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Ulcerative colitis (UC) is a chronic relapsing inflammatory disorder of the colon. Patients with UC have an increased risk of developing colorectal cancer. However, appendix adenocarcinoma associated with UC is extremely rare. [ABSTRACT FROM AUTHOR]

Hamartomatous polyposis syndromes (HPS) are a heterogeneous spectrum of diseases that are characterized by diffuse hamartomatous polyps lining the gastrointestinal (GI) tract together with extra‐GI manifestations. Classical HPS includes juvenile polyposis syndrome, Peutz–Jeghers syndrome, PTEN hamartoma tumor syndrome and hereditary mixed polyposis syndrome. Patients with HPS have a higher risk of GI and extra‐GI malignancies than the general population, although the underlying mechanisms remain unclear and are obviously different from the carcinogenesis of classical adenocarcinoma and colitis‐associated malignancy. In this review we aimed to clarify the risks, possible mechanism and endoscopic surveillance of HPS‐associated GI malignancies. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) is highly prevalent worldwide. In 2018, there were over 1.8 million new cases. Most sporadic CRC develop from polypoid adenomas and are preceded by intramucosal carcinoma (stage 0), which can progress into more malignant forms. This developmental process is known as the adenoma‐carcinoma sequence. Early detection and endoscopic removal are crucial for CRC management. Accumulating evidence suggests that the gut microbiota is associated with CRC development in humans. Comprehensive characterization of this microbiota is of great importance to assess its potential as a diagnostic marker in the very early stages of CRC. In this review, we summarized recent studies on CRC‐associated bacteria and their carcinogenic mechanisms in animal models, human cell lines and human cohorts. High‐throughput technologies have facilitated the identification of CRC‐associated bacteria in human samples. We have presented our metagenome and metabolome studies on fecal samples collected from a large Japanese cohort that revealed stage‐specific phenotypes of the microbiota in CRC. Furthermore, we have discussed the potential carcinogenic mechanisms of the gut microbiota, from which we can infer whether changes in the gut microbiota are a cause or effect in the multi‐step process of CRC carcinogenesis. [ABSTRACT FROM AUTHOR]

Aims Dickkopf-1 (Dkk1), an antagonist of the Wnt-β-catenin signalling pathway, has been reported to play a role in cancer progression. However, little is known about the role of Dkk1 during the colorectal adenoma-carcinoma sequence. This study aimed to elucidate the role of Dkk1 in tumorigenesis and angiogenesis in colorectal cancer. Methods and results We examined Dkk1 expression immunohistochemically in 476 colorectal tissue samples, including 46 sets of matched specimens. Dkk1 expression was down-regulated during the colorectal adenoma-carcinoma sequence, both among the 476 samples and in the 46 sets of matched specimens. Dkk1 expression was correlated with decreased microvessel density ( P < 0.05) and VEGF expression. In-vitro 3D coculture experiments showed that Dkk1 overexpression in HCT116 cells inhibited tube-like structure formation and down-regulated VEGF expression in human umbilical vein endothelial cells. Xenografts of Dkk1-overexpressing colorectal cancer cells were smaller, and showed lower microvessel density and VEGF expression levels, than those of control cells. Conclusions This study is the first to show the roles of Dkk1 during the colorectal adenoma-carcinoma sequence, which may involve suppression of the tumorigenesis and angiogenesis of CRC. Dkk1 could therefore serve as a potential target for tumour therapy. [ABSTRACT FROM AUTHOR]

Mature ovarian teratomas rarely undergo transformation into malignancy. Carcinomas, mostly squamous cell carcinoma, are the most common malignancy arising in mature cystic teratoma. In the present report we describe a 13-year-old girl who developed a large mass in her ovary. Fine needle biopsy identified intestinal type mucinous adenocarcinoma, which was also identified in the full surgical specimen. Extensive sampling of the surgical specimen also identified areas of mature cystic teratoma. Interestingly, molecular analysis of DNA extracted from various components of the lesion identified KRAS mutation in the carcinoma, borderline mucinous tumor and benign intestinal-type epithelium but not in the epidermal component of the teratoma. To the best of our knowledge this is the first report of KRAS mutation in mucinous carcinoma originating in mature cystic teratoma. We discuss the importance of extensive tissue sampling to differentiate between carcinoma originating in teratoma and metastatic colorectal carcinoma to the ovary. Additionally, the identification of KRAS mutation in the morphologically benign intestinal-type epithelium indicated that it is an early event in the carcinogenic sequence and that the molecular pathway of carcinogenesis in teratoma is similar to that in the carcinogenic process of somatic tissue. [ABSTRACT FROM AUTHOR]

Aims To clarify the lineage-specific carcinogenesis of gland-forming gastric neoplasms, by characterizing mucin phenotypes and proliferation patterns immunohistochemically using monoclonal antibodies against MUC2, MUC5 AC, MUC6, CD10 and Ki67. Methods and results We analysed 49 gland-forming intramucosal neoplasms, including 15 non-invasive low-grade neoplasms (group A), 10 non-invasive high-grade neoplasms (group B) and 24 intramucosal adenocarcinomas (group C). The mode of gland-forming gastric carcinoma development was different between the intestinal and gastric lineages. The pure intestinal-type accounted for 93% of group A, 50% of group B and 4.2% of group C tumours. A zonal pattern of cell proliferation was well retained in group A tumours and was lost size-dependently in group B tumours. These findings suggest that non-invasive low-grade neoplasms of the intestinal lineage progress to non-invasive high-grade neoplasms, but rarely to intramucosal adenocarcinomas. In tumours of the gastric lineage, which exhibited pure gastric or mixed phenotypes, the polarity of cell proliferation and differentiation was well retained in small (≦5 mm) tumours but was lost in larger tumours in groups B and C. Conclusions Intramucosal adenocarcinomas of the gastric lineage may often arise de novo, develop in the proper gastric mucosa, and are partially derived from non-invasive high-grade neoplasms. [ABSTRACT FROM AUTHOR]

Aims Neuropilin-1 ( NRP1) and neuropilin-2 ( NRP2) are transmembrane glycoproteins which interact with vascular endothelial growth factor ( VEGF) to prevent tumour cell apoptosis and regulate angiogenesis. However, the precise role of NRP1 and NRP2 in the adenoma-carcinoma sequence ( ACS) of colorectal cancer remains unclear, and we aimed to determine this in surgical specimens comprising the ACS. Methods and results Histological analysis demonstrated that epithelial NRP1 expression increased significantly across the ACS ( P = 0.0007), and correlated with microvessel density ( MVD; r = 0.505, P = 0.0003) and weakly with VEGF ( r = 0.251, P = 0.001). In contrast, although NRP2 epithelial expression was increased significantly in all carcinomas ( P < 0.002), there was no correlation with MVD, VEGF or NRP1. Furthermore, patients showing coexpression of NRP1 and NRP2 had a potentially worse prognosis than those expressing a single neuropilin or neither one. Although vascular expression of NRP1 increased significantly across the ACS ( P = 0.0004) and correlated with MVD ( r = 0.361, P = 0.0006), NRP2 vascular expression decreased significantly ( P = 0.0001) and showed an inverse correlation with MVD ( r=−0.506, P = 0.0001), suggesting differential roles for neuropilins in the angiogenic process during colorectal cancer development. Conclusions These data suggest that an increase in NRP1 and NRP2 epithelial/tumour expression, as well as in NRP1 vascular expression, may be associated with disease progression in colorectal cancer. [ABSTRACT FROM AUTHOR]

Aims:  The lamina propria is inevitably involved in epithelial transformation. The aim was to evaluate the dynamic cellular changes in the tumour lamina propria throughout the colorectal adenoma–carcinoma sequence. Methods and results:  Using immunohistochemistry and double immunohistochemistry, we examined lamina propria cellular changes in 41 colorectal adenomas, 25 colorectal cancers and 15 control tissues. The results showed that the proliferation labelling index in lamina propria cells began to increase in the precancerous lesions (adenomas) and became even higher in the colorectal cancers; these proliferative cells were primarily identified as myofibroblasts and lymphocytes. Phenotypic analysis revealed gradually increasing lymphocytic infiltration in both the lamina propria and adenomatous epithelium, as well as myofibroblasts in the lamina propria. However, the intraepithelial macrophage density also showed a tendency to increase gradually. Furthermore, cyclooxygenase-2-expressing cell density and microvessel density gradually increased in the tumour lamina propria throughout the adenoma–carcinoma sequence. Conclusions:  Progressive cellular responses in the lamina propria could be involved in the adenoma–carcinoma transition. [ABSTRACT FROM AUTHOR]

Aims: CD10+ colorectal carcinomas have a high risk of giving rise to liver metastasis. The aim was to examine phenotypic expression in colorectal neoplasia and to elucidate changes in such expression through the adenoma–carcinoma sequence. Methods and results: We examined the expression of various proteins immunohistochemically in 111 flat [non-polypoid growth (NPG)] colorectal neoplasms, categorized into 28 low-grade (NPG-LGN), 44 high-grades (NPG-HGN) and 39 cases of invasive neoplasia (NPG-IN), as well as in 96 polypoid [polypoid growth (PG)] neoplasms, categorized into 26 PG-LGN, 39 PG-HGN and 31 PG-IN according to the Vienna classification. CD10 was more frequently expressed in NPG than in PG neoplasia. MUC2 and MUC5AC were more frequently expressed in PG than in NPG neoplasias. Nuclear β-catenin was more frequently expressed in NPG-LGN than in PG-LGN. No difference in p53 expression was found between NPG and PG neoplasia. Conclusions: From the viewpoint of the expression of CD10 and β-catenin, it would appear that NPG-LGN differs significantly from PG-LGN, thereby indicating that NPG-LGN is a precursor of CD10+ carcinoma. It is important to ensure that NPG neoplasia is not overlooked if cases of CD10+ carcinoma are to be detected at an early stage. [ABSTRACT FROM AUTHOR]

The article focuses on a study which aimed to determine whether and where bone morphogenetic protein (BMP) signaling is disrupted during the adenoma-carcinoma sequence of colorectal cancer (CRC) formation. A tissue microarray and immunohistochemistry of BMP receptors and signal transduction elements in adenomas and CRC specimens were used to elucidate the role of BMP signalling in CRC carcinogenesis. The results of the study showed that the loss of BMP signalling correlates with progression of adenomas to cancer occurs during cancer progression.

Objective Evidence exists to support alternative pathways to the adenoma carcinoma sequence. Some mutations in key onco-suppressor genes relate to the anatomical site of the tumour. This link is typified by microsatellite instability and proximal neoplasia. However, rectal tumours are rarely considered separately. We hypothesized that tumour behaviour in the rectum may differ in terms of pathogenesis and malignant propensity. Therefore, we aimed to look for an association between the histopathological features of adenomas and their anatomical location as compared with the distribution of cancers. Methods A single centre prospective study was undertaken over a four-year period. Patients referred to a colorectal assessment clinic with bowel symptoms underwent a minimum investigation of flexible sigmiodoscopy. Neoplastic lesions were either biopsied or removed after noting distance from the anal margin. Adenomas, differentiated by size, villous architecture and degree of dysplasia were compared to both early and advanced carcinomas. Results Of 4089 patients, polyps were identified in 8.0% and cancer in 4.2%. There was a clear difference between the distribution of cancer and adenomas > 1 cm, P < 0.001. All degrees of dysplasia in large adenomas were more prevalent in the sigmoid colon as compared to cancer, P < 0.001. Seventy-five percent of high risk diminutive adenomas were rectal in origin. Conclusion Our data provides indirect evidence to support the concept that a significant proportion of rectal cancers may arise via an alternative pathway to the Vogelstein model. Polyp behaviour along with malignant propensity may actually be site dependent, with rectal polyps harbouring a more aggressive phenotype. [ABSTRACT FROM AUTHOR]

Abstract Background and Aims: Morphologically, colorectal nodule-aggregating tumors are quite different from polypoid-type colorectal tumors that develop via the adenoma–carcinoma sequence. Although polypoid-type colorectal tumors are well known to have a high incidence of K-ras gene mutation and p53 overexpression, colorectal nodule-aggregating tumors have not been examined in terms of genetic changes and clinicopathological features. In the present study, therefore, we analysed the clinicopathological features, genetic changes in K-ras codon 12, and p53 overexpression in colorectal nodule-aggregating tumors. Methods: A total of 18 colorectal nodule-aggregating tumors were surgically resected and then analysed clinicopathologically. Immunohistochemistry and polymerase chain reaction–single stranded conformational polymorphism were performed to analyse p53 abnormalities in the tumors. K-ras codon 12 mutations were screened out by the polymerase chain reaction–restriction fragment length polymorphism method and analysed by fluorescence direct sequencing. Results: p53 overexpression was observed in six lesions (33%). p53-overexpressing cells were observed in parts of carcinoma or adenoma showing high-grade atypia. Four of the 10 (40%) samples had a p53 gene mutation. Nine of the 18 (50%) samples had a K-ras codon 12 point mutation. In eight cases (89%), the mutations of the K-ras codon 12 were of the same type: GGT (glycine) to GTT (valine). Conclusions: The colorectal nodule-aggregating tumor has distinctive characteristics showing a morphological phenotype of the superficial-type tumors and genotype of the polypoid tumors in terms of K-ras gene mutation and p53 overexpression. [ABSTRACT FROM AUTHOR]