A retrospective observational study of intraductal breast papilloma and its coexisting lesions: a real-world experience

Background: Breast intraductal papilloma are a heterogeneous group. The aim of this study is to investigate the intraductal breast papilloma and its coexisting lesions retrospectively in real-world practice. Methods: We retrospectively identi�ed 4450 intraductal breast papilloma and its coexisting lesions. Results: 18.36% coexisted with malignant lesions of the breast, 37.33% coexisted with atypia hyperplasia, 25.24% coexisted with benign lesions and only 19.10% coexisted without concomitant lesions. In addition, 36.80% of intraductal breast papilloma had nipple discharge, 51.46% had a palpable breast mass and 16.45% had both nipple discharge and a palpable breast mass. 28.18% experienced discomfort or were asymptomatic. Furthermore, 98.99% had ultrasound abnormalities, 53.06% had intraductal hypoechoic upon ultrasound. 31.89% had mammographic distortion, 14.45% had microcalci�cation upon mammography. Intraductal breast papilloma with malignancy had signi�cant correlations with clinical manifestations. Conclusion: Coexisting malignancy was also related to ultrasound abnormality (BIRADS 4C and 5), mammographic distortion and microcalci�cation upon mammography but was not related to the intraductal hypoechoic upon ultrasound. Coexisting atypical hyperplasia correlated with nipple discharge but not palpable mass, mammographic distortion or intraductal hypoechoic upon ultrasound. The coexisting atypia hyperplasia was also related to abnormality upon ultrasound or microcalci�cation compared with the benign lesions. The intraductal papilloma coexists with malignancy or atypia hyperplasia accounted for more than 50%, the clinical information on papilloma and its coexisting lesions is nonspeci�c. We recommended surgical treatment for benign intraductal papillary lesions. Impact: The current study provides insight into the real-world pattern of intraductal papillomas and their coexisting lesions in a population of Chinese women.


Introduction
An intraductal papilloma is a benign, or noncancerous breast tumor which originated from the epithelium of mammary ducts that forms in a milk duct.A brovascular stroma supported both the luminal epithelial and the outer myoepithelial cell layers for the formation of epithelial fronds, which is a characteristic of the intraductal papilloma [1] .The morphologic changes of epithelial component include from metaplasia to hyperplasia, atypical intraductal hyperplasia, or in situ carcinoma [2] .The symptoms, clinical signs and supersonical appearances widely differ.These lesions may present clinically either as ultrasound abnormalities or palpable breast masses, with or without nipple discharge.Central papilloma originates from large ducts, often accompanied by pathological nipple discharge, while most peripheral papillomas occur in TDLU, involving small ducts. [3,4] The prognosis and treatment of papillomas have been in uenced by views on their "precancerous" potential, and papillomas can harbor occult atypia hyperplasia or carcinomas.The management of benign intraductal papilloma remains controversial because of its nonspeci c clinical ndings, as well as its association with surrounding malignant pathology [5][6][7] .Herein, we present the results from an observational study carried out according to a retrospective design.Our study aimed to address intraductal breast papilloma and its coexisting lesions.

Study Design
In this study, patients with intraductal papilloma of the breast who underwent surgical resection in the rst a liated Hospital of China Medical University from November 1999 to July 2017 were analyzed retrospectively.During the period of 18-year, a total of 5,708 women were examined.Two pathologists whose subspecialty focus on breast lesions, reviewed each case independently.Only those cases where both pathologists had the same diagnosis can be used.Of those, 4,450 cases were eligible and selected into the research queue, according to the criteria of agreement and ethical approval.We reviewed the clinicopathological data of each patient.The patients before 2010 Feb weren't sign informed consent due to the exemption of the retrospective format.All patients after February 2010 involved in the study signed informed consent to participate in the study and agreed to publish the results.

Patients
We retrospectively identi ed 4450 intraductal breast papilloma patients with surgical excision from November 1999 through July 2017 at the First A liated Hospital of China Medical University.The patients' ages ranged from 13 to 88, with an average age of 47.86±11.93years.

The Concomitant Lesion Of The Breast
We classi ed all pathological types of breast lesions according to World Health Organization standards published by Tavassoli FA et al. [8,9] .A comprehensive list of pathologic features was reviewed, including margins whose tissue-free ranges were de ned as <15 mm; concomitant adenosis; atypia hyperplasia (AH, including atypia ductal hyperplasia and atypia lobular hyperplasia); ductal or lobular carcinoma in situ; invasive ductal cancer and other malignancies.

Statistical Analysis
All the statistical analyses were descriptive in nature.The independent two-sample t-test was performed to evaluate continuous categorical variables between benign, atypical and malignant lesions.The chisquare or Fisher's exact tests were used for comparing categorical variables.One-way ANOVA was used to identify the association between different groups and patients' age.A p value <0.05 was considered statistically signi cant.

Ethics
The research was reviewed and approved by the Ethics Committee of China Medical University and its rst a liated hospital.All of the methods were performed in accordance with the Declaration of Helsinki and the relevant guidelines.

Results
A total of 18.36% (817/4450) of intraductal breast papilloma coexisted with malignant lesions of the breast, 37.30% (1660/4450) coexisted with AH (including ADH and ALH), 25.24% (1123/4450) coexisted with benign lesions, and only 19.10% (850/4450) coexisted without concomitant lesions, Figure 1. Figure 2 shows the papilloma and its coexisting benign lesions.Figure 3 shows the papilloma and its coexisting ductal carcinoma in situ.Figure 4 shows the typical papillocarcinoma.Figure 5 shows the papilloma and its coexisting invasive ductal carcinoma.For the coexisting benign lesions, 157 cases coexisted with broma.For the coexisting benign lesions, 157 cases coexisted with broma.The clinical symptoms of papilloma and its coexisting lesions including asymptomatic lesions, nipple discharge and a palpable mass are non-speci c.A papilloma usually involves nipple discharge, which contains serous uid sometimes or blood and both.In our results, 36.80%(1638/4450) of the intraductal breast papilloma had nipple discharge, 51.46% (2290/4450) had a palpable breast mass.A total of 16.45% (732/4450) had both nipple discharge and a palpable breast mass.In addition, 28.18% (1254/4450) experienced discomfort in their breast or were asymptomatic, without nipple discharge or a palpable mass.
In this cohort, the intraductal breast papilloma with malignancy was related to clinical manifestations, which contain a palpable breast mass (p 0.01), concurrent nipple discharge and a palpable mass (p<0.01).Coexisting malignancy had signi cant correlations with ultrasound abnormality (BIRADS 4C and 5) (p<0.01),but mammographic distortion and microcalci cation upon mammograms had no correlations with intraductal hypoechoic by ultrasound, Table 1.
In the subgroup of coexisting benign lesions and atypical lesions, coexisting atypical hyperplasia correlated with nipple discharge (p<0.05) but did not correlate with a palpable mass (p >0.05), mammographic distortion or intraductal hypoechoic by ultrasound (p >0.05).Coexisting AH was also correlated with abnormalities found by ultrasound or microcalci cation (p<0.01)compared with the benign lesions, Table 2.

Discussion
Intraductal papillomas are benign tumors of the breast which arise from the epithelium of the lactiferous ducts (i.e., a system that links the lobules of the mammary gland with the tip of the nipple) [10] .
Intraductal papillomas require histopathological con rmaion because it may turn out carcinogenesis [11,12] .Studies have also shown that intraductal papilloma with atypia increases the risk of ductal carcinoma in situ (DCIS) or invasive breast cancer [13,14] .The treatment of breast intraductal papillomas has been controversial.Some advocate surgical resection of all lesions, despite benign pathological features, while others advocate removal only of specimens that are atypical or malignant.However, only a few studies have investigated this type of breast lesion and its coexisting cancers in Chinese women.We retrospectively reviewed 4450 intraductal papilloma of breast with surgical excision in Chinese women.The current study provides insight into the real-world pattern of intraductal papillomas and their coexisting lesions in a population of Chinese women.
Core needle biopsy (CNB) plays an important role in the diagnosis of breast lesions.This biopsy is usually performed earlier than any other treatment.CNB has limitations, such as the incomplete removal of the representative sampling of the target [15][16][17] .Published data was reviewed and provides estimates of the accuracy of percutaneous CNB and the upgrade to malignancy in diagnosing papillary breast lesions.Previous results strongly suggest that the diagnosis of intraductal papilloma by CNB should be surgical excision because a large number of lesions escalate into atypical lesions and malignant tumors at the time of resection. [18,19] The data in these studies vary widely, especially in cases of intraductal papilloma with malignant tumors.Tabulated data from the investigations done by Mercado CL et al., are listed in Table 3.The literature contained data demonstrating papillomas with benign ndings in approximately 72% of cases, with atypical ductal or lobular cells (ADH, ALH or LCIS) in approximately 14%, and with DCIS or invasive carcinoma in approximately 13%, which were diagnosed by CNB and subsequent surgical resection.Wen X, et al recently reported a meta-analysis that contains 34 studies including 2236 nonmalignant breast papillary lesions at CNB were histologically reviewed after surgical resection [20] .In this research, 7.0-36.9%cases of benign papillomas were upgrade diagnosed as atypical papillary lesions and 15.7% cases of nonmalignant papillary lesions were upgrade diagnosed as malignancy.Three factors showed signi cant correlations with higher underestimation, including atypical papillary lesions (P<0.001),positive mammographic results (P=0.022), and published earlier than 2005 (P<0.05).Our study showed that 18.36% of intraductal papillomas coexist with malignancy, and 37.33% coexist with ADH, ALH or LCIS.The rate of coexistence with AH or LCIS is obviously higher than the rate previously indicated in Table 2. Most of the previous studies surveyed intraductal papilloma diagnosed with CNB and evaluated their potential coexisting risk of associated AH and malignancy, as identi ed by follow-up surgical excision.Some research excluded part of the data of intraductal papilloma coexisting with malignancy or AH diagnosed with CNB.The patients in our research had a diagnosed papilloma by surgical excision without CNB.The data were the real-world description data on intraductal papilloma and its coexisting lesions in China.If a patient had a diagnosed papilloma, she had an upgrade rate of 60% with ADH, ALH or LCIS or with malignancy after undergoing surgical excision in China.Thus, we recommend surgically resect all benign intraductal papillary lesions as a more aggressive approach.
In our research, most women experienced asymptomatic lesions, pain or discomfort in their breast without nipple discharge or a palpable mass.If the recommended breast imaging indicated ultrasound abnormality or mammographic distortion, the risk assessment of breast malignancy was performed.If necessary, standard treatment for this condition involved surgery to remove the abnormality, especially the papilloma and the affected part of the milk duct.The diagnosed papilloma was removed by excision.The patient's demographics and clinical features were extracted and retrospectively reviewed from the medical records.The clinical presentation of ductal papilloma varied from asymptomatic, nipple discharge, palpable mass, breast pain or discomfort.Based on our data, 41.30% of intraductal breast papilloma had nipple discharge, 16.22% had a palpable breast mass, and 28.18% were asymptomatic or only had breast discomfort.In addition, intraductal breast papilloma with malignancy had signi cant correlations with clinical manifestations such as nipple discharge, a palpable breast mass, ultrasound abnormality (BIRADS 4C and 5), mammographic distortion and micro-calci cation upon mammography.
Clinical manifestations, supersonic ndings and micro-calci cation upon mammography were signi cantly associated with the coexisting lesions of malignancy.In our results, coexisting AH associated with nipple discharge, with abnormality by ultrasound or with micro-calci cation upon mammography compared with the benign lesions.It is not easy to distinguish the coexisting benign lesion with papilloma from the occulted malignancy or ADH by clinical manifestations.Coexisting AH was also correlated with abnormalities found by ultrasound or microcalci cation compared with the benign lesions.It need the professional mammogram and breast ultrasound in clinic.
Evidence supporting the excision of papilloma with AH is certainly incontrovertible [21,22] .The treatment of intraductal papilloma without atypia is controversial and presents the notion, to observe or to excise?Some researchers have advocated that if the radiologic and pathologic results are concordant, regular clinical and radiologic follow-up are safety for the treatment of intraductal papilloma without atypia [23][24][25][26][27][28] , whereas others suggest surgical resection for this group of patients to avoid the possibility of breast cancer [17,[29][30][31] .As is known, CNB-proven intraductal papilloma is removed by CNB, either partly or completely.This approach is the diagnostic challenge in papilloma of the breast.The sensitivity of CNB was based on the complete removal of the representative sampling of the target and thus was partly insu cient.A larger core needle biopsy sample can identify breast papillary lesions and can identify patient that do not need surgical resection.With CNB, Shamonki J et al reported that they identi ed 51 patients with benign papilloma without atypia who subsequently had surgical resection [32] .A total of 11.7% (6/51) of those who had excision revealed ADH, DCIS or invasive carcinoma near the papilloma.Amon g the malignant cases, one excision showed DCIS within the residual papilloma, one excision showed DCIS within the ducts surrounding the papilloma and within an immediately adjacent 0.15 cm invasive carcinoma, and one excision revealed ADH within the excised papilloma with an adjacent incidental 0.1 cm tubular carcinoma.These results indicate that excision of a larger tissue sample with CNB can signi cantly improve the predictive value for benign lesions.Several investigators reported that papillary lesions sampled with larger vacuum-assisted excision (VAE) have lower upgrade rates and it is suggested that surgical resection may not be necessary in many of these cases [33][34][35] .VAE provided a method with 9 or 11 needles to obtain more tissue than an automated large-core biopsy device usually that has a 14-gauge needle [36][37][38] .Research from Korea found that the US 14G automated core needle biopsy (ACNB) has a higher false-negative rate and histological upgrading rate in the diagnosis for papillary breast lesions than US-guided VAE [34] .Kim SY et al point out that for asymptomatic benign papilloma, if it has benign or low suspicious ultrasound features or imaging is consistent with pathology, it does not need to be resected immediately and can be followed up [33] .The researchers included 197 women, of whom 230 cases of asymptomatic benign papilloma were diagnosed by ultrasound-guided CNB and, if necessary, immunohistochemical staining.A total of 144 women underwent surgery, 86 of whom had a VAE and after the benign VAE results all the patients were followed-up for at least 12 months.86 women treated with VAE were followed up for an average of 26.3 ±10.3 months (mean range 12 to 46 months).No sign of malignant tumor was found in the same quadrant.Nayak A points out that conservative treatment may be more appropriate for women diagnosed papilloma by CNB with adequate sampling and precise pathological/radiological correlation, especially those who have received VAB treatment. [23].When the patient has symptoms or lesions greater than 1.5 cm, the recommended surgical indications include pathological / radiological inconsistencies or ultrasound-guided CNB sampling without vacuum assistance.
Intraductal papilloma can be single or multiple, located around the breast and can be found occasionally on imaging [39,40] .A study has shown that for the treatment of benign intraductal solitary papilloma diagnosed by CNB, instead of mandated surgical resection, clinical follow-up can be selected when the imaging results are consistent and there are no related high-risk lesions or concurrent malignant tumors in the same quadrant. [24].This study is important for the research on solitary intraductal papillomas.A question that remains is how to determine solitary or multiple intraductal papillomas, whether by sonography, pathology or both.Clinically, multiple papilloma is de ned as the presence of at least ve distinct independent papillomas in a segment of breast tissue, usually around or under the areola. [2,41] In ultrasound, solitary papilloma can be seen as an independent mass in the dilated mammary duct, a cystic or solid mass with a clear boundary.[41,42] .Yi W et al con rmed single papilloma by ultrasound, [43] and Zhu Y et al de ned it with a histopathologic diagnosis of solitary intraductal papilloma [44] .Clinically, there are discordant conclusions between sonography and pathology.Our study was limited, owing to the vague de nition regarding solitary or multiple intraductal papillomas.We did not distinguish the papilloma by the solitary or multiple lesion criteria.
What are the recommendations for papillomas, or the intermediated risk lesions?The intraductal papilla of the breast represents a series of lesions, the pathological basis of which is the proliferation of intraductal epithelium and myoepithelial cells, covering the brous vascular stalk.For the diagnostically challenging intraductal papilloma with limited sampling via CNB, all papillary lesions should be resected for de nite diagnosis.The entire lesion may need to be evaluated to exclude occult AH or malignancy.Therefore, the surgical excision is clearly justi ed.If the completely removed intraductal papilloma lesions with large VAE are con rmed by radiologic and pathologic ndings, a strict clinical follow-up is essential.The discordance between pathology and radiology leads to the upgrade rate of malignancy as well as unnecessary surgical incision.In the future, it is time for an integration of radiology and pathology.In our research, ultrasound was a very useful tool in the preoperative evaluation of breast papilloma and its coexisting lesions, and mammography was powerful for small nodules or clusters of microcalci cations.For an asymptomatic patient with intracystic hypoechoic lesions as seen by ultrasound, a reexamination one month later is suggested to eliminate intracystic deposits.It is obvious that any improvements to resolving the discordance between radiology and pathology and to ensure the timely exchange of clinical features could reduce false negative results and unnecessary surgical excision.Further studies investigating papilloma are needed.
The  The papilloma and its coexisting ductal carcinoma in situ.The papilloma and its coexisting invasive ductal carcinoma.

TABLE 2
The clinical characteristics of 3633 intraductal papilloma patients with coexisting benign or atypical lesions with surgical excision