Rafael Jimenez - Academia.edu (original) (raw)

Papers by Rafael Jimenez

Research paper thumbnail of Re: Stanley Weng, Renzo G. DiNatale, Andrew Silagy, et al. The Clinicopathologic and Molecular Landscape of Clear Cell Papillary Renal Cell Carcinoma: Implications in Diagnosis and Management. Eur Urol 2021;79:468–77

Research paper thumbnail of Proteomic and Clinicopathologic Assessment of Penile Amyloidosis: A Single Institutional Review of 12 Cases

American Journal of Clinical Pathology

Objectives There is a paucity of data on penile amyloidosis. We aimed to assess the frequency of ... more Objectives There is a paucity of data on penile amyloidosis. We aimed to assess the frequency of different amyloid types in surgical specimens from the penis involved by amyloidosis and correlate relevant clinicopathologic parameters with proteomic findings. Methods Since 2008, our reference laboratory has performed liquid chromatography/tandem mass spectrometry (LC-MS/MS) for amyloid typing. The institutional pathology archive and reference laboratory database were queried to retrospectively identify all penile surgical pathology specimens with LC-MS/MS results between January 1, 2008, and November 23, 2022. Archived H&E-stained and Congo red–stained sections were re-reviewed. Results Twelve cases of penile amyloidosis were identified, which represented 0.35% (n = 3,456) of penile surgical specimens. AL-type amyloid was most frequent (n = 7), followed by keratin-type amyloid (n = 3) and ATTR (transthyretin)–type amyloid (n = 2). AL-type amyloid cases often showed diffuse dermal/lam...

Research paper thumbnail of Deepfake Histologic Images for Enhancing Digital Pathology

Research paper thumbnail of Penile squamous cell carcinoma exclusive to the shaft, with a proposal for a novel staging system

Research paper thumbnail of Lessons from histopathologic examination of nephrectomy specimens in patients with tuberous sclerosis complex: cysts, angiomyolipomas, and renal cell carcinoma

Research paper thumbnail of Reply to Yang Zhao, Wenda Wang, and Yushi Zhang’s Letter to the Editor re: Sounak Gupta, Christine M. Lohse, Ross Rowsey, et al. Renal Neoplasia in Polycystic Kidney Disease: An Assessment of Tuberous Sclerosis Complex–associated Renal Neoplasia and PKD1/TSC2 Contiguous Gene Deletion Syndrome. Eu...

Research paper thumbnail of Renin Production by Juxtaglomerular Cell Tumors and Clear Cell Renal Cell Carcinoma and the Role of Angiotensin Signaling Inhibitors

Research paper thumbnail of Cytogenetics of spermatocytic tumors with a discussion of gain of chromosome 12p in anaplastic variants

Human Pathology

Most spermatocytic tumors (ST) have an excellent prognosis. In rare instances metastatic disease ... more Most spermatocytic tumors (ST) have an excellent prognosis. In rare instances metastatic disease has been documented. However, it is unclear if aggressive tumors have specific molecular alterations. Herein, we have studied primary ST with (n=4) and without (n=3) "anaplastic" features, including single nucleotide polymorphism microarrays for 5 ST (non-anaplastic: 3; anaplastic: 2). The mean age at orchiectomy and tumor size was 49 years and 6.5 cm, respectively. Lymphovascular invasion and necrosis were identified in 3 (of 4, 75%) "anaplastic" ST, including one with clinically metastatic disease and one with locally aggressive disease. None of the cases in this study exhibited sarcomatoid change. The mean mitotic count was higher in "anaplastic" tumors (59/10 versus 10/10 high power fields). All ST in this study were positive for SALL4 and CD117 and negative for OCT3/4 and CD30 (7/7, 100%). SSX-C positivity was identified in all but the locally aggressive "anaplastic" ST (5 of 6, 83%). All ST showed a consistent gain of chromosome 9 including the locus for the DMRT1 gene (5 of 5 cases, 100%), while gains of chromosome 12p were only seen in 2 (of 2) "anaplastic" variants. Gains of 12p in "anaplastic" ST may represent a biomarker of transformation into more aggressive tumors. Alternatively, ST with gain of 12p may represent an intermediate state between type II and type III germ cell tumors. Future studies are needed to validate whether gain of 12p is a consistent feature of ST with "anaplastic" morphology and its association with aggressive clinical behavior.

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

Urologic Oncology: Seminars and Original Investigations, 2021

Purpose: To survey urologic clinicians regarding interpretation of and practice patterns in relat... more 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 imagingtargeted 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.

Research paper thumbnail of Renal Neoplasia in Polycystic Kidney Disease: An Assessment of Tuberous Sclerosis Complex–associated Renal Neoplasia and PKD1/TSC2 Contiguous Gene Deletion Syndrome

European Urology, 2021

To determine the incidence of renal neoplasia among patients undergoing nephrectomy for polycysti... more To determine the incidence of renal neoplasia among patients undergoing nephrectomy for polycystic kidney disease (PKD), we queried our institutional nephrectomy registry (years 2000-2020). Approximately 4% (231 of 5757) of patients who underwent nephrectomy had PKD, and 26 of these 231 patients (11.3%) had renal neoplasia. Tumors from an additional two patients with PKD were also evaluated. Patients with PKD who had tuberous sclerosis complex (TSC)-associated renal neoplasia were screened for PKD1/TSC2 contiguous gene deletion syndrome (CGS) using single nucleotide polymorphism arrays. The median age of patients with PKD and renal neoplasia at nephrectomy was 54 yr. The median tumor size was 2.0 cm and the tumors were predominantly of low grade and stage. The tumors consisted of 23 renal cell carcinomas (RCCs), one epithelioid angiomyolipoma, and four angiomyolipomas. The median follow-up was 59.5 mo (n = 26) and only one patient with clear cell RCC developed metastases. Two patients with angiomyolipomas had PKD1/TSC2 CGS. Our results support screening of patients with PKD and TSC-associated renal neoplasia as well as TSC patients with cystic renal disease for CGS, as identification of patients with CGS can better define the manifestation and prognosis of CGS and guide counseling regarding patterns of inheritance. PATIENT SUMMARY: We identified patients with abnormal kidney cell growth (called renal neoplasia) among those undergoing removal of kidney tissue for polycystic kidney disease (PKD) and patients with a syndrome involving deletions in two genes, called PKD1/TSC2 contiguous gene deletion syndrome (CGS) at our institution. Of 231 PKD patients with removal of kidney tissue, 11.3% had renal neoplasia, and two patients with angiomyolipoma tumors had PKD1/TSC2 CGS. Detection of renal neoplasia associated with a condition called tuberous sclerosis complex in PKD may increase the identification of patients with PKD1/TSC2 CGS and guide patient counseling regarding outcomes and patterns of inheritance.

Research paper thumbnail of A contemporary guide to chromosomal copy number profiling in the diagnosis of renal cell carcinoma

Urologic Oncology: Seminars and Original Investigations, 2021

The routine clinical implementation of molecular methods other than fluorescence in situ hybridiz... more The routine clinical implementation of molecular methods other than fluorescence in situ hybridization in the evaluation of renal neoplasia is currently limited, as the current standard of care primarily involves a combination of morphologic and immunophenotypic analysis of such tumors. Amongst various molecular techniques, global copy number profiling using single nucleotide polymorphism-based microarrays, colloquially referred to as SNP-arrays, is being increasingly utilized to profile renal tumors, as several subtypes have characteristic recurrent patterns of copy number alterations. Recurrent copy number alterations in common tumor types include loss of chromosome 3p in clear cell renal cell carcinoma (RCC), gain of chromosomes 7 and 17 in papillary RCC and multiple losses in chromosomes 1, 2, 6, 10, 13, 17, and 21 in chromophobe RCC. Such assays are being increasingly utilized in the clinical setting. Herein, we discuss some common clinical applications of such testing that includes high yield diagnostic and prognostic applications. Diagnostic utility includes evaluation of tumor types that are primarily defined by underlying copy number alterations, establishing the underlying subtype in high grade dedifferentiated (unclassified) renal tumors, as well as assessment of loss of heterozygosity, which is an important component in the workup for germline alterations in tumor suppressor genes. Universal adoption of these techniques across clinical laboratories will likely be significantly affected by variables such as cost, reimbursement, and turnaround time.

Research paper thumbnail of Secondary renal neoplasia following chemotherapy or radiation in pediatric patients

Human Pathology, 2020

This is a PDF file of an article that has undergone enhancements after acceptance, such as the ad... more This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Research paper thumbnail of Renal Neoplasia in Tuberous Sclerosis: A Study of 41 Patients

Mayo Clinic Proceedings, 2021

OBJECTIVE To study the clinical features and identify unique renal neoplasia subtypes and their p... more OBJECTIVE To study the clinical features and identify unique renal neoplasia subtypes and their prognostic implications in individuals with tuberous sclerosis complex (TSC). PATIENTS AND METHODS The Mayo Clinic nephrectomy registry included 37 patients with TSC diagnosed between 1970 and 2018. Four additional patients were identified from the pathology consultation and autopsy files. All available renal tumors were further characterized using immunohistochemistry and fluorescence in situ hybridization. Clinicopathologic features and follow-up were obtained from the medical record. The American Association for Cancer Research Project GENIE registry was accessed using cBioPortal for molecular profiling of angiomyolipoma (AML). RESULTS A total of 276 renal tumors from 41 patients were analyzed. Renal tumors were classified into 9 distinct morphological subtypes, with AML predominating (238 [86%]). Interestingly, all these tumors acted in a benign fashion except one renal cell carcinoma with clear cells and fibromyomatous stroma and one epithelioid AML that metastasized. Molecular profiling studies revealed that epithelioid AMLs were enriched for alterations of TP53, RB1, and ATRX. Eight patients died of direct complications of TSC, including 3 of end-stage renal disease. To date, none have died of a renal epithelial neoplasm. CONCLUSION The identification of unique renal neoplasia subtypes may provide important clues to establish a diagnosis of TSC, and in the somatic setting, this finding has important implications for accurate prognostication. These tumors tend to be indolent, and only 2 of 276 tumors in our study exhibited metastatic behavior. Our results support multidisciplinary management with a focus on preservation of renal function.

Research paper thumbnail of Low-Grade Oncocytic Tumor of Kidney (CK7-Positive, CD117-Negative): Incidence in a single institutional experience with clinicopathological and molecular characteristics

Human Pathology, 2021

AIMS Low-grade oncocytic tumor of the kidney (LOT) is characterized by cytoplasmic eosinophilia a... more AIMS Low-grade oncocytic tumor of the kidney (LOT) is characterized by cytoplasmic eosinophilia and a CK7-positive/CD117-negative immunophenotype. Morphologically, they exhibit overlapping features with oncocytoma and chromophobe renal cell carcinoma (chRCC). Our aim was to obtain long-term clinical follow-up data, clinicopathological and molecular characteristics, and incidence of LOT. METHODS Tissue microarrays were constructed from 574 tumors historically diagnosed as oncocytoma and surgically treated at Mayo Clinic between 1970 and 2012, and immunostained for CK7 and CD117. An extended immunophenotype was obtained on whole slide sections, along with FISH for CCND1 rearrangement status and chromosomal microarray for copy number status. Additionally, two cases were retrospectively identified in a set of tuberous sclerosis complex (TSC)-associated neoplasms and three more cases diagnosed on needle core biopsies were obtained during routine clinical practice. RESULTS Twenty-four cases of LOT were identified amongst 574 consecutive tumors diagnosed as oncocytoma and treated with partial or radical nephrectomy, corresponding to an incidence of 4.18% of tumors historically diagnosed as oncocytomas, and 0.35% of 6944 nephrectomies performed between 1970 and 2012. Overall, 29 cases of LOT were identified in three clinical settings: sporadic, TSC-associated, and end-stage renal disease (ESRD). Multifocality was seen only in the setting of TSC and ESRD. No metastases attributable to LOT were identified (median follow up 9.6 years). There were no recurrent arm level copy number changes detected by chromosomal microarray and all tested cases were negative for CCND1 rearrangement by FISH. CONCLUSIONS LOT is an uncommon eosinophilic renal neoplasm with an indolent prognosis that constitutes ∼ 4% of tumors historically diagnosed as oncocytoma. The morphologic, immunophenotypic, and molecular features of this neoplasm suggest it is a distinct entity of renal neoplasia.

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

Archives of Pathology & Laboratory Medicine, 2020

Context.— Controversies and uncertainty persist in prostate cancer grading. Objective.— To update... more 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...

Research paper thumbnail of Incidence of succinate dehydrogenase and fumarate hydratase–deficient renal cell carcinoma based on immunohistochemical screening with SDHA/SDHB and FH/2SC

Human Pathology, 2019

Mutations of the succinate dehydrogenase (SDHX) enzyme subunits commonly lead to a loss of functi... more Mutations of the succinate dehydrogenase (SDHX) enzyme subunits commonly lead to a loss of function of the holoenzyme complex, and germline SDHX mutations lead to a genetic predisposition to SDH-deficient neoplasms, including renal cell carcinomas (RCC). Similarly, loss of function alterations of fumarate hydratase (FH) leads to a genetic predisposition to hereditary leiomyomatosis and renal cell cancer (HLRCC)-associated RCC. Loss of FH leads to an accumulation of fumarate and aberrantly high levels of S-(2-succino)-cysteine (2SC). Subtype-specific consecutively diagnosed renal cell neoplasms were selected for the study and cases were not otherwise selected based on clinicopathologic features. Tissue Microarrays were constructed from 1009 renal cell neoplasms [papillary: 400, clear cell: 203, chromophobe: 87, oncocytomas (original diagnosis): 273, unclassified: 46] and these cases were immunostained for SDHA/SDHB to screen for SDH loss. A smaller subset (n=730; oncocytomas, papillary and unclassified RCCs) were screened for FH-deficiency using immunohistochemistry for FH/2SC. Loss of SDHA/SDHB was seen in three of 273 tumors originally diagnosed as oncocytomas (1.1%). Diffuse nuclear and cytoplasmic 2SC staining, with retained FH expression was seen in one case (suggestive of dysfunctional FH protein), while absent FH was seen in 3 cases (2/400 papillary RCCs, 0.5% and 2/46 unclassified RCCs, 4.35%). No aberrant FH/2SC expression was noted in 273 cases originally diagnosed as oncocytomas. SDH-deficient RCCs were identified only in the cases originally diagnosed as oncocytomas (1.1%), while FH-deficient RCCs were identified in the papillary (0.5%) and unclassified RCC cohorts (4.35%). These results can help guide immunohistochemistry-based screening strategies for these tumors.

Research paper thumbnail of Prognostic significance of lymphatic, vascular and perineural invasion for bladder cancer patients treated by radical cystectomy

Pathology, 2017

In radical cystectomy specimens with bladder cancer, lymphatic and vascular invasion are often re... more In radical cystectomy specimens with bladder cancer, lymphatic and vascular invasion are often reported as 'angiolymphatic' or 'lymphovascular' invasion, terms that combine the findings of tumour within simple endothelial-lined lymphatic spaces and tumour within muscle-lined blood vessels. It is unclear if these patterns of invasion have different prognostic significance. In addition, there are conflicting data regarding the significance of lymphatic, vascular and perineural invasion in patients with bladder cancer. Herein, we studied 1504 patients treated by radical cystectomy for bladder cancer at our institution and followed for a mean of 10.6 years. Cases were re-reviewed by a urological pathologist for lymphatic invasion defined as tumour within a non-muscle-lined endothelial-lined lymphatic space, vascular invasion defined as tumour in a muscle-lined blood vessel, and perineural invasion defined as tumour within the perineural sheath. Associations of clinical a...

Research paper thumbnail of High grade neuroendocrine carcinoma of the urinary bladder treated by radical cystectomy: a series of small cell, mixed neuroendocrine and large cell neuroendocrine carcinoma

Pathology, 2015

High grade neuroendocrine carcinomas (HGNEC) treated by cystectomy often carry an original diagno... more High grade neuroendocrine carcinomas (HGNEC) treated by cystectomy often carry an original diagnosis of typical urothelial carcinoma (UC). The correct diagnosis of HGNEC is critical in influencing the decision for early chemotherapy, potentially followed by cystectomy. The objective of this study was to characterise the features of HGNEC treated by radical cystectomy. The study consisted of 79 patients with HGNEC including small cell (68 patients), large cell neuroendocrine (LCNEC) (5 patients) and mixed neuroendocrine (mixed-NEC) carcinoma (6 patients) matched with 122 patients with UC, treated at our institution between 1987 and 2014. Morphometric analysis for cell and nuclear size as well as immunophenotyping for neuroendocrine markers and cell-cycle regulators were applied to tissue microarrays. Small cell, LCNEC and mixed-NEC are a morphological spectrum of high grade neuroendocrine carcinoma with overlapping histological features, identical immunophenotype, Ki-67 proliferative rate and patient outcomes. Finally, the nuclear size criteria is misleading as HGNEC, particularly cases of LCNEC and mixed-NEC, may have enlarged nuclei compared to small cell carcinomas and are more prone to be misdiagnosed as UC, thereby preventing appropriate management.

Research paper thumbnail of Flat urothelial carcinoma in situ of the bladder with glandular differentiation

Human Pathology, 2011

We present the clinicopathologic and immunonohistochemical features of 25 cases of flat urothelia... more We present the clinicopathologic and immunonohistochemical features of 25 cases of flat urothelial carcinoma in situ with glandular differentiation. Previously, cases on this category have been reported as in situ adenocarcinoma (a term not currently preferred). Fourteen of 25 cases had concurrent conventional urothelial carcinoma in situ. Five of the cases were primary carcinoma in situ with glandular differentiation; twenty cases of secondary carcinoma in situ with glandular differentiation were associated with urothelial carcinoma alone (n = 11) or with glandular differentiation (n = 7), discohesive (n = 1) or micropapillary carcinoma (n = 1). The individual tumor cells were columnar. The architectural pattern of the carcinoma in situ with glandular differentiation consisted of 1 or more papillary, flat or cribriform glandular patterns. Univariate statistical analysis showed no survival differences between urothelial carcinoma in situ with glandular differentiation and conventional urothelial carcinoma in situ (log-rank 0.810; P = .368). Carcinoma in situ with glandular differentiation showed high ki-67 index and p53 accumulation, high nuclear and cytoplasmic p16 expression and diffuse PTEN expression, a phenotype that also characterized concurrent conventional carcinoma in situ. MUC5A, MUC2, CK20, and c-erbB2 were positive in all 25 cases of urothelial carcinoma in situ with glandular differentiation, and CDX-2 was present in 19 cases; MUC1, CK7, or 34βE12 was focally present in 21, 19, and 18 cases, respectively. MUC1core was negative in all cases. We concluded that urothelial carcinoma in situ with glandular differentiation is a variant of carcinoma in situ that follows the natural history of conventional urothelial carcinoma in situ. The immunophenotype suggests urothelial origin with the expression of MUC5A and CDX2 as signature for glandular differentiation.

Research paper thumbnail of Relationship of Cytokeratin 20 and CD44 Protein Expression with WHO/ISUP Grade in pTa and pT1 Papillary Urothelial Neoplasia

Modern Pathology, 2000

The aim of this study was to assess the relationship of immunoreactivity of cytokeratin 20 (CK20)... more The aim of this study was to assess the relationship of immunoreactivity of cytokeratin 20 (CK20) and CD44 across the spectrum of urothelial neoplasia using the WHO/ISUP consensus classification. A total of 120 papillary urothelial pTa and pT1 tumors (8 papillomas, 8 neoplasms of low malignant potential, and 42 low-grade and 62 high-grade carcinomas) were immunostained by using CK20 and CD44 antibodies. The relationships of tumor grade, pathologic stage, recurrences, and progression in stage with CK20 and CD44 immunoreactivity were assessed. WHO/ISUP grade correlated with tumor stage (P < 0.005), recurrence (P ‫؍‬ 0.02), and progression in stage (P ‫؍‬ 0.031). Normal urothelium showed CK20 immunoreactivity restricted to a few umbrella cells. Expression of CD44 in normal urothelium was restricted to the basal cell layer. Loss of CD44 immunoreactivity and increasing CK20 positivity were significantly associated with increasing tumor grade and stage (P < 0.005). An inverse relationship was observed in the staining patterns of CK20 and CD44 within individual cases, as well as in the aggregate data, with 79.2% of tumors with CD44 loss showing CK20 positivity (P < 0.001). In conclusion, CK20 and CD44 immunoreactivity are significantly related to the WHO/ISUP grade and to each other, and our data suggest their potential combined utility in predicting biologic behavior in patients with papillary urothelial pTa and pT1 neoplasms.

Research paper thumbnail of Re: Stanley Weng, Renzo G. DiNatale, Andrew Silagy, et al. The Clinicopathologic and Molecular Landscape of Clear Cell Papillary Renal Cell Carcinoma: Implications in Diagnosis and Management. Eur Urol 2021;79:468–77

Research paper thumbnail of Proteomic and Clinicopathologic Assessment of Penile Amyloidosis: A Single Institutional Review of 12 Cases

American Journal of Clinical Pathology

Objectives There is a paucity of data on penile amyloidosis. We aimed to assess the frequency of ... more Objectives There is a paucity of data on penile amyloidosis. We aimed to assess the frequency of different amyloid types in surgical specimens from the penis involved by amyloidosis and correlate relevant clinicopathologic parameters with proteomic findings. Methods Since 2008, our reference laboratory has performed liquid chromatography/tandem mass spectrometry (LC-MS/MS) for amyloid typing. The institutional pathology archive and reference laboratory database were queried to retrospectively identify all penile surgical pathology specimens with LC-MS/MS results between January 1, 2008, and November 23, 2022. Archived H&E-stained and Congo red–stained sections were re-reviewed. Results Twelve cases of penile amyloidosis were identified, which represented 0.35% (n = 3,456) of penile surgical specimens. AL-type amyloid was most frequent (n = 7), followed by keratin-type amyloid (n = 3) and ATTR (transthyretin)–type amyloid (n = 2). AL-type amyloid cases often showed diffuse dermal/lam...

Research paper thumbnail of Deepfake Histologic Images for Enhancing Digital Pathology

Research paper thumbnail of Penile squamous cell carcinoma exclusive to the shaft, with a proposal for a novel staging system

Research paper thumbnail of Lessons from histopathologic examination of nephrectomy specimens in patients with tuberous sclerosis complex: cysts, angiomyolipomas, and renal cell carcinoma

Research paper thumbnail of Reply to Yang Zhao, Wenda Wang, and Yushi Zhang’s Letter to the Editor re: Sounak Gupta, Christine M. Lohse, Ross Rowsey, et al. Renal Neoplasia in Polycystic Kidney Disease: An Assessment of Tuberous Sclerosis Complex–associated Renal Neoplasia and PKD1/TSC2 Contiguous Gene Deletion Syndrome. Eu...

Research paper thumbnail of Renin Production by Juxtaglomerular Cell Tumors and Clear Cell Renal Cell Carcinoma and the Role of Angiotensin Signaling Inhibitors

Research paper thumbnail of Cytogenetics of spermatocytic tumors with a discussion of gain of chromosome 12p in anaplastic variants

Human Pathology

Most spermatocytic tumors (ST) have an excellent prognosis. In rare instances metastatic disease ... more Most spermatocytic tumors (ST) have an excellent prognosis. In rare instances metastatic disease has been documented. However, it is unclear if aggressive tumors have specific molecular alterations. Herein, we have studied primary ST with (n=4) and without (n=3) "anaplastic" features, including single nucleotide polymorphism microarrays for 5 ST (non-anaplastic: 3; anaplastic: 2). The mean age at orchiectomy and tumor size was 49 years and 6.5 cm, respectively. Lymphovascular invasion and necrosis were identified in 3 (of 4, 75%) "anaplastic" ST, including one with clinically metastatic disease and one with locally aggressive disease. None of the cases in this study exhibited sarcomatoid change. The mean mitotic count was higher in "anaplastic" tumors (59/10 versus 10/10 high power fields). All ST in this study were positive for SALL4 and CD117 and negative for OCT3/4 and CD30 (7/7, 100%). SSX-C positivity was identified in all but the locally aggressive "anaplastic" ST (5 of 6, 83%). All ST showed a consistent gain of chromosome 9 including the locus for the DMRT1 gene (5 of 5 cases, 100%), while gains of chromosome 12p were only seen in 2 (of 2) "anaplastic" variants. Gains of 12p in "anaplastic" ST may represent a biomarker of transformation into more aggressive tumors. Alternatively, ST with gain of 12p may represent an intermediate state between type II and type III germ cell tumors. Future studies are needed to validate whether gain of 12p is a consistent feature of ST with "anaplastic" morphology and its association with aggressive clinical behavior.

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

Urologic Oncology: Seminars and Original Investigations, 2021

Purpose: To survey urologic clinicians regarding interpretation of and practice patterns in relat... more 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 imagingtargeted 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.

Research paper thumbnail of Renal Neoplasia in Polycystic Kidney Disease: An Assessment of Tuberous Sclerosis Complex–associated Renal Neoplasia and PKD1/TSC2 Contiguous Gene Deletion Syndrome

European Urology, 2021

To determine the incidence of renal neoplasia among patients undergoing nephrectomy for polycysti... more To determine the incidence of renal neoplasia among patients undergoing nephrectomy for polycystic kidney disease (PKD), we queried our institutional nephrectomy registry (years 2000-2020). Approximately 4% (231 of 5757) of patients who underwent nephrectomy had PKD, and 26 of these 231 patients (11.3%) had renal neoplasia. Tumors from an additional two patients with PKD were also evaluated. Patients with PKD who had tuberous sclerosis complex (TSC)-associated renal neoplasia were screened for PKD1/TSC2 contiguous gene deletion syndrome (CGS) using single nucleotide polymorphism arrays. The median age of patients with PKD and renal neoplasia at nephrectomy was 54 yr. The median tumor size was 2.0 cm and the tumors were predominantly of low grade and stage. The tumors consisted of 23 renal cell carcinomas (RCCs), one epithelioid angiomyolipoma, and four angiomyolipomas. The median follow-up was 59.5 mo (n = 26) and only one patient with clear cell RCC developed metastases. Two patients with angiomyolipomas had PKD1/TSC2 CGS. Our results support screening of patients with PKD and TSC-associated renal neoplasia as well as TSC patients with cystic renal disease for CGS, as identification of patients with CGS can better define the manifestation and prognosis of CGS and guide counseling regarding patterns of inheritance. PATIENT SUMMARY: We identified patients with abnormal kidney cell growth (called renal neoplasia) among those undergoing removal of kidney tissue for polycystic kidney disease (PKD) and patients with a syndrome involving deletions in two genes, called PKD1/TSC2 contiguous gene deletion syndrome (CGS) at our institution. Of 231 PKD patients with removal of kidney tissue, 11.3% had renal neoplasia, and two patients with angiomyolipoma tumors had PKD1/TSC2 CGS. Detection of renal neoplasia associated with a condition called tuberous sclerosis complex in PKD may increase the identification of patients with PKD1/TSC2 CGS and guide patient counseling regarding outcomes and patterns of inheritance.

Research paper thumbnail of A contemporary guide to chromosomal copy number profiling in the diagnosis of renal cell carcinoma

Urologic Oncology: Seminars and Original Investigations, 2021

The routine clinical implementation of molecular methods other than fluorescence in situ hybridiz... more The routine clinical implementation of molecular methods other than fluorescence in situ hybridization in the evaluation of renal neoplasia is currently limited, as the current standard of care primarily involves a combination of morphologic and immunophenotypic analysis of such tumors. Amongst various molecular techniques, global copy number profiling using single nucleotide polymorphism-based microarrays, colloquially referred to as SNP-arrays, is being increasingly utilized to profile renal tumors, as several subtypes have characteristic recurrent patterns of copy number alterations. Recurrent copy number alterations in common tumor types include loss of chromosome 3p in clear cell renal cell carcinoma (RCC), gain of chromosomes 7 and 17 in papillary RCC and multiple losses in chromosomes 1, 2, 6, 10, 13, 17, and 21 in chromophobe RCC. Such assays are being increasingly utilized in the clinical setting. Herein, we discuss some common clinical applications of such testing that includes high yield diagnostic and prognostic applications. Diagnostic utility includes evaluation of tumor types that are primarily defined by underlying copy number alterations, establishing the underlying subtype in high grade dedifferentiated (unclassified) renal tumors, as well as assessment of loss of heterozygosity, which is an important component in the workup for germline alterations in tumor suppressor genes. Universal adoption of these techniques across clinical laboratories will likely be significantly affected by variables such as cost, reimbursement, and turnaround time.

Research paper thumbnail of Secondary renal neoplasia following chemotherapy or radiation in pediatric patients

Human Pathology, 2020

This is a PDF file of an article that has undergone enhancements after acceptance, such as the ad... more This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Research paper thumbnail of Renal Neoplasia in Tuberous Sclerosis: A Study of 41 Patients

Mayo Clinic Proceedings, 2021

OBJECTIVE To study the clinical features and identify unique renal neoplasia subtypes and their p... more OBJECTIVE To study the clinical features and identify unique renal neoplasia subtypes and their prognostic implications in individuals with tuberous sclerosis complex (TSC). PATIENTS AND METHODS The Mayo Clinic nephrectomy registry included 37 patients with TSC diagnosed between 1970 and 2018. Four additional patients were identified from the pathology consultation and autopsy files. All available renal tumors were further characterized using immunohistochemistry and fluorescence in situ hybridization. Clinicopathologic features and follow-up were obtained from the medical record. The American Association for Cancer Research Project GENIE registry was accessed using cBioPortal for molecular profiling of angiomyolipoma (AML). RESULTS A total of 276 renal tumors from 41 patients were analyzed. Renal tumors were classified into 9 distinct morphological subtypes, with AML predominating (238 [86%]). Interestingly, all these tumors acted in a benign fashion except one renal cell carcinoma with clear cells and fibromyomatous stroma and one epithelioid AML that metastasized. Molecular profiling studies revealed that epithelioid AMLs were enriched for alterations of TP53, RB1, and ATRX. Eight patients died of direct complications of TSC, including 3 of end-stage renal disease. To date, none have died of a renal epithelial neoplasm. CONCLUSION The identification of unique renal neoplasia subtypes may provide important clues to establish a diagnosis of TSC, and in the somatic setting, this finding has important implications for accurate prognostication. These tumors tend to be indolent, and only 2 of 276 tumors in our study exhibited metastatic behavior. Our results support multidisciplinary management with a focus on preservation of renal function.

Research paper thumbnail of Low-Grade Oncocytic Tumor of Kidney (CK7-Positive, CD117-Negative): Incidence in a single institutional experience with clinicopathological and molecular characteristics

Human Pathology, 2021

AIMS Low-grade oncocytic tumor of the kidney (LOT) is characterized by cytoplasmic eosinophilia a... more AIMS Low-grade oncocytic tumor of the kidney (LOT) is characterized by cytoplasmic eosinophilia and a CK7-positive/CD117-negative immunophenotype. Morphologically, they exhibit overlapping features with oncocytoma and chromophobe renal cell carcinoma (chRCC). Our aim was to obtain long-term clinical follow-up data, clinicopathological and molecular characteristics, and incidence of LOT. METHODS Tissue microarrays were constructed from 574 tumors historically diagnosed as oncocytoma and surgically treated at Mayo Clinic between 1970 and 2012, and immunostained for CK7 and CD117. An extended immunophenotype was obtained on whole slide sections, along with FISH for CCND1 rearrangement status and chromosomal microarray for copy number status. Additionally, two cases were retrospectively identified in a set of tuberous sclerosis complex (TSC)-associated neoplasms and three more cases diagnosed on needle core biopsies were obtained during routine clinical practice. RESULTS Twenty-four cases of LOT were identified amongst 574 consecutive tumors diagnosed as oncocytoma and treated with partial or radical nephrectomy, corresponding to an incidence of 4.18% of tumors historically diagnosed as oncocytomas, and 0.35% of 6944 nephrectomies performed between 1970 and 2012. Overall, 29 cases of LOT were identified in three clinical settings: sporadic, TSC-associated, and end-stage renal disease (ESRD). Multifocality was seen only in the setting of TSC and ESRD. No metastases attributable to LOT were identified (median follow up 9.6 years). There were no recurrent arm level copy number changes detected by chromosomal microarray and all tested cases were negative for CCND1 rearrangement by FISH. CONCLUSIONS LOT is an uncommon eosinophilic renal neoplasm with an indolent prognosis that constitutes ∼ 4% of tumors historically diagnosed as oncocytoma. The morphologic, immunophenotypic, and molecular features of this neoplasm suggest it is a distinct entity of renal neoplasia.

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

Archives of Pathology & Laboratory Medicine, 2020

Context.— Controversies and uncertainty persist in prostate cancer grading. Objective.— To update... more 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...

Research paper thumbnail of Incidence of succinate dehydrogenase and fumarate hydratase–deficient renal cell carcinoma based on immunohistochemical screening with SDHA/SDHB and FH/2SC

Human Pathology, 2019

Mutations of the succinate dehydrogenase (SDHX) enzyme subunits commonly lead to a loss of functi... more Mutations of the succinate dehydrogenase (SDHX) enzyme subunits commonly lead to a loss of function of the holoenzyme complex, and germline SDHX mutations lead to a genetic predisposition to SDH-deficient neoplasms, including renal cell carcinomas (RCC). Similarly, loss of function alterations of fumarate hydratase (FH) leads to a genetic predisposition to hereditary leiomyomatosis and renal cell cancer (HLRCC)-associated RCC. Loss of FH leads to an accumulation of fumarate and aberrantly high levels of S-(2-succino)-cysteine (2SC). Subtype-specific consecutively diagnosed renal cell neoplasms were selected for the study and cases were not otherwise selected based on clinicopathologic features. Tissue Microarrays were constructed from 1009 renal cell neoplasms [papillary: 400, clear cell: 203, chromophobe: 87, oncocytomas (original diagnosis): 273, unclassified: 46] and these cases were immunostained for SDHA/SDHB to screen for SDH loss. A smaller subset (n=730; oncocytomas, papillary and unclassified RCCs) were screened for FH-deficiency using immunohistochemistry for FH/2SC. Loss of SDHA/SDHB was seen in three of 273 tumors originally diagnosed as oncocytomas (1.1%). Diffuse nuclear and cytoplasmic 2SC staining, with retained FH expression was seen in one case (suggestive of dysfunctional FH protein), while absent FH was seen in 3 cases (2/400 papillary RCCs, 0.5% and 2/46 unclassified RCCs, 4.35%). No aberrant FH/2SC expression was noted in 273 cases originally diagnosed as oncocytomas. SDH-deficient RCCs were identified only in the cases originally diagnosed as oncocytomas (1.1%), while FH-deficient RCCs were identified in the papillary (0.5%) and unclassified RCC cohorts (4.35%). These results can help guide immunohistochemistry-based screening strategies for these tumors.

Research paper thumbnail of Prognostic significance of lymphatic, vascular and perineural invasion for bladder cancer patients treated by radical cystectomy

Pathology, 2017

In radical cystectomy specimens with bladder cancer, lymphatic and vascular invasion are often re... more In radical cystectomy specimens with bladder cancer, lymphatic and vascular invasion are often reported as 'angiolymphatic' or 'lymphovascular' invasion, terms that combine the findings of tumour within simple endothelial-lined lymphatic spaces and tumour within muscle-lined blood vessels. It is unclear if these patterns of invasion have different prognostic significance. In addition, there are conflicting data regarding the significance of lymphatic, vascular and perineural invasion in patients with bladder cancer. Herein, we studied 1504 patients treated by radical cystectomy for bladder cancer at our institution and followed for a mean of 10.6 years. Cases were re-reviewed by a urological pathologist for lymphatic invasion defined as tumour within a non-muscle-lined endothelial-lined lymphatic space, vascular invasion defined as tumour in a muscle-lined blood vessel, and perineural invasion defined as tumour within the perineural sheath. Associations of clinical a...

Research paper thumbnail of High grade neuroendocrine carcinoma of the urinary bladder treated by radical cystectomy: a series of small cell, mixed neuroendocrine and large cell neuroendocrine carcinoma

Pathology, 2015

High grade neuroendocrine carcinomas (HGNEC) treated by cystectomy often carry an original diagno... more High grade neuroendocrine carcinomas (HGNEC) treated by cystectomy often carry an original diagnosis of typical urothelial carcinoma (UC). The correct diagnosis of HGNEC is critical in influencing the decision for early chemotherapy, potentially followed by cystectomy. The objective of this study was to characterise the features of HGNEC treated by radical cystectomy. The study consisted of 79 patients with HGNEC including small cell (68 patients), large cell neuroendocrine (LCNEC) (5 patients) and mixed neuroendocrine (mixed-NEC) carcinoma (6 patients) matched with 122 patients with UC, treated at our institution between 1987 and 2014. Morphometric analysis for cell and nuclear size as well as immunophenotyping for neuroendocrine markers and cell-cycle regulators were applied to tissue microarrays. Small cell, LCNEC and mixed-NEC are a morphological spectrum of high grade neuroendocrine carcinoma with overlapping histological features, identical immunophenotype, Ki-67 proliferative rate and patient outcomes. Finally, the nuclear size criteria is misleading as HGNEC, particularly cases of LCNEC and mixed-NEC, may have enlarged nuclei compared to small cell carcinomas and are more prone to be misdiagnosed as UC, thereby preventing appropriate management.

Research paper thumbnail of Flat urothelial carcinoma in situ of the bladder with glandular differentiation

Human Pathology, 2011

We present the clinicopathologic and immunonohistochemical features of 25 cases of flat urothelia... more We present the clinicopathologic and immunonohistochemical features of 25 cases of flat urothelial carcinoma in situ with glandular differentiation. Previously, cases on this category have been reported as in situ adenocarcinoma (a term not currently preferred). Fourteen of 25 cases had concurrent conventional urothelial carcinoma in situ. Five of the cases were primary carcinoma in situ with glandular differentiation; twenty cases of secondary carcinoma in situ with glandular differentiation were associated with urothelial carcinoma alone (n = 11) or with glandular differentiation (n = 7), discohesive (n = 1) or micropapillary carcinoma (n = 1). The individual tumor cells were columnar. The architectural pattern of the carcinoma in situ with glandular differentiation consisted of 1 or more papillary, flat or cribriform glandular patterns. Univariate statistical analysis showed no survival differences between urothelial carcinoma in situ with glandular differentiation and conventional urothelial carcinoma in situ (log-rank 0.810; P = .368). Carcinoma in situ with glandular differentiation showed high ki-67 index and p53 accumulation, high nuclear and cytoplasmic p16 expression and diffuse PTEN expression, a phenotype that also characterized concurrent conventional carcinoma in situ. MUC5A, MUC2, CK20, and c-erbB2 were positive in all 25 cases of urothelial carcinoma in situ with glandular differentiation, and CDX-2 was present in 19 cases; MUC1, CK7, or 34βE12 was focally present in 21, 19, and 18 cases, respectively. MUC1core was negative in all cases. We concluded that urothelial carcinoma in situ with glandular differentiation is a variant of carcinoma in situ that follows the natural history of conventional urothelial carcinoma in situ. The immunophenotype suggests urothelial origin with the expression of MUC5A and CDX2 as signature for glandular differentiation.

Research paper thumbnail of Relationship of Cytokeratin 20 and CD44 Protein Expression with WHO/ISUP Grade in pTa and pT1 Papillary Urothelial Neoplasia

Modern Pathology, 2000

The aim of this study was to assess the relationship of immunoreactivity of cytokeratin 20 (CK20)... more The aim of this study was to assess the relationship of immunoreactivity of cytokeratin 20 (CK20) and CD44 across the spectrum of urothelial neoplasia using the WHO/ISUP consensus classification. A total of 120 papillary urothelial pTa and pT1 tumors (8 papillomas, 8 neoplasms of low malignant potential, and 42 low-grade and 62 high-grade carcinomas) were immunostained by using CK20 and CD44 antibodies. The relationships of tumor grade, pathologic stage, recurrences, and progression in stage with CK20 and CD44 immunoreactivity were assessed. WHO/ISUP grade correlated with tumor stage (P < 0.005), recurrence (P ‫؍‬ 0.02), and progression in stage (P ‫؍‬ 0.031). Normal urothelium showed CK20 immunoreactivity restricted to a few umbrella cells. Expression of CD44 in normal urothelium was restricted to the basal cell layer. Loss of CD44 immunoreactivity and increasing CK20 positivity were significantly associated with increasing tumor grade and stage (P < 0.005). An inverse relationship was observed in the staining patterns of CK20 and CD44 within individual cases, as well as in the aggregate data, with 79.2% of tumors with CD44 loss showing CK20 positivity (P < 0.001). In conclusion, CK20 and CD44 immunoreactivity are significantly related to the WHO/ISUP grade and to each other, and our data suggest their potential combined utility in predicting biologic behavior in patients with papillary urothelial pTa and pT1 neoplasms.