Wo m e n ’s I m a g i n g • R ev i ew Bitencourt et al. MRI of Mucinous Breast Cancer
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Women’s Imaging Review
Almir G. V. Bitencourt 1 Luciana Graziano1 Cynthia A. B. T. Osório 2 Camila S. Guatelli1 Juliana A. Souza1 Maria Helena S. Mendonça3 Elvira F. Marques1 Bitencourt AGV, Graziano L, Osório CABT, et al.
Keywords: breast neoplasms, MRI, mucinous neoplasms DOI:10.2214/AJR.15.14851 Received April 20, 2015; accepted after revision July 1, 2015. 1 Department of Imaging, AC Camargo Cancer Center, Rua Prof. Antônio Prudente 211, São Paulo, Brazil 01509-010. Address correspondence to A. G. V. Bitencourt ([email protected]). 2 Department of Pathology, AC Camargo Cancer Center, São Paulo, Brazil. 3 DASA - Breast MRI Scientific Coordinator, São Paulo, Brazil.
This article is available for credit. AJR 2016; 206:238–246 0361–803X/16/2062–238 © American Roentgen Ray Society
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MRI Features of Mucinous Cancer of the Breast: Correlation With Pathologic Findings and Other Imaging Methods OBJECTIVE. Mucinous breast carcinoma is an uncommon histologic type of invasive breast carcinoma that can be differentiated in pure and mixed forms, which have different prognosis and treatment. CONCLUSION. MRI features of both types of mucinous breast carcinomas are discussed, illustrated, and compared with pathologic findings and with other imaging methods, including mammography, ultrasound, and PET/CT. ucinous breast carcinoma, also known as colloid carcinoma, is a well-differentiated type of adenocarcinoma that typically contains abundant extracellular mucin secreted by tumor cells. It is an uncommon histologic type that accounts for about 2% of all invasive breast carcinomas. This neoplasm usually occurs in women older than 55 years and is generally considered to have a favorable prognosis. However, mucinous carcinoma is often intermixed with invasive ductal carcinoma not otherwise specified (NOS), and the prognosis is less favorable in such cases [1, 2]. There are two types of mucinous breast carcinoma. In pure mucinous carcinomas, less than 10% of the tumor is composed of other histologic types of breast cancer, whereas in mixed mucinous carcinomas, more than 10% of the tumor is composed of other histologic subtypes, mainly invasive ductal carcinoma NOS. This distinction has important implications because pure mucinous cancers tend to be less aggressive and have a lower frequency of axillary metastases and a better overall survival rate than do mixed tumors [3, 4]. This neoplasm usually presents with benign clinical, mammographic, and sonographic features, possibly leading to a delayed diagnosis [5]. Breast MRI is now widely used to diagnose and characterize suspected breast lesions identified by mammography and sonography. Several reports have been published regarding the MRI findings of mucinous breast carcinoma with respect to the lesion’s shape, signal intensity on fat-saturated T2-weighted
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images, DWI findings, and enhancement pattern on dynamic MRI [6–13]. The aims of this study are to discuss and illustrate the MRI features of mucinous cancer of the breast and to correlate MRI findings with those of other imaging methods and pathologic findings. Pathologic Analysis According to the World Health Organization [14], mucinous carcinoma contains large amounts of extracellular epithelial mucin sufficient to be visible grossly and recognizable microscopically surrounding and within tumor cells. On gross pathologic examination, mucinous carcinomas are round circumscribed nonencapsulated tumors with a typical gelatinous cut surface. On microscopic examination, mucinous carcinoma consists of well-differentiated carcinoma cells arranged in small clusters that are surrounded by mucin lakes. Pathologic specimens vary in the amount of mucin, and cells and are described as having the hypercellular and hypocellular properties of breast mucinous carcinoma. Hypocellular, or type A, mucinous carcinomas show larger quantities of extracellular mucin and have favorable prognosis, whereas hypercellular, or type B, mucinous carcinomas have large cell clusters, frequent neuroendocrine differentiation, and worse prognosis [15]. According to the mucinous content of the carcinoma, it can be histologically categorized as pure mucinous carcinoma, in which more than 90% of tumor cells are composed by extracellular mucin without other associ-
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MRI of Mucinous Breast Cancer ated subtypes, or as the mixed form, which contains an admixture with invasive subtypes, mainly invasive ductal carcinoma NOS (Fig. 1). Histologically, pure mucinous carcinomas usually have circumscribed margins, whereas mixed mucinous carcinomas tend to have infiltrative margins [16]. It is important to apply strict histologic criteria to differentiate pure and mixed mucinous carcinomas because the former usually have a better prognosis and a lower rate of axillary lymph node metastasis. Although these two subtypes are defined, a standard threshold for clear distinction has never been defined. Some authors suggest a mucin component of at least 90% for pure mucinous carcinomas [17, 18]. Pure mucinous breast carcinoma has a favorable prognosis. Tumor size does not appear to significantly affect survival, perhaps because the large volume of mucin may lead to overestimation of tumor burden. The number of involved axillary lymph nodes is the most important predictor of death from disease [19]. Usually, pure mucinous carcinomas exhibit a rate of metastasis of less than 15% and an overall 10-year survival of almost 100% [4]. Because mixed mucinous carcinoma has more-invasive histologic characteristics, this subtype exhibits more aggressive behavior with a higher metastatic nodal involvement rate and a decreased survival rate. Regarding hormonal status, mucinous tumors generally have a high proportion of hormone receptor expression, which often confers a better prognosis. Both pure and mixed mucinous carcinomas show similar estrogen receptor– and progesterone receptor–positive statuses, indicating that both types can benefit from hormonal treatment [1]. Associated intraductal cancer can be seen among the histopathologic specimens in as many as 75% of cases, and extensive intraductal component can be seen in up to 38% of cases [6]. Extensive intraductal component is a common cause of positive surgical margins after conservative surgery for invasive breast cancer, and its preoperative diagnosis may be challenging for the radiologist. Mammography and Ultrasound The mammographic and sonographic features of mucinous breast carcinoma show differences between the pure and mixed types of the tumor. The imaging appearance of mucin-containing carcinomas reflects the percentage of the mucin component. Pure
mucinous carcinoma with high percentages of mucin commonly manifests as a circumscribed round or oval mass that sometimes has microlobulated margins. Pure type carcinomas with small percentages of mucin and mixed type carcinomas have more-aggressive imaging characteristics [16, 17, 20]. Most mucinous carcinomas are readily detected on mammography. They usually appear as low-density, round, or oval masses with circumscribed margins. Microlobulated margins have been associated with higher mucin content, whereas irregular or spiculated margins correspond to lower percentages of mucin and infiltrating margins histologically [20]. Calcifications are a rare but reported histologic feature of mucinous breast carcinomas, and they frequently correspond to the invasive ductal component of the cancer in mixed tumors. Sonographically, mucinous carcinomas of the breast are isoechoic or hypoechoic to subcutaneous fat. Internal echo may be homogeneous or heterogeneous, with cystic and solid components. Posterior acoustic enhancement is a common finding [21]. Homogeneity on sonography is associated with the pure type of mucinous carcinoma and, hence, a better prognosis [22]. Most pure type carcinomas show isoechogenic echotexture relative to subcutaneous fat echo and a good sound transmission, whereas all mixed type carcinomas were hypoechogenic with acoustic shadowing in half of them [20]. MRI The typical MRI findings of pure mucinous carcinoma include a circumscribed mass with extremely high signal intensity on fat-saturated T2-weighted imaging and benign-appearing kinetics with gradual and persistent enhancement. These MRI features might be difficult to differentiate from those of benign lesions, such as cysts or fibroadenomas, and the radiologist must be aware of this to avoid misinterpretation. Higher-grade or mixed mucinous lesions might have more suspicious imaging features [6, 9, 10, 12, 13, 23]. As with ultrasound, mucinous carcinomas might be difficult to differentiate from such benign lesions as fibroadenomas on MRI. Although most well-circumscribed breast masses are benign lesions, 10–20% of breast malignancies are also well-circumscribed masses, and these malignant masses include papillary, mucinous, medullary, and metaplastic carcinomas as well as malignant phyllodes tumors [9, 24].
Mucinous carcinomas show variable signal intensity on fat-saturated T1-weighted MR images, depending on the differences in protein composition of the tumor, and are homogeneously or heterogeneously hyperintense on fat-saturated T2-weighted images, which correlates with the large mucinous component at histologic examination. Both the pure and mixed forms of mucinous carcinoma had varying shapes. Although irregular margins are often seen with mixed tumors, pure tumors also can present with this finding. After contrast agent administration, most mucinous carcinomas gradually and progressively enhance, often with a rim of heterogeneous enhancement. The presence of enhancing internal septations has been suggested to differentiate mucinous carcinoma from myxoid fibroadenoma; however, this is an uncommon finding [7, 10]. Fat-Saturated T2-Weighted Imaging Typical invasive breast carcinomas have shorter T2 relaxation times and display lower signal intensity on fat-saturated T2-weighted images than do benign lesions. However, various histopathologic components in malignant breast lesions may generate hyperintense signal on fat-saturated T2-weighted MR images. Histopathologic features that may produce high signal intensity in breast lesions include necrotic carcinoma, a cystic or microcystic component, an adipose or sebaceous component, mucinous stroma, loose myxoid stroma, stromal edema, and hemorrhagic changes [25]. Nonmucinous carcinomas can present with high signal intensity on fat-saturated T2-weighted images because of a mixture of background matrix, a higher proportion of cells than stroma, abundant cytoplasm, edematous stroma, and hemorrhage [7]. The presence of very high signal intensity on fat-saturated T2-weighted images is a common feature of pure and mixed mucinous tumors [10]. In pure mucinous carcinoma, almost all parts of the tumor are filled with mucin component, and homogeneous high signal intensity on fat-saturated T2-weighted images may reflect this histologic type (Fig. 2). The solid component in mixed mucinous carcinoma can be identified by lower signal intensity than the mucinous component (Fig. 3). However, in cases of mixed tumors with a small amount of solid components, the signal intensity can be homogeneously very high, as seen in pure mucinous carcinoma [8].
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Bitencourt et al. DWI DWI is emerging as an important tool in breast MRI. Lesions with high cellularity, such as most breast malignancies, have restricted diffusion of water molecules, which results in high signal intensity on DWI and a low apparent diffusion coefficient (ADC). However, because of low cellularity and abundant mucin, mucinous tumors do not restrict diffusion and show lower signal intensity on DWI and increased ADC values when compared with those of other malignant breast tumors (Fig. 4). The ADC of mucinous carcinoma is also higher than that of most benign breast tumors, such as fibroadenomas. Woodhams et al. [11] studied breast lesions for 276 patients and found that the mean ADC of mucinous carcinoma (1.8 ± 0.4 × 10−3 mm2/s) was statistically significantly higher than that of benign lesions (1.3 ± 0.3 × 10−3 mm2/s) and other malignant tumors (0.9 ± 0.2 × 10−3 mm2/s). Hatakenaka et al. [26] found that, although the difference in ADC between fibroadenomas and mucinous carcinoma was significant, the difference in cellularity was not. Thus, the water in the mucin pool can probably move more randomly compared with that in the interstitium or cytoplasm of fibroadenomas. However, some benign breast tumors, particularly fibroadenomas and benign phyllodes tumors, have high ADCs overlapping those of mucinous carcinoma because of the presence of myxomatous or edematous stroma [26–28]. The ADC of a mixed mucinous tumor depends on the proportion of mucinous to nonmucinous components within the lesion. Because of greater cellularity and lower mucin content, a mixed tumor will likely have a lower ADC than a pure tumor. In general, the ADC of a pure mucinous lesion will be higher than that of a mixed lesion, and the ADC of a mixed lesion might not be significantly different from that of typical breast lesions [11, 13]. Dynamic MRI The contrast enhancement pattern of dynamic MRI is reported to be useful for differentiation between malignant and benign breast tumor. A washout or plateau pattern, with peak contrast in approximately 1 minute on a kinetic curve, has been stated to be suggestive of malignancy. However, 5–14% of breast cancers exhibit a gradual enhancement pattern, including tumors rich in stroma, such as breast cancer with a large fibrous component, and mucinous carcinoma [29].
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After injection of gadolinium-based contrast agent, mucinous carcinomas can show three different enhancement patterns depending on the amount and spatial distribution of the solid and mucinous components [23]: first, no appreciable enhancement, when mucin is the predominant tumor component (Fig. 5); second, heterogeneous enhancement, corresponding to islands of neoplastic epithelial cells floating in the pool of mucin (Fig. 6); and third, rim enhancement, corresponding to a peripheral distribution of tumor cells and central location of mucin (Fig. 7). Time–signal intensity curves obtained from dynamic contrast-enhanced MRI of mucinous carcinomas usually show a gradually enhancing pattern (Fig. 8). One reason for this finding is that the presence of a large amount of mucin delays the intralesional diffusion of the contrast material [8]. The enhancement pattern during the early phase is closely related to the cellularity of pure tumors and the distribution of nonmucinous components in mixed tumors. Some authors have suggested that early enhancement of a mucinous carcinoma on MRI might suggest a higher grade more-aggressive lesion, with a worse prognosis [10, 24]. Hypocellular pure mucinous tumors have a typical pattern of gradual enhancement. Hypercellular pure tumors have strong early enhancement and can be difficult to differentiate from mixed tumors. The presence of an area exhibiting isointensity or low intensity on fat-saturated T2-weighted images and strong early enhancement imply the presence of a mixed mucinous tumor [10]. The presence of nonmasslike enhancement, such as linear-ductal, segmental, or regional distribution around the main tumor, may be a predictor of the presence of associated extensive intraductal component (Fig. 9). According to the literature [6], the sensitivity of MRI for the diagnosis of extensive intraductal component of invasive breast cancer is higher than that of mammography or ultrasound, ranging from 55% to 94%. 18 F-FDG
PET/CT FDG PET/CT is capable of providing information related to glucose metabolism in the various organs and tissues. For patients with breast cancer, FDG PET/CT is being increasingly used for staging and evaluation of therapeutic response after neoadjuvant chemotherapy [30, 31]. To our knowledge, there are no specific articles that evaluate the use of FDG PET/CT
for imaging of mucinous breast carcinoma. It is well known that PET/CT is less sensitive for small, low-grade, and slow-growing cancers, such as mucinous carcinoma. Low tumor cell density and a high concentration of mucin may help explain the lower FDG uptake on pure mucinous carcinomas. However, many articles have shown that high uptake of FDG would be predictive of poor prognosis and aggressive features of cancer cells in patients with early breast cancer [32–35]. Invasive ductal carcinomas have higher FDG uptake than do other histologic types [36, 37]. Thus, FDG PET/CT may help to differentiate pure from mixed mucinous carcinoma and to evaluate the aggressiveness of the tumor. Although pure tumors will present with no or mild FDG uptake (Fig. 10), mixed tumors should present with moderate to high FDG uptake because of the presence of associated invasive ductal carcinoma (Fig. 11). The combination of PET and MRI offers multiple functional data that complement each other, along with high-resolution anatomy. Initial studies using PET and MRI with multiparametric evaluation have shown that this method is promising in the diagnosis and characterization of breast lesions [38, 39]. Conclusion Several MRI features of pure mucinous carcinoma, such as lobular shape, high signal intensity on fat-saturated T2-weighted images, high ADC values, and gradually enhancing pattern on dynamic studies, are commonly seen in cases of benign lesions such as fibroadenomas. Therefore, cases of pure mucinous carcinoma can be misdiagnosed on MRI. However, other MRI features and correlation with other imaging methods may facilitate the differential diagnosis between mucinous carcinoma and benign lesions on MRI. The distinction between the pure and mixed forms of mucinous carcinoma is important because mixed tumors more frequently develop lymph node metastasis and have a worse prognosis. Patients with pure tumors are thought to be good candidates for conservative surgery. Thus, the imaging methods should be used to identify more-aggressive mucinous carcinomas and to target biopsy sampling to the most suspicious areas for hypercellular or nonmucinous components on preoperative biopsy. Besides the assessment of the index lesion, MRI may also play an important role in the identification of associated intraductal components, to improve the likelihood of successful surgical excision.
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MRI of Mucinous Breast Cancer
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Bitencourt et al.
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Fig. 1—Pathologic examinations of two histologic types of breast carcinoma. A, Photomicrograph of pure mucinous breast carcinoma (H and E, ×10). Carcinoma cells are arranged in small groups surrounded by lakes of extracellular mucin. B, Photomicrograph of mixed mucinous breast carcinoma (H and E, ×10). Invasive ductal poorly differentiated component is observed on left, and mucinous component is seen on right.
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Fig. 2—54-year-old woman with pure mucinous breast carcinoma. A, Mammogram shows two adjacent masses (oval) in superior quadrants of right breast. B, On MR image, these nodules (oval) show high signal intensity on fat-saturated T2-weighted sequence. C, After mastectomy, two nodules (circles) were identified on macroscopic evaluation and presented with gelatinous aspect.
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MRI of Mucinous Breast Cancer
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Fig. 3—60-year-old woman with mixed mucinous breast carcinoma. A and B, MR image obtained in fat-saturated T2-weighted sequence shows irregular mass in inferior quadrants of left breast with heterogeneous high signal intensity. Superior and anterior areas of lesion show lower signal intensity on fat-saturated T2-weighted sequence (arrow, A) and present with heterogeneous enhancement on contrast-enhanced T1-weighted sequence (arrow, B), corresponding to area of invasive ductal carcinoma component found on pathologic examination.
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Fig. 4—77-year-old woman with mixed mucinous breast carcinoma. A–C, MRI shows two adjacent masses in left breast with high signal intensity on fat-saturated T2-weighted sequence (A), high signal intensity on DW image (B), and no signs of restriction on apparent diffusion coefficient (ADC) map (C), with ADC of 2.30 mm2 /s.
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Bitencourt et al.
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Fig. 5—54-year-old woman with pure mucinous breast carcinoma. A, Mammogram shows lobulated partially obscured mass (oval) in superior quadrants of right breast. B and C, On MRI, this lesion (ovals) shows high signal on fat-saturated T2-weighted image (B) but no significant enhancement on fat-saturated T1-weighted contrast-enhanced image (C).
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Fig. 6—63-year-old woman with mixed mucinous breast carcinoma. A and B, MRI shows lobulated mass (arrows) in inferior quadrants of right breast with high signal intensity on fat-saturated T2-weighted image (A) and heterogeneous enhancement after contrast agent administration (B).
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MRI of Mucinous Breast Cancer
Fig. 7—55-year-old woman with mixed mucinous breast carcinoma. A and B, MR images show small regular mass (arrows) in lateral quadrants of left breast with homogeneous high signal intensity on fat-saturated T2-weighted image (A) and peripheral enhancement after contrast agent administration (B).
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Fig. 8—64-year-old woman with mixed mucinous breast carcinoma. A–C, MR images show irregular mass on superior quadrants of right breast, with hyperintensity on fat-saturated T2-weighted image (A), heterogeneous enhancement (B), and persistent enhancing pattern (type 1) on time–signal intensity curve obtained from dynamic contrast-enhanced MRI (C).
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Fig. 9—60-year-old-woman with mixed mucinous carcinoma in right breast. Three-dimensional volume-reconstructed maximum-intensity-projection subtraction breast MR image shows irregular mass on outer quadrants of right breast associated with mild nonmass enhancement with regional distribution around main tumor, extending to nipple-areola complex. Pathologic analysis of surgical specimen confirmed presence of associated extensive low-grade intraductal carcinoma of cribriform architecture.
Fig. 10—54-year-old woman with pure mucinous carcinoma. A and B, Mass in right breast is seen on CT images (arrow, A) with mild FDG uptake (standardized uptake value, 0.8) on PET/CT (circle, B) image.
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Fig. 11—63-year-old woman with high-grade mixed mucinous carcinoma. A and B, Mass in right breast is seen on CT image (arrow, A) with increased FDG uptake (standardized uptake value, 5.2) on PET/CT (oval, B) image.
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Women’s Imaging Review
Almir G. V. Bitencourt 1 Luciana Graziano1 Cynthia A. B. T. Osório 2 Camila S. Guatelli1 Juliana A. Souza1 Maria Helena S. Mendonça3 Elvira F. Marques1 Bitencourt AGV, Graziano L, Osório CABT, et al.
Keywords: breast neoplasms, MRI, mucinous neoplasms DOI:10.2214/AJR.15.14851 Received April 20, 2015; accepted after revision July 1, 2015. 1 Department of Imaging, AC Camargo Cancer Center, Rua Prof. Antônio Prudente 211, São Paulo, Brazil 01509-010. Address correspondence to A. G. V. Bitencourt ([email protected]). 2 Department of Pathology, AC Camargo Cancer Center, São Paulo, Brazil. 3 DASA - Breast MRI Scientific Coordinator, São Paulo, Brazil.
This article is available for credit. AJR 2016; 206:238–246 0361–803X/16/2062–238 © American Roentgen Ray Society
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MRI Features of Mucinous Cancer of the Breast: Correlation With Pathologic Findings and Other Imaging Methods OBJECTIVE. Mucinous breast carcinoma is an uncommon histologic type of invasive breast carcinoma that can be differentiated in pure and mixed forms, which have different prognosis and treatment. CONCLUSION. MRI features of both types of mucinous breast carcinomas are discussed, illustrated, and compared with pathologic findings and with other imaging methods, including mammography, ultrasound, and PET/CT. ucinous breast carcinoma, also known as colloid carcinoma, is a well-differentiated type of adenocarcinoma that typically contains abundant extracellular mucin secreted by tumor cells. It is an uncommon histologic type that accounts for about 2% of all invasive breast carcinomas. This neoplasm usually occurs in women older than 55 years and is generally considered to have a favorable prognosis. However, mucinous carcinoma is often intermixed with invasive ductal carcinoma not otherwise specified (NOS), and the prognosis is less favorable in such cases [1, 2]. There are two types of mucinous breast carcinoma. In pure mucinous carcinomas, less than 10% of the tumor is composed of other histologic types of breast cancer, whereas in mixed mucinous carcinomas, more than 10% of the tumor is composed of other histologic subtypes, mainly invasive ductal carcinoma NOS. This distinction has important implications because pure mucinous cancers tend to be less aggressive and have a lower frequency of axillary metastases and a better overall survival rate than do mixed tumors [3, 4]. This neoplasm usually presents with benign clinical, mammographic, and sonographic features, possibly leading to a delayed diagnosis [5]. Breast MRI is now widely used to diagnose and characterize suspected breast lesions identified by mammography and sonography. Several reports have been published regarding the MRI findings of mucinous breast carcinoma with respect to the lesion’s shape, signal intensity on fat-saturated T2-weighted
M
images, DWI findings, and enhancement pattern on dynamic MRI [6–13]. The aims of this study are to discuss and illustrate the MRI features of mucinous cancer of the breast and to correlate MRI findings with those of other imaging methods and pathologic findings. Pathologic Analysis According to the World Health Organization [14], mucinous carcinoma contains large amounts of extracellular epithelial mucin sufficient to be visible grossly and recognizable microscopically surrounding and within tumor cells. On gross pathologic examination, mucinous carcinomas are round circumscribed nonencapsulated tumors with a typical gelatinous cut surface. On microscopic examination, mucinous carcinoma consists of well-differentiated carcinoma cells arranged in small clusters that are surrounded by mucin lakes. Pathologic specimens vary in the amount of mucin, and cells and are described as having the hypercellular and hypocellular properties of breast mucinous carcinoma. Hypocellular, or type A, mucinous carcinomas show larger quantities of extracellular mucin and have favorable prognosis, whereas hypercellular, or type B, mucinous carcinomas have large cell clusters, frequent neuroendocrine differentiation, and worse prognosis [15]. According to the mucinous content of the carcinoma, it can be histologically categorized as pure mucinous carcinoma, in which more than 90% of tumor cells are composed by extracellular mucin without other associ-
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MRI of Mucinous Breast Cancer ated subtypes, or as the mixed form, which contains an admixture with invasive subtypes, mainly invasive ductal carcinoma NOS (Fig. 1). Histologically, pure mucinous carcinomas usually have circumscribed margins, whereas mixed mucinous carcinomas tend to have infiltrative margins [16]. It is important to apply strict histologic criteria to differentiate pure and mixed mucinous carcinomas because the former usually have a better prognosis and a lower rate of axillary lymph node metastasis. Although these two subtypes are defined, a standard threshold for clear distinction has never been defined. Some authors suggest a mucin component of at least 90% for pure mucinous carcinomas [17, 18]. Pure mucinous breast carcinoma has a favorable prognosis. Tumor size does not appear to significantly affect survival, perhaps because the large volume of mucin may lead to overestimation of tumor burden. The number of involved axillary lymph nodes is the most important predictor of death from disease [19]. Usually, pure mucinous carcinomas exhibit a rate of metastasis of less than 15% and an overall 10-year survival of almost 100% [4]. Because mixed mucinous carcinoma has more-invasive histologic characteristics, this subtype exhibits more aggressive behavior with a higher metastatic nodal involvement rate and a decreased survival rate. Regarding hormonal status, mucinous tumors generally have a high proportion of hormone receptor expression, which often confers a better prognosis. Both pure and mixed mucinous carcinomas show similar estrogen receptor– and progesterone receptor–positive statuses, indicating that both types can benefit from hormonal treatment [1]. Associated intraductal cancer can be seen among the histopathologic specimens in as many as 75% of cases, and extensive intraductal component can be seen in up to 38% of cases [6]. Extensive intraductal component is a common cause of positive surgical margins after conservative surgery for invasive breast cancer, and its preoperative diagnosis may be challenging for the radiologist. Mammography and Ultrasound The mammographic and sonographic features of mucinous breast carcinoma show differences between the pure and mixed types of the tumor. The imaging appearance of mucin-containing carcinomas reflects the percentage of the mucin component. Pure
mucinous carcinoma with high percentages of mucin commonly manifests as a circumscribed round or oval mass that sometimes has microlobulated margins. Pure type carcinomas with small percentages of mucin and mixed type carcinomas have more-aggressive imaging characteristics [16, 17, 20]. Most mucinous carcinomas are readily detected on mammography. They usually appear as low-density, round, or oval masses with circumscribed margins. Microlobulated margins have been associated with higher mucin content, whereas irregular or spiculated margins correspond to lower percentages of mucin and infiltrating margins histologically [20]. Calcifications are a rare but reported histologic feature of mucinous breast carcinomas, and they frequently correspond to the invasive ductal component of the cancer in mixed tumors. Sonographically, mucinous carcinomas of the breast are isoechoic or hypoechoic to subcutaneous fat. Internal echo may be homogeneous or heterogeneous, with cystic and solid components. Posterior acoustic enhancement is a common finding [21]. Homogeneity on sonography is associated with the pure type of mucinous carcinoma and, hence, a better prognosis [22]. Most pure type carcinomas show isoechogenic echotexture relative to subcutaneous fat echo and a good sound transmission, whereas all mixed type carcinomas were hypoechogenic with acoustic shadowing in half of them [20]. MRI The typical MRI findings of pure mucinous carcinoma include a circumscribed mass with extremely high signal intensity on fat-saturated T2-weighted imaging and benign-appearing kinetics with gradual and persistent enhancement. These MRI features might be difficult to differentiate from those of benign lesions, such as cysts or fibroadenomas, and the radiologist must be aware of this to avoid misinterpretation. Higher-grade or mixed mucinous lesions might have more suspicious imaging features [6, 9, 10, 12, 13, 23]. As with ultrasound, mucinous carcinomas might be difficult to differentiate from such benign lesions as fibroadenomas on MRI. Although most well-circumscribed breast masses are benign lesions, 10–20% of breast malignancies are also well-circumscribed masses, and these malignant masses include papillary, mucinous, medullary, and metaplastic carcinomas as well as malignant phyllodes tumors [9, 24].
Mucinous carcinomas show variable signal intensity on fat-saturated T1-weighted MR images, depending on the differences in protein composition of the tumor, and are homogeneously or heterogeneously hyperintense on fat-saturated T2-weighted images, which correlates with the large mucinous component at histologic examination. Both the pure and mixed forms of mucinous carcinoma had varying shapes. Although irregular margins are often seen with mixed tumors, pure tumors also can present with this finding. After contrast agent administration, most mucinous carcinomas gradually and progressively enhance, often with a rim of heterogeneous enhancement. The presence of enhancing internal septations has been suggested to differentiate mucinous carcinoma from myxoid fibroadenoma; however, this is an uncommon finding [7, 10]. Fat-Saturated T2-Weighted Imaging Typical invasive breast carcinomas have shorter T2 relaxation times and display lower signal intensity on fat-saturated T2-weighted images than do benign lesions. However, various histopathologic components in malignant breast lesions may generate hyperintense signal on fat-saturated T2-weighted MR images. Histopathologic features that may produce high signal intensity in breast lesions include necrotic carcinoma, a cystic or microcystic component, an adipose or sebaceous component, mucinous stroma, loose myxoid stroma, stromal edema, and hemorrhagic changes [25]. Nonmucinous carcinomas can present with high signal intensity on fat-saturated T2-weighted images because of a mixture of background matrix, a higher proportion of cells than stroma, abundant cytoplasm, edematous stroma, and hemorrhage [7]. The presence of very high signal intensity on fat-saturated T2-weighted images is a common feature of pure and mixed mucinous tumors [10]. In pure mucinous carcinoma, almost all parts of the tumor are filled with mucin component, and homogeneous high signal intensity on fat-saturated T2-weighted images may reflect this histologic type (Fig. 2). The solid component in mixed mucinous carcinoma can be identified by lower signal intensity than the mucinous component (Fig. 3). However, in cases of mixed tumors with a small amount of solid components, the signal intensity can be homogeneously very high, as seen in pure mucinous carcinoma [8].
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Bitencourt et al. DWI DWI is emerging as an important tool in breast MRI. Lesions with high cellularity, such as most breast malignancies, have restricted diffusion of water molecules, which results in high signal intensity on DWI and a low apparent diffusion coefficient (ADC). However, because of low cellularity and abundant mucin, mucinous tumors do not restrict diffusion and show lower signal intensity on DWI and increased ADC values when compared with those of other malignant breast tumors (Fig. 4). The ADC of mucinous carcinoma is also higher than that of most benign breast tumors, such as fibroadenomas. Woodhams et al. [11] studied breast lesions for 276 patients and found that the mean ADC of mucinous carcinoma (1.8 ± 0.4 × 10−3 mm2/s) was statistically significantly higher than that of benign lesions (1.3 ± 0.3 × 10−3 mm2/s) and other malignant tumors (0.9 ± 0.2 × 10−3 mm2/s). Hatakenaka et al. [26] found that, although the difference in ADC between fibroadenomas and mucinous carcinoma was significant, the difference in cellularity was not. Thus, the water in the mucin pool can probably move more randomly compared with that in the interstitium or cytoplasm of fibroadenomas. However, some benign breast tumors, particularly fibroadenomas and benign phyllodes tumors, have high ADCs overlapping those of mucinous carcinoma because of the presence of myxomatous or edematous stroma [26–28]. The ADC of a mixed mucinous tumor depends on the proportion of mucinous to nonmucinous components within the lesion. Because of greater cellularity and lower mucin content, a mixed tumor will likely have a lower ADC than a pure tumor. In general, the ADC of a pure mucinous lesion will be higher than that of a mixed lesion, and the ADC of a mixed lesion might not be significantly different from that of typical breast lesions [11, 13]. Dynamic MRI The contrast enhancement pattern of dynamic MRI is reported to be useful for differentiation between malignant and benign breast tumor. A washout or plateau pattern, with peak contrast in approximately 1 minute on a kinetic curve, has been stated to be suggestive of malignancy. However, 5–14% of breast cancers exhibit a gradual enhancement pattern, including tumors rich in stroma, such as breast cancer with a large fibrous component, and mucinous carcinoma [29].
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After injection of gadolinium-based contrast agent, mucinous carcinomas can show three different enhancement patterns depending on the amount and spatial distribution of the solid and mucinous components [23]: first, no appreciable enhancement, when mucin is the predominant tumor component (Fig. 5); second, heterogeneous enhancement, corresponding to islands of neoplastic epithelial cells floating in the pool of mucin (Fig. 6); and third, rim enhancement, corresponding to a peripheral distribution of tumor cells and central location of mucin (Fig. 7). Time–signal intensity curves obtained from dynamic contrast-enhanced MRI of mucinous carcinomas usually show a gradually enhancing pattern (Fig. 8). One reason for this finding is that the presence of a large amount of mucin delays the intralesional diffusion of the contrast material [8]. The enhancement pattern during the early phase is closely related to the cellularity of pure tumors and the distribution of nonmucinous components in mixed tumors. Some authors have suggested that early enhancement of a mucinous carcinoma on MRI might suggest a higher grade more-aggressive lesion, with a worse prognosis [10, 24]. Hypocellular pure mucinous tumors have a typical pattern of gradual enhancement. Hypercellular pure tumors have strong early enhancement and can be difficult to differentiate from mixed tumors. The presence of an area exhibiting isointensity or low intensity on fat-saturated T2-weighted images and strong early enhancement imply the presence of a mixed mucinous tumor [10]. The presence of nonmasslike enhancement, such as linear-ductal, segmental, or regional distribution around the main tumor, may be a predictor of the presence of associated extensive intraductal component (Fig. 9). According to the literature [6], the sensitivity of MRI for the diagnosis of extensive intraductal component of invasive breast cancer is higher than that of mammography or ultrasound, ranging from 55% to 94%. 18 F-FDG
PET/CT FDG PET/CT is capable of providing information related to glucose metabolism in the various organs and tissues. For patients with breast cancer, FDG PET/CT is being increasingly used for staging and evaluation of therapeutic response after neoadjuvant chemotherapy [30, 31]. To our knowledge, there are no specific articles that evaluate the use of FDG PET/CT
for imaging of mucinous breast carcinoma. It is well known that PET/CT is less sensitive for small, low-grade, and slow-growing cancers, such as mucinous carcinoma. Low tumor cell density and a high concentration of mucin may help explain the lower FDG uptake on pure mucinous carcinomas. However, many articles have shown that high uptake of FDG would be predictive of poor prognosis and aggressive features of cancer cells in patients with early breast cancer [32–35]. Invasive ductal carcinomas have higher FDG uptake than do other histologic types [36, 37]. Thus, FDG PET/CT may help to differentiate pure from mixed mucinous carcinoma and to evaluate the aggressiveness of the tumor. Although pure tumors will present with no or mild FDG uptake (Fig. 10), mixed tumors should present with moderate to high FDG uptake because of the presence of associated invasive ductal carcinoma (Fig. 11). The combination of PET and MRI offers multiple functional data that complement each other, along with high-resolution anatomy. Initial studies using PET and MRI with multiparametric evaluation have shown that this method is promising in the diagnosis and characterization of breast lesions [38, 39]. Conclusion Several MRI features of pure mucinous carcinoma, such as lobular shape, high signal intensity on fat-saturated T2-weighted images, high ADC values, and gradually enhancing pattern on dynamic studies, are commonly seen in cases of benign lesions such as fibroadenomas. Therefore, cases of pure mucinous carcinoma can be misdiagnosed on MRI. However, other MRI features and correlation with other imaging methods may facilitate the differential diagnosis between mucinous carcinoma and benign lesions on MRI. The distinction between the pure and mixed forms of mucinous carcinoma is important because mixed tumors more frequently develop lymph node metastasis and have a worse prognosis. Patients with pure tumors are thought to be good candidates for conservative surgery. Thus, the imaging methods should be used to identify more-aggressive mucinous carcinomas and to target biopsy sampling to the most suspicious areas for hypercellular or nonmucinous components on preoperative biopsy. Besides the assessment of the index lesion, MRI may also play an important role in the identification of associated intraductal components, to improve the likelihood of successful surgical excision.
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Fig. 1—Pathologic examinations of two histologic types of breast carcinoma. A, Photomicrograph of pure mucinous breast carcinoma (H and E, ×10). Carcinoma cells are arranged in small groups surrounded by lakes of extracellular mucin. B, Photomicrograph of mixed mucinous breast carcinoma (H and E, ×10). Invasive ductal poorly differentiated component is observed on left, and mucinous component is seen on right.
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Fig. 2—54-year-old woman with pure mucinous breast carcinoma. A, Mammogram shows two adjacent masses (oval) in superior quadrants of right breast. B, On MR image, these nodules (oval) show high signal intensity on fat-saturated T2-weighted sequence. C, After mastectomy, two nodules (circles) were identified on macroscopic evaluation and presented with gelatinous aspect.
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Fig. 3—60-year-old woman with mixed mucinous breast carcinoma. A and B, MR image obtained in fat-saturated T2-weighted sequence shows irregular mass in inferior quadrants of left breast with heterogeneous high signal intensity. Superior and anterior areas of lesion show lower signal intensity on fat-saturated T2-weighted sequence (arrow, A) and present with heterogeneous enhancement on contrast-enhanced T1-weighted sequence (arrow, B), corresponding to area of invasive ductal carcinoma component found on pathologic examination.
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Fig. 4—77-year-old woman with mixed mucinous breast carcinoma. A–C, MRI shows two adjacent masses in left breast with high signal intensity on fat-saturated T2-weighted sequence (A), high signal intensity on DW image (B), and no signs of restriction on apparent diffusion coefficient (ADC) map (C), with ADC of 2.30 mm2 /s.
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Bitencourt et al.
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Fig. 5—54-year-old woman with pure mucinous breast carcinoma. A, Mammogram shows lobulated partially obscured mass (oval) in superior quadrants of right breast. B and C, On MRI, this lesion (ovals) shows high signal on fat-saturated T2-weighted image (B) but no significant enhancement on fat-saturated T1-weighted contrast-enhanced image (C).
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Fig. 6—63-year-old woman with mixed mucinous breast carcinoma. A and B, MRI shows lobulated mass (arrows) in inferior quadrants of right breast with high signal intensity on fat-saturated T2-weighted image (A) and heterogeneous enhancement after contrast agent administration (B).
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MRI of Mucinous Breast Cancer
Fig. 7—55-year-old woman with mixed mucinous breast carcinoma. A and B, MR images show small regular mass (arrows) in lateral quadrants of left breast with homogeneous high signal intensity on fat-saturated T2-weighted image (A) and peripheral enhancement after contrast agent administration (B).
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Fig. 8—64-year-old woman with mixed mucinous breast carcinoma. A–C, MR images show irregular mass on superior quadrants of right breast, with hyperintensity on fat-saturated T2-weighted image (A), heterogeneous enhancement (B), and persistent enhancing pattern (type 1) on time–signal intensity curve obtained from dynamic contrast-enhanced MRI (C).
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Fig. 9—60-year-old-woman with mixed mucinous carcinoma in right breast. Three-dimensional volume-reconstructed maximum-intensity-projection subtraction breast MR image shows irregular mass on outer quadrants of right breast associated with mild nonmass enhancement with regional distribution around main tumor, extending to nipple-areola complex. Pathologic analysis of surgical specimen confirmed presence of associated extensive low-grade intraductal carcinoma of cribriform architecture.
Fig. 10—54-year-old woman with pure mucinous carcinoma. A and B, Mass in right breast is seen on CT images (arrow, A) with mild FDG uptake (standardized uptake value, 0.8) on PET/CT (circle, B) image.
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Fig. 11—63-year-old woman with high-grade mixed mucinous carcinoma. A and B, Mass in right breast is seen on CT image (arrow, A) with increased FDG uptake (standardized uptake value, 5.2) on PET/CT (oval, B) image.
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