Paediatric renal tumors: An insight into molecular characteristics, histomorphology and syndromic association

Abstract

Paediatric renal tumors are rare and accounts for about 7% of all paediatric malignant tumors. The spectrum of paediatric renal tumors ranges from benign to malignant. Benign tumors include cystic nephroma, metanephric tumors and ossifying renal tumor of infancy. Tumor with low grade malignancy includes mesoblastic nephroma. Malignant tumors are nephroblastoma, clear cell sarcoma, malignant rhabdoid tumor, anaplastic sarcoma and Ewing sarcoma. Additionally, there are molecularly defined renal tumors, which includes renal cell carcinoma (RCC) with MiT translocations, ALK-rearranged RCC, eosinophilic solid and cystic RCC and SMARCB1- deficient renal medullary carcinoma. These tumors apart from having characteristic clinical presentation and histomorphology, also carry typical molecular mutations and translocations. Certain renal tumors have association with various genetic syndromes such as Beckwith-Weidmann syndrome, Wilm’s tumor, aniridia, genitourinary anomalies and mental retardation syndrome, Denys-Drash syndrome, rhabdoid tumor predisposition syndrome and DICER syndrome. This review article focusses on molecular characteristics, histomorphology and syndromic association of pediatric renal tumors, their immunohistochemical approach to diagnosis with recent updates in molecularly defined renal tumors.

Key Words: Genetic syndrome; Immunohistochemistry; Paediatric; Renal tumor; Benign; Malignant; Molecular characteristics

Core Tip: This article outlines about paediatric renal tumors. They can have asymptomatic to symptomatic presentation. Every tumor has its own unique histomorphology, immunohistochemistry and molecular pathology. Certain tumors have association with genetic syndromes, which makes it prognostically more challenging for children. Knowledge and awareness of these tumors are essential for their accurate diagnosis and early treatment.

INTRODUCTION

Renal tumors are rare in children and comprise approximately 7% of all paediatric malignant tumors. Renal tumors have variable presentation. At times they are detected incidentally and sometimes present with abdominal mass, pain or haematuria[1,2]. Renal tumors are heterogenous group of tumors, with each having their own treatment, prognosis, and relationship to genetic predispositions[2]. The spectrum of paediatric renal tumors ranges from benign to malignant[3]. Benign tumors include cystic nephroma, metanephric tumors and ossifying renal tumor of infancy (ORTI). Tumor with low grade malignancy includes mesoblastic nephroma (MN). Malignant tumors are nephroblastoma, clear cell sarcoma, malignant rhabdoid tumor, anaplastic sarcoma and Ewing sarcoma[4-6].

Molecularly defined renal tumors includes renal cell carcinoma (RCC) with MiT translocations, ALK driven RCC, Eosinophilic, solid and cystic (ESC) RCC (TSC related) and SMARCB1-deficient renal medullary carcinoma[6]. Various syndromes associated with increased risk of childhood renal tumors are DICER syndrome, rhabdoid tumor predisposition syndrome (RTPS) Denys–Drash syndrome, Wilm’s tumor, aniridia, genitourinary anomalies and mental retardation (WAGR) syndrome and Beckwith-Weidmann syndrome[7-11].

The tumors can be unilateral or bilateral. Majority of the childhood renal tumors are unilateral; except paediatric cystic nephroma which can be bilateral in 25% cases and nephroblastoma which can occur bilateral in 5%-8% of cases[12-13].

BENIGN TUMORS OR TUMORS OF LOW MALIGNANT POTENTIAL

Paediatric cystic nephroma

It is a benign uncommon renal cystic neoplasm[7,14]. It is generally observed in children younger than 4 years old[14]. It accounts for 2%-3% of primary renal tumors[15]. The tumors can present as a palpable abdominal lump or can be found during screening in a child who has a germline DICER1 mutation. The tumors are large, well-defined, comprised of cysts that vary in size and shape and lack solid nodules. The cysts contain clear fluid[7]. On histopathology, the lesion consists of cysts separated by fibrous septa; the cystic spaces are lined by flattened cuboidal epithelium, often showing hob nailing at places. Matured renal tubules are sometimes present surrounding the septae. These lesions lack blastemal component, if present, then they categorized as-cystic partially differentiated nephroblastoma[7]. The subepithelial stromal cells are Estrogen Receptor positive[16]. Molecularly paediatric cystic nephroma exhibits DICER1 mutation[12]. Paediatric cystic nephroma are associated with DICER syndrome, which is autosomal dominant characterized by mutation in DICER gene[7,17].

The endoribonuclease Dicer protein of the ribonuclease III family is encoded by the DICER1 gene, which is situated on chromosome 14. DICER 1 syndrome is a rare autosomal dominant genetic disorder that predisposes the patients to both benign and malignant tumors. It has been identified that DICER1 germline mutations are nonsense mutations, which results in truncated proteins or nonsense-mediated RNA degradation as well as forming stop codons within the coding sequence. The spectrum of lesions observed in DICER 1 syndrome includes multinodular goiter, pleuropulmonary blastoma, cystic nephroma, Sertoli-Leydig cell tumors, Hodgkin lymphoma, pinealoblastoma, global developmental delay, lung cysts, Wilms tumors and macrocephaly[18].

On imaging study [computed tomography (CT)/magnetic resonance imaging (MRI)], the tumors appear as multilocular, cystic lesion frequently having pseudocapsule. Its differential diagnosis includes cystic Wilm’s tumors[7]. These tumors are treated by complete nephrectomy and have an excellent prognosis[19]. Table 1 outlines molecular characteristics of paediatric renal tumors.

Table 1 Molecular characteristics of paediatric renal tumors.

Renal tumor	Molecular feature
Paediatric cystic nephroma	DICER1 mutation[12]
Metanephric adenoma	BRAFV600E mutation[25]; KANK1::NTRK3 gene fusion in BRAF negative cases[26]
Metanephric stromal tumor	BRAFV600E mutation[32]
Metanephric adenofibroma	BRAFV600E mutation[35]
Ossifying renal tumor of infancy	Clonal trisomy 4[39]
MN	(1) Cellular MN: t(12;15)(p13;q25) resulting in fusion of ETV6 and NTRK3 genes[45]; (2) Classic MN: EGFR ITD[47] (3) Mixed MN: Either EGFR ITD or ETV6::NTRK3 gene fusion[47]
Nephroblastoma (Wilms tumor)	Genetic changes in WT1, CTNNB1, IGF2, TP53, MYCN genes and 1q gain[56]
Malignant rhabdoid tumor of the kidney	Biallelic inactivation of SMARCB1/INI1[65]
Clear cell sarcoma of the kidney	(1) BCOR-ITD exon 15[74]; (2) YWHAE: NUTM2 gene fusion[76]; (3) BCOR::CCNB3 gene fusion[75]
Anaplastic sarcoma of the kidney	DICER 1 and RNAase IIIb mutation[82]
Renal Ewing sarcoma	(1) t(11;22)(q24;q12) resulting EWSR1-FLI1 fusion[89]; (2) t(21;22)(q22;q12) resulting in EWSR1-ERG fusion[90]
Renal cell carcinoma with MiT translocations	TFE3 rearranged RCCs-fusion of TFE3 with other genes like ASPL, PRCC, PSF, CLTC[93]; TFEB rearranged RCCs-MALAT1 (Alpha)::TFEB fusion[94]
ALK-rearranged renal cell carcinomas	VCL-ALK fusion[98]; TPM3-ALK fusion [97]; Rarely STRN-ALK, EML4-ALK, HOOK1-ALK fusions[96,99]
Eosinophilic solid and cystic renal cell carcinoma	Biallelic somatic mutations of TSC1 or TSC2 genes[106]
SMARCB1-deficient renal medullary carcinoma	Inactivation of SMARCB1 gene[112]

MN: Mesoblastic nephroma; ITD: Internal tandem duplication.

Metanephric adenoma

Metanephric adenomas are asymptomatic benign tumors, mostly diagnosed incidentally. They can be found in the age range of 5 to 84 years. It is very rare, comprising less than 0.5% of all kidney tumors. Fever, haematuria, abdominal pain and mass are presenting symptoms, if patients are symptomatic. Characteristically, at times, these patients present with polycythaemia, due to increased erythropoietin production by the neoplasm[20]. Grossly, the tumors are unifocal, well circumscribed, unencapsulated, grey white and soft to firm. Numerous calcified areas can be seen[21].

Microscopically, MA is made up of uniformly arranged, closely spaced, small epithelial cells, having round regular nuclei and high nucleus: Cytoplasmic ratio. The tumor is mitotically inactive[22]. Psammomatous calcifications can be seen[23]. Immunohistochemically, the tumor shows dual expression for WT1 and CD57[24]. The immunohistochemical approach for definitive diagnosis is summarized in Table 2.

Table 2 Immunohistochemistry of paediatric renal tumors.

Renal tumor	Immunohistochemistry expression
Paediatric cystic nephroma	ER positive[16]
Metanephric adenoma	WT1 and CD57 positive[24]
Metanephric stromal tumor	CD34 positive[29,31]
Metanephric adenofibroma	CD34 positive[33]
Ossifying renal tumor of infancy	EMA and Vimentin positive [38]
Nephroblastoma (Wilms tumor)	The blastemal component is WT1 and PAX8 positive; the epithelial component is cytokeratin and Epithelial Membrane Antigen and positive; stromal component is vimentin positive[2]
Malignant rhabdoid tumor of the kidney	SMARCB1/INI1 loss[64]
Clear cell sarcoma of the kidney	Cyclin D1 and BCOR positive[73]
Renal Ewing sarcoma	CD99 and NKX2-2 positive[87-88]
Renal cell carcinoma with MiT translocations	TFE3 positive[92]
ALK-rearranged renal cell carcinomas	ALK positive, INI1/SMARCB1 retained[97]
Eosinophilic solid and cystic renal cell carcinoma	CK20 and PAX8 positive whereas CK7 and C-kit negative[105]
SMARCB1-deficient renal medullary carcinoma	PAX8, Epithelial Membrane Antigen and vimentin positive [110]; SMARCB1/INI1 loss[111]

The most common molecular pathology observed is BRAFV600E mutation[25]. However, two cases have been reported having KANK1::NTRK3 gene fusion due to t(9;15)(p24;q24) translocation; seen in BRAF negative cases[26].

Its differential diagnosis includes solid subtype of low-grade papillary RCC and epithelial-predominant Wilm’s tumors. Metanephric adenomas are diagnosed on routine histopathological examination of the excised mass[24]. The treatment of choice is surgical resection and prognosis is better with disappearance of associated polycythaemia. However, passive seeding into perinephric lymph nodes has also been reported[27].

Metanephric stromal tumor

It is a rare benign mesenchymal renal tumor, diagnosed at 2 years of age[28]. Till date, less than 50 cases are reported in the literature. Most patients present with an abdominal mass; however, a small number of cases show signs of extrarenal vasculopathy, such as bleeding and hypertension[29]. McDonald et al[30] reported a case describing occurrence of metanephric stromal tumor in NF-1 patient; the patient had hypertension and the metanephric stromal tumor revealed Juxtaglomerular (JG) cell hyperplasia and florid angiodysplasia.

On histopathology, the tumor has a nodular appearance, scallop-like border, and onion skin cuffing around entrapped tubules. Vascular changes include angiodysplasia and JG cell hyperplasia. In 20% cases, heterologous elements such as glial and chondroid tissue are observed[31]. The tumor is CD34 positive[31,29]. Molecularly, the tumor has BRAFV600E mutation[32].

Its close differential is metanephric adenofibroma. These tumors are diagnosed on routine histopathology. Surgery is the main treatment and patients have a favorable outcome[29].

Metanephric adenofibroma

Metanephric adenofibroma is a rare biphasic renal tumor composed of epithelial and stromal components. It was previously termed as “nephrogenic adenofibroma”[33]. Patients present with haematuria and polycythaemia. Their age of presentation ranges from 13 months to 36 years. Less than 30 cases have been documented[34]. Microscopically, the tumor has dual epithelial and stromal components. The epithelial component has uniform small cuboidal cells with hyperchromatic nuclei and scant cytoplasm, forming tubules at places. The stromal component display spindle shaped cells having tapered hyperchromatic nuclei; strongly positive for CD34[33]. The molecular pathology of metanephric adenofibroma involves BRAFV600E mutation[35].

Its differential includes metanephric adenoma and metanephric stromal tumor. Metanephric adenofibroma is diagnosed on histopathological examination. The treatment of choice is excision and patients have benign course with good prognosis. Interestingly, one case of metanephric adenofibroma in combination with Wilms tumors and RCC has been reported[36].

ORTI

ORTI is an intracalyceal neoplasm with male preponderance. ORTI is very rare, with approximately 25 cases reported in literature. It is diagnosed in children 6 days to 2.5 years of age. Patients present with haematuria[37]. On microscopic examination, the tumor is composed of osteoblast-like cells (ossifying component); small undifferentiated blastemal like cells and sometimes spindle cells. Mitotic activity can also be observed in few cases. The osteoblast-like cells show strong immuno-expression for Epithelial Membrane Antigen (EMA) and Vimentin[38]. Clonal trisomy 4 is seen in ORTI[39]. Diagnosis is made on histopathology. On imaging, it is seen as a calcified pelvic mass[40]. Very rarely, its differential can be Wilm’s tumors with predominant heterologous osteoid differentiation. Conservative surgical care is adequate. Prognosis is favourable. Evidence of recurrence or metastasis has not been reported yet[41].

MN

Earlier it was known as congenital MN. MN accounts for 3%-4% of childhood renal tumors[42]. Most of the cases have been reported in first 9 months of life[43]. MN virtually never arises after the age of 3 years. Clinically, children present with abdominal mass[44]. It includes three subtypes: Cellular, classic and mixed[45]. Majority of the cases are diagnosed within first 9 months of life[43]. On histopathology, each subtype of MN has specific microscopic morphology.

Cellular MN: This is the most common subtype, comprising 65% cases. On gross examination, the tumor and renal parenchyma can be distinguished easily. Microscopically, the tumor is highly cellular, comprised of plump cells arranged in sheets, have vesicular nuclear chromatin, moderate cytoplasm and increased mitotic activity[46].

Classic MN: It comprises 25% of MN. In classic MN, a clear demarcation between tumor and renal parenchyma cannot be appreciated as the tumor cells are seen protruding into the renal parenchyma as finger like fashion. Islands of hyaline cartilage can be seen at tumor-parenchymal junction. The tumor displays spindle cells with collagen deposition, dilated thin-walled blood vessels and low mitotic activity[46].

Mixed MN: It comprises 10% of MN and includes features of both subtypes in varying amounts[46]. Similar to histopathology, each subtype of MN exhibits specific molecular abnormality.

Cellular MN: Chromosomal translocation t(12;15)(p13;q25) resulting in fusion of ETV6 and NTRK3 fusion genes[45].

Classic MN: EGFR internal tandem duplication (ITD)[47].

Mixed MN: Either EGFR ITD or ETV6::NTRK3 gene fusion[47].

MN can be diagnosed prenatally on ultrasound and has been shown to be associated with polyhydramnios[44]. Its differential diagnosis includes Wilms tumor and neuroblastoma[48].

Treatment for MN is nephrectomy with surgical margin clearance. Chemotherapy is routinely not administered. Overall, children have an excellent prognosis. Very rarely, patients can have local relapse and metastasis to lung, liver and brain[44,49].

MALIGNANT TUMORS

Nephroblastoma (Wilms tumor)

It is a malignant embryonal tumor, usually diagnosed at the age of 3-4 years with slight female preponderance[50]. It is the most common pediatric renal cancer affecting 1 in 10000 children[50,13]. Its precursor lesion is nephrogenic rests, which is present in more than 90% of bilateral tumors and approximately 40% of unilateral tumors[51,52]. Classically, it is a triphasic tumor which includes three components - blastemal, stromal and epithelial[53]. Teratoid Wilm’s tumor is termed when there is predominance of heterologous elements in the tumor tissue, such as glial, adipose, muscle, cartilage or bone. Children generally present with an abdominal mass[54].

The most important histological parameter in Wilm’s tumor is anaplasia, its presence indicates high-risk tumor with worse prognosis. Anaplasia includes three characteristic features- hyperchromatic nuclei, marked nuclear enlargement with nuclear diameter at least three times those of neighboring cells and presence of enlarged atypical tripolar or multipolar mitotic figures. Anaplasia is further subdivided into focal or diffuse[55].

On immunohistochemistry, the blastemal component is positive for WT1 and PAX8; the epithelial component shows strong immunoexpression with cytokeratin and EMA whereas stromal component immunostains with vimentin[2].

Molecularly, Wilms tumor has several genetic changes, such as in WT1 on chromosome 11p13, CTNNB1 on chromosome 3p22, IGF2 on chromosome 11p15, TP53 on chromosome 17p13, MYCN on chromosome 2p24and 1q gain[56]. According to our literature search, we found that Wilms tumor has been associated with multiple syndromes such as WAGR syndrome, Denys–Drash syndrome, Beckwith–Wiedemann syndrome and Simpson-Golabi-Behmel Syndrome Type I[9-11,57].

The genetic syndromes associated with various paediatric renal tumors are described in Table 3 highlighting their specific renal and extra-renal manifestations.

Table 3 Genetic syndromes associated with paediatric renal tumors.

Genetic syndromes	Renal tumors	Extra renal manifestations	Ref.
DICER 1 syndrome	Wilms tumor, cystic nephroma, anaplastic sarcoma of kidney	Pinealoblastoma, pleuropulmonary blastoma	Caroleo et al[83]
WAGR syndrome	Wilms tumor	Aniridia, genitourinary anomaly, developmental delay	Hol et al[10]
Denys–Drash syndrome	Wilms tumor, rapid progressive nephropathy	Male pseudo-hermaphroditism	Kucinskas et al[9]
Beckwith–Wiedemann syndrome	Wilms tumor	Hepatoblastoma, neuroblastoma, hemihypertrophy, macroglossia, macrosomia, organomegaly, omphalocele	MacFarland et al[11]
Simpson-Golabi-Behmel Syndrome Type I	Wilms tumor	Hepatoblastoma, adrenal neuroblastoma, macrocephaly, cardiovascular and skeletal abnormalities, visceromegaly	Tenorio et al[57]
Rhabdoid tumor predisposition syndrome	Malignant rhabdoid tumor of the kidney	Malignant rhabdoid tumors at various sites like central nervous system, liver, bladder, mediastinum	Nemes et al[66]

Various studies have been conducted for understanding the management of Wilms Tumor. Amongst these, the two most revolutionizing studies were NWTS and SIOP. The National Wilms Tumor Study (NWTS), a cancer research co-operative group was formed in 1969 which emphasized on upfront surgery principle. NWTS conducted five trials, of which NWTS 1 to NWTS 4 were randomized trial whereas NWTS 5 was purely clinical trial. Each NWTS trial had a specific purpose to study, such as NWTS 1 was to ascertain how surgical technique affects the course of treatment; NWTS 2 studied the prognosis; NWTS 3 focused on reducing the course of treatment for low-risk individuals while developing more effective chemotherapy for patients who are at high-risk for relapse; NWTS 4 studied the efficacy, toxicity and cost of administration of various regimens and NWTS 5 was for identifying prognostic factors. Another group was Societe Internationale D'oncologie Pediatrique (SIOP) which started study on Wilms Tumor in 1971. SIOP gave the concept of providing preoperative chemotherapy in all stages to the patients. Preoperative chemotherapy will shrink the tumor size and would reduce the chances of intra-operative rupture of tumor. However, some researchers believe that pre-nephrectomy chemotherapy might alter the tumor's histology and would downstage the tumor[58].

For Wilms tumors, at present, Children's Oncology Group (COG) and SIOP protocols are being followed which uses a wide range of prognostic factors for guiding treatment. Stage, tumor histology, patient age, tumor weight, completeness of lung nodule response, and loss of heterozygosity at chromosomes 1p and 16q are prognostic criteria employed in the current COG research. Whereas, the current SIOP studies use tumor stage, histology, tumor volume, and therapeutic responsiveness as prognostic parameters[59].

Diagnosis of Wilms tumors can be made by combination of imaging techniques (such as ultrasound/CT scan/MRI abdomen)[60]. Triphasic Wilms tumors can easily be diagnosed on histopathology. However, monophasic component makes challenging; in such cases application of immunohistochemistry markers along with molecular study helps to arrive at a conclusive diagnosis. It should also be noted that before concluding a tumor as monophasic nephroblastoma, extensive grossing of excised mass from all representative areas should be undertaken to avoid any error. Differentials for pure blastemal Wilms tumor includes neuroblastoma, Ewing sarcoma; for pure epithelial component is metanephric adenoma, hyperplastic perilobar nephrogenic rests; and for pure stromal type includes MN and metanephric stromal tumors[2]. Treatment for nephroblastoma includes multimodal approach of chemotherapy, surgical excision and radiotherapy (if necessary)[59]. Overall survival is 90%; relapse can be seen in 15% children[61].

Malignant rhabdoid tumor of the kidney

This is the most aggressive renal parenchymal tumor, diagnosed at around 1 year of age[62]. Malignant rhabdoid tumor of the kidney (MRTK) are extremely rare tumors accounting for 2% of all paediatric renal tumors. Generally, children present with an abdominal mass. Histopathologically, various patterns are observed in MRTK, which includes classical, sclerosing, epithelioid, spindled or mixed. The individual tumor cells have large eccentrically placed vesicular nuclei with prominent nucleoli and abundant eosinophilic cytoplasm. Mitotic activity is high[63]. On immunohistochemistry, the tumor cells display loss of nuclear staining with SMARCB1/INI1[64].

Molecularly, MRTK are characterized by biallelic inactivation of SMARCB1/INI1 gene located on chromosome 22q11.23 occurring due to mutation, chromosomal deletion or loss of heterozygosity[65]. MRTK is classically associated with RTPS[66]. It is further subdivided into RTPS type 1 and RTPS type 2. RTPS type 1 involves mutation in SMARCB1 gene whereas RTPS type 2 occurs when mutation occurs in SMARCA4 gene[8].

Very rarely, its differential diagnosis can be renal medullary carcinoma[65]. Histopathological examination with loss of INI1 marker is diagnostic for MRTK. Imaging studies are not useful[67]. Since, there is no standard treatment established yet, majority of patients are currently treated using intense multimodal regimens that combine early surgical excision of the primary tumor, chemotherapy and local radiotherapy, or high dose chemotherapy followed by autologous stem-cell rescue[68]. These tumors carry a poor prognosis[69].

Clear cell sarcoma of the kidney

It is a rare malignant tumor, generally arising in the renal medulla. Previously, it was also termed as “bone metastasizing renal tumor of childhood” because of its predilection for bony metastasis; but this terminology is no more recommended. Children present with palpable abdominal mass[70]. These tumors are generally diagnosed at 3 years of age. It accounts of 3%-5% of pediatric malignant renal tumors[71]. On microscopy, clear cell sarcoma of the kidney (CCSK) exhibits various patterns. The most common pattern includes classic - characterized by plump ovoid tumor cells with dispersed nuclear chromatin and clear cytoplasm. The tumor cells are arranged in nests or trabeculae and are separated by arborizing fibrovascular septae[72]. Other patterns include myxoid, cellular, epithelioid, spindled, storiform, anaplastic and palisading verocay body[71]. On immunohistochemistry, the tumor cells show dual nuclear positivity for Cyclin D1 and BCOR[73].

The molecular pathology of CCSK includes three mutations[74-76]: BCOR ITD exon 15; BCOR::CCNB3 gene fusion; YWHAE::NUTM2 gene fusion.

Its differential includes stromal predominant Wilms tumors[2]. Diagnosis is made on histopathology. Imaging study helps to locate origin of tumors. Nephrectomy followed by post operative chemotherapy (doxorubicin) and flank radiation therapy is the treatment administered in CCSK patients[71,77]. Prognosis is variable. Approximately 15% of patients experience relapse[78].

Anaplastic sarcoma of the kidney

Anaplastic sarcoma of the kidney is a rare tumor, usually presenting with a large renal mass[79]. The age range of the patients is 10 months to 41 years. Less than 30 cases are reported in the literature. On microscopy, the tumor has cystic and solid sarcomatous areas. Predominantly, the tumor is comprised of sarcomatous component having tumor cells with large hyperchromatic pleomorphic nuclei; surrounded by cystic component at periphery. Malignant cartilaginous and embryonal rhabdomyosarcoma foci can also be present[80-81]. Two mutation patterns are observed in these tumors, DICER 1 and RNAaseIIIb mutation[82]. DICER1 syndromic association has been reported[83].

Histopathology is main diagnostic modality. Its closest differential includes anaplastic Wilms tumors, mesenchymal chondrosarcoma and sarcomatoid RCC[81]. Due to very less number of reported cases and lack of follow up of patients; standardized treatment care and prognosis still needs to be determined. However, surgical removal of mass followed by chemotherapy / radiotherapy are being tried. In reported cases, survival rate is around 75%[84,80]. Table 4 outlines the common modes of presentation of paediatric renal tumors.

Table 4 Modes of presentation of paediatric renal tumors.

Renal tumor	Presentation
Paediatric cystic nephroma	Palpable abdominal lump[7]
Metanephric adenoma	Asymptomatic to symptomatic (fever, haematuria, abdominal pain and mass), polycythaemia[20]
Metanephric stromal tumor	Abdominal mass, extrarenal vasculopathy, such as bleeding and hypertension[29]
Metanephric adenofibroma	Haematuria and polycythaemia[34]
Ossifying renal tumor of infancy	Haematuria[37]
Mesoblastic nephroma	Abdominal mass[44]
Nephroblastoma (Wilms tumor)	Abdominal mass[54]
Malignant rhabdoid tumor of the kidney	Abdominal mass[63]
Clear cell sarcoma of the kidney	Abdominal mass[70]
Anaplastic sarcoma of the kidney	Large renal mass[79]
Renal Ewing sarcoma	Abdominal pain, mass, hematuria[85]
Renal cell carcinoma with MiT translocations	Asymptomatic to symptomatic abdominal pain and haematuria[92]
ALK-rearranged renal cell carcinomas	Haematuria, abdominal pain or periumbilical pain[96]
Eosinophilic solid and cystic renal cell carcinoma	Asymptomatic[103]
SMARCB1-deficient renal medullary carcinoma	Haematuria, flank or abdominal pain, dysuria, weight loss[107]

Renal Ewing sarcoma

It is an extremely rare tumor seen in children and adolescents with median age of diagnosis being 27 years. Patients present with nonspecific symptoms like abdominal pain, mass and haematuria. According to one study, primary renal Ewing sarcoma accounts for 1.5% of all Ewing sarcoma cases[85]. The tumor is characterized by small round blue tumor cells, having round monomorphic nuclei, with fine stippled chromatin, inconspicuous nucleoli and scant clear to eosinophilic cytoplasm. Homer-Wright pseudo rosettes can be seen[86]. On immunohistochemistry, the tumor cells show membranous CD99 and nuclear NKX2.2 expression[87,88].

Molecularly, two types of translocations are observed in these tumors[89,90]: t(11;22)(q24;q12) resulting in fusion of EWSR1-FLI1; seen in 85%-90% cases. t(21;22)(q22;q12) resulting in fusion of EWSR1-ERG; seen in 5%-10% cases.

Differential diagnosis can be other small round cell tumors such as blastemal predominant Wilms tumor and neuroblastoma[2]. Histopathological examination with immunohistochemistry and molecular confirmation is diagnostic. Treatment includes chemotherapy, radiotherapy and surgery[91]. Prognosis is poor in patients who present with metastasis at the time of diagnosis[85].

MOLECULARLY DEFINED TUMORS

RCC with MiT translocations

The tumor affects children and young adults. The two types of RCCs that belong to the MiT family includes Xp11 translocation RCC with TFE3 gene fusions and t(6;11) RCC with TFEB gene fusions. TFE3 rearranged RCCs comprises about 40% of paediatric RCCs whereas TFEB rearranged RCCs are comparatively less, having only about 100 cases reported in the literature. Prior exposure to cytotoxic therapy is an important risk factor implicated in these tumors. The presentation ranges from asymptomatic to symptomatic abdominal pain and haematuria. TFE3 rearranged RCCs exhibit papillary and alveolar growth pattern, having pseudostratified tumor cells with pleomorphic nuclei and clear to eosinophilic cytoplasm. Psammoma bodies may be seen. The tumor cells are nuclear immunopositive for TFE3. TFEB rearranged RCCs have biphasic appearance comprising large epithelioid cells and small cells around basement membrane[92].

Both TFE3 and TFEB rearranged RCCs exhibit different molecular pathology. TFE3 rearranged RCCs include fusion of TFE3 with other genes like ASPL, PRCC, PSF, CLTC and many more[93]. On the other hand, TFEB rearranged RCCs displays MALAT1 (Alpha)::TFEB fusion[94].

The tumors can be diagnosed on imaging, histopathology, immunohistochemistry and fluorescent in situ hybridization (FISH) analysis. The differential diagnosis includes clear cell RCC, papillary RCC and clear cell papillary RCC. Surgery remains the mainstay treatment for localized tumors including regional nodal metastasis. Immunotherapy and therapies targeting vascular endothelial growth factor receptor are being tried in metastatic cases. Prognosis is variable; prognosis is worse compared to papillary RCC and similar as that of clear cell RCC[95].

ALK-rearranged RCCs

ALK-rearranged RCCs comprises less than 1% of all renal neoplasms. Patients present with haematuria, abdominal pain or periumbilical pain[96]. Patient age ranges from 3 to 85 years. It comprises 3.5%-3.8% of paediatric renal cancers. Microscopically, the tumor cells are infiltrative having vesicular nuclei and small nucleoli. The tumor cells have granular eosinophilic cytoplasm. Mucin pools, lymphoplasmacytic infiltrate and intravascular sickled red blood cells (RBCs) can be found. On immunohistochemistry, the tumor cells are ALK positive. INI1/SMARCB1 is retained in tumor cells[97]. Various fusions with ALK gene observed are VCL-ALK fusion; associated with sickle cell trait[98]. TPM3-ALK fusion; not associated with sickle cell trait[97]. Rarely STRN-ALK, EML4-ALK, HOOK1-ALK fusions[96,99].

Diagnosis can be made by ultrasonography and CT scan. On contrast CT scan, a heterogeneous enhancing mass is seen[96]. Its differential diagnosis includes renal medullary carcinoma[100]. For small tumors confined to kidney, radical nephrectomy or nephroureterectomy is preferred. ALK targeted inhibitors (alectinib) are tried in metastatic cases. The reported cases have limited follow-up; however dramatic responses has been seen in patients who received ALK targeted inhibitors[101].

Eosinophilic solid and cystic RCC

Eosinophilic solid and cystic RCC (ESC-RCC) is a rare and indolent renal tumor that affects female individuals both with and without tuberous sclerosis complex[102]. Around 70 cases are reported in literature. The age of presentation ranges from 14 to 75 years. Patients have mostly asymptomatic presentation[103]. On histopathology, eosinophilic tumor cells are seen arranged in compact nests surrounded by macro and microscopic cysts demonstrating hob nailing pattern of single layered neoplastic cells[104]. On immunohistochemistry, the tumor cells are positive for CK20 and PAX8 whereas negative for CK7 and C-kit[105]. Biallelic somatic mutations of TSC1 (hamartin) or TSC2 (tuberin) genes, resulting in upregulation of mTOR pathway are seen in these tumors[106].

Children are generally asymptomatic and the tumor may be discovered incidentally on routine imaging. Its differential diagnosis includes renal oncocytoma and chromophobe RCC. Surgical resection is the treatment of choice. mTOR pathway inhibitors are tried in metastatic cases[103]. Although there is little follow-up data, surgical resection seems to have cured most ESC-RCCs[106].

SMARCB1-deficient renal medullary carcinoma

Patients have broad age of presentation ranging from childhood to old age. This tumor predominantly involves right kidney and is strongly associated with sickle cell trait patients[107-108]. It comprises less than 0.5% of all renal carcinomas. These patients are always almost symptomatic and present with haematuria, flank or abdominal pain, dysuria and weight loss[107]. The tumor cells are arranged in cords, tubules, sheets and nests. The tumor cells have pleomorphic nuclei, vesicular nuclear chromatin, prominent nucleoli and eosinophilic cytoplasm. Sickled RBCs are present[109]. On immunohistochemistry, the tumor cells are PAX8, cytokeratin, EMA and vimentin positive[110]. SMARCB1/INI1 is lost in tumor cells[111]. Chromosomal translocation or deletion leading to inactivation of SMARCB1 gene are seen in these cases[112].

Histopathology along with immunohistochemistry demonstrating infiltrating high-grade adenocarcinoma with SMARCB1 loss is diagnostic. Its differential diagnosis includes VCL::ALK fusion RCC[100]. Treatment includes radical nephrectomy and chemotherapy administering platinum-based regimens[113]. Prognosis is poor. Most patients present with nodal or liver / lung metastasis at the time of diagnosis[114].

ROLE OF ULTRASOUND GUIDED RENAL MASS BIOPSY

Diagnosis of renal masses can be made safely and accurately using ultrasound guided method which has low rate of non-diagnostic outcome and complications[115]. Apart from routine histopathology and immunohistochemistry, the biopsy can also be utilized for molecular characterization and ancillary techniques. FISH analysis, chromosomal study, microarray technique for understanding gene expression profiling of renal tumors can also be performed[116].

CONCLUSION

This review article summarizes the spectrum of paediatric renal tumors. Every tumor has its own unique histomorphology, immunohistochemistry and molecular pathology. Histopathology followed by immunohistochemistry is always the gold standard for definitive diagnoses of these tumors. Certain tumors have association with genetic syndromes, which makes it prognostically more challenging for children. Thus, management goal should always be early diagnosis of these tumors.