**3. Ultrasonography (US)**

Breast US is a non-invasive diagnostic method that has proven to be useful in the evaluation of patients with ND (Sakorafas, 2001). However, US has limitations with respect to depicting causative lesions of small masses and ductal carcinomas in situ (DCIS), especially those in peripheral regions without ductal dilatation or those in high adipose-containing breasts (Berg & Gilbreath., 2000; Nakahara et al., 2003 citing Chung et al., 1995).

The most common sonographic features are duct dilatation, particularly in cases associated with solid internal echoes and duct wall thickening in generally central and/or subareolar areas (Ballesio et al., 2008). Berg & Gilbreath (2000) reported that US identified 45 of 48 (94%) invasive tumor foci and 7 of 16 (44%) foci of DCIS while only 9 of 64 (14%) malignant foci were detected by US. Rissanen et al. (2007) reported that in 52 patients with unilateral nipple discharge, 80% of papillomatous lesions, 58% of other benign lesions, and 20% of malignant lesions were sonographically positive, and among the 6 cases in which duct dilatation was the only sonographic finding, 3 (50%) were malignant lesions and the other 3 (50%) were papillomas and other benign lesions. In a study of 55 patients with bloody ND, Nakahara et al. (2003) reported that of all findings, only the hypoechoic masses with smooth margins (NPV = 90.9%) and hypoechoic masses with irregular margins (positive predictive value (PPV) = 85.7%) were statistically significant.

In addition to the patient's clinical history and cytological evaluation of the ND, performing a US-guided FNA is fundamental for differentiating between malignant and benign lesions (Ballesio et al, 2008 citing Sardanelli et al., 1997).

## **4. Nipple discharge (ND) cytology**

ND cytology is a simple and noninvasive method that includes simply touching the nipple, obtaining a smear of the fluid, or gently scraping the surface of a lesion. Breast

 In this chapter, we review several methods of diagnostic evaluation including MMG, US, conventional ductography (DG), ND cytology, fine needle aspiration (FNA) and histopathology. We also demonstrate how to use the findings of contrast-enhanced magnetic resonance imaging (CEMRI) studies, including direct and indirect MR ductography (MRDG), to localize the causative lesion and to differentiate malignant lesions from benign

While MMG is considered the standard initial imaging examination and may reveal microcalcifications and other signs of malignancy, it rarely provides information about the etiology of ND (Rissanen et al., 2007 citing Cabioglu et al., 2003; Dillon et al., 2006; Funovics et al., 2003; Sardanelli et al., 1997; Tabar et al., 1983). In the study by Tabar et al. (1983), only half of the patients who presented with ND and were diagnosed with breast cancer had an abnormal mammogram. In the study by Morrogh et al. (2010), the sensitivity of MMG among all patients with pathological ND was 18%. Conversely, MMG had a high negative predictive value (NPV) and specificity (94%), suggesting that MMG can be used to select patients with physiological ND for whom clinical observation alone may be a reasonable

Breast US is a non-invasive diagnostic method that has proven to be useful in the evaluation of patients with ND (Sakorafas, 2001). However, US has limitations with respect to depicting causative lesions of small masses and ductal carcinomas in situ (DCIS), especially those in peripheral regions without ductal dilatation or those in high adipose-containing breasts

The most common sonographic features are duct dilatation, particularly in cases associated with solid internal echoes and duct wall thickening in generally central and/or subareolar areas (Ballesio et al., 2008). Berg & Gilbreath (2000) reported that US identified 45 of 48 (94%) invasive tumor foci and 7 of 16 (44%) foci of DCIS while only 9 of 64 (14%) malignant foci were detected by US. Rissanen et al. (2007) reported that in 52 patients with unilateral nipple discharge, 80% of papillomatous lesions, 58% of other benign lesions, and 20% of malignant lesions were sonographically positive, and among the 6 cases in which duct dilatation was the only sonographic finding, 3 (50%) were malignant lesions and the other 3 (50%) were papillomas and other benign lesions. In a study of 55 patients with bloody ND, Nakahara et al. (2003) reported that of all findings, only the hypoechoic masses with smooth margins (NPV = 90.9%) and hypoechoic masses with irregular margins (positive predictive

In addition to the patient's clinical history and cytological evaluation of the ND, performing a US-guided FNA is fundamental for differentiating between malignant and benign lesions

ND cytology is a simple and noninvasive method that includes simply touching the nipple, obtaining a smear of the fluid, or gently scraping the surface of a lesion. Breast

(Berg & Gilbreath., 2000; Nakahara et al., 2003 citing Chung et al., 1995).

value (PPV) = 85.7%) were statistically significant.

(Ballesio et al, 2008 citing Sardanelli et al., 1997).

**4. Nipple discharge (ND) cytology** 

ones in cases of suspicious ND.

**2. Mammography (MMG)** 

management approach.

**3. Ultrasonography (US)** 

pumping, breast massage, or nipple aspiration may be attempted if the discharge does not occur spontaneously during collection of the samples (Gupta et al., 2004; Krishnamurthy, et al., 2003). Gupta et al. (2004) have suggested that the use of routine ND cytology is limited by the small samples obtained and that ND cytology cannot always distinguish between physiological processes, fibrocystic disease, and papillomas. However, studies based on a large number of cases suggest that ND cytology is a reasonable method for diagnosing malignant and suspicious cases (Das et al., 2001; El-Daly & Gudi, 2010; Gupta et al., 2004; Pritt et al., 2004). Cytological examination of ND is valuable mainly for detecting such cancers. The efficiency of ND cytology remains controversial, as an older study has demonstrated low sensitivity, for detection of malignancy, ranging from 11% to 31.2% (Dinkel et al., 2001). However, studies that are more recent have reported higher sensitivity of ND cytology. For example, Pritt et al. (2004) determined a sensitivity and specificity of 85% and 97%, respectively. Likewise, a sensitivity of 58.3% and 63% and a specificity of 100% and 100% were reported by Lee (2003) and El-Daly & Gudi (2010), respectively. Therefore, ND cytology can be useful in the diagnosis of malignant and suspicious cases.

Foam cells are the predominant cytological feature in tissues being subjected to in inflammatory processes, mastopathy, or fibrocystic disease (Fig. 1a). Its secretion occasionally contains duct epithelial cells (Fig. 1b). Apocrine metaplasia of duct epithelial cells is sometimes seen. In intraductal papillomas, large, cohesive clusters of normal duct cells may be observed (Fig. 2).

Fig. 1. Nipple discharge cytology of benign lesions. (a) Several foam cells are observed but no epithelial cells are present. (b) A number of clusters composed of duct cells forming a papillary structure can be seen. (Histological diagnosis, duct papillomatosis)

Clusters of apocrine cells may also be seen. In some cases, papillary structures composed of spherical clusters of large duct cells with atypical features such as cytoplasmic vacuoles, enlarged nuclei, and visible nucleoli may be present. In ductal carcinoma, the clusters composed of atypical cells may be loosely structured and are sometimes thick or spherical. They may also form papillary structures. Necrosis is commonly seen in high-grade lesions (Fig. 3).

Suspicious Nipple Discharge Diagnostic Evaluation 203

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).

undefined ultrasonographic findings (Schwab et al., 2008).

Vichweg et al., 2000).

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

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

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;

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

Fig. 2. ND cytology of intraductal papilloma. (a, b) Cohesive clusters composed of benign duct cells. The histological diagnosis was intraductal papilloma (see Fig. 8)

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 cells in the background.
