MUC1, MUC2, MUC5AC, and MUC6 in colorectal cancer: expression profiles and clinical significance.

Mucin glycoprotein expression can be altered during the carcinogenic process. The impact on the prognosis of patients with colorectal cancer (CRC) is controversial. We analyzed tumors from 381 patients for MUC1, MUC2, MUC5AC, and MUC6 expression by immunohistochemical staining, using tissue microarrays. Progression-free and cancer-specific survival were determined using the Kaplan-Meier method. Expression of intestinal mucin MUC2 was lost in 85 (23 %) CRCs, and patients with MUC6-negative tumors showed shorter progression-free survival (PFS, p = 0.043). Gastric mucins MUC5AC and MUC6 showed high (>50 %) aberrant expression in 28 (8 %) and 9 (2 %) cases, respectively. High expression of MUC5AC was associated with longer PFS (p = 0.055). High expression of MUC6 was associated with 100 % PFS (p = 0.024) and longer cancer-specific survival (CSS, p = 0.043). MUC1 was expressed in 238 (64 %) tumors and had no impact on outcome. When analysis was restricted to stages II and III, loss of MUC2 was associated with adverse outcome. Overexpression of both MUC5AC and MUC6 significantly predicted favorable PFS and CSS. In conclusion, loss of MUC2 expression proved to be a predictor of adverse outcome, while the gain of aberrant expression of MUC5AC and particularly of MUC6 was associated with favorable outcome in CRC, notably in intermediate stages II and III.

Pathological evaluation of colorectal cancer specimens: advanced and early lesions.

Surgical resection is the treatment of choice for patients with locally confined disease, but early cancers may be adequately treated by endoscopic resection alone. In advanced colorectal cancers, accurate staging including pathological lymph node assessment is crucial for patient counselling and decision making. In addition to the extent of surgical lymph node removal and the thoroughness of the pathologist in dissecting the cancer specimen lymph node recovery is related to the actual number of regional lymph nodes that is related to patient demographics, tumor location and biology. Current guidelines recommend a minimum of twelve nodes harvested as the standard of care. In patients with node-negative tumors a variety of histological features may be used for adjusted risk assessment, including histological subtyping, lymphatic and venous invasion, tumor budding and tumor necrosis as well as the anti-tumor host inflammatory response which has been identified as favorable feature in several studies. In rectal cancer, involvement of the circumferential resection margin and the plane of surgery are important prognostic factors. Early or superficial colorectal cancer is defined as invasive adenocarcinoma invading into, but not beyond the submucosa. A number of features require special attention because they are used to determine the necessity for radical surgery. In addition to the assessment of completeness of excision, these include the recording of parameters that predict the presence of lymph node metastasis, namely the depth of invasion into the submucosa, tumor grade, and the presence of additional risk factors, such as angioinvasion and tumor budding. The combination of these parameters allows the stratification of affected individuals into low-risk and high-risk categories.

Prognostic stratification of colorectal cancer patients: current perspectives.

Tumor staging according to the American Joint Committee on Cancer/Union for International Cancer Control tumor, node, metastasis (TNM) system is currently regarded as the standard for staging of patients with colorectal cancer. This system provides the strongest prognostic information for patients with early stage disease and those with advanced disease. For patients with intermediate levels of disease, it is less able to predict disease outcome. Therefore, additional prognostic markers are needed to improve the management of affected patients. Ideal markers are readily assessable on hematoxylin and eosin-stained tumor slides, and in this way are easily applicable worldwide. This review summarizes the histological features of colorectal cancer that can be used for prognostic stratification. Specifically, we refer to the different histological variants of colorectal cancer that have been identified, each of these variants carrying distinct prognostic significance. Established markers of adverse outcomes are lymphatic and venous invasion, as well as perineural invasion, but underreporting still occurs in the routine setting. Tumor budding and tumor necrosis are recent advances that may help to identify patients at high risk for recurrence. The prognostic significance of the antitumor inflammatory response has been known for quite a long time, but a lack of standardization prevented its application in routine pathology. However, scales to assess intra- and peritumoral inflammation have recently emerged, and can be expected to strengthen the prognostic significance of the pathology report.

Validation study of the Esohisto consensus guidelines for the recognition of microscopic esophagitis (histoGERD Trial).

In patients with gastroesophageal reflux disease (GERD), histology is generally believed to be a tool of limited diagnostic value. Our study aimed to assess the prevalence of microscopic esophageal lesions as defined by the Esohisto consensus guidelines, which have proven high interobserver agreement in previous studies. In the prospective Central European multicenter histoGERD trial, we recruited 1071 individuals (576 females and 495 males; median age, 53 years; range, 15-93 years) undergoing gastroscopy for nonselected reasons. Biopsy material was systematically sampled from above and below the gastroesophageal junction. Overall, histologic diagnosis of mild and severe esophagitis was made in 423 (39.5%) and 296 (27.6%) individuals, respectively, whereas the squamous mucosa of 352 individuals (32.9%) was normal upon histology or showed only insignificant findings. Proliferative changes of the squamous epithelium, in particular basal cell layer hyperplasia, papillary elongation, and intercellular space dilation, were more common than inflammatory cell infiltration. The presence of microscopic esophagitis was associated with male sex (P = .009), patients' symptoms (P = .003), history of proton pump inhibitor intake (P < .001), and the endoscopic diagnosis of esophagitis (P < .001). Notably, among the 450 patients with no endoscopic signs of esophagitis (Los Angeles Category N), 41.8% and 17.1% were identified with mild and severe (microscopic) esophagitis, respectively, indicating higher sensitivity of histologic diagnosis. In conclusion, our data illustrate the value of histology in the workup of patients with reflux disease. We suggest that biopsies should routinely be obtained when patients undergo upper gastrointestinal endoscopy for evaluation of GERD and may particularly be beneficial in patients with nonerosive reflux disease.

Multilayered epithelium at the gastroesophageal junction is a marker of gastroesophageal reflux disease: data from a prospective Central European multicenter study (histoGERD trial).

Multilayered epithelium is defined as hybrid epithelium with characteristics of both squamous and columnar epithelia. Our aim was to evaluate the clinicopathological significance of the lesion by relating its presence to various histological and clinical and/or endoscopic features indicating gastroesophageal reflux disease (GERD). A total of 1,071 individuals participated in a prospective cross-sectional study (576 females and 495 males; median age 53 years). Biopsy material was systematically sampled from the gastroesophageal junction. The histological diagnosis of esophagitis was made according to the Esohisto consensus guidelines. The endoscopic diagnosis of esophagitis was made according to the modified Los Angeles classification and the diagnosis of Barrett's esophagus according to Prague's C & M criteria, respectively. Multilayered epithelium was identified in 103 (9.6 %) individuals, frequently within or adjacent to the ducts of esophageal glands. Its presence was associated with increasing age (p < 0.001), high BMI (p = 0.026), hiatal hernia (p < 0.001), and the endoscopic diagnoses of esophagitis (p = 0.002) and Barrett's esophagus (p < 0.001). Upon histology, multilayered epithelium was associated with features of the squamous epithelium indicating GERD, particularly intercellular space dilation (p = 0.005), and presence of cardiac mucosa (<0.001). For intestinal metaplasia, a trend was noted (p = 0.094). In conclusion, multilayered epithelium was observed in about every tenth individual undergoing upper gastrointestinal endoscopy. The association with histological and clinical features indicating GERD advocates the lesion as a promising new marker for reflux esophagitis. The association with cardiac mucosa and Barrett's esophagus suggests multilayered epithelium to be an intermediate step in the development of columnar metaplasia and, ultimately, Barrett's esophagus.

Changing prevalence patterns in endoscopic and histological diagnosis of gastritis? Data from a cross-sectional Central European multicentre study.

BACKGROUND AND AIMS: Traditionally, Helicobacter infection is considered to be the most common cause of gastritis. In the cross-sectional Central European histoGERD trial, we assessed the prevalence of different types of gastritis, correlating histological and endoscopic diagnoses. METHODS: A total of 1123 individuals participated in an observational multicentre study. Endoscopists classified individuals as positive or negative for gastritis and rendered the putative cause. Pathologists evaluated biopsy specimens based upon the Updated Sydney System. RESULTS: Histological diagnosis of gastritis was made in 639 (56.9%) participants. In all, 210 (18.7%) individuals were diagnosed with Helicobacter gastritis, 215 (19.1%) with post Helicobacter gastritis, 234 (20.8%) with reactive gastropathy, 26 (2.3%) with autoimmune gastritis, and 6 (0.5%) with focally enhanced gastritis related to Crohn's disease. In 46 out of 639 (7.2%) individuals diagnosed with gastritis, combinations of different histological subtypes were noted the most common being reactive gastropathy and post Helicobacter gastritis. Endoscopic diagnosis of gastritis was made in 534 (47.6%) individuals. CONCLUSIONS: Reactive gastropathy was more common than active Helicobacter gastritis, and the majority of cases attributable to Helicobacter infection were no longer ongoing, i.e. post Helicobacter gastritis. Agreement between histological and endoscopic diagnoses was better in reactive gastropathy than in Helicobacter gastritis.

Cardiac mucosa at the gastro-oesophageal junction: indicator of gastro-oesophageal reflux disease? Data from a prospective central European multicentre study on histological and endoscopic diagnosis of oesophagitis (histoGERD trial).

AIMS: The origin and significance of cardiac mucosa at the gastro-oesophageal junction are controversial. In the prospective Central European multicentre histoGERD trial, we aimed to assess the prevalence of cardiac mucosa, characterized by the presence of glands composed of mucous cells without parietal cells, and to relate its presence to features related to gastro-oesophageal reflux disease (GORD). METHODS AND RESULTS: One thousand and seventy-one individuals (576 females and 495 males; median age 53 years) were available for analysis. Overall, in biopsy specimens systematically taken from above and below the gastro-oesophageal junction, cardiac mucosa was observed in 713 (66.6%) individuals. Its presence was associated with patients' symptoms and/or complaints (P = 0.0025), histological changes of the squamous epithelium (P < 0.001) indicative of GORD, intestinal metaplasia (P < 0.001), and an endoscopic diagnosis of oesophagitis (P < 0.001). No association with an endoscopic diagnosis of Barrett's oesophagus or with gastric pathology, particularly Helicobacter infection, was observed. CONCLUSIONS: Cardiac mucosa is a common finding in biopsy specimens taken from the gastro-oesophageal junction. Its association with reflux symptoms, histological changes indicating GORD and the endoscopic diagnosis of oesophagitis suggests that injury and repair related to GORD contribute to its development and/or expansion.

Pancreatic acinar cells--a normal finding at the gastroesophageal junction? Data from a prospective Central European multicenter study.

Pancreatic acinar cells are a well-recognized finding at the gastroesophageal junction, but their histogenesis and biological significance are unclear. From the prospective Central European multicenter histoGERD trial, we recruited 1,071 individuals undergoing gastroscopy for various non-selected reasons. Biopsy material was systematically sampled from the gastroesophageal junction and from the stomach. The study aimed to assess the prevalence of pancreatic acinar cells and to relate their presence to various histologic and clinical features. Overall, pancreatic acinar cells were observed in 184 (17.2%) participants. Individuals diagnosed with pancreatic acinar cells were slightly younger than those without (median 50 vs. 53 years; p = 0.009). There was no association with patients' symptoms and/or complaints or with an endoscopic diagnosis of esophagitis or Barrett's esophagus. Regarding histology, pancreatic acinar cells were not associated with features of the squamous epithelium indicating reflux disease, such as basal cell hyperplasia, papillary elongation, dilation of intercellular spaces, and inflammatory cell number, but were associated with the presence of cardiac mucosa (p < 0.001), oxyntocardiac mucosa (p < 0.001), and intestinal metaplasia (p = 0.038), respectively. No association with Helicobacter pylori infection or diagnosis of gastritis was noted. In conclusion, pancreatic acinar cells are a common finding at the gastroesophageal junction, and no association with either reflux disease (histologically or endoscopically) or diagnosis of gastritis was observed. These data suggest a congenital rather than an acquired (metaplastic) origin of pancreatic acinar cells at the gastroesophageal junction. This questions the term "pancreatic acinar metaplasia" which is currently widely used for their diagnosis.

Small cell carcinoma of the urinary bladder: a rare tumor with propensity for hepatic involvement.

Small cell (neuroendocrine) carcinoma of the bladder is a rare entity, accounting for less than 1% of all bladder tumors. The authors report 2 new cases of the disease, both presenting with liver metastasis. In the first case, small cell carcinoma occurred in an 85-year-old woman as tumor recurrence of previous micropapillary carcinoma and urothelial carcinoma in situ, illustrating the common coexistence with conventional urothelial carcinoma. In the second case of a 58-year-old man, non-small cell tumor components were not observed. Accurate diagnosis of small cell carcinoma may be challenging. A panel of different antibodies, including neuron-specific enolase, chromogranin A, synaptophysin and CD56 (neural cell adhesion molecule) is recommended. In conclusion, small cell carcinoma represents a rare and aggressive form of bladder malignancy. As illustrated by the 2 cases and according to the literature review, the tumor shows a so far underrecognized propensity for hepatic involvement.

Is there a rationale to record lymphatic invasion in node-positive colorectal cancer?

This study aimed to evaluate the prognostic significance of lymphatic invasion in colorectal cancers that have already spread to regional lymph nodes. 168 patients with node-positive tumours (colon, n=98; rectum, n=70) were retrospectively evaluated. Lymphatic invasion was assessed on H&E stained slides and univariable and multivariable analyses were applied. Lymphatic invasion was detected in 95 (57%) cases and was significantly associated with tumour and node classification and tumour differentiation. Patients with tumours showing lymphatic invasion had decreased progression-free survival (p=0.025) and cancer-specific survival (p=0.082). Stratified by location, lymphatic invasion was significantly associated with decreased progression-free (p=0.010) and cancer-specific (p=0.023) survival in colon cancers, yet not in rectal cancers. Multivariable analysis proved T4 (HR 2.18, 95% CI 1.40 to 3.39; p<0.001) and N2 (HR 1.68, 95% CI 1.07 to 2.66; p=0.03) as independent predictors of progression-free survival and T4 (HR 1.90, 95% CI 1.17 to 3.07; p=0.009), N2 (HR 2.27, 95% CI 1.38 to 3.73; p=0.001) and poor tumour differentiation (HR 2.18, 95% CI 1.39 to 3.43; p<0.001) as independent predictors of cancer-specific survival, while for lymphatic invasion no influence on outcome was noted. In conclusion, only tumour and node classification, and tumour differentiation proved to be independent prognostic variables in node-positive colorectal cancer and merit special attention in clinical decision-making.