WILMS’ TUMOR

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WILMS’ TUMOR Mohan S. Gundeti

Wilms’ tumor (nephroblastoma) is the most common primary malignant solid renal tumor of the kidney in childhood. The incidence rate in the United Kingdom is 7 per 1 million children, accounting for approximately 80 to 90 cases each year. In the United States, the incidence is similar with 8.1 cases per 1 million children accounting for 450 to 500 cases each year.1 Since the first description of Wilms’ tumor by Wilms in the 18th century, the first nephrectomy by Jessop2 in 1877, and the addition of radiotherapy in 1915, there have been many advances in the treatment of this tumor, especially in the ­latter part of the 20th century. The chemotherapeutic agent actinomycin was added in 1953 by Farber and colleagues,3 and vincristine was added in 1963 by Sutow and coworkers.4 Wilms’ tumor is an ideal example of the progress made by a multidisciplinary team (i.e., surgeon, oncologist, geneticist, and pathologist) working toward a single goal—improving survival of these children. The introduction of trials by the International Society of Pediatric Oncology in Europe (SIOP) and the National Wilms’ Tumor Study (NWTS) in the United States has been extremely beneficial in treatment guidelines and strategies. These trials have resulted in an overall improved survival rate and reduced morbidity compared with previous survivals rate of 15% with surgery alone5 and 40% with surgery and radiotherapy.6 Present and future work is directed toward finding new therapeutic strategies for high-risk patients, reducing the therapy for low-risk patients, and studying the new biologic parameters of the tumor.

EPIDEMIOLOGY Tumor occurrence is almost equal in boys and girls, with a slightly higher predominance in girls in the United States.7 The median age of presentation is 40 months (3.5 years), and the tumor is seen until age 5 to 6 years. Most tumors at presentation are unilateral; about 5% to 6% are bilateral. Bilateral tumors are especially common in girls with an earlier age of presentation (28 months).8 There is some ethnic variation in the incidence, with lower reported rates in east Asia compared with the United States and Europe.7 Familial Wilms’ tumor occurs in 1% to 2% of all cases.9

HIGH-RISK FACTORS AND ASSOCIATED  SYNDROMES Wilms’ tumor usually develops in otherwise healthy children, but in about 8% cases, there are recognized malformations.10,11 These associated syndromes can be divided into overgrowth and non-overgrowth syndromes (Table 50-1). Beckwith-Wiedemann syndrome is a classic example of an overgrowth syndrome, characterized by excessive overgrowth at the cellular and organ levels (macroglossia, nephromegaly, and hepatomegaly), and hemihypertrophy (Fig. 50-1A). The characteristic clinical features are neonatal hypoglycemia, exomphalos, macroglossia, high birth weight, and

gigantism. In addition to Wilms’ tumor, these children are at risk of adrenal and hepatic malignancies.12 The nephromegaly in this spectrum is a high-risk factor for the development of Wilms’ tumor. Hemihypertrophy, another common overgrowth syndrome occurring either in isolation or in association with Beckwith-Wiedemann syndrome, is also a risk factor (Fig. 50-1B). Perlman syndrome (visceromegaly, macrosomia, polyhydramnios, and abnormal facies) and Sotos syndrome (macrocephaly, developmental delay) are other rare overgrowth syndromes associated with Wilms’ tumor. Nephroblastomatosis is a common feature of Perlman syndrome.13 The important non-overgrowth syndromes are WAGR (Wilms’ tumor, aniridia, genital anomalies, and mental retardation) syndrome and Denys-Drash syndrome. Isolated aniridia is also a risk factor for the development of Wilms’ tumor. Denys-Drash syndrome is a syndrome associated with Wilms’ tumor with male pseudohermaphroditism and glomerulosclerosis leading to nephropathy. Trisomy 18 also is reported to be a risk factor. The most common genitourinary anomalies associated with Wilms’ tumor are hypospadias and undescended testis in about 4%.14 Other reported associations are horseshoe kidney, pigmented nevi, and neurofibromatosis.

GENETICS OF WILMS’ TUMOR The theory proposed by Knudson and Strong,15 the loss of tumor-suppressor gene leading to the tumor, strongly correlates to the Wilms’ tumorigenesis. Various chromosomal loci have been found to be responsible for Wilms’ tumor ­formation.

WT1 (11p13) WT1 gene is usually expressed in the developing genitourinary tract and has been detected in the developing kidney at 20 weeks of gestation; it is rarely found in adults. This pattern suggests its importance in the role of renal development and differentiation. Abnormal expression, lack of expression, or deletion usually leads to Wilms’ tumor. The exact location of this gene is on short chromosome 11 at the p13 position. This abnormality of WT1 is associated with WAGR syndrome16 and Denys-Drash syndrome.17

WT2 (11p15) An excess of material on the chromosome as an extra band at 11p15 in the WT2 gene coding for insulin-like growth factor has been found. This excess material is responsible for the overgrowth as seen in hemihypertrophy and Beckwith­Wiedemann syndrome.18

Other Chromosomal Abnormalities Abnormalities at chromosomes 17 q12-21,19 16q1p,20 7p,21 and p53 in anaplastic tumor22 have been found. 671

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TUMORIGENESIS (TUMOR FORMATION) AND NEPHROBLASTOMATOSIS Abnormal collections of blastemal cells are found in about 1% of kidneys on postmortem examination, yet these are found in approximately 40% of kidneys removed for Wilms’ tumor. These histologic abnormalities are found uniformly in the kidneys of children with an inherited susceptibility to Wilms’ tumor. When multiple nephrogenic rests are found, or when the presence of rests can be inferred, such as in multicentric or bilateral Wilms’ tumor, the condition is described as nephroblastomatosis.23 Not all nephroblastomatoses develop into Wilms’ tumor; most regress or develop into a clinically insignificant benign entity. Detection of these rests is challenging on conventional imaging, and they are found only on extensive histologic search. Table 50-1     Syndromes Associated with Wilms’ Tumor Overgrowth

Non-overgrowth

Beckwith-Wiedemann

Denys-Drash

Hemihypertrophy

WAGR

Perlman

Aniridia

Sotos

A

Depending on their location in the kidney, these nephrogenic rests are divided into intralobar rests (i.e., within the lobe of the kidney) or perilobar rests (i.e., at the periphery of the kidney). Perilobar nephrogenic rests are associated with 11p15 (WT2): Beckwith-Wiedemann syndrome and synchronous bilateral Wilms’ tumor. Intralobar nephrogenic rests are associated with 11p13 (WT1): aniridia, Denys-Drash syndrome, and metachronous Wilms’ tumor (Fig. 50-2).24

PATHOLOGY OF WILMS’ TUMOR On gross specimen, Wilms’ tumor has a varied appearance of smooth to cystic and variegated on cut section. There is no distinct capsule, but the surrounding mesenchyme condenses to form a pseudocapsule. Occasionally, hemorrhage and necrosis are noted on gross specimen examination. The whole specimen is handled very carefully, and gross specimen examination, microscopic study, and further biologic studies are performed according to the protocols by SIOP 2002 in Europe and the American College of Pathologists in the United States.25 For macroscopic examination, the tumor should be send to the pathology department intact without formalin preservative. The examination includes specimen weight, tumor location, capsule invasion, renal vein and sinus invasion, ureter, and cut surface of the kidney if a heminephrectomy was performed.

B

Figure 50-1  A, Beckwith-Wiedemann syndrome in high-risk syndromes. B, Isolated hemihypertrophy in high-risk syndromes. (A, Courtesy of Mr. D. T. Wilcox.)

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Perilobar nephroblastomatosis (PLNR)

Intralobar nephroblastomatosis (ILNR)

Pelvis

Figure 50-4  Histology of diffuse anaplastic variety Wilms’ tumor.

Ureter

Calyces

Figure 50-2  Location of various types of nephroblastomatosis.

Figure 50-3  Favorable-histology Wilms’ tumor.

Figure 50-5  Abdominal distention owing to a large tumor.

The most vital thing on pathologic examination, apart from staging, is to classify the tumor into favorable-­histology and anaplastic tumor because this is the key factor for prognosis and further treatment. Classic favorable-histology Wilms’ tumor, also called triphasic Wilms’ tumor, has three components: blastemal, stromal, and epithelial. Occasionally, other embryonic cells, such as skeletal, squamous, or cartilage, are found. Perilobar nephrogenic rests resemble these microscopic findings, and the distinction is made by the absence of a peritumoral fibrous capsule in a perilobar nephrogenic rest (Fig. 50-3). Anaplasia refers to gigantic polypoid nuclei with increased chromatin content and the presence of multipolar mitotic figures.25 The anaplasia may be focal or diffuse depending on location. This feature is uncommon; it is found in about 5% to 10% of the total Wilms’ tumor population (Fig. 50-4).26 Most tumors are unicentric; 7% to 10% are multicentric.

such as fever and malaise. Sometimes the presentation includes hematuria and pain. Pain is usually rare, and it may indicate tumor rupture; this is associated with hypotension and anemia.27,28 The clinical spectrum mimics an acute abdomen. Hypertension is occasionally found, probably related to the increased renin formation,29 or compression effect of the tumor on vascular structures. If the tumor extends into the inferior vena cava (10% as reported by NWTS),30 this may result in bilateral lower limb edema and varicocele in a boy. Hepatic vein obstruction leads to hepatomegaly and ascites. The tumor thrombus extending into the atrium has rarely resulted in congestive heart failure. Lung metastasis may manifest with recurrent respiratory tract infection or a pleural effusion31 with cough. The clinical examination should look at all of these aspects and should specifically look for the signs of associated syndromes as mentioned earlier.

PRESENTATION

EXTRARENAL WILMS’ TUMOR

A clinically palpable, painless abdominal mass in an otherwise healthy child is the most common presentation (Fig. 50-5). Often, a child may present with only constitutional ­symptoms,

Extrarenal Wilms’ tumor is rare but often noted. The presence of ectopic metanephric blastemal cells or the Wt gene that causes transformation of extrarenal primitive mesonephric

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Table 50-2    Differential Diagnoses of Renal Tumor  

in Childhood

Benign

Malignant

Renal abscess

Nephroblastoma

Multicystic kidney

Neuroblastoma

Multilocular cyst Xanthogranulomatous pyelonephritis

remnants into Wilms’ tumor during embryogenesis is considered the cause. These tumors are located in the retroperitoneum,32 in the uterus, in the cervix, in the pelvis, along the line of spermatic cord testes, and in the thorax. The histologic characteristics are the same.

EVALUATION, INVESTIGATIONS, AND IMAGING OF TUMOR The aim of the evaluation is a preoperative diagnosis, staging, and assessment of the vascular anatomy and surrounding organs from the surgical aspect and to rule out bilaterality of the tumor (Table 50-2). The initial simple workup includes complete blood count, renal biochemistry, and coagulation studies because acquired von Willebrand’s disease is known in 8% of patients.33 Urinalysis for proteins and catecholamines is performed to rule out neuroblastoma.

Ultrasonography Ultrasound scan is the initial fast noninvasive test to help to distinguish between a cyst and tumor, and to detect small tumor in the opposite kidney or liver and abdominal ­metastasis. Ultrasound with Doppler also detects inferior vena caval patency. The SIOP protocol places emphasis on three-­dimensional measurement of the tumor on ultrasound scans. The challenge with ultrasound is differentiating the nephrogenic rests from tumor. The nephrogenic rests are usually ovoid, static, superficial, and multiple compared with tumor, which is rounded, expanding, deeply situated, and solitary.

Computed Tomography Scan of Abdomen and Pelvis Computed tomography (CT) provides cross-sectional ­imaging to help in identifying the renal origin of the tumor, extent, regional nodes, and surrounding organ involvement. Inferior vena caval thrombus is also clearly seen. The more recent sophistication in CT scanners and awareness among radiologists have been effective in reducing the radiation dosage. Plain and contrast images are important to see the details of the tumor and vascular anatomy. Contralateral kidney anatomy is also assessed for small lesions (Fig. 50-6).

Figure 50-6  CT scan of left Wilms’ tumor.

Magnetic Resonance Imaging When involvement of the inferior vena cava is suspected, magnetic resonance imaging (MRI) is the best way of mapping intravascular extension.34 The other advantage of MRI is that it also differentiates thrombus involvement in the lumen from the vascular wall (Fig. 50-7).

Echocardiography Echocardiography is performed to detect the intra-atrial extension of the tumor thrombus, which was found in 20% of children with thrombus. Echocardiography is also mandatory before starting doxorubicin (Adriamycin) as part of chemotherapy in high-risk children.

Positron Emission Tomography Positron emission tomography (PET) with the glucose analog fluorodeoxyglucose is a recent addition to the imaging armamentarium and is still under review. PET detects the primary tumor and metastases. In a more recent review, a combination of PET with CT scan was superior in staging for solid tumors in adults.35

Bone Scan and Brain Magnetic Resonance Imaging Bone scan and brain MRI are performed in clear cell sarcoma of the kidney and rhabdoid tumor of the kidney.

Imaging of Bilateral Renal Tumors In addition to the above-mentioned imaging, a dimercaptosuccinic acid radioisotope renal scan is mandatory to evaluate the split renal function. In selective cases, arteriography or MR angiography is important to delineate the renal arterial anatomy before partial nephrectomy or bench surgery.

Chest Radiograph Posteroanterior and lateral radiographic views to detect pulmonary metastasis are mandatory. The chest radiograph has limitations in detecting micrometastasis, however. Most ­centers prefer performing a CT scan of the chest at the same time as the abdomen, which may be more convenient and specific for the detection of metastasis.

STAGING OF WILMS’ TUMOR Staging is crucial in the management of Wilms’ tumor because treatment and prognosis depend on accurate staging. NWTS staging is based on the surgical and histopathologic ­findings (Table 50-3). Lymph node sampling is important to

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B Figure 50-7  A, CT scan showing inferior vena cava thrombus. B, MRI scan showing inferior vena cava thrombus with tumor.

a­ ccurate ­staging. Complete nodal clearance is not needed. The ­distribution of tumor according the NWTS-4 study group was as follows: stage 1, 41.8%; stage 2, 27.5%; stage 3, 21.5%; and stage 4, 9.3%.

MANAGEMENT OF WILMS’ TUMOR Management consists of surgery for removal of the primary tumor with the kidney (radical nephrectomy), with chemotherapy and radiotherapy in some cases. The management is guided by the NWTS protocol in the United States and the SIOP protocol in Europe according to the stage of the tumor.

Surgery Radical nephrectomy for removal of the primary tumor with the kidney is the mainstay of treatment. This procedure allows the removal of the primary tumor and accurate staging of the tumor. The usual approach is transperitoneal through a transverse abdominal incision, which gives good access to the tumor and vasculature. The principles of surgery are as follows: 1. Palpation of liver, abdomen, and para-aortic region for regional spread of disease 2. Removal of intact specimen in total 3. Avoidance of local spillage because these children have a sixfold increase in local abdominal relapse36 4. Nodal sampling rather than clearance because there is no added advantage in the long-term survival37 5. Proper identification and avoidance of injury to ­contralateral renal vessels, aorta, and iliac and superior mesenteric arteries38 6. Palpation of the renal vein and inferior vena cava before ligation to rule out thrombus

Exploration of Contralateral Kidney In the past, careful examination of the contralateral kidney as a part of the exploratory laparotomy was widely accepted, but not always done. This was done at the outset to rule out the

Table 50-3    National Wilms’ Tumor Study Staging  

of Wilms’ Tumor

Stage 1

Tumor limited to kidney and completely ­resected. Renal capsule intact. Tumor not ruptured or ­biopsied before removal. No residual tumor ­beyond margins of resection

Stage 2

Tumor extends beyond kidney, but completely resected. Regional extension of tumor (vascular ­invasion outside renal parenchyma or ­capsular penetration with negative excision margin). ­Operative tumor spill confined to flank (no peritoneal contamination). Tumor biopsy (except fine-needle aspiration) before surgery

Stage 3

Nonhematogenous metastases confined to the abdomen (e.g., tumor in regional lymph nodes) including tumor implants on or penetrating the peritoneum. Gross or microscopic tumor remains postoperatively. Tumor spill before or during ­surgery not confined to flank. Piecemeal excision of the tumor (removal in >1 piece)

Stage 4

Hematogenous metastasis or lymph node ­metastases outside the abdominopelvic region (­beyond renal drainage system, e.g., lung and liver)

Stage 5

Bilateral renal involvement at diagnosis (each side should be staged separately, according to above criteria, as stage 1-4)

From Qualman SJ, Bowen J, Amin MB, et al. Protocol for the examination of specimen from patients with Wilms’ tumor or other renal tumors of childhood. Arch Pathol Lab Med. 2003;127:1280-1289.

potential bilaterality of the tumor. Modern imaging techniques (CT and MRI) are much more likely to identify the intrarenal tumor than palpation with the surgeon’s hand. Palpation of the contralateral kidney is mandatory according to NWTS, however, because there have been reports of missed bilateral cases despite imaging: in 0.3% of 3335 registered cases, but the outcome was not affected.39

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Tumor

IVC

Kidney

Renal artery

Colon

Ureter Colon

A

Renal vein

B

Kidney with tumor

Aorta

IVC

Figure 50-8  Surgical steps showing tumor nephrec-

tomy on left side. A, Reflection of colon from kidney. B, Identification of major vessels and control at renal ­hilum. C, Ligation of renal vessels. D, Removal of t­umor with ­ kidney, and ligation of ureter. IVC, inferior vena cava.

A

Ureter

C

D B

Right renal tumor

Right kidney & tumor

IVC

Left renal tumor

Aorta

IVC

Aorta

Left kidney & tumor

Left renal artery Left renal vein RRV

RRV

RRA*

LRV*

Figure 50-9  Risk of vascular in-

jury during right (A) and left (B) renal tumor nephrectomy. IVC, inferior vena cava; LRA, left renal artery; LRV, left renal vein; RRA, right renal artery; RRV, right renal vein; SMA, superior ­ mesenteric artery.

Left kidney Ureter

Ureter

Right kidney Ureter SMA

*Danger to left renal vein and inferior vena cava during right nephrectomy

Surgical Steps After initial palpation of the abdomen, the colon is reflected and moved completely away from the kidney. Major vessels (i.e., aorta, inferior vena cava, renal artery and vein, superior mesenteric artery) are identified. Mobilization of the tumor toward the surgeon helps in exposure of the renal hilum. Renal vessels are ligated after confirmation. The ureter is divided, and the specimen is removed in total. The adrenal may not need to be removed if it is clearly away from the tumor (Fig. 50-8).

LRA LRV

*Danger to right renal artery, superior mesenteric artery, and aorta during left nephrectomy

The vessels most at risk during excision of a right renal tumor are the vena cava and left renal vein (Fig. 50-9). During removal of a left renal tumor, the vessels at risk are the aorta, superior mesenteric artery, and right renal artery.

Surgery in Tumor with Caval Thrombus After confirmation of imaging in regard to the superior extension, a proper surgical approach is decided. For thrombus extension, up to retrohepatic level as a good control

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of the vena cava above and below the thrombus level allows complete removal of the thrombus. Suprahepatic level and extension into the atrium, where a superior control is impossible, needs a cardiac bypass (extracorporeal circulation) team with a cardiothoracic surgeon. These children have chemotherapy before surgical intervention. Occasionally, the tumor may be adherent or involve the inferior vena cava, and cavectomy may be performed safely.40

Surgical Complications

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evolved with individual stages of the study, the current stage being NWTS-5.

NWTS-1 (1969-1973) During NWTS-1, 606 patients were included in the study group. The conclusion was that postoperative radiotherapy is effective for selected patients. The combination of vincristine and actinomycin D is more effective than either drug alone. There is no evidence for a role for preoperative vincristine, but numbers were too small to be conclusive.45

NWTS-2 (1975-1978)

NWTS has reported a surgical complication rate of 11% for primary nephrectomy.41 Common complications were hemorrhage and small intestinal obstruction. Other complications are intussusception and damage to adjacent organs. The cause of intestinal obstruction in the immediate postoperative period is mostly intussusception. Risk factors identified were higher local tumor stage, intravascular extension, and en bloc resection of other visceral organs.

For NWTS-2, 775 patients were included in the study group. The conclusion was that there is no indication that prolonged postoperative chemotherapy is of any value. Doxorubicin is an effective drug in Wilms’ tumor. NWTS-2 has also allowed refinements in the staging system and identified that lymph node positivity is a poor prognostic factor on survival.46

Laparoscopic Approach

For NWTS-3, 2495 patients were studied. The conclusion was that in low-stage tumors postoperative chemotherapy could be reduced further. Radiotherapy, if necessary, does not have to be high dose. Doxorubicin adds to the effect of the vincristine and actinomycin D combination. Addition of cyclophosphamide does not improve survival.47

In a more recent report,42 the primary nephrectomy was performed by a transperitoneal approach after preoperative chemotherapy. There are no randomized control studies looking at the beneficial role of this approach.

Primary Nephrectomy (NWTS) and Neoadjuvant Chemotherapy Followed by Nephrectomy (SIOP) According to the NWTS protocol, following confirmation on imaging, the nephrectomy is performed enabling the collection of tissue for histologic diagnosis, primary removal of the tumor, and exact staging. This surgery is often challenging, however, in view of the tumor size and the need to adhere to strict principles of surgery, especially regarding intraoperative tumor spilling. According to the SIOP protocol, after imaging of the tumor, a fine-needle biopsy is performed to obtain a histologic diagnosis. Under the same anesthesia, vascular access (Hickman line) is obtained for administering the chemotherapy. After 4 weeks of chemotherapy, the response is assessed by repeat ultrasound scan, and nephrectomy is performed on week 5 or 6 (SIOP-9 2001). The potential advantage is that the tumor is small, and the risk of intraoperative spillage is reduced.43 According to the UKW3 study group, this approach has also resulted in a shift toward a more advantageous stage distribution and reduction in therapy and late effects of doxorubicin and radiotherapy.44 The disadvantage is that studying tumor specimen histology after chemotherapy may not be the same as the NWTS protocol, especially nodal histology for defining postoperative chemotherapy.

Postoperative Further Treatment Depending on imaging, operative and histologic staging in NWTS, and postchemotherapy nephrectomy with intraoperative find­ings by SIOP, further treatment is decided in ­individual cases.

NWTS Protocols NWTS was established in 1969 to determine treatment protocols to improve the survival and reduce the toxicity of adjuvant treatment. Over the last 40 years, the treatment has

NWTS-3 (1979-1985)

NWTS-4 (1986-1994) In NWTS-4, 905 previously untreated children were randomly assigned for duration of treatment or for single dose versus divided dose of drug administration. The aim was to evaluate the efficacy, toxicity, and costs of the administration of different regimens for the treatment of Wilms’ tumor. The conclusion was that 6-month treatment was more effective than 15-month treatment with lower cost of treatment.48

NWTS-5 The aim of NWTS-5 is the evaluation of biologic prognostic factors on tumor specimens to predict the risk of relapse (e.g., 16q1p),20 which would allow a reduction in the amount of therapy for low-risk patients, while maximizing therapy for high-risk patients (Table 50-4).

Indications of Preoperative Chemotherapy for Wilms’ Tumor (NWTS) As discussed earlier, primary nephrectomy is performed according to the NWTS protocol, but there is a role for preoperative chemotherapy in patients with the following conditions: 1. Inoperable tumor at the primary nephrectomy because removal of surrounding organs can result in an increased risk of surgical complications49 2. Inferior vena cava thrombus, especially the suprahepatic level, reducing the need for cavotomy and cardiopulmonary bypass as per NWTS and UKW3 trial50,51 3. Bilateral tumor at the diagnosis or incidental finding, at the primary nephrectomy52

International Society of Pediatric Oncology This SIOP treatment guideline is followed in most of Europe. A good collaborative multidisciplinary team has determined the protocols over several years to improve the survival of Wilms’ tumor patients.

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Table 50-4    Postoperative Treatment Protocol (after Nephrectomy) According to National Wilms’ Tumor Study–5 Radiotherapy

Chemotherapy

Stage 1, 2 FH

None

EE-4A: pulse-intensive AMD plus VCR (18 wk)

Stage 1 anaplasia

1080 cGY*

DD-4A: pulse-intensive AMD, VCR, and DOX (24 wk)

Yes†

Regimen 1: AMD, VCR, DOX, CPM, and etoposide

Yes†

Regimen RTK: carboplatin, etoposide, and CPM

Stage 3, 4 FH Stage 2-4 focal anaplasia Stage 2-4 diffuse anaplasia Stage 1-4 CCSK Stage 1-4 RTK *Stage

4 FH—patients are given radiation based on the local tumor stage. †Radiation therapy is given to all patients with CCSK and RTK; consult protocol for specific treatment. AMD, actinomycin D; CCSK, clear cell sarcoma of the kidney; CPM, cyclophosphamide; DOX, doxorubicin; FH, favorable histology; RTK, rhabdoid tumor of the kidney; VCR, vincristine.

SIOP-1 (1971-1974) In SIOP-1, 398 patients were studied, and the conclusion was that prenephrectomy radiotherapy reduces the number of tumor ruptures and produces a more favorable stage distribution after surgery. Postoperative prolonged administration of actinomycin D does not contribute to better disease-free ­survival.53

SIOP-2 (1974-1976) In SIOP-2, 138 patients were studied to confirm the findings of SIOP-1 without randomization. The conclusion was that there was no need for a two-drug combination (vincristine and actinomycin D) to be given for more than 9 months in the postoperative period.

SIOP-5 (1977-1979) In SIOP-5, 433 patients were randomly assigned for preoperative chemotherapy with vincristine/actinomycin D and ­radiotherapy. The conclusion was that chemotherapy is comparable to radiotherapy in regard to tumor rupture or stage distribution during the nephrectomy.54

SIOP-6 (1980-1987) In SIOP-6, 1095 patients were enrolled in this study, which answered the following questions: 1. After preoperative chemotherapy and surgery, 17 weeks of postoperative chemotherapy with vincristine and actinomycin D is as effective as 38 weeks in stage 1. 2. The arm looking at the need for postoperative ­radiotherapy in stage 2 without nodal involvement was prematurely withdrawn because of relapse in cases ­without radiotherapy. 3. Stage 2 nodal involvement and stage 3 patients had overall better disease-free survival with the addition of ­doxorubicin.55

SIOP-9 (1987-1991) Of 852 patients in SIOP-9, 382 had eligible localized tumors and were randomly assigned for the duration of the preoperative chemotherapy. At the end of the study, it was shown that 4 weeks of chemotherapy is equivalent to 8 weeks in terms of

proportion of stage 1, intraoperative tumor rupture, and 2- to 5-year survival.56

SIOP 93-01 (1993-1999) In SIOP 93-01, 1104 patients were studied to determine the duration of postoperative chemotherapy in stage 1 tumors with intermediate-risk histology or anaplasia. The preliminary results showed that the reduction of postoperative ­chemotherapy from 18 weeks to 4 weeks in this group is safe.

SIOP 2001 SIOP 2001 is the current ongoing study (Tables 50-5 and 50-6). On the basis of previous SIOP studies, the aims are as follows: 1. Confirm continued use of preoperative chemotherapy for 4 weeks (vincristine and actinomycin D) in stage 1 patients; patients with metastasis at diagnosis would continue to receive chemotherapy for 6 weeks with addition of ­doxorubicin 2. Perform a multicenter prospective study to find out if doxorubicin is necessary in intermediate-risk tumors and local stage 2 and 3 3. Study specific histologic subtypes in relation to prognosis (e.g., epithelial and stromal dominant are good prognostic factors, blastemal is a poor prognostic factor), studying significance of necrosis in postchemotherapy specimens 4. Minimize acute and late toxicity of therapy without ­affecting survival in focal anaplasia and intermediate-risk tumors 5. Determine the relationship of tumor volume after ­chemotherapy and histologic subtypes 6. Establish single-dose actinomycin D as opposed to a ­fractionated schedule 7. Perform a biologic study to correlate allele loss at 16q1p with relapse-free and overall survival

Treatment of Metastatic Diseases (stage 4) According to SIOP 2001 Pulmonary Metastasis.  If there are micrometastases (<10 mm nodule) on CT scan, but not visible on chest x-ray, the clinician should evaluate after nephrectomy. If repeat CT scan does not show a nodule, the local disease should be treated. If CT scan is positive, and the lesion is resectable, surgery is performed

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for the excision of the nodule. If the lesion is not resectable, a biopsy specimen is obtained. For viable tumor, chemotherapy according to stage 4 and radiotherapy are indicated. Liver Metastasis.  Stage 4 chemotherapy and radiotherapy are indicated for liver metastasis. If the tumor is resectable, surgery is performed. Brain Metastasis.  For brain metastasis, stage 4 chemotherapy and radiotherapy to the brain are indicated. Bone Metastasis.  Stage 4 chemotherapy and radiotherapy to the lesion seen on imaging (with a margin of ≥3 cm in any direction) are indicated for bone metastasis.

Table 50-5    Revised International Society of Pediatric

Oncology Working Classification of Renal Tumors of Childhood (SIOP 2001)

For Pretreated Cases

For Primary ­Nephrectomy Cases

Low-risk tumors

Low-risk tumors

  Mesoblastic nephroma

  Mesoblastic nephroma

  Cystic partially differentiated ­nephroblastoma

  Cystic partially ­ differentiated ­nephroblastoma

  Completely necrotic ­ nephroblastoma Intermediate-risk tumors

Intermediate-risk tumors

  Nephroblastoma—epithelial type

  Nonanaplastic ­nephroblastoma and its variant

  Nephroblastoma—stromal type

  Nephroblastoma— ­focal anaplasia

  Nephroblastoma—mixed type   Nephroblastoma—regressive type   Nephroblastoma—focal ­anaplasia High-risk tumors

High-risk tumors

  Nephroblastoma—blastemal type

  Nephroblastoma— ­diffuse anaplasia

  Nephroblastoma—diffuse anaplasia

  Clear cell sarcoma of the kidney

  Clear cell sarcoma

  Rhabdoid tumor of the kidney

  Rhabdoid tumor of the kidney

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Role of Partial Nephrectomy in Unilateral Wilms’ Tumor Partial nephrectomy has been performed for localized disease, especially stage 1 tumors after chemotherapy for small lesions and histologically favorable or intermediate lesions,57 the aim being to preserve the nephrons and avoid future renal failure. The reported rate of renal failure in NWTS was 0.25%.58 The risk factor for renal insufficiency in this study was DenysDrash syndrome, which has inherent renal impairment. There are no randomized studies for partial nephrectomy, and the multicentric nature of the tumor may make this a less than ideal approach. There is probably a role for partial nephrectomy in patients who already have renal impairment; patients with solitary kidney tumors; and patients with high-risk syndromes, such as Beckwith-Wiedemann syndrome, hemihypertrophy, and aniridia, who are at increased risk for metachronous bilateral diseases.

Management of Bilateral Wilms’ Tumor Bilateral tumor constitutes about 5% of all Wilms’ tumors. The challenges associated with bilateral Wilms’ tumor include optimal control of the tumor and preserving the nephrons. NWTS and SIOP have similar modes of treatment: histologic diagnosis with open surgery (NWTS) or fine-needle biopsy (SIOP) followed by chemotherapy. The response to chemotherapy is assessed by repeat imaging (ultrasound or CT scan) in SIOP, whereas a second-look laparotomy is performed to assess the response in the NWTS protocol.59 If there is no response, the histology should be reviewed; sometimes a repeat biopsy is needed, or changing the chemotherapeutic regimen needs to be considered (Figs. 50-10 and 50-11). During the definitive surgery, the kidney with less tumor volume is operated on first, then after an interval, the other side is operated on. If the tumor volume on the contralateral side occupies the whole kidney, a complete nephrectomy with partial nephrectomy on the less affected side is performed at the same time. Surgery consists of partial nephrectomy or occasionally wedge excision or enucleation. The most important aspect of surgery is getting negative margins of the resection and vasculature control. A map of the arterial anatomy guides in the management (Fig. 50-12). The postoperative treatment depends on the individual side tumor stage and grade. Overall, these children have a good prognosis with survival of 74% with a median follow-up of 52 months.60 The renal function in the long-term is promising; renal failure was 9.1% in synchronous tumors and 18.8% in metachronous tumors.58

Table 50-6    Summary of Postoperative Treatment Strategies for Localized Tumors (SIOP 2001) Stage 1

Stage 2

Stage 3

Low risk

No further treatment

AV-2†

AV-2

Intermediate risk

AV-1*

DOX + AVD; R < DOX − AV-2‡

RT/DOX + AVD; R < RT/DOX − AV-2‡

High risk

AVD§

High-risk¶ + RT

High-risk¶ + RT

*Regimen

AV-1 consists of actinomycin and vincristine for 4 wk. †Regimen AV-2 consists of actinomycin and vincristine for 27 wk. ‡R< stage 2 and stage 3 intermediate risk is randomized to with (+) and without (−) DOX. §Regimen AVD consists of actinomycin, vincristine, and doxorubicin for 27 wk. ¶High-risk regimen consists of alternating courses with combination of two drugs, DOX + cyclophosphamide alternating with etoposide+ carboplatin for 34 wk. DOX, doxorubicin; R, randomized; RT, radiotherapy.

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Total nephrectomy Excision biopsy Partial nephrectomy Figure 50-12  Surgical options for bilateral Wilms’ tumor depending on the tumor volume. (Courtesy of Mr. P. G. Duffy.)

Figure 50-10  CT scan of bilateral Wilms’ tumor.

Figure 50-11  CT scan of the same patient with bilateral Wilms’ tumor shown in Figure 50-10 after chemotherapy. Rarely, when partial nephrectomy is impossible on either side because of the tumor volume, bilateral nephrectomy is performed. The child is placed on renal replacement therapy for a 2-year disease-free interval and then transplantation is performed; this allows a metastasis-free interval.61 Bilateral tumors detected incidentally on exploration should be managed with the above-described plan after biopsy of both sides at the exploration. Metachronous bilateral tumors refer to tumor arising in the remaining kidney after a complete remission of the unilateral tumor. The treatment protocol is biopsy, chemotherapy, and partial nephrectomy (nephron-sparing surgery).

PROGNOSIS AND SURVIVAL Staging of the disease is crucial because it determines treatment and survival. The SIOP 93-01 data show approximate 5-year event-free survival rates as follows: • Stage 1—87% • Stage 2—85% • Stage 3—74% • Stage 4—60% to 70%

The favorable-histology tumors have good survival compared with the anaplastic variety. According to NWTS-3, in patients of all stages randomized, the disease-free survival was 86% for favorable-histology tumors and 64% for anaplastic tumors. Although age is not an independent prognostic factor, it has significance in extremes of ages, such as in neonates and adults. In regard to chromosomal abnormalities, patients with tumor-specific loss of heterozygosity for chromosomes 1p and 16q have a higher relapse rate than patients without loss of heterozygosity.20 Expression of high levels of telomerase (TERT mRNA, or telomerase RNA template) is associated with a high recurrence rate.62 DNA flow cytometry, vascular endothelial growth factor, hyaluronic acid, fibroblast growth factor, and serum renin are under study to determine their exact prognostic role and the potential ability to identify recurrence early with these markers (Table 50-7). The NWTS follow-up protocol is somewhat similar to SIOP. The aim is to detect potential metastasis early and the sequelae of therapy (i.e., radiotherapy and chemotherapy) on various organs.

MANAGEMENT OF NEPHROBLASTOMATOSIS The characteristic feature of nephroblastomatosis is nonenhancement (homogeneous) with contrast CT and MRI. Wilms’ tumor is generally heterogeneous and enhances with contrast CT. The management of nephroblastomatosis is controversial. A more recent retrospective long-term study of the perilobar hyperplastic variety of Wilms’ tumor showed that children who were not treated all developed Wilms’ tumor compared with children treated with chemotherapy or surgery. The interval between diagnosis and development of tumor was 13 to 116 months (median 42 months).63 Children with multifocal nephroblastomatosis in a kidney removed for Wilms’ tumor are at an increased risk for contralateral Wilms’ tumor and need ultrasound scans every 3 months. If these contralateral tumors are increasing in size during the follow-up period, a local excision (nephron-­sparing surgery) should be contemplated. Another report ­suggested that chemotherapy or local excision (nephron-sparing surgery) for multifocal enlarging nephroblastomatosis is effective.64

SIOP 2001 Protocol for Management of Nephroblastomatosis The SIOP 2001 protocol for management of nephroblastomatosis is as follows:

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Table 50-7    International Society of Pediatric Oncology Recommended Follow-up Investigations on Treatment  

and off Treatment

On Treatment Chest x-ray

Every 3 mo for localized tumors At weeks 6 and 12 and then every 3 mo for metastatic disease

Abdominal ultrasound

At diagnosis (three-dimensional measurement) Immediately before nephrectomy (three-dimensional measurement) Every 3 mo during treatment

Full blood count

Before each chemotherapy

Serum creatinine

At diagnosis and before each chemotherapy

Liver function test

Before each chemotherapy with AMD or DOX

Blood pressure

At diagnosis and during each visit

Echocardiography

At diagnosis Before DOX At end of therapy

Renal function monitoring

GFR with 51Cr EDTA before and after every third course of carboplatin End of treatment In children with renal dysfunction

Off Treatment Chest x-ray

Every 3 mo until 3 yr after end of treatment

Abdominal ultrasound

Every 3 mo to age 7 yr if patient was <12 mo old at initial diagnosis, nephrogenic rest on ­nephrectomy specimen, initial bilateral tumors, partial nephrectomy Every 3 mo for 2 years or clinical examination in compliant patients for all other patients

Blood pressure

Annually

Growth

Monitor annually (every 6 mo through puberty) Examine for scoliosis

Echocardiography

Every 5 yr if end of treatment study was normal If abnormal, more frequently

Renal function monitoring

Every 5 yr (more frequently if renal dysfunction) Assess serum urea/electrolytes/creatinine Measure urine protein-to-creatinine ratio Measure magnesium in high-risk patients or patients treated with carboplatin

AMD, actinomycin D; DOX, doxorubicin; 51Cr EDTA; chromium 51 ethylenediaminetetraacetic acid; GFR, glomerular filtration rate.

1. After diagnosis is established, chemotherapy with vincristine and actinomycin D combination 2. First response assessment after 4 weeks of therapy by ultrasound or CT scan or both; if decrease in tumor size, chemotherapy until complete resolution of lesion 3. Surgery if progression of lesion despite chemotherapy or lesion becomes heterogeneous; partial nephrectomy or wedge excision as in cases of bilateral lesions 4. When lesion has disappeared with chemotherapy or with surgery, maintenance chemotherapy continued for 1 year

HIGH-RISK PATIENTS: RISK OF TUMOR  FORMATION AND SCREENING Screening with ultrasound every 3 months in children with high-risk syndromes is suggested until age 7 years to detect the tumors earlier.65 The risk of tumor formation in

Beckwith-Wiedemann syndrome is 4% to 7%. Beckwith­ iedemann syndrome is related to the imprinting status of W the H19 and LIT1 genes on chromosome 11p15. In a metaanalysis, it was found that loss of imprinting of H19 implies a higher tumor risk—almost 54%.66 NWTS has reported that these children are noted to have small tumors detected on regular screening. There is also a high risk of bilateral diseases in this group. The outcome is good in these patients, and there is a role for partial nephrectomy for small tumors.67 In a more recent multicenter prospective study, the incidence of tumor formation (including adrenal, liver, and visceral) in isolated hemihypertrophy was 5.9%.68 Children with Denys-Drash syndrome also have a high risk of Wilms’ tumor formation, especially bilateral. It is recommended to perform bilateral nephrectomy of native kidneys before renal transplantation for end-stage renal disease.69 The risk of Wilms’ tumor in sporadic aniridia was 6.3% in a population-based Danish study.70 The salient features of

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children with WAGR syndrome were low birth weight and short stature at time of diagnosis. The outcome does not differ compared with children with WAGR syndrome except that late mortality secondary to end-stage renal disease is more common among the survivors.71

OTHER CHILDHOOD RENAL TUMORS Congenital Mesoblastic Nephroma Congenital mesoblastic nephroma is a tumor of infancy manifesting with asymptomatic palpable abdominal mass. Occasionally, infants may present with hematuria or hypercalcemia.72 On CT scan, the tumor is cystic and often difficult to differentiate from cystic Wilms’ tumor. More recently, a vascular ring sign (anechoic ring sign around the tumor) on ultrasound has been described; this is due to the vascularity (Fig. 50-13).73 Histologically, the tumor may be classic, cellular, or mixed pattern. The tumor tends to infiltrate the surrounding tissue because of lack of a pseudocapsule. Radical nephrectomy is the treatment of choice. There is a tendency for relapse especially with the cellular type in about 10% cases. These relapses usually occur within the first year of life.25 Chemotherapy has been suggested for the cellular type and gross residual disease or incomplete resection.74

Clear Cell Sarcoma of the Kidney Clear cell sarcoma of the kidney was previously considered to be a variant of Wilms’ tumor, but it is actually a distinct variety of the primary renal tumor and accounts for 5% of the total renal tumors in childhood. There have been no associations with genetics or syndromes. The salient features are that these tumors tend to metastasize to brain and bone, and are unicentric and unilateral. Histologically, there are three patterns: classic (evenly dispersed network of fine arborizing vessels accompanied by a variable stroma), hyalinizing, and epithelioid. Immunohistochemistry shows positivity for vimentin. The primary treatment is nephrectomy followed by the adjuvant therapy as described earlier. The survival for stage 1 was 98% with an overall survival of 64% in NWTS. The prognostic factors were treatment with doxorubicin, stage, age at diagnosis, and tumor necrosis.75

Rhabdoid Tumors of the Kidney Rhabdoid tumor of the kidney is another distinctive renal neoplasm in infants, becoming uncommon after age 5 years and constituting about 2% of pediatric renal tumors. The characteristic of this tumor is presentation with hypercalcemia and synchronous or metachronous brain metastasis. Histologically, the distinctive features are large cells with large vesicular nuclei, prominent single nucleolus, and large oval intracytoplasmic hyaline inclusions. Immunohistochemistry shows positivity for vimentin. These tumors are aggressive and invasive. Renal and extrarenal rhabdoid tumors carry homozygous deletion or mutation of the hSNF/INI1 gene located at 22q11.2.76 The treatment is nephrectomy and adjuvant therapy as described earlier. The overall survival is poor because of presentation at an advanced stage. NWTS has reported about 50% survival for completely resected and node-negative patients.77

Renal Cell Carcinoma Renal cell carcinoma accounts for about 2% to 6% of childhood renal tumors. In a more recent review, the age of presentation was 7.9 years.78 Symptomatic presentation in the

Figure 50-13  Ultrasound scan of mesoblastic nephroma.

form of hematuria and abdominal mass is common. Radiologically, it may be difficult to differentiate renal cell carcinoma from Wilms’ tumor. The common histologic variety is papillary cell carcinoma.79 Treatment is radical nephrectomy, although ­partial nephrectomy has been reported.78 The overall survival is more than 80% with a mean follow-up of 4.9 years.78

PRENATAL RENAL TUMORS Congenital mesoblastic nephroma is an infantile tumor, as discussed earlier. It can be diagnosed at 22 weeks of gestation with ultrasound, three-dimensional ultrasound, or MRI scan.80 This tumor may be associated with polyhydramnios or hydrops fetalis. Occasionally, neonates may have hypertension.81 Nephrectomy is performed when the neonate is stable. There are few case reports of prenatal Wilms’ tumor, which is a diagnostic dilemma. Prenatal biopsy has been suggested for confirmation of diagnosis and deciding the course of pregnancy.82 In a complicated pregnancy, an emergency cesarean section has been suggested.83 Prenatal Wilms’ tumor needs further work and guidelines for management in view of its rarity. According to the SIOP protocol, infants younger than 6 months with renal tumor should undergo primary nephrectomy after preoperative imaging and postoperative chemotherapy for appropriate tumor stage and histology. There is an option of close follow-up without chemotherapy in selected cases.84

ADULT WILMS’ TUMOR Wilms’ tumor in adults has been reported by SIOP 93- 01 with a median age at presentation of 25.4 years. These tumors tend to manifest at a more advanced stage and with the intermediate histology variety being the most common. The diagnosis and treatment are similar to the pediatric protocol. The event-free survival was reported as 57%, with an overall survival of 83% (median observation time 4 years).85

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LATE EFFECTS OF THERAPY (CHEMOTHERAPY AND RADIOTHERAPY) The long-term survival has improved because of the advances in the treatment of Wilms’ tumor. Consequently, treatmentrelated factors have been shown to have an impact on various organs, subsequent health status, and quality of life in surviving children. Late effects of therapy were seen in more than two thirds of children treated for Wilms’ tumor who had a combination of chemotherapy and radiotherapy.86

Second Malignant Neoplasm SIOP has reported that the cumulative incidence of a second cancer observed at 15 years after Wilms’ tumor diagnosis was 0.65%. This incidence was lower compared with previous SIOP trials and probably related to longer follow-up or might reflect changes in the treatment protocols.87 NWTS has reported that the cumulative incidence of a second malignant neoplasm was 1.6% and increased steadily with duration of follow-up. The risk factor was radiotherapy and the addition of doxorubicin to the treatment regimen.88 In a more recent review, there was a 5.4% incidence of a second malignant neoplasm after radiotherapy for solid tumors, including Wilms’ tumor. The median interval was 10.1 years (median radiation dosage was 45 Gy) from the diagnosis of initial primary tumor.89 The incidence of acute myelogenous leukemia is also high according to NWTS. Of 5278 patients treated during the study period, 43 had second malignant neoplasms, and 7 of these 43 had acute myelogenous leukemia.90 The other second neoplasms were chronic myelogenous leukemia and osteosarcoma.

Cardiac Dysfunction Doxorubicin is known for its cardiotoxicity. SIOP has shown that post-treatment left ventricular fractional shortening was reduced in 2.5% of patients. Abnormal electrocardiogram findings that were not detectable before therapy were found in 5.6% of children. The median interval was 2.9 years from the median post-treatment interval.91 This was very low, presumably secondary to the short post-treatment interval. In a large single institutional study, 25% of the anthracycline-treated group showed cardiac abnormalities. All but one of these patients had increased left ventricular afterload. The median interval for follow-up was 7.1 years. There was direct correlation with the dose and intensity.92

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radiation dose–dependent and age-dependent.94 Osteopenia and imbalance of bone turnover, independent of radiotherapy, is seen in 27% of surviving children.95

Reproductive System The germ cells are more sensitive to radiation damage than Leydig cells. In a long-term follow-up, survivors have shown impaired spermatogenesis.96 Vincristine is also implicated as a risk factor for spermatogenesis. Ovarian failure after abdominal radiation was about 68%,97 and there have been one or two small or absent ovaries and a small uterus98 during the follow-up. Fertility can be preserved if the pelvis is excluded from the radiation field; NWTS has reported pregnancy in these patients.99 Women who received flank radiation therapy as girls as part of their treatment for Wilms’ tumors are at increased risk of fetal malposition and premature labor. The offspring of these women are at risk for low birth weight, premature (<36 weeks’ gestation) birth, and occurrence of congenital malformations.100

Liver Dysfunction Acute and chronic hepatitis is a sequela of radiation therapy. Concurrent administration of actinomycin D and vincristine causes severe toxicity and is dose-dependent.101

Renal Dysfunction Chemotherapy or radiation field covering the remaining kidney or hyperfiltration leads to temporary or chronic nephropathy. A single institutional study showed renal dysfunction in 32%, including 19% with a low glomerular filtration rate (<80 mL/min/1.73 m2), 11% with hypertension, and 9% with increased urinary albumin excretion, over a 13-year follow-up after treatment.102 In contrast, in another study with a median follow-up of 8.8 years, there was an encouraging report that the treatment for Wilms’ tumor rarely causes long-term renal impairment.103 This change may be due to modified new protocols of treatment over last 15 years.

Behavioral and Educational Limitations Children with Wilms’ tumor, requiring various long-term therapies and frequent hospitalizations, can be presumed to have some behavioral and educational difficulties. This has not been seen in these children, however, compared with ­children with acute lymphoblastic leukemia from a multicenter study.104

Pulmonary Dysfunction The survivors of Wilms’ tumor who have received the either whole-lung irradiation or abdominal radiation have abnormal pulmonary function in the form of reduced vital and total lung capacity.93 Chemotherapeutic agents actinomycin D and doxorubicin potentiate the pulmonary dysfunction. Interstitial pneumonitis is also reported in the long-term follow-up.

Musculoskeletal System Another consequence of radiotherapy with the addition of chemotherapy is abnormal musculoskeletal development. In a long-term review (median follow-up 15 years), the percentages of patients who developed muscular hypoplasia, limblength inequality, kyphosis, and iliac wing hypoplasia were 16.7%, 11.9%, 7.1%, and 7.1%. Scoliosis was seen in 42.9% and was directly related to the duration of follow-up and radiation dose.86 The surviving children have stature loss, which is

FUTURE CHALLENGES Work of NWTS and SIOP in relation to optimizing the management protocols for children with Wilms’ tumor and finding the biologic parameters is ongoing and is expected to add to improved survival and reduction of long-term therapy-related toxicity. Immunotherapy105 is a potential challenge for the future, with the hope that the current research will transpire into future therapy, especially the characteristic expression of WT1 gene peptides and recognition by cellular and humoral immune responses, which acts as a potential target antigen in immunotherapeutic trials.

REFERENCES For complete list of references log onto www.expertconsult.com