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Background: Tumor testing utility in Lynch syndrome (LS) diagnosis is established., Aims: Analyze the differences between tumor testing efficiency in rectal (RC) and colon cancer (CC)., Methods: We performed immunohistochemistry (IHC) for MisMatch Repair (MMR) proteins (IHC-MMR) and MicroSatellite Instability analysis (MSI) on 482 unselected primary tumors: 320 CCs and 162 RCs. Samples had proficient-IHC, deficient-IHC or borderline-IHC ("patchy" expression). MSI-H borderline-IHC tumors were considered as likely MMR-deficient. Germline testing was offered to MMR-deficient patients without BRAF mutation or MLH1 promoter hypermetilation (MLH1-Hy)., Results: We identified 51/482 (10.6%) MMR-defective tumors. Multivariable analysis demonstrated a significant correlation between tumor testing results with histotype, lymph-node involvement and tumor location. In particular, RC showed a lower MMR-deficiency rate than CC (p<0.0001). Interestingly, MLH1 loss was detected in 0% RCs and 76.1% CCs, with 80% of them showing BRAF mutation/MLH1-Hy. A germline variant was detected in 12 out of 18 patients (mutation detection rate of 66.7%)., Conclusion: Tumor testing results showed molecular differences between CCs and RCs, in terms of MMR proteins expression, and presence of BRAF mutation/MLH1-Hy. MSH6 variants were the most frequent ones (50%). Although young age at diagnosis was associated with mutation detection (p = 0.045), 33.3% of LS patients were >50 years., Competing Interests: Conflict of interest None declared., (Copyright © 2020 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Purpose: The issue of whether colon and rectal cancer should be considered as a single entity or two distinct entities is still debated, and there is a need to improve studies addressing the heterogeneity of the pathogenetic pathway leading to sporadic colorectal cancers (SCRCs) as well as to identify biological and/or molecular differences between colon and rectal cancers., Experimental Design: Specimens of SCRCs were analyzed for somatic mutations in APC, K-ras, and TP53 genes and loss-of-heterozygosity of chromosome 18., Results: Eleven SCRCs showed microsatellite instability. APC mutation frequency was significantly lower in microsatellite instability (MIN+) than in MIN- SCRCs. All MIN- SCRCs showed beta-catenin overexpression. A combined analysis of the biomarkers revealed two pathways mainly represented by MIN- SCRCs and differently followed on the basis of tumor location, APC-K-ras-TP53-Ch18q and APC-TP53-Ch18q., Conclusions: The APC-beta-catenin pathway is inactivated in MIN- SCRCs and represents the first hit of SCRC development. Two preferential pathways followed by SCRCs occur, one K-ras dependent, in agreement with the Fearon and Vogelstein model, and the other K-ras independent. Significant differences between colon and rectal tumors occur in our series of MIN- SCRCs. The different pathways observed and their distribution can be summarized as follows: (a) K-ras mutations were more commonly detected in colon than in rectum; (b) the number of mutations detected was significantly higher in colon than in rectal tumors; and (c) a mutational pattern restricted to the APC gene was more common in rectal than in colon tumors. This molecular characterization can be translated into a clinical setting to improve diagnosis and to direct a rationale pharmacological treatment.

Purpose: In modern management of rectal carcinoma, the preoperative evaluation of disease parameters is important for selection of therapeutic options. Such parameters are currently defined through endorectal ultrasonography or endoscopic ultrasonography. A retrospective analysis of the parameters obtained with double-contrast barium enema (DCBE) and endorectal balloon computed tomography (CT) was conducted to verify the diagnostic reliability of the radiological techniques and to establish whether there is still an indication for their use., Methods: 53 consecutive patients with adenocarcinoma of the distal half of the rectal ampulla underwent double contrast barium enema examination and CT of the pelvis with endorectal balloon. On the basis of the DCBE and CT assessment we evaluated: 1) the distance between the cranial extremity of the anal canal and the distal margin of the neoplasm; 2) the radial diffusion of the tumor; 3) the metastatic involvement of the perirectal and inferior mesenteric lymph nodes., Results: 1) CT and DBCE measurements of the distal margin tended to coincide, but both tended to overestimate the measurement when compared to the pathologic examination; 2) in the identification of neoplastic infiltration of perirectal fat (T3) CT had 100% sensitivity, 78.7% specificity and 86.8% accuracy; 3) the CT sensitivity for detecting lymph node metastasis was 52.6%, specificity 85.3% and accuracy 73.6%., Conclusions: The diagnostic information provided by the radiological examinations is comparable to that of clinical and instrumental methods currently employed for staging of rectal carcinoma, although the latter are preferred because they are more readily accessible and less costly. DCBE and CT can therefore be usefully employed for staging of cancer of the rectum in those cases in which there are limitations of the current standard methods.

Objective: To identify factors influencing the occurrence of cancer in the rectal remnant in patients with familial adenomatous polyposis (FAP) after colectomy and ileorectal anastomosis (IRA)., Summary Background Data: The risk for rectal cancer in patients with FAP after colectomy and IRA remains a major concern., Methods: Between 1955 and 1997, 371 patients (206 men, 165 women) from the Registry of Hereditary Colorectal Tumors underwent colectomy and IRA as a primary surgical procedure. Survival was estimated using the Kaplan-Meier method. Cox proportional hazard models were fitted to assess the relative excess risk of rectal cancer and to control for confounding factors. A multivariate analysis was performed to assess the relation between cancer risk in the rectum and sex, age, number of rectal polyps, colon cancer, and APC germline mutation., Results: Median follow-up was 81 months. Eighty-nine patients (24%) had colon cancer at the time of surgery. The APC mutation was found in 200 patients. In 27 patients, cancer developed in the retained rectum 1 to 26 years after surgery. The incidence of rectal carcinoma appears to increase with time: at 10, 15, and 20 years after surgery, the cumulative risk was 7.7%, 13.1%, and 23.0%, respectively. Multivariate analysis identified as independent predictors the presence of colon cancer at IRA and a mutation occurring between codons 1250 and 1464; both factors increased the risk nine times., Conclusions: The presence of cancer at IRA and APC mutation type are the most important risk factors for the future development of cancer in the rectal remnant in patients with FAP.

Background: The aim of this study was to determine the effects of preoperative radiation therapy (RT) on the objective responses of patients with rectal carcinoma to their treatment. These effects were assessed with endorectal ultrasound (EUS) evaluation, histopathologic grading of postirradiation tumor mass reduction in the surgical specimen, and analysis of local and distant recurrences., Methods: Fifty-nine consecutive patients with palpable adenocarcinoma of the rectum, classified by EUS examination as uT2-uT3 (which meant involvement of the muscular layer and the perirectal adipose tissue, respectively), received 45 grays (Gy) over 3 weeks (2 fractions per day of 1.5 Gy each) given as photons supplied through a high-energy linear accelerator (18 MeV) through 3 fields: 1 posterior and 2 opposed lateral. Surgery was scheduled 2-3 weeks after the end of RT and included a sphincter-saving resection (39 patients) and an abdominoperineal resection (20 patients)., Results: Greatest tumor dimension, which was evaluated with rectal endoscopy before RT and measurement of the lesion in the fresh specimen, showed a decrease among two-thirds of the patients; the decrease amounted to approximately one-third of the initial measurement. An echoendoscopic downstaging of the T component was observed among 24.5% of the patients. Complete tumor regression occurred in 8.5% of patients, whereas in 69% only the presence of rare residual cancer cells and prominent fibrosis were found at the pathologic examination of the specimen. Finally, the tumor regressed to pT0 and pT1 in 13.6% of the patients. The overall and disease free 2-year survival rates were 94.0% and 73.7%, respectively, for pT2 and pT3 patients, and 100% for those whose tumors regressed to pT0-pT1 after a median follow-up of 2 years., Conclusions: Hyperfractionated preoperative RT appears to be efficient in achieving tumor shrinkage and destroying the tumor. In this study, the subset of patients with a good response to RT therapy had an excellent clinical outcome at the time of a 2-year follow-up.

Purpose: This study was performed to analyze the outcomes of patients with local (pelvic) recurrence (following radical surgery for rectal cancer) who subsequently underwent a new operation., Methods: Forty-five patients (19 percent of 213 local recurrences) were explored surgically because the disease was deemed to be confined to the pelvis with a limited extension and, therefore, amenable to surgical cure., Results: Only 21 of the 45 patients who underwent surgical exploration had an oncologically radical operation (R0). In the remaining 24 patients, either a simple exploration or palliation or a nonradical procedure (R1-R2) was performed. In the R0 group, there was a 19 percent five-year survival rate vs. a 0 percent rate in the R1-R2 group (median survival, 4 months). Site of recurrence (anastomosis vs. other sites) was statistically associated with a higher chance of long-term survival for those who underwent an R0 operation., Conclusions: The prognosis of locally recurrent rectal cancer is dismal; less than 10 percent of all patients who underwent surgical treatment benefit from reoperation with an overall survival for five years. On the basis of these results, we no longer consider the surgical approach as the primary option for treating locally recurrent rectal cancer.

Objective: The authors analyzed the incidence of rectal cancer in patients with hereditary nonpolyposis colorectal cancer (HNPCC) after an abdominal colectomy., Summary Background Data: The treatment of choice for a newly diagnosed patient with HNPCC with colon cancer is an abdominal colectomy. The incidence of rectal cancer after abdominal colectomy in HNPCC is not known., Materials and Methods: A questionnaire was mailed to all International Collaborative Group on HNPCC members to identify patients in whom rectal cancer developed after total, subtotal or completion colectomy. Statistics were performed using the log-rank test, Kaplan-Meier method, and Cox's proportional hazards model., Results: Rectal cancer developed in 8 (11%) of 71 patients a median of 158 months (range, 38-282 months) from their primary procedure. Of these eight patients, adenomas in the rectal mucosa developed in five at risk either before (4) or synchronous (1) with the diagnosis of rectal cancer. At the time of diagnosis of rectal cancer, six of eight patients were being observed. Age at first procedure and whether the patient was under surveillance were the only significant variables (p < 0.05) in the multivariate analysis in terms of rectal cancer risk. The risk of developing rectal cancer was estimated to be 3% every 3 years after abdominal colectomy for the first 12 years., Conclusions: The risk of rectal cancer in patients with HNPCC after an abdominal colectomy is approximately 12% at 12 years. Age at first surgical procedure and surveillance correlated with rectal cancer risk. Aggressive endoscopic surveillance of the rectum should be performed after abdominal colectomy.

The authors report about a survey on the behaviour of 51 departments of surgery in Lazio and Lombardia as to diagnosis, staging and therapy of carcinoma of the medium-lower one-third of the rectum. A set of 722 patients treated in 1993 was considered. A questionnaire was distributed and answers collected about the staging protocols, the therapeutic choices and some details of surgical technique as the ligation of the lower mesenteric artery or the extent of the lymphadenectomy. The results indicate some stable trends as to preoperative study (digital examination and fibre optic endoscopy in almost all cases) and as to the choice of the technique of anastomosis (43.1% of termino-terminal stapled anastomosis). Intrarectal ultrasound gains consensus but is still not much diffuse (18.6% of cases). Almost all of the participating Institutions agreed in joining further prospective studies.

20 patients with rectal cancer within 8 cm of the anal verge were studied. Endoscopic endosonography was carried out before and after pre-operative radiotherapy (45 Gy over three weeks). The local extent (tumour stage and diameter) was compared with the results of histopathological examination of the resected specimen after anterior resection or total rectal excision. The Tumour Regression Grade (TRG) and lymph node status were also estimated. Two patients were not evaluated endosonographically. Two (11%) of the remaining 18 patients showed ultrasound evidence of down staging (14/18 uT3/4 pre-radiotherapy: 12/18 uT3/4 after) and tumour diameter was significantly reduced. Tumour Regression Grade estimation showed evidence of response to treatment, showing regression of more than 50% in 13 (65%) of cases. Involved nodes were less than 5 mm in diameter in 45% of cases. Histopathological evidence of nodal metastatic regression was seen in 13 (28%) of all involved nodes found. The ultrasonically determined response to radiotherapy may offer useful information in predicting outcome and possibly in selecting surgery.

The performances of three faecal occult blood tests, rehydrated Hemoccult (HOR), Hemoccult sensa (HOS) and Hemeselect (HSEL) on 3 days were compared in 1,725 subjects consecutively recruited in two oncological institutions in Milan and Florence. Significant differences between the results were evident as far as HOR positivity rates (7.5% vs 4.0%, respectively) and specificity (94.3% vs 97.5%, respectively) are concerned. Overall positivity rates of HOR, HOS and HSEL were 5.9%, 5.4% and 12%, respectively; significant differences were evident between HSEL and each of the two guaiac tests. Cancer was detected in eight subjects, adenoma/s in 47. Specificity estimates were 95.8%, 90.2% and 90.5% for HOR, HOS and HSEL, respectively; significant differences were evident between HSEL and the other two tests. No significant difference between tests was evident for sensitivity or positive predictive values for cancer or adenomas. In the CSPO (Florence) population (1,223 subjects; five with cancer, 16 with adenoma/s) the performances of 1-day HSEL testing were determined on the basis of the first faecal sample only and compared with 3-day HOR, HOS and HSEL testing. The positivity rates of 1-day HSEL, 3-day HOR, HOS and HSEL testing were 7.0%, 5.0%, 5.5% and 12.9%, respectively. Only 3-day HSEL positivity rate was significantly higher than 1-day HSEL. One-day HSEL specificity (94.9%) was significantly higher than 3-day HSEL (90.0%), whereas no significant difference was seen between 1-day HSEL, HOR (96.5%), and HOS (96.1%) specificity. No significant difference between tests is evident in the CSPO population as far as positive predictive values and sensitivity for cancer and adenomas are concerned.(ABSTRACT TRUNCATED AT 250 WORDS)

A retrospective analysis to compare the single vs double stapled technique for rectal anastomosis was carried out on patients that underwent radical surgical resection between January 1986 and January 1989 at the Istituto Nazionale Tumori of Milan. In 143 patients anastomotic integrity had been checked both intraoperatively with air insufflation and postoperatively by water soluble contrast enema. A single stapled anastomosis (SST) was performed using the EEA instrument in 94 patients, and in 49 patients a double stapled (DST) using the EEA and TA instruments was performed. The level of the anastomosis was less than or equal to 10 cm from the anal margin in 94 patients (54 SST, 40 DST). In 52 patients it was greater than 10 cm (40 SST, 12 DST) (SST vs DST ns). The presence of anastomotic dehiscence occurred in 29 (20%) patients (17 SST, 12 DST). This was not related either to the anastomotic site or to the suture technique used. The dehiscence was located on the posterior wall in 79% of cases and in 58% the size was less than 1 cm. In 78% clinical symptoms were evident. There was no difference between SST and DST patients. Further surgery (colostomy) was necessary in six patients (2 SST, 4 DST). Two patients died through complications (1 SST, 1 DST); making an overall mortality rate of 1.0% and 2.0% in each group. There was no difference in infection rate and length of postoperative stay in the two groups. Our data demonstrate that both methods give similar results.(ABSTRACT TRUNCATED AT 250 WORDS)

The radiographic appearance at double contrast enema of 33 cases of invasive cancer on adenomatous polyps (AP) of the colon is reviewed. The radiologic diagnosis of malignancy was prospectively made in 54.5% of the cases. In 45.5% of the cases, malignancy was not suspected at the time of examination. The endoscopic appearance of these lesions was identical to that seen on the barium study. There are no radiologic criteria able to entirely rule out the possibility of a carcinomatous transformation of an AP. However, the radiologic features of malignancy (indentation of the intestinal wall and/or irregular outline of the surface of the polyp) have to be considered quite reliable.

The presence of cellular retinoic acid binding protein (cRABP) was analyzed in 13 consecutive patients with large bowel cancer (one right colon and 12 rectum-sigmoid, classified as three Duke B, eight C, and two D). Specimens of neoplastic tissue and of adjacent mucosa were obtained at surgery, and cRABP was determined by an assay based on incubation of partially purified cytosol with labeled retinoic acid and ultracentrifugation in sucrose density gradients. Sixty-one percent of tumors contained detectable levels of cRABP, whereas 58.3% of normal mucosal specimens were positive for cRABP. Among the positive tumors 62.5% contained cRABP also in the corresponding mucosa; in the group of cRABP-negative tumors, 40% showed cRABP in the adjacent mucosa. No correlation could be established with the grading or the stage of the tumors; however, interestingly, 100% (three cases) of gelatinous carcinomas were cRABP positive. Since cRABP seems to be a character of neoplastic cells contrary to normal ones, it would be interesting to investigate the conditions that influence the presence of this protein in normal appearing mucosa adjacent to carcinoma.

In a retrospective study, we investigated 56 consecutive patients who had undergone radical intestinal resection for colorectal adenocarcinoma and who had developed local or distant recurrences of the disease. We found that the presence of a predominant sialomucin pattern at the margins of resection of the surgical specimen was correlated with a high percentage of local, endoluminal recurrence in the anastomotic mucosa. In contrast, no correlation could be found when the recurrences occurred in the outer tissues around the anastomosis or at some distance from it.