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.     

Complete necrosis induced by preoperative chemotherapy in Wilms tumor as an indicator of low risk: report of the international society of paediatric oncology (SIOP) nephroblastoma trial and study 9

BACKGROUND: The SIOP Nephroblastoma therapeutic protocols include a period of preoperative chemotherapy followed by nephrectomy and a period of postoperative chemotherapy. From the outset, identification of low-risk groups has been an aim of the SIOP Nephroblastoma Trials and Studies. Now that 90% of children with Wilms tumor can be cured, attention is even more focused on the identification of patients who could benefit from less aggressive postoperative therapy, thus minimizing the morbidity and late effects associated with treatment. The prognostic implications of total necrosis in nephroblastoma after chemotherapy have not been investigated hitherto. PROCEDURE: Between November 1, 1987 and June 30, 1993, 599 patients referred to the SIOP-9 Nephroblastoma Trial and Study were preoperatively treated and classified as stages I-IV nonanaplastic Wilms tumor. RESULTS: Of these 599 patients, pathologic examination of the nephrectomy specimen revealed a completely necrotic Wilms tumor (CNWT) with no viable tumor remaining in 59 (10%): these comprised 37 stages I-III and 22 stage IV. Of these patients, 58 (98%) had no evidence of disease at 5 years vs. 90% for the rest of the cohort (P < 0.05). Stages I-III patients represented 63% of CNWT and had a 97% overall survival rate. The only death was related to veno-occlusive disease and occurred in a stage I patient in the month following nephrectomy. Stage IV patients represented 37% of CNWT (vs. only 10% of all other cases of unilateral nonanaplastic Wilms tumor) and had a 100% rate of survival. Children with CNWT were older (mean 59 months vs. 43 months); their tumor at diagnosis was larger and had regressed more significantly at subsequent ultrasound examination. The data also uphold the hypothesis that Wilms tumors of blastemic pattern are most aggressive, but also are extremely responsive to chemotherapy. CONCLUSIONS: Patients with unilateral nonanaplastic WT that showed total necrosis following preoperative chemotherapy had excellent outcome and should benefit from less aggressive postoperative treatment in further trials. Other very responsive tumors, such as Wilms with <10% viable tumor, should also be assessed.     

Treatment of children with stage IV favorable histology Wilms tumor: A report from the National Wilms Tumor Study Group

The purpose of this study was to evaluate the effect of the sequential addition of doxorubicin and cyclophosphamide to the combination of vincristine and actinomycin D on the relapse-free survival of children with stage IV/favorable histology Wilms tumor. We reviewed the clinical courses of all randomized patients from National Wilms Tumor Study (NWTS)-2 and 3 with stage IV/favorable histology (FH) Wilms tumor. We determined the four-year relapse-free survival percentage for patients treated on NWTS-2 with the combination of vincristine (VCR) and actinomycin D (AMD) with (regimen D) or without (regimen C) doxorubicin (DOX), and for patients treated on NWTS-3 with the combination of VCR + AMD + DOX with (regimen J) or without (regimen DD-RT) cyclophosphamide (CTX). All children received whole lung radiation therapy. The four-year relapse-free survival percentage for children with stage IV/FH Wilms tumor treated with regimen C was 53.3%, compared to 57.7% for those treated with regimen D (P = 0.63). The four-year relapse-free survival percentage for children with stage IV/FH Wilms tumor treated with regimen DD-RT was 79.0%, compared to 80.9% for those treated on regimen J (P = 0.79). The four-year relapse-free survival for children with lung metastases only treated with regimen D on NWTS-2 was significantly lower than that of children treated with the related regimen DD-RT on NWTS-3 (P = 0.03). We conclude that the addition of doxorubicin to the combination of vincristine and actinomycin D and pulmonary irradiation did not clearly improve the four-year relapse-free survival percentage of children with stage IV/FH Wilms tumor, although the benefit may have been masked by the greater frequency of death due to toxicity in NWTS-2. There was no evidence that the addition of CTX to the three-drug treatment regimen improved the four-year relapse-free survival percentage of children with stage IV/FH Wilms tumor. The data with only two drugs derived from NWTS-2 suggest that there is a population of children with stage IV/FH Wilms tumor who can be successfully treated without an anthracycline. The goal of future research will be to identify this subgroup at the time of initial diagnosis. © 1996 Wiley-Liss, Inc.     

Intracranial relapse in Wilms tumor patients

BACKGROUND: In children with nephroblastoma, recurrence with metastases in the central nervous system is rare. Recently, previous reports (NWTSG and UKCCSG) reported brain metastases with an incidence of respectively 0.5% and 0.6% in Wilms tumor (WT) patients (respectively n = 30/5,852 and n = 7/1,249). PROCEDURE: We retrospectively investigated the incidence and survival of patients with central nervous system relapse in WT patients, treated according to the consecutive SIOP protocols 1, 2, 5, 6, 9, and 93-01. All children with WT from 1971 until 2000 were enrolled in the study (3,040 eligible patients). Specimens at diagnosis and if possible at relapse were centrally reviewed. Patients with renal neoplasms other than WT were excluded. RESULTS: CNS relapse was documented in 14 patients (0.5%). Median time to CNS relapse was 16 months (3-69). The occurrence of relapse was not associated with specific histological subtypes. In seven patients intracranial metastases occurred at first relapse, of which two were isolated relapses. In five patients no treatment was started because of the poor condition of the patient, the other nine cases were treated with (a combination of) chemotherapy (n = 6), surgery (n = 4), and radiotherapy (n = 6). CONCLUSIONS: CNS relapse in WNT is rare. In contrast to reports of other Wilms tumor study groups, although four patients reached (local) CR, the SIOP registry showed that eventually none of the documented WT patients survived.     

Paratesticular metastasis from Wilms tumor associated with a hydrocele

Metastatic sites other than the lungs, lymph nodes, and liver are unusual for Wilms tumor (WT). Intra-scrotal metastasis is very rare. We report a 3-year-old boy with stage IIA WT, who experienced paratesticular metastasis 2 months after surgery for an abdominal recurrence. He had right scrotal hydrocele at initial diagnosis. The patient underwent right radical orchiectomy, and pathological examination revealed paratesticular WT metastasis. Intra-abdominal and peritoneal disseminated metastases followed. We considered that tumor cells spread through the patent processus vaginalis and grew at paratesticular space in hydrocele. One month after the end of 12 months of salvage chemotherapy and abdominal radiotherapy, the patient has no evidence of disease.     

Postoperative limited volume irradiation in a child with a solitary brain metastasis from Wilms tumor: A case report

An 11-year-old boy presented with a solitary cerebral metastasis 2.5 years after initial diagnosis and 4 months after successful combined modality treatment of a stage II recurrent Wilms tumor in the chest. Resection of the brain metastasis was followed by limited volume irradiation with 30.0 Gy total dose. After a follow-up of 2.5 years the boy is in complete remission and shows no neurological or neuropsychological deficits indicating the possibility of curative postoperative radiotherapy of low toxicity and restricted to the tumor site in the presence of solitary brain metastases. Med. Pediatr. Oncol. © 1997 Wiley-Liss, Inc.     

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.     

Ⅲ、Ⅳ期肾母细胞瘤综合治疗15年经验

目的总结近15年来对Ⅲ、Ⅳ期。肾母细胞瘤患儿的多模式综合治疗经验。方法1995年5月至2010年12月浙江大学医学院附属儿童医院共对26例单侧Ⅲ、Ⅳ期肾母细胞瘤患儿采用多模式的综合治疗。诊断标准：肾门、主动脉旁淋巴结转移;弥漫性腹腔播散或术时散落;腹膜有肿瘤种植;镜检或肉眼有肿瘤残留;局部浸润至重要脏器;肿瘤远处转移。全部病例按年限和治疗方式分为两组：①术前单纯介入治疗组（TACE组）11例,为1995年至2002年收治病例,采用术前肾动脉化疗栓塞（TACE）,1周后手术切除瘤肾,术后化疗或加放疗的综合治疗;②术前介入治疗加短期全身化疗组（T＋S组）15例,为2003年至2010年收治病例,采用术前TACE加2～3周静脉化疗,然后手术切除瘤肾,术后化疗或加放疗的综合治疗。TACE采用吡柔比星40mg／m。,长春地辛3mg／m2,超液碘油5～10mL。术前短期静脉化疗采用长春地辛3mg／（m2·周）,共2次;放线菌素D10we／（kg·d）,共5次。术后化疗和放疗按照北京儿童医院肾母细胞瘤治疗方案。TACE组与T＋s组分别有3例和9例接受术后放疗。结果两组患儿术后分期为：TACE组Ⅲ期10例,Ⅳ期1例;T＋S组Ⅲ期11例,Ⅳ期4例。两组各有弥漫问变型2例。两组肿瘤完整切除率分别为63．6％（7／11）和80．0％（12／15）,P=0．407。随访至2010年12月,两组平均随访时间分别为118（102—186）个月和43．5（1～92）个月,无瘤生存率分别为72．7％和100．0％,Kaplan-Meier生存分析显示两组差异有统计学意义（P=0．040）。结论本研究表明,术前动脉栓塞化疗加短期静脉化疗,手术切除瘤肾,术后继续化疗和放疗的多模式综合治疗是对Ⅲ、Ⅳ期肾母细胞瘤患儿的合理治疗方案。     

Massive bilateral nephroblastomatosis in a 13-year-old girl

A 13-year-old girl on chronic hemodialysis with renal failure thought to be due to polycystic renal disease, underwent bilateral nephrectomy as a pretransplant procedure. Microscopic examination of the grossly enlarged nodular kidneys revealed a bilateral diffuse tumor infiltration which was not Wilms tumor. Eventually the diagnosis of bilateral nephroblastomatosis was established. This is apparently unique at this age without coexistent Wilms tumor. Four months after nephrectomy metastases-exceedingly rare in nephroblastomatosis-developed. Local radiation and cytostatic therapy with Actinomycin D, Vincristine and Adriamycin were initiated. All drugs were administered 24 h before the beginning of hemodialysis; only Actinomycin D was reduced to 70% of the usual dosage. Therapeutic side effects remained within the usual limits. Renal transplantation was performed 34 months after metastases had developed, i.e. 10 months after cessation of cytostatic therapy.Massive bilateral nephroblastomatosis can also occur in older children and can easily be mistaken for polycystic renal discase. It's early clinical and microscopic recognition could enable appropriate management, which should consist of open biopsy, chemotherapy and scrupulous follow-up procedures, rather than aggressive therapy. The latter probably had to be administered in this patient, initially uremic and on chronic hemodialysis.     

Catastrophic intracerebral hemorrhage in a young infant with Wilms tumor

We present a 7-month-old male infant with stage I Wilms tumor who unexpectedly died from a catastrophic intracerebral hemorrhage, 4 months after completion of chemotherapy and complete surgical resection of the tumor. The precise etiology underlying the fatal event remains unclear as postmortem was refused, but we postulate spontaneous hemorrhage from an underlying cerebral vascular malformation as the most likely cause, which led to the child's unfortunate demise. Although extremely rare, cerebral vascular anomalies have previously been reported in children with Wilms tumor. The coexistence of the 2 uncommon disorders may be related to their congenital origin. Wilms tumor diagnosed in very young infants have clinical and morphologic attributes that do not pertain in older children and the risk of associated congenital anomalies is also much higher among those discovered in the first year of life. This raises the question whether routine magnetic resonance imaging should not be performed in infants less than a year with Wilms tumor, as part of the initial evaluation, to exclude cerebral metastases and underlying vascular malformations.     

Recurrent metastatic neuroblastoma followed by myelodysplastic syndrome: possible leukemogenic role of temozolomide

An 8-year old child had a pelvic MYCN-nonamplified neuroblastoma (NB) with retroperitoneal nodal extension. Multi-modality therapy achieved complete remission (CR). Small recurrences confined to left supraclavicular nodes were treated with surgery alone at 4.9, 6.5, 7.5, 9.5, and 12.9 years from diagnosis. Monitoring through 12 months after the last resection showed CR. When she returned 34 months later (16.8 years from diagnosis), she had massive disease in the left neck and upper trunk, without osteomedullary metastases. Salvage therapy featured 11 cycles of temozolomide. She developed myelodysplastic syndrome with 45,XX,der(7)t(7;21) (p15;q11),-21 at age 24 and refused treatment; 19 months later she was transfusion-dependent but her NB remained in CR.     

Nephropathy gonadal dysgenesis--or incomplete Drash syndrome?]

This is a report about a phenotypical normal girl with nephropathy and gonadal dysgenesis. At the age of 2 years 8 months she presented with steroid resistant nephrotic syndrome. Focal segmental glomerulosclerosis was found by biopsy. Because of delayed puberty karyotyping was performed, which revealed 46 XY. Thirteen years after onset of proteinuria she reached end stage renal failure. Gonadal dysgenesis and nephropathy are often indistinguishable from incomplete Drash syndrome. Children with early nephropathy of unknown origin or gonadal dysgenesis should be observed for development of Wilms tumor. When chronic nephropathies are present in girls, karyotyping should be considered.     

Needle track recurrence after biopsy of non-metastatic Wilms tumour

A 2-year-old girl presented with a left-sided Wilms tumour. She was randomised to have a needle biopsy and preoperative chemotherapy according to the United Kingdom Children's Cancer Study Group (UKCCSG) protocol, a trial of preoperative chemotherapy in biopsy-proven Wilms tumour versus immediate nephrectomy (UK 9101). A nephrectomy was performed 6 weeks later. Six months later she presented with an abdominal wall recurrence at the needle biopsy site, which was resected. The value of needle biopsy in localised Wilms tumour is debated.     

Metachronous Wilms tumor associated with pulmonary embolism: how can we detect these cases early? A case report and literature review

A 4-year-old girl developed right metachronous Wilms tumor 2 years after completing treatment for a left-sided stage I Wilms tumor. The original treatment included 7 weeks of chemotherapy, delayed nephrectomy, and another 3 weeks of chemotherapy. The metachronous tumor on the right side extended into the inferior vena cava and right atrium. She developed pulmonary embolism as a result. She received chemotherapy and developed liquifaction of the tumor and toxic shock. She also had surgery. The patient is alive 3 years after the original diagnosis and 10 months after the relapse. The authors report this unusual case and discuss whether these cases can be identified early.     

Adriamycin cardiomyopathy in a child with Wilms tumor and liver metastases (author's transl)]

Nephrectomy with irradiation was performed in a 3;2 year old boy with Wilms tumor stage IV (livermetastases (liver metastases). Six months later a hemihepatectomy was performed on account of the liver metatases which persisted under a combined Actinomycin Vincristin therapy. A monotherapy with Adriamycin was instituted. The patient developed acute congestive heart failure. The patient developed acute congestive heart failure and showed typical EKG changes after a total dose of 700 mg/M2 of Adriamycin. In comparison to adults children reportedly tolerate somewhat higher total doses of Adriamycin. Therefore it is discussed, if in this case a limitation of liver function by hemihepatectomy and by irradiation has favored the appearance of the Adriamycin-induced cardiomyopathy.     

Collins' law revisited: can we reliably predict the time to recurrence in common pediatric tumors?

Collins' law states that the period of risk for tumor recurrence is the age of the child at diagnosis plus 9 months. The purpose of this study is to validate this rule through a retrospective review of common pediatric tumors seen at 1 institution. Inclusion criteria for this study included an age at diagnosis of < 16 years old, minimum follow-up time of the Collins risk period (CRP) if child did not relapse and treatment with curative intent. The records of 424 children seen and treated for neuroblastoma (n = 98), Wilms tumor (n = 86), rhabdomyosarcoma (n = 82), medulloblastoma (n = 59), Ewing sarcoma (n = 43), ependymoma (n = 25), supratentorial PNET (n = 22), and synovial sarcoma (n = 9) from 1960 to 2001 were reviewed. CRP was calculated using the age of child at initial diagnosis plus 9 months. The median follow-up time was 164 months (range, 11-484 months), while the median follow-up/CRP ratio was 4.89 (range, 1.0-48.0). A total of 183 of 424 (43.2%) patients relapsed, with 180 (98.4%) relapses occurring during the CRP. Relapses beyond the CRP were seen in 3 young children (ages 7 months, 24 months, and 2 weeks at initial diagnosis) with a diagnosis of Wilms tumor (n = 2) and supratentorial PNET (n = 1) at 1, 3, and 26 months post-CRP. Collins' law is a useful and simple way of predicting risk period for relapse in the tumor types studied.     

Treatment of pediatric ocular melanoma with high-dose interleukin-2 and thalidomide

Uveal melanoma is the most common primary ocular malignancy, although it is rare in children, and patients presenting with metastatic disease have a median survival of only 2 to 5 months. The tumor is generally unresponsive to systemic chemotherapy, but immunotherapy may be effective in selected patients. This report describes an 8-year-old girl with metastatic uveal melanoma treated with high-dose, bolus interleukin-2 (IL-2) and the antiangiogenic agent thalidomide. She tolerated treatment well and initially responded with stable disease in the liver and pancreas for 23 months. New pulmonary metastases developed and she was re-treated with high-dose IL-2, resulting in regression of her liver lesions and stable pulmonary disease for more than 18 months. These results suggest that IL-2 at high doses, and in combination with thalidomide, may be useful for uveal melanoma with tolerable side effects in children. Further study of this combination in children with immune-responsive tumors is warranted.     

Wilms’ Tumor: A 24-year Retrospective Study from a Single Center

Medical records of 71 children with Wilms’ tumor at Sisli Etfal Education and Research Hospital between 1990 and 2014 were reviewed. Mean age at diagnosis was 3.11 years (2 days–7 years). Male to female ratio was M/F = 6/10. The incidence of associated anomaly was 16.9%. Clinical manifestations included abdominal mass (89%), hematuria (30%), hypertansion (25%), abdominal pain (15%), fever (5%), restlessness (2%), weight loss (2%), varicocele (1%). Ultrasound (USG) was the most often initial study in a child presenting with abdominal mass. Doppler USG was also made to evaluate the inferior vena cava (IVC) for the presence of tumor extension in children with renal mass. The left kidney was affected in 33 patients (46.5%), the right was affected in 31 patients (43.7%). Two patients was extrarenal (2.8%). And 5 patients (7.04%) were bilateral on the presentation. Preoperative chemotheraphy was done in 14 cases. In 63 patients with unilateral Wilm tm, unilateral radical nefrectomy is performed. In one patient with solitary kidney, nephron sparing surgery (NSS) is performed. In 3 patients with bilateral tm NSS is performed and in 2 patients with bilateral Wilms’ tm NSS is performed in one side and nefrectomy on the other side. Out of 71 Wilms tumor (WT) patients, 17 of them has been out of our follow. And 4 of them are died. Ten of them has metastases. Forty children are under follow with no metastases. Patients with WT needs a multimodal, multidisiplinary treatment with the cooperation of pediatric oncologist and pediatric surgeon and needs close follow-up.     

Association between the HER2 expression and histological differentiation in Wilms tumor

Human epidermal growth factor receptors (HER) play a critical role in the branching morphogenesis of renal tubules. In the current study, we analyzed the expression of HER2 in Wilms tumor and assessed the role of this gene in the tumorgenesis of Wilms tumor. During the period from 1960 to 2005, 40 patients with Wilms tumor were treated in our department. Twenty-four of those patients (except those with clear cell sarcoma of the kidney and malignant rhabdoid tumor of the kidney) were collected and assessed. The histological component of each Wilms tumor was divided into three categories (epithelial, blastemal, and mesenchymal) and the extent of HER2 protein expression was analyzed immunohistochemically. The normal kidney tissue accompanied with 12 cases of Wilms tumor was also examined. In the normal kidney, HER2 showed a strong immunoreactivity in the cell membranes of the collecting tubules and in the endothelial cells. Of 24 cases, 15 cases showed an epithelial component, while 24 cases had a blastemal component and 21 cases had a mesenchymal component, respectively. Among the 15 specimens with epithelial cell differentiation, eight (53.3%) showed HER2 immunoreactive epithelial cells. HER2 immunoreactive blastemal cells were present in 11 (45.8%) of 24 specimens with blastemal cells. On the other hand, only 3 (14.3%) of 21 specimens containing mesenchymal cells showed HER2 immunoreactivity. These results suggest that the extent of HER2 expression is associated with epithelial differentiation in Wilms tumor. These histological findings may therefore help to explain the development of Wilms tumor from the standpoint of histological differentiation.