Carbon dating cancer: defining the chronology of metastatic progression in colorectal cancer.

Background: Patients often ask oncologists how long a cancer has been present before causing symptoms or spreading to other organs. The evolutionary trajectory of cancers can be defined using phylogenetic approaches but lack of chronological references makes dating the exact onset of tumours very challenging. Patients and methods: Here, we describe the case of a colorectal cancer (CRC) patient presenting with synchronous lung metastasis and metachronous thyroid, chest wall and urinary tract metastases over the course of 5 years. The chest wall metastasis was caused by needle tract seeding, implying a known time of onset. Using whole genome sequencing data from primary and metastatic sites we inferred the complete chronology of the cancer by exploiting the time of needle tract seeding as an in vivo 'stopwatch'. This approach allowed us to follow the progression of the disease back in time, dating each ancestral node of the phylogenetic tree in the past history of the tumour. We used a Bayesian phylogenomic approach, which accounts for possible dynamic changes in mutational rate, to reconstruct the phylogenetic tree and effectively 'carbon date' the malignant progression. Results: The primary colon cancer emerged between 5 and 8 years before the clinical diagnosis. The primary tumour metastasized to the lung and the thyroid within a year from its onset. The thyroid lesion presented as a tumour-to-tumour deposit within a benign Hurthle adenoma. Despite rapid metastatic progression from the primary tumour, the patient showed an indolent disease course. Primary cancer and metastases were microsatellite stable and displayed low chromosomal instability. Neo-antigen analysis suggested minimal immunogenicity. Conclusion: Our data provide the first in vivo experimental evidence documenting the timing of metastatic progression in CRC and suggest that genomic instability might be more important than the metastatic potential of the primary cancer in dictating CRC fate.

Impact of the bowel-screening programme on the diagnosis of colorectal cancer in Ayrshire and Arran.

AIM: Bowel screening aims to reduce colorectal-cancer mortality by the detection and treatment of early-stage asymptomatic disease and the removal of precancerous adenomas. Bowel screening started in Ayrshire and Arran in September 2007. We report the impact of this screening on the diagnosis and stage of colorectal cancer and characterize screen-detected cancers in comparison with those diagnosed through other pathways. METHOD: Diagnoses were identified from an audit database. Referrals were grouped into screen detected, routine, urgent and emergency presentations. RESULTS: Between January 2001 and December 2010, 2289 diagnoses of colorectal cancer were made. From 2001 to 2006, the mean (range) number of new colorectal-cancer diagnoses per year was 210 (198-220). Between 2007 and 2010, the mean (range) number of diagnoses per year was 256 (239-274), a significant (P = 0.008) increase. Since September 2007, 877 colorectal cancers have been diagnosed: 17% were screen detected; 11% were detected as a result of routine GP referral; 51% were detected after urgent GP referral; and 21% were emergency presentations. TNM stage increased with urgency of referral. Approximately two-thirds (66%) of screen-detected colorectal cancers were node negative vs 25% of emergency presentations (P < 0.001). Most screen-detected cancers were distal to the splenic flexure (75%). Screened cancers had favourable pathology; lower T and N stages (both P < 0.001), less venous invasion (P < 0.001) and better differentiation (P < 0.05). Similar results were seen after stratification for TNM stage. Screening has not yet resulted in a significant shift towards early-stage disease since 2007. CONCLUSION: Screening has been associated with an increase in the numbers of both new and early-stage colorectal cancers. Screen-detected cancers are predominantly early-stage disease with favourable pathology. At present, it remains to be seen whether screening will ultimately translate into an overall reduction in advanced-stage disease.

Sclerosing mesenteritis presenting with complete small bowel obstruction, abdominal mass and hydronephrosis.

Sclerosing mesenteritis is an uncommon and poorly understood inflammatory condition of the bowel mesentery which can often be confused with neoplasia, Crohn's disease and other inflammatory conditions. We describe a case of complete small bowel obstruction and right sided hydronephrosis due to sclerosing mesenteritis.

Endoscopists' estimation of size should not determine surveillance of colonic polyps.

OBJECTIVE: Current British Society of Gastroenterology guidelines use adenomatous polyp size as one of the key factors in determining polyp follow-up. This study aimed to compare polyp size assessment by colonoscopists and pathologists before and after fixation to determine the optimal method for measurement. METHOD: Thirty-five colorectal polyps were found during pre-arranged colonoscopies in one centre. Polyp size was measured to the nearest 1 mm by three different methods: 1. by the endoscopist at colonoscopy; 2. by the pathologist fresh, following removal; 3. by the pathologist fixed, following fixation. The endoscopist and the pathologist were blinded to each other's measurements. RESULTS: Seventeen men, eighteen women with mean age of 66.2 years (SD: 9.4, range: 38.7-85.5) underwent polypectomy/s with all polyps removed intact. Polypectomies were performed by consultants (43%), nurse specialists (34%) and specialist registrars (23%). The median size (mm) of polyps measured were endoscopically, 6.5 (2-25 mm); fresh specimen 7.0 (4-28 mm) and fixed 7.0 (4-28 mm). Endoscopic measurements were significantly lower than that of fresh and fixed sizes (P < 0.001 and P = 0.003 respectively), with poor correlation [correlation of variance (CV): 21.0% and intraclass correlation coefficient (ICCC): 0.841 for endoscopic and fresh measurements; CV: 21.1% and ICCC: 0.838 for endoscopic and fixed measurements]. There was no statistical difference between fresh and fixed specimen measurements (P > 0.05; CV: 4.2%, ICCC: 0.974). In three patients, the endoscopic measurement was < 1 cm in polyps that were found to be >or= 1 cm on pathological measurement. CONCLUSIONS: Endoscopists consistently underestimated polyp size. Fixation had no effect on polyp size. Pathologists' measurement of polyp size on fixed specimens should determine the need for further colonoscopic follow-up.

Positive lymph node retrieval ratio optimises patient staging in colorectal cancer.

Alternative lymph node (LN) parameters have been proposed to improve staging in colorectal cancer. This study compared these alternative parameters with conventional TNM staging in predicting long-term survival in patients undergoing curative resection. A total of 295 consecutive patients (mean age 70 years; range 39-95; s.d. 10.4) underwent resection for colorectal cancer from 2001 to 2004. Age, sex, primary tumour site, TNM stage and chemotherapy/radiotherapy were recorded. Patients with colon and rectal cancers were analysed separately for LN parameters: LN total; adequate LN retrieval (> or =12) and inadequate (<12); total number of negative LN; total number of positive LN and the ratio of positive LN to total LN (pLNR). Univariate and multivariate survival analysis was performed. The median number of LN retrieved was 10 (1-57) with adequate LN retrieval in 147 cases (49.8%). For each T and N stage, inadequate LN retrieval did not adversely affect long-term survival (P>0.05). On multivariate analysis, only pLNR was an independent predictor of overall survival in both colon and rectal cancers (HR 11.65, 95% CI 5.00-27.15, P<0.001 and HR 13.40, 95% CI 3.64-49.10, P<0.001, respectively). Application of pLNR subdivided patients into four prognostic groups. Application of the pLNR improved patient stratification in colorectal cancer and should be considered in future staging systems.

Radiation-induced angiosarcoma of the rectum: a case report and review of literature.

We report a case of rectal angiosarcoma after prostatic radiotherapy, illustrating diagnostic difficulty. Awareness of this potential diagnosis is important with increasing use of radiotherapy in the treatment of pelvic cancers.

Gastric carcinoid: germline and somatic mutation of the neurofibromatosis type 1 gene.

Neurofibromatosis type 1 (NF1) is one of the most common autosomal dominantly inherited conditions. A range of complications has been described, including gastrointestinal manifestations. Gastric carcinoid tumours are associated with multiple endocrine neoplasia, atrophic gastritis and pernicious anaemia but have not been reported in NF1 in the absence of other predisposing factors. We report the occurrence and investigation of a gastric carcinoid tumour in a 23-year-old woman with previously uncomplicated NF1. Analysis of the tumour tissue revealed loss of heterozygosity at the NF1 gene locus but a normal karyotype and an absence of microsatellite instability. A germline NF1 gene nonsense mutation in exon 37 was detected by denaturing high-performance liquid chromatography and DNA sequence analysis. This is the first reported occurrence of a gastric carcinoid tumour in a patient with NF1 in the absence of other predisposing factors such as pernicious anaemia. The analyses indicate that the carcinoid arose through NF1 gene inactivation but in the absence of an inherited NF1 gene microdeletion. This case adds to the range of gastrointestinal tumours that may be encountered in patients with NF1, particularly in those who present with upper gastrointestinal haemorrhage.

Gastric epithelial anti-microbial peptides--histological correlation and influence of anatomical site and peptic ulcer disease.

BACKGROUND AND AIMS: Natural anti-microbial peptides are increasingly recognised for their protective effects in mucosal surfaces. We, therefore, aimed at investigating their expression in the human stomach in a range of peptic conditions. METHODS: We assessed the expression of epithelial secretory leukocyte protease inhibitor, human beta-defensins (HBD1 and HBD2), and alpha-defensin (HD5) in gastric biopsies taken from 52 patients, median age of 55 years. Expression of peptide mRNA was determined using real-time quantitative polymerase chain reaction. The activity of gastritis was graded on a 0-3 scale. RESULTS: The antrum had a median secretory leukocyte protease inhibitor of 0.93 and HBD1 of 0.42, compared with 0.13 (P = 0.001) and 0.08 units (P = 0.002) respectively in the gastric body. The antral histological scores correlated positively with HBD2 expression (r = 0.69; P< 0.001) and negatively with HBD1 (r = -0.47; P = 0.006) particularly in the absence of aspirin. Patients with Helicobacter pylori gastritis, gastric or duodenal ulcers had lower expression of HBD1 and greater expression of HBD2 than in controls. The intake of aspirin by patients infected with H. pylori was associated with marked rise in the expression of HD5 and less expression of secretory leukocyte protease inhibitor. CONCLUSIONS: Gastric epithelial anti-microbial peptides are influenced by anatomical site, grade of gastritis, peptic ulceration, and can be modulated by aspirin.

Colonic angiodysplasia and true diverticula: is there an association?

AIMS: To investigate the pathology of colectomy specimens, from patients presenting with lower gastrointestinal haemorrhage, who had undergone preoperative mesenteric angiography. The angiography diagnoses ranged from active bleeding of unknown aetiology to angiodysplasia. METHODS AND RESULTS: The macroscopic and microscopic pathology of 11 colectomy specimens was studied. All the specimens contained blood on receipt with no obvious macroscopic source of haemorrhage identified. In all cases the large bowel demonstrated diverticula with an unusual topography. These were wide-mouthed, up to 20 mm across and exhibited a partly scattered distribution across the bowel; in two cases the diverticula contained blood clot. Histology demonstrated true diverticula invested by all muscle layers, exhibiting thick-walled vessels, within the submucosa and within the muscularis propria fibres, resembling the vascular elements identified in congenital vascular malformations. The two cases that contained blood clot revealed the thick-walled vessels to have ruptured into the diverticular lumen. Histology from the background colon between the diverticula demonstrated vascular lesions fulfilling the histological criteria for angiodysplasia; these features were also represented in the true-type diverticula. Most cases showed right-sided angiodysplasia and right-sided true diverticula. However, left-sided angiodysplastic lesions were also seen in association with left-sided true-type diverticula. CONCLUSIONS: We have identified the dual pathologies of angiodysplasia and multiple true-type diverticula, and suggest a topographical relationship between these two lesions. Furthermore, we propose that the thick-walled vessels within the true diverticula are congenitally abnormal, and raise the possibility that these vessels exert local haemodynamic effects, that effectively predispose the colon to acquired angiodysplastic phenomena.

Oesophagitis and bile reflux gastritis--clinical and histological assessments.

BACKGROUND AND AIMS: Little is known concerning the relationship between oesophagitis and bile reflux (chemical) gastritis despite the numerous studies on gastritis related to Helicobacter pylori. Given the importance of bile in the pathogenesis of both gastric and oesophageal disorders, we aimed at assessing the chemical gastritis score in patients with or without oesophagitis. METHODS: Chemical/bile reflux gastritis score and bile reflux index were assessed in gastric biopsies taken from patients with oesophagitis and gastric surgery (group 1, n=9), gastric surgery without oesophagitis (group 2, n= 11), and oesophagitis without gastric surgery (group 3, n= 10). Endoscopic oesophageal damage was also graded on a 0-5 scale. RESULTS: Group 1 had a median (interquartile range) chemical score of 6 (4-9) compared with 8 (6-10) in group 2, and 1 (0-2) in group 3 (p=0.001; Kruskal-Wallis test for multiple group comparisons). Both the reflux gastritis score and bile reflux index were lowest in patients with intact stomachs. However, the oesophageal scores were 2 (1-2) in group 1 compared with 3 (2-5) in group 3 (p=0.01). CONCLUSION: Patients with post-surgical stomachs have similar chemical and related scores regardless of the presence or absence of oesophagitis. Despite the higher chemical gastritis scores, patients with gastric surgery, exposed mainly to bile reflux, have milder oesophagitis than those with intact stomachs, exposed to both gastric acid and bile.

Is microscopic assessment of macroscopically normal hysterectomy specimens necessary?

AIM: To determine whether microscopic examination of macroscopically normal hysterectomy specimens yields findings that could alter subsequent clinical management. METHODS: All pathology reports on hysterectomy specimens submitted to the department of histopathology at the Northern General Hospital from January 1997 to December 1998 were reviewed. Cases were included for further assessment if the hysterectomy specimen was regarded as macroscopically normal by a consultant pathologist and if the patient had no history of, or suspicion of, neoplastic disease. The subsequent microscopic findings from these cases were assessed to determine whether any lesions of clinical importance were identified. RESULTS: Eight hundred and fifty four specimens were reviewed, of which 139 were suitable for inclusion. Only one of the 139 cases harboured a microscopic abnormality that necessitated specific clinical follow up; this was a focus of cervical intraepithelial neoplasia 2 (CIN 2). On follow up of that patient, no further neoplastic disease was identified. CONCLUSION: Microscopic assessment of macroscopically normal hysterectomy specimens does not contribute to patient management and is unnecessary in an era of manpower shortage and cost containment.

Male breast neoplasia in association with selective serotonin re-uptake inhibitor therapy: a report of three cases.

Male breast cancer is a rare condition with very poorly understood risk factors. We report three cases of men with malignant and pre-malignant breast disease who had all been prescribed selective serotonin re-uptake inhibitors (SSRIs) for depression. Concerns about an association between this group of drugs and breast cancer in women have been previously raised and experimental evidence has suggested that these drugs could influence regulation of cellular proliferation acting through internal cellular messengers. Risk factors for the development of breast cancer are likely to be multifactorial, possibly more so in women given the complex physiological changes that occur in the female breast. Whilst the cases we report are anecdotal and other risk factors may be present, we suggest that assessment of any possible contribution that SSRI therapy may make to the development of breast neoplasia may be more easily assessed in a male population.

Histopathological detection of lymph node metastases from colorectal carcinoma.

AIM: To evaluate whether the assessment of multiple sections from retrieved nodes yields an increased number of metastases compared with the number that would be detected by the commonly applied method of microscopy of a single section of lymph node only. METHODS: A prospective study of 72 colorectal carcinoma resection specimens. Lymph node sampling was based on the current guidelines for the detection of breast cancer metastases in axillary nodes. Lymph nodes up to approximately 5 mm in maximum extent were processed in entirety, without prior sectioning, and assessed histologically at three levels; larger lymph nodes were processed in entirety as multiple sections and histologically assessed at one level. RESULTS: From a total of 72 carcinomas, eight were Dukes's A, 26 were Dukes's B, and 38 were Dukes's C. The mean and median numbers of nodes identified were 13 and 12, respectively (range, three to 44). Of the Dukes's C cases, four contained lymph node metastases identified by our method that might have gone undetected by the current, generally applied method. In one case, this led to the detection of the only nodal metastasis present and therefore "upstaged" the tumour from Dukes's B to C. On average, six extra tissue blocks were processed for each case in applying this method. CONCLUSION: The assessment of multiple sections of lymph nodes from colorectal specimens leads to the detection of only a small number of additional nodal metastases. The method involves increased workload for pathologists and laboratory staff.

Gangrenous cystitis: a rare cause of colovesical fistula.

A case of gangrenous cystitis presenting as a colovesical fistula in an elderly woman is described. The literature on this rare condition is reviewed.

The use of a proforma improves colorectal cancer pathology reporting.

The detail and accuracy of pathological reporting for colorectal cancer is becoming increasingly recognised as important in the overall management of the patient. However, there is criticism of the variable standards of reporting. We assessed how the use of a proforma affected the completeness of reporting within one hospital. Data on all colorectal cancer patients attending one teaching hospital has been collected prospectively over a 15 month period from 1997 to 1998. The Royal College of Surgeons/Association of Coloproctology proforma lists all items considered to be essential for a complete pathological report of colorectal cancer. Its introduction in September 1997 allowed us to compare reporting before the proforma to that after. Of 54 patients, 46 (85%) had one or more items missing from their report before introduction of the proforma compared with only 8/44 (18%) patients after the proforma (P < 0.001). Circumferential resection margins and apical node status were the items most often absent, being significantly more frequently reported after the proforma (P < 0.05 and P < 0.001, respectively). There was no difference in the median number of lymph nodes harvested after proforma introduction. The introduction of the proforma has not only resulted in improvements in reporting, but has increased the dialogue between surgical oncologists and pathologists. These features should result in improved overall management of the colorectal cancer patient.

Clarification of the link between polyunsaturated fatty acids and Helicobacter pylori-associated duodenal ulcer disease: a dietary intervention study.

Epidemiological evidence has suggested that the declining prevalence of duodenal ulcer disease may be attributable to rising consumption of polyunsaturated fatty acids, a hypothesis supported by in vitro evidence of toxicity of such substances to Helicobacter pylori. The objective of the present study was to establish whether this association is causal. Forty patients with proven infection with H. pylori and endoscopic evidence of past or present duodenal ulcer disease were randomized to receive either polyunsaturated fatty acids (PUFA group), in the form of capsules and margarine, or a placebo (control). Both groups received concurrent H2 antagonist therapy. Efficacy of therapy was determined endoscopically by assessment of ulcer healing while H. pylori status was determined by antral biopsy, urease (EC 3.5.1.5) culture and histological assessment of the severity of H. pylori infection. Antral levels of prostaglandin E2 (PGE2) and leukotriene B4 (LTB4) were quantified. Compliance was monitored. Before treatment, both groups were comparable for severity of H. pylori infection, smoking status and levels of LTB4 and PGE2. Despite a significant difference in consumption of linoleic acid (19.9 (SE 1.6) g for PUFA group v. 6.7 (SE 0.8) g for controls (P < 0.01) and linolenic acid (2.6 (SE 0.2) g v. 0.6 (SE 0.03) g (P < 0.01) there was no significant change in either the severity of H. pylori infection or prostaglandin levels in either group at 6 weeks. Consumption of a considerable amount of PUFA does not inhibit the colonization of the stomach by H. pylori nor does this alter the inflammatory changes characteristic of H. pylori gastritis. We conclude that the association between duodenal ulceration and a low level of dietary PUFA is likely to be spurious, probably reflecting the effect of confounding factors such as affluence, social class or smoking.