The colorectal malignant polyp: scoping a dilemma.

Colorectal adenomas containing invasive carcinoma represent the majority of early colorectal cancers. The malignant polyp carries a significant risk of lympho-haematic metastasis and mortality due to the penetration of cancerous cells into the submucosal layer. The therapeutic dilemma is whether to perform endoscopic or surgical resection. A thorough assessment of the endoscopic, histological and clinical variables is needed to unravel the best treatment for each patient. In particular, a unique staging of such lesions, based on certain histopathological features, has been deeply implicated in the therapeutic choice. Aim of this article is to review the main endoscopic, histological and clinical features of the malignant polyp in order to propose a systematic management of this lesion.

Endoscopic follow-up after colorectal cancer resection: an Italian multicentre study.

BACKGROUND: Endoscopic follow-up is advised in patients operated for colorectal cancer due to a high risk for both metachronous colorectal cancer and adenomas. Such issue has been scarcely addressed in Italy. This study aimed to evaluate the incidence of neoplastic lesions at a scheduled endoscopic follow-up and to identify the patients at higher risk of recurrence. METHODS: Colorectal cancer patients diagnosed in the three participating hospitals (one North, one Centre and one South Italy) were scheduled for colonoscopies at 1, 3 and 5 years after surgery. Incidence of adenomas, advanced adenomas and colorectal cancer was assessed in all patients. Neoplastic incidence in patients with and without synchronous lesions at entry was also compared. RESULTS: Overall, 318 consecutive patients were prospectively enrolled including 108 (34%, group A) with a synchronous lesion and 210 (group B) without it. A cumulative neoplastic incidence of 20.1, 32.4 and 44% was observed at 1, 3 and 5 years of follow-up, respectively. The cumulative incidence of all the lesions was 70% in group A and 30.2% in group B at 5-year follow-up, being 39.5 and 15.5% after excluding the lesions detected at 1-year examination. A neoplastic lesion was detected more frequently in group A at 1year (30.5% versus 14.7%; p = 0.0013), 3 years (21.4% versus 7.6%; p = 0.0008) and at 5years (18.1% versus 7.8%; p = 0.02). CONCLUSIONS: Our data showed that the incidence of adenomas in patients operated for colorectal cancer is fairly high. Colorectal cancer patients with synchronous lesions are at higher risk of neoplastic recurrence at follow-up as compared to those without them.

Clinical identification and long-term surveillance of 22 hereditary non-polyposis colon cancer Italian families.

OBJECTIVE: To assess the efficacy of a hereditary non-polyposis colon cancer (HNPCC) identification and surveillance policy. METHODS: Familial clustering of colorectal cancer (CRC) and extracolonic cancers (ECs) was investigated in 1520 consecutive CRC patients and relatives. HNPCC was identified by Amsterdam criteria, and individuals at risk were offered biennial colonoscopy and other examinations, starting from age 25 years. RESULTS: Twenty-two HNPCC families were identified. The CRC prevalence was 27.8% (121/435), decreasing from 59.4% in the first generation to 24.4% and 8% in the second and third generation, respectively. Twenty-nine patients had multiple CRC and 34 patients (in 12 families) had ECs.A total of 199/331 at-risk individuals accepted surveillance. The mean follow-up was 48+/-32 months. CRCs were detected at first surveillance in four out of 199 surveilled individuals (2%); in two surveilled individuals (1%), three CRCs developed during follow-up. The overall CRC incidence was 7/199 (3.5%) in surveilled individuals and 5/132 (3.7%) in unsurveilled individuals. CRCs were less advanced in surveilled than in unsurveilled patients. Eleven individuals had 22 adenomas (one with high-grade dysplasia). Three individuals had adenomas at first surveillance; two of them and eight more individuals during surveillance. Seven surveilled individuals and six unsurveilled individuals, all belonging to families with a history of EC, had EC during the study period. All patients with CRC detected by surveillance are alive. One of the unsurveilled patients who had CRC died 18 months after the diagnosis. CONCLUSIONS: Data confirm the importance of the family history collected in each patient with CRC for identification of HNPCC and support the efficacy of repeated colonoscopies for early diagnosis and prevention of CRC in at-risk members. Reasons for surveillance failure could be an accelerated progression of small adenomas and a lesion missing at colonoscopy. Longer follow-up is required to assess the efficacy of surveillance for EC.

Gastric metaplasia and small bowel ulcerogenesis in a case of ulcerative jejunitis not related to celiac disease.

The possible relationship between gastric metaplasia and ulcerative lesions in an unusual case of ulcerative jejunitis not related to celiac disease and with extensive gastric metaplasia is discussed. Previous studies have described gastric metaplasia in duodenal ulcers on the basis of endoscopic data, and some authors maintain that acid secretion in metaplastic mucosa could represent a pathogenetic factor of ulcerogenesis, with a self-amplifying mechanism. In the absence of functional evidence, we could provide data, in a case of ulcerative jejunitis, about morphologic signs of acid secretion in gastric metaplastic epithelium using an antibody against HMFG-1, a good marker of acid-secreting fundic cells. Metaplastic areas demonstrated a focal positivity for HMFG-1, and these finding are suggestive of local acid secretion.

Infliximab for treatment of steroid-refractory ulcerative colitis.

BACKGROUND: Success achieved in two subtypes of Crohn's disease has persuaded a few investigators to experiment the monoclonal anti-tumour necrosis factor antibody infliximab in the treatment of ulcerative colitis. So far, however, the results (achieved in some 30 steroid-refractory patients included in two independent full-papers) indicate a rate of initial response of 50% and of remission of 25%. AIMS: To analyse data of an open trial conducted on consecutive steroid-refractory severely ill patients admitted to our referral Unit. PATIENTS AND METHODS: In 9 months, infliximab was given to 8 patients (4 male, 4 female aged 20-60 years) with uncontrolled ulcerative colitis of whom 6 were non-responders to parenteral steroids. All received the first infliximab dose as an intravenous infusion of 5 mg/kg. RESULTS: Of the 8, 4 (50%) did not respond to the first injection and were submitted to urgent colectomy; the other four responded clinically. Two have maintained clinical remission for 7 months, without the need for steroids; both have received daily azathioprine at 2 mg/kg, and only one has received two further infliximab injections. Of the other two, one received a second injection at week 5, despite this relapsed, and underwent elective colectomy at that time; the other relapsed at 6 months and showed a partial response to a repeat infliximab infusion. Thus, the rate of sustained response is 2/8 (25%) in this study. CONCLUSION: These results, achieved in an open uncontrolled fashion, seem to reflect those of other independent studies. In our opinion, these findings warrant an in-depth reappraisal of the indication to use infliximab as rescue treatment for refractory ulcerative colitis.

Cancer surveillance in ulcerative colitis: critical analysis of long-term prospective programme.

BACKGROUND: Patients with longstanding ulcerative colitis are at increased risk of colorectal cancer. In the literature, no agreement has yet been reached regarding prevention strategies. Our report sums up a prospective study started in 1980. METHODS: A total of 65 patients affected by ulcerative colitis for more than seven years were admitted to a regular colonoscopic and biopsy follow-up programme. RESULTS: Some 20 years after the beginning of the study, 23 (35.3%) patients have been operated upon, 2 patients have died but not from cancer 29 (44.66%) patients have abandoned the programme. Only 11 (16.9%) patients have remained under colonoscopic surveillance. CONCLUSION: These results cast some doubts on the significance of such a programme and on its long-term feasibility.

Two novel mutations and a new STK11/LKB1 gene isoform in Peutz-Jeghers patients.

Peutz-Jeghers syndrome (PJS) is a rare autosomal dominantly inherited disorder with variable expression and incomplete penetrance characterized by mucocutaneous pigmentation, predisposition to hamartomatous intestinal polyposis, and various other neoplasms. It occurs in approximately 1 in 8,300 to 29,000 live births. In nearly 50% of patients PJS is caused by germ line mutations in the STK11/LKB1 serine/threonine kinase gene, the only kinase gene currently known to act as a tumor suppressor. We have performed a mutation search in the STK11/LKB1 gene in 8 sporadic cases and 3 PJS families using a combination of different screening techniques. We have identified four mutations, two of which I177N and the IVS2+1A->G, were previously unreported. We have also evaluated the presence of cDNA alterations by means of RT-PCR analysis and direct cDNA sequencing and have found two aberrant transcripts in a single PJS case despite the lack of any apparent genomic alteration. Finally, we report the presence of a novel STK11/LKB1 cDNA isoform observed in all the normal subjects studied as well as in the majority of the PJS patients.

Small-bowel endoscopy.

During the last year, promising results with the first clinical applications of capsule endoscopy have been reported; this is a new, revolutionary diagnostic method for endoscopic study of the small bowel. The method has chiefly been used in patients with obscure gastrointestinal bleeding, and in some cases has allowed additional diagnoses to be made in comparison with push enteroscopy, with a positive influence on patient management. New therapeutic possibilities have also been developed in push enteroscopy, emphasizing the role of this technique as an essential component of gastrointestinal endoscopy. Important innovations in enteroscopy technique have been described, aimed at increasing the depth of examination, and these will probably make it possible to extend endoscopic treatments to include the entire small bowel. Finally, numerous articles are still being published concerning intraoperative enteroscopy. It is to be hoped that, in future, the use of this invasive procedure will be based on data acquired by capsule endoscopy.

Idiopathic myenteric ganglionitis underlying intractable vomiting in a young adult.

Inflammatory infiltration of intestinal myenteric plexuses (i.e. myenteric ganglionitis), along with severe intestinal motor abnormalities, may accompany paraneoplastic syndromes, neurological disorders and gastrointestinal infections, although rare cases can be idiopathic. In this report, we describe the case of a patient who presented with chronic intractable vomiting and weight loss associated with idiopathic myenteric ganglionitis mainly involving the stomach. Tissue analysis showed that the inflammatory infiltrate comprised T lymphocytes (CD4+ and CD8+), and peptide immunolabelling revealed a marked decrease of substance P/tachykinin immunoreactive staining in nerve fibres and myenteric neurones. Following systemic steroid therapy, the patient's symptoms dramatically improved, and after one year of follow-up his general condition remains satisfactory. The possible mechanisms leading to symptom generation and gastric dysmotility in the context of an idiopathic myenteric ganglionitis are discussed.

Small bowel polyps in Peutz-Jeghers syndrome: management by combined push enteroscopy and intraoperative enteroscopy.

BACKGROUND: Polyps occur throughout the GI tract in Peutz-Jeghers syndrome; the major problem in the management of the syndrome lies in the small bowel. METHODS: From January 1979 to January 1998, seven patients with Peutz-Jeghers syndrome underwent surveillance. Between 1979 and 1992 they were managed with upper and lower endoscopy every 2 to 3 years and surgery when intestinal obstruction occurred. From 1993 they also underwent enteroclysis and, on the basis of radiologic findings, push enteroscopy and/or intraoperative enteroscopy. Push enteroscopy was then performed every 2 years in all patients. RESULTS: During the first period, 5 of 7 patients underwent emergency small bowel resection (2 operated twice). The patients were divided into 2 groups based on enteroclysis findings; the first comprised 4 patients with multiple polyps throughout the small bowel, and the second included 3 patients with polyps only in the proximal small bowel. Three of the 4 patients with diffuse polyposis underwent intraoperative enteroscopy during which on average 16 polyps per patient were removed (range 10 to 25 polyps; mean diameter 16 mm, range 3 to 50 mm). The remaining patient with diffuse polyposis had a single 25 mm polyp in the terminal ileum removed by retrograde ileoscopy; the more proximal polyps were removed by push enteroscopy. The patients with diffuse polyposis remained asymptomatic during follow-up (mean 50 months, range 47 to 57 months) and also underwent periodic push enteroscopy (mean 2.25 enteroscopies per patient, range 2 to 3) at which a mean of 8.5 polyps per patient (range 4 to 13 polyps) were removed (mean diameter 7.2 mm, range 3 to 15 mm). The 3 patients of the second group underwent periodic push enteroscopy alone (mean 3 per patient) during which a mean of 11.7 polyps per patient were removed (range 7 to 15 polyps: mean diameter 10.9 mm, range 3 to 40 mm). Enteroclysis was not repeated in these patients, who remained asymptomatic during follow-up (mean 47 months, range 46 to 48 months). CONCLUSIONS: More effective clearance of small bowel polyps via enteroscopy will help reduce the need for emergency surgery with extensive intestinal resection in patients with Peutz-Jeghers syndrome.

Small-bowel endoscopy.

During the last year, several interesting publications have further confirmed the role of enteroscopy in clinical practice. Of particular interest have been various articles concerning the use of two-way enteroscopy in large series of patients with obscure gastrointestinal bleeding or with radiological abnormalities. Reports continue to appear describing a high incidence of gastroduodenal or colonic lesions that were missed or misinterpreted during previous upper and lower endoscopies in patients with recurrent obscure bleeding. By contrast, there have been few outcome studies on patients with obscure bleeding, and the conclusions reached are not in full agreement. Other important publications have stressed the value of enteroscopy in selected cases of chronic unexplained diarrhea, for diagnosing small-bowel lesions caused by nonsteroidal anti-inflammatory drugs, and in identifying small-bowel tumors. In addition to numerous reports on intraoperative enteroscopy, the results of initial experience with laparoscopically assisted enteroscopy have also been reported.

Programmed cell death, proliferating cell nuclear antigen and p53 expression in mouse colon mucosa during diet-induced tumorigenesis.

Western-style diets (WDs) trigger and sustain the early phases of tumorigenesis in mouse colon, and when continued throughout the life span lead to the development of dysplastic crypts. In order to evaluate the roles both of cell proliferation and programmed cell death (PCD) in WD-induced tumorigenesis, immunohistochemical detection of proliferating nuclear antigen (PCNA), in situ end labeling (TUNEL) of DNA breaks, and p53 protein were carried out in mouse colonic mucosa during prolonged feeding of two WDs. PCNA Labeling Index of colonic crypts was significantly higher in WD-treated animals than in controls only at the beginning of the nutritional study, the gap rapidly bridged by increased cell proliferation spontaneously occurring in the colonic mucosa during aging. A transient early homeostatic activation of PCD at the base of the crypt also was observed in WD groups. No changes in PCD were seen in the upper third of the crypt or in surface epithelium throughout the study, indicating that PCD in that colonic crypt segment produces a constant flux of cell loss, uninfluenced by homeostatic fluctuations. A major finding was an irreversible, progressive, age-related decline of PCD at the crypt base in both control and treated animals that occurred during the second half of the rodents' life span. p53 protein was not immunohistochemically detected, suggesting that neither overexpression of wild-type nor mutated forms of the protein are involved in the above mentioned changes.

Enteroscopic identification of an adenocarcinoma of the small bowel in a patient with previously unrecognized hereditary nonpolyposis colorectal cancer syndrome.

Tumors of the small bowel are uncommon and seldom suspected on a clinical basis. Together with the relative inaccessibility of the small bowel to endoscopic investigation, the rarity of these tumors undoubtedly delays their diagnosis. The case reported is of a patient with an adenocarcinoma of the jejunum presenting as gastrointestinal bleeding of obscure origin. Diagnosis was by push enteroscopy, after several years of unsuccessful radiological and upper and lower endoscopic evaluation. The patient's family fulfilled the Amsterdam criteria for hereditary nonpolyposis colorectal cancer syndrome, which was previously unrecognized. This report emphasizes the value of push enteroscopy and the limits of radiography of the small bowel when investigating patients with obscure GI bleeding. It also underlines the importance of a careful evaluation of the pedigree (concerning history of colorectal and extracolonic cancer) of all patients, including those who present with adenocarcinoma of the small bowel; it is similarly important to consider the possibility of small bowel cancer in members of families with hereditary nonpolyposis colorectal cancer (HNPCC) syndrome.

Dysplastic changes in gastric fundic gland polyps of patients with familial adenomatous polyposis.

BACKGROUND: Fundic gland polyps are the most common gastric lesion in patients with familial adenomatous polyposis and are traditionally considered a condition with no malignancy potential. However, some reports have recently questioned this view. AIMS: To prospectively evaluate their prevalence and the associated dysplastic/malignant changes in a series of affected patients. PATIENTS AND METHODS: Thirty-seven affected patients were carefully investigated by upper endoscopy over a three-year period. Multiple (at least 10) complete excisions of any representative polyp of the body-fundus were performed and a thorough pathological search for microscopic adenomatous/dysplastic changes carried out. RESULTS: Of 37 patients, 19 (51.3%) showed gastric fundic gland polyposis and 18 of them gave consent for polypectomies. Overall, 425 endoscopic polypectomies were performed, with a mean of 23.6 +/- 14.6 per patient. At pathology, all excised polyps of the body-fundus were found to be fundic glandular. Microscopic adenomatous changes within such polyps were identified in 8 (44.4%) patients. All the adenomatous foci revealed mild dysplasia with no case of severe atypia or carcinoma. Patients with microadenomas showed a significantly higher total number of gastric polyps compared with those without microadenomas (p < 0.03). No other differences between the two groups were observed. Two further patients presented microadenomas in apparently normal antral mucosa and one also showed a 6 mm antral adenoma with mild dysplasia. Finally, the search for Helicobacter pylori was always negative. CONCLUSIONS: Patients with familial adenomatous polyposis and gastric fundic gland polyps have a high prevalence of microscopic adenomatous foci within such lesions; nevertheless, these foci seem not to be associated with signs of severe atypia or carcinoma. Moreover, microadenomas are ubiquitous throughout the stomach, as well as in the rest of the gut, and their natural history is still undefined. Thus, their malignancy potential remains uncertain. More extensive follow-up is warranted to better investigate the long-term biological behaviour of these lesions but, at present, our data do not support the need for a change in the usual intervals of upper endoscopy surveillance in familial polyposis patients with or without gastric fundic glands polyps.

Small bowel tumors and polyposis syndromes.

Tumors of the small bowel are uncommon and seldom suspected on a clinical basis. Together with the relative inaccessibility of the small bowel to endoscopic investigation, the rarity of these tumors undoubtedly delays the diagnosis. Small bowel tumors may be an interesting field of application for enteroscopy, which now can be readily performed with dedicated enteroscopic evaluation in patients with suspected small bowel neoplasia could improve prognosis and treatment. Enteroscopy may also play an important role in the surveillance of inherited polyposis syndromes, as in other precancerous condition of the small bowel. In Peutz-Jeghers syndrome it may reduce polyp-induced complications and improve planning for surgery; in familial adenomatous polyposis it may contribute to preventing upper gastrointestinal tract cancer.

K-ras2 activation and genome instability increase proliferation and size of FAP adenomas.

The possible role of K-ras2 mutations and aneuploidy toward increase of proliferation and adenoma size in Familial Adenomatous Polyposis (FAP) adenomas is not known. The present study addresses these issues by investigating 147 colorectal adenomas obtained from four FAP patients. The majority of adenomas had size lower than or equal to 10 mm (86%), low grade dysplasia (63%), and were preferentially located in the right colon (60%). Normal mucosa samples were obtained from 19 healthy donors. Three synchronous adenocarcinomas were also investigated. K-ras2 mutation spectrum was analysed by PCR and Sequence Specific Oligonucleotide (SSO) hybridization, while flow cytometry (FCM) was used for evaluating degree of DNA ploidy and S-phase fraction. Overall, incidences of K-ras2 mutations, DNA aneuploidy and high S-phase values (>7.2%) were 6.6%, 5.4% and 10.5%, respectively. In particular, among the adenomas with size lower than 5 mm, K-ras2 mutation and DNA aneuploidy frequencies were only slightly above 1%. Statistically significant correlations were found between K-ras2 and size, DNA ploidy and size and K-ras2 and S-phase (p < 0.001). In particular, among the wild type K-ras2 adenomas, high S-phase values were detected in 8% of the cases versus 57% among the K-ras2 mutated adenomas (p = 0.0005). The present series of FAP adenomas indicates that K-ras2 activation and gross genomic changes play a role toward a proliferative gain and tumour growth in size.

STK11 mutations in Peutz-Jeghers syndrome and sporadic colon cancer.

A potential tumor suppressor gene, STK11 , encoding a serine threonine kinase, has recently been identified on chromosome 19p13. Germ-line mutations of this gene have been found in patients with Peutz-Jeghers syndrome (PJS). To further investigate the relevance of STK11 mutations in PJS, we analyzed its coding sequence in nine patients and identified two deletions and three missense mutations. Because intestinal carcinomas have been observed to develop in association with PJS, we analyzed tumors from 71 patients for allelic deletions (loss of heterozygosity) and STK11 gene mutations, to elucidate the etiological role of STK11 gene in sporadic colorectal cancer. Loss of heterozygosity, evaluated using the microsatellite D19S886, was observed in 10 of 52 informative cases. No somatic mutations were detected except for a missense alteration in one tumor. Our data indicate the heterogeneity of PJS and the infrequent involvement of the STK11 gene in colorectal cancer.

Specific K-ras2 mutations in human sporadic colorectal adenomas are associated with DNA near-diploid aneuploidy and inhibition of proliferation.

Recent studies indicate that p21ras proteins mediate their multiple cell functions through interactions with multiple effectors and that the number of new effectors is growing. We recently reported that K-ras2 mutations in human colorectal adenomas were associated with chromosome instability and proliferation changes. In the present study, we extend these previous observations. Hereditary and multiple (n > or = 5) adenomas and adenomas with early cancer were excluded. Dysplasia was moderate in 91 cases and high in 25, and the median adenoma size was 1.5 cm. K-ras2 spectrum analysis was done by sequence-specific oligonucleotide hybridization using nuclear suspensions provided by analysis and sorting of multiparameter flow cytometry. In particular, tissue inflammatory cells were separated for DNA diploid tumors, whereas DNA aneuploid epithelial subclones were analyzed separately. K-ras2 mutations and DNA aneuploidy were both detected in 29 of 116 (25%) cases. DNA aneuploid index was in the near-diploid region in the majority of cases. DNA aneuploidy was strongly associated with G-->C/T transversions. An association was also found between low S-phase values and G-->A transitions. These findings were confirmed using multivariate logistic regression analysis to account for the effects of size, dysplasia, site, type, age, and sex. These data suggest that specific K-ras2 mutations in a subgroup of human sporadic colorectal adenomas play a role in chromosome instability and, contrary to expectations, are associated with inhibition of proliferation.