Enhanced Sonographic Imaging to Diagnose Lymph Node Metastasis: Importance of Blood Vessel Volume and Density

Abstract

Lymph node size is an important variable in ultrasound diagnosis of lymph node metastasis. However, the size criterion often leads to oversight of tumor-positive lymph nodes within the range of "normal" size, such that more accurate diagnostic criteria for lymph node metastasis are required. In this study, we show how diagnosis of lymph node metastasis can be improved by evaluating changes in blood vessel volume and density using a novel contrast-enhanced high-frequency ultrasound (CE-HFUS) system with Sonazoid. An MRL/MpJ-lpr/lpr (MRL/lpr) mouse model of lymph node metastasis was used in which lymph nodes are similar in size to humans. Metastasis via lymphatic vessels to proper axillary lymph nodes (proper ALN) was induced by injection of tumor cells into the subiliac lymph nodes. Within 21 days of injection, significant increases in blood vessel volume and density, but no increases in the size of the proper ALNs, were observed. The increase in blood vessel density was confirmed with immunohistochemical analysis and was positively related to tumor cell proliferation as measured using bioluminescence imaging. Together, our results showed that alterations in blood vessel volume and density precede alterations in lymph node size in the early stages of lymph node metastasis. Detection of these changes by ultrasonography may offer new criteria for early diagnosis of lymph node metastasis. Cancer Res; 73(7); 2082-92. Ó2013 AACR.

Visualization of fluid drainage pathways in lymphatic vessels and lymph nodes using a mouse model to test a lymphatic drug delivery system

“…To improve diagnostic accuracy, it will be vital to establish a new set of diagnostic criteria for LN metastasis based on the development and use of high-resolution imaging techniques and specific contrast agents. Recently, we have demonstrated, using a novel contrast-enhanced high-frequency ultrasound system, that alterations in blood vessel volume and density precede alterations in LN size in the early stages of LN metastasis [12,25]. Detection of these changes by ultrasonography may offer new criteria for the early diagnosis of LN metastasis.…”

Activation of latent metastases in the lung after resection of a metastatic lymph node in a lymph node metastasis mouse model

“…Malignant fibrous histiocytoma-like KM-Luc/GFP cells, stably expressing a fusion of luciferase and enhanced-green fluorescent protein genes and C3H/He mouse mammary carcinoma cells (FM3A-Luc), stably expressing the Luc gene, were used [8,11]. The relative growth rates of KM-Luc/GFP and FM3A-Luc cells were 3.8/ day and 1.1/day, respectively.…”

“…Tumor development in the SiLN and metastasis to the PALN and lungs were detected using an in vivo bioluminescence imaging system (IVIS; Xenogen, USA) [11]. This procedure was carried out separately at 6 h, 3 days, 6 days and 9 days postinoculation of KM-Luc/GFP cells into the SiLN, and at 6 h, 3 days, 7 days, 14 days, 21 days and 28 days post-inoculation of FM3A-Luc cells into the SiLN.…”

What’s up in nanomedicine?

“…Animal models to investigate lymph node metastasis are limited and therefore treatment methods are not fully explored yet. In earlier work done by this group, animal models (mice; MXH10/Mo/lpr) were developed with lymph node sizes similar to those found in humans (10 mm in mice 2.5-3 months age) (6,7). When tumor cells are injected into the subiliac lymph nodes, metastasis in the proper axillary lymph can be introduced (7).…”