead to its discovery, but more and more frequently, adrenocortical malignancy is fortuitously discovered as an incidentaloma. Cross-sectional imaging (CT and MRI) often points to the malignant character of the adrenal mass. Needle biopsy is contraindicated. Laboratory testing showing combined hypersecretion of cortisol, androgens or inactive corticosteroid precursors is highly suggestive of ACC. An 18F-fluoro-deoxyglucose Positron Emission Tomography (PET scan) should be performed to evaluate the malignancy of an adrenal mass and to detect regional or distant metastases. Although the majority of ACC are diagnosed at a locally advanced or metastatic stage, radical resection offers the only hope of cure. The peri-operative management of patients with ACC is not yet standardized. The aim of this review is to summarize the actual knowledge of the surgical management of ACC.

There are no approved therapeutic regimes for adrenal carcinoma following progression to a first line of chemotherapy/mitotane although a high percentage of patients are candidates to receive them. In the present article we review the possible therapeutic alternatives after the progression to a first line of treatment in patients with adrenal carcinoma and we report a case in which a prolonged overall survival is achieved, much higher than expected, probably in relation to the multidisciplinary management of the case and the use of most of the therapeutic arsenal available.En el carcinoma suprarrenal metastásico no existen esquemas de tratamiento aprobados tras la progresión a una primera línea de quimioterapia/mitotane, si bien un alto porcentaje de pacientes son candidatos a recibirlos. En este artículo realizamos una revisión sobre las posibles alternativas terapéuticas tras la progresión a una primera línea de tratamiento en pacientes con carcinoma suprarrenal metastásico. A propósito de la misma, se presenta un caso clínico en el que se consigue una prolongada supervivencia global, mucho mayor de la esperable, probablemente debido al manejo multidisciplinario del caso y a la utilización de la mayor parte del arsenal terapéutico disponible.

Whether primary aldosteronism (PA) is the consequence of a monoclonal or multiclonal process is unclear.A 48-year-old man with severe bilateral PA refractory to medical therapy underwent unilateral adrenalectomy of the dominant adrenal. Although computed tomography showed three left-sided cortical nodules, postsurgical histopathology and genetic analysis revealed five different adrenocortical adenomas. Two zona fasciculata (ZF)-like aldosterone-producing adenomas (APAs) each harbored distinct known somatic KCNJ5 mutations (L168R and T158A). A zona glomerulosa-like APA harbored a known CACNA1D G403R somatic mutation, whereas a zona reticularis-like adenoma, which was grossly black in pigmentation with histologic characteristics more associated with cortisol-producing adenomas, expressed CYP11B2, CYP17, and DHEA-ST by immunohistochemistry (IHC) and harbored no known somatic mutations. The fifth adenoma was ZF-type, negative for CYP11B2 and CYP17 IHC, and harbored no known somatic mutations.This case highlights complex intertumor heterogeneity in histology, steroidogenesis, and somatic mutations in multiple adrenocortical adenomas arising in a single patient with PA. These findings suggest that the syndrome of PA can involve heterogeneous and multiclonal functional adrenal adenomas.

Untargeted, next generation sequencing approaches have provided deep insights into genetic events that result in unopposed steroidogenesis from the adrenal cortex. In particular, somatic mutations in the gene encoding the catalytic subunit α of protein kinase A (PKA) (PRKACA) were identified independently by several groups as the most frequently altered gene in cortisol-producing adenomas. Detailed functional studies could explore the molecular consequences of these hot-spot mutations and large international cohorts have provided the basis to explore the clinical characteristics associated with this mutation. Thereby, PRKACA mutations are highly specific for cortisol over-secretion, while they are absent or very rare in the context of other adrenal diseases. Patients carrying these somatic mutations are affected by a more severe phenotype and are identified at a younger age. Thus, these genotype/phenotype correlations provide further evidence for the importance of PKA-dependent pathways for adrenal physiology and disease.

Adrenocortical cancer is a rare malignancy. While surgery is the cornerstone of the management of localized disease, metastatic disease is hard to treat. Cytotoxic chemotherapy and mitotane have been utilized with a variable degree of benefit and few long-term responses. A growing understanding of the molecular pathogenesis of this malignancy as well as multidisciplinary and multi-institutional collaborative efforts will result in better defined targets and subsequently, effective novel therapies.