Publications by authors named "Maria S Tretiakova"

64 Publications

New developments in existing WHO entities and evolving molecular concepts: The Genitourinary Pathology Society (GUPS) update on renal neoplasia.

Mod Pathol 2021 Mar 4. Epub 2021 Mar 4.

Sydney Medical School, University of Sydney, Sydney, NSW, Australia.

The Genitourinary Pathology Society (GUPS) reviewed recent advances in renal neoplasia, particularly post-2016 World Health Organization (WHO) classification, to provide an update on existing entities, including diagnostic criteria, molecular correlates, and updated nomenclature. Key prognostic features for clear cell renal cell carcinoma (RCC) remain WHO/ISUP grade, AJCC/pTNM stage, coagulative necrosis, and rhabdoid and sarcomatoid differentiation. Accrual of subclonal genetic alterations in clear cell RCC including SETD2, PBRM1, BAP1, loss of chromosome 14q and 9p are associated with variable prognosis, patterns of metastasis, and vulnerability to therapies. Recent National Comprehensive Cancer Network (NCCN) guidelines increasingly adopt immunotherapeutic agents in advanced RCC, including RCC with rhabdoid and sarcomatoid changes. Papillary RCC subtyping is no longer recommended, as WHO/ISUP grade and tumor architecture better predict outcome. New papillary RCC variants/patterns include biphasic, solid, Warthin-like, and papillary renal neoplasm with reverse polarity. For tumors with 'borderline' features between oncocytoma and chromophobe RCC, a term "oncocytic renal neoplasm of low malignant potential, not further classified" is proposed. Clear cell papillary RCC may warrant reclassification as a tumor of low malignant potential. Tubulocystic RCC should only be diagnosed when morphologically pure. MiTF family translocation RCCs exhibit varied morphologic patterns and fusion partners. TFEB-amplified RCC occurs in older patients and is associated with more aggressive behavior. Acquired cystic disease (ACD) RCC-like cysts are likely precursors of ACD-RCC. The diagnosis of renal medullary carcinoma requires a negative SMARCB1 (INI-1) expression and sickle cell trait/disease. Mucinous tubular and spindle cell carcinoma (MTSCC) can be distinguished from papillary RCC with overlapping morphology by losses of chromosomes 1, 4, 6, 8, 9, 13, 14, 15, and 22. MTSCC with adverse histologic features shows frequent CDKN2A/2B (9p) deletions. BRAF mutations unify the metanephric family of tumors. The term "fumarate hydratase deficient RCC" ("FH-deficient RCC") is preferred over "hereditary leiomyomatosis and RCC syndrome-associated RCC". A low threshold for FH, 2SC, and SDHB immunohistochemistry is recommended in difficult to classify RCCs, particularly those with eosinophilic morphology, occurring in younger patients. Current evidence does not support existence of a unique tumor subtype occurring after chemotherapy/radiation in early childhood.
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http://dx.doi.org/10.1038/s41379-021-00779-wDOI Listing
March 2021

Patterns and timing of perioperative blood transfusion and association with outcomes after radical cystectomy.

Urol Oncol 2021 Feb 4. Epub 2021 Feb 4.

Department of Urology, University of Washington, Seattle, WA; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA. Electronic address:

Background: Perioperative blood transfusion (PBT) has been associated with worse outcomes across tumor types, including bladder cancer. We report our institutional experience with PBT utilization in the setting of radical cystectomy (RC) for patients with bladder cancer, exploring whether timing of PBT receipt influences perioperative and oncologic outcomes.

Methods: Consecutive patients with bladder cancer treated with RC were identified. PBT was defined as red blood cell transfusion during RC or the postoperative admission. Clinicopathologic and peri and/or postoperative parameters were extracted and compared between patients who did and did not receive PBT using Mann Whitney U Test, chi-square, and log-rank test. Overall (OS) and recurrence-free survival (RFS) were estimated with the Kaplan Meier method. Univariate/multivariate logistic and Cox proportional hazards regression were used to identify variables associated with postoperative and oncologic outcomes, respectively.

Results: The cohort consisted of 747 patients (77% men; median age 67 years). Median follow-up was 61.5 months (95% CI 55.8-67.2) At least one postoperative complication (90-day morbidity) occurred in 394 (53%) patients. Median OS and RFS were 91.8 months (95% CI: 76.0-107.6) and 66.0 months (95% CI: 48.3-83.7), respectively. On multivariate analysis, intraoperative, but not postoperative, BT was independently associated with shorter OS (HR: 1.74, 95% CI: 1.32-2.29) and RFS (HR: 1.55, 95%CI: 1.20-2.01), after adjusting for relevant clinicopathologic variables. PBT (intra- or post- operative) was significantly associated with prolonged postoperative hospitalization ≥10 days.

Conclusions: Intraoperative BT was associated with inferior OS and RFS, and PBT overall was associated with prolonged hospitalization following RC. Further studies are needed to validate this finding and explore potential causes for this observation.
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http://dx.doi.org/10.1016/j.urolonc.2021.01.009DOI Listing
February 2021

Novel, emerging and provisional renal entities: The Genitourinary Pathology Society (GUPS) update on renal neoplasia.

Mod Pathol 2021 Feb 1. Epub 2021 Feb 1.

Department of Pathology, Charles University in Prague, Faculty of Medicine and University Hospital in Plzen, Plzen, Czech Republic.

The Genitourinary Pathology Society (GUPS) undertook a critical review of the recent advances in renal neoplasia, particularly focusing on the newly accumulated evidence post-2016 World Health Organization (WHO) classification. In the era of evolving histo-molecular classification of renal neoplasia, morphology is still key. However, entities (or groups of entities) are increasingly characterized by specific molecular features, often associated either with recognizable, specific morphologies or constellations of morphologies and corresponding immunohistochemical profiles. The correct diagnosis has clinical implications leading to better prognosis, potential clinical management with targeted therapies, may identify hereditary or syndromic associations, which may necessitate appropriate genetic testing. We hope that this undertaking will further facilitate the identification of these entities in practice. We also hope that this update will bring more clarity regarding the evolving classification of renal neoplasia and will further reduce the category of "unclassifiable renal carcinomas/tumors". We propose three categories of novel entities: (1) "Novel entity", validated by multiple independent studies; (2) "Emerging entity", good compelling data available from at least two or more independent studies, but additional validation is needed; and (3) "Provisional entity", limited data available from one or two studies, with more work required to validate them. For some entities initially described using different names, we propose new terminologies, to facilitate their recognition and to avoid further diagnostic dilemmas. Following these criteria, we propose as novel entities: eosinophilic solid and cystic renal cell carcinoma (ESC RCC), renal cell carcinoma with fibromyomatous stroma (RCC FMS) (formerly RCC with leiomyomatous or smooth muscle stroma), and anaplastic lymphoma kinase rearrangement-associated renal cell carcinoma (ALK-RCC). Emerging entities include: eosinophilic vacuolated tumor (EVT) and thyroid-like follicular renal cell carcinoma (TLFRCC). Finally, as provisional entities, we propose low-grade oncocytic tumor (LOT), atrophic kidney-like lesion (AKLL), and biphasic hyalinizing psammomatous renal cell carcinoma (BHP RCC).
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http://dx.doi.org/10.1038/s41379-021-00737-6DOI Listing
February 2021

Diagnostic approach in TFE3-rearranged renal cell carcinoma: a multi-institutional international survey.

J Clin Pathol 2021 Jan 29. Epub 2021 Jan 29.

Department of Pathology & Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA.

Transcription factor E3-rearranged renal cell carcinoma (TFE3-RCC) has heterogenous morphologic and immunohistochemical (IHC) features.131 pathologists with genitourinary expertise were invited in an online survey containing 23 questions assessing their experience on TFE3-RCC diagnostic work-up.Fifty (38%) participants completed the survey. 46 of 50 participants reported multiple patterns, most commonly papillary pattern (almost always 9/46, 19.5%; frequently 29/46, 63%). Large epithelioid cells with abundant cytoplasm were the most encountered cytologic feature, with either clear (almost always 10/50, 20%; frequently 34/50, 68%) or eosinophilic (almost always 4/49, 8%; frequently 28/49, 57%) cytology. Strong (3+) or diffuse (>75% of tumour cells) nuclear TFE3 IHC expression was considered diagnostic by 13/46 (28%) and 12/47 (26%) participants, respectively. Main TFE3 IHC issues were the low specificity (16/42, 38%), unreliable staining performance (15/42, 36%) and background staining (12/42, 29%). Most preferred IHC assays other than TFE3, cathepsin K and pancytokeratin were melan A (44/50, 88%), HMB45 (43/50, 86%), carbonic anhydrase IX (41/50, 82%) and CK7 (32/50, 64%). Cut-off for positive fluorescent in situ hybridisation (FISH) was preferably 10% (9/50, 18%), although significant variation in cut-off values was present. 23/48 (48%) participants required FISH testing to confirm TFE3-RCC regardless of the histomorphologic and IHC assessment. 28/50 (56%) participants would request additional molecular studies other than FISH assay in selected cases, whereas 3/50 participants use additional molecular cases in all cases when TFE3-RCC is in the differential.Optimal diagnostic approach on TFE3-RCC is impacted by IHC and/or FISH assay preferences as well as their conflicting interpretation methods.
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http://dx.doi.org/10.1136/jclinpath-2020-207372DOI Listing
January 2021

Dopamine secreting adrenal tumor-ganglioneuroma rather than pheochromocytoma: case report.

Gland Surg 2020 Dec;9(6):2204-2210

Department of Surgery, University of Washington, Seattle, WA, USA.

Ganglioneuromas are rare, benign, well-differentiated neural crest tumors arising in the paravertebral sympathetic chain, and are classically non-secretory and clinically asymptomatic. As the diagnosis of ganglioneuroma is based on histopathology, the clinical presentation prior to surgical excision often mirrors that of pheochromocytoma or adrenal cortical adenoma. We describe a case of an incidentally found right sided calcified adrenal mass with evidence of marked dopamine excess, suspicious for pheochromocytoma in a 70-year-old female. The patient endorsed a 6-month history of intermittent right flank pain and a 2-year history of weight loss and fatigue. She reported mild symptoms of hypomania but denied other symptoms of dopamine excess including agitation, anxiety, nausea, and vomiting. Exam revealed isolated mild hypertension. The imaging features of this mass were concerning for malignancy including the presence of macrocalcification and irregular borders. After preoperative alpha blockade, the patient underwent open right adrenalectomy and the final pathology was consistent with ganglioneuroma rather than pheochromocytoma. Following resection, the dopamine level normalized, confirming the resected right adrenal ganglioneuroma as the source of dopamine excess. This case represents a rare presentation of dopamine-secreting adrenal ganglioneuroma. This illustrates that although rare, ganglioneuroma should be included on the differential diagnosis for functional adrenal tumors.
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http://dx.doi.org/10.21037/gs-20-475DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7804545PMC
December 2020

Response to Neoadjuvant Chemotherapy and Survival in Micropapillary Urothelial Carcinoma: Data From a Tertiary Referral Center and the Surveillance, Epidemiology, and End Results (SEER) Program.

Clin Genitourin Cancer 2020 Oct 14. Epub 2020 Oct 14.

Department of Urology, University of Washington, Seattle, WA; Fred Hutchinson Cancer Research Center, Seattle, WA. Electronic address:

Background: Micropapillary urothelial carcinoma (MPC) is a rare urothelial carcinoma variant with conflicting data guiding clinical practice. In this study, we explored oncologic outcomes in relation to neoadjuvant chemotherapy (NAC) in a retrospective cohort of patients with MPC, alongside data from Surveillance, Epidemiology, and End Results (SEER)-Medicare.

Patients And Methods: We retrospectively identified patients with MPC or conventional urothelial carcinoma (CUC) without any variant histology undergoing radical cystectomy (RC) in our institution (2003-2018). SEER-Medicare was also queried to identify patients diagnosed with MPC (2004-2015). Clinicopathologic data and treatment modalities were extracted. Overall survival (OS) was estimated with the Kaplan-Meier method. Mann-Whitney-Wilcoxon and chi-square tests were used for comparative analysis and Cox regression for identifying clinical covariates associated with OS.

Results: Our institutional database yielded 46 patients with MPC and 457 with CUC. In SEER-Medicare, 183 patients with MPC were identified, and 63 (34%) underwent RC. In the institutional cohort, patients with MPC had significantly higher incidence of cN+ (17% vs. 8%), pN+ stage (30% vs. 17%), carcinoma-in-situ (43% vs. 25%), and lymphovascular invasion (30% vs. 16%) at RC versus those with CUC (all P < .05). Pathologic complete response (ypT0N0) to NAC was 33% for MPC and 35% for CUC (P = .899). Median OS was lower for institutional MPC versus CUC in univariate analysis (43.6 vs. 105.3 months, P = .006); however, MPC was not independently associated with OS in the multivariate model. Median OS was 25 months in the SEER MPC cohort for patients undergoing RC, while NAC was not associated with improved OS in that group.

Conclusion: Pathologic response to NAC was not significantly different between MPC and CUC, while MPC histology was not an independent predictor of OS. Further studies are needed to better understand biological mechanisms behind its aggressive features as well as the role of NAC in this histology variant.
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http://dx.doi.org/10.1016/j.clgc.2020.10.002DOI Listing
October 2020

Practice patterns related to prostate cancer grading: results of a 2019 Genitourinary Pathology Society clinician survey.

Urol Oncol 2020 Sep 15. Epub 2020 Sep 15.

Departments of Pathology, The Johns Hopkins Medical Institutions, Baltimore, MD; Departments of Urology and Oncology, The Johns Hopkins Medical Institutions, Baltimore, MD.

Purpose: To survey urologic clinicians regarding interpretation of and practice patterns in relation to emerging aspects of prostate cancer grading, including quantification of high-grade disease, cribriform/intraductal carcinoma, and impact of magnetic resonance imaging-targeted needle biopsy.

Materials And Methods: The Genitourinary Pathology Society distributed a survey to urology and urologic oncology-focused societies and hospital departments. Eight hundred and thirty four responses were collected and analyzed using descriptive statistics.

Results: Eighty percent of survey participants use quantity of Gleason pattern 4 on needle biopsy for clinical decisions, less frequently with higher Grade Groups. Fifty percent interpret "tertiary" grade as a minor/<5% component. Seventy percent of respondents would prefer per core grading as well as a global/overall score per set of biopsies, but 70% would consider highest Gleason score in any single core as the grade for management. Seventy five percent utilize Grade Group terminology in patient discussions. For 45%, cribriform pattern would affect management, while for 70% the presence of intraductal carcinoma would preclude active surveillance.

Conclusion: This survey of practice patterns in relationship to prostate cancer grading highlights similarities and differences between contemporary pathology reporting and its clinical application. As utilization of Gleason pattern 4 quantification, minor tertiary pattern, cribriform/intraductal carcinoma, and the incorporation of magnetic resonance imaging-based strategies evolve, these findings may serve as a basis for more nuanced communication and guide research efforts involving pathologists and clinicians.
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http://dx.doi.org/10.1016/j.urolonc.2020.08.027DOI Listing
September 2020

Renal Cell Tumors: Molecular Findings Reshaping Clinico-pathological Practice.

Arch Med Res 2020 11 21;51(8):799-816. Epub 2020 Aug 21.

Department of Laboratory Medicine and Pathology, University of Washington, Seattle, Washington, USA. Electronic address:

Over the past 20 years, the number of subtypes of renal epithelial cell neoplasia has grown. This growth has resulted from detailed histological and immunohistochemical characterization of these tumors and their correlation with clinical outcomes. Distinctive molecular phenotypes have validated the unique nature of many of these tumors. This growth of unique renal neoplasms has continued after the 2016 World Health Organization (WHO) Classification of Tumours. A consequence is that both the pathologists who diagnose the tumors and the clinicians who care for these patients are confronted with a bewildering array of renal cell carcinoma variants. Many of these variants have important clinical features, i.e. familial or syndromic associations, genomics alterations that can be targeted with systemic therapy, and benignancy of tumors previously classified as carcinomas. Our goal in the review is to provide a practical guide to help recognize these variants, based on small and distinct sets of histological features and limited numbers of immunohistochemical stains, supplemented, as necessary, with molecular features.
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http://dx.doi.org/10.1016/j.arcmed.2020.08.003DOI Listing
November 2020

Sporadic oncocytic tumors with features intermediate between oncocytoma and chromophobe renal cell carcinoma: comprehensive clinicopathological and genomic profiling.

Hum Pathol 2020 Oct 13;104:18-29. Epub 2020 Jul 13.

Department of Pathology, University of Washington, Seattle, WA, 98105, United States. Electronic address:

Morphology, clinical behavior, and genomic profiles of renal oncocytoma (RO) and its malignant counterpart chromophobe renal cell carcinoma (ChRCC) are distinctly different. However, there is a substantial group of sporadic oncocytic tumors with peculiar hybrid phenotypes as well as a perplexing degree of morphologic and immunohistochemical overlap between classic RO and ChRCC with eosinophilic cytoplasm. The aim of this study is to provide detailed characterization of these hybrid tumors.Thirty-eight sporadic oncocytic neoplasms with ambiguous morphology from two institutions were reviewed by 4 pathologists. CKIT positivity was used as a selection criterion. We correlated CK7 and S100A1 immunostaining and detailed morphologic features with cytogenetic profiles. DNA from the formalin-fixed paraffin-embedded tissues was extracted and analyzed using cytogenomic microarray analysis (CMA) to evaluate copy number alterations (CNA) and ploidy. CMA categorized cases into 3 groups: RO (N = 21), RO variant (N = 7), and ChRCC (N = 10). Cytogenetic RO had either no CNA (48%) or loss of chromosome 1p, X, or Y (52%). RO variant had additional chromosomal losses [-9q, -14 (n = 2), -13] and chromosomal gains [+1q (n = 2), +4, +7 (n = 2), +13, +19, +20, and +22]. ChRCCs were either hypodiploid with numerous monosomies (40%) or hypotetraploid with multiple relative losses (60%). RO, RO variant, and ChRCC groups differed significantly in tumor architecture (p < 0.01), stroma (p = 0.013), presence of nuclear wrinkling, perinuclear halos, and well-defined cell borders in >5% of cells (p < 0.01), focal cell clearing (p = 0.048) and CK7 expression (p < 0.02). Pathologic prediction of the cytogenetic subtype using only two categories (benign RO or malignant ChRCC) would overcall or undercall up to 40% of tumors that were ChRCC based on cytogenetics. This finding provides the rationale for an intermediate diagnostic category of the so-called hybrid tumors (hybrid oncocytic/chromophobe tumor [HOCT]). HOCT was a heterogeneous group enriched for cytogenetic RO variant. Other HOCTs have a profile of either RO or ChRCC. The genomic profile allows classification of oncocytic tumors with ambiguous morphology into RO, RO variant, and ChRCC. Several architectural and cytologic features combined with CK7 expression are significantly associated with cytogenetic RO, RO variant, or ChRCC tumors. Doubled hypodiploidy by whole-genome endoduplication is a common phenomenon in eosinophilic ChRCC.
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http://dx.doi.org/10.1016/j.humpath.2020.07.003DOI Listing
October 2020

The 2019 Genitourinary Pathology Society (GUPS) White Paper on Contemporary Grading of Prostate Cancer.

Arch Pathol Lab Med 2020 Jun 26. Epub 2020 Jun 26.

From the Departments of Pathology (Drs Epstein, DeMarzo, and Lotan), Urology (Dr Epstein), and Oncology (Dr Epstein), The Johns Hopkins Medical Institutions, Baltimore, Maryland; Department of Pathology and Laboratory Medicine and Urology, University of Tennessee Health Science, Memphis (Dr Amin); Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York (Dr Fine); Department of Pathology, Fundacio Puigvert, Barcelona, Spain (Dr Algaba); Department of Pathology, University of Southern California, Los Angeles (Dr Aron); Department of Pathology, Faculty of Medicine, Koç University, İstanbul, Turkey (Dr Baydar); Department of Pathology, Champalimaud Centre for the Unknown, Lisbon, Portugal (Dr Beltran); Department of Pathology, McGill University Health Center, Montréal, QC, Canada (Dr Brimo); Department of Pathology, Mayo Clinic, Rochester, Minnesota (Drs Cheville and Jimenez); Department of Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy (Dr Colecchia); Department of Pathology, Hôpital Tenon, Sorbonne University, Paris, France (Dr Comperat); Pathology Department, Rede D'OR-Sao Luiz, Sao Paulo, SP, Brazil (Dr da Cunha); Douglass Hanly Moir Pathology, Sydney, Australia (Dr Delprado); Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee (Drs Giannico and Gordetsky); Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston (Dr Guo); Department of Pathology, Oregon Health and Science University, Portland (Dr Hansel); Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts (Dr Hirsch); Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California (Dr Huang); Department of Pathology, Yale School of Medicine, New Haven, Connecticut (Dr Humphrey); Department of Pathology and Laboratory Medicine and Urology, Weill Cornell Medicine, New York, New York (Drs Khani and Robinson); Department of Pathology, Qingdao Municipal Hospital, Qingdao, Shandong, China (Dr Kong); Departments of Pathology and Laboratory Medicine and Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida (Dr Kryvenko); Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan (Drs Kunju and Mehra); Perelman School of Medicine, University of Pennsylvania, Philadelphia (Dr Lal); Department of Pathology, CHUM, Université de Montréal, Montréal, QC, Canada (Dr Latour); Douglass Hanly Moir Pathology, Faculty of Medicine and Health Sciences Macquarie University, North Ryde, Australia (Dr Maclean); Department of Pathology, The University of Alabama at Birmingham, Birmingham (Drs Magi-Galluzzi and Netto); Department of Surgical Pathology, Tata Memorial Hospital, Parel, Mumbai, India (Dr Menon); Departments of Pathology and Laboratory Medicine and Urology, University of Rochester Medical Center, Rochester, New York (Dr Miyamoto); Section of Pathological Anatomy, School of Medicine, Polytechnic University of the Marche Region, United Hospitals, Ancona, Italy (Dr Montironi); Robert J. Tomsich Pathology and Laboratory Medicine Institute, Cleveland Clinic, Cleveland, Ohio (Dr Nguyen); Department of Pathology, Emory University School of Medicine, Atlanta, Georgia (Dr Osunkoya); Department of Pathology, Ohio State University, Columbus (Drs Parwani and Zynger); Department for BioMedical Research, University of Bern, Bern, Switzerland (Dr Rubin); Department of Pathology, The University of Texas Southwestern Medical Center, Dallas (Dr Shah); Institute of Pathology, St Luke's Medical Center, Quezon City and Global City, Philippines (Dr So); Department of Pathology, The Jikei University School of Medicine, Tokyo, Japan (Dr Takahashi); Argos Laboratory, Federal University of Ceara, Fortaleza, Brazil (Dr Tavora); Department of Pathology, University of Washington School of Medicine, Seattle (Drs Tretiakova and True); Departments of Pathology and Laboratory Medicine and Urology, University of North Carolina, Chapel Hill (Dr Wobker); Department of Pathology, Northwestern University, Chicago, Illinois (Dr Yang); Department of Pathology, Tufts Medical Center, Boston, Massachusetts (Dr Zhou); and Department of Pathology and Laboratory Medicine, University of Calgary, Calgary, AB, Canada (Dr Trpkov). Dr Kong is currently located at Kaiser Permanente Sacramento Medical Center, Sacramento, California.

Context.—: Controversies and uncertainty persist in prostate cancer grading.

Objective.—: To update grading recommendations.

Data Sources.—: Critical review of the literature along with pathology and clinician surveys.

Conclusions.—: Percent Gleason pattern 4 (%GP4) is as follows: (1) report %GP4 in needle biopsy with Grade Groups (GrGp) 2 and 3, and in needle biopsy on other parts (jars) of lower grade in cases with at least 1 part showing Gleason score (GS) 4 + 4 = 8; and (2) report %GP4: less than 5% or less than 10% and 10% increments thereafter. Tertiary grade patterns are as follows: (1) replace "tertiary grade pattern" in radical prostatectomy (RP) with "minor tertiary pattern 5 (TP5)," and only use in RP with GrGp 2 or 3 with less than 5% Gleason pattern 5; and (2) minor TP5 is noted along with the GS, with the GrGp based on the GS. Global score and magnetic resonance imaging (MRI)-targeted biopsies are as follows: (1) when multiple undesignated cores are taken from a single MRI-targeted lesion, an overall grade for that lesion is given as if all the involved cores were one long core; and (2) if providing a global score, when different scores are found in the standard and the MRI-targeted biopsy, give a single global score (factoring both the systematic standard and the MRI-targeted positive cores). Grade Groups are as follows: (1) Grade Groups (GrGp) is the terminology adopted by major world organizations; and (2) retain GS 3 + 5 = 8 in GrGp 4. Cribriform carcinoma is as follows: (1) report the presence or absence of cribriform glands in biopsy and RP with Gleason pattern 4 carcinoma. Intraductal carcinoma (IDC-P) is as follows: (1) report IDC-P in biopsy and RP; (2) use criteria based on dense cribriform glands (>50% of the gland is composed of epithelium relative to luminal spaces) and/or solid nests and/or marked pleomorphism/necrosis; (3) it is not necessary to perform basal cell immunostains on biopsy and RP to identify IDC-P if the results would not change the overall (highest) GS/GrGp part per case; (4) do not include IDC-P in determining the final GS/GrGp on biopsy and/or RP; and (5) "atypical intraductal proliferation (AIP)" is preferred for an intraductal proliferation of prostatic secretory cells which shows a greater degree of architectural complexity and/or cytological atypia than typical high-grade prostatic intraepithelial neoplasia, yet falling short of the strict diagnostic threshold for IDC-P. Molecular testing is as follows: (1) Ki67 is not ready for routine clinical use; (2) additional studies of active surveillance cohorts are needed to establish the utility of PTEN in this setting; and (3) dedicated studies of RNA-based assays in active surveillance populations are needed to substantiate the utility of these expensive tests in this setting. Artificial intelligence and novel grading schema are as follows: (1) incorporating reactive stromal grade, percent GP4, minor tertiary GP5, and cribriform/intraductal carcinoma are not ready for adoption in current practice.
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http://dx.doi.org/10.5858/arpa.2020-0015-RADOI Listing
June 2020

Abundant CD8+ tumor infiltrating lymphocytes and beta-2-microglobulin are associated with better outcome and response to interleukin-2 therapy in advanced stage clear cell renal cell carcinoma.

Ann Diagn Pathol 2020 Aug 19;47:151537. Epub 2020 May 19.

Oregon Health & Science University, Department of Pathology, Portland, OR 97239, United States of America. Electronic address:

Studies assessing tumor-infiltrating lymphocytes (TILs) in clear cell renal cell carcinoma (ccRCC) and clinical outcomes have mixed results. Given fundamental interaction of MHC class I with CD8+ T-cells, we hypothesized that expression of MHC class I associated protein, beta-2-microglobulin (B2M), may be an important immunologic marker in RCC. We sought to understand potential implications of CD8 + TILs and tumor B2M expression on overall survival and response to high-dose interleukin-2 (IL-2) therapy, in a cohort of patients with high-stage (clinical stage III and IV) ccRCC. Four tumor regions from 56 patients with ccRCC were retrospectively assessed immunohistochemically. At a median follow-up time of 33 months, 22 (39%) patients had died of disease, 23 (41%) were alive disease, and 11 (20%) had no evidence of disease. Tumors with high CD8 + TILs had a significantly lower death rate [hazard ratio (HR): 0.33, p = 0.02]. CD8 + TILs correlated with B2M expression (p = 0.007). On multivariable analyses, patients with both high B2M and CD8 + TILs had lower death rate (HR: 0.27, p = 0.03). Within the subgroup treated with IL-2 (n = 27, 48%), tumors with high CD8 + TILs were more likely to respond to IL-2 therapy [coefficient (coef): 1.6, p = 0.05]. On multivariable analyses, tumors with a combination of both high B2M expression and high CD8 + TILs also showed trend to responding to IL-2 therapy (coef: 2.5, p = 0.06). In conclusion, abundant CD8+ TILs and high tumor expression of beta-2-microglobulin were good prognostic indicators associated with longer survival in patients with high-stage ccRCC. Abundant CD8+ TILs may predict response to IL-2 therapy.
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http://dx.doi.org/10.1016/j.anndiagpath.2020.151537DOI Listing
August 2020

Malignant Intrarenal/Renal Pelvis Paraganglioma with Co-Occurring SDHB and ATRX Mutations.

Endocr Pathol 2019 Dec;30(4):270-275

Department of Pathology, University of Washington, Seattle, WA, USA.

Paragangliomas are rare neuroendocrine tumors which originate from embryonic neural crest cells. These tumors may arise from parasympathetic or sympathetic paraganglia, may secrete catecholamines, and can occur in varied anatomic locations, with some locations being less common than others. Hereditary paraganglioma-pheochromocytoma (PGL/PCC) syndromes are characterized by paragangliomas and pheochromocytomas and have been associated with germline heterozygous mutations in MAX, SDHA, SDHAF2, SDHB, SDHC, SDHD, or TMEM127. Herein, we report a case of a middle-aged male who was diagnosed with an intrarenal/renal pelvis paraganglioma after presenting in hypertensive crisis with palpitations, headache, and diaphoresis. He was later found to have extensive metastatic disease, as well as genetic testing that showed biallelic inactivation of SDHB and a co-occurring somatic ATRX mutation. Respectively, these germline and somatic mutations have been associated with increased risk of metastatic spread and clinical aggressiveness. Despite multiple surgical resections and various treatment modalities, the patient eventually elected for palliative care measures and died of disease. Together, the findings seen in this patient are unique and serve as an appropriate catalyst for discussing the unusual locations, interesting genetic profiles, and metastatic risk factors that may be associated with paragangliomas.
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http://dx.doi.org/10.1007/s12022-019-09594-1DOI Listing
December 2019

An Unusual Manifestation of Blastic Plasmacytoid Dendritic Cell Neoplasm as a Testicular Tumor.

Case Rep Pathol 2019 7;2019:9196167. Epub 2019 Oct 7.

University of Washington School of Medicine, 1959 NE Pacific Street, Seattle, WA 98195, USA.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a clinically aggressive hematologic malignancy arising from precursors of plasmacytoid dendritic cells that represent less than 1% of hematological malignancies. BPDCN initially presents with cutaneous involvement and a characteristic immunophenotype of CD4, CD56, and CD123 co-expression. Upon disease progression, BPDCN shows a strong predilection for bone marrow, peripheral blood, and lymph nodes, whereas manifestations in visceral organs are rare. Significant heterogeneity in clinical presentation and immunophenotypic profile makes BPDCN challenging to diagnose without an integrated approach based on patient history, clinical features, tumor pathology, and comprehensive immunohistochemical studies. Herein we report the first case of relapsed BPDCN manifesting as a unilateral testicular tumor.
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http://dx.doi.org/10.1155/2019/9196167DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6800931PMC
October 2019

Gene fusion analysis in renal cell carcinoma by FusionPlex RNA-sequencing and correlations of molecular findings with clinicopathological features.

Genes Chromosomes Cancer 2019 Aug 10. Epub 2019 Aug 10.

Department of Pathology, University of Washington School of Medicine, Seattle, Washington.

Translocation renal cell carcinoma (tRCC) affects younger patients and often presents as advanced disease. Accurate diagnosis is required to guide clinical management. Here we evaluate the RNA-sequencing FusionPlex platform with a 115-gene panel including TFE3 and TFEB for tRCC diagnosis and correlate molecular findings with clinicopathological features. We reviewed 996 consecutive RCC cases from our institution over the preceding 7 years and retrieved 17 cases with histological and immunohistochemical features highly suggestive of either TFE3 (n = 16) or TFEB (n = 1). Moderate to strong labeling for TFE3 was present in 15 cases; two cases with weak TFE3 expression were melan-A or cathepsin-K positive. RNA-sequencing detected gene rearrangements in eight cases: PRCC-TFE3 (3), ASPSCR1-TFE3 (2), LUC7L3-TFE3 (1), SFPQ-TFE3 (1), and a novel SETD1B-TFE3 (1). FISH assays of 11 tumors verified six positive cases concordant with FusionPlex analysis results. Two other cases were confirmed by RT-PCR. FusionPlex was superior to FISH by providing precise breakpoints for tRCC-related genes in a single assay and allowing identification of both known and novel fusion partners, thereby facilitating clinicopathological correlations as fusion partners can influence tumor appearance, immunophenotype, and behavior. Cases with partner genes PRCC and novel partner SETD1B were associated with prominent papillary architecture while cases with partner genes ASPSCR1 and LUC7L3 were associated with a predominantly nested/alveolar pattern. The case with SFPQ-TFE3 fusion was characterized by biphasic morphology mimicking TFEB-like translocation RCC. We recommend FusionPlex analysis of RCC in patients under age 50 or when the histologic appearance suggests tRCC.
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http://dx.doi.org/10.1002/gcc.22798DOI Listing
August 2019

Thyroid-Like Follicular Renal Cell Carcinoma Arising Within Benign Mixed Epithelial and Stromal Tumor.

Int J Surg Pathol 2020 Feb 25;28(1):80-86. Epub 2019 Jul 25.

University of Washington Medical Center, Seattle, WA, USA.

Thyroid-like follicular renal cell carcinoma (TLF-RCC) is an extremely rare tumor with less than 40 published reports. These tumors are morphologically distinct with striking resemblance to thyroid follicular tumors, but immunohistochemically different due to lack of thyroglobulin and thyroid transcription factor 1 expression. TLF-RCCs arise in younger patients (mean age = 41 years) with female predominance and in all reported cases were solitary tumors without coexisting epithelial or mesenchymal kidney neoplasms. In this article, we report a case of a 42-year-old woman who presented with an incidental 4-cm solid and cystic left renal mass of the upper pole, which was resected. A detailed imaging assessment, pathologic findings, and immunohistochemical studies revealed a partially encapsulated TLF-RCC arising in a background of mixed epithelial and stromal tumor.
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http://dx.doi.org/10.1177/1066896919863478DOI Listing
February 2020

Genomic Characterization of Prostatic Ductal Adenocarcinoma Identifies a High Prevalence of DNA Repair Gene Mutations.

JCO Precis Oncol 2019 18;3. Epub 2019 Apr 18.

University of Washington, Seattle, WA.

Purpose: Ductal prostate cancer (dPC) is a rare variant of prostatic adenocarcinoma associated with poor outcomes. Although its histopathologic features are well characterized, the underlying molecular hallmarks of this aggressive subtype are not well described. We sought to provide a comprehensive overview of the spectrum of mutations associated with dPC.

Methods: Three case series across multiple institutions were assembled. All patients had a diagnosis of dPC, and histopathologic classification was confirmed by an expert genitourinary pathologist. Case series 1 included men who were prospectively enrolled in a tumor sequencing study at the University of Washington (n = 22). Case series 2 and 3 included archival samples from men treated at Johns Hopkins Hospital (n = 21) and University of Calgary (n = 8), respectively. Tumor tissue was sequenced on a targeted next-generation sequencing assay, UW-OncoPlex, according to previously published methods. The frequency of pathogenic/likely pathogenic mutations are reported.

Results: Overall, 25 patients (49%) had at least one DNA damage repair gene alteration, including seven (14%) with a mismatch repair gene mutation and 16 (31%) with a homologous repair mutation. Germline autosomal dominant mutations were confirmed or suspected in 10 patients (20%). Activating mutations in the PI3K pathway (n = 19; 37%), WNT pathway (n = 16; 31%), and MAPK pathway (n = 8; 16%) were common.

Conclusion: This study strongly suggests that dPCs are enriched for actionable mutations, with approximately 50% of patients demonstrating DNA damage repair pathway alteration(s). Patients with dPC should be offered next-generation sequencing to guide standard-of-care treatment (eg, immune checkpoint inhibitors) or triaged toward an appropriate clinical trial (eg, poly [ADP-ribose] polymerase inhibitors).
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http://dx.doi.org/10.1200/PO.18.00327DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6528668PMC
April 2019

Clinical Utility of Chromosome Genomic Array Testing for Unclassified and Advanced-Stage Renal Cell Carcinomas.

Arch Pathol Lab Med 2019 04 1;143(4):494-504. Epub 2018 Nov 1.

From the Department of Pathology, University of Washington, Seattle (Drs Andeen and Tretiakova); the Department of Pathology, Oregon Health & Science University, Portland (Dr Andeen); Cytogenetics, Seattle Cancer Care Alliance, Seattle, Washington (Dr Qu); the Department of Pathology, University of Chicago, Chicago, Illinois (Dr Antic); and the Division of Medical Oncology, Department of Medicine (Dr Tykodi), and the Department of Pathology (Dr Fang), University of Washington, and Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle. Drs Andeen and Qu contributed equally to this work.

Context.—: Cytogenomic analysis provides a useful adjunct to traditional pathology in the categorization of renal cell carcinomas (RCCs), particularly in morphologically ambiguous cases, but it has disadvantages, including cost.

Objective.—: To define the clinical scenarios in which this technology has direct clinical applications.

Design.—: DNA was isolated from paraffin-embedded tissue from 40 selected cases of RCC. Chromosome genomic array testing was performed using the OncoScan.

Results.—: Of 23 cases of unclassified renal tumors, 19 (83%) were reclassified with incorporation of cytogenetic and histologic features, including 10 as clear cell RCC, 2 as collecting duct carcinoma, 2 as papillary RCC, and 1 as novel TFEB-amplified tumor lacking TFEB translocation. Of 5 tumors with "hybrid" oncocytic features, 3 were reclassified as an eosinophilic variant of chromophobe RCC and 1 as oncocytoma. Appropriate staging in 2 patients was determined by identifying distinct, nonshared cytogenetic profiles. Of 11 cases of metastatic clear cell RCC, 7 (63%) had cytogenetic features associated with a poor prognosis.

Conclusions.—: We identified 5 scenarios in which chromosome genomic array testing has direct clinical utility: (1) to investigate unclassified RCCs, (2) to understand tumors with "hybrid" features and "collision" tumors, (3) to determine appropriate staging in questions of bilateral tumors and/or metastases, (4) to identify chromosomal aberrations in metastatic clear cell RCCs associated with a worse prognosis, and (5) to identify new entities. This has practical value in our institution, where a molecular profile diagnostically separating morphologically difficult to classify clear cell, papillary, chromophobe, and unclassified RCC influences treatment recommendations and clinical trial eligibility.
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http://dx.doi.org/10.5858/arpa.2018-0104-OADOI Listing
April 2019

Eosinophilic solid and cystic renal cell carcinoma mimicking epithelioid angiomyolipoma: series of 4 primary tumors and 2 metastases.

Hum Pathol 2018 10 6;80:65-75. Epub 2018 Jun 6.

Department of Pathology, University of Washington Medical Center, Seattle, WA 98105, USA. Electronic address:

Eosinophilic solid and cystic renal cell carcinoma (ESC-RCC) is a novel entity of rare tumors with rather unique morphology and immunohistochemical profile. Until recently these tumors were characterized by indolent behavior. Herein, we describe a series of six primary and metastatic ESC-RCCs morphologically and immunophenotypically mimicking epithelioid angiomyolipoma (eAML). Retrospective review of unclassified RCCs with oncocytic phenotype yielded several candidate cases, 4 of which fulfilled diagnostic criteria after additional work-up. Three female patients and one male (median age 46) presented with unifocal tumors ranging from 1.5 cm to 20.5 cm (median 5 cm). On follow-up (median 32 months), 2 younger patients had no signs of tumor recurrence, but older patients presented with advanced disease. A 50 year-old female developed numerous bone metastases and tumor progression despite aggressive treatment. Two of these metastases were analyzed showing morphology and immunoprofile similar to the primary tumor. 50 year-old male had locally aggressive tumor invading adrenal gland and retroperitoneum. All cases exhibited ESC-like architecture of solid sheets, tight nests and variably sized cysts with hobnailed lining, as well as foci of diffuse growth with poorly cohesive brightly eosinophilic cells. Characteristic cytoplasmic stippling and coarse granularity was present in all cases including compact cytoplasmic "Leishmaniasis-like" globules. Due to high suspicion of eAML, immunostaining panels included melanocytic markers, cytokeratins and RCC-specific markers. All ESC-RCC were positive for CK20 and melanocytic markers Melan-A, Cathepsin-K or HMB45, as well as PAX8, whereas EMA, pan-cytokeratin, CK7, CKIT, CD10, CAIX were negative. Comparison with 5 eAML cases including 2 malignant tumors showed similar morphology and immune reactivity except for more frequent expression of HMB45 and lack of PAX8 positivity. In conclusion, we report 2 cases of aggressive ESC-RCC course including widespread bone metastases in addition to 2 typical indolent tumors. ESC-RCC and eAML could present with overlapping morphology and immunophenotype causing diagnostic difficulty and expanding our understanding of these rare tumors.
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http://dx.doi.org/10.1016/j.humpath.2018.05.023DOI Listing
October 2018

Challenges in Pathologic Staging of Renal Cell Carcinoma: A Study of Interobserver Variability Among Urologic Pathologists.

Am J Surg Pathol 2018 09;42(9):1253-1261

University of Calgary and Calgary Laboratory Services, Calgary, AB, Canada.

Staging criteria for renal cell carcinoma differ from many other cancers, in that renal tumors are often spherical with subtle, finger-like extensions into veins, renal sinus, or perinephric tissue. We sought to study interobserver agreement in pathologic stage categories for challenging cases. An online survey was circulated to urologic pathologists interested in kidney tumors, yielding 89% response (31/35). Most questions included 1 to 4 images, focusing on: vascular and renal sinus invasion (n=24), perinephric invasion (n=9), and gross pathology/specimen handling (n=17). Responses were collapsed for analysis into positive and negative/equivocal for upstaging. Consensus was regarded as an agreement of 67% (2/3) of participants, which was reached in 20/33 (61%) evaluable scenarios regarding renal sinus, perinephric, or vein invasion, of which 13/33 (39%) had ≥80% consensus. Lack of agreement was especially encountered regarding small tumor protrusions into a possible vascular lumen, close to the tumor leading edge. For gross photographs, most were interpreted as suspicious but requiring histologic confirmation. Most participants (61%) rarely used special stains to evaluate vascular invasion, usually endothelial markers (81%). Most agreed that a spherical mass bulging well beyond the kidney parenchyma into the renal sinus (71%) or perinephric fat (90%) did not necessarily indicate invasion. Interobserver agreement in pathologic staging of renal cancer is relatively good among urologic pathologists interested in kidney tumors, even when selecting cases that test the earliest and borderline thresholds for extrarenal extension. Disagreements remain, however, particularly for tumors with small, finger-like protrusions, closely juxtaposed to the main mass.
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http://dx.doi.org/10.1097/PAS.0000000000001087DOI Listing
September 2018

Epitope Preservation Methods for Tissue Microarrays: Longitudinal Prospective Study.

Am J Clin Pathol 2017 Nov;148(5):380-389

Department of Pathology, University of Washington, Seattle.

Objectives: We sought to test recent guidelines for preserving immunoreactivity of precut slides, to quantify loss of immunoreactivity, and to determine potential for preservation by altering storage conditions.

Methods: Precut slides from tissue microarrays were stored under one of several conditions: exposed to ambient air at room temperature, 4°C, or -20°C or in a vacuum-sealed container at room temperature, -20°C, -80°C, or with paraffin coating. At multiple intervals over 1 year, slides were stained with antibodies against p53, isocitrate dehydrogenase 1, Ki-67, synaptophysin, and androgen receptor and evaluated.

Results: Compared with time 0, the overall median percentage immunoreactivity was 66% at 6 months and 51% at 1 year. During the experiment, this was as low as 55% for precut slides stored in paraffin coating and up to 87% for those stored at -20°C. Vacuum sealing was an effective preservative for some antibody targets and detrimental for others. Storage at -80°C did not have added value.

Conclusions: For precut slides, there is a time, storage condition, and antibody-dependent loss of immunoreactivity that could compromise analysis of prognostic, predictive, and diagnostic markers. Our findings support previous recommendations and suggest that the best storage conditions are at -20°C, without paraffin coating or vacuum sealing.
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http://dx.doi.org/10.1093/ajcp/aqx062DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6951944PMC
November 2017

Primary Renal Carcinoid with Bilateral Multiple Clear Cell Papillary Renal Cell Carcinomas.

Case Rep Pathol 2017 23;2017:9672368. Epub 2017 May 23.

Department of Pathology, University of Washington, 325 Ninth Avenue, P.O. Box 359791, Seattle, WA 98104, USA.

Clear cell papillary renal cell carcinoma (CCPRCC) is a newly recognized entity in the 2016 WHO classification and usually presents as a small, circumscribed, solitary mass of indolent nature. CCPRCCs could seldom occur in conjunction with other synchronous or metachronous kidney tumors and even less frequently as bilateral masses. To our knowledge, multiple bilateral CCPRCCs have never been described with the existence of a synchronous well-differentiated neuroendocrine tumor of the kidney and hence reported here as a unique case. This case report highlights the importance in considering this entity and its unusual presentation in the differential diagnosis as a possible mimicker of Von Hippel-Lindau syndrome.
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http://dx.doi.org/10.1155/2017/9672368DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5460381PMC
May 2017

Neoadjuvant Enzalutamide Prior to Prostatectomy.

Clin Cancer Res 2017 May 9;23(9):2169-2176. Epub 2016 Nov 9.

Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.

Prostate cancer is dependent on androgen receptor (AR) activation. Optimal AR antagonism may effectively cytoreduce local disease and suppress or eliminate micrometastases. We evaluated neoadjuvant therapy prior to prostatectomy with the potent AR antagonist enzalutamide (enza) either alone or in combination with dutasteride (dut) and leuprolide (enza/dut/luteinizing hormone-releasing hormone analogues [LHRHa]). Forty-eight of 52 men with intermediate or high-risk localized prostate cancer proceeded to prostatectomy after neoadjuvant enzalutamide or enza/dut/LHRHa for 6 months. We assessed pathologic complete response (pCR), minimal residual disease (MRD; ≤3 mm maximum diameter of residual disease), residual cancer burden (RCB), and expression of PSA and serum and tissue androgen concentrations. We compared the proportion of patients with pCR in each treatment arm with a historical control rate of 5%, based on previous reports of flutamide with LHRHa. In the enzalutamide arm, none of the 25 patients achieved pCR or MRD. In the enza/dut/LHRHa arm, one of 23 patients (4.3%) achieved pCR and 3 of 23 (13.0%) achieved MRD. Median RCB was higher in the enzalutamide arm than in the enza/dut/LHRHa arm (0.41 cm vs. 0.06 cm, respectively). Tissue testosterone and dihydrotestosterone levels correlated with RCB. No adverse events leading to study drug discontinuation were reported. Combination therapy with enza/dut/LHRHa resulted in pCR and MRD rates comparable with historical controls. Evidence of continued AR activity in residual tumor suggests that AR signaling may contribute to survival. Strategies to more effectively ablate AR activity are warranted to determine whether more substantial antitumor effects are observed. .
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http://dx.doi.org/10.1158/1078-0432.CCR-16-1357DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5570479PMC
May 2017

Mismatch repair deficiency may be common in ductal adenocarcinoma of the prostate.

Oncotarget 2016 Dec;7(50):82504-82510

Department of Laboratory Medicine, University of Washington, Seattle, WA, USA.

Precision oncology entails making treatment decisions based on a tumor's molecular characteristics. For prostate cancer, identifying clinically relevant molecular subgroups is challenging, as molecular profiling is not routine outside of academic centers. Since histologic variants of other cancers correlates with specific genomic alterations, we sought to determine if ductal adenocarcinoma of the prostate (dPC) - a rare and aggressive histopathologic variant - was associated with any recurrent actionable mutations. Tumors from 10 consecutive patients with known dPC were sequenced on a targeted next-generation DNA sequencing panel. The median age at diagnosis was 59 years (range, 40-73). Four (40%) patients had metastases upon presentation. Archival tissue from formalin-fixed paraffin-embedded prostate tissue samples from nine patients and a biopsy of a metastasis from one patient with castration-resistant prostate cancer were available for analysis. Nine of 10 samples had sufficient material for tumor sequencing. Four (40%) patients' tumors had a mismatch repair (MMR) gene alteration (N = 2, MSH2; N = 1, MSH6; and N = 1, MLH1), of which 3 (75%) had evidence of hypermutation. Sections of the primary carcinomas of three additional patients with known MMR gene alterations/hypermutation were histologically evaluated; two of these tumors had dPC. MMR mutations associated with hypermutation were common in our cohort of dPC patients. Since hypermutation may predict for response to immune checkpoint blockade, the presence of dPC may be a rapid means to enrich populations for further screening. Given our small sample size, these findings require replication.
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http://dx.doi.org/10.18632/oncotarget.12697DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5347709PMC
December 2016

Histologic Grading of Prostatic Adenocarcinoma Can Be Further Optimized: Analysis of the Relative Prognostic Strength of Individual Architectural Patterns in 1275 Patients From the Canary Retrospective Cohort.

Am J Surg Pathol 2016 11;40(11):1439-1456

*Cleveland Clinic, Cleveland, OH †University of Texas MD Anderson Cancer Center, Houston ††University of Texas Health Sciences Center San Antonio, San Antonio, TX ‡Canary Foundation, Palo Alto #University of California- San Francisco, San Francisco ‡‡Stanford University Medical Center, Stanford, CA §Fred Hutchinson Cancer Research Center ∥University of Washington Medical Center, Seattle, WA **Eastern Virginia Medical School, Norfolk, VA ¶University of British Columbia, Vancouver, BC, Canada.

Histologic grading remains the gold standard for prognosis in prostate cancer, and assessment of Gleason score plays a critical role in active surveillance management. We sought to optimize the prognostic stratification of grading and developed a method of recording and studying individual architectural patterns by light microscopic evaluation that is independent of standard Gleason grade. Some of the evaluated patterns are not assessed by current Gleason grading (eg, reactive stromal response). Individual histologic patterns were correlated with recurrence-free survival in a retrospective postradical prostatectomy cohort of 1275 patients represented by the highest-grade foci of carcinoma in tissue microarrays. In univariable analysis, fibromucinous rupture with varied epithelial complexity had a significantly lower relative risk of recurrence-free survival in cases graded as 3+4=7. Cases having focal "poorly formed glands," which could be designated as pattern 3+4=7, had lower risk than cribriform patterns with either small cribriform glands or expansile cribriform growth. In separate multivariable Cox proportional hazard analyses of both Gleason score 3+3=6 and 3+4=7 carcinomas, reactive stromal patterns were associated with worse recurrence-free survival. Decision tree models demonstrate potential regrouping of architectural patterns into categories with similar risk. In summary, we argue that Gleason score assignment by current consensus guidelines are not entirely optimized for clinical use, including active surveillance. Our data suggest that focal poorly formed gland and cribriform patterns, currently classified as Gleason pattern 4, should be in separate prognostic groups, as the latter is associated with worse outcome. Patterns with extravasated mucin are likely overgraded in a subset of cases with more complex epithelial bridges, whereas stromogenic cancers have a worse outcome than conveyed by Gleason grade alone. These findings serve as a foundation to facilitate optimization of histologic grading and strongly support incorporating reactive stroma into routine assessment.
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http://dx.doi.org/10.1097/PAS.0000000000000736DOI Listing
November 2016

Flat Urothelial Lesions With Atypia: Interobserver Concordance and Added Value of Immunohistochemical Profiling.

Appl Immunohistochem Mol Morphol 2018 Mar;26(3):180-185

Department of Pathology, University of Washington, Seattle, WA.

Background: Distinguishing urothelial carcinoma in situ (CIS) from other flat lesions of the urinary bladder with cytologic atypia is critically important for the management of patients with bladder neoplasia. However, there is high interpathologist variability in making these distinctions.

Objective: The aim of this study is to assess interobserver agreement between general and specialized genitourinary pathologists, and to compare these diagnoses with those rendered after an immunohistochemical panel is performed. We hypothesized that addition of a set of immunohistochemical stains would reduce the number of cases classified within intermediate categories of atypia of uncertain significance and low-grade dysplasia.

Design: Two genitourinary pathologists independently assessed haematoxylin and eosin (H&E)-stained sections of 127 bladder biopsies from each of the 4 International Society of Urological Pathology/World Health Organization categories of flat lesions diagnosed by general pathologists. A subset of biopsies from 49 patients was reassessed after staining with a 3-antibody panel (CD44, CK20, and p53) and the results were correlated with patient follow-up.

Results: Based on these immunohistochemistry (IHC) stains, 26 cases (53.1%) were recategorized. Of most clinical importance, 5 of 27 cases (18.5%) originally diagnosed as either atypia of uncertain significance or low-grade dysplasia were recategorized as CIS, and recurrent disease was identified on subsequent biopsies. None of the 10 cases diagnosed as CIS based on H&E stains were recategorized.

Conclusions: This triad of IHC stains can improve the precision of pathologic diagnosis of histologically atypical urothelial lesions of flat bladder mucosa. We recommend that pathologists apply this set of IHC stains to such lesions they find problematic based on H&E stains.
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http://dx.doi.org/10.1097/PAI.0000000000000401DOI Listing
March 2018

Outcomes of Active Surveillance for Clinically Localized Prostate Cancer in the Prospective, Multi-Institutional Canary PASS Cohort.

J Urol 2016 Feb 29;195(2):313-20. Epub 2015 Aug 29.

Fred Hutchinson Cancer Research Center, Seattle, Washington; University of Washington, Seattle, Washington; Veterans Affairs Puget Sound Health Care System, Seattle, Washington. Electronic address:

Purpose: Active surveillance represents a strategy to address the overtreatment of prostate cancer, yet uncertainty regarding individual patient outcomes remains a concern. We evaluated outcomes in a prospective multicenter study of active surveillance.

Materials And Methods: We studied 905 men in the prospective Canary PASS enrolled between 2008 and 2013. We collected clinical data at study entry and at prespecified intervals, and determined associations with adverse reclassification, defined as increased Gleason grade or greater cancer volume on followup biopsy. We also evaluated the relationships of clinical parameters with pathology findings in participants who underwent surgery after a period of active surveillance.

Results: At a median followup of 28 months 24% of participants experienced adverse reclassification, of whom 53% underwent treatment while 31% continued on active surveillance. Overall 19% of participants received treatment, 68% with adverse reclassification, while 32% opted for treatment without disease reclassification. In multivariate Cox proportional hazards modeling the percent of biopsy cores with cancer, body mass index and prostate specific antigen density were associated with adverse reclassification (p=0.01, 0.04, 0.04, respectively). Of 103 participants subsequently treated with radical prostatectomy 34% had adverse pathology, defined as primary pattern 4-5 or nonorgan confined disease, including 2 with positive lymph nodes, with no significant relationship between risk category at diagnosis and findings at surgery (p=0.76).

Conclusions: Most men remain on active surveillance at 5 years without adverse reclassification or adverse pathology at surgery. However, clinical factors had only a modest association with disease reclassification, supporting the need for approaches that improve the prediction of this outcome.
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http://dx.doi.org/10.1016/j.juro.2015.08.087DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4970462PMC
February 2016

Trends in Metastatic Kidney Cancer Survival From the Cytokine to the Targeted Therapy Era.

Urology 2015 Aug 18;86(2):262-8. Epub 2015 Jul 18.

Department of Urology, University of Washington, Seattle, WA; Fred Hutchinson Cancer Research Center, Seattle, WA.

Objective: To evaluate population-based survival trends, compared to optimistic trial benchmarks, in metastatic renal cell carcinoma (mRCC). Advances in medical therapy for mRCC may be associated with survival improvements. Yet, targeted therapy trial results focus on patients with favorable-risk mRCC and may not be well disseminated at the population level.

Methods: Surveillance, Epidemiology, and End Results identified adult mRCC patients diagnosed between 1990 and 2009. Survival was analyzed by treatment era (cytokine, 1990-2005; targeted therapy, 2006-2009) and stratified by histology. Multivariate Cox regression identified factors independently associated with overall survival.

Results: We identified 14,521 eligible patients. For clear cell mRCC (N = 4149), median survival improved from 11 to 14 months before and after targeted therapy (P <.001). For RCC with sarcomatoid features (N = 608) and RCC not otherwise specified (N = 8860), survival did not change (median survival 4 months for both). For non-clear cell subtypes (N = 904), median survival improved from 7 to 9 months (P = .008). On multivariate analysis, factors associated with increased overall survival were as follows: treatment in the targeted era (hazard ratio [HR], 0.87; 95% confidence interval [CI], 0.84-0.91), clear cell histology (HR, 0.76; 95% CI, 0.73-0.80), and receipt of surgery (HR, 0.43; 95% CI, 0.41-0.46).

Conclusion: Population-based mRCC median survival improved but to a lesser degree than that reported in clinical trials. This represents opportunity for quality improvement in histologically guided care, use of cytoreductive nephrectomy, and development of strategies for trial-ineligible, poor-risk patients.
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http://dx.doi.org/10.1016/j.urology.2015.05.008DOI Listing
August 2015

ERG Activates the YAP1 Transcriptional Program and Induces the Development of Age-Related Prostate Tumors.

Cancer Cell 2015 Jun;27(6):797-808

Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA; Department of Pathology, University of Washington, Seattle, WA 98195, USA; Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA 98195, USA. Electronic address:

The significance of ERG in human prostate cancer is unclear because mouse prostate is resistant to ERG-mediated transformation. We determined that ERG activates the transcriptional program regulated by YAP1 of the Hippo signaling pathway and found that prostate-specific activation of either ERG or YAP1 in mice induces similar transcriptional changes and results in age-related prostate tumors. ERG binds to chromatin regions occupied by TEAD/YAP1 and transactivates Hippo target genes. In addition, in human luminal-type prostate cancer cells, ERG binds to the promoter of YAP1 and is necessary for YAP1 expression. These results provide direct genetic evidence of a causal role for ERG in prostate cancer and reveal a connection between ERG and the Hippo signaling pathway.
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http://dx.doi.org/10.1016/j.ccell.2015.05.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4461839PMC
June 2015

Metastatic Treated Malignant Germ Cell Tumors: Is SALL4 a Better Marker Than Placental Alkaline Phosphatase?

Appl Immunohistochem Mol Morphol 2016 Mar;24(3):210-4

Department of Pathology, University of Washington, Seattle, WA.

Studies have shown that in the metastatic setting and after treatment, expression of immunohistochemical markers may be diminished or lost. Transcription factor SALL4 (sal-like protein 4) has been recognized as a sensitive marker for both primary and metastatic malignant germ cell tumors (MGCTs), but has not been tested in the posttreatment setting. We sought to determine the level of SALL4 expression in treatment-resistant metastatic MGCT in comparison with pan-GCT marker placental alkaline phosphatase (PLAP). Thirty-six previously treated MGCTs, 16 untreated primary testicular MGCTs, and 4 cytology specimens were immunostained for SALL4 and PLAP, and staining characteristics were evaluated. In the treated MGCT group, there was diffuse SALL4 nuclear immunoreactivity in the majority of cases (27/36, 75%), labeling seminoma, yolk-sac tumor, embryonal carcinoma, and primitive neuroectodermal components. No treated metastatic MGCT lacked SALL4 immunoreactivity. In contrast, PLAP was diffusely expressed in only 14/36 (39%) cases of treated MGCTs, showed scattered focal weak to moderate positivity in 13/36 (36%), and was virtually absent in 9/36 (25%) cases. Both markers had scattered expression limited to the epithelial components of teratomatous regions. SALL4 also outperformed PLAP on a small sample of cytology blocks. Although SALL4 is not entirely specific, it is a highly sensitive marker with strong diffuse nuclear reactivity in the majority of MGCTs in the posttreatment setting, at significantly higher levels than PLAP (P<0.001). Persistent expression of SALL4 in metastatic MGCTs resistant to chemoradiation also raises the possibility for targeted systemic therapy as the anti-SALL4 peptide continues to be developed.
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http://dx.doi.org/10.1097/PAI.0000000000000174DOI Listing
March 2016

Expression of the EPHB4 receptor tyrosine kinase in head and neck and renal malignancies--implications for solid tumors and potential for therapeutic inhibition.

Growth Factors 2014 Dec 13;32(6):202-6. Epub 2014 Nov 13.

Department of Surgery, University of Chicago , Chicago, IL , USA .

Solid malignancies are often characterized by overexpression of various receptor tyrosine kinases (RTKs) against which many targeted therapies are currently in use and in active development. EPHB4 has recently emerged as a frequently overexpressed RTK in many types of cancer. Here, we demonstrate expression patterns of EPHB4 in two solid malignancies: squamous cell carcinoma of the head and neck (HNSCC) and renal cell carcinoma (RCC), by immunohistochemical analysis. We demonstrate the first association between EPHB4 expression and progression of HNSCC from normal tissue to dysplasia and to cancer. Interestingly, most RCC subtypes exhibited expression patterns that were opposite from that found in HNSCC, possibly owing to their unique biology and high degree of organ and tumor vasculature. Taken together, these results suggest a possible role for EPHB4 as a therapeutic target in these malignancies.
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http://dx.doi.org/10.3109/08977194.2014.980904DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4278660PMC
December 2014