Publications by authors named "Maria Tretiakova"

179 Publications

Eosinophilic vacuolated tumor (EVT) of kidney demonstrates sporadic TSC/MTOR mutations: next-generation sequencing multi-institutional study of 19 cases.

Mod Pathol 2021 Sep 14. Epub 2021 Sep 14.

Department of Pathology, University of Toronto, Toronto, ON, Canada.

A distinct renal tumor has recently been described as "high-grade oncocytic renal tumor" and "sporadic renal cell carcinoma with eosinophilic and vacuolated cytoplasm". The Genitourinary Pathology Society (GUPS) consensus proposed a unifying name "eosinophilic vacuolated tumor" (EVT) for this emerging entity. In this multi-institutional study, we evaluated 19 EVTs, particularly their molecular features and mutation profile, using next-generation sequencing. All cases were sporadic and none of the patients had a tuberous sclerosis complex. There were 8 men and 11 women, with a mean age of 47 years (median 50; range 15-72 years). Average tumor size was 4.3 cm (median 3.8 cm; range 1.5-11.5 cm). All patients with available follow-up data (18/19) were alive and without evidence of disease recurrence or progression during the follow-up, ranging from 12 to 198 months (mean 56.3, median 41.5 months). The tumors were well circumscribed, but lacked a well-formed capsule, had nested to solid growth, focal tubular architecture, and showed ubiquitous, large intracytoplasmic vacuoles, round to oval nuclei, and prominent nucleoli. Immunohistochemically, cathepsin K, CD117, CD10, and antimitochondrial antigen were expressed in all cases. Other positive stains included: PAX8, AE1/AE3 and CK18. CK7 was typically restricted only to rare scattered cells. Vimentin, HMB45, melan-A, and TFE3 were negative in all cases. All tumors showed retained SDHB. All cases (19/19) showed non-overlapping mutations of the mTOR pathway genes: TSC1 (4), TSC2 (7), and MTOR (8); one case with MTOR mutation showed a coexistent RICTOR missense mutation. Low mutational rates were found in all samples (ranged from 0 to 6 mutations/Mbp). Microsatellite instability and copy number variations were not found in any of the 17 analyzable cases. EVT represents an emerging renal entity that shows a characteristic and readily identifiable morphology, consistent immunohistochemical profile, indolent behavior, and mutations in either TSC1, TSC2, or MTOR genes.
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http://dx.doi.org/10.1038/s41379-021-00923-6DOI Listing
September 2021

Co-existence of ESC-RCC, EVT, and LOT as synchronous and metachronous tumors in six patients with multifocal neoplasia but without clinical features of tuberous sclerosis complex.

Hum Pathol 2021 Oct 19;116:1-11. Epub 2021 Jun 19.

Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, 98195, USA.

Renal cell tumors with oncocytic phenotypes represent a daily challenge, with several novel, emerging, and provisional entities enriching the diagnostic repertoire. Eosinophilic solid and cystic renal cell carcinoma (ESC-RCC), low-grade oncocytic tumor (LOT), and eosinophilic vacuolated tumor (EVT) have been recognized as unique entities, although their distinctive nature remains controversial. Although most of these tumors are sporadic, rare reports of similar tumors in tuberous sclerosis complex (TSC) have been published. We describe multifocal, often bilateral, tumors in six patients without personal or family history of syndromic diseases. More than 60 tumors in various combinations were identified in 10 nephrectomies and one biopsy encompassing ESC-RCC (n = 6), LOT (n = 14), EVT (n = 1), clear cell RCC with fibromyomatous stroma (n = 12), clear cell RCC (n = 2), angiomyolipomas (AMLs; n > 20), unclassified renal cell tumors (n = 2), papillary adenomas (n = 4), and renomedullary interstitial cell tumor (n = 1). TSC1 germline pathogenic mutations were confirmed in two patients. A tumor without germline testing in a third patient revealed TSC1 biallelic inactivation. Two additional patients had molecular testing, which excluded common renal mutations and syndromes. We provide the first evidence of co-existence in the same organ and unequivocal relatedness of ESC-RCC, EVT, and LOT. End-stage renal disease was present in three of six patients with precursor lesions to all above tumors within adjacent renal parenchyma. In conclusion, identification of multifocal tumors with TSC-like morphology, especially in association with AMLs, could be the first manifestation of clinically silent TSC guiding clinical recommendations for further genetic testing and/or treatment recommendations.
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http://dx.doi.org/10.1016/j.humpath.2021.06.002DOI Listing
October 2021

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

Mod Pathol 2021 07 4;34(7):1392-1424. Epub 2021 Mar 4.

Department of Pathology MD Anderson Cancer Center, Houston, TX, USA.

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
July 2021

A comparison of sunitinib with cabozantinib, crizotinib, and savolitinib for treatment of advanced papillary renal cell carcinoma: a randomised, open-label, phase 2 trial.

Lancet 2021 02 13;397(10275):695-703. Epub 2021 Feb 13.

University of California Davis Comprehensive Cancer Center, Sacramento, CA, USA.

Background: MET (also known as hepatocyte growth factor receptor) signalling is a key driver of papillary renal cell carcinoma (PRCC). Given that no optimal therapy for metastatic PRCC exists, we aimed to compare an existing standard of care, sunitinib, with the MET kinase inhibitors cabozantinib, crizotinib, and savolitinib for treatment of patients with PRCC.

Methods: We did a randomised, open-label, phase 2 trial done in 65 centres in the USA and Canada. Eligible patients were aged 18 years or older with metastatic PRCC who had received up to one previous therapy (excluding vascular endothelial growth factor-directed and MET-directed agents). Patients were randomly assigned to receive sunitinib, cabozantinib, crizotinib, or savolitinib, with stratification by receipt of previous therapy and PRCC subtype. All drug doses were administered orally: sunitinib 50 mg, 4 weeks on and 2 weeks off (dose reductions to 37·5 mg and 25 mg allowed); cabozantinib 60 mg daily (reductions to 40 mg and 20 mg allowed); crizotinib 250 mg twice daily (reductions to 200 mg twice daily and 250 mg once daily allowed); and savolitinib 600 mg daily (reductions to 400 mg and 200 mg allowed). Progression-free survival (PFS) was the primary endpoint. Analyses were done in an intention-to-treat population, with patients who did not receive protocol therapy excluded from safety analyses. This trial is registered with ClinicalTrials.gov, NCT02761057.

Findings: Between April 5, 2016, and Dec 15, 2019, 152 patients were randomly assigned to one of four study groups. Five patients were identified as ineligible post-randomisation and were excluded from these analyses, resulting in 147 eligible patients. Assignment to the savolitinib (29 patients) and crizotinib (28 patients) groups was halted after a prespecified futility analysis; planned accrual was completed for both sunitinib (46 patients) and cabozantinib (44 patients) groups. PFS was longer in patients in the cabozantinib group (median 9·0 months, 95% CI 6-12) than in the sunitinib group (5·6 months, 3-7; hazard ratio for progression or death 0·60, 0·37-0·97, one-sided p=0·019). Response rate for cabozantinib was 23% versus 4% for sunitinib (two-sided p=0·010). Savolitinib and crizotinib did not improve PFS compared with sunitinib. Grade 3 or 4 adverse events occurred in 31 (69%) of 45 patients receiving sunitinib, 32 (74%) of 43 receiving cabozantinib, ten (37%) of 27 receiving crizotinib, and 11 (39%) of 28 receiving savolitinib; one grade 5 thromboembolic event was recorded in the cabozantinib group.

Interpretation: Cabozantinib treatment resulted in significantly longer PFS compared with sunitinib in patients with metastatic PRCC.

Funding: National Institutes of Health and National Cancer Institute.
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http://dx.doi.org/10.1016/S0140-6736(21)00152-5DOI Listing
February 2021

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

Urol Oncol 2021 08 5;39(8):496.e1-496.e8. Epub 2021 Feb 5.

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
August 2021

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

Mod Pathol 2021 06 1;34(6):1167-1184. Epub 2021 Feb 1.

Department of Pathology, The University of Texas, MD Anderson Cancer Center, Houston, TX, USA.

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
June 2021

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

J Clin Pathol 2021 May 29;74(5):291-299. Epub 2021 Jan 29.

Pathology, University Hospital Center of Martinique, Fort-de-France, Martinique.

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
May 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

Characterizing Viral Infection by Electron Microscopy: Lessons from the Coronavirus Disease 2019 Pandemic.

Am J Pathol 2021 02 20;191(2):222-227. Epub 2020 Nov 20.

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

The severe acute respiratory syndrome coronavirus 2 pandemic has infected millions of individuals in the United States and caused hundreds of thousands of deaths. Direct infection of extrapulmonary tissues has been postulated, and using sensitive techniques, viral RNA has been detected in multiple organs in the body, including the kidney. However, direct infection of tissues outside of the lung has been more challenging to demonstrate. This has been in part due to misinterpretation of electron microscopy studies. In this perspective, we will discuss what is known about coronavirus infection, some of the basic ultrastructural cell biology that has been confused for coronavirus infection of cells, and rigorous criteria that should be used when identifying pathogens by electron microscopy.
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http://dx.doi.org/10.1016/j.ajpath.2020.11.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7678435PMC
February 2021

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 2021 04 14;19(2):144-154. 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
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8044249PMC
April 2021

Comprehensive Review of Numerical Chromosomal Aberrations in Chromophobe Renal Cell Carcinoma Including Its Variant Morphologies.

Adv Anat Pathol 2021 Jan;28(1):8-20

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

Chromophobe renal cell carcinoma (ChRCC) accounts for 5% to 7% of all renal cell carcinomas. It was thought for many years that ChRCC exhibits a hypodiploid genome. Recent studies using advanced molecular genetics techniques have shown more complex and heterogenous pattern with frequent chromosomal gains. Historically, multiple losses of chromosomes 1, 2, 6, 10, 13, 17, and 21 have been considered a genetic hallmark of ChRCC, both for classic and eosinophilic ChRCC variants. In the last 2 decades, multiple chromosomal gains in ChRCCs have also been documented, depicting a considerably broader genetic spectrum than previously thought. Studies of rare morphologic variants including ChRCC with pigmented microcystic adenomatoid/multicystic growth, ChRCC with neuroendocrine differentiation, ChRCC with papillary architecture, and renal oncocytoma-like variants also showed variable chromosomal numerical aberrations, including multiple losses (common), gains (less common), or chromosomal changes overlapping with renal oncocytoma. Although not the focus of the review, The Cancer Genome Atlas (TCGA) data in ChRCC show TP53, PTEN, and CDKN2A to be the most mutated genes. Given the complexity of molecular genetic alterations in ChRCC, this review analyzed the existing published data, aiming to present a comprehensive up-to-date survey of the chromosomal abnormalities in classic ChRCC and its variants. The potential role of chromosomal numerical aberrations in the differential diagnostic evaluation may be limited, potentially owing to its high variability.
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http://dx.doi.org/10.1097/PAP.0000000000000286DOI Listing
January 2021

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

Urol Oncol 2021 05 15;39(5):295.e1-295.e8. Epub 2020 Sep 15.

Departments of Pathology, 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
May 2021

Biphasic Squamoid Alveolar Renal Cell Carcinoma of the Kidney Involved by Atypical CD5-Positive B-Cells.

Int J Surg Pathol 2021 Jun 10;29(4):427-432. Epub 2020 Sep 10.

21617University of Washington Medical Center, Seattle, WA, USA.

Biphasic squamoid alveolar renal cell carcinoma (BSARCC) is a recently described kidney cancer entity with <60 published cases so far. Some unique features of BSARCC include distinct squamoid and alveolar morphology forming glomeruloid configurations and 2 types of tumor cells with different immunoprofiles. Although the mechanism is unknown, neutrophils and cellular materials engulfed by larger tumor cells (described as "emperipolesis") are observed in all reported cases including the current one. In this article, we report a case of a 70-year-old man who presented with an incidental renal mass during workup for immunoglobulin M monoclonal gammopathy of unknown significance and cold agglutinin autoimmune hemolytic anemia. A detailed pathologic evaluation and immunohistochemical studies revealed BSARCC colliding with atypical CD5+ monoclonal B-cells.
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http://dx.doi.org/10.1177/1066896920957089DOI Listing
June 2021

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 10 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 2021 04;145(4):461-493

Douglass Hanly Moir Pathology, Faculty of Medicine and Health Sciences Macquarie University, North Ryde, Australia (Maclean).

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
April 2021

ALK rearranged renal cell carcinoma (ALK-RCC): a multi-institutional study of twelve cases with identification of novel partner genes CLIP1, KIF5B and KIAA1217.

Mod Pathol 2020 12 28;33(12):2564-2579. Epub 2020 May 28.

Department of Pathology, Faculty of Medicine in Pilsen, Charles University, Pilsen, Czech Republic.

ALK rearranged renal cell carcinoma (ALK-RCC) has recently been included in 2016 WHO classification as a provisional entity. In this study, we describe 12 ALK-RCCs from 8 institutions, with detailed clinical, pathological, immunohistochemical (IHC), fluorescence in situ hybridization (FISH), and next generation sequencing (NGS) analyses. Patients' age ranged from 25 to 68 years (mean, 46.3 years). Seven patients were females and five were males (M:F = 1:1.4). Tumor size ranged from 17 to 70 mm (mean 31.5, median 25 mm). The pTNM stage included: pT1a (n = 7), pT1b (n = 1), and pT3a (n = 4). Follow-up was available for 9/12 patients (range: 2 to 153 months; mean 37.6 months); 8 patients were alive without disease and one was alive with distant metastases. The tumors demonstrated heterogeneous, 'difficult to classify' morphology in 10/12 cases, typically showing diverse architectural and cellular morphologies, including papillary, tubular, tubulocystic, solid, sarcomatoid (spindle cell), rhabdoid, signet-ring cell, and intracytoplasmic vacuoles, often set in a mucinous background. Of the remaining two tumors, one showed morphology resembling mucinous tubular and spindle cell renal cell carcinoma (MTSC RCC-like) and one was indistinguishable from metanephric adenoma. One additional case also showed a focal metanephric adenoma-like area, in an otherwise heterogeneous tumor. By IHC, all tumors were diffusely positive for ALK and PAX8. In both cases with metanephric adenoma-like features, WT1 and ALK were coexpressed. ALK rearrangement was identified in 9/11 tumors by FISH. ALK fusion partners were identified by NGS in all 12 cases, including the previously reported: STRN (n = 3), TPM3 (n = 3), EML4 (n = 2), and PLEKHA7 (n = 1), and also three novel fusion partners: CLIP1 (n = 1), KIF5B (n = 1), and KIAA1217 (n = 1). ALK-RCC represents a genetically distinct entity showing a heterogeneous histomorphology, expanded herein to include unreported metanephric adenoma-like and MTSC RCC-like variants. We advocate a routine ALK IHC screening for "unclassifiable RCCs" with heterogeneous features.
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http://dx.doi.org/10.1038/s41379-020-0578-0DOI Listing
December 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

17-Gene Genomic Prostate Score Test Results in the Canary Prostate Active Surveillance Study (PASS) Cohort.

J Clin Oncol 2020 05 4;38(14):1549-1557. Epub 2020 Mar 4.

Cancer Prevention Program, Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA.

Purpose: The 17-gene Onco DX Genomic Prostate Score (GPS) test predicts adverse pathology (AP) in patients with low-risk prostate cancer treated with immediate surgery. We evaluated the GPS test as a predictor of outcomes in a multicenter active surveillance cohort.

Materials And Methods: Diagnostic biopsy tissue was obtained from men enrolled at 8 sites in the Canary Prostate Active Surveillance Study. The primary endpoint was AP (Gleason Grade Group [GG] ≥ 3, ≥ pT3a) in men who underwent radical prostatectomy (RP) after initial surveillance. Multivariable regression models for interval-censored data were used to evaluate the association between AP and GPS. Inverse probability of censoring weighting was applied to adjust for informative censoring. Predictiveness curves were used to evaluate how models stratified risk of AP. Association between GPS and time to upgrade on surveillance biopsy was evaluated using Cox proportional hazards models.

Results: GPS results were obtained for 432 men (median follow-up, 4.6 years); 101 underwent RP after a median 2.1 years of surveillance, and 52 had AP. A total of 167 men (39%) upgraded at a subsequent biopsy. GPS was significantly associated with AP when adjusted for diagnostic GG (hazards ratio [HR]/5 GPS units, 1.18; 95% CI, 1.04 to 1.44; = .030), but not when also adjusted for prostate-specific antigen density (PSAD; HR, 1.85; 95% CI, 0.99 to 4.19; = .066). Models containing PSAD and GG, or PSAD, GG, and GPS may stratify risk better than a model with GPS and GG. No association was observed between GPS and subsequent biopsy upgrade ( = .48).

Conclusion: In our study, the independent association of GPS with AP after initial active surveillance was not statistically significant, and there was no association with upgrading in surveillance biopsy. Adding GPS to a model containing PSAD and diagnostic GG did not significantly improve stratification of risk for AP over the clinical variables alone.
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http://dx.doi.org/10.1200/JCO.19.02267DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7213589PMC
May 2020

Expanding the morphologic spectrum of chromophobe renal cell carcinoma: A study of 8 cases with papillary architecture.

Ann Diagn Pathol 2020 Feb 14;44:151448. Epub 2019 Dec 14.

Department of Pathology, Charles University, Medical Faculty and Charles University Hospital Plzen, Czech Republic. Electronic address:

Although typically arranged in solid alveolar fashion, chromophobe renal cell carcinoma (RCC) may also show several other architectural growth patterns. We include in this series 8 chromophobe RCC cases with prominent papillary growth, a pattern very rarely reported or only mentioned as a feature of chromophobe RCC, which is lacking wider recognition The differential diagnosis of such cases significantly varies from the typical chromophobe RCC with its usual morphology, particularly its distinction from papillary RCC and other relevant and clinically important entities. Of 972 chromophobe RCCs in our files, we identified 8 chromophobe RCCs with papillary growth. We performed immunohistochemistry and array Comparative Genomic Hybridisation (aCGH) to investigate for possible chromosomal aberrations. Patients were 3 males and 5 females with age ranging from 30 to 84 years (mean 57.5, median 60 years). Tumor size was variable and ranged from 2 to 14 cm (mean 7.5, median 6.6 cm). Follow-up was available for 7 of 8 patients, ranging from 1 to 61 months (mean 20.1, median 12 months). Six patients were alive with no signs of aggressive behavior, and one died of the disease. Histologically, all cases were composed of dual cell population consisting of variable proportions of leaf-like cells with pale cytoplasm and eosinophilic cells. The extent of papillary component ranged from 15 to 100% of the tumor volume (mean 51%, median 50%). Sarcomatoid differentiation was identified only in the case with fatal outcome. Immunohistochemically, all tumors were positive for CK7, CD117 and Hale's Colloidal Iron. PAX8 was positive in 5 of 8 cases, TFE3 was focally positive 3 of 8 tumors, and Cathepsin K was focally positive in 2 of 8 tumors. All cases were negative for vimentin, AMACR and HMB45. Fumarate hydratase staining was retained in all tested cases. The proliferative activity was low (up to 1% in 7, up to 5% in one case). Three cases were successfully analyzed by aCGH and all showed a variable copy number variation profile with multiple chromosomal gains and losses. CONCLUSIONS: Chromophobe RCC demonstrating papillary architecture is an exceptionally rare carcinoma. The diagnosis can be challenging, although the cytologic features are consistent with the classic chromophobe RCC. Given the prognostic and therapeutic implications of accurately diagnosis other RCCs with papillary architecture (i.e., Xp11.2 translocation RCC, FH-deficient RCC), it is crucial to differentiate these cases from chromophobe RCC with papillary architecture. Based on this limited series, the presence of papillary architecture does not appear to have negative prognostic impact. However, its wider recognition may allow in depth studies on additional examples of this rare morphologic variant.
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http://dx.doi.org/10.1016/j.anndiagpath.2019.151448DOI Listing
February 2020

Plasmacytoid urothelial carcinoma: response to chemotherapy and oncologic outcomes.

Bladder Cancer 2020 28;6(1):71-81. Epub 2020 Mar 28.

Fred Hutchinson Cancer Research Center, 1100 Fairview Ave N, Seattle, WA 98109, USA.

Background: Plasmacytoid urothelial carcinoma is a rare bladder cancer variant with scarce data on outcomes and prognostic factors.

Objective: We report our institutional experience with this histology to determine response to neoadjuvant chemotherapy, definitive surgery and survival.

Methods: We conducted a retrospective chart review of consecutive patients with plasmacytoid, as well as conventional urothelial carcinoma (for comparison) seen in our institution (2007 - 2018). Baseline characteristics, clinicopathologic and treatment data were captured. T-test, chi-squared and log-rank test was used for group comparison. Kaplan Meier method was used for estimation of overall survival and Cox regression for identification of prognostic factors.

Results: 64 patients with plasmacytoid and 418 with conventional urothelial histology were identified; 53% of those with plasmacytoid presented with cT3/4 stage and 67% underwent extirpative surgery. Patients with plasmacytoid histology had higher rates of pT3/4 (65% vs. 28%), nodal disease (37% vs. 16%) and positive surgical margins (23% vs. 5%) compared to urothelial group (p < 0.01), as well as higher incidence of post-operative recurrence (47% vs. 29%, p = 0.05) and lower ypT0N0 rates after neoadjuvant chemotherapy (10% vs. 33%, p = 0.03). Plasmacytoid histology was associated with lower median overall survival compared to conventional urothelial (24 vs. 154 months, p < 0.01).

Conclusions: Plasmacytoid urothelial carcinoma frequently presented with advanced stage at diagnosis and extirpative surgery, poor pathologic response to neoadjuvant chemotherapy, and inferior outcomes, when compared to conventional urothelial. Prospective trials evaluating upfront cystectomy versus preoperative chemotherapy and/or novel treatments should be considered.
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http://dx.doi.org/10.3233/blc-190258DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8186525PMC
March 2020

Multiparametric MRI as a Biomarker of Response to Neoadjuvant Therapy for Localized Prostate Cancer-A Pilot Study.

Acad Radiol 2020 10 18;27(10):1432-1439. Epub 2019 Dec 18.

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.

Rationale And Objectives: To explore a role for multiparametric MRI (mpMRI) as a biomarker of response to neoadjuvant androgen deprivation therapy (ADT) for prostate cancer (PCa).

Materials And Methods: This prospective study was approved by the institutional review board and was HIPAA compliant. Eight patients with localized PCa had a baseline mpMRI, repeated after 6-months of ADT, followed by prostatectomy. mpMRI indices were extracted from tumor and normal regions of interest (TROI/NROI). Residual cancer burden (RCB) was measured on mpMRI and on the prostatectomy specimen. Paired t-tests compared TROI/NROI mpMRI indices and pre/post-treatment TROI mpMRI indices. Spearman's rank tested for correlations between MRI/pathology-based RCB, and between pathological RCB and mpMRI indices.

Results: At baseline, TROI apparent diffusion coefficient (ADC) was lower and dynamic contrast enhanced (DCE) metrics were higher, compared to NROI (ADC: 806 ± 137 × 10 vs. 1277 ± 213 × 10 mm/sec, p = 0.0005; K: 0.346 ± 0.16 vs. 0.144 ± 0.06 min, p = 0.002; AUC: 0.213 ± 0.08 vs. 0.11 ± 0.03, p = 0.002). Post-treatment, there was no change in TROI ADC, but a decrease in TROI K (0.346 ± 0.16 to 0.188 ± 0.08 min; p = 0.02) and AUC (0.213 ± 0.08 to 0.13 ± 0.06; p = 0.02). Tumor volume decreased with ADT. There was no difference between mpMRI-based and pathology-based RCB, which positively correlated (⍴ = 0.74-0.81, p < 0.05). Pathology-based RCB positively correlated with post-treatment DCE metrics (⍴ = 0.76-0.70, p < 0.05) and negatively with ADC (⍴ = -0.79, p = 0.03).

Conclusion: Given the heterogeneity of PCa, an individualized approach to ADT may maximize potential benefit. This pilot study suggests that mpMRI may serve as a biomarker of ADT response and as a surrogate for RCB at prostatectomy.
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http://dx.doi.org/10.1016/j.acra.2019.10.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7297658PMC
October 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

"Interchangeability" of PD-L1 immunohistochemistry assays: a meta-analysis of diagnostic accuracy.

Mod Pathol 2020 01 5;33(1):4-17. Epub 2019 Aug 5.

Cross Cancer Institute, Edmonton, AB, Canada.

Different clones, protocol conditions, instruments, and scoring/readout methods may pose challenges in introducing different PD-L1 assays for immunotherapy. The diagnostic accuracy of using different PD-L1 assays interchangeably for various purposes is unknown. The primary objective of this meta-analysis was to address PD-L1 assay interchangeability based on assay diagnostic accuracy for established clinical uses/purposes. A systematic search of the MEDLINE database using PubMed platform was conducted using "PD-L1" as a search term for 01/01/2015 to 31/08/2018, with limitations "English" and "human". 2,515 abstracts were reviewed to select for original contributions only. 57 studies on comparison of two or more PD-L1 assays were fully reviewed. 22 publications were selected for meta-analysis. Additional data were requested from authors of 20/22 studies in order to enable the meta-analysis. Modified GRADE and QUADAS-2 criteria were used for grading published evidence and designing data abstraction templates for extraction by reviewers. PRISMA was used to guide reporting of systematic review and meta-analysis and STARD 2015 for reporting diagnostic accuracy study. CLSI EP12-A2 was used to guide test comparisons. Data were pooled using random-effects model. The main outcome measure was diagnostic accuracy of various PD-L1 assays. The 22 included studies provided 376 2×2 contingency tables for analyses. Results of our study suggest that, when the testing laboratory is not able to use an Food and Drug Administration-approved companion diagnostic(s) for PD-L1 assessment for its specific clinical purpose(s), it is better to develop a properly validated laboratory developed test for the same purpose(s) as the original PD-L1 Food and Drug Administration-approved immunohistochemistry companion diagnostic, than to replace the original PD-L1 Food and Drug Administration-approved immunohistochemistry companion diagnostic with a another PD-L1 Food and Drug Administration-approved companion diagnostic that was developed for a different purpose.
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http://dx.doi.org/10.1038/s41379-019-0327-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6927905PMC
January 2020

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

Ultra-Sensitive TP53 Sequencing for Cancer Detection Reveals Progressive Clonal Selection in Normal Tissue over a Century of Human Lifespan.

Cell Rep 2019 07;28(1):132-144.e3

Department of Pathology, University of Washington, Seattle, WA 98195, USA. Electronic address:

High-accuracy next-generation DNA sequencing promises a paradigm shift in early cancer detection by enabling the identification of mutant cancer molecules in minimally invasive body fluid samples. We demonstrate 80% sensitivity for ovarian cancer detection using ultra-accurate Duplex Sequencing to identify TP53 mutations in uterine lavage. However, in addition to tumor DNA, we also detect low-frequency TP53 mutations in nearly all lavages from women with and without cancer. These mutations increase with age and share the selection traits of clonal TP53 mutations commonly found in human tumors. We show that low-frequency TP53 mutations exist in multiple healthy tissues, from newborn to centenarian, and progressively increase in abundance and pathogenicity with older age across tissue types. Our results illustrate that subclonal cancer evolutionary processes are a ubiquitous part of normal human aging, and great care must be taken to distinguish tumor-derived from age-associated mutations in high-sensitivity clinical cancer diagnostics.
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http://dx.doi.org/10.1016/j.celrep.2019.05.109DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6639023PMC
July 2019
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