Ductal Carcinoma In Situ of the Breast

Ductal carcinoma in situ (DCIS) of the breast is a potentially invasive neoplasm. Risk factors include high estrogen states such as use of oral contraceptive (OC) pills, nulliparity, advanced age at first birth, and also family history and genetic mutations. The incidence of this usually clinically silent condition has risen in the past few decades due to widespread screening and diagnostic mammography, with final diagnosis confirmed by biopsy. At present, treatment options include total or simple mastectomy or lumpectomy with radiation. Adjuvant therapy includes antiestrogens like tamoxifen and human epidermal growth factor receptor 2 (HER2) suppression therapy. With the latest advances in chemotherapy and better understanding on the pathogenesis of the lesion, it is anticipated that more effective modalities of treatment may soon be available.     

Clinical Trials for Ductal Carcinoma In Situ of the Breast

Ductal carcinoma in situ (DCIS) of the breast is a non-obligatory precursor to invasive breast carcinoma, with a variable natural history and biological potential for progression to invasive disease. Over the past 30 years, clinical trials have applied the therapeutic principles used for invasive carcinoma to treat DCIS (surgery, with or without breast radiotherapy, and post-operative endocrine therapy), with excellent survival outcomes, and in-breast recurrence rates that range from 0.5 to 1% annually. However, half of such recurrences are again in-situ lesions, and intensive therapy is likely not necessary for all patients. Current clinical research is focused on a better characterization of the potential of individual lesions to progress to invasive disease, and to identify women who would do well with lesser treatment. Three ongoing trials in the United States and Europe randomize women to active surveillance (with or without endocrine therapy) versus usual treatment with surgery and radiotherapy. The use of pre-operative endocrine therapy has been evaluated in a recently completed trial of letrozole use in postmenopausal women with DCIS; and in on-going trials of tamoxifen, used either orally, or as a 4-hydroxytamoxifen gel formulation for application to the breast skin. This review summaries the major past and current clinical trials of DCIS, and the likely trajectories of DCIS management in the near future.     

Targeted Intraoperative Radiotherapy for the Management of Ductal Carcinoma In Situ of the Breast

Multiple long‐term studies have demonstrated a propensity for breast cancer recurrences to develop near the site of the original breast cancer. Recognition of this local recurrence pattern laid the foundation for the development of accelerated partial breast irradiation (APBI) approaches designed to limit the radiation treatment field to the site of the malignancy. However, there is a paucity of data regarding the efficacy of APBI in general, and intraoperative radiotherapy (IORT), in particular, for the management of ductal carcinoma in situ (DCIS). As a result, use of APBI, remains controversial. A prospective nonrandomized trial was designed to determine if patients with pure DCIS considered eligible for concurrent IORT based on preoperative mammography and contrast‐enhanced magnetic resonance imaging (CE‐MRI) could be successfully treated using IORT with minimal need for additional therapy due to inadequate surgical margins or excessive tumor size. Between November 2007 and June 2014, 35 women underwent bilateral digital mammography and bilateral breast CE‐MRI prior to selection for IORT. Patients were deemed eligible for IORT if their lesion was ≤4 cm in maximal diameter on both digital mammography and CE‐MRI, pure DCIS on minimally invasive breast biopsy or wide local excision, and considered resectable with clear surgical margins using breast‐conserving surgery (BCS). Postoperatively, the DCIS lesion size determined by imaging was compared with lesion size and surgical margin status obtained from the surgical pathology specimen. Thirty‐five patients completed IORT. Median patient age was 57 years (range 42–79 years) and median histologic lesion size was 15.6 mm (2–40 mm). No invasive cancer was identified. In more than half of the patients in our study (57.1%), MRI failed to detect a corresponding lesion. Nonetheless, 30 patients met criteria for negative margins (i.e., margins ≥2 mm) whereas five patients had positive margins (<2 mm). Two of the five patients with positive margins underwent mastectomy due to extensive imaging‐occult DCIS. Three of the five patients with positive margins underwent successful re‐excision at a subsequent operation prior to subsequent whole breast irradiation. A total of 14.3% (5/35) of patients required some form of additional therapy. At 36 months median follow‐up (range of 2–83 months, average 42 months), only two patients experienced local recurrences of cancer (DCIS only), yielding a 5.7% local recurrence rate. No deaths or distant recurrences were observed. Imaging‐occult DCIS is a challenge for IORT, as it is for all forms of breast‐conserving therapy. Nonetheless, 91.4% of patients with DCIS were successfully managed with BCS and IORT alone, with relatively few patients requiring additional therapy.     

The Diagnosis and Treatment of Ductal Carcinoma In Situ of the Breast

Abstract: Ductal carcinoma in situ of the breast is the most favorable presentation of breast cancer; therefore appropriate local treatment is imperative. Intraductal carcinoma is being diagnosed more frequently with the increasing use of screening mammography. A number of pathologic features have been identified which are useful for classification and for prognostic information. In addition, the molecular pathology and its relationship to tumor behavior and prognosis is becoming more well understood. The role of axillary dissection has been examined in a number of series and is generally agreed to be unnecessary for this presentation of breast cancer, allowing many women to avoid the sequela of axillary surgery. This review discusses the use of breast conservation treatment and the evolving indications for excision alone in the treatment of ductal carcinoma in situ. The outcomes for breast conservation therapy from both randomized trials and institutional series have confirmed excellent survival rates. Salvage therapy for local recurrence is frequently successful, resulting in nearly equivalent survivals in women undergoing breast conservation therapy compared to mastectomy. In addition, intriguing but preliminary results from both breast cancer prevention studies and trials looking at the use of tamoxifen for intraductal cancer suggest a local control benefit in women using the drug.     

Ductal Carcinoma In Situ with Microinvasion

Abstract: The natural history of patients with ductal carcinoma in situ (DCIS) and microinvasion is poorly defined and the clinical management of these patients, with particular reference to management of the axilla, has been controversial. Studies addressing this lesion have used highly varied and sometimes arbitrary criteria for the evaluation of microinvasion. At the Armed Forces Institute of Pathology, we have defined microinvasion as a single focus of invasive carcinoma ≤ 2 mm or up to three foci of invasion, each ≤ 1 mm in greatest dimension. Such minuscule invasive carcinomas are apparently rare, accounting for considerably less than 1% of cases of breast carcinoma reviewed in consultation at our institution. To determine the frequency of axillary lymph node metastases associated with this lesion, we retrospectively reviewed 38 cases of DCIS with microinvasion (n= 29) or probable microinvasion (n= 9), all treated with mastectomy and axillary node dissection between 1980 and 1996. The foci of microinvasion ranged from 0.25 to 1.75 mm (mean 0.6 mm) in greatest dimension and were present adjacent to DCIS in 95.3% of cases. The extent of DCIS did not correlate with the number of foci of microinvasion. Axillary node dissections yielded a mean of 19.3 lymph nodes (range 7-38) and all lymph nodes were negative for metastatic tumor. None of 33 patients, followed for a mean of 7.5 years (range 1.0-14.4 years), developed local recurrence or metastasis. While the cases of microinvasive carcinoma evaluated in this study were not associated with axillary node metastases and appear to have an excellent prognosis, further study is indicated to determine the appropriate management and long-term prognosis of patients with this lesion.     

Dynamic Contrast‐Enhanced MRI Reveals the Extent and the Microvascular Pattern of Breast Ductal Carcinoma In Situ

To report the role of magnetic resonance imaging (MRI) in assessing the extent of breast ductal carcinoma in situ (DCIS). To assess whether the microvascularity pattern in DCIS correlates with magnetic resonance enhancement. Eighty‐five histologically proven DCIS (77 pure DCIS, eight microinvasive DCIS) were prospectively studied with MRI. The morphology of magnetic resonance enhancement and the kinetic curve was recorded. Histopathologically, intraductal lesions were classified according to Van Nuys score. Tumor microvascularity was immunohistochemically assessed in a subset of 24 DCIS evaluating the number of microvessels, microvascularity area, and microvascularity pattern (diffuse or periductal). On the mammogram, 74% of DCIS appeared as microcalcifications. On MRI, 70% of DCIS showed enhancement. Non‐mass‐like uptake was observed in 78% of cases. The mean size of nonenhancing carcinomas was significantly lower than that of enhancing carcinomas (p = 0.033). The diffuse pattern was more frequent than the periductal pattern. A significant relationship between the morphology of MR enhancement and the microvascularity pattern was observed (p = 0.036); thus, 90% of DCIS showing segmental enhancement on MRI displayed a diffuse pattern while all DCIS with ductal enhancement showed a periductal pattern. There was a significant relationship between the maximum area of microvascularity and the vascular pattern (p = 0.015); periductal patterns showed larger areas than diffuse patterns. The lesion size was significantly larger as the Van Nuys score increased (p < 0.001) and was also related to the number of microvessels (p = 0.012). The mean area of microvascularity of DCIS was significantly larger as the Van Nuys score increased (p = 0.02). Breast MRI helps depict the extent of DCIS and reveals its microvascular pattern.     

Apoptosis in Ductal Carcinoma in Situ of the Breast

Abstract: Programmed cell death (apoptosis) may play a role in tumor development and progression. The importance of apoptosis dysregulations in ductal carcinoma in situ (DCIS) and its relationships with p53 mutations and expression of bcl-2 has received little attention in the literature. In a series of 58 DCIS patients, we evaluated the number of apoptotic cells by the TUNEL technique in subgroups of DCIS and correlated it with immunohistochemical expression of hormone receptors, c- erb B-2, p53, bcl-2, and Ki-67 (MIB-1) and DNA content measured by image cytometry. High apoptotic index (greater than 3%) was related to high tumor grade, negative hormone receptors, c- erb B-2 overexpression, aneuploidy and lack of bcl-2 immunohistochemical stain. Apoptosis was not related to p53 or proliferative index. The findings are similar to those found in infiltrating breast cancer.     

Ductal Carcinoma In Situ of the Breast: The Van Nuys Experience by Treatment

Abstract: Ductal carcinoma in situ (DCIS) represents a broad biologic spectrum of disease with a wide range of treatment approaches. A lack of clear and universally accepted treatment criteria has resulted in a diverse range of confusing clinical recommendations, distressing to both patients and clinicians. Data is presented on 543 patients treated at The Breast Center in Van Nuys, California: 228 by mastectomy, 185 by excision plus radiation therapy, and 130 by excision alone. The local recurrence-free survival at 5 years was 98% for mastectomy patients, 87% for those who received excision plus radiation therapy, and 79% for those treated with excision alone. The difference between each of the recurrence-free survival curves was statistically significant. Margin width was an important predictor of which breast preservation patients were most likely to benefit from postexcisional radiation therapy. There was no benefit from the addition of radiation therapy for patients with margin widths of 10 mm in every direction. The benefit was intermediate for patients with margin widths of 1–9 mm. Patients with margin widths less than 1 mm received the most benefit from postoperative radiation therapy. Radiation therapy is not without side effects and it should not be routinely added to every breast preservation patient's therapeutic plan. Careful consideration must be given to its risks versus its potential benefits. Numerous prognostic factors, such as nuclear grade, the presence of comedo-type necrosis, tumor size, and margin width can all be used to aid in the treatment decision-making process.     

An Overview of the History and Epidemiology of Ductal Carcinoma In Situ of the Breast

Abstract: Since the first pathologic studies of breast cancer were undertaken in the nineteenth century, an intraepithelial stage has been recognized in the transition from normal tissue to invasive cancer. In 1932 this was labeled in situ breast carcinoma, but was rarely diagnosed and considered only a clinical oddity. With the establishment of screening mammography over the past 20 years, both the ductal and lobular types of in situ breast carcinoma have been increasingly diagnosed. The lobular variant, lobular carcinoma in situ (LCIS), is now considered a marker of risk for subsequent invasive cancer, and is managed expectantly without surgical ablation. The ductal form, ductal carcinoma in situ (DCIS), is considered a true premalignant lesion, which should be treated largely in the same way as invasive breast carcinoma. An understanding of the epidemiology and biologic implications of DCIS is necessary for a rational approach to treatment.     

Characterization and Treatment of Local Recurrence Following Breast Conservation for Ductal Carcinoma In Situ

Purpose

The optimal treatment strategy for ductal carcinoma in situ (DCIS) continues to evolve and should consider the consequences of initial treatment on the likelihood, type, and treatment of recurrences.

Methods

We conducted a retrospective cohort study using two data sources of patients who experienced a recurrence (DCIS or invasive cancer) following breast-conserving surgery (BCS) for index DCIS: patients with an index DCIS diagnosed from 1997 to 2008 at the academic institutions of the National Comprehensive Cancer Network (NCCN; N = 88) and patients with an index DCIS diagnosed from 1990 to 2001 at community-based integrated healthcare delivery sites of the Health Maintenance Organization Cancer Research Network (CRN) (N = 182).

Results

Just under half of local recurrences in both cohorts were invasive cancer. While 40 % of patients in both cohorts underwent mastectomy alone at recurrence, treatment of the remaining patients varied. In the earlier CRN cohort, most other patients underwent repeat BCS (39 %) with only 18 % receiving mastectomy with reconstruction, whereas only 16 % had repeat BCS and 44 % had mastectomy with reconstruction in the NCCN cohort. Compared with patients not treated with radiation, those who received radiation for index DCIS were less likely to undergo repeat BCS (NCCN: 6.6 vs. 37 %, p = 0.001; CRN: 20 vs. 48 %, p = 0.0004) and more likely to experience surgical complications after treatment of recurrence (NCCN: 15 vs. 4 %, p = 0.17; CRN: 40 vs. 25 %, p = 0.09).

Conclusion

We found that treatment of recurrences after BCS and subsequent complications may be affected by the use of radiotherapy for the index DCIS. Initial treatment of DCIS may have long-term implications that should be considered.     

Prognostic Factors and Local Recurrence in Patients with Ductal Carcinoma In Situ of the Breast

Abstract: Local recurrence is an important event when it occurs in a patient previously treated for ductal carcinoma in situ. Therefore, the ability to predict the probability of local recurrence after breast preservation therapy would be extremely valuable in the treatment decision-making process. In an attempt to predict the likelihood of local recurrence, 30 prognostic factors were evaluated in 622 patients with ductal carcinoma in situ treated at the Van Nuys Breast Center from 1979 through June 1996. Four factors emerged as significant independent predictors of local recurrence. These included treatment, tumor size, margin width, and pathologic classification.     

Modeling Human Ductal Carcinoma In Situ in the Mouse

Breast cancer development is a multi-step process in which genetic and molecular heterogeneity occurs at multiple stages. Ductal carcinoma arises from pre-invasive lesions such as atypical ductal hyperplasia (ADH) and ductal carcinoma in situ (DCIS), which progress to invasive and metastatic cancer. The feasibility of obtaining tissue samples from all stages of progression from the same patient is low, and thus molecular studies dissecting the mechanisms that mediate the transition from pre-invasive DCIS to invasive carcinoma have been hampered. In the past 25 years, numerous mouse models have been developed that partly recapitulate the histological and biological properties of early stage lesions. In this review, we discuss in vivo model systems of breast cancer progression from syngeneic mouse models to human xenografts, with particular focus on how accurately these models mimic human disease.     

Molecular Distinction Between Atypical Ductal Hyperplasia and Ductal Carcinoma In Situ

Abstract: The increasing use of screening mammography has led to an increased detection of high-risk proliferative breast disease and premalignant breast lesions. This change in the pattern of disease presentation has highlighted the existing limitations in the understanding of the biology of these entities. It has also emphasized the significance of deficiencies involved in the morphologic recognition of the spectrum of changes that occur in precursor lesions. The criteria for morphologic distinction between atypical ductal hyperplasia (ADH) and low-grade ductal carcinoma in situ (DCIS) have remained controversial. There are also difficulties in subclassification of DCIS. To resolve some of these issues, attempts have been made to use new and emerging technologies to study these borderline breast lesions and to distinguish between ADH and DCIS. This article discusses the significance of the newly recognized biomarkers and emphasizes the need for further prospective studies.