Showing papers by "James G. Kench published in 2013"

The International Society of Urological Pathology (ISUP) Vancouver classification of renal neoplasia

Abstract: The classification working group of the International Society of Urological Pathology consensus conference on renal neoplasia was in charge of making recommendations regarding additions and changes to the current World Health Organization Classification of Renal Tumors (2004). Members of the group performed an exhaustive literature review, assessed the results of the preconference survey and participated in the consensus conference discussion and polling activities. On the basis of the above inputs, there was consensus that 5 entities should be recognized as new distinct epithelial tumors within the classification system: tubulocystic renal cell carcinoma (RCC), acquired cystic disease-associated RCC, clear cell (tubulo) papillary RCC, the MiT family translocation RCCs (in particular t(6;11) RCC), and hereditary leiomyomatosis RCC syndrome-associated RCC. In addition, there are 3 rare carcinomas that were considered as emerging or provisional new entities: thyroid-like follicular RCC; succinate dehydrogenase B deficiency-associated RCC; and ALK translocation RCC. Further reports of these entities are required to better understand the nature and behavior of these highly unusual tumors. There were a number of new concepts and suggested modifications to the existing World Health Organization 2004 categories. Within the clear cell RCC group, it was agreed upon that multicystic clear cell RCC is best considered as a neoplasm of low malignant potential. There was agreement that subtyping of papillary RCC is of value and that the oncocytic variant of papillary RCC should not be considered as a distinct entity. The hybrid oncocytic chromophobe tumor, which is an indolent tumor that occurs in 3 settings, namely Birt-Hogg-Dube Syndrome, renal oncocytosis, and as a sporadic neoplasm, was placed, for the time being, within the chromophobe RCC category. Recent advances related to collecting duct carcinoma, renal medullary carcinoma, and mucinous spindle cell and tubular RCC were elucidated. Outside of the epithelial category, advances in our understanding of angiomyolipoma, including the epithelioid and epithelial cystic variants, were considered. In addition, the apparent relationship between cystic nephroma and mixed epithelial and stromal tumor was discussed, with the consensus that these tumors form a spectrum of neoplasia. Finally, it was thought that the synovial sarcoma should be removed from the mixed epithelial and mesenchymal category and placed within the sarcoma group. The new classification is to be referred to as the International Society of Urological Pathology Vancouver Classification of Renal Neoplasia.

The International Society of Urological Pathology (ISUP) Grading System for Renal Cell Carcinoma and Other Prognostic Parameters

Abstract: The International Society of Urological Pathology 2012 Consensus Conference made recommendations regarding classification, prognostic factors, staging, and immunohistochemical and molecular assessment of adult renal tumors. Issues relating to prognostic factors were coordinated by a workgroup who identified tumor morphotype, sarcomatoid/rhabdoid differentiation, tumor necrosis, grading, and microvascular invasion as potential prognostic parameters. There was consensus that the main morphotypes of renal cell carcinoma (RCC) were of prognostic significance, that subtyping of papillary RCC (types 1 and 2) provided additional prognostic information, and that clear cell tubulopapillary RCC was associated with a more favorable outcome. For tumors showing sarcomatoid or rhabdoid differentiation, there was consensus that a minimum proportion of tumor was not required for diagnostic purposes. It was also agreed upon that the underlying subtype of carcinoma should be reported. For sarcomatoid carcinoma, it was further agreed upon that if the underlying carcinoma subtype was absent the tumor should be classified as a grade 4 unclassified carcinoma with a sarcomatoid component. Tumor necrosis was considered to have prognostic significance, with assessment based on macroscopic and microscopic examination of the tumor. It was recommended that for clear cell RCC the amount of necrosis should be quantified. There was consensus that nucleolar prominence defined grades 1 to 3 of clear cell and papillary RCCs, whereas extreme nuclear pleomorphism or sarcomatoid and/or rhabdoid differentiation defined grade 4 tumors. It was agreed upon that chromophobe RCC should not be graded. There was consensus that microvascular invasion should not be included as a staging criterion for RCC.

Renal tumors: diagnostic and prognostic biomarkers.

Abstract: The International Society of Urological Pathology convened a consensus conference on renal cancer, preceded by an online survey, to address issues relating to the diagnosis and reporting of renal neoplasia. In this report, the role of biomarkers in the diagnosis and assessment of prognosis of renal tumors is addressed. In particular we focused upon the use of immunohistochemical markers and the approach to specific differential diagnostic scenarios. We enquired whether cytogenetic and molecular tools were applied in practice and asked for views on the perceived prognostic role of biomarkers. Both the survey and conference voting results demonstrated a high degree of consensus in participants' responses regarding prognostic/predictive markers and molecular techniques, whereas it was apparent that biomarkers for these purposes remained outside the diagnostic realm pending clinical validation. Although no individual antibody or panel of antibodies reached consensus for classifying renal tumors, or for confirming renal metastatic disease, it was noted from the online survey that 87% of respondents used immunohistochemistry to subtype renal tumors sometimes or occasionally, and a majority (87%) used immunohistochemical markers (Pax 2 or Pax 8, renal cell carcinoma [RCC] marker, panel of pan-CK, CK7, vimentin, and CD10) in confirming the diagnosis of metastatic RCC. There was consensus that immunohistochemistry should be used for histologic subtyping and applied before reaching a diagnosis of unclassified RCC. At the conference, there was consensus that TFE3 and TFEB analysis ought to be requested when RCC was diagnosed in a young patient or when histologic appearances were suggestive of the translocation subtype; whereas Pax 2 and/or Pax 8 were considered to be the most useful markers in the diagnosis of a renal primary.

Histomolecular Phenotypes and Outcome in Adenocarcinoma of the Ampulla of Vater

Abstract: Purpose Individuals with adenocarcinoma of the ampulla of Vater demonstrate a broad range of outcomes, presumably because these cancers may arise from any one of the three epithelia that converge at that location. This variability poses challenges for clinical decision making and the development of novel therapeutic strategies.

Handling and staging of renal cell carcinoma the international society of urological pathology consensus (ISUP) conference recommendations

Abstract: The International Society of Urologic Pathology 2012 Consensus Conference on renal cancer, through working group 3, focused on the issues of staging and specimen handling of renal tumors. The conference was preceded by an online survey of the International Society of Urologic Pathology members, and the results of this were used to inform the focus of conference discussion. On formal voting a Z65% majority was considered a consensus agreement. For specimen handling it was agreed that with radical nephrectomy specimens the initial cut should be made along the long axis and that both radical and partial nephrectomy specimens should be inked. It was recommended that sampling of renal tumors should follow a general guideline of sampling 1 block/cm with a minimum of 3 blocks (subject to modification as needed in individual cases). When measuring a renal tumor, the length of a renal vein/caval thrombus should not be part of the measurement of the main tumor mass. In cases with multiple tumors, sampling should include at a minimum the 5 largest tumors. There was a consensus that perinephric fat invasion should be determined by examining multiple perpendicular sections of the tumor/perinephric fat interface and by sampling areas suspicious for invasion. Perinephric fat invasion was defined as either the tumor touching the fat or extending as irregular tongues into the perinephric tissue, with or without desmoplasia. It was agreed upon that renal sinus invasion is present when the tumor is in direct contact with the sinus fat or the loose connective tissue of the sinus, clearly beyond the renal parenchyma, or if there is involvement of any endothelium-lined spaces within the renal sinus, regardless of the size. When invasion of the renal sinus is uncertain, it was recommended that at least 3 blocks of the tumor-renal sinus interface should be submitted. If invasion is grossly evident, or obviously not present (small peripheral tumor), it was agreed that only 1 block was needed to confirm the gross impression. Other recommendations were that the renal vein margin be considered positive only when there is adherent tumor visible microscopically at the actual margin. When a specimen is submitted separately as "caval thrombus, "the recommended sampling strategy is to take 2 or more sections to look for the adherent caval wall tissue. It was also recommended that uninvolved renal parenchyma be sampled by including normal parenchyma with tumor and normal parenchyma distant from the tumor. There was consensus that radical nephrectomy specimens should be examined for the purpose of identifying lymph nodes by dissection/palpation of the fat in the hilar area only; however, it was acknowledged that lymph nodes are found in <10% of radical nephrectomy specimens. Copyright

Epigenetic-induced repression of microRNA-205 is associated with MED1 activation and a poorer prognosis in localized prostate cancer

Abstract: Deregulation of microRNA (miRNA) expression can have a critical role in carcinogenesis. Here we show in prostate cancer that miRNA-205 (miR-205) transcription is commonly repressed and the MIR-205 locus is hypermethylated. LOC642587, the MIR-205 host gene of unknown function, is also concordantly inactivated. We show that miR-205 targets mediator 1 (MED1, also called TRAP220 and PPARBP) for transcriptional silencing in normal prostate cells, leading to reduction in MED1 mRNA levels, and in total and active phospho-MED1 protein. Overexpression of miR-205 in prostate cancer cells negatively affects cell viability, consistent with a tumor suppressor function. We found that hypermethylation of the MIR-205 locus was strongly related with a decrease in miR-205 expression and an increase in MED1 expression in primary tumor samples (n=14), when compared with matched normal prostate (n=7). An expanded patient cohort (tumor n=149, matched normal n=30) also showed significant MIR-205 DNA methylation in tumors compared with normal, and MIR-205 hypermethylation is significantly associated with biochemical recurrence (hazard ratio=2.005, 95% confidence interval (1.109, 3.625), P=0.02), in patients with low preoperative prostate specific antigen. In summary, these results suggest that miR-205 is an epigenetically regulated tumor suppressor that targets MED1 and may provide a potential biomarker in prostate cancer management.

Dataset for reporting of prostate carcinoma in radical prostatectomy specimens: recommendations from the International Collaboration on Cancer Reporting

Abstract: This project was designed to harmonise the Royal College of Pathologists, College of American Pathologists and Royal College of Pathologists of Australasia datasets, checklists and structured reporting protocols for examination of radical prostatectomy specimens, with the aim of producing a common, internationally agreed, evidence-based dataset for prostate cancer reporting. The International Collaboration on Cancer Reporting prostate cancer expert review panel analysed the three existing datasets, identifying concordant items and classified these data elements as 'required' (mandatory) or 'recommended' (non-mandatory), on the basis of the published literature up to August 2011. Required elements were defined as those that have agreed evidentiary support at NHMRC level III-2 or above. Consensus response values were formulated for each item. Twelve concordant pathology data elements were identified, and, on review, all but one were included as required elements for tumour staging, grading, or prediction of prognosis. There was minor discordance between the three existing datasets for another eight items, with two of these being added to the required data set. Another 11 elements with a lesser level of evidentiary support were included in the recommended dataset. This process was found to be an efficient method for producing an evidence-based dataset for prostate cancer. Such internationally agreed datasets should facilitate meaningful comparison of benchmarking data, epidemiological studies, and clinical trials.

EGFR mutant-specific immunohistochemistry has high specificity and sensitivity for detecting targeted activating EGFR mutations in lung adenocarcinoma

Abstract: Aim We assessed the diagnostic accuracy of epidermal growth factor receptor ( EGFR ) mutant-specific antibodies for detecting two common activating EGFR mutations. Methods Immunohistochemical expression of mutation-specific antibodies against EGFR exon 19 deletion E746-A750 ((c.2235_2249del15 or c.2236_2250del15, p. Glu746_Ala750del) and exon 21 L858R point mutation (c.2573T>G, p.Leu858Arg) were assessed in a cohort of 204 resected early stage node negative lung adenocarcinomas, and protein expression was compared with DNA analysis results from mass spectrometry analysis. Results Of seven cases with L858R point mutation, six were positive by immunohistochemistry (IHC). There were three false positive cases using L858R IHC (sensitivity 85.7%, specificity 98.5%, positive predictive value 66.7%, negative predictive value 99.5%). All seven E746-A750 exon 19 deletions identified by mutation analysis were positive by IHC. Four additional cases were positive for exon 19 IHC but negative by mutation analysis. The sensitivity of exon 19 IHC for E746-A750 was 100%, specificity 98.0%, positive predictive value 63.6% and negative predictive value 100%. Conclusions Mutant-specific EGFR IHC has good specificity and sensitivity for identifying targeted activating EGFR mutations. Although inferior to molecular genetic analysis of the EGFR gene, IHC is highly specific and sensitive for the targeted EGFR mutations. The antibodies are likely to be of clinical value in cases where limited tumour material is available, or in situations where molecular genetic analysis is not readily available.

Biopsy-proven brain metastases from prostate cancer: a series of four cases with review of the literature

Abstract: Prostate cancer is very common and is the second most common cause of cancer death in males in Australia; however, brain metastases are exceedingly rare. We review four cases of biopsy-proven brain metastases from prostate cancer and review the relevant literature. Three of four patients had acinar adenocarcinoma of prostate with one patient having ductal adenocarcinoma variant on histopathology. Three patients had the brain as the only site of metastatic disease. All patients underwent surgery, and three of four patients underwent adjuvant palliative radiotherapy to the brain. Brain metastases from prostate cancer are rare, but brain metastases without other sites of metastatic disease are exceedingly rare and may be more common with ductal adenocarcinoma variant.

The dilemmas of prostate cancer screening.

Abstract: MJA 199 (9) · 4 November 2013 582 The Medical Journal of Australia ISSN: 0025729X 4 November 2013 199 9 585-585 ©The Medical Journal of Australia 2013 www.mja.com.au Letters The dilemmas of prostate cancer screening TO THE EDITOR: Recent articles in the Journal reflect the continuing polarisation of the debate on prostatespecific antigen-based screening and the extent to which major clinical trials reveal whether lives are saved by intervention and/or watchful waiting.1,2 All clinical trials have limitations, and the ERSPC (European Randomized Study of Screening for Prostate Cancer)3 and the United States PLCO (Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial) are no exception.3,4 The calls by two senior authors of the ERSPC trial to evaluate only highquality studies and to avoid pooling heterogeneous data are commendable.1 However, to then argue that only their trial satisfies these criteria is scientifically questionable, since this multi-country trial is compromised precisely by this action. In the ERSPC, prostate cancer mortality data from Finland, Italy, Switzerland, Belgium and Spain showed minimal mortality differences between the screening and control arms, and were congruent with the PLCO data, in which no lives were saved by intervention. The data from Sweden and the Netherlands, however, were clearly divergent from other European countries and yet were inexplicably pooled with them. Further, no consideration was given to the equally plausible alternative of an increase in prostate cancer mortality in some control cohorts owing to their differential treatment. This would also yield fewer deaths in the screening arm, but not because of lives saved by intervention. It is therefore still premature to so boldly claim that significant numbers of lives are saved by screening. In terms of avoiding harm and maximising hope, is it not prudent to more closely and carefully scrutinise such crucial aspects of clinical trial data?

Oxidative stress is closely associated with insulin resistance in genotypes 1 and 3 chronic hepatitis C

Abstract: Chronic hepatitis C (CHC) infection is associated with insulin resistance and with oxidative stress, but the relationship between the two has not been thoroughly examined. To evaluate the association between insulin resistance and oxidative stress in CHC patients. In 115 CHC patients (68 with genotype 1 and 47 with genotype 3), the relationship between the serum concentration of malondialdehyde (MDA), a marker of oxidative stress and insulin resistance as defined by the homeostasis model (HOMA-IR) was examined. There was no significant difference in MDA levels between genotype 1- and genotype 3-infected subjects (12.882 vs. 12.426 ng/mL, p = 0.2). By univariate analysis, factors associated with HOMA-IR in both genotypes were oxidative stress as measured by MDA (p = 0.002), body mass index (BMI), portal activity, and fibrosis. Genotype-specific differences in HOMA-IR association were steatosis and triglycerides (TG) for genotype 1, and age and glutathione (GSH) for genotype 3. In a stepwise multiple linear regression analysis in both genotypes, MDA was a significant and independent predictor of HOMA-IR (p = 0.04). As expected, BMI and fibrosis were likewise independently correlated to HOMA-IR. In addition, MDA levels were higher (p < 0.001) and GSH levels were lower (p = 0.023) in insulin-resistant subjects compared to their insulin-sensitive counterparts. It is concluded that in CHC, oxidative stress is an independent predictor of HOMA-IR, irrespective of virus genotype. Further studies on the role of oxidative stress in the development of insulin resistance in CHC are warranted.

restricted miRNA antagonists of miR-27 - general and VE-cadherin Regulation of vascular leak and recovery from ischemic injury by

Abstract: doi:10.1182/blood-2012-12-473017Prepublished online September 5, 2013;2013 122: 2911-2919€€€€Geoffrey McCaughan, Mathew A. Vadas and Jennifer R. GambleTsykin, Ilana Lichtenstein, Christopher N. Hahn, Nham Tran, Nicholas Shackel, James G. Kench,Prado-Lourenco, Levon M. Khachigian, Martin Ng, Philip A. Gregory, Gregory J. Goodall, Anna Jennifer A. Young, Ka Ka Ting, Jia Li, Thorleif Moller, Louise Dunn, Ying Lu, Joshua Moses, Leonel€

Hepatobiliary and Pancreatic: Clear cell myomelanotic tumor of ligamentum teres

Abstract: A 30-year-old woman was found to have a mass in the right upper quadrant of her abdomen during a routine medical examination. The mass was non-tender and extended into the epigastrium. The mass had not resulted in any significant symptoms and she had previously been well. Various blood tests were normal including liver function tests and tumor markers including CEA, Ca19.9 and alpha fetoprotein. Various imaging studies were performed including an upper abdominal ultrasound, computed tomography (CT) and magnetic resonance imaging scans. Of these, the most helpful was CT. A non-contrast scan showed a lesion, 5 cm in diameter, with significant internal calcification. With contrast in the arterial phase, there was heterogeneous enhancement of the lesion with hypervascular areas at the periphery of the lesion surrounding a hypovascular central lesion. In addition, there was a hypervascular area in the left lobe of the liver (Figure 1). The patient was treated with an extended left hemihepatectomy. Macroscopically, the specimen was a calcified, vascular mass that appeared to arise from a pedicle originating from the ligamentum teres (Figure 2). Histologically, the mass was largely composed of spindle and oval tumor cells. These were separated from non-cirrhotic liver parenchyma by thick hyalinised collagen bands. Occasional epithelioid cells and sparse mitoses were noted. Clear cell areas were identified but the majority of cells had a lightly eosinophilic cytoplasm. Occasional foci of calcification and bone were present but there were no adipocytes. Immunohistochemical staining of the tumor demonstrated strong positivity for HMB-45 (3+) and SMA (3+). The tumor was also weakly positive for Melan A (1+). Relevant negatives included D2-40, CD31, CD34, AE1/AE3, and desmin. The immunohistochemical findings were consistent with a diagnosis of a perivascular epithelioid cell tumor (PEComa). PEComas are a group of rare mesenchymal tumors characterized by the exhibition of melanocytic and myoid differentiation. PEComa is an umbrella term encompassing a number of specific tumors including angiomyolipomas, clear cell “sugar” tumor of the lung, lymphangioleiomyomastosis, clear cell “sugar” myomelanotic tumor of the falciform ligament and ligamentum teres and clear cell tumors found in a number of varied anatomical sites. The tumor we describe lacks the finding of mature adipocytes and, as such, does not sit well within the classification of angiomyolipoma. Rather, the tumor bears similarity with isolated case reports in the literature of the extremely rare clear cell myomelanotic tumor of the ligamentum teres and falciform ligament. In the above patient, metastases were identified in the left lobe of the liver but the majority of these tumors are thought to be benign.