How do small, peripheral intraductal papillomas (IDPs) affect the risk for invasive breast cancer (IBC)?

Updated: Dec 25, 2019
  • Author: Joshua I Warrick, MD; Chief Editor: Chandandeep Nagi, MD  more...
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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 papillo 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.

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