Image-guided core needle biopsy has become a standard

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1 Pathologic Review of Atypical Hyperplasia Identified by Image-Guided Breast Needle Core Biopsy Correlation With Excision Specimen I-Tien Yeh, MD; Diana Dimitrov, MD; Pamela Otto, MD; Alexander R. Miller, MD; Morton S. Kahlenberg, MD; Anatolio Cruz, MD Context. Management of breast needle core biopsies diagnosed as atypical ductal hyperplasia, atypical lobular hyperplasia, and lobular carcinoma in situ is controversial. Current recommendations involve excisional biopsy to rule out ductal carcinoma in situ and/or invasive carcinoma, which have been reported in more than 5% of cases in some series. Objective. To determine how frequently these diagnoses made on needle core biopsy are ultimately found to represent in situ or invasive carcinoma based on excisional biopsy specimens, in order to identify predictive factors. Design. One thousand eight hundred thirty-six imageguided needle core biopsies were performed between January, 995 and May,. Fifty-four (.9%) patients diagnosed with atypical ductal hyperplasia (n 6), atypical lobular hyperplasia (n ), atypical ductal hyperplasia atypical lobular hyperplasia (n ), or lobular carcinoma in situ (n ) subsequently underwent breast excisions. Pathologic features were reviewed in each of the needle core biopsies using Page s criteria and were then correlated with excision specimens. Setting. University medical center. Results. Review of the needle core biopsy cases with either ductal carcinoma in situ or invasive carcinoma ductal carcinoma in situ on final excision showed that nucleoli were evident in most of the needle core cases, with foci of nuclear pleomorphism and individual cell necrosis or apoptosis. Conclusion. A more precise diagnosis can be made by using strict criteria for atypical ductal hyperplasia versus ductal carcinoma in situ on needle core biopsy. Cytologic atypia, even if in a small area, particularly when there is apoptosis/individual cell necrosis, correlates with the finding of a more serious lesion on excision. (Arch Pathol Lab Med. ;7:49 54) Image-guided core needle biopsy has become a standard procedure in many hospitals. Pathologic interpretation of biopsy specimens is limited by small sample size. Therefore, an excisional biopsy is recommended in patients in whom a diagnosis containing the word atypical is rendered, including atypical ductal hyperplasia (ADH) and atypical lobular hyperplasia (ALH). These limitations of interpretation of small-core needle biopsies are particularly important when the diagnosis is dependent on the size of the lesion in question. It is also relevant to the distinction between ADH and low-grade ductal carcinoma in situ (DCIS)., Lobular carcinoma in situ (LCIS) is also difficult to assess and was included in this study because this lesion is thought to be a marker for subsequent invasive carcinoma, rather than a direct precursor lesion. Lobular carcinoma in situ is therefore treated in the same way as ADH is treated, that is, with careful clinical follow- Accepted for publication July,. From the Departments of Pathology (Drs Yeh and Dimitrov), Radiology (Dr Otto), and Surgery (Drs Miller, Kahlenberg, and Cruz), University of Texas Health Science Center, San Antonio. Presented in part at the San Antonio Breast Cancer Symposium, San Antonio, Tex, December,. Reprints: I-Tien Yeh, MD, Department of Pathology, University of Texas Health Science Center, San Antonio, 77 Floyd Curl Dr, San Antonio, TX 789 ( yehi@uthscsa.edu). up and possibly chemoprevention. We undertook this study to establish pathologic and mammographic features in needle core biopsies interpreted as ADH, ALH, and LCIS, which are correlated with a significant lesion in a follow-up excisional biopsy specimen, defined as DCIS or invasive carcinoma of any type. MATERIALS AND METHODS Surgical pathology archives at our institution were queried for breast needle core (NC) biopsies diagnosed as ADH, ALH, and LCIS with follow-up excisional biopsies between January, 995 and May,. There were a total of 86 image-guided NC biopsies performed by the breast mammography unit during this time, and 54 cases were determined to fit these criteria. An additional NC cases were excluded because of lack of follow-up excisional biopsies ( with ADH, 5 with ALH, and with LCIS). The image-guided NC biopsies were performed using either ultrasound (n 6) or stereotactic (n 48) guidance between the dates of January, 995 and May,. The 6 ultrasound-guided procedures were performed on either a General Electric Logiq 4MD or an Acoustic Imaging 5B unit. A 4-gauge automated needle of BIP (Bard Peripheral Technologies, Covington, Ga), BARD (Bard Peripheral Technologies), or Manan (Manan Medical Products, Wheeling, Ill) was used for ultrasound-guided biopsies. An average of 5.8 passes were made using ultrasound guidance. The stereotactic-guided procedures were all performed on a Lo-Rad (Danbury, Conn) table with conventional techniques. From January, 995 until June 5, 998, 8 procedures were Arch Pathol Lab Med Vol 7, January Atypical Hyperplasia on Breast Needle Core Biopsy Yeh et al 49

2 Table. Lesion Type on Mammogram Lesion Type No. of Cases (N 54) Clustered calcifications ( mass/distortion/ density) Clustered calcifications ( mass) Clustered calcifications ( distortion) Clustered calcifications ( density) Soft tissue mass Architectural distortion Increasing density performed using an automated 4-gauge Bard needle. When using this needle, an average of 8.6 passes were performed. From June 5, 998 until May,, a vacuum-assisted, automated, 8-gauge MIBB (USS, Norwalk, Conn) or an -gauge BIOPSYS Mammotome (Ethicon, Somerville, NJ) needle was used. Seven of the biopsies were performed using the 8-gauge MIBB needle, with an average of 9.6 passes. Twenty-three of the biopsies were performed with the -gauge Mammotome needle, with an average of. passes. Lesions were classified as () soft tissue mass, defined as a radiodense lesion visualized in views on the mammogram; () architectural distortion, defined as disturbed tissue architecture; () density, defined as a radiodense lesion visualized only on view on the mammogram; and (4) microcalcifications, defined as 5 or more clustered calcifications, each measuring less than.5 mm. Notation was made if any of the first lesion types (soft tissue mass, architectural distortion, or density) was associated with microcalcifications. Pathologic diagnoses on these 54 cases included 6 biopsies with ADH, with ALH, with both AHD and ALH, and with LCIS. The NC biopsies were completely submitted for microscopic examination, and a minimum of hematoxylin-eosin levels were examined on each block. Excisional breast biopsies were examined by a minimum of hematoxylin-eosin level. Immunoperoxidase stains were performed on cases for E-cadherin (Zymed Laboratories, South San Francisco, Calif; :5) when the lesion had intermediate features between ductal and lobular differentiation. Criteria for determination of ADH were derived from Page and Rogers, 4 using size criteria from Tavassoli and Norris. 5 Criteria for determination of ALH and LCIS were derived from Page et al. All slides and mammograms from these cases were reviewed, and the following data were recorded on each of the NC and excisional biopsies: size of lesion, associated calcifications/mass lesion on mammogram, original diagnosis, and review diagnosis. For specimens in which the final diagnosis was carcinoma on the excisional specimen, nuclear and/or histologic grade were recorded as well, using the Van Nuys grading system for DCIS 6 and the Elston modification of the Scarff-Bloom-Richardson criteria for invasive carcinoma. 7 RESULTS Radiologic Findings The types of lesions for which biopsies were performed were classified according to the presence or absence of microcalcifications and also soft tissue masses (Table ). There were cases of clustered microcalcifications without mass, distortion, or density. There were cases of clustered microcalcifications within a soft tissue mass, case Table. Lesion Class Clustered calcifications Clustered calcifications mass/ distortion/density Mass/distortion/density Lesion Size on Mammogram Size, mm No. of Cases (N 54) of clustered microcalcifications within an area of architectural distortion, and case of clustered microcalcifications within an area of increased soft tissue density. There were cases of architectural distortion and case of increasing density. The remaining cases were soft tissue masses. The sizes of the clustered microcalcifications ranged from to 5 mm (Table ). The average size was 7 mm, and the median size was 5 mm. The soft tissue masses measured an average of mm, with a median of mm. The microcalcifications within a soft tissue mass had an average measurement of 7 mm, with a median of mm. The single case of clustered microcalcifications within an area of architectural distortion measured mm. The lone case of clustered microcalcifications within an area of increased soft tissue density measured mm. The cases of architectural distortion had an average measurement of 9 mm, and case of increasing density measured 7 mm. Review of the mammographic findings of the 7 cases that had a final diagnosis of DCIS invasion revealed no specific mammographic features in the cases diagnosed as carcinomas that could distinguish them from the nonmalignant cases. These positive cases were sampled by either -gauge ( cases) or 4-gauge (4 cases) needles. All NC cases that were reviewed as DCIS were sampled by 4- gauge needles (see Pathologic Findings ). In cases that were upgraded to DCIS, there were residual calcifications after NC biopsy, extensive enough that they were easily localized for excision. Pathologic Findings Calcifications were seen microscopically in all NC cases that were biopsied for microcalcifications, with or without mass, architectural distortion, or density. Of the cases biopsied only for calcifications, of cases had calcifications associated with the atypical foci. All cases that had a final excision diagnosis of in situ or invasive ductal carcinoma had calcifications associated with the malignant epithelium, when the initial mammogram showed abnormal calcifications. The mass lesions included 5 fibroadenomas, complex Figure. a, Needle core biopsy of breast with 4-mm area of cribriform glands, initially called atypical ductal hyperplasia, reclassified as ductal carcinoma in situ on review (hematoxylin-eosin, original magnification ). b, Excisional biopsy (same case as Figure, a) with final diagnosis of ductal carcinoma, in situ and invasive (hematoxylin-eosin, original magnification ). 5 Arch Pathol Lab Med Vol 7, January Atypical Hyperplasia on Breast Needle Core Biopsy Yeh et al

3 Figure. a, Breast needle core biopsy diagnosis of atypical ductal hyperplasia, duct with abnormality, -mm area. Note focal individual cell necrosis (N) (hematoxylin-eosin, original magnification 4). b, Excisional biopsy (same patient as Figure, a) diagnosed as in situ and invasive ductal carcinoma (hematoxylin-eosin, original magnification ). Figure. Needle core biopsy diagnosis of atypical ductal hyperplasia. Note cribriform architecture, monomorphic nuclei, and no necrosis. Single duct with abnormality ( mm). Excisional biopsy shows only usual ductal hyperplasia (hematoxylin-eosin, original magnification ). Arch Pathol Lab Med Vol 7, January Atypical Hyperplasia on Breast Needle Core Biopsy Yeh et al 5

4 NC Biopsy Diagnosis ADH (n 6) ALH (n ) LCIS (n ) ADH ALH (n ) Table. Needle Core Biopsy Diagnosis Versus Excision Diagnosis* Excision Diagnosis UDH ADH ALH LCIS 6 ADH ALH/LCIS DCIS Invasion * UDH indicates usual ductal hyperplasia; ADH, atypical ductal hyperplasia; ALH, atypical lobular hyperplasia; LCIS, lobular carcinoma in situ; and DCIS, ductal carcinoma in situ. Three of these cases were reclassified as DCIS on review of the needle core biopsy. 6 Table 4. Final Diagnosis Pathologic Size of Atypia* Size of Atypia Focus on Needle Core Biopsy mm mm mm UDH (n 5) ADH (n 6) ALH (n 4) LCIS (n 8) ADH ALH/LCIS (n 4) 6 DCIS/invasive carcinoma (n 7) 5 * UDH indicates usual ductal hyperplasia; ADH, atypical ductal hyperplasia; ALH, atypical lobular hyperplasia; LCIS, lobular carcinoma in situ; and DCIS, ductal carcinoma in situ. The size of case could not be measured. Both cases were reclassified on review as DCIS on the original needle core biopsy. sclerosing lesion, and invasive carcinoma (on final excision diagnosis), with the remaining mass lesions showing stromal fibrosis. All cases with abnormal densities showed evidence of stromal fibrosis microscopically. Among cases of architectural distortion, there was case with a radial scar, with the remainder showing stromal fibrosis. The foci of atypia were in the lesion in every case that had a distinct diagnosis other than stromal fibrosis. On pathologic review, (8.5%) of the 6 ADH NC biopsies were reclassified as DCIS. These cases each had small foci of necrosis, as well as mildly enlarged nuclei with nucleoli. Two of the cases had foci of abnormal ducts that extended over an area greater than 5 mm, with multiple foci of involvement (Figure, a). The remaining case involved only terminal-duct lobular unit, measuring less than mm in diameter. Excision of all lesions demonstrated DCIS, and excision specimen also contained invasive carcinoma (Figure, b). The needle track in the invasive carcinoma case was present at the edge of the lesion, in an area of DCIS. Final review diagnoses of the excisions (Table ) on the remaining NC ADH cases showed diagnosed as DCIS, as in situ and invasive ductal carcinoma, 6 as residual ADH, as LCIS, as ADH ALH/LCIS, and as usual ductal hyperplasia. The sizes of the lesions on NC biopsy, as compared to the final excision diagnoses, are specified in Table 4. Most of the ADH lesions had or foci of atypia, with measurements less than mm when diameters of foci were added. Two cases were mm in dimension (additive diameters), but the lesions did not involve the entire ducts in the affected areas. The cases that showed DCIS on excision each had -mm foci of abnormal ducts with features bordering on DCIS on the core biopsy. These cases had focal individual cell necrosis in the abnormal ducts. The excision specimens were very similar in appearance, but quantitative criteria were met (lesions mm in size), and ducts that showed more classical changes of nonnecrotic DCIS were evident, with foci of grade nuclei. The case containing both in situ and invasive carcinoma (histologic grade ) had mild nuclear hyperchromasia, as well as nucleoli in abnormal duct and rare individual cell necrosis on the NC biopsy (Figure, a). This lesion measured less than mm in diameter. The excision specimen demonstrated that the NC biopsy site was adjacent to, but not in, the area of carcinoma (Figure, b). Cases classified as ADH either did not fulfill criteria for DCIS or the foci were too small to be regarded as DCIS (Figure ). Of the ALH cases, excisions revealed cases of ALH, LCIS, ADH ALH/LCIS, in situ carcinoma with both ductal and lobular features, and cases demonstrating usual ductal hyperplasia. The NC cases that contained combined features of ADH and ALH showed LCIS in cases and usual ductal hyperplasia in the other, based on analysis of excision specimens. The case with combined lobular and ductal characteristics on hematoxylin-eosin staining was immunostained for E-cadherin and showed areas with partial loss of staining in the areas with lobular appearance, but retention of E-cadherin in the ductal areas. Another case, which showed possible ductal differentiation, was stained for E-cadherin and partial loss of E- cadherin was noted. This case was classified as LCIS. The NC LCIS cases showed LCIS in final excision specimens and ALH in final excision specimen. In summary, based on excisional biopsies, 7 (%) of 54 cases in our study showed either DCIS or in situ and invasive carcinoma. Three of the original NC diagnoses of ADH were reclassified on review to DCIS, leaving 4 (8%) of 5 correctly classified cases in our study as either DCIS or in situ and invasive carcinoma on the final excision. These cases were originally diagnosed as ADH (n ) and ALH (n ). Three of these cases were associated with calcifications (pure in situ lesions), and was associated with a mass lesion on mammography studies (in situ and invasive carcinoma). The average size of these 4 lesions was.8 cm (range,.5. cm). These cases were sampled with -gauge needles in cases and a 4-gauge needle in case, with an average of.8 passes (range, 7 4 passes). The mammographic findings are not significantly different from the overall group. COMMENT Diagnosis on an NC biopsy does not always correlate with the final diagnosis in breast excisions because of the inherent sampling error that occurs in partial sampling of a larger lesion. In this study, 7 (%) of 54 cases originally diagnosed as ADH, ALH, or LCIS were found to contain 5 Arch Pathol Lab Med Vol 7, January Atypical Hyperplasia on Breast Needle Core Biopsy Yeh et al

5 either DCIS or in situ and invasive ductal carcinoma on final excision. No specific distinguishing mammographic characteristics were evident in these cases. Pathologic features that were present in of these 7 cases included multiple foci of involvement in cases and focal necrosis in all cases. These cases were reclassified on review as DCIS because these features were believed to be diagnostically sufficient, using published criteria. 4,5 All cases were sampled by 4-gauge needles, the smallest needles used in this study. This finding suggests that smaller samples may be more difficult to diagnose correctly. The remaining 4 cases that had a final diagnosis of in situ or invasive ductal carcinoma had abnormal areas that were quantitatively too small to make a definitive diagnosis of DCIS, but did have foci of individual cell necrosis and nucleoli in the atypical ducts/lobules. In the cases with a final excision diagnosis of invasive carcinoma, the needle tracks were found at the edge of the lesion. Ductal carcinoma in situ is frequently seen at the edge of invasive carcinomas, and if the center of the lesion is not sampled on the NC biopsy, the diagnosis will be missed. Interobserver reproducibility is known to be a problem in the diagnosis of proliferative breast lesions. 8,9 Even when using published criteria and study sets of representative examples, there was complete agreement in only 58% of cases among 6 expert pathologists in a study by Schnitt et al. One of the guidelines provided to the pathologists in that study stated, when in doubt between atypical ductal hyperplasia and ductal carcinoma in situ, use the more benign term. This was the principle applied at our institution in the underread cases. Clinically, this principle is logical, because a diagnosis of ADH would warrant an excisional biopsy, whereas a diagnosis of DCIS could possibly trigger more extensive surgery or other therapy (radiation), even if no additional DCIS is present on the excision. A recent study of ADH in NC biopsies concluded that cases with more than 4 foci of ADH were more likely to have a more advanced lesion on excision than cases with fewerthanfociofadh. Another study suggested that the most important variables in the rate of carcinoma in excisional biopsy specimens are the initial mammographic size of the lesion and the amount of residual lesion after NC biopsy, an observation that attests to the size of the lesion as an important parameter. We agree that multiple foci of ADH did correlate with carcinoma on excision, given that our original set of ADH cases included 4 of 9 with multiple foci of ADH, and of these cases were reviewed as DCIS. However, the 4 cases that were subsequently diagnosed as carcinoma in our study all had only or foci of ADH, making up an area less than mm in maximal diameter. All 4 of these cases correlated with lesions smaller than cm on mammography. If cases of ALH and LCIS are excluded, then 6 (5%) of 9 of the ADH cases showed either in situ or invasive carcinoma on excision. Previously published data demonstrated that % to 87% of ADH cases on NC biopsy reveal a more significant lesion on excision. 7 The highest percentage reported in these past studies was from a study with a small number of ADH cases (8 cases with follow-up 6 ), and the smallest percentage (% 8 ) was reported in a study in which the pathologic analysis was performed at several hospitals, pathology was not reviewed, and ADH was not given a specific definition. Considering lobular lesions only, (7%) of 5 of our cases showed DCIS on the excision, in a case with combined characteristics of DCIS and LCIS. This incidence of DCIS is in the range of previously reported studies. 8 Ductal and lobular lesions may coexist, and features may overlap histologically. Solid DCIS involving lobules (cancerization of lobules) may be difficult to distinguish from LCIS, especially in a small NC biopsy. Recently, E-cadherin expression has been shown to be lost in lobular lesions and retained in ductal lesions, and indeterminate lesions generally lose E-cadherin expression. 9, The case in our study showed partial loss of E-cadherin in the areas that appeared to be lobular in differentiation, and retention of E- cadherin in the ductal areas. In summary, our study shows that cytologic atypia, in association with individual cell necrosis on the NC biopsy specimen, correlates with the finding of ductal carcinoma (in situ and invasive) in excision specimens. These data also underscore the continued utility of excisional biopsy to clarify and provide additional tissue for difficult diagnoses. References. 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