American Journal of Surgical Pathology:
Incidental Minimal Atypical Lobular Hyperplasia on Core Needle Biopsy: Correlation With Findings on Follow-up Excision
Subhawong, Andrea Proctor MD*; Subhawong, Ty K. MD†; Khouri, Nagi MD†; Tsangaris, Theodore MD‡; Nassar, Hind MD*
Departments of *Pathology
‡Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD
Supported by the NIH SPORE P50 CA88843.
Correspondence: Hind Nassar, MD, Department of Pathology, Weinberg Building 2242, 401 North Broadway, Baltimore, MD 21231 (e-mail: firstname.lastname@example.org).
The authors report no conflicts of interest.
Introduction: Atypical lobular hyperplasia (ALH), often an incidental finding in breast core biopsies, is largely considered to be a risk factor for carcinoma rather than a direct precursor. However, management of ALH is controversial. We review our experience with incidental minimal ALH on core biopsy, and correlate with excision and follow-up results.
Design: We evaluated all cases of ALH on core biopsy from 1999 to 2009 from our institution, focusing on cases with ≤3 foci of ALH (minimal), paired excision, and no other lesion on the core biopsy that by itself would require excision. Cases with discordant clinical/radiologic impressions, suggesting that a suspicious lesion had been missed on biopsy, were excluded. Therefore, the excisions were performed because of the diagnosis of ALH.
Results: Of 56 cases with ALH on biopsy and paired excision, 42 showed minimal ALH. On excision, 26 had residual ALH and 13 were benign. Three cases had other atypical lesions: lobular carcinoma in situ (2 cases) and mild atypical ductal hyperplasia separate from the biopsy site (1 case). On follow-up, only 1 patient developed subsequent ALH in the same breast. No other ipsilateral lesions were later diagnosed (mean follow-up 3.2 y).
Conclusions: No case with ALH on biopsy had a lesion on excision requiring further treatment, suggesting that these patients can be managed more conservatively. Furthermore, no patients were diagnosed with a higher grade lesion in the same breast on follow-up. We propose that, if there is close radiologic correlation and follow-up, minimal incidental ALH on core biopsy (≤3 foci) does not require excision.
The term “lobular neoplasia” was first used by Haagensen et al16 in 1978 to include a spectrum of noninvasive monomorphic epithelial proliferations involving the breast terminal ductal lobular unit, and encompasses the diagnoses of atypical lobular hyperplasia (ALH) and lobular carcinoma in situ (LCIS). Most frequently diagnosed in premenopausal women (aged 40 to 50 y),33 lobular neoplasia usually does not present with clinical or radiographic findings, as it is not mass-forming in most cases, and is rarely associated with nonspecific microcalcifications.3 Therefore, its diagnosis on core biopsy is usually incidental, and the true incidence is unknown.33 Lobular neoplasia has generally been considered a risk factor for invasive breast cancer rather than a direct cancer precursor.21 This predisposition largely affects the breast in which it was diagnosed, but does include a long-term bilateral risk to both sides.30 A diagnosis of ALH is estimated to increase the risk of subsequent breast cancer 4 to 5 fold compared with the normal population,28 whereas LCIS is associated with an 8 to 10-fold increase29 with a cumulative risk of invasive cancer of 7.1% at 10 years.8 Recent data have supported the concept that the LCIS could be a direct precursor of invasive lobular carcinoma in certain cases,2 but these were cases of LCIS (not ALH) with extensive involvement of the breast tissue. For these reasons, there is considerable controversy in the literature over the management of lobular neoplasia, with conflicting suggestions regarding excision after core biopsy. Many of these studies do not specifically separate ALH from LCIS diagnosed on core biopsy when making recommendations. In this study, we review our experience with minimal incidental ALH diagnosed on core biopsy over the past 10 years, and correlate with excision results and follow-up data.
MATERIALS AND METHODS
Institutional Review Board Approval
This study was approved by the Institutional Review Board of the Johns Hopkins Medical Institutions.
All core biopsies with a diagnosis of ALH and LCIS, performed and processed at our institution between 1999 and 2009, and followed by an excisional biopsy were evaluated. We did not include any breast biopsies that were performed at outside institutions and reviewed “in-house,” we excluded these cases from our database search because of difficulty in obtaining patient history, needle gauge information, information on subsequent excision, etc. We first reviewed the core biopsy and counted the number of ALH foci in each case of isolated ALH, and then paired the biopsy with results from a follow-up excision. In general, core biopsies were obtained with 14-gauge core biopsy needles when ultrasound guidance was used or with 11-gauge vacuum-assisted device (mammotome) when stereotactic guidance was used; although, in several cases 14-gauge needles were used for stereotactic sampling of microcalcifications. Tissue was processed in routine fashion with 10% neutral-buffered formalin fixation, paraffin embedding, and staining with hematoxylin/eosin. If available, E-cadherin immunolabeling [using the Benchmark XT autostainer (Ventana Medical Systems, Inc, Tucson, AZ); monoclonal antibody; 15 mL prediluted, Ventana, catalog ♯CMA582] to confirm the diagnosis of ALH was reviewed, but the majority of cases were diagnosed by morphology alone.
We used Dr David Page28,29 criteria for diagnosis of lobular neoplasia; all biopsies were reviewed by 2 authors (A.P.S. and H.N.). ALH was diagnosed when several acini of a lobular unit showed a monotonous neoplastic proliferation of discohesive cells with round nuclei and occasional small nucleoli29; often the characteristic perinuclear vacuole of “lobular morphology” was identified. By contrast, classic LCIS was diagnosed when all acini were filled and there was expansion of at least half of a lobular unit with the uniform neoplastic population29; these cases, along with cases that had necrosis or marked nuclear pleomorphism interpreted as “pleomorphic LCIS,”7 were evaluated separately. Isolated pagetoid spread along the ducts in cases of minimal ALH did not constitute an exclusion criterion.
For each case, we counted the number of foci of ALH present in the tissue cores; we defined a “focus” as involvement by one or more (up to 3) adjacent lobules by ALH, using the Page et al's criteria described above. We limited our study to those biopsies that were not associated with discordant calcifications or a suspicious mass. In addition, none of the biopsies that we included contained another lesion that by itself would require excision [such as atypical ductal hyperplasia (ADH) or intraductal papilloma]. The films and/or radiology reports for the cases were reviewed; cases in which the clinical and radiologic impressions suggested that a mass lesion had been missed on biopsy, or in which the quality of calcifications seen on mammography did not match those observed in the biopsy, were excluded. Therefore, the excisions in these cases were performed because of the foci of ALH or LCIS. Case examples are shown in Figures 1 and 2.
Equation (Uncited)Image Tools
Demographics and Case Characteristics
There were 10,024 breast core biopsies performed at our institution during this time period. Of these, 117 biopsies had a diagnosis of isolated ALH, without another finding that by itself would be an indication for excisional biopsy (such as ADH), and without discordant radiology/clinical impression. Two additional cases were excluded due to missing slides and/or history. An additional 26 cases showed LCIS (with or without ALH, and without other findings such as ADH); these cases also did not have discordant radiology/clinical impressions at biopsy.
Of the 117 ALH cases, 42 had 3 or fewer foci of ALH and a follow-up excision (35.9%), representing biopsies from 41 patients; and 14 biopsies had more than 3 foci and a corresponding follow-up excision (12.0%), representing biopsies from 13 patients. The group with 3 or fewer foci (minimal ALH) represented 75.0% of the 56 biopsies with a paired excision. These findings are shown in Figure 3. In most cases, a focus was composed of one lobular unit with ALH; in rare cases a focus was composed of up to 3 adjacent lobular units with ALH.
Cases With Minimal ALH
The patients with minimal ALH were all women with an age range of 40.6 to 85.5 years, a mean age of 54.4 years, and a median age of 52.9 years. Thirty-five of 41 patients were White and 6 were African-American. Nine patients had a family history of invasive breast cancer in a first-degree relative. Four patients had a history of prior invasive breast cancer (2 cases in the same breast and 2 in the contralateral breast). One patient had a prior history of LCIS in the same breast. Thirty-five core biopsies (83.3%) were performed for microcalcifications, with the remaining 7 (16.7%) performed for a mass or sonographic abnormality. Sixteen biopsies were obtained using 14-gauge needles, with the remaining 26 obtained with 11-gauge needles. The average number of ALH foci was 1.7, with a median of 1 focus. Twenty-two cases had 1 focus, 10 cases had 2 foci, and 10 cases had 3 foci. Additional findings in the core biopsies included nonproliferative changes (cysts, apocrine metaplasia, fibrosis, and columnar cell change), proliferative changes (sclerosing adenosis, usual ductal hyperplasia, columnar cell hyperplasia, and micropapillomas), and fibroadenomas. The most significant of these findings in each biopsy are included in Table 1.
On follow-up excision, 26 cases (61.9%) showed residual ALH and 13 cases (31.0%) were entirely non-neoplastic. Three cases (7.1%) had atypical lesions other than ALH: 2 cases showed LCIS (1 focally), and 1 case had focal mild ADH away from the biopsy site. The details of these individual cases are listed in Table 1.
Of the 41 patients in the minimal ALH group, there was a mean of 3.2 years of follow-up, with a range of 1 month to 10.6 years (median follow-up 2.8 y). Two patients died during this time period from unrelated causes. One woman developed a focus of ductal carcinoma in situ (DCIS) in the contralateral breast 1.5 years after core biopsy. Another woman had concurrent and subsequent DCIS in the contralateral breast; she was also diagnosed with ALH on core biopsy in the same breast as the original biopsy 2.3 years later, followed by an excision also revealing ALH (this patient had 2 biopsies in our minimal ALH group). None of the other women in this group were subsequently diagnosed with high-risk breast lesions in either breast, as per the records available at our institution.
Cases With More than 3 Foci of ALH on Core Biopsy
In this group, foci of ALH ranged from 4 to 11, with a mean of 7.1 foci and a median of 7 foci. On excision, 9 cases showed residual ALH, 4 cases showed LCIS, and 1 case had focal ADH in addition to ALH. No cases were entirely benign.
Cases With LCIS on Core Biopsy
Of the 26 cases with LCIS on core biopsy, 12 cases had in-house follow-up excision (46.1%). Of these cases, 8 (61.5%) had another type of lesion on excision: infiltrating carcinoma with LCIS (3 cases), DCIS with LCIS (2 cases), LCIS with ADH (1 case), and ADH (2 cases). Two cases showed residual LCIS and 2 showed isolated ALH. No cases were entirely benign. It is noteworthy that in the 3 cases of invasive carcinoma (2 infiltrating carcinomas with ductal and lobular features as well as 1 infiltrating lobular carcinoma), the invasive component was small (0.15, 0.3, and 0.8 cm), and there was a background of extensive LCIS.
Although general guidelines for the management of ADH and DCIS diagnosed on core biopsy have been established,32 there is persistent controversy regarding management of noninvasive lobular neoplasia, and especially ALH, in the literature. Part of this disagreement stems from the issue of whether lobular neoplasia is a true precursor to invasive carcinoma, or rather a predictor of increased risk. Although it does seem to share some of the molecular alterations of invasive lobular carcinoma,2,6,18 lobular neoplasia still does not confer the same degree of risk to patients as a diagnosis of DCIS.10,32
Studies have shown a significant incidence (up to 52% of cases) of upstaging ADH to DCIS or invasive carcinoma on follow-up excision.1,4,22,23,25 However, the literature is conflicting on the likelihood of finding a higher grade lesion than ALH after core biopsy. Rates of upstaging as high as 19% to 20% have recently been reported,12,20 with many authors recommending excision for any diagnosis of atypia, including ALH.1,5,12,15,24 However, other studies assert the opposite, citing very low rates of DCIS or invasive cancer on immediate surgical excision of ALH.14,19,21,26,27,31,34 Differences may be attributable to technical aspects of imaging and/or performing the biopsy, histologic interpretation,9,19 or patients at higher risk for disease because of other factors.
We note in our study that the group of 14 cases with 4 or more foci of ALH showed ALH, LCIS, or ADH on follow-up excision; these findings are similar to that of our minimal ALH group, (although there were no entirely benign cases). However, we justify the focus of our study population on minimal incidental ALH (with 3 or fewer foci) for several reasons. First, this minimal ALH group represents a tightly clustered majority of the biopsies we reviewed (75.0%), whereas the biopsies with more than 3 foci were varied and dissimilar; some of those cases had extensive ALH that could be interpreted as LCIS by some pathologists. Second, the group with more than 3 foci only had 14 biopsies from 13 patients, likely too small to draw conclusions about the risks of upgrade in these cases. Therefore, we believe that limiting our recommendations to cases with 3 or fewer foci will lead to more reproducible findings, and will hopefully allow us to avoid some of the disparities that have been seen between some other studies.
We chose to evaluate “pure” cases that were not associated with more aggressive lesions or suspicious radiologic findings to get a better estimate of the true risk of isolated ALH. Unlike the upgrade rate with LCIS in our study (with at least 41.7% showing infiltrating carcinoma or DCIS—this rate may even be artificially low because 14 women did not have follow-up excision in-house), our cases of minimal ALH did not show lesions on excision that would have required further surgery. Although the need for excision of more extensive ALH or LCIS may remain a topic of debate, we propose that follow-up surgery should not be necessary for minimal ALH, if strict criteria are used to separate out these lesions. Along these lines, Ely et al13 have shown that examples of minimal ADH diagnosed on core biopsy may not require follow-up surgery.
Our findings are in keeping with those of Nagi et al27 and Hwang et al,19 who similarly suggest that of utmost importance is the radiographic and clinical impression of the lesion. If there is discordance with the biopsy findings, an excision is still warranted. Furthermore, these patients will continue to require close follow-up, as ALH carries a bilateral increased risk of invasive disease (4 to 5 times the general population),11,17,28 approximately 3 times more likely to arise in the ipsilateral than contralateral breast.30
It should be noted that all of our cases had biopsies with either 11 or 14-gauge needles under stereotactic or ultrasound guidance, and our findings may not be able to be extrapolated to populations of patients who have core needle biopsies using other devices or needle sizes. Additional limitations include the relatively small number of biopsies with minimal ALH and paired excisions as well as short-term follow-up in some cases; with a larger sample size, it is possible that rare higher risk lesions might be detected. The retrospective nature of the review also introduced an inherent bias due to our knowledge of patients' clinical courses over the decade; this may have influenced our exclusion of some cases in which the initial biopsy clearly missed the lesion. However, the uniformity of our study population, gained by the opportunity to evaluate both the biopsies and the excisions in the proper clinical and radiographic context, strengthens our findings. Indeed, the available follow-up on these patients validates our risk stratification by biopsy when minimal ALH is present; in fact only 3 woman were diagnosed with lesions more significant than ALH at the immediate excision (none of which would require more surgery), with only one additional patient diagnosed with subsequent disease in the same breast during our study period. This might be another indication that a more serious lesion was not missed in these cases.
In conclusion, none of our minimal ALH cases had a lesion on excision that would have required further treatment, suggesting that these patients could have been managed more conservatively. We propose that minimal incidental ALH (limited to 3 or fewer foci) on core biopsy, with close radiologic correlation, clinical observation, and follow-up, does not require excision.
The authors thank Dr Pedram Argani and Dr Ralph Hruban for critically reviewing this manuscript.
1. Arpino G, Allred DC, Mohsin SK, et al. Lobular neoplasia on core-needle biopsy—clinical significance. Cancer. 2004;101:242–250.
2. Aulmann S, Penzel R, Longerich T, et al. Clonality of lobular carcinoma in situ (LCIS) and metachronous invasive breast cancer. Breast Cancer Res Treat. 2008;107:331–335.
3. Beute BJ, Kalisher L, Hutter RV. Lobular carcinoma in situ of the breast: clinical, pathologic, and mammographic features. AJR Am J Roentgenol. 1991;157:257–265.
4. Brown TA, Wall JW, Christensen ED, et al. Atypical hyperplasia in the era of stereotactic core needle biopsy. J Surg Oncol. 1998;67:168–173.
5. Cangiarella J, Guth A, Axelrod D, et al. Is surgical excision necessary for the management of atypical lobular hyperplasia and lobular carcinoma in situ diagnosed on core needle biopsy? A report of 38 cases and review of the literature. Arch Pathol Lab Med. 2008;132:979–983.
6. Cao D, Polyak K, Halushka MK, et al. Serial analysis of gene expression of lobular carcinoma in situ identifies down regulation of claudin 4 and overexpression of matrix metalloproteinase 9. Breast Cancer Res. 2008;10:R91.
7. Chen Y, Hwang ES, Roy R, et al. Genetic and phenotypic characteristics of pleomorphic lobular carcinoma in situ of the breast. Am J Surg Pathol. 2009;33:1683–1694.
8. Chuba PJ, Hamre MR, Yap J, et al. Bilateral risk for subsequent breast cancer after lobular carcinoma-in-situ: analysis of surveillance, epidemiology, and end results data. J Clin Oncol. 2005;23:5534–5541.
9. Cohen MA. Cancer upgrades at excisional biopsy after diagnosis of atypical lobular hyperplasia or lobular carcinoma in situ at core-needle biopsy: some reasons why. Radiology. 2004;231:617–621.
10. Collins LC, Tamimi RM, Baer HJ, et al. Outcome of patients with ductal carcinoma in situ untreated after diagnostic biopsy: results from the Nurses' Health Study. Cancer. 2005;103:1778–1784.
11. Dupont WD, Page DL. Risk factors for breast cancer in women with proliferative breast disease. N Engl J Med. 1985;312:146–151.
12. Elsheikh TM, Silverman JF. Follow-up surgical excision is indicated when breast core needle biopsies show atypical lobular hyperplasia or lobular carcinoma in situ: a correlative study of 33 patients with review of the literature. Am J Surg Pathol. 2005;29:534–543.
13. Ely KA, Carter BA, Jensen RA, et al. Core biopsy of the breast with atypical ductal hyperplasia: a probabilistic approach to reporting. Am J Surg Pathol. 2001;25:1017–1021.
14. Esserman LE, Lamea L, Tanev S, et al. Should the extent of lobular neoplasia on core biopsy influence the decision for excision? Breast J. 2007;13:55–61.
15. Foster MC, Helvie MA, Gregory NE, et al. Lobular carcinoma in situ or atypical lobular hyperplasia at core-needle biopsy: is excisional biopsy necessary? Radiology. 2004;231:813–819.
16. Haagensen CD, Lane N, Lattes R, et al. Lobular neoplasia (so-called lobular carcinoma in situ) of the breast. Cancer. 1978;42:737–769.
17. Hartmann LC, Sellers TA, Frost MH, et al. Benign breast disease and the risk of breast cancer. N Engl J Med. 2005;353:229–237.
18. Hwang ES, Nyante SJ, Yi Chen Y, et al. Clonality of lobular carcinoma in situ and synchronous invasive lobular carcinoma. Cancer. 2004;100:2562–2572.
19. Hwang H, Barke LD, Mendelson EB, et al. Atypical lobular hyperplasia and classic lobular carcinoma in situ in core biopsy specimens: routine excision is not necessary. Mod Pathol. 2008;21:1208–1216.
20. Karabakhtsian RG, Johnson R, Sumkin J, et al. The clinical significance of lobular neoplasia on breast core biopsy. Am J Surg Pathol. 2007;31:717–723.
21. Lavoué V, Graesslin O, Classe JM, et al. Management of lobular neoplasia diagnosed by core needle biopsy: study of 52 biopsies with follow-up surgical excision. Breast. 2007;16:533–539.
22. Liberman L. Clinical management issues in percutaneous core breast biopsy. Radiol Clin North Am. 2000;38:791–807.
23. Liberman L, Cohen MA, Dershaw DD, et al. Atypical ductal hyperplasia diagnosed at stereotaxic core biopsy of breast lesions: an indication for surgical biopsy. AJR Am J Roentgenol. 1995;164:1111–1113.
24. Londero V, Zuiani C, Linda A, et al. Lobular neoplasia: core needle breast biopsy underestimation of malignancy in relation to radiologic and pathologic features. Breast. 2008;17:623–630.
25. Moore MM, Hargett CW, Hanks JB, et al. Association of breast cancer with the finding of atypical ductal hyperplasia at core breast biopsy. Ann Surg. 1997;225:726–731; discussion 731–733.
26. Mulheron B, Gray RJ, Pockaj BA, et al. Is excisional biopsy indicated for patients with lobular neoplasia diagnosed on percutaneous core needle biopsy of the breast? Am J Surg. 2009;198:792–797.
27. Nagi CS, O'Donnell JE, Tismenetsky M, et al. Lobular neoplasia on core needle biopsy does not require excision. Cancer. 2008;112:2152–2158.
28. Page DL, Dupont WD, Rogers LW, et al. Atypical hyperplastic lesions of the female breast. A long-term follow-up study. Cancer. 1985;55:2698–2708.
29. Page DL, Kidd TE, Dupont WD, et al. Lobular neoplasia of the breast: higher risk for subsequent invasive cancer predicted by more extensive disease. Hum Pathol. 1991;22:1232–1239.
30. Page DL, Schuyler PA, Dupont WD, et al. Atypical lobular hyperplasia as a unilateral predictor of breast cancer risk: a retrospective cohort study. Lancet. 2003;361:125–129.
31. Renshaw AA, Derhagopian RP, Martinez P, et al. Lobular neoplasia in breast core needle biopsy specimens is associated with a low risk of ductal carcinoma in situ or invasive carcinoma on subsequent excision. Am J Clin Pathol. 2006;126:310–313.
32. Simpson JF. Update on atypical epithelial hyperplasia and ductal carcinoma in situ. Pathology. 2009;41:36–39.
33. Simpson PT, Gale T, Fulford LG, et al. The diagnosis and management of pre-invasive breast disease: pathology of atypical lobular hyperplasia and lobular carcinoma in situ. Breast Cancer Res. 2003;5:258–262.
34. Sohn VY, Arthurs ZM, Kim FS, et al. Lobular neoplasia: is surgical excision warranted? Am Surg. 2008;74:172–177.
atypical lobular hyperplasia; core biopsy; excision
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