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Core Biopsies and Histologic Predictors of Occult Breast Cancer.

Introduction

Occult radiographic breast lesions are commonly approached by percutaneous core needle biopsy, either by stereotactic or ultrasound guidance. (1) Benefits to this approach are economic and cosmetic, though histologic findings from this minimally invasive approach may result in the need for surgery. (2) Several, non-malignant risk factors have been associated with an underlying occult breast cancer and, as a result, a core biopsy diagnosis of atypical ductal hyperplasia, atypical lobular hyperplasia, radial scar formation, and intraductal papilloma have prompted an excisional biopsy. Recent data has added to the controversy surrounding the need for surgery following a core biopsy showing high risk non-malignant breast lesions, (3) and we have reviewed our large community hospital experience since the initiation of core biopsy in the management of occult radiographic breast lesions.

Materials and Methods

Beginning in 2006 our comprehensive breast program at Wheeling Hospital initiated a rigorous effort to offer minimally invasive core biopsies of occult breast lesions to all patients who could tolerate the procedure and whose lesions could be adequately targeted. Due to the gradual evolution away from needle-localization and toward core biopsy alone as an initial diagnostic procedure, data collection was delayed until a uniform approach was adopted and accepted by surgical and radiology faculty.

Between 2009-2016, 4589 core needle biopsies of breast tissue were performed at our facility in response to a Breast Imaging Reporting and Data System (BI-RADS) assessment category 4. A BI-RADS 3 categorizes a lesion as probably benign and a BI-RADS 4 categorizes the lesion as suspicious. A 6- month follow up is typically recommended for BI-RADS 3, while a biopsy is recommended for BI-RADS 4. (4) Following a BIRADS 4 assessment, the target lesion was localized by stereotactic or ultrasound guidance and an 8- or 11-gauge vacuum-assisted core biopsy was performed. During the period of study, 378 patients were found to have a high risk, nonmalignant lesion referred to a breast surgeon. 286 patients had both core and excisional biopsy performed at Wheeling Hospital and are the subject of this report. None of the patients evaluated had a prior history of breast cancer. The 92 patients who did not have an excision either refused biopsy (55) or went elsewhere for care (37). The 4303 biopsy specimens excluded from this analysis either revealed a cancer at core biopsy or did not reveal a high risk, non-malignant lesion warranting further surgical investigation.

Those patients with a core biopsy diagnosis of atypical ductal hyperplasia (ADH), atypical lobular hyperplasia (ALH), radial scar formation (RS), or intraductal papilloma (PAP) were referred to a breast surgeon for excision. The needle-localized excision removed the biopsy site plus a 10 mm margin of tissue. If a breast malignancy was identified, the standard surgical margin was at least 1 mm for both DCIS and invasive disease. All core biopsy and excision specimens were reviewed by faculty of The Pathology Department at Wheeling Hospital.

Statistical Analysis

All core biopsies revealing ADH, ALH, RS, and/or PAP were subjected to a logistic regression. An analysis of the total of the study population, and populations excluding patients with more than one and more than 2 diagnoses, was used to determine the significance of the differences. A Pearson's chi square statistic was also performed to distinguish whether the presence of atypia was a significant variable. All data were analyzed using Statistical Package for Social Sciences, version 17.0 software (SPSS, Inc., Chicago, IL). Statistical significance was set at p<0.05.

Results

Of the 4589 core biopsies performed, 46% were by stereotactic and 54% were by ultrasound guidance. No association was identified between the method used for biopsy and the likelihood of either identifying a high risk lesion or an eventual underlying breast malignancy. The 286 patients (6% of the overall population biopsied) who were found to have ADH, ALH, RS, or PAP then underwent definitive surgery and 20 (7% of those with high risk lesions and 0.4% overall) were diagnosed with an associated breast malignancy. Table 1 illustrates the patients subjected to breast surgery and their core biopsy needle diagnoses. The majority of the patients had a unique diagnosis (ie. ADH only) with a smaller number having more than one high risk feature found at core biopsy. Table 2 describes the results of the excision. Five of the patients were found to have an invasive cancer (2 with lobular and 3 with ductal histology) while the remaining 15 had DCIS. Table 3 describes the characteristics of the 20 women who were ultimately found to have an associated breast malignancy. One-quarter of the women had a history of oral contraceptive medication use, 10% had used hormone replacement medication, and 30% had a 1st degree family history of breast cancer (15% additional women had a second degree family history). All lesions were occult and non-palpable and the median largest tumor diameter was 8 mm (range 2-15 mm). The majority of the women underwent adjuvant radiotherapy, 40% overall who received partial breast radiotherapy. 40% of the women diagnosed with breast cancer did not undergo adjuvant radiotherapy because they either had a mastectomy (20%) or had significant co-morbidities making adjuvant therapies inappropriate (20%). None of the women received adjuvant systemic cytotoxic chemotherapy and 55% received anti-endocrine therapy, either tamoxifen or an aromatase inhibitor. None of the women had previously received chemoprevention such as raloxifene or tamoxifen. Table 4 represents the results of the logistic regression analysis. This statistic was used in an effort to separate the influence of co-diagnoses at core biopsy. That is, several of the core biopsies showed more than one diagnosis. Table 2 shows that 5 of the 20 patients ultimately found to have an underlying breast malignancy went to definitive surgery with a diagnosis of at least two high risk features. The logistic regression revealed PAP as the sole variable significantly associated with an underlying malignancy. Further analysis of the PAP lesions, depicted in Pearson's chi square analysis (table 5), demonstrated that those with atypia within the papilloma predicted for an occult breast malignancy; those without atypia did not. The numerical values set in the chi square refer to the number of patients with and without a breast malignancy as they relate to those with and without atypia within the PAP at core biopsy.

Discussion

The biological progression from high risk precursor breast lesion to breast malignancy has been described as step wise from atypical hyperplasia to carcinoma in situ, eventually leading to the development of invasive disease. Both ADH and ALH have been identified as important early cellular changes and, as a result, these lesions have been targeted for removal as well as for chemoprevention. (5,6)

The risk of developing breast cancer following a diagnosis of ALH has been estimated at 4-5 times higher than baseline. (7) In a small study from MD Anderson Cancer Center, women with lobular neoplasia (ALH, lobular carcinoma in situ; LCIS) by core biopsy underwent an excision and 40% were found to have a more significant lesion. A more significant lesion was one with extensive LCIS or ALH and those patients were recommended for surgery. The authors offered that more than 3 terminal lobular units involved by ALH was considered extensive enough to have surgery. Those with focal areas of ALH or LCIS were observed. At a median follow up of more than 3 years, none of the observed patients had developed a malignancy and clinical and radiologic follow up continued. (8) Similarly in a European series, women with ALH or LCIS at core biopsy were found to have a 31% risk of an associated malignancy when the high risk lesion was found to be more extensive, and less extensive lesions were thought to be adequately managed by observation alone. (9) In our series 61 women were diagnosed with ALH alone, while an additional 17 had more than one diagnosis, including ALH, at core biopsy; a total of 78 women with ALH were assessed with surgery (Table 1). Five women (7%) with ALH alone or in concert with other risk factors were found to have a breast malignancy at surgery (Table 2). We did not evaluate the extent of ALH found at core biopsy, but the absence of significance in our study does not support a relationship between extent of ALH and risk of associated malignancy.

ADH has likewise been considered to be a common histologic precursor to breast malignancies and, as such, surgery has been regularly advocated. In a most recent study of 1727 women with ADH, less than 6% were found to develop a breast malignancy 10 years following surgery for ADH. (3) A recent series from Buffalo evaluated 203 patients with ADH on core biopsy followed by surgical resection. More than 28% of the patients had an upgrade in their diagnosis at surgery (23% with DCIS and 5% with invasive cancer). Based on their experience, the authors developed a nomogram to stratify patients as having a low, intermediate, or high likelihood of an upgrade at surgery. The variables chosen to build the nomogram included age, menopausal status, prior hormonal therapy, prior history of breast cancer, number of cores found to contain ADH, size of lesion, mass versus calcifications, and presence of a solid ADH pattern. They concluded that their data set should be verified before observing patients whose core biopsy reveals ADH with a low risk nomogram score. (17) In our series, 62 women were diagnosed with ADH only and another 25 with ADH in combination with other high risk lesions at core biopsy (Table 1). Three patients (5%) with ADH alone, and another five (20%) when ADH was identified with other high risk features, were found to be associated with an underlying malignancy (Table 2). Given the lack of statistical significance associated with a core biopsy diagnosis of ADH and an associated breast malignancy, a nomogram would not have added to risk stratification in our series.

RS has been described as a common finding in cancerous and non-cancerous breasts at autopsy. In a report of women dying of non-breast cancer causes, the authors found 15.5 radial scars in the breast of women with breast cancer and 4 scars in women without breast cancer. This finding led the authors to conclude that RS was "at least a marker" for breast cancer. (10) In a clinical series from The University of Pittsburgh, RS was identified on core biopsy and was described as unique or associated with other high risk features (ADH, ALH; termed combined). All were referred for surgery and 6% of the combined group were found to be associated with an occult malignancy. The authors found that postmenopausal women with RS lesions, when combined with other high risk lesions at core biopsy, were appropriate candidates for breast surgery. (11) In a corroborative series from Harvard, 1556 patients with RS (84% of whom had unique RS) underwent surgery, 0.8% of whom were upgraded overall to invasive cancer. Of the patients with unique RS, only 1% were found to have an associated cancer while those with a combination of high risk lesions had a 14% likelihood of cancer at surgery. The authors argued against breast surgery for unique RS. (12) Our series did not reveal a significant association between RS at core biopsy, either alone or in combination with other high risk lesions, and an underlying breast malignancy. Specifically, 77 women with RS alone and an additional 13 women with RS in combination with other high risk lesions were evaluated in our study (Table 1). Only 2 patients (RS + ADH; RS + ALH) were diagnosed with breast cancer at surgery (Table 2).

PAP are commonly divided into benign or atypical and several reports have addressed the appropriate management of these high risk lesions accordingly. In a series from Miami, 0% of papillary lesions with no or minimal atypia were associated with a malignancy, while 29% with definite atypia were associated with an occult malignancy at surgery. (13) In a Mt Sinai study of 104 women with pure benign papillomas without atypia at core biopsy, 9% were found to have cancer in the surgical specimen and 7% had ADH. Based on their data, the authors resect all papillomas identified at core biopsy. (14) A Polish study reviewing their series of intraductal papillomas found a 3% rate of malignant change in atypical papillomas while none of the 60 women with benign papillomas developed a malignancy after core biopsy and close observation only at short follow-up. (15) This series was limited by the absence of a confirmatory breast surgery following a diagnosis of a benign papilloma, as follow up may not have been long enough to identify tumor development. In a most contemporary series from MSKCC of 166 women with benign PAP, all of whom underwent surgery, the upgrade rate was 2.3% leading the authors to conclude that benign PAP lesions at core biopsy can be safely observed. (16) In our study, 51 women with PAP alone and an additional 20 with PAP plus other high risk lesions underwent breast surgery (Table 1). Eight women with PAP alone (16%) and three with PAP plus another high risk lesion (15%) were found to have an associated breast malignancy at surgery (Table 2). We then divided the PAP lesions into benign and atypical and found that 5 of the patients with atypia and 6 without were associated with an underlying cancer. Because there were far fewer patients overall with atypia (15 vs 53), there was a statistically significant association between PAP with atypia and an underlying cancer, and this was not demonstrated in the benign PAP lesions (Table 4). The underlying cancer rate in those women with atypia was 33%; the rate in the benign PAP was 11%.

An inherent limitation to our series includes the limited data we gathered regarding a potential relationship between patient-related factors and the likelihood of an underlying breast malignancy. Because we did not collect data on the women who were not found to have an underlying breast malignancy, we cannot offer details on the influences of OCP or hormone replacement medication use or the impact of family history on the potential of an occult breast malignancy in women presenting with high risk breast lesions. We have since introduced a comprehensive survey to be completed by all women diagnosed with a high risk breast lesion by core biopsy planning to undergo breast surgery.

Identifying premalignant or high risk benign precursor lesions serves as an indisputable and fundamental way of improving cure rates in various solid tumors including cancers of the cervix and colon. (18,19) Determining whether the identification of such lesions in the management of breast cancer changes the natural history of the disease or improves cure rates remains controversial. (20) Improvements in radiologic imaging have identified high risk, non malignant breast lesions with greater frequency, making their appropriate surgical management important. Whether excising more breast parenchyma around the high risk lesion results in the diagnosis of a clinically significant breast cancer or more importantly, improves cure rates, remains debatable.

Conclusion

Despite the small number of patients ultimately included in the analysis, our series demonstrated that intraductal papillomas with atypia significantly predicted for an associated breast malignancy, the majority of which were DCIS. This finding is supported by the literature, prompting our team to resect all intraductal papillomas with atypia. We offer observation to postmenopausal women with RS alone but, based on the youth of our program, the small numbers thus far evaluated, and the controversy in the literature, we feel it is premature to abandon an excision following a core biopsy diagnosis of ADH, ALH, or benign PAP.

References

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(2.) Jackman RJ, Nowels KW, Rodriguez-Soto J, Marzoni FA, Finkelstein SI, Shepard MJ, Stereotactic, automated, large-core needle biopsy of nonpalpable breast lesions:falsenegative and histologic underestimation rates after long-term followup. Radiology 210(3):799-805 (1999).

(3.) Menes TS, Kerlikowske K, Lange J, Jaffer S, Rosenberg R, Miglioretti DL, Subsequent breast cancer risk following diagnosis of atypical ductal hyperplasia on needle biopsy. JAMA Oncol23(1):36-41 (2017)

(4.) Orel SG, Kay N, Reynolds C, Sullivan DC. BI-RADS categorization as a predictor of malignancy. Radiology 211(3), 845-50 (1999).

(5.) Hartmann LC, Radisky DC, Frost MH, Santen RJ, Vierkant RA, Benetti LL, Tarabishy Y, Ghosh K, Visscher DW, Degnim AC. Understanding the premalignant potential of atypical hyperplasia through its natural history: a longitudinal cohort study. Cancer Prev Res 7(2), 211-217 (2014).

(6.) Vogel VG, Costantino JP, Wickerham DL, Cronin WM, National surgical adjuvant breast and bowel project update:prevention trials and endocrine therapy of ductal carcinoma in situ. Clin Cancer Res 9(1Pt2), 495S-501S (2003).

(7.) London SJ, Connolly JL, Schnitt SJ, Colditz GA. A prospective study of benign breast disease and the risk of breast cancer. JAMA 267, 941-944 (1992).

(8.) Middleton LP, Sneige N, Coyne R, Shen Y, Dong W, Dempsey P, Bevers TB. Most lobular carcinoma in situ and atypical lobular hyperplasia diagnose don core needle biopsy can be managed clinically with radiologic follow-up in a multidisciplinary setting. Cancer Med 3(3), 492-499 (2014).

(9.) Polom K, Murawa D, Pawelska A, Murawa P. Atypical lobular hyperplasia and lobular carcinoma in situ without other high-risk lesions diagnosed on vacuum-assisted core needle biopsy. The problem with excisional biopsy. Tumori 95(1), 32-5 (2009).

(10.) Wellings SR, Alpers CE. Subgross pathologic features and incidence of radial scars in breast. Hum Pathol 15(5), 475-9 (1984).

(11.) Andacoglu O, Kanbour-Shakir A, The YC, Bonaventura M, Ozbek U, Anello M, Ganott M, Kelley J, Dirican A, Soran A. Rationale of excisional biopsy after the diagnosis of benign radial scar on core biopsy: a single institutional outcome analysis. Am J Clin Oncol 36(1), 7-11 (2013).

(12.) Miller CL, West JA, Bettini AC, Koerner FC, Gudewicz TM, Freer PE, Coopey SB, Gadd MA, Hughes KS, Smith BL, Rafferty E, Specht MC. Surgical excision of radial scars diagnosed by core biopsy may help predict future risk of breast cancer. Breast Cancer Res Treat 145(2), 331-8 (2014).

(13.) Renshaw AA, Derhagopian RP, Tizol-Blanco DM, Gould EW. Papillomas and atypical papillomas in breast core needle biopsy specimens: risk of carcinoma in subsequent excision. Am J Clin Pathol 122(2), 217-21 (2004).

(14.) Jaffer S, Nagi C, Bleiweiss IJ. Excision is indicated for intraductal papilloma of the breast diagnosed on core needle biopsy. Cancer 115(13), 2837-43 (2009).

(15.) Kibil W, Hodorowicz-Zaniewska D, Popiela TJ, Szpor J, Kulig J. Mammotome biopsy in diagnosing and treatment of intraductal papilloma of the breast. Pol Przegl Chir 85(4), 210-5 (2013).

(16.) Pareja F, Corben AD, Brennan SB, Murray MP, Bowser ZL, Jakate K, Sebastiano C, Morrow M, Morris EA, Brogi E. Breast intraductal papillomas without atypia in radiologic-pathologic concordant core-needle biopsies:rate of upgrade at excision. Cancer 122(18), 2819-27 (2016).

(17.) Khoury T, Chen X, Wang D, Kumar P, Qin M, Liu S, Turner B. Nomogram to predict the likelihood of upgrade of atypical ductal hyperplasia diagnosed on a core needle biopsy in mammographically detected lesions. Histopathology 67, 106-20 (2015).

(18.) Rosenthal AN. Screening for gynecologic cancers. Curr Opin Oncol 10(5), 447-51 (1998).

(19.) Meester RG, Doubeni CA, Lansdorp-Vogelaar I, Goede SL, Levin TR, Quinn VP, Ballegooijen M, Corley DA, Zauber AG. Colorectal cancer deaths attributable to nonuse of screening in the United States. Ann Epidemiol 25(3), 208-213 (2015).

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Ariel E. Pollock, MD Icahn School of Medicine, Mt. Sinai, NY, NY

Scott Nestor, DO Department of Pathology, Wheeling Hospital

Carter Kenamond, MD Department of Radiology, Wheeling Hospital

Rosemarie Hardin, MD Department of Surgery, Wheeling Hospital

David A. Ghaphery, MD Department of Surgery, Wheeling Hospital

Jondavid Pollock, MD, PhD Schiffler Cancer Center, Wheeling Hospital, Wheeling, WV

Corresponding Author: Jondavid Pollock, MD. Schiffler Cancer Center, Wheeling Hospital, Wheeling, WV 26003. Email: jpollock@wheelinghospital.org.
Table 1. Count data of core biopsy diagnosis on 286 patients

  Diagnosis    Count

     RS        77
     ALH       61
     ADH       62
     PAP       51
  ALH & PAP     4
  ADH & PAP    11
  ADH & RS      3
  ADH & ALH     6
  RS & PAP      3
  RS & ALH      3
ADH, ALH, PAP   1
ADH, RS, PAP    1
ADH, ALH, RS    3

RS = Radial Scar
ALH = Atypical Lobular Hyperplasia
ADH = Atypical Ductal Hyperplasia
PAP = Intraductal Papilloma

Table 2. Relationship between high risk lesion at core biopsy and
surgery result

Core Biopsy   Surgery (number of malignancies)

   PAP        Grade 1 DCIS (4)
   PAP        Grade 2 DCIS (2)
   PAP        Grade 3 DCIS (1)
   PAP        Grade 2 IDC (1)
   ADH        Grade 1 DCIS (2)
   ADH        Grade 3 DCIS (1)
   ALH        Grade 1 DCIS (1)
   ALH        Grade 1 IDC (1)
   ALH        Grade 1 ILC (1)
PAP, ADH      Grade 1 DCIS (2)
PAP, ADH      Grade 2 ILC (1)
ADH, RS       Grade 1 DCIS (1)
ADH, ALH, RS  Grade 1 DCIS (1)
  ALH, RS     Grade 1 IDC (1)

DCIS = ductal carcinoma in situ
IDC = Invasive ductal carcinoma
ILC = Invasive lobular carcinoma

Table 3: Clinical characteristics of 20 patients with breast malignancy

Median age (range):                      60 years (41-79)
% with 1st degree family history of
breast and/or ovarian cancer:            30% (another 15% with <1st
                                         degree)
% prior OCP use:                         25%
% prior hormone replacement medication
use:                                     10%
Median tumor diameter (range):           8 mm (range 2-15)
% receiving adjuvant radiotherapy:       60% (40% PBI; 20% WBI)
% receiving adjuvant chemotherapy:       0%
% receiving adjuvant endocrine therapy:  55% (35% AI; 20% Tamoxifen)
Median disease free interval (range):    30 months (4-96)

OCP: oral contraceptive medication
PBI: partial breast irradiation
WBI: whole breast irradiation
AI: aromatase inhibitor

Table 4. Logistic Regression

Variables                     [beta]  Degrees of  p-value
                                      Freedom

Radial Scar                    2.144  1           0.143
Atypical Lobular Hyperplasia    .356  1           0.550
Atypical Ductal Hyperplasia    2.762  1           0.097
Intraductal Papilloma (*)     11.926  1           0.001

(*) Intraductal Papilloma with and without atypia

Table 5. Chi square analysis of intraductal papilloma

Condition  Cancer  No Cancer  Total
Atypia      5      10         15
No Atypia   6      47         53
Total      11      27         76

[X.sup.2] = 4.18
P = 0.041
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Author:Pollock, Ariel E.; Nestor, Scott; Kenamond, Carter; Hardin, Rosemarie; Ghaphery, David A.; Pollock,
Publication:West Virginia Medical Journal
Article Type:Report
Date:May 1, 2018
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