We report a case of two synchronous non-related tumors, a TCRC and a ccRCC occurring in the same kidney with molecular characterization of both neoplasms.
TCRC was originally described by Masson who named it "Bellinian epithelioma" or "carcinoma of the collecting ducts" as he believed it originated from collecting ducts of Bellini . MacLennan et al.  in 1997 hypothesized that this tumor represented the low grade of the spectrum of collecting duct carcinoma, as it shares similar characteristics with the latter tumor (i.e., immunopositivity for 34βE12 and UEA-1). In 2004, Amin et al. named the tumor "tubulocystic carcinoma" in a series of 29 cases .
TCRC is a rare entity that characteristically has a small size at presentation (mean 2 cm) and rarely progresses, recurs, or metastasizes [7, 8, 12, 13]. It has been reported in association with other RCCs, primarily papillary RCC . Recent immunohistochemical, ultrastuctural, and molecular studies (RNA expression levels and genomic profile analyses) have shown that TCRC is different from collecting duct carcinoma and may be related to papillary RCCs [5, 7, 8, 13–15]. Supportive findings include the expression of proximal convoluted tubule markers (CD10 and AMACR), distal nephron proteins (parvalbumin, HMWCK and CK19) [5, 7], and the detection of cells reminiscent of proximal tubule and intercalated cells by electron microscopy [5, 13–15]. Further supporting the notion that TCRC is related to papillary RCC is the report of one group that described that TCRC has a gene expression profile similar to that of papillary RCCs using cluster analysis . However, another study showed a distinct gene expression profile characterized by expression of cell cycle and biomolecule metabolism genes although this group did not compare this profile directly to papillary tumors . Using fluorescence in situ hybridization (FISH) and array-based comparative genomic hybridization (aCGH), Zhou et al.  and Yang et al.  have shown gains in chromosome 17, as is seen with papillary RCCs and thus have proposed that these two entities are closely related.
Our case showed classic features of TCRC, such as positive immunohistochemistry for CD10, AMACR and CK19, as well as gains of chromosome 17 in the virtual karyotyping analysis. In addition, the TCRC also showed gains in chromosome 8 and loss of chromosome 9 (Figure 5). The chromosomal imbalance pattern observed in our TCRC case is distinct from that found in papillary RCC which commonly shows gains of 7 and 17 and rarely shows gains of 8 or loss of 9 . Importantly, loss of chromosome 9 and gain of 17 seem to be recurrent chromosomal imbalances in TCRC tumors (Monzon and Amin, unpublished observations). If this is confirmed in a large case series, it could help establish TCRC as a genetically separate entity from papillary RCC. It is important to note that the cystic and somewhat paucicellular nature of the tumor may be an important consideration when performing molecular analyses of this tumor subtype, since stromal cells may play a role as contaminants. Also, the role of stromal cells in the pathogenesis of TCRC remains uncertain, since metastatic cases not only show the cystic glandular configurations but also the intervening stroma .
The differential diagnosis of TCRC includes mixed epithelial and stromal tumor and cystic nephroma . The former, another variant of RCC, is easily ruled out as typically displays an ovarian-like stroma that is usually estrogen receptor positive and occurs predominantly in female patients [17, 18]. The so-called cystic nephroma has become basically a non-existent entity [17, 19]. In the WHO classification of renal tumors  there is an illustration of a cystic nephroma which looks identical to the TCRC. We suspect that the "cystic nephroma" is actually the tumor now known as TCRC.
There are sporadic reports about the coexistence of TCRC with other renal tumors of different subtypes. Yang et al. reported 5 cases of TCRC associated with either papillary RCC or papillary adenomas . Gonul et al. reported a case of synchronous ccRCC, micropapillary urothelial carcinoma and TCRC in a 57-year-old male with hematuria . Brennan et al. presented a case of a 72-year-old male with end stage renal disease who developed a TCRC, a type 2 papillary RCC, a clear cell papillary and cystic RCC as well as renal oncocytosis, hybrid tumors and chromophobe RCC . More recently, Deshmukh et al. reported a synchronous TCRC and papillary RCC in a young female with metastatic papillary RCC in para-aortic lymph nodes . Thus, although TCRC has been reported in association with multiple other renal cell tumor subtypes, it appears that there is a slight predominance for synchronous TCRC and papillary tumors. An interesting question raised by the coexistence of TCRC with other renal tumors is whether there are common predisposing factors for these histologically different tumors.
The ccRCC in this case showed a spectrum of morphologic variations ranging from low grade to high grade and a distinct nodule with oncocytic changes which allowed us to inquire about molecular differences within morphologic progression in a single tumor. We analyzed the areas in the ccRCC showing different grade and morphology using virtual karyotyping and demonstrated that a higher Fuhrman grade correlated with an increase in chromosomal imbalances (Figure 5). In a similar fashion, studies on chromophobe RCCs have shown that multiple chromosomal gains are associated with sarcomatoid transformation . More recently, Patani et al. using high-resolution aCGH and FISH have also demonstrated that morphologically distinct regions from a case of triple-negative breast carcinoma (apocrine vs. non-apocrine areas) correlate with different genetic aberrations .
In addition to the somatically acquired genetic changes in the tumors, the patient's tumor had regions of inherited uniparental disomy (UPD, i.e. two chromosomal regions inherited from one parent only) in chromosomes 2 and 6 (Figure 5, asterisks). The presence of these genetic lesions in the normal kidney tissue suggests a possible inherited origin. Although uniparental disomy has been implicated as a risk factor for colon and other cancers, its role in the predisposition of renal tumors is currently unknown .
In conclusion, this case allowed us to explore two uses of whole genome analysis with virtual karyotyping. The first was to confirm that ccRCC and TCRC have distinct genomic copy number profiles and that TCRC appears to have recurrent gains in chromosome 17 which might be implicated in the pathogenesis of this tumor. Second, the presence of a ccRCC with varying degrees of differentiation allowed us to evaluate the sequence of chromosomal imbalances acquired during tumor progression. These findings support the concept that chromosomal imbalances are associated with tumor progression , and possibly explain why Fuhrman grading is a strong prognostic factor in ccRCC  even when high grade cells are present in a minority of the specimen .