Renal Tumors

Hsin-Hsiao Wang, MD, MPH; Jonathan Routh, MD, MPH; Richard Lee, MD

 

 

 

 

Wilms’ Tumor
Introduction
Max Wilms’ description of a solid kidney tumor of triphasic pathology was first published in 1899.[1]   At the time, the pathological entity which would eventually come to be known as Wilms’ tumor (WT) was a near-universally lethal disease, despite aggressive surgical and chemotherapeutic interventions. 

Luckily, however, the world of pediatric renal tumors has dramatically changed since that time.  Beginning in the 1960s and 1970s, cooperative multi-institutional and international trials such as the National Wilms’ Tumor Study Group (NWTSG), the Children’s Oncology Group (COG), the United Kingdom Children’s Cancer Study Group (UKCCSG), and the Société Internationale d’Oncologie Pédiatrique (SIOP), among others, began to coordinate the care and study of children with renal tumors.  Currently, the overall five-year survival rates for WT are roughly 90 percent in the most recent trials of NWTS/COG and SIOP groups.[2-4]

Epidemiology
WT is the most common solid renal malignancy in children with an annual incidence rate of approximately 7 to 10 cases per million for children younger than 15 years; tumors occur in approximately 500 children per year in the United States.[5-8]  More than three-quarters of WT cases are diagnosed before age 5 with median age at 3.5 years.  WT is seen slightly more in females than males.  There are racial/ethnic differences in the development of WT; for example, African-Americans are at a slightly higher risk of developing WT, whereas Asian-Americans are found to have a lower risk of WT compared with Caucasians.[7, 9]  Bilateral WT are diagnosed at an earlier age than unilateral tumors, typically at a mean of 2.5 years.[7, 10]

Multi-disciplinary management of WT has revolutionized disease outcomes, although at an associated higher cost.  This translates into worse outcomes in developing countries, where factors such as an inability to afford chemotherapy or proper follow-up may lessen survival rates.[11, 12]  The total chemotherapy-related costs have been estimated at approximately USD 1,500 to 4,500 in a previous NWTSG report.[13]  Follow-up imaging costs have also been reported to be substantial.[14] Efforts to develop more cost-effective protocols without sacrificing patient survival are under investigation.[13, 15-17]

Etiology/Biology
Histopathology
The classic triphasic WT histologic pattern includes blastemal cells, stromal cells, and epithelial cells.  Blastemal cells, frequently referred to as “small round blue cells,” are undifferentiated cells characterized by a tightly packed pattern with basophilia and high nuclear-to-cytoplasmic ratio.  Stromal cells are most commonly observed as immature smooth and skeletal muscle, osseous, adipose, or cartilaginous cells. Epithelial cells frequently form tubular, glomerular, or papillary structures.[18]  The diagnosis of WT is complicated by the fact that there may only be one or two of the cell types found instead of the classic triphasic appearance.[19]  
Anaplasia, defined as large nuclear diameter, hyperchromatism, and abnormal mitotic figures,[20] is defined as an unfavorable histologic (UH) feature; anaplasia has an approximate 5% incidence across NWTS and SIOP.  Since it was first described, anaplasia has been consistently associated with a poor prognosis – specifically, with a significantly higher rate of death and tumor recurrence.[21-23]  Anaplasia is further categorized as a focal or diffuse pattern, with the latter found to be associated with an even worse prognosis[22].  In the absence of anaplasia, other WT histology types are categorized as favorable histology (FH). 
In FH WT, differentiated epithelial-predominant cell type was found to be associated with earlier stage but poor chemotherapy response; on the contrary, diffuse blastemal pattern was highly aggressive with a good response to chemotherapy.  Whether the predominant cell type plays an important role in FH WT prognosis with modern WT treatment strategies has been disputed, with some data suggesting equivalent outcomes,[24] while other reports suggest that epithelial- or blastemal-predominant tumors may have a worse event-free survival rate.[25]  In anaplastic WT, blastemal cell predominance has been identified to be an independent predictor for poor outcomes.[26
Nephrogenic rests (NR) are precursor lesions to WT that are found in more than a third of resected WT.[27, 28]  Most NR does not progress into WT cells as they are incidentally identified in around 1% of infant autopsy studies.[29]  Distinguishing between hyperplastic NRs and WT can be challenging.[29]  WT can present with a pseudocapsule composed of compressed atrophic renal tissue adjacent to normal renal parenchyma.  NR can be further categorized into perilobar nephrogenic rests (PLNRs) and intralobar nephrogenic rests (ILNRs).  ILNRs are associated with WT1 related condition such as aniridia, WAGR, and Deny-Drash syndrome.  PLNRs are seen in patients with Beckwith-Wiedemann syndrome related to the 11p15 locus.

NRs tend to occur bilaterally.[27] WT patients with NR, especially PLNRs, should have frequent and regular surveillance of their contralateral kidney due to an increased risk for metachronous tumor development.[15, 30]  Diffuse hyperplastic perilobar nephrogenic rests are associated with a higher risk of developing WT and with an increased incidence of anaplasia.[31]

Genetics
Like other pediatric malignancies, the genetic components of WT development are the subject of extensive research inquiry, including associated syndromes.  One of the first genetic alterations associated with WT identified was WT1(located at 11p13) deletion in patients with WAGR syndrome - a rare syndrome with features of WT, aniridia, genitourinary abnormalities, and mental retardation.[32PAX6 gene (highly associated with aniridia) is adjacent to WT1 gene; higher WT rates in aniridia patients with deletion of both WT1 and PAX6 have been reported.[33] Interestingly, further research has revealed that WT1 plays an essential role in differentiating genitourinary tissue[34-36]. 
Unlike WAGR syndrome, which is commonly associated with WT1 deletion, children with Denys-Drash syndrome (male pseudohermaphroditism, renal mesangial sclerosis, and nephroblastoma) have WT1 missense mutation.[37, 38]  WAGR syndrome and Denys-Drash syndrome patients were found to have higher risk of bilateral WT.[39]
Beckwith-Wiedermann syndrome (BWS) constitutes features including macroglossia, macrosomia, hypoglycemia, visceromegaly, omphalocele, and predisposition to several tumors, most commonly WT.  Genetic mutations with BWS affect the WT2 gene, located at the 11p15 region.[40, 41]  Imprinted genes expressing either maternally or paternally inherited gene are found at the 11p15 locus and alterations to those imprinted genes (such as loss of imprinting (LOI) of IGF-2) may be responsible for WT development in subsets of patients.[42]
Loss of heterozygosity (LOH) is defined as loss of one of two copies of a chromosomal region also plays an important role in WT tumorigenesis.  Approximately 20% of WT patients have been recently reported to have LOH at 16q,[43]  while LOH at chromosome 1p occurs in 10% of children with WT.[44]  Data from NWTS-5 suggested that tumor-specific LOH at chromosome 16q and 1p are associated with significantly worse outcomes, specifically with increased relapse and death.[45]  By contrast, LOH at 11q has been associated with diffuse anaplastic tumors, but is not independently associated with worse outcomes unless the entire long arm of chromosome 11 is lost.[46]
New techniques such as DNA microarray expression profiling and array comparative genomic hybridization are being utilized more to investigate the molecular genetics of WT.  They provided new perspectives on WT genetics by examining global gene expressions in specific tumor types/histologies.[47, 48]

Other genes reported to be associated with WT include: WTX (a tumor suppressor gene on X chromosome) ,[49] CTNNB1 (β-catenin gene in WNT/β-catenin signaling pathway associated with WT1 and WTX in WT),[50, 51] FWT1 (located at 17q12-q21) and FWT2 (located at 19q13.4).[52, 53]

Biomarkers
In order to avoid the twin extremes of over-treatment with excessive complications and under-treatment with compromised survival, prognostic biomarkers that can achieve better risk stratification are actively sought worldwide.  Multiple biomarkers have been reported to predict WT recurrence, including markers of genetic abnormalities,[54] chromosomal LOH,[55] disordered apoptosis,[56] abnormal cell/nuclear proliferation,[57] anomalous growth factor production,[58] and altered regulation of tumor suppressor genes and/or oncogenes.[59, 60]
Loss of apoptosis in tumor cells is identified as one of the important mechanisms in tumor progression.  Apoptosis-associated regulatory protein Bcl-2, Bax , and Bcl-X were found to be related to WT progression.[56]  Survivin, an inhibitor of apoptosis, was reported to be potentially associated with favorable outcome of WT with decreased cytoplasmic survivin expression.[61]  The tumor suppressor protein p53 has been reported to occur more frequently in anaplastic WT and in more advanced disease stages.[62, 63]  Interestingly, p53 expression has been reported to be altered after chemotherapy.[59] Tumor expression of B7-H1, a cell-surface glycoprotein of the B7 family of T-cell coregulatory molecules, is associated with an increased risk of tumor recurrence and of treatment failure in patients with both favorable histology and anaplastic tumors.[64, 65]

Table 1- Syndromes associated with WT

Syndromes

Gene

Characteristics

Overgrowth syndromes

Beckwith-Wiedemann syndrome 

WT2

macrosomia, macroglossia, omphalocele, prominent eyes, ear creases, large kidneys, pancreatic hyperplasia

Perlman syndrome

DIS3L2

fetal gigantism, visceromegaly, unusual face, bilateral renal hamartomas with nephroblastomatosis

Sotos syndrome

NSD1

facial, extremity, and cognitive abnormalities

Simpson-Golabi-Behmel syndrome

GPC3

organomegaly, bulldog appearance, congenital heart disease, polydactyly

Non-overgrowth syndromes

WAGR syndrome

WT1

aniridia, GU abnomalities, Renal impairement, intellectual disability

Deny-Drash syndrome

WT1

progressive renal disease, male pseudohermaphroditism

Frasier syndrome

WT1

progressive glomerulonephropathy, male pseudohermaphroditism, streak gonads, gonadoblastoma

 

 

 

 


 

Associated Syndomes
 There are a number of congenital anomalies and syndromes associated with development of WT (Table 1).  These can be broadly categorized as overgrowth and non-overgrowth syndromes.  Overgrowth syndromes include Beckwith-Wiedemann syndrome (BWS), Perlman syndrome, Sotos syndrome, and the Simpson-Golabi-Behmel syndromes.  The most studied non-overgrowth syndromes are WAGR syndrome and Deny-Drash syndrome.  Other reported syndromes that are associated with WT include Frasier syndrome, familial WT syndrome, Mosaic variegated aneuploidy, Fanconi syndrome, Li-Fraumeni syndrome, neurofibromatosis, and Bloom–Torre–Machacek syndrome.

Prognostic Factors

Current WT treatment strategies depend heavily on risk of tumor progression and recurrence.  Major prognostic factors include tumor staging, histology, and biology markers. 
Staging criteria are base upon anatomical extent of the tumor without considering other factors such as histology or biological prognostic markers.  Higher stage tumor is associated with worse prognosis.  The most commonly used staging systems are developed from COG and SIOP.  Unilateral tumors are classified as stage I to IV; bilateral tumors are classified as stage V.  The major difference is that NWTS/COG stages tumor before chemotherapy is administered and SIOP stages are determined after initial chemotherapy.  The details of staging are addressed in detail below. 
Tumor histology is perhaps the most critical factor affecting prognosis.  Anaplastic histology, especially diffuse type anaplasia, forebodes poor prognosis. Studies suggested the presence of anaplasia was associated with higher rate of recurrence, metastasis, and death.[21, 26]  NWTS/COG determines favorable or unfavorable histology based on presence of anaplasia.  SIOP has three histologic classifications: low-risk (completely necrotic or cystic partially differentiated nephroblastoma); intermediate-risk (epithelial, stromal, mixed, regressive, or focal anaplastic nephroblastoma); and high risk (blastemal or diffuse anaplastic nephroblastoma).[66
Biological factors provide additional information to further stratify the risk and depict prognosis for WT patients.  In NWTS-5, LOH of either chromosome 16q or 1p was found to have a significantly higher rate of relapse independent of tumor stage or histology.[45, 55, 67]  LOH of 11p15 was associated with more tumor relapse in very low risk WT patients who were not treated with chemotherapy, but rather were surgically excised and then observed.[60]  
Historically, other factors such as age were also heavily considered in prognostic evaluation.  Children less than 24 months old were found to have lower relapse rate.[68]  With the new advancement in WT regimens, the role of age greatly diminished.[21, 69]

Presentation
            The typical presentation of WT is a palpable, firm, smooth, non-tender abdominal mass.  Other symptoms include abdominal pain, hematuria, fever, and hypertension.  Subcapsular hemorrhage can cause rapidly increasing in abdominal size, anemia, hypertension, and fever.  Tumor rupture can present as an acute abdomen. Tumor extension to renal vein or IVC can lead to varicocele, hepatomegaly, ascites, and congestive heart failure.[70]  Due to the fact that WT is commonly associated with congenital syndromes, children should be assessed for associated anomalies including aniridia, hemihypertrophy, or genitourinary abnormalities. 

Differential Diagnosis
            The differential diagnosis of WT includes neuroblastoma and other renal tumors.  Their histologic and other major characteristics are listed in Table 2.


Table 2- WT differential diagnosis

Diagnosis

Histology and Major characteristics

Neuroblastoma

Homer-Wright pseudo-rosettes: small, round and blue, and rosette patterns

accumulation and excretion of the intermediates HVA, VMA, and dopaminem in urine

most common cancer in infancy

Clear cell sarcoma of the kidney

cords and nests of pale-stained tumor cells with abundant extracellular matrix separated by a network of fine capillary arcades

bone-metastasizing renal tumor of childhood 

typically presents between the ages of two and three years of life

Rhabdoid tumor of the kidney

presence of monomorphic cells with vesicular nuclei and prominent nucleoli

metastatic presentation

occurs most frequently in children less than two years of age and almost never in those older than five years of age

Congenital mesoblastic nephroma

classic CMN: locally-infiltrative fascicles of spindle cells; cellular CMN: hypercellular with sheets of closely-packed spindle cells

associated with hypertension and elevated concentrations of calcium and renin

common within the first year of life

Renal cell carcinoma

papillary or pseudopapillary architecture with or without psammoma bodies and clear cells with copious cytoplasm

frequently associated with genetic translocations

more common during the second decade of life and beyond

Renal medullary carcinoma

large nuclei with prominent vesicles and nucleoli as well as intensely eosinophilic cytoplasm with intense inflammatory response

almost exclusively in African-Americans with sickle cell trait or sickle cell disease

reported mostly in adolescent and young adults

                                                                                      
Workup
            Laboratory tests should include complete blood count, renal and liver function tests, serum calcium, urinalysis, and a coagulation panel.  Complete blood count can detect anemia. Serum creatinine and BUN can help evaluate pre-interventional renal function.  Liver function tests may be abnormal with liver metastasis.  Hypercalcemia can be found in patients with rhabdoid tumor of the kidney or congenital mesoblastic nephroma.[71] Urinalysis may reveal proteinuria which can be seen in patients with Denys-Drash syndrome.  Acquired von Willebrand's disease has been reported in around 8 percent of WT patients at presentation, which is obviously significant for operative planning.[72]

Abdominal ultrasound is the first-line imaging study for children with an abdominal mass.  Doppler can be used to further detect tumor extension to renal vein or inferior vena cava that occurs in 4 percent of WT patients.[73]  Once the mass has been confirmed on US, CT scan should be ordered in order to provide more detailed anatomy of the renal mass, contralateral kidney tumor evaluation, and metastasis detection.  In contrast to earlier recommendations, thin-sliced helical CT is recommended rather than routine surgical exploration of the contralateral kidney.[74, 75]  Controversy exists in the choice of imaging study between chest CT and chest X-ray for lung metastasis.[76, 77]  MRI is utilized when tumor infiltration of renal vein or IVC detection is equivocal by ultrasound or when the patient cannot tolerate CT contrast dyes.

Staging

Tumor staging and histology are the most potent predictors of WT outcomes.  The most commonly used staging systems are developed by NWTS/COG and SIOP.  Unilateral tumors are categorized as stage I to IV and bilateral tumors at presentation are categorized as stage V.  The central difference lies in the timing of the staging.  NWTS/COG system assigns staging at primary surgery.  The staging system by SIOP is performed after pre-operative chemotherapy.  The detailed staging criteria are listed in Table 3.

table 3- NWTS/COG & SIOP staging systems

Stage

Criteria

Stage I

Tumor confined to the kidney and completely resected. Intact renal capsule.  No tumor rupture or renal sinus extension.

Stage II

Complete resection with negative margins and lymph node involvement.  Regional tumor extension (extracapsular penetration, renal sinus extension, vascular involvement)

Stage III

Residual nonhematogenous tumor confined to the abdomen (lymph nodes , any tumor spillage, pre-operative biopsy, tumor removed more than one piece)

Stage IV

Hematogenous metastases (lung, liver, bone, brain), or lymph node metastases outside the abdominopelvic region

Stage V

Bilateral renal involvement at diagnosis

Treatment
Unless a tumor is deemed to be unresectable, biopsy prior to chemotherapy is not typically recommended due to risk of tumor spillage and seeding – a biopsied tumor will typically be upstaged based on the violation of the tumor capsule.  This is controversial, however, as some centers have adopted pre-chemotherapy biopsy to reduce inappropriate treatment such as giving chemotherapy to benign conditions or inadequate chemotherapy to non-WT.[78-80]  UKCCSG trials demonstrated no significant difference of 5-year survival between immediate nephrectomy compared with initial biopsy with chemotherapy and delayed nephrectomy.[81]  Open biopsy rather than percutaneous biopsy is indicated in bilateral WT with poor chemotherapy response in order to achieve accurate assessment of anaplasia.[82]
Radical nephrectomy with transperitoneal approach is the mainstay of WT management.  Proper surgical staging along with tumor extent evaluation and abdominal cavity exploration are essential for adjuvant therapy planning including chemotherapy and radiation therapy.  Sampling of suspicious nodes is recommended for tumor staging as well.  Gentle handling of the tumor is mandatory throughout the entire process to prevent tumor spillage; spillage is known to be a significant risk factor for local tumor relapse and requires more aggressive adjuvant therapy.[83]
NWTS/COG and SIOP differ in terms of timing of surgical excision relative to chemotherapy.  The NWTS/COG approach (pre-chemo surgical excision) provides accurate assessment of the disease extent and tumor histology.  It also identifies patients with benign disease and thus avoids unnecessary chemotherapy.  By contrast, the SIOP approach (post-chemo surgical excision) has the advantage that surgery is often technically easier with reduced tumor size and lower tumor spillage rate after initial chemotherapy.[84]  Currently both groups report an excellent 5-year overall survival rate of approximately 90%.[2-4]

            Concerning chemotherapy, the most significant recent advance has been the adoption of dactinomycin and vincristine; these drugs dramatically improved WT patient survival even in advanced disease.  NWTS/COG and SIOP conducted multiple randomized trials to adjust the combination of regimen in order to further improve survival with lower complication rates.  The recommended NWTS/COG treatment protocol is organized in Table 4.

Table 4 - COG treatment protocol

Stage/Histology/Biomarker

Chemothereapy

Radiation

Stage I FH <2y/o <550gm

none

none

Stage I FH >2y/o >550gm

EE-4A

none

Stage II FH

EE-4A

none

Stage I-II FH with 1p/16q LOH

DD-4A

none

Stage III FH without 1p/16q LOH

DD-4A

yes

Stage I-III FA

DD-4A

yes

Stage I DA

DD-4A

yes

Stage III-IV FH with 1p/16q LOH

M

yes

Stage IV FH non-pulmonary mets

M

yes

Stage IV FH pulmonary mets

 

 

Lesions persist after 6 wks of chemo

M

yes

Lesions resected at diagnosis

DD-4A

yes

Lesions resolve after 6 wks of chemo

DD-4A

none

Stage II-III DA

UH-1

yes

Stage IV FA

UH-1

yes

Stage IV DA (no measurable disease*)

UH-1

yes

Stage IV DA (measurable disease)

VCR+IRIN window

yes

Stage IV DA (CR/PR after VCR+IRIN window)

UH-2

yes

FH= favorable histology; FA= focal anaplasia; DA= diffuse anaplasia

EE-4A= Vincristine, dactinomycin

DD-4A= Vincristine, dactinomycin, doxorubicin

M= Vincristine, dactinomycin, doxorubicin, cyclophosphamide, etoposide

UH-1=Vincristine, dactinomycin, doxorubicin, cyclophosphamide, etoposide, carboplatin

UH-2=Vincristine, doxorubicin, cyclophosphamide, etoposide, carboplatin, Irinotecan

VCR= vincristine; IRIN= irinotecan; CR= complete response; PR= partial response

*measurable disease: presence of lesion with longest diameter at least 1cm on CT or MRI

There are some exceptions in which COG protocols recommend pre-operative chemotherapy.  These include WT patients who are undergoing a planned partial nephrectomy/nephron sparing surgery, who have inoperable tumor, and who have caval thrombus extending above the hepatic veins.[10, 70, 85-87]
            In the SIOP protocol, a 4-week course of preoperative vincristine and dactinomycin are given prior to surgery.  Vincristine, dactinomycin, and doxorubicin are administered for six weeks preoperatively if there is any extra-abdominal metastasis.  The post-operative regimen is organized in Table 5.

table 5 - SIOP treatment protocol

Stage

Chemothereapy

Radiation

Stage I

AMD+VCR x 4wks

none

Stage II

AMD+VCR+DOX x 27wks

15 Gy at regional LN

Stage III

AMD+VCR+DOX x 27wks

15 Gy

Stage IV

AMD+VCR+DOX x 27wks

12 Gy if persistent lung lesion at wk 9

add ifosfamide, carboplatin, etoposide at wk9 if complete response not achieved for 34 wks

AMD, dactinomycin; DOX, doxorubicin;  VCR, vincristine

 

 

            The COG recommended radiation regimen in detail is organized in Table 6.


table 6 - Radiation treatment recommendation by COG

Treatment site

Clinical presentation

 

Flank irradiation

Stage III FH, Stage I-III FA or DA

 

Whole abdomen irradiation

Abdominal stage III

 

1. preop tumor rupture

 

2. peritoneal mets

 

3. tumor spillage

 

Whole lung irradiation

Lung mets

 

1. 1p/16q LOH

 

2. No CR after chemo at wk6

 

3. Other sites of mets

 

Whoe brain irradiation

Brain mets

 

Liver irradiation

focal mets not resected at diagnosis or diffused mets

 

Bone irradiation

Bone mets

 

Lymph node irradiation

Lymph node mets

 

Laparoscopic nephrectomy techniques have a limited role in WT management due to the concern for tumor spillage and inadequate tumor staging.  Duarte described the initial experience of laparoscopic nephrectomy on WT patients treated with neoadjuvant chemotherapy.[88]  Since then, there have been multiple reported series of laparoscopic nephrectomy for WT, typically restricted to patients treated with neoadjuvant chemotherapy.[89, 90

           

Historically, nephron sparing surgery (NSS) was generally reserved for bilateral WT or children with a solitary kidney in whom preservation of renal function was mandatory.[3]  Recently, this technique has garnered increasing attention from investigators.  Data on NSS in preserving long-term renal function, cardiovascular function, and overall health provide an insight of the potential wider applicability of NSS on selected WT.[91, 92]  The AREN0534 trial of COG allows for NSS in children with bilateral WT, or for unilateral WT in children with syndromes which predispose to renal failure or bilateral WT.[93]  Although contemporary data on NSS seems quite promising,[89, 94-96] data on NSS outcomes in children with WT remain scarce.  As practice patterns continue to evolve, NSS will likely be primarily utilized mainly at high-volume referral centers. 

Bilateral WT
            Bilateral WT is found in roughly 5-7% of WT patients.[10, 97]  The major challenge in these children is to preserve renal function while adequately treating the tumors.  Historically, bilateral WT was managed by radical nephrectomy of the more involved side and NSS on the contralateral kidney.  However, these patients were found to have a significant risk of ESRD due to tumor recurrence and subsequent nephrectomy.[98, 99] Modern management of bilateral WT incorporates neoadjuvant chemotherapy along with NSS as first-line treatment.[100-102] The most current COG protocol (AREN0534, as noted above) recommends 6 weeks of vincristine, dactinomycin, and doxorubicin, followed by re-evaluation.  Depending on tumor response, the patient then receives either an attempt at NSS or an additional 6 weeks of chemotherapy. Following surgery, adjuvant chemotherapy and radiation therapy regimen depend on tumor histology and staging.  Open bilateral biopsy may be considered if the tumor has a poor response to adjuvant chemotherapy; poor chemotherapy response has been reported to be due to tumor differentiation, which has a good prognosis if completely resected.[82, 103]

Of note, true tumor enucleation is generally reserved for large, centrally located tumors due to the concern for positive margin.  Anaplasia with positive margin will require additional resection to avoid worse survival.[102, 104-106]

Late Effects of WT Treatments

            WT survivors may suffer from long-term complications depending on the therapy regimen.[107] The major reported sequelae include development of a second malignancy, cardiotoxicity, renal impairment, musculoskeletal problems, and reproductive issues. Patient who received more aggressive chemotherapy and radiation therapy are obviously at higher risk.
            Second malignancy is one of the concerning late effects from WT therapy.  WT survivors have been reported to have a 1% cumulative incidence at 10 years post-diagnosis and increasing incidence developing second tumor thereafter.[108-110] Radiation therapy is associated with a significantly higher risk of late tumor; most second tumors have been reported to occur within the radiation field.[109, 110] Additionally, doxorubicin may potentiate this radiation effect.[111]
            Cardiotoxicity is a well-established late effect of doxorubicin, specifically myocardial dysfunction and reduced contractility.  Common manifestations include congestive heart failure and increased left ventricular afterload.[112, 113] The risk of cardiac dysfunction is closely related to the total cumulative dose of doxorubicin.
            Renal impairment in WT survivors can be caused by loss of renal parenchyma from surgery or from nephrotoxicity related to chemotherapy and radiation.  Severe renal dysfunction is usually associated with bilateral WT involvement especially if they receive radiation therapy.[98, 114, 115] Other significant risk factors for late renal impairment include Denys-Drash and WAGR syndromes in addition to radiation nephritis.
            Musculoskeletal problems such as scoliosis and short stature were found to be associated with radiation treatment.[116-118] Females who received high-dose abdominal radiation therapy are at risk of abnormal ovary development, higher incidence of infertility, spontaneous miscarriages, premature birth and intrauterine growth retardation of offspring.[119-121]

Prognosis       
            Overall five-year survival rate of WT patient has dramatically improved to greater than 90% at present.[2-4] Event-free survival (EFS) rates rely heavily upon prognostic factors like tumor staging, histology, biologic markers, and to a lesser extent, age at diagnosis and tumor weight. 

           

In the past, only 30% of WT patients survived with tumor recurrence.  With salvage therapy, the five-year survival rate of patient who have recurrence improves to 50-60% [122, 123].  Lung is the most common site for recurrence.  Prognostic factors that are associated with favorable prognosis include favorable histology, lower tumor stage, lower number of pulmonary nodules, no prior radiotherapy, recurrence beyond 6-12 months after initial diagnosis, only dactinomycin and vincristine as initial treatment, and complete resection of original tumor.[2, 123, 124] The ideal salvage therapy strategy remains under investigation.[122, 125-129]

Non-Wilms’ Pediatric Renal Tumors
Congenital Mesoblastic Nephroma
Congenital Mesoblastic Nephroma(CMN) is the most common renal tumor in infants within the first several months of life, with 90% diagnosed within the first year of life.[130, 131]  In one large series, the median age at diagnosis was reported to be 19 days.[132]  Beyond three years of age, CMN is rarely encountered.[130-136]  CMN has been noted to be more common in males, with a roughly 2:1 male to female ratio.  CMN is thought to originate from the nephrogenic mesenchyme, with two distinct histologic subtypes: the classic and cellular varieties. 
            Classic CMN typically presents with a lower tumor stage, smaller tumor volume, and at a younger age than cellular CMN.[132]  Classic CMN was initially described in 1967 and noted to be composed of locally-infiltrative fascicles of spindle cells.  Vascular invasion at the tumor periphery has been reported.[137]  By contrast, cellular CMN is hypercellular, with sheets of closely-packed spindle cells.[138, 139]  Both types may coexist in a mixed pattern as well. 

Recent studies have shown that the classic and cellular variants have differing genetic features.  In the cellular variant, a t(12;15)(p13;q25) translocation has been shown to produce a ETV6-NTRK gene fusion product which over activates tyrosine kinase signaling; this translocation has not been demonstrated in classic CMN, however.[140, 141]  Interestingly, this same translocation is found in infantile fibrosarcoma, leading many authors to conclude that cellular CMN is in fact the renal manifestation of that disease process.[140, 141]
Prognosis for CMN is generally excellent, particularly in comparison to other renal tumors.[131]  Most patients can be successfully treated with radical nephrectomy alone; attempts to preserve renal parenchyma in these patients through the use of partial nephrectomy are often unsuccessful, perhaps due to the tumors’ locally invasive nature.[132]  For patients with Stage III tumors, particularly older infants with the cellular variant, some authors have suggested the use of adjuvant chemotherapy.[132]  Given the relative chemosensitivity of infantile fibrosarcoma, this approach would seem logical in high-risk patients.[142

Clear Cell Sarcoma of the Kidney
Clear Cell Sarcoma of the Kidney (CCSK) is one of the more common “high-risk” renal tumors of childhood, representing 3% of pediatric renal tumors in the United States.[143]  CCSK is typically described as a large, homogenous, and often multi-cystic mass arising from the renal medulla; necrosis and hemorrhage are common.  Histologically, these tumors are classically defined by cords of oval or spindle-shaped cells separated by regularly spaced fibrovascular septa.[20, 143, 144]  CCSK typically presents between the ages of two and three years of life (range 2 months to 14 years) with a 2:1 male to female ratio.  No cases of bilateral CCSK have been reported.[131, 143

Perhaps the most notable feature of CCSK is its propensity to metastasize to bone.   Among 351 tumors from the NWTSG, 4% of CCSK tumors presented with metastatic lesions; after lymph node involvement (20%), bone lesions were the most common metastatic site at presentation (1.4%), followed by lung and liver (1.1% each).  Importantly, bone was the most common site of tumor recurrence (14%), followed by lung (11%) and abdomen (7%).[143]  CCSK recurrences commonly occur years after the initial diagnosis; interestingly, this phenomenon is heightened among patients receiving doxorubicin, despite a reduced overall recurrence rate in patients receiving this drug.[143

Overall survival among children with CCSK is reduced as compared to other renal tumors.  Eight-year overall survival has been reported to be as high as 83% among children 1 to 3 years of age; however, this figure is reduced among both infants and children older than 4 years of age.[131, 143, 145]  Other negative prognostic factors include increased tumor stage and the presence of histologic tumor necrosis.  Therapy with doxorubicin is perhaps the most important modifiable risk factor for tumor recurrence, as its use reduced the risk of relapse by 68% in the largest series reported to date.[143]

Rhabdoid Tumor of the Kidney
            Rhabdoid Tumor of the Kidney (RTK) is a rare but lethal pediatric renal tumor, comprising less than 2% of all renal tumors in the combined European and US data.[131]  Initially described as a sarcomatoid variant of WT, RTK was subsequently recognized as a distinct pathologic entity.[20]  RTK is characterized histologically by the presence of monomorphic cells with vesicular nuclei and prominent nucleoli.  Immunohistochemical staining commonly shows perinuclear vimentin staining,[146] as well as complete lack of expression of the tumor suppressor gene product INI1.[147]  
RTK commonly presents with hematuria and metastatic disease.[131, 148]  Median age was 11 months (range 1 month to 5 years) with a slight male predominance (male to female ratio 1.4:1).  In a combined analysis of data from both NWTSG and European trials, 29% of infants with RTK presented with metastatic disease, far more than other tumor types.[131]    Importantly, RTK has been noted to have a predilection for concurrent central nervous system involvement, which may be either metastatic RTK or synchronous primary CNS malignancies.[148]  Among RTK patients with metastatic disease at presentation, the most common metastatic sites were lung (83%), brain (73%), liver (7%), and bone (5%).[131]Overall survival among patients with RTK in the NWTSG trials was 23%.   Survival has been shown to be decreased with higher stage tumors (42% vs. 16% 4-year survival), presence of CNS tumors (universal mortality in NWTS 1-5), and decreased patient age (41% 4-year survival above age 2 years vs. 9% survival below age 6 months).  By contrast, patient gender, chemotherapy regimen, and the use of radiotherapy have not been associated with survival.[148-150]  Recently, cases of long-term survival after autologous stem cell transplant have been reported.[151

Renal Cell Carcinoma/Translocation Renal Cell Carcinomas
Although WT is the most common primary renal neoplasm during the first decade of life, renal cell carcinoma (RCC) is more common during the second decade of life and beyond.[152, 153]  RCC constitutes 2-6% of pediatric renal tumors overall,[154-156] and with a roughly 2:1 female to male ratio is more common among girls.[157-160]  Pediatric RCC has recently been shown to significantly differ from adult RCC, in terms of both tumor biology and clinical behavior.[157, 161-163]
  In particular, pediatric RCC has been characterized by its unique genetic features, specifically by chromosome Xp11 or t(6;11) translocation and lack of chromosome 3p mutations.  This insight has led to the coining of the terms “translocation RCC” or “translocation carcinoma of the kidney”, now recognized as a distinct pathologic subtype under the 2004 WHO classification.[164-166]  Xp11.2 is the locus of the TFE3 gene, a member of the microphthalmia-associated transcription factor (MiTF) family; at least 6 specific TFE3-related cytogenetic translocations and gene fusion products have been reported, with the most common being ASPL-TFE3 (t(X;17)(p11.2;q25)) and PRCC-TFE3 (t(X;1)(p11.2;q21)).[167-169]  A second member of the MiTF family, TFEB, is also associated with a subset of pediatric RCC, characterized by the Alpha-TFEB gene fusion product and a t(6;11)(p21;q12) translocation.[164, 170] Histologically, Xp11.2 translocation RCC most commonly exhibits papillary or pseudopapillary architecture with or without psammoma bodies and clear cells with copious cytoplasm.[160] t(6;11) translocation RCC is morphologically similar, but tends to stain positive for HMB-45, while Xp11.2 translocation RCC typically does not.[164]  Importantly, the development of translocation RCC has been recently reported to be associated with a history of exposure to cytotoxic chemotherapy, particularly topoisomerase II inhibitors or alkylating agents such as cyclophosphamide.[166, 171]  The mechanism behind this association is at present unclear.
Just as translocation RCC can also occur in adults, so too can non-translocation RCC occur in the pediatric age range;[168] however, the average age of non-translocation RCC patients is between 60 and 65 years.[172]  Although non-translocation RCC may develop spontaneously even in young patients, multiple familial syndromes predispose to the development of RCC at young ages.  In particular, von Hippel-Lindau syndrome,[173, 174] tuberous sclerosis,[175] Birt-Hogg-Dube,[176] hereditary papillary renal carcinoma,[177] and hereditary leiomyomatosis renal cell carcinoma[178] have been reported to be associated with the development of RCC among children and adolescents.[175, 179, 180]   
In addition to genetic and etiologic differences, pediatric RCC differs from adult RCC in terms of clinical behavior.  While adult RCC patients with lymph node involvement tend to fare poorly, pediatric RCC patients with lymph node involvement have a surprisingly good prognosis.[160, 161]  Importantly, these tumors have been reported to occur more commonly than expected among children who have experienced prior chemotherapy.[159, 166, 181]  Depending on tumor characteristics (in particular tumor size), some authors have noted that some pediatric RCCs may be suitable for treatment with partial nephrectomy;[158] the role of retroperitoneal lymph node dissection in these patients has been debated as well.[182, 183]  Regardless of treatment strategy, the prognosis for RCC has been shown to be somewhat better than for other pediatric renal tumors, with five-year survival rates of 72-87%.[155, 161

Renal Medullary Carcinoma
Renal Medullary Carcinoma (RMC) is a rare and extremely aggressive primary renal tumor which has been reported to occur almost exclusively in African-American adolescents and young adults with sickle cell trait or sickle cell disease; indeed, RMC has been labeled as the “seventh nephropathy” of sickle cell disease.[184]  RMC was originally described in 1995, with fewer than 100 cases of RMC described since then.[184, 185]  The reported mean age of RMC patients is 21 years, ranging from 5 to 39 years, with a 2:1 male to female ratio.[186, 187
As their name implies, RMC tumors arise centrally within the kidney, perhaps from the transitional epithelium of the renal calyces; RMC is generally believed to be a variant of collecting duct RCC.[188]  Tumor growth patterns is often reticular, though a variety of growth patterns have been described.[189]  Microscopically, RMC is characterized by large nuclei with prominent vesicles and nucleoli as well as intensely eosinophilic cytoplasm; the tumors are often accompanied by an intense inflammatory response.[184]  Cytologically, RMC appears similar to other high-grade carcinomas.[190]   Similar to RTK, RMC specimens have also been shown to have complete loss of INI1 expression.[189

RMC often presents with gross hematuria and abdominal or flank pain, reflecting its propensity to invade the renal sinus and/or pelvis as well as other local structures.  Of 61 patients reported in the two largest case series, all presented at tumor Stage III or IV.[184, 187]  Despite a wide variety of attempted therapies,[185, 191] the prognosis of RMC patients is dismal.  With the exception of a single patient who was alive at 2 years’ follow-up (and whose tumor was discovered at 1.8 cm in size),[192] the longest reported survival of any RMC patient is 17 months.[193]

Renal Angiomyolipoma
Renal angiomyolipoma (AML) is a generally benign neoplasm of the kidney consisting of a varying proportion of dysplastic blood vessels, smooth muscle, and adipose tissue.[194]  These tumors are found much more frequently in women than men (female to male ratio 4:1) at a mean age of 48 years (range 1-86).  Though classically associated with tuberous sclerosis (TS), 80% of AML occur spontaneously.[195]  Among TS patients, however, up to 70% may develop AML, and up to 10% will have renal complications due to their AML.[196, 197]  AML in TS patients tend to develop at a young age, often during infancy; once present, AML is likely to grow over time.  This has prompted some authors to recommend annual renal ultrasound screening of TS patients.[196

AML is typically a solid tumor, though cystic variants have been described.[198]  The triphasic components of AML are classically present in roughly equal proportions, although any one can be predominant in individual tumors.[194]  On imaging studies, fat-poor AML in particular can be quite difficult to differentiate from RCC or other renal tumors.[199]  AML is generally located at the renal poles, may be bilateral or multifocal, and may extend into the perirenal fat.  Classic AML is most often cytologically bland, although the smooth muscle component may assume an atypical appearance with hyperchromatic nuclei and prominent nucleoli.[194]  Recently, a rare malignant AML variant known as epithelioid AML has been reported, with the possibility of widespread tumor metastasis.[200]
Although AML may be incidentally discovered on imaging studies, 60% of patients present symptomatically, most commonly with flank pain, a palpable mass, or hematuria.[195]  In 15% of patients, AML presents with retroperitoneal hemorrhage (Wunderlich syndrome), which can be life-threatening.[195, 201]  Previous studies have shown that tumor size of 4 cm or greater is the most significant predictor of tumor rupture; it is therefore recommended that asymptomatic AML larger than 4 cm be treated in order to prevent their rupture.[201]  Although rare, AML-related renal hemorrhage during pregnancy may result in fetal or maternal demise; thus this guideline is particularly recommended for women of child-bearing age who desire to become pregnant.[195, 202]

 

Given the generally benign nature of AML, and given the propensity for multiple or recurrent tumors in TS patients, preservation of renal function is a paramount concern in treatment planning.  Nephron-sparing techniques such as partial nephrectomy[199, 203, 204] or vascular embolization[205, 206] are thus preferred to radical nephrectomy in most patients, particularly children and young adults.  Although it is more invasive than vascular embolization, partial nephrectomy is less likely to result in the need for repeated treatments; up to 40% of embolized tumors require further therapy.[203-206]   

 

Metanephric tumors: Metanephric Adenoma, Metanephric Adenofibroma, & Metanephric Stromal Tumor
Metanephric tumors represent a spectrum of tumor pathology, varying based on the relative proportion of stroma and epithelium. Some authors have suggested that these tumors represent the most hyperdifferentiated, mature form of WT.[207]   These tumors arise from the renal medulla and are generally benign, although there have been rare (and controversial) reports of malignant behavior.[207, 208]

Metanephric adenoma (MA) is a purely epithelial lesion occurring across a wide range of ages (5 to 83 years in the largest reported series).  Most patients with MA are adults, though children may be affected as well; there is a roughly 2:1 female predominance.[209, 210]  The tumors are typically solid, though cysts may occur.  Microscopically, these tumors are unencapsulated but well demarcated, and are composed of embryonal epithelial cells forming regular, closely packed tubular structures.  Mitotic activity is rare.[209, 210]  On immunohistochemistry, MA stains positive for WT-1, lending support to its putative connection with WT;[211] further support comes from reported cases of MA occurring in patients with hemihypertrophy.[212]  Clinically, MA tends to be found incidentally or as a palpable mass; approximately 10% of MA patients also present with polycythemia, perhaps due to direct production of erythropoietin.[213]  Given their benign behavior, these tumors are generally best managed by partial nephrectomy.[199]

Metanephric stromal tumor (MST) is a purely stromal lesion occurring predominantly in children (median age 13 months, range 2 days to 11 years), though rare adult cases have been reported.[214, 215]  Both sexes are equally effected.  Like MA, MST are more commonly solid, though 10% demonstrate cystic components, and are typically unencapsulated.[214]  Unlike MA, these centrally-located lesions often infiltrate into the renal pelvis and occasionally into the renal sinus and ureter.[214, 216]  Microscopically, MST is also superficially infiltrative, enclosing native renal tubules and vessels in an “onion-skinning” pattern; these “collarettes” are typically surrounded by bland spindle cell fascicles.  Because of their tendency to entrap entire glomeruli, MST induce juxtaglomerular cell hyperplasia in up to 25% of affected kidneys, resulting in rennin-dependent hypertension. On immunohistochemistry, MST tends to stain positive for CD34 and vimentin.[214]  MST has been hypothesized to arise from intralobar nephrogenic rests, further supporting the connection between WT and metanephric tumors.[207, 214]  Clinically, these tumors may present with a palpable renal mass or with hematuria due to renal pelvis involvement; MST are generally treated with nephrectomy, though partial nephrectomy may be an adequate treatment if negative margins can be achieved.[214-216]  There are no reports of MST exhibiting malignant behavior.[207]

Metanephric adenofibroma (MAF) is a biphasic epithelial & stromal tumor, with a varying ratio of epithelium to stroma.[217, 218] Although the stromal component is identical to the bland spindle cell stroma seen in MST, the epithelial component may be more mitotically active than MA.[217, 218]   Importantly, either WT and papillary RCC may arise from the epithelial component of MAF,[217] and spindle-cell sarcomas (dubbed “metanephric adenosarcoma”) may arise from the stromal component.[219]  Similar to MA and MST, MAF is also unencapsulated, but with indistinct borders.  These tumors generally presents in children, though adults may be affected (median age 2.5 years, range 5 months to 36 years); males are more commonly affected (male to female ratio 2:1).[217]  As with MST, most patients have been treated with radical nephrectomy, though partial nephrectomy is likely a reasonable option provided that negative margins can be obtained.  Because most of the reported patients were initially diagnosed with WT, most received adjuvant chemotherapy; it is thus impossible to comment on the natural history of patients treated with surgery alone.  However, prognosis in patients with available follow-up has been universally excellent.[217]

Cystic Kidney Tumors: Cystic Nephroma, Cystic Partially Differentiated Nephroblastoma, Cystic Renal Cell Carcinoma, and Mixed Epithelial Stromal Tumors

Cystic renal tumors are relatively uncommon among young children, accounting for 0.5% of the renal tumors reported to both NWTSG and SIOP.[220, 221]  The first description of these tumors was published in 1892;[222] since then, however, the classification of these entities has proven controversial.[223-226]  Although they are considered as separate entities under the 2004 WHO classification, some authors have suggested that Cystic Nephroma (CN), Cystic Partially Differentiated Nephroblastoma (CPDN), and Mixed Epithelial Stromal Tumors (MEST) represent a pathologic spectrum which may be related to WT.[225, 226]  In general, these tumors follow a benign course, with surgical resection alone typically sufficient to ensure a cure.[220, 221, 224, 227, 228]

Like many renal tumors, CN can occur in adults or children.  While in adults CN occurs far more commonly in women (female to male ratio 8:1), the opposite is true in children (female to male ratio 1:2).[226]  In children, these tumors often present as a palpable abdominal mass at a median 18 months of age.[221, 224, 229]  Pathologically, CN is defined according to the criteria of Joshi and Beckwith[224] as a discrete cystic tumor, well-demarcated from the normal non-cystic renal parenchyma, without significant solid components.  The cysts are lined by flattened, cuboidal, or hobnail epithelium, while the septa contain only fibrous tissue or well-differentiated renal tubules.[224]  Owing to their benign clinical course and well-demarcated structure, these tumors can be removed using nephron-sparing surgery with no need for adjuvant chemotherapy.[227, 230
Similar to pediatric CN, CPDN occurs predominantly among boys, with a 3:1 male to female ratio.[220]  These tumors also present similarly to WT and CN, most commonly as a palpable abdominal mass at a median age of 16 months.[220, 224]  CPDN is pathologically quite similar to CN, with the primary difference between the two being the presence of immature or blastemal cells in the septa of CPDN.[223, 224]  Two pathologic subtypes of CPDN, conventional and papillonodular, have been described.[228]  Also similar to CN, CPDN follows a generally benevolent course with few reported tumor recurrences following surgical removal, which can be performed by either partial or radical nephrectomy.[220, 221

MEST is another tumor which is clinically and pathologically similar to CN; several authors have proposed that these tumors are in fact the same identity.[225, 226, 231]  However, unlike CN or CPDN, MEST occurs almost exclusively in adults, and as such will not be discussed in detail here.
Lastly, multilocular cystic RCC can also occur among children, though they are markedly more common among adults.[232, 233]  Cystic RCC is pathologically and taxonomically distinct from other pediatric cystic neoplasms such as CN or CPDN,[223, 233] and is generally considered to be a rare variant of clear cell RCC.[232, 234]  Cystic RCC can occur in the setting of genetic predisposition, such as VHL or TS, or in the setting of acquired renal conditions such as acquired cystic kidney disease.  Importantly, cystic RCC is characterized by a uniformly good prognosis following surgical resection by partial or radical nephrectomy.[232-234

Miscellaneous Rare Renal Tumors
Intrarenal Neuroblastoma
Although neuroblastoma has been previously reported to arise from within the kidney parenchyma,[235, 236] this entity is described in detail elsewhere in this text and we will therefore refrain from discussing it further here.  

Desmoplastic Small Round Cell Tumor
            Desmoplastic Small Round Cell Tumor (DSRCT) is an uncommon but aggressive tumor, with roughly 150 cases described since the original report in 1989.[237]  DSRCT most commonly arises from the peritoneal serosa, with roughly 25% of tumors found in genitourinary sites.[237, 238]  Rarely, these tumors may originate within the renal parenchyma.[239]  Regardless of site of origin, DSRCT is characterized by a single chromosomal translocation, t(11;22)(p13;q12).  This translocation results in the fusion of exon 7 of the Ewing sarcoma gene with exon 7 of Wilms’ tumor suppressor gene, leading to a unique gene fusion product, EWS-WT1.[240-242

As the name implies, DSRCT are microscopically characterized by sheets of abundant small undifferentiated cells with scant cytoplasm and hyperchromatic nuclei.  DSRCT of the kidney typically demonstrates abundant mitotic figures and prominent apoptosis and necrosis.  The tumors are unencapsulated, and tumor borders are uniformly infiltrative.[239, 241]  Because the histologic appearance of DSRCT can easily be confused with other tumor types, notably blastema-predominant WT and PNET,[243] the diagnosis of DSRCT should be applied to a primary renal tumor only in the presence of EWS-WT1staining.[239]
With the exception of a single case report in an adult,[244] DSRCT of the kidney occurs in young children (mean age 6.8 years), and, in contradistinction to extrarenal DSRCT, is slightly more common in girls.[239, 245]  Tumors tend to appear hypovascular, heterogeneous, and well-circumscribed by ultrasound and computed tomography.[246]  Although extrarenal DSRCT has a dismal prognosis, 2 of 4 reported patients had no evidence of disease at last follow-up, while the remaining 2 have had a stable clinical course following multi-modality therapy.[239

Primitive Neuroectodermal Tumor
            Primitive Neuroectodermal Tumor (PNET) is thought to be a part of the Ewing’s sarcoma family, most commonly found in bone or soft tissue.  Although Ewing’s is a relatively common tumor, primary intrarenal PNET is quite rare, with roughly 50 pediatric cases reported in the literature.[247-252]  PNET is frequently noted to have one of two balanced chromosomal translocations (t(11;22)(q24;q12) and t(21;22)(q22;q12)), which result in fusion of the EWS gene with FLI1 or ERG, respectively.[253]  These gene fusion products are expressed in >95% of tumors and can be readily detected by FISH or PCR for diagnostic purposes.[249, 250
            Intrarenal PNET typically occurs in adolescents or young adults at a median age of 24 years (range 4 to 66 years).[247]  Histologically, intrarenal PNET is identical to PNET in other locations, with sheets or rosettes of small ovoid cells and a high nuclear to cytoplasmic ratio.[251]  Strong membrane immunohistochemical staining for CD99 is a nearly universal feature.[248
PNET typically presents with abdominal or flank pain, hematuria, or the presence of a palpable mass; most tumors are detected at an advanced stage.[247, 248]  Inferior vena cava thrombi are not uncommonly present (33%) at the time of diagnosis, as are metastases to the lymph nodes (25%), lung (20%), and liver (14%).[247, 249]  Of patients with available follow-up data, 43% had died of disease within 2 years of their diagnosis, despite an aggressive multi-modality treatment regimen.

Anaplastic Sarcoma of the Kidney
            Anaplastic Sarcoma of the Kidney (ASK) has only recently been described as a distinct pathologic entity.[254]  These tumors are quite rare with only 21 reported cases,[254, 255]  and may be confused with anaplastic WT.  Grossly, ASK is typically a large, soft, and friable tumor, with mixed cystic and solid architecture in one-third of cases.  Histologically, these tumors consistently demonstrate a spindle cell component arranged in fascicles; as the name implies, anaplasia is universally present, with “bizarre, pleomorphic, multinucleated” cells commonly present.  Chondroid differentiation is commonly present, and ASK tumors often stain positive for vimentin and desmin.[254]

 ASK occurs at a median age of 5 years (range 10 months to 41 years), with a slight female predominance (female to male ratio 1.5 to 1).[254]  A palpable renal mass and/or flank pain are the most common presenting symptoms, with hematuria occurring less frequently.  The most common sites of metastases were lung (15%), liver (10%), and bone (10%). Of 14 patients with known follow-up, 3 (21%) had died at a mean 1.6 years after diagnosis; the remaining 11 (79%) were alive at a mean follow-up of 7.4 years.[254, 255]

Miscellaneous Rare Primary Renal Tumors
In addition to the non-WT pediatric primary renal tumors detailed above, multiple other neoplastic entities have been reported to rarely originate within the kidney parenchyma.  These include tumors which are typically extrarenal or typically occur in adults, such as synovial sarcoma,[256, 257] rhabdomyosarcoma,[258] lymphoma,[259, 260] leiomyosarcoma,[261] liposarcoma,[262] malignant fibrous histiocytoma,[263] and even melanoma.[264]  However, it should be noted that these tumors are prohibitively rare among children. 

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