The Biology and Management of Ductal Carcinoma in Situ of the Breast: In Brief

An excerpt from an original article published by Elsevier journals: Current Problems in Surgery, Volume 60 Number 8 August 2023

The Biology and Management of Ductal Carcinoma in Situ of the Breast: In Brief

Ismail Jatoi, MD, PhDa, Abeer M. Shaaban, PhD, FRCPathb , Eric Jou, MB BChir, PhDc , John R. Benson, MD, DM, FRCS

Ductal carcinoma in situ (DCIS), sometimes referred to as intraductal carcinoma, is generally a nonpalpable lesion of the breast, detected on screening mammography. The incidence of DCIS is closely intertwined with the usage of mammography screening, as most patients who are diagnosed with DCIS are asymptomatic. Hence, the greater usage of screening mammography has led to dramatic increases in detection and incidence rates of DCIS. In the United States prior to the advent of mammography screening in the late 1970s, DCIS accounted for less than 5% of all breast tumors, but with the widespread use of mammography screening in recent years, it now comprises 20% to 25% of all breast tumors.

DCIS often appears as an area of suspicious microcalcification on screening mammography. However, only approximately 75% of all DCIS cases may contain calcifications, and therefore many cases are not detectable with screening mammography, with the implication that the true incidence of DCIS may be substantially underestimated. Nonetheless, as the practice of screening mammography continues to increase throughout the world, the detection rates of DCIS have increased as well, and the optimal management of these lesions has generated intense interest and controversy.

Although most patients diagnosed with DCIS are asymptomatic and the lesion is detected on screening mammography, in rare instances some do present with symptoms, specifically nipple discharge, Paget’s disease of the breast, or a palpable breast mass. There is now epidemiological evidence suggesting that patients diagnosed with DCIS have a higher risk of dying of breast cancer when compared to the general population, and yet they have a lower risk of dying from all causes (ie, DCIS patients seem to have a higher breast cancer-specific mortality, but a lower all-cause mortality). What might account for this paradox?

This paradox is likely attributable to the fact that DCIS is very rarely detectable on clinical examination, and almost always detected with mammography screening, and women who elect to undergo mammography screening tend to be more health conscious than those who do not. Participants of cancer screening programs are more likely to lead healthier lifestyles. Furthermore, women who undergo screening generally have improved access to good quality health care. Thus, there is a strong selection bias with respect to women who undergo mammography screening, with screening programs selecting out healthier cohorts of women from the general population. This selection bias likely accounts for the lower all-cause mortality among women diagnosed with DCIS on mammographic screening.

Despite their lower all-cause mortality, DCIS patients have a 3-fold greater risk overall of dying from breast cancer when compared to the general population. At 20 years following a diagnosis of DCIS, breast cancer-specific mortality is 3.3% overall, and it is higher for women who received their DCIS diagnosis before age 35 when compared to older women, and higher for Black women diagnosed with DCIS when compared to non-Hispanic White women.

In 1989, Peeters and colleagues defined “overdiagnosis” as “a histologically established diagnosis of invasive or intraductal breast cancer that would never have developed into a clinically manifest tumor during the patient’s normal life expectancy if no screening examination had been carried out.” The detection of DCIS with mammography screening is often used as a good example of overdiagnosis and often serves to illustrate the potential harms of overdiagnosis. Many cases of DCIS that are detected with mammography screening would likely never have been detected in the absence of screening and pose no threat to life. Hence, the overdiagnosis of DCIS may lead to unnecessary treatments, and patients may incur a small excess risk of morbidity and mortality from those unnecessary treatments. Overdiagnosis may have a profound adverse effect on quality of life.

Asymptomatic patients with DCIS generally present with a suspicious finding on a screening mammogram. This triggers an image-guided core biopsy of the area of concern in the breast, and subsequent histological evaluation of the biopsy specimen may confirm a diagnosis of DCIS or show a proliferative lesion with or without atypia. Ultimately, after surgical removal of the lesion, the diagnosis of DCIS is established. However, approximately 15% of patients diagnosed with DCIS alone on image-guided core biopsy will be upstaged pathologically to invasive breast cancer (IBC) following surgical removal of the area of concern.

Under the current paradigm, DCIS is not considered to be a systemic disease. Treatments are intended to prevent local recurrence, both of pure DCIS and invasive disease. Surgery, radiotherapy (RT), and endocrine therapy (for estrogen receptor [ER]-positive DCIS) are utilized either alone or in combination to reduce the risk of local recurrence. Systemic treatments (ie, tamoxifen and aromatase inhibitors) are administered to reduce the risk of local recurrence. At the present time, there is no role for adjuvant chemotherapy for the management of DCIS. To date, none of the trials that have assessed the various permutations of treatment for DCIS have shown a mortality benefit for 1 treatment option over another. However, differences in local recurrence rates between various therapeutic regimens have emerged in clinical trials, and treatments that reduce the risk of local recurrence have now been widely implemented into routine clinical practice.

DCIS that is localized to 1 quadrant of the breast is generally amenable to some form of breast-conserving surgery (variously also referred to as lumpectomy, partial mastectomy, wide local excision, or segmentectomy). It is important that DCIS is completely excised, with clear surgical margins around the lesion. However, there is persistent controversy as to what constitutes a “clear margin,” but current guidelines recommend a 2 mm tumor-free margin around the DCIS, based on nonrandomized evidence from meta-analyses and large data sets.

Nonetheless, despite clear resection margins after lumpectomy, there is approximately a 25% risk of local recurrence, with one half these cases being DCIS and the rest invasive dis[1]ease. Adjuvant RT may be administered and reduces the risk of local recurrence by approximately 50% for all age groups. Moreover, RT has a similar magnitude of effect for IBC and DCIS I. Jatoi, A.M. Shaaban and E. Jou et al. / Current Problems in Surgery 60 (2023) 101362 3 (approximately 50% reduction in risk of local recurrence for each). Following surgery and RT, the risk of local recurrence can be reduced even further by the administration of endocrine therapy (ie, tamoxifen or an aromatase inhibitor) for 5 years for patients with hormone receptor (HR)- positive DCIS. Approximately 70% to 80% of all DCIS are positive for ER and/or progesterone receptor (PR). Tamoxifen can be administered to either premenopausal or postmenopausal women, while aromatase inhibitors are used only for postmenopausal women.

For patients with multicentric DCIS (ie, foci of DCIS in more than 1 quadrant of the breast), total mastectomy is usually mandatory, but a very wide excision with partial breast reconstruction may be possible. Under such circumstances, RT is usually not required. However, endocrine therapy might still be recommended by some oncologists after unilateral total mastectomy to reduce the risk of a new breast cancer (IBC or DCIS) in the contralateral breast. For patients treated with bilateral mastectomy, there is rarely any indication for either RT or endocrine therapy.

Sentinel lymph node biopsy is not usually indicated for screen-detected DCIS treated with lumpectomy. However, if a patient presents with a palpable lump in the breast and the core biopsy reveals DCIS alone, then sentinel node biopsy should be considered. In such cases, failure to detect IBC might be attributable to under-sampling of the breast mass with core biopsy, and the IBC will often be evident on histology after extirpation of the entire palpable breast mass. Moreover, if core biopsy reveals DCIS with microinvasion, sentinel node biopsy should be considered with lumpectomy, because many of these patients will be upgraded to IBC (ie, IBC discovered on histology) following lumpectomy.

Sentinel node biopsy should be considered for patients with extensive DCIS who undergo mastectomy. There is approximately a 15% chance that DCIS diagnosed on core biopsy will be upstaged to IBC following histological examination of the surgical specimen. As the lymphatic connections between the breast and axillary lymph nodes are abrogated following extirpation of all breast tissue, it may not be possible to subsequently identify the sentinel node if invasion is discovered upon histological evaluation of the mastectomy specimen. Hence, it is justifiable to perform sentinel node biopsy at the time of the mastectomy for multicentric DCIS.

Several clinicopathological and treatment factors have been linked to increased risk of DCIS recurrence after breast-conserving surgery. Those include younger age, adverse histological features such as high grade and comedonecrosis, large lesion size, involved margins, and molecular profile (higher risk for HER-2 positive DCIS). Adjuvant RT and/or endocrine therapy have consistently been shown to provide a protective effect and reduce the risk of recurrence. This protective effect was particularly evident in older women, with 10-year absolute risks of 18.5% vs 29.1% at ages = 50 years.

The natural history of DCIS is incompletely understood, and epidemiological and clinical observations often seem inconsistent with the commonly accepted paradigm. Considerable research is now directed towards better elucidating the natural history of DCIS. In the years ahead, our treatment recommendations will undoubtedly continue to evolve as we gain a better understanding of this perplexing clinical entity.