Maintenance chemotherapy to reduce the risk of a metachronous Wilms tumor in children with bilateral nephroblastomatosis

From 2009 to 2018, 10 consecutive patients with Wilms tumors and bilateral nephroblastomatosis, who had completed standard therapy, were provided a maintenance chemotherapy regimen consisting of vincristine and dactinomycin every 3 months for 12 months in order to prevent an early metachronous Wilms tumor. One patient (10%) with Beckwith‐Wiedemann syndrome developed a new tumor, without anaplasia. There were no significant toxicities reported during maintenance. All patients are currently alive with no evidence of disease. Further investigations are recommended to determine the utility of this approach.     

Hyperplastic perilobar nephroblastomatosis: long-term survival of 52 patients

BACKGROUND: This study provides insight into the clinical behavior, diagnostic complexities, and long-term management of patients with hyperplastic perilobar nephroblastomatosis (HPLN). PROCEDURE: Fifty-two patients with HPLN with available long-term follow-up were retrospectively analyzed for pathologic, radiologic, and clinical features. RESULTS: The mean age at diagnosis was 16 months; the lesions were bilateral in 49 patients. Of 33 patients who initially underwent diagnostic biopsy and adjuvant chemotherapy, 18 (55%) developed Wilms tumor (WT) at a mean of 35 months from diagnosis. Of 16 patients whose initial therapy included nephrectomy and adjuvant therapy, three (19%) developed WT at a mean of 36 months from diagnosis. All three patients who underwent initial diagnostic biopsy and received no adjuvant therapy during their initial course developed WT 4, 4, and 10 months following diagnosis. 24/52 patients developed either a single (13 patients) or multiple (11 patients) WT throughout their course; 8/24 (33%) of WT were anaplastic. The time from initial diagnosis to the development of the last WT ranged from 13 to 116 months (mean 42 months). Three children with HPLN died of WT at 3, 5, and 6 years of age; 2/3 were anaplastic. CONCLUSIONS: HPLN is a self-limited, pre-neoplastic proliferative process associated with a high risk of developing WT. The accurate diagnosis and the choices of therapy during the often-complex course of HPLN depend on the availability and accurate interpretation of a combination of pathologic, radiologic, and clinical information. When such information is appropriately obtained, the long-term survival of patients with HPLN is excellent.     

Hepatotoxicity of chemotherapy following nephrectomy and radiation therapy for right-sided Wilms tumor.

Two children developed hepatotoxicity during treatment for right-sided Wilms Tumor. Treatment consisted of nephrectomy, irradiation, and chemotherapy with actinomycin D and vincristine. Hepatic enlargement, thrombocytopenia, and abnormalities in liver function and seen on the liver scan occurred at the time of the course of chemotherapy administered 20 days after completion of irradiation. These abnormalities disappeared when treatment was temporarily suspended. Vincristine and actinomycin D were subsequently reintroduced without evidence of hepatotoxicity. Actinomycin D after irradiation for right-sided Wilms tumor may produce severe liver toxicity.     

Long‐term remission of bilateral Wilms tumors that developed from premature separation of chromatids/mosaic variegated aneuploidy syndrome due to bilateral nephrectomy and peritoneal dialysis

We report a 38‐month‐old Japanese male with premature chromatid separation/mosaic variegated aneuploidy syndrome bearing biallelic BUB1B germline mutations who suffered from bilateral Wilms tumor. After right nephrectomy, dactinomycin monotherapy was administered for the left Wilms tumor; however, severe adverse reaction prevented the patient from receiving further chemotherapy. Left nephrectomy was then performed without postoperative chemotherapy. The patient survived for 15 months after bilateral nephrectomy without peritoneal relapse, metastasis of Wilms tumor, or the occurrence of rhabdomyosarcoma and maintained a good quality of life while receiving peritoneal dialysis at home.     

The varied spectrum of nephroblastomatosis,nephrogenic rests,and Wilms tumors: Review of current definitions and challenges of the field

The diagnosis of multiple or diffuse renal lesions in a child is challenging by imaging and/or pathology. Optimal management requires distinguishing benign lesions such as nephrogenic rests from cancerous lesions such as Wilms tumor, but this is often difficult or impossible. This difficulty is compounded by the overlapping nature of our current radiologic and pathologic definitions of lesions along the spectrum of nephrogenic rests/nephroblastomatosis. We provide a review of these issues, as a collaborative effort between the Children's Oncology Group Renal Tumor Committee and International Society of Pediatric Oncology Renal Tumor Study Group. Our aim is to discuss current challenges in diagnosis and management of these renal lesions, encouraging future work toward consensus definitions for research and patient care.     

Severe intrarenal fibrosis,infundibular stenosis,renal cysts,and persistent perilobar nephrogenic rests in a patient with Beckwith-Wiedemann syndrome 27 years after diffuse nephroblastomatosis and Wilms tumor: natural progression or a consequence of treatment?

A27-year-old woman presented with back and abdominal pain. She was diagnosed in infancy with Beckwith-Wiedemann syndrome and bilateral multifocal perilobar nephrogenic rests that progressed to diffuse nephroblastomatosis with neoplastic nephroblastomatous rests at 14 months of age and subsequently to a right Wilms tumor at 5 years of age. Computed tomography of the abdomen during the current admission showed multiple obstructed calices. Ureteroscopic inspection of the left kidney revealed severe intrarenal scarring with multiple infundibular stenosis, hydrocalices, and nephrocalcinosis. Renal biopsy showed sclerotic glomeruli with calcification and scarring and persistent subcapsular nodular renal blastema. Electrocautery incision and balloon dilatation provided temporary pain relief. After discharge, the patient has had two or three episodes of recurrent pain associated with new areas of infundibular stenoses and renal cysts. Bilateral nephrectomy and renal transplantation is being considered for management of progressive disease and relief of intractable pain. The potential causes of progressive and severe intrarenal fibrosis, infundibular stenosis and nephrocalcinosis, and renal cysts in this patient may include abnormal renal development secondary to Beckwith-Wiedemann syndrome itself, radiation or chemotherapy damage, or a combination.     

Bilaterally multicentric synchronous Wilms' tumor: Successful conservative treatment despite persistence of nephrogenic rests

We report a case of synchronous bilateral Wilms' tumor in a girl with incomplete Beckwith-Wiedemann syndrome and hemihypertrophy. Multiple small tumors were present in both kidneys. The initial diagnostic biopsy showed stage I monophasic blastematous Wilms' tumor of favorable histology, with multiple perilobar nephrogenic rests (nephroblastomatosis). By flow cytometry, tumor was diploid, with an S-phase fraction of 13.9%. Dactinomycin and vincristine were begun as per the National Wilms' Tumor Study IV (18 week course). After 1 month, only a single small lesion was evident, which persisted unchanged. Excisional biopsy 5 months after beginning chemotherapy showed entirely necrotic tumor but apparently unaltered nephrogenic rests. After completing chemotherapy, the child has done well, with normal renal function and no evidence of disease 3 years after diagnosis. Management of stage V Wilms' tumor is tailored to the individual case, being as conservative as possible to spare renal parenchyma. Given the high incidence of coexisting nephrogenic rests in bilateral Wilms' tumor, careful follow-up is required, as these potentially pre-malignant rests may resist chemotherapy. Med. Pediatr. Oncol. 28:420–423, 1997. © 1997 Wiley-Liss, Inc.     

Successful treatment of renal hypertension in a 2 1/2-year-old girl with the converting enzyme inhibitor captopril (author's transl)

A girl aged 2 1/2 year on chronic hemodialysis, treated with converting enzyme inhibitor Captopril because of severe uncontrollable renal hypertension, returned for the first time to a satisfactory stable blood pressure. After three months of this therapy the bilateral nephrectomy was performed. Two weeks later the patient showed a stable blood pressure, normal for age. None of the known side effects was seen. Whether the oxalat deposits found with nephrectomy were due to the treatment with Captopril, cannot yet be answered.     

Recurrence of Wilms tumor after apparent cure

The recurrence of Wilms tumor after a 5-year disease-free interval is rare. We present two patients who had recurrent disease after a disease-free interval of greater than 7 years. Three additional patients, registered with the National Wilms Tumor Study who had a recurrence after 5 years, are also described. Of these three patients, two had nephroblastomatosis. Because more patients are achieving long-term survival, careful surveillance after apparent "cure" is recommended, particularly if nephroblastomatosis is identified in the original nephrectomy specimen.     

Pediatric Renal Tumors: Practical Updates for the Pathologist

Pediatric renal tumors were targeted by the National Wilms Tumor Study Group for 4 decades with extraordinary success. Within this historic context, this review provides a summary of the new Children’s Oncology Group renal tumor protocols that will be opening in the very near future, focusing on their pathologic requirements. All renal tumors must first be registered on the Renal Tumor Classification and Banking Protocol, followed by registration on 1 of 4 primary therapeutic protocols based on histology, stage, and molecular analysis. This requires prompt submission of samples for molecular analysis and central pathologic review. Changes in staging criteria include classification of all tumor spillage as stage III, and requirement of regional lymph node evaluation for eligibility for stage I Wilms tumors (WTs) weighing less than 550 g in infants younger than 24 months and for stage I clear cell sarcoma. Patients with unilateral favorable histology WT with loss of heterozygosity for chromosomes 1p and 16q will receive more aggressive chemotherapy at each stage. Patients with bilateral WT and patients with diffuse hyperplastic perilobar nephroblastomatosis will be eligible for a novel therapeutic protocol requiring pathologic classification based on response of tumor to previous therapy. Stage I anaplastic WT will be targeted with more aggressive chemotherapy than in the past. For the first time, pediatric renal cell carcinoma will be eligible for a cooperative group protocol. All rhabdoid tumors outside the central nervous system will be eligible for a single protocol. In conclusion, these new protocols bring considerable change in their overall organization, in eligibility, and in therapy.     

Management of Wilms tumors in Drash and Frasier syndromes

Background

Children with WT1 gene‐related disorders such as Denys–Drash syndrome (DDS) and Frasier syndrome (FS) are at increased risk of Wilms tumor and end‐stage renal disease. We investigated whether Wilms tumors in these patients displayed a specific phenotype or behavior and whether nephron‐sparing surgery was beneficial.

Procedure

We retrospectively studied all patients with DDS, FS, or other WT1 mutations treated at our institutions between 1980 and 2007.

Results

We identified 20 patients, of whom 18 had benign or malignant tumors. Wilms tumors occurred in 15 patients, being unilateral in 10 and bilateral in 5 (20 tumors). Median age at Wilms tumor diagnosis was 9 months. No patients had metastases. According to the International Society of Pediatric Oncology Working Classification, there were 19 intermediate‐risk tumors and one high‐risk tumor; no tumor was anaplastic. In patients with nephropathy who underwent unilateral nephrectomy for Wilms tumor or nephron‐sparing surgery for bilateral Wilms tumor, mean time to dialysis was 11 or 9 months, respectively. Other tumors included three gonadoblastomas (in two patients), one retroperitoneal soft‐tissue tumor, and one transitional cell papilloma of the bladder. Two patients, both with stage I Wilms tumor, died from end‐stage renal disease‐related complications. The median follow‐up time for the 18 survivors was 136 months (range, 17–224 months).

Conclusion

Most Wilms tumors in children with WT1‐related disorders were early‐stage and intermediate‐risk tumors, with a young age at diagnosis. In patients without end‐stage renal disease, nephron‐sparing surgery should be considered for delaying the onset of renal failure. Pediatr Blood Cancer 2009;52:55–59. © 2008 Wiley‐Liss, Inc.     

Treatment of Wilms tumor relapsing after initial treatment with vincristine and actinomycin D: a report from the National Wilms Tumor Study Group

PURPOSE: NWTS-5 was a multi-institutional clinical trial for patients less than 16 years of age at diagnosis with specific renal neoplasms who were diagnosed between August 1, 1995 and May 31, 2002. A uniform approach to the treatment of patients with relapse was employed. PATIENTS AND METHODS: Seventy-two patients who relapsed after immediate nephrectomy (stages I and II), initial chemotherapy with vincristine (VCR) and actinomycin D and no radiation therapy were registered on stratum B of the NWTS-5 relapse protocol. Four patients were not evaluable: one due to insufficient data and three due to major protocol violations. Among the 68 remaining patients, one who was 19 years of age at initial diagnosis of Wilms tumor, five with bilateral Wilms tumor at diagnosis, three who developed a contralateral relapse, and one with persistent disease were not included in this analysis. Relapse treatment included surgical excision, when feasible, radiation therapy and alternating courses of VCR, doxorubicin and cyclophosphamide and etoposide and cyclophosphamide. RESULTS: The outcomes of 58 patients were analyzed. The lung was the only site of relapse for 31 patients. Event-free survival 4 years after relapse was 71.1% and 4-year overall survival was 81.8% for all patients and were 67.8 and 81.0% for those who relapsed only to their lungs. The most frequent toxicities were hematological. CONCLUSIONS: These results demonstrate that a significant proportion of children with Wilms tumor who relapse after initial treatment with VCR and actinomycin D can be successfully re-treated.     

Infantile polycystic disease. Renal pseudotumoral growth in the postnatal period

In the most common clinical expression of infantile polycystic disease, the kidneys are greatly enlarged in the neonatal period. When the child gets older the kidneys become smaller. In this case report, both kidneys kept growing after birth causing abdominal distention and respiratory distress. The differential diagnosis was a bilateral massive nephroblastomatosis, but the renal pathology showed characteristic features of infantile polycystic disease.     

Nephron-sparing procedures in 11 patients with Wilms' tumor

PURPOSE: In unilateral Wilms' tumor (WT), tumor nephrectomy is the standard surgical approach, whereas partial nephrectomy (PN) is controversially discussed. The aim of our retrospective study was to show that in selected cases of unilateral WT kidney-sparing operations could be a reasonable alternative to nephrectomy and to discuss the results of patients with bilateral WT treated by tumor enucleation. MATERIALS AND METHODS: From 1981 to 1998, seven patients with unilateral nephroblastoma (four stage I, one stage III and two stage IV) had tumor resection by PN (five right side, two left side), which was planned when the tumor volume was reduced after 4 to 6 weeks of chemotherapy by at least 50%, when the tumor occupied one pole or was easily resectable, when 50% or more of the kidney tissue remained and when paraaortic lymph nodes were free by intraoperative histological examination. In four patients with bilateral WT (stage V) bilateral tumor enucleation was carried out-except in one patient in whom the contralateral kidney had to been removed because of extension of the tumor via the inferior vena cava to the right atrium. All patients ( n = 11) received pre- and postoperative chemotherapy followed by radiotherapy in four patients. RESULTS: All patients with unilateral WT ( n = 7) are still alive and disease free (follow-up time: mean 6.6 years, range: 28 months to 11 years) with normal renal function, although two patients with secondary nephrectomy revealed creatinine clearance levels at the lower range. In six patients primary PN was performed successfully. In a stage III tumor patient (intraperitoneal metastasis, free lymph nodes), secondary nephrectomy was necessary due to renal arterial thrombosis 2 days after PN. In one stage IV tumor patient (lung metastasis, free lymph nodes), the primary resection was not far enough away from the tumor margin so that an additional slice of tissue with then tumor-free margins had to be resected. This patient evolved a local relapse 19 months after PN and had to be nephrectomised thereafter. In the group of bilateral WT patients ( n = 4), one child died 2 months after surgery during chemotherapy because of central venous line sepsis. One patient who additionally suffered from inferior vena cava tumor thrombosis extending to the right atrium making nephrectomy of the right kidney necessary developed chronic renal failure 4.7 years postoperatively. The other two stage V tumor patients have creatinine clearance levels within the normal range. CONCLUSIONS: Kidney-sparing procedures remain the operative approach of choice in patients with bilateral WT, but bear the risk of chronic renal failure when one kidney has to be removed. PN in children with unilateral WT, carried out by an experienced surgeon, is a reasonable alternative to nephrectomy if strict guidelines such as excellent tumor response to preoperative chemotherapy and easy resectability far away from the tumor margins through healthy kidney tissue are followed. Paraaortic lymph nodes must be free of tumor invasion in order to avoid local radiotherapy. PN prevents the patient from having to have dialysis in cases of contralateral nephrectomy resulting from metachronous WT or subsequent renal trauma.     

A case of Perlman syndrome presenting with hemorrhagic hemangioma

The presence of enlarged, echogenic kidneys in a newborn with generalized macrosomia points toward diagnosis of an overgrowth syndrome. These include Beckwith-Wiedemann, Perlman and Simpson-Golabi-Behmel syndromes. Perlman syndrome is an autosomal recessively inherited overgrowth syndrome characterized by fetal gigantism, visceromegaly, unusual face, bilateral renal hamartomas with nephroblastomatosis, and Wilms tumor. We report a male infant who exhibits typical features of Perlman syndrome with an unusual presentation. In this report, it is emphasized that hemangioma in neonatal period may be an unusual finding in Perlman syndrome.     

Combined local treatment and chemotherapy in the management of bilateral retinoblastomas in Hungary

This retrospective study supports that brachytherapy combined with cytostatic therapy may effectively contribute to tumor control. The second eye of 13 patients with bilateral retinoblastoma was treated with plaque brachytherapy after the enucleation of the first eye. Eleven patients received systemic cytostatic therapy. The mean follow up was 60 (+/-42 SD) months. Twelve patients are alive and free of tumor, 8 of them with acceptable visual acuity. After cytostatic therapy, late nephropathy was observed in 2 patients. In conclusion, brachytherapy combined with cytostatic therapy will be an option in the management of bilateral retinoblastoma after the enucleation of the first eye.     

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.     

Post‐transplant lymphoproliferative disorder resembling Wilms tumor. Diagnostic dilemma: Renal biopsy or nephrectomy?

Cheng E, Fustino N, Klesse L, Chinnakotla S, Sanghavi R. Post‐transplant lymphoproliferative disorder resembling Wilms tumor. Diagnostic dilemma: Renal biopsy or nephrectomy?
Pediatr Transplantation 2011: 15: E187–E191. © 2010 John Wiley & Sons A/S. Abstract: Post‐transplant lymphoproliferative disorder is a life‐threatening neoplasm that can occur after orthotopic liver transplant. We report a 14‐month‐old female status‐post OLT with an atypical presentation of PTLD as a solitary renal mass. At eight‐wk post‐transplant, she presented with elevated transaminases, CMV counts (73 000 copies/mL), and EBV counts (35 000 copies/mL). CT scan revealed a solid heterogeneously enhancing right renal mass measuring 2.6 × 2.4 × 3.3 cm. The radiological diagnosis was Wilms tumor, although PTLD could not be excluded. Complete resection of a Wilms tumor is potentially curative. A needle biopsy would upstage the malignancy and result in radiochemotherapy that is deleterious to a liver graft. The mass was not amenable to partial nephrectomy. A total nephrectomy, given life‐long nephrotoxic immunosuppressants, was an unfavorable option. Thus, needle biopsy was performed. Histology confirmed monoclonal, EBV‐associated PTLD and diffuse large B‐cell lymphoma. Her therapy included immunosuppression reduction, cyclophosphamide, steroids, and anti‐CD20 monoclonal antibody. Concomitantly, she received Cytogam and gancyclovir. Complete remission was achieved three months after chemotherapy. This case illustrates that young age, CMV infection, and EBV infection are strong risk factors for PTLD. With such risk factors present, any mass or lesion in a solid organ transplant patient should be considered PTLD until proven otherwise.     

Bilateral Wilms' tumour. Results of treatment in 29 children

Retrospective analysis of 29 children with bilateral Wilms' Tumour, 14 boys and 15 girls, aged 4m-5 years, from regional centres of paediatric oncology in Poland, treated according to the O1-92 PPGL Protocol of Wilms' tumour, was performed. All patients were treated with two (ACT + VCR) or three (ACT, VCR, DOX) cytostatic drugs preoperatively, and 26 were operated upon after cytoreductive pretreatment. In 12 children nephrectomy was performed. In 28, kidney sparing surgery was possible and made with success. 2 patients who presented disseminated disease and 1 with nephroblastomatosis were given chemotherapy. 19 out of 29 (65.5%) are alive including 1 patient with nephroblastoma. EFS calculated according to Kaplan-Meier analysis for this group, was 58% at 67 months.     

Renal functional reserve in long-term survivors of unilateral Wilms tumor.

We hypothesized that long-term survivors of unilateral Wilms tumor would have a decreased renal functional reserve secondary to the consequences of hyperfiltration in the nephrons of the remaining kidney. Therefore we evaluated the renal functional reserve in 12 long-term survivors of Wilms tumor after unilateral nephrectomy (mean +/- SE: 15 +/- 1.1 years; range 9 to 23 years). We measured the creatinine clearance before and after an acute, oral protein load to determine the renal functional reserve. Study subjects and control subjects were matched for age, gender, and body surface area. The basal creatinine clearances were similar (Wilms group 132 +/- 13 vs control group 142 +/- 11 ml/min/1.73 m2; p = not significant (NS]. There was no significant difference in the renal functional reserve between long-term survivors of Wilms tumor and matched control subjects (Wilms group 17 +/- 11 vs control group 25 +/- 11 ml/min/1.73 m2; p = NS). The change in creatinine clearance was not secondary to volume expansion because the fractional excretion of sodium was unchanged with protein loading (Wilms group before loading 0.92 +/- 0.12 vs after loading 0.99 +/- 0.13 (p = NS); control group before loading 0.91 +/- 0.12 vs after loading 1.0 +/- 0.14 (p = NS)). We conclude that up to 15 years after nephrectomy for unilateral Wilms tumor in childhood, there is no evidence of hyperfiltration injury.