DOI: 10.2478/v10163-012-0008-6

ACTA CHIRURGICA LATVIENSIS • 2011 (11)

ORIGINAL ARTICLE

Morphological and Immunohistochemical Characteristics of Surgically Removed Paediatric Renal Tumours in Latvia (1997–2010)

Ivanda Franckeviča*,**, Regīna Kleina*, Ivars Melderis** *Riga Stradins University, Riga, Latvia **Children’s Clinical University Hospital, Riga, Latvia

Summary Introduction. Paediatric renal tumours represent 7% of all childhood . The variable appearances of the tumours and their rarity make them especially challenging group of lesions for the paediatric pathologist. In Latvia diagnostics and treatment of childhood malignancies is concentrated in Children’s Clinical University Hospital. Microscopic evaluation of them is realised in Pathology office of this hospital. Aim of the study is to analyze morphologic spectrum of children tumours in Latvia and to characterise them from modern positions with wide range of immunohistochemical markers using morphological material of Pathology bureau of Children’s Clinical University Hospital. Materials and methods. We have analyzed surgically removed primary renal tumours in Children Clinical University Hospital from the year 1997 till 2010. Samples were fixed in 10% formalin fluid, imbedded in paraffin and haematoxylin-eosin stained slides were re-examined. Immunohistochemical re-investigation was made in 65.91% of cases. For differential diagnostic purposes were used antibodies for the detection of bcl-2, CD34, EMA, , desmin, , CKAE1/AE3, CK7, Ki67, LCA, WT1, CD99, NSE, chromogranin, synaptophyzin, S100, myoglobin, miogenin, MyoD1 (DakoCytomation) and INI1 (Santa Cruz Biotechnology). Results. During the revised period there were diagnosed 44 renal tumours. Accordingly of morphological examination data were divided: 1) nephroblastoma – 75%, 2) clear cell – 2.27%, 3) rhabdoid tumour – 4.55%, 4) – 4.55%, 5) embrional – 2.27%, 6) – 4.55%, 7) multicystic nephroma – 4.55%, 8) angiosarcoma – 2.27%. Immunohistochemical investigation specify the diagnosis in 4.55% of patients. In case of embryonal rhabdomyosarcoma we found that immunophenotype is more typical for cellular mesoblastic nephroma (infantile renal ) but one neuroblastoma was misdiagnosed as nephroblastoma. Conclusions. 1. The most common childhood renal tumours in Latvia like in the world is nephroblastoma. 2. In Latvia there are diagnosed such rare pediatric tumours as and rhabdoid tumour; amount of first one is like in the world, but rhabdoid tumour was more common in Latvia then in the world. 3. No cases of was diagnosed under age of 18 what differs from the data of the world. 4. The results of our investigations proved that immunohistochemical analytic schemes for blastemal type nephroblastoma and mesenchymal kidney tumours in our hospital should be extend but for the precise diagnosis of rhabdoid tumour of kidney would be recommended cooperation between laboratories of several countries for the detection of INI1 protein expression. Keywords: Paediatric renal tumours in Latvia, immunohistochemistry Abbreviations: WT – Wilms’ tumour, CCSK - clear cell sarcoma of the kidney, RTK - rhabdoid tumour of kidney, MN - mesoblastic nephroma, IFS - infantile fibrosarcoma, CMN - cellular mesoblastic nephroma WT1 – Wilms’ tumour gene marker, CKAE1/AE3 - common EMA - epithelial membrane antigen, LCA - leukocyte common antigen, NSE - neuron-specific enolase, H&E - haematoxylin- eosin, PNET – primitive neuroectodermal tumour, MA - .

INTRODUCTION the development of accurate diagnostic criteria, stage Paediatric renal tumours represent 7% of all tumours in and -based therapeutic stratifications, and first 15 years of life. Wilms’ tumour or nephroblastoma appropriate surgical techniques. In relation to 5 year is the most common (85% of cases), followed by renal survival of patients there is a dramatic improvement cell carcinomas (3-5%), mesoblastic nephroma (3%), in prognosis in WT case – from 8% at the beginning clear cell sarcoma of the kidney, rhabdoid tumour of the of 20th century, to approximately 50% in 1960 kidney (2%) and miscellaneous rare tumours (2%) [6]. and greater than 90% in 2000 [13]. Equally 5 year Accurate histological diagnosis and staging of these survival of patients with CCSK has increased from tumours are critical because their treatment and only 20% up to 70% due to the addition doxorubicin prognosis are very different. During the past 40 years to chemotherapeutic protocols [3]. At the same time cooperative groups targeting paediatric renal tumours outcome of RTK is typical dismal, as over 80% of have been remarkably successful. They have enabled patients will die of tumour within 2 years of diagnosis

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[18]. Mesoblastic nephroma in general is benign RESULTS tumour that classical variant histological is identical to Due to the clinically diagnosed primary renal tumours the with a survival rate 100%. The cellular 45 and 3 partial kidney resection were variant is associated with the worse prognosis as a done in years 1997-2010. The tumour diagnosis was survival rate of 5 years is 85% [1]. Histological cellular confirmed in 91.67% of cases (n=44), but in 8.33% (n=4) variant is identical to the infantile fibrosarcoma and pathologist findings did not meet the clinical diagnosis of shows translocation t(12; 15)(p13;q25) which leads to tumour. 6.25% (n=3) of cases the clinical diagnosis was the ETV6-NTRK3 gene fusion. Identical translocation primary renal tumour (lymphoma, renal cell cancer) has also been reported in fibrosarcoma suggesting that but histologically was found xanthogranulomatous the cellular subtype MN would represent an intrarenal pyelonephritis. In 2.08% (n=1) pathological process IFS [16]. 5% of the patients with mesoblastic cellular morphologically was not found. The amount of analyzed nephroma have recurrence usually within the first paediatric renal tumours during overviewed period year after the and only few cases had 1997-2010 is showed in Fig.1. metastases [1]. It is believed that completely excised MN 10 is associated with an excellent prognosis. Effectiveness 1997 9 of in CMN case is discussible as not all of them are chemosensitive. Candidates to adjuvant 8 chemotherapy are patients older than 3 month with the 7 cellular variant of tumour, neoplastic tissues in surgical 6 2008 margins, rupture of tumour during resection or vascular 5 2002 2009 microinvasions [1]. 4 1998 2000 2004 2005 2006 2007 3 AIM TO THE STUDY 2010 2 Aim of the study is to analyze morphologic spectrum of 1999 2003 1 children kidney tumours in Latvia and to characterise 2001 them from modern positions with wide range of 0 immunohistochemical markers using morphological material of Pathology bureau of Children’s Clinical Fig. 1. Number of Primary Paediatric Renal University Hospital. Tumours in Children’s Clinical University Hospital (1997_2010), Riga, Latvia. MATERIALS AND METHODS Our morphological examinations had proved such We have analyzed all surgically removed primary different subtypes of renal tumours: renal tumours cases in Children Clinical University 1) nephroblastoma – 75% (n=33), 2) clear cell sarcoma – Hospital from 1997 till 2010. In this study we have 2.27% (n=1), 3) rhabdoid tumour - 4, 55% (n=2), not included surgical material and biopsies from 4) angiomyolipoma – 4, 55% (n=2), 5) embrional kidneys due to others reasons: e.g., secondary tumours rhabdomyosarcoma – 2,27% (n=1), 6) mesoblastic of kidney or due to retroperitoneal like nephroma – 4,55% (n=2), 7) multicystic nephroma – neuroblastoma with into kidney. Primary 4,55% (n=2), 8) angiosarcoma- 2, 27% (n=1). morphological examination data and tissue material of After modern immunohistochemical analysis one case diagnosed tumours were retrieved from the archive of of nephroblastoma was interpreted as neuroblastoma. the Pathology bureau of Children Clinical University Histologically the tumour cells were small and Hospital. All tumour tissues were fixed in 10% formalin regular, with round, deeply staining nuclei and fluid, imbedded in paraffin, stained with haematoxylin– little cytoplasm. Few Homer Wright rosettes were eosin and re-tested. Complete immunohistochemical present. Immunohistochemistry showed complete investigation was provided in 65.91 % of cases. In lack of WT1expression, the tumour had no EMA and all analysed cases were detected WT1, vimentin, CKAE1/AE3 positive epithelial structures but reaction CKAE1/AE3, EMA, Ki67 antigen (all antibodies with neuronal markers as NSE, synatophysin and DakoCytomation, Denmark). In addition we have used chromogranin showed strong immunoexpression. antibodies for the detection of bcl-2, actin, desmin, CK7, Reactions for other childhood small round cell tumours LCA, CD99, NSE, chromogranin, synaptophyzin, S100, markers as LCA, desmin, vimentin, aktin, myoglobin, myoglobin, miogenin, MyoD1, CD34 (DakoCytomation, myogenin and CD99 were negative. Ki67 labelling Denmark) and INI1 protein (Santa Cruz Biotechnology, index was 40%. In one other nephroblastoma case re- USA). Proliferation activity of tumours was assessed investigation was encountered differential diagnostic counting Ki67 positive cells by magnification x400 and difficulty. Histological diagnosis in the morphological expressed as percentage. Obtained data were analyzed investigation was nephroblastoma mixed (epithelial mathematically using computer program Microsoft blastemal) type. Tumour was well circumscribed but Excel. Descriptive statistics was used. There is no ethical not encapsulated, the entire tumour was composed of conflict in this report; the principles outlined in the primitive, compactly arranged small acinar epithelial Declaration of Helsinki were followed by authors. structures, necrosis and vascular invasion were not found. The acini were variably arranged, dense to loosely

45 ACTA CHIRURGICA LATVIENSIS • 2011 (11) scattered in acellular stroma. Immunohistochemically (n=4), mesenchymal - 12.5% (n=4), regressive - 6.25% was found diffuse membranous CKAE1/AE3 positivity (n=2), 3.12% (n=1) was found cystic nephroblastoma. in all tumour cells but EMA and vimentin were Only in one case or 3.12% of the all analyzed samples negative. Nuclear reaction with WT1 was positive in all diffuse (unfavourable histology) was found. tumour cells (Fig.2), CK7 was negative in tumour cells Tumour belonged to the blastemal type nephroblastoma but positive in normal tubular showed. Ki67 group. Patient was 8 months old boy, 4 months after expression was patchy. The average size of Ki67 was 18, the first surgery developed tumour recurrence. Nine 44%. Histological and immunohistochemical picture (90%) of the ten epithelial type nephroblastoma cases of this case is more characteristic for metanephric showed tubular differentiation, in one case (10%) could adenoma [12] but finding of proliferation index excludes be seen glomerular differentiation. In one of the tubular diagnosis of adenoma therefore was decided to establish differentiation case has been above described pattern a diagnosis nephroblastoma epithelial type (pattern like like metanephric adenoma. metanephric adenoma). During the analysis of other non WT cases immunohistochemistry was made in six cases of them. In two cases the primary morphological investigation approved diagnosis of rhabdoid tumour. In one of cases the tumour cells typically showed the cytological triad of vesicular chromatin, prominent cherry-red nucleoli and hyaline pink cytoplasm inclusions. In the second case cytoplasm inclusions were not prominent and diagnostic difficulties were caused by extensive tumour necrosis too. Immunohistochemical analysis in both cases showed strong vimentin positivity and focal positivity of EMA and CKAE1/AE3. Reaction for the detection of WT1, bcl-2, muscle specific actin, S100, CD99, NSE, LCA, desmin, synaptophysin, and CD34 mainly were negative in tumour cells. In both cases there was detected INI1 protein expression in tumour cells and was found extensive loss of nuclear staining in tumour cells, whilst the nuclei of adjacent normal Fig. 2. Wilms’ tumour epithelial (pattern like cells retain their pattern (Fig.3) corresponding to the metanephric adenoma) WT1 immunoexpression described immunoprofile of rhabdoid tumour [2]. in epithelial cells nuclei. Magnification x200. During reviewed period there was also diagnosed such rare primary renal tumour as clear cell sarcoma. Histologically tumour was composed of spindled cells, which were separated by extracellular myxoid material that mimics clear cytoplasm. Immunohistochemical investigation showed bcl-2 and vimentin positivity (Fig.4), reaction for the detection of WT1, CD34, EMA, muscle specific actin, desmin, CKAE1/AE3, LCA was negative (Fig.5). That pattern is consistent with literature data about immunoprofile of clear cell sarcoma of kidney [17].

Fig. 3. Rhabdoid tumour of kidney – loss of INI1 protein expression in tumour cell nuclei. Magnification x200. From 32 nephroblastoma patients 16 were male and 16 were female (M/F =1). Patients age was from 8 months till 17 years 11 months (average 64.15 months, standard deviation 61.31, mode 36) but 62.5% (n=20) were patients till the age of 4 years. The morphologic types of WT were: blastemal - 34.37% (n=11), epithelial - 31.25% (n=10), mixed (epithelial blastemal) - 12.5% Fig. 4. Clear cell sarcoma of kidney. Bcl-2 positivity in the cytoplasm of tumour cells. Magnification x200. 46 ACTA CHIRURGICA LATVIENSIS • 2011 (11)

nephroblastoma (75% after histological investigation and 72.73% after immunohistochemistry). In our research also rare paediatric primary renal tumours have been approved as rhabdoid tumour, clear cell sarcoma and angiomyolipoma. In two cases (4.54%) immunohistochemical re-investigation clarified the diagnosis. Diagnosis of embrional rhabdomiosarcoma was changed to cellular mesoblastic nephroma and one of nephroblastoma diagnosis was changed to neuroblastoma. Primary and re-investigation data are showed in Fig.6.

Fig. 5. Clear cell sarcoma of kidney. Nuclear WT1 negativity, non-specific reaction in the cytoplasm of tumour cells Magnification x200. By immunohistochemical re-investigation diagnosis of embryonal rhabdomyosarcoma was changed to cellular mesoblastic nephroma. Patient was 25 days old girl with congenital tumour of kidney. Tumour was composed of plump spindle cells with histologically features of myofibroblasts that infiltrate adjacent tissue. Some necroses were present. Complete immunohistochemistry showed: vimentin positivity, reaction for muscular markers as MyoD1, muscle specific actin, desmin, myogenin was negative. Others markers as WT1, EMA, CKAE1/AE3, CD34, CD31, Fig. 6. The amount of renal tumours in percentage LCA were negative, reaction with bcl-2 showed rare accordingly primary morphological and cells positivity. Ki67 labelling index was 44.44%. immunohistochemical re-investigation data. Accordingly to clinical data, histological picture and complete immunohistochemistry there were decided DISCUSSION to specify a diagnosis as cellular mesoblastic nephroma Analyzing the results of current research everyone (infantile renal fibrosarcoma). should take into account the fact that all investigated Both cases of angiomyolipoma were analyzed renal children tumours are rare in Latvia and the total immunohistochemically too and they had typical number of tumours is small. In our investigation we met histological pattern. Tumours were composed of the situations that tumour’s tissue quality not always adipose tissue, spindle and epitheloid allowed the full imunohistochemical investigation but cells and abnormal thick-walled blood vessels [8]. the review of H&E slides of all tissue material showed Immunohistochemistry showed desmin and muscle that there was insufficient justification to change an specific actin positivity, epithelial markers as EMA existing morphological diagnosis and exclude cases and CKAE1/AE3 were negative, CD34 was positive from a primary renal tumours group. Therefore, some in vascular structures corresponding to the picture of mesoblastic nephroma cases as well as angiosarcoma angiomiolipoma. Ki67 labelling index was 4% in first were included in the total spectrum of tumours. case and less than 1% in second case. Despite the problems we believe that it is absolutely Both cases of were revised only in H&E necessary to research diagnosed material to gather specimens as tumours had characteristic histological experience and improve the diagnostic quality as well pattern and there were lack of immunohistochemical as present paediatric renal tumour spectrum of Latvia. markers. Histologically tumours were composed entirely Our study showed that in Children’s Clinical University of with delicate septa, cysts were lined with Hospital like in the world between renal tumours cuboidal epithelium or lack lining epithelium, and septa of kids mainly was nephroblastoma but spectrum of were variably cellular and contained undifferentiated the other morphological type was enough broad and and differentiated . Blastema and are diagnosed such rare primary renal neoplasms as nephroblastomatous epithelial elements were no found. rhabdoid tumour and clear cell sarcoma. In comparison Summarizing the data of all analyzed tumours, it can be Lithuanian colleagues in Vilnius University Children’s seen, that accordingly of morphological investigation as Hospital from 1997 till 2008 were investigated 30 well as immunohistochemical analysis data in general primary renal tumours. 93.7% of them were WT but between renal tumours of kids in Latvia mainly is 6.3% renal cell carcinoma [11]. Opposite in our hospital

47 ACTA CHIRURGICA LATVIENSIS • 2011 (11) there was not detected malignant renal epithelial and young children. [2;14]. In one of our cases was neoplasm in children and this diagnosis was not not a classic picture of tumour therefore INI1 protein established in our immunohistochemical investigation expression was immunohistochemicaly investigated in too. Our re-investigation of all surgically removed both cases and diagnosis were verified in Our Lady’s renal tumours diagnosis has clarified in 4.54% of cases. Children’s Hospital, Dublin (Ireland). Currently in Latvia Results of immunohistochemical analysis revealed some detection of INI1 protein is too expensive as RTK is rare questions which should be addressed to practitioners. tumour and the period between our two RTK cases Each must take into consideration that usually WT is was five years. Therefore we recommend cooperation a tumour with classic histological picture composed of between laboratories of some countries to detection of variable mixtures of blastema, epithelium and stroma, INI1 protein expression to specify diagnosis. but there are cases when in some tumours only two The case of diagnosed rhabdomyosarcoma was also and occasionally only one component is present. carefully immunohistochemicaly investigated but Diagnostic problems usually provide differentiation it is really rare one. Grignon et al. reviewed the between blastemal type WT and other “small round literature and found only eight convincing cases [10]. cell tumour” especially neuroblastoma, PNET, renal Most renal tumours with appearances suggesting lymphoma as well as CCSK and RTK [15]. In our study rhabdomyosarcoma are something another [8]. In complete immunohistochemical investigation showed our case, detailed immunohistochemical investigation immunoprofile of neuroblastoma in one of blastemal findings with vimentin positivity, above mentioned type WT case. This problem must be solved with a broad muscular markers, WT1 and bcl-2 negativity is more immunohistochemical investigation scheme including appropriate for cellular mesoblastic nephroma [4]. detection of WT1, neuroendocrine, epithelial markers, Proliferative activity was high. Ki67 level was 44, 44% LCA and CD99 markers [15; 7]. It should be noted that in comparison with that one described in literature nephroblastoma is characterized by vimentin positivity 20% -15% [21]. Therefore pathologist’s choice to make in blastemal cells while the mature epithelial structures diagnosis of malignant tumour during morphological showed positivity of epithelial markers [7].Positive investigation is understandable but next one could staining of Wilms’ tumour gene marker in blastemal be recommended critically to evaluate diagnosis of cells and early epithelial structures is present around primary renal rhabdomyosarcoma taking into account 70% of WT cases [5]. Morphological differentiation differential diagnosis of cellular mesoblastic nephroma between metanephric adenoma and WT may be especially since here is the question about adequate difficult too. MA is an uncommon renal epithelial chemotherapy. neoplasm of primitive appearance that belongs to the spectrum of nephrogenic rest- derived tumours, which CONCLUSIONS also include WT, metanephric adenofibroma and 1. The most common childhood renal tumours in metanephric stromal tumour. Although WT is thought Latvia like in the world is nephroblastoma. to represent the malignant end of this spectrum, the 2. In Latvia there are diagnosed such rare pediatric other metanephric neoplasms are generally regarded tumours as clear cell sarcoma and rhabdoid as benign. Immunohistochemistry of MA often shows tumour; amount of first one is like in the world, diffuse nuclear positivity with WT1 and variable but rhabdoid tumour was more common in Latvia expression of epithelial markers. In our case critical was then in the world. detection of Ki67 labelling index because in described 3. No cases of renal cell carcinoma was diagnosed adenomas cases it was low. It may be less than 1% under age of 18 what differs from the data of the and sometimes achieves the 5% level [9, 12] therefore world. the diagnosis of adenoma was not confirmed. Correct 4. The results of our investigations proved that diagnosis of RTK really is difficult question in paediatric immunohistochemical analytic schemes for pathologist practice too. Although in most of cases blastemal type nephroblastoma and mesenchymal diagnosis could be made correctly on the basis of careful kidney tumours in our hospital should be extend interpretation of light microscopic details but there but for the precise diagnosis of rhabdoid tumour is sufficient opportunity to make mistakes. Tumours of kidney would be recommended cooperation originally diagnosed as rhabdoid tumour of kidney often between laboratories of several countries for the were found to be other renal tumour and vice versa in detection of INI1 protein expression. a lot of studies in other countries too [19; 20]. A wide range of renal neoplasms mimicking RTK was described. ACKNOWLEDGEMENT It consist of a diverse group of neoplasms, including This study is supported in part by European Social anaplastic WT, congenital mesoblastic nephroma, Foundation (ESF). Our special thanks to Maureen renal cell carcinoma, rhabdomyosarcoma, malignant J.O’Sullivan (Our Lady’s Children’s Hospital, Dublin, neuroepithelial tumours and lymphoma [20].Molecular Ireland) for the assistance in investigation of INI1 hallmark of rhabdoid tumour is biallelic inactivation protein expression. of the hsNF5/INI1 tumour suppressor gene. This leads to loss of INI1 protein expression, which may serve Conflict of interest: None as a useful immunohistochemical marker in infants

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