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Verlinde L, Kinet S, Van Den Heede K, Brusselaers N, Van Slycke S. Adrenal cortical carcinoma - a case series and literature review of aggressive adrenal incidentalomas. Acta Chir Belg 2025:1-9. [PMID: 40375728 DOI: 10.1080/00015458.2025.2506935] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2023] [Accepted: 05/09/2025] [Indexed: 05/18/2025]
Abstract
OBJECTIVE Adrenal cortical carcinoma (ACC) is a rare and aggressive endocrine malignancy. Clinical symptoms are mainly related to excess hormone secretion. Hypercortisolism and virilisation are among the most common presentations. METHODS We report a case series of five patients with ACC, three of which presented as adrenal incidentalomas. Additionally, a literature review on current diagnosis and management of ACC was performed. RESULTS ACCs are often incidentally detected because of the liberal use of medical imaging. Management of ACC remains challenging, and the poor prognosis makes early diagnosis of crucial importance to increase chances of a better outcome. Biochemical evaluation should be performed to diagnose hormonally active tumours. CONCLUSION Surgery is the main and only potentially curative treatment option. Adjuvant treatment with mitotane may improve survival and is indicated for patients with a perceived high risk of recurrence. Aggressive cytotoxic therapy should be given to patients with an unfavourable prognosis.
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Affiliation(s)
- Liesbeth Verlinde
- Faculty of Medicine, KU Leuven, Leuven, Belgium
- Department of General and Endocrine Surgery, Onze-Lieve-Vrouw (OLV) Hospital Aalst-Asse-Ninove, Aalst, Belgium
| | - Sam Kinet
- Faculty of Medicine, KU Leuven, Leuven, Belgium
- Department of General and Endocrine Surgery, Onze-Lieve-Vrouw (OLV) Hospital Aalst-Asse-Ninove, Aalst, Belgium
| | - Klaas Van Den Heede
- Department of General and Endocrine Surgery, Onze-Lieve-Vrouw (OLV) Hospital Aalst-Asse-Ninove, Aalst, Belgium
| | - Nele Brusselaers
- Department of Microbiology, Tumour and Cell Biology, Centre for Translational Microbiome Research, Karolinska Institute, Karolinska Hospital, Stockholm, Sweden
- Global Health Institute, University of Antwerp, Wilrijk, Belgium
- Department of Head and Skin, University Hospital Ghent, Ghent, Belgium
| | - Sam Van Slycke
- Department of General and Endocrine Surgery, Onze-Lieve-Vrouw (OLV) Hospital Aalst-Asse-Ninove, Aalst, Belgium
- Department of Head and Skin, University Hospital Ghent, Ghent, Belgium
- Department of General Surgery, AZ Damiaan, Ostend, Belgium
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Prinzi A, Guarnotta V, Di Dalmazi G, Canu L, Ceccato F, Ferraù F, Badalamenti G, Albertelli M, De Martino MC, Fanciulli G, Modica R, Pani A, Arcidiacono F, Barca I, Donnarumma F, Zanatta L, Torchio M, Alessi Y, Vitiello C, Frasca F, Malandrino P. Multicentric Retrospective Analysis of Oncocytic Adrenocortical Carcinoma: Insights into Clinical and Management Strategies. Endocr Pathol 2025; 36:11. [PMID: 40214939 PMCID: PMC11991974 DOI: 10.1007/s12022-025-09857-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 04/02/2025] [Indexed: 04/14/2025]
Abstract
Oncocytic adrenocortical carcinoma (OAC) is a rare variant of conventional adrenocortical carcinoma (ACC), characterized by oncocytic tumor cells comprising more than 90% of the tumor. Due to its rarity, there is a lack of reliable data on the clinicopathological features and outcomes of OAC. The aim of this study was to assess the clinical presentation, treatment modalities, and outcomes of patients with OAC, comparing these results with a cohort of patients with conventional ACC. Data from 9 referral centers in Italy on 44 patients with OAC were retrospectively analyzed and compared with data from 145 patients with conventional ACC. Patients with OAC had a smaller median tumor size, more favorable resection margin status, and lower incidences of venous invasion and persistent/recurrent disease during follow-up. Additionally, patients with OAC exhibited longer times to progression (TTP) and overall survival (OS) compared to patients with conventional ACC. Multivariable analyses identified Ki67 and tumor size as features independently associated with disease progression during post-surgical follow-up, while Ki67 and distant metastases at diagnosis were independently associated with OS in OAC patients. After complete tumor removal, the risk of recurrent disease was higher in patients with either Ki67 ≥ 20% or ENSAT stage III/IV. OAC appears to have a more indolent clinical course and better prognosis than conventional ACC. Similar to conventional ACC, Ki67 remains a significant prognostic marker for OAC and, along with ENSAT stage, serves as a reliable biomarker for identifying patients who may benefit from adjuvant mitotane therapy.
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Affiliation(s)
- Antonio Prinzi
- Endocrinology Unit, Department of Clinical and Experimental Medicine, Garibaldi-Nesima Medical Center, University of Catania, 95122, Catania, Italy.
| | - Valentina Guarnotta
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties, Section of Endocrinology, University of Palermo, Piazza Delle Cliniche 2, 90127, Palermo, Italy
| | - Guido Di Dalmazi
- Division of Endocrinology and Diabetes Prevention and Care, IRCCS Azienda Ospedaliero-Universitaria Di Bologna, 40138, Bologna, Italy
- Department of Medical and Surgical Sciences (DIMEC), Alma Mater Studiorum University of Bologna, 40138, Bologna, Italy
| | - Letizia Canu
- Department of Experimental and Clinical Biomedical Sciences, Endocrinology Unit, University of Florence, 50139, Florence, Italy
| | - Filippo Ceccato
- Department of Medicine DIMED, University of Padova, Padova, Italy
- Endocrine Disease Unit, University-Hospital of Padova, Padova, Italy
| | - Francesco Ferraù
- Department of Human Pathology of Adulthood and Childhood "G. Barresi" DETEV, University of Messina, Messina, Italy
| | - Giuseppe Badalamenti
- Department of Precision Medicine in Medical, Surgical and Critical Care (Me.Pre.C.C.), University of Palermo, Palermo, Italy
| | - Manuela Albertelli
- Department of Internal Medicine and Medical Specialties (DiMI), University of Genova, Genova, Italy
- Endocrinology, IRCCS Ospedale Policlinico San Martino, Genova, Italy
| | | | - Giuseppe Fanciulli
- NET Unit, Department of Medicine, Surgery and Pharmacy, University Hospital of Sassari, Sassari, Italy
| | - Roberta Modica
- Endocrinology, Diabetology and Andrology Unit, Department of Clinical Medicine and Surgery, Federico II University of Naples, 80131, Naples, Italy
| | - Angelo Pani
- Endocrinology Unit, ASL Gallura, 07026, Olbia, Italy
| | - Francesco Arcidiacono
- Endocrinology Unit, Department of Clinical and Experimental Medicine, Garibaldi-Nesima Medical Center, University of Catania, 95122, Catania, Italy
| | - Ignazio Barca
- Endocrinology Unit, Department of Clinical and Experimental Medicine, Garibaldi-Nesima Medical Center, University of Catania, 95122, Catania, Italy
| | - Francesca Donnarumma
- Division of Endocrinology and Diabetes Prevention and Care, IRCCS Azienda Ospedaliero-Universitaria Di Bologna, 40138, Bologna, Italy
- Department of Medical and Surgical Sciences (DIMEC), Alma Mater Studiorum University of Bologna, 40138, Bologna, Italy
| | - Lorenzo Zanatta
- Department of Experimental and Clinical Biomedical Sciences, Endocrinology Unit, University of Florence, 50139, Florence, Italy
| | - Marianna Torchio
- Department of Medicine DIMED, University of Padova, Padova, Italy
- Endocrine Disease Unit, University-Hospital of Padova, Padova, Italy
| | - Ylenia Alessi
- Department of Biomedical, Dental and Morphological and Functional Imaging Sciences, University of Messina, 98125, Messina, Italy
| | - Chiara Vitiello
- Dipartimento Di Medicina Clinica E Chirurgia, Università Federico II Di Napoli, Naples, Italy
| | - Francesco Frasca
- Endocrinology Unit, Department of Clinical and Experimental Medicine, Garibaldi-Nesima Medical Center, University of Catania, 95122, Catania, Italy
| | - Pasqualino Malandrino
- Endocrinology Unit, Department of Clinical and Experimental Medicine, Garibaldi-Nesima Medical Center, University of Catania, 95122, Catania, Italy
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3
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Zheng Y, Ren S, Yan Z, Hu T, Feng Y, Wang D, Fan S, Ren S. Causes of death in patients with malignant adrenal tumours: a population-based analysis. J Endocrinol Invest 2025:10.1007/s40618-025-02555-y. [PMID: 39992618 DOI: 10.1007/s40618-025-02555-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/14/2024] [Accepted: 02/11/2025] [Indexed: 02/26/2025]
Abstract
OBJECTIVE This study aimed to characterize the causes of death and compute the risk of mortality due to each cause among patients with malignant adrenal tumours. METHODS Data from malignant adrenal tumour patients were collected from the Surveillance, Epidemiology, and End Results (SEER) database (2004-2020). With reference data from the general population, the standardized mortality ratio (SMR) was calculated to assess all causes of death for malignant adrenal tumour patients. RESULTS A total of 1651 patients who died from primary malignant adrenal neoplasms were included; 854 cases of adrenocortical carcinoma (ACC)-related death, 118 cases of pheochromocytoma (PCC)-related death and 333 cases of neuroblastoma (NB)-related death were identified for further analysis. Approximately 56.78%~87.69% of patients died from primary malignant adrenal tumours, 7.21%~13.56% died from secondary malignant neoplasms (SMNs), and 5.11%~29.66% died from noncancer diseases. The main causes of death associated with SMNs included lung and bronchial cancer and soft tissue cancers, including heart, kidney and renal pelvis cancers; the noncancer causes of death included mainly heart disease, septicemia, and cerebrovascular disease. Compared with chemotherapy-naïve patients, chemotherapy-treated patients had higher SMRs of SMNs, including cancers of the colon (excluding the rectum), lung, bronchus, bones and joints; soft tissues, including the heart, kidney and renal pelvis; the brain and peripheral nervous system; and leukaemia, as well as nontumor diseases, including heart disease, septicemia, and cerebrovascular disease. Patients with NB were more likely to die from SMNs, including soft-tissue malignancies of the heart, bones and joints; brain; peripheral nervous system; the female genital system, including the ovary; leukaemia, including lymphocytic leukaemia; myeloid and monocytic leukaemia; and lymphoma, including non-Hodgkin lymphoma. CONCLUSION In addition to primary cancer, SMNs and nontumor diseases were important causes of death in patients with malignant adrenal tumours. Neuroblastoma patients and chemotherapy- treated patients are more likely to die from SMNs and should monitored closely.
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Affiliation(s)
- Yang Zheng
- School of Medicine, University of Electronic Science and Technology of China, Chengdu, 610054, China
- Robotic Minimally Invasive Surgery Center, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, 610072, China
| | - Song Ren
- Department of Nephrology, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, 610072, China
| | - Zeyi Yan
- The First Clinical Medicine College of Lanzhou University, Lanzhou, 730000, Gansu Province, China
| | - Ting Hu
- School of Medicine, University of Electronic Science and Technology of China, Chengdu, 610054, China
- Robotic Minimally Invasive Surgery Center, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, 610072, China
| | - Yunlin Feng
- Department of Nephrology, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, 610072, China.
| | - Dong Wang
- Robotic Minimally Invasive Surgery Center, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, 610072, China.
| | - Shida Fan
- Robotic Minimally Invasive Surgery Center, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, 610072, China.
| | - Shangqing Ren
- Robotic Minimally Invasive Surgery Center, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, 610072, China.
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4
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Flauto F, De Martino MC, Vitiello C, Pivonello R, Colao A, Damiano V. A Review on Mitotane: A Target Therapy in Adrenocortical Carcinoma. Cancers (Basel) 2024; 16:4061. [PMID: 39682247 DOI: 10.3390/cancers16234061] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2024] [Revised: 11/28/2024] [Accepted: 12/02/2024] [Indexed: 12/18/2024] Open
Abstract
Adrenocortical carcinomas (ACCs) are rare and aggressive malignancies of adrenal cortex, associated with largely unknown mechanisms of biological development and poor prognosis. Currently, mitotane is the sole approved drug for treating advanced adrenocortical carcinomas (ACCs) and is being utilized more frequently as postoperative adjuvant therapy. Although it is understood that mitotane targets the adrenal cortex and disrupts steroid production, its precise mechanism of action requires further exploration. Additionally, mitotane affects cytochrome P450 enzymes, causes the depolarization of mitochondrial membranes, and leads to an accumulation of free cholesterol, ultimately resulting in cell death. Many patients treated with mitotane develop disease progression over time, underlying the need to understand the mechanisms of primary and acquired resistance. In this manuscript, we provide an overview on the intracellular mechanisms of action of mitotane, exploring data regarding predictive factors of response and evidence associated with the development of primary and acquired resistance mechanisms. In this discussion, mitotane is considered a real target therapy.
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Affiliation(s)
- Fabiano Flauto
- Department of Clinical Medicine and Surgery, University of Naples Federico II, 80131 Naples, Italy
| | | | - Chiara Vitiello
- Department of Clinical Medicine and Surgery, University of Naples Federico II, 80131 Naples, Italy
| | - Rosario Pivonello
- Department of Clinical Medicine and Surgery, University of Naples Federico II, 80131 Naples, Italy
| | - Annamaria Colao
- Department of Clinical Medicine and Surgery, University of Naples Federico II, 80131 Naples, Italy
| | - Vincenzo Damiano
- Department of Clinical Medicine and Surgery, University of Naples Federico II, 80131 Naples, Italy
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5
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Casey RT, Hendriks E, Deal C, Waguespack SG, Wiegering V, Redlich A, Akker S, Prasad R, Fassnacht M, Clifton-Bligh R, Amar L, Bornstein S, Canu L, Charmandari E, Chrisoulidou A, Freixes MC, de Krijger R, de Sanctis L, Fojo A, Ghia AJ, Huebner A, Kosmoliaptsis V, Kuhlen M, Raffaelli M, Lussey-Lepoutre C, Marks SD, Nilubol N, Parasiliti-Caprino M, Timmers HHJLM, Zietlow AL, Robledo M, Gimenez-Roqueplo AP, Grossman AB, Taïeb D, Maher ER, Lenders JWM, Eisenhofer G, Jimenez C, Pacak K, Pamporaki C. International consensus statement on the diagnosis and management of phaeochromocytoma and paraganglioma in children and adolescents. Nat Rev Endocrinol 2024; 20:729-748. [PMID: 39147856 DOI: 10.1038/s41574-024-01024-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 07/17/2024] [Indexed: 08/17/2024]
Abstract
Phaeochromocytomas and paragangliomas (PPGL) are rare neuroendocrine tumours that arise not only in adulthood but also in childhood and adolescence. Up to 70-80% of childhood PPGL are hereditary, accounting for a higher incidence of metastatic and/or multifocal PPGL in paediatric patients than in adult patients. Key differences in the tumour biology and management, together with rare disease incidence and therapeutic challenges in paediatric compared with adult patients, mandate close expert cross-disciplinary teamwork. Teams should ideally include adult and paediatric endocrinologists, oncologists, cardiologists, surgeons, geneticists, pathologists, radiologists, clinical psychologists and nuclear medicine physicians. Provision of an international Consensus Statement should improve care and outcomes for children and adolescents with these tumours.
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Affiliation(s)
- Ruth T Casey
- Department of Medical Genetics, University of Cambridge and NIHR Cambridge Biomedical Research Centre, Cambridge, UK.
- Department of Endocrinology, Cambridge Cancer Centre and Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
| | - Emile Hendriks
- Department of Paediatric Diabetes and Endocrinology, Cambridge Cancer Centre and Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
| | - Cheri Deal
- Endocrine and Diabetes Service, CHU Sainte-Justine and University of Montreal, Montreal, Québec, Canada
| | - Steven G Waguespack
- Department of Endocrine Neoplasia and Hormonal Disorders, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Verena Wiegering
- University Children's Hospital, Department of Paediatric Hematology, Oncology and Stem Cell Transplantation, University of Würzburg, Würzburg, Germany
| | - Antje Redlich
- Paediatric Oncology Department, Otto von Guericke University Children's Hospital, Magdeburg, Germany
| | - Scott Akker
- St Bartholomew's Hospital, Barts Health NHS Trust, London, UK
| | - Rathi Prasad
- Centre for Endocrinology, William Harvey Research Institute, Queen Mary University of London, London, UK
| | - Martin Fassnacht
- Department of Medicine, Division of Endocrinology and Diabetes, University Hospital, University of Würzburg, Würzburg, Germany
| | - Roderick Clifton-Bligh
- Department of Diabetes and Endocrinology, Royal North Shore Hospital, Sydney, New South Wales, Australia
| | - Laurence Amar
- Université de Paris, Paris, France
- Hypertension Unit, Hôpital Européen Georges Pompidou, Assistance Publique - Hôpitaux de Paris, Paris, France
| | - Stefan Bornstein
- Department of Medicine III, University Hospital Carl Gustav Carus, Medical Faculty Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
| | - Letizia Canu
- Department of Experimental and Clinical Biomedical Sciences "Mario Serio", University of Florence, Florence, Italy
- Centro di Ricerca e Innovazione sulle Patologie Surrenaliche, Azienda Ospedaliera Universitaria (AOU) Careggi, Florence, Italy
| | - Evangelia Charmandari
- Division of Endocrinology, Metabolism and Diabetes, First Department of Paediatrics, National and Kapodistrian University of Athens Medical School, 'Aghia Sophia' Children's Hospital, Athens, Greece
| | | | - Maria Currás Freixes
- Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre (CNIO) and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Institute of Health Carlos III (ISCIII), Madrid, Spain
| | - Ronald de Krijger
- Princess Maxima Center for Paediatric Oncology, Utrecht, Netherlands
- Department of Pathology, University Medical Center Utrecht, Utrecht, Netherlands
| | - Luisa de Sanctis
- Department of Public Health and Paediatric Sciences, University of Turin, Turin, Italy
| | - Antonio Fojo
- Division of Hematology/Oncology, Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY, USA
| | - Amol J Ghia
- Department of Radiation Oncology, University Hospital of Texas, MD Anderson Cancer Center, Houston, TX, USA
| | - Angela Huebner
- Department of Paediatrics, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
| | - Vasilis Kosmoliaptsis
- Department of Surgery, University of Cambridge and National Institute for Health Research Cambridge Biomedical Research Centre, Addenbrooke's Hospital, Cambridge, UK
- Blood and Transplant Research Unit in Organ Donation and Transplantation, National Institute for Health Research, University of Cambridge, Cambridge, UK
| | - Michaela Kuhlen
- Paediatrics and Adolescent Medicine, Faculty of Medicine, University of Augsburg, Augsburg, Germany
| | - Marco Raffaelli
- U.O.C. Chirurgia Endocrina e Metabolica, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
- Istituto di Semeiotica Chirurgica, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Charlotte Lussey-Lepoutre
- Service de médecine nucléaire, Inserm U970, Sorbonne université, Groupe hospitalier Pitié-Salpétrière, Paris, France
| | - Stephen D Marks
- Department of Paediatric Nephrology, Great Ormond Street Hospital for Children NHS Foundation Trust and NIHR GOSH Biomedical Research Centre, University College London Great Ormond Street Institute of Child Health, London, UK
| | - Naris Nilubol
- Surgical Oncology Program, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Mirko Parasiliti-Caprino
- Endocrinology, Diabetes and Metabolism, Department of Medical Sciences, University of Turin, Corso Dogliotti, Turin, Italy
| | - Henri H J L M Timmers
- Department of Internal Medicine, Radboud University Medical Centre, Nijmegen, Netherlands
| | - Anna Lena Zietlow
- Clinical Child and Adolescent Psychology, Institute of Clinical Psychology and Psychotherapy, Department of Psychology, TU Dresden, Dresden, Germany
| | - Mercedes Robledo
- Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre (CNIO) and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Institute of Health Carlos III (ISCIII), Madrid, Spain
| | - Anne-Paule Gimenez-Roqueplo
- Université Paris Cité, PARCC, INSERM, Paris, France
- Service de Génétique, Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Paris, France
| | - Ashley B Grossman
- Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK
- Centre for Endocrinology, Barts and the London School of Medicine, London, UK
- ENETS Centre of Excellence, Royal Free Hospital, London, UK
| | - David Taïeb
- Department of Nuclear Medicine, La Timone University Hospital, CERIMED, Aix-Marseille University, Marseille, France
| | - Eamonn R Maher
- Department of Medical Genetics, University of Cambridge and NIHR Cambridge Biomedical Research Centre, Cambridge, UK
| | - Jacques W M Lenders
- Department of Internal Medicine, Radboud University Medical Centre, Nijmegen, Netherlands
| | - Graeme Eisenhofer
- Department of Medicine III, University Hospital Carl Gustav Carus, Medical Faculty Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
| | - Camilo Jimenez
- Department of Endocrine Neoplasia and Hormonal Disorders, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Karel Pacak
- Section on Medical Neuroendocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Rockville, MD, USA
| | - Christina Pamporaki
- Department of Medicine III, University Hospital Carl Gustav Carus, Medical Faculty Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
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Feciche BO, Barbos V, Big A, Porav-Hodade D, Cumpanas AA, Latcu SC, Zara F, Barb AC, Dumitru CS, Cut TG, Ismail H, Novacescu D. Posterior Retroperitoneal Laparoscopic Adrenalectomy: An Anatomical Essay and Surgical Update. Cancers (Basel) 2024; 16:3841. [PMID: 39594796 PMCID: PMC11593218 DOI: 10.3390/cancers16223841] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2024] [Revised: 11/09/2024] [Accepted: 11/11/2024] [Indexed: 11/28/2024] Open
Abstract
Posterior retroperitoneal laparoscopic adrenalectomy (PRLA) has emerged as a revolutionary, minimally invasive technique for adrenal gland surgery, offering significant advantages over traditional open approaches. This narrative review aims to provide a comprehensive update on PRLA, focusing on its anatomical foundations, surgical technique, and clinical implications. We conducted an extensive review of the current literature and surgical practices to elucidate the key aspects of PRLA. The procedure leverages a unique "backdoor" approach, accessing the adrenal glands through the retroperitoneum, which necessitates a thorough understanding of the posterior abdominal wall and retroperitoneal anatomy. Proper patient selection, meticulous surgical planning, and adherence to key technical principles are paramount for successful outcomes. In this paper, the surgical technique is described step by step, emphasizing critical aspects such as patient positioning, trocar placement, and adrenal dissection. PRLA demonstrates reduced postoperative pain, shorter hospital stays, and faster recovery times compared to open surgery, while maintaining comparable oncological outcomes for appropriately selected cases. However, the technique presents unique challenges, including a confined working space and the need for surgeons to adapt to a posterior anatomical perspective. We conclude that PRLA, in the right clinical setting, offers a safe and effective alternative to traditional adrenalectomy approaches. Future research should focus on expanding indications and refining techniques to further improve patient outcomes.
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Affiliation(s)
- Bogdan Ovidiu Feciche
- Department of Surgical Disciplines, Discipline of Urology, Faculty of Medicine and Pharmacy, University of Oradea, University Street, No. 1, 410087 Oradea, Romania;
- Department of Urology, Emergency County Hospital Oradea, Gheorghe Doja Street, No. 65, 410169 Oradea, Romania;
| | - Vlad Barbos
- Department of Urology, Emergency County Hospital Oradea, Gheorghe Doja Street, No. 65, 410169 Oradea, Romania;
- Doctoral School, Victor Babes University of Medicine and Pharmacy Timisoara, E. Murgu Square, No. 2, 300041 Timisoara, Romania;
| | - Alexandru Big
- Department of Urology, Emergency County Hospital Oradea, Gheorghe Doja Street, No. 65, 410169 Oradea, Romania;
| | - Daniel Porav-Hodade
- Department of Urology, George Emil Palade University of Medicine, Pharmacy, Sciences and Technology of Targu-Mures, Gh. Marinescu Street, No. 38, 540142 Targu-Mures, Romania;
| | - Alin Adrian Cumpanas
- Department XV, Discipline of Urology, Victor Babes University of Medicine and Pharmacy Timisoara, E. Murgu Square, No. 2, 300041 Timisoara, Romania;
| | - Silviu Constantin Latcu
- Doctoral School, Victor Babes University of Medicine and Pharmacy Timisoara, E. Murgu Square, No. 2, 300041 Timisoara, Romania;
- Department XV, Discipline of Urology, Victor Babes University of Medicine and Pharmacy Timisoara, E. Murgu Square, No. 2, 300041 Timisoara, Romania;
| | - Flavia Zara
- Department II of Microscopic Morphology, Victor Babes University of Medicine and Pharmacy Timisoara, E. Murgu Square, No. 2, 300041 Timisoara, Romania; (F.Z.); (A.C.B.); (C.-S.D.); (D.N.)
| | - Alina Cristina Barb
- Department II of Microscopic Morphology, Victor Babes University of Medicine and Pharmacy Timisoara, E. Murgu Square, No. 2, 300041 Timisoara, Romania; (F.Z.); (A.C.B.); (C.-S.D.); (D.N.)
| | - Cristina-Stefania Dumitru
- Department II of Microscopic Morphology, Victor Babes University of Medicine and Pharmacy Timisoara, E. Murgu Square, No. 2, 300041 Timisoara, Romania; (F.Z.); (A.C.B.); (C.-S.D.); (D.N.)
| | - Talida Georgiana Cut
- Department XIII, Discipline of Infectious Diseases, Victor Babes University of Medicine and Pharmacy Timisoara, E. Murgu Square, No. 2, 300041 Timisoara, Romania;
- Center for Ethics in Human Genetic Identifications, Victor Babes University of Medicine and Pharmacy Timisoara, E. Murgu Square, No. 2, 300041 Timisoara, Romania
| | - Hossam Ismail
- Department of Urology, Lausitz Seeland Teaching Hospital, University of Dresden, Maria-Grollmuß-Straße, No. 10, 02977 Hoyerswerda, Germany;
| | - Dorin Novacescu
- Department II of Microscopic Morphology, Victor Babes University of Medicine and Pharmacy Timisoara, E. Murgu Square, No. 2, 300041 Timisoara, Romania; (F.Z.); (A.C.B.); (C.-S.D.); (D.N.)
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7
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Zhang J, Wu L, Su T, Liu H, Jiang L, Jiang Y, Wu Z, Chen L, Li H, Zheng J, Sun Y, Peng H, Han R, Ning G, Ye L, Wang W. Pharmacogenomic analysis in adrenocortical carcinoma reveals genetic features associated with mitotane sensitivity and potential therapeutics. Front Endocrinol (Lausanne) 2024; 15:1365321. [PMID: 38779454 PMCID: PMC11109426 DOI: 10.3389/fendo.2024.1365321] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2024] [Accepted: 04/24/2024] [Indexed: 05/25/2024] Open
Abstract
Background Adrenocortical carcinoma (ACC) is an aggressive endocrine malignancy with limited therapeutic options. Treating advanced ACC with mitotane, the cornerstone therapy, remains challenging, thus underscoring the significance to predict mitotane response prior to treatment and seek other effective therapeutic strategies. Objective We aimed to determine the efficacy of mitotane via an in vitro assay using patient-derived ACC cells (PDCs), identify molecular biomarkers associated with mitotane response and preliminarily explore potential agents for ACC. Methods In vitro mitotane sensitivity testing was performed in 17 PDCs and high-throughput screening against 40 compounds was conducted in 8 PDCs. Genetic features were evaluated in 9 samples using exomic and transcriptomic sequencing. Results PDCs exhibited variable sensitivity to mitotane treatment. The median cell viability inhibition rate was 48.4% (IQR: 39.3-59.3%) and -1.2% (IQR: -26.4-22.1%) in responders (n=8) and non-responders (n=9), respectively. Median IC50 and AUC were remarkably lower in responders (IC50: 53.4 µM vs 74.7 µM, P<0.0001; AUC: 158.0 vs 213.5, P<0.0001). Genomic analysis revealed CTNNB1 somatic alterations were only found in responders (3/5) while ZNRF3 alterations only in non-responders (3/4). Transcriptomic profiling found pathways associated with lipid metabolism were upregulated in responder tumors whilst CYP27A1 and ABCA1 expression were positively correlated to in vitro mitotane sensitivity. Furthermore, pharmacologic analysis identified that compounds including disulfiram, niclosamide and bortezomib exhibited efficacy against PDCs. Conclusion ACC PDCs could be useful for testing drug response, drug repurposing and guiding personalized therapies. Our results suggested response to mitotane might be associated with the dependency on lipid metabolism. CYP27A1 and ABCA1 expression could be predictive markers for mitotane response, and disulfiram, niclosamide and bortezomib could be potential therapeutics, both warranting further investigation.
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Affiliation(s)
- Jie Zhang
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai Key Laboratory for Endocrine Tumor, State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Luming Wu
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai Key Laboratory for Endocrine Tumor, State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Tingwei Su
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai Key Laboratory for Endocrine Tumor, State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Haoyu Liu
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai Key Laboratory for Endocrine Tumor, State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Lei Jiang
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai Key Laboratory for Endocrine Tumor, State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yiran Jiang
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai Key Laboratory for Endocrine Tumor, State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Zhiyuan Wu
- Department of Interventional Radiology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Lu Chen
- Department of Urology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Haorong Li
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai Key Laboratory for Endocrine Tumor, State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jie Zheng
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai Key Laboratory for Endocrine Tumor, State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yingkai Sun
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai Key Laboratory for Endocrine Tumor, State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Hangya Peng
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai Key Laboratory for Endocrine Tumor, State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Rulai Han
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai Key Laboratory for Endocrine Tumor, State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Guang Ning
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai Key Laboratory for Endocrine Tumor, State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Lei Ye
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai Key Laboratory for Endocrine Tumor, State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Weiqing Wang
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai Key Laboratory for Endocrine Tumor, State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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8
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Riedmeier M, Antonini SRR, Brandalise S, Costa TEJB, Daiggi CM, de Figueiredo BC, de Krijger RR, De Sá Rodrigues KE, Deal C, Del Rivero J, Engstler G, Fassnacht M, Fernandes Luiz Canali GC, Molina CAF, Gonc EN, Gültekin M, Haak HR, Guran T, Hendriks Allaird EJ, Idkowiak J, Kuhlen M, Malkin D, Meena JP, Pamporaki C, Pinto E, Puglisi S, Ribeiro RC, Thompson LDR, Yalcin B, Van Noesel M, Wiegering V. International consensus on mitotane treatment in pediatric patients with adrenal cortical tumors: indications, therapy, and management of adverse effects. Eur J Endocrinol 2024; 190:G15-G24. [PMID: 38552173 DOI: 10.1093/ejendo/lvae038] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/21/2023] [Revised: 01/17/2024] [Accepted: 02/19/2024] [Indexed: 04/17/2024]
Abstract
OBJECTIVE Mitotane is an important cornerstone in the treatment of pediatric adrenal cortical tumors (pACC), but experience with the drug in the pediatric age group is still limited and current practice is not guided by robust evidence. Therefore, we have compiled international consensus statements from pACC experts on mitotane indications, therapy, and management of adverse effects. METHODS A Delphi method with 3 rounds of questionnaires within the pACC expert consortium of the international network groups European Network for the Study of Adrenal Tumors pediatric working group (ENSAT-PACT) and International Consortium of pediatric adrenocortical tumors (ICPACT) was used to create 21 final consensus statements. RESULTS We divided the statements into 4 groups: environment, indications, therapy, and adverse effects. We reached a clear consensus for mitotane treatment for advanced pACC with stages III and IV and with incomplete resection/tumor spillage. For stage II patients, mitotane is not generally indicated. The timing of initiating mitotane therapy depends on the clinical condition of the patient and the setting of the planned therapy. We recommend a starting dose of 50 mg/kg/d (1500 mg/m²/d) which can be increased up to 4000 mg/m2/d. Blood levels should range between 14 and 20 mg/L. Duration of mitotane treatment depends on the clinical risk profile and tolerability. Mitotane treatment causes adrenal insufficiency in virtually all patients requiring glucocorticoid replacement shortly after beginning. As the spectrum of adverse effects of mitotane is wide-ranging and can be life-threatening, frequent clinical and neurological examinations (every 2-4 weeks), along with evaluation and assessment of laboratory values, are required. CONCLUSIONS The Delphi method enabled us to propose an expert consensus statement, which may guide clinicians, further adapted by local norms and the individual patient setting. In order to generate evidence, well-constructed studies should be the focus of future efforts.
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Affiliation(s)
- Maria Riedmeier
- University Hospital Würzburg, Department of Pediatrics, Division of Pediatric Hematology, Oncology and Stem Cell Transplantation, University of Wuerzburg, Wuerzburg 97080, Germany
| | - Sonir R R Antonini
- Department of Pediatrics, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Sao Paulo 14051-200, Brazil
| | - Silvia Brandalise
- Boldrini Children's Hospital, Department of Pediatrics, São Paulo 13083-210, Brazil
| | - Tatiana El Jaick B Costa
- Service of Pediatric Oncology, Hospital Infantil Joana de Gusmão, Florianópolis, SC 88025-301, Brazil
| | - Camila M Daiggi
- Boldrini Children's Hospital, Department of Pediatrics, São Paulo 13083-210, Brazil
| | | | - Ronald R de Krijger
- Department of Pathology, University Medical Center Utrecht, Utrecht 3584 CS, The Netherlands
| | | | - Cheri Deal
- Research Center, CHU Sainte-Justine and University of Montreal, Montreal, Québec H3T 1C5, Canada
| | - Jaydira Del Rivero
- Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, United States
| | - Gernot Engstler
- St. Anna Kinderspital, Department of Pediatrics, Medical University Vienna, Vienna 1090, Austria
| | - Martin Fassnacht
- Department of Medicine, Division of Endocrinology and Diabetes, University Hospital, University of Wuerzburg, Wuerzburg 97080, Germany
| | | | - Carlos A Fernandes Molina
- Department of Surgery and Anatomy, Ribeirao Preto Medical School, University of Sao 15 Paulo, Ribeirao Preto, Sao Paulo 14049-900, Brazil
| | - Elmas Nazli Gonc
- Department of Pediatric Endocrinology, Faculty of Medicine, Hacettepe University, Ankara 06230, Turkey
| | - Melis Gültekin
- Department of Radiation Oncology, Faculty of Medicine, Hacettepe University, Ankara 06100, Turkey
| | - Harm R Haak
- Department of Internal Medicine, Máxima MC, Eindhoven 5631 BM/Veldhoven 5504 DB, The Netherlands
- CAPHRI School for Public Health and Primary Care, Ageing and Long-Term Care, Maastricht University, Maastricht 616 6200 MD, The Netherlands
| | - Tulay Guran
- Department of Paediatric Endocrinology and Diabetes, Marmara University School of Medicine, Istanbul 34722, Turkey
| | - Emile J Hendriks Allaird
- Department of Paediatrics, University of Cambridge, Cambridge CB20QQ, United Kingdom
- Department of Paediatric Endocrinology and Diabetes, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB20QQ, United Kingdom
| | - Jan Idkowiak
- Institute of Metabolism and Systems Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham B152TT, United Kingdom
- Department of Endocrinology, Birmingham Women's and Children's Hospital NHS Foundation Trust, Birmingham B46NH, United Kingdom
| | - Michaela Kuhlen
- Pediatrics and Adolescent Medicine, Faculty of Medicine, University of Augsburg, Augsburg 86135, Germany
| | - David Malkin
- Division of Haematology/Oncology, The Hospital for Sick Children, University of Toronto, Toronto, Ontario M5G1X8, Canada
| | - Jagdish Prasad Meena
- Division of Pediatric Oncology, Department of Pediatrics, Mother & Child Block, All India Institute of Medical Sciences, New Delhi 110029, India
| | - Christina Pamporaki
- Department of Medicine III, University Hospital Carl Gustav Carus, TU Dresden, Dresden 01307, Germany
| | - Emilia Pinto
- St. Jude Children's Research Hospital, Memphis, TN 38105, United States
| | - Soraya Puglisi
- Internal Medicine, Department of Clinical and Biological Sciences, San Luigi Gonzaga Hospital, University of Turin, Orbassano 10043, Italy
| | - Raul C Ribeiro
- Department of Oncology, St Jude Children's Research Hospital, Memphis, TN 38105, United States
| | - Lester D R Thompson
- Pathology, Head and Neck Pathology Consultations, Woodland Hills, CA 91364, United States
| | - Bilgehan Yalcin
- Department of Pediatric Oncology, Faculty of Medicine, Hacettepe University, Ankara 06230, Turkey
| | - Max Van Noesel
- Pediatric Oncology, Princess Máxima Center for Pediatric Oncology, Utrecht 3584 CS, The Netherlands
- Division Imaging & Cancer, University Medical Center Utrecht, Utrecht 3584 CS, The Netherlands
| | - Verena Wiegering
- University Hospital Würzburg, Department of Pediatrics, Division of Pediatric Hematology, Oncology and Stem Cell Transplantation, University of Wuerzburg, Wuerzburg 97080, Germany
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Wu K, Liu Z, Liang J, Zhu Y, Wang X, Li X. Discovery of a glucocorticoid receptor (GR) activity signature correlates with immune cell infiltration in adrenocortical carcinoma. J Immunother Cancer 2023; 11:e007528. [PMID: 37793855 PMCID: PMC10551943 DOI: 10.1136/jitc-2023-007528] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/07/2023] [Indexed: 10/06/2023] Open
Abstract
BACKGROUND Adrenocortical carcinoma (ACC) is a rare and highly aggressive endocrine malignancy, of which >40% present with glucocorticoid excess. Glucocorticoids and glucocorticoid receptor (GR) signaling have long been thought to suppress immunity and promote tumor progression by acting on immune cells. Here, we provide new insights into the interaction between GR signaling activity and the immune signature of ACC as a potential explanation for immune escape and resistance to immunotherapy. METHODS First, GR immunohistochemical staining and immunofluorescence analysis of tumor-infiltrating lymphocyte (CD4 T, CD8 T cells, natural killer (NK) cells, dendritic cells and macrophages) were performed in 78 primary ACC tissue specimens. Quantitative data of immune cell infiltration in ACC were correlated with clinical characteristics. Second, we discovered a GR activity signature (GRsig) using GR-targeted gene networks derived from global gene expression data of primary ACC. Finally, we identified two GRsig-related subtypes based on the GRsig and assessed the differences in immune characteristics and prognostic stratification between the two subtypes. RESULTS GR was expressed in 90% of the ACC tumors, and CD8+ cytotoxic T lymphocytes were the most common infiltrating cell type in ACC specimens (88%, 8.6 cells/high power field). GR expression positively correlated with CD8+ T cell (Phi=0.342, p<0.001), CD4+ T cell (Phi=0.280, p<0.001), NK cell (Phi=0.280, p<0.001), macrophage (Phi=0.285, p<0.001), and dendritic cell (Phi=0.397, p<0.001) infiltration. Clustering heatmap analysis also displayed high immune cell infiltration in GR high-expressing tumors and low immune cell infiltration in GR-low tumors. High GR expression and high immune cell infiltration were significantly associated with better survival. Glucocorticoid excess is associated with low immune cell abundance and unfavorable prognosis. A GRsig comprizing n=34 GR-associated genes was derived from Gene Expression Omnibus/The Cancer Genome Atlas (TCGA) data sets and used to define two GRsig-related subtypes in the TCGA cohort. We demonstrated distinct differences in the immune landscape and clinical outcomes between the two subtypes. CONCLUSION GR expression positively correlates with tumor-infiltrating immune cells in ACC. The GRsig could serve as a prognostic biomarker and may be helpful for prognosis prediction and response to immunotherapy. Consequently, targeting the GR signaling pathway might be pivotal and should be investigated in clinical studies.
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Affiliation(s)
- Kan Wu
- Department of Urology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Zhihong Liu
- Department of Urology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Jiayu Liang
- Department of Urology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Yuchun Zhu
- Department of Urology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Xianding Wang
- Department of Urology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Xiang Li
- Department of Urology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
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10
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Karapanagioti A, Nasiri-Ansari N, Moustogiannis A, Trigas GC, Zografos G, Aggeli C, Kyriakopoulos G, Choreftaki T, Philippou A, Kaltsas G, Kassi E, Angelousi A. What is the role of CHCHD2 in adrenal tumourigenesis? Endocrine 2023:10.1007/s12020-023-03393-9. [PMID: 37221428 DOI: 10.1007/s12020-023-03393-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/21/2022] [Accepted: 05/01/2023] [Indexed: 05/25/2023]
Abstract
PURPOSE CHCHD2 is an antiapoptotic mitochondrial protein acting through the BCL2/BAX pathway in various cancers. However, data on the regulatory role of CHCHD2 in adrenal tumourigenesis are scarce. METHODS We studied the expression of CHCHD2, BCL2, and BAX in human adrenocortical tissues and SW13 cells. mRNA and protein levels were analyzed through qPCR and immunoblotting, respectively, in 16 benign adrenocortical neoplasms (BANs), along with their adjacent normal adrenal tissues (controls), and 10 adrenocortical carcinomas (ACCs). BCL2/BAX mRNA expression was also analyzed in SW13 cells after CHCHD2 silencing. MTS, flow cytometry and scratch assays were performed to assess cell viability, apoptosis, and invasion, respectively. RESULTS BCL2 and CHCHCD2 mRNA and protein expression was increased in BANs compared to normal adrenal tissues whereas BAX was decreased. BAX and CHCHD2 mRNA and protein levels were significantly downregulated and upregulated, respectively, in ACCs compared with either BANs or controls. Expression of the studied genes was not different among cortisol-secreting and nonfunctional ACAs. No significant association was found between genes' expression and other established prognostic markers of ACCs patients. In vitro analysis showed that CHCHD2 silencing resulted in reduced cell viability and invasion as well as increased SW13 cells apoptosis. CONCLUSIONS CHCHD2 expression seems to be implicated in adrenal tumourigenesis and its absence resulted to increased apoptosis in vitro. However, the exact mechanism of action and particularly its association with the BAX/BCL2 pathway needs to be further studied and evaluate whether it could be a protentional therapeutic target.
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Affiliation(s)
- Angeliki Karapanagioti
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, Athens, Greece
- 1st Department of Propaedeutic Internal Medicine, Laikon University Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - Narjes Nasiri-Ansari
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Athanasios Moustogiannis
- Department of Experimental Physiology, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - George C Trigas
- Department of Histology and Embryology, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Georgios Zografos
- 3rd Department of Surgery, General Hospital of Athens "G. Gennimatas", Athens, Greece
| | - Chrysanthi Aggeli
- 3rd Department of Surgery, General Hospital of Athens "G. Gennimatas", Athens, Greece
| | | | - Theodosia Choreftaki
- Department of Pathology, General Hospital of Athens "G. Gennimatas", Athens, Greece
| | - Anastassios Philippou
- Department of Experimental Physiology, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Gregory Kaltsas
- 1st Department of Propaedeutic Internal Medicine, Laikon University Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - Eva Kassi
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, Athens, Greece
- 1st Department of Propaedeutic Internal Medicine, Laikon University Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - Anna Angelousi
- 1st Department of Internal Medicine, Laikon University Hospital, National and Kapodistrian University of Athens, Athens, Greece.
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11
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Balajam NZ, Mousavian AH, Sheidaei A, Gohari K, Tavangar SM, Ghanbari-Motlagh A, Ostovar A, Shafiee G, Heshmat R. The 15-year national trends of endocrine cancers incidence among Iranian men and women; 2005-2020. Sci Rep 2023; 13:7632. [PMID: 37164997 PMCID: PMC10172312 DOI: 10.1038/s41598-023-34155-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2022] [Accepted: 04/25/2023] [Indexed: 05/12/2023] Open
Abstract
Cancer is one of the important health problems in Iran, which is considered as the third cause of death. Endocrine cancers are rare but mostly curable. Thyroid cancer, the most common endocrine tumors, includes about one percent of malignant cancer. In this study, we examined the 15-year national trend of endocrine cancer incidence in Iranian men and women. The data in each province were evaluated based on age, gender, and cancer type according to International Classification of Disease Codes version 10 (ICD-10) from 2005 to 2020 in Iran. All data were obtained from the reports of the Statistics Center of Iran (SCI), 6 phases of the step-by-step approach to monitoring the risk factors of chronic diseases over 18 years old (STEPs), and 3 periods of the CASPIAN study (survey of non-communicable diseases in childhood and adolescence). Statistical analyzes and graph generation were done using R statistical software. Poisson regression with mixed effects was used for data modeling and incidence rate estimation. The incidence of thyroid gland malignancy is higher in women than in men. On the other hand, the incidence of adrenal gland cancer is slightly higher in men than in women. The same pattern is observed for other endocrine neoplasms and related structures. The incidence rate of these types of cancers has generally increased from 2005 to 2020 in Iran. This increase is more in women than in men. In addition, in the middle of the country, there is a strong region in terms of the occurrence of these types of cancers. The incidence rate in these provinces is relatively higher for both sexes and all studied periods. We conducted a study to observe the changing trends for various types of endocrine cancers over 15 years in men and women. Considering the increasing trend of thyroid cancers in Iran, therefore, creating essential policies for the management of these types of cancers for prevention, rapid diagnosis, and, timely treatment is particularly important.
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Affiliation(s)
- Narges Zargar Balajam
- Chronic Diseases Research Center, Endocrinology and Metabolism Population Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Amir-Hossein Mousavian
- Chronic Diseases Research Center, Endocrinology and Metabolism Population Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Ali Sheidaei
- Department of Epidemiology and Biostatics, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
| | - Kimiya Gohari
- Department of Biostatistics, Faculty of Medicine Sciences, Tarbiat Modares University, Tehran, Iran
| | - Seyed Mohammad Tavangar
- Chronic Diseases Research Center, Endocrinology and Metabolism Population Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Ali Ghanbari-Motlagh
- Department of Radiotherapy, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Afshin Ostovar
- Osteoporosis Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Gita Shafiee
- Chronic Diseases Research Center, Endocrinology and Metabolism Population Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran.
| | - Ramin Heshmat
- Chronic Diseases Research Center, Endocrinology and Metabolism Population Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran.
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12
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Tsai WH, Dai SH, Lee CC, Chien MN, Zeng YH. A Clinicopathological Analysis of Asian Patients with Adrenocortical Carcinoma: A Single-Center Experience. Curr Oncol 2023; 30:4117-4125. [PMID: 37185426 PMCID: PMC10136886 DOI: 10.3390/curroncol30040313] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2023] [Accepted: 04/06/2023] [Indexed: 05/17/2023] Open
Abstract
BACKGROUND There is limited information regarding the immunohistochemistry stain and its prognostic role in adrenocortical carcinoma (ACC), and few studies focus on Asian patients. Our study aims to identify the correlation between immunohistochemistry staining and the prognosis of ACC in Asian patients. METHODS We searched the database of a single center in Taiwan for cases with a pathological diagnosis of ACC in the past 25 years. We collected patient data on age, sex, initial presentation, staging, metastatic site, and survival duration. Immunohistochemical studies using antibodies to CDK4, ATRX, beta-catenin, Ki-67, SSTR2, and p53 were performed. Survival analysis was performed using the log-rank test, the Cox proportional hazards model and bootstrapping with 5000 samplings. RESULTS Fourteen patients were identified, and the median age was 49.5 (range 1-70) years. There were eight male and six female patients. Four patients presented with Cushing's syndrome, and half were diagnosed with stage IV ACC at presentation. Only three patients survived (21%). The median survival time was 15.5 (range 0.67-244) months. SSTR2 expression score > 50 (log-rank test: p = 0.009) and Ki-67 > 50% (log-rank test: p = 0.017) were associated with mortality. However, after adjusting for stage, the bootstrapping analysis demonstrated that Ki-67 [B 2.04, p = 0.004], Beta-catenin [B 2.19, p = 0.009], ATRX [B 1.48, p = 0.026], P53 [B 1.58, p = 0.027], SSTR2 [B 1.58, p = 0.015] and SSTR2 expression score [B 0.03, p < 0.001] were all significantly associated with mortality. CONCLUSIONS After adjusting for stage, Ki-67 > 50%, Beta-catenin, ATRX, P53, SSTR2 and SSTR2 expression score > 50 were associated with mortality in Asian patients with ACC.
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Affiliation(s)
- Wen-Hsuan Tsai
- Division of Endocrinology and Metabolism, Department of Internal Medicine, MacKay Memorial Hospital, Taipei 104, Taiwan
| | - Shuen-Han Dai
- Department of Pathology, MacKay Memorial Hospital, Taipei 104, Taiwan
| | - Chun-Chuan Lee
- Division of Endocrinology and Metabolism, Department of Internal Medicine, MacKay Memorial Hospital, Taipei 104, Taiwan
- Department of Medicine, MacKay Medical College, New Taipei City 252, Taiwan
| | - Ming-Nan Chien
- Division of Endocrinology and Metabolism, Department of Internal Medicine, MacKay Memorial Hospital, Taipei 104, Taiwan
- Department of Medicine, MacKay Medical College, New Taipei City 252, Taiwan
| | - Yi-Hong Zeng
- Division of Endocrinology and Metabolism, Department of Internal Medicine, MacKay Memorial Hospital, Taipei 104, Taiwan
- Department of Medicine, MacKay Medical College, New Taipei City 252, Taiwan
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13
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Ayhan E, Rasa KH. Robotic surgery for malignant and large adrenal masses: A doable and safe option. J Minim Access Surg 2023; 19:212-216. [PMID: 37056086 PMCID: PMC10246634 DOI: 10.4103/jmas.jmas_115_22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2022] [Revised: 06/02/2022] [Accepted: 08/03/2022] [Indexed: 11/06/2022] Open
Abstract
BACKGROUND Laparoscopic adrenalectomy is currently considered the gold standard method for adrenal surgery. Open surgery is the most frequent technique preferred amongst surgeons who are faced with tumours of larger sizes or challenging lesions. Despite the increasing interest in laparoscopy, most centres still utilise open surgery for challenging adrenal cases. AND METHODS We retrospectively evaluated our successive 30 robotic adrenalectomies performed in the past 10 years and assigned the patients into 'difficult' and 'easy' groups. Patients with malignant tumours or tumour size of over 8 cm were assigned to the 'difficult group' and others to the 'easy group'. Groups were evaluated according to the demographic features of the patients, side of the operation, the body mass index (BMI) and laparotomy history. The duration of anaesthesia, amount of bleeding during surgery and the hospitalisation periods were also evaluated. RESULTS There is no statistically significant difference between the two groups considering age, gender, BMI value, operation side, presence or absence of a laparotomy history, the amount of bleeding during the operation and hospitalisation duration (P > 0.05). The anaesthesia duration was found to be higher in the 'difficult' patient group (P < 0.05). CONCLUSION Our results present robust evidence to support the idea that robotic adrenalectomy is not only a doable but also a safe option for malignant and large adrenal masses.
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Affiliation(s)
- Erdemir Ayhan
- Department of General Surgery, Anadolu Medical Center Hospital, Kocaeli, Turkey
| | - Kemal Hüseyin Rasa
- Department of General Surgery, Anadolu Medical Center Hospital, Kocaeli, Turkey
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The Characteristics of Tumor Microenvironment Predict Survival and Response to Immunotherapy in Adrenocortical Carcinomas. Cells 2023; 12:cells12050755. [PMID: 36899891 PMCID: PMC10000893 DOI: 10.3390/cells12050755] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2023] [Revised: 02/23/2023] [Accepted: 02/24/2023] [Indexed: 03/02/2023] Open
Abstract
Increasing evidence confirms that tumor microenvironment (TME) can influence tumor progression and treatment, but TME is still understudied in adrenocortical carcinoma (ACC). In this study, we first scored TME using the xCell algorithm, then defined genes associated with TME, and then used consensus unsupervised clustering analysis to construct TME-related subtypes. Meanwhile, weighted gene co-expression network analysis was used to identify modules correlated with TME-related subtypes. Ultimately, the LASSO-Cox approach was used to establish a TME-related signature. The results showed that TME-related scores in ACC may not correlate with clinical features but do promote a better overall survival. Patients were classified into two TME-related subtypes. Subtype 2 had more immune signaling features, higher expression of immune checkpoints and MHC molecules, no CTNNB1 mutations, higher infiltration of macrophages and endothelial cells, lower tumor immune dysfunction and exclusion scores, and higher immunophenoscore, suggesting that subtype 2 may be more sensitive to immunotherapy. 231 modular genes highly relevant to TME-related subtypes were identified, and a 7-gene TME-related signature that independently predicted patient prognosis was established. Our study revealed an integrated role of TME in ACC and helped to identify those patients who really responded to immunotherapy, while providing new strategies on risk management and prognosis prediction.
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15
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Kitsugi K, Kawata K, Kakizawa K, Noritake H. A Case of Adrenocortical Carcinoma With a Favorable Tumor Control by Radiofrequency Ablation for Liver Metastasis. J Investig Med High Impact Case Rep 2023; 11:23247096231218135. [PMID: 38105189 PMCID: PMC10729623 DOI: 10.1177/23247096231218135] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2023] [Revised: 11/13/2023] [Accepted: 11/16/2023] [Indexed: 12/19/2023] Open
Abstract
A 57-year-old woman was diagnosed with adrenocortical carcinoma. Following the adrenalectomy, she underwent adjuvant radiation and mitotane therapy; however, liver metastases were observed. Repeated radiofrequency ablation (RFA) was performed for liver metastases. In addition, a multidisciplinary approach combining systemic chemotherapy, radiotherapy, and surgery was used for lung and distant lymph node metastases that arose during the course of treatment. Notably, 49 months have passed since the adrenalectomy and 36 months since the recurrence of the liver metastases, and the patient remains on multidisciplinary therapy. Thus, RFA for liver metastasis of adrenocortical carcinoma may be an effective component of a multidisciplinary treatment.
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Parisien-La Salle S, Corbeil G, El-Haffaf Z, Duranceau C, Latour M, Karakiewicz PI, Lacroix A, Bourdeau I. Genetic Dissection of Primary Aldosteronism in a Patient With MEN1 and Ipsilateral Adrenocortical Carcinoma and Adenoma. J Clin Endocrinol Metab 2022; 108:26-32. [PMID: 36179244 DOI: 10.1210/clinem/dgac564] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/05/2022] [Revised: 09/23/2022] [Indexed: 02/03/2023]
Abstract
BACKGROUND Adrenal tumors are found in up to 40% of patients with multiple endocrine neoplasia type 1 (MEN1). However, adrenocortical carcinomas (ACC) and primary aldosteronism (PA) are rare in MEN1. CASE A 48-year-old woman known to have primary hyperparathyroidism and hypertension with hypokalemia was referred for a right complex 8-cm adrenal mass with a 38.1 SUVmax uptake on 18F-FDG PET/CT. PA was confirmed by saline suppression test (aldosterone 1948 pmol/L-1675 pmol/L; normal range [N]: <165 post saline infusion) and suppressed renin levels (<5 ng/L; N: 5-20). Catecholamines, androgens, 24-hour urinary cortisol, and pituitary panel were normal. A right open adrenalectomy revealed a concomitant 4-cm oncocytic ACC and a 2.3-cm adrenocortical adenoma. Immunohistochemistry showed high expression of aldosterone synthase protein in the adenoma but not in the ACC, supporting excess aldosterone production by the adenoma. GENETIC ANALYSIS After genetic counseling, the patient underwent genetic analysis of leucocyte and tumoral DNA. Sequencing of MEN1 revealed a heterozygous germline pathogenic variant in MEN1 (c.1556delC, p.Pro519Leufs*40). The wild-type MEN1 allele was lost in the tumoral DNA of both the resected adenoma and carcinoma. Sequencing analysis of driver genes in PA revealed a somatic pathogenic variant in exon 2 of the KCNJ5 gene (c.451G>A, p.Gly151Arg) only in the aldosteronoma. CONCLUSION To our knowledge, we describe the first case of adrenal collision tumors in a patient carrying a germline pathogenic variant of the MEN1 gene associated with MEN1 loss of heterozygosity in both oncocytic ACC and adenoma and a somatic KCNJ5 pathogenic variant leading to aldosterone-producing adenoma. This case gives new insights on adrenal tumorigenesis in MEN1 patients.
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Affiliation(s)
- Stéfanie Parisien-La Salle
- Division of Endocrinology, Department of Medicine, Research Center, Centre hospitalier de l'Université de Montréal (CHUM), Montreal, QC, H2X 0C1, Canada
| | - Gilles Corbeil
- Division of Endocrinology, Department of Medicine, Research Center, Centre hospitalier de l'Université de Montréal (CHUM), Montreal, QC, H2X 0C1, Canada
| | - Zaki El-Haffaf
- Division of Genetics, Department of Medicine, Research Center, Centre hospitalier de l'Université de Montréal (CHUM), Montreal, QC, H2X 0C1, Canada
| | - Caroline Duranceau
- Division of Endocrinology, Department of Medicine, Chicoutimi Hospital, Université du Québec à Chicoutimi, Chicoutimi, QC, H2X 0C1, Canada
| | - Mathieu Latour
- Department of Pathology and Cellular Biology, Centre hospitalier de l'Université de Montréal (CHUM), Montreal, QC, H2X 0C1, Canada
| | - Pierre I Karakiewicz
- Division of Urology, Department of Surgery, Centre Hospitalier de l'Université de Montréal, Montréal, QC, H2X 0C1, Canada
| | - André Lacroix
- Division of Endocrinology, Department of Medicine, Research Center, Centre hospitalier de l'Université de Montréal (CHUM), Montreal, QC, H2X 0C1, Canada
| | - Isabelle Bourdeau
- Division of Endocrinology, Department of Medicine, Research Center, Centre hospitalier de l'Université de Montréal (CHUM), Montreal, QC, H2X 0C1, Canada
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Chihara I, Nagumo Y, Kandori S, Kojo K, Sano K, Hamada K, Tanuma K, Tsuchiya H, Shiga M, Sakka S, Kimura T, Kawahara T, Hoshi A, Negoro H, Kojima T, Bryan MJ, Okuyama A, Higashi T, Nishiyama H. Clinicopathological features of adrenal malignancies: Analysis of hospital-based cancer registry data in Japan. Int J Urol 2022; 29:1331-1337. [PMID: 35976672 DOI: 10.1111/iju.14996] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2021] [Accepted: 07/04/2022] [Indexed: 01/17/2023]
Abstract
OBJECTIVE To identify the clinicopathological features of adrenal malignancies and analyze the prognoses of patients with adrenal cortical carcinoma (ACC) and malignant pheochromocytoma (MPCC). PATIENTS AND METHODS We used a hospital-based cancer registry data in Japan to extract cases of adrenal malignancies that were histologically confirmed, diagnosed, and initially treated from 2012-2015. For survival analysis, we used data from the 2008-2009 cohort to estimate 5-year overall survival (OS) by the Kaplan-Meier method. RESULTS A total of 989 adrenal malignancies were identified in the 2012-2015 cohort. The most common histologies were ACC (26.4%), diffuse large B-cell lymphoma (DLBCL; 25.4%), neuroblastoma (22.2%), and MPCC (11.9%). While most ACC and MPCC patients were in their 60s, DLBCL patients accounted for 61.5% of adrenal malignancies in the over-70 cohort. Among ACC patients with clinical staging data, 46.3% of patients were stage IV. Although surgery was a chief strategy for all stages, younger patients tended to receive combination therapy, including surgery and chemotherapy or hormone therapy. In the 2008-2009 cohort, the 5-year OS rates of ACC (n = 49) and MPCC (n = 23) patients were 56.2% and 86.4% while ACC patients without surgery had 1- and 2-year OS rates of 25.0% and 12.5%. CONCLUSION In Japan, DLBCL accounted for the majority of adrenal malignancies in older patients. Despite advanced staging, ACC patients were mainly treated with surgery and their prognosis was not satisfactory. Such epidemiological data may be useful in considering initial management strategies.
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Affiliation(s)
- Ichiro Chihara
- Department of Urology, University of Tsukuba, Tsukuba, Japan
| | | | - Shuya Kandori
- Department of Urology, University of Tsukuba, Tsukuba, Japan
| | - Kosuke Kojo
- Department of Urology, University of Tsukuba, Tsukuba, Japan
| | - Keisuke Sano
- Department of Urology, University of Tsukuba, Tsukuba, Japan
| | - Kazuki Hamada
- Department of Urology, University of Tsukuba, Tsukuba, Japan
| | - Kozaburo Tanuma
- Department of Urology, University of Tsukuba, Tsukuba, Japan
| | - Haruki Tsuchiya
- Department of Urology, University of Tsukuba, Tsukuba, Japan
| | - Masanobu Shiga
- Department of Urology, University of Tsukuba, Tsukuba, Japan
| | - Shotaro Sakka
- Department of Urology, University of Tsukuba, Tsukuba, Japan
| | - Tomokazu Kimura
- Department of Urology, University of Tsukuba, Tsukuba, Japan
| | | | - Akio Hoshi
- Department of Urology, University of Tsukuba, Tsukuba, Japan
| | | | | | - Mathis J Bryan
- International Medical Center, University of Tsukuba Affiliated Hospital, Tsukuba, Japan
| | - Ayako Okuyama
- Center for Cancer Registries, National Cancer Center Institute for Cancer Control, Chuo-ku, Japan
| | - Takahiro Higashi
- Center for Cancer Registries, National Cancer Center Institute for Cancer Control, Chuo-ku, Japan
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Wang K, Zhang T, Ni J, Chen J, Zhang H, Wang G, Gu Y, Peng B, Mao W, Wu J. Identification of prognostic factors for predicting survival of patients with malignant adrenal tumors: A population-based study. Front Oncol 2022; 12:930473. [PMID: 36324596 PMCID: PMC9619049 DOI: 10.3389/fonc.2022.930473] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2022] [Accepted: 09/27/2022] [Indexed: 11/24/2022] Open
Abstract
Background This study aimed to identify the prognostic factors for overall survival (OS) and cancer-specific survival (CSS) in patients with malignant adrenal tumors and establish a predictive nomogram for patient survival. Methods The clinical characteristics of patients diagnosed with malignant adrenal tumors between 1988 and 2015 were retrieved from the Surveillance, Epidemiology and End Results (SEER) database. As the external validation set, we included 110 real-world patients from our medical centers. Univariate and multivariate Cox regressions were implemented to determine the prognostic factors of patients. The results from Cox regression were applied to establish the nomogram. Results A total of 2,206 eligible patients were included in our study. Patients were randomly assigned to the training set (1,544; 70%) and the validation set (662; 30%). It was determined that gender, age, marital status, histological type, tumor size, SEER stage, surgery, and chemotherapy were prognostic factors that affected patient survival. The OS prediction nomogram contained all the risk factors, while gender was excluded in the CSS prediction nomogram. The receiver operating characteristic (ROC) curve and decision curve analysis (DCA) indicated that the nomogram had a better predictive performance than SEER stage. Moreover, the clinical impact curve (CIC) showed that the nomograms functioned as effective predictive models in clinical application. The C-index of nomogram for OS and CSS prediction was 0.773 (95% confidence interval [CI]: 0.761–0.785) and 0.689 (95% CI: 0.675–0.703) in the training set. The calibration curves exhibited significant agreement between the nomogram and actual observation. Additionally, the results from the external validation set also presented that established nomograms functioned well in predicting the survival of patients with malignant adrenal tumors. Conclusions The following clinical variables were identified as prognostic factors: age, marital status, histological type, tumor size, SEER stage, surgery, and chemotherapy. The nomogram for patients with malignant adrenal tumors contained the accurate predictive performance of OS and CSS, contributing to optimizing individualized clinical treatments.
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Affiliation(s)
- Keyi Wang
- Department of Urology, Putuo People's Hospital, Tongji University School of Medicine, Shanghai, China
- Department of Urology, Shanghai Tenth People’s Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Tao Zhang
- Department of Urology, Putuo People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Jinliang Ni
- Shanghai Clinical College, Anhui Medical University, Hefei, China
| | - Jianghong Chen
- Department of Surgery, Traditional Chinese Medicine Hospital of Jiulongpo District, Chongqing, China
| | - Houliang Zhang
- Department of Urology, Putuo People's Hospital, Tongji University School of Medicine, Shanghai, China
- Department of Urology, Shanghai Tenth People’s Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Guangchun Wang
- Department of Urology, Shanghai Tenth People’s Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Yongzhe Gu
- Department of Neurology, Shanghai Tenth People’s Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Bo Peng
- Department of Urology, Putuo People's Hospital, Tongji University School of Medicine, Shanghai, China
- Department of Urology, Shanghai Tenth People’s Hospital, School of Medicine, Tongji University, Shanghai, China
- *Correspondence: Jianping Wu, ; Weipu Mao, ; Bo Peng,
| | - Weipu Mao
- Department of Urology, Putuo People's Hospital, Tongji University School of Medicine, Shanghai, China
- Department of Urology, Affiliated Zhongda Hospital of Southeast University, Nanjing, China
- *Correspondence: Jianping Wu, ; Weipu Mao, ; Bo Peng,
| | - Jianping Wu
- Department of Urology, Affiliated Zhongda Hospital of Southeast University, Nanjing, China
- *Correspondence: Jianping Wu, ; Weipu Mao, ; Bo Peng,
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Insights into Clinical Features and Outcomes of Adrenal Cortical Carcinosarcoma. Diagnostics (Basel) 2022; 12:diagnostics12102419. [PMID: 36292108 PMCID: PMC9600293 DOI: 10.3390/diagnostics12102419] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2022] [Revised: 10/02/2022] [Accepted: 10/02/2022] [Indexed: 11/17/2022] Open
Abstract
Adrenal cortical carcinosarcomas are a rare and typically aggressive malignancy with few reported cases in medical literature. We present a case of a 78-year-old female who presented with complaints of fatigue and right shoulder pain. Imaging of the abdomen with computed tomography visualized a large mass in the right upper quadrant. The mass was radiologically described as a 22 × 17 × 13 cm heterogeneous mass with its epicenter in the area of the right adrenal gland, with medial and peripheral effacement of all structures in the right upper quadrant. Non-contrasted images demonstrated anterior mid-portion calcifications. The mass parasitized its blood supply from several surrounding structures, including the liver and right psoas muscle, and extensively invaded the psoas muscle. Resection of the mass was performed with pathology, which revealed a high mitotic index and nuclear atypia with two morphologically and immunophenotypically distinct components. One of these components stained positively for calretinin and inhibin, which is indicative of adrenal cortical carcinoma; the other exhibited strong expression of vimentin and desmin, which was concordant with sarcomatous change and confirmed the diagnosis of adrenal cortical carcinosarcoma. This unique histology with both carcinomatous and sarcomatous components presents a diagnostic challenge for clinicians. As such, adrenal carcinosarcomas should be kept on the differential when evaluating retroperitoneal masses. Additionally, this study includes a review of 34 previously reported cases of adrenal cortical carcinosarcomas along with a discussion about the future exploration of this pathology.
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20
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Terzolo M, Fassnacht M. ENDOCRINE TUMOURS: Our experience with the management of patients with non-metastatic adrenocortical carcinoma. Eur J Endocrinol 2022; 187:R27-R40. [PMID: 35695575 DOI: 10.1530/eje-22-0260] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2022] [Accepted: 06/13/2022] [Indexed: 11/08/2022]
Abstract
Adrenocortical carcinoma (ACC) accounts for a minority of all malignant tumors in adults. Surgery remains the most important therapeutic option for non-metastatic ACC. Whether a subset of patients with small ACC may benefit from minimally invasive surgery remains a debated issue, but we believe that surgeon's expertise is more important than surgical technique to determine outcome. However, even a state-of-the-art surgery cannot prevent disease recurrence that is determined mainly by specific tumor characteristics. We consider that the concomitant presence of the following features characterizes a cohort of patients at low risk of recurrence, (i) R0 resection (microscopically free margin), (ii) localized disease (stage I-II ACC), and (iii) low-grade tumor (ki-67 <10%). After the ADIUVO study, we do not recommend adjuvant mitotane as a routine measure for such patients, who can be managed with active surveillance thus sparing a toxic treatment. Patients at average risk of recurrence should be treated with adjuvant mitotane. For patients at very high risk of recurrence, defined as the presence of at least one of the following: Ki67 >30%, large venous tumor thrombus, R1 resection or stage IV ACC, we increasingly recommend to combine mitotane with four cycles of platinum-based chemotherapy. However, patients at moderate-to-high risk of recurrence should be ideally enrolled in the ongoing ADIUVO2 trial. We do not use adjuvant radiotherapy of the tumor bed frequently at our institutions, and we select patients with incomplete resection, either microscopically or macroscopically, for this treatment. In the long-term, prospective multicenter trials are required to improve patient care.
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Affiliation(s)
- Massimo Terzolo
- Internal Medicine, Department of Clinical and Biological Sciences, S. Luigi Hospital, Orbassano, University of Turin, Turin, Italy
| | - Martin Fassnacht
- Division of Endocrinology and Diabetes, Department of Internal Medicine, University Hospital, University of Würzburg, Würzburg, Germany
- Comprehensive Cancer Center Mainfranken, University of Würzburg, Würzburg, Germany
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Cremaschi V, Abate A, Cosentini D, Grisanti S, Rossini E, Laganà M, Tamburello M, Turla A, Sigala S, Berruti A. Advances in adrenocortical carcinoma pharmacotherapy: what is the current state of the art? Expert Opin Pharmacother 2022; 23:1413-1424. [PMID: 35876101 DOI: 10.1080/14656566.2022.2106128] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
INTRODUCTION Surgery, followed or not by adjuvant mitotane, is the current mainstay of therapy for patients with early-stage adrenocortical carcinoma (ACC). Mitotane, either alone or in association with EDP (Etoposide-Doxorubicin-Cisplatin) combination chemotherapy, is the standard approach for patients with metastatic ACC. AREAS COVERED The activity of newer cytotoxic drugs, radioligands, targeted therapies and immunotherapy, both in preclinical and in clinical studies, will be reviewed in this paper. EXPERT OPINION ADIUVO trial revealed that the administration of adjuvant mitotane is not advantageous in patients with good prognosis. Future strategies are to intensify efforts in adjuvant setting in patients with high risk of relapse. In patients with advanced/metastatic disease, modern targeted therapies have shown significant cytotoxicity in preclinical studies, however, studies in ACC patients reported disappointing results so far. The absence of targeted agents specifically inhibiting the major molecular pathways of ACC growth is the main cause of the failure of these drugs. Since ACC is often antigenic but poorly immunogenic, the results of immunotherapy trials appeared inferior to those achieved in the management of patients with other malignancies. Radioligand therapy may also be a promising approach. Combination of chemotherapy plus immunotherapy could be interesting to be tested in the future.
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Affiliation(s)
- Valentina Cremaschi
- Medical Oncology Unit, Department of Medical and Surgical Specialties, Radiological Sciences, and Public Health, University of Brescia, ASST Spedali Civili, Piazzale Spedali Civili 1, 25123, Brescia, Italy
| | - Andrea Abate
- Section of Pharmacology, Department of Molecular and Translational Medicine, University of Brescia, Viale Europa 11, 25123, Brescia, Italy
| | - Deborah Cosentini
- Medical Oncology Unit, Department of Medical and Surgical Specialties, Radiological Sciences, and Public Health, University of Brescia, ASST Spedali Civili, Piazzale Spedali Civili 1, 25123, Brescia, Italy
| | - Salvatore Grisanti
- Medical Oncology Unit, Department of Medical and Surgical Specialties, Radiological Sciences, and Public Health, University of Brescia, ASST Spedali Civili, Piazzale Spedali Civili 1, 25123, Brescia, Italy
| | - Elisa Rossini
- Section of Pharmacology, Department of Molecular and Translational Medicine, University of Brescia, Viale Europa 11, 25123, Brescia, Italy
| | - Marta Laganà
- Medical Oncology Unit, Department of Medical and Surgical Specialties, Radiological Sciences, and Public Health, University of Brescia, ASST Spedali Civili, Piazzale Spedali Civili 1, 25123, Brescia, Italy
| | - Mariangela Tamburello
- Section of Pharmacology, Department of Molecular and Translational Medicine, University of Brescia, Viale Europa 11, 25123, Brescia, Italy
| | - Antonella Turla
- Medical Oncology Unit, Department of Medical and Surgical Specialties, Radiological Sciences, and Public Health, University of Brescia, ASST Spedali Civili, Piazzale Spedali Civili 1, 25123, Brescia, Italy
| | - Sandra Sigala
- Section of Pharmacology, Department of Molecular and Translational Medicine, University of Brescia, Viale Europa 11, 25123, Brescia, Italy
| | - Alfredo Berruti
- Medical Oncology Unit, Department of Medical and Surgical Specialties, Radiological Sciences, and Public Health, University of Brescia, ASST Spedali Civili, Piazzale Spedali Civili 1, 25123, Brescia, Italy
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22
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Dobrindt EM, Saeger W, Bläker H, Mogl MT, Bahra M, Pratschke J, Rayes N. The challenge to differentiate between sarcoma or adrenal carcinoma—an observational study. Rare Tumors 2021; 13:20363613211057746. [PMID: 34917301 PMCID: PMC8669116 DOI: 10.1177/20363613211057746] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Background Adrenal sarcomas are rare malignant tumors with structural and clinical similarities to sarcomatoid adrenocortical carcinoma. Preoperative diagnosis of tumors of the adrenal gland can be challenging and often misleading thus detaining patients from appropriate oncological strategies. Objective This analysis of a case series evaluated the predictive capability of the primary clinical diagnosis in case of malignancies of the adrenal gland. Methods Thirty two patients were treated from 2009 to 2015 at our clinic and analyzed retrospectively. All patients had computed tomography and/or magnet resonance imaging and a primary histopathological examination at our institution after surgery. Ten questionable cases were surveyed by a reference pathologist. Results Twelve out of 32 diagnoses had to be revised (37.5%). Only 15 out of 24 tumors primarily classified as adrenocortical carcinoma were finally described as primary adrenal cancer. We found two leiomyosarcomas, one liposarcoma, one sarcomatoid adrenocortical carcinoma, and one epitheloid angiosarcoma among 12 misleading diagnoses. Other tumors turned out to be metastases of lung, hepatocellular, and neuroendocrine tumors. Larger tumors were significantly more often correctly diagnosed compared to smaller tumors. Four patients of the group of revised diagnoses died whereas all patients with confirmed diagnoses survived during the follow-up. Conclusion Preoperative assessment of tumors of the adrenal gland is still challenging. In case of wrong primary diagnosis, the prognosis could be impaired due to inadequate surgical procedures or insufficient preoperative oncological treatment.
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Affiliation(s)
- Eva M Dobrindt
- Department of Surgery, Berlin Institute of Health, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany
| | - Wolfgang Saeger
- Institute of Pathology, University of Hamburg, Hamburg, Germany
| | - Hendrik Bläker
- Institute of Pathology, University of Leipzig, Leipzig, Germany
| | - Martina T Mogl
- Department of Surgery, Berlin Institute of Health, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany
| | - Marcus Bahra
- Department of Surgery, Berlin Institute of Health, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany
| | - Johann Pratschke
- Department of Surgery, Berlin Institute of Health, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany
| | - Nada Rayes
- Department of Surgery, Berlin Institute of Health, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany
- Department of General, Visceral, Thoracic and Transplant Surgery, University of Leipzig, Leipzig, Germany
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Grisanti S, Cosentini D, Laganà M, Turla A, Berruti A. Different management of adrenocortical carcinoma in children compared to adults: is it time to share guidelines? Endocrine 2021; 74:475-477. [PMID: 34559356 PMCID: PMC8571231 DOI: 10.1007/s12020-021-02874-z] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/23/2021] [Accepted: 09/09/2021] [Indexed: 11/24/2022]
Abstract
Pediatric and adult adrenocortical carcinomas differ in many respects but treatment is often similar in both age groups. The Journal of Clinical Oncology recently published the results of a risk-stratified single-arm interventional trial conducted by the Children's Oncology Group in which 77 patients were treated in three different interventional cohorts. In this Point of View paper we comment on the treatment strategies adopted within the ARAR0332 trial in terms of surgery approach, duration of adjuvant therapies, and palliative chemotherapy. We focus on the differences in the treatment of pediatric ACC patients compared to the ESE/ENSAT and ESMO guidelines released in 2018 for adult patients. For example, patients in stratum 3 and 4 received 8 (instead of 6) cycles of EDP chemotherapy but 8 months (instead of 24) of mitotane adjuvant therapy. Bearing clearly in the mind that pediatric and adult ACC patients represent different settings, we wonder whether there could be some areas of intervention overlapping to constitute a continuum of disease across ages. Thus, pediatric and adult cohoperative groups should be encouraged to collaborate in order to reach common guidelines for the treatment of such a rare disease.
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Affiliation(s)
- Salvatore Grisanti
- Medical Oncology Unit, Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, University of Brescia at ASST Spedali Civili, Brescia, Italy
| | - Deborah Cosentini
- Medical Oncology Unit, Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, University of Brescia at ASST Spedali Civili, Brescia, Italy
| | - Marta Laganà
- Medical Oncology Unit, Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, University of Brescia at ASST Spedali Civili, Brescia, Italy
| | - Antonella Turla
- Medical Oncology Unit, Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, University of Brescia at ASST Spedali Civili, Brescia, Italy
| | - Alfredo Berruti
- Medical Oncology Unit, Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, University of Brescia at ASST Spedali Civili, Brescia, Italy.
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Heinze B, Schirbel A, Nannen L, Michelmann D, Hartrampf PE, Bluemel C, Schneider M, Herrmann K, Haenscheid H, Fassnacht M, Buck AK, Hahner S. Novel CYP11B-ligand [ 123/131I]IMAZA as promising theranostic tool for adrenocortical tumors: comprehensive preclinical characterization and first clinical experience. Eur J Nucl Med Mol Imaging 2021; 49:301-310. [PMID: 34215922 PMCID: PMC8712301 DOI: 10.1007/s00259-021-05477-y] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2020] [Accepted: 06/20/2021] [Indexed: 11/15/2022]
Abstract
PURPOSE Adrenal tumors represent a diagnostic and therapeutic challenge. Promising results have been obtained through targeting the cytochrome P450 enzymes CYP11B1 and CYP11B2 for molecular imaging, and [123/131I]iodometomidate ([123/131I]IMTO) has even been successfully introduced as a theranostic agent. As this radiopharmaceutical shows rapid metabolic inactivation, we aimed at developing new improved tracers. METHODS Several IMTO derivatives were newly designed by replacing the unstable methyl ester by different carboxylic esters or amides. The inhibition of aldosterone and cortisol synthesis was tested in different adrenocortical cell lines. The corresponding radiolabeled compounds were assessed regarding their stability, in vitro cell uptake, in vivo biodistribution in mice, and their binding specificity to cryosections of human adrenocortical and non-adrenocortical tissue. Furthermore, a first investigation was performed in patients with known metastatic adrenal cancer using both [123I]IMTO and the most promising compound (R)-1-[1-(4-[123I]iodophenyl)ethyl]-1H-imidazole-5-carboxylic acid azetidinylamide ([123I]IMAZA) for scintigraphy. Subsequently, a first endoradiotherapy with [131I]IMAZA in one of these patients was performed. RESULTS We identified three analogues to IMTO with high-affinity binding to the target enzymes and comparable or higher metabolic stability and very high and specific accumulation in adrenocortical cells in vitro and in vivo. Labeled IMAZA exhibited superior pharmacokinetic and imaging properties compared to IMTO in mice and 3 patients, too. An endoradiotherapy with [131I]IMAZA induced a 21-month progression-free interval in a patient with rapidly progressing ACC prior this therapy. CONCLUSION We developed the new radiopharmaceutical [123/131I]IMAZA with superior properties compared to the reference compound IMTO and promising first experiences in humans.
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Affiliation(s)
- Britta Heinze
- Division of Endocrinology and Diabetes, Department of Medicine I, University Hospital of Wuerzburg, University of Wuerzburg, Oberduerrbacher Strasse 6, 97080, Wuerzburg, Germany
| | - Andreas Schirbel
- Department of Nuclear Medicine, University Hospital of Wuerzburg, University of Wuerzburg, Oberduerrbacher Strasse 6, D-97080, Wuerzburg, Germany.
| | - Lukas Nannen
- Division of Endocrinology and Diabetes, Department of Medicine I, University Hospital of Wuerzburg, University of Wuerzburg, Oberduerrbacher Strasse 6, 97080, Wuerzburg, Germany
| | - David Michelmann
- Division of Endocrinology and Diabetes, Department of Medicine I, University Hospital of Wuerzburg, University of Wuerzburg, Oberduerrbacher Strasse 6, 97080, Wuerzburg, Germany
| | - Philipp E Hartrampf
- Department of Nuclear Medicine, University Hospital of Wuerzburg, University of Wuerzburg, Oberduerrbacher Strasse 6, D-97080, Wuerzburg, Germany
| | - Christina Bluemel
- Department of Nuclear Medicine, University Hospital of Wuerzburg, University of Wuerzburg, Oberduerrbacher Strasse 6, D-97080, Wuerzburg, Germany
| | - Magdalena Schneider
- Division of Endocrinology and Diabetes, Department of Medicine I, University Hospital of Wuerzburg, University of Wuerzburg, Oberduerrbacher Strasse 6, 97080, Wuerzburg, Germany
- Department of Nuclear Medicine, University Hospital of Wuerzburg, University of Wuerzburg, Oberduerrbacher Strasse 6, D-97080, Wuerzburg, Germany
| | - Ken Herrmann
- Department of Nuclear Medicine, University Hospital of Wuerzburg, University of Wuerzburg, Oberduerrbacher Strasse 6, D-97080, Wuerzburg, Germany
- Department of Nuclear Medicine, Medical Faculty, University Hospital Essen, Hufelandstrasse 55, D-45122, Essen, Germany
| | - Heribert Haenscheid
- Department of Nuclear Medicine, University Hospital of Wuerzburg, University of Wuerzburg, Oberduerrbacher Strasse 6, D-97080, Wuerzburg, Germany
| | - Martin Fassnacht
- Division of Endocrinology and Diabetes, Department of Medicine I, University Hospital of Wuerzburg, University of Wuerzburg, Oberduerrbacher Strasse 6, 97080, Wuerzburg, Germany
- Comprehensive Cancer Center Mainfranken, University of Wuerzburg, Josef-Schneider-Str. 2, D-97080, Wuerzburg, Germany
| | - Andreas K Buck
- Department of Nuclear Medicine, University Hospital of Wuerzburg, University of Wuerzburg, Oberduerrbacher Strasse 6, D-97080, Wuerzburg, Germany
| | - Stefanie Hahner
- Division of Endocrinology and Diabetes, Department of Medicine I, University Hospital of Wuerzburg, University of Wuerzburg, Oberduerrbacher Strasse 6, 97080, Wuerzburg, Germany
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Yeap BT, Teah KM, Tan JBG, Azizan N. Case report: A giant hemorrhagic adrenocortical carcinoma causing cardiorespiratory embarrassment. Ann Med Surg (Lond) 2021; 71:102996. [PMID: 34840751 PMCID: PMC8606848 DOI: 10.1016/j.amsu.2021.102996] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2021] [Revised: 10/25/2021] [Accepted: 10/28/2021] [Indexed: 11/30/2022] Open
Abstract
Background Adrenocortical carcinoma (ACC) is a rare aggressive tumor that can be hormone or non-hormone secreting. It is usually associated with fatal outcomes due to its physiological hormonal interaction. We report a successful anaesthetic and surgical management for a patient who presented to us with a huge hemorrhagic ACC which was complicated with acute respiratory failure. Case presentation A 56-year-old lady presented to us with progressive abdominal distension and right hypochondriac pain for two months. She was anemic with elevated liver enzymes. Urgent computed tomography (CT) of the abdomen and pelvis showed a huge right supra renal mass. She subsequently developed respiratory failure due to splinting of diaphragm, of which successfully underwent an emergency exploratory laparotomy. Subsequent endocrine and histopathological work up showed an adrenocortical carcinoma (ACC). Discussion Suprarenal masses usually originate from the adrenal glands. They should be investigated to rule out phaeochromocytoma, which originate from the inner adrenal medulla or outer cortex to form ACC. The latter usually occur in women and of poor prognosis. Huge ACC may cause acute respiratory failure by way of splinting of diaphragm. Both anaesthetic and surgical teams should be well trained in handling patients who undergo adrenal surgeries. Conclusion A giant hemorrhagic functional ACC is extremely uncommon with very poor prognosis. Such conditions should be investigated to rule out phaeochromocytoma. Its potential neuro-hormonal interactions and anatomical correlations can cause fatal perioperative cardio-respiratory embarrassment. The anaesthetic and surgical teams should be capable in managing the hemodynamic instabilities that may present during surgical manipulation and resection of a large ACC.
A gigantic hemorrhagic functional ACC is extremely uncommon with very poor outcome. Patients with a huge suprarenal mass should be thoroughly investigated to rule out phaeochromocytoma. The anaesthetic team should be capable in managing the hemodynamic instabilities that may present during resection of a large ACC.
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Affiliation(s)
- Boon Tat Yeap
- Department of Anaesthesiology and Intensive Care, Faculty of Medicine and Health Sciences, Universiti Malaysia Sabah, 88400, Kota Kinabalu, Sabah, Malaysia
| | - Kai Ming Teah
- Department of Anaesthesiology and Intensive Care, Faculty of Medicine and Health Sciences, Universiti Malaysia Sabah, 88400, Kota Kinabalu, Sabah, Malaysia
| | - Janes Belinda GeilNii Tan
- Department of Anaesthesiology and Intensive Care, Hospital Sultanah Aminah, 81000, Johor Bahru, Malaysia
| | - Nornazirah Azizan
- Department of Pathobiology, Faculty of Medicine and Health Sciences, Universiti Malaysia Sabah, 88400, Kota Kinabalu, Sabah, Malaysia
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Riss P, Scheuba K, Strobel O. [Endocrine and neuroendocrine tumors]. Chirurg 2021; 92:996-1002. [PMID: 34618164 PMCID: PMC8536547 DOI: 10.1007/s00104-021-01512-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/09/2021] [Indexed: 11/30/2022]
Abstract
Endocrine tumors and here in particular gastrointestinal neuroendocrine neoplasms (GEP-NET), pheochromocytomas (PC), paragangliomas (PGL) and thyroid tumors are prime examples of the importance of molecular pathology and molecular biology for the diagnostics, classification and ultimately also the (surgical) treatment of these diseases. The GEP-NETs are graded using the Ki-67 index. This determines the type of molecular imaging (DOTA/DOPA/FDG-PET/CT), the possible treatment (surgical and/or radiopeptide therapy), antiproliferative and symptom-controlling treatment with somatostatin analogues and ultimately also the prognosis. The PC/PGLs can be hereditary (MEN2A, VHL, NF1, SDH mutations), which significantly influences the surgical treatment and preoperative medication. Molecular imaging is very important and can lead the way in cases of borderline biochemistry. Adrenal carcinomas can also be genetically determined. In the case of thyroid tumors, the pathology of the C‑cell (C-cell hyperplasia, medullary thyroid carcinoma) should be emphasized. In the case of hereditary diseases (FMTC, MEN2), early prophylactic surgery is often necessary and prevents the occurrence of advanced carcinomas; however, the determination of the extent of resection in follicular lesions or the distinction between noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) and follicular variants of papillary thyroid carcinoma can also be determined with the help of specific markers. Overall, molecular pathology has an increasingly more important role in these entities and is also the topic of ongoing research projects.
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Affiliation(s)
- Philipp Riss
- Klinische Abteilung für Viszeralchirurgie, Medizinische Universität Wien, ENETS- Center of Excellence, Universitätsklinik für Allgemeinchirurgie, Währinger Gürtel 18-20, 1090, Wien, Österreich.
| | - Katharina Scheuba
- Klinische Abteilung für Viszeralchirurgie, Medizinische Universität Wien, ENETS- Center of Excellence, Universitätsklinik für Allgemeinchirurgie, Währinger Gürtel 18-20, 1090, Wien, Österreich
| | - Oliver Strobel
- Klinische Abteilung für Viszeralchirurgie, Medizinische Universität Wien, ENETS- Center of Excellence, Universitätsklinik für Allgemeinchirurgie, Währinger Gürtel 18-20, 1090, Wien, Österreich
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Parianos C, Kyriakopoulos G, Kostakis ID, Nasiri-Ansari N, Aggeli C, Dimitriadi A, Angelousi A, Papavassiliou AG, Kaltsas GA, Zografos G, Kassi E. Adrenocortical Cancer: A 20-Year Experience of a Single Referral Center in Prognosis and Outcomes. Horm Metab Res 2021; 53:709-716. [PMID: 34740271 DOI: 10.1055/a-1666-9026] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
Adrenocortical carcinoma (ACC) is a rare but very aggressive endocrine malignancy with poor survival. Histopathology is important for diagnosis, while in some cases immunohistochemical markers and gene profiling of the resected tumor may be superior to current staging systems to determine prognosis. We aimed to present the 20-year experience at a tertiary hospital in patients with ACCs and correlate the immunohistochemical characteristics of ACCs with the clinical and morphological characteristics of the tumors and the survival of the patients. Forty-five patients with ACC were included in the study. All the resections were R0. The tumor size and weight, the disease stage (ENSAT classification), Weiss score and Helsinki score were examined along with immunohistochemical expression of inhibin-A, melan A, calretinin, Ki67, synaptophysin, p53, vimentin, CKAE1/AE3. The male to female ratio was 1:1.37. The median age at diagnosis was 55.5 years (IQR 19-77). The median size of ACCs was 9 cm (IQR 3.5-22 cm) and the median weight 127 g (IQR 18-1400 g). The median follow up period was 18 months (IQR 1-96). Ki67 varied from<1% to 75% (median: 16.4%). The expression of melan-A and lower expression of Ki-67 (≤4) were independently associated with longer OS time (p=0.01 and p=0.04, respectively). In multivariable analysis, tumor volume>400 cm3 (p=0.046), Weiss score>5 (p=0.007) and overexpression of p53 (p=0.036) were independent risk factors for shorter survival. Adrenocortical carcinoma is a rare and very aggressive endocrine malignancy. The most important factors that determine long-term prognosis of ACC are the disease stage at diagnosis, the Weiss score, and the Ki67 index. Immunohistochemical markers such as melan A could also serve as prognostic factors.
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Affiliation(s)
- Christos Parianos
- Department of Biological Chemistry, National and Kapodistrian University of Athens, Athens, Greece
- Department of Surgery, General Hospital of Athens "G. Gennimatas", Athens, Greece
| | - Georgios Kyriakopoulos
- Department of Biological Chemistry, National and Kapodistrian University of Athens, Athens, Greece
- Department of Pathology, Evaggelismos Hospital, Athens, Greece
| | - Ioannis D Kostakis
- Department of Hepato-Pancreato-Biliary Surgery and Liver Transplantation, Royal Free Hospital, London, UK
| | - Narjes Nasiri-Ansari
- Department of Biological Chemistry, National and Kapodistrian University of Athens, Athens, Greece
| | - Chrysanthi Aggeli
- Department of Surgery, General Hospital of Athens "G. Gennimatas", Athens, Greece
| | - Anastasia Dimitriadi
- Department of Pathology, General Hospital of Athens "G. Gennimatas", Athens, Greece
| | - Anna Angelousi
- Unit of Endocrinology, First Department of Internal Medicine, Laiko Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | | | - Gregory A Kaltsas
- Unit of Endocrinology, First Department of Propaedeutic Internal Medicine, Laiko Hospital, National & Kapodistrian University of Athens, Athens, Greece
| | - George Zografos
- Department of Surgery, General Hospital of Athens "G. Gennimatas", Athens, Greece
| | - Eva Kassi
- Department of Biological Chemistry, National and Kapodistrian University of Athens, Athens, Greece
- Unit of Endocrinology, First Department of Propaedeutic Internal Medicine, Laiko Hospital, National & Kapodistrian University of Athens, Athens, Greece
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Beltsevich DG, Troshina EA, Melnichenko GA, Platonova NM, Ladygina DO, Chevais A. Draft of the clinical practice guidelines “Adrenal incidentaloma”. ENDOCRINE SURGERY 2021. [DOI: 10.14341/serg12712] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
The wider application and technical improvement of abdominal imaging procedures in recent years has led to an increasingly frequent detection of adrenal gland masses — adrenal incidentaloma, which have become a common clinical problem and need to be investigated for evidence of hormonal hypersecretion and/or malignancy. Clinical guidelines are the main working tool of a practicing physician. Laconic, structured information about a specific nosology, methods of its diagnosis and treatment, based on the principles of evidence-based medicine, make it possible to give answers to questions in a short time, to achieve maximum efficiency and personalization of treatment. These clinical guidelines include data on the prevalence, etiology, radiological features and assessment of hormonal status of adrenal incidentalomas. In addition, this clinical practice guideline provides information on indications for surgery, postoperative rehabilitation and follow-up.
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Metabolic and Endocrine Toxicities of Mitotane: A Systematic Review. Cancers (Basel) 2021; 13:cancers13195001. [PMID: 34638485 PMCID: PMC8508479 DOI: 10.3390/cancers13195001] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2021] [Revised: 09/29/2021] [Accepted: 10/02/2021] [Indexed: 12/05/2022] Open
Abstract
Simple Summary This is, to our knowledge, the first systematic review conducted on the endocrine effects of mitotane, which aims to collect all available evidence in the literature and provide complete and useful information regarding the management of the endocrine and metabolic side effects of mitotane in clinical practice. Abstract Despite the pivotal role of mitotane in adrenocortical carcinoma (ACC) management, data on the endocrine toxicities of this treatment are lacking. The aim of this systematic review is to collect the available evidence on the side effects of mitotane on the endocrine and metabolic systems in both children and adults affected by adrenal carcinoma. Sixteen articles on 493 patients were included. Among the adrenal insufficiency, which is an expected side effect of mitotane, 24.5% of patients increased glucocorticoid replacement therapy. Mineralocorticoid insufficiency usually occurred late in treatment in 36.8% of patients. Thyroid dysfunction is characterized by a decrease in FT4, which occurs within 3–6 months of treatment in 45.4% of patients, while TSH seems to not be a reliable marker. Dyslipidemia is characterized by an increase in both LDL-c and HDL-c (54.2%). Few studies have found evidence of hypertriglyceridemia. In males, gynecomastia and hypogonadism can occur after 3–6 months of treatment (38.4% and 35.6%, respectively), while in pre-menopausal women, mitotane can cause ovarian cysts and, less frequently, menstrual disorders. Most of these side effects appear to be reversible after mitotane discontinuation. We finally suggest an algorithm that could guide metabolic and endocrine safety assessments in patients treated with mitotane for ACC.
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Mao Y, Alimu P, Wang C, Ma W, Zhuo R, Sun F. High TNFSF13B expression as a predictor of poor prognosis in adrenocortical carcinoma. Transl Androl Urol 2021; 10:3275-3285. [PMID: 34532252 PMCID: PMC8421843 DOI: 10.21037/tau-21-232] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2021] [Accepted: 06/30/2021] [Indexed: 11/12/2022] Open
Abstract
Background Adrenocortical carcinoma (ACC) is an extremely rare malignant tumor with poor prognosis. Existing treatment options have limited effects, and new therapeutic targets urgently need to be discovered. TNFSF13B has been reported to be associated with the prognosis of clear cell renal cell carcinoma, but it has not been studied in ACC. Methods TNFSF13B expression was analyzed and compared between ACC tumors and normal tissues by using public datasets from TCGA and GTEx. Kaplan-Meier analysis was employed to evaluate survival, and Cox regression was employed to evaluate clinicopathologic features. The upstream and downstream regulatory mechanisms of TNFSF13B were also analyzed. GSEA was performed to explore the mechanisms of TNFSF13B in ACC. Finally, 14 ACC clinical samples were used to verify the relationships between TNFSF13B expression and disease-free survival (DFS) and overall survival (OS). Results TNFSF13B expression was significantly higher in ACC tissues than in normal tissues. The prognosis of ACC patients with high TNFSF13B expression was worse than that of patients with low TNFSF13B expression. High TNFSF13B expression was strongly correlated with poor prognosis, and TNFSF13B was a prognostic factor. TNFSF13B expression is modified by upstream miRNAs, methylation and ubiquitination, and downstream, it interacts with other proteins. GSEA showed that regulation of cholesterol biosynthesis by SREBP and SREBF, downstream signaling events of the B cell receptor (BCR) and activation of gene expression by SREBF and SREBP were significantly enriched in the TNFSF13B high-expression phenotype. Clinical samples confirmed that TNFSF13B expression was significantly associated with DFS but not with OS. Conclusions TNFSF13B may be a potential prognostic molecular marker of poor survival in ACC patients, offering a new therapeutic target.
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Affiliation(s)
- Yongxin Mao
- Department of Urology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Parehe Alimu
- Department of Urology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Chenghe Wang
- Department of Urology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Wenming Ma
- Department of Urology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Ran Zhuo
- Department of Urology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Fukang Sun
- Department of Urology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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Kiesewetter B, Riss P, Scheuba C, Mazal P, Kretschmer-Chott E, Haug A, Raderer M. Management of adrenocortical carcinoma: are we making progress? Ther Adv Med Oncol 2021; 13:17588359211038409. [PMID: 34484430 PMCID: PMC8411624 DOI: 10.1177/17588359211038409] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2021] [Accepted: 07/22/2021] [Indexed: 01/05/2023] Open
Abstract
Adrenocortical carcinoma (ACC) is a rare malignancy characterized by aggressive
biology and potential endocrine activity. Surgery can offer cure for localized
disease but more than half of patients relapse and primary unresectable or
metastasized disease is frequent. Prognosis of metastatic ACC is still limited,
with less than 15% of patients alive at 5 years. Recent advances in
understanding the molecular profile of ACC underline the high complexity of this
disease, which is characterized by limited drugable molecular targets as well as
by a complex interplay between a yet scarcely understood microenvironment and
potential endocrine activity. Particularly steroid-excess further complicates
therapeutic concepts such as immunotherapy, which have markedly improved outcome
in other disease entities. To date, mitotane remains the only approved drug for
adjuvant and palliative care in ACC. Standard chemotherapy-based protocols with
cisplatin, doxorubicin and etoposide offer only marginal improvement in
long-term outcome and the number of clinical trials conducted is low due to the
rarity of the disease. In the current review, we summarize principles of
oncological management for ACC from localized to advanced disease and discuss
novel therapeutic strategies, including targeted therapies such as tyrosine
kinase inhibitors and antibodies, immunotherapy with a focus on checkpoint
inhibitors, individualized treatment concepts based on molecular
characterization by next generation sequencing methods, the role of theranostics
and evolvement of adjuvant therapy.
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Affiliation(s)
- Barbara Kiesewetter
- Department of Medicine I, Division of Oncology, Medical University of Vienna, Waehringer Guertel 18-20, Vienna, A-1090, Austria
| | - Philipp Riss
- Department of General Surgery, Division of Visceral Surgery, Medical University of Vienna, Vienna, Austria
| | - Christian Scheuba
- Department of General Surgery, Division of Visceral Surgery, Medical University of Vienna, Vienna, Austria
| | - Peter Mazal
- Department of Pathology, Medical University of Vienna, Vienna, Austria
| | | | - Alexander Haug
- Department of Radiology and Nuclear Medicine, Medical University of Vienna, Vienna, Austria
| | - Markus Raderer
- Department of Medicine I, Division of Oncology, Medical University of Vienna, Vienna, Austria
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The Challenging Pharmacokinetics of Mitotane: An Old Drug in Need of New Packaging. Eur J Drug Metab Pharmacokinet 2021; 46:575-593. [PMID: 34287806 PMCID: PMC8397669 DOI: 10.1007/s13318-021-00700-5] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/24/2021] [Indexed: 01/10/2023]
Abstract
Adrenocortical carcinoma (ACC) is a malignant tumor originating from the adrenal gland cortex with a heterogeneous but overall dismal prognosis in advanced stages. For more than 50 years, mitotane has remained a cornerstone for the treatment of ACC as adjuvant and palliative therapy. It has a very poor aqueous solubility of 0.1 mg/l and high partition coefficient in octanol/water (log P) value of 6. The commercially available dosage form is 500 mg tablets (Lysodren®). Even at doses up to 6 g/day (12 tablets in divided doses) for several months, > 50% patients do not achieve therapeutic plasma concentration > 14 mg/l due to poor water solubility, large volume of distribution and inter/intra-individual variability in bioavailability. This article aims to give a concise update of the clinical challenges associated with the administration of high-dose mitotane oral therapy which encompass the issues of poor bioavailability, difficult-to-predict pharmacokinetics and associated adverse events. Moreover, we present recent efforts to improve mitotane formulations. Their success has been limited, and we therefore propose an injectable mitotane formulation instead of oral administration, which could bypass many of the main issues associated with high-dose oral mitotane therapy. A parenteral administration of mitotane could not only help to alleviate the adverse effects but also circumvent the variable oral absorption, give better control over therapeutic plasma mitotane concentration and potentially shorten the time to achieve therapeutic drug plasma concentrations considerably. Mitotane as tablet form is currently the standard treatment for adrenocortical carcinoma. It has been used for 5 decades but suffers from highly variable responses in patients, subsequent adverse effects and overall lower response rate. This can be fundamentally linked to the exceedingly poor water solubility of mitotane itself. In terms of enhancing water solubility, a few research groups have attempted to develop better formulations of mitotane to overcome the issues associated with tablet dosage form. However, the success rate was limited, and these formulations did not make it into the clinics. In this article, we have comprehensively reviewed the properties of these formulations and discuss the reasons for their limited utility. Furthermore, we discuss a recently developed mitotane nanoformulation that led us to propose a novel approach to mitotane therapy, where intravenous delivery supplements the standard oral administration. With this article, we combine the current state of knowledge as a single piece of information about the various problems associated with the use of mitotane tablets, and herein we postulate the development of a new injectable mitotane formulation, which can potentially circumvent the major problems associated to mitotane's poor water solubility.
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Oliveira RC, Martins MJ, Moreno C, Almeida R, Carvalho J, Teixeira P, Teixeira M, Silva ET, Paiva I, Figueiredo A, Cipriano MA. Histological scores and tumor size on stage II in adrenocortical carcinomas. Rare Tumors 2021; 13:20363613211026494. [PMID: 34262677 PMCID: PMC8243092 DOI: 10.1177/20363613211026494] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2020] [Accepted: 06/01/2021] [Indexed: 11/18/2022] Open
Abstract
Adrenocortical carcinomas (ACC) are aggressive tumors with a poor prognosis.
Histological scores are advised for the diagnosis, however, there are borderline
cases that may be misjudged as adrenocortical adenomas (ACA). The three main
scores used are: Weiss Modified System (WMS), Reticulin Algorithm (RA), and
Helsinki Score (HS). We intend to compare the accuracy of the three scores in
ACC diagnosis and to identify predictive factors of overall survival (OS).
Retrospective study (2004–2016) at Centro Hospitalar e Universitário de Coimbra
of the adrenal tumors, classified as ACC or ACA, with a history of posterior
tumor relapse/metastases, without lesions in the contralateral adrenal gland:
13F and 6M, with a median age of 51 ± 12.41 years. Nodules’ median size was
9.20 ± 6.2 cm. Patients had a median OS of 52 ± 18.6 months, with 57.9% and
46.3%, at 3 and 5 years. Seven patients had local recurrence and nine had
metastases. Thirteen cases were in stage II. The WMS and the HS allowed a
diagnosis of ACC in 15 cases and the RA defined ACC in 17 cases. All cases had,
at least, focal disruption of the reticulin framework. More than
5 mitosis/50 HPF was associated with worse OS: 49.67 ± 21.43 versus
108.86 ± 14.02 months (p = 0.026). In patients with stage II,
tumor size ⩾10 cm was associated with worse OS: 19.25 ± 7.15 versus
96.11 ± 16.7 months (p = 0.007), confirmed by multivariate
analysis (p = 0.031). The correct diagnosis of ACC is a
pathologist responsibility. The RA seems the most accurate. Any loss of the
reticulin framework should raise awareness for malignancy. In patients on stage
II, a size ⩾10 cm is a predictor of worse prognosis.
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Affiliation(s)
- Rui Caetano Oliveira
- Pathology Department, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal.,Biophysics Institute, Faculty of Medicine, University of Coimbra, Coimbra, Portugal.,Coimbra Institute for Clinical and Biomedical Research (iCBR) area of Environment Genetics and Oncobiology (CIMAGO), Faculty of Medicine, University of Coimbra, Coimbra, Portugal
| | - Maria João Martins
- Pathology Department, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal.,Faculdade de Medicina da Universidade de Coimbra, Coimbra, Portugal
| | - Carolina Moreno
- Faculdade de Medicina da Universidade de Coimbra, Coimbra, Portugal.,Endocrinology, Diabetes and Metabolism Department, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal
| | - Rui Almeida
- Pathology Department, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal.,Faculdade de Medicina da Universidade de Coimbra, Coimbra, Portugal
| | - João Carvalho
- Urology and Renal Transplantation, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal
| | - Paulo Teixeira
- Pathology Department, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal
| | - Miguel Teixeira
- Coimbra Institute for Clinical and Biomedical Research (iCBR) area of Environment Genetics and Oncobiology (CIMAGO), Faculty of Medicine, University of Coimbra, Coimbra, Portugal
| | - Edgar Tavares Silva
- Biophysics Institute, Faculty of Medicine, University of Coimbra, Coimbra, Portugal.,Coimbra Institute for Clinical and Biomedical Research (iCBR) area of Environment Genetics and Oncobiology (CIMAGO), Faculty of Medicine, University of Coimbra, Coimbra, Portugal.,Faculdade de Medicina da Universidade de Coimbra, Coimbra, Portugal.,Urology and Renal Transplantation, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal
| | - Isabel Paiva
- Faculdade de Medicina da Universidade de Coimbra, Coimbra, Portugal
| | - Arnaldo Figueiredo
- Coimbra Institute for Clinical and Biomedical Research (iCBR) area of Environment Genetics and Oncobiology (CIMAGO), Faculty of Medicine, University of Coimbra, Coimbra, Portugal.,Faculdade de Medicina da Universidade de Coimbra, Coimbra, Portugal.,Urology and Renal Transplantation, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal
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Hue JJ, Alvarado C, Bachman K, Wilhelm SM, Ammori JB, Towe CW, Rothermel LD. Outcomes of malignant pheochromocytoma based on operative approach: A National Cancer Database analysis. Surgery 2021; 170:1093-1098. [PMID: 33958205 DOI: 10.1016/j.surg.2021.04.001] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2021] [Revised: 03/30/2021] [Accepted: 04/01/2021] [Indexed: 12/31/2022]
Abstract
BACKGROUND Malignant pheochromocytoma is often managed with adrenalectomy. Most literature focusing on postoperative outcomes are from single institutions. This study aimed to describe outcomes of adrenalectomy for malignant pheochromocytoma using a national database. We hypothesized that minimally invasive approaches might be associated with improved short-term outcomes but potentially inferior oncologic efficacy. METHODS Patients who underwent adrenalectomy for malignant pheochromocytoma were identified in the National Cancer Database (2010-2016). Patients were categorized as minimally invasive adrenalectomy or open adrenalectomy. Short- and long-term outcomes were compared. RESULTS A total of 276 patients underwent adrenalectomy for malignant pheochromocytoma: 50.7% open adrenalectomy and 49.3% minimally invasive adrenalectomy. Demographics were similar, except those who underwent open adrenalectomy had larger tumors compared to minimally invasive adrenalectomy (8.2 cm vs 4.7 cm; P < .001). Tumor size ≥6 cm was associated with a reduced likelihood of minimally invasive adrenalectomy (relative to open adrenalectomy) on multivariable regression (odds ratio = 0.23; P < .001). Open adrenalectomy was associated with longer duration of stay relative to minimally invasive adrenalectomy (6 vs 3 days; P < .001). Rates of positive margins, unplanned readmissions, or 30-/90-day mortalities were similar based on operative approach. Five-year survival rates were similar (open adrenalectomy 74.3%, minimally invasive adrenalectomy 79.1%). There was no association between overall survival and operative approach on multivariable Cox analysis when controlling for tumor size, laterality, and clinicodemographic variables. CONCLUSION Patients with larger malignant pheochromocytomas were more likely to undergo an open adrenalectomy. With the exception of an increased duration of stay, there was no difference in short- or long-term postoperative outcomes. These data suggest that minimally invasive adrenalectomy appears safe among tumors <6 cm.
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Affiliation(s)
- Jonathan J Hue
- Department of Surgery, University Hospitals Cleveland Medical Center, OH. https://twitter.com/jj_hue
| | - Christine Alvarado
- Department of Surgery, University Hospitals Cleveland Medical Center, OH. https://twitter.com/calvaradomd
| | - Katelynn Bachman
- Department of Surgery, University Hospitals Cleveland Medical Center, OH
| | - Scott M Wilhelm
- Department of Surgery, University Hospitals Cleveland Medical Center, OH
| | - John B Ammori
- Department of Surgery, University Hospitals Cleveland Medical Center, OH. https://twitter.com/ammorijohn
| | - Christopher W Towe
- Department of Surgery, University Hospitals Cleveland Medical Center, OH
| | - Luke D Rothermel
- Department of Surgery, University Hospitals Cleveland Medical Center, OH.
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Buller DM, Hennessey AM, Ristau BT. Open versus minimally invasive surgery for suspected adrenocortical carcinoma. Transl Androl Urol 2021; 10:2246-2263. [PMID: 34159107 PMCID: PMC8185676 DOI: 10.21037/tau.2020.01.11] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2019] [Accepted: 12/11/2019] [Indexed: 12/12/2022] Open
Abstract
Adrenocortical carcinoma (ACC) is a rare malignancy with a poor prognosis. Although laparoscopy has been widely adopted for management of benign adrenal tumors, minimally invasive surgery for ACC remains controversial. Retrospective analyses, frequently with fewer than one hundred participants, comprise the majority of the literature. High-quality data regarding the optimal surgical approach for ACC are lacking due to the rarity of the disease and the fact that determination of tumor type (e.g., adenoma or carcinoma) is determined after adrenalectomy, since adrenal tumors are generally not biopsied. While the benefits of minimally invasive surgery including lower intra-operative blood loss and decreased hospital length-of-stay have been consistently demonstrated, clinical equipoise for long-term survival and recurrence outcomes between open and minimally invasive adrenalectomy (MIA) remains. This review examines retrospective studies that directly compare patients with ACC who underwent either open or laparoscopic adrenalectomy, and considers these findings in the context of current guideline recommendations for surgical management of ACC.
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Allegra S, Puglisi S, Brescia I, Chiara F, Basile V, Calabrese A, Reimondo G, De Francia S. Sex Differences on Mitotane Concentration and Treatment Outcome in Patients with Adrenocortical Carcinoma. Life (Basel) 2021; 11:life11030266. [PMID: 33807024 PMCID: PMC8004922 DOI: 10.3390/life11030266] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2021] [Revised: 03/16/2021] [Accepted: 03/19/2021] [Indexed: 12/13/2022] Open
Abstract
(1) Background: In clinical settings, data regarding sex are rarely investigated. In women, factors such as body size and composition, hormonal variations, metabolism, and access to care systems and therapy could strongly influence the pharmacological management and the outcome of the therapy. To underline this sex-related difference, we retrospectively collected data from adrenocortical carcinoma patients treated with mitotane, and then evaluated sex-related pharmacokinetics parameters. (2) Methods: A fully validated chromatographic method was used to quantify mitotane concentration in plasma collected from adult patients, also considering the active metabolite ortho,para,dichlorodiphenylethene (o,p'-DDE). Statistical analyses were used to evaluate the sex influence on drugs pharmacokinetics. (3) Results: We found that sex resulted as predictive factor of plasma mitotane and o,p'-DDE concentrations and significantly influenced the attainment of the therapeutic target of mitotane, implying that female sex could be a risk factor of treatment failure. (4) Conclusions: These results suggest that mitotane therapy should be modulated according to patient sex. Furthermore, the proposed approach could contribute to facilitating and disseminating sex-specific pharmacology.
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Affiliation(s)
- Sarah Allegra
- Laboratory of Clinical Pharmacology “Franco Ghezzo”, Department of Clinical and Biological Sciences, University of Turin, S. Luigi Gonzaga Hospital, 10043 Orbassano, TO, Italy; (I.B.); (F.C.); (S.D.F.)
- Correspondence: ; Tel.: +39-011-6705442
| | - Soraya Puglisi
- Internal Medicine, Department of Clinical and Biological Sciences, University of Turin, S. Luigi Gonzaga Hospital, 10043 Orbassano, TO, Italy; (S.P.); (V.B.); (A.C.); (G.R.)
| | - Irene Brescia
- Laboratory of Clinical Pharmacology “Franco Ghezzo”, Department of Clinical and Biological Sciences, University of Turin, S. Luigi Gonzaga Hospital, 10043 Orbassano, TO, Italy; (I.B.); (F.C.); (S.D.F.)
| | - Francesco Chiara
- Laboratory of Clinical Pharmacology “Franco Ghezzo”, Department of Clinical and Biological Sciences, University of Turin, S. Luigi Gonzaga Hospital, 10043 Orbassano, TO, Italy; (I.B.); (F.C.); (S.D.F.)
| | - Vittoria Basile
- Internal Medicine, Department of Clinical and Biological Sciences, University of Turin, S. Luigi Gonzaga Hospital, 10043 Orbassano, TO, Italy; (S.P.); (V.B.); (A.C.); (G.R.)
| | - Anna Calabrese
- Internal Medicine, Department of Clinical and Biological Sciences, University of Turin, S. Luigi Gonzaga Hospital, 10043 Orbassano, TO, Italy; (S.P.); (V.B.); (A.C.); (G.R.)
| | - Giuseppe Reimondo
- Internal Medicine, Department of Clinical and Biological Sciences, University of Turin, S. Luigi Gonzaga Hospital, 10043 Orbassano, TO, Italy; (S.P.); (V.B.); (A.C.); (G.R.)
| | - Silvia De Francia
- Laboratory of Clinical Pharmacology “Franco Ghezzo”, Department of Clinical and Biological Sciences, University of Turin, S. Luigi Gonzaga Hospital, 10043 Orbassano, TO, Italy; (I.B.); (F.C.); (S.D.F.)
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Solak M, Kraljević I, Zibar Tomšić K, Kaštelan M, Kakarigi L, Kaštelan D. Neutrophil-Lymphocyte Ratio as a Prognostic Marker in Adrenocortical Carcinoma. Endocr Res 2021; 46:74-79. [PMID: 33416409 DOI: 10.1080/07435800.2020.1870234] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
PURPOSE The purpose of the present study was to analyze the impact of the neutrophil-lymphocyte ratio (NLR) on the long-term outcomes of patients with adrenocortical carcinoma (ACC). METHODS This retrospective, single-institution study included 48 patients with the diagnosis of ACC. The primary outcomes of the study were differences in overall survival (OS) and disease-specific survival (DSS) with respect to the NLR level. RESULTS Patients with ENSAT stage IV had higher levels of NLR compared to those with ENSAT stage I-III (5.7 (1.6-12.5) vs 3.3 (1.3-11); p = .01). A higher NLR was also observed among patients with cortisol-secreting tumors (4.6 (1.7-12.5) vs 2.8 (1.3-10.3); p = .003) and those with Ki-67 index >10% (4.3 (1.3-12.5) vs 2.6 (1.6-11.0); p = .005). With respect to survival, the univariate analysis revealed worse ACC-related survival (p = .02) and OS (p = .004) in patients with NLR >3.9 than in those with NLR ≤3.9. In addition, patients with NLR >3.9 had a higher Weiss score (p = .046), a higher Ki-67 index (p = .006) and a higher disease stage (p = .01) compared to patients with NLR ≤3.9. No differences between the groups were observed regarding excess glucocorticoid secretion. CONCLUSION The study demonstrated that a higher NLR level in ACC patients was associated with unfavorable outcomes in terms of DSS and OS. These results indicate that NLR might be used as an additional marker in ACC risk stratification and identification of patients with the most adverse prognosis.
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Affiliation(s)
- Mirsala Solak
- Department of Endocrinology, University Hospital Center Zagreb, Zagreb, Croatia
| | - Ivana Kraljević
- Department of Endocrinology, University Hospital Center Zagreb, Zagreb, Croatia
- School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Karin Zibar Tomšić
- Department of Endocrinology, University Hospital Center Zagreb, Zagreb, Croatia
| | - Marko Kaštelan
- School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Luka Kakarigi
- School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Darko Kaštelan
- Department of Endocrinology, University Hospital Center Zagreb, Zagreb, Croatia
- School of Medicine, University of Zagreb, Zagreb, Croatia
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Adrenal Surgery for Synchronously Metastatic Adrenocortical Carcinoma: A Population-Based Analysis. World J Surg 2021; 45:1457-1465. [PMID: 33481081 DOI: 10.1007/s00268-021-05957-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/05/2021] [Indexed: 02/05/2023]
Abstract
BACKGROUND Metastatic adrenocortical carcinoma (ACC) is an aggressive cancer with poor prognosis, with limited treatment options. The survival benefit of adrenal surgery in patients with synchronous metastatic disease has not been well explored. METHODS Patients with ACC with synchronous metastases were identified from the Surveillance, Epidemiology, and End Results database (2010-2016). The effect of adrenal surgery on different patterns of distant metastases was assessed. The overall survival was estimated by the Kaplan-Meier method. Multivariable Cox regression analysis was performed to identify prognostic factors associated with survival outcome. RESULTS A total of 202 patients with synchronous metastatic ACC were identified from the SEER database, 76 (37.6%) patients underwent adrenal surgery. Compared to nonsurgical patients, patients who underwent adrenal surgery had a better survival (median overall survival: 4 vs. 13 months, P < 0.001). In sub-analyses, except for patients with liver metastases (P = 0.670), adrenalectomy could consistently confer a significant survival benefit in patients with lung metastases (P = 0.003), bone metastases (P = 0.020), and multiple metastases (P = 0.002). Cox regression analysis revealed that in addition to adrenalectomy [hazard ratio (HR) = 0.64, 95% confidence interval (CI) 0.45-0.92; P = 0.017], metastasectomy (HR = 0.48, 95% CI 0.26-0.86; P = 0.013), and chemotherapy (HR = 0.59, 95% CI 0.42-0.82; P = 0.002) were also associated with improved survival. CONCLUSIONS Our findings support the view that adrenal surgery may be associated with improved survival in patients with synchronous metastatic ACC (except for patients with liver metastases), and the metastatic sites have significant prognostic implications on survival outcomes with adrenal surgery.
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Manso J, Sharifi-Rad J, Zam W, Tsouh Fokou PV, Martorell M, Pezzani R. Plant Natural Compounds in the Treatment of Adrenocortical Tumors. Int J Endocrinol 2021; 2021:5516285. [PMID: 34567112 PMCID: PMC8463247 DOI: 10.1155/2021/5516285] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2021] [Revised: 05/14/2021] [Accepted: 08/31/2021] [Indexed: 01/08/2023] Open
Abstract
Plant natural products are a plethora of diverse and complex molecules produced by the plant secondary metabolism. Among these, many can reserve beneficial or curative properties when employed to treat human diseases. Even in cancer, they can be successfully used and indeed numerous phytochemicals exert antineoplastic activity. The most common molecules derived from plants and used in the fight against cancer are polyphenols, i.e., quercetin, genistein, resveratrol, curcumin, etc. Despite valuable data especially in preclinical models on such compounds, few of them are currently used in the medical practice. Also, in adrenocortical tumors (ACT), phytochemicals are scarcely or not at all used. This work summarizes the available research on phytochemicals used against ACT and adrenocortical cancer, a very rare disease with poor prognosis and high metastatic potential, and wants to contribute to stimulate preclinical and clinical research to find new therapeutic strategies among the overabundance of biomolecules produced by the plant kingdom.
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Affiliation(s)
- Jacopo Manso
- Endocrinology Unit, Department of Medicine (DIMED), University of Padova, Via Ospedale 105, Padova 35128, Italy
| | - Javad Sharifi-Rad
- Phytochemistry Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
- Facultad de Medicina, Universidad del Azuay, Cuenca, Ecuador
| | - Wissam Zam
- Analytical and Food Chemistry Department, Faculty of Pharmacy, Tartous University, Tartous, Syria
| | | | - Miquel Martorell
- Department of Nutrition and Dietetics, Faculty of Pharmacy, Centre for Healthy Living, University of Concepción, Concepción 4070386, Chile
- Universidad de Concepción, Unidad de Desarrollo Tecnológico, UDT, Concepción 4070386, Chile
| | - Raffaele Pezzani
- Endocrinology Unit, Department of Medicine (DIMED), University of Padova, Via Ospedale 105, Padova 35128, Italy
- Phytotherapy Lab, Endocrinology Unit, Department of Medicine (DIMED), University of Padova, via Ospedale 105, 35128 Padova, Italy
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Jungels C. Editorial: Endocrine tumors, rare tumors. Curr Opin Oncol 2021; 33:1-2. [PMID: 33273300 DOI: 10.1097/cco.0000000000000690] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Affiliation(s)
- Christiane Jungels
- Department of Oncological Medicine, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium
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Savoie PH, Murez T, Fléchon A, Rocher L, Ferretti L, Morel-Journel N, Camparo P, Méjean A. [French ccAFU guidelines - update 2020-2022: malignancy assessment of an adrenal incidentaloma]. Prog Urol 2020; 30:S331-S352. [PMID: 33349429 DOI: 10.1016/s1166-7087(20)30756-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
INTRODUCTION - The objective of this publication is to recall the initial oncological management of adrenal incidentalomas. MATERIAL & METHODS - The multidisciplinary working group updated french urological guidelines established by the CCAFU in 2018, based on an exhaustive literature review carried out on PubMed. RESULTS - Although the majority of the adrenal masses are benign and non-functional, it is important to investigate them, as a percentage of these can cause serious endocrine diseases or be cancers. Malignant adrenal tumors are mainly represented by Adrenocortical Carcinomas (ACC), malignant pheochromocytomas (MPC) and adrenal metastases (AM). The malignancy assessment of an adrenal incident includes a complete history, a physical examination, a biochemical / hormonal assessment to look for subclinical hormonal secretion. Diagnostic hypotheses are sometimes available at this stage, but it is the morphological and functional imaging and the histological analysis which will make it possible to close the malignancy assessment and make the oncological diagnosis. CONCLUSIONS - AC and MPC are mainly sporadic but a hereditary origin is always possible. ACC is suspected preoperatively but the diagnosis of certainty is histological. The diagnosis of MPC is more delicate and is based on clinic, biology and imagery. The diagnosis of certainty of AM requires a percutaneous biopsy. At the end, the files must be discussed within the COMETE - adrenal cancer network (Appendix 1).
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Affiliation(s)
- P-H Savoie
- Comité de cancérologie de l'Association française d'urologie, groupe vessie, Maison de l'urologie, 11, rue Viète, 75017 Paris, France; Service de chirurgie urologique, hôpital d'instruction des armées Sainte-Anne, BP 600, 83800 Toulon Cedex 09, France.
| | - T Murez
- Comité de cancérologie de l'Association française d'urologie, groupe vessie, Maison de l'urologie, 11, rue Viète, 75017 Paris, France; service d'urologie et de transplantation rénale, CHU de Montpellier, 371, avenue du Doyen-Gaston-Giraud, 34295 Montpellier Cedex 5, France
| | - A Fléchon
- Comité de cancérologie de l'Association française d'urologie, groupe vessie, Maison de l'urologie, 11, rue Viète, 75017 Paris, France; Centre Léon-Bérard, 28, rue Laennec, 69008 Lyon, France
| | - L Rocher
- Comité de cancérologie de l'Association française d'urologie, groupe vessie, Maison de l'urologie, 11, rue Viète, 75017 Paris, France; Service de radiologie, hôpital Antoine-Béclère, AP-HP, 157 rue de la Porte-de-Trivaux, 92140 Clamart, France; Université Paris-Saclay, BIOMAPS, 63, avenue Gabriel-Péri, 94270 Le Kremlin-Bicêtre, France
| | - L Ferretti
- Comité de cancérologie de l'Association française d'urologie, groupe vessie, Maison de l'urologie, 11, rue Viète, 75017 Paris, France; MSP Bordeaux Bagatelle 203, route de Toulouse, 33401 Talence, France
| | - N Morel-Journel
- Comité de cancérologie de l'Association française d'urologie, groupe vessie, Maison de l'urologie, 11, rue Viète, 75017 Paris, France; Service d'urologie, CHU de Lyon, 165, chemin du Grand-Revoyet, 69310 Pierre-Bénite
| | - P Camparo
- Comité de cancérologie de l'Association française d'urologie, groupe vessie, Maison de l'urologie, 11, rue Viète, 75017 Paris, France; Institut de pathologie des Hauts-de-France, 51, rue Jeanne-d'Arc, 80000 Amiens, France
| | - A Méjean
- Comité de cancérologie de l'Association française d'urologie, groupe vessie, Maison de l'urologie, 11, rue Viète, 75017 Paris, France; Service d'urologie et transplantation rénale, hôpital européen Georges-Pompidou, AP-HP, 20, rue Leblanc, 75015 Paris, France
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Miele E, Di Giannatale A, Crocoli A, Cozza R, Serra A, Castellano A, Cacchione A, Cefalo MG, Alaggio R, De Pasquale MD. Clinical, Genetic, and Prognostic Features of Adrenocortical Tumors in Children: A 10-Year Single-Center Experience. Front Oncol 2020; 10:554388. [PMID: 33178583 PMCID: PMC7593337 DOI: 10.3389/fonc.2020.554388] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2020] [Accepted: 08/20/2020] [Indexed: 12/16/2022] Open
Abstract
Background and Aims: Pediatric adrenocortical tumors (ACTs) are very rare endocrine neoplasms in childhood. In this study, we performed a retrospective analysis of children with ACT treated at our institution by examining clinical and genetic disease features, treatment strategies, and outcomes. Methods: We retrospectively analyzed a cohort of 13 children treated at the Bambino Gesù Children's Hospital from November 2010 to March 2020. Results: The median age at diagnosis was 17 months (range = 0–82 months). The female: male ratio was 3.3/1. Mixed symptomatology (>1 hormone abnormality) was the most common presentation (46.1%). In three cases, the tumor was detected during prenatal or perinatal echographic screening. All patients presented with localized disease at diagnosis and underwent total adrenalectomy. Six patients were identified as having malignancies according to the Wieneke scoring system, five benign, and two undetermined. Seven patients underwent mitotane adjuvant therapy for 12 months. There was metastatic disease in three patients, with no correlation with age or Wieneke score. The most common sites of metastases were the liver and lungs. Metastatic patients were treated with surgery (n = 2), mitotane (n = 1), chemotherapy (n = 2) associated with anti-EGFR (n = 1), or immunotherapy with anti-PD1 (pembrolizumab) (n = 1); two patients achieved complete disease remission. Overall 2- and 5-year survival rates were 100%, with a median follow-up of 5 years (range = 2–9.5 years). Two- and 5-year disease free survival was 76.9 and 84.6%, respectively (95% confidence interval = −66.78–114.76 months). All patients are alive, 12 without disease, and one with stable disease. Genetic analyses showed TP53 germline mutations in six of eight patients analyzed (five inherited, one de novo). One patient had Beckwith–Wiedemann syndrome, with mosaic paternal uniparental disomy of chromosome 11, in both neoplastic and healthy adrenal tissue. Conclusion: We report the cases of 13 patients treated for ACT, including 12 aged <4 years at diagnosis, with a relative short time from symptoms onset. Our cohort experienced an excellent prognosis. TP53 mutation was found in 75% of tested patients (6/8) confirming the need to perform genetic tests and familial counseling in this disease.
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Affiliation(s)
- Evelina Miele
- Department of Paediatric Haematology/Oncology Cell and Gene Therapy, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
| | - Angela Di Giannatale
- Department of Paediatric Haematology/Oncology Cell and Gene Therapy, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
| | - Alessandro Crocoli
- Department of Surgery, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
| | - Raffaele Cozza
- Department of Paediatric Haematology/Oncology Cell and Gene Therapy, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
| | - Annalisa Serra
- Department of Paediatric Haematology/Oncology Cell and Gene Therapy, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
| | - Aurora Castellano
- Department of Paediatric Haematology/Oncology Cell and Gene Therapy, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
| | - Antonella Cacchione
- Department of Paediatric Haematology/Oncology Cell and Gene Therapy, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
| | - Maria Giuseppina Cefalo
- Department of Paediatric Haematology/Oncology Cell and Gene Therapy, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
| | - Rita Alaggio
- Department of Laboratories, Pathology Unit, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
| | - Maria Debora De Pasquale
- Department of Paediatric Haematology/Oncology Cell and Gene Therapy, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
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Durmuşoğlu J, Timmers HJLM, van Houten P, Langenhuijsen JF, Hermus ARMM, van de Ven AC. Venous thromboembolism in patients with adrenocortical carcinoma after surgery. Endocr Connect 2020; 9:874-881. [PMID: 32784266 PMCID: PMC7487187 DOI: 10.1530/ec-20-0299] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/07/2020] [Accepted: 08/12/2020] [Indexed: 12/15/2022]
Abstract
BACKGROUND Adrenocortical carcinoma is a rare malignancy with a poor prognosis. We hypothesized that patients with adrenocortical carcinoma are at high risk for venous thromboembolism, given the numerous risk factors such as malignancy, abdominal surgery, immobility and hormonal excess. The aim of this study was to determine retrospectively the incidence of venous thromboembolisms after surgical treatment in patients with adrenocortical carcinoma. MATERIALS AND METHODS A retrospective study was performed, collecting data from all patients diagnosed with adrenocortical carcinoma from 2003 to 2018 at the Radboud University Medical Centre, The Netherlands. RESULTS In 34 patients, eight postoperative venous thromboembolisms, all pulmonary embolisms, were diagnosed in the first 6 months after adrenalectomy (23.5%). In addition, one patient developed pulmonary embolism just prior to surgery and one patient 7 years after surgery. Five of the eight patients with postoperative venous thromboembolisms presented with symptomatic pulmonary embolism whereas the other three pulmonary embolisms were incidentally found on regular follow up CT scans. Seven of the eight venous thromboembolisms occurred within 10 weeks after surgery. Seven of the eight patients had advanced stage adrenocortical carcinoma and four patients already received low-molecular weight heparin during the development of the venous thromboembolism. There was one case of fatal pulmonary embolism in a patient with a cortisol producing tumor with pulmonary metastases, despite the use of a therapeutic dose thromboprophylaxis. CONCLUSION Patients with adrenocortical carcinoma are at high risk of developing postoperative venous thromboembolisms. Prolonged postoperative thromboprophylaxis could be considered in these patients.
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Affiliation(s)
- Jülide Durmuşoğlu
- Division of Endocrinology, Department of Medicine, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands
| | - Henri J L M Timmers
- Division of Endocrinology, Department of Medicine, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands
| | - Pepijn van Houten
- Division of Endocrinology, Department of Medicine, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands
- Correspondence should be addressed to P van Houten:
| | - Johan F Langenhuijsen
- Department of Urology, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands
| | - Ad R M M Hermus
- Division of Endocrinology, Department of Medicine, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands
| | - Annenienke C van de Ven
- Division of Endocrinology, Department of Medicine, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands
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Abstract
PURPOSE OF REVIEW Although the majority of pheochromocytoma and paraganglioma are benign, 15-17% develop metastatic disease, being present at the initial diagnosis in about 11-31% of cases. The natural course of metastasized disease is highly heterogeneous, with an overall 5-year survival rate varying between 40% and 85%. For individual patients, overall survival, progression-free survival, and clinical outcome are difficult to predict. Management of metastasized pheochromocytoma and paraganglioma is challenging. Currently available therapeutic options are surgical debulking, treatment with radiopharmaceuticals (I-MIBG, Y and Lu-DOTATATE), chemotherapy and targeted therapy. RECENT FINDINGS The pathogenesis of pheochromocytoma and paraganglioma (PPGL) is largely driven by genomic alterations in PPGL susceptibility genes related to three different clusters: altered pseudo-hypoxic signaling (cluster-1), altered MAP-kinase signaling (cluster-2) and altered Wnt signaling (cluster-3). Novel targeted therapies (tyrosine kinase inhibitors) and potential future therapeutic options, guided by improved knowledge about the oncogenic cluster 1-3 signaling pathways, will be discussed. SUMMARY Treatment of metastasized pheochromocytoma and paraganglioma remains challenging. Profiling of gene expression and methylation can serve as a powerful tool for characterizing disease clusters and for guiding targeted therapy to improve selectivity and efficacy. Current knowledge of signatures involved in molecular signaling, metabolism, and resistance mechanisms of PPGLs suggests that therapeutic regimens can be optimized to each molecular subtype.
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Unwanted Hormonal and Metabolic Effects of Postoperative Adjuvant Mitotane Treatment for Adrenocortical Cancer. Cancers (Basel) 2020; 12:cancers12092615. [PMID: 32937772 PMCID: PMC7565701 DOI: 10.3390/cancers12092615] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2020] [Revised: 09/07/2020] [Accepted: 09/09/2020] [Indexed: 12/17/2022] Open
Abstract
Simple Summary Mitotane is the only drug approved for treatment of adrenocortical cancer. Although mitotane is a derivative of the pesticide dichlorodiphenyltrichloroethane (DDT), limited data are available on its toxicity. Herein, we reported on the type and frequency of mitotane adverse events and on supportive therapies used to deal with toxicity in 74 mitotane-treated patients. Beyond the expected glucocorticoid insufficiency, a significant number of patients had a deficit of mineralocorticoid hormones, hypothyroid state and impaired testicular function, while fertile women frequently developed ovarian cysts during mitotane treatment. Multiple hormone replacement therapies were needed in >30% of patients. Statins were used in 50% of patients for significant hypercholesterolemia. Supportive therapies were able to revert the biochemical alterations, although higher doses were frequently used due to pharmacokinetic interactions with mitotane. Our study underlines the need of a careful and global approach to manage mitotane toxicity, to make adjuvant therapy safer and easier for patients. Abstract Mitotane is widely used for the treatment of adrenocortical cancer (ACC), although the drug-related toxicity complicates its use. The aim of this study is to assess comprehensively the different endocrine and metabolic unwanted effects of the drug, and to provide data on the supportive therapies. We retrospectively analyzed 74 ACC patients adjuvantly treated with mitotane for ≥12 months. During the treatment period (40 months, 12–195), 32.4% of patients needed replacement therapy for mineralocorticoid deficit, 36.2% for hypothyroidism and 34.3% for male hypogonadism. In fertile women, hypogonadism was uncommon, while 65.4% of women developed ovarian cysts. Although no significant change in low-density lipoprotein (LDL) was observed, statins were started in 50% of patients for a significant increase in total cholesterol and triglycerides. Dyslipidemia occurred early, after a median time of 6 months from mitotane start. Conversely, testosterone replacement was usually started after >2 years. In many cases, ranging from 29.4% to 50% according to the side effect, toxicity occurred well before the achievement of the target mitotane concentrations. Supportive therapies were able to revert the biochemical alterations induced by mitotane, although higher doses were needed for a likely pharmacokinetic interaction of exogenous steroids and statins with mitotane. In conclusion, adjuvant mitotane therapy is associated with a spectrum of unwanted effects encompassing the function of different endocrine glands and requires a careful clinical and biochemical assessment associated with the therapeutic drug monitoring.
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Ardolino L, Hansen A, Ackland S, Joshua A. Advanced Adrenocortical Carcinoma (ACC): a Review with Focus on Second-Line Therapies. HORMONES & CANCER 2020; 11:155-169. [PMID: 32303972 PMCID: PMC10355245 DOI: 10.1007/s12672-020-00385-3] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/28/2020] [Accepted: 04/01/2020] [Indexed: 02/07/2023]
Abstract
Advanced adrenocortical cancer (ACC) is a rare, highly aggressive malignancy, which typically has a poor prognosis. In advanced ACC, the overall trend is toward a short PFS interval following first-line systemic therapy, highlighting a clear need for improved second-/third-line treatment strategies. We conducted a review of the literature and relevant scientific guidelines related to systemic therapy for advanced ACC. Public indexes including PubMed/MEDLINE were searched. Treatment selection in the second-line setting is based on small phase 2 trials, case reports, and pre-clinical evidence. The best data available for initial second-line therapy selection supports the use of gemcitabine and capecitabine (G + C) or streptozotocin (S), both with or without mitotane. G + C is becoming increasingly recommended based on phase 2 clinical trial data in patients of good PS, due to the inferred superior PFS and OS from non-comparative trials. Alternatively, streptozotocin was better tolerated than EDP + M in the FIRM-ACT study and remains an option when warranted. Beyond this, further treatment approaches should be tailored to individual patient characteristics, utilizing a mixture of systemic therapies, local therapies, and enrolment in clinical trials where available. Additionally, the role of molecular stratification, predictive biomarkers, and immune checkpoint inhibitors in specific individuals, such as Lynch syndrome, is evolving and may become increasingly utilized in clinical practice. Advanced ACC necessitates a multidisciplinary approach and is best managed in a specialist center. Although there is no one definitive second-line treatment strategy, there are some favorable approaches, which require further validation in larger clinical trials.
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Affiliation(s)
- Luke Ardolino
- The Kinghorn Cancer Centre, St. Vincent's Hospital, Sydney, NSW, Australia.
| | - Aaron Hansen
- Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
| | - Stephen Ackland
- Calvary Mater Newcastle Hospital, University of Newcastle, Newcastle, NSW, Australia
| | - Anthony Joshua
- The Kinghorn Cancer Centre, St. Vincent's Hospital, Sydney, NSW, Australia
- St. Vincent's Clinical School, UNSW, Sydney, NSW, Australia
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Trêpa M, Silveira I, Amaral C, Luz A. Innovative approach to a functional mediastinal paraganglioma with anomalous coronary supply: a case report. Eur Heart J Case Rep 2020; 4:1-6. [PMID: 32617509 PMCID: PMC7319854 DOI: 10.1093/ehjcr/ytaa062] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2019] [Revised: 09/17/2019] [Accepted: 03/05/2020] [Indexed: 11/23/2022]
Abstract
Background Mediastinal paragangliomas (PGs) are rare and particularly challenging neuroendocrine tumours. Clinical presentation is heterogeneous and tumour resection can be challenging due to bleeding and the risk of catecholamine surges in functional tumours. Case Summary A 36-year-old man with multiple cardiovascular risk factors was admitted with subacute heart failure. Investigations revealed a large non-metastatic functional mediastinal PG irrigated mainly by a left circumflex coronary anomalous feeder branch. The surgical risk was deemed very high due to patient comorbidities, tumour vascularization, and close relation to major thoracic structures. A multidisciplinary team decided to perform embolization of the anomalous coronary branch followed by peptide-receptor radionuclide therapy with 177-LuDOTATE aiming to decrease tumour size and perioperative risk. Follow-up studies showed a reduction in tumour vascularization, size, and hormonal production. Discussion The innovative strategy of combining embolization of the anomalous feeder branch with radionuclide therapy proved to be a promising approach.
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Affiliation(s)
- Maria Trêpa
- Cardiology Unit, Centro Hospitalar Universitário do Porto, Largo do Prof. Abel Salazar, 4099-001 Porto, Portugal
| | - Inês Silveira
- Cardiology Unit, Centro Hospitalar Universitário do Porto, Largo do Prof. Abel Salazar, 4099-001 Porto, Portugal
| | - Cláudia Amaral
- Cardiology Unit, Centro Hospitalar Universitário do Porto, Largo do Prof. Abel Salazar, 4099-001 Porto, Portugal
| | - André Luz
- Cardiology Unit, Centro Hospitalar Universitário do Porto, Largo do Prof. Abel Salazar, 4099-001 Porto, Portugal
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Lim JS, Lee SE, Kim JH, Kim JH, The Korean Adrenal Gland and Endocrine Hypertension Study Group, Korean Endocrine Society. Characteristics of adrenocortical carcinoma in South Korea: a registry-based nationwide survey. Endocr Connect 2020; 9:519-529. [PMID: 32438344 PMCID: PMC7354716 DOI: 10.1530/ec-20-0196] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2020] [Accepted: 05/18/2020] [Indexed: 01/09/2023]
Abstract
PURPOSE To evaluate the clinical characteristics and prognostic factors in patients with adrenocortical carcinoma (ACC) in South Korea. METHODS A nationwide, registry-based survey was conducted to identify pathologically proven ACC at 25 tertiary care centers in South Korea between 2000 and 2014. Cox proportional hazard model and log-rank test were adopted for survival analysis. RESULTS Two hundred four patients with ACC were identified, with a median follow-up duration of 20 months (IQR 5-52 months). The median age at diagnosis was 51.5 years (IQR 40-65.8 years), and ACC was prevalent in women (n = 110, 53.9%). Abdominal pain was the most common clinical symptom (n = 70, 40.2%), and ENSAT stage 2 was most common (n = 62, 30.4%) at the time of diagnosis. One hundred sixty-nine patients underwent operation, while 17 were treated with other modalities. The remission rate was 48%, and median recurrence-free survival time was 46 months. Estimated 5-year recurrence-free rate was 44.7%. There were more women, large tumor, atypical mitosis, venous invasion, and higher mitotic count in cancer recurrence group. Estimated 5-year overall survival and disease-specific survival rates were 64.5 and 70.6%, respectively. Higher ENSAT stage and advanced pathologic characteristics were risk factors for all-cause mortality of ACC. Large tumor size and cortisol-secreting tumor were additional risk factors for ACC-specific death. CONCLUSIONS We report the first epidemiologic study regarding ACC in an Asian population. ENSAT stage 4; lymph node involvement; non-operative group; and invasion of vein, sinusoid, or capsule were associated with an increased risk for all-cause mortality.
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Affiliation(s)
- Jung Soo Lim
- Department of Internal Medicine, Institute of Evidence-Based Medicine, Wonju Severance Christian Hospital, Yonsei University Wonju College of Medicine, Wonju, Gangwon-do, South Korea
| | - Seung-Eun Lee
- Department of Internal Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Gangnam-gu, Seoul, South Korea
| | - Jung Hee Kim
- Department of Internal Medicine, Seoul National University College of Medicine, Jongno-gu, Seoul, South Korea
- Correspondence should be addressed to J H Kim or J H Kim: or
| | - Jae Hyeon Kim
- Department of Internal Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Gangnam-gu, Seoul, South Korea
- Correspondence should be addressed to J H Kim or J H Kim: or
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Souteiro P, Donato S, Costa C, Pereira CA, Simões-Pereira J, Oliveira J, Belo S, Santos AP, Cardoso H, Leite V, Carvalho D, Torres I. Diagnosis, treatment, and survival analysis of adrenocortical carcinomas: a multicentric study. Hormones (Athens) 2020; 19:197-203. [PMID: 31823340 DOI: 10.1007/s42000-019-00161-1] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2019] [Accepted: 11/14/2019] [Indexed: 10/25/2022]
Abstract
INTRODUCTION Current guidelines specify controversial areas in adrenocortical carcinomas (ACC), such as optimal follow-up time after remission and identification of prognostic markers. We aim to address these topics by analyzing four reference centers in our country. METHODS Cross-sectional multicentric study of 69 patients (mean age: 51.7 ± 16.7 years-old; women, 72.5%). Kaplan-Meier survival curves and Cox regression analysis were used to calculate overall survival and its predictors. RESULTS Thirty-eight individuals (55.0%) had hormonal autonomous production, and 40.6% of the patients presented with metastasis. Surgery was performed in 84.1% of them. Most of these patients (72.4%) were then assigned to adjuvant therapy, while 27.6% were actively surveilled. Among patients undergoing surgery, those who achieved transient remission presented a longer survival time (66 months) than those who never reached the disease-free status (21 months) (p = 0.021). One patient presented with recurrence more than 7 years after complete tumor resection. The lowest overall survival was observed in patients (n = 11) assigned to palliative care since diagnosis (9 months). Tumor stage was identified as the only independent predictor of survival in our cohort (p = 0.006). Five-year survival was 67% for tumors confined to the adrenal space (stage I/II), 56% for locally advanced disease (stage III), and 0% for metastatic disease (stage IV). CONCLUSION This study reinforces the dismal prognosis of ACC, the need for long-term follow-up, and tumor stage as the most important survival predictor. Reviewing medical records in such rare conditions is an opportunity to identify insufficiencies and to improve medical care.
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Affiliation(s)
- Pedro Souteiro
- Department of Endocrinology, Diabetes and Metabolism, Centro Hospitalar Universitário de São João, Porto, Portugal.
- Faculty of Medicine, Universidade do Porto, Porto, Portugal.
- Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal.
| | - Sara Donato
- Department of Endocrinology, Instituto Português de Oncologia de Lisboa Francisco Gentil, Lisbon, Portugal
| | - Cláudia Costa
- Department of Endocrinology, Instituto Português de Oncologia do Porto Francisco Gentil, Porto, Portugal
| | - Catarina A Pereira
- Department of Endocrinology, Centro Hospitalar Universitário do Porto, Porto, Portugal
| | - Joana Simões-Pereira
- Department of Endocrinology, Instituto Português de Oncologia de Lisboa Francisco Gentil, Lisbon, Portugal
- NOVA Medical School, Faculdade de Ciências Médicas, Universidade Nova de Lisboa, Lisbon, Portugal
- Unidade de Investigação em Patobiologia Molecular (UIPM), Instituto Português de Oncologia de Lisboa Francisco Gentil, Lisbon, Portugal
| | - Joana Oliveira
- Department of Endocrinology, Instituto Português de Oncologia do Porto Francisco Gentil, Porto, Portugal
| | - Sandra Belo
- Department of Endocrinology, Diabetes and Metabolism, Centro Hospitalar Universitário de São João, Porto, Portugal
| | - Ana Paula Santos
- Department of Endocrinology, Instituto Português de Oncologia do Porto Francisco Gentil, Porto, Portugal
| | - Helena Cardoso
- Department of Endocrinology, Centro Hospitalar Universitário do Porto, Porto, Portugal
| | - Valeriano Leite
- Department of Endocrinology, Instituto Português de Oncologia de Lisboa Francisco Gentil, Lisbon, Portugal
- NOVA Medical School, Faculdade de Ciências Médicas, Universidade Nova de Lisboa, Lisbon, Portugal
- Unidade de Investigação em Patobiologia Molecular (UIPM), Instituto Português de Oncologia de Lisboa Francisco Gentil, Lisbon, Portugal
| | - Davide Carvalho
- Department of Endocrinology, Diabetes and Metabolism, Centro Hospitalar Universitário de São João, Porto, Portugal
- Faculty of Medicine, Universidade do Porto, Porto, Portugal
- Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal
| | - Isabel Torres
- Department of Endocrinology, Instituto Português de Oncologia do Porto Francisco Gentil, Porto, Portugal
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A computational drug repositioning method applied to rare diseases: Adrenocortical carcinoma. Sci Rep 2020; 10:8846. [PMID: 32483162 PMCID: PMC7264316 DOI: 10.1038/s41598-020-65658-x] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2019] [Accepted: 05/08/2020] [Indexed: 01/12/2023] Open
Abstract
Rare or orphan diseases affect only small populations, thereby limiting the economic incentive for the drug development process, often resulting in a lack of progress towards treatment. Drug repositioning is a promising approach in these cases, due to its low cost. In this approach, one attempts to identify new purposes for existing drugs that have already been developed and approved for use. By applying the process of drug repositioning to identify novel treatments for rare diseases, we can overcome the lack of economic incentives and make concrete progress towards new therapies. Adrenocortical Carcinoma (ACC) is a rare disease with no practical and definitive therapeutic approach. We apply Heter-LP, a new method of drug repositioning, to suggest novel therapeutic avenues for ACC. Our analysis identifies innovative putative drug-disease, drug-target, and disease-target relationships for ACC, which include Cosyntropin (drug) and DHCR7, IGF1R, MC1R, MAP3K3, TOP2A (protein targets). When results are analyzed using all available information, a number of novel predicted associations related to ACC appear to be valid according to current knowledge. We expect the predicted relations will be useful for drug repositioning in ACC since the resulting ranked lists of drugs and protein targets can be used to expedite the necessary clinical processes.
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