Although there is no universally accepted histopathologic classification, most pathologists divide DCIS into five major architectural subtypes (papillary, micropapillary, cribriform, solid, and comedo), often comparing the first four (noncomedo) with comedo (6,19,20). Comedo DCIS is frequently associated with high-nuclear-grade (6,19,20,21), aneuploidy, a higher proliferation rate (22), HER2/neu gene amplification or protein overexpression (23,24,25,26,27), and clinically more aggressive behavior (28,29,30,31). Noncomedo lesions tend to be just the opposite.

The division by architecture alone, comedo versus noncomedo, is an oversimplification and does not work if the purpose of the division is to sort the patients into those with a high risk of local recurrence versus those with a low risk. It is not uncommon for high-nuclear-grade noncomedo lesions to express markers similar to those of high-grade comedo lesions and to have a risk of local recurrence similar to comedo lesions. Adding to the confusion is the fact that mixtures of various architectural subtypes within a single biopsy specimen are common. In my series, more than 70% of all lesions had significant amounts of two or more architectural subtypes, making division into a predominant architectural subtype problematic.

Regarding comedo DCIS, there is no uniform agreement among pathologists of exactly how much comedo DCIS needs to be present to consider the lesion a comedo DCIS. Although it is clear that lesions exhibiting a predominant high-grade comedo DCIS pattern are generally more aggressive and more likely to recur if treated conservatively than are low-grade noncomedo lesions, architectural subtyping does not reflect current biologic thinking. Rather, it is the concept of nuclear grading that has assumed importance. Nuclear grade is a better biologic predictor than architecture, and therefore it has emerged as a key histopathologic factor for identifying aggressive behavior (28,31,32,33,34,35). In 1995, the Van Nuys group introduced a new pathologic DCIS classification (36) based on the presence or absence of high-nuclear-grade and comedo-type necrosis (the Van Nuys classification).

The Van Nuys group chose high nuclear grade as the most important factor in their classification because there was general agreement that patients with high-nuclear-grade lesions were more likely to recur at a higher rate and in a shorter time period after breast conservation than patients with low-nuclear-grade lesions (28,31,34,37,38,39). Comedo-type necrosis was chosen because its presence also suggests a poorer prognosis (40,41) and it is easy to recognize (42).

The pathologist, using standardized criteria as noted below, first determines whether the lesion is high nuclear grade (nuclear grade 3) or non–high nuclear grade (nuclear grade 1 or 2). Then, the presence or absence of necrosis is assessed in the non–high-grade lesions. This results in three groups (Fig. 7.1).

Nuclear grade is scored by previously described methods (36). Essentially, low-grade nuclei (grade 1) are defined as nuclei 1 to 1.5 red blood cells in diameter with diffuse chromatin and unapparent nucleoli. Intermediate nuclei (grade 2) are defined as nuclei 1 to 2 red blood cells in diameter with coarse chromatin and infrequent nucleoli. High-grade nuclei (grade 3) are defined as nuclei with a diameter greater than 2 red blood cells, with vesicular chromatin, and one or more nucleoli.

In the Van Nuys classification, no requirement is made for a minimum or specific amount of high-nuclear-grade DCIS, nor is any requirement made for a minimum amount of comedo-type necrosis. Occasional desquamated or individually necrotic cells are ignored and are not scored as comedo-type necrosis.

The most difficult part of most classifications is nuclear grading, particularly the intermediate-grade lesions. The subtleties of the intermediate-grade lesion are not important to the Van Nuys classification; only nuclear grade 3 need be recognized. The cells must be large and pleomorphic, lack architectural differentiation and polarity, have prominent nucleoli and coarse, clumped chromatin, and generally show mitoses (36,40).

The Van Nuys classification is useful because it divides DCIS into three different biologic groups with different risks of local recurrence after breast conservation therapy (Fig. 7.2). This pathologic classification, when combined with tumor size, age, and margin status, is an integral part of the USC/Van Nuys Prognostic Index (USC/VNPI), a system that will be discussed in detail.

Which DCIS lesions will become invasive, and when will that happen? These are the most important questions in the DCIS field. There is intense molecular genetic study and knowledge
regarding the progression of normal breast epithelium through hyperplastic and atypical hyperplastic changes to DCIS and then to invasive breast cancer. Most of the genetic and epigenetic changes present in invasive breast cancer are already present in DCIS. No genes uniquely associated with invasive cancer have been identified (2,11). As DCIS progresses to invasive breast cancer, quantitative changes in the expression of genes related to angiogenesis, adhesion, cell motility, and the composition of the extracellular matrix may occur (2,11). Using gene-array technology, researchers are attempting to identify high-risk patterns, which will require quicker and more aggressive treatment.

Because most patients with DCIS have been treated with mastectomy, knowledge of the natural history of this disease is relatively scant. In a study of 110 consecutive, medicolegal autopsies of young and middle-aged women between the ages of 20 and 54 years, 14% were found to have DCIS (43), suggesting that the subclinical prevalence of DCIS is significantly higher than the clinical expression of the disease.

The studies of Page et al. (44,45) and Rosen et al. (46) shed light on the nontreatment of DCIS. In these studies, patients with noncomedo DCIS were initially misdiagnosed as having benign lesions and therefore went untreated. Subsequently, approximately 25% to 35% of these patients developed invasive breast cancer, generally within 10 years (44,45). Had the lesions been high-grade comedo DCIS, the invasive breast cancer rate likely would have been higher than 35% and the time to invasive recurrence shorter. With few exceptions, in both of these studies, the invasive breast carcinoma was of the ductal type and was located at the site of the original DCIS. These findings and the fact that autopsy series have shown up to a 14% incidence of DCIS suggest that not all DCIS lesions progress to invasive breast cancer or become clinically significant (43,47). There is far more microscopic DCIS than clinically apparent DCIS.

Page and associates recently updated their series (44,45,48). Of 28 women with low-grade DCIS misdiagnosed with benign lesions and treated with biopsy between 1950 and 1968, 11 patients recurred locally with invasive breast cancer (39%). Eight patients developed recurrence within the first 12 years. The remaining 3 were diagnosed over 23 to 42 years. Five patients developed metastatic breast cancer (18%) and died from the disease within 7 years of developing invasive breast cancer. These recurrence and mortality rates, at first glance, seem alarmingly high. However, they are only slightly worse than what can be expected with long-term follow-up of patients with lobular carcinoma in situ, a disease that most clinicians are willing to treat with careful clinical follow-up. In addition, these patients were treated with biopsy only. No attempt was made to excise these lesions with a clear surgical margin. The natural history of low-grade DCIS can extend over 40 years and is markedly different from that of high-grade DCIS.

The incidence of microinvasion is difficult to quantitate because until recently there was no formal and universally accepted definition of exactly what constitutes microinvasion. The 1997 edition of AJCC Cancer Staging Manual (5th ed.) carried the first official definition of what is now classified as pT1mic and read as follows (114):

The reported incidence of occult invasion (invasive disease at mastectomy in patients with a biopsy diagnosis of DCIS) varies greatly, ranging from as little as 2% to as much as 21% (49). This problem was addressed in the investigations of Lagios et al. (28).

Lagios et al. performed a meticulous serial subgross dissection correlated with specimen radiography. Occult invasion was found in 13 of 111 mastectomy specimens from patients who had initially undergone excisional biopsy of DCIS. All occult invasive cancers were associated with DCIS greater than 45 mm in diameter; the incidence of occult invasion approached 50% for DCIS greater than 55 mm. In the study of Gump et al. (50), foci of occult invasion were found in 11% of patients with palpable DCIS but in no patients with clinically occult DCIS. These results suggest a correlation between the size of the DCIS lesion and the incidence of occult invasion. Clearly, as the size of the DCIS lesion increases, microinvasion and occult invasion become more likely.

If even the smallest amount of invasion is found, the lesion should not be classified as DCIS. It is a T1mic (if the largest invasive component is 1 mm or less) with an extensive intraductal component (EIC). If the invasive component is 1.1 to 5 mm, it is a T1a lesion with EIC. If there is only a single focus of invasion, these patients do quite well. When there are many tiny foci of invasion, these patients have a poorer prognosis than expected (51). Unfortunately, the TNM staging system does not have a T category that fully reflects the malignant potential of lesions with multiple foci of invasion since they are all classified by their largest single focus of invasion.

Multicentricity is generally defined as DCIS in a quadrant other than the quadrant in which the original DCIS (index quadrant) was diagnosed. There must be normal breast tissue separating the two foci. However, definitions of multicentricity vary among investigators. Hence, the reported incidence of multicentricity also varies. Rates from 0% to 78% (7,46,52,53),
averaging about 30%, have been reported. Twenty years ago, the 30% average rate of multicentricity was used by surgeons as the rationale for mastectomy in patients with DCIS.

Holland et al. (54) evaluated 82 mastectomy specimens by taking a whole-organ section every 5 mm. Each section was radiographed. Paraffin blocks were made from every radiographically suspicious spot. In addition, an average of 25 blocks were taken from the quadrant containing the index cancer; random samples were taken from all other quadrants, the central subareolar area, and the nipple. The microscopic extension of each lesion was verified on the radiographs. This technique permitted a three-dimensional reconstruction of each lesion. This study demonstrated that most DCIS lesions were larger than expected (50% were greater than 50 mm), involved more than one quadrant by continuous extension (23%), but most important, were unicentric (98.8%). Only one of 82 mastectomy specimens (1.2%) had “true” multicentric distribution with a separate lesion in a different quadrant. This study suggests that complete excision of a DCIS lesion is possible due to unicentricity but may be extremely difficult due to larger than expected size. In a recent update, Holland and Faverly reported whole-organ studies in 119 patients, 118 of whom had unicentric disease (55). This information, when combined with the fact that most local recurrences are at or near the original DCIS, suggests that the problem of multicentricity per se is not important in the DCIS treatment decision-making process.

Multifocality is defined as separate foci of DCIS within the same ductal system. The studies of Holland et al. (54,55) and Noguchi et al. (56) suggest that a great deal of multifocality may be artifactual, resulting from looking at a three-dimensional arborizing entity in two dimensions on a glass slide. It would be analogous to saying that the branches of a tree were not connected if the branches were cut at one plane, placed separately on a slide, and viewed in cross section (44). Multifocality may be due to small gaps of DCIS or skip areas within ducts as described by Faverly et al. (39).

If radiologic workup shows an occult lesion that requires biopsy, there are multiple approaches: fine-needle aspiration biopsy (FNAB), core biopsy (with various types and sizes of needles), and directed surgical biopsy using guide wires or radioactivity. FNA is generally of little help for nonpalpable DCIS. With FNA, it is possible to obtain cancer cells, but because there is insufficient tissue, there is no architecture. Thus, although the cytopathologist can say that malignant cells are present, the cytopathologist generally cannot say whether the lesion is invasive.

Stereotactic core biopsy became widely available in the early 1990s, and it is now widely used. Dedicated digital tables make this a precise tool in experienced hands. Currently, large-gauge (11 gauge or larger) vacuum-assisted needles are the tools of choice for diagnosing DCIS. Ultrasound-guided biopsy also became very popular in the 1990s but is of less value for DCIS since most DCIS lesions do not present with a mass that can be visualized by ultrasound. All suspicious microcalcifications should be evaluated by ultrasound since a mass will be found in 5% to 15% of cases (58).

Open surgical biopsy should only be used if the lesion cannot be biopsied using minimally invasive techniques. This should be a rare event with current image-guided biopsy techniques (58,59) and occur in less than 5% of cases. Needle localization segmental resection should be a critical part of the treatment not the diagnosis.

Whenever needle localization excision is performed, whether for diagnosis or treatment, intraoperative specimen radiography and correlation with the preoperative mammogram should be performed. Margins should be inked or dyed, and specimens should be serially sectioned at 3- to 4-mm intervals. The tissue sections should be arranged and processed in sequence. Pathologic reporting should include a description of all architectural subtypes, a determination of nuclear grade, an assessment of the presence or absence of necrosis, the measured size or extent of the lesion, and the margin status with measurement of the closest margin.

Tumor size should be determined by direct measurement or ocular micrometry from stained slides for smaller lesions. For larger lesions, a combination of direct measurement and estimation, based on the distribution of the lesion in a sequential series of slides, should be used. The proximity of DCIS to an inked margin should be determined by direct measurement or ocular micrometry. The closest single distance between any involved duct containing DCIS and an inked margin should be reported.

If the lesion is large and the diagnosis unproven, either stereotactic or ultrasound-guided vacuum-assisted biopsy should be the first step. If the patient is motivated for breast conservation, a multiple-wire–directed oncoplastic excision can be planned. This will give the patient her best chance at two opposing goals: clear margins and good cosmesis. The best chance at completely removing a large lesion is with a large initial excision. The best chance at good cosmesis is with a small initial excision. It is the surgeon’s job to optimize these opposing goals. A large-quadrant resection should not be performed unless there is histologic proof of malignancy. This type of resection may lead to breast deformity, and should the diagnosis prove to be benign, the patient will be unhappy.

Removal of nonpalpable lesions is best performed by an integrated team of surgeon, radiologist, and pathologist. The radiologist who places the wires and interprets the specimen radiograph must be experienced, as must the surgeon who removes the lesion and the pathologist who processes the tissue.

It is never easy to tell a patient that she has breast cancer. But is DCIS really cancer? From a biologic point of view, DCIS is unequivocally cancer. When we think of cancer, however, we generally think of a disease that, if untreated, runs an inexorable course toward death. That is certainly not the case with DCIS (45). We must emphasize to the patient that she has a borderline cancerous lesion, a preinvasive lesion, which at this time is not a threat to her life. In our series of 1,411 patients with DCIS, the breast cancer–specific mortality rate is 0.5%. Numerous other DCIS series (62,63,64,65,66,67) confirm an extremely low mortality rate.

Patients often ask why there is any mortality rate at all if DCIS is truly a noninvasive lesion. If DCIS recurs as an invasive lesion and the patient goes on to die from metastatic breast cancer, the source of the metastases is clear. But what about the patient who undergoes mastectomy and sometime later develops metastatic disease, or a patient who is treated with breast preservation who never develops a local invasive recurrence but still dies of metastatic breast cancer? These latter patients probably had an invasive focus with established metastases at the time of their original treatment, but the invasive focus was missed during routine histopathologic evaluation. No matter how carefully and thoroughly a specimen is examined, it is still a sampling process, and a 1- to 2-mm focus of invasion can be missed.

One of the most frequent concerns expressed by patients once a diagnosis of cancer has been made is the fear that the cancer has spread. We are able to assure patients with DCIS that no invasion was seen microscopically and the likelihood of systemic spread is minimal.

The patient needs to be educated that the term “breast cancer” encompasses a multitude of lesions of varying degrees of aggressiveness and lethal potential. The patient with DCIS needs to be reassured that she has a minimal lesion and that she is likely going to need some additional treatment, which may include surgery, radiation therapy, an antiestrogen, or some combination. She needs reassurance that she will not need chemotherapy, that her hair will not fall out, and that it is highly unlikely that she will die from this lesion. She will, of course, need careful clinical follow-up.

When evaluating the results of treatment for patients with breast cancer, a variety of endpoints must be considered. Important endpoints include local recurrence (both invasive and DCIS), regional recurrence (such as the axilla), distant recurrence, breast cancer–specific survival, overall survival, and quality of life. The importance of each endpoint varies depending on whether the patient has DCIS or invasive breast cancer

When treating invasive cancer, the most important endpoints are distant recurrence and breast cancer–specific survival, in other words, living with or dying from breast cancer. For invasive breast cancer, a variety of different systemic treatments have been shown to significantly improve survival. These include a wide range of chemotherapeutic regimens and endocrine treatments. Variations in local treatment were incorrectly thought not to affect survival (18,68). They do, however, affect local recurrence. Recently the literature has shown that for every four local recurrences prevented, one breast cancer death is prevented (69).

DCIS is similar to invasive breast cancer in that variations in local treatment affect local recurrence, but no study has shown a significant difference in distant disease-free or breast cancer–specific survival, regardless of any treatment (systemic or local), and no study is likely to show a difference since there are so few breast cancer deaths in patients with pure DCIS. The most important outcome measure, breast cancer–specific survival, is essentially the same no matter what local or systemic treatment is given. Consequently, local recurrence has become the most commonly used endpoint when evaluating treatment for patients with DCIS.

A meta-analysis of four randomized DCIS trials comparing excision plus radiation therapy versus excision alone was published in 2007. It contained 3,665 patients. Radiation therapy decreased local control by a statistically significant 60%, but overall survival was slightly worse in the radiotherapy group, with a relative risk of 1.08 (66). These data are dissimilar to those of the Early Breast Cancer Trialists’ Collaborative Group and deserve further analysis (69). Half of the recurrences in the meta-analysis were DCIS and could not possibly affect survival. Of the remaining invasive recurrences, 80% to 90% were cured by early detection and treatment. This should result in a slight trend toward a lower survival for the excision-alone group, but exactly the opposite was seen, a nonsignificant trend toward a better survival. The authors of the meta-analysis felt that with longer follow-up, the higher local recurrence rate for excision alone will likely result in a lower overall survival at some point in time. For the time being, however, that has not happened, and a detrimental effect secondary to radiation therapy must be considered a possibility.

Local recurrences are clearly important to prevent in patients treated with DCIS. They are demoralizing. They often lead to mastectomy and, theoretically, if they are invasive, they increase the stage of the patient and are a threat to life. However, protecting DCIS patients from local recurrence must be balanced against the potential detrimental effects of the treatments given.

Following treatment for DCIS, 40% to 50% of all local recurrences are invasive. About 10% to 20% of DCIS patients who develop local invasive recurrences develop distant metastases and die from breast cancer (70,71). Long term, this could translate into a mortality rate of about 0% to 0.5% for patients treated with mastectomy, 1% to 2% for conservatively treated patients who receive radiation therapy (if there is no mortality associated with radiation therapy), and 2% to 3% for patients treated with excision alone. In order to save their breasts, many patients are willing to accept this theoretical, and as of now statistically unproven, small absolute risk associated with breast conservation therapy.