Wilms Tumor (Nephroblastoma), Version 2.2021, NCCN Clinical Practice Guidelines in Oncology.

The NCCN Guidelines for Wilms Tumor focus on the screening, diagnosis, staging, treatment, and management of Wilms tumor (WT, also known as nephroblastoma). WT is the most common primary renal tumor in children. Five-year survival is more than 90% for children with all stages of favorable histology WT who receive appropriate treatment. All patients with WT should be managed by a multidisciplinary team with experience in managing renal tumors; consulting a pediatric oncologist is strongly encouraged. Treatment of WT includes surgery, neoadjuvant or adjuvant chemotherapy, and radiation therapy (RT) if needed. Careful use of available therapies is necessary to maximize cure and minimize long-term toxicities. This article discusses the NCCN Guidelines recommendations for favorable histology WT.

Addition of Vincristine and Irinotecan to Standard Therapy in a Patient With Refractory High-risk Hepatoblastoma Achieving Long-term Relapse-free Survival.

Children with metastatic hepatoblastoma have a poor prognosis, even with dose intensification of cisplatin and doxorubicin. Vincristine and irinotecan have demonstrated activity in high risk disease. This report describes a 3-year-old girl with metastatic hepatoblastoma with unresectable disease after 5 cycles of cisplatin, 5-fluorouracil, vincristine, and doxorubicin who had a complete response of her metastatic disease to vincristine and irinotecan (intravenous and oral forms), allowing surgical resection of her liver disease. She remains in remission 48 months since therapy completion.

Is surgical resection and observation sufficient for stage I and II sacrococcygeal germ cell tumors? A case series and review.

BACKGROUND: Sacrococcygeal teratoma (SCT) is the most common germ cell tumor (GCT) of infancy. Up to 35% of infants may have malignant elements. The standard of care for SCT with malignant elements (SCT-ME) has been surgery and chemotherapy. However, cases where low-stage SCT-ME have been successfully observed following resection have been reported. PROCEDURE: To better understand the outcomes of low-stage SCT-ME that do not receive chemotherapy, we reviewed SCT pathology reports from five children's hospitals from 1999 to 2009. Information regarding staging workup, tumor markers, treatment, and outcome was collected for patients with stage I or II SCT-ME. An English language literature review was also performed. RESULTS: Seventy-four SCT were identified: 51 stage I and 23 stage II; 13 (18%) were SCT-ME: 5 stage I and 8 stage II; four stage I and four stage II tumors were not treated with chemotherapy. No stage I tumors recurred; all of the stage II tumors recurred and were successfully salvaged, two had no ME at recurrence. We identified another 10 stage I SCT-ME in the literature managed with active surveillance-two recurred and were successfully treated with surgery and chemotherapy. CONCLUSIONS: Overall, of the 14 cases of stage I SCT-ME, 12 survived with no recurrence and the two who did recur were successfully treated with platinum-based chemotherapy (EFS = 86%, overall survival [OS] = 100%); this suggests that patients with stage I SCT-ME could be observed after surgery and treated only upon recurrence. Stage II SCT-ME require further study in a clinical trial setting.

Risk stratification of pubertal children and postpubertal adolescents with clinical stage I testicular nonseminomatous germ cell tumors.

PURPOSE: The COG (Children's Oncology Group) currently recommends surveillance for all children and adolescents with clinical stage I testicular germ cell tumors. However, up to 30% of adults with clinical stage I testicular germ cell tumors harbor occult metastatic disease. In adults with clinical stage I nonseminoma some groups advocate a risk stratified approach. Occult metastases were noted in 50% of patients with features such as lymphovascular invasion or embryonal carcinoma predominance in the orchiectomy. However, to our knowledge there are no data on the impact of high risk features in such pubertal children and postpubertal adolescents. MATERIALS AND METHODS: We reviewed an institutional testis cancer database for pubertal children and postpubertal adolescents younger than 21 years. We tested the hypothesis that lymphovascular invasion, or 40% or greater embryonal carcinoma in the orchiectomy specimen, would increase the risk of occult metastases, ie relapse during surveillance or positive nodes on retroperitoneal lymph node dissection. RESULTS: We identified 23 patients with a median age of 18.6 years (range 7.1 to 20.9) at diagnosis. Of these patients 14 (60.9%) were on surveillance, 9 (39.1%) underwent primary retroperitoneal lymph node dissection and none received initial chemotherapy. Seven patients (30.4%) had occult metastatic disease. High risk pathological features were found in the orchiectomy specimen in 12 patients (52.2%), including all 12 (52.2%) with 40% or greater embryonal carcinoma and 3 (13.0%) with lymphovascular invasion. Seven patients (58.3%) with high risk features had occult metastatic disease vs none (0%) without high risk features (log rank p = 0.031). CONCLUSIONS: Approximately half of pubertal children and postpubertal adolescents with high risk clinical stage I testicular germ cell tumors harbor occult metastatic disease. These results may be useful when discussing prognosis and treatment with patients and families.

A comparison of pediatric, adolescent, and adult testicular germ cell malignancy.

BACKGROUND: Testicular germ cell tumors (T-GCTs) occur from infancy to adulthood, and are the most common solid tumor in adolescent and young adult males. Traditionally, pediatric T-GCTs were perceived as more indolent than adult T-GCTs. However, there are few studies comparing these groups and none that specifically evaluate adolescents. METHODS: An institutional database of T-GCT patients was reviewed and patients were categorized into Pediatric, aged 0-12 years, Adolescent, aged 13-19 years, and Adult, older than 20 years, cohorts. Demographics, tumor characteristics, disease stage, treatment, event-free survival (EFS), and overall survival (OS) were compared between groups. RESULTS: Overall, 413 patients (20 pediatric, 39 adolescent, 354 adult) met study criteria and were followed for a median of 2.0 years (0.1-23.6). Adolescents presented with more advanced stage than children (P = 0.018) or adults (P = 0.008). There was a higher rate of events in Adolescents (13, 33.3%) than in Adults (61, 17.2%) or Children (2, 10.0%). Three-year EFS was 87.2% in the Pediatric group, 59.9% in Adolescents and 80.0% in Adults (P = 0.011). In a multivariate analysis, controlling for stage, IGCCCG risk, and histology, the hazard ratio (HR) for an event was: 1 (Reference) for Adults, HR = 0.82 (95% CI 0.19-3.46; P = 0.33) for the Pediatric group, and HR = 2.22 (95% CI 1.21-4.07; P = 0.01) for Adolescents. Five-year OS was 100% in the Pediatric group, 84.8% in Adolescents, and 92.8% in Adults (P = 0.388). CONCLUSION: Lower EFS in adolescent T-GCT patients was observed than in either children or adults. Elucidating factors associated with inferior outcomes in adolescents is an important focus of future research.

Pathological review of Wilms tumor nephrectomy specimens and potential implications for nephron sparing surgery in Wilms tumor.

PURPOSE: Nephron sparing surgery is accepted as standard of care for children with bilateral Wilms tumor or Wilms tumor in a solitary kidney and some study protocols allow nephron sparing surgery in select cases of unilateral Wilms tumor. With the increasing use of nephron sparing surgery in Wilms tumor, we reviewed pathological features from Wilms tumor radical nephrectomy specimens to determine the potential efficacy of a nephron sparing approach. MATERIALS AND METHODS: Medical records of children undergoing pre-chemotherapy radical nephrectomy for unilateral Wilms tumor at our institution were reviewed. Ideal candidates for nephron sparing surgery were defined as those having a unifocal mass outside the renal hilum, sparing a third or more of the kidney, favorable histology, no signs of renal sinus or segmental vascular invasion, no metastatic lymph nodes or gross regional disease, and a distinct interface on pathological review between tumor and remaining parenchyma. RESULTS: A total of 78 children at a median age of 3.2 years (range 0.3 to 16.2) underwent pre-chemotherapy radical nephrectomy for unilateral Wilms tumor. Median tumor diameter was 11 cm (range 2.5 to 22). Of these children 36 (46.2%) had tumors sparing a third or more of the kidney and 70 (89.7%) had unifocal tumors. There were 73 specimens (94.6%) that showed favorable histology, and 56 (71.8%) of the specimens had a distinct border between tumor and remaining parenchyma. In total, 19 (24.4%) of the patients reviewed met all of our strict pathological criteria as ideal partial nephrectomy candidates. CONCLUSIONS: In a post hoc analysis using strict pathological criteria and accepted surgical oncologic principles, as many as 1 in 4 children undergoing pre-chemotherapy surgery for nonmetastatic, unilateral Wilms tumor have post-resection pathological tumor characteristics favorable for nephron sparing surgery.

Correlation between preoperative staging computerized tomography and pathological findings after nodal sampling in children with Wilms tumor.

PURPOSE: Guidelines for staging Wilms tumor mandate regional lymph node sampling at nephrectomy. However, the usefulness of preoperative computerized tomography in staging lymph nodes has not been rigorously investigated. Thus, we correlated preoperative computerized tomography and pathological lymph node findings to establish a radiological criterion for pathological lymph node enlargement. MATERIALS AND METHODS: We reviewed the medical records of children with Wilms tumor at our institution who underwent pre-chemotherapy surgery with lymph node sampling and had preoperative computerized tomography with contrast medium available for interpretation. Computerized tomography was independently reviewed by 2 radiologists blinded to the pathological findings. We collected data on the diameter of the largest regional lymph node identified and this measurement was correlated with the pathological results. RESULTS: A total of 52 children (25 male, 27 female) with a median age of 3.1 years (range 0.4 to 9.6) were identified. The median largest regional lymph node diameter was 6 mm (range 2 to 15). Of the children 10 (19.2%) had metastatic involvement of sampled lymph nodes. A radiological cutoff of 7 mm for lymph node positivity corresponded to a negative predictive value of 89.0%, a sensitivity of 70.0% and a specificity of 57.1%. A ROC curve was constructed with these data describing the prognostic ability of the diameter of the largest regional lymph node on preoperative computerized tomography to determine lymph node positivity in Wilms tumor, which revealed an AUC of 0.67 (95% CI 0.48-0.87, p = 0.09). CONCLUSIONS: By defining a radiological size cutoff for suspicious lymph nodes, preoperative computerized tomography for staging lymph nodes in Wilms tumor demonstrates potential clinical usefulness through risk stratification for therapy and future study design.

TP53 codon 72 polymorphisms in favorable histology Wilms tumors.

In Wilms tumor (WT), mutations in the gene encoding p53, TP53, are correlated with anaplasia; however TP53 variants have not been studied in favorable histology (FH) WTs. A single nucleotide polymorphism of TP53 encoding either arginine or proline at codon 72 is suggested to alter in vitro p53 behavior. Therefore, we analyzed tissue from 23 consecutive patients with FHWT to determine allelic and genotypic frequencies of Pro72 and Arg72 variants and correlate this with clinical outcomes. Interestingly, our cohort showed a statistically significant over-representation of the Arg allele and Arg/Arg genotype. However, the genotypic and allelic frequencies showed no significant correlation with age, stage, or disease recurrence.

Oncologic outcomes of partial versus radical nephrectomy for unilateral Wilms tumor.

BACKGROUND: Radical nephrectomy (RN) is the recommended surgical management as part of multi-modality therapy for unilateral Wilms tumor (UWT). Based on recent data demonstrating that renal preserving surgery decreases the likelihood of chronic renal disease and associated co-morbidities, we analyzed oncologic outcomes of patients after partial nephrectomy (PN) for UWT. METHODS: We identified all published cases of PN for UWT. Cases of elective PN for UWT were analyzed for tumor stage, presence, timing and location of disease recurrence, and overall survival (OS). Eighty-two patients had adequate data for analysis. For comparison, these endpoints were collected on consecutive children undergoing RN for UWT from 1985 to 2010 at our institution. RESULTS: Of the 82 PN patients, tumor stage was: I-64, II-10, III-6, IV-2. Of the 121 RN patients, the staging was: I-24, II-45, III-29, IV-23. In the PN group, at a median of 48 months (3-372), the recurrence-free survival (RFS), local RFS and OS were 89.1%, 92.7%, and 95.1%, respectively. In the RN group, at a median of 69 months (0-214), the RFS, local RFS, and OS were 83.1%, 95.0%, and 95.0%, respectively. After controlling for stage, there were no statistically significant differences in the above oncologic outcomes between the groups. CONCLUSION: Based on reported data, the oncologic outcomes of PN for UWT in selected patients do not appear to differ from those of RN. PN for appropriately selected patients with UWT should be studied in prospective, co-operative group trials.

Wilms tumor: preoperative risk factors identified for intraoperative tumor spill.

PURPOSE: We identified preoperative parameters associated with increased risk of intraoperative Wilms tumor spill. MATERIALS AND METHODS: We retrospectively reviewed an institutional database of patients diagnosed with Wilms tumor between 2000 and 2008. Inclusion criteria consisted of available abdominal computerized tomogram and pathological stage I to IV disease. Patient characteristics and neoadjuvant chemotherapy use were noted. After blinding, a radiologist reviewed preoperative computerized tomogram parameters, calculating tumor volume and assigning a preoperative radiological stage. RESULTS: Of 67 patients diagnosed with Wilms tumor 41 (22 males, 19 females) met inclusion criteria, while 26 had incomplete imaging for analysis. Comparison of patients with and without intraoperative tumor spill demonstrated no significant differences in age (3.8 vs 3.6 years), sex (3 males and 3 females vs 19 males and 16 females), body weight or tumor capsule thickness. Preoperative radiological staging was unable to predict pathological stage I to III disease. Six intraoperative tumor spills (15%) were identified (left in 4, right in 2), of which 3 were stage III disease and 3 stage IV. Without neoadjuvant chemotherapy, patients with tumors greater than 1,000 cc had an increased risk of spill (2 of 2 [100%] vs 4 of 33 [12%], p = 0.03). Of 9 patients with stage IV disease 0% (0 of 4) receiving neoadjuvant chemotherapy experienced tumor spill, while lack of neoadjuvant chemotherapy was associated with a 60% (3 of 5 patients, 1 male and 2 females) risk of stage IV spill (p = 0.17). CONCLUSIONS: The sole significant tumor spill risk factor identifiable preoperatively was tumor volume greater than 1,000 cc. However, spill occurred at volumes less than 400 cc. Although not statistically significant, neoadjuvant chemotherapy for stage IV disease trended toward diminishing spill risk. Patients with Wilms tumors greater than 1,000 cc may benefit from neoadjuvant chemotherapy with less tumor spill, while stage IV tumors warrant further study in this regard.

De novo SDHB gene mutation in a family with extra-adrenal paraganglioma.

A 14-year-old male presented with abdominal pain. Imaging illustrated a left-sided adrenal mass; he underwent a left nephrectomy, confirming an extra-adrenal PGL. Germline genetic testing revealed a heterozygous, likely pathogenic mutation in the SDHB gene. The patient's family subsequently underwent genetic testing; his mother and sister were both positive for the familial SDHB mutation. Cascade testing for the proband's maternal aunt and maternal grandparents was negative for the familial mutation. SNP genotyping was used to confirm relationships. This is the second reported case of a de novo SDHB gene mutation and the first reported case of a confirmed de novo mutation in a patient who was not the initial proband. As SDHB-associated PGLs and PCCs are expected to be more aggressive and malignant, it is imperative to identify patients with SDHB mutations early. Given that many patients with germline mutations have no family history of PGL of PCC, the possibility of de novo mutations must be considered. Further studies are needed to determine the rate of de novo mutation in SDHB and other SDH-complex genes. Up to 41% of patients with paragangliomas (PGL) or pheochromocytomas (PCC) have an identifiable hereditary cancer predisposition syndrome. Mutations in 12 genes are known to increase the risk of PGL and/or PCC; however, the de novo rate is mostly unknown. Only one case report exists of a de novo SDHB mutation. We present the second case of a family with a de novo SDHB mutation.

Erratum: Publisher Correction: Somatic mutations in DROSHA and DICER1 impair microRNA biogenesis through distinct mechanisms in Wilms tumours.

[This corrects the article DOI: 10.1038/ncomms5802.].

Somatic mutations in DROSHA and DICER1 impair microRNA biogenesis through distinct mechanisms in Wilms tumours.

Wilms tumour is the most common childhood kidney cancer. Here we report the whole-exome sequencing of 44 Wilms tumours, identifying missense mutations in the microRNA (miRNA)-processing enzymes DROSHA and DICER1, and novel mutations in MYCN, SMARCA4 and ARID1A. Examination of tumour miRNA expression, in vitro processing assays and genomic editing in human cells demonstrates that DICER1 and DROSHA mutations influence miRNA processing through distinct mechanisms. DICER1 RNase IIIB mutations preferentially impair processing of miRNAs deriving from the 5'-arm of pre-miRNA hairpins, while DROSHA RNase IIIB mutations globally inhibit miRNA biogenesis through a dominant-negative mechanism. Both DROSHA and DICER1 mutations impair expression of tumour-suppressing miRNAs, including the let-7 family, important regulators of MYCN, LIN28 and other Wilms tumour oncogenes. These results provide new insights into the mechanisms through which mutations in miRNA biogenesis components reprogramme miRNA expression in human cancer and suggest that these defects define a distinct subclass of Wilms tumours.

Single institution experience with Tru-Cut renal mass biopsy for diagnosing Wilms tumor.

PURPOSE: To evaluate the efficacy of needle biopsy for diagnosing Wilms tumor (WT) before chemotherapy. MATERIALS AND METHODS: We reviewed our institutional experience with Tru-Cut biopsy of pediatric renal masses in patients who subsequently underwent nephrectomy. We compared biopsy pathology with nephrectomy specimens to determine if biopsy accurately predicted final pathology. RESULTS: Seven children underwent Tru-Cut renal mass biopsy followed by surgical resection. In 4 patients, the final biopsy pathology was definitively read as WT and in 3 subjects, the pathology was read as WT versus hyperplastic nephrogenic rest. In all 7 patients, the nephrectomy pathology confirmed a diagnosis of WT. There were no complications after biopsy, and no patients have had local or regional recurrence. CONCLUSION: In our experience, pre-therapy Tru-Cut biopsy safely provides an adequate specimen for pathologic review in diagnosing WT.

Robot-assisted laparoscopic retroperitoneal lymph node dissection in an adolescent population.

Abstract Laparoscopic retroperitoneal lymph node dissection (RPLND) has been shown to be safe and effective in appropriately selected pediatric and adolescent patients with paratesticular rhabdomyosarcoma (RMS) and testicular germ-cell tumors (T-GCT). While the use of robot-assisted laparoscopy has expanded rapidly in many areas, there are very limited reports of its use with RPLND. We present two cases of adolescents who were treated using robot-assisted laparoscopic RPLND (R-RPLND)-one with paratesticular RMS (PT-RMS) and one with testicular GCT (T-GCT)-with good outcomes and low morbidity.

Extracorporeal membrane oxygenation (ECMO) initiation without intubation in two children with mediastinal malignancy.

We report the cases of two children presenting with severe airway compromise secondary to a mediastinal malignancy managed with extracorporeal membrane oxygenation without intubation. Results are presented on the use of ECMO as a primary means of stabilizing a pediatric patient with a critical mediastinal mass, thus providing another management strategy for this difficult situation.

Henoch-Schönlein purpura in a child with hyperimmunoglobulinemia D and periodic fever syndrome.

This report describes a 3-year-old girl with a long history of periodic fever who presented with Henoch-Schönlein purpura. She was diagnosed with hyperimmunoglobulinemia D and periodic fever syndrome by means of mutation analysis of the mevalonate kinase gene. The serum IgA concentration was markedly elevated, but the serum IgD concentration was normal. This report emphasizes that Henoch-Schönlein purpura may be an important clinical feature of hyperimmunoglobulinemia D and periodic fever syndrome. In addition, this syndrome should be considered in patients with Henoch-Schonlein purpura in whom there is a history of recurrent fevers, even when the serum IgD concentration is normal.