Mismatch repair deficient (dMMR) colorectal cancer (CRC) despite its association with poor histologic grade often has improved prognosis compared with MMR proficient CRC. Tumor budding and poorly differentiated clusters (PDCs) may predict metastatic potential of colorectal adenocarcinoma (CRC). In addition, their assessment may be more reproducible than the evaluation of other histopathologic parameters. Therefore, we wished to determine their potential as prognostic indicators in a cohort of dMMR CRC patients relative to histologic grade. We investigated the predictive value of conventional WHO grade, budding, PDC grade and other histopathologic parameters on the presence of lymph node metastasis (LNM) and clinical outcome in 238 dMMR CRCs. MMR status was determined by immunohistochemistry for the mismatch repair proteins hMLH1, hMSH2, hMSH6, and hPMS2. Tumor budding and PDCs were highly correlated (r=0.701; P<0.000). Both budding and PDC grade were associated with WHO grade, perineural invasion, lympho-vascular invasion, and extramural vascular invasion, and the presence of LNM in dMMR CRC (P<0.009). Independent predictors of LNM were PDC grade (odds ratio, 4.12; 95% confidence interval [CI], 1.69-10.04; P=0.011) and EMVI (odds ratio, 3.81; 95% CI, 1.56-9.19; P<0.000). Only pTstage (hazard ratio [HR], 4.11; 95% CI, 1.48-11.36; P=0.007) and tumor budding (HR, 2.99; 95% CI, 1.72-5.19; P<0.000) were independently associated with worse disease-free survival (DFS). If tumor budding was excluded from the model, PDC grade became significant for DFS (HR, 2.34; 95% CI, 1.34-4.09; P=0.003). WHO Grade does not independently correlate with clinical outcome in dMMR CRC. PDC grade and extramural vascular invasion are independent predictors of LNM. Tumor budding and pTstage are the best predictors of DFS. If tumor budding cannot be assessed, PDC grade may be used as a prognostic surrogate.

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BackgroundCaudal‐related homeobox transcription factor 2 (CDX2) is an intestine‐specific transcription factor implicated in tumour differentiation, proliferation, cell adhesion and migration. Negative CDX2 status (CDX2−) is associated with worse prognosis in colorectal cancer and may identify high‐risk stage II disease that benefits from adjuvant chemotherapy. This observational study investigated whether CDX2− is associated with prognosis or response to chemotherapy in the mismatch repair‐deficient (dMMR) phenotype of colorectal cancer.MethodsPatients with resectable dMMR colorectal cancer were eligible for inclusion. The prognostic and predictive value of CDX2 expression on the presence of lymph node metastasis (LNM) and survival was investigated. CDX2 status was determined via immunohistochemistry using the Leica Bond™ CDX2 (clone EP25) ready‐to‐use primary antibody.ResultsSome 235 of 238 consecutive dMMR tumours were assessed for CDX2 status. CDX2− was observed in 15·7 per cent of colorectal cancer. Interobserver agreement was excellent (κ = 0·863; P < 0·001). CDX2− was significantly associated with female sex, increased size, advanced stage, worse conventional and poorly differentiated cluster (PDC) grade, mucinous morphology, perineural and lymphovascular invasion, and pN status (all P ≤ 0·038). CDX2− was not associated with LNM or survival in multivariable analysis. Independent predictors of LNM were PDC grade (odds ratio (OR) 4·12, 95 per cent c.i. 1·76 to 9·63; P = 0·001) and extramural venous invasion (OR 3·79, 1·62 to 8·85; P = 0·002). Budding (hazard ratio (HR) 2·79, 95 per cent c.i. 1·60 to 4·87; P < 0·001), pT status (HR 3·59, 1·29 to 10·01; P = 0·015) and adjuvant chemotherapy (HR 2·07, 1·15 to 3·74; P = 0·016) were independently associated with worse disease‐free survival.ConclusionCDX2− does not confer a worse prognosis in the dMMR phenotype of colorectal cancer. The MMR status of patients with colorectal cancer should be determined before assessing CDX2 status.

Primary Intrahepatic Small-Cell CarcinomaArising From Combined Hepatocellular and Cholangiocarcinomas We report a small-cell carcinoma (SmCC) arising from combined hepatocellular (HCC) and cholangiocarcinomas (CC). Combined HCC and CC comprise less than 1% of liver carcinomas, 1 and only 13 cases of primary hepatic SmCC have been reported to date. To our knowledge, ours is the first described case of SmCC arising from combined hepatic carcinoma. In addition, synchronous intrahepatic CC was present in the same liver. We discuss the diagnostic and therapeutic challenges of SmCC as well as the tumorigenesis of the tumor components. Case ReportA 51-year-old man was referred to our institution for consideration of liver transplantation after an incidental discovery of a 3.5-cm hepatic lesion. Significant background history included alcoholic liver cirrhosis and insulin-dependent diabetes mellitus. Other etiologies of cirrhosis had been ruled out. Serum ␣-fetoprotein (AFP) levels at presentation were not elevated.Radiologic findings. The initial triphasic computed tomography (CT) scan showed a 3.5-cm lesion in segment three of the liver with a hypervascular rim and low attenuation center. There was a small amount of arterial phase hyperenhancement within the lesion. Primovist (Bayer Schering Pharma, Berlin, Germany) magnetic resonance imaging performed 3 months later also showed peripheral enhancement postcontrast on the arterial phase. Lesion size remained the same. Primovist uptake was noted in the delayed phase. A contrastenhanced ultrasound scan showed a solid mass and echo-poor surrounding halo. The arterial phase could not be assessed because of technical difficulties. The tumor was isoenhanced during the portal venous phase, followed by contrast washout in the sinusoidal phase. Four-phase CT scan showed no arterial phase hyperenhancement, but there was central washout on portal venous (Fig 1; arrow) and delayed phases with rim enhancement. There was no significant adenopathy at the porta hepatis, celiac axis, or retroperitoneum. Progression of pneumobilia occurred over a 6-month period.These findings did not meet the imaging diagnostic criteria for HCC. After multidisciplinary discussions, consensus was reached on a diagnosis of HCC based on the combination of arterial phase hyperenhancement on the first CT, tumor size, and portal venous and delayed phase washout. Despite alcohol abstinence, he suffered from recurrent decompensated liver disease. He underwent orthotopic liver transplantation 4 months postworkup.Histopathologic findings. The explanted liver was cirrhotic. Further inspection revealed two malignant lesions. The first neoplasm (Fig 2A), located in the left lobe, was solid with ill-defined white nodules at the periphery. Histologically, it consisted of nod-

Synchronous colorectal cancers (syCRCs) are two or more primary tumours identified simultaneously in a patient. Previous studies report high inter-tumour heterogeneity between syCRCs, suggesting independent origin and different treatment response, making their management particularly challenging, with no specific guidelines currently in place. Here, we performed in-depth bioinformatic analyses of genomic and transcriptomic data of a total of eleven syCRCs and one metachronous CRC collected from three patients. We found mixed microsatellite status between and within patients. Overlap of mutations between synchronous tumours was consistently low (<0.5%) and heterogeneity of driver events across syCRCs was high in all patients. Microbial analysis revealed the presence of Fusobacterium nucleatum species in patients with MSI tumours, while quantification of tumour immune infiltration showed varying immune responses between syCRCs. Our results suggest high heterogeneity of syCRCs within patients but find clinically actionable biomarkers that help predict responses to currently available targeted therapies. Our study highlights the importance of personalised genome and transcriptome sequencing of all synchronous lesions to aid therapy decision and improve management of syCRC patients.