Nephroblastoma (Wilms Tumor)
Paul Imbach
Definition – 130 Incidence – 130
Chromosomal Association – 130 Pathology – 131
Clinical Manifestations – 131 Laboratory Diagnosis – 132 Radiological Diagnosis – 132 Differential Diagnosis – 132 Staging – 133
Therapy – 133
Therapy in Relapse – 134 Prognosis – 134
Subtypes – 135
Bilateral Wilms Tumor – 135
Congenital Mesoblastic Nephroblastoma (Fetal Renal Hamartoma) – 135
Renal Cell Carcinoma – 136
Definition
Malignant embryonal tumor of renal tissue
First described in 1899 by Max Wilms as “Mischgeschwülste der Niere” (mixed tu- mors of the kidney)
Incidence
Six percent of all neoplasias in children
Annually new diagnosis in 8 in 1 million children less than 16 years old
Seventy-eight percent of children with nephroblastoma are less than 5 years old
Peak incidence between 2nd and 3rd year of age
Congenital form at delivery or during neonatal period
Rarely in adolescents and adults
Different frequency between the different ethnic groups of origin
Incidence in boys slightly higher than in girls
Chromosomal Association
Association with chromosomal parts responsible for growth functions and devel- opment of nephroblastoma or other anomalies of the germ cell line
Chromosomal association:
– Chromosome 11p13 with Wilms tumor suppressor gene WT1 in 10–30% of nephroblastomas
– Chromosome 11p15 with Wilms tumor suppressor gene WT2
– Chromosome 17q with familial FWT-1 (chromosomal association in familial Wilms tumor)
– Chromosome 19q with familial FWT-2
– Chromosomes 16q, 1p, 7p und 17q with TP53 mutations
Association with congenital anomalies
WAGR syndrome (Wilms tumor, aniridia, genital malformations, mental retarda- tion):
– Genital malformations: cryptorchidism, hypospadias, pseudohermaphroditism, gonadal dysgenesis
– Deletion of chromosome 11p13
Denys-Drash syndrome:
– Pseudohermaphroditism – Glomerulopathy
– Mutation of chromosome 11p (only one allele of WT1 with mutation; see below)
Beckwith-Wiedemann syndrome (BWS) – Hemihypertrophy
– Macroglossia – Omphalocele – Visceromegaly
– Associated with WT2 (see below) on chromosome 11p15 at a rate of 15%
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Isolated hemihypertrophy
In neurofibromatosis, Perlman syndrome, Simpson-Golabi-Behmel syndrome
Familial occurrence:
– 1–2 % of nephroblastomas with chromosomal anomalies and familial gene loci (familial WT-1, familial WT-2; see below)
– Sometimes bilateral nephroblastoma – Increased risk in homozygous twins
Pathology
Macroscopic features
High variation in tumor size and tissue morphology
Tumor often with lobular structure of gray to pink color and with a capsule
Occasionally with cysts and hemorrhages
Tumor growth in the renal vein
Bilateral 5–7.5%, multifocal 12% spread in one kidney Microscopic features
Mostly mixed form of epithelial blastemic and stromal cellular components as well as with various degrees of cell differentiation
In well-differentiated forms glandular acini or glomerular structures separated by stroma elements which arrange cells in cords or nests
Stroma with fibroblastic or myxomatous components containing smooth muscle, skeletal muscle, cartilage and fatty tissue
Nephrogenic residual tissue:
– In 1% of all autopsies of small children: in 35% of children with unilateral nephroblastoma and in the majority of children with bilateral nephroblastoma – Hyperplastic nephrogenic tissue with differentiation and disappearance under
chemotherapy
Minority with undifferentiated histology:
– Anaplastic nephroblastoma at a rate of 5%: focal or diffuse anaplasia with large and atypical nuclei, hyperchromatism and abnormal mitosis
– Clear-cell sarcoma (3%): polygonal cells with crystal-clear cytoplasm separated into nests by thin spindle-cell septa containing blood vessels; high incidence of bone or lung metastases; high rate of relapse; age less than 2 years in 85% of children; occasionally deletion 22q11–12
– Rhabdoid nephroblastoma (2%): acidophilic cytoplasm, metastatic spread also in fossa posterior of the neurocranium
– Mesoblastic nephroma: congenital form, mean age at diagnosis 2 months; occa- sionally translocation t(12;15) (p13;q25); similar to infantile fibrosarcoma
Clinical Manifestations
Visible and palpable abdominal mass
Palpation must be done with care – risk of tumor rupture or dissemination
Unclear febrile episodes, anorexia, vomiting
Micro- or macrohematuria in 20–25% of patients
Hypertension in children with renin-producing tumor cells
Rarely association with secondary polycythemia due to high production of eryth- ropoietin by tumor cells
Occasionally varicocele, inguinal hernia, acute renal failure, coughing, pleural pain, and/or pleural effusion in children with pulmonary metastases
Special symptoms in association with congenital anomalies (see above)
Laboratory Diagnosis
Chemistry: exclusion of renal failure, high level of serum calcium in children with rhabdoid nephroblastoma
Urine: microhematuria; after concentrating urine malignant cells may be detected
Acquired von Willebrand coagulopathy in about 8% of patients
Differential diagnosis of neuroblastoma: 24-h urine catecholamine analysis
Radiological Diagnosis
Conventional abdominal radiography: intestinal displacement by tumor mass with punctuated calcifications (in 2–3%)
Ultrasound, computed tomography (CT) and/or magnetic resonance imaging (MRI;
with contrast urography) of the abdomen including the hepatic area (metastases) and chest CT
Angiography may be indicated in bilateral nephroblastoma
Radioisotope scans and/or skeletal survey in patients with suspected skeletal me- tastases
Central nervous system (CNS) MRI in patients with clear-cell sarcoma or rhabdoid kidney sarcoma and in patients with possible brain metastases
Differential Diagnosis
Multicystic kidney, hydronephrosis, cystic nephroma
Renal abscess
Cyst of ductus choledochus or mesenteric cyst
Neuroblastoma, rhabdomyosarcoma, hepatoblastoma
Other solid tumors in retroperitoneal area
In neonates: congenital mesoblastic nephroma (fetal hamartoma)
Lymphoma of the kidney (rare)
Renal cell carcinoma
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Staging
National Wilms Tumor Study Group staging system Stage Description
I Tumor confined to the kidney and completely resected. No penetration of the renal capsule or involvement of renal sinus vessels
II Tumor extends beyond the kidney but is completely resected (none at margins; no lymph nodes). At least one of the following has occurred: (a) penetration of the renal capsule, (b) invasion of the renal sinus vessels, (c) biopsy of tumor before removal, (d) spillage of tumor locally during removal
III Gross or microscopic residual tumor remains postoperatively including inoperable tumor, tumor at surgical margins, tumor spillage involving peritoneal surfaces, regional lymph node metastases, or transected tu- mor thrombus
IV Hematogenous metastases or lymph node metastases outside the ab- domen (e.g., lung, liver, bone, brain)
V Bilateral renal Wilms tumors at onset
Therapy
Due to Wilms tumor study groups the prognosis has changed from a 90% lethality rate to a 90% cure rate
Treatment according to staging (see above) aims to eliminate the nephroblastoma while avoiding short-term or long-term side effects/complications
Primary surgical resection or preoperative chemotherapy (mostly with marked tu- mor regression and reduction of intraoperative tumor rupture) has to be consid- ered according to staging
Biopsy: only in children with unclear presentation or diagnosis
After biopsy stage I is excluded
Primary surgery in infants less than 6 months old and in adolescents more than 16 years of age
Surgical procedures
Transabdominal tumor resection with abdominal exploration including liver and contralateral kidney
Biopsy of suspected tissue especially lymph nodes
Where there is large tumor mass: preoperative chemotherapy, probably radiotherapy (see below)
Chemotherapy
Preoperative chemotherapy: vincristine and actinomycin D; in children with pri- mary metastases addition of anthracycline
Postoperative chemotherapy: duration and drug combination according to stage and histology
Toxicity: veno-occlusive disease (VOD) of the liver especially in infants and small children
Radiotherapy
Nephroblastoma is radiosensitive
Due to combined chemotherapy irradiation is indicated only in high-risk patients:
i.e. Stage II with lymph node involvement, high malignancy and metastatic spread
Start of radiotherapy within the first 10 postoperative days
Dose: 15–30 Gy with higher doses to the tumor bed and remaining tumors
Therapy in Relapse
Favorable prognosis in children with relapse 6 months after tumor resection, in nonirradiated areas with one organ system involvement only, without lymph node metastases excluding highly malignant variants; chemotherapy with combination of vincristine, actinomycin D, doxorubicin, ifosfamide, carboplatin, and etoposide
Relapse with poor prognosis: high-dose chemotherapy with autologous stem cell transplantation
Prognosis
Before era of radiotherapy and chemotherapy, surgery only: survival rate 20–40%
After multidisciplinary approaches according to tumor stage and standard therapy 85–90% cure rate
Prognosis depends on stage and histology
Prognosis according to stage
Favorable histology Survival 94–100%
Standard histology Survival 90%
Unfavorable histology Survival 70%
Unfavorable factors:
– Diffuse anaplasia
– Viable malignant cells after preoperative chemotherapy – Infiltration of tumor capsule
– Invasion of tumor cells into vessels – Nonradical surgical resection of tumor
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– Lymph node involvement
– Tumor rupture (also after biopsy) – Metastatic spread
– Large tumor volume – Histology: rhabdoid tumor
– Molecular genetics: alteration of loss of heterozygosity on 1p, 11q, 16q, and 22q;
p53 mutations Subtypes
Bilateral Wilms Tumor
Often initially bilateral tumor characterized by:
– Mean age: 15 months (unilateral Wilms tumor: 42 months) – Age of mother: mean age 34 years (unilateral: 28 years of age) – Association with other malformations: 45% (unilateral: 4%) Therapy
Individual procedure
Unilateral nephrectomy, partial resection of the contralateral kidney or bilateral partial resection
Preoperative chemotherapy, possibly in combination with radiotherapy
Bilateral resection of both kidneys followed by renal transplantation after chemo- therapy
Radiotherapy with low-dose irradiation: 10–20 Gy Prognosis
Usually favorable
Congenital Mesoblastic Nephroblastoma (Fetal Renal Hamartoma)
Frequency: more than 80% of neonatal nephroblastomas and 50% of nephroblastoma in infancy (fibromatous variant)
Potential malignant cellular variants in infants and small children Pathology
Mostly marked kidney enlargement, with bundles of spindle cells and frequent mi- toses
Clinical manifestations
Mostly large abdominal tumor masses in children after birth until 1 year of age
Staging according to Wilms tumor (see above)
Rarely hyperreninemia with hypertension, secondary aldosteronism and high se- rum level of renin
Therapy
Nephrectomy
After incomplete resection occasionally tumor relapses
Where there is suspicion of malignant histology or after subtotal resection therapy as in nephroblastoma
Renal Cell Carcinoma
Frequent renal tumor in adulthood
1–2% in patients over the age of 21 years, mostly in children over the age of 5 years
Possible abnormality of chromosome 3 Pathology
Tumor origin of epithelial tissue of the proximal tubule Clinical manifestations
Pain, intra-abdominal tumor, hematuria
Diagnostic procedure as in nephroblastoma (see above); often tumor calcifications
Metastatic spread often in lung, liver, regional lymph nodes and bone Therapy
Complete resection
In high-risk patients after surgery combination treatment with interferon-a, interleukin-2 or high-dose radio- and chemotherapy since renal cell carcinoma is only moderately sensitive to radio- and chemotherapy
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