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Dr. Max Coppes is a Pediatric Oncologist (specialist in the treatment of childhood cancers) and the Director of the Southern Alberta Children's Cancer Program at the Tom Baker Cancer Centre and Alberta Children's Hospital in Calgary, Alberta, Canada. He also is an Associate Professor of Oncology and Pediatrics at the University of Calgary. He is a Board member of the National Wilms Tumor Study Group (NWTSG), an international cooperative group devoted to the treatment of kidney cancer in children. Devoted to finding clinical applications for laboratory discoveries (translational research), he leads a laboratory that aims to characterize Wilms tumors at the genetic level. These efforts should lead to a better understanding of the behavior of some of these tumors and as a consequence provide novel strategies for cure.

Wilms tumor, named after the German surgeon Dr. Carl Max Wilhelm Wilms, is the commonest form of renal cancer in children. It is also referred to as nephroblastoma. The tumor develops from remnants of immature kidney. Our current knowledge suggests that environmental risk factors likely play a minor role in the development of this cancer, certainly as compared with adult cancers. Wilms tumor accounts for 6-7% of all childhood cancers in North America. As a result, approximately 450-500 children are affected by this tumor each year in the US and Canada together. It typically affects young children (under the age of 6), although older children and occasionally even adults can be affected. Patients with certain congenital defects, including anomalies of the male genitourinary system, aniridia (the absence of the iris), the Denys-Drash syndrome, hemihypertrophy, and the Beckwith-Wiedemann syndrome are at increased risk of developing this cancer.

The most common manifestation of Wilms tumor is that of a lump in the belly (abdominal mass), often found by either parents or relatives while bathing or dressing the child. Occasionally, children with Wilms tumor may complain of abdominal pain, or may feel sick and vomit. A child with Wilms tumor may also have fever. Finally, although not frequent, a child with Wilms tumor may have blood in the urine. The signs and symptoms of this cancer are not typical and as a consequence many children with Wilms tumor present with very large tumors. Luckily, the size of the tumor does not seem to prevent doctors from curing most children with Wilms tumor.

It is very important for the medical team caring for a child with Wilms tumor, to know the exact extent of the tumor. First, the medical team needs to confirm that the child has a tumor of the kidney and not, for example, on top of the kidney (which is another form of childhood cancer). Then, they need to determine whether a surgeon would be able to safely remove the tumor or whether the tumor is attached to vital structures and removal would be hazardous. In order to remove the tumor (and the remaining kidney tissue on the affected side), the doctors need to make sure that the other kidney (we have two kidneys) is present and functioning. Finally, they have to investigate whether the tumor has spread beyond the abdomen, e.g. to the lungs. If this is the case, treatment will be somewhat different and it is only in the interest of the child to make sure that the best treatment is given from the start. The most commonly used imaging techniques include ultrasound of the abdomen (a study commonly used in pregnant women to check on their unborn babies), and computed axial tomography (CAT) scan of the abdomen and chest. Although Magnetic Resonance (MR) imaging appears to be a safe non-invasive imaging technique very well suited for use in children, this imaging modality currently still is hampered by some limitations.

The stage of the tumor is determined by its extent. In North America, physicians use the stage system developed by the National Wilms Tumor Study Group (NWTSG). Stage I The tumor is limited to the kidney and was completely excised. The renal capsule has an intact outer surface. The tumor was not ruptured or biopsied prior to removal (fine needle aspiration biopsies are excluded from this restriction). The vessels of the renal sinus are not involved. There is no evidence of tumor at or beyond the margins of resection. Stage II The tumor extends beyond the kidney, but was completely excised. There may be regional extension of tumor (i.e., penetration of the renal capsule or extensive invasion of the renal sinus). The blood vessels outside the renal parenchyma, including those of the renal sinus, may contain tumor. The tumor was biopsied (except for fine needle aspiration), or there was spillage of tumor before or during surgery that is confined to the flank, and does not involve the peritoneal surface. There must be no evidence of tumor at or beyond the margins of resection. Stage III Residual non-hematogenous tumor is present, and confined to the abdomen. Any one of the following may occur: 1) Lymph nodes within the abdomen or pelvis are found to be involved by tumor (renal hilar, para-aortic or beyond). (Lymph node involvement in the thorax, or other extra-abdominal sites would be a criterion for stage IV); 2) The tumor has penetrated through the peritoneal surface; 3) Tumor implants are found on the peritoneal surface; 4) Gross or microscopic tumor remains post-operatively (e.g., tumor cells are found at the margin of surgical resection on microscopic examination); 5) The tumor is not completely resectable because of local infiltration into vital structures; 6) Tumor spill beyond the flank occurred either before or during surgery. Stage IV Hematogenous metastases (lung, liver, bone, brain, etc.), or lymph node metastases outside the abdomino-pelvic region are present. Stage V Bilateral renal involvement is present at diagnosis. An attempt should be made to stage each side according to the above criteria on the basis of the extent of disease prior to biopsy or treatment.

Once removed by the surgeon, it is important to have the tumor carefully analyzed by a pathologist. Over the past decades, several studies have revealed that certain features of Wilms tumor, recognisable under the microscope, correlate with poorer outcome and therefore require more intensive therapy. The most important feature associated with unfavorable outcome is nuclear atypia (anaplasia), which can be focal or diffuse. However, over 90% of childhood renal tumors lack these features and are referred to as favorable histology Wilms tumors. Also, cancer specialists have come to recognise that certain features previously considered to identify Wilms tumors with unfavorable outcome, in fact are characteristic of tumor categories distinct from Wilms tumor. These include clear cell sarcoma of the kidney and rhabdoid tumor of the kidney. Finally, the presence of Wilms tumor within a kidney is often associated with additional renal developmental abnormalities. Twenty five to 40 percent of children with Wilms tumor have small areas composed of persistent embryonal cells within otherwise normal kidney tissue. These lesions are called nephrogenic rests and may convey an increased risk of tumor development in the remaining kidney.

Treatment of Wilms tumor is one of the remarkable success stories in childhood cancer. Before the advent of modern therapy, 2-year survival rates were 50% or less. However, the combined use of surgery, radiation therapy and chemotherapy (multimodal treatment approach) permits most patients treated today to be able to reach adulthood. All patients receive chemotherapy and surgery, while those with more extensive disease or those with adverse prognostic features receive additional radiotherapy. In North America, most children are registered on and subsequently treated according to a NWTSG clinical trial, while in Europe most children are managed based on studies designed by the International Society of Paediatric Oncology (SIOP). The NWTSG recommends immediate surgical removal of the tumor, the SIOP investigators suggest the use of chemotherapy before removing the tumor. The rationale for the NWTSG approach is that accurate assessment of the extent of disease at diagnosis allows safe administration of the intensity of treatment for each individual. The ability to stratify patients into different treatment groups based on extent of disease and histopathologic features, has allowed a reduction in the intensity of therapy for most patients while maintaining the excellent overall survival. Refining treatment in this way is important since it makes it possible to avoid unwanted side effects (morbidity) associated with some treatment modalities. Surgery, the standard approach, remains through a generous abdominal incision. This allows for a thorough exploration of the all the organs inside the abdomen. Special attention is given to the liver, para-aortic area and the opposite kidney. Lymph node sampling of suspicious nodes in order to achieve correct staging is highly recommended. Attempts to remove very large (massive) tumors are not justified as this is associated with increased surgical morbidity if not mortality. Similarly, the finding of synchronous bilateral Wilms tumor is a relative contra-indication to primary removal of the tumor and associated kidney. It is therefore important to inspect the opposite kidney before removing the tumor and kidney of the affected side. Patients with synchronous bilateral Wilms tumor (i.e. Wilms tumor in both kidneys at the same time) should receive chemotherapy and potentially also radiotherapy before surgical excision of the tumors. This will allow for the tumors to shrink making it possible to spare as much unaffected kidney tissue as possible . Chemotherapy The drugs used in the treatment of Wilms tumor include vincristine and dactinomycin, given to all patients, and doxorubicin given to those with more extensive disease or those with adverse prognostic features. Briefly, those with stage I and II disease (and favorable histology) receive vincristine and dactinomycin for 18 weeks, those with stage III and IV disease (and favorable histology) receive vincristine, dactinomycin and doxorubicin for 24 weeks. The same treatment is given to those with stage II, III and IV Wilms tumor with focal anaplasia (those with stage I Wilms tumor and focal anaplasia are treated in the same way as those with stage I favorable histology). Those with stage II, III or IV Wilms tumor with diffuse anaplasia are treated with vincristine, doxorubicin, cyclophosphamide and etoposide for 24 weeks. Radiation Therapy In the past two decades, doctors have identified which patients can be cured without the addition of radiation therapy. In addition, doctors have been able to show that the radiation dose initially recommended for children with Wilms tumor could be reduced significantly. Currently patients in North America receive 1080 cGy and those in Europe 1500 cGy, both given in combination with chemotherapy.

Over 80% of patients with Wilms tumor can be cured with modern multimodality therapy. Much of the effort of recent studies has been to intensify treatment for patients with poor prognostic features while decreasing therapy, and thereby adverse late effects, in favorable cases. Meanwhile, the last few years have provided dramatic breakthroughs in understanding the genetic factors involved in the development of Wilms tumor and hence in normal kidney development. The implications of these findings for the clinical management of children with Wilms tumor are unclear but the focus of ongoing research.