Nephroblastoma

Overview

Wilms tumor, also known as nephroblastoma, is the most frequent pediatric renal cancer, as well as the most common pediatric abdominal cancer and the fourth most common pediatric cancer in general. Wilms tumor is most commonly encountered in children under the age of five. Wilms' tumor care requires cautious attention to tumor staging and a coordinated effort by paediatric oncologists, specialized surgeons, radiologists, pathologists, and radiation oncologists.

Nephroblastoma definition

Wilms tumor (also known as Wilms' tumor or nephroblastoma) is a kind of pediatric cancer that begins in the kidneys. It is the most frequent kind of pediatric kidney cancer. Wilms tumors account for about 9 out of 10 kidney malignancies in children. Wilms tumor is most commonly encountered in children under the age of five. The tumor is named after Dr. Max Wilms, a German physician who originally characterized it in 1899.

Epidemiology

Wilms tumor is the most prevalent kind of juvenile abdomen cancer and usually appears between the ages of 3 and 5 years. Every year, roughly 650 new cases are reported in the United States. Wilms is somewhat more common in girls than in boys.

Wilms disease is more frequent in Africans and African Americans, whereas it is less common among East Asians. Asian patients also have fewer tumors with poor histology, have lower-stage disease, and have better survival results.

Ninety percent of Wilms tumors are discovered before the age of six, with the median age of discovery being 3.5 years.

With significant advancements in chemotherapy, the vast majority of afflicted children now survive.

The overall 5-year survival rate in the United States is 92 percent, while in poorer regions of the world with less resources, the percentage is only 78 %.

Wilms tumor is linked to a number of diseases, including WAGR syndrome. The occurrence of Wilms tumor, aniridia, genitourinary abnormalities, and mental retardation is referred to as WAGR syndrome. Wilms tumor has a 50/50 risk of forming in children with WAGR syndrome. The WT1 gene, which is important in both renal and gonadal development, has a distinct chromosomal aberration in children with this syndrome.

Denys-Drash syndrome, often known as Drash syndrome, is another condition related with Wilms. Male pseudo-hermaphroditism and gradual renal failure beginning in infancy are examples of this. In neonates and babies, the renal illness begins with simple proteinuria and develops to nephrotic syndrome and, finally, full-blown renal failure. Ninety percent of those who are afflicted will develop Wilms tumor.

Hemihypertrophy, pancreatic enlargement, hypertrophic kidneys, omphalocele, ear creases, macrosomia, and macroglossia are clinical symptoms of Beckwith-Wiedemann syndrome. Wilms disease has a 5% to 10% likelihood of developing in affected persons.

Wilms tumor in boys can cause cryptorchidism, varicocele, or hypospadias, while around 10% of afflicted girls will have congenital uterine abnormalities. Other renal congenital anomalies are not rare, such as duplication and renal ectopia.

Perilobar nephrogenic rests in children less than one year of age are related with a significantly increased chance of acquiring a contralateral Wilms tumor.

Etiology

The exact etiology of Wilms tumor is unknown, however it is thought to be caused by genetic changes that affect the normal embryological development of the genitourinary tract. Some of the genetic markers linked with Wilms tumor include WT1, CTNNB1, and WTX gene abnormalities, which have been detected in approximately one-third of all Wilms tumors. Only approximately 1% of Wilms patients have a relative with the condition who isn't a parent.

Wilms' disease is assumed to be caused by persistent metanephric tissue or nephrogenic resting. These can develop in 1% of infantile kidneys but usually resolve during childhood. These aberrant metanephric cells are seen in up to 100% of bilateral Wilms tumors but only 35% of unilateral tumors.

Although hemihypertrophy and aniridia, as well as a number of urological abnormalities like as cryptorchidism, horseshoe kidney, and hypospadias, are linked to the disease, it is unclear that they have any role in real carcinogenesis.

Bilateral disease accounts for only about 5% of all Wilms tumor patients and is more common in females.

Symptoms of Wilms tumor

The majority of children with Wilms tumor appear with an asymptomatic abdominal lump. The tumor might have been noticed by the mother while washing the child. Among the other features are:

• Abdominal pain
• Gross hematuria
• Urinary tract infections
• Varicocele
• Hypertension or hypotension 
• Fever
• Anemia

If the patient has lung metastases, dyspnea or tachypnea may occur.

The most common initial presenting symptom is abdominal pain (30% to 40%), followed by hypertension (25%), and hematuria (5%). (12 percent to 25 percent)

Around 25% of children with Wilms' tumor have associated hypertension, most likely due to elevated renin activity. The presence of a renal tumor can cause hypertension, which normally disappears following nephrectomy. A severe or protracted hypertension, on the other hand, necessitates further study and assessment of the potential of an underlying genetic condition such as Denys-Drash syndrome.

Atypical presentations occur in fewer than 10% of cases and are caused by compression of adjacent organs or vascular infiltration. Tumor extension into the renal vein or inferior vena cava, for example, occurs in less than 4% of individuals. Ascites, congestive heart failure, and hepatomegaly are common symptoms in children with vascular extension.

A kid may arrive with an acute abdomen (rapidly expanding abdominal mass, anaemia, hypertension, discomfort, and fever) owing to tumor rupture or for study of a varicocele or other genitourinary disorders on rare occasions. The synthesis of hormonal chemicals by tumors can result in paraneoplastic disorders such as hypercalcaemia, erythrocytosis, and acquired von Willebrand disease.

Diagnosis

The standard labs are not specific for Wilms tumor and must be done to rule out other disorders. Routine blood tests include the following: 

• Complete blood count to look for anemia
• Chemistry profile
• Renal function
• Urinalysis
• Coagulation studies
• Cytogenetics studies to look for 1p and 16q deletion.

Imaging studies utilized include the following:

• Renal ultrasonography 
• Chest x-ray to look for lung metastases
• Abdominal and chest CT with sedation
• Abdominal MRI is an optional study.

Imaging is especially useful in surgical planning. Larger tumor size, contralateral tumor expansion, and displacement of the major vessels are surgical risk factors that often result in longer surgery periods, more blood loss, and higher problems rates.

Because the lungs are the most prevalent location of metastases, chest imaging is advised. Both abdominal CT and MRI appear to be roughly equally effective in identifying Wilms' disease, therefore either can be utilized. Metastases to the bones are infrequent yet concerning, because they usually occur later as a relapse or recurrence.

Recently, MRI diffusion studies may have made it simpler to distinguish Wilms tumor from neuroblastoma, the other prevalent pediatric abdominal cancer.

Wilms' tumor extends intravenously in roughly 11% of children. Thrombus extension into the inferior vena cava occurs in around 4% of cases, and echocardiography should be explored in the rare incidence of intracardiac tumor infiltration. 

Management

Wilms' tumor care necessitates the collaboration of paediatric oncologists, specialized surgeons, radiologists, pathologists, and radiation oncologists. The function of surgery in Wilms' tumor therapy is crucial because a precise and well-performed procedure reduces the danger of tumor rupture and the requirement for radiation, both of which can be reduced in more skilled hands.

The standard treatment for Wilms tumor is nephrectomy followed by systemic chemotherapy, while alternative procedures start with chemotherapy and then execute the nephrectomy. If imaging is negative, the opposite kidney may be examined to check that the cancer has not spread. However, if imaging is negative, this is not essential for low-stage tumors with good histology. Lymph nodes around the aorta are taken for staging and survival.

There is no discernible difference between standard open surgery and minimally invasive procedures in terms of short-term morbidity, mortality over three years, hospital readmission rate, or surgical margin status. Open surgery, on the other hand, usually results in more lymph nodes in the operative specimen.

Biopsies are not routinely advised unless there are exceptional conditions, as they immediately raise tumor staging to Stage III. Radiation and chemotherapy are required at this stage.

Depending on the tumor's histology and the extent of spread, postoperative radiation may or may not be administered. Starting radiation therapy within 14 days following surgery tends to enhance overall survival in individuals without metastases who will be receiving radiation.

Combination chemotherapy is typically used for more aggressive cancers. Initial treatment usually consists of vincristine and dactinomycin. Also utilized include doxorubicin, cyclophosphamide, etoposide, and carboplatin.

Immediate nephrectomy is not performed in children with bilateral illness. Some doctors use high-dose chemotherapy to eliminate the tumor cells and, perhaps, save the kidney. Because bilateral nephrectomy necessitates dialysis right once, every attempts are done to save the kidneys. Repeat biopsies are necessary to establish whether or not the tumor is responding to treatment. In some circumstances, nephron sparing surgery can be undertaken.

Patients who relapse after receiving first combination treatment have a worse prognosis than freshly diagnosed Wilms patients.

Patients undergoing Wilms treatment may develop hepatic veno-occlusive disease. It is distinguished by right upper quadrant discomfort that is accompanied by jaundice, ascites, weight gain, and/or hepatomegaly. The mainstay of treatment for hepatic veno-occlusive disease is palliative care.

For suitable cases of children with synchronous disease in both kidneys, who account for approximately 5% of all Wilms' tumor patients, as well as those with syndromes that predispose to late renal failure, such as Denys-Drash syndrome, partial nephrectomy or wedge excision of the tumor is advocated.

Because of the higher risk of positive surgical margins and local tumor recurrence, these procedures should not be used as a regular strategy for unilateral Wilms' tumor. Patients with bilateral Wilms' tumor face the danger of renal failure. End-stage renal disease affects about 15% of patients 15 years after surgery, however this varies depending on hereditary etiology.

Because surgery is such an important part of Wilms' tumor treatment, getting a high cure rate while retaining acceptable long-term renal function in these individuals can be extremely difficult. The great majority of tumors at initial presentation are too big for a partial nephrectomy, making obtaining negative margins to reduce recurrence difficult. Aside from that, there are inherent dangers to surgically removing a big renal tumor in a tiny child.

The most frequent problem during surgery is hemorrhage, whereas the most common post-surgical consequence is small intestinal obstruction, which occurs in more than 5% of children. As a result, pre-treatment chemotherapy can be utilized to reduce tumor burden to a size amenable to renal-sparing surgery. 

Differential Diagnosis

Wilms tumor differential diagnosis might be difficult. While Wilms tumor is the most frequent juvenile renal tumor, clear cell renal sarcoma is the second most prevalent. Because of increased mortality and recurrence rates, the prognosis is not as excellent as Wilms. It frequently spreads to the bone. Histological appearance might be similar to Wilms, leading to a misdiagnosis.

Rhabdoid kidney tumors are very malignant and are most commonly encountered in children under the age of two, and nearly never in children above the age of five. It is frequently broadly metastatic at the time of initial presentation and has an extremely dismal prognosis, with an 80% death rate within one year of diagnosis.

Congenital mesoblastic nephroma is typically found in the first year of life, most often by ultrasound. Hypertension and elevated renin levels usually accompany it.

Renal cell carcinoma is rare in the pediatric age group. However, when present, it is often at a more advanced stage than in adults. Neuroblastoma patients who are post-radiation and post-chemotherapy are at increased risk.

Renal medullary carcinoma is a very aggressive and dangerous cancer that is found almost exclusively in individuals with sickle cell disease, usually trait. It tends to be highly locally invasive and metastasizes early.

Staging

Stage I tumors are fully contained inside the kidney, with no fractures or leakage outside the renal capsule and no vascular invasion. This stage is responsible for 40 to 45 percent of all Wilms tumors.

A tumor in stage II has expanded outside the kidney to some extent, such as into adjacent fatty tissue. Normally, surgeons would be able to totally remove the tumor, and regional lymph nodes would be negative. This stage is present in around 20% of all Wilms tumors.

Stage III Wilms tumors account for around 20% to 25% of all Wilms tumors and represent a tumor that could not be entirely eliminated surgically, such as the following:

• Cancer has spread to regional lymph nodes but not to further away nodes, such as those in the chest.
• Because the cancer had spread to neighboring important structures, it could not be totally removed surgically.
• Tumor deposits (tumor implants) are discovered in the peritoneum, or there are positive surgical margins.
• During surgery, cancer cells were inadvertently "spilled" into the abdominal cavity.
• The tumor was surgically removed in sections, such as one from the kidney and another from the adrenal gland.
• Before the tumor was surgically removed, a kidney biopsy was performed.

Stage IV cancers have progressed via the vascular system to distant organs such as the lungs, liver, brain, or bones, as well as distant lymph nodes. These account for around 10% of all Wilms tumors.

Stage V instances are those in which both kidneys are affected by tumor at the time of initial diagnosis. This stage is present in around 5% of all Wilms tumors. Individual staging of each renal unit is also required.

Prognosis

The prognosis differs depending on tumor stage and histology. Survival rates for favorable histology range from 99 percent to 86 percent, whereas survival rates for unfavorable histology range from 84 percent to 38 percent, depending on the stage.

End-stage renal failure affects roughly 1% of individuals, and is mainly caused by metachronous bilateral tumors.

A poorer prognosis is associated with the following characteristics:

• Anaplastic histology in stage II to IV tumors
• Diffuse anaplasia is worse than focal
• Loss of heterozygosity at chromosomes 1p, 1q, 11p15, and 16q or presence of TP53 
• Higher stage (most epithelial predominant tumors are stage I; most blastema predominant tumors are stage III and IV)
• Age older than two years
• Higher positive lymph node density
• Large tumor size
• Even small tumor foci can be associated with a poorer prognosis due to resistance to chemotherapy.

Complications

Radiation and chemotherapy improve survival in individuals with advanced Wilms tumor, but they may potentially raise the chance of subsequent cancers years later.

It is commonly known that radiation therapy increases the chance of developing bone, breast, colon, and thyroid cancers later in life. It also raises the risk of osteoporosis.

Chemotherapy with dactinomycin, doxorubicin, and vincristine increases the risk of subsequent cancers as well as particular toxicities such hearing loss (carboplatin), cardiac function (adriamycin), and peripheral neuropathy (vincristine)

Von Willebrand's disease affects around 5% to 10% of Wilms patients and might complicate therapy. DDAVP should be used as the first line of treatment. If the first attempt fails, cryoprecipitate (concentrated Von Willebrand Factor) might be utilized.

Postoperative and Rehabilitation Care

Follow-up visits for Wilms tumor are usually scheduled: 

• Every 3 months for 2 years after diagnosis
• Then every 6 months for another 2 years
• Then once every 2 years

Follow-up visits for Wilms tumor may include:

• Feeling the abdomen for signs of any local recurrence or a liver tumor
• Listening to the lungs for any signs of metastasis
• Feeling the thyroid for any growths 
• Breast examination in female patients who received radiation therapy to the chest
• Check for peripheral neuropathy (a complication of Vincristine therapy)
• Check for liver/veno-occlusive disease in patients with right-sided tumors who received radiation therapy

Tests are part of follow-up care. These will include:

• Abdominal ultrasound (yearly is recommended)
• CT scan
• MRI
• Chest x-ray
• Liver function testing
• Renal function blood tests
• Early screening for infertility
• Hearing tests for patients who received carboplatin
• Cardiac function tests, such as an echocardiogram or electrocardiogram at least every 3 years for patients who received doxorubicin
• Early screening for colon cancer in patients who received abdominal radiation (should start 10 years after radiotherapy treatment or by age 35, whichever is later)

After lung or chest radiation, the following is added:

• Thyroid-stimulating hormone (TSH) and free thyroxine (T4) to monitor thyroid function
• Thyroid US is recommended every 3 years to screen for thyroid nodules and masses
• Bone density testing should be started 10 years before it would normally be done due to early osteoporosis
• Early screening for breast cancer in women

Adult Wilms’ tumor

Wilms' tumor is exceedingly uncommon in adults, accounting for fewer than 1% of kidney tumors in this age range. Each year, just 70 new instances of this tumor are detected in Europe. The diagnosis is frequently unexpected and comes after a nephrectomy for suspected renal cell carcinoma, the most common adult kidney cancer. Adults have a worse outcome than children because there is sometimes a delay in starting chemotherapy while adult oncologists and pathologists do a diagnostic assessment.

As a result, in 2011, European and American pediatric oncologists presented a worldwide consensus-based standardized approach to the identification, staging, and treatment of adults with Wilms' tumor. A pathological examination by a pediatric pathologist who specializes in Wilms' tumors is advised. Severe neurotoxicity caused by Vincristine and hepatotoxicity caused by Actinomycin D, which are more common in adults than children, should also be avoided.

Although open partial nephrectomy has become the gold standard for a single small kidney tumor in adults, the worldwide consensus supports whole nephrectomy as per adult nephrectomy guidelines for any renal malignancy when Wilms' tumor has been diagnosed prior to nephrectomy.

Previously published data showed that adults had lower survival rates than children, although adults treated according to modern pediatric standards may have somewhat better results. Wherever possible, the worldwide consensus urges patients to enroll in pediatric clinical studies.

Neuroblastoma vs Nephroblastoma

Neuroblastoma is the most frequent extracranial tumor in children  and often manifests as an abdominal mass. Nephroblastoma, also known as a Wilms' tumor, is the most common kidney tumor in children and often manifests as abdominal pathology.

Conclusion 

Wilms tumors are still uncommon, although the majority of patients survive, particularly those with "favorable" histology who are detected early and undergo appropriate therapy. The vast majority of patients initially visit a pediatrician, nurse practitioner, or primary care physician. These professionals must be cautious of babies who complain of stomach pain, since Wilms tumor may be the reason.

A early referral to an oncologist is essential for increased survival. Because the diagnosis is typically distressing to the families, a mental health nurse should work with the doctor to give counseling. The pharmacist should inform the family about the chemotherapeutic drugs and their potential side effects.

New techniques are being developed for patients who do not react well to therapy at first. Bilateral Wilms tumors are especially difficult to treat and necessitate close collaboration among oncologists, pediatricians, nurse practitioners, primary care providers, radiologists, and surgeons in the timing and implementation of neoadjuvant chemotherapy with bilateral nephron-sparing surgery or nephrectomies.

The oncology nurse should educate the family about the operation, post-operative care, and follow-up, as well as support the doctor in monitoring and providing regular follow-up.