Histological grading of colorectal cancer: a simple and objective method.

OBJECTIVE: Tumor grade employed for colorectal cancer has long been based on the degree of differentiation, which is difficult to judge objectively. The aim of this study was to determine whether the extent of the poorly differentiated component (POR) could be a valuable criterion for a grading system. PATIENTS AND METHODS: A total of 1075 patients with advanced colorectal cancer were pathologically reviewed. POR was newly defined as a region in which a cancer has no glandular formation, irrespective of a mucin-producing or invasive pattern, and we quantitatively classified the POR into 6 degrees using the microscopic field of an objective lens as a standard. RESULTS: Survival analyses of the extent of POR demonstrated that a 3-category grading system provides the most efficient survival stratification. Grade III was applied to tumors (n = 339) for which the POR fully occupied the microscopic field of a 40x objective lens. For tumors having a smaller POR, cancer clusters without a gland structure composed of > or = 5 cancer cells ("clusters") were counted in the microscopic field of a 4x objective lens, where "clusters" were observed most intensively. Tumors with < 10 "clusters" were classified as grade I (n = 161), and those with > or = 10 "clusters" as grade II (n = 575). Patients classified as grade I demonstrated a very favorable prognosis, with a 99.3% cancer-related 5-year survival rate, whereas the survival was 86.0% for grade II and 68.9% for grade III (P < 0.0001 in each group). Multivariate analysis demonstrated that the grades of POR function as an independent prognosticator, as do T-stage and N-stage. CONCLUSIONS: The grading system utilizing POR is distinctive in terms of the simplicity of judgment based on its quantification and the ability to determine which patients will likely be cured by surgery alone. It will aid in selecting postoperative treatment strategies.

Idiopathic small-intestinal inflammation after colectomy for ulcerative colitis.

BACKGROUND & AIMS: Severe ileostomy dysfunction with high ileostomy volumes or severe diarrhea after panproctocolectomy and restorative ileo-anal pouch formation are a rare but serious development after surgery for ulcerative colitis (UC). The incidence, severity, morbidity, and mortality are poorly documented in the literature. METHODS: We describe the case of a patient who developed life-threatening diarrhea after surgery for UC and review the literature. RESULTS: Eight cases have now been described in the literature. Small-bowel disease has developed up to 17 months after colectomy. Most cases responded to corticosteroid therapy. A single case in which this treatment was delayed was fatal. CONCLUSIONS: This is a rare sequel to colectomy for UC, but one which is serious and can be fatal. If the diagnosis is made promptly, a full response to treatment can be expected and the long-term outlook is excellent.

Allele-specific loss of heterozygosity in multiple colorectal adenomas: toward an integrated molecular cytogenetic map II.

Colorectal cancer (CRC) remains a significant public health challenge despite our increased understanding of the genetic defects underlying the pathogenesis of this common disease. It has been thought that multiple mechanisms lead to the malignant phenotype, with familial predisposition syndromes accounting for only a small proportion of all CRC cases. To identify additional loci likely involved in CRC and to test the hypothesis of allele-specific loss of heterozygosity (LOH) for the localization of CRC susceptibility genes, we initially conducted a genome-wide allelotyping analysis of 48 adenomas from a patient with familial adenomatous polyposis coli (FAP) and 63 adenomas from 7 patients with sporadic CRC using 79 fluorescently tagged oligonucleotide primers amplifying microsatellite loci covering the human genome. Frequent allelic losses were identified at D17S802 (41%), D7S518 (40%), D18S53 (38%), D10S249 (32%), D2S391 (29%), D16S419 (27%), D15S1005 and D15S120 (24%), D9S274 and D11S1318 (23%), D14S65 (20%), D14S274 and D17S953 (19%), D19S424 (18%), D5S346 and D1S397 (15%), and D6S468 (13%) in multiple FAP adenomas. Common LOH was also detected at D4S1584 (42%), D11S968 (31%), D17S953 (28%), D5S394, D9S286 and D10S249 (24%), D8S511 (23%), D13S158 (21%), D7S669 (20%), D18S58 (19%), D2S162 and D16S432 (16%), D2S206 (15%), D7S496 and D17S946 (14%), D6S292 (13%), D4S1586 and D8S283 (11%), and D1S2766 (10%) in multiple CRC adenomas. In addition, allele-specific LOH at D5S346, D15S1005, and D15S120 was observed in multiple FAP adenomas (P < 0.01) and at D2S206 and D16S423 in multiple CRC (P < 0.05). To compare our data to previous reports, we determined the band-specific frequency of chromosomal imbalances in CRC karyotypes reported in the Mitelman database, and from the CGH results of cases accessible through the PROGENETIX website. Furthermore, published genome-wide allelotyping analysis of CRC and other allele-specific LOH studies were compiled and collated with our LOH data. The combined results not only provide a comprehensive view of genetic losses in CRC, indicating the comparability of these different techniques, but they also reveal different novel loci in multiple adenomas from FAP and sporadic CRC patients, suggesting that they represent a distinct subtype of CRC in terms of allelic losses. Allele-specific LOH is an alternative approach for cancer gene mapping.

Aberrant cytological localization of p16 and CDK4 in colorectal epithelia in the normal adenoma carcinoma sequence.

AIM: To study the correlation between the patterns of subcellular expression of p16 and CDK4 in colorectal epithelia in the normal-adenoma-carcinoma sequence. METHODS: Paraffin sections of 43 cases of normal colorectal epithelia and corresponding adenomas as well as carcinomas were analysed immunocytochemically for subcellular expression of p16 and CDK4 proteins. RESULTS: Most carcinomas showed more cytoplasmic overexpression for p16 and CDK4 than the adenomas from which they arised or the adjacent normal mucosa. Most normal or non-neoplastic epithelia showed more p16 and CDK4 expression in the nucleus than their adjacent adenomas and carcinomas. There was a significant difference between the subcellular expression pattern of p16 and CDK4 in normal-adenoma-carcinoma sequence epithelia (P < 0.001). Neither p16 nor CDK4 subcellular patterns correlated with histological grade or Dukes' stage. CONCLUSION: Interaction of expression of p16 and CDK4 plays an important role in the Rb/p16 pathway. Overexpression of p16 and CDK4 in the cytoplasm, as well as loss expression of p16 in the nucleus might be important in the evolution of colorectal carcinoma from adenoma and, of adenoma from normal epithelia.

Clinico-pathological aspects of colorectal serrated adenomas.

AIM: To study the association of colorectal serrated adenomas (SAs) with invasive carcinoma, local recurrence, synchronicity and metachronicity of lesions. METHODS: A total of 4,536 polyps from 1,096 patients over an eight-year period (1987-1995) were retrospectively examined. Adenomas showing at least 50% of serrated architecture were called SAs by three reviewing pathologists. RESULTS: Ninety-one (2%) of all polyps were called SAs, which were found in 46 patients. Invasive carcinomas were seen in 3 out of 46 (6.4%) patients, of whom one was a case of familial adenomatous polyposis (FAP). A male preponderance was noted and features of a mild degree of dysplasia were seen in majority (n=75, 83%) of serrated adenomas. Follow-up ranged 1-12 years with a mean time of 5.75 years. Recurrences of SAs were seen in 3 (6.4%) cases, synchronous SAs in 16 (34.8%) cases and metachronous SAs in 9 (19.6%) cases. CONCLUSION: Invasive carcinoma arising in serrated adenoma is rare, accounting for 2 (4.3%) cases studied in this series.

Beta-catenin expression and allelic loss at APC in sporadic colorectal carcinogenesis.

beta-catenin is involved in E-cadherin-mediated cell adhesion, intracellular signal transduction, and also interacts with adenomatous polyposis coli (APC) protein. We previously found that 31% of colorectal adenomas and 84% of carcinomas showed reduced membranous staining of beta-catenin, while 46% of adenomas and 79% of carcinomas displayed beta-catenin nuclear expression. Importantly, a reciprocal relationship between reduced membranous and increased nuclear beta-catenin expression was demonstrated in the development from adenoma to carcinoma. To clarify whether this relates to an abnormality of the APC gene ( APC), we have now studied allele loss in microdissected tissues from 74 adenomas and 21 carcinomas (sporadic cases, previously immunostained for beta-catenin) by analysis of the microsatellites D5S346, D5S82 and D5S299. Fifty-five tumors (57.8%) showed allele loss at APC (no difference between adenomas and carcinomas). Thirty-one of these 55 (31/55, 56.4%) displayed both increased nuclear localization and reduced membranous staining of beta-catenin, and thirteen tumors (13/55, 23.6%) manifested either nuclear expression without changes in membranous expression or reduced membranous staining without nuclear expression (9 and 4 cases, respectively), while 11 (11/55, 20.0%) preserved normal membranous expression. Adenomas and carcinomas showing both nuclear and reduced membranous expression of beta-catenin, compared with those with normal membranous expression, tended to show allele loss ( P<0.01). In addition, 24 (24/95, 25.6%) tumors showed a change in the pattern of beta-catenin expression, but did not exhibit allele loss. These results suggest that although there may be a number of mechanisms responsible for changes in beta-catenin expression in colorectal tumors, dysfunction of APC may be the major cause of this phenomenon.

Morphometric quantification of normal submucous plexus in the distal rectum of adult healthy volunteers.

OBJECTIVE: Inadequate morphometric characterization of the normal adult submucous plexus has precluded the diagnosis of colonic dysganglionoses associated with constipation, such as intestinal neuronal dysplasia type B (IND B). The internal submucous plexus (Meissner plexus) was morphometrically quantified in adult healthy volunteers. DESIGN: Open, prospective morphometric study in balanced groups of female and male volunteers. PARTICIPANTS: Thirty-seven adult healthy male and female volunteers with normal bowel function and no history of gastrointestinal disease. METHODS: Four jumbo rectal biopsies (3-5 mm3) were taken 5 and 10 cm above the pectinate line. Two expert gastrointestinal pathologists assessed biopsy sections after specific nerve cell staining for lactic dehydrogenase, nitric oxide synthase and acetylcholinesterase, mainly for characteristics of ganglia and nerve cells in the submucous plexus. RESULTS: No healthy individual demonstrated over 20% of submucosal ganglia as giant ganglia or more than four giant ganglia per 30 sections (the morphometric criteria for IND B). Single submucosal nerve cells and ganglion numbers halved between 10 and 5 cm above the pectinate line, but there were no age or gender differences. The biological variability of nerve cell and ganglion density in the submucous plexus was large. CONCLUSIONS: Healthy adults show less than 20% of submucosal ganglia as giant ganglia and no more than four giant ganglia per 30 rectal biopsy sections. There is therefore no overlap with the histomorphological criteria of IND B. These data therefore support the specificity of the previously defined criteria for IND B in adults.

Microscopic colitis: the tip of the iceberg?

OBJECTIVES: The aims were to determine whether a wide variation exists between hospitals in the diagnosis of microscopic colitis and to assimilate clinical data. DESIGN: Retrospective study of 90 patients with microscopic colitis aged between 16 and 92 years from 11 hospitals in south-east England. METHODS: A questionnaire was designed to collect relevant data from all patients in whom a new diagnosis of microscopic colitis had been made at the source hospital between January 1990 and December 1996. The inclusion criteria were presentation with watery diarrhoea, a normal endoscopy and a histological report of microscopic colitis. Histology slides were then requested and reviewed. Clinical data were analysed with reference to the confirmed diagnosis. RESULTS: The number of patients diagnosed at each hospital ranged between zero and 30, with a median of six. Sixty-eight patients had histological slides reviewed. The numbers of patients with a final reviewed diagnosis of collagenous colitis, lymphocytic colitis and microscopic colitis, type undesignated, were 37, 18 and seven respectively. In thirty-one patients (34%) there was a recent history of the use of non-steroidal anti-inflammatory drugs. CONCLUSIONS: These data confirm that there is wide hospital variation in the diagnosis of microscopic colitis. Furthermore, the small group with the undesignated type may be associated with the use of non-steroidal anti-inflammatory drugs.

Expressing patterns of p16 and CDK4 correlated to prognosis in colorectal carcinoma.

AIM: To describe the correlation between immunostaining patterns of p16 and CDK4 and prognosis in colorectal carcinoma. METHODS: Paraffin sections of 74 cases of colorectal carcinoma were analysed immunohistochemically for expression of p16 and CDK4 proteins. RESULTS: Most carcinomas showed stronger p16 and CDK4 immunostaining in the cytoplasm than the adenomas or the adjacent normal mucosa. Strong immunostaining of p16 was a predictor for better prognosis whereas strong cytoplasmic immunostaining of CDK4 was a predictor for poor prognosis. Both p16 and CDK4 immunostainings were correlated with histological grade or Dukes' stage. CONCLUSION: These results support the experimental evidence that interaction of expression of p16 and CDK4 may play an important role in the Rb/p16 pathway, and the expression patterns of CDK4 and p16 may be imperative in the development of colorectal carcinoma, thus becoming a new prognostic marker in colorectal cancer.

Association between a high number of isolated lymph nodes in T1 to T4 N0M0 colorectal cancer and the microsatellite instability phenotype.

HYPOTHESIS: Stage I or II colorectal carcinomas with microsatellite instability (MSI) are characterized by more isolated lymph nodes in the resected specimen than their counterparts with microsatellite stability (MSS). DESIGN: Prospective study. SETTING: Academic research. PATIENTS: Using a pentaplex polymerase chain reaction assay, MSI status was determined prospectively for 135 operative patients. MAIN OUTCOME MEASURES: Mismatch repair defects were investigated by immunohistochemistry on tumors demonstrating MSI. RESULTS: Among 82 stage I or II colorectal carcinomas, 11 had MSI, and 71 had MSS, with a mean (SD) number of 23.6 (3.1) and 13.7 (1.0) negative lymph nodes, respectively (P = .001). The mean number of lymph nodes for all resected stage I or II colorectal carcinomas analyzed at our hospital was 15. The prevalence of MSI among tumors with more than 15 lymph nodes in the specimen was 25% (9 of 36), and 82% (9 of 11) of MSI tumors belonged to this group. CONCLUSIONS: A high number of isolated lymph nodes in stage I or II colorectal carcinomas was associated with the MSI phenotype. Good prognosis that is usually associated with tumors having a high number of uninvolved lymph nodes might reflect the high prevalence of MSI among these tumors. The number of examined lymph nodes as a quality criterion should be used with caution. For stage I or stage II colorectal carcinomas, restricting MSI phenotyping to tumors with more than the mean number of lymph nodes identifies almost all MSI tumors.

Number and size of lymph nodes recovered from dukes B rectal cancers: correlation with prognosis and histologic antitumor immune response.

PURPOSE: In rectal cancer variation in lymph node recovery influences the detection of nodal metastases and prognosis among Dukes B (Stage II) cases. However, the possible prognostic importance of node size and inherent patient/tumor characteristics in determining node recovery has not been studied. METHODS: We examined 269 Dukes B (Stage II) rectal tumors, with a mean of 12 nodes per case. Primary tumor characteristics were correlated with the number and size of recovered nodes. Clinical follow-up permitted determination of long-term survival. RESULTS: The five-year survival of 94 Dukes B cases with nine or fewer nodes was 69.4 percent vs. 87.6 percent in 175 cases with ten or more nodes (P = 0.001). Lymph nodes were smaller in patients dying of recurrence; among 130 Dukes B patients whose mean node diameter was <4 mm, survival was 73.3 vs. 88 percent when mean nodal diameter was > or =4 mm. The number and size of recovered nodes was related to patient age, histologic antitumor immune response, and tumor growth pattern. By combining the number and size of nodes, a poor prognosis subgroup of 98 Dukes B patients with relatively few large nodes (no more than 5 measuring > or =4 mm) was identified with a five-year survival of 65.6 percent compared with 89.6 percent for the remaining 158 Dukes B cases (P < 0.0001). CONCLUSIONS: In Dukes B rectal tumors, the number and size of lymph nodes are related to inherent patient and tumor characteristics and permit the identification of Dukes B cases at increased risk of recurrence. A valid comparison of nodal sampling efficiency between centers necessitates measuring and counting harvested lymph nodes.

Extent of mesorectal tumor invasion as a prognostic factor after curative surgery for T3 rectal cancer patients.

OBJECTIVE: To determine the significance of the extent of mesorectal tumor invasion as a prognostic factor for T3 rectal cancer patients. SUMMARY BACKGROUND DATA: There is controversy as to which primary lesion characteristics, other than regional lymph node involvement, in T3 rectal cancer are reliable prognostic factors. PATIENTS AND METHODS: The extent of mesorectal tumor invasion was evaluated using 2 data sets comprising 196 and 247 patients undergoing curative surgery at separate institutes. When the outer aspect of the muscular layer was not identifiable, an estimate was obtained by drawing a straight line between the 2 break points of the muscular layer. RESULTS: We selected 6 mm as the optimal value for subclassification of T3 rectal patients into 2 groups, based on the extent of mesorectal invasion, using the first data set. The overall 5-year survival rate was significantly higher in patients with <6 mm than in those with > or =6 mm of mesorectal invasion (72% versus 50%; P< 0.01). Similarly, in the second data set, the overall 5-year survival rates of patients with mesorectal invasion <6 mm and > or =6 mm were 59% and 37%, respectively (P < 0.01). In both data sets, multivariate analyses verified the extent of mesorectal invasion to be an independent prognostic factor, together with nodal involvement. Regarding positive nodal involvement and mesorectal invasion > or =6 mm as risk factors, the overall 5-year survival rates with none, one, and both of these factors were 84%, 61%, and 38%, respectively, in the first data set (P < 0.01). Prognostic results were similar for the second data set. CONCLUSION: Extent of mesorectal invasion, based on a 6-mm cutoff value, is useful for subclassification of T3 rectal cancer patients.

Flat colorectal neoplasms and the impact of the revised Vienna Classification on their reporting: a case-control study in UK and Japanese patients.

OBJECTIVE: The prevalence and interpretation of flat colorectal neoplasms in the East or West remain highly variable. Several factors may contribute to this variability including differences in reporting techniques between Japanese and Western histopathologists when lesions are classified. The aims of this study were (i) to determine the frequency and characteristics of flat colorectal neoplasms in British and Japanese patients, (ii) to examine whether histopathological discrepancies exist between Western and Japanese-trained pathologists applying conventional classification methods and (iii) to determine the impact of the revised Vienna Classification on any differences observed. MATERIAL AND METHODS: One hundred and forty-four patients in the United Kingdom with neoplastic lesions prospectively identified by a colonoscopist, fully-trained in Japan, were age and gender-matched with 144 Japanese patients with neoplastic lesions detected by the same colonoscopist. Two British and two Japanese pathologists were independently asked to assess all neoplasms using both conventional and revised Vienna Classification methods. RESULTS: No significant difference in the frequency of flat neoplasms was found between British and Japanese patients; however, flat neoplasia from Japanese patients tended to contain more advanced pathologies. Discrepancies in histological diagnoses were observed between pathologists but which were reduced with the revised Vienna Classification. Japanese pathologists tended to diagnose higher grades of dysplasia for the same lesion compared to their British counterparts. CONCLUSIONS: The frequency of flat neoplasms in British and Japanese patients is similar. However, Japanese lesions, especially flat (IIb) and slightly depressed (IIc) neoplasms tend to be more biologically aggressive. The revised Vienna Classification achieves greater consensus.

Thirty-year analysis of a colonoscopic surveillance program for neoplasia in ulcerative colitis.

BACKGROUND & AIMS: The value of colonoscopic surveillance for neoplasia in long-standing extensive ulcerative colitis remains controversial. This study reports on prospectively collected data from a surveillance program over a 30-year period. METHODS: Data were obtained from the prospective surveillance database, medical records, colonoscopy, and histology reports. The primary end point was defined as death, colectomy, withdrawal from surveillance, or census date (January 1, 2001). Follow-up information was obtained for patients who left the program. RESULTS: Six hundred patients underwent 2627 colonoscopies during 5932 patient-years of follow-up. The cecal intubation rate was 98.7%, with no significant complications. Seventy-four patients (12.3%) developed neoplasia, including 30 colorectal cancers (CRCs). There was no difference in median age at onset of colitis for those with or without CRC (P = .8, Mann-Whitney). The cumulative incidence of CRC by colitis duration was 2.5% at 20 years, 7.6% at 30 years, and 10.8% at 40 years. The 5-year survival rate was 73.3%. Sixteen of 30 cancers were interval cancers. CRC incidence decreased over time (r = -.40, P = .04; linear regression). CONCLUSIONS: Colonoscopic surveillance is safe and allows the vast majority of patients to retain their colon. Although two thirds of patients with potentially life-threatening neoplasia benefited from surveillance, the program was not wholly effective in cancer prevention. The cancer incidence, however, was considerably lower than in the majority of other studies, and was constant for up to 40 years of colitis duration, suggesting there is no need to intensify surveillance over time.

Decreased density of interstitial cells of Cajal and neuronal cells in patients with slow-transit constipation and acquired megacolon.

BACKGROUND: The pathophysiology of constipation is not clearly identified as yet, and the interstital cells of Cajal (ICC), known to generate the slow wave activity and to be involved in intestinal neurotransmission and the enteric nervous system (ENS), are suspected to play an important role. The aims of the present study were to assess the distribution of ICC and neuronal cells of ENS in patients with slow-transit constipation and acquired megacolon. METHODS: Sigmoid colon specimens were obtained from patients who underwent colectomy due to slow-transit constipation (n = 10), acquired megacolon (n = 9) and non-obstructive colon cancer (n = 10) as a control group. The ICC were visualized by c-Kit immunohistochemistry and neuronal cells of the ENS were demonstrated by protein gene product (PGP) 9.5. Density of cells stained by c-Kit and PGP 9.5 was calculated as percent area (area stained/area of X-Y plane) x 100, when images were collected at a magnification of x40 objective, with maximum area examined in the horizontal X-Y plane of 400 microm x 400 microm using an image analyzer. RESULTS: The densities of ICC and PGP 9.5 reactive neuronal structures were significantly decreased in all layers of sigmoid colon specimens in patients with slow-transit constipation and acquired megacolon, compared with that of the control group. However, there was no statistically significant difference in either the density of ICC or that of neuronal structures between the patients with slow-transit constipation and acquired megacolon. CONCLUSIONS: Slow-transit constipation and acquired megacolon were associated with alteration of ICC and neuronal cells of ENS in the sigmoid colon.

Prevalence and morphology of pouch and ileal adenomas in familial adenomatous polyposis.

PURPOSE: In familial adenomatous polyposis, the long-term risk of pouch polyposis and potential for pouch cancer are unknown. Our aim was to evaluate prospectively the prevalence, nature, and etiology of pouch ileal adenomas with that of nonpouch ileal adenomas in familial adenomatous polyposis. METHODS: Sixty patients with familial adenomatous polyposis pouch, 47 familial adenomatous polyposis patients with ileorectal anastomosis, and 20 younger patients with familial adenomatous polyposis who had prophylactic colectomy were examined with videoendoscopy. RESULTS: Adenomatous polyps were found in the pouches of 34 patients (57 percent). A total of 362 polyps were identified (range, 0-50 per patient). A logistic regression model confirmed that there was a significant association between the increasing age of the patient and the presence of pouch adenomas (P < 0.02) and the length of follow-up since pouch surgery (P < 0.05). There was no apparent relationship between the development of pouch adenomas and the severity of either colonic or duodenal polyposis and there were no clear genotype or phenotype correlations. Most polyps were tubular adenomas with mild dysplasia, but 11 patients had more advanced histology, including two patients with large villous adenomas. Nonpouch ileal mucosa was spared from visually observed adenomas, with only 1 of 48 (2 percent) patients with ileorectal anastomosis adenomas and 0 of 20 (0 percent) younger, precolectomy patients having terminal ileal adenomas. However, microadenomas were present on random biopsy in 4 percent to 5 percent of nonpouch ileum. CONCLUSION: The risk of pouch cancer in familial adenomatous polyposis is unclear, but follow-up periods since surgery remain relatively short. Long-term endoscopic surveillance of familial adenomatous polyposis pouches is thus recommended along with evaluation of potential therapeutic options for pouch adenomas.

The expression of E-cadherin and catenins in colorectal tumours from familial adenomatous polyposis patients.

Familial adenomatous polyposis patients (FAP) harbour a germline mutation of the adenomatous polyposis coli gene (APC), and APC mutations are early events in the development of sporadic colorectal neoplasms. The APC protein interacts with beta-catenin and gamma-catenin and APC mutations are believed to play a role in the altered levels of beta-catenin in colorectal tumours. Immunohistochemical studies have shown changes in the expression and distribution of E-cadherin and catenins in sporadic colorectal neoplasms. This study assessed the expression and distribution of E-cadherin and catenins in colorectal neoplasms and non-neoplastic mucosa from FAP patients. The expression and cellular distribution of E-cadherin and catenins were studied by immunohistochemistry in 61 adenomas, five carcinomas, and non-neoplastic mucosa from 18 FAP patients. mRNA levels in the carcinomas were studied by in situ hybridization. The expression of E-cadherin and catenins was increased in over 80% of the adenomas, with evident cytoplasmic immunoreactivity. There was increased expression of E-cadherin and catenin in the carcinomas, with a notable increase in the levels of mRNA, in comparison with the non-neoplastic mucosa.

Histologic indices in biopsy specimens for estimating the probability of extended local spread in patients with rectal carcinoma.

BACKGROUND: Although precise preoperative assessment of the extent of local cancer spread is important to determine the appropriate treatment strategy, imaging modalities have not been sufficient. The aim of this study was to establish effective preoperative indices that would predict the degree of local spread in patients with rectal carcinoma. METHODS: In specimens from 437 patients with advanced rectal carcinoma, the submucosal horizontal invasive frontal region was examined histologically with reference to three unfavorable characteristics: 1) tumor "budding", 2) poor differentiation, and 3) vascular invasion. In addition, a transanal submucosal biopsy, which targets the tumor edge, was performed on 85 patients to verify the utility of preoperative evaluation of these parameters. RESULTS: Multivariate logistic analysis showed that three unfavorable parameters had independent impact on the degree of nodal involvement. These parameters related significantly to the number of lymph nodes involved, the development of extranodal tumor deposits, circumferential surgical margin involvement, and lateral pelvic lymph node metastases. Regarding patients without unfavorable parameters as a standard, the odds ratio of pelvic recurrence was 1.8 (0.9-3.4) in patients with one unfavorable parameter and 5.3 (2.7-10.2) in patients with multiple unfavorable parameters. Based on the transanal biopsy, the submucosal invasive frontal region could be estimated in 73 patients (85.9%). Among these cases, the multiple unfavorable parameters were relevant to an increased risk of extensive local spread. In addition, pelvic recurrence developed in 36% of patients with multiple unfavorable parameters (no-risk patients, 5%; single-risk patients, 13%). CONCLUSION: Histology in the submucosal invasive frontal region reflects the extent of local spread and can be evaluated preoperatively by transanal biopsy, which should become a useful tool for therapy selection for patients with advanced rectal carcinoma.

A new prognostic staging system for rectal cancer.

OBJECTIVE: To clarify the appropriateness of tumor "budding," a quantifiable histologic variable, as 1 parameter in the construction of a new prognostic grading system for rectal cancer. SUMMARY BACKGROUND DATA: Patient division according to an accurate prognostic prediction could enhance the effectiveness of postoperative adjuvant therapy and follow-up. PATIENTS AND METHODS: Tumor budding was defined as an isolated cancer cell or a cluster composed of fewer than 5 cells in the invasive frontal region, and was divided into 2 grades based on its number within a microscopic field of x250. We analyzed 2 discrete cohorts comprising 638 and 476 patients undergoing potentially curative surgery. RESULTS: In the first cohort, high-grade budding (10 or more foci in a field) was observed in 30% of patients and was significantly associated with a lower 5-year survival rate (41%) than low-grade budding (84%). Similarly, in the second cohort, the 5-year survival rate was 43% in high-grade budding patients and 83% in low-grade budding patients. In both cohorts, multivariate analyses verified budding to be an independent prognosticator, together with nodal involvement and extramural spread. These 3 variables were given weighted scores, and the score range was divided to provide 5 prognostic groups (97%; 86%; 61%; 39%; 17% 5-year survival). The model was tested on the second cohort, and similar prognostic results were obtained. CONCLUSIONS: We propose that because of its relevance to prognosis and its reproducibility, budding is an excellent parameter for use in a grading system to provide a confident prediction of clinical outcome.

Multi-detector row CT colonography: effect of collimation, pitch, and orientation on polyp detection in a human colectomy specimen.

PURPOSE: To investigate the effects of orientation, collimation, pitch, and tube current setting on polyp detection at multi-detector row computed tomographic (CT) colonography and to determine the optimal combination of scanning parameters for screening. MATERIALS AND METHODS: A colectomy specimen containing 117 polyps of different sizes was insufflated and imaged with a multi-detector row CT scanner at various collimation (1.25 and 2.5 mm), pitch (3 and 6), and tube current (50, 100, and 150 mA) settings. Two-dimensional multiplanar reformatted images and three-dimensional endoluminal surface renderings from the 12 resultant data sets were examined by one observer for the presence and conspicuity of polyps. The results were analyzed with Poisson regression and logistic regression to determine the effects of scanning parameters and of specimen orientation on polyp detection. RESULTS: The percentage of polyps that were detected significantly increased when collimation (P =.008) and table feed (P =.03) were decreased. Increased tube current resulted in improved detection only of polyps with a diameter of less than 5 mm. Polyps of less than 5 mm were optimally depicted with a collimation of 1.25 mm, a pitch of 3, and a tube current setting of 150 mA; polyps with a diameter greater than 5 mm were adequately depicted with 1.25-mm collimation and with either pitch setting and any of the three tube current settings. Small polyps in the transverse segment (positioned at a 90 degrees angle to the z axis of scanning) were significantly less visible than those in parallel or oblique orientations (P <.001). The effective radiation dose, calculated with a Monte Carlo simulation, was 1.4-10.0 mSv. CONCLUSION: Detection of small polyps (<5 mm) with multi-detector row CT is highly dependent on collimation, pitch, and, to a lesser extent, tube current. Collimation of 1.25 mm, combined with pitch of 6 and tube current of 50 mA, provides for reliable detection of polyps 5 mm or larger while limiting the effective radiation dose. Polyps smaller than 5 mm, however, may be poorly depicted with use of these settings in the transverse colon.