Over the past twenty years, only seven cases of colorectal tumors with a rhabdoid phenotype have been reported [1–3]. These tumors are generally found in elderly patients at the proximal colon and show an aggressive behaviour characterized by an overall survival time shorter than 12 months [1, 2]. The main differential diagnosis is with the malignant rhabdoid tumors (MRTs), a neoplasm more common in childhood characterized by genetic inactivation of SMARCB1 (SNF5, INI-1), a component of the SWI/SNF chromatin remodelling complex or deletions at chromosome 22q [4–6]. Loss of epithelial markers, such as CK20, CDX2 and E-cadherin was observed in RCTs but neither in the matched normal mucosa nor adenomas. Although loss of CK20 and CDX2 is commonly observed in right-sided colorectal carcinoma [15, 16] with high tumor grades and high microsatellite instability, the progressive increase of vimentin immunoreactivity may indicate that the sarcomatous dedifferentiation occurs in late stages of rhabdoid carcinogenesis and could be a crucial event in the transition from adenocarcinoma to RCT [1–3]. Usually, RCTs express high levels of EGFR [1, 2], a finding that is recurrent also in other subgroups of highly aggressive CRCs. These results suggest that a combined assessment of CDX2, Vimentin and EGFR may be of clinical value to make a differential diagnosis, to predict a poor patients’ outcome or to choose the best fit biological therapy [17, 18]. INI1 loss-of-function mutations have been identified in pediatric MRTs, whereas their role in adult extra-renal rhabdoid tumors is still elusive [5, 6]. Although loss of INI1 expression is a constant finding in MRT of soft tissues, kidney or central nervous system (CNS), INI1 staining was positive in the normal mucosa, adenomas and intensely in pure RCT, and negative in the composite RCT. Loss of INI1 in MRT is mainly due to mutations and/or deletions of the 22q11.2 locus; alternatively, it may be due to epigenetic events. The 22q12 locus was normal in composite RCT with lack of INI1 whereas it was rearranged in pure RCT with an intense INI1 staining, supporting the hypothesis of gene inactivation possibly by epigenetic mechanisms. The EWS gene is located on chromosome 22q12 and its translocation with members of the ETS families is a recurrent alteration in Ewing sarcoma, although other EWS rearrangements or deletions have been identified in different pathologies including composite rhabdoid tumors of the endometrium [10, 19]. A rearrangement was detected in the pure RCT, the epithelial origin of which has already been reported . Although chromosome 22 alterations are common in MRTs, their role in CRC and RCT is still unknown and further studies are required .
The APC/β-catenin pathway seems to be not affected ruling out that RTC originates through the traditional adenoma–carcinoma pathogenetic pathway underlying most CRCs (Figure 3D). A KRAS mutation was found only in the CTA, while nuclear p53 accumulation was observed exclusively in its cancerized component. Interestingly, no mutations were found in the base excision repair gene MYH, whose mutations predispose to an hereditary colorectal cancer syndrome defined “MYH associated polyposis” (MAP) characterized by multiple adenomas mainly at the right colon [9, 11]. While our data do not exclude that RCT may bear causative mutations in other yet unknown loci, they, however, confirm that MYH is not responsible either for the precursor or tumor lesions.
Microsatellite instability (MSI) due to deficiency of the mismatch repair system has been described in about 15-20% of sporadic CRCs, characterized by poor differentiation, infiltrating lymphocytes, a mucinous phenotype and a more proximal localization than inherited HNPCCs [12–14]. MLH1 epigenetic silencing is the most frequent event responsible for MSI and is associated with BRAF mutations in the serrated pathway [13, 20]. In our RTCs, MLH1 staining was negative, while it was nuclear and diffuse in all adenomas and adjacent normal mucosa. Remarkably, this expression profile was associated with the presence of BRAF mutations in the same tissues, strongly supporting our hypothesis that RTC does not arise through the traditional adenoma-carcinoma sequence (Figure 3D). Rather, it suggests that RCT may evolve through the serrated pathway . At the best of our knowledge, these genetic alterations have not been reported in MRT suggesting a colonic origin of RCT.
MLH1 silencing is usually associated with hypermethylation at the CpG islands in multiple gene promoters . Interestingly, we found a progressive accumulation of promoter methylation at specific CIMP loci and additional genes from the normal mucosa to tubular adenoma, CTA and RCT. A CpG island methylation threshold seems to be required for repression of MLH1 and other important CIMP loci in the composite RCT: a promoter methylation above 60% was, in fact, required for MLH1 down-regulation, as reported [21, 22]. At the right colon, a CIMP+ phenotype and microsatellite instability (CIMP+/MSI+) may predispose to RCT development, in agreement with recent studies reporting that CIMP+/MSI+ subtypes have a worse clinical behaviour and prognosis than patients with CIMP-/MSI+ .