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Renal cell carcinoma with level IV tumor thrombus is a condition necessitating aggressive surgical management. Many solid organ malignancies often benefit from neoadjuvant treatments for tumor debulking and improvement of surgical outcomes. However, neoadjuvant treatments for renal cell carcinoma have been limited by its resistance to traditional chemotherapy and radiation. Emerging treatment modalities, such as immunotherapies, are exciting new options that may be therapeutically effective. The combination of nivolumab and ipilimumab has exhibited success in managing metastatic renal cell carcinoma. Limited data exist for its use in nonmetastatic renal cell carcinoma with tumor thrombus. This case illustrates the use of nivolumab and ipilimumab combination therapy in delaying tumor growth, producing observable tumor thrombus histologic and radiologic treatment changes, and, most importantly, facilitating a less invasive surgical approach of a level IV renal cell carcinoma tumor thrombus.

Development of malignancy is a rare complication following augmentation cystoplasty, and the majority of tumors observed in this setting are adenocarcinomas. Here, we sought to genetically profile these tumors by targeted DNA sequencing of a multi-institutional cohort of adenocarcinomas that developed in the urinary bladder following augmentation cystoplasty. Carcinomas arising in the urinary bladder of patients with history of augmentation cystoplasty were obtained from 4 major academic institutions, with cases diagnosed as urothelial carcinoma excluded from the study. The cases were analyzed using a DNA sequencing panel that includes 529 genes and genome-wide copy number assessment. The most frequently altered genes included TP53, KRAS, and MYC, and the vast majority of cases demonstrated mutational profiles consistent with gastrointestinal adenocarcinomas. One case demonstrated an EML4::ALK fusion together with an MSH3 frameshift mutation and hypermutated phenotype, characteristic of a rare but aggressive subtype of colorectal adenocarcinoma that may benefit from targeted ALK inhibition therapy. Importantly, six other tumors in the cohort also had potentially targetable molecular alterations, involving ATM (2 cases), BRCA1 (2 cases), EGFR (1 case), and ERBB2 (1 case). To our knowledge, this study represents the most comprehensive molecular characterization to date of adenocarcinomas arising in the urinary bladder following augmentation cystoplasty. Despite the unique environment of the augmented tissue, the resulting tumors demonstrate a spectrum of driver mutations similar to that of primary gastrointestinal adenocarcinomas. Importantly, molecular alterations potentially amenable to targeted therapy were identified in the majority of cases.

We evaluated the clinicopathologic and molecular characteristics of mostly incidentally detected, small, papillary renal neoplasms with reverse polarity (PRNRP). The cohort comprised 50 PRNRP from 46 patients, divided into 2 groups. The clinically undetected (5 mm) neoplasms (n = 34; 68%) had a median size of 1.1 mm (range 0.2-4.3 mm; mean 1.4 mm), and the clinically detected (≥5 mm) neoplasms (n = 16; 32%) which had a median size of 13 mm (range 9-30 mm; mean 16 mm). Neoplasms were positive for GATA3 (n = 47; 100%) and L1CAM (n = 34/38; 89%) and were negative for vimentin (n = 0/44; 0%) and, to a lesser extent, AMACR [(n = 12/46; 26%; weak = 9, weak/moderate = 3)]. KRAS mutations were found in 44% (n = 15/34) of the clinically undetected PRNRP and 88% of the clinically detected PRNRP (n = 14/16). The two clinically detected PRNRP with wild-type KRAS gene were markedly cystic and contained microscopic intracystic tumors. In the clinically undetected PRNRP, the detected KRAS mutations rate was higher in those measuring ≥1 mm vs1 mm [n = 14/19 (74%) vs n = 1/15 (7%)]. Overall, the KRAS mutations were present in exon 2-codon 12: c.35 G T (n = 21), c.34 G T (n = 3), c.35 G A (n = 2), c.34 G C (n = 2) resulting in p.Gly12Val, p. Gly12Asp, p.Gly12Cys and p.Gly12Arg, respectively. One PRNRP had a G12A/V/D complex mutation. Twenty-six PRNRP were concurrently present with other tumors of different histologic subtypes in the ipsilateral kidney; molecular testing of 8 of the latter showed wild-type KRAS gene despite the presence of KRAS mutations in 5 concurrent PRNRP. On follow up, no adverse pathologic events were seen (range 1-160 months; mean 44 months). In conclusion, the presence of KRAS mutations in small, clinically undetected PRNRP provides a unique finding to this entity and supports its being an early event in the development of these neoplasms.

Prostatic malakoplakia (MP) is rare, with only case reports and small series ( five patients) available in the literature. In this study we analysed an international multi-institutional series of 49 patients with prostatic MP to more clearly define its clinicopathological features. The median age was 67 years and the median serum prostate-specific antigen (PSA) was 7.5 ng/ml. MP was clinically manifest in most cases (28 of 45 patients with data available, 62%). Of 43 patients with detailed clinical history available, 21 (49%) had concurrent or metachronous malignancies (including prostate cancer). Diabetes or insulin resistance was present in 11 patients (26%). Additionally, three patients had a history of solid organ transplantation and one had HIV. Of note, six of 34 patients (18%) without concurrent prostate cancer had an abnormal digital rectal examination and/or lesions on magnetic resonance imaging (MRI) with prostate imaging reporting and data system (PIRADS) scores 4-5. The initial diagnosis was made on core biopsies (25 of 49, 51%), transurethal resection specimens (12 of 49, 24%), radical prostatectomies (10 of 49, 20%), Holmium-laser enucleation (one of 49, 2%) and cystoprostatectomy (one of 49, 2%). Tissue involvement was more commonly diffuse or multifocal (40 of 49, 82%). Von Kossa and periodic acid-Schiff stains were positive in 35 of 38 (92%) and 26 of 27 lesions (96%), respectively. Of note, two cases were received in consultation by the authors with a preliminary diagnosis of mesenchymal tumour/tumour of the specialised prostatic stroma. The present study suggests that prostatic MP is often associated with clinical findings that may mimic those of prostate cancer in a subset of patients. Moreover, MP may be found incidentally in patients with concurrent prostate cancer.

Metastases from primary prostate cancers to rare locations, such as the brain, are becoming more common due to longer life expectancy resulting from improved treatments. Epigenetic dysregulation is a feature of primary prostate cancer, and distinct DNA methylation profiles have been shown to be associated with the mutually exclusive SPOP-mutant or TMPRSS2-ERG fusion genetic backgrounds. Using a cohort of prostate cancer brain metastases (PCBM) from 42 patients, with matched primary tumors for 17 patients, we carried out a DNA methylation analysis to examine the epigenetic distinction between primary prostate cancer and PCBM, the association between epigenetic alterations and mutational background, and particular epigenetic alterations that may be associated with PCBM. Multiregion sampling of PCBM revealed epigenetic stability within metastases. Aberrant methylation in PCBM was associated with mutational background and PRC2 complex activity, an effect that is particularly pronounced in SPOP-mutant PCBM. While PCBM displayed a CpG island hypermethylator phenotype, hypomethylation at the promoters of genes involved in neuroactive ligand–receptor interaction and cell adhesion molecules such as GABRB3, CLDN8, and CLDN4 was also observed, suggesting that cells from primary tumors may require specific reprogramming to form brain metastasis. This study revealed the DNA methylation landscapes of PCBM and the potential mechanisms and effects of PCBM-associated aberrant DNA methylation.Significance:DNA methylation analysis reveals the molecular characteristics of PCBM and may serve as a starting point for efforts to identify and target susceptibilities of these rare metastases.

Supplementary Figures

Supplementary Figure Legends, Table Legends

Supplementary Tables S1 - S6. Supplementary Table S1. Patient clinical characteristics and summary of the observed molecular aberrations in the MTSCC cases studied. Supplementary Table S2. Sequencing quality metrics. Supplementary Table S3. Detailed list of somatic mutation calls in MTSCC cohort. Supplementary Table S4. Twenty three genes commonly regulated by PTPN14 siRNAs in the 3 cell lines identified by analysis of RNAseq data. (Supplementary Fig S4E). Supplementary Table S5. Geneset Enrichment analysis dataset details. Supplementary Table S6. Summary of immunohistochemistry staining results.

Supplementary Figures S1 - S8. Supplementary Figure S1. Intra-tumor mutational heterogeneity in MTSCC. Supplementary Figure S2. Copy number variation and Hippo pathway mutation in the MTSCC validation cohort and the TCGA KIRP outlier samples. Supplementary Figure S3. MTSCC Gene Expression Analyses. Supplementary Figure S4. PTPN14 function and Hippo pathway signature in kidney. Supplementary Figure S5. Gene set enrichment analysis. Supplementary Figure S6. HNF genes expression in normal human tissues, MTSCC and TCGA kidney cancer RNA-seq data. Supplementary Figure S7. Summary of YAP1 immunohistochemistry. Supplementary Figure S8. Gene expression correlation between MTSCC and nephron sections.

PDF file - 1288K, Distribution of genes with FPKM > 1. Genes are binned into deciles of percentage of samples in which the FPKM was > 1. Thus for a gene with FPKM > 1 in 65% of samples, the gene would be included in 60-70% bin. Y-axis is the number of genes in each decile.

PDF file - 2194K, RNAseq data from the IGFBP3 gene in the IGV browser for representative FFPE samples (top four tracks) and TCGA prostate samples (bottom three tracks) showing intronic reads.

XLSX file - 10K, Clinical characteristics of patients analyzed by RNAseq.

Supplemental Figure 3 Figure S3. Low power H&E images of wild-type, PTEN-/-, and PTEN-/-/SOX4-/- prostates.

XLSX file - 42K, Set of 894 genes with a univariate CoxPH q-value < 0.10 that were subjected to pathway enrichment and upstream analyses using Ingenuity Pathway Analysis (IPA).

XLSX file - 28K, RNA-QC, sequencing, and clinical metadata on the 106 samples sequenced in this study.

Supplemental Figure 2 Figure S2. Probasin-Cre mice (3) obtained from the NCI mouse repository were crossed to ROSA-lox-stop-lox-GFP mice (C57/BL6;129-ROSA26-Lox-Stop-Lox-EGFP (Charles River Laboratories)). Tissues were harvested from male mice after reaching sexual maturity at 8 weeks of age. GFP imaging of organs was performed on an Olympus OV-100 In Vivo Imaging System. Representative tissues from double transgenic mice are shown on the left, and from control mice on the right. Strong GFP signal was detected in pancreas and all three lobes of the prostate.

XLSX file - 14K, Set of most significantly enriched biological functions as deterermined by IPA analysis based on the gene list in Supplementary Table 5.

Supplemental Figure Legends

XLSX file - 9K, Summary of sequencing statistics from RNAseq analysis of 106 FFPE RNA samples.

PDF file - 766K, TaqMan validation of RNAseq data. Taqman Fold Change was calculated for three genes (PTN, SYNM, and TMSB10) and plotted against FPKM values.

Supplemental Figure 1 Figure S1. Breeding scheme for generation of prostate epithelium-specific Sox4 and Pten conditional double-knockout mice. Male PSA-CRE-ER/PTENfl/fl mice (1) were crossed with female Sox4fl/fl mice (2) and bred to homozygosity.

Understanding remains incomplete of the mechanisms underlying initiation and progression of prostate cancer, the most commonly diagnosed cancer in American men. The transcription factor SOX4 is overexpressed in many human cancers, including prostate cancer, suggesting it may participate in prostate tumorigenesis. In this study, we investigated this possibility by genetically deleting Sox4 in a mouse model of prostate cancer initiated by loss of the tumor suppressor Pten. We found that specific homozygous deletion of Sox4 in the adult prostate epithelium strongly inhibited tumor progression initiated by homozygous loss of Pten. Mechanistically, Sox4 ablation reduced activation of AKT and β-catenin, leading to an attenuated invasive phenotype. Furthermore, SOX4 expression was induced by Pten loss as a result of the activation of PI3K–AKT–mTOR signaling, suggesting a positive feedback loop between SOX4 and PI3K–AKT–mTOR activity. Collectively, our findings establish that SOX4 is a critical component of the PTEN/PI3K/AKT pathway in prostate cancer, with potential implications for combination-targeted therapies against both primary and advanced prostate cancers. Cancer Res; 76(5); 1112–21. ©2015 AACR.

XLSX file - 15K, Set of most significantly enriched canonical pathways as deterermined by IPA analysis based on the gene list in Supplementary Table 5.

XLSX file - 9K, Prediction Model based on Clinical Variables alone, namely, tGleason score, Log(prePSA + ), pStage, Surgical Margin Status, and Age.

XLSX file - 33K, Set of 304 genes differentially expressed between Gleason 3+4 pattern and Gleason 4+3 pattern patients based on DEseq analysis (p < 0.05).

PDF file - 1172K, Log2 FPKM+1 values are plotted for the six samples that were sequenced in duplicate. Plots include data for the 5265 detected genes used in the biomarker analysis. R-squared values are indicated for the best fit linear curve for each duplicate sample.

Secondary involvement of the prostate by urothelial or hematolymphoid neoplasms is relatively common and well-described. In contrast, less is known about the clinicopathologic spectrum of secondary solid tumors of the prostate of nonurothelial origin. This study evaluated a series of secondary nonurothelial solid tumors of the prostate diagnosed at 21 institutions. Eighty-five patients with a median age at diagnosis of 64 years were included. Sixty-two patients had clinically manifest disease (62/85, 73%), 10 were diagnosed incidentally (10/85, 12%), and 13 (13/85, 15%) had no detailed clinical data available about symptomatology at presentation. Among patients with clinically manifest disease, the most common symptoms and signs were lower urinary tract symptoms (either obstructive of irritative; 36/62, 58%), abdominal or pelvic pain or discomfort (16/62, 26%), and hematuria (12/62, 19%). Metastasis and direct invasion occurred at roughly similar frequencies (47% vs. 42%) in this series, and in 11% of the cases, the mechanism of spread to the prostate was unclear/uncertain. Overall, among tumors with confirmed sites of origin, the most common primary sites were gastrointestinal tract (53/85, 62%), lung (9/85, 11%), skin (6/85, 7%), and testis (4/85, 5%). Among metastases, the most common tumor types were lung carcinomas (9/40, 23%), colorectal adenocarcinomas (7/40, 18%), melanoma (6/40, 15%), and germ cell tumors (6/40, 15%). This study demonstrated that secondary involvement of the prostate by solid tumors of nonurothelial origin is commonly symptomatic and that the most frequent sites of origin are the gastrointestinal tract, lung, skin, and testis. These findings are worth considering when lesions with unusual cytomorphology and/or architecture are encountered in prostate specimens.

Metastases to the kidney are rare and were historically described in autopsy series, and the incidence ranged between 2.36% and 12.6%. However, in the contemporary literature with the improvements in imaging modalities (computed tomography scan and magnetic resonance imaging) and other health care screening services, metastatic tumors to the kidney are being diagnosed more frequently in surgical specimens. The utility of needle core biopsies in the primary evaluation of renal masses has also increased the number of sampled metastases, and as a result, only limited histologic material is available for evaluation in some cases and may potentially lead to diagnostic pitfalls. In the last decade, a few large clinical series have been published. In these series, the majority of metastatic tumors to the kidney are carcinomas, with the lung being the most common primary site. A significant number of the various tumor types with metastasis to the kidney are also associated with widespread metastases to other organs, and the renal metastasis may present several years after diagnosis of the primary tumor. The majority of secondary tumors of the kidney are asymptomatic, incidentally discovered, and solitary. There should be a high index of suspicion of metastasis to the kidney in patients with an associated enlarging renal lesion with minimal to no enhancement on imaging and tumor progression of a known high-grade nonrenal malignancy. Secondary tumors of the kidney can be accurately diagnosed by correlating histopathologic features with clinical and radiographic findings and the judicious use of ancillary studies.

Background: The need to better understand the molecular underpinnings of the heterogeneous outcomes of patients with prostate cancer is a pressing global problem and a key research priority for Movember. To address this, the Movember Global Action Plan 1 Unique tissue microarray (GAP1-UTMA) project constructed a set of unique and richly annotated tissue microarrays (TMA) from prostate cancer samples obtained from multiple institutions across several global locations. Methods: Three separate TMA sets were built that differ by purpose and disease state. Results: The intended use of TMA1 (Primary Matched LN) is to validate biomarkers that help determine which clinically localized prostate cancers with associated lymph node metastasis have a high risk of progression to lethal castration-resistant metastatic disease, and to compare molecular properties of high-risk index lesions within the prostate to regional lymph node metastases resected at the time of prostatectomy. TMA2 (Pre vs. Post ADT) was designed to address questions regarding risk of castration-resistant prostate cancer (CRPC) and response to suppression of the androgen receptor/androgen axis, and characterization of the castration-resistant phenotype. TMA3 (CRPC Met Heterogeneity)'s intended use is to assess the heterogeneity of molecular markers across different anatomic sites in lethal prostate cancer metastases. Conclusions: The GAP1-UTMA project has succeeded in combining a large set of tissue specimens from 501 patients with prostate cancer with rich clinical annotation. Impact: This resource is now available to the prostate cancer community as a tool for biomarker validation to address important unanswered clinical questions around disease progression and response to treatment.

The 8th Edition of the American Joint Committee on Cancer (AJCC) Staging Manual designates discontinuous involvement of spermatic cord soft tissue by testicular germ cell tumors as a metastatic deposit. We conducted a retrospective international multi-institutional study to validate the current recommendations. Thirty-three (72%) nonseminomatous and 13 (28%) seminomatous testicular germ cell tumors were collected from 15 institutions in America, Europe, and Asia. Testicular tumor size ranged from 1.3 to 18.0 cm (mean: 6.1). Cases were classified as discontinuous involvement of spermatic cord soft tissue (n = 26), continuous cord involvement (n = 17), or cord lymphovascular invasion (n = 3). The mean follow-up was 39 months. Clinical stage for discontinuous involvement of spermatic cord soft-tissue patients was I (local disease) in 2/24 (8%), II (regional disease) in 6/24 (25%), and III (distant disease) in 16/24 (67%) cases; 16 (67%) patients presented with distant metastasis. Clinical stage for continuous cord involvement patients was I in 9/17 (53%), II in 4/17 (23%), and III in 4/17 (23%); 4 (23%) patients presented with distant metastasis. Disease progression was seen in 4 patients with discontinuous involvement of spermatic cord soft tissue and 5 with continuous cord-involvement (p = 0.699). When comparing discontinuous and continuous cord involvement, a significant difference was found in cord margin status (p = 0.044), spermatic cord tumor size (p = 0.016), lymph-node involvement (p = 0.037), distant metastasis (p = 0.010), individual clinical stage (p = 0.003), and nonadvanced vs. advanced disease (p = 0.003) at presentation. In multivariate analysis, after adjusting for age, histology, testicular tumor size, percent of embryonal carcinoma, lymphovascular invasion, and cord margin status, discontinuous involvement of spermatic cord soft tissue was significantly associated (p = 0.011) with advanced clinical stage at presentation. Our findings support the designation of metastatic disease for discontinuous involvement of spermatic cord soft tissue, as introduced by the 8th edition of the AJCC staging.

AimsA subset of patients with urothelial carcinoma (UCa) and lamina propria (LP) invasion in bladder biopsies/transurethral resections (TURs) are at significant risk for recurrence and have increased rates of progression to UCa with muscularis propria (MP) invasion. The clinicopathologic features of this patient population has not been well characterised in the Pathology literature.MethodsWe performed a search through our urologic pathology files and expert consult cases of the senior author for bladder biopsies/TURs of UCa with LP invasion and variant/divergent histology from 2014 to 2020. Patients with a prior diagnosis of UCa with MP invasion or upper tract UCa were excluded. Clinicopathologic data were obtained.ResultsNinety-five patients with at least one biopsy/TUR of UCa with LP invasion and variant/divergent histology were identified. Mean patient age was 72 years (range: 46–92 years) with a male predominance 2.3:1. Initial variant/divergent histologies identified were: glandular (35.8%), squamous (23.2%), micropapillary (20%), clear cell/lipid rich (12.6%), diffuse/signet ring/plasmacytoid (10.5%), nested (9.5%), sarcomatoid (6.3%), poorly differentiated/anaplastic (4.2%), small cell (2.1%), lymphoepithelioma-like (2.1%), osteoclast-like giant cells (1.1%) and tumour giant cells (1.1%). Two or more variant histologies were identified in 18.9% of these cases. The rate of micropapillary UCa was significantly higher in multifocal tumours compared with unifocal tumours (37% vs 7.1%).ConclusionsIn our cohort of patients undergoing early repeat biopsy/TUR, 75% of patients had persistent UCa. Additionally, almost 25% of patients had a prior diagnosis of UCa without a variant/divergent histology identified. Our findings highlight the critical role of repeat biopsy/TUR especially in a subset of patients who have variant/divergent histology, even in the absence of MP invasion.

Background Clear cell adenocarcinoma of the lower urinary tract (CCACLUT) is a rare primary malignant neoplasm with heterogenous morphology. There is a paucity of data in the literature regarding its immunohistochemical profile. Methods The immunohistochemical features (extent and intensity) of a multinational cohort of CCACLUT were evaluated with comparison between clear cell adenocarcinoma of the female genital tract (CCACFGT, tissue microarray) and nephrogenic adenoma (NA). Results 33 CCACLUT (24 female, 9 male; mean age 59 years) were collected. CCACLUT most commonly arose from the urinary bladder (26/33, 78%), particularly from the trigone (10/33, 30.3%) followed by the urethra (8/33, 22%). All 12 NA cases were located at the urinary bladder, whereas the most common CCACFGT location was the ovary (29/56, 52%). None of the CCACLUT patients had, intestinal metaplasia, NA, or urothelial carcinoma. One patient had concurrent endometriosis of the sigmoid colon. Most frequently observed morphology in CCACLUT was papillary/tubulocystic (9/3; 27.3%), followed by papillary/tubular (6/33; 18.2%) and papillary/solid (5/33; 15.2%). GATA3 expression was significantly higher in CCACLUT (18/33, 54.5%) and NA (6/12, 50%), when compared to CCACFGT cases 6/56, 11.7%)(p = 0.001 and p = 0.022, respectively). The extent of GATA3 was significantly higher in CCACLUT group (19.2 ± 16.6%) than the other groups (9.6 ± 22.5% in NA and 2.6 ± 9% in CCACFGT group) (p = 0.001). 4/33 patients (12.1) had weak, 10/33 patients (30.3%) had moderate, and 4/33 patients (12.1%) had strong GATA3 intensity in CCACLUT group. In NA group, one patient (8.3%, 1/12) had weak, one patient (8.3%, 1/12) had moderate and 4 patients (33.3%, 4/12) had strong GATA3 intensity. Most cases (CCACLUT 29/33, 88%; NA 11/12, 92%; CCACFGT 46/56, 82.1%) had positive Napsin A expression, by which CCACLUT had significantly more cases with Napsin A expression (p = 0.034). p63 was consistently negative in all cases (30/33 (91.9%) CCACLUT; 12/12 (100%) NA; 42/56 (75%) CCACFGT. Ki67 (MIB) proliferation index was significantly higher in CCACLUT group (54.6 ± 21%) when compared to NA group (4.5 ± 2.7%) and CCACFGT group (35.5 ± 25.8%) (p = 0.001). Conclusion CCACLUT has consistent GATA3 expression, which may cause challenge in the diagnosis of urothelial carcinoma but can be used to distinguish CCACLUT from CCACFGT.

Primary urothelial carcinoma (UCa) of the urethra is relatively uncommon, and the underlying pathogenesis has not been well characterized, especially in the absence of concurrent UCa at other sites. A search for cases of primary UCa of the urethra was conducted. Patients with concurrent UCa of the renal pelvis, ureter, or bladder at the time of diagnosis of the primary tumor were excluded. Clinicopathologic and follow-up data were obtained. A total of 35 cases from 30 patients (27 male and 3 female) were included in the study. The mean patient age at the initial diagnosis was 71 years (range: 41-90 years). Cases were composed of high-grade UCa (26 of 35 = 74%), low-grade UCa (4 of 35 = 11%), and UCa in situ (5 of 35 = 14%). Invasion was present in 14 of 26 (54%) cases of high-grade UCa. Interestingly, 23 of 30 (77%) patients had a previous history of UCa including 7 (30%) cases with divergent differentiation or variant histology. Follow-up data were available in 23 patients with a mean duration of 26.7 months (range: 0.6-87 months). Eleven patients (31%) died of metastatic UCa. This is one of the largest studies to date of primary UCa of the urethra without concurrent UCa of the renal pelvis, ureter, or bladder. Previous history of UCa of the bladder, especially with divergent differentiation or variant histology is conceivably a key risk factor for developing subsequent primary UCa of the urethra. These findings are important for the development of surveillance protocols and therapeutic strategies.