Background. The prognostic significance of microsatellite instability (MSI) in colorectal cancers (CRCs) has been addressed in many studies since the initial description of better survival rates in MSI-positive (MSI?) tumors than in MSI-negative (MSI-) tumors. Recent studies have demonstrated that a higher degree of hypomethylation of long interspersed nuclear element-1 (L1) is related to poor prognosis of CRCs and that a wide variation of L1 methylation levels exist within MSI? CRCs. Our aim was to identify whether L1 and Alu methylation status could predict clinical outcomes within MSI? CRCs. Methods. We analyzed 207 MSI? CRCs for their methylation levels in L1 and Alu repetitive DNA elements using pyrosequencing and correlated them with clinicopathological information including survival data. Results. Univariate survival analysis showed that low Alu methylation status (\18.60 %) and low L1 methylation status (\53.00 %) were significantly associated with shorter overall survival time (log-rank test, P = 0.009 and P \ 0.001, respectively). Multivariate analysis using nine parameters (Alu methylation status, L1 methylation status, patient's age, disease stage [tumor, node, metastasis staging system], differentiation, Crohn-like lymphoid reaction, KRAS/BRAF mutation status, CpG island methylator phenotype [CIMP] status, and peritumoral lymphocytic infiltration), which were significantly prognostic in MSI? CRCs, revealed that low L1 methylation status was an independent prognostic factor of MSI? CRCs (P = 0.009), whereas low Alu methylation status was not.Conclusions. Clinical outcomes of MSI? CRCs depend on L1 methylation status, suggesting that lower L1 methylation status serves as a significant prognostic parameter of adverse prognosis in MSI? CRCs.

The expression and distribution profile of ISC markers possibly provides insights into the organization of stem and progenitor-like cells in each type of precancerous lesion of CRC.

Background Tumor budding is associated with lymph node (LN) metastasis in submucosal colorectal cancer (CRC). However, the rate of LN metastasis associated with the number of tumor buds is unknown. Here, we determined the optimal tumor budding cut-off number and developed a composite scoring system (CSS) for estimating LN metastasis of submucosal CRC. Methods In total, 395 patients with histologically confirmed T1N0–2M0 CRC were evaluated. The clinicopathological characteristics were subjected to univariate and multivariate analyses. The Akaike information criterion (AIC) values of the multivariate models were evaluated to identify the optimal cut-off number. A CSS for LN metastasis was developed using independent risk factors. Results The prevalence of LN metastasis was 13.2%. Histological differentiation, lymphatic or venous invasion, and tumor budding were associated with LN metastasis in univariate analyses. In multivariate models adjusted for histological differentiation and lymphatic or venous invasion, the AIC value was lowest for five tumor buds. Unfavorable differentiation (odds ratio [OR], 8.16; 95% confidence interval [CI], 1.80–36.89), lymphatic or venous invasion (OR, 5.91; 95% CI, 2.91–11.97), and five or more tumor buds (OR, 3.01; 95% CI, 1.21–7.69) were independent risk factors. In a CSS using these three risk factors, the rates of LN metastasis were 5.6%, 15.5%, 31.0%, and 52.4% for total composite scores of 0, 1, 2, and ≥ 3, respectively. Conclusions For the estimation of LN metastasis in submucosal CRC, the optimal tumor budding cut-off number was five. Our CSS can be utilized to estimate LN metastasis.

in 15/16 (93.7%) cases, including CK20, mostly 'dot-like' (12/13, 92.3%); CK (6/7, 85.7%), AE1/AE3 (3/3, 100%) and CK7 (1/6, 16.6%), along with neuroendocrine markers (16/16, 100%), including synaptophysin (11/13, 84.6%), chromogranin (12/15, 80%) and CD56 (4/4, 100%). Other positive IHC marker was CKIT/CD117 (3/3). Surgical resection was performed in 11/11 (100%) cases, with adjuvant chemotherapy offered in a single case. On follow-up (n=4 cases), two cases with large-sized tumours developed lymph node metastasis, including 1 who also developed pulmonary metastasis. Two patients were free-ofdisease (16 months, 21 months) and 2 were alive-with-disease. Conclusions: MCCs exhibit a wide histopathological spectrum, including co-existing Bowen's and rhabdomyoblastic de-differentiation. Careful analysis of key histopathological features and optimal IHC results with CK20, synaptophysin, chromogranin and CD56 are helpful in a timely diagnosis, as these are aggressive. MCCs also express CKIT.

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