Intraductal papilloma of the breast is a benign lesion, accounting for about 5.3% of all benign lesions and about 3% of solid lesions in the breast. Most cases lack specific clinical manifestations and imaging signs, and often require puncture biopsy and surgery to obtain a correct diagnosis, while there are many differences in pathological definitions and diagnostic criteria for carcinoma, and a lack of standardized diagnostic and treatment procedures. This is a benign lesion and there are no prospective randomized clinical controlled studies. The evidence in this article is mainly based on the findings of large case-control studies and retrospective studies.
Classification of intraductal papillomas of the breast
Intraductal papillomas are classified into two types based on anatomic location and histologic features: central (solitary) and peripheral (multiple). Central-type intraductal papillomas originate from the large ducts, usually located under the areola, and do not involve the lobular units of the terminal ducts; peripheral-type intraductal papillomas originate from the lobular units of the terminal ducts. The disease is mostly central and commonly seen in women aged 30 to 50 years; the peripheral type accounts for only about 10% of the total. In the past, peripheral intraductal papilloma was called papillomatosis, but it has been abandoned.
I. Clinical symptoms
The central type of intraductal papilloma is mainly manifested by unilateral uniportal papillary discharge, which is often bloody or plasmacytic. In some patients, breast masses can be palpated during physical examination, mostly located around the areola, and when the tumor is squeezed in the area, there can be bloody or other nature fluid overflowing from the nipple at the corresponding milk duct opening.
When the papilloma grows in clusters, sometimes the mass can be palpated.
Second, auxiliary examination results
1.Ultrasound.
The sensitivity of ultrasound in diagnosing intraductal papilloma is higher than that of mammography [5]. The American College of Radiology Breast Imaging Reporting and Data System (BI-RADS) classification for most lesions is usually category 3. The presentation is often a solid hypoechoic mass with regular morphology and well-defined borders; sometimes it may appear as a mixed cystic-solid mass with well-defined borders. Papillomas located in dilated ducts are sometimes confused with intracapsular nodules, but the diagnosis can be confirmed by detecting adjacent non-dilated milk ducts with careful scanning [5]. When infarcts or calcifications are present, or multiple lesions are distributed in clusters, the BI-RADS classification can be category 4 or higher.
2. mammogram.
An isolated mass shadow with round or ovoid shape and well-defined borders may be seen, typically located around the areola. The periphery is not accompanied by structural disorder, and sometimes a transparent halo is seen around the mass. In about 25% of papillomas, microcalcifications or coarse calcifications may be present within the mass [6]. When sclerosis or infarction is present within the papilloma, it can cause structural disorganization, a presentation that is sometimes easily confused with invasive carcinoma [7]. Smaller, central-type intraductal papillomas are often not found positively on mammography. Peripheral type papillomas often have no abnormal changes on mammograms, and some may show peripheral type microcalcifications or multiple small nodules.
3.MRI.
MRI has a high sensitivity for the diagnosis of papillary lesions. It is more valuable for the evaluation of peripheral lesions, whether to determine the extent of surgical resection before surgery or to detect lesions that cannot be detected by ultrasound [8]. Papillomas may present as well-defined, high-signal images. Larger lesions may show irregular borders and rapid contrast enhancement. Assessment of the enhancement curve is usually not useful [8].
4. Cytologic examination of nipple discharge.
Cytologic smears of papillary overflow provide information about normal, heterogeneous or malignant lesions, but their positivity rate for diagnosing papilloma is low. The morphologic features of papilloma sometimes resemble those of low-grade cancer cells, when tissue biopsy is required to further clarify the diagnosis [9].
5.Mammary ductography.
When selective mammography of the breast ducts is performed, smooth round filling defects in the ducts are seen in about 90% of cases, or abrupt interruptions of the breast ducts with smooth cup-shaped severed ends are seen, which may also show tortuous and dilated ducts. The proximal ducts in the area of the break or filling defect may be significantly dilated. In larger intraductal papillomas, the lesioned duct is seen to be dilated and cystic in shape, with smooth walls and lobulated filling defects.
6. Breast ductoscopy.
The microscopic manifestation of intraductal papilloma is a red or light red and red, yellow and white substantial occupancy in the duct with smooth surface or small granular shape, which can move back and forth in a small extent in the lumen and the surrounding duct wall is smooth and elastic. Ductal lavage can be performed under direct vision through ductoscopy or for intraoperative guidance of deeper lesions in the ductal system [10]. Compared with direct collection of nipple discharge for cytologic diagnosis, ductal lavage after ductoscopy can result in a significant increase in the number of ductal epithelial cells in the lavage fluid, which facilitates cytologic diagnosis [11].
Diagnosis and differential diagnosis of intraductal papilloma of the breast
I. Diagnosis
The clinical diagnosis should include history, clinical manifestations, physical examination and ultrasound and mammography. Although the disease often lacks specific imaging signs, information from routine imaging examinations can help in differential diagnosis. For those with swelling as the main manifestation, histopathological diagnosis can be made by hollow-core needle puncture under ultrasound guidance to obtain tissue. In cases where nipple discharge is the main manifestation, further cytologic examination of nipple discharge, ductoscopy or mammography may be performed.
The role of MRI in the evaluation of papillary lesions remains controversial [12].MRI is indicated in patients with ultrasound findings of ductal dilatation, >3 mm in diameter, previous history of papilloma, family history of breast cancer, or suspected peripheral intraductal papilloma. Breast ductography is an invasive test with limitations in lesion detection and may be used at discretion [3,13].
Puncture biopsy is often helpful in the diagnosis of intraductal papilloma. Fine needle aspiration is significantly less accurate than coarse needle aspiration for the diagnosis of malignant lesions and sometimes results in false positives, especially in the presence of sclerosing papillary lesions. The accuracy of crude needle aspiration for the diagnosis of malignant lesions is approximately 84% [14] and is not a complete substitute for surgical biopsy [15,16,17]. The results of a Meta-analysis including 34 studies of 2236 cases showed that 346 cases diagnosed as non-malignant papillary lesions by hollow needle aspiration were found to be malignant at the time of subsequent surgical resection, with an underestimation rate of 15.7% [18].
II. Histopathological features
Both central and peripheral intraductal papillomas are characterized by a dense and branching structure consisting of a fibrovascular axis, a single layer of myoepithelial cells, and overlying epithelial cells. Myoepithelial cells are usually inconspicuous and immunohistochemical staining using myoepithelial cell markers, such as smooth muscle myosin heavy chain, calmodulin, and p63, are helpful in confirming their presence. The epithelial component consists of a single layer of cuboidal, columnar cells that may be accompanied by foci of common type ductal hyperplasia.
Hemorrhage or infarction may occur secondary to puncture biopsy or fibrovascular axis torsion. Interstitial fibrosis is common and may obscure papillary structures in extensive cases; this lesion was once called sclerosing papilloma, a subtype of ductal adenoma. Epithelial nests may be embedded in areas of fibrosis, resembling invasive carcinoma, and preservation of the myoepithelial layer may confirm its benign nature. The ducts in which papillomas are located are usually dilated, which can be a clue to the presence of papillomatous lesions in biopsy or resection specimens.
Differential diagnosis
Intraductal papilloma of the breast needs to be differentiated from the following diseases.
1. Fibroadenoma.
Parenchymal papillomas need to be differentiated from fibroadenomas. Fibroadenomas can be palpated during physical examination when they are large and superficial. Ultrasound mostly shows hypoechoic masses with clear borders and regular morphology, sometimes with the presence of small lobes, and the BI-RADS classification is mostly 2 to 3 categories. Mammography may show a regular morphology and clear border of equal or slightly high-density masses, and the BI-RADS classification is mostly 3 categories.
2. Other intraductal papillary lesions.
Compared with intraductal papilloma, other intraductal papillary lesions (such as intraductal papilloma with atypical hyperplasia or ductal carcinoma in situ, papillary ductal carcinoma in situ, encapsulated papillary carcinoma, solid papillary carcinoma) lack specificity in clinical manifestations and imaging signs and require histopathology to confirm the diagnosis (see the fourth edition of the WHO classification of breast tumors issued in 2012). When sclerosis or infarction is present within the papilloma, its imaging BI-RADS classification can reach category 4C or 5, making it difficult to distinguish from a malignant lesion. When papillomas are accompanied by microcalcifications, their malignancy may also be increased.
There are two ways to define papilloma with atypical hyperplasia and carcinoma in situ, and it is controversial which one to use. First, a papilloma with atypical ductal epithelial proliferation ≤3 mm is considered an atypical intraductal papilloma, and if it is >3 mm, it is diagnosed as intraductal papilloma with intraductal carcinoma. Second, 30% of the range of atypical hyperplasia was used as the diagnostic threshold [23]. The WHO currently recommends the first method for differentiation.
Surgical treatment of intraductal papilloma of the breast
All lesions diagnosed as intraductal papilloma, especially peripheral intraductal papilloma and intraductal papilloma with hemorrhagic discharge, should be routinely treated with segmental resection including the diseased duct. For benign papillomas that are solitary and not associated with papillary overflow, more than half of the participating experts recommend open surgical excision; in equipped hospitals, complete excision can also be performed under ultrasound guidance using a vacuum-assisted biopsy system. Intraoperative localization by mammography can also be used to guide open surgery or direct excision of intraductal papillomas. If multiple lesions involve the entire breast, more than 90% of the experts involved in the discussion favor total mastectomy + breast reconstruction; therefore, total mastectomy or total mastectomy + breast reconstruction may be considered, as appropriate. If intraoperative or postoperative pathology diagnoses malignant intraductal papilloma, the principles of breast cancer management are followed.
Prognosis of intraductal papilloma of the breast.
Peripheral intraductal papillomas and papillomas with atypical lesions have an increased risk of secondary breast cancer.