Under the auspices of the College of American Pathologists, the current state of knowledge regarding pathologic prognostic factors (factors linked to outcome) and predictive factors (factors ...predicting response to therapy) in colorectal carcinoma was evaluated. A multidisciplinary group of clinical (including the disciplines of medical oncology, surgical oncology, and radiation oncology), pathologic, and statistical experts in colorectal cancer reviewed all relevant medical literature and stratified the reported prognostic factors into categories that reflected the strength of the published evidence demonstrating their prognostic value. Accordingly, the following categories of prognostic factors were defined. Category I includes factors definitively proven to be of prognostic import based on evidence from multiple statistically robust published trials and generally used in patient management. Category IIA includes factors extensively studied biologically and/or clinically and repeatedly shown to have prognostic value for outcome and/or predictive value for therapy that is of sufficient import to be included in the pathology report but that remains to be validated in statistically robust studies. Category IIB includes factors shown to be promising in multiple studies but lacking sufficient data for inclusion in category I or IIA. Category III includes factors not yet sufficiently studied to determine their prognostic value. Category IV includes factors well studied and shown to have no prognostic significance.
The medical literature was critically reviewed, and the analysis revealed specific points of variability in approach that prevented direct comparisons among published studies and compromised the quality of the collective data. Categories of variability recognized included the following: (1) methods of analysis, (2) interpretation of findings, (3) reporting of data, and (4) statistical evaluation. Additional points of variability within these categories were defined from the collective experience of the group. Reasons for the assignment of an individual prognostic factor to category I, II, III, or IV (categories defined by the level of scientific validation) were outlined with reference to the specific types of variability associated with the supportive data. For each factor and category of variability related to that factor, detailed recommendations for improvement were made. The recommendations were based on the following aims: (1) to increase the uniformity and completeness of pathologic evaluation of tumor specimens, (2) to enhance the quality of the data needed for definitive evaluation of the prognostic value of individual prognostic factors, and (3) ultimately, to improve patient care.
Factors that were determined to merit inclusion in category I were as follows: the local extent of tumor assessed pathologically (the pT category of the TNM staging system of the American Joint Committee on Cancer and the Union Internationale Contre le Cancer AJCC/UICC); regional lymph node metastasis (the pN category of the TNM staging system); blood or lymphatic vessel invasion; residual tumor following surgery with curative intent (the R classification of the AJCC/UICC staging system), especially as it relates to positive surgical margins; and preoperative elevation of carcinoembryonic antigen elevation (a factor established by laboratory medicine methods rather than anatomic pathology). Factors in category IIA included the following: tumor grade, radial margin status (for resection specimens with nonperitonealized surfaces), and residual tumor in the resection specimen following neoadjuvant therapy (the ypTNM category of the TNM staging system of the AJCC/UICC). (ABSTRACT TRUNCATED)
Chronic infections with the hepatitis B virus (HBV) and high-risk human papillomaviruses (HPVs) are important risk factors for hepatocellular carcinoma (HCC) and cervical cancer (CC), respectively. ...HBV and HPV are DNA viruses that almost invariably integrate into the host genome in invasive tumors. The viral integration sites occur throughout the genome, leading to the presumption that there are no preferred sites of integration. A number of viral integrations have been shown to occur within the vicinity of important cancer-related genes. In studies of HBV-induced HCC and HPV-induced CC, we have identified two HBV and three HPV integrations into the human telomerase reverse transcriptase (hTERT) gene. Detailed characterization of the integrations revealed that four integrations occurred within the hTERT promoter and upstream region and the fifth integration occurred in intron 3 of the hTERT gene. None of the integrations altered the hTERT coding sequence and all resulted in juxtaposition of viral enhancers near hTERT, with potential activation of hTERT expression. Our work supports the hypothesis that the sites of oncogenic viral integration are nonrandom and that genes at the sites of viral integration may play important roles in carcinogenesis.
A comprehensive analysis of somatic and germline mutations related to DNA mismatch–repair (MMR) genes can clarify the prevalence and mechanism of inactivation in colorectal carcinoma (CRC). In the ...present study, 257 unselected patients referred for CRC resection were examined for evidence of defective DNA MMR. In particular, we sought to determine the frequency of hereditary defects in DNA MMR in this cohort of patients. MMR status was assessed by testing of tumors for the presence or absence of hMLH1, hMSH2, and hMSH6 protein expression and for microsatellite instability (MSI). Of the 257 patients, 51 (20%) had evidence of defective MMR, demonstrating high levels of MSI (MSI-H) and an absence of either hMLH1 (
n=48) or hMSH2 (
n=3). All three patients lacking hMSH2, as well as one patient lacking hMLH1, also demonstrated an absence of hMSH6. DNA sequence analysis of the 51 patients with defective MMR revealed seven germline mutations—four in
hMLH1 (two truncating and two missense) and three in
hMSH2 (all truncating). A detailed family history was available for 225 of the 257 patients. Of the seven patients with germline mutations, only three had family histories consistent with hereditary nonpolyposis colorectal cancer. Of the remaining patients who had tumors with defective MMR, eight had somatic mutations in
hMLH1. In addition, hypermethylation of the hMLH1 gene promoter was present in 37 (88%) of the 42 hMLH1-negative cases available for study and in all MSI-H tumors that showed loss of hMLH1 expression but no detectable
hMLH1 mutations. Our results suggest that, although defective DNA MMR occurs in ∼20% of unselected patients presenting for CRC resection, hereditary CRC due to mutations in the MMR pathway account for only a small proportion of patients. Of the 257 patients, only 5 (1.9%) appear to have unequivocal evidence of hereditary defects in MMR. The epigenetic (nonhereditary) mechanism of
hMLH1 promoter hypermethylation appears to be responsible for the majority of the remaining patients whose tumors are characterized by defective DNA MMR.
Background & Aims: The identifcation of any high-grade dysplasia (HGD) in Barrett;s esophagus has been considered to be an indication for esophagectomy because of the increased risk of cancer. The ...aim of this study was to determine if a limited extent of HGD has the same potential for cancer as diffuse HGD. Methods: A retrospective cohort study was performed to assess the risk of developing adenocarcinoma in relationship to the extent of HGD found on endoscopic surveillance. The extent of HGD was defined as focal if cytologic and/or architectural changes of HGD were limited to a single focus of 5 or fewer crypts and diffuse if more than 5 crypts were involved in a single biopsy specimen or if HGD involved more than one biopsy fragment. The relative risk of cancer was assessed using a Cox proportional hazard model, and cancer-free survival was determined using survival curves. Results: Sixty-seven patients with diffuse HGD and 33 with focal HGD satisfied selection criteria. Cancer-free survival rates at 1 and 3 years were 93% and 86% for focal HGD compared with 62% and 44% for diffuse HGD (P<0.001). On univariate analysis, extent of HGD (relative risk, 5.36; 95% confidence interval, 1.84–15.56), nodularity on endoscopy (relative risk, 3.98; 95% confidence interval, 1.97–8.04), and lack of acid suppression (relative risk, 2.48; 95% confidence interval, 1.16–5.28) were associated with an increased risk of esophageal adenocarcinoma. Diffuse HGD had a 3.7-fold increase in the risk of esophageal cancer compared with focal HGD (P = 0.02) on multivariate analysis. Conclusions: Patients with focal HGD are less likely to have cancer during the first year after diagnosis or on subsequent follow-up compared with diffuse HGD.
The pathogenesis of nonalcoholic steatohepatitis (NASH) remains poorly understood. Although apoptosis is a common mechanism of liver injury, the extent and clinical significance of apoptosis in NASH ...has not been examined. Thus, the aims of this study were to quantify hepatocyte apoptosis in NASH, correlate it with disease severity, and identify possible mechanisms of apoptosis induction.
Hepatocyte apoptosis was assessed in NASH, simple steatosis, alcoholic hepatitis, and controls without liver disease using the TUNEL assay and immunohistochemistry for activated caspases 3 and 7. Liver specimens were also graded according to the magnitude of inflammation and fibrosis.
TUNEL-positive cells were significantly increased in liver biopsy specimens from patients with NASH compared with simple steatosis and controls. Unexpectedly, TUNEL-positive cells were also greater in NASH vs. alcoholic hepatitis. Immunohistochemistry demonstrated active caspases 3 and 7 in NASH specimens, confirming the occurrence of apoptosis in this disease. A positive correlation was observed between hepatocyte apoptosis and hepatic fibrosis and inflammatory activity, respectively. The Fas receptor was strongly expressed in hepatocytes in liver specimens from NASH patients as compared with controls.
Hepatocyte apoptosis is significantly increased in patients with NASH and correlates with disease severity, suggesting that antiapoptotic therapy may be useful in this syndrome.
Recent studies have demonstrated the presence of microsatellite instability (MSI) in tumors from patients with hereditary nonpolyposis colorectal cancer and in a large number of sporadic tumors. To ...further characterize the type of alterations at these loci and their frequency of involvement in colon cancer, we studied DNA extracted from paraffin-embedded tissue from 508 patients using 11 microsatellites localized to chromosomes 5, 8, 15, 17, and 18. Overall, MSI at each locus varied in character and frequency and was observed with at least one marker in 191 cases (37.6%). Based on the number of markers displaying instability per tumor, three groups of patients were defined: those with <30% of the markers showing instability (MSI-L,, n = 109, 21.5%); those with > or = 30% (MSI-H, n = 82, 16.1%); and those showing no instability (MSS, n = 317, 62.4%). These groups were tested for correlations with a number of clinical and pathological parameters, including age, sex, stage, ploidy status, and site of tumor. Comparing across the three groups and verified by pair-wise comparisons, the MSI-H group was associated with tumor site (proximal colon, P = 0.001), sex (females, P = 0.005), stage (Dukes' B, P = 0.01), and ploidy status (diploid, P = 0.03). No significant differences were noted between the MSI-L and MSS group for any of the parameters tested. An additional 188 consecutive surgical colorectal cancer cases were examined for the presence of MSI and for the immunohistochemical expression of hMLH1 and hMSH2 proteins. Of this group, 129 (68.6%) were classified as MSS, 17 (9.0%) as MSI-L, and 42 (22.3%) as MSI-H. None of the MSS and none of the MSI-L tumors had altered expression of either hMLH1 or hMSH2. However, the majority of MSI-H (40 of 42, 95%) cases demonstrated absence of staining for these proteins. The most frequently altered protein was hMLH1, occurring in 95% of the tumors with altered expression. Cumulatively, these data suggest that the tumor phenotype MSI-H is distinct from tumor phenotypes MSI-L and MSS, with no apparent differences between MSI-L and MSS. Furthermore, altered hMLH1 protein expression appears to be responsible for the mutator phenotype in the vast majority of MSI-H tumors.
Nonalcoholic fatty liver disease (NAFLD) is a serious health problem. Although NAFLD represents a form of lipotoxicity, its pathogenesis remains poorly understood. The aim of this study was to ...examine the cellular mechanisms involved in free fatty acid (FFA)‐mediated hepatic lipotoxicity. FFA treatment of liver cells resulted in Bax translocation to lysosomes and lysosomal destabilization with release of cathepsin B (ctsb), a lysosomal cysteine protease, into the cytosol. This process was also partially dependent on ctsb. Lysosomal destabilization resulted in nuclear factor κB–dependent tumor necrosis factor α expression. Release of ctsb into the cytoplasm was also observed in humans with NAFLD and correlated with disease severity. In a dietary murine model of NAFLD, either genetic or pharmacological inactivation of ctsb protected against development of hepatic steatosis, liver injury, and insulin resistance with its associated “dysmetabolic syndrome.” In conclusion, these data support a lipotoxic model of FFA‐mediated lysosomal destabilization. Supplemental material for this article can be found on the HEPATOLOGY website (http://www.interscience.wiley.com/jpages/0270‐9139/suppmat/index.html). (HEPATOLOGY 2004;40:185–194.)
To assess the value of arterial, pancreatic, and hepatic phase imaging at multi-detector row computed tomography (CT) of the pancreas for pancreatic malignancy.
Thirty-nine patients suspected of ...having resectable pancreatic adenocarcinoma underwent triple-phase multi-detector row CT. Images obtained during each phase were interpreted by one radiologist who evaluated presence of tumor, vascular invasion, and flow artifacts in the superior mesenteric vein and measured attenuation of tumor, normal pancreas, aorta, and superior mesenteric vein. Results were compared with histologic, follow-up, and correlative imaging findings.
Mean tumor-to-gland attenuation difference was greatest on images obtained in the pancreatic phase (42 HU) versus that on those obtained in the hepatic phase (35 HU) and in the arterial phase (25 HU). For tumor detection, sensitivity of the images obtained in pancreatic (0.97 29 of 30) and hepatic (0.93 28 of 30) phases was superior to that of those obtained in arterial phase (0.63 19 of 30) (P < or =.008). For vascular invasion detection, sensitivity of images obtained in the hepatic phase (0.83) was better than that of those obtained in the pancreatic (0.58) and arterial (0.25) phases. Images obtained in the pancreatic phase demonstrated more flow artifacts and decreased attenuation in the superior mesenteric vein, compared with the artifacts revealed on images obtained in the hepatic phase.
Routine acquisition of images in the arterial phase is unnecessary for detection of pancreatic adenocarcinoma. Images of the pancreas obtained in the hepatic phase with multi-detector row CT most accurately display vascular invasion.
Some reports describe an increased risk for cancer in patients with the Peutz-Jeghers syndrome.
To characterize occurrences of cancer in a large cohort of patients with the Peutz-Jeghers syndrome.
...Retrospective cohort study.
Tertiary care center.
34 patients with the Peutz-Jeghers syndrome identified from Mayo Clinic records from 1945 to 1996.
Cases of cancer documented by chart review and telephone follow-up.
26 cases of noncutaneous cancer developed in 18 of the 34 patients: 10 cases of gastrointestinal cancer and 16 cases of extraintestinal cancer. With the use of SEER (Surveillance, Epidemiology, and End Results) data for comparison, the relative risk for cancer was 18.5 (95% CI, 8.5 to 35.2) in women with the Peutz-Jeghers syndrome and 6.2 (CI, 2.5 to 12.8) in men with the syndrome (P = 0.001). In women, the relative risk for breast and gynecologic cancer was 20.3 (CI, 7.4 to 44.2).
The Peutz-Jeghers syndrome is associated with an increased risk for cancer. The relative risk for breast and gynecologic cancers is particularly high.
To clarify clinicopathologic features of idiopathic chronic pancreatitis with lymphoplasmacytic infiltration, we carried out a study of 35 cases. There were two histologic groups, which we have ...designated lymphoplasmacytic sclerosing pancreatitis and idiopathic duct-centric chronic pancreatitis. Lymphoplasmacytic sclerosing pancreatitis (22 cases) was a fibrosing process with diffuse lymphoplasmacytic infiltrates involving pancreatic lobules and ducts, adipose tissue, blood vessels, and common bile duct. Obliterative phlebitis was found in every case except for one. The histologic features were similar to other idiopathic fibrosclerosing disorders, and one patient also had retroperitoneal fibrosis. Affected patients tended to be elderly men. Idiopathic duct-centric chronic pancreatitis (13 cases) was characterized by inflammatory infiltrates (including neutrophils) that were denser in the lobules than in interlobular fibrotic areas. Neutrophils were also prominent in the ducts, and destruction of the duct epithelium was commonly seen. Patient ages were more broadly distributed than in lymphoplasmacytic sclerosing pancreatitis. Two patients had inflammatory bowel disease. We conclude that idiopathic chronic pancreatitis with lymphoplasmacytic infiltration, sometimes called autoimmune pancreatitis, consists of at least two different processes. One of these, lymphoplasmacytic sclerosing pancreatitis, is a histologically unique lesion and could be a pancreatic manifestation of idiopathic fibrosclerosing disorders.
PDF
