Clear - cell renal carcinoma: review of literature in pediatric population

Introduction : The first reports of renal tumors originated from the renal tubule epithelium date from 1855, Robin, and 1867, Waldeyer. However, at the same era, some pathologists wrong believed these tumors were originated from adrenal gland tissues due to the fat content of the tumor (hypernephroid tumor theory - origin above the kidney, 1894). The first diagnostic test for renal tumor was excretory urography. Over the years, with the emergence of ultrasonography (US), it has been replaced. Nowadays, after the US screening, all renal lesions should be evaluated, in a complementary way, with computed tomography (CT) - gold standard - in the pre-contrast, arterial, portal, nephrographic phases. This is necessary to characterize the presence of enhancement after contrast. A kidney injury that enhances more than 15 Housfield units (UH) is suspected of kidney cell cancer. There are different subtypes of renal tumors derived from various sites of the nephron. Clear cell Renal Cell Carcinoma (RCC) is one of the subtypes that originates from the renal cortex. It is a rare tumor in children. Objective: The aim of this chapter is to review de incidence, pathology, diagnosis and treatment in clear-cell renal carcinoma in pediatric population. Methods: The authors performed a literary review about clear-cell renal carcinoma in pediatric population using Pubmed Database and Campbell-Walsh Urology as source search.


Introduction
The first reports of renal tumors originated from the renal tubule epithelium date from 1855, Robin, and 1867, Waldeyer.However, at the same era, some pathologists wrong believed this tumors were originated from adrenal gland tissues due to the fat content of the tumor (hypernephroid tumor theory -origin above the kidney, 1894) (1) .

Microscopically
From 1883 to 1928, several pathologists expanded the study of renal tumors to what is known today: there are different subtypes, derived from various sites of the nephron (clear cell and papilary viariant are originated from proximal convoluted tubules; while chromophobe and collecting duct carcinoma are derived from the more distal components of the nefron).Each one has different biological and genetical bases (1) .
Microscopically, it resembles renal tubules, and four major patterns of growth have been described: papillary, solid, cystic, and sarcomatoid.The papillary subtype predominates in children (1) .
Clear cell Renal Cell Carcinoma (RCC) originates from the proximal convoluted tubules epithelium (renal cortex) and presents a predominantly expansile growth pattern.

Macroscopically
Macroscopically, it is a solid, yellowish lesion with variable degrees of internal necrosis, hemorrhage and cystic degeneration.Such findings are most frequently observed in large-volume, fast-growing tumors.Tumor calcifications may also be found (FIGURE 1).
Histologically, such lesions present clear cells because of their lipid-and glycogen-rich cytoplasmic content (2) .Frequently, such tumors also present eosinophil granular cytoplasm cell (2) .
Renal cell carcinoma is rare in pediatric population and the incidence is estimated in 0.1-0.3% of all neoplasm and 1.8 -6.3 % of malignant renal tumors (2) .It has the same incidence in male and female.Mean age presentantion in children is 9-10 years.It corresponds to 1.4% of renal tumors in patients under 4 years old, between 5 and 9 years incidence is 15.2% and 52.6% between 10 and 15 years old (3) .In the second decade of life, it is as common as Wilms tumor.Since 1986, approximately 160 well-documented cases have been published in the literature (4) .
The more often seen subtype of RCC in children is renal medullary carcinoma; it occurs in patients with sickle cell disease and hemoglobinopaties.The mean age at presentation is 13 years or younger and its mortality is higher.
Despite the risk factors observed in adults (obesity, smoking, dialysis, hypertenstion, abuse of nonsteroidal anti-inflammatory drugs, syndromes such as tuberous sclerosis, radiotherapy for testicular tumors), there is no such correlation in children (3) .

Objective
The aim of this chapter is to review de incidence, pathology, diagnosis and treatment in clear-cell renal carcinoma in pediatric population.

Methods
The authors performed a literary review about clear-cell renal carcinoma in pediatric population using Pubmed Database and Campbell-Walsh Urology as source search.

A) Genetic Association
Renal cell carcinoma in adults is often associated with tuberous sclerosis complex or the von Hippel-Lindau disease.RCC with nonpapillary histology is associated with translocations or terminal deletions of the short arm of chromosome 3 beginning at 3p13.This chromosomal 3p cytogenetic abnormality is uncommon in pedriatic patients with RCC (4) .Several children with RCC associated with Von Hippel-Lindau syndrome or tuberous sclerosis have been reported (5) .
Using immunohistochemical staining, recent studies have reported Xp11.2 translocations in 20% to 70% of pediatric RCC (3) .There is also translocation related with PRCC-TFE3 gene and X chromosomes, which leads to overexpression of TFE3 protein in children and young adults.These finding can be related to different response to some chemotherapeutic agents (Table 1) (1,(6)(7) .

B) Pathology
Renal cell carcinoma is circumscribed by a pseudo capsule of fibrous tissue.There is a classification of nuclear components which is based on nuclear size, shape and presence or absence of nucleoli.These features were gathered into a system graduation nominated Fuhrman´s system, which is also an independent prognostic and predictor of outcome factor for clear cell renal carcinoma (Table 2) (8) .

C) Diagnosis
Renal cell carcinoma in children and young adults is more likely to be asymptomatic.About 50% to 68% of RCC patients are diagnosed incidentally.When the children is symptomatic, the tumor generally is advanced and has worst prognosis.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 (9)(10)(11)(12) .Stachowicz-Stencel et al reported that 52.4% of pediatric RCC cases were asymptomatic and diagnosed during routine examination (10) .Paraneoplastic phenomena in adults are common and well reported but they are infrequently documented in children.
The complete clinical triad (gross hematuria, palpable mass, and flank pain) is seen in only 6% to 9% of affected children (5) .
Metastatic disease at presentation has the same incidence both children and adults..

Grade
Nuclear Size Nuclear Feature Nucleoli

D) Staging
Staging is based on Robson modified staging classification system.Stage I is disease confined by the renal capsule.Stage II disease invading renal capsule but confined by Gerota´s fascia.Stage III is divided into A (involvement of renal vein or inferior vena cava) and B (regional lymph node involvement).Stage IV is metastatic disease (Tables 3 and 4) (1,13) .

E) Radiological Exams
The first diagnostic test for renal tumor was excretory urography.Over the years, with the emergence of ultrasonography, it has been replaced.Ultrasound (USG) is a simple, low cost examination with good screening capability for potentially malignant lesions, in that it can differentiate solid lesions from cystic, characterize septa and calcifications, evaluate cystic density and suggest greasy content.After the ultrasound, screening, renal lesions should be evaluated in a complementary way with computed tomography (CT) -gold standard -in the pre-contrast, arterial, portal, nephrographic phases (Figure 2).This is necessary to characterize the presence of enhancement after contrast.A kidney injury that enhances more than 15 Housfield units (UH) is suspected of kidney cell cancer.
However, up to 20% of the findings may be inconclusive, requiring other interventions.Magnetic resonance imaging is the alternative radiological modality, especially to those allergic to contrast.Evaluation of the enhancement is done by injection of gadoliniumlabeled diethylenetriaminepentaacetic acid.Nephrogenic systemic fibrosis is a direct complication of contrast injection and occurs most commonly in patients with chronic kidney disease (Table 5).

F) Treatment
Treatment depends on tumor stage.In stage I, surgery can be curative.The completeness of the surgical resection with radical nephrectomy has been shown to be a significant prognostic factor, with survival rates as low as 10% after incomplete resection, given that current adjuvant medical therapies are not typically curative for unresected disease (3,12,14) .
If children present lymph node involvement, the ressection may be usefull to control tumor growth and staging.Depending on size and metastatic loca- tion, it can be also usefull to ressect metastatic sites (metastasectomy) (15) .
Immunotherapy based on interleukin-2 (IL-2) and interferon-alfa were used in the past to the treatment for advanced disease (stage III and IV), mostly used in combination.VEGF (vascular endothelial growth factor) inhibitors, mTOR inhibitors and monoclonal antibodies are currently gold standart in treatment of adult advanced tumors, with few literature based on evidence in its use for children.Table 6 represents combinations of targeted therapies in renal cell carcinoma (16)(17) .
Chemotherapy with vincristine, vinblastine, actinomycin D, cisplatin, gemcitabine, and 5-FU are related with sucess in only a few cases, especially if related to renal medullary carcinoma (2,12) .Cisplatin toxicity may lead to decreased creatinine clearance, hypomagnesemia, renal tubular acidosis.
Patients in stage II can be treated with radiotherapy of 2,000-6,000 cGY to the renal bed and para-aortic region with and without chemotherapy.

G) Prognosis
The main prognosis factors are tumor stage and size, vascular invasion, age, location, celular sub-type.However, tumor stage appears to be the most important factor for the survival (3) .Reports of RCC found overall survival rate of 56-64% in pediatric population, which can be improved to 66.6% the use of adjuvant chemotherapy and radiotherapy.Regional lymph node involvement does not have the same poor prognosis as adult RCC.
Five years survival is more than 90% for patients with stage 1, 50-80% for patients with stages 2 (which is better than adult population) and 3 and less than 10% for stage 4 (3).Most recurrances occur in 2 years after diagnosis and the lung and liver are the sites that should receive careful monitoring (4) .There are recurrances described after 15 months from the time of diagnosis (4) .

Figure 1 .
Figure 1.CT revealed a 7cm mass with high attenuation at the upper pole of left kidney.After contrast administration, the tumor was enhanced heterogenously (Fig. 1b)

Figure 2 .
Figure 2. A -CT scan without contrast.B -Enhance of more than 15 HU is suggestive of clear cell carcinoma.