Intraductal papillomas are benign intraluminal neoplastic proliferations characterized by the presence of arborizing fibrovascular cores lined by bilayered populations of basal (myoepithelial) and luminal (epithelial) cells (O’Malley et al. 2012). Papillomas may be centrally or peripherally located in the breast. Central papillomas with predominant glandular differentiation are also known as ductal adenomas. Large, often complex papillomas containing a cystic component are sometimes called papillary cystadenomas (Wei 2016).
Incidence: Intraductal papillomas account for less than 10% of all benign breast tumors. They are however the most common papillary lesions of the breast.
Age: Though there is a wide age distribution, most intraductal papillomas occur in the fourth and fifth decades. While central lesions are more common in perimenopausal women, peripheral papillomas typically affect slightly younger patients.
Sex: Vast majority of cases are diagnosed in females. Intraductal papillomas in the male breast are extremely rare. Isolated case reports exist in the literature of intraductal papillomas occurring in males ranging in age from 11 to 73 years.
Site: Central papillomas are more common (about 75% of all papillomas) and arise in the lactiferous ducts in the subareolar region of the breast. They are usually solitary but less frequently may also be multiple. Peripheral or small duct papillomas on the other hand arise in smaller branches or even in the terminal ductolobular units and are frequently multiple. Some papillomas grow within cystically dilated ducts (intracystic papillomas).
Clinical symptoms: Patients with central papillomas frequently present with serous or serosanguinous nipple discharge (Wei 2016). Small retroareolar papillomas can be occult on mammography because of the breast density in the area. Larger lesions on the other hand appear as well-circumscribed round or oval masses. Up to a quarter of central papillomas are associated with benign appearing mammographic calcifications. On ultrasound, cystic lesions with solid components may be observed. Galactography (ductography) shows well-defined filling defects and may be useful in identifying affected ducts prior to excision (MacGrogan and Tavassoli 2003).
Sclerosing papillomas may mimic malignancy both clinically and on imaging. Patients may present with a palpable mass fixed to the skin. Radiographically these lesions may present as stellate soft tissue densities, sometimes with microcalcifications.
Peripheral papillomas are usually clinically occult and nipple discharge is rare. Patients may present with a palpable mass.
Treatment: Papillary lesions may be heterogeneous; therefore, papillomas with atypia (focal atypical epithelial proliferation usually with low-grade nuclei) diagnosed on core needle biopsy are usually recommended for excision as the likelihood of discovering malignancy on excision is up to 67%. Complete surgical excision is also recommended for papillomas without atypia as no features predictive of upgrading on examination of the entire lesion have been identified (Shiino et al. 2015). Imaging-guided large-volume vacuum-assisted percutaneous biopsy has been suggested as a possible alternative to surgical excision (Bianchi et al. 2015). When a papilloma without atypia is diagnosed with vacuum biopsy, there is a high likelihood that it is benign; however, if surgical excision is not performed, long-term follow-up is still required.
Patients with multiple papillomas are at increased risk of developing malignancy thus long-term follow-up is appropriate. As no significant increase of risk of malignancy development has been demonstrated in patients with solitary papillomas, their regular follow-up is not justified.
Outcome: Intraductal papillomas with no other changes in the surrounding breast tissue are associated with a slight increase in relative risk of subsequent invasive breast carcinoma, equivalent to that of florid ductal hyperplasia.
In a study of 193 papillomas diagnosed on core needle biopsy, Cyr et al. reported that 12% of the papillomas were upgraded to malignant on excision; these carcinomas were early stage and usually hormone receptor positive and thus likely to have favorable prognosis (Cyr et al. 2011).
Macroscopically, central papillomas may appear as exophytic shagged masses attached to the wall within dilated ducts. Papillomas vary greatly in size, ranging from a few millimeters to several centimeters. Peripheral papillomas are macroscopically unidentifiable.
Cytologically, smears from papillomas are moderately cellular. The fronds of intraductal papillomas show sharp delineation and cells in tissue fragments are more cohesive. The papillae feature fibrovascular stalks lined by columnar cells. Frequently, epithelial cells arranged in a honeycomb pattern are seen. Alternatively, columnar cells can be arranged in small papillae and/or can be seen isolated. The presence of apocrine metaplasia and bipolar naked nuclei is very frequent (Gomez-Aracil et al. 2002).
Inflammatory cell infiltrate as well as epithelial and myoepithelial hyperplasia may also be observed in intraductal papillomas. Metaplastic changes are quite common, especially apocrine metaplasia. Squamous-, clear cell-, sebaceous-, osseous-, chondroid- and mucinous metaplasia may also occur. Squamous metaplasia may be present more frequently in the vicinity of infarction.
Molecular studies are not relevant for routine diagnosis and assessment of papillary lesions. However, Volckmar et al. described recurrent missense mutations affecting AKT1, GNAS, and PIK3CA in ductal adenomas (Volckmar et al. 2017). They concluded that mutations in so-called cancer-related genes do not necessarily indicate malignant behavior but are also present in benign tumors.
Papillomas frequently contain foci of benign epithelial proliferation showing features of usual ductal hyperplasia (UDH). This includes the presence of nuclei of variable shape, often elongated or spindled, without atypia. The cells grow in a lace-like pattern with irregular unevenly shaped lumina. The cells demonstrate the phenomenon of nuclear streaming (Bianchi et al. 2015). Immunohistochemically, it is possible to demonstrate a mosaic co-expression of low (e.g., CK18) and high (e.g., CK5/6) molecular weight cytokeratins with variable intensity of staining in individual cells (Wei 2016).
Atypical epithelial proliferations (ADH and DCIS) may involve intraductal papillomas, and they are usually of low grade. They are typically characterized by the presence of small, evenly spaced cells with round, bland, uniform nuclei. Intraductal papilloma with ADH and intraductal papilloma with DCIS are distinguished from one another using quantitative criteria; when the atypical proliferation is smaller than or equal to 3 mm, it is classified as ADH within a papilloma. Atypical proliferations larger than 3 mm fulfill criteria for intraductal papilloma with low-grade DCIS (O’Malley et al. 2012).
Intraductal papillary carcinoma is one of the architectural patterns of DCIS (see “Ductal Carcinoma In Situ”). It is not associated with intraductal papillomas. The neoplastic intraductal proliferations in intraductal papillary carcinomas (papillary DCIS) show slender, delicate fibrovascular cores lined by stratified columnar epithelial cells with palisading nuclei arranged perpendicular to the fibrovascular cores. When diagnosed cytologically, smears from malignant papillary lesions are usually more cellular than those from papillomas (Gomez-Aracil et al. 2002).
The state of the myoepithelial cell layer is a useful indicator of the nature of the papillary lesion. Atypical papillomas show reduced numbers of myoepithelial cells, while in intraductal papillary carcinomas, there is a paucity or complete absence of myoepithelial cells in the papillary fronds. However, it should be kept in mind that the sole absence of demonstrable myoepithelial cells does not automatically mean a diagnosis of malignancy, as these may be completely or almost completely absent in papillomas with apocrine metaplasia (Cserni 2012).
During different diagnostic interventions for intraductal papillomas (such as fine-needle aspiration cytology, core-cut biopsy, wire placement, etc.), so-called epithelial displacement may occur (Nagi et al. 2005). This phenomenon – although relatively rare – is well known and represents an important diagnostic pitfall. Displaced benign epithelial structures are usually represented by small isolated clusters of cells present in the stroma or lymphatic channels. Unlike truly invasive nests of neoplastic cells, displaced epithelial clusters are always located within the biopsy tract and lack desmoplastic stromal reaction (Ueng et al. 2009). Though the biologic significance of epithelial displacement is unknown, preliminary studies suggest that displaced cells most probably do not survive the preceding trauma or eventually die as time progresses (Nagi et al. 2005).
References and Further Reading
- Bianchi, S., Bendinelli, B., Saladino, V., Vezzosi, V., Brancato, B., Nori, J., & Palli, D. (2015). Non-malignant breast papillary lesions – b3 diagnosed on ultrasound – guided 14-gauge needle core biopsy: Analysis of 114 cases from a single institution and review of the literature. Pathology and Oncology Research, 21(3), 535–546.CrossRefPubMedGoogle Scholar
- O’Malley, F., Visscher, D., MacGrogan, G., & Tan, P. H. (2012). Intraductal papilloma. In S. R. Lakhani, I. O. Ellis, S. J. Schnitt, P. H. Tan, & M. J. van de Vijver (Eds.), WHO classification of tumours of the breast (pp. 100–102). Lyon: IARC Press.Google Scholar
- Shiino, S., Tsuda, H., Yoshida, M., Jimbo, K., Asaga, S., Hojo, T., & Kinoshita, T. (2015). Intraductal papillomas on core biopsy can be upgraded to malignancy on subsequent excisional biopsy regardless of the presence of atypical features. Pathology International, 65(6), 293–300.CrossRefPubMedGoogle Scholar
- Volckmar, A. L., Leichsenring, J., Flechtenmacher, C., Pfarr, N., Siebolts, U., Kirchner, M., Budczies, J., Bockmayr, M., Ridinger, K., Lorenz, K., Herpel, E., Noske, A., Weichert, W., Klauschen, F., Schirmacher, P., Penzel, R., Endris, V., & Stenzinger, A. (2017). Tubular, lactating, and ductal adenomas are devoid of MED12 Exon2 mutations, and ductal adenomas show recurrent mutations in GNAS and the PI3K-AKT pathway. Genes, Chromosomes & Cancer, 56(1), 11–17.CrossRefGoogle Scholar