Robert Sigal, MD

The clinical importance of tumor angiogenesis in primary breast cancer is well known. Studies have shown that intratumoral microvessel density is an independent prognostic indicator that correlates with a higher incidence of metastases.

Angiogenesis can be imaged by tracking the uptake and washout of contrast in tissue. Both CT and MR imaging agents have been used to explore this phenomenon in the breast. Contrast-enhanced breast MRI using gadolinium-based agents is considered the most sensitive imaging technique for breast cancer detection. MRI has limited specificity, however, and it is expensive. In Europe, there are not enough units to perform breast MRI every time it is necessary, and mammography thus remains the standard imaging tool for breast cancer screening.

Conventional mammography also has limitations, however. Its performance can be less than optimal for imaging dense breast tissue and/or fibrocystic disease and in follow-up examinations after breast-conserving therapy. The technology now available for full-field digital mammography (FFDM) examinations offers capabilities not provided by conventional screen-film systems.

Contrast-enhanced digital mammography (CEDM) combines the advantages of contrast-enhanced imaging with those of FFDM. Two techniques are under development: dynamic CEDM and dual-energy CEDM.

Dynamic CEDM involves the acquisition of high-energy digital mammography images before and after injection of iodinated contrast. Postcontrast images are subtracted from precontrast images to enhance visualization of lesions. The digital mammography unit must be adapted to maximize imaging sensitivity to low concentrations of iodine. This involves ensuring that x-rays have energies just above the K-edge of iodine (33.2 keV). Our digital mammography system (Senographe 2000D, GE Healthcare) has been modified accordingly by inserting a copper filter in the x-ray beam in addition to the usual molybdenum and rhodium filters. We also use voltages in the 45 to 49 kVp range for CEDM, compared with a range of 26 to 32 kVp for conventional digital mammography.

Patients must be settled comfortably to avoid motion. We use light breast compression that is strong enough to limit motion but not sufficient to reduce blood flow. All images are taken with the patient in the same position during a single breast compression. Choice of mAs depends on the thickness and composition of breast tissue.

The procedure begins with a single mask mammogram followed by monophasic intravenous injection of the iodinated contrast, preferably using a power injector at a high rate. Between five and 10 postcontrast images are acquired. The entire examination takes around 15 minutes and provides a patient dose of between 1 and 3 mGy, similar to the radiation dose from a conventional single-view mammogram.

During imaging analysis, corrections to breast motion must be made to minimize artifacts in subtracted images. Regions of interest are placed at areas of early enhancement and adjacent breast tissue to analyze the uptake and washout of contrast. Values of differential enhancement between lesions and normal breast tissue are then plotted against time.

Dual-energy CEDM exploits the energy dependence of x-ray attenuation components in mammography images. This radiographic technique uses the weighted subtraction of low- and high-energy digital images. Pairs of low- and high-energy images are acquired after contrast medium administration and then combined to enhance areas of contrast uptake.

The high-energy exposures require the digital mammography system to be adapted to permit high voltages. An additional filter material (aluminum or copper) should also be fitted. Low-energy images are acquired at a voltage of 30 kV. Mean time between the low- and high-energy images is 30 seconds.

We first acquire a standard mammogram during a single breast compression, either in the craniocaudal or mediolateral oblique projection. Iodinated contrast is then injected, again preferably using a power injector at a high rate, before the low- and high-energy images are acquired. Breast compression may be relaxed prior to the postcontrast imaging if this aids contrast administration. The examination duration ranges from five to 10 minutes depending on the number of projections. Total x-ray dose for a pair of low- and high-energy images is 0.7 mGy above that needed for conventional mammography.

Each CEDM technique has certain advantages and drawbacks.

Initial clinical use of these techniques is encouraging, confirming the ability of digital mammography to detect breast cancer angiogenesis. One study of dynamic CEDM in 22 patients scheduled for breast biopsies showed enhancement in eight out of 10 patients with histologically proven breast carcinoma.5 The two false-negative results corresponded to one case of ductal carcinoma in situ and one case of invasive ductal carcinoma. Among the 12 patients with a benign breast lesion, seven had no enhancement and five had nodular enhancement. These false-positive results corresponded to three cases of fibroadenoma and two cases of fibrocystic change with focal intraductal hyperplasia.

Another group has looked at dual-energy CEDM in 26 patients with suspicious breast lesions warranting biopsy.

 The researchers found strong enhancement in eight of the 14 malignant tumors, moderate enhancement in three, and weak enhancement in two. Among the 12 patients with benign tumors, 10 had no subjective enhancement and two had a weak enhancement. These two false-positive results corresponded to one case of atypical ductal carcinoma and one case of fibrocystic curve.

 Our study concentrated on 20 patients with suspicious breast abnormalities, all of whom had been referred to our institution for surgical resection. Histologic analysis of surgical specimens showed 22 malignant tumors (bifocal tumor in two patients). Sensitivity of dynamic CEDM for the detection of breast carcinoma was 80%. Correlation between the tumor size at histology and the size of enhancement measured on subtraction images was excellent (97%).

We had four false-positive results, each corresponding to invasive ductal carcinoma. We observed one case of "black carcinoma," that is, an illogical density decrease (negative enhancement) inside the tumor after contrast administration. Motion artifacts are most likely to blame for this. We found that the median value of intratumoral microvessel density was higher in true positives (79.2 microvessels/mm2) than false negatives (56.5 microvessels/mm2), although the difference was not statistically significant (p = 0.72).

Kinetic curves of enhancement from dynamic CEDM show that malignant tumors are generally characterized by early enhancement followed by a plateau or a gradually increasing enhancement. We observed only the typical MRI kinetic findings of malignancy-rapid enhancement and washout

 This tallies with other published data on dynamic CEDM kinetics that demonstrate a typical MRI-observed kinetic pattern in just two malignant tumors (out of 14) and one benign tumor.

 These differences between CEDM and breast MRI are probably due to the breast compression needed to perform dynamic CEDM. Even light compression can alter blood flow.

CEDM is a promising breast imaging technique that can be implemented easily and with little cost, and it is weakly irradiating, fast, and practical. It is a complementary tool to FFDM that can be performed in the same examination time as a conventional mammogram at a slightly higher cost because of the contrast material. Early clinical studies have shown that CEDM can detect breast carcinoma. Its future role may be the detection of lesions that are occult on conventional mammography, particularly in dense breast tissue. Another application of interest is the clarification of lesions that are conventionally classed as equivocal, particularly in follow-up after breast-conserving therapy. CEDM is also likely to benefit other digital mammography improvements such as tomosynthesis.

1. Weidner N, Semple JP, Welch WR, Folkman J. Tumor angiogenesis and metastasis-correlation in invasive breast carcinoma. NEJM 1991;324:1-8.

2. Chu JS, Lee WJ, Chang TC, et al. Correlation between tumor angiogenesis and metastasis in breast cancer. J Formos Med Assoc 1995;94:373-378.

3. Skarpathiotakis M, Yaffe MJ, Bloomquist AK, et al. Development of contrast digital mammography. Med Phys 2002;29:2419-2426.

4. Lewin JM, Isaacs PK, Vance V, Larke FJ. Dual-energy contrast-enhanced digital subtraction mammography: feasibility. Radiology 2003;229:261-268.

5. Jong RA, Yaffe MJ, Skarpathiotakis M, et al. Contrast-enhanced digital mammography: initial clinical experience. Radiology 2003;228:842-850.

6. Dromain CB, Jeunehomme C, Oppolon F, et al. Evaluation of tumor angiogenesis of breast carcinoma using contrast full-field digital mammography: preliminary results. Scientific Assembly and Annual Meeting Program 2004, RSNA, Chicago:567, 717.

7. Heywang-Kobrunner SH, Haustein J, Pohl C, et al. Contrast-enhanced MR imaging of the breast: comparison of two different doses of gadopentetate dimeglumine. Radiology 1994;191:639-646.

8. Kaiser WA, Zeitler E. MR imaging of the breast: fast imaging sequences with and without Gd-DTPA. Preliminary observations. Radiology 1989;170:681-686.

9. Smith AP, Hall PA, Marcello DM. Emerging technologies in breast cancer detection. Radiol Manage 2004;26:16-24; quiz 25-17.

DR. DROMAIN is a staff radiologist, and PROF. SIGAL is head of radiology, both at the Institut Gustave-Roussy in Villejuif, France. DR. JEUNEHOMME is an engineer with GE Healthcare.

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The clinical importance of tumor angiogenesis in primary breast cancer is well known. Studies have shown that intratumoral microvessel density is an independent prognostic indicator that correlates with a higher incidence of metastases.1,2

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