G J A Offerhaus

Impact of endoscopic biopsy surveillance of Barrett's oesophagus on pathological stage and clinical outcome of Barrett's carcinoma

Background—The efficacy of endoscopic biopsy surveillance of Barrett’s oesophagus in reducing mortality from oesophageal cancer has not been confirmed. Aims—To investigate the impact of endoscopic biopsy surveillance on pathological stage and clinical outcome of Barrett’s carcinoma. Methods—A clinicopathological comparison was made between patients who initially presented with oesophageal adenocarcinoma (n=54), and those in whom the cancer had been detected during surveillance of Barrett’s oesophagus (n=16). Results—The surveyed patients were known to have Barrett’s oesophagus for a median period of 42 months (range 6–144 months). Prior to the detection of adenocarcinoma or high grade dysplasia, 13 of 16 patients (81%) were previously found to have low grade dysplasia. Surgical pathology showed that surveyed patients had significantly earlier stages than non-surveyed patients (p=0.0001). Only one surveyed patient (6%) versus 34 non-surveyed patients (63%) had nodal involvement (p=0.0001). Two year survival was 85.9% for surveyed patients and 43.3% for non-surveyed patients (p=0.0029). Conclusions—The temporal course of histological progression in our surveyed patients supports the theory that adenocarcinoma in Barrett’s oesophagus develops through stages of increasing severity of dysplasia. Endoscopic biopsy surveillance of Barrett’s oesophagus permits detection of malignancy at an early and curable stage, thereby potentially reducing mortality from oesophageal adenocarcinoma.

Predictors for neoplastic progression in patients with Barrett's Esophagus: a prospective cohort study

OBJECTIVES:Patients with Barretts esophagus (BE) have an increased risk of developing esophageal adenocarcinoma (EAC). As the absolute risk remains low, there is a need for predictors of neoplastic progression to tailor more individualized surveillance programs. The aim of this study was to identify such predictors of progression to high-grade dysplasia (HGD) and EAC in patients with BE after 4 years of surveillance and to develop a prediction model based on these factors.METHODS:We included 713 patients with BE (≥2 cm) with no dysplasia (ND) or low-grade dysplasia (LGD) in a multicenter, prospective cohort study. Data on age, gender, body mass index (BMI), reflux symptoms, tobacco and alcohol use, medication use, upper gastrointestinal (GI) endoscopy findings, and histology were prospectively collected. As part of this study, patients with ND underwent surveillance every 2 years, whereas those with LGD were followed on a yearly basis. Log linear regression analysis was performed to identify risk factors associated with the development of HGD or EAC during surveillance.RESULTS:After 4 years of follow-up, 26/713 (3.4%) patients developed HGD or EAC, with the remaining 687 patients remaining stable with ND or LGD. Multivariable analysis showed that a known duration of BE of ≥10 years (risk ratio (RR) 3.2; 95% confidence interval (CI) 1.3–7.8), length of BE (RR 1.11 per cm increase in length; 95% CI 1.01–1.2), esophagitis (RR 3.5; 95% CI 1.3–9.5), and LGD (RR 9.7; 95% CI 4.4–21.5) were significant predictors of progression to HGD or EAC. In a prediction model, we found that the annual risk of developing HGD or EAC in BE varied between 0.3% and up to 40%. Patients with ND and no other risk factors had the lowest risk of developing HGD or EAC (<1%), whereas those with LGD and at least one other risk factor had the highest risk of neoplastic progression (18–40%).CONCLUSIONS:In patients with BE, the risk of developing HGD or EAC is predominantly determined by the presence of LGD, a known duration of BE of ≥10 years, longer length of BE, and presence of esophagitis. One or combinations of these risk factors are able to identify patients with a low or high risk of neoplastic progression and could therefore be used to individualize surveillance intervals in BE.

Prevention and management of duodenal polyps in familial adenomatous polyposis

Familial adenomatous polyposis (FAP) is one of two well described forms of hereditary colorectal cancer. The primary cause of death from this syndrome is colorectal cancer which inevitably develops usually by the fifth decade of life. Screening by genetic testing and endoscopy in concert with prophylactic surgery has significantly improved the overall survival of FAP patients. However, less well appreciated by medical providers is the second leading cause of death in FAP, duodenal adenocarcinoma. This review will discuss the clinicopathological features, management, and prevention of duodenal neoplasia in patients with familial adenomatous polyposis. FAP is an autosomal dominant disorder caused by a germline mutation in the adenomatous polyposis coli ( APC ) gene. FAP is characterised by the development of multiple (⩾100) adenomas in the colorectum. Colorectal polyposis develops by age 15 years in 50% and age 35 years in 95% of patients. The lifetime risk of colorectal carcinoma is virtually 100% if patients are not treated by colectomy.1 Patients with FAP can also develop a wide variety of extraintestinal findings. These include cutaneous lesions (lipomas, fibromas, and sebaceous and epidermoid cysts), desmoid tumours, osteomas, occult radio-opaque jaw lesions, dental abnormalities, congenital hypertrophy of the retinal pigment epithelium, and nasopharyngeal angiofibroma. In addition, FAP patients are at increased risk for several malignancies, such as hepatoblastoma, pancreatic, thyroid, biliary-tree, and brain tumours.1 Other gastrointestinal manifestations commonly found in FAP patients are duodenal adenomas, and gastric fundic gland and adenomatous polyps. Of concern, duodenal cancer is the second leading cause of death after colorectal cancer in these individuals. After the colorectum, the duodenum is the second most commonly affected site of polyp development in FAP (fig 1).2,3 Duodenal adenomas can be found in 30–70% of FAP patients2–4 and the lifetime risk of these lesions approaches 100%.4,5 …

Neoadjuvant chemoradiation followed by surgery versus surgery alone for patients with adenocarcinoma or squamous cell carcinoma of the esophagus (CROSS)

BackgroundA surgical resection is currently the preferred treatment for esophageal cancer if the tumor is considered to be resectable without evidence of distant metastases (cT1-3 N0-1 M0). A high percentage of irradical resections is reported in studies using neoadjuvant chemotherapy followed by surgery versus surgery alone and in trials in which patients are treated with surgery alone. Improvement of locoregional control by using neoadjuvant chemoradiotherapy might therefore improve the prognosis in these patients. We previously reported that after neoadjuvant chemoradiotherapy with weekly administrations of Carboplatin and Paclitaxel combined with concurrent radiotherapy nearly always a complete R0-resection could be performed. The concept that this neoadjuvant chemoradiotherapy regimen improves overall survival has, however, to be proven in a randomized phase III trial.Methods/designThe CROSS trial is a multicenter, randomized phase III, clinical trial. The study compares neoadjuvant chemoradiotherapy followed by surgery with surgery alone in patients with potentially curable esophageal cancer, with inclusion of 175 patients per arm.The objectives of the CROSS trial are to compare median survival rates and quality of life (before, during and after treatment), pathological responses, progression free survival, the number of R0 resections, treatment toxicity and costs between patients treated with neoadjuvant chemoradiotherapy followed by surgery with surgery alone for surgically resectable esophageal adenocarcinoma or squamous cell carcinoma. Over a 5 week period concurrent chemoradiotherapy will be applied on an outpatient basis. Paclitaxel (50 mg/m2) and Carboplatin (Area-Under-Curve = 2) are administered by i.v. infusion on days 1, 8, 15, 22, and 29. External beam radiation with a total dose of 41.4 Gy is given in 23 fractions of 1.8 Gy, 5 fractions a week. After completion of the protocol, patients will be followed up every 3 months for the first year, every 6 months for the second year, and then at the end of each year until 5 years after treatment. Quality of life questionnaires will be filled out during the first year of follow-up.DiscussionThis study will contribute to the evidence on any benefits of neoadjuvant treatment in esophageal cancer patients using a promising chemoradiotherapy regimen.Trial registrationISRCTN80832026

Epstein-Barr virus in gastric carcinomas and gastric stump carcinomas: a late event in gastric carcinogenesis

Background: To determine at what stage during gastric carcinogenesis Epstein-Barr virus (EBV) enters the gastric epithelial cells, the presence of EBV was investigated in two pathogenetically related but distinct forms of adenocarcinoma of the stomach—gastric carcinoma of the intact stomach (GCIS) and gastric stump carcinoma (GSC)—and their presumed precursor lesions. Patients and methods: Eleven patients with EBV positive GCIS and eight patients with EBV positive GSC, demonstrated by the highly sensitive EBV encoded RNA 1/2 (EBER1/2) RNA in situ hybridisation (RISH) technique, were studied. Paraffin wax embedded tissue available from preoperative gastric biopsies and tumour adjacent tissue from the resection specimens containing normal gastric mucosa, inflamed gastric mucosa, and preneoplastic lesions (intestinal metaplasia and dysplasia) was investigated by EBER1/2 RISH, in addition to EBV nuclear antigen 1 (EBNA-1) and latent membrane protein 1 (LMP-1) immunohistochemistry (IHC). Results: In both GCIS and GSC and their precursor lesions EBER1/2 transcripts were restricted to the carcinoma cells. In addition, positivity of EBNA-1 IHC was also restricted to the tumour cells. IHC for LMP-1 was negative in all cases tested. Conclusions: The absence of EBER1/2 transcripts in preneoplastic gastric lesions (intestinal metaplasia and dysplasia) and their presence in two distinct types of gastric carcinoma strongly suggest that EBV can only infect neoplastic gastric cells and thus is a late event in gastric carcinogenesis.

Routine morphometrical analysis can improve reproducibility of dysplasia grade in Barrett's oesophagus surveillance biopsies

Background: The grade of dysplasia found in Barrett’s oesophagus surveillance biopsies is a major factor to determine follow up and treatment. However, it has been reported that the reproducibility of the grading system is not optimal. Aims: To compare routine and expert dysplasia grades in Barrett’s oesophagus surveillance biopsies. To evaluate prospectively morphometrical grading support and to assess the pitfalls in its daily application. Methods: Consecutive biopsies (n = 143) were graded routinely by experienced general surgical pathologists as no dysplasia (ND), indefinite for dysplasia, low grade dysplasia (LGD), and high grade dysplasia (HGD). Two expert gastrointestinal pathologists blindly reviewed all sections. The stratification index of nuclei, mean nuclear area, and Ki67area% were assessed routinely according to a strict protocol. With these features, the previously described morphometrical grade was calculated for each case. The grades provided by the experts, surgical pathologists, and morphometry were compared. Results: The general pathologists graded many more cases as dysplastic than did the experts. Complete agreement between the experts’ grades and the original grades was 50 of 143 (35%). Sixty four of the 71 original LGDs and 11 of the 23 original HGDs were downgraded by the experts, whereas one LGD was upgraded. In 93 of the 143 biopsies, at review pitfalls or special characteristics of a technical nature (tangential cutting, severe inflammation, ulcer or the squamocylindrical junction very close by, among others) were seen in the part of the biopsy marked as diagnostic. These probably contributed in part to the original overdiagnoses and could have been prevented or corrected. The morphometrical grading model has not been developed to compensate for this; application of the current morphometrical grading method is not allowed and may result in erroneous (usually too high) morphometrical grades. In spite of this, all HGDs according to the experts were recognised as such by morphometry, also in these technically less adequate sections or areas. However, 46% of the experts’ downgrades occurred in technically adequate sections and thus were caused by a difference in interpretation. Here, morphometrical support proved to be useful because, in agreement with the experts, it downgraded 51% of the original LGDs, upgraded one of eight NDs to LGD and one of 39 LGDs to HGD. Conclusions: Experts downgraded a high proportion of biopsies graded as LGDs and HGDs by the surgical pathologists. Morphometrical grading can be used for daily quality control; the results were close to those of the experts and corrected a large number of cases erroneously graded by surgical pathologists.

Comparison of cyclooxygenase 2 expression in adenocarcinomas of the gastric cardia and distal oesophagus.

Background: Adenocarcinomas of the gastric cardia and distal oesophagus are at present often considered as one clinical entity because of their comparable increasing incidence, prognosis, and optimal treatment options. However, it is still a matter of debate whether these malignancies have the same pathogenesis and genotype. Aims: The aim of this study was to analyse expression of cyclooxygenase 2 (COX-2) in cardia carcinomas, and correlate this expression with clinicopathological parameters and survival. The results were compared with the prognostic value of COX-2 found for Barrett carcinomas. Methods: Tumour sections of 134 consecutive patients undergoing potentially curative surgery for an adenocarcinoma of the gastric cardia and substantially invading the distal oesophagus were immunohistochemically stained using a COX-2 monoclonal antibody. Specimens were blindly scored based on intensity and extent of COX-2 immunopositivity. Results: COX-2 expression was negative to weak in 59% (“COX-2 low”) and moderate to strong in 41% (“COX-2 high”) of tumours. This was significantly lower than in Barrett carcinomas (p<0.0001). COX-2 expression was not correlated with any clinicopathological parameter. A correlation between elevated COX-2 expression and reduced survival, as described for Barrett carcinomas, was not identified for cardiac carcinomas. Conclusions: There is a difference in COX-2 expression with respect to intensity and prognostic significance between adenocarcinomas of the gastric cardia and distal oesophagus. This suggests a different pathogenesis and different genetic constitution of these two cancers. Based on these findings, the role of selective COX-2 inhibitors in the treatment of adenocarcinomas of the gastric cardia is less promising than in Barrett carcinomas.

Report of an Amsterdam working group on Barrett esophagus.

More than 50 years have passed since Barrett described a case of peptic ulcer disease of the esophagus and the condition that would carry his name [1]. It is now generally accepted that Barrett esophagus is the result of long-standing gastroesophageal reflux disease leading to replacement of the normal stratified squamous epithelial lining of the esophagus by glandular epithelium of various types [24, 32]. The importance of a diagnosis of Barrett esophagus is its association with the development of an esophageal adenocarcinoma. In contrast to what Norman Barrett originally thought, Barrett esophagus is a premalignant condition, and the incidence of Barrett carcinoma has increased dramatically since his publication in 1950 [12]. Barrett adenocarcinoma is preceded by a well-defined premalignant lesion, i.e., dysplasia (intraepithelial neoG. J. A. Offerhaus · S. van Eeden · F. J. W. ten Kate · A. Bosma Department of Pathology, Academic Medical Center Amsterdam, The Netherlands

mTOR in squamous cell carcinoma of the oesophagus: a potential target for molecular therapy?

Aims: The mammalian target of rapamycin (mTOR), an important regulator of protein translation and cell proliferation, is activated in various malignancies. In a randomised controlled trial of advanced renal cell carcinoma patients, targeted therapy to mTOR by means of rapamycin analogues has been shown to significantly improve survival. An in vitro study has revealed that mTOR is activated in oesophageal squamous cell carcinoma (OSCC) cell lines and that mTOR expression is inhibited by rapamycin. The objectives of this histological study were to determine the proportion of OSCC tissues with activated mTOR (p-mTOR) expression, thereby assessing the percentage of patients with OSCC that would possibly benefit from neoadjuvant rapamycin therapy, and to identify the clinicopathological features of these potentially rapamycin-sensitive tumours. Methods: The expression of p-mTOR (Ser2448) was immunohistochemically assessed in a validated tissue microarray comprising triplicate tissue biopsy cores of 108 formalin-fixed, paraffin-embedded OSCCs. Staining results were correlated with clinicopathological data. Results: Normal oesophageal epithelium was negative for p-mTOR. Activated mTOR expression was located in the cytoplasm of oesophageal tumour cells. 26 (25%) of 105 assessable OSCCs showed tumour cells with positive staining for activated mTOR. Activated mTOR expression was associated with a lesser degree of differentiation only (p = 0.024). No correlation was detected between p-mTOR and the proliferation marker Ki-67. Conclusions: Activated mTOR can be detected in one-quarter of OSCCs. Since this subset of patients may potentially benefit from mTOR inhibiting therapy, a phase II clinical trial of neoadjuvant mTOR-inhibiting therapy in patients with OSCC may be considered.

The serrated polyp: getting it right!

In the beginning, colorectal cancer (CRC) was a simple disease. It was considered a single entity, be it with different faces.1 Also, the precursor lesions of CRC were known, and the adenoma–carcinoma sequence as a model for the stepwise progression from an adenoma to an invasive CRC became a paradigm for similar lesions in other organs. Even the underlying molecular genetic alterations driving the consecutive steps of the adenoma–carcinoma were clarified.2 And so CRC was conceived to be the result of the accumulation of specific genetic mutations, at least partly due to chromosomal instability, with activated oncogenes and inactivated tumour suppressor genes causing uncontrollable cell growth. Loss of function of the APC tumour suppressor gene, the gatekeeper of the colorectum, was the initiating genetic event of adenoma formation, and familial adenomatous polyposis, caused by a germline mutation in APC , was perceived as the hereditary counterpart of sporadic CRC in the general population.3 Soon, however, the above picture became a bit more complicated, when a second form of familial CRC was discovered: the Lynch syndrome.4 The Lynch syndrome is caused by a germline defect in one of the mismatch repair genes ( MLH1 , MSH2 , MSH6 , PMS1 and PMS2 ) resulting in microsatellite instability. This new pathway leading to CRC was paralleled by characteristic clinicopathological features.5 Since then, through advances in endoscopical technology resulting in high-resolution views of the colonic mucosa, as well as advances in molecular genetic technology, the picture has evolved of CRC arising through a variety of pathways that can be defined at the molecular level, each accompanied by more or less specific morphology.6 The conventional adenoma no longer has the monopoly of being at the origin of …