Negative immunoreactivity for E-cadherin in the constituent neoplastic cells supported lobular differentiation in all the 4 cases of florid LCIS and in the 1 case of pleomorphic variants. E-cadherin was negative in the 4 additional cases in which the differential diagnosis included solid type of intraductal carcinoma. Three cases had synchronous DCIS of solid, cribriform, or micropapillary types; however, the DCIS lesion was not in the immediate vicinity of MILC in any case (DCIS did not appear in the same histologic slide as MILC in all 3 cases). Six cases showed calcifications within the LCIS, including 5 of the classical type and 1 of the pleomorphic type. One case showed calcifications only in inactive ducts.
Each of 6 MILC cases, in which results could be obtained, was found to be positive for ER and PR (Fig. 1F). MILC was no longer present in the subsequently prepared ER-stained and PR-stained sections in 5 additional cases. HER2/neu was not overexpressed in each of 5 cases in which results could be obtained (MILC was not present in HER2/neu-stained sections of 5 cases), and 1 case showed equivocal 2+ (on a scale of 0 to 3+) immunostaining—with no fluorescence in situ hybridization confirmation.
The final surgical procedure was excisional biopsy in 8 cases, ipsilateral mastectomy in 6 cases, and bilateral mastectomies in 2 cases. Four cases showed additional significant disease in a different region of the ipsilateral breast: 1 case showed MIDC associated with DCIS, 2 cases showed DCIS, and 1 case showed atypical duct hyperplasia. One case showed invasive ductal carcinoma (9 mm) associated with DCIS in the contralateral breast. Eight of 16 cases had residual LCIS or atypical lobular hyperplasia (ALH) in a subsequent specimen. No lymphovascular involvement by tumor cells was evident in any case of MILC.
Nine of 16 cases had a sentinel lymph node biopsy procedure, and 4 of 16 cases had axillary lymph node dissection, with negative results obtained in all 13 cases. All patients remained alive without evidence of recurrence and/or metastases in a mean follow-up of 24 months (range, 1 to 72 mo).
Five cases had tissue sampled from the contralateral breast (2 excisional biopsies, 2 mastectomies, and 1 reduction mammoplasty), with significant diseases in 3 cases (including 1 case each of ALH, LCIS, and invasive and in situ ductal carcinoma).
At a practical level, LCIS can be divided into 3 main types: classical, florid (ie, necrotic type with massive distension of the acini, as per World Health Organization classification), and pleomorphic.26 The cells of the classical type of LCIS are uniformly small, noncohesive, bear round nuclei and inconspicuous nucleoli, and may contain intracytoplasmic mucoid globules (lending a signet ring cell appearance).20 The appellation florid is applied to LCIS when the noninvasive neoplastic process diffusely involves numerous lobules, considerably distends and distorts the individual lobules, and exhibits central necrosis.1 Pleomorphic LCIS shares the architectural features of florid LCIS; however, in terms of cytology, the cells are larger and variable (ie, pleomorphic).4 All types of LCIS can be associated with invasive carcinoma, either of the ductal or of the lobular type. In this series, 11 cases of microinvasive carcinoma showed classical lobular type of architectural and cytologic features and in 5 others, in which such features were nonclassical, absence of E-cadherin immunostaining supported lobular differentiation. Currently, pleomorphic and florid LCIS are regarded as more aggressive forms of LCIS,1,4 and as such more attention ought to be paid to the perilesional stroma in these variants to detect early invasive carcinoma.
The classical type of invasive lobular carcinoma is characterized by a linear (so-called “Indian filing”) or circumferential arrangement around lobules and ducts (in a “targetoid” or “bulls-eye” manner). The reported frequency of finding LCIS in association with the classical type of invasive lobular carcinoma varies widely from 65% to 98%.7,17 The pleomorphic type of invasive lobular carcinoma is its most distinctive (and potentially aggressive) variant.21 The architectural pattern of invasive pleomorphic lobular carcinoma is similar to that of the classical type; however, the cytologic appearance of this variant lives up to its name—the individual tumor cells are larger with variable nuclei.
The histologic and cytologic features of most forms of lobular and ductal carcinoma (in situ and invasive) are different enough to enable distinction between these. However, immunohistochemistry can be helpful for this purpose in equivocal cases. With rare exceptions in which it is a manifestation of nonfunctional cadherin-catenin complex, cytoplasmic membrane immunoreactivity of in situ carcinoma cells for E-cadherin supports the diagnosis of ductal differentiation.6 p120 (intracytoplasmic reactivity) and 34 βE12 (also intracytoplasmic reactivity) can be used to further support lobular differentiation.3,5
Mammary ducts and lobules afflicted by high-grade intraductal carcinoma are usually surrounded by a cuff of myxoid-appearing specialized connective tissue. It has been suggested that the presence of invasive carcinoma into the aforementioned cuff does not constitute true invasion, and that only invasive carcinoma into nonspecialized interlobular or interductal fibrous or adipose tissue ought to be considered as truly invasive.12 This suggestion may be of value in cases of intraductal carcinoma involving radial scars or sclerosing papillary lesions in which there may be considerable stromal activation and sclerosing entrapment of neoplastic cells. However, it may not apply to MILC cases in which such a cuff is generally not in evidence.
Minute foci of invasive carcinoma may be difficult to detect on histologic sections stained with routine H&E stain. The detection of such obscure invasive foci may be facilitated by paying attention to changes in the stroma immediately in the vicinity of LCIS—because such invasive foci are usually present close to a focus of LCIS in lobules or its extension into ducts. In some cases of LCIS, there are subtle irregularities in the borders of the afflicted glands, which in combination with perilesional enhanced cellularity lend an appearance that is suspicious of microinvasion. This increased cellularity is due to the presence of either lymphocytes, plasma cells, histiocytes, or epithelioid myofibroblasts. CK immunostains (including those for CK AE1/3 and CK 7) can highlight any occult invasive carcinoma. Minimal trimming of the tissue block should be ensured to avoid losing diagnostic tissue. Neither granulomatous inflammation nor lymphovascular involvement is typically associated with invasive lobular carcinoma (and these findings were absent in all MILC cases in this series).
The use of imunohistochemical stains in diagnostic breast pathology has become ubiquitous. Unfortunately, it is rare that a contemporaneous H&E-stained section is obtained at the time of requesting immunostains. Hoda and Rosen10 reported the case of a 63-year-old woman (not included in this series) who underwent an excisional biopsy for a palpable breast mass. The original H&E-stained sections had shown in situ carcinoma, which could either have been of the ductal or lobular type. Recut slides prepared for immunostains showed in situ carcinoma, and a focus of microinvasive carcinoma was negative for E-cadherin; a result supportive of LCIS and MILC. No contemporaneous H&E-stained section was available, and a diagnosis of MILC was made solely on the basis of the E-cadherin-immunostained slide.
We have encountered additional cases in which sections obtained for assessing hormonal receptor stains on in situ carcinoma have shown microinvasive carcinoma. Conversely, immunostains for biomarkers on microinvasive carcinoma have occasionally shown either no residual microinvasive carcinoma or invasive carcinoma larger than 1 mm.
In our opinion, barring artifactual dislodgement thereof, the presence of neoplastic epithelial cells (beyond the limits of myoepithelial cells and basement membrane) constitutes evidence of invasive carcinoma. Needling procedures of the breast (including needle core biopsies and fine needle aspirations) can disrupt, and dislodge, breast tissue. Such dislodged cells usually take the form of single cells or minute cell clusters, or minuscule glands that lie along the tract of biopsy.30 These cells, which are almost invariably derived from the targeted hyperplastic or neoplastic lesions, cytologically (if not architecturally) resemble the parent lesion. We have not encountered such dislodgement in the setting of classical type of LCIS; however, it may potentially be observed in the setting of either florid or pleomorphic types of LCIS (ie, more cellular types of LCIS). These displaced cells of LCIS can be distinguished from MILC by virtue of their distribution exclusively along the healing biopsy tract. Immunostains for myoepithelial cells are of limited help, but study of at least 3 deeper sections taken from the corresponding block could be helpful in this regard.
No metastasis in any lymph node was identified in any of the 16 MILC cases in this series. The reported incidence of axillary metastases in MIDC has ranged from 0% to 28%,11 and in a review of the literature of axillary lymph node involvement in MIDC by Guth et al,9 the cumulative total extent of nodal involvement was 6% (43 of 709 cases in which axillary staging was performed). Cumulative data have helped ordain the role of sentinel lymph node biopsy in the management of MIDC.23,27,29 Until such information is amassed for MILC, it would be prudent to perform sentinel lymph biopsy in these cases as well.
Patients with invasive lobular carcinoma are generally considered to have a relatively high frequency of bilateral carcinoma when compared with women who have other types of carcinoma. In this series, significant breast disease (1 case each of ALH, LCIS, and invasive ductal carcinoma) was found in 3 of the 5 cases in which tissue was sampled from the contralateral (clinically asymptomatic) breast. Clinical and radiologic evaluation of the contralateral breast is recommended in all cases of MILC.
Finally, clinicians and pathologists should be wary of the term microinvasive carcinoma in needle core biopsies, even if only <1 mm of invasive carcinoma is identified in such samples.22 In such cases, it is prudent to state the maximal extent and number of foci of invasive carcinoma therein with the caveat that additional residual invasive carcinoma may be identified in subsequent samples.
MILC is a rare, histologically subtle, lesion associated with classical LCIS. MILC comprised 0.02% of all breast specimens examined in our Department from 1991 through 2009. The disease constituted approximately 0.4% of all invasive lobular carcinomas and was seen in association with approximately 0.4% of all LCISs in this period. MILC seems to be a low morbidity disease with neither recurrences nor metastases observed (at least in the short term).
The assistance of Ms Pat Kuharic with preparation of photomicrographs is gratefully acknowledged.
1. Alvardo-Cabrero I, Picon CG, Valencia CR, et al. Florid lobular intraepithelial neoplasia with signet ring cells, central necrosis and calcifications: a clinicopathological and immunohistochemical analysis of ten cases with invasive lobular carcinoma Arch Med Res.. 2010;41:436–441
2. Bianchi S, Vezzosi V. Microinvasive carcinoma of the breast Pathol Oncol Res.. 2008;14:105–111
3. Bratthauer GL, Moinfar F, Starmatokos MD, et al. Combined E-cadherin and high molecular weight cytokeratin immunoprofile differentiates lobular, ductal and hybrid mammary intraepithelial neoplasia Hum Pathol.. 2002;33:620–627
4. Chen YY, 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
5. Dabbs DJ, Bhargava R, Chivukula M. Lobular versus ductal breast neoplasms: the diagnostic utility of p120 catenin Am J Surg Pathol.. 2007;31:427–437
6. DaSilva L, Parry S, Reid L, et al. Aberrant expression of E-cadherin in lobular carcinomas of the breast Am J Surg Pathol.. 2008;32:773–778
7. DiCostanzo D, Rosen PP, Gareen I, et al. Prognosis in infiltrating lobular carcinoma: an analysis of “classical” and variant tumors Am J Surg Pathol.. 1990;14:12–23
8. Edge SB, Byrd DR, Compton CC, et al. eds. . Breast AJCC Cancer Staging Manual. 2010 New York Springer:347–376
9. Guth AA, Mercado C, Roses DF, et al. Microinvasive breast cancer and the role of sentinel node biopsy: an institutional experience and review of the literature Breast J.. 2008;14:335–339
10. Hoda SA, Rosen PP. Contemporaneous H&E sections should be standard practice in diagnostic immunopathology Am J Surg Pathol.. 2007;31:1627
11. Hoda SA, Prasad ML, Moore A, et al. Microinvasive carcinoma of the breast: can it be diagnosed reliably and is it clinically significant? Histopathol.. 1999;35:468–470
12. Howat AJ, Armour A, Ellis IO. Microinvasive lobular carcinoma of the breast Histopathol.. 2000;37:477–478
13. Kuroda N, Sugimoto T, Numoto S, et al. Microinvasive lobular carcinoma associated with intraductal spread arising in a mammary hamartoma J Clin Pathol.. 2002;55:76–77
14. Li CI, Anderson BO, Daling JR, et al. Trends in incidence rates of invasive lobular and ductal breast carcinoma JAMA.. 2003;289:1421–1424 1998;67:41–46.
15. Mathieu MC, Rouzier R, Llombart-Cussac A, et al. The poor responsiveness of infiltrating lobular breast carcinomas to neoadjuvant chemotherapy can be explained by their biological profile Eur J Cancer.. 2004;40:342–351
16. Nemoto T, Castillo N, Tsukada Y, et al. Lobular carcinoma in situ with microinvasion Breast J.. 2008;14:335–339
17. Newman W. Lobular carcinoma of the female breast: report of 73 cases Ann Surg.. 1966;164:305–314
18. Prasad ML, Hyjek E, Giri DD, et al. Double immunolabeling with cytokeratin and smooth-muscle actin in confirming early invasive carcinoma of breast Am J Surg Pathol.. 1999;23:176–181
19. Prasad ML, Osborne MP, Giri DD, et al. Microinvasive carcinoma (T1mic
) of the breast: clinicopathologic profile of 21 cases Am J Surg Pathol.. 2000;24:422–428
20. Rakha EA, Ellis IO. Lobular breast carcinoma and its variants Semin Diagn Pathol.. 2010;27:49–61
21. Rakha EA, Patel A, Powe DG, et al. Clinical and biological significance of E-cadherin protein expression in invasive lobular carcinoma of the breast Am J Surg Pathol.. 2010;34:1472–1479
22. Renshaw AA. Minimal (≤0.1 cm) invasive carcinoma in breast core needle biopsies. Incidence, sampling, associated findings, and follow-up Arch Pathol Lab Med.. 2004;128:996–999
23. Sakr R, Antoine M, Barranger E, et al. Value of sentinel lymph node biopsy in breast ductal carcinoma in situ upstaged to invasive carcinoma Breast J.. 2008;14:55–60
24. Silverstein MJSilverstein MJ. Ductal carcinoma. In situ with microinvasion Ductal Carcinoma In situ of the Breast. 1997 Baltimore Williams and Wilkins:557–562
25. Solin LJ, Fowble BL, Yeh IT, et al. Microinvasive ductal carcinoma of the breast treated with breast-conserving surgery and definitive irradiation Int J Radiat Oncol Biol Phys.. 1992;23:961–968
26. Tavassoli FA, Millis RR, Boecker W, et al.Tavassoli FA, Devilee P Lobular Neoplasia World Health Organization Classification of Tumors. Pathology and Genetics of Tumors of the Breast and Female Genital Organs. 2005 Lyon IARC Press:60–62
27. Tunon-de-Lara C, Giard S, Buttarelli M, et al. Sentinel node procedure is warranted in ductal carcinoma in situ with high risk of occult invasive carcinoma and microinvasive carcinoma treated by mastectomy Breast J.. 2008;14:135–140
28. Vieira CC, Mercado CL, Cangiarella JF, et al. Microinvasive ductal carcinoma in situ: clinical presentation, imaging features, pathologic findings, and outcome Eur J Radiol.. 2010;73:102–107
29. Yi M, Krishnamurthy S, Kuerer HM, et al. Role of primary tumor characteristics in predicting positive sentinel lymph nodes in patients with ductal carcinoma in situ or microinvasive breast cancer Am J Surg.. 2008;196:81–87
30. Youngson BJ, Cranor M, Rosen PP. Epithelial displacement in surgical breast specimens following needling procedures Am J Surg Pathol.. 1994;18:896–903
Keywords:© 2011 Lippincott Williams & Wilkins, Inc.
breast; carcinoma; lobular carcinoma; microinvasive carcinoma