CME/CE

October 2007

Ductal and Lobular Carcinoma in Situ of the Breast: Histopathology and Significance

Heather R. Macdonald, MD; Raquel D. Arias, MD

For many years, ductal and lobular carcinoma in situ of the breast represented a “gray area” with regard to diagnosis, risk, and treatment. Recently, however, data are emerging that can help women and their surgeons make better informed, evidence-based treatment decisions.

Continuing Medical Education

GOAL To clarify the implications of ductal and lobular carcinoma in situ of the breast with regard to diagnostic techniques, risk assessment, and treatment recommendations in women. OBJECTIVES To differentiate between ductal carcinoma in situ (DCIS) and lobular carcinoma in situ (LCIS) in terms of their potential for progression to invasive breast cancer in women. To review diagnostic techniques for their likelihood of detecting or missing DCIS/LCIS in women. To assess surgical and adjuvant treatments regarding their benefit for preventing cancer recurrence and progression in women. ACCREDITATION This activity has been planned and implemented in accordance with the Essential Areas and Policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of Albert Einstein College of Medicine and Quadrant HealthCom Inc. Albert Einstein College of Medicine is accredited by the ACCME to provide continuing medical education for physicians. This activity has been peer reviewed and approved by Brian Cohen, MD, professor of clinical OB/GYN, Albert Einstein College of Medicine. Review date: September 2007. It is designed for -OB/GYNs, primary care physicians, and nurse practitioners. Albert Einstein College of Medicine designates this educational activity for a maximum of 1 AMA PRA Category 1 Credit™. Physicians should only claim credit commensurate with the extent of their participation in the activity. Participants who answer 70% or more of the questions correctly will obtain credit. To earn credit, see the instructions on page 59 and mail your answers according to the instructions on page 60. CONFLICT OF INTEREST STATEMENT The “Conflict of Interest Disclosure Policy” of Albert Einstein College of Medicine requires that authors participating in any CME activity disclose to the audience any relationship(s) with a pharmaceutical or equipment company. Any author whose disclosed relationships prove to create a conflict of interest, with regard to their contribution to the activity, will not be permitted to present. The Albert Einstein College of Medicine also requires that faculty participating in any CME activity disclose to the audience when discussing any unlabeled or investigational use of any commercial product, or device, not yet approved for use in the United States. Dr Macdonald reports that she is a consultant to Senarus, Inc. The disclosure reported by the author presents no conflict of interest to this article. Dr Arias reports that she is a consultant to Barr/Duramed Pharmaceuticals, Inc; Bayer; Berlex; Johnson & Johnson; Novo Nordisk; Novogyne; Organon; Pfizer Inc; Pharmacia; Schering AG; Upsher-Smith; Warner/Chilcott; and Wyeth. All disclosures reported by the author present no conflict of interest to this article. The authors report no discussion of off-label use. Dr Cohen reports no conflict of interest.

Ductal carcinoma in situ (DCIS) and lobular carcinoma in situ (LCIS) are lesions of the breast that (by definition) are confined to the structures from which they arise, and limited in growth by their inability to breach basement membranes. However, similarities between the two entities end there. Whereas DCIS is a preinvasive malignancy, there is controversy regarding the significance and treatment of LCIS. This review summarizes recent data and recommendations regarding these pathologic entities.

DUCTAL CARCINOMA IN SITU

Ductal carcinoma in situ describes pathologic changes that are the final steps in a spectrum of ductal cell proliferation (Figure 1), that is:

• Benign proliferation (ductal hyperplasia of the usual type)
• Atypical ductal hyperplasia (ADH), which requires surgical excision due to an increased risk of undiagnosed cancer nearby
• Ductal carcinoma in situ (malignant ductal epithelial cells confined to branches of the ductal tree).

In the final step of this progression, the malignant ductal cells invade surrounding breast tissue and become invasive ductal carcinoma.

The incidence of DCIS has increased in the past 3 decades due to the advent of mammographic screening. In the 1970s in situ carcinoma comprised only 4% of breast cancers; today, DCIS represents 20% of newly diagnosed breast cancers.1

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Natural History

Ductal carcinoma in situ is a precursor lesion with the potential to progress to invasive carcinoma. Longitudinal studies of patients with breast biopsy findings initially diagnosed as benign but retrospectively identified as DCIS reveal high rates of recurrence or progression. In the Nurses’ Health Study, 13 patients were identified with previously undiagnosed DCIS.2 Follow-up of these women found 10 who experienced recurrence or developed invasive breast cancer.2 Another study of patients in whom excisional biopsy had missed DCIS revealed a 50% occurrence of ipsilateral breast cancer after undertreatment of DCIS.1 In most, the disease recurred or progressed within 5 years, but some arose over 15 to 20 years. Likewise, follow-up from studies that treated DCIS via excision with no attempt to achieve clear margins confirms a high rate of recurrence or progression.3

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Diagnosis

Most DCIS is identified by screening mammography—usually as a suspicious cluster of calcifications in a linear or branching pattern. The 2005 International Consensus Conference on Image Detected Breast Cancer concluded that all mammographically detected lesions should be evaluated by core needle biopsy before proceeding to open excision.4 If minimally invasive diagnostic procedures (eg, stereotactic or ultrasonographically guided core needle biopsy) are utilized, diagnosis can be established before surgery. This allows for optimal planning by patient and surgeon regarding possible breast conservation or immediate breast reconstruction postmastectomy. These minimally invasive diagnostic approaches have the potential to accomplish oncologic treatment in a single operation, rather than using an excisional biopsy (which may not achieve clear margins) followed by a second procedure. Minimally invasive breast biopsy may also obviate the need for excisional biopsy if the core needle biopsy results are benign. At times, a lesion may not be amenable to percutaneous core needle biopsy because it is too superficial or too close to the chest wall; these cases require open surgical evaluation.

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Treatment

In the past, DCIS was treated with modified radical mastectomy. However, in keeping with the general trend toward breast conservation when possible, DCIS is increasingly treated with breast conservation plus radiation to decrease local recurrence, with or without hormone manipulation to decrease contralateral breast disease and distant metastasis.

Subgroup analyses of randomized, controlled trials have determined that patients with localized DCIS can be treated safely with breast conservation.5 Survival rates are equivalent to those among women undergoing mastectomy. In a comparison of DCIS treated by simple excision (lumpectomy) or excision plus radiation (breast conservation),6 the risk of recurrence was reduced from 32% to 16%, respectively (Figure 2).6 Survival rates were the same for both groups. This study led to the current recommendations for the surgical management of DCIS—simple mastectomy versus lumpectomy with adjuvant radiation. Women who choose breast conservation must be informed of an increased recurrence risk over mastectomy, although survival is unaffected. Additionally, patients with extensive DCIS or small breast volume may not be eligible for breast conservation due to cosmetic concerns.

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FIGURE 2. National Surgical Adjuvant Breast and Bowel Project B-17, 12-Year, Data.6

Subsequent studies have shown that the addition of adjuvant tamoxifen further decreases rates of local recurrence and contralateral disease, but has no impact on survival.7 There is also no proven benefit for adjuvant chemotherapy in the treatment of DCIS, or for adjuvant radiation postmastectomy.

There is controversy regarding the need for adjuvant radiation in all DCIS patients treated by excision. Factors affecting local recurrence include (Figure 3):

• Tumor size
• Nuclear grade
• Patient age
• Surgical margin width.

Clinical Pearls Patients who undergo excisional biopsy in which ductal carcinoma in situ (DCIS) is missed have a 50% rate of subsequent ipsilateral breast cancer. All patients with mammographically detected lesions should undergo core needle biopsy prior to open excision. Minimally invasive diagnostic techniques allow the surgeon and the patient to choose between breast conservation and immediate breast reconstruction postmastectomy. In patients with DCIS survival rates for breast conservation are equivalent to those for mastectomy. Current recommendations for surgical management of DCIS are simple mastectomy or lumpectomy with adjuvant radiation. Older patients with small, low-grade, well-excised DCIS do not benefit from radiation. Lobular carcinoma in situ (LCIS) is a multicentric, bilateral, low-malignancy, indolent lesion that increases the lifetime risk of breast cancer by 12-fold. Diagnosis of LCIS or atypical lobular hyperplasia (ALH) is usually made on core needle biopsy triggered by a mammographic abnormality. Core needle biopsy can underestimate breast disease in cases of lobular neoplasia. Among LCIS patients, tamoxifen reduces the risk of breast cancer by 56%, but increases the incidence of endometrial cancer and pulmonary emboli in women over the age of 50 years. In a patient with LCIS, the potential for an underlying malignancy is 20% to 50%.

The University of Southern California-Van Nuys Prognostic Index uses these factors to identify women with a recurrence risk too low to benefit from radiation—such as older patients with small, low-grade, well excised DCIS.1,8,9 At the other end of the spectrum, young patients with large, high-grade lesions have a recurrence risk too high to be affected by excision plus radiation; these women are better treated with mastectomy.8,9

As DCIS cannot spread to the lymphatic system, axillary node dissection and sentinel node biopsy are generally not appropriate.10 Sentinel node biopsies may be performed if there is a suspicion of invasive cancer at surgery, or if mastectomy disrupts lymphatics and precludes future assessment of sentinel nodes.

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LOBULAR CARCINOMA IN SITU

Definition and Incidence

Lobular carcinoma in situ refers to a disorderly proliferation of epithelial cells confined to the terminal ductal-lobular units of breast tissue. It is considered to be the culmination of a spectrum of atypical lobular hyperplasia (ALH) or lobular neoplasia.

The incidence of LCIS is increasing. Before 1980, when breast disease was commonly identified by abnormal physical findings and treated with excisional biopsy, LCIS comprised 0.6% of breast pathology in the United States.11 With the advent of mammography this incidence rose to 1.6%, climbing to 1.2/100,000 in the 1970s and 2.8/100,000 by the mid-1990s.12 The incidence of LCIS in core needle biopsy specimens is 1.2%.13

Significance and Treatment

First identified in 1942, LCIS has been described as multicentric, bilateral breast change—an indolent lesion of low malignancy that increases a woman’s lifetime risk of breast cancer by 12-fold.6,11 There is a 7% incidence of invasive breast cancer within 10 years of diagnosis14; subsequent breast cancers can occur as late as 15 years postdiagnosis. No distinctive mammographic characteristics have been identified for LCIS or ALH.12,15 In the past, treatment ranged from close observation to bilateral prophylactic mastectomy.

Currently, a diagnosis of LCIS or ALH is most often made on core needle biopsy triggered by a mammographic abnormality, raising questions about the necessity of surgical excision. Reports of the incidence of preinvasive or invasive cancer—all after core needle biopsy findings of lobular neoplasia—range from 2% to 50%,12,16-18 but most studies show a risk of 15% to 20%. For example, 13 breast malignancies (four preinvasive, nine invasive) were identified in 28 patients who underwent excision for lobular neoplasia,17 with similar findings in five of 21 patients undergoing excision or observation for LCIS or ALH.18 Ductal carcinoma in situ or invasive cancer was diagnosed in four of 13 LCIS and five of 20 ALH patients who underwent excision12; this study included a review of the literature describing 39 breast cancers in 284 patients (16%) with ALH, and 50 breast cancers in 255 patients (19%) with LCIS. Another review of 159 cases of ALH or LCIS noted invasive cancer in 19% of patients.19 These findings indicate an underestimation of breast disease by core needle biopsy in cases of lobular neoplasia. As LCIS and ALH do not have distinctive mammographic appearances, this undersampling error suggests that these lesions must be excised.12

In the past local excision of LCIS was discouraged due to the purported bilateral tendency of the disease, but this may have been overstated.20 In a study of 252 women diagnosed with ALH, 50 developed invasive cancer—68% in the ipsilateral breast and 24% in the contralateral breast (3:1).20

Chemoprophylaxis of invasive cancer is an option for patients with ALH or LCIS. Lobular neoplastic epithelial cells are usually estrogen-receptor-positive.16 The National Surgical Adjuvant Breast and Bowel Project conducted a prevention trial using tamoxifen,21 and of the subjects with LCIS, tamoxifen reduced the risk of breast cancer by 56%. Among patients with ALH, 23 in the placebo group developed cancer versus three in the tamoxifen group. Statistically significant adverse effects included an increased incidence of endometrial cancer and pulmonary emboli among women over age 50 years.

A subsequent trial compared tamoxifen with raloxifene for chemoprophylaxis.22 It found similar breast cancer risk reductions for both drugs, with a trend toward fewer cases of thromboembolism and endometrial cancer in raloxifene users (Figure 4). However, raloxifene was not shown to prevent DCIS or preinvasive breast cancer, whereas tamoxifen did.

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FIGURE 4. Breast cancer risk modification: study of tamoxifen and raloxifene trial.22

Lobular neoplasia, which includes LCIS and ALH, confers an elevated lifetime risk of breast cancer. Due to the risk of sampling error with core needle biopsy, consideration should be given to complete excision. The potential for an underlying malignancy is 20% to 50%. Additionally, the patient should be counseled regarding her lifetime elevated risk of breast cancer, and offered chemoprophylaxis after a careful evaluation of risks and benefits.

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CONCLUSION

In the future, the diagnosis of lobular neoplasia will likely be refined with a grading system (analogous to cervical neoplasia) that assigns levels of suspicion and risk. Even now, studies have begun to identify pathologic characteristics that may allow for identification of high- and low-risk lesions.19,23

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Heather R. Macdonald, MD, is assistant professor, Clinical Obstetrics and Gynecology and Breast Surgery, Keck School of Medicine, University of Southern California, Los Angeles; and director, Women’s Breast Diagnostic Clinic at Women’s Hospital, Los Angeles County, CA. Raquel D. Arias, MD, is associate professor and associate dean for women, University of Southern California Health Care Consultation Center, Los Angeles.

References

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3. Sanders ME, Schuyler PA, Dupont WD, Page DL. The natural history of low-grade ductal carcinoma in situ of the breast in women treated by biopsy only revealed over 30 years of long term follow-up. Cancer. 2005;103(12):2481-2484.
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22. Vogel VG, Costantino JP, Wickerham DL, et al. Effects of tamoxifen vs raloxifene on the risk of developing invasive breast cancer and other disease outcomes: the NSABP Study of Tamoxifen and Raloxifene (STAR) P-2 trial. JAMA 2006;295(23): 2727-2741.
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