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Abstract

BACKGROUND:

The management of papillary lesions is controversial with studies showing different rates of upstaging to malignancy. There is a paucity of research into race as an independent risk factor. The aim of this study is to identify if race is correlated with upstaging to malignancy with a secondary focus of analyzing for other personal and tumor specific risk factors for upstaging.

METHODS:

We performed a retrospective review of 123 papillary lesions with univariate analysis to identify risk factors for upstaging.

RESULTS:

The incidence of papillary lesions found on core needle biopsy was 6%. Atypical papillary lesions were most likely to be upstaged to malignancy at a rate of 27.7%. Papillary lesions and papillary lesions with hyperplasia were also upstaged to cancer at a lower rate of 8.3% and 12.5%, respectively. A univariate analysis of all papillary lesions and a separate analysis of atypical lesions demonstrated a higher likelihood of upstage based on BIRADS classification. Race, age, size of tumor and other radiographic features were not associated with an increased risk for upstaging to malignancy.

CONCLUSIONS:

Atypia remains the most significant contributor to the risk of upstaging papillary lesions to malignancy. Our research supports the practice of excising all atypical papillary lesions with selected excision of those without atypia. In our cohort, there was no association between race and risk of upstaging to malignacy.

Keywords

Papillary lesion papillary carcinoma atypical papillary lesion breast cancer risk factors

1. Background

In the workup of breast lesions, core needle biopsy (CNB) is commonly performed prior to definitive surgical excision. The pathology results between these two modalities can be disconcordant, and the final pathology may even be upstaged to malignancy in lesions that were previously thought to be benign. A study looking at 4035 core needle biopsies concluded that malignancy is underestimated on core needle biopsy by 27.7% [1]. In particular, the incidence of upstaging of papillary lesions to cancer has been controversial and the management remains to be fully elucidated. Prior studies of these lesions have shown variable rates of upstaging to malignancy. Identifying risk factors for upstaging, apart from atypia seen on core needle biopsy has not been consistently observed. Moreover there is a paucity of research with regard to the effects of race on upstaging.

Table 1
Patient characteristics

Number Mean Std Dev

Age 58.54 12.4

Size (cm) 1.309 1.335

Calcifications 56

Asymmetry 63

Distortion 8

Race Black 78

Asian 16

White 15

Latino 10

Other 4

BIRADs 0 8

2 2

3 5

4 100

5 7

6 1

Laterality Left 63

Right 60

There have been studies that have found a very low upstaging or no significant upstaging to malignancy [2–8]. Other studies have reported upstaging to malignancy [9–18] with one study finding a 38% rate of upstaging [9]. Simple intraductal papillomas without evidence of atypia on core needle biopsy have historically been thought to have a very small risk of upstaging to malignancy and have not been routinely resected for the purpose of removing potential malignancy [14]. However a recent study of benign intraductal papilloma by Tatarian et al. found that the upstage rate was 21.3% to atypia and 2.7% to malignancy [19]. They were not able to find any risk factors associated with a higher likelihood to upstage to malignancy, which has historically been the case with papillary lesions. Arora et al. found that only atypical lesions were upstaged to malignancy with risk factors for upstaging being atypia and patient age greater than 65 [20]. Holley et al. found that mass lesions on core needle biopsy were more likely to be upstaged to malignancy on final pathology than lesions characterized by calcifications or distortion, without a defined mass [21]. The difference between the rates of upstaging or the lack of upstaging in these different studies that looked at heterogeneous populations suggests that there may be inherent differences between papillary lesions among these patients, such as racial influences [2–21]. Thus far a single study of sixty four papillary lesions has looked at the rate of upstaging of papillary lesions with regard to African American race [22]. The aim of this study is to identify whether African American race is associated with upstaging of papillary lesions with a secondary aim of evaluating for clinical, radiographic and pathology risk factors for upstaging of papillary lesions to carcinoma.

Table 2

Rates of upstaging to malignancy by core needle biopsy pathology

CNB	N malignancy	N total	% malignancy	OR	P	95% CI
Papillary	3	37	8.30%	1
Hyperplasia	3	21	12.50%	1.5	0.6	0.33–6.82
Atypia	13	47	27.70%	3.3	0.05	1.02–10.78

2. Methods

All patients over the age of eighteen undergoing breast core needle biopsy between 11/12/2008 and 2/27/2014 at Mercy Hospital and Medical Center with the descriptor “papillary” or “papilloma” who went on to have surgical excision within six months were eligible for inclusion. These were sub classified in our analysis into three categories which consisted of papillary lesion or papilloma; papillary lesion with hyperplasia and papillary lesion with atypia. Any single patient with multiple lesions over time and space were eligible to have each papillary lesion included as a separate data point. Results with synchronous DCIS or with “papillary type” DCIS were excluded. Specimen that were excised more than six months after core needle biopsy were also excluded in order to distinguish between a true upstaging of the papillary lesion from an evolving new primary breast cancer. By excluding specimen that were excised in a delayed fashion, the real-time scenario that breast surgeons face when making clinical decisions would be most closely simulated. A retrospective analysis of the medical record was then performed by a single investigator. Patient characteristics that were collected for analysis were patient age and race. Lesion characteristics that were investigated included: laterality, o’clock location, size, presence of calcifications; asymmetry or distortion and BIRAD classification. The final histopathological results were also collected and sub classified in the same manner as the biopsy specimen. An additional sub classification of malignancy was added to the three other categories of papillary lesion or papilloma, papillary lesion with hyperplasia and papillary lesion with atypia. The malignant designation included invasive breast cancer as well as DCIS.

All statistics were conducted using IBM SPSS Statistics for Windows, Version 21.0. Armonk, NY: IBM Corp. Descriptive statistics include means and standard deviations. Means comparisons were run using one-way ANOVAs and independent samples t tests where appropriate. All comparisons were tested at the p $\leq$ 0.05 level. Means comparisons include 95% confidence intervals.

Table 3
(A) Univariate analysis predicting upstaging to malignancy for all papillary lesions on core needle biopsy. (B) Univariate analysis atypical lesions

(A) Mean (SD) Malignancy Mean (SD) Benign P

Age 55.71 (10.73) 59.66 (12.952) 0.11

BIRADS 4.71 (1.34) 4.22 (1.12) 0.04

Size 1.15 (1.129) 1.37 (1.41) 0.42

OR P CI

African American 1.08 0.25 0.79–1.47

Calc 1.17 0.69 0.80–1.72

Asym 0.93 0.14 0.63–1.37

Dist 1.03 0.34 0.92–1.16

(B) Mean (SD) Malignancy Mean (SD) Benign P

Age 54.65 (9.99) 57.65 (13.51) 0.5

BIRADS 5.23 (0.60) 4.53 (1.11) 0.04

Size 0.97 (0.82) 1.26 (1.21) 0.42

OR P CI

African American 1 0.99 0.70–1.44

Calc 0.96 0.81 0.67–1.37

Asym 0.88 0.49 0.60–1.29

Dist 2.25 0.12 0.45–11.25

(A)	Mean (SD) Malignancy	Mean (SD) Benign	P
Age	55.71 (10.73)	59.66 (12.952)	0.11
BIRADS	4.71 (1.34)	4.22 (1.12)	0.04
Size	1.15 (1.129)	1.37 (1.41)	0.42
	OR	P	CI
African American	1.08	0.25	0.79–1.47
Calc	1.17	0.69	0.80–1.72
Asym	0.93	0.14	0.63–1.37
Dist	1.03	0.34	0.92–1.16
(B)	Mean (SD) Malignancy	Mean (SD) Benign	P
Age	54.65 (9.99)	57.65 (13.51)	0.5
BIRADS	5.23 (0.60)	4.53 (1.11)	0.04
Size	0.97 (0.82)	1.26 (1.21)	0.42
	OR	P	CI
African American	1	0.99	0.70–1.44
Calc	0.96	0.81	0.67–1.37
Asym	0.88	0.49	0.60–1.29
Dist	2.25	0.12	0.45–11.25

3. Results

3.1. Pathology results

Six percent of all breast core needle biopsies performed during the six year study period at our institution were for papillary lesions. Sixteen patients were found to have papillary carcinoma on the original core needle biopsy. 123 patients met inclusion criteria. Among the patients within the study population who upstaged to malignancy on surgical pathology, five upstaged to papillary carcinoma, one to invasive ductal carcinoma and the remaining thirteen upstaged to DCIS.

3.2. Patient characteristics association with upstaging

The mean age of our study population was 58-years-old with a standard deviation of 12.4 years. Seventy eight of patients were African American, which was the predominant race that was studied and reflected the majority of patients treated at our institution. The rest of the patient cohort was represented as Asian (sixteen), Caucasian (fifteen), Hispanic (ten) and four patients who identified as Other. On multivariate analysis, there was no association between race or age and upstaging to malignancy.

3.3. Radiographic characteristics association with upstaging

The mean size was 1.3 cm (0.35 cm–7 cm). Eleven lesions were identified by calcifications alone with no associated mass. Findings on mammogram of calcification, asymmetry and distortion were observed in 56, 63 and 8 specimen respectively. None of these were found to be associated with upstaging to malignancy on univariate analysis. Furthermore a larger size was not associated with upstaging to malignancy. There was no difference in laterality of lesions identified, with sixty four lesions biopsied from the left breast and sixty on the right. There was also little difference between the o-clock location of biopsies obtained. Thirty one lesions were identified in the upper outer quadrant, thirty six in the upper inner quadrant, 21 in the lower outer quadrant and seventeen in the lower inner quadrant. Eighteen lesions were noted to be subareolar. The predominant BIRADs classification that was seen in these lesions was 4, which comprised one hundred of specimen. One patient had a known malignancy in another segment of the breast, with the final report listing the lesion being biopsied as a 6, however this reflected the other known malignancy. There were a total of 8 lesions that were listed as BIRAD of 0 that went straight to biopsy and excision without further imaging. Two of these were papillary carcinoma and the remaining six were papillary lesions without hyperplasia or atypia. Increasing BIRAD classification was associated with an increased risk of upstaging to malignancy however the standard deviation of the malignant and nonmalignant group crossed one another showing that this was a modest increase. When looking at an analysis of atypical lesions alone, this association remained. It is important to note that the numerical figures representing BIRAD score in our study did not reflect true BIRAD classification, as we distinguished between BIRAD 4A, 4B and 4C along a numerical gradient.

3.4. Core needle biopsy characteristics associated with upstaging

Atypical papillary lesions were most likely to be upstaged to malignancy at a rate of 27.7%. When comparing this to papillary lesions without atypia or hyperplasia, there was a significant risk of upstaging to malignancy based on the pre-excision presence of atypia with an odds ratio of 3.3 P = 0.05 (CI 1.02–10.78). In addition a stepwise increase in the rate of upstaging to malignancy was observed in papillary lesions and papillary lesions with hyperplasia at a lower rate of 8.3% and 12.5%, respectively. With an odds ratio of upstaging to cancer of 1.5, P = 0.6 (CI 0.33–6.82) in papillary lesions with hyperplasia.

4. Discussion

We present a study of papillary lesions at an urban hospital with a high African American population that showed 6% of all core needle biopsies yielding some form of papillary lesion. This was a higher incidence compared to other studies which have demonstrated an incidence of 2–4% [2,6]. The results of this study demonstrate that African American race is not a risk factor for upstaging to malignancy in papillary lesions. As with previous studies, there were no identifiable patient or radiographic risk factors that increased the likelihood of upstaging, with the exception of BIRADS classification. The rate of upstaging atypical lesions to malignancy was 27.7% which was within the range reported by previous studies. In our analysis, pure papillary lesions and those with hyperplasia were also found to have a rate of upstaging along a gradient.

This study reflects what has been observed before; that papillary lesions are extremely variable without any readily identifiable patient or lesion risk factors to guide excision versus watchful waiting. A study by Jaffer et al. found that 16.4% of pure intraductal papillomas on core needle biopsy were upstaged to atypia or malignancy on final pathology [14]. However the atypical or malignant cells were not found within the intraductal papilloma itself but rather adjacent to it. Thus the inherent variability between core needle biopsy and final excision may be from a heterogeneity of cell types within the lesion and can be postulated to be a result of insufficient sampling by core needle biopsy. In addition the variability among samples may be influenced by operator experience, radiology and pathology practices and the number of core needle biopsy specimen obtained. A study looking at samples examined by pathologists specialized in breast compared to pathologists that were not specialized in breast found that there was a marked increase in concordance among the specialized pathologists [23]. This finding supports the hypothesis that the quality of classification of these lesions is dependent on the practices of individual pathologists or pathology departments. In addition, one meta analysis discovered that a shorter interval between core needle biopsy and final excision also yielded a lower incidence of upstaging among final excision [24]. In addition there appears to be significant classification differences across pathologists suggesting that there may be a role for these lesions being examined by pathologists or pathology departments that process a high volume of breast specimen. Based on our results we advocate for excision of all papillary lesions with atypia given the increased rate of upstaging. Other papillary lesions may be followed with serial imaging, however they should be managed on a case-by-case basis taking into account patient condition and preferences.

Although we did not find African American race to be associated with upstaging, there was a higher prevalence of papillary lesions at our institution which may reflect an inherent predisposition for the development of papillary lesions in African Americans. It is important to note that in this study we only studied the rate of upstaging to malignancy and did not investigate the clinical course of the woman diagnosed with cancer. African American women when compared to Caucasian women have been found to have more advanced disease at diagnosis of breast cancer, as well as a higher likelihood of ER receptor negative status and higher risk of recurrence [25]. Meta-Analysis has shown that mortality in African Americans is 1.28 times that of Caucasians [26]. Furthermore equal treatments in clinical trials have resulted in equal outcomes across all races except for in African Americans [27]. A study by Jiagge et al discovered that women from Ghana had a higher incidence of triple negative disease compared to African American women suggesting that genetic predisposition plays a large role in these disparities [28]. As with other studies that have found advanced disease and poorer outcome in African American women, this may also be the case with papillary breast cancer in this group of woman, however this is yet to be studied.

The major weakness of this study is that it is retrospective analysis and is underpowered due to the rarity of this disease entity. Although this was the largest series of papillary lesions being studied to investigate racial disparities, there were not enough data points to perform a multivariate analysis which could help reveal risk factors for upstaging. Our results open up future directions to be investigated on this topic. Why does there appear to be a higher incidence of papillary lesions among African American patients? What process is responsible for upstaging and can that answer be found by looking at the genetic makeup of these lesions rather than populations studies? Finally, do these African American women have a similar course once diagnosed with papillary carcinoma compared to Caucasian women?

5. Conclusion

Atypia and pathologic examination remains the most significant contributor to the risk of upstaging papillary lesions to malignancy. Our research supports the practice of excising all atypical papillary lesions with selected excision of papillary lesions without atypia. While our study doesn’t link upstaging with African American race, further investigation into the clinical course after diagnosis is warranted.

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