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Breast Imaging |
1 From the Departments of Pathology (R.M., G.E., T.S., O.T.) and Radiology (R.M., Y.M., S.K.), Saga Medical School, Nabeshima 5-1-1, Saga, 849-8501, Japan. Received September 30, 1999; revision requested November 5; final revision received March 2, 2000; accepted March 7. Address correspondence to R.M. (e-mail: g9805@post.saga-med.ac.jp).
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODS RESULTSDISCUSSIONREFERENCES |
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MATERIALS AND METHODS: Dynamic MR images of breast lesions (invasive carcinoma, n = 29; other, n = 6) in 35 women were reviewed. In each patient, subtraction images of the dynamic contrast-enhanced study were obtained, and early and delayed rim enhancement and delayed internal enhancement were evaluated. The MR findings were correlated with the ratio of microvessel density of the peripheral to the central portion of the lesion, fibrosis, and other histologic features, including expression of vascular endothelial growth factor (VEGF) and transforming growth factor ß1.
RESULTS: Early rim enhancement was observed in 29% and delayed rim enhancement was noted in 60% of all patients. Small cancer nests, a high ratio of peripheral-to-central microvessel density, peripheral VEGF expression, and a low ratio of peripheral-to-central fibrosis were correlated with early rim enhancement. Delayed rim enhancement was correlated with a high degree of fibrosis and inflammatory changes. Delayed internal enhancement was correlated with a high degree of fibrosis.
CONCLUSION: Rim enhancement of breast lesions at MR imaging is due to a combination of angiogenesis, distribution and degree of fibrosis, expression pattern of VEGF, and various histologic features.
Index terms: Breast neoplasms, diagnosis, 00.31, 00.32 • Breast neoplasms, MR, 00.121411, 00.121415, 00.12143 • Magnetic resonance (MR), contrast enhancement, 00.12143
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTSDISCUSSIONREFERENCES |
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We evaluated breast masses on subtracted MR images, which were originally obtained in the early and delayed phases of a dynamic contrast-enhanced study, and correlated them with morphologic features, including the size of the cancer nest, angiogenesis, fibrosis, inflammation, and expression pattern of growth factors. Our purpose was to establish the histologic causes of rim enhancement on dynamic contrast-enhanced MR images.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTSDISCUSSIONREFERENCES |
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MR imaging performed before the administration of contrast material comprised transverse T1-weighted (500/9 [repetition time msec/echo time msec]) spin-echo imaging and transverse T2-weighted (4,000/100) fast spin-echo imaging with fat saturation. The images were obtained by using a 16–20-cm field of view with 8–10-mm thick sections, 1.0-mm gaps, and a 256 x 224 matrix with two to three signals acquired. After the initial examination, dynamic contrast-enhanced images were obtained by using a fat-saturated fast spoiled gradient-echo sequence (180/1.7; flip angle, 60°), 20-cm field of view, 256 x 192 matrix, and 7–10-mm section thickness with a 1.0–2.0-mm intersection gap.
A bolus of gadopentetate dimeglumine (Magnevist; Schering, Berlin, Germany) was injected intravenously by hand at a dose of 0.1 mmol per kilogram of body weight within 10–15 seconds, followed by a 20-mL saline solution flush. Sequential multisection, whole-breast images were obtained in the transverse plane at 30-second intervals for 5 minutes. In all patients, late transverse T1-weighted (500/9) and/or three-dimensional fast spoiled gradient-echo (40/4.2; flip angle, 30°) images were obtained after the dynamic study. All lesions were depicted clearly at MR imaging.
Image Analysis
Postprocessing subtraction of dynamic images was performed in all patients. We obtained two different series of subtracted images for each patient: Images obtained before the administration of contrast material were subtracted from early phase (60 seconds) images obtained after the administration of contrast material, and early phase postcontrast images were subtracted from delayed phase (300 seconds) images. The first set of the subtracted images showed early enhancement of the lesions, and the second set showed temporal changes in the enhancement pattern between each pair of early and delayed phase images. All images were assessed by two authors (R.M., Y.M.) together by means of consensus.
For each set of subtracted images, enhancement patterns were categorized and the degree scored. The degree of early rimlike enhancement (early rim enhancement) was scored as none, 0; partially seen, 1; or clearly and circularly depicted, 2 (Fig 1). Delayed enhancement was evaluated for both rimlike enhancement surrounding the lesion and internal enhancement. The degree of surrounding rimlike enhancement (delayed rim enhancement) was scored in the same manner as was early rim enhancement (Fig 1). The patterns of internal enhancement (delayed internal enhancement) were categorized as none, focal, or entire (Fig 1).
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Histopathologic Analysis
All histopathologic features were evaluated by two authors (R.M., T.S.) together by means of consensus. Evaluation of morphologic features was performed on the basis of slices stained with hematoxylin-eosin in each case. We noted the size of the cancer nests at the tumor invasion front, architectural features of the stroma between cancer nests in cases of invasive carcinoma, degree of chronic inflammatory changes, and central scar formation in all cases.
The tumor invasion front is defined as the most advanced site of stromal invasion by cancer cells, and it may closely reflect the growth pattern of the cancer. We hypothesized that the growth pattern of the cancer cells must affect angiogenesis. In addition, stroma between cancer nests was considered an important factor to determine the diffusion of contrast material.
We measured the major axis of 10 cancer nests with an ocular micrometer in each case and recorded the mean value. The width of the stroma was also measured in 10 points in each case, and we recorded their mean value. The size of the cancer nests was determined on the basis of the mean length of the major axis and was classified as small (major axis, 10–50 µm; mean, 24 µm), medium (40–75 µm; mean, 59 µm), or large (90–300 µm; mean, 170 µm) (Fig 2). The features of the stroma between cancer nests were determined on the basis of the mean width and morphology and were classified as delicate (3–8 µm; mean, 4 µm), narrow (10–30 µm; mean, 21 µm), or broad (50–100 µm; mean, 70 µm) (Fig 2). Inflammatory changes were labeled as minimal, mild, moderate, or severe.
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The CD34 was used for microvessel quantification. Microvessels were counted in 10 fields at a magnification of 200 in both the peripheral and central portions of each lesion, which were designated on the basis of subtracted MR images of the lesions. Vessels of a caliber larger than approximately eight red blood cells, vessels with thick muscular walls, and vessels in sclerotic areas were excluded from the count. Ten fields were chosen at random in both portions. The mean counts of the fields were recorded (microvessel density), and ratios of peripheral to central microvessel density were calculated for each lesion.
Evaluation of stainings for VEGF and TGFß1 was performed according to a previously reported method (8). This entails a three-step categorization based on the intensity of the staining: 0, negative; 1, clearly identified at a magnification of 100; and 2, clearly identified at a magnification of 40. Areas with positivity were coded into four levels: 0, when none of the tumor or epithelial cells were stained; 1, one-third or fewer of the tumor or epithelial cells were stained; 2, two-thirds or less of the tumor or epithelial cells were stained; and 3, two-thirds or more of the tumor or epithelial cells were stained. When the total score—the sum of the stain intensity and quantification measurements—was 4 or greater, the staining was considered positive for VEGF or TGFß1 (Fig 3). We evaluated the grades in both the peripheral and central areas of each lesion.
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2 test. We compared each histologic parameter, ratio of peripheral to central microvessel density, ratio of peripheral to central fibrosis, and VEGF expression between the groups, which were determined by the status of early or delayed rim enhancement and delayed internal enhancement. A P value less than .05 was considered statistically significant. Data are expressed as the mean plus or minus SD. |
RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTSDISCUSSIONREFERENCES |
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Histopathologic Analysis
Eight (23%) of all patients showed minimal inflammatory change, 12 (34%) showed mild inflammatory change, 11 (31%) showed moderate inflammatory change, and four (11%) showed severe inflammatory change (Table 1). The carcinoma classifications were eight (28%) grade 1, 17 (59%) grade 2, and four (14%) grade 3. Eleven (38%) carcinomas were classified as showing small cancer nests, 11 (38%) as showing medium nests, and seven (24%) as showing large nests. Fifteen (52%) carcinomas had narrow stroma, 10 (34%) had broad stroma, and four (14%) had delicate stroma. Central scar formation was observed in seven of 29 patients with carcinoma (Tables 1, 3).
Imaging Analysis
Early rim enhancement.—Early rim enhancement was shown in 10 lesions (29%)—nine carcinomas and one malignant fibrous histiocytoma. For the histologic parameters, a smaller cancer nest was correlated significantly with the depiction of early rim enhancement (P = .048). Stroma between cancer nests, inflammatory change, and carcinoma grade did not correlate with early rim enhancement (Table 4). A high ratio of peripheral to central microvessel density (P < .001) and a low ratio of peripheral to central fibrosis (P = .007) correlated significantly with early rim enhancement depiction (Table 4).
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Delayed rim enhancement.—Twenty-one lesions (60%)—17 carcinomas and four other lesions—had delayed rim enhancement. A higher degree of surrounding fibrosis, inflammatory changes, and carcinoma grade were correlated significantly with depiction of delayed rim enhancement. Stroma between cancer nests that were classified as narrow correlated with delayed rim enhancement depiction (Table 5). Smaller cancer nests correlated with a high degree of surrounding fibrosis (Fig 5). No correlation was found between VEGF expression and delayed rim enhancement.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTSDISCUSSIONREFERENCES |
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Many previous studies (9–12) classified enhancement patterns on the basis of the time–signal intensity curve (dynamic curve) in each case. In contrast, our method could easily show the temporal changes between the early and delayed phase images, and the images correlated well with the histologic features.
Although the authors of several studies (5,6,13,14) have investigated a correlation between angiogenesis or tumor grade and rim enhancement of breast lesions, to our knowledge, no studies have also examined the general histologic features, including growth factor expression for the rim enhancement of breast lesions, at dynamic MR imaging. In addition, no studies have described the temporal changes in rim enhancement and internal enhancement separately.
Results of one study (15) suggested that the transport rate of contrast material determined by capillary permeability and blood flow was an important factor in rim (ringlike or peripheral) enhancement and washout of contrast material. The results of our study demonstrate that general pathologic construction was a more important factor to rim enhancement.
VEGF is a glycoprotein with two important functions: to stimulate the growth of vascular endothelial cells and to increase microvessel permeability. It is approximately 50,000 times more potent than histamine on a molar basis (16,17). Results of several studies (18–24) have shown that the expression of VEGF and its receptor in breast carcinoma correlates with a variety of clinical and prognostic factors. VEGF regulates tumor oxygenation by increasing blood vessel density and vascular permeability. Grunstein et al (25) reported that the surface area of blood vessels per unit volume of tumor that expressed wild-type (nonmutated) levels of VEGF was six times higher than that of tumors with no expression. The induction of fenestrations and caveolae of vessels depended on VEGF production by the tumor cells. Fenestrations were correlated with increased permeability of the vasculature, and the caveolae were associated with the induction of fenestrations (25).
In our study, a high ratio of peripheral to central microvessel density and VEGF expression pattern (peripheral and central) correlated significantly with early rim enhancement. These facts suggest that VEGF serves as an angiogenetic inducer and increases extravasation of gadopentetate dimeglumine from intravascular to interstitial tissue in breast tumors.
Histologic features of a small cancer nest correlate significantly with early rim enhancement. We believe that smaller invasive cancer nests may indicate the rapid growth of carcinoma, causing the peripheral invasive site of the carcinoma to show a higher degree of neovascularity than that of the central portion. Results of previous studies (26,27) demonstrated that slow-growing and fast-growing adenocarcinomas could be differentiated by means of microvessel density and permeability, with fast-growing tumors showing a higher degree of both microvessel density and permeability.
In the current study, the amount and location of fibrosis related to the depiction of delayed rim enhancement and patterns of delayed internal enhancement. These may depend on the volume and distribution of contrast material in interstitial spaces. A higher degree of surrounding fibrosis was found in patients with smaller cancer nests, which reflects a more prominent stromal reaction induced by rapid growth and a strong desmoplastic tendency in this type of carcinoma. Narrow stroma between cancer nests correlated with a high degree of delayed rim enhancement, which indicates that narrow stroma facilitate diffusion of contrast material.
TGFß1 is an isoform of the group of TGFßs, which are multifunctional regulatory proteins. These have the mutually opposing functions of stimulating and inhibiting cell proliferation. Their effects include stimulation of extracellular matrix formation and modification of immune function. They also may enhance tumor cell invasion and metastasis through effects on the extracellular matrix in advanced breast carcinomas (28). Results of studies (29,30) have shown TGFß1 regulation of VEGF production. Harmey et al (30) found that production of VEGF by macrophages was regulated by means of hypoxia and TGFß1.
In our study, there was no correlation between expression of TGFß1 and VEGF, but TGFß1 expression correlated significantly with a low degree of inflammatory changes (P = .031). The TGFß can suppress the growth of T and B lymphocytes (31,32), and TGFß provides a chemotactic gradient for leukocytes and other cells participating in an inflammatory response and inhibits them once they have become activated. Increased production and activation of latent TGFß has been linked to immune defects associated with malignancy or autoimmune disorders and to susceptibility to opportunistic infection (33). Our results suggest the possibility that the expression of TGFß1 indirectly influences delayed rim enhancement.
In the current study, we showed that rim enhancement reflected several histologic features, including the expression of VEGF and TGFß1 in breast lesions, but it is possible that some other growth factors also affect rim enhancement. Therefore, further investigations may be required.
In conclusion, rim enhancement of breast tumors at dynamic MR imaging was affected by angiogenetic features, morphologic features of the tumors, and various histologic factors, including growth pattern, inflammatory changes, fibrosis, and the expression patterns of growth factors.
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FOOTNOTES |
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Author contributions: Guarantors of integrity of entire study, S.K., O.T.; study concepts, R.M.; study design, R.M., Y.M.; definition of intellectual content, S.K., O.T.; literature research, R.M.; clinical and experimental studies, R.M., G.E.; data acquisition and analysis, R.M., Y.M., T.S.; statistical analysis, R.M.; manuscript preparation, R.M.; manuscript editing, R.M., S.K., O.T.; manuscript review, S.K., O.T.
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REFERENCES |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTSDISCUSSIONREFERENCES |
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