ABSTRACT: 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.
Introduction
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.[1-3]
What we now refer to as LCIS was first described by James Ewing in 1919 as a noninvasive proliferation of the lobules and terminal ducts of the breast. This lesion was not named, however, until 1941, when Foote and Stewart coined the term "lobular carcinoma in situ."[4] 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.
NCCN Algorithm for the Management of LCIS
As additional histopathologic information on LCIS emerged in the 1970s, the proliferative changes within the breast lobule were recognized as a spectrum of changes including both atypical lobular hyperplasia (ALH) and LCIS, and efforts were made to reclassify these two lesions as LN.[2] This nomenclature was not universally adopted, however, and some authors continue to report on these two lesions independently, while others do not, resulting in some difficulty in making comparisons across series. More recently, advances in immunohistochemistry and molecular biology have led to an appreciation of greater diversity within the spectrum of LN, and there is considerable speculation that the pleomorphic variant of LCIS will prove to have a different clinical behavior than the “classical” LCIS subtype.[5] This article will review current management trends for women with classical LCIS.
Incidence
LCIS is typically an incidental finding in a breast biopsy performed for another reason. As such, the true incidence of LCIS in the population has been difficult to ascertain. Several approaches to determining the true incidence, including autopsy series, individual institution biopsy series, and population-based studies, have been undertaken. The results achieved with these various approaches have been somewhat different, yet they all suggest that LCIS is likely a rare lesion among women in the general population.[6] Two classic studies by Haagensen[7] and Page[8] reported LCIS in 3.7% and 0.5% of otherwise benign breast biopsies performed at their respective institutions. Other studies report LCIS in 0.8% to 3.8% of open surgical biopsies and in 0.02% to 3.30% of image-guided core needle biopsies.[9] Population-based data reported to Surveillance, Epidemiology, and End Results (SEER) from 1978 to 1998 demonstrate a much lower incidence—3.19 per 100,000 women[6]—yet during this time there was an observed four-fold increase in the number of LCIS cases reported among women over 40 years of age, with the highest incidence rate (11.47 per 100,000 person-years) occurring in 1998 among women aged 50 to 59 years. While this trend may reflect the increasing use of mammography and image-guided biopsies during this period, the impact of other factors, such as the increased use of combination hormone replacement therapy during this time, remains uncertain.
Presentation and Diagnosis
Historically, LCIS has been considered a clinically occult lesion not associated with changes on physical examination or mammographic imaging; when identified, it was frequently found to be multicentric and bilateral.[2,4,7] In the era of widespread screening mammography, more recent data suggest that LCIS is associated with calcifications in 21% to 67% of cases.[10] LCIS has also been reported to enhance on MRI,[11] although these data remain relatively limited. In their original description, Foote and Stewart described LCIS as a proliferation of small, uniform, discohesive cells that fill and often distend the acinar units within a lobule.[4] Criteria for diagnosis, later outlined by Page and Anderson, are as follows:
(1) The characteristic and uniform cells must comprise the entire population of cells within the lobular unit.
(2) All of the lobule must be filled with these cells (ie, no intercellular empty spaces between cells).
(3) There must be distension and expansion of at least half of the acini in the lobular unit.[12]
A diagnosis of LCIS made by surgical excision does not require further surgical intervention, and there is no indication to document margin status in a specimen that contains only LN.[13] Similarly, the finding of LCIS in the surrounding breast parenchyma of a lumpectomy specimen containing DCIS or invasive carcinoma does not alter surgical management of the breast primary and does not increase the rate of in-breast recurrence in patients undergoing breast conservation.[14-16] The scenario that often results in controversy regarding management is that of LCIS diagnosed on core biopsy. The most recent National Comprehensive Cancer Network (NCCN) guidelines state that a core biopsy diagnosis of LCIS should always be followed by surgical excision to rule out an associated malignancy, with subsequent management decisions to be made based on the final pathologic diagnosis (Figure).[17]
