Publications by authors named "Maria Del Carmen Rodriguez Pena"

26 Publications

  • Page 1 of 1

Well-differentiated neuroendocrine tumors of the lower urinary tract: biologic behavior of a rare entity.

Hum Pathol 2021 Mar 8;109:53-58. Epub 2020 Dec 8.

Department of Pathology, Johns Hopkins Hospital, Baltimore, MD, 21287, USA; Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, 35233, USA. Electronic address:

The spectrum of neuroendocrine (NE) tumors in the genitourinary tract ranges from the aggressive large and small cell carcinomas to the often benign paraganglioma and well-differentiated neuroendocrine tumor (WD-NET). At least 15 pure lower urinary tract (LUT) WD-NETs have been described. Owing to the rarity of WD-NET in the LUT and the limited number of reported cases, a better definition of their biologic long-term behavior is warranted. Herein, we aim to describe 10 new cases of WD-NET arising in the LUT and expand on follow-up findings. Ten consultation cases were identified and included 6 men and 4 women who ranged from 45 to 73 years of age. Seven cases arose in the bladder with one located in the bladder neck, 1 arose in the prostatic urethra, 1 arose in the female urethra, and 1 arose in the left ureteral orifice. All lesions were confined to the lamina propria, and tumor architecture was pseudoglandular in all cases. Associated cystitis cystica et glandularis was identified in 5 cases; urothelial papilloma and florid von Brunn's nests were found in 2 additional cases. Immunohistochemical staining for synaptophysin and chromogranin was diffusely positive in 9 cases and focal in 1 case, and the Ki-67 proliferation index was 5% or less in all tumors. Follow-up ranged from 37 to 137 months (mean = 82; median = 77), and there was no evidence of residual disease or recurrence in any of the 10 patients during the follow-up period.
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http://dx.doi.org/10.1016/j.humpath.2020.11.014DOI Listing
March 2021

Expression of Nectin-4 and PD-L1 in Upper Tract Urothelial Carcinoma.

Int J Mol Sci 2020 Jul 29;21(15). Epub 2020 Jul 29.

Department of Urology, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan.

Enfortumab vedotin is a novel antibody-drug conjugate targeting Nectin-4, which is highly expressed in urothelial carcinoma. However, the expression status of Nectin-4 in upper tract urothelial carcinoma (UTUC) remains unclear. The relationship between Nectin-4 and Programmed Death Ligand 1 (PD-L1) in UTUC is also ambiguous. We performed immunohistochemical analysis of 99 UTUC tissue microarray to assess the expression of Nectin-4 and PD-L1 in UTUC. Nectin-4-positivity was detected in 65 (65.7%) samples, and PD-L1 was detected in 24 (24.2%) samples. There was no correlation between the expression of Nectin-4 and PD-L1. Patients with strong Nectin-4-expressing tumors had a significantly higher risk of progression ( = 0.031) and cancer-specific mortality ( = 0.036). Strong Nectin-4 expression was also an independent predictor of disease progression in the high-risk group (pT3 ≤ or presence of lymphovascular invasion or lymph node metastasis) (Hazard ratio, 3.32 [95% confidence interval, 1.20-7.98; = 0.027]). In conclusion, we demonstrated that Nectin-4 expression rate in UTUC was 65.7% and independent of PD-L1 expression. Strong Nectin-4 expression was associated with worse progression-free survival in high-risk UTUC. These findings suggested that enfortumab vedotin may be effective in a broad range of patients with UTUC, regardless of PD-L1 expression.
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http://dx.doi.org/10.3390/ijms21155390DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7432817PMC
July 2020

Squamous Cell Carcinoma of the Bladder Is Not Associated With High-risk HPV.

Urology 2020 Oct 16;144:158-163. Epub 2020 Jul 16.

Department of Urology, University of Alabama at Birmingham, Birmingham, AL; Department of Radiology, University of Alabama at Birmingham, Birmingham, AL; O'Neal Comprehensive Cancer Center at UAB, University of Alabama at Birmingham, Birmingham, AL.

Objective: To evaluate the clinical features, pathologic features, and prevalence of human papilloma virus (HPV) in squamous cell carcinoma (SCC) of the bladder. SCC of the bladder is known to be associated with conditions that cause chronic inflammation/irritation. The literature is inconsistent regarding the association of HPV with pure SCC of the bladder.

Methods: A multi-institutional study identified cases of SCC of the bladder. Pure squamous histology and the absence of urothelial carcinoma in situ were required for inclusion. Clinical and pathologic features were collected, and tissues were evaluated for high-risk HPV using p16 immunohistochemistry and in situ hybridization.

Results: We identified 207 cases of SCC of the bladder. Risk factors for bladder cancer included smoking (133/207, 64%) and chronic bladder irritation (83/207, 40%). The majority (155/207, 75%) of patients had > pT2 disease. Mean tumor size was 5.6 ± 3.0 cm and 36/207 (17%) patients had lymph node positive disease. p16 immunohistochemistry was positive in 52/204 (25%) cases but high-risk HPV was identified with in situ hybridization in only 1 (0.5%) case. Tumor size, stage, number of lymph nodes removed, number of positive lymph nodes, lymphovascular invasion, perineural invasion, and positive margins each were associated with cancer-specific mortality when adjusted for demographic factors. A multivariate analysis of variable importance further revealed sex and race as important factors in predicting cancer-specific mortality.

Conclusion: SCC of the bladder is an aggressive histologic subtype. Although bladder SCC can express p16, it is not typically associated with high-risk HPV, although rare cases can occur.
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http://dx.doi.org/10.1016/j.urology.2020.06.065DOI Listing
October 2020

Rare MDM2 amplification in a fat-predominant angiomyolipoma.

Virchows Arch 2020 Nov 15;477(5):661-666. Epub 2020 May 15.

Pathology Department, University of Alabama at Birmingham, Birmingham, AL, USA.

Angiomyolipomas (AMLs) are triphasic tumors (smooth muscle, vascular and adipocytic components) with myomelanocytic differentiation, arising most commonly in the kidneys, which can show predominant epithelioid morphology and fat-predominant or fat-poor variants. Fat-predominant AMLs can show areas of hypercellularity and lipoblast-like cells, and these features can mimic well-differentiated liposarcoma (WDLS). To date, only one documented metastatic epithelioid AML showed unequivocal MDM2 amplification by fluorescence in situ hybridization. We describe our findings in a series of 35 AMLs including epithelioid, fat-poor, and fat-predominant variants, following interrogation of the MDM2 locus by FISH and CISH assays. MDM2 amplification was detected in 1 fat-predominant AML. Our findings demonstrate that rare MDM2 amplifications can occur in AMLs. We favor that this finding likely represents a "molecular bystander" event since these tumors are mainly driven by aberrations in the TSC1/TSC2 genes. Nevertheless, the presence of MDM2 amplification in a fat-predominant AML could present a potential diagnostic pitfall, particularly when confronted with the differential diagnosis of fat-predominant AML and WDLS in limited material from the retroperitoneum.
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http://dx.doi.org/10.1007/s00428-020-02813-9DOI Listing
November 2020

Immune checkpoint status and tumor microenvironment in vulvar squamous cell carcinoma.

Virchows Arch 2020 Jul 28;477(1):93-102. Epub 2020 Jan 28.

Department of Pathology, The University of Alabama at Birmingham, West Pavilion P210, 619 19th Street, South Birmingham, AL, 35249-7331, USA.

Vulvar squamous cell carcinoma accounts for 5% of cancers of the female genital tract. Current guidelines recommend wide local excision with negative surgical margins as the standard treatment. However, the extent of the tumor-free resection margin after wide local excision is still controversial in many cases. Drugs targeting immune checkpoints such as PD-1 or its ligand PD-L1 have potential clinical utility in these patients. We examined the expression of PD-L1 in tumor cells and immune cells, as well as the proportion of PD-1, CD8, and FOXP3 positive lymphocytes. Twenty-one cases of invasive vulvar squamous cell carcinomas were reviewed. Whole slides of representative formalin-fixed, paraffin-embedded archival material were used for analysis. Odds ratios (OR) and hazard ratios (HR) were used to estimate risk for disease recurrence, overall mortality, and cancer mortality. PD-L1 expression was found in 43% of tumor cells, with higher proportions in intratumoral (67%) and peritumoral (81%) immune cells. OR and HR for disease recurrence and cancer mortality were higher in tumors with higher CD8 expression. OR and HR for overall mortality were also higher in tumors with higher PD-L1 and CD8 expression. In conclusion, nearly half of cases were PD-L1 positive in tumor cells with over two-third of cases demonstrating PD-L1 positivity in immune cells. Immunohistochemical expression of PD-L1 and CD8 could be used to suggest higher risk of disease recurrence, overall mortality, and cancer mortality. Furthermore, our data contributes to the growing evidence that targeting the PD-1/PD-L1 pathway may be beneficial in vulvar squamous cell carcinomas.
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http://dx.doi.org/10.1007/s00428-020-02759-yDOI Listing
July 2020

Morphology, p16, HPV, and outcomes in squamous cell carcinoma of the penis: a multi-institutional study.

Hum Pathol 2020 02 5;96:79-86. Epub 2019 Nov 5.

Department of Pathology, Vanderbilt University, Nashville, TN, 37212 USA; Department of Urology, Vanderbilt University, Nashville, TN, 37212 USA. Electronic address:

Our objective was to evaluate the pathologic features and clinical outcomes in cases of invasive penile squamous cell carcinoma (SCC) and the association with p16 immunohistochemistry (IHC) and human papilloma virus (HPV) in situ hybridization (ISH). A retrospective multi-institutional database search was conducted for invasive SCC of the penis diagnosed between 2007 and 2018 that had undergone surgical resection. Pathologic features, p16 IHC, and HPV ISH were investigated with clinical outcomes. A total of 102 patients were included in the study. The average age was 63 ± 13.3 years. Based on histology, 46% of tumors displayed an HPV-related subtype, whereas p16 was positive in 52% of all cases. Tumor histology correlated well with p16 positivity (P < .001), and p16 IHC accurately predicted the presence of HPV in 25/26 (96%) cases. On multivariate analysis, perineural invasion was associated with local disease recurrence (P = .02), whereas lymphovascular invasion was associated with progression to metastatic disease (P = .002) and increased overall mortality (P = .02). Urethral involvement was also associated with increased overall mortality (P = .02). In addition, HPV-related tumors based on histologic features correlated with lower rates of metastatic disease (P = .007). HPV is a common cause of penile SCC and can be diagnosed by tumor histology and confirmed by overexpression of p16 on IHC. The presence of lymphovascular invasion, perineural invasion, and urethral involvement are poor prognostic indicators, whereas HPV-related tumors based on histology may have lower risk for metastatic disease.
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http://dx.doi.org/10.1016/j.humpath.2019.09.013DOI Listing
February 2020

Tumour immune microenvironment in primary and metastatic papillary renal cell carcinoma.

Histopathology 2020 Feb 11;76(3):423-432. Epub 2019 Dec 11.

Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA.

Aims: Among renal cell carcinoma (RCC) the tumour immune microenvironment has been best characterised in clear cell RCC. In this study we investigated the expression of several immune markers, including PD-L1, FoxP3 and CD8 in primary and metastatic papillary RCC.

Methods And Results: Three tissue microarrays were constructed from 78 cases with primary papillary RCC and paired metastatic tumour (24 cases) from 78 patients treated between 1982 and 2014. Immunohistochemistry analysis was performed using commercially available antibodies for PD-L1 (clone E1L3N), FoxP3, CD8 and Ki-67. Markers expression level in tumour and/or associated immune cells was analysed by tissue type (non-tumour versus primary tumour versus metastatic tumour) and correlated to clinicopathological features and outcome.

Conclusion: We found PD-L1 expression in up to one-quarter of primary and metastatic papillary RCC. On univariate analysis, CD8/FoxP3 ratio >1 was associated with favourable outcome, whereas papillary RCCs with high numbers of dual CD8/Ki-67-positive lymphocytes showed an increased likelihood for tumour progression and overall and cancer-related mortality. The association of CD8/FoxP3 ratio >1 and high count of CD8/Ki-67 with outcome remained significant on multivariate analysis when adjusting for stage, grade and patient's age.
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http://dx.doi.org/10.1111/his.13987DOI Listing
February 2020

Performance of novel non-invasive urine assay UroSEEK in cohorts of equivocal urine cytology.

Virchows Arch 2020 Mar 3;476(3):423-429. Epub 2019 Sep 3.

Department of Pathology, The University of Alabama at Birmingham, Birmingham, AL, 35233, USA.

Urine cytology is an essential element of the diagnostic work up of hematuria. A significant proportion of cases continue to be placed in the "atypical" or "suspicious" categories of the Paris system for urine cytology, posing difficulty in patient management. We report on the performance of our recently described urine-based assay "UroSEEK" in cases with equivocal diagnosis in patients who are investigated for bladder cancer. Urine samples were collected from two cohorts. The first consisted of patients who presented with hematuria or lower urinary tract symptoms (early detection cohort) and the second of patients that are in follow-up for prior bladder cancer (surveillance cohort). Urine samples were analyzed for mutations in 11 genes and aneuploidy. In the early detection setting, we found high sensitivity and specificity (96% and 88%, respectively) and a strong negative predictive value of 99%. The assay performance was less robust in the surveillance cohort (sensitivity of 74%, specificity of 72%, and negative predictive value of 53%). UroSEEK demonstrated a notable lead time to cancer diagnosis. Seven cases in the early detection cohort and 71 surveillance cases were detected at least 6 months prior to clinical diagnosis. Our results suggest a potential role for UroSEEK assay in guiding management of patients with atypical urine cytology if confirmed in future prospective trials.
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http://dx.doi.org/10.1007/s00428-019-02654-1DOI Listing
March 2020

Expression and Role of Methylenetetrahydrofolate Dehydrogenase 1 Like (MTHFD1L) in Bladder Cancer.

Transl Oncol 2019 Nov 8;12(11):1416-1424. Epub 2019 Aug 8.

Department of Pathology, The University of Alabama at Birmingham, Birmingham, AL, USA; O'Neal Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, USA. Electronic address:

Cancer cells utilize vitamin folate to fulfill their excessive demand for nucleotides and amino acids. Dihydrofolate reductase (DHFR), an enzyme involved in folate metabolism converts dihydrofolate into tetrahydrofolate, which is required for the de novo synthesis of purines, and certain amino acids. DHFR inhibitors are used as a chemotherapeutic agent. Cancer sequencing analysis has identified additional enzymes in folate metabolism that are dysregulated in cancer. Methylenetetrahydrofolate dehydrogenase 1 like (MTHFD1L), one such enzyme is overexpressed in bladder cancer. MTHFD1L is a mitochondrial enzyme involved in the folate cycle by catalyzing the reaction of formyl-tetrahydrofolate to formate and tetrahydrofolate (THF). THF is crucial for de novo purine and thymidylate synthesis and is also involved in the regeneration of methionine. Cancer cells rely on purines derived from the de novo pathway for the nucleotides whereas normal cells favor the salvage pathway. In this study we examined MTHFD1L expression in bladder cancer. By using publicly available cancer transcriptome data analysis web-portal UALCAN, we found overexpression of MTHFD1L in bladder cancer and expression was associated with overall survival. RT-PCR and immunoblot analysis confirmed the overexpression of MTHFD1L in muscle invasive bladder cancer tissues compared to normal urothelium. Furthermore, our investigations suggested a critical role for MTHFD1L in bladder cancer cell proliferation, colony formation and invasion. Thus, in this study, we show the significance of the folate metabolic enzyme MTHFD1L in aggressive bladder cancers and suggest that being an enzyme, MTHFD1L serves as a valuable therapeutic target.
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http://dx.doi.org/10.1016/j.tranon.2019.07.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6700437PMC
November 2019

Focused Submission of Tissue for Radical Prostatectomy Following Multiparametric Magnetic Resonance Imaging/Ultrasound Fusion-Targeted Biopsy.

Int J Surg Pathol 2020 Feb 25;28(1):44-50. Epub 2019 Jul 25.

Vanderbilt University Medical Center, Nashville, TN, USA.

Prostate cancer can be difficult to appreciate grossly and therefore partial sampling of the gland can lead to incorrect grading, staging, or margin status. However, submitting the entire prostate is more time consuming and costly. We investigated the use of magnetic resonance imaging/ultrasound-targeted biopsy for the selective submission of prostatectomy specimens. We performed a retrospective review for patients with cancer on targeted prostate biopsy who underwent subsequent radical prostatectomy. Prostatectomy specimens were submitted in their entirety and assessed for Grade Group, extraprostatic extension (EPE), margins, and number of blocks. For Targeted-Grossing (TG) assessment, apex margin, bladder neck margin, seminal vesicles, and vas deferens sections were included. For the remainder of the prostate, only sections from areas shown to be positive for cancer on targeted biopsy were included in the analysis. With total tissue submission, EPE was found in 39/81 (48.1%) cases and positive margins in 19/81 (23.5%) cases. The TG method required significantly fewer blocks: 15.8 ± 5.9 versus 44.9 ± 11.9 ( < .0001). The TG method would have diagnosed the correct stage in 73/81 (90.1%) cases, Grade Group in 74/81 (91.4%) cases, and margin status in 79/81 (97.5%) cases. EPE was missed completely by the TG method in 7 cases ( = .008), of which 5/7 (71.4%) had focal EPE. There was no significant difference in stage ( = .24), Grade Group ( = .95), or margin status ( = .16) between the 2 methods. Grossing utilizing selective tissue submission from areas found to be positive for prostate cancer on magnetic resonance imaging/ultrasound-targeted prostate biopsy remains inferior to complete submission of tissue for radical prostatectomy specimens.
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http://dx.doi.org/10.1177/1066896919865026DOI Listing
February 2020

Immunohistochemical assessment of basal and luminal markers in non-muscle invasive urothelial carcinoma of bladder.

Virchows Arch 2019 Sep 12;475(3):349-356. Epub 2019 Jul 12.

Department of Pathology, The University of Alabama at Birmingham, WP Building, Suite P230, 619 19th Street South, Birmingham, AL, 35249-7331, USA.

The Cancer Genome Atlas project introduced genomic taxonomy of basal and luminal molecular subtypes in muscle invasive bladder cancer. Fewer studies have addressed the molecular classification in non-muscle invasive bladder cancer (NMIBC). Our aim is to assess the applicability of the proposed phenotypic classification for NMIBC. Three TMAs were constructed from 193 TURBT specimens of 60 bladder cancer patients treated at one of the authors' institutions (1998-2008). Follow-up data on recurrence, grade, or stage progression was obtained. Immunohistochemistry was performed using an automated Ventana System for markers indicative of luminal (GATA3, CK20, ER, Uroplakin II, and HER2/neu) and basal (CK5/6 and CD44) phenotype. Marker expression was evaluated by 3 urologic pathologists. Using unadjusted logistic regression, we found significant association between tumor recurrence at next biopsy and CD44 expression (OR = 2.51, P = 0.03), tumor recurrence at any subsequent biopsy and ER expression (OR = 0.24, P = 0.04), and tumor grade progression at any subsequent biopsy and HER2/neu expression (OR = 0.24, P = 0.04). After adjusting for pathologic stage, we found a significant association between CK5/6 expression and tumor stage progression at either next or any subsequent biopsy (OR = 0.94, P = 0.006; and OR = 0.97, P = 0.02, respectively). Our findings suggest that individual immunohistochemical markers may be of value as prognostic factors in NMIBC.
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http://dx.doi.org/10.1007/s00428-019-02618-5DOI Listing
September 2019

PTEN and ERG detection in multiparametric magnetic resonance imaging/ultrasound fusion targeted prostate biopsy compared to systematic biopsy.

Hum Pathol 2019 08 7;90:20-26. Epub 2019 May 7.

Vanderbilt University Medical Center, Departments and Pathology and Urology, Nashville, TN 37232. Electronic address:

Multiparametric magnetic resonance imaging (MRI)/ultrasound fusion targeted prostate biopsy has been shown to outperform systematic biopsy in the detection of clinically significant prostate cancer. Aside from tumor grade, tumor biomarkers such as phosphatase and tensin homolog (PTEN) and ETS-related gene (ERG) have prognostic significance in prostate cancer and may help direct management of patients with low-grade tumors. Our objective was to compare the detection of PTEN and ERG expression in MRI-targeted versus systematic prostate biopsies. We compared immunohistochemical expression for PTEN and ERG on prostate biopsy cores from patients with Grade Group (GG) 1 or GG2 prostate cancer who had undergone systematic biopsy with concurrent targeted biopsy. Fifty-three cases had both systematic and MRI-targeted prostate tissue available for staining for PTEN; and 52 cases, for ERG. ERG positivity was seen in 37/52 (71.2%) cases, and PTEN loss was seen in 15/53 (28.3%) cases. The detection of ERG expression was not significantly different between MRI-targeted and systematic biopsy (P = .4). Targeted biopsy was superior to systematic biopsy in the detection of PTEN loss (P = .02). MRI-targeted cores detected 14/15 (93.3%) cases of PTEN loss compared to 7/15 (46.7%) cases detected by systematic cores. Most cases with PTEN loss showed heterogeneous expression in both systematic and targeted cores. In 14/15 (93.3%) cases with PTEN loss, GG was the same between targeted and systematic biopsy. Targeted biopsy is superior to systematic biopsy in the detection of PTEN loss in GG1 and GG2 tumors. Inclusion of targeted cores may be helpful for evaluation of certain prognostic biomarkers.
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http://dx.doi.org/10.1016/j.humpath.2019.04.016DOI Listing
August 2019

Incidence and distribution of UroSEEK gene panel in a multi-institutional cohort of bladder urothelial carcinoma.

Mod Pathol 2019 10 25;32(10):1544-1550. Epub 2019 Apr 25.

Department of Pathology, The University of Alabama at Birmingham, Birmingham, AL, USA.

Noninvasive approaches for early detection of bladder cancer are actively being investigated. We recently developed a urine- based molecular assay for the detection and surveillance of bladder neoplasms (UroSEEK). UroSEEK is designed to detect alterations in 11 genes that include most common genetic alterations in bladder cancer. In this study, we analyzed 527 cases, including 373 noninvasive and 154 invasive urothelial carcinomas of bladder from transurethral resections or cystectomies performed at four institutions (1991-2016). Two different mutational analysis assays of a representative tumor area were performed: first, a singleplex PCR assay for evaluation of the TERT promoter region (TERTSeqS) and second, a multiplex PCR assay using primers designed to amplify regions of interest of 10 (FGFR3, PIK3CA, TP53, HRAS, KRAS, ERBB2, CDKN2A, MET, MLL, and VHL) genes (UroSeqS). Overall, 92% of all bladder tumors were positive for at least one genetic alteration in the UroSEEK panel. We found TERT promoter mutations in 77% of low-grade noninvasive papillary carcinomas, with a relatively lower incidence of 65% in high-grade noninvasive papillary carcinomas and carcinomas in situ; p = 0.017. Seventy-two percent of pT1 and 63% of muscle-invasive bladder tumors harbored TERT promoter mutations with g.1295228C>T alteration being the most common in all groups. FGFR3 and PIK3CA mutations were more frequent in low-grade noninvasive papillary carcinomas compared with high-grade noninvasive papillary carcinomas and carcinomas in situ (p < 0.0001), while the opposite was true for TP53 (p < 0.0001). Significantly higher rates of TP53 and CDKN2A mutation rates (p = 0.005 and 0.035, respectively) were encountered in muscle-invasive bladder tumors compared with those of pT1 stage. The overwhelming majority of all investigated tumors showed at least one mutation among UroSEEK assay genes, confirming the comprehensive coverage of the panel and supporting its potential utility as a noninvasive urine-based assay.
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http://dx.doi.org/10.1038/s41379-019-0276-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6872189PMC
October 2019

Tumor immune microenvironment in non-muscle-invasive urothelial carcinoma of the bladder.

Hum Pathol 2019 07 24;89:24-32. Epub 2019 Apr 24.

Department of Pathology, The University of Alabama at Birmingham, Birmingham, AL 35249, USA. Electronic address:

Immunotherapy has gained significance in a variety of tumor types including advanced urothelial carcinoma. Noninvasive urothelial lesions have been treated with intravesical Bacillus-Calmette-Guerin (BCG) for decades. Given treatment failure in a subset of these tumors, ongoing clinical trials investigating the role of checkpoint inhibitors are actively pursued in this group of patients. The present study aims to delineate PD-L1, CD8, and FOXP3 expression in tumor microenvironment in non-muscle-invasive urothelial carcinoma samples obtained via sequential biopsies and to assess its potential role in predicting disease outcome. Cases with >1% and> 5% PD-L1 expression in tumor cells showed lower relative risk (RR) to recur at any subsequent biopsy compared with those with lower PD-L1 expression (RRs, 0.83 [P = .009] and 0.81 [P = .03], respectively). Cases with higher expression of FOXP3 in peritumoral lymphocytes were at lower risk for tumor grade progression at any biopsy (RR, 0.2; P = .02). Tumors with FOXP3/CD8 expression ratio of >1 in intratumoral lymphocytes had lower risk of grade progression (RR, 0.28; P = .04). Although higher number of FOXP3-, CD8-, and PD-L1-positive lymphocytes were encountered after BCG treatment, the findings did not reach statistical significance. In patients without BCG treatment, PD-L1 expression in tumor cells and peritumoral lymphocytes varied across serial biopsies, suggesting the need for additional approaches to assess eligibility for immunotherapy in non-muscle-invasive urothelial carcinoma patients.
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http://dx.doi.org/10.1016/j.humpath.2019.04.003DOI Listing
July 2019

Targeted sequencing of plasmacytoid urothelial carcinoma reveals frequent TERT promoter mutations.

Hum Pathol 2019 03 14;85:1-9. Epub 2018 Nov 14.

Department of Pathology, Johns Hopkins University, Baltimore, MD 21287, USA; Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35249, USA. Electronic address:

Activating mutations in the promoter of the telomerase reverse transcriptase (TERT) gene are the most common genetic alterations in urothelial carcinoma (UC) of the bladder and upper urinary tract. Although the cadherin 1 (CDH1) gene is commonly mutated in the clinically aggressive plasmacytoid variant of urothelial carcinoma (PUC), little is known about their TERT promoter mutation status. A retrospective search of our archives for PUC and UC with plasmacytoid and/or signet ring cell features (2007-2014) was performed. Ten specimens from 10 patients had archived material available for DNA analysis and were included in the study. Intratumoral areas of nonplasmacytoid histology were also evaluated when present. Samples were analyzed for TERT promoter mutations with Safe-SeqS, a sequencing error-reduction technology, and sequenced using a targeted panel of the 10 most commonly mutated genes in bladder cancer on the Illumina MiSeq platform. TERT promoter mutations were detected in specimens with pure and focal plasmacytoid features (6/10). Similar to conventional UC, the predominant mutation identified was g.1295228C>T. In heterogeneous tumors with focal variant histology, concordant mutations were found in plasmacytoid and corresponding conventional, glandular, or sarcomatoid areas. Co-occurring mutations in tumor protein p53 (TP53, 2 cases) and kirsten rat sarcoma (KRAS) viral proto-oncogene (1 case) were also detected. TERT promoter mutations are frequently present in PUC, which provides further evidence that TERT promoter mutations are common events in bladder cancer, regardless of histologic subtype, and supports their inclusion in any liquid biopsy assay for bladder cancer.
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http://dx.doi.org/10.1016/j.humpath.2018.10.033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6728909PMC
March 2019

Active Surveillance of Small Renal Masses.

Urology 2019 Jan 26;123:157-166. Epub 2018 Sep 26.

Department of Urology, The University of Alabama at Birmingham, Birmingham, AL; Department of Radiology, The University of Alabama at Birmingham, Birmingham, AL.

Most renal masses in the United States are incidentally detected via abdominal imaging. This has led to an increase in the incidence of small renal masses (≤4 cm). Active surveillance is, an oncologically safe option in slow growing and indolent tumors in other organs and has recently become more widely studied in small renal masses. For selected patients, particularly those who harbor significant comorbidities, active surveillance is a safe option for small renal masses. Renal biopsy may be helpful in the decision making process, but remains an optional component for the active surveillance of small renal masses.
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http://dx.doi.org/10.1016/j.urology.2018.09.017DOI Listing
January 2019

Histologic findings associated with false-positive multiparametric magnetic resonance imaging performed for prostate cancer detection.

Hum Pathol 2019 01 1;83:159-165. Epub 2018 Sep 1.

Department of Urology, University of Alabama at Birmingham, Birmingham, AL 35249, USA; Department of Radiology, University of Alabama at Birmingham, Birmingham, AL 35249, USA.

Magnetic resonance imaging (MRI)/ultrasound fusion-targeted biopsy (TB) has been shown to more accurately identify higher-grade prostate cancers compared with standard-of-care systematic sextant prostate biopsy (SB). However, occasional false-positive imaging findings occur. We investigated the histologic findings associated with false-positive prostate MRI findings. A retrospective review was performed on our surgical pathology database from 2014 to 2017 selecting patients with no cancer detected on TB with concurrent SB after at least 1 prior benign SB session. Histologic features evaluated included percentage of core involvement by chronic inflammation, percentage of core composed of stroma, percentage of glands involved by atrophy, and presence of the following features: acute or granulomatous inflammation, stromal nodular hyperplasia, adenosis, squamous metaplasia, basal cell hyperplasia, and presence of skeletal muscle. Histologic findings were compared between TB and concurrent SB. We identified 544 patients who underwent TB. Of these, 41 patients, including 62 targeted lesions, met criteria. Compared with SB tissue, the mean percentage of stroma was increased in TB (P = .02). Basal cell hyperplasia was also found to be more common on TB (P = .02). Both high percentage of stroma (P = .046) and presence of basal cell hyperplasia (P = .038) were independent predictors on multivariate analysis. The combination of high chronic inflammation, high stroma, acute inflammation, and basal cell hyperplasia was associated with TB (P = .001). Atrophic glands and chronic inflammation showed a positive correlation (r = 0.67, P = .003), which was especially seen in high prostate imaging reporting and data system lesions. Specific benign histologic entities are associated with false-positive findings on prostate MRI.
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http://dx.doi.org/10.1016/j.humpath.2018.08.021DOI Listing
January 2019

A Role for De Novo Purine Metabolic Enzyme PAICS in Bladder Cancer Progression.

Neoplasia 2018 09 15;20(9):894-904. Epub 2018 Aug 15.

Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA; Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, USA; Informatics Institute, University of Alabama at Birmingham, Birmingham, AL, USA. Electronic address:

Genomic and transcriptome sequencing of bladder cancer (BLCA) has identified multiple molecular alterations during cancer progression. Many of these identified genetic and epigenetic changes play a role in the progression of this disease. Studies have identified molecular subtypes in muscle-invasive bladder cancer (MIBC) with different sensitivities to frontline therapy suggesting the heterogeneity in these tumors and the importance of molecular characterization of MIBC to provide effective treatment. Specifically, it has become increasingly evident, as demonstrated by The Cancer Genome Atlas project, that metabolic enzymes are commonly dysregulated in BLCA. Elevated expression of multiple metabolic enzymes is due to the increased demand from rapidly proliferating BLCA cells requiring extensive nucleotide synthesis. Cancer cells utilize the de novo purine and pyrimidine biosynthetic pathway as a source of their nucleotide needs. In this study, we show that phosphoribosyl aminoimidazole succinocarboxamide synthetase (PAICS), an enzyme involved in de novo purine biosynthetic pathway, is significantly overexpressed in BLCA. Immunohistochemical staining of paraffin-embedded tissue sections showed that PAICS is overexpressed in MIBC. Furthermore, we found that tumor suppressor miR-128 negatively regulated PAICS expression by binding to its 3'-untranslated region. We also found that PAICS induces EMT by positively regulating SNAI1 and by a reduction in E-cadherin expression. Additionally, our in vitro functional studies and in vivo chicken chorioallantoic membrane assay show that PAICS plays a critical role in BLCA cell proliferation, invasion, and tumor growth. Collectively, our data suggest that targeting PAICS may provide a therapeutic option in BLCA.
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http://dx.doi.org/10.1016/j.neo.2018.07.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6098199PMC
September 2018

High-Fat Diet-Induced Inflammation Accelerates Prostate Cancer Growth via IL6 Signaling.

Clin Cancer Res 2018 09 18;24(17):4309-4318. Epub 2018 May 18.

Department of Urology, Osaka University Graduate School of Medicine, Suita, Japan.

High-fat diet (HFD) could induce prostate cancer progression. The aim of this study is to identify mechanisms of HFD-induced prostate cancer progression, focusing on inflammation. We administered HFD and celecoxib to autochthonous immunocompetent Pb-Cre;(fl/fl) model mice for prostate cancer. Tumor growth was evaluated by tumor weight and Ki67 stain, and local immune cells were assessed by flow cytometry at 22 weeks of age. Cytokines which correlated with tumor growth were identified, and the changes of tumor growth and local immune cells after inhibition of the cytokine signals were evaluated in the mice. IHC analyses using prostatectomy specimens of obese patients were performed. HFD accelerated tumor growth and increased the myeloid-derived suppressor cells (MDSCs) fraction and M2/M1 macrophage ratio in the model mice. Celecoxib-suppressed tumor growth, and decreased both local MDSCs and M2/M1 macrophage ratio in HFD-fed mice. HFD-induced tumor growth was associated with IL6 secreted by prostatic macrophages, as were phosphorylated STAT3 (pSTAT3)-positive tumor cells. Anti-IL6 receptor antibody administration suppressed tumor growth, and decreased local MDSCs and pSTAT3-positive cell fractions in HFD-fed mice. The tumor-infiltrating CD11b-positive cell count was significantly higher in prostatectomy specimens of obese than those of nonobese patients with prostate cancer. HFD increased MDSCs and accelerated prostate cancer tumor growth via IL6/pSTAT3 signaling in the mice. This mechanism could exist in obese patients with prostate cancer. IL6-mediated inflammation could be a therapeutic target for prostate cancer. .
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http://dx.doi.org/10.1158/1078-0432.CCR-18-0106DOI Listing
September 2018

Non-invasive detection of urothelial cancer through the analysis of driver gene mutations and aneuploidy.

Elife 2018 03 20;7. Epub 2018 Mar 20.

Masonic Cancer Center, University of Minnesota, Minneapolis, United States.

Current non-invasive approaches for detection of urothelial cancers are suboptimal. We developed a test to detect urothelial neoplasms using DNA recovered from cells shed into urine. UroSEEK incorporates massive parallel sequencing assays for mutations in 11 genes and copy number changes on 39 chromosome arms. In 570 patients at risk for bladder cancer (BC), UroSEEK was positive in 83% of those who developed BC. Combined with cytology, UroSEEK detected 95% of patients who developed BC. Of 56 patients with upper tract urothelial cancer, 75% tested positive by UroSEEK, including 79% of those with non-invasive tumors. UroSEEK detected genetic abnormalities in 68% of urines obtained from BC patients under surveillance who demonstrated clinical evidence of recurrence. The advantages of UroSEEK over cytology were evident in low-grade BCs; UroSEEK detected 67% of cases whereas cytology detected none. These results establish the foundation for a new non-invasive approach for detection of urothelial cancer.
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http://dx.doi.org/10.7554/eLife.32143DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5860864PMC
March 2018

Defining the optimal method for reporting prostate cancer grade and tumor extent on magnetic resonance/ultrasound fusion-targeted biopsies.

Hum Pathol 2018 06 16;76:68-75. Epub 2018 Mar 16.

Department of Urology, University of Alabama at Birmingham, Birmingham, AL, 35249, USA; Department of Radiology, University of Alabama at Birmingham, Birmingham, AL, 35249, USA.

Magnetic resonance (MR)/ultrasound fusion-targeted biopsy (TB) routinely samples multiple cores from each MR lesion of interest. Pathologists can evaluate the extent of cancer involvement and grade using an individual core (IC) or aggregate (AG) method, which could potentially lead to differences in reporting. We reviewed patients who underwent TB followed by radical prostatectomy (RP). TB cores were evaluated for grade and tumor extent by 2 methods. In the IC method, the grade for each TB lesion was based on the core with the highest Gleason score. Tumor extent for each TB was based on the core with the highest percent of tumor involvement. In the AG method, the tumor from all cores within each TB lesion was aggregated to determine the final composite grade and percentage of tumor involvement. Each method was compared with MR lesional volume, MR lesional density (lesion volume/prostate volume), and RP. Fifty-five patients underwent TB followed by RP. Extent of tumor by the AG method showed a better correlation with target lesion volume (r= 0.27,P= .022) and lesional density (r = 0.32, P = .008) than did the IC method (r= 0.19 [P = .103] andr= 0.22 [P = .062]), respectively. Extent of tumor on TB was associated with extraprostatic extension on RP by the AG method (P= .04), but not by the IC method. This association was significantly higher in patients with a grade group (GG) of 3 or higher (P= .03). A change in cancer grade occurred in 3 patients when comparing methods (2 downgraded GG3 to GG2, 1 downgraded GG4 to GG3 by the AG method). For multiple cores obtained via TB, the AG method better correlates with target lesion volume, lesional density, and extraprostatic extension.
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http://dx.doi.org/10.1016/j.humpath.2018.03.005DOI Listing
June 2018

YAP1 and COX2 Coordinately Regulate Urothelial Cancer Stem-like Cells.

Cancer Res 2018 01 27;78(1):168-181. Epub 2017 Nov 27.

Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland.

Overcoming acquired drug resistance remains a core challenge in the clinical management of human cancer, including in urothelial carcinoma of the bladder (UCB). Cancer stem-like cells (CSC) have been implicated in the emergence of drug resistance but mechanisms and intervention points are not completely understood. Here, we report that the proinflammatory COX2/PGE2 pathway and the YAP1 growth-regulatory pathway cooperate to recruit the stem cell factor SOX2 in expanding and sustaining the accumulation of urothelial CSCs. Mechanistically, COX2/PGE2 signaling induced promoter methylation of let-7, resulting in its downregulation and subsequent SOX2 upregulation. YAP1 induced SOX2 expression more directly by binding its enhancer region. In UCB clinical specimens, positive correlations in the expression of SOX2, COX2, and YAP1 were observed, with coexpression of COX2 and YAP1 particularly commonly observed. Additional investigations suggested that activation of the COX2/PGE2 and YAP1 pathways also promoted acquired resistance to EGFR inhibitors in basal-type UCB. In a mouse xenograft model of UCB, dual inhibition of COX2 and YAP1 elicited a long-lasting therapeutic response by limiting CSC expansion after chemotherapy and EGFR inhibition. Our findings provide a preclinical rationale to target these pathways concurrently with systemic chemotherapy as a strategy to improve the clinical management of UCB. These findings offer a preclinical rationale to target the COX2 and YAP1 pathways concurrently with systemic chemotherapy to improve the clinical management of UCB, based on evidence that these two pathways expand cancer stem-like cell populations that mediate resistance to chemotherapy. .
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http://dx.doi.org/10.1158/0008-5472.CAN-17-0836DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5754245PMC
January 2018

Spectrum of genetic mutations in de novo PUNLMP of the urinary bladder.

Virchows Arch 2017 Dec 8;471(6):761-767. Epub 2017 Jun 8.

Department of Pathology, Johns Hopkins University, Baltimore, MD, 21287, USA.

Our group and others have previously demonstrated the presence of TERT promoter mutations (TERT-mut) in 60-80% of urothelial carcinomas and some of their histologic variants. Five other genes have been frequently implicated in bladder cancer: FGRF3, TP53, PIK3CA, HRAS, and CDKN2A. In the current study, we sought to determine the prevalence of mutations in TERT and these five other genes in de novo papillary urothelial neoplasms of low malignant potential (PUNLMP) of the urinary bladder. A retrospective search of our archives for PUNLMP was performed and 30 de novo cases were identified and included in the study. We found mutations in TERT (TERT-mut) and FGFR3 (FGFR3-mut) to be the most common alterations in the cohort (63 and 60%, respectively). The majority of the TERT-mut-positive tumors (84%) had a g.1295228C > T alteration with the remaining tumors demonstrating g.1295250C > T. Approximately one fourth of tumors had TP53 mutations. These findings support the potential utility of a uniform genetic mutation panel to detect bladder cancers of various subtypes.
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http://dx.doi.org/10.1007/s00428-017-2164-5DOI Listing
December 2017

Detection of TERT promoter mutations in primary adenocarcinoma of the urinary bladder.

Hum Pathol 2016 07 10;53:8-13. Epub 2016 Mar 10.

Department of Pathology, Johns Hopkins University, Baltimore, MD 21287; Department of Urology, Johns Hopkins University, Baltimore, MD 21287. Electronic address:

TERT promoter mutations (TERT-mut) have been detected in 60% to 80% of urothelial carcinomas. A molecular urine-based screening assay for the detection of TERT-mut is currently being pursued by our group and others. A small but significant number of bladder carcinomas are adenocarcinoma. The current study assesses the incidence of TERT-mut in primary adenocarcinomas of urinary bladder. A retrospective search of our institutional pathology records identified 23 cystectomy specimens with a diagnosis of adenocarcinoma (2000-2014). All slides were reviewed by a senior urologic pathologist to confirm tumor type and select a representative formalin-fixed, paraffin-embedded block for mutational analysis. Adequate material for DNA testing was available in 14 cases (7 enteric type and 7 not otherwise specified). TERT-mut sequencing analysis was performed using previously described SafeSeq technique. Overall, 28.5% of primary adenocarcinoma harbored TERT-mut. Interestingly, 57% of nonenteric adenocarcinomas were mutation positive, whereas none of the enteric-type tumors harbored mutations. Similar to urothelial carcinoma, we found a relatively higher rate of TERT-mut among nonenteric-type adenocarcinomas further supporting the potential utility of TERT-mut urine-based screening assay for bladder cancer.
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http://dx.doi.org/10.1016/j.humpath.2016.02.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5561423PMC
July 2016
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