Intravenous Cellular MR Contrast Agent* with a Great Clinical Potential

Jelle Barentsz, M.D., Ph.D.
UMCN, Nijmegen, The Netherlands
 |  24-05-2006

Ultra small super paramagnetic iron oxide particles (ferumoxtran- 10) with a long plasma circulation time have been shown to be suitable as an MR contrast agent for intravenous MR lymphangiography [1, 2]. After IV injection, the ferumoxtran-10 particles are taken up by macrophages are transported to the interstitial space and from there through the lymph vessels to the lymph nodes (Fig. 2). Thus this contrast agent is cell specific (for macrophages).
Once within normally functioning nodes, the intracellular ferumoxtran- 10 within the macrophages reduces the signal intensity of normal node tissue, because of the T1 and T2*- susceptibility effect of iron oxide, thus producing a signal drop or negative enhancement.
In areas of lymph nodes that are involved with malignant cells, macrophages are replaced by cancer cells.
 

Fig. 1 Normal node and small positive node in 60-year-old male with prostate cancer.
Fig. 1A CT scan in semi-sagittal plane shows normal size (6 mm) node (circle).

 

Fig. 1B Post ferumoxtran-10 T1-weighted TSE MR image (which is insensitive to iron) shows 2 grey normal size nodes (circle, arrow).

 

Fig. 1C On post ferumoxtran-10 T2*- weighted MEDIC MR image (which is iron sensitive) one node is black (arrow) and the other one is white (circle). On histopathology the black node was normal and the white one was metastatic.

 

Optimal evaluation of post ferumoxtran-10 images should be done by comparing pre- with post-contrast MR images in the same plane. On the pre-contrast images the shape, the size, and the location of the nodes can be assessed. On the post-contrast MRI the signal intensity change can be evaluated. However, this requires two MRI examinations, which limits this technique. This problem can be solved by only performing a post-ferumoxtran-10 MR exam, using both a sequence which is insensitive for iron such as a T1- or proton weighted TSE sequence, and a sequence which is sensitive to iron. For the latter purpose a good sequence is a high resolution T2*-weighted MEDIC (TE ~18 ms). The T1/PW TSE sequences yield high resolution images without (susceptibility) artifacts, whereas the T2*-sequence gives information about the iron content of the nodes. It is, therefore, important to apply both sequences w.ith the same resolution and slice positioning parameters. In pelvic tumors (prostate cancer), this can be best done in a plane parallel to the psoas muscles (obturator, or semi-sagittal plane, Figure 1), and the axial plane, covering the para-aortic until the femoral region (Fig. 3). In the greadingh of the images, a one-by-one comparison gives the best results (Fig. 1). Incidentally in this way even a 2 mm metastatic node can be found (Fig. 3).

Fig. 3 58-year-old patient treated for prostate cancer with nodal recurrence. CT and MRI obtained 2 years after lymphadenectomy, prostatectomy and hormonal therapy. Now PSA increased from 0 to 1.8.

 

Fig. 3A CT scan in axial plane shows 3 normal size node (circle right 5 mm; circle left 2 mm).

 

Fig. 3B Post ferumoxtran-10 T1-weighted TSE MR image (which is insensitive to iron) shows the same 3 grey nodes (circles, arrow).

 

Fig. 3C On post ferumoxtran-10 T2*- weighted MEDIC MR image (which is iron sensitive) one node is black (arrow) and the other 2 are white (circles). On histopathology the black node was normal and the whites were metastatic.

Clinical value

When using high resolution MR-technique small metastases can be prospectively recognized in small (3–10 mm) size lymph nodes [5]. These small lymph nodes would be considered to be benign in plain MRI or CT examinations. In addition, hyperplastic enlarged nodes can be correctly recognized as non metastatic, based on their low signal intensity. This results in improved sensitivity (~ 90%), with remaining equal high specificity (~ 95%) in various tumors (Fig. 4) [5–8].

Fig. 5 55-year-old patient with breast cancer and positive lymph node.

Sagittal post ferumoxtran- 10 T2*-weighted MEDIC MR image shows one white (circle) and 2 dark nodes (arrows). The white node showed on histopathology metastases, the dark ones were normal.