Emily Chan

All Publications

• Pancreatic Serous Neoplasm and Metastatic Clear Cell Renal Cell Carcinoma: Diagnostic Pitfalls Resolvable by a Panel of Immunohistochemical Stains to Include PAX8 and CK7 But Not CAIX. The American journal of surgical pathology Theparee, T., Umetsu, S. E., Chan, E. 2025; 49 (4): 394-402

  Abstract

  Pancreatic serous neoplasms can morphologically resemble metastatic clear cell renal cell carcinoma (ccRCC) and may present a diagnostic dilemma, particularly if the solid variant is in small biopsy specimens and/or in patients with von Hippel Lindau (VHL) syndrome. We investigate the utility of immunohistochemical staining in this differential diagnosis by performing head-to-head comparisons of commonly used immunohistochemical markers for these 2 tumor types. We examined 16 pancreatic serous neoplasms and 24 ccRCCs (12 metastatic to pancreas and 12 primaries in patients with VHL). All pancreatic serous neoplasms stained positive for CK7, and most were positive for CAIX (15/16) and GLUT1 (15/16), variable for alpha-inhibin and vimentin (each 8/16 weak/focal; and 7/16 and 8/16, respectively, positive), and weak/focal for synaptophysin (14/16). All pancreatic serous neoplasms were negative for PAX8 and Periodic acid-Schiff without diastase. In contrast, ccRCC, both metastatic and in VHL patients, were mostly positive for PAX8 (18/24; 6/24 were weak/focal), negative for CK7 (15/24; 8/24 were weak/focal, one case diffuse positive), and negative for alpha-inhibin (100%) and synaptophysin (22/24). Like pancreatic serous neoplasms, all ccRCC showed weak/focal or positive staining for GLUT1, CAIX, and vimentin, and were negative for PAS-D. In conclusion, CK7 and PAX8 are the most useful stains in distinguishing between pancreatic serous neoplasm and ccRCC; however, weak/focal CK7 or PAX8 staining can be seen in a minority of ccRCC, thereby presenting a diagnostic pitfall. Alpha-inhibin was at least weak/focal in most pancreatic serous neoplasms and negative in all ccRCC and may be useful as an adjunct stain in difficult cases.

  View details for DOI 10.1097/PAS.0000000000002357

  View details for PubMedID 40096283

• MAPK1IP1L::TFE3-rearranged renal cell carcinoma: a novel fusion adding to the differential diagnosis of oncocytic renal neoplasms. Virchows Archiv : an international journal of pathology Cheng, A. V., Wu, D. J., Friedman, L. A., Chan, E., Williamson, S. R., Galea, L. A., Sangoi, A. R. 2025

  Abstract

  Beyond the more common TFE3 fusion partners PRCC, ASPSCR1, and SFPQ, additional less common fusion partners of TFE3-rearranged renal cell carcinoma (RCC) have been described. Herein, we present an example of TFE3-rearranged renal cell carcinoma harboring fusion partner MAPK1IP1L, a rare rearrangement with only one other reported tumor found in the literature. The currently reported TFE3-rearranged RCC demonstrates unique histological features compared to the previously reported tumor including dense eosinophilic cytoplasm and nuclear pseudoinclusions (corroborated by electron microscopic evaluation), with features not typically seen in other TFE3-rearranged RCCs. Recognizing this novel fusion may be important in the identification, classification, and development of potential therapeutic agents of kidney tumors in the future.

  View details for DOI 10.1007/s00428-025-04031-7

  View details for PubMedID 39862330

• Gamna-Gandy bodies in renal neoplasms: A multi-institutional clinicopathologic study of 350 consecutive nephrectomies. Annals of diagnostic pathology Mubeen, A., Pacheco, R., Akgul, M., Williamson, S. R., Collins, K., Chan, E., Sangoi, A. R. 2025; 75: 152440

  Abstract

  Gamna-Gandy (GG) bodies are sclerosiderotic nodules composed of iron pigment and calcium, that have been described predominantly in the spleens of patients with sickle cell disease. Their formal depiction in the kidney is mainly limited to case reports and small series. We aimed to investigate the incidence of GG bodies and associated clinicopathologic features in consecutive nephrectomies performed for renal tumors. Slides of consecutive nephrectomies for renal neoplasms at 3 institutions were reviewed by genitourinary pathologists, with detailed clinicopathologic features recorded. The incidence of GG bodies in our nephrectomy cohort was 13% (44/350). The most common tumor exhibiting GG bodies was clear cell renal cell carcinoma (RCC) (40/44), followed by papillary RCC (2/44), chromophobe RCC (1/44), and epithelioid angiomyolipoma (1/44). Most RCCs were pathologic stage pT3a (46%). GG bodies were intratumoral in 77%, peritumoral in 5%, and both in 18% of patients. They were focal in 43% and multifocal in 57%, with the largest focus ranging from 0.2 to 7mm (mean 1.7mm). Background fibrosis and hemosiderin laden macrophages were commonly associated (93% for both). All tumors demonstrated cystic elements. In 2 renal tumor specimens, an extensive fungal workup was performed and was negative; the "structures" were not formally recognized as GG bodies in either specimen. GG bodies are not an uncommon finding in renal tumors, particularly in clear cell RCC. Awareness of the morphologic appearance is crucial to avoid mistaking them for fungal structures or other organisms.

  View details for DOI 10.1016/j.anndiagpath.2025.152440

  View details for PubMedID 39826481

• Unexpectedly high variability in determining tumour extent in prostatic biopsies: implications for active surveillance. Histopathology Bernhardt, M., Weinhold, L., Bremmer, F., Chan, E., Cheng, L., Collins, K., Downes, M., Greenland, N., Hommerding, O., Iczkowski, K. A., Jufe, L., Kreft, T., van Leenders, G., Oxley, J., Perry-Keene, J., Reis, H., Schmid, M., Tsuzuki, T., Wobker, S., Wiliamson, S. R., Kweldam, C., Kristiansen, G. 2024

  Abstract

  Tumour content in prostatic biopsies is an important indicator of prostate cancer volume and patient prognosis. Consequently, guidelines typically recommend reporting it as a percentage or linear length (mm). This study aimed to determine the current practices for reporting tumour content in prostatic biopsies and evaluated the consistency among pathologists in diagnosing 10 standard biopsy cases of prostate cancer to assess interobserver variability.A web-based survey gathered data on demographics, experience and attitudes regarding the reporting of prostate cancer and its extent in biopsies. Virtual microscopy allowed analysis of 10 biopsy cases, each consisting of a single slide of prostate cancer. Self-reports from 304 participants recruited via the International Society of Urological Pathology and the German Society of Pathology were analysed. Most participants (43.4%) reported tumour extent as percentage of the biopsy core, 37.6% reported percentages and mm and 18.3% reported mm exclusively. The methods used to determine percentages showed an unexpected spread of choices, leading to considerable variability in results. Additionally, 40.8% of participants took part in the practical segment of the survey. The reported measures of tumour extent confirmed a notable interobserver variability, which was significantly higher for reported percentages.A high rate of interobserver variability in reporting tumour content in prostatic biopsies was found. This matter is especially critical for patients who are candidates for active surveillance. Reporting absolute measures of tumour content has the advantage of lower variability in comparison to percentages.

  View details for DOI 10.1111/his.15372

  View details for PubMedID 39610035

• Aggressiveness classification of clear cell renal cell carcinoma using registration-independent radiology-pathology correlation learning. Medical physics Bhattacharya, I., Stacke, K., Chan, E., Lee, J. H., Tse, J. R., Liang, T., Brooks, J. D., Sonn, G. A., Rusu, M. 2024

  Abstract

  Renal cell carcinoma (RCC) is a common cancer that varies in clinical behavior. Clear cell RCC (ccRCC) is the most common RCC subtype, with both aggressive and indolent manifestations. Indolent ccRCC is often low-grade without necrosis and can be monitored without treatment. Aggressive ccRCC is often high-grade and can cause metastasis and death if not promptly detected and treated. While most RCCs are detected on computed tomography (CT) scans, aggressiveness classification is based on pathology images acquired from invasive biopsy or surgery.CT imaging-based aggressiveness classification would be an important clinical advance, as it would facilitate non-invasive risk stratification and treatment planning. Here, we present a novel machine learning method, Correlated Feature Aggregation By Region (CorrFABR), for CT-based aggressiveness classification of ccRCC.CorrFABR is a multimodal fusion algorithm that learns from radiology and pathology images, and clinical variables in a clinically-relevant manner. CorrFABR leverages registration-independent radiology (CT) and pathology image correlations using features from vision transformer-based foundation models to facilitate aggressiveness assessment on CT images. CorrFABR consists of three main steps: (a) Feature aggregation where region-level features are extracted from radiology and pathology images at widely varying image resolutions, (b) Fusion where radiology features correlated with pathology features (pathology-informed CT biomarkers) are learned, and (c) Classification where the learned pathology-informed CT biomarkers, together with clinical variables of tumor diameter, gender, and age, are used to distinguish aggressive from indolent ccRCC using multi-layer perceptron-based classifiers. Pathology images are only required in the first two steps of CorrFABR, and are not required in the prediction module. Therefore, CorrFABR integrates information from CT images, pathology images, and clinical variables during training, but for inference, it relies solely on CT images and clinical variables, ensuring its clinical applicability. CorrFABR was trained with heterogenous, publicly-available data from 298 ccRCC tumors (136 indolent tumors, 162 aggressive tumors) in a five-fold cross-validation setup and evaluated on an independent test set of 74 tumors with a balanced distribution of aggressive and indolent tumors. Ablation studies were performed to test the utility of each component of CorrFABR.CorrFABR outperformed the other classification methods, achieving an ROC-AUC (area under the curve) of 0.855 ± 0.0005 (95% confidence interval: 0.775, 0.947), F1-score of 0.793 ± 0.029, sensitivity of 0.741 ± 0.058, and specificity of 0.876 ± 0.032 in classifying ccRCC as aggressive or indolent subtypes. It was found that pathology-informed CT biomarkers learned through registration-independent correlation learning improves classification performance over using CT features alone, irrespective of the kind of features or the classification model used. Tumor diameter, gender, and age provide complementary clinical information, and integrating pathology-informed CT biomarkers with these clinical variables further improves performance.CorrFABR provides a novel method for CT-based aggressiveness classification of ccRCC by enabling the identification of pathology-informed CT biomarkers, and integrating them with clinical variables. CorrFABR enables learning of these pathology-informed CT biomarkers through a novel registration-independent correlation learning module that considers unaligned radiology and pathology images at widely varying image resolutions.

  View details for DOI 10.1002/mp.17476

  View details for PubMedID 39447001

• Utility of The Paris System for Reporting Urinary Cytology in patients with HPV-positive urinary tract carcinoma CANCER CYTOPATHOLOGY Tanaka, K., Kayraklioglu, N., Chan, E., Ding, C. C., Vohra, P. 2024

  Abstract

  Human papillomavirus (HPV)-positive urinary tract carcinomas (UTCas) have distinct morphology and molecular features with potential treatment implications. Cytomorphologic analysis of these tumors on urine cytology specimens has not yet been reported. The authors evaluated the cytomorphologic findings of HPV-positive UTCa on urine cytology using The Paris System for Reporting Urinary Cytology (TPS) criteria.HPV-positive cases were identified by a retrospective review of surgical specimens that had UTCa confirmed by HPV in situ hybridization. Cases that had concurrent urine cytology were reviewed using TPS. Cytomorphologic features of high-grade urothelial carcinoma (HGUC) were evaluated as well as the presence of atypical squamous cells (ASCs) and basaloid features.Sixteen cytology specimens from eight patients with HPV-positive UTCa were included. On original diagnosis, none of the cytology specimens were suggested to be HPV-associated. TPS diagnostic criteria identified eight cases with at least atypical findings, including five HGUC cases, one case that was suspicious for HGUC, and two atypical urothelial cases. Common cytomorphologic features included basaloid clusters (six of eight cases; 75%) and ASCs (four of eight cases; 50%) that matched the corresponding surgical specimens. Most cases exhibited urothelial cell hyperchromasia (seven of eight cases; 88%), and hypochromasia was a frequently observed variant (four of eight cases; 50%), either alone or in addition to hyperchromasia.HPV-positive UTCa can be identified reliably as HGUC by using TPS criteria; however, these cases may not be recognized as HPV-associated. The presence of basaloid cells or ASCs can help suggest screening for HPV in urine specimens. Larger scale studies are warranted to validate cytomorphologic differences and determine the impact of HPV infection on clinical outcomes for patients with UTCa.

  View details for DOI 10.1002/cncy.22914

  View details for Web of Science ID 001331200600001

  View details for PubMedID 39403894

• Cowper Glands Identified in Prostate and Urethral Specimens: A Comprehensive Immunohistochemical Characterization and Potential Diagnostic Pitfall. International journal of surgical pathology Sangoi, A. R., Al-Obaidy, K. I., Akgul, M., Mehra, R., Chan, E., Williamson, S. R. 2024: 10668969241268375

  Abstract

  Cowper glands recognition remains one of the key histoanatomic benign mimics of prostatic adenocarcinoma. In most instances, these can be identified based on the dimorphic population of lobulated acini and duct(s). However, in the prostate biopsy setting with incomplete/distorted cores, this may not be immediately apparent and may warrant use of immunohistochemistry to argue against prostatic adenocarcinoma. Although immunohistochemical pitfalls in Cowper glands have been described, to our knowledge a comprehensive evaluation of both traditional and purportedly prostate-specific novel markers in Cowper glands has not been previously performed. Herein, we studied the clinicopathological and immunohistochemical features of 21 male patients (age range 39-81 years; mean=63 years), including 15 prostate biopsies (7 of which also had prostate cancer in the same specimen set and 2 of which had both prostate cancer and Cowper glands in the same biopsy core). Immunohistochemistry showed the following results in Cowper glands: 100% positive for NKX3.1, 100% positive (basal cells) for both high molecular weight keratin and p63, 57% positive for PSAP, 25% positive for PSMA, 5% positive for AMACR, and 0% positive for PSA. In conclusion, for specimens lacking appreciable dimorphic morphology, caution should be rendered when using prostate-specific markers (PSA, PSAP, PSMA, and NKX3.1) as these can show considerable staining in Cowper glands and be a pitfall. Instead, findings from this cohort indicate relying on basal markers (high molecular weight keratin/p63; either individually or in a "cocktail" approach) and PSA are most useful in distinguishing Cowper glands (retained basal cell markers staining) from prostatic adenocarcinoma.

  View details for DOI 10.1177/10668969241268375

  View details for PubMedID 39165181

• Next-generation sequencing has diagnostic utility in challenging small/flat urothelial lesions. Annals of diagnostic pathology Pinard, A., Chen, C., Van Ziffle, J., Simko, J. P., Stohr, B. A., Chan, E. 2024; 73: 152370

  Abstract

  Small/flat urothelial lesions are challenging and currently available ancillary immunohistochemistry testing often cannot reliably distinguish between reactive lesions and urothelial carcinoma (UCa). UCa has a characteristic molecular profile, but small/flat urothelial lesions are typically considered too small to perform next generation sequencing (NGS). Herein, we present our institution's experience with utilizing comprehensive DNA-based NGS to evaluate small/flat urothelial lesions (n=13 cases). NGS was ordered on 7/13 small/flat urothelial lesions initially diagnosed as urothelial atypia, ordered by the pathologist to aid in further diagnosis; the remaining 6/13 cases were diagnosed as urothelial carcinoma in situ (uCIS), ordered by a treating oncologist. The test was considered as adding value if it yielded pathogenic or likely pathogenic alterations previously associated with urothelial carcinoma in the literature. Macroscopic dissection was determined necessary in all cases and obtained either by scraping (7), punch biopsy (5) or scooping (1) of paraffin tissue blocks. In 4/13 cases, tumor content was considered low (<25%); in 2/13 cases, DNA quantity yield was considered below optimal (<250ng); all cases met required DNA quantity for testing (>50ng). Mean target coverage ranged: 498 to 985 (optimal >500 reads). NGS testing identified mutations compatible with urothelial carcinoma in all 7 cases initially diagnosed as atypical; and in one case, the tumor recurred as a lung metastasis. All 6 uCIS had NGS testing results concordant with UCa. In conclusion, despite small sample quantity with low tumor content and DNA concentration yield, NGS testing with appropriate methodology can be considered in the setting of small/flat urothelial lesions to aid in diagnosis or per oncologist request and yield interpretable results.

  View details for DOI 10.1016/j.anndiagpath.2024.152370

  View details for PubMedID 39180886

• HER2 overexpression in urothelial carcinoma with GATA3 and PPARG copy number gains ONCOLOGIST Zhu, X., Chan, E., Turski, M. L., Mendez, C., Hsu, S. C., Kumar, V., Shipp, C., Jindal, T., Chang, K., Onodera, C., Devine, W., Grenert, J. P., Stohr, B. A., Ding, C., Stachler, M. D., Quigley, D. A., Feng, F. Y., Chu, C. E., Porten, S. P., Chou, J., Friedlander, T. W., Koshkin, V. S. 2024

  Abstract

  HER2, encoded by the ERBB2 gene, is an important druggable driver of human cancer gaining increasing importance as a therapeutic target in urothelial carcinoma (UC). The genomic underpinnings of HER2 overexpression in ERBB2 nonamplified UC are poorly defined. To address this knowledge gap, we investigated 172 UC tumors from patients treated at the University of California San Francisco, using immunohistochemistry and next-generation sequencing. We found that GATA3 and PPARG copy number gains individually predicted HER2 protein expression independently of ERBB2 amplification. To validate these findings, we interrogated the Memorial Sloan Kettering/The Cancer Genome Atlas (MSK/TCGA) dataset and found that GATA3 and PPARG copy number gains individually predicted ERBB2 mRNA expression independently of ERBB2 amplification. Our findings reveal a potential link between the luminal marker HER2 and the key transcription factors GATA3 and PPARG in UC and highlight the utility of examining GATA3 and PPARG copy number states to identify UC tumors that overexpress HER2 in the absence of ERBB2 amplification. In summary, we found that an increase in copy number of GATA3 and PPARG was independently associated with higher ERBB2 expression in patient samples of UC. This finding provides a potential explanation for HER2 overexpression in UC tumors without ERBB2 amplification and a way to identify these tumors for HER2-targeted therapies.

  View details for DOI 10.1093/oncolo/oyae127

  View details for Web of Science ID 001251792600001

  View details for PubMedID 38908022

• Proposal for an optimised definition of adverse pathology (unfavourable histology) that predicts metastatic risk in prostatic adenocarcinoma independent of grade group and pathological stage. Histopathology Nguyen, J. K., Harik, L. R., Klein, E. A., Li, J., Corrigan, D., Liu, S., Chan, E., Hawley, S., Auman, H., Newcomb, L. F., Carroll, P. R., Cooperberg, M. R., Filson, C. P., Simko, J. P., Nelson, P. S., Tretiakova, M. S., Troyer, D., True, L. D., Vakar-Lopez, F., Weight, C. J., Lin, D. W., Brooks, J. D., McKenney, J. K. 2024

  Abstract

  Histological grading of prostate cancer is a powerful prognostic tool, but current criteria for grade assignment are not fully optimised. Our goal was to develop and test a simplified histological grading model, based heavily on large cribriform/intraductal carcinoma, with optimised sensitivity for predicting metastatic potential.Two separate non-overlapping cohorts were identified: a 419-patient post-radical prostatectomy cohort with long term clinical follow-up and a 209-patient post-radical prostatectomy cohort in which all patients had pathologically confirmed metastatic disease. All prostatectomies were re-reviewed for high-risk histological patterns of carcinoma termed 'unfavourable histology'. Unfavourable histology is defined by any classic Gleason pattern 5 component, any large cribriform morphology (> 0.25 mm) or intraductal carcinoma, complex intraluminal papillary architecture, grade 3 stromogenic carcinoma and complex anastomosing cord-like growth. For the outcome cohort, Kaplan-Meier analysis compared biochemical recurrence, metastasis and death between subjects with favourable and unfavourable histology, stratified by pathological stage and grade group. Multivariable Cox proportional hazards models evaluated adding unfavourable histology to the Memorial Sloan Kettering Cancer Center (MSKCC) post-prostatectomy nomogram and stratification by percentage of unfavourable histology. At 15 years unfavourable histology predicted biochemical recurrence, with sensitivity of 93% and specificity of 88%, metastatic disease at 100 and 48% and death at 100 and 46%. Grade group 2 prostate cancers with unfavourable histology were associated with metastasis independent of pathological stage, while those without had no risk. Histological models for prediction of metastasis based on only large cribriform/intraductal carcinoma or increasing diameter of cribriform size improved specificity, but with lower sensitivity. Multivariable Cox proportional hazards models demonstrated that unfavourable histology significantly improved discriminatory power of the MSKCC post-prostatectomy nomogram for biochemical failure (likelihood ratio test P < 0.001). In the retrospective review of a separate RP cohort in which all patients had confirmed metastatic disease, none had unequivocal favourable histology.Unfavourable histology at radical prostatectomy is associated with metastatic risk, predicted adverse outcomes better than current grading and staging systems and improved the MSKCC post-prostatectomy nomogram. Most importantly, unfavourable histology stratified grade group 2 prostate cancers into those with and without metastatic potential, independent of stage. While unfavourable histology is driven predominantly by large cribriform/intraductal carcinoma, the recognition and inclusion of other specific architectural patterns add to the sensitivity for predicting metastatic disease. Moreover, a simplified dichotomous model improves communication and could increase implementation.

  View details for DOI 10.1111/his.15231

  View details for PubMedID 38828674

• Morphologic patterns observed in prostate biopsy cases with discrepant grade group and molecular risk classification. The Prostate Greenland, N. Y., Cooperberg, M. R., Carroll, P. R., Cowan, J. E., Simko, J. P., Stohr, B. A., Chan, E. 2024

  Abstract

  Molecular-based risk classifier tests are increasingly being utilized by urologists and radiation oncologists to guide clinical decision making. The Decipher prostate biopsy test is a 22-gene RNA biomarker assay designed to predict likelihood of high-grade disease at radical prostatectomy and risk of metastasis and mortality. The test provides a risk category of low, intermediate, or high. We investigated histologic features of biopsies in which the Grade Group (GG) and Decipher risk category (molecular risk) were discrepant.Our institutional urologic outcomes database was searched for men who underwent prostate biopsies with subsequent Decipher testing from 2016 to 2020. We defined discrepant GG and molecular risk as either GG1-2 with high Decipher risk category or GG ≥ 3 with low Decipher risk category. The biopsy slide on which Decipher testing was performed was re-reviewed for GG and various histologic features, including % Gleason pattern 4, types of Gleason pattern 4 and 5, other "high risk" features (e.g., complex papillary, ductal carcinoma, intraductal carcinoma [IDC]), and other unusual and often "difficult to grade" patterns (e.g., atrophic carcinoma, mucin rupture, pseudohyperplastic carcinoma, collagenous fibroplasia, foamy gland carcinoma, carcinoma with basal cell marker expression, carcinoma with prominent vacuoles, and stromal reaction). Follow-up data was also obtained from the electronic medical record.Of 178 men who underwent prostate biopsies and had Decipher testing performed, 41 (23%) had discrepant GG and molecular risk. Slides were available for review for 33/41 (80%). Of these 33 patients, 23 (70%) had GG1-2 (GG1 n = 5, GG2 n = 18) with high Decipher risk, and 10 (30%) had GG ≥ 3 with low Decipher risk. Of the 5 GG1 cases, one case was considered GG2 on re-review; no other high risk features were identified but each case showed at least one of the following "difficult to grade" patterns: 3 atrophic carcinoma, 1 collagenous fibroplasia, 1 carcinoma with mucin rupture, and 1 carcinoma with basal cell marker expression. Of the 18 GG2 high Decipher risk cases, 2 showed GG3 on re-review, 5 showed large cribriform and/or other high risk features, and 10 showed a "difficult to grade" pattern. Of the 10 GG ≥ 3 low Decipher risk cases, 5 had known high risk features including 2 with large cribriform, 1 with IDC, and 1 with Gleason pattern 5.In GG1-2 high Decipher risk cases, difficult to grade patterns were frequently seen in the absence of other known high risk morphologic features; whether these constitute true high risk cases requires further study. In the GG ≥ 3 low Decipher risk cases, aggressive histologic patterns such as large cribriform and IDC were observed in half (50%) of cases; therefore, the molecular classifier may not capture all high risk histologic patterns.

  View details for DOI 10.1002/pros.24725

  View details for PubMedID 38734990

• GATA3 Expression in Prostatic Adenosquamous Carcinoma: A Potential Diagnostic Pitfall. International journal of surgical pathology Potterveld, S. K., Williamson, S. R., Al-Obaidy, K. I., Akgul, M., Chan, E., Giannico, G. A., Sangoi, A. R. 2024: 10668969241241640

  Abstract

  Urothelial carcinoma and prostatic adenocarcinoma can have overlapping histologic features and in some instances pose challenges to pathologists. GATA binding protein 3 (GATA3) immunohistochemistry (IHC) is a well-established tool to aid in this specific diagnostic dilemma as it has been shown to be a sensitive marker for urothelial carcinoma and a putatively specific marker in excluding prostatic adenocarcinoma. However, in encountering an index tumor of prostatic adenosquamous carcinoma positive for GATA3, herein we sought to investigate this potential diagnostic pitfall in a larger series of tumors. In this study, we retrospectively reviewed prostatic adenosquamous carcinomas diagnosed in 17 patients across the authors' institutions and personal consult collections in the past 10 years. GATA3 IHC was either reviewed or performed on tumors not previously tested. We also recorded other immunostains that were performed at initial diagnosis. Positivity for GATA3 was found in 9 of 17 (53%) tumors, all within squamous regions (2 tumors also showed concomitant moderate GATA3 positivity within glandular elements). The GATA3 positive tumors were all positive for p63 in the 7 tumors where p63 was also performed. Of all tumors tested, NKX3.1 was positive in 100% (13/13) of the glandular elements (3 tumors also showed NKX3.1 concomitant positivity within squamous regions). In summary, when encountering a carcinoma with mixed glandular/squamous features in which prostatic origin is being considered, awareness of GATA3 immunoreactivity in a subset of prostatic adenosquamous carcinoma is critical to avoid diagnostic pitfalls.

  View details for DOI 10.1177/10668969241241640

  View details for PubMedID 38562047

• Testing and Interpretation of HER2 Protein Expression and Gene Amplification in Urothelial Carcinoma Chan, E., Boyiddle, C., Scherrer, E., Schwartz, N., Yu, J., Fang, Q., Schafer, J., Baker, A., Sayedian, F., Koshkin, V. ELSEVIER SCIENCE INC. 2024: S920

  View details for Web of Science ID 001302363403026

• Paratesticular Clear Cell Papillary Cystadenomas: A Morphologic and Immunohistochemical Comparison with Metastatic Renal Cell Carcinoma Morrison, C., Chan, E., Acosta, A., Panizo, A., Williamson, S., Mubeen, A., Nova-Camacho, L., Sangoi, A. ELSEVIER SCIENCE INC. 2024: S1022-S1023

  View details for Web of Science ID 001302363403107

• Highlighting the Differential Pattern of GPNMB Expression in a Cohort of ELOC-mutated RCC Mohanty, S., Lobo, A., Aron, M., Chan, E., Jha, S., Sangoi, A., Akgul, M., Deshwal, A., Acosta, A., Williamson, S., Kaushal, S., Cheng, L., Rao, B., Parwani, A., Osunkoya, A., Jia, L., Amin, M., Shah, R. ELSEVIER SCIENCE INC. 2024: S1017-S1018

  View details for Web of Science ID 001302363403104

• Immunohistochemistry and MYB fluorescence in-situ Hybridization Differentiate Basal Cell Carcinoma of Prostate From Adenoid Cystic Carcinoma Ding, C., Haffner, M., Chan, E., Stohr, B., Rooper, L., Epstein, J. ELSEVIER SCIENCE INC. 2024: S934-S935

  View details for Web of Science ID 001302363403039

• Large cribriform glands (> 0.25 mm diameter) as a predictor of adverse pathology in men with Grade Group 2 prostate cancer. Histopathology Greenland, N. Y., Cowan, J. E., Stohr, B. A., Simko, J. P., Carroll, P. R., Chan, E. 2023

  Abstract

  A recent outcome-based, radical prostatectomy study defined > 0.25 mm diameter to distinguish large versus small cribriform glands, with > 0.25 mm associated with worse recurrence-free survival. This study evaluates whether identification of > 0.25 mm cribriform glands in Grade Group 2 patients at biopsy is associated with adverse pathology at radical prostatectomy.Tumours containing biopsy slides for 133 patients with Grade Group 2 prostate cancer with subsequent radical prostatectomy were re-reviewed for large cribriform glands (diameter > 0.25 mm). The primary outcome was adverse pathology (Grade Groups 3-5; stage pT3a or greater, or pN1). The secondary outcome was recurrence-free survival. Cribriform pattern was present in 52 of 133 (39%) patients; of these, 16 of 52 (31%) had large cribriform glands and 36 of 52 (69%) had only small cribriform glands. Patients with large cribriform glands had significantly more adverse pathology at radical prostatectomy compared to patients with small cribriform glands and no cribriform glands (large = 11 of 16, 69%; small = 12 of 36, 33%; no cribriform = 25 of 81, 31%; χ2 P-value 0.01). On multivariate analysis, large cribriform glands were also associated with adverse pathology, independent of age, prostate-specific antigen (PSA)/PSA density at diagnosis, year of diagnosis and biopsy cores percentage positive (global P-value 0.02). Large cribriform glands were also associated with increased CAPRA-S surgical risk score (Kruskal-Wallis P-value 0.02).Large cribriform glands using a diameter > 0.25 mm definition in Grade Group 2 patients on biopsy are associated with increased risk of adverse pathology at radical prostatectomy. The presence of large cribriform histology should be considered when offering active surveillance for those with Grade Group 2 disease.

  View details for DOI 10.1111/his.15102

  View details for PubMedID 38012532

• Positive NKX3.1 as a diagnostic pitfall for prostate cancer in extramammary Paget's disease of genitourinary sites. Histopathology Chen, C. V., Francois, R. A., Mully, T. W., Sangoi, A., LeBoit, P. E., Simko, J. P., Chan, E. 2023

  View details for DOI 10.1111/his.15061

  View details for PubMedID 37794658

• Wilms Tumor: An Unexpected Diagnosis in Adult Patients. Archives of pathology & laboratory medicine Chan, G. J., Stohr, B. A., Osunkoya, A. O., Croom, N. A., Cho, S. J., Balassanian, R., Charu, V., Bean, G. R., Chan, E. 2023

  Abstract

  Wilms tumor (WT) in adult patients is rare and has historically been a diagnostic and therapeutic conundrum, with limited data available in the literature.To provide detailed diagnostic features, molecular profiling, and patient outcomes in a multi-institutional cohort of adult WT patients.We identified and retrospectively examined 4 adult WT cases.Two patients presented with metastatic disease, and diagnoses were made on fine-needle aspiration of their renal masses. The aspirates included malignant primitive-appearing epithelioid cells forming tubular rosettes and necrosis, and cell blocks demonstrated triphasic histology. In the remaining 2 cases, patients presented with localized disease and received a diagnosis on resection, with both patients demonstrating an epithelial-predominant morphology. Tumor cells in all cases were patchy variable positive for PAX8 and WT1 immunohistochemistry. Next-generation sequencing identified alterations previously reported in pediatric WT in 3 of 4 cases, including mutations in ASXL1 (2 of 4), WT1 (1 of 4), and the TERT promoter (1 of 4), as well as 1q gains (1 of 4); 1 case showed no alterations. Three patients were treated with pediatric chemotherapy protocols; during follow up (range, 26-60 months), 1 patient died of disease.WT is an unexpected and difficult entity to diagnose in adults and should be considered when faced with a primitive-appearing renal or metastatic tumor. Molecular testing may help exclude other possibilities but may not be sensitive or specific because of the relatively large number of driver mutations reported in WT.

  View details for DOI 10.5858/arpa.2023-0127-OA

  View details for PubMedID 37756569

• 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