| disease | Wilms Tumor |
| alias | Wilms'tumor, Nephroblastoma |
Wilms' tumor is the most common abdominal malignant tumor, ranking first in incidence among pediatric abdominal tumors. The tumor primarily occurs within the first five years of life, especially between the ages of 2 to 4. The incidence is similar on both sides, with 3-10% being bilateral, either simultaneously or sequentially. There is almost no gender difference, though most reports indicate a slightly higher incidence in males. Rare cases occur in adults. In 1899, German physician Max Wilms first described this disease, which later became widely known by his name. Modern terminology refers to it as nephroblastoma, as it originates from the metanephros during embryonic development and consists of components highly resembling nephrogenic cells. Since the advent of chemotherapy, particularly the remarkable efficacy of actinomycin D and vincristine against this tumor, combined with comprehensive treatment protocols, the prognosis has significantly improved. The two-year survival rate for all stages can exceed 80%, even reaching 92%, making it one of the great successes in cancer treatment.
bubble_chart Pathological Changes
The tumor originates from the undifferentiated metanephric blastema and can form various components of the kidney. The tumor varies in size and is covered by a thin, fragile pseudocapsule. The cut surface appears uniform and fish-like, grayish-white, with necrosis, hemorrhage, and cystic changes. Microscopically, undifferentiated mixed epithelial and mesenchymal tissues are observed, with epithelial differentiation forming irregular glandular structures or masses resembling renal glomeruli. Mesenchymal tissue can develop into striated muscle, smooth muscle, bone, cartilage, blood vessels, connective tissue, etc. The tumor grows extremely rapidly and may directly rupture the capsule to invade surrounding renal tissues or metastasize to local lymph nodes, liver, etc. Hematogenous metastasis is common, with lung metastasis being the most frequent. Renal vein tumor thrombi occur in 10–45% of cases, while inferior vena cava tumor thrombi occur in 4.5%. Bone metastasis is relatively rare.
bubble_chart Clinical ManifestationsClinical pathological staging is closely related to understanding the disease condition, formulating treatment plans, and influencing prognosis, making it extremely important. After years of observation and research, it is now recognized that congenital mesoblastic nephroma often occurs during infancy, with well-differentiated tissues and typically follows a benign course. Cystic nephroblastoma also exhibits a benign course with a favorable prognosis. According to the International Society of Pediatric Oncology, the histological type of cells is emphasized as critically important for prognosis. Therefore, nephroblastoma can be classified into two types based on pathological histology.
(1) Favorable histology group: Examples include classic nephroblastoma, cystic nephroblastoma, and mesoblastic nephroma.
(2) Unfavorable histology group: Accounts for about 10%, including undifferentiated nephroblastoma, clear cell fleshy tumor, and rhabdoid tumor. Nearly 60% of these cases result in death.
Factors affecting prognosis were previously thought to be related to tumor size and the patient's age, but with the development of highly effective treatments, these factors have lost their significance. Other factors, such as infiltration of the capsule, extension into the renal vein or inferior vena cava, local extrarenal spread, intraoperative rupture, and peritoneal dissemination, can be managed by complete surgical resection of visible tumors and multi-drug chemotherapy. Currently, the most important prognostic factors are the tumor's histological structure, complete resection of the primary tumor, metastatic lesions, and bilateral disease. Therefore, recent clinical pathological staging methods place less emphasis on local tumor spread than before, shifting from Stage III to Stage II. Conversely, lymph node metastasis, due to its significantly worse prognosis, is now considered more severe than previously estimated, shifting from Stage II to Stage III.
Clinical pathological staging:Stage I: The tumor is confined to the kidney and can be completely resected. The renal capsule is intact, and the tumor has not ruptured preoperatively or intraoperatively. There is no residual tumor at the resection margin.
Stage II: The tumor has extended beyond the kidney but can be completely resected. There is regional spread, such as penetration of the renal capsule into perirenal tissues, tumor thrombi or infiltration in extrarenal vessels, biopsy of the tumor, or local spillage confined to the renal fossa. No significant residual tumor is present at the resection margin.
Stage III: Non-hematogenous residual tumor is present in the abdomen.
1. Pathological examination reveals tumor infiltration in the renal hilar or para-aortic lymph nodes.
2. Extensive tumor contamination within the abdominal cavity, such as preoperative or intraoperative tumor spillage or tumor growth penetrating the peritoneal surface.
3. Peritoneal tumor implants.
4. Residual tumor at the resection margin (gross or microscopic).
5. Incomplete tumor resection due to infiltration of surrounding vital organs.
Stage IV: Hematogenous metastases, such as to the lungs, liver, bones, or brain.
Stage V: Bilateral tumors at diagnosis, with each side staged according to the above criteria.
The condition often presents as an asymptomatic upper abdominal mass protruding toward the flank. The mass is smooth, solid, and relatively fixed, with larger masses possibly crossing the abdominal midline. In the early stages, it is usually unaccompanied by other symptoms and is often discovered incidentally by parents or caregivers during infant dressing or bathing. As the tumor grows larger, symptoms such as abdominal pain, hematuria, fever, hypertension, and anemia may appear. Pain may result from local infiltration, tumor hemorrhage and necrosis, or compression of surrounding tissues and organs. In rare cases, acute abdominal pain may occur due to pathological renal rupture. Hematuria, caused by infiltration of the renal pelvis and calyces, is uncommon, occurring in about 10–15% of cases. Low-grade fever is a common symptom, caused by proteins released by the tumor, indicating rapid tumor progression. Hypertension, often due to elevated renin levels from renal ischemia, is relatively common, occurring in 30–60% of cases. Anemia is usually due to intratumoral hemorrhage. Advanced-stage tumors may lead to cachexia. Recent attention has been given to endocrine changes, as the tumor may produce erythropoietin, leading to elevated erythropoietin levels, though polycythemia is rarely observed.
Approximately 15% of cases are associated with other congenital malformations, such as imperforate anus, hemihypertrophy, Beckwith-Wiedemann syndrome, etc. The most common are genitourinary system malformations, such as horseshoe kidney. In recent years, there has been more research on familial occurrence tendencies and hereditary relationships, revealing chromosomal abnormalities, specifically intermediate deletions in the short arm of chromosome 11, which has advanced the understanding of its etiology.When an abdominal mass is detected in an infant, it should be examined using modern diagnostic techniques. Excretory urography may reveal an enlarged kidney with deformed, elongated, displaced, or destroyed renal pelvis and calyces. In some cases, renal function is reduced or completely absent, requiring high-dose contrast imaging. Plain films may show scattered or linear calcifications. Ultrasound helps differentiate hydronephrosis. CT scans assist in determining the extent of tumor invasion. Serum erythropoietin and renin levels can also be measured. If necessary, renal 99mTc-DMSA scintigraphy or other examinations may be performed.
To date, there is no diagnostic tumor marker for Wilms' tumor. For differentiation from neuroblastoma and other tumors, bone marrow aspiration, urinary VMA and HVA quantification, serum lactate dehydrogenase (LDH), alpha-fetoprotein (AFP) quantification, and neuron-specific enolase (NSE) quantification may be conducted.
During laparotomy, the typical appearance of Wilms' tumor is a solid, smooth, spherical mass with dilated collateral vessels on the surface, slightly bluish in color, partially replacing the affected kidney and displacing it. Due to the tumor being surrounded by a high-tension renal capsule and its fragile, cell-rich nature, preoperative or intraoperative needle or incisional biopsies should be avoided to prevent seeding and dissemination. To rule out bilateral tumors, biopsies are sometimes necessary, especially during the second or third surgery, with careful selection of the biopsy site. An effective treatment plan can only be formulated after a definitive diagnosis is obtained. One study reported that among pediatric bilateral Wilms' tumor cases, 17 out of 19 biopsy-confirmed cases survived, demonstrating the importance of biopsy. Fear of biopsy-induced seeding should not compromise the determination of tumor histology, as this could reduce survival rates. Of course, in cases where unilateral lesions are resected, biopsies come at a cost. For cases with tumor spillage, even if the tumor is completely resected and the stage is favorable, chemotherapy and radiotherapy are still required. In contrast, cases with complete tumor resection and no biopsy may achieve similar cure rates with minimal chemotherapy.
Preoperative diagnosis must address the following issues:
(1) Is the contralateral kidney normal? Since the treatment for Wilms' tumor is nephrectomy, the contralateral kidney must be functional. Bilateral tumors may occur simultaneously, or the contralateral kidney may be absent or congenitally malformed. Based on history, physical examination, ultrasound, blood and urine laboratory tests, and excretory urography, a basic diagnosis can be made regarding whether the contralateral kidney is functional, impaired, or resectable. In special cases, renal scans, stirred pulse angiography, or CT scans may provide further clarification. Even if tests are negative, surgeons must carefully inspect the contralateral kidney during surgery to avoid missing smaller tumors undetected by imaging.
(2) Are there metastases? Due to the rapid growth of Wilms' tumor, it is often quite large at initial detection. Although preliminary examinations may suggest localized disease, 15% of cases already have metastases at diagnosis, commonly to the lungs, followed by the liver, bones, and brain. Since lymph node specimens are not routinely examined, statistical data on the relationship between lymph node metastasis and survival rates are limited. The 2-year survival rate is 82% for lymph node-negative cases and 54% for lymph node-positive cases.
(3) Is the tumor resectable? The tumor is usually confined within the renal capsule, compressing and displacing surrounding organs but rarely invading them. Even if the tumor has ruptured the capsule, it is rarely unresectable. Even when enveloping major blood vessels, a plane for dissection can often be found. Tumor thrombi may directly invade the renal vein, inferior vena cava, or even the right atrium. Therefore, preoperative assessment of vascular invasion is crucial, and inferior vena cavography or right heart catheterization may be necessary. During surgery, manipulation should be minimized to prevent tumor spread into the renal vein.
bubble_chart Treatment Measures
Before treatment, a thorough understanding of the tumor's specificity and prognostic factors is essential. A suitable treatment plan should be formulated based on the specific case to improve therapeutic outcomes. During treatment, it is crucial to avoid harmful and unnecessary overtreatment. After the primary treatment, regular follow-up is of utmost importance.
The comprehensive approach combining surgery with chemotherapy and radiotherapy has been widely recognized as the standard treatment. However, how to optimize the combination, dosage, and treatment duration to minimize harm while maximizing efficacy remains a subject for in-depth research.
Nephrectomy is the primary treatment, often involving minor blood loss during surgery. For large tumors, especially those involving the inferior vena cava, there is a risk of significant hemorrhage. Therefore, preoperative preparation should include central venous catheterization and monitoring, with rapid blood volume replenishment if necessary. Radial artery catheterization and monitoring allow timely blood gas analysis, while urinary catheter placement and postoperative urine output monitoring are also essential.
The tumor is often fragile and prone to rupture, so the abdominal incision must provide ample exposure to facilitate examination of the renal vein and other potential tumor sites. The best approach is a transverse incision extending from the anterior axillary line of the 12th rib to the contralateral margin. For large tumors, a thoracic extension may be required to ensure safer and easier surgery. A meticulous exploration of the abdominal cavity is necessary, as lymph node and/or liver metastases may be present. Suspicious lymph nodes should be biopsied and marked with metal clips. The contralateral kidney should be carefully inspected and palpated. The surgeon's goal is to remove all tumor tissue, which may require extensive lymph node dissection or resection of adjacent infiltrated organs such as the stomach, intestines, or liver. The renal vein should be palpated carefully to ensure ligation distal to any tumor thrombus. If the thrombus extends into the inferior vena cava, the vein should be opened to remove it. For thrombi reaching the right atrium, extracorporeal circulation may be necessary for successful removal.
Traditionally, early ligation of the renal vein during surgery was believed to reduce the risk of pulmonary tumor embolism. However, evidence suggests that the timing of venous ligation does not affect prognosis. Ligating the renal vein before the renal artery results in outflow obstruction preceding inflow obstruction, causing tumor congestion, swelling, increased fragility, and potential rupture of perirenal tumor veins. Therefore, when technically feasible, early arterial occlusion should be prioritized to reduce tumor size and fragility, facilitating the procedure. For very large tumors where the renal vein cannot be exposed initially, it is advisable to free the surrounding tissues first and approach the renal hilum laterally. A thoracoabdominal incision may be more convenient in such cases.
In rare cases where the tumor is extremely large and/or the patient's condition is poor, preoperative treatment with a course of vincristine, radiotherapy, or renal artery embolization may be used to shrink the tumor and simplify safe resection. However, preoperative treatment does not improve survival rates and has several drawbacks: ① Even low-dose chemotherapy can disrupt tumor histology, complicating staging and leading to inappropriate treatment plans. ② Misdiagnosis may occur. Some abdominal masses are found during laparotomy not to be Wilms' tumors. ③ Infants with Stage I tumors may receive unnecessary preoperative treatment.
Based on tumor staging and histopathological classification, the following specific treatment plans can be adopted.
(1) Favorable Histology
Stage I: Nephrectomy, chemotherapy (vincristine + actinomycin D) for 10 weeks or 6 months, no radiotherapy.
Stage II: Surgery, chemotherapy (vincristine + actinomycin D + doxorubicin) for 15 months, no radiotherapy or 20Gy radiotherapy.
Stage III: Surgery, same chemotherapy as Stage II, radiotherapy 10Gy or 20Gy.
Stage IV: Surgery, three-drug chemotherapy as in Stages II and III, or four-drug chemotherapy with cyclophosphamide, radiotherapy 20Gy.
(2) Unfavorable Histology
Any stage: Nephrectomy, three- or four-drug chemotherapy, radiotherapy dose increased to 40Gy based on age.
1. Chemotherapy drugs ① Actinomycin D 15μg/(kg﹒d) for 5 consecutive days, repeated at the 6th week and 3 months, thereafter, every 3 months as a course. ② Vincristine 1.5mg/m2, once a week, 8-10 weeks as a course. ③ Adriamycin 40mg/m2, divided into 2-3 days for intravenous injection, once every 4 weeks, total dose 300-400mg/m2. ④ Cyclophosphamide 10mg/(kg﹒d) for 3 consecutive days, thereafter, every 6 weeks as a course.
2. Radiotherapy should be performed within 48 to 72 hours after surgery and should not be delayed beyond 10 days.
Treatment of bilateral tumors: The optimal approach is selected based on individual cases, with the goal of preserving more functional renal tissue. The larger tumor may be treated with nephrectomy, while the other side may undergo biopsy or partial resection, followed by chemotherapy and radiotherapy. Synchronous bilateral tumors often have a favorable histological type and prognosis, favoring a more conservative approach. For tumors with poor histological prognosis, a more aggressive treatment plan is required.
Treatment of metastatic tumors: Currently, chemotherapy is considered the first-line treatment, with surgery as the second-line option. For example, in the case of lung metastases, chemotherapy is administered first, followed by surgical resection of residual lesions. However, surgical removal of metastatic tumors should be performed only after intensive chemotherapy.
For cases where the treatment plan is fully executed, being recurrence-free for 2 years can be considered a cure. For those with incomplete treatment plans, a conclusion should be deferred until after 5 years. The prognosis for comprehensive treatment is better, with a 2-year tumor-free survival rate of 88% and a 2-year survival rate of 93% for tumors confined to the kidney. For locally advanced stage lesions and distant metastases, the 2-year tumor-free survival rate is 77%. Analysis by histological type shows a 2-year survival rate of 90% for favorable prognoses and only 54% for poor prognoses.
