A 40-year-old premenopausal woman with a new diagnosis of invasive lobular carcinoma occurring in a background of lobular carcinoma in situ presents to a multidisciplinary second opinion clinic. Herein, we describe the appropriate management of both noninvasive and invasive lobular carcinoma and provide a literature-based review of this controversial topic.
DR. NICOLE KOULANAKIS, surgical oncologist: The patient presented for baseline screening mammogram and was found to have a suspicious area of calcifications in the upper outer quadrant of her right breast (Figures 1 and 2). Stereotactic core needle biopsy revealed pleomorphic lobular carcinoma in situ (LCIS). Her history and physical exam were unremarkable. Family history was significant for two paternal cousins diagnosed with breast cancer in their 50s and a paternal uncle with a “stomach cancer.” The patient underwent a follow-up stereotactic guided biopsy which revealed a 7-mm focus of ER-positive, PR-negative, HER2/neu-negative invasive pleomorphic lobular carcinoma in the setting of diffuse LCIS (Figures 3 and 4). After discussion of her treatment and future cancer-prevention options, the patient elected to undergo bilateral mastectomies, right axillary sentinel lymph node biopsy, and immediate reconstruction. The final pathology demonstrated multiple foci of LCIS present in both mastectomy specimens, and no additional invasive cancer. The sentinel lymph nodes were negative for any metastatic disease.
This case brings up the role of LCIS in breast cancer diagnosis, management, and prevention, as well as the unique histologic subtype of pleomorphic lobular carcinomas. Let's start by discussing LCIS, a continuing conundrum in breast cancer.
How Is LCIS Diagnosed?
DR. WENDY HORN, mammographer: LCIS is a clinically and radiographically occult tumor. Detection usually occurs as an incidental finding during surgery, although increased use of mammographic screening has led to a greater identification on core needle biopsy. The incidence of LCIS is low: < 5% of all surgical excisions and approximately 3% of all core needle biopsies are diagnosed as LCIS.[1,2]
DR. NICOLE KOULANAKIS: Although LCIS is usually radiographically silent, are there any specific lesions on mammography associated with LCIS? What is the role of MRI in detection, and of surveillance after the diagnosis is made?
DR. WENDY HORN: Despite its predominantly occult nature, LCIS has been shown to be associated with mammographic calcifications, and radiologic-pathologic concordance must be established after every biopsy.[3,4] Mammographic findings occur more commonly with the pleomorphic variant of LCIS, given its tendency to undergo comedo necrosis and thus form calcifications. This was the case with our patient: she underwent a stereotactic biopsy for abnormal calcifications found on a screening mammogram, which led to her diagnosis of pleomorphic LCIS.
There are no specific findings of LCIS on MRI. Currently, MRI is recommended for screening only in women with a greater than 20% lifetime risk of breast cancer. There are several high-risk groups for which data are insufficient to recommend for or against MRI screening. These are women with a history of breast cancer, ductal or lobular in situ disease, or atypical hyperplasia, and those with dense breasts on mammogram. The presence of atypia, LCIS, or markedly dense breasts can be taken into account when calculating lifetime risk of breast cancer, and so may contribute to the breast cancer risk estimate of greater than 20% for a woman.
DR. NICOLE KOULANAKIS: LCIS is characterized as an indolent disease found predominantly in premenopausal women 40–50 years old. Interestingly, the incidence of LCIS in postmenopausal women has been steadily rising. Older women also have a greater risk of developing a subsequent cancer once they have been diagnosed with LCIS. More than 50% of patients diagnosed with LCIS will have multicentric ipsilateral involvement, and approximately 30% will have contralateral LCIS. This supports the findings in our patient, although the clinical impact of multicentric and contralateral LCIS remains unclear.
How Does LCIS Differ Pathologically From Atypical Lobular Hyperplasia and Invasive Lobular Carcinoma?
DR. SONALI JINDAL AND DR. JOSH WISELL, pathologists: Lobular malignancy represents a spectrum of disease varying from noninvasive lobular proliferations, including atypical lobular hyperplasia (ALH) and LCIS, to invasive lobular carcinoma (ILC).
In ALH, neoplastic cells replace the normal epithelium of a terminal ductal lobular unit, often a relatively subtle finding. With progression to LCIS, the neoplastic proliferation increases and the changes become more prominent, expanding the lobules and extending into larger ducts, but still constrained by a basement membrane. ILC results once the neoplastic cells have extended beyond the basement membrane.
There are two known histologic types of LCIS. The “classic” variant demonstrates small cells with scant cytoplasm and small, round nuclei that lack nucleoli. The more aggressive “pleomorphic” variant has abundant cytoplasm, large variably shaped nuclei, and more prominent nucleoli. As explained earlier in the case discussion, this variant is more likely to undergo comedo necrosis, form calcifications, and be detected on screening mammograms.
Recent investigation has indicated that ILC advances from ALH/LCIS, as they all share a common molecular profile: ER/PR positive, HER2/neu negative, cytokeratin positive, and loss of E-cadherin.[9,10] The risk of progression of LCIS to invasive cancer of either the ductal or lobular type varies from 23%–36% in reported studies, with most demonstrating predominance toward development of ILC.[4,5]
The loss of heterozygosity at 11q13 in LCIS may be a marker for increased risk of developing invasive cancer and may prove to be a useful prognostic tool in the future. Further understanding of the lobular neoplastic spectrum is required to permit improved identification and treatment of noninvasive lesions with greater malignant potential.
DR. VIRGINIA BORGES: What should the surgical management of LCIS be?
Surgical Management of LCIS
DR. NICOLE KOULANAKIS AND DR. CHRISTINA FINLAYSON: The surgical management of LCIS differs based on how the diagnosis is made. When LCIS is diagnosed as an incidental finding on a surgical excision, additional surgery is not indicated. We do not advocate negative margin resection for LCIS. It is well understood that in patients with invasive cancer, detection of LCIS at the margin of the lumpectomy is not associated with an increased risk of local recurrence.[12,13] In a recent analysis of LCIS treated with local excision with microscopically negative margins, the ipsilateral breast cancer recurrence was still 14.4% at 12 years. These outcomes are comparable to those of studies in which patients received local excision without attention to margins: 10%–18% at 10 years.[8,15]
When LCIS is the only pathology found on a core needle biopsy associated with a mammographically detected lesion, a sampling error becomes a valid concern. LCIS may not accurately represent this radiographic finding, and more advanced disease could be present. In several studies, further surgical excision of LCIS revealed either DCIS or invasive cancer in 25%–31% of all cases.[1,2,16] Thus, surgical excision is warranted if LCIS is diagnosed on core needle biopsy.
DR. VIRGINIA BORGES: What is the risk of developing cancer?
Cancer Risk in Patients With LCIS
DR. NICOLE KOULANAKIS AND DR. CHRISTINA FINLAYSON: In the majority of patients, LCIS is an indolent disease. As discussed, when patients are treated with surgical excision alone, the reported rate of ipsilateral local recurrence ranges from 10%–18% at 10 years.[8,14,15] The risk of subsequent contralateral invasive disease becomes more significant only with longer follow-up: 14% at 10 years and up to 18% at 25 years.[8,17] Older patients with LCIS are at an increased risk for developing an invasive cancer. For patients with LCIS who are younger than 40 years of age, the incidence of invasive breast cancer in either breast is 8.3% after 25 years of follow-up but rises to 25% in patients diagnosed with LCIS who are over the age of 60 years.
The pathology of the subsequent invasive cancers after LCIS differs significantly among the studies, although the most recent data show a trend toward ILC occurring in the previous biopsy site. A SEER (Surveillance, Epidemiology and End Results) database review showed that the histology of invasive breast cancer diagnosed after LCIS was lobular in 23% of patients and ductal in 6.5%. These findings support the histological evidence that ALH/LCIS may serve as a precursor to ILC. This observation at the pathological level has not led to changes in the operative treatment of LCIS. The clinical significance of these pathologic findings will require further investigation and, it is hoped, will lead to means of identifying patients who may benefit from greater local treatment of LCIS.