HER2 gene amplification and EGFR expression in a large cohort of surgically staged patients with nonendometrioid (type II) endometrial cancer.

Type II endometrial cancers (uterine serous papillary and clear cell histologies) represent rare but highly aggressive variants of endometrial cancer (EC). HER2 and EGFR may be differentially expressed in type II EC. Here, we evaluate the clinical role of HER2 and EGFR in a large cohort of surgically staged patients with type II (nonendometrioid) EC and compare the findings with those seen in a representative cohort of type I (endometrioid) EC. In this study HER2 gene amplification was studied by fluorescence in situ hybridisation (FISH) and EGFR expression by immunohistochemistry. Tissue microarrays were constructed from 279 patients with EC (145 patients with type I and 134 patients with type II EC). All patients were completely surgically staged and long-term clinical follow up was available for 258 patients. The rate of HER2 gene amplification was significantly higher in type II EC compared with type I EC (17 vs 1%, P<0.001). HER2 gene amplification was detected in 17 and 16% of the cases with uterine serous papillary and clear cell type histology, respectively. In contrast, EGFR expression was significantly lower in type II compared with type I EC (34 vs 46%, P=0.041). EGFR expression but not HER2 gene amplification was significantly associated with poor overall survival in patients with type II EC, (EGFR, median survival 20 vs 33 months, P=0.028; HER2, median survival 18 vs 29 months, P=0.113) and EGFR expression retained prognostic independence when adjusting for histology, stage, grade, and age (EGFR, P=0.0197; HER2, P=0.7855). We conclude that assessment of HER2 gene amplification and/or EGFR expression may help to select type II EC patients who could benefit from therapeutic strategies targeting both HER2 and EGFR.

Factors that influence the measurement of prostate cancer DNA ploidy and proliferation in paraffin embedded tissue evaluated by flow cytometry.

DNA ploidy and proliferation have been shown in several studies to be prognostic markers for prostate cancer. Flow cytometry (FCM) is often used in the determination of ploidy and proliferation. However, FCM cannot readily distinguish among benign epithelium, stromal and inflammatory cells, high grade prostatic intraepithelial neoplasia (HGPIN), and cancer cells. In this study, we evaluated H&E histologic features of 322 radical prostatectomy formalin-fixed, paraffin-embedded tissue blocks used for determining DNA ploidy, percent S-phase (%S), and %S + %G2M by FCM. The microscopic findings included Gleason score, extent of cancer and HGPIN in the tissue block, and presence of a needle track. The amount of cancer in the block was expressed as a percentage of the total tissue surface area in quartiles: < or =25%, 26-50%, 51-75%, and > or =76%. The extent of HGPIN was recorded in rough 5% intervals. Needle track effect was defined as a combination of fibrohistiocytic reaction, fibrin clot, granuloma formation, and chronic inflammation. The associations between these histologic features and DNA ploidy and proliferation (%S and %S + %G2M) were assessed. In multivariate analyses, Gleason score, the amount of tumor in the tissue block, and the extent of HGPIN were significantly associated with ploidy. Gleason score was the only parameter significantly associated with the proliferation measure of %S. If we included %G2M as part of the proliferative fraction of the histogram, however, both Gleason score and the amount of tumor in the block were significantly associated with this measure of proliferation. The presence of a needle track was not significantly associated with DNA ploidy, %S, or %S + %G2M. In summary, prostate cancer DNA ploidy and proliferation results assessed by FCM in paraffin-embedded tissue blocks were associated with the Gleason score, amount of cancer in the tissue block, and extent of HGPIN. However, the presence of a needle track was not associated with the FCM results.

Predicting prostate carcinoma volume and stage at radical prostatectomy by assessing needle biopsy specimens for percent surface area and cores positive for carcinoma, perineural invasion, Gleason score, DNA ploidy and proliferation, and preoperative serum prostate specific antigen: a report of 454 cases.

BACKGROUND: DNA ploidy analysis of prostate carcinoma is a generally accepted prognostic marker, particularly when tumors are extraprostatic at the time of surgery. In the past decade, the DNA content of prostate carcinoma frequently has been assessed in needle biopsy specimens based on the assumption that ploidy, in conjunction with serum prostate specific antigen (PSA) and Gleason score, provides valuable pretreatment information. METHODS: Between 1995 and 1998, the authors identified a consecutive series of 454 prostate carcinomas, verified by needle biopsies and followed by radical retropubic prostatectomies (RRP). Based on the needle biopsies, DNA ploidy and MIB-I immunostaining were measured by digital image analysis (DIA). The authors also quantified the percent of nuclei in four categories from the DNA histograms. The DIA data were combined with the age of the patient at diagnosis, the serum PSA, Gleason score, percent cores and percent surface area positive for carcinoma, and status of perineural invasion in multivariate models using tumor volume and risk of extraprostatic extension (EPE) at RRP as the outcome variables. RESULTS: Joint predictors of tumor volume at RRP were the percent cores positive for carcinoma (P < 0.0001), serum PSA (P < 0.0001), the percent surface area positive for carcinoma (P < 0.0001), and the percent nuclei classified by DNA quantification to be in the "S-phase" category (P = 0.03). Joint predictors of risk of EPE were the percent cores positive for carcinoma (P = 0.0004), a Gleason score of 7 (P < 0.0001), a Gleason score of 8 or 9 (P < 0.0001), serum PSA (P = 0.006) and perineural invasion (P = 0.02). CONCLUSIONS: After adjusting for traditional prognostic markers, DNA ploidy interpretation and MIB-I quantitation of prostate carcinoma did not appear to jointly predict either outcome variable in the multivariate models. However, a quantitative measure related to both ploidy and proliferation, the percent of nuclei in the putative "S-phase" category from the DIA histograms, was found to jointly predict for tumor volume.

Extent of high-grade dysplasia in Barrett's esophagus correlates with risk of adenocarcinoma.

BACKGROUND & AIMS: The identification 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.

Inverted urothelial papilloma: is ploidy, MIB-1 proliferative activity, or p53 protein accumulation predictive of urothelial carcinoma?

BACKGROUND: Inverted urothelial papilloma is an unusual neoplasm of the urinary tract. Although the association between inverted urothelial papilloma and urothelial carcinoma is not entirely clear, many studies indicate that patients with inverted papilloma are at increased risk for the development of urothelial carcinoma. In addition, aneuploid inverted papillomas have been associated with the subsequent development of urothelial carcinoma. The objective of this study was to determine whether ploidy, MIB-1 proliferative activity, or p53 protein staining in inverted papilloma were predictive of urothelial carcinoma. METHODS: Fifty-one cases of inverted papilloma were retrieved from the Tissue Registry of the Mayo Clinic. Clinical records were reviewed for patient age, length of follow-up, and history of urothelial carcinoma (defined as carcinoma prior to, concurrent with, or subsequent to the diagnosis of inverted papilloma). DNA ploidy analysis was determined using Feulgen stained sections from paraffin embedded tissues using an image analysis system. Quantitation of MIB-1 proliferative activity and p53 immunostaining was determined similarly using immunoperoxidase stained sections from paraffin embedded tissues. RESULTS: The mean age at diagnosis of inverted papilloma was 63.9 years (range, 37-87 years), and there were 39 men and 12 women. Patients were followed for a mean of 56.5 months (range, 1-252 months). Tumors ranged in size from 0.2 to 4.3 cm (mean, 0.9 cm). Eight patients (15.7%) had a prior, concurrent, or subsequent noninvasive World Health Organization and International Society of Urologic Pathology (WHO/ISUP) papillary neoplasm of low malignant potential or papillary carcinoma of low grade (formerly WHO Grade 1 or 2 papillary urothelial carcinoma). Inverted papillomas in patients with a history of urothelial carcinoma were all diploid and had a mean MIB-1 activity of 6.3% (range, 0.04-24.8%) and mean p53 protein staining of 12.6% (range, 0.5-24.9%). These inverted papillomas ranged in size from 0.3 to 1.0 cm (mean, 0.5 cm). Inverted papillomas in patients without a history of urothelial carcinoma were aneuploid in 6 cases (14.3%) and diploid in the remaining cases. These inverted papillomas had a mean MIB-1 activity of 1.6% (range, 0.06-9.0%) and mean p53 protein staining of 9.7% (range, 0.05-38.0%). Tumor size ranged from 0.2 to 4.3 cm (mean, 1.0 cm). There were no statistically significant differences in MIB-1 activity, p53 protein staining, ploidy, and morphologic features between inverted papillomas in patients with and without a history of urothelial carcinoma. CONCLUSIONS: Ploidy, MIB-1 proliferative activity, and p53 immunostaining in inverted urothelial papilloma were not useful in identifying patients who had a history of urothelial carcinoma.