Publications by authors named "Ximing J Yang"

134 Publications

Malignant melanoma arising in a primary mediastinal germ cell tumor.

Pathol Res Pract 2020 Nov 11;216(11):153210. Epub 2020 Sep 11.

Department of Pathology, Northwestern University Feinberg School of Medicine, 303 E Chicago Ave, Chicago, IL, 60611, USA.

Primary mediastinal germ cell tumors with somatic malignancies are rare. We report a case of a 34-year old man with melanoma arising in a primary mediastinal mixed germ cell tumor. On initial biopsy, the patient was found to have a germ cell tumor containing yolk sac and embryonal components only. After chemotherapy, histopathological evaluation of the residual tumor in the wide local resection specimen revealed a mature teratoma with melanoma. Molecular studies demonstrated that the residual germ cell tumor harbored KIT and NRAS mutations associated with malignant melanoma.
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http://dx.doi.org/10.1016/j.prp.2020.153210DOI Listing
November 2020

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

Urol Oncol 2020 Sep 15. Epub 2020 Sep 15.

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

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

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

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

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

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

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

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

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

Objective.—: To update grading recommendations.

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

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

Application and Pitfalls of Immunohistochemistry in Diagnosis of Challenging Genitourinary Cases.

Arch Pathol Lab Med 2020 03;144(3):290-304

From the Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, Illinois.

Context.—: Immunohistochemistry (IHC) has become increasingly important in the evaluation of pathologic conditions in the genitourinary (GU) organs. In addition to careful evaluation of hematoxylin-eosin sections and generation of a differential diagnosis, choosing the optimal panel of IHC markers becomes even more important when the biopsy material is very limited. The following summary of our experience supplemented with relevant literature review exemplifies how to use IHC to facilitate pathologic diagnosis in the GU system.

Objective.—: To describe our experience with the most common immunohistochemical markers used in GU pathology.

Data Sources.—: Institutional experience and literature search comprise our data sources.

Conclusions.—: Application of IHC provides enormous benefits to the interpretation of GU pathologic conditions, including benign and malignant lesions. However, both insufficient and excessive types of use of IHC, as well as incorrect interpretations in common and rare GU conditions, could present pitfalls in diagnosis.
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http://dx.doi.org/10.5858/arpa.2019-0550-RADOI Listing
March 2020

Pathologic characterization of renal epithelial neoplasms arising in nonfunctioning kidneys.

Hum Pathol 2020 03 17;97:1-7. Epub 2019 Dec 17.

Department of Pathology, Northwestern University, Chicago, IL 60611. Electronic address:

Nonfunctioning kidneys secondary to various etiologies display different histopathological features. Studies focused on incidence and types of renal neoplasms using the new World Health Organization and International Society of Urological Pathology classification system in various types of nonfunctioning kidneys are very limited. We identified 311 nephrectomies of nonfunctioning kidneys and categorized them into 5 categories: acquired cystic kidney disease (ACKD, n = 61); end-stage renal disease, nonspecific (ESRD, n = 63); adult polycystic kidney disease (APKD, n = 49); failed transplant kidney (FTK, n = 96); and those caused by obstructive conditions in the kidney (OCK, n = 42). ACKD (70%) and ESRD (43%) had higher cancer incidences than the other 3 groups (APKD = 2%, FTK = 0%, and OCK = 5%). Besides clear cell renal cell carcinoma (RCC) and papillary RCC, clear cell papillary RCC had a much higher incidence within ACKD patients (13/61) compared to other groups. ACKD-associated RCC was only identified in ACKD patients. ACKD patients had significantly longer dialysis duration compared to ESRD, APKD, and FTK. Although they had similar risk for clear cell RCC and papillary RCC, ACKD patients had a much higher risk for ACKD-associated RCC and clear cell papillary RCC than ESRD patients. Although most RCCs arising in these nonfunctioning kidneys were early pT1 stage, 6 ACKD patients and 3 ESRD patients had higher-stage diseases, which can be fatal if not treated appropriately. Therefore, precise clinicopathological classification of these nonfunctioning kidneys is important for predicting kidney cancer risk. These results indicate the need for active monitoring of the patients with high-risk nonfunctioning kidney diseases and appropriate surgical treatment when necessary.
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http://dx.doi.org/10.1016/j.humpath.2019.09.011DOI Listing
March 2020

Activation of MAPK Signaling by CXCR7 Leads to Enzalutamide Resistance in Prostate Cancer.

Cancer Res 2019 05 5;79(10):2580-2592. Epub 2019 Apr 5.

Division of Hematology/Oncology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois.

Castration-resistant prostate cancer (CRPC) that has developed resistance to the new-generation androgen receptor (AR) antagonist enzalutamide is a lethal disease. Transcriptome analysis of multiple prostate cancer models identified CXCR7, an atypical chemokine receptor, as one of the most upregulated genes in enzalutamide-resistant cells. AR directly repressed by binding to an enhancer 110 kb downstream of the gene and expression was restored upon androgen deprivation. We demonstrate that CXCR7 is a critical regulator of prostate cancer sensitivity to enzalutamide and is required for CRPC growth and . Elevated CXCR7 activated MAPK/ERK signaling through ligand-independent, but β-arrestin 2-dependent mechanisms. Examination of patient specimens showed that CXCR7 and pERK levels increased significantly from localized prostate cancer to CRPC and further upon enzalutamide resistance. Preclinical studies revealed remarkable efficacies of MAPK/ERK inhibitors in suppressing enzalutamide-resistant prostate cancer. Overall, these results indicate that CXCR7 may serve as a biomarker of resistant disease in patients with prostate cancer and that disruption of CXCR7 signaling may be an effective strategy to overcome resistance. SIGNIFICANCE: These findings identify CXCR7-mediated MAPK activation as a mechanism of resistance to second-generation antiandrogen therapy, highlighting the therapeutic potential of MAPK/ERK inhibitors in CRPC.
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http://dx.doi.org/10.1158/0008-5472.CAN-18-2812DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6522281PMC
May 2019

Anaplastic Lymphoma Kinase Mutation ( F1174C) in Small Cell Carcinoma of the Prostate and Molecular Response to Alectinib.

Clin Cancer Res 2018 06 20;24(12):2732-2739. Epub 2018 Mar 20.

The Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, Illinois.

Small cell carcinoma of the prostate (SCCP) is an aggressive disease that can arise or by transdifferentiation from prostate adenocarcinoma. Alterations in anaplastic lymphoma kinase () gene are involved in neuroblastoma, lung cancer, and other malignancies, but its role in SCCP has not been documented. We describe a patient with refractory SCCP with F1174C-activating mutation who obtained clinical benefit from treatment with ALK inhibitor. Next-generation sequencing (NGS) was used to analyze primary and circulating tumor DNA (ctDNA). Prostate cancer databases were queried for alterations in gene, mRNA, and its impact in clinical outcomes. prostate cell line/organoid models were generated by lentiviral-mediated expression of ALK and ALK F1174C and assessed for response to ALK inhibitors crizotinib and alectinib. NGS analysis of the primary tumor and ctDNA of a 39-year-old patient with refractory SSCP identified F1174C mutation. Treatment with second-generation ALK inhibitor alectinib resulted in radiographic stable disease for over 6 months, symptomatic improvement, and significant molecular response as reflected by declining ctDNA allele fraction. Analysis of prostate cancer datasets showed that amplification was associated with poor outcome. In prostate cancer cells and organoids, F1174C expression enhanced growth and induced expression of the neuroendocrine marker neuron-specific enolase. Alectinib was more effective than crizotinib in inhibiting F1174C-expressing cell growth. These findings implicate -activating mutations in SCCP pathogenesis and suggest the therapeutic potential of targeting molecular alterations in some patients with SCCP. .
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http://dx.doi.org/10.1158/1078-0432.CCR-18-0332DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6715284PMC
June 2018

Preparation and characterization of the antibody recognizing AMACR inside its catalytic center.

Int J Oncol 2018 Feb 11;52(2):547-559. Epub 2017 Dec 11.

Robert H. Lurie Comprehensive Cancer Center, Department of Pathology, Northwestern University, Chicago, IL 60611, USA.

Alpha-methylacyl-CoA racemase (AMACR) catalyzes the β-oxidation of fatty acids and is overexpressed in carcinomas in various organs, while its inactivation results in the inhibition of cancer growth. In the present study, we prepared and characterized 20 different mouse monoclonal antibodies against human AMACR. In the course of biopanning of a phage peptide commercial library against in-house prepared 6H9 and 2A5, and commercial 13H4 antibodies, 10 phage mimotopes recognized by each type of the antibody were selected. Using the program Pepitope and the crystal structure of AMACR from Mycobacterium tuberculosis, we reveal for the first time, at least to the best of our knowledge, that the epitopes recognizing the antibody against AMACR are composed of conformation sequences localized inside the AMACR catalytic center. When delivered into live HeLa cells using cationic lipid-based PULSin reagent, the specific antibodies against AMACR were co-localized with peroxisomes. The in-house made 6H9 antibody exhibited a low level of this co-localization compared to the commercially available 63340 antibody, and did not inhibit the growth rate of HeLa and T98G cells. The results obtained suggest that antibody against AMACR may possess anti-AMACR catalytic activity and needs to be further investigated as a potential drug for use in anticancer therapy. On the whole, in this study, we generated several clones of AMACR antibodies and demonstrated that these antibodies can be colonized into live cells. Currently, we are testing the growth inhibitory properties of these antibodies against AMACR.
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http://dx.doi.org/10.3892/ijo.2017.4220DOI Listing
February 2018

Efficacy Against Human Prostate Cancer by Prostate-specific Membrane Antigen-specific, Transforming Growth Factor-β Insensitive Genetically Targeted CD8 T-cells Derived from Patients with Metastatic Castrate-resistant Disease.

Eur Urol 2018 05 21;73(5):648-652. Epub 2017 Dec 21.

Department of Medicine, Division of Hematology/Oncology and Cell Therapy, Rush University, Chicago, IL, USA.

Current immunotherapy has limited efficacy on metastatic castrate-resistant prostate cancer (mCRPC). We therefore sought to improve the antitumor ability of mCRPC patient-derived CD8 T-cells by the endowment of specificity to prostate-specific membrane antigen (PSMA) and insensitivity to immunosuppressant molecule transforming growth factor-β (TGF-ß) under the control of herpes simplex virus-1 thymidine kinase. CD8 T-cells were collected by leukapheresis and cultured in a Food and Drug Administration-approved Cell Processing Work Station. We developed a chimeric antigen receptor retroviral construct using an anti-PSMA chimeric immunoglobulin-T-cell receptor(ζ) gene (PZ1) and dominant negative TGF-ß type II receptor (TßRIIDN), that could induce CD8 T-cells to be PSMA reactive and insensitive to TGF-ß. Cr release assay was performed on PC-3 and PC-3-PSMA. The further antitumor functions of PSMA-specific, TGF-ß insensitive CD8 T-cells was evaluated using an immunodeficient RAG-1 mouse model. We found PSMA-specific, TGF-ß insensitive CD8 T-cells from mCRPC were expanded with strong expression of PZ1 and thymidine kinase genes, and their growth was not suppressed by TGF-ß. The survival of these cells decreased sharply after treatment with ganciclovir. Treatment of PSMA-specific TGF-ß, insensitive CD8 T-cells was associated with 61.58% specific lysis on PC-3-PSMA, and significantly suppressed PC3-PSMA tumor compared with the PC3 tumor. A large amount of tumor apoptosis and CD8 T-cell infiltration were found only in the PC3-PSMA tumor. This study verified that PSMA-specific, TGF-ß insensitive CD8 T-cells derived from mCRPC patients could be successfully expanded and used to overcome the immunosuppressive effects of the tumor microenvironment to control PSMA-expressing PC in vitro and in vivo. This may provide a promising approach for men with mCRPC who fail androgen deprivation therapy.

Patient Summary: We investigated the role of a novel chimeric antigen receptor T-immunotherapy based on autologous metastatic castrate-resistant prostate cancer patient-derived prostate-specific membrane antigen (PSMA)-specific, transforming growth factor-ß insensitive CD8 T-cells on PSMA-positive prostate cancer. We found that this chimeric antigen receptor T-cells could kill PSMA-positive prostate cancer specifically. The results suggest that this novel immunotherapy treatment is a potential new approach for men with metastatic castrate-resistant prostate cancer.
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http://dx.doi.org/10.1016/j.eururo.2017.12.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6682506PMC
May 2018

Practical Applications of Immunohistochemistry in the Diagnosis of Genitourinary Tumors.

Arch Pathol Lab Med 2017 Sep 13;141(9):1181-1194. Epub 2017 Jun 13.

Context: - Pathologic diagnosis of tumors in the genitourinary system can be challenging based on morphology alone, particularly when diagnostic material is limited, such as in core biopsies. Immunohistochemical stain can be a useful tool to aid in the diagnosis.

Objective: - To provide an update on practical applications and interpretation of immunohistochemical stains in the diagnosis of tumors in prostate, kidney, bladder, and testis. We particularly focus on difficult differential diagnoses, providing our insights in frequently encountered challenging situations. Commonly used immunohistochemical panels are discussed.

Data Sources: - Review of literature and our own experience.

Conclusion: - Immunohistochemical stain is a valuable tool in the diagnosis of genitourinary tumors when appropriately used.
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http://dx.doi.org/10.5858/arpa.2016-0530-RADOI Listing
September 2017

Extraprostatic Extension Is Extremely Rare for Contemporary Gleason Score 6 Prostate Cancer.

Eur Urol 2017 09 13;72(3):455-460. Epub 2016 Dec 13.

Section of Urology, University of Chicago, Chicago, IL, USA.

Background: A significant proportion of men with Gleason score 6 (GS6) prostate cancer undergo treatment with radiation or surgery.

Objective: To assess pathologic stage of pure GS6 at radical prostatectomy (RP).

Design, Setting, And Participants: In the period 2003-2014, 7817 patients underwent RP at two institutions. Of 2502 patients with GS6 at surgery, 60 were identified as stage pT3a-b on initial pathologic review, 55 with pT3a (extraprostatic extension, EPE), and five with pT3b (seminal vesicle invasion; SVI). All cases of GS6 with pT3 disease underwent contemporary pathologic evaluation for Gleason grade, stage, and extent of EPE. At one institution, all GS≥7 pT3b cases were re-reviewed for downgrading. The 2014 International Society of Urological Pathology (ISUP) Gleason grading criteria and 2009 ISUP recommendations on pT3 staging were applied.

Outcome Measurements And Statistical Analysis: Calculated incidence (%) of pT3a, pT3b, pT4, and lymph node-positive disease.

Results And Limitations: Of the 60 GS6 pT3a-b cases identified in the period 2003-2014, seven (0.28% of entire GS6 cohort) with GS6 and pT3a were identified after re-review, all focal EPE. Among the re-examined cohort, no cases of GS6 with pT3b were observed. None of the 132 GS≥7 pT3b cases were downgraded to GS6. Limitations include partial embedding of specimens and separate pathologic review at each institution.

Conclusions: In a large prostatectomy cohort, GS6 never had seminal vesicle invasion (0%) and was very rarely (0.28%) associated with extraprostatic extension.

Patient Summary: GS6 prostate cancer rarely spreads outside the prostate. A new finding in this study was that GS6 prostate cancer never spread to the seminal vesicles.
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http://dx.doi.org/10.1016/j.eururo.2016.11.028DOI Listing
September 2017

Nuclear size measurement for distinguishing urothelial carcinomas from reactive urothelium on tissue sections.

Diagn Pathol 2016 Jun 30;11(1):57. Epub 2016 Jun 30.

Department of Pathology, Northwestern University Feinberg School of Medicine, 251 E. Huron St., Feinberg 5-705, Chicago, IL, 60611, USA.

Background: Pathological diagnosis of urothelial carcinoma (UC) is primarily based on cytological atypia. It has previously been shown that high-grade (HG) UC, particularly UC in situ cells (CIS), can be over five times the size of a lymphocyte. However, this has not been demonstrated in comparison to reactive urothelium. The objective of this study was to empirically compare the difference in nuclear size of UC cells with reactive urothelial cells.

Methods: Using CellSens imaging software, we measured urothelial nuclear length (l) and width (w) on digital images of H&E sections. The area (a) of a nucleus was calculated based on the oval shape of most urothelial cells. Lymphocytes were measured to calculate normalized urothelial linear and area ratios.

Results: A total of 1085 urothelial cell nuclei from 60 cases were measured from reactive urothelium, low grade (LG) UC, HG UC and CIS. CIS nuclei were found to have an a 2.75 times larger than reactive nuclei (p < 0.001). A nuclear size cut-off of 11 um for l and 7 um for w was found to be sensitive [98.09 % (95 % CI: 95.60-99.38 %) and 89.31 % (95 % CI: 83.6-91.82 %) for l and w, respectively] and specific [92.60 % (95 % CI: 87.13-95.82 %) and 85.71 % (95 % CI: 79.49-90.63 %) for l and w, respectively] for distinguishing CIS from reactive atypia.

Conclusions: Nuclear morphometry can be used to differentiate CIS from reactive atypia. A l over 11 um and a w over 7 um and is highly sensitive and specific for CIS compared to reactive urothelium. This difference in nuclear size may be used as a tool for differentiating the flat urothelial lesions from reactive urothelium in daily practice.
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http://dx.doi.org/10.1186/s13000-016-0501-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4928350PMC
June 2016

Value of SATB2 immunostaining in the distinction between small intestinal and colorectal adenocarcinomas.

J Clin Pathol 2016 Dec 11;69(12):1046-1050. Epub 2016 May 11.

Department of Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, California, USA.

Aims: Special AT-rich sequence-binding protein 2 (SATB2) is a novel immunomarker that is expressed in glandular cells of the lower gastrointestinal tract with retained expression in the majority of primary and metastatic colorectal adenocarcinomas (CRCs). Because of its tissue specificity, SATB2 has been shown to be a clinically useful marker to distinguish CRC from non-CRC. In this study, we investigated whether or not SATB2 can help differentiate CRC from small intestinal adenocarcinoma (SIA), a practical diagnostic challenge due to their morphological and immunophenotypic similarities.

Methods: Fifty surgically resected primary SIAs and 50 CRCs were immunohistochemically examined for the expression of SATB2. Positive staining was graded as 1+ (5-25% of the tumour cells stained), 2+ (26-50%), 3+ (51-75%) or 4+ (>75%), as well as weak, intermediate or strong for staining intensity.

Results: Positive SATB2 immunoreactivity was observed in 23 (46%) SIAs in contrast to 48 (96%) CRCs (p<0.0001). Among these, only 4 (8%) SIAs showed strong and diffuse (4+) SATB2 staining compared with 38 (76%) of CRCs (p<0.0001).

Conclusions: SATB2 is not entirely CRC-specific and is expressed in a subset of SIAs. Unlike CRC, however, SIA infrequently shows a strong and diffuse staining pattern, which still makes SATB2 a useful immunomarker to distinguish SIA from CRC.
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http://dx.doi.org/10.1136/jclinpath-2015-203588DOI Listing
December 2016

Update on the Diagnosis and Management of Renal Angiomyolipoma.

J Urol 2016 04 21;195(4 Pt 1):834-46. Epub 2015 Nov 21.

Department of Urology, Northwestern University Feinberg School of Medicine, Chicago, Illinois. Electronic address:

Purpose: Advances in minimally invasive therapies and novel targeted chemotherapeutics have provided a breadth of options for the management of renal masses. Management of renal angiomyolipoma has not been reviewed in a comprehensive fashion in more than a decade. We provide an updated review of the current diagnosis and management strategies for renal angiomyolipoma.

Materials And Methods: We conducted a PubMed(®) search of all available literature for renal or kidney angiomyolipoma. Further sources were identified in the reference lists of identified articles. We specifically reviewed case series of partial nephrectomy, selective arterial embolization and ablative therapies as well as trials of mTOR inhibitors for angiomyolipoma from 1999 to 2014.

Results: Renal angiomyolipoma is an uncommon benign renal tumor. Although associated with tuberous sclerosis complex, these tumors occur sporadically. Risk of life threatening hemorrhage is the main clinical concern. Due to the fat content, angiomyolipomas are generally readily identifiable on computerized tomography and magnetic resonance imaging. However, fat poor angiomyolipoma can present a diagnostic challenge. Novel research suggests that various strategies using magnetic resonance imaging, including chemical shift magnetic resonance imaging, have the potential to differentiate fat poor angiomyolipoma from renal cell carcinoma. Active surveillance is the accepted management for small asymptomatic masses. Generally, symptomatic masses and masses greater than 4 cm should be treated. However, other relative indications may apply. Options for treatment have traditionally included radical and partial nephrectomy, selective arterial embolization and ablative therapies, including cryoablation and radio frequency ablation, all of which we review and update. We also review recent advances in the medical treatment of patients with tuberous sclerosis complex associated angiomyolipomas with mTOR inhibitors. Specifically trials of everolimus for patients with tuberous sclerosis complex suggest that this agent may be safe and effective in treating angiomyolipoma tumor burden. A schema for the suggested management of renal angiomyolipoma is provided.

Conclusions: Appropriately selected cases of renal angiomyolipoma can be managed by active surveillance. For those patients requiring treatment nephron sparing approaches, including partial nephrectomy and selective arterial embolization, are preferred options. For those with tuberous sclerosis complex mTOR inhibitors may represent a viable approach to control tumor burden while conserving renal parenchyma.
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http://dx.doi.org/10.1016/j.juro.2015.07.126DOI Listing
April 2016

Disruption of tubular Flcn expression as a mouse model for renal tumor induction.

Kidney Int 2015 Nov 17;88(5):1057-69. Epub 2015 Jun 17.

NCCS-VARI Translational Cancer Research Laboratory, National Cancer Centre, Singapore, Singapore.

The study of kidney cancer pathogenesis and its treatment has been limited by the scarcity of genetically defined animal models. The FLCN gene that codes for the protein folliculin, mutated in Birt-Hogg-Dubé syndrome, presents a new target for mouse modeling of kidney cancer. Here we developed a kidney-specific knockout model by disrupting the mouse Flcn in the proximal tubules, thus avoiding homozygous embryonic lethality or neonatal mortality, and eliminating the requirement of loss of heterozygosity for tumorigenesis. This knockout develops renal cysts and early onset (6 months) of multiple histological subtypes of renal neoplasms featuring high tumor penetrance. Although the majority of the tumors were chromophobe renal cell carcinomas in affected mice under 1 year of age, papillary renal cell carcinomas predominated in the kidneys of older knockout mice. This renal neoplasia from cystic hyperplasia at 4 months to high-grade renal tumors by 16 months represented the progression of tumorigenesis. The mTOR and TGF-β signalings were upregulated in Flcn-deficient tumors, and these two activated pathways may synergetically cause renal tumorigenesis. Treatment of knockout mice with the mTOR inhibitor rapamycin for 10 months led to the suppression of tumor growth. Thus, our model recapitulates human Birt-Hogg-Dubé kidney tumorigenesis, provides a valuable tool for further study of Flcn-deficient renal tumorigenesis, and tests new drugs/approaches to their treatment.
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http://dx.doi.org/10.1038/ki.2015.177DOI Listing
November 2015

Diagnosis of Gleason pattern 5 prostate adenocarcinoma on core needle biopsy: an interobserver reproducibility study among urologic pathologists.

Am J Surg Pathol 2015 Sep;39(9):1242-9

*Division of Urologic Pathology, Miraca Life Sciences Research Institute, Miraca Life Sciences, Irving ‡‡Houston Methodist Hospital, Houston, TX †Cleveland Clinic Foundation, Cleveland, OH ‡Indiana University, Indianapolis, IN ∥New York University Medical Center ¶Memorial Sloan Kettering Cancer Center, New York, NY #The University of Michigan, Ann Arbor, MI **Emory University, Atlanta, GA ††University of Chicago ¶¶Northwestern Memorial Hospital, Chicago, IL §Karolinska Institutet, Stockholm, Sweden §§Japanese Red Cross Nagoya Daini Hospital, Nagoya, Japan ∥∥University of Calgary and Calgary Laboratory Services, Calgary, AB, Canada.

Accurate recognition of Gleason pattern 5 (GP5) prostate adenocarcinoma on needle biopsy is critical as it is associated with disease progression and adverse clinical outcome. Despite important implications of this diagnosis, interobserver variation in the diagnosis of GP5 has not been adequately studied. Digital images of 66 prostate adenocarcinoma cases that potentially contained a GP5 component were distributed to 16 urologic pathologists who were asked to classify whether GP5 was present. Each image was initially classified into 1 of 4 morphologic subpatterns by 2 coauthors (R.B.S. and M.Z.): solid nests (15), comedocarcinoma (8), single cells and/or cords (35), and variant morphology (8). Additional features captured included: size (large: >20 cells, medium: 10 to 20 cells, and small: <10 cells) and distribution of nuclei (uniform vs. nonuniform) for nests pattern; intraluminal coagulative tumor necrosis, karyorrhectic debris, and amorphous material for comedocarcinoma pattern; and quantity (≤5, 6 to 10, and >10) and distribution (clustered vs. intermixed with adjacent well-formed glands) for single cells/cords pattern. Interobserver reproducibility of a diagnosis of GP5 was assessed and the morphologic subpatterns and features were correlated with the consensus diagnosis (defined as 75% agreement). Interobserver reproducibility for overall diagnostic agreement was fair (κ=0.376). Among subpatterns, comedocarcinoma had highest reproducibility (κ=0.499), followed by variant morphology (κ=0.443), single cells/cords (κ=0.369), and nests (κ=0.347). All cases with the following features achieved consensus for GP5: large nests regardless of nuclear distribution; coagulative necrosis with or without karyorrhectic debris; single cells/cords >10 or 6 to 10 in a cluster; and signet ring-like cells in single cells or within nests pattern. A majority of cases with the following features achieved consensus against GP5: medium-size nests; exclusive intraluminal amorphous material; single cells/cords ≤5; and Paneth cell change. Remaining morphologic features did not reach consensus for or against GP5. A majority (86%) of participants would diagnose a small focus of GP5 only when it is present in >1 level. The diagnostic reproducibility of GP5 within certain morphologies was only fair among urologic pathologists. However, the diagnosis of GP5 was more reproducible when certain restrictive morphologic and quantitative criteria were applied. These findings suggest that additional studies are needed to find highly reproducible features of GP5 associated with documented aggressive clinical outcome.
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http://dx.doi.org/10.1097/PAS.0000000000000442DOI Listing
September 2015

Neuroendocrine differentiation of prostate cancer: a review.

Am J Clin Exp Urol 2014 9;2(4):273-85. Epub 2014 Dec 9.

Robert H Lurie Comprehensive Cancer Center Chicago, IL ; Department of Pathology, Northwestern University Chicago, IL.

Neuroendocrine cells are one of the epithelial populations in the prostate. Neuroendocrine differentiation (NED) has been observed in prostate cancer. In addition to small cell neuroendocrine carcinomas and carcinoid tumors of the prostate, prostatic adenocarcinomas may have NED. The incidence and clinical relevance of NED in prostatic adenocarcinoma is not clearly understood because of conflicting results in the reported studies, and evaluation of NED is not routinely performed in clinical practice. This review is an overall synthesis with an aim to develop a more comprehensive understanding and practical approach towards the current knowledge of neuroendocrine differentiation. In this review we are stratifying these lesions into separate subtypes based on histologic parameters such as tumor morphology, neuroendocrine cell density and distribution and clinical parameters. We also want to identify current controversies and confusing issues not totally resolved in this topic for further investigations. Eventually a clearer understanding of this phenomenon and appropriate handling NED in prostate cancer will benefit clinical practice.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4297323PMC
January 2015

Glypican 3 overexpression in primary and metastatic Wilms tumors.

Virchows Arch 2015 Jan 4;466(1):67-76. Epub 2014 Nov 4.

Department of Pathology, University of Washington, 325 9th Ave, Seattle, WA, 98104, USA,

Glypican 3 (GPC3), a heparan sulfate proteoglycan, plays a role in cell growth and differentiation. Mutations of the GPC3 gene are responsible for Simpson-Golabi-Behmel syndrome, which is characterized by anomalies of postnatal overgrowth and an increased risk of developing pediatric malignancies, mostly Wilms tumor and liver cancer. In order to understand the possible role of GPC3 in renal development and Wilms tumor formation, we analyzed messenger RNA (mRNA) and protein levels of GPC3 in sporadic Wilms tumors and compared it to normal kidneys and other common renal epithelial tumors. By using Affymetrix HGU133 oligonucleotide gene expression microarray data from 191 renal tumors and 12 normal kidneys, we found significant overexpression of GPC3 in Wilms tumors (p < 0.01), with 3.5-fold higher expression in comparison to normal kidneys and 6.5-fold higher than any type of renal tumors. The GPC3 gene product in Wilms tumor was further evaluated by immunohistochemistry and quantified by an automated image analysis. Cytoplasmic and membranous GPC3 immunoreactivity was present in 77 % of primary Wilms tumors (23/30), 93 % of metastatic Wilms tumors (13/14), 50 % of metanephric adenomas (4/8), 33 % of congenital mesoblastic nephromas (2/6), 100 % of nephrogenic rests (11/11), and 100 % of fetal kidneys (5/5). GPC3 staining was predominantly identified in blastemal and epithelial components of Wilms tumors, similar to that of fetal non-neoplastic kidney. All adult renal tumors (n = 60) and normal kidneys (n = 15) were GPC3 negative. These findings suggest the utility of GPC3 in differential diagnosis and follow-up of Wilms tumors. Our data also indicate that GPC3 is an oncofetal protein with a potential therapeutic value.
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http://dx.doi.org/10.1007/s00428-014-1669-4DOI Listing
January 2015

Discovery and diagnostic value of a novel oncofetal protein: glypican 3.

Adv Anat Pathol 2014 Nov;21(6):450-60

*Department of Biology, Stanford University, Stanford, CA †Department of Pathology, The Ohio State University Medical Center, Columbus, OH §Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL ‡Department of Pathology, The Charles University and University Hospital, Plzen, Czech Republic.

Glypican 3 is a membrane-bound heparan sulfate proteoglycan, which has recently been identified as a marker for liver cancer and germ cell malignancies. Individuals with loss-of-function mutations for the glypican 3 gene exhibit Simpson-Golabi-Behmel syndrome, a rare X-linked overgrowth disorder. Expression of glypican 3 mRNA and protein is normally silenced in most adult organs and may reappear during malignant transformation. In the past few years, immunohistochemical and molecular characteristics of glypican 3 in hepatocellular carcinoma have been elucidated. More recently, glypican 3 has been emerging as a new diagnostic marker for germ cell tumors and especially testicular and ovarian yolk sac tumors. However, in other tumors such as renal cell carcinomas, squamous cell carcinomas, and melanomas, studies disagree on the level of glypican 3 expression. Finally, there is the controversial notion of glypican 3 as a tumor suppressor gene. In this review article, we update current knowledge on glypican 3 expression in normal and neoplastic tissues, evaluate its utility as a tumor marker in clinical practice, and explore its role as a novel oncofetal protein with clinical implications. Our focus is on the diagnostic value of glypican 3 in germ cell tumors and other neoplasms in addition to hepatocellular carcinoma. In conclusion, glypican 3 has been proven to be a useful immunohistochemical marker in distinguishing yolk sac tumors, choriocarcinomas, and Wilms tumors from other malignancies histologically mimicking these primitive tumors. Clinically, we recommend that glypican 3 be used as part of a panel of markers in subtyping testicular germ cell tumors.
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http://dx.doi.org/10.1097/PAP.0000000000000043DOI Listing
November 2014

Distinguishing nested variants of urothelial carcinoma from benign mimickers by TERT promoter mutation.

Am J Surg Pathol 2015 Jan;39(1):127-31

*Department of Pathology, Westchester Medical Center/New York Medical College, Valhalla ‡James J Peters VA Medical Center at Bronx and Icahn School of Medicine at Mount Sinai §Mount Sinai Medical Center, New York, NY ∥Department of Pathology, Northwestern University, Chicago, IL †Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD.

Nested variant of urothelial carcinoma (NVUC) is an uncommon variant with minimally atypical cytology, which may overlap with benign urothelial lesions such as von Brunn nests, cystitis cystica, cystitis glandularis, and nephrogenic adenoma. Because of the tumor's deceptively bland appearance, these cancers can potentially be misdiagnosed as benign lesions, leading in some cases to a significant delay in correct diagnosis and appropriate treatment. Prior studies suggest that Ki67 and p53 are useful markers in distinguishing NVUC from benign lesions. However, the overlap in the rates of immunoreactivity has prevented pathologists from using these markers as reliable adjunct markers in differentiating NVUC from mimickers. In addition, large nested variant urothelial carcinoma (LNVUC), a relatively new entity, shares features of both the NVUC and papillary urothelial carcinomas with an inverted growth pattern. They also mimic benign lesions, such as proliferation of von Brunn nests and inverted urothelial papilloma. With the recent demonstration of a strong association of TERT promoter mutations and urothelial carcinoma, we hypothesized that TERT promoter mutations would be a useful marker to distinguish NVUC and LNVUC from other benign urothelial lesions. We have therefore sequenced the TERT promoter region of 20 cases of NVUC, 10 cases of LNVUC, 5 cases of von Brunn nests, 3 cases of cystitis cystica, 3 cases of cystitis glandularis, and 3 cases of nephrogenic adenoma. We found that 17 of 20 cases of NVUC and 8 of 10 cases of LNVUC had TERT promoter mutation: C228T; no mutation was found in any of the benign mimickers (0/14). This result strongly suggests that TERT promoter mutation is a useful adjunct biomarker to distinguish NVUC and LNVUC from benign mimickers.
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http://dx.doi.org/10.1097/PAS.0000000000000305DOI Listing
January 2015

High frequency of TERT promoter mutation in small cell carcinoma of bladder, but not in small cell carcinoma of other origins.

J Hematol Oncol 2014 Jul 20;7:47. Epub 2014 Jul 20.

TERT promoter mutations were recently discovered in melanoma by next generation sequencing. Subsequently, several malignancies including urothelial carcinoma were also found to be associated with the same TERT promoter mutations. Small cell carcinoma (SCC) of the urinary bladder is a rare subtype with an aggressive clinical course. Despite the frequent occurrence of TERT promoter mutations in urothelial carcinoma, the incidence of the mutations in SCC of the urinary bladder is unknown. In addition, as a potential molecular marker to distinguish SCC of the urinary bladder from SCC of the prostate, lung (SCLC) and other origins, this information may be clinically useful. We collected a total of 11 cases of SCC of the urinary bladder (10 cases are primary SCC of the urinary bladder; 1 case has primary SCC of the urinary bladder and liver metastasis). We also included 20 cases of SCLC, 2 cases of SCC of the prostate, 5 cases of Merkel cell carcinoma, and 6 cases of SCC from other sites (cervical, GE junction, breast, and soft tissue). In addition, 3 cases of non-neoplastic tissue from the matched SCC of bladder patient and 14 cases of benign urinary bladder were also included. All tumor sections have been examined to confirm the diagnosis and to make sure more than 20% are of tumor content. Genomic DNA was isolated from FFPE tissue and a fragment of the TERT promoter (145 bp) was amplified by PCR. The TERT promoter mutations are determined by bi-directional Sanger sequencing. All (11/11) SCC of the urinary bladder bear TERT promoter mutation C228T. Neither of SCC from all other origins nor matched non-neoplastic tissue contains the TERT promoter mutations. We demonstrated a high frequency TERT promoter mutation in SCC of the urinary bladder, but not in SCC of other origin, such as the prostate. The findings further illustrate molecular differences between SCC of the urinary bladder and SCC of other origins, despite their shared morphologic and immunophenotypic similarities. The TERT promoter mutation may be a biomarker differentiating SCC of the urinary bladder from SCC of other origins.
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http://dx.doi.org/10.1186/s13045-014-0047-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4223615PMC
July 2014

The utility of p63, p40, and GATA-binding protein 3 immunohistochemistry in diagnosing micropapillary urothelial carcinoma.

Hum Pathol 2014 Sep 8;45(9):1824-9. Epub 2014 May 8.

Department of Pathology, Northwestern Memorial Hospital, Northwestern University Feinberg School of Medicine, Chicago, IL 60611. Electronic address:

Micropapillary urothelial carcinoma (MPUC) is an uncommon variant of urothelial carcinoma (UC) with an aggressive clinical course. There have been limited studies on the UC markers GATA-binding protein 3 (GATA3), p63, and p40 in MPUC. Our study investigated the immunoreactivity of these 3 markers in MPUC compared with conventional UC of different grades and stages. Immunohistochemistry was performed on 62 cases of high-grade urothelial carcinoma (HGUC), 16 low-grade urothelial carcinoma (LGUC), and 20 MPUC. p63 expression was strong and diffuse in all LGUC, significantly decreased in high stage and HGUC, and virtually absent in MPUC. p40 expression was decreased in HGUC and markedly decreased in MPUC relative to LGUC. These results suggest that loss of p63 expression in a UC appears to be associated with adverse features--including cases with micropapillary differentiation. Decreased GATA3 expression was seen frequently in high-grade and high-pathologic stage (≥pT2) tumors but was retained in MPUC cases. The findings of retained GATA3 expression in MPUC, which often shows a loss of expression of other urothelial markers such as p63, may be helpful for determining the origin of micropapillary carcinoma of unknown primary. Compared with the traditional markers p63 and p40, GATA3 is the most sensitive marker of conventional UC and MPUC.
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http://dx.doi.org/10.1016/j.humpath.2014.04.015DOI Listing
September 2014

Lichen sclerosus and isolated bulbar urethral stricture disease.

J Urol 2014 Sep 21;192(3):775-9. Epub 2014 Mar 21.

Departments of Urology and Pathology (SP, XJY), Northwestern University Feinberg School of Medicine, Chicago, Illinois.

Purpose: Lichen sclerosus is a chronic inflammatory genital skin condition that can cause destructive urethral scarring. To our knowledge no prior study has described lichen sclerosus in isolated bulbar urethral stricture segments without progressive disease originating from the penile urethra. We report the incidence of lichen sclerosus in isolated bulbar urethral stricture segments.

Materials And Methods: We retrospectively reviewed the records of 70 patients after urethroplasty for isolated bulbar stricture disease was performed from 2007 to 2013. Stricture specimens were re-reviewed by a single uropathologist. Cases were evaluated using common histological features of lichen sclerosus, including hyperkeratosis or epithelial atrophy, basal cell vacuolar degeneration, lichenoid lymphocytic infiltrate and superepithelial sclerosis.

Results: Average patient age was 46.5 years (range 19 to 77) and average stricture length was 3.5 cm (range 1 to 7). Of the patients 51 (73.0%) underwent excision and primary anastomosis, and 19 (27.1%) underwent buccal mucosal onlay. In 6 patients (8.6%) stricture recurred during a median followup of 22 months (IQR 14, 44). Three of those patients had lichen sclerosus. Initial pathology assessment revealed lichen sclerosus in 5 patients (7.1%, 95% CI 1.0-13.3). On re-review of specimens using pathology criteria specific to lichen sclerosus 31 patients (44.3%, 95% CI 32.4-56.2) showed pathology findings highly suggestive of (13) or diagnostic for (18) lichen sclerosus (p = 0.0001). On pathological re-review lichen sclerosus was associated with recurrent stricture.

Conclusions: On re-review of surgical specimens we noted a significant incidence of lichen sclerosus in isolated bulbar strictures in men undergoing urethroplasty. The incidence of lichen sclerosus may be higher than reported in isolated bulbar urethral segments without evidence of distal to proximal progressive urethral disease.
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http://dx.doi.org/10.1016/j.juro.2014.03.090DOI Listing
September 2014

Differential diagnosis of renal tumors with clear cytoplasm: clinical relevance of renal tumor subclassification in the era of targeted therapies and personalized medicine.

Arch Pathol Lab Med 2013 Apr;137(4):467-80

Department of Pathology, Northwestern Memorial Hospital, Northwestern University, Feinberg School of Medicine, Chicago, Illinois 60611, USA.

Context: The World Health Organization classification of renal tumors synthesizes morphologic, immunohistochemical, and molecular findings to define more than 40 tumor types. Of these, clear cell (conventional) renal cell carcinoma is the most common malignant tumor in adults and-with the exception of some rare tumors-the most deadly. The diagnosis of clear cell renal cell carcinoma on morphologic grounds alone is generally straightforward, but challenging cases are not infrequent. A misdiagnosis of clear cell renal cell carcinoma has clinical consequences, particularly in the current era of targeted therapies.

Objective: To highlight morphologic mimics of clear cell renal cell carcinoma and provide strategies to help differentiate clear cell renal cell carcinoma from other renal tumors and lesions. The role of the pathologist in guiding treatment for renal malignancies will be emphasized to stress the importance of proper tumor classification in patient management.

Data Sources: Published literature and personal experience.

Conclusions: In challenging cases, submission of additional tissue is often an inexpensive and effective way to facilitate a correct diagnosis. If immunohistochemical stains are to be used, it is best to use a panel of markers, as no one marker is specific for a given renal tumor subtype. Selection of limited markers, based on a specific differential diagnosis, can be as useful as a large panel in reaching a definitive diagnosis. For renal tumors, both the presence and absence of immunoreactivity and the pattern of labeling (membranous, cytoplasmic, diffuse, focal) are important when interpreting the results of immunohistochemical stains.
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http://dx.doi.org/10.5858/arpa.2012-0085-RADOI Listing
April 2013

Immunohistochemical evaluation of ERG expression in various benign and malignant tissues.

Ann Clin Lab Sci 2013 ;43(1):3-9

Department of Laboratory Medicine, Geisinger Medical Center, Danville, PA 17822, USA.

The transmembrane protease, serine 2-E twenty-six related gene (TMPRSS2-ERG) fusion leading to ERG overexpression, was detected in approximately 50% of prostate cancers (ranging from 35-70%). However, the published data on ERG expression in tumors from other organs and normal tissues were limited. In this study, we investigated the expression of ERG in TMA sections of various normal tissues (N=452) and carcinomas (N=1,129) from various organs, including 90 cases of low to intermediate-grade (L-MG) prostatic adenocarcinomas and 36 cases of high-grade (HG) prostatic adenocarcinomas, using a single immunostaining system (Dako). Also included were prostatic biopsies of radiation atypia (N=20), atrophy (N=20), and high-grade prostatic intraepithelial lesion (HGPIN) (N=18). ERG expression was detected in 44% (40/90) of L-MG prostatic adenocarcinomas; in 22% (8/36) of HG prostatic adenocarcinomas; and in 22% (4/18) of HGPIN. No ERG expression was detected in non-prostate carcinomas, normal tissues including prostate and seminal vesicles, benign prostatic tissue with radiation atypia, and atrophy. Our data demonstrate that ERG is a highly specific marker, which may have important implications in the interpretation of prostate biopsies with limited cancers. In addition, its high diagnostic specificity may be useful in identifying a prostatic primary when working on a tumor of uncertain origin. Partly presented at the United States and Canadian Academy of Pathology Annual Meeting in March 2011.
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August 2013

Primary adenocarcinoma of the urinary bladder: differential diagnosis and clinical relevance.

Arch Pathol Lab Med 2013 Mar;137(3):371-81

Department of Pathology, Northwestern Memorial Hospital, Northwestern University, Feinberg School of Medicine, Chicago, IL 60611, USA.

Context: Glandular lesions of the urinary bladder include a broad spectrum of entities ranging from completely benign glandular lesions to primary and secondary malignancies. Common benign bladder lesions that exhibit glandular differentiation include cystitis cystica, cystitis glandularis, von Brunn nests, nephrogenic adenoma, intestinal metaplasia, urachal remnant, endometriosis, and prostatic-type polyp. The World Health Organization defines primary adenocarcinoma of the bladder as an epithelial malignancy with pure glandular differentiation without evidence of typical urothelial carcinoma. Malignant lesions that should be included in the differential diagnosis of a primary adenocarcinoma of the bladder include noninvasive and invasive urothelial carcinoma with glandular differentiation and secondary malignancies involving the bladder by direct extension or metastasis. The recognition and distinction of these different entities may be a challenge for pathologists, but they are of great clinical importance.

Objective: To review features of primary bladder adenocarcinoma as well as those entities that need to be differentiated from primary bladder adenocarcinoma, with emphasis on clinical findings, pathologic characteristics, and immunoprofiles.

Data Sources: Selected original articles published in the PubMed service of the US National Library of Medicine.

Conclusions: The accurate diagnosis of adenocarcinoma of the urinary bladder is important and challenging. It has to prompt an extensive clinical workup to rule out other glandular lesions in the urinary bladder, especially the possibility of secondary involvement of the bladder by an adenocarcinoma from a different site.
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http://dx.doi.org/10.5858/arpa.2012-0076-RADOI Listing
March 2013

Protein markers of malignant potential in penile and vulvar lichen sclerosus.

J Urol 2013 Aug 8;190(2):399-406. Epub 2013 Feb 8.

Department of Urology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.

Purpose: Lichen sclerosus is an inflammatory skin disorder affecting anogenital areas in males and females that is associated with squamous cell carcinoma. However, there is a lack of data on the role of biomarkers for predicting lichen sclerosus progression to squamous cell carcinoma. We focused on early protein markers of squamous cell carcinoma and their expression in lichen sclerosus to improve the mechanistic and diagnostic understanding of lichen sclerosus.

Material And Methods: We performed an extensive PubMed® and MEDLINE® search for protein markers found in early stages of vulvar and penile squamous cell carcinoma, and their prevalence in associated lichen sclerosus lesions.

Results: In recent years several markers have been implicated as precursor markers for malignant transformation of lichen sclerosus into squamous cell carcinoma, including p53, Ki-67, γ-H2AX, MCM3 and cyclin D1. These proteins are up-regulated in lichen sclerosus of the vulva/penis and squamous cell carcinoma. Various levels of evidence show an association between lichen sclerosus and squamous cell carcinoma. p16 is over expressed in penile and vulvar squamous cell carcinoma associated with human papillomavirus infection but conflicting reports exist about its expression in lichen sclerosus. The angiogenesis markers vascular endothelial growth factor and cyclooxygenase-2 are expressed at higher levels, and microvessel density is increased in vulvar lichen sclerosus and squamous cell carcinoma, indicating a possible similar association in penile lichen sclerosus.

Conclusions: Only a minority of lichen sclerosus cases are associated with squamous cell carcinoma. However, the therapeutic implications of a squamous cell carcinoma diagnosis are severe. Clinically, we lack an understanding of how to separate indolent lichen sclerosus cases from those in danger of progression to squamous cell carcinoma. Several protein markers show promise for further delineating the pathobiology of lichen sclerosus and the potential malignant transformation into squamous cell carcinoma.
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http://dx.doi.org/10.1016/j.juro.2013.01.102DOI Listing
August 2013

Trends in prostatic adenocarcinoma tumor volume by visual estimation in prostatectomy specimens.

Pathol Res Pract 2012 Oct 17;208(10):578-83. Epub 2012 Aug 17.

Department of Pathology, The Ohio State University Medical Center, 410 W 10th Ave., 401 Doan Hall, Columbus, OH 43210, United States.

We retrospectively reviewed 1792 consecutive radical prostatectomies (RP) from 2003 to 2006 at a single institution to establish tumor volume reference values, to determine current trends in visually estimated prostate adenocarcinoma tumor volume, and to characterize cases with no residual cancer on RP. Tumor volumes were recorded and subsequently stratified as very low, 0-1%; low, 1.1-10%; intermediate, 10.1-20%; high, 20.1-50%; and very high, >50%, with incidences of 11.7%, 52.1%, 21.5%, 13.2%, and 1.5%, respectively. The incidence of very low volume tumors increased within the time period (p=0.04). Seminal vesicle involvement was detected in 5.0% of cases and lymph node metastasis occurred in 1.4%. Volume categories statistically correlated with seminal vesicle invasion (p=0) and lymph nodes metastases (p=0). Eleven cases of no residual cancer (0.6%) were identified with a non-statically significant increase during the study (p=0.07). The rising incidence of very low volume tumors should be considered by clinicians when discussing treatment options with patients. A discrete tumor volume should be provided for RP specimens as it may be an important prognostic factor.
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http://dx.doi.org/10.1016/j.prp.2012.06.006DOI Listing
October 2012

The desmosomal armadillo protein plakoglobin regulates prostate cancer cell adhesion and motility through vitronectin-dependent Src signaling.

PLoS One 2012 30;7(7):e42132. Epub 2012 Jul 30.

Department of Pathology, Northwestern University, Chicago, Illinois, United States of America.

Plakoglobin (PG) is an armadillo protein that associates with both classic and desmosomal cadherins, but is primarily concentrated in mature desmosomes in epithelia. While reduced levels of PG have been reported in localized and hormone refractory prostate tumors, the functional significance of these changes is unknown. Here we report that PG expression is reduced in samples of a prostate tumor tissue array and inversely correlated with advancing tumor potential in 7 PCa cell lines. Ectopically expressed PG enhanced intercellular adhesive strength, and attenuated the motility and invasion of aggressive cell lines, whereas silencing PG in less tumorigenic cells had the opposite effect. PG also regulated cell-substrate adhesion and motility through extracellular matrix (ECM)-dependent inhibition of Src kinase, suggesting that PG's effects were not due solely to increased intercellular adhesion. PG silencing resulted in elevated levels of the ECM protein vitronectin (VN), and exposing PG-expressing cells to VN induced Src activity. Furthermore, increased VN levels and Src activation correlated with diminished expression of PG in patient tissues. Thus, PG may inhibit Src by keeping VN low. Our results suggest that loss of intercellular adhesion due to reduced PG expression might be exacerbated by activation of Src through a PG-dependent mechanism. Furthermore, PG down-regulation during PCa progression could contribute to the known VN-dependent promotion of PCa invasion and metastasis, demonstrating a novel functional interaction between desmosomal cell-cell adhesion and cell-substrate adhesion signaling axes in prostate cancer.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0042132PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3408445PMC
January 2013