|
1
|
Zahedi K, Morgan M, Prieto B, Brooks M, Howard TA, Barone S, Bissler JJ, Argyropoulos C, Soleimani M. Role of Extracellular Vesicles in TSC Renal Cystogenesis. Int J Mol Sci 2025; 26:3154. [PMID: 40243914 PMCID: PMC11989098 DOI: 10.3390/ijms26073154] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2025] [Revised: 03/17/2025] [Accepted: 03/26/2025] [Indexed: 04/18/2025] Open
Abstract
Tuberous sclerosis complex (TSC) is caused by mutations in TSC1 or TSC2 genes and affects multiple organs. TSC proteins control cell growth by regulating the activity of the mechanistic target of rapamycin complex 1. Extracellular vesicles (EVs) are membrane-bound particles produced by cells that mediate cellular communication, function, and growth. Although extensive studies regarding the genetic basis of TSC exist, the exact mechanism contributing to its pathogenesis remains unresolved. It has been proposed that EVs generated by renal cyst epithelia of mice and cells with Tsc gene mutations contain factors that alter the function and proliferation of TSC-sufficient cells. To test this, EVs from the kidneys and kidney explants of wildtype and Tsc1KO mice were isolated and characterized by Western blotting, transmission electron microscopy, dynamic light scattering, and fluorescent nanoparticle tracking. Our results show an enrichment in EV-associated markers and particle sizes of similar ranges. RNA-seq and proteomic analyses identified EV shuttle factors. EV RNA and protein shuttle factors showed significant differences. Furthermore, EVs isolated from Tsc1KO mice inhibited the proliferation of M-1 cells. Understanding the role of EVs in cell proliferation and cystogenesis in TSC may lead to the development of new approaches for the treatment of this disease.
Collapse
Affiliation(s)
- Kamyar Zahedi
- Division of Nephrology, Department of Internal Medicine, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA; (M.M.); (B.P.); (M.B.); (T.A.H.); (S.B.); (C.A.)
- Research Services, Raymond J. Murphy Veterans Health Care Center, Albuquerque, NM 87108, USA
| | - Mackenzie Morgan
- Division of Nephrology, Department of Internal Medicine, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA; (M.M.); (B.P.); (M.B.); (T.A.H.); (S.B.); (C.A.)
| | - Brenda Prieto
- Division of Nephrology, Department of Internal Medicine, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA; (M.M.); (B.P.); (M.B.); (T.A.H.); (S.B.); (C.A.)
| | - Marybeth Brooks
- Division of Nephrology, Department of Internal Medicine, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA; (M.M.); (B.P.); (M.B.); (T.A.H.); (S.B.); (C.A.)
- Research Services, Raymond J. Murphy Veterans Health Care Center, Albuquerque, NM 87108, USA
| | - Tamara A. Howard
- Division of Nephrology, Department of Internal Medicine, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA; (M.M.); (B.P.); (M.B.); (T.A.H.); (S.B.); (C.A.)
| | - Sharon Barone
- Division of Nephrology, Department of Internal Medicine, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA; (M.M.); (B.P.); (M.B.); (T.A.H.); (S.B.); (C.A.)
- Research Services, Raymond J. Murphy Veterans Health Care Center, Albuquerque, NM 87108, USA
| | - John J. Bissler
- University of Tennessee Health Sciences Center, Le Bonheur Children’s Hospital, Memphis, TN 38163, USA;
- The Department of Pediatrics, St. Jude Children’s Hospital, Memphis, TN 38105, USA
| | - Christos Argyropoulos
- Division of Nephrology, Department of Internal Medicine, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA; (M.M.); (B.P.); (M.B.); (T.A.H.); (S.B.); (C.A.)
| | - Manoocher Soleimani
- Division of Nephrology, Department of Internal Medicine, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA; (M.M.); (B.P.); (M.B.); (T.A.H.); (S.B.); (C.A.)
- Research Services, Raymond J. Murphy Veterans Health Care Center, Albuquerque, NM 87108, USA
| |
Collapse
|
|
2
|
Wang S, Ma R, Gao C, Tian YN, Hu RG, Zhang H, Li L, Li Y. Unraveling the function of TSC1-TSC2 complex: implications for stem cell fate. Stem Cell Res Ther 2025; 16:38. [PMID: 39901197 PMCID: PMC11792405 DOI: 10.1186/s13287-025-04170-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2024] [Accepted: 01/23/2025] [Indexed: 02/05/2025] Open
Abstract
BACKGROUND Tuberous sclerosis complex is a genetic disorder caused by mutations in the TSC1 or TSC2 genes, affecting multiple systems. These genes produce proteins that regulate mTORC1 activity, essential for cell function and metabolism. While mTOR inhibitors have advanced treatment, maintaining long-term therapeutic success is still challenging. For over 20 years, significant progress has linked TSC1 or TSC2 gene mutations in stem cells to tuberous sclerosis complex symptoms. METHODS A comprehensive review was conducted using databases like Web of Science, Google Scholar, PubMed, and Science Direct, with search terms such as "tuberous sclerosis complex," "TSC1," "TSC2," "stem cell," "proliferation," and "differentiation." Relevant literature was thoroughly analyzed and summarized to present an updated analysis of the TSC1-TSC2 complex's role in stem cell fate determination and its implications for tuberous sclerosis complex. RESULTS The TSC1-TSC2 complex plays a crucial role in various stem cells, such as neural, germline, nephron progenitor, intestinal, hematopoietic, and mesenchymal stem/stromal cells, primarily through the mTOR signaling pathway. CONCLUSIONS This review aims shed light on the role of the TSC1-TSC2 complex in stem cell fate, its impact on health and disease, and potential new treatments for tuberous sclerosis complex.
Collapse
Affiliation(s)
- Shuang Wang
- Institute of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Ruishuang Ma
- Institute of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Chong Gao
- School of Medicine, Institute of Brain and Cognitive Science, Hangzhou City University, Hangzhou, Zhejiang, China
| | - Yu-Nong Tian
- Institute of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Rong-Gui Hu
- State Key Laboratory of Brain-Machine Intelligence, Liangzhu Laboratory, School of Medicine, Zhejiang University, Zhejiang, China.
| | - Han Zhang
- Institute of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China.
| | - Lan Li
- Institute of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China.
| | - Yue Li
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau, China.
- Department of Pharmaceutical Sciences, Faculty of Health Sciences, University of Macau, Macau, China.
| |
Collapse
|
|
3
|
Perotti D, O'Sullivan MJ, Walz AL, Davick J, Al-Saadi R, Benedetti DJ, Brzezinski J, Ciceri S, Cost NG, Dome JS, Drost J, Evageliou N, Furtwängler R, Graf N, Maschietto M, Mullen EA, Murphy AJ, Ortiz MV, van der Beek JN, Verschuur A, Wegert J, Williams R, Spreafico F, Geller JI, van den Heuvel-Eibrink MM, Hong AL. Hallmark discoveries in the biology of non-Wilms tumour childhood kidney cancers. Nat Rev Urol 2025:10.1038/s41585-024-00993-6. [PMID: 39881003 DOI: 10.1038/s41585-024-00993-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/17/2024] [Indexed: 01/31/2025]
Abstract
Approximately 20% of paediatric and adolescent/young adult patients with renal tumours are diagnosed with non-Wilms tumour, a broad heterogeneous group of tumours that includes clear-cell sarcoma of the kidney, congenital mesoblastic nephroma, malignant rhabdoid tumour of the kidney, renal-cell carcinoma, renal medullary carcinoma and other rare histologies. The differential diagnosis of these tumours dates back many decades, when these pathologies were identified initially through clinicopathological observation of entities with outcomes that diverged from Wilms tumour, corroborated with immunohistochemistry and molecular cytogenetics and, subsequently, through next-generation sequencing. These advances enabled near-definitive recognition of different tumours and risk stratification of patients. In parallel, the generation of new renal-tumour models of some of these pathologies including cell lines, organoids, xenografts and genetically engineered mouse models improved our understanding of the development of these tumours and have facilitated the identification of new therapeutic targets. Despite these many achievements, paediatric and adolescent/young adult patients continue to die from such rare cancers at higher rates than patients with Wilms tumour. Thus, international coordinated efforts are needed to answer unresolved questions and improve outcomes.
Collapse
Affiliation(s)
- Daniela Perotti
- Predictive Medicine: Molecular Bases of Genetic Risk, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy
| | - Maureen J O'Sullivan
- Histology Laboratory, Children's Health Ireland at Crumlin, Dublin, Ireland
- Histopathology, School of Medicine, Trinity College, Dublin, Ireland
- Departments of Histopathology and Paediatrics, School of Medicine, Trinity College Dublin, Dublin, Ireland
| | - Amy L Walz
- Ann & Robert H. Lurie Children's Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Jonathan Davick
- University of Iowa Hospitals and Clinics Stead Family Children's Hospital, Carver College of Medicine, Iowa City, IA, USA
| | - Reem Al-Saadi
- UCL Great Ormond Street Institute of Child Health, University College London, London, UK
| | - Daniel J Benedetti
- Division of Pediatric Hematology/Oncology, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Jack Brzezinski
- Division of Haematology/Oncology, Hospital for Sick Children, Toronto, Ontario, Canada
- Department of Paediatrics, University of Toronto, Toronto, Ontario, Canada
| | - Sara Ciceri
- Predictive Medicine: Molecular Bases of Genetic Risk, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy
| | - Nicholas G Cost
- Department of Surgery, Division of Urology, University of Colorado School of Medicine and the Surgical Oncology Program at Children's Hospital Colorado, Denver, CO, USA
| | - Jeffrey S Dome
- Division of Oncology, Center for Cancer and Blood Disorders, Children's National Hospital, Washington, DC, USA
- Department of Pediatrics, George Washington University School of Medicine and Health Sciences, Washington, DC, USA
| | - Jarno Drost
- Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands
- Oncode Institute, Utrecht, the Netherlands
| | | | - Rhoikos Furtwängler
- Pediatric Hematology and Oncology, Children's Hospital, Inselspital Bern University, Bern, Switzerland
- Childhood Renal Tumour Center Saarland University, Homburg, Germany
| | - Norbert Graf
- Department Paediatric Oncology & Hematology, Saarland University, Homburg, Germany
| | | | - Elizabeth A Mullen
- Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, MA, USA
| | - Andrew J Murphy
- St. Jude Children's Research Hospital Memphis, Memphis, TN, USA
| | | | - Justine N van der Beek
- Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands
- University Medical Center Utrecht, Utrecht, the Netherlands
| | - Arnauld Verschuur
- Department of Pediatric Hematology and Oncology, Hôpital d'Enfants de la Timone, APHM, Marseille, France
| | - Jenny Wegert
- Theodor-Boveri-Institute/Biocenter, Developmental Biochemistry, Wuerzburg University, Wuerzburg, Germany
| | - Richard Williams
- Developmental Biology and Cancer Research and Teaching Department, UCL Great Ormond Street Institute of Child Health, University College London, London, UK
- Section of Genetics and Genomics, Faculty of Medicine, Imperial College London, London, UK
| | - Filippo Spreafico
- Paediatric Oncology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy
| | - James I Geller
- Division of Oncology, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, OH, USA
| | | | - Andrew L Hong
- Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA.
- Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, Atlanta, GA, USA.
| |
Collapse
|
|
4
|
Zhao N, Xiong Q, Li P, Chen G, Xiao H, Wu C. TSC complex decrease the expression of mTOR by regulated miR-199b-3p. Sci Rep 2025; 15:1892. [PMID: 39806027 PMCID: PMC11730325 DOI: 10.1038/s41598-025-85706-8] [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] [Received: 07/31/2024] [Accepted: 01/06/2025] [Indexed: 01/16/2025] Open
Abstract
The TSC complex formed by TSC1 and TSC2 is the most important upstream negative regulator of mTORC1. Genetic variations in either TSC1 or TSC2 cause tuberous sclerosis complex (TSC) disease which is a rare autosomal dominant disorder resulting in impairment of multiple organ systems. In this study, besides a reported variation, c.2509_2512del (p.Asn837Valfs*11, p.N837fs) in TSC1, we found a de novo TSC2 variation c.1113delG (p.Gln371Hisfs*18, p.Q371fs), which these two mutation influence the formation of TSC complex. We found that the decrease of TSC complex with the appearance of the decreased miR-199b-3p expression. At the same time, the reduction of miR-199b-3p increased the expression of mTOR and the activation of mTORC1 and mTORC2, the additional miR-199b-3p caused the decrease the expression of mTOR and the activation of mTORC1 and mTORC2. In brief, our results may illustrate a novel mechanism of TSC caused by variations in either TSC1 or TSC2, and a new mTOR expression regulator, miR-199b-3p.
Collapse
Affiliation(s)
- Na Zhao
- Key Laboratory of Chemical Biology and Molecular Engineering of National Ministry of Education, Institutes of Biomedical Sciences, Shanxi University, Taiyuan, 030006, China
- Department of Pathology, The Second Hospital of ShanXi Medical University, No.382 WuYi Road, Tai Yuan, ShanXi, Taiyuan, 030000, China
| | - Qiuhong Xiong
- Key Laboratory of Chemical Biology and Molecular Engineering of National Ministry of Education, Institutes of Biomedical Sciences, Shanxi University, Taiyuan, 030006, China
| | - Ping Li
- Key Laboratory of Chemical Biology and Molecular Engineering of National Ministry of Education, Institutes of Biomedical Sciences, Shanxi University, Taiyuan, 030006, China
| | - Guangxin Chen
- Key Laboratory of Chemical Biology and Molecular Engineering of National Ministry of Education, Institutes of Biomedical Sciences, Shanxi University, Taiyuan, 030006, China
| | - Han Xiao
- Key Laboratory of Chemical Biology and Molecular Engineering of National Ministry of Education, Institutes of Biomedical Sciences, Shanxi University, Taiyuan, 030006, China.
| | - Changxin Wu
- Key Laboratory of Chemical Biology and Molecular Engineering of National Ministry of Education, Institutes of Biomedical Sciences, Shanxi University, Taiyuan, 030006, China.
| |
Collapse
|
|
5
|
Akbari A, Villanueva CR, Hes O, Williamson SR, Kandukuri S, Sharma S, Aditi A, Pivovarcikova K, Argani P, Mohanty SK, Asrani K, Lotan TL. Genetic validation of a TSC2 immunohistochemistry assay in TSC/mTOR-pathway altered renal tumors. Hum Pathol 2024; 154:105693. [PMID: 39571694 DOI: 10.1016/j.humpath.2024.105693] [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: 08/18/2024] [Revised: 11/08/2024] [Accepted: 11/18/2024] [Indexed: 11/25/2024]
Abstract
Pathogenic mutations in the genes associated with tuberous sclerosis complex (TSC)/mTOR pathway are linked to histologically diverse renal cell neoplasms, including eosinophilic solid and cystic renal cell carcinoma (ESC RCC), low grade oncocytic tumor (LOT), eosinophilic vacuolated tumor (EVT), and xanthomatous giant cell renal cell carcinoma (XGC RCC). Here, we validate a TSC2 immunohistochemistry (IHC) assay by comparison to genomic data in these neoplasms. Automated TSC2 IHC was performed on formalin-fixed paraffin embedded (FFPE) tissues from 38 genetically-confirmed TSC/mTOR-associated renal tumors (6 ESCs, 16 EVTs, 13 LOTs, 2 XGC and 1 clear cell RCC) and visually scored in a semi-dichotomous fashion compared to internal control tissue. The positive predictive value (PPV) of TSC2 protein loss for underlying pathogenic mutation in TSC2 was 92% (11/12), while the negative predictive value (NPV) of intact TSC2 by IHC for lack of underlying pathogenic mutation in TSC2 was 81% (21/26). Intact TSC2 by IHC was 95% (21/22) specific for absence of underlying pathogenic TSC2 mutation. All the cases lacking TSC2 mutation with intact TSC2 protein had an underlying mutation in TSC1, MTOR or PIK3CA. Loss of TSC2 was 77% (10/13) sensitive for underlying TSC2 truncation mutations and 33% (1/3) sensitive for underlying TSC2 missense mutations. Overall, 73% (8/11) tumors with TSC2 IHC loss and underlying pathogenic alterations in TSC2 showed heterogeneous protein loss, with rare interspersed positively staining tumor cells. These data support TSC2 IHC as a potentially useful assay for the diagnostic workup of renal tumors suspected to belong to the TSC/mTOR-associated subgroups.
Collapse
Affiliation(s)
- Amir Akbari
- Department of Pathology, Johns Hopkins School of Medicine, USA; Department of Pathology, University of Southern California Keck School of Medicine, USA.
| | | | - Ondrej Hes
- Department of Pathology, Faculty of Medicine in Pilsen, Charles University, Pilsen, Czech Republic
| | | | - Shivani Kandukuri
- Department of Pathology, University of Southern California Keck School of Medicine, USA
| | | | | | - Kristyna Pivovarcikova
- Department of Pathology, Faculty of Medicine in Pilsen, Charles University, Pilsen, Czech Republic
| | - Pedram Argani
- Department of Pathology, Johns Hopkins School of Medicine, USA
| | - Sambit K Mohanty
- Department of Pathology and Laboratory Medicine, Advanced Medical Research Institute, Bhubaneswar, OR, India
| | - Kaushal Asrani
- Department of Pathology, Johns Hopkins School of Medicine, USA.
| | - Tamara L Lotan
- Department of Pathology, Johns Hopkins School of Medicine, USA; Department of Urology, Johns Hopkins School of Medicine, USA; Department of Oncology, Johns Hopkins School of Medicine, USA.
| |
Collapse
|
|
6
|
Alesi N, Asrani K, Lotan TL, Henske EP. The Spectrum of Renal "TFEopathies": Flipping the mTOR Switch in Renal Tumorigenesis. Physiology (Bethesda) 2024; 39:0. [PMID: 39012319 DOI: 10.1152/physiol.00026.2024] [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: 05/17/2024] [Revised: 07/11/2024] [Accepted: 07/11/2024] [Indexed: 07/17/2024] Open
Abstract
The mammalian target of Rapamycin complex 1 (mTORC1) is a serine/threonine kinase that couples nutrient and growth factor signaling to the cellular control of metabolism and plays a fundamental role in aberrant proliferation in cancer. mTORC1 has previously been considered an "on/off" switch, capable of phosphorylating the entire pool of its substrates when activated. However, recent studies have indicated that mTORC1 may be active toward its canonical substrates, eukaryotic translation initiation factor 4E-binding protein 1 (4EBP1) and S6 kinase (S6K), involved in mRNA translation and protein synthesis, and inactive toward TFEB and TFE3, transcription factors involved in the regulation of lysosome biogenesis, in several pathological contexts. Among these conditions are Birt-Hogg-Dubé syndrome (BHD) and, recently, tuberous sclerosis complex (TSC). Furthermore, increased TFEB and TFE3 nuclear localization in these syndromes, and in translocation renal cell carcinomas (tRCC), drives mTORC1 activity toward the canonical substrates, through the transcriptional activation of the Rag GTPases, thereby positioning TFEB and TFE3 upstream of mTORC1 activity toward 4EBP1 and S6K. The expanding importance of TFEB and TFE3 in the pathogenesis of these renal diseases warrants a novel clinical grouping that we term "TFEopathies." Currently, there are no therapeutic options directly targeting TFEB and TFE3, which represents a challenging and critically required avenue for cancer research.
Collapse
Affiliation(s)
- Nicola Alesi
- Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States
| | - Kaushal Asrani
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States
| | - Tamara L Lotan
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States
| | - Elizabeth P Henske
- Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States
| |
Collapse
|
|
7
|
Jones VM, Thompson LDR, Pettus JR, Green DC, Lefferts JA, Shah PS, Tsongalis GJ, Sajed DP, Guilmette JM, Lewis JS, Fisch AS, Tafe LJ, Kerr DA. Angiomyolipomatous Lesions of the Nasal Cavity (Sinonasal Angioleiomyoma with Adipocytic Differentiation): A Multi-Institutional Immunohistochemical and Molecular Study. Head Neck Pathol 2024; 18:93. [PMID: 39400771 PMCID: PMC11473525 DOI: 10.1007/s12105-024-01700-y] [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: 08/01/2024] [Accepted: 08/31/2024] [Indexed: 10/15/2024]
Abstract
PURPOSE Mesenchymal neoplasms composed of vascular, smooth muscle, and adipocytic components are uncommon in the nasal cavity. While angioleiomyoma (AL) is a smooth muscle tumor in the Head & Neck WHO classification, it is considered of pericytic origin in the Skin as well as Soft Tissue and Bone classifications. For nasal AL with an adipocytic component, the terms AL with adipocytic differentiation and angiomyolipoma (AML) have been applied, among others. AML is a type of perivascular epithelioid cell tumor (PEComa), most often arising in the kidney, sometimes associated with the tuberous sclerosis complex (TSC). It is uncertain whether nasal cavity AML and AL are best considered hamartomas or neoplasms, as their genetics are largely unexplored. METHODS We performed a multi-institutional retrospective study of nasal cavity mesenchymal lesions. Patient demographics, clinical histories, and histologic and immunohistochemical findings were collected. DNA and RNA were extracted from formalin-fixed, paraffin-embedded tissue and analyzed by SNP-based chromosomal microarray, targeted RNA fusion sequencing, and whole-exome sequencing. RESULTS Fifteen lesions (3-42 mm) were identified, predominantly in male (87%) patients with a median age of 60. Patients typically presented with obstructive symptoms, and none had a history of TSC. One AL was a recurrence from six years prior; 11 cases showed no recurrence (median 4.7 years, range: 0.88-12.4). Morphologically, 11 AML contained 30-80% smooth muscle, 10-25% vasculature, and 2-60% adipose tissue, while four AL contained 70-80% smooth muscle and 20-30% vasculature. Other histologic observations included ulceration, thrombosis, inflammation, myxoid change, senescent nuclei, and extramedullary hematopoiesis; no well-developed epithelioid cell morphology was identified. Immunohistochemically, all cases were positive for smooth muscle markers (actin, desmin, and/or caldesmon) and negative for melanocytic markers. Molecular analysis revealed loss of 3p and 11q in a single AML. No other known pathogenic copy number or molecular alterations were seen, including in TSC1/2, TFE3, or NOTCH2. CONCLUSION Nasal cavity AML lacks morphologic, immunophenotypic, and genetic features of PEComa family AML. The significant histologic overlap between nasal AML and AL without distinguishing molecular features in either entity suggests "sinonasal angioleiomyoma with adipocytic differentiation" may be the most appropriate terminology for hybrid vascular and smooth muscle lesions containing adipocytic components.
Collapse
Affiliation(s)
- Victoria M Jones
- Department of Pathology and Laboratory Medicine, Dartmouth Hitchcock Medical Center, Lebanon, NH, USA
- Geisel School of Medicine at Dartmouth, Hanover, NH, USA
| | | | - Jason R Pettus
- Department of Pathology and Laboratory Medicine, Dartmouth Hitchcock Medical Center, Lebanon, NH, USA
- Geisel School of Medicine at Dartmouth, Hanover, NH, USA
| | - Donald C Green
- Department of Pathology and Laboratory Medicine, Dartmouth Hitchcock Medical Center, Lebanon, NH, USA
| | - Joel A Lefferts
- Department of Pathology and Laboratory Medicine, Dartmouth Hitchcock Medical Center, Lebanon, NH, USA
- Geisel School of Medicine at Dartmouth, Hanover, NH, USA
| | - Parth S Shah
- Department of Pathology and Laboratory Medicine, Dartmouth Hitchcock Medical Center, Lebanon, NH, USA
- Geisel School of Medicine at Dartmouth, Hanover, NH, USA
| | - Gregory J Tsongalis
- Department of Pathology and Laboratory Medicine, Dartmouth Hitchcock Medical Center, Lebanon, NH, USA
- Geisel School of Medicine at Dartmouth, Hanover, NH, USA
| | - Dipti P Sajed
- Department of Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, CA, USA
| | - Julie M Guilmette
- Department of Pathology, Hôpital Charles-Lemoyne, Faculty of Medicine and Health Sciences, University of Sherbrooke, Greenfield Park, QC, Canada
| | - James S Lewis
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA
- Department of Laboratory Medicine and Pathology, Mayo Clinic Arizona, Scottsdale, AZ, USA
| | - Adam S Fisch
- Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Laura J Tafe
- Department of Pathology and Laboratory Medicine, Dartmouth Hitchcock Medical Center, Lebanon, NH, USA
- Geisel School of Medicine at Dartmouth, Hanover, NH, USA
| | - Darcy A Kerr
- Department of Pathology and Laboratory Medicine, Dartmouth Hitchcock Medical Center, Lebanon, NH, USA.
- Geisel School of Medicine at Dartmouth, Hanover, NH, USA.
| |
Collapse
|
|
8
|
Jones VM, Thompson LDR, Pettus JR, Green DC, Lefferts JA, Shah PS, Tsongalis GJ, Sajed DP, Guilmette JM, Lewis JS, Fisch AS, Tafe LJ, Kerr DA. Angiomyolipomatous Lesions of the Nasal Cavity (Sinonasal Angioleiomyoma with Adipocytic Differentiation): A Multi-Institutional Immunohistochemical and Molecular Study. RESEARCH SQUARE 2024:rs.3.rs-4843357. [PMID: 39281855 PMCID: PMC11398573 DOI: 10.21203/rs.3.rs-4843357/v1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/18/2024]
Abstract
Purpose Mesenchymal neoplasms composed of vascular, smooth muscle, and adipocytic components are uncommon in the nasal cavity. While angioleiomyoma (AL) is a smooth muscle tumor in the Head & Neck WHO classification, it is considered of pericytic origin in the Skin as well as Soft Tissue and Bone classifications. For nasal AL with an adipocytic component, the terms AL with adipocytic differentiation and angiomyolipoma (AML) have been applied, among others. AML is a type of perivascular epithelioid cell tumor (PEComa), most often arising in the kidney, sometimes associated with the tuberous sclerosis complex (TSC). It is uncertain whether nasal cavity AML and AL are best considered hamartomas or neoplasms, as their genetics are largely unexplored. Methods We performed a multi-institutional retrospective study of nasal cavity mesenchymal lesions. Patient demographics, clinical histories, and histologic and immunohistochemical findings were collected. DNA and RNA were extracted from formalin-fixed, paraffin-embedded tissue and analyzed by SNP-based chromosomal microarray, targeted RNA fusion sequencing, and whole-exome sequencing. Results Fifteen lesions (3 to 42 mm) were identified predominantly in male (87%) patients with a median age of 60. Patients typically presented with obstructive symptoms, and none had a history of TSC. One AL was a recurrence from six years prior; 11 cases showed no recurrence (median 4.7 years, range: 0.88-12.4). Morphologically, 11 AMLs contained 30-80% smooth muscle, 10-25% vasculature, and 2-60% adipose tissue, while four ALs contained 70-80% smooth muscle and 20-30% vasculature. Other histologic observations included surface ulceration, vascular thrombosis, chronic inflammation, and myxoid change; no well-developed epithelioid cell morphology was identified. Immunohistochemically, all cases were positive for smooth muscle markers (actin and/or desmin) and negative for melanocytic markers. Molecular analysis revealed loss of 3p and 11q in a single AML. No other known pathogenic copy number or molecular alterations were seen, including in TSC1/2, TFE3, or NOTCH2. Conclusion Nasal cavity AML lacks morphologic, immunophenotypic, and genetic features of PEComa family AMLs. The significant histologic overlap between nasal AML and AL without distinguishing molecular features in either entity suggests "sinonasal angioleiomyoma with adipocytic differentiation" may be the most appropriate terminology for hybrid vascular and smooth muscle lesions containing adipocytic components.
Collapse
Affiliation(s)
| | | | | | | | | | | | | | | | | | | | - Adam S Fisch
- Massachusetts General Hospital, Harvard Medical School
| | | | | |
Collapse
|
|
9
|
Monich AG, Bissler JJ, Barreto FC. Tuberous Sclerosis Complex and the kidneys: what nephrologists need to know. J Bras Nefrol 2024; 46:e20240013. [PMID: 38991206 PMCID: PMC11239183 DOI: 10.1590/2175-8239-jbn-2024-0013en] [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: 01/18/2024] [Accepted: 04/24/2024] [Indexed: 07/13/2024] Open
Abstract
Tuberous sclerosis complex (TSC) is an autosomal dominant disease characterized by the development of hamartomas in the central nervous system, heart, skin, lungs, and kidneys and other manifestations including seizures, cortical tubers, radial migration lines, autism and cognitive disability. The disease is associated with pathogenic variants in the TSC1 or TSC2 genes, resulting in the hyperactivation of the mTOR pathway, a key regulator of cell growth and metabolism. Consequently, the hyperactivation of the mTOR pathway leads to abnormal tissue proliferation and the development of solid tumors. Kidney involvement in TSC is characterized by the development of cystic lesions, renal cell carcinoma and renal angiomyolipomas, which may progress and cause pain, bleeding, and loss of kidney function. Over the past years, there has been a notable shift in the therapeutic approach to TSC, particularly in addressing renal manifestations. mTOR inhibitors have emerged as the primary therapeutic option, whereas surgical interventions like nephrectomy and embolization being reserved primarily for complications unresponsive to clinical treatment, such as severe renal hemorrhage. This review focuses on the main clinical characteristics of TSC, the mechanisms underlying kidney involvement, the recent advances in therapy for kidney lesions, and the future perspectives.
Collapse
Affiliation(s)
- Aline Grosskopf Monich
- Universidade Federal do Paraná, Departamento de Clínica Médica, Programa de Pós-Graduação em Medicina Interna e Ciências da Saúde, Curitiba, PR, Brazil
- Hospital Universitário Evangélico Mackenzie, Serviço de Nefrologia, Curitiba, PR, Brazil
| | - John J. Bissler
- University of Tennessee, Health Science Center, Le Bonheur Children's Hospital, Department of Pediatrics, Memphis, TN, USA
- Le Bonheur Children's Hospital, Children's Foundation Research Institute, Memphis, TN, USA
- St. Jude Children’s Research Hospital, Pediatric Medicine Department, Memphis, TN, USA
| | - Fellype Carvalho Barreto
- Universidade Federal do Paraná, Departamento de Clínica Médica, Programa de Pós-Graduação em Medicina Interna e Ciências da Saúde, Curitiba, PR, Brazil
- Universidade Federal do Paraná, Departamento de Clínica Médica, Serviço de Nefrologia, Curitiba, PR, Brazil
| |
Collapse
|
|
10
|
Yan S, Lu JJ, Chen L, Cai WH, Wu JZ. Hepatic perivascular epithelioid cell tumors: The importance of preoperative diagnosis. World J Gastroenterol 2024; 30:1926-1933. [PMID: 38659487 PMCID: PMC11036502 DOI: 10.3748/wjg.v30.i13.1926] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/22/2024] [Revised: 03/17/2024] [Accepted: 03/19/2024] [Indexed: 04/03/2024] Open
Abstract
Accurate preoperative diagnosis is highly important for the treatment of perivascular epithelioid cell tumors (PEComas) because PEComas are mainly benign tumors and may not require surgical intervention. By analyzing the causes, properties and clinical manifestations of PEComas, we summarize the challenges and solutions in the diagnosis of PEComas.
Collapse
Affiliation(s)
- Shuai Yan
- Department of Medical School, Nantong University, Nantong 226300, Jiangsu Province, China
- Department of Hepatobiliary Surgery, Affiliated Nantong Hospital 3 of Nantong University, Nantong 226006, Jiangsu Province, China
| | - Jia-Jie Lu
- Department of Medical School, Nantong University, Nantong 226300, Jiangsu Province, China
- Department of Hepatobiliary Surgery, Affiliated Nantong Hospital 3 of Nantong University, Nantong 226006, Jiangsu Province, China
| | - Lin Chen
- Nantong Institute of Liver Disease, Affiliated Nantong Hospital 3 of Nantong University, Nantong 226006, Jiangsu Province, China
| | - Wei-Hua Cai
- Department of Medical School, Nantong University, Nantong 226300, Jiangsu Province, China
- Department of Hepatobiliary Surgery, Affiliated Nantong Hospital 3 of Nantong University, Nantong 226006, Jiangsu Province, China
| | - Jin-Zhu Wu
- Department of Medical School, Nantong University, Nantong 226300, Jiangsu Province, China
- Department of Hepatobiliary Surgery, Affiliated Nantong Hospital 3 of Nantong University, Nantong 226006, Jiangsu Province, China
| |
Collapse
|
|
11
|
Hammer PM, Tan SY. Soft Tissue Perivascular Epithelioid Cell Tumors. Surg Pathol Clin 2024; 17:105-118. [PMID: 38278600 DOI: 10.1016/j.path.2023.06.002] [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] [Indexed: 01/28/2024]
Abstract
Perivascular epithelioid cell tumors (PEComas) are a heterogenous group of mesenchymal neoplasms with a mixed myomelanocytic immunophenotype. PEComa-family tumors include angiomyolipoma, lymphangioleiomyomatosis, and a large category of rare neoplasms throughout the body that are now classified under the umbrella term "PEComa." This review focuses on recent advances in the clinicopathological and molecular features of PEComas, with an emphasis on PEComas that originate in soft tissue.
Collapse
Affiliation(s)
- Phoebe M Hammer
- Department of Pathology, Stanford University School of Medicine, 1291 Welch Road, Lane Building L235, Stanford, CA 94305, USA
| | - Serena Y Tan
- Department of Pathology, Stanford University School of Medicine, 1291 Welch Road, Lane Building L235, Stanford, CA 94305, USA.
| |
Collapse
|
|
12
|
Zhang J, Wang WJ, Chen LH, Wang N, Wang MW, Liu H, Pang LJ, Jiang HG, Qi Y. Primary renal malignant epithelioid angiomyolipoma with distant metastasis: a case report and literature review. Front Oncol 2023; 13:1207536. [PMID: 37675231 PMCID: PMC10477911 DOI: 10.3389/fonc.2023.1207536] [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: 04/17/2023] [Accepted: 07/28/2023] [Indexed: 09/08/2023] Open
Abstract
Epithelioid angiomyolipoma (EAML) is a rare type of mesenchymal angiomyolipoma with potential malignancy in the kidney that can cause lymph node metastases, local recurrence, and distant metastases. Herein, we describe a case of EAML in the right kidney of a 51-year-old man who was admitted to the hospital with a right abdominal mass. Computed tomography revealed a heterogeneously enhanced mass with blurred margins, which was considered a malignant tumor. A radical nephrectomy was then performed. Two years later, the patient developed liver metastases from EAML and was administered sintilimab combined with bevacizumab. The patient survived after 6 months of follow-up. Histologically, the tumors showed clear boundaries and no obvious capsules. The tumor tissue mainly consisted of epithelioid tumor cells, thick-walled blood vessels, and a small amount of adipose tissue. Tumor cells with lipid vacuoles and acinar areas were large, round, polygonal, eosinophilic, or transparent in the cytoplasm. The enlarged and hyperchromatic nuclei were accompanied by distinct nucleoli and pathological mitosis. These histopathological findings resembled those of renal cell carcinoma, and immunohistochemical analysis was performed. The tumor cells were diffusely positive for HMB45, Melan-A, CK20, vimentin antibodies, and TFE3, suggesting that the tumor originated from perivascular epithelioid cells, excluding renal cell carcinoma. The Ki-67 index was 10%. These histopathological features were observed in liver mass puncture tissues. We also summarized 46 cases of EAML with distant metastasis and explored the clinicopathological features of EAML to improve the treatment of the disease. EAML is often ignored in the clinical setting, leading to metastasis and recurrence. Therefore, EAMLs require long-term follow-up, and timely detection of recurrent disease can improve the prognosis.
Collapse
Affiliation(s)
- Jun Zhang
- Department of Pathology, Zhanjiang Central Hospital, Guangdong Medical University, Guangdong, China
| | - Wen-Juan Wang
- Department of Pathology, Zhanjiang Central Hospital, Guangdong Medical University, Guangdong, China
| | - Li-Hong Chen
- Department of Pathology, Zhanjiang Central Hospital, Guangdong Medical University, Guangdong, China
| | - Ning Wang
- Department of Pathology, Shihezi University School of Medicine & the First Affiliated Hospital to Shihezi University School of Medicine, Xinjiang, China
| | - Ming-Wen Wang
- Department of Pathology, Shihezi University School of Medicine & the First Affiliated Hospital to Shihezi University School of Medicine, Xinjiang, China
| | - Hao Liu
- Department of Pathology, Shihezi University School of Medicine & the First Affiliated Hospital to Shihezi University School of Medicine, Xinjiang, China
| | - Li-Juan Pang
- Department of Pathology, Zhanjiang Central Hospital, Guangdong Medical University, Guangdong, China
| | - Han-Guo Jiang
- Department of Pathology, Zhanjiang Central Hospital, Guangdong Medical University, Guangdong, China
| | - Yan Qi
- Department of Pathology, Zhanjiang Central Hospital, Guangdong Medical University, Guangdong, China
| |
Collapse
|
|
13
|
Kapur P, Brugarolas J, Trpkov K. Recent Advances in Renal Tumors with TSC/mTOR Pathway Abnormalities in Patients with Tuberous Sclerosis Complex and in the Sporadic Setting. Cancers (Basel) 2023; 15:4043. [PMID: 37627070 PMCID: PMC10452688 DOI: 10.3390/cancers15164043] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2023] [Revised: 08/04/2023] [Accepted: 08/04/2023] [Indexed: 08/27/2023] Open
Abstract
A spectrum of renal tumors associated with frequent TSC/mTOR (tuberous sclerosis complex/mechanistic target of rapamycin) pathway gene alterations (in both the germline and sporadic settings) have recently been described. These include renal cell carcinoma with fibromyomatous stroma (RCC FMS), eosinophilic solid and cystic renal cell carcinoma (ESC RCC), eosinophilic vacuolated tumor (EVT), and low-grade oncocytic tumor (LOT). Most of these entities have characteristic morphologic and immunohistochemical features that enable their recognition without the need for molecular studies. In this report, we summarize recent advances and discuss their evolving complexity.
Collapse
Affiliation(s)
- Payal Kapur
- Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
- Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
- Kidney Cancer Program at Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - James Brugarolas
- Kidney Cancer Program at Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
- Hematology-Oncology Division of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Kiril Trpkov
- Department of Pathology and Laboratory Medicine, Cumming School of Medicine, University of Calgary, Calgary, AB T2L 2K5, Canada
- Alberta Precision Labs, Rockyview General Hospital, 7007 14 St., Calgary, AB T2V 1P9, Canada
| |
Collapse
|
|
14
|
Klonowska K, Giannikou K, Grevelink JM, Boeszoermenyi B, Thorner AR, Herbert ZT, Afrin A, Treichel AM, Hamieh L, Kotulska K, Jozwiak S, Moss J, Darling TN, Kwiatkowski DJ. Comprehensive genetic and phenotype analysis of 95 individuals with mosaic tuberous sclerosis complex. Am J Hum Genet 2023; 110:979-988. [PMID: 37141891 PMCID: PMC10257004 DOI: 10.1016/j.ajhg.2023.04.002] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2023] [Accepted: 04/12/2023] [Indexed: 05/06/2023] Open
Abstract
Tuberous sclerosis complex (TSC) is a neurogenetic disorder due to loss-of-function TSC1 or TSC2 variants, characterized by tumors affecting multiple organs, including skin, brain, heart, lung, and kidney. Mosaicism for TSC1 or TSC2 variants occurs in 10%-15% of individuals diagnosed with TSC. Here, we report comprehensive characterization of TSC mosaicism by using massively parallel sequencing (MPS) of 330 TSC samples from a variety of tissues and fluids from a cohort of 95 individuals with mosaic TSC. TSC1 variants in individuals with mosaic TSC are much less common (9%) than in germline TSC overall (26%) (p < 0.0001). The mosaic variant allele frequency (VAF) is significantly higher in TSC1 than in TSC2, in both blood and saliva (median VAF: TSC1, 4.91%; TSC2, 1.93%; p = 0.036) and facial angiofibromas (median VAF: TSC1, 7.7%; TSC2 3.7%; p = 0.004), while the number of TSC clinical features in individuals with TSC1 and TSC2 mosaicism was similar. The distribution of mosaic variants across TSC1 and TSC2 is similar to that for pathogenic germline variants in general TSC. The systemic mosaic variant was not present in blood in 14 of 76 (18%) individuals with TSC, highlighting the value of analysis of multiple samples from each individual. A detailed comparison revealed that nearly all TSC clinical features are less common in individuals with mosaic versus germline TSC. A large number of previously unreported TSC1 and TSC2 variants, including intronic and large rearrangements (n = 11), were also identified.
Collapse
Affiliation(s)
- Katarzyna Klonowska
- Cancer Genetics Laboratory, Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
| | - Krinio Giannikou
- Cancer Genetics Laboratory, Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Division of Hematology/Oncology, Cancer and Blood Disease Institute, Children's Hospital Los Angeles, Los Angeles, CA 90027, USA
| | - Joannes M Grevelink
- Boston Dermatology and Laser Center, Massachusetts General Hospital, Boston, MA 02114, USA
| | - Barbara Boeszoermenyi
- Cancer Genetics Laboratory, Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Aaron R Thorner
- Center for Cancer Genomics, Dana-Farber Cancer Institute, Boston, MA 02215, USA
| | - Zachary T Herbert
- Molecular Biology Core Facilities, Dana-Farber Cancer Institute, Boston, MA 02215, USA
| | - Antara Afrin
- Department of Dermatology, Uniformed Services University, Bethesda, MA 20814, USA; Pulmonary Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - Alison M Treichel
- Department of Dermatology, Uniformed Services University, Bethesda, MA 20814, USA; Pulmonary Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA; Department of Dermatology, University Hospitals Cleveland Medical Center, Case Western Reserve University Cleveland, Cleveland, OH 44106, USA
| | - Lana Hamieh
- Cancer Genetics Laboratory, Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Division of Hospital Medicine, Barnes Jewish Hospital, Washington University in St Louis, St. Louis, MO 63110, USA
| | - Katarzyna Kotulska
- Department of Neurology and Epileptology, Children's Memorial Health Institute, Warsaw 04-736, Poland
| | - Sergiusz Jozwiak
- Department of Neurology and Epileptology, Children's Memorial Health Institute, Warsaw 04-736, Poland; Research Department, Children's Memorial Health Institute, Warsaw 04-736, Poland
| | - Joel Moss
- Pulmonary Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - Thomas N Darling
- Department of Dermatology, Uniformed Services University, Bethesda, MA 20814, USA
| | - David J Kwiatkowski
- Cancer Genetics Laboratory, Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
| |
Collapse
|
|
15
|
Zhang H, Hu Z, Wang S, Wu K, Yang Q, Song X. Clinical features and outcomes of male patients with lymphangioleiomyomatosis: A review. Medicine (Baltimore) 2022; 101:e32492. [PMID: 36596036 PMCID: PMC9803497 DOI: 10.1097/md.0000000000032492] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/22/2022] [Accepted: 12/07/2022] [Indexed: 12/31/2022] Open
Abstract
BACKGROUND Lymphangioleiomyomatosis (LAM) is a rare disease involving multiple systems, which is divided into sporadic LAM (S-LAM) and tuberous sclerosis complex-LAM, mostly affecting women who are in childbearing age stage. Data on male patients are limited and scattered. Therefore, it is necessary to conduct a systematic review to investigate the clinical features, diagnosis, treatment, and outcomes of LAM in male. METHODS We performed a literature review by searching for all the published reported cases of LAM in male during the past 35 years (April 1986-October 2021). RESULTS 36 male patients described in 26 references were included in this article. The median age of onset was 34 years (interquartile range: 1-79). The most common initial manifestations were cough, dyspnea, respite, and hemoptysis, with pulmonary complications such as pneumothorax and chylothorax. Five patients (13.9%) were asymptomatic at admission. Nearly half of the 36 male patients had thin-walled air-filled cysts that were visible throughout both lungs. Considering the abovementioned atypical clinical features, misdiagnosis was committed in 8 patients (22.2%). In addition, patients with tuberous sclerosis complex lymphangioleiomyomatosis often have no pulmonary manifestations at onset but present multiple extrapulmonary manifestations and have higher rates of renal angiomyolipomas than patients with S-LAM (P < 0.01). Eventually, 4 patients with S-LAM eventually died. CONCLUSION Physicians should increase the awareness of LAM in male. Early monitoring of various systems should be recommended to ensure early management and active follow-up. Tuberous sclerosis complex patients should immediately be tracked for the onset of LAM disease to improve prognosis.
Collapse
Affiliation(s)
- Haoyu Zhang
- Department of Respiratory and Critical Care Medicine, the first College of Clinical Medicine science, China Three Gorges University, Yichang, People’s Republic of China
- Department of Respiratory and Critical Care Medicine, Yichang Central People’s Hospital., Wuhan, Hubei, China
| | - Zhigang Hu
- Department of Respiratory and Critical Care Medicine, the first College of Clinical Medicine science, China Three Gorges University, Yichang, People’s Republic of China
- Department of Respiratory and Critical Care Medicine, Yichang Central People’s Hospital., Wuhan, Hubei, China
| | - Sufei Wang
- Department of Respiratory and Critical Care Medicine, NHC Key Laboratory of Pulmonary Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Kanhao Wu
- Department of Respiratory and Critical Care Medicine, the first College of Clinical Medicine science, China Three Gorges University, Yichang, People’s Republic of China
- Department of Respiratory and Critical Care Medicine, Yichang Central People’s Hospital., Wuhan, Hubei, China
| | - Qiaoyu Yang
- Department of Respiratory and Critical Care Medicine, the first College of Clinical Medicine science, China Three Gorges University, Yichang, People’s Republic of China
- Department of Respiratory and Critical Care Medicine, Yichang Central People’s Hospital., Wuhan, Hubei, China
| | - Xinyu Song
- Department of Respiratory and Critical Care Medicine, the first College of Clinical Medicine science, China Three Gorges University, Yichang, People’s Republic of China
- Department of Respiratory and Critical Care Medicine, Yichang Central People’s Hospital., Wuhan, Hubei, China
| |
Collapse
|
|
16
|
Asrani K, Woo J, Mendes AA, Schaffer E, Vidotto T, Villanueva CR, Feng K, Oliveira L, Murali S, Liu HB, Salles DC, Lam B, Argani P, Lotan TL. An mTORC1-mediated negative feedback loop constrains amino acid-induced FLCN-Rag activation in renal cells with TSC2 loss. Nat Commun 2022; 13:6808. [PMID: 36357396 PMCID: PMC9649702 DOI: 10.1038/s41467-022-34617-7] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2021] [Accepted: 11/01/2022] [Indexed: 11/12/2022] Open
Abstract
The mechanistic target of rapamycin complex 1 (mTORC1) integrates inputs from growth factors and nutrients, but how mTORC1 autoregulates its activity remains unclear. The MiT/TFE transcription factors are phosphorylated and inactivated by mTORC1 following lysosomal recruitment by RagC/D GTPases in response to amino acid stimulation. We find that starvation-induced lysosomal localization of the RagC/D GAP complex, FLCN:FNIP2, is markedly impaired in a mTORC1-sensitive manner in renal cells with TSC2 loss, resulting in unexpected TFEB hypophosphorylation and activation upon feeding. TFEB phosphorylation in TSC2-null renal cells is partially restored by destabilization of the lysosomal folliculin complex (LFC) induced by FLCN mutants and is fully rescued by forced lysosomal localization of the FLCN:FNIP2 dimer. Our data indicate that a negative feedback loop constrains amino acid-induced, FLCN:FNIP2-mediated RagC activity in renal cells with constitutive mTORC1 signaling, and the resulting MiT/TFE hyperactivation may drive oncogenesis with loss of the TSC2 tumor suppressor.
Collapse
Affiliation(s)
- Kaushal Asrani
- grid.21107.350000 0001 2171 9311Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD USA
| | - Juhyung Woo
- grid.21107.350000 0001 2171 9311Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD USA
| | - Adrianna A. Mendes
- grid.21107.350000 0001 2171 9311Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD USA
| | - Ethan Schaffer
- grid.21107.350000 0001 2171 9311Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD USA
| | - Thiago Vidotto
- grid.21107.350000 0001 2171 9311Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD USA
| | - Clarence Rachel Villanueva
- grid.21107.350000 0001 2171 9311Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD USA
| | - Kewen Feng
- grid.21107.350000 0001 2171 9311Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD USA
| | - Lia Oliveira
- grid.21107.350000 0001 2171 9311Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD USA
| | - Sanjana Murali
- grid.21107.350000 0001 2171 9311Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD USA
| | - Hans B. Liu
- grid.21107.350000 0001 2171 9311Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD USA
| | - Daniela C. Salles
- grid.21107.350000 0001 2171 9311Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD USA
| | - Brandon Lam
- grid.21107.350000 0001 2171 9311Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD USA
| | - Pedram Argani
- grid.21107.350000 0001 2171 9311Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD USA
| | - Tamara L. Lotan
- grid.21107.350000 0001 2171 9311Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD USA ,grid.21107.350000 0001 2171 9311Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD USA ,grid.21107.350000 0001 2171 9311Department of Urology, Johns Hopkins University School of Medicine, Baltimore, MD USA
| |
Collapse
|
|
17
|
Sanchez NG, Ávila Romay AA, Martínez Luna E, Padilla Rodríguez AL. Cutaneous Angiomyolipoma-A Distinct Entity That Should Be Separated From Classic Angiomyolipoma: Complete Review of Existing Cases and Defining Fundamental Features. JMIR DERMATOLOGY 2022; 5:e40168. [PMID: 37632898 PMCID: PMC10334929 DOI: 10.2196/40168] [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: 06/09/2022] [Revised: 09/07/2022] [Accepted: 09/17/2022] [Indexed: 11/13/2022] Open
Abstract
Cutaneous angiomyolipoma is a rare mesenchymal tumor that is demographically, clinically, and immunohistochemically distinct from its renal and extrarenal counterparts. We present a case of cutaneous angiomyolipoma in the right retroauricular area of a 35-year-old male patient and provide a broad systematic review of the literature and the largest compilation of cutaneous angiomyolipomas reported to date. According to the findings presented in this review, we conclude that cutaneous angiomyolipoma should be completely separated from renal and extrarenal angiomyolipomas and therefore be considered a distinct entity in the classification of skin tumors.
Collapse
Affiliation(s)
- Natalia Gabriela Sanchez
- DIGIPATH: Digital Pathology Laboratory, Mexico City, Mexico
- Instituto Tecnológico y de Estudios Superiores De Monterrey Campus Ciudad de México, Mexico City, Mexico
| | | | | | - Alvaro Lezid Padilla Rodríguez
- DIGIPATH: Digital Pathology Laboratory, Mexico City, Mexico
- Instituto Tecnológico y de Estudios Superiores De Monterrey Campus Ciudad de México, Mexico City, Mexico
- Escuela de Medicina Universidad Panamericana Campus Ciudad de México, Mexico City, Mexico
| |
Collapse
|
|
18
|
Klonowska K, Grevelink JM, Giannikou K, Ogorek BA, Herbert ZT, Thorner AR, Darling TN, Moss J, Kwiatkowski DJ. Ultrasensitive profiling of UV-induced mutations identifies thousands of subclinical facial tumors in tuberous sclerosis complex. J Clin Invest 2022; 132:e155858. [PMID: 35358092 PMCID: PMC9106361 DOI: 10.1172/jci155858] [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] [Received: 10/15/2021] [Accepted: 03/29/2022] [Indexed: 11/17/2022] Open
Abstract
BackgroundTuberous sclerosis complex (TSC) is a neurogenetic syndrome due to loss-of-function mutations in TSC2 or TSC1, characterized by tumors at multiple body sites, including facial angiofibroma (FAF). Here, an ultrasensitive assessment of the extent and range of UV-induced mutations in TSC facial skin was performed.MethodsA multiplex high-sensitivity PCR assay (MHPA) was developed, enabling mutation detection at extremely low (<0.1%) variant allele frequencies (VAFs).ResultsMHPA assays were developed for both TSC2 and TP53, and applied to 81 samples, including 66 skin biopsies. UV-induced second-hit mutation causing inactivation of TSC2 was pervasive in TSC facial skin with an average of 4.8 mutations per 2-mm biopsy at median VAF 0.08%, generating more than 150,000 incipient facial tumors (subclinical "micro-FAFs") in the average TSC subject. The MHPA analysis also led to the identification of a refined UV-related indel signature and a recurrent complex mutation pattern, consisting of both a single-nucleotide or dinucleotide variant and a 1- to 9-nucleotide deletion, in cis.ConclusionTSC facial skin can be viewed as harboring a patchwork of clonal fibroblast proliferations (micro-FAFs) with indolent growth, a small proportion of which develop into clinically observable FAF. Our observations also expand the spectrum of UV-related mutation signatures.FundingThis work was supported by the TSC Alliance; the Engles Family Fund for Research in TSC and LAM; and the NIH, National Heart, Lung, and Blood Institute (U01HL131022-04 and Intramural Research Program).
Collapse
Affiliation(s)
- Katarzyna Klonowska
- Cancer Genetics Laboratory, Division of Pulmonary and Critical Care Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Joannes M. Grevelink
- Boston Dermatology and Laser Center, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Krinio Giannikou
- Cancer Genetics Laboratory, Division of Pulmonary and Critical Care Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Barbara A. Ogorek
- Cancer Genetics Laboratory, Division of Pulmonary and Critical Care Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | | | - Aaron R. Thorner
- Center for Cancer Genomics, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
| | - Thomas N. Darling
- Department of Dermatology, Uniformed Services University, Bethesda, Maryland, USA
| | - Joel Moss
- Pulmonary Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - David J. Kwiatkowski
- Cancer Genetics Laboratory, Division of Pulmonary and Critical Care Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA
| |
Collapse
|
|
19
|
Genotype-phenotype correlation of renal lesions in the tuberous sclerosis complex. Hum Genome Var 2022; 9:5. [PMID: 35145067 PMCID: PMC8831580 DOI: 10.1038/s41439-022-00181-1] [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: 08/03/2021] [Revised: 12/14/2021] [Accepted: 12/14/2021] [Indexed: 01/15/2023] Open
Abstract
Tuberous sclerosis complex (TSC) is an autosomal dominant disease caused by loss-of-function mutations in either of two tumor suppressor genes, TSC1 and TSC2. These mutations lead to the growth of benign tumors and hamartomas in many organs, including those of the central nervous system, the skin, and the kidneys. To investigate the genotype-phenotype correlation, we performed sequence analysis of the TSC1/2 genes using next-generation sequencing. We classified 30 patients with TSC whose pathogenic variants were identified into two groups: those with mutations producing premature termination codons (PTCs) and those with missense mutations. Then, we compared the phenotypes between the two groups. Patients with a PTC were significantly more likely to manifest the major symptoms of the diagnostic criteria than those without a PTC (P = 0.035). The frequencies of subependymal nodules (P = 0.026), cortical tubers (P = 0.026), and renal cysts (P = 0.026) were significantly higher in PTC-containing variants than in cases without a PTC. When the analyses were limited to renal angiomyolipoma (AML) cases with TSC2 mutations, there was no difference in tumor size between cases with and without a PTC. However, the cases with a PTC showed a trend toward disease onset at a younger age and multiple tumors, and bilateral disease was observed in their AML lesions. TSC patients with PTC-producing mutations might potentially manifest more severe TSC phenotypes than those with missense mutations. A larger-scale study with appropriate samples deserves further investigation.
Collapse
|
|
20
|
Algashaamy K, Montgomery EA, Garcia-Buitrago M. Liver mesenchymal neoplasms: something old, something new. Pathology 2021; 54:225-235. [PMID: 34965900 DOI: 10.1016/j.pathol.2021.09.022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2021] [Accepted: 09/12/2021] [Indexed: 10/19/2022]
|
|
21
|
Kruseová J, Gottfriedová B, Zichová A, Švojgr K, Hošek P, Lukš A, Kynčl M, Eckschlager T. Is There a Higher Incidence of Sporadic Renal Angiomyolipoma in Childhood Cancer Survivors? Clin Epidemiol 2021; 13:707-716. [PMID: 34408499 PMCID: PMC8364828 DOI: 10.2147/clep.s317903] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2021] [Accepted: 07/06/2021] [Indexed: 12/25/2022] Open
Abstract
Background Cancer treatment can cause various long-term side effects, including those that impact ultrasound findings. During follow-up of childhood cancer survivors (CCSs), we often detected sporadic renal angiomyolipomas without histological confirmation (SAMLs), which is why we initiated this study. We compared the occurrence of SAML in CCSs to the previously reported data from a non-cancer population and correlated SAML with cancer treatment-related factors. Methods The cohort included 1098 CCSs (median age at cancer diagnosis (dg) 4.3 years) who had ultrasound follow-up (2014-2019). Of the CCSs, 525 (48%) were female, 132 (12%) had subsequent neoplasms (SNs), and 110 (10%) had genetic syndromes. CCSs were treated for lymphomas 269 (24%) and solid tumors 829 (76%). None of the CCSs had tuberous sclerosis complex (TSC). Results SAML developed in 48 (4.4%) CCSs; of these, 20 (42%) had SNs. The coincidence of SAMLs and SNs was found in CCSs with a follow-up period exceeding 20 years. The median age at SAML dg was 27.9 years (interquartile range (IQR) 22.3-34.1), and the median time to SAML dg was 22.6 years (IQR 17.4-27.6). Twenty-one (44%) CCSs developed multiple or bilateral SAMLs lesions; of these, six (12%) were in the radiotherapy field. SAML occurrence correlated with radiotherapy of the retroperitoneum (1.65-fold higher with 95% CI 0.90-3.02). The correlations with other cancer treatment factors and with female sex were less clear. Conclusion This study revealed the occurrence of SAMLs in CCSs to be 10 times higher than that in non-cancer studies. The current characteristics of CCSs with SAMLs: younger age, and more bilateral or multiple lesions are more similar to TSC associated angiomyolipoma. Moreover, we observed a coincidence of SAMLs with SNs. Our results support the hypothesis that SAML development in CCSs is not simply a late effect of therapy, and indicates other factors are involved in SAML development.
Collapse
Affiliation(s)
- Jarmila Kruseová
- Department of Paediatric Haematology and Oncology, 2nd Faculty of Medicine, Charles University and Motol University Hospital, Prague, Czech Republic
| | - Barbora Gottfriedová
- Department of Radiology, 2nd Faculty of Medicine, Charles University and Motol University Hospital, Prague, Czech Republic
| | - Andrea Zichová
- Department of Paediatric Haematology and Oncology, 2nd Faculty of Medicine, Charles University and Motol University Hospital, Prague, Czech Republic
| | - Karel Švojgr
- Department of Paediatric Haematology and Oncology, 2nd Faculty of Medicine, Charles University and Motol University Hospital, Prague, Czech Republic
| | - Petr Hošek
- Biomedical Center, Faculty of Medicine in Pilsen, Charles University, Pilsen, Czech Republic
| | - Aleš Lukš
- Department of Paediatric Haematology and Oncology, 2nd Faculty of Medicine, Charles University and Motol University Hospital, Prague, Czech Republic
| | - Martin Kynčl
- Department of Radiology, 2nd Faculty of Medicine, Charles University and Motol University Hospital, Prague, Czech Republic
| | - Tomáš Eckschlager
- Department of Paediatric Haematology and Oncology, 2nd Faculty of Medicine, Charles University and Motol University Hospital, Prague, Czech Republic
| |
Collapse
|
|
22
|
Rebaine Y, Nasser M, Girerd B, Leroux C, Cottin V. Tuberous sclerosis complex for the pulmonologist. Eur Respir Rev 2021; 30:30/161/200348. [PMID: 34348978 PMCID: PMC9488995 DOI: 10.1183/16000617.0348-2020] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2020] [Accepted: 01/20/2021] [Indexed: 12/18/2022] Open
Abstract
Tuberous sclerosis complex (TSC) is a rare multisystem genetic disorder affecting almost all organs with no sex predominance. TSC has an autosomal-dominant inheritance and is caused by a heterozygous mutation in either the TSC1 or TSC2 gene leading to hyperactivation of the mammalian target of rapamycin (mTOR). TSC is associated with several pulmonary manifestations including lymphangioleiomyomatosis (LAM), multifocal micronodular pneumocyte hyperplasia (MMPH) and chylous effusions. LAM is a multisystem disorder characterised by cystic destruction of lung parenchyma, and may occur in either the setting of TSC (TSC-LAM) or sporadically (S-LAM). LAM occurs in 30–40% of adult females with TSC at childbearing age and is considered a nonmalignant metastatic neoplasm of unknown origin. TSC-LAM is generally milder and, unlike S-LAM, may occur in males. It manifests as multiple, bilateral, diffuse and thin-walled cysts with normal intervening lung parenchyma on chest computed tomography. LAM is complicated by spontaneous pneumothoraces in up to 70% of patients, with a high recurrence rate. mTOR inhibitors are the treatment of choice for LAM with moderately impaired lung function or chylous effusion. MMPH, manifesting as multiple solid and ground-glass nodules on high-resolution computed tomography, is usually harmless with no need for treatment. Tuberous sclerosis complex is associated with diverse pulmonary manifestations including LAM, multiple micronodular pneumocyte hyperplasia and chylous effusions. LAM occurs in 30–40% of adult females with tuberous sclerosis complex.https://bit.ly/3iLqZ08
Collapse
Affiliation(s)
- Yasmine Rebaine
- Dept of Respiratory Medicine, National Reference Coordinating Centre for Rare Pulmonary Diseases, Louis Pradel Hospital, Hospices Civils de Lyon, Lyon, France.,Division of Pulmonology, Dept of Medicine, Hôpital Charles-LeMoyne, Montréal, QC, Canada.,Faculté de Médecine et des Sciences de la Santé, Université de Sherbrooke, Sherbrooke, QC, Canada.,Both authors contributed equally
| | - Mouhamad Nasser
- Dept of Respiratory Medicine, National Reference Coordinating Centre for Rare Pulmonary Diseases, Louis Pradel Hospital, Hospices Civils de Lyon, Lyon, France.,Both authors contributed equally
| | - Barbara Girerd
- Université Paris-Saclay, Faculté de Médecine, Le Kremlin-Bicêtre, France.,AP-HP, Centre de Référence de l'Hypertension Pulmonaire, Service de Pneumologie et Soins Intensifs Respiratoires, Hôpital Bicêtre, Le Kremlin-Bicêtre, France.,INSERM UMR_S 999, Hôpital Marie Lannelongue, Le Plessis Robinson, France
| | - Caroline Leroux
- Université Claude Bernard Lyon 1, Université de Lyon, INRAE, UMR754, Member of ERN-LUNG, RespiFil, OrphaLung, Lyon, France
| | - Vincent Cottin
- Dept of Respiratory Medicine, National Reference Coordinating Centre for Rare Pulmonary Diseases, Louis Pradel Hospital, Hospices Civils de Lyon, Lyon, France .,Université Claude Bernard Lyon 1, Université de Lyon, INRAE, UMR754, Member of ERN-LUNG, RespiFil, OrphaLung, Lyon, France
| |
Collapse
|
|
23
|
McBride A, Garcia AJ, Sanders LJ, Yiu K, Cranmer LD, Kuo PH, Kay M, Kraft AS. Sustained response to pembrolizumab in recurrent perivascular epithelioid cell tumor with elevated expression of programmed death ligand: a case report. J Med Case Rep 2021; 15:400. [PMID: 34301321 PMCID: PMC8305520 DOI: 10.1186/s13256-021-02997-x] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2021] [Accepted: 06/02/2021] [Indexed: 12/30/2022] Open
Abstract
Background Perivascular epithelioid cell tumors are defined by the World Health Organization as “a collection of rare mesenchymal tumors composed of histologically and immunohistochemically distinctive perivascular epithelioid cells.” Whereas localized perivascular epithelioid cell tumor is typically benign and treated successfully with surgical resection, prognosis for patients with advanced or metastatic perivascular epithelioid cell tumor is unfavorable, and there is no standard curative treatment. Case presentation We report a Caucasian case of metastatic perivascular epithelioid cell tumor previously treated with chemotherapy and surgery with elevated surface expression of programmed cell death ligand 1. Based on this result, treatment via immune checkpoint inhibition with the monoclonal antibody pembrolizumab was pursued. After 21 cycles, the patient sustained a complete response. Therapy was stopped after the 40th cycle, and she was moved to surveillance. She remained disease free 19 months off treatment. Conclusions This case report of a patient with perivascular epithelioid cell tumor treated successfully with programmed cell death protein-1 targeted therapy suggests that programmed cell death ligand-1 levels should be measured in patients with perivascular epithelioid cell tumor and immunotherapy considered for recurrent or metastatic patients. Future phase II/III studies in this disease should focus on sequencing of surgery and immunotherapy with a design of curative intent.
Collapse
Affiliation(s)
- Ali McBride
- University of Arizona Cancer Center, 1515 N. Campbell Ave., Tucson, AZ, 85718, USA
| | - Andrew J Garcia
- College of Pharmacy, University of Arizona, Tucson, AZ, USA.,College of Medicine, George Washington University, Washington, DC, USA
| | - Lauren J Sanders
- University of Arizona Cancer Center, 1515 N. Campbell Ave., Tucson, AZ, 85718, USA
| | - Kelly Yiu
- College of Pharmacy, University of Arizona, Tucson, AZ, USA
| | - Lee D Cranmer
- University of Arizona Cancer Center, 1515 N. Campbell Ave., Tucson, AZ, 85718, USA.,Seattle Cancer Care Alliance, Seattle, WA, USA
| | - Phillip H Kuo
- Department of Medical Imaging, Medicine and Biomedical Engineering, University of Arizona College of Medicine, Tucson, AZ, USA
| | - Matthew Kay
- Department of Medical Imaging, Medicine and Biomedical Engineering, University of Arizona College of Medicine, Tucson, AZ, USA
| | - Andrew S Kraft
- University of Arizona Cancer Center, 1515 N. Campbell Ave., Tucson, AZ, 85718, USA.
| |
Collapse
|
|
24
|
Schmiester M, Dolnik A, Kornak U, Pfitzner B, Hummel M, Treue D, Hartmann A, Agaimy A, Weyerer V, Lekaj A, Brakemeier S, Peters R, Öllinger R, Märdian S, Bullinger L, Striefler JK, Flörcken A. TFE3 activation in a TSC1-altered malignant PEComa: challenging the dichotomy of the underlying pathogenic mechanisms. JOURNAL OF PATHOLOGY CLINICAL RESEARCH 2020; 7:3-9. [PMID: 33180365 PMCID: PMC7737753 DOI: 10.1002/cjp2.187] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/02/2020] [Revised: 09/25/2020] [Accepted: 09/30/2020] [Indexed: 02/06/2023]
Abstract
Perivascular epithelioid cell tumors (PEComas) form a family of rare mesenchymal neoplasms that typically display myomelanocytic differentiation. Upregulation of mTOR signaling due the inactivation of TSC1/2 (Tuberous Sclerosis 1 and 2) is believed to be a key oncogenic driver in this disease. Recently, a subgroup of PEComas harboring TFE3 (Transcription Factor E3) rearrangements and presenting with a distinctive morphology has been identified. TSC1/2 and TFE3 aberrations are deemed to be mutually exclusive in PEComa, with two different pathogenic mechanisms assumed to lead to tumorigenesis. Here, we challenge this dichotomy by presenting a case of a clinically aggressive TCS1‐mutated PEComa displaying a TFE3‐altered phenotype. FISH analysis was suggestive of a TFE3 inversion; however, RNA and whole genome sequencing was ultimately unable to identify a fusion involving the gene. However, a copy number increase of the chromosomal region encompassing TFE3 was detected and transcriptome analysis confirmed upregulation of TFE3, which was also seen at the protein level. Therefore, we believe that the TSC1/2‐mTOR pathway and TFE3 overexpression can simultaneously contribute to tumorigenesis in PEComa. Our comprehensive genetic analyses add to the understanding of the complex pathogenic mechanisms underlying PEComa and harbor insights for clinical treatment options.
Collapse
Affiliation(s)
- Maren Schmiester
- Department of Hematology, Oncology, and Tumor Immunology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.,Berlin Institute of Health (BIH), Berlin, Germany
| | - Anna Dolnik
- Department of Hematology, Oncology, and Tumor Immunology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
| | - Uwe Kornak
- Institute of Medical Genetics and Human Genetics, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.,Institute of Human Genetics, University Medical Center Göttingen, Göttingen, Germany
| | - Berit Pfitzner
- Institute of Pathology, DRK Kliniken Berlin Westend, Berlin, Germany
| | - Michael Hummel
- Institute of Pathology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
| | - Denise Treue
- Institute of Pathology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
| | - Arndt Hartmann
- Institute of Pathology, Friedrich-Alexander-University Erlangen-Nürnberg, University Hospital Erlangen, Erlangen, Germany
| | - Abbas Agaimy
- Institute of Pathology, Friedrich-Alexander-University Erlangen-Nürnberg, University Hospital Erlangen, Erlangen, Germany
| | - Veronika Weyerer
- Institute of Pathology, Friedrich-Alexander-University Erlangen-Nürnberg, University Hospital Erlangen, Erlangen, Germany
| | - Anja Lekaj
- Institute of Medical Genetics and Human Genetics, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
| | - Susanne Brakemeier
- Department of Nephrology and Medical Intensive Care, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
| | - Robert Peters
- Department of Urology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
| | - Robert Öllinger
- Department of Surgery, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
| | - Sven Märdian
- Center for Musculoskeletal Surgery, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
| | - Lars Bullinger
- Department of Hematology, Oncology, and Tumor Immunology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.,German Cancer Consortium (DKTK), Partner Site Berlin, and German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Jana Käthe Striefler
- Department of Hematology, Oncology, and Tumor Immunology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
| | - Anne Flörcken
- Department of Hematology, Oncology, and Tumor Immunology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
| |
Collapse
|
|
25
|
Bennett JA, Oliva E. Perivascular epithelioid cell tumors (PEComa) of the gynecologic tract. Genes Chromosomes Cancer 2020; 60:168-179. [PMID: 33099813 DOI: 10.1002/gcc.22908] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2020] [Accepted: 10/21/2020] [Indexed: 12/13/2022] Open
Abstract
PEComas of the female genital tract are rare mesenchymal neoplasms that are most common in the uterus, but also may occur in other gynecologic locations. As they morphologically and immunohistochemically resemble smooth muscle tumors, distinction between the two entities is often challenging, and may be aided by molecular analysis. Thus far, two distinct molecular groups-classic PEComas with TSC mutations and TFE3-translocation associated PEComas with TFE3 fusions have been described. Recognition of the first group is imperative as these patients may benefit from targeted therapy with mTOR inhibitors, if malignant. This review will focus on recognition of the morphologic and immunophenotypic features of PEComas, as well as the role of molecular testing in their diagnosis and treatment, analysis of the different algorithms to predict behavior, and differential diagnosis.
Collapse
Affiliation(s)
- Jennifer A Bennett
- Department of Pathology, University of Chicago Medicine, Chicago, Illinois, USA
| | - Esther Oliva
- Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts, USA
| |
Collapse
|
|
26
|
Afshar Saber W, Sahin M. Recent advances in human stem cell-based modeling of Tuberous Sclerosis Complex. Mol Autism 2020; 11:16. [PMID: 32075691 PMCID: PMC7031912 DOI: 10.1186/s13229-020-0320-2] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2019] [Accepted: 02/03/2020] [Indexed: 12/13/2022] Open
Abstract
Tuberous sclerosis complex (TSC) is an autosomal dominant disorder characterized by epilepsy, intellectual disability, and benign tumors of the brain, heart, skin, and kidney. Animal models have contributed to our understanding of normal and abnormal human brain development, but the construction of models that accurately recapitulate a human pathology remains challenging. Recent advances in stem cell biology with the derivation of human-induced pluripotent stem cells (hiPSCs) from somatic cells from patients have opened new avenues to the study of TSC. This approach combined with gene-editing tools such as CRISPR/Cas9 offers the advantage of preserving patient-specific genetic background and the ability to generate isogenic controls by correcting a specific mutation. The patient cell line and the isogenic control can be differentiated into the cell type of interest to model various aspects of TSC. In this review, we discuss the remarkable capacity of these cells to be used as a model for TSC in two- and three-dimensional cultures, the potential variability in iPSC models, and highlight differences between findings reported to date.
Collapse
Affiliation(s)
- Wardiya Afshar Saber
- Department of Neurology, Harvard Medical School, Boston Children's Hospital, 300 Longwood Ave, Boston, MA, 02115, USA
| | - Mustafa Sahin
- Department of Neurology, Harvard Medical School, Boston Children's Hospital, 300 Longwood Ave, Boston, MA, 02115, USA.
| |
Collapse
|
|
27
|
Idogawa M, Hida T, Tanaka T, Ohira N, Tange S, Sasaki Y, Uhara H, Masumori N, Tokino T, Natori H. Renal angiomyolipoma (AML) harboring a missense mutation of TSC2 with copy-neutral loss of heterozygosity (CN-LOH). Cancer Biol Ther 2019; 21:315-319. [PMID: 31847710 DOI: 10.1080/15384047.2019.1702406] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023] Open
Abstract
Angiomyolipoma (AML) is classified as a perivascular epithelioid cell neoplasm, mostly occurring in the kidney. Twenty percent of patients with renal AML have tuberous sclerosis complex (TSC) caused by germline variation in the TSC1 or TSC2 gene. In this paper, we report the first case of renal AML harboring somatic missense mutations of the TSC2 gene and concomitant copy-neutral loss of heterozygosity (CN-LOH). The patient presented with solitary renal AML and pulmonary lymphangiomyomatosis and without other findings suggestive of TSC. Exome sequencing analysis of the renal AML, however, identified a pathogenic somatic missense mutation in the TSC2 gene (NM_000548:c.5228G>A:p. R1743Q), although no other somatic mutation was detected. Furthermore, no germline mutation in TSC1 or TSC2 was detected. Interestingly, the mutant allele ratio was too high for a somatic heterozygous mutation without loss of heterozygosity (LOH). Furthermore, no copy number variation was detected around the TSC2 locus (16p13.3). To clarify the allelic status, we analyzed heterozygous single-nucleotide polymorphisms (SNPs) in chromosome 16. In these SNPs, an unbalanced allele ratio was accumulated inside the 16p13.3 region. These results suggested copy-neutral LOH (CN-LOH). Consequently, we concluded that the missense mutation of the TSC2 gene and CN-LOH of the TSC2 locus caused renal AML.
Collapse
Affiliation(s)
- Masashi Idogawa
- Department of Medical Genome Sciences, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan.,Department of Gastroenterology and Hepatology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Tokimasa Hida
- Department of Dermatology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Toshiaki Tanaka
- Department of Urology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | | | - Shoichiro Tange
- Department of Medical Genome Sciences, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Yasushi Sasaki
- Biology, Department of Liberal Arts and Sciences Center for Medical Education, Sapporo Medical University, Sapporo, Japan
| | - Hisashi Uhara
- Department of Dermatology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Naoya Masumori
- Department of Urology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Takashi Tokino
- Department of Medical Genome Sciences, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan
| | | |
Collapse
|
|
28
|
Margaria JP, Campa CC, De Santis MC, Hirsch E, Franco I. The PI3K/Akt/mTOR pathway in polycystic kidney disease: A complex interaction with polycystins and primary cilium. Cell Signal 2019; 66:109468. [PMID: 31715259 DOI: 10.1016/j.cellsig.2019.109468] [Citation(s) in RCA: 52] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2019] [Revised: 11/08/2019] [Accepted: 11/08/2019] [Indexed: 12/19/2022]
Abstract
Over-activation of the PI3K/Akt/mTOR network is a well-known pathogenic event that leads to hyper-proliferation. Pharmacological targeting of this pathway has been developed for the treatment of multiple diseases, including cancer. In polycystic kidney disease (PKD), the mTOR cascade promotes cyst growth by boosting proliferation, size and metabolism of kidney tubule epithelial cells. Therefore, mTOR inhibition has been tested in pre-clinical and clinical studies, but only the former showed positive results. This review reports recent discoveries describing the activity and molecular mechanisms of mTOR activation in tubule epithelial cells and cyst formation and discusses the evidence of an upstream regulation of mTOR by the PI3K/Akt axis. In particular, the complex interconnections of the PI3K/Akt/mTOR network with the principal signaling routes involved in the suppression of cyst formation are dissected. These interactions include the antagonism and the reciprocal negative regulation between mTOR complex 1 and the proteins whose deletion causes Autosomal Dominant PKD, the polycystins. In addition, the emerging role of phopshoinositides, membrane components modulated by PI3K, will be presented in the context of primary cilium signaling, cell polarization and protection from cyst formation. Overall, studies demonstrate that the activity of various members of the PI3K/Akt/mTOR network goes beyond the classical transduction of mitogenic signals and can impact several aspects of kidney tubule homeostasis and morphogenesis. These properties might be useful to guide the establishment of more effective treatment protocols to be tested in clinical trials.
Collapse
Affiliation(s)
- Jean Piero Margaria
- Molecular Biotechnology Center, Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino 10126, Italy
| | - Carlo Cosimo Campa
- Department of Biosystems Science and Engineering, ETH Zurich, 4058 Basel, Switzerland
| | - Maria Chiara De Santis
- Molecular Biotechnology Center, Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino 10126, Italy
| | - Emilio Hirsch
- Molecular Biotechnology Center, Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino 10126, Italy
| | - Irene Franco
- Department of Biosciences and Nutrition, Center for Innovative Medicine, Karolinska Institutet, 14157 Huddinge, Sweden.
| |
Collapse
|
|
29
|
Bissler JJ, Zadjali F, Bridges D, Astrinidis A, Barone S, Yao Y, Redd JR, Siroky BJ, Wang Y, Finley JT, Rusiniak ME, Baumann H, Zahedi K, Gross KW, Soleimani M. Tuberous sclerosis complex exhibits a new renal cystogenic mechanism. Physiol Rep 2019; 7:e13983. [PMID: 30675765 PMCID: PMC6344348 DOI: 10.14814/phy2.13983] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2018] [Accepted: 12/20/2018] [Indexed: 02/06/2023] Open
Abstract
Tuberous sclerosis complex (TSC) is a tumor predisposition syndrome with significant renal cystic and solid tumor disease. While the most common renal tumor in TSC, the angiomyolipoma, exhibits a loss of heterozygosity associated with disease, we have discovered that the renal cystic epithelium is composed of type A intercalated cells that have an intact Tsc gene that have been induced to exhibit Tsc-mutant disease phenotype. This mechanism appears to be different than that for ADPKD. The murine models described here closely resemble the human disease and both appear to be mTORC1 inhibitor responsive. The induction signaling driving cystogenesis may be mediated by extracellular vesicle trafficking.
Collapse
Affiliation(s)
- John J. Bissler
- Department of PediatricsUniversity of Tennessee Health Science Center and Le Bonheur Children's HospitalMemphisTennessee
- St. Jude Children's Research HospitalMemphisTennessee
| | - Fahad Zadjali
- Department of Clinical BiochemistryCollege of Medicine & Health SciencesSultan Qaboos UniversityMuscatOman
| | - Dave Bridges
- Department of Nutritional SciencesUniversity of Michigan School of Public HealthAnn ArborMichigan
| | - Aristotelis Astrinidis
- Department of PediatricsUniversity of Tennessee Health Science Center and Le Bonheur Children's HospitalMemphisTennessee
| | - Sharon Barone
- Departments of MedicineUniversity of Cincinnati College of MedicineCincinnatiOhio
- Center on Genetics of TransportUniversity of Cincinnati College of MedicineCincinnatiOhio
- Research ServicesVeterans Affairs Medical CenterCincinnatiOhio
| | - Ying Yao
- Department of PediatricsUniversity of Tennessee Health Science Center and Le Bonheur Children's HospitalMemphisTennessee
| | - JeAnna R. Redd
- Department of Nutritional SciencesUniversity of Michigan School of Public HealthAnn ArborMichigan
| | - Brian J. Siroky
- Department of PediatricsUniversity of Cincinnati College of MedicineCincinnatiOhio
| | - Yanqing Wang
- Department of Molecular and Cellular BiologyRoswell Park Cancer InstituteBuffaloNew York
| | - Joel T. Finley
- Department of PediatricsUniversity of Tennessee Health Science Center and Le Bonheur Children's HospitalMemphisTennessee
| | - Michael E. Rusiniak
- Department of Molecular and Cellular BiologyRoswell Park Cancer InstituteBuffaloNew York
| | - Heinz Baumann
- Department of Molecular and Cellular BiologyRoswell Park Cancer InstituteBuffaloNew York
| | - Kamyar Zahedi
- Departments of MedicineUniversity of Cincinnati College of MedicineCincinnatiOhio
- Center on Genetics of TransportUniversity of Cincinnati College of MedicineCincinnatiOhio
- Research ServicesVeterans Affairs Medical CenterCincinnatiOhio
| | - Kenneth W. Gross
- Department of Molecular and Cellular BiologyRoswell Park Cancer InstituteBuffaloNew York
| | - Manoocher Soleimani
- Departments of MedicineUniversity of Cincinnati College of MedicineCincinnatiOhio
- Center on Genetics of TransportUniversity of Cincinnati College of MedicineCincinnatiOhio
- Research ServicesVeterans Affairs Medical CenterCincinnatiOhio
| |
Collapse
|
|
30
|
De Bree E, Stamatiou D, Chryssou E, Michelakis D, Tzardi M. Late local, peritoneal and systemic recurrence of renal angiomyolipoma: A case report. Mol Clin Oncol 2019; 10:43-48. [PMID: 30655976 PMCID: PMC6313948 DOI: 10.3892/mco.2018.1755] [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: 03/19/2018] [Accepted: 10/25/2018] [Indexed: 12/30/2022] Open
Abstract
Renal angiomyolipoma (AML) is a relatively rare tumor that is generally considered as merely benign. However, epithelioid AML (EAML), an uncommon subtype, is associated with potentially malignant behavior. We herein present the case of a 60-year old male patient who had undergone left nephrectomy with left adrenalectomy and lymphadenectomy for a renal tumor 12 years earlier, and presented to our hospital with dull abdominal pain. The histology report after the previous surgery had revealed an AML of the left kidney with a maximal diameter of 17 cm. Imaging studies demonstrated a large tumor of 13 cm in diameter in the area of the resected kidney, as well as hepatic and peritoneal metastases. Computed tomography-guided core needle biopsy of the mass and revision of the histology of the nephrectomy revealed an EAML. Four years after a two-stage resection of the recurrences the patient is in excellent condition and free of disease. From this case report and the literature review on EAML, it appears that correct histological diagnosis of this subtype of renal AML is crucial. Erroneous diagnosis of simple renal AML instead of EAML may lead to insufficient postoperative management. Clinicians should be aware of the malignant potential of EAML and the need for long-term follow-up. As effective surgical and emerging medical treatment options are available, timely detection of recurrent disease may lead to improved outcome.
Collapse
Affiliation(s)
- Eelco De Bree
- Department of Surgical Oncology, Medical School of Crete University Hospital, 71110 Heraklion, Greece
| | - Dimitris Stamatiou
- Department of Surgical Oncology, Medical School of Crete University Hospital, 71110 Heraklion, Greece
| | - Evangelia Chryssou
- Department of Radiology, Medical School of Crete University Hospital, 71110 Heraklion, Greece
| | - Dimosthenis Michelakis
- Department of Surgical Oncology, Medical School of Crete University Hospital, 71110 Heraklion, Greece
| | - Maria Tzardi
- Department of Pathology, Medical School of Crete University Hospital, 71110 Heraklion, Greece
| |
Collapse
|
|
31
|
Hatfield BS, Mochel MC, Smith SC. Mesenchymal Neoplasms of the Genitourinary System: A Selected Review with Recent Advances in Clinical, Diagnostic, and Molecular Findings. Surg Pathol Clin 2018; 11:837-876. [PMID: 30447845 DOI: 10.1016/j.path.2018.07.008] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Mesenchymal neoplasms of the genitourinary (GU) tract often pose considerable diagnostic challenges due to their wide morphologic spectrum, relative rarity, and unexpected incidence at GU sites. Soft tissue tumors arise throughout the GU tract, whether from adventitia surrounding or connective tissues within the kidneys, urinary bladder, and male and female genital organs. This selected article focuses on a subset of these lesions, ranging from benign to malignant and encompassing a range of patterns of mesenchymal differentiation, where recent scholarship has lent greater insight into their clinical, molecular, or diagnostic features.
Collapse
Affiliation(s)
- Bryce Shawn Hatfield
- Department of Pathology, VCU School of Medicine, 1200 East Marshall Street, PO Box 980662, Richmond, VA 23298, USA
| | - Mark Cameron Mochel
- Department of Pathology, VCU School of Medicine, 1200 East Marshall Street, PO Box 980662, Richmond, VA 23298, USA
| | - Steven Christopher Smith
- Departments of Pathology and Urology, VCU School of Medicine, 1200 East Marshall Street, PO Box 980662, Richmond, VA 23298, USA.
| |
Collapse
|
|
32
|
Filippakis H, Belaid A, Siroky B, Wu C, Alesi N, Hougard T, Nijmeh J, Lam HC, Henske EP. Vps34-mediated macropinocytosis in Tuberous Sclerosis Complex 2-deficient cells supports tumorigenesis. Sci Rep 2018; 8:14161. [PMID: 30242175 PMCID: PMC6155086 DOI: 10.1038/s41598-018-32256-x] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2018] [Accepted: 09/03/2018] [Indexed: 01/04/2023] Open
Abstract
Tuberous Sclerosis Complex (TSC), a rare genetic disorder with mechanistic target of rapamycin complex 1 (mTORC1) hyperactivation, is characterized by multi-organ hamartomatous benign tumors including brain, skin, kidney, and lung (Lymphangioleiomyomatosis). mTORC1 hyperactivation drives metabolic reprogramming including glucose and glutamine utilization, protein, nucleic acid and lipid synthesis. To investigate the mechanisms of exogenous nutrients uptake in Tsc2-deficient cells, we measured dextran uptake, a polysaccharide internalized via macropinocytosis. Tsc2-deficient cells showed a striking increase in dextran uptake (3-fold, p < 0.0001) relative to Tsc2-expressing cells, which was decreased (3-fold, p < 0.0001) with mTOR inhibitor, Torin1. Pharmacologic and genetic inhibition of the lipid kinase Vps34 markedly abrogated uptake of Dextran in Tsc2-deficient cells. Macropinocytosis was further increased in Tsc2-deficient cells that lack autophagic mechanisms, suggesting that autophagy inhibition leads to dependence on exogenous nutrient uptake in Tsc2-deficient cells. Treatment with a macropinocytosis inhibitor, ethylisopropylamiloride (EIPA), resulted in selective growth inhibition of Atg5-deficient, Tsc2-deficient cells (50%, p < 0.0001). Genetic inhibition of autophagy (Atg5−/− MEFs) sensitized cells with Tsc2 downregulation to the Vps34 inhibitor, SAR405, resulting in growth inhibition (75%, p < 0.0001). Finally, genetic downregulation of Vps34 inhibited tumor growth and increased tumor latency in an in vivo xenograft model of TSC. Our findings show that macropinocytosis is upregulated with Tsc2-deficiency via a Vps34-dependent mechanism to support their anabolic state. The dependence of Tsc2-deficient cells on exogenous nutrients may provide novel approaches for the treatment of TSC.
Collapse
Affiliation(s)
- Harilaos Filippakis
- Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
| | - Amine Belaid
- Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
| | - Brian Siroky
- Division of Nephrology and Hypertension, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
| | - Constance Wu
- Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
| | - Nicola Alesi
- Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
| | - Thomas Hougard
- Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
| | - Julie Nijmeh
- Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
| | - Hilaire C Lam
- Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
| | - Elizabeth P Henske
- Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
| |
Collapse
|
|
33
|
Zhang R, Wang J, Wang Q, Han Y, Liu X, Bottillo I, Lang Y, Shao L. Identification of a novel TSC2 c.3610G > A, p.G1204R mutation contribute to aberrant splicing in a patient with classical tuberous sclerosis complex: a case report. BMC MEDICAL GENETICS 2018; 19:173. [PMID: 30236073 PMCID: PMC6149227 DOI: 10.1186/s12881-018-0686-6] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/11/2018] [Accepted: 09/12/2018] [Indexed: 01/27/2023]
Abstract
Background Tuberous sclerosis complex (TSC) is an autosomal dominant disorder characterized by hamartomas in any organ systems. Mutations in the TSC1 or TSC2 gene lead to the dysfunction of hamartin or tuberin proteins, which cause tuberous sclerosis complex. Case presentation We describe the clinical characteristics of patients from a Chinese family with tuberous sclerosis complex and analyze the functional consequences of their causal genetic mutations. A novel heterozygous mutation (c.3610G > A) at the last nucleotide of exon 29 in TSC2 was identified. On the protein level, this variant was presumed to be a missense mutation (p.Gly1204Arg). However, the splicing assay revealed that this mutation also leads to the whole TSC2 exon 29 skipping, besides the wild-type transcript. The mutated transcript results in an in-frame deletion of 71 amino acids (p.Gly1133_Thr1203del) and its ratio with the normal splice product is of about 44:56. Conclusions The novel c.3610G > A TSC2 mutation was identified in association with tuberous sclerosis complex. And it was proven to code both for a missense-carrying transcript (56%), and for an isoform lacking exon 29 (44%). Electronic supplementary material The online version of this article (10.1186/s12881-018-0686-6) contains supplementary material, which is available to authorized users.
Collapse
Affiliation(s)
- Ruixiao Zhang
- Department of Nephrology, the Affiliated Qingdao Municipal Hospital of Qingdao University, No.5 Donghai Middle Road, Qingdao, 266071, People's Republic of China.,Central Laboratory, the Affiliated Hospital of Qingdao University, Qingdao, 266003, People's Republic of China
| | - Jianhong Wang
- Organ Transplantation Center, the Affiliated Hospital of Qingdao University, Qingdao, 266003, People's Republic of China
| | - Qing Wang
- Department of Ophthalmology, the Affiliated Hospital of Qingdao University, Qingdao, 266003, People's Republic of China
| | - Yue Han
- Department of Nephrology, the Affiliated Qingdao Municipal Hospital of Qingdao University, No.5 Donghai Middle Road, Qingdao, 266071, People's Republic of China.,Central Laboratory, the Affiliated Hospital of Qingdao University, Qingdao, 266003, People's Republic of China
| | - Xuejun Liu
- Department of Radiology, the Affiliated Hospital of Qingdao University, Qingdao, 266003, People's Republic of China
| | - Irene Bottillo
- Division of Medical Genetics, Department of Molecular Medicine, Sapienza University, San Camillo-Forlanini Hospital, 00185, Rome, Italy
| | - Yanhua Lang
- Department of Nephrology, the Affiliated Qingdao Municipal Hospital of Qingdao University, No.5 Donghai Middle Road, Qingdao, 266071, People's Republic of China
| | - Leping Shao
- Department of Nephrology, the Affiliated Qingdao Municipal Hospital of Qingdao University, No.5 Donghai Middle Road, Qingdao, 266071, People's Republic of China. .,Central Laboratory, the Affiliated Hospital of Qingdao University, Qingdao, 266003, People's Republic of China.
| |
Collapse
|
|
34
|
Lam HC, Siroky BJ, Henske EP. Renal disease in tuberous sclerosis complex: pathogenesis and therapy. Nat Rev Nephrol 2018; 14:704-716. [DOI: 10.1038/s41581-018-0059-6] [Citation(s) in RCA: 54] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
|
|
35
|
Yan Z, Grenert JP, Joseph NM, Ren C, Chen X, Shafizadeh N, Kakar S. Hepatic angiomyolipoma: mutation analysis and immunohistochemical pitfalls in diagnosis. Histopathology 2018; 73:101-108. [PMID: 29512829 PMCID: PMC6472908 DOI: 10.1111/his.13509] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2017] [Revised: 02/28/2018] [Accepted: 02/28/2018] [Indexed: 02/06/2023]
Abstract
AIMS Hepatic angiomyolipoma (AML) often shows epithelioid morphology with inconspicuous fat. Epithelioid component can mimic hepatocellular adenoma (HCA) or carcinoma (HCC). The aims of this study were to examine the expression of commonly used markers for HCA or HCC in hepatic AML and highlight pitfalls in diagnosis. METHODS AND RESULTS Resected hepatic AMLs (n = 16) were reviewed; reticulin stain, immunohistochemistry for glutamine synthetase (GS), β-catenin and liver fatty acid binding protein (LFABP) were performed along with Sanger sequencing of exon 3 of CTNNB1 and next-generation sequencing (NGS). Predominant epithelioid component (≥50%) was seen in 80% of cases. Foamy macrophage was present in 33% of cases. High-risk histological features were often present in tumours with benign outcome: marked atypia (19%), mitoses (20%) and necrosis (33%). GS staining (≥10% of tumour) was seen in epithelioid components in 13 (87%) cases, and was diffuse (>50% of tumour) in six (40%) cases. LFABP staining or nuclear β-catenin staining was not seen in any case. Sanger sequencing and NGS did not reveal CTNNB1 mutation in any tested case. NGS demonstrated TSC2 mutations in all five cases tested. CONCLUSIONS The predominance of epithelioid component resembling HCA or HCC is common in hepatic AML. Absence of LFABP and presence of fat can be mistaken for HNF1α-inactivated HCA. Diffuse GS staining can be mistaken for β-catenin-activated HCA or HCC. Diffuse GS expression is not related to CTNNB1 mutation. All tested cases showed TSC2 mutation, supporting this as the driving genetic event for hepatic AML.
Collapse
Affiliation(s)
- Zhen Yan
- Department of Pathology, University of California, San Francisco, San Francisco, CA, USA
| | - James P Grenert
- Department of Pathology, University of California, San Francisco, San Francisco, CA, USA
| | - Nancy M Joseph
- Department of Pathology, University of California, San Francisco, San Francisco, CA, USA
| | - Chuanli Ren
- Department of Laboratory Medicine and Cancer Institute, Northern Jiangsu People's Hospital, Clinical Medical College of Yangzhou University, Yangzhou, China
| | - Xin Chen
- Department of Bioengineering/Therapeutic Sciences, University of California, San Francisco, San Francisco, CA, USA
| | - Nafis Shafizadeh
- Department of Pathology, Southern California Permanente Medical Group, Woodland Hills, CA, USA
| | - Sanjay Kakar
- Department of Pathology, University of California, San Francisco, San Francisco, CA, USA
| |
Collapse
|
|
36
|
Balestrini S, Sisodiya SM. Personalized treatment in the epilepsies: challenges and opportunities. EXPERT REVIEW OF PRECISION MEDICINE AND DRUG DEVELOPMENT 2018. [DOI: 10.1080/23808993.2018.1486189] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Affiliation(s)
- Simona Balestrini
- Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, London, and Epilepsy Society, Chalfont-St-Peter, Bucks, United Kingdom
| | - Sanjay M Sisodiya
- Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, London, and Epilepsy Society, Chalfont-St-Peter, Bucks, United Kingdom
| |
Collapse
|
|
37
|
Hung YP, Hornick JL. Immunohistochemical Biomarkers of Mesenchymal Neoplasms in Endocrine Organs: Diagnostic Pitfalls and Recent Discoveries. Endocr Pathol 2018; 29:189-198. [PMID: 29340997 DOI: 10.1007/s12022-018-9513-z] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Mesenchymal neoplasms rarely present in or adjacent to endocrine organs. In this context, the recognition of these rare tumor types can be challenging, with significant potential for misdiagnosis as sarcomatoid carcinomas (i.e., anaplastic thyroid carcinoma and sarcomatoid adrenal cortical carcinoma) or neuroendocrine carcinomas, depending upon the dominant histologic patterns. In this review, we address potential pitfalls in diagnosing selected mesenchymal neoplasms arising within or near endocrine organs, including dedifferentiated liposarcoma, synovial sarcoma, angiosarcoma, PEComa, proximal-type epithelioid sarcoma, Ewing sarcoma, and neuroblastoma. For each of these tumor types, we review clinical and pathologic features, histologic clues to distinguish them from endocrine neoplasms, and recently developed immunohistochemical markers that can be particularly useful for establishing the correct diagnosis.
Collapse
Affiliation(s)
- Yin P Hung
- Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, 75 Francis Street, Boston, MA, 02115, USA
| | - Jason L Hornick
- Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, 75 Francis Street, Boston, MA, 02115, USA.
| |
Collapse
|
|
38
|
Espinosa M, Roldán-Romero JM, Duran I, de Álava E, Apellaniz-Ruiz M, Cascón A, Garrigos C, Robledo M, Rodriguez-Antona C. Advanced sporadic renal epithelioid angiomyolipoma: case report of an extraordinary response to sirolimus linked to TSC2 mutation. BMC Cancer 2018; 18:561. [PMID: 29764404 PMCID: PMC5952422 DOI: 10.1186/s12885-018-4467-6] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2017] [Accepted: 04/30/2018] [Indexed: 02/04/2023] Open
Abstract
Background Renal epithelioid angiomyolipomas (EAML) are rare tumors with aggressive behavior. EAML can be sporadic or develop within the tuberous sclerosis complex syndrome, where mutations of TSC1 or TSC2 genes (critical negative regulators of mTOR Complex 1) result in an increased activation of mTOR pathway. Optimal EAML treatment, including mTOR inhibitors, remains undetermined. Case presentation Here we present the case of a young adult with a renal EAML that after radical nephrectomy developed metastases, first in liver and then in lumbar vertebrae. After complete surgical resection of these lesions, liver recurrence was detected, this time with incomplete surgical resection. After finding a new liver lesion, systemic treatment with sirolimus started. The patient exhibited a complete and durable response to this drug, being disease free at the time of publication, after 36 months of treatment. Targeted next generation sequencing (NGS) of MTOR, TSC1 and TSC2 genes in the primary tumor, metastasis and blood of the patient, revealed one inactivating TSC2 mutation (c.2739dup; p.K914*) in the tumor cells. Immunohistochemistry revealed decreased TSC2 protein content and increased phospho-S6 in the tumor cells, demonstrating mTOR pathway activation. Conclusion NGS on an EAML patient with an extraordinary response to sirolimus uncovered TSC2 inactivation as the mechanism for the response. This study supports NGS as a useful tool to identify patients sensitive to mTOR inhibitors and supports the treatment of malignant EAML with these drugs.
Collapse
Affiliation(s)
- Marta Espinosa
- Medical Oncology Department, Hospital Virgen del Rocío, Servicio de Oncología Medica, Avenida Manuel Siurot s/n, 41013, Sevilla, Spain
| | - Juan Maria Roldán-Romero
- Hereditary Endocrine Cancer Group, Human Cancer Genetics Programme, Spanish National Cancer Research Centre (CNIO), Melchor Fernández Almagro 3, 28029, Madrid, Spain
| | - Ignacio Duran
- Medical Oncology Department, Hospital Virgen del Rocío, Servicio de Oncología Medica, Avenida Manuel Siurot s/n, 41013, Sevilla, Spain. .,Instituto de Biomedicina de Sevilla, IBiS/Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Sevilla, Spain.
| | - Enrique de Álava
- Pathology Department, Instituto de Biomedicina de Sevilla, IBiS/Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla-CIBERONC, Sevilla, Spain
| | - María Apellaniz-Ruiz
- Hereditary Endocrine Cancer Group, Human Cancer Genetics Programme, Spanish National Cancer Research Centre (CNIO), Melchor Fernández Almagro 3, 28029, Madrid, Spain
| | - Alberto Cascón
- Hereditary Endocrine Cancer Group, Human Cancer Genetics Programme, Spanish National Cancer Research Centre (CNIO), Melchor Fernández Almagro 3, 28029, Madrid, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Valencia, Spain
| | - Carmen Garrigos
- Instituto de Biomedicina de Sevilla, IBiS/Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Sevilla, Spain
| | - Mercedes Robledo
- Hereditary Endocrine Cancer Group, Human Cancer Genetics Programme, Spanish National Cancer Research Centre (CNIO), Melchor Fernández Almagro 3, 28029, Madrid, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Valencia, Spain
| | - Cristina Rodriguez-Antona
- Hereditary Endocrine Cancer Group, Human Cancer Genetics Programme, Spanish National Cancer Research Centre (CNIO), Melchor Fernández Almagro 3, 28029, Madrid, Spain. .,Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Valencia, Spain.
| |
Collapse
|
|
39
|
Sager RA, Woodford MR, Shapiro O, Mollapour M, Bratslavsky G. Sporadic renal angiomyolipoma in a patient with Birt-Hogg-Dubé: chaperones in pathogenesis. Oncotarget 2018; 9:22220-22229. [PMID: 29774133 PMCID: PMC5955167 DOI: 10.18632/oncotarget.25164] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2018] [Accepted: 04/02/2018] [Indexed: 11/25/2022] Open
Abstract
Birt-Hogg-Dubé (BHD) is an autosomal dominant genetic syndrome caused by germline mutations in the FLCN gene that predisposes patients to develop renal tumors. Renal angiomyolipoma (AML) is not a renal tumor sub-type associated with BHD. AML is, however, a common phenotypic manifestation of Tuberous Sclerosis Complex (TSC) syndrome caused by mutations in either the TSC1 or TSC2 tumor suppressor genes. Previous case reports of renal AML in patients with BHD have speculated on the molecular and clinical overlap of these two syndromes as a result of described involvement of the gene products in the mTOR pathway. Our recent work provided a new molecular link between these two syndromes by identifying FLCN and Tsc2 as clients of the molecular chaperone Hsp90. Folliculin interacting proteins FNIP1/2 and Tsc1 are important for FLCN and Tsc2 stability as new Hsp90 co-chaperones. Here we present a case of sporadic AML as a result of somatic Tsc1/2 loss in a patient with BHD. We further demonstrate that FNIP1 and Tsc1 are capable of compensating for each other in the chaperoning of mutated FLCN tumor suppressor. Our findings demonstrate interconnectivity and compensatory mechanisms between the BHD and TSC pathways.
Collapse
Affiliation(s)
- Rebecca A Sager
- Department of Urology, SUNY Upstate Medical University, Syracuse, NY, USA.,Upstate Cancer Center, SUNY Upstate Medical University, Syracuse, NY, USA.,Department of Biochemistry and Molecular Biology, SUNY Upstate Medical University, Syracuse, NY, USA
| | - Mark R Woodford
- Department of Urology, SUNY Upstate Medical University, Syracuse, NY, USA.,Upstate Cancer Center, SUNY Upstate Medical University, Syracuse, NY, USA.,Department of Biochemistry and Molecular Biology, SUNY Upstate Medical University, Syracuse, NY, USA
| | - Oleg Shapiro
- Department of Urology, SUNY Upstate Medical University, Syracuse, NY, USA.,Upstate Cancer Center, SUNY Upstate Medical University, Syracuse, NY, USA
| | - Mehdi Mollapour
- Department of Urology, SUNY Upstate Medical University, Syracuse, NY, USA.,Upstate Cancer Center, SUNY Upstate Medical University, Syracuse, NY, USA.,Department of Biochemistry and Molecular Biology, SUNY Upstate Medical University, Syracuse, NY, USA
| | - Gennady Bratslavsky
- Department of Urology, SUNY Upstate Medical University, Syracuse, NY, USA.,Upstate Cancer Center, SUNY Upstate Medical University, Syracuse, NY, USA
| |
Collapse
|
|
40
|
Maloney N, Giannikou K, Lefferts J, Bridge JA, Linos K. Expanding the histomorphologic spectrum of TFE3-rearranged perivascular epithelioid cell tumors. Hum Pathol 2018; 82:125-130. [PMID: 29626599 DOI: 10.1016/j.humpath.2018.03.023] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/24/2018] [Revised: 03/13/2018] [Accepted: 03/18/2018] [Indexed: 10/17/2022]
Abstract
Perivascular epithelioid cell tumors (PEComas) are a family of mesenchymal neoplasms that have smooth muscle and melanocytic differentiation. They can be sporadic or associated with tuberous sclerosis complex and commonly present in the kidney as angiomyolipoma or in the lung as pulmonary clear cell sugar tumors or lymphangioleiomyomatosis. However, they can present at any visceral or soft tissue site. They usually have a benign clinical course, but rarely can behave in a malignant fashion. Most PEComas demonstrate abnormalities of TSC2, but a recently described subset harbor TFE3 rearrangements that seem to be mutually exclusive of TSC2 alterations. TFE3-rearranged PEComas demonstrate a distinct alveolar morphology that lacks spindle cells and smooth muscle differentiation. Distinction between these may have important therapeutic consequences. Herein, we present a case of a TFE3-rearranged PEComa without the customary morphology that required ancillary investigation with TFE3 immunohistochemistry and break-apart fluorescence in situ hybridization for proper categorization.
Collapse
Affiliation(s)
- Nolan Maloney
- Department of Pathology and Laboratory Medicine, Dartmouth Hitchcock Medical Center and Geisel School of Medicine at Dartmouth, Lebanon, NH 03756, USA
| | - Krinio Giannikou
- Department of Pulmonary and Critical Care Medicine and of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Joel Lefferts
- Department of Pathology and Laboratory Medicine, Dartmouth Hitchcock Medical Center and Geisel School of Medicine at Dartmouth, Lebanon, NH 03756, USA
| | - Julia A Bridge
- Department of Pathology and Microbiology, University of Nebraska Medical Center, 983135 Nebraska Medical Center, Omaha, NE 68198-3135, USA
| | - Konstantinos Linos
- Department of Pathology and Laboratory Medicine, Dartmouth Hitchcock Medical Center and Geisel School of Medicine at Dartmouth, Lebanon, NH 03756, USA.
| |
Collapse
|
|
41
|
Liver Angiomyolipomas in Tuberous Sclerosis Complex-Their Incidence and Course. Pediatr Neurol 2018; 78:20-26. [PMID: 29249553 DOI: 10.1016/j.pediatrneurol.2017.09.012] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/02/2017] [Revised: 09/16/2017] [Accepted: 09/19/2017] [Indexed: 11/22/2022]
Abstract
BACKGROUND The purpose of this study was to evaluate the epidemiology and clinical significance of hepatic angiomyolipomas in patients with tuberous sclerosis complex. METHODS We performed a retrospective analysis of clinical and imaging data from 187 patients with tuberous sclerosis complex. The prevalence, progression, and potential relationship between liver lesions and other clinical findings, including genetic associations, were assessed. RESULTS Twenty-eight of 187 patients (14.9%) had hepatic lesions. There was a predominance of female over male patients in individuals with liver lesions (17 versus 11), with statistical significance in patients under five years of age (P < 0.05). All individuals having hepatic lesions who also had available genetic testing data (n = 20) were diagnosed with a TSC2 gene mutation. All patients with liver lesions had coexisting renal angiomyolipomas (AMLs) (P < 0.05). The age of onset of renal lesions was lower and their prevalence was significantly higher in patients with liver involvement (P < 0.05). In most instances, hepatic lesions measured several millimeters in diameter and were clinically asymptomatic. Progressive lesion growth was documented in six individuals but with no clinical consequences to date. CONCLUSIONS This study confirms the association of hepatic lesions with TSC2 mutations, a common origin of liver and renal AMLs, as well as the predominance of female patients in this group. Hepatic AMLs are relatively common but mostly benign lesions.
Collapse
|
|
42
|
Evidence of renal angiomyolipoma neoplastic stem cells arising from renal epithelial cells. Nat Commun 2017; 8:1466. [PMID: 29133867 PMCID: PMC5684212 DOI: 10.1038/s41467-017-01514-3] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2016] [Accepted: 09/25/2017] [Indexed: 12/20/2022] Open
Abstract
Renal angiomyolipomas (AML) contain an admixture of clonal tumour cells with features of several different mesenchymal lineages, implying the existence of an unidentified AML neoplastic stem cell. Biallelic inactivation of TSC2 or TSC1 is believed to represent the driving event in these tumours. Here we show that TSC2 knockdown transforms senescence-resistant cultured mouse and human renal epithelial cells into neoplastic stem cells that serially propagate renal AML-like tumours in mice. mTOR inhibitory therapy of mouse AML allografts mimics the clinical responses of human renal AMLs. Deletion of Tsc1 in mouse renal epithelia causes differentiation in vivo into cells expressing characteristic AML markers. Human renal AML and a renal AML cell line express proximal tubule markers. We describe the first mouse models of renal AML and provide evidence that these mesenchymal tumours originate from renal proximal tubule epithelial cells, uncovering an unexpected pathological differentiation plasticity of the proximal tubule. Renal angiomyolipomas (AML) contain a mix of clonal tumour cells. Here, through reverse tumour engineering experiments, mouse genetics and analyses of human AML tumours, the authors provide evidence that these mesenchymal tumours originate from renal proximal tubule epithelial cells.
Collapse
|
|
43
|
Clinical presentations and molecular studies of invasive renal epithelioid angiomyolipoma. Int Urol Nephrol 2017; 49:1527-1536. [DOI: 10.1007/s11255-017-1629-4] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2017] [Accepted: 05/19/2017] [Indexed: 02/01/2023]
|
|
44
|
Caban C, Khan N, Hasbani DM, Crino PB. Genetics of tuberous sclerosis complex: implications for clinical practice. APPLICATION OF CLINICAL GENETICS 2016; 10:1-8. [PMID: 28053551 PMCID: PMC5189696 DOI: 10.2147/tacg.s90262] [Citation(s) in RCA: 83] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Tuberous sclerosis complex (TSC) is a multisystem disorder that results from heterozygous mutations in either TSC1 or TSC2. The primary organ systems that are affected include the brain, skin, lung, kidney, and heart, all with variable frequency, penetrance, and severity. Neurological features include epilepsy, autism, and intellectual disability. There are more than 1,500 known pathogenic variants for TSC1 and TSC2, including deletion, nonsense, and missense mutations, and all pathogenic mutations are inactivating, leading to loss of function effects on the encoded proteins TSC1 and TSC2. These proteins form a complex to constitutively inhibit mechanistic target of rapamycin (mTOR) signaling cascade, and as a consequence, mTOR signaling is constitutively active within all TSC-associated lesions. The mTOR inhibitors rapamycin (sirolimus) and everolimus have been shown to reduce the size of renal and brain lesions and improve pulmonary function in TSC, and these compounds may also decrease seizure frequency. The clinical application of mTOR inhibitors in TSC has provided one of the first examples of precision medicine in a neurodevelopmental disorder.
Collapse
Affiliation(s)
- Carolina Caban
- Department of Neurology; Shriners Hospitals Pediatric Research Center, Temple University School of Medicine
| | - Nubaira Khan
- Department of Neurology; Shriners Hospitals Pediatric Research Center, Temple University School of Medicine
| | - Daphne M Hasbani
- Department of Neurology, St. Christopher's Hospital for Children, Drexel University College of Medicine, Philadelphia, PA, USA
| | - Peter B Crino
- Department of Neurology; Shriners Hospitals Pediatric Research Center, Temple University School of Medicine
| |
Collapse
|
|
45
|
Lam HC, Nijmeh J, Henske EP. New developments in the genetics and pathogenesis of tumours in tuberous sclerosis complex. J Pathol 2016; 241:219-225. [PMID: 27753446 DOI: 10.1002/path.4827] [Citation(s) in RCA: 65] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2016] [Revised: 10/07/2016] [Accepted: 10/10/2016] [Indexed: 12/11/2022]
Abstract
In just the past 5 years, dramatic changes have occurred in the clinical management of tuberous sclerosis complex (TSC). Detailed knowledge about the role of the TSC proteins in regulating the activity of the mammalian target of rapamycin complex 1 (mTORC1) underlies this paradigm-shifting progress. Advances continue to be made in understanding the genetic pathogenesis of the different tumours that occur in TSC, including pivotal discoveries using next-generation sequencing (NGS). For example, the pathogenesis of angiofibromas is now known to involve UV-induced mutations, and the pathogenesis of multifocal renal cell carcinoma (RCC) in TSC is now known to result from distinct second-hit mutations. In parallel, the pathological features of TSC-associated tumours, including TSC-associated renal cell carcinoma, continue to be defined, despite the fact that TSC was first described 180 years ago. Here, we review recent discoveries related to the pathological features and genetic pathogenesis of TSC-associated tumours. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Collapse
Affiliation(s)
- Hilaire C Lam
- Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
| | - Julie Nijmeh
- Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
| | - Elizabeth P Henske
- Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
| |
Collapse
|
|
46
|
Giannikou K, Malinowska IA, Pugh TJ, Yan R, Tseng YY, Oh C, Kim J, Tyburczy ME, Chekaluk Y, Liu Y, Alesi N, Finlay GA, Wu CL, Signoretti S, Meyerson M, Getz G, Boehm JS, Henske EP, Kwiatkowski DJ. Whole Exome Sequencing Identifies TSC1/TSC2 Biallelic Loss as the Primary and Sufficient Driver Event for Renal Angiomyolipoma Development. PLoS Genet 2016; 12:e1006242. [PMID: 27494029 PMCID: PMC4975391 DOI: 10.1371/journal.pgen.1006242] [Citation(s) in RCA: 89] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2016] [Accepted: 07/14/2016] [Indexed: 11/19/2022] Open
Abstract
Renal angiomyolipoma is a kidney tumor in the perivascular epithelioid (PEComa) family that is common in patients with Tuberous Sclerosis Complex (TSC) and Lymphangioleiomyomatosis (LAM) but occurs rarely sporadically. Though histologically benign, renal angiomyolipoma can cause life-threatening hemorrhage and kidney failure. Both angiomyolipoma and LAM have mutations in TSC2 or TSC1. However, the frequency and contribution of other somatic events in tumor development is unknown. We performed whole exome sequencing in 32 resected tumor samples (n = 30 angiomyolipoma, n = 2 LAM) from 15 subjects, including three with TSC. Two germline and 22 somatic inactivating mutations in TSC2 were identified, and one germline TSC1 mutation. Twenty of 32 (62%) samples showed copy neutral LOH (CN-LOH) in TSC2 or TSC1 with at least 8 different LOH regions, and 30 of 32 (94%) had biallelic loss of either TSC2 or TSC1. Whole exome sequencing identified a median of 4 somatic non-synonymous coding region mutations (other than in TSC2/TSC1), a mutation rate lower than nearly all other cancer types. Three genes with mutations were known cancer associated genes (BAP1, ARHGAP35 and SPEN), but they were mutated in a single sample each, and were missense variants with uncertain functional effects. Analysis of sixteen angiomyolipomas from a TSC subject showed both second hit point mutations and CN-LOH in TSC2, many of which were distinct, indicating that they were of independent clonal origin. However, three tumors had two shared mutations in addition to private somatic mutations, suggesting a branching evolutionary pattern of tumor development following initiating loss of TSC2. Our results indicate that TSC2 and less commonly TSC1 alterations are the primary essential driver event in angiomyolipoma/LAM, whereas other somatic mutations are rare and likely do not contribute to tumor development. We performed comprehensive genome analysis of a kidney tumor called angiomyolipoma. These tumors are known to develop in most individuals who have Tuberous Sclerosis Complex (TSC) and those who have sporadic lymphangioleiomyomatosis (LAM), and are seen rarely in the general population. In these angiomyolipomas, we found consistent involvement of the TSC2 and TSC1 genes that are known to cause TSC, but very few (<5 on average) mutations elsewhere in the protein-coding regions. This is in stark contrast to other adult solid tumours that typically harbor hundreds to thousands of such mutations. Our results indicate that genetic alterations in TSC2/TSC1 are the primary and essential driver genetic events for development and progression of renal angiomyolipoma. Analysis of multiple angiomyolipomas from a single patient showed distinct genetic aberrations in the majority of samples, indicating that most of the tumors had developed independently. Branched clonal evolution was evident from the observation of three tumors that shared 2 mutations in addition to mutations private to each. Our results indicate that therapeutic approaches for treatment of patients with angiomyolipoma should focus on the consequences of TSC2/TSC1 loss, including but not limited to mTOR activation.
Collapse
Affiliation(s)
- Krinio Giannikou
- Division of Pulmonary and Critical Care Medicine and of Genetics, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, United States of America
| | - Izabela A. Malinowska
- Division of Pulmonary and Critical Care Medicine and of Genetics, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, United States of America
| | - Trevor J. Pugh
- Broad Institute of Harvard and MIT, Cambridge, Massachusetts, United States of America
| | - Rachel Yan
- Division of Pulmonary and Critical Care Medicine and of Genetics, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, United States of America
| | - Yuen-Yi Tseng
- Broad Institute of Harvard and MIT, Cambridge, Massachusetts, United States of America
| | - Coyin Oh
- Broad Institute of Harvard and MIT, Cambridge, Massachusetts, United States of America
| | - Jaegil Kim
- Broad Institute of Harvard and MIT, Cambridge, Massachusetts, United States of America
| | - Magdalena E. Tyburczy
- Division of Pulmonary and Critical Care Medicine and of Genetics, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, United States of America
| | - Yvonne Chekaluk
- Division of Pulmonary and Critical Care Medicine and of Genetics, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, United States of America
| | - Yang Liu
- Division of Pulmonary and Critical Care Medicine and of Genetics, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, United States of America
| | - Nicola Alesi
- Division of Pulmonary and Critical Care Medicine and of Genetics, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, United States of America
| | - Geraldine A. Finlay
- Tufts New England Medical Center, Boston, Massachusetts, United States of America
| | - Chin-Lee Wu
- Massachusetts General Hospital, Boston, Massachusetts, United States of America
| | - Sabina Signoretti
- Division of Pulmonary and Critical Care Medicine and of Genetics, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, United States of America
| | - Matthew Meyerson
- Broad Institute of Harvard and MIT, Cambridge, Massachusetts, United States of America
| | - Gad Getz
- Broad Institute of Harvard and MIT, Cambridge, Massachusetts, United States of America
| | - Jesse S. Boehm
- Broad Institute of Harvard and MIT, Cambridge, Massachusetts, United States of America
| | - Elizabeth P. Henske
- Division of Pulmonary and Critical Care Medicine and of Genetics, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, United States of America
- Broad Institute of Harvard and MIT, Cambridge, Massachusetts, United States of America
- * E-mail: (EPH); (DJK)
| | - David J. Kwiatkowski
- Division of Pulmonary and Critical Care Medicine and of Genetics, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, United States of America
- Broad Institute of Harvard and MIT, Cambridge, Massachusetts, United States of America
- * E-mail: (EPH); (DJK)
| |
Collapse
|
|
47
|
Abstract
Tuberous sclerosis complex (TSC) is an autosomal dominant disorder that affects multiple organ systems and is caused by loss-of-function mutations in one of two genes: TSC1 or TSC2. The disorder can affect both adults and children. First described in depth by Bourneville in 1880, it is now estimated that nearly 2 million people are affected by the disease worldwide. The clinical features of TSC are distinctive and can vary widely between individuals, even within one family. Major features of the disease include tumours of the brain, skin, heart, lungs and kidneys, seizures and TSC-associated neuropsychiatric disorders, which can include autism spectrum disorder and cognitive disability. TSC1 (also known as hamartin) and TSC2 (also known as tuberin) form the TSC protein complex that acts as an inhibitor of the mechanistic target of rapamycin (mTOR) signalling pathway, which in turn plays a pivotal part in regulating cell growth, proliferation, autophagy and protein and lipid synthesis. Remarkable progress in basic and translational research, in addition to several randomized controlled trials worldwide, has led to regulatory approval of the use of mTOR inhibitors for the treatment of renal angiomyolipomas, brain subependymal giant cell astrocytomas and pulmonary lymphangioleiomyomatosis, but further research is needed to establish full indications of therapeutic treatment. In this Primer, we review the state-of-the-art knowledge in the TSC field, including the molecular and cellular basis of the disease, medical management, major knowledge gaps and ongoing research towards a cure.
Collapse
Affiliation(s)
- Elizabeth P Henske
- Pulmonary and Critical Care Medicine Division, Brigham and Women's Hospital, Harvard Medical School, 15 Francis Street, Boston, Massachusetts 02115, USA
| | - Sergiusz Jóźwiak
- Department of Pediatric Neurology, Medical University of Warsaw, Warsaw, Poland.,Children's Memorial Health Institute, Warsaw, Poland
| | | | - Julian R Sampson
- Institute of Medical Genetics, Division of Cancer and Genetics, Cardiff University School of Medicine, Cardiff, UK
| | - Elizabeth A Thiele
- Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| |
Collapse
|
|
48
|
Omodon M, Ayuba G, Patel IJ. Review of renal artery embolization for treatment of renal angiomyolipoma. ACTA ACUST UNITED AC 2016. [DOI: 10.7243/2054-7161-3-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
|
|
49
|
Chebib N, Khouatra C, Lazor R, Archer F, Leroux C, Gamondes D, Thivolet-Bejui F, Cordier JF, Cottin V. [Pulmonary lymphangioleiomyomatosis: From pathogenesis to management]. Rev Mal Respir 2015; 33:718-734. [PMID: 26604019 DOI: 10.1016/j.rmr.2015.10.005] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2015] [Accepted: 10/06/2015] [Indexed: 12/24/2022]
Abstract
INTRODUCTION Pulmonary lymphangioleiomyomatosis (LAM) is a rare disease affecting mainly young women. BACKGROUND The respiratory manifestations are characterized by a progressive cystic destruction of the lung parenchyma. Extrapulmonary involvement includes benign renal tumours called angiomyolipomas and abdominal lymphatic masses called lymphangioleiomyomas. At the pathological level, the cellular proliferation found in LAM is in part due to the presence of mutations in the tumour suppressor genes TSC1 and TSC2 (Tuberous Sclerosis Complex). These mutations lead to the activation of the mTOR pathway, which is currently the main therapeutic target. mTOR inhibitors such as sirolimus or everolimus have shown a beneficial effect on the decline in pulmonary function and a reduction of angiomyolipoma size, but are necessary in only some patients. PERSPECTIVES LAM cells have migratory properties mediated by the formation of new lymphatic vessels. They are also able to secrete metalloproteases, which enhance their invasiveness. Moreover, the expression of estrogen and progesterone receptors by LAM cells suggests a possible role for sex hormones in the pathogenesis of the disease. CONCLUSION A better understanding of mTOR-independent mechanisms would allow the development of novel therapeutic approaches.
Collapse
Affiliation(s)
- N Chebib
- Service de pneumologie, centre de référence des maladies pulmonaires rares, hôpital Louis-Pradel, hospices civils de Lyon, 8, avenue du Doyen-Lépine, 69677 Lyon cedex, France; UMR 754 Inra, université de Lyon, université Claude-Bernard Lyon 1, 69366 Lyon cedex, France
| | - C Khouatra
- Service de pneumologie, centre de référence des maladies pulmonaires rares, hôpital Louis-Pradel, hospices civils de Lyon, 8, avenue du Doyen-Lépine, 69677 Lyon cedex, France
| | - R Lazor
- Service de pneumologie, centre de référence des maladies pulmonaires rares, hôpital Louis-Pradel, hospices civils de Lyon, 8, avenue du Doyen-Lépine, 69677 Lyon cedex, France; Unité des pneumopathies interstitielles et maladies pulmonaires rares, service de pneumologie, centre hospitalier universitaire vaudois, 1011 Lausanne, Suisse
| | - F Archer
- UMR 754 Inra, université de Lyon, université Claude-Bernard Lyon 1, 69366 Lyon cedex, France
| | - C Leroux
- UMR 754 Inra, université de Lyon, université Claude-Bernard Lyon 1, 69366 Lyon cedex, France
| | - D Gamondes
- Service de radiologie, hôpital Louis-Pradel, hospices civils de Lyon, 69677 Lyon cedex, France
| | - F Thivolet-Bejui
- Centre de pathologie Est, groupement hospitalier Est, hospices civils de Lyon, 69677 Lyon cedex, France
| | - J F Cordier
- Service de pneumologie, centre de référence des maladies pulmonaires rares, hôpital Louis-Pradel, hospices civils de Lyon, 8, avenue du Doyen-Lépine, 69677 Lyon cedex, France; UMR 754 Inra, université de Lyon, université Claude-Bernard Lyon 1, 69366 Lyon cedex, France
| | - V Cottin
- Service de pneumologie, centre de référence des maladies pulmonaires rares, hôpital Louis-Pradel, hospices civils de Lyon, 8, avenue du Doyen-Lépine, 69677 Lyon cedex, France; UMR 754 Inra, université de Lyon, université Claude-Bernard Lyon 1, 69366 Lyon cedex, France.
| |
Collapse
|
|
50
|
Kumar S, Jayant K, Singh SK, Agrawal S. A Case Series & Review of Literature of Angiomyolipoma with Medical & Surgical Perspective. J Clin Diagn Res 2015; 9:PD05-PD7. [PMID: 26500947 PMCID: PMC4606276 DOI: 10.7860/jcdr/2015/13700.6430] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2015] [Accepted: 05/20/2015] [Indexed: 11/24/2022]
Abstract
The angiomyolipoma of renal origin is a rare benign tumour composed of fat cells, smooth muscle cells, and thick-wall blood vessels. Mostly these are sporadic origin, asymptomatic and benign in nature. Here we present two cases of Renal angiomyolipoma (AML) presenting as fever, pain, perirenal haematoma & frank haematuria. After initial stabilization, evaluated by contrast enhanced computer tomography (CECT) & diagnosed as renal angiomyolipoma because of low Hounsfield areas (10-20HU) suggestive for fat. Patient later underwent angiography with selective angioembolisation. Post intervention period was uneventful and was treated by an oral Everolimus 10 mg daily for a period of one year in first case & partial resection was done in second case. On two year follow-up both patients were doing well & had normal renal function without any recurrence. Embolisation is the emergency treatment of choice for bleeding angiomyolipoma. When preventive treatment is considered a nephron sparing approach by either transarterial embolisation or partial nephrectomy is clearly important. While angiomyolipoma in both kidneys or in solitary functioning kidneys, renal preservation is mandatory in order to avoid need for renal replacement therapy. Also, recently approved drug Everolimus may be considered for patients not suitable for surgery particularly in tumour seen with tuberous sclerosis.
Collapse
Affiliation(s)
- Santosh Kumar
- Assistant Professor, Department of Urology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Kumar Jayant
- Resident, Department of Urology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Shrawan Kumar Singh
- Professor, Department of Urology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Swati Agrawal
- Faculty, Department of Maternal & Fetal Medicine, The University of Chicago Medicine5841 S. Maryland Avenue, Chicago, IL 60637
| |
Collapse
|