Emily Chan

All Publications

• Artificial Intelligence-Based PTEN Loss Assessment as an Early Predictor of Prostate Cancer Metastasis After Surgery: a Multi-Center Retrospective Study. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc Patel, P., Harmon, S., Iseman, R., Ludkowski, O., Auman, H., Hawley, S., Newcomb, L. F., Lin, D. W., Nelson, P. S., Feng, Z., Boyer, H. D., Tretiakova, M. S., True, L. D., Vakar-Lopez, F., Carroll, P. R., Cooperberg, M. R., Chan, E., Simko, J., Fazli, L., Gleave, M., Hurtado-Coll, A., Thompson, I. M., Troyer, D., McKenney, J. K., Wei, W., Choyke, P. L., Bratslavsky, G., Turkbey, B., Siemens, D. R., Squire, J., Peng, Y. P., Brooks, J. D., Jamaspishvili, T. 2023: 100241

  Abstract

  Phosphatase and tensin homolog (PTEN) loss associates to adverse outcomes in prostate cancer and can be measured via immunohistochemistry (IHC). The purpose of the study was to establish the clinical application of an in-house developed artificial intelligence (AI) image analysis workflow for automated detection of PTEN loss on digital images for identifying patients at risk of early recurrence and metastasis. Post-surgical tissue microarray sections from the Canary Foundation (n=1264) stained with anti-PTEN antibody were evaluated independently by pathologist conventional visual scoring (cPTEN) and an automated AI-based image analysis pipeline (AI-PTEN). The relationship of PTEN evaluation methods with cancer recurrence and metastasis was analyzed using multivariable Cox proportional hazard and decision curve models. Both cPTEN scoring by pathologist and quantification of PTEN loss by AI (High-Risk AI-qPTEN) were significantly associated to shorted MFS in univariable analysis (cPTEN HR: 1.54, CI:1.07-2.21, p=0.019; AI-qPTEN HR: 2.55, CI:1.83,3.56), p<0.001). In multivariable analyses, AI-qPTEN showed a statistically significant association with shorter metastasis-free survival (MFS) (HR:2.17, CI:1.49-3.17, p<0.001) and recurrence-free survival (HR:1.36, CI:1.06-1.75, p=0.016) when adjusting for relevant post-surgical clinical nomogram (CAPRA-S) while cPTEN does not show a statistically significant association (HR:1.33, CI:0.89-2, p=0.2 and HR:1.26, CI:0.99-1.62, p=0.063, respectively) when adjusting for CAPRA-S risk stratification. More importantly, AI-qPTEN was associated with shorter MFS in patients with favorable pathological stage and negative surgical margins (HR: 2.72, CI:1.46-5.06, p=0.002). Workflow also demonstrated enhanced clinical utility in decision curve analysis, more accurately identifying men who might benefit from adjuvant therapy post-surgery. This study demonstrates the clinical value of an affordable and fully automated AI-powered PTEN assessment for evaluating the risk of developing metastasis or disease recurrence after radical prostatectomy. Adding AI-qPTEN assessment workflow to clinical variables may affect post-operative surveillance or management options, particularly in low-risk patients.

  View details for DOI 10.1016/j.modpat.2023.100241

  View details for PubMedID 37343766

• IgG4-Related Prostatitis: A Potentially Underappreciated Finding for Pathologists. International journal of surgical pathology Sangoi, A. R., Maclean, F., Myint, E., Chan, E. 2023: 10668969231171659

  View details for DOI 10.1177/10668969231171659

  View details for PubMedID 37143307

• Current Practices in Prostate Pathology Reporting: Results From A Survey of Genitourinary Pathologists Williamson, S., Alaghehbandan, R., Amin, A., Amin, M., Aron, M., Brimo, F., Chan, E., Cheng, L., Colecchia, M., Dhillon, J., Downes, M., Evans, A., Harik, L., Hassan, O., Haider, A., Humphrey, P., Jha, S., Kandukuri, S., Kao, C., Kaushal, S., Khani, F., Kryvenko, O., Kweldam, C., Lal, P., Lobo, A., Maclean, F., Magi-Galluzzi, C., Mehra, R., Menon, S., Miyamoto, H., Mohanty, S., Montironi, R., Nesi, G., Netto, G., Nguyen, J., Nourieh, M., Osunkoya, A., Paner, G., Sangoi, A., Shah, R., Srigley, J., Tretiakova, M., Troncoso, P., Trpkov, K., Van Der Kwast, T., Zhang, M., Zynger, D., Giannico, G. ELSEVIER SCIENCE INC. 2023: S826-S827

  View details for Web of Science ID 000990969801345

• Clear Cell Renal Cell Carcinoma with Focal Psammomatous Calcifications: A Rare Occurrence Mimicking Translocation Carcinoma. Histopathology Sangoi, A. R., Al-Obaidy, K. I., Cheng, L., Kao, C., Chan, E., Sadasivan, S., Levin, A. M., Alvarado-Cabrero, I., Kunju, L. P., Mehra, R., Mannan, R., Wang, X., Dhillon, J., Tretiakova, M., Smith, S. C., Hes, O., Williamson, S. R. 2022

  Abstract

  AIMS: Renal cell carcinoma (RCC) with clear cells and psammoma-like calcifications would often raise suspicion for MITF family translocation RCC. However, we have rarely encountered tumors consistent with clear cell RCC that contain focal psammomatous calcifications.METHODS & RESULTS: We identified clear cell RCCs with psammomatous calcifications from multiple institutions and performed immunohistochemistry and fluorescence and RNA in situ hybridization (FISH and RNA ISH). Twenty-one tumors were identified: 12 men, 9 women, ages 45 to 83years. Tumor size was 2.3 to 14.0 cm (median 6.75 cm). Nucleolar grade was 3 (n=14), 2 (n=4), or 4 (n=3). In addition to clear cell pattern, morphology included eosinophilic (n=12), syncytial giant cell (n=4), rhabdoid (n=2), branched glandular (n=1), early spindle cell (n=1), and poorly differentiated components (n=1). Labeling for CA9 was usually 80-100% of the tumor cells (n=17/21) but was sometimes decreased in areas of eosinophilic cells (n=4). All (19/19) were positive for CD10. Most (19/20) were positive for AMACR (variable staining, 20-100%). Staining was negative for keratin 7, although 4 showed rare positive cells (4/20). Results were negative for cathepsin K (0/19), melan A (0/17), HMB45 (0/17), TFE3 (0/5), TRIM63 RNA-ISH (0/13), and TFE3 (0/19) and TFEB rearrangements (0/12). Seven of 19 (37%) showed chromosome 3p deletion. One (1/19) showed trisomy 7 and 17 without papillary features.CONCLUSIONS: Psammomatous calcifications in RCC with a clear cell pattern suggests a diagnosis of MITF family translocation RCC; however, psammomatous calcifications can rarely be found in true clear cell RCC.

  View details for DOI 10.1111/his.14854

  View details for PubMedID 36564980

• Granulomas associated with renal neoplasms: A multi-institutional clinicopathological study of 111 cases. Histopathology Sangoi, A. R., Maclean, F., Mohanty, S., Hes, O., Daniel, R., Lal, P., Canete-Portillo, S., Magi-Galluzzi, C., Cornejo, K. M., Collins, K., Hwang, M., Falzarano, S. M., Feely, M. M., Dababneh, M., Harik, L., Tretiakova, M., Akgul, M., Manucha, V., Chan, E., Kao, C., Siadat, F., Arora, K., Barkan, G., Cheng, L., Hirsch, M., Lei, L., Wasco, M., Williamson, S. R., Acosta, A. M. 2022

  Abstract

  AIMS: Formal depiction of granulomatous inflammation associated with renal neoplasms has mainly consisted of case reports. Herein, we investigate the clinicopathological features and potential significance of granulomas associated with renal tumours from a large multi-institutional cohort.METHODS AND RESULTS: One hundred and eleven study cases were collected from 22 institutions, including 57 partial nephrectomies and 54 radical nephrectomies. Patient ages ranged from 27 to 85years (average=60.1years; male=61%). Renal neoplasms included clear cell renal cell carcinoma (RCC; 86%), papillary RCC (8%), chromophobe RCC (3%), clear cell papillary RCC (1%), mixed epithelial stromal tumour (1%) and oncocytoma (1%). Granulomas were peritumoral in 36%, intratumoral in 24% andboth in 40% of cases. Total granuloma count per case ranged from one to 300 (median=15) withsizes ranging from 0.15 to 15mm (mean= 1.9mm). Necrotising granulomas were seen in 14%of cases. Histochemical stains for organisms were performed on 45% of cases (all negative). Sixteen cases (14%) had a prior biopsy/procedure performed, and eight patients had neoadjuvant immunotherapy or chemotherapy. Eleven patients (10%) had a confirmed diagnosis of sarcoidosis, including five in whom sarcoidosis was diagnosed after nephrectomy.CONCLUSION: Based on this largest case-series to date, peri-/intratumoral granulomas associated with renal neoplasms may be more common than initially perceived. The extent of granulomatous inflammation can vary widely and may or may not have necrosis with possible aetiologies, including prior procedure or immunotherapy/chemotherapy.Although a clinical association with sarcoidosisis infrequent it can still occur, and the presence of granulomas warrants mention in pathology reports.

  View details for DOI 10.1111/his.14633

  View details for PubMedID 35347739

• Clear Cell Renal Cell Carcinoma with Psammomatous Calcifications: A Rare Occurrence Mimicking Translocation Carcinoma Sangoi, A., Al-Obaidy, K., Cheng, L., Kao, C., Chan, E., Sadasivan, S., Alvarado-Cabrero, I., Kunju, L., Dhillon, J., Tretiakova, M., Smith, S., Hes, O., Williamson, S. SPRINGERNATURE. 2022: 664

  View details for Web of Science ID 000770361801245

• Clear Cell Renal Cell Carcinoma with Psammomatous Calcifications: A Rare Occurrence Mimicking Translocation Carcinoma Sangoi, A., Al-Obaidy, K., Cheng, L., Kao, C., Chan, E., Sadasivan, S., Alvarado-Cabrero, I., Kunju, L., Dhillon, J., Tretiakova, M., Smith, S., Hes, O., Williamson, S. SPRINGERNATURE. 2022: 664

  View details for Web of Science ID 000770360201245

• Analysis of separate training and validation radical prostatectomy cohorts identifies 0.25 mm diameter as an optimal definition for "large" cribriform prostatic adenocarcinoma. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc Chan, E., McKenney, J. K., Hawley, S., Corrigan, D., Auman, H., Newcomb, L. F., Boyer, H. D., Carroll, P. R., Cooperberg, M. R., Klein, E., Fazli, L., Gleave, M. E., Hurtado-Coll, A., Simko, J. P., Nelson, P. S., Thompson, I. M., Tretiakova, M. S., Troyer, D., True, L. D., Vakar-Lopez, F., Lin, D. W., Brooks, J. D., Feng, Z., Nguyen, J. K. 2022

  Abstract

  Cribriform growth pattern is well-established as an adverse pathologic feature in prostate cancer. The literature suggests "large" cribriform glands associate with aggressive behavior; however, published studies use varying definitions for "large". We aimed to identify an outcome-based quantitative cut-off for "large" vs "small" cribriform glands. We conducted an initial training phase using the tissue microarray based Canary retrospective radical prostatectomy cohort. Of 1287 patients analyzed, cribriform growth was observed in 307 (24%). Using Kaplan-Meier estimates of recurrence-free survival curves (RFS) that were stratified by cribriform gland size, we identified 0.25 mm as the optimal cutoff to identify more aggressive disease. In univariable and multivariable Cox proportional hazard analyses, size >0.25 mm was a significant predictor of worse RFS compared to patients with cribriform glands ≤0.25 mm, independent of pre-operative PSA, grade, stage and margin status (p < 0.001). In addition, two different subset analyses of low-intermediate risk cases (cases with Gleason score ≤ 3 + 4 = 7; and cases with Gleason score = 3 + 4 = 7/4 + 3 = 7) likewise demonstrated patients with largest cribriform diameter >0.25 mm had a significantly lower RFS relative to patients with cribriform glands ≤0.25 mm (each subset p = 0.004). Furthermore, there was no significant difference in outcomes between patients with cribriform glands ≤ 0.25 mm and patients without cribriform glands. The >0.25 mm cut-off was validated as statistically significant in a separate 419 patient, completely embedded whole-section radical prostatectomy cohort by biochemical recurrence, metastasis-free survival, and disease specific death, even when cases with admixed Gleason pattern 5 carcinoma were excluded. In summary, our findings support reporting cribriform gland size and identify 0.25 mm as an optimal outcome-based quantitative measure for defining "large" cribriform glands. Moreover, cribriform glands >0.25 mm are associated with potential for metastatic disease independent of Gleason pattern 5 adenocarcinoma.

  View details for DOI 10.1038/s41379-022-01009-7

  View details for PubMedID 35145197

• Expanding the clinicopathological spectrum of succinate dehydrogenase-deficient renal cell carcinoma with a focus on variant morphologies: a study of 62 new tumors in 59 patients. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc Fuchs, T. L., Maclean, F., Turchini, J., Vargas, A. C., Bhattarai, S., Agaimy, A., Hartmann, A., Kao, C., Ellis, C., Bonert, M., Leroy, X., Kunju, L. P., Schwartz, L., Matsika, A., Williamson, S. R., Rao, P., Divatia, M., Guarch, R., Algaba, F., Balancin, M. L., Zhou, M., Samaratunga, H., da Cunha, I. W., Brimo, F., Ryan, A., Clouston, D., Aron, M., O'Donnell, M., Chan, E., Hirsch, M. S., Moch, H., Pang, C., Wah, C., Yin, W., Perry-Keene, J., Yilmaz, A., Chou, A., Clarkson, A., van der Westhuizen, G., Morrison, E., Zwi, J., Hes, O., Trpkov, K., Gill, A. J. 1800

  Abstract

  Most succinate dehydrogenase (SDH)-deficient renal cell carcinomas (RCCs) demonstrate stereotypical morphology characterized by bland eosinophilic cells with frequent intracytoplasmic inclusions. However, variant morphologic features have been increasingly recognized. We therefore sought to investigate the incidence and characteristics of SDH-deficient RCC with variant morphologies. We studied a multi-institutional cohort of 62 new SDH-deficient RCCs from 59 patients. The median age at presentation was 39 years (range 19-80), with a slight male predominance (M:F=1.6:1). A relevant family history was reported in 9 patients (15%). Multifocal or bilateral tumors were identified radiologically in 5 patients (8%). Typical morphology was present at least focally in 59 tumors (95%). Variant morphologies were seen in 13 (21%) and included high-grade nuclear features and various combinations of papillary, solid, and tubular architecture. Necrosis was present in 13 tumors, 7 of which showed variant morphology. All 62 tumors demonstrated loss of SDHB expression by immunohistochemistry. None showed loss of SDHA expression. Germline SDH mutations were reported in all 18 patients for whom the results of testing were known. Among patients for whom follow-up data was available, metastatic disease was reported in 9 cases, 8 of whom had necrosis and/or variant morphology in their primary tumor. Three patients died of disease. In conclusion, variant morphologies and high-grade nuclear features occur in a subset of SDH-deficient RCCs and are associated with more aggressive behavior. We therefore recommend grading all SDH-deficient RCCs and emphasize the need for a low threshold for performing SDHB immunohistochemistry in any difficult to classify renal tumor, particularly if occurring at a younger age.

  View details for DOI 10.1038/s41379-021-00998-1

  View details for PubMedID 34949766

• Molecular Characterization of Metanephric Adenomas Beyond BRAF: Genetic Evidence for Potential Malignant Evolution. Histopathology Chan, E., Stohr, B. A., Croom, N. A., Cho, S., Garg, K., Troxell, M. L., Higgins, J. P., Bean, G. R. 2020

  Abstract

  AIMS: Metanephric adenomas (MA) are conventionally regarded as rare renal tumors with indolent behavior; limited case reports describe MA with aggressive features. Conventional MA harbor hotspot BRAF V600E mutations. A BRAF V600E senescence pathway, mediated by CDKN2A/p16, has been proposed to confer MA benignity. Aside from BRAF, the molecular landscape in both conventional MA and those with aggressive features has not been fully characterized. In this study we molecularly profiled a series of MA to investigate the correlation between genomic findings and clinical outcome.METHODS AND RESULTS: We retrospectively examined the histomorphology and patient outcomes of 11 conventional MA and one MA with aggressive features. Each was subjected to capture-based next-generation DNA sequencing of 479 cancer-related genes and immunohistochemical profiling. All tumors were positive for WT1 immunostaining and BRAF V600E mutation. One conventional MA contained an additional somatic BRCA2 pathogenic mutation. The MA with aggressive features showed a biphasic appearance: one component was epithelial with areas morphologically consistent with conventional MA; the second component was sarcomatous with areas of solid and angiosarcomatous growth. Differential profiling of the two populations revealed identical BRAF, EIF1AX, and TERT promoter hotspot mutations in the epithelial and sarcomatous components. Deep deletion of CDKN2A and MYC amplification were identified only in the sarcomatous component.CONCLUSIONS: While the vast majority of MA show indolent behavior, rare pathogenic alterations can occur in conventional MA in addition to BRAF. Molecular profiling of a case with aggressive clinical and pathologic features shows genetic evidence for malignant evolution in MA.

  View details for DOI 10.1111/his.14094

  View details for PubMedID 32064677

• A Clinicopathologic and Molecular Analysis of Fumarate Hydratase-Deficient Renal Cell Carcinoma in 32 Patients. The American journal of surgical pathology Lau, H. D., Chan, E., Fan, A. C., Kunder, C. A., Williamson, S. R., Zhou, M., Idrees, M. T., Maclean, F. M., Gill, A. J., Kao, C. 2019

  Abstract

  Fumarate hydratase-deficient renal cell carcinoma (FH-deficient RCC) is a rare and recently described entity associated with hereditary leiomyomatosis and RCC syndrome. FH-deficient RCC may show variable clinical and pathologic findings, but commonly presents with locally advanced and metastatic disease and carries a poor prognosis. We identified 32 patients with FH-deficient RCC, confirmed by FH immunohistochemistry (IHC) and/or FH mutation analysis, and performed a retrospective review of the clinical and pathologic features. Median age at presentation was 43 years (range, 18 to 69y), and the M:F ratio was 2.2:1. Median tumor size was 6.5cm (range, 2.5 to 28cm), and 71% presented at stage ≥pT3a. After a median follow-up of 16 months (range, 1 to 118mo) in 26 patients, 19% showed no evidence of disease, 31% were alive with disease, and 50% were dead of disease. The vast majority of cases showed multiple histologic growth patterns, with papillary (52%) being the most common predominant pattern, followed by solid (21%), cribriform/sieve-like (14%), sarcomatoid (3%), tubular (3%), cystic (3%), and low-grade oncocytic (3%). Viral inclusion-like macronucleoli with perinucleolar clearing were present in almost all cases (96%). All cases were evaluated using FH IHC, and 3 cases (9%) showed retained FH expression. Nineteen cases had germline or tumor mutation analysis confirming a FH mutation, with 79% (11/14) of cases showing mutations within coding regions and 21% (3/14) showing mutations within intronic splice-sites. By IHC, 97% (32/33) of cases were negative for CK7, 93% (27/29) were negative for p63, and 52% (15/29) were negative for GATA3. All cases stained were positive for PAX8 and showed retained succinate dehydrogenase B expression. Our overall findings show that FH-deficient RCC is considerably heterogenous in morphology and frequently behaves aggressively. Suspicion for this entity should be raised even in the absence of predominantly papillary architecture and characteristic nucleolar features. We have included cases with uncommonly seen features, including 4 cases with predominantly cribriform/sieve-like architecture as well as one case with pure low-grade oncocytic morphology (9y of clinical follow-up without evidence of disease). Although FH IHC is a useful tool for identifying cases of FH-deficient RCC, not all cases of FH-deficient RCC show loss of FH staining, and FH mutation analysis should be considered for patients with suspicious clinical or pathologic features, even in cases with retained FH IHC expression.

  View details for DOI 10.1097/PAS.0000000000001372

  View details for PubMedID 31524643

• Molecular Characterization of Metanephric Adenomas Beyond BRAF: Are All Benign? Chan, E., Stohr, B., Croom, N., Cho, S., Garg, K., Troxell, M., Higgins, J., Bean, G. NATURE PUBLISHING GROUP. 2019

  View details for Web of Science ID 000478915502232

• Molecular Characterization of Metanephric Adenomas Beyond BRAF: Are All Benign? Chan, E., Stohr, B., Croom, N., Cho, S., Garg, K., Troxell, M., Higgins, J., Bean, G. NATURE PUBLISHING GROUP. 2019

  View details for Web of Science ID 000478081101273