Original Research

Breast Imaging

May 19, 2021

Analysis of 612 Benign Papillomas Diagnosed at Core Biopsy: Rate of Upgrade to Malignancy, Factors Associated With Upgrade, and a Proposal for Selective Surgical Excision

Authors: Su-Ju Lee, MD, Rifat A. Wahab, DO, Lawrence D. Sobel, MD, Bin Zhang, PhD, Ann L. Brown, MD, Kyle Lewis, MD, Charmi Vijapura, MD, and Mary C. Mahoney, MDAuthor Info & Affiliations

Volume 217, Issue 6

https://doi.org/10.2214/AJR.21.25832

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Abstract

Please see the Editorial Comment by Shruthi Ram discussing this article.

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BACKGROUND. Despite numerous published studies, management of benign papillomas without atypia remains controversial.

OBJECTIVE. The purpose of this study was to determine the malignancy upgrade rate of benign papillomas, identify risk factors for upgrade, and formulate criteria for selective surgery.

METHODS. This retrospective study included benign papillomas without atypia diagnosed on percutaneous biopsy between December 1, 2000, and December 31, 2019. Papillomas that did not undergo surgical excision or at least 2 years of imaging and/or clinical follow-up were excluded. Clinical, imaging, and histopathologic features were extracted from the electronic medical record. Features associated with upgrade to malignancy were identified. Multivariable logistic regression was performed.

RESULTS. The study included 612 benign papillomas in 543 women (mean age, 54.5 ± 12.1 [SD] years); 466 papillomas were excised, and 146 underwent imaging or clinical surveillance. The upgrade rate to malignancy was 2.3% (14/612). Upgrade rate was associated (p < .05) with radiology-pathology correlation (50.0% if discordant vs 2.1% if concordant), patient age (5.6% for 60 years and older vs 0.7% for younger than 60 years), presenting symptoms (6.7% if palpable mass or pathologic nipple discharge vs 1.3% if no symptoms), and lesion size (7.3% if ≥ 10 mm vs 0.6% if < 10 mm). Three of 14 upgraded papillomas were associated with four or more metachronous or concurrent peripheral papillomas. No incidental papilloma or papilloma reported as completely excised on core biopsy histopathologic analysis was upgraded. A predictive model combining radiology-pathology discordance, symptoms (palpable mass or nipple discharge), age 60 years old and older, size 10 mm or larger, and presence of four or more metachronous or concurrent peripheral papillomas achieved an AUC of 0.91, sensitivity of 79%, and spec-ificity of 89% for upgrade. Selective surgery based on presence of any of these five factors, although excluding from surgery incidental papillomas and papillomas reported as completely excised on histopathology, would have spared 294 of 612 lesions from routine excision and identified all 14 upgraded lesions.

CONCLUSION. Benign nonatypical papillomas have a low malignancy upgrade rate; routine surgical excision may not be necessary. Selective excision is recommended for lesions satisfying any of the five criteria. Incidental papillomas or papillomas completely excised on histopathology may undergo imaging follow-up.

CLINICAL IMPACT. The proposed criteria for selective surgery of benign papillomas on core biopsy would reduce surgeries without delaying diagnosis of malignancy.

HIGHLIGHTS

Key Finding

▪ Malignancy upgrade rate in 612 nonatypical BPs was 2.3%. Selective surgical excision based on radiology-pathology discordance, symptoms, age ≥ 60, size ≥ 10 mm, or ≥ 4 peripheral papillomas, in absence of incidental papilloma or complete excision on biopsy, would spare 294 lesions from surgery and identify all 14 malignancies.

Importance

▪ BPs have a low upgrade rate to malignancy. Selective excision can be safely accomplished based on the risk factors identified in this large single-institution study.

Papillomas are intraductal breast lesions composed of a frondlike fibrovascular core covered with proliferative epithelium resting on a layer of myoepithelial cells. Papillary lesions encompass a spectrum of lesions, ranging from benign papillomas and papillomas with atypia to malignant lesions including papillary ductal carcinoma in situ (DCIS) and invasive carcinoma [1]. To date, no well-established imaging findings allow distinction of benign from malignant papillomas [2]. Core needle biopsy (CNB) may underestimate an atypical or malignant papilloma because of histologic heterogeneity or undersampling [3].

There is consensus that papillomas with atypia diagnosed on CNB require surgical excision given a pooled upgrade rate to malignancy of up to 36.9% [4]. However, despite numerous published studies, the management of benign papillomas without atypia on CNB (hereafter referred to as BPs) remains controversial, and an evidence-based standard of care is elusive [5]. The reported upgrade rates to malignancy among BPs vary widely from 0% to 33% [6–12]. Comparison of results is hampered by these studies' heterogeneity in sample size, inclusion or exclusion of atypical papillomas, inclusion or exclusion of patients with a history of breast cancer, biopsy technique, and method and length of follow-up. Some researchers recommend routine surgical excision of all BPs given the risk of malignancy or atypia [6, 7, 11]. Others recommend clinical and imaging follow-up, citing low upgrade rates [8, 10, 12]. Recent published literature proposes selective surgical excision based on risk factors of upgrade [9, 13–15]. Further, the American Society of Breast Surgeons 2018 Consensus Guidelines [16] state that palpable papillomas and papillomas with atypia or pathology-imaging discordance should be excised, whereas incidental benign papillomas may be followed with an individualized decision to excise according to risk factors, size, and symptoms. However, no specific size cutoffs are provided.

A meta-analysis of 34 studies published before 2012 showed a pooled upgrade rate to malignancy of 7% for BPs diagnosed on CNB [4]. This suggests that many patients with purely benign papillomas could be spared surgery if properly selected. The objectives of this study are to determine the upgrade rates to malignancy and atypia in a large sample of BPs diagnosed by CNB, to identify the risk factors that may lead to cancer upgrade, and to propose criteria for selection of patients with BPs who can be safely followed with serial imaging, thereby avoiding unnecessary surgery without delaying breast cancer diagnosis.

Methods

Study Population

The institutional review board of University of Cincinnati College of Medicine approved this retrospective HIPAA-compliant study and waived informed consent. A retrospective review of our institution's breast biopsy database between December 1, 2000, and December 31, 2019, identified 836 papillomas diagnosed at CNB in 742 women. Subsequent breast imaging as well as surgical and pathologic records were reviewed. Papillomas were excluded if there was associated atypia (n = 108) or malignancy (n = 65) on CNB, if lost to follow-up (n = 13), or if imaging or clinical follow-up was not documented for at least 2 years in the absence of excision (n = 38). The final study cohort included 612 BPs on CNB (mean size 9.4 ± 7.3 mm; range, 1–72 mm) in 543 women (mean age 54.5 ± 12.1 [SD] years; range, 14–97 years). Figure 1 summarizes the patient selection flow.

Fig. 1 —Diagram shows inclusion and exclusion criteria, with outcome of benign papillomas on core biopsy.

Clinical, Imaging, and Histopathologic Features

For all lesions, clinical, imaging, and histopathologic features were extracted from the electronic medical record; the original radiology reports were used for the imaging characteristics. The medical record for each patient was reviewed by one of six breast radiologists with 3–32 years of experience. When imaging features or completeness of lesion removal at the end of biopsy were not adequately documented in the original reports, the images were reevaluated retrospectively by the principal investigator, who had 31 years of experience (S.J.L.). All data were recorded in Research Electronic Data Capture (REDCap, version 10.6.13, a web application provided by the Center for Clinical and Translational Science and Training at the University of Cincinnati funded by NIH grant 2UL1TR001425-05A1). A breast radiologist with 32 years of experience (M.C.M.), who was not among the six radiologists who performed the primary medical record review, audited the data in a random 10% sample of patients to confirm the accuracy of data extraction, though no formal data were recorded from this audit.

Clinical information recorded for each lesion included patient age, presenting symptoms, presence of single versus multiple papillomas, history of prior or concurrent breast cancer, history of prior or concurrent papillomas, and risk factors, including mammographic breast density, family history of breast cancer, and genetic breast cancer mutation. The presenting symptoms analyzed included palpable mass at the site of BP, pathologic nipple discharge (i.e., spontaneous clear or bloody discharge from a single orifice) in the breast with BP, and focal pain at the site of BP; any other recorded symptom was classified as “Other.” The lesion was considered one of multiple papillomas if there were other papillomas in the ipsilateral or contralateral breast or if there was a previous diagnosis of papilloma in either breast. The mammographic breast density was classified according to the American College of Radiology (ACR) BI-RADS [17] using both the individual density category (a, b, c, d) and the nondense versus dense breast classification. Family history of breast cancer was defined as either one first-degree relative with breast cancer before 50 years old, two relatives (excluding cousins) with breast cancer, or one male relative with breast cancer.

The imaging features documented included lesion size on imaging, lesion location (central vs peripheral), imaging findings on various modalities, imaging guidance used for biopsy, type and gauge of biopsy device, and number of cores obtained. The lesion size reflected the largest dimension of the lesion identified across available radiology reports. The lesion location was classified as central for lesions in the anterior third of the breast and as peripheral for lesions in the middle or posterior third of the breast on mammography and MRI reports. Because of the wide variation of breast size, such classification more accurately depicts central versus peripheral location than the distance from the nipple described on ultrasound. For lesions evaluated by mammography, presence of mass, asymmetry, focal asymmetry, microcalcifications, and ductal dilatation were recorded. For lesions evaluated by ultrasound, classification of the lesion as mass with irregular hypoechoic appearance, mass with circumscribed or noncircumscribed margins, mass with complex cystic and solid appearance, ductal dilatation with or without contents, or other correlate was recorded. Ductal dilatation was defined as a duct greater than 2 mm in diameter or ampullary portion greater than 3 mm in diameter. Vascularity of a mass or of intraductal contents on color Doppler (absent, internal, or vessels in rim) was assessed as part of the routine ultrasound protocol but was not incorporated into the features extracted and analyzed in this investigation. Ductal content with internal vascularity was interpreted as intraductal mass and grouped with complex cystic and solid mass for analysis. For lesions evaluated by galactography, duct abnormalities including dilatation, intraductal filling defect, and abrupt duct cutoff were recorded. When intraductal filling defect was present, the measurement of the filling defect was used to indicate lesion size. As part of clinical care, ultrasound targeted to the area of duct abnormality had been performed immediately after galactography for lesion localization to facilitate tissue sampling or surgical excision. For lesions evaluated by MRI, lesion type (enhancing mass or nonmass enhancement), rate of initial enhancement (slow, medium, or fast), and delayed enhancement kinetics (persistent, plateau, washout, or mixed) were recorded. Finally, complete lesion excision reported on imaging immediately after CNB was recorded.

All biopsies were performed by radiologists with breast imaging fellowship training or equivalent training. The Supplemental Methods describe the biopsy techniques (Supplemental Methods can be viewed in the AJR electronic supplement to this article, available at https://doi.org/10.2214/AJR.21.25832). The histopathologic findings recorded included pathologic size, central versus peripheral location, sclerosis of the papilloma, incidental papilloma, complete versus incomplete lesion excision, and radiology-pathology concordance versus discordance. On histo-pathology, central papillomas arise from large subareolar ducts, whereas peripheral papillomas arise from terminal ductal lobular units. The radiology-pathology concordance or discordance for each lesion had been determined and documented by the radiologist performing the biopsy and then potentially adjusted after review during the breast imaging section's weekly conference among six breast radiologists with 3–32 years of experience.

The outcome for each BP was recorded according to surgical histopathology or imaging or clinical follow-up. During the study period, patients were routinely referred to surgery for possible excision, though lesion factors or patient or referring physician preference resulted in some lesions undergoing imaging and clinical follow-up. Among the cohort of 612 BPs, 466 (76.1%) underwent surgical excision, whereas 146 (23.9%) underwent surveillance. Among the 146 BPs that underwent surveillance, the reasons for a nonsurgical approach included lesion resolved (i.e., no longer visible) on imaging at the end of CNB (n = 38), lesion completely excised on histopathology from CNB (n = 34), incidental papilloma was 2 mm or smaller (n = 21), surgery declined by patient (n = 20), nonsurgical candidate because of comorbidi-ties (n = 13), and surgeon's decision (n = 4) because of small lesion size, delayed surgical consult, or additional lesions requiring imaging surveillance; in 16 BPs that underwent surveillance, no reason was documented. Our surveillance protocol entails follow-up imaging at 6 and 12 months and then annually. For BPs managed by surveillance rather than by excision, benignity was established by at least 2 years of imaging follow-up using the modality by which the lesion was detected and/or by the absence of a breast cancer diagnosis in the institution's medical record for at least 2 years from the time of CNB. Most nonexcised BPs (122/146, 83.6%) had at least 24 months of imaging follow-up (range, 24–218 months; mean, 70.7 months). Of the remaining 24 BPs, 21 had imaging follow-up of less than 2 years (range, 6–19 months; mean, 12.6 months) combined with at least 2 years of documented clinical follow-up (range, 24–132 months; mean, 49.8 months). The remaining three BPs were described on histopathology from CNB as “completely excised” and had only clinical follow-up (range, 24–52 months; mean, 35.7 months).

Statistical Analysis

Descriptive analysis was performed to summarize the patient characteristics. Continuous variables were compared between upgraded BPs—that is, BP upgraded to malignancy at the time of surgical excision (not atypia, unless otherwise specified)—and BPs that were not upgraded using two sample t test, and categoric variables were compared between these two groups using chi-square test or Fisher exact test, as appropriate. The upgrade rate was defined as the percentage of BPs on CNB upgraded to malignancy at surgical excision. A multivariable logistic regression model was used to assess the relation between upgrade to malignancy and the clinical, imaging, and histopathologic features. ROC analysis was used to assess the proposed model's predictive performance. The model's AUC, as well as sensitivity and specificity at the optimal threshold of the predicted probability determined using the Youden index (J), were reported. All analyses were performed using SAS version 9.4 (SAS Institute). p values less than .05 were considered statistically significant.

Results

Benign Papillomas Upgraded to Malignancy

Among the 466 of 612 BPs on CNB that were excised, 14 (3.0%) were upgraded to malignancy (including nine DCIS, two intracystic papillary carcinomas, and three invasive ductal carcinomas [IDCs]), and 33 (7.1%) were upgraded to atypia (24 atypical ductal hyperplasia, four flat epithelial atypia, two lobular neoplasia, and three atypical papillomas). Of the 146 BPs managed by surveillance, no malignancy was diagnosed after 2 years of imaging and clinical follow-up. Considering the entire cohort of 612 BPs, the upgrade rate to malignancy was 2.3% (14/612). Table 1 details the clinical, histopathologic, and imaging features of the 14 BPs upgraded to malignancy.

TABLE 1: Clinical, Histopathologic, and Imaging Features of 14 Benign Papillomas at Core Needle Biopsy That Were Upgraded to Malignancy at Excision

Case	Age (y)	Histopathology of Cancer	Clinical Presentation^a	History of Papilloma or Cancer	Key Imaging Finding		Size^b (mm)	Biopsy Device
Case	Age (y)	Histopathology of Cancer	Clinical Presentation^a	History of Papilloma or Cancer	Modality	Finding	Size^b (mm)	Biopsy Device
1	77	DCIS	Palpable mass	None relevant	US	Ductal ectasia without contents	23	Vac 10 G
2	65	DCIS	Nipple discharge	Multiple (4) peripheral papillomas	MAM	Microcalcifications	26	Vac 8 G
3	66	IDC, DCIS	Nipple discharge	Multiple (4) peripheral papillomas	US	Mass, complex cystic and solid	12	Vac 10 G
4	44	IDC	Nipple discharge	None relevant	US	Mass, complex cystic and solid	13	Vac 11 G
5	54	DCIS	Screen detected	Multiple (5) peripheral papillomas	US	Masses, noncircumscribed margins^c	7	Vac 10 G
6	72	DCIS	Screen detected	Concurrent ipsilateral IDC	US	Mass, noncircumscribed margins	4	Vac 10 G
7	63	ICPC	Screen detected	None relevant	US	Mass, noncircumscribed margins	10	Vac 10 G
8	62	DCIS	Screen detected	None relevant	US	Mass, circumscribed margins	12	Vac 11 G
9	52	DCIS	Screen detected	None relevant	US	Mass, noncircumscribed margins	10	Vac 10 G
10	61	DCIS	Palpable mass	None relevant	US	Mass, circumscribed margins	12	Spring 14 G
11	75	IDC, DCIS	Nipple discharge	Prior contralateral IDC, mastectomy	MRI	Nonmass enhancement	14	Vac 10 G
12	63	DCIS	Palpable mass	None relevant	US	Mass, complex cystic and solid	18	Vac 10 G
13	66	DCIS	Screen detected	Peripheral papilloma on histology	MAM	Microcalcifications	3	Vac 9 G
14	59	ICPC	Palpable mass	None relevant	US	Mass, complex cystic and solid	16	Vac 11 G

Note—DCIS = ductal carcinoma in situ, US = ultrasound, Vac = vacuum-assisted, G = needle gauge, MAM = mammogram, IDC = invasive ductal carcinoma, ICPC = intracystic papillary carcinoma, Spring = spring-loaded.

Nipple discharge indicates pathologic nipple change.

Size on imaging.

Multiple masses in segmental distribution on mammogram.

Table 2 summarizes the characteristics of the 14 cancers found on excision of BPs. Two of the three IDCs were associated with DCIS. Histologic tumor grade was available in 11 cancers and was grade 1 or 2 in all cases. Among 10 lesions with biomarker information, nine were estrogen receptor (ER) and progesterone receptor (PR) positive. A single case (case 7, Table 2) was ER, PR negative and human epidermal growth factor receptor 2 (HER2, also known as ERBB2) negative. The HER2 status was unavailable for the remaining cancers. Thirteen of 14 cancers were lymph node negative, with case 12 showing isolated tumor cells in one node. No cancer showed distant metastases. The pathologic tumor size, when available (n = 8), was smaller than the imaging size in all cancers, likely because of partial removal of tumor during CNB.

TABLE 2: Histopathologic Characteristics of Cancers Found at Excision of 14 Lesions Diagnosed as Benign Papillomas at Core Needle Biopsy

Case	Diagnosis	Grade	Size (mm) on Histopathology	T Category	N Category	ER	PR	HER2
1	DCIS	2	NA	Tis	N0	Positive	Positive	NA
2	DCIS	1	NA	T1a	N0	NA	NA	NA
3	IDC, DCIS	2	5	T1a	N0	Positive	Positive	NA
4	IDC	NA	NA	NA	N0	NA	NA	NA
5	DCIS	1–2	4	Tis	N0	Positive	Positive	NA
6	DCIS	1	NA	Tis	N0	Positive	Positive	NA
7	ICPC	NA	NA	T1a	N0	Negative	Negative	Negative
8	DCIS	1	9	Tis	N0	Positive	Positive	NA
9	DCIS	2	3	Tis	N0	Positive	Positive	NA
10	DCIS	1	3	Tis	NX	Positive	Positive	NA
11	IDC, DCIS	1	1.5 IDC, 9 DCIS	T1a	N0	NA	NA	NA
12	DCIS	2	4	Tis	N0 (ITC)^a	Positive	Positive	NA
13	DCIS	2	2	Tis	N0	Positive	Positive	NA
14	ICPC	NA	NA	T1a	NX	NA	NA	NA

Note—ER = estrogen receptor, PR = progesterone receptor, HER2 = human epidermal growth factor receptor 2 (also known as ERBB2), DCIS = ductal carcinoma in situ, NA = not available, IDC = invasive ductal carcinoma, ICPC = intracystic papillary carcinoma.

Isolated tumor cells (ITC) in otherwise negative node.

Clinical Characteristics

Table 3 compares the clinical and histopathologic characteristics of BPs upgraded versus those not upgraded to malignancy. The mean patient age was significantly greater (p = .007) for upgraded BPs (63.2 ± 9.0 years) than for nonupgraded BPs (54.4 ± 12.1). The upgrade rate was 5.6% (11/196) for BPs in women 60 years old and older, compared with 0.7% (3/416) in women younger than 60 years (p < .001).

TABLE 3: Association of Clinical and Histopathologic Characteristics With Upgrade to Malignancy in 612 Benign Papillomas (BPs) at Core Needle Biopsy

Feature	Entire Cohort (n = 612^a)	BPs Not Upgraded (n = 598^a)	Upgraded BPs (n = 14^a)	Upgrade Rate	p^b
Clinical characteristics
Age					< .001
< 60 y	68.0 (416)	69.1 (413)	21.4 (3)	0.7 (3/416)
≥ 60 y	32.0 (196)	30.9 (185)	78.6 (11)	5.6 (11/196)
Presenting symptoms					.002^C
Palpable mass at site of BP	8.7 (53)	8.2 (49)	28.6 (4)	7.5 (4/53)
Pathologic nipple discharge in breast with BP	12.3 (75)	11.9 (71)	28.6 (4)	5.3 (4/75)
Palpable mass or nipple discharge	19.4 (119)	18.6 (111)	57.1 (8)	6.7 (8/119)
Focal pain	2.1 (13)	2.2 (13)	0.0 (0)	0.0 (0/13)
Other^d	0.7 (4)	0.7 (4)	0.0 (0)	0.0 (0/4)
None	77.8 (476)	78.6 (470)	42.9 (6)	1.3 (6/476)
Single vs multiple papilloma					.67
Single	88.6 (542)	88.8 (531)	78.6 (11)	2.0 (11/542)
Multiple (counting both breasts)	11.4 (70)	11.2 (67)	21.4 (3)	4.3 (3/70)
Prior or concurrent breast cancer					.09
Yes	12.9 (79)	12.9 (77)	14.3 (2)	2.5 (2/79)
No	87.1 (533)	87.1 (521)	85.7 (12)	2.3 (12/533)
Prior or concurrent papilloma					> .99
Yes	18.6 (114)	18.7 (112)	14.3 (2)	1.8 (2/114)
No	81.4 (498)	81.3 (486)	85.7 (12)	2.4 (12/498)
Risk factors
Mammographic breast density category^e					.43
a: Entirely fatty	2.3 (14)	2.4 (14)	0.0 (0)	0.0 (0/14)
b: Scattered fibroglandular density	54.0 (327)	53.7 (318)	64.3 (9)	2.8 (9/327)
c: Heterogeneously dense	40.6 (246)	40.9 (242)	28.6 (4)	1.6 (4/246)
d: Extremely dense	3.1 (19)	3.0 (18)	7.1 (1)	5.3 (1/19)
Mammographic breast density^e					.54
Nondense (a or b)	56.3 (341)	56.1 (332)	64.3 (9)	2.6 (9/341)
Dense (c or d)	43.7 (265)	43.9 (260)	35.7 (5)	1.9 (5/265)
Family history of breast cancer^f					.09
Yes	20.1 (120)	20.6 (120)	0.0 (0)	0.0 (0/120)
No	79.9 (476)	79.4 (462)	100.0 (14)	2.9 (14/476)
Genetic breast cancer mutation^g					> .99
Yes	0.8 (5)	0.8 (5)	0.0 (0)	0.0 (0/5)
No	99.2 (601)	99.2 (587)	100.0 (14)	2.3 (14/601)
Histopathologic characteristics
Central vs peripheral papilloma (on histopathology)					.19
Peripheral	12.4 (76)	12.1 (72)	28.6 (4)	5.3 (4/76)
Central	0.8 (5)	0.8 (5)	0.0 (0)	0.0 (0/5)
Not reported	86.8 (531)	87.1 (521)	71.4 (10)	1.9 (10/531)
Sclerosis of papilloma					> .99
Yes	14.7 (90)	14.7 (88)	14.3 (2)	2.2 (2/90)
No	85.3 (522)	85.3 (510)	85.7 (12)	2.3 (12/522)
Complete excision on histology					.62
Yes	7.5 (46)	7.7 (46)	0.0 (0)	0.0 (0/46)
No	92.5 (566)	92.3 (552)	100.0 (14)	2.5 (14/566)
Incidental papilloma					.24
Yes	13.9 (85)	14.2 (85)	0.0 (0)	0.0 (0/85)
No	86.1 (527)	85.8 (513)	100.0 (14)	2.7 (14/527)
Radiology-pathology concordance					.045
Discordant	0.3 (2)	0.2 (1)	7.1 (1)	50.0 (1/2)
Concordant	99.7 (610)	99.8 (597)	92.9 (13)	2.1 (13/610)

Note—Data reported as percentage with numbers of patients in parentheses.

Unless otherwise indicated.

Comparison of distribution of characteristic between BPs upgraded and not upgraded to malignancy; statistically significant at p < .05.

Reflects p value of palpable mass or nipple discharge.

Other includes burning sensation of nipple (n = 1), new nipple inversion (n = 1), physiologic nipple discharge (n = 1), and generalized pain (n = 1).

Mammographic breast density was analyzed in 606 lesions overall, in 592 in the no upgrade group, and in 14 in the upgrade group. Six lesions in six women did not undergo mammographic evaluation due to young age (< 30 y).

Family history was analyzed in 596 lesions, in 582 in the no upgrade group, and in 14 in the upgrade group.

Genetic mutation was analyzed in 606 lesions overall, in 592 in the no upgrade group, and 14 in the upgrade group.

Overall, 126 women with 144 lesions presented with symptoms, and the remaining 417 women with 468 lesions presented at screening mammography. Among the 14 upgraded BPs, 28.6% (4/14) presented with a palpable mass, and 28.6% (4/14) presented with pathologic nipple discharge. The upgrade rate was 7.5% (4/53) among BPs presenting as palpable mass, 5.3% (4/75) among BPs presenting with pathologic nipple discharge, 6.7% (8/119) among BPs presenting with palpable mass or nipple discharge, 0.0% (0/13) among BPs presenting with focal pain, and 0.0% (0/4) among BPs presenting with other symptoms (p = .002). The upgrade rate of those with no symptoms was 1.3% (6/476).

A total of 64.3% (9/14) of the upgraded BPs occurred in breasts with scattered areas of fibroglandular density, and the remaining 35.7% (5/14) occurred in heterogeneously dense (n = 4) or extremely dense (n = 1) breasts (Table 3). All 14 BPs upgraded to malignancy occurred in women with no family history of breast cancer and no reported genetic breast cancer mutation.

Neither single versus multiple papilloma nor a history of prior or concurrent breast cancer or papilloma were significantly associated with upgrade to malignancy (all p > .05). However, four of 14 upgraded BPs were peripheral papillomas on histopathology. Three of these were found in two women with four or more metachronous or concurrent peripheral papillomas. One woman had four concurrent peripheral papillomas; the other woman had three prior and two concurrent peripheral papillomas and was treated with segmental partial mastectomy for the right breast as well as bilateral reduction mammoplasty (Fig. 2). Regarding radiology-pathology correlation, the upgrade rate was associated with correlation: 50.0% if discordant and 2.1% if concordant.

Fig. 2A —54-year-old woman with history of three prior peripheral papillomas in right breast that were proven benign at excision who presented with concerning changes at screening mammography.
A, Right mediolateral oblique (MLO) mammogram 2 years earlier shows numerous masses of varied margin characteristics in segmental distribution.

Fig. 2B —54-year-old woman with history of three prior peripheral papillomas in right breast that were proven benign at excision who presented with concerning changes at screening mammography.
B, Right MLO mammogram at presentation shows interval increase in number and size of masses.

Fig. 2C —54-year-old woman with history of three prior peripheral papillomas in right breast that were proven benign at excision who presented with concerning changes at screening mammography.
C, Sagittal T1-weighted fat-suppressed contrast-enhanced MRI of right breast shows numerous heterogeneously enhancing masses with plateau or washout kinetics corresponding to mammographic masses.

Fig. 2D —54-year-old woman with history of three prior peripheral papillomas in right breast that were proven benign at excision who presented with concerning changes at screening mammography.
D, Longitudinal ultrasound shows irregular hypoechoic mass with indistinct margins surrounded by echogenic rim in “not parallel” orientation (between *arrows*).

Fig. 2E —54-year-old woman with history of three prior peripheral papillomas in right breast that were proven benign at excision who presented with concerning changes at screening mammography.
E, Longitudinal color Doppler ultrasound of same mass shows internal vascularity (*arrow*). Core needle biopsy revealed benign papilloma with upgrade to ductal carcinoma in situ at excision.

Imaging Characteristics

Table 4 summarizes the imaging characteristics and biopsy techniques of BPs upgraded versus those not upgraded to malignancy. The mean lesion size was significantly greater (p = .07) for upgraded BPs (12.9 ± 6.5 [SD] mm) than for nonupgraded BPs (9.3 ± 7.3 mm). The upgrade rate was 7.3% (11/150) for BPs with size 10 mm or greater compared with 0.6% (3/462) for BPs with size smaller than 10 mm (p = .001). Central versus peripheral location of BP was not significantly associated with upgrade to malignancy (p = .89).

TABLE 4: Association of Imaging Characteristics and Biopsy Techniques With Upgrade to Malignancy in 612 Benign Papillomas at Core Needle Biopsy

Features	Entire Cohort (n = 612^a)	BPs Not Upgraded (n = 598^a)	Upgraded BPs (n = 14^a)	Upgrade Rate	p^b
Imaging characteristics
Lesion size					< .001
≥ 10 mm	24.5 (150)	23.2 (139)	78.6 (11)	7.3 (11/150)
< 10 mm	75.5 (462)	76.8 (459)	21.4 (3)	0.6 (3/462)
Lesion location					.89
Central (anterior third)	48.2 (295)	48.2 (288)	50.0 (7)	2.4 (7/295)
Peripheral (middle or posterior thirds)	51.8 (317)	51.8 (310)	50.0 (7)	2.2 (7/317)
Mammography features
Mass					.44
Yes	46.9 (287)	46.7 (279)	57.1 (8)	2.8 (8/287)
No	53.1 (325)	53.3 (319)	42.9 (6)	1.8 (6/325)
Asymmetry					> .99
Yes	5.1 (31)	5.2 (31)	0.0 (0)	0.0 (0/31)
No	94.9 (581)	94.8 (567)	100.0 (14)	2.4 (14/581)
Focal asymmetry					> .99
Yes	6.7 (41)	6.7 (40)	7.1 (1)	2.4 (1/41)
No	93.3 (571)	93.3 (558)	92.9 (13)	2.3 (13/571)
Microcalcifications					> .99
Yes	23.4 (143)	23.4 (140)	21.4 (3)	2.1 (3/143)
No	76.6 (469)	76.6 (458)	78.6 (11)	2.3 (11/469)
Ductal dilatation					.50
Yes	4.7 (29)	4.7 (28)	7.1 (1)	3.4 (1/29)
No	95.3 (583)	95.3 (570)	92.9 (13)	2.2 (13/583)
Ultrasound features^c					.14
Mass, irregular hypoechoic	3.8 (18)	3.9 (18)	0.0 (0)	0.0 (0/18)
Mass, circumscribed margins	23.2 (109)	23.3 (107)	18.2 (2)	1.8 (2/109)
Mass, noncircumscribed margins	17.2 (81)	16.8 (77)	36.4 (4)	4.9 (4/81)
Mass, complex cystic and solid	33.2 (156)	33.1 (152)	36.4 (4)	2.6 (4/156)
Ductal dilatation with contents	6.0 (28)	6.1 (28)	0.0 (0)	0.0 (0/28)
Ductal dilatation without contents	1.1 (5)	0.9 (4)	9.1 (1)	20.0 (1/5)
Other^d	4.2 (20)	4.4 (20)	0.0 (0)	0.0 (0/20)
No ultrasound correlate	11.3 (53)	11.5 (53)	0.0 (0)	0.0 (0/53)
Galactography features^e					.46
Ductal dilatation	25 (2)	16.7 (1)	50 (1)	50.0 (1/2)
Intraductal filling defect	75 (6)	83.3 (5)	50 (1)	16.7 (1/6)
Abrupt duct cutoff	0.0 (0)	0.0 (0)	0.0 (0)	NA
MRI features^f
Type					> .99
Enhancing mass	58.3 (42)	58.2 (39)	60.0 (3)	7.1 (3/42)
Nonmass enhancement	41.7 (30)	41.8 (28)	40.0 (2)	6.7 (2/30)
Rate of enhancement (mass only)					.09
Slow	0.0 (0)	0.0 (0)	0.0 (0)	NA
Medium	4.7 (2)	2.6 (1)	33.3 (1)	50.0 (1/2)
Fast	28.6 (12)	28.2 (11)	33.3 (1)	8.3 (1/12)
Not reported	66.7 (28)	69.2 (27)	33.3 (1)	3.6 (1/28)
Enhancement kinetics (mass only)					.81
Persistent	11.9 (5)	10.2 (4)	33.3 (1)	20.0 (1/5)
Plateau	14.3 (6)	15.4 (6)	0.0 (0)	0.0 (0/6)
Washout	23.8 (10)	23.1 (9)	33.3 (1)	10.0 (1/10)
Mixed	11.9 (5)	12.8 (5)	0.0 (0)	0.0 (0/5)
Not reported	38.1 (16)	38.5 (15)	33.3 (1)	6.3 (1/16)
Biopsy techniques
Modality for biopsy guidance
Ultrasound	66.8 (409)	66.6 (398)	78.6 (11)	2.7 (11/409)
Mammogram	28.6 (175)	28.9 (173)	14.3 (2)	1.1 (2/175)
MRI	4.6 (28)	4.5 (27)	7.1 (1)	3.6 (1/28)
Biopsy device					> .99
Vacuum assisted	89.9 (550)	89.8 (537)	92.9 (13)	2.4 (13/550)
Spring loaded	10.1 (62)	10.2 (61)	7.1 (1)	1.6 (1/62)
Biopsy needle gauge					.63
7–9	26.1 (160)	26.4 (158)	14.3 (2)	1.3 (2/160)
10–12	65.7 (402)	65.4 (391)	78.6 (11)	2.7 (11/402)
14–18	8.2 (50)	8.2 (49)	7.1 (1)	2.0 (1/50)
No. of cores obtained	5.2 ± 3.1	5.2 ± 3.1	6.4 ± 2.5		.21

Note—Data reported as percentage with numbers of patients in parentheses. BPs = benign papillomas, NA = not applicable.

Unless otherwise indicated.

Comparison of distribution of characteristic between BPs upgraded and not upgraded to malignancy; statistically significant at p < .05.

Ultrasound features were analyzed in 470 lesions, 459 in the no upgrade group, and 11 in the upgrade group.

Includes clustered microcysts (n = 4), calcifications (n = 1), architectural distortion (n = 1), fibrocystic change (n = 1), and lesions with non-BI-RADS miscellaneous descriptors (n = 13).

Galactography features were analyzed in eight lesions overall; six in the no upgrade group and two in the upgrade group.

MRI features were analyzed in 72 lesions overall: 67 in the no upgrade group and five in the upgrade group.

On mammography, BPs most commonly appeared as a mass (46.9%, 287/612) or microcalcifications (23.4%, 143/612). Thirteen of 14 upgraded BPs were visualized on mammography (eight masses, three microcalcifications, one focal asymmetry, one ductal dilatation). No studied mammographic feature was significantly associated with malignancy (all p > .05).

Of 470 BPs evaluated with ultrasound, 77.4% (364/470) were masses, most commonly (33.2%, 156/470) complex cystic and solid masses (Fig. 3). Eleven of 14 upgraded BPs were visualized on ultrasound (10 masses, one ductal dilatation). Of the 10 upgraded masses depicted on ultrasound, the most common abnormal features were noncircumscribed margins (n = 4) and complex cystic and solid echotexture (n = 4) (Fig. 4). No studied sonographic feature was significantly associated with upgrade to malignancy (all p > .05).

Fig. 3A —29-year-old woman with family history of breast cancer who presented with 2-month history of spontaneous bloody discharge from left nipple.
A, Radial ultrasound of left breast shows intraductal mass (*arrows*).

Fig. 3B —29-year-old woman with family history of breast cancer who presented with 2-month history of spontaneous bloody discharge from left nipple.
B, Radial color Doppler ultrasound of same mass shows internal vascularity (*arrow*). Core biopsy of mass revealed benign papilloma on histopathology, with no upgrade on excision.

Fig. 4A —63-year-old woman with new mass on screening mammography.
A, Transverse right breast ultrasound shows solid mass with small cystic components (*short arrows*) and indistinct margins (*long arrow*).

Fig. 4B —63-year-old woman with new mass on screening mammography.
B, Transverse color Doppler ultrasound shows prominent internal vascularity (*arrow*) within mass. Core needle biopsy revealed benign papilloma at histopathology, which was upgraded to intracystic papillary carcinoma on excision.

Of eight BPs evaluated with galactography, six exhibited intraductal filling defect and two exhibited ductal dilatation. One lesion with ductal dilatation (50.0%, 1/2) and one lesion appearing as filling defect (16.7%, 1/6) were upgraded to malignancy. No studied galactography feature was significantly associated with upgrade to malignancy (p = .46).

Of 72 BPs evaluated with MRI, 58.3% (42/72) were enhancing masses, and 41.7% (30/72) were regions of nonmass enhancement. Five BPs visualized on MRI were upgraded to malignancy (three masses, two regions of nonmass enhancement). Mass versus non-mass presentation, rate of enhancement, and enhancement kinetics were not significantly associated with upgrade to malignancy (all p > .05).

Of 191 BPs assessed as completely removed by CNB on imaging immediately after biopsy, six were upgraded, three to malignancy (two DCIS, one IDC) and three to atypia.

Biopsy Technique

Biopsies were most commonly guided by sonography (66.8%, 409/612), followed by mammography (28.6%, 175/612) and MRI (4.6%, 28/612). Biopsies were most commonly performed using vacuum-assisted devices (89.8%, 550/612) and needle gauge 10–12 (65.7%, 402/612) or larger (26.1%, 160/612). Thirteen of 14 upgraded BPs were biopsied with vacuum-assisted devices 12 gauge or larger. None of the 12 lesions biopsied with 12-gauge spring-loaded needles under ultrasound guidance were upgraded to malignancy. All 50 biopsies using 14-gauge (n = 45) or 18-gauge (n = 5) spring-loaded needles were guided by ultra-sound, with only one lesion that was biopsied with a 14-gauge needle upgraded to malignancy. The mean number of core specimens obtained during biopsies was 5.2 ± 3.1 for nonupgraded BPs and 6.4 ± 2.5 for upgraded BPs. Biopsy device, needle gauge, and number of core specimens were not significantly associated with upgrade to malignancy (all p > .05).

Histopathologic Characteristics

On histopathology, neither central versus peripheral papilloma nor lesion sclerosis was significantly associated with upgrade to malignancy (all p > .05) (Table 3). Eighty-five BPs were incidental papillomas, of which 54 measured 2 mm or smaller on histopathology; none was upgraded to malignancy on excision (n = 64) or surveillance (n = 21). Of 46 BPs reported as completely excised at histopathologic evaluation of the CNB specimen (i.e., BPs small enough to be contained within a single large tissue core, allowing the pathologist to make the determination of complete excision), none was upgraded to malignancy. Thirteen of 14 upgraded BPs were deemed concordant on radiology-pathology correlation. Two discordant lesions underwent excision with one upgraded to malignancy. Radiology-pathology discordance was significantly associated with upgrade to malignancy (p = .045).

Logistic Regression Analysis

Table 5 describes multivariable logistic regression analysis of radiology-pathology correlation (discordance vs concordance), age group (≥ 60 years vs < 60 years), symptoms (presence versus absence of either palpable mass or pathologic nipple discharge), lesion size on imaging (≥ 10 mm vs < 10 mm), and total number of prior and concurrent peripheral papillomas (≥ 4 vs < 4) as predictors of upgrade to malignancy. To predict upgrade to malignancy, this model had an AUC of 0.91 (95% CI, 0.84–0.99) as well as a sensitivity of 79% (11/14) and specificity of 89% (531/598). Figure 5 shows the ROC curve of this model. If using any of the five factors in Table 5 as criteria for surgery, and excluding from surgery incidental papillomas and BPs described as completely excised on CNB according to histopathology, then 294 of the 612 lesions would avoid surgical excision compared with routine excision of all lesions, without missing any of the 14 BPs upgraded to cancer.

TABLE 5: Multivariable Logistic Regression Analysis of a Model Using Combination of Predictors for Upgrade of Benign Papilloma at Core Needle Biopsy to Malignancy at Excision

Factor	Predictor	Reference	Odds Ratio	95% CIs	p
Radiology-pathology correlation	Discordance	Concordance	0.1	0.001–5.3	.24
Age	≥ 60 y	< 60 y	13.4	3.4–53.2	< .001
Palpable mass or pathologic nipple discharge	Presence	Absence	3.2	0.9–10.9	.07
Lesion size on imaging	≥ 10 mm	< 10 mm	19.5	4.0–96.0	< .001
No. of metachronous or concurrent peripheral papillomas	≥ 4	< 4	156	3.6 to > 999	.009

Note—Model achieved AUC of 0.91 (95% CI, 0.84–0.99), sensitivity of 79%, and specificity of 89%.

Fig. 5 —ROC curve of model using multiple variables to predict upgrade of benign papillomas to malignancy. Variables in model included radiology-pathology discordance, age group (≥ 60 vs < 60 years), lesion size on imaging (≥ 10 mm vs < 10 mm), number of peripheral papillomas (≥ 4 vs < 4), and symptoms (palpable mass, pathologic nipple discharge). AUC was 0.91.

Discussion

There are currently no well-established imaging features that allow distinction of benign from malignant papillomas [2, 18, 19]. Lam et al. [18] found that mammographic and sonographic features were not sufficiently sensitive or specific to differentiate benign from malignant papillary lesions. Eiada et al [2]. reported a wide spectrum of appearances of papillary lesions on MRI, ultra-sound, and mammography that creates difficulty in differentiating benign from malignant pathologies on imaging. Although MRI is useful in the detection of papillary lesions and mapping the extent of disease, a clear distinction between benign and malignant papillomas may not be possible because of overlapping findings [19]. In our study, imaging features (other than size) were not significantly associated with upgrade to malignancy, and most BPs upgraded to malignancy had been deemed concordant on initial CNB. This underscores the difficulty in differentiating benign from malignant papillary lesions on imaging and substantiates the results of these earlier author groups.

Because of the lack of reliable clinical and imaging features predictive of upgrade, the management of BPs diagnosed on CNB remains controversial. Among studies with large sample sizes (150–388 cases), the upgrade rates to malignancy ranged from 0% to 12%, leading to divergent recommendations [6, 8, 10, 13]. The 612 BPs in our study comprise to our knowledge the largest cohort to date, which should reduce the results' margin of error. Our observed 2.3% upgrade rate to malignancy confirms the low upgrade rate reported by recent studies with sample sizes of at least 100 [20–22]. Some authors state that malignancy found in a separate coexisting higher risk lesion or in the tissue adjacent to, but not within, the BP does not reflect true upgrade of the BP in question [8, 20]. However, such lesions were not treated as a true upgrade in our study. Authors also assert that radiology-pathology discordant cases artificially inflate the upgrade rate and should be excluded from calculation [8, 14]. However, if the single case of an upgraded BP with radiology-pathology discordance were to be excluded, our upgrade rate would be 2.1%.

Most cancers identified in our study had favorable characteristics, being low to intermediate grade, node negative, and ER and PR positive and having no distant metastases. There was one triple negative cancer and one case with isolated tumor cells in one node. No cancer was diagnosed among the 146 lesions that underwent surveillance after 2 years of follow-up. These lesions managed by surveillance included 34 lesions completely excised on histopathology from CNB, 21 incidental papillomas 2 mm or smaller, and 38 lesions no longer visible on imaging at the end of CNB. The careful selection of patients for nonsurgical management may explain these lesions' favorable outcomes compared with the lesions that underwent surgical excision.

Symptoms of a palpable mass or pathologic nipple discharge, as well as radiology-pathology discordance on CNB, were significantly associated with upgrade of BP to malignancy. These associates are in line with numerous previous reports of symptomatic [9, 23, 24] and discordant [14, 21, 25] papillomas. Older age and postmenopausal status are also associated with upgrade to malignancy [6, 26], with past authors applying a cutoff age of 50 or 65 years to recommend surgical excision [23, 27]. In our study, age of 60 years old and older was significantly associated with upgrade to malignancy. Finally, in our study, lesion size of 10 mm and larger was significantly associated with upgrade to malignancy, which is in line with prior reports [14, 23, 24]; past studies have used a size threshold ranging from 5 mm [13] to 15 mm [9] for predicting malignancy.

As in previous reports, other clinical, histologic, and imaging features were not significantly associated with upgrade to malignancy [15, 20]. Some studies identified family history of breast cancer [28], dense mammogram [29], history of prior or concurrent breast cancer [12, 14, 25], mass-forming lesions [15, 25], presence of calcifications [30, 31], peripheral lesion location [9, 23], non–vacuum-assisted biopsy [32, 33], or multiple papillomas [28, 34] as predictors or malignancy. Our study did not confirm these associations. Specifically, although family history of breast cancer, mammographically dense breast, and genetic breast cancer mutation are risk factors for developing breast cancer in general, these factors were not significantly associated with upgrade to malignancy for BPs in our study.

All 50 BPs biopsied with 14- and 18-gauge spring-loaded needles used ultrasound guidance, with only one upgraded to malignancy. Similar reliability of ultrasound-guided 14-gauge core biopsy has been reported [35, 36]. The precision of real-time ultra-sound-guided needle placement likely explains this observation.

Among 191 BPs that appeared to have been completely removed by CNB on imaging immediately after biopsy, three were upgraded to malignancy on excision. This is in line with a previous report that residual cancers were found at surgery in almost 80% of cases after mammographic targets were completely removed by percutaneous excision [37]. Because the biopsy site is often obscured by local anesthetics and air, assessment of lesion removal on images after biopsy may be inaccurate. Therefore, complete removal of BPs on imaging should not be used as a criterion for triage in the management of BPs. However, among 46 BPs reported as completely excised on histopathology, none was proven malignant.

Jaffer et al. [38] defined incidental papilloma as papilloma 2 mm or smaller in size and not associated with mass effect, calcifications, or any pathologic feature that would necessitate excision. The authors reported that none of 38 incidental papillomas was upgraded to malignancy after excision or imaging follow-up. Zaleski et al. [39] defined incidental papillomas as papillomas without a corresponding imaging correlate. By following either criteria, we identified 85 incidental papillomas in our series, of which 54 measured 2 mm or smaller on histopathology. No incidental papilloma was upgraded to malignancy on excision or surveillance. Therefore, incidental papillomas can be safely followed with serial imaging if carefully classified as such after radiology-pathology correlation.

Given the higher risk of malignancy in cases of multiple peripheral papillomas, and supported by our data, women with four or more concurrent or metachronous peripheral papillomas optimally should undergo excision of most peripheral papillomas if clinically feasible [34, 40, 41]. This may be challenging in women with innumerable peripheral papillomas, and the decision regarding excision should be individualized.

Given the low upgrade rate to malignancy of BPs, routine excision of all BPs may be unnecessary. However, our upgrade rate remained above the 2% threshold, precluding assignment as category 3 (probably benign) for imaging surveillance according to ACR BI-RADS [17]. Hence, many radiologists are uncomfortable placing BPs under surveillance. Nonetheless, the 0% malignant upgrade rate among lesions that underwent surveillance confirms the favorable outcome of imaging follow-up in selected cases [20, 23]. Selective surgical excision is a reasonable approach to the management of BPs to avoid both the delayed diagnosis of malignancy and unnecessary surgeries. Among numerous prior studies of BPs, few provide clinically useful algorithms for selective surgical excision [9, 15]. Our selection model, which is based on radiology-pathology discordance and risk factors such as patient age of 60 years old and older, symptoms of palpable mass or nipple discharge, lesion size on imaging of 10 mm or larger, and the presence of four or more metachronous or concurrent peripheral papillomas, shows satisfactory diagnostic accuracy. Using this model, once excluding all lesions completely excised on histopathology as well as incidental papillomas, our approach for selective surgery would have spared many BPs from routine surgical excision without delaying diagnosis of the 14 lesions upgraded to malignancy.

As an alternative to surgical excision of BPs, Yi et al. [42] reported excision of 136 solitary intraductal papillomas using an ultra-sound-guided 8-gauge Mammotome system (Ethicon Endosurgery, Johnson & Johnson), with no recurrences during the follow-up period. In a study of 233 BPs that underwent ultrasound-guided directional vacuum-assisted removal, Choi et al. [43] found a low rate of upgrade (2.1%) and recurrence (3.6%), with the recurrent lesions proven benign after surgical excision. Ultrasound-guided vacuum-assisted ablation may emerge as a future more conservative alternative than surgical excision in the management of BPs and may be particularly useful in women with numerous peripheral papillomas needing excision.

Our study has limitations. This is a retrospective study at a single academic breast center with experienced subspecialized breast radiologists. Our results may not be transferable to other institutions. The relatively small number of upgrades limits more substantive analysis of upgrade predictors. Further validation of this proposal with a prospective multiinstitutional study would help refine the model before wider clinical distribution.

In summary, our study confirms a low malignant upgrade rate of BPs, identifies significant predictors of upgrade to malignancy among BPs, and proposes several criteria for selective surgical excision that would spare many BPs from routine surgical excision without delaying the diagnosis of breast cancer. BPs associated with radiology-pathology discordance, patient age of 60 years old and older, symptoms of palpable mass or nipple discharge, lesion size of 10 mm or larger, or four or more metachronous or concurrent peripheral papillomas should be excised unless they are incidental papillomas or papillomas completely excised on histopathology.

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References

Koerner FC. Papilloma and related-benign lesions. In: Hoda S, Brogi E, Koerner FC, Rosen PP, eds. Rosen's Breast Pathology, 4th ed. Lippincott Williams and Wilkins, 2014:95–152

Abstract

HIGHLIGHTS

Methods

Study Population

Clinical, Imaging, and Histopathologic Features

Statistical Analysis

Results

Benign Papillomas Upgraded to Malignancy

Clinical Characteristics

Imaging Characteristics

Biopsy Technique

Histopathologic Characteristics

Logistic Regression Analysis

Discussion

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