I. Pre-operative auxiliary examinations for DCIS
1.Mammography
DCIS mostly appears as multiple small clusters of microcalcifications on mammograms, occasionally accompanied by soft tissue masses, of which about 62-75% show microcalcifications, about 12-14% show dense tissue with calcifications, about 10-23% may show simple masses or asymmetric dense tissue, but there are still 6%-16% of DCIS without any abnormal radiographic signs [11 ,12,13]. The use of mammograms in breast cancer screening has increased the proportion of DCIS in breast cancer from 0.8-5% to 15-20%. Ernster et al [14] reported the results of screening mammograms in American women over 40 years of age (more than 540,000), which showed that DCIS accounted for 20.2% of breast cancers detected at screening, and the sensitivity of mammograms for the diagnosis of DCIS was 86%. At present, mammography is still the main means to detect DCIS.
2. Ultrasound examination of the breast
The ultrasound image of DCIS generally shows irregular hypoechoic shadow in the ducts and abnormal duct expansion. Because it is difficult to distinguish the acoustic contrast between normal breast tissue or highly echogenic fibrous tissue and calcified foci, it is generally believed that diffuse microcalcifications are more difficult to be detected by breast ultrasound. However, with the improvement of high-frequency ultrasound technology, many DCIS microcalcifications can be identified by ultrasound. Nagashima et al [15] reported 73 cases of DCIS (mammograms showing only microcalcifications without masses or dense tissue shadows), of which 54 cases (74%) could be detected by ultrasound; for microcalcifications of BI-RADS grade 3 to 5, the detection rate of ultrasound was 65.5%, 65.5%, and 65.5%, respectively. The detection rate of B-ultrasound was 65.5%, 78.6%, and 80.0%, respectively, while the area of calcified foci identified by B-ultrasound was about 242.750000000000000003px2 and the area of unidentified calcified foci was about 3.82 cm2. For patients with dense glands without calcification, breast ultrasound could improve the detection rate of DCIS.
3.Magnetic resonance imaging (MRI) of the breast
MRI has higher spatial and temporal resolution in soft tissues, and is not affected by the denseness of the breast gland, so it can clearly show DCIS tumor lesions and has higher sensitivity for multicenter and multifocal lesions. Kim et al [17] compared the accuracy of MRI and mammogram in showing the size of DCIS lesions, analyzing 72 cases of DCIS, and showed that the accuracy of MRI in assessing the extent of the lesions was 72%, and the underestimation of the lesions was accuracy was 72%, with 17% underestimation of lesion extent (underestimation >25px) and 11% overestimation of lesion extent (overestimation >25px), whereas the accuracy of mammogram assessment was 43%, with 35% underestimation of lesion extent and 22% overestimation of lesion extent.
4.Breast-specific gamma imaging (BSGI)
BSGI is performed by injecting the radiopharmaceutical 99mTc- Staphylococcus and then detecting the retention of the radiopharmaceutical in the tumor cells by a special gamma photography instrument, which can improve the detection rate of micro lesions. 22 cases of DCIS (pathology of lesions ranging from 2 to 22 mm, mean 9.9 mm) reported by Brem et al [18] showed that the sensitivity of breast-specific gamma imaging was higher than that of MRI (91% vs 88%). MRI (91% vs 88%). However, after all, breast-specific gamma imaging and other nuclear medicine detection means are still difficult to be widely used, and its accuracy and specificity still need further study.
5.Mammary duct endoscopy
Breast ductal endoscopy is a miniature endoscope that can directly observe breast ductal lesions and perform intraductal biopsy and cytological examination, which is important for the diagnosis, treatment and localization of intraductal lesions. Clinically, pathologic nipple discharge is an important indication for ductoscopy. The literature reports that papilloma accounts for 40-70% of pathologic nipple discharge, papillary epithelial hyperplasia for 14%, and breast cancer for approximately 1-23% [19].DCIS presents on ductoscopy as multiple elevated lesions with peripheral punctate bleeding or lesions that are multi-colored, and may also present as terminal milk duct bleeding. Approximately 80-85% of breast cancers originate from the ductal epithelium, and ductoscopy has the advantage of direct visualization of lesions in the ducts and obtaining a large number of epithelial cells from the surface of the lesions, thus its potential to detect breast cancer years earlier than imaging.
II. Clinical treatment of DCIS
1. Total mastectomy and breast-conserving treatment
Because of the multicentric and multifocal pathology of DCIS, total mastectomy is traditionally used to reduce local recurrence. In a study of 227 patients with pure DCIS reported by Silverstein et al [21], a total of 98 patients in the total mastectomy group (mean tumor diameter 82.5 px, multiple lesions in 41% of cases, and multicentric lesions in 15% of cases) had a recurrence rate of 22.5% (95% CI = 16.9-28.2), 8.9% (95% CI = 6.8-11.0), and 1.4% (95% CI = 0.7-2.1), respectively. percent of cases had multicentric lesions) and 103 cases in the breast-conserving surgery plus radiotherapy group (mean tumor diameter 35 px), the 7-year disease-free survival rate was significantly higher in the total mastectomy group than in the breast-conserving surgery plus radiotherapy group (98% vs. 84%, P=0.038), but there was no difference in the overall survival rate between the two groups. Previous data showed that total mastectomy further reduced local recurrence compared with breast-conserving surgery, but there was no significant difference in overall survival. In addition total mastectomy is highly invasive, while DCIS itself has a relatively good survival prognosis. Therefore, breast-conserving surgery plus postoperative radiotherapy is preferred for DCIS patients without contraindications to breast-conserving surgery.
2. The need for radiotherapy after breast-conserving surgery for DCIS
In the NSABP B-17 trial, 818 patients with DCIS were randomized to receive either segmental resection alone or segmental resection plus postoperative radiotherapy, and the median follow-up of 43 months showed that the 5-year disease-free survival rates were 84.4% and 73.8 in the postoperative radiotherapy and surgery alone groups, respectively (P=0.001). The results of the 12-year follow-up also showed a significantly lower local recurrence rate in the postoperative radiotherapy group than in the surgery alone group (8% vs. 17%, P=0.01), but there was no significant difference in overall survival between the two groups [22,23]. radiotherapy groups had 10-year recurrence-free survival rates of 74% and 85%, respectively (P<0.001< span="">), and postoperative radiotherapy reduced the 10-year risk of local recurrence by up to 47% [24].
However, it is still controversial whether radiotherapy can be dispensed with after breast-conserving surgery for low-risk DCIS. macdonald et al [25] retrospectively analyzed 272 cases of DCIS with incisional margins greater than 10 mm, with a median follow-up of 53 months. local recurrence occurred in 12 of 212 patients (5.7%) in the local surgery alone group, including 9 cases of DCIS recurrence and 3 cases of invasive cancer recurrence; in addition In the local surgery plus radiotherapy group, local recurrence occurred in 1 out of 60 patients (1.7%), and there was no statistical difference between the two groups (P = 0.06).A Meta-analysis reported by Gustavo et al [26] showed that although the addition of radiotherapy after DCIS breast-conserving surgery reduced the risk of local recurrence by 60% compared with breast-conserving surgery alone, it did not reduce the risk of distant metastases (OR = Silverstein et al [27] divided 333 DCIS patients undergoing breast-conserving surgery into three groups according to the Van Nuys Prognostic Index (VNPI) score and analyzed the effect of postoperative radiotherapy The results showed that the 8-year recurrence-free survival rates were 97% and 100% for surgery alone and postoperative radiotherapy in VNPI score groups 3-4, respectively (p-value not statistically different), while the 8-year recurrence-free survival rates were 68% and 85% for surgery alone and postoperative radiotherapy in VNPI score groups 5-7, respectively (p=0.017). This shows that whether or not radiotherapy was given after DCIS breast-conserving surgery did not affect overall patient survival, and exemption from radiotherapy in some low-risk patients did not significantly increase local recurrence. Therefore, it is feasible to dispense with radiotherapy after breast-conserving surgery for low-risk DCIS, but further clinical studies are needed to define the low-risk DCIS.
3. Application of Sentinel lymph node biopsy (SLNB) for DCIS
Theoretically, malignant cells in DCIS are confined to the basement membrane of ducts and do not metastasize to lymph nodes. Previous literature has reported that the rate of positive DCIS lymph nodes with axillary clearance is less than 1% [28,29]. Therefore, axillary lymph node dissection is not routinely recommended for DCIS. The accuracy of SLNB in predicting axillary lymph node status is now well established, and its use in DCIS remains controversial despite the less invasive nature of SLNB.
The positive rate of sentinel lymph node (SLN) in DCIS has been reported in the literature to be about 6-13% [30], which is significantly higher than the positive rate of axillary lymph nodes in DCIS reported in the previous literature. It should be noted that DCIS was diagnosed by hollow needle aspiration biopsy (CNB) in many studies, and the rate of missed invasive carcinoma in cases diagnosed with DCIS by CNB can be 26-33% [31,32].Yen et al [33] reported that of 398 patients with a first diagnosis of DCIS, 80 (20%) were found postoperatively to have invasive cancer component, while age less than 55 years, diagnosis based on hollow needle aspiration biopsy only, mammograms showing tumors larger than 100 px and high-grade DICS were all risk factors for combined invasive cancer. If DCIS is combined with an invasive carcinoma component, it will undoubtedly increase the chance of developing metastasis in SLN. a Meta-analysis by Ansari et al [34], who synthesized 22 clinical studies of sentinel lymph node biopsies in DCIS, showed that the rate of SLN positivity was 7.4% for cases with a preoperative diagnosis of DCIS and only 3.7% for cases with a final definitive postoperative diagnosis of DCIS, therefore Intra et al [35] reviewed 854 cases of simple DCIS with SLNB at the European College of Oncology and showed that only 12 cases (1.4%) were positive for SLN, of which 7 were micro-metastases and 11 of them had axillary lymph node dissection. It is important to note that the current use of immunohistochemistry and other methods to detect micrometastases in SLN has increased the rate of SLN positivity, but it is still unclear whether SLN micrometastases have a negative impact on the clinical prognosis of DCIS or even invasive carcinoma. However, whether SLN micrometastases have a negative impact on the clinical prognosis of DCIS or even invasive cancer remains unclear. Therefore, SLN micrometastases on the other hand may lead to false positive SLN, while the true positive rate of SLN in DCIS may be lower.
4. The value of endocrine therapy for DCIS
The NSABP B-24 trial of 1804 DCIS patients who were randomized to local excision plus radiotherapy for 5 years with Tamoxifen or placebo, with a median follow-up of 74 months, showed that the recurrence rate was significantly lower in the Tamoxifen group than in the placebo group (8.2% vs 13.4%, P=0.0009), with a more significant reduction in the probability of invasive carcinoma in particular ( 4.1% vs 7.2%, P=0.0004); and Tamoxifen reduced the risk of local recurrence by 45.1% in patients with indeterminate or positive cut margins and 21.1% in patients with negative cut margins; however, there was no statistical difference in overall survival between the two groups [36]. However, the results of the UK DCIS trial did not show that Tamoxifen reduced local recurrence in the breast affected by DCIS. 1701 patients with DCIS in the UK DCIS trial randomized to local excision alone, local excision plus Tamoxifen, local excision plus radiotherapy, and local excision plus radiotherapy and Tamoxifen were treated with a median follow-up of 53 months, showing that local recurrence rate on the affected side was 15% and 13% in patients treated with and without Tamoxifen, respectively, with no statistical difference between them (P=0.42) [37]. The reason for this may be due to the fact that the proportion of patients younger than 50 years was greater in the NSABP B-24 trial than in the UK DCIS trial (33.5% vs. 9.5%), whereas Tamoxifen had a more significant effect on reducing local recurrence in patients younger than 50 years; in addition, 16% of patients in the NSABP B-24 trial had positive cut margins, whereas the UK DCIS trial excluded Patients with positive margins were excluded from the UK DCIS trial. Therefore, the need for Tamoxifen in patients with negative margins, especially in older patients with cardiovascular disease, who are older than 50 years of age, is questionable, as Tamoxifen did not improve overall survival in DCIS patients, but may increase cardiovascular risk.
Aromatase inhibitors have shown superior efficacy to Tamoxifen in the adjuvant treatment of postmenopausal breast invasive cancer. However, the effectiveness of aromatase inhibitors applied to postmenopausal DCIS adjuvant therapy has not been clearly answered. The NSABP B-35 trial, which has completed case collection, is a phase III randomized clinical trial comparing the efficacy of Anastrozole and Tamoxifen in the postoperative adjuvant treatment of postmenopausal DCIS [38], and its final results are expected to clarify the value of aromatase inhibitors in the treatment of DCIS.
III. Prediction of DCIS prognosis
The prediction of DCIS prognosis is of great importance for the formulation of rational individualized treatment in clinical practice. At present, the prognosis of DCIS is more often evaluated based on clinical and pathological indicators, including tumor size, presence of acantholytic necrosis, and surgical margin distance, etc. The Van Nuys Prognostic Index (VNPI) revised by Silverstein in 1995 is based on three factors (histological classification, tumor size, and margin distance). Gilleard et al [39] retrospectively analyzed 215 patients with DCIS who underwent breast-conserving surgery alone, and the results of a mean follow-up of 53 months showed that VNPI subgroups 3 to 4, 5 to 7, and 8 to 9 had no local recurrence at 8 years. ~9 subgroups had 8-year local recurrence-free survival rates of 100%, 78.5%, and 67.9%, respectively (P=0.002).
However, traditional clinicopathological indicators do not fully reflect the biological characteristics of DCIS and accurately predict the possibility of DCIS progression to invasive cancer. Many scholars hope to find effective biological indicators to further predict the prognosis of DCIS. These biological indicators include ER, PR, HER-2/neu, p21, Ki-67, P-53, Bcl-2, etc., but studies have shown that various single molecular biological indicators have failed to be independent prognostic factors for DCIS [40,41]. Therefore, attempts have been made to further typify DICS by integrating various molecular or genetic markers to provide a further basis for evaluating the prognosis of DCIS.
Since Perou and Sorlie et al [42,43] proposed genotyping of breast cancer based on clustering analysis of gene expression, breast cancer can now be clinically classified into at least four different subtypes: Luminal A, Luminal B, HER2 overexpressing, and Basal-like subtypes.Livasy et al [44] performed a study of 245 pure DCIS cases Immunotyping: Luminal A (ER+, HER2-), luminal B (ER+, HER2+), HER2 overexpression (ER-, HER2+) and Basal-like (ER-, HER2-, EGFR+, and/or CK 5/6+), showed that Luminal A accounted for 149 cases (61%), Luminal B accounted for 23 cases (9%), HER2 overexpression for 38 cases (16%), and Basal-like subtype for 19 cases (8%); and Basal-like subtype was associated with poor prognostic indicators (including high nuclear grade, P53 overexpression, and elevated Ki-67 index, P<0.0001), thus suggesting that Basal-like subtype of DCIS may be a potential precancerous lesion for the development of invasive carcinoma.
Meijnen et al [45] used immunohistochemistry to detect the expression of a total of 16 molecular markers in 163 cases (well differentiated, moderately differentiated and poorly differentiated 36, 55 and 72 cases, respectively) of pure DCIS, and later classified DCIS into six of them (ER, PR, AR, Bcl-2, p53 and Her-2) by unsupervised cluster analysis based on two major types, namely ER/Bcl-2 positive group and ER/Bcl-2 negative group. The ER/Bcl-2 positive group was further divided into three subgroups: AR positive subgroup, AR negative subgroup and mixed subgroup. the ER/Bcl-2 negative group was further divided into Her2 positive subgroup and mixed subgroup. The ER/Bcl-2 positive group included 34 (94%) well-differentiated, 46 (84%) moderately differentiated and 27 (38%) poorly differentiated DCIS; while the ER/Bcl-2 negative group included 2 (6%) well-differentiated, 9 (16%) moderately differentiated and 45 (62%) poorly differentiated DCIS; in addition, the immunohistochemical indexes of moderately differentiated DCIS were The distribution characteristics of immunohistochemical indexes in moderately differentiated DCIS were similar to those in well-differentiated DCIS, and all of them were statistically different from those in poorly differentiated DCIS (P<0.001). These results suggest that DCIS with different immunohistochemical molecular typing have different biological characteristics, and further molecular typing may have important clinical significance in evaluating the prognosis of DCIS.
IV. Outlook
There is still a paucity of knowledge about the biological characteristics of DCIS and its natural course to invasive carcinoma, and DCIS is not a clinically homogeneous disease, but should be considered as a heterogeneous group of diseases with different biological characteristics representing the precancerous category of invasive carcinoma of the breast. On the other hand, the overall prognosis of DCIS is good, and a significant proportion of DCIS does not progress to invasive carcinoma, while various treatments are currently used to reduce postoperative recurrence of DCIS, especially invasive carcinoma, but different treatment combination modalities have not improved the overall survival of DCIS. Therefore, how to manage DCIS rationally and avoid overtreatment is still a major clinical confusion. With the continuous improvement of molecular typing of DCIS genes, further clarification of which type of DCIS will progress to invasive cancer and which type of DICS has worse biological characteristics can hopefully provide an important basis for the formulation of reasonable individualized treatment strategies in the clinic in the near future.