Surgical pathology and upgrade following core biopsy of intraductal papillomas

Introduction

IPs are benign tumors of the breast caused by an overgrowth of epithelial cells surrounded by a fibrovascular core. They can occur in women of all ages, but most commonly in premenopausal and perimenopausal women between 35 and 55 years of age. The spectrum of papillary lesions of the breast includes benign intraductal papillomas (IPs), IPs with atypia, papillary ductal carcinoma in situ (DCIS), encapsulated papillary carcinoma (EPC) and invasive papillary carcinomas or invasive ductal carcinoma. Papillary lesions of the breast makeup less than 10% of breast lesions seen in women (1). However, the significance of IPs of the breast should not be underestimated because of its potential association with atypia and malignancy.

Furthermore, papillary lesions are divided into two broad groups based on their location. Solitary IPs are located centrally and posterior to the nipple as they grow from the large central ducts beneath the nipple. Patients often present with bloody or clear nipple discharge. However, patients with small solitary lesions can be completely asymptomatic and these are incidentally found on breast imaging. In comparison, multiple papillomas are peripherally located and can be found in any breast quadrant affecting one of many peripheral terminal ducts. These papillomas are less frequently associated with nipple discharge and more often present as a palpable mass. Multiple papillomas tend to occur in the younger population. The workup of any breast mass is crucial, as benign IP and papillary malignancy cannot be differentiated based on physical symptoms alone but instead requires a core biopsy for histologic evaluation.

The clinical management of papillary lesions of the breast, particularly IPs, has remained controversial. Genco et al. (2) found that only 1.58% of patients with IPs without atypia diagnosed on core needle biopsy (CNB) upgraded to DCIS. Several factors, including location of the lesion as well as clinical and radiological findings, do not assure benignity. They found that IP greater than 1 cm was the only significant predictor to upgrading.

Overall, this study recommended that non-surgical management can be appropriate in patients with IP without atypia on biopsy. In another study (3) of 142 patients, Rizzo et al. recommended surgical excision of papillary lesions identified on CNB due to a significant rate of upgrade of 24.5% to atypical ductal hyperplasia (ADH) or DCIS. The overall rates of upgrade have been reported to range from 1.5–25 percent. More recent literature (4,5) notes the persistence of the controversial argument regarding when to excise benign IP. Given this high variability of rates of upgrade to atypia or malignancy, we investigated this at our institution. We conducted a retrospective study to determine the need for surgical excision in patients with CNB proven IP to look for histopathology that may denote high risk and delineate the need for surgical excision versus observation with or without close follow-up. We present this article in accordance with the STROBE reporting checklist (available at https://abs.amegroups.com/article/view/10.21037/abs-23-63/rc).

Methods

Study population

This study entailed retrospective review of patients with benign breast lesions identified in the database at our institution (Michigan State University) for the time period between January 1, 2011 to December 31, 2021. A total of 133 patients with benign IP on CNB were included in the cohort.

These patients with papillomas on CNB included 111 patients who subsequently underwent surgical excision and 22 patients who did not (Figure 1). Biopsy specimens of 111 patients with benign papillomatous tissue using 14-gauge CNB were compared with the surgically excised counterpart.

Figure 1 Flow chart of study results. CNB, core needle biopsy; IP, intraductal papilloma.

Demographic, clinical, and histopathological features

Electronic medical records for all patients in our cohort were reviewed. Information relating to demographics, clinical, radiographic, and histopathologic findings was extracted. All information was recorded in an Excel database. Demographic data was extracted (Table 1). Though race and ethnicity data collection was attempted, there was such a significant number of patients that had refused to answer, therefore enough meaningful data was not available for this parameter given the number of those responding. Clinical data collected for each patient included information regarding menopausal state, smoking history, personal history of cancer, family history of breast or ovarian cancer, date of mammogram and/or ultrasound, radiology findings, CNB type, date & findings, surgery date, final surgical histopathology, and other breast pathology. Due to the retrospective nature of the study, many patients were not assessed for the palpability of the IP. Therefore, analysis based on this characteristic is not included. After final pathology was determined, each IP lesion was categorized into one of three groups: IP that retained benignity, upgraded to atypia or upgraded to malignancy as DCIS or invasive ductal carcinoma. Those tumors that are benign maintain usual ductal epithelium (Figure 2). Papilloma with atypia shows focal population of monotonous cells with cytological and architectural features of low-grade ductal neoplasm (Figure 3). When IP is associated with malignancy it is usually DCIS or invasive ductal carcinoma (Figure 4). Though invasive papillary carcinoma can occur, it is very rare for patients who did not undergo surgery. Information regarding the reasons for not undergoing surgical excision and surveillance imaging during subsequent 6–12 months follow-up was collected.

Figure 2 Benign intraductal papilloma. Image at 4× shows arborizing fronds lined by epithelial and myoepithelial cells with central fibrovascular cores. Image at 40× shows cohesive proliferation of heterogeneous cells. Magnification 4× (inset, 40×). Hematoxylin and eosin staining.

Figure 3 Intraductal papilloma with usual ductal hyperplasia. Image at 4× shows proliferation of epithelial and myoepithelial cells with central fibrovascular cores. Image at 40× reveals monomorphic population of epithelial cells. Magnification 4× (inset, 40×). Hematoxylin and eosin staining.

Figure 4 Invasive ductal carcinoma. Image at 4× reveals infiltrative growth of neoplastic epithelial cells with associated desmoplasia. Image at 40× shows pleomorphic tumor cells which are mitotically active. Magnification 4× (inset, 40×). Hematoxylin and eosin staining.

Data analysis

Descriptive analysis was performed to summarize the patient characteristics and identifiable risk factors including tumor size, age, menopausal status, personal and family history of breast or ovarian cancer.

Data collected was analyzed for potential common risk factors in patients who upgraded to atypia or malignancy. Mean age of patients who retained benignity, upgraded to atypia, and upgraded to malignancy was compared. Sizes of the papilloma were also compared among the three different groups.

Statistical analysis

Statistical analysis was performed using analysis of analysis (ANOVA) results for age and tumor size among the three groups. P value was obtained for the determination of statistical significance with P<0.05. Mean, median and standard deviation of the two variables in the three different groups were obtained and compared.

Ethical consideration

The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). This study was approved by the Michigan State University Institutional Review Board (#6977) and individual consent for this retrospective analysis was waived.

Results

Of the 133 patients included in this study, 111 (83.5%) underwent surgical excision. Ninety-seven (87.4%) patients retained benignity, 9 (8.1%) patients upgraded to atypia and 5 (4.5%) patients upgraded to malignancy (DCIS or invasive carcinoma). The mean age of patients with persistence of benignity was 51.54 years [standard deviation (SD), 13.41], upgraded to atypia was 59.89 years (SD, 9.53) and upgraded to cancer was 59.60 years (SD, 10.50). The age range of patients in the groups with persistence of benignity, upgraded to atypia, and upgraded to cancer was 26.00 to 83.00, 46.00 to 72.00, and 47.00 to 71.00 years, respectively. No statistically significant difference between the ages for the three groups was found (P=0.25) as shown in Table 2.

The size of IP in patients with persistence of benignity ranged from 3.00–54.00 mm (mean =10.53 mm), upgraded to atypia ranged from 3.50–19.00 mm (mean =10.76 mm) and upgraded to cancer ranged from 3.00–12.30 (mean =8.28 mm) as shown in Table 2. There was no statistically significant difference for papilloma size between the three groups, P value of 0.82 (ANOVA testing).

On CNB, microcalcifications were seen in 4 out of 97 (4.12%) patients that retained benignity compared to 8 out of 9 (88.89%) patients that upgraded to atypia (P<0.001), and retained benignity compared to 4 out of 5 (80%) patients that upgraded to malignancy (P<0.001). Microcalcifications were significantly associated with upgraded IPs compared to those retaining benignity on CNB (Fisher’s exact test) (Table 3).

Discussion

Management of IP on CNB has remained controversial and has undergone major changes over the years.

Historically, mastectomy was frequently used as the standard of care for all IP due to concern for malignancy (6). More recently, local excision has been pursued due to an understanding of its benign nature but risk of upgrade. Rizzo and colleagues [2008] recommended surgical excision of all IP identified on CNB because 24.5% of 142 patients upgraded to atypia or malignancy (3). Renshaw et al. [2017] concluded that atypical papillary lesions are associated with increased risk of cancer, however, they concluded that lesions with no atypia are benign and do not need to be excised (7). In a prospective study by Nakhlis et al., it was determined the upgrade rate of IP on CNB adjacent to malignancy alone was 1.7% and they suggested that routine excision of IP without atypia on CNB was not indicated (8). The endpoint of their upgrade was malignancy. However, they did find atypia associated with excised IPs, local versus central pathology, in this multi-institutional study was 3% and 13%, respectively. While few studies (2,8-10) have recommended close follow up without surgical excision for concordant benign appearing IPs clinically and on imaging, a few others still recommend surgical excision of IP (3,11-15). The literature shows a paradigm shift over time between 2002 and 2017 from watching IP to excising all IP. Now the recommendation to excise based on clinical and pathological findings (16) is becoming the accepted standard of practice. In this study we sought to identify demographic and clinicopathologic features that would be the basis for upgrading IP to high risk with atypia or malignancy thus leading to early excision. Our study showed that 12.6% of IP were upgraded. This indicated that some patients may have cancer prevention by removal of atypia or the early detection of occult malignancy, e.g., DCIS. This research attempted to delineate factors that might have influenced this rate of upgrade. Several risk factors for upgrade have been considered in prior studies, including contraceptive use, long-term estrogen exposure, hormone replacement therapy, family history, age, and symptoms at presentation such as a palpable mass and/or nipple discharge. Carter et al. found that 2 (33%) out of 6 patients with multiple IPs developed cancer, whereas only 4 (7%) out of 58 with solitary IPs developed cancer (17). This led to the conclusion that multiple IP should be excised. Though there were a small number of patients with multiple IPs, the probability was higher for harboring malignancy compared to the solitary IP. In another study by Shouhed et al. they found that of 103 patients 17 upgraded to atypia and 6 to carcinoma, 16.5% and 5.8%, respectively. They identified a clinically palpable mass as the only significant predictor of this 22% upgrade (18). Our retrospective analysis was limited by lack of available data regarding the presence of a palpable mass and nipple discharge. Our study sought to determine the need for complete excision of IP based on histopathologic features. In this study, benign IP on CNB upgraded to atypia or malignancy at a rate of 12.6%, which was greater than the rates in studies noted that recommended against surgical excision, and it was similar to the rates in those studies that recommended surgical excision. This study suggested that older age was correlated with an increased risk of upgrade to atypia or cancer in similarity to some other authors (19,20). However, this was not statistically significant. Family history data for breast cancer was sparsely available for patients with initial diagnosis of benign IP. No statistically significant difference was found in the risk of atypia or cancer based on the size of IP. This study indicated that microcalcifications on CNB were associated with increased risk of upgrade to both, atypia and cancer. This is one of only two studies to our knowledge to make this observation. A study by Xin Li et al. (21) suggested an increased risk of upgrade to cancer in IP with microcalcifications noted on CNB or imaging. Though our study is suggestive that older age and menopausal status may play a role in IP upgrading to atypia and malignancy, more research with prospective studies is needed to better define the need for complete excision in these patients.

Conclusions

Despite controversial opinions regarding excision of IP, based on this study it is recommended that all patients with IP containing microcalcifications on CNB should have complete excision. Furthermore, older patients (peri- and post-menopausal) should be considered for excision after patient-centered discussions of risks and benefits.

Acknowledgments

Funding: None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://abs.amegroups.com/article/view/10.21037/abs-23-63/rc

Data Sharing Statement: Available at https://abs.amegroups.com/article/view/10.21037/abs-23-63/dss

Peer Review File: Available at https://abs.amegroups.com/article/view/10.21037/abs-23-63/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://abs.amegroups.com/article/view/10.21037/abs-23-63/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). This study was approved by the Michigan State University Institutional Review Board (#6977) and individual consent for this retrospective analysis was waived.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Bloom C. Breast Papillomas: A Comprehensive Review. Journal of Diagnostic Medical 281 Sonography 2015;31:282-9.
2. Genco IS, Tugertimur B, Manolas PA, et al. Upgrade rate of intraductal papilloma without atypia on breast core needle biopsy: A clinical, radiological and pathological correlation study. Am J Surg 2020;220:677-81. [Crossref] [PubMed]
3. Rizzo M, Lund MJ, Oprea G, et al. Surgical follow-up and clinical presentation of 142 breast papillary lesions diagnosed by ultrasound-guided core-needle biopsy. Ann Surg Oncol 2008;15:1040-7. [Crossref] [PubMed]
4. Tierney SN. Intraductal Papillomas. Surg Clin North Am 2022;102:965-72. [Crossref] [PubMed]
5. Abbassi-Rahbar S, Sack S, Larson KE, et al. Multidisciplinary Review of Intraductal Papilloma of the Breast can Identify Patients who may Omit Surgical Excision. Ann Surg Oncol 2021;28:5768-74. [Crossref] [PubMed]
6. Al Sarakbi W, Worku D, Escobar PF, et al. Breast papillomas: current management with a focus on a new diagnostic and therapeutic modality. Int Semin Surg Oncol 2006;3:1. [Crossref] [PubMed]
7. Renshaw AA, Derhagopian RP, Tizol-Blanco DM, et al. Papillomas and atypical papillomas in breast core needle biopsy specimens: risk of carcinoma in subsequent excision. Am J Clin Pathol 2004;122:217-21. [Crossref] [PubMed]
8. Nakhlis F, Baker GM, Pilewskie M, et al. The Incidence of Adjacent Synchronous Invasive Carcinoma and/or Ductal Carcinoma In Situ in Patients with Intraductal Papilloma without Atypia on Core Biopsy: Results from a Prospective Multi-Institutional Registry (TBCRC 034). Ann Surg Oncol 2021;28:2573-8. [Crossref] [PubMed]
9. Bennett LE, Ghate SV, Bentley R, et al. Is surgical excision of core biopsy proven benign papillomas of the breast necessary? Acad Radiol 2010;17:553-7. [Crossref] [PubMed]
10. Chang JM, Han W, Moon WK, et al. Papillary lesions initially diagnosed at ultrasound-guided vacuum-assisted breast biopsy: rate of malignancy based on subsequent surgical excision. Ann Surg Oncol 2011;18:2506-14. [Crossref] [PubMed]
11. Holley SO, Appleton CM, Farria DM, et al. Pathologic outcomes of nonmalignant papillary breast lesions diagnosed at imaging-guided core needle biopsy. Radiology 2012;265:379-84. [Crossref] [PubMed]
12. Bernik SF, Troob S, Ying BL, et al. Papillary lesions of the breast diagnosed by core needle biopsy: 71 cases with surgical follow-up. Am J Surg 2009;197:473-8. [Crossref] [PubMed]
13. Mercado CL, Hamele-Bena D, Oken SM, et al. Papillary lesions of the breast at percutaneous core-needle biopsy. Radiology 2006;238:801-8. [Crossref] [PubMed]
14. Tran HT, Mursleen A, Mirpour S, et al. Papillary Breast Lesions: Association with Malignancy and Upgrade Rates on Surgical Excision. Am Surg 2017;83:1294-7. [Crossref] [PubMed]
15. Youk JH, Kim EK, Kwak JY, et al. Benign papilloma without atypia diagnosed at US-guided 14-gauge core-needle biopsy: clinical and US features predictive of upgrade to malignancy. Radiology 2011;258:81-8. [Crossref] [PubMed]
16. Brogi E, Krystel-Whittemore M. Papillary neoplasms of the breast including upgrade rates and management of intraductal papilloma without atypia diagnosed at core needle biopsy. Mod Pathol 2021;34:78-93. [Crossref] [PubMed]
17. Carter D. Intraductal papillary tumors of the breast: a study of 78 cases. Cancer 1977;39:1689-92. [Crossref] [PubMed]
18. Shouhed D, Amersi FF, Spurrier R, et al. Intraductal papillary lesions of the breast: clinical and pathological correlation. Am Surg 2012;78:1161-5. [Crossref] [PubMed]
19. Rizzo M, Linebarger J, Lowe MC, et al. Management of papillary breast lesions diagnosed on core-needle biopsy: clinical pathologic and radiologic analysis of 276 cases with surgical follow-up. J Am Coll Surg 2012;214:280-7. [Crossref] [PubMed]
20. Ashkenazi I, Ferrer K, Sekosan M, et al. Papillary lesions of the breast discovered on percutaneous large core and vacuum-assisted biopsies: reliability of clinical and pathological parameters in identifying benign lesions. Am J Surg 2007;194:183-8. [Crossref] [PubMed]
21. Li X, Weaver O, Desouki MM, et al. Microcalcification is an important factor in the management of breast intraductal papillomas diagnosed on core biopsy. Am J Clin Pathol 2012;138:789-95. [Crossref] [PubMed]