Browsing by Author "MacLennan, Gregory T."
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Item Distinct clinicopathological features in metanephric adenoma harboring BRAF mutation(Impact Journals, 2016-07-08) Caliò, Anna; Eble, John N.; Hes, Ondrej; Martignoni, Guido; Harari, Saul E.; Williamson, Sean R.; Brunelli, Matteo; Osunkoya, Adeboye O.; Wang, Lisha; Comperat, Eva; Lopez-Beltran, Antonio; Wang, Mingsheng; Zhang, Shaobo; Curless, Kendra L.; Post, Kristin M.; Chang, Hsim-Yee; Luchini, Claudio; Baldrige, Lee Ann; MacLennan, Gregory T.; Montironi, Rodolfo; Grignon, David J.; Cheng, Liang; Pathology and Laboratory Medicine, School of MedicineBRAF mutation recently has been reported in metanephric adenoma. We sought to determine the clinical and morphologic features of BRAF-mutated metanephric adenoma and to correlate BRAF mutation with BRAF V600E immunohistochemical staining results. A series of 48 metanephric adenomas and 15 epithelial-predominant nephroblastomas were analyzed for the occurrence of BRAF mutation (BRAF V600E/V600E complex, BRAF V600D, BRAF V600K and BRAF V600R) using the BRAF RGQ PCR kit (Qiagen). Immunohistochemistry was performed using monoclonal mouse antibodies against p16INK4 and VE1 (Spring Bioscience), recognizing the BRAF V600E mutant protein. Forty-one of 48 cases (85%) showed BRAF V600E mutation; none of the other BRAF variants was detected. Of 41 BRAF-mutated metanephric adenomas, 33 showed positive VE1 immunostaining (sensitivity 80%, specificity 100%); in all cases we detected p16INK4 expression regardless of BRAF mutation status. All epithelial-predominant nephroblastomas were BRAF-wild-type and none expressed VE1. The following features were associated with BRAF V600E mutation: older patients (p=0.01), female predominance (p=0.005) and the presence of a predominantly acinar architecture (p=0.003). In summary, BRAF-mutated metanephric adenomas were associated with older age, female predominance, and the presence of a predominant acinar component. A subset (20%) of BRAF-mutated metanephric adenomas was not detected by VE1 immunostaining.Item Distinct Mutational Landscape of Inverted Urothelial Papilloma(Wiley, 2019-09) Akgul, Mahmut; MacLennan, Gregory T.; Cheng, Liang; Pathology and Laboratory Medicine, School of MedicineA recent study has identified gene mutations involving the MAPK/ERK pathway, particularly the HRAS gene, in all inverted urothelial papillomas (IUPs), in the absence of pathway mutations in TERT promoter, FGFR3, and TP53/RB1genes. Neither recurrence nor progression was observed in IUPs. These data support several longstanding hypotheses: (1) IUPs are benign and do not recur or progress; (2) they harbor mutations that are different from those of urothelial carcinoma; and (3) they arise through different molecular mechanisms than low‐ or high‐grade urothelial carcinoma. As the most critical differential diagnosis in this context is inverted‐type urothelial carcinoma, more comprehensive studies are needed to compare and contrast these entities.Item Evidence for Polyclonal Origin of Multifocal Clear Cell Renal Cell Carcinoma(American Association of Cancer Research, 2008-12) Cheng, Liang; MacLennan, Gregory T.; Zhang, Shaobo; Wang, Mingsheng; Zhou, Ming; Tan, Puay-Hoon; Foster, Stephanie; Lopez-Beltran, Antonio; Montironi, Rodolfo; Urology, School of MedicinePurpose: Renal cell carcinomas are often multifocal. We investigated the genomic signatures of multifocal clear cell renal cell carcinoma to determine whether multiple tumors in the same kidney bear a clonal relationship to one another. Experimental Design: A total of 62 tumors from 26 patients who underwent radical nephrectomy were examined. All patients had multiple separate clear cell renal carcinomas. Loss of heterozygosity analyses were done using five microsatellite polymorphic markers that represent putative tumor suppressor genes on chromosome 3p14 (D3S1300), 7q31 (D7S522), 8p22 (D8S261), 9p21 (D9S171), and 17p13 (TP53). X chromosome inactivation analyses were also done on the renal tumors from the 10 female patients. Chromosome 3p deletion status was determined by dual color interphase fluorescence in situ hybridization analysis in all tumors. Results: Nineteen of the 26 (73%) patients with multifocal clear cell renal cell carcinoma showed allelic loss in at least 1 of 5 microsatellite loci in separate tumors analyzed. A disconcordant pattern of allelic loss between coexisting kidney tumors was observed in 7 cases. Six cases showed discordant 3p deletion patterns by dual color interphase fluorescence in situ hybridization analysis. Of the eight informative female cases studied by X chromosome inactivation, one showed a discordant nonrandom pattern of X chromosome inactivation. Overall, evidence of independent origin of the multifocal renal tumors was observed in 12 of 26 cases (46%). Conclusions: Our data suggest that in a significant number of cases of multifocal clear cell renal cell carcinoma, the spatially separate tumors are of different clonal origin and arise independently.Item Fluorescence in situ Hybridization in Surgical Pathology: Principles and Applications(Wiley, 2017) Cheng, Liang; Zhang, Shaobo; Wang, Lisha; MacLennan, Gregory T.; Davidson, Darrell D.; Department of Pathology and Laboratory Medicine, IU School of MedicineIdentification of recurrent tumour-specific chromosomal translocations and novel fusion oncogenes has important diagnostic, therapeutic and prognostic implications. Over the past decade, fluorescence in situ hybridization (FISH) analysis of tumour samples has been one of the most rapidly growing areas in genomic medicine and surgical pathology practice. Unlike traditional cytogenetics, FISH affords a rapid analysis of formalin-fixed, paraffin-embedded cells within a routine pathology practice workflow. As more diagnostic and treatment decisions are based on results of FISH, demand for the technology will become more widespread. Common FISH-detected alterations are chromosome deletions, gains, translocations, amplifications and polysomy. These chromosome alterations may have diagnostic and therapeutic implications for many tumour types. Integrating genomic testing into cancer treatment decisions poses many technical challenges, but rapid progress is being made to overcome these challenges in precision medicine. FISH assessment of chromosomal changes relevant to differential diagnosis and cancer treatment decisions has become an important tool for the surgical pathologist. The aim of this review is to provide a theoretical and practical survey of FISH detected translocations with a focus on strategies for clinical application in surgical pathology practice.Item GATA3 expression in clear cell adenocarcinoma of the lower urinary tract: a potential diagnostic pitfall(Springer, 2022-11-01) Akgul, Mahmut; Humble, Robert; Osme, Abdullah; Yuce, Servet; Kocak, Elif N.; Najafzade, Parisa; Sangoi, Ankur; Pattnaik, Niharika; Mishra, Sourav; Sharma, Shivani; Shaker, Nada; Kaushal, Seema; Baisakh, Manas; Lightle, Andrea R.; Balzer, Bonnie L.; Xiao, Guang-Qian; MacLennan, Gregory T.; Osunkoya, Adeboye O.; Parwani, Anil; Cheng, Liang; Bellizzi , Andrew; Mohanty, Sambit K.; Pathology and Laboratory Medicine, School of MedicineBackground Clear cell adenocarcinoma of the lower urinary tract (CCACLUT) is a rare primary malignant neoplasm with heterogenous morphology. There is a paucity of data in the literature regarding its immunohistochemical profile. Methods The immunohistochemical features (extent and intensity) of a multinational cohort of CCACLUT were evaluated with comparison between clear cell adenocarcinoma of the female genital tract (CCACFGT, tissue microarray) and nephrogenic adenoma (NA). Results 33 CCACLUT (24 female, 9 male; mean age 59 years) were collected. CCACLUT most commonly arose from the urinary bladder (26/33, 78%), particularly from the trigone (10/33, 30.3%) followed by the urethra (8/33, 22%). All 12 NA cases were located at the urinary bladder, whereas the most common CCACFGT location was the ovary (29/56, 52%). None of the CCACLUT patients had, intestinal metaplasia, NA, or urothelial carcinoma. One patient had concurrent endometriosis of the sigmoid colon. Most frequently observed morphology in CCACLUT was papillary/tubulocystic (9/3; 27.3%), followed by papillary/tubular (6/33; 18.2%) and papillary/solid (5/33; 15.2%). GATA3 expression was significantly higher in CCACLUT (18/33, 54.5%) and NA (6/12, 50%), when compared to CCACFGT cases 6/56, 11.7%)(p = 0.001 and p = 0.022, respectively). The extent of GATA3 was significantly higher in CCACLUT group (19.2 ± 16.6%) than the other groups (9.6 ± 22.5% in NA and 2.6 ± 9% in CCACFGT group) (p = 0.001). 4/33 patients (12.1) had weak, 10/33 patients (30.3%) had moderate, and 4/33 patients (12.1%) had strong GATA3 intensity in CCACLUT group. In NA group, one patient (8.3%, 1/12) had weak, one patient (8.3%, 1/12) had moderate and 4 patients (33.3%, 4/12) had strong GATA3 intensity. Most cases (CCACLUT 29/33, 88%; NA 11/12, 92%; CCACFGT 46/56, 82.1%) had positive Napsin A expression, by which CCACLUT had significantly more cases with Napsin A expression (p = 0.034). p63 was consistently negative in all cases (30/33 (91.9%) CCACLUT; 12/12 (100%) NA; 42/56 (75%) CCACFGT. Ki67 (MIB) proliferation index was significantly higher in CCACLUT group (54.6 ± 21%) when compared to NA group (4.5 ± 2.7%) and CCACFGT group (35.5 ± 25.8%) (p = 0.001). Conclusion CCACLUT has consistent GATA3 expression, which may cause challenge in the diagnosis of urothelial carcinoma but can be used to distinguish CCACLUT from CCACFGT.Item Intraductal carcinoma of the prostate is not a diagnostic entity(Wiley, 2021) Delahunt, Brett; Egevad, Lars; Samaratunga, Hemamali; Srigley, John R.; Cheng, Liang; Clouston, David; Furusato, Bungo; Kench, James; Leite, Katia R. M.; MacLennan, Gregory T.; Moch, Holger; Pan, Chin-Chen; Ro, Jae; Tsuzuki, Toyonori; van der Kwast, Theodorus; Wheeler, Thomas; Yaxley, John W.; Pathology and Laboratory Medicine, School of MedicineItem Molecular testing for BRAF mutations to inform melanoma treatment decisions: a move toward precision medicine(Nature Publishing Group, 2018-01) Cheng, Liang; Lopez-Beltran, Antonio; Massari, Francesco; MacLennan, Gregory T.; Montironi, Rodolfo; Pathology and Laboratory Medicine, School of MedicineApproximately one-half of advanced (unresectable or metastatic) melanomas harbor a mutation in the BRAF gene, with V600E being the most common mutation. Targeted therapy with BRAF and MEK inhibitors is associated with significant long-term treatment benefit in patients with BRAF V600-mutated melanoma. Therefore, molecular testing for BRAF mutations is a priority in determining the course of therapy. A literature search was performed using MEDLINE/PubMed and scientific congress databases using the terms 'BRAF,' 'mutation,' and 'cancer/tumor.' These results were filtered to include manuscripts that focused on diagnostic tests for determining BRAF mutation status. Numerous BRAF testing methods were identified, including DNA-based companion diagnostic tests and DNA- and protein-based laboratory-developed tests. Herein we review the characteristics of each method and highlight the strengths and weaknesses that should be considered before use and when interpreting results for each patient. Molecular profiling has shown that mutation load increases with melanoma tumor progression and that unique patterns of genetic changes and evolutionary trajectories for different melanoma subtypes can occur. Discordance in the BRAF mutational status between primary and metastatic lesions, as well as intratumoral heterogeneity, is known to occur. Additionally, the development of acquired resistance to combination BRAF and MEK inhibitor therapy is still a formidable obstacle. Therefore, tumor heterogeneity and the development of acquired resistance have important implications for molecular testing and ultimately the treatment of patients with advanced-stage melanoma. Overall, this information may help community oncologists more accurately and effectively interpret results of diagnostic tests within the context of recent data characterizing melanoma tumor progression.Item Solitary fibrous tumour of the genitourinary tract: a clinicopathological study of 11 cases and their association with the NAB2-STAT6 fusion gene(BMJ, 2017) Kouba, Erik; Simper, Novae B.; Chen, Shaoxiong; Williamson, Sean R.; Grignon, David J.; Eble, John N.; MacLennan, Gregory T.; Montironi, Rodolfo; Lopez-Beltran, Antonio; Osunkoya, Adeboye O.; Zhang, Shaobo; Wang, Mingsheng; Wang, Lisha; Tran, Thu; Emerson, Robert E.; Baldridge, Lee Ann; Monn, M. Francesca; Linos, Konstantinos; Cheng, Liang; Department of Pathology and Laboratory Medicine, School of MedicineAims To characterise clinicopathological features and clinical outcomes of the genitourinary tract solitary fibrous tumours, incorporating NAB2-STAT6 gene fusion status. Methods The presence of the molecular hallmark NAB2-STAT6 gene fusion and for the defining fusion partner product STAT6 was assessed in 11 cases of the genitourinary tract solitary fibrous tumours. NAB2-STAT6 gene fusion analysis was performed using a break-apart fluorescence in situ hybridisation (FISH) probe using a probe cocktail with Bacterial artificial chromosome (BAC) clones for STAT6 and NAB2. Results Eleven solitary fibrous tumours were diagnosed in eight male patients and three female patients with a mean age of 46 years (range: 11–64 years). Four of the tumours had malignant histological features, and three were considered moderate risk for metastasis. With a mean follow-up time of 61 months, 1 recurred locally and 2 presented at distant metastatic sites. Using a break-apart FISH probe cocktail, we found the NAB2-STAT6 gene fusion and nuclear STAT6 expression in 58% and 91% of cases, respectively. However, the NAB2-STAT6 fusion status was not correlated with STAT6 expression or useful in discriminating between malignant histological features or subsequent clinical outcomes in the genitourinary solitary fibrous tumours. Conclusions A subset of solitary fibrous tumours of the genitourinary tract behaved aggressively. Using a break-apart FISH probe cocktail, we found the NAB2-STAT6 gene fusion in 64% of cases. However, the NAB2-STAT6 fusion status was not correlated with STAT6 expression or useful in discriminating between low-risk or high-risk tumours and subsequent clinical outcomes.Item TMPRSS2-ERG gene fusion is rare compared to PTEN deletions in stage T1a prostate cancer(Wiley, 2016-03) Fisher, Kurt W.; Zhang, Shaobo; Wang, Mingsheng; Montironi, Rodolfo; Wang, Lisha; Baldridge, Lee Ann; Wang, Jonas Y.; MacLennan, Gregory T.; Williamson, Sean R.; Lopez-Beltran, Antonio; Cheng, Liang; Department of Pathology and Laboratory Medicine, IU School of MedicineT1a prostate cancers (cancer found incidentally in transurethral resection, <5% of the tissue) are indolent tumors of the transition zone. The overexpression of ERG and the inactivation of PTEN have been shown to be important drivers of carcinogenesis in large series of prostate cancer, but the genetics of transition zone tumors have not been well characterized. We evaluated the status of ERG and PTEN in formalin-fixed paraffin-embedded tissue using immunohistochemical and FISH analysis in 54 T1a transition zone tumors. The protein expression of ERG was determined using a rabbit monoclonal antibody and nuclear staining was scored as positive or negative. The genomic status of ERG was determined using three colored FISH using an ERG-TMPRSS2 tri-color probe set. The protein expression of PTEN was determined using a rabbit monoclonal antibody and cytoplasmic, and nuclear staining was scored as positive or negative. The genomic status of PTEN was determined using dual color FISH with a PTEN probe and a CEP10 probe. We found ERG rearrangement in 2 of 54 tumors (4%), one with protein overexpression by immunohistochemistry. PTEN inactivation was seen in 13 of 54 tumors (24%). Nine of the 13 PTEN alleles were inactivated by hemizygous deletion. No homozygous PTEN deletion was observed. PTEN deletion and ERG rearrangement were mutually exclusive. ERG rearrangement was rare compared to peripheral zone tumors and to PTEN inactivation in T1a transition zone tumors.