**6. Ductography (DG, also called Galactography)**

DG is a diagnostic modality used for identification of the secreting duct, which is cannulated and injected with a sterile water-soluble contrast material. This is followed by

(a) (b)

Fig. 2. ND cytology of intraductal papilloma. (a, b) Cohesive clusters composed of benign

Fig. 3. ND cytology of a malignant lesion. The smear shows clusters of atypical cells with enlarged, irregular-shaped nuclei, and high nuclear cytoplasmic ratios. There are necrotic

FNA cytology is now a popular widely used tool for assessing breast tumors. It has been reported that ND cytology is as specific as concomitant FNA cytology but slightly less sensitive for detecting papillomas or malignant lesions (Lee, 2003). However, ND samples are often inadequate. Gupta et al. (2004) showed that 492 of 1948 ND smears (25%) were inadequate for diagnosis. Lee (2003) reported that ND cytology was non-diagnostic in 43 of 82 cases (52%), whereas FNA cytology was non-diagnostic in only 1 of 34 cases (2.9%). Therefore, ND cytology has little complementary diagnostic value. FNA cytology is a

DG is a diagnostic modality used for identification of the secreting duct, which is cannulated and injected with a sterile water-soluble contrast material. This is followed by

cells in the background.

**5. Fine needle aspiration (FNA)** 

sensitive and effective method of diagnosing breast cancer.

**6. Ductography (DG, also called Galactography)** 

duct cells. The histological diagnosis was intraductal papilloma (see Fig. 8)

MMG (Sakorafas, 2001). DG is more sensitive than ND cytology and MMG in detecting intraductal lesions (Rongione et al., 1996; Chung et al., 1995; Orel et al., 2000). It was found that when a standard evaluation was negative for a lesion, the addition of DG localized 19 of 25 (76%) otherwise occult malignant/high-risk lesions and 80 of 88 (91%) benign lesions (Morrogh et al., 2010). The incidence of malignancy, despite negative clinical breast examination and conventional imaging, was found to be as high as 10% (Morrogh et al., 2008). Ductographic findings suggestive of carcinoma include irregular filling defects, ductal irregularities (distortion, displacement, complete obstruction of contrast flow, and noniatrogenic contrast extravasation), and a deeper position of the lesion (Cardenosa et al., 1994; Ciatto et al., 1998; Tabar et al., 1983). Smooth intraductal filling defects, complete ductal obstruction, ductal expansion with apparent distortion, and irregularity of the ductal wall are more common ductographic features obsreved for solitary papillomas (Cardenosa et al., 1994; Nakahara et al., 2003). Unfortunately, evidence for a predictive role for DG is less convincing because a positive study does not differentiate between malignant and benign causes of discharge and a negative study does not exclude the presence of an underlying carcinoma. The PPV and NPVs of DG have been reported to be 19% and 63%, respectively (sensitivity, 76%; specificity, 11%); these values are consistent with those of other studies and confirm that DG is not effective in distinguishing between malignant and benign causes of nipple discharge (Morrogh et al., 2007). The routine use of DG in cases of suspicious ND remains controversial (Rongione et al., 1996; Chung et al., 1995; Orel et al., 2000).

DG is invasive and time-consuming with potential complications including intense pain, mastitis, lymphatic opacification, and duct perforation (Cardenosa et al., 1994; Lorenzon et al., 2011; Tabar et al., 1983). The rate of incomplete and/or technically inadequate conventional DG has been reported to be as high as 10–15% (Morrogh et al., 2008; Sickles, 2000). All of these technical difficulties may result in the failure to detect and surgically treat the lesion, as most cases of pathological ND have no detectable lump and negative or undefined ultrasonographic findings (Schwab et al., 2008).

#### **7. Contrast-Enhanced Magnetic Resonance Imaging (CEMRI)**

Negative or benign findings identified by physical examination, MMG, US, cytological analysis of discharge, and DG are not sufficient to rule out the presence of underlying malignant lesion (Rongione et al., 1996; Tabar et al., 1983), but the physician must still decide whether to manage expectantly or proceed to major duct excision (Morrogh et al., 2010). CEMRI is increasingly being used as a diagnostic modality for breast cancer, with diagnostic sensitivities of 86–100% and 40–100% for invasive and intraductal cancers, respectively (Orel et al., 2001; Tjalma & Verslebers, 2004 citing Esserman et al., 1999; Vichweg et al., 2000).

Preliminary research on the application of CEMRI for evaluation of patients with ND suggests that it is useful for the localization of otherwise occult diseases, identification of both benign and malignant causes of ND, and noninvasiveness relative to DG. However, the available data are limited (Nakahara et al., 2003; Orel et al., 2000; Tjalma & Verslebers, 2004). Therefore, the gold standard diagnostic and therapeutic approach for patients with pathological ND is surgical duct excision (Morrogh et al., 2010 citing Nelson & Hoehn, 2006). However, a frequent criticism of this blind approach is that the pathologists may not always identify a discrete lesion responsible for the discharge. In addition, major duct

Suspicious Nipple Discharge Diagnostic Evaluation 205

4 diagnosis in 11/32 (34%) patients. Seven of 11 (64%) patients proceeded directly to major duct excision and demonstrated 1 invasive cancer, 2 DCIS, 2 high-risk lesions, and 2 benign lesions. MRI was negative in 21 patients (BI-RADS MRI score, ≤3). Among this group, 4 patients proceeded to major duct excision, yielding 1 invasive cancer and 3 benign lesions. Therefore, an evaluation based using only BI-RADS MRI descriptors has a limited ability to

We analyzed MRI findings in patients with suspicious ND using BI-RADS MRI descriptors and clustered ring enhancement criteria (Tokuda et al., 2009), and compared them with histopathological diagnoses to assess the accuracy of differentiating between malignant and benign lesions. Clustered ring enhancement is characterized by clusters of minute ring enhancements. The clusters include enhanced foci constituting enhanced ring-like patterns, and heterogeneous enhancement of minute internal ring patterns (Tozaki et al., 2006) (Fig. 4). Breast CEMRI was performed on 47 patients to identify lesions causing suspicious ND. The 39 lesions for which histopathological diagnoses were obtained consisted of 17 carcinomas and 22 benign lesions. The types of carcinoma identified included DCIS (n = 10), invasive ductal carcinoma (IDC) with intraductal components (n = 2), and IDC (n = 5). The benign lesions included fibrocystic disease (n = 11), intraductal papillomas (n = 5), duct papillomatosis (n = 2), fibrosis (n = 3), and a fibrous nodule (n = 1). Table 1 shows the frequencies of the BI-RADS MRI descriptors and the presence of clustered ring enhancement for benign and malignant lesions. Among the non-mass-like enhancement patterns, no distribution modifiers such as "linear," "regional," or "multiple regions" were observed, and no internal enhancements such as "reticular" enhancement were detected. Only 2

lesions showing mass enhancement were not diagnosed by histopathology.

(a) (b)

in the enhancement cannot be ruled out. Reprinted from Tozaki et al. (2006)

Fig. 4. Images of the breast of a 54-year-old woman with suspicious microcalcifications

observed by mammography. (a) Coronal first contrast-enhanced T1-weighted MR image of the left breast shows regional enhancement in the upper outer quadrant (arrow). The lesion demonstrates heterogeneous enhancement with interior clustered minute ring enhancements (clustered ring enhancement). (b) A photomicrograph of the histopathological specimen shows a ductal carcinoma in situ with intraluminal necrosis and microcalcifications. Clustered ring enhancement corresponds to periductal stroma. However, intraductal cancer cell involvement

distinguish between malignant and benign lesions.

excision is expected to be undesirable for a woman of childbearing age. Therefore, there is a need to develop more effective tools for localizing the lesions responsible for ND and for distinguishing between malignant and benign causes of ND, the 2 most important roles of imaging (Morrogh et al., 2007; Yau et al., 2011).

#### **7.1 Localization of the disease causing the ND**

There is evidence in the literatures that CEMRI offers high diagnostic performance for detecting lesions in patients with suspicious ND, even when no lesions are identified by conventional imaging and when DG is not feasible or inconclusive (Sardanelli et al., 2008 citing Daniel et al., 2003; Hirose et al., 2006; Nakahara et al., 2003; Orel et al., 2000). Lorenzon et al. (2011) found that CEMRI could identify 5/5 cancers (sensitivity = 100%) and 13/14 high-risk lesions (sensitivity = 92.9%) (overall sensitivity, 94.7%; overall specificity, 78.9%). In addition, it was found that 3 of 5 cancers (1 invasive, 1 in situ, 1 contralateral invasive) and 2 of 14 highrisk lesions could be detected only by CEMRI. CEMRI was significantly more sensitive than either MMG or US (p < 0.0001 and p = 0. 042, respectively). Morrogh et al. (2007) reported that the PPV and NPV of CEMRI for detection of the disease causing the ND were 56% and 87%, respectively (sensitivity, 83%; specificity, 62%), and CEMRI performed after negative standard evaluation detected 75% of otherwise occult malignant/high risk lesions. Nakahara et al. (2003) reported that CEMRI identified all malignant lesions (100%) including DCIS. Kramer et al. (Van Goethem et al., 2009 citing Kramer et al., 2000) used CEMRI alone and in combination with MMG and DG to assess 48 women with pathological ND. The sensitivity and specificity values of DG for detection of papillomas were 94% and 79%, respectively, whereas only 1 carcinoma was detected by MMG/DG. CEMRI had a sensitivity of 89% (8/9) for malignant lesions. These authors have concluded that while MMG in combination with DG remains the primary diagnostic tool, the addition of CEMRI can demonstrate the location and distribution of lesions, especially in malignant cases, and therefore recommend performing a CEMRI to detect underlying lesions that may have been misdiagnosed by conventional imaging (Lorenzon et al., 2011; Van Goethem et al., 2009).

#### **7.2 Differentiation of malignant and benign lesions**

Predicting whether the causative lesion is malignant or benign is important because it affects the physician's choice of clinical follow-up or surgical treatment.

Nakahara et al. (2003) reported that segmental clumped enhancement (PPV = 100%), a focal mass with a smooth border (NPV = 91.7%), and diffuse or regional stippled enhancement (NPV = 94.1%) were statistically significant features that can be used for differentiating between malignant and benign lesions. Ballesio et al. (2008) reported that 5 papillomatosis lesions appeared as patchy, homogeneously enhanced areas, that among 15 intraductal papillomas, some had an oval appearance with well-defined margins, while other had areas of homogeneous enhancement with a linear shape at the periareolar or subareolar sites, moreover, they reported 2 cases of atypical ductal hyperplasias with diffuse nodular enhancement. One micropapillary DCIS, 1 papillary carcinoma, and 1 invasive ductal carcinoma were visualized as 2 segmental areas of enhancement and 1 mass-like enhancement with poorly defined margins. Morrogh et al. (2007) reported that MRI was use as the first-line test in 32/52 (63%) patients in whom it was performed and yielded a breast imaging reporting and data system (BI-RADS) MRI (American College of Radiology, 2003) ≥

excision is expected to be undesirable for a woman of childbearing age. Therefore, there is a need to develop more effective tools for localizing the lesions responsible for ND and for distinguishing between malignant and benign causes of ND, the 2 most important roles of

There is evidence in the literatures that CEMRI offers high diagnostic performance for detecting lesions in patients with suspicious ND, even when no lesions are identified by conventional imaging and when DG is not feasible or inconclusive (Sardanelli et al., 2008 citing Daniel et al., 2003; Hirose et al., 2006; Nakahara et al., 2003; Orel et al., 2000). Lorenzon et al. (2011) found that CEMRI could identify 5/5 cancers (sensitivity = 100%) and 13/14 high-risk lesions (sensitivity = 92.9%) (overall sensitivity, 94.7%; overall specificity, 78.9%). In addition, it was found that 3 of 5 cancers (1 invasive, 1 in situ, 1 contralateral invasive) and 2 of 14 highrisk lesions could be detected only by CEMRI. CEMRI was significantly more sensitive than either MMG or US (p < 0.0001 and p = 0. 042, respectively). Morrogh et al. (2007) reported that the PPV and NPV of CEMRI for detection of the disease causing the ND were 56% and 87%, respectively (sensitivity, 83%; specificity, 62%), and CEMRI performed after negative standard evaluation detected 75% of otherwise occult malignant/high risk lesions. Nakahara et al. (2003) reported that CEMRI identified all malignant lesions (100%) including DCIS. Kramer et al. (Van Goethem et al., 2009 citing Kramer et al., 2000) used CEMRI alone and in combination with MMG and DG to assess 48 women with pathological ND. The sensitivity and specificity values of DG for detection of papillomas were 94% and 79%, respectively, whereas only 1 carcinoma was detected by MMG/DG. CEMRI had a sensitivity of 89% (8/9) for malignant lesions. These authors have concluded that while MMG in combination with DG remains the primary diagnostic tool, the addition of CEMRI can demonstrate the location and distribution of lesions, especially in malignant cases, and therefore recommend performing a CEMRI to detect underlying lesions that may have been misdiagnosed by conventional imaging

Predicting whether the causative lesion is malignant or benign is important because it

Nakahara et al. (2003) reported that segmental clumped enhancement (PPV = 100%), a focal mass with a smooth border (NPV = 91.7%), and diffuse or regional stippled enhancement (NPV = 94.1%) were statistically significant features that can be used for differentiating between malignant and benign lesions. Ballesio et al. (2008) reported that 5 papillomatosis lesions appeared as patchy, homogeneously enhanced areas, that among 15 intraductal papillomas, some had an oval appearance with well-defined margins, while other had areas of homogeneous enhancement with a linear shape at the periareolar or subareolar sites, moreover, they reported 2 cases of atypical ductal hyperplasias with diffuse nodular enhancement. One micropapillary DCIS, 1 papillary carcinoma, and 1 invasive ductal carcinoma were visualized as 2 segmental areas of enhancement and 1 mass-like enhancement with poorly defined margins. Morrogh et al. (2007) reported that MRI was use as the first-line test in 32/52 (63%) patients in whom it was performed and yielded a breast imaging reporting and data system (BI-RADS) MRI (American College of Radiology, 2003) ≥

imaging (Morrogh et al., 2007; Yau et al., 2011).

**7.1 Localization of the disease causing the ND** 

(Lorenzon et al., 2011; Van Goethem et al., 2009).

**7.2 Differentiation of malignant and benign lesions** 

affects the physician's choice of clinical follow-up or surgical treatment.

4 diagnosis in 11/32 (34%) patients. Seven of 11 (64%) patients proceeded directly to major duct excision and demonstrated 1 invasive cancer, 2 DCIS, 2 high-risk lesions, and 2 benign lesions. MRI was negative in 21 patients (BI-RADS MRI score, ≤3). Among this group, 4 patients proceeded to major duct excision, yielding 1 invasive cancer and 3 benign lesions. Therefore, an evaluation based using only BI-RADS MRI descriptors has a limited ability to distinguish between malignant and benign lesions.

We analyzed MRI findings in patients with suspicious ND using BI-RADS MRI descriptors and clustered ring enhancement criteria (Tokuda et al., 2009), and compared them with histopathological diagnoses to assess the accuracy of differentiating between malignant and benign lesions. Clustered ring enhancement is characterized by clusters of minute ring enhancements. The clusters include enhanced foci constituting enhanced ring-like patterns, and heterogeneous enhancement of minute internal ring patterns (Tozaki et al., 2006) (Fig. 4). Breast CEMRI was performed on 47 patients to identify lesions causing suspicious ND. The 39 lesions for which histopathological diagnoses were obtained consisted of 17 carcinomas and 22 benign lesions. The types of carcinoma identified included DCIS (n = 10), invasive ductal carcinoma (IDC) with intraductal components (n = 2), and IDC (n = 5). The benign lesions included fibrocystic disease (n = 11), intraductal papillomas (n = 5), duct papillomatosis (n = 2), fibrosis (n = 3), and a fibrous nodule (n = 1). Table 1 shows the frequencies of the BI-RADS MRI descriptors and the presence of clustered ring enhancement for benign and malignant lesions. Among the non-mass-like enhancement patterns, no distribution modifiers such as "linear," "regional," or "multiple regions" were observed, and no internal enhancements such as "reticular" enhancement were detected. Only 2 lesions showing mass enhancement were not diagnosed by histopathology.

Fig. 4. Images of the breast of a 54-year-old woman with suspicious microcalcifications observed by mammography. (a) Coronal first contrast-enhanced T1-weighted MR image of the left breast shows regional enhancement in the upper outer quadrant (arrow). The lesion demonstrates heterogeneous enhancement with interior clustered minute ring enhancements (clustered ring enhancement). (b) A photomicrograph of the histopathological specimen shows a ductal carcinoma in situ with intraluminal necrosis and microcalcifications. Clustered ring enhancement corresponds to periductal stroma. However, intraductal cancer cell involvement in the enhancement cannot be ruled out. Reprinted from Tozaki et al. (2006)

Suspicious Nipple Discharge Diagnostic Evaluation 207

washout pattern had the highest PPV for carcinoma, 100% (p = 0.02). The highest PPVs for carcinoma were associated with a clumped internal enhancement (100%), clustered ring

Tozaki et al. (Tozaki et al, 2006) reported that clustered ring enhancement combined with the BI-RADS MRI descriptors appear to be useful in differentiating between benign and malignant lesions. Most of the lesions causing suspicious ND were observed to have nonmass-like enhancement. Many DCISs have been reported to have non-mass-like enhancement and a segmental or ductal distribution and clumped internal enhancement (Liberman et al., 2002; Morakkabati-Spitz et al., 2005). Tozaki et al. (2006) reported that all lesions showing segmental distribution were malignant. In this study, of the lesions showing segmental distribution, 8 were benign and 10 were malignant. In addition, among the lesions showing ductal distribution, 10 and 3 were benign and malignant, respectively, and the difference was insignificant. The PPV of segmental distribution alone was 44%. Morakkabati-Spitz et al. reported that segmental distribution and linear enhancement were the most common features of DCIS on dynamic MRI. In that study, 13 fibrocystic disease lesions showed segmental distribution. The PPV of segmental distribution in our study was similar to that reported by Morakkabati-Spitz et al. (2005), but was markedly lower than that of Tozaki et al. (2006). This may be due to different biases in patient selection for MRI. We analyzed lesions causing suspicious ND, Morakkabati-Spitz et al. (2005) examined lesions showing a segmental distribution and linear enhancement, and Tozaki et al. (2006) evaluated lesions showing non-mass- like enhancement. Similar to the results reported by Tozaki et al. (2006), the most common internal enhancement patterns was a heterogeneous pattern for the malignant lesions (59%) and a stippled/punctuate pattern for the benign lesions (45%); this difference was not significant. In this study, both the clumped internal enhanced lesions (2/2) were found to be malignant. Although the number of cases studied was small, Liberman et al.

All lesions (4/4) showing a washout kinetic pattern were malignant. Ten benign and 6 malignant lesions showed a plateau pattern. Kuhl et al. (Kuhl et al., 1999) pointed out that segmental and ductal enhancements are the imaging hallmarks of DCIS in breast MRI and concluded that the sensitivity of breast MRI for the detection of DCIS can be increased by performing additional morphological analysis of the enhancement pattern. However, in this study, the combination of distribution modifiers and a washout pattern was not significant. The presence of clustered ring enhancement was useful for differentiating between malignant and benign lesions (p = 0.002) and had a high PPV (82%) for breast cancer. Although the distribution pattern alone was not useful for differentiating between malignant and benign lesions, the combination of segmental distribution and clustered ring enhancement showed a significant association with breast cancer (p = 0.004) and a high PPV (88%). This indicates that clustered ring enhancement is a useful parameter in CEMRI

We conclude that the most common CEMRI finding in patients with suspicious ND is nonmass-like enhancement. The combination of segmental distribution and clustered ring enhancement showed the highest PPV for malignancy, and MRI can provide clinically useful information for distinguishing between benign and malignant causes of suspicious

enhancement (82%), and a washout pattern (100%).

(2002) reported similar results (Liberman et al., 2002).

analysis.

ND.


Numbers shown in parentheses indicate percentages.

Masses were not diagnosed by histopathology were excluded from this table.

\*Fisher's exact test was used.

NS indicates not significant.

Table 1. Frequency of MRI parameters in cases of suspicious nipple discharge. Reprinted from Tokuda et al. (Tokuda et al., 2009)

The 22 benign and the 17 malignant lesions comprised 15 non-mass-like enhancements and 2 non-enhanced lesions, which had DCIS foci measuring 2 and 2.5 mm in diameter without stromal changes.

 The most common findings of the benign lesions were stippled (50%), ductal (45%), and heterogeneous (41%), whereas those of the malignant lesions were segmental (59%) and heterogeneous (57%). Both lesions (2/2) showing clumped internal enhancement were IDCs with an intraductal component. Clustered ring enhancement was observed in 60% (9/15) of the malignant enhancing lesions but in only 9% (2/22) of the benign lesions (p = 0.002). Of the 11 lesions showing clustered ring enhancement, 9 were malignant and 2 were benign. The highest PPVs for carcinoma were associated with the clumped (100% or 2/2), clustered ring enhancement (82% or 9/11), and segmental (56% or 10/18) descriptors.

The specificity of clustered ring enhancement was 90% (20/22). Among the lesions showing clustered ring enhancement, 8 exhibited segmental distribution and 3 ductal enhancement. Both the malignant lesions with clumped enhancement (100% or 2/2) also showed clustered ring enhancement. Although the distribution pattern alone was not useful for differentiating between malignant and benign lesions, the combination of segmental distribution and clustered ring enhancement showed a significant association with breast cancer (p = 0.004). Twelve patients did not undergo a surgical procedure, and no histopathological diagnoses were obtained. We show cases with (Fig. 5) and without (Fig. 6) clustered ring enhancement. Images in Figures 5 and 6 are similar to images in Tokuda et al., (2009) but were obtained using a MRI device with a standard breast-dedicated coil. The most common kinetic pattern observed in the malignant lesions was the plateau pattern (40% or 6/15), and the most common kinetic pattern in the benign lesions was the persistent pattern (55% or 12/22). The

Ductal 10 (45) 3 (18) NS Focal 1 (5) 1 (6) NS Regional 0 (0) 0 NS Segmental 8 (36) 10 (59) NS Diffuse 3 (14) 1 (6) NS No enhancement 0 2 (11) NS

Homogeneous 2 (9) 1 (7) NS Heterogeneous 9 (41) 9 (57) NS Stippled,punctuate 11 (50) 3 (22) NS Clumped 0 2 (14) NS Reticular 0 0 NS Clustered ring enhancement 2 9 0.002

Table 1. Frequency of MRI parameters in cases of suspicious nipple discharge. Reprinted

The 22 benign and the 17 malignant lesions comprised 15 non-mass-like enhancements and 2 non-enhanced lesions, which had DCIS foci measuring 2 and 2.5 mm in diameter without

 The most common findings of the benign lesions were stippled (50%), ductal (45%), and heterogeneous (41%), whereas those of the malignant lesions were segmental (59%) and heterogeneous (57%). Both lesions (2/2) showing clumped internal enhancement were IDCs with an intraductal component. Clustered ring enhancement was observed in 60% (9/15) of the malignant enhancing lesions but in only 9% (2/22) of the benign lesions (p = 0.002). Of the 11 lesions showing clustered ring enhancement, 9 were malignant and 2 were benign. The highest PPVs for carcinoma were associated with the clumped (100% or 2/2), clustered

The specificity of clustered ring enhancement was 90% (20/22). Among the lesions showing clustered ring enhancement, 8 exhibited segmental distribution and 3 ductal enhancement. Both the malignant lesions with clumped enhancement (100% or 2/2) also showed clustered ring enhancement. Although the distribution pattern alone was not useful for differentiating between malignant and benign lesions, the combination of segmental distribution and clustered ring enhancement showed a significant association with breast cancer (p = 0.004). Twelve patients did not undergo a surgical procedure, and no histopathological diagnoses were obtained. We show cases with (Fig. 5) and without (Fig. 6) clustered ring enhancement. Images in Figures 5 and 6 are similar to images in Tokuda et al., (2009) but were obtained using a MRI device with a standard breast-dedicated coil. The most common kinetic pattern observed in the malignant lesions was the plateau pattern (40% or 6/15), and the most common kinetic pattern in the benign lesions was the persistent pattern (55% or 12/22). The

**(n=22)** 

**Malignant** 

**(n=17) P***\** 

Descriptor **Benign** 

Numbers shown in parentheses indicate percentages.

Masses were not diagnosed by histopathology were excluded from this table.

ring enhancement (82% or 9/11), and segmental (56% or 10/18) descriptors.

Non-mass-like enhancement Distribution modifiers

Internal enhancement

\*Fisher's exact test was used. NS indicates not significant.

stromal changes.

from Tokuda et al. (Tokuda et al., 2009)

washout pattern had the highest PPV for carcinoma, 100% (p = 0.02). The highest PPVs for carcinoma were associated with a clumped internal enhancement (100%), clustered ring enhancement (82%), and a washout pattern (100%).

Tozaki et al. (Tozaki et al, 2006) reported that clustered ring enhancement combined with the BI-RADS MRI descriptors appear to be useful in differentiating between benign and malignant lesions. Most of the lesions causing suspicious ND were observed to have nonmass-like enhancement. Many DCISs have been reported to have non-mass-like enhancement and a segmental or ductal distribution and clumped internal enhancement (Liberman et al., 2002; Morakkabati-Spitz et al., 2005). Tozaki et al. (2006) reported that all lesions showing segmental distribution were malignant. In this study, of the lesions showing segmental distribution, 8 were benign and 10 were malignant. In addition, among the lesions showing ductal distribution, 10 and 3 were benign and malignant, respectively, and the difference was insignificant. The PPV of segmental distribution alone was 44%. Morakkabati-Spitz et al. reported that segmental distribution and linear enhancement were the most common features of DCIS on dynamic MRI. In that study, 13 fibrocystic disease lesions showed segmental distribution. The PPV of segmental distribution in our study was similar to that reported by Morakkabati-Spitz et al. (2005), but was markedly lower than that of Tozaki et al. (2006). This may be due to different biases in patient selection for MRI. We analyzed lesions causing suspicious ND, Morakkabati-Spitz et al. (2005) examined lesions showing a segmental distribution and linear enhancement, and Tozaki et al. (2006) evaluated lesions showing non-mass- like enhancement. Similar to the results reported by Tozaki et al. (2006), the most common internal enhancement patterns was a heterogeneous pattern for the malignant lesions (59%) and a stippled/punctuate pattern for the benign lesions (45%); this difference was not significant. In this study, both the clumped internal enhanced lesions (2/2) were found to be malignant. Although the number of cases studied was small, Liberman et al. (2002) reported similar results (Liberman et al., 2002).

All lesions (4/4) showing a washout kinetic pattern were malignant. Ten benign and 6 malignant lesions showed a plateau pattern. Kuhl et al. (Kuhl et al., 1999) pointed out that segmental and ductal enhancements are the imaging hallmarks of DCIS in breast MRI and concluded that the sensitivity of breast MRI for the detection of DCIS can be increased by performing additional morphological analysis of the enhancement pattern. However, in this study, the combination of distribution modifiers and a washout pattern was not significant. The presence of clustered ring enhancement was useful for differentiating between malignant and benign lesions (p = 0.002) and had a high PPV (82%) for breast cancer. Although the distribution pattern alone was not useful for differentiating between malignant and benign lesions, the combination of segmental distribution and clustered ring enhancement showed a significant association with breast cancer (p = 0.004) and a high PPV (88%). This indicates that clustered ring enhancement is a useful parameter in CEMRI analysis.

We conclude that the most common CEMRI finding in patients with suspicious ND is nonmass-like enhancement. The combination of segmental distribution and clustered ring enhancement showed the highest PPV for malignancy, and MRI can provide clinically useful information for distinguishing between benign and malignant causes of suspicious ND.

Suspicious Nipple Discharge Diagnostic Evaluation 209

(a) (b)

(c) (d)

Fig. 6. Images of the breasts of a 49-year-old woman who presented with bloody discharge from the left nipple. (a) Pre-contrast fat-suppressed T1-weighted MR image showing no intraductal abnormal intensity. (b) STIR MR image showing duct ectasia and intraductal fluid accumulation. (c) A contrast-enhanced T1-weighted MR image showing homogeneous ductal enhancement. (d) Mapping of the lesion (green line area, intraductal papilloma.).

MRI findings may improve patient selection and treatment planning. However, MRI should not be used as an alternative for a breast biopsy to determine whether a given lesion is malignant, and it should not replace major duct excision as the gold standard for ruling out malignancy in patients with ND and a negative evaluation (Morrogh et al., 2007; Bluemke et

Several approaches to MRI of the secreting breast have been suggested, including direct (Schwab, 2008; Wenkel, 2011) and indirect MRDG and fusion MR imaging of contrast-

Direct MRDG is performed by filling the discharging duct with gadolinium-diethylenetriamine-pentaacetic acid (Gd-DTPA) diluted in saline, using a DG needle as for the conventional DG procedure, and obtaining 3D MRI sequences (Schwab et al., 2008). Schwab et al. (2008) reported findings in 23 patients with pathological discharge. Direct MRDG showed pathological findings in 82% of all findings, while indirect MRDG produced

**7.3 MR ductography (MRDG, also called MR galactography)** 

enhanced and indirect ductography (Hirose et al., 2007).

**7.3.1 Direct MRDG (direct MR galactography)** 

al., 2004).

Fig. 5. Images of the breasts of a 70-year-old woman who presented with bloody discharge from the right nipple. (a) Pre-contrast enhanced fat-suppressed T1-weighted image showing intraductal high intensity corresponding to bloody discharge. (b) A fast short-tau inversionrecovery (STIR) image showing peripheral duct ectasia and intraductal fluid accumulation. (c) Dynamic contrast-enhanced early phase image showing clumped enhancement with segmental distribution. (d) Post-contrast-enhanced sagittal image showing heterogeneous tramline-like and clustered ring enhancement. The histopathological diagnosis was invasive ductal carcinoma with predominant intraductal components. (e) Mapping of the lesion (green line area, ductal carcinoma in situ; red line area, invasive ductal carcinoma).

(a) (b)

(e) (d)

Fig. 5. Images of the breasts of a 70-year-old woman who presented with bloody discharge from the right nipple. (a) Pre-contrast enhanced fat-suppressed T1-weighted image showing intraductal high intensity corresponding to bloody discharge. (b) A fast short-tau inversionrecovery (STIR) image showing peripheral duct ectasia and intraductal fluid accumulation. (c) Dynamic contrast-enhanced early phase image showing clumped enhancement with segmental distribution. (d) Post-contrast-enhanced sagittal image showing heterogeneous tramline-like and clustered ring enhancement. The histopathological diagnosis was invasive ductal carcinoma with predominant intraductal components. (e) Mapping of the lesion (green line area, ductal carcinoma in situ; red line area, invasive ductal carcinoma).

(c)

Fig. 6. Images of the breasts of a 49-year-old woman who presented with bloody discharge from the left nipple. (a) Pre-contrast fat-suppressed T1-weighted MR image showing no intraductal abnormal intensity. (b) STIR MR image showing duct ectasia and intraductal fluid accumulation. (c) A contrast-enhanced T1-weighted MR image showing homogeneous ductal enhancement. (d) Mapping of the lesion (green line area, intraductal papilloma.).

MRI findings may improve patient selection and treatment planning. However, MRI should not be used as an alternative for a breast biopsy to determine whether a given lesion is malignant, and it should not replace major duct excision as the gold standard for ruling out malignancy in patients with ND and a negative evaluation (Morrogh et al., 2007; Bluemke et al., 2004).

#### **7.3 MR ductography (MRDG, also called MR galactography)**

Several approaches to MRI of the secreting breast have been suggested, including direct (Schwab, 2008; Wenkel, 2011) and indirect MRDG and fusion MR imaging of contrastenhanced and indirect ductography (Hirose et al., 2007).

#### **7.3.1 Direct MRDG (direct MR galactography)**

Direct MRDG is performed by filling the discharging duct with gadolinium-diethylenetriamine-pentaacetic acid (Gd-DTPA) diluted in saline, using a DG needle as for the conventional DG procedure, and obtaining 3D MRI sequences (Schwab et al., 2008). Schwab et al. (2008) reported findings in 23 patients with pathological discharge. Direct MRDG showed pathological findings in 82% of all findings, while indirect MRDG produced

Suspicious Nipple Discharge Diagnostic Evaluation 211

(a) (b)

(c) (d)

Fig. 7. Images of an intraductal papilloma in a 75-year-old woman. (a) The conventional ductogram and (b) indirect MR ductogram (MIP image) both show a dilated duct with a filling or signal defect (arrow), which represents an intraductal papilloma. (c) The MR mammogram (MIP image) shows a well-circumscribed enhanced lesion (arrow) that indicates the presence of a tiny papilloma. (d) The 3D fusion image shows the dilated duct

(green) and the intraductal lesion (red). Reprinted from Hirose et al. (2006).

pathological findings in 33% of all findings with significant (p < 0.01) differences in the detection of ductal disease between indirect MRDG and all direct MRDG sequences. Wenkel et al. (2011) reported observations of 30 women who underwent conventional DG and direct MRDG. There was no significant difference in sector localization between conventional DG and direct MRDG. It was concluded that because direct MRDG is more effective in identifying the disease than indirect MRDG, conventional DG, direct MRDG may have the potential to become an alternative to conventional DG.

## **7.3.2 Indirect MRDG (indirect MR galactography)**

Intraductal fluid accumulation and duct ectasia can be detected in 40–73% with patients with pathological ND (Daniel et al., 2003; Orel et al., 2000; Schwab et al., 2008), just as MR hydrography can noninvasively depict fluid-fluid tubular structures such as the bile and pancreatic ducts, the ureters, and the semicircular canals (Jara et al., 1998). This method, known as indirect MRDG, can demonstrate the peripheral part of the duct of the point obstructed by an intraductal lesion (Hirose et al., 2006). Advantages to this technique are that it is noninvasive; uses no radiation or contrast material; and causes none of the potential complications associated with cannulation of the duct and injection of contrast medium, including duct perforation, extravasation, and mastitis (Hirose et al., 2007).

The EUSOMA working group suggests that in countries where DG is considered a routine test for suspicious ND, non-contrast T2-weighted and CEMRI can be considered if DG fails for technical reasons or if the patient refuses the procedure.

Indirect MRDG does not identify ducts that are not dilated, although conventional DG may show an undilated duct after cannulation. In some cases, the fluid within the duct has a high signal intensity on T1-weighted images and a low signal intensity on heavily T2-weighted images. This suggests either hemorrhage or the presence of proteins (Hirose et al., 2007).

The single 3D fused image obtained by combining data from indirect MRDG and CEMRI not only demonstrates the existence of an intraductal abnormality but also reveals the shape, size, and extent of the lesion, and can clarify the relationship between the duct and the intraductal lesion (Hirose et al., 2006) (Fig.7).

#### **8. Histopathological diagnosis**

Most NDs are caused by benign lesions such as papillomas and duct ectasia. Microdochectomy or major duct excision is often performed on patients with ND to exclude the possibility of underlying ductal carcinoma. Morrogh et al. (2010) analyzed the histopathological findings in biopsies or surgical specimens obtained from patients with pathological ND and identified cancer in 65 of 287 (22%) cases. Among the 287 cases, 121 (42%) were papillomas (Morrogh et al., 2010). Another report identified cancer in 9 of 211 cases (4.3%). Among the 211 cases, 81 (38%) were papillomas (Dillon et al., 2006). A papilloma (Fig. 8a, b) consists of a proliferation of ductal epithelium supported by a fibrovascular stroma. The epithelium of the stromal supporting layer is composed of epithelial and myoepithelial cells. Many papillomas have a complex structure as a result of stromal overgrowth (Fig. 8c), epithelial hyperplasia, or a combination of both of these processes. Foci of apocrine metaplasia are often observed in papillomas (Fig. 8d). Ductal carcinoma (Fig. 9) shows various histopathological patterns.

pathological findings in 33% of all findings with significant (p < 0.01) differences in the detection of ductal disease between indirect MRDG and all direct MRDG sequences. Wenkel et al. (2011) reported observations of 30 women who underwent conventional DG and direct MRDG. There was no significant difference in sector localization between conventional DG and direct MRDG. It was concluded that because direct MRDG is more effective in identifying the disease than indirect MRDG, conventional DG, direct MRDG may have the

Intraductal fluid accumulation and duct ectasia can be detected in 40–73% with patients with pathological ND (Daniel et al., 2003; Orel et al., 2000; Schwab et al., 2008), just as MR hydrography can noninvasively depict fluid-fluid tubular structures such as the bile and pancreatic ducts, the ureters, and the semicircular canals (Jara et al., 1998). This method, known as indirect MRDG, can demonstrate the peripheral part of the duct of the point obstructed by an intraductal lesion (Hirose et al., 2006). Advantages to this technique are that it is noninvasive; uses no radiation or contrast material; and causes none of the potential complications associated with cannulation of the duct and injection of contrast medium,

The EUSOMA working group suggests that in countries where DG is considered a routine test for suspicious ND, non-contrast T2-weighted and CEMRI can be considered if DG fails

Indirect MRDG does not identify ducts that are not dilated, although conventional DG may show an undilated duct after cannulation. In some cases, the fluid within the duct has a high signal intensity on T1-weighted images and a low signal intensity on heavily T2-weighted images. This suggests either hemorrhage or the presence of proteins (Hirose et al., 2007).

The single 3D fused image obtained by combining data from indirect MRDG and CEMRI not only demonstrates the existence of an intraductal abnormality but also reveals the shape, size, and extent of the lesion, and can clarify the relationship between the duct and the

Most NDs are caused by benign lesions such as papillomas and duct ectasia. Microdochectomy or major duct excision is often performed on patients with ND to exclude the possibility of underlying ductal carcinoma. Morrogh et al. (2010) analyzed the histopathological findings in biopsies or surgical specimens obtained from patients with pathological ND and identified cancer in 65 of 287 (22%) cases. Among the 287 cases, 121 (42%) were papillomas (Morrogh et al., 2010). Another report identified cancer in 9 of 211 cases (4.3%). Among the 211 cases, 81 (38%) were papillomas (Dillon et al., 2006). A papilloma (Fig. 8a, b) consists of a proliferation of ductal epithelium supported by a fibrovascular stroma. The epithelium of the stromal supporting layer is composed of epithelial and myoepithelial cells. Many papillomas have a complex structure as a result of stromal overgrowth (Fig. 8c), epithelial hyperplasia, or a combination of both of these processes. Foci of apocrine metaplasia are often observed in papillomas (Fig. 8d). Ductal

including duct perforation, extravasation, and mastitis (Hirose et al., 2007).

for technical reasons or if the patient refuses the procedure.

carcinoma (Fig. 9) shows various histopathological patterns.

intraductal lesion (Hirose et al., 2006) (Fig.7).

**8. Histopathological diagnosis** 

potential to become an alternative to conventional DG.

**7.3.2 Indirect MRDG (indirect MR galactography)** 

Fig. 7. Images of an intraductal papilloma in a 75-year-old woman. (a) The conventional ductogram and (b) indirect MR ductogram (MIP image) both show a dilated duct with a filling or signal defect (arrow), which represents an intraductal papilloma. (c) The MR mammogram (MIP image) shows a well-circumscribed enhanced lesion (arrow) that indicates the presence of a tiny papilloma. (d) The 3D fusion image shows the dilated duct (green) and the intraductal lesion (red). Reprinted from Hirose et al. (2006).

Suspicious Nipple Discharge Diagnostic Evaluation 213

The authors wish to thank the breast radiologists Tozaki M. and Hirose M. for offering the

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Galactography and exfoliative cytology in women with abnormal nipple discharge.

images from their papers, and the surgeon Masuda N. for providing many cases.

**10. Acknowledgments** 

ISBN-13: 978-0096505054

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**11. References** 

Fig. 8. Intraductal papilloma. (a) Low magnification. (b) Part of the papilloma in a cystically dilated duct. (c) Well-developed stromal sclerosis is present. (d) Apocrine metaplasia is observed.

Fig. 9. Ductal carcinoma. (a) Ductal carcinoma in situ. Cystically dilated ducts contain hemorrhage. (b) Invasive ductal carcinoma.

#### **9. Conclusion**

MRI provides clinically useful information in patients with suspicious ND and negative standard evaluation. A larger prospective study to determine the use of MRI in the detection and differentiation of benign and malignant lesions causing ND is warranted.

#### **10. Acknowledgments**

The authors wish to thank the breast radiologists Tozaki M. and Hirose M. for offering the images from their papers, and the surgeon Masuda N. for providing many cases.

#### **11. References**

212 Imaging of the Breast – Technical Aspects and Clinical Implication

(a) (b)

(c) (d)

(a) (b)

MRI provides clinically useful information in patients with suspicious ND and negative standard evaluation. A larger prospective study to determine the use of MRI in the detection

Fig. 9. Ductal carcinoma. (a) Ductal carcinoma in situ. Cystically dilated ducts contain

and differentiation of benign and malignant lesions causing ND is warranted.

hemorrhage. (b) Invasive ductal carcinoma.

Fig. 8. Intraductal papilloma. (a) Low magnification. (b) Part of the papilloma in a cystically dilated duct. (c) Well-developed stromal sclerosis is present. (d) Apocrine metaplasia is

observed.

**9. Conclusion** 


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**10** 

**Radiotherapy After Surgery for Small Breast** 

Laszlo Tabar1, Nadja Lindhe1, Amy M.F. Yen2, Tony H.H. Chen2,3, Sherry Y.H. Chiu3, Jean C.Y. Fann2, Sam L.S. Chen4, Grace H.M. Wu2, Rex C.C. Huang2, Judith Offman5, Fiona A. Dungey6, Wendy Y.Y. Wu2,

Radiotherapy is widely used in breast cancer treatment, particularly in patients undergoing breast conserving surgery, principally in order to reduce risk of local recurrence (Liljegren et al. 1999; Fisher et al. 2002). Although radiation therapy has been observed in a major metaanalysis to confer a net survival benefit (Clarke et al. 2005), it is not without side-effects. It has been observed to confer increased risks of cardiovascular events and lung tumours (Clarke et al. 2005; Darby et al. 2005). The fact that radiation therapy confers both benefits and harms raises issues pertinent to all treatments, i.e., the importance of selecting patient populations for which the balance of benefits to harms is optimised, and of excluding those patients who will not benefit from the treatment, or at least not sufficiently to outweigh the risk of adverse effects. Given the current lack of confidence that the prognostic indicators for such selection exist, conservative therapy includes post-surgical radiotherapy as a standard

It has been reported that patients with invasive breast tumours less than 15 mm in size have mammographic tumour features that are good indicators of prognosis, and in particular, good long term survival has been observed in stellate lesions of this size without accompanying calcifications or with only non-specific calcifications (Smith et al. 2004; Tabar et al. 2000). The large majority of these patients did not receive adjuvant therapy other than radiotherapy, and since long-term survival was very high, the potential for modern adjuvant therapies to further improve upon the survival of these cases is very small. However, the extent to which these patients benefited from radiotherapy, in terms of reduction of risk of local recurrence, is not known. In this paper, we review the treatment and tumour features of 425 stellate invasive breast cancers of

**1. Introduction** 

of care.

\**1 Mammography Department, Central Hospital, Sweden 2 College of Public Health, National Taiwan University, Taiwan* 

*6 Cancer Research UK & UCL Cancer Trials Centre, UK* 

*5 Centre for Cancer Prevention, Queen Mary, University of London, UK* 

*3 Tampere School of Public Health, Finland 4 Changhua Christian Hospital, Taiwan* 

*7 American Cancer Society, USA* 

**Cancers of Stellate Appearance** 

Robert A. Smith7 and Stephen W. Duffy5\*

M., Zuiani, C., Alfano, C., Bazzocchi, M., Belli, P., Bianchi, S., Cilotti, A., Calabrese, M., Carbonaro, L., Cortesi, L., Di Maggio, C., Del Maschio, A., Esseridou, A., Fausto, A., Gennaro, M., Girometti, R., Ienzi, R., Luini, A., Manoukian, S., Morassutt, S., Morrone, D., Nori, J., Orlacchio, A., Pane, F., Panzarola, P., Ponzone, R., Simonetti, G., Torricelli, P. & Valeri, G. (2008). Indications for breast magnetic resonance imaging. Consensus Document, "Attualita in Senologia," Florence 2007. *Radiology Medicine,* Vol. 113, No. 8, (December 2008), pp. 1085-1095. ISSN: 0033-8362 (Print), 1826-6983 (Electronic), 0033-8362 (Linking)

