Natural history

• Loss of function of tumor suppressor genes (WT1, etc.)
• Most common renal malignancy in children (6-7% of all childhood cancers)
• Arise from embryonal nephrogenic rests - abnormally retained embryonic renal precursor cells
• Perilobar (PLNR) - in periphery of kidney; a/w Beckwidth-Wiedeman syndrome, later development of tumor (median age 36mo)
• Intralobar (ILNR) - a/w WAGR, Denys-Drash, earlier development of tumor (median age 24mo)
• Diffuse hyperplastic perilobar (DPLNR) - majority of kidney surface replaced with rests; considered pre-neoplastic condition
• AKA nephroblastoma
• Typically "triphasic" with 3 cell types - blastemal, stromal, epithelial
• Metastasis: lungs most common

Associated genetic syndromes (90% sporadic, 10% congenital):

• High-risk for Wilms (>5%): abdominal US q3mo until 8 years old
• WAGR, Denys-Drash, Frasier, Beckwith-Wiedemann
• Hemihypertrophy, aniridia
• WAGR (11p13, WT1) - Wilms, aniridia, GU abnormality (cryptorchidism, ambiguous genitalia), renal impairment, intellectual disability 
• Denys-Drash (11p13, WT1) - Wilms, male pseudohermaphroditism, progressive renal disease (diffuse mesangial sclerosis)
• Beckwith-Wiedemann syndromes (11p15) - macrosomia, hemihypertrophy
• Frasier (11p13) - ambiguous genitalia, streak gonads
• Simpson-Golabi-Behmel (Xq26) - overgrowth, coarse facial features, mental retardation
• Perlman (2q37.1) - fetal gigantism, organomegaly, cryptorchidism, renal hamartoma

Physical exam

• 66% diagnosed < 5 yo (mean age of presentation ~4 yo)
• Most commonly incidentally detected
• Abdominal swelling/mass, abdominal pain, hematuria, fever, hypertension (renin secretion; use ACEi to treat)
• Caution not to rupture capsule on abdominal exam - tumor spillage increases tumor stage/therapy requirements
• 2% with ureteral involvement - recommend cystoscopy if + gross hematuria
• Other congenital anomalies from genetic syndromes (above): hemihypertrophy (BWS), aniridia (WAGR), etc 

• CBC, CMP, UA
• Coags (2% of Wilms have acquired von Willebrand deficiency)
• Abdominal ultrasound
• Evaluate contralateral kidney
• If below findings present, would get prenephrectomy chemo
• Tumor thrombus above level of hepatic veins
• Pulmonary compromise from massive tumor or extensive pulmonary metastases
• Resection requiring removal of contiguous structures (other than adrenal gland)
• Surgeon judges that attempting nephrectomy would result in significant morbidity, tumor spill, or residual tumor
• CT/MRI showing normal contralateral kidney = no longer need surgical exploration of that kidney
• CXR or CT chest to rule out lung metastases
• Biopsy automatically upstages to local stage III; reserve for unusual presentation only
• Stage III = adjuvant chemo/rads (doxorubicin = cardiotoxicity)

Pre-chemo COG staging

Prognosis

• 90% overall survival for favorable histology (eg not anaplastic)
• Worse prognosis
• Anaplastic histology (diffuse worse than focal) (70-80% overall survival stage I-III)
• Higher stage (30% overal survival stage IV anaplastic)
• Loss of heterozygosity (LOH) at 1p and 16q with FH, or gain of 1q with FH

Treatment

• COG - Children's Oncology Group can help walk through treatment if little institutional experience
• Focus on minimizing morbidity - varies by region
• North America upfront surgery vs Europe upfront chemotherapy
• Pre-operative chemo if: bilateral, solitary kidney, or syndromic patient
• Surgery = open radical nephrectomy
• Nephron sparing - only if bilateral, or unilateral with + predisposition syndrome (otherwise greater risk of tumor spillage, microscopic residual disease)
• Minimally invasive - some reports of peritoneal mets after
• Lymph nodes must be sampled to accurately stage
• Formal lymphadenectomy not required
• Do frozen on excised specimen, wait on pathology - in meantime perform LND, close.
• If needs chemo, place a port at time of surgery
• Chemo
• 2 drug chemo = EE4a = VA (Vincristine, Actinomycin-D=dactomycin)
• 3 drug chemo = DD4a = VAD (Vincristine, Actinomycin-D, Doxorubicin)
• 5 drug chemo = M or UH = VAC (Vincristine, Actinomycin-D, Doxorubicin, cyclophosphamide, etoposide)
• FH, Stage I, tumor < 550g, age < 2y - observation vs EE4a
• FH Stage I or II, any size - EE4a
• FH Stage III - DD4a + XRT
• FH Stage IV - what is the local stage? May require additional/more intense therapy based on extent of mets
• Radiation - post-surgical
• Effects of treatment
• Radiation - MSK effects
• Cyclophosphomide - hemorrhagic cystitis
• Doxorubicin - cardiotoxicity
• Vincristine - neuropathy