Atypical lobular hyperplasia (ALH) and lobular carcinoma in situ (LCIS) represent a spectrum of breast disease referred to as "lobular neoplasia" (LN). Although LN occurs relatively infrequently, it is associated with an increased risk of breast cancer, ranging from a three- to four-fold increased risk with ALH up to an eight- to ten-fold increased risk with LCIS. Initially regarded as a direct precursor to invasive lobular carcinoma, LCIS used to be treated by mastectomy. Subsequent studies demonstrating that the risk of invasive disease was conferred bilaterally and that subsequent cancers were of both the ductal and lobular phenotype led to the acceptance of LCIS as a marker of increased risk rather than a true precursor. Today, a diagnosis of LCIS remains one of the greatest identifiable risk factors for the subsequent development of breast cancer. As such, patients are offered one of three options: (1) lifelong surveillance with the goal of detecting subsequent malignancy at an early stage; (2) chemoprevention; or (3) bilateral prophylactic mastectomy. Paralleling changes in the management of invasive breast cancer, trends in the management of LCIS have moved toward more conservative management. However, we have made little progress in understanding the biology of LCIS and therefore remain unable to truly optimize recommendations for individual patients.
The Management of LCIS on Core Biopsy
While routine surgical excision following a core biopsy diagnosis of LCIS is employed by many clinicians, a review of the reported rates of upstaging to malignancy demonstrates a wide range of findings, making it difficult to define the true rate of cancer at excision (Table).[18-35] These series also demonstrate that not all patients with LCIS on core biopsy go on to excision, raising the possibility of an inherent selection bias for excision in certain cases, such as those with radiographic-pathologic discordance, thereby increasing the likelihood of finding an associated malignancy. In a pooled analysis of studies published from 1999 to 2008, Hussain et al identified 1229 reported cases of LN on core biopsy, of which only 789 (64%) underwent surgical excision. Among those who proceeded to excision, 241 cases (31%) were further classified as LCIS. Following surgical excision, 32% of LCIS cases were upstaged to either ductal carcinoma in situ (DCIS) or invasive cancer, compared with 19% and 29% of cases defined as either ALH (280 cases) and/or unspecified LN (246 cases), respectively. Information about outcomes for patients not undergoing excision are rarely reported; however, for women who are not found to have an associated malignancy at immediate surgical excision yet go on to develop breast cancer during surveillance, there is often little relation between the site of the original core biopsy and the subsequent cancer diagnosis.
At Memorial Sloan-Kettering Cancer Center (MSKCC), the breast surgical service adopted the practice of routine surgical excision for a core biopsy diagnosis of LN in early 2004. A recent retrospective review of pathology reports by Luedtke et al from June 2004 to May 2009 identified 80 patients (82 core biopsies) with LN as the only indication for surgical excision following core biopsy. A single radiologist reviewed the pre-biopsy imaging studies for radiographic-pathologic correlation and excluded 11 patients, leaving 69 patients with 71 core biopsies for analysis. Among these, 29 (41%) were ALH and 42 (59%) were LCIS. Overall, 2 of 71 cases (3%) were upstaged to cancer after surgical excision: 1 patient was found to have a 2-mm focus of low-grade DCIS and the other a 2.3-mm tubular cancer. Both cases occurred in the ALH subgroup. While the retrospective nature of this report remains a limitation, and while it is possible that there were additional patients with LN who did not undergo surgical excision during this time period, the adoption of a standard policy makes it unlikely that a large number of cases were missed. In contrast to other series, these data—by eliminating cases with synchronous lesions, such as atypia requiring excision, as well as those with radiographic—pathologic discordance—suggest that the likelihood of upstaging to cancer following a core biopsy diagnosis of LCIS is actually quite low and that routine excision may not be warranted. Although we have not yet changed our practice and continue to recommend surgical excision following a core biopsy diagnosis of LCIS, efforts to document the rate of upstaging in a prospective manner are underway.
Subsequent Cancer Risk
A diagnosis of LCIS is one of the greatest identifiable risk factors for the subsequent development of breast cancer. Compared to the general population, women with LCIS have an eight-fold to ten-fold increased risk of breast cancer. In the series with the longest follow-up, the probability of developing carcinoma in situ or invasive cancer was 13% in the first 10 years after diagnosis, 26% after 20 years, and 35% by 35 years, or roughly 1% per year. When counseling women about their risk, it is important to stress that the risk remains steady over their lifetime, and that the absolute risk of breast cancer for a given individual is therefore impacted by her age at LCIS diagnosis. Still, most women with LCIS will not develop breast cancer.
Parallel to the increasing incidence of LCIS, recent studies have also reported that the incidence of invasive lobular carcinoma increased from the late 1980s to the mid-1990s among women 50 years of age and older. Recent studies have also highlighted the high proportion of infiltrating lobular carcinomas that occur following a diagnosis of LCIS. These observations, combined with emerging laboratory evidence, have generated renewed interest in the biology of LCIS and have reopened the debate over its clinical significance as a "risk factor or precursor lesion." The presence of shared molecular alterations in LCIS and co-existing invasive lobular carcinoma[41-43] have led some investigators to suggest that LN is a nonobligate precursor of low-grade invasive breast cancer. Increasingly, these observations are resulting in confusion regarding the proper management of LCIS, highlighting the need for an improved understanding of the risk imparted by this lesion.
Surveillance is the minimum necessary action for women in whom LCIS is diagnosed. Recommendations from the NCCN Breast Cancer Screening and Diagnosis Clinical Practice Guidelines include annual mammography and clinical breast exam every 6 to 12 months. Although the lifetime risk for an individual woman with LCIS may exceed 20% (depending on age at diagnosis), the American Cancer Society guidelines for MRI screening do not support routine use of MRI in this setting, stating that there is not enough evidence to recommend for or against MRI screening in women at increased risk from LCIS. The increased sensitivity of MRI in women at high risk because of an inherited predisposition or strong family history of breast cancer may be related to the biology of the particular breast cancers that develop in those settings, whereas it is unknown whether MRI screening significantly increases the cancer identification rate in women at increased risk because of LCIS.
Port et al performed a retrospective review of women with atypia and/or LCIS who participated in the MSKCC high-risk screening program from 1999 to 2005. A total of 378 women, including 126 with atypical hyperplasia (either ductal or lobular) and 252 women with LCIS were identified. All patients were offered yearly mammography and twice-yearly clinical breast examination, and during the study period, MRI screening was performed in 182 patients (48%) at the discretion of the physician and patient. Patients who had MRI screening were younger (P < .001) and more likely to have one or more first-degree relatives with breast cancer (P = .02). While the frequency of MRI screening varied, a total of 478 screening MRIs were performed, and 55 biopsies were recommended in 46 of the 182 patients (25%) during the study period; 46 of the 55 biopsies (84%) were recommended based on MRI findings alone. Cancer was detected in 6 out of 46 MRI-generated biopsies (13%), which represented 5 out of 182 patients (3%) and 5 out of 478 MRIs (1% of all MRIs performed). All 6 cancers were mammographically occult and were detected in patients with LCIS; thus, cancer was detected in 5 out of 135 patients with LCIS who underwent MRI screening (4%). Among those who did not have MRI screening, 22 biopsies were performed in 21 of 196 patients (11%), and cancer was found in 8 of 22 biopsies (36%) in 7 patients, 5 of whom had LCIS. The overall cancer detection rate in patients with LCIS who did not undergo MRI screening (5/117, [4%]) was equal to that in patients who had MRI screening, with only a trend toward earlier diagnosis in those screened with MRI.
More recently, King et al presented updated results from the MSKCC high-risk surveillance program, which now includes more than 900 women with a diagnosis of LCIS. Limiting the analysis to the 646 patients diagnosed with LCIS after 1999 when MRI screening became available at our institution, we identified 339 women (52%) who were participating in MRI screening. Similar to the earlier findings, women having MRI were younger (P < .0001), more likely to have at least one first-degree relative with breast cancer (P = .005), and more likely to undergo at least one biopsy during surveillance (P < .001). There was no difference between the two groups in Breast Imaging Reporting and Data System breast density or in the presence of concurrent atypia. At a median follow-up of 41.5 months (range, 0 to 139 months), 95 screen-detected cancers have been diagnosed in 89 of 646 patients (13.7%). The crude cancer detection rate remained similar between the two groups: 54 out of 339 (16%) in the MRI group vs 41 out of 307 (13%) in the no-MRI group. However, in this data set with a larger number of cancers detected, there was not a trend toward smaller tumor size or earlier stage at diagnosis with MRI screening. Further analysis of this data set to explore the relationship between patient age and length of follow-up are underway; however, at this time, the use of MRI screening in patients with LCIS remains controversial.
1. 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;23:5534-41.
2. Haagensen CD, Lane N, Lattes R Bodian C. Lobular neoplasia (so-called lobular carcinoma in situ) of the breast. Cancer. 1978;42:737-69.
3. Page DL, Dupont WD Rogers LW. Ductal involvement by cells of atypical lobular hyperplasia in the breast: a long-term follow-up study of cancer risk. Hum Pathol. 1988;19:201-7.
4. Foote FW Stewart FW. Lobular carcinoma in situ: A rare form of mammary cancer. Am J Pathol. 1941;17:491-96 3.
5. Anderson BO, Calhoun KE Rosen EL. Evolving concepts in the management of LN. J Natl Compr Canc Netw. 2006;4:511-22.
6. Li CI, Anderson BO, Daling JR Moe RE. Changing incidence of lobular carcinoma in situ of the breast. Breast Cancer Res Treat. 2002;75:259-68.
7. Haagensen CD. Diseases of the breast. 3rd edition. Philadelphia: WB Saunders; 1986.
8. Page DL, Kidd TE, Jr., Dupont WD, et al. Lobular neoplasia of the breast: higher risk for subsequent invasive cancer predicted by more extensive disease. Hum Pathol. 1991;22:1232-9.
9. Hussain M Cunnick GH. Management of lobular carcinoma in-situ and atypical lobular hyperplasia of the breast—a review. Eur J Surg Oncol. 2011;37:279-89.
10. Li CI, Malone KE, Saltzman BS Daling JR. Risk of invasive breast carcinoma among women diagnosed with ductal carcinoma in situ and lobular carcinoma in situ, 1988-2001. Cancer. 2006;106:2104-12.
11. Liberman L, Holland AE, Marjan D, et al. Underestimation of atypical ductal hyperplasia at MRI-guided 9-gauge vacuum-assisted breast biopsy. Am J Roentgenol. 2007;188:684-90.
12. Page DL Anderson TJ. Diagnostic histopathology of the breast. Edinburgh: Churchill Livingstone; 1987.
13. Goldschmidt RA Victor TA. Lobular carcinoma in situ of the breast. Semin Surg Oncol. 1996;12:314-20.
14. Abner AL, Connolly JL, Recht A, et al. The relation between the presence and extent of lobular carcinoma in situ and the risk of local recurrence for patients with infiltrating carcinoma of the breast treated with conservative surgery and radiation therapy. Cancer. 2000;88:1072-7.
15. Ciocca RM, Li T, Freedman GM Morrow M. Presence of lobular carcinoma in situ does not increase local recurrence in patients treated with breast-conserving therapy. Ann Surg Oncol. 2008;15:2263-71.
16. Moran M Haffty BG. Lobular carcinoma in situ as a component of breast cancer: the long-term outcome in patients treated with breast-conservation therapy. Int J Radiat Oncol Biol Phys. 1998;40:353-8.
17. National Comprehensive Cancer Network. http://www.nccn.org. Accessed July 27, 2011.
18. Berg WA, Mrose HE, Ioffe OB. Atypical lobular hyperplasia or lobular carcinoma in situ at core-needle breast biopsy. Radiology. 2001;218:503-9.
19. Brem RF, Lechner MC, Jackman RJ, et al. Lobular neoplasia at percutaneous breast biopsy: variables associated with carcinoma at surgical excision. Am J Roentgenol. 2008;190:637-41.
20. 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;132:979-83.
21. Crisi GM, Mandavilli S, Cronin E Ricci A, Jr. Invasive mammary carcinoma after immediate and short-term follow-up for LN on core biopsy. Am J Surg Pathol. 2003;27:325-33.
22. 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;29:534-43.
23. 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;231:813-9.
24. Lechner MC, Jackman RJ, Brem RF, et al. Lobular carcinoma in situ and atypical lobular hyperplasia at percutaneous biopsy with surgical correlation: a multi-institutional study. Radiology. 1999;213:106.
25. Liberman L, Drotman M, Morris EA, et al. Imaging-histologic discordance at percutaneous breast biopsy. Cancer. 2000;89:2538-46.
26. 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;17:623-30.
27. Mahoney MC, Robinson-Smith TM Shaughnessy EA. Lobular neoplasia at 11-gauge vacuum-assisted stereotactic biopsy: correlation with surgical excisional biopsy and mammographic follow-up. Am J Roentgenol. 2006;187:949-54.
28. Margenthaler JA, Duke D, Monsees BS, et al. Correlation between core biopsy and excisional biopsy in breast high-risk lesions. Am J Surg. 2006;192:534-7.
29. Meloni GB, Becchere MP, Soro D, et al. Percutaneous vacuum-assisted core breast biopsy with upright stereotactic equipment. Indications, limitations and results. Acta Radiol. 2002;43:575-8.
30. O’Driscoll D, Britton P, Bobrow L, et al. Lobular carcinoma in situ on core biopsy-what is the clinical significance? Clin Radiol. 2001;56:216-20.
31. Pacelli A, Rhodes DJ Amrami KK. Outcome of atypical lobular hyperplasia and lobular carcinoma in situ diagnosed by core needle biopsy: clinical and surgical follow-up of 30 cases. Am J Clin Pathol. 2001;116:591–92.
32. Philpotts LE, Shaheen NA, Jain KS, et al. Uncommon high-risk lesions of the breast diagnosed at stereotactic core-needle biopsy: clinical importance. Radiology. 2000;216:831-7.
33. Renshaw AA, Cartagena N, Derhagopian RP Gould EW. Lobular neoplasia in breast core needle biopsy specimens is not associated with an increased risk of ductal carcinoma in situ or invasive carcinoma. Am J Clin Pathol. 2002;117:797-9.
34. Shin SJ Rosen PP. Excisional biopsy should be performed if lobular carcinoma in situ is seen on needle core biopsy. Arch Pathol Lab Med. 2002;126:697-701.
35. Zhang RR, O’Hea BJ, Brebbia JR, et al. Atypical lobular hyperplasia or lobular carcinoma in situ on large core needle biopsy of the breast: is surgical excision necessary? Am J Clin Pathol. 2001;116:610.
36. Luedtke C, Murray M, Nehhozina T, et al, editors. Outcomes of prospective excision for classic LCIS and ALH on percutaneous breast core biopsy. Abstract No. 209. United States and Canadian Academy of Pathology Annual Meeting; 2011.
37. Translational Breast Cancer Research Consortium. TBCRC 020: The incidence of adjacent synchronous ipsilateral infiltrating carcinoma and/or DCIS in patients diagnosed with lobular neoplasia of the breast by core needle biopsy. http://pub.emmes.com/study/bcrc/ Accessed July 28, 2011.
38. Bodian CA, Perzin KH Lattes R. Lobular neoplasia. Long term risk of breast cancer and relation to other factors. Cancer. 1996;78:1024-34.
39. Li CI, Anderson BO, Porter P, et al. Changing incidence rate of invasive lobular breast carcinoma among older women. Cancer. 2000;88:2561-9.
40. Fisher ER, Land SR, Fisher B, et al. Pathologic findings from the National Surgical Adjuvant Breast and Bowel Project: twelve-year observations concerning lobular carcinoma in situ. Cancer. 2004;100:238-44.
41. De Leeuw WJ, Berx G, Vos CB, et al. Simultaneous loss of E-cadherin and catenins in invasive lobular breast cancer and lobular carcinoma in situ. J Pathol. 1997;183:404-11.
42. Hwang ES, Nyante SJ, Yi Chen Y, et al. Clonality of lobular carcinoma in situ and synchronous invasive lobular carcinoma. Cancer. 2004;100:2562-72.
43. Lakhani SR, Collins N, Sloane JP Stratton MR. Loss of heterozygosity in lobular carcinoma in situ of the breast. Clin Mol Pathol. 1995;48:M74-8.
44. Simpson PT, Reis-Filho JS, Gale T Lakhani SR. Molecular evolution of breast cancer. J Pathol. 2005;205:248-54.
45. Bevers TB, Anderson BO, Bonaccio E, et al. Breast cancer screening and diagnosis. J Natl Compr Canc Netw. 2006;4:480-508.
46. Saslow D, Boetes C, Burke W, et al. American Cancer Society guidelines for breast screening with MRI as an adjunct to mammography. CA Cancer J Clin. 2007;57:75-89.
47. Port ER, Park A, Borgen PI, et al. Results of MRI screening for breast cancer in high-risk patients with LCIS and atypical hyperplasia. Ann Surg Oncol. 2007;14:1051-7.
48. Oskar S, Muhsen S, Sung J, et al. Chemoprevention among women with lobular carcinoma in situ. Ann Surg Oncol. 2011;18:S59.
49. Fisher B, Costantino JP, Wickerham DL, et al. Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer Inst. 1998;90:
50. Gail MH, Brinton LA, Byar DP, et al. Projecting individualized probabilities of developing breast cancer for white females who are being examined annually. J Natl Cancer Inst. 1989;81:1879-86.
51. Cummings SR, Eckert S, Krueger KA, et al. The effect of raloxifene on risk of breast cancer in postmenopausal women: results from the MORE randomized trial. Multiple Outcomes of Raloxifene Evaluation. JAMA. 1999;281:2189-97.
52. Vogel VG, Costantino JP, Wickerham DL, et al. Effects of tamoxifen vs raloxifene on the risk of developing invasive breast cancer and other disease outcomes: the NSABP Study of Tamoxifen and Raloxifene (STAR) P-2 trial. JAMA. 2006;295:2727-41.
53. Visvanathan K, Chlebowski RT, Hurley P, et al. American society of clinical oncology clinical practice guideline update on the use of pharmacologic interventions including tamoxifen, raloxifene, and aromatase inhibition for breast cancer risk reduction. J Clin Oncol. 2009;27:3235-58.
54. Port ER, Montgomery LL, Heerdt AS Borgen PI. Patient reluctance toward tamoxifen use for breast cancer primary prevention. Ann Surg Oncol. 2001;8:580-5.
55. Tchou J, Hou N, Rademaker A, et al. Acceptance of tamoxifen chemoprevention by physicians and women at risk. Cancer. 2004;100:1800-6.
56. Hartmann LC, Schaid DJ, Woods JE, et al. Efficacy of bilateral prophylactic mastectomy in women with a family history of breast cancer. N Engl J Med. 1999;340:77-84.