WILMS TUMOR

Gaurav NaharDNB Urology(Std)MMHRC, Madurai

INTRODUCTION

• Wilms tumor - Nephroblastoma.

• Most common primary malignant renal tumor of childhood.

• This embryonal tumor develops from remnants of immature kidney.

EPIDEMIOLOGY

• Accounts for 6% to 7% of all childhood cancers.

• Children<15 yrs: annual incidence rate 7 to 10 cases per million.

• More than 80% of cases are diagnosed before 5 years of age, with a median age of 3.5 years.

• B/L Wilms tumors present at earlier age.

• Incidence lower in East Asian populations & higher in black populations compared with North American and European whites.

• Environmental risk factors play a minor role.

ETIOLOGY

• Majority of Wilms tumors arise from somatic mutations restricted to tumor tissue.

• A much smaller percentage originate from germline mutations.

• Several genetic events result in Wilms tumor development.

• 10% tumors- have coexistent congenital anomalies and syndromes.

• 5% to 10% tumors- bilateral/multicentric.

• 1% to 2% are familial.

WT1:• 1st Wilms tumor gene to be identified.

• Gross deletions at chromosome 11p13.

• Associated syndromes:1.WAGR syndrome2.Denys-Drash syndrome3.Frasier syndrome

• WT1 gene is important for normal kidney & gonadal development.

• WT1 encodes a zinc-finger transcription factor expressed in kidney, gonads, spleen, & mesothelium

• WT1 is necessary for ureteric bud outgrowth and nephrogenesis.

• WAGR (Wilms tumor, Aniridia, Genital anomalies, mental Retardation) syndrome.

• Aniridia, found in 1.1% of Wilms tumor patients, is caused by an abnormality of the PAX6 gene located adjacent to WT1.

• Wilms tumor develops in 40% to 70% of aniridia patients with deletions of WT1.

• Denys-Drash syndrome (DDS): specific association of male pseudohermaphroditism, renal mesangial sclerosis, and nephroblastoma.

• Caused by point mutations in zinc finger DNA binding region of WT1.

• >90% of DDS patients harbor germline point mutations in only one WT1 allele.

• WAGR and DDS patients- more likely to have bilateral tumors & are diagnosed at a younger age.

• WAGR patients- increased risk of renal failure if they survive into puberty.

• Genitourinary anomalies- renal fusion anomalies, cryptorchidism, hypospadias are present in 4.5% of patients with Wilms tumor.

WT2:• 11p15 locus- LoH(Loss of Heterozygosity)

a/w Beckwith-Wiedemann Syndrome.

• Genes involved- H19 & IGF-2.

• Beckwith-Wiedemann syndrome(BWS) characterized by excess growth at cellular, organ (macroglossia, nephromegaly, hepatomegaly), or body segment (hemihypertrophy) levels.

• Adrenocortical neoplasms and hepatoblastoma also occur in BWS.

• Most cases sporadic; 15% heritable- AD.

WTX:• Tumor suppressor gene, Wilms Tumor gene

on the X chromosome, at Xq11.1,

• Inactivated in up to one third of Wilm's tumors.

• Targets single X chromosome in males & active X chromosome in females with tumors.

Familial Wilm's Tumor : (FWT1, FWT2)

• 1% to 2% of Wilms tumor patients have a family h/o Wilms tumor.

• Earlier age of onset & increased frequency of B/L disease.

• TP53 mutations- increased frequency in anaplastic histology.

• LoH at 1p and 16q are associated with an increased risk of tumor relapse and death.

SCREENING

• Ultrasound surveillance- from time of diagnosis until 5 years of age, with a frequency of every 3 to 4 months.

• BWS, Simpson-Golabi-Behmel, and familial Wilms- continue to 7 years.

• Screening recommended when WT incidence > 5%.

• Screening of contralateral kidney after nephrectomy for U/L Wilm's.

• CT or MRI if USG shows any suspicious lesion.

• 7-fold increased risk of Wilm's tumor in HK.

• an increased risk of müllerian duct anomalies in girls with Wilms tumor- Approx.10% girls will have abnormalities, such as duplication of cervix or uterus, or bicornuate uterus.

PATHOLOGY

Favorable-Histology Wilms Tumor(FH):

• Wilms tumor compresses adjacent normal renal parenchyma, forming an "intrarenal pseudocapsule."

• Tremendous histologic diversity.

• 90% of all renal tumors have favorable histology.

• “Classical” Wilms tumor is characterized by

islands of compact undifferentiated blastema,presence of variable epithelial differentiation

in the form of embryonic tubules, rosettes, and glomeruloid structures,

separated by a significant stromal component.

• Predominantly epithelial differentiation- low degree of aggressiveness, majority are stage I tumors,

• But may be more resistant to therapy, if they present as advanced-stage disease.

Survival Rates in Patients with Favorable-Histology Wilms Tumor

Anaplastic Wilms Tumor:• Anaplasia is characterized by the presence of

three abnormalities:1.nuclear enlargement to three or more times the

diameter of adjacent cells,2.hyperchromasia of enlarged nuclei, and3.abnormal mitotic figures.

• Rarely seen in children< 3 years.

• Resistant to chemotherapy.

• Poor prognosis.

• Further divided into focal & diffuse patterns.

Nephrogenis Rests:• Precursor lesions; still most don't form Wilm's

tumor.

• A rest can undergo maturation, sclerosis, involution, or complete disappearance.

• Two types based on location: Perilobar & Intralobar(PLNRs & ILNRs).

• Perilobar NRs- found only in the lobar periphery, elaborated late in embryogenesis.

• Subcortical, sharply demarcated, and contain predominantly blastema & tubules.

• Usually found in BWS, linked to 11p15 locus.

• Intralobar NRs found anywhere within the lobe, renal sinus and wall of PCS.

• Result of earlier gestational aberrations.

• ILNRs are commonly stroma rich.

• Typically seen in aniridia, WAGR, DDS or other features a/w WT1.

CLINICAL PRESENTATION• A palpable smooth abdominal mass- 90%.

Incidentally discovered.

• Abdominal pain, gross hematuria & fever- less frequent.

• Tumor rupture with hemorrhage into peritoneal cavity- mimics acute abdomen.

• Extension into renal vein & IVC- varicocoele, hepatomegaly due to hepatic vein obstruction, ascites, and congestive heart failure- <10%.

• Hypertension- common at diagnosis, d/t elevated plasma renin levels; resolves shortly after removal.

• Acquired von Willebrand disease found in 8% of newly diagnosed Wilms tumor.

IMAGING

• FOUR FIELD CHEST RADIOGRAPHY:may show lung metastasis.

RENAL ULTRASOUND:1st study to evaluate child with abd.mass.demonstrate solid nature of the lesion.Doppler USG helps to exclude intracaval

tumor extension, & its proximal extent.

Solid renal tumor: CT demonstrates that lesion is amenable to renal-sparing surgery

• CT SCAN:helps to determine origin of the tumor, lymph

node involvement, B/L kidney involvement, invasion into major vessels (IVC), and liver metastases.

CT chest to rule out lung metastasis.

CT scan of a left Wilms tumor with a small rim offunctioning renal parenchyma

• MRI ABDOMEN:Most sensitive imaging modality for caval

patency, to determine tumor extension into IVC.

low signal intensity on T1-weighted images and high signal intensity on T2-weighted images.

MRI depicting extension of Wilms tumor into theinferior vena cava.

STAGING

DIFFERENTIAL DIAGNOSIS• Mesoblastic nephroma - Most common renal tumor in the first

month of life.• Renal cell carcinoma• Clear cell sarcoma of the kidney• Rhabdoid tumor of the kidney• Nonmalignant mass• Hydronephrosis• Multicystic kidney disease• Renal cyst• Renal thrombosis• Dysplastic kidney• Renal hemorrhage

• Differential Diagnoses

• Neuroblastoma• Polycystic Kidney Disease• Rhabdomyosarcoma

PROGNOSTIC FACTORS• Most Important determinants of outcome:

histopathology & tumor stage.• Chromosomal Abnormalities: LOH for

chromosome 16q and/or 1p (20% of Wilms tumors) a/w increased risk for relapse & death.

• High telomerase activity- an unfavourable prognostic feature.

• DNA Content: Aneuploidy & DNA index . 1.5- strongly a/w anaplastic histology.

• Cytokines: VEGF angiogenic cytokine.

TREAMENT• Usual approach- nephrectomy followed by

chemotherapy, with or without postoperative radiotherapy.

• Multiple RCTs to determine therapeutic protocols by:1. National Wilm's Tumor Study Group/Children's

Oncology Group(NWTSG/COG),2. International Society of Pediatric Oncology(SIOP),

and 3. United Kingdom Children’s Cancer Study Group

(UKCCSG) .

COG AREN0321 protocol for high risk Wilms tumor

• Focal anaplastic stage I-III Wilms tumors and diffuse anaplastic stage I Wilms tumors - Nephrectomy followed by vincristine, actinomycin-D, and doxorubicin in addition to local radiotherapy

• Focal anaplastic stage IV Wilms tumors and diffuse anaplastic stage II-III tumors –Patients undergo the same treatment, with the addition of cyclophosphamide, etoposide, and carboplatin

• Stage IV diffuse anaplastic Wilms tumors - More aggressive treatment is delivered; nephrectomy is followed by initial irinotecan and vincristine administration, which in turn is followed by actinomycin-D, doxorubicin, cyclophosphamide, carboplatin, etoposide, and radiotherapy.

SURGICAL CONSIDERATIONS:• Radical nephrectomy by transperitoneal approach.• Thorough exploration of the abdominal cavity to

exclude local tumor extension, liver and nodal metastases, or peritoneal seeding.

• Accurate staging to determine appropriate chemotherapy & need for radiation therapy.

• Selective sampling of suspicious nodes is essential.• Formal RPLND is not recommended.

• Risk factors for local tumor recurrence (Shamberger):

1. tumor spillage,2.unfavorable histology,3. incomplete tumor removal, and4.absence of any lymph node sampling.

PREOPERATIVE CHEMOTHERAPY:

• Situations where preoperative chemotherapy is recommended:-

1. Children for whom renal-sparing surgery is planned,2. Tumors are inoperable at surgical exploration, and3. There is tumor extension into IVC above hepatic

veins.

• An inoperable tumor should be considered stage III and treated accordingly.

• Inoperability should not be based on preoperative imaging studies, which can overestimate local tumor extension.

• Pretreatment with chemotherapy almost always reduces the bulk of tumor and renders it resectable.

• Majority of reduction in tumor volume occurs in first 4 weeks of chemotherapy.

A, MRI of a Wilms tumor that was pretreated with chemotherapy.B, After 6 weeks of chemotherapy, the tumor is much smaller in size

MANAGEMENT OF LUNG METASTASIS:

• CXR negative but CT positive: tissue diagnosis of lung nodules because several conditions (eg, histoplasmosis, atelectasis, pseudotumor, intrapulmonary lymph node, pneumonia) can mimic pulmonary metastases.

• WT FH with lung mets, no other mets/1p or 16q deletion: 6 weeks of actinomycin-D, doxorubicin, and vincristine.

Complete resolution- No radiation required.No resolution- cyclophosphamide and

etoposide in addition + radiation therapy.

MANAGEMENT OF B/L WILMS TUMORS:• No initial radical nephrectomy.• Preoperative chemotherapy for 6 weeks.• tumors amenable to renal-sparing procedures

can proceed with surgery.• Tumors not responding- B/L open biopsy &

additional chemo based on biopsy findings.

• Proceed to Sx at 12 weeks of therapy (no benefit beyond 12 weeks).

• Partial nephrectomy, tumor enucleation or wedge excision of tumor.

• In FH tumors, even with positive margins or large B/L residual masses, adjuvant therapy provides a good outcome.

LATE EFFECTS OF Rx

RADIATION:• Musculoskeletal problems like scoliosis.• Reduction in stature.• Hypogonadism & temporary azoospermia.• Delayed sexual maturation.• Ovarian failure.• Adverse pregnancy outcomes with increased

risk for miscarriage, LBW, prematurity & congenital malformations.

• Increased risk of 2nd malignant neoplasms.

CHEMO:• Congestive heart failure caused by

anthracyclines(DOX)

FOLLOW-UP

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