Cut section showing two halves of a nephroblastoma specimen. Note the prominent septa subdividing the sectioned surface and the protrusion of tumor into the renal pelvis, resembling botryoid rhabdomyosarcoma. | By The Armed Forces Institute of Pathology - Image and description are from the AFIP Atlas of Tumor Pathology, according to entry #407018 in Pathology Education Instructional Resource. The Armed Forces Institute of Pathology Electronic Fascicles (CD-ROM Version of the Atlas of Tumor Pathology) contains U.S. Government work which may be used without restriction.[1], Public Domain, https://commons.wikimedia.org/w/index.php?curid=3741629
Contents
Wilms’ tumor (nephroblastoma) is an embryonal renal cancer.
Also known as nephroblastoma (as cancer arises from metanephric blastema cells of kidney)
History:
Timeline of key clinical advances that established the modern clinical management of children with Wilms tumour: 1) The National Wilms Tumour Study group (NWTS), which was supplanted by the Children’s Oncology Group (COG) in 2002, and the International Society of Paediatric Oncology (SIOP) initiated organized protocols. 2) Researchers started to collect data on the associations between Wilms tumour (WT)-specific therapies and late toxicity in survivors. 3. In 1978, anaplastic morphology was shown to correlate with an increased mortality from WT 4) SIOP progressively recognized that histological subtypes after neoadjuvant chemotherapy were a prognostic factor 5) In 1990, SIOP established the Paediatric Oncology in Developing Countries (PODC) committee to promote paediatric oncology in poorly-resourced countries. 6) Researchers showed that lung radiotherapy could be avoided in subgroups of patients with metastases (good responders), setting the new standard. 7) SIOP-9 trial (1987–1991) showed no benefit from prolonging pre-nephrectomy chemotherapy to 8 weeks with respect to stage distribution, the 4-week schedule becoming the standard for non-metastatic WT. 8) Actinomycin D could be administered in a single dose rather than divided over 5 days, thereby reducing hospital visits for children and health-care delivery costs. 9) Nephrectomy alone in children with very low-risk WT (defined as <24 months of age, with a stage I favourable histology tumour weighing <550 g) was shown to be a valid option, avoiding the risks of central line placement and chemotherapy. 10) Risk stratification of WTs implemented with loss of heterozygosity (LOH) at chromosomes 1p and 16q as adverse prognostic markers. 11) Current standard treatment for children with stage II and III intermediate-risk histology after preoperative chemotherapy omits doxorubicin (vincristine and actinomycin D). 12) In 2018, WHO launched the Global Initiative for Childhood Cancer, with the goal of improving outcome in children with cancer around the world, initially focusing on six common cancers including WT. | Spreafico, F., Fernandez, C.V., Brok, J. et al. Wilms tumour. Nat Rev Dis Primers 7, 75 (2021). https://doi.org/10.1038/s41572-021-00308-8
Epidemiology
Wilms tumor is the most common abdominal cancer in childhood and typically presents between ages 3 to 5 years.
Wilms is more common in Africans and African Americans while it is least common in East Asians. Asian patients also had fewer unfavorable histology tumors, tend to have lower-stage disease, and enjoy better survival outcomes.
M/C renal malignancy in children (~85% of pediatric renal tumors)
#2 M/C abdominal intraabdominal malignancy in children
#4 M/C pediatric cancer overall
Estimated age-standardized mortality rates in 2020 for kidney cancers in children aged 0–14 years in the world | International Agency for Research on Cancer. Estimated age-standardized mortality rates (world) in 2020, kidney, both sexes, ages 0–14. IARC https://gco.iarc.fr/today/online-analysis-map?v=2020&mode=population&mode_population=continents&population=900&populations=900&key=asr&sex=0&cancer=29&type=1&statistic=5&prevalence=0&population_group=0&ages_group%5B%5D=0&ages_group%5B%5D=2&nb_items=10&group_cancer=1&include_nmsc=1&include_nmsc_other=1&projection=natural-earth&color_palette=default&map_scale=quantile&map_nb_colors=5&continent=0&show_ranking=0&rotate=%255B10%252C0%255D (2020).
Etiopathogenesis
Genetic associations:
Wilms tumor is believed to be due to genetic alterations that deal with the normal embryological development of the genitourinary tract.
WT1, CTNNB1, and WTX gene alterations (⅓ of all cases)
Other associated genes: TP53 and MYNC
Poor prognosis: TP53 and with the loss of heterozygosity at chromosomes 1p, 1q, 11p15 and 16q
Biology of paediatric renal tumours: Cells deriving from intermediate mesoderm form the nephrogenic niche and develop into the various cell types of the normal kidney. Molecular alterations in these cells may result in diverse renal tumours: ~90% being Wilms tumours (WTs) and ~10% other primary renal tumours. In a paradigm of disrupted organ development eventually leading to tumorigenesis, remains of the multipotent nephrogenic zone of the fetal kidney may persist after birth and appear in up to 1% of routine infant autopsies as nephrogenic rests. The natural history and fate of nephrogenic rests is, however, uncertain. These cells may terminate their differentiation, or eventually regress and become sclerotic and obsolescent, whereas others can progress to form hyperplastic nephrogenic rests, with typical genetic changes. Nephrogenic rests are found in >90% of patients with bilateral WTs and in ~30–40% of patients with unilateral sporadic WT. WTs are then characterized by the acquisition of additional genetic and epigenetic changes, some of them being quite specific for histological subtypes. The percentages indicate the frequency of mutation in sporadic cases. It is unclear whether WTs originate directly from nephrogenic blastema without progression through nephrogenic rest stages. CCSK, clear cell sarcoma of the kidney; CMN, congenital mesoblastic nephroma; LOH, loss of heterozygosity; LOI, loss of imprinting; miRNA, microRNA; RCC, renal cell carcinoma; RTK, rhabdoid tumour of the kidney. aIGF2–H19 LOH/LOI have not been shown in epithelial WTs. | Spreafico, F., Fernandez, C.V., Brok, J. et al. Wilms tumour. Nat Rev Dis Primers 7, 75 (2021). https://doi.org/10.1038/s41572-021-00308-8
Denys-Drash syndrome: Male pseudo-hermaphroditism and progressive renal failure starting in infancy due to mesangial sclerosis leading to early-onset nephrotic syndrome
WT2 gene (11p15.5) associated syndromes:
Beckwith-Wiedemann syndrome: Clinically diagnosed by hemihypertrophy, pancreatic enlargement, hypertrophic kidneys, omphalocele, ear creases, macrosomia, and macroglossia
Other syndromes: Sotos syndrome, Perlman syndrome, Trisomy 18 (Edward’s syndrome), Frasier syndrome, Bloom syndrome, Li-Fraumeni syndrome, and Simpson-Golabi-Behmel syndrome.
Associated malformations:
These are associated with the malignancy although it is unlikely they play any role in actual carcinogenesis.
Hemihypertrophy and aniridia
Urological disorders: Cryptorchidism, horseshoe kidney, and hypospadias
Presentation
Wilms tumor usually presents as an asymptomatic abdominal mass in the majority of children. The mother may have discovered the mass during bathing the infant.
Abdominal pain
Gross hematuria
Urinary tract infections
Varicocele
Fever
Anemia
Paraneoplastic syndromes:
Hypertension /hypotension (up to ⅓ cases demonstrate hypertension which normalizes after nephrectomy)
Erythrocytosis/polycythemia
Hypercalcemia
Cushing syndrome
Acquired von Willebrand disease
Metastasis:
Lung metastases (M/C): Dyspnea or tachypnea
Regional lymph nodes
Liver
Diagnosis
Tissue biopsy:
Triphasic blastoma (recapitulating stages of normal renal development):
Stromal, epithelia, & blast cells
Favorable histology (90% cases): Classical histological features of a “favorable” Wilms tumor include a triphasic pattern of blastema, epithelial, and stromal tissues
Unfavorable histology: Wilms tumors with “unfavorable” histology will demonstrate much higher degrees of anaplasia and are associated with a relatively poorer prognosis and survival
Different histological patterns of Wilms tumour: a | Mixed type, with the blastemal and epithelial component. b | Blastemal type. c | Mixed type consisting of the mature epithelial and stromal components. d | Epithelial type composed of moderately differentiated tubules. e | Stromal type with heterologous elements including cartilage and skeletal muscle. f | Anaplasia in Wilms tumour with atypical mitoses, nuclear enlargement and hyperchromasia. | Spreafico, F., Fernandez, C.V., Brok, J. et al. Wilms tumour. Nat Rev Dis Primers 7, 75 (2021). https://doi.org/10.1038/s41572-021-00308-8
Rhabdoid renal tumors: Highly malignant and most often < 2 years and almost never in children older than 5 years
Congenital mesoblastic nephroma: Typically found in 1st year of life, most often by ultrasound. Hypertension and elevated renin levels usually accompany it.
Renal cell carcinoma (rare in pediatric age group)
Renal medullary carcinoma: Very aggressive and dangerous cancer found almost exclusively in sickle cell disease, usually trait
Laparoscopic nephrectomy after chemotherapy: A. Large left renal mass; B. shrinkage of the tumor after chemotherapy, although it is still not amenable for a partial nephrectomy; C. left laparoscopic transperitoneal radical nephrectomy; D. dissection of renal artery and vein; E. final cosmetic result. | Lopes, R. I., & Lorenzo, A. (2017). Recent advances in the management of Wilms’ tumor. F1000Research, 6, 670. https://doi.org/10.12688/f1000research.10760.1
