ABSTRACT: Utilizing routine histopathologic parameters obtained from appropriately handled lumpectomy and mastectomy specimens, a rational therapeutic plan based on epidemiologic and outcome-based data can be devised for any patient diagnosed with ductal carcinoma in situ (DCIS). In order to make a sound decision when weighing the current treatment options for DCIS—which include excision alone, excision plus radiation, and mastectomy—the following are mandatory: 1) assurance of an accurate diagnosis, 2) assessment of DCIS size and grade, and 3) careful margin evaluation. Accurate grading of DCIS is critical, since high nuclear grade and the presence of necrosis are highly predictive of the inability to achieve adequate margins, of local recurrence, and of the probability of missed areas of invasion. Margin status is the single most important determinant of local control following breast conservation for DCIS; numerous studies have shown that as the margin width increases, the risk of local failure decreases. The pros and cons of irradiating conservatively treated patients with DCIS should be carefully weighed on a case-by-case basis. Despite the 20-year-old dogma that all patients treated with breast conservation should receive postoperative radiation, a subset of patients who can be successfully treated by excision alone has been identified.
It is ironic that while huge strides have been made in the treatment of invasive breast carcinoma, resulting in breast conservation for many women, the most appropriate treatment of noninvasive breast carcinoma remains a topic of hot debate. This article explores some of the issues related to this controversy, with an emphasis on critical therapy-guiding information that can be derived from appropriately handled specimens using routine histopathologic parameters.
The diagnosis of ductal carcinoma in situ (DCIS) was rare before the 1980s; however, DCIS now represents a significant proportion of breast cancers, with an estimated 54,010 new cases diagnosed in 2010. This markedly increased incidence is a reflection of the widespread use of high-quality mammography as well as the histologic recognition of a wide spectrum of disease. Before a definitive treatment plan can be devised for any patient diagnosed with DCIS, three things are mandatory: 1) assurance of an accurate diagnosis, 2) assessment of DCIS size and grade, and 3) careful margin evaluation. The information these provide should be considered when weighing the current therapeutic options for DCIS, which include excision alone, excision plus radiation, and mastectomy.
What is the most important entity in the differential diagnosis for DCIS?
Atypical ductal hyperplasia (ADH) is the most important entity included in the differential diagnosis for low-grade DCIS. ADH has histologic and molecular features that are similar to those of DCIS, but its natural history and therapeutic implications are quite different. ADH is associated with a bilateral increased risk of later cancer development (verified by several large epidemiologic studies) that is four to five times higher than that in age-matched controls.[1-4] This contrasts sharply with DCIS, a nonobligate local precursor for which subsequent risk is localized to the same breast and same site as the index DCIS.[5-7] Although establishing the diagnosis of DCIS is usually straightforward, distinguishing small, low-grade DCIS lesions from ADH can occasionally be difficult; however, this difficulty has recently been exaggerated. In general practice, when strict epidemiologically validated criteria are followed, pathologists are able to accurately diagnose DCIS and can easily make this important distinction (Figure 1). For the uncommon but clearly acknowledged borderline cases, a conservative diagnostic stance is favored to assure that the patient is not overtreated.
What is the natural history of DCIS?
Natural history studies from the premammographic era that retrospectively identified small, incidental, low-grade examples of DCIS clearly demonstrated that untreated DCIS carries a 25% to 30% absolute risk of recurrence localized to the same breast and same site as the index DCIS.[7,10] For low- and intermediate-grade DCIS, this risk may extend more than 20 years (although the greatest risk is in the first 10 years following biopsy). The interval of increased recurrence risk following a diagnosis of high-grade DCIS is significantly shorter. Because under normal circumstances no woman today would go untreated when DCIS is diagnosed, these data do not apply directly. However, they can be used to make informed decisions regarding close or involved margins. Women with large DCIS lesions (greater than 5 cm) may not be candidates for breast conservation, since 10-year follow-up studies show that radiation cannot adequately compensate for close or involved margins and may delay recurrence detection, resulting in a greater proportion of invasive recurrences than are seen with excision only.[13,14] In contrast, for small, completely excised DCIS, especially cases that are low grade and in older women, the recurrence interval may well extend beyond the life expectancy of the patient. Such lesions carry a low potential for subsequent invasive cancer development—approximately 1% per year. This risk is only slightly greater than that associated with lobular carcinoma in situ, a lesion typically treated with close clinical follow-up. This wide spectrum of behavior underscores the important contributions made by studies that seek to identify a subset of low-risk patients who can be successfully treated by excision alone (see below). Indeed, Ozanne et al have suggested, using statistical models, that the potential for DCIS to progress to invasive cancer is currently overestimated, often resulting in overtreatment.
How should an excisional biopsy specimen containing DCIS be handled?
The majority of DCIS are now diagnosed by stereotactic core biopsy performed to evaluate mammographically detected microcalcifications. Establishing a diagnosis of DCIS on core biopsy allows for proper handling of a subsequent excisional biopsy specimen; proper handling is necessary in order that essential diagnostic elements not be compromised. Recent studies have shown that a systematic approach, including serial sectioning and sequential submission of lumpectomy specimens (which enables the extent of the DCIS to be measured in three dimensions), is a reliable and accurate method for documenting DCIS size.[17,18] The importance of the pathologist's careful attention to this measurement cannot be overemphasized, as it directly impacts further treatment considerations. DCIS size has been shown by numerous studies to correlate with close or positive margins, the likelihood of residual disease, and the probability of local recurrence and missed areas of invasion.[19-28] In addition, radiographs of the whole specimen should be obtained at the time of surgery—preferably in at least two dimensions—to document the presence of microcalcifications and their relationship to the surgical margins. This can facilitate removal of additional margins at the time of the initial surgery, thereby avoiding a second surgical procedure. Although not mandatory, obtaining additional radiographs of the sliced specimen can also be very useful in guiding the sampling of large specimens for which complete embedding is not feasible.