A renal cell carcinoma tumorgraft platform to advance precision medicine.

Renal cell carcinoma (RCC) encompasses a heterogenous group of tumors, but representative preclinical models are lacking. We previously showed that patient-derived tumorgraft (TG) models recapitulate the biology and treatment responsiveness. Through systematic orthotopic implantation of tumor samples from 926 ethnically diverse individuals into non-obese diabetic (NOD)/severe combined immunodeficiency (SCID) mice, we generate a resource comprising 172 independently derived, stably engrafted TG lines from 148 individuals. TG lines are characterized histologically and genomically (whole-exome [n = 97] and RNA [n = 102] sequencing). The platform features a variety of histological and oncogenotypes, including TCGA clades further corroborated through orthogonal metabolomic analyses. We illustrate how it enables a deeper understanding of RCC biology; enables the development of tissue- and imaging-based molecular probes; and supports advances in drug development.

Deciphering Intratumoral Molecular Heterogeneity in Clear Cell Renal Cell Carcinoma with a Radiogenomics Platform.

PURPOSE: Intratumoral heterogeneity (ITH) challenges the molecular characterization of clear cell renal cell carcinoma (ccRCC) and is a confounding factor for therapy selection. Most approaches to evaluate ITH are limited by two-dimensional ex vivo tissue analyses. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) can noninvasively assess the spatial landscape of entire tumors in their natural milieu. To assess the potential of DCE-MRI, we developed a vertically integrated radiogenomics colocalization approach for multi-region tissue acquisition and analyses. We investigated the potential of spatial imaging features to predict molecular subtypes using histopathologic and transcriptome correlatives. EXPERIMENTAL DESIGN: We report the results of a prospective study of 49 patients with ccRCC who underwent DCE-MRI prior to nephrectomy. Surgical specimens were sectioned to match the MRI acquisition plane. RNA sequencing data from multi-region tumor sampling (80 samples) were correlated with percent enhancement on DCE-MRI in spatially colocalized regions of the tumor. Independently, we evaluated clinical applicability of our findings in 19 patients with metastatic RCC (39 metastases) treated with first-line antiangiogenic drugs or checkpoint inhibitors. RESULTS: DCE-MRI identified tumor features associated with angiogenesis and inflammation, which differed within and across tumors, and likely contribute to the efficacy of antiangiogenic drugs and immunotherapies. Our vertically integrated analyses show that angiogenesis and inflammation frequently coexist and spatially anti-correlate in the same tumor. Furthermore, MRI contrast enhancement identifies phenotypes with better response to antiangiogenic therapy among patients with metastatic RCC. CONCLUSIONS: These findings have important implications for decision models based on biopsy samples and highlight the potential of more comprehensive imaging-based approaches.

Mammary Paget's Disease of the Male Breast: A Rare Case With an Unusual Immunohistochemical Profile.

Mammary Paget's disease is rare and comprises about 0.62% of all breast cancer cases, only 1.65% of which occur in male patients. This case report involves a 76-year-old man who presented to his primary care physician with an itching, scaly, unilateral lesion involving the nipple skin. He underwent wide local excision of the lesion for a diagnosis of Bowen's disease (squamous cell carcinoma in situ). Histologic examination of the specimen revealed mammary Paget's disease with ductal carcinoma in situ in the underlying breast tissue. A panel of immunohistochemical stains revealed the Paget cells to be positive for cytokeratin 7, MUC1, GATA3, and androgen receptor and negative for cytokeratins 5/6, p63, SOX10, and MART-1/Melan-A. Paget cells were also negative for estrogen receptor and progesterone receptor, and positive for HER2/neu. However, the underlying ductal carcinoma in situ was positive for both estrogen receptor and progesterone receptor and negative for HER2/neu. This discordance, supported by the current literature, suggests an alternative etiology for Paget's disease in certain cases that cannot be explained by the well-established epidermotropic and transformative theories of Paget's disease evolution.

Improved Magnetic Resonance Imaging-Pathology Correlation With Imaging-Derived, 3D-Printed, Patient-Specific Whole-Mount Molds of the Prostate.

OBJECTIVES: The aim of this study was to compare the anatomical registration of preoperative magnetic resonance imaging (MRI) and prostate whole-mount obtained with 3D-printed, patient-specific, MRI-derived molds (PSM) versus conventional whole-mount sectioning (WMS). MATERIALS AND METHODS: Based on an a priori power analysis, this institutional review board-approved study prospectively included 50 consecutive men who underwent 3 T multiparametric prostate MRI followed by radical prostatectomy. Two blinded and independent readers (R1 and R2) outlined the contours of the prostate, tumor, peripheral, and transition zones in the MRI scans using regions of interest. These were compared with the corresponding regions of interest from the whole-mounted histopathology, the reference standard, using PSM whole-mount results obtained in the study group (n = 25) or conventional WMS in the control group (n = 25). The spatial overlap across the MRI and histology data sets was calculated using the Dice similarity coefficient (DSC) for the prostate overall (DSCprostate), tumor (DSCtumor), peripheral (DSCPZ), and transition (DSCTZ) zone. Results in the study and control groups were compared using Wilcoxon rank sum test. RESULTS: The MRI histopathology anatomical registration for the prostate gland overall, tumor, peripheral, and transition zones were significantly superior with the use of PSMs (DSCs for R1: 0.95, 0.86, 0.84, and 0.89; for R2: 0.93, 0.75, 0.78, and 0.85, respectively) than with the use of standard WMS (R1: 0.85, 0.46, 0.66, and 0.69; R2: 0.85, 0.46, 0.66, and 0.69) (P < 0.0001). CONCLUSIONS: The use of PSMs for prostate specimen whole-mount sectioning provides significantly superior anatomical registration of in vivo multiparametric MRI and ex vivo prostate whole-mounts than conventional WMS.