Answer
In the early 20th century, many breast pathologists considered all papillary lesions in the breast to be malignant. [13] However, it later became clear that many are benign, and that some are associated with a slightly increased risk of developing invasive breast cancer (IBC). Nonetheless, intraductal papillomas require workup to exclude the possibility of occult carcinoma and owing to their association with atypia and ductal carcinoma in situ (DCIS). [2] Thus, despite an initial diagnosis of intraductal papilloma on core biopsy, the potential exists for surgical upgrade to atypical ductal hyperplasia, DCIS, and carcinoma at excision. [2, 14, 15]
Carter was one of the first to recognize this association. [16] In a landmark paper, he studied 64 women with breast papilloma and demonstrated that multiple papillomas increased the risk of developing invasive carcinoma more than solitary lesions. He showed that although 2 of 6 patients diagnosed with multiple papillomas later developed IBC, only 4 of 58 patients with solitary papilloma did so. [17]
Around the same time, Haagensen studied women with multiple papillomas and those with solitary papilloma as separate cohorts and found that 6 of 52 women with multiple papillomas developed IBC (relative risk [RR] 3.7; multiple papilloma vs normal), whereas 7 of 172 women with solitary papilloma developed IBC (RR 1.3; solitary papilloma vs normal). [3]
Lewis et al later reported the largest series to date (480 women with papilloma) that also showed multiple papillomas increased the risk of IBC more than solitary papilloma (RR 3.01 for multiple papillomas; RR 2.04 for solitary papilloma; both vs normal). [9] These reports are represented in the image below.
Pathology of small, peripheral intraductal papillomas. Comparison of the risk of developing invasive breast cancer (IBC) in patients with multiple papillomas relative to patients with a solitary papilloma.
The question as to whether IDP (S/P ST) is a cancer precursor or merely a risk factor has been a topic of debate. Azzopardi did not consider papilloma to be a direct precursor based on what he believed to be a false association between papilloma and IBC in studies available during his time, which he thought were confounded by an overdiagnosis of "pseudo-infiltration" in benign papilloma and the misdiagnosis of papilloma as papillary carcinoma. [18] In contrast, Haagensen believed "multiple papilloma" was a precancerous lesion, because all 6 women in his study who developed IBC did so in the ipsilateral breast, in the same area where the initial papilloma had been diagnosed. [3]
However, in the largest series to date, although woman diagnosed with papilloma had an overall increased risk of developing IBC, they had equal bilateral risk, showing no statistically significant difference in breast cancer risk between the breast ipsilateral to and contralateral to the papilloma. [9, 19, 20] Studies evaluating loss of heterozygosity (LOH) in papilloma and subsequent development of breast cancer have also failed to identify LOH at the same allele in both the papilloma and the invasive carcinoma. [10, 17] On balance, it appears that IDP (S/P ST) is best viewed as a benign proliferative lesion that is a risk factor for developing carcinoma rather than as a direct cancer precursor.
Additionally, considering the known increased carcinoma risk in patients with other benign proliferative lesions, which is similar in magnitude to the increased risk associated with multiple papillomas, it must be recognized that the increased IBC risk seen in studies involving IDP (S/P ST) may not be a factor of IDP (S/P ST) itself; instead, it may be related to fundamental abnormalities in the breasts that develop proliferative disease.
-
Pathology of small, peripheral intraductal papillomas. Comparison of the risk of developing invasive breast cancer (IBC) in patients with multiple papillomas relative to patients with a solitary papilloma.
-
Pathology of small, peripheral intraductal papillomas. Small, peripheral intraductal papilloma (IDP) (small/peripheral subtype [S/P ST]) (40×). The fibrovascular core in this example shows extensive branching.
-
Pathology of small, peripheral intraductal papillomas. Same small, peripheral intraductal papilloma (IDP) (small/peripheral subtype [S/P ST]) as in the previous image (200×). The fibrovascular core is lined by a layer of columnar epithelium. A layer of flat, pale myoepithelial cells is present between the epithelium and the fibrovascular core (arrow).
-
Pathology of small, peripheral intraductal papillomas. Small, peripheral intraductal papilloma (IDP) (small/peripheral subtype [S/P ST]) (200×). This image shows slightly more complex branching than the sample seen two images ago.
-
Pathology of small, peripheral intraductal papillomas. Small, peripheral intraductal papilloma (IDP) (small/peripheral subtype [S/P ST]) (100×) with dense fibrovascular core.
-
Pathology of small, peripheral intraductal papillomas. Small, peripheral intraductal papilloma (IDP) (small/peripheral subtype [S/P ST]) (100×) within a cystic space.
-
Pathology of small, peripheral intraductal papillomas. Small, peripheral intraductal papilloma (IDP) (small/peripheral subtype [S/P ST]) (200×) within a cystic space. Note the extensive branching of the fibrovascular core. Tissue folding artifact is present at the top of the image.
-
Pathology of small, peripheral intraductal papillomas. Small, peripheral intraductal papilloma (IDP) (small/peripheral subtype [S/P ST]) (200×) within a cystic space.
-
Pathology of small, peripheral intraductal papillomas. Same small, peripheral intraductal papilloma (IDP) (small/peripheral subtype [S/P ST]) (400×) as in the previous image. Myoepithelial cells (arrows) are present beneath the epithelial layer.
-
Pathology of small, peripheral intraductal papillomas. Small, peripheral intraductal papilloma (IDP) (small/peripheral subtype [S/P ST]) (100×). This example may represent two IDPs (S/P ST) or a single one involving a tortuous, dilated terminal duct-lobular unit (TDLU).
-
Pathology of small, peripheral intraductal papillomas. Same small, peripheral intraductal papilloma (IDP) (small/peripheral subtype [S/P ST]) (200×) as in the previous image. Myoepithelial cells are identified (arrows).
-
Pathology of small, peripheral intraductal papillomas. Small, peripheral intraductal papilloma (IDP) (small/peripheral subtype [S/P ST]) (100×) within a cystic space. This papilloma is attached to the cyst wall by a relatively narrow base.
-
Pathology of small, peripheral intraductal papillomas. Same small, peripheral intraductal papilloma (IDP) (small/peripheral subtype [S/P ST]) (400×) as in the previous image. There is an abundant, hyperplastic-appearing proliferation of myoepithelial cells beneath the epithelium.
-
Pathology of small, peripheral intraductal papillomas. Small, peripheral intraductal papilloma (IDP) (small/peripheral subtype [S/P ST]) (100×) involved by a usual ductal hyperplasia (UDH)-like epithelial proliferation.
-
Pathology of small, peripheral intraductal papillomas. Same small, peripheral intraductal papilloma (IDP) (small/peripheral subtype [S/P ST]) (200×) as in the previous image. A usual ductal hyperplasia (UDH)-like epithelial proliferation involves the IDP (arrow).
-
Pathology of small, peripheral intraductal papillomas. Solid small, peripheral intraductal papilloma (IDP) (small/peripheral subtype [S/P ST]) (100×).
-
Pathology of small, peripheral intraductal papillomas. Same small, peripheral intraductal papilloma (IDP) (small/peripheral subtype [S/P ST]) (400×) as in the previous image. The fibrovascular core branches are tightly packed. Myoepithelial cells (arrows) are identified beneath the epithelium. This example also has central calcification.
-
Pathology of small, peripheral intraductal papillomas. Solid small, peripheral intraductal papilloma (IDP) (small/peripheral subtype [S/P ST]) (40×).
-
Pathology of small, peripheral intraductal papillomas. Same small, peripheral intraductal papilloma (IDP) (small/peripheral subtype [S/P ST]) (200×) as in the previous image. At higher power, this IDP has an adenomalike appearance. Myoepithelial cells (arrowhead) can be seen beneath the epithelium.
-
Pathology of small, peripheral intraductal papillomas. Mild usual ductal hyperplasia (UDH) with a micropapillary pattern (400×).
-
Pathology of small, peripheral intraductal papillomas. More pronounced usual ductal hyperplasia (UDH) with a micropapillary pattern (200×).
-
Pathology of small, peripheral intraductal papillomas. Usual ductal hyperplasia (UDH) (200×). This example consists of a benign epithelial proliferation that fills a considerable fraction of the duct lumen. The left aspect of the photomicrograph has vaguely papillary features (arrow).
-
Pathology of small, peripheral intraductal papillomas. Usual ductal hyperplasia (UDH) (200×). This example shows a benign epithelial proliferation involving a fibrovascular process (arrow). The lesion consists primarily of proliferative epithelium, and the fibrovascular process shows no convincing branching.
-
Pathology of small, peripheral intraductal papillomas. Usual ductal hyperplasia (UDH) (200×). This example consists of a proliferation of benign epithelium involving a fibrovascular process. The epithelial proliferation comprises the majority of this lesion, and the fibrovascular process shows no branching. Although this was diagnosed as UDH, it should be recognized that this lesion has compelling features of both UDH and small, peripheral intraductal papilloma (IDP) (small/peripheral subtype [S/P ST]), and distinguishing between these two lesions in this case is somewhat artificial.
-
Pathology of small, peripheral intraductal papillomas. Small, peripheral intraductal papilloma (IDP) (small/peripheral subtype [S/P ST]) involved by an abundant usual ductal hyperplasia (UDH)-like epithelial proliferation (arrow) (100×).
-
Pathology of small, peripheral intraductal papillomas. Same small, peripheral intraductal papilloma (IDP) (small/peripheral subtype [S/P ST]) (200×) as in the previous image. In this field, the lesion has the appearance of a common IDP (S/P ST).
-
Pathology of small, peripheral intraductal papillomas. Same small, peripheral intraductal papilloma (IDP) (small/peripheral subtype [S/P ST]) (200×) as in the previous two images. This field shows the IDP (S/P ST) (black arrow) and the abundant usual ductal hyperplasia (UDH)-like proliferation (blue arrow) that involves it. Although this lesion was diagnosed as IDP (S/P ST), it should be recognized that it has strong features of both UDH and IDP (S/P ST), and strict distinction between these lesions is somewhat artificial in this case.
-
Pathology of small, peripheral intraductal papillomas. Papillary ductal carcinoma in situ (DCIS) (40×).
-
Pathology of small, peripheral intraductal papillomas. Papillary ductal carcinoma in situ (DCIS) (200×). Several fibrovascular cores show delicate branching, and the epithelium shows moderate cytologic atypia.
-
Pathology of small, peripheral intraductal papillomas. Papillary ductal carcinoma in situ (DCIS) (400×). Note the delicate fibrovascular cores and moderate cytologic atypia of the overlying epithelium. The epithelial cells directly abut the fibrovascular core, with no intervening myoepithelial layer (arrow).
-
Pathology of small, peripheral intraductal papillomas. Papillary ductal carcinoma in situ (DCIS) (40×).
-
Pathology of small, peripheral intraductal papillomas. Same papillary ductal carcinoma in situ (DCIS) as in the previous image (100×).
-
Pathology of small, peripheral intraductal papillomas. Same papillary ductal carcinoma in situ (DCIS) as in the previous two images (400×). The epithelial cells are moderately atypical and lie directly against the fibrovascular core without an intervening myoepithelial layer (arrow).
-
Pathology of small, peripheral intraductal papillomas. Papillary apocrine metaplasia (100×). The cells have abundant pink cytoplasm. The papillary processes have no fibrovascular cores in this example.
-
Pathology of small, peripheral intraductal papillomas. Same papillary apocrine metaplasia as in the previous image (200×).
-
Pathology of small, peripheral intraductal papillomas. Myoepithelial cells are highlighted by p63, which has a nuclear staining pattern (400×).
-
Pathology of small, peripheral intraductal papillomas. CD10 highlights the myoepithelial cells in this image (400×). Note the staining is cytoplasmic, in contrast to the nuclear staining seen with p63 in the previous image. Calponin would show a similar staining pattern.
-
Pathology of small, peripheral intraductal papillomas. Smooth muscle actin (SMA) highlights the myoepithelial cells (400×). Note the cytoplasmic staining.
-
Pathology of small, peripheral intraductal papillomas. Cytokeratin (CK) 8/18 highlights the luminal epithelial cells overlying the myoepithelial layer (400×).
