Renal tumors in children have been described since as early as 1814.1 However, the classical description and identification of the entity of Wilms' tumor dates from 1899.1 Prior to the advent of radiation therapy and chemotherapy for the treatment of malignant tumors, the only available treatment for Wilms' tumor was surgical resection. Early attempts at nephrectomy were associated with significant mortality, with survival rates of only approximately 15%.2 As a result of improved surgical techniques, between 1930 and 1940 the survival rate of children who underwent surgery for resection of malignant renal tumors increased to about 40%.3 Furtherslight improvement in survival rates to about 47% were reported from the Children's Hospital Medical Center of Boston in 1947; perhaps this improvement was due to the addition of postoperative radiotherapy to the tumor bed.4
Subsequently, the addition of effective chemotherapy further improved the outcome in WiIm 's tumor, with survival rates of 80% in patients with non-metastatic disease treated with dactinomycin alone postoperatively and 50% in patients with metastatic disease treated with this agent.4 The addition of vincristine further improved survival to approximately 92% to 95% in patients who not have evidence of metastases at the time of diagnosis. The use of Adriamycin in the treatment of patients in whom there are metastases has improved their prognosis.6
Currently, for those patients who develop metastases during or following initial therapy, intensive treatment with surgery, chemotherapy and irradiation has resulted in salvage of some. As a result of a coordinated, aggressive, combined modality approach, prolonged disease-free survival in patients with Wilms'tumor is now greater than 80%.7
NATIONAL WILMS' TUMOR STUDIES I AND II (NWTS I AND NWTS II)
Much of the progress in the treatment of children with Wilms' tumor has resulted from the large national randomized studies. NWTS I was carried out between 1969 and 1974. This study grouped patients by extent of disease. The study attempted to answer questions relating to chemotherapy and radiation therapy by systematically testing competing treatment regimens. The study demonstrated that irradiation to the tumor bed did not alter the otherwise good prognosis in patients under two years of age with group I disease who were treated with dactinomycin postoperatively. In children over the age of two years, the addition of radiation therapy, even in patients with group I disease, did appear to increase disease-free survival. Furthermore, this study demonstrated that two-drug chemotherapy with vincristine and dactinomycin was superior to single-agent chemotherapy in children with groups II and III tumors. Finally, the use of preoperative vincristine in patients with group IV disease did not alter survival in these patients.5
Based upon the results of NWTS I, National Wilms' Tumor Study II was developed. This study demonstrated that six months of chemotherapy with vincristine and dactinomycin, without radiation therapy and without regard to age, resulted in two-year disease-free survival rates of 90% in children with group I Wilms' tumors. Furthermore, the addition of adriamycin to vincristine and dactinomycin in the treatment of patients with groups II, III and IV disease significantly increased relapse-free survival in these patients to approximately 85%.6
CLINICAL AND PATHOLOGICAL CRITERIA FOR STAGING OF WILMS' TUMORS
Further results of the two National Wilms' Tumor Studies included descriptions and incidence data on associated congenital anomalies, establishing important prognostic criteria, and definition of different histological subtypes of Wilms' tumor. This information allowed assessment of the prognostic significance associated with these histological subtypes.
Congenital anomalies associated with Wilms' tumor were studied in. the first National Wilms' Tumor Study. Aniridia was found in 1.1%, hemihypertrophy was found in 2.9%, and genitourinary anomalies were present in 4.4%. Also, there was a noted increased incidence of Wilms' tumor in association with Beckwith-Wiedmann syndrome and neurofibromatosis.7
PRETREATMENT WORKUP FOR PATIENTS WITH WILMS' TUMOR
The use of more sophisticated radiological equipment and techniques has simplified and improved the preoperative workup of the child with an abdominal mass (Figures 1 and 2). Previously, intravenous pyelography was used to determine whether a lesion was intrarenal or extrarenal, and subsequent workup would then be planned. In the patient with an intrarenal tumor, only a preoperative chest x-ray to ascertain the presence or absence of pulmonary metastases was required. Currently, ultrasonographic examination of the abdomen usually can accurately demonstrate the relationship of the lesion to the kidney. Furthermore, ultrasonography can frequently identify extension of the lesion not only into the inferior vena cava, but even extension into the heart. Preoperative knowledge of this cardiac complication significantly influences the surgical approach.
In the case of classical Wilms' tumor (that is, tumors with a favorable histology), further workup either immediately preoperatively or following surgery, consists only of computerized tomography of the lungs. Other examinations are superfluous in most patients. In those patients having unfavorable histology, postoperative workup prior to starting chemotherapy should also include a bone scan because these tumors show an increased tendency to metastasize to bone. Brain radionuclide scan or CT scan may also be considered in children with rhabdoid tumors since these tumors are commonly associated with intracranial metastases.
The staging system for Wilms' tumor has recently been revised based on the findings from the first two National Wilms' Tumor Studies. Staging criteria are based on surgical and pathological findings and are summarized in Table 1.
PATHOLOGY OF WILMS' TUMOR
In patients treated in the first two National Wilms' Tumor Studies, treatment outcome was correlated with the tumor histopathology. The results of these studies defined two basic groups of tumors; namely, those with so-called "favorable histology" and those with "unfavorable histology."8 The histopathologic characteristics of the various types of tumor are outlined in Table 2.
Figure 1. This IVP is an example of bilateral Wilms' tumor demonstrating typical splaying of the renal calyces.
Figure 2. This CT scan of the abdomen shows a large right flank mass with distortion of the renal parenchyma (RK). There are cystic spaces (CS) within the mass which are often seen in Wilms' Tumor. The left kidney (LK) is normal.
HISTOLOGICAL CLASSIFICATION OF WILMS' TUMORS
Both clinical stage and histology of the tumor have been shown to be important prognostic features in children with Wilms' tumor. Additional important prognostic features include size of the tumor and presence or absence of involved lymph nodes. Age, namely in children under two years old, does not appear to be an important prognostic feature in predicting duration of disease-free survival.9 Findings at the time of surgery that at one time were considered important, including finding of a tumor thrombus in the renal vein or inferior vena cava or tumor spill localized to the flank at the time of surgery, have proven to be insignificant.10
CURRENT THERAPY FOR NEWLY DIAGNOSED WILMS' TUMORS (STAGES I, II, III AND IV)
Surgery Improvements in surgical technique constituted the earliest change which significantly improved the prognosis of children with malignant renal tumors.3 Today, a transabdominal approach is recommended for the child suspected of having a Wilms' tumor. The abdomen is thoroughly explored for the presence of extrarenal tumor, including hepatic and lymph node involvement; lymph nodes are sampled for histologic examination; and Gerota's fascia surrounding the contralateral (uninvolved) kidney is opened and the kidney is visualized and palpated. Nephrectomy and complete excision of tumor should be accomplished with the tumor intact, if possible. Tumor thrombi may be found in renal veins and may extend into the inferior vena cava or occasionally as far as the right atrium. Likewise, these should be removed along with the primary tumor with a minimum of fragmentation.10
Radiation Therapy The approach used in the second National Wilms' Tumor Study included radiation of the tumor bed in patients with stages II, III and IV Wilms' tumors. Both lungs are given radiotherapy in patients with pulmonary metastases. The dosage of radiotherapy administered to the abdomen is 2000 to 2400 rad, while lung dosage is 1200 rad.6 The effects of reducing the dose or omitting radiation therapy in some patients with stage I tumors is being tested in the third National Wilms' Tumor Study. The dosage needed and whether all children with Wilms' tumor need radiotherapy has not yet been determined. Patients with extensive intraabdominal disease or massive tumor spill still receive whole abdominal irradiation, at a dose of about 2000 rad. Higher doses of radiotherapy may be necessary in patients whose tumors have an unfavorable histology.
Chemotherapy Vincristine and dactinomycin are the two standard chemotherapeutic agents used in the treatment of all patients with Wilms' tumor.12 The length of treatment is approximately 15 months for patients whose tumor is classified as being in stage II, III or IV. For patients in stage I, the second National Wilms' Tumor Study showed that giving chemotherapy for six months was as effective as giving chemotherapy for 15 months.6 In the third National Wilms* Tumor Study the effectiveness of giving chemotherapy for only ten weeks is being tested.13
Adriamycin is also active against Wilms' tumor. When added to dactinomycin and vincristine, Adriamycin significantly increased relapse-free survival time of patients who were classified as being in stage II, III or IV. Also, patients with unfavorable histology may be given cyclophosphamide, an agent which was initially believed to be inactive in Wilms' tumor, but which is very active in sarcomas.6 Results of the second National Wilms' Tumor Study show a two-year relapse-free survival time of 88% for children in stage land 77% for children in stages II, III or IV.6 Those patients whose tumors have a favorable histology and are in stages II and III have a better outcome than those who either have a tumor with unfavorable histology or who are classified as being in stage IV.
Follow-up Evaluation Treatment of children with Wilms' tumor is extremely effective, and the majority of the patients will enjoy long-term survival. The most common initial site of recurrence in patients whose tumor has a favorable histology is the lung, where lesions maybe single or multiple.15 Other locations of recurrence include intraabdominal sites, especially the liver and the contralateral kidney.15 Thus, patients can be followed after initiation of therapy, and subsequently after completion of therapy, with a minimum of investigative procedures, by attention to the sites where recurrences are most likely to be found. Chest x-rays should be performed every three months for at least three years following diagnosis. Study of the abdomen for evidence of recurrence can be accomplished by intravenous pyelography (IVP). However, the newer diagnostic techniques including ultrasonography and computerized tomography have largely replaced the IVP and should be performed every six to 12 months for the first two to three years.16 Subsequently, yearly or biannual physical examination should be continued not only to detect tumor recurrence, but also to detect evidence of associated late effects of chemotherapy and radiotherapy.
Computerized tomography of the chest is useful in detecting small metastatic deposits. As a minimum, a CT scan of the chest should be performed at the time of completion of the course of chemotherapy and when the chest x-ray shows any abnormality.16 Patients with stage IV tumors who have intraabdominal spread of their tumor require study with either ultrasonography or CT scans; if liver involvement is present, liver/ spleen scans should also be performed.16 Patients who have stage V tumors (bilateral Wilms' tumor) also require more frequent evaluation of the kidneys by either ultrasonography or abdominal CT scans.16
Treatment of Metastatic Wilms' Tumors Patients in whom metastases are present at the time of initial diagnosis should be treated aggressively, since long-term survival is still achievable in a significant proportion of these children.11 The two-year relapse-free survival in such patients treated in the second National Wilms' Tumor Study was approximately 50%.6 Patients who present with pulmonary metastases may be treated with pulmonary irradiation and chemotherapy following primary tumor resection; these patients have shown survival rates of 40% to 50%.6,11 Even those patients with extensive intraabdominal spread of their tumor or who have extension of metastases through the venous system, even to the heart, have a high probability of prolonged survival if modern, aggressive surgical techniques are employed to achieve maximal tumor resection.6,17,18
Patients whose metastases occur during or following therapy often can be approached with curative intent.11 Multiple pulmonary metastases developing while the patient is being given the initial course of therapy carry a worse prognosis." Intraabdominal metastases with the exception of contralateral renal involvement also appear to carry a worse prognosis.11 Hepatic metastases, particularly when there is only a single lesion, or metastases in the contralateral kidney should be removed surgically if possible.
Occasionally, the development of metastases in the contralateral kidney cannot be surgically removed without sacrifice of the kidney, either at the time of recurrence or following attempts to reduce the lesion with chemotherapy or radiotherapy. These kidney metastases may require a second nephrectomy followed by appropriate support with renal dialysis and subsequent renal transplantation. This therapy has resulted in long-term survival in a few patients.19 Both radiation therapy and further chemotherapy have a role in the aggressive approach to metastases developing during or following initial therapy. Radiation therapy may be limited by tolerance of the involved organs as well as by the amount of radiation which was given as part of the therapy administered at the time of diagnosis."
Treatment of Stage IV Wilms' Tumors Salvage chemotherapy for the patient who develops metastases or other evidence of recurrence of Wilms' tumor during the initial course of chemotherapy has no established guidelines. This therapy must be selected based on the patient's prior history of exposure to chemotherapeutic agents. However, many patients whose disease recurs following completion of chemotherapy may respond again to aggressive use of agents to which they had previously been exposed.11,12 Patients with Wilms' tumor of the sarcomatous type may occasionally benefit from being given cisplatinum.14
In patients with Wilms' tumors which are of a sarcomatous type, the development of metastases carries a worse prognosis.11 Many of these patients develop skeletal metastases which are not amenable to surgical approach and must be treated with irradiation and chemotherapy, if appropriate drugs are available.20 The overall prognosis in patients with sarcomatous types of Wilms' tumor is extremely poor;8 the appearance of metastases is an ominous sign and prolonged survival is extremely rare.
Bilateral Wilms' Tumor The reported incidence of bilateral Wilms' tumor is 1.4% to 11. 6%.11,15 These patients are potentially curable, as shown by long-term survival rates of 40% to 50% having been observed in recently treated cases. The approach to therapy of such patients must be individualized. Where possible, partial nephrectomy, with removal of tumor and preserving as much normal kidney as possible, followed by radiation therapy and chemotherapy is the preferred approach. Removal of all gross tumor may necessitate total nephrectomy even on the less involved side. But if adequate kidney tissue cannot be preserved to sustain renal function, total tumor resection has frequently been delayed. The patient is then initially treated with chemotherapy, radiation therapy, or both, with the dose of radiotherapy to the kidney limited to 2000 rad. This is followed by a subsequent attempt at removal of residual tumor from both kidneys.12 Occasionally, bilateral nephrectomy with subsequent dialysis and renal transplantation may be considered, if the patient cannot be otherwise rendered free of disease with one of the above approaches.19
Metachronous, bilateral Wilms' tumors, that is, those in which the second kidney is found to have a tumor at some time after a unilateral Wilms' tumor is diagnosed, are unusual. They make up one-third of the bilateral occurrences, with two-thirds of bilateral Wilms' tumors being synchronous.19 In the first two National Wilms' Tumor Studies, only seven of 18 patients with metachronous development of bilateral Wilms' tumor are surviving disease-free.19
The treatment results in Wilms' tumor have greatly improved due to improved use of surgery, radiation therapy, and chemotherapy and in the combined use of these modalities. The challenge now is to improve the outlook for those with a poor prognosis, such as those children with presence of metastases at the time of initial diagnosis, those who are classified as stage IV and those with tumors having an unfavorable histology. Also, the goal in treating those patients with a good prognosis is to determine the least amount of cancer therapy that is needed, so as to minimize the toxic effects of therapy and possibly to also minimize or prevent long-term late effects.
Clinical research in the treatment of children with cancer, including Wilms' tumor, is in a dynamic state. Improvements are quickly disseminated. Thus, it is urged that these children be referred to centers involved in clinical research in cancer therapy in children.
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CLINICAL AND PATHOLOGICAL CRITERIA FOR STAGING OF WILMS' TUMORS
HISTOLOGICAL CLASSIFICATION OF WILMS' TUMORS