The vast majority (83%) of newly diagnosed in situ breast cancers are DCIS. DCIS refers to a condition in which abnormal cells arising in the terminal duct lobular units replace the epithelium of terminal and subsegmental ducts and sometimes the acini as well; however, the basement membrane remains intact, with no evidence of stromal invasion. Criteria for the diagnosis of DCIS and its various subtypes take into account the degree of cytologic abnormality, the architectural patterns formed by the abnormal cells, the presence or absence of necrosis (cellular death and degeneration), and a minimum required size (measured diameter or number of involved ducts) of the lesion (although the details of how these features are applied to individual cases are beyond the scope of this review).
DCIS is viewed as a true (nonobligatory) precursor lesion for invasive cancer; however, data are limited about the proportion of detected DCIS lesions that will progress to invasive cancer without treatment. Long-term studies of women whose DCIS was untreated because the biopsy was misclassified as benign found that 20% to 53% were diagnosed with an invasive breast cancer over the course of 10 or more years.[13-17] A recent update of one of those studies reported follow-up on 45 women with low-grade DCIS who were treated by biopsy only and were recognized retrospectively during a larger review of surgical pathology diagnoses and original histological slides for 26,539 consecutive breast biopsies performed at Vanderbilt, Baptist, and Saint Thomas Hospitals in Nashville, Tennessee, from 1950 to 1989, including 28 women whose long-term follow-up was reported previously. Sixteen women (36%) developed invasive breast carcinoma, all in the same breast and quadrant as their incident DCIS. Eleven of these invasive breast carcinomas were diagnosed within 10 years of the DCIS biopsy. Subsequent cases were diagnosed at 12, 23, 25, 29, and 42 years. Seven women, including one who developed invasive breast cancer 29 years after her DCIS biopsy, developed distant metastases, resulting in death from 1 to 7 years postdiagnosis of invasive breast carcinoma.
The relevance of historical studies to the natural history of more contemporary lesions should be interpreted with caution, as characteristics of contemporary DCIS lesions differ from those of DCIS lesions diagnosed before mammographic screening was widespread, and, in some studies, the extent of resection is unclear. Additional insight into the behavior of small DCIS lesions treated with excision alone comes from a multicenter intergroup trial that was open to patients who were diagnosed during 1997 through 2002 with low-grade or intermediate-grade DCIS >0.3 cm and <2.5 cm in size (n = 565) or with high-grade DCIS >0.3 cm and <1.0 cm in size (n = 105) in which all lesions were completely excised with margins of at least 3 mm, and had negative postexcision mammograms. With a median follow-up period of 6.3 years, the 7-year rates of local recurrence were 10.5% for the low-grade/intermediate grade group and 18% for the high-grade DCIS group, with invasive carcinoma comprising 53% of recurrences in the low-grade/intermediate-grade group and 35% of recurrences in the high-grade group. In a subset of 327 patients, 10-year rates of invasive cancer recurrence were 3.7%, 12.3%, and 19.2% in the low-grade, intermediate-grade, and high-grade groups, respectively.[1, 19]
Although DCIS can present as a palpable mass, it is most often detected by the appearance of microcalcifications in a mammogram. The histologic diagnosis of DCIS is commonly made by examination of core-needle biopsy, followed by excision and definitive pathologic examination. Approximately 25% of lesions diagnosed as DCIS on core biopsy will be found to also include invasive carcinoma after surgical resection; factors associated with the finding of invasive cancer include larger lesion size, intermediate or high nuclear grade, and negative hormone receptor status.[20, 21] Because of the potential for finding invasive disease, the National Comprehensive Cancer Network (NCCN) guidelines recommend that sentinel lymph node biopsy (SLNB) be considered for patients to be treated with mastectomy or with excision in an anatomic location (eg, tail of the breast) that could compromise the performance of a future sentinel lymph node biopsy.
The identification of foci of invasion within a lesion consisting largely of DCIS is influenced by the proportion of excised tissue that is examined microscopically. There is good interrater reliability among pathologists in agreeing whether or not the microscopic images they are viewing indicate invasion. Atypical ductal hyperplasia (ADH), like DCIS, is an intraductal proliferation of abnormal cells, but the two are distinguished based on criteria involving the degree of cytologic abnormality and the size of the lesion. Interobserver reliability is somewhat lower for distinguishing DCIS from ADH (compared with distinguishing DCIS with or without invasion), although there has been variation among studies quantifying this issue, due in part to differences in methodological points, such as selection of cases and specification of standardized diagnostic criteria.[23-25]
Prognostic and predictive factors for local in situ or invasive recurrence that are measured for DCIS include nuclear grade, histologic type, size, estrogen receptor (ER) status, margin status, and distance from nearest margin. Nuclear grade for DCIS is classified based on 6 morphologic features described in Table 1.
Table 1. Nuclear Grade of Ductal Carcinoma In Situ
|Pleomorphism||Monotonous (monomorphic)||Intermediate||Markedly pleomorphic|
|Size||From 1.5 to 2 times the size of a normal RBC or a normal duct epithelial cell nucleus||Intermediate||Greater than 2 times the size of a normal RBC or a normal duct epithelial cell nucleus|
|Chromatin||Usually diffuse, finely dispersed chromatin||Intermediate||Usually vesicular with irregular chromatin distribution|
|Nucleoli||Only occasional|| ||Prominent, often multiple|
|Mitoses||Only occasional||Intermediate||May be frequent|
|Orientation||Polarized toward luminal spaces||Intermediate||Usually not polarized toward the luminal space|
DCIS is classified based on architectural pattern (the term used by clinicians), and more than one pattern may be present. Registries refer to these patterns as histologic type or histology as a matter of consistency with the classification of all other neoplasms. Because these registries are the source of data reported in this review, we refer to DCIS architectural patterns as histologic types. DCIS is generally classified as papillary, solid, comedo, micropapillary, or cribriform. Comedo DCIS typically has a higher nuclear grade and a higher proliferation rate than noncomedo DCIS. Although not captured by cancer registries, the pathology report usually describes the degree of necrosis and microscopically visible calcification, which is correlated with the finding of mammographic calcifications. In central or comedo necrosis, the central portion of an involved ductal space is replaced by an area of extensive necrosis that is easily detected at low magnification. In contrast, punctate necrosis describes either small foci of necrosis, which are indistinct at low magnification, or single-cell necrosis. Although central necrosis is typically associated with high-grade nuclei (as in the comedo DCIS subtype), it can also occur with DCIS of low or intermediate grade.
Size of the DCIS lesion is also a prognostic factor associated with recurrence. Size may be difficult to measure, because DCIS often involves the ductal system in a complex, 3-dimensional branching pattern. Positive or close surgical margins are associated with a higher risk of recurrence, and some women who undergo BCS require reexcision to achieve clear margins.[20, 22, 29] In addition to having prognostic significance, ER status is important because tamoxifen therapy is an option for women with ER-positive tumors to decrease the risk of recurrence or to prevent second primary breast cancers from developing.
Treatment for DCIS usually involves either BCS with radiation therapy (RT) or mastectomy. RT is recommended for most women who have BCS, because randomized trials show strong and consistent evidence that RT after BCS approximately halves the rate of recurrence in the affected breast. A meta-analysis of 4 clinical trials that included a total of 3925 women with DCIS found that, at 5 years after treatment, 18% of women who had BCS without RT experienced a recurrence compared with 8% of women who had BCS plus RT. At 10 years of follow-up, 28% of women who received BCS without RT had experienced a recurrence compared with 13% of women who received BCS plus RT. In both treatment groups, about half of the recurrences were DCIS, and half were invasive breast cancer. Updated evidence from these clinical trials was summarized in 2014 by Recht, who found that rates of local failure at median follow-up intervals of approximately 13 to 17 years were 25% to 35% in the unirradiated arms compared with 10% to 20% in the irradiated arms.[31-35] A more recent prospective randomized trial (Radiation Therapy Oncology Group trial 9804; 1998-2006) involving 636 women with mammographically detected, good-risk DCIS (low-grade or intermediate-grade DCIS >0.3 cm and <2.5 cm in size) found that, at median follow-up of 7.7 years, the 7-year failure rate was 0.9% in the RT arm and 6.7% in the observation arm. The histology of the localized failures in the observation arm was invasive in 42.1% and noninvasive in 57.9% of patients; in the RT arm, there were only 2 localized failures, one patient each experienced invasive and noninvasive localized failure. Approximately 62% of women in that trial received tamoxifen therapy.
Although RT has been shown to reduce the risk of recurrence among DCIS patients, it also has some drawbacks and risks. These include the patient burden of daily treatment for 6 weeks and short-term side effects, such as fatigue and skin toxicity, as well as a slightly increased risk of secondary cancers.[37, 38] An additional drawback of RT is that, once a woman has received it after BCS for DCIS, she cannot receive it again in the ipsilateral breast should an invasive cancer develop. The NCCN treatment guidelines suggest that BCS followed by observation is a reasonable option for some women with low-risk disease.
Mastectomy is considered an acceptable option for treatment of DCIS and is the recommended therapy for some women, including patients with extensive and/or multifocal DCIS, those with a large tumor-to-breast-tissue ratio, those who should not receive radiation because of certain medical conditions or who have received prior RT, and those for whom negative margins could not be achieved with BCS. Women who have a mastectomy for DCIS have a very low probability of local recurrence but remain at increased risk of developing DCIS or invasive breast cancer in the contralateral breast. In addition to being followed by clinical breast examination and mammography, magnetic resonance imaging (MRI) of the contralateral breast may also be recommended for some women with a history of DCIS who are at high risk because of certain other risk factors.
Some women with unilateral DCIS choose to have bilateral mastectomy to prevent cancer in the unaffected breast. Studies suggest that the decision to have a bilateral mastectomy may be influenced by the presence of other breast cancer risk factors, including a family history, whereas other women may make this decision based primarily on concern about future breast cancer risk.
Women who undergo mastectomy for treatment of DCIS may also elect to have breast reconstruction. In a population-based study of 2428 DCIS patients in southern California who were treated with mastectomy between 2003 and 2007, 1118 (46%) had immediate reconstruction, with higher use of reconstruction among younger women, non-Hispanic (NH) white women, and privately insured women.
For women with ER-positive DCIS, hormone therapy with tamoxifen is associated with a significantly decreased risk of future breast events, including invasive cancer and DCIS in either breast.[33, 45, 46] NCCN guidelines recommend tamoxifen for women with ER-positive DCIS treated with BCS and RT to reduce the risk of recurrence or invasive cancer in the ipsilateral breast. Women with DCIS treated with unilateral mastectomy may also be offered tamoxifen to reduce their risk of cancer in the contralateral breast. In either situation, the use of tamoxifen would be contraindicated by a history of deep vein thrombosis, pulmonary embolism, or uterine cancer. Clinical trials are currently evaluating aromatase inhibitors as an alternative to tamoxifen therapy in postmenopausal women with DCIS. A recent presentation from one of these studies reported decreased total breast cancer events and lower rates of invasive cancer at 10 years among women who received anastrozole compared with tamoxifen; this benefit was observed primarily in women younger than age 60 years.
The University of Southern California/Van Nuys Prognostic Index, which takes into account tumor size, margins, grade, presence of necrosis, and age, may be used to guide treatment decisions. A nomogram has also been published that estimates the probability of 5-year and 10-year ipsilateral breast tumor recurrences after BCS based on 10 factors (age at diagnosis, family history, initial presentation, radiation, adjuvant endocrine therapy, nuclear grade, necrosis, margins, number of excisions, and year of surgery).
More recently, studies have found that a 12-gene assay performed on tumor tissue, the Oncotype DX DCIS Score (Genomic Health, Redwood City, Calif), can predict the risk of local recurrence at 10 years in women treated with BCS without RT. This assay, which is discussed in more detail below, is used by some clinicians to identify women who may be able to forgo RT.[54-56]
NCCN guidelines for follow-up for patients with DCIS include interval history and physical examination every 6 to 12 months for 5 years, then annually; mammogram every 12 months (and 6-12 months post-RT if the breast is conserved [category 2B]); and, if treated with tamoxifen, monitoring per NCCN guidelines.[22, 47]
LCIS refers to a monomorphic population of dyshesive cells filling and distending the terminal duct lobular units. LCIS frequently occurs in conjunction with atypical lobular hyperplasia (ALH), and the term “lobular neoplasia” is sometimes used to refer to both ALH and LCIS. The distinction between ALH and LCIS is made based on the percentage of acini in the affected terminal duct lobular unit distended by lobular proliferation (<50% for ALH and ≥50% for LCIS) and whether the abnormal cells completely fill at least one lobular unit.[12, 57] Pleomorphic LCIS, a variant of LCIS in which the cells have a greater degree of nuclear pleomorphism and usually contain abundant cytoplasm, shows the characteristic molecular changes of classical lobular neoplasia as well as additional molecular changes, including human epidermal growth factor receptor 2 (HER2) amplification, which raise concern that it might have a different clinical outcome than classic LCIS. Pleomorphic LCIS is often found in association with invasive breast cancer. Both pleomorphic LCIS and classic LCIS can be associated with comedo necrosis and calcifications and may be difficult to distinguish from DCIS based on the appearance of routinely stained tissue preparations alone. E-cadherin staining is useful in the diagnosis of LCIS because loss of this transmembrane protein (which, when present, mediates cell adhesion) is a very common characteristic of LCIS.[58, 59]
LCIS is primarily viewed as a marker for increased risk of developing invasive breast cancer and not a precursor of invasive cancer. The strongest evidence that LCIS is more of a risk indicator than a direct cancer precursor comes from registry-based studies. One study of women diagnosed with LCIS from 1973 to 1998 and treated with BCS found that 7% of women developed invasive breast cancer within 10 years, with the increased risk of invasive disease equally distributed between both breasts. Thus, rather than an emphasis on local treatment, such as BCS plus RT, as is recommended for DCIS patients, care for women with LCIS emphasizes medical surveillance and risk-reduction strategies for both breasts. However, there is increasing evidence that LCIS may also act as a nonobligate precursor in the progression to invasive carcinoma.
Pure LCIS is not typically associated with clinical findings, such as a lump or mammographic abnormality (microcalcifications); thus, it is most often diagnosed incidentally during a breast biopsy performed for another indication. Although the entire suspicious area is often removed as part of the diagnostic workup to rule out the presence of DCIS or invasive cancer, complete removal with adequate margins is generally considered unnecessary. There is some debate about whether an excisional biopsy is indicated for all women diagnosed with LCIS on core biopsy. The most recent NCCN guidelines panel recommended that, “for LCIS of the usual type (<4 terminal duct lobular units found in a single core) found on core biopsy as a result of routine screening for calcifications and without imaging discordance may be managed by imaging follow-up.” Although some guidelines recommend treating pleomorphic LCIS as a cancer precursor, with complete removal with negative margins, the available literature is too limited to consider this an evidence-based recommendation.[22, 61]
Guidelines do not recommend unilateral mastectomy as a standard treatment for usual-type LCIS because of evidence that the risk of breast cancer subsequent to an LCIS diagnosis is equal for both breasts. Bilateral mastectomy may be considered as a risk-reduction strategy, especially for women with LCIS and a strong family history of breast cancer. Medical surveillance recommendations from the NCCN include annual mammography and clinical breast examination every 6 to 12 months from the time of diagnosis for women with LCIS. Although the lifetime risk of invasive breast cancer for a woman with LCIS may exceed 20% (depending on her age at diagnosis), the American Cancer Society guidelines do not support routine use of magnetic resonance imaging screening for surveillance of women with LCIS, because the evidence for its effectiveness as an addition to mammography has not been demonstrated in this population. Both the American Society of Clinical Oncology and the NCCN recommend discussing chemoprevention therapy with LCIS patients; tamoxifen is the only option for premenopausal women, and tamoxifen or raloxifene may be recommended for postmenopausal women, depending on other health conditions.[47, 49] The American Society of Clinical Oncology also lists exemestane as an option in postmenopausal women; however, this is not a US Food and Drug Administration-approved indication for this drug.