Introduction

MiT translocation renal cell carcinomas (TRCC) constitute a group of recently described rare kidney tumours. These tumours predominantly occur in younger patients with only about 25% affecting patients over 40 year of age (see Table 1). TRCC contains two main subgroups: Srigley et al. 2013 Tumours with translocation 6p21 [t (6;11)] have characteristic histopathological features and imunohistochemical properties and have been labelled “rosette forming HMB45 positive renal tumour” in addition to “TFEB RCC”. Hora et al. 2008 The second subgroup is composed of tumours with translocations involving Xp11.2 [t (X; 1 or X or 17)]. TRCC Xp11.2 is included in the 2004 WHO renal tumours classification already. In the ISUP (International Society of Urological Pathology) Vancouver classification of renal neoplasia Srigley et al. 2013 these tumours have been added as a new subgroup of RCC: “MiT family TRCC” with two subgroup – Xp11 TRCC and t (6;11) RCC.

Table 1 Review of literature about MiT TRCC since 2007
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Papers dealing with TRCCs have been published mostly by pathologists and geneticists. It is difficult and time consuming to get clinically relevant data useful for daily urological practice. We present 10 cases of TRCC collected from the whole Czech Republic (10 million of inhabitants) focusing on data important from to point of view of practicing urologists.

Material and methods

During 2001 to 2012, 1653 kidney tumours were surgically treated at the urological department of the main author. Eight of them were TRCC (0.48%). Two more cases were identified in the tumour registry of the Department of Pathology, Faculty Hospital, Pilsen, CZ. The registry includes over 16000 cases of renal tumours, of which a significant component is international consult cases. Due to easy access to clinical data including CT and to avoid ethical problems with approving the study in different countries, only cases from CZ were included. These ten cases are presented in detail. Five cases have previously been published Hora et al. 2008; Hora et al. 2009. Extended follow-up information is provided for these cases in this paper. These cases are: two TRCC Xp.11 (in Table 2 cases 2 and 5) Hora et al. 2008 and three TFEB TRCC (in Table 2 cases 1, 3, 4) Hora et al. 2009. The morphological diagnosis was supported by immunohistochemical examination. In 1 of 4 cases of Xp11.2 TRCC, morphological and immunohistochemical results were extended by FISH analysis of TFE3 break. See Table 3. In one case, the diagnosis was verified. The other 4 cases were not analysable due to low quality of DNA. Among 4 cases of 6p21, three were morphological and immunohistochemical analysis supported by FISH and RT PCR (reverse transcription polymerase chain reaction) analysis. The presence of the translocation t (6;11) (Alpha-TFEB) was confirmed in these 3 analysed cases. In one case (percutaneous biopsy only), the diagnosis was established without molecular genetic confirmation, i.e. based exclusively on morphology and results of immunohistochemistry.

Table 2 Results
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Table 3 Types of translocation renal cell carcinoma Xp11.2 Hora et al. ( 2008 )
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Results

The results are summarised in the Table 2. Selected cases, see Figures 1, 2 and 3. Based on these, we can conclude that TRCCs were more common in females (70%). Patient with TRCC type 6p21 were younger than those with Xp11.2 TRCC (average 40.7 ± 25.8 vs. 54.6 ± 20.3 years, median 31.9 vs. 51.2). The biological behaviour of the two main group of MiT TRCC is probably different. Type Xp11.2 TRCC is a more aggressive neoplasm with (malignant course in 3/6 cases – 50%). In four patients with 6p21 TRCC, one (25%) died due to generalisation.

Figure 1
figure 1

Dissected specimen at operation: woman, 75-year-old, a tumour of the right kidney. In table case No. 5. Tumour was on CT spheroid, 34 mm in maximal diameter, relatively homogenous, native density13-26HU, postcontrast density (venous phase) 15–43 HU. R was performed. A dissected specimen at operation: ochre-orange relatively homogenous spheroid tumour very different from clear renal cell carcinoma, maybe a little similar to any papillary RCC. Histological diagnosis: Translocation carcinoma Xp11.2, subtype ASPL-TFE3, verified genetically.

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Figure 2
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Woman 34-year-old, tumour of the left kidney (a) T3aN2M1, metastases to the paraaortal lymph nodes (b), left pubic bone (c), liver (d). Biopsy Translocation carcinoma Xp11.2. In Table 2 case No. 10.

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Figure 3
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Postcontrast CT: woman 78-year-old, left kidney tumour T3aN0M1 (metastases to lung), maximal diameter of tumour 172 mm. In Table 2, case No. 9. She underwent cytoreductive nephrectomy, specimen 1850 g. Histology TRCC 6p21. She died in 3 months. The forth case of aggressive TRCC 6p21 described in literature.

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Discussion

MiT (F) (microphtalmia transcription factor) TRCCs most likely originate from the proximal tubule of the nephron. TRCCs are found predominantly in children and young adults, but are increasingly being recognized in adults. These tumours are characterized by the occurrence of recurrent chromosomal translocations, which result in disruption and fusion of either the TFE3 or TFEB genes, both members of the MiT family of basic helix-loop-helix/leucine-zipper transcription factor genes. Hence the name MiT translocation subgroup of RCCs. The MiT family (MiTF/TFE family) includes TFE3, TFEB, and also TFEC and MiTF transcription factors Srigley et al. 2013.

In clinical practise, we most commonly encounter TRCC TFE3 (divided in at least 6 subtypes, see Table 3) and TFEB type. We have identified 110 published cases of Xp11.2 TRCC in the English literature since 2007 to October 2013. See Table 1. The TFE3 gene is located on the X chromosome, locus p11.2. Translocations result in fusions of the TFE3 gene with several other genes which are listed in Table 3. Question The correct diagnosis is reached through a combination of histomorphology, immunohistochemistry and, in selected cases, molecular genetic studies. Since the translocations lead to overexpression of the TFE3 protein, immunohistochemical staining for TFE3 is widely used as a surrogate marker for the Xp11.2 translocation Klatte et al. 2012 Komai et al. Komai et al. 2009 described 7 cases of TRCC Xp11.2, 4 of them were diagnosed cytogenetically, 3 by immunohistochemistry only. Argani et al. 2007 confirmed genetically in group of 28 Xp11 TRCC only three. But Klatte et al. 2012 found in 17 TFE3 positive tumours Xp11.2 translocation in only 2 cases and they recommended making diagnosis of Xp.11.2 translocation RCC only genetically. Other group verified Xp11.2 by RT-PCR 2 cases in 6 TFE3 positive Gaillot-Durand et al. 2013 TFE3 negative tumours on immunohistochemistry can be FISH positive Rao et al. 2013. Our ten cases of TRCC were diagnosed by morphology and immunohistochemistry and only one verified genetically because the limitation of the quality of DNA. But we hope that modern reliable imunohistochemical staining can be very precise and more exact. Sensitivity and specificity of TFE3 tests are now being discussed by pathologists. Manual overnight labelling seems to be more precise than automated immunostainer with 30 min incubation Gaillot-Durand et al. 2013. However precise histological diagnosis verified by cytogenetic studies is missing in some cases and it can be source of bias of this study.

There is little information on clinically relevant data when dealing with patients with Xp11.2 TRCC. The tumours most commonly affect patient under 45 year up to 15% Kuroda et al. 2012. In some previous studies data on the radiological features (CT and MRI) of Xp11 TRCC have been presented. These have failed to identify any specific radiological features of this tumour Liu et al. 2013;Koo et al. 2013; Kato et al. 2011).

Xp11.2 RCC is a biologically aggressive neoplasm with a bad prognosis and previously published data suggest that the prognosis may be even worse in men over 50 years Kuroda et al. 2012; Arnoux et al. 2012. In our group of 6 cases, the ages were similar in patients with aggressive vs. with benign clinical course 52.4 vs. 56.8 years). The oncological therapy is reviewed in Table 1. The same oncological treatment protocols as for clear cell RCC have been used. No firm conclusions regarding the efficacy can be drawn based on this data. In our group, 2/3 of cases have a fatal course in relatively short follow-up.

The other (rare) but more commonly encountered MiT TRCC is “CC with t (6;11) translocation” (abbreviated “6p21 TRCC” or “t (6;11) TRCC”). Owing to the characteristic histopathological features and imunohistochemical properties of this tumour, it has been termed “osette-like forming, HMB45-positive renal tumour” Hora et al. 2009. An alternative designation/term that is used is “TFEB RCC”. This tumour harbours translocations involving the transcription factor EB (TFEB) and Alpha (the latter also known as MALATI). Genetically, TFEB RCC has been characterized by the fusion of the 5’ portion of Alpha, also known as MALATI (Genbank accession number AF203815), an intronless gene mapped at 11q12, with TFEB at 6p21 Inamura et al. 2012; Rao et al. 2012 with fewer than 30 cases reported to date Hora et al. 2009; Inamura et al. 2012; Rao et al. 2012; Camparo et al. 2008; Suarez-Vilela et al. 2011. First 11 cases were reviewed by Hora et al. 2009, cases published since 2007 are summarised in Table 1. The morphology of TFEB TRCC is distinctive and the diagnosis can be established based on a combination of histopathological examination in conjunction with immunohistochemistry. Role of molecular genetic studies is not as crucial as in Xp11.2 TRCC Hora et al. 2009. The malignant potential is low. Only three cases with aggressive behaviour have been published (approximately 10%) Inamura et al. 2012; Pecciarini et al. 2007; Ishihara et al. 2011. We add one more case with aggressive clinical course.

Conclusion

TRCCs were more common in females. Patient with 6p21 were younger than those with Xp11.2. Both types have definitive malignant potential, type Xp11.2 TRCC seem to be more aggressive neoplasm. Metastatic 6p21 is 4th case described in literature. From a clinical point of view, subclassification of TRCCs is of utmost clinical relevance.

Citations of articles used in the table: Argani et al. 2007 Rais-Bahrami et al. 2007 LaGrange et al. 2007 Franzini et al. 2007 Hora et al. 2008 Camparo et al. 2008 Hora et al. 2009 Suarez-Vilela et al. 2011, Koie et al. 2009 Armah et al. 2009 Kuroda et al. 2010 Choueiri et al. 2010 Ishihara et al. 2011 Liu et al. 2011 Nelius et al. 2011 Numakura et al. 2011, Kato et al. 2011 Klatte et al. 2012 Morii et al. 2012 Rao et al. 2012 Inamura et al. 2012 Arnoux et al. 2012 Komai et al. 2009 Gaillot-Durand et al. 2013.