Wilms’ Tumor

Foreword
Preface
Contents
Editor and Contributors
About the Editor
Contributors
1: The History of Renal Tumors in Children
1.1 Introduction
1.2 Prehistoric Era
1.2.1 The Parshve Gulma of Sushruta
1.2.2 Ayurvedic Treatment of Gulma
1.3 Era of Pathological Understanding
1.3.1 Phase of Morphological Descriptions
1.3.2 Interest in Histological Studies
1.3.3 American Scenario
1.3.4 Unified Nomenclature
1.3.5 Etiologic Theories
1.3.6 Arrival of Max Wilms
1.3.7 The Erroneous Eponym
1.4 Era of Therapeutic Discoveries
1.4.1 Surgical Remedy
1.4.2 Radiotherapy
1.4.3 Chemotherapy
1.5 Era of Cooperative Groups
1.5.1 The North American Cooperative Groups and NWTSG
1.5.2 Societe International d’Oncologie Pediatrique (SIOP)
1.6 A Century of Wilms’ Tumor
References
2: Epidemiology
2.1 Introduction
2.2 Incidence and Geographical Variation
2.3 Age and Sex Predisposition
2.4 Causative Hypothesis and Role of Environmental Factors
2.5 Syndromic and Non-syndromic Associations
2.6 WT in Low-Income Countries
2.7 Role of Tumor Registries
References
3: Genetics and Molecular Biology
3.1 Introduction
3.2 Genetic Events in Normal and Abnormal Nephrogenesis
3.2.1 Nephrogenesis Pathways
3.3 Multistep Model for Sporadic WT Development
3.4 Genetic Changes and WT
3.4.1 WT1 and WT2
3.4.2 CTNNβ1
3.4.3 WTX
3.4.4 MYCN, 16q and 1P, and TP53
3.5 Newer Genes
3.6 Other Forms of WT and Associated Genetic Changes
3.7 Syndromes Associated with WT
3.8 Epigenetic Changes and WT
3.8.1 Epigenetic Changes at 11p15
3.8.2 Epigenetic Changes at 11p13
References
4: Tumor Microenvironment and Inflammatory Markers
4.1 Tumor Microenvironment
4.2 TME and Genesis of WT
4.3 Immune cells, Inflammation, and Their Effect on Tumor Progression
4.3.1 WT and Immune Cells
4.3.2 WT and B Lymphocytes
4.3.3 WT and T Lymphocytes
4.3.4 WT and Macrophages
4.3.5 WT and Tumor-Infiltrating Neutrophils (TIN)
4.3.6 WT and Mast Cells
4.3.7 Tumor Cell-Immune Cell Interaction and Expression of Inflammatory Mediators in WT
4.3.8 WT and COX2
4.3.9 WT and Phosphorylated Extracellular Signal-Regulated Kinase 1 and 2
4.3.10 WT and HIF-1α
4.3.11 WT and VEGF
4.3.12 WT and Phosphorylated STAT 3
4.3.13 WT and Inducible Nitric Oxide Synthase (iNOS)
4.3.14 WT and Nitrotyrosine (NT)
4.3.15 WT and Chemokines/Cytokines
4.3.16 WT and CBP/p300 Interacting Transactivators with Glutamic Acid [E]/Aspartic Acid [D]-rich Carboxy-Terminal Domain (CITED1)
4.3.17 WT and B7 Homolog 1
4.3.18 WT and CD44
4.3.19 WT and Carbonic Anhydrase 9
4.3.20 WT and PDGF
4.4 Future Directions
References
5: Syndromic Wilms’ Tumor
5.1 Introduction
5.2 Incidence and Genetic Penetrance
5.3 Syndromes and Clinical Conditions
5.4 WT1-Associated Phenotypes
5.4.1 WAGR Syndrome
5.4.2 WAGRO Syndrome
5.4.3 Denys-Drash Syndrome
5.4.4 Frasier Syndrome
5.4.5 Other WT1 Phenotypes
5.5 Overgrowth Syndromes
5.5.1 Beckwith-Wiedemann Syndrome
5.5.2 Simpson-Golabi-Behmel Syndrome
5.5.3 Perlman Syndrome
5.5.4 Sotos Syndrome
5.6 Familial Wilms’ Tumor
5.7 Other Tumor Predisposition Syndromes
5.7.1 Bloom Syndrome
5.7.2 Mosaic Variegated Aneuploidy
5.7.3 Fanconi Anemia
5.7.4 Other Syndromes
5.8 Constitutional Chromosomal Disorders
5.9 Conditions with Uncertain Association with WT
5.10 Evaluation and Surveillance in Predisposed Children
5.10.1 Evaluation
5.10.2 Molecular Genetic Testing
5.10.3 Surveillance
5.11 Surgical and Medical Management in Syndromic Patient
5.11.1 Oncological Management
5.11.2 Nephron-Sparing Surgery (NSS) in Syndromic WT
5.12 Future Directions
References
6: Familial Non-syndromic Wilms’ Tumor
6.1 Introduction
6.2 Epidemiology of FWT
6.3 Risk of WT in Kindreds of WT Families
6.4 Pathology of Familial WT
6.5 Genetics and Molecular Biology
6.5.1 WT1 Gene
6.5.2 Familial Predisposition Gene
6.5.3 Novel Predisposition Genes for Familial WT
6.6 Genetic Counseling and Surveillance
References
7: Pathology
7.1 Introduction
7.2 Gross Features
7.3 Microscopy
7.3.1 Blastemal Component
7.3.2 Epithelial Component
7.3.3 Stromal Component
7.4 Anaplasia
7.5 Nuclear Unrest
7.6 Chemotherapy-Induced Changes
7.7 Role of Pre-Therapy Biopsy/Fine Needle Aspiration Cytology
7.8 Immunohistochemistry (IHC)
7.9 Differential Diagnosis
7.10 Cystic Nephroma (CN) and Cystic Partially Differentiated Nephroblastoma (CPDN)
7.11 Handling of Nephrectomy Specimen
7.11.1 Frozen Section
7.11.2 Sample Handling
7.12 Nephrogenic Rests and Nephroblastomatosis
7.13 Adult Wilms’ Tumor
7.14 Extrarenal Wilms’ Tumor
7.15 Conclusions
References
8: Clinical Presentation
8.1 Clinical Presentation
8.2 Examination
8.3 Associated Syndromes
References
9: Laboratory Workup
9.1 Panel of Biochemical Investigations
9.1.1 Complete Hemogram
9.1.2 Renal Function Tests
9.1.3 Serum Electrolyte Panel
9.1.4 Urine Examination
9.1.5 Clotting Screen
9.1.6 Novel Tumor Markers
9.1.7 Investigations to Exclude Other Differentials
9.1.8 Pre and Post Chemotherapy Investigations
References
10: Imaging Studies
10.1 Imaging Modalities
10.1.1 Conventional Radiography
10.1.2 Ultrasonography
10.1.3 Magnetic Resonance Imaging (MRI)
10.1.4 Computed Tomography
10.2 Tumor Staging
10.2.1 Local Extent
10.2.2 Size of the Tumor
10.2.3 Distant Metastases
10.2.3.1 Pulmonary Metastases
10.2.3.2 Other Metastatic Sites
10.3 SIOP Post Chemotherapy Evaluation
10.4 Evaluation of Contralateral Kidney
10.5 Nephrogenic Rests
10.6 Role of Imaging in Nephron-Sparing Surgery
10.7 Role of PET/PET-CT Imaging
10.8 Pretreatment Biopsy
10.9 Differential Diagnosis
10.10 Posttreatment Imaging Surveillance and Screening
10.11 Conclusion
References
11: Diagnostic Biopsy
11.1 Introduction
11.2 Fallacies of Imaging Alone
11.3 Children Cancer and Leukemia Group Guidelines–UK [11]
11.4 Limitations
11.5 The Technique
11.6 Complications
11.6.1 Tract Recurrence
11.6.2 Others
11.7 The Future
References
12: General Surgical Guidelines
12.1 Introduction
12.2 General Surgical Guidelines for Nephroureterectomy for Unilateral Wilms’ Tumor
12.2.1 Access
12.2.2 Inspection of the Abdominal Cavity
12.2.3 The Procedure
12.2.4 Tumor Thrombus in the Renal Vein and Inferior Vena Cava
12.2.5 Adrenal Gland
12.2.6 Lymph Nodes
12.2.7 Translocation of Ovary
References
13: Nephron-Sparing Surgery
13.1 Introduction
13.2 Historical Background
13.3 Neoadjuvant Chemotherapy
13.4 Operative Technique [22, 26]
13.5 NSS and MIS
13.6 New Classification System for NSS
13.7 NSS in Non-syndromic Unilateral Tumors
13.7.1 Rationale and Selection Criteria
13.7.2 Follow-Up
13.7.3 Prognosis After NSS in uWT
References
14: Lymph Node Sampling
14.1 Introduction
14.2 Lymphatic Drainage of Kidneys
14.3 Pattern of Lymphatic Spread in WT
14.4 Role of Imaging for Assessment of LN Involvement
14.4.1 PET Scan
14.5 Method of LN Sampling
14.6 Processing and Reporting of Lymph Nodes
14.7 Adverse Events of LN Sampling
14.8 Outcomes of LN Positive FH WT
14.9 Future Directions
14.9.1 Reducing Toxicity of Treatment
14.9.2 Rapid Central Pathology and Radiology Review
14.9.3 Lymph Node Sampling During Surgery
References
15: Minimally Invasive Surgery
15.1 Introduction
15.2 Laparoscopic Surgery
15.3 Indications and Contraindications
15.4 Transperitoneal Approach
15.4.1 Patient and Team Positioning
15.4.2 Surgical Technique
15.5 Retroperitoneal Approach
15.5.1 Patient Positioning
15.5.2 Surgical Technique
15.6 Nephron Sparing Surgery
15.7 Robotic Surgery
15.8 Complications of MIS
15.9 Postoperative Care
15.10 Conclusions
References
16: Bench Surgery and Auto-Transplantation
16.1 Introduction
16.2 Advantages
16.3 Technique
16.4 Outcomes
References
17: Anesthesia
17.1 Introduction
17.2 Preoperative Concerns and Optimization
17.3 Intraoperative Management
17.4 Anesthesia for Special Circumstances
17.4.1 Anesthesia in a Case of Tumor Extension to the Right Atrium
17.4.2 Anesthesia in Bench Surgery
17.4.3 Anesthesia for Laparoscopic Nephrectomy
17.5 Postoperative Concerns
17.6 Conclusions
References
18: Staging
18.1 Introduction
18.2 COG and SIOP Staging
18.3 Salient Differences Between the SIOP and COG Staging System
18.4 Role of Surgeon in Appropriate Staging
References
19: Chemotherapy
19.1 Introduction
19.2 NWTSG/COG vs. SIOP Philosophy of Management
19.3 National Wilms’ Tumor Study Group (NWTSG)/Children’s Oncology Group (COG)
19.3.1 Role of Neoadjuvant ChT in COG
19.3.2 Treatment Overview of Unilateral WT
19.3.3 Current COG Protocols
19.3.3.1 AREN0532
19.3.3.2 AREN0533
19.3.3.3 AREN05321
19.3.4 Treatment Overview of Bilateral WT/Solitary Kidney with WT
19.3.4.1 AREN0534
Initial Therapy
Therapy at the End of 6 Weeks
Complete Response (CR)
PR or Greater and Feasible for Bilateral NSS
Partial Response or Greater, But Not Feasible for Surgery
Less than Partial Response
Therapy at the End of 12 Weeks
19.3.5 Treatment Overview of Patients with High Risk of Developing Metachronous Tumors
19.3.5.1 Initial Therapy
19.3.5.2 Therapy at the End of 6 Weeks
19.3.5.3 Therapy at the End of 12 Weeks
19.3.6 Treatment Overview of Diffuse Hyperplastic Perilobar Nephroblastomatosis (DHPLNB)
19.4 Société Internationale D’Oncologie Pédiatrique (SIOP)
19.4.1 Therapy for Unilateral WT in SIOP
19.4.1.1 Preoperative ChT
19.4.1.2 Postoperative ChT Regimen for Localized WT in SIOP [10]
AV1
Regimen AV2
AVD Regimen
Regimen HR-1
Postoperative ChT for Metastatic Disease (Stage IV) in SIOP [10]
19.4.2 Bilateral WT Management (SIOP) [10]
19.4.3 Management of Patients with Unilateral Tumor and Predisposition Syndromes/ Contralateral Nephroblastomatosis
References
20: Radiotherapy
20.1 Introduction
20.2 Technical Considerations of Radiotherapy
20.2.1 Pediatric Radiation Oncology
20.2.2 Target Volume Definition
20.2.3 Equipment and Treatment Techniques
20.2.4 Simulation and Shielding
20.2.5 Radiation Dose and Fractionation
20.2.6 Sequelae of Radiation
20.3 Indications for Radiation
20.3.1 Locoregional Disease
20.3.2 Metastatic Disease
20.3.3 Recurrent Disease
20.4 Comparison of Radiotherapy Schedules in COG and SIOP-RTSG (Umbrella Protocol)
20.5 Conclusions
References
21: Novel Tumor Directed Interventions
21.1 Intra-tumoral Chemotherapy for Wilms’ Tumor
21.1.1 Indications for IT-ChT
21.1.2 Mode of Action
21.1.3 Administration of IT-ChT
21.1.4 Results
21.2 Trans-arterial Chemo-embolization (TACE)
21.2.1 Technique
21.2.2 Post-procedural Care
21.3 TACE in WT
21.3.1 Contraindications
21.3.2 Adverse Events
21.4 Ablation Techniques
21.4.1 Radiofrequency Ablation (RFA)
21.4.2 Microwave Ablation (MWA)
21.4.3 MR-Guided High-Intensity Focused Ultrasound Ablation (MR-HIFU)
References
22: Wilms’ Tumor in Resource-Challenged Nations
22.1 Introduction
22.2 Challenges to WT Care in LMIC
22.2.1 Late Presentations
22.2.2 Abandonment of Therapy
22.2.3 Malnutrition
22.2.4 Socioeconomic Factors
22.2.5 Cultural Issues
22.2.6 Biology
22.3 SIOP PODC and Adapted Regimens
22.4 Suggested Management for LMIC
22.5 SIOP PODC Clinical Guidelines for LIC [18]
22.6 Post-treatment Surveillance in LMIC
References
23: Management of Resected Wilms’ Tumor with Unknown Staging Status
23.1 Background to the Vexed Problem
23.2 Management
23.2.1 Management of Favorable Histology Tumors
23.2.2 Management of Anaplastic Tumors
23.2.3 Management of Metastatic Tumors
23.2.4 Management of Small-Sized Favorable Histology Tumors in Young Children (<2 Years)
23.2.5 Management of Tumors Where Both Histopathology and Staging Are Not Known
References
24: Bilateral Wilms’ Tumors
24.1 Introduction
24.2 Definition of BWT from a Management Point of View
24.3 Molecular Genetics and Predisposing Factors
24.4 Epidemiology
24.5 Clinical Features
24.6 Investigations
24.7 Management of BWT
24.7.1 Neoadjuvant Therapy
24.7.2 Surgical Management
24.7.3 Adjuvant Therapy for BWT
24.8 Special Circumstances
24.8.1 Completely Resolved Tumors
24.8.2 Metastatic Disease
24.8.3 Positive Margins
24.9 Renal Transplantation
24.10 Follow-Up and Outcomes
24.11 Prognosis and Long-TermOutcomes
24.12 Future Directions
References
25: Wilms’ Tumor in Horseshoe Kidney and Solitary Kidney
25.1 Wilms’ Tumor in Horseshoe Kidney
25.2 Wilms’ Tumor in Solitary Kidney
References
26: Very Large Tumors Not Responding to Chemotherapy/Locally Infiltrating Tumors
26.1 Introduction
26.2 Definition of Large Inoperable Tumor
26.3 Imaging Technology
26.4 Pre-treatment Core-Needle Biopsy
26.5 Preoperative Chemotherapy
26.6 Tumor Embolization
26.7 Surgical Considerations
26.8 Role of MIS
26.9 Adjunct Therapy
26.10 Situation in Developing Countries
26.11 Conclusion
References
27: Intravascular Extension and Tumor Thrombosis
27.1 Incidence
27.2 Clinical Features
27.3 Preoperative Diagnosis and Imaging
27.4 Staging and Classification
27.5 Neoadjuvant Chemotherapy
27.6 Surgery
27.7 Cavectomy
27.8 Radiotherapy
27.9 Complications and Outcomes
27.10 Conclusions
References
28: Ureteral Extension
28.1 Incidence, Presentation
28.2 Pathology
28.3 Diagnosis
28.4 Treatment
28.5 Outcomes
References
29: Ruptured Tumors
29.1 Introduction
29.2 Defining Tumor Rupture/Spill
29.3 Preoperative Chemotherapy
29.4 Tumor Size and Volume
29.5 Laterality
29.6 Surgeon Skill and Quality Assurance
29.7 Diagnosis and Investigations
29.8 Management
29.9 Local Versus Diffuse Spill
29.10 Tumor Biopsy and Its Repercussions on Tumor Spill
29.11 Prevention of Tumor Rupture/Spill
29.12 Conclusion
References
30: Metastatic Wilms’ Tumor
30.1 Introduction
30.2 Pathophysiology
30.3 Metastasis to Other Sites
30.4 Diagnosis
30.4.1 CT Chest
30.4.2 CT Chest for Response Assessment
30.4.3 Volumetric Assessment
30.4.4 CECT Abdomen
30.4.5 MRI Head and Spine
30.4.6 Bone Scan and Skeletal Survey
30.4.7 Biological Studies
30.4.8 Biopsy
30.4.9 18F-Flourodeoxyglucose (18F-FDG) Positron Emission Tomography (PET)-CT
30.5 Management
30.5.1 COG Protocol
30.5.2 SIOP-RTSG UMBRELLA 2016 Protocol
30.5.3 UKCCLG Protocol
30.6 Management of Unfavorable Histology Metastatic WT
30.7 Response, Outcomes, and Late Effects
30.7.1 Outcome
30.7.2 Late Effects
30.8 Follow-Up
30.9 Future Directions
30.10 Conclusions
References
31: Recurrent/Relapsed Wilms’ Tumor
31.1 Introduction
31.2 Site(s) of Relapse and Presentation
31.3 Time of Recurrence
31.4 Factors Influencing Occurrence of Relapse
31.5 Therapy for RWT
31.6 Management: Patient Risk Stratification Approach
31.6.1 Management of Standard Risk RWT
31.6.1.1 Stratum B of the NWTS-5 Relapse Protocol [33]
31.6.1.2 UKW-R Protocol of UKCCLG [34]
31.6.2 Management of High-Risk RWT
31.6.2.1 Conventional-Dose Chemotherapy
31.6.2.2 High-Dose ChT with Autologous SCR
31.6.3 Management of Very-High-Risk RWT
31.7 Other Strategies
31.8 Role of Surgery and XRT in the Management of RWT
31.9 Treatment of RWT in SIOP-RTSG Umbrella protocol
31.10 Surveillance Schedule After a Complete Response (CR) Following Relapse
References
32: Wilms’ Tumor in Less Than 6-Month-Old Infants
32.1 Introduction
32.2 Clinical Presentation
32.2.1 Antenatal Diagnosis
32.2.2 Presentation
32.3 Diagnosis
32.4 Pathology
32.4.1 Preoperative Biopsy
32.5 Staging
32.6 Management
32.6.1 Surgery
32.6.2 Chemotherapy
32.6.3 Radiotherapy
32.7 Prognosis
References
33: Wilms’ Tumor in Adults
33.1 Introduction
33.2 Incidence
33.3 Genetics and Pathology
33.4 Clinical Presentation
33.5 Diagnosis
33.6 Staging
33.7 Management
33.8 Treatment Toxicity
33.9 WT in Pregnancy
33.10 Prognosis
33.11 Conclusions
References
34: Nephrogenic Rests and Nephroblastomatosis
34.1 Introduction
34.2 Incidence
34.3 Types
34.4 Embryo Pathology
34.5 Ectopic NRs
34.6 Natural History
34.7 Pathology
34.7.1 Subtypes
34.8 Diagnosis
34.8.1 Differential Diagnosis
34.8.2 Imaging
34.8.2.1 Ultrasonography
34.8.2.2 Computerized Tomography
34.8.2.3 Magnetic Resonance Imaging
34.9 Clinical Significance
34.10 Management
34.11 Follow-Up
34.12 Future Directions
References
35: Extrarenal Wilms’ Tumor
35.1 Introduction
35.2 Embryogenesis
35.2.1 Location
35.3 Pathology of ERWT
35.3.1 Teratoid ERWT
35.4 Clinical Presentation
35.5 Diagnosis
35.6 Staging
35.7 Treatment
35.7.1 Prognosis
35.8 ERWT So Far: A Systemic Review
35.9 Conclusions
References
36: Complications of Treatment
36.1 Introduction
36.2 Complications of ChT
36.2.1 Complications During ChT: Immediate Complications
36.2.2 Complications of ChT: After Treatment
36.3 Complications of Ports/Lines
36.4 Complications of Peripheral Lines
36.5 Complications of Surgical Intervention
36.6 Intraoperative Complications
36.7 Postoperative Complications
36.8 Complications Following Nephron Sparing Surgery (NSS)
36.9 Complications Following Laparoscopic/Robotic Nephrectomy
36.10 Complications of Radiation Therapy
36.10.1 Complications During XRT
36.10.2 Complications After XRT
References
37: Post-Therapy Surveillance of Wilms’ Tumor Survivors
37.1 Introduction
37.2 Role of Surveillance and Allied Controversies
37.2.1 Post-Therapy Follow-Up
37.2.2 Healthcare Records
37.3 COG Surveillance Protocol
37.3.1 Blood and Other Investigations for Long-Term Follow-Up of Organ-Systems at Risk and Assessment of Overall Well-Being
37.3.2 Early Screening for Infertility
37.3.3 Hearing Tests
37.3.4 Cardiac Function
37.3.5 Screening for Colon Cancer
37.3.6 Thyroid Tests
37.3.7 Breast Screening
37.4 SIOP Surveillance Protocol
37.4.1 Surveillance Program of SIOP-RTSG Umbrella Protocol 2016
37.5 UKCCLG Surveillance Protocol
37.6 Differences Between Various Collaborative Groups’ Post-Therapy Surveillance Protocols
37.7 Challenges in Resource Challenged Nations
37.8 Palliative and Near End of Life Care
References
38: Prognosis and Outcomes
38.1 Introduction
38.2 Prognostic Factors
38.2.1 Tumor Stage
38.2.2 Tumor Histology
38.2.2.1 Anaplastic Histology
38.2.2.2 Blastemal Histology
38.2.3 Tumor Weight (COG) and Volume (SIOP)
38.2.4 Age
38.2.5 Molecular and Genetic Markers
38.2.5.1 Loss of Heterozygosity
38.2.5.2 Gene Expression Profiles
38.3 Prognosis in Special Population
38.3.1 Children with Bilateral Wilms’ Tumor
38.3.2 Children with Lung Metastasis
38.3.3 Children with Recurrence
38.3.4 Children with Syndromic WT
38.4 Survival Outcomes
38.5 Summary and Conclusions
References
39: Non-Wilms’ Renal Tumors
39.1 Congenital Mesoblastic Nephroma
39.1.1 Incidence and Epidemiology
39.1.2 Clinical Presentation
39.1.3 Radiological Diagnosis
39.1.4 Pathology
39.1.5 Management
39.2 Malignant Rhabdoid Tumor of the Kidney
39.2.1 Incidence and Epidemiology
39.2.2 Clinical Presentation
39.2.3 Radiological Diagnosis
39.2.4 Pathology
39.2.5 Management
39.3 Clear-Cell Sarcoma of the Kidney
39.3.1 Incidence and Epidemiology
39.3.2 Clinical Presentation
39.3.3 Radiological Diagnosis
39.3.4 Pathology
39.3.5 Management
39.3.6 NWTS/COG Protocol
39.3.7 SIOP Protocol
39.4 Renal Cell Carcinoma
39.4.1 Incidence and Epidemiology
39.4.2 Clinical Presentation
39.4.3 Radiological Diagnosis
39.4.4 Pathology
39.4.5 Management
39.5 Intrarenal Neuroblastoma
39.6 Primitive Neuroectodermal Tumor (PNET) or Renal Ewing’s Tumor
39.7 Renal Lymphoma
39.8 Angiomyolipoma
39.9 Renal Cystic Tumors
39.10 Ossifying Renal Tumor of Infancy
39.11 Metanephric Stromal Tumors
References