Pediatric Annals

Wilms' Tumor

Nathan L Kobrinsky, MD; Michael Talgoy, MSc; Bruce Shuckett, MD; Hilda L Gritter, MD

Abstract

Wilms' tumor is a malignant neoplasm of the kidney occurring predominantly in childhood. Although rare, the tumor has been of considerable importance as a model of chemotherapeutic response and, on a fundamental biologic level, as a model for understanding cancer etiology.

The cure of Wilms' tumor has been a reality for over 20 years. In 1920, the cure rate was less than 10%. At present, the overall cure rate, regardless of stage at presentation, is over 80%. 1 Much of this improvement has been achieved through clinical trials in the United States by the National Wilms' Tumor Study (NWTS) group and in Europe by the International Society of Pediatric Oncology (SIOP). The coordinated multidisciplinary approach combining surgery, radiation therapy, and chemotherapy used by these groups has served as a model for cooperative clinical trials in the study of other malignant tumors.

Wilms' tumor has been used as a model for the study of cancer etiology by many disciplines, including epidemiology, pathology, genetics, and molecular biology.

Epidemiologists have been intrigued by the constant worldwide incidence of Wilms' tumor among children of diverse ethnic backgrounds and geographic locations. This latter observation has, in fact, led to the proposal that the incidence of Wilms' tumor be used as a marker against which to measure the incidence of other tumors.

Pathologists have studied Wilms' tumor as an example of a neoplasm of embryonal origin. The relationship between Wilms' tumor and the mesoblastic nephroma, a benign embryonal kidney tumor of infancy, is of particular interest. The study of mesoblastic nephroma may hold clues concerning the relationship between normal and abnormal embryogenesis and oncogenesis.

Geneticists have studied Wilms' tumor as an example of a potentially heritable neoplasm. Studies by Knudson and others, for example, on the inheritance of Wilms' tumor have led to the "two hit" model for cancer etiology.2 According to this model, both genetic and environmental factors are required for growth of a malignant tumor.

Cytogeneticists have defined an association between aniridia, Wilms' tumor, and a deletion of the short arm of chromosome 11 band 13 (llpl3). A relationship between this chromosomal region and the heritable form of Wilms' tumor appears likely. 3

Molecular biologists have studied the relationship between Wilms' tumor and cancer promoting genes called oncogenes. The llpl3 deletion, for example, has been found to be close to the ras oncogene.4 The llpl3 deletion is also close (mapping at llpl4. 1) to the gene for an insulin-like growth factor (IGF-Il) which is highly expressed in Wilms' tumor tissue compared to adjacent normal kidney. 5 Furthermore, the N-myc oncogene, which plays a major role in the oncogenesis of neuroblastoma, is expressed in particularly high levels in the developing kidney and in Wilms' tumor.6 Two reports have recently contributed detailed maps of chromosome 11, specifically supplying further insight into the structure of the region of Wilms' tumor and associated syndromes. 7·8 These maps will represent an excellent starting point for isolating and characterizing the individual genes coding for "the Wilms' tumor complex."

Clearly, the results of research in Wilms' tumor represent a major success in cancer treatment and in the understanding of cancer biology.

EPIDEMIOLOGY

The incidence of Wilms' tumor, according to the Third National Cancer Survey (1969-1971), is 7.8 cases per million per year for children under 15 years of age. This is approximately 1 case for every 15,000 births. This represents 6.9% of all major forms oí cancer in the United States.9 Next to neuroblastoma, Wilms' tumor is the most common retroperitoneal tumor of childhood. Most children are 1 to 5 years oí age (mean 3.1 years) at diagnosis. In earlier reports…

Wilms' tumor is a malignant neoplasm of the kidney occurring predominantly in childhood. Although rare, the tumor has been of considerable importance as a model of chemotherapeutic response and, on a fundamental biologic level, as a model for understanding cancer etiology.

The cure of Wilms' tumor has been a reality for over 20 years. In 1920, the cure rate was less than 10%. At present, the overall cure rate, regardless of stage at presentation, is over 80%. 1 Much of this improvement has been achieved through clinical trials in the United States by the National Wilms' Tumor Study (NWTS) group and in Europe by the International Society of Pediatric Oncology (SIOP). The coordinated multidisciplinary approach combining surgery, radiation therapy, and chemotherapy used by these groups has served as a model for cooperative clinical trials in the study of other malignant tumors.

Wilms' tumor has been used as a model for the study of cancer etiology by many disciplines, including epidemiology, pathology, genetics, and molecular biology.

Epidemiologists have been intrigued by the constant worldwide incidence of Wilms' tumor among children of diverse ethnic backgrounds and geographic locations. This latter observation has, in fact, led to the proposal that the incidence of Wilms' tumor be used as a marker against which to measure the incidence of other tumors.

Pathologists have studied Wilms' tumor as an example of a neoplasm of embryonal origin. The relationship between Wilms' tumor and the mesoblastic nephroma, a benign embryonal kidney tumor of infancy, is of particular interest. The study of mesoblastic nephroma may hold clues concerning the relationship between normal and abnormal embryogenesis and oncogenesis.

Geneticists have studied Wilms' tumor as an example of a potentially heritable neoplasm. Studies by Knudson and others, for example, on the inheritance of Wilms' tumor have led to the "two hit" model for cancer etiology.2 According to this model, both genetic and environmental factors are required for growth of a malignant tumor.

Cytogeneticists have defined an association between aniridia, Wilms' tumor, and a deletion of the short arm of chromosome 11 band 13 (llpl3). A relationship between this chromosomal region and the heritable form of Wilms' tumor appears likely. 3

Molecular biologists have studied the relationship between Wilms' tumor and cancer promoting genes called oncogenes. The llpl3 deletion, for example, has been found to be close to the ras oncogene.4 The llpl3 deletion is also close (mapping at llpl4. 1) to the gene for an insulin-like growth factor (IGF-Il) which is highly expressed in Wilms' tumor tissue compared to adjacent normal kidney. 5 Furthermore, the N-myc oncogene, which plays a major role in the oncogenesis of neuroblastoma, is expressed in particularly high levels in the developing kidney and in Wilms' tumor.6 Two reports have recently contributed detailed maps of chromosome 11, specifically supplying further insight into the structure of the region of Wilms' tumor and associated syndromes. 7·8 These maps will represent an excellent starting point for isolating and characterizing the individual genes coding for "the Wilms' tumor complex."

Clearly, the results of research in Wilms' tumor represent a major success in cancer treatment and in the understanding of cancer biology.

EPIDEMIOLOGY

The incidence of Wilms' tumor, according to the Third National Cancer Survey (1969-1971), is 7.8 cases per million per year for children under 15 years of age. This is approximately 1 case for every 15,000 births. This represents 6.9% of all major forms oí cancer in the United States.9 Next to neuroblastoma, Wilms' tumor is the most common retroperitoneal tumor of childhood. Most children are 1 to 5 years oí age (mean 3.1 years) at diagnosis. In earlier reports many of the tumors diagnosed under 1 year of age have been shown to be benign mesoblastic nephromas. Males and females are equally affected.

ETIOLOGY

Familial Wilms' Tumor

As in retinoblastoma, Wilms' tumor occurs in both heritable and sporadic forms.10 In children with the heritable form, the neoplasm develops at an earlier age and is more likely to be bilateral and multicentric. All bilateral cases and from 15% to 20% of unilateral cases may be examples of the heritable form of the disease. Familial cases are inherited in an autosomal dominant fashion, with incomplete (approximately 40%) penetrance. Based on these observations, Knudson has proposed a two-hit model of carcinogenesis. In the heritable form of Wilms' tumor, the first hit is inherited and the second hit is acquired, possibly being an environmental event. In the sporadic form of Wilms' tumor, both hits are acquired. According to this model, approximately 8% of the offspring of children with unilateral, unifocal disease, and 20% of the offspring of children with known familial disease, will be similarly affected.

Associated Malformations

Wilms' tumor is strongly associated with various malformations. Out of 1,192 patients with Wilms' tumor culled from three large series, 1.3% had aniridia, 1.9% had hemi-hypertrophy, 5. 7% had genitourinary malformations, and 12.7% had malformations of any type. Several chromosomal anomalies including trisomy 8, trisomy 18, lip-, and XX/XY mosaicism have been associated with Wilms' tumor.

The prevalence of aniridia in the general population is 1 per 50,000. The prevalence among children with Wilms' tumor is 650 per 50,000. Aniridia with or without Wilms' tumor occurs in both heritable and sporadic forms. Chromosomal analysis by high-resolution banding has demonstrated that the complex of Wilms' tumor and aniridia is associated with a chromosomal deletion at llpl3.H Hemi-hypertrophy has been familial in several reported cases.

CLINICAL FEATURES

Wilms' tumor usually presents as an asymptomatic upper abdominal mass, bulging into the flank, often discovered by a parent. The mass is smooth, firm, fixed in position and often extends across the midline of the abdomen. Abdominal pain, fever and anemia (from bleeding into the tumor), hematuria (from tumor extension into the renal pelvis), and hypertension (from distortion of renal vasculature) are other, less frequent, presenting symptoms and signs.

Wilms' tumor, even when massive, has metastases to the lung at the time of diagnosis in less than 25% of cases. Neuroblastoma, on the other hand, is metastatic to bone, bone marrow, liver, spleen, retroorbital structures, skin or other sites at the time of diagnosis in more than 70% of cases. Thus, systemic symptoms (such as weight loss, cachexia, anorexia, and bone pain) and the signs and symptoms of pancytopenia are more characteristic of neuroblastoma than Wilms' tumor when an abdominal mass is discovered. Profuse diarrhea is also a symptom of neuroblastoma rather than Wilms' tumor. Diarrhea is due to secretion of vasoactive intestinal peptide and catecholamine metabolites.

Figure IA. A 9-month-old girl with a left-sided Wilms' tumor. This ultrasound image demonstrates a normal right kidney |K) seen between the cross hairs (upper pole of the kidney is on the viewer's left), with liver (L) adjacent. The renal capsule (thin arrows), renal pyramids (solid thick arrows) and renal collecting system (open arrows) are seen.

Figure IA. A 9-month-old girl with a left-sided Wilms' tumor. This ultrasound image demonstrates a normal right kidney |K) seen between the cross hairs (upper pole of the kidney is on the viewer's left), with liver (L) adjacent. The renal capsule (thin arrows), renal pyramids (solid thick arrows) and renal collecting system (open arrows) are seen.

Figure IB. Ultrasound of the same patient as in IA. Left kidney (K) is markedly enlarged and demonstrates none of the normal anatomy seen in the right kidney. There are areas of necrosis (arrows) within the tumor. Spleen (S) is seen adjacent to the upper pole of the kidney

Figure IB. Ultrasound of the same patient as in IA. Left kidney (K) is markedly enlarged and demonstrates none of the normal anatomy seen in the right kidney. There are areas of necrosis (arrows) within the tumor. Spleen (S) is seen adjacent to the upper pole of the kidney

Figure 2. Same patient as in Figure I. CT scan with oral contrast given to outline loops of bowel (B) and intravenous contrast given to differentiate normal renal parenchyma from hypodense Wilms' tumor. The right kidney (R) shows normal contrast enhancement. The left kidney (L) shows massive enlargement and diminished contrast enhancement compared to the right, with necrotic areas (arrows) within the tumor. Wilms' tumor, unlike neuroblastoma, does not characteristically demonstrate calcification, which is seen with greater sensitivity by CT than by plain radiography.

Figure 2. Same patient as in Figure I. CT scan with oral contrast given to outline loops of bowel (B) and intravenous contrast given to differentiate normal renal parenchyma from hypodense Wilms' tumor. The right kidney (R) shows normal contrast enhancement. The left kidney (L) shows massive enlargement and diminished contrast enhancement compared to the right, with necrotic areas (arrows) within the tumor. Wilms' tumor, unlike neuroblastoma, does not characteristically demonstrate calcification, which is seen with greater sensitivity by CT than by plain radiography.

DIFFERENTIAL DIAGNOSIS OF AN ABDOMINAL MASS

Finding a palpable abdominal mass in childhood is a medical emergency requiring immediate evaluation. The mass may be acutely life-threatening, such as by hemorrhage into a centrally necrotic tumor or by intra-abdominal rupture. Alternatively, the mass may be a sign of a condition that is potentially correctable by surgery, if it is a genitourinary condition, such as bilateral hydronephrosis, secondary to posterior urethral valves. The urinary tract is the site of 75% of abdominal masses in the newborn period, and 50% in later childhood. Neoplasm is uncommon in the newborn period (8%), but quite common thereafter (48%). I2·15

RADIOLOGIC INVESTIGATION

Optimal imaging of an abdominal mass begins with a plain antero-posterior radiograph of the abdomen taken with the patient supine. In Wilms' tumor, a mass with soft tissue density may be seen displacing the airfilled intestines. Calcification is characteristically absent in Wilms' tumor in contrast to neuroblastoma, where it may be seen in approximately 50% of cases on plain x-ray as diffuse, punctate densities within the primary tumor mass.

Subsequently, abdominal ultrasonography should be performed. This procedure is simple, safe, and painless and provides an excellent panoramic examination of the solid viscera of the abdomen. Ultrasound can locate the site of origin of a solid mass. It is also capable of evaluating the opposite kidney and can detect tumor extension into the renal veins and inferior vena cava (Figure 1).

Ultrasound is recommended for initial localization o the tumor mass. However, abdominal computerized tomography (CT) has become the imaging modality of choice for determining the location and extent of the primary tumor, as well as for assessing the stage of the tumor prior to surgery (Figure 2).

With the advent of ultrasound and CT, an excretory urogram (IVP) is no longer considered necessary in the initial imaging workup of Wilms' tumor. Nevertheless, this study is still performed in some institutions and may be required by radiation therapists in planning treatment fields. Classically, the excretory urogram demonstrates distortion and displacement of the renal collecting system (Figure 3). Nonvisualization of a kidney that is almost completely replaced by tumor may occur. Angiography may be requested by the surgeon preoperatively for assessment of the vascular supply to the tumor mass, particularly when the tumor is exceptionally large (Figure 4).

Figure 3. A 3-year-old girl with a right-sided Wilms' tumor. This excretory urogram demonstrates enlargement of the right kidney (R) with splaying and distortion of the right renal collecting system. The left kidney is normal, with a normal pericaliceal system.

Figure 3. A 3-year-old girl with a right-sided Wilms' tumor. This excretory urogram demonstrates enlargement of the right kidney (R) with splaying and distortion of the right renal collecting system. The left kidney is normal, with a normal pericaliceal system.

Since Wilms' tumor metastasizes most commonly to the lungs, a preoperative chest x-ray is required. A CT of the chest should be done at the same time the abdominal CT is performed. Computerized tomography demonstrates small metastases which may not be evident by plain tomography or plain radiographs (Figure 5).

TUMOR MARKERS

An abnormal protein-polysaccharide complex has been detected in the serum, urine, and cell-free tumor extracts from patients with Wilms' tumor. However, attempts to find a chemical marker, analogous to catecholamines in neuroblastoma, have been largely unsuccessful.14 Serum lactate dehydrogenase (LDH) is often nonspecifically elevated in patients with Wilms' tumor. Serum erythropoietin and renin may be elevated, although these markers are neither sensitive nor specific. Normal levels of urinary catecholamine metabolites usually exclude a diagnosis of neuroblastoma in a child with an abdominal mass.1

PATTERNS OF SPREAD

Wilms' tumors may spread by local extension, tumor rupture, or by lymphatic or hematogenous dissemination to distant sites. Local spread beyond the renal pseudocapsule occurs commonly; actual invasion of contiguous organs, such as liver with right sided disease, is uncommon. Extension into the renal vein, inferior vena cava, and right atrium may rarely occur. Spillage with gross abdominal seeding may occur sponaneously, as a result of abdominal trauma, following too vigorous abdominal palpation by the clinician, or during surgery.

Figure 4. Same patient as in Figure I. Right renal arteriogram demonstrates normal vascularity and contrast enhancement of the inferior and superior poles of the right kidney. Wilms' tumor involves the lateral aspect of the right kidney. Hypodensity associated with dilated and irregular tumor vessels (arrows) is angiographic evidence of neoplasia.

Figure 4. Same patient as in Figure I. Right renal arteriogram demonstrates normal vascularity and contrast enhancement of the inferior and superior poles of the right kidney. Wilms' tumor involves the lateral aspect of the right kidney. Hypodensity associated with dilated and irregular tumor vessels (arrows) is angiographic evidence of neoplasia.

Figure 5. Same patient as in Figure I. CT of the lungs demonstrates metastatic lesions not seen on the plain chest x-ray. Three lesions are demonstrated in the right hemithorax and two on the left (arrows).

Figure 5. Same patient as in Figure I. CT of the lungs demonstrates metastatic lesions not seen on the plain chest x-ray. Three lesions are demonstrated in the right hemithorax and two on the left (arrows).

Figure 6. A 6-year-old girl with a right-sided Wilms' tumor. On ultrasound the tumor mass (M) is seen transversely with echolucent necrotic areas (arrows). Also seen are the liver (L), gallbladder (G) and spine (S). The inferior vena cava (curved arrow) is either displaced or invaded by tumor.

Figure 6. A 6-year-old girl with a right-sided Wilms' tumor. On ultrasound the tumor mass (M) is seen transversely with echolucent necrotic areas (arrows). Also seen are the liver (L), gallbladder (G) and spine (S). The inferior vena cava (curved arrow) is either displaced or invaded by tumor.

Lymphatic spread to regional nodes is associated with more advanced disease. It carries an increased risk oí widespread metastases and local recurrence in the renal bed. Hematogenous spread most commonly involves the lungs. Liver and brain metastases also rarely occur. Metastases to bone occur exclusively with the clear cell variant o Wilms tumor.

SURGICAL PRINCIPLES

Nephrectomy is required for virtually all patients with Wilms' tumor, except for patients with extensive bilateral disease. Thus, normal function of the contralateral kidney must be assured preoperatively.

Unlike the approach to the management of most other solid tumors, definitive initial treatment of Wilms' tumor may be undertaken without histological confirmation of malignancy. Confinement within the renal pseudocapsule considerably increases the prospect of complete tumor removal by radical nephrectomy. Furthermore, the friable, cellular nature of the tumor, confined by a tautly stretched renal capsule, makes abdominal seeding or gross rupture likely upon needle biopsy or incisional biopsy. An exception is made with bilateral tumors where biopsy, especially at the time of second- or third-look surgery may be required as a guide to curative treatment.

Wilms' tumor commonly invades the renal vein, and may extend up the inferior vena cava to the right atrium. The presence of tumor in the renal vein must be looked for preoperatively by appropriate imaging (Figures 6 and 7). Cross-clamping of the renal vasculature could otherwise have lethal consequences from tumor embolization.

Figure 7. An 8-year-old boy with a right-sided Wilms' tumor. Inferior vena cavogram demonstrates marked displacement of the contrast-filled inferior vena cava to the left (arrows), with compression of the inferior vena cava and no intraluminal invasion by tumor. Filling of the paravertebral plexus (open arrows) is seen as a collateral pathway for the compressed inferior vena cava.

Figure 7. An 8-year-old boy with a right-sided Wilms' tumor. Inferior vena cavogram demonstrates marked displacement of the contrast-filled inferior vena cava to the left (arrows), with compression of the inferior vena cava and no intraluminal invasion by tumor. Filling of the paravertebral plexus (open arrows) is seen as a collateral pathway for the compressed inferior vena cava.

A transverse transperitoneal incision is preferred for the following reasons: 1) the incision is large enough to permit en bloc resection of the tumor and involved kidney with the least risk of tumor rupture during its removal from the abdominal cavity; 2) because of the 4.2% incidence of bilateral synchronous Wilms' tumor, the opposite kidney must be mobilized, inspected and palpated on both sides and biopsy performed on suspicious areas; and 3) the liver and paraaortic lymph nodes may be inspected and biopsy done on suspected areas.

Meticulous surgical technique is mandatory because tumor spillage during surgery results in an increased incidence of abdominal recurrence and consequently, a higher mortality. If spillage occurs, more extensive chemotherapy and radiation therapy are required, with their potential side effects. Heroic surgical efforts to remove all tumor are not needed in the case of widespread abdominal disease. Adjuvant chemotherapy and radiation therapy postoperatively have proved to be extremely effective in eliminating residual tumor.

For patients with massive abdominal disease with or without renal vein and inferior vena cava extension, preoperative radiotherapy and/or chemotherapy may play a role in 1) decreasing the risk of intraoperative rupture, 2) decreasing the amount of normal renal parenchyma which must be removed from patients with bilateral disease, and 3) downstaging the disease (from groups Il and III to groups I and II).16 This approach should only be considered where the surgical risk is significant.

Table

TABLEStaging of Wilms' Tumor

TABLE

Staging of Wilms' Tumor

Regional lymphadenectomy, with selective surgical sampling of suspicious nodes, is recommended. Formal and aggressive lymph node dissection, however, is not warranted and adds little to overall survival. ' ' Staging of Wilms' tumor is based on pathological confirmation of the findings at surgery (Table).

PATHOLOGY

One of the major advances in the treatment of Wilms' tumor has been the discovery of the importance of histopathology in predicting biological behavior and prognosis.18 Treatments are now stratified according to so-called "favorable" and "unfavorable" characteristics. The pathological features of the various histologic patterns of Wilms' tumor are described below.

Grossly, Wilms' tumor is separated from normal tissue by a fibrous pseudocapsule. The renal vein may be involved. Large tumors are often centrally necrotic (Figure 8).

Figure 8. Gross appearance of a Wilms' tumor. Note the small residual pole of normal kidney.

Figure 8. Gross appearance of a Wilms' tumor. Note the small residual pole of normal kidney.

Figure 9. Well differentiated Wilms' tumor demonstrating tubules, blastema, and stroma. (H and E stain, x 100)

Figure 9. Well differentiated Wilms' tumor demonstrating tubules, blastema, and stroma. (H and E stain, x 100)

Well differentiated Wilms' tumor is the most common histologic pattern and is associated with the best prognosis. It is said to have a favorable histology. All other histologies are associated with a poor prognosis. Microscopically, well differentiated Wilms' tumor resembles developing embryonic renal tissue. Classically, three features are observed. These are tubules, blastema, and stroma. The tubules are surrounded by islands of compact uniform cells that comprise the blastema. The blastema, in turn, is surrounded by stromal proliferation (Figure 9).

The clear cell variant of Wilms' tumor is unique in its tendency to metastasize to bone. Clear cell tumors are associated with a particularly poor prognosis.

Figure 10. Clear cell Wilms' tumor variant. Note the uniform nuclei and characteristic ill-defined "clear" cytoplasm. (H and E stain, x 400).

Figure 10. Clear cell Wilms' tumor variant. Note the uniform nuclei and characteristic ill-defined "clear" cytoplasm. (H and E stain, x 400).

Figure 11. Anaplastic Wilms' tumor variant. Note the large pleomorphic and hyperchromatic nuclei in the tubule cells. (H and E stain, x 100).

Figure 11. Anaplastic Wilms' tumor variant. Note the large pleomorphic and hyperchromatic nuclei in the tubule cells. (H and E stain, x 100).

Figure 12. Mesoblastic nephroma. Note the mature, uniform, spindle cells. (H and E stain, x 400).

Figure 12. Mesoblastic nephroma. Note the mature, uniform, spindle cells. (H and E stain, x 400).

Microscopically, the tumor is quite homogeneous with a fibrovascular supporting network. The cells have uniform nuclei and ill-defined "clear" cytoplasm. The lack of acinar formation distinguishes this tumor from renal cell carcinoma (Figure 10).

Anaplastic Wilms' tumor is associated with advanced disease at diagnosis, local recurrence, pulmonary metastases, and an overall poor prognosis.19 Microscopically, the anaplastic variant demonstrates tubules that consist of cells with very large and pleomorphic nuclei, some of which are hyperchromatic. Abnormal mitoses are also a feature (Figure 11).

Mesoblastic nephroma is a benign, often congenital renal tumor of infancy and has in the past been mistaken for Wilms' tumor, despite its quite characteristic histologic appearance. Microscopically, the tumor consists of mature, uniform spindle cells (Figure 12).

The rhabdoid tumor is an extremely unusual tumor. Primary rhabdoid tumors have been found in extrarenal sites, including the posterior fossa of the brain and the mediastinum. It is, therefore, not a Wilms' tumor and accordingly, does not respond well to Wilms' tumor therapy.

TREATMENT

Advances in the treatment of childhood cancer are being reported at an ever increasing rate. "Optimal" therapy is therefore constantly changing and is usually best provided by institutions affiliated with one of the major pediatric cooperative groups such as the Children's Cancer Study Group (CCSG) or the Pediatric Oncology Group (POG).

In North America, Wilms' tumor is treated according to protocols developed by both of these groups, ie, those of the National Wilms' Tumor Study (NWTS) group. At present, three cooperative clinical trials under the aegis of the NWTS group have been completed, NWTS 1, 2, and 3.20'22 A fourth National Wilms' Tumor study is ongoing at present. For optimal patient care, participation in the NWTS 4 is strongly recommended. State of the art therapeutic recommendations, based on the NWTS 3 protocol are discussed below. These recommendations provide optimal curative potential with the least therapyrelated morbidity.

Patients With Tumors of Favorable Histology

Recommended therapy for group I patients includes vincristine and actinomycin-D. Optimal length of therapy has yet to be defined. Radiation therapy is not required.

Recommended therapy for group II patients includes intensive administration of vincristine and actinomycin-D for at least six months. Doxorubicin is not required, nor is radiation therapy needed.

Recommended therapy for group III and IV patients includes vincristine, actinomycin-D, and doxorubicin together with 1000 cGy of radiotherapy to the tumor bed.

Patients With Tumors of Unfavorable Histology

Recommended therapy for patients of all groups with clear cell histology includes vincristine, actinomycin-D, and adriamycin, together with 1000 cGy of irradiation to the tumor bed.

Recommended therapy for group I patients with anaplastic histology includes vincristine and actinomycin-D without radiation therapy, just as for group I patients with favorable histology.

Optimal therapy for group II, III, and IV patients with anaplastic histology remains unclear, although there seems to be some evidence of benefit for those patients that received cyclophosphamide.

Unsolved Therapeutic Questions

The NWTS 3 and NWTS 4 will address several unsolved therapeutic questions: 1) Can actinomycinD be equally or more effectively administered in a pulse intensive fashion, such as a single high dose versus five low doses per treatment course? 2) What is the optimal length of therapy for each histology and clinical group? and 3) Does cyclophosphamide improve the outcome for patients with anaplastic histology and advanced (groups I, II, III and IV) diseases?

FOLLOW-UP

Children undergoing treatment for Wilms' tumor must be monitored closely for complications of therapy and disease recurrence.

General Supportive Care

Radiotherapy to the hemi- or whole abdomen may be associated with radiation enteritis. This syndrome is characterized by crampy abdominal pain, mucosy or bloody diarrhea, food intolerance, anorexia, nausea, vomiting and weight loss - up to 20% of the body weight or more. Severe radiation enteritis requires complete gut rest and parenteral alimentation via a central venous catheter. Radiotherapy to the lungs is usually well tolerated but may be associated with a transient interstitial pneumonitis. Patients who have had pulmonary radiation are at increased risk of developing viral or bacterial pneumonic processes as well.

Chemotherapy-related side effects are drug specific. The side effects of vincristine, actinomycin-D, and doxorubicin, the most common drugs used in the treatment of Wilms' tumor, are considered below.

Vincristine produces hair loss and a moderate to severe peripheral neuropathy. This entity is manifest clinically by areflexia, a shuffling gait, difficulty climbing stairs, and clumsiness of the fingers. Constipation often results from involvement of the autonomic nerves of the bowel. Treatment with stool softeners for the latter problem is often required.

Actinomycin-D may produce nausea and acute vomiting. Neutropenia, thrombocytopenia and anemia, occasionally requiring blood product support develop ten to 14 days after the start of each course. Recovery usually occurs by day 21 to 25. Other side effects of actinomycin-D include hair loss, photosensitivity, and "radiation recall." The latter phenomenon may result in the reappearance of radiation dermatitis, enteritis, and pneumonitis. A diffuse idiosyncratic maculopapular eruption may also occur with the use of this drug.

Doxorubicin has many of the side effects of actinomycin-D including nausea and vomiting, hair loss, suppression of the blood counts, and radiation recall. The drug also may produce an irreversible cardiomyopathy. This latter complication is related to the total cumulative dose (usually greater than 400 mg/ m2), previous cardiac irradiation and the rate of drug administration (bolus versus slow infusion). To prevent this complication, echocardiography or radionuclide gated-pool flow (MUGA) studies are performed at regular intervals (every 60 mg/m2 after a cumulative dose of 240 mg/m2 has been reached).

All three of the above drugs are sclerotic to tissues and extreme care must be taken to prevent extravasation.

Disease Surveillance

Many patients who develop recurrent disease may be cured. The detection of early recurrences is therefore most important.

At the time of initial diagnosis, CT scans of the chest and abdomen are recommended. These studies should be repeated at six, 12, and 18 months thereafter. If there is a history of pre- or intra-operative tumor rupture with gross abdominal spillage, the CT should be extended to include the pelvis - a common site of abdominal seeding. An interim assessment with plain chest x-ray and abdominal (with or without pelvic) ultrasound should be performed at three, nine and 15 months. After 18 months, most patients can be monitored by chest x-ray and abdominal ultrasound alone performed at six month intervals to three years and then yearly to five years postdiagnosis. Appropriate compensatory hypertrophy of the remaining kidney should be evaluated during this off-therapy follow-up period.

Patients at high risk of recurrent disease (eg, patients with unfavorable histology, pulmonary metastases, or multifocal renal involvement at diagnosis) may require more frequent monitoring. Patients with clear cell tumors should have bone scans performed at diagnosis and then at six, 12, and 18 months because of their high risk for developing bony metastases.

RECURRENT DISEASE AND OUTCOME

Despite the overall excellent outcome for patients with Wilms' tumor, approximately 25% of patients with favorable histology group IV disease and 50% of patients with unfavorable histology groups II to IV disease experience primary progression or tumor recurrence. With aggressive, multi-modal therapy, many of these patients can be cured.

Outside of the context of a cooperative multiinstitutional phase II study for recurrent disease, "salvage" therapy should be individualized and based on 1) time (ie, on or off therapy); 2) site (ie, tumor bed or distant) of recurrence; 3) tumor histology (well differentiated, anaplastic, or clear cell); and 4) therapeutic history (ie, chemotherapy and radiotherapy initially delivered). Accordingly, the original pathology, chemotherapy doses, radiotherapy doses and fields, treatment schedules and delays, etc., should be carefully reviewed.

Patients should then have a complete re-evaluation. This evaluation should include a CT of the chest, abdomen and, if clinically indicated, brain, and pelvis (often a site of recurrence in patients who have had previous tumor rupture). A bone scan should also be performed on patients with clear cell histology even in the absence of bone pain or other symptoms of bony involvement. Renal function should be evaluated by creatinine clearance in view of previous nephrectomy and consideration of chemotherapy regimens containing nephrotoxic agents (eg, cisplatin or ifosfamide/ mesna). Cardiac function should be evaluated by echocardiography or MUGA in view of previous cardiotoxic therapy (ie, doxorubicin) and consideration of chemotherapy regimens containing additional doxorubicin or other anthracyclines.

Surgery should be strongly considered for all patients with presumed recurrent Wilms' tumor to: 1) confirm the diagnosis (and rule out other diagnostic possibilities, such as a second malignant neoplasm arising in a previously irradiated site); 2) confirm the histologic subtype (eg, well differentiated versus anaplastic); and, if possible, 3) remove all gross recurrent disease (eg, removal of an isolated peripheral pulmonary nodule).

Radiation therapy should be strongly considered for all previously unirradiated sites of tumor recurrence.

Chemotherapy should be administered to all patients with recurrent disease, whether or not the patients were rendered free of gross disease by surgery and radiation therapy. In general, patients with recurrent disease do not respond to retreatment with vincristine and actinomycin-D unless the recurrences developed more than six months after completion of initial therapy. Patients who have not previously received doxorubicin should be treated with regimens containing this agent. Patients with unfavorable histology who have not previously received cyclophosphamide should be treated with regimens containing this agent or the analog ifosfamide, administered with the uroprotectant mesna. Ifosfamide/mesna appears to be quite promising in the treatment of recurrent Wilms' tumor with an estimated response rate of 41% (20 out of 52 cases culled from the recent literature and 2 of 2 in the authors' institution).2*'25 The combination of cisplatin and VP-16-213 also appears to be effective with a response rate of 64% (9 out of 14 cases).26,27 The length of chemotherapy treatment in patients with recurrent Wilms' tumor rendered free of disease is unknown, although 12 to 18 months would seem reasonable.

Based on data in patients with recurrent disease (presented above) it would appear that ifosfamide/ mesna and cisplatin and VP-16-213 are active agents in the treatment of Wilms' tumor. It is hoped that future cooperative multi-institutional studies will evaluate the role of these drugs in the front-line treatment of patients with advanced disease.

The long-term disease-free survival for children with Wilms' tumor is excellent. The majority of patients survive with few or no sequelae. Based on these findings, the insurability of these patients has now become a realistic possibility.28

CONCLUSIONS

Major advances in the treatment of Wilms' tumor have been made over the last 20 years, largely through the efforts of cooperative clinical groups such as the National Wilms' Tumor Study Group. Accordingly, the majority of children diagnosed with Wilms' tumor in 1988 will be cured with few or no long-term sequelae. If advances in understanding of the biology of Wilms' tumor parallel these clinical advances, the day may come when prevention will be possible.

REFERENCES

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TABLE

Staging of Wilms' Tumor

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