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The current method for staging in gastric cancer is not sufficient as even after a complete primary tumor resection, patients with node-negative gastric cancer suffer from disease recurrence. In this study, the relation between disease recurrence and the presence of occult tumor cells (OTC) in lymph nodes from gastric cancer patients was evaluated. In a case-control design, lymph nodes from 40 cases (disease recurrence) and 41 controls (no disease recurrence and followed for at least five years) with gastric cancer were examined for the presence of OTC, that comprised micrometastases (MM; >0.2 mm and < or =2.0 mm) and isolated tumor cells (ITC; < or =0.2 mm). The original hematoxylin and eosin-stained sections of all lymph nodes from cases and controls were previously considered as tumor-negative by the local pathologist. Fresh hematoxylin and eosin-stained sections were screened by conventional microscopy. Histologic sections stained by immunohistochemistry with anticytokeratin antibodies CAM5.2 were screened by conventional and automated microscopy. Tumor cells were detected in lymph nodes from 40 of 81 (49%) patients. There was no significant difference in the presence of OTC, MM, or ITC between the case and control groups (P = 0.658, P = 0.691, P = 0.887, respectively). However, significantly more cases presented with 20% or more OTC-positive lymph nodes (P = 0.015). A multivariate logistic regression analysis showed that examination of less than five lymph nodes (odds ratio, 13.8; 95% confidence interval, 1.6-120.6, P = 0.018) was the only significant independent risk factor for disease recurrence, especially for locoregional disease recurrence (odds ratio, 20.4; 95% confidence interval, 2.2-190.8, P = 0.008). A similar analysis for distant disease recurrence showed a percentage of 20% or more OTC-positive lymph nodes to be the only significant independent risk factor (odds ratio, 15.6, 95% confidence interval, 1.6-151.4, P = 0.018). The sensitivity of immunohistochemistry evaluated by microscopy to identify cases with 20% or more OTC-positive lymph nodes increased from 8% for conventional microscopy to 22% for automated microscopy (McNemar's test, P = 0.063). The mere presence of OTC-positive lymph nodes in gastric cancer patients did not predict disease recurrence. However, the number of examined lymph nodes and the percentage of OTC-positive lymph nodes were independent risk factors for locoregional disease recurrence and distant disease recurrence, respectively. Automated microscopy was essential in identifying patients with 20% or more OTC-positive lymph nodes. Therefore, a maximum number of lymph nodes should be removed and meticulously examined for OTC to identify high-risk patients. These patients should be considered for additional treatment.

(De-)regulation of apoptosis plays an important role in normal and malignant lymphopoiesis. Apoptosis-regulating genes of the BCL-2 family and the recently identified inhibitors of apoptosis (IAP) family have been implicated in different types of non-Hodgkin lymphoma (NHL). To investigate whether expression of specific apoptosis-regulating genes correlated with different types of lymphoid malignancies, we measured the expression of five BCL-2 family genes, four IAP family genes and SMAC by real-time quantitative polymerase chain reaction in patient samples. In total, 137 samples from B- and T-cell acute lymphoblastic leukaemia (ALL), B-cell chronic lymphocytic leukaemia (CLL), six different NHL types and three control tissue types were analysed. The data were further analysed using cluster and discriminant analysis. Three specific expression patterns were identified for CLL, ALL and NHL respectively. CLL samples, as well as B-ALL and follicular lymphoma samples showed high similarity in the expression of these apoptosis-regulating genes and could be distinguished from each other and other diseases and controls. Discriminant analysis identified three members of the IAP family, C-IAP1, C-IAP2 and SURVIVIN, as the most informative genes to discriminate between these lymphoid malignancies.

Background: The prognosis of pancreatic cancer (PC) is highly dependent on the stage of the disease, and early recognition improves survival. Positron emission tomography (PET) using (18)F-fluoro-2-deoxyglucose ([(18)F]FDG) has been established as an important clinical tool for PC diagnosis, but it is not known whether FDG-PET detects premalignant stages of PC. We speculate that [(18)F]FDG uptake precedes the onset of PC in a hamster model. We used the N-nitrosobis(2-oxopropyl)amine (BOP) model, as these animals consistently develop PC within 20 weeks after first injection., Methods: Male Syrian hamsters were injected once a week with 10 mg BOP/kg body weight for 10 consecutive weeks. Terminal autopsy took place in groups of five hamsters from 4 weeks until 28 weeks after first BOP injection. After an 8-h fast, hamsters were injected with [(18)F]FDG and sacrificed 1 h after [(18)F]FDG injection. The pancreata were histopathologically examined, and the [(18)F]FDG uptake was determined and expressed as percentage of the injected dose per gram tissue (%ID/g)., Results: Seven of 55 hamsters developed macroscopic signs of tumor. Histopathological examination revealed PC in 13 hamsters. [(18)F]FDG uptake increased gradually with time and was significantly higher in the group with PC compared to the group without PC., Conclusion: [(18)F]FDG accumulates preferentially in PC, and pancreata exposed to BOP showed a gradual increase in [(18)F]FDG accumulation.

Purpose: Recognition of hereditary nonpolyposis colorectal cancer (HNPCC)-related endometrial carcinoma from sporadic carcinoma by histologic features as compared with colonic cases., Study Design: Case-control study., Methods and Materials: From the files of the Nijmegen Hereditary Cancer Clinic, HNPCC-related (n = 6) endometrial and colorectal (n = 18) carcinomas were selected. For every HNPCC-related tumor, 2 sporadic control cases were included. The tumors were evaluated for the following 7 pathologic features: tumor differentiation, T-stage, growth pattern, presence of Crohn-like lymphoid reaction, mucinous differentiation, presence of lymphangioinvasive growth, and the amount of tumor-infiltrating lymphocytes., Results: HNPCC-related endometrial carcinomas were significantly more often poorly differentiated (83% versus 27%), more often showed the presence of a Crohn-like lymphoid reaction (100% versus 13%) and lymphangioinvasive growth (67% versus 0%), and high number of tumor-infiltrating lymphocytes were more often present (100% versus 36%) compared with sporadic endometrial carcinomas. The differences between HNPCC and sporadic colorectal cancer specimens were less discriminating., Conclusions: HNPCC-related endometrial carcinomas are characterized by poor differentiation, more frequent Crohn-like lymphoid reaction, lymphangioinvasive growth and more tumor-infiltrating lymphocytes. These features therefore might form the basis for selecting patients for counseling in a hereditary cancer clinic or testing for microsatellite instability or mutation analysis of mismatch repair genes, especially when they are of relatively young age.

Human airways are frequently exposed to potentially harmful agents that cause tissue injury. Upon such injury, a repair process is initiated that comprises cell migration, proliferation, and differentiation. We have previously shown that human neutrophil defensins (human neutrophil peptides 1-3 [HNP1-3]) induce airway epithelial cell proliferation. Because of the role of cell proliferation in epithelial wound repair, we investigated the effect of HNP1-3 on airway epithelial wound closure and mucin gene expression in vitro. Using NCI-H292 airway epithelial cell cultures, we demonstrated that HNP1-3 cause a dose- and time-dependent increase of wound closure as well as increased cell migration. Furthermore, HNP1-3 caused a biphasic activation of the mitogen-activated protein kinase extracellular-regulated kinase 1 and 2 (ERK1/2). Both the effects of HNP1-3 on wound closure and ERK1/2 activation were blocked by specific inhibitors of the mitogen-activated protein kinase kinase MEK, whereas inhibitors of epidermal growth factor receptor tyrosine kinase, phosphatidylinositol 3-kinase, and Src did block defensin-enhanced wound closure but not ERK1/2 activation. Finally, HNP1-3 increased mRNA encoding the mucins MUC5B and MUC5AC, suggesting a role for defensins in mucous cell differentiation. These results indicate that neutrophil defensins increase epithelial wound repair in vitro, which involves migration and proliferation, and mucin production. Neutrophil defensin-enhanced wound repair appears to require epidermal growth factor receptor activation and downstream signaling pathways.

Cell adhesion receptors (CAMs) are actively involved in regulating various cell processes, including growth, differentiation, and cell death. Therefore, CAMs represent a large group of morphoregulating molecules, mediating cross-talk between cells and of cells with their environment. From this perspective, CAMs do contribute to cells and tissue organization, and in diseased tissue, to the disease development and biological characteristics. Therefore, observed changes in expression patterns of adhesion molecules may contribute to establish a diagnosis. A distinct shift in expression patterns in neoplastic epithelium has been described, for example for cadherins, integrins, and CD44. A relatively novel cell CAM, Ep-CAM, was first reported to be a pan-carcinoma antigen, although it is rather a marker of epithelial lineage. Several antibodies directed to Ep-CAM have been generated, and many epithelial tissues and their neoplastic appendages have been studied. This article outlines the results of these studies. Based on the results of these studies, we conclude that Ep-CAM immunohistochemistry can be a useful tool in the diagnosis of disturbed epithelial tissues.

Gastric non-Hodgkin's lymphomas can be divided histologically into mucosa-associated lymphoid tissue (MALT) lymphoma (ML) and diffuse large cell lymphoma (DLCL) with or without evidence of preceding/accompanying ML (DLCL + ML). We studied the incidence of the most frequent structural chromosomal aberration in ML, t(11;18)(q21;q21), and numerical aberrations of seven chromosomes in 36 ML, 39 DLCL + ML and ten gastric DLCL cases, by dual-colour interphase fluorescence in situ hybridization (FISH) and reverse transcriptase polymerase chain reaction (RT-PCR). t(11;18)(q21;q21) was exclusively detected in ML (FISH 22%; RT-PCR 24%), being completely absent in DLCL + ML and DLCL. No other translocations involving 11q21 or 18q21 and other partner chromosomes were detected by FISH. In lymphomas harbouring t(11;18)(q21;q21), this translocation was the sole genetic abnormality. In contrast, 45% of the t(11;18)(q21;q21)-negative ML showed trisomies, especially of chromosome 3 and 18. In DLCL + ML with separate small and large cell components, trisomies were either detected in both components or occurred exclusively in large tumour cells. Our results suggest that ML can be divided in lymphomas characterized by the t(11;18)(q21;q21), which are unlikely to transform into high-grade tumours, and t(11;18)(q21;q21)-negative ML that may develop into DLCL + ML after the acquisition of additional genetic aberrations.

Small human lung specimens are frequently used for cell biological studies of the pathogenesis of emphysema. In general, lung function and other clinical parameters are used to establish the presence and severity of emphysema/chronic obstructive pulmonary disease without morphological analysis of the specimens under investigation. In this study we compared three morphological methods to analyze emphysema, and evaluated whether clinical data correlate with the morphological data of individual lung samples. A total of 306 lung specimens from resected lung(lobes) from 221 patients were inflated and characterized using three morphological parameters: the Destructive Index, the Mean Linear Intercept, and Section Assessment. Morphological data were related to each other, to lung function data, and to smoking behavior. Significant correlations (P < .001) were observed between Section Assessment and Destructive Index (r = 0.92), Mean Linear Intercept with Destructive Index (r = 0.69) and Mean Linear Intercept with Section Assessment (r = 0.65). Section Assessment, being much less time consuming than Mean Linear Intercept and Destructive Index, is the parameter of choice for initial analysis. Destructive Index is the most sensitive parameter. There was a significant (P < .001), but weak correlation for all three parameters with the diffusion capacity for CO (K(CO)) (Destructive Index: r = -0.28; Mean Linear Intercept: r = -0.34; Section Assessment: r = -0.32), and with FEV(1)/IVC (Destructive Index: r = -0.29; Mean Linear Intercept: r = -0.33; Section Assessment: r = -0.28), but not with other lung function parameters. A significant difference (P < .05) between (ex-) smokers and never-smokers was observed for Destructive Index and Section Assessment. It is concluded that the application of the three morphological parameters represents a useful method to characterize emphysematous lesions in a (semi-)quantitative manner in small human lung specimens, and that Section Assessment is a suitable and fast method for initial screening. The extent of emphysema of individual lung specimens should be established by means of morphometry, rather than lung function data.

Short-term preoperative radiotherapy in combination with surgery has been shown to decrease the rate of local recurrence in rectal cancer patients. The effects of this type of radiotherapy on the histopathology of rectal carcinoma has been hitherto unknown. Since various histopathological factors are associated with prognosis, the study of alterations induced by irradiation is an important issue. This paper examines the histopathology of resection specimens from 1306 patients who were treated in a randomized trial that evaluated the benefits of preoperative radiotherapy. In this trial, patients were treated with short-term radiotherapy (5 x 5 Gy) and operated on within 5 days after radiation. Histopathological parameters were determined by the Pathology Review Committee of the trial and we compared tumours of patients with and without preoperative radiotherapy. Tumours of patients who were treated with preoperative radiotherapy were smaller, more often mucinous carcinomas (13% versus 7%, p < 0.001) and more often poorly differentiated (35% versus 24%, p<0.001). After radiotherapy, there was less inflammatory reaction around the tumour (extensive in 7% versus 18%, p<0.001), which was mainly caused by a decrease in T lymphocytes and neutrophil granulocytes. The fibroblastic reaction was more pronounced in the radiotherapy group (extensive in 22% versus 10%, p <0.001). Remarkable histological alterations occurred within a week after 5 days of irradiation of rectal carcinomas. The prognostic value of these factors therefore needs to be re-evaluated for irradiated patients.

Objective: To identify markers that are relevant as predictors of lymph node metastasis in head and neck squamous cell cancer., Design: Expression of p53, Rb, cyclin D1, E-cadherin, and epithelial cell adhesion molecule was examined using immunohistochemical analysis and traditional histological parameters, and the correlation of these markers with the histologically verified presence of regional metastases was determined., Subjects: The study sample comprised 121 patients with head and neck squamous cell cancer from whom paraffin-embedded material of primary tumors was used., Results: Lymph node metastasis was correlated with the loss of expression of Rb (P =.04) and marginally correlated with the loss of expression of E-cadherin (P =.06). If the results are broken down to subsites, loss of E-cadherin expression in oral cancer (P =.04) and absence of eosinophilic infiltration in laryngeal cancer (P =.003) correlated with nodal metastasis. None of the other markers correlated. A combination of relevant parameters did not result in a much stronger correlation., Conclusions: The expression of the investigated genetic markers and histopathological features of primary tumors can supply limited information on the metastatic behavior of tumors. Although the use of markers for regional metastasis would be a welcome additional tool, these results do not warrant the use of these parameters for clinical decision making concerning the treatment of the neck in patients with head and neck squamous cell cancer.

Purpose: Quality assessment and assurance are important issues in modern health care. For the evaluation of surgical procedures, there are indirect parameters such as complication, recurrence, and survival rates. These parameters are of limited value for the individual surgeon, and there is an obvious need for direct parameters. We have evaluated criteria by which pathologists can judge the quality or completeness of the resection specimen in a randomized trial for rectal cancer., Patients and Methods: The pathology reports of all patients entered onto a Dutch multicenter randomized trial were reviewed. All participating pathologists had been instructed by workshops and videos in order to obtain standardized pathology work-up. A three-tiered classification was applied to assess completeness of the total mesorectal excision (TME). Prognostic value of this classification was tested using log-rank analysis of Kaplan-Meier survival curves using the data of all patients who did not receive any adjuvant treatment., Results: Included were 180 patients. In 24% (n = 43), the mesorectum was incomplete. Patients in this group had an increased risk for local and distant recurrence, 36.1% v. 20.3% recurrence in the group with a complete mesorectum (P =.02). Follow-up is too short to observe an effect on survival rates., Conclusion: A patient's prognosis is predicted by applying a classification of macroscopic completeness on a rectal resection specimen. We conclude that pathologists are able to judge the quality of TME for rectal cancer. With this direct interdisciplinary assessment instrument, we establish a new role of the pathologist in quality control.