N A C S Wong

β-Catenin—A Linchpin in Colorectal Carcinogenesis?

An important role for β-catenin pathways in colorectal carcinogenesis was first suggested by the proteins association with adenomatous polyposis coli (APC) protein, and by evidence of dysregulation of β-catenin protein expression at all stages of the adenoma-carcinoma sequence. Recent studies have, however, shown that yet more components of colorectal carcinogenesis are linked to β-catenin pathways. Pro-oncogenic factors that also release β-catenin from the adherens complex and/or encourage translocation to the nucleus include ras, epidermal growth factor (EGF), c-erbB-2, PKC-βII, MUC1, and PPAR-γ, whereas anti-oncogenic factors that also inhibit nuclear β-catenin signaling include transforming growth factor (TGF)-β, retinoic acid, and vitamin D. Association of nuclear β-catenin with the T cell factor (TCF)/lymphoid enhancer factor (LEF) family of transcription factors promotes the expression of several compounds that have important roles in the development and progression of colorectal carcinoma, namely: c- myc , cyclin D1, gastrin, cyclooxygenase (COX)-2, matrix metalloproteinase (MMP)-7, urokinase-type plasminogen activator receptor (aPAR), CD44 proteins, and P-glycoprotein. Finally, genetic aberrations of several components of the β-catenin pathways, eg, Frizzled (Frz), AXIN, and TCF-4, may potentially contribute to colorectal carcinogenesis. In discussing the above interactions, this review demonstrates that β-catenin represents a key molecule in the development of colorectal carcinoma.

Prognostic indicators for gastrointestinal stromal tumours: a clinicopathological and immunohistochemical study of 108 resected cases of the stomach

Aims:  Whether immunohistochemical markers increase accuracy in predicting prognosis for gastrointestinal stromal tumours (GISTs) remains uncertain. However, past studies have used only small, heterogeneous patient groups. Our aim was to test previously studied and more novel morphological features as well as four immunohistochemical markers as prognostic indicators amongst a large cohort of surgically resected, gastric GISTs.

Immunohistochemical assessment of Ki67 and p53 expression assists the diagnosis and grading of ulcerative colitis-related dysplasia

Aims

Colorectal neoplasia in ulcerative colitis—recent advances

Colorectal neoplasia in ulcerative colitis—recent advances

Colorectal disease in liver allograft recipients: a clinicopathological study with follow-up

Objective To determine the spectrum and outcome of colorectal diseases occurring in adult liver allograft recipients. Design A retrospective cohort analysis of clinical, microbiological and histopathological data regarding colorectal disease. Patients Forty three out of 302 adult primary liver allograft recipients were transplanted and followed up (at median 42 months) at a tertiary referral centre/teaching hospital. Results Out of 302 patients, 43 (14%) were investigated (by endoscopy and/or laparotomy) for symptoms of colorectal disease after orthotopic liver transplantation. The symptoms were: diarrhoea (n = 31); per-rectal bleeding (n = 5); and symptoms relating to pre-transplant ulcerative colitis (n = 7). Among the patients without known ulcerative colitis, per-rectal bleeding occurring early after orthotopic liver transplantation was most commonly caused by cytomegalovirus colitis and carried a poor prognosis. Excluding ulcerative colitis, the commonest causes of diarrhoea were Clostridium difficile, cytomegalovirus infection and medications, particularly during the first 2 months after orthotopic liver transplantation. No cases of colorectal graft-versus-host disease, cryptosporidiosis, amoebiasis, atypical mycobacterial infection or post-transplant lymphoproliferative disease were demonstrated. The activity of pre-transplant ulcerative colitis was unchanged or increased after orthotopic liver transplantation. Two further patients developed new-onset ulcerative colitis after orthotopic liver transplantation. Conclusions Ulcerative colitis, C. difficile, cytomegalovirus infection and medications are the commonest colorectal causes of morbidity after orthotopic liver transplantation. Adult liver allograft recipients are, however, unlikely to show certain large bowel diseases encountered in other immunosuppressed groups. Amongst non-ulcerative colitis patients, those presenting with diarrhoea show a good outcome with appropriate management, whereas those with per-rectal bleeding have a more guarded prognosis.

Intra-abdominal spindle cell lesions: a review and practical aids to diagnosis

Intra‐abdominal spindle cell lesions: a review and practical aids to diagnosis

Cyclin D1 and p21WAF1/CIP1 in ulcerative colitis-related inflammation and epithelial neoplasia: a study of aberrant expression and underlying mechanisms

It is unclear whether and how cyclin D1 and/or p21(WAF1/CIP1) dysregulation contribute to ulcerative colitis (UC)-related inflammation and colorectal carcinogenesis. Cases of quiescent UC (QUC; n = 15), active UC (AUC; n = 23), UC-related dysplasia (n = 35) and UC-related colorectal adenocarcinomas (CRCs; n = 11) were studied with cyclin D1 and p21(WAF1/CIP1) immunohistochemistry. The CRCs were also studied with beta-catenin, bcl2, and p53 immunohistochemistry, p53 and k-ras mutation analyses, and cyclin D1 gene fluorescence in situ hybridization. QUC showed cyclin D1 (negative/weak staining) and p21(WAF1/CIP1) (surface epithelial and upper-third crypt staining) expression similar to that of normal colorectum. Moderate or strong cyclin D1 immunostaining was seen in 9% of AUC cases, 40% of dysplasia cases, and 36% of UC-related CRCs. Although these carcinomas showed neither cyclin D1 gene amplification nor any association between k-ras mutation and cyclin D1 overexpression, the latter was closely related to nuclear beta-catenin expression. Increased lower-third crypt p21(WAF1/CIP1) staining was seen in 57% of AUC cases; decreased upper-third crypt p21(WAF1/CIP1) staining, in 23% of dysplasia cases; and absent or weak p21(WAF1/CIP1) staining, in 55% of UC-related CRCs. The latter change was always associated with p53 mutation but could not be related to p53 or bcl2 expression. In conclusion, AUC shows up-regulated cyclin D1 and p21(WAF1/CIP1) expression. Cyclin D1 up-regulation and p21(WAF1/CIP1) down-regulation occur early in UC-related carcinogenesis. Cyclin D1 up-regulation is less common in UC-related CRCs than in sporadic CRCs, and is related to beta-catenin nuclear signaling. p21(WAF1/CIP1) down-regulation is seen at an equal or higher frequency among UC-related CRCs compared with sporadic CRCs and is attributable to p53 mutation.

Polymorphisms of the gene for microsomal epoxide hydrolase and susceptibility to alcoholic liver disease and hepatocellular carcinoma in a Caucasian population

The gene encoding the xenobiotic-metabolising microsomal enzyme, epoxide hydrolase (mEPHX), shows two common mutations, i.e. at exons 3 and 4. It is unknown how these genetic polymorphisms relate to risk of developing alcoholic liver disease (ALD) and/or hepatocellular carcinoma (HCC) in a Caucasian population. DNA samples extracted from the blood of 61 ALD patients and 203 healthy controls, and from archival liver tissue of 46 cases of HCC, were subjected to polymerase chain reaction amplification followed by digestion with EcoR V or Rsa I to demonstrate polymorphisms of exon 3 or 4, respectively. The distributions of the genotypes of exon 3 in the ALD and HCC patients, and exon 4 in the HCC patients did not differ significantly from those of the control group. However, compared with the control group, the ALD group contained a significantly greater number of individuals homozygous or heterozygous for the exon 4 mutation. This suggested association between possession of the exon 4 mutant mEPHX allele and increased risk of developing ALD may relate to known interactions between mEPHX and alcohol-metabolising enzyme systems, or to linkage disequilibrium between the mutation and other genetic risk factors for ALD.

Gastrointestinal stromal tumor in ascitic fluid: A case report

BACKGROUND There are few published data on the cytologic features of gastrointestinal stromal tumors (GISTs) in ascitic fluid and whether these features may mimic those of other malignancies. CASE An 80-year-old woman presented with ascitics associated with multiple intraperitoneal masses. Cytologic examination of the ascitic fluid showed numerous three-dimensional clusters of epithelioid cells. These features and the presence of large, intracytoplasmic vacuoles raised a possible diagnosis of adenocarcinoma. However, mucin could not be demonstrated in the vacuoles, and the cells showed immunoreactivity for vimentin and c-kit but not for cytokeratins. Eighteen months earlier the patient had undergone a partial gastrectomy for a GIST, which predominantly comprised vacuolated, epithelioid cells. The immunoprofile of the primary tumor was identical to that of the ascitic fluid cells. CONCLUSION GIST cells may closely mimic adenocarcinoma cells in ascitic fluid. Distinguishing between the two neoplasms has important clinical repercussions and is aided by histochemical and immunocytochemical studies--in particular, c-kit immunostaining.

Mucin expression in the ileoanal reservoir reflects incomplete mucosal adaptation.

Restorative proctocolectomy is regarded as a standard surgical procedure for patients who require a proctocolectomy for ulcerative colitis and familial adenomatous polyposis. The ileal mucosa undergoes colonic phenotypic change with time, but the extent and relevance of these changes to the long‐term safety of the ileoanal pouch are unclear. The aim of this study was to study the mucin biology of this adaptive process in order to assess its extent and possible impact on pouch safety. Ileoanal pouch biopsies from a cohort of patients and normal ileal and colonic controls were subjected to histological, biochemical, histochemical, and immunohistochemical mucin analysis. Mucin sulphation and sialic acid O‐acetylation were studied as parameters of colonic phenotypic change. Fifty‐one patients, 16 ileal, and 22 colonic controls were studied. Seventy percent of biopsies retained villous mucosal architecture, with no cases of dysplasia detected. Ileoanal pouch mucosal sulphation and sialic acid O‐acetylation did not reach colonic levels, thus indicating limited evidence for a more colonic phenotype. The data from this study suggest that colonic phenotypic change within the ileoanal reservoir is incomplete, with no cases of dysplasia detected. The degree of phenotypic change is less than in previous studies, which may support, butnot prove, our hypothesis that there may be a process of reversion to an ileal type mucosa in the ileoanal reservoir with time. Copyright