and Aysegul A. Sahin2
Division of Pathology, Singapore General Hospital, Singapore, Singapore
The University of Texas, M. D. Anderson Cancer Center, Houston, TX, USA
These are benign lesions and encompass diverse entities that range from ectopic breast tissue to duct ectasia, fat necrosis, mastitis, Rosai–Dorfman disease, diabetic mastopathy, amyloidosis, IgG4-related mastitis, biopsy site changes, reaction to foreign material including implants, and infections.
Ectopic Breast Tissue
Ectopic breast tissue refers to breast tissue discovered at anatomic locations other than on the anterior chest wall where the normal breasts reside. It appears along the embryological mammary ridges, or milk lines, which extend from the axilla to the upper medial thigh.
Clinical and Epidemiological Features
Ectopic breast tissue is reported to occur in between 1 % and 6 % of women and can be bilateral or unilateral. It is rare in men. Clinically, it may present as an accessory nipple or a lump, commonly in the axilla.
The imaging appearance of ectopic fibroglandular tissue is similar to that in the breast. On mammography, fibroglandular tissue of higher density is mixed with low-density fatty tissue. On ultrasound examination, the fibroglandular tissue appears hyperechoic relative to adjacent subcutaneous fat. MRI shows physiological background enhancement similar to the breast parenchyma. Fibroadenoma, papilloma, cysts, apocrine metaplasia, epithelial hyperplasia, and carcinoma may arise from ectopic breast tissue with corresponding imaging changes.
Accessory nipples may appear as brown-coloured skin protuberances. Ectopic breast tissue can be fibrofatty in gross appearance or may be predominantly fatty.
Histologically, accessory nipples incorporate lactiferous ducts, while ectopic breast tissue displays varying numbers of ducts and lobules (Figs. 2.1, 2.2, 2.3, 2.4, and 2.5). Some cases may be primarily composed of fat. Physiological changes can be observed in ectopic breast tissue, including pregnancy and lactational hyperplasia. Cysts, apocrine metaplasia, epithelial hyperplasia, fibroadenoma (Fig. 2.6), papilloma, and a wide range of lesions occurring in the normally located breast can be encountered in ectopic breast tissue. When ectopic breast tissue is found within axillary lymph nodes, it may be mistaken for metastasis [1, 2].
Accessory nipple shows skin with sebaceous glands and bundles of smooth muscle fibres in the dermis. A small duct (arrow) is seen among the smooth muscle fibres (Courtesy of Dr. Kenneth Chang)
Accessory nipple. A skin “papilloma” removed from the abdominal skin of an adult woman. Histologically, the protuberant skin with sebaceous glands shows a lobular cluster of glands at the resection base
Accessory nipple. High magnification shows crowded glands with dilatation and luminal pink secretions. Some of the lining epithelial cells disclose cytoplasmic vacuolation. These glands are consistent with a breast lobule
Axillary breast tissue. A few scattered breast lobules are seen deep in the skin and subcutis, embedded within fibrous stroma. Several apocrine glands are also observed in the deep dermis and superficial subcutaneous fat
Axillary breast tissue. A few breast ductules are loosely aggregated, forming small lobules. There is pseudoangiomatous stromal hyperplasia
Ectopic breast tissue with a fibroadenoma. Lump in the fourchette that was excised shows a fibroadenoma
Normal Skin Adnexa
Adnexal apocrine glands and sweat ducts of the axilla may mimic breast ducts and lobules of axillary ectopic breast tissue. Whereas adnexal tissue generally occurs in the dermis, breast ducts and lobules are seen deep to the dermis and within adipose tissue. Usually, a terminal duct with surrounding acini or ductules can be observed.
When ectopic breast tissue is predominantly fatty, it can resemble a lipoma. The presence of ducts and acini, especially within fibrous areas of the adipose tissue, gives the diagnosis of ectopic breast tissue.
An accessory nipple may resemble a fibroepithelial polyp, but the finding of lactiferous ducts can be used to make the distinction.
Lymph Node Metastasis
Ectopic breast tissue in axillary lymph nodes may lead to false positive diagnoses of nodal metastases. Clues to the benign nature are the presence of myoepithelial cells around the glands, lack of nuclear atypia, and histological divergence from the corresponding primary breast carcinoma (Fig. 2.7).
Ectopic breast tissue in a sentinel lymph node. (a) The lymph node which was evaluated on frozen section shows a cystically dilated gland lined by flattened epithelium with a few luminal protrusions, within the nodal parenchyma. The primary breast tumour was an invasive ductal carcinoma, grade 1. (b) High magnification shows an apparent bilayering of the lining epithelium. Nuclei of the epithelial cells are bland. Inset shows p63 positive myoepithelial cells along the wall of the benign breast gland within the sentinel lymph node. (c) Primary breast carcinoma shows invasive grade 1 tumour. The appearances are distinctly different from the cystic glandular inclusion in the sentinel lymph node. Comparison of the histology of both the primary breast tumour and the epithelial inclusions in the lymph node may be helpful in determining if the latter represents a metastasis
Prognosis and Therapy Considerations
Ectopic breast tissue may undergo physiological changes as with the normal breast. Pathologic lesions can also develop for which the management approach will be similar to those occurring in the breast.
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Duct ectasia is a common inflammatory condition of the breast. Many different terms, including plasma cell mastitis, comedomastitis, granulomatous mastitis, and periductal mastitis, have been used to describe the same lesion in the literature. Duct ectasia refers to dilatation of breast ducts with inspissated luminal secretions and accompaniment by inflammatory cells. Luminal histiocytes that spill out into the stroma around the disrupted dilated duct are often present.
Clinical and Epidemiological Features
Duct ectasia most commonly occurs in perimenopausal women, although it has been reported in all age groups. The relatively high frequency of duct ectasia in breast specimens excised for other lesions and in post-mortem evaluations of the breast indicates that many lesions are asymptomatic and never become a clinical problem. The process is usually bilateral and infrequently symptomatic. Nipple discharge, which is usually serous and rarely bloody, is the most common clinical symptom. Nipple retraction or inversion, a palpable mass, or mastalgia can occur. The aetiology of duct ectasia is unknown. Some authors suggest that breast ductal dilatation with involution in postmenopausal women is the initial event in the occurrence of duct ectasia. Others believe that periductal inflammation is the inciting event leading to periductal fibrosis, stasis, and duct ectasia. Cigarette smoking has been linked to the development of periductal mastitis with a higher incidence of lactiferous fistula formation.
Mammographic findings can mimic cancer, with radiological calcifications, spiculated masses, or lobulated lesions . Duct ectasia can be seen as dilated tubular intramammary ducts filled with fluid that can appear clear or demonstrate mobile internal echoes on real-time sonography due to secretions and cellular debris. On magnetic resonance imaging, duct ectasia may present with a pattern of enhancement that can mimic ductal carcinoma in situ (DCIS).
Duct ectasia can be seen grossly as cystically dilated spaces that may exude pasty material or as a yellowish firm area due to the collections of foamy histiocytes (Fig. 2.8). Fibrosis related to chronic inflammation may be present.
Duct ectasia. Serial gross sections show a fibrofatty appearance with small cysts and surrounding haemorrhage
Histologically, duct ectasia features cystically dilated ducts with inspissated, luminal proteinaceous secretions. Inflammatory cells are invariably present, mostly composed of foamy histiocytes accompanied by variable numbers of lymphocytes and plasma cells (Fig. 2.9). An acute component with polymorphs can also be seen. Histiocytes in periductal stroma that show an accumulation of ceroid pigment which imparts a brown colour to the cells are commonly referred to as “ochrocytes”. When the duct wall is damaged from inflammation and is disrupted, luminal contents seeping into the surrounding stroma may incite a granulomatous response with epithelioid histiocytes, foreign-body-type multinucleated giant cells, and cholesterol granulomas. The epithelium lining the distended duct wall may be obscured and effaced by the inflammation, to the extent that only a collection of inflammatory cells may be seen on microscopy. Residual ductal epithelial cells and elastic fibres around the ectatic duct may be unveiled with keratin immunohistochemistry or elastic stains, respectively (Fig. 2.10). In the later stages of duct ectasia, marked fibrosis of duct walls, sometimes accompanied by elastosis, is the main histologic feature.
Duct ectasia. (a) A distended duct with attenuated epithelial lining shows luminal foamy histiocytes which have spilled out into the surrounding stroma. Scattered lymphocytes are seen among the histiocytes. (b) High magnification shows a residual flattened epithelial lining of the effaced duct wall. (c) Sheets of foamy histiocytes extend around adjacent ductules
Duct ectasia. (a) CD68 immunohistochemistry shows histiocytes that disclose granular cytoplasmic positivity. (b) CK7 immunohistochemistry unveils the attenuated epithelial lining of the duct wall which has been obscured by histiocytes
Xanthogranulomatous mastitis refers to an inflammatory reaction in the breast with a predominance of foamy histiocytes, admixed with granulomas featuring epithelioid histiocytes and multinucleated giant cells. Histologically, the inflammation associated with duct ectasia may be indistinguishable from xanthogranulomatous inflammation, except that the inflammatory process is centred around ectatic ducts in duct ectasia.
Fat necrosis may result from trauma, surgery, and radiation. While the histiocytes and inflammation that accompany necrotic adipocytes are similar to the inflammatory response associated with duct ectasia, fat necrosis primarily occurs within the fatty tissue of the breast, unrelated to ducts. In post-biopsy or postsurgical fat necrosis, there is often a biopsy or surgical cavity rimmed by inflamed granulation tissue, sometimes with sutures or other foreign materials related to the procedure.
Rosai–Dorfman Disease (RDD)
RDD is also known as sinus histiocytosis with massive lymphadenopathy. While it involves predominantly lymph nodes, RDD may be encountered in extranodal sites, including the breast. The sheets of histiocytes with voluminous pale cytoplasm may resemble those seen in duct ectasia, but the hallmark feature of emperipolesis where lymphocytes and plasma cells are found in spaces within histiocytic cytoplasm is an important diagnostic clue of RDD (Fig. 2.11). Extranodal RDD may show fewer histiocytes with more fibrosis. Plasma cells and lymphocytes are frequently seen among the histiocytes. The aetiology remains unknown, with infection and immunologic dysfunction being possibilities.
Rosai–Dorfman disease. (a) Gross appearance shows an ill-defined whitish-grey and yellowish-brown mass which is of firm consistency, merging with surrounding tissue, without any discrete or well discerned lesional borders. (b) Scanning magnification shows fibrous bands within adipose, interspersed with pale zones and scattered lymphocytic aggregates. (c) Sheets of pale histiocytes with copious amounts of cytoplasm are found effacing the breast parenchyma. The pale histiocytes may resemble those of duct ectasia. In contrast to RDD, however, the histiocytes accompanying duct ectasia are centred on dilated ducts which often show a disrupted epithelial lining. The histiocytes in duct ectasia are found both within the dilated duct and in the surrounding parenchyma. (d) Sheets of pale histiocytes contain vesicular nuclei with abundant pale-to-slightly pink cytoplasm. Within the cytoplasm of some histiocytes, there are lymphocytes and plasma cells in keeping with emperipolesis. Emperipolesis refers to the process in which lymphocytes and plasma cells enter the cytoplasm without undergoing degradation. (e) S100 immunohistochemistry decorates the histiocytes which contain inflammatory cells in their cytoplasm. These intracytoplasmic lymphocytes and plasma cells are surrounded by haloes representing spaces enclosed by the histiocytic cytoplasm, as the lymphocytes and plasma cells “wander” through the histiocytes. (f) CD68 immunohistochemistry shows granular and clumpy cytoplasmic positivity in histiocytes (arrows indicate several positively stained histiocytes)
Pagetoid Spread of Lobular Neoplasia
Histiocytes within the ductal epithelium of duct ectasia may resemble pagetoid extension of lobular neoplasia along the ducts. The presence of histiocytes within the ectatic duct lumen and surrounding stroma supports a histiocytic origin of the cells in the epithelium (Figs. 2.12 and 2.13).
Histiocytes along the duct wall, lying deep to the attenuated luminal epithelium, may mimic lobular neoplasia. In this duct, a few apocrine cells are found in the duct lumen. Several lymphocytes are seen among the foamy histiocytes, which have slightly folded vesicular nuclei with finely vacuolated cytoplasm
Pagetoid extension of lobular neoplasia along a terminal duct shows rounded cells with pale cytoplasm undermining the luminal epithelium of the terminal duct. Adjacent acini show filling by a similar population of slightly discohesive rounded cells (a). E-cadherin immunohistochemistry shows loss of membrane reactivity of the lobular neoplastic cells, with preserved staining of the luminal ductal epithelial cells (b)
Granular Cell Tumour
Cells of a granular cell tumour show abundant granular eosinophilic cytoplasm that may resemble histiocytes of duct ectasia. However, unlike duct ectasia, where the histiocytes reside within the ductal lumen and around the duct, cells of granular cell tumour are observed within the breast parenchyma and tend to be permeative, with granular cells extending among lobules (Figs. 2.14 and 2.15). Also unlike duct ectasia, where other inflammatory cells accompany histiocytes, granular cell tumour is not usually associated with a significant inflammatory reaction. Immunohistochemistry shows diffuse S100 reactivity in granular cell tumour .
Granular cell tumour. (a) Sheets of granular cells with ample granular cytoplasm, ill-defined cytoplasmic borders, and small nuclei are seen extending through stroma among collagen bundles and around a breast lobule. Note the absence of accompanying inflammatory cells, which are usually seen in duct ectasia. (b) High magnification shows the granularity of the cytoplasm, with small ovoid nuclei without atypia nor discernible mitoses
Granular cell tumour. (a) S100 immunohistochemistry diffusely decorates the cytoplasm of granular cells. (b) CK7 highlights small ducts in the section, whereas tumour cells are negative.MNF116, an epithelial marker, is also negative in the granular cells (inset)
Histiocytoid Invasive Lobular Carcinoma
The histiocytoid variant of invasive lobular carcinoma has a particularly bland appearance on cursory view, with tumour cells mimicking histiocytes (Figs. 2.16, 2.17, 2.18, 2.19, 2.20, and 2.21). Instead of the diffuse sheets of histiocytes that are intermingled with other inflammatory cells frequently observed in duct ectasia, histiocytoid invasive lobular carcinoma often shows areas with more typical linear cords of classical invasive lobular carcinoma as well as lobular neoplasia. Immunohistochemistry shows positive reactivity for epithelial markers, and the tumour cells are also generally ER positive .
Histiocytoid invasive lobular carcinoma. Histiocyte-like tumour cells percolate through the breast parenchyma. These tumour cells have ample pale-to-pink cytoplasm with hyperchromatic nuclei, some of which are eccentrically placed. Several tumour cells show cytoplasmic vacuoles. Lobular neoplasia (atypical lobular hyperplasia) is present
Histiocytoid invasive lobular carcinoma. Histiocyte-like tumour cells with hyperchromatic nuclei and ample pale cytoplasm extend in between the adipocytes, the latter potentially mimicking fat necrosis where histiocytes are seen among degenerate adipocytes. Clues to the malignant nature of histiocytoid invasive lobular carcinoma are the nuclear pleomorphism and hyperchromasia and the absence of accompanying inflammation which is usually observed in an inflammatory histiocytic lesion
Histiocytoid invasive lobular carcinoma. Sheets of pale histiocyte-like tumour cells surround resident ducts and lobules
Histiocytoid invasive lobular carcinoma. Higher magnification shows pale histiocyte-like cells surrounding a benign duct, extending among pink collagen fibres. The tumour cells possess ill-defined cytoplasmic membranes
Histiocytoid invasive lobular carcinoma. Focally, the tumour usually features more conventional invasive lobular carcinoma patterns of linear cords and pearl-like strands of bland tumour cells
Histiocytoid invasive lobular carcinoma. Immunohistochemistry for E-cadherin shows negative staining of the tumour cells, while the residual benign ducts are positively decorated
Invasive Apocrine Carcinoma
The ample cytoplasm of tumour cells of invasive apocrine carcinoma may resemble histiocytes. However, apocrine carcinoma cells have pink cytoplasm and occur in invasive trabeculae and cohesive nests, contrasting against the pale gentle cytoplasm of histiocytes disposed in sheets accompanied by other inflammatory cells. In addition, in apocrine carcinomas, the nuclei tend to be enlarged and round with prominent nucleoli (Figs. 2.22, 2.23, 2.24, 2.25, 2.26, 2.27, and 2.28).