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The Mammographic Correlations with Basal-Like Phenotype of Invasive Breast Cancer
The Mammographic Correlations with Basal-Like Phenotype of Invasive Breast Cancer Xiao Wang, MD, PhD, Lan Chao, MD, PhD, Liansheng Chen, MD, Guohui Ma, MD, Guangchao Jin, MD, Mei Hua, MD, Gengyin Zhou, MD Rationale and Objectives: Mammography contributes to the improvement of breast carcinoma survival through early detection and treatment of breast lesions. The basal-like phenotype has been found to be an independent poor prognostic factor for breast cancer. The aim of this study was to determine the mammographic correlates of the basal-like phenotype of invasive breast cancer, and to more precisely predict patient outcome and those individuals who will be responsive to a specific therapeutic regimen. Materials and Methods: The mammographic findings in 267 patients with operable breast cancer were correlated with the basal-like subtype identified using immunohistochemical assessment of breast cancer cases, including estrogen receptor, progesterone receptor, HER-2/neu status, cytokeratin (CK5/6), and epidermal growth factor receptor. Results: Of the 267 invasive breast cancers, 40 (15%) were of the basal-like phenotype. Basal-phenotype tumors were significantly more likely to manifest as a mass (P = .002), most of which were indistinct margin (P =.035), at mammography, and architecture distortion at mammography (P = .002). Conclusion: The mammographic appearances of basal-like tumors, more mass and architecture distortion, suggest more rapid carcinogenesis. Additional studies are warranted to further refine prognosis, and to optimize treatment in patients with basal-like breast cancer. Key Words: Mammography; basal-like phenotype; breast cancer; mass; architectural distortion. ªAUR, 2010
A
nalysis of breast cancer tissue with DNA microarrays has categorized breast carcinoma into the following five distinct subtypes: luminal A (estrogen receptor [ER] positive and/or progesterone receptor [PR] positive, human epidermal growth factor receptor 2 [HER-2/neu) negative], luminal B (ER positive and/or PR positive, HER-2/neu positive), HER-2/neu overexpression (ER negative, PR negative, HER-2/neu positive), basal-like (ER negative, PR negative, HER-2/neu negative, cytokeratin 5 and 6 [CK5/6] positive and/or epidermal growth factor receptor [EGFR] positive) and normal breast-like tumors. Although this classification system is based on extensive genetic profiling assays, a simplified method of classification (based on ER, PR, HER-2/neu, CK5/6, and EGFR status) is appealing and more clinically useful. The basal-like subtype is associated with aggressive histology, poor prognosis, unresponsiveness to the usual endocrine therapies, and shorter
Acad Radiol 2010; 17:333–339 From the Departments of Breast Surgery (X.W., L.C., G.M., G.J.), Radiology (M.H.), Jinan Central Hospital, Shandong University School of Medicine, Jinan 250013, China; Infertility Center, Qilu Hospital, Shandong University, Jinan, China (L.C.), Department of Pathology, Shandong University School of Medicine, Jinan, China (G.Z.). Received August 27, 2009; accepted October 1, 2009. Address correspondence to: X.W. e-mail: wangxiao@ sdu.edu.cn ªAUR, 2010 doi:10.1016/j.acra.2009.10.011
survival (1,2). The pathways that drive proliferation of these tumors are still poorly understood; however, after they have been elucidated, targeted agents can be developed, which could result in better outcomes for patients with basal-like tumors. Several studies have attempted to evaluate and interpret the clinical perspective of the relationship between mammographic features and HER-2/neu overexpression in breast carcinomas, and shown that mammographic calcifications are correlated with HER-2/neu overexpression in breast carcinomas (3–6). Furthermore, the clinical perspective of the relationship between mammographic calcifications and the expression of selected biological markers, such as ER, PR, EGFR, Bax, Fas, Bcl-2, and DNA fragmentation factor in breast carcinomas have been interpreted (7,8). Recently, Luck et al reported that basal-phenotype tumors were significantly more likely to manifest as an illdefined mass or with comedo calcification in a cohort of 356 screening-detected breast tumors (9), and Yang et al found that triple receptor negative breast cancers were more frequently associated with a mass, and were less frequently associated with calcifications in 198 young, premenopausal breast cancer patients (10). To better understand the associations between the mammographic features including calcifications and basal-like breast carcinoma, we performed immunohistochemical staining to category phenotypes of breast carcinoma, aimed to retrospectively 333
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evaluate the association between mammographic features and basal-like breast carcinoma, and to assess its clinical perspective. MATERIALS AND METHODS Patients
We searched the pathology database to identify women who underwent surgical breast treatment between May 2003 and August 2008. Patients were excluded when we could not obtain archival paraffin-embedded tumor specimens, clinical information, or preoperative mammograms for analysis, and patients with evidence of disease within 1 month after primary surgery were excluded. Furthermore, patients with only carcinoma in situ were also excluded from this study. All 267 patients included in this study had primary breast cancer without distant metastases at the time of diagnosis. The median age of the patients was 54 years (range, 27–78 years). A waiver of informed consent was obtained from patients, and the institutional review board at the University School of Medicine approved this study. A waiver of informed consent was obtained for this study. A breast and gynecologic pathologists (G.Z.) reevaluated pathologic features. The tumor subtypes of invasive carcinoma were classified as ductal carcinoma and others. Other invasive carcinomas included medullary, mucinous, or lobular carcinomas. Tumor grade of invasive carcinomas was classified according to the Scarff-Bloom-Richardson system (11). Based on the frequency of cell mitosis, tubule formation, and nuclear pleomorphism, invasive carcinoma was graded as grade 1 (low), grade 2 (moderate), or grade 3 (high grade). Presence of lymph node metastases were reviewed for each patient. The tumor stage was determined according to the American Joint Committee on Cancer Cancer Staging Manual, sixth edition (12). The clinical data were collected from the medical files. Conventional clinical features were evaluated including age, menopause status, pathological grading, tumor T stage, and lymph node metastasis. Mammography
The mammograms were obtained with the Gold Standard DR 17 Mammography System (Pan-Pacific Enterprises, Inc., Brewster, NY). The standard craniocaudal and lateral views were carried out in all patients. Full-resolution mammography of calcifications included orthogonal magnification projections, usually craniocaudal and mediolateral projections. Cone-down magnification views were obtained when necessary. All the mammograms were evaluated independently by two experienced breast radiologists (X.W., and M.H.). All the mammograms were reviewed according to the analytic criteria of Breast Imaging Reporting and Data System, 4th edition (13,14). Both radiologists who read an image had to agree on an interpretation before the results 334
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were recorded. Mammographic findings were categorized as mass, calcifications, architectural distortions, and asymmetric densities. For carcinomas presenting as masses on mammography, we evaluated the shape, margin, density, and associated findings. For carcinomas with calcifications on mammography, their morphology and distribution were evaluated. Morphologic aspects of calcification were classified into four groups: pleomorphic, fine linear, punctuate, and coarse calcifications. Distribution features were classified as: clustered, segmental, regional, linear, and diffuse. Basal-like Breast Carcinoma Tissues
ER, PR, and HER-2/neu status were assessed by standard immunohistochemical methods. Immunohistochemical markers were assayed in paraffin-embedded, formalin-fixed tissue using antibodies against ER, PR, and HER-2/neu (Dako, Glostrup, Denmark). For ER and PR, receptor positivity was scored as more than 10% of cells testing positive. HER-2/neu was assessed through immunohistochemistry (IHC) and was scored on a qualitative scale from 0 to 3+, based on interpretation of staining, with 0 and 1+ classified as negative and 3+ as positive. Tumor specimens that showed an intermediate HER-2/neu staining score of 2+ were further assayed with fluorescent in situ hybridization (Vysis, Des Plaines, IL) to determine HER-2/neu amplification. All samples that had intense, complete, membranous staining in >10% of invasive neoplastic cells determined by IHC or the presence of HER-2/neu gene amplification determined by fluorescent in situ hybridization were considered HER-2/ neu positive. Additional IHC was performed with antibodies against CK5/6 (clone D5/16B4, Carpinteria, CA; 1:50 dilution, DAKO), and EGFR (clone ab2430, Cambridge, MA; 1:200 dilution, Abcam) using a streptavidin-biotin horseradish peroxidase detection kit (Biogenex, San Ramon, CA). Secondary antibody was applied for 1 hour and staining was visualized according to the manufacturer’s instructions (Santa Cruz Biotechnology, Santa Cruz, CA). Omission of the primary antibody was used as a negative control. Cases of invasive ductal carcinoma previously known to be positive for CK5/6 and EGFR were used as positive controls. The expression of CK5/6 was cytoplasmic, whereas the expression of EGFR was both cytoplasmic and membranous. Sections with cytoplasmic expression in $10% of tumor cells for CK5/6 and membranous staining in $10% of tumor cells for EGFR were considered positive. The breast cancers were divided into subtypes included luminal A (positive for ER and/or PR and negative for HER-2/neu), luminal B (positive for ER or PR and positive for HER-2/neu), HER-2/neu overexpression (negative for ER and PR and positive for HER-2/neu), and basal-like (negative for ER, PR, and HER-2/neu and positive for CK5/6 and/or EGFR) (15). In the current study, luminal A, luminal B, and HER-2/neu overexpression subtypes were combined into a single non–basal-like group and were compared to the basal-like group.
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Figure 1. Representative immunohistochemical staining of protein markers in basal-like breast cancers. (a) Negative expression of cytokeratins 5 and 6 (CK5/6); (b) negative expression of epidermal growth factor (EGFR); (c) positive cytoplasmic expression of CK5/6; (d) positive cytoplastic and membranous expression of EGFR. Original magnification: (a, b) 200; (c, d) 400.
Statistical Analysis 2
The c and Fisher’s exact tests were used to evaluate the association of phenotypes of breast carcinoma with mammographic and clinicopathological features. All statistical tests were two-sided and statistical significance of observed difference was set at P < .05. All data were analyzed using SPSS statistical software (Version 13.0, SPSS Inc., Chicago, IL).
RESULTS Correlation between Basal-like Breast Carcinomas and Clinicopathological Parameters
In the current study, 52 of 267 (19%) patients were of the triple-negative phenotype. Additional immunohistochemical staining for CK5/6 and EGFR was performed to determine what proportion of the triple-negative tumors had the basallike phenotype. Of 52 triple negative tumors, 40 (77%) were CK5/6 and/or EGFR positive (Fig 1). Thus, of the 267 invasive breast cancers, 40 (15%) were of the basal-like phenotype, and 227 (85%) were grouped as non–basal-like phenotype. The two more striking differences between the basal-like and the non–basal-like phenotypes were the higher percentage of younger women (#35 years) and premenopausal patients with basal-like tumors, with 35% of the patients with basal-like tumors younger than age 35 years at diagnosis compared with 9% of the patients with non–basallike phenotype (P = .001), and 78% of the basal-like group were premenopausal patients compared with 51% of the non–basal-like cohort (P = .003) (Table 1). Patients in the basal-like group were more likely to have higher grade of tumors, with 40% of the basal-like group being Grade 3 at
TABLE 1. Difference of Clinicopathological Characteristics between Basal-like and Non–basal-like Breast Cancers Tumor Phenotype (%)
Characteristics Age at diagnosis #35 36–49 $50 Menopause status Premenopausal Postmenopausal Histology Ductal Lobular Others T stage T1 T2 T3 Nodal status Negative Positive Tumor grade 1 2 3
n
Basal-like Non–basal-like (n = 40) (n = 227) P Value
34 126 107
14 (35%) 15 (38%) 11 (27%)
20 (9%) 111 (49%) 96 (42%)
.001
147 120
31 (78%) 9 (22%)
116 (51%) 111 (49%)
.003
218 22 27
36 (90%) 2 (5%) 2 (5%)
182 (80%) 20 (9%) 2 5(11%)
.33
108 136 23
9 (23%) 20 (50%) 11 (27%)
99 (44%) 116 (51%) 12 (5%)
.001
176 91
25 (62%) 15 (38%)
151 (67%) 76 (33%)
.75
90 116 61
10 (25%) 14 (35%) 16 (40%)
80 (35%) 102 (45%) 45 (20%)
.019
diagnosis compared with 20% of the non–basal-like cohort (P = .019). Furthermore, basal-like phenotype was more frequently associated with advanced T stage (27%) when compared with that of non–basal-like phenotype (5%) (P = .001) (Table 1). 335
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TABLE 2. Association between Mammographic Features and Basal-like Breast Cancers Tumor Phenotype (%) Mammographic Findings Mass + Calcification + Architectural distortion + Asymmetric density +
Basal-like (n = 40)
Non–basal-like (n = 227)
P Value
22 (55%) 18 (45%)
65 (29%) 162 (71%)
.002
14 (35%) 26 (65%)
87 (38%) 140 (62%)
13 (33%) 27 (67%)
28 (12%) 199 (88%)
.002
3 ( 8%) 37 (92%)
12 (5%) 215 (95%)
.85
.82
Table 4 shows comparison between breast carcinomas with basal-like phenotype and those with non–basal-like phenotype with respect to mammographic calcification features. Although pleomorphic morphology of calcifications was more frequent in carcinomas with basal-like phenotype (9 of 14, 64%) compared to those with non–basal-like phenotype (33 of 87, 38%), there was no significant difference between the two groups (P = .38). Furthermore, there was no significant difference in distribution of mammographic calcifications between the two groups with basal-like or non–basal-like breast carcinomas (P > .05).
DISCUSSION
Correlation between Mammographic Features and Basal-like Phenotype
All patients had diagnostic mammograms available for review. The associations between mammographic features and phenotypes of breast carcinoma are showed in Table 2. Of the 267 invasive breast cancers, 87 cases with breast cancers presented as a mass (39 with associated calcifications), 41 as calcifications alone, 31 as architectural distortion (14 with associated calcification), and 15 as asymmetric density (7 with associated calcification). Represent mammographic masses, calcifications, and architectural distortion were shown in Figure 2. There was a significant association between presence of masses and basal-like breast cancer (P =.002). Masses were more frequent in carcinomas with basal-like phenotype (22 of 40, 55%) than in those with non–basal-like phenotype (65 of 227, 29%). Furthermore, basal-like phenotype was more frequently to have architectural distortion (13 of 40, 33%) than non–basal-like phenotype (28 of 227, 12%) (P = .002). There was no significant difference in other mammographic features including calcifications and asymmetric density between the two groups with basal-like and non– basal-like phenotype (P > .05). Correlation between Shape, Margin, Density, and Associated Findings of Mass on Mammography and Basal-like Phenotype
In the 85 carcinomas presenting with masses on mammography, indistinct margin was more common in masses with basal-like phenotype (8 of 22, 36%) than in those with non–basal-like phenotype (6 of 65, 9%) (P =.035) (Table 3). There were no significant differences in shape, density, and associated findings of the masses between the two groups with basal-like or non–basal-like breast carcinomas (P > .05) (Table 3). 336
Correlation between Mammographic Calcification Features and Basal-like Phenotype
Mammography contributes to the improvement of breast carcinoma survival through early detection and treatment of breast lesions. Knowledge of mammographic appearances, such as mass, calcification, architectural distortions, and asymmetric densities, is fundamental to screening detection of the various types of breast cancer. Developing a unified classification schema that incorporates imaging findings, molecular subtype, and predictive biomarkers should help to more precisely predict patient outcome and those individuals who will be responsive to a specific therapeutic regimen. Protein expression profiling of breast cancer has identified specific subgroups with potential clinical, biological, and therapeutic implications. Luminal tumors have been associated with the most favorable prognoses, while HER-2/neu overexpressing and basal-like tumors, or their surrogate triple negative tumors, have been associated with the worst prognoses (16,17). Approximately 70% of triple-negative phenotype breast cancers express basal markers (18–20). Because the basal-like phenotype is not amenable to any form of endocrine therapy, efforts are under way to develop appropriate targeted therapies. Greater understanding of the pathologic and molecular characteristics of this phenotype may lead to better tailored treatments for these patients. Our results are in agreement with previous studies that basal-like phenotype is commonly associated with younger age at diagnosis (21,22), more advanced T stage (23,24), higher grade (17,25), and premenopausal status (10). In the current study, we have found that 15% of the cases of 267 invasive breast cancers are basal-like phenotype. This percentage is largely in agreement with the overall staining levels reported previously (15,16). Mammographic masses were more significantly frequent in carcinomas with basallike phenotype than in those with non–basal-like phenotype. In the view of margin category of mass, basal-like phenotype cancers that appeared as masses were most frequently with indistinct margins. This is in agreement with observations from other groups (9,10). However, they were no significant difference in shapes of mammographic masses between the two groups with basal-like and non–basal-like breast
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Figure 2. Representative mammographic features of basal-like breast carcinomas. (a) Mammogram shows architectural distortion with pleomorphic calcifications (CC). (b) Mammogram shows architectural distortion (MLO). (c) Mammogram shows an irregular mass with spiculated margin (CC). (d) Mammogram shows a mass with indistinct margin (MLO).
carcinomas, this is in contrast with Yang, who observed that masses of triple receptor negative cancers were most frequently round, oval, or lobular in shape in a cohort of young, symptomatic patients. Possibly this discrepancy is due to the different use of categories and different cohorts of women. Calcifications represent one of the most important mammographic findings of breast carcinoma and are often the only mammographic sign of a malignant breast disease. There are well-established diagnostic criteria basing on the morphology and distribution of the calcifications radiologically (13,14). The presence of pleomorphic calcifications in small breast cancers was an independent predictor of poor prognosis (26,27). Recently, Luck et al reported that basal tumors are more likely to be found in association with comedo calcification at mammograms. However, there were no significant differences in mammographic calcifications,
even for the distribution and morphology characteristics, between the two groups with basal-like and non–basal-like breast carcinomas in the present study. In addition, it is worth noting that basal-like tumors were significantly more likely than non–basal-like tumors to appear as architecture distortion on mammograms in the present study. Architectural distortion as such is not a mass but rather a local disruption of the normal breast tissue pattern. Patients showing architectural distortion on the mammogram often have an invasive carcinoma with noticeable fibrosis, such as scirrhous carcinoma and invasive lobular carcinoma. As a mammographic finding, architectural distortion has a low prevalence yet demonstrates a high positive predictive value for cancer at screening and diagnostic examinations (28). Specifically, architectural distortion accounts for 12%–45% of breast cancers overlooked or misinterpreted at screening mammography (29). A recent study that analyzed false337
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TABLE 3. Associations between Shape, Margin, Density, and Associated Findings of Mass on Mammography and Basallike Breast Cancers Tumor Phenotypes (%) Mammographic Mass Features Mass shape Round Oval Lobulated Irregular Mass margin Circumscribed Microlobulated Obscured Indistinct Spiculated Density High Equal Low Associated findings Calcifications Architectural distortion Skin retraction
Basal-like (n = 22)
Non–basal-like (n = 65)
P Value
5 (23%) 4 (18%) 4 (18%) 9 (41%)
16 (25%) 21 (32%) 13 (20%) 15 (23%)
.99 .48 .87 .35
2 ( 9%) 5 (23%) 3 (14%) 8 (36%) 4 (18%)
11 (17%) 17 (26%) 10 (15%) 6 (9%) 21 (32%)
.66 .89 .86 .035 .48
9 (41%) 10 (45%) 3 (14%)
25 (38%) 30 (46%) 10 (16%)
.89 .97 .86
14 (63%) 3 (14%)
25 (38%) 7 (11%)
.32 .99
2 (9%)
5 (8%)
.99
TABLE 4. Associations between Mammographic Calcification Features and Basal-like Breast Cancers Tumor Phenotype (%) Mammographic Calcification Features Distribution Clustered Segmental Regional Linear Diffuse Morphologic aspects Pleomorphic Fine linear Punctate Coarse
Basal-like (n = 14)
Non–basal-like (n = 87)
P Value
6 (42%) 3 (21%) 1 (7%) 1 (7%) 3 (21%)
34 (39%) 13 (15%) 9 (10%) 16 (18%) 15 (17%)
.99 .89 .99 .60 .99
9 (64%) 2 (14%) 2 (14%) 1 (7%)
33 (38%) 21 (24%) 19 (22%) 14 (16%)
.38 .75 .86 .72
negative mammograms showed that improvement in the detection of architectural distortion could lead to significant improvement in the prognosis of breast cancer patients (30). Thus, further evaluation of the diagnostic efficacy of architectural distortion, the association with basal-like tumor, and other biological markers, is warranted. The retrospective nature and relatively small sample size presents potential limitations with respect to the interpretation of this study. Further study with a larger patient cohort is 338
recommended to confirm these results and could offer more clues about their prognostic and predictive value in basal-like breast carcinoma, as well as more efficacious treatment. In summary, this study offers a further radiological perspective to the proposed taxonomy and describes mammographic differences in tumor appearance between the basal-like and non–basal-like phenotype of breast cancers. Compared with non–basal-like breast cancers, basal-like tumors were more likely to have indistinct masses, and associate with architectural distortion on mammograms. Given the facts that basallike breast cancer tends to occur in younger women and is associated with poor prognosis, these characteristics may reflect an aggressive, rapidly proliferating phenotype of breast cancer. The biological reasons for these findings and their implications regarding imaging protocols require further study and may enable improved detection of basal-like breast cancer.
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17. Carey LA, Perou CM, Livasy CA, et al. Race, breast cancer subtypes, and survival in the Carolina Breast Cancer Study. JAMA 2006; 295:2492–2502. 18. Bertucci F, Finetti P, Cervera N, et al. How basal are triple-negative breast cancers? Int J Cancer 2008; 123:236–240. 19. Bidard FC, Conforti R, Boulet T, et al. Does triple negative phenotype accurately identify basal-like tumour? An immunohistochemical analysis based on 143 ‘triple-negative’ breast cancers. Ann Oncol 2007; 18:1285–1286. 20. Tan DS, Marchio C, Jones RL, et al. Triple negative breast cancer molecular profiling and prognostic impact in adjuvant anthracycline-treated patients. Breast Cancer Res Treat 2008; 111:27–44. 21. Bauer KR, Brown M, Cress RD, et al. Descriptive analysis of estrogen receptor (ER)-negative, progesterone receptor (PR)-negative, and HER2negative invasive breast cancer, the so-called triple-negative phenotype: a population-based study from the California Cancer Registry. Cancer 2007; 109:1721–1728. 22. Dent R, Trudeau M, Pritchard KI, et al. Triple-negative breast cancer: clinical features and patterns of recurrence. Clin Cancer Res 2007; 13: 4429–4434. 23. Brown M, Tsodikov A, Bauer KR, et al. The role of human epidermal growth factor receptor 2 in the survival of women with estrogen and progesterone receptor-negative, invasive breast cancer: the California Cancer Registry, 1999–2004. Cancer 2008; 112:737–747.
24. Lund MJ, Butler EN, Bumpers HL, et al. High prevalence of triple-negative tumors in an urban cancer center. Cancer 2008; 113:608–615. 25. Rakha EA, El-Rehim DA, Paish C, et al. Basal phenotype identifies a poor prognostic subgroup of breast cancer of clinical importance. Eur J Cancer 2006; 42:3149–3156. 26. Tabar L, Chen H-H, Duffy SW, et al. A novel method for prediction of longterm outcome of women with T1a, T1b, and 10–14 mm invasive breast cancers: a prospective study. Lancet 2000; 355:429–433. 27. Thurfjell E, Thurfjell MG, Lindgren A. Mammographic finding as predictor of survival in 1–9 mm invasive breast cancers. Worse prognosis for cases presenting as calcifications alone. Breast Cancer Res Treat 2001; 67: 177–180. 28. Broeders MM, Onland-Moret NC, Rijken HM, et al. Use of previous screening mammograms to identify features indicating cases that would have a possible gain in prognosis following earlier detection. Eur J Cancer 2003; 39:1770–1775. 29. Yankaskas BC, Schell MJ, Bird RE, et al. Reassessment of breast cancers missed during routine screening mammography: a community-based study. Am J Roentgenol 2001; 177:535–541. 30. Venkatesan A, Chu P, Kerlikowske K, et al. Positive predictive value of specific mammographic findings according to reader and patient variables. Radiology 2009; 250:648–657.
339
A
nalysis of breast cancer tissue with DNA microarrays has categorized breast carcinoma into the following five distinct subtypes: luminal A (estrogen receptor [ER] positive and/or progesterone receptor [PR] positive, human epidermal growth factor receptor 2 [HER-2/neu) negative], luminal B (ER positive and/or PR positive, HER-2/neu positive), HER-2/neu overexpression (ER negative, PR negative, HER-2/neu positive), basal-like (ER negative, PR negative, HER-2/neu negative, cytokeratin 5 and 6 [CK5/6] positive and/or epidermal growth factor receptor [EGFR] positive) and normal breast-like tumors. Although this classification system is based on extensive genetic profiling assays, a simplified method of classification (based on ER, PR, HER-2/neu, CK5/6, and EGFR status) is appealing and more clinically useful. The basal-like subtype is associated with aggressive histology, poor prognosis, unresponsiveness to the usual endocrine therapies, and shorter
Acad Radiol 2010; 17:333–339 From the Departments of Breast Surgery (X.W., L.C., G.M., G.J.), Radiology (M.H.), Jinan Central Hospital, Shandong University School of Medicine, Jinan 250013, China; Infertility Center, Qilu Hospital, Shandong University, Jinan, China (L.C.), Department of Pathology, Shandong University School of Medicine, Jinan, China (G.Z.). Received August 27, 2009; accepted October 1, 2009. Address correspondence to: X.W. e-mail: wangxiao@ sdu.edu.cn ªAUR, 2010 doi:10.1016/j.acra.2009.10.011
survival (1,2). The pathways that drive proliferation of these tumors are still poorly understood; however, after they have been elucidated, targeted agents can be developed, which could result in better outcomes for patients with basal-like tumors. Several studies have attempted to evaluate and interpret the clinical perspective of the relationship between mammographic features and HER-2/neu overexpression in breast carcinomas, and shown that mammographic calcifications are correlated with HER-2/neu overexpression in breast carcinomas (3–6). Furthermore, the clinical perspective of the relationship between mammographic calcifications and the expression of selected biological markers, such as ER, PR, EGFR, Bax, Fas, Bcl-2, and DNA fragmentation factor in breast carcinomas have been interpreted (7,8). Recently, Luck et al reported that basal-phenotype tumors were significantly more likely to manifest as an illdefined mass or with comedo calcification in a cohort of 356 screening-detected breast tumors (9), and Yang et al found that triple receptor negative breast cancers were more frequently associated with a mass, and were less frequently associated with calcifications in 198 young, premenopausal breast cancer patients (10). To better understand the associations between the mammographic features including calcifications and basal-like breast carcinoma, we performed immunohistochemical staining to category phenotypes of breast carcinoma, aimed to retrospectively 333
WANG ET AL
evaluate the association between mammographic features and basal-like breast carcinoma, and to assess its clinical perspective. MATERIALS AND METHODS Patients
We searched the pathology database to identify women who underwent surgical breast treatment between May 2003 and August 2008. Patients were excluded when we could not obtain archival paraffin-embedded tumor specimens, clinical information, or preoperative mammograms for analysis, and patients with evidence of disease within 1 month after primary surgery were excluded. Furthermore, patients with only carcinoma in situ were also excluded from this study. All 267 patients included in this study had primary breast cancer without distant metastases at the time of diagnosis. The median age of the patients was 54 years (range, 27–78 years). A waiver of informed consent was obtained from patients, and the institutional review board at the University School of Medicine approved this study. A waiver of informed consent was obtained for this study. A breast and gynecologic pathologists (G.Z.) reevaluated pathologic features. The tumor subtypes of invasive carcinoma were classified as ductal carcinoma and others. Other invasive carcinomas included medullary, mucinous, or lobular carcinomas. Tumor grade of invasive carcinomas was classified according to the Scarff-Bloom-Richardson system (11). Based on the frequency of cell mitosis, tubule formation, and nuclear pleomorphism, invasive carcinoma was graded as grade 1 (low), grade 2 (moderate), or grade 3 (high grade). Presence of lymph node metastases were reviewed for each patient. The tumor stage was determined according to the American Joint Committee on Cancer Cancer Staging Manual, sixth edition (12). The clinical data were collected from the medical files. Conventional clinical features were evaluated including age, menopause status, pathological grading, tumor T stage, and lymph node metastasis. Mammography
The mammograms were obtained with the Gold Standard DR 17 Mammography System (Pan-Pacific Enterprises, Inc., Brewster, NY). The standard craniocaudal and lateral views were carried out in all patients. Full-resolution mammography of calcifications included orthogonal magnification projections, usually craniocaudal and mediolateral projections. Cone-down magnification views were obtained when necessary. All the mammograms were evaluated independently by two experienced breast radiologists (X.W., and M.H.). All the mammograms were reviewed according to the analytic criteria of Breast Imaging Reporting and Data System, 4th edition (13,14). Both radiologists who read an image had to agree on an interpretation before the results 334
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were recorded. Mammographic findings were categorized as mass, calcifications, architectural distortions, and asymmetric densities. For carcinomas presenting as masses on mammography, we evaluated the shape, margin, density, and associated findings. For carcinomas with calcifications on mammography, their morphology and distribution were evaluated. Morphologic aspects of calcification were classified into four groups: pleomorphic, fine linear, punctuate, and coarse calcifications. Distribution features were classified as: clustered, segmental, regional, linear, and diffuse. Basal-like Breast Carcinoma Tissues
ER, PR, and HER-2/neu status were assessed by standard immunohistochemical methods. Immunohistochemical markers were assayed in paraffin-embedded, formalin-fixed tissue using antibodies against ER, PR, and HER-2/neu (Dako, Glostrup, Denmark). For ER and PR, receptor positivity was scored as more than 10% of cells testing positive. HER-2/neu was assessed through immunohistochemistry (IHC) and was scored on a qualitative scale from 0 to 3+, based on interpretation of staining, with 0 and 1+ classified as negative and 3+ as positive. Tumor specimens that showed an intermediate HER-2/neu staining score of 2+ were further assayed with fluorescent in situ hybridization (Vysis, Des Plaines, IL) to determine HER-2/neu amplification. All samples that had intense, complete, membranous staining in >10% of invasive neoplastic cells determined by IHC or the presence of HER-2/neu gene amplification determined by fluorescent in situ hybridization were considered HER-2/ neu positive. Additional IHC was performed with antibodies against CK5/6 (clone D5/16B4, Carpinteria, CA; 1:50 dilution, DAKO), and EGFR (clone ab2430, Cambridge, MA; 1:200 dilution, Abcam) using a streptavidin-biotin horseradish peroxidase detection kit (Biogenex, San Ramon, CA). Secondary antibody was applied for 1 hour and staining was visualized according to the manufacturer’s instructions (Santa Cruz Biotechnology, Santa Cruz, CA). Omission of the primary antibody was used as a negative control. Cases of invasive ductal carcinoma previously known to be positive for CK5/6 and EGFR were used as positive controls. The expression of CK5/6 was cytoplasmic, whereas the expression of EGFR was both cytoplasmic and membranous. Sections with cytoplasmic expression in $10% of tumor cells for CK5/6 and membranous staining in $10% of tumor cells for EGFR were considered positive. The breast cancers were divided into subtypes included luminal A (positive for ER and/or PR and negative for HER-2/neu), luminal B (positive for ER or PR and positive for HER-2/neu), HER-2/neu overexpression (negative for ER and PR and positive for HER-2/neu), and basal-like (negative for ER, PR, and HER-2/neu and positive for CK5/6 and/or EGFR) (15). In the current study, luminal A, luminal B, and HER-2/neu overexpression subtypes were combined into a single non–basal-like group and were compared to the basal-like group.
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Figure 1. Representative immunohistochemical staining of protein markers in basal-like breast cancers. (a) Negative expression of cytokeratins 5 and 6 (CK5/6); (b) negative expression of epidermal growth factor (EGFR); (c) positive cytoplasmic expression of CK5/6; (d) positive cytoplastic and membranous expression of EGFR. Original magnification: (a, b) 200; (c, d) 400.
Statistical Analysis 2
The c and Fisher’s exact tests were used to evaluate the association of phenotypes of breast carcinoma with mammographic and clinicopathological features. All statistical tests were two-sided and statistical significance of observed difference was set at P < .05. All data were analyzed using SPSS statistical software (Version 13.0, SPSS Inc., Chicago, IL).
RESULTS Correlation between Basal-like Breast Carcinomas and Clinicopathological Parameters
In the current study, 52 of 267 (19%) patients were of the triple-negative phenotype. Additional immunohistochemical staining for CK5/6 and EGFR was performed to determine what proportion of the triple-negative tumors had the basallike phenotype. Of 52 triple negative tumors, 40 (77%) were CK5/6 and/or EGFR positive (Fig 1). Thus, of the 267 invasive breast cancers, 40 (15%) were of the basal-like phenotype, and 227 (85%) were grouped as non–basal-like phenotype. The two more striking differences between the basal-like and the non–basal-like phenotypes were the higher percentage of younger women (#35 years) and premenopausal patients with basal-like tumors, with 35% of the patients with basal-like tumors younger than age 35 years at diagnosis compared with 9% of the patients with non–basallike phenotype (P = .001), and 78% of the basal-like group were premenopausal patients compared with 51% of the non–basal-like cohort (P = .003) (Table 1). Patients in the basal-like group were more likely to have higher grade of tumors, with 40% of the basal-like group being Grade 3 at
TABLE 1. Difference of Clinicopathological Characteristics between Basal-like and Non–basal-like Breast Cancers Tumor Phenotype (%)
Characteristics Age at diagnosis #35 36–49 $50 Menopause status Premenopausal Postmenopausal Histology Ductal Lobular Others T stage T1 T2 T3 Nodal status Negative Positive Tumor grade 1 2 3
n
Basal-like Non–basal-like (n = 40) (n = 227) P Value
34 126 107
14 (35%) 15 (38%) 11 (27%)
20 (9%) 111 (49%) 96 (42%)
.001
147 120
31 (78%) 9 (22%)
116 (51%) 111 (49%)
.003
218 22 27
36 (90%) 2 (5%) 2 (5%)
182 (80%) 20 (9%) 2 5(11%)
.33
108 136 23
9 (23%) 20 (50%) 11 (27%)
99 (44%) 116 (51%) 12 (5%)
.001
176 91
25 (62%) 15 (38%)
151 (67%) 76 (33%)
.75
90 116 61
10 (25%) 14 (35%) 16 (40%)
80 (35%) 102 (45%) 45 (20%)
.019
diagnosis compared with 20% of the non–basal-like cohort (P = .019). Furthermore, basal-like phenotype was more frequently associated with advanced T stage (27%) when compared with that of non–basal-like phenotype (5%) (P = .001) (Table 1). 335
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TABLE 2. Association between Mammographic Features and Basal-like Breast Cancers Tumor Phenotype (%) Mammographic Findings Mass + Calcification + Architectural distortion + Asymmetric density +
Basal-like (n = 40)
Non–basal-like (n = 227)
P Value
22 (55%) 18 (45%)
65 (29%) 162 (71%)
.002
14 (35%) 26 (65%)
87 (38%) 140 (62%)
13 (33%) 27 (67%)
28 (12%) 199 (88%)
.002
3 ( 8%) 37 (92%)
12 (5%) 215 (95%)
.85
.82
Table 4 shows comparison between breast carcinomas with basal-like phenotype and those with non–basal-like phenotype with respect to mammographic calcification features. Although pleomorphic morphology of calcifications was more frequent in carcinomas with basal-like phenotype (9 of 14, 64%) compared to those with non–basal-like phenotype (33 of 87, 38%), there was no significant difference between the two groups (P = .38). Furthermore, there was no significant difference in distribution of mammographic calcifications between the two groups with basal-like or non–basal-like breast carcinomas (P > .05).
DISCUSSION
Correlation between Mammographic Features and Basal-like Phenotype
All patients had diagnostic mammograms available for review. The associations between mammographic features and phenotypes of breast carcinoma are showed in Table 2. Of the 267 invasive breast cancers, 87 cases with breast cancers presented as a mass (39 with associated calcifications), 41 as calcifications alone, 31 as architectural distortion (14 with associated calcification), and 15 as asymmetric density (7 with associated calcification). Represent mammographic masses, calcifications, and architectural distortion were shown in Figure 2. There was a significant association between presence of masses and basal-like breast cancer (P =.002). Masses were more frequent in carcinomas with basal-like phenotype (22 of 40, 55%) than in those with non–basal-like phenotype (65 of 227, 29%). Furthermore, basal-like phenotype was more frequently to have architectural distortion (13 of 40, 33%) than non–basal-like phenotype (28 of 227, 12%) (P = .002). There was no significant difference in other mammographic features including calcifications and asymmetric density between the two groups with basal-like and non– basal-like phenotype (P > .05). Correlation between Shape, Margin, Density, and Associated Findings of Mass on Mammography and Basal-like Phenotype
In the 85 carcinomas presenting with masses on mammography, indistinct margin was more common in masses with basal-like phenotype (8 of 22, 36%) than in those with non–basal-like phenotype (6 of 65, 9%) (P =.035) (Table 3). There were no significant differences in shape, density, and associated findings of the masses between the two groups with basal-like or non–basal-like breast carcinomas (P > .05) (Table 3). 336
Correlation between Mammographic Calcification Features and Basal-like Phenotype
Mammography contributes to the improvement of breast carcinoma survival through early detection and treatment of breast lesions. Knowledge of mammographic appearances, such as mass, calcification, architectural distortions, and asymmetric densities, is fundamental to screening detection of the various types of breast cancer. Developing a unified classification schema that incorporates imaging findings, molecular subtype, and predictive biomarkers should help to more precisely predict patient outcome and those individuals who will be responsive to a specific therapeutic regimen. Protein expression profiling of breast cancer has identified specific subgroups with potential clinical, biological, and therapeutic implications. Luminal tumors have been associated with the most favorable prognoses, while HER-2/neu overexpressing and basal-like tumors, or their surrogate triple negative tumors, have been associated with the worst prognoses (16,17). Approximately 70% of triple-negative phenotype breast cancers express basal markers (18–20). Because the basal-like phenotype is not amenable to any form of endocrine therapy, efforts are under way to develop appropriate targeted therapies. Greater understanding of the pathologic and molecular characteristics of this phenotype may lead to better tailored treatments for these patients. Our results are in agreement with previous studies that basal-like phenotype is commonly associated with younger age at diagnosis (21,22), more advanced T stage (23,24), higher grade (17,25), and premenopausal status (10). In the current study, we have found that 15% of the cases of 267 invasive breast cancers are basal-like phenotype. This percentage is largely in agreement with the overall staining levels reported previously (15,16). Mammographic masses were more significantly frequent in carcinomas with basallike phenotype than in those with non–basal-like phenotype. In the view of margin category of mass, basal-like phenotype cancers that appeared as masses were most frequently with indistinct margins. This is in agreement with observations from other groups (9,10). However, they were no significant difference in shapes of mammographic masses between the two groups with basal-like and non–basal-like breast
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Figure 2. Representative mammographic features of basal-like breast carcinomas. (a) Mammogram shows architectural distortion with pleomorphic calcifications (CC). (b) Mammogram shows architectural distortion (MLO). (c) Mammogram shows an irregular mass with spiculated margin (CC). (d) Mammogram shows a mass with indistinct margin (MLO).
carcinomas, this is in contrast with Yang, who observed that masses of triple receptor negative cancers were most frequently round, oval, or lobular in shape in a cohort of young, symptomatic patients. Possibly this discrepancy is due to the different use of categories and different cohorts of women. Calcifications represent one of the most important mammographic findings of breast carcinoma and are often the only mammographic sign of a malignant breast disease. There are well-established diagnostic criteria basing on the morphology and distribution of the calcifications radiologically (13,14). The presence of pleomorphic calcifications in small breast cancers was an independent predictor of poor prognosis (26,27). Recently, Luck et al reported that basal tumors are more likely to be found in association with comedo calcification at mammograms. However, there were no significant differences in mammographic calcifications,
even for the distribution and morphology characteristics, between the two groups with basal-like and non–basal-like breast carcinomas in the present study. In addition, it is worth noting that basal-like tumors were significantly more likely than non–basal-like tumors to appear as architecture distortion on mammograms in the present study. Architectural distortion as such is not a mass but rather a local disruption of the normal breast tissue pattern. Patients showing architectural distortion on the mammogram often have an invasive carcinoma with noticeable fibrosis, such as scirrhous carcinoma and invasive lobular carcinoma. As a mammographic finding, architectural distortion has a low prevalence yet demonstrates a high positive predictive value for cancer at screening and diagnostic examinations (28). Specifically, architectural distortion accounts for 12%–45% of breast cancers overlooked or misinterpreted at screening mammography (29). A recent study that analyzed false337
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TABLE 3. Associations between Shape, Margin, Density, and Associated Findings of Mass on Mammography and Basallike Breast Cancers Tumor Phenotypes (%) Mammographic Mass Features Mass shape Round Oval Lobulated Irregular Mass margin Circumscribed Microlobulated Obscured Indistinct Spiculated Density High Equal Low Associated findings Calcifications Architectural distortion Skin retraction
Basal-like (n = 22)
Non–basal-like (n = 65)
P Value
5 (23%) 4 (18%) 4 (18%) 9 (41%)
16 (25%) 21 (32%) 13 (20%) 15 (23%)
.99 .48 .87 .35
2 ( 9%) 5 (23%) 3 (14%) 8 (36%) 4 (18%)
11 (17%) 17 (26%) 10 (15%) 6 (9%) 21 (32%)
.66 .89 .86 .035 .48
9 (41%) 10 (45%) 3 (14%)
25 (38%) 30 (46%) 10 (16%)
.89 .97 .86
14 (63%) 3 (14%)
25 (38%) 7 (11%)
.32 .99
2 (9%)
5 (8%)
.99
TABLE 4. Associations between Mammographic Calcification Features and Basal-like Breast Cancers Tumor Phenotype (%) Mammographic Calcification Features Distribution Clustered Segmental Regional Linear Diffuse Morphologic aspects Pleomorphic Fine linear Punctate Coarse
Basal-like (n = 14)
Non–basal-like (n = 87)
P Value
6 (42%) 3 (21%) 1 (7%) 1 (7%) 3 (21%)
34 (39%) 13 (15%) 9 (10%) 16 (18%) 15 (17%)
.99 .89 .99 .60 .99
9 (64%) 2 (14%) 2 (14%) 1 (7%)
33 (38%) 21 (24%) 19 (22%) 14 (16%)
.38 .75 .86 .72
negative mammograms showed that improvement in the detection of architectural distortion could lead to significant improvement in the prognosis of breast cancer patients (30). Thus, further evaluation of the diagnostic efficacy of architectural distortion, the association with basal-like tumor, and other biological markers, is warranted. The retrospective nature and relatively small sample size presents potential limitations with respect to the interpretation of this study. Further study with a larger patient cohort is 338
recommended to confirm these results and could offer more clues about their prognostic and predictive value in basal-like breast carcinoma, as well as more efficacious treatment. In summary, this study offers a further radiological perspective to the proposed taxonomy and describes mammographic differences in tumor appearance between the basal-like and non–basal-like phenotype of breast cancers. Compared with non–basal-like breast cancers, basal-like tumors were more likely to have indistinct masses, and associate with architectural distortion on mammograms. Given the facts that basallike breast cancer tends to occur in younger women and is associated with poor prognosis, these characteristics may reflect an aggressive, rapidly proliferating phenotype of breast cancer. The biological reasons for these findings and their implications regarding imaging protocols require further study and may enable improved detection of basal-like breast cancer.
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