Detection ofin situmammary cancer in a transgenic mouse model:in vitroandin vivoMRI studies demonstrate histopathologic correlation

Abstract

Improving the prevention and detection of preinvasive ductal carcinoma in situ (DCIS) is expected to lower both morbidity and mortality from breast cancer. Transgenic mouse models can be used as a ‘test bed’ to develop new imaging methods and to evaluate the efficacy of candidate preventive therapies. We hypothesized that despite its microscopic size, early murine mammary cancer, including DCIS, might be accurately detected by MRI. C3(1) SV40 TAg female mice (n = 23) between 10 and 18 weeks of age were selected for study. Eleven mice were subjected to in vitro imaging using a T2-weighted spin echo sequence and 12 mice were selected for in vivo imaging using a T1-weighted gradient echo, a T2-weighted spin echo and high spectral and spatial resolution imaging sequences. The imaged glands were carefully dissected, formalin fixed and paraffin embedded, and then H&E stained sections were obtained. The ratio of image-detected versus histologically detected cancers was obtained by reviewing the MR images and H&E sections independently and using histology as the gold standard. MR images were able to detect 12/12 intramammary lymph nodes, 1/1 relatively large (~5 mm) tumor, 17/18 small (~1 mm) tumors and 13/16 ducts distended with DCIS greater than 300 μm. Significantly, there were no false positives—i.e., image detection always corresponded to a histologically detectable cancer in this model. These results indicate that MR imaging can reliably detect both preinvasive in situ and early invasive mammary cancers in mice with high sensitivity. This technology is an important step toward the more effective use of non-invasive imaging in pre-clinical studies of breast cancer prevention, detection and treatment.

Ductal Carcinoma in Situ: X-ray Fluorescence Microscopy and Dynamic Contrast-enhanced MR Imaging Reveals Gadolinium Uptake within Neoplastic Mammary Ducts in a Murine Model

“…Prior work has shown that MR imaging enables excellent morphologic evaluation of early murine mammary cancers (14). We have used DCE MR imaging to perform functional characterization of the contrast kinetics of murine DCIS, and-along with use of XFM-have demonstrated gadolinium uptake inside and along neoplastic mammary ducts.…”

“…Intramammary lymph nodes, invasive tumors, and ducts distended with DCIS that had a diameter larger than 300 m were identified and used as the reference standard. MR images were correlated with hematoxylin-eosin-stained slices by using an agar grid, as detailed in a prior report (14), to enable us to identify DCIS, invasive tumors, lymph nodes, and areas of normal mammary gland on the images. …”

T2* relaxation times of intraductal murine mammary cancer, invasive mammary cancer, and normal mammary gland

“…5,6 This is difficult in humans because single ducts containing pure DCIS can rarely be resolved in clinical MR images. Typical spatial resolution of clinical MRI is 1 mm in-plane with 2 mm thickness, and the spatial resolution is even lower when contrast enhanced MRI data are acquired with high temporal resolution.…”

In vivo MRI of early stage mammary cancers and the normal mouse mammary gland

“…Early stage murine mammary cancers are too small to be visible or palpable and thus in vivo imaging methods are required to assess longitudinal progression. However, relatively few previous reports have explored such imaging strategies (15–17). In particular, what is currently lacking is a minimally invasive screening examination that can quickly and reliably identify in situ and early invasive malignancies stochastically arising in any of the 10 mouse mammary glands, and accurately assess tumor morphology and volume over time.…”

“…In previous studies we developed MRI techniques to detect early stage murine mammary cancer with high sensitivity (17). While these techniques illustrated the potential for MRI to be a valuable tool for preclinical studies of early breast cancer, they would not be suitable as a screening examination as they could only be used to image two out of ten mammary glands using specialized instrumentation.…”