occurring within 12 months of presentation.

•The most common sites of metastasis at presentation are:

–The lungs

–Abdominal lymph nodes

–Liver

–Brain

–Bone

•Malignant rhabdoid tumor of the kidneys has the worst prognosis of all malignant renal tumors.

•Infants and children with malignant rhabdoid tumors of the kidneys have aggressive disease, typically with distant tumor spread at diagnosis.

•Frequently, they die early, an 86 % mortality rate (within 1–2 years) and 90 % tumor relapse despite intense multi-drug chemotherapy.

•As many as 20 % of patients with a malignant rhabdoid tumor of the kidney have synchronous or metachronous CNS lesions, including both metastases and second primary cancers.

•Mutations or deletions of the SMARCB1/INI1 gene play a role in the development of malignant rhabdoid tumor.

4.5.7Mortality/Morbidity

•The overall survival rate for patients with malignant rhabdoid tumor enrolled in NWTS 1–5 was only 23.2 %.

•Most patients present with stage III or IV disease.

•Patients with germline mutations of SMARCB1 likely manifest disease at an earlier age, with a high risk of progression and inferior prognosis.

•Malignant rhabdoid tumor is a rapidly progressive tumor, with most deaths occurring within 12 months of presentation.

•The most common sites of metastasis at presentation are the lungs, abdominal lymph nodes, liver, brain and bone.

•A young age at diagnosis is strongly associated with an adverse outcome.

•The 4-year event-free survival rates according to age at diagnosis were:

–8.8 % for patients aged 0–5 months

–17.2 % for patients aged 6–11 months

–28.6 % for patients aged 12–23 months

–41.1 % for patients aged 24 months or older

•High-stage (stage III/IV) disease is correlated with an adverse outcome.

•The survival of patients with malignant rhabdoid tumor in NWTS was as follows:

–Stage I (33.3 %)

–Stage II (46.9 %)

–Stage III (21.8 %)

–Stage IV (8.4 %)

–Stage V (0 %)

4.6Renal Cell Carcinoma in Children

4.6.1Introduction

•Renal cell carcinoma (RCC) is also known as hypernephroma, Grawitz tumor, and renal adenocarcinoma.

•It originates in the lining of the proximal convoluted tubules.

•In 1883, Paul Grawitz was the first to describe the morphology of small, yellow renal tumors.

•In 1894, Otto Lubarsch, coined the term hypernephroid tumor, which was amended to hypernephroma by Felix Victor Birch-Hirschfeld.

•Foot and Humphreys introduced the term Renal Celled Carcinoma to emphasize its origin from the renal tubules.

•Fetter modified the term to the now widely accepted term Renal Cell Carcinoma.

•In 1959, Oberling et al. described convincing histological evidence that RCC arise from the epithelial cells of the renal convoluted tubules.

–They found that the tumor cell cytoplasm contained numerous mitochondria and deposits of glycogen and fat.

–They identified cytoplasmic membranes inserted perpendicularly onto basement membrane with occasional cells containing microvilli along the free borders.

•RCC is the most common renal tumor in adults, responsible for approximately 90–95 % of cases.

•Renal cell carcinoma represents 2 % of malignant tumors in adults and is the third most frequent tumor of the urinary tract after prostate and bladder tumors.

•Renal cell carcinoma usually occurs in the age range of 50–70 years.

•On the other hand, in pediatric ages, only 2–3% of malignant renal tumors are proved to be RCC.

•Whereas the peak of incidence in Wilms’ tumor occurs around 3 years of age, RCC presents between 9 and 15 years of age.

•Renal cell carcinomas are rare in children, and they show significant differences in their histology and pathogenesis when compared to those seen in adults.

•The incidence of RCC increases with age.

•The incidence of renal cell carcinoma is estimated in 0.1–0.3 % of all tumors and 1.8–6.3 % of all malignant renal tumors in childhood.

•Recent studies showed that the RCC corresponds to:

– 1.4 % of renal tumors in patients under 4 years old

–15.2 % of renal tumors in patients between

5 and 9 years

–52.6 % of renal tumors in patients from 10 to 15 years old

•In the pediatric age group, RCC is seen in patients with Von Hippel-Lindau disease, which is associated with retinal and central nervous system hemangioblastomas, pheochromocytomas, and pancreatic neuroendocrine tumors.

•RCC is generally symptomatic at diagnosis, and most children with RCC present with more locally advanced disease.

•Generally, there is no sex predominance for RCC in children unlike in adults, in which the tumor predominates in males.

•The most common form of presentation of RCC in children is macroscopic hematuria and abdominal or flank pain.

•Other less frequent symptoms are palpable abdominal mass, anemia, and fever.

•RCC is diagnosed as a solid mass with US and CT. However, it is generally difficult to differentiate it from Wilms’ tumor before surgery in children.

•Calcification or high-density areas on CT have been reported in 14–28 % of RCCs in children.

•So far, no treatment protocols have been defined for children with RCC.

•Surgery is the mainstay of treatment and results in cure when the tumor is localized and completely resected.

•The importance of radiotherapy and immunotherapy is not clear and different chemotherapy regimens showed only minimal benefits when tested in clinical trials.

•Tumor staging is the most important prognostic factor.

•The overall 5-year survival is approximately 60 % and patients with stage IV has the worst prognosis.

•Radical nephrectomy associated with regional lymphadenectomy is the best treatment for RCC in childhood.

4.6.2Histopathology

•The gross and microscopic appearance of renal cell carcinomas is highly variable.

•Gross features:

–A yellowish, multilobulated tumor in the renal cortex, which frequently contains areas of necrosis, hemorrhage and scarring.

–The tumor compresses the surrounding parenchyma, producing a pseudocapsule.

–Most translocation-RCC and papillary RCC are circumscribed, single lesions.

–Multifocality in pediatric RCC is unusual and when present may suggest an underlying syndrome, such as tuberous sclerosis or von Hippel-Lindau disease.

–Renal medullary carcinomas have a strikingly infiltrative growth pattern typically involving the medulla.

–Neuroblastoma-associated oncocytic RCCs are often multifocal or bilateral.

•Microscopic Features:

–There are four major histologic subtypes of renal cell cancer:

•Clear cell (conventional RCC, 75 %)

•Papillary (15 %)

•Chromophobic (5 %)

•Collecting duct (2 %)

•Sarcomatoid changes can be observed within any RCC subtype and are associated with more aggressive clinical course and worse prognosis.

•The tumor cells are quite large, atypical, and polygonal.

•They can be arranged in papillae, tubules or nests.

•The cells often contain large amounts of clear to variably eosinophilic cytoplasm and possess distinct cell borders separated by thin fibrovascular septa.

•The most common cell type exhibited by renal cell carcinoma is the clear cell, which is characterized by high lipid content in the cytoplasm.

•The clear cells are thought to be the least likely to spread and usually respond more favorably to treatment.

•Most of these tumors however, contain a mixture of cells.

•Small psammomatous calcifications are variably present.

•The majority have a Furman nuclear grade of 3, with easily identified nucleoli.

•Tumors containing the ASPL-TFE3 phenotype tend to have abundant, voluminous cytoplasm that often contains cytoplasmic granules and eosinophilic bodies.

•Tumors with PRCC-TFE3 gene fusion often have less abundant cytoplasm, are arranged more compactly, contain fewer calcifications, and display lower nuclear grades.

•Papillary RCCs:

–Are composed of cells arranged in tubular and papillary configurations.

–Often contain foamy macrophages.

–Are typically encapsulated, although the tumor often penetrates its fibrous pseudocapsule.

–Two types of papillary RCC are identified within the WHO classification.

•Type 1 tumors are composed of cuboidal cells with little cytoplasm arranged in a single layer.

•Type 2 tumors contain pseudostratified cells with higher nuclear grade and typically more eosinophilic cytoplasm.

•Renal Medullary Carcinomas:

–These are usually composed of high-grade epithelial cells with acidophilic cytoplasm, arranged in a tubular, often cribriform architecture.

–They occasionally are solid or sarcomatoid.

–Characteristic microscopic features include desmoplasia and an acute inflammatory reaction.

–The nuclei are large with prominent nucleoli in most cases.

–The cells contain prominent eosinophilic cytoplasm with occasional rhabdoid-like cytoplasmic inclusion.

–The nucleoli are often prominent.

•Post-neuroblastoma renal cell carcinomas:

–These are single, bilateral, or multifocal tumors.

–They are composed of solid and occasionally papillary cells with oncocytoid features and cellular heterogeneity.

–Many cells contain copious eosinophilic cytoplasm with high nuclear grade, but others may lack these features.

•In 1982, Fuhrman recommended histologic grading for RCC.

•This is based on the microscopic morphology of a neoplasm with hematoxylin and eosin (H&E staining).

•This system categorizes renal cell carcinoma into four grades based on nuclear characteristics as follows:

–Grade I:

•Nuclei appear round and uniform, 10 μm; nucleoli are inconspicuous or absent.

–Grade II:

•Nuclei have an irregular appearance with signs of lobe formation, 15 μm;

nucleoli are evident.

–Grade III:

•Nuclei appear very irregular, 20 μm; nucleoli are large and prominent.

–Grade IV:

•Nuclei appear bizarre and multilobated, 20 μm or more; nucleoli are prominent.

•Nuclear grade is believed to be one of the most imperative prognostic factors in patients with renal cell carcinoma.

4.6.3Classification

•Pediatric renal cell carcinomas (RCC) account for approximately 2–3 % of all pediatric renal tumors.

•RCC arises from the cells of the proximal renal tubular epithelium.

•It is considered an adenocarcinoma.

•In 1826, Koenig published the first classification of renal tumors based on macroscopic morphology. He divided them into four forms:

–Scirrhous

–Steatomatous

–Fungoid

–Medullary

•There are two subtypes of renal cell carcinoma:

–Sporadic

–Hereditary

–Both subtypes are associated with mutations in the short-arm of chromosome 3, with the implicated genes being either tumor suppressor genes (VHL and TSC) or oncogenes (like c-Met).

•RCCs is a heterogeneous group of tumors and have been classified into five subtypes based on the location within the nephron in which the tumors originate.

–Clear-cell RCCs

–Papillary RCCs

–Chromophobe RCCs

–Collecting duct carcinomas

–Unclassified RCCs

•The most common subtypes of RCC seen preferentially in children are:

–The translocation-associated renal cell carcinoma

–Papillary renal cell carcinoma

–Renal medullary carcinoma

–Oncocytic renal cell carcinoma following neuroblastoma

•The histological diagnosis of renal cell carcinoma is made difficult by the considerable heterogeneity within and overlap between each of the above subtypes and by similarities to other pediatric renal neoplasms.

•Up to 25 % of pediatric RCC cannot be readily classified due to atypical features.

•Translocation-RCC may occur following chemotherapy for other diseases.

•Papillary RCC comprises approximately 30 % of the total.

•Papillary RCC in children may arise in the setting of pre-existing neoplasms, including Wilms tumor, metanephric adenoma, and metanephric adenofibroma.

•True clear cell RCC are extraordinarily rare in childhood.

•Conventional clear cell RCC comprises 6–20 % of the total.

•Renal medullary carcinoma is a highly aggressive tumor arising in patients with the sickle cell gene.

•Oncocytic RCC had been identified in patients previously diagnosed with neuroblastoma.

•Pediatric RCC differ in histologic appearance and genetic features from those seen in adults.

–The most common are the Xp11 (TFE3) translocation-RCC (20–40 % of total).

–TFE3 translocations involving a multitude of variant partners.

–Translocations involving chromosome 17 [t(X;17)(p11.2;q25), ASPL-TFE3 fusion] and chromosome 1 [t(X;1)(p11.2;q21), PRCC-TFE3 fusion].

–Contemporary investigation of pediatric RCC has demonstrated that a large percentage of these tumors bear cytogenetic translocations involving the MiT family of transcription factors.

4.6.4Staging

•The staging of renal cell carcinoma is the most important factor in predicting its prognosis.

•There are several staging systems for renal cell carcinoma.

•Staging can follow the TNM staging system based on:

–T: The size and extent of the tumor

–N: Involvement of lymph nodes

–M: Metastases

•It should be noted that tumor size, as measured in greatest dimension, is a critical fea-