Pediatrics: Renal and Adrenal Oncology

Pediatric Abdominal Mass

• Differential diagnosis of pediatric abdominal mass (9):
  1. Neuroblastoma
     • Most common malignant tumour in infants
     • Most common extracranial solid tumour in children
  2. Wilms tumour
     • Most common primary malignant renal tumour in children
  3. Congenital mesoblastic nephroma
     • Most common renal tumour in infants§
  4. Renal cell carcinoma
  5. Clear cell sarcoma
  6. Rhabdoid tumour
  7. Other rare tumours
  8. Hydronephrosis
  9. Renal cystic disease

Neuroblastoma

Background

• Arises from cells of the neural crest that form the adrenal medulla and sympathetic ganglia
• Tumors may occur anywhere along the sympathetic chain within the neck, thorax, retroperitoneum, pelvis or adrenal gland
  • 75% originate in the retroperitoneum of which 50% originate in the adrenal and 25% in the paravertebral ganglia
• These tumors can undergo spontaneous regression, differentiate to benign neoplasms, or exhibit extremely malignant behavior

Epidemiology

• Most common malignant tumour in infants (child age < 1)§
• Most common extracranial solid tumor of childhood
  • In children, leukemia most common, followed by brain tumours
• Median age at diagnosis of 19 months (vs. Wilm’s 3.5 years)
• Screening discovers tumours with an improved prognosis, but does not reduce occurrence of neuroblastoma in older children and its subsequent mortality

Genetics

• PHOX2B and ALK as hereditary predisposition genes
• ≥20% of patients with familial neuroblastoma have bilateral adrenal or multifocal primary tumors; bilateral adrenal or multifocal primary tumors are quite unusual in spontaneous cases

Pathology

• Shimada classification
  • An age-linked histopathologic classification
  • An important aspect is determining whether the tumor is stroma poor or stroma rich.
    • Subgroups of stroma-rich tumors (3):
      1. Nodular
      2. Intermixed
      3. Well differentiated
      • Ganglioneuroma is a stroma-rich tumour
    • Subgroups of stroma-poor tumors (2)
      1. Favorable
      2. Unfavorable
      • Based on (3):
        1. Age at diagnosis
        2. Degree of histologic maturation
        3. Mitotic rate
        • These histologic patterns are independently predictive of outcome.
          • Stroma-poor tumors with unfavorable histopathologic features have a very poor prognosis (< 10% survival)
• In situ neuroblastoma
  • Small nodules of neuroblastoma cells found incidentally within the adrenal gland
  • Histologically indistinguishable from neuroblastoma
  • These small tumors regress spontaneously in most cases

Diagnosis and Evaluation

• History and physical exam
  • Clinical manifestations vary widely
    • Most children have abdominal pain or a palpable mass
      • Most primary tumors arise within the abdomen (65%);
        • Physical examination often reveals a fixed, hard abdominal mass
      • Pelvic neuroblastoma arising from the organ of Zuckerkandl account for 4% of tumors.
        • Extrinsic compression of the bowel and bladder can produce symptoms of urinary retention and constipation.
    • Other are identified because of manifestations of metastatic disease, including bone or joint pain and periorbital ecchymosis.
      • Metastases are present in 70% of patients with neuroblastoma at diagnosis
    • Symptoms produced by catecholamines
      • Release may mimic those seen in pheochromocytoma: paroxysmal hypertension, palpitations, flushing, and headache
      • Secretion of vasoactive intestinal peptide (VIP) can produce severe watery diarrhea and hypokalemia
• Labs
  • Increased levels of urinary metabolites of catecholamines, vanillylmandelic acid (VMA) and homovanillic acid (HVA), are found in 90% to 95% of patients
    • These metabolites can be monitored to detect tumor relapse and response to therapy
  • Anemia is found with widespread bone marrow involvement.
    • Marrow biopsies add substantially to the detection of marrow involvement by tumor, compared with marrow aspirates alone.
      • 2 marrow aspirates and 2 biopsies are recommended
• Imaging
  • Plain radiographs
    • May demonstrate a calcified abdominal or posterior mediastinal mass
  • CT and MRI
    • Provide more information about the local extent of the primary tumors and vascular involvement
    • Advantages of MRI over CT
      • Evaluating intraspinal tumor extension, which is not uncommon in paravertebral lesions
      • Demonstrating the relationship between the major vessels and the tumor
    • CT findings
      1. Crossing midline
      2. Vascular encasement
      3. Intra-tumoral stippled calcifications
         • Note that egg-shell calcifications are found in adrenal hemorrhage, which may also present in the neonate as an abdominal mass
      • These imaging characteristics are absent in Wilms tumor
  • A radionuclide bone scan and metaiodobenzylguanidine (MIBG) scans for can be used staging
• Insert figure

Staging

Stage	Description
1	Localized tumor Complete gross excision Ipsilateral lymph nodes involvement negative under microscopic examination
2A	Localized tumor Incomplete gross resection Ipsilateral lymph nodes involvement negative under microscopic examination
2B	Localized tumor Complete or incomplete gross resection Ipsilateral ymph nodes involvement positive under microscopic examination Enlarged contralateral lymph nodes but with negative involvement under microscopic examination
3	Localized unilateral tumor with contralateral lymph nodes involvement positive under microscopic examination or Unresectable unilateral tumor infiltrating across the midline with positive or negative regional lymph node involvement or Unresectable midline tumor with bilateral infiltration or lymph node involvement
4	Metastasis of the tumor to distant lymph nodes Metastasis of the tumor to liver, skin, organs (except as defined by Stage 4S)
4S	Limited to infants <1 year of age Localized primary tumor (as defined for stage 1, 2A, or 2B) Metastasis of the tumor limited to skin, liver and/or bone marrow Bone marrow involvement in stage 4S should be minimal (<10% of total nucleated cells identified as malignant on bone marrow biopsy)

Prognosis

• Adverse prognostic factors (7): SSANDS-1
  • Clinical Variables
    1. Stage: powerful independent prognostic indicator
    2. Site of origin: adrenal primary
    3. Age > 1; may be attributed to more unfavorable biologic parameters in tumors diagnosed at this age
  • Biologic Variables
    1. Amplification of the MYCN oncogene (20-25% of primary tumors)
       • Present in 40% of patients with advanced-stage disease but in only 5-10% of children with low-stage disease
       • Associated with rapid tumor progression and poor outcome
    2. DNA index: normal or tetraploid DNA number when compared with tumors that have aneuploidy of the tumor DNA
    3. Shimada histopathology (stroma rich vs. poor, mitotic rate, differentiation)
    4. Deletion of the short arm of chromosome 1p

Management

• Primary treatment modalities:
  1. Surgery
  2. Chemotherapy
  3. Radiation therapy
  • The role of each depends on tumor stage, age, and biologic prognostic factors.
• Infants < 6 months with localized small adrenal masses can be managed with serial observation.
  • Frequently associated with spontaneous regression
  • Surgical resection can be avoided in 80% of such patients
• Low-Risk Disease (Stages 1 and 2): surgery
  • Disease-free survival with surgical excision (adrenalectomy) alone in children with stage 1 neuroblastoma: > 90%
  • Radical resection resulting in removal of normal organs, particularly the kidney, is not justified
  • Radiation of the local tumor bed has been advocated for treatment of residual disease in stage 2
  • In stage 3 disease, or in stage 2 with extensive tumor around the kidney and renal vessels, preoperative treatment with chemotherapy significantly decreases the risk of nephrectomy as a result of resection of the tumor.
  • Patients with extensive metastatic disease and MYCN amplification represent a high-risk group. These patients should be considered for a more aggressive treatment with multimodal therapy, according to the risk group classification.
  • Those with favorable biologic markers and no symptoms can be followed with supportive care and limited chemotherapy. Intensive chemotherapy is reserved for those with adverse markers, although these infants do poorly even with therapy.
    • Indications for adjuvant chemotherapy
      • MYCN amplification and unfavorable histology
      • Disease recurrence
• Stage 4S
  • The vast majority of these infants with stage 4S disease have tumors with entirely favorable markers, explaining their favorable behavior. However, a small fraction have adverse markers, and it is these children who have progressive disease that often is fatal.
  • Resection of the primary is not mandatory
• Intermediate- and High-Risk Disease (Stages 3 and 4): neoadjuvant chemotherapy
  • Usually the safest approach for advanced tumors is to defer resection until after initial chemotherapy
  • Neoadjuvant chemotherapy, given the efficacy of modern agents, is very successful in reducing the size of primary tumors
  • There is debate regarding the extent of surgical resection that is required for stage 3 lesions
  • Conflicting evidence regarding the benefit of extensive resection in children with stage 4 disease  
  • Surgery usually is performed 13-18 weeks after initiation of chemotherapy, allowing 3-4 courses of treatment
  • Infants age <1 year with extensive local disease or stage 4 disease comprise a special subset of patients. They have historically fared much better than children older than 1 year of age with comparable disease, but not as well as infants with stage 4S disease. It is now recognized that the biologic markers can be used to identify which infants have high-risk disease and require intensive therapy and which have intermediate-risk disease requiring less intensive therapy.
• Chemotherapy
  • A variety of multiagent regimens have been developed to treat high-risk patients with neuroblastoma
• Radiotherapy
  • Radiotherapy is effective for local control in neuroblastoma, and risk of local relapse can be correlated with the biologic markers. Although irradiation has not provided a benefit in low-stage tumors, it has increased local control in children with advanced stage 4 or bulky stage 3 tumors

Wilms Tumour (Nephroblastoma)

• An embryonal tumor that develops from remnants of immature kidney

Epidemiology

• 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
• 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

• Majority arise from somatic mutations restricted to tumor tissue; much smaller percentage originate from germline mutations
• Genes identified as having a role in the development of 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
  • WT1 mutations
• Syndromes associated with Wilms tumours (4): B.W.’s Dick Feels Warm
  1. Beckwith-Weideman
  2. Denys Drash
  3. Frasier
  4. WAGR

Syndrome	Genetics	Associated Features	Risk of WT (%)
Beckwith-Weideman	11p15.5 WT2	Wilm's Tumour Macroglossia Nephromegaly Hepatomegaly Pre- and post-natal overgrowth Hemihypertrophy (growth asymmetry) Anterior abdominal wall defects Ear creases/pits	7
Denys Drash	WT1	Wilm's Tumour Genital abnormalities (under-masculanized male manifested by cryptorchidism and proximal hypospadias) Nephropathy (mesangial sclerosis, membranoproliferative glomerulonephritis) with early onset proteinuria (common denominator of syndrome)	74
Frasier	WT1	Wilm's Tumour Genital abnormalities Nephropathy (focal segmental glomerulonephritis) Gonadoblastoma	6
WAGR	11p13 WT1, PAX6	Wilm's Tumour Aniridia Genital abnormalities Mental Retardation	98

• 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.
• Beckwith-Wiedemann syndrome (BWS)
  • 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
• Aniridia
  • Absence of the iris
  • 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
• 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%), such as children with aniridia, hemihypertrophy, and BWS
• 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
    • > 90% have an asymptomatic abdominal mass discovered incidentally 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.
    • ≈20% have hematuria at diagnosis
      • Gross hematuria warrants further evaluation to rule out tumor extension into the collecting system
    • ≈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
  • 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
  • Preoperative laboratory evaluation of a child with an abdominal mass should include
    1. CBC
    2. Liver enzymes
    3. Serum electrolytes, including calcium
    4. Renal function assessment (blood urea nitrogen, creatinine)
    5. Urinalysis
  • As many as 8% of newly diagnosed patients with Wilms tumor will have acquired von Willebrand disease, coagulation panel should be considered
• Imaging
  • Regional
    • 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
    • All patients with suspected Wilms tumour should undergo either CT or MRI of the abdomen/pelvis with IV contrast
      • See 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
        • Doppler ultrasonography is particularly helpful to exclude intracaval tumor extension that occurs in 4% of Wilms tumor patients.
        • 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
    • Determination of inoperability must be made at surgical exploration, not based on imaging.
  • Distant metastases
    • Chest CT
      • The lung is the most common site of distant metastasis in children with Wilms tumor.
      • Preoperative chest CT with or without contrast is performed to rule out pulmonary metastases
• Other
  • Pre-operative tumor biopsy
    • 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

• The current staging system used by the Children’s Oncology Group (COG) is based primarily on the surgical and histopathologic findings.

Stage
I	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
II	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
III	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)
IV	Presence of haematogenous metastases or metastases to distant lymph nodes
V	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: https://www.ncbi.nlm.nih.gov/books/NBK373364/table/tab1_4/ 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

• Upfront open transperitoneal radical, adrenal-sparing, nephrectomy with LN sampling and without tumour spillage is the mainstay of initial treatment of unilateral, non-syndromic tumors, even in patients with metastatic disease
  • In general, COG advocates for upfront nephrectomy, confirmation of diagnosis and then chemotherapy, while the 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
  • Indications for nephron-sparing surgery (NSS) as per COG (4):
    1. Bilateral tumors
    2. Tumor in a solitary kidney
    3. Pre-disposition syndrome
    4. Clinical trials
    • Typically, patients undergoing NSS for the above indications will undergo preoperative chemotherapy with an assumed diagnosis of WT (COG does not recommend routine biopsy in this setting) to allow tumor shrinkage followed by NSS to preserve as much normal renal tissue as possible
  • 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 (open radical nephrectomy is standard).
  • 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%
  • Thorough exploration of the abdominal cavity is necessary to exclude local tumor extension, liver and nodal metastases, and peritoneal seeding.
    • Accurate staging is essential for the subsequent determination of the need for radiation therapy and the appropriate chemotherapy regimen.
  • 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
  • The renal vein and IVC are palpated to exclude intravascular tumor extension before vessel ligation.
  • The adrenal gland can be spared without increasing the risk for tumor spill or recurrence if it is not in close proximity to the tumor
  • LN sampling must be included at the same time as resection even with NSS.
    • 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.
• Adjuvant treatment§ and UpToDate
  • Chemotherapy
    • Routinely used in all patients with WT except those at a very low risk
      • Very low risk criteria (4):
        1. Age < 2 at diagnosis and
        2. Stage I with favorable histology and
        3. Tumor weighing <550 g and
        4. Confirmed negative lymph nodes
    • 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 (Children’s Oncology Group Recommendations)
  • Indications (Campbell’s and §) (7):
    1. Solitary kidney
    2. Bilateral tumours
    3. Tumor extension into the IVC above the hepatic veins
    4. Tumor involving contiguous structures whereby removing the kidney tumor would require removal of the other organs, such as spleen, pancreas, or colon
    5. Tumors inoperable at surgical exploration
    6. 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
    7. 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):
  1. 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
  2. Stage
  3. 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)
  1. Renal dysfunction
  2. Infertility
     • Hypogonadism
     • Premature ovarian failure and early menopause have been linked to XRT and alkylating agent exposure.
  3. 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
  4. Cardiotoxicity
     • Related to doxorubicin exposure and radiation fields that include the heart (chest, abdomen, left flank), which may lead to heart failure
  5. Second Malignancies
     • Related to chemotherapy and radiation exposure.

Other renal tumors

• Clear Cell Sarcoma of the Kidney
  • Unlike Wilms tumor, clear cell sarcoma of the kidney is associated with bone and brain metastases.
  • Bilateral involvement has not been reported, nor has the presence of Wilms tumor–associated congenital anomalies such as aniridia or hemihypertrophy.
• Rhabdoid Tumor of the Kidney
  • Most aggressive and lethal childhood renal tumor
• Congenital Mesoblastic Nephroma
  • Most common renal tumor in infants
    • Most common renal tumor diagnosed on pre-natal US
    • Most common tumor in infants > 4 months of age
  • Mean age at diagnosis of 3.5 months (in contrast, the median age for diagnosis of a Wilms' tumor is 3.5 years)
  • Typically infiltrative on imaging (whereas Wilms' tumors displace and compress renal architecture)
  • Subtypes (2)
    1. Classic type
       • Far more common
       • Rarely recur, provided surgical margins are negative
    2. Cellular variant
       • Consists of atypical spindle cells with frequent mitotic figures (25-30/10 hpf) and necrosis
       • Considered a variant of a fibrosarcoma
       • Associated with both local recurrence and widespread metastasis.
  • Management
    • Radical nephrectomy
      • Biopsy and partial nephrectomy are not recommended since the tumour occasionally extends into the hilum or perirenal soft tissue; complete excision is important to prevent local recurrence.
  • Follow-up
    • Surveillance by interval 6 month abdominal US for the first 2 years is usually recommended for the classic variant and more aggressive follow-up with interval CT or MRI scans of the lungs and abdomen are recommended at 3-6 intervals for the first two years for the cellular variant
• Solitary Multilocular Cyst and Cystic Partially Differentiated Nephroblastoma
  • Solitary multilocular cyst, or multilocular cystic nephroma, is an uncommon, benign renal tumor
• Metanephric Adenofibroma
• Renal Cell Carcinoma
  • RCC is the most likely diagnosis in a child age >12 with a renal mass
  • Staging
    • Same TNM system as that used for adults
    • 63% of children present with locally advanced or metastatic disease (N1 or M1)
  • Pathology
    • Most common histology seen in pediatric RCC is translocation (47% of cases)
      • Clear cell RCC is rare in pediatrics, unlike adults in whom clear cell RCC is the most common histology,
    • [Campbell’s] Higher incidence of papillary RCC in children
      • These tumors are genetically unique in that they have chromosome translocations involving a common breakpoint in the TFE gene located at Xp11.2
    • Another type of RCC more often seen in children is renal medullary carcinoma
      • Median age at presentation is 13 years
      • Found in patients with sickle cell hemoglobinopathy
  • Diagnosis and Evaluation
    • History and Physical Exam
      • Children tend to present with an abdominal mass or hematuria
    • Imaging
      • Cannot differentiate RCC from other solid renal tumors
  • Management
    • Nephrectomy is mainstay of treatment
      • NSS should only be advocated in highly select patients when the lesion can be completely excised and the surgeon has adequate experience
        • Important to remember that the application of MIS and NSS to children with RCC is likely limited as children are frequently treated under the assumption of a preoperative diagnosis of WT.
    • LN sampling is recommended at the time of nephrectomy in all cases of suspected RCC (regardless of preoperative imaging, tumor size, NSS, MIS) due to the high prevalence of nodal involvement
      • In adults, LN involvement is rare in smaller tumors, which is not the case in children. Almost half (47.5%) of children with T1 tumors have regional LN involvement; pathologically involved LNs were missed on preoperative imaging alone in >42% of cases
• Angiomyolipoma (AML)
  • The renal lesions of the TSC include:
    1. AML
    2. Simple cysts
    3. Polycystic kidney disease
    4. RCC
    • AML develops in up to 80% of patients with TSC. Renal cysts occur in up to 30% of patients with TSC.
    • Mutations of 1 of 2 genes on chromosome 9 (TSC1) and chromosome 16 (TSC2) are found in 85% of TSC patients
  • Management
    • Children with growing lesions can be managed with embolization or partial nephrectomy before they become symptomatic with bleeding.
      • The risk of serious bleeding appears to correlate with a diameter > 4 cm
    • mTOR inhibitors have shown promise as a new type of therapy for reducing the size of TSC-associated AMLs

References

• Wein AJ, Kavoussi LR, Partin AW, Peters CA (eds): CAMPBELL-WALSH UROLOGY, ed 11. Philadelphia, Elsevier, 2015, vol 4, chap 155
• AUA Update Series (2018) Lesson 19: Childhood Kidney Tumors