Editing Pediatrics: Renal and Adrenal Oncology (section)

== Wilms Tumour (Nephroblastoma) ==

* '''An embryonal tumor that develops from remnants of immature kidney'''

=== Epidemiology ===
* '''<span style="color:#ff0000">Most common primary malignant renal tumor of childhood'''
** Accounts for 95% of all kidney cancers in children age < 15 in the United States
* Incidence: 500/year in US
* Slightly more common in females than in males
* '''<span style="color:#ff0000">Median age at diagnosis: 3.5 years'''
** 95% diagnosed before age 10
** Presents at an earlier age among males
* African-Americans are at higher risk for WT

=== Genetics ===
* '''<span style="color:#ff0000">Majority arise from somatic mutations</span>''' restricted to tumor tissue; '''much smaller percentage originate from germline mutations'''
*'''Genes associated with Wilms tumor (4): WT1''', 11p15, WTX, CTNNB1, TP53
** '''WT1'''
***'''Tumor suppressor gene''' 
***'''Located on chromosome 11'''
***'''Mutations''' 
****'''Found in Denys Drash, Frasier, and WAGR syndromes'''
****'''Predispose patients to renal insufficiency'''
* '''<span style="color:#ff0000">Syndromes associated with Wilms tumours (4):</span><span style="color:#0000ff"> Bruce Willis' Dish Feels Warm'''
*#'''<span style="color:#0000ff">B</span><span style="color:#ff0000">eckwith-</span><span style="color:#0000ff">W</span><span style="color:#ff0000">eideman'''
*#'''<span style="color:#0000ff">D</span><span style="color:#ff0000">enys Drash'''
*#'''<span style="color:#0000ff">F</span><span style="color:#ff0000">rasier'''
*#'''<span style="color:#0000ff">W</span><span style="color:#ff0000">AGR'''

{| class="wikitable"
|'''Syndrome'''
|'''Genetics'''
|'''Associated Features'''
|'''Risk of WT (%)'''
|-
|'''<span style="color:#ff0000">Beckwith-Weideman'''
|11p15.5

WT2
|'''Wilm's Tumour'''

'''<span style="color:#ff0000">Hemihypertrophy (growth asymmetry)'''

'''Macroglossia'''

'''Nephromegaly'''

'''Hepatomegaly'''

Pre- and post-natal overgrowth

Anterior abdominal wall defects

Ear creases/pits
|7
|-
|'''<span style="color:#ff0000">Denys Drash'''
|'''WT1'''
|'''Wilm's Tumour'''

'''Genital abnormalities''' (under-masculinized male manifested by cryptorchidism and proximal hypospadias)

'''Nephropathy''' (mesangial sclerosis, membranoproliferative glomerulonephritis) with early onset proteinuria (common denominator of syndrome)
|74
|-
|'''<span style="color:#ff0000">Frasier'''
|'''WT1'''
|'''Wilm's Tumour'''

'''Genital abnormalities'''

'''Nephropathy (focal segmental glomerulonephritis)'''

'''Gonadoblastoma'''
|6
|-
|'''<span style="color:#ff0000">WAGR'''
|11p13

'''WT1,''' PAX6
|'''Wilm's Tumour'''

'''<span style="color:#ff0000">Aniridia (absence of the iris)'''

'''G'''enital abnormalities

Mental '''R'''etardation
|98
|}

* '''Beckwith-Wiedemann syndrome (BWS)'''
** '''Results in excess growth at the cellular,''' '''organ (macroglossia, nephromegaly, hepatomegaly),''' '''or body segment (hemihypertrophy) levels'''
** '''Children with nephromegaly are at the greatest risk for the development of Wilms tumor.'''
* '''Denys-Drash syndrome'''
** Majority progress to end-stage renal disease.
** Although XY individuals have been reported most often, the syndrome has been reported in genotypic/phenotypic females.
** One should have a high index of suspicion for the development of renal failure and Wilms tumor in patients with under-masculanized male disorder of sexual differentiation
* '''Other syndrome associated with Wilm’s tumour:''' 
**'''Perlman'''
**'''Mosaic variegated aneuploidy'''
**'''Fanconi anemia D1'''
**'''Simpson-Golabi-Behmel'''
**'''Li-Fraumeni'''
**'''Neurofibromatosis'''
**'''Sotos'''
**'''Trisomy 18'''
**'''Bloom'''

=== Screening ===
* Recommended in children at high risk (incidence > 5%)
**Presence of (3)
***Aniridia
***Hemihypertrophy
***Beckwith-Wiedemann syndrome
* Every 3-4 months is the appropriate screening interval
* Tumors detected by screening will generally be at a lower stage.

=== Pathology ===
* '''Favorable-Histology'''
** '''Wilms tumor usually compresses the adjacent normal renal parenchyma'''
** '''Most Wilms tumors are unicentric'''
* '''Anaplastic'''
** '''Associated with resistance to chemotherapy and poor prognosis'''
* Pathology after Preoperative Chemotherapy
** Stromal- and epithelial-predominant tumors are found more often after chemotherapy.
*** These histologic subtypes may demonstrate a poor clinical response to therapy but have an excellent prognosis if the tumor is completely excised.
** The proportion of blastemal-predominant tumors is decreased after chemotherapy, indicating some response of this tumor type to the preoperative chemotherapy. However, patients with blastemal-predominant tumors after chemotherapy have a high rate of relapse
* '''Nephrogenic Rests'''
** Nephroblastomatosis refers to the presence of multiple nephrogenic rests
** Children age < 12 months diagnosed with Wilms tumor who also have nephrogenic rests have an '''increased risk of developing contralateral disease''' and require frequent and regular surveillance for several years

=== Diagnosis and Evaluation ===

==== History and Physical Exam ====
* '''Classically presents with a palpable mass or gross hematuria but abdominal pain and hypertension can also be present'''
** '''<span style="color:#ff0000">> 90% have an asymptomatic abdominal mass discovered incidentally</span>''' by a family member or physician
*** '''Abdominal mass may be firm, non-tender and classically does not cross the midline (neuroblastoma can cross midline)'''
*** '''Other symptoms include fever, anorexia, and weight loss in 10% of patients'''
*** Rarely, children may have acute abdominal pain from tumor rupture into the peritoneal cavity or bleeding within the tumour.
** '''<span style="color:#ff0000">≈20% have hematuria at diagnosis'''
*** '''Gross hematuria warrants further evaluation to rule out tumor extension into the collecting system'''
** '''<span style="color:#ff0000">≈25% have hypertension at diagnosis'''
*** Hypertension can be caused by elevated plasma renin levels
* Compression or invasion of adjacent structures may result in an atypical presentation. A persistent varicocele in the supine position or hepatomegaly may be reflective of inferior vena cava obstruction from tumor thrombus
*Aniridia
**
** Found in 1% of Wilms tumor patients
** Caused by an abnormality of the PAX6 gene located adjacent to the WT1 gene
*** A deletion of chromosome 11 has been found most frequently in Wilms tumor patients with aniridia
*'''The development of a renal tumor in a child known to have aniridia, hemihypertrophy, or other syndromes associated with an increased incidence of nephroblastoma is most likely to be a Wilms tumor.'''
*'''Genitourinary anomalies (renal fusion anomalies, cryptorchidism, hypospadias) are present in 4.5% of patients with Wilms tumor'''
** '''May be associated with horseshoe kidney'''
** '''Increased risk of Müllerian duct anomalies in girls with Wilms tumor'''

==== Labs ====
* '''<span style="color:#ff0000">Preoperative laboratory evaluation of a child with an abdominal mass should include''' 
*#'''<span style="color:#ff0000">CBC'''
*#'''<span style="color:#ff0000">Liver enzymes'''
*#'''<span style="color:#ff0000">Serum electrolytes, including calcium'''
*#'''<span style="color:#ff0000">Renal function assessment (blood urea nitrogen, creatinine)'''
*#'''<span style="color:#ff0000">Urinalysis'''
* '''<span style="color:#ff0000">As many as 8% of newly diagnosed patients with Wilms tumor will have acquired von Willebrand disease, coagulation panel should be considered'''

==== Imaging ====
* '''<span style="color:#ff0000">Regional'''
** '''<span style="color:#ff0000">Abdominal ultrasound''' 
***'''<span style="color:#ff0000">For all patients with a suspected renal mass, evaluation should begin with an abdominal ultrasound to confirm a solid renal mass and preliminarily evaluate the contralateral kidney.''' 
****This approach guides subsequent imaging specific to the primary renal tumor
** '''<span style="color:#ff0000">CT or MRI abdomen/pelvis with IV contrast'''
***'''<span style="color:#ff0000">All patients with suspected Wilms tumour should undergo either CT or MRI of the abdomen/pelvis''' with IV contrast
**** '''See [https://radiopaedia.org/articles/wilms-tumour Figures]'''
**** '''MRI avoids radiation but typically requires anesthesia or sedation in young children.'''
**** A precise histologic diagnosis cannot be obtained on the preoperative imaging studies
**** The renal origin of the mass is usually apparent on CT, but it can be mistaken for neuroblastoma.
**** Bilateral or multicentric tumors are more typical of Wilms tumor, but renal lymphoma can manifest in this fashion.
** '''IVC involvement'''
*** Occurs in 4% of Wilms tumor patients
***Doppler ultrasonography is particularly helpful to exclude intracaval tumor extension
*** MRI can reliably identify extension of tumor into the IVC.
*** CT was able to detect all clinically significant IVC tumor extension when compared with ultrasonography
** '''<span style="color:#ff0000">Determination of inoperability must be made at surgical exploration, not based on imaging.'''
* '''<span style="color:#ff0000">Distant metastases'''
** '''<span style="color:#ff0000">Chest CT'''
*** '''Lung is the most common site of distant metastasis'''

==== Other ====
* '''Pre-operative tumor biopsy'''
** '''<span style="color:#ff0000">Rarely indicated and has serious treatment implications due to concern for tumor spillage and risk of local recurrence'''
* '''Ureteral involvement'''
** Ureteral tumor extension has been reported in 2-5% of patients with WT
** '''Any patient with a renal mass and gross hematuria should undergo cystoscopy with a retrograde pyelogram at the time of nephrectomy to determine if ureteral extension is present.'''
*** Complete resection of tumor en bloc is important in the management of these cases, as determining the distal extent of ureteral involvement can ensure complete resection

=== Staging ===
* '''<span style="color:#ff0000">Current staging system used by the Children’s Oncology Group (COG) is based primarily on the surgical and histopathologic findings (not imaging)'''

{| class="wikitable"
|Stage
| colspan="1" |
|-
| rowspan="1" |I
| colspan="1" rowspan="1" |
# Tumour limited to the kidney and completely resected
# Renal capsule intact
# The tumour was not ruptured or biopsied prior to removal
# Renal vein contains no tumour (intrarenal vessel involvement may be present)
# No residual tumour apparent beyond the margins of excision
|-
| rowspan="1" |II
| colspan="1" rowspan="1" |
# Tumour extends beyond the kidney but is completely resected
# Regional extension of tumour (vascular invasion outside the renal parenchyma or within the renal sinus and/or capsular penetration with negative excision margin)
# Operative tumour spill confined to flank (no peritoneal contamination)
# Tumour biopsy (except fine-needle aspiration) prior to surgery
|-
| rowspan="1" |III
| colspan="1" rowspan="1" |
# Non-haematogenous metastases confined to the abdomen (e.g., tumour in regional lymph nodes), including tumour implants on or penetrating the peritoneum
# Gross or microscopic tumour remains post-operative (tumour at the margins of resection)
# '''Tumour spill before or during surgery not confined to flank'''
# Piecemeal excision of the tumour (removal in >1 piece)
|-
| rowspan="1" |IV
| colspan="1" rowspan="1" |
# Presence of haematogenous metastases or metastases to distant lymph nodes
|-
| rowspan="1" |V
| colspan="1" rowspan="1" |
# Bilateral renal involvement at the time of initial diagnosis
|}


Source: Popov SD, Sebire NJ, Vujanic GM. Wilms’ Tumour – Histology and Differential Diagnosis. In: van den Heuvel-Eibrink MM, editor. Wilms Tumor [Internet]. Brisbane (AU): Codon Publications; 2016 Mar. Table 4. [COG staging system]. Available from: <nowiki>https://www.ncbi.nlm.nih.gov/books/NBK373364/table/tab1_4/</nowiki> doi: 10.15586/codon.wt.2016.ch1

* '''Any tumor spill leads to a stage III designation owing to the increased risk for local tumor recurrence'''

=== Management ===

==== Initial Management ====
*'''<span style="color:#ff0000">Principles of initial treatment of unilateral, non-syndromic tumors, even in patients with metastatic disease:'''
*#'''<span style="color:#ff0000">Upfront open transperitoneal radical, adrenal-sparing, nephrectomy with''' 
*#'''<span style="color:#ff0000">Lymph node sampling and''' 
*#'''<span style="color:#ff0000">Without tumour spillage''' 
*#* '''In general, Children's Oncology Group advocates for upfront nephrectomy, confirmation of diagnosis and then chemotherapy'''
*#**International Society of Pediatric Oncology (SIOP) advocates for an assumed diagnosis of WT, followed by pre-operative chemotherapy and then surgery for all patients.
*#*** Outcomes are similar, regardless of which protocol is used but there are differences in cumulative doses of therapies and the number of patients exposed to various therapies.
*#*** In North America children, and adolescents are generally treated per COG guidelines
* '''<span style="color:#ff0000">Nephron-sparing surgery'''
**'''<span style="color:#ff0000">Indications (4):'''
**# '''<span style="color:#ff0000">Bilateral tumors'''
**# '''<span style="color:#ff0000">Tumor in a solitary kidney'''
**# '''<span style="color:#ff0000">Pre-disposition syndrome'''
**# '''<span style="color:#ff0000">Clinical trials'''
*** '''Typically, patients undergoing nephron-sparing surgery will undergo preoperative chemotherapy''' with an assumed diagnosis of WT (COG does not recommend routine biopsy in this setting) '''to allow tumor shrinkage to preserve as much normal renal tissue as possible'''
* '''<span style="color:#ff0000">Approach'''
**'''<span style="color:#ff0000">Open radical nephrectomy is standard'''
***'''Extreme caution must be used applying minimally-invasive surgery to nephron-sparing surgery in children,''' and neither is advocated nor been studied by COG or SIOP
* '''<span style="color:#ff0000">Principles in Wilm's Tumor Surgery (6)'''
*#'''<span style="color:#ff0000">Thorough exploration of the abdominal cavity is necessary to exclude local tumor extension, liver and nodal metastases, and peritoneal seeding</span>'''
*#* Accurate staging is essential for the subsequent determination of the need for radiation therapy and the appropriate chemotherapy regimen.
*# '''<span style="color:#ff0000">Perform surgery without tumor spillage</span>'''
*#* Local recurrence is increased in patients with local tumor spillage, and is classified as stage III disease. 2-year survival rate after local recurrence is 43%
*#'''<span style="color:#ff0000">Palpate the renal vein and IVC</span>''' to exclude intravascular tumor extension before vessel ligation.
*#'''<span style="color:#ff0000">Lymph node sampling must be included at the same time as resection even with nephron-sparing.'''
*#* '''Selective sampling of suspicious nodes is an essential component of local tumor staging'''.
*#** '''Formal retroperitoneal lymph node dissection is not recommended'''
*#*The extent of LN dissection and location of nodal sampling need to be better defined to allow further study.
*#'''<span style="color:#ff0000">Adrenal gland can be spared</span> without increasing the risk for tumor spill or recurrence if it is not in close proximity to the tumor'''
*#'''<span style="color:#ff0000">Routine exploration of the contralateral kidney at the time of nephrectomy is not necessary when preoperative imaging with CT or MRI demonstrates a normal contralateral kidney</span>'''

==== Adjuvant Treatment[https://wjps.bmj.com/content/2/3/e000038 §] ====
* '''<span style="color:#ff0000">Chemotherapy'''
** '''<span style="color:#ff0000">Routinely used in all patients with WT except those at a very low risk'''
*** '''Very low risk criteria (4):'''
***# '''Age < 2 at diagnosis and'''
***# '''Stage I with favorable histology and'''
***# '''Tumor weighing <550 g and'''
***# '''Confirmed negative lymph nodes'''
** '''<span style="color:#ff0000">Regimen: vincristine, doxorubicin, +/- dactinomycin/adriamycin'''
*** '''Generally:'''
**** '''Stage I and II: vincristine and doxorubicin'''
**** '''Stage III+: vincristine, doxorubicin, and dactinomycin/adriamycin'''
*** '''Anaplastic/unfavourable histology: vincristine, doxorubicin, cyclophosphamide, etopiside'''
* '''Radiation: all patients with tumor stage III'''+
* Details available on UpToDate.com

==== Pre-operative Chemotherapy ====
* '''<span style="color:#ff0000">Indications</span>''' (Campbell’s and [https://wjps.bmj.com/content/2/3/e000038 §]) '''(7):'''
*# '''<span style="color:#ff0000">Solitary kidney'''
*# '''<span style="color:#ff0000">Bilateral tumours'''
*# '''<span style="color:#ff0000">Tumor extension into the IVC above the hepatic veins'''
*# '''<span style="color:#ff0000">Tumor involving contiguous structures whereby removing the kidney tumor would require removal of the other organs, such as spleen, pancreas, or colon'''
*# '''<span style="color:#ff0000">Tumors inoperable at surgical exploration'''
*# '''<span style="color:#ff0000">Tumour not amenable to partial nephrectomy [in patients with indication for nephron-sparing surgery]'''
*#* Most Wilms tumors are too large at diagnosis to allow partial nephrectomy. After preoperative chemotherapy, partial nephrectomy can be performed in 10-5% of patients
*# '''<span style="color:#ff0000">Extensive pulmonary metastases'''
** '''Bilateral tumors'''
*** Occurs in 5-10% of WT cases
*** Associated with worse outcomes
*** Increased risk of renal impairment
*** MRI is the imaging modality of choice
*** '''Because bilateral Wilms is overwhelmingly likely in a child 1-7 years old with bilateral renal masses,''' '''preoperative biopsy is not indicated''' and will up stage the disease to local stage III
*** '''Preoperative chemotherapy''' with vincristine, actinomycin and doxorubicin '''will be given''' for 2 cycles (6 weeks), after which imaging is repeated.
*** '''LN sampling on each side must be included with surgical intervention for patients with bilateral renal tumors, just like all patients with WT'''
* '''Tumors not responding to chemotherapy require bilateral open biopsy to determine histology.'''
** '''Open biopsies are recommended because they are more accurate than percutaneous needle biopsies when assessing for anaplasia, and bilateral biopsies are recommended'''

=== Prognosis ===
* With the advent of radiation therapy followed by the addition of chemotherapy, survival now > 90% and salvage is possible even for relapse
* '''Adverse prognostic factors (3):'''
*# '''Tumour histology'''
*#* '''Most important prognostic factor''' (more than presence of pulmonary metastasis)
*#* Anaplastic histology, especially diffuse anaplasia, is resistant to chemotherapy and associated with a poor prognosis
*# '''Stage'''
*# '''Loss of heterozygosity for chromosome 16q'''

=== Follow-up ===
* Imaging surveillance after treatment of the primary tumor is recommended to detect tumor recurrence

* '''Late Effects of Treatment (5)'''
*# '''Renal dysfunction'''
*# '''Infertility'''
*#* '''Hypogonadism'''
*#* Premature ovarian failure and early menopause have been linked to XRT and alkylating agent exposure.
*# '''Pregnancy complications'''
*#* Offspring of irradiated female patients are at risk for '''low birth weights and''' '''premature birth'''
*#* Does not appear to increase risk of congenital malformations
*# '''Cardiotoxicity'''
*#* Related to doxorubicin exposure and radiation fields that include the heart (chest, abdomen, left flank), which may lead to heart failure
*# '''Second Malignancies'''
*#* Related to chemotherapy and radiation exposure.