**1. Introduction**

Nipple discharge (ND) is the third most common breast-related complaint after breast pain and breast mass, and accounts for nearly 7% of all breast symptoms (Hussain et al., 2006; Simmons et al., 2003 citing Leis et al., 1998).

The diagnosis of ND begins with its characterization as either a physiological or pathological condition (Simmons et al., 2003). Physiological discharge, often a manifestation of breast manipulation, is usually bilateral, is white or green, and emanates from many ducts (Simmons et al., 2003). Possible causes of persistent physiological discharge include oral contraceptives, antihypertensives, tranquilizers, hypothyroidism, and pituitary adenoma (Simmons et al., 2003). Most NDs are physiological and are not associated with an underlying benign or malignant breast neoplasm (Sickles, 2000). A pathological discharge is generally unilateral, spontaneous, persistent, clear, watery, serous or bloody in appearance, and emanates from a single duct (Morrogh et al., 2007). Most of the common pathological causes of ND are benign (Hou et al., 2001; Hussain et al., 2006), and the most frequently encountered benign causes are intraductal papilloma, followed by ductal ectasia and fibrocystic disease (Hou et al., 2001; Morrogh et al., 2010; Sickles, 2000). The most important cause of pathological discharge is breast cancer. For single duct nipple discharges, the incidence of malignant or high-risk pathology is reported to be as high as 15% (Orel et al., 2000 citing Carty et al., 1994; Fung et al., 1990; Leis et al., 1989; Piccoli et al., 1998; Tabar et al., 1983; Winchester et al., 1996). In some cases, ND is the only sign of carcinoma (Hou et al., 2001). NDs that are bloody or serous in appearance, associated with a mass, and present in an elderly patient are more likely to be caused by malignant tumors (Das et al., 2001; El-Daly & Gudi, 2010; Pritt et al., 2004; Tabar, 1983; Tjalma, 2004 citing Seltzer et al., 1970).

We defined suspicious ND as pathological ND, which is spontaneous, unilateral, and localized to a single duct, combined with at least one of the following characteristic findings associated a high risk of malignant disease: bloody or serous appearance, associated with a mass, and occurrence in elderly patients.

If ND is multi-duct or bilateral, breast imaging is not required. However, single-duct ND is considered an indication for further investigation by mammography (MMG) and/or ultrasonography (US) (EUSOMA, 2010).

<sup>1</sup> Current Affiliation: NTT West Osaka Hospital, Japan

Suspicious Nipple Discharge Diagnostic Evaluation 201

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

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

(a) (b)

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

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

papillary structure can be seen. (Histological diagnosis, duct papillomatosis)

suspicious cases.

(Fig. 3).

cells may be observed (Fig. 2).

 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 ones in cases of suspicious ND.
