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Editorials |
1 From the Memorial Sloan-Kettering Guttman Diagnostic Center, 55 Fifth Ave, 12th Floor, New York, NY 10003. Received January 26, 2004; accepted January 30. Address correspondence to the author (e-mail: cohen1@mskcc.org).
Index terms: Breast, biopsy, 00.1261 • Breast neoplasms, diagnosis, 00.31, 00.32 • Editorials
The question of whether excisional biopsy is required following a diagnosis of atypical lobular hyperplasia (ALH) or lobular carcinoma in situ (LCIS) at core-needle biopsy is both controversial and perplexing. The controversy derives from the limited data available on which to base this treatment decision, and the perplexity relates to a lingering uncertainty with regard to the biologic behavior and risk of malignancy of these lesions in general. Each relates to the other: If more biopsy data were available, then insights into the relationship of these lobular lesions to breast cancer could be gleaned, and if research permitted a more definitive impression as to the premalignant potential of these lesions, then more certain core-needle biopsy treatment could be formulated. In this issue of Radiology, Foster et al (1) describe their experience with 35 patients with ALH or LCIS diagnosed at core-needle biopsy. Twenty-six of these patients immediately underwent excisional biopsy. To my knowlege, to date this is the largest published series of patients who underwent core-needle biopsy with subsequent excisional biopsy. The results support the cumulative published experience: A certain small percentage of lesions in patients with a diagnosis of ALH or LCIS at core-needle biopsy will be upgraded to frank malignancy.
What is really known? Data in the following paragraphs were culled from 14 published peer-reviewed articles (1–14), and I extracted only those cases of core-needle biopsy in which the patients underwent subsequent excisional biopsy. Abstracts presented at scientific meetings were not included because of the limited data included in the published abstract and the absence of peer review of the final data set that would normally occur prior to manuscript publication. Cases included in this review are instances in which ALH or LCIS is the lesion with highest risk at core-needle biopsy. Cases in which ALH or LCIS was associated with cancer or a high-risk lesion (radial scar, atypical ductal hyperplasia) were omitted, as they would require excisional biopsy.
A total of 159 cases of ALH, LCIS, or lobular neoplasia (a term encompassing the spectrum of ALH and LCIS) were diagnosed as the lesion with highest risk at core-needle biopsy, and in these cases, patients underwent subsequent surgery. From four to 26 cases were reported in each of these 14 publications.
Lesions in 30 (19%) of 159 cases were upgraded to ductal carcinoma in situ (DCIS) or invasive cancer following excisional biopsy. The imaging appearance of the upgraded lesions that triggered the recommendation for core-needle biopsy was reported in 15 of 30 cases: In masses, nine upgrades occurred, and in calcifications, six upgrades occurred.
In 30 total upgrades, there were six (20%) cases of invasive ductal carcinomas, nine (30%) cases of invasive lobular carcinomas, one (3%) case of tubular carcinoma, one (3%) case of mixed lobular and ductal carcinoma, and 13 (43%) cases of DCIS.
In 73 cases of LCIS, 16 (22%) lesions were upgraded. There were seven cases of invasive lobular carcinoma, two cases of invasive ductal carcinoma, one case of tubular carcinoma, one case of mixed ductal and lobular carcinoma, and five cases of DCIS.
In 73 cases of ALH, 13 (18%) lesions were upgraded. There were two cases of invasive lobular carcinoma, three cases of invasive ductal carcinoma, and eight cases of DCIS.
In 13 cases of lobular neoplasia, one lesion was upgraded to invasive ductal carcinoma.
There are limited data that show a correlation between findings at core-needle biopsy and surgical outcome. When specified, needle gauges ranged from eight to 20, and both automated needle devices and vacuum-assisted probes were used. When specified, numbers of cores per lesion ranged from three to 43. Upgrades were noted with all needle gauges and biopsy devices. There were several upgrades reported with a vacuum-assisted 11-gauge probe and more than 10 cores of tissue (11–13), and one upgrade of ALH to DCIS was reported following core-needle biopsy with a vacuum-assisted 8-gauge probe and "11–17 cores" (8).
Among the 14 studies, authors in one investigation (3) did not draw any conclusions with regard to treatment. In seven investigations (3,5–7,11,13), including the current study by Foster et al (1), excisional biopsy was recommended in all cases. Researchers in one investigation (9) determined that excisional biopsy was not necessary following core-needle biopsy. In another study (10), researchers recommended excisional biopsy for masses, and in two other studies (5,13), researchers recommended excisional biopsy for calcifications. Researchers in one study recommended no surgery except in cases of prior or synchronous breast cancer, cases in which the lesion was associated with another high-risk lesion, or cases in which histologic features overlapped with those of DCIS (11). In another study (2), investigators recommended excisional biopsy in cases of discordance between imaging and histologic findings, cases in which the lesion was associated with another high-risk lesion, and cases in which the histologic features overlapped with those of DCIS.
This brief review highlights the paucity of hard data available. To be sure, each contribution has served to advance what little is known. In the aggregate, these contributions have already served notice that, despite the current low-key approach to LCIS following excisional biopsy (in most cases, ongoing observation), the limitations imposed by sample size and other factors may require a more aggressive approach for these same lesions when they are encountered at core-needle biopsy. Individual reports, however, vary markedly in content. All studies are retrospective, and each is subject to selection bias; only a portion of the patients with a diagnosis of ALH or LCIS at core-needle biopsy underwent surgery, while others were observed. Selection criteria are rarely provided. Details that include the imaging features of the core target lesions, the precise delineation of core-needle biopsy materials and methods, the presence or absence of concordance between imaging and histologic findings, and the specific correlation of these details with the ultimate surgical outcome are variable. Dershaw (15) outlined in detail the shortcomings of the available reports and provided suggestions for future research design and data collection. More important, ALH or LCIS is a rare finding, which is reported to occur in only 0.5%–2.7% of benign excisional breast biopsies (16). Liberman et al (2) identified LCIS in 16 (1.2%) of 1,315 lesions at percutaneous core-needle biopsy. The infrequency of this diagnosis accounts for the fragmented and inconsistent nature of the published data and virtually mandates a multi-institutional trial to harvest sufficient cases with uniform data collection to reach meaningful conclusions.
The existing data, though limited, suggest that percutaneous core-needle biopsy that yields a diagnosis of ALH or LCIS may miss frank breast cancer approximately 19% of the time. This is similar to the upgrade percentage for atypical ductal hyperplasia sampled with 11-gauge vacuum-assisted probes (17,18). Why should this be? Unlike atypical ductal hyperplasia, which is considered precancerous and for which excisional biopsy is the standard following a diagnosis at core-needle biopsy, ALH or LCIS is generally considered only a risk indicator for future development of cancer, with each breast at equal risk, and for subsequent development of invasive tumors that are as frequently ductal as lobular. Where undersampling can readily explain the missing of carcinoma at a site where premalignant disease is present, why should cancer exist around a lesion (ALH or LCIS) considered incapable of evolving into malignancy? The answer to this question is probably multifactorial. Four possibilities will be discussed, but there may be others.
1. The target lesion is simply missed at core-needle biopsy, and the target represents the malignant lesion that is ultimately diagnosed at excisional biopsy. In this case, ALH or LCIS is an incidental finding. This is an inherent possibility in any percutaneous biopsy. At core-needle biopsy, the failure to adequately diagnose underlying pathologic abnormalities ranges from 2% to 17% in reported series (19). Larger needles and improved sampling with vacuum-assisted probes have improved the sampling accuracy but have not entirely eliminated the need to repeat the biopsy of the target lesion in some cases.
2. The upgraded diagnosis of cancer in these cases is a reflection of the percentage of malignancies that are not suspected but are diagnosed in addition to the benign lesion that is targeted at excisional biopsy. The identification of cancer at excisional biopsy is serendipitous in these cases, and the ALH or LCIS identified at core-needle biopsy is incidental and unrelated. Rosenfeld et al (20) found a 13% association of malignancy in tissue adjacent to benign microcalcifications that were targeted at excisional biopsy. The undersampling of tissue at core-needle biopsy as compared with the amount of tissue removed at excisional biopsy is an inherent limitation of percutaneous biopsy and will exist theoretically until sample size at percutaneous biopsy equals lesion size at excisional biopsy. As new techniques and probes allow increased sample size, the frequency of discordance between diagnosis at core-needle biopsy and that at excisional biopsy will decrease.
3. LCIS or ALH is a premalignancy and may evolve into a frank malignancy in a percentage of cases. As with the multistep progression from atypical ductal hyperplasia to DCIS to invasive ductal carcinoma, upgrades at excisional biopsy would reflect core undersampling of a continuum of histologic progression as lobular pathologic findings evolve from benign to frankly malignant.
The prevailing treatment of ALH or LCIS chiefly is based on epidemiologic data. Only rarely does subsequent cancer develop in women with LCIS. In a review of 14 studies encompassing 703 patients treated for LCIS with biopsy alone, Fisher et al (21) found that 12% of patients developed ipsilateral invasive breast tumor recurrence and 8% developed contralateral invasive breast tumor recurrence. They observed an even lower frequency of tumor recurrence in a review of their own data from the National Surgical Adjuvant Breast Project Protocol B-17: In a cohort of 182 patients treated only with excisional biopsy, there was an incidence of only 2.2% of ipsilateral invasive breast tumor recurrence and 1.1% of contralateral invasive breast tumor recurrence at 5 years. Five years is an admittedly short follow-up period, in view of the fact that following the diagnosis of LCIS the majority of cancers develop after 15 years. The low incidence, bilaterality, and long delay to development of invasive cancer are taken as prima facie evidence of the absence of direct progression of ALH or LCIS to malignancy.
Additional support is derived from the fact that at least half of the invasive tumors that develop after the diagnosis of LCIS are ductal in origin. As there is little risk of focal progression, surgeons do not repeat excision of ALH or LCIS lesions to clear the margins, radical surgery is avoided, and ancillary cancer therapy is withheld (except for tamoxifen [Nolvadex; Zeneca Pharmaceuticals, Wilmington, Del], which is used as a preventive measure in selected cases). The predictive role of these lobular lesions is predicated on an increased long-term risk for the development of invasive carcinoma in women who have them compared with normal control subjects. This increased risk is estimated at seven to 12 times the risk for LCIS and about half that for ALH.
There is, however, an accumulation of data that may cast a different light on the prevailing concept of ALH or LCIS as a predictor only and may also provide a partial explanation for the observed frequency of cancers identified at excisional biopsy subsequent to the diagnosis of ALH or LCIS at core-needle biopsy. These new data suggest that there may be progression of at least some populations of ALH or LCIS lesions to invasive cancer, which is a model identical to that of ductal lesions, although the former evolve more slowly (16,22–29).
For example, pathologists have noted that some forms of LCIS appear more aggressive histologically and are also more frequently associated with invasive cancer than the classic histologic LCIS. Pleomorphic LCIS is the most notable and well described of these histologic variants. Though the cells of pleomorphic LCIS grow in a fashion consistent with those of classic LCIS—including distention of the acini, loss of cellular cohesion, and pagetoid extension into adjacent ducts—they are cytologically distinct from the classic LCIS cells, with more pleomorphism, increased cytoplasm, more prominent nucleoli, and association with central necrosis and calcification. This necrotic calcification may also be evident mammographically as clustered pleomorphic microcalcifications that mimic comedonecrosis in DCIS and trigger recommendation for biopsy (22). Pleomorphic LCIS is frequently associated with the pleomorphic variant of invasive lobular carcinoma, which appears to be a particularly aggressive form of breast cancer. Eusebi et al (23) reported 10 patients with pleomorphic invasive lobular carcinoma, and six of these patients had cases associated with pleomorphic LCIS as well. Six of the 10 patients died within 42 months, and three of the remaining four patients developed recurrence or distant metastasis. Equally aggressive were pleomorphic invasive lobular carcinomas in 12 patients described by Bentz et al (24). Seven of these 12 patients also had associated pleomorphic LCIS. In 11 patients with adequate clinical follow-up, nine died, with a median survival of 2.1 years. Core-needle or excisional biopsy results and long-term data in patients with only pleomorphic LCIS are not available. By virtue of its aggressive histologic appearance and its frequent association with invasive lobular carcinoma, particularly the apparently aggressive pleomorphic variant, excisional biopsy following a diagnosis of this LCIS variant at core-needle biopsy is strongly recommended.
Rosen (16) describes "florid LCIS" as a variant of classic LCIS in which "extreme ductal and lobular enlargement occurs, often with necrosis and calcification." When this histologic finding is evident, he recommends careful evaluation of the sample for evidence of microinvasion. Liberman et al (2) describe findings at core-needle biopsy for four LCIS lesions; the pathologist recommended excision because of features that overlapped those of DCIS. In these indeterminate cases, findings were described as pronounced ductal distention or mixed large- and small-cell cytologic features. In two of these cases, findings were associated with malignancy at excisional biopsy. From their description, some or all of these lesions may have been florid LCIS. In fact, in their review of the literature and of the cases of Liberman et al (2) specifically, Shin and Rosen (7) considered all four lesions to be florid LCIS. In this same review, Shin and Rosen reported 13 (62%) invasive carcinomas in their own series of 21 cases of florid LCIS; of the 13 carcinomas, nine were lobular (unpublished data). Sapino et al (25) reported 10 florid LCIS lesions; four of them were associated with concurrent invasive lobular carcinoma. Florid LCIS has been described recently and is not universally recognized or reported. Its precise differentiation from the pleomorphic and classic form, its incidence, and clinical importance require further research and description. For the present, radiologists in breast imaging should be aware of this LCIS variant and its suggested increased association with carcinoma, particularly the lobular type. A recommendation for excisional biopsy following this diagnosis based on findings at core-needle biopsy would seem appropriate at this time.
Contributions from the molecular geneticists also lend support to a premalignant role for LCIS. Lakhani et al (26) reported that the loss of heterozygosity, an indicator of genetic alteration, that involves chromosomal loci at high frequency in cases of invasive carcinoma could also be detected in the adjacent foci of LCIS. These genetic alterations were identified in LCIS that occurred with and without invasive carcinoma.
Nayar et al (27) studied loss of heterozygosity on chromosome 11q13 in 38 cases of lobular lesions, which included various combinations of ALH, LCIS, and invasive lobular carcinoma. Loss of heterozygosity at chromosome 11q13 was identified in one-third of cases of LCIS and invasive lobular carcinoma. LCIS that occurred in association with invasive lobular carcinoma showed a loss of heterozygosity in 50% of cases, whereas pure LCIS in the absence of invasive lobular carcinoma had a much lower frequency of loss of heterozygosity, which was comparable with the loss of heterozygosity of pure ALH. The authors interpreted the results to mean that loss of heterozygosity on chromosome 11q13 may play an important role in the development of invasive lobular carcinoma; this role may be similar to that in the development of invasive ductal carcinoma from DCIS or atypical ductal hyperplasia. Further, frequent loss of heterozygosity in invasive lobular carcinoma and LCIS associated with invasive lobular carcinoma and a markedly lower frequency of loss of heterozygosity in LCIS without invasive lobular carcinoma, which is comparable with that in ALH, implies that the genetic alteration on chromosome 11q13 may be important in the transition from LCIS to invasive lobular carcinoma. The authors hypothesized a potential future clinical role for use of loss of heterozygosity to separate morphologically similar yet genetically different subgroups of ALH and LCIS into one group with genetic changes and an increased potential to develop into invasive cancer and another group without these changes that would function in the role of a more traditional LCIS predictor for the development of future malignancy.
Finally, loss of heterozygosity also has been identified in phenotypically normal cells that were found in tissue adjacent to breast tumors (28,29). Most of the foci of loss of heterozygosity identified in the normal tissue were also found in adjacent tumor. It is hypothesized that loss of heterozygosity identified in normal tissue reflects early critical events ("genetic hits") in a cascade of events that may, but not always, culminate in an invasive tumor.
How does this information relate to the fundamental issue of whether or not excisional biopsy is necessary in patients in whom ALH or LCIS is diagnosed at core-needle biopsy? If the geneticists and molecular biologists are correct, then at least some foci of ALH and LCIS are genetically armed and capable of evolving into invasive tumors. In addition, this predisposition may involve surrounding phenotypically normal cells. The ALH or LCIS identified at core-needle biopsy may reside within a larger field of tissue that has a distinct predisposition to evolve into carcinoma and, in fact, may have done so. Small samples from this field may not provide a comprehensive analysis of all that resides in it. This concept of "field cancerization" was initially described by Slaughter et al (30) in 1953 and was further elucidated by Braakhuis et al (31) in 2003 for tumors of the oral mucosa but is applicable in many cancers, and these include cancer in the breast. The simple point relevant to radiologists in breast imaging is that discovery of LCIS or ALH at core-needle biopsy may represent discovery (usually inadvertent) of an abnormal field of tissue. The entire field of tissue is at risk, and a broader surgical resection may uncover more advanced changes that result in an upgrade of the lesion to DCIS or frank invasive tumor. Thus, as for atypical ductal hyperplasia, a premalignant role for some LCIS lesions seems plausible and may explain at least a portion of the upgraded cases identified in the current literature.
4. The original diagnosis of ALH or LCIS at core-needle biopsy is incorrect, and the sample actually represents DCIS. Findings at subsequent surgery either confirm the DCIS diagnosis or upgrade the diagnosis to invasive cancer. The distinction between LCIS and DCIS is usually straightforward. DCIS frequently manifests identifying architectural and structural features such as cribriform or micropapillary growth patterns. Similarly, LCIS usually has distinctive features that include extensive lobular involvement with a uniform population of nonatypical, but discohesive, cells often with pagetoid extension into adjacent terminal ducts. Occasionally, however, LCIS can be mimicked by low-grade solid-type DCIS that involves terminal ducts and lobules. LCIS can populate ducts, and DCIS can involve lobules. Even central necrosis and calcifications, formerly mainstays in the diagnosis of ductal lesions, can also be seen in LCIS. To confound matters, there are also cases in which DCIS and LCIS coexist in the same ductal-lobular unit, and these cases truly are not one or the other but both.
Although histologic criteria have been established to permit identification and separation of the two entities, none have been broadly accepted and applied, and final interpretation often remains subjective. Liberman et al (2) were the first investigators to call attention to the difficulty as it relates to core biopsy specimens: They found cancer in two of four excisional biopsy specimens when core samples showed overlapping features of ductal and lobular cancer. These findings led these authors to recommend that the lesions should be surgically excised in all cases with overlapping features of LCIS and DCIS at core histologic analysis.
There is increasing evidence that immunostaining for E-cadherin may greatly assist pathologists in distinguishing between lesions of ductal and those of lobular origin and in identifying those rare cases in which the two coexist. E-cadherin is a transmembrane glycoprotein that binds cells of similar type, and its altered expression or function has been postulated to play a role in the detachment process that results in tumor metastasis. Lesions such as signet-ring carcinoma of the stomach and invasive lobular carcinoma of the breast that spread in a diffuse infiltrative pattern (as opposed to a concentric mass pattern) have been shown to lack E-cadherin.
Conversely, the distinct architectural growth patterns manifested by ductal breast lesions require structural adhesion and have been shown to maintain the E-cadherin glycoprotein on their membrane surfaces. Maluf et al (32) correlated the E-cadherin staining pattern of 12 in situ carcinomas that were histologically indeterminate with the staining pattern of the invasive component of each of these same tumors. E-cadherin–positive in situ cancers were invariably associated with invasive ductal cancers. E-cadherin–negative in situ cancers were associated with invasive carcinoma of lobular origin in five of six cases. In all cases, the E-cadherin staining pattern of the in situ carcinomas and the corresponding invasive carcinomas were identical. Jacobs et al (33) found E-cadherin immunostaining helpful in suggesting the lobular origin of cases in which the histologic features were typical of LCIS, with the exception of either comedo-type necrosis or marked nuclear pleomorphism and in suggesting the lobular or ductal origin in cases in which histologic features were truly equivocal. In some of these latter cases, they found that mixed E-cadherin staining results suggested a lesion with both ductal and lobular cell populations.
It appears that E-cadherin staining will permit more accurate discrimination between ductal and lobular in situ lesions at biopsy. Equivocal lesions that are E-cadherin positive (ductal in origin) and those that stain in a mixed fashion (and are suggestive of both ductal and lobular cell populations) will require surgical excision if for no other reason than for complete excision of the DCIS component. At issue remains treatment of patients with cases in which histologic findings are equivocal and in which E-cadherin–negative staining patterns suggest a lobular origin. In a recent review article about core-needle biopsy of benign breast lesions, Jacobs et al (34) caution
that until additional data are available, it is prudent to recommend excision, even if the neoplastic cells are negative for E-cadherin by immunohistochemistry (suggesting a lobular phenotype) if the features on routine histologic sections are ambiguous.
In summary, what we actually know with regard to the need for surgical excision following a diagnosis of ALH or LCIS at core-needle biopsy is limited by scant and incomplete data. There are several reasons that explain the false-negative core-needle biopsy rate for ALH or LCIS: Some are technical, as in the failure to adequately target the lesion; some are interpretive, as in the misdiagnosis of low-grade solid DCIS as LCIS; and some are biological, as would occur if a population of LCIS lesions were truly premalignant. All are likely responsible or operative to some degree. Some of these false-negative core-needle biopsy results may be prospectively avoided with assiduous attention to biopsy technique (precise targeting and large sample size) and pathologic analysis of the core specimens. Other reasons are inherent in the disease process itself. On the basis of findings in the current literature, excision for lesions with ALH or LCIS as the pathologic finding with the highest risk at core-needle biopsy would seem prudent and appropriate. Fortunately, the number of women affected by this decision to repeat the biopsy is small, and the number of women who harbor cancer that is undiagnosed at core-needle biopsy is even smaller still, but the potential benefit to each woman who ultimately receives a diagnosis of cancer would be great. Inherent in this recommendation is the necessity for rigorous data collection, analysis, and publication so that a truly evidence-based management plan can ultimately be promulgated.
FOOTNOTES
See also the article by Foster et al in this issue.
REFERENCES
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