The proportion of tumor-stroma as a strong prognosticator for stage II and III colon cancer patients: validation in the VICTOR trial.

BACKGROUND: The intra-tumor stroma percentage in colon cancer (CC) patients has previously been reported by our group as a strong independent prognostic parameter. Patients with a high stroma percentage within the primary tumor have a poor prognosis. PATIENTS AND METHODS: Tissue samples from the most invasive part of the primary tumor of 710 patients (52% Stage II, 48% Stage III) participating in the VICTOR trial were analyzed for their tumor-stroma percentage. Stroma-high (>50%) and stroma-low (≤50%) groups were evaluated with respect to survival times. RESULTS: Overall and disease-free survival times (OS and DFS) were significantly lower in the stroma-high group (OS P<0.0001, hazard ratio (HR)=1.96; DFS P<0.0001, HR=2.15). The 5-year OS was 69.0% versus 83.4% and DFS 58.6% versus 77.3% for stroma-high versus stroma-low patients. CONCLUSION: This study confirms the intra-tumor stroma ratio as a prognostic factor. This parameter could be a valuable and low cost addition to the TNM status and next to current high-risk parameters such as microsatellite instability status used in routine pathology reporting. When adding the stroma-parameter to the ASCO criteria, the rate of 'undertreated' patients dropped from 5.9% to 4.3%, the 'overtreated' increased with 6.8% but the correctly classified increased with an additional 14%.

Quality control in upper gastrointestinal endoscopy: detection rates of gastric cancer in Oxford 2005-2008.

BACKGROUND: Gastric cancer (GC) represents the sum of advanced gastric cancer (AGC) and early gastric cancer (EGC). Endoscopy (with biopsies) is the gold standard for detection of GC, but a false-negative rate of up to 19% is reported. AIM: To determine whether patients with GC had had an oesophagogastroduodenoscopy (OGD) in the year preceding diagnosis that might reasonably have been expected to detect the cancer, as a measure of quality assurance of endoscopic practice. METHODS: Patients with histologically proven GC were identified from pathology records. Endoscopy reports and case notes were examined to identify any OGD before diagnosis, the interval and endoscopic findings. A false-negative OGD was defined as one where GC was neither suspected nor shown at pathology, but where a diagnosis of GC was made within 12 months. RESULTS: Between January 2005 and February 2008, 9764 OGDs were performed. GC was diagnosed in 74 patients (male/female ratio 2.89; median age 76, range 38-95). Nine (12%) patients had EGC. There were no differences in age, sex or symptoms between the EGC and AGC group. Sixty-eight of the 74 patients with GC (92%) presented with alarm symptoms. Ten of the 74 had had an OGD within 12 months before definitive diagnosis; all these were planned because of suspicious lesions. Significantly fewer biopsies were performed at OGDs preceding definitive diagnosis (median 2 (0-10) vs 6 (2-12); p=0.002). CONCLUSION: False-negative rates of 0% (within 12 months) and 8% (within 3 years) for diagnosis of GC are reassuring, but an inadequate number of biopsies compromises the quality assurance of endoscopy. GC presents without alarm symptoms in <10%.

Are we reporting ileal pouch biopsies correctly?

AIM: The accuracy of ileo-anal pouch biopsy reporting was assessed. METHOD: The pathology reports of 100 consecutive pouch biopsies were reviewed to assess the accuracy and consistency with which the St Mark's histological scoring criteria were applied. The quality of pouch biopsy sampling and provision of clinical and endoscopic information on pathology request forms was also assessed. RESULTS: In 27% of cases no relevant endoscopic or clinical information was provided with the pathology request form. Separately labelled biopsies from the prepouch ileum, pouch and columnar cuff were submitted in only 4% of cases. In 32% of pathology reports, no acute or chronic St Mark's score was included. In 2% of cases the St Mark's scoring criteria were applied inappropriately. Twenty per cent of cases histologically diagnosed as pouchitis did not include a numerical score. In 30% of cases diagnosed histologically as pouchitis, an acute inflammatory score of < 4 (i.e. insufficient for this diagnosis) was included in the report. CONCLUSION: Pouchitis is a combined clinical, endoscopic and histological diagnosis. The correct interpretation and application of the St Mark's histological scoring criteria for pouch biopsies is an important part of this diagnostic process.

Delayed surgery for acute severe colitis is associated with increased risk of postoperative complications.

BACKGROUND: This study determined the long-term outcome after colectomy for acute severe ulcerative colitis (ASUC) and assessed whether the duration of in-hospital medical therapy is related to postoperative outcome. METHODS: All patients who underwent urgent colectomy and ileostomy for ASUC between 1994 and 2000 were identified from a prospective database. Patient details, preoperative therapy and complications to last follow-up were recorded. RESULTS: Eighty patients were identified, who were treated with intravenous steroids for a median of 6 (range 1-22) days before surgery. Twenty-three (29 per cent) also received intravenous ciclosporin. There were 23 complications in 22 patients in the initial postoperative period. Sixty-eight patients underwent further planned surgery, including restorative ileal pouch-anal anastomosis in 57. During a median follow-up of 5.4 (range 0.5-9.0) years, 48 patients (60 per cent) developed at least one complication. Patients with a major complication at any time during follow-up had a significantly longer duration of medical therapy before colectomy than patients with no major complications (median 8 versus 5 days; P = 0.036). CONCLUSION: Delayed surgery for patients with ASUC who do not respond to medical therapy is associated with an increased risk of postoperative complications.

Management of early rectal cancer.

BACKGROUND: Early rectal cancer (ERC) is adenocarcinoma that has invaded into, but not extended beyond, the submucosa of the rectum (that is a T1 tumour). Local excision is curative for low-risk ERCs but for high-risk cancers such management is controversial. METHODS: This review is based on published literature obtained by searching the PubMed and Cochrane databases, and the bibliographies of extracted articles. RESULTS AND CONCLUSION: ERC presents as a focus of malignancy within an adenoma, as a polyp, or as a small ulcerating adenocarcinoma. Preoperative staging relies on endorectal ultrasonography and magnetic resonance imaging. Pathological staging uses the Haggitt and Kikuchi classifications for adenocarcinoma in pedunculated and sessile polyps respectively. Lymph node metastases increase with the Kikuchi level, with a 1-3 per cent risk for submucosal layer (Sm) 1, 8 per cent for Sm2 and 23 per cent for Sm3 lesions. Low-risk ERCs may be treated endoscopically or by a transanal procedure. Transanal excision or transanal endoscopic microsurgery may be inadequate for high-risk ERCs and adjuvant chemoradiotherapy may be appropriate. There is a low rate of recurrence after local surgery for low-risk ERCs but this increases to up to 29 per cent for high-risk cancers.

Effect of neoadjuvant chemotherapy on circumferential margin positivity and its impact on prognosis in patients with resectable oesophageal cancer.

BACKGROUND: The significance of circumferential resection margin (CRM) involvement in oesophageal cancer surgery is controversial. This study investigated the relationship between CRM involvement, locoregional recurrence and survival, after surgery alone or with neoadjuvant chemotherapy. METHODS: Patients operated on by one surgeon at a tertiary referral centre between October 1997 and May 2004 were identified from a prospective database. RESULTS: Some 242 patients underwent oesophagectomy; 91 had surgery alone, 142 had neoadjuvant chemotherapy and nine neoadjuvant chemoradiotherapy. Among patients with histologically confirmed T3 tumours, 26 (55 per cent) of 47 who underwent surgery alone had CRM involvement, compared with 27 (31 per cent) of 88 patients who completed two cycles of neoadjuvant chemotherapy (P = 0.005). Thirty-seven (42 per cent) of 89 patients with a negative CRM developed locoregional recurrence, compared with 33 (59 per cent) of 56 with a positive margin (P = 0.032); median survival was 28 and 12 months respectively (P < 0.001). Cox multivariable regression analysis identified CRM involvement as an independent prognostic factor (P = 0.006). CONCLUSION: A positive CRM is an independent predictor of overall survival after oesophageal cancer resection. There has been a significant decrease in CRM involvement with the introduction of neoadjuvant chemotherapy.

Proposals for the management of gastrointestinal stromal tumours of the stomach.

BACKGROUND AND AIMS: It has been reported that gastric gastrointestinal stromal tumours (GIST) are aggressive, rare and difficult to treat. Some have advocated radical resection as the only potential cure. We present data to support treatment of gastric GISTs with a limited surgical approach and minimal morbidity. Furthermore, we propose that surveillance for recurrence is unnecessary based upon the follow-up of a cohort of patients with gastric GISTs. METHODS: Database and case notes analysis of 20 patients diagnosed with gastric GIST (1998-2004) and managed by one surgeon in a single centre over seven years. Main outcome measures were inpatient adverse events, positive resection margins and symptom free survival. OUTCOMES: Three cases have been managed with surveillance only. Successful resection was performed in 17 patients without mortality. No patient had positive margins on histological assessment. Fifteen out of seventeen samples were positive for the c-Kit proto-oncogene (CD117) and 14117 positive for CD34. Only two patients required en-bloc resections due to the tumour size and involvement of adjacent structures. One patient developed metastatic disease during follow-up of 19-86 months. CONCLUSIONS: We recommend local excision of gastric GISTs to allow macroscopically clear margins. This policy then allows symptomatic follow-up due to the indolent nature of the majority of the tumours resected. A tailored follow-up with endoscopy and radiological imaging has been advocated by others but appears unnecessary in most cases. Imatinib (anti c-Kit) can now be offered to patients presenting with recurrent GIST, if further surgery is deemed inappropriate.

Local excision of rectal tumours by transanal endoscopic microsurgery.

BACKGROUND: Transanal endoscopic microsurgery (TEM) allows locally complete excision of rectal tumours and provides an alternative to conventional surgery for benign tumours. However, its role in the curative treatment of invasive carcinoma is controversial. The aim of this study was to determine the morbidity and long-term results for rectal tumours excised by TEM. METHODS: Between February 1993 and January 2005, 200 patients underwent TEM for excision of adenomas (148) or carcinomas (52). The median tumour distance from the anal verge was 8 (range 1-16) cm. RESULTS: Mortality and morbidity rates were 0.5 and 14.0 per cent respectively. At a median follow-up of 33 (range 2-133) months, local recurrence had developed in 11 patients (7.6 per cent) with an adenoma. Histological examination of carcinomas revealed pathological tumour (pT) stage 1 in 31 patients, pT2 in 17 and pT3 in four. Immediate salvage surgery was performed in seven patients (13 per cent). At a median follow-up of 34 (range 1-102) months, eight patients (15 per cent) with carcinomas had developed local recurrence. The overall and disease-free 5-year survival rates for patients with carcinomas were 76 and 65 per cent respectively. CONCLUSION: TEM is an appropriate surgical treatment option for benign rectal tumours. For carcinomas, it is oncologically safe provided that resection margins are clear, but strict patient selection is required.

Local therapy for rectal cancer: still controversial?

PURPOSE: Many considerations, such as morbidity, sexual and urinary dysfunction, or risk of definitive stoma have led to the increased popularity of local therapy in the therapeutic strategy for rectal cancer. However, its role in curative intent is still controversial with oncologic long-term results lower than those obtained by radical surgery. METHODS: MEDLINE, EMBASE, LILACS, Abstract books, and reference lists from reviews were searched with English language publications to review the current status of evidence for local therapy in rectal cancer, looking especially at the oncologic results and patient selection. We have focused on the new strategies combining neoadjuvant and adjuvant treatment to explain their place in the management of rectal cancer. RESULTS AND CONCLUSIONS: The key to potentially curative local treatment for rectal cancer is patient selection by identifying the best candidates with preoperative tumor staging and clinical and pathologic assessment of favorable features. Low-risk T1 is suitable for local excision alone. Limited data suggest that adjuvant chemoradiotherapy may be helpful in patients with unfavorable T1 and T2 lesions, achieving a local recurrence rate<20 percent. However, the efficacy of salvage surgery after local excision is uncertain.

Histopathological mimicry in mucosal prolapse.

Mucosal prolapse solitary rectal ulcer syndrome is a condition which has frequently confused both pathologists and surgeons alike. Despite its recognition in the nineteenth century, it continues to be a diagnostic challenge. The significance of correctly diagnosing this condition is that it avoids the morbidity and mortality associated with major surgery or the side-effects of long-term medical treatment. This review considers the histological features of mucosal prolapse and how it may mimic other pathological conditions.

EpCAM and gpA33 are markers of Barrett's metaplasia.

AIMS: To characterise a specific and sensitive marker of Barrett's metaplasia (BM). METHODS: Cases of normal oesophageal squamous mucosa (11 fresh endoscopic biopsies and 10 formalin fixed, paraffin embedded tissue blocks), BM (11 biopsies and 11 tissue blocks), and normal gastric body mucosa (five biopsies and five tissue blocks) were analysed using reverse transcriptase PCR, Western blotting, and immunohistochemistry for EpCAM, and reverse transcriptase PCR for gpA33. RESULTS: Strong EpCAM mRNA expression was detected in all the BM cases, in contrast to weak expression in all the normal gastric mucosal samples and no expression in any of the normal oesophageal mucosal samples tested. Strong gpA33 mRNA expression was detected in all the BM cases, in contrast to weak expression in a quarter of the normal gastric mucosal samples and no expression in any of the normal oesophageal mucosal samples tested. Western blotting showed EpCAM protein expression in all the BM cases and in none of the normal gastric or oesophageal mucosal samples tested. Immunohistochemistry showed strong EpCAM protein expression in BM and complete absence of expression in normal oesophageal squamous epithelium. Scattered EpCAM expressing cells were found in the gland bases of normal gastric body mucosa. CONCLUSIONS: EpCAM protein and gpA33 mRNA expressions are specific and sensitive markers of BM.

Toward an integrated clinical, molecular and serological classification of inflammatory bowel disease: report of a Working Party of the 2005 Montreal World Congress of Gastroenterology.

The discovery of a series of genetic and serological markers associated with disease susceptibility and phenotype in inflammatory bowel disease has led to the prospect of an integrated classification system involving clinical, serological and genetic parameters. The Working Party has reviewed current clinical classification systems in Crohn's disease, ulcerative colitis and indeterminate colitis, and provided recommendations for clinical classification in practice. Progress with respect to integrating serological and genetic markers has been examined in detail, and the implications are discussed. While an integrated system is not proposed for clinical use at present, the introduction of a widely acceptable clinical subclassification is strongly advocated, which would allow detailed correlations among serotype, genotype and clinical phenotype to be examined and confirmed in independent cohorts of patients and, thereby, provide a vital foundation for future work.

Cancer surveillance in ulcerative colitis.

BACKGROUND: Patients with ulcerative colitis are at a higher risk of developing colorectal cancer than those without the disease. Surveillance programmes are used routinely to detect dysplasia and cancer in patients with ulcerative colitis. However, such programmes are poorly effective. This article discusses possible improvements suggested by recent research. METHODS: Papers relating to cancer associated with ulcerative colitis and surveillance programmes to detect such cancer were identified using Medline searches. Further papers were identified from the reference lists of identified papers. RESULTS: The probability of cancer for all patients with ulcerative colitis regardless of disease extent was 2 per cent at 10 years, 8 per cent at 20 years and 18 per cent at 30 years; the overall prevalence of colorectal cancer in any patient was 3.7 per cent. Indications for colonoscopic surveillance are extensive disease for 8-10 years, especially in those with active inflammation, a family history of colorectal cancer and primary sclerosing cholangitis. Problems affecting surveillance include the diagnosis of dysplasia, difficulty in differentiating 'sporadic' adenomas from a dysplasia-associated lesion or mass, and decision making based on surveillance findings. Molecular genetic and endoscopic advances to alleviate these problems are discussed. CONCLUSION: Rates of detection of dysplasia can be improved by chromoendoscopy. Molecular genetics has the potential to identify patients most at risk of cancer and can differentiate between different types of lesion.

CDX1 is an important molecular mediator of Barrett's metaplasia.

The molecular pathogenesis of Barrett's metaplasia (BM) of the esophagus is poorly understood. The change to an intestinal phenotype occurs on a background of esophagitis due to refluxing acid and bile. CDX1, an important regulator of normal intestinal development, was studied as a potential key molecule in the pathogenesis of BM. CDX1 mRNA and protein were universally expressed in all samples of BM tested but not in normal esophageal squamous or gastric body epithelia. This tissue-specific expression was attributable to the methylation status of the CDX1 promoter. Conjugated bile salts and the inflammatory cytokines TNF-alpha and IL-1beta were all found to increase CDX1 mRNA expression in vitro. These effects were primarily mediated by NF-kappaB signaling but only occurred when the CDX1 promoter was unmethylated or partially methylated. The data suggest that CDX1 is a key molecule linking etiological agents of BM to the development of an intestinal phenotype. Although the initial trigger for CDX1 promoter demethylation is not yet identified, it seems likely that demethylation of its promoter may be the key to the induction and maintenance of CDX1 expression and so of the BM phenotype.

The retroperitoneal surface in distal caecal and proximal ascending colon carcinoma: the Cinderella surgical margin?

BACKGROUND: Mesorectal margin tumour involvement is a predictor of local recurrence in rectal carcinoma and an indication for postoperative radiotherapy in suitable patients. However, the prevalence of non-peritonealised surgical margin involvement in ascending colon carcinoma is unknown. AIMS: To test the hypothesis that retroperitoneal surgical margin (RSM) tumour involvement occurs in distal caecal and proximal ascending colon carcinoma. METHODS/RESULTS: One hundred right hemicolectomy specimens, removed for adenocarcinoma of the caecum or proximal ascending colon, were studied. During routine specimen dissection, at least one additional tissue block was taken to include the tumour and the RSM. The tumour distance from the RSM was recorded. RSM tumour involvement was present in seven cases (7%). Direct (non-nodal) RSM tumour involvement (five cases) only occurred in posterior or circumferential tumours. CONCLUSIONS: RSM tumour involvement occurs within a considerable number of distal caecal and proximal ascending colon carcinomas. The rate of RSM tumour involvement identified here is similar to a previously published local recurrence rate of 10% in caecal carcinoma, suggesting that RSM tumour involvement may be a predictor of recurrence in these tumours. Therefore, patients with distal caecal or proximal ascending colon carcinoma and RSM tumour involvement may benefit from postoperative radiotherapy.