INDIVIDUALS AT HIGH RISK FOR WILMS TUMOR
Although Wilms tumor occurs sporadically in children, 8% of Wilms tumors will develop in individuals who have a recognizable pattern of malformation. High-risk Wilms tumor phenotypes can generally be grouped as “overgrowth” syndromes or “non-overgrowth” syndromes.
1. Overgrowth Syndrome
The most common disorders in the overgrowth category are Beckwith-Wiedemann syndrome and isolated hemihypertrophy.
A. Beckwith-Wiedemann Syndrome
Beckwith-Wiedemann Syndrome (BWS) is characterized by pre and postnatal overgrowth, omphalocele, macro-glossia, nephromegaly and ear lobe creases. Somatic hemihypertrophy may or may not be present. While 80% of BWS cases are sporadic, 20% show a complex familial inheritance pattern explained by alteration of genes at 11P15. For BWS in general, over-expression of the insulin-like growth factor II gene located at 11P15 is believed to cause the characteristic overgrowth and perhaps confer increased risk of Wilms tumor. The overall risk of neoplasia with BWS may approach about 8%, and specifically the Wilms tumor risk appears to be in the range of 3-5%.
B. Isolated Hemihypertrophy
Unlike BWS, isolated hemihypertrophy is usually not hereditary, but this condition still confers an increased risk for the development of Wilms tumor.
2. Non-Overgrowth Syndromes
This group is important because of the high incidence of genital anomalies requiring surgical correction in this group. The WAGR syndrome is a rare disorder characterized by a 30% risk for Wilms tumor, aniridia, genital anomalies (such as undescended testicles and hypospadias) and mental retardation. The Denys-Drash syndrome (DDS) is a related disorder with more severe genital phenotype such as streak gonads, penoscrotal hypospadias, “sex reversal” in XY individuals or normal genitalia in XX individuals, renal failure due to glomerular sclerosis, and an 80% of chance of Wilms tumor risk, often bilateral.
FOLLOW UP
Once identified, the child at high risk for Wilms tumor should be periodically screened with abdominal ultrasound.
Surveillance of children at increased risk for Wilms tumor is pursued aggressively through 3-monthly abdominal ultrasounds for the first 8 years or so of their lives, as this is the usual period at which the tumor appears. Three-monthly ultrasounds are necessary because Wilms tumor can grow very rapidly and achieve enormous size within 6 months.
MARKERS IN SCREENING FOR WILMS TUMOR
1. Hypertension (Renin and Prorenin)
While the incidence of hypertension in Wilms tumor is generally estimated to be about 25%, its use as a specific marker for Wilms tumor is limited by the fact that many childhood disorders can result in hypertension. Surprisingly, the etiology of hypertension in Wilms tumor still needs to be determined.
It is also clear that other childhood malignancies may present with elevated levels of renin, prorenin or both.
2. Erythrocytosis (Erythropoietin)
This hormone is synthesized primarily in the kidney by cells in and/or around the proximal tubules and acts on late progenitor cells in the bone marrow as a feedback signal to maintain the normal red blood cell mass optimal for oxygen transport in response to tissue hypoxia.
However, erythrocytosis is not present in the majority of patients with Wilms tumor even though the incidence of erythropoietin activity is greater; and the reason for this is not known.
3. Acquired Von Willebrand’s Disease
About 5-10% of Wilms tumors will be affected by this problem.
4. Insulin Growth Factor
Insulin growth factors I and II are growth-promoting polypeptides associated with specific binding proteins which may modulate their action.
A number of patients with Wilms tumor have elevated insulin growth factor binding protein-2 compared with normal controls.
5. Hyaluronic Acid Products
This molecule is present in many embryonic tissues and is prominent whenever rapid tissue turnover occurs. Urinary levels of hyaluronic acid, hyaluronic acid stimulating activity (a glycoprotein) and hyaluronidase have been found in children with Wilms tumor.
MULTICYSTIC DYSPLASTIC KIDNEYS
Wilms tumor usually arises from abnormal remnants of developmentally immature nephrogenic cells in the postnatal kidney which are termed “nephrogenic rests” or “nodular renal blastema.”
Because these abnormal cell remnants are present in 20-40% of kidneys resected for Wilms tumor and because these same remnants have been found in kidneys with multicystic dysplasia (MCD) and in the kidneys of infants and children with congenital obstructive uropathy, it was suggested that multicystic dysplastic kidneys should be resected to prevent the possibility of Wilms tumor formation.
However, 0.01% of live-born infants are destined to develop a Wilms tumor. On the other hand, these primitive nephrogenic rests that may predispose to tumor formation are much more numerous in younger infants than in older ones, suggesting that many of these rests disappear spontaneously. Therefore, the majority of these primitive nephrogenic rests do not give rise to Wilms tumor, and most of them involute spontaneously without forming tumors. In part, this may be because nephrogenic rests appear to be of two types: (a) perilobar, commonly found in routine autopsies with little likelihood of giving rise to Wilms tumor, or (b) intralobar, which carry a high risk.
Studies reviewing the incidence of Wilms tumor in severely dysplastic and congenitally obstructed kidneys show that the risk for developing Wilms tumors is close to that of the general population, and therefore the risk seems too low to justify routine nephrectomy in children with multicystic dysplasia or congenitally obstructed kidneys unless other urological/ medical conditions apply.
SCREENING CRYPTORCHID BOYS AND INFERTILE MALES FOR TESTIS TUMORS
Boys with undescended testes have about a 4-fold increased risk of subsequently developing testicular cancer. However, this pertains more to those with intra-abdominal undescended testicles. Intratubular germ neoplasia has been found in about 23% of undescended testes. Testicular intratubular neoplasia (TIN) has been recognized as a precursor to testicular germ cell tumors. Seminoma is the usual type of tumor that develops in cryptorchidism and infertile males, and its incidence is significantly higher when compared with the normal population.
SCREENING FOR NEUROBLASTOMA IN INFANTS
Neuroblastoma is the most frequent and least curable cancer in infants. Only about 20% of children are cured. VMA (vanillylmandalic acid) and HVA (homovanillic acid) can be found in the urine of 85% of affected patients. A study using these urinary markers to screen for neuroblastoma has demonstrated that a screening at 3 weeks and 6 months of age does not make a difference in the incidence of advanced stage disease in children over one year of age. Neuroblastoma is a unique disease that may undergo spontaneous maturation, particularly in younger infants. That screening for neuroblastoma does not appear beneficial suggests that some of these tumors are either undetectable by the screening, arise after the age of screening, or exhibit rapid growth and spread.
SCREENING OTHER ANOMALIES WITH POSSIBLE RISK FOR MALIGNANCY
1. Horseshoe Kidneys
The claim for increased risk of adenocarcinoma or transitional cell carcinoma of the kidney has not been substantiated for this developmental anomaly.
2. Megaureter
In this anomaly, there may be an increased risk for transitional cell carcinoma developing (usually in the mid third ureter).
3. Ureteral stumps
There may be some malignant potential for transitional cell carcinoma development in ureteral stumps after nephrectomy and partial ureterectomy.
4. Vesicoureteral reflux
Patients with bladder carcinoma and vesicoureteral reflux have a 15-fold greater incidence of ureteral or renal carcinoma than non-refluxers.
5. Urinary diversion
A. The mixture of urinary and fecal stream, as in ureterosigmoid urinary diversion, carries at least a 100-fold increased risk for development of bowel cancer, usually at the anastomotic site of the ureters with the sigmoid.
B. Chronic mixed bacterial infections resulting in high levels of nitrosamines may predispose the mucosa of bowel segments used for urinary diversion to undergo malignant change.
6. Exstrophy
The untreated exstrophy bladder has about a 4% chance of developing a carcinoma, usually adenocarcinoma, probably resulting from chronic urinary infections.
7. Intersex
A. Gonadal dysgenesis or Turners syndrome is usually XO, but XY mosaicism has a much greater risk of gonadal malignancy.
B. Mixed gonadal dysgenesis is characterized by a unilateral testis with streak gonad and mullerian structures on the contralateral side and/or a uterus.
C. Pure gonadal dysgenesis patients have bilateral streak gonads and usually present as females with sexual immaturity. Both the testicular tissue and the streak gonad are at risk for tumor formation. The testis has about a 30% incidence of gonadoblastoma (a non-seminomatous tumor) which may become invasive. The highest risk is in those with pure gonadal dysgenesis with 46 XY chromosomes.
Most of these gonadoblastomas occur in the second and third decade of life and may undergo spontaneous regression; but when they metastasize, they usually do so from the germ cell element. The streak gonad may give rise to malignant neoplasms such as dysgerminoma (seminoma arising in ovary). Streak gonads rarely produce non-seminomatous tumors.
D. True hermaphrodites. These patients have both ovarian and testicular tissue and the chromosome pattern is variable. Almost half the cases are described as unilateral, in which an ovotestis is found on one side and an ovary or testis on the other. Next most common is the lateral form, where there is a testis on one side and an ovary on the other. The ovary is usually on the left side. In the bilateral form (20% of cases) there is an ovotestis on each side. Those with a Y chromosome, and especially those with a testis rather than an ovotestis, are at risk for either a gonadoblastoma (non-seminomatous) or a dysgerminoma/seminoma (seminomatous) tumor.
E. Male pseudohermaphrodites. The only group in this category at risk are those with androgen insensitivity bringing about testicular feminization. These patients have a normal female phenotype but XY karyotype and present with primary amenorrhea, as they have no female internal genitalia, or they present with hernias containing testes. Retained intra-abdominal testes may give rise to seminoma.
8. Bilharzia
In the Middle East, the rate of schistosoma infection in boys in endemic areas is high and may lead to carcinoma of the bladder, usually squamous, in young adults.
9. Radiation
Abdominal or retroperitoneal external beam radiation may increase the chance for developing carcinoma of the kidney.