University of Medicine and Pharmacy [306555]

University of Medicine and Pharmacy

“Iuliu Hațieganu”

Cluj-Napoca

Faculty of Medicine

LICENSE THESIS

Renal Tumors In Children

Coordinator:

Dr. Dan GHEBAN

Graduate:

Johanna RUF

2019

Introduction

Paediatric renal tumors are a [anonimizat] 7% of all childhood cancers. [anonimizat] a significant improvement of the prognosis not only because of improved accuracy of diagnostic criteria like staging and histologic examination but also because of the surgical approach conjointly with the use of irradiation and chemotherapy.

Several protocols exist as to when chemotherapy should be introduced in the course of the therapy. The International Society of Paediatric Oncology in Europe suggests according to their protocol to use both preoperative neoadjuvant and postoperative chemotherapy depending on the pathologic response. [anonimizat]. Both approaches are showing similar good results.

A very extensive study is conducted in North America since 1969, namely The National Wilm’s Tumor Study NWTS. It comprises 85% of the newly diagnosed cases in this area and joins several hundred paediatric oncology care centers. [anonimizat]-term outcome for the patients and to make research achievements available to clinicians internationally.

One of most challenging parts for pathologists is to differentiate between malignant or benign renal neoplasms. [anonimizat].

General Review

Wilm’s Tumors

Wilm’s tumor is a malignant tumor of the kidney with the highest incidence of all extracranial malignant findings in childhood. [anonimizat], [anonimizat], Denys-[anonimizat]. The incidence rate shows that females are slightly more often affected and rarely neonates or infants. There is a very low number of documented adults presenting with Wilm’s tumor.

Macroscopic characteristics

It most commonly presents in a [anonimizat] (5% of the cases). It is usually a round, [anonimizat]. Tumor mass can range from 60 to 6350g, with 550g as median. [anonimizat], friable, and lobulated areas including sites of haemorrhage necrosis and cystic formations. A [anonimizat]. The renal vein might be invaded up until the right atrium of the heart through the inferior vena cava.

[anonimizat]. Appropriate handling preparation of all sections is also of high importance.

Microscopic characteristics

Generalities

Wilm’s [anonimizat] appearance. It presents as mono-, bi- and most commonly as a triphasic tumor with blastemal, stromal and epithelial cell types with different levels of differentiation , even though it can vary tremendously in each tumor. The majority of Wilm’s tumors have a mix of all three cell types.

Cell types

If one of the cell types predominates by more than two thirds, it is labelled accordingly.

Blastemal predominated tumors, without identifiable differentiation levels, present with two types of cell patterns. Either with unclear, infiltrative margins and diffuse cell pattern. These tumors are known to be very aggressive, but usually respond well to therapy . Or they present with an organoid blastemal pattern, with sets of aggregated primitive cells surrounded by myxoid mesenchyma. Therefore, they are less aggressive as they have well demarcated margins. The latter type of cell pattern is more common .

Tumors with predominantly epithelial components are mostly of nephrogenic type. Here one can find several different stages of tubular and glomeruloid differentiation. They are structured in a heterologous pattern, including cell types like mucinous, squamous but also neuroepithelial and neuroendocrine.

Also, stromal pattern can be found as most abundant cell type in a tumor. It presents as either nephrogenic or heterologous.

Anaplasia

The term “Unfavourable histology” in Wilm’s tumor is used when anaplasia is detected. There are three criteria which need to be met in order to define it as anaplasia. These include :

The finding of stromal, epithelial or blastemal cell types, except skeletal muscle cells, with an at least three times enlarged diameter of their nuclei compared to the adjacent nuclei of the same cell type.

These enlarged nuclei showing clear hyperchromatism.

Multipolar mitotic structures.

In short, anaplasia is understood as extreme cellular pleomorphism . It is known to indicate, that the tumor is usually more towards the malignant end of the entire tumor spectrum of Wilm’s tumor . It is also connected to a higher relapse rate (55%) and mortality (47%) in comparison to tumors without anaplasia. Despite all of this, staging of Wilm’s tumor is made regardless the presence or absence of anaplasia, as it is an indicator for resistance to therapy rather than for aggressiveness of the tumor . Therefore, the higher the grade of anaplasia, the worse the prognosis. As in anaplasia grade one Wilm’s tumor, the conventional therapy tends to have good results . Focal anaplasia is limited to one or more well demarcated foci in the primary tumor, and limited to the kidney, and thus is an indicator for a low anaplastic grade. On the contrary diffuse anaplasia refers to a high anaplastic grade . Therapy seems to not affect anaplasia . Therefore, the pathologists are able to stage the tumor post nephrectomy, even after chemotherapy, and give a prognosis.

Metastasis

Non-contiguous metastasis are most commonly found in regional lymph nodes. Also, peritoneum, lung and liver are sites to find metastasis. Less common are bone marrow and skeletal metastasis, and even less so in bones .

Staging according to National Wilm’s Tumor Study

Prognosis is based on the National Wilm’s Tumor Study Staging Definitions. It takes both the stage of the largest tumor and the existence of anaplasia, into account. In the following table the definition of stage I to V is described.

Table 1 – National Wilm's Tumor Study Staging Definitions

Bilateral Wilm’s tumors, stage V, have a three-year survival rate of 76% . They represent 5% of all Wilm’s tumor cases. They are known to appear conjointly with clinical and pathological features. These findings are genitourinary tract anomalies, young age at diagnosis, appearance of nephroblastomatosis, multicentricity and favourable histology. These features are distinguishing the stage V tumors from the other stages.

Cystic variants

Cystic variants of the Wilm’s tumor are found in two benign tumors: Cystic nephroma and cystic partially differentiated nephroblastoma. Both are at this time included as a part of the spectrum of nephroblastoma. Septa divide the cystic spaces. The septa of cystic nephroma contain mature cell types. On the contrary in cystic partially differentiated nephroblastoma the septa show microscopically embryonal cell types without anaplasia.

The diagnostic criteria for cystic partially differentiated nephroblastoma include:

An entirely cystic tumor which may contain luminal papillonodules

The only solid content of the tumor are septa or papillonodules, containing blastemal cells and its derivatives

The classification differentiates between the papillonodular type with findings of papillonodules and the conventional type without these findings

In the presence of larger solid regions, these tumors are considered to be conventional Wilm’s tumors .

Nephrogenic Rest and Nephroblastomatosis

The origin of Wilm’s tumors are considered to be abnormally persistent foci of embryonal cells, called nephrogenic rests. These cells have potential to develop into a Wilm’s tumor and are found in 25% to 40% of all Wilm’s tumors. Nephroblastomatosis is defined as the nephrogenic rest which is structured either in a multifocal or diffuse pattern.

Macroscopically it can be entirely inapparent, or manifest with nodules, capsular thickening or a scar beneath the capsule or the deep cortex of the kidney. There are two types of nephrogenic rests: Perilobar type and intralobar type. Both contain blastemal, epithelial and stromal components but differ in their potential to develop into a Wilm’s tumor . The perilobar cell types occur in Wilm’s tumors associated with hemihypertrophy, Beckwith-Wiedemann Syndrome or sporadic tumors. Occasionally they are connected to cystic renal dysplasia and rarely to mesoblastic nephroma. They arise in the periphery with well delimited borders. The intralobar cell types, known to have an increased progression rate into Wilm’s tumors , are associated with two rare syndromes: WAGR Syndrome (shortening for Wilm’s tumor, Aniridia, Genitourinary anomalies, mental Retardation) and Denys-Drash Syndrome . The intralobar cell types are also found to be incoherently dispersed in cortex and medulla with an irregular border .

Whilst only a minor part of the nephrogenic rests will develop into Wilm’s tumors, with remnants at the outer boundaries, the majority will regress to become fibrotic. They may feature dormant, sclerosing or hyperplastic entities. The latter is impossible to differentiate cytologically from Wilm’s tumor cells. The hyperplastic perilobar cells can be recognized by its distinct interface with the neighbouring renal parenchyma. Whereas the hyperplastic intralobar rest amalgamates with the adjacent renal cells .

Differentiating Wilm’s Tumors from other Tumors

Differentiating Wilm’s tumors from other renal neoplasms by histologic specimen is difficult but important for correct diagnosing and treatment choice. Therefore, the role of biopsy is in discussion of having an increased importance to conclude a diagnosis as compared to analysis of specimen taken after nephrectomy.

As Wilm’s tumors present as a triphasic embryonal renal neoplasm, with blastemal, stromal and epithelial cell types, the difficulty lies within the high range of variety of different maturity or differentiation levels of the cells found . Therefore, even if the specimen does not show a triphasic pattern, it is yet not possible to rule out the diagnosis of Wilm’s tumor. Some rare findings suggest that the Wilm’s tumor might also be present with monomorphous or biphasic cell pattern. Also, it has to be taken into consideration that fundamentally all renal neoplasms derive from blastemal origin and thus are related to Wilm’s tumors.

In the following other renal neoplasms in childhood are described together with their potential relationship to Wilm’s tumors.

Non-Wilm’s Tumors

Congenital mesoblastic nephroma

Generalities

Up until 1967, congenital mesoblastic nephroma (CMN) was considered to be a variant of Wilm’s tumors, it was subsequently discovered to be a Non-Wilm’s mesenchymal renal tumor in children, based on cytogenetic data . It presents as the most common renal tumor in infancy, with an incidence rate of 3 –10% of all renal tumors in childhood . There is no predisposition on gender, although it may be associated with Beckwith-Wiedemann syndrome .

Morphopathological features

Macroscopically congenital mesoblastic nephroma presents as a solitary, unilateral tumor, with dimensions ranging from 3x2x2 cm to 20x16x14 cm, an average volume of 1,310 cm3 and 20 cm of maximum diameter . With grey-white to yellow coloured tissue and distinctively whorled or trabeculated appearance, it displays an ill-defined interface between the neoplastic structure and the kidney. Once cut, the surface appears soft and bulging. The neoplasm mostly emerges from a central point within the kidney and largely affects the renal sinus.

The following list presents the three types of the neoplasm, their frequency and mean age of appearance :

Classic CMN – 24% – presenting at age of 7 days

Cellular CMN – 66% – presenting at age of 4 months

Mixed type CMN – 10% – presenting at age of 2 months

Table 2 includes a list of features of both macro- and microscopic nature and genetic correlations, showing the differences between the classic and the cellular type of CMN.

Table 2 – Macro- and microscopic features of Classic and Cellular type of CMN

The mixed type of CMN combines the appearance of a classic type CMN with areas of cellular mesoblastic nephroma inside.

Prognosis

The different types of CMN not only differ in their histological appearance but also in their prognostic outcome for the patient. Whereas the classic CMN shows good overall prognosis , the cellular CMN proved to be the more aggressive type, being associated to a higher rate of malignant features as well as the possibility of recurrence or developing metastasis, most commonly found in the lungs. The incidence rate of recurrences and metastasis is 5% to 10%. Risk factors, other than cellular type of CMN, are tumors stage III or higher, and affected intrarenal or sinus vessels .

Differential Diagnosis

Differentiating between CMN and Wilm’s tumor is difficult, but crucial for choosing the correct therapy. Especially as findings by clinical examination and imaging are very similar for both, particularly for the cellular type of CMN, the focus should lie on the detectable differences. Tools useful for detecting such, are immunohistochemistry, age at appearance, association of congenital syndromes or anomalies and morphopathological findings.

Therefore, Wilm’s tumor should be the suspected diagnosis if bilateral tumors were found, or congenital syndromes or anomalies are present. On the other hand, if the patient is under three months of age or genetic findings by immunohistochemistry typical for CMN were identified, the diagnosis of CMN is suggested.

Clear Cell Sarcoma of the Kidney

Generalities

The tumor called ‘great masquerader’ is known as Clear Cell Sarcoma of the Kidney (CCSK). Its name derives from its features of being able to mimic or being mimicked by other renal tumors of children. Among these features are the rarity of its occurrence, a high variety of its morphology and no specific diagnostic markers discovered yet. This leads to a high rate of misdiagnosis. Even though it is a rare neoplasm, it stands out as the most common tumor manifesting with ‘unfavourable histology’. Just like Congenital Mesoblastic Nephroma, CCSK was only in time considered to be a distinct entity from Wilm’s tumors. In 1978 it was first recognized as such, with a tendency to bone metastasis which lead to the name ‘bone metastasising renal tumor of children’. In 40% to 60% of cases this kind of metastasis were found .

The age of occurrence is very wide, ranging from two years up to 54 years, though the peak incidence is at two years. CCSK is not discovered to be connected to anomalies or syndromes.

Morphopathological features

Macroscopic findings

Gross pathologic features of CCSK illustrate a large, unicentric mass partially or nearly completely deforming the kidney and appearing to arise from deep within the renal parenchyma . Its diameter spans from 2,3 to 24 cm with a mean diameter at 11,3 cm and mean weight of 661 g, ranging from 43,5 to 1950 g. The cut section reveals a grey, soft and mucoid mass with cystic foci universally dispersed. The differential diagnosis of Cystic Nephroma needs to be made by microscopic investigations, clearly showing its ability to mimic other tumors. Also haemorrhage and foci of necrosis are depicted in a usually homogenous appearance. The border between the kidney and the tumoral tissue is well circumcised and sharp.

Microscopic findings

On microscopic examination, three components can be identified described in table 3 :

Table 3 – Findings on microscopic examination of CCSK

CCSK can develop in a high variety of different patterns. However, a classic pattern (in 91% of all CCSK tumors ) can be described. It distinguishes itself by having an evenly distributed network of vascular septa with parallel capillary-sized vessels running through the tumor tissue and creating nests and cord shaped appearances. These nests contain six to ten cells in width. The cord cells can either look plump and ovoid or depict a spindle shape. Their nuclei present in a widely uniform shape and the chromatin shows a characteristically fine, dusty composition without apparent nucleoli. The vascular septa vary from thin sized capillaries resembling those of myxoid liposarcoma, to capillaries dispersed by fibroblast-like-cells in the surrounding of a collagenous matrix. These thin septa are considered as a characteristic landmark of CCSK. In case of dilation, the septa assume a staghorn, hemangiopericytomatous shape. The clear cell appearance is created by the extracellular mucopolysaccharide matrix surrounding the loosely spaced cord cells. Despite the name suggesting differently, not all CCSK tumors present with a clear cell appearance .

Variant patterns are listed below together with their incidence of appearance:

Myxoid pattern – 50%

Sclerosing pattern – 35%

Cellular pattern – 26%

Epitheloid pattern: trabecular or acinar type – 13%

Palisading pattern – 11%

Spindle cell pattern – 7%

Storiform pattern – 4%

Anaplastic pattern – 2,6%

These patterns differ from the classic type by modifications of the morphology of the cord or septal cells. However, despite presenting with a variant pattern, there will always be found traces of classic cell pattern in a CCSK .

Prognosis

The prognosis depends on the stage of the tumor at presentation to the physician. Overall there is a 97% six-year survival chance for stage I and for stage IV it is 50%.

The most significant prognostic factors for CCSK are :

Treatment with doxorubicin (chemotherapy)

Stage of tumor

Patient age

Tumor necrosis

The latter, presence of tumor necrosis, generally is the feature of a highly aggressive sarcoma, and on the contrary, the absence of necrosis, implies high chances for a favourable outcome.

Differential Diagnosis

Tumors possible to be mistaken for CCSK are Wilm’s tumors, rhabdoid tumors and cellular variant of mesoblastic nephroma. Besides distinct clinical features pointing towards an unlikely diagnosis of CCSK like development of bone metastasis, immunohistochemistry yet presents the most reliable tool for distinguishing CCSK from others, by generating a genetic expression profile. This profile suggests that upregulated genes in CCSK are responsible for neural differentiation, development or function. Moreover, it was found that CCSK shares two activated pathways as identified in other paediatric neural tumors. In addition the discovery of therapeutic targets, such as nerve growth factor receptor, CD 117 and epidermal growth factor receptors, will help to treat CCSK more accurately. Unlike Wilm’s tumor, CCSK is known to not be associated with sporadic aniridia or hemihypertrophy .

Rhabdoid Tumor

Generalities

So far only little was possible to be discovered about the Rhabdoid tumor of the Kidney (RTK) in children, despite it has been studied extensively. First considered to be a variant of the Wilm’s tumor, studies declared its distinct entity by now. Yet, no exact cell type of derivation was discovered. It was disclosed that it is not connected to Wilm’s tumors but is associated with the familial rhabdoid tumor predisposition syndrome, primitive neuroectodermal brain tumors (15% of the cases) and rarely with hypercalcemia. In terms of frequency it is very rare, only 2,5% of all National Wilm’s Tumor Study cases but presents with high malignancy and consequently 80% mortality. The male-to-female ration shows a 1,5:1 disposition. This kind of neoplasm emerges as a primary tumor both from renal and extrarenal origins such as from the central nervous system (CNS). Nevertheless, it was also discovered in all soft tissue sites . Metastasis manifest all over and usually are found already widespread at the time of diagnosis . The peak incidence is at the age of one to four years. In their first year of life, commonly more than one primary Rhabdoid tumor is found, disclosing a genetic predisposition for cancer. Typically, they either present with a primary Rhabdoid tumor of the CNS (known as atypical teratoid-rhabdoid tumors AT/RT ) and of the kidney, or the Rhabdoid tumor of the CNS is found conjointly with a liver or lung tumor. Only 2% of RTK arise bilateral as opposed to the higher bilateral Wilm’s tumor incidence . The only feature connecting all these different manifestations is the finding of a mutation or deletion of the INI1 gene located at the chromosome 22q11.

Morphopathological features

Macro- and Microscopic findings

Macroscopically the tumor presents without a capsule and can be described as pale and round with its texture being soft. Satellite tumors may form.

On histologic examination the cells present in high variety of different cell patterns including neural, epithelial, mesenchymal or ependymal patterns . They contain vesicular nuclei with prominent central nucleoli and ample eosinophilic cytoplasm characteristically showing filamentous inclusions. Especially in case of AT/RT appearance, it is hard to differentiate such from a primitive neuroectodermal tumor (PNET) as it might comprise rhabdoid cells and areas of primitive neuroepithelial tissue resembling PNET. Also, mesenchymal or epithelial cells might be found in an AT/RT such as in PNET. Therefore, only molecular analysis can give a clear statement about which exact tumor type was found. RTK is believed to be originating from a primitive stem cell with the ability for divergent differentiation and might be deriving from the neural crest. It is important to mention that the discovery of rhabdoid cell patterns or features in other tumors such as Wilm’s tumor or mesoblastic nephroma is not necessarily indicative for a poor prognosis.

Immunohistochemical findings

Immunohistochemically it was possible to consistently find vimentin with coexpression of cytokeratin, epithelial membrane antigen, desmin and neurofilaments in RTK cells. The staining pattern depicted in over 90% a patchy and strong appearance with small clusters of positive cells surrounded by non-reactive tumor cells. The already mentioned genetic mutations or deletions present in RTK are leading to the inactivation of hSNF5/INI1 gene, which is in charge of altering the conformation of the DNA-histone complex to make transcription factors available to target genes. The staining pattern, which was described above, using antibodies for hSNF5/INI1 and B AF47, has proved to be highly sensitive and specific for detecting the non-functioning hSFN5/INI1 gene, which is also closely associated with the biallelic inactivation of the tumor suppressor gene.

Prognosis

Generally speaking RTK is known to have a bad prognosis. As already mentioned for patients diagnosed in their first year of life the likelihood of developing a CNS AT/RT is increased as well as their survival rate is decreased compared to an older age at diagnosis. It is yet to be determined to what extent the age at diagnosis really plays a part for verifying the accurate prognosis. Difficulty lies in the rarity of this tumor and hence the struggle to complete a study investigating this issue.

Renal Cell Carcinoma

Generalities

Renal Cell Carcinoma (RCC) is the second most common renal neoplasm in children right after Wilm’s tumor. Though when reviewing the statistics, Wilm’s tumor most commonly appears up until 5 years of age and later on only very rarely. It appears that RCC has its highest frequency of diagnosis in the second decade of life representing in this period the tumor with the highest incidence rate. Yet, bearing in mind that renal neoplasm is a very rare entity itself, the total amount of diagnosed RCC is significantly lower in comparison to the Wilm’s tumor frequency. It is important to mention that the adult RCC should not be confused with the same appearing in childhood.

Morphological subtypes

RCC can be divided in certain subtypes with different findings and incidence rates each:

Table 4 – Paediatric Renal Tumors common in 2nd Decade of Life

Prognosis

The factors affecting the survival rate for paediatric patients with RCC are

The stage of the tumor

The age of the patient at diagnosis

The histological pattern described

Vascular invasion

Metastasis

Accurate rates for prognosis are hard to achieve due to the rarity of this tumor. Hence, finding a sufficiently sized study group to draw conclusive numbers from proves to be difficult. Discovery of metastasis is a clear factor for worsening the survival rate. In cases of localized RCC the prognosis is quite well with a survival rate of 84,6% to 92,4%, whereas RCC cases with distant metastasis propose a significantly worse outcome with 13,9%. Yet, if there is only invasion of the lymph nodes detected, the survival rate is at 77,6%.

Differential Diagnosis

The most significant factor for distinguishing RCC from other tumors such as Wilm’s tumors is the age of occurrence. As already mentioned above, the highest frequency of appearance of RCC is in the age group of 15-19 years, whereas Wilm’s tumors are only rarely diagnosed at this age. Also features revealed by histologic examination of the tumor, shows that RCC is typically smaller than Wilm’s tumors and also more prone to present with calcifications (in 25% of RCC cases). In terms of metastasis, RCC is more likely to spread to the bones in comparison to Wilm’s tumors. Concerning the differentiation between the different types of RCC it is necessary to consider the features specific for each subtype of RCC mentioned in table 4 above. Manifestations like expansile growth indicates the presence of translocation, papillary and rarely clear cell RCC subtypes, when in fact infiltrative expansion is suggestive for medullary carcinoma and others. Also, detection of hypervascularity may signify the differential diagnosis of clear cell carcinoma as this tumor has distinguishably higher vascularization than the others.

Overview of Non-Wilm’s Tumors

In order to provide an overview and only present essential information, the following Table 5 sets out the different Non-Wilm’s tumors, discussed in the chapters before. In depth details have been omitted and it should be highlighted that it is a controversary which of the tumors are still considered to belong to the spectrum of Wilm’s tumors and which should be declared as Non-Wilm’s tumors. Therefore, the table is meant to only provide a structured overview.

Table 5 – A Summary of Characteristics of Non-Wilm's Tumors of Children

Summary of Diagnosing Paediatric Renal Tumors

Misdiagnosis of paediatric renal tumors is a considerable problem as diagnosis dictates the treatment choice. Issues arise in diagnosing these tumors because of their rarity, which makes it hard to be confident about the diagnosis even for the trained eye of an experienced morphopathologist, but also due to its huge variety of appearances both macro- and microscopically.

When facing the challenge of choosing between the vast amount of potential differential diagnosis, the following flowchart Figure 1 (available from ) is meant to shed some light on this issue. Its approach is to establish the main cell pattern found in the subject, which then leads on to an already narrowed down spectrum of differential diagnosis. Now the arrangement of these cells together with further findings like characteristic vasculature are indicating that only a few more variants of paediatric renal tumors still fit the pattern.

Special Review

Introduction

Paediatric nephrectomy is a rare procedure in Children’s Hospitals in Romania, as paediatric urology is not yet recognized as a separate specialty in the country.

Yet, paediatric surgeons are occasionally performing such nephrectomies, mostly because of tumor formations.

In this license thesis, the cases of nephrectomies in the children’s hospital in Cluj were analysed from an anatomo-pathological point of view, in order to present the findings of the last 20 years in this field.

Material and Method

For this prospective observational primary study, data from patients who had undergone nephrectomy between the years of 2000 – 2018, was extracted from the data base of the Children’s Hospital in Cluj.

After introducing this data in an Excel database, it was analysed with the Student’s t-test. Illustrations of the cases were based on the images from the data base of the laboratory of the same hospital.

Microscopic images were obtained using an Olympus Bx40 microscope with Olympus Camedia C4040 camera.

Results

In the study period (2000 – 2018) in the Childrens Surgery Hospital in Cluj, 51 total and partial nephrectomies were performed. Repartition of these cases according to year, age and gender of the patients are presented in the next graphs.

Figure 2 – Annual repartition of nephrectomies in children

Figure 3 – Age distribution of the nephrectomy cases

Figure 4 – Gender distribution of the nephrectomy cases

Figure 5 – The causes of the 51 nephrectomies

Tumoral Nephrectomies

In the study group, 30 nephrectomies were performed because of masses of tumoral origin. After microscopic examination the following diagnoses were found:

24 Nephroblastoma – 77%

3 Congenital Cystic Mesoblastic Nephroma – 10%

2 Clear Cell Sarcomas – 7%

1 Renal Rhabdoid Tumor – 3%

1 Adrenal Gland Neuroblastoma invading the Kidney – 3%

Figure 6 – Frequency of the renal tumors in the study group

Nephroblastoma

In the last 18 years, 24 nephroblastomas were excised in the children’s hospital in Cluj. In the following figures the distribution of age and gender in these cases are presented.

Figure 7 – Annual distribution of the nephroblastoma cases

Figure 8 – Age distribution of the nephroblastoma cases

Figure 9 – Gender distribution of the nephroblastoma cases

Figure 10 – Macroscopic image of a cystic nephroblastoma

Figure 11 – Solid nephroblastoma with secondary necrosis and haemorrhages

Figure 12 – Massive post-chemotherapy necrosis and haemorrhages in a solid nephroblastoma

Nephroblastoma was found to be localised on the right kidney in 7 cases and on the left kidney in 16 cases.

Figure 13 – Localisation of the nephroblastoma cases

Microscopic analysis revealed the classic triphasic aspect in 21 cases and 3 cases with biphasic appearance.

Figure 14 – Microscopic aspects of the nephroblastoma

Figure 15 – The classic triphasic aspect of the nephroblastoma

Figure 16 – Biphasic nephroblastoma

Figure 17 – Leiomyomatous stroma in a case of biphasic nephroblastoma

Figure 18 – Rhabdomyomatous stroma in a case of triphasic nephroblastoma

Figure 19 – Bone formation in the stroma of a nephroblastoma

The most frequent stromal aspect found in nephroblastoma was connective tissue, present in all tumors. 11 cases showed also a leiomyomatous component, and 2 cases with rhabdomyomatous tissue. In rare isolated cases depiction of bone-, nervous-, hematogenous- and cartilaginous tissue was discovered.

Only 4 out of 24 cases had developed anaplastic aspects which is a negative prognostic factor, as stated in a previous chapter.

Figure 20 – Anaplasia in blastemal component of a nephroblastoma

The tumor staging after SIOP European system ranks 9 cases in the 1st stage, 9 cases in the 2nd stage and 6 cases in the 3rd stage.

Figure 21 – SIOP Staging of the studied cases

Figure 22 – Necrotic and haemorrhagic tumoral areas, secondary to chemotherapy

According to European protocol, all 24 cases of nephroblastoma from the study group received chemotherapy before surgery; so inevitably, they had secondary necrotic and haemorrhagic areas in the tumor, ranging from 10 to 99% of the tumor mass.

Figure 23 – Vascular invasion in one of the cases studied

4 out of 24 cases were diagnosed as cystic nephroblastoma which despite their names, are known to have benign features.

Figure 24 – Triphasic nephroblastoma with a cystic component

Figure 25 – Pure cystic nephroblastoma

Mesoblastic nephroma

Also 3 cases of mesoblastic nephroma were encountered in 2 boys and a girl, which were all diagnosed in the first month of life.

Figure 26 – Macroscopy of 2 cases with mesoblastic nephroma

Figure 27 – Typical microscopic image of a mesoblastic nephroma

Malformations

In the study group of childhood nephrectomies, the following malformations were present:

Hydronephrosis

Renal dysplasia

Autosomal recessive (AR) polycystic renal diseases

Hydronephrosis

In the study group, a total of 57 cases of congenital hydronephrosis were diagnosed.

The majority, 50 cases, were treated surgically without the necessity of removing the kidney.

Figure 28 – Macroscopy of a giant congenital hydronephrosis post-extraction

However, the remaining 7 cases required a total nephrectomy.
Primary congenital urinary tract occlusion was discovered to be the reason for the development of congenital hydronephrosis in these 7 cases. Whereas only 1 case was diagnosed as bilateral hydronephrosis, the remaining 6 cases were found to be unilateral, of which half affected the left and the other half the right kidney.

The following graph shows the distribution of these 7 cases on gender and age:

Figure 29 – Age and gender distribution of hydronephrosis cases which required total nephrectomy

Whilst female cases dominate in the age group of 1-7 and 7-18 years of age, the patients beneath the age of one were only male.

Renal dysplasia

In the series, we encountered 6 cases of renal dysplasia. 4 of these were boys and 2 girls. All but 1 case was operated on before the age of 1, the only exception being a 7 year old girl who was operated at the age of 1.

Figure 30 – Age and gender repartition of 6 studied cases with renal dysplasia

Figure 31 – Cartilage island in a cyst wall, characteristic image for renal dysplasia

Figure 32 – Abnormal epithelial duct in a fibro-myomatous stroma

Figure 33 – Abnormal epithelial duct in a fibro-myomatous stroma

Polycystic kidney

In all of the studied samples, there was only one case treated with unilateral nephrectomy. It was performed because of the finding of autosomal recessive (AR) polycystic kidney disease. Usually the lesions were bilateral, but one of the kidneys still had some functional reserves and was spared for the moment. It was the only case found with AR polycystic kidney disease, which didn’t evolve to a stillbirth or death in the first hours of life with Potter syndrome.

Figure 34 – MRI and macroscopic images of this unique case of unilateral nephrectomy

Figure 35 – Microscopic image of an autosomal recessive polycystic kidney

Discussion

Over time, the nephrectomy incidence in the children’s hospital seemed to remain at a constant number, averaging about 3 nephrectomies each year.

This number is not sufficient enough to encourage a paediatric surgeon to subspecialise in urology in the children’s hospital. But many other urologic surgical procedures besides nephrectomy are performed, which may in the future prompt the opening of such subspecialisation.

The children who are diagnosed with a pathology that’s necessary to be treated by nephrectomy, are mostly beneath the age of 6, or usually younger than the age of 2 , with boys being affected more frequently.

By far the most frequent indication for nephrectomy is renal tumors, followed by urinary tract malformations, which generate congenital hydronephrosis.

Resembling our study, an older study analysed renal tumors (between 1974 and 2004) and covered 542 cases with tumoral findings. 162 (29,62 %) were diagnosed with lymphoma, 99 cases (18,26%) with renal tumors, 95 cases (17,36%) with bone tumors, 40 cases (7,31%) with neuroblastoma, 38 cases (6,94%) with rhabdomyosarcoma, 25 cases (4,57%) of liver tumors and 83 cases (15,31%) were included in the category of other tumors. Brain tumors and leukaemia were not included in this study because these diseases were not amongst the diagnosed pathologies. The majority of renal tumors were represented by Wilm’s tumor (91%), the mean age of patients was 5,97 years with a slightly higher frequency in favour of the male gender (54,4%). The remaining renal tumors (9%) belonged to rare entities like renal carcinoma, mesoblastic nephroma, rhabdoid tumor and clear cell sarcoma.

In our study group 59% of all nephrectomies were performed because of the finding of tumoral pathologies.

These tumors are diagnosed and operated on a relatively constant rate over the years, with both genders being affected almost equally.

In our study group, nephroblastoma appeared to be two times more frequent on the left kidney in comparison to the right. This tendency was not observed in the older study mentioned above conducted on 77 nephroblastoma, but is mentioned in literature.

87% of these nephroblastoma cases showed the classic triphasic histology, whereas 12% had a biphasic structure and only in one case monophasic epithelial structure was found.

Only 16.66% of cases showed anaplastic histology. Hence, most of the nephroblastoma had a favourable histology and good prognosis.

16.66% of all nephroblastoma cases showed cystic aspects, therefore suggesting a benign clinical course which was even better.

Additionallty, in the studied time period there was one lethal case with a triphasic nephroblastoma with unfavourable histology and multiorgan metastasis, in a 1,1-year-old boy.

The SIOP European staging system applied to our cases shows that approximately 1/3 of cases are distributed in each of the first 3 SIOP stages. The above-mentioned lethal case was SIOP stage 4, yet no cases in the SIOP stage 5 with bilateral tumors were diagnosed.

Mesoblastic nephroma is the second most frequent type of renal tumors in children and is classified as a benign tumor.

Malformations of the urinary tract, generating congenital or secondary hydronephrosis, are a major indication for nephrectomy in children. These malformations are more frequently encountered in boys, an observation also mentioned in literature.

Renal dysplasia is the second type of renal malformations which requires nephrectomy. In our study group, boys were two times more frequently affected by dysplasia in comparison to girls, and needed to be operated on early before the age of one.

Renal dysplasia is frequently misdiagnosed, being clinically mistaken with polycystic disease or hydronephrosis.

The adult type of the polycystic kidney disease manifests clinically later in life, hence it was not included in our study. The juvenile AR type usually leads to the lethal Potter syndrome. Yet in our series, only one case of the juvenile type appeared which showed residual functioning in one kidney, despite the bilateral renal lesions. Therefore, the appearance of the Potter syndrome was avoided even though one of the kidneys ceased to function soon after birth and was surgically removed by nephrectomy.

Conclusions

In the children’s hospital in Cluj, an average of 3 nephrectomies are performed on children every year.

The patients are mainly male and mostly beneath the age of 2.

The main reasons for performing a nephrectomy in children are kidney tumors, followed by urinary tract and kidney malformations.

Nephroblastoma is markedly the most frequent tumor of kidneys in children and is by far the most abundant indication for nephrectomy in childhood.

Although rare, mesoblastic nephroma and clear cell sarcoma of the kidney can also appear in children.

Nephroblastoma has a maximum incidence at the age of 2 and does not have a significant predilection on gender.

Two thirds of nephroblastoma are located in the left kidney.

The vast majority of nephroblastomas have a classical triphasic histology without anaplasia.

Despite this, two thirds are staged SIOP 2 or 3, indicating an advanced stage with penetration of capsule or renal sinus.

All operated nephroblastoma were treated with chemotherapy before removal (European protocol), displaying necrotic and haemorrhagic secondary changes.

Hydronephrosis and cystic dysplasia are secondary reasons for nephrectomy in children and have a significant predilection for male gender.