Publications by authors named "Tatjana Antic"

110 Publications

A prospective clinical and transcriptomic feasibility study of oral-only hormonal therapy with radiation for unfavorable prostate cancer in men 70 years of age and older or with comorbidity.

Cancer 2021 Apr 21. Epub 2021 Apr 21.

Department of Radiation and Cellular Oncology, University of Chicago Medicine, Chicago, Illinois.

Background: Androgen deprivation therapy (ADT) improves outcomes in unfavorable-risk prostate cancer (PCa) treated with radiation therapy (RT). It was hypothesized that replacing luteinizing hormone-releasing hormone (LHRH) agonists with a 5-α-reductase inhibitor (5-ARI) would improve hormonal health-related quality of life (HRQOL) without differentially suppressing androgen-responsive (AR) gene expression.

Methods: Patients with localized unfavorable-risk PCa, aged ≥70 years or Charlson Comorbidity Index score ≥2 were treated with oral ADT (oADT), consisting of 4 months of bicalutamide, a 5-ARI, and RT at 78 Gy. The primary end point was Expanded Prostate Cancer Index Composite HRQOL at 6 months ≤30%, and improvement compared with a synchronous standard of care (SOC) cohort receiving 4 months of bicalutamide and long-term LHRH agonist with RT. RNA sequencing was performed from matched pre-/post-ADT prostate tumor biopsies in a subset of men. Differential gene and pathway expressional changes were examined using gene set enrichment.

Results: Between 2011 and 2018, 40 and 30 men were enrolled in the oADT and SOC cohorts, respectively. Median follow-up was 40 months. Those with ≤30% decline in hormonal HRQOL at 6 months was 97% (oADT) and 93% (SOC). The average 6-month hormonal decline was 1% (oADT) versus 12% (SOC; P = .04). The 4-year freedom from biochemical failure was 88% (oADT) versus 81% (SOC; P = .48). RNA sequencing (n = 9) showed similar numbers of downregulated and upregulated genes between the treatment groups (fold-change = 2; false-discovery rate-adjusted P ≤ .05). Both treatments comparably decreased the expression of 20 genes in canonical androgen receptor signaling.

Conclusions: For men with PCa undergoing RT, oral versus standard ADT may improve 6-month QOL and appears to have a similar impact on androgen-responsive gene expression.
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http://dx.doi.org/10.1002/cncr.33556DOI Listing
April 2021

Histopathologic and clinical outcomes of Milan System categories "non-diagnostic" and "non-neoplastic" of salivary gland fine needle aspirations.

J Am Soc Cytopathol 2021 Mar 19. Epub 2021 Mar 19.

Department of Pathology, The University of Chicago, Chicago, Illinois.

Introduction: The Milan System for Reporting Salivary Gland Cytopathology (MSRSGC) specifies six categories with estimated risks of malignancy (ROM) and suggested management. The estimated ROM is 25% for Non-Diagnostic (ND) category, and 10% for Non-Neoplastic (NN). This study aimed to investigate histopathologic and clinical outcomes of MSRSGC categories ND and NN at the authors' institution.

Materials And Methods: Cytopathology fine needle aspiration reports from 2008-2020 were searched for the word "salivary", "parotid", and "submandibular". Cases fitting Non-Diagnostic (ND) and Non-Neoplastic (NN) categories were identified. Follow-up cyto-/histopathologic and clinical data were extracted.

Results: There were 43 ND and 46 NN cases. The average age was 58.3 years. Neoplastic lesions were found in 13 of 43 (30%) ND and 3 of 46 (6.5%) NN. The rate of malignancy in ND category was 14.0% (6/43) and 0% (0/46) in NN category. Four cases in ND (9.3%) and 6 (13.0%) in NN had no neoplasm and instead had an underlying reactive condition (e.g., chronic sialadenitis) or inflammatory lesion (e.g., lymphoepithelial cyst) on histologic follow-up. There was no follow-up pathology in 46.5% NDs (20/43) and 82.6% NNs (38/46); however, no lesions were apparent clinically with a mean follow-up of 3 years and 1.5 years, respectively.

Conclusions: MSRSGC categories ND and NN are helpful for reporting salivary gland FNA results. With proper clinical and radiologic correlation, ROM of NN is low; however, ROM of ND remains significant. Repeat FNA after correlation for ND cases seems prudent as neoplasms and malignancies may have gone undetected.
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http://dx.doi.org/10.1016/j.jasc.2021.03.001DOI Listing
March 2021

Accuracy of Subclassification and Grading of Renal Tumors on Fine Needle Aspiration Cytology Alone.

Acta Cytol 2021 3;65(2):140-149. Epub 2021 Feb 3.

Department of Pathology, The University of Chicago Hospitals, Chicago, Illinois, USA.

Background: Fine needle aspiration (FNA) of renal masses can distinguish between benign and malignant neoplasms in 73-94% of cases. Previous studies suggested the correct subclassification of renal cell carcinomas (RCCs) by cytomorphology can be achieved in up to 80% of cases. However, as RCCs become increasingly subclassified by molecular signatures, correct subclassification based on cytology alone is increasingly difficult.

Design: Two FNA passes (2 stained with Diff-Quik® and 2 with the Papanicolaou method) were performed on all fresh nephrectomy specimens for a 1-year period. There were 30 cases in this study, with 29 primary renal tumors and 1 case of metastatic lung adenocarcinoma. Each case was assigned a random number and came with 2 slides (1 from each staining method). Eight cytopathologists were asked to provide a diagnosis and the World Health Organization/International Society of Urological Pathology (WHO/ISUP) grading if applicable. Fleiss' Kappa and Cohen's Kappa equations were used to look at inter-rater variability.

Results: When compared to the surgical pathology diagnosis, the average percent correct diagnosis for all cytopathologist was 35%. Chromophobe RCCs had the best average percent accuracy at 72% followed by clearcell RCC at 48%. Average accuracy for grading RCCs was 40%. Inter-rater variability among the cytopathologists for all RCC diagnoses was fair with a Fleiss' Kappa coefficient of 0.28. For the WHO/ISUP grade, the weighted coefficient for each pathologist ranged from 0.11 to 0.45, ranging from fair to moderate, respectively.

Conclusions: Renal tumors are difficult to classify on cytopathology alone. Core needle biopsy and ancillary studies are necessary if diagnosis will change management.
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http://dx.doi.org/10.1159/000513065DOI Listing
March 2021

Eosinophilic renal cell carcinoma with isolated MTOR mutation metastatic to the liver: a novel case.

Pathology 2021 Jan 25. Epub 2021 Jan 25.

Department of Pathology, The University of Chicago, Chicago, USA. Electronic address:

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http://dx.doi.org/10.1016/j.pathol.2020.10.013DOI Listing
January 2021

TSC/MTOR mutated eosinophilic renal tumors are a distinct entity that are CK7+/CK20-/vimentin-: a validation study.

Hum Pathol 2020 Dec 19. Epub 2020 Dec 19.

Department of Pathology, The University of Chicago, IL. Electronic address:

Unclassified renal cell carcinoma (RCC) accounts for ∼10% of renal tumors, and the most common histologic findings in these cases is eosinophilic cytoplasm. We previously demonstrated that a subset of eosinophilic renal tumors with heterogeneous morphology and immunohistochemical staining harbored pathogenic mutations in tuberous sclerosis complex (TSC) or mammalian target of rapamycin (MTOR) as the primary defining mutation. We identified an additional 8 cases of eosinophilic tumors with unusual morphology that were originally diagnosed as chromophobe RCC (CHRCC) or CHRCC, eosinophilic variant. As a comparison, we included four classic CHRCC cases and one CHRCC, eosinophilic variant case. Gross examination revealed solid or solid and cystic patterns. The solid areas were composed of eosinophilic tumor cells divided by congested vessels while the cystic areas were lined by cytologically bland eosinophilic cells with septae containing nests, ribbons, and single eosinophilic tumor cells. The tumor cells had abundant granular eosinophilic cytoplasm with round nuclei and inconspicuous nucleoli. IHC analysis demonstrated diffuse staining for CK7 and negative staining for CK20 and vimentin. Next generation sequencing identified pathogenic variants in three genes: TSC1, TSC2, and MTOR. They also lacked significant copy number variations in contrast to our control cases. We have demonstrated with our expanded study that cases previously diagnosed as CHRCC or CHRCC, eosinophilic variant with discordant histology and IHC staining patterns may represent a separate subtype of RCC characterized by mutations in the TSC/MTOR pathway.
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http://dx.doi.org/10.1016/j.humpath.2020.12.006DOI Listing
December 2020

BAP1-Mutated Clear Cell Renal Cell Carcinoma.

Am J Clin Pathol 2021 Apr;155(5):718-728

Department of Pathology, University of Chicago, Chicago, IL.

Objectives: While aberrations in the VHL gene and chromosome 3p resulting in clear cell renal cell carcinoma (CCRCC) are well established, we know that additional mutations in chromatin remodeling genes PBRM1, SETD2, and BRCA1-associated protein 1 (BAP1) contribute to pathogenesis in some cases. Given the known aggressive clinical behavior of BAP1-mutated CCRCC, we sought to define the pathologic phenotype of BAP1-mutated CCRCC.

Methods: We identified 14 cases of molecularly proven BAP1-mutated CCRCC and investigated their clinicopathologic features.

Results: BAP1-mutated CCRCC frequently showed papillary, tubulopapillary, or expanded nested architecture; demonstrated granular to diffusely eosinophilic cytoplasm with prominent eosinophilic globules; and contained high-grade nuclei. This morphology demonstrates significant overlap with Xp11 translocation renal cell carcinoma (RCC). Immunohistochemistry notably demonstrates loss of BAP1 expression in almost all tumors, in addition to strong p504S expression. A conventional CCRCC component was frequently present adjacent to the characteristic BAP1 areas and showed retained BAP1 expression and only patchy p504S. Approximately two-thirds of BAP1-mutated CCRCCs were stage pT3, renal vein invasion was common, and 50% developed metastases.

Conclusions: Herein, we describe the histologic and immunohistochemical findings in BAP1-mutated CCRCC, which has important implications for utilization of molecular testing, prognosis, future therapeutics, and distinction from other RCC subtypes such as Xp11 translocation RCC.
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http://dx.doi.org/10.1093/ajcp/aqaa176DOI Listing
April 2021

Radio-pathomic mapping model generated using annotations from five pathologists reliably distinguishes high-grade prostate cancer.

J Med Imaging (Bellingham) 2020 Sep 9;7(5):054501. Epub 2020 Sep 9.

Medical College of Wisconsin, Department of Radiology, Milwaukee, Wisconsin, United States.

Our study predictively maps epithelium density in magnetic resonance imaging (MRI) space while varying the ground truth labels provided by five pathologists to quantify the downstream effects of interobserver variability. Clinical imaging and postsurgical tissue from 48 recruited prospective patients were used in our study. Tissue was sliced to match the MRI orientation and whole-mount slides were stained and digitized. Data from 28 patients ( slides) were sent to five pathologists to be annotated. Slides from the remaining 20 patients ( slides) were annotated by one of the five pathologists. Interpathologist variability was measured using Krippendorff's alpha. Pathologist-specific radiopathomic mapping models were trained using a partial least-squares regression using MRI values to predict epithelium density, a known marker for disease severity. An analysis of variance characterized intermodel means difference in epithelium density. A consensus model was created and evaluated using a receiver operator characteristic classifying high grade versus low grade and benign, and was statistically compared to apparent diffusion coefficient (ADC). Interobserver variability ranged from low to acceptable agreement (0.31 to 0.69). There was a statistically significant difference in mean predicted epithelium density values ( ) between the five models. The consensus model outperformed ADC (areas under the curve = 0.80 and 0.71, respectively, ). We demonstrate that radiopathomic maps of epithelium density are sensitive to the pathologist annotating the dataset; however, it is unclear if these differences are clinically significant. The consensus model produced the best maps, matched the performance of the best individual model, and outperformed ADC.
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http://dx.doi.org/10.1117/1.JMI.7.5.054501DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7479263PMC
September 2020

A Tale of 2 Morphologies: Diagnostic Pitfalls in -Associated Renal Cell Carcinomas, Including a Novel Fusion.

Int J Surg Pathol 2021 Feb 4;29(1):21-29. Epub 2020 Sep 4.

University of Chicago Medical Center, Chicago, IL, USA.

Aims: Translocation-associated renal cell carcinomas (RCCs) have been extensively subcharacterized in recent years, such that each is largely recognized by the 2016 World Health Organization as categorical neoplastic entities in the genitourinary tract. Those belonging to the (6;11) family of tumors classically have a fusion between TFEB and MALAT1/α, and display a particular histomorphology. Specifically, they show a biphasic population of both small and large epithelioid cells, the smaller component of which surrounds basement membrane-type material. Despite this apt description, the tumors have variable morphology and mimic other RCCs including those with TFE3 translocations. Therefore, a high degree of suspicion is required to make the correct diagnosis.

Methods: The 2 cases described in this article were of strikingly different appearance, and initially considered consistent with other non-translocation-associated renal tumors. These included clear cell RCC (CCRCC), perivascular epithelioid cell tumor (PEComa), and other eosinophilic RCCs (mainly papillary RCC type 2).

Results: Using RNA sequencing techniques, they were found to harbor distinct pathogenic rearrangements involving the TFEB gene, namely, fusions with CLTC and NEAT1 (the latter partnering heretofore never reported).

Conclusions: These alterations manifested in 2 notably dissimilar lesions, underscoring the importance of including this family of carcinomas in the differential of any renal neoplasm that does not display immunophenotypic characteristics consistent with its morphology.
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http://dx.doi.org/10.1177/1066896920956272DOI Listing
February 2021

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

Eosinophilic Renal Cell Tumors With a TSC and MTOR Gene Mutations Are Morphologically and Immunohistochemically Heterogenous: Clinicopathologic and Molecular Study.

Am J Surg Pathol 2020 07;44(7):943-954

Department of Pathology, The University of Chicago, Chicago, IL.

Eosinophilic renal neoplasms have a wide spectrum of histologic presentations, and several studies have demonstrated a subtype of renal cell carcinomas (RCCs) associated with the tuberous sclerosis complex (TSC)/mammalian target of rapamycin pathway. A review of our institutional archives led to the identification of 18 cases of renal eosinophilic tumors with unusual morphology. Immunohistochemical analysis demonstrated that these could be separated into 3 groups: group 1 had solid architecture and morphology similar to chromophobe RCC but was negative for CK20 and vimentin, and had weak focal staining for CK7 and P504S; group 2 had solid architecture and morphology similar to either renal oncocytoma or chromophobe RCC, eosinophilic variant and had diffuse staining of CK7 and P504S, absent to weak staining of CK20, and negative staining for vimentin; and group 3 had solid, cystic and papillary architecture and was negative for CK7, except for 1 case, along with moderate to strong staining of CK20, P504S, and vimentin. The cases were then sent for next-generation sequencing to determine whether molecular pathogenic variants were present. In group 1, all 3 cases had mutations in TSC2. In group 2, pathogenic variants were identified in 3 genes: TSC1, TSC2, and MTOR. In group 3, genetic alterations and pathogenic variants were identified in TSC1 and TSC2. Our results support TSC/MTOR-associated neoplasms as a distinct group that exhibits heterogenous morphology and immunohistochemical staining.
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http://dx.doi.org/10.1097/PAS.0000000000001457DOI Listing
July 2020

Effect of Echo Times on Prostate Cancer Detection on T2-Weighted Images.

Acad Radiol 2020 11 26;27(11):1555-1563. Epub 2020 Jan 26.

Department of Radiology, University of Chicago, 5841 South Maryland Avenue, Chicago, IL 60637; Sanford J. Grossman Center of Excellence in Prostate Imaging and Image Guided Therapy, University of Chicago, Chicago, Illinois. Electronic address:

Purpose: To compare the effect of different echo times (TE) on the detection of prostate cancer (PCa) on T2-weighted MR images.

Materials And Methods: This study recruited patients (n = 38) with histologically confirmed PCa who underwent preoperative 3T MRI. Three radiologists independently marked region on interests (ROIs) on suspected PCa lesions on T2-weighted images at different TEs: 90, 150, and 180 ms obtained with Turbo Spin Echo imaging protocol with multiple echoes. The ROIs were assigned a value 1-5 indicating the reviewer's confidence in accurately detecting PCa. These ROIs were compared to histologically confirmed PCa (n = 95) on whole mount prostatectomy sections to calculate sensitivity, positive predictive value (PPV), and confidence score.

Results: Two radiologists (R1, R2) showed significantly increased sensitivity for PCa detection at 180 ms TE compared to 90 ms (R1: 43.2, 50.5, 50.5%, R2: 45.3, 44.2, 53.7% at TE of 90, 150, 180 ms, respectively) (p = 0.048, 0.033 for R1 and R2). Sensitivity was similar for radiologist 3 (45.3%-46.3%) at different TE values (p = 0.953). No significant difference in the PPV (R1: 64.1%-70.6%, R2: 46.7%-56.0%, R3: 70.5%-81.5%) and the confidence score assigned (R1: 4.6-4.8, R2: 4.6-4.8 R3: 4.3-4.4) was found for either of the radiologists.

Conclusion: Our results suggest improved detection of PCa with similar PPV and confidence scores when higher TE values are utilized for T2-weighted image acquisition.
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http://dx.doi.org/10.1016/j.acra.2019.12.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7381367PMC
November 2020

Clinicopathologic Features of Small Renal Masses Associated With Distant Metastatic Disease.

Am J Clin Pathol 2020 04;153(5):613-617

Department of Pathology, University of Chicago, Chicago, IL.

Objectives: To assess the clinicopathologic features of small renal masses (≤4 cm) associated with distant metastatic disease.

Methods: We identified radical or partial nephrectomies with renal cell carcinomas (RCCs) measuring 4 cm or less in size (pT1a or pT3a) from 2005 to 2015. Clinicopathologic features were compiled.

Results: A total of 590 RCCs 4 cm or less were identified, of which 3.9% were associated with distant metastatic RCC. Metastasis was more common in pT3a tumors 4 cm or less than pT1a tumors (19% vs 2.7%; P < .01). Seventy percent of tumors were clear cell RCCs. Overall, 43% of patients had previously (30%) or subsequently (13%) diagnosed RCC prior to development of metastasis, 80% of which were the same histologic subtype as the small renal mass.

Conclusions: Distant metastatic disease was rarely encountered in patients with small renal masses. Many of the patients with distant metastases had previously or subsequently diagnosed RCC, which could represent the true source of metastatic disease.
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http://dx.doi.org/10.1093/ajcp/aqz202DOI Listing
April 2020

An abdominal wall mass of exogenous insulin amyloidosis in setting of metastatic sarcoma.

J Cutan Pathol 2020 Apr 1;47(4):406-408. Epub 2019 Dec 1.

Department of Pathology, University of Chicago, Chicago, Illinois.

Exogenous insulin amyloidosis (AIns) is an iatrogenic form of amyloidosis which is found in diabetic patients, generally localized to the site of subcutaneous insulin administration. It may form a discrete mass that could come to clinical attention, and can contribute to abnormal pharmacokinetics of the exogenous insulin, resulting in worsened control of diabetes. In this case report, we describe such a lesion in a 72-year-old man with a history of type 2 diabetes and primary adrenal gland epithelioid sarcoma and discuss the diagnostic challenges it poses.
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http://dx.doi.org/10.1111/cup.13613DOI Listing
April 2020

Loss of microfibril-associated protein 5 (MFAP5) expression in colon cancer stroma.

Virchows Arch 2020 Mar 18;476(3):383-390. Epub 2019 Aug 18.

Department of Pathology, University of Chicago Medical Center, Chicago, IL, USA.

MFAP5, a 25-kD microfibril-associated glycoprotein that is involved in elastic microfibril assembly, has been demonstrated to be significantly downregulated in tumor stroma by previous gene expression study. The aim of this study was to confirm the reduced expression of MFAP5 in colonic tumor stroma using immunohistochemistry and to explore the utility of MFAP5 as a marker to facilitate diagnosing an invasive component versus pseudoinvasion in colon polyps. In all 19 colon cancer resection cases evaluated, while there was intact MFAP5 immunoreactivity in the uninvolved normal connective tissue, there was marked reduction of MFAP5 immunoreactivity in the desmoplastic stroma surrounding the invasive component. The difference in MFAP5 expression levels was most pronounced within the tumor, while a more heterogeneous expression pattern was observed at the tumor invasive front. Reduction of MFAP5 staining was also observed in the stroma around mucin pools in 6 out of 9 sections from mucinous adenocarcinomas and in areas with high-grade dysplasia. For the polypectomy cases, intact expression of MFAP5 was seen in the stroma surrounding the displaced adenomatous glands in 9 out of 12 polyps with pseudoinvasion. Loss of expression of MFAP5 was observed in the stroma surrounding small foci of invasive adenocarcinoma in 8 of 10 malignant polyps. MFAP5 is a useful marker that may help distinguish normal connective tissue from stroma within invasive colonic adenocarcinoma. MFAP5 may facilitate the distinction between pseudoinvasion and true invasive cancer in colonic adenomatous polyps with a sensitivity of 80% (confidence interval 44-96%) and a specificity of 75% (confidence interval 43-93%) in this small cohort.
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http://dx.doi.org/10.1007/s00428-019-02649-yDOI Listing
March 2020

Rhabdomyosarcoma of the Adult Prostate: A Case Report With Complete Molecular Profile.

Int J Surg Pathol 2020 Feb 13;28(1):92-98. Epub 2019 Aug 13.

University of Chicago, Chicago, IL, USA.

Primary rhabdomyosarcoma of the adult prostate is rare and associated with an aggressive clinical course. Given the limited number of cases reported about the prostate, little is known about the impact of molecular mutations on tumor biology and prognosis in adults. In this article, we present a case of primary embryonal rhabdomyosarcoma of the adult prostate with a complete molecular mutational profile of the tumor.
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http://dx.doi.org/10.1177/1066896919867763DOI Listing
February 2020

Genomic Alterations in Undifferentiated Malignant Tumors with Rhabdoid Phenotype and Loss of BRG1 Immunoexpression Identified by Fine Needle Aspirates.

Acta Cytol 2019 21;63(5):438-444. Epub 2019 Jun 21.

Department of Pathology, The University of Chicago, Chicago, Illinois, USA,

Objective: Evidence shows that the switch/sucrose nonfermenting chromatin remodeling complex plays a critical role in DNA repair, cancer progression and dedifferentiation. BRG1 is one of its key catalytic subunits. While the loss of BRG1 expression by immunocytochemistry has been identified in a subset of malignancies arising in various sites with undifferentiated/rhabdoid morphology and poor prognosis, the underlying basis for its loss is unclear.

Methods: A retrospective search was conducted in our cytopathology archive for undifferentiated malignant tumors with rhabdoid phenotype and BRG1 loss. Clinical information was obtained from electronic medical records. Next-generation sequencing was performed following macro-dissection of paraffin-embedded cellblock tissue.

Results: Three cases were identified; all presented with widely metastatic disease with no previously diagnosed primary malignancy, and subsequently died within 6 months of initial presentation. Cytologically, the aspirates showed dyshesive and undifferentiated cells with rhabdoid features. Extensive immunocytochemical workup demonstrated immunoreactivity with vimentin only and could not establish a specific lineage. BRG1 expression was absent, while INI1 expression was retained. Two cases harbored deleterious mutations in BRG1/SMARCA4. Pathogenic mutations in TP53 were identified in all tumors.

Conclusions: BRG1 deficiency reflects underlying mutation in SMARCA4 gene in some but not all cases, suggesting that additional mechanisms may be causing BRG1 silencing. Pathogenic mutations in TP53 in all tumors are consistent with their highly aggressive nature. Recognizing the cytomorphology of this group of neoplasms and confirming their BRG1-deficient status by immunocytochemistry not only has prognostic implications, but may also impart potentially therapeutic value in the near future.
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http://dx.doi.org/10.1159/000500684DOI Listing
September 2019

A compact solution for estimation of physiological parameters from ultrafast prostate dynamic contrast enhanced MRI.

Phys Med Biol 2019 08 7;64(15):155012. Epub 2019 Aug 7.

College of Medicine and Biological Information Engineering, Northeastern University, Shenyang, People's Republic of China. Department of Radiology, University of Chicago, Chicago, IL 60637, United States of America.

The Tofts pharmacokinetic model requires multiple calculations for analysis of dynamic contrast enhanced (DCE) MRI. In addition, the Tofts model may not be appropriate for the prostate. This can result in error propagation that reduces the accuracy of pharmacokinetic measurements. In this study, we present a compact solution allowing estimation of physiological parameters K and v from ultrafast DCE acquisitions, without fitting DCE-MRI data to the standard Tofts pharmacokinetic model. Since the standard Tofts model can be simplified to the Patlak model at early times when contrast efflux from the extravascular extracellular space back to plasma is negligible, K can be solved explicitly for a specific time. Further, v can be estimated directly from the late steady-state signal using the derivative form of Tofts model. Ultrafast DCE-MRI data were acquired from 18 prostate cancer patients on a Philips Achieva 3T-TX scanner. Regions-of-interest (ROIs) for prostate cancer, normal tissue, gluteal muscle, and iliac artery were manually traced. The contrast media concentration as function of time was calculated over each ROI using gradient echo signal equation with pre-contrast tissue T1 values, and using the 'reference tissue' model with a linear approximation. There was strong correlation (r  =  0.88-0.91, p   <  0.0001) between K extracted from the Tofts model and K estimated from the compact solution for prostate cancer and normal tissue. Additionally, there was moderate correlation (r  =  0.65-0.73, p   <  0.0001) between extracted versus estimated v . Bland-Altman analysis showed moderate to good agreement between physiological parameters extracted from the Tofts model and those estimated from the compact solution with absolute bias less than 0.20 min and 0.10 for K and v , respectively. The compact solution may decrease systematic errors and error propagation, and could increase the efficiency of clinical workflow. The compact solution requires high temporal resolution DCE-MRI due to the need to adequately sample the early phase of contrast media uptake.
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http://dx.doi.org/10.1088/1361-6560/ab2b62DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7227457PMC
August 2019

Diagnosis of Prostate Cancer by Use of MRI-Derived Quantitative Risk Maps: A Feasibility Study.

AJR Am J Roentgenol 2019 08 30;213(2):W66-W75. Epub 2019 Apr 30.

1 Department of Radiology, University of Chicago, 5841 S Maryland Ave, Chicago, IL 60637.

The purpose of this study was to develop a new quantitative image analysis tool for estimating the risk of cancer of the prostate by use of quantitative multiparametric MRI (mpMRI) metrics. Thirty patients with biopsy-confirmed prostate cancer (PCa) who underwent preoperative 3-T mpMRI were included in the study. Quantitative mpMRI metrics-apparent diffusion coefficient (ADC), T2, and dynamic contrast-enhanced (DCE) signal enhancement rate (α)-were calculated on a voxel-by-voxel basis for the whole prostate and coregistered. A normalized risk value (0-100) for each mpMRI parameter was obtained, with high risk values associated with low T2 and ADC and high signal enhancement rate. The final risk score was calculated as a weighted sum of the risk scores (ADC, 40%; T2, 40%; DCE, 20%). Data from five patients were used as training set to find the threshold for predicting PCa. In the other 25 patients, any region with a minimum of 30 con-joint voxels (≈ 4.8 mm) with final risk score above the threshold was considered positive for cancer. Lesion-based and sector-based analyses were performed by matching prostatectomyverified malignancy and PCa predicted with the risk analysis tool. The risk map tool had sensitivity of 76.6%, 89.2%, and 100% for detecting all lesions, clinically significant lesions (≥ Gleason 3 + 4), and index lesions, respectively. The sensitivity, specificity, positive predictive value, and negative predictive value for PCa detection for all lesions in the sector-based analysis were 78.9%, 88.5%, 84.4%, and 84.1%, respectively, with an ROC AUC of 0.84. The risk analysis tool is effective for detecting clinically significant PCa with reasonable sensitivity and specificity in both peripheral and transition zones.
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http://dx.doi.org/10.2214/AJR.18.20702DOI Listing
August 2019

Genetic Underpinnings of Renal Cell Carcinoma With Leiomyomatous Stroma.

Am J Surg Pathol 2019 08;43(8):1135-1144

Department of Pathology, The University of Chicago, Chicago, IL.

Renal cell carcinoma (RCC) with leiomyomatous stroma is a provisional category of RCC in the 2016 World Health Organization Classification of Tumors of the Urinary System. Microscopic examination of hematoxylin and eosin-stained sections reveals this entity to be well-circumscribed with tubulopapillary growth of cells with clear cytoplasm in a background of leiomyomatous stroma. Herein we describe the genetic features of 15 University of Chicago Medical Center archived cases with hematoxylin and eosin histology matching the provisional diagnosis. Immunohistochemical (IHC) stains revealed 1/15 of these tumors to be clear cell renal cell carcinoma (ccRCC) and 6/15 to be clear cell papillary renal cell carcinoma (ccpRCC), demonstrating the morphologic overlap with these discrete known entities. Interestingly 3/6 of the ccpRCCs had chromosome 18 gain suggesting there may be novel specific genetic changes in ccpRCC with leiomyomatous stroma. Of the remaining 8 tumors with IHC staining patterns that do not fit either ccRCC or ccpRCC only 3 of these had mutations in the recently described TCEB1 gene with concurrent monosomy of chromosome 8. These 3 cases had a somewhat unique IHC pattern that possibly could separate them from the 5 other non-ccRCC/non-ccpRCC cases. This descriptive study, although small, demonstrates the difficulty in applying the current World Health Organization provisional criteria at a single institution with suggestion of an immunohistochemcial panel that may assist in the diagnosis of TCEB1-mutated RCC with leiomyomatous stroma.
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http://dx.doi.org/10.1097/PAS.0000000000001255DOI Listing
August 2019

Revisiting quantitative multi-parametric MRI of benign prostatic hyperplasia and its differentiation from transition zone cancer.

Abdom Radiol (NY) 2019 06;44(6):2233-2243

Department of Radiology, University of Chicago, 5841 South Maryland Avenue, Chicago, IL, 60637, USA.

Purpose: This study investigates the multiparametric MRI (mpMRI) appearance of different types of benign prostatic hyperplasia (BPH) and whether quantitative mpMRI is effective in differentiating between prostate cancer (PCa) and BPH.

Materials And Methods: Patients (n = 60) with confirmed PCa underwent preoperative 3T MRI. T2-weighted, multi-echo T2-weighted, diffusion weighted and dynamic contrast enhanced images (DCE) were obtained prior to undergoing prostatectomy. PCa and BPH (cystic, glandular or stromal) were identified in the transition zone and matched with MRI. Quantitative mpMRI metrics: T2, ADC and DCE-MRI parameters using an empirical mathematical model were measured.

Results: ADC values were significantly lower (p < 0.001) in PCa compared to all BPH types and can differentiate between PCa and BPH with high accuracy (AUC = 0.87, p < 0.001). T2 values were significantly lower (p < 0.001) in PCa compared to cystic BPH only, while glandular (p = 0.27) and stromal BPH (p = 0.99) showed no significant difference from PCa. BPH mimics PCa in the transition zone on DCE-MRI evidenced by no significant difference between them. mpMRI values of glandular (ADC = 1.31 ± 0.22 µm/ms, T2 = 115.7 ± 37.3 ms) and cystic BPH (ADC = 1.92 ± 0.43 µm/ms, T2 = 242.8 ± 117.9 ms) are significantly different. There was no significant difference in ADC (p = 0.72) and T2 (p = 0.46) between glandular and stromal BPH.

Conclusions: Multiparametric MRI and specifically quantitative ADC values can be used for differentiating PCa and BPH, improving PCa diagnosis in the transition zone. However, DCE-MRI metrics are not effective in distinguishing PCa and BPH. Glandular BPH are not hyperintense on ADC and T2 as previously thought and have similar quantitative mpMRI measurements to stromal BPH. Glandular and cystic BPH appear differently on mpMRI and are histologically different.
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http://dx.doi.org/10.1007/s00261-019-01936-1DOI Listing
June 2019

Assessment of histotripsy-induced liquefaction with diagnostic ultrasound and magnetic resonance imaging in vitro and ex vivo.

Phys Med Biol 2019 05 2;64(9):095023. Epub 2019 May 2.

The University of Chicago, Chicago, IL, United States of America.

Histotripsy is a therapeutic ultrasound modality under development to liquefy tissue mechanically via bubble clouds. Image guidance of histotripsy requires both quantification of the bubble cloud activity and accurate delineation of the treatment zone. In this study, magnetic resonance (MR) and diagnostic ultrasound imaging were combined to assess histotripsy treatment in vitro and ex vivo. Mechanically ablative histotripsy pulses were applied to agarose phantoms or porcine livers. Bubble cloud emissions were monitored with passive cavitation imaging (PCI), and hyperechogenicity via plane wave imaging. Changes in the medium structure due to bubble activity were assessed with diagnostic ultrasound using conventional B-mode imaging and T -, T -, and diffusion-weighted MR images acquired at 3 Tesla. Liquefaction zones were correlated with diagnostic ultrasound and MR imaging via receiver operating characteristic (ROC) analysis and Dice similarity coefficient (DSC) analysis. Diagnostic ultrasound indicated strong bubble activity for all samples. Histotripsy-induced changes in sample structure were evident on conventional B-mode and T -weighted images for all samples, and were dependent on the sample type for T - and diffusion-weighted imaging. The greatest changes observed on conventional B-mode or MR imaging relative to baseline in the samples did not necessarily indicate the regions of strongest bubble activity. Areas under the ROC curve for predicting phantom or liver liquefaction were significantly greater than 0.5 for PCI power, plane wave and conventional B-mode grayscale, T , T , and ADC. The acoustic power mapped via PCI provided a better prediction of liquefaction than assessment of the liquefaction zone via conventional B-mode or MR imaging for all samples. The DSC values for T -weighted images were greater than those derived from conventional B-mode images. These results indicate diagnostic ultrasound and MR imaging provide complimentary sets of information, demonstrating that multimodal imaging is useful for assessment of histotripsy liquefaction.
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http://dx.doi.org/10.1088/1361-6560/ab143fDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6706274PMC
May 2019

Fine-needle aspiration of dermatofibrosarcoma protuberans metastasizing to hemithorax with superior vena cava compression: Case report and literature review.

Diagn Cytopathol 2019 Aug 27;47(8):797-802. Epub 2019 Mar 27.

Department of Pathology, The University of Chicago, Chicago, Illinois.

Dermatofibrosarcoma protuberans (DFSP) is a low-grade spindle cell tumor of the skin commonly arising on the trunk and extremities which tends to be slow growing yet locally aggressive. DFSPs are associated with a good prognosis when surgical excision with negative margins is achieved. Although local recurrences occur up to 50% of incompletely resected cases, distant metastases are very rare. Here, we report a case of DFSP metastasizing to the right hemithorax diagnosed by an endobronchial ultrasound-guided fine-needle aspiration (FNA) 9 years after initial presentation. The aspirate showed a bland spindle cell proliferation that was morphologically similar to the original skin excision; the storiform pattern was particularly prominent in tumor-tissue fragments in the cellblock. Immunostaining showed strong, diffuse positivity for CD34. Molecular studies demonstrated a characteristic COL1A1/PDGFB fusion in both original and metastatic specimens. A review of the literature revealed that metastatic DFSP most often involves the lungs, occurs usually in cases with fibrosarcomatous transformation and after a local recurrence, and presents on average 4.5 years after the original diagnosis. This case did not show fibrosarcomatous transformation or local recurrence prior to metastasis 9 years later. In summary, it is important to consider the potential for metastases years after a nonrecurring primary DFSP, despite its rarity. Cytologic features when complemented by ancillary studies and awareness of the patient's prior clinical history permit a confident diagnosis of metastatic DFSP by FNA. In addition, by confirming the characteristic translocation, tyrosine-kinase inhibitor imatinib can provide additional treatment options for unresectable metastatic DFSP.
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http://dx.doi.org/10.1002/dc.24179DOI Listing
August 2019

Correlation of cytopathology with flow cytometry and histopathology for the diagnosis of hematologic malignancies in young adults presenting with cervical lymphadenopathy.

Diagn Cytopathol 2019 Jun 22;47(6):579-583. Epub 2019 Feb 22.

Department of Pathology, University of Chicago, Chicago, Illinois.

Background: Fine-needle aspiration (FNA) is frequently utilized in the diagnostic workup of lymphadenopathy. We evaluated the correlation of cytopathology with flow cytometry and tissue biopsy results and assessed the prevalence of specific malignancies in young adults presenting with cervical lymphadenopathy.

Methods: Database was searched for cervical lymph node FNA performed by a cytopathologist in patients aged 18-30 years from 2005 to 2017.

Results: Cervical lymph node FNA was performed on 48 patients without prior history of malignancy. Nineteen patients had cytology results only, of which all were interpreted as benign reactive lymph node. None developed subsequent malignancies. The remaining 29 patients had cytology with flow cytometry and/or tissue biopsy results. A benign reactive cytology diagnosis was rendered in 18 (62%) cases, of which 11 had concordant diagnosis on flow cytometry, 2 had tissue biopsy, and 3 had both. Eleven (38%) patients had cytology results concerning for a hematologic malignancy, of which 7 were confirmed by flow cytometry and 3 by both flow cytometry and tissue biopsy. Cervical lymph node FNA has 94.1% sensitivity, 83.3% specificity, 88.9% positive predictive value, and 90.9% negative predictive value. The most common hematologic malignancy in our young adult population presenting with cervical lymphadenopathy was Hodgkin lymphoma.

Conclusion: FNA is a useful first-line diagnostic procedure for assessing cervical lymphadenopathy in young adults to allow for better triage of specimens for flow cytometry and/or tissue biopsy concerning for a hematologic malignancy and potentially avoid invasive excisional biopsy in a proportion of cases.
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http://dx.doi.org/10.1002/dc.24157DOI Listing
June 2019

Comparison of T2-Weighted Imaging, DWI, and Dynamic Contrast-Enhanced MRI for Calculation of Prostate Cancer Index Lesion Volume: Correlation With Whole-Mount Pathology.

AJR Am J Roentgenol 2019 02 12;212(2):351-356. Epub 2018 Dec 12.

1 Department of Radiology, University of Chicago, 5841 S Maryland Ave, Chicago, IL 60637.

Objective: The objective of our study was to investigate the comparative effectiveness of different MRI sequences for the estimation of index lesion volume in patients with prostate cancer (PCa) compared with ground truth volume measured on whole-mount pathology.

Materials And Methods: Patients with PCa underwent multiparametric MRI (mpMRI) on a 3-T MRI scanner before radical prostatectomy. Forty PCa index lesions were identified and outlined on histology by a pathologist. Two radiologists who were informed about the presence of PCa but were not aware of lesion outlines on histology worked in consensus to delineate PCa lesions on T2-weighted imaging, apparent diffusion coefficient (ADC) maps, and early-phase dynamic contrast-enhanced MRI (DCE-MRI). The lesion volumes from different mpMRI sequences and the percentage of volume underestimation compared with pathology were calculated and correlated with volume at pathology. The repeated-measures ANOVA with the posthoc Bonferroni test was performed to evaluate whether the difference between the estimated tumor volumes was statistically significant.

Results: The mean PCa lesion volume estimated from pathology, T2-weighted imaging, DWI (ADC maps), and DCE-MRI were 4.61 ± 4.99 (SD) cm, 2.03 ± 2.96 cm, 1.81 ± 2.76 cm, and 3.48 ± 4.06 cm, respectively. The lesion volumes on T2-weighted images (p = 0.000002), ADC maps (p = 0.000003), and DCE-MR images (p = 0.004412) were significantly lower than those from pathology. PCa lesion volume was significantly underestimated on T2-weighted images, ADC maps, and DCE-MR images compared with pathology by 54.98% ± 22.60% (mean ± SD), 58.59% ± 18.58%, and 18.33% ± 30.11%, respectively; underestimation using T2-weighted imaging (p = 1.01 × 10) and DWI (p = 2.94 × 10) was significantly higher than underestimation using DCE-MRI. Correlations between lesion volume estimated on T2-weighted images, ADC maps, and DCE-MR images with pathology were 0.91 (p = 9.03 × 10), 0.86 (p = 7.32 × 10), and 0.93 (p = 8.22 × 10), respectively.

Conclusion: DCE-MRI performed better than T2-weighted imaging and DWI for estimation of index PCa volume and therefore can be preferred over these other two sequences for volume estimation.
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http://dx.doi.org/10.2214/AJR.18.20147DOI Listing
February 2019

MRI-guided transurethral insonation of silica-shell phase-shift emulsions in the prostate with an advanced navigation platform.

Med Phys 2019 Feb 7;46(2):774-788. Epub 2018 Dec 7.

The University of Chicago, Chicago, IL, 60637, USA.

Purpose: In this study, the efficacy of transurethral prostate ablation in the presence of silica-shell ultrasound-triggered phase-shift emulsions (sUPEs) doped with MR contrast was evaluated. The influence of sUPEs on MR imaging assessment of the ablation zone was also investigated.

Methods: sUPEs were doped with a magnetic resonance (MR) contrast agent, Gd O , to assess ultrasound transition. Injections of saline (sham), saline and sUPEs alone, and saline and sUPEs with Optison microbubbles were performed under guidance of a prototype interventional MRI navigation platform in a healthy canine prostate. Treatment arms were evaluated for differences in lesion size, T  contrast, and temperature. In addition, non-perfused areas (NPAs) on dynamic contrast-enhanced (DCE) MRI, 55°C isotherms, and areas of 240 cumulative equivalent minutes at 43°C (CEM ) dose or greater computed from MR thermometry were measured and correlated with ablated areas indicated by histology.

Results: For treatment arms including sUPEs, the computed correlation coefficients between the histological ablation zone and the NPA, 55°C isotherm, and 240 CEM area ranged from 0.96-0.99, 0.98-0.99, and 0.91-0.99, respectively. In the absence of sUPEs, the computed correlation coefficients between the histological ablation zone and the NPA, 55°C isotherm, and 240 CEM area were 0.69, 0.54, and 0.50, respectively. Across all treatment arms, the areas of thermal tissue damage and NPAs were not significantly different (P = 0.47). Areas denoted by 55°C isotherms and 240 CEM dose boundaries were significantly larger than the areas of thermal damage, again for all treatment arms (P = 0.009 and 0.003, respectively). No significant differences in lesion size, T contrast, or temperature were observed between any of the treatment arms (P > 0.0167). Lesions exhibiting thermal fixation on histological analysis were present in six of nine insonations involving sUPE injections and one of five insonations involving saline sham injections. Significantly larger areas (P = 0.002), higher temperatures (P = 0.004), and more frequent ring patterns of restricted diffusion on ex vivo diffusion-weighted imaging (P = 0.005) were apparent in lesions with thermal fixation.

Conclusions: T contrast suggesting sUPE transition was not evident in sUPE treatment arms. The use of MR imaging metrics to predict prostate ablation was not diminished by the presence of sUPEs. Lesions generated in the presence of sUPEs exhibited more frequent thermal fixation, though there were no significant changes in the ablation areas when comparing arms with and without sUPEs. Thermal fixation corresponded to some qualitative imaging features.
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http://dx.doi.org/10.1002/mp.13279DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6367027PMC
February 2019

Multiparametric MRI Features and Pathologic Outcome of Wedge-Shaped Lesions in the Peripheral Zone on T2-Weighted Images of the Prostate.

AJR Am J Roentgenol 2019 01 7;212(1):124-129. Epub 2018 Nov 7.

1 Department of Radiology, University of Chicago, 5841 S Maryland Ave, Chicago, IL 60637.

Objective: This study investigates the multiparametric MRI (mpMRI) characteristics and pathologic outcome of wedge-shaped lesions observed on T2-weighted images.

Materials And Methods: Seventy-six patients with histologically confirmed prostate cancer underwent preoperative 3-T MRI before undergoing radical prostatectomy. Two radiologists worked in consensus to mark wedge-shaped regions of hypointensity on T2-weighted images and assess their appearance on apparent diffusion coefficient (ADC) maps (to determine the degree of hypointensity) and dynamic contrast-enhanced (DCE) MRI (DCE-MRI) (to assess whether they showed early enhancement). The pathologic outcome of wedge-shaped lesions was assessed by matching MR images with whole-mount histologic specimens retrospectively. The difference in quantitative ADC values between malignant and benign wedge-shaped lesions was assessed using a t test.

Results: Thirty-five wedge-shaped regions were identified, 12 (34%) of which were found be malignant. Most malignant wedge-shaped regions were highly hypointense (10/12; 83%) on ADC maps and showed early enhancement on DCE-MRI (7/12; 58%). However, benign wedge-shaped lesions were predominantly mildly hypointense (13/23; 57%) on ADC maps and showed no early enhancement (15/23; 65%). Histologic correlates of the benign wedge-shaped regions showed prostatitis (acute inflammation [7/23; 30%] or chronic inflammation [9/23; 39%]), hemosiderin-laden macrophages (6/23; 26%), prominent blood vessels (7/23; 30%), intraluminal blood (6/23; 26%), and nonspecific atrophy (6/23; 26%). The mean (± SD) quantitative ADC value of malignant wedge-shaped regions (1.13 ± 0.11 μm/ms) was significantly lower (p = 0.0001) than that of benign wedge-shaped regions (1.52 ± 0.27 μm/ms).

Conclusion: This study shows that a greater percentage of wedge-shaped features are malignant than was previously thought. Of importance, mpMRI (specifically, ADC maps) can distinguish between malignant and benign wedge-shaped features.
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http://dx.doi.org/10.2214/AJR.18.19742DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6437777PMC
January 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

Can computer-aided diagnosis assist in the identification of prostate cancer on prostate MRI? a multi-center, multi-reader investigation.

Oncotarget 2018 Sep 18;9(73):33804-33817. Epub 2018 Sep 18.

Molecular Imaging Program, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.

For prostate cancer detection on prostate multiparametric MRI (mpMRI), the Prostate Imaging-Reporting and Data System version 2 (PI-RADSv2) and computer-aided diagnosis (CAD) systems aim to widely improve standardization across radiologists and centers. Our goal was to evaluate CAD assistance in prostate cancer detection compared with conventional mpMRI interpretation in a diverse dataset acquired from five institutions tested by nine readers of varying experience levels, in total representing 14 globally spread institutions. Index lesion sensitivities of mpMRI-alone were 79% (whole prostate (WP)), 84% (peripheral zone (PZ)), 71% (transition zone (TZ)), similar to CAD at 76% (WP, p=0.39), 77% (PZ, p=0.07), 79% (TZ, p=0.15). Greatest CAD benefit was in TZ for moderately-experienced readers at PI-RADSv2 <3 (84% vs mpMRI-alone 67%, p=0.055). Detection agreement was unchanged but CAD-assisted read times improved (4.6 vs 3.4 minutes, p<0.001). At PI-RADSv2 ≥ 3, CAD improved patient-level specificity (72%) compared to mpMRI-alone (45%, p<0.001). PI-RADSv2 and CAD-assisted mpMRI interpretations have similar sensitivities across multiple sites and readers while CAD has potential to improve specificity and moderately-experienced radiologists' detection of more difficult tumors in the center of the gland. The multi-institutional evidence provided is essential to future prostate MRI and CAD development.
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http://dx.doi.org/10.18632/oncotarget.26100DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6173466PMC
September 2018

A Proposal for Separation of Nuclear Atypia and Architectural Atypia in Bethesda Category III (AUS/FLUS) Based on Differing Rates of Thyroid Malignancy.

Am J Clin Pathol 2019 01;151(1):86-94

Department of Pathology, University of Chicago, Chicago, IL.

Objectives: Bethesda category III (atypia of undetermined significance/follicular lesion of undetermined significance) includes sparsely cellular specimens with nuclear atypia (3N) and/or architectural atypia (3A). This study investigates whether the two types of atypia have different rates of malignancy (ROMs).

Methods: Cytologic and histologic diagnoses of resected thyroid nodules were recorded. ROM was calculated for all Bethesda categories and for 3N and 3A subcategories. Possible noninvasive follicular thyroid neoplasms with papillary-like nuclear features were reviewed and removed from malignancies, and ROM was recalculated.

Results: A total of 1,396 nodules were included. ROM of 3N (33.3%-26.0%) was higher than 3A (7.7%-5.0%) (P < .0001) and was similar to suspicious for follicular neoplasm (25.0%-20.3%) (P = .3). ROM of 3A approached benign (2.4%-1.5%) (P = .02).

Conclusions: Strong consideration should be given to separating 3N (nuclear atypia with higher risk for papillary thyroid carcinoma) from 3A (architectural atypia with higher chance of being benign) to convey different ROMs.
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http://dx.doi.org/10.1093/ajcp/aqy109DOI Listing
January 2019

CD8 lymphocytes in tumors and nonsynonymous mutational load correlate with prognosis of bladder cancer patients treated with immune checkpoint inhibitors.

Cancer Rep (Hoboken) 2018 06 10;1(1):e1002. Epub 2018 Apr 10.

Department of Medicine, The University of Chicago, Chicago, IL, USA.

Background: Anti-programed cell death 1 checkpoint inhibitors have recently demonstrated effectiveness against metastatic cancers including urothelial carcinoma.

Aims: To identify biomarkers/factors that correlate with the clinical response in advanced bladder cancer patients who received immune checkpoint inhibitor treatment.

Methods And Results: We investigated tumors from 18 bladder cancer patients who had received anti-programed cell death 1 (pembrolizumab) or anti-programmed death-ligand 1 therapy (atezolizumab or durvalumab) and performed exome analysis, T-cell receptor sequencing of the tumor-infiltrating lymphocytes (TILs), and immunohistochemical analysis of CD8 and programmed death-ligand 1 in cancer tissues. Immunohistochemical analysis of bladder cancer tissues demonstrated that a higher number of CD8 T-cell infiltration into cancer tissues was significantly associated with longer cancer-specific survival of the patients (P = .0012). T-cell receptor beta sequencing of TILs using genomic DNAs extracted from the tissues of 15 cases revealed that patients with higher clonal expansion of TILs had some tendency of longer cancer-specific survival (P = .055), than those with lower clonal expansion. We performed whole exome sequencing of 14 cases and found that patients carrying higher numbers of somatic mutations received greater benefit from immunotherapy (P = .034) and one patient who had high microsatellite instability has survived for 1034 days.

Conclusion: CD8 infiltration in tumors and nonsynonymous mutation load might be useful predictive markers for immune checkpoint inhibitors for bladder cancer patients.
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http://dx.doi.org/10.1002/cnr2.1002DOI Listing
June 2018