Adjunctive radiofrequency ablation of metastatic neuroendocrine cancer to the liver complements surgical resection.

BACKGROUND: Resection of liver metastases from neuroendocrine cancer (NEC) prolongs survival and provides durable symptom relief. Not all hepatic lesions are amenable to resection, particularly when there is multifocal involvement. In this study, it was hypothesized that ablation of concomitant non-resectable NEC liver metastases is safe and salvages patients who would not have been selected for cytoreductive surgery. METHODS: Patients who underwent adjuvant ablation of NEC liver metastases between 1995 and 2008 were reviewed. NEC was classified by patient and tumour characteristics. Regression and Kaplan-Meier models were used to compare variables and generate survival curves. RESULTS: Ninety-four patients underwent hepatic resection and intra-operative ablation of metastatic NEC. The median number of lesions ablated was 3, and median size was 1.4 cm. One abscess occurred at an ablation site. Local recurrence was detected in four patients (3.8%). Overall survival was 80% and 59% at 5 and 10 years. Age, gender, tumour type, grade, primary site and need for repeat ablation had no significant association with survival. The Ki67 proliferative index was a significant predictor of decreased survival. Symptom-free survival was 34% at 3 years and 16% at 5 years, independent of the tumour grade. CONCLUSION: Concurrent ablation of NEC metastases to the liver not amenable to resection is safe and increases the candidacy of patients for cytoreductive surgery. Ablation performed intra-operatively and repeated post-operatively as needed provides significant symptom control regardless of the tumour grade.

Comparison of methods to detect neoplasia in patients undergoing endoscopic ultrasound-guided fine-needle aspiration.

BACKGROUND & AIMS: Digital image analysis (DIA) and fluorescence in situ hybridization (FISH) can be used to evaluate biliary strictures with greater accuracy than conventional cytology (CC). We performed a prospective evaluation of the accuracy of CC, compared with that of DIA and FISH, in detection of malignancy in patients undergoing endoscopic ultrasonography (EUS) fine-needle aspiration (FNA). METHODS: We collected a minimum of 6 FNA samples from each of 250 patients during EUS. CC or DIA and FISH analyses were performed on every other specimen (from every other FNA pass); patients were randomly assigned to the first test performed. CC slides were reviewed by gastrointestinal cytopathologists who were blinded to all data. Findings from cytohistologic analysis, after a minimum 24-month follow-up period, were used as the standard (n = 202; median age, 65 years). RESULTS: Aspirates were collected from lymph nodes (n = 111), pancreas (n = 61), gastrointestinal lumen wall (n = 9), periluminal mass (n = 4), liver (n = 8), and miscellaneous sites (n = 9). Matched samples provided a mean of 3.2 passes for CC and 1.6 passes for DIA and FISH. The data indicate a potential lack of utility for DIA. The combination of CC and FISH detected malignancy with 11% greater sensitivity than CC alone (P = .0002), but specificity was reduced from 100% to 96%. CONCLUSIONS: FISH analysis identifies neoplastic lesions with significantly greater sensitivity than CC in patients with diverse pathologies who underwent EUS with FNA, despite limited tissue sampling for FISH analysis.

Assessment of hepatocyte growth factor in ovarian cancer mortality.

BACKGROUND: Invasive ovarian cancer is a significant cause of gynecologic cancer mortality. METHODS: We examined whether this mortality was associated with inherited variation in approximately 170 candidate genes/regions [993 single-nucleotide polymorphisms (SNPs)] in a multistage analysis based initially on 312 Mayo Clinic cases (172 deaths). Additional analyses used The Cancer Genome Atlas (TCGA; 127 cases, 62 deaths). For the most compelling gene, we immunostained Mayo Clinic tissue microarrays (TMA, 326 cases) and conducted consortium-based SNP replication analysis (2,560 cases, 1,046 deaths). RESULTS: The strongest initial mortality association was in HGF (hepatocyte growth factor) at rs1800793 (HR = 1.7, 95% CI = 1.3-2.2, P = 2.0 × 10(-5)) and with overall variation in HGF (gene-level test, P = 3.7 × 10(-4)). Analysis of TCGA data revealed consistent associations [e.g., rs5745709 (r(2) = 0.96 with rs1800793): TCGA HR = 2.4, CI = 1.4-4.1, P = 2.2 × 10(-3); Mayo Clinic + TCGA HR = 1.6, CI = 1.3-1.9, P = 7.0 × 10(-5)] and suggested genotype correlation with reduced HGF mRNA levels (P = 0.01). In Mayo Clinic TMAs, protein levels of HGF, its receptor MET (C-MET), and phospho-MET were not associated with genotype and did not serve as an intermediate phenotype; however, phospho-MET was associated with reduced mortality (P = 0.01) likely due to higher expression in early-stage disease. In eight additional ovarian cancer case series, HGF rs5745709 was not associated with mortality (HR = 1.0, CI = 0.9-1.1, P = 0.87). CONCLUSIONS: We conclude that although HGF signaling is critical to migration, invasion, and apoptosis, it is unlikely that HGF genetic variation plays a major role in ovarian cancer mortality. Furthermore, any minor role is not related to genetically-determined expression. IMPACT: Our study shows the utility of multiple data types and multiple data sets in observational studies.

Comparison of fluorescence in situ hybridization, p57 immunostaining, flow cytometry, and digital image analysis for diagnosing molar and nonmolar products of conception.

Pathologic examination of products of conception (POC) is used to differentiate hydropic abortus (HA), partial hydatidiform mole (PM), and complete hydatidiform mole (CM). Histologic classification of POC specimens can be difficult, and ancillary testing is often required for a definitive diagnosis. This study evaluated 66 POC specimens by flow cytometry, digital image analysis, p57 immunohistochemical analysis, and fluorescence in situ hybridization (FISH). The final diagnosis, based on the combined analysis of all test results, included 33 HAs, 24 PMs, and 9 CMs. The p57 immunostain identified 9 CMs that were evaluated as nontriploid by all other techniques. FISH seems to have the best accuracy (100%) for determining whether a specimen contains a triploid chromosome complement. These data suggest that the combination of p57 and FISH seems to be the best ancillary testing strategy to aid pathologists in the appropriate identification of CM, PM, and HA in POC specimens.

Comparison of p16INK4a and ProEx C immunostaining on cervical ThinPrep cytology and biopsy specimens.

ProEx C and p16(INK4a) staining of cytology/histology specimens have recently been explored to help distinguish high-grade squamous intraepithelial lesions (HSIL) from benign mimics. The goal of this study was to evaluate the performance characteristics of p16 and ProEx C in tissue and patient matched ThinPrep liquid-based cytology specimens. Residual cervical ThinPrep cytology specimens and tissue blocks (N = 64) from 63 patients were stained with p16 and ProEx C. Review of immunostained material, Papanicolaou and H&E stained slides was performed by two cytopathologists. The cytology slides were evaluated for the presence or absence of squamous atypia as well as immunoreactivity. Histologic specimens were interpreted as negative, indeterminate, or positive for each immunostain. There was 86% agreement (55/64) between the p16 and ProEx C stains on tissue specimens. Eleven specimens were interpreted as positive for both stains. All had a low- or high-grade squamous lesion on the corresponding H&E section. ProEx C was able to identify four low-grade squamous intraepithelial lesion specimens that were interpreted as negative by p16. All four HSIL specimens demonstrated p16 and ProEx C staining. However, 84% of cytology negative specimens demonstrated false-positive staining. Clinical utilization of both stains, combined with morphologic features, may be beneficial for confirming HSIL on histologic specimens. ProEx C and/or p16 immunostains may lead to a false-positive result in cytology specimens due to staining of normal appearing cells.

A multivariable model using advanced cytologic methods for the evaluation of indeterminate pancreatobiliary strictures.

BACKGROUND & AIMS: Ancillary cytologic tests including digital image analysis (DIA) and fluorescence in situ hybridization (FISH) have been developed to improve the sensitivity of routine cytology (RC) for the diagnosis of malignancy in pancreatobiliary strictures. The goal of this study was to retrospectively compare the performance of RC, DIA, and FISH on clinical brushing specimens. METHODS: Endoscopic retrograde cholangiopancreatography brushings were obtained from 498 consecutive patients with pancreatobiliary strictures and analyzed by RC, DIA, and FISH as per standard practice. RC diagnostic categories included negative, atypical, suspicious, or positive. Aneuploid/tetraploid histograms were considered positive for DIA. FISH was performed using UroVysion (Abbott Molecular, Inc, Des Plaines, IL) and classified as negative, trisomy, tetrasomy, or polysomy. RESULTS: The sensitivity of polysomy FISH (42.9%) was significantly higher than RC (20.1%) when equivocal RC results were considered negative (P < .001) with identical specificity (99.6%). There was a significant difference in time for diagnosis of carcinoma between FISH diagnostic categories (P < .001) and between RC diagnostic categories (P < .001). Logistic regression analysis revealed that polysomy FISH, trisomy FISH, suspicious cytology, primary sclerosing cholangitis status, and age were associated with carcinoma (P < .05). CONCLUSIONS: Polysomy FISH had high sensitivity without compromise to specificity. DIA was not a significant independent predictor of malignancy. Multivariable modeling using RC, FISH, age, and primary sclerosing cholangitis status can be used to estimate the probability of carcinoma for an individual patient. We recommend including FISH as a routine test where available, along with RC, in the evaluation of indeterminate pancreatobiliary strictures.

A study of the reproducibility of a fluorescence in situ hybridization bladder cancer detection assay.

OBJECTIVE: To assess the reproducibility of the UroVysion fluorescence in situ hybridization (FISH) bladder cancer detection assay. STUDY DESIGN: Thirteen specimens (2 negative, 3 low-level positive [1-10% abnormal cells], 5 mid-level positive [11-75%], and 3 high-level positive [>75%]) were analyzed by 7 cytotechnologists. Each cytotechnologist rendered an overall diagnosis of positive or negative and determined the percentage of abnormal urothelial cells for all positive specimens. RESULTS: The interobserver reproducibility of the assay was 100% for mid-level and high-level positive specimens, 93% for negative specimens, and 78% for low-level positive specimens. The range of percent abnormal determinations was highest for mid-level positive specimens, with mean SDs of 1.8%, 16.4% and 10.1% for the low-, mid-, and high-level positives, respectively. CONCLUSION: There was a high level of reproducibility among the mid- and high-level positive specimens. The reproducibility for low-level positive specimens was lowest, suggesting that such specimens should be reviewed by a second technologist to ensure an accurate diagnosis. The findings of this study are important for further elucidating the clinical value of quantitative FISH analysis in the management of patients undergoing FISH testing for bladder cancer.