Comedo-type Ductal Carcinoma In Situ Research Articles

Histopathological and Clinical Differences Between Primary Breast Carcinomas With Neuroendocrine Features and Primary Breast Carcinomas Mimicking Neuroendocrine Features

We aimed to determine the histopathological differences between primary breast carcinomas with neuroendocrine features (NEBC) and carcinomas mimicking neuroendocrine features (NEBC-like). Twenty-three cases with NEBC, all showing positive staining for synaptophysin and/or chromogranin-A in ≥50% of tumor cells and 36 cases with NEBC-like (no staining for neuroendocrine [NE] markers but suspicious for NE morphology in terms of solid/trabecular growth patterns) were included in the study. Significant differences were found between the groups in terms of the patients' ages, histologic/nuclear grade of tumor, lymphovascular invasion, comedo-type ductal carcinoma in situ (DCIS), microcalcification, Ki-67 proliferation index, nuclear shape, and level of peritumoral lymphocytic infiltration. The presence of large-size solid cohesive groups of tumor cells; plasmocytoid, spindle, and/or columnar shapes of tumor cells; and eosinophilic-granular appearance of cytoplasm were mostly noted in the NEBC group. The presence of small- to medium-sized solid cohesive groups of tumor cells; high-grade histologic and nuclear features; clear cytoplasm; and round to ovoid nucleus were mostly noted in the NEBC-like group. No significant differences were found in terms of tumor size, ER/PR/HER2 status, as well as the presence of DCIS, elastosis, extracellular/intracellular mucin, signet ring cells, apocrine features, and accompanying papilloma or ductal ectasia. In conclusion, small- to medium-sized solid cohesive groups of tumor cells, high-grade features, clear cytoplasm, round to ovoid shape of nucleus, lymphovascular invasion, comedo-type DCIS, microcalcification, high level of Ki-67 proliferation index (≥20%), and moderate/strong level of peritumoral lymphocytic infiltration might support non-NE features in breast carcinomas.

Correlations of ER, PR, Her-2 and CK5/6 expression with histological characteristics features and prognosis of breast ductal carcinoma in situ

This study aimed to investigate the correlations of Estrogen Receptor (ER), Progesterone Receptor (PR), human epidermal growth factor receptor 2 (Her-2) and cytokeratin 5/6 (CK5/6) protein expression with histological characteristics features and prognosis of breast Ductal Carcinoma in situ (DCIS). Fortyeight cases of breast DCIS specimen were enrolled in this study. The samples were histologically typed and graded. The immunohistochemical analysis was performed to determine the expression of ER, PR, Her-2 and CK5/6 protein. Results showed that, the positive rates of ER and PR protein expression in non-comedo type DCIS group were significantly higher than those in comedo type DCIS group, respectively (P 0.05). There was significant difference of positive rate of ER, PR, Her-2 protein expression among histological grades I-III (P 0.05). The expression of ER protein was positively correlated with PR protein expression (r=0.764, P<0.001) and negatively correlated with Her-2 protein expression (r=-0.643, P<0.001); the expression of PR protein was negatively correlated with Her-2 protein expression (r=-0.622, P<0.001). In 4 recurrent DCIS cases, Her-2 protein expression was positive in 3 cases. ER, PR and CK5/6 protein expressions were negative in all 4 cases. In conclusion, ER, PR, Her-2 protein expressions are significantly correlated with the histological types and histological grades of breast DCIS. The positive Her-2 protein expression is related to the prognosis of breast DCIS.

Preliminary results of centralized HER2 testing in ductal carcinoma in situ (DCIS): NSABP B-43

NSABP B-43 is the first prospective, randomized phase III multi-institution clinical trial targeting high-risk, HER2-positive DCIS. It compares whole breast irradiation alone with WBI given concurrently with trastuzumab in women with HER2-positive DCIS treated by lumpectomy. The primary aim is to determine if trastuzumab plus radiation will reduce in-breast tumor recurrence. HER2-positive DCIS was previously estimated at >50%, occurring primarily in ER-negative, comedo-type DCIS of high nuclear grade. There has been no documented centralized multi-institutional HER2 analysis of DCIS. NSABP B-43 provides a unique opportunity to evaluate this in a large cohort of DCIS patients. Patients undergoing lumpectomy for DCIS without evidence of an invasive component are eligible. A central review of each patient's pure DCIS lesion is carried out by immunohistochemistry analysis. If the lesion is 2+, FISH analysis is performed. Patients whose tumors are HER2 3+ or FISH-positive are randomly assigned to receive two doses of trastuzumab during WBI or WBI alone. NSABP B-43 opened 11/9/08. As of 7/31/2013, 5,861 patients have had specimens received centrally, and 5,645 of those had analyzable blocks; 1,969 (34.9%) were HER2 positive. A total of 1,428 patients have been accrued, 1,137 (79.6%) of whom have follow-up information. The average follow-up time for the 1,137 patients is 23.3months. No grade 4 or 5 toxicity has been observed. In NSABP B-43 the HER2-positive rate for pure DCIS among patients undergoing breast-preserving surgery is 34.9%, lower than the previously reported rate. No trastuzumab-related safety signals have been observed. Interest in this trial has been robust.

Breast Scintigraphy with Breast-Specific γ-Camera in the Detection of Ductal Carcinoma In Situ: A Correlation with Mammography and Histologic Subtype

Ductal carcinoma in situ (DCIS) is a subtype of breast cancer encountered increasingly in clinical practice because of the widespread use of screening mammography. In the present study, we evaluated the usefulness of breast-specific γ-camera (BSGC) scintigraphy in DCIS identification, describing the scintigraphic findings and their correlation with mammography and histologic subtype. Thirty-three women, aged 41-81 y, with surgically proven DCIS were retrospectively reviewed. Before surgery, all patients underwent breast scintigraphy using a high-resolution semiconductor-based BSGC, starting 10 min after intravenous injection of 740 MBq of (99m)Tc-tetrofosmin. All patients had previously undergone mammography. A definitive histologic diagnosis was obtained in all cases after scintigraphy, and the scintigraphic findings were correlated with mammography and histologic subtype. Mammography was positive in 30 of 33 patients (sensitivity, 90.9%), showing calcifications in 22 of 30 (73.3%), masses in 3 of 30 (10%), and masses plus calcifications in the remaining 5 of 30 (16.7%). Scintigraphy was positive in 31 of 33 patients (sensitivity, 93.9%), showing patchy irregular uptake in patients with calcifications and focal uptake in masses; sensitivity was higher in low- to intermediate-grade DCIS than in intermediate/high- and high-grade DCIS (100% vs. 91.3%), but the difference was not statistically significant. Two comedo-type DCIS (one 20-mm intermediate/high-grade and one 15-mm high-grade) with heterogeneously or highly dense breasts at mammography and one papillary low/intermediate-grade DCIS associated with Paget disease were true positive only at scintigraphy. Moreover, scintigraphy better assessed disease extent than did mammography in 5 additional patients. Two comedo-type DCIS (one 6-mm intermediate/high-grade and one 15-mm high-grade) were true positive only at mammography. The difference in sensitivity between scintigraphy and mammography was not statistically significant. The combined use of mammography and scintigraphy achieved 100% sensitivity. BSGC scintigraphy proved to be a highly sensitive diagnostic tool in the detection of DCIS, irrespective of histologic subtype, and with a scintigraphic pattern of uptake that correlated well with mammography findings. In our series, BSGC scintigraphy demonstrated a slightly higher sensitivity than mammography and a better assessment of local disease extent. Thus, BSGC scintigraphy should represent a useful adjunctive tool in breast cancer diagnosis.

Silencing of HSulf-2 expression in MCF10DCIS.com cells attenuate ductal carcinoma in situ progression to invasive ductal carcinoma in vivo

IntroductionDuctal carcinoma in situ (DCIS) of the breast is a heterogeneous group of proliferative cellular lesions that have the potential to become invasive. Very little is known about the molecular alterations involved in the progression from DCIS to invasive ductal carcinoma (IDC). Heparan endosulfatase (HSulf-2) edits sulfate moieties on heparan sulfate proteoglycans (HSPGs) and has been implicated in modulating heparin binding growth factor signaling, angiogenesis and tumorigenesis. However, the role of HSulf-2 in breast cancer progression is poorly understood. MCF10DCIS.com cells (referred as MCF10DCIS) express HSulf-2 and form comedo type DCIS and progress to IDC when transplanted in immune-deficient mice and, therefore, is an ideal model to study breast cancer progression. We evaluated the role of HSulf-2 in progression from DCIS to IDC using mouse fat pad mammary xenografts.MethodsNon-target control (NTC) and HSulf-2 knockdown in MCF10DCIS breast cancer cells were achieved by NTC shRNA and two different lentiviral shRNA against HSulf-2 respectively. Xenografts were established by injecting NTC and HSulf-2 deficient MCF10DCIS cells in mouse mammary fat pads. Xenografts were subjected to H&E staining for morphological analysis, TUNEL and Propidium iodide staining (to determine the extent of apoptosis), Western blot analysis and zymography.ResultsUsing a mouse mammary fat pad derived xenograft model, we observed that compared to control treated xenografts, down-regulation of HSulf-2 was associated with significant delays in growth at Week 7 (P-value < 0.05). Histological examination of the tumors demonstrated substantial differences in comedo necrosis, with marked luminal apoptosis and up-regulation of apoptotic markers Bim, cleaved PARP and cleaved caspase 3 in HSulf-2 depleted xenografts. Furthermore, HSulf-2 depleted xenografts retained the basement membrane integrity with decreased activity and expression of matrix metalloproteinase 9 (MMP-9), an enzyme critical for degradation of extracellular matrix compared to nontargeted control.ConclusionOur data suggest that HSulf-2 expression may be critical for human breast cancer progression. Down-regulation of HSulf-2 leads to retention of comedo type DCIS and delays the progression of DCIS to IDC. Further studies are necessary to determine if therapeutic targeting of HSulf-2 expression might delay the progression of DCIS to IDC.

Abstract P1-15-09: Ductal Carcinoma In Situ of the Breast: Clinico-Pathological Features Predicting Residual Disease in Postlumpectomy Re-Excision Specimens

Abstract INTRODUCTION: Ductal carcinoma in situ (DCIS) is a non-invasive breast cancer, which often grows discontinuously within the breast tissue. Younger age, residual mammographic microcalcifications, positive surgical margins, tumor size, nuclear grade and architectural type are consistently related to ipsilateral breast tumor recurrence in DCIS. To re-excise or not when a lumpectomy margin is close is a controversial issue for breast pathologists, surgeons and oncologists, and often no residual disease is found when a re-excision is performed. The aim of this study is to investigate the clinico-pathological features of DCIS that might predict residual disease in the re-excision specimen in patients treated by lumpectomy with either positive or close margins. METHODS: Consecutive patients with DCIS who required postlumpectomy re-excision either for positive or for close margins were selected in this retrospective analysis. Close margin was defined as less than 0.1 cm. The initial lumpectomy specimens were examined for tumor size, architectural type, nuclear grade and margin status, and patient age was considered. The subsequent re-excision specimens were analyzed for residual disease. The clinico-pathological features of original lumpectomy specimens were correlated with the presence or absence of residual DCIS in the re-excision specimens. Logistic regression statistical test was used to determine if any of these clinico-pathological features predicted the presence or absence of DCIS in the subsequent re-excision specimens. RESULTS: There were 37 cases of DCIS without accompanying invasive carcinoma that had positive or close resection margins (positive margin n=8; 21.6%, close margin n=29; 78.4%). Age of the patients ranged from 30 to 93 years. DCIS present in the original lumpectomy specimen was comedo type with necrosis n=8; 21.6% and non-comedo type n-29; 78.4%. Twenty-one lumpectomy specimens (57%) exhibited more than one type of DCIS. Four tumors were nuclear grade 1 (10.8%). 17 were nuclear grade 2 (45.9%), and 16 were nuclear grade 3 (43.2%). Residual DCIS was present in 20 out of 37 (54.1%) re-excision specimens. Six out of 8 (75%) comedo DCIS had residual disease, compared to 14 out of 29 (48.3%) non-comedo DCIS. Eleven out of 20 patients (55%) with residual disease were younger than 60 years. The correlation of patient age and type of DCIS to residual disease in the re-excision specimens was short of statistical significance due to small size of study sample (p value = 0.178 and 0.175 respectively). There was no statistically significant association between nuclear grade and distance to margin with residual disease in re-excision specimens (p value = 0.757 and 0.734 respectively). CONCLUSION: Younger age and comedo type DCIS may be important factors in predicting residual disease in the re-excision specimens. If this can be confirmed in a larger, multi-institutional data set, there could be a more tailored selection of who needs a re-excision. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P1-15-09.

MDCT Is Very Useful for Evaluating the Spread of DCIS.

Abstract Introduction: Ductal carcinoma in situ (DCIS) may occasionally spread widely in the duct-lobular segment, thereby complicating the complete resection of the lesion in breast-conserving surgery. In order to perform a safe operation for DCIS, the lesion area must be precisely evaluated in the preoperative imaging studies. We performed multidetector-row computed tomography (MDCT) for patients with DCIS and investigated the potential of MDCT for detecting DCIS lesions.Patients and methods: A total of 74 patients with DCIS underwent MDCT. The size of the DCIS lesion in each patient was measured in the volume-rendering view, and these sizes were compared with the lesion sizes obtained by mapping from the pathological tests. The differences between the lengths obtained from pathological tests and those obtained from MDCT (L-path-L-CT) were calculated, and the relationships between the differences and some factors were investigated.Results: Among the 74 DCIS patients who underwent MDCT, DCIS was detected in 61 patients (82.4%). Among these 61 cases, 45.8% were cases of comedo-type DCIS, but the detection rates for comedo and noncomedo cases were not different. The L-path-L-CT values for histological grade I DCIS (1.55 cm) and grade II &amp; III DCIS (0.23 cm) were statistically different. Higher-grade DCIS was more detectable than low-grade DCIS (p = 0.013). Among the other factors, the MDCT assessments and the pathological assessments for comedo-type DCIS and Her-2-positive cases were more consistent than the corresponding results for noncomedo DCIS and Her-2-negative cases. However, these differences were not significant.Conclusion: MDCT shows high efficiency in detecting DCIS. More aggressive types of DCIS, such as higher grade, comedo type, and Her-2-positive DCIS were more precisely detected by MDCT. In comparison with magnetic resonance imaging (MRI), the patient's position during MDCT testing is more similar to that during surgery. Therefore, MDCT is a highly useful presurgical imaging technique for the assessment of DCIS. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5029.

Reproductive and hormonal risk factors for ductal carcinoma in situ of the breast.

One-fifth of all newly diagnosed breast cancer cases are ductal carcinoma in situ (DCIS), but little is known about DCIS risk factors. Recent studies suggest that some subtypes of DCIS (high grade or comedo) share histopathologic and epidemiologic characteristics with invasive disease, whereas others (medium or low grade or non-comedo) show different patterns. To investigate whether reproductive and hormonal risk factors differ among comedo and non-comedo types of DCIS and invasive breast cancer (IBC), we used a population-based case-control study of 1,808 invasive and 446 DCIS breast cancer cases and their age and race frequency-matched controls (1,564 invasive and 458 DCIS). Three or more full-term pregnancies showed a strong inverse association with comedo-type DCIS [odds ratio (OR), 0.53; 95% confidence interval (95% CI), 0.30-0.95] and a weaker inverse association for non-comedo DCIS (OR, 0.73; 95% CI, 0.42-1.27). Several risk factors (age at first full-term pregnancy, breast-feeding, and age at menopause) showed similar associations for comedo-type DCIS and IBC but different associations for non-comedo DCIS. Ten or more years of oral contraceptive showed a positive association with comedo-type DCIS (OR, 1.31; 95% CI, 0.70-2.47) and IBC (OR, 2.33; 95% CI, 1.06-5.09) but an inverse association for non-comedo DCIS (OR, 0.51; 95% CI, 0.25-1.04). Our results support the theory that comedo-type DCIS may share hormonal and reproductive risk factors with IBC, whereas the etiology of non-comedo DCIS deserves further investigation.

Does the receptor expression pattern in ductal carcinoma in situ predict recurrence?

22189 Background: Ductal carcinoma in situ (DCIS) of breast is a heterogeneous disease, and the treatment strategy is based on tumor size and pathologic features. We evaluated the value of estrogen, progesterone and Her-2/neu receptors expression in DCIS for predicting recurrence. Methods: This retrospective study included 50 patients with DCIS treated at Barretos Cancer Hospital between January 2000 and December 2002. DCIS with microinvasion was not included. Results: Fifty patients were included and the median age and tumor size was 56.5 years and 17 mm, respectively. Thirty five patients (70%) had wide excision with final margins of > or = 10 mm or a re-excision without residual DCIS and only two patients had margin < 1mm. Twenty four DCIS were comedo-type DCIS and 15 were classified as high-grade DCIS. The ER, PR, HER-2 receptors were assessed in 27 patients and we found positive expression of ER, PR, and HER-2 in 85.2%, 74.0% and 26.9%, respectively. Median follow-up was 65.3 months. Four patients de...

Expression patterns of lymphangiogenic and angiogenic factors in a model of breast ductal carcinoma in situ

Background Foci of invasion are found in greater than 20% of excised specimens of breast ductal carcinoma in situ (DCIS). Since lymphangiogenesis markers are associated with the potential for increased lymph node metastasis, the purpose of the current study was to determine expression of lymphangiogenesis molecular markers in a model of aggressive DCIS. Methods From the MCF10A xenograft model, comedo type MCF10DCIS.com cells, premalignant MCF10AT, and invasive MCF10CA1a.cl1 cells were tested. Invasion was tested by Matrigel invasion assays (Becton-Dickinson, Bedford, MA). Gene expression was determined by reverse transcriptase–polymerase chain reaction and protein expression by immunoblot, normalized to β-actin. Results MCF10DCIS.com cells were 4-fold more invasive than MCF10AT cells ( P < .01), and expressed several-fold more mRNA and protein than MCF10AT and MCF10CA1a.cl1 cells for vascular endothelial growth factor C, vascular endothelial growth factor D, and lymphatic vessel endothelial hyaluronan receptor 1 ( P < .01). Conclusions A subset of comedo-type DCIS cells are invasive, and expression of lymphangiogenesis markers is greater at the mRNA and protein levels than by invasive cancer cells ( P < .01). These additional molecular markers may characterize aggressive DCIS more precisely.

Angiogenic potential of ductal carcinoma in situ (DCIS) of human breast

Comedo carcinoma is generally regarded as the subtype of ductal carcinoma in situ (DCIS) most likely to progress to invasive carcinoma. Increased angiogenesis could be associated with an enhanced risk of progression and might therefore be a marker of poor prognosis, as can be demonstrated for invasive breast tumours. Therefore, the present study investigates the correlations between the expression of oncoproteins (HER2, HER1/EGFR), angiogenic growth factors (VEGF and PD-ECGF/TP) and microvessel density (MVD) in DCIS. Forty-six breast cancer specimens of DCIS were tested immunohistochemically for the expression of angiogenic factors and oncoproteins. Different vascular distribution patterns of DCIS were examined semiquantitatively. Our results showed a significantly inverse correlation between HER1/EGFR and comedo-type DCIS (P = 0.048), but HER1/EGFR expression seemed to be independent of HER2 overexpression. VEGF expression was significantly associated with endoglin expression (P = 0.031) and the cuffing phenomenon (P = 0.017). The significantly inverse correlation between HER1/EGFR and comedo-type DCIS and the observation that VEGF and the other angiogenic factors tested are independent of HER2 overexpression, suggest that progression of comedo-type DCIS and angiogenesis in breast carcinoma are not regulated via the HER1/EGFR or HER2 pathway.

Ultrasound demonstration of mammographically detected microcalcifications in patients with ductal carcinomain situ of the breast

Breast microcalcifications are difficult to depict by ultrasound (US). However, recent advances in US equipment and the refinement of breast imaging techniques have improved the detection and characterization of small breast lesions. The present study attempts to determine whether US examination is able to demonstrate nonpalpable breast lesions associated with mammographically detected microcalcifications without mass density or distortion, and to evaluate the clinical reliability of US-guided procedures, especially in cases of ductal carcinoma in situ(DCIS)of the breast. The subjects consisted of 73 patients with breast cancer diagnosed preoperatively as DCIS by stereotactic core needle biopsies, all of whom had microcalcifications without other abnormalities on mammography. The radiological appearance and size of the clustered microcalcifications were evaluated. US examinations were performed preoperatively, and the detection rates were assessed. Sonographically detected lesions underwent US-guided wire localization followed by surgical excision. The lesions associated with microcalcifications were identified sonographically in 54 of 73 cases (74%), and the pathological examination revealed breast cancer in all of the corresponding specimens. Lesions with linear-branching shape, segmental-linear distribution and category-5 calcifications on mammography had a high level of visibility on US. The US visible cases had a larger size of calcified area on mammography when compared with US invisible cases. Pathologically, the lesions were more frequently seen on US in cases with minimally invasive cancer or with comedo type DCIS. US examination is an effective method for identifying and localizing breast microcalcifications, and can be used as an alternative to stereotactic localization in selected patients with early breast cancer.

In situ and minimally invasive breast cancer: morphologic and kinetic features on contrast-enhanced MR imaging.

This retrospective study was undertaken to investigate the morphologic and dynamic features of in situ and minimally invasive breast cancer on contrast-enhanced (c.-e.) MR imaging and to examine possible associations to pathology features. A total of 71 patients underwent MR imaging. T1-weighted FLASH-3D images were obtained before and after intravenous administration of Gd-DTPA. Histopathologic analysis of 78 lesions revealed ductal carcinoma in situ (DCIS) n = 50 and DCIS with microinvasion n = 28. MR features were correlated with histopathologic findings. Enhancement in DCIS was focal (73%), diffuse (10%) or ductal (17%). No enhancement occurred in two cases (4%). In 65% enhancement speed was classified as delayed. There was a tendency toward a more ill-defined (83 vs. 43%) enhancement pattern in high grade DCIS and a more ductal (29 vs. 12%) and faster (50 vs. 29%) enhancement in comedo type DCIS. However, significant differences in the enhancement behaviour could neither be demonstrated between high grade and non high grade DCIS nor between comedo and non comedo type DCIS. No significant differences were noted between pure and microinvasive DCIS. In this retrospective analysis the majority (96%) of DCIS lesions show contrast enhancement. However, in only about 50% of DCIS the criteria of a so-called 'typical' enhancement behaviour was fulfilled, that means strong, early, focal ill-circumscribed or ductal. Enhancement that follows a duct is often associated with malignancy, however this feature was only present in 17% of the cases. c.-e. MR imaging allowed the detection of 25 additional foci of DCIS. Therefore malignant in situ lesions can be present with atypical enhancement, and should be taken into consideration in high-risk patients in particular.

P53 protein expression in ductal carcinoma in situ (DCIS) of the breast.

Abnormalities in p53 gene expression have been implicated in many inherited and sporadic forms of malignancies in humans. Immunohistochemical staining using monoclonal antibody D0-7 for the p53 protein expression was performed in 81 cases of pure DCIS, 14 benign breast lesions and 2 cases with normal breast tissue. Expression of p53 protein was detected in 15 (18.5%) cases of pure DCIS. Thirteen (25%) of the 52 comedo type DCIS showed p53 protein expression compared with 2 (6.9%) of the 29 non-comedo types (P < 0.02). p53 protein expression was also associated with high nuclear grade (P < 0.001) and high mitotic index (P < 0.05). The pattern of p53 protein staining was diffuse in one comedo type DCIS, regional in 6 comedo types, and focal in the remaining 8 cases (6 comedo type and 2 micropapillary type DCIS). The patient with comedo type DCIS showing diffuse staining has a family history of breast cancer in the first and second degree relatives (sister and maternal aunt). Clinical follow-up data was available in 52 cases. Follow-up period ranged from 9 to 55 months. Three patients, who were primarily treated by local excision, have had a documented local recurrence in the form of residual tumor within a short interval of 5 to 11 months. In all these three patients both the original and the recurrent tumors are negative for p53 protein expression. The difference in the local recurrence rate between p53 positive (0/15) and p53 negative (3/37) cased does not reach statistical significance (p > 0.05). We interpret that the local tumor recurrence in these three cases within a short period after primary excision is due to the presence of residual tumor at the excision site and is independent of the p53 gene alteration. It is concluded that p53 protein expression in DCIS is associated with comedo subtype, high nuclear grade, and high mitotic index, and is a promising new parameter to evaluate the cellular biology and prognosis of DCIS.

Ductal carcinoma in situ: MR imaging-histopathologic correlation.

To correlate histopathologic and magnetic resonance (MR) imaging findings of ductal carcinoma in situ (DCIS). Thirty-six women with DCIS underwent preoperative contrast material-enhanced subtraction dynamic MR imaging. Concomitant early contrast enhancement in the breast parenchyma with normal vessels was considered a positive finding. The size and shape of early enhancement were correlated with the size and density packing of ducts involved by DCIS. Tumor angiogenesis in the stroma that surrounded the ducts was evaluated with immunoperoxidase staining. Early contrast enhancement was demonstrated in 34 patients with DCIS but not in two patients with comedo-type DCIS. Tumor angiogenesis was demonstrated in the stroma. The size and morphology of contrast-enhanced lesions significantly correlated with the size (P = .0085) and density packing of ducts involved by DCIS (P = .012). Contrast enhancement on dynamic MR images of DCIS may be due to the presence of tumor angiogenesis in the stroma.

Expression of vascular permeability factor (vascular endothelial growth factor) and its receptors in breast cancer

Solid tumors must induce a vascular stroma to grow beyond a minimal size, and the intensity of the angiogenic response has been correlated with prognosis in breast cancer patients. Vascular permeability factor (VPF), also known as vascular endothelial growth factor (VEGF), is a secreted protein that has been implicated in tumor-associated angiogenesis. Vascular permeability factor directly stimulates endothelial cell growth and also increases microvascular permeability, leading to the extravasation of plasma proteins, which alter the extracellular matrix in a manner that promotes angiogenesis. To determine whether VPF has a role in breast cancer, we used in situ hybridization to study VPF mRNA expression in normal breast tissue (13 specimens), comedo-type ductal carcinoma in situ (DCIS) (four specimens), infiltrating ductal carcinoma (12 specimens), infiltrating lobular carcinoma (two specimens), metastatic ductal carcinoma (three specimens) and metastatic lobular carcinoma (one specimen). Vascular permeability factor mRNA was expressed at a low level by normal duct epithelium but was expressed at high levels in tumor cells in all cases of comedo-type DCIS, infiltrating ductal carcinoma, and metastatic ductal carcinoma. In contrast, VPF mRNA was not expressed at high levels in infiltrating lobular carcinoma. We also used in situ hybridization to study the expression of two recently described endothelial cell surface VPF receptors, flt-1 and kdr. Vascular permeability factor receptor mRNA was strongly expressed in endothelial cells of small vessels adjacent to malignant tumor cells in DCIS, infiltrating ductal carcinoma, and metastatic ductal carcinoma. In contrast, no definite labeling for receptor mRNA was detected in infiltrating lobular carcinoma or nonmalignant breast tissue. The intense expression of VPF mRNA by breast carcinoma cells and of VPF receptor mRNA by endothelial cells of adjacent small blood vessels provides strong evidence linking VPF expression to the angiogenesis associated with comedo-type DCIS, infiltrating ductal, and metastatic ductal breast carcinoma.