Publications by authors named "Sara E Wobker"

33 Publications

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

Mod Pathol 2021 Mar 4. Epub 2021 Mar 4.

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

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

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

Mod Pathol 2021 Feb 1. Epub 2021 Feb 1.

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

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

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

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

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

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

Pediatric Mesothelioma With ALK Fusions: A Molecular and Pathologic Study of 5 Cases.

Am J Surg Pathol 2021 May;45(5):653-661

Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY.

Pediatric mesotheliomas are rare and their pathogenesis remains undefined. In this study, we report 5 cases of malignant mesothelioma in children, characterized by fusions involving the anaplastic lymphoma kinase (ALK) gene. Four cases occurred in females involving the abdominal cavity and were characterized by a pure epithelioid morphology. The fifth arose in the tunica vaginalis of a 15-year-old male and displayed a biphasic epithelioid-sarcomatoid phenotype. All cases demonstrated the classic morphologic and immunohistochemical features of malignant mesothelioma, including tubulopapillary architecture and cuboidal epithelioid cells with eosinophilic cytoplasm and uniform nuclei with vesicular chromatin. Immunohistochemically, all cases showed labeling for ALK, cytokeratins, WT1, and calretinin, while lacking expression of adenocarcinoma immunomarkers. Four cases demonstrated weak-moderate labeling for PAX8 protein, which resulted in diagnostic challenges with primary peritoneal serous carcinoma. The ALK genetic abnormalities were investigated by a combination of molecular methods. Archer FusionPlex was performed in 2 cases, showing fusions between ALK with either STRN or TPM1 genes, resulting in a transcript that retained the ALK kinase domain. One case was further studied by DNA targeted sequencing, but no additional genetic alterations were observed. In 1 case, cytogenetic analysis showed the presence of a t(2;15)(p23;q22) and fluorescence in situ hybridization confirmed the ALK gene break-apart. In the remaining 2 cases, ALK gene rearrangements were demonstrated by fluorescence in situ hybridization. Unlike adult mesotheliomas, which are tightly linked to asbestos exposure, often show loss of BAP1 expression and have complex karyotypes, ALK-rearranged mesothelioma appears to be similar to other fusion-positive mesotheliomas, such as those harboring EWSR1/FUS-ATF1 fusions, sharing significant morphologic overlap, occurring in young patients and displaying a simple, translocation-driven genetic profile.
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http://dx.doi.org/10.1097/PAS.0000000000001656DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8035308PMC
May 2021

Development and validation of a NanoString BASE47 bladder cancer gene classifier.

PLoS One 2020 17;15(12):e0243935. Epub 2020 Dec 17.

Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.

Background: Recent molecular characterization of urothelial cancer (UC) has suggested potential pathways in which to direct treatment, leading to a host of targeted therapies in development for UC. In parallel, gene expression profiling has demonstrated that high-grade UC is a heterogeneous disease. Prognostic basal-like and luminal-like subtypes have been identified and an accurate transcriptome BASE47 classifier has been developed. However, these phenotypes cannot be broadly investigated due to the lack of a clinically viable diagnostic assay. We sought to develop and evaluate a diagnostic classifier of UC subtype with the goal of accurate classification from clinically available specimens.

Methods: Tumor samples from 52 patients with high-grade UC were profiled for BASE47 genes concurrently by RNAseq as well as NanoString. After design and technical validation of a BASE47 NanoString probeset, results from the RNAseq and NanoString were used to translate diagnostic criteria to the Nanostring platform. Evaluation of repeatability and accuracy was performed to derive a final Nanostring based classifier. Diagnostic classification resulting from the NanoString BASE47 classifier was validated on an independent dataset (n = 30). The training and validation datasets accurately classified 87% and 93% of samples, respectively.

Results: Here we have derived a NanoString-platform BASE47 classifier that accurately predicts basal-like and luminal-like subtypes in high grade urothelial cancer. We have further validated our new NanoString BASE47 classifier on an independent dataset and confirmed high accuracy when compared with our original Transcriptome BASE47 classifier.

Conclusions: The NanoString BASE47 classifier provides a faster turnaround time, a lower cost per sample to process, and maintains the accuracy of the original subtype classifier for better clinical implementation.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0243935PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7745986PMC
February 2021

Nested Variant of Urothelial Carcinoma Is a Luminal Bladder Tumor With Distinct Coexpression of the Basal Marker Cytokeratin 5/6.

Am J Clin Pathol 2021 Mar;155(4):588-596

Department of Pathology and Laboratory Medicine, University of North Carolina School of Medicine, Chapel Hill.

Objectives: The nested variant of urothelial carcinoma (NVUC) is a rare bladder tumor that may possess a luminal molecular phenotype. We sought to determine whether a small immunohistochemical (IHC) panel using common surrogates for molecular phenotypes would reliably classify a cohort of pure NVUC cases.

Methods: IHC staining with a panel composed of markers for basal subtypes (CK5/6, CK14) and luminal subtypes (FOXA1, GATA3) was performed on pure small NVUC cases (n = 23) and 5 large NVUC cases (n = 5). Scoring of IHC stains was performed semiquantitatively. Individual cases were analyzed using previously reported IHC-based surrogates for molecular subtype.

Results: The phenotype of NVUC was classified as luminal from 60.1% (FOXA1+/CK5/6-) to 100% (GATA3+/CK14-) of cases using composite phenotypes. No cases possessed a basal or squamous cell carcinoma-like phenotype. The majority of small NVUC cases (69.5%) showed subset CK5/6 expression distinctly localized to the basal layers of tumor cell nests. Intratumoral heterogeneity was also noted in CK5/6 (21.7% of small NVUC cases) but no other markers.

Conclusions: NVUC appears to express markers of both basal and luminal bladder tumors. Definitive gene expression profiling may be valuable to further characterize this unique histologic variant.
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http://dx.doi.org/10.1093/ajcp/aqaa160DOI Listing
March 2021

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

Urol Oncol 2020 Sep 15. Epub 2020 Sep 15.

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

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

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

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

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

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

Arch Pathol Lab Med 2021 Apr;145(4):461-493

and Department of Pathology and Laboratory Medicine, University of Calgary, Calgary, Alberta, Canada (Trpkov).

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

The Surgical Treatment and Genomic Analysis of a Rare Case of Oligometastatic Renal Cell Carcinoma of the Prostate.

Urology 2020 Aug 11;142:e11-e14. Epub 2020 May 11.

University of North Carolina at Chapel Hill (UNC) Department of Urology, Chapel Hill, NC; UNC Lineberger Comprehensive Cancer Center, Chapel Hill, NC. Electronic address:

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http://dx.doi.org/10.1016/j.urology.2020.04.101DOI Listing
August 2020

RNA Expression Profiling of Lymphoepithelioma-Like Carcinoma of the Bladder Reveals a Basal-Like Molecular Subtype.

Am J Pathol 2020 01 11;190(1):134-144. Epub 2019 Oct 11.

UNC Lineberger Comprehensive Cancer Center, Chapel Hill, North Carolina; Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina. Electronic address:

Lymphoepithelioma-like carcinoma of the bladder (LELC-B) is a rare subtype of urothelial carcinoma consisting of undifferentiated epithelial cells within a dense inflammatory cell infiltrate. We set out to molecularly characterize LELC-B through RNA expression profiling as well as immunohistochemistry (IHC) to understand its underlying biology. Sixteen cases of LELC-B were identified at Johns Hopkins University. RNA sequencing was performed on 14 cases. IHC staining for programmed cell death ligand 1 (PD-L1) and mismatch repair proteins MutL homolog 1 (MLH1), MutS homolog 2 (MSH2), MSH6, and PMS1 homolog, mismatch repair system component 2 (PMS2) was performed. Transcriptomic profiling of LELC-B showed that they are enriched in a basal-like phenotype, with 12 of 14 LELC-B cases correlating to the basal centroid of the bladder cancer analysis of subtypes by gene expression 47 (BASE47) predictive analysis of microarrays (PAM) classifier. Gene signature analysis confirmed the lymphocyte infiltration profile consistent with the histomorphology. LELC-B lacked features to explain the robust lymphocytic infiltrate, such as loss of mismatch repair protein expression or expression of Epstein-Barr virus transcripts. Nonetheless, PD-L1 IHC was positive in 93% of LELC cases. Our study demonstrates that LELC-B tumors are enriched in a basal-like molecular subtype and share a high level of immune infiltration and PD-L1 expression, similar to basal tumors. The basal-like phenotype is consistent with the known sensitivity of LELC-B to chemotherapy and suggests that immune checkpoint therapy should be explored in this rare disease.
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http://dx.doi.org/10.1016/j.ajpath.2019.09.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6943801PMC
January 2020

Metanephric Adenoma-Epithelial Wilms Tumor Overlap Lesions: An Analysis of BRAF Status.

Am J Surg Pathol 2019 09;43(9):1157-1169

Departments of Pathology.

Metanephric adenoma (MA) has historically been considered to represent a differentiated form of epithelial Wilms tumor (WT), based in part upon cases that morphologically overlap these 2 neoplasms. More recently, BRAF V600E mutations have been demonstrated in the majority of MAs but not in unselected or even epithelial-predominant WTs, suggesting 2 genetically distinct entities. However, no prior study has examined BRAF status in neoplasms with overlapping histologic features of epithelial WT and MA. We studied a cohort of 11 such overlapping lesions, 2 of which we considered morphologically to be otherwise typical MAs with unusually prominent mitotic activity and 9 of which we classified as epithelial WTs with areas resembling MA. Both mitotically active MAs demonstrated the BRAF V600E mutation. While the majority (5/9) of epithelial WTs with areas resembling MA were negative for BRAF V600E mutation, 4 such cases were positive. Two BRAF V600E mutation-positive WTs occurred in children. One case in a 6-year-old male was morphologically similar to the BRAF V600E mutation-positive adult cases and subsequently metastasized to the lungs; remarkably, the metastases then completely resolved on Braf targeted therapy. A second occurred in a 3-year-old girl whose posttherapy nephrectomy specimen's tumor was encapsulated and mitotically active like a typical WT, but also had more differentiated areas resembling MA. Immunohistochemistry for Braf V600E paralleled the molecular findings, demonstrating immunoreactivity in both the WT and MA-like areas of all 4 of these neoplasms. In summary, we demonstrate that BRAF V600E mutations are not entirely restricted to typical MA, as they may be seen in MAs showing mitotic activity along with a subset of epithelial-predominant WTs in adults and children that have foci which overlap morphologically with MA.
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http://dx.doi.org/10.1097/PAS.0000000000001240DOI Listing
September 2019

Intraductal carcinoma of the prostate in the absence of high-grade invasive carcinoma represents a molecularly distinct type of in situ carcinoma enriched with oncogenic driver mutations.

J Pathol 2019 09 24;249(1):79-89. Epub 2019 May 24.

Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Intraductal carcinoma of the prostate (IDC-P) most often appears associated with high-grade invasive prostate carcinoma (PCa), where it is believed to represent retrograde spread. However, IDC-P rarely occurs as an isolated finding at radical prostatectomy or with concurrent low-grade (Grade Group 1) invasive carcinoma. We hypothesized that isolated IDC-P (iIDC-P) in these unusual cases may represent a distinct in situ lesion and molecularly profiled 15 cases. iIDC-P was characterized by copy number alteration (CNA) profiling and targeted next generation sequencing in cases with sufficient tissue (n = 7). Immunohistochemistry for PTEN and ERG was performed on the total cohort (n = 15), where areas of iIDC-P and associated invasive disease were evaluated separately (n = 9). By copy number profiling, iIDC-P alterations were similar to those previously described in high-grade invasive PCa (PTEN, RB1, and CHD1 loss; MYC gain). However, in four cases, targeted sequencing revealed a striking number of activating oncogenic driver mutations in MAPK and PI3K pathway genes, which are extraordinarily rare in conventional PCa. In addition, pathogenic mutations in DNA repair genes were found in two cases of iIDC-P (BRCA2, CHEK2, CDK12) and other known PCa-associated mutations (FOXA1, SPOP) in two cases. Overall, ERG was expressed in 7% (1/15) of the iIDC-P lesions and PTEN was lost in 53% (8/15). Discordance for ERG or PTEN status between IDC-P and the low-grade PCa was observed in five of nine cases, with intact PTEN in the invasive tumor and PTEN loss in IDC-P in four. Despite a CNA profile similar to conventional PCa, iIDC-P is enriched with potentially targetable oncogenic driver mutations in MAPK/PI3K genes. Based on PTEN and ERG status, iIDC-P is not likely a precursor to the associated low-grade invasive PCa, but represents a molecularly unique in situ tumor of unclear clinical significance. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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http://dx.doi.org/10.1002/path.5283DOI Listing
September 2019

Going Bone Deep: Osseous Rosai-Dorfman Disease in an Adult with Recurrent, Culture-Negative Osteomyelitis.

Case Rep Infect Dis 2018 17;2018:6151738. Epub 2018 May 17.

Department of Medicine, Division of Infectious Diseases, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.

A patient presented for medical care on three separate occasions over the course of two years with recurrent right knee pain attributed to chronic osteomyelitis. Careful assessment revealed that his symptoms were caused by osseous Rosai-Dorfman disease. This case presents an alternative diagnostic possibility for culture-negative chronic osteomyelitis.
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http://dx.doi.org/10.1155/2018/6151738DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5985093PMC
May 2018

Molecular Subtype-Specific Immunocompetent Models of High-Grade Urothelial Carcinoma Reveal Differential Neoantigen Expression and Response to Immunotherapy.

Cancer Res 2018 07 21;78(14):3954-3968. Epub 2018 May 21.

Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.

High-grade urothelial cancer contains intrinsic molecular subtypes that exhibit differences in underlying tumor biology and can be divided into luminal-like and basal-like subtypes. We describe here the first subtype-specific murine models of bladder cancer and show that Upk3a-Cre; Trp53; Pten; Rosa26 (UPPL, luminal-like) and BBN (basal-like) tumors are more faithful to human bladder cancer than the widely used MB49 cells. Following engraftment into immunocompetent C57BL/6 mice, BBN tumors were more responsive to PD-1 inhibition than UPPL tumors. Responding tumors within the BBN model showed differences in immune microenvironment composition, including increased ratios of CD8:CD4 and memory:regulatory T cells. Finally, we predicted and confirmed immunogenicity of tumor neoantigens in each model. These UPPL and BBN models will be a valuable resource for future studies examining bladder cancer biology and immunotherapy. This work establishes human-relevant mouse models of bladder cancer. .
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http://dx.doi.org/10.1158/0008-5472.CAN-18-0173DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6157276PMC
July 2018

Northern Italy in the American South: Assessing interobserver reliability within the Milan System for Reporting Salivary Gland Cytopathology.

Cancer Cytopathol 2018 06 26;126(6):390-396. Epub 2018 Mar 26.

Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, North Carolina.

Background: The Milan System for Reporting Salivary Gland Cytopathology (MSRSGC) has been proposed to standardize salivary gland fine-needle aspiration (FNA) diagnoses. This study assessed salivary gland FNA results and risk of malignancy (ROM) rates at the University of North Carolina as well as the interobserver reliability (IOR) of the atypia of undetermined significance (AUS) and salivary gland neoplasm of uncertain malignant potential (SUMP) categories.

Methods: The electronic medical record was searched for FNA cases from 2010 to 2017 with subsequent surgical resections. Histologic diagnosis was used for gold-standard comparison. The original cytologic results were then converted into MSRSGC categories (nondiagnostic, nonneoplastic, AUS, benign neoplasm, SUMP, suspicious, and malignant). For the assessment of IOR, 23 cases were selected with enrichment for cases diagnosed as AUS (n = 11) or SUMP (n = 9). Six boarded cytopathologists and 1 cytopathology fellow assessed representative slides and provided an MSRSGC diagnosis for each case. Fleiss' κ coefficients were calculated to determine IOR.

Results: The ROM was 33% for both AUS and SUMP cases; however, the risk of neoplasia was 56% for AUS cases and 100% for SUMP cases. Fleiss' κ for the AUS category was 0.217 (P < .05), and Fleiss' κ for the SUMP category was 0.024 (P = .74).

Conclusions: In this study assessing the IOR of MSRSGC categories, fair agreement and slight agreement were found for the AUS and SUMP categories, respectively. Observers preferentially used the AUS or benign neoplasm category for SUMP cases, perhaps because of unfamiliarity with SUMP as a diagnostic option. The initial adoption of a new reporting system will require a quality assessment to ensure that the system is reliable and useful for clinicians. Cancer Cytopathol 2018;126:390-6. © 2018 American Cancer Society.
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http://dx.doi.org/10.1002/cncy.21989DOI Listing
June 2018

Margin Assessment in Renal Surgery Using a Handheld Optical Coherence Tomography Probe.

Urology 2018 Mar 28;113:241-245. Epub 2017 Nov 28.

The James Buchanan Brady Urological Institute and Department of Urology, Johns Hopkins University School of Medicine, Baltimore, MD.

Objective: To assess the use of a handheld optical coherence tomography (OCT) probe for the evaluation of intraoperative surgical margins during partial nephrectomy (PN).

Methods: In an initial feasibility study, a radical nephrectomy specimen with a 9-cm tumor was cut into 19 sections, exposing 0 mm (n = 8), 1 mm (n = 6), and 2 mm (n = 5) gross margins. OCT was used to determine the margin width in each specimen. Second, a prospective ex vivo assessment of 15 PN tumor specimens was performed with OCT to determine margin status and to measure the attenuation coefficient of tumor and renal parenchyma.

Results: Median OCT margin width measurements for sectioned samples were 0 mm, 0.9 mm (range 0.7-2.9 mm), and 2.7 (range 1.65-2.8 mm) for grossly 0 mm (positive), 1 mm, and 2 mm margins, respectively. The difference between measurements from all margin groups was statistically significant (P <.04). The sensitivity and specificity for identifying positive margins were both 100%. In the PN specimens, OCT correctly found that all specimens had negative margins (within <.0001).

Conclusion: We have demonstrated the feasibility of using a handheld OCT probe to assess margins ex vivo during PN. OCT may reduce the need for intraoperative frozen section and aid in minimizing parenchymal excision.
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http://dx.doi.org/10.1016/j.urology.2017.11.029DOI Listing
March 2018

Modern Pathologic Diagnosis of Renal Oncocytoma.

J Kidney Cancer VHL 2017 9;4(4):1-12. Epub 2017 Oct 9.

Department of Pathology and Laboratory Medicine and Henry Ford Cancer Institute, Henry Ford Health System, Detroit, MI, USA.

Oncocytoma is a well-defined benign renal tumor, with classic gross and histologic features, including a tan or mahogany-colored mass with central scar, microscopic nested architecture, bland cytology, and round, regular nuclei with prominent central nucleoli. As a result of variations in this classic appearance, difficulty in standardizing diagnostic criteria, and entities that mimic oncocytoma, such as eosinophilic variant chromophobe renal cell carcinoma and succinate dehydrogenase-deficient renal cell carcinoma, pathologic diagnosis remains a challenge. This review addresses the current state of pathologic diagnosis of oncocytoma, with emphasis on modern diagnostic markers, areas of controversy, and emerging techniques for less invasive diagnosis, including renal mass biopsy and advanced imaging.
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http://dx.doi.org/10.15586/jkcvhl.2017.96DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5634396PMC
October 2017

Intraosseous Rosai-Dorfman disease diagnosed by touch imprint cytology evaluation: A case series.

Diagn Cytopathol 2018 Jan 23;46(1):83-87. Epub 2017 Aug 23.

Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.

Sinus histiocytosis with massive lymphadenopathy, also known as Rosai-Dorfman disease (RDD) is a rare benign disorder that primarily affects the lymph nodes. Localized lymphadenopathy is the most common clinical manifestation of this disorder. However, RDD has been described in several extra-nodal sites including the head and neck region, soft tissue, skin, upper respiratory tract, gastro-intestinal tract and central nervous system (CNS). Involvement of the bone is considered very rare, occurring in less than 10% patients. RDD is one of the histiocytoses and the differential diagnosis includes entities such as Langerhans cell histiocytosis and Erdheim-Chester disease. In the rare intraosseous variant, the clinical and radiologic differential diagnosis is broader and includes neoplasms such as osteosarcoma and Ewing sarcoma. In this report, we describe three cases of extra-nodal, intraosseous RDD where touch imprint cytology played a crucial role in diagnosis. Two of the cases initially presented with involvement of the head and neck region and later developed intraosseous disease; while the third patient presented with primary bone involvement. The diagnosis was established by core biopsy with touch imprints of the bone lesions. The cytologic samples showed numerous histiocytes, often with neutrophils within their cytoplasm (emperipolesis) in addition to lymphocytes and plasma cells. The diagnosis of RDD was confirmed with appropriate immunohistochemical stains. Our account of these three cases of intraosseous Rosai-Dorfman disease highlights the role of cytology in the diagnosis of this rare entity.
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http://dx.doi.org/10.1002/dc.23802DOI Listing
January 2018

Comprehensive Molecular Characterization of Urachal Adenocarcinoma Reveals Commonalities With Colorectal Cancer, Including a Hypermutable Phenotype.

JCO Precis Oncol 2017 6;1. Epub 2017 Jul 6.

, , , , , , , , , , , , , , , and , University of North Carolina at Chapel Hill, Chapel Hill, NC; and , University of British Columbia, Vancouver, British Columbia, Canada.

Purpose: Urachal adenocarcinoma is a rare type of primary bladder adenocarcinoma that comprises less than 1% of all bladder cancers. The low incidence of urachal adenocarcinomas does not allow for an evidence-based approach to therapy. Transcriptome profiling of urachal adenocarcinomas has not been previously reported. We hypothesized that an in-depth molecular understanding of urachal adenocarcinoma would uncover rational therapeutic strategies.

Patients And Methods: We performed targeted exon sequencing and global transcriptome profiling of 12 urachal tumors to generate a comprehensive molecular portrait of urachal adenocarcinoma. A single patient with an mutation was treated with the anti-programmed death-ligand 1 antibody, atezolizumab.

Results: Urachal adenocarcinoma closely resembles colorectal cancer at the level of RNA expression, which extends previous observations that urachal tumors harbor genomic alterations that are found in colorectal adenocarcinoma. A subset of tumors was found to have alterations in genes that are associated with microsatellite instability ( and ) and hypermutation (). A patient with an mutation was treated with immune checkpoint blockade, which resulted in stable disease.

Conclusion: Because clinical trials are next to impossible for patients with rare tumors, precision oncology may be an important adjunct for treatment decisions. Our findings demonstrate that urachal adenocarcinomas molecularly resemble colorectal adenocarcinomas at the level of RNA expression, are the first report, to our knowledge, of and mutations in this disease, and support the consideration of immune checkpoint blockade as a rational therapeutic treatment of this exceedingly rare tumor.
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http://dx.doi.org/10.1200/PO.17.00027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7446420PMC
July 2017

MYC activation cooperates with Vhl and Ink4a/Arf loss to induce clear cell renal cell carcinoma.

Nat Commun 2017 06 8;8:15770. Epub 2017 Jun 8.

Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.

Renal carcinoma is a common and aggressive malignancy whose histopathogenesis is incompletely understood and that is largely resistant to cytotoxic chemotherapy. We present two mouse models of kidney cancer that recapitulate the genomic alterations found in human papillary (pRCC) and clear cell RCC (ccRCC), the most common RCC subtypes. MYC activation results in highly penetrant pRCC tumours (MYC), while MYC activation, when combined with Vhl and Cdkn2a (Ink4a/Arf) deletion (VIM), produce kidney tumours that approximate human ccRCC. RNAseq of the mouse tumours demonstrate that MYC tumours resemble Type 2 pRCC, which are known to harbour MYC activation. Furthermore, VIM tumours more closely simulate human ccRCC. Based on their high penetrance, short latency, and histologic fidelity, these models of papillary and clear cell RCC should be significant contributions to the field of kidney cancer research.
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http://dx.doi.org/10.1038/ncomms15770DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5472759PMC
June 2017

Loss Induces Senescence and Stat3 Activation Coinciding with Tubulointerstitial Fibrosis.

Mol Cell Biol 2017 06 31;37(12). Epub 2017 May 31.

Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA

Tubulointerstitial fibrosis (TIF) is recognized as a final phenotypic manifestation in the transition from chronic kidney disease (CKD) to end-stage renal disease (ESRD). Here we show that conditional inactivation of in the mouse renal epithelium resulted in upregulated expression of profibrotic genes and TIF. Loss of induced Stat3 activation and a senescence-associated secretory phenotype (SASP) that coincided with the development of tubulointerstitial fibrosis. Treatment of mice with the YAP inhibitor verteporfin (VP) inhibited activation of genes associated with senescence, SASPs, and activation of Stat3 as well as impeded the development of fibrosis. Collectively, our studies offer novel insights into molecular events that are linked to fibrosis development from loss and implicate VP as a potential pharmacological inhibitor to treat patients at risk for developing CKD and TIF.
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http://dx.doi.org/10.1128/MCB.00565-16DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5452723PMC
June 2017

GATA3 Positivity in Benign Radiated Prostate Glands: A Potential Diagnostic Pitfall.

Am J Surg Pathol 2017 Apr;41(4):557-563

*Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC Departments of †Pathology ‡Urology §Oncology, The Johns Hopkins Medical Institutions, Baltimore, MD.

Histologic changes following radiation therapy to the prostate include multilayering of glands, atrophy, squamous metaplasia, and often marked random nuclear atypia. We have seen multiple consultation cases where the differential diagnosis of these radiated prostate glands included urothelial carcinoma, with multilayered to solid-appearing proliferations that were positive by immunohistochemistry for GATA3. To formally investigate this issue, 30 cases of benign prostate tissue with radiation atypia, from 1990 to 2015, were obtained from our institution. Cases were evaluated by immunohistochemistry for the prostate-specific markers prostate-specific antigen (PSA), P501S (Prostein), and NKX3.1 and urothelial markers GATA3 and uroplakin 2. GATA3 was positive in 100% of cases, with 70% showing moderately strong to strong staining in a mostly patchy manner within a gland. PSA was positive in 93.3% of cases, with 89.2% showing moderately strong to strong staining in a mostly diffuse manner. P501S was positive in 96.7% of cases, with 93.1% showing moderately strong to strong staining in a mostly patchy manner. NKX3.1 was positive in 82.8% of cases, with 33.3% showing moderately strong to strong staining in a mostly patchy manner. Uroplakin 2 was negative in 100% of cases. Our findings highlight that GATA3 is often positive in benign prostate glands with radiation atypia, which along with the morphologic features present a pitfall for the misdiagnosis of urothelial carcinoma. A combination of PSA and P501S is the best prostate-specific panel for use in radiated prostate, with the caveat that they are often patchy and do not stain all radiated glands.
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http://dx.doi.org/10.1097/PAS.0000000000000798DOI Listing
April 2017

Mechanical Implantation of Urothelium Into Periureteral Soft Tissue: A Series of 4 Cases Mimicking High-stage Urothelial Carcinoma.

Am J Surg Pathol 2016 11;40(11):1564-1570

*Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC †Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, CA Departments of ‡Pathology §Urology ∥Oncology, The Johns Hopkins Medical Institutions, Baltimore, MD.

In the upper genitourinary tract of the ureter and renal pelvis, any invasion of urothelial carcinoma (UC) beyond the thin muscularis is considered pT3 disease, which may prompt adjuvant chemotherapy. Ureteroscopy is commonly used in the workup of these lesions to obtain tissue biopsies and cytology specimens, or to place stents for the relief of obstructive symptoms. The current study describes 4 cases in which the presence of small nests of urothelium in periureteral and peripelvic soft tissue was noted after ureteroscopic instrumentation, mimicking high-stage UC. All 4 cases had a history of ureteral instrumentation with biopsy of the suspected UC. The diagnostic biopsies showed low-grade noninvasive papillary UC (n=2), papillary urothelial neoplasm of uncertain malignant potential (n=1), and benign inverted urothelial papilloma (n=1). In the definitive resection specimens, small nests of bland urothelium were present in the periureteral or peripelvic soft tissue, raising the possibility of pT3 UC. We interpreted these displaced small nests to be the result of mechanical implantation occurring during the ureteroscopic procedure on the basis of the finding of associated linear fibrosis, inflammation, hemorrhage, and foreign body giant cells. In the setting of low-grade or benign urothelial neoplasms in the upper urinary tract, caution is warranted when cytologically bland nests of the urothelium are identified beyond the muscularis that could represent mechanically induced implants as opposed to invasive UC extending into peripelvic or periureteral soft tissue.
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http://dx.doi.org/10.1097/PAS.0000000000000731DOI Listing
November 2016

The Binding Site Barrier Elicited by Tumor-Associated Fibroblasts Interferes Disposition of Nanoparticles in Stroma-Vessel Type Tumors.

ACS Nano 2016 Oct 28;10(10):9243-9258. Epub 2016 Sep 28.

Division of Molecular Pharmaceutics and Center of Nanotechnology in Drug Delivery, Eshelman School of Pharmacy, ‡Lineberger Comprehensive Cancer Center, §Departments of Mathematics and Applied Physical Science, ∥Department of Medicine, ⊥Department of Pathology, University of North Carolina at Chapel Hill , Chapel Hill, North Carolina 27599, United States.

The binding site barrier (BSB) was originally proposed to describe the binding behavior of antibodies to cells peripheral to blood vessels, preventing their further penetration into the tumors. Yet, it is revisited herein to describe the intratumoral cellular disposition of nanoparticles (NPs). Specifically, the BSB limits NP diffusion and results in unintended internalization of NPs by stroma cells localized near blood vessels. This not only limits the therapeutic outcome but also promotes adverse off-target effects. In the current study, it was shown that tumor-associated fibroblast cells (TAFs) are the major component of the BSB, particularly in tumors with a stroma-vessel architecture where the location of TAFs aligns with blood vessels. Specifically, TAF distance to blood vessels, expression of receptor proteins, and binding affinity affect the intensity of the BSB. The physical barrier elicited by extracellular matrix also prolongs the retention of NPs in the stroma, potentially contributing to the BSB. The influence of particle size on the BSB was also investigated. The strongest BSB effect was found with small (∼18 nm) NPs targeted with the anisamide ligand. The uptake of these NPs by TAFs was about 7-fold higher than that of the other cells 16 h post-intravenous injection. This was because TAFs also expressed the sigma receptor under the influence of TGF-β secreted by the tumor cells. Overall, the current study underscores the importance of BSBs in the delivery of nanotherapeutics and provides a rationale for exploiting BSBs to target TAFs.
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http://dx.doi.org/10.1021/acsnano.6b02776DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5515694PMC
October 2016

Polypoid urothelial tumor with inverted growth pattern in the renal pelvis: morphologic and molecular characteristics of a unique diagnostic entity.

Hum Pathol 2017 01 27;59:26-33. Epub 2016 Aug 27.

Department of Pathology, The Johns Hopkins Medical Institutions, Baltimore, MD 21231; Department of Urology, The Johns Hopkins Medical Institutions, Baltimore, MD 21231; Department of Oncology, The Johns Hopkins Medical Institutions, Baltimore, MD 21231. Electronic address:

We report 13 cases of unique polypoid urothelial tumors with inverted growth pattern (PUTIPs) occurring in the proximal ureter and renal pelvis. We describe their morphologic features and further characterize them in regard to TERT promoter mutation status and microsatellite instability. Thirteen cases were identified in our consult archives from 1994 to present. Patients ranged in age from 52 to 83 years at the time of diagnosis (mean, 68.4 years). Grossly, lesions were described variously as pink-tan to white exophytic and friable lesions that were polypoid or pedunculated, located in the renal pelvis or proximal ureter. The masses ranged in size from 0.5 to 3.2 cm (mean, 1.6 cm). PUTIP is a polypoid, plaque-like lesion with features of the following: (1) inverted papillary urothelial neoplasm of low malignant potential, lacking an exophytic papillary component; (2) florid von Brunn nest proliferation within and radiating outward from the polypoid lesion; and (3) in some cases, an inverted papilloma with densely hyalinized collagenous stroma. All 4 PUTIPs with formalin-fixed, paraffin-embedded material available were positive for the TERT promoter mutation 228G>A by polymerase chain reaction and were microsatellite stable. Given that PUTIP clinically forms a tumor and is typically treated by nephroureterectomy, it is best regarded as a unique benign urothelial neoplasm that exclusively occurs in the renal pelvis/proximal ureter.
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http://dx.doi.org/10.1016/j.humpath.2016.07.030DOI Listing
January 2017

Renal oncocytoma with vascular invasion: a series of 22 cases.

Hum Pathol 2016 12 3;58:1-6. Epub 2016 Aug 3.

Department of Pathology, The Johns Hopkins Medical Institutions, Baltimore, MD 21231; Department of Urology, The Johns Hopkins Medical Institutions, Baltimore, MD 21231; Department of Oncology, The Johns Hopkins Medical Institutions, Baltimore, MD 21231. Electronic address:

Renal oncocytomas are benign neoplasms that are often excised, as clinically they cannot be distinguished with certainty from renal cell carcinoma. One of the least common findings in oncocytomas is vascular invasion, and their behavior is not well characterized with only reports of isolated examples and smaller case series. Whether vascular invasion is acceptable for the diagnosis of oncocytoma still remains controversial, even amongst genitourinary pathologists with expertise in renal tumor pathology. Of 1474 cases of renal oncocytoma identified at 3 large medical centers, 22 (1.5%) had vascular invasion. Patients included 12 men and 10 women with an average age at diagnosis of 67.5 years (range, 48-91 years). Thirteen cases showed large vessel invasion, and the remainder involved medium or small vessels. Tumor was grossly visible in the renal vein in 2 cases. Clinical data were available on 16 of the 22 cases with an average follow-up time of 29.9 months (range, 7.5-94.5 months). Of the cases with clinical follow-up, all but one individual was alive. All living individuals were free of recurrence or metastatic disease at the time of last follow-up. Our cohort showed no metastasis or recurrence and overall survival of 94.7% at 2.5 years following diagnosis, supporting the finding that vascular invasion does not alter the favorable prognosis of oncocytoma. The presence of vascular invasion should not lead to any uncertainty about the diagnosis in an otherwise typical oncocytoma.
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http://dx.doi.org/10.1016/j.humpath.2016.07.020DOI Listing
December 2016

Lumbosacral Plexus Involvement as the First Site of Metastatic Recurrence in a Patient With CTNNB1-Mutant Prostate Cancer.

Clin Genitourin Cancer 2016 08 23;14(4):e417-22. Epub 2016 Feb 23.

Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD.

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http://dx.doi.org/10.1016/j.clgc.2016.02.001DOI Listing
August 2016

Differential Diagnosis of Intraductal Lesions of the Prostate.

Am J Surg Pathol 2016 06;40(6):e67-82

Departments of *Pathology †Urology ‡Oncology, The Johns Hopkins Medical Institutions, Baltimore, MD.

The category of intraductal lesions of the prostate includes a range of primary prostatic and nonprostatic processes with wide variation in prognosis and recommended follow-up. Studies have shown that pathologists are uncomfortable with the diagnosis of these lesions and that the diagnostic reproducibility is low in this category. Despite the diagnostic difficulty, their accurate and reproducible diagnosis is critical for patient management. This review aims to highlight the diagnostic criteria, prognosis, and treatment implications of common intraductal lesions of the prostate. It focuses on the recognition of intraductal carcinoma of the prostate (IDC-P) in prostate needle biopsies and how to distinguish it from its common mimickers, including high-grade prostatic intraepithelial neoplasia, invasive cribriform prostatic adenocarcinoma, urothelial carcinoma extending into prostatic ducts, and prostatic ductal adenocarcinoma. IDC-P is independently associated with higher risk disease, and its identification in a needle biopsy, even in the absence of invasive carcinoma, should compel definitive treatment. Conversely, high-grade prostatic intraepithelial neoplasia has a much better prognosis and in limited quantities does not even warrant a repeat biopsy. IDC-P must be distinguished from urothelial carcinoma involving prostatic ducts, as recommended treatment varies markedly. Ductal adenocarcinoma may confuse the pathologist and clinician by overlapping terminology, and morphology may also mimic IDC-P on occasion. The use of ancillary testing with immunohistochemistry and molecular markers has also been reviewed.
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http://dx.doi.org/10.1097/PAS.0000000000000609DOI Listing
June 2016

Use of BRAF v600e immunocytochemistry on FNA direct smears of papillary thyroid carcinoma.

Cancer Cytopathol 2015 Sep 16;123(9):531-9. Epub 2015 Jun 16.

Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, North Carolina.

Background: Mutations of v-Raf murine sarcoma viral oncogene homolog B1 (BRAF) are identified in almost half of all papillary thyroid carcinomas (PTCs). These mutations are specific for PTC and may confer a worse prognosis. An immunohistochemical (IHC) stain for BRAF is commercially available and has been validated in surgical specimens. Fine-needle aspiration (FNA) is frequently used as a diagnostic tool for risk stratification of thyroid nodules. Therefore, the authors evaluated the performance of immunostaining with the anti-BRAF antibody VE1 on FNA direct smears.

Methods: The authors identified 51 FNA specimens that had subsequent surgical resection specimens with a diagnosis of PTC. BRAF VE1 IHC was performed on the surgical specimens to determine their mutation status. The corresponding direct smears were then stained using the same VE1 stain to assess correlation.

Results: Twenty-two of the 46 included surgical specimens were positive for BRAF mutations (47.8%) by IHC, consistent with the published rates. The paired cytologic smears from these cases revealed 65.3% concordance. The overall sensitivity of BRAF staining on cytologic smears was 63.6%, and the specificity was 58.3%. Concordance rates were highest in specimens that were diagnosed as malignant or suspicious for malignancy (75% and 85.7%, respectively). The negative predictive value increased to 77.8% when suspicious for follicular neoplasm/suspicious cases were combined.

Conclusions: Specimens that were malignant or suspicious on FNA were most likely to be BRAF concordant. Limitations to the interpretation of smears included low cellularity and obscuring blood, macrophages, or colloid. With further refinement, it is possible that BRAF immunocytochemistry can be applied prospectively to thyroid FNAs for risk stratification and to reduce false-negative rates.
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http://dx.doi.org/10.1002/cncy.21575DOI Listing
September 2015