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What Is Atypical Lobular Hyperplasia and What Does It Mean for the Patient?

Vanderbilt University, Nashville, TN

One of the most remarkable things about invasive lobular carcinoma and its certain nonobligate precursors (atypical lobular hyperplasia[ALH] and lobular carcinoma-in-situ [LCIS])^1,2 is that, unless presenting in a higher cytologic and histologic grade, it has the clinical pattern of a slow-growing tumor,³ invariably expressing estrogen and progesterone receptors, with responsiveness to modulators of the estrogen receptor complex. Therefore, in the spectrum of precursor lesions of invasive breast cancer, where do lobular neoplasia (ALH/LCIS) and its variable presentations stand? Minimal examples (so-called minimal ALH) contain the characteristic cells without distention of the lobules⁴; we reserve the diagnosis of LCIS for characteristic changes that grossly distort lobular units.⁵

In the formal cohort follow-up studies that have been performed on these lesions since 1980, the concept of ALH has been used by the two largest studies from Vanderbilt^4-6 and Harvard.⁷ Neither of these groups diagnose LCIS often in their series of patients; when they do, a higher risk for more extensive lesions has been indicated.⁵

The study by Chuba et al⁸ in this issue presents balanced conclusions from a Surveillance, Epidemiology, and End Results (SEER) database in which the specific pathologic type of lobular neoplasia is not specified and undoubtedly includes a dominant number of patients with ALH. The overall 7.1% incidence of invasive breast cancer after a diagnosis of lobular neoplasia is lower than what others have reported, and this is probably a result of the inclusion of so-called minimal examples of ALH, which is a lesion that was not associated with increased risk of invasive breast cancer in early studies.⁴ The fact that the subsequent risk of invasive breast cancer in the SEER study is equal in the two breasts is remarkable because most of the formal studies that have looked at laterality have actually documented an incidence of invasive cancer in the contralateral breast that is less than one half of the incidence documented in the ipsilateral breast.^7,9,10 The reasons for this discrepancy are not apparent. We know that there is a risk for the contralateral breast when lobular neoplasia is diagnosed, and it is possible that removal of larger amounts of breast tissue in women who had partial mastectomy in this SEER study led to equal risk of the opposite breast. The importance of unilateral risk is documented in the experience of Rosen et al¹¹ presented in 1981. Women in that study who underwent single mastectomy experienced no deaths from cancer and had a risk in the contralateral breast that was not demonstrably greater than the general population. It is important to note that some women with demonstrated LCIS in the contralateral breast were offered bilateral mastectomy.

Also, there is an important indication that there is a regional risk associated with ALH that should be studied carefully. Anecdotal experience indicates there are anatomic areas of the breast that are more likely to be involved than others. Indeed, occasionally, a patient has quite dense disease that presents in a single location similar to ductal carcinoma-in-situ that has lobular cytology. This is another special area that needs some formal attention.¹²

Both the Nashville series and the Nurses' Health Study found that the incidence of invasive breast cancer after a diagnosis of lobular neoplasia decreased after menopause.^6,7,9 However, the SEER data show an increasing incidence after menopause; more than half of the patients at risk were greater than 50 years old, and more than a quarter of the patients were diagnosed with LCIS after the age of 60 years. As Chuba et al⁸ point out, the time frame of the study included patients who were detected later through mammography, which also will introduce ambiguity in the results. One wonders how many of the LCIS lesions diagnosed in the SEER database were truly incidental (ie, unassociated with prebiopsy detection), as was the case in the early defining studies of lobular neoplasia.

We conclude with some enduring facts and some open clinical questions. First, lobular neoplasia places both breasts at risk for subsequent invasive carcinoma that may be dominantly hormone receptor positive. Second, there is a minimal lobular neoplasia that carries little or no implication for increased risk. Third, ALH and LCIS are precursor lesions,¹ but the multiplicity and multicentricity makes the location of later disease probably dependent on density and distribution of these lesions. Fourth, dense and locally extensive disease mimics ductal carcinoma-in-situ in its distortion, distension of adjacent lobular units, and intervening ducts. Such cases may be best approached by removing the densest disease.¹² Finally, there are important associations with age and probably hormone therapy (HT), but several cohort studies have shown that ALH patients receiving estrogenic HT did not have further increased risk compared with ALH patients not receiving HT.^13,14

We need to have better understanding of the associations between the incidence of lobular neoplasia, magnitude of cancer risk, age, mammographic density, and distributions of lesions within the breast. We conclude that there are many special aspects of lobular neoplastic disease in situ and invasive in the female breast; what remains to be clarified is the practical implementation of this knowledge, particularly in the implementation of preventive strategies.

Authors' Disclosures of Potential Conflicts of Interest

The authors indicated no potential conflicts of interest.

REFERENCES

1. Lakhani SR: In-situ lobular neoplasia: Time for an awakening. Lancet 361:96, 2003[CrossRef][Medline]

2. 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 5:258-262, 2003[CrossRef][Medline]

3. Page DL, Jensen RA, Simpson JF: Routinely available indicators of prognosis in breast cancer. Breast Cancer Res Treat 51:195-208, 1998[CrossRef][Medline]

4. 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 19:201-207, 1988[CrossRef][Medline]

5. 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 22:1232-1239, 1991[CrossRef][Medline]

6. Page DL, Schuyler PA, Dupont WD, et al: Atypical lobular hyperplasia as a unilateral predictor of breast cancer risk: A retrospective cohort study. Lancet 361:125-129, 2003[CrossRef][Medline]

7. Marshall LM, Hunter DJ, Connolly JL, et al: Risk of breast cancer associated with atypical hyperplasia of lobular and ductal types. Cancer Epidemiol Biomarkers Prev 6:297-301, 1997[Abstract]

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 23:5534-5541, 2005[Abstract/Free Full Text]

9. Page DL, Dupont WD, Rogers LW, et al: Atypical hyperplastic lesions of the female breast: A long-term follow-up study. Cancer 55:2698-2708, 1985[CrossRef][Medline]

10. Rosen PP, Kosloff C, Lieberman PH, et al: Lobular carcinoma in situ of the breast: Detailed analysis of 99 patients with average follow-up of 24 years. Am J Surg Pathol 2:225-251, 1978[Medline]

11. Rosen PP, Braun DWJ, Lyngholm B, et al: Lobular carcinoma in situ of the breast: Preliminary results of treatment by ipsilateral mastectomy and contralateral breast biopsy. Cancer 47:813-819, 1981[CrossRef][Medline]

12. 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 100:238-244, 2004[CrossRef][Medline]

13. Byrne C, Connolly JL, Colditz GA, et al: Biopsy confirmed benign breast disease, postmenopausal use of exogenous female hormones, and breast carcinoma risk. Cancer 89:2046-2052, 2000[CrossRef][Medline]

14. Dupont WD, Page DL, Parl FF, et al: Estrogen replacement therapy in women with a history of proliferative breast disease. Cancer 85:1277-1283, 1999[CrossRef][Medline]

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