and Aysegul A. Sahin2
(1)
Division of Pathology, Singapore General Hospital, Singapore, Singapore
(2)
The University of Texas, M. D. Anderson Cancer Center, Houston, TX, USA
Keywords
PapillaryIntraductalPapillomaAtypicalIn situSolid papillaryInvasivePapillary lesions of the breast demonstrate arborescent fronds or papillae composed of fibrovascular septa covered by epithelial cells.
Intraductal Papilloma
Definition
The intraductal papilloma is a benign lesion which shows bilayered epithelium composed of both luminal and myoepithelial cells surmounting well-developed fibrovascular cores. Solitary or central papillomas arise from large breast ducts occurring near the nipple-areolar region, while multiple or peripheral papillomas originate from the terminal ductal lobular units. Peripheral papillomas tend to be microscopic and are sometimes referred to as micropapillomas or papillomatosis. The term papillomatosis has also been used to refer to usual ductal hyperplasia, although it is preferably applied to lesions with papillary fronds and fibrovascular cores.
Clinical and Epidemiological Features
Patients with central papillomas may present with nipple discharge or a subareolar lump. Asymptomatic cases are detected on mammographic screening. Intraductal papillomas affect women over a wide age range and comprised 5.3 % of a series of benign breast biopsies [1].
Imaging Features
The intraductal papilloma can be mammographically occult or appear as well-defined or ill-defined soft tissue nodules on mammogram and ultrasound examination. The best imaging clue is an intraductal mass near the nipple. The ducts may or may not be dilated. The intraductal papilloma can appear as an intracystic mass when associated with a focally dilated duct (Fig. 4.1). Sometimes it can contain clustered microcalcifications or dense heterogeneous coarse calcifications. On galactography, it gives rise to an intraductal filling defect. Papillomas extending along the breast ductal system with ill-defined borders, as well as sclerosing papillomas presenting with distortion, are difficult to differentiate from malignancy.
Fig. 4.1
Intraductal papilloma. Ultrasound shows a dilated duct with a mural nodule (arrow)
Pathologic Features
Macroscopic Pathology
Intraductal papillomas form circumscribed rounded masses comprising fused papillary fronds attached to the wall of the dilated duct into which the papilloma protrudes (Figs. 4.2, 4.3, 4.4, and 4.5). The lumen of the dilated duct can be seen as the cystic component of the whitish-grey tumour mass, while other times the mass can appear solidified with small spaces in between solid areas. Haemorrhage into the cyst may be present. Intraductal papillomas ramifying into ducts and their branches may appear less well defined.
Fig. 4.2
Intraductal papilloma (central). Gross appearance shows a partially circumscribed yellowish-white lesion with a whitish fibrous wall. Occasional cystic spaces are seen. An area shows brownish discolouration that may be related to prior haemorrhage. Some whitish areas are also seen within the lesion, which correspond to fibrotic zones within the papilloma
Fig. 4.3
Intraductal papilloma. Serial sections of a breast excision containing an intraductal papilloma which was confirmed histologically. In some of the breast slices, cystic areas are identified (black arrows). Solid portions are seen, which in some slices do not have a cystic component (red arrow), while in others they lie juxtaposed to the cystic areas with broad protrusions into the cystic cavity (green arrows)
Fig. 4.4
Intraductal papilloma. (a) A solid-cystic tumour mass is seen. The cystic component is filled with altered blood which appears chocolate black in colour. The solid mass is adherent to the wall of the cavity which histologically corresponds to the cystically dilated duct from which the intraductal papilloma arises. The solid mass has a lobulated appearance. (b) A broad fronded appearance of the mass protruding into and filling up the cystic cavity is seen. The mass is connected to the wall of the cystic cavity by a broad base (arrows)
Fig. 4.5
Intraductal papilloma (peripheral). An excision specimen for multiple papillomas shows cysts of varying sizes within rubbery fibrous parenchyma. Within some cysts are mural nodules representing the micropapillomas
Microscopic Pathology
Distinct and anastomosing fronds with well-developed fibrovascular cores are covered by bilayered epithelial cells with myoepithelial preservation (Figs. 4.6 and 4.7). Usual ductal hyperplasia (UDH), apocrine metaplasia, and sclerotic hyalinised zones are often encountered (Figs. 4.8, 4.9, 4.10, and 4.11). Squamous metaplasia may be seen, especially adjacent to infarcted areas (Fig. 4.12). Myoepithelial cells may also be hyperplastic with spindled or epithelioid morphology (Figs. 4.13 and 4.14). Collagenous spherulosis can be seen (Fig. 4.15). Epithelial nests and tubules can be entrapped within sclerotic portions of the intraductal papilloma. These epithelial nests and tubules may be distorted, angulated, and squamoid, raising concern for invasion that may be refuted by confirming the presence of myoepithelial cells on immunohistochemistry (Figs. 4.16, 4.17, and 4.18).
Fig. 4.6
Peripheral papilloma. This intraductal papilloma arises in the terminal ductal lobular unit and is also referred to as microscopic papilloma or micropapilloma
Fig. 4.7
Peripheral papilloma. A microscopic papilloma shows finger-like papillary fronds projecting into the dilated duct, resembling a glomerulus-like structure
Fig. 4.8
Intraductal papilloma with apocrine metaplasia. The presence of apocrine metaplasia in a papilloma is often used as a feature supporting benignity. The apocrine cells contain ample pink cytoplasm, and nuclei are enlarged with discernible nucleoli. Apocrine metaplasia is usually observed in conjunction with usual ductal hyperplasia in the papilloma
Fig. 4.9
Intraductal papilloma with florid (marked) usual ductal hyperplasia (UDH). Papillary fronds are obscured by the proliferation of epithelial cells, with the papillary architecture inferred from the congested fibrovascular septa coursing in between the epithelial cells
Fig. 4.10
Intraductal papilloma with florid UDH. Medium magnification shows the heterogeneous population of epithelial cells with areas of nuclear crowding and overlapping. Narrow fibrovascular septa are seen coursing among the epithelial cells
Fig. 4.11
Intraductal papilloma with florid UDH. Some ductal epithelial nuclei show pink intranuclear inclusions (arrows indicate some of these intranuclear inclusions), which have been described in florid UDH and ultrastructurally represent cytoplasmic invaginations into nuclei. Sometimes these intranuclear inclusions may have a more eosinophilic hue
Fig. 4.12
Intraductal papilloma with infarction and squamous metaplasia. (a) Biopsy cores show portions of a benign intraductal papillary lesion with a solidified appearance composed of anastomosed papillary fronds. Infarction with haemorrhage is seen (arrow). (b) Higher magnification of the haemorrhagic edge of the infarcted zone shows squamous metaplasia composed of anastomosing pavemented trabeculae of polygonal cells with ample pink cytoplasm. Squamous metaplasia merges with epithelial nests and tubules in the non-metaplastic portions of the intraductal papilloma
Fig. 4.13
Intraductal papilloma with florid UDH. Sometimes the epithelial proliferation may have a slightly spindled appearance with a sweeping sheet-like pattern. The spindle cells may be either of luminal epithelial or myoepithelial origin
Fig. 4.14
Intraductal papilloma with myoepithelial hyperplasia. (a) Low magnification shows an intraductal papilloma distending the duct lumen. Several broad fronds are seen projecting into the cystically dilated duct lumen. (b) Higher magnification shows sheets of spindle cells in between tubules. Some of the spindle cells merge with myoepithelial cells of tubules. (c) Immunohistochemistry for p63 shows nuclear staining of the spindle cells, indicating a myoepithelial origin. Note the positive reactivity of myoepithelial cells rimming the tubules. (d) Immunohistochemistry for CK14 shows positive staining of the spindle cells corroborating a myoepithelial origin. These cells blend with the myoepithelial cells surrounding the luminal epithelial cells of tubules
Fig. 4.15
Peripheral papilloma (micropapilloma) with collagenous spherulosis and calcifications. The papillary fronds are anastomosed. A clue to the underlying papillary architecture is the subtle presence of congested fibrovascular septa (arrows). Spaces containing basement membrane spherules may mimic the luminal spaces of cribriform ductal carcinoma in situ; however, the epithelial population in collagenous spherulosis is heterogeneous, which may be affirmed on immunohistochemistry with ER and high-molecular-weight keratins. Cells rimming the spherules are myoepithelial in nature
Fig. 4.16
Intraductal papilloma with florid UDH. Immunohistochemistry for CK14 (a high-molecular-weight cytokeratin) shows heterogeneous reactivity of the epithelial cells. This staining pattern is in contrast to papillary DCIS in which epithelial cells are usually uniformly nonreactive due to their clonal and luminal nature
Fig. 4.17
Intraductal papilloma with florid UDH. Aside from demonstrating the mosaic-like heterogeneous staining in the epithelial population, immunohistochemistry for CK14 can also highlight preserved peripheral myoepithelial cells (arrows) in entrapped epithelial nests within sclerotic portions of the papilloma. These entrapped epithelial nests and tubules may mimic an invasive process due to their distorted outlines within fibrotic stroma
Fig. 4.18
Intraductal papilloma with epithelial nests within fibrotic stroma. Immunohistochemistry for p63 shows preserved peripheral myoepithelial cells around these epithelial nests and tubules, indicating a non-invasive nature. These slightly distorted epithelial nests and tubules can be found within sclerotic centres or fibrotic walls of the papilloma
The epithelial displacement phenomenon may be seen in surgical specimens of papillomas that have undergone prior instrumentation, and this may mimic invasive cancer [2]. These displaced epithelial nests are mostly limited to granulation tissue or fibrotic zones of the biopsy tract (Figs. 4.19 and 4.20). Immunohistochemistry may be helpful in confirming myoepithelial cuffing, but some displaced epithelial elements are devoid of a surrounding myoepithelial cell layer.
Fig. 4.19
Intraductal papilloma with epithelial displacement phenomenon. (a) Part of the intraductal papilloma is present in the upper field. In contiguity with the intraductal papilloma is an area of fibrosis with chronic inflammation and scattered small epithelial nests and tubules, related to prior instrumentation. (b) There are epithelial nests with a squamoid appearance within the loose, lightly inflamed reactive stroma. These should not be mistaken as invasive tumour nests. The epithelial displacement phenomenon is often seen after instrumentation, especially in papillary lesions
Fig. 4.20
Intraductal papilloma with epithelial displacement phenomenon. (a) At low magnification, the intraductal papilloma is surrounded by a fibrotic wall. A fibrotic zone in the left lower field is seen in contiguity with the wall of the intraductal papilloma, extending into the fat. Scattered small epithelial nests and tubules are seen in this fibrotic zone. (b) The fibrotic zone extends into the skeletal muscle, and epithelial nests and tubules are seen among the skeletal muscle fibres, which raised concern for invasion. (c) Review of the prior core biopsy shows portions of a benign intraductal papillary lesion with a fragment composed of skeletal muscle fibres, correlating with the organizing fibrosis extending into skeletal muscle in the subsequent excision specimen. (d) Immunohistochemistry for CK14 highlights many small epithelial nests and tubules within fibrosis, reflecting marked epithelial displacement. These epithelial elements are mostly confined to the reparative fibrotic areas and do not permeate into breast parenchyma elsewhere. Inset shows high magnification of a few epithelial nests and tubules. Some of the epithelial nests can possess a squamoid appearance on light microscopy, and together with their haphazard placement, may be erroneously interpreted as low grade adenosquamous carcinoma. (e) Immunohistochemistry for ER shows generally negative staining in the epithelial tubules and nests, with one tubule disclosing patchy epithelial nuclear reactivity (arrow). (f) Immunohistochemistry for p63 shows a patchily preserved rim of myoepithelial cells around epithelial nests and tubules (highlighted with nuclear p63 staining), which is helpful in affirming their displaced rather than invasive nature. Not always however, will p63 immunohistochemistry be able to detect a peripheral rim of myoepithelial cells, and in such instances, the diagnosis of displaced epithelium will rely on other histological features
Differential Diagnosis
Intraductal Papilloma with Florid Usual Ductal Hyperplasia, Atypical Ductal Hyperplasia, and Low Nuclear Grade Ductal Carcinoma In Situ
Florid usual ductal hyperplasia (UDH) can make the papilloma seem solidified, with variable accompaniment by mitotic activity and even necrosis (Figs. 4.21, 4.22, 4.23, and 4.24). This can lead to overdiagnosis of malignancy. Hyperplastic ductal epithelial cells, however, show heterogeneity in size, shape, and placement, crowded and overlapping nuclei with intranuclear cytoplasmic inclusions [3], and irregular slit-like spaces, giving an appearance identical to UDH in background breast tissue. Lobular neoplasia (atypical lobular hyperplasia and lobular carcinoma in situ) may be seen within the intraductal papilloma (Fig. 4.25).
Fig. 4.21
Intraductal papilloma with florid UDH, showing a mitosis in an epithelial cell. Mitoses can be observed in UDH (arrow) and their presence does not connote malignancy. Epithelial nuclei may also vary in size with ovoid to more elongated forms. Nuclear crowding and overlapping are present in UDH in an intraductal papilloma
Fig. 4.22
Intraductal papilloma with florid UDH may show necrosis (arrow), seen here as a zone of pink amorphous material among hyperplastic ductal epithelial cells. The presence of necrosis should not necessarily lean towards a diagnosis of malignancy unless other characteristic features are present
Fig. 4.23
Intraductal papilloma with florid UDH. Necrosis may also be focal and punctate, with scattered degenerate cells among some debris (arrow)
Fig. 4.24
Intraductal papilloma with perineural involvement in its fibrotic wall. The wall of an intraductal papilloma can be sclerotic, and apart from epithelial nests being entrapped in the fibrosclerotic stroma, perineural wrapping by epithelial cells (arrow) can also be rarely encountered
Fig. 4.25
Intraductal papilloma with atypical lobular hyperplasia. (a) Low magnification shows a population of rounded cells occupying the papillae. Inset shows cellular discohesion. (b) Discohesive rounded lobular neoplastic cells are seen within the intraductal papilloma. The distinction between atypical lobular hyperplasia and lobular carcinoma in situ may be challenging in the context of an intraductal papilloma, as the reference to the degree of lobular acinar distension and distortion which distinguishes them is not readily available. Comparison with lobular neoplastic changes in the surrounding breast tissue if present, and assessment of the degree of effacement of underlying papillary architecture by lobular neoplastic cells, are helpful. (c) Immunohistochemistry for E-cadherin shows negative staining of the lobular neoplastic cells. (d) Higher magnification of lobular neoplastic cells that display loss of E-cadherin immunohistochemical reactivity. Some lobular neoplastic cells show diminished and incomplete staining rather than complete absence of immunoreactivity.
Atypical ductal hyperplasia (ADH) within an intraductal papilloma is diagnosed when a monotonous uniform epithelial population measuring less than 3 mm in extent is found within a recognisable benign intraductal papilloma (Fig. 4.26). When the abnormal epithelial population is 3 mm or more, low nuclear grade ductal carcinoma in situ (DCIS) within an intraductal papilloma is diagnosed [4]. Immunohistochemistry with high-molecular-weight keratins and oestrogen receptor (ER) can serve as an adjunct to diagnosing ADH/DCIS versus UDH within the intraductal papilloma (Figs. 4.27 and 4.28) [5].
Fig. 4.26
Complex intraductal papilloma with atypical ductal hyperplasia and clear-cell squamous metaplasia. (a) Gross appearance shows a multilobulated lesion with partial cystic change. (b) At low magnification, the tumour shows predominantly rounded and nodular solidified papillary areas with fibrous enclosures. Areas of haemorrhage are present in the fibrous wall. The nodules project into the cystic spaces. (c) Atypical ductal hyperplasia (ADH) is observed as duct spaces containing a cribriform proliferation (circled). The cribriform spaces are well defined and are lined by relatively uniform epithelial cells. Rigid epithelial arches are also seen. Distinction of ADH from low nuclear grade ductal carcinoma in situ (DCIS) within an intraductal papilloma is based on size or extent of the cytoarchitecturally atypical alterations. The WHO working group recommends a threshold of 3 mm, with cytoarchitecturally atypical lesions measuring less than 3 mm being diagnosed as ADH, while those that are 3 mm and above are considered DCIS. The size criterion applies only to low nuclear grade lesions, as high nuclear grade alterations warrant a diagnosis of DCIS regardless of extent. (d) Haemorrhagic infarction is surrounded by epithelial nests with clear-cell change. Reactive nuclear atypia may be seen adjacent to infarction. (e) Immunohistochemistry for p63 shows positive nuclear staining in clear-cell areas, while adjacent ducts disclose peripheral myoepithelial nuclear reactivity. (f) Immunohistochemistry for CK5/6 shows positive staining of the clear cells supporting a squamous metaplastic origin
Fig. 4.27
Intraductal papilloma with ductal carcinoma in situ (DCIS). (a) This intraductal papilloma shows an area of relatively monotonous cribriform epithelial proliferation that exceeds 3 mm in extent (horizontal line). (b) Higher magnification of low nuclear grade DCIS composed of a uniform population of epithelial cells punctuated by well-defined cribriform spaces. (c) Immunohistochemistry for CK14 shows diminished staining of the epithelial cells. Only the peripheral myoepithelial cuff is decorated. (d) Immunohistochemistry for ER shows diffuse and intense nuclear staining of the epithelial cells, supporting a clonal neoplastic process
Fig. 4.28
Intraductal papilloma colonized by neuroendocrine DCIS. (a) In this sliced open mastectomy specimen, a lobulated brownish grey mass is seen, partially rimmed by whitish fibrous tissue. Histologically, this showed an intraductal papilloma with neuroendocrine DCIS. (b) In this intraductal papilloma in which the underlying papillary architecture is preserved, there is a population of relatively monotonous cells with amphophilic cytoplasm expanding papillary fronds and located deep to the luminal epithelium, focally giving a pagetoid appearance (arrow) of insinuation in between luminal and myoepithelial cells. (c) Higher magnification shows the monomorphic cells containing vesicular rounded nuclei with small inconspicuous nucleoli and pink to amphophilic cytoplasm. A focal pagetoid appearance is seen (arrow). (d) Immunohistochemistry for synaptophysin shows positive staining of the neuroendocrine cells within the intraductal papilloma
Sclerosing Intraductal Papilloma
This is an intraductal papilloma which has undergone extensive sclerosis with effacement of the underlying papillary architecture. Histologically, closely placed bilayered tubules are seen within a fibrotic wall (Fig. 4.29). The ductal adenoma is considered by some authors as representing one end of the spectrum of sclerosing papillomas, where there is complete effacement and solidification of papillary structures [6].
