Interobserver variation in the classification of tumor deposits in rectal cancer-is the use of histopathological characteristics the way to go?

The focus on lymph node metastases (LNM) as the most important prognostic marker in colorectal cancer (CRC) has been challenged by the finding that other types of locoregional spread, including tumor deposits (TDs), extramural venous invasion (EMVI), and perineural invasion (PNI), also have significant impact. However, there are concerns about interobserver variation when differentiating between these features. Therefore, this study analyzed interobserver agreement between pathologists when assessing routine tumor nodules based on TNM 8. Electronic slides of 50 tumor nodules that were not treated with neoadjuvant therapy were reviewed by 8 gastrointestinal pathologists. They were asked to classify each nodule as TD, LNM, EMVI, or PNI, and to list which histological discriminatory features were present. There was overall agreement of 73.5% (κ 0.38, 95%-CI 0.33-0.43) if a nodal versus non-nodal classification was used, and 52.2% (κ 0.27, 95%-CI 0.23-0.31) if EMVI and PNI were classified separately. The interobserver agreement varied significantly between discriminatory features from κ 0.64 (95%-CI 0.58-0.70) for roundness to κ 0.26 (95%-CI 0.12-0.41) for a lone arteriole sign, and the presence of discriminatory features did not always correlate with the final classification. Since extranodal pathways of spread are prognostically relevant, classification of tumor nodules is important. There is currently no evidence for the prognostic relevance of the origin of TD, and although some histopathological characteristics showed good interobserver agreement, these are often non-specific. To optimize interobserver agreement, we recommend a binary classification of nodal versus extranodal tumor nodules which is based on prognostic evidence and yields good overall agreement.

Current and Emerging Biomarkers and Imaging Modalities for Nonalcoholic Fatty Liver Disease: Clinical and Research Applications.

PURPOSE: Nonalcoholic fatty liver disease (NAFLD) is a metabolic disorder that frequently coexists with obesity, metabolic syndrome, and type 2 diabetes. The NAFLD spectrum, ranging from hepatic steatosis to nonalcoholic steatohepatitis, fibrosis, and cirrhosis, can be associated with long-term hepatic (hepatic decompensation and hepatocellular carcinoma) and extrahepatic complications. Diagnosis of NAFLD requires detection of liver steatosis with exclusion of other causes of chronic liver disease. Screening for NAFLD and identification of individuals at risk of end-stage liver disease represent substantial challenges that have yet to be met. NAFLD affects up to 25% of adults, yet only a small proportion will progress beyond steatosis to develop advanced disease (steatohepatitis and fibrosis) associated with increased morbidity and mortality. Identification of this cohort has required the gold standard liver biopsy, which is both invasive and expensive. The use of serum biomarkers and noninvasive imaging techniques is an area of significant clinical relevance. This narrative review outlines current and emerging technologies for the diagnosis of NAFLD, nonalcoholic steatohepatitis, and hepatic fibrosis. METHODS: We reviewed the literature using PubMed and reviewed national and international guidelines and conference proceedings to provide a comprehensive overview of the evidence. FINDINGS: Significant advances have been made during the past 2 decades that have enhanced noninvasive assessment of NAFLD without the need for liver biopsy. For the detection of steatosis, abdominal ultrasonography remains the first-line investigation, although a controlled attenuation parameter using transient elastography is more sensitive. For detecting fibrosis, noninvasive serum markers of fibrosis and algorithms based on routine biochemistry are available, in addition to transient elastography. These techniques are well validated and have been incorporated into national and international screening guidelines. These approaches have facilitated more judicious use of liver biopsy but are yet to entirely replace it. Although serum biomarkers present a pragmatic and widely available screening approach for NAFLD in large population-based studies, magnetic resonance imaging techniques offer the benefit of achieving high degrees of accuracy in disease grading, tumor staging, and assessing therapeutic response. IMPLICATIONS: This diagnostic clinical and research field is rapidly evolving; increasingly combined applications of biomarkers and transient elastography or imaging of selective (intermediate or high risk) cases are being used for clinical and research purposes. Liver biopsy remains the gold standard investigation, particularly in the context of clinical trials, but noninvasive options are emerging, using multimodality assessment, that are quicker, more tolerable, more widely available and have greater patient acceptability.

Variation in histopathological assessment and association with surgical quality indicators following oesophagectomy.

BACKGROUND: Histopathological outcomes, such as lymph node yield and margin positivity, are used to benchmark and assess surgical centre quality, and are reported annually by the National Oesophago-Gastric Cancer Audit (NOGCA) in England and Wales. The variation in pathological specimen assessment and how this affects these outcomes is not known. METHODS: A survey of practice was circulated to all tertiary oesophagogastric cancer centres across England and Wales. Questions captured demographic data, and information on how specimens were prepared and analysed. National performance data were retrieved from the NOGCA. Survey results were compared for tertiles of lymph node yield, and circumferential and longitudinal margins. RESULTS: Survey responses were received from 32 of 37 units (86 per cent response rate), accounting for 93.1 per cent of the total oesophagectomy volume in England and Wales. Only 5 of 32 units met or exceeded current guidelines on specimen preparation according to the Royal College of Pathologists guidelines. There was wide variation in how centres defined positive (R1) margins, and how margins and lymph nodes were assessed. Centres with the highest nodal yield were more likely to use systematic fat blocking, and to re-examine specimens when the initial load was low. Systematic blocking of lesser curve fat resulted in significantly higher rates of patients with at least 15 lymph nodes examined (91.4 versus 86.5 per cent; P = 0.027). CONCLUSION: Preparation and histopathological assessment of specimens varies significantly across institutions. This challenges the validity of currently used surgical quality metrics for oesophageal and other tumours.

Lower gastrointestinal endoscopy: guidance on indications for biopsy.

Lower gastrointestinal endoscopy is a commonly undertaken procedure and has assumed even greater prominence with the inception of the NHS Bowel Cancer Screening Programme (BCSP). Workloads are also constantly increasing within histopathology departments and this has led to a need for workload management by laboratories. Advanced endoscopic techniques now allow for targeted biopsies within settings such as inflammatory bowel disease surveillance and the BCSP. In this article, we provide guidance to the endoscopist for optimal biopsy protocols that are designed to maximise the chance of a subsequent histopathological examination providing definitive results and to reduce the number of unnecessary biopsies, in which histopathology is unlikely to deliver clinically useful information. The majority of the article focuses on biopsy taking within a defined range of clinical situations that are commonly encountered by endoscopists.

Colorectal cancer staging using TNM 7: is it time to use this new staging system?

The authors audited pathological colorectal cancer staging according to tumour node metastasis (TNM) 7 and using TNM 5 as a gold standard. 144 consecutive colorectal cancer resection specimens were staged prospectively using both TNM 5 and TNM 7 criteria during routine reporting by specialist gastrointestinal pathologists within a single institution. The pN stage remained the same under both systems apart from the required subclassification of pN1 and pN2 under TNM 7. The TNM 7 pN1c category was used in only 3% of cases. All cases staged as pT4 underwent reversal of pT4 subclassification using TNM 7 compared with TNM 5. A previous study revealed stage migration from pN1 to pN2 in 32.6% of cases under TNM 7 compared with TNM 5. The difference in frequency of pN stage migration between this study and our audit suggests that the application of TNM 7 to the assessment of discontinuous/satellite tumour foci is subject to significant inter-observer variability.

The endoscopically normal colon: when is mapping biopsy histopathologically justifiable?

OBJECTIVE: Mapping biopsy of endoscopically normal colon is a contentious area and generates considerable work for histopathology services. Managing demand for pathological testing is a current healthcare priority. In this retrospective audit, the authors aimed to establish diagnostic yield of mapping biopsy in this specific subgroup and identify situations where practice could be safely streamlined. DESIGN: Cases were retrieved over a 10-month period. Histopathology results were correlated with relevant endoscopy reports. The data were anonymised and analysed. SETTING: Department of Cellular Pathology, Southampton General Hospital, UK. RESULTS: 717 cases were retrieved. 308 (43%) cases were reported as endoscopically normal. 278 (90%) cases with endoscopically normal/near normal mucosa showed normal/near normal histology. 30/308 (9.7%) endoscopically normal cases showed pathological abnormalities. 9/308 (2.9%) cases of microscopic colitis were detected. Of the 30 cases with pathological abnormalities, 20 (66.7%) presented with change in bowel habit and 6 (20%) had a pre-existing diagnosis of inflammatory bowel disease. CONCLUSIONS: Pathological abnormalities in endoscopically normal colon are found most frequently in those who present with change in bowel habit or a known history of inflammatory bowel disease. The authors support biopsy in these individuals and believe that mapping biopsy of endoscopically normal colon in patients referred for other reasons (eg, bright red rectal bleeding or iron deficiency anaemia) should not be performed routinely as diagnostic yields are very low. Guidelines on appropriate use of mapping biopsy in this setting are limited. Streamlining patients based on reason for referral or presenting symptoms may be a useful step towards more effective management of histopathological demand.

A novel HER2-positive breast cancer phenotype arising from germline TP53 mutations.

INTRODUCTION: The Li-Fraumeni Syndrome is caused by a germline TP53 mutation and is associated with a high risk of breast cancer at young ages. Basal (triple negative) breast cancers are now well recognised to be a typical sub-type of breast cancer developing in a large proportion of BRCA1 gene carriers. We considered whether a similar narrow sub-type of breast cancer was found in TP53 gene mutation carriers. OBJECTIVE: A hypothesis generating study to investigate whether there are specific breast tumour characteristics associated with germline TP53 mutations. METHODS: Pathological characteristics in 12 breast cancers arising in nine patients carrying pathogenic TP53 mutations were compared to a reference panel of 231 young onset breast tumours included in the POSH study. RESULTS: Patients carrying a TP53 mutation showed a significantly higher likelihood of developing a breast cancer with Human Epidermal growth factor Receptor (HER2) amplification (83%) when compared to the cohort of young onset breast cancer cases (16%); ER and PR status were equivalent between groups. CONCLUSION: These findings suggest that breast cancer developing on a background of an inherited TP53 mutation is highly likely to present with amplification of HER2.

Spindle cell tumour with glandular elements: an unusual ileal neoplasm.

This report describes a tumour in the ileum with clinical features initially suggestive of a gastrointestinal stromal tumour (GIST). Histopathological examination revealed a biphasic tumour in which the spindle cell component showed immunohistochemical evidence of smooth muscle differentiation but without the characteristic profile of a GIST. A well-differentiated epithelial component was also present, comprising glandular structures with immunohistochemical features suggestive of Mullerian differentiation. Similar glandular differentiation has been described in uterine leiomyomas but not, to our knowledge, in tumours associated with the small bowel. None of the characteristic mutations of GISTs were identified in this case. There were no overt features of malignancy but, because of the unusual nature of the case, we assessed the biological behaviour as uncertain.

Patterns of histological change in liver disease: my approach to 'medical' liver biopsy reporting.

The aim of this review was to emphasize the benefit of a methodical approach to 'medical' liver biopsy reporting and to illustrate that recognition of patterns of disease can greatly aid correct interpretation of these often-complex specimens. This applies both to assessment of the liver architecture and to evaluation of the likely disease aetiology. Therefore, a great deal of information can be obtained by examining biopsy material at low- and medium-power magnification, prior to confirming detailed features with high-power examination. A range of recommended special histochemical stains that personal experience has shown to be valuable is included. Emphasis is also placed on the absolutely key requirement for appropriate knowledge of the clinical situation within which the biopsy specimen was taken.

Hyperplastic polyps of the duodenum: an unusual histological finding.

A 58-year-old man underwent upper gastrointestinal surveillance endoscopy for Barrett's oesophagus. This showed a possible gastric ulcer, although histological examination was normal. Follow-up endoscopy showed white ridges in the distal duodenum and these were subjected to biopsy. Histological examination of the biopsy specimens showed polypoid duodenal mucosa showing features similar to those of a hyperplastic polyp of the colon. In addition, the mucosal surface was focally of gastric surface type. The features were interpreted overall as most likely to represent an unusual form of regenerative change in the setting of previous chronic inflammatory mucosal damage. The case is presented as an unusual histological phenomenon at this site; it would be important not to overdiagnose neoplasia in this situation.

ICAM-1 polymorphisms and development of cutaneous malignant melanoma.

Tumour growth in cutaneous malignant melanoma (CMM) is mediated by cell adhesion molecules, including intercellular adhesion molecule-1 (ICAM-1). ICAM-1 expression is associated with increasing Breslow thickness of vertical growth-phase tumours and, in patients with stage 1 disease, may be associated with disease free and patient survival. In this study we have investigated whether two single nucleotide polymorphisms (SNPs) in the ICAM-1 gene encoding amino acid substitutions in codons 241 and 469 of the expressed ICAM-1 molecule are associated with susceptibility to and markers of prognosis (including tumour Breslow thickness) in CMM. A total of 164 CMM patients and 264 cancer-free controls were genotyped for these SNPs by the 5' nuclease assay for allelic discrimination (TaqMan). No genotypes showed any significant associations with CMM susceptibility, although there was a non-significant increase in frequency of the ICAM-1 469 AA genotype among CMM patients vs. controls (38.4% vs. 29.9%; P = 0.11). However, the ICAM-1 241 GG genotype was significantly decreased in frequency among patients with primary invasive tumours of greater Breslow thickness (72.5% vs. 91.2%; P = 0.013; OR = 0.25 (0.072-0.85)). These results provide no evidence for a role for the ICAM-1 codon 241 and 469 SNPs in determining susceptibility to CMM, but provide preliminary evidence that the role of ICAM-1 polymorphism in modulating tumour growth in CMM requires further investigation in a larger study group.

Influence of cytokine and ICAM-1 gene polymorphisms on susceptibility to chronic pancreatitis.

AIMS: To test the hypothesis that single nucleotide polymorphisms (SNPs) within genes (or their promoter regions) encoding cytokines, growth factors, and intercellular adhesion molecules modulate the risk of development of chronic pancreatitis (CP). METHODS: DNA was extracted from peripheral blood leucocytes or formalin fixed, paraffin wax embedded tissue from 53 patients with CP and 266 healthy controls. SNPs within the interleukin 1beta (IL-1beta), IL-6, IL-8, tumour necrosis factor alpha (TNFalpha) and vascular endothelial growth factor (VEGF) gene promoter regions and the transforming growth factor beta1 (TGFbeta1) and intercellular cell adhesion molecule 1 (ICAM-1) genes were genotyped by the amplification refractory mutation system polymerase chain reaction or 5' nuclease (Taqman) techniques. Patient-control comparisons were made using 2 x 2 contingency tables and chi2 analyses. RESULTS: A non-significant decrease in the frequency of the IL-8 -251 AA genotype and a non-significant increase in the frequency of the ICAM-1 +469 GA genotype was seen in patients compared with controls. No associations were identified between SNPs in the promoter regions of the IL-1beta, IL-6, or TNFalpha proinflammatory cytokines genes or the TGFbeta1 and VEGF genes and susceptibility to CP. CONCLUSIONS: This preliminary study suggests that genetic polymorphism within several cytokine genes is unlikely to influence susceptibility to CP, but the possible role of IL-8 and ICAM-1 polymorphisms in the development of this disease requires further investigation.

The retroperitoneal surface in distal caecal and proximal ascending colon carcinoma: the Cinderella surgical margin?

BACKGROUND: Mesorectal margin tumour involvement is a predictor of local recurrence in rectal carcinoma and an indication for postoperative radiotherapy in suitable patients. However, the prevalence of non-peritonealised surgical margin involvement in ascending colon carcinoma is unknown. AIMS: To test the hypothesis that retroperitoneal surgical margin (RSM) tumour involvement occurs in distal caecal and proximal ascending colon carcinoma. METHODS/RESULTS: One hundred right hemicolectomy specimens, removed for adenocarcinoma of the caecum or proximal ascending colon, were studied. During routine specimen dissection, at least one additional tissue block was taken to include the tumour and the RSM. The tumour distance from the RSM was recorded. RSM tumour involvement was present in seven cases (7%). Direct (non-nodal) RSM tumour involvement (five cases) only occurred in posterior or circumferential tumours. CONCLUSIONS: RSM tumour involvement occurs within a considerable number of distal caecal and proximal ascending colon carcinomas. The rate of RSM tumour involvement identified here is similar to a previously published local recurrence rate of 10% in caecal carcinoma, suggesting that RSM tumour involvement may be a predictor of recurrence in these tumours. Therefore, patients with distal caecal or proximal ascending colon carcinoma and RSM tumour involvement may benefit from postoperative radiotherapy.

Deficient alpha smooth muscle actin expression as a cause of intestinal pseudo-obstruction: fact or fiction?

AIMS: To test the hypothesis that deficient alpha smooth muscle actin (ASMA) expression in intestinal smooth muscle, as assessed by immunohistochemistry, is specifically associated with clinical evidence of intestinal pseudo-obstruction. METHODS: Seventeen archival, formalin fixed, paraffin wax embedded samples of small intestine and 12 samples of large intestine were studied. Two of the small bowel samples and one large bowel sample were from patients with symptoms of intestinal pseudo-obstruction. The controls were longitudinal surgical margins from hemicolectomies performed for carcinoma. Immunohistochemistry was performed using primary antibodies to ASMA, smooth muscle myosin heavy chain (SMMHC), and desmin. The relative intensities of immunohistochemical expression in the circular and longitudinal muscle layers of the muscularis propria were assessed in each sample, for all three markers. RESULTS: All samples showed strong SMMHC and desmin expression in the inner circular and outer longitudinal layers of the muscularis propria. Both small intestinal samples from the cases and 11 of 15 controls showed no or minimal ASMA expression in the inner circular layer, with the remaining four controls also showing ASMA labelling in this layer that was weaker than within the longitudinal muscle. In contrast, intense ASMA expression was seen in both muscle layers within the large intestine in the remaining case, and in the controls. CONCLUSIONS: There is insufficient evidence from this study to support the hypothesis that ASMA deficiency in intestinal smooth muscle, as determined by immunohistochemistry on archival tissues, is specifically associated with intestinal pseudo-obstruction.

Cytokine gene polymorphisms and breast cancer susceptibility and prognosis.

Single nucleotide polymorphisms (SNPs) in the promoter regions of cytokine genes are associated with differential levels of cytokine expression. We hypothesized that these SNPs might influence breast tumour development and progression by affecting the efficiency of the antitumour immune response and/or pathways of angiogenesis. A total of 144 female breast cancer patients and 263 cancer-free population controls were genotyped for the interleukin (IL)-1beta-511 (T/C), IL-6 -174 (G/C), tumour necrosis factor (TNF)-alpha-308 (A/G), IL-10 -1082 (A/G), IL-8 -251 (A/T) and vascular endothelial growth factor (VEGF) -1154 (A/G) SNPs, using amplification refractory mutation system polymerase chain reaction (ARMS-PCR) and TaqMan (Applied Biosystems, Foster City, CA, USA) 5' nuclease assays for allelic discrimination. No significant associations were seen. Patient-control comparisons revealed a non-significant trend for association between the TNF-alpha-308 GG genotype and breast cancer compared to controls (79.7 vs. 68.2%, P = 0.03, Pc = 0.54). Stratification of the patient group according to the Nottingham Prognostic Index and individual prognostic factors revealed trends for association between IL-6 -174 GC and IL-8 -251 AA genotypes and markers of poor prognosis (P = 0.04, Pc = 0.72 and P = 0.02, Pc = 0.36, respectively). There were also trends for associations between VEGF -1154 AG and IL-1beta-511 TC genotypes and markers of good prognosis (P = 0.02, Pc = 0.36 and P = 0.05, Pc = 0.90, respectively). These results suggest that the role of cytokine promoter SNPs in both susceptibility to and prognosis in breast cancer requires further investigation in a larger study.

Cytokine gene single nucleotide polymorphisms and susceptibility to and prognosis in cutaneous malignant melanoma.

Cutaneous malignant melanoma (CMM) is a potentially fatal malignancy in which exposure to UV light is the most important risk factor. Several lines of evidence suggest that CMM patients develop an immune response to their tumours, although, in most cases, anti-tumour immune responses are insufficient to abrogate tumour development. Polymorphism in genes regulating the immune response and cell growth may result in increased susceptibility to and/or poorer prognosis in certain individuals. In this study, we addressed whether single nucleotide polymorphisms (SNPs) associated with differential expression of selected pro- and anti-inflammatory cytokines and growth factors [interleukin (IL)-1beta-35 and -511, IL-2 -330, IL-4 -590, IL-6 -174, IL-8 -251, interferon (IFN)-gamma+874 and transforming growth factor (TGF)beta1 +915] or as markers of candidate cytokine genes (IL-12 +1188) are associated with susceptibility to or known prognostic indicators (e.g. initial tumour growth phase, Breslow thickness, mitotic count in vertical growth phase tumours, tumour regression) in CMM. One hundred and sixty-nine British caucasian CMM patients and 261 controls were included in the study and all SNPs were genotyped by ARMS-PCR. No SNP genotypes or alleles showed significant associations with CMM susceptibility and only the IL-1beta-511 TT genotype was associated with thinner invasive tumours at presentation, as assessed by Breslow thickness at the clinically significant cut-off point of 1.5 mm [occurring in 2/51 (3.9%) thicker vs. 14/78 (17.9%) thinner tumours (P = 0.03; relative risk = 0.29 (95% confidence interval 0.05-0.95)]. These findings suggest that - with the possible exception of IL-1beta- genetic variation associated with differential expression of the selected pro- and anti-inflammatory cytokines is unlikely to play a major role in susceptibility to and prognosis in CMM.

BAG-1 expression and function in human cancer.

BAG-1 is a multifunctional protein that interacts with a wide range of target molecules to regulate apoptosis, proliferation, transcription, metastasis and motility. Interaction with chaperone molecules may mediate many of the effects of BAG-1. The pathways regulated by BAG-1 play key roles in the development and progression of cancer and determining response to therapy, and there has been considerable interest in determining the clinical significance of BAG-1 expression in malignant cells. There is an emerging picture that BAG-1 expression is frequently altered in a range of human cancers relative to normal cells and a recent report suggests the exciting possibility that BAG-1 expression may have clinical utility as a prognostic marker in early breast cancer. However, other studies of BAG-1 expression in breast cancer and other cancer types have yielded differing results. It is important to view these findings in the context of current knowledge of BAG-1 expression and function. This review summarises recent progress in understanding the clinical significance of BAG-1 expression in cancer in light of our understanding of BAG-1 function.

Influence of vascular endothelial growth factor single nucleotide polymorphisms on tumour development in cutaneous malignant melanoma.

Vascular endothelial growth factor (VEGF) is a potent regulator of vasculogenesis and tumour angiogenesis. We have investigated whether the VEGF -2578, -1154, +405 and +936 SNPs and associated haplotypes confer susceptibility to and/or influence prognosis in cutaneous malignant melanoma (CMM) skin cancer. A total of 152 CMM patients and 266 controls were genotyped for VEGF promoter SNPs by ARMS-PCR. Strong linkage disequilibrium between the -2578, -1154 and +405 SNPs was detected (association, rho = 0.488-0.965), but not between these SNPs and SNP +936 (association, rho = 0.004-0.130). No SNPs or three SNP haplotypes (-2578, -1154, +405) were significantly associated with CMM, although a number of non-significant trends were observed. However, the VEGF -1154 AA genotype and -2578, -1154, +405 CAC haplotype were both significantly associated with less advanced (Stage 1) disease (P = 0.03). In addition, the VEGF -1154 AA genotype was associated with thinner primary vertical growth phase tumours (P = 0.002), while VEGF -1154 GG was associated with thicker primary tumours (P = 0.02). These preliminary results indicate that VEGF genotype may influence tumour growth in CMM, possibly via the effects of differential VEGF expression on tumour angiogenesis.

Apoptosis and proliferation of acinar and islet cells in chronic pancreatitis: evidence for differential cell loss mediating preservation of islet function.

BACKGROUND: Chronic pancreatitis is characterised clinically by early exocrine insufficiency, with diabetes mellitus occurring as a late phenomenon. This is mirrored pathologically by extensive acinar cell destruction and islet preservation. The mechanisms underlying this differential rate of cellular destruction are unknown. AIMS: To test the hypothesis that acinar loss and islet preservation in chronic pancreatitis occurs due to differential epithelial kinetics and investigate the role of inflammatory cells and cell cycle associated molecules. METHODS: Archival tissue from six chronic pancreatitis cases was compared with six normal controls using TUNEL and immunohistochemistry for CD3, CD20, CD68, MIB-1, Bcl-2, Bax, Fas, Fas ligand, retinoblastoma protein (Rb), and tissue inhibitor of metalloproteinases 1 (TIMP-1) and 2 (TIMP-2). RESULTS: The acinar cell apoptotic index (AI) and proliferation index were higher in chronic pancreatitis than controls. T lymphocytes diffusely infiltrated fibrous bands and acini but rarely islets. Acinar Bcl-2 expression exceeded islet expression in chronic pancreatitis and controls while Bax was strongly expressed by a subset of islet cells and weakly by centroacinar cells. Islet Fas and Fas ligand expression exceeded acinar expression in chronic pancreatitis and controls. Acinar Rb expression was higher in chronic pancreatitis than in controls. Islets in chronic pancreatitis and controls showed intense TIMP-1 and TIMP-2 expression. CONCLUSION: Apoptosis plays a significant role in acinar loss in chronic pancreatitis. Acinar Bcl-2 and islet Bax expression indicates complex AI control. Increased acinar Rb expression in chronic pancreatitis may differentially promote acinar loss. Fas ligand expression may be restricted to islet cell membranes through TIMP-1 expression and inhibit islet damage by promoting apoptosis of cytotoxic T lymphocytes.