Noninvasive Breast Cancer

Introduction

Noninvasive breast cancer is composed of three distinct histological entities: lobular carcinoma in situ (LCIS); Paget disease; and ductal carcinoma in situ (DCIS). They comprise a large percentage of all breast cancers diagnosed today owing to the widespread use of screening mammography. Mastectomy was frequently used to treat these conditions in the past, but improved understanding of these diseases led to much greater use of breast-conserving therapy (BCT) and systemic risk-reduction options. There remains substantial controversy regarding their optimal treatment.

Lobular Carcinoma in Situ

LCIS was first described by Foote and Stewart in 1941. It is a noninfiltrating lobular proliferation characterized by loose, noncohesive epithelial cells filling the acinar space. Multicentric breast involvement is seen in up to 90% of mastectomy specimens, with bilateral involvement in 35% to 59%. The degree of lobular involvement ranges from a simple filling of the ductal lumens to moderate distention to overt distention with extension into the adjacent extralobular ducts. Distinguishing between atypical ductal hyperplasia, LCIS, and (when ductal extension is present) DCIS can be difficult, with controversy over how best to do this. There is also debate over how to classify LCIS. Molecular markers may help in problematic cases. LCIS cells are frequently ER positive, and rarely overexpress HER2 or contain p53 mutations, with the exception of pleomorphic LCIS (which has high rates of Ki-67 and p53 positivity). Loss of CDH1 gene expression occurs in more than 95% of LCIS cases. The CDH1 gene is a calcium-dependent cellular adhesion molecule that is responsible for epithelial organization. Its absence may thus explain the noncohesive morphological characteristics of LCIS.

LCIS constitutes 0.5% to 3.6% of neoplastic findings on breast biopsies, representing less than 15% of all noninvasive lesions; however, population-based analyses suggest that this rate may be increasing. LCIS does not typically have clinical or mammographic indicators of its presence and is typically an incidental finding when a biopsy is performed for alternative reasons. The presence of calcifications not explained by other pathological findings warrants excisional biopsy. DCIS, invasive disease, or both, are identified on excisional biopsy in 22% to 27% of cases when LCIS is the sole histological entity seen on core biopsy. There is no consensus on a scenario in which patients can be observed without excisional biopsy following core biopsy showing LCIS.

About 12% of early-stage breast cancers have an associated component of LCIS. Several institutional experiences have evaluated the potential impact of the presence of LCIS on BCT outcomes. While the number of patients in these studies is small and there are differences in pathological assessment, length of follow-up, and use of endocrine therapy in these cohorts, the majority of studies found no difference in ispilateral breast tumor recurrence (IBTR), distant disease-free survival (DFS), and overall survival (OS) in the presence or absence of LCIS. Therefore, currently, DCIS or invasive disease are managed without reference to the presence of LCIS. Additional surgery is not pursued to obtain clear margins for LCIS.

The significance of LCIS was unknown when it was first described. Patients were routinely treated with mastectomy. The discovery that LCIS was frequently bilateral led to recommendations to perform random contralateral biopsies and bilateral mastectomy. Observational studies in patients treated with lumpectomy led to a better understanding of the natural history of this disease, and a more conservative approach is now commonly practiced. One population-based study found that 73% of patients recently diagnosed with LCIS underwent excision alone, 16% mastectomy, 10% biopsy, and 1% excision with radiotherapy.

Studies of CDH1 and loss of heterozygosity (LOH) suggest that LCIS may be a precursor to invasive disease for some patients. However, LCIS has more commonly been thought to be a marker for an increased risk of developing invasive disease (9–12 times that of the normal population). This risk extends beyond at least 20 years, implying that patients with LCIS require continuing surveillence.

Studies differ on the risk of patients with LCIS treated with breast-conserving surgery for developing ipsilateral cancers or contralateral breast cancer (CBC). These studies are summarized in Table 72.1 . This variation results in part from differences in the length of follow-up, definitions used for histological classification (atypical lobular hyperplasia vs. LCIS), and the extent of excision.

These studies also have different implications with regard to the ability of LCIS to give rise to an invasive cancer. For example, the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-17 trial registered 182 patients with LCIS who were treated with lumpectomy alone. The 12-year IBTR rate was 14.4%, and the CBC rate was 7.8%. Of the 26 IBTRs, 9 (34.6%, or 5% of the total cohort) were invasive and 17 (65.4%, or 9% of the total cohort) were noninvasive, consisting of DCIS alone in 6 patients, LCIS alone in 10 patients, and both DCIS and LCIS in 1 patient. These results should be interpreted carefully, as there is controversy regarding whether LCIS should be defined as a tumor recurrence. Although the frequency of CBCs was less than that of IBTRs, the frequency of invasive CBCs (5.6% of the total cohort) was similar to that of invasive IBTRs (5% of the total cohort). All of the IBTRs were documented to be at the site of the index lesion except for one, characterized as pure LCIS, which was found at a remote site.

The mortality rate for patients with LCIS treated with local excision due to the subsequent development of invasive breast cancer in past studies has been as high as 5% to 7% at 10 years. More recent data have demonstrated lower rates. This likely reflects the use of close mammographic and clinical follow-up, leading to early detection of subclinical abnormalities with much better prognosis. This is reflected in the lower mortality risk (1%) reported by the NSABP.

The currently accepted management approach for patients with LCIS is close observation with regular physical examinations and mammographic surveillance. There is no role for radiotherapy in their management at present. Since patients with LCIS are at roughly equal risk of developing invasive cancer in either breast, performing ipsilateral mastectomy is not a logical approach.

As noted, patients with LCIS are at substantially elevated risk of developing invasive cancer over time. Hence, preventive strategies are appropriate. Bilateral prophylactic mastectomy is thought to be excessive except for patients believed to be at highest risk (i.e., young patients, those with diffuse process, or a significant family history of disease). Endocrine therapy significantly lowers the risk. The 5-year risk of subsequent disease was reduced by 56% in patients with receiving tamoxifen compared with placebo in the NSABP P-01 trial.

There has been increasing recognition that pleomorphic LCIS has a different biological behavior than classic LCIS, as reflected by expression of molecular markers and higher rates of underlying invasive malignancy on excision. Several studies found that variants of LCIS, including pleomorphic LCIS, were misinterpreted as solid DCIS in up to 15% of cases and that 40% of such cases had underlying invasive lobular carcinoma at the time of surgery. The management of patients with pleomorphic LCIS is controversial. Some data suggest that the risk of local recurrence can be reduced with the use of surgical margins wider than 2 mm and adjuvant radiotherapy. However, studies of pleomorphic LCIS are limited by small patient numbers, and firm conclusions regarding the use of adjuvant radiotherapy cannot be made until further studies are available.

Paget Disease

Paget disease constitutes 0.5% to 5% of all breast cancers. The clinical presentation of crusting, bleeding, and ulceration of the nipple was first described in 1856, but it was not until 1874 that the association with an underlying breast carcinoma was recognized by Sir James Paget. Patients describe itching and burning of the nipple and areola and often crusting. There is a slow progression toward an eczematoid appearance, which can extend to the skin. If neglected, bleeding, pain, and ulceration can occur. A palpable mass is detected in about 50% of patients at diagnosis. It is most commonly unilateral, but bilateral and male Paget disease have been reported. Evaluation should include bilateral breast examination, mammography, and full-thickness biopsy to confirm the diagnosis as well as fully evaluating the extent of the underlying malignant disease. The use of magnetic resonance imaging (MRI) should be considered for individuals with a positive biopsy for Paget disease without an underlying mass.

Paget disease is characterized histologically by the presence of unique, clearly identifiable Paget cells that are described as large, round to oval cells that contain hyperchromatic nuclei and prominent nucleoli with frequent mitoses. Paget cells occur singly or in clusters and are scattered throughout the epidermis. The differential diagnosis includes superficial spreading melanoma, pagetoid squamous cell carcinoma in situ, and clear cells of Toker. More than 90% of patients have invasive carcinoma if there is a palpable mass. About 66% to 86% of patients will have underlying DCIS if there is no palpable mass. These adjacent underlying malignant tumors are usually located centrally; however, they can also be located elsewhere in the breast.

The appropriate management of patients with Paget disease remains unsettled. Mastectomy is effective. Pathological evaluation of mastectomy specimens suggests that BCT should be feasible if adequate margins can be obtained.

Small series have described results with limited surgical resection alone, radiotherapy alone, and limited resection followed by radiotherapy ( Table 72.2 ). Local control rates appear highest with the latter combination. European Organization for Research and Treatment of Cancer (EORTC) Study 10873 was a multi-institutional registry study in which 61 patients were treated with complete excision of the nipple-areolar complex and underlying breast tissue with tumor-free margins followed by whole-breast radiotherapy (50 Gy). The majority of patients had underlying DCIS without a palpable mass. With median follow-up of 6.4 years, the 5-year local recurrence rate was 5.2%. A 7-institution collaborative study included 36 patients with Paget disease without a palpable mass or mammographic density undergoing complete (69%) or partial (25%) excision of the nipple-areolar complex and underlying breast tissue, with 6% of cases reported as biopsy only. The final margin status was negative in 56% of cases, positive in 6%, and unknown in 39%. All patients received whole-breast irradiation (median dose, 50 Gy), and the majority received an additional boost to the tumor bed. With median follow-up of 9.4 years, actuarial rates of IBTR as the only site of first recurrence were 9% at 5 years and 13% at both 10 years and 15 years. No clinical, pathological, or treatment factors were significantly associated with local recurrence. Finally, a series of 223 patients treated in Sweden found no difference in breast cancer-specific survival or DFS rates between patients treated with breast-conserving surgery or mastectomy.

An individual's prognosis and local and systemic therapies should be based on the nature of any associated underlying malignancy as well as the presence of Paget disease. Therefore, local treatment decisions and systemic therapy should be based on the underlying disease. Patients with no or limited underlying disease who have complete resection of the nipple-areolar complex excision in conjunction with any underlying disease with a negative microscopic surgical margin can have BCT, which should include whole-breast irradiation. Sentinel node biopsy should be performed for patients undergoing mastectomy or those treated with BCT if there is underlying invasive cancer. Systemic therapy should be given as appropriate for patients with invasive cancer. The role of chemoprevention in patients with Paget disease is not known.

Ductal Carcinoma in Situ