Does previous history of cancer or atypia predict histologic upgrade for pure intraductal papillomas diagnosed via core biopsy? A study of 490 cases at a single institution

Abstract Background Management of pure intraductal papillomas (IDP) without atypia diagnosed on core needle biopsy (CNB) remains controversial given highly variable rates of upgrade in the literature. Aim We sought to identify clinical and histologic factors that predict upgrade to atypia or malignancy in a large population. Methods and results A retrospective review was performed of all cases of pure IDP diagnosed on CNB and then surgically excised at a single institution from 2008 to 2018. Clinical, radiologic, and pathologic factors were compared in the no upgrade, upgrade to atypia, or upgrade to cancer groups. Univariate analysis was performed comparing no upgrade and upgrade to cancer or atypia. Four hundred and thirty nine patients were identified with a total of 490 IDP and a median age of 50 years (range 16–85). Of these patients, 54 (12.3%) were upgraded to atypia after surgical excision and five (1.1%) were upgraded to cancer. The presence of multiple papillomas in a single patient was a significant predictor of upgrade to cancer or atypia (p < .01), as well as age over ≥55 years (p < .01) and a prior history of cancer (p < .01). No other clinical, radiologic and histologic factors were found to be significant predictors of upgrade. 40/439 (9.1%) patients in the total cohort had prior history of cancer, and of these, 2/40 (5%) were found to have a new cancer after excision. Conclusions In patients with pure IDP on CNB, the upgrade rate to malignancy was 1.1%, while 12.3% were upgraded to atypia. The clinical significance of identifying atypia in a papilloma is unknown, especially in a patient with a prior history of atypia or cancer. However, the majority of patients who were upgraded to either atypia or cancer had no prior history of high‐risk or malignant breast disease and are therefore considered true clinical upgrades. As such excision for IDP should be considered.


| INTRODUCTION
Intraductal papillomas (IDP) are benign papillary lesions of the breast with fibrovascular cores comprised of ductal and myoepithelial cells. 1,2 General consensus exists that IDP with atypia should be surgically excised, as these lesions have unacceptably high rates of upgrade when undergoing observation as opposed to excision, reported to be anywhere from 6.8% to 38.1%. [3][4][5][6][7] Management of pure IDP-those without atypia or malignancy identified after core needle biopsy (CNB)-remains controversial even today, due to highly variable rates of upgrade in the literature. [8][9][10][11][12] Previous studies have failed to consistently identify clinical, radiologic, and pathologic factors associated with possibility of upgrade, although some have suggested increased likelihood related to IDP size, multiplicity, presence of microcalcifications on imaging, nipple discharge on presentation, peripheral rather than central location, and patient older age. 13,14 Additionally, there is a paucity of data on how a patient's history of atypical breast disease or breast cancer (BC) may affect possibility of upgrade.
We sought to identify clinical, histologic and radiologic factors that predict upgrade of pure IDP to either atypia or malignancy, and to investigate the relevance of prior history of breast disease as it relates to the upgrade of these lesions on surgical excision after CNB.

| METHODS
In this institutional review board (IRB) approved study, we retrospectively queried the pathology database at our institution for all cases of pure IDP diagnosed on CNB and subsequently surgically excised from 2008 to 2018. Core needle biopsies were performed by radiologists under stereotactic guidance, ultrasound guidance or magnetic resonance imaging (MRI) guidance. Pathology from core biopsy and surgical excision were reviewed by dedicated breast pathologists at our academic institution at the time of the procedure. Figure 1 is a representative microphotography of a pure IDP at time of biopsy and surgical excision (no upgrade), while Figure 2 highlights a case where upgrade from pure IDP to ductal carcinoma in-situ (DCIS) was seen after surgical excision. We excluded cases of pathologic atypia or malignancy found on CNB at the site of IDP. After exclusions, we identified a total of 490 cases of pure IDP discovered on biopsies performed in 439 patients, as several patients had multiple sampled lesions.
The electronic medical records of these 439 patients were then reviewed, and the following information was recorded: patient demographics, associated physical findings and/or presenting complaint, prior history of breast disease including papillary lesions, high risk or atypical lesions and carcinoma of the breast, imaging modality used in the diagnostic evaluation, radiologic factors including size and location of lesion, biopsy gauge size, and pathologies from core biopsies and subsequent surgical excisions. On surgical excision, pathologic upgrades were separated into two groups: (1) high-risk lesions (HRLs), defined as any atypia including atypical ductal hyperplasia (ADH) or lobular neoplasia (LN) and (2) carcinoma, including both DCIS and invasive disease. Information from the electronic medical records was then compared in the no upgrade, upgrade to HRL and upgrade to carcinoma groups, and quantitatively analyzed to determine which characteristics would prove statistically significant for predicting upgrade.
Patient and papilloma related characteristics were summarized overall and by upgrade status. Continuous variables were reported as median (range: min-max) and nominal variables were reported as N (%). Univariable comparisons were made with modified Poisson regression models using a robust error variance, introduced by Zou, implemented with SAS's Proc Genmod. 15 Multivariable adjusted prevalence ratios and corresponding 95% confidence intervals were estimated using the modified Poisson regression models. A backward elimination process was used to select variables in the final adjusted models. All statistical analyses described above were performed using SAS Version 9.4 (SAS Institute, Cary, NC). Hypothesis testing was two-sided and conducted at the 5% level of significance.

| RESULTS
Our study identified 490 distinct IDP in 439 patients in the overall cohort. Patient demographics and presenting symptoms are summarized in Table 1 (Table 3).

| DISCUSSION
Although most studies generally recommend surgical excision for IDP with atypia found on CNB, appropriate management of pure IDP without atypia or malignancy remains unclear. The main worry espoused by those who recommend excision for all papillomas is a missed malignant disease diagnosis due to sampling error during a diagnostic CNB when complete surgical excision is not performed.
In our study, for example, pathologist review of the CNB slides from the five patients that ultimately upgraded to carcinoma determined most of these were likely due to sampling error, while only one was felt to be a true misinterpretation of the core biopsy (atypical cells were present upon review). This study was retrospective, which presents well known biases in the abstraction of data from available electronic medical records. Additionally, our work stems from a breast cancer center, where a high overall volume of malignant disease is treated and where routine imaging follow up is the standard. To our understanding, at 490 discrete IDP (in 439 patients), this is one of the largest series to examine pure IDP on CNB followed by surgical excision-but even then, the study is still limited by stemming from a single academic institution.
In conclusion, management of pure IDP without atypia continues to vary among institutions and practicing breast surgeons, even within the same institutions. Our data do suggest a low upgrade to malignancy, 1.1% in this large patient cohort, and even then, mostly DCIS.
Meanwhile, 12.3% of patients were upgraded to atypia or other HRL-patients that could benefit from changes in risk-reducing clinical/radiologic management and follow-up. The clinical significance of identifying atypia in a papilloma remains unknown, especially in a patient with a prior history of atypia, who may already be followed more closely. However, when we looked at prior history of breast disease, the majority of patients who were upgraded to either atypia or cancer had none, and would therefore be considered true clinical upgrades. As such, we conclude that excision for pure IDP after CNB without atypia should be considered if an upgrade to atypia would be of clinical value in management, and in patients with a prior history of malignancy where upgrade rate to a second malignancy was higher.