Significant variation in histopathological assessment of endoscopic resections for Barrett's neoplasia suggests need for consensus reporting: propositions for improvement.

Endoscopic resection (ER) is an important diagnostic step in management of patients with early Barrett's esophagus (BE) neoplasia. Based on ER specimens, an accurate histological diagnosis can be made, which guides further treatment. Based on depth of tumor invasion, differentiation grade, lymphovascular invasion, and margin status, the risk of lymph node metastases and local recurrence is judged to be low enough to justify endoscopic management, or high enough to warrant invasive surgical esophagectomy. Adequate assessment of these histological risk factors is therefore of the utmost importance. Aim of this study was to assess pathologist concordance on these histological features on ER specimens and evaluate causes of discrepancy. Of 62 challenging ER cases, one representative H&E slide and matching desmin and endothelial marker were digitalized and independently assessed by 13 dedicated GI pathologists from 8 Dutch BE expert centers, using an online assessment module. For each histological feature, concordance and discordance were calculated. Clinically relevant discordances were observed for all criteria. Grouping depth of invasion categories according to expanded endoscopic treatment criteria (T1a and T1sm1 vs. T1sm2/3), ≥1 pathologist was discrepant in 21% of cases, increasing to 45% when grouping diagnoses according to the traditional T1a versus T1b classification. For differentiation grade, lymphovascular invasion, and margin status, discordances were substantial with 27%, 42%, and 32% of cases having ≥1 discrepant pathologist, respectively. In conclusion, histological assessment of ER specimens of early BE cancer by dedicated GI pathologists shows significant discordances for all relevant histological features. We present propositions to improve definitions of diagnostic criteria.

Prognostic Value of the Circumferential Resection Margin in Esophageal Cancer Patients After Neoadjuvant Chemoradiotherapy.

BACKGROUND: Circumferential resection margins (CRM) for esophageal cancer (EC), defined by the College of American Pathologists (CAP; >0 mm) or the Royal College of Pathologists (RCP; >1 mm) as tumor-free (R0), are based on a surgery-alone approach. We evaluated the usefulness of both definitions in current practice with neoadjuvant chemoradiotherapy (nCRT). METHODS: CRMs were measured in 209 patients (104 with nCRT) with locally advanced EC after transthoracic esophagectomy. Local recurrence and cancer related death were scored as events. Patients were followed for at least 2 years or until death. Prognostic factors (P < 0.1 in univariate analyses) for 2-year disease-free survival (DFS) and local recurrence-free survival (LRFS) were incorporated in multivariate Cox regression analyses. Both CRM measurements were analyzed separately and prognostic cutoff values (0-1.0 mm) were assessed in both groups. RESULTS: Independent prognostic factors (P < 0.05) for 2-year DFS were tumor length, lymph node ratio, angioinvasion, and CAP R0 in the surgery-alone group and pN stage (P < 0.01) in the nCRT group. Prognostic factors (P < 0.05) for 2-year LRFS were CAP, lymph node ratio, and tumor length in the surgery-alone group, and CAP and grade in the nCRT group. Optimal CRM cutoff values between 0.0 and 0.2 mm were prognostic for 2-year DFS in the surgery-alone and at 0.3 mm for the nCRT group. CONCLUSIONS: nCRT affected the CRM cutoff values. After nCRT, the CRM R0 according to the CAP was only prognostic for 2-year LRFS. However, in the surgery-alone group, it was prognostic for both the 2-year DFS and LRFS.

Microscopic colitis: an unfamiliar but treatable disease.

Chronic diarrhoea is a frequent complaint in clinical practice. Microscopic colitis is the cause of this symptom in 10% of these cases and the prevalence is rising. To exclude microscopic colitis a colonoscopy with multiple biopsies of different regions of the colon is mandatory. A sigmoidoscopy alone is insufficient. Two histopathological types of microscopic colitis can be distinguished: collagenous colitis and lymphocytic colitis. Nowadays, there is sufficient evidence to recommend budesonide as the first-choice treatment. Bismuth can also be recommended, but this drug is not easily available in the Netherlands. Evidence of efficacy of other drugs is scant.

Adherence to pre-set benchmark quality criteria to qualify as expert assessor of dysplasia in Barrett's esophagus biopsies - towards digital review of Barrett's esophagus.

Background: Dysplasia assessment of Barrett's esophagus biopsies is associated with low observer agreement; guidelines advise expert review. We have developed a web-based review panel for dysplastic Barrett's esophagus biopsies. Objective: The purpose of this study was to test if 10 gastrointestinal pathologists working at Dutch Barrett's esophagus expert centres met pre-set benchmark scores for quality criteria. Methods: Ten gastrointestinal pathologists twice assessed 60 digitalized Barrett's esophagus cases, enriched for dysplasia; then randomised (7520 assessments). We tested predefined benchmark quality criteria: (a) percentage of 'indefinite for dysplasia' diagnoses, benchmark score ≤14% for all cases, ≤16% for dysplastic subset, (b) intra-observer agreement; benchmark score ≥0.66/≥0.39, (c) percentage agreement with 'gold standard diagnosis'; benchmark score ≥82%/≥73%, (d) proportion of cases with high-grade dysplasia underdiagnosed as non-dysplastic Barrett's esophagus; benchmark score ≤1/78 (≤1.28%) assessments for dysplastic subset. Results: Gastrointestinal pathologists had seven years' Barrett's esophagus-experience, handling seven Barrett's esophagus-cases weekly. Three met stringent benchmark scores; all cases and dysplastic subset, three met extended benchmark scores. Four pathologists lacked one quality criterion to meet benchmark scores. Conclusion: Predefined benchmark scores for expert assessment of Barrett's esophagus dysplasia biopsies are stringent and met by some gastrointestinal pathologists. The majority of assessors however, only showed limited deviation from benchmark scores. We expect further training with group discussions will lead to adherence of all participating gastrointestinal pathologists to quality criteria, and therefore eligible to join the review panel.

[Eosinophilic oesophagitis in young men with food swallowing complaints]. / Eosinofiele oesofagitis bij jonge mannen met voedselpassageklachten.

Three men, aged 20, 24 and 42 years, reported difficulties in passing food through the oesophagus. The diagnosis of eosinophilic oesophagitis was made after endoscopic investigation, laboratory tests and histological tests. In all three patients the symptoms disappeared: respectively spontaneously, during systemic treatment with corticosteroids due to a kidney complaint, and after topical corticosteroid treatment lasting 6 weeks. Eosinophilic oesophagitis occurs in particular in young men. There are complaints about the passage of food through the oesophagus, with frequent food impaction, also without any obvious stenosis. Endoscopic features are subtle and comprise a vulnerable oesophageal mucosa with a ringed appearance or small white spots on the oesophageal mucosa. Histopathology reveals an eosinophilic infection infiltrate in the oesophageal epithelium. Food allergies may play a causal role. With respect to the treatment, favourable results have been described for oral fluticasone, while endoscopic treatment may consist of dilation.

[Small bowel transplantation as a treatment option for intestinal failure in children and adults]. / Dunnedarmtransplantatie als behandeling van darmfalen bij kinderen en volwassenen.

Small bowel transplantation for intestinal failure is no longer an experimental procedure, but an accepted treatment for patients where total parenteral nutrition (TPN) therapy for intestinal failure is unsuccessful. Early referral for screening for small bowel transplantation should be considered in patients with permanent intestinal failure who have occlusion of more than 2 major veins, frequent line-related septic episodes, impairment of liver function or an unacceptable quality of life. With the increased experience in post-transplant patient care and newer forms of induction (thymoglobulin, IL-2 receptor antagonists) and maintenance (tacrolimus) therapies, the 1-year graft survival has increased to 65% for isolated and to 59% for liver/small bowel transplantation and is further improving. Rejection, bacterial, fungal and viral (Cytomegalovirus, Epstein-Barr-virus) infections, post-transplant lymphoproliferative disease and graft versus host disease are the most common complications after intestinal transplantation. Although most of the long-term survivors are TPN-independent and have a good quality of life, the risk of the procedure and long-term adverse effects ofimmunosuppressive medication limits small bowel, or liver/small bowel transplantation only to patients with severe complications of TPN therapy.

Review article: anthranoid laxatives and their potential carcinogenic effects.

Anthranoid laxatives are widely used laxatives of natural origin. Because of their chemical structure they are carried unabsorbed to the large bowel, where metabolism to the active aglycones takes place. These aglycones exert their laxative effect by damaging epithelial cells, which leads directly and indirectly to changes in absorption, secretion and motility. Damaged epithelial cells can be found as apoptotic bodies in the pigmented colonic mucosa, characteristic for pseudomelanosis coli. Pseudomelanosis coli is a condition caused by chronic (ab)use of anthranoid laxatives and has recently been associated with an increased risk of colorectal carcinoma. In vitro and animal studies have shown a potential role of anthranoid laxatives in both the initiation and promotion of tumorigenesis. Studies in humans have also suggested tumour promoting activities for these laxatives. Although the short-term use of these substances is generally safe, long-term use cannot be recommended.

Adrenocortical adenocarcinoma in an MSH2 carrier: coincidence or causal relation?

A woman is described who developed an ovarian adenocarcinoma, 3 metachronous colorectal adenocarcinomas, and a primary adrenocortical adenocarcinoma. Genetic investigation of the mismatch repair genes MLH1 and MSH2 showed a germline mutation in MSH2. Colorectal and ovarian carcinoma belong to the tumor spectrum of hereditary nonpolyposis colorectal cancer (HNPCC). Adrenocortical adenocarcinoma, however, has never been described as 1 of the HNPCC-associated tumors. To investigate whether the adrenocortical adenocarcinoma in this patient was caused by the MSH2 germline mutation, determination of microsatellite instability (MSI) and immunohistochemical analysis were performed on 1 of the colorectal tumors and the adrenocortical adenocarcinoma. MSI and general loss of MSH2 protein expression could be seen in the colorectal tumor but not in the adrenocortical adenocarcinoma. Therefore, it is highly unlikely that the adrenocortical adenocarcinoma found in this patient was due to her genetic predisposition for HNPCC. HUM PATHOL 31:1522-1527.

Fatal respiratory failure caused by pulmonary infiltration by pseudo-Gaucher cells.

Pseudo-Gaucher cells are reticuloendothelial cells that are found in several diseases. We report a case of pulmonary tuberculosis in which extensive pulmonary involvement with these cells resulted in fatal respiratory failure.

Comprehensive TP53-denaturing gradient gel electrophoresis mutation detection assay also applicable to archival paraffin-embedded tissue.

A comprehensive mutation detection assay is described for the entire coding region and all splice site junctions of TP53. The assay is based on denaturing gradient gel electrophoresis, which follows either multiplex polymerase chain reaction (PCR) applied to DNA extracted from fresh or frozen tissue samples or nested PCR applied to DNA extracted from paraffin-embedded tissue samples. In both instances, the analysis can be performed under a single set of conditions. When testing the assay on DNA from cultured lung cancer cell lines and from paraffin-embedded Dukes C colorectal carcinomas, significant TP53 mutations were observed at high frequencies in 15 of 16 lung cancer cell lines (94%) and in 21 of 30 paraffin-embedded tissue samples of Dukes C colorectal carcinomas (70%). A substantial proportion of these significant mutations occurred outside the evolutionary conserved region of TP53 in 4 of 16 lung cancer cell lines (25%) and in 11 of 30 paraffin-embedded colorectal carcinomas (37%). This underscores the importance of a comprehensive TP53 mutation analysis in those instances that TP53 mutation is taken into account for diagnostic and prognostic purposes.

Selective use of preoperative radiotherapy in the treatment of cancer in the lower two thirds of the rectum.

PURPOSE: The authors review the result of the selection of patients with a low rectal cancer for pre-operative radiotherapy. METHODS: The selection was based on the findings of digital examination eventually combined with surgical staging consisting of bimanual palpation during a staging laparotomy or "trial" operation. This selection was used to divide the patients into three groups: one where local radicality could be expected from primary surgery (group 1), one with deeply infiltrating, but mobile tumours requiring 10 x 3 Gy pre-operative radiotherapy (group 2) and one with fixed or borderline resectable tumours requiring protracted pre-operative radiotherapy with 55-59 Gy (group 3). One hundred and one patients were eligible for this study. A resection aiming for pelvic radicality was carried out in 94 patients: primary resection in 38 (group 1), surgery subsequent to 10 x 3 Gy pre-operative radiotherapy in 20 (group 2) and 55-59 Gy in 36 (group 3). RESULTS: The calculated risk of local recurrence at 5 years was 15% (95% C.I. 4-27) for group 1, 8% (95% C.I. 0-20) for group 2 and 30% (95% C.I. 16-44) for group 3. The calculated 5 years survival for the 3 groups was respectively 60%, 49% and 39%. CONCLUSION: The overlap in local recurrence rate between the three groups suggests a substantial downgrading by this approach of selective use of pre-operative radiotherapy in the patients with the most advanced tumour. Notwithstanding recent improvements of imaging techniques there still is a place for the staging laparotomy in the selection of the treatment strategy for advanced rectal cancers.

Pelvic exenteration for advanced primary rectal cancer in male patients.

Between November 1987 and January 1996 pelvic exenteration for primary rectal cancer was carried out in 11 male patients. Two underwent a primary resection with subtotal cystectomy. In the remaining nine patients, the treatment commenced with a staging laparotomy and the fashioning of an end colostomy of the descending colon, followed by preoperative radiotherapy (50-56 Gy in 5 weeks). Total exenteration with uretero-ileo-cutaneostomy was carried out 4-6 weeks later. In two patients, the exenteration was performed despite the detection of hepatic metastases during the second laparotomy. The pathological staging was T4 in six and T3 in five patients. The immediate postoperative course was uneventful in eight patients and their hospital stay averaged 20 days. Serious postoperative complications prolonged the hospital stay of three patients. Three died during the first 6 months. Recurrent disease caused the death of three of the eight remaining patients: one locoregional (7.5 years after surgery), one from pre-existing hepatic metastases (18 months after surgery) and one from the combination of locoregional and distant recurrence (15 months after surgery). Four patients are on follow-up without evidence of disease, 96, 43, 23 and 22 months after surgery. One patient is alive 20 months after exenteration, with two pulmonary metastases having been recently excised. We conclude that, notwithstanding the morbidity rate, total pelvic exenteration is an acceptable option for advanced primary rectal cancer in male patients. Preoperative radiotherapy should be administered for cancers seated in the lower two-thirds of the rectum and perioperative chemotherapy should be considered seriously.

[A patient with a cytomegalovirus infection and multiple stomach ulcers]. / Een patiënt met een cytomegalovirusinfectie en multipele maagulcera.

In a 64-year-old, previously healthy woman an upper gastrointestinal endoscopy was performed because of serious dyspeptic complaints during fourteen days. Multiple fundic gastric ulcers were found without Helicobacter pylori and the patient did not take non-steroidal anti-inflammatory drugs (NSAIDs). The diagnosis was primary cytomegalovirus infection, based on the demonstration of infected cells in the biopsy specimens, using specific monoclonal anti-cytomegalovirus antibodies.

[Sodium polystyrene sulfonate (Resonium A) as possible cause of rectal blood loss]. / Natriumpolystyreensulfonaat (Resonium A) als mogelijke oorzaak van rectaal bloedverlies.

A 67-year-old man underwent laparotomy for a ruptured aneurysm of the abdominal aorta. Postoperatively he was treated with haemodialysis because of perioperatively developed acute renal failure. Hyperkalaemia was temporarily treated with sodium polystyrene sulfonate (Resonium A) after which he lost blood per rectum. A hemicolectomy was necessary because of intractable blood loss due to ulceration of the colon. This complication is related to uraemia and the use of sodium polystyrene sulfonate with or without sorbitol.

Hepatitis B-associated liver cirrhosis as an indication for liver transplantation.

Fourteen HBsAg-positive patients received a liver transplant in Groningen. Two were HBeAg-positive and 12 HBeAg-negative. No anti-HBs immunoglobulin was given at the time. Both HBeAg-positive and 9 of 12 of the HBeAg-negative patients became HBsAg-positive again after transplantation. Virus titers were tested in eight patients. Two HBeAg-negative patients were HBV-DNA-negative at transplantation and are still HBV-DNA-negative one-and-half-years after transplantation, both by the branched DNA hybridization technique and by PCR (cut-off values 0.7 x 10(6) and 10(3) HBV genomes/ml, respectively). One patient who had a low HBV-DNA titer at transplantation remained PCR-positive thereafter, but became HBsAg-negative. All other patients were HBV-DNA-positive and had a recurrence that rapidly led to high HBV titers. The liver histology was characterized by fibrosis and cirrhosis, centrilobular cholestasis and high expression of HBsAg and HBcAg, but with little inflammatory infiltrate. We conclude from these results that without anti-HBs immunoglobulin prophylaxis there is a high rate of HBV recurrence after transplantation. The current policy is that patients who test negative in the HBV-DNA dot-blot assay (< 10(7) genomes/ml) are transplantation candidates and are treated with high-dose anti-HBs immunoglobulin after transplantation. HBV-DNA-positive patients (> 10(7) genomes/ml) remain poor candidates for liver transplantation, even with anti-HBs immunoprophylaxis.

Identification of mismatch repair gene mutations in young patients with colorectal cancer and in patients with multiple tumours associated with hereditary non-polyposis colorectal cancer.

BACKGROUND: Patients with early-onset colorectal cancer (CRC) or those with multiple tumours associated with hereditary non-polyposis colorectal cancer (HNPCC) raise suspicion of the presence of germline DNA mismatch repair (MMR) gene mutations. AIM: To analyse the value of family history, microsatellite instability (MSI) analysis and MMR protein staining in the tumour to predict the presence of an MMR gene mutation in such patients. METHODS: In 281 patients diagnosed with CRC before the age of 50 years or with CRC and at least one additional HNPCC-associated cancer, germline mutation analysis in MLH1, MSH2 and MSH6 was carried out with denaturing gradient gel electrophoresis and multiplex ligation-dependent probe amplification. MSI analysis with five consensus markers and MMR protein staining for MLH1, MSH2 and MSH6 were carried out in the tumours. RESULTS: 25 pathogenic mutations (8 in MLH1, 9 in MSH2 and 8 in MSH6) were found. MSI analysis missed three and immunohistochemistry (IHC) missed two mutation carriers. Sensitivities of family history, MSI analysis and IHC for the presence of a mutation were 76%, 82% and 88%, specificities were 64%, 70% and 84%, and positive predictive values were 19%, 23% and 38%, respectively. Multivariate analysis showed the highest odds ratio for IHC (38.3, 95% confidence interval 9.0 to 184). Prevalence of pathogenic germline MMR gene mutations in patients with CRC before the age of 50 years was 6% and in those with > or =2 HNPCC-associated tumours was 22%. In the second group, no mutation carriers were found among the 29 patients who were diagnosed with their first tumour after the age of 60 years. CONCLUSION: Family history, MSI analysis and IHC are indicative parameters to select patients with CRC for MMR gene mutation analysis. The data show that IHC is the best single selection criterion.

The effect of sennosides on colonic mucosal histology and bowel preparation.

INTRODUCTION: A single high dose of sennosides is often used to optimize bowel preparation for diagnostic procedures. From previous studies it is suspected that sennosides in such a dose cause acute damage to the colonic mucosa. This study was designed to determine any effects of sennosides on histology of colonic mucosa and on bowel preparation. RESULTS: In a prospective study 171 patients were randomized for bowel preparation. 84 patients received 1 ml/kg (maximal 75 ml) of a syrup containing 2.0 mg/ml sennoside A and B and 3-5 l of a lavage solution (Sen), 87 patients only received 3-5 l lavage solution (NSen). All patients completed a questionnaire on which patient tolerance was scored. Another questionnaire was completed by the endoscopist, recording quality of the preparation. From the 40 patients with a normal colon (19 Sen, 21 NSen) a biopsy was taken from the sigmoid colon and analyzed for morphological abnormalities. No difference could be demonstrated in tolerance or quality of bowel preparation between the two groups. A marked increase of mononuclear infiltrate in the lamina propria was observed in Sen compared to NSen: in 10/19 vs. 2/21 patients respectively, p < 0.0005. CONCLUSION: As these microscopic effects could hamper the interpretation of colonic biopsies, bowel preparation without sennosides is to be recommended.