Bilateral disease and new trends in Wilms tumour

Wilms tumour is a great therapeutic success story within paediatric oncology; its prognosis is excellent. Although mainly sporadic, occurring in otherwise well children, it occurs in a small number of genetically predisposed children. Thus regular surveillance imaging is performed in predisposed children in parts of the USA and Europe. The risks and benefits of surveillance are unclear, as the existing ad-hoc surveillance protocols are lacking in consistency of practice and equity of provision. We present guidelines for Wilms tumour surveillance based on a review of current practice and available evidence, outlined by a multidisciplinary working group in the UK. Wilms tumours are bilateral in 4–13% of affected children. Bilateral synchronous nephroblastomas are observed in 5% of affected children and are usually associated with the presence of nephrogenic rests, congenital malformations and predisposing syndromes. The major challenge in bilateral disease is to achieve a cure and at the same time to preserve sufficient functional renal tissue for normal growth and development. The association among Wilms tumour, nephrogenic rests and nephroblastomatosis makes detection and characterization of renal lesions with imaging extremely important. We discuss the relative strengths and weaknesses of the different modalities used for diagnosis and follow-up in bilateral renal disease. We also discuss newly emerging diagnostic imaging tests such as ¹⁸F-fluorodeoxyglucose positron emission tomography (FDG-PET). This technique, when fused with CT (PET-CT), allows accelerated metabolic activity to be accurately anatomically localised and so is potentially useful for staging, assessment of treatment response, and for surgical and radiotherapy planning. In addition, quantitative MRI techniques have been proved to be valuable in intracranial tumours, but no such role has been validated in abdominal disease. Diffusion-weighted imaging with calculation of ADC maps is feasible in abdominal tumours, and our own preliminary data suggest that tissue cellularity is an important determinant of ADC value, which might help in terms of early prediction of therapy response.     

Screening for Wilms tumor and hepatoblastoma in children with Beckwith-Wiedemann syndromes: a cost-effective model

BACKGROUND: We undertook a cost-benefit analysis of screening for Wilms tumor and hepatoblastoma in children with Beckwith-Wiedemann syndrome (BWS), a known cancer predisposition syndrome. The purpose of this analysis was twofold: first, to assess whether screening in children with BWS has the potential to be cost-effective; second, if screening appears to be cost-effective, to determine which parameters would be most important to assess if a screening trial were initiated. PROCEDURES: We used data from the BWS registry at the National Cancer Institute, the National Wilms Tumor Study (NWTS), and large published series to model events for two hypothetical cohorts of 1,000 infants born with BWS. One hypothetical cohort was screened for cancer until a predetermined age, representing the base case. The other cohort was unscreened. For our base case, we assumed: (a) sonography examinations three times yearly (triannually) from birth until 7 years of age; (b) screening would result in one stage shift downward at diagnosis for Wilms tumor and hepatoblastoma; (c) 100% sensitivity and 95% specificity for detecting clinical stage I Wilms tumor and hepatoblastoma; (d) a 3% discount rate; (e) a false positive result cost of $402. We estimated mortality rates based on published Wilms tumor and hepatoblastoma stage specific survival. RESULTS: Using the base case, screening a child with BWS from birth until 4 years of age results in a cost per life year saved of $9,642 while continuing until 7 years of age results in a cost per life-year saved of $14,740. When variables such as cost of screening examination, discount rate, and effectiveness of screening were varied based on high and low estimates, the incremental cost per life-year saved for screening up until age four remained comparable to acceptable population based cancer screening ranges (< $50,000 per life year saved). CONCLUSIONS: Under our model's assumptions, abdominal sonography examinations in children with BWS represent a reasonable strategy for a cancer screening program. A cancer screening trial is warranted to determine if, when, and how often children with BWS should be screened and to determine cost-effectiveness in clinical practice.     

Screening for Wilms tumor in children with Beckwith-Wiedemann syndrome or idiopathic hemihypertrophy

BACKGROUND: Children with Beckwith-Wiedemann syndrome and idiopathic hemihypertrophy (BWS/HH) are at increased risk for developing Wilms tumor and screening with abdominal sonography is frequently recommended. However, there is a paucity of published data supporting this strategy. The purpose of this study was to determine whether sonographic screening at intervals of 4 months or less reduced the proportion of late-stage Wilms Tumor (WT) in children with BWS/HH. PROCEDURE: A case series analysis was employed to compare the proportion of late-stage (stage III or IV) Wilms tumor in patients with BWS/HH who were screened with sonography (n = 15) to the proportion of late-stage Wilms tumor in unscreened patients with BWS/HH (n = 59). Patients were identified from the BWS Registry and from previously published studies. Screened patients had sonograms at intervals of 4 months or less. RESULTS: None of the 12 screened children with Wilms tumor had late-stage disease, whereas 25 of 59 (42%) of unscreened children had late-stage Wilms tumor, a difference that was statistically significant (P < 0.003). Three children had false positive screening studies. They were operated on for suspected Wilms tumor but the lesions proved to be complicated renal cysts (n = 2) or nephroblastomatosis (n = 1). CONCLUSIONS: This study suggests that children with BWS/HH may benefit from screening sonograms at intervals of 4 months or less. However, false positive screening exams may result in unnecessary surgery. Given the rarity of BWS/HH, a larger, prospective international screening study is necessary to determine if the benefits of screening outweigh the risks.     

Surgery for the complex Wilms tumour

The prognosis of children with Wilms tumour has greatly improved since the introduction of adjuvant radiotherapy and chemotherapy more than 70 years ago with a current overall long-term survival approaching 90%. Before this, surgery was the only option with around 20% survival, even in low-risk categories. The focus is now on management options for those patients in specific subgroups, who continue to have lower event-free survival and who suffer from the long-term effects of treatment. These include those with anaplastic histology, bilateral Wilms, biologically high-risk tumours and those that relapse (Aldrink et al. in J Pediatr Surg 54(3):390–397, 2019). The major advances that have already been made in risk assessment and tailoring the chemotherapy/radiotherapy to achieve maximum advantage with minimum toxicity and long-term morbidity have been predicated on safe and complete resection and staging of the tumour. There are, however, still surgical challenges faced with respect to resection of ‘complex’ tumours; thus, surgeons need to understand their role and advance their expertise in the overall treatment of children with Wilms tumour. These include very large tumours not responding to chemotherapy, ruptured tumours, tumours with intravascular invasion into the inferior vena cava (± 10%), heart and hepatic veins (± 4%) and Wilms tumours in horseshoe kidneys (< 1%) (Kieran and Ehrlich in Urol Oncol https://doi.org/10.1016/j.urolonc.2015.05.029, 2015). This review describes surgical strategies and techniques used in these situations, gleaned from the authors’ experience in the surgical management of over 300 children with Wilms tumours in our centres over the last 30 years.     

Extrarenal Wilms tumour.

INTRODUCTION: Nephroblastoma is one of the most common solid tumours in children. It also is the most frequent tumour found in the kidneys. In 5 % of cases it affects both kidneys at the same time. About 70 - 80 new cases of Wilms tumour are registered in Poland annually, usually in patients aged from 1 to 7 years. Extrarenal Wilms tumours are extremely rare. Due to its rarity, series with more cases are based upon material collected from many clinical centers. AIM: We would like to present a case of a boy in whom we diagnosed nephroblastoma in the retroperitoneal space 14 years after he had completed a complex therapy for bilateral Wilms tumour. CONCLUSION: The development of an extrarenal tumour 14 years after complex treatment for bilateral nephroblastoma is related to the survival of metanephros located outside the kidney.     

Controversies and advances in the management of Wilms' tumour

Wilms tumour is one of the success stories of paediatric oncology with long term survival approaching 90% in localised disease and over 70% for metastatic disease. Although appearing relatively simple compared to other cancer treatment regimens, successful treatment of Wilms tumour requires meticulous attention to correct staging of the tumour and good communication between the paediatric surgeon, pathologist and oncologist. The controversy of whether pre-operative chemotherapy results in a reduced overall burden of treatment compared to immediate nephrectomy has been addressed by the recently closed UKW3 randomised trial. Challenges remain in identification of histological and molecular risk factors for stratification of treatment intensity to allow safe reduction in therapy and avoidance of late sequelae for the majority while leading to increased biological insights and ultimately novel therapies for the minority of high risk tumours. Genetic predisposition to Wilms tumour is conferred by several genes, some of which cause malformation rather than cancer and may be of low penetrance. The proportion of children with heritable disease is uncertain and there remains a need to collect data on the need for screening in this susceptible population.     

Controversies and advances in the management of Wilms' tumour.

Wilms tumour is one of the success stories of paediatric oncology with long term survival approaching 90% in localised disease and over 70% for metastatic disease. Although appearing relatively simple compared to other cancer treatment regimens, successful treatment of Wilms tumour requires meticulous attention to correct staging of the tumour and good communication between the paediatric surgeon, pathologist and oncologist. The controversy of whether pre-operative chemotherapy results in a reduced overall burden of treatment compared to immediate nephrectomy has been addressed by the recently closed UKW3 randomised trial. Challenges remain in identification of histological and molecular risk factors for stratification of treatment intensity to allow safe reduction in therapy and avoidance of late sequelae for the majority while leading to increased biological insights and ultimately novel therapies for the minority of high risk tumours. Genetic predisposition to Wilms tumour is conferred by several genes, some of which cause malformation rather than cancer and may be of low penetrance. The proportion of children with heritable disease is uncertain and there remains a need to collect data on the need for screening in this susceptible population.     

Malignant tumours of the kidney: imaging strategy

Primitive malignant renal tumours comprise 6% of all childhood cancers. Wilms tumour (WT) or nephroblastoma is the most frequent type accounting for more than 90%. Imaging alone cannot differentiate between these tumours with certainty but it plays an important role in screening, diagnostic workup, assessment of therapy response, preoperative evaluation and follow-up. The outcome of WT after therapy is excellent with an overall survival around 90%. In tumours such as those where the outcome is extremely good, focus can be shifted to a risk-based stratification to maintain excellent outcome in children with low risk tumours while improving quality of life and decreasing toxicity and costs. This review will discuss the imaging issues for WT from the European perspective and briefly discuss the characteristics of other malignant renal tumours occurring in children and new imaging techniques with potential in this matter.     

Should children at risk for familial adenomatous polyposis be screened for hepatoblastoma and children with apparently sporadic hepatoblastoma be screened for APC germline mutations?

BACKGROUND: Hepatoblastoma (HB) is the most frequent liver tumor in childhood, occurring in the first few years of life. Surgery combined with chemotherapy has resulted in dramatic improvements in prognosis. However, even today, about one quarter of affected children do not survive the disease. Compared to the general population, the risk of HB is 750-7,500 times higher in children predisposed to familial adenomatous polyposis (FAP), an autosomal-dominant cancer predispostion syndrome caused by germline mutations in the tumor suppressor gene APC. Only limited data exist about the frequency of APC germline mutations in cases of apparently sporadic HB without a family history of FAP. PROCEDURE: In our sample of 1,166 German FAP families, all known cases of HB were registered. In addition, 50 patients with apparently sporadic HB were examined for APC germline mutations. RESULTS: In the FAP families, seven unrelated cases of HB are documented; three had been detected at an advanced stage. In patients with apparently sporadic HB, germline mutations in the APC gene were identified in 10%. CONCLUSIONS: These data raise the issue of the appropriate screening for HB in children of FAP patients. To date, the efficiency of surveillance for HB is unclear. In Beckwith-Wiedemann syndrome (BWS), recent studies suggest an earlier detection of both Wilms tumor and HB by frequent screening. We discuss the rationale and implications of a screening program; besides the examination procedure itself, screening for HB in children of FAP patients would have important consequences for the policy of predictive testing in FAP. In a substantial fraction of sporadic HB, the disease is obviously the first manifestation of a de novo FAP. These patients should be identified by routine APC mutation screening and undergo colorectal surveillance thereafter.     

Anaesthetic outcome and predictive risk factors in children with mediastinal tumours

PURPOSE: The aims were to identify and test the significance of specific factors associated with risks for anaesthesia in children with mediastinal tumours. PATIENTS AND METHOD: Clinical information was retrospectively collected from the records of 63 children presented with mediastinal tumour (1964-2002) in a regional Paediatric Oncology centre and correlated with the type and outcome of anaesthesia, using non-parametric analyses. RESULTS: Thirteen patients had local anaesthesia or sedation for diagnostic procedures and none developed any complication. Fifty children received general anaesthesia (GA) for diagnostic investigations or tumour resection. Two patients were excluded from the analysis because of treatment prior to GA. Problems with intubation, ventilation and cardiovascular collapse were encountered in 7 of 48 (15%) patients and this resulted in tracheostomy in one patient and death in 2 other cases. When compared with the 41 uncomplicated cases, the presence of at least 3 respiratory symptoms/signs, tracheal and vascular compression, and infection significantly increased the risk of GA. Of these, tracheal compression remained the strongest predictive factor. CONCLUSIONS: Decision to postpone GA should be considered if all these risk factors (tracheal compression, vascular compression, the presence of at least three respiratory symptoms/signs) are present in the same patient.     

Surveillance imaging in children with medulloblastoma (posterior fossa PNET)

Background. The use of surveillance imaging in children with medulloblastoma has been criticised. The aim of this study was to determine what proportion of relapses are detected by surveillance and whether these are found at a relatively favourable stage.¶Methods. This study was a retrospective review of the medical charts and imaging studies of 89 patients treated at a single children's cancer centre. Relapse was defined as evidence of an increase in volume of residual tumour of greater than 25 % or the presence of metastases, or new onset of positive CSF cytology. Relapse was termed symptomatic if it was diagnosed by tests performed because of new symptoms that occurred in the interval between surveillance examinations. Asymptomatic relapse was diagnosed solely on the basis of surveillance imaging. Survival time to relapse was calculated from the date of the first surgical procedure.¶Results. Surveillance imaging detected 17 (71 %) of the 24 relapses that occurred later than 6 months after diagnosis. All seven patients who presented with symptoms between scans have died, with a median survival from relapse of 5 months. Median survival from relapse in the patients detected by surveillance was 44 months, and four remain alive at 44–75 months. The patients detected by surveillance tended to have less advanced disease, which was more amenable to salvage therapy.¶Conclusion. This type of study cannot prove that surveillance imaging improves survival in children with medulloblastoma because of the effects of lead time and length biases. Despite this, surveillance does appear to be effective in detecting potentially curable medulloblastoma relapses and should be offered to all patients.     

Management of bilateral Wilms tumours

Wilms tumour is named after Max Wilms. It is an embryonal tumour derived from the metanephros. It is the commonest childhood renal tumour and the third commonest paediatric malignancy. Synchronous bilateral Wilms tumours (BWT) represent 4–7% of all Wilms tumours (WT) and present at a younger age than unilateral Wilms tumours. At least 10% of synchronous BWTs have unfavourable histology, and up to 22% are associated with genitourinary abnormalities, aniridia, WAGR syndrome, Denys–Drash Syndrome, hemihypertrophy, or one of the other overgrowth syndromes. The long-term disease-free survival (DFS) rate for patients with unilateral Wilms’ tumours is approaching 90%, and is around 70% for those with metastatic disease. For both synchronous and metachronous Wilms tumours the prognosis is less favourable with reported cure rates approaching 80% in the best centres and lower in resource poor settings. There is potential for a reduced quality of life due to renal insufficiency and the possible need for renal transplantation. The major clinical challenge in BWTs is preservation of functioning renal tissue using nephron sparing surgical techniques, while achieving cure with minimum therapy-related morbidity. Mortality is generally associated with progressive disease of anaplastic tumours. Chemotherapy followed by nephron sparing surgery has been able, in most cases, to eradicate the tumour while preserving renal function. Radiotherapy has largely been avoided because of fears of long term radiation injury to the residual functioning renal mass. Patient selection, appropriate pre- and post-operative chemotherapy and skilled surgical techniques all contribute to excellent outcomes where these are achievable.     

SIOP PODC: Clinical guidelines for the management of children with Wilms tumour in a low income setting

Wilms tumour is a relatively common and curable paediatric tumour. Known challenges to cure in low income countries are late presentation with advanced disease, malnutrition, failure to complete treatment and limited facilities. In this article, management recommendations are given for a low income setting where only the minimal requirements for treatment with curative intent are available (setting 1). These include general management, supportive care, social support and registration of patients. Recommendations specific for Wilms tumour care include diagnostic procedures with emphasis on the role of ultrasonography, preoperative chemotherapy with a reduced dosage for malnourished children and postoperative chemotherapy based on surgical staging. Pediatr Blood Cancer 2013; 60: 5–11. © 2012 Wiley Periodicals, Inc.     

Clear cell sarcoma of the kidney in children: experience in a developing country

Introduction  

Clear cell sarcoma of the kidney (CCSK) is a rare tumour comprising 4% of primary renal tumours in children. It has a unique constellation of chromosomal and molecular features and should no longer be viewed as an unfavourable histological variant of Wilms tumour. Little is known of its clinical presentation and pathological profile in children living in a developing country.     

SIOP PODC adapted treatment recommendations for standard‐risk medulloblastoma in low and middle income settings

Effective treatment of children with medulloblastoma requires a functioning multi‐disciplinary team with adequate neurosurgical, neuroradiological, pathological, radiotherapy and chemotherapy facilities and personnel. In addition the treating centre should have the capacity to effectively screen and manage any tumour and treatment‐associated complications. These requirements have made it difficult for many low and middle‐income countries (LMIC) centres to offer curative treatment. This article provides management recommendations for children with standard‐risk medulloblastoma (localised tumours in children over the age of 3–5 years) according to the level of facilities available. Pediatr Blood Cancer 2015;62:553–564. © 2014 Wiley Periodicals, Inc.     

An unusually severe phenotype for familial adenomatous polyposis

Familial adenomatous polyposis (FAP) is a dominantly inherited predisposition to the development of many hundreds to thousands of adenomatous polyps of the colon. The mean age of onset is around 15 years, symptoms may arise in the third decade, and the median age for the development of colonic cancer is 35-40 years. Prophylactic colectomy reduces the risk of death from colorectal cancer to such an extent that late sequelae such as upper gastrointestinal tumours have become the main cause of mortality in appropriately managed patients. The age at which colonic surveillance begins reflects the natural history of the disease. Onset of polyp formation and cancer in childhood is very unusual, but has recently been associated with a specific mutation at codon 1309 in exon 15 where a more severe phenotype is sometimes observed. The case histories of two families are reported in which there is childhood onset of polyps in the youngest generation and in one case a carcinoma, in whom mutations have been identified in exon 11 of the APC gene. Several other affected relatives were diagnosed at ages ranging from 5-48 years, some already with a cancer at the time of first screening. Since the aim of screening for colonic polyps is prevention of colonic cancer, family members at risk should be offered genetic assessment and direct mutation testing where this is possible, usually in the early teens. In the absence of a genetic test (the situation in about one third of families) or in a known gene carrier, annual colonoscopy examination is advised from the same age. Clinicians should take note of the family history and be prepared to consider much earlier intervention if symptoms occur in a child with a family history of FAP. Where childhood onset of polyps has occurred, other children at risk in the family must be offered earlier genetic testing and endoscopic surveillance.

     

Spontaneous regression of residual low-grade cerebellar pilocytic astrocytomas in children

Background: Cerebellar low-grade astrocytomas (CLGAs) of childhood are benign tumours and are usually curable by surgical resection alone or combined with adjuvant radiotherapy. Objective: To undertake a retrospective study of our children with CLGA to determine the optimum schedule for surveillance imaging following initial surgery. In this report we describe the phenomenon of spontaneous regression of residual tumour and discuss its prognostic significance regarding future imaging. Materials and methods: A retrospective review was conducted of children treated for histologically proven CLGA at Great Ormond Street Hospital from 1988 to 1998. Results: Of 83 children with CLGA identified, 13 (15.7%) had incomplete resections. Two children with large residual tumours associated with persistent symptoms underwent additional treatment. Eleven children were followed by surveillance imaging alone for a mean of 6.83 years (range 2–13.25 years). Spontaneous tumour regression was seen in 5 (45.5%) of the 11 children. There were no differences in age, gender, symptomatology, histological grade or Ki-67 fractions between those with spontaneous tumour regression and those with progression. There was a non-significant trend that larger volume residual tumours progressed. Conclusions: Residual tumour followed by surveillance imaging may either regress or progress. For children with residual disease we recommend surveillance imaging every 6 months for the first 2 years, every year for years 3, 4 and 5, then every second year if residual tumour is still present 5 years after initial surgery. This would detect not only progressive or recurrent disease, but also spontaneous regression which can occur later than disease progression.     

High birth weight and other risk factors for Wilms tumour: results of a population-based case-control study

Wilms tumour, or nephroblastoma, is one of the childhood cancers included in two recent population-based case-control studies in West Germany. Altogether, 177 children under the age of 10 years with Wilms tumour diagnosed between 1988 and 1994 and 2006 control children sampled from population registration files participated. Information on potential risk factors was obtained from the parents using a questionnaire and by subsequent telephone interview. We found an association with a high birth weight >4000 g (odds ratio 1.58; 95% confidence interval 1.01–2.48), which was somewhat stronger for children aged 2 years or older. Findings for young maternal age at birth and certain parental occupationally related exposures were not reported by previous studies and thus may be chance findings. As opposed to previous studies, we failed to confirm associations with high parental age at birth, maternal coffee and tea consumption during pregnancy, and exposure to pesticides. Conclusion Based on this large population-based case-control study, high birth weight may play a role in the aetiology of Wilms tumour, but many risk factors previously suggested are of less importance. Received: 31 July 2000 and in revised form 9 October 2000 and 14 November 2000 /  Accepted: 5 September 2000     

Genetic syndromes predisposing to paediatric brain tumours: the chicken or the egg?

Cancer in childhood is a disorder of growth and development. Up to 10% of patients diagnosed with cancer during childhood have a known underlying genetic predisposition syndrome. Affected individuals usually have multisystem involvement from the underlying syndrome and certain syndromes are associated with development of characteristic tumours with sites of predilection within the neuraxis. For the healthcare professionals involved with paediatric patients it is important to have basic knowledge of the cancer susceptibility syndromes. A holistic multidisciplinary approach is required for the overall management of the syndrome itself with specific recommendations for imaging surveillance and genetic counselling based on the pattern of inheritance and the relative risk of developing a tumour. Appropriate knowledge of these syndromes will help paediatricians manage and refer patients at risk to specialist neuro-oncology centres. A typical brain tumour diagnosis can also indicate certain underlying genetic disorders and examples of such tumours include optic pathway glioma, choroid plexus carcinoma and subependymal giant cell astrocytoma. A detailed family history can be helpful in identifying at risk patients and families as the typical clinical signs associated with the genetic condition are often not fully apparent in young children. This article focuses on well-known genetic diagnoses associated with or predisposing to childhood brain tumours. In some instances, the brain tumour diagnosis subsequently leads to the diagnosis of an underlying genetic syndrome.     

Sonographic detection of brain tumors in infancy

Using the open fontanelle as an acoustic window brain tumours were diagnosed by gray scale ultrasonography in 3 infants aged 1 day to 5 months. The tumours were characterized by their echo dense structure and their good delimination from the surrounding brain. In 2 children the tumour was localized infratentorially (medulloblastoma and unclassified neuroectodermal tumour) and had caused an occlusive hydrocephalus. Both children died aged 3 and 5 months in central nervous dysregulation. One child suffered from plexus papilloma which had caused a hypersecretory hydrocephalus. After resection of the tumour the hydrocephalus decreased without any further treatment. Comparison with axial computed tomography and autopsy findings showed, that gray scale ultrasonography is equally efficient in diagnosing brain tumours and associated hydrocephalus.